WO2007137962A1 - Thiazole derivatives - Google Patents

Thiazole derivatives Download PDF

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Publication number
WO2007137962A1
WO2007137962A1 PCT/EP2007/054908 EP2007054908W WO2007137962A1 WO 2007137962 A1 WO2007137962 A1 WO 2007137962A1 EP 2007054908 W EP2007054908 W EP 2007054908W WO 2007137962 A1 WO2007137962 A1 WO 2007137962A1
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WIPO (PCT)
Prior art keywords
carbamoyl
bromo
thiazol
methyl
sulfonamide
Prior art date
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Ceased
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PCT/EP2007/054908
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French (fr)
Inventor
Marcel Gubler
Wolfgang Haap
Paul Hebeisen
Eric A. Kitas
Bernd Kuhn
Rudolf E. Minder
Brigitte Schott
Hans P. Wessel
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to CA002652162A priority Critical patent/CA2652162A1/en
Priority to JP2009512545A priority patent/JP2009538860A/en
Priority to EP07729351A priority patent/EP2032548A1/en
Priority to MX2008015143A priority patent/MX2008015143A/en
Priority to BRPI0712144-0A priority patent/BRPI0712144A2/en
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to KR1020087029281A priority patent/KR101156367B1/en
Priority to AU2007267191A priority patent/AU2007267191B2/en
Publication of WO2007137962A1 publication Critical patent/WO2007137962A1/en
Priority to IL195007A priority patent/IL195007A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/58—Nitro radicals
    • 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
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds useful as FBPase inhibitors.
  • the invention is concerned particularly with compounds of formula
  • R 1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R 4 , -O-R 4 or nitro;
  • R 2 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxyalkyl, hydroxyalkyl or alkoxycarbonyl;
  • R 3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino, nitro, alkoxyalkyl, hydroxyalkyl, alkoxyalkoxy and hydroxyalkoxy;
  • R 4 is alkyl, cycloalkyl, heterocyclylalkyl, aralkyl or haloalkyl;
  • R 1 and R 2 are not both at the same time hydrogen and, wherein N-((2-benzothiazolylamino)carbonyl)-4-methyl-benzenesulfonamide;
  • the present invention relates to new chemical compounds that are inhibitors of Fructose- 1,6-bisphosphatase (FBPase), a rate-limiting enzyme of gluconeogenesis that is allosterically regulated by AMP and responsible for the hydrolysis of Fructose- 1,6- bisphosphate to Fructose-6-phosphate.
  • FBPase Fructose- 1,6-bisphosphatase
  • Compounds of the present invention represent novel FBPase AMP site inhibitors and have valuable pharmacological properties suitable in both human and veterinary medicine.
  • compounds of the present invention are hypoglycaemic agents and are indicated for the treatment and/or the prophylaxis of disorders of glucose homeostasis, such as Diabetes Mellitus, in particular Type II and Type I Diabetes Mellitus (NIDDM and IDDM), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) , and for the prevention of the progression of disorders of the Metabolic Syndrome (MetS, also described as Syndrome X or Insulin Resistance Syndrome) which most important components are insulin resistance (with or without IGT), obesity, dyslipidemia, hypertension, prothrombic and proinflammatory states.
  • disorders of glucose homeostasis such as Diabetes Mellitus, in particular Type II and Type I Diabetes Mellitus (NIDDM and IDDM), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT)
  • IGT Impaired Glucose Tolerance
  • MetS also described as Syndrome X or Insulin Resistance Syndrome
  • compounds of the present invention are also indicated for the prevention and/or the treatment of diabetic complications or diabetic- associated diseases such as cardiomyopathy, macrovascular atherosclerotic disorders, including coronary, cerebrovascular and peripheral artery diseases, microvascular diseases including retinopathy, cataracts, blindness and nephropathy, neuropathy (peripheral neuropathy and sympathetic nerve disorders), diabetic necrosis, infection or depression, and so forth.
  • diabetic complications or diabetic- associated diseases such as cardiomyopathy, macrovascular atherosclerotic disorders, including coronary, cerebrovascular and peripheral artery diseases, microvascular diseases including retinopathy, cataracts, blindness and nephropathy, neuropathy (peripheral neuropathy and sympathetic nerve disorders), diabetic necrosis, infection or depression, and so forth.
  • compounds of the present invention have cytoprotective effects as anti-ischaemic agents and are useful for preventing ischaemia- induced tissue damage. Therefore, compounds of the present invention can be used in a variety of ischaemic and inflammatory conditions where acute management of tissue injury could be beneficial such as surgical trauma, myocardial infarction, congestive heart failure, stroke, sickle cell disease, and so forth, and have further utility in cardioprotection, in improving cardiac function and tolerance to exercise, in improving red-blood cells and pulmonary endothelial functions, in organ preservation in transplants, and so forth. As such, compounds of the present invention can also be used to treat asthma attacks, hypertension, atheriosclerosis and so forth, and in the management of certain excess glycogen storage diseases such as McArdle disease (GSD-Type V) and others.
  • McArdle disease GSD-Type V
  • compounds of the present invention can have further utility in the prevention and/or the management of a large set of diseases including obesity, atherosclerosis, inflammation, Alzheimer disease, cancer or respiratory disorders such as excess mucus production and allergic asthma, excess surfactant synthesis, cystic fibrosis, and so forth.
  • compounds of the present invention can be used in any disease, syndrome, symptom or organ malfunction found associated with increased expression and/or activity of one or another FBPase isoform, at the obvious exception of certain deficiencies where FBPase upregulation might be beneficial for ensuring normal body function, e.g. certain glycogen storage diseases, such as GSD-Type 0 (glycogen synthase deficiency) .
  • GSD-Type 0 glycogen storage diseases
  • the compounds of formula I and their pharmaceutically acceptable salts and esters are novel and have valuable pharmacological properties.
  • they are FBPase inhibitors and can be used in the prophylaxis and/or treatment of Diabetes Mellitus such as Type I, Type II and Type III Diabetes, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), Metabolic Syndrome, insulin resistance, dyslipidemia, obesity, hypertension, atherosclerosis, diabetic complications, inflammation, respiratory diseases or ischaemia.
  • IGF Impaired Fasting Glucose
  • ITT Impaired Glucose Tolerance
  • Metabolic Syndrome insulin resistance, dyslipidemia, obesity, hypertension, atherosclerosis, diabetic complications, inflammation, respiratory diseases or ischaemia.
  • Preferred is the prophylaxis and/or prevention of progression and/or treatment of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III,
  • Impaired Fasting Glucose IGF
  • Impaired Glucose Tolerance ITT
  • Metabolic Syndrome diabetic complications and ischaemia.
  • prophylaxis and/or treatment of Diabetes Mellitus Type II and Diabetes Mellitus Type I is particularly preferred.
  • Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts and esters, the use of the said compounds, esters and salts for the prophylaxis and/or therapy of illnesses, especially in the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia, particularly Diabetes Mellitus Type II and Diabetes Mellitus Type I
  • the compounds of the present invention can be combined with one or more additional active substances indicated for the management of human and veterinary homeostasis in any suitable ratio.
  • Such substances may be insulin sensitizers such as peroxisome proliferator- activated receptor modulators (PPAR alpha, gamma, delta agonists, particularly with thiazolinediones such as rosiglitazone and pioglitazone), insulin secretagogues (sulfonylureas such as glyburide, glimepiride and glipizide, and non- sulfonylurea secretagogues such as the meglitinides repaglinide and nateglinide), insulin, metformin, alpha- glucosidase inhibitors (e.g.
  • PPAR alpha, gamma, delta agonists particularly with thiazolinediones such as rosiglitazone and pioglitazone
  • insulin secretagogues sulfon
  • acarbose miglitol
  • GLP-I glucagon-like peptide
  • DPP-IV dipeptidyl peptidase- IV
  • glycogen phosphorylase inhibitors glycogen synthase kinase-3 inhibitors
  • ll ⁇ -hydroxysteroid dehydrogenase- 1 inhibitors glycogen synthase kinase-3 inhibitors
  • ll ⁇ -hydroxysteroid dehydrogenase- 1 inhibitors ll ⁇ -hydroxysteroid dehydrogenase- 1 inhibitors
  • carnitine palmitoyltranferase- 1 inhibitors glucocorticoid receptor antagonists
  • glucagon receptor antagonists Adenosine (A 2B ) receptor agonists
  • amylin agonists e.g. pramlintide
  • lipase inhibitor e.g. orlistat
  • alkyl signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms
  • straight- chain and branched Ci-Cs alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.
  • cycloalkyl signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
  • Examples of C 3 -Cs cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl- cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl- cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.
  • alkoxy signifies a group of the formula alkyl-O- in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, preferably methoxy and ethoxy and most preferred methoxy.
  • haloalkyl signifies an alkyl group as previously defined, wherein one to five hydrogen atoms are substituted by halogen, preferably fluoro.
  • halogen preferably fluoro.
  • Preferred examples are pentafluoroethyl and particularly trifluoromethyl and difluoromethyl.
  • haloalkoxy alone or in combination, signifies a group of the formula haloalkyl-O- in which the term “haloalkyl” is defined as beofore.
  • hydroxyalkyl signifies an alkyl group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by a hydroxy group.
  • hydroxyalkyl are hydroxymethyl and hydroxyethyl.
  • aryl signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more substituents, preferably one to three, each independently selected from halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO2-, amino-SO2-, cycloalkyl and the like.
  • Examples are phenyl or naphthyl, particularly phenyl optionally substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.
  • Preferred examples are phenyl or phenyl substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen and alkoxy.
  • aryloxy alone or in combination, signifies an aryl-O- group in which the term “aryl” has the previously given significance.
  • alkoxyalkyl signifies an alkyl group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an alkoxy group as defined before.
  • alkoxyalkyl are methoxymethyl and methoxyethyl.
  • alkoxycarbonyl alone or in combination, signifies an alkoxy-CO- group in which the term “alkoxy” has the previously given significance.
  • alkoxyalkoxy signifies an alkoxy group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an alkoxy group as defined before.
  • alkoxyalkoxy are methoxymethoxy and methoxyethoxy.
  • hydroxyalkoxy signifies an alkoxy group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an hydroxy group.
  • An example of hydroxyalkoxy is hydroxyethoxy.
  • heterocyclyl alone or in combination signifies a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. If desired, it can be substituted on one or more carbon atoms e.g. by halogen, alkyl, alkoxy, oxo etc. and/or on a secondary nitrogen atom (i.e.
  • alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e. N-) by oxido, with halogen, alkyl, cycloalkyl and alkoxy being preferred.
  • heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazoyl, imidazoyl (e.g.
  • Preferred are oxazolyl, thienyl, pyrazolyl, thiazolyl, 1,2,3-thiadiazolyl and pyrrolidinyl, wherein oxazolyl, thienyl, pyrazolyl, thiazolyl, 1,2,3-thiadiazolyl and pyrrolidinyl are optionally substituted with one to three substituents, preferably one or two substituents independently selected from alkyl, halogen and cyclalkyl, particularly cyclohexyl.
  • heterocyclylalkyl signifies the heterocyclyl- alkyl group, wherein the terms “heterocyclyl” and “alkyl” are as priviously defined.
  • amino signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, -NH 2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably primary amino, dimethylamino and diethylamino and particularly dimethylamino.
  • halogen alone or in combination, signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.
  • carbonyl alone or in combination, signifies the -C(O)- group.
  • aralkyl alone or in combination, signifies the aryl-alkyl group, wherein the terms “aryl” and “alkyl” are as priviously defined. Preferred is benzyl.
  • nitro alone or in combination signifies the -NO 2 group.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like.
  • the compound of formula I can also be present in the form of zwitterions.
  • a preferred pharmaceutically acceptable salt of compounds of formula I is the sodium salt.
  • the compounds of formula I can also be solvated, e.g. hydrated.
  • the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • pharmaceutically acceptable salts also includes physiologically acceptable solvates.
  • “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I) , similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • R 1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R 4 or -O-R 4 ;
  • R 2 is hydrogen, alkyl, cycloalkyl, halogen or haloalkyl
  • R 3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino and nitro;
  • R 4 is alkyl, cycloalkyl, heterocyclylalkyl or aralkyl
  • R 1 is hydrogen, methyl, halogen, thienyl or -S-R 4 .
  • Particularly preferred are those compounds of formula I, wherein R 1 is bromo.
  • R 2 is hydrogen, methyl, or halogen. Particularly preferred are those, wherein R is hydrogen. Further preferred are those compounds of formula I, wherein R 2 alkoxyalkyl, hydroxyalkyl or alkoxycarbonyl.
  • R 3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents, preferably one or two substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, dichloro-methyl-lH-pyrazolyl)oxy, methylthiazolyl, cyclohexyl-methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)-pyrrolidinyl and methoxypyridinyl.
  • R 3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents, particularly one or two substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, 3,4-dichloro- 1- methyl- lH-pyrazol-5-yl)oxy, 2-methyl-4-thiazolyl, 4-cyclohexyl-2-methyl-5-oxazolyl, oxazolyl, l,2,3-thiadiazol-4-yl, 4-methyl-5-oxazolyl, 2-methyl-l-pyrrolidinyl, 2- (methoxymethyl)-l-pyrrolidinyl, 2-(l-methylethyl)-l-pyrrolidinyl and 6-methoxypyridin- 3-yl.
  • R 3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, cyclopropyl, halogen, haloalkoxy, phenyl, difluorophenyl, methylpenyl, methoxyphenyl, methyloxazolyl and methoxypyridinyl.
  • R 3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, dichloro-methyl- IH- pyrazolyl)oxy, methylthiazolyl, cyclohexyl-methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)- pyrrolidinyl, methoxypyridinyl, 6-methoxy-4-methyl-pyridin-3-yl, alkoxy-alkyl-phen
  • R 3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, 3,4-dichloro-l-methyl-lH- pyrazol-5-yl)oxy, 2-methyl-4-thiazolyl, 4-cyclohexyl-2-methyl-5-oxazolyl, oxazolyl, 1,2,3- thiadiazol-4-yl, 4-methyl-5-oxazolyl, 2-methyl-l-pyrrolidinyl, 2-(methoxymethyl)-l- pyrrolidinyl, 2-(l-methylethyl)-l-pyrrolidinyl, 6-
  • R 4 is alkyl, alkyloxazolylmethyl or phenylmethyl. Particularly preferred are those, wherein R 4 is methyl or ((l,l-dimethylethyl)-2-oxazolyl)methyl.
  • Preferred compounds of formula I are those, wherein R 4 is haloalkyl.
  • Examples of particularly preferred compounds of formula (I) are: N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-(difluoromethoxy)benzenesulfonamide; 4-bromo-N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-chlorothiophene- 2- sulfonamide;
  • aminothiazole III was reacted with phenyl chloroformate IV in the presence of pyridine to prepare the bis-carbamate derivative V (lit.: DE 19501174) .
  • An aryl or heteroaryl sulfonamide VI was then reacted with V in the presence of base such as DBU to yield compounds of type I.
  • Phenyl sulfonyl chlorides HA were prepared from the corresponding bromide VII by first, lithium halogen exchange at low temperature in an inert solvent such as THF and trapping the lithiated species with SO 2 gas. The resultant intermediate was reacted with a chlorinating reagent such as sulfuryl chloride or N-chlorosuccinimide to prepare HA. Alternatively, an aryl amine VIII underwent diazotisation with sodium nitrite. The diazonium salt intermediate, in the presence of SO 2 gas, copper (I) chloride and in an acidic solution, underwent the Meerwein reaction to yield HA. A third method employed was the direct reaction of activated phenyl IX and chlorosulfonic acid.
  • Thiophene sulfonyl chlorides HB were prepared from thiophene prucursors X by reacting with a preformed DMF-SO 2 Cl 2 complex. Alternatively, lithiation with butyl lithium at low temperature and subsequent reaction with sulfuryl chloride also furnished compounds of type HB (Scheme 2). Scheme 2
  • a further object of the invention are the compounds according to formula I for the preparation of medicaments for the prophylaxis and/or therapy of illnesses which are caused by disorders associated with the enzyme Fructose- 1,6-bisphosphatase, preferrably Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia.
  • Fructose- 1,6-bisphosphatase preferrably Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia.
  • composition comprising a compound of formula I as described and a therapeutically inert carrier.
  • a further preferred embodiment of the invention is the use of a compound according to formula I as described for the preparation of medicaments for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia and particularly preferred for the treatment and/or prophylaxis of Diabetes Mellitus Type II or Diabetes Mellitus Type I.
