WO2016112863A1 - Composé benzamide n-substitué-3,5-disubstitué et ses procédé de préparation et application - Google Patents

Composé benzamide n-substitué-3,5-disubstitué et ses procédé de préparation et application Download PDF

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WO2016112863A1
WO2016112863A1 PCT/CN2016/070899 CN2016070899W WO2016112863A1 WO 2016112863 A1 WO2016112863 A1 WO 2016112863A1 CN 2016070899 W CN2016070899 W CN 2016070899W WO 2016112863 A1 WO2016112863 A1 WO 2016112863A1
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oxy
compound
alkyl
methoxy
methylethyl
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段文虎
沈旭
陈静
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapy, and in particular to N-substituted-3,5-disubstituted benzoic acid amide compounds, pharmaceutically acceptable salts thereof, prodrugs thereof and hydrates or solvates thereof, and to A method of preparing a compound, a pharmaceutical composition comprising the compound, and the use thereof as a glucokinase agonist for the preparation of a medicament for preventing and/or treating type 2 diabetes.
  • Glucose kinase (GK) is mainly distributed in hepatocytes and islet ⁇ cells. Glucose kinase catalyzes the conversion of glucose from hepatocytes to glucose-6-phosphate, which is the first step in glucose metabolism in hepatocytes. Glucose kinase also acts as a glucose receptor for islet beta cells, controlling the response of insulin to a particular sugar load.
  • glucokinase gene located on chromosome 7p is closely related to the pathogenesis of diabetes (Nissim I. et al, The Biochemical journal 2012, 444(3): 537-51). Highly active homozygous GK causes hyperinsulinemia and hypoglycemia; and loss of functioning heterozygous GK leads to juvenile adult diabetes (MODY-2) (Shammas C. et al, Metabolism 2013, 62(11) :1535-42). In addition, decreased liver GK activity may be involved in the induction of insulin resistance, resulting in elevated blood glucose, impaired islet function and increased insulin resistance.
  • GK is mainly regulated by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, PFK-2/FBPase- in regulating blood glucose balance. 2) Regulation of proapoptotic proteins BAD and glucokinase regulatory protein (GKRP).
  • PFK-2/FBPase-2 acts as a binding partner for GK activation, a bifunctional enzyme that binds to GK via a diphosphatase site.
  • activation of PFK-2/FBPase-2 in islet beta cells to activate GK can cause glucose-stimulated insulin secretion.
  • the proapoptotic protein BAD which is a GK-binding protein, is mainly present in the mitochondria of liver and islet cells, promotes glycogen synthesis, enhances insulin secretion, and protects beta cell survival by regulating glucose-stimulated mitochondrial respiration.
  • GKRP is a protein with a molecular weight of 68 kDa and is an endogenous inhibitor of GK. It binds to GK at a low glucose concentration to form a complex and allows GK to stay in the nucleus. GKRP determines the subcellular location of GK and the release of the enzyme in the nucleus under fast-changing conditions.
  • Bourbonais F J et al reported that some glucokinase agonists can directly act on GK or destabilize GK-GKRP to transfer GK from nuclear to extranuclear to activate GK (Bourbonais F J. et al, The Biochemical journal 2012) , 441 (3): 881-7).
  • GK activity is an important strategy for the treatment of type 2 diabetes.
  • a number of compounds have been discovered that are effective in activating GK and have a regulation of blood glucose balance. More research is needed to activate or enhance the activity of glucokinase.
  • An object of the present invention is to provide an N-substituted-3,5-disubstituted benzamide compound, a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate or solvate thereof, and a preparation method and application.
  • a compound of formula I a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof:
  • n 0, 1, 2 or 3;
  • X is -O-, -S-, -(CH 2 ) n - or -C(O)-, wherein n is 1, 2 or 3;
  • Y is -O-, -S-, -N- or -CH-;
  • R 1 is a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 3 -8 membered heteroaryl, wherein said substitution means having a substituent selected from the group consisting of C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, 3 -8 membered heteroaryl;
  • R 2 is a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 3-8 membered heteroaryl group, wherein the substitution means having an option Substituents from the following group: halogen, cyano, halogenated C 1 -C 6 alkyl, -SO 2 (C 1 -C 6 alkyl), -SO 2 (C 3 -C 8 cycloalkyl), - SO 2 (3-8 membered heterocycloalkyl), -CO (3-8 membered heterocycloalkyl)-, -CO(C 1 -C 6 alkyl)-, -CO (C 3 -C 8 naphthenic) Base, -, -CO 2 (3-8 membered heterocycloalkyl)-, -CO 2 (C 1 -C 6 alkyl)-, -CO 2 (C 3
  • R 3 is none, hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 3 carboxyl, -COO(C 1 -C 6 alkyl), 3-8 membered heteroaryl, -NR 4 R 5 -, -CO(C 1 -C 6 alkyl), -COO (C 6 -C 10 aryl), -COO (3-8 membered heteroaryl), -CO (C 6 -C) 10 aryl), -CO (3-8 membered heteroaryl);
  • Each R 4 and R 5 are independently selected from the group consisting of: C 1 -C 6 alkyl, hydrogen, -COC 1 -C 6 alkyl;
  • R 1 and R 2 are not simultaneously unsubstituted C 1 -C 6 alkyl groups; and when R 2 is a substituted or unsubstituted 3-8 membered heteroaryl group, Y is -O-, -S-, -N- or R 3 is not hydrogen.
  • R 1 is a substituted or unsubstituted C 1 -C 6 alkyl group, or a substituted or unsubstituted C 3 -C 8 cycloalkyl group, wherein the substitution means having a group selected from the group consisting of Substituents: C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy.
