ES2526192T3 - Glucokinase activators - Google Patents

Abstract

A compound of general formula (Ib) ** Formula ** in which R24 is selected from the group consisting of F, Cl, Br and methyl L1 is a bond, -D-alkylene-E-, -O-, -S -, -S (O) -, -S (O) 2-, -C (O) -, -N (R11) - or -C (> = N-OR12); D is a direct link or -O- and E is a direct link or -O-; R11 is hydrogen; R12 is hydrogen; G1 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-cycloalkyl or C3-10-heterocyclyl, optionally substituted with one or more substituents chosen from the group consisting of -CN, -CF3 , -OCF3, -OR18, -NR18R19, C3-10-cycloalkyl and C1-6-alkyl; R18 and R19, independently of one another, are hydrogen or C1-6-alkyl; L2 is -N-R20-; R20 is hydrogen; L3 is -C (O) -; R1 is hydrogen; G2 is R43 is -C1-6-alkylene-C (O) OR54; R54 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, 2-pentyl or 3- methyl-butyl; or one of its salts, pharmaceutically acceptable solvates.

Description

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DESCRIPTION
Glucokinase activators
Field of the Invention
[0001] This invention relates to compounds that are activators of glucokinase (GK), which may be useful for the management, treatment, control or auxiliary treatment of diseases, in which the increased activity of glucokinase it's profitable.
Background of the invention
[0002] Diabetes is characterized by a deterioration in glucose metabolism that is manifested among other things by high blood glucose in diabetic patients. The underlying defects lead to a classification of diabetes into two main groups: type 1 diabetes, or diabetes mellitus that requires insulin (IDDM), which appears when patients lack insulin-producing β cells in their pancreatic glands, and the Type 2 diabetes, or diabetes mellitus that does not require insulin (NIDDM), which occurs in patients with impaired β-cell function in addition to a number of other abnormalities.
[0003] Patients with type 1 diabetes are usually treated with insulin, while most patients with type 2 diabetes are treated with either sulfonylureas that stimulate the function of β cells or with other drugs that increase the tissue sensitivity of patients to insulin, or with insulin. Among these drugs applied to increase tissue sensitivity to insulin, metformin is a representative example.
[0004] Although sulfonylureas are widely used in the treatment of NIDDM, this therapy is not, in most cases, satisfactory: in a large number of patients with NIDDM, sulfonylureas are not sufficient to normalize glycemia, and by Therefore, patients are at risk of diabetes complications. Likewise, many patients gradually lose the ability to respond to sulfonylurea treatment and are consequently gradually forced to insulin treatment. This change of patients of oral hypoglycemic agents to insulin treatment is generally attributed in patients with NIDDM to the depletion of β cells.
[0005] In normal subjects as well as in diabetics, the liver produces glucose to avoid hypoglycemia. This glucose production derives from the release of glucose from glycogen stores or from gluconeogenesis, which is the de novo glucose intracellular synthesis. In type 2 diabetes, however, the regulation of liver glucose production is poorly controlled and increases, and may double after a fast night. In addition, in these patients there is a strong correlation between the highest fasting plasma glucose concentrations and the hepatic glucose production rate. Similarly, hepatic glucose production will increase in type 1 diabetes, if the disease is not adequately controlled by insulin treatment.
[0006] Since some existing forms of diabetes treatment do not result in sufficient glycemic control and are therefore unsatisfactory, there is a great demand for new therapeutic approaches.
[0007] Atherosclerosis, a disease of the arteries, is recognized as the leading cause of death in the United States and Western Europe. The pathological sequence that leads to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of "fatty stretch marks" in the aorta and the carotid, coronary and cerebral arteries. These lesions are yellow due to the presence of lipid deposits found mainly in smooth muscle cells and in macrophages of the intimate layer of arteries and aorta. In addition, it is postulated that most of the cholesterol found in fatty stretch marks, in turn, leads to the development of the "fibrous plaque" which consists of accumulated smooth muscle cells of the intima, loaded with lipids and surrounded by lipid extracellular, collagen, elastin and proteoglycans. The cells plus the matrix form a fibrous covering that covers a deeper deposit of cellular debris and more extracellular lipid. The lipid is mainly free and esterified cholesterol. Fibrous plaque forms slowly and is likely to become calcified and necrotic over time, evolving into the "complicated lesion" that explains arterial occlusion and the tendency to wall thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
[0008] Epidemiological evidence has firmly established hyperlipidemia as a major risk factor in cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed a renewed emphasis on reducing plasma cholesterol levels and in particular of low-density lipoproteins (LDL), as an essential step in the prevention of CVD. It is known that the upper limits of the "normal" range are significantly lower than what was considered before. As a result, large segments of Western populations have now realized that they are at risk
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particularly high. Independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and being male. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part due to the existence of multiple independent risk factors in this population. The successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
[0009] Hypertension (or high blood pressure) is a condition, which occurs in the human population as a secondary symptom of various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also found in many patients in whom the disorder or the causative drug is unknown. While such “essential” hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders is not yet elucidated. In addition, many patients have symptoms of hypertension in the total absence of other signs of disease or disorder.
[0010] It is known that hypertension can lead directly to heart failure, kidney failure and stroke (cerebral hemorrhage). These conditions are capable of causing the short-term death of a patient. Hypertension can also contribute to the condition of atherosclerosis and coronary heart disease. These conditions gradually weaken the patient and can lead to long-term death.
[0011] The exact cause of essential hypertension is unknown, although it is believed that a number of factors contribute to the onset of the disease. These factors include stress, uncontrolled emotions, deregulated release of hormones (renin, angiotensin aldosterone system), excess salt and water due to renal malfunction, thickening of the walls and hypertrophy of the vasculature that They produce the contraction of blood vessels, and genetic factors.
[0012] The treatment of essential hypertension has been addressed with the preceding factors in mind. Therefore, a wide range of beta blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like, which are marketed as antihypertensives, have been developed. The treatment of hypertension that uses these compounds has proven beneficial in preventing short-term deaths such as heart failure, kidney failure and brain hemorrhage. However, the appearance of atherosclerosis or heart disease due to hypertension for a prolonged period of time remains a problem. This implies that although blood pressure is reduced, the underlying cause of essential hypertension is not responding to this treatment.
[0013] Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose main actions are to promote the use of glucose, protein synthesis and the formation and storage of neutral lipids, also has the function of promoting vascular cell growth and increasing renal sodium retention, among others. stuff. These latter functions can be carried out without affecting glucose concentrations and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries, while sodium retention increases blood volume. Therefore, reducing insulin concentrations in hyperinsulinemic agents can prevent abnormal vascular growth and renal sodium retention, caused by elevated insulin concentrations, and thereby relieve hypertension.
[0014] Cardiac hypertrophy is a significant risk factor in sudden death, myocardial infarction and congestive heart failure. These cardiac phenomena are due, at least in part, to a greater propensity to suffer a myocardial lesion after ischemia and reperfusion, which can occur in non-hospitalized patients as well as in perioperative settings. There is an unsatisfied medical need to prevent or minimize adverse perioperative myocardial phenomena, particularly perioperative myocardial infarction. Both cardiac and non-cardiac surgery are associated with a significant risk of myocardial infarction or death. It is considered that around 7 million patients who are going to undergo non-cardiac surgery are at risk, with incidences of perioperative death and serious cardiac complications as high as 20 to 25% in some cases. In addition, of the 400,000 patients who annually undergo coronary artery bypass surgery (coronary bypass), it is estimated that 5% cause perioperative myocardial infarction and 1% to 2% death. There is currently no pharmacotherapy in this area that reduces damage to cardiac tissue due to perioperative myocardial ischemia or increases cardiac resistance to ischemic events. Such therapy is expected to safeguard life and reduce hospitalizations, improve the quality of life and reduce the overall health care costs of high-risk patients.
[0015] Obesity is a well-known risk factor for many common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and consequently also of these diseases is increasing throughout the industrialized world. Except for exercise, diet and food restriction, there is currently no pharmacological treatment to reduce body weight effectively and acceptable. However, due to its indirect but important effect as a risk factor in common and fatal diseases, it will be important to find a treatment for obesity and / or means to regulate appetite.
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[0016] The term obesity implies an excess of adipose tissue. In this context obesity is considered rather as any degree of excess adiposity that implies a health risk. The separation between normal and obese individuals can only be approximate, but the health risk imparted by obesity is probably a continuum that increases with adiposity. The Framingham study showed that a 20% excess over the weight considered desirable clearly imparts a health risk (Mann GV N.Engl.J. Med 291: 226, 1974). In the United States a consensus group of the National Institutes of Health on obesity agreed that a 20% increase in relative weight or body mass index (BMI = body weight in kilograms divided by the square of height in meters) by Above the 85th percentile for young adults constitutes a health risk. Applying that criterion, 20 to 30% of adult men and 30 to 40% of adult women in the United States are obese. (NIH, Ann Intern Med 103: 147, 1985).
[0017] Even mild obesity increases the risk of premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized western world the prevalence of obesity has increased considerably in recent decades. Due to the high prevalence of obesity and its consequences on health, its prevention and treatment should be a high priority of public health.
[0018] When energy intake exceeds expenditure, excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity occurs, that is, there are two components to balance weight, and an abnormality in any From the sides (intake or expense) can lead to obesity.
[0019] Regulation of eating behavior is not fully understood. To some extent, appetite is controlled by discrete areas of the hypothalamus: a feeding center in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety center in the ventromedial nucleus of the hypothalamus (VMH). The cerebral cortex receives positive signals from the feeding center that stimulates ingestion, and the satiety center modulates this process by sending inhibitory impulses to the feeding center. Several regulatory processes can act on these hypothalamic centers. The satiety center can be activated by increases in the concentration of plasma glucose and / or insulin that follow the intake of a meal. Gastric distention induced by a meal is another possible inhibitory factor. In addition, hypothalamic centers are sensitive to catecholamines, and beta-adrenergic stimulation inhibits eating behavior. Finally, the cerebral cortex controls eating behavior, and the impulses from the feeding center to the cerebral cortex are only a contribution. Psychological, social and genetic factors also act on food intake.
[0020] Various techniques are currently available to effect the initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients gain weight again over time. An effective way to establish and / or maintain weight loss is the main challenge in the current treatment of obesity.
[0021] WO 00/58293, WO 01/44216, WO / 0183465, WO / 0183478, WO / 0185706, WO 01/85707; WO 02/46173 and WO02 / 08209, for Hoffman-La Roche, disclose compounds as glucokinase activators.
Summary of the Invention
[0022] This invention provides amide derivatives of general formula (I), such as those described below, as glucokinase activators. The compounds of the present invention are useful as glucokinase activators and are therefore useful in the management, treatment, control and auxiliary treatment of diseases in which an increase in glucokinase activity is beneficial. Such diseases include type I diabetes and type II diabetes. The present invention provides compounds such as those described above, pharmaceutical compositions containing the compounds, their use to increase glucokinase activity, their use in the preparation of a medicament for treating said diseases and conditions, and pharmaceutical compounds or preparations of the present. invention for treating diseases and conditions as well as compounds for use in methods intended to treat said diseases and conditions, which comprise administering to an individual in need thereof an effective amount of a compound according to the present invention.
[0023] The present invention also provides glucokinase activators, for example of general formula (I), which are glucose sensitive glucokinase activators, that is glucokinase activators whose activity decreases with increasing glucose concentrations.
[0024] The present invention also provides glucokinase activators, for example of general formula (I), which are liver-specific glucokinase activators, that is, glucokinase activators that increase glucose utilization in the liver (ie say they increase glycogen deposition) without inducing any increase in insulin secretion in response to glucose.
[0025] The use of a compound or a pharmaceutical preparation according to the present invention for the invention is described.
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Treatment of metabolic disorders.
[0026] The use of a compound or a pharmaceutical preparation according to the present invention to reduce blood glucose is described.
[0027] The use of a compound or a pharmaceutical preparation according to the present invention to prevent hyperglycemia is described.
[0028] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of glucose intolerance (IGT) is described.
[0029] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of syndrome X is described.
[0030] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of fasting glucose intolerance (IFG) is described.
[0031] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of type 2 diabetes is described.
[0032] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of type 1 diabetes is described.
[0033] The use of a compound or a pharmaceutical preparation according to the present invention to delay the evolution of glucose intolerance (IGT) to type 2 diabetes is described.
[0034] The use of a compound or a pharmaceutical preparation according to the present invention to delay the evolution of type 2 diabetes that does not require insulin to type 2 diabetes that requires insulin is described.
[0035] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of dyslipidemia or hyperlipidemia is described.
[0036] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of hypertension is described.
[0037] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of obesity is described.
[0038] The use of a compound or a pharmaceutical preparation according to the present invention to reduce food intake is described.
[0039] The use of a compound or a pharmaceutical preparation according to the present invention to regulate appetite is described.
[0040] The use of a compound or a pharmaceutical preparation according to the present invention to regulate the feeding behavior is described.
[0041] The use of a compound or a pharmaceutical preparation according to the present invention to increase the secretion of enteroincretins, such as GLP-1, is described.
[0042] The use of a compound or a pharmaceutical preparation according to the present invention for the auxiliary treatment of type 1 diabetes is described in order to prevent the onset of diabetes complications.
[0043] The use of a compound or a pharmaceutical preparation according to the present invention to increase the amount and / or size of beta cells in a mammalian subject is described.
[0044] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of beta cell degeneration, in particular beta cell apoptosis, is described.
[0045] The use of a compound or a pharmaceutical preparation according to the present invention for the treatment of functional dyspepsia, in particular irritable bowel syndrome, is described.
[0046] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of metabolic disorders.
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[0047] The present invention provides the use of a compound according to the present invention for the preparation of a medicament intended to reduce blood glucose.
[0048] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hyperglycemia.
[0049] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of glucose intolerance (IGT).
[0050] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of syndrome X.
[0051] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of fasting glucose intolerance (IFG).
[0052] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of type 2 diabetes.
[0053] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of type 1 diabetes.
[0054] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for delaying the evolution of glucose intolerance (IGT) to type 2 diabetes.
[0055] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for delaying the evolution of type 2 diabetes that does not require insulin to type 2 diabetes that requires insulin.
[0056] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of dyslipidemia.
[0057] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hyperlipidemia.
[0058] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of hypertension.
[0059] The present invention provides the use of a compound according to the present invention for the preparation 40 of a medicament intended to reduce food intake.
[0060] The present invention provides the use of a compound according to the present invention for the preparation of a medicament intended to regulate appetite.
[0061] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of obesity.
[0062] The present invention provides the use of a compound according to the present invention for the preparation of a medicament intended to regulate eating behavior.
[0063] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for increasing the secretion of enteroincretins, such as GPL-1.
[0064] The present invention provides the use of a compound according to the present invention for the preparation of a medicament intended for the auxiliary treatment of type 1 diabetes in order to prevent the onset of diabetes complications.
[0065] The present invention provides the use of a compound according to the present invention for the preparation of a medicament intended to increase the amount and / or size of beta cells in a mammalian subject.
[0066] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of beta cell degeneration, in particular beta cell apoptosis.
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[0067] The present invention provides the use of a compound according to the present invention for the preparation of a medicament for the treatment of functional dyspepsia, in particular irritable bowel syndrome.
[0068] The present invention provides a method for preventing hypoglycemia comprising administering a liver-specific glucokinase activator.
[0069] The present invention provides the use of a liver-specific glucokinase activator for the preparation of a medicament intended to prevent hypoglycemia.
[0070] Other embodiments and aspects are defined below and in the appended claims.
Definitions
[0071] In the structural formulas provided here and throughout this report, the following terms have the indicated meaning:
[0072] The term "optionally substituted" as used herein means that the group in question is substituted, or not, with one or more of the specified substituents. When the group in question is substituted with more than one substituent the substituent may be the same or different.
[0073] The term "adjacent" as used herein refers to the relative positions of two atoms or variables, these two atoms or variables that share a bond or a variable that precedes or succeeds the other in a variable specification. As an example, "atom A adjacent to atom B" means that the two atoms A and B share a bond.
[0074] The terms "halogen" or "halo" mean fluorine, chlorine, bromine or iodine.
[0075] The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
[0076] The use of prefixes of this structure: Cx-y-alkyl, Cx-y-alkenyl, Cx-y-alkynyl, Cx-y-cycloalkyl or Cx-ycycloalkyl-Cx-y-alkenyl designates radicals of the designated type that they have carbon atoms between x and y.
[0077] The term "alkyl" as used herein, alone or in combination, refers to monovalent straight or branched chain saturated hydrocarbon radicals having between one and ten carbon atoms, for example C1-8-alkyl or C1-6-alkyl. Typical C1-8-alkyl groups and typical C1-6-alkyl groups include, but not exclusively, eg. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2 methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C1-8-alkyl" as used herein also includes C3-8-secondary alkyls and C4-8-tertiary alkyls. The term "C1-6-alkyl" as used herein also includes C3-6 secondary alkyl and C4-6-tertiary alkyl.
[0078] The term "alkylene" as used herein, alone or in combination, refers to divalent linear or branched saturated hydrocarbon radicals having between one and ten carbon atoms, for example C1-8-alkylene or C1-6-alkylene. Examples of "alkylene" as used herein include, but not exclusively, methylene, ethylene and the like.
[0079] The term "alkenyl" as used herein, alone or in combination, refers to monovalent straight or branched chain hydrocarbon radicals having between two and ten carbon atoms and at least one carbon-carbon double bond, for example C2-8-alkenyl or C2-6-alkenyl. Typical C2-8-alkenyl groups and C2-6-alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4- hexadienyl, 5-hexenyl and the like.
[0080] The term "alkenylene" as used herein, alone or in combination, refers to divalent straight or branched chain hydrocarbon radicals having between two and ten carbon atoms and at least one carbon-carbon double bond, for example C2-8-alkenylene or C2-6-alkenylene. Typical C2-8-alkenylene groups and typical C2-6-alkenylene groups include, but not exclusively, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl and the like.
[0081] The term "alkynyl" as used herein, alone or in combination, refers to monovalent straight or branched chain hydrocarbon radicals having between two and ten carbon atoms and at least one carbon-carbon triple bond, for example C2-8-alkynyl or C2-6-alkynyl. Typical C2-8-alkynyl groups and typical C26-alkynyl groups include, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1
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pentinyl, 2-pentinyl, 3-pentinyl, 4-pentinyl, 1-hexinyl, 2-hexinyl, 3-hexinyl, 5-hexinyl, 2,4-hexadienyl and the like.
[0082] The term "alkynylene" as used herein, alone or in combination, refers to divalent straight or branched chain hydrocarbon radicals having between two and ten carbon atoms and at least one carbon-carbon triple bond, for example C2-8-alkynylene or C2-6-alkynylene. Typical C2-8-alkynylene groups and typical C2-6-alkynylene groups include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl and the like.
[0083] The term "cycloalkyl" as used herein, alone or in combination, refers to a non-aromatic monovalent hydrocarbon radical having three to twelve carbon atoms, and optionally one or more degrees of unsaturation, for example C3-8-cycloalkyl. Such a ring may optionally be fused to one or more benzene rings or one or more other cycloalkyl rings. Typical C3-8-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and the like.
[0084] The term "cycloalkylene" as used herein, alone or in combination, refers to a non-aromatic carbocyclic divalent hydrocarbon radical having three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, for example C3-8-cycloalkylene. Such a ring may optionally be fused to one or more benzene rings or one or more other cycloalkyl rings. Typical C3-8cycloalkylene groups include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4- diyl, cycloheptyl-1,4-diyl or cyclooctyl-1,5-diyl and the like.
[0085] The term "heterocyclic" or the term "heterocyclyl" as used herein, alone or in combination, refers to heterocyclic rings of three to twelve members that have one or more degrees of unsaturation and contain one or more substitutions. heteroatomics chosen from S, SO, SO2, O or N, for example C38-heterocyclyl. Such a ring may optionally be fused to one or more other "heterocyclic" rings or cycloalkyl rings. Typical C3-8-heterocyclyl groups include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidone, morpholine, piperazine and the like.
[0086] The term "heterocyclylene" as used herein, alone or in combination, refers to a three to twelve member biradical heterocyclic ring that optionally has one or more degrees of unsaturation and that contains one or more heteroatoms chosen from S, SO, SO2, O or N. A ring of this type may optionally be fused to one or more benzene rings or one more other "heterocyclic" or cycloalkyl rings. Examples of "heterocyclylene" include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3- dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-diyl and the like.
[0087] The term "alkoxy" as used herein, alone or in combination, refers to the monovalent radical RaO-, in which Ra is alkyl as defined above, for example C1-8-alkyl giving C1- 8-alkoxy. Typical C1-8alkoxy groups include, but not exclusively, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
[0088] The term "alkylthio" as used herein, alone or in combination, refers to a linear or branched monovalent radical containing an alkyl group as defined above linked through a divalent sulfur atom having its free valence bond of the sulfur atom, for example C1-8-alkylthio. Typical C1-8alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
[0089] The term "alkoxycarbonyl" as used herein refers to the monovalent radical RaOC (O) -, wherein Ra is alkyl as described above, for example C1-8-alkoxycarbonyl. Typical C1-8-alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
[0090] The term "carbamoyl" as used herein refers to NH2C (O) -.
[0091] The term "aryl" as used herein refers to a carbocyclic aromatic ring radical or an aromatic ring system radical. Aryl also intends to include partially hydrogenated derivatives of carbocyclic systems.
[0092] The term "heteroaryl", as used herein, alone or in combination, refers to an aromatic ring radical with for example 5 to 7 member atoms, or to an aromatic ring system radical with for example between 7 and 18 member atoms, containing one or more heteroatoms chosen from nitrogen, oxygen heteroatoms
or sulfur, where the N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions; as for example furanyl, thienyl, thiopentyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl and the like. Heteroaryl is also intended to include
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partially hydrogenated derivatives of the heterocyclic systems listed below.
[0093] Examples of "aryl" and "heteroaryl" include, but not limited to, phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazoline, fluorenyl, xanthenyl, isoindanyl, benzinyl, acryloyl, acryloyl, acrylate , pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5 -imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl, 1,2,4-triazol-3 -yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl, 4oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl, isooxazo-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo4-yl, isothiazo-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl , 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinol, 4- quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7benzo [b] furanyl), 2,3-dihydro-benzo [b] furanyl (2- (2,3-dihydro-benzo [b] furanyl), 3- (2,3-dihydro-benzo [b] furanyl), 4 (2 , 3-dihydro-benzo [b] furanyl), 5- (2,3-dihydro-benzo [b] furanyl), 6- (2,3-dihydro-benzo [b] furanyl), 7- (2,3 -dihydrobenzo [b] furanyl)), benzo [b] thiophenyl (benzo [b] thiophen-2-yl, benzo [b] thiophene-3-yl, benzo [b] thiophene-4-yl, benzo [b] thiophene -5yl, benzo [b] thiophene-6-yl, benzo [b] thiophene-7-yl), 2,3-dihydro-benzo [b] thiophenyl (2,3-dihydro-benzo [b] thiophene-2- ilo, 2,3-dihydro-benzo [b] thiophene-3-yl, 2,3-dihydro-benzo [b] thiophen-4-yl, 2,3-dihydro-benzo [b] thiophene-5-yl, 2,3-dihydrobenzo [b] thiophene -6-yl, 2,3-dihydro-benzo [b] thiophene-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl) , indazol (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl 7benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl, 4-benzoxazolyl, 5benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5Hdibenz [b, f] azepine (5H-dibenz [b, f] azepin-1-yl, 5H-dibenz [ b, f] azepine-2-yl, 5H-dibenz [b, f] azepin-3-yl, 5Hdibenz [b, f] azepin-4-yl, 5H-dibenz [b, f] azepine-5-yl) , 10,11-dihydro-5H-dibenz [b, f] azepinea (10,11-dih idro-5Hdibenz [b, f] azepin-1-yl, 10,11-dihydro-5H-dibenz [b, f] azepin-2-yl, 10,11-dihydro-5H-dibenz [b, f] azepin- 3-yl, 10,11 dihydro-5H-dibenz [b, f] azepin-4-yl, 10,11-dihydro-5H-dibenz [b, f] azepin-5-yl), benzo [1,3] dioxol (2-benzo [1,3] dioxol, 4benzo [1,3] dioxol, 5-benzo [1,3] dioxol, 6-benzo [1,3] dioxol, 7-benzo [1,3] dioxol), purinyl and tetrazolyl (5-tetrazolyl, Ntetrazolyl).
[0094] The present invention also relates to partially or fully saturated analogs of the ring systems mentioned above.
[0095] When two of these terms are used in combination, as in aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl-C16-alkyl-and the like, it should be understood that the first radical mentioned is a substituent of the radical mentioned last term, where the substitution point is in the last of the radicals, for example aryl-alkyl-: image 1
[0096] The term "arylene," as used herein, alone or in combination, refers to a birradical carbocyclic aromatic ring or a birradical aromatic ring system. Examples of "arylene" include, but not exclusively, benzene-1,4-diyl, naphthalene-1,8-diyl and the like. The term "arylene" alone or in combination also includes other divalent radicals of the monovalent radicals mentioned in the definition of aryl.
[0097] The term "heteroarylene," as used herein, alone or in combination, refers to a biradical aromatic ring of five to seven members, or a birradical aromatic ring system, which contains one or more
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heteroatoms chosen from nitrogen, oxygen or sulfur heteroatoms, in which the N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions. Examples of "heteroarylene" used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazol-2,5-diyl, 1,3,4-thiadiazol-2 , 5-diyl, 1,3-thiazol-2,4-diyl, 1,3-thiazol-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5 -diyl, pyrimidine-2,4-diyl,
5 quinoline-2,3-diyl and the like. The term "heteroarylene" alone or in combination also includes other divalent radicals of the monovalent radicals mentioned in the definition of heteroaryl.
[0098] As used herein, the term "fused cycloalkylaryl" refers to a cycloalkyl group fused to an aryl group, where the two have two atoms in common, and where the aryl group is the point of substitution. Examples of "fused cycloalkylaryl" used herein include 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl, image2
and the like
[0099] As used herein, the term "fused cycloalkylarylene" refers to a fused cycloalkylaryl, where the aryl group is divalent. Examples include image3
and the like
[0100] As used herein, the term "fused arylcycloalkyl" refers to an aryl group fused to a cycloalkyl group, where the two have two atoms in common, and where the cycloalkyl group is the substitution point. Examples of "fused arylcycloalkyl" used herein include 1-indanyl, 2 image4
[0101] As used herein, the term "fused arylcycloalkylene" refers to an arylcycloalkyl. image5
30 and the like.
[0102] As used herein, the term "fused heterocyclylaryl" refers to a heterocyclyl group fused to an aryl group, where the two have two atoms in common, and where the aryl group is the substitution point. Examples of "fused heterocyclylaryl" used herein include 3,4-methylenedioxy-1.
35 phenyl, image6
and the like
[0103] As used herein, the term "fused heterocyclylarylene" refers to a fused heterocyclylaryl, where the aryl group is divalent. Examples include
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and the like
[0104] As used herein, the term "fused arylheterocyclyl" refers to an aryl group fused to a heteroaryl group, where the two have two atoms in common, and where the heterocyclyl group is the substitution point. Examples of "fused arylheterocyclyl" used herein include 2- (1,3-benzodioxolyl), image8
and the like [0105] As used herein, the term "fused arylheterocyclylene" refers to an arylheterocyclyl image9
and the like
[0106] As used herein, the term "fused cycloalkyl heteroaryl" refers to a cycloalkyl group fused to a heteroaryl group, where the two have two atoms in common, and where the heteroaryl group is the substitution point. Examples of "fused cycloalkyl heteroaryl" used in this image10
25 and the like.
[0107] As used herein, the term "fused heteroarylcycloalkylene" refers to a fused heteroarylcycloalkyl, where the cycloalkyl group is divalent. Examples include image11
30 and the like.
[0108] As used herein, the term "fused heterocyclylheteroaryl" refers to a heterocyclyl group fused to a heteroaryl group, where the two have two atoms in common, and where the heteroaryl group is the substitution point. Examples of "fused heterocyclylheteroaryl" used in this
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document include 1,2,3,4-tetrahydro-beta-carbolin-8-yl, image12
and the like
[0109] As used herein, the term "fused heterocyclylheteroarylene" refers to a fused heterocyclylheteroaryl, where the heteroaryl group is divalent. Examples include image13
and the like
[0110] As used herein, the term "fused heteroarylheterocyclyl" refers to a heteroaryl group fused to a heterocyclyl group, where the two have two atoms in common, and where the heterocyclyl group is the substitution point. Examples of "fused heteroarylheterocyclyl" used in this image14
15 and the like.
[0111] As used herein, the term "fused heteroarylheterocyclylene" refers to a fused heteroarylheterocyclyl, where the heterocyclyl group is divalent. Examples include image15
20 and the like.
[0112] The term "alkylsulfanyl," as used herein, refers to the group RaS-, in which Ra is alkyl as described above.
[0113] The term "alkylsulfenyl", as used herein, refers to the group RaS (O) -, in which Ra is alkyl as described above.
[0114] The term "alkylsulfonyl", as used herein, refers to the group RaSO2-, in which Ra is alkyl as described above.
[0115] The term "acyl", as used herein, refers to the group RaC (O) -, in which Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl as described above.
[0116] The term "aroyl," as used herein, refers to the group RaC (O) -, in which Ra is aryl as described above.
[0117] The term "heteroaroyl", as used herein, refers to the group RaC (O) -, in which Ra is heteroaryl as described above.
[0118] The term "aryloxycarbonyloxy", as used herein, refers to the group Ra-OC (O) -, in which Ra is aryl as described above.
[0119] The term "acyloxy", as used herein, refers to the group RaC (O) O-, in which Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl as described above. [0120] The term "aryloxy", as used herein, refers to the group Ra-O-, in which Ra is aryl as per 12
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described before.
[0121] The term "aroyloxy", as used herein, refers to the group RaC (O) O-, in which Ra is aryl as described above.
[0122] The term "heteroaroyloxy", as used herein, refers to the group RaC (O) O-, in which Ra is heteroaryl as described above.
[0123] Whenever the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl" or the like appear or the roots of their prefixes appear in the name of a substituent (eg arylalkoxyaryloxy) they should be interpreted as which include the limitations established for "alkyl" and "aryl" above.
[0124] As used herein, the term "oxo" refers to the substituent = O.
[0125] As used herein, the term "mercapto" refers to the substituent -SH.
[0126] As used herein, the term "carboxy" refers to the substituent -COOH.
[0127] As used herein, the term "cyano" refers to the substituent -CN. [0128] As used herein, the term "aminosulfonyl" refers to the substituent -SO2NH2.
[0129] As used herein, the term "sulfanyl" refers to the substituent -S-.
[0130] As used herein, the term "sulfenyl" refers to the substituent -S (O) -.
[0131] As used herein, the term "sulfonyl" refers to the substituent -S (O) 2-.
[0132] As used herein, the term "direct link", when part of a variable structural specification 30, refers to the direct binding of substituents flanking (preceding and following) the variable taken as a "link direct".
[0133] The term "lower", as used herein, refers to a group having between one and six carbon atoms, which may be indicated by the prefix Cx-6-. The lower alkyl may therefore be indicated as C1-635 alkyl, while the lower alkylene may be indicated as C2-6-alkylene.
[0134] A radical such as Cx-y-cycloalkyl-Ca-b-alkenyl will designate that the point of attachment of the radicals is in part of the radical mentioned last.
[0135] As used herein, the term "optionally" means that the case or cases described below may or may not occur, and includes both cases that occur and those that do not occur.
[0136] As used herein, the term "substituted" refers to the substitution with the substituent or the named substituents, multiple degrees of substitution being allowed unless otherwise indicated.
[0137] As used herein, the terms "contains (n)" or "which contains (n)" may refer to online substitutions at any position along the substituents alkyl, alkenyl, alkynyl or cycloalkyl defined above with one or more of any of O, S, SO, SO2, N or N-alkyl including, for example, -CH2-O-CH2-, -CH2-SO2-CH2-, -CH2-NH-CH3, etc.
50 [0138] Some of the terms defined above may appear more than once in the structural formula, and in each of these occurrences each term must be defined independently of the other.
[0139] As used herein, the term "solvate" is a complex of variable stoichiometry formed by
A solute (in this invention, a compound of formula (I)) and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. The solvents can be, by way of example, water, ethanol or acetic acid.
[0140] As used herein, the term "biohydrolyzable ester" is an ester of a substance
Pharmacological (in this invention, a compound of formula (I)) which a) or does not interfere with the biological activity of the original substance but gives that substance advantageous properties in vivo such as the duration of the action, the onset of the action and the like, or b) is biologically inactive but is easily converted in vivo by the subject into the biologically active principle. The advantage is that, for example, the biohydrolizable ester is absorbed orally from the intestine and transformed into (I) in the plasma. Many examples of such esters are known that
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by way of example, they include lower alkyl esters (eg, C1-4), lower acyloxyalkyl esters, lower alkoxyaxyoxyalkyl esters, alkoxycyloxy esters, alkyl acylamino alkyl esters, and choline esters.
[0141] As used herein, the term "biohydrolyzable amide" is an amide of a pharmacological substance (in this invention, a compound of formula (I)) which a) or does not interfere with the biological activity of the substance original but gives that substance advantageous properties in vivo such as the duration of the action, the onset of the action and the like, or b) it is biologically inactive but is easily converted in vivo by the subject into the biologically active principle. The advantage is that, for example, the biohydrolizable amide is absorbed orally from the intestine and transformed into (I) in the plasma. Many examples of such amides are known which include, for example, lower alkyl amides, α-amino acid amides, alkoxyacyl amides and alkylaminoalkylcarbonyl amides.
[0142] The term "pharmacologically effective amount" means the amount of a drug or pharmaceutical substance that produces the biological or medical response of a tissue, an animal or a human being that is being sought by a researcher or a clinician. This amount may be a therapeutically effective amount. The term "therapeutically effective amount" means that amount of a drug or pharmaceutical substance that produces the therapeutic response of an animal or a human being that is being sought.
[0143] The terms "treatment" and "treat" as used herein mean the management and care of a patient for the purpose of combating a disease, disorder or condition. The terms are intended to include the entire spectrum of treatments for a particular disorder that a patient suffers from, such as the delay of disease progression, the disorder or condition, the relief or mitigation of symptoms and complications, the prevention of disease and / or cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being. The term "human insulin" as used herein refers to naturally produced insulin or insulin produced by recombination. Recombinant human insulin can be produced in any suitable host cell, for example the host cells can be bacterial, fungal (including yeast), insect, animal or plant cells.
[0144] The term "insulin-derived" as used herein (and related expressions) refers to human insulin or an analogue thereof in which at least one organic substituent is attached to one or more of the amino acids. .
[0145] By "human insulin analogue" as used herein (and related expressions) is meant human insulin in which one or more amino acids have been removed and / or replaced by other amino acids, including amino acids. non-encodable, or human insulin that contains additional amino acids, that is, more than 51 amino acids, so that the resulting analog possesses insulin activity.
Detailed description of the invention