  • IGF Impaired Fasting Glucose
  • ITT Impaired Glucose Tolerance
  • a further object of the present invention is a compound according to formula I, when manufactured according to any one of the described processes.
  • a method for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia which method comprises administering an effective amount of a compound of formula I as described.
  • Human liver FBPase cDNA (NM_000507) was purchased from Origene Technologies, Inc, subcloned in a vector for expression in ECoIi., and sequenced.
  • Recombinant human liver FBPase (hlFBPase) was purified according to the following protocol that uses heat denaturation similarly to that described by El-Maghrabi et. al. [El- Maghrabi,M.R. et al. "Isolation of a human liver fructose- 1,6-bisphosphatase cDNA and expression of the protein in Escherichia coli.” J Biol Chem 268:9466-9472, 1993.] .
  • E coli cells transiently expressing very high levels of soluble and active human liver FBPase, were suspended in 20 mM Tris-HCl pH 7.5, 1 mM EDTA, 1 mM DTT and were lysed by French press.
  • the soluble extract was heat denatured at 65 0 C for 5 min, and insoluble, denatured proteins were removed by centrifugation.
  • the extract was then applied to a BioRad Macro-Prep High Q column equilibrated with 20 mM Tris-HCl pH 7.5, 1 mM EDTA, 1 mM DTT and the flow-through (containing FBPase activity) was collected and applied to a BioRad Macro-Prep HS column equilibrated with 20 mM HEPES pH 7.2, 1 mM DTT. A gradient of increasing NaCl concentration was then applied to the HS column and fractions were collected.
  • Fractions containing active FBPase were pooled and further purified by size exclusion chromatography on a Sephacryl S200 column equilibrated in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM DTT. Purity of the enzyme preparation was > 90% as assessed by Mass spectrometry.
  • in vitro activity Recombinant human liver FBPase (hlFBPase) activity was assayed through measuring the inorganic phosphate release that results from the hydrolysis of Fructose- 1,6- bisphosphate by the enzyme.
  • inorganic phosphate can be readily quantified by spectrophotometry at 620 nm after complexation with ammonium molybdate/malachite green reagent.
  • Enzymatic reaction was carried out with modifications of the procedure described by Wright S.W. et al. [Wright S.W. et al., "Anilinoquinazoline inhibitors of Fructose- 1,6-bisphosphatase bind to a novel allosteric site: synthesis, in vitro characterization , and X-ray crystallography". J.Med.Chem. 45:3865- 3877, 2002] . Specifically, the reaction was carried out in 96 well plates in a final volume of 100 ⁇ l in the presence or in the absence of allosteric inhibitors.
  • Reaction was started adding 25 ng of hlFBPase to the reaction mixture containing 50 rnM HEPES-KOH buffer pH 7.2, 2mM MgCl 2 , 2mM EDTA, ImM DTT, 50 ⁇ M fructose- 1,6-bisphosphate and 1% DMSO.
  • the phosphate released was allowed to form a colored complex for 10 min by adding 150 ⁇ l of ammonium molybdate/malachite green reagent containing 0.03% malachite green, 0.2% ammonium molybdate, 0.05% Triton X-100 and 0.7 M H 2 SO 4 in water that was stirred for 30 min at room temperature and filtered through 0.2 ⁇ m filter. Under these conditions, the assay was linear with time and able to detect FBPase inhibition after spectrophotometric read-out at 620 nm.
  • Glucose lowering activity of representative compounds of the present invention was demonstrated after acute treatment in male adult and diabetic db/db mice, db/db mice ( 12-20 weeks of age) were purchased from Jackson laboratories and time- course effect of compounds on blood glucose levels was measured from tail vein samplings using fluorometric method (Glucotrend systems (Roche AG)).
  • the compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), as aerosol formulations or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula I and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsif ⁇ ers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used e.g. for the prophylaxis and/or treatment of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 0.1 mg to 100 mg per kg body weight, preferably about 0.5 mg to 10 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given above can be exceeded when this is shown to be indicated.
  • Phenyl chloroformate (1.4 ml, 11.0 mmol) was slowly added to a suspension of 5-bromo- thiazol-2-ylamine hydrobromide ( 1.3 g, 5.0 mmol) in 20 ml pyridine under an argon atmosphere. The reaction mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. The residue was suspended in water and acidified using cone. HCl to yield light brown crystals (2.3 g, 93%), m/e 419.2 (MH + ).
  • 2,6-Dimethylbiphenyl-4-sulfonyl chloride (0.147 g, 0.53 mmol, 1.4 equiv.) and pyridine (0.152 ml, 1.87 mmol, 5.0 equiv.) were added to a stirred suspension of sodium cyanate (56 mg, 0.86 mmol, 2.3 equiv.) in dry acetonitrile (1.5 ml) and the mixture stirred at room temperature for 3 hours.
  • 5-Bromo-thiazol-2-ylamine hydrobromide (97 mg, 0.38 mmol, 1.0 equiv.) was added and the reaction stirred for 1 hour. Water (2 ml) and acetic acid (3 drops) were added.
  • N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]- 5,6-dichloropyridine-3-sulfonamide (20 mg, 0.05 mmol) was dissolved in DMF (1 ml) and reacted with 2-methylpyrrolidine (0.10 ml, 1 mmol) at 5O 0 C for 2.5 hours.
  • the reaction mixture was diluted with ethyl acetate (30 ml) and washed with water, NaHCO 3 (half sat. 3x) , 5% KHSO 4 / 10% K 2 SO 4 , NaCl sat., dried (MgSO 4 .2H 2 O), filtered and concentrated under reduced pressure.
  • the crude was purified by preparative RP-HPLC: 6 mg, MS: m/e 477.9 (MH " ) .
  • 3-Ethyl-phenylamine (2.4 g, 20 mmol) was added dropwise to a stirred mixture containing HCl cone. (37%, 12 ml) and acetic acid (5 ml) at 5 0 C (ice-salt bath).
  • a solution of sodium nitrite ( 1.5 g, 22 mmol) in water (3 ml) was added dropwise at O 0 C and the resultant black slurry was further stirred at the low temperature for 30 min.
  • a copper (I) chloride (0.5 g, 5 mmol) solution in acetic acid (50 ml) was saturated with SO 2 gas .
  • N-chlorosuccinimide (1.1 g, 8.2 mmol, 1.1 equiv.) was added in one portion. After two hours stirring, the mixture is filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetone and an excess of 25% aq. ammonium hydroxide solution was added and the mixture was stirred for 30 min. at room temp. The solvent was evaporated and the remaining oil was dissolved in ethyla ceteate and extracted with water, washed with brine, dried over magnesiumsulfate dihydrate, filtered and evaporated. After purification on silica- gel with ethyl acetate/n-heptane, 210 mg of the title compound were obtained as a light brown solid. MS (ES): m/e 206.0 (M-H)
  • 1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight.
  • the reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate.
  • the pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate.
  • the aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated.
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

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Abstract

Compounds of formula (I) as well as pharmaceutically acceptable salts and esters thereof, wherein R1 to R3 have the significance given in claim 1 and which can be used in the form of pharmaceutical compositions.

Description

THIAZOLE DERIVATIVES
The present invention relates to novel compounds useful as FBPase inhibitors.
The invention is concerned particularly with compounds of formula
Figure imgf000002_0001
wherein
R1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R4 , -O-R4 or nitro;
R2 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxyalkyl, hydroxyalkyl or alkoxycarbonyl;
or R1 and R2 together with the carbon atoms to which they are attached form aryl;
R3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino, nitro, alkoxyalkyl, hydroxyalkyl, alkoxyalkoxy and hydroxyalkoxy;
R4 is alkyl, cycloalkyl, heterocyclylalkyl, aralkyl or haloalkyl;
and pharmaceutically acceptable salts and esters thereof, with the proviso that R1 and R2 are not both at the same time hydrogen and, wherein N-((2-benzothiazolylamino)carbonyl)-4-methyl-benzenesulfonamide;
N-((2-benzothiazolylamino)carbonyl)-2-methyl-benzenesulfonamide;
N-(((5,6-dimethyl-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide;
N-(((4-chloro-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide;
2-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide;
N-(((6-ethoxy-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide; and
4-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide are excluded.
The present invention relates to new chemical compounds that are inhibitors of Fructose- 1,6-bisphosphatase (FBPase), a rate-limiting enzyme of gluconeogenesis that is allosterically regulated by AMP and responsible for the hydrolysis of Fructose- 1,6- bisphosphate to Fructose-6-phosphate. Compounds of the present invention represent novel FBPase AMP site inhibitors and have valuable pharmacological properties suitable in both human and veterinary medicine.
As inhibitors of FBPase and of the production of Fructose-6-phosphate that is reversibly converted to Glucose-6-phosphate, a metabolite which represents a common precursor for diverse essentiel metabolic pathways generating glucose, glycogen, ATP, amino acids, nucleotides, NADPH and so forth, compounds of present invention have a large variety of indications related to the management of body homeostasis and the prevention of metabolic dysfunctions.
As inhibitors of FBPase and of gluconeogenesis in the liver, or in other organs capable of producing glucose like kidney or intestine, compounds of the present invention are hypoglycaemic agents and are indicated for the treatment and/or the prophylaxis of disorders of glucose homeostasis, such as Diabetes Mellitus, in particular Type II and Type I Diabetes Mellitus (NIDDM and IDDM), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) , and for the prevention of the progression of disorders of the Metabolic Syndrome (MetS, also described as Syndrome X or Insulin Resistance Syndrome) which most important components are insulin resistance (with or without IGT), obesity, dyslipidemia, hypertension, prothrombic and proinflammatory states. As such, compounds of the present invention are also indicated for the prevention and/or the treatment of diabetic complications or diabetic- associated diseases such as cardiomyopathy, macrovascular atherosclerotic disorders, including coronary, cerebrovascular and peripheral artery diseases, microvascular diseases including retinopathy, cataracts, blindness and nephropathy, neuropathy (peripheral neuropathy and sympathetic nerve disorders), diabetic necrosis, infection or depression, and so forth.
In addition, as inhibitors of FBPase that cause the accumulation of Fructose- 1,6- bisphosphate capable for increasing the glycolytic production of ATP, compounds of the present invention have cytoprotective effects as anti-ischaemic agents and are useful for preventing ischaemia- induced tissue damage. Therefore, compounds of the present invention can be used in a variety of ischaemic and inflammatory conditions where acute management of tissue injury could be beneficial such as surgical trauma, myocardial infarction, congestive heart failure, stroke, sickle cell disease, and so forth, and have further utility in cardioprotection, in improving cardiac function and tolerance to exercise, in improving red-blood cells and pulmonary endothelial functions, in organ preservation in transplants, and so forth. As such, compounds of the present invention can also be used to treat asthma attacks, hypertension, atheriosclerosis and so forth, and in the management of certain excess glycogen storage diseases such as McArdle disease (GSD-Type V) and others.
Also as inhibitors of FBPase, and thereby of the production from the gluconeogenic pathway of Fructose-6-phosphate and Glucose-6-phosphate that serve as precursors for other pathways of hexose metabolism (e.g. synthesis of amino-sugars/hexosamines that are used for the biosynthesis of glycoproteins, glycosphin go lipids or glycosaminoglycans, and uronic acid pathway that leads to glucuronate, a precursor of proteoglycans and conjugated glucuronides, and so forth), or for the pentose phosphate pathway (PPP, also called phosphogluconate pathway) which provides the carbon source for common aromatic biosynthetic pathways (nucleotides and amino-acids synthesis) and generates NADPH for reductive biosyn theses (lipogenesis, steroidogenesis), compounds of the present invention can have further utility in the prevention and/or the management of a large set of diseases including obesity, atherosclerosis, inflammation, Alzheimer disease, cancer or respiratory disorders such as excess mucus production and allergic asthma, excess surfactant synthesis, cystic fibrosis, and so forth.
Furthermore, compounds of the present invention can be used in any disease, syndrome, symptom or organ malfunction found associated with increased expression and/or activity of one or another FBPase isoform, at the obvious exception of certain deficiencies where FBPase upregulation might be beneficial for ensuring normal body function, e.g. certain glycogen storage diseases, such as GSD-Type 0 (glycogen synthase deficiency) .
The compounds of formula I and their pharmaceutically acceptable salts and esters are novel and have valuable pharmacological properties. In particular they are FBPase inhibitors and can be used in the prophylaxis and/or treatment of Diabetes Mellitus such as Type I, Type II and Type III Diabetes, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), Metabolic Syndrome, insulin resistance, dyslipidemia, obesity, hypertension, atherosclerosis, diabetic complications, inflammation, respiratory diseases or ischaemia. Preferred is the prophylaxis and/or prevention of progression and/or treatment of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III,
Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), Metabolic Syndrome, diabetic complications and ischaemia. Particularly preferred is the prophylaxis and/or treatment of Diabetes Mellitus Type II and Diabetes Mellitus Type I.
Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts and esters, the use of the said compounds, esters and salts for the prophylaxis and/or therapy of illnesses, especially in the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia, particularly Diabetes Mellitus Type II and Diabetes Mellitus Type I
The compounds of the present invention can be combined with one or more additional active substances indicated for the management of human and veterinary homeostasis in any suitable ratio. Such substances may be insulin sensitizers such as peroxisome proliferator- activated receptor modulators (PPAR alpha, gamma, delta agonists, particularly with thiazolinediones such as rosiglitazone and pioglitazone), insulin secretagogues (sulfonylureas such as glyburide, glimepiride and glipizide, and non- sulfonylurea secretagogues such as the meglitinides repaglinide and nateglinide), insulin, metformin, alpha- glucosidase inhibitors (e.g. acarbose, miglitol), glucagon-like peptide (GLP-I) analogues (e.g. exenatide), dipeptidyl peptidase- IV (DPP-IV) inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase-3 inhibitors, llβ-hydroxysteroid dehydrogenase- 1 inhibitors, carnitine palmitoyltranferase- 1 inhibitors, glucocorticoid receptor antagonists, glucagon receptor antagonists, Adenosine (A2B) receptor agonists, amylin agonists (e.g. pramlintide), lipase inhibitor (e.g. orlistat), or any other synthetic or natural substance presenting valuable pharmacological properties useful for the treatment and /or the prevention of metabolic dysfunctions.
In the present description the term "alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms Examples of straight- chain and branched Ci-Cs alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl and most preferred methyl.
The term "cycloalkyl", alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C3-Cs cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl- cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl- cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.
The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, preferably methoxy and ethoxy and most preferred methoxy.
The term "haloalkyl", alone or in combination, signifies an alkyl group as previously defined, wherein one to five hydrogen atoms are substituted by halogen, preferably fluoro. Preferred examples are pentafluoroethyl and particularly trifluoromethyl and difluoromethyl.
The term "haloalkoxy", alone or in combination, signifies a group of the formula haloalkyl-O- in which the term "haloalkyl" is defined as beofore.
The term "hydroxyalkyl", alone or in combination, signifies an alkyl group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by a hydroxy group. Examples of hydroxyalkyl are hydroxymethyl and hydroxyethyl.
The term "aryl", alone or in combination, signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more substituents, preferably one to three, each independently selected from halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO2-, amino-SO2-, cycloalkyl and the like. Examples are phenyl or naphthyl, particularly phenyl optionally substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl. Preferred examples are phenyl or phenyl substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen and alkoxy.
The term "aryloxy", alone or in combination, signifies an aryl-O- group in which the term "aryl" has the previously given significance.
The term "alkoxyalkyl", alone or in combination, signifies an alkyl group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an alkoxy group as defined before. Examples of alkoxyalkyl are methoxymethyl and methoxyethyl.
The term "alkoxycarbonyl", alone or in combination, signifies an alkoxy-CO- group in which the term "alkoxy" has the previously given significance.
The term "alkoxyalkoxy", alone or in combination, signifies an alkoxy group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an alkoxy group as defined before. Examples of alkoxyalkoxy are methoxymethoxy and methoxyethoxy.
The term "hydroxyalkoxy", alone or in combination, signifies an alkoxy group as defined before, wherein one or more hydrogen atoms, preferably one hydrogen atom is replaced by an hydroxy group. An example of hydroxyalkoxy is hydroxyethoxy.