  • R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted C 1 -C 6 alkyl, C 1 -C 4 Alkoxy-substituted C 1 -C 6 alkyl, phenyl-substituted C 1 -C 4 alkyl.
  • R 1 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 4 alkyl, C 1 -C 4 Alkoxy-substituted C 1 -C 4 alkyl, phenyl-substituted C 1 -C 3 alkyl.
  • R 1 is isopropyl, -CH(CH 3 )CH 2 OCH 3 , cyclopentyl, -CH 2 C 5 H 9 , cyclohexyl or benzyl.
  • R 2 is a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-7 membered heteroaryl group, wherein The substitution means having a substituent selected from the group consisting of halogen, -SO 2 (C 1 -C 4 alkyl), -SO 2 (C 3 -C 6 cycloalkyl), -SO 2 (3-6) Aminoheterocycloalkyl), -CO(3-6 membered heterocycloalkyl)-, -CON(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)-, C 6 -C 10 aryl .
  • R 2 is a phenyl-substituted C 1 -C 4 alkyl group, or a C 6 -C 10 aryl group or a 5-7 membered heteroaryl group substituted with a group selected from the group consisting of halogen, -SO 2 (C 1 -C 4 alkyl), -SO 2 (C 3 -C 6 cycloalkyl), -SO 2 (3-6 membered heterocycloalkyl), -CO (3-6 membered heterocyclic ring) Alkyl)-, -CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl)-.
  • R 2 is:
  • m is 0 or 1.
  • X is -CH 2 - or -C(O)-.
  • Y is -N-, -CH-, or -O-.
  • R 3 is none, hydrogen, C 1 -C 4 alkyl, C 1 -C 2 carboxyl, -COO(C 1 -C 6 alkyl), C 6 -C 10 aryl, 3 -8 membered heteroaryl, -NH(COC 1 -C 6 alkyl)-, -N(C 1 -C 6 alkyl)(COC 1 -C 4 alkyl)-, -CO(C 1 -C 6 alkyl).
  • R 3 is none, hydrogen, C 1 -C 4 alkyl, -COOH, -COO(C 1 -C 6 alkyl), phenyl, 5-7 membered heteroaryl, -NH (COC 1 -C 4 alkyl)-, -CO(C 1 -C 4 alkyl).
  • R 3 is none, hydrogen, -COOH, -COOC(CH 3 ) 3 , phenyl, pyridyl, -NHCOCH 3 , -COCH 3 , -CH(CH 3 ) 2 , -CH 2 CH 3 , -CH 3 .
  • the compound of the formula I is any one of the groups I-1 to I-44 prepared in the examples.
  • a process for the preparation of a compound of formula I according to the first aspect comprising the step of reacting a compound of formula II with a compound of formula III to give a compound of formula I,
  • a pharmaceutical composition comprising:
  • a fourth aspect of the invention provides the use of the compound of the formula I or the pharmaceutical composition of the third aspect of the first aspect, characterized in that it is used for:
  • a medicament for preventing and/or treating a disease associated with abnormal glucose metabolism (1) A medicament for preventing and/or treating a disease associated with abnormal glucose metabolism.
  • the disease associated with abnormal glucose metabolism is a disease or disorder associated with a lack of glucokinase activity.
  • the disease or disorder associated with a lack of glucokinase activity is microvascular complications associated with diabetes and diabetes, macrovascular complications associated with diabetes, cardiovascular disease, metabolic syndrome, and various component disorders thereof ( Componentconditions), hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, active sequelae of atherosclerosis, abnormal cardiac function, acute heart failure Blood, stroke, metabolic syndrome, hypertension, obesity, abnormal dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, blood vessels Restenosis, pancreatitis, neurodegenerative diseases, lipid disorders, cognitive dysfunction and dementia, bone disease, glaucoma and human immunodeficiency virus protease-associated lipid metabolism disorders.
  • Componentconditions Componentconditions
  • hyperglycemia impaired glucose tolerance
  • insulin resistance hyperinsulinemia
  • retinopathy neuropathy
  • the disease or disorder associated with a lack of glucokinase activity is type 2 diabetes.
  • a method of preventing, inhibiting or treating the progression or onset of a disease or disorder as defined above and below in connection with a deficiency in glucokinase activity wherein a therapeutically effective amount of a compound of formula (I) is administered to a mammal. , that is, people and patients in need.
  • the present invention provides a method for preventing, inhibiting or treating a disease as defined above and below, wherein a compound of the formula (I) and another compound of the formula (I) and/or at least one other type are provided.
  • a therapeutically effective amount of the combination is administered to a mammal, ie, a human or patient in need thereof.
  • the invention in another embodiment, relates to a method of preventing, inhibiting or treating the progression or onset of diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive dysfunction, including administration requiring prevention, inhibition Or a therapeutic mammalian patient, for example, a human patient, in a therapeutically effective amount of a compound of the invention, alone or optionally in combination with another compound of the invention and/or at least one other type of therapeutic agent.
  • Figure 1 shows the effect of I-13 on fasting blood glucose in ob/ob mice. *, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001.
  • Figure 2 shows the effect of I-20 on fasting blood glucose in ob/ob mice. *, P ⁇ 0.05.
  • Figure 3 shows the effect of I-13 on glycosylated hemoglobin in ob/ob mice. ***, P ⁇ 0.001.
  • Figure 4 shows the effect of I-20 on glycosylated hemoglobin in ob/ob mice. *, P ⁇ 0.05; **, P ⁇ 0.01.