[0146] Glucokinase (GK) plays an essential role in glucose homeostasis. GK catalyzes the phosphorylation of glucose, and is the speed-limiting reaction for glycolysis in hepatocytes and pancreatic β cells. In the liver, GK determines the rates of both glucose uptake and glycogen synthesis, and is also believed to be essential for the regulation of several glucose sensitive genes (Girard, J. et al., Annu Rev Nutr 17, 325-352 (1997)). In β cells, GK determines the use of glucose and is therefore necessary for glucose stimulated insulin secretion. GK is also expressed in a population of neurons in the hypothalamus where it could be involved in eating behavior, and in the intestines where it could contribute to the secretion of enteroincretins.
[0147] GK has two main distinguishing features: its expression, which is limited to tissues that need to measure glucose (mainly the liver and pancreatic β cells), and its S0.5 for glucose, which is much higher ( 8-12 mM) than that of other members of the hexokinase family. Due to these kinetic characteristics, changes in serum glucose concentration are matched by changes in the metabolism of glucose in the liver which in turn regulates the balance between hepatic glucose production and glucose consumption.
[0148] Glucokinase activators may therefore be useful for treating diseases in which increasing glucokinase activity is beneficial. Therefore, there is a need for drugs that activate glucokinase and increase the enzymatic activity of glucokinase. Such drugs would be useful for the treatment of type I diabetes and type II diabetes.
[0149] Glucokinase activators also play a role in the detection of low glucose concentrations and the generation of neurohumoral responses to hypoglycemia and may thus be useful for treating patients with type 1 diabetes, who have a greater tendency to suffer hypoglycemia.
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[0150] Type I diabetes mellitus is a complex disease characterized by high blood sugar and polyuria. Collaterally to the persistent increase in blood glucose, patients present devastating complications such as retinopathy, nephropathy, neuropathy and cardiovascular disease. A fundamental objective to improve the diabetic phenotype is to reduce fasting and postprandial hyperglycemia and thus avoid or delay the onset of diabetes complications. The Diabetes and Complications Control clinical trial has indicated that rigorous glycemic control through daily administration of multiple insulin injections delays the onset of complications. However, such intensive therapy is associated with an increase in body weight and an increased risk of hypoglycemic phenomena. Therefore, alternative treatments are being developed to achieve glucose control without these side effects. The combination of overexpression of GK in the liver and subcutaneous insulin injections provides better glycemic control in animals with type 1 diabetes than treatment with insulin alone (Morral, N., et al. Human Gene Therapy 13, 1561-1570 (2002)). In addition, overexpression of hepatic GK can compensate, in part, for metabolic disorders developed by mice lacking an insulin receptor (Jackerott, M. et al. Diabetologia 45, 1292-1297 (2002)).
[0151] The present invention also relates to the use of a GK activator for the combined treatment of diabetes and obesity. GK, the GK regulatory protein and the KATP channel are expressed in the neurons of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake. It has been shown that these neurons express orectic and anorectic neuropeptides and are thought to be glucose sensing neurons within the hypothalamus that are inhibited or excited by changes in environmental glucose concentrations (Mobbs, CV et al, American Journal of Physiology , Endocrinology & Metabolism 281, E649-54 (2001)). The ability of these neurons to detect changes in glucose concentration is defective in various models of genetic obesity and experimentally induced (Spanswick, D. et al, Nature Neuroscience 3, 757-8 (2000), Levin, BE et al, Brain Research 808, 317-9 (1998)). Intracerebroventricular infusion (icv) of glucose analogs, which are competitive inhibitors of glucokinase, stimulates food intake in lean rats (Kurata, K. et al, Metabolism: Clinical & Experimental 38, 46-51 (1989)). In contrast, the icv glucose infusion suppresses feeding (Kurata, K. et al, Physiology & Behavior 37, 615-20 (1986)). The small molecule activators of GK can thus decrease food intake and weight gain through central effects on GK. Therefore, GK activators may have therapeutic utility to treat eating disorders, such as obesity, in addition to diabetes. The hypothalamic effects will be additive or synergistic to the effects of the same compound that act in the liver and / or the pancreas in the normalization of glucose homeostasis, for the treatment of type 2 diabetes. Therefore the GK system / GK regulatory protein can be described as a potential beneficial target for both diabetes and obesity.
[0152] The extent of glucose-induced insulin release is highly dependent on the action of the gastrointestinal hormones GLP-1 (glucagon-like type 1 peptide) and GIP. Unlike sulfonylureas, which stimulate insulin release at both low and high glucose concentrations, the action of GLP-1 on β cells is glucose dependent (Gromada, J. et al., Pflügers Arch 435, 583 -594 (1998)). Therefore, GLP-1 receptor agonists and drugs that slow the degradation of active GLP-1 are under development as new treatments for type 2 diabetes. An alternative strategy would be to increase levels of endogenous GLP-1. Of potential interest is the possibility that the release of GLP-1 and GIP could be regulated by endocrine cells expressing glucokinase (Jetton, TL et al., J. Biol. Chem. 269, 3641-3654 (1994)) and neurons sensitive to glucose (Liu, M. et al., J. Neurosci. 19, 10305-10317 (1999)). It has been reported that the release of GIP by intestinal K cells is directly controlled by glucose (Kieffer, TJ et al., Am J Physiol 267, E489-E496 (1994)), and the secretion of GLP-1 from cells GLUTag is caused by glucose through a mechanism similar to that found in β cells for insulin secretion (Reimann, F. et al, Diabetes 51, 2757-2763 (2002)). Accordingly, small molecule glucokinase activators can be used to increase the secretion of GLP-1 and / or GIP and therefore for treatment, modulation, inhibition, decrease, reduction, arrest or prevention of degeneration of beta cells, such as necrosis or apoptosis of β cells.
[0153] The present invention provides substituted heteroaryls and arylureas in the ortho position or glucokinase activating carboxamides or sulfonamides.
Embodiment 1. A compound of the general formula (Ib)
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in which
R24 is selected from the group consisting of F, Cl, Br and methyl. L1 is a bond, -D-alkylene-E-, -O-, -S-, -S (O) -, -S (O) 2 -, -C (O) -, -N (R11) -o -C (= N-OR12); D is a direct link or -Oy E is a direct link or -O-; R11 is hydrogen; R12 is hydrogen;
G1 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-cycloalkyl or C3-10-heterocyclyl, optionally substituted with one or more substituents chosen from the group consisting of -CN, - CF3, -OCF3, -OR18, -NR18R19, C3-10-cycloalkyl and C1-6-alkyl; R18 and R19, independently of one another, are hydrogen or C1-6-alkyl; L2 is -N-R20-;
R20 is hydrogen; L3 is -C (O) -; R1 is hydrogen; G2 is image17
twenty
R43 is C1-6-alkylene-C (O) OR54; R54 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, 2-pentyl or 3-methyl-butyl;
25
or one of its pharmaceutically acceptable salts or solvates.
Embodiment 2. A compound according to embodiment 1, wherein L1 is a bond, -D-C1-6-alkylene-E-, -O-, -C (O) -, -N (R11) -o -C (= N-OR12) -. Embodiment 3. A compound according to embodiment 1, wherein L1 is -O-.
Embodiment 4. A compound according to Embodiment 1, wherein L1 is -S-.
Embodiment 5. A compound according to embodiment 1, wherein L1 is a bond.
Embodiment 6. A compound according to Embodiment 1, wherein L1 is -C (O) -.
Embodiment 7. A compound according to any of embodiments 1 to 6, wherein D is a direct link.
Embodiment 8. A compound according to any of embodiments 1 to 6, wherein D is -O-.
Embodiment 9. A compound according to any of embodiments 1 to 8, wherein E is a direct link.
Embodiment 10. A compound according to any of embodiments 1 to 8, wherein E is -O-.
Embodiment 11. A compound according to any of embodiments 1 to 10, wherein
50 G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3pentyl, 2-pentyl, 3-methyl-butyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl, 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydropyridazinyl ,
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imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl or thiamorpholinyl.
Embodiment 12. A compound according to embodiment 11, wherein G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl or tiepanyl.
Embodiment 13. A compound according to embodiment 12, wherein G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl or hexahydroazepinyl.
Embodiment 14. A compound according to embodiment 13 wherein G1 is selected from the group consisting of isobutyl, cyclopentyl and piperidyl.
15 Embodiment 15. A compound according to embodiment 14, wherein G1 is isobutyl.
Embodiment 16. A compound according to embodiment 14, wherein G1 is cyclopentyl.
Embodiment 17. A compound according to embodiment 14, wherein G1 is piperidyl.
Embodiment 18. A compound according to any of embodiments 1 to 17, wherein R18 is hydrogen.
Embodiment 19. A compound according to any of embodiments 1 to 17, wherein R19 is hydrogen.
Embodiment 20. A compound according to any of embodiments 1 to 19, wherein R43 is -CH2C (O) OR54.
Embodiment 21. A compound according to any of embodiments 1 to 19, wherein R54 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
Embodiment 22. A compound according to embodiment 21, wherein R54 is hydrogen, methyl or ethyl.
Embodiment 23. A compound according to embodiment 22, wherein R54 is hydrogen.
Embodiment 24. The compound according to embodiment 1, wherein the compound is {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or one of its salts or of your pharmaceutically acceptable solvates.
Embodiment 25. The compound according to embodiment 24, wherein the compound is {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or one of its salts pharmaceutically acceptable.
Embodiment 26. The compound according to embodiment 24, wherein the compound is {2- [3- (245 cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid.
Embodiment 27. The compound according to embodiment 1, wherein the compound is {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or a of its pharmaceutically acceptable salts or solvates.
Embodiment 28. The compound according to embodiment 27, wherein the compound is {2- [3- (4-methyl-2 [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or one of its pharmaceutically acceptable salts.
Embodiment 29. The compound according to embodiment 27, wherein the compound is {2- [3- (4-methyl-255 [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid.
Embodiment 30. The compound according to any of embodiments 1 to 29 for use as a medicament.
60 Embodiment 31. A combination comprising a compound according to any of embodiments 1 to 29 and one or more additional active ingredients.
Embodiment 32. The combination of Embodiment 31, wherein said additional active ingredients are chosen from the group consisting of antidiabetics, antihyperlipidemic drugs, anti-obesity drugs, antihypertensives and drugs.
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for the treatment of complications that result from, or associated with, diabetes.
Embodiment 33. The combination of Embodiment 31, wherein the other additional active ingredient is metformin.
Embodiment 34. A pharmaceutical composition containing a compound according to any of embodiments 1 to 29 or a combination according to any of embodiments 31 to 33, and one or more pharmaceutically acceptable carriers or excipients.
Embodiment 35. The pharmaceutical composition of embodiment 34 in a unit dosage form, containing between about 0.05 mg and about 1000 mg, or between about 0.1 mg and about 500 mg, or between about 0.5 mg and about 200 mg of the compound.
Embodiment 36. The compound according to any of embodiments 1 to 29, or the combination according to any of embodiments 31 to 33 or the pharmaceutical composition according to embodiment 34 for the treatment of metabolic disorders, to reduce blood glucose , for the treatment of hyperglycemia, for the treatment of glucose intolerance (IGT), for the treatment of syndrome X, for the treatment of fasting glucose intolerance (IFG), for the treatment of diabetes type 2, for the treatment of type 1 diabetes, to delay the evolution of glucose intolerance (IGT) to type 2 diabetes, to delay the evolution of type 2 diabetes that does not require insulin to type diabetes 2 that requires insulin, for the treatment of dyslipidemia, for the treatment of hyperlipidemia, for the treatment of hypertension, for the treatment or prophylaxis of obesity, to reduce ing It is food, to regulate appetite, to regulate eating behavior or to increase the secretion of enteroincretinas.
Embodiment 37. The compound, combination or pharmaceutical composition of embodiment 36 for the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), insulin resistance syndrome, syndrome X, type diabetes 2, type 1 diabetes, dyslipidemia, hypertension and obesity.
Embodiment 38. The use of a compound of any of embodiments 1 to 29 for the preparation of a medicament intended for the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes , type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension or obesity.
Embodiment 39. {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.
Embodiment 40. {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension or obesity.
Embodiment 41. {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or a pharmaceutically acceptable salt or solvate thereof for use as a medicine
Embodiment 42. {2- [3- (4-Methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension or obesity.
[0154] Other embodiments clearly arise from the appended claims.
[0155] The individual enantiomers of the compounds represented by formula (I) above, as well as any partial or totally racemic mixture thereof, are included within the scope of the present invention. The present invention also encompasses the individual enantiomers of the compounds represented by the above formula (I) as mixtures with their diastereoisomers in which one or more stereocenters are inverted.
[0156] The present invention provides glucose sensitive glucokinase activators, ie glucokinase activators, for example of the general formula (I), which provide a greater increase in glucokinase activity at lower glucose concentrations. This should be understood to mean that when the glucose concentration is low, then the glucose-sensitive glucokinase activator provides an increase in glucokinase activity, an increase that is greater than the increase in glucokinase activity provided by the compound when glucose concentration is high. The compound can, for example, provide a 4.0-fold increase in glucokinase activity at a glucose concentration of 5 mM and
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a 2.0-fold increase in glucokinase activity at a glucose concentration of 15 mM, thus providing an increase in glucokinase activity at a glucose concentration of 5 mM, which is 2.0 times greater than the increase in the glucokinase activity provided by the compound at a glucose concentration of 15 mM. For the purpose of describing the present invention, glucose sensitivity can be determined by the Glucokinase Activity Test (I) in which the activity of the glucokinase activator is measured at different glucose concentrations.
[0157] The glucose sensitivity of a glucokinase activator can be measured for example at a 5 mM glucose concentration and a 15 mM glucose concentration using the same glucokinase activator concentration, eg. a concentration of 10 µM. The two measurements can then be compared and if the number of times the activity increases at a 5 mM glucose concentration (the lowest glucose concentration) - in the previous example 4.0 times - is significantly greater than the number of times it increases the activity at a glucose concentration of 15 mM (the highest concentration of glucose - in the previous example 2.0 times - then the glucokinase activator is considered to be a glucose sensitive glucokinase activator. In the previous example, the The increase in glucokinase activity at a glucose concentration of 5 mM is 2.0 times greater than the increase in glucokinase activity at a glucose concentration of 15 mM. The increase in glucokinase activity provided by the activator of Glucokinase at a glucose concentration of 5 mM can be for example at least 1.1 times higher, at least 1.2 times higher, for example at least 1.3 times higher, at least 1.4 v you are older, for example 1.5 times greater, at least 1.6 times greater, for example at least 1.7 times greater, at least 1.8 times greater, for example at least 1.9 times greater, at least 2.0 times greater than the activity of the activator of glucokinase at a glucose concentration of 15 mM.
[0158] The present invention also provides liver-specific glucokinase activators, that is, glucokinase activators for example of general formula (I), which increase the utilization of glucose in the liver (ie increase glycogen deposition) without inducing any increase in insulin secretion in response to glucose. For the purpose of describing this invention, the potential selectivity of a glucokinase activator by the liver can be determined by comparing the results obtained in response to the glucokinase activator in isolated hepatocytes and the results obtained in response to the glucokinase activator in the cells. Ins-1 Glucokinase activators, which show significantly greater activity in isolated hepatocytes, measured as described in the Glucokinase (II) Activity Test, compared to the activity in Ins-1 cells measured as described in the Test of glucokinase (III) activity, are considered to be liver-specific glucokinase activators. The activity of the glucokinase activator in the Glucokinase (II) Activity Test (hepatocytes) can be for example at least 1.1 times higher, at least 1.2 times higher, for example at least 1.3 times higher, at least 1.4 times greater, for example 1.5 times greater, such as at least 1.6 times greater, for example at least 1.7 times greater, such as at least
1.8 times greater, for example at least 1.9 times greater, at least 2.0 times greater, for example at least 3.0 times greater, at least 4.0 times greater, for example at least 5.0 times greater, at least 10 times greater than the glucokinase activator activity in the Glucokinase (III) Activity Test (Ins1 cells). Alternatively, the glucokinase activator may not show activity in the Ins-1 cells measured as described in the Glucokinase (III) Activity Test, but show significant activity in the hepatocytes measured as described in the Activity Test. of glucokinase (II).
[0159] Such liver-specific glucokinase activators may be particularly useful in patients at risk of hypoglycemia. Since hepatic glucokinase is very sensitive to serum glucose concentration, the effect of reducing GK glycemia in the liver will only occur when the serum glucose concentration is relatively high. When the serum glucose concentration is relatively low, the effect of GK in the liver decreases, and therefore does not continue to reduce blood glucose. This mechanism is maintained even when liver GK is affected by a GK activator. The effect of GK on pancreatic beta cells is not similarly sensitive to glucose. Therefore a GK activator that affects both the liver and beta cells can have a glucose lowering effect even at low serum glucose concentration, resulting in a risk of hypoglycemia. A GK activator that affects only, or primarily affects, liver GK will therefore provide a treatment with a lower risk of hypoglycemia. Accordingly, the invention provides a method for preventing hypoglycemia comprising administering a liver-specific glucokinase activator, as well as the use of a liver-specific glucokinase activator for the preparation of a medicament for the prevention of hypoglycemia.
[0160] Examples of liver-specific glucokinase activators are 2- {3- [2- (2,3-dimethoxyphenoxy) -5-fluorophenyl] ureido} thiazole-4-carboxylic acid ethyl ester, ethyl acid ester (2 - {3- [2- (2,3-dimethoxyphenoxy) -5fluorophenyl] ureido} thiazol-4-yl) acetic acid (2- {3- [5-fluoro-2- (2-fluoro-6-methoxyphenoxy)) phenyl] ureido} thiazol-4-yl) acetic acid, 2- {3- [2- (2,3-dimethoxyphenoxy) -5-fluorophenyl] ureido} thiazol-4-carboxylic acid, 2- (2- {3- [ 5-fluoro-2- (2-fluoro-6methoxyphenoxy) phenyl] ureido} thiazol-4-yl) -N- (2-morpholin-4-ylethyl) acetamide, acid [2- (2- {3- [5- fluoro-2- (2-fluoro-6methoxyphenoxy) phenyl] ureido} thiazol-4-yl) acetylamino] acetic acid, {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] thiazol-4- il} acetic acid and {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid.
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[0161] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of hyperglycemia.
[0162] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of glucose intolerance (IGT).
[0163] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of syndrome X.
[0164] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of type 2 diabetes.
[0165] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of type 1 diabetes.
[0166] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of hyperlipidemia.
[0167] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of dyslipidemia.
[0168] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of hypertension.
[0169] In one embodiment, a compound according to the present invention is intended to be used as a medicament in the treatment of obesity.
[0170] In one embodiment, a compound according to the present invention is intended to be used as a medicament for reducing food intake.
[0171] In one embodiment, a compound according to the present invention is intended to be used as a medicament for regulating appetite.
[0172] In one embodiment, a compound according to the present invention is intended to be used as a medicament for regulating eating behavior.
[0173] In one embodiment, a compound according to the present invention is intended to be used as a medicament for increasing the secretion of enteroincretins, such as GLP-1.
[0174] The compounds herein are glucokinase activators and as such are useful for glucokinase activation.
[0175] A method for activating glucokinase is described in a patient in need, comprising
Administering to a subject in need a compound according to the present invention, preferably in a pharmacologically effective amount, more preferably in a therapeutically effective amount. A method for reducing blood glucose is described in a patient in need, comprising administering to a subject in need a compound according to the present invention, preferably in a pharmacologically effective amount, more preferably in a therapeutically effective amount. A method for prevention and / or the
Treatment of human diseases mediated by glucokinase deficiency, which comprises administration to a human in need of a therapeutically effective amount of a compound according to the present invention. As used herein, the phrase "a subject that needs it" includes mammalian subjects, preferably human, who either suffer from one or more of the diseases or pathological conditions mentioned above or are at risk of suffering them. Accordingly, in the context of the method
Therapeutic method as described, this method also consists of a method to treat mammalian subjects prophylactically, or before the onset of the diagnosis of said diseases or pathological conditions.
[0176] A method for the treatment of hyperglycemia is described, which comprises administering to an individual in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0177] A method for the treatment of glucose intolerance (IGT) is described, which comprises administering to an individual in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
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[0178] A method for the treatment of syndrome X is described, which comprises administering to an individual in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0179] A method for the treatment of type 2 diabetes is described, which comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0180] A method for the treatment of type 1 diabetes is described, which comprises administering to an individual in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0181] A method for the treatment of dyslipidemia or hyperlipidemia is described, which comprises administering to an individual in need thereof an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0182] A method for the treatment of obesity is described, which comprises administering to a subject in need of an effective amount of a compound or a pharmaceutical composition according to the present invention.
[0183] In one embodiment, the effective amount of the compound is in the range between about 0.05 mg and about 2000 mg, preferably between about 0.1 mg and about 1000 mg and especially between about 0.5 mg and about 500 mg per day.
[0184] The method may be part of a regimen, comprising treatment with another antidiabetic, for example an antidiabetic such as insulin or an insulin analogue, a sulfonylurea, a biguanide, a meglitinide, an insulin sensitizer, a insulin sensitizing thiazolidinedione, an α-glucosidase inhibitor, a glycogen phosphorylase inhibitor, or a drug acting on the ATP-dependent potassium channel of the
25 pancreatic β cells.
[0185] The method may be part of a regimen, comprising treatment with another antihyperlipidemic, for example an antihyperlipidemic such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
30 [0186] The method may be part of a regimen, which includes treatment with another antihypertensive.
[0187] The method according to the present invention may be part of a regimen, comprising treatment with another antiobesity drug or appetite regulator.
[0188] The method according to the present invention may be part of a regimen, comprising treatment with another antihypertensive.
[0189] Other embodiments of such methods will be apparent from the following description.
[0190] The compounds according to the present invention are useful for the treatment of disorders, diseases and conditions, in which the activation of glucokinase is beneficial.
[0191] Accordingly, the compounds herein are useful for the treatment of hyperglycemia, IGT
45 (glucose intolerance), insulin resistance syndrome, syndrome X, type 1 diabetes, type 2 diabetes, dyslipidemia, dyslipoproteinemia (abnormal lipoproteins in the blood) including diabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemia (excess lipoproteins in blood) including hyperlipoproteinemias type I, II-a (hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V (hypertriglyceridemia), and obesity. In addition, they can be useful for the treatment of albuminuria, cardiovascular diseases such as cardiac hypertrophy,
50 hypertension and atherosclerosis including atherosclerosis; gastrointestinal disorders; acute pancreatitis; and appetite regulation or energy expenditure disorders.
[0192] Accordingly, in another aspect the invention relates to a compound according to the present invention intended to be used as a medicament.
[0193] The invention also relates to pharmaceutical compositions containing, as an active ingredient, at least one compound according to the present invention, with one or more pharmaceutically acceptable carriers or excipients.
[0194] The pharmaceutical composition is preferably in a unit dosage form, comprising between about 0.05 mg and about 1000 mg, preferably between about 0.1 mg and about 500 mg and especially between about 0.5 mg and about 200 mg of the compound according to the present. invention.
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[0195] In one embodiment, the pharmaceutical composition according to the present invention contains another antidiabetic, for example an antidiabetic such as insulin, an insulin derivative or an insulin analogue, a sulfonylurea, a biguanide, a meglitinide, a sensitizer to the insulin, an insulin sensitizing thiazolidinedione, an α-glucosidase inhibitor, a glycogen phosphorylase inhibitor, or a drug acting on the ATP-dependent potassium channel of pancreatic β cells.
[0196] In one embodiment, the pharmaceutical composition according to the present invention contains another antihyperlipidemic, for example an antihyperlipidemic such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
[0197] In one embodiment, the pharmaceutical composition according to the present invention contains another antiobesity drug or appetite regulator.
[0198] In one embodiment, the pharmaceutical composition according to the present invention contains another antihypertensive.
[0199] In one embodiment of the present invention, the pharmaceutical composition according to the present invention contains a compound according to the present invention in combination with one or more of the drugs mentioned above for example in combination with metformin and a sulfonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
[0200] In one embodiment of the present invention, the compounds of the present are used for the preparation of a medicament for the treatment of hyperglycemia. As used herein, hyperglycemia should be considered as generally understood in the area, with reference, for example, to the Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus, published in Diabetes Care 20, 1183-1197, (1997) , but it is generally considered to mean a high plasma glucose concentration that exceeds 110 mg / dl. The compounds herein are effective in reducing fasting and postprandial glycemia.
[0201] In one embodiment of the present invention, the compounds of the present invention are used for the preparation of a pharmaceutical composition intended for the treatment of glucose intolerance (IGT).
[002] In one embodiment of the present invention, the compounds of the present are used for the preparation of a pharmaceutical composition intended for the treatment of syndrome X.
[0203] In one embodiment of the present invention, the compounds of the present invention are used for the preparation of a pharmaceutical composition intended for the treatment of type 2 diabetes. Said treatment includes treatment for the purpose of delaying the evolution of intolerance. to glucose (IGT) to type 2 diabetes as well as to delay the evolution of type 2 diabetes that does not require insulin to type 2 diabetes that requires insulin.
[0204] In one embodiment of the present invention, the compounds of the present invention are used for the preparation of a pharmaceutical composition intended for the treatment of type 1 diabetes. Such therapy is normally accompanied by the administration of insulin.
[0205] In one embodiment of the present invention, the compounds of the present invention are used for the preparation of a pharmaceutical composition intended for the treatment of dyslipidemia and hyperlipidemia.
[0206] In one embodiment of the present invention, the compounds of the present invention are used for the preparation of a pharmaceutical composition intended for the treatment of obesity.
[0207] In another aspect the treatment of a patient with the compounds herein is combined with diet and / or exercise.
[0208] Methods for activating glucokinase activity in a mammal are described, which comprise administering, to a mammal in need of glucokinase activity activation, a therapeutically defined amount of a compound according to the present invention defined above, as a single form or several crystalline polymorphic forms, an amorphous form, an individual enantiomer, a racemic mixture, an individual stereoisomer, a mixture of stereoisomers, an individual diastereoisomer, a mixture of diastereoisomers, a solvate, or a salt, a solvate, a biohydrolizable ester or a biohydrolizable amide thereof, pharmaceutically acceptable.
[0209] A method for activating glucokinase is described, which comprises the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound according to the present invention. The invention
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it further provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound according to the present invention sufficient to activate glucokinase. A glucokinase activating amount may be an amount that reduces or inhibits a PTPase activity in the subject.
[0210] Furthermore, the present invention provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound according to the present invention sufficient to treat type I diabetes.
[0210] The present invention also provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound according to the present invention sufficient to treat type II diabetes.
[0212] The compounds of the present invention can be administered to any mammal in need of activation of glucokinase activity. Such mammals include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, macaques of India, and most preferably humans.
[0213] In another aspect of the present invention the compounds of the present are administered in combination with one or more other active ingredients in any suitable proportion. Said other active ingredients can be chosen among antidiabetics, antihyperlipidemic drugs, anti-obesity drugs, antihypertensives and drugs for the treatment of complications resulting from, or associated with, diabetes.
[0214] Such suitable antidiabetics include insulin, derivatives of GLP-1 (glucagon-like peptide 1) such as those disclosed in WO 98/08871 (Novo Nordisk A / S), as well as orally active hypoglycemic agents.
[0215] Suitable orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, αglucosidase inhibitors, drugs acting on the ATP-dependent potassium channel of pancreatic β cells for example potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), potassium channel openers such as ormitiglinide, potassium channel blockers such as nateglinide or BTS-67582, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), GLP-1 agonists as disclosed in WO 00 / 42026 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), DPP-IV inhibitors (dipeptidyl peptidase-IV), PTPase inhibitors (protein tyrosine phosphatase), liver enzyme inhibitors involved in e Stimulation of gluconeogenesis and / or glycogenolysis, glucose uptake modulators, GSK-3 inhibitors (glycogen synthase kinase-3), compounds that modify lipid metabolism as antihyperlipidemic, and antilipidemic, compounds that reduce intake of food and agonists of PPAR (receptor activated by peroxisome proliferators) and agonists of RXR (retinoid X receptor) such as ALRT-268, LG-1268 or LG-1069.
[0216] In one embodiment of the present invention, the compounds of the present are administered in combination with insulin, insulin derivatives or insulin analogs.
[0217] In one embodiment of the present invention, the compounds of the present are administered in combination with a sulfonylurea eg. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glycanzide or glyburide.
[0218] In one embodiment of the present invention, the compounds of the present are administered in combination with a biguanide eg. metformin
[0219] In one embodiment of the present invention, the compounds of the present are administered in combination with a meglitinide eg. Repaglinide or Senaglinide / Nateglinide.
[0220] In one embodiment of the present invention, the compounds of the present are administered in combination with an insulin sensitizing thiazolidinedione for example. troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / CI-1037 or T 174 or the compounds disclosed in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120 , WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).
[0221] In one embodiment of the present invention, the compounds of the present can be administered in combination with an insulin sensitizer eg. such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313 (NN622 / DRF-2725), WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193
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(Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00 / 63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A / S).
[0222] In one embodiment of the present invention, the compounds of the present are administered in combination with an α-glucosidase inhibitor eg. Voglibose, emiglitato, miglitol or acarbose.
[0223] In one embodiment of the present invention, the compounds of the present are administered in combination with a glycogen phosphorylase inhibitor eg. the compounds described in WO 97/09040 (Novo Nordisk A / S).
[0224] In one embodiment of the present invention, the compounds of the present are administered in combination with a drug acting on the ATP-dependent potassium channel of pancreatic β cells eg. Tolbutamide, Glibenclamide, Glipizide, Glicazide, BTS-67582 or Repaglinide.
[0225] In one embodiment of the present invention, the compounds of the present are administered in combination with nateglinide.
[0226] In one embodiment of the present invention, the compounds of the present are administered in combination with an antihyperlipidemic or an antilipidemic for example. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
[0227] In another aspect of the present invention, the compounds of the present are administered in combination with more than one of the compounds mentioned above for example in combination with metformin and a sulfonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
[0228] In addition, the compounds according to the invention can be administered in combination with one or more anti-obesity drugs or appetite regulators.
[0229] Such drugs can be chosen from the group consisting of CART agonists (transcript regulated by cocaine and amphetamine), NPY antagonists (neuropeptide Y), MC3 receptor agonists (melanocortin 3), MC4 receptor agonists (melanocortin 4 ), orexin antagonists, TNF agonists (tumor necrosis factor), CRF agonists (corticotropin release factor), CRF BP antagonists (corticotropin release factor binding protein), urocortin agonists, receptor agonists β3 adrenergic agents such as CL316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH agonists (melanocyte stimulating hormone), MCH antagonists (melanocyte concentrating hormone), CCK agonists (cholecystokinin), inhibitors of serotonin reuptake (fluoxetine, seroxat or citalopram), serotonin and norepinephrine reuptake inhibitors, 5HT agonists (serotonin), bombesin agonists, galan antagonists ina, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, HRT agonists (thyrotropin releasing hormone), CPU modulators 2 or 3 (decoupling proteins 2 or 3), agonists leptin, DA (dopamine) agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators, TR β agonists, CNS adrenergic stimulants, AGRP inhibitors (agouti-related protein) , histamine H3 receptor antagonists as disclosed in WO 00/42023, WO 00/63208 and WO 00/64884, exendin-4, GLP-1 agonists and ciliary neurotrophic factor. Other antiobesity drugs are bupropion (antidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1 / D5 receptor antagonist) and naltrexone (opioid antagonist).
[0230] In one embodiment of the present invention the antiobesity drug is leptin.
[0231] In one embodiment of the present invention the antiobesity drug is a serotonin and norepinephrine reuptake inhibitor eg. Sibutramine
[0232] In one embodiment of the present invention the antiobesity drug is a lipase inhibitor eg. Orlistat
[0233] In one embodiment of the present invention the antiobesity drug is an adrenergic CNS stimulant for example. dexamfetamine, amphetamine, phentermine, mazindole, phendimetrazine, diethylpropion, fenfluramine or dexfenfluramine.
[0234] In addition, the compounds herein can be administered in combination with one or more antihypertensives. Examples of antihypertensives are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril calcium channel like nifedipine, felodipine,
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nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. For more information, see Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
[0235] In another aspect the invention provides a pharmaceutical preparation containing a glucokinase activator and an insulin derivative. In one embodiment of the invention the insulin derivative is chosen from the group consisting of B29-Nε-myristoyl-des (B30) human insulin, B29-Nε-palmitoyl-des (B30) human insulin, B29-Nε-myristoyl human insulin , B29-Nεpalmitoil human insulin, B28-Nε-myristoyl LysB28ProB29 human insulin, B28-Nε-palmitoyl LysB28ProB29 human insulin, B30-Nε-miristoyl-ThrB29LysB30 human insulin, B30-Nε-palmitoyl-ThrB29LysB30 human insulin (B29-N Npalmitoyl-γ-glutamyl) -des (B30) human insulin, B29-Nε- (N-lithocolyl-γ-glutamyl) -des (B30) human insulin, B29-Nε- (ωcarboxiheptadecanoyl) -des (B30) human insulin and B29-Nε- (ω-carboxyheptadecanoyl) human insulin.
[0236] In another embodiment of the invention the insulin derivative is B29-Nε-myristoyl-des (B30) human insulin.
[0237] It should be understood that any suitable combination of the compounds according to the invention with diet and / or exercise, one or more of the aforementioned compounds and optionally one or more other active ingredients, is considered to be covered by the scope of the present invention.
Pharmaceutical compositions
[0238] The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in a single dose or in multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as with any other helper and excipient known, in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition , Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
[0239] Pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including oral and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous) , intramuscular, intrathecal, intravenous and intradermal), the oral route being preferred. It will be understood that the preferred route will depend on the general condition and the age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
[0240] Pharmaceutical compositions for oral administration include solid pharmaceutical forms such as hard or soft capsules, tablets, troches, dragees, pills, pills, powders and granules. When appropriate, they can be prepared with coatings as enteric coatings or can be formulated so as to provide a controlled release of the active ingredient as a sustained or prolonged release according to methods well known in the area.
[0241] Liquid pharmaceutical forms for oral administration include, solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
[0242] Pharmaceutical compositions for parenteral administration include sterile injectable, aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted into sterile injectable solutions or dispersions before use. Depot injectable formulations are also considered to be encompassed by the scope of the present invention.
[0243] Other suitable forms of administration include suppositories, aerosols, ointments, creams, gels, inhalants, skin patches, implants, etc.
[0244] A usual oral dose is in the range between about 0.001 and about 100 mg / kg of body weight per day, preferably between about 0.01 and about 50 mg / kg of body weight per day, and more preferably between about 0.05 and about 10 mg / kg body weight per day administered in one or more doses, for example 1 to 3 doses. The exact dose will depend on the frequency and mode of administration, gender, age, weight and general condition of the subject to be treated, the nature and severity of the condition being treated and any other concomitant disease that should be treated and Other obvious factors for experts.
[0245] The formulations may conveniently be presented in unit dosage forms by methods known to the experts. A typical unit dosage form for oral administration one or more times per day as 1 to 3 times per day may contain between 0.05 and approximately 1000 mg, preferably between approximately 0.1 and approximately 500 mg, and more preferably between approximately 0.5 mg and approximately 200 mg. .
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Principio activo (como compuesto libre o una de sus sales)