The term "heterocyclyl", alone or in combination signifies a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. If desired, it can be substituted on one or more carbon atoms e.g. by halogen, alkyl, alkoxy, oxo etc. and/or on a secondary nitrogen atom (i.e. -NH-) by alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e.= N-) by oxido, with halogen, alkyl, cycloalkyl and alkoxy being preferred. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazoyl, imidazoyl (e.g. imidazol-4-yl and 1-benzyloxycarbonyl- imidazol-4-yl), pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, indolyl (e.g. 2- indolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl and l-oxido-2-quinolyl), isoquinolyl (e.g. 1- isoquinolyl and 3-isoquinolyl), tetrahydroquinolyl, 1, 2,3,4- tetrahydroisoquinolyl and quinoxalinyl. Preferred are oxazolyl, thienyl, pyrazolyl, thiazolyl, 1,2,3-thiadiazolyl and pyrrolidinyl, wherein oxazolyl, thienyl, pyrazolyl, thiazolyl, 1,2,3-thiadiazolyl and pyrrolidinyl are optionally substituted with one to three substituents, preferably one or two substituents independently selected from alkyl, halogen and cyclalkyl, particularly cyclohexyl.
The term "heterocyclylalkyl", alone or in combination, signifies the heterocyclyl- alkyl group, wherein the terms "heterocyclyl" and "alkyl" are as priviously defined.
The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, -NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably primary amino, dimethylamino and diethylamino and particularly dimethylamino.
The term "halogen", alone or in combination, signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.
The term "carbonyl", alone or in combination, signifies the -C(O)- group.
The term "aralkyl", alone or in combination, signifies the aryl-alkyl group, wherein the terms "aryl" and "alkyl" are as priviously defined. Preferred is benzyl.
The term "oxy", alone or in combination, signifies the -O- group.
The term "hydroxy", alone or in combination signifies the group -OH.
The term "nitro", alone or in combination signifies the -NO2 group.
The term "cyano", alone or in combination signifies the group -CN.
The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like. The compound of formula I can also be present in the form of zwitterions. A preferred pharmaceutically acceptable salt of compounds of formula I is the sodium salt.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also includes physiologically acceptable solvates.
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I) , similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
Preferred are the compounds of formula I and pharmaceutically acceptable salts thereof, particularly the compounds of formula I.
Further preferred are the ompounds of formula
Figure imgf000009_0001
(l) wherein
R1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R4 or -O-R4;
R2 is hydrogen, alkyl, cycloalkyl, halogen or haloalkyl;
or R1 and R2 together with the carbon atoms to which they are attached form aryl;
R3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino and nitro;
R4 is alkyl, cycloalkyl, heterocyclylalkyl or aralkyl;
and pharmaceutically acceptable salts and esters thereof, with the proviso that R1 and R2 are not both at the same time hydrogen and, wherein
N-((2-benzothiazolylamino)carbonyl)-4-methyl-benzenesulfonamide;
N-((2-benzothiazolylamino)carbonyl)-2-methyl-benzenesulfonamide;
N-(((5,6-dimethyl-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide;
N-(((4-chloro-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide;
2-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide;
N-(((6-ethoxy-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide; and
4-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide are excluded.
Further preferred are compounds of formula I, wherein R1 is hydrogen, methyl, halogen, thienyl or -S-R4. Particularly preferred are those compounds of formula I, wherein R1 is bromo.
Also preferred are those compounds according to formula I, wherein R1 is nitro.
Moreover, preferred are the compounds of formula I, wherein R2 is hydrogen, methyl, or halogen. Particularly preferred are those, wherein R is hydrogen. Further preferred are those compounds of formula I, wherein R2 alkoxyalkyl, hydroxyalkyl or alkoxycarbonyl.
Additionally preferred are the compounds of formula I, wherein R1 and R2 together with the carbon atoms to which they are attached form phenyl.
Another preferred aspect of the present invention are compounds according to formula I, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents, preferably one or two substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, dichloro-methyl-lH-pyrazolyl)oxy, methylthiazolyl, cyclohexyl-methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)-pyrrolidinyl and methoxypyridinyl.
Further preferred are those compounds according to formula I, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents, particularly one or two substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, 3,4-dichloro- 1- methyl- lH-pyrazol-5-yl)oxy, 2-methyl-4-thiazolyl, 4-cyclohexyl-2-methyl-5-oxazolyl, oxazolyl, l,2,3-thiadiazol-4-yl, 4-methyl-5-oxazolyl, 2-methyl-l-pyrrolidinyl, 2- (methoxymethyl)-l-pyrrolidinyl, 2-(l-methylethyl)-l-pyrrolidinyl and 6-methoxypyridin- 3-yl.
Particularly preferred are the compounds of formula I, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, cyclopropyl, halogen, haloalkoxy, phenyl, difluorophenyl, methylpenyl, methoxyphenyl, methyloxazolyl and methoxypyridinyl.
Further preferred are compounds of formula I, wherein R3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, dichloro-methyl- IH- pyrazolyl)oxy, methylthiazolyl, cyclohexyl-methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)- pyrrolidinyl, methoxypyridinyl, 6-methoxy-4-methyl-pyridin-3-yl, alkoxy-alkyl-phenyl, alkoxypyridinyl, fluoropyridinyl and methoxy-thiazolyl. Particularly preferred are compounds of formula I, wherein R3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, 3,4-dichloro-l-methyl-lH- pyrazol-5-yl)oxy, 2-methyl-4-thiazolyl, 4-cyclohexyl-2-methyl-5-oxazolyl, oxazolyl, 1,2,3- thiadiazol-4-yl, 4-methyl-5-oxazolyl, 2-methyl-l-pyrrolidinyl, 2-(methoxymethyl)-l- pyrrolidinyl, 2-(l-methylethyl)-l-pyrrolidinyl, 6-methoxypyridin-3-yl, 6-methoxy-4- methylpyridin-3-yl, 4-methoxy-2-methylphenyl, methoxy-pyridinyl, 5-isobutyl-4- methylthiophenyl, 6-fluoropyridin-3-yl, 5-fluoropyridin-3-yl and 2-methoxy-l,3-thiazol- 4-yl.
Another preferred aspect of the present invention are the compounds of formula I, wherein R4 is alkyl, alkyloxazolylmethyl or phenylmethyl. Particularly preferred are those, wherein R4 is methyl or ((l,l-dimethylethyl)-2-oxazolyl)methyl.
Preferred compounds of formula I are those, wherein R4 is haloalkyl.
Examples of preferred compounds of formula (I) are:
1. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]- 3(difluoromethoxy)benzenesulfonamide;
2. 4-bromo-N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chlorothiophene-2- sulfonamide;
3. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-dichlorobenzenesulfonamide;
4. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-3-methylbenzenesulfonamide;
5. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
6. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl] -2' ,4'-difluorobiphenyl-4- sulfonamide;
7. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide;
8. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-4,5-dichlorothiophene- 2- sulfonamide;
9. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-chlorophenoxy)- benzenesulfonamide; 10. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-dimethylbenzenesulfonamide;
11. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-[(3,4-dichloro-l-methyl-lH-pyrazol- 5-yl) oxy] benzenesulfonamide;
12. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methyl-l,3-thiazol-4- yl)benzenesulfonamide;
13. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-methylthiophene- 2- sulfonamide;
14. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-phenylthiophene- 2- sulfonamide;
15. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]biphenyl-4- sulfonamide;
16. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-chlorothiophene- 2- sulfonamide;
17. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-fluorobenzenesulfonamide;
18. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-methoxybenzenesulfonamide;
19. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-2,5-dichlorothiophene-3-sulfonamide;
20. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-difluorobenzenesulfonamide;
21. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-methoxybenzenesulfonamide;
22. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chlorobenzenesulfonamide;
23. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-cyclohexyl-2-methyl-l,3-oxazol- 5-yl)-2-fluorobenzenesulfonamide;
24. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methoxyphenoxy)- benzenesulfonamide;
25. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-nitrobenzenesulfonamide;
26. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,3-oxazol-5- yl)benzenesulfonamide;
27. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-difluorobenzenesulfonamide; 28. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-fluorobenzenesulfonamide;
29. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-methylbenzenesulfonamide;
30. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-ethylbenzenesulfonamide;
31. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide;
32. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,2,3-thiadiazol-4- yl)benzenesulfonamide;
33. N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-(trifluoromethoxy)- benzenesulfonamide;
34. N-[(5-{[(5-tert-butyl-l,3-oxazol-2-yl)methyl]thio}-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide;
35. 3-methyl-N-{[5-(2-thienyl)- 1,3-thiazo 1- 2- yl] carbamoyl Jbenzenesulfonamide;
36. N-[(4-chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
37. N- {[5-(benzylthio)- 1,3-thiazo 1- 2- yl] carbamoyl }-3-methylbenzenesulfonamide;
38. N-(l,3-benzothiazol-2-ylcarbamoyl)-3-methylbenzenesulfonamide;
39. N- [(4,5-dimethyl- 1,3-thiazo 1- 2- yl)carbamoyl]-3-methylbenzenesulfonamide;
40. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-2-ethyl-2'-methylbiphenyl-4- sulfonamide;
41. N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-ethylbiphenyl-4- sulfonamide;
42. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-2-ethyl-3'-methylbiphenyl-4- sulfonamide;
43. N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2,6-dimethylbiphenyl-4- sulfonamide;
44. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-methyl-l,3-oxazol-5- yl)benzenesulfonamide; 45. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-(2-methylpyrrolidin-l- yl)pyridine-3-sulfonamide;
46. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-[(2S)-2- (methoxymethyl)pyrrolidin-l-yl]pyridine-3-sulfonamide;
47. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-(2-isopropylpyrrolidin-l- yl)pyridine-3-sulfonamide;
48. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-ethylbenzenesulfonamide;
49. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-isopropylbenzenesulfonamide;
50. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxyphenyl)thiophene-2- sulfonamide;
51. N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-isobutylthiophene- 2- sulfonamide;
52. N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-5-(4-methoxyphenyl)-4-methyl- thiophene- 2- sulfonamide;
53. N-[(5-Chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
54. 3-Chloro-N-{[5-(methylthio)- 1,3-thiazo 1- 2- yl] carbamoyl Jbenzenesulfonamide;
55. N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl] -3- cyclopropyl-benzenesulfonamide;
56. N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-chlorobenzenesulfonamide; and
57. N- [(5-Bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-(6-methoxypyridin-3-yl)-4- methylthiophene- 2- sulfonamide.
Examples of particularly preferred compounds of formula (I) are: N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-(difluoromethoxy)benzenesulfonamide; 4-bromo-N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-chlorothiophene- 2- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3,4-dichlorobenzenesulfonamide; N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-3-methylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl] -2' ,4'-difluorobiphenyl-4- sulfonamide;
N-[(5-{[(5-tert-butyl-l,3-oxazol-2-yl)methyl]thio}-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-2-ethyl-2'-methylbiphenyl-4- sulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-2-ethylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-4-(4-methyl-l,3-oxazo 1-5- yl)benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-ethylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxyphenyl)thiophene-2- sulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-isobutylthiophene- 2- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-5-(4-methoxyphenyl)-4-methyl- thiophene-2-sulfonamide;
N-[(5-chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
3-chloro-N-{[5-(methylthio)- 1,3-thiazo 1- 2- yl] carbamoyl Jbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3- cyclopropyl-benzenesulfonamide and
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-(6-methoxypyridin-3-yl)-4- methylthiophene- 2- sulfonamide.
Further preferred compounds according to formula I are
58. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-5-(2- methoxyethyl)thiophene- 2- sulfonamide; 59. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxy-2-methylphenyl)-4- methylthiophene- 2- sulfonamide;
60. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-methoxypyridin-3-yl)-3- methylbenzenesulfonamide;
61. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-isobutyl-4-methylthiophene-2- sulfonamide;
62. 3-methyl-N-({4-methyl-5-[(trifluoromethyl)thio]-l,3-thiazol-2- yl}carbamoyl)benzenesulfonamide;
63. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethyl)-4- methylthiophene- 2- sulfonamide;
64. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-fluoropyridin-3-yl)-3- methylbenzenesulfonamide;
65. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-fluoropyridin-3-yl)-4- methylthiophene- 2- sulfonamide;
66. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-chloro-4-fluorobenzenesulfonamide;
67. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(3-methoxypropyl)-4- methylthiophene- 2- sulfonamide;
68. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methoxy-l,3-thiazol-4-yl)-3- methylbenzenesulfonamide;
69. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(5-fluoropyridin-3-yl)-3- methylbenzenesulfonamide;
70. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-methoxy-4-methylthiophene-2- sulfonamide; 71. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethoxy)-4- methylthiophene- 2- sulfonamide;
72. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxy-4-methylpyridin-3-yl)-4- methylthiophene-2-sulfonamide;
73. N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(methoxymethyl)-4- methylthiophene- 2- sulfonamide;
74. N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide;
75. N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- (difluoromethoxy)benzenesulfonamide;
76. 3-methyl-N-[(4-methyl-5-nitro-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide;
77. N- {[5-bromo-4-(methoxymethyl)-l,3-thiazo 1-2- yl] carbamoyl }-3- methylbenzenesulfonamide;
78. ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl] carbamoyl }amino)-l,3-thiazole-4- carboxylate;
79. N-[(5-methoxy-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide; and
80. N- {[5-bromo-4-(hydroxymethyl)-l,3-thiazo 1-2- yl] carbamoyl }-3- methylbenzenesulfonamide.
Further particularly preferred compounds of formula I are
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-isobutyl-4-methylthiophene- 2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-fluoropyridin-3-yl)-3- methylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(3-methoxypropyl)-4-methylthiophene-2- sulfonamide; N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethoxy)-4-methylthiophene-2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxy-4-methylpyridin-3-yl)-4- methylthiophene- 2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(methoxymethyl)-4-methylthiophene-2- sulfonamide;
N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- (difluoromethoxy)benzenesulfonamide;
ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl] carbamoyl }amino)-l,3-thiazole-4- carboxylate; and
N-[(5-methoxy-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide.
Processes for the manufacture of compounds of formula I are an object of the invention.
The preparation of compounds of formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following Schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given above unless indicated to the contrary.
Compounds of formula I can be prepared as shown in in Schemes 1-2 and in the preparative examples 1 -55. The starting material of formula II are known compounds or may be prepared by methods well known in the art. Sulfonylurea derivatives of aminothiazoles III were mainly prepared by approaches described in Scheme 1. An aryl or heteroaryl sulfonyl chloride derivative II was converted to an intermediate isocyanate complex following reaction with sodium cyanate in pyridine (lit.: USP 5,550,238). The intermediate was directly reacted with aminothiazoles III to yield inhibitors I. Alternatively, aminothiazole III was reacted with phenyl chloroformate IV in the presence of pyridine to prepare the bis-carbamate derivative V (lit.: DE 19501174) . An aryl or heteroaryl sulfonamide VI was then reacted with V in the presence of base such as DBU to yield compounds of type I.
Scheme 1
Figure imgf000020_0001
V
Phenyl sulfonyl chlorides HA were prepared from the corresponding bromide VII by first, lithium halogen exchange at low temperature in an inert solvent such as THF and trapping the lithiated species with SO2 gas. The resultant intermediate was reacted with a chlorinating reagent such as sulfuryl chloride or N-chlorosuccinimide to prepare HA. Alternatively, an aryl amine VIII underwent diazotisation with sodium nitrite. The diazonium salt intermediate, in the presence of SO2 gas, copper (I) chloride and in an acidic solution, underwent the Meerwein reaction to yield HA. A third method employed was the direct reaction of activated phenyl IX and chlorosulfonic acid. Thiophene sulfonyl chlorides HB were prepared from thiophene prucursors X by reacting with a preformed DMF-SO2Cl2 complex. Alternatively, lithiation with butyl lithium at low temperature and subsequent reaction with sulfuryl chloride also furnished compounds of type HB (Scheme 2). Scheme 2
SOoCL
Figure imgf000021_0002
Figure imgf000021_0001
VI I NA
Figure imgf000021_0003
VIII NA
Figure imgf000021_0004
IX NA
Figure imgf000021_0005
X NB
A preferred process for the preparation of a compound of formula
Figure imgf000021_0006
as described before comprises one of the following reactions, wherein R1 to R3 are defined as before
a) reaction of a compound according to formula
R3 -SO2CI in the presence of NaOCN and a compound of formula
Figure imgf000022_0001
in order to obtain a compound of formula I. Particularly preferred are those reactions according to a) wherein the reaction is performed in the presence of pyridine; or
b) reaction of a compound according to formula
Figure imgf000022_0002
in the presence of a compound of formula
R3SO2NH2 Vl
in order to obtain a compound according to formula I. Particularly preferred are those reactions according to b) wherein the reaction is performed in the presence of a base such as e.g. DBU (l,8-diazabicyclo[5.4.0]undec-7-ene).