  • the inventors of the present application have extensively and intensively studied to develop an N-substituted-3,5-disubstituted benzamide compound for the first time, which can be used as a glucokinase agonist for preventing and/or treating abnormal glucose metabolism.
  • Related diseases On the basis of this, the present invention has been completed.
  • substituted means that one or more hydrogens of any given atom or ring are substituted, provided that the normal chemical valence of the specified atom is not exceeded and that the substitution results in a stable compound.
  • the substitution is a mono-, di-, tri- or tetra-substitution.
  • each substituent group may be the same or different.
  • alkyl or “alk”, when used alone or as part of another group, includes both straight-chain and branched “alkyl” or “alk” having from 1 to 6 carbons in the normal chain, Such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, various branched isomers thereof, etc.; such a group may be optional Including 1 to 4 substituents such as F, Cl, Br, I, halogenated C 1 -C 6 alkyl such as CF 3 , C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-8 membered heteroaryl, amino, hydroxy, acyl, alkylthio, nitro, cyano, thiol, -SO 2 (C 1 -C 6 alkyl), -SO 2
  • cycloalkyl as used herein, alone or as part of another group, includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups.
  • the cycloalkyl group includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane, and cyclododecyl, and any of these groups may be optionally Substituted with 1 to 4 substituents which are halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy , C 6 -C 10 aryl C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heteroaryl, C 1 -C 6 alkylamido, C 1 -C 6 alkan
  • halogen or "halo" alone or as part of another group, refers to fluorine, chlorine, bromine, and iodine as well as CF 3, preferably fluorine and chlorine.
  • aryl refers to a monocyclic and bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, the aryl group being optionally available through the available carbon atoms Substituted by 1, 2 or 3 substituents, for example, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, 3-8 membered heteroaryl , halo, haloalkyl, haloalkoxy, CF 3 , OCF 3 , cycloheteroalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, aryloxy, cycloalkyl Baseoxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, aryl Alkylthio
  • heterocycle or “heterocyclyl” or “heterocycloalkyl” refers to substituted and unsubstituted non-aromatic 3-8 membered monocyclic groups, 7 to 11 membered bicyclic groups and 10 to 15 membered three.
  • a cyclic group wherein at least one ring has at least one hetero atom and the hetero atom is O, S or N.
  • Each ring of a “heterocycle” or “heterocyclyl” or “heterocycloalkyl” containing a hetero atom may contain one or two oxygen or sulfur atoms and/or from 1 to 4 nitrogen atoms, provided that each ring The total number of heteroatoms is 4 or less, and a further premise is that the ring contains at least one carbon atom.
  • the bicyclic and tricyclic groups forming the fused ring may contain only carbon atoms and may be saturated, partially saturated or unsaturated.
  • the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atom can optionally be quaternized.
  • Heterocycle” or “heterocyclyl” or “heterocycloalkyl” can be attached to any available nitrogen or carbon atom.
  • "Heterocycle” or “heterocyclyl” or “heterocycloalkyl” may contain 0, 1, 2 or 3 substituents which are halogen, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, hydroxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3- 8-membered heteroaryl, C 1 -C 6 alkylamido, C 1 -C 6 alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkane sulphide base.
  • heteroatom shall include O, S, N.
  • heteroaryl denotes an aromatic ring group containing from 1 to 4 heteroatoms selected from N, O, S, including, without limitation, pyrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, quinazolinyl, quinolyl, isoquinolyl and anthracenyl.
  • phrases "pharmaceutically acceptable” as used herein refers to compounds, substances, compositions, and/or dosage forms that are suitable for use in fish human and animal body tissues without undue toxicity, within reasonable medical judgment. Irritant, allergic reactions or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • salt is preferably hydrochloride, hydrobromide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, oxalic acid. Salt, succinate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, arginine or horse To the acid salt.
  • prodrug refers to a compound which, upon administration to a patient, undergoes a chemical transformation by metabolic or chemical processes to give a compound of the formula and/or a salt and/or solvate thereof.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester which acts to hydrolyze in vivo to give a prodrug of the compound of the formula itself.
  • Such prodrugs are preferably administered orally, Because in many cases, hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be employed when the ester itself is active, or where hydrolysis occurs in the blood.
  • the compound of formula I may contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in either (R) or (S) conformation or (R, S) conformation. Substituents on the ring may also be present in cis or trans form. All such conformations, including enantiomers and diastereomers, are included within the scope of the invention.
  • Preferred isomers are those which have a conformation which produces a more desirable biological activity. Isolated, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included within the scope of the invention.
  • the compound of the formula (I) can be produced as shown in the following reaction scheme and its description, and can be prepared according to the related literature methods which can be employed by those skilled in the art. Exemplary reagents and procedures for these reactions are shown below and in working examples.
  • Compound I is obtained by the reaction of compound 3 with compound 7, for example by using the procedure described in WO 2008/154563, using a suitable amide condensation reagent selected from the group consisting of 1-hydroxybenzotriazole, N-hydroxy- 7-Azobenzotriazole, N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or a salt thereof Acid salt (EDC or EDC.HCl), carbonyl diimidazole (CDI), N, N'-diisopropylcarbodiimide (DIC), O-benzotriazole-N, N, N', N'-tetramethylurea tetrafluoroborate (TBTU), O-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate (HATU , benzotriazole-N,
  • Compound 4 and R 1 OH can be obtained by a photo-delay reaction to obtain compound 5, and the catalytic reagent used in the reaction is diisopropyl azodicarboxylate/triphenylphosphine or diethyl azodicarboxylate/triphenylphosphine, or in the field. Other condensation reagents used by the skilled person. Subsequent use of compound 5 and R 2 Br by cesium carbonate / cuprous iodide / 2,2,6,6-tetramethyl-3,5-heptanedione or potassium carbonate / N,N-dimethylformamide, Or other coupled catalytic reagents used by those skilled in the art to give compound 6 under heating. Compound 6 is further subjected to a hydrolysis reaction of a benzoic acid ester by using 2 moles of an aqueous sodium hydroxide solution per liter of a sodium hydroxide to obtain a benzoic acid compound 7.