5.0 mg

Lactosa Ph. Eur.

67.8 mg

Celulosa microcristalina (Avicel)

31.4 mg

Amberlite®IRP88*

1.0 mg

Estearato de magnesio Ph. Eur.

c.s.

Recubrimiento: [0266]

Hidroxipropilmetilcelulosa

aprox. 9 mg

Mywacett 9-40 T**

aprox. 0.9 mg

* Polacrilina potásica NF, desintegrante de comprimidos, Rohm and Haas. **Monoglicérido acilado utilizado como plastificante para recubrimiento con película.

[0267] Si se desea, la composición farmacéutica de la presente invención puede contener un compuesto según la presente invención en combinación con otros principios activos como los descritos precedentemente.
[0268] La presente invención también proporciona un método para la síntesis de compuestos útiles como productos intermedios en la preparación de compuestos de fórmula (I) junto con los métodos para la preparación de los compuestos de fórmula (I). Los compuestos se pueden preparar fácilmente según los esquemas de reacción siguientes (en los cuales todas las variables son las definidas antes, a menos que se especifique algo diferente) empleando materiales de partida fácilmente disponibles, reactivos y procedimientos de síntesis convencionales. En estas reacciones, también es posible emplear variantes que son conocidas por los expertos pero no se mencionan detalladamente.
ABREVIATURAS
[0269] Las abreviaturas empleadas en los esquemas y los ejemplos son las siguientes: d = días g = gramos h = horas Hz = hertz kD = kiloDalton L = litros M = molar mbar = milibar mg = miligramos min = minutos ml = mililitros mM = milimolar mmol = milimoles mol = moles N = normal ppm = partes por millón
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psi = libras por pulgada cuadrada APCI = ionización química a presión atmosférica ESI = ionización por electronebulización
i.v. = intravenosa m/z = relación masa a carga pf = punto de fusión MS = espectrometría de masas RMN = espectroscopía de resonancia magnética nuclear
p.o. = por vía oral Rf = movilidad relativa de TLC rt = temperatura ambiente
s.c. = subcutánea TLC = cromatografía en capa delgada tr = tiempo de retención BOP = hexafluorofosfato de (1-benzotriazoliloxi)tris(dimetilamino)fosfonio DCM = diclorometano DIEA = diisopropiletilamina DMF = N,N-dimetilformamida DMPU = 1,3-dimetilpropileno urea DMSO = dimetilsulfóxido EDC = clorhidrato de 1-etil-3-(3-dimetilaminopropil)-carbodiimida éter = éter dietílico EtOAc = acetato de etilo HMPA = triamida hexametilfosfórica HOBt = 1-hidroxibenzotriazol LAH = hidruro de litio y aluminio LDA = diisopropilamida de litio MeOH = metanol NMM = N-metilmorfolina, 4-metilmorfolina TEA = trietilamina TFA = ácido trifluoroacético THF = tetrahidrofurano THP = tetrahidropiranilo TTF = hexafluorofosfato de fluoro-N,N,N'-tetrametilformamidinio
Esquemas de reacción
[0270] A menos que se especifique lo contrario, las variables de los esquemas son las definidas por la fórmula (I).
[0271] El esquema 1 describe la preparación de los compuestos de fórmula (74).
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Esquema 1 imagen18
5 [0272] A2 es heteroarilo, heterociclilheteroarilo fusionado o cicloalquilheteroarilo fusionado.
[0273] R100 y R101, independientemente uno de otro, son sustituyentes como, pero no exclusivamente, H, alquilo, alquenilo, alquinilo, -alquileno-arilo, alquileno-cicloalquilo, y análogos.
10 [0274] K es halógeno o 1-imidazolilo.
[0275] La amina (71) se puede tratar con carbonildiimidazol, cloroformiato de 4-nitrofenilo, fósgeno o un derivado de fósgeno como difósgeno o trifósgeno, en un solvente como DCM o DCE. Se puede utilizar DMAP como catalizador en esta reacción. La reacción se puede llevar a cabo a una temperatura entre 0 °C y 100 °C. La mezcla de reacción
15 se puede tratar después con el compuesto (73) y el todo se puede incubar a una temperatura entre 25 °C y 100 °C para obtener la urea (75). Se entiende también que (73) se puede tratar con el reactivo (72) en condiciones similares, seguido de tratamiento con la amina (71), para obtener (74).
[0276] El esquema 2 describe la preparación de los compuestos de fórmula (79). 20
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Esquema 2 imagen19
[0277] L11 tiene el significado de L1 en la fórmula (I), con la condición de que cuando L11 es -D-alquileno-E-, -D5 alquenileno-E-, -D-alquinileno-E-, -D-cicloalquileno-E-o -D-heterociclileno-E-, entonces D se elige entre -O-o -S-, y L11 no es -S(O)-, -S(O)2-, -C(O)-ni -C(=N-OR12)-.
[0278] Lg1 es un grupo saliente como F, Cl, Br o I.
10 [0279] R101 es un sustituyente como, pero no exclusivamente, H, alquilo, alquenilo, alquinilo, -alquileno-arilo, alquileno-cicloalquilo y análogos.
[0280] Un compuesto cíclico arilo o heteroarilo sustituido con nitro como (75) se puede tratar con (76) en presencia de una base como NaH o tert-butóxido de potasio, en un solvente como THF, DMF o NMP a una temperatura entre 15 0 °C y 100 °C, para obtener (77). El aducto resultante (77) se puede tratar con cloruro de estaño(II) en etanol u otro solvente alcohólico, a una temperatura entre 25 °C y 100 °C, en presencia de HCl acuoso, para obtener la amina (78). La amina (78) se puede tratar, si se desea, con un haluro de alquilo R101-Lg2, en el que Lg2 es un grupo saliente como Br, I o p-toluenosulfonato, y una base como DBU o hidruro de sodio, para obtener (79). Alternativamente, (78) se puede tratar con un reactivo R102-C(O)-R103, en el que R102 y R103, independientemente uno de otro, son
20 sustituyentes como, pero no exclusivamente, H, alquilo, alquenilo, alquinilo, -alquileno-arilo, alquileno-cicloalquilo y análogos, en presencia de un reductor como cianoborohidruro de sodio o triacetoxiborohidruro de sodio, para obtener (79) en el que R101 debe ser entendido como R102-C(H)(R103)-.
[0281] Alternativamente, (78) se puede tratar con un reactivo R102C(O)-OH en presencia de un deshidratante como
25 EDC, para obtener una amida intermedia, que se puede reducir con un reactivo como DIBAL o LAH, en un solvente como THF, a una temperatura entre 0 °C y 80 °C, para obtener (71) en el que R102 se debe entender como -CH2-R102. Alternativamente, (79) cuando R101 es -CH3 se puede preparar por tratamiento de (78) con un reactivo R102-O-CO-Cl o R102O-CO-O-CO-O-R102, en presencia de una base como TEA o un álcali acuoso, para obtener un producto intermedio que se puede reducir como antes empleando DIBAL o LAH para dar (79). El compuesto (79) se puede
30 emplear de la misma manera que el compuesto (73) de acuerdo con la química del esquema (1).
[0282] El esquema 3 describe la síntesis de un compuesto de fórmula (71). imagen20
[0283] A2 es un heteroarilo sustituido o no, un heterociclilheteroarilo fusionado sustituido o no, o un cicloalquilheteroarilo fusionado sustituido o no.
40 [0284] R100 es un sustituyente como, pero no exclusivamente, H, alquilo sustituido o no, alquenilo sustituido o no, alquinilo sustituido o no, -alquileno-arilo sustituido o no, -alquileno-cicloalquilo sustituido o no, y análogos.
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[0285] La amina (80) se puede tratar, si se desea, con un haluro de alquilo R100-Lg2, en el que Lg2 es un grupo saliente como Br, I o p-toluenosulfonato, y una base como DBU o hidruro de sodio, para obtener (71). Alternativamente, (80) se puede tratar con un reactivo R102-C(O)-R103, en el que R102 y R103, independientemente uno de otro, son sustituyentes como, pero no exclusivamente, H, alquilo, alquenilo, alquinilo, -alquileno-arilo, alquileno
5 cicloalquilo y análogos, en presencia de un reductor como cianoborohidruro de sodio o triacetoxiborohidruro de sodio, para obtener (71) en el que R100 debe ser entendido como R102-C(H)(R103)-.
[0286] Alternativamente, (78) se puede tratar con un reactivo como R102C(O)-Cl y una base como TEA o R102C(O)-OH en presencia de un deshidratante como EDC, para obtener una amida intermedia, que se puede reducir después 10 con un reactivo como DIBAL o LAH, en un solvente como THF, a una temperatura entre 0 °C y 80 °C, para obtener
(71) en el que R100 se debe entender como -CH2-R102. Alternativamente, (71) cuando R100 es -CH3 se puede preparar mediante tratamiento de (78) con un reactivo R102-O-C(O)-Cl o R102O-C(O)-O-C(O)-O-R102, en presencia de una base como TEA o un álcali acuoso, para obtener un producto intermedio que se puede reducir como antes empleando DIBAL o LAH para dar (71).
15 [0287] El esquema 4 describe la síntesis de un compuesto de fórmula (81). imagen21
20 [0288] A2 es un heteroarilo sustituido o no, un heterociclilheteroarilo fusionado sustituido o no, o un cicloalquilheteroarilo fusionado sustituido o no.
[0289] R100 y R101 son, independientemente uno de otro, sustituyentes como, pero no exclusivamente, H, alquilo 25 sustituido o no, alquenilo sustituido o no, alquinilo sustituido o no, -alquileno-arilo sustituido o no, -alquilenocicloalquilo sustituido o no, y análogos.
[0290] La amina (73) se puede tratar con el reactivo isocianato de clorocarbonilo en presencia de una base como DIEA, en un solvente como THF, DCE o dioxano, a una temperatura entre -60 °C y 25 °C. El producto intermedio así 30 formado se puede tratar a una temperatura entre 0 °C y 80 °C con (71) para obtener (81).
[0291] El esquema 5 describe la preparación de un producto intermedio de fórmula (87). imagen22
[0292] L11 es, en este caso, un grupo como un alquileno sustituido o no, o un enlace directo.
[0293] R104 es un sustituyente como, pero no exclusivamente, alquilo sustituido o no, arilo sustituido o no, alquenilo 40 sustituido o no, alquinilo sustituido o no, -alquileno-arilo sustituido o no, -alquileno-cicloalquilo sustituido o no, y análogos.
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[0294] El ácido antranílico (82) se puede tratar con un cloruro de ácido R104-CO-Cl en presencia de una base como TEA o un álcali acuoso para obtener una amida intermedia, que se puede tratar con un deshidratante como POCl3 o SOCl2 en un solvente como DCE, a una temperatura entre 0 °C y 80 °C, para obtener (83). Se puede preparar un reactivo (84) derivado de un agente de metalación activo como el metal litio o magnesio y G1-L11-Br o G1-L11-I. Por 5 ejemplo, cuando G1 es arilo y L11 es un enlace directo, G1-L11-Br se puede tratar con n-butillitio en un solvente como éter, a una temperatura entre -78 °C y 0 °C, para obtener el reactivo (84) en el que M1 es Li. (84) se puede tratar con
(83) en un solvente como THF, a una temperatura entre -78 °C y 50 °C, para obtener (85). La amida (85) se puede tratar con un álcali acuoso en un solvente como etanol, a una temperatura entre 25 °C y 100 °C, para obtener (86).
10 [0295] El esquema 6 describe la síntesis alternativa de un compuesto de fórmula (88).
Esquema 6 imagen23
[0296] L12 es, en este caso, un grupo como, pero no exclusivamente, un alquileno sustituido o no, un cicloalquileno sustituido o no, o un enlace directo.
25 [0297] Un compuesto amina (87) se puede tratar con un cloruro de ácido u otro haluro de ácido, en presencia de tricloruro de boro, a una temperatura entre -40 °C y 25 °C, seguido de tratamiento con cloruro de galio (III) y clorobenceno y calentamiento a una temperatura entre 50 °C y 150 °C, para obtener (88).
[0298] El esquema 7 describe la síntesis de productos intermedios de las fórmulas (91), (92), (93), (94) y (95). 30 imagen24
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[0299] L13 es un grupo como oxígeno, o puede ser un grupo ampliamente definido como para L12 y L11. R106, R107 y R108 son grupos como, pero no exclusivamente, alquilo sustituido o no, -alquileno-arilo sustituido o no, o H.
5 [0300] El nitrotolueno (89) se puede bromar con un reactivo como N-bromosuccinimida en tetracloruro de carbono para obtener el bromuro intermedio (90). El grupo metilo de (89) también puede ser un grupo alquilo más elaborado con hidrógeno(s) en el carbono adyacente a A1. El bromuro (90) se puede tratar con metanosulfinato de sodio para obtener el producto intermedio (91) y con aminas primarias o secundarias para obtener el producto intermedio (92). Alternativamente, los grupos R106 y R107 del compuesto R106R107NH se pueden tomar juntos para constituir un grupo
10 heteroarilo o heterociclilo, y el tratamiento de (90) con dicho compuesto en presencia de una base como tertbutóxido de potasio produce (92) en el que los grupos R106 y R107 se toman juntos para constituir un grupo heteroarilo o heterociclilo. Alternativamente, (90) se puede tratar con tiolacetato de sodio, seguido de hidrólisis con un álcali acuoso, para obtener el tiol (91). A partir de (91), se pueden preparar varios compuestos. Por ejemplo, el tratamiento de (91) con un alquilante como un bromuro de alquilo en presencia de una base como hidruro de sodio
15 produce (93) en el que L14 es S y R105 es alquilo. La oxidación de esta especie con un reactivo como ácido mcloroperbenzoico puede producir el compuesto en el que L14 es -SO2-. El compuesto (92) en el que R106 es H se puede tratar con un compuesto R108SO2Cl en presencia de una base como piridina para preparar (95). Alternativamente, (92) en el que R106 es H se puede tratar con un ácido carboxílico R108COOH en presencia de un agente de acoplamiento de péptidos como diciclohexilcarbodiimida para preparar (94).
20 [0301] El esquema 8 describe la síntesis de compuestos de fórmula (97). imagen25
25 [0302] L16 es oxígeno. G1 y L16, en este caso, preferentemente no contienen grupos cetona, aldehído ni amina primaria o secundaria.
[0303] R109, R110 y R111 son grupos como, pero no exclusivamente, alquilo sustituido o no, H, o alquileno-arilo 30 sustituido o no. R110 y R111 pueden opcionalmente tomarse juntos para constituir un anillo heterocíclico.
[0304] Las ureas de fórmula (91) se pueden aminar reductoramente empleando aminas R110NHR111 y un reactivo como triacetoxiborohidruro de sodio en un solvente como 1,2-dicloroetano en presencia o ausencia de ácido acético para obtener compuestos de fórmula (92).
35 [0305] El esquema 9 describe la síntesis de compuestos de las fórmulas (100) y (101).
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Esquema 9 imagen26
[0306] L17 es un grupo carbonilo o sulfonilo.
5 [0307] Las nitrofenilureas (98) se pueden reducir a derivados de anilina de fórmula (99). El tratamiento del producto intermedio (99) con cloruros de ácido o cloruros de sulfonilo puede producir compuestos de fórmula (100). La alquilación del producto intermedio (99) usando aldehídos o cetonas en presencia de triacetoxiborohidruro de sodio produce (101). Alternativamente, (99) se puede tratar con haluro de dialquilo y una base como DIEA para obtener
10 (101) en el que R113 y R114 y el nitrógeno al cual están unidos constituyen un anillo. imagen27
15 [0308] L19 en este caso es un grupo como un alquileno sustituido o no. R115 y R116 son independientemente, grupos como alquilo sustituido o no, alquileno-arilo sustituido o no, o H. Alternativamente, R115 y R116 se pueden tomar juntos para constituir un anillo heterocíclico.
[0309] El ácido (102) se puede acoplar con una amina R115NHR116 en presencia de un agente de acoplamiento como 20 diciclohexilcarbodiimida en un solvente como THF o diclorometano para obtener (103).
[0310] Esquema 11 35
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Esquema 11 imagen28
[0311] A3 es un grupo como heteroarileno sustituido o no, heterociclilheteroarileno fusionado sustituido o no, o 5 cicloalquilheteroarileno fusionado sustituido o no.
[0312] R117 es un grupo como alquilo sustituido o no, alquileno-arilo sustituido o no, arilo sustituido o no, o heteroarilo sustituido o no.
10 [0313] El compuesto (104) se puede tratar con un reactivo tiol en presencia de una base como DIEA a una temperatura entre 50 °C y 150 °C para obtener el tioéter (105). (105) se puede oxidar con un reactivo oxidante como ácido m-cloroperbenzoico en un solvente como diclorometano para obtener la sulfona (106). Cuando se emplea un solo equivalente del oxidante, se puede obtener el sulfóxido. Cuando se emplean 2 o más equivalentes del oxidante, se obtiene la sulfona.
15 [0314] El esquema 12 describe la síntesis de los compuestos de fórmula (109). imagen29
20 [0315] A3 es un grupo como heteroarileno sustituido o no, heterociclilheteroarileno fusionado sustituido o no, o cicloalquilheteroarileno fusionado sustituido o no.
[0316] L20 en este caso es un grupo como un alquileno sustituido o no. R117 es un grupo como alquilo sustituido o no, 25 alquileno-arilo sustituido o no, arilo sustituido o no, o heteroarilo sustituido o no. Lg2 es un grupo saliente como cloruro, metanosulfonato o p-toluenosulfonato.
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[0317] El compuesto (107) en el que Lg2 es metanosulfonato se puede sintetizar a partir del precursor en el que Lg2 es hidroxilo mediante tratamiento con cloruro de metanosulfonilo en presencia de piridina. Después (107) se puede tratar con un reactivo tiol en presencia de una base como DIEA, tert-butóxido de potasio o hidruro de sodio, para
5 obtener el producto de desplazamiento (108). El producto tioéter (108) se puede oxidar al sulfóxido o la sulfona (109) como se describió en el esquema 11.
[0318] El esquema 13 describe la síntesis de los compuestos de fórmula (111).
10 Esquema 13 imagen30
[0319] L21 en este caso es un grupo como un alquileno. R115 y R116 pueden tener el significado indicado previamente,
o pueden ser, independientemente, grupos como alquilo sustituido o no, alquileno-arilo sustituido o no, arilo
15 sustituido o no, H, o heteroarilo sustituido o no. A3 es un grupo como heteroarileno sustituido o no, heterociclilheteroarileno fusionado sustituido o no, o cicloalquilheteroarileno fusionado sustituido o no.
[0320] El ácido (110) se puede acoplar con una amina R115NHR116 en presencia de un agente de acoplamiento como diciclohexilcarbodiimida para obtener (111). 20 [0321] El esquema 14 describe una síntesis de productos intermedios de fórmula (113). imagen31
25 [0322] R118 y R119 pueden ser, independientemente, grupos como alquilo sustituido o no, alquileno-arilo sustituido o no, arilo sustituido o no, H, o heteroarilo sustituido o no.
[0323] La tiourea se puede condensar con el compuesto bromo carbonilo (112) en presencia o ausencia de una base
30 suave como carbonato de potasio o trietilamina, en un solvente como etanol, a una temperatura entre 25 °C y 120 °C, para obtener (113). Se puede llegar al compuesto de bromo (112) por diversos métodos conocidos en el área. Por ejemplo, la bromación de la cetona con hidrotribromuro de pirrolidinio en THF o N-bromosuccinimida en THF en presencia de una base suave como carbonato de potasio produce (112).
35 [0324] El esquema 15 describe la síntesis de productos intermedios de fórmula (117).
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Esquema 15 imagen32
[0325] El esquema 15 muestra la ruta de síntesis de diamidas del tipo (117), en las que A1, L1, R20, R1, G1, G2 son las definidas en la fórmula (I). La amina (114) se puede acoplar con un éster oxálico o malónico activado utilizando EDC/HOBt para dar la amida (115). La desprotección del éster t-butílico de B se hace con hidróxido de litio para dar el ácido carboxílico (116), que se puede acoplar usando reactivos de acoplamiento de amida estándar (por ej. PyBOP) para dar diamidas del tipo (115).
[0326] Los productos intermedios de los esquemas anteriores pueden estar sustituidos con grupos amino, hidroxilo o carboxilo que pueden requerir protección y desprotección durante el transcurso de la preparación de los compuestos de los ejemplos.
[0327] "Protección de amino" se refiere a los sustituyentes del grupo amino empleados comúnmente para bloquear o proteger la funcionalidad amino mientras reaccionan otros grupos funcionales del compuesto. Los ejemplos de dichos grupos protectores de amino incluyen el grupo formilo, el grupo tritilo, el grupo ftalimido, el grupo tricloroacetilo, los grupos cloroacetilo, bromoacetilo y yodoacetilo, grupos protectores tipo uretano como benciloxicarbonilo, 4-fenilbenciloxicarbonilo, 2-metilbenciloxicarbonilo, 4-metoxibenciloxicarbonilo, 4fluorobenciloxicarbonilo, 4-clorobenciloxicarbonilo, 3-clorobenciloxicarbonilo, 2-clorobenciloxicarbonilo, 2,4diclorobenciloxicarbonilo, 4-bromobenciloxicarbonilo, 3-bromobenciloxicarbonilo, 4-nitrobenciloxicarbonilo, 4cianobenciloxicarbonilo, 2-(4-xenil)iso-propoxicarbonilo, 1,1-difenilet-1-iloxicarbonilo, 1,1-difenilprop-1-iloxicarbonilo, 2-fenilprop-2-iloxicarbonilo, 2-(p-toluil)prop-2-iloxicarbonilo, ciclopentaniloxicarbonilo, 1-metilciclopentaniloxicarbonilo, ciclohexaniloxicarbonilo, 1-metilciclohexaniloxicarbonilo, 2-metilciclohexaniloxicarbonilo, 2-(4toluilsulfonil)etoxicarbonilo, 2(metilsulfonil)etoxicarbonilo, 2-(trifenilfosfino)etoxicarbonilo, 9-fluorenilmetoxicarbonilo ("FMOC"), t-butoxicarbonilo ("BOC"), 2-(trimetilsilil)etoxicarbonilo, aliloxicarbonilo, 1-(trimetilsililmetil)prop-1eniloxicarbonilo, 5-bencisoxalilmetoxicarbonilo, 4-acetoxibenciloxicarbonilo, 2,2,2-tricloroetoxicarbonilo, 2-etinil-2propoxicarbonilo, ciclopropilmetoxicarbonilo, 4-(deciloxi)benciloxicarbonilo, isoborniloxicarbonilo, 1piperidiloxicarbonilo y análogos; el grupo benzoilmetilsulfonilo, el grupo 2-(nitro)fenilsulfonilo, el grupo óxido de difenilfosfina y grupos protectores de amina similares. La especie del grupo protector de amino empleado no es crucial en la medida en que el grupo amino derivatizado sea estable para la condición de la reacción o las reacciones siguientes en otras posiciones del compuesto de fórmula (I) y pueda ser eliminado en el momento deseado sin alterar el resto de la molécula. Los grupos protectores de amino preferidos son los grupos aliloxicarbonilo, t-butoxicarbonilo, 9-fluorenilmetoxicarbonilo y tritilo. Los grupos protectores de amino similares utilizados en el campo de la cefalosporina, la penicilina y los péptidos también son abarcados por los términos anteriores. Otros ejemplos de grupos aludidos por los términos anteriores son descritos por J. W. Barton, "Protective Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, Nueva York, N.Y., 1973, y T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, Nueva York, N.Y., 1981. La expresión relacionada "amino protegido" define un grupo amino sustituido con un grupo protector de amino como los mencionados antes.
[0328] "Protección de hidroxilo" se refiere a los sustituyentes del grupo alcohol empleados comúnmente para bloquear o proteger la funcionalidad alcohol mientras reaccionan otros grupos funcionales del compuesto. Los ejemplos de dichos grupos protectores de alcohol incluyen el grupo 2-tetrahidropiranilo, el grupo 2-etoxietilo, el grupo tritilo, el grupo tricloroacetilo, los grupos bloqueadores tipo uretano como benciloxicarbonilo, y el grupo trialquilsililo,
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cuyos ejemplos son trimetilsililo, tert-butildimetilsililo, fenildimetilsililo, triisopropilsililo y t-hexildimetilsililo. La elección del grupo protector de alcohol empleado no es crucial en la medida en que el grupo alcohol derivatizado sea estable para la condición de la reacción o las reacciones siguientes en otras posiciones del compuesto de fórmula (I) y pueda ser eliminado en el momento deseado sin alterar el resto de la molécula. Otros ejemplos de grupos aludidos por los términos anteriores son descritos por J. W. Barton, "Protective Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, Nueva York, N.Y., 1973, y T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, Nueva York, N.Y., 1981. La expresión relacionada "hidroxilo protegido" o "alcohol protegido" define un grupo hidroxilo sustituido con un grupo protector de hidroxilo como los mencionados antes.
[0329] "Protección de carboxilo" se refiere a los sustituyentes del grupo carboxilo empleados comúnmente para bloquear o proteger la funcionalidad -OH mientras reaccionan otros grupos funcionales del compuesto. Los ejemplos de dichos grupos protectores de alcohol incluyen el grupo 2-tetrahidropiranilo, el grupo 2-etoxietilo, el grupo tritilo, el grupo alilo, el grupo trimetilsililetoximetilo, el grupo 2,2,2-tricloroetilo, el grupo bencilo y el grupo trialquilsililo, cuyos ejemplos son trimetilsililo, tert-butildimetilsililo, fenildimetilsililo, triisopropilsililo y t-hexildimetilsililo. La elección del grupo protector de carboxilo empleado no es crucial en la medida en que el grupo alcohol derivatizado sea estable para la condición de la reacción o las reacciones siguientes en otras posiciones del compuesto de fórmula (I) y pueda ser eliminado en el momento deseado sin alterar el resto de la molécula. Otros ejemplos de grupos aludidos por los términos anteriores son descritos por J. W. Barton, "Protective Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, Nueva York, N.Y., 1973, y T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, Nueva York, N.Y., 1981. La expresión relacionada "carboxilo protegido" define un grupo carboxilo sustituido con un grupo protector de carboxilo como los mencionados antes.
Ejemplos
Procedimiento general A: Preparación de 1-ariloxi-2-nitrobencenos,1-arilsulfanil-2-nitrobencenos y 2-ariloxi-3nitropiridinas
[0330] A una solución de t-butóxido de potasio (0.62 g, 5.5 mmol) en DMF anhidra (10 ml) se le agregó un fenol, arilmercaptano o 2-mercaptopiridina (5.5 mmol) a temperatura ambiente y la mezcla se agitó durante 30 min. Se le agregó un derivado de 1-fluoro-2-nitrobenceno o 2-bromo-3-nitropiridina (5.0 mmol) y el contenido se calentó a 80 °C durante 12 h. El contenido se vertió en agua y se extrajo con acetato de etilo. La capa orgánica se lavó (NaOH dil., agua, solución saturada de cloruro de sodio), se secó (Na2SO4) y se concentró. En general, los productos deseados fueron >90% puros y se usaron como tales en manipulaciones posteriores.
Procedimiento general B: Preparación de 2-ariloxianilinas, 2-arilsulfanilanilinas y 3-amino-2-ariloxipiridinas
[0331] El 2-sustituido-1-nitrobenceno crudo del procedimiento A se disolvió en etanol (10 ml). A esta solución se le agregaron cloruro de estaño (II) anhidro (3.8 g, 20 mmol) y HCl conc. (0.2 ml). La mezcla resultante se calentó a 80 °C durante 10 h, se enfrió y se concentró. El residuo se diluyó con agua (100 ml), se neutralizó hasta pH 8-9. A la suspensión se le agregó acetato de etilo (40 ml), se agitó durante 5 min y se filtró a través de celite. Las capas se separaron y la fase acuosa se extrajo con acetato de etilo (2 x 10 ml). La capa orgánica combinada se lavó con solución saturada de cloruro de sodio, se secó (Na2SO4) y se concentró a presión reducida para obtener la anilina deseada con un rendimiento de 60-70%. En general, las anilinas deseadas fueron >85% puras (LC-MS) y se usaron como tales en manipulaciones posteriores.
Procedimiento general C para la preparación de 2-ariloxianilinas y 2-arilsulfanilanilinas
[0332] El 2-sustituido-1-nitrobenceno crudo (∼5 mmol) se disolvió en metanol (10 ml) en un matraz de fondo redondo de 100 ml. A esta solución se le agregó 10% de paladio sobre carbón (300 mg) y el matraz se evacuó. El matraz se llenó con hidrógeno con ayuda de un balón y el contenido se agitó toda la noche. La mezcla se filtró a través de celite y se concentró para obtener la anilina deseada (>90% de pureza por LC-MS).
Procedimiento general D: Preparación de urea
[0333] Una mezcla de 1,1'-carbonildiimidazol (98 mg, 0.6 mmol), 2-aminoheteroareno (0.6 mmol) y 4-(N,Ndimetilamino)piridina (5 mg) en dicloroetano (5 ml) se calentó a 80 °C durante 2 h. La mezcla de reacción se enfrió hasta temperatura ambiente y se le agregó solución de una anilina sustituida (0.5 mmol) en dicloroetano (2 ml). La suspensión resultante se calentó a 80 °C durante 10 h y se concentró. El residuo se purificó por cromatografía en columna (sílice, CH2Cl2 después 10-30% de acetato de etilo en CH2Cl2) para obtener la urea deseada con un rendimiento de 60-80%.
Procedimiento general E: Preparación de urea
[0334] Una mezcla de isocianato (0.5 mmol) y 2-aminoheteroareno (0.5 mmol) en dicloroetano (4 ml) se calentó a 80
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°C durante 12 h. La mezcla de reacción se concentró a presión reducida. El residuo se purificó por cromatografía en columna (sílice, CH2Cl2 después 10-30% de acetato de etilo en CH2Cl2) para obtener la urea deseada con un rendimiento de 60-80%.
Procedimiento general F: Preparación de 2-ariloxi-1-nitrobencenos
[0335] A una solución de t-butóxido de potasio (0.62 g, 5.5 mmol) en THF anhidro (20 ml) se le agregó un fenol (5.5 mmol) a -10 °C y la mezcla se agitó durante 30 min. Se agregó un derivado de fluoro-1-nitrobenceno (5.0 mmol) a 10 °C y se agitó durante 12 h a temperatura ambiente. El contenido se vertió en agua (25 ml) y se extrajo con acetato de etilo (3 x 20 ml). La capa orgánica se lavó (NaOH dil., agua, solución saturada de cloruro de sodio), se secó (Na2SO4) y se concentró para dar los productos deseados con una pureza >90% por LC-MS que se usaron como tales en el paso siguiente.
Procedimiento general G: Preparación de 1-alcoxi-2-nitrobencenos
[0336] A una suspensión de NaH (60%, 0.20 g, 5.0 mmol) en THF anhidro (10 ml) se le agregó gota a gota un alcohol (5.0 mmol) a temperatura ambiente y la mezcla se agitó durante 30 min. Se le agregó 1-fluoro-2nitrobenceno (5.0 mmol) y el contenido se calentó a 60 °C durante 12 h. El contenido se vertió en agua y se extrajo con acetato de etilo. La capa orgánica se lavó (NaOH dil., agua, solución saturada de cloruro de sodio), se secó (Na2SO4) y se concentró. En general, los productos deseados fueron >90% puros (LC-MS) y se usaron como tales en manipulaciones posteriores.
Procedimiento general H: Procedimiento general para la preparación de compuestos de fórmula general I que contienen una porción urea en el núcleo central
[0337] Se disolvió un equivalente de una anilina mono-di-o tri-sustituida en un solvente orgánico como acetato de etilo, tolueno o diclorometano y se agregó clorhidrato disuelto en un solvente orgánico como acetato de etilo, tolueno o diclorometano. La mezcla se concentró al vacío para dar el clorhidrato de la anilina. El residuo se disolvió o suspendió en un solvente orgánico aprótico como tolueno o diclorometano y se le agregó un exceso (por ej. 2 a 5 equivalentes) de difósgeno u otro fósgeno equivalente. La mezcla se dejó a temperatura ambiente o se calentó (hasta la temperatura de reflujo del solvente) durante 5 a 20 horas. La mezcla de reacción se concentró al vacío y el residuo intermedio se utilizó en el paso siguiente sin purificación adicional.
[0338] El isocianato intermedio crudo se disolvió en un solvente orgánico como acetato de etilo, tolueno, diclorometano, dioxano, DMSO o DMF y se le agregó un equivalente de una amina heterocíclica. La mezcla de reacción se dejó a temperatura ambiente o se calentó hasta que tuvo lugar la reacción. La temperatura de reacción dependerá de la reactividad del isocianato y de la nucleofilicidad de la amina y se puede seguir usando HPLC o TLC. La mezcla de reacción se diluyó con un solvente orgánico como acetato de etilo, tolueno o diclorometano y la mezcla se extrajo con agua. El producto se purificó usando procedimientos estándar como los descritos en el área o como se ejemplifica a continuación.
Procedimiento general H1: Preparación de amidas a partir de ácidos carboxílicos preparados utilizando el procedimiento H:
[0339] Un equivalente de un ácido aminotiazol-4-ilcarboxílico N-sustituido o un ácido aminotiazol-4-ilacético Nsustituido preparando utilizando el procedimiento general H se disolvió en un solvente orgánico como 1,2dicloropropano, dimetilformamida o una mezcla de dos solventes orgánicos como una mezcla de 1,2-dicloropropano y dimetilformamida. Se agregó un equivalente de PyBOP (hexafluorofosfato de benzotriazol-1-il-oxi-tris-pirrolidinofosfonio), la mezcla de reacción se dejó en reposo durante 20 minutos seguido de la adición de dos equivalentes de una amina adecuada y DIPEA (diisopropiletilamina), y la mezcla se dejó en reposo durante toda la noche.
[0340] La mezcla de reacción se diluyó con acetato de etilo y se extrajo utilizando un procedimiento de lavado general como un lavado dos veces con agua, dos veces con HCl 4 N, una vez con agua, dos veces con bicarbonato de sodio saturado al 50%, y tres veces con agua. El solvente orgánico se evaporó al vacío para dar un producto amorfo. El producto se purificó por recristalización en un solvente orgánico como éter dietílico o por HPLC (por ej. un Waters Deltprep 4000).
[0341] En el caso de los productos aislados que contenían una funcionalidad éster de ácido carboxílico, el grupo éster se pudo hidrolizar al ácido correspondiente disolviendo el compuesto en etanol al 96% y agregando NaOH 2 N. La mezcla se dejó en reposo durante cierto tiempo (por ej. 2 horas) mientras el metanol se evaporaba al vacío, se agregaba agua, y el pH se ajustaba a ácido con HCl 2 N. La mezcla se extrajo con un solvente orgánico como acetato de etilo y las fases orgánicas combinadas se evaporaron al vacío para dar un producto amorfo.
Procedimiento general H2: Preparación de isocianatos intermedios:
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Isocianato de 2-bencilfenilo
[0342]
[0343] Se disolvió 2-bencilanilina (2.0 g, 11 mmol) en acetato de etilo (5 ml) y se agregó clorhidrato en acetato de etilo (3 N, 5 ml). Después de 2 horas se eliminó el solvente orgánico al vacío para dar un residuo sólido. Se agregó tolueno (50 ml), después difósgeno (2.2 g, 33 mmol) y la mezcla de reacción se calentó a 110 °C durante 16 horas.
10 Se eliminó el solvente y el exceso de difósgeno al vacío para dar un aceite residual que se usó en el paso siguiente sin purificación adicional.
[0344] Los isocianatos siguientes se prepararon empleando el mismo procedimiento utilizado para la preparación de isocianato de bencilfenilo: 15 (5-Cloro-2-isocianatofenil)fenil metanona imagen34
Isocianato de 2-(2-metilfenoxi)fenilo [0346] imagen35
Isocianato de 2-(4-metoxifenoxi)-5-(trifluorometil)fenilo imagen36
Isocianato de 2-(fenilsulfonil)fenilo [0348] imagen37
35 Procedimiento general I: Preparación de 2-acil anilinas
[0349] Una solución de tricloruro de boro 1 M en diclorometano (110 mL, 0.11 mol) se enfrió hasta -20 °C. A esta solución se le agregó una solución de anilina (0.1 mol) en diclorometano (100 mL). La mezcla se calentó hasta
40 temperatura ambiente y se agitó durante 3 h. La mezcla se volvió a enfriar hasta -20 °C. Se le agregó alquil nitrilo
(0.1 mol) en el transcurso de 5 min, seguido de solución 1 M de GaCl3 (anhidro) (100 mL, 0.1 mol) en diclorometano. A esta solución se le agregó clorobenceno (300 mL) y la mezcla se calentó a reflujo durante 24 h. Después de ser enfriada hasta temperatura ambiente, la mezcla se vertió en agua helada (1 L) y se agitó durante 3 h. Se separó la
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capa orgánica y la capa acuosa se extrajo con diclorometano (4 x 400 mL). La capa orgánica combinada se lavó con agua (4 x 500 mL) y solución saturada de cloruro de sodio (2 x 500 mL) y se secó en Na2SO4 anhidro. Después la capa acuosa se basificó hasta pH 7.5 con Na2CO3 y la mezcla se extrajo con diclorometano (2 x 400 mL). La capa orgánica se lavó con agua (4 x 500 mL) y solución saturada de cloruro de sodio (2 x 500 mL) y se secó en Na2SO4 anhidro. Se combinaron ambas capas orgánicas y se concentraron al vacío. La mezcla cruda se purificó por cromatografía en columna con hexanos-acetato de etilo (9:1) como eluyente, para dar las 2-amino-alquilfenonas con un rendimiento de 10-50%.
Procedimiento general J: Preparación de ácidos a partir de ésteres
[0350] Se disolvió el éster (1 mmol) en una mezcla 1:1 de THF y metanol (5 mL). A esta solución se le agregó solución de LiOH 2 M (2 mL, 4 mmol). La mezcla se agitó durante 1 h y se concentró. El residuo se diluyó con agua (10 mL) y la capa acuosa se extrajo con éter (2 x 10 mL). La capa acuosa se acidificó con HCl hasta pH 6.0 y el ácido precipitado se extrajo con acetato de etilo (2 x 50 mL). La capa orgánica se lavó con agua (2 x 20 mL), se secó (Na2SO4) y se concentró al vacío para dar el ácido deseado en rendimiento casi cuantitativo.
Procedimiento general K: Preparación de amidas
[0351] Una mezcla de ácido (0.5 mmol) y HBTU (0.5 mmol) se disolvió en DMF anhidra (2 mL). A esta solución se le agregó DIEA (0.6 mmol) y se agitó durante 2-3 minutos. Se agregó una solución de alquilamina (0.5 mmol) en DMF (1 mL) y la mezcla se agitó a temperatura ambiente durante 30 min. La mezcla se vertió en agua (20 mL) y se extrajo con acetato de etilo (2 x 20 mL). La capa orgánica se lavó con solución saturada de ácido cítrico (5 mL), NaHCO3 (2 x 10 mL), agua (2 x 0 mL) y solución saturada de cloruro de sodio (2 x 10 mL), se secó (Na2SO4) y se concentró al vacío para dar la amida deseada. La mezcla cruda se purificó por cromatografía en columna (sílice, CH2Cl2 después 10-50% de acetato de etilo en CH2Cl2) para proporcionar la amida con un rendimiento de 50-75%.
Procedimiento general L: Preparación de sulfonamidas/amidas
[0352] A una solución de ácido (1.0 mmol) y DIEA (1.5 mmol) en THF anhidro (20 mL) se le agregó difenilfosforil azida (1.5 mmol) y se calentó a reflujo durante 8-12 horas. La mezcla de reacción se concentró después al vacío para dar isocianato crudo. A este producto crudo se le agregó HCl diluido (1.2 M, 20 mL) y la mezcla se calentó a reflujo durante 2 horas. La mezcla de reacción se neutralizó con Na2CO3 y la capa acuosa se extrajo con acetato de etilo (3 x 30 mL). La capa orgánica se lavó con agua (2 x 30 mL) y solución saturada de cloruro de sodio (1 x 30 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para dar la amina deseada. Esta amina cruda (1.0 mmol) se hizo reaccionar con cloruro de arilo/alquilsulfonilo (1 mmol) y Et3N (2 mmol) para dar las sulfonamidas deseadas. Las amidas se prepararon como se describió en el procedimiento K. El producto crudo se purificó por cromatografía en gel de sílice [hexanos:EtOAc/MeOH (70:30:0 a 5:90:5)] para proporcionar las sulfonamidas deseadas con un rendimiento de 20-30%.