Preferred intermediates are:
4-(4-cyclohexyl-2-methyl-oxazol-5-yl)-2-fluoro-benzenesulfonamide;
2-eth yl-2'-methyl-biphenyl-4- su lfonyl chloride;
2-ethyl-biphenyl-4-sulfonyl chloride;
2,6-dimethyl-biphenyl-4- su lfonyl chloride;
4-(4-methyl-oxazol-5-yl)-benzenesu lfonyl chloride;
3-ethyl-benzenesu lfonyl chloride;
3-isopropyl-benzenesu lfonyl chloride;
3-cyclopropyl-benzenesulfonyl chloride;
5-isobutyl-thiophene- 2- su lfonyl chloride; 5-(4-methoxy-phenyl)-thiophene-2-sulfonyl chloride;
5-(4-methoxy-phen yl)-4-methyl-thiophene- 2- su lfonyl chloride;
5-(6-methoxy-pyridin-3-yl)-4-meth yl-thiophene- 2- su lfonyl chloride and
5-(6-methoxy-pyridin-3-yl)-4-methyl-thiophene- 2- sulfonic acid amide. The compounds of formula I as described above for use as therapeutically active substance are a further object of the invention.
A further object of the invention are the compounds according to formula I for the preparation of medicaments for the prophylaxis and/or therapy of illnesses which are caused by disorders associated with the enzyme Fructose- 1,6-bisphosphatase, preferrably Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia.
Likewise preferred is a pharmaceutical composition comprising a compound of formula I as described and a therapeutically inert carrier.
A further preferred embodiment of the invention is the use of a compound according to formula I as described for the preparation of medicaments for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia and particularly preferred for the treatment and/or prophylaxis of Diabetes Mellitus Type II or Diabetes Mellitus Type I.
A further object of the present invention is a compound according to formula I, when manufactured according to any one of the described processes.
Likewise preferred is a method for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia, which method comprises administering an effective amount of a compound of formula I as described. Preferred is this method for the treatment and/or prophylaxis of Diabetes Mellitus Type II or Diabetes Mellitus Type I. Assay Procedures
FBPase assay description:
The following tests were carried out for evaluating the inhibitory activity of the compounds of the present invention against human liver FBPase (Swissprot Data base reference PO9467, entry F16P_HUMAN).
Enzyme preparation: Human liver FBPase cDNA (NM_000507) was purchased from Origene Technologies, Inc, subcloned in a vector for expression in ECoIi., and sequenced. Recombinant human liver FBPase (hlFBPase) was purified according to the following protocol that uses heat denaturation similarly to that described by El-Maghrabi et. al. [El- Maghrabi,M.R. et al. "Isolation of a human liver fructose- 1,6-bisphosphatase cDNA and expression of the protein in Escherichia coli." J Biol Chem 268:9466-9472, 1993.] . Briefly, E coli cells, transiently expressing very high levels of soluble and active human liver FBPase, were suspended in 20 mM Tris-HCl pH 7.5, 1 mM EDTA, 1 mM DTT and were lysed by French press. The soluble extract was heat denatured at 650C for 5 min, and insoluble, denatured proteins were removed by centrifugation. The extract was then applied to a BioRad Macro-Prep High Q column equilibrated with 20 mM Tris-HCl pH 7.5, 1 mM EDTA, 1 mM DTT and the flow-through (containing FBPase activity) was collected and applied to a BioRad Macro-Prep HS column equilibrated with 20 mM HEPES pH 7.2, 1 mM DTT. A gradient of increasing NaCl concentration was then applied to the HS column and fractions were collected. Fractions containing active FBPase were pooled and further purified by size exclusion chromatography on a Sephacryl S200 column equilibrated in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM DTT. Purity of the enzyme preparation was > 90% as assessed by Mass spectrometry.
In vitro activity: Recombinant human liver FBPase (hlFBPase) activity was assayed through measuring the inorganic phosphate release that results from the hydrolysis of Fructose- 1,6- bisphosphate by the enzyme. As described by Baykov A.A. et al. in [Baykov A.A et al., "Malachite Green procedure for orthophosphate determination and its use in alkaline phosphatase-based enzyme immunoassays". Anal. Biochem., 171:266-270, 1988], inorganic phosphate can be readily quantified by spectrophotometry at 620 nm after complexation with ammonium molybdate/malachite green reagent. Enzymatic reaction was carried out with modifications of the procedure described by Wright S.W. et al. [Wright S.W. et al., "Anilinoquinazoline inhibitors of Fructose- 1,6-bisphosphatase bind to a novel allosteric site: synthesis, in vitro characterization , and X-ray crystallography". J.Med.Chem. 45:3865- 3877, 2002] . Specifically, the reaction was carried out in 96 well plates in a final volume of 100 μl in the presence or in the absence of allosteric inhibitors. Reaction was started adding 25 ng of hlFBPase to the reaction mixture containing 50 rnM HEPES-KOH buffer pH 7.2, 2mM MgCl2, 2mM EDTA, ImM DTT, 50 μM fructose- 1,6-bisphosphate and 1% DMSO. After 50 minutes incubation at room temperature, the phosphate released was allowed to form a colored complex for 10 min by adding 150 μl of ammonium molybdate/malachite green reagent containing 0.03% malachite green, 0.2% ammonium molybdate, 0.05% Triton X-100 and 0.7 M H2SO4 in water that was stirred for 30 min at room temperature and filtered through 0.2 μm filter. Under these conditions, the assay was linear with time and able to detect FBPase inhibition after spectrophotometric read-out at 620 nm.
Results obtained in the assay above using representative compounds of the invention as the test compounds are shown in the following table:
Figure imgf000025_0001
Compounds as described above have IC50 values of 1.0 μM to 1 nM; preferred compounds have IC50 values of 500 to 1 nM. More preferred compounds have IC50 values of 200 to 1 nM. These results have been obtained by using the foregoing test.
In vivo activity: Glucose lowering activity of representative compounds of the present invention was demonstrated after acute treatment in male adult and diabetic db/db mice, db/db mice ( 12-20 weeks of age) were purchased from Jackson laboratories and time- course effect of compounds on blood glucose levels was measured from tail vein samplings using fluorometric method (Glucotrend systems (Roche AG)).
The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), as aerosol formulations or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The compounds of formula I and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifϊers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically acceptable salts can be used e.g. for the prophylaxis and/or treatment of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 100 mg per kg body weight, preferably about 0.5 mg to 10 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given above can be exceeded when this is shown to be indicated.
The invention is illustrated hereinafter by Examples, which have no limiting character.
Examples Example 1
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-(difluoromethoxy)benzenesulfonamide
The title compound, MS: m/e 429.9 (MH+), was prepared analogously to the procedure described for Example 2, using 3-difluoromethoxy-benzenesulfonyl chloride.
δH (400 MHz; d6-dimethylsulfoxide) 7.84 (IH, d), 7.69-7.73 (2H, m), 7.50-7.54 (2H, m), 7.36 (IH, t)
Example 2
4-Bromo-N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chlorothiophene-2-sulfonamide
4-Bromo-5-chloro-thiophene-2-sulfonyl chloride (0.44 g, 1.50 mmol) and pyridine (0.27 ml, 3.40 mmol) were added to a stirred suspension of sodium cyanate (0.14 g, 2.20 mmol) in dry acetonitrile ( 1 ml) and the mixture stirred at room temperature for 4 hours. 5- Bromo-thiazol-2-ylamine hydrobromide (0.26 g, 1.00 mmol) was added and the reaction stirred for 30 minutes. Water (2 ml) and acetic acid (3 drops) were added. The resulting precipitate was filtered and the solid was washed with water, cold methanol and diethyl ether. The solid was dried under reduced pressure to give 4-bromo-N-[(5-bromo-l,3- thiazo 1- 2- yl)carbamoyl]-5-chlorothiophene- 2- sulfonamide, 0.29 g (60%), m/e 477.8 (MH").
Example 3
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-dichlorobenzenesulfonamide
The title compound, MS: m/e 427.9 (MH"), was prepared analogously to the procedure described for Example 2, using 3,4-dichloro-benzenesulfonyl chloride.
Example 4
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-3-methylbenzenesulfonamide
The title compound, MS: m/e 411.9 (MH+), was prepared analogously to the procedure described for Example 2, using 4-chloro-3-methyl-benzenesulfonyl chloride.
Example 5 N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
The title compound, MS: m/e 374.0 (MH"), was prepared analogously to the procedure described for Example 2, using 3-methyl-benzenesulfonyl chloride.
Example 6
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2',4'-difluorobiphenyl-4-sulfonamide
The title compound, MS: m/e 475.9 (MH+), was prepared analogously to the procedure described for Example 2, using 2',4'-difluoro-biphenyl-4-sulfonyl chloride.
Example 7
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide
The title compound, MS: m/e 393.9 (MH"), was prepared analogously to the procedure described for Example 2, using 3-chloro-benzenesulfonyl chloride.
Example 8
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4,5-dichlorothiophene-2-sulfonamide
The title compound was prepared analogously to the procedure described for Example 2, using 4,5-dichloro-thiophene-2-sulfonyl chloride: δH (400 MHz; dό-dimethylsulfoxide) 7.67 (IH, s), 7.46 (IH, s)
Example 9
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-chlorophenoxy)benzenesulfonamide
The title compound, MS: m/e 486.0 (MH"), was prepared analogously to the procedure described for Example 2, using 4-(2-chloro-phenoxy)-benzenesulfonyl chloride.
Example 10
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-dimethylbenzenesulfonamide
The title compound, MS: m/e 388.0 (MH"), was prepared analogously to the procedure described for Example 2, using 3,5-dimethyl-benzenesulfonyl chloride.
Example 11 N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-[(3,4-dichloro-l-methyl-lH-pyrazol-5- yl)oxy]benzenesulfonamide
i) diphenyl (5-bromo-l,3-thiazol-2-yl)imidodicarbonate
Phenyl chloroformate (1.4 ml, 11.0 mmol) was slowly added to a suspension of 5-bromo- thiazol-2-ylamine hydrobromide ( 1.3 g, 5.0 mmol) in 20 ml pyridine under an argon atmosphere. The reaction mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. The residue was suspended in water and acidified using cone. HCl to yield light brown crystals (2.3 g, 93%), m/e 419.2 (MH+).
ii) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-4-r(3,4-dichloro-l-methyl-lH-pyrazol-5- yl) oxyl benzenesulfonamide
4-(4,5-dichloro-2-methyl-2H-pyrazol-3-yloxy)-benzenesulfonamide (77.3 mg, 0.24 mmol) and diphenyl (5-bromo-l,3-thiazol-2-yl)imidodicarbonate (lOOmg, 0.24 mmol) were suspended in DMF (0.4 ml). A solution of DBU (0.04 ml, 0.26 mmol) in DMF (0.1 ml) was added drop wise and the clear mixture was shaken for 1.5 h at rt and kept overnight at 4 0C. The mixture was acidified using acetic acid (0.2 ml) and diluted with water (0.2 ml) and purified directly using preparative RP(Ci8)chromatography: lyophilisate 9 mg , MS: m/e 523.8 (MH").
Example 12
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methyl-l,3-thiazol-4- yl)benzenesulfonamide
The title compound, MS: m/e 457.1 (MH"), was prepared analogously to the procedure described for Example 2, using 4-(2-methyl-thiazol-4-yl)-benzenesulfonyl chloride.
Example 13
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-methylthiophene-2-sulfonamide
The title compound, MS: m/e 380.0 (MH+), was prepared analogously to the procedure described for Example 2, using 5-methyl-thiophene-2-sulfonyl chloride.
Example 14
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-phenylthiophene-2-sulfonamide The title compound, MS: m/e 445.7 (MH+), was prepared analogously to the procedure described for Example 2, using 5-phenyl-thiophene-2-sulfonyl chloride.
Example 15
N- [(5-Bromo-l,3-thiazol- 2- yl)carbamoyl]biphenyl-4- sulfonamide
The title compound, MS: m/e 436.0 (MH"), was prepared analogously to the procedure described for Example 2, using biphenyl-4-sulfonyl chloride.
Example 16
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-chlorothiophene-2-sulfonamide
The title compound, MS: m/e 399.9 (MH"), was prepared analogously to the procedure described for Example 2, using 5-chloro-thiophene-2-sulfonyl chloride.
Example 17
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-fluorobenzenesulfonamide
The title compound, MS: m/e 378.0 (MH"), was prepared analogously to the procedure described for Example 2, using 3-fluoro-benzenesulfonyl chloride.
Example 18
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-methoxybenzenesulfonamide
The title compound, MS: m/e 389.9 (MH"), was prepared analogously to the procedure described for Example 2, using 3-methoxy-benzenesulfonyl chloride.
Example 19
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2,5-dichlorothiophene-3-sulfonamide
The title compound, MS: m/e 437.6 (MH+), was prepared analogously to the procedure described for Example 2, using 2,5-dichloro-thiophene-3-sulfonyl chloride.
Example 20
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-difluorobenzenesulfonamide The title compound, MS: m/e 395.9 (MH"), was prepared analogously to the procedure described for Example 2, using 3,4-difluoro-benzenesulfonyl chloride.
Example 21
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-methoxybenzenesulfonamide
The title compound, MS: m/e 389.9 (MH"), was prepared analogously to the procedure described for Example 2, using 4-methoxy-benzenesulfonyl chloride.
Example 22
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-chlorobenzenesulfonamide
The title compound, MS: m/e 394.0 (MH"), was prepared analogously to the procedure described for Example 2, using 4-chloro-benzenesulfonyl chloride.
Example 23
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-cyclohexyl-2-methyl-l,3-oxazol-5-yl)-2- fluorobenzenesulfonamide
The title compound, MS: m/e 541.0 (MH"), was prepared analogously to the procedure described for Example 11, using 4-(4-cyclohexyl-2-methyl-oxazol-5-yl)-2-fluoro- benzenesulfonamide.
Example 24
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methoxyphenoxy)benzenesulfonamide
The title compound, MS: m/e 482.1 (MH"), was prepared analogously to the procedure described for Example 2, using 4-(2-methoxy-phenoxy)-benzenesulfonyl chloride.
Example 25
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-nitrobenzenesulfonamide
The title compound, MS: m/e 405 (MH+), was prepared analogously to the procedure described for Example 2, using 3-nitro-benzenesulfonyl chloride.
Example 26 N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,3-oxazol-5-yl)benzenesulfonamide
The title compound, MS: m/e 429.1 (MH"), was prepared analogously to the procedure described for Example 2, using 4-oxazol-5-yl-benzenesulfonyl chloride.
Example 27
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-difluorobenzenesulfonamide
The title compound, MS: m/e 395.9 (MH+), was prepared analogously to the procedure described for Example 2, using 3,5-difluoro-benzenesulfonyl chloride.
Example 28
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-fluorobenzenesulfonamide
The title compound, MS: m/e 378.0 (MH"), was prepared analogously to the procedure described for Example 2, using 4-fluoro-benzenesulfonyl chloride.
Example 29
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-methylbenzenesulfonamide
A solution of toluene-4- sulfonylurea isocyanate (2.6 g, 13 mmol) in CH2Cl2 (10 ml) was added slowly to a mixture containing 2-amino-5-bromothiazole hydrochloride (3.4 g, 13 mmol) and triethylamine (5.4 ml, 39 mmol) in CH2Cl2 (60 ml) under an argon atmosphere and stirred overnight at rt. The reaction mixture was concentrated under reduce pressure, diluted with ethyl acetate and washed with NaHCO3 (half sat. 3x), 5% KHSO4/ 10% K2SO4, water, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. Recrystallization from MeOH/water yielded a beige solid: 2.8 g (58%), MS: m/e 376.1 (MH+).
Example 30
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-ethylbenzenesulfonamide
The title compound, MS: m/e 390.1(MH"), was prepared analogously to the procedure described for Example 2, using 4-ethyl-benzenesulfonyl chloride.
Example 31 N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide
The title compound, MS: m/e 359.9 (MH"), was prepared analogously to the procedure described for Example 2, using benzenesulfonyl chloride.
Example 32
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,2,3-thiadiazol-4-yl)benzenesulfonamide
The title compound, MS: m/e 443.9 (MH"), was prepared analogously to the procedure described for Example 2, using 4-[l, 2, 3] thiadiazol-4-yl-benzenesulfonyl chloride.
Example 33
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-(trifluoromethoxy)benzenesulfonamide
The title compound, MS: m/e 444 (MH+), was prepared analogously to the procedure described for Example 2, using 4-trifluoromethoxy-benzenesulfonyl chloride.
Example 34
N-[(5-{[(5-Tert-butyl-l,3-oxazol-2-yl)methyl]thio}-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide
The title compound, MS: m/e 467 (MH+), was prepared analogously to the procedure described for Example 39, using 5-(5-tert-butyl-oxazol-2-ylmethylsulfanyl)-thiazol-2- ylamine.