  • the corresponding thiazole ring compound 3 can be obtained by refluxing with aminonitrile and sulfur powder in pyridine or ethylenediamine, or an alkaline reagent used by those skilled in the art.
  • the compound 2 is used as a starting material, and a bromine-substituted compound 2 is obtained by a reaction with bromine.
  • Compound 2 can then be co-heated with thiourea to obtain the corresponding thiazole ring compound 3.
  • the compounds of the present invention are capable of activating or enhancing the activity of glucokinase and are useful as glucokinase agonists for the prevention and/or treatment of diseases associated with abnormal glucose metabolism such as type 2 diabetes.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount or a safe and effective amount of the N-substituted-3,5-disubstituted benzamide compound of the formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof and One or more of hydrates and solvates and, optionally, a pharmaceutically acceptable carrier, which is useful for the prevention and/or treatment of diseases associated with abnormal glucose metabolism, such as type 2 diabetes and the like.
  • the "active ingredient” as used herein means a compound of the formula I according to the invention.
  • the active ingredients of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents.
  • “Therapeutically effective amount” is intended to include effective treatment or prevention of diseases associated with abnormal glucose metabolism such as diabetes and/or The amount of the compound of the invention alone or the combination of the claimed compounds, or the amount of the compound of the invention combined with other active agents.
  • safety and effective amount is meant an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the administration route is not particularly limited, and representative administration routes include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • the compound of the formula I of the present invention can form a complex with a macromolecular compound or a polymer by non-bonding.
  • the compound of the formula I of the present invention can be linked as a small molecule to a macromolecular compound or a polymer by a chemical bond.
  • the macromolecular compound may be a biological macromolecule such as a polysaccharide, a protein, a nucleic acid, a polypeptide, or the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the compositions may also contain adjuvants such as wetting agents, emulsifying And suspending agents, sweeteners, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • Step 1 Preparation of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)carboxylate
  • the reaction solution was concentrated in vacuo to give a pale-yellow solid.
  • the solid was washed with 50.0 ml of acetone, then dissolved in 0.1 liters of water to obtain a yellow transparent solution.
  • the pH was adjusted to 9.0-9.5 with 2N sodium hydroxide solution, and a large amount of pale yellow solid was precipitated.
  • the filter cake was collected by filtration, and the filter cake was washed with 30.0 ml of methanol to obtain 21.8 g of a white solid as the compound 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)carboxylic acid tert-butyl.
  • the ester had a yield of 85.4%.
  • the organic phase was washed once with 0.5 liters of brine, dried over anhydrous sodium sulfate, filtered and evaporated.
  • the powder was the compound 1-bromo-4-methylsulfonylbenzene in a yield of 92.1%.
  • Step 4 Preparation of methyl 3-isopropyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 5 Preparation of 3-isopropyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoic acid
  • Step 6 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methyl) Sulfonyl)phenyl)oxy)-5-isopropyloxybenzamide (I-1)
  • the mixture was stirred under an ice bath, and the gas in the reaction apparatus was sufficiently substituted with argon gas.
  • the reaction was stirred at room temperature for 6 hours. After completion of the reaction, it was diluted with 10.0 ml of saturated aqueous ammonium chloride and extracted with ethyl acetate.
  • Step 2 Preparation of methyl 3-cyclopentyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methyl) Sulfonyl)phenyl)oxy)-5-cyclopentyloxybenzamide (I-2)
  • Step 2 Preparation of methyl 3-cyclopentylmethoxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 3 Preparation of 3-cyclopentylmethoxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methyl) Sulfonyl)phenyl)oxy)-5-cyclopentylmethoxybenzamide (I-3)
  • the isopropanol was changed to cyclohexanol, and the remaining raw materials, reagents and preparation methods were the same as those in the step 3 in Example I-1, and the grayish white powder was obtained as the compound methyl 3-cyclohexyloxy-5-hydroxybenzoate. .
  • Step 2 Preparation of methyl 3-cyclohexyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methyl) Sulfonyl)phenyl)oxy)-5-cyclohexyloxybenzamide (I-4)
  • Step 2 Preparation of methyl 3-benzyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 4 gave the yellow oil as the compound methyl 3-benzyloxy-5-((4-(methylsulfonyl)phenyl)oxy)benzoate.
  • Step 4 N-(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonate) Acyl)phenyl)oxy)-5-benzyloxybenzamide (I-5)
  • the white powder is the compound N-(6-tert-butoxycarbonyl-4,5,6,7 -tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl)phenyl)oxy)-5-benzyloxybenzamide (I- 5).
  • Step 1 Preparation of methyl 3-hydroxy-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • the isopropanol was changed to propylene glycol methyl ether, and the remaining raw materials, reagents and preparation methods were the same as those in the step 3 in Example I-1 to obtain a pale yellow oil as the compound 3-hydroxy-5-(2-methoxy- Methyl (1-methylethyl)oxy)benzoate.