Procedimiento general M: Preparación de bis-ureas o carbamatos
[0353] Una mezcla de ácido (1.0 mmol) y DIEA (1.5 mmol) se disolvió en THF anhidro o CH3CN (30 mL). Después se agregó difenilfosforil azida (1.5 mmol) a la mezcla de reacción. La mezcla de reacción se calentó a reflujo durante 8-12 horas. La mezcla de reacción se concentró después al vacío para dar isocianato crudo. A este producto crudo se le agregaron las aminas o los alcoholes deseados (2.0 mmol) y se agitó a temperatura ambiente durante 2 h. Después la mezcla de reacción se concentró al vacío. Luego la mezcla de reacción cruda se purificó por cromatografía en gel de sílice (hexanos:EtOAc 70:30 a 10:90) para proporcionar las bis-ureas o los carbamatos deseados con un rendimiento de 30-45%.
Procedimiento general N: Preparación de alcoholes
[0354] A una solución de acetato de etil-2-amino-4-tiazolilo o carboxilato de etil-2-amino-4-tiazolilo (100 mmol) en THF anhidro (100 mL) se le agregó borohidruro de litio (200 mmol, solución 2.0 M en THF) a -10 °C, se permitió que la mezcla alcanzara la temperatura ambiente y se agitó durante 8-10 h. Después la mezcla se concentró al vacío. Se agregó metanol (200 mL) para desactivar el exceso de borohidruro de litio y se filtró a través de una almohadilla de gel de sílice para obtener el aminoalcohol.
[0355] A este aminoalcohol crudo (100 mmol) e imidazol (500 mmol) en DMF anhidra (50 ml) se le agregó cloruro de tert-butildimetilsililo (500 mmol) y se agitó a temperatura ambiente durante 6 h. Después la mezcla de reacción se lavó con agua (5 x 100 mL) y solución saturada de cloruro de sodio (2 x 100 mL) y se extrajo con acetato de etilo (3 x 200 mL), se secó en Na2SO4 y se concentró al vacío para dar el aminoalcohol protegido con TBS.
[0356] El aminoalcohol protegido con TBS (50 mmol) se sometió a formación de urea siguiendo el procedimiento general D para dar la urea deseada. Esta urea cruda (25 mmol) se trató después con TBAF (50 mmol, solución 1.0
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M en THF) y se agitó a temperatura ambiente durante 4 h. La mezcla de reacción se vertió en agua y se extrajo con acetato de etilo. Los extractos orgánicos se combinaron, se lavaron (agua), se secaron (Na2SO4) y se concentraron al vacío. La mezcla de reacción cruda se purificó por cromatografía en gel de sílice (hexanos:EtOAc 70:30 a 10:90) para obtener el alcohol deseado con un rendimiento de 70-80%.
Procedimiento general O: Preparación de aminas por aminación reductora
[0357] Al aldehído (0.11 mmol) en dicloroetano o THF (5 mL) se le agregó la amina respectiva (0.11 mmol) y se agitó a temperatura ambiente durante 15 min. A esta solución se le agregó triacetoxiborohidruro de sodio (0.16 mmol). Después de agitar a temperatura ambiente durante toda la noche, la mezcla se concentró al vacío y se purificó por cromatografía en columna (sílice, 2-8% de MeOH en DCM) para obtener el producto deseado con un rendimiento de 30-50%.
Procedimiento general P: Preparación de ariléteres por la reacción de Mitsunobu
[0358] A una solución de 1-[2-(ciclopentanocarbonil-4-metil-fenil]-3-[4-(2-hidroxi-etil)-tiazol-2-il]-urea (0.268 mmol), fenol (0.536 mmol) y trifenilfosfina (0.268 mmol) en THF (2 mL) se le agregó azodicarboxilato de diisopropilo (0.268 mmol) a 0°C. La solución resultante se agitó a temperatura ambiente durante toda la noche. La mezcla se concentró y se purificó por cromatografía en columna en gel de sílice (10-50% EtOAc/hexano) para dar el producto deseado con un rendimiento de 28-40%.
Procedimiento general Q: Síntesis de 1-(2-ciclopentanoil-4-metil-fenil)-3-(5-alquiltio-2-tiazolil)ureas
[0359] Una mezcla de 1-(2-ciclopentanoil-4-metil-fenil)-3-(5-bromo-2-tiazolil)urea (1 mmol), alquiltiol (2 mmol) y DIEA (2 mmol) en DMF (5 mL) se calentó a 80 °C durante 3 h. La mezcla se vertió en agua (20 mL) y se extrajo con acetato de etilo (3 x 25 mL). La capa orgánica se lavó con agua (2 x 30 mL) y solución saturada de cloruro de sodio (1 x 30 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para proporcionar un residuo que contenía 1-(2ciclopentanoil-4-metil-fenil)-3-(5-alquiltio-2-tiazolil)urea junto con 1-(2-ciclopentanoil-4-metil-fenil)-3-(tiazol-2-il)urea. El producto crudo se purificó por cromatografía en columna (sílice, CH2Cl2 después 5-20% de acetato de etilo en CH2Cl2) para obtener el producto deseado con un rendimiento de 25-35%.
[0360] Se adoptó el mismo procedimiento para la síntesis de 1-(2-ciclopentanoil-4-metilfenil)-3-(5-ariltio-2tiazolil)ureas. Los productos crudos se purificaron por cromatografía en columna (sílice, CH2Cl2 después 5-20% de acetato de etilo en CH2Cl2 y 2% de MeOH en CH2Cl2) para obtener el producto deseado con un rendimiento de 2535%.
Procedimiento general R: Oxidación de tiazolil ureas, alquil y ariltio sustituidas
[0361] Se disolvió tiazolil urea alquil o ariltio sustituida (0.5 mmol) en CH2Cl2 (5 mL) y se enfrió hasta 0 °C en un baño de hielo. A esta solución se le agregó m-cpba (133 mg, 0.75 mmol) en CH2Cl2 (3 mL). La mezcla se agitó a 0 °C durante 4 h y se diluyó con CH2Cl2 (30 mL). La capa orgánica se lavó con solución saturada de NaHCO3 (2 x 20 mL), agua (3 x 20 mL) y solución saturada de cloruro de sodio (1 x 20 mL), se secó (Na2SO4 anhidro) y se concentró al vacío. La mezcla cruda se purificó por cromatografía en columna (sílice, CH2Cl2 después 5-20% de acetato de etilo en CH2Cl2 y 2% de MeOH en CH2Cl2) para dar la alquil o aril sulfona deseada con un rendimiento de 60-80%.
Procedimiento general S: Preparación de 2-amino arilfenonas
[0362] A una solución de ácido 2-aminobenzoico (10 mmol) en THF se le agregó cloruro de benzoilo (2.8 g, 20 mmol) seguido de piridina (1.58 g, 20 mmol). La mezcla se agitó durante 1 h a temperatura ambiente. La 2-fenilbenzo[d][1,3]oxazin-4-ona formada se filtró y el residuo se lavó con agua y se secó en un desecador al vacío.
[0363] A una solución de 2-fenil-benzo[d][1,3]oxazin-4-ona (5 mmol) en CH2Cl2 seco (20 mL) se le agregó una solución 1 N de bromuro de aril magnesio en THF (5 mL) a 0° C. La mezcla se agitó a temperatura ambiente durante 2 h y se vertió en agua (30 mL). La capa acuosa se extrajo con acetato de etilo (3 x 30 mL) y se lavó con agua (3 x 50 mL) y solución saturada de cloruro de sodio (1 x 50 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para obtener N-(2-benzoil-fenil)-benzamida con un rendimiento de 60-70%.
[0364] A una solución de N-(2-benzoil-fenil)-benzamida cruda (2 mmol) en THF (10 mL) se le agregó una solución de NaOH 10 N (5 mL) y se calentó a reflujo durante 18 h. La mezcla se vertió en agua (50 mL) y se extrajo con acetato de etilo (3 x 30 mL). La capa orgánica se lavó con agua (3 x 50 mL) y, solución saturada de cloruro de sodio (1 x 50 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para dar 2-amino arilfenona. El producto crudo se purificó por cromatografía en columna (sílice, hexanos después 5-20% de acetato de etilo) para obtener el producto deseado con un rendimiento de 28-40%.
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Procedimiento general T: Preparación de amidas/sulfonamidas
[0365] A una solución de amina (0.5 mmol) en DCM (5 mL) se le agregó trietilamina (1 mmol) y la mezcla de reacción se enfrió hasta 0 °C. Se le agregó gota a gota ácido clorhídrico o cloruro de sulfonilo (0.5 mmol) y se agitó durante toda la noche. La mezcla de reacción se concentró al vacío y el residuo se purificó por cromatografía en columna [sílice, DCM:acetato de etilo (80:20 a 20:80)] para producir las amidas o sulfonamidas deseadas, respectivamente.
Procedimiento general U: Preparación de hidantoinas a partir de aminoácidos:
[0366] A una solución de Boc-Gly-resina de Merrifield (1.2 g, 0.96 mmol) se le agregó ácido trifluoroacético (5 ml, 20% en DCM), después la resina se lavó con tres ciclos de DMF, metanol y DCM. A esta resina en DCM (20 mL) se le agregó lentamente fósgeno (10 mL, 20% en tolueno, 2.0 mmol)) y trietilamina (0.56 ml, 4.0 mmol) a -20 °C. Se permitió que la mezcla de reacción alcanzara la temperatura ambiente. El exceso de fósgeno se lavó con tres ciclos de DCM. A esta resina en DCM (20 mL) se le agregó 1-(4-aminometil-tiazol-2-il)-3-(2-ciclopentanocarbonil-4-metilfenil)-urea (0.9 g, 2.5 mmol) en DCM (10 mL) y la mezcla de reacción se colocó en un agitador y se hizo reaccionar durante 4 h para dar la urea correspondiente. Después la resina se lavó con tres ciclos de DMF, metanol y DCM, y se secó durante 2 h. A la resina se le agregó trietilamina (10 mL, solución al 20% en THF) y la mezcla de reacción se calentó durante 16 h. La mezcla se filtró y el filtrado se concentró al vacío para obtener hidantoinas con un rendimiento general de 60-75%.
Procedimiento general V: Preparación de análogos de 2-aminotiazol específicos:
[0367] A una solución de 1,3-dicloroacetona, 1,3-dibromoacetona, 1-acetoxi-3-cloroacetona, bromomalonaldehído o 1,4-dibromobutan-2,3-diona (100 mmol) en metanol (100 ml) se le agregó tiourea (7.6 g, 100 mmol) y la mezcla se agitó a temperatura ambiente durante 3 h. La mezcla de reacción se concentró al vacío para dar los productos deseados con un rendimiento casi cuantitativo.
[0368] Se hizo reaccionar 4-clorometil-tiazol-2-ilamina (172 mg, 1.0 mmol) con ariltioles (2 mmol) y DIEA (2 mmol) en THF (5 mL) siguiendo el procedimiento general Z. Estos productos intermedios se acoplaron con CDI y 2-amino-5metil-fenil)-ciclopentil-metanona (203 mg, 1.0 mmol) siguiendo el procedimiento general D.
Procedimiento general W: Preparación de alquilamino nitrobencenos
[0369] Se calentaron derivado de 1-fluoro-2-nitrobenceno (5.0 mmol) y una amina (10 mmol) en THF (25 mL) a 60 °C durante 12 h. El contenido se vertió en agua y se extrajo con acetato de etilo. La capa orgánica se lavó (agua, solución saturada de cloruro de sodio), se secó (Na2SO4) y se concentró. El residuo se disolvió en metanol (25 mL) y se sometió a reducción siguiendo el procedimiento general C. En general, los productos deseados fueron >90% puros y se usaron como tales en manipulaciones posteriores.
Procedimiento general X: Preparación de alquenos por la reacción de Wittig
[0370] Se agitaron el aldehído (0.10 g, 0.28 mmol) y (carbetoximetileno)-trifenilfosforano (0.12 g, 0.34 mmol) a temperatura ambiente en benceno durante toda la noche. La mezcla de reacción se concentró al vacío y se purificó por cromatografía en columna (sílice,15% EtOAc/hexanos) para obtener el producto con un rendimiento del 80%.
Procedimiento general Y: Síntesis de 1-(2-ciclopentanoil-4-metil-fenil)-3-(5-ariltio-2-tiazolil)ureas
[0371] Una mezcla de 1-(2-ciclopentanoil-4-metil-fenil)-3-(5-bromo-2-tiazolil)urea (1 mmol), ariltiol (2 mmol) y tert-BuOK (2 mmol; se usaron 4 equivalentes de tert-BuOK para ácidos ariltio carboxílicos) en DMF (5 mL) se calentó a 80 °C durante 3 h. La mezcla se vertió en agua (20 mL). La urea que contenía ácido ariltio carboxílico se neutralizó con solución saturada de NaHCO3. La capa acuosa se extrajo con acetato de etilo (3 x 25 mL). La capa orgánica se lavó con agua (2 x 30 mL), solución saturada de cloruro de sodio (1 x 30 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para proporcionar un residuo que contenía 1-(2-ciclopentanoil-4-metil-fenil)-3-(5-ariltio-2tiazolil)urea junto con 1-(2-ciclopentanoil-4-metil-fenil)-3-(2-tiazolil)urea. El producto crudo se purificó por cromatografía en columna (sílice, CH2Cl2 después 5-20% de acetato de etilo en CH2Cl2 y 2% de MeOH en CH2Cl2) para obtener el producto deseado con un rendimiento de 25-35%.
Procedimiento general Z: Síntesis de 1-(2-ciclopentanocarbonil-4-metilfenil)-3-[4-(aril-sulfanilmetil)-tiazol-2-il]-ureas y 1-(2-ciclopentanocarbonil-4-metilfenil)-3-{4-[arilsulfanil)-etil]-tiazol-2-il}-ureas
[0372] Una mezcla de 1-(4-clorometil-tiazol-2-il)-3-(2-ciclopentanocarbonil-4-metilfenil)-urea (1 mmol), ariltiol (2 mmol) y DIEA (2 mmol) en THF (5 mL) se calentó a 80 °C durante 3 h. La mezcla se vertió en agua (20 mL) y se extrajo con acetato de etilo (3 x 25 mL). La capa orgánica se lavó con agua (2 x 30 mL) y solución saturada de
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cloruro de sodio (1 x 30 mL), se secó (Na2SO4 anhidro) y se concentró al vacío para proporcionar un residuo que contenía 1-(2-ciclopentanocarbonil-4-metil-fenil)-3-[4-(arilsulfanilmetil)-tiazol-2-il]-urea. El producto crudo se purificó por cromatografía en columna (sílice, CH2Cl2 después 5-20% de acetato de etilo en CH2Cl2 y 2% de MeOH en CH2Cl2) para obtener el producto deseado con un rendimiento de 79-85%.
5 [0373] De manera similar, la síntesis de 1-(2-ciclopentanocarbonil-4-metil-fenil)-3-{4-[arilsulfanil)-etil]-tiazol-2-il}-urea se llevó a cabo haciendo reaccionar éster 2-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-etílico del ácido metanosulfónico con ariltiol y Et3N. Esto dio el producto deseado con un rendimiento de 60-80%.
10 Procedimiento general AA: Preparación de urea.
[0374] Una mezcla de 1,1'-carbonildiimidazol (98 mg, 0.6 mmol), éster etílico del ácido (2-aminotiazol-4-il)acético (0.6 mmol) y 4-(N,N-dimetilamino)piridina (2 mg) en diclorometano (5 ml) se agitó a ambiente durante 2 h. Se le agregó una solución de un derivado de anilina sustituida (0.6 mmol) en diclorometano (1 ml) y se continuó con la agitación a
15 temperatura ambiente durante 24 h. La mezcla de reacción se concentró y el residuo se purificó por cromatografía en columna (sílice, CH2Cl2 después 10-30% de acetato de etilo en CH2Cl2) para obtener la urea deseada.
HPLC-MS (Método A)
20 [0375] Se usó el equipamiento siguiente:
 Hewlett Packard serie 1100 G1312A Bin Pump  Hewlett Packard serie 1100 compartimiento de columna  Hewlett Packard serie 1100 G1315A DAD detector de arreglo de diodo
25  Hewlett Packard serie 1100 MSD  Sedere 75 detector evaporativo de dispersión de la luz
[0376] El instrumento es controlado por el software HP Chemstation.
30 [0377] La bomba de HPLC se conecta a dos recipientes de eluyente que contienen:
A: 0.01% de TFA en agua
B: 0.01% de TFA en acetonitrilo
35 [0378] El análisis se realiza a 40 °C inyectando un volumen adecuado de la muestra (preferentemente 1 µl) en la columna que se eluye con un gradiente de acetonitrilo.
[0379] Las condiciones de HPLC, parámetros del detector y parámetros del espectrómetro de masas utilizados se indican en la tabla siguiente.
40 Columna: Waters Xterra MS C-18 X 3 mm id 5 µm Gradiente: 5% -100% de acetonitrilo lineal durante 7.5 min a 1.5 ml/min Detección: 210 nm (salida análoga del DAD (detector de arreglo de diodos)) ELS (salida análoga del ELS)
45 MS modo de ionización API-ES Scan 100-1000 amu paso 0.1 amu
[0380] Después del DAD el flujo se divide dando aproximadamente 1 ml/min al ELS y 0.5 ml/min al MS.
50 Ejemplo 1 (Procedimiento general (H))
Ácido (2-[3-(2-benzoil-4-clorofenil)ureido]tiazol-4-il)acético
[0381]
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[0382] El compuesto del título se preparó utilizando (5-cloro-2-isocianatofenil)fenil metanona (procedimiento general H2) como isocianato intermedio.
5 [0383] El producto intermedio 5-cloro-2-isocianatofenil)fenil metanona (0.31 g, 1.2 mmol) (procedimiento general H2) se disolvió en in DMF(5 ml) y se le agregó ácido 2-amino-4-tiazol acético (0.20 g, 1.2 mmol). Después de 16 horas a 20 °C se le agregó acetato de etilo (60 ml) y la mezcla se extrajo con agua (5 x 20 ml). El solvente se eliminó al vacío y el aceite remanente se purificó en un Waters Deltprep 4000 para dar el compuesto del título.
10 1H RMN (DMSO-d6): Datos seleccionados: δ 9.48 (ancho, 1 H); 8.12 (ancho, 1H); (multi, 9H); 6.87 (s, 1 H); 3.57 (s, 2H). HPLC-MS (método A): m/z = 415 (M+1); Rt = 3.79 min
Ejemplo 2 15 Ester etílico del ácido {2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen39
20 [0385] Se preparó éster etílico del ácido {2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (154 mg) a partir de (2-amino-5-metilfenil)(ciclopentil)metanona (102 mg, 0.5 mmol) y 2-amino-4-tiazolilacetato de etilo (93 mg, 0.5 mmol) siguiendo el procedimiento general D. LC-MS (m/z): 416 (M+1)+
25 1H RMN (400 MHz, CDCl3): δ 1.23 (t, 3H), 1.67 (m, 2H), 1.87 (m, 2H), 2.34 (s, 3H), 3.70 (s, 2H), 4.18 (m, 3H), 6.68 (s, 1 H), 7.25 (s, 2H), 7.32 (d, 1 H), 7.67 (s, 1H), 8.45 (s, 1 H), 9.75 (a, 1 H), 11.51 (a, 1H) ppm.
Ejemplo 3
30 Ácido {2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}acético imagen40
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[0387] Se preparó ácido {2-[3-(2-ciclopentanocarbonil-4-metilfenil)-ureido]-tiazol-4-il}-acético (198 mg) a partir de éster etílico del ácido {2-[3-(2-ciclopentanocarbonil-4-metilfenil)-ureido]-tiazol-4-il}-acético (208 mg, 0.5 mmol) siguiendo el procedimiento general J. LC-MS (m/z): 388 (M+1)+ 1H RMN (400 MHz,DMSO-d6): δ 1.73 (m, 2H), 1.86 (m, 2H), 2.32 (s, 3H), 3.55 (s, 2H), 3.86 (m 1 H), 6.84 (s, 1H),
5 7.36 (d, 1 H), 7.84 (d, 1H), 8.15 (d, 1 H), 10.62 (a, 1H), 11.92 (a, 1 H), 12.24 (a, 1H) ppm.
Ejemplo 4
Ácido {2-[3-(4-metil-2-[2-metilpropoxi]fenil)-ureido]-tiazol-4-il}-acético 10 imagen41
[0389] Se preparó 3-(2-metilpropoxi)-4-nitrotolueno (0.78 g) a partir de 2-metilpropanol (0.46 ml, 5.0 mmol) y 3-fluoro15 4-nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general G. Éste se reduce para obtener 4-metil-2-(2metilpropoxi)anilina (0.47 g) siguiendo el procedimiento general C.
[0390] Se preparó éster etílico del ácido {2-[3-(4-metil-2-[2-metilpropoxi]fenil)-ureido]-tiazol-4-il}-acético (485 mg) a partir de 4-metil-2-(2-metilpropoxi)anilina (360 mg, 2.0 mmol) y 2-amino-4-tiazolilacetato de etilo (372 mg, 2.0 mmol)
20 siguiendo el procedimiento general D. La hidrólisis este éster siguiendo el procedimiento general J dio ácido {2-[3-(4metil-2-[2-metilpropoxi]fenil)-ureido]-tiazol-4-il}-acético (400 mg). LC-MS (m/z): 464 (M+1)+ 1H RMN (400 MHz, DMSO-d6): δ 1.01 (d, 6H), 2.07 (m, 1H), 2.23 (s, 3H), 3.53 (s, 2H), 3.77 (d, 2H), 6.67 (d, 1 H),
6.81 (s, 2H), 7.91 (d, 1 H), 8.01 (a, 1 H), 11.45 (a, 1H), 12.35 (a, 1 H) ppm.
25 Ejemplo 5
Éster etílico del ácido {2-[3-(4-bromo-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético imagen42
[0392] Se preparó éster etílico del ácido {2-[3-(4-bromo-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético (192 mg, 80%) a partir de 2-amino-5-bromo-fenil-ciclopentil-metanona (134 mg, 0.5 mmol) y 2-amino-4-tiazolilacetato de
35 etilo (112 mg, 0.6 mmol) siguiendo el procedimiento general D. LC-MS (m/z): 481 (M+1)+; 1H RMN (400 MHz, CDCl3): δ 1.27 (t, 3H), 1.70 (m, 4H), 1.87 (m, 4H), 3.67 (m, 1 H), 3.72 (s, 2H), 4.19 (m, 2H), 6.70 (s, 1 H), 7.59 (dd, 1 H), 7.99 (s, 1 H), 8.53 (a, 1 H), 9.59 (a, 1 H), 11.56 (a, 1 H).
Ejemplo 6 40 Ácido {2-[3-(4-bromo-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético
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[0393] imagen43
[0394] Se preparó ácido {2-[3-(4-bromo-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético (204 mg, 90%) a
5 partir de éster etílico del ácido {2-[3-(4-bromo-2-ciclopentanocarbonil-fenil)ureido]-tiazol-4-il}-acético (240 mg, 0.5 mmol) siguiendo el procedimiento general J. LC-MS (m/z): 453 (M+1)+; 1H RMN (400 MHz, DMSO-d6): δ 1.72 (m, 4H), 1.82 (m, 4H), 3.54 (s 2H), 3.78 (m, 1 H),
6.86 (s, 1 H), 7.72 (a, 1 H), 8.10 (a, 1 H), 8.22 (s, 1 H), 10.65 (a, 1 H), 11.70 (a, 1H), 12.40 (a, 1H).
10 Ejemplo 7
Éster etílico del ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-propiónico imagen44
[0396] Se preparó 1-(2-ciclopentanocarbonil-4-metil-fenil)-3-(4-formil-tiazol-2-il)-urea (116 mg, 65%) a partir de (2amino-5-metil-fenil)-ciclopentil-metanona (102 mg, 0.5 mmol) y 2-amino-tiazol-5-carbaldehído (77 mg, 0.6 mmol) siguiendo el procedimiento general D.
20 [0397] Se preparó éster etílico del ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acrílico (70 mg, 58%) a partir de 1-(2-ciclopentanocarbonil-4-metil-fenil)-3-[4-(1-oxo-metil)-tiazol-2-il]-urea (0.10 g, 0.28 mmol) y (carbetoximetileno)-trifenilfosforano (0.12 g, 0.34 mmol) siguiendo el procedimiento general X.
25 [0398] Se preparó éster etílico del ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-propiónico (48 mg, 96%) por hidrogenación del éster etílico del ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol4-il}-acrílico (0.05 g, 0.12 mmol) con Pd/C. LC/MS (m/z): 430 (M+1)+; 1H RMN (400 MHz, CDCl3) δ 1.22 (t, 3H), 1.64-1.70 (m, 4H), 1.80-1.95 (m, 4H), 2.35 (s, 3H), 2.69 (t, 2H), 2.98 (t, 2H), 3.67-3.80 (m, 1H), 4.01-4.15 (c, 2H), 6.50 (s, 1 H), 7.32 (d, 1 H), 7.68 (s, 1 H), 8.45 (a,
30 1 H), 11.60 (a, 1 H).
Ejemplo 8
Ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-propiónico 35 imagen45
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[0400] Se preparó ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-propiónico (15 mg, 88%) a partir de éster etílico del ácido 3-{2-[3-(2-ciclopentanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-propiónico (0.03 g,
0.04 mmol) y LiOH 2.5 M (20 µL) siguiendo el procedimiento general J. 5 [0401] LC/MS (m/z): 402 (M+1)+; 1H RMN (400 MHz, CD3OD) δ 1.70-1.80 (m, 4H), 1.82-1.95 (m, 4H), 2.34 (s, 3H),
2.58 (t, 2H), 2.80 (t, 2H), 3.82-3.94 (m, 1H), 6.69 (s, 1 H), 7.38 (d, 1H), 7.85 (s, 1H), 8.19 (a, 1 H), 10.65 (a, 1 H).
Ejemplo 9 10 Ácido {2-[3-(2-ciclopropilmetoxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen46
15 [0403] Se preparó 3-ciclopropilmetoxi-4-nitrotolueno (0.77 g, 75%) a partir de ciclopropilmetanol y 3-fluoro-4nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general G. Esto se redujo a 2-ciclopropilmetoxi-4-metilanilina (0.47 g, 71%) siguiendo el procedimiento general C.
[0404] Se preparó éster etílico del ácido {2-[3-(2-ciclopropilmetoxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético (253 mg,
20 65%) a partir de 2-ciclopropilmetoxi-4-metil-anilina (177 mg, 1.0 mmol) y éster etílico del ácido (2-amino-tiazol-4-il)acético (186 mg, 1.0 mmol) siguiendo el procedimiento general D. LC-MS (m/z): 390 (M+1)+, 1H RMN (400 MHz, DMSO-d6): δ 0.36 (m, 2H), 0.59 (m, 2H), 1.18 (t, 3H), 1.28 (m, 1 H),
2.24 (s, 3H), 3.64 (s, 2H), 3.88 (d, 2H), 4.08 (c, 2H), 6.71 (dd, 1H), 6.83 (d, 1 H), 6.86 (d, 1 H), 7.94 (d, 1 H), 8.40 (a, 1 H), 11.36 (a, 1 H).
25 Se preparó ácido {2-[3-(2-ciclopropilmetoxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético (165 mg, 92%) a partir de éster etílico del ácido {2-[3-(2-ciclopropilmetoxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético (195 mg, 0.5 mmol) siguiendo el procedimiento general J. LC-MS (m/z): 362 (M+1)+.
30 Ejemplo 10
Ácido {2-[3-(2-ciclopentiloxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen47
[0406] Se preparó 3-ciclopentiloxi-4-nitrotolueno (0.68 g, 62%) a partir de ciclopentanol y 3-fluoro-4-nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general G. Éste se redujo a 2-ciclopentiloxi-4-metil-anilina (0.43 g, 70%) siguiendo el procedimiento general C.
[0407] Se preparó éster etílico del ácido {2-[3-(2-ciclopentiloxi-4-metil-fenil)-ureido]-tiazol-4-il}-acético (250 mg, 62%) a partir de 2-ciclopentiloxi-4-metil-anilina (191 mg, 1.0 mmol) y éster etílico del ácido (2-amino-tiazol-4-il)-acético (186 mg, 1.0 mmol) siguiendo el procedimiento general D. Se preparó ácido {2-[3-(2-ciclopentiloxi-4-metil-fenil)-ureido]
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tiazol-4-il}-acético (170 mg, 91%) a partir de éster etílico del ácido {2-[3-(2-ciclopropilmetoxi-4-metil-fenil)-ureido]tiazol-4-il}-acético (200 mg, 0.5 mmol) siguiendo el procedimiento general J. LC-MS (m/z): 376 (M+1)+.
Ejemplo 11
Éster etílico del ácido {2-[3-(2-isobutilsulfanil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen48
[0409] Se preparó 3-(isobutilsulfanil)-4-nitrotolueno (0.75 g, 67%) a partir de 2-metil-propanotiol y 3-fluoro-4nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general A. Éste se redujo a 2-isobutilsulfanil-4-metilanilina (0.46 g, 63%) siguiendo procedimientos general B.
15 [0410] Se preparó éster etílico del ácido {2-[3-(2-isobutilsulfanil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (276 mg, 68%) a partir de 2-isobutilsulfanil-4-metil-anilina (195 mg, 1.0 mmol) y 2-amino-4-tiazolilacetato de etilo (186 mg, 1.0 mmol) siguiendo el procedimiento general D. La hidrólisis de este éster siguiendo el procedimiento general J dio ácido {2-[3-(2-isobutilsulfanil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (230 mg, 90%). LC-MS (m/z): 380 (M+1)+, 1H
20 RMN (400 MHz, DMSO-d6): δ 0.85 (m, 6H), 1.49 (m, 1 H), 2.26 (s, 3H), 2.83 (m, 2H), 3.56 (s, 2H), 6.85 (s, 1 H), 7.09 (d, 1 H), 7.29 (d, 1 H), 7.89 (d, 1 H), 8.65 (a, 1 H), 11.28 (a, 2H).
Ejemplo 12
25 Éster etílico del ácido {2-[3-(2-ciclopentanosulfonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen49
30 [0412] Se preparó 3-ciclopentanosulfanil-4-nitrotolueno (0.83 g, 70%) a partir de ciclopentil mercaptano y 3-fluoro-4nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general A. Éste se oxidó a 3-ciclopentanosulfonil-4nitrotolueno (0.84 g, 90%) siguiendo el procedimiento general R. Se redujo 3-ciclopentanosulfonil-4-nitrotolueno a 2ciclopentanosulfonil-4-metil-anilina (0.53 g, 70%) siguiendo el procedimiento general C.
35 [0413] Se preparó éster etílico del ácido {2-[3-(2-ciclopentanosulfonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (305 mg, 68%) a partir de 2-ciclopentanosulfonil-4-metil-anilina (239 mg, 1.0 mmol) y 2-amino-4-tiazolilacetato de etilo (186 mg, 1.0 mmol) siguiendo el procedimiento general D. LC-MS (m/z): 452 (M+1)+, 1H RMN (400 MHz, DMSO-d6): δ
1.19 (t, 3H), 1.58 (m, 4H), 1.84 (m, 4H), 2.35 (s, 3H), 3.65 (s, 2H), 3.77 (m, 1H), 4.08 (c, 2H), 6.91 (s, 1 H), 7.52 (d, 1 H), 7.63 (s, 1H), 8.00 (d, 1H), 8.91 (a, 1H), 11.89 (a, 1H). 40
Ejemplo 13 50
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Ácido {2-[3-(2-ciclopentanosulfonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético
[0414]
[0415] Siguiendo el procedimiento general J, se hidrolizó éster etílico del ácido {2-[3-(2-ciclopentanosulfonil-4-metilfenil)-ureido]-tiazol-4-il}-acético (225 mg, 0.5 mmol) para obtener ácido {2-[3-(4-metil-2-[2-metilpropoxi]fenil)-ureido]tiazol-4-il}-acético (193 mg, 92%).
10 LC-MS (m/z): 424 (M+1)+, 1H RMN (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 1.84 (m, 4H), 2.36 (s, 3H), 3.57 (s, 2H),
3.77 (m, 1 H), 6.87 (s, 1 H), 7.52 (d, 1H), 7.63 (s, 1 H), 8.01 (d, 1H), 8.95 (a, 1 H), 12.32 (a, 2H).
Ejemplo 14
15 Ácido {2-[3-(4-metil-2-piperidin-1-il-fenil)-ureido]-tiazol-4-il}-acético imagen50 imagen51
20 [0417] Se preparó 4-metil-2-(piperidin-1-il)-anilina (0.63 g, 67%) a partir de piperidina (0.85 g, 10.0 mmol) y 3-fluoro4-nitrotolueno (0.77 g, 5.0 mmol) siguiendo el procedimiento general W.
[0418] Se preparó éster etílico del ácido {2-[3-(4-metil-2-piperidin-1-il-fenil)-ureido]-tiazol-4-il}-acético (285 mg, 71%) a partir de 4-metil-2-(piperidin-1-il)-anilina (190 mg, 1.0 mmol) y 2-amino-4-tiazolilacetato de etilo (186 mg, 1.0 mmol)
25 siguiendo el procedimiento general D. La hidrólisis de este éster siguiendo el procedimiento general J dio ácido {2-[3(4-metil-2-piperidin-1-il-fenil)-ureido]-tiazol-4-il}-acético (238 mg, 90%). LC-MS (m/z): 375 (M+1)+; 1H RMN (400 MHz, DMSO-d6): δ 1.53 (a, 2H), 1.75 (m, 4H), 2.23 (s, 3H), 2.70 (m, 4H),
3.55 (s, 2H), 6.83 (s, 1 H), 6.87 (d, 1 H), 6.99 (s, 1 H), 7.92 (d, 1H), 8.40 (a, 1 H), 11.28 (a, 1 H), 12.42 (a, 1H).
30 Ejemplo 15 (Procedimiento general AA)
Éster etílico del ácido {2-[3-(2-ciclopropanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen52
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en atmósfera de nitrógeno se le agregó gota a gota solución 1.7 M de t-BuLi en pentano (6.5 mL, 11.1 mmol) en un período de 10 min a -20 °C. La mezcla se agitó a -10 °C durante 2.5 h y después se le agregó metoxi-metil-amida del ácido ciclopropanocarboxílico (0.92 g, 6.3 mmol) en el transcurso de 5 min. Se permitió que la mezcla alcanzara la temperatura ambiente y se agitó durante 1 h más antes de detener la reacción con NH4Cl acuoso. La fase
5 orgánica se aisló y la fase acuosa se extrajo con CH2Cl2, y las fases orgánicas combinadas se secaron y se concentraron al vacío. El material crudo se disolvió en CH2Cl2 (15 mL) y TFA (15 mL) y se agitó a temperatura ambiente durante 3 h. La mezcla de reacción se evaporó al vacío y se le agregó NaHCO3 acuoso hasta pH 7 y se extrajo con CH2Cl2. Las fases orgánicas combinadas se secaron y se concentraron al vacío para dar 0.80 g de (2amino-5-metil-fenil)-ciclopropil-metanona cruda como un aceite amarillo.
10 [0421] El compuesto del título (190 mg, 43%) se preparó a partir de (2-amino-5-metil-fenil)-ciclopropil-metanona cruda (200 mg, 1.14 mmol) y 2-amino-4-tiazolilacetato de etilo (212 mg, 1.14 mmol) siguiendo el procedimiento general AA.1H RMN (400MHz; CDCl3): δ 1.04-1.10 (m, 2H), 1.24-1.30 (m, 5H), 2.39 (s, 3H), 2.62-2.72 (m, 1H), 3.73 (s, 2H), 4.20
15 (c, 2H), 6.78 (s, 1 H), 7.37 (dd, 1H), 7.89 (d, 1H), 8.37 (d, 1 H), 9.42 (s. a., 2H), 11.50 (s, 1 H); HPLC-MS : m/z =
410.0 (M+23); Rt = 4.11 min.
Ejemplo 16 (Procedimiento general J)
20 Ácido {2-[3-(2-ciclopropanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen53
25 [0423] El compuesto del título (111 mg, 99%) se preparó a partir de éster etílico del ácido {2-[3-(2ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético (120 mg, 0.31 mmol) siguiendo el procedimiento general J.1H RMN (400MHz; DMSO d6): δ 1.04 (br s, 4H), 2.38 (s, 3H), 2.76 (s. a., 1 H), 3.58 (s, 2H), 6.86 (s, 1 H), 6.92 (d, 1H), 8.02 (s, 1H), 8.14 (d, 1H), 10.46 (s, 1H), 12.05 (s. a., 2H); HPLC-MS : m/z = 382.0 (M+23); Rt = 3.38 min.
30 Ejemplo 17 (Procedimiento general AA)
Éster etílico del ácido {2-[3-(2-ciclobutanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen54
[0425] Se preparó (2-amino-5-metil-fenil)-ciclobutil-metanona cruda (80%, aceite) de manera similar a la descrita para (2-amino-5-metil-fenil)-ciclopropil-metanona utilizando metoxi-metil-amida del ácido ciclobutanocarboxílico en vez de metoxi-metil-amida del ácido ciclopropanocarboxílico.
40 [0426] El compuesto del título (210 mg, 49%) se preparó a partir de (2-amino-5-metil-fenil)-ciclobutilo-metanona cruda (200 mg, 1.06 mmol) y 2-amino-4-tiazolilacetato de etilo (197 mg, 1.06 mmol) siguiendo el procedimiento general AA.1H RMN (400MHz; CDCl3): δ 1.30 (t, 3H), 1.83-2.50 (m, 6H), 2.36 (s, 3H), 3.76 (s, 2H), 4.05 (p, 1H), 4.22 (c, 2H),
45 6.80 (s, 1H), 7.35 (d, 1H), 7.52(s, 1H), 8.41 (d. a., 1 H), 11.9 (s. a., 1 H); HPLC-MS : m/z = 424.1 (M+23); Rt = 4.48 min.
Ejemplo 18 (Procedimiento general J)
50 Ácido {2-[3-(2-ciclobutanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético
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[0427] imagen55
[0428] El compuesto del título (112 mg, 73%) se preparó a partir de éster etílico del ácido {2-[3-(25 ciclobutanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (165 mg, 0.41 mmol) siguiendo el procedimiento general
J. 1H RMN (400MHz; DMSO d6): δ 1.70-2.30 (m, 6H), 2.32 (s, 3H), 3.56 (s, 2H), 4.19 (t. a., 1H), 6.86 (s, 1 H), 7.39 (d, 1 H), 7.63 (s, 1 H), 8.22 (d, 1H), 10.81 (s, 1 H), 12.15 (s. a., 2H); HPLC-MS : m/z = 396.1 (M+23); Rt = 3.75 min.
10 Ejemplo 19 (Procedimiento general AA)
Ester etílico del ácido {2-[3-(2-ciclohexanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético imagen56
[0430] Se preparó (2-amino-5-metil-fenil)-ciclohexil-metanona cruda (75%, aceite) de manera similar a la descrita para (2-amino-5-metil-fenil)-ciclopropil-metanona utilizando metoxi-metil-amida del ácido ciclohexanocarboxílico en vez de metoxi-metil-amida del ácido ciclopropanocarboxílico.
20 [0431] El compuesto del título (188 mg, 48%) se preparó a partir de (2-amino-5-metilfenil)-ciclohexil-metanona cruda (200 mg, 0.92 mmol) y 2-amino-4-tiazolilacetato de etilo (171 mg, 1.06 mmol) siguiendo el procedimiento general AA.1H RMN (400MHz; CDCl3): δ 1.30 (t, 3H), 1.37-1.59 (m, 5H), 1.71-1.91 (m, 5H), 2.37 (s, 3H), 3.30 (s. a., 1 H), 3.73 (s, 2H), 4.22 (c, 2H), 6.78 (s, 1 H), 7.34 (d, 1 H), 7.68 (s, 1 H), 8.39 (d. a., 1 H), 11.78 (s. a., 1 H); HPLC-MS : m/z =
25 452.2 (M+23); Rt = 4.92 min.
Ejemplo 20 (Procedimiento general J)
Ácido {2-[3-(2-ciclohexanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético 30 imagen57
[0433] El compuesto del título (100 mg, 89%) se preparó a partir de éster etílico del ácido {2-[3-(235 ciclohexanocarbonil-4-metil-fenil)-ureido]-tiazol-4-il}-acético (112 mg, 0.28 mmol) siguiendo el procedimiento general
J. 1H RMN (400MHz; DMSO d6): δ 1.13-1.45 (m, 5H), 1.62-1.83 (m, 5H), 2.34 (s, 3H), 3.42 (s. a., 1H), 3.57 (s, 2H), 6.83 (s, 1H), 7.39 (d, 1 H), 7.81 (s, 1H), 8.15 (d, 1 H), 10.50 (s, 1 H), 12.07 (s. a., 2H); HPLC-MS : m/z = 402.0 (M+1); Rt =
4.18 min.
40 Ejemplo 21 (Procedimiento general (AA))
Éster etílico del ácido {2-[3-(4-cloro-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético
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[0434] imagen58
5 [0435] A una solución en agitación de éster tert-butílico del ácido (4-cloro-fenil)-carbámico (35 mmol) en Et2O (80 mL) en atmósfera de nitrógeno se le agregó gota a gota una solución 1.7 M de t-BuLi en pentano (88 mmol) en un período de 10 min a -20 °C. La mezcla se agitó a 0 °C durante 1.5 h y después se le agregó metoxi-metil-amida del ácido ciclopentanocarboxílico (45 mmol) en el transcurso de 5 min. Se permitió que la mezcla alcanzara la temperatura ambiente y se agitó durante 1 h más antes de detener la reacción con NH4Cl acuoso. La fase orgánica
10 se aisló y la fase acuosa se extrajo con CH2Cl2, y las fases orgánicas combinadas se secaron y se concentraron al vacío. El material crudo se disolvió en CH2Cl2 (50 mL) y TFA (50 mL) y se agitó a temperatura ambiente durante 1 h. La mezcla de reacción se evaporó al vacío, se le agregó NaHCO3 acuoso hasta pH 7 y se extrajo con CH2Cl2, se secó y se concentró para dar un producto crudo que se purificó mediante cromatografía en columna por desorción súbita (Quad flash 65, heptano 0:1 ->1:3). Esto dio 75% de (2-amino-5-cloro-fenil)-ciclopentil-metanona como un
15 aceite.
[0436] El compuesto del título (30%) se preparó a partir de (2-amino-5-cloro-fenil)-ciclopentil-metanona y 2-amino-4tiazolilacetato de etilo siguiendo el procedimiento general AA.1H RMN (400MHz; CDCl3): δ 1.28 (t, 3H), 1.62-1.99 (m, 8H), 3.3.67 (t. a., 1 H), 3.73 (s, 2H), 4.20 (c, 2H), 6.72 (s, 1
20 H), 7.46 (dd, 1 H), 7.84 (d, 1 H), 8.56 (s. a., 1 H), 9.50 (s. a., 1 H), 11.58 (s. a., 1 H); HPLC-MS : m/z = 458.0 (M+23); Rt = 4.86 min.
Ejemplo 22 (Procedimiento general J)
25 Ácido {2-[3-(4-cloro-2-ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético imagen59
30 [0438] El compuesto del título (39 mg, 85%) se preparó a partir de éster etílico del ácido {2-[3-(4-cloro-2ciclopentanocarbonil-fenil)-ureido]-tiazol-4-il}-acético (49 mg, 0.11 mmol) siguiendo el procedimiento general J.1H RMN (400MHz; DMSO d6): δ 1.67-1.92 (m, 8H), 3.59 (s, 2H), 3.89 (s. a., 1 H), 6.88 (s, 1 H), 7.63 (d, 1H), 8.04 (s. a., 1H), 8.32 (s. a., 1 H), 10.64 (s, 1 H), 12.20 (s. a., 2H); HPLC-MS : m/z = 430.0 (M+23); Rt = 4.11 min.
35 Ejemplo 23 (Procedimiento general (AA))
Ester etílico del ácido {2-[3-(2-ciclopentanocarbonil-4-fluoro-fenil)-ureido]-tiazol-4-il}-acético imagen60
10
15
20
25
30
35
40
45
50
55
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[0440] A una solución en agitación de éster tert-butílico del ácido (4-fluoro-fenil)-carbámico (9.5 mmol) en Et2O (20 mL) en atmósfera de nitrógeno se le agregó gota a gota una solución 1.7 M de t-BuLi en pentano (22 mmol) en un período de 10 min a -30 °C. La mezcla se agitó a -20 °C durante 1.5 h y después se le agregó metoxi-metil-amida del ácido ciclopentanocarboxílico (10.5 mmol) en el transcurso de 5 min. Se permitió que la mezcla alcanzara la temperatura ambiente y se agitó durante 1 h más antes de detener la reacción con NH4Cl acuoso. La fase orgánica se aisló y la fase acuosa se extrajo con CH2Cl2, y las fases orgánicas combinadas se secaron y se concentraron al vacío. El material crudo se disolvió en CH2Cl2 (25 mL) y TFA (25 mL) y se agitó a temperatura ambiente durante 2 h. La mezcla de reacción se evaporó al vacío, se le agregó NaHCO3 acuoso hasta pH 7 y se extrajo con CH2Cl2, se secó y se concentró para dar un producto crudo que se purificó mediante cromatografía en columna por desorción súbita (Quad flash 40, heptano 0:1 ->1:3). Esto dio 60% de (2-amino-5-fluoro-fenil)-ciclopentil-metanona como un aceite.
[0441] El compuesto del título (26%) se preparó a partir de (2-amino-5-fluoro-fenil)-ciclopentil-metanona y 2-amino-4tiazolilacetato de etilo siguiendo el procedimiento general AA.1H RMN (400MHz; CDCl3): δ 1.28 (t, 3H), 1.63-1.97 (m, 8H), 3.64 (t. a., 1 H), 3.73 (s, 2H), 4.20 (c, 2H), 6.72 (s, 1 H), 7.22-7.29 (m, 1 H), 7.58 (dd, 1 H), 8.55 (s. a., 1 H), 9.40 (s. a., 1 H), 11.45 (s. a., 1 H); HPLC-MS : m/z = 442.0 (M+23); Rt = 4.49 min.
Ejemplo 24 (Procedimiento general J)
Ácido {2-[3-(2-ciclopentanocarbonil-4-fluoro-fenil)-ureido]-tiazol-4-il}acético imagen61
[0443] El compuesto del título (75 mg, 87%) se preparó a partir de éster etílico del ácido {2-[3-(2ciclopentanocarbonil-4-fluoro-fenil)-ureido]-tiazol-4-il}-acético (92 mg, 0.22 mmol) siguiendo el procedimiento general
J. 1H RMN (400MHz; DMSO d6): δ 1.65-1.94 (m, 8H), 3.57 (s, 2H), 3.84 (s. a., 1 H), 6.88 (s, 1H), 7.45(t, 1 H), 7.85 (s. a., 1 H), 8.25 (brs, 1H), 10.48 (s, 1H), 12.10 (s. a., 2H); HPLC-MS : m/z = 414.1 (M+23); Rt = 3.74 min.
Ensayo biológico
Ensayo de actividad de la glucocinasa (I)
[0444] Se analizó la actividad de la glucocinasa espectrométricamente acoplada a glucosa 6-fosfato deshidrogenasa para determinar la activación de la glucocinasa por el compuesto. El ensayo final contenía Hepes 50 mM, pH 7.1, KCI 50 mM, MgCl2 5 mM, ditiotreitol 2 mM, NADP 0.6 mM, ATP 1 mM, G-6-P deshidrogenasa (de Roche, 127 671)