Example 35
3-Methyl-N-{[5-(2-thienyl)-l,3-thiazol-2-yl]carbamoyl}benzenesulfonamide
The title compound, MS: m/e 378.1(MH"), was prepared analogously to the procedure described for Example 39, using 5-thiophen-2-yl-thiazol-2-ylamine.
Example 36
N-[(4-Chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
The title compound, MS: m/e 332 (MH+), was prepared analogously to the procedure described for Example 39, using 4-chloro-thiazol-2-ylamine. Example 37
N-{[5-(Benzylthio)-l,3-thiazol-2-yl]carbamoyl}-3-methylbenzenesulfonamide
The title compound, MS: m/e 420 (MH+), was prepared analogously to the procedure described for Example 39, using 5-benzylsulfanyl-thiazol-2-ylamine.
Example 38
N-(l,3-Benzothiazol-2-ylcarbamoyl)-3-methylbenzenesulfonamide
The title compound, MS: m/e 348 (MH+), was prepared analogously to the procedure described for Example 39, using benzothiazol-2-ylamine.
Example 39
N-[(4,5-Dimethyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
m-Toluenesulfonyl chloride (0.076 ml, 0.53 mmol, 1.4 equiv.) and pyridine (0.103 ml, 1.27 mmol, 3.4 equiv.) were added to a stirred suspension of sodium cyanate (56 mg, 0.86 mmol, 2.3 equiv.) in dry acetonitrile ( 1 ml) and the mixture stirred at room temperature for 3 hours. 2-Amino-4,5-dimethylthiazole hydrochloride (34 mg, 0.28 mmol, 1.0 equiv.) was added and the reaction stirred for 1 hour. Water (2 ml) and acetic acid (3 drops) were added. The resulting precipitate was centrifuged for 10 minutes and the supernatant decanted. The solid was washed with water (2 ml), the material centrifuged and supernatant decanted. The solid was dried under reduced pressure at 40 0C to give N- [ (4,5- dimethyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide, 49 mg (55% yield). LC @UV215nm; Rt 1.81: 93%, m/z (ES+): 326 (MH+), 651 (2MH+); δπ (400 MHz; d4- methanol) 7.54-7.98 (4H, m), 2.57 (3H, s), 2.31 (3H, s), 2.27 (3H, s).
Example 40
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2-ethyl-2'-methylbiphenyl-4-sulfonamide, monosodium salt
The title compound, MS: m/e 478.0 (MH"), was prepared analogously to the procedure described for Example 43, using 4-bromo-2-ethyl-l-iodo-benzene and l-bromo-2-methyl- benzene in the first step. The sodium salt was prepared as a lyophilisate by dissolving the free acid in acetonitrile and adjusting the pH to 7.2 using 0.01 M NaOH and freeze-drying. Example 41
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2-ethylbiphenyl-4-sulfonamide
The title compound, MS: m/e 464.1 (MH"), was prepared analogously to the procedure described for Example 43, using 4-bromo-2-ethyl-l-iodo-benzene and bromobenzene in the first step.
Example 42
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2-ethyl-3'-methylbiphenyl-4-sulfonamide, monosodium salt
The title compound, MS: m/e 480.2 (MH"), was prepared analogously to the procedure described for Example 43, using 4-bromo-2-ethyl- 1-iodo-benzene and l-bromo-3-methyl- benzene in the first step.
Example 43
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2,6-dimethylbiphenyl-4-sulfonamide
i) Preparation of 4-bromo-2,6-dimethylbiphenyl
2.5 M π-Butyllithium, in tetrahydrofuran, (1.42 ml, 3.54 mmol, 1.1 equiv.) was added dropwise to a solution of bromobenzene (0.34 ml, 3.22 mmol, 1.0 equiv.) in dry tetrahydrofuran (18 ml), under nitrogen at -78 0C and the mixture stirred for 30 minutes. Zinc chloride (0.48 g, 3.54 mmol, 1.1 equiv.) was added and the mixture allowed to warm to room temperature while stirring for 2 hours. Palladium tetrakistriphenylphosphine (0.19 g, 0.16 mmol, 0.05 equiv.) and a solution of 5-bromo-2-iodo-l,3-dimethyl-benzene (1.00 g, 3.22 mmol, 1.0 equiv.) in tetrahydrofuran (2 ml) were added and the mixture stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the crude product purified by column chromatography (SiO2, heptane). The fractions were combined to afford 4-bromo-2,6-dimethylbiphenyl, 278 mg (33% yield) as a clear oil δH (400 MHz; d4-methanol) 7.28-7.39 (3H, m), 7.18 (2H, s), 7.03 (2H, d), 1.90 (6H, s).
ii) Preparation of 2,6-dimethylbiphenyl-4-surfonyl chloride
2.5 M π-butyllithium, in tetrahydrofuran, (0.46 ml, 1.17 mmol, 1.1 equiv.) was added dropwise to a solution of 4-bromo-2,6-dimethylbiphenyl (0.28 g, 1.06 mmol, 1.0 equiv.) in dry tetrahydrofuran (5 ml), under nitrogen at -78 0C and the mixture stirred for 15 minutes. This solution was added, by canula, to a solution of sulfur dioxide (3 mL) and tetrahydrofuran (3 ml) under nitrogen at -78 0C. The solution was allowed to warm to room temperature while stirring for 16 hours. The solvent was evaporated under reduced pressure and the residue suspended in hexane (4 ml) and dichloromethane (4 ml). The suspension was cooled to 0 0C, a solution of sulfuryl chloride (0.14 g, 1.06 mmol, 1.0 equiv.) in hexane (2 ml) was added and the mixture was allowed to warm to room temperature while stirring for 1.5 hours. The hexane and dichloromethane were evaporated under reduced pressure to afford crude 2,6-dimethylbiphenyl-4-sulfonyl chloride, 0.22 g (74% yield) as a red gum, this material was used in the next step without further purification.
iii) Preparation of N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-2,6-dimethylbiphenyl-4- sulfonamide
2,6-Dimethylbiphenyl-4-sulfonyl chloride (0.147 g, 0.53 mmol, 1.4 equiv.) and pyridine (0.152 ml, 1.87 mmol, 5.0 equiv.) were added to a stirred suspension of sodium cyanate (56 mg, 0.86 mmol, 2.3 equiv.) in dry acetonitrile (1.5 ml) and the mixture stirred at room temperature for 3 hours. 5-Bromo-thiazol-2-ylamine hydrobromide (97 mg, 0.38 mmol, 1.0 equiv.) was added and the reaction stirred for 1 hour. Water (2 ml) and acetic acid (3 drops) were added. The product was extracted into dichloromethane (2 ml), dried over sodium sulfate and evaporated to a brown gum. The gum was purified by preparative HPLC to give N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-2,6-dimethylbiphenyl-4- sulfonamide, 15 mg (9% yield). LC @UV215nm; Rt 2.64: 96%, m/z (ES+): 467, 468 (M+H).
Example 44
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-methyl-l,3-oxazol-5- yl)benzenesulfonamide
i) 4-Methyl-5-phenyl-oxazole
To a solution of 1-methyl-l-tosylmethyl isocyanide (2.1 g, 10 mmol) in ethanol (20 ml) were added benzaldehyde (1.0 ml, 10 mmol) and potassium carbonate (2.1 g, 15 mmol). The reaction mixture was refluxed for 5 h under argon. The reaction mixture was concentrated and the residue extracted in ethyl acetate and washed with water, 1 N HCl (3x), NaHCO3 (Vi sat., 3x) NaCl sat., dried (MgSO4.2H2O), filtered and solvent was removed under reduced pressure. The crude brown oil was purified over silica gel (ethyl acetane/ n-heptane 1:5 to 1:3): crystalline solid, 0.75 g (45%), MS: m/e 160.2 (MH+).
ii) 4-(4-Methyl-oxazol-5-yl)-benzenesulfonyl chloride
To a chilled solution (ice-bath) of 4-methyl-5-phenyl-oxazole (0.2 g, 1.3 mmol) in CHCI3 (1 ml) was added drop- wise chlorosulfonic acid (0.5 ml, 7.7 mmol). The dark-brown reaction mixture was stirred at 40C for 30 min and slowly warmed to reflux. After 2 h the reaction mixture was poored into ice- water and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and evaporated to yield a light-brown solid: 0.19 g, (56%), MS: m/e 257.1 .
iii) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-4-(4-methyl-l,3-oxazol-5- vDbenzenesulfonamide
The title compound, MS: m/e 443.1 (MH"), was prepared analogously to the procedure described for Example 2, using 4-(4-methyl-oxazol-5-yl)-benzenesulfonyl chloride.
Example 45
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-(2-methylpyrrolidin-l-yl)pyridine- 3-sulfonamide
i) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll- 5,6-dichloropyridine-3-sulfonamide
The title compound, MS: m/e 529.0 (MH"), was prepared analogously to the procedure described for Example 2, using 2,3-dichloropyridine-5-sulfonyl chloride.
ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-chloro-6-(2-methylpyrrolidin-l- yl)pyridine-3-sulfonamide
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]- 5,6-dichloropyridine-3-sulfonamide (20 mg, 0.05 mmol) was dissolved in DMF (1 ml) and reacted with 2-methylpyrrolidine (0.10 ml, 1 mmol) at 5O0C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water, NaHCO3 (half sat. 3x) , 5% KHSO4/ 10% K2SO4, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC: 6 mg, MS: m/e 477.9 (MH") .
Example 46 N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-[(2S)-2- (methoxymethyl)pyrrolidin-l-yl]pyridine-3-sulfonamide
The title compound, MS: m/e 508.0 (MH"), was prepared analogously to the procedure described for Example 45, using (S)-2-(methoxymethyl) pyrrolidine in step 2.
Example 47
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-chloro-6-(2-isopropylpyrrolidin-l- yl)pyridine-3-sulfonamide
The title compound, MS: m/e 506.0 (MH"), was prepared analogously to the procedure described for Example 45, using 2-(methylethyl)pyrrolidine in step 2.
Example 48
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-ethylbenzenesulfonamide
i) 3-Ethyl-benzenesulfonyl chloride
3-Ethyl-phenylamine (2.4 g, 20 mmol) was added dropwise to a stirred mixture containing HCl cone. (37%, 12 ml) and acetic acid (5 ml) at 50C (ice-salt bath). A solution of sodium nitrite ( 1.5 g, 22 mmol) in water (3 ml) was added dropwise at O0C and the resultant black slurry was further stirred at the low temperature for 30 min. A copper (I) chloride (0.5 g, 5 mmol) solution in acetic acid (50 ml) was saturated with SO2 gas . To this saturated solution was added the above, black slurry at 0-50C and the reaction was allowed to warm to room temperature and further stirred for 45 min. Ice-water (300 ml) was added the resultant mixture was extracted with ethyl acetate (3x) and the combined organic extracts were washed with water, brine, dried (MgSO4^H2O) filtered and concentrated under reduced pressure. The crude black oil was purified over silica gel (diethyl ether/ n-heptane 1:10): yellow oil, 0.68 g (14%), MS: m/e 204.2 (MH+).
ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-3-ethylbenzenesulfonamide
The title compound, MS: m/e 388.0 (MH"), was prepared analogously to the procedure described for Example 2, using 3-ethyl-benzenesulfonyl chloride.
Example 49
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-isopropylbenzenesulfonamide The title compound, MS: m/e 402.2 (MH"), was prepared analogously to the procedure described for Example 48, using 3-isopropyl-phenylamine in the first step.
Example 50
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxyphenyl)thiophene-2-sulfonamide
i) 5-(4-Methoxy-phenyl)-thiophene-2-sulfonyl chloride
Sulfuryl chloride (0.32 g, 2.34 mmol) was added dropwise a stirred solution of dry DMF (0.18 ml, 2.34 mmol) at O0C under an argon atmosphere resulting in the formation of a white solid. After 15 min, 2-(4-methoxy-phenyl)-thiophene (0.38 g, 2 mmol) was added and the mixture was warmed to 1000C and the melt was further stirred for 45 min. Crushed ice was added and the reaction mixture was extracted with ethyl acetate (2x) and the combined organic extracts were washed with water, brine, dried (MgSO4.2H2O) filtered and concentrated under reduced pressure. The crude, green solid was purified over silica gel (ethyl acetate/ n-heptane 1:9): green solid, 0.13 g (18%).
ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(4-methoxyphenyl)thiophene-2- sulfonamide
The title compound, MS: m/e 471.9 (MH"), was prepared analogously to the procedure described for Example 2, using 5-(4-methoxy-phenyl)-thiophene-2-sulfonyl chloride.
Example 51
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-isobutylthiophene-2-sulfonamide
i) 2-Methyl- l-thiophen-2-yl-propan- 1-one
Amixture containing thiophene (10.1 g, 120 mmol), isobutyric acid (8.8 g, 100 mmol) and 20 g of polyphosphoric acid was magnetically stirred at 750C fo 2 hours. The reaction mixture was diluted with water (100 ml) and extracted with CH2Cl2 (2x). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a brown oil: 14 g (77%) GC-MS: M= 154.0.
ii) 2-Isobutyl-thiophene
To a mixture of potassium hydroxide (2.24 g, 40 mmol) and hydrazine monohydrate (3.0 g, 60 mmol) in diethylene glycol (25 ml) was added 2-methyl-l-thiophen-2-yl-propan-l- one (1.54 g, 10 mmol). The combined mixture was heated at 180 0C for 1 h and then at 210 0C for a further 2 h. The mixture was cooled to rt and diluted with water ( 100 ml) and extracted with diethyl ether (3x). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a yellow oil: 0.9 g (61%) GC-MS: M= 140.0.
iii) 5-Isobutyl-thiophene-2-surfonyl chloride
The title compound, GC-MS: M = 238.0, was prepared analogously to the procedure described for Example 50 using 2-isobutyl-thiophene in the first step.
iv) N- r(5-Bromo-l,3-thiazol- 2- yl)carbamoyll-5-isobutylthiophene- 2- sulfonamide
The title compound, MS: m/e 422.0 (MH"), was prepared analogously to the procedure described for Example 2, using 5-isobutyl-thiophene-2-sulfonyl chloride.
Example 52
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxyphenyl)-4-methyl-thiophene-2- su lfon amide
i) 2-(4-Methoxy-phenyl)-3-methyl-thiophene
2-Bromo-3-methyl-thiophene (0.53 g, 3.00 mmol) was dissolved in 1,4-dioxane (35 ml) under an argon atmosphere. To this solution were added Pd(PPlIs)4 (0.33 g, 0.28 mmol), 4-methoxyphenyl boronic acid (0.50 g, 3.30 mmol) and 2 M Na2CO3 (6 ml). The resultant mixture was stirred at 1000C for 2 hours. The reaction was cooled to rt diluted with tert.butyl methyl ether and poored into water and extracted with tert.butyl methyl ether (2x). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O) , filtered and concentrated under reduced pressure to yield a yellow oil that was purified over silica gel (n-heptane) to yield an oil: 0.32 g (48%), GC-MS: M= 204.
ii) 5-(4-Methoxy-phen yl)-4-methyl-thiophene- 2- sulfonyl chloride
The above sulfonyl chloride, EI- MS: M= 304.1, was prepared analogous to Example 50 using 2-(4-methoxy-phenyl)-3-methyl-thiophene in the first step.
ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(4-methoxyphenyl)-4-methyl-thiophene- 2-sulfonamide The title compound, MS: m/e 486.2 (MH"), was prepared analogously to the procedure described for Example 2, using 5-(4-methoxy-phenyl)-4-methyl-thiophene-2-sulfonyl chloride.
Example 53
N-[(5-Chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
The title compound, MS: m/e 330.1 (MH"), was prepared analogously to the procedure described for Example 39, using 5-chloro-thiazol-2-ylamine.
Example 54
3-Chloro-N-{[5-(methylthio)-l,3-thiazol-2-yl]carbamoyl}benzenesulfonamide Sodium methane thiolate (0.42 g, 6.0 mmol) was added to a suspension of N-[(5-bromo- l,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide (0.60 g, 1.5 mmol) in methanol (30 ml). The mixture was heated under refluxed for 60 hours and concentrated under reduced pressure. Apart of the crude (80 mg) was dissolved in acetonitrile- water and acidified using acetic acid. The precipitate formed was redissolved in DMSO and purified by preparative RP-HPLC: 14 mg lyophilisate, MS: m/e 362.1 (MH") .