  • Step 2 Preparation of methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(methylsulfonyl)phenyl)oxy)benzoate
  • Methyl 3-hydroxy-5-isopropyloxybenzoate was replaced with methyl 3-hydroxy-5-(2-methoxy-(1-methylethyl)oxy)benzoate, the rest
  • the desired starting materials, reagents and preparation methods are the same as those in the step 4 of Example I-1 to give the compound 3-(2-methoxy-(1-methylethyl)oxy)-5-(( Methyl 4-(methylsulfonyl)phenyl)oxy)benzoate.
  • Step 3 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(methylsulfonyl)phenyl)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methyl) Sulfonyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-6)
  • Step 2 Preparation of methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((6-(methylsulfonyl)pyridine)oxy)benzoate
  • the 1-bromo-4-methylsulfonylbenzene was replaced by 5-bromo-2-methylsulfonylpyridine, and the remaining starting materials, reagents and preparation methods were the same as those in the step 4 in Example I-1 to obtain a pale yellow oil.
  • Step 3 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((6-(methylsulfonyl)pyridine)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((6-(methyl) Sulfonyl)pyridinyloxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-7)
  • Step 1 Methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((3-(methylsulfonyl)phenyl)oxy)benzoate
  • Step: 2 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((3-(methylsulfonyl)phenyl)oxy)benzoic acid
  • Step 3 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((3-(methyl) Sulfonyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-8)
  • the white powder is the compound N- (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((3-(methylsulfonyl)phenyl) Oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-8).
  • Step 1 Methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((2-(methylsulfonyl)phenyl)oxy)benzoate
  • Step 2 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((2-(methylsulfonyl)phenyl)oxy)benzoic acid
  • Example I-1 which is light yellow
  • the powder is the compound 3-(2-methoxy-(1-methylethyl)oxy)-5-((2-(methylsulfonyl)phenyl)oxy)benzoic acid.
  • Step 3 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((2-(methyl) Sulfonyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-9)
  • the white powder is the compound N- (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((2-(methylsulfonyl)phenyl) Oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-9).
  • Step 1 Preparation of methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(ethylsulfonyl)phenyl)oxy)benzoate
  • Step: 2 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(ethylsulfonyl)phenyl)oxy)benzoic acid
  • Example I-1 which is light yellow
  • the powder is the compound 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(ethylsulfonyl)phenyl)oxy)benzoic acid.
  • Step 3 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(ethyl) Sulfonyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-10)
  • the white powder is the compound N- (6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(ethylsulfonyl)phenyl) Oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-10).
  • Step 2 Preparation of methyl 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(cyclopropylsulfonyl)phenyl)oxy)benzoate
  • Step 3 Preparation of 3-(2-methoxy-(1-methylethyl)oxy)-5-((4-(cyclopropylsulfonyl)phenyl)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(cyclopropane) Sulfonyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-11)
  • the white powder is the compound N -(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(cyclopropylsulfonyl)benzene ()oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-11).
  • Step 2 Preparation of methyl 3-(4-(azetidin-1-sulfonyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • the 1-bromo-4-methylsulfonylbenzene is replaced by 1-(4-bromophenylsulfonyl)azetidine, and the remaining raw materials, reagents and preparation methods are the same as those in the step 4 of the embodiment I-1.
  • the oil is the compound methyl 3-(4-(azetidin-1-sulfonyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate .
  • Step 3 Preparation of 3-(4-(azetidine-1-sulfonyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(nitrogen heterocycle) Butane-1-sulfonyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-12)
  • Step 2 Preparation of methyl 3-(4-(azetidin-1-yl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • the 1-bromo-4-methylsulfonylbenzene is replaced by 1-(4-bromobenzoyl)azetidine, and the remaining raw materials, reagents and preparation methods are the same as those in the step 4 of the embodiment I-1.
  • the oil is the compound methyl 3-(4-(azetidin-1-yl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate .
  • Step 3 Preparation of 3-(4-(azetidin-1-yl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(nitrogen heterocycle) Butane-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-13)
  • azetidine hydrochloride is replaced by methylamine hydrochloride, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example I-13 to obtain a yellow powder as the compound N,N-dimethyl. 4-bromobenzamide.
  • Step 2 Preparation of methyl 3-(4-(dimethylaminoformyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • the 1-bromo-4-methylsulfonylbenzene is replaced by N,N-dimethyl-4-bromobenzamide, and the remaining raw materials, reagents and preparation methods are the same as those in the step 4 of the embodiment I-1.
  • the yellow oil is the compound methyl 3-(4-(dimethylaminoformyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate.
  • Step 3 Preparation of 3-(4-(dimethylaminoformyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoic acid
  • Step 4 N-(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(dimethylamino) Formyl)phenoxy))-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-14)
  • Step 1 Preparation of methyl 3-(3,5-difluorophenyloxy)-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • the brownish yellow oil was dissolved in 10.0 ml of ethyl acetate, and then washed twice with a 20.0% aqueous citric acid solution and a 1N aqueous NaHCO 3 solution to give a pale yellow organic phase.
  • the organic phase was concentrated in vacuo and purified eluted elut elut elut elut elut elut elut elut elut elut elut elut Methyl 2-methoxy-(1-methylethyl)oxy)benzoate in a yield of 21.2%.
  • Step 3 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(3,5-difluoro Phenyloxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-15)
  • Step 1 Preparation of methyl 3-benzyloxy-5-(2-methoxy-(1-methylethyl)oxy)benzoate
  • Step 3 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-benzyloxy-5- ( 2-methoxy-(1-methylethyl)oxy)benzamide (I-16)
  • the gray powder is the compound N-(6-tert-butoxycarbonyl-4,5,6 ,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-benzyloxy-5-(2-methoxy-(1-methylethyl)oxy)benzene Amide (I-16).