0.195

µM, glucocinasa humana recombinada 15 nM. La glucocinasa es glucocinasa hepática humana truncada en el extremo N-terminal con un marcador (tag) His N-terminal ((His)8-VEQILA......Q466) y se expresa en E. coli como una proteína soluble con actividad enzimática semejante a la GK extraída del hígado.

[0445] La purificación de la glucocinasa humana marcada con His (hGK) se llevó a cabo de la manera siguiente: El sedimento celular de 50 ml de cultivo de E. coli se resuspendió en 5 ml de tampón de extracción A (HEPES 25 mM, pH 8.0, MgCl2 1 mM, NaCl 150 mM, mercaptoetanol 2 mM) con adición de 0.25 mg/ml de lisozima y 50 µg/ml de azida de sodio. Después de 5 minutos a temperatura ambiente se agregaron 5 ml de tampón de extracción B (NaCl

1.5

M, CaCl2 100 mM, MgCl2 100 mM, 0.02 mg/ml de DNasa 1, comprimido de inhibidor de proteasa (Complete® 1697498): 1 comprimido para 20 ml de tampón). Después el extracto se centrifugó a 15 000 g durante 30 minutos. El sobrenadante resultante se cargó en una columna de 1 ml de cromatografía de afinidad a quelatos metálicos (MCAC) cargada con Ni2+. La columna se lavó con 2 volúmenes de tampón A que contenía imidazol 20 mM y la hGK marcada con his unida, se eluyó a continuación utilizando un gradiente de 20 minutos de imidazol de 20 a 500 mM en tampón A. Las fracciones se examinaron usando electroforesis en gel con SDS, y las fracciones que contenían hGK (PM: 52 KDa) se juntaron. Finalmente se usó un paso de filtración en gel para el pulido final y el intercambio de tampón. Las fracciones que contenían hGK se cargaron en una columna de filtración en gel Superdex 75 (16/60) y se eluyeron con tampón B (HEPES 25 mM, pH 8.0, MgCl2 1 mM, NaCl 150 mM, ditiotreitol 1 mM). La hGK purificada

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se examinó por electroforesis en gel con SDS y espectrometría de masas MALDI y finalmente se le agregó glicerol al 20% antes de congelarla. El rendimiento a partir de 50 ml de cultivo de E. coli fue generalmente de 2-3 mg de hGK con una pureza >90%.
[0446] El compuesto a ensayar se agregó a un pocillo en una concentración final de DMSO al 2.5% en una cantidad suficiente para dar una concentración del compuesto deseada, por ejemplo de 1, 5, 10, 25 o 50 µM. La reacción comenzó después agregar glucosa hasta una concentración final de 2, 5, 10 o 15 mM. El ensayo utilizó una placa para UV de 96 pocillos y el volumen de ensayo final utilizado fue de 200 µl/pocillo. La placa se incubó a 25 °C durante 5 min y se midió la cinética a 340 nm en un SpectraMax cada 30 segundos durante 5 minutos. Los resultados para cada compuesto se expresaron como la cantidad de veces que se activó la actividad de la glucocinasa en comparación con la activación de la enzima glucocinasa en un ensayo sin compuesto después de haber sido sustraída de un "blanco", que es sin enzima glucocinasa y sin compuesto. Los compuestos en cada uno de los ejemplos mostraron activación de la glucocinasa en este ensayo. Un compuesto que a una concentración menor o igual de 30 µM produzca 1.5 veces más actividad de glucocinasa que la que resulta del ensayo sin compuesto, se considera un activador de la glucocinasa.
[0447] La sensibilidad a la glucosa de los compuestos se midió a una concentración del compuesto de 10 µM y a concentraciones de glucosa de 5 y 15 mM.
[0448] Si bien la invención se ha descrito e ilustrado con referencia a ciertas realizaciones preferidas, los expertos en el área apreciarán que se les pueden realizar diversos cambios, modificaciones y sustituciones sin apartarse del espíritu y el alcance de la presente invención. Por ejemplo, pueden ser aplicables dosis eficaces diferentes de las dosis preferidas indicadas en este documento como consecuencia de las variaciones en la respuesta del mamífero que se está tratando por la enfermedad o las enfermedades mediadas por la deficiencia de glucocinasa. Del mismo modo, las respuestas farmacológicas específicas observadas pueden variar de acuerdo con y dependiendo del principio activo particular elegido o de si hay presentes portadores farmacéuticos, así como del tipo de formulación y del modo de administración empleados, y dichas variaciones o diferencias esperadas en los resultados se contemplan de conformidad con los objetivos y las prácticas de la presente invención.
Ensayo de actividad de la glucocinasa (II)
Determinación del depósito de glucógeno en hepatocitos aislados de rata:
[0449] Se aislaron hepatocitos de ratas alimentadas a voluntad, mediante una técnica de perfusión en dos pasos. La viabilidad celular, evaluada por exclusión con azul de tripano, fue uniformemente superior a 80%. Las células se sembraron en placas de 96 pocillos recubiertos con colágeno en medio basal (Medio 199 (glucosa 5.5 mM) complementado con dexametasona 0.1 µM, 100 unidades/ml de penicilina, 100 mg/ml de estreptomicina, Lglutamina 2 mM e insulina 1 nM) con FCS al 4% a una densidad celular de 30 000 células/pocillo. El medio se reemplazó con medio basal 1 hora después de la siembra en placas inicial para retirar las células muertas. El medio se cambió después de 24 horas a medio basal complementado con glucosa 9.5 mM e insulina 10 nM para inducir la síntesis de glucógeno, y los experimentos se realizaron al día siguiente. Los hepatocitos se lavaron dos veces con tampón A (NaCl 117.6 mM, KCI 5.4 mM, Mg2SO4 0.82 mM, KH2PO4 1.5 mM, HEPES 20 mM, NaHCO3 9 mM, HSA al 0.1% p/v, y CaCl2 2.25 mM, pH 7.4 a 37 °C) precalentado (37 °C), y se incubaron en 100 µl de tampón A que contenía glucosa 15 mM y concentraciones crecientes del compuesto de prueba, como por ejemplo 1, 5, 10, 25, 50 o 100 µM, durante 180 minutos. El contenido de glucógeno se midió empleando procedimientos estándar (Agius, L.et al, Biochem J. 266, 91-102 (1990). Un compuesto, que cuando se usa en este ensayo da un aumento significativo en el contenido de glucógeno en comparación con el resultado del ensayo sin compuesto, se considera que tiene actividad en este ensayo.
Ensayo de actividad de la glucocinasa (III)
Estimulación de la secreción de insulina por activadores de la glucocinasa en células INS-1E
[0450] Se cultivó la línea de células β sensibles a la glucosa INS-1 E como describen Asfari M et al., Endocrinology, 130, 167-178 (1992). Después las células se sembraron en placas de cultivo celular de 96 pocillos y se cultivaron hasta una densidad de aproximadamente 5 x 104 por pocillo. Se analizó la estimulación de la secreción de insulina dependiente de glucosa por incubación durante 2 horas en tampón de Krebs Ringer Hepes a concentraciones de glucosa entre 2.5 y 15 mM con o sin adición de compuestos activadores de la glucocinasa a concentraciones por ejemplo de 1, 5, 10, 25, 50 o 100 µM, y los sobrenadantes se recogieron para mediciones de concentraciones de insulina por ELISA (n= 4). Un compuesto, que cuando se usa en este ensayo da un aumento significativo en la secreción de insulina en respuesta a la glucosa, en comparación con el resultado del ensayo sin compuesto, se considera que tiene actividad en este ensayo.
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[0246] For parenteral routes such as intravenous, intrathecal, intramuscular and the like, the usual doses are in the order of half the dose used for oral administration.
[0247] The compounds of this invention are generally employed as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound that has the utility of a free base and a base addition salt of a compound that has the utility of a free acid. The term "pharmaceutically acceptable salts" refers to the non-toxic salts of the compounds of this invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When a compound according to the present invention contains a free base said salts are prepared in a conventional manner by treating a solution.
or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compound according to the present invention contains a free acid, said salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as a sodium or ammonium ion. Other salts that are not pharmaceutically acceptable may be useful in the preparation of the compounds of the present invention and these form a further aspect of the present invention.
[0248] For parenteral administration, solutions of the new compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil can be used. Such aqueous solutions should be adequately buffered if necessary and the liquid diluent must first be made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed can be easily obtained by standard techniques known to the experts.
[0249] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl cellulose ethers. Examples of liquid carriers are syrups, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the area as glyceryl monostearate or distearate, alone or mixed with a wax. The pharmaceutical compositions prepared by combining the new compounds of the present invention and pharmaceutically acceptable carriers are then easily administered in various pharmaceutical forms suitable for the aforementioned routes of administration. The formulations can be conveniently presented in unit dosage forms and can be prepared by methods well known in the pharmaceutical area.
[0250] The formulations of the present invention suitable for oral administration may be presented as discrete units for example capsules or tablets, each of which contains a predetermined amount of the active ingredient, and may also contain a suitable excipient. On the other hand, formulations for oral administration may be in the form of powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil emulsion.
[0251] Compositions intended for oral use may be prepared according to any known method, and said compositions may contain one or more drugs chosen from the group consisting of sweeteners, flavorings, dyes and preservatives in order to provide palatable pleasing preparations. and pharmaceutically elegant. The tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulants and disintegrants, for example, corn starch or alginic acid; binders, for example, starch, gelatin or acacia; and lubricants, for example, magnesium stearate, stearic acid or talc. The tablets may have no coating or be coated using known techniques to delay disintegration and absorption in the digestive tract and thus provide sustained action for a longer period of time. For example, a retarding material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated with the techniques described in US Pat. Nos. 4,356,108; 4,166,452 and 4,265,874, incorporated herein by reference, to prepare controlled release osmotic therapeutic tablets.
[0252] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin,
or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid petrolatum or olive oil.
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[0253] Aqueous suspensions may contain the active ingredients mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersants or humectants that can be natural phosphatides, such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example monooleate of polyethylene sorbitan. Aqueous suspensions may also contain one or more dyes, one or more flavorings, and one or more sweeteners such as sucrose or saccharin.
[0254] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid petrolatum. The oil suspensions may contain a thickener, for example beeswax, hard petrolatum or cetyl alcohol. Sweeteners, such as those indicated above, and flavorings can be added to provide an appetizing oral preparation. These compositions can be preserved by adding an antioxidant as ascorbic acid.
[0255] Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersant or humectant, a suspension and one or more preservatives. Dispersants or humectants and suitable suspensions are exemplified by those mentioned above. Additional excipients such as sweeteners, flavorings and dyes may also be present.
[0256] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid petrolatum, or a mixture of these. Suitable emulsifiers can be natural gums, for example acacia gum or tragacanth gum, natural phosphatides, for example soy, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.
[0257] Syrups and elixirs can be formulated with sweeteners, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative and flavorings and colorants. The pharmaceutical preparations may be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known methods using the appropriate dispersants or humectants and suspensions described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic solvent or solvent acceptable for parenteral use, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conveniently employed as a solvent or suspension medium. To this end, any soft fixed oil can be used using synthetic mono or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
[0258] The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at current temperatures but liquid at the rectal temperature and therefore melts in the rectum to release the drug. Such materials include, for example, butter and polyethylene glycols.
[0259] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are contemplated. For the purposes of this application, the topical application will include mouth washes and gargles.
[0260] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be made from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
[0261] In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed by the scope of the present invention.
[0262] Therefore, in another embodiment, a pharmaceutical composition containing a compound is provided.
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according to the present invention, or one of its pharmaceutically acceptable salts or solvates, and one or more pharmaceutically acceptable carriers, excipients or diluents.
[0263] If a solid carrier is used for oral administration, the preparation can be compressed, placed in a hard gelatin capsule in the form of powder or granules, or it may be in the form of a troccus or tablet. The amount of solid carrier will vary widely but will generally be between about 25 mg and about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid as an aqueous or non-aqueous liquid solution or suspension.
[0264] A typical tablet may be prepared by conventional compression techniques and may contain:
Nucleus:
[0265]

Active ingredient (as a free compound or one of its salts)

5.0 mg

Lactose Ph. Eur.

67.8 mg

Microcrystalline cellulose (Avicel)

31.4 mg

Amberlite®IRP88 *

1.0 mg

Magnesium stearate Ph. Eur.

cs

Coating: [0266]

Hydroxypropyl methylcellulose

approx. 9 mg

Mywacett 9-40 T **

approx. 0.9 mg

* Potassium Polacriline NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating.