Example 55
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3- cyclopropyl-benzenesulfonamide
i) 3-Cvclopropyl-benzenesurfonyl chloride
l-Bromo-3-cyclopropyl-benzene (1.0 g, 5.1 mmol) [prep.: J.Org.Chem. vol. 41, 2262-6 ( 1976)] was dissolved in dry THF/ diethyl ether ( 1:1, 30 ml) under an argon atmosphere and cooled to -780C. BuIi (1.6 M in hexanes, 3.2 ml, 5.1 mmol) was added dropwise and the reaction mixture was further stirred at low temperature for 15 min. This reaction mixture was added via cannula to a SO2 gas saturated solution of diethyl ether (20 ml) precooled to -780C. The reacton mixture was stirred overnight at room temperature and concentrated under reduced pressure. The crude intermediate was suspended in n-hexane (4A sieves dried, 20 ml) and chilled (ice- water). A solution of sulfuryl chloride (0.3 ml, 3.6 mmol) in dry hexane (8 ml) was added dropwise to the stirred suspension and then the cold bath was removed. After 90 min at room temperature the reaction mixture was filtered (Speedex pad) and the filtrate was concentrated under reduced pressure to yield a yellow oil: 0.6 g, (67%) GC-MS: M= 216. ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-3- cvclopropyl-benzenesurfonamide
The title compound, MS: m/e 402.3 (MH"), was prepared analogously to the procedure described for Example 2, using 3-cyclopropyl-benzenesulfonyl chloride.
Example 56
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-2-chlorobenzenesulfonamide
The title compound, MS: m/e 393.9 (MH"), was prepared analogously to the procedure described for Example 2, using 2-chloro-benzenesulfonyl chloride.
Example 57
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxypyridin-3-yl)-4- methylthiophene-2-sulfonamide
i) 2-Methoxy-5-(3-methyl-thiophen-2-yl)-pyridine
The title intermediate, MS: m/e 206.1 (MH+), was prepared analogously to Example 52 from 2-bromo-3-methyl-thiophene and 2-methoxy-5-pyridineboronic acid.
ii) 5-(6-Methoxy-pyridin-3-yl)-4-meth yl-thiophene- 2- sulfonyl chloride
2-Methoxy-5-(3-methyl-thiophen-2-yl)-pyridine (0.32 g, 1.6 mmol) was dissolved in THF/diethyl ether (10 ml, 1:1 v/v) and cooled to -7O0C. BuU (1.6M hexanes, 1 ml, 1.6 ml) was added dropwise and after a further 15 min at -7O0C the reaction mixture was added via canula to a condensed solution of SO2 (5 ml) in diethyl ether ( 10ml) . The yellow colored reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether and dried. The crude solid (0.31 g) was suspended in dry n-hexane (7 ml), cooled using an ice bath to O0C and treated with a solution of sulfuryl chloride (I M, 1.2 ml, 1.2 mmol) in CH2Cl2. The reaction mixture was slowly warmed to room temperature and analysed (TLC) showing no starting material. Solvent was removed under reduced pressure and the crude product was purified over silica gel (n-heptane/ tert.butylmethyl ether 1:9 to 1:4 v/v) to yield a white solid: 0.19 g (38%), MS: m/e 304.0 (MH+). iii) 5-(6-Methoxy-pyridin-3-yl)-4-methyl-thiophene-2-sulfonic acid amide
5-(6-Methoxy-pyridin-3-yl)-4-methyl-thiophene-2-sulfonyl chloride (0.19 g, 0.63 mmol) was dissolved in acetone (6 ml) and added dropwise to an aqueous ammonium hydroxide solution (25%, 1.2 ml). After 1 hour the solvent was removed under reduced pressure, the residue diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4^H2O) , filtered and concentrated under reduced pressure to yield a crude that was purified over silica gel (n-heptane-ethyl acetate 1:2 to 2:1 v/v) to yield a beige solid: 0.12 g (62%), MS: m/e 283.0 (MH").
iv) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-5-(6-methoxypyridin-3-yl)-4- methylthiophene- 2- sulfonamide
Example 58
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-5-(2-methoxyethyl)thiophene- 2-sulfonamide
i) 3-Bromo-2-(2-methoxy-ethyl)-thiophene
To a solution of 2,3-dibromothiophene (12.6 g, 50 mmol) in THF abs. (125 mL) was added at -75 0C n-BuIi (1.6M/hexane, 31 mL) over 30 minutes. The reaction mixture was further stirred at -75 0C for 30 minutes, and p-toluenesulfonic acid-2-methoxyethylester ( 11.8 g, 50 mmol) was added dropwise over 1 h. The mixture stirred for 2 h without cooling, quenched with brine, and extracted with ether. The organics were washed, dried, and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 3-bromo-2-(2-methoxy-ethyl)-thiophene (1.8 g) as a colorless liquid.MS (EI): 221.1 (M)
ii) 3-Chloro-2-(2-methoxy-ethyl)-thiophene
To a solution of 3-bromo-2-(2-methoxy-ethyl)-thiophene (1.7 g, 8 mmol) in DMF (8 mL) was added copper(I) -chloride (1.42 g, 12 mmol). The reaction mixture was stirred at 140 0C for 18h, quenched with ice/ water, extracted with ether, the organics were washed, dried and concentrated, the residue chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 3-chloro-2-(2-methoxy-ethyl)-thiophene (1.25 g) as a light brown liquid. MS (EI) m/e 176.1 (M) iii) 4-Chloro-5-(2-methoxy-eth vD-thiophene- 2- su lfonyl chloride
To a suspension of sulfur trioxide dimethylformamide complex (1.40 g, 9 mmol) in 1,2- dichloroethane (10 rnL) was added 3-chloro-2-(2-methoxy-ethyl)-thiophene (Yun, Sangmin; Kim, Eun Sook; Kim, Hee Seock; Ha, Tae Hee; Suh, Kwee-Hyun; Lee, Gwan Sun, WO 2005087779 ( 1.35 g, 8 mmol) . The reaction mixture was stirred at rt for 1 h, thionyl chloride (1.2 g, 10 mmol) was added, and the mixture was stirred at 55-60 0C for 3- 4 h and chromatographed directly on silica gel using heptane/ethyl acetate or dichloromethane/ethyl acetate as eluents to obtain 4-chloro-5-(2-methoxy-ethyl)- thiophene-2-sulfonyl chloride (1.6 g) a light yellow liquid. MS (EI) m/e 274.0 (M)
iv) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-4-chloro-5-(2-methoxyethyl)thiophene-2- sulfonamide
The title compound was prepared in analogy to the procedure described for Example 2 starting from 4-chloro-5-(2-methoxy-ethyl)-thiophene-2-sulfonyl chloride to obtain the desired compound as a brownish solid. MS (ISN): m/e 458.0, 459.9, (M-H)+
Example 59
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(4-methoxy-2-methylphenyl)-4- methylthiophene-2-sulfonamide
i) 2-(4-Methoxy-2-methyl-phenyl)-3-methyl-thiophene
The compound was prepared analogously to the procedure described for example 52i) using 4-methoxy-2-methyl-phenyl boronic acid to give 2-(4-methoxy-2-methyl-phenyl)-3- methyl-thiophene, 910 mg, m/e 218.2 (MH+).
ii) 5-(4-Methoxy- 2-methyl-phenyl)-4-methyl-thiophene- 2- sulfonyl chloride
The compound was prepared analogously to the procedure described for example 5Oi) using 2-(4-methoxy-2-methyl-phenyl)-3-methyl-thiophene to give 5-(4-methoxy-2- methyl-phenyl)-4-methyl-thiophene-2-sulfonyl chloride as a light yellow oil, 350 mg, m/e 316.1 (MH+). iii)N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-5-(4-methoxy-2-methylphenyl)- methylthiophene- 2- sulfonamide
5-(4-Methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-sulfonyl chloride (95 mg, 0.30 mmol, 1.5 equiv.) was dissolved in 0.3 ml MeCN, followed by the addition of sodium cyanate (28.6 mg, 0.44 mmol, 2.2 equiv.). Under strong stirring, pyridine (0.055 ml, 0.68 mmol, 3.4 equiv.) was added dropwise to the reaction mixture which was further stirred for 4 hrs at rt. 2-Amino-5-bromothiazole. HBr (52 mg, 0.20 mmol, 1.0 equiv.), was added and the reaction stirred for 1 hour. Water (20 ml) and 70% acetic acid (2 ml) were added to the suspension which was filtered, washed with water and cold MeOH. The crude solid was dissolved in MeCN - DMSO and chromatographed on a HPLC 75x30 mm RP 18 5 μm column, with A= 0.1% HCOOH and B=MeCN and with a gradient of 40% to 90% B in 10 min. The desired fractions were lyophilized to give N-[(5-bromo-l,3-thiazol-2- yl)carbamoyl] -5-(4-methoxy-2-methylphenyl)-4-methylthiophene-2-sulfonamide, 16 mg, m/e 499.9 (MH").
Example 60
N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-4-(6-methoxypyridin-3-yl)-3- methylbenzenesulfonamide
i) N-tert-Butyl-4-(6-methoxy-pyridin-3-yl)-3-methyl-benzenesulfonamide
This compound was prepared analogous to Example 64, starting with 4-bromo-n-tert- butyl-3-methyl-benze (Ig, 3.26 mmol) and 2-methoxy-5-pyridineboronic acid (550 mg, 3.6 mmol, 1.1 equiv.) to obtain 995 mg of the title compound as a colorless gum. MS (ES): m/e 333.3 (M-H)
ii) 4-(6-Methoxy-pyridin-3-yl)-3-methyl-benzenesulfonamide
This compound was prepared analogous to Example 64 starting with n-tert-butyl-4-(6- methoxy-pyridin-3-yl)-3-methyl-benzenesulfonamide (930mg, 2.78 mmol) to obtain 750 mg of the title compound as a white solid. MS (ES): m/e 277.3 (M-H)
iii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-4-(6-methoxypyridin-3-yl)-3- methylbenzenesulfonamide This compound was prepared analogous to Example 64, starting with 4-(6-methoxy- pyridin-3-yl)-3-methyl-benzenesulfonamide (200mg, 0.72 mmol) to obtain 33 mg of the title compound as a light brown, amorphous solid. MS (ES): m/e 481.2 (M-H)
Example 61
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-isobutyl-4-methylthiophene-2-sulfonamide i) 2-Isobutyl-3-methyl-thiophene
A part of a solution containing 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) in dry diethyl ether is added drop- wise to a suspension of magnesium (308mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether until the mixture starts to reflux. The remaining solution is added dropwise. A solution of toluene-4- sulfonic acid isobutyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether is added dropwise at room temp., then the mixture is further refluxed for two hours. After cooling to room temp., the mixture is quenched with sat. ammonium chloride solution and extracted with tert. butylmethy lether. The combined organic extracts are washed with water, brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated to give a yellow oil. After Kugelrohr-distillation, 630 mg of the title compound is obtained as a colorless oil. GC-MS (EI): M= 154
ii) 5-Isobutyl-4-methyl-thiophene-2-surfonyl chloride
190 mg of the title compound, GC-MS: M =252, was prepared analogously to the procedure described for Example 50 starting from 2-isobutyl-3-methyl-thiophene (350 mg, 1.93 mmol).
iii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-isobutyl-4-methylthiophene-2- sulfonamide
This compound is prepared analogous to Example 2 starting with 5-isobutyl-4-methyl- thiophene-2-sulfonyl chloride (187 mg, 0.74 mmol) and 5-bromo-thiazol-2-ylamine hydrobromide (140 mg, 0.54 mmol, 0.73 equiv.). After purification on preparative HPLC, 49 mg of the title compound was obtained as a white, amorphous solid. MS (ES): m/e 436.1 (M-H)
Example 62 3-methyl-N-({4-methyl-5-[(trifluoromethyl)thio]-l,3-thiazol-2- yl}carbamoyl)benzenesulfonamide
This compound was prepared analogous to Example 2, starting with 3-methyl- > benzenesulfonyl chloride ( 122 mg, 0.64 mmol) and 4-methyl-5-trifluoromethylsulfanyl- thiazol-2-ylamine (100 mg, 0.466 mmol, 0.73 equiv.). After purification on preparative HPLC, 46 mg of the title compound is obtained as a white, amorphous solid. MS (ES): m/e 410.0 (M-H)
Example 63
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethyl)-4-methylthiophene-2- su lfon amide
i) 2-(2-Methoxy-ethyl)-3-methyl-thiophene
This compound was prepared analogous to Example 61, starting with 2-bromo-3- methylthiophene (1.5 g, 8.5 mmol) and toluene-4- sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) The crude product was purified on silica gel with eluent n- heptane and tert.butylmethyl ether. The title compound was obtained as a light yellow oil, 490mg. GC-MS (EI) : M= 156
ii) 5-(2-Methoxy-ethyl)-4-methyl-thiophene-2-sulfonyl chloride
This compound was prepared analogous to Example 61, starting with 2-(2-methoxy- ethyl)-3-methyl-thiophene. (250 mg, 1.6 mmol). The title compound was obtained as a light yellow oil 220 mg . GC-MS (EI): M=254.
iii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(2-methoxyethyl)-4-methylthiophene-2- sulfonamide
This compound was prepared analogous to Example 2, starting with 5- (2-methoxy-ethyl) - 4-methyl-thiophene-2-sulfonyl chloride (210 mg, 0.742 mmol) and 5-bromo-thiazol-2- ylamine hydrobromide (141 mg, 0.542 mmol, 0.73 equiv.). After purification on preparative HPLC, the title compound was obtained as a white, amorph, freeze-dried solid: 38 mg. MS (ES): m/e 438.0 (M-H)
Example 64
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-fluoropyridin-3-yl)-3- methylbenzenesulfonamide
i) 4-Bromo-N-tert-butyl-3-methyl-benzenesulfonamide
To a stirred, ice-cold solution of 4-bromo-3-methyl-benzenesulfonyl chloride (H g, 40.8 mmol) and N'N-diisopropylethylamine (8.5 ml, 49 mmol,1.2 equiv.) in dichloromethane was added dropwise tert. butylamine (5.2 ml, 49 mmol, 1.2 equiv.). After two hours at room temp., the reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were concnetrated under reduced pressure, the residue stirred with n-heptane and filtered to obtain 11.2 g of the desired compound as a yellow solid. MS (ES) : m/e 304.2 (M-H)
ii) N-tert-Butyl-4-(6-fluoro-pwidin-3-yl)-3-methyl-benzenesulfonamide
This compound was prepared analogous to Example 52 starting from 4-bromo-n-tert- butyl-3-methyl-benzenesulfonamide (H g, 36.2 mmol) to obtain 10.8g of the desired compound as a light yellow gum. MS (ES): m/e 321.3 (M-H)
iii) 4-(6-Fluoro-pyridin-3-yl)-3-methyl-benzenesulfonamide
n-tert-Butyl-4-(6-fluoro-pyridin-3-yl)-3-methyl-benzenesulfonamide (10.4 g, 32.4 mmol) was treated with a mixture of 225 ml triflu or o acetic adid and 25ml water, for 2 hours at 5O0C. The mixutre was concentrated and the residue dissolved in ethyl acetate and extracted with an aqueous sodium bicarbonate solution. The combined organic extracts were washed with brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated to give 7.3 g of the title compound as a light yellow solid. MS (ES): m/e 264.9 (M-H)
iv) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-4-(6-methoxypyridin-3-yl)-3- methylbenzenesulfonamide To a solution of 4-(6-fluoro-pyridin-3-yl)-3-methyl-benzenesulfonamide (4.2 g, 16 mmol) and triethylamine (5.1 ml, 36.8 mmol, 2.3 equiv.) in 130 ml acetonitrile was added dropwise at O0C phenyl chloroformate (2.4 ml, 19.2 mmol, 1.2 equiv.) After stirring the solution for one hour at room temp., 5-bromo-thiazol-2-ylamine (4.3 g, 24 mmol, 1.5 equiv.) is added in one portion. The mixture wass warmed to 6O0C, then methanesulfonic acid (1.5 ml, 24 mmol, 1.5 equiv.) was added and the reaction mixture was stirred for one hour at 6O0C. After cooling to room temp., the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium- dihydrate, filtered and evaporated. The crude product was purified on silica-gel with ethyl acetate/n-heptane to give 2.67 g of the title compound as a light brown solid. MS (ES): m/e 470.7 (M-H)
Example 65
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-fluoropyridin-3-yl)-4-methylthiophene-2- su lfon amide
i) 2-Fluoro-5-(3-methyl-thiophen-2-yl)-pyridine
This compound was prepared in analogy to Example 52, starting from 2-bromo-3- methylthiophene (2.6 g, 15 mmol) and 2-fluoro-5-pyridine-boronic acid (2.3 g, 16.5 mmol, 1.1 equiv.) to obtain 2.2 g of the desired compound as a light yellow oil. MS (ES): m/e 194.2 (M+H)
ii) 5-(6- Fluoro-pyridin-3-yl)-4- methyl- thiophene- 2- sulfonyl chloride This compound was prepared in analogy to Example 5Oi), starting with 2-fluoro-5-(3- methyl-thiophen-2-yl) -pyridine (1.1 g, 5.7 mmol). 350 mg of the title compound was obtained as a light yellow solid. MS (EI): M=291.1
iii) 5-(6-Fluoro-pyridin-3-yl)-4-methyl-thiophene-2-sulfonic acid amide
5-(6-Fluoro-pyridin-3-yl)-4-methyl-thiophene-2-sulfonyl chloride (310 mg, 1.06 mmol) was dissolved in dioxane and cooled with an ice-bath. Under stirring was added dropwise an excess of ammonium hydroxide solution 25%. After two hours at room temp the reaction was neutralized and the dioxane was evaporated. The reaction mixutre was extracted with ethyl acetate, the combined organice extracts were washed with brine, dried over magnesiumsulfat- dihydrate, filtered and evaporated. The crude product was purified on silica-gel with eluent ethyl acetate/n-heptane to give 218 mg of the title compound as a white solid. MS (ES): m/e 271.2 (M-H)
iv) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(6-fluoropyridin-3-yl)-4- methylthiophene- 2- sulfonamide
This compound was prepared in analogy to Example 64 iv), starting with 5-(6-fluoro- pyridin-3-yl)-4-methyl-thiophene-2-sulfonic acid amide (200 mg, 0.734 mmol) and 5- bromo-thiazol-2-ylamine hydrobromide (286 mg, 1.1 mmol, 1.5 equiv.). After purification on preparative HPLC, yielding 13 mg of the title compound as a white, amorphous solid. MS (ES) : m/e 474.7 (M-H)
Example 66
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3-chloro-4-fluorobenzenesulfonamide
This compound was prepared analogously to the procedure described for Example 59 iii), using 3-chloro-4-fluoro-benzenesulfonyl chloride to obtain after crystallization N-[(5- bromo-l,3-thiazol-2-yl)carbamoyl]-3-chloro-4-fluorobenzenesulfonamide, 257 mg, m/e 412.1 (MH").