  • Step 2 Preparation of N-(6-phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl) Phenyl)oxy)benzamide)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-17)
  • the gray powder is the compound N-(6-phenyl-4,5, 6,7-Tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl)phenyl)oxy)benzamide)-5-( 2-Methoxy-(1-methylethyl)oxy)benzamide (I-17).
  • the yellow powder was transferred directly to a dry 100 ml two-necked flask without further treatment, and then 30.0 ml of tetrahydrofuran was added and stirred at room temperature until dissolved. After cooling in an ice bath until the internal temperature was lower than 10 ° C, 6 mol of a hydrochloric acid aqueous solution per liter was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was concentrated in vacuo to give a yellow solid.
  • Step 4 Preparation of N-(6-(4-pyridyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-( Methylsulfonyl)phenyl)oxy)benzamide)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-18)
  • N-tert-butoxycarbonyl-4-piperidone is replaced by 1-tert-butoxycarbonyl-3-pyrrolidone, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of the embodiment I-1 to obtain a yellow powder.
  • Step 2 Preparation of N-(5-tert-butoxycarbonyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-3-((4-(methylsulfonyl) Phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-19)
  • Step 2 Preparation of N-(6-acetylamino-4,5,6,7-tetrahydro-tetrahydro-benzo(d)thiazol-2-yl)-3-(4-(methylsulfonyl)benzene Oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-20)
  • Step 2 Preparation of N-(6-acetylamino-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonate) Acyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-21)
  • Step 2 Preparation of N-(6-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonate) Acyl)phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-22)
  • N-tert-butoxycarbonyl-4-piperidone is replaced by N-ethyl-4-piperidone, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of the embodiment I-1 to obtain a brownish yellow powder.
  • Step 2 Preparation of N-(6-ethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl) Phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-23)
  • Step 2 Preparation of N-(6-ethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl) Phenyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-24)
  • Step 1 Preparation of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(methylsulfonyl)phenoxy)- 5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-25)
  • Step 1 Preparation of N-(5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-3-((4-(methylsulfonyl)phenyl)oxy) -5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-26)
  • Step 2 Preparation of N-(4,5,6,7-tetrahydro-benzo(d)thiazol-2-yl)-3-(4-(methylsulfonyl)phenoxy)-5-(2 -methoxy Base-(1-methylethyl)oxy)benzamide (I-27)
  • Step 2 Preparation of N-(5,6-dihydro-4H-cyclopenta(d)thiazol-2-yl)-3-(4-(methylsulfonyl)phenoxy)-5-(2- Methoxy-(1-methylethyl)oxy)benzamide (I-28)
  • the light yellow oil was transferred to a dry 50 ml two-necked flask, and 1.3 g of 3-bromotetrahydro-4H-pyran-4-one, 0.5 g of thiourea and 20 ml of acetone were added, and refluxed under argon atmosphere. The solution turned from pale yellow to yellow, and heating was stopped after one hour and stirred at room temperature overnight. Dissolved, a small amount of methanol was dissolved, and ethyl acetate was added to give an off-white solid.
  • Step 2 Preparation of N-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-3-(4-(methylsulfonyl)phenoxy)-5 -(2-methoxy-(1-methylethyl)oxy)benzamide (I-29)
  • Step 2 Preparation of N-(7-oxo-4,5,6,7-tetrahydro-benzo(d)thiazol-2-yl)-3-(4-(methylsulfonyl)phenoxy) -5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-30)
  • Step 1 Preparation of methyl 3-(4-(azetidin-1-yl)phenoxy)-5-isopropyloxybenzoate
  • the 1-bromo-4-methylsulfonylbenzene was replaced by 1-(4-bromobenzoyl)azetidine, and the remaining raw materials, reagents and preparation methods were the same as those in the step 4 of Example I-1.
  • the oil is the compound methyl 3-(4-(azetidin-1-yl)phenoxy)-5-isopropyloxybenzoate.
  • Step 3 Preparation of N-(6-acetamido-4,5,6,7-tetrahydrobenzo(d)thiazol-2-yl)-(3(4-(azetidin-1-yl) Phenoxy)-5-isopropoxybenzamide (I-31)
  • the gray powder is the compound N-(6-acetylamino-4,5, 6,7-tetrahydrobenzo(d)thiazol-2-yl)-(3(4-(azetidin-1-yl)phenoxy)-5-isopropoxybenzamide ( I-31).
  • Step 2 Preparation of 3-(3-(6-(azetidin-1-yl)pyridyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy) Methyl benzoate
  • the 1-bromo-4-methylsulfonylbenzene is replaced by 1-(5-bromo-2-pyridinecarbonyl)azetidine, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of the embodiment I-1.
  • the colorless oil is obtained as the compound 3-(3-(6-(azetidin-1-yl)pyridyl)oxy)-5-(2-methoxy-(1-methylethyl) )oxy)methyl benzoate.
  • Step 3 Preparation of 3-(3-(6-(azetidin-1-yl)pyridyl)oxy)-5-(2-methoxy-(1-methylethyl)oxy Benzoic acid
  • Step 4 Preparation of N-(6-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(3-(6-( Azetidine-1-formyl)pyridine)oxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-32)
  • Step 2 Preparation of N-(6-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(methylsulfonyl) Phenyl)oxy)benzamide)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-33)
  • the yellow oil was transferred to a dry 100 ml two-necked flask without further treatment, and then 3.0 ml of tetrahydrofuran was added and stirred at room temperature until dissolved. After cooling in an ice bath until the internal temperature was lower than 10 ° C, 8.5 ml of 6 mol of an aqueous hydrochloric acid solution was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was concentrated in vacuo to give a yellow solid.