[0267] If desired, the pharmaceutical composition of the present invention may contain a compound according to the present invention in combination with other active ingredients such as those described above.
[0268] The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of formula (I) together with the methods for the preparation of compounds of formula (I). The compounds can be easily prepared according to the following reaction schemes (in which all the variables are those defined above, unless something different is specified) using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to employ variants that are known to the experts but are not mentioned in detail.
ABBREVIATIONS
[0269] The abbreviations used in the schemes and examples are as follows: d = days g = grams h = hours Hz = hertz kD = kiloDalton L = liters M = molar mbar = millibar mg = milligrams min = minutes ml = milliliters mM = millimolar mmol = millimoles mol = moles N = normal ppm = parts per million
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psi = pounds per square inch APCI = chemical ionization at atmospheric pressure ESI = electrospray ionization
iv = intravenous m / z = mass to charge ratio pf = melting point MS = NMR mass spectrometry = nuclear magnetic resonance spectroscopy
po = orally Rf = relative mobility of TLC rt = room temperature
sc = subcutaneous TLC = thin layer chromatography tr = retention time BOP = (1-benzotriazolyloxy) tris (dimethylamino) phosphonium hexafluorophosphate DCM = dichloromethane DIEA = diisopropylethylamine DMF = N, N-dimethylformamide DMPU = 1,3-dimethylpropylene urea DMSO = dimethyl sulfoxide EDC = 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride ether = diethyl ether EtOAc = ethyl acetate HMPA = hexamethylphosphoric triamide HOBt = 1-hydroxybenzotriazole LAH = lithium aluminum lithium hydride LDA = diis lithium lithium hydroxide LDA = diis lithium hydroxide LDA = diis lithium lithium hydroxide LDA = diis lithium lithium hydroxide = NMM methanol = N-methylmorpholine, 4-methylmorpholine TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyranyl TTF = fluorohexafluorophosphate-N, N, N'-tetramethylformamidinium
Reaction schemes
[0270] Unless otherwise specified, the schema variables are those defined by formula (I).
[0271] Scheme 1 describes the preparation of the compounds of formula (74).
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Scheme 1 image18
[0272] A2 is heteroaryl, fused heterocyclylheteroaryl or fused cycloalkylheteroaryl.
[0273] R100 and R101, independently of one another, are substituents such as, but not exclusively, H, alkyl, alkenyl, alkynyl, -alkylene-aryl, alkylene-cycloalkyl, and the like.
[0274] K is halogen or 1-imidazolyl.
[0275] The amine (71) can be treated with carbonyldiimidazole, 4-nitrophenyl chloroformate, phosgene or a phosgene derivative such as diphosgene or triphosgene, in a solvent such as DCM or DCE. DMAP can be used as a catalyst in this reaction. The reaction can be carried out at a temperature between 0 ° C and 100 ° C. Reaction mixture
15 can then be treated with the compound (73) and the whole can be incubated at a temperature between 25 ° C and 100 ° C to obtain urea (75). It is also understood that (73) can be treated with reagent (72) under similar conditions, followed by treatment with the amine (71), to obtain (74).
[0276] Scheme 2 describes the preparation of the compounds of formula (79). twenty
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Scheme 2 image19
[0277] L11 has the meaning of L1 in formula (I), with the proviso that when L11 is -D-alkylene-E-, -D5 alkenylene-E-, -D-alkynylene-E-, -D- cycloalkylene-Eo-D-heterocyclylene-E-, then D is chosen from -Oo -S-, and L11 is not -S (O) -, -S (O) 2-, -C (O) -ni -C (= N-OR12) -.
[0278] Lg1 is a leaving group such as F, Cl, Br or I.
[0279] R101 is a substituent such as, but not exclusively, H, alkyl, alkenyl, alkynyl, -alkylene-aryl, alkylene-cycloalkyl and the like.
[0280] A nitro substituted aryl or heteroaryl cyclic compound such as (75) can be treated with (76) in the presence of a base such as NaH or potassium tert-butoxide, in a solvent such as THF, DMF or NMP at a temperature between 15 0 ° C and 100 ° C, to obtain (77). The resulting adduct (77) can be treated with tin (II) chloride in ethanol or other alcoholic solvent, at a temperature between 25 ° C and 100 ° C, in the presence of aqueous HCl, to obtain the amine (78). The amine (78) can be treated, if desired, with an alkyl halide R101-Lg2, in which Lg2 is a leaving group such as Br, I or p-toluenesulfonate, and a base such as DBU or sodium hydride, for get (79). Alternatively, (78) can be treated with a reagent R102-C (O) -R103, in which R102 and R103, independently of one another, are
20 substituents such as, but not exclusively, H, alkyl, alkenyl, alkynyl, -alkylene-aryl, alkylene-cycloalkyl and the like, in the presence of a reducer such as sodium cyanoborohydride or sodium triacetoxyborohydride, to obtain (79) in which R101 It should be understood as R102-C (H) (R103) -.
[0281] Alternatively, (78) can be treated with an R102C (O) -OH reagent in the presence of a dehydrator such as
25 EDC, to obtain an intermediate amide, which can be reduced with a reagent such as DIBAL or LAH, in a solvent such as THF, at a temperature between 0 ° C and 80 ° C, to obtain (71) in which R102 is due understand as -CH2-R102. Alternatively, (79) when R101 is -CH3 it can be prepared by treating (78) with a reagent R102-O-CO-Cl or R102O-CO-O-CO-O-R102, in the presence of a base such as TEA or an aqueous alkali, to obtain an intermediate product that can be reduced as before using DIBAL or LAH to give (79). The compound (79) can be
Use in the same manner as the compound (73) according to the chemistry of the scheme (1).
[0282] Scheme 3 describes the synthesis of a compound of formula (71). image20
[0283] A2 is a substituted or not substituted heteroaryl, a fused or not substituted heterocyclylheteroaryl, or a fused or unsubstituted substituted cycloalkyl heteroaryl.
[0284] R100 is a substituent such as, but not exclusively, H, alkyl substituted or not, substituted alkenyl or not, substituted alkynyl or not, -alkylene-aryl substituted or not, -alkylene-cycloalkyl substituted or not, and the like.
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[0285] The amine (80) can be treated, if desired, with an alkyl halide R100-Lg2, in which Lg2 is a leaving group such as Br, I or p-toluenesulfonate, and a base such as DBU or hydride of sodium, to obtain (71). Alternatively, (80) can be treated with an R102-C (O) -R103 reagent, in which R102 and R103, independently of one another, are substituents such as, but not exclusively, H, alkyl, alkenyl, alkynyl, -alkylene -aryl, alkylene
5 cycloalkyl and the like, in the presence of a reducer such as sodium cyanoborohydride or sodium triacetoxyborohydride, to obtain (71) in which R100 should be understood as R102-C (H) (R103) -.
[0286] Alternatively, (78) it can be treated with a reagent such as R102C (O) -Cl and a base such as TEA or R102C (O) -OH in the presence of a dehydrator such as EDC, to obtain an intermediate amide, which can be then reduce with a reagent such as DIBAL or LAH, in a solvent such as THF, at a temperature between 0 ° C and 80 ° C, to obtain
(71) in which R100 should be understood as -CH2-R102. Alternatively, (71) when R100 is -CH3 can be prepared by treating (78) with a reagent R102-OC (O) -Cl or R102O-C (O) -OC (O) -O-R102, in the presence of a base such as ASD or an aqueous alkali, to obtain an intermediate product that can be reduced as before using DIBAL or LAH to give (71).
[0287] Scheme 4 describes the synthesis of a compound of formula (81). image21
[0288] A2 is a substituted or not substituted heteroaryl, a fused or unsubstituted fused heterocyclylheteroaryl, or a fused or unsubstituted fused cycloalkyl heteroaryl.
[0289] R100 and R101 are, independently of one another, substituents such as, but not exclusively, H, substituted or non-substituted alkyl, alkenyl substituted or not, alkynyl substituted or not, substituted-alkylene-aryl or not, substituted-alkylenecycloalkyl or No, and the like.
[0290] The amine (73) can be treated with the chlorocarbonyl isocyanate reagent in the presence of a base such as DIEA, in a solvent such as THF, DCE or dioxane, at a temperature between -60 ° C and 25 ° C. The intermediate thus formed can be treated at a temperature between 0 ° C and 80 ° C with (71) to obtain (81).
[0291] Scheme 5 describes the preparation of an intermediate product of formula (87). image22
[0292] L11 is, in this case, a group such as a substituted or not substituted alkylene, or a direct bond.
[0293] R104 is a substituent such as, but not exclusively, substituted or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted alkenyl, substituted or non-substituted alkynyl, -alkylene-substituted or non-substituted alkylene, -alkylene-cycloalkyl, and analogues.
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[0294] Anthranilic acid (82) can be treated with an R104-CO-Cl acid chloride in the presence of a base such as TEA or an aqueous alkali to obtain an intermediate amide, which can be treated with a dehydrator such as POCl3 or SOCl2 in a solvent such as DCE, at a temperature between 0 ° C and 80 ° C, to obtain (83). A reagent (84) derived from an active metalation agent such as lithium or magnesium metal and G1-L11-Br or G1-L11-I can be prepared. For example, when G1 is aryl and L11 is a direct bond, G1-L11-Br can be treated with n-butyllithium in a solvent such as ether, at a temperature between -78 ° C and 0 ° C, to obtain the reagent (84) in which M1 is Li. (84) can be treated with
(83) in a solvent such as THF, at a temperature between -78 ° C and 50 ° C, to obtain (85). The amide (85) can be treated with an aqueous alkali in a solvent such as ethanol, at a temperature between 25 ° C and 100 ° C, to obtain (86).
[0295] Scheme 6 describes the alternative synthesis of a compound of formula (88).
Scheme 6 image23
[0296] L12 is, in this case, a group such as, but not exclusively, a substituted or not substituted alkylene, a substituted or not substituted cycloalkylene, or a direct bond.
[0297] An amine compound (87) can be treated with an acid chloride or other acid halide, in the presence of boron trichloride, at a temperature between -40 ° C and 25 ° C, followed by treatment with Gallium (III) and chlorobenzene and heating at a temperature between 50 ° C and 150 ° C, to obtain (88).
[0298] Scheme 7 describes the synthesis of intermediates of formulas (91), (92), (93), (94) and (95). 30 image24
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[0299] L13 is a group such as oxygen, or it can be a broadly defined group as for L12 and L11. R106, R107 and R108 are groups such as, but not exclusively, alkyl substituted or not, -alkylene-aryl substituted or not, or H.
[0300] Nitrotoluene (89) can be brominated with a reagent such as N-bromosuccinimide in carbon tetrachloride to obtain intermediate bromide (90). The methyl group of (89) may also be an alkyl group more elaborated with hydrogen (s) in the carbon adjacent to A1. The bromide (90) can be treated with sodium methanesulphinate to obtain the intermediate product (91) and with primary or secondary amines to obtain the intermediate product (92). Alternatively, groups R106 and R107 of compound R106R107NH can be taken together to form a group
10 heteroaryl or heterocyclyl, and treatment of (90) with said compound in the presence of a base such as potassium tertbutoxide produces (92) in which the R106 and R107 groups are taken together to constitute a heteroaryl or heterocyclyl group. Alternatively, (90) can be treated with sodium thiolacetate, followed by hydrolysis with an aqueous alkali, to obtain the thiol (91). From (91), various compounds can be prepared. For example, the treatment of (91) with an alkylating agent such as an alkyl bromide in the presence of a base such as sodium hydride
15 produces (93) in which L14 is S and R105 is alkyl. Oxidation of this species with a reagent such as mloroperbenzoic acid can produce the compound in which L14 is -SO2-. The compound (92) in which R106 is H can be treated with a compound R108SO2Cl in the presence of a base such as pyridine to prepare (95). Alternatively, (92) in which R106 is H can be treated with a carboxylic acid R108COOH in the presence of a peptide coupling agent such as dicyclohexylcarbodiimide to prepare (94).
[0301] Scheme 8 describes the synthesis of compounds of formula (97). image25
[0302] L16 is oxygen. G1 and L16, in this case, preferably do not contain ketone, aldehyde or primary or secondary amine groups.
[0303] R109, R110 and R111 are groups such as, but not exclusively, alkyl substituted or not, H, or alkylene-aryl substituted or not. R110 and R111 can optionally be taken together to constitute a heterocyclic ring.
[0304] The ureas of formula (91) can be amined reductively using R110NHR111 amines and a reagent such as sodium triacetoxyborohydride in a solvent such as 1,2-dichloroethane in the presence or absence of acetic acid to obtain compounds of formula (92).
[0305] Scheme 9 describes the synthesis of compounds of formulas (100) and (101).
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Scheme 9 image26
[0306] L17 is a carbonyl or sulfonyl group.
[0307] Nitrophenylureas (98) can be reduced to aniline derivatives of formula (99). Treatment of the intermediate product (99) with acid chlorides or sulfonyl chlorides can produce compounds of formula (100). Alkylation of the intermediate product (99) using aldehydes or ketones in the presence of sodium triacetoxyborohydride produces (101). Alternatively, (99) can be treated with dialkyl halide and a base such as DIEA to obtain
10 (101) in which R113 and R114 and the nitrogen to which they are attached constitute a ring. image27
[0308] L19 in this case is a group such as a substituted or not alkylene. R115 and R116 are independently, groups such as substituted or non-substituted alkyl, substituted or non-substituted alkylene-aryl, or H. Alternatively, R115 and R116 can be taken together to constitute a heterocyclic ring.
[0309] The acid (102) can be coupled with an R115NHR116 amine in the presence of a coupling agent such as dicyclohexylcarbodiimide in a solvent such as THF or dichloromethane to obtain (103).
[0310] Scheme 11 35
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Scheme 11 image28
[0311] A3 is a group such as heteroarylene substituted or not, fused heterocyclylheteroarylene substituted or not, or fused cycloalkyl heteroarylene substituted or not.
[0312] R117 is a group such as substituted or non-substituted alkyl, substituted or non-substituted alkylene-aryl, substituted or not substituted aryl, or substituted or not substituted heteroaryl.
[0313] The compound (104) can be treated with a thiol reagent in the presence of a base such as DIEA at a temperature between 50 ° C and 150 ° C to obtain the thioether (105). (105) can be oxidized with an oxidizing reagent such as m-chloroperbenzoic acid in a solvent such as dichloromethane to obtain sulfone (106). When a single equivalent of the oxidant is used, the sulfoxide can be obtained. When 2 or more equivalents of the oxidant are used, sulfone is obtained.
[0314] Scheme 12 describes the synthesis of the compounds of formula (109). image29
[0315] A3 is a group such as heteroarylene substituted or not, fused heterocyclylheteroarylene substituted or not, or fused cycloalkyl heteroarylene substituted or not.
[0316] L20 in this case is a group such as a substituted or not alkylene. R117 is a group such as substituted or non-substituted alkyl, substituted or non-substituted alkylene-aryl, or unsubstituted aryl, or substituted or not heteroaryl. Lg2 is a leaving group such as chloride, methanesulfonate or p-toluenesulfonate.
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[0317] The compound (107) in which Lg2 is methanesulfonate can be synthesized from the precursor in which Lg2 is hydroxyl by treatment with methanesulfonyl chloride in the presence of pyridine. Then (107) it can be treated with a thiol reagent in the presence of a base such as DIEA, potassium tert-butoxide or sodium hydride, to
5 obtain the displacement product (108). The thioether product (108) can be oxidized to sulfoxide or sulfone (109) as described in scheme 11.
[0318] Scheme 13 describes the synthesis of the compounds of formula (111).
10 Scheme 13 image30
[0319] L21 in this case is a group like an alkylene. R115 and R116 may have the meaning indicated previously,
or they can be, independently, groups such as substituted alkyl or not, substituted alkylene aryl or not, aryl
15 substituted or not, H, or substituted or not heteroaryl. A3 is a group such as substituted or unsubstituted heteroarylene, fused or unsubstituted fused heterocyclylheteroarylene, or fused or unsubstituted substituted cycloalkyl heteroarylene.
[0320] The acid (110) can be coupled with an R115NHR116 amine in the presence of a coupling agent such as dicyclohexylcarbodiimide to obtain (111). [0321] Scheme 14 describes a synthesis of intermediates of formula (113). image31
[0322] R118 and R119 can be, independently, groups such as substituted or non-substituted alkyl, alkylene-aryl substituted or not, substituted aryl or not, H, or substituted or non-substituted heteroaryl.
[0323] Thiourea can be condensed with the bromine carbonyl compound (112) in the presence or absence of a base
Soft as potassium carbonate or triethylamine, in a solvent such as ethanol, at a temperature between 25 ° C and 120 ° C, to obtain (113). The bromine compound (112) can be reached by various methods known in the area. For example, bromination of the ketone with pyrrolidinium hydrotribromide in THF or N-bromosuccinimide in THF in the presence of a soft base such as potassium carbonate produces (112).
[0324] Scheme 15 describes the synthesis of intermediates of formula (117).
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Scheme 15 image32
[0325] Scheme 15 shows the route of synthesis of diamides of type (117), in which A1, L1, R20, R1, G1, G2 are those defined in formula (I). The amine (114) can be coupled with an activated oxalic or malonic ester using EDC / HOBt to give the amide (115). Deprotection of the t-butyl ester of B is done with lithium hydroxide to give the carboxylic acid (116), which can be coupled using standard amide coupling reagents (eg PyBOP) to give diamides of type (115).
[0326] The intermediates of the above schemes may be substituted with amino, hydroxyl or carboxyl groups that may require protection and deprotection during the course of the preparation of the compounds of the examples.
[0327] "Amino protection" refers to the amino group substituents commonly used to block or protect amino functionality while other functional groups of the compound react. Examples of such amino protecting groups include the formyl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-like protecting groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4fluorobenciloxicarbonilo, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4diclorobenciloxicarbonilo, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4cianobenciloxicarbonilo, 2- (4-Xenil) iso-propoxycarbonyl, 1,1-difenilet -1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- (p-toluyl) prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methyloxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methyloxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1-methoxycarbonyl, 1- Methylcyclohexanyloxycarbonyl, 2- (4-tolylsulfonyl) ethoxycarbonyl, 2 (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) ethoxycarbonyl, 9- fluorenylmethoxycarbonyl ("FMOC"), t-butoxycarbonyl ("BOC"), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-yloxycarbonyl, 5-benzyloxyalylmethoxycarbonyl, 4-acetoxycarbonyloxybenzyloxycarbonyloxycarbonyloxybenzyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyl 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2- (nitro) phenylsulfonyl group, the diphenylphosphine oxide group and similar amine protecting groups. The species of the amino protecting group employed is not crucial insofar as the derivatized amino group is stable for the reaction condition or the following reactions at other positions of the compound of formula (I) and can be removed at the desired time. without altering the rest of the molecule. Preferred amino protecting groups are the allyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl and trityl groups. Similar amino protecting groups used in the field of cephalosporin, penicillin and peptides are also encompassed by the above terms. Other examples of groups referred to by the above terms are described by JW Barton, "Protective Groups In Organic Chemistry", JGW McOmie, Ed., Plenum Press, New York, NY, 1973, and TW Greene, "Protective Groups in Organic Synthesis" , John Wiley and Sons, New York, NY, 1981. The related expression "protected amino" defines an amino group substituted with an amino protecting group as mentioned above.
[0328] "Hydroxyl protection" refers to the substituents of the alcohol group commonly used to block or protect the alcohol functionality while other functional groups of the compound react. Examples of such alcohol protecting groups include the 2-tetrahydropyranyl group, the 2-ethoxyethyl group, the trityl group, the trichloroacetyl group, the urethane-like blocking groups such as benzyloxycarbonyl, and the trialkylsilyl group,
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Examples of which are trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and t-hexyldimethylsilyl. The choice of the alcohol protecting group employed is not crucial insofar as the derivatized alcohol group is stable for the reaction condition or the following reactions at other positions of the compound of formula (I) and can be eliminated at the desired time. without altering the rest of the molecule. Other examples of groups referred to by the above terms are described by JW Barton, "Protective Groups In Organic Chemistry", JGW McOmie, Ed., Plenum Press, New York, NY, 1973, and TW Greene, "Protective Groups in Organic Synthesis" , John Wiley and Sons, New York, NY, 1981. The related expression "protected hydroxyl" or "protected alcohol" defines a hydroxyl group substituted with a hydroxyl protecting group as mentioned above.
[0329] "Carboxyl protection" refers to the substituents of the carboxyl group commonly used to block or protect the -OH functionality while other functional groups of the compound react. Examples of such alcohol protecting groups include the 2-tetrahydropyranyl group, the 2-ethoxyethyl group, the trityl group, the allyl group, the trimethylsilylethoxymethyl group, the 2,2,2-trichlorethyl group, the benzyl group and the trialkylsilyl group , whose examples are trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and t-hexyldimethylsilyl. The choice of the carboxyl protecting group employed is not crucial insofar as the derivatized alcohol group is stable for the reaction condition or the following reactions at other positions of the compound of formula (I) and can be eliminated at the desired time. without altering the rest of the molecule. Other examples of groups referred to by the above terms are described by JW Barton, "Protective Groups In Organic Chemistry", JGW McOmie, Ed., Plenum Press, New York, NY, 1973, and TW Greene, "Protective Groups in Organic Synthesis" , John Wiley and Sons, New York, NY, 1981. The related expression "protected carboxyl" defines a carboxyl group substituted with a carboxyl protecting group as mentioned above.
Examples
General procedure A: Preparation of 1-aryloxy-2-nitrobenzenes, 1-arylsulfanyl-2-nitrobenzenes and 2-aryloxy-3-nitropyridines
[0330] To a solution of potassium t-butoxide (0.62 g, 5.5 mmol) in anhydrous DMF (10 ml) was added a phenol, arylmercaptane or 2-mercaptopyridine (5.5 mmol) at room temperature and the mixture was stirred for 30 min. A derivative of 1-fluoro-2-nitrobenzene or 2-bromo-3-nitropyridine (5.0 mmol) was added and the content was heated at 80 ° C for 12 h. The content was poured into water and extracted with ethyl acetate. The organic layer was washed (dil. NaOH, water, saturated sodium chloride solution), dried (Na2SO4) and concentrated. In general, the desired products were> 90% pure and were used as such in subsequent manipulations.
General procedure B: Preparation of 2-aryloxyanilines, 2-arylsulfanilanilines and 3-amino-2-aryloxypyridines
[0331] The crude 2-substituted-1-nitrobenzene from procedure A was dissolved in ethanol (10 ml). To this solution anhydrous tin (II) chloride (3.8 g, 20 mmol) and conc. HCl were added. (0.2 ml). The resulting mixture was heated at 80 ° C for 10 h, cooled and concentrated. The residue was diluted with water (100 ml), neutralized to pH 8-9. To the suspension was added ethyl acetate (40 ml), stirred for 5 min and filtered through celite. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic layer was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated under reduced pressure to obtain the desired aniline in a yield of 60-70%. In general, the desired anilines were> 85% pure (LC-MS) and were used as such in subsequent manipulations.
General procedure C for the preparation of 2-aryloxyanilines and 2-arylsulfanilanilines
[0332] The crude 2-substituted-1-nitrobenzene (mmol5 mmol) was dissolved in methanol (10 ml) in a 100 ml round bottom flask. To this solution was added 10% palladium on carbon (300 mg) and the flask was evacuated. The flask was filled with hydrogen with the help of a balloon and the contents were stirred overnight. The mixture was filtered through celite and concentrated to obtain the desired aniline (> 90% purity by LC-MS).
General Procedure D: Urea Preparation
[0333] A mixture of 1,1'-carbonyldiimidazole (98 mg, 0.6 mmol), 2-aminoheteroarene (0.6 mmol) and 4- (N, N-dimethylamino) pyridine (5 mg) in dichloroethane (5 ml) was heated to 80 ° C for 2 h. The reaction mixture was cooled to room temperature and solution of a substituted aniline (0.5 mmol) in dichloroethane (2 ml) was added. The resulting suspension was heated at 80 ° C for 10 h and concentrated. The residue was purified by column chromatography (silica, CH2Cl2 then 10-30% ethyl acetate in CH2Cl2) to obtain the desired urea in a yield of 60-80%.
General Procedure E: Urea Preparation
[0334] A mixture of isocyanate (0.5 mmol) and 2-aminoheteroarene (0.5 mmol) in dichloroethane (4 ml) was heated to 80
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° C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica, CH2Cl2 then 10-30% ethyl acetate in CH2Cl2) to obtain the desired urea in a yield of 60-80%.
General procedure F: Preparation of 2-aryloxy-1-nitrobenzenes
[0335] To a solution of potassium t-butoxide (0.62 g, 5.5 mmol) in anhydrous THF (20 ml) was added a phenol (5.5 mmol) at -10 ° C and the mixture was stirred for 30 min. A derivative of fluoro-1-nitrobenzene (5.0 mmol) was added at 10 ° C and stirred for 12 h at room temperature. The content was poured into water (25 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layer was washed (dil. NaOH, water, saturated sodium chloride solution), dried (Na2SO4) and concentrated to give the desired products with> 90% purity by LC-MS which were used as such in the next step.
General procedure G: Preparation of 1-alkoxy-2-nitrobenzenes
[0336] To an suspension of NaH (60%, 0.20 g, 5.0 mmol) in anhydrous THF (10 ml) was added dropwise an alcohol (5.0 mmol) at room temperature and the mixture was stirred for 30 min. 1-Fluoro-2-nitrobenzene (5.0 mmol) was added and the content was heated at 60 ° C for 12 h. The content was poured into water and extracted with ethyl acetate. The organic layer was washed (dil. NaOH, water, saturated sodium chloride solution), dried (Na2SO4) and concentrated. In general, the desired products were> 90% pure (LC-MS) and were used as such in subsequent manipulations.
General procedure H: General procedure for the preparation of compounds of general formula I containing a urea portion in the central core
[0337] An equivalent of a mono-di-or tri-substituted aniline was dissolved in an organic solvent such as ethyl acetate, toluene or dichloromethane and hydrochloride dissolved in an organic solvent such as ethyl acetate, toluene or dichloromethane was added. The mixture was concentrated in vacuo to give the aniline hydrochloride. The residue was dissolved or suspended in an aprotic organic solvent such as toluene or dichloromethane and an excess (eg 2 to 5 equivalents) of diphosgene or other equivalent phosgene was added. The mixture was left at room temperature or heated (to the reflux temperature of the solvent) for 5 to 20 hours. The reaction mixture was concentrated in vacuo and the intermediate residue was used in the next step without further purification.
[0338] The crude intermediate isocyanate was dissolved in an organic solvent such as ethyl acetate, toluene, dichloromethane, dioxane, DMSO or DMF and an equivalent of a heterocyclic amine was added. The reaction mixture was left at room temperature or heated until the reaction took place. The reaction temperature will depend on the reactivity of the isocyanate and the nucleophilicity of the amine and HPLC or TLC can still be used. The reaction mixture was diluted with an organic solvent such as ethyl acetate, toluene or dichloromethane and the mixture was extracted with water. The product was purified using standard procedures such as those described in the area or as exemplified below.
General procedure H1: Preparation of amides from carboxylic acids prepared using procedure H:
[0339] An equivalent of an N-substituted aminothiazol-4-ylcarboxylic acid or a N-substituted aminothiazol-4-ylacetic acid prepared using the general procedure H was dissolved in an organic solvent such as 1,2-dichloropropane, dimethylformamide or a mixture of two organic solvents as a mixture of 1,2-dichloropropane and dimethylformamide. An equivalent of PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate) was added, the reaction mixture was allowed to stand for 20 minutes followed by the addition of two equivalents of a suitable amine and DIPEA (diisopropylethylamine), and the mixture was allowed to stand overnight.
[0340] The reaction mixture was diluted with ethyl acetate and extracted using a general washing procedure such as a wash twice with water, twice with 4N HCl, once with water, twice with saturated sodium bicarbonate at 50%, and three times with water. The organic solvent was evaporated in vacuo to give an amorphous product. The product was purified by recrystallization from an organic solvent such as diethyl ether or by HPLC (eg, Waters Deltprep 4000).
[0341] In the case of isolated products containing a carboxylic acid ester functionality, the ester group could be hydrolyzed to the corresponding acid by dissolving the compound in 96% ethanol and adding 2N NaOH. The mixture was allowed to stand for a certain period. time (eg 2 hours) while the methanol was evaporated in vacuo, water was added, and the pH was adjusted to acid with 2N HCl. The mixture was extracted with an organic solvent such as ethyl acetate and the combined organic phases were combined. evaporated in vacuo to give an amorphous product.
General procedure H2: Preparation of intermediate isocyanates:
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2-benzylphenyl isocyanate
[0342]
[0343] 2-Benzylaniline (2.0 g, 11 mmol) was dissolved in ethyl acetate (5 ml) and hydrochloride was added in ethyl acetate (3 N, 5 ml). After 2 hours the organic solvent was removed in vacuo to give a solid residue. Toluene (50 ml), then diphosgene (2.2 g, 33 mmol) was added and the reaction mixture was heated at 110 ° C for 16 hours.
The solvent and excess diphosgene was removed in vacuo to give a residual oil that was used in the next step without further purification.
[0344] The following isocyanates were prepared using the same procedure used for the preparation of benzylphenyl isocyanate: 15 (5-Chloro-2-isocyanophenyl) phenyl methanone image34
2- (2-methylphenoxy) phenyl isocyanate [0346] image35
2- (4-Methoxyphenoxy) -5- (trifluoromethyl) phenyl isocyanate image36
2- (phenylsulfonyl) phenyl isocyanate [0348] image37
35 General procedure I: Preparation of 2-acyl anilines
[0349] A solution of 1 M boron trichloride in dichloromethane (110 mL, 0.11 mol) was cooled to -20 ° C. To this solution was added a solution of aniline (0.1 mol) in dichloromethane (100 mL). The mixture was heated until
40 room temperature and stirred for 3 h. The mixture was cooled again to -20 ° C. Alkyl nitrile was added
(0.1 mol) over the course of 5 min, followed by 1 M solution of GaCl3 (anhydrous) (100 mL, 0.1 mol) in dichloromethane. To this solution was added chlorobenzene (300 mL) and the mixture was heated at reflux for 24 h. After being cooled to room temperature, the mixture was poured into ice water (1 L) and stirred for 3 h. The
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organic layer and the aqueous layer was extracted with dichloromethane (4 x 400 mL). The combined organic layer was washed with water (4 x 500 mL) and saturated sodium chloride solution (2 x 500 mL) and dried over anhydrous Na2SO4. The aqueous layer was then basified to pH 7.5 with Na2CO3 and the mixture was extracted with dichloromethane (2 x 400 mL). The organic layer was washed with water (4 x 500 mL) and saturated sodium chloride solution (2 x 500 mL) and dried over anhydrous Na2SO4. Both organic layers were combined and concentrated in vacuo. The crude mixture was purified by column chromatography with hexanes-ethyl acetate (9: 1) as eluent, to give the 2-amino-alkylphenones in a yield of 10-50%.
General procedure J: Preparation of acids from esters
[0350] The ester (1 mmol) was dissolved in a 1: 1 mixture of THF and methanol (5 mL). To this solution was added 2M LiOH solution (2 mL, 4 mmol). The mixture was stirred for 1 h and concentrated. The residue was diluted with water (10 mL) and the aqueous layer was extracted with ether (2 x 10 mL). The aqueous layer was acidified with HCl to pH 6.0 and the precipitated acid was extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water (2 x 20 mL), dried (Na2SO4) and concentrated in vacuo to give the desired acid in almost quantitative yield.
General procedure K: Preparation of amides
[0351] A mixture of acid (0.5 mmol) and HBTU (0.5 mmol) was dissolved in anhydrous DMF (2 mL). DIEA (0.6 mmol) was added to this solution and stirred for 2-3 minutes. A solution of alkylamine (0.5 mmol) in DMF (1 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with saturated citric acid solution (5 mL), NaHCO3 (2 x 10 mL), water (2 x 0 mL) and saturated sodium chloride solution (2 x 10 mL), dried (Na2SO4) and concentrated in vacuo to give the desired amide. The crude mixture was purified by column chromatography (silica, CH2Cl2 then 10-50% ethyl acetate in CH2Cl2) to provide the amide in a 50-75% yield.
General procedure L: Preparation of sulfonamides / amides
[0352] To a solution of acid (1.0 mmol) and DIEA (1.5 mmol) in anhydrous THF (20 mL) was added diphenylphosphoryl azide (1.5 mmol) and heated at reflux for 8-12 hours. The reaction mixture was then concentrated in vacuo to give crude isocyanate. To this crude product was added diluted HCl (1.2 M, 20 mL) and the mixture was heated at reflux for 2 hours. The reaction mixture was neutralized with Na2CO3 and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (2 x 30 mL) and saturated sodium chloride solution (1 x 30 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to give the desired amine. This crude amine (1.0 mmol) was reacted with aryl chloride / alkylsulfonyl (1 mmol) and Et3N (2 mmol) to give the desired sulfonamides. The amides were prepared as described in procedure K. The crude product was purified by silica gel chromatography [hexanes: EtOAc / MeOH (70: 30: 0 to 5: 90: 5)] to provide the desired sulfonamides with a 20-30% yield.