Example 67
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(3-methoxypropyl)-4-methylthiophene-2- sulfonamide
i) Toluene-4-sulfonic acid 3-methoxy-propyl ester
4-Methyl-benzenesulfonyl chloride (21 g, 110.0 mmol, 1.1 equiv.) was added at 0 0C to a solution of 3-methoxy-propan-l-ol (9 g, 100.0 mmol, 1.0 equiv.) in pyridine (16.1 ml, 200.0 mmol, 2.0 equiv.). After 1 hr at 0 0C a white solid was formed. It was diluted with water and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and crystallized from ether (hygroscopic) to give toluene-4-sulfonic acid 3-methoxy-propyl ester, 21. 4 g, m/e 245.0 (MH+). ii) 2-(3-Methoxy-propyl)-3-methyl-thiophene
Magnesium turnings (365 mg, 15.0 mmol, 1.5 equiv.) were suspended in 15 ml dry diethyl ether. A crystal of iodine and a few drops of 2-bromo-3-methylthiophene in 10 ml ether were added till the reaction started (3 min. with heating to 30 0C). The remaining solution of 2-bromo-3-methylthiophene (total 2.44 g, 10.0 mmol, 1.0 equiv.) was added dropwise to maintain the reaction at reflux. The reaction mixture was refluxed for 30 min. To Iu en e- 4- sulfonic acid 3-methoxy-propyl ester (2.13 g, 12.0 mmol, 1.2 equiv.) dissolved in 5 ml diethyl ether was added dropwise and the yellow solution was refluxed again for 2 hours. The brown suspension was cooled, acidified with IN HCl and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and chromatographied on a 50 g Silicagel cartridge with heptane and than MTBE-heptane 1:9 as solvent to give 2-(3-methoxy-propyl)-3-methyl- thiophene, 410 mg, m/e 170.0 (MH+) by GC/MS.
iii) 5-(3-Methoxy-propyl)-4-meth yl-thiophene- 2- sulfonyl chloride
2-(3-Methoxy-propyl)-3-methyl-thiophene (409 mg, 2.4 mmol, 1.0 equiv.) dissolved in 1 ml DCE was added drop wise to a suspension of sulfur trioxide dimethylformamide complex (441 mg, 2.88 mmol, 1.2 equiv.) in 2 ml DCE. The reaction mixture was heated to 55 0C for 15 min. and than cooled to rt. Thionyl chloride (0.21 ml, 2.88 mmol, 1.2 equiv.) was added drop wise to the mixture which was than heated to 80 0C for 1 hr. At rt the reaction was treated with ice for 15 min. and than extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and chromatographied on a 20 g Silicagel cartridge with ethyl acetate-heptane 1:2 as solvent to give a brown liquid identified as 5-(3-methoxy-propyl)-4-methyl-thiophene-2- sulfonyl chloride, 400 mg, m/e 268.0 (MH+).
iiii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(3-methoxypropyl)-4-methylthiophene-
2-sulfonamide
The compound was prepared analogously to the procedure described for Example 59 iii), using 5-(3-methoxy-propyl)-4-methyl-thiophene-2-sulfonyl chloride to obtain after crystallization N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(3-methoxypropyl)-4- methylthiophene- 2-sulfonamide, 18 mg, m/e 452.0 (MH").
Example 68 N-tCS-Bromo-US-thiazol-l-y^carbamoyy-ΦCl-methoxy-US-thiazol-Φy^-S- methylbenzenesulfonamide
i) N-tert-Butyl-3-methyl-benzenesulfonamide boronic acid
4-Bromo-N-tert-butyl-3-methyl-benzenesulfonamide (10 g, 32.6 mmol) was disolved in dry tetrahydrofurane, then cooled to -780C. Triisopropyl borate (27.7 ml, 120.8 mmol, 3.7 equiv.) was added in one portion, followed by the dropwise addition of n-butyllithium solution 1.6M (75.5 ml, 120.8 mmol, 3.7 equiv.) at -780C. The mixture was stirred overnight, then quenched dropwise with water. The organic solvent was evaporated and the pH adjusted to 3 with 0.5 M HCl. The residue was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated. The crude product was purified on silica-gel with ethyl acetate/n- heptane to give 2.82 g of the title product as yellow, waxy solid. MS (ES): m/e 270 (M-H)
ii) 4-(2-methoxy-4H-llambda*4*-thiazol-4-yl)-3-methyl-benzenesulfonamide
This compound was prepared analogously to Example 52, starting from N-tert-butyl-3- methyl-benzenesulfonamide boronic acid (1.0 g, 3.69 mmol) and 4-bromo-2-methoxy- thiazole (0.78 g, 4.05 mmol, 1.1 equiv.) After purification on silica- gel with n- heptane/tert.butylmethyl ether 510 mg of the t-butyl protected sulfonamide were obtained. Deprotection analogous to Example 98 yielded 260 mg of the title compound as a light yellow solid. MS (ES): m/e 270 (M-H)
iii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-4-(2-methoxy-l,3-thiazol-4-yl)-3- methylbenzenesulfonamide
This compound was prepared analogous to Example 64 starting from 4-(2-methoxy-4H- llambda*4*-thiazol-4-yl)-3-methyl-benzenesulfonamide (180 mg, 0.633 mmol) to obtain 118 mg of the desired compound as a light brown solid. MS (ES): m/e 487.0 (M-H)
Example 69
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-4-(5-fluoropyridin-3-yl)-3- methylbenzenesulfonamide i) N-tert-Butyl-4-(5-fluoro-pwidin-3-yl)-3-methyl-benzenesulfonamide
This compound was prepared analogous to Example 52, starting from N-tert-butyl-3- methyl-benzenesulfonamide boronic acid (0.5 g, 1.84 mmol) and 5-bromo-3- fluoropyridine (357 mg, 2.03 mmol, 1.1 equiv.) After purification on silica- gel with n- heptane/ethyl acetate, 335 mg of the title compound were obtained as a light yellow solid MS (ES): m/e 321.1 (M-H)
ii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-4-(5-fluoropyridin-3-yl)-3- methylbenzenesulfonamide
This compound was prepared analogous to Example 64, starting from N-tert-butyl-4-(5- fluoro-pyridin-3-yl)-3-methyl-benzenesulfonamide. (174 mg; 0.653 mmol) After purification on silica- gel using ethyl acetate/n-heptane, 107 mg of the title compound were obtained as a light brown solid. MS (ES): m/e 468.9 (M-H)
Example 70
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-methoxy-4-methylthiophene-2-sulfonamide i) 5-methoxy-4-methyl-thiophene-2-sulfonic acid amide
2-methoxy-3-methyl-thiophene (I g, 7.8 mmol) was dissolved in dry tetrahydrofuran. At - 780C n-butyllithium 1.6 M in n-hexane (5.1 ml, 8.2 mmol, 1.1 equiv.) were added drop wise. After one hour at -780C, sulfur dioxide gas was bubbled over the surface of the reaction mixture for 30 min. The reaction mixture was diluted with diethyl ether and allowed to warm to room temp. The solvent was evaporated and the residue is dissloved in dichloromethane. N-chlorosuccinimide (1.1 g, 8.2 mmol, 1.1 equiv.) was added in one portion. After two hours stirring, the mixture is filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetone and an excess of 25% aq. ammonium hydroxide solution was added and the mixture was stirred for 30 min. at room temp. The solvent was evaporated and the remaining oil was dissolved in ethyla ceteate and extracted with water, washed with brine, dried over magnesiumsulfate dihydrate, filtered and evaporated. After purification on silica- gel with ethyl acetate/n-heptane, 210 mg of the title compound were obtained as a light brown solid. MS (ES): m/e 206.0 (M-H)
ii) N-r(5-bromo-l,3-thiazol-2-yl)carbamoyll-5-methoxy-4-methylthiophene-2- sulfonamide This compound was prepared analogously to Example 64, starting from 5-methoxy-4- methyl-thiophene- 2- sulfonic acid amide (100 mg, 0.482 mmol). After purification on silica- gel using ethyl acetate/n-heptane 53 mg of title compound were obtained as a light brown solid. MS (ES): m/e 409.9 (M-H)
Example 71
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethoxy)-4-methylthiophene-2- su lfon amide
i) 2-(2-Methoxy-ethoxy)-3-methyl-thiophene
2-methoxy-3-methyl-thiophene, (1.5 g, 11.7 mmol) 2-methoxy-ethanol (3.8 g, 50.5 mmol, 4.3 equiv.) and sodium hydrogen sulfate anhydrous (100 mg, 0.833 mmol, 0.07 equiv.) were stirred in toluene at 12O0C for 3.5 hours. The mixture was diluted with ethyl acetate and extracted with sodium bicarbonate solution. The organic solvent was washed with brine, dried over magnesium sulfat dihydrat, filtered and evaporated. After Kugelrohr distillation, 980 mg of the title compound were obtained as a light yellow oil GC-MS (EI) M= 172.
ii) 5-(2-Methoxy-ethoxy)-4-methyl-thiophene-2-surfonic acid amide
This compound was prepared analogous to Example 70, starting from 2-(2-methoxy- ethoxy)-3-methyl-thiophene (910 mg, 5.28 mmol). After purification on silica-gel using ethyl acetate/n-heptane, 180 mg of title compound were obtained as a light brown solid. MS (ES): m/e 250.0 (M-H)
iii) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(2-methoxyethoxy)-4-methylthiophene-
2-sulfonamide
This compound was prepared analogous to Example 64, starting from 5-(2-methoxy- ethoxy)-4-methyl-thiophene-2-sulfonic acid amide. (165 mg, 0.657 mmol). After purification on silica- gel with ethyl acetate/n-heptane, 106 mg of the title compound were obtained as a light brown solid. MS (ES): m/e 453.8 (M-H)
Example 72
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxy-4-methylpyridin-3-yl)-4- methylthiophene-2-sulfonamide i) 5-Bromo-2-methoxy-4-methyl-pyridine boronic acid
The title compound, MS: m/e 166.0 (M-H) was prepared analogously to the procedure described for Example 68, using 5-bromo-2-methoxy-4-methyl-pyridine.
ii) 2-Methoxy-4-methyl-5-(3-methyl-thiophen-2-yl)-pyridine
The title compound, MS: m/e 220.3 (M+H) was prepared analogously to the procedure described for Example 52, using 5-bromo-2-methoxy-4-methyl-pyridine boronic acid.
iii) 5-(6-Methoxy-4-methyl-pyridin-3-yl)-4-methyl-thiophene-2-sulfonic acid amide The title compound, MS: m/e 297.2 (M-H) was prepared analogously to the procedure described for Example 70, using 2-methoxy-4-methyl-5-(3-methyl-thiophen-2-yl)- pyridine.
iv) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(6-methoxy-4-methylpyridin-3-yl)-4- methylthiophene- 2- sulfonamide
The title compound, MS: m/e 500.8 (M-H) was prepared analogously to the procedure described for Example 64, using 5-(6-methoxy-4-methyl-pyridin-3-yl)-4-methyl- thiophene-2-sulfonic acid amide.
Example 73
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(methoxymethyl)-4-methylthiophene-2- su lfon amide i) (3-Methyl-thiophen-2-yl)-methanol
Sodium borohydride (6.0 g, 158.5 mmol, 2 equiv.) was suspended in dry tetrahydrofuran under an inert atmosphere. At 1O0C a solution of 3-methyl-thiophene-2-carbaldehyde (10 g, 79.2 mmol, 1 equiv.) in dry tetrahydrofuran was added dropwise. The mixture was stirred at room temp, for 3 hours. The reaction mixture was quench edwith diluted acid and filtered. The filtrate was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesiumsulfate dihydrate, filtered and evaporated. Kugelrohr distillation of the crude product gave 8.33 g of the title compound as a light yellow oil. GC-MS (EI) M= 128
ii) 2-Methoxymethyl-3-methyl-thiophene
Sodium hydride (2.2 g -60%, 55.2 mmol, 1.2 equiv.) was suspended in dry tehtrahydrofuran under an inert atmosphere. At 50C a solution of (3-methyl-thiophen-2- yl)-methanol (5.16 g, 46 mmol) in dry tetrahydrofuran was added dropwise. The mixture was stirred at room temp, for 1 hour, then iodomethane (7.8 g, 55.2 mmol, 1.2 equiv.) was added drop wise. The mixture was stirred overnight at roomtemp. and then quenched with diluted acid and extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated to give 5.7 g of the title compound as a light green oil. GC-MS (EI) M= 142.
iii) 5-Methoxymethyl-4-methyl-thiophene-2-sulfonic acid amide
The title compound, MS: m/e 204.0 (M-H) was prepared analogously to the procedure described for Example 70, using 2-methoxymethyl-3-methyl-thiophene
iv) N-r(5-Bromo-l,3-thiazol-2-yl)carbamoyll-5-(methoxymethyl)-4-methylthiophene-2- sulfonamide
The title compound, MS: m/e 423.7 (M-H) was prepared analogously to the procedure described for Example 64, using 5-methoxymethyl-4-methyl-thiophene-2-sulfonic acid amide
Example 74
N-[(5-Bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
The title compound, MS: m/e 388.0 (M-H) was prepared analogously to the procedure described for Example 64, using toluene-3-sulfonamide and 5-bromo-4-methyl-thiazol-2- ylamine.
Example 75
N-[(5-Bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- (difluoromethoxy)benzenesulfonamide
The title compound, MS: m/e 439.9 (M-H) was prepared analogously to the procedure described for Example 2, using 3-difluoromethoxy-benzenesulfonyl chloride and 5- bromo-4-methyl-thiazol-2-ylamine.
Example 76
3-Methyl-N-[(4-methyl-5-nitro-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide The title compound, MS: m/e 355.0 (M-H) was prepared analogously to the procedure described for Example 64, using toluene-3-sulfonamide and 4-methyl-5-nitro-thiazol-2- ylamine.