  • Step 4 N-(6-(2-pyridyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(A) Sulfonyl)phenyl)oxy)benzamide)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-34)
  • the yellow oil was transferred to a dry 100 ml two-necked flask without further treatment, and then 3.0 ml of tetrahydrofuran was added and stirred at room temperature until dissolved. After cooling in an ice bath until the internal temperature was lower than 10 ° C, 8.0 ml of 6 mol of aqueous hydrochloric acid per liter was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was concentrated in vacuo to give a yellow solid.
  • Step 4 N-(6-(3-Pyridyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-((4-(A) Sulfonyl)phenyl)oxy)benzamide)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-35)
  • Step 1 Preparation of ethyl 2-amino-4,5,6,7-tetrahydro-benzo[d]thiazole-6-carboxylate
  • Step 2 Preparation of 2-(3-(2-methoxy-(1-methylethyl)oxy)-5-(4-(methylsulfonyl)phenyloxy)benzoylamino)- 4,5,6,7-tetrahydro-benzo[d]thiazole-6-carboxylic acid ethyl ester (I-36)
  • Step 1 Preparation of 2-(3-(2-methoxy-(1-methylethyl)oxy)-5-(4-(methylsulfonyl)phenyloxy)benzoylamino)- 4,5,6,7-tetrahydro-benzo[d]thiazole-6-carboxylic acid (I-37)
  • Step 1 Preparation of tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-b]pyridine-4(5H)carboxylate
  • Step 2 Preparation of N-(7-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-b]pyridin-2-yl)-3-(4-(nitrogen heterocycle) Butane-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-38)
  • the yellow powder is the compound N-(7-tert-butoxycarbonyl-4 ,5,6,7-tetrahydro-thiazolo[5,4-b]pyridin-2-yl)-3-(4-(azetidin-1-yl)phenoxy)-5- (2-Methoxy-(1-methylethyl)oxy)benzamide (I-38).
  • Step 1 Preparation of tert-butyl 2-amino-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)carboxylate
  • Step 2 Preparation of N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridin-2-yl)-3-(4-(nitrogen heterocycle) Butane-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-39)
  • Step 1 Preparation of ethyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)carboxylate
  • Step 2 Preparation of N-(6-ethoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(azetidine) Alkyl-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-40)
  • Step 1 Preparation of methyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)carboxylate
  • Example I-1 Replacing N-tert-butoxycarbonyl-4-piperidone with N-methoxycarbonyl-4-piperidone, the remaining starting materials, reagents and preparation methods are the same as step 1 in Example I-1, which is light yellow
  • the powder was the compound methyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)carboxylate.
  • Step 2 Preparation of N-(6-methoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-(azetidine) Alkyl-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-41)
  • Step 1 Preparation of N,N-bis(3,3'-methoxy-3,3'-oxopropyl)-2-hydroxyethylamine
  • Step 4 Preparation of N-(6-(2-hydroxyethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4-( Azetidine-1-formyl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-43)
  • Step 1 Preparation of N,N-bis(3,3'-methoxy-3,3'-oxopropyl)-2-methoxyethylamine
  • the 2-aminoethanol is replaced by 2-methoxyethylamine, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example I-43 to obtain a yellowish oil as the compound N,N-di(3, 3'-Methoxy-3,3'-oxopropyl)-2-methoxyethylamine.
  • Step 4 Preparation of N-(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-(4 -(azetidin-1-yl)phenoxy)-5-(2-methoxy-(1-methylethyl)oxy)benzamide (I-44)
  • Step 1 Establishment of a screening system for glucokinase activity screening
  • G6P Based on glucose catalyzed by glucokinase to become glucose-6-phosphate (G6P), G6P is converted to 6-catalyzed by glucose-6-phosphate dehydrogenase (G6PD).
  • G6PD glucose-6-phosphate dehydrogenase
  • Glucose phosphate in which a portion of (1-naphthylacetamide) is simultaneously catalyzed into ( ⁇ -nicotinamide adenine dinucleoside disodium), while NADH has an absorbance at 340 nm, by absorbance
  • the size can reflect the principle of the activity of glucokinase.
  • An enzyme activity screening system for the glucokinase agonist shown in Table 1 was established.
  • a total of 120 ⁇ L of the system was assayed for activity in a 96-well plate.
  • Each well included: 25 mmol/L Hepes, 25 mmol/L KCl, 2 mmol/L MgCl 2 , 1 mmol/L ATP, 1 mmol/L DTT, 1 mmol/ LNAD, 0.1% BSA, 5 ⁇ mol/mL G6PD, 5 mmol/L glucose, 18.7 ⁇ g/mL LGK2 protein, add 1.2 ⁇ L of the corresponding concentration of compound, mix gently, and incubate at 37 ° C for half an hour. Finally, 12 ⁇ L of ATP (1 mmol/L) was added to each well to initiate the reaction, the kinetic absorbance was measured at 340 nM, and the maximum reaction rate was selected as the level of the level of the reaction enzyme.
  • the maximum reaction rate is compared to DMSO to give the agonism at this concentration.
  • the agonistic rate of the compound is obtained by the following formula:
  • Compound agonism % (average OD of compound group - mean OD of negative control DMSO group) / OD average of negative control DMSO group
  • the agonism at different concentrations was plotted using the Origin8 software to obtain a concentration-agonistic S-curve of the compound.
  • the plateau period agonism is reached as the maximum agonistic rate of the compound.
  • the enzyme activity test based on the glucokinase enzyme activity screening evaluation system established in the step 1 shows that the N-substituted-3,5-disubstituted benzamide compound of the present invention has a very high concentration of glucokinase at a micromolar level.