General procedure M: Preparation of bis-ureas or carbamates
[0353] A mixture of acid (1.0 mmol) and DIEA (1.5 mmol) was dissolved in anhydrous THF or CH3CN (30 mL). Then diphenylphosphoryl azide (1.5 mmol) was added to the reaction mixture. The reaction mixture was heated at reflux for 8-12 hours. The reaction mixture was then concentrated in vacuo to give crude isocyanate. To this crude product, the desired amines or alcohols (2.0 mmol) were added and stirred at room temperature for 2 h. Then the reaction mixture was concentrated in vacuo. The crude reaction mixture was then purified by silica gel chromatography (hexanes: EtOAc 70:30 to 10:90) to provide the desired bis-ureas or carbamates in a yield of 30-45%.
General procedure N: Preparation of alcohols
[0354] To a solution of ethyl-2-amino-4-thiazolyl acetate or ethyl-2-amino-4-thiazolyl carboxylate (100 mmol) in anhydrous THF (100 mL) was added lithium borohydride (200 mmol , 2.0 M solution in THF) at -10 ° C, the mixture was allowed to reach room temperature and stirred for 8-10 h. Then the mixture was concentrated in vacuo. Methanol (200 mL) was added to deactivate the excess lithium borohydride and filtered through a pad of silica gel to obtain the amino alcohol.
[0355] To this crude amino alcohol (100 mmol) and imidazole (500 mmol) in anhydrous DMF (50 ml) was added tert-butyldimethylsilyl chloride (500 mmol) and stirred at room temperature for 6 h. The reaction mixture was then washed with water (5 x 100 mL) and saturated sodium chloride solution (2 x 100 mL) and extracted with ethyl acetate (3 x 200 mL), dried over Na2SO4 and concentrated to vacuum to give the amino alcohol protected with TBS.
[0356] The TBS-protected amino alcohol (50 mmol) was subjected to urea formation following general procedure D to give the desired urea. This crude urea (25 mmol) was then treated with TBAF (50 mmol, solution 1.0
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M in THF) and stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed (water), dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (hexanes: EtOAc 70:30 to 10:90) to obtain the desired alcohol in a yield of 70-80%.
General procedure O: Preparation of amines by reductive amination
[0357] To the aldehyde (0.11 mmol) in dichloroethane or THF (5 mL) the respective amine (0.11 mmol) was added and stirred at room temperature for 15 min. To this solution was added sodium triacetoxyborohydride (0.16 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo and purified by column chromatography (silica, 2-8% MeOH in DCM) to obtain the desired product in 30-50% yield.
General procedure P: Preparation of arylethers by Mitsunobu reaction
[0358] To a solution of 1- [2- (cyclopentanecarbonyl-4-methyl-phenyl] -3- [4- (2-hydroxy-ethyl) -thiazol-2-yl] -urea (0.268 mmol), phenol ( 0.536 mmol) and triphenylphosphine (0.268 mmol) in THF (2 mL) was added diisopropyl azodicarboxylate (0.268 mmol) at 0 ° C. The resulting solution was stirred at room temperature overnight, the mixture was concentrated and purified by column chromatography on silica gel (10-50% EtOAc / hexane) to give the desired product in a yield of 28-40%.
General procedure Q: Synthesis of 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (5-alkylthio-2-thiazolyl) ureas
[0359] A mixture of 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (5-bromo-2-thiazolyl) urea (1 mmol), alkylthiol (2 mmol) and DIEA (2 mmol) in DMF (5 mL) was heated at 80 ° C for 3 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with water (2 x 30 mL) and saturated sodium chloride solution (1 x 30 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to provide a residue containing 1- (2-cyclopentanoyl-4 -methyl-phenyl) -3- (5-alkylthio-2-thiazolyl) urea together with 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (thiazol-2-yl) urea. The crude product was purified by column chromatography (silica, CH2Cl2 then 5-20% ethyl acetate in CH2Cl2) to obtain the desired product in a yield of 25-35%.
[0360] The same procedure was adopted for the synthesis of 1- (2-cyclopentanoyl-4-methylphenyl) -3- (5-arylthio-2-thiazolyl) ureas. The crude products were purified by column chromatography (silica, CH2Cl2 then 5-20% ethyl acetate in CH2Cl2 and 2% MeOH in CH2Cl2) to obtain the desired product in 2535% yield.
General procedure R: Oxidation of substituted thiazolyl ureas, alkyl and arylthio
[0361] Thiazolyl urea alkyl or substituted arylthio (0.5 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0 ° C in an ice bath. To this solution was added m-cpba (133 mg, 0.75 mmol) in CH2Cl2 (3 mL). The mixture was stirred at 0 ° C for 4 h and diluted with CH2Cl2 (30 mL). The organic layer was washed with saturated NaHCO3 solution (2 x 20 mL), water (3 x 20 mL) and saturated sodium chloride solution (1 x 20 mL), dried (anhydrous Na2SO4) and concentrated in vacuo. The crude mixture was purified by column chromatography (silica, CH2Cl2 then 5-20% ethyl acetate in CH2Cl2 and 2% MeOH in CH2Cl2) to give the desired alkyl or aryl sulfone in a yield of 60-80%.
General procedure S: Preparation of 2-amino arylphenones
[0362] To a solution of 2-aminobenzoic acid (10 mmol) in THF was added benzoyl chloride (2.8 g, 20 mmol) followed by pyridine (1.58 g, 20 mmol). The mixture was stirred for 1 h at room temperature. The 2-phenylbenzo [d] [1,3] oxazin-4-one formed was filtered and the residue was washed with water and dried in a vacuum desiccator.
[0363] To a solution of 2-phenyl-benzo [d] [1,3] oxazin-4-one (5 mmol) in dry CH2Cl2 (20 mL) was added a 1 N solution of aryl magnesium bromide in THF (5 mL) at 0 ° C. The mixture was stirred at room temperature for 2 h and poured into water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 30 mL) and washed with water (3 x 50 mL) and saturated sodium chloride solution (1 x 50 mL), dried (anhydrous Na2SO4) and concentrated to vacuum to obtain N- (2-benzoyl-phenyl) -benzamide in a yield of 60-70%.
[0364] To a solution of crude N- (2-benzoyl-phenyl) -benzamide (2 mmol) in THF (10 mL) was added a solution of 10 N NaOH (5 mL) and heated at reflux for 18 h . The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (3 x 50 mL) and, saturated sodium chloride solution (1 x 50 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to give 2-amino arylphenone. The crude product was purified by column chromatography (silica, hexanes after 5-20% ethyl acetate) to obtain the desired product in a yield of 28-40%.
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General procedure T: Preparation of amides / sulfonamides
[0365] To a solution of amine (0.5 mmol) in DCM (5 mL) was added triethylamine (1 mmol) and the reaction mixture was cooled to 0 ° C. Hydrochloric acid or sulfonyl chloride (0.5 mmol) was added dropwise and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography [silica, DCM: ethyl acetate (80:20 to 20:80)] to produce the desired amides or sulfonamides, respectively.
General procedure U: Preparation of hydantoins from amino acids:
[0366] To a solution of Boc-Gly-Merrifield resin (1.2 g, 0.96 mmol) was added trifluoroacetic acid (5 ml, 20% in DCM), then the resin was washed with three cycles of DMF, methanol and DCM . To this resin in DCM (20 mL) was added slowly phosgene (10 mL, 20% in toluene, 2.0 mmol)) and triethylamine (0.56 ml, 4.0 mmol) at -20 ° C. The reaction mixture was allowed to reach room temperature. The excess phosgene was washed with three cycles of DCM. To this resin in DCM (20 mL) was added 1- (4-aminomethyl-thiazol-2-yl) -3- (2-cyclopentanecarbonyl-4-methylphenyl) -urea (0.9 g, 2.5 mmol) in DCM (10 mL) and the reaction mixture was placed on a stirrer and reacted for 4 h to give the corresponding urea. The resin was then washed with three cycles of DMF, methanol and DCM, and dried for 2 h. Triethylamine (10 mL, 20% solution in THF) was added to the resin and the reaction mixture was heated for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to obtain hydantoins with a general yield of 60-75%.
General procedure V: Preparation of specific 2-aminothiazole analogs:
[0367] To a solution of 1,3-dichloroacetone, 1,3-dibromoacetone, 1-acetoxy-3-chloroacetone, bromomalonaldehyde or 1,4-dibromobutan-2,3-dione (100 mmol) in methanol (100 ml) Thiourea (7.6 g, 100 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give the desired products with almost quantitative yield.
[0368] 4-Chloromethyl-thiazol-2-ylamine (172 mg, 1.0 mmol) was reacted with arylthiols (2 mmol) and DIEA (2 mmol) in THF (5 mL) following the general procedure Z. These intermediates were coupled with CDI and 2-amino-5-methyl-phenyl) -cyclopentyl-methanone (203 mg, 1.0 mmol) following the general procedure D.
General procedure W: Preparation of alkylamino nitrobenzenes
[0369] 1-fluoro-2-nitrobenzene derivative (5.0 mmol) and an amine (10 mmol) in THF (25 mL) were heated at 60 ° C for 12 h. The content was poured into water and extracted with ethyl acetate. The organic layer was washed (water, saturated sodium chloride solution), dried (Na2SO4) and concentrated. The residue was dissolved in methanol (25 mL) and subjected to reduction following the general procedure C. In general, the desired products were> 90% pure and were used as such in subsequent manipulations.
General procedure X: Preparation of alkenes by the Wittig reaction
[0370] The aldehyde (0.10 g, 0.28 mmol) and (carbetoxymethylene) -triphenylphosphorane (0.12 g, 0.34 mmol) were stirred at room temperature in benzene overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, 15% EtOAc / hexanes) to obtain the product in 80% yield.
General procedure Y: Synthesis of 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (5-arylthio-2-thiazolyl) ureas
[0371] A mixture of 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (5-bromo-2-thiazolyl) urea (1 mmol), arylthiol (2 mmol) and tert-BuOK (2 mmol; 4 equivalents of tert-BuOK were used for arylthio carboxylic acids) in DMF (5 mL) heated at 80 ° C for 3 h. The mixture was poured into water (20 mL). Urea containing arylthiocarboxylic acid was neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with water (2 x 30 mL), saturated sodium chloride solution (1 x 30 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to provide a residue containing 1- (2-cyclopentanoyl) -4-methyl-phenyl) -3- (5-arylthio-2-thiazolyl) urea together with 1- (2-cyclopentanoyl-4-methyl-phenyl) -3- (2-thiazolyl) urea. The crude product was purified by column chromatography (silica, CH2Cl2 then 5-20% ethyl acetate in CH2Cl2 and 2% MeOH in CH2Cl2) to obtain the desired product in a 25-35% yield.
General procedure Z: Synthesis of 1- (2-cyclopentanecarbonyl-4-methylphenyl) -3- [4- (aryl-sulfanylmethyl) -thiazol-2-yl] -ureas and 1- (2-cyclopentanecarbonyl-4-methylphenyl) - 3- {4- [arylsulfanyl) -ethyl] -thiazol-2-yl} -ureas
[0372] A mixture of 1- (4-chloromethyl-thiazol-2-yl) -3- (2-cyclopentanecarbonyl-4-methylphenyl) -urea (1 mmol), arylthiol (2 mmol) and DIEA (2 mmol) in THF (5 mL) was heated at 80 ° C for 3 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with water (2 x 30 mL) and saturated solution of
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sodium chloride (1 x 30 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to provide a residue containing 1- (2-cyclopentanecarbonyl-4-methyl-phenyl) -3- [4- (arylsulfanylmethyl) - thiazol-2-yl] -urea. The crude product was purified by column chromatography (silica, CH2Cl2 then 5-20% ethyl acetate in CH2Cl2 and 2% MeOH in CH2Cl2) to obtain the desired product in a yield of 79-85%.
[0373] Similarly, the synthesis of 1- (2-cyclopentanecarbonyl-4-methyl-phenyl) -3- {4- [arylsulfanyl) -ethyl] -thiazol-2-yl} -urea was carried out by making React methanesulfonic acid 2- {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -ethyl ester with arylthiol and Et3N. This gave the desired product with a yield of 60-80%.
10 General procedure AA: Preparation of urea.
[0374] A mixture of 1,1'-carbonyldiimidazole (98 mg, 0.6 mmol), (2-aminothiazol-4-yl) acetic acid ethyl ester (0.6 mmol) and 4- (N, N-dimethylamino) pyridine ( 2 mg) in dichloromethane (5 ml) was stirred at room temperature for 2 h. A solution of a substituted aniline derivative (0.6 mmol) in dichloromethane (1 ml) was added and stirring was continued at
15 room temperature for 24 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica, CH2Cl2 then 10-30% ethyl acetate in CH2Cl2) to obtain the desired urea.
HPLC-MS (Method A)
20 [0375] The following equipment was used:
 Hewlett Packard 1100 series G1312A Bin Pump  Hewlett Packard 1100 series column compartment  Hewlett Packard 1100 series G1315A DAD diode array detector
25  Hewlett Packard 1100 MSD series  Sedere 75 evaporative light scattering detector
[0376] The instrument is controlled by HP Chemstation software.
[0377] The HPLC pump is connected to two eluent containers containing:
A: 0.01% TFA in water
B: 0.01% TFA in acetonitrile
[0378] The analysis is performed at 40 ° C by injecting a suitable volume of the sample (preferably 1 µl) into the column eluted with a gradient of acetonitrile.
[0379] The HPLC conditions, detector parameters and parameters of the mass spectrometer used are indicated in the following table.
40 Column: Waters Xterra MS C-18 X 3 mm id 5 µm Gradient: 5% -100% linear acetonitrile for 7.5 min at 1.5 ml / min Detection: 210 nm (analogue DAD output (diode array detector)) ELS (analog output of ELS)
45 MS ionization mode API-ES Scan 100-1000 amu step 0.1 amu
[0380] After DAD the flow is divided giving approximately 1 ml / min to the ELS and 0.5 ml / min to the MS.
50 Example 1 (General procedure (H))
(2- [3- (2-Benzoyl-4-chlorophenyl) ureido] thiazol-4-yl) acetic acid
[0381]
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[0382] The title compound was prepared using (5-chloro-2-isocyanophenyl) phenyl methanone (general procedure H2) as intermediate isocyanate.
5 [0383] The intermediate 5-chloro-2-isocyanophenyl) phenyl methanone (0.31 g, 1.2 mmol) (general procedure H2) was dissolved in DMF (5 ml) and 2-amino-4-thiazole acid was added acetic (0.20 g, 1.2 mmol). After 16 hours at 20 ° C, ethyl acetate (60 ml) was added and the mixture was extracted with water (5 x 20 ml). The solvent was removed in vacuo and the remaining oil was purified on a Waters Deltprep 4000 to give the title compound.
10 1 H NMR (DMSO-d6): Selected data: δ 9.48 (width, 1 H); 8.12 (width, 1H); (multi, 9H); 6.87 (s, 1 H); 3.57 (s, 2H). HPLC-MS (method A): m / z = 415 (M + 1); Rt = 3.79 min
Example 2 {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image39
[0385] {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ester (154 mg) was prepared from (2-amino -5-methylphenyl) (cyclopentyl) methanone (102 mg, 0.5 mmol) and ethyl 2-amino-4-thiazolyl acetate (93 mg, 0.5 mmol) following the general procedure D. LC-MS (m / z): 416 ( M + 1) +
1 H NMR (400 MHz, CDCl3): δ 1.23 (t, 3H), 1.67 (m, 2H), 1.87 (m, 2H), 2.34 (s, 3H), 3.70 (s, 2H), 4.18 (m, 3H), 6.68 (s, 1 H), 7.25 (s, 2H), 7.32 (d, 1 H), 7.67 (s, 1H), 8.45 (s, 1 H), 9.75 (a, 1 H), 11.51 (a, 1 H) ppm.
Example 3
30 {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid image40
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[0387] {2- [3- (2-Cyclopentanecarbonyl-4-methylphenyl) -ureido] -thiazol-4-yl} -acetic acid (198 mg) was prepared from ethyl ester of {2- [3- (2-Cyclopentanecarbonyl-4-methylphenyl) -ureido] -thiazol-4-yl} -acetic acid (208 mg, 0.5 mmol) following the general procedure J. LC-MS (m / z): 388 (M + 1) + 1 H NMR (400 MHz, DMSO-d6): δ 1.73 (m, 2H), 1.86 (m, 2H), 2.32 (s, 3H), 3.55 (s, 2H), 3.86 (m 1 H), 6.84 (s , 1 HOUR),
5 7.36 (d, 1 H), 7.84 (d, 1H), 8.15 (d, 1 H), 10.62 (a, 1H), 11.92 (a, 1 H), 12.24 (a, 1H) ppm.
Example 4
{2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid 10 image41
[0389] 3- (2-methylpropoxy) -4-nitrotoluene (0.78 g) was prepared from 2-methylpropanol (0.46 ml, 5.0 mmol) and 3-fluoro15 4-nitrotoluene (0.77 g, 5.0 mmol) following the procedure General G. This is reduced to obtain 4-methyl-2- (2-methylpropoxy) aniline (0.47 g) following the general procedure C.
[0390] {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid (485 mg) ethyl ester was prepared from 4- methyl methyl 2- (2-methylpropoxy) aniline (360 mg, 2.0 mmol) and ethyl 2-amino-4-thiazolyl acetate (372 mg, 2.0 mmol)
20 following the general procedure D. Hydrolysis this ester following the general procedure J gave {2- [3- (4methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid (400 mg) LC-MS (m / z): 464 (M + 1) + 1H NMR (400 MHz, DMSO-d6): δ 1.01 (d, 6H), 2.07 (m, 1H), 2.23 (s, 3H), 3.53 (s, 2H), 3.77 (d, 2H), 6.67 (d, 1 H),
6.81 (s, 2H), 7.91 (d, 1 H), 8.01 (a, 1 H), 11.45 (a, 1H), 12.35 (a, 1 H) ppm.
25 Example 5
{2- [3- (4-Bromo-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image42
[0392] {2- [3- (4-Bromo-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester (192 mg, 80%) was prepared from 2- amino-5-bromo-phenyl-cyclopentyl-methanone (134 mg, 0.5 mmol) and 2-amino-4-thiazolyl acetate
Ethyl (112 mg, 0.6 mmol) following the general procedure D. LC-MS (m / z): 481 (M + 1) +; 1H NMR (400 MHz, CDCl3): δ 1.27 (t, 3H), 1.70 (m, 4H), 1.87 (m, 4H), 3.67 (m, 1 H), 3.72 (s, 2H), 4.19 (m, 2H), 6.70 (s, 1 H), 7.59 (dd, 1 H), 7.99 (s, 1 H), 8.53 (a, 1 H), 9.59 (a, 1 H), 11.56 (a, 1 H) .
Example 6 {{[[3- (4-Bromo-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid
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[0393] image43
[0394] {2- [3- (4-Bromo-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (204 mg, 90%) was prepared at
5 from {2- [3- (4-Bromo-2-cyclopentanecarbonyl-phenyl) ureido] -thiazol-4-yl} -acetic acid ethyl ester (240 mg, 0.5 mmol) following the general procedure J. LC- MS (m / z): 453 (M + 1) +; 1 H NMR (400 MHz, DMSO-d6): δ 1.72 (m, 4H), 1.82 (m, 4H), 3.54 (s 2H), 3.78 (m, 1 H),
6.86 (s, 1 H), 7.72 (a, 1 H), 8.10 (a, 1 H), 8.22 (s, 1 H), 10.65 (a, 1 H), 11.70 (a, 1H), 12.40 (a , 1 HOUR).
10 Example 7
3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -propionic acid ethyl ester image44
[0396] 1- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -3- (4-formyl-thiazol-2-yl) -urea (116 mg, 65%) was prepared from (2 amino-5- methyl -phenyl) -cyclopentyl-methanone (102 mg, 0.5 mmol) and 2-amino-thiazol-5-carbaldehyde (77 mg, 0.6 mmol) following the general procedure D.
[0397] 3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acrylic acid ester (70 mg, 58%) was prepared from 1- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -3- [4- (1-oxo-methyl) -thiazol-2-yl] -urea (0.10 g, 0.28 mmol) and (carbetoxymethylene) -triphenylphosphorane ( 0.12 g, 0.34 mmol) following the general procedure X.
[0398] 3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -propionic acid ethyl ester (48 mg, 96%) was prepared by hydrogenation of the ethyl ester of 3- {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol4-yl} -acrylic acid (0.05 g, 0.12 mmol) with Pd / C. LC / MS (m / z): 430 (M + 1) +; 1H NMR (400 MHz, CDCl3) δ 1.22 (t, 3H), 1.64-1.70 (m, 4H), 1.80-1.95 (m, 4H), 2.35 (s, 3H), 2.69 (t, 2H), 2.98 ( t, 2H), 3.67-3.80 (m, 1H), 4.01-4.15 (c, 2H), 6.50 (s, 1 H), 7.32 (d, 1 H), 7.68 (s, 1 H), 8.45 (a ,
30 1 H), 11.60 (a, 1 H).
Example 8
3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -propionic acid 35 image45
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[0400] 3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -propionic acid (15 mg, 88%) was prepared from ethyl ester of 3- {2- [3- (2-Cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -propionic acid (0.03 g,
0.04 mmol) and 2.5 M LiOH (20 µL) following the general procedure J. 5 [0401] LC / MS (m / z): 402 (M + 1) +; 1H NMR (400 MHz, CD3OD) δ 1.70-1.80 (m, 4H), 1.82-1.95 (m, 4H), 2.34 (s, 3H),
2.58 (t, 2H), 2.80 (t, 2H), 3.82-3.94 (m, 1H), 6.69 (s, 1 H), 7.38 (d, 1H), 7.85 (s, 1H), 8.19 (a, 1 H), 10.65 (a, 1 H).
Example 9 10 {2- [3- (2-Cyclopropylmethoxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid image46
[0403] 3-Cyclopropylmethoxy-4-nitrotoluene (0.77 g, 75%) was prepared from cyclopropyl methanol and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure G. This was reduced to 2-cyclopropylmethoxy -4-methylaniline (0.47 g, 71%) following the general procedure C.
[0404] {2- [3- (2-Cyclopropylmethoxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester (253 mg,
20 65%) from 2-cyclopropylmethoxy-4-methyl-aniline (177 mg, 1.0 mmol) and ethyl ester of (2-amino-thiazol-4-yl) acetic acid (186 mg, 1.0 mmol) following the procedure General D. LC-MS (m / z): 390 (M + 1) +, 1H NMR (400 MHz, DMSO-d6): δ 0.36 (m, 2H), 0.59 (m, 2H), 1.18 (t, 3H), 1.28 (m, 1 H),
2.24 (s, 3H), 3.64 (s, 2H), 3.88 (d, 2H), 4.08 (c, 2H), 6.71 (dd, 1H), 6.83 (d, 1 H), 6.86 (d, 1 H) , 7.94 (d, 1 H), 8.40 (a, 1 H), 11.36 (a, 1 H).
{2- [3- (2-Cyclopropylmethoxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (165 mg, 92%) was prepared from ethyl ester of acid {2- [3- (2-Cyclopropylmethoxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (195 mg, 0.5 mmol) following the general procedure J. LC-MS (m / z): 362 ( M + 1) +.
30 Example 10
{2- [3- (2-Cyclopentyloxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid image47
[0406] 3-Cyclopentyloxy-4-nitrotoluene (0.68 g, 62%) was prepared from cyclopentanol and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure G. This was reduced to 2- cyclopentyloxy-4-methyl-aniline (0.43 g, 70%) following the general procedure C.
[0407] {2- [3- (2-Cyclopentyloxy-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ester (250 mg, 62%) was prepared from 2- cyclopentyloxy-4-methyl-aniline (191 mg, 1.0 mmol) and (2-amino-thiazol-4-yl) -acetic acid ethyl ester (186 mg, 1.0 mmol) following the general procedure D. {2 acid was prepared - [3- (2-Cyclopentyloxy-4-methyl-phenyl) -ureido]
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thiazol-4-yl} -acetic acid (170 mg, 91%) from ethyl ester of {2- [3- (2-cyclopropylmethoxy-4-methyl-phenyl) -ureido] thiazol-4-yl} -acetic acid (200 mg, 0.5 mmol) following the general procedure J. LC-MS (m / z): 376 (M + 1) +.
Example 11
{2- [3- (2-Isobutylsulfanyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image48
[0409] 3- (Isobutyl sulfanyl) -4-nitrotoluene (0.75 g, 67%) was prepared from 2-methyl-propanothiol and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure A. This was reduced to 2-isobutyl sulfanyl-4-methylaniline (0.46 g, 63%) following general procedures B.
[0410] {2- [3- (2-Isobutylsulfanyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (276 mg, 68%) ethyl ester was prepared from 2 -butylsulfanyl-4-methyl-aniline (195 mg, 1.0 mmol) and ethyl 2-amino-4-thiazolyl acetate (186 mg, 1.0 mmol) following the general procedure D. Hydrolysis of this ester following the general procedure J gave acid {2- [3- (2-Isobutyl sulfanyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (230 mg, 90%). LC-MS (m / z): 380 (M + 1) +, 1H
20 NMR (400 MHz, DMSO-d6): δ 0.85 (m, 6H), 1.49 (m, 1 H), 2.26 (s, 3H), 2.83 (m, 2H), 3.56 (s, 2H), 6.85 ( s, 1 H), 7.09 (d, 1 H), 7.29 (d, 1 H), 7.89 (d, 1 H), 8.65 (a, 1 H), 11.28 (a, 2H).
Example 12
{2- [3- (2-Cyclopentanesulfonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image49
[0412] 3-Cyclopentanesulfanyl-4-nitrotoluene (0.83 g, 70%) was prepared from cyclopentyl mercaptan and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure A. This was oxidized to 3- Cyclopentanesulfonyl-4-nitrotoluene (0.84 g, 90%) following the general procedure R. 3-Cyclopentanesulfonyl-4-nitrotoluene was reduced to 2-cyclopentanesulfonyl-4-methyl-aniline (0.53 g, 70%) following the general procedure C.
[0413] {2- [3- (2-Cyclopentanesulfonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (305 mg, 68%) ethyl ester was prepared from 2 -cyclohentanesulfonyl-4-methyl-aniline (239 mg, 1.0 mmol) and ethyl 2-amino-4-thiazolyl acetate (186 mg, 1.0 mmol) following the general procedure D. LC-MS (m / z): 452 (M +1) +, 1H NMR (400 MHz, DMSO-d6): δ
1.19 (t, 3H), 1.58 (m, 4H), 1.84 (m, 4H), 2.35 (s, 3H), 3.65 (s, 2H), 3.77 (m, 1H), 4.08 (c, 2H), 6.91 (s, 1 H), 7.52 (d, 1 H), 7.63 (s, 1H), 8.00 (d, 1H), 8.91 (a, 1H), 11.89 (a, 1H). 40
Example 13 50
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{2- [3- (2-Cyclopentanesulfonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid
[0414]
[0415] Following the general procedure J, {2- [3- (2-cyclopentanesulfonyl-4-methylphenyl) -ureido] -thiazol-4-yl} -acetic acid ester (225 mg, 0.5 mmol) was hydrolyzed to obtain {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] thiazol-4-yl} -acetic acid (193 mg, 92%).
10 LC-MS (m / z): 424 (M + 1) +, 1 H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 1.84 (m, 4H), 2.36 (s, 3H) , 3.57 (s, 2H),
3.77 (m, 1 H), 6.87 (s, 1 H), 7.52 (d, 1H), 7.63 (s, 1 H), 8.01 (d, 1H), 8.95 (a, 1 H), 12.32 (a, 2H).
Example 14
15 {2- [3- (4-Methyl-2-piperidin-1-yl-phenyl) -ureido] -thiazol-4-yl} -acetic acid image50 image51
[0417] 4-Methyl-2- (piperidin-1-yl) -aniline (0.63 g, 67%) was prepared from piperidine (0.85 g, 10.0 mmol) and 3-fluoro4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure W.
[0418] {2- [3- (4-Methyl-2-piperidin-1-yl-phenyl) -ureido] -thiazol-4-yl} -acetic acid (285 mg, 71%) was prepared at from 4-methyl-2- (piperidin-1-yl) -aniline (190 mg, 1.0 mmol) and ethyl 2-amino-4-thiazolyl acetate (186 mg, 1.0 mmol)
25 following the general procedure D. Hydrolysis of this ester following the general procedure J gave {2- [3 (4-methyl-2-piperidin-1-yl-phenyl) -ureido] -thiazol-4-yl} - acetic (238 mg, 90%). LC-MS (m / z): 375 (M + 1) +; 1H NMR (400 MHz, DMSO-d6): δ 1.53 (a, 2H), 1.75 (m, 4H), 2.23 (s, 3H), 2.70 (m, 4H),
3.55 (s, 2H), 6.83 (s, 1 H), 6.87 (d, 1 H), 6.99 (s, 1 H), 7.92 (d, 1H), 8.40 (a, 1 H), 11.28 (a, 1 H), 12.42 (a, 1H).
30 Example 15 (General Procedure AA)
{2- [3- (2-Cyclopropanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image52
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under a nitrogen atmosphere, 1.7 M solution of t-BuLi in pentane (6.5 mL, 11.1 mmol) was added dropwise over a period of 10 min at -20 ° C. The mixture was stirred at -10 ° C for 2.5 h and then cyclopropanecarboxylic acid methoxymethyl amide (0.92 g, 6.3 mmol) was added over the course of 5 min. The mixture was allowed to reach room temperature and stirred for an additional 1 h before stopping the reaction with aqueous NH4Cl. The phase
The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved in CH2Cl2 (15 mL) and TFA (15 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo and aqueous NaHCO3 was added until pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 0.80 g of crude (2-amino-5-methyl-phenyl) -cyclopropyl-methanone as a yellow oil.
[0421] The title compound (190 mg, 43%) was prepared from crude (2-amino-5-methyl-phenyl) -cyclopropyl-methanone (200 mg, 1.14 mmol) and 2-amino-4- ethyl thiazolyl acetate (212 mg, 1.14 mmol) following the general procedure AA.1H NMR (400MHz; CDCl3): δ 1.04-1.10 (m, 2H), 1.24-1.30 (m, 5H), 2.39 (s, 3H), 2.62-2.72 (m, 1H), 3.73 (s, 2H), 4.20
15 (c, 2H), 6.78 (s, 1 H), 7.37 (dd, 1H), 7.89 (d, 1H), 8.37 (d, 1 H), 9.42 (sa, 2H), 11.50 (s, 1 H ); HPLC-MS: m / z =
410.0 (M + 23); Rt = 4.11 min.
Example 16 (General Procedure J)
20 {2- [3- (2-Cyclopropanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid image53
[0423] The title compound (111 mg, 99%) was prepared from {2- [3- (2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester (120 mg , 0.31 mmol) following the general procedure J.1H NMR (400MHz; DMSO d6): δ 1.04 (br s, 4H), 2.38 (s, 3H), 2.76 (sa, 1 H), 3.58 (s, 2H), 6.86 (s, 1 H), 6.92 (d, 1H), 8.02 (s, 1H), 8.14 (d, 1H), 10.46 (s, 1H), 12.05 (sa, 2H); HPLC-MS: m / z = 382.0 (M + 23); Rt = 3.38 min.
30 Example 17 (General Procedure AA)
{2- [3- (2-Cyclobutanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image54
[0425] Crude (2-amino-5-methyl-phenyl) -cyclobutyl-methanone (80%, oil) was prepared in a manner similar to that described for (2-amino-5-methyl-phenyl) -cyclopropyl-methanone using Cyclobutanecarboxylic acid methoxymethyl amide instead of cyclopropanecarboxylic acid methoxymethyl amide.
[0426] The title compound (210 mg, 49%) was prepared from crude (2-amino-5-methyl-phenyl) -cyclobutyl-methanone (200 mg, 1.06 mmol) and 2-amino-4- Ethyl thiazolyl acetate (197 mg, 1.06 mmol) following the general procedure AA.1H NMR (400MHz; CDCl3): δ 1.30 (t, 3H), 1.83-2.50 (m, 6H), 2.36 (s, 3H), 3.76 ( s, 2H), 4.05 (p, 1H), 4.22 (c, 2H),
45 6.80 (s, 1H), 7.35 (d, 1H), 7.52 (s, 1H), 8.41 (da, 1 H), 11.9 (sa, 1 H); HPLC-MS: m / z = 424.1 (M + 23); Rt = 4.48 min.
Example 18 (General Procedure J)
50 {2- [3- (2-Cyclobutanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid
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[0427] image55
[0428] The title compound (112 mg, 73%) was prepared from {2- [3- (25 cyclobutanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} - ethyl ester acetic acid (165 mg, 0.41 mmol) following the general procedure
J. 1H NMR (400MHz; DMSO d6): δ 1.70-2.30 (m, 6H), 2.32 (s, 3H), 3.56 (s, 2H), 4.19 (ta, 1H), 6.86 (s, 1 H), 7.39 (d, 1 H), 7.63 (s, 1 H), 8.22 (d, 1H), 10.81 (s, 1 H), 12.15 (sa, 2H); HPLC-MS: m / z = 396.1 (M + 23); Rt = 3.75 min.
10 Example 19 (General Procedure AA)
{2- [3- (2-Cyclohexanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image56
[0430] Crude (2-amino-5-methyl-phenyl) -cyclohexyl-methanone (75%, oil) was prepared in a manner similar to that described for (2-amino-5-methyl-phenyl) -cyclopropyl-methanone using Cyclohexanecarboxylic acid methoxymethyl amide instead of cyclopropanecarboxylic acid methoxymethyl amide.
[0431] The title compound (188 mg, 48%) was prepared from (2-amino-5-methylphenyl) -cyclohexyl-methanone crude (200 mg, 0.92 mmol) and 2-amino-4-thiazolyl acetate ethyl (171 mg, 1.06 mmol) following the general procedure AA.1H NMR (400MHz; CDCl3): δ 1.30 (t, 3H), 1.37-1.59 (m, 5H), 1.71-1.91 (m, 5H), 2.37 ( s, 3H), 3.30 (sa, 1 H), 3.73 (s, 2H), 4.22 (c, 2H), 6.78 (s, 1 H), 7.34 (d, 1 H), 7.68 (s, 1 H) , 8.39 (da, 1 H), 11.78 (sa, 1 H); HPLC-MS: m / z =
25 452.2 (M + 23); Rt = 4.92 min.
Example 20 (General Procedure J)
{2- [3- (2-Cyclohexanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid 30 image57
[0433] The title compound (100 mg, 89%) was prepared from {2- [3- (235 cyclohexanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} - ethyl ester acetic acid (112 mg, 0.28 mmol) following the general procedure
J. 1H NMR (400MHz; DMSO d6): δ 1.13-1.45 (m, 5H), 1.62-1.83 (m, 5H), 2.34 (s, 3H), 3.42 (sa, 1H), 3.57 (s, 2H) , 6.83 (s, 1H), 7.39 (d, 1 H), 7.81 (s, 1H), 8.15 (d, 1 H), 10.50 (s, 1 H), 12.07 (sa, 2H); HPLC-MS: m / z = 402.0 (M + 1); Rt =
4.18 min.
40 Example 21 (General Procedure (AA))
{2- [3- (4-Chloro-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester
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[0434] image58
[0435] To a stirring solution of tert-butyl ester of (4-chloro-phenyl) -carbamic acid (35 mmol) in Et2O (80 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentane (88 mmol) over a period of 10 min at -20 ° C. The mixture was stirred at 0 ° C for 1.5 h and then cyclopentanecarboxylic acid methoxymethyl amide (45 mmol) was added over the course of 5 min. The mixture was allowed to reach room temperature and stirred for an additional 1 h before stopping the reaction with aqueous NH4Cl. The organic phase
10 was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved in CH2Cl2 (50 mL) and TFA (50 mL) and stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo, aqueous NaHCO3 was added to pH 7 and extracted with CH2Cl2, dried and concentrated to give a crude product that was purified by flash column chromatography (Quad flash 65, heptane 0 : 1 -> 1: 3). This gave 75% of (2-amino-5-chloro-phenyl) -cyclopentyl-methanone as a
15 oil
[0436] The title compound (30%) was prepared from (2-amino-5-chloro-phenyl) -cyclopentyl-methanone and ethyl 2-amino-4-thiazolyl acetate following the general procedure AA.1H NMR (400MHz; CDCl3): δ 1.28 (t, 3H), 1.62-1.99 (m, 8H), 3.3.67 (ta, 1 H), 3.73 (s, 2H), 4.20 (c, 2H), 6.72 (s, 1
20 H), 7.46 (dd, 1 H), 7.84 (d, 1 H), 8.56 (sa, 1 H), 9.50 (sa, 1 H), 11.58 (sa, 1 H); HPLC-MS: m / z = 458.0 (M + 23); Rt = 4.86 min.
Example 22 (General Procedure J)
25 {2- [3- (4-Chloro-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} -acetic acid image59
[0438] The title compound (39 mg, 85%) was prepared from {2- [3- (4-chloro-2-cyclopentanecarbonyl-phenyl) -ureido] -thiazol-4-yl} - ethyl ester acetic acid (49 mg, 0.11 mmol) following the general procedure J.1H NMR (400MHz; DMSO d6): δ 1.67-1.92 (m, 8H), 3.59 (s, 2H), 3.89 (sa, 1 H), 6.88 ( s, 1 H), 7.63 (d, 1H), 8.04 (sa, 1H), 8.32 (sa, 1 H), 10.64 (s, 1 H), 12.20 (sa, 2H); HPLC-MS: m / z = 430.0 (M + 23); Rt = 4.11 min.
35 Example 23 (General Procedure (AA))
{2- [3- (2-Cyclopentanecarbonyl-4-fluoro-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester image60
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[0440] To a stirring solution of tert-butyl ester of (4-fluoro-phenyl) -carbamic acid (9.5 mmol) in Et2O (20 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t -BuLi in pentane (22 mmol) over a period of 10 min at -30 ° C. The mixture was stirred at -20 ° C for 1.5 h and then cyclopentanecarboxylic acid methoxymethyl amide (10.5 mmol) was added within 5 min. The mixture was allowed to reach room temperature and stirred for an additional 1 h before stopping the reaction with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved in CH2Cl2 (25 mL) and TFA (25 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, aqueous NaHCO3 was added to pH 7 and extracted with CH2Cl2, dried and concentrated to give a crude product that was purified by flash column chromatography (Quad flash 40, heptane 0 : 1 -> 1: 3). This gave 60% of (2-amino-5-fluoro-phenyl) -cyclopentyl-methanone as an oil.
[0441] The title compound (26%) was prepared from (2-amino-5-fluoro-phenyl) -cyclopentyl-methanone and ethyl 2-amino-4-thiazolyl acetate following the general procedure AA.1H NMR (400MHz; CDCl3): δ 1.28 (t, 3H), 1.63-1.97 (m, 8H), 3.64 (ta, 1 H), 3.73 (s, 2H), 4.20 (c, 2H), 6.72 (s, 1 H), 7.22-7.29 (m, 1 H), 7.58 (dd, 1 H), 8.55 (sa, 1 H), 9.40 (sa, 1 H), 11.45 (sa, 1 H); HPLC-MS: m / z = 442.0 (M + 23); Rt = 4.49 min.
Example 24 (General Procedure J)
{2- [3- (2-Cyclopentanecarbonyl-4-fluoro-phenyl) -ureido] -thiazol-4-yl} acetic acid image61
[0443] The title compound (75 mg, 87%) was prepared from {2- [3- (2-cyclopentanecarbonyl-4-fluoro-phenyl) -ureido] -thiazol-4-yl} -acetic acid ethyl ester (92 mg, 0.22 mmol) following the general procedure
J. 1H NMR (400MHz; DMSO d6): δ 1.65-1.94 (m, 8H), 3.57 (s, 2H), 3.84 (sa, 1 H), 6.88 (s, 1H), 7.45 (t, 1 H) , 7.85 (sa, 1 H), 8.25 (brs, 1H), 10.48 (s, 1H), 12.10 (sa, 2H); HPLC-MS: m / z = 414.1 (M + 23); Rt = 3.74 min.
Biological test
Glucokinase Activity Test (I)
[0444] The activity of glucokinase spectrometrically coupled to glucose 6-phosphate dehydrogenase was analyzed to determine the activation of glucokinase by the compound. The final test contained 50 mM Hepes, pH 7.1, 50 mM KCI, 5 mM MgCl2, 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, G-6-P dehydrogenase (de Roche, 127 671)