Example 77
N-{[5-Bromo-4-(methoxymethyl)-l,3-thiazol-2-yl]carbamoyl}-3- methylbenzenesulfonamide
i) 4-Methoxymethyl-thiazol-2-ylamine
1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated. The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid: 340 mg. MS (ES) m/e 145 (M+H)
ii) 5-Bromo-4-methoxymethyl-thiazol-2-ylamine
4-Methoxymethyl-thiazol-2-ylamine (170 mg, 1.1 mmol) is dissolved in acetonitrile and N-bromosuccinimide. (231 mg, 1.3 mmol, 1.1 equiv.) was added in one portion. The mixture was stirred at room temp, for 2 hours, then filtered and the filtrate was evaporated. After purification on silica-gel with ethyl acetate/n-heptane as eluent, 260 mg of a light red solid were obtained: MS: m/e 222.8 (M+H).
iii) N- {r5-Bromo-4-(methoxymethyl)-l,3-thiazo 1-2- yll carbamoyl j-3- methylbenzenesulfonamide
The title compound, MS: m/e 417.9 (M-H) was prepared analogously to the procedure described for Example 64, using toluene-3-sulfonamide and 5-bromo-4-methoxymethyl- thiazol-2-ylamine. Example 78
Ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl]carbamoyl}amino)-l,3-thiazole-4- carboxylate
i) 2-Amino-5-bromo-thiazole-4-carboxylic acid ethyl ester
2-Amino-thiazole-4-carboxylic acid ethyl ester (1.4 g, 8 mmol) is dissolved in acetonitrile (15 ml) and N-bromosuccinimide. (1.7 g, 9.6 mmol, 1.2 equiv.) was added in one portion. The mixture was stirred at room temp, for 3 hours, then filtered and the filtrate was evaporated. After purification on silica- gel with ethyl acetate/n-heptane as eluent, 0.71 g of an off- white solid were obtained: MS: m/e 248.9 (M-H).
ii) Ethyl 5-bromo-2-({r(3-methylphenyl)sulfonyll carbamoyl |amino)-l,3-thiazole-4- carboxylate
The title compound, MS: m/e 449.9 (M+H) was prepared analogously to the procedure described for Example 64, using toluene-3-sulfonamide and 2-amino-5-bromo-thiazole-4- carboxylic acid ethyl ester.
Example 79
N-[(5-Methoxy-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide
N-[(5-Bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide (41 mg, 0.11 mmol) was treated with sodium methanethiolate (31 mg, 0.42 mmol) in methanol (3.1 ml) at 8O0C for 4 days. After purification on preparative HPLC, 9 mg of the title compound were unexpectedly obtained as a white, amorph, freeze-dried solid. MS (ES): m/e 340.1 (M-H)
Example 80
N-{[5-Bromo-4-(hydroxymethyl)-l,3-thiazol-2-yl]carbamoyl}-3- methylbenzenesulfonamide Ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl] carbamoyl }amino)-l,3-thiazole-4- carboxylate ( 50 mg, 0.11 mmol) was treated with sodium borohydride (21 mg, 0.56 mmol) in tetrahydrofuran (2 ml) for 2 days at room temp. 0.5 M HCl was added and the quenched reaction mixture was purified on preparative HPLC yielding 21 mg of the title compound as an amorphous solid. MS (ES): m/e 404.1 (M-H)
The title compound, MS: m/e 487.1 (MH"), was prepared analogously to the procedure described for Example 11, using 5-(6-methoxy-pyridin-3-yl)-4-methyl-thiophene-2- sulfonic acid amide.
Example A
A compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
Per tablet
Active ingredient 200 mg Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulose 20 mg
425 ms
Example B
A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg
220.0 mg

Claims

1. Compounds of formula
Figure imgf000061_0001
wherein
R1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R4 , -O-R4 or nitro;
R2 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxyalkyl, hydroxyalkyl or alkoxycarbonyl;
or R1 and R2 together with the carbon atoms to which they are attached form aryl;
R3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino, nitro, alkoxyalkyl, hydroxyalkyl, alkoxyalkoxy and hydroxyalkoxy;
R4 is alkyl, cycloalkyl, heterocyclylalkyl, aralkyl or haloalkyl;
and pharmaceutically acceptable salts and esters thereof, with the proviso that R1 and R2 are not both at the same time hydrogen and, wherein
N-((2-benzothiazolylamino)carbonyl)-4-methyl-benzenesulfonamide;
N-((2-benzothiazolylamino)carbonyl)-2-methyl-benzenesulfonamide;
N-(((5,6-dimethyl-2-benzothiazolyl)amino)carbonyl)-2-methyl- benzenesulfonamide;
N-(((4-chloro-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide; 2-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide;
N-(((6-ethoxy-2-benzothiazolyl)amino)carbonyl)-2-methyl-benzenesulfonamide; and
4-methyl-N-(((4-methyl-2-thiazolyl)amino)carbonyl)-benzenesulfonamide are excluded.
2. Compounds according to claim 1, wherein
R1 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, heterocyclyl, heterocyclylalkyl, aralkyl, -S-R4 or -O-R4;
R2 is hydrogen, alkyl, cycloalkyl, halogen or haloalkyl;
or R1 and R2 together with the carbon atoms to which they are attached form aryl;
R3 is phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl or isoxazoyl, wherein phenyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyradizinyl, oxazoyl and isoxazoyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, amino and nitro; and
R4 is alkyl, cycloalkyl, heterocyclylalkyl or aralkyl.
3. Compounds according to claim 1 or 2, wherein R1 is hydrogen, methyl, halogen, thienyl or -S-R4.
4. Compounds according to any one of claims 1 to 3, wherein R1 is bromo.
5. Compounds according to any one of claims 1 to 4, wherein R2 is hydrogen, methyl, or halogen.
6. Compounds according to any one of claims 1 to 5, wherein R2 is hydrogen.
7. Compounds according to claim 1 or 2, wherein R1 and R2 together with the carbon atoms to which they are attached form phenyl.
8. Compounds according to any one of claims 1 to 7, wherein R3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, dichloro- methyl-lH-pyrazolyl)oxy, methylthiazolyl, cyclohexyl-methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)-pyrrolidinyl, methoxypyridinyl, 6-methoxy-4-methyl-pyridin-3-yl, alkoxy-alkyl-phenyl, alkoxypyridinyl, fluoropyridinyl and methoxy-thiazolyl.
9. Compounds according to any one of claims 1 to 8, wherein R3 is phenyl, thiophenyl, pyridinyl or thiazolyl, wherein phenyl, thiophenyl, pyridinyl and thiazolyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, aryloxy, 3,4- dichloro- 1-methyl- lH-pyrazol-5-yl)oxy, 2-methyl-4-thiazolyl, 4-cyclohexyl-2- methyl- 5- oxazolyl, oxazolyl, l,2,3-thiadiazol-4-yl, 4-methyl-5-oxazolyl, 2-methyl-l- pyrrolidinyl, 2-(methoxymethyl)-l-pyrrolidinyl, 2-(l-methylethyl)-l-pyrrolidinyl, 6- methoxypyridin-3-yl, 6-methoxy-4-methylpyridin-3-yl, 4-methoxy-2-methylphenyl, methoxy-pyridinyl, 5-isobutyl-4-methylthiophenyl, 6-fluoropyridin-3-yl, 5- fluoropyridin-3-yl and 2-methoxy-l,3-thiazol-4-yl.
10. Compounds according to any one of claims 1 to 9, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, dichloro-methyl-lH-pyrazolyl)oxy, methylthiazolyl, cyclohexyl- methyl-oxazolyl, oxazolyl, thiadiazolyl, methyloxazolyl, methylpyrrolidinyl, (methoxymethyl)-pyrrolidinyl, (methylethyl)-pyrrolidinyl and methoxypyridinyl.
11. Compounds according to any one of claims 1 to 10, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, cycloalkyl, halogen, haloalkoxy, aryloxy, 3,4-dichloro- 1-methyl- lH-pyrazol-5-yl)oxy, 2-methyl-4- thiazolyl, 4-cyclohexyl-2-methyl-5-oxazolyl, oxazolyl, l,2,3-thiadiazol-4-yl, 4- methyl- 5- oxazolyl, 2-methyl-l-pyrrolidinyl, 2-(methoxymethyl)-l-pyrrolidinyl, 2- (l-methylethyl)-l-pyrrolidinyl and 6-methoxypyridin-3-yl.
12. Compounds according to any one of claims 1 to 11, wherein R3 is phenyl, thiophenyl or pyridinyl, wherein phenyl, thiophenyl and pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, cyclopropyl, halogen, haloalkoxy, phenyl, difluorophenyl, methylpenyl, methoxyphenyl, methyloxazolyl and methoxypyridinyl.
13. Compounds according to any one of claims 1 to 12, wherein R4 is alkyl, alkyloxazolylmethyl or phenylmethyl.
14. Compounds according to any one of claims 1 to 13, wherein R4 is methyl or ((1,1- dimethylethyl)-2-oxazolyl)methyl.
15. Compounds according to any one of claims 1 to 14 selected from
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl] 3(difluoromethoxy)benzenesulfonamide;
4-bromo-N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-chlorothiophene-2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-dichlorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chloro-3-methylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl] -2' ,4'-difluorobiphenyl-4- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-4,5-dichlorothiophene- 2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-chlorophenoxy)- benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-dimethylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-[(3,4-dichloro-l-methyl-lH-pyrazol-5- yl) oxy] benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methyl-l,3-thiazol-4- yl)benzenesulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-methylthiophene- 2- sulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-phenylthiophene- 2- sulfonamide; N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]biphenyl-4- sulfonamide;
N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-chlorothiophene- 2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-fluorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-methoxybenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-2,5-dichlorothiophene-3-sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,4-difluorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-methoxybenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-chlorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-cyclohexyl-2-methyl-l,3-oxazol-5- yl)-2-fluorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(2-methoxyphenoxy)- benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-nitrobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,3-oxazol-5-yl)benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3,5-difluorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-fluorobenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-methylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-ethylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(l,2,3-thiadiazol-4- yl)benzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-3-(trifluoromethoxy)- benzenesulfonamide; N-[(5-{[(5-tert-butyl-l,3-oxazol-2-yl)methyl]thio}-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide;
3-methyl-N-{[5-(2-thienyl)-l,3-thiazol- 2- yl] carbamoyl Jbenzenesulfonamide;
N-[(4-chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
N- {[5-(benzylthio)- 1,3-thiazo 1- 2- yl] carbamoyl }-3-methylbenzenesulfonamide;
N-(l,3-benzothiazol-2-ylcarbamoyl)-3-methylbenzenesulfonamide;
N- [(4,5-dimethyl- 1,3-thiazo 1- 2- yl)carbamoyl]-3-methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-2-ethyl-2'-methylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-ethylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-ethyl-3'-methylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2,6-dimethylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-4-(4-methyl-l,3-oxazo 1-5- yl)benzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-chloro-6-(2-methylpyrrolidin-l- yl)pyridine-3-sulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl] -5-chloro-6-[(2S)-2- (methoxymethyl)pyrrolidin-l-yl]pyridine-3-sulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-chloro-6-(2-isopropylpyrrolidin-l- yl)pyridine-3-sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-ethylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-isopropylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-(4-methoxyphenyl)thiophene- 2- sulfonamide; N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-isobutylthiophene- 2- sulfonamide;
N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-5-(4-methoxyphenyl)-4-methyl- thiophene- 2- sulfonamide;
N-[(5-Chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
3-Chloro-N- {[5-(methylthio)- 1,3-thiazo 1- 2- yl] carbamoyl Jbenzenesulfonamide; and
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3- cyclopropyl-benzenesulfonamide.
16. Compounds according to any one of claims 1 to 15 selected from
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-3-(difluoromethoxy)- benzenesulfonamide;
4-bromo-N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyi]-5-chlorothiophene- 2- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3,4-dichlorobenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-4-chloro-3-methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl] -2' ,4'-difluorobiphenyl-4- sulfonamide;
N-[(5-{[(5-tert-butyl-l,3-oxazol-2-yl)methyl]thio}-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-2-ethyl-2'-methylbiphenyl-4- sulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-ethylbiphenyl-4- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(4-methyl-l,3-oxazol-5- yl)benzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-ethylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-(4-methoxyphenyl)thiophene- 2- sulfonamide; N- [(5-bromo-l,3-thiazol- 2- yl)carbamoyl]-5-isobutylthiophene- 2- sulfonamide;
N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-5-(4-methoxyphenyl)-4-methyl- thiophene- 2- sulfonamide;
N-[(5-Chloro-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
3-Chloro-N- {[5-(methylthio)- 1,3-thiazo 1- 2- yl] carbamoyl Jbenzenesulfonamide;
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-3- cyclopropyl-benzenesulfonamide; N- [(5-Bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-2-chlorobenzenesulfonamide;
N-[(5-Bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxypyridin-3-yl)-4- methylthiophene- 2- sulfonamide; and N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-5-(6-methoxypyridin-3-yl)-4- methylthiophene- 2- sulfonamide.
17. Compounds according to any one of claims 1 to 14 selected from
N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-4-chloro-5-(2-methoxyethyl)thiophene-
2-sulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl] -5-(4-methoxy- 2-methylphen yl)-4- methylthiophene- 2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-methoxypyridin-3-yl)-3- methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-isobutyl-4-methylthiophene- 2- sulfonamide;
3-methyl-N-({4-methyl-5-[(trifluoromethyl)thio]-l,3-thiazol-2- yl}carbamoyl)benzenesulfonamide; N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl]-5-(2-methoxyethyl)-4-methylthiophene-
2-sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(6-fluoropyridin-3-yl)-3- methylbenzenesulfonamide;
N- [(5-bromo- 1,3-thiazo 1-2- yl)carbamoyl] -5-(6-fluoropyridin-3-yl)-4- methylthiophene- 2- sulfonamide; N- [(5-bromo- 1,3-thiazo 1- 2- yl)carbamoyl]-3-chloro-4-fluorobenzenesulfonamide; N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(3-methoxypropyl)-4- methylthiophene- 2- sulfonamide;
N-CCS-bromo-US-thiazol-l-y^carbamoyy-ΦCl-methoxy-US-thiazol-Φy^-S- methylbenzenesulfonamide; N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-4-(5-fluoropyridin-3-yl)-3- methylbenzenesulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-methoxy-4-methylthiophene-2- sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(2-methoxyethoxy)-4- methylthiophene-2-sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(6-methoxy-4-methylpyridin-3-yl)-4- methylthiophene-2-sulfonamide;
N-[(5-bromo-l,3-thiazol-2-yl)carbamoyl]-5-(methoxymethyl)-4-methylthiophene-
2-sulfonamide; N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide;
N-[(5-bromo-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3-
(difluoromethoxy)benzenesulfonamide;
3-methyl-N-[(4-methyl-5-nitro-l,3-thiazol-2-yl)carbamoyl]benzenesulfonamide;
N-{[5-bromo-4-(methoxymethyl)-l,3-thiazol-2-yl]carbamoyl}-3- methylbenzenesulfonamide; ethyl 5-bromo-2-({[(3-methylphenyl)sulfonyl] carbamoyl }amino)-l,3-thiazole-4- carboxylate;
N-[(5-methoxy-4-methyl-l,3-thiazol-2-yl)carbamoyl]-3- methylbenzenesulfonamide; and N-{[5-bromo-4-(hydroxymethyl)-l,3-thiazol-2-yl]carbamoyl}-3- methylbenzenesulfonamide.
18. A process for the preparation of a compound of formula I
Figure imgf000069_0001
according to any one of claims 1 to 17 comprising one of the following reactions:
a) reaction of a compound according to formula R3 -SO2CI
in the presence of NaOCN and a compound of formula
Figure imgf000070_0001
b) reaction of a compound according to formula
Figure imgf000070_0002
in the presence of a compound of formula
R3SO2NH2 Vl .
wherein R1 to R3 are defined according to any one of claims 1 to 17.
19. Compounds according to any one of claims 1 to 17 for use as therapeutically active substance.
20. Compounds according to any one of claims 1 to 17 for the preparation of medicaments for the prophylaxis and therapy of illnesses which are caused by disorders associated with the enzyme Fructose- 1,6-bisphosphatase.
21. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 17 and a therapeutically inert carrier.
22. The use of a compound according to any one of claims 1 to 17 for the preparation of medicaments for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia.
23. The use of claim 22 for the preparation of medicaments for the treatment and/or prophylaxis of Diabetes Mellitus Type II or Diabetes Mellitus Type I.
24. A compound according to any one of claims 1 to 17, when manufactured according to the process of claim 18.
25. A method for the treatment and/or prophylaxis of Diabetes Mellitus Type II, Diabetes Mellitus Type I, Diabetes Mellitus Type III, Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT), diabetic complications or ischaemia, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 17.
26. The method of claim 25 for the treatment and/or prophylaxis of Diabetes Mellitus Type II or Diabetes Mellitus Type I.
27. The invention as hereinbefore described.
***
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