  • Good agonistic effect the half-maximal effect concentration of most compounds on glucokinase is 0.04-50 ⁇ mol/L, and the half-maximal effect concentration of some compounds on glucokinase is about 40 nanomoles per liter, which is stronger than the positive control compound RO28-0450.
  • the present invention studies the fasting blood glucose and glycated hemoglobin of type I diabetes model mice (ob/ob mice) after I-13 and I-20, respectively, by intraperitoneal injection to study the two compounds for hyperglycemia of type 2 diabetes. Treatment or improvement. The results showed that both I-13 and I-20 have good hypoglycemic effects.
  • Ob/ob mice belong to the animal model of type 2 diabetes.
  • mice of this strain were used as an animal model for evaluating compounds against type 2 diabetes.
  • mice Animal grouping and dosing schedule of A and I-13: Ob/ob mice were housed in SPF animal houses and adapted for one week after domestication. The mice were divided into a blank control group, a positive control group and a test group according to the mean value of fasting blood glucose results after 6 hours of fasting, with 8 rats in each group. Each group of mice was given intraperitoneal injection of solvent (6% Tween80, 2% DMSO, solvent group), 5 mg/kg positive compound (Rosiglitazone, positive compound group), 40 mg, daily from 10:00 to 11:00. /kgI-13 (I-13 high dose group), 20 mg/kg I-13 (I-13 low dose group).
  • solvent 6% Tween80, 2% DMSO, solvent group
  • mice Animal grouping and dosing schedule of B and I-20: Ob/ob mice were housed in SPF animal houses and adapted for one week after domestication. The mice were divided into a blank control group, a positive control group and a test group according to the mean value of fasting blood glucose results after 6 hours of fasting, with 8 rats in each group. Each group of mice was given intraperitoneal injection of solvent (4% Tween80, 1% DMSO, solvent group), 5 mg/kg positive compound (Rosiglitazone, positive compound group), 30 mg, daily from 10:00 to 11:00. /kgI-20 (I-20 high dose group), 10 mg/kg I-20 (I-20 low dose group).
  • HbA1c glycated hemoglobin
  • the fasting blood glucose of the blank control group was maintained at a relatively high level during the experiment.
  • the fasting blood glucose of the positive control group was always below the solvent group, and this phenomenon continued until the end of the experiment.
  • the I-13 high and low dose groups also showed a phenomenon below the solvent group from the first week, and the high dose group reduced the phenomenon of fasting blood glucose until the end of the experiment, that is, the I-13 high dose group Shows good hypoglycemic activity ( Figure 1).
  • the fasting blood glucose of the blank control group was maintained at a relatively high level during the experiment.
  • the fasting blood glucose of the positive control group was always below the solvent group, and this phenomenon continued until the end of the experiment.
  • the I-20 high-dose group also showed a phenomenon below the solvent group from the first week, and this phenomenon continued until the end of the experiment, that is, the I-20 high-dose administration group showed good hypoglycemic activity (Fig. 2).
  • the glycated hemoglobin of the positive compound group and the high dose group I-13 was significantly lower than that of the solvent group, indicating that the I-13 administration group had good hypoglycemic activity (Fig. 3).
  • both the positive compound group and the high dose group of I-20 had significantly lower glycated hemoglobin than the solvent group, indicating that the I-20 administration group had good hypoglycemic activity (Fig. 4).

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Abstract

L'invention concerne un composé benzamide N-substitué-3,5-disubstitué et ses procédé de préparation et application associée. La structure du composé est représentée par la formule (I), dans laquelle m, X, Y, R1, R2, et R3 dans la formule (I) sont représentés comme dans les revendications et les descriptions. L'invention concerne également une composition pharmaceutique contenant un composé représenté par la formule (I). Le composé de la présente invention peut être utilisé comme activateur de la glucokinase afin de prévenir et/ou de traiter des maladies associées à un métabolisme anormal du glucose.
PCT/CN2016/070899 2015-01-14 2016-01-14 Composé benzamide n-substitué-3,5-disubstitué et ses procédé de préparation et application Ceased WO2016112863A1 (fr)

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CN111153879A (zh) * 2020-03-17 2020-05-15 南京昊绿生物科技有限公司 霉酚酸-13cd3的合成方法
WO2024220635A1 (fr) * 2023-04-18 2024-10-24 Vanderbilt University Dérivés de thiazolopyridine utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4

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CN109134510A (zh) * 2018-11-13 2019-01-04 井冈山大学 制备2-氨基-5-cbz-4,5,6,7-四氢噻唑并[5，4-c]吡啶的新方法

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CN101711238A (zh) * 2007-06-11 2010-05-19 百时美施贵宝公司 1,3-二羟基取代的苯基酰胺葡糖激酶激活剂
WO2011095997A1 (fr) * 2010-02-08 2011-08-11 Advinus Therapeutics Private Limited Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique

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CN100591671C (zh) * 2003-02-26 2010-02-24 万有制药株式会社 杂芳基氨基甲酰基苯衍生物
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WO2011095997A1 (fr) * 2010-02-08 2011-08-11 Advinus Therapeutics Private Limited Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique

Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN111153879A (zh) * 2020-03-17 2020-05-15 南京昊绿生物科技有限公司 霉酚酸-13cd3的合成方法
CN111153879B (zh) * 2020-03-17 2022-09-27 南京昊绿生物科技有限公司 霉酚酸-13cd3的合成方法
WO2024220635A1 (fr) * 2023-04-18 2024-10-24 Vanderbilt University Dérivés de thiazolopyridine utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
US12139498B1 (en) 2023-04-18 2024-11-12 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor M4

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