0.195

µM, recombinant human glucokinase 15 nM. Glucokinase is human hepatic glucokinase truncated at the N-terminal end with a His-N-terminal ((His) 8-VEQILA ...... Q466) tag and is expressed in E. coli as a soluble protein with Enzymatic activity similar to GK extracted from the liver.

[0445] Purification of His-labeled human glucokinase (hGK) was carried out as follows: The 50 ml cell pellet of E. coli culture was resuspended in 5 ml of extraction buffer A (25 mM HEPES , pH 8.0, 1 mM MgCl2, 150 mM NaCl, 2 mM mercaptoethanol) with the addition of 0.25 mg / ml lysozyme and 50 µg / ml sodium azide. After 5 minutes at room temperature 5 ml of extraction buffer B (NaCl was added

1.5

M, 100 mM CaCl2, 100 mM MgCl2, 0.02 mg / ml DNase 1, protease inhibitor tablet (Complete® 1697498): 1 tablet for 20 ml of buffer). The extract was then centrifuged at 15,000 g for 30 minutes. The resulting supernatant was loaded on a 1 ml column of metal chelate affinity chromatography (MCAC) loaded with Ni2 +. The column was washed with 2 volumes of buffer A containing 20 mM imidazole and the hGK labeled with its bound, then eluted using a 20 minute gradient of 20 to 500 mM imidazole in buffer A. Fractions were examined using electrophoresis. gel with SDS, and the fractions containing hGK (PM: 52 KDa) were pooled. Finally, a gel filtration step was used for final polishing and buffer exchange. Fractions containing hGK were loaded on a Superdex 75 gel filtration column (16/60) and eluted with buffer B (25 mM HEPES, pH 8.0, 1 mM MgCl2, 150 mM NaCl, 1 mM dithiothreitol). The purified hGK

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It was examined by gel electrophoresis with SDS and MALDI mass spectrometry and finally 20% glycerol was added before freezing. The yield from 50 ml of E. coli culture was generally 2-3 mg of hGK with a purity> 90%.
[0446] The compound to be tested was added to a well in a final concentration of 2.5% DMSO in an amount sufficient to give a concentration of the desired compound, for example 1, 5, 10, 25 or 50 µM. The reaction then began adding glucose to a final concentration of 2, 5, 10 or 15 mM. The test used a 96-well UV plate and the final test volume used was 200 µl / well. The plate was incubated at 25 ° C for 5 min and the kinetics were measured at 340 nm in a SpectraMax every 30 seconds for 5 minutes. The results for each compound were expressed as the number of times that glucokinase activity was activated compared to the activation of the glucokinase enzyme in a test without compound after being subtracted from a "blank", which is without glucokinase enzyme and without compound. The compounds in each of the examples showed glucokinase activation in this assay. A compound that at a concentration less than or equal to 30 µM produces 1.5 times more glucokinase activity than that resulting from the test without compound, is considered a glucokinase activator.
[0447] The glucose sensitivity of the compounds was measured at a concentration of the compound of 10 µM and glucose concentrations of 5 and 15 mM.
[0448] While the invention has been described and illustrated with reference to certain preferred embodiments, those skilled in the area will appreciate that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. For example, effective doses different from the preferred doses indicated herein may be applicable as a result of variations in the response of the mammal being treated for the disease or diseases mediated by glucokinase deficiency. Similarly, the specific pharmacological responses observed may vary according to and depending on the particular active ingredient chosen or whether pharmaceutical carriers are present, as well as the type of formulation and the mode of administration employed, and such expected variations or differences in the Results are contemplated in accordance with the objectives and practices of the present invention.
Glucokinase (II) activity test
Determination of glycogen deposition in rat hepatocytes isolated:
[0449] Hepatocytes from rats fed at will were isolated by a two-step perfusion technique. The cell viability, assessed by trypan blue exclusion, was uniformly greater than 80%. The cells were seeded in collagen-coated 96-well plates in basal medium (Medium 199 (5.5 mM glucose) supplemented with 0.1 µM dexamethasone, 100 units / ml penicillin, 100 mg / ml streptomycin, 2 mM Lglutamine and 1 nM insulin ) with 4% FCS at a cell density of 30,000 cells / well. The medium was replaced with basal medium 1 hour after initial plating to remove dead cells. The medium was changed after 24 hours to basal medium supplemented with 9.5 mM glucose and 10 nM insulin to induce glycogen synthesis, and the experiments were performed the next day. The hepatocytes were washed twice with buffer A (117.6 mM NaCl, 5.4 mM KCI, 0.82 mM Mg2SO4, 1.5 mM KH2PO4, 20 mM HEPES, 9 mM NaHCO3, 0.1% w / HSA, and 2.25 mM CaCl2, pH 7.4 a 37 ° C) preheated (37 ° C), and incubated in 100 µl of buffer A containing 15 mM glucose and increasing concentrations of the test compound, such as 1, 5, 10, 25, 50 or 100 µM, during 180 minutes Glycogen content was measured using standard procedures (Agius, L. et al, Biochem J. 266, 91-102 (1990). A compound, which when used in this test gives a significant increase in glycogen content in comparison With the result of the test without compound, it is considered to have activity in this test.
Glucokinase (III) activity test
Stimulation of insulin secretion by glucokinase activators in INS-1E cells
[0450] The glucose-sensitive β-cell line INS-1 E was cultured as described by Asfari M et al., Endocrinology, 130, 167-178 (1992). The cells were then seeded in 96-well cell culture plates and cultured to a density of approximately 5 x 104 per well. Stimulation of glucose-dependent insulin secretion was analyzed by incubation for 2 hours in Krebs Ringer Hepes buffer at glucose concentrations between 2.5 and 15 mM with or without addition of glucokinase activating compounds at concentrations for example 1.5 , 10, 25, 50 or 100 µM, and the supernatants were collected for measurements of insulin concentrations by ELISA (n = 4). A compound, which when used in this test gives a significant increase in insulin secretion in response to glucose, compared to the result of the test without compound, is considered to have activity in this test.

Claims (34)

E03761446 12-16-2014 image 1 1. A compound of general formula (Ib) in which R24 is chosen from the group consisting of F, Cl, Br and methyl. L1 is a bond, -D-alkylene-E-, -O-, -S-, -S (O) -, -S (O) 2- , -C (O) -, -N (R11) -o -C (= N-OR12); 10 D is a direct link or -O- and E is a direct link or -O-; R11 is hydrogen; R12 is hydrogen; G1 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-cycloalkyl or C3-10-heterocyclyl, optionally substituted with one or more substituents chosen from the group consisting of -CN, -CF3 , -OCF3, -OR18, -NR18R19, C3-10 Cycloalkyl and C1-6-alkyl, R18 and R19, independently of one another, are hydrogen or C1-6-alkyl; L2 is -N-R20-; R20 is hydrogen; L3 is -C (O) -; R1 is hydrogen; 20 G2es image2 ; R54 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, 2-pentyl or 325 or one of its salts, pharmaceutically acceptable solvates.

2.

A compound according to claim 1, wherein L1 is a bond, -D-C1-6-alkylene-E-, -O-, -C (O) -, -N (R11) -o -C (= N-OR12) -.

3. A compound according to claim 1, wherein L1 is -O-.

Four.

A compound according to claim 1, wherein L1 is -S-. 35

5.

A compound according to claim 1, wherein L1 is a bond.

6.

A compound according to claim 1, wherein L1 is -C (O) -.

A compound according to any one of claims 1 to 6, wherein D is a direct bond. 8. A compound according to any one of claims 1 to 6 wherein D is -O-. 9. A compound according to any one of claims 1 to 8, wherein E is a direct bond. Four. Five

10.

A compound according to any one of claims 1 to 8, wherein E is -O-.

eleven.

A compound according to any one of claims 1 to 10, wherein: G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl,

50 2-pentyl, 3-methyl-butyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl, thiepanyl, 1,4-oxathianyl , 1,3-dioxolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, hexahydropyridazinyl, imidazolidyl, 1,3-dioxanyl, morpholinyl, 1,3-dithianyl, 1,4-dioxanyl, 1,4-dithianyl or thiomorpholinyl. 57 E03761446 12-16-2014 12. A compound according to claim 11, wherein G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidyl, piperidyl, hexahydroazepinyl, thiolanyl, tetrahydrothiopyranyl or tiepanyl. 5 13. A compound according to claim 12, wherein G1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl or hexahydroazepinyl. 14. A compound according to claim 13 wherein G1 is selected from the group consisting of isobutyl, cyclopentyl and piperidyl. 15. A compound according to claim 14 wherein G1 is isobutyl. 16. A compound according to claim 14 wherein G1 is cyclopentyl. 17. A compound according to claim 14 wherein G1 is piperidyl. 18. A compound according to any one of claims 1 to 17, wherein R18 is hydrogen. twenty

19.

A compound according to any one of claims 1 to 18, wherein R19 is hydrogen.

twenty.

A compound according to any one of claims 1 to 19, wherein R43 is -CH2-C (O) OR54.

21. A compound according to any one of claims 1 to 20, wherein R54 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl. 22. A compound according to claim 21, wherein R54 is hydrogen, methyl or ethyl. 23. A compound according to claim 22, wherein R54 is hydrogen. 24. The compound according to claim 1, wherein the compound is {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or one of its salts or your pharmaceutically acceptable solvates. 25. The compound according to claim 24, wherein the compound is {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid, or a pharmaceutically salt thereof acceptable. 26. The compound according to claim 24, wherein the compound is {2- [3- (2-cyclopentanecarbonyl-4 acid] methyl-phenyl) -ureido] -thiazol-4-yl} acetic. 40 27. The compound according to claim 1, wherein the compound is {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or one of its pharmaceutically acceptable salts or solvates. 28. The compound according to claim 27, wherein the compound is {2- [3- (4-methyl-2- [245 methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid, or a of its pharmaceutically acceptable salts. 29. The compound according to claim 27, wherein the compound is {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid. The compound according to any of claims 1 to 29 to be used as a medicament. 31. A combination comprising a compound according to any one of claims 1 to 29 and one or more additional active ingredients. 32 32. The combination of claim 31, wherein said additional active ingredients are chosen from the group consisting of antidiabetics, antihyperlipidemic drugs, anti-obesity drugs, antihypertensives and drugs for the treatment of complications resulting from, or associated with, diabetes. 33. The combination of claim 31, wherein the additional active ingredient is metformin. 60

3. 4.

A pharmaceutical composition containing a compound according to any one of claims 1 to 29 or a combination according to any one of claims 31 to 33, and one or more pharmaceutically acceptable carriers or excipients.

35

The pharmaceutical composition of claim 34 in a unit dosage form, containing

58 5 10 fifteen twenty 25 30 35 E03761446 12-16-2014 about 0.05 mg and about 1000 mg, or between about 0.1 mg and about 500 mg, or between about 0.5 mg and about 200 mg of the compound.

36.

The compound according to any of claims 1 to 29, or the combination according to any of claims 31 to 33 or the pharmaceutical composition according to claim 34 for the treatment of metabolic disorders, to reduce blood glucose, for the treatment of hyperglycemia, for the treatment of glucose intolerance (IGT), for the treatment of syndrome X, for the treatment of fasting glucose intolerance (IFG), for the treatment of type 2 diabetes, for the treatment of type 1 diabetes, to delay the evolution of glucose intolerance (IGT) to type 2 diabetes, to delay the evolution of type 2 diabetes that does not require insulin to type 2 diabetes that requires insulin, for the treatment of dyslipidemia, for the treatment of hyperlipidemia, for the treatment of hypertension, for the treatment or prophylaxis of obesity, to reduce the intake of food, to regulate appetite, to regulate eating behavior or to increase the secretion of enteroincretinas.

37.

The compound, combination or pharmaceutical composition of claim 36 for the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), insulin resistance syndrome, syndrome X, type 2 diabetes, diabetes Type 1, dyslipidemia, hypertension and obesity.

38.

The use of a compound of any one of claims 1 to 29 for the preparation of a medicament for the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes, diabetes of type 1, dyslipidemia, hyperlipidemia, hypertension or obesity.

39.

The {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid according to claim 1, or a pharmaceutically acceptable salt or solvate thereof for use as a medicine

40

The {2- [3- (2-cyclopentanecarbonyl-4-methyl-phenyl) -ureido] -thiazol-4-yl} acetic acid according to claim 1, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension or obesity.

41.

The {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} acetic acid according to claim 1, or a pharmaceutically acceptable salt or solvate thereof acceptable to use as a medicine.

42

The {2- [3- (4-methyl-2- [2-methylpropoxy] phenyl) -ureido] -thiazol-4-yl} -acetic acid according to claim 1, or one of its salts or solvates Pharmaceutically acceptable for use in the treatment of an indication chosen from the group consisting of hyperglycemia, glucose intolerance (IGT), syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension or obesity.

59