WO2006048330A1 - 11βετα-hsd1 inhibitors - Google Patents

11βετα-hsd1 inhibitors Download PDF

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Publication number
WO2006048330A1
WO2006048330A1 PCT/EP2005/011933 EP2005011933W WO2006048330A1 WO 2006048330 A1 WO2006048330 A1 WO 2006048330A1 EP 2005011933 W EP2005011933 W EP 2005011933W WO 2006048330 A1 WO2006048330 A1 WO 2006048330A1
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alkyl
cycloalkyl
optionally substituted
phenyl
halogen
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PCT/EP2005/011933
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French (fr)
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WO2006048330A8 (en
Inventor
Thomas Stephen Coulter
Taylor Steven
Tara Fryatt
Babette Aicher
Martin Schneider
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Evotec Ag
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Priority to DE602005013812T priority Critical patent/DE602005013812D1/en
Priority to EP05806462A priority patent/EP1814846B1/en
Priority to US11/667,114 priority patent/US20090069323A1/en
Priority to DK05806462T priority patent/DK1814846T3/en
Priority to JP2007539549A priority patent/JP2008518999A/en
Publication of WO2006048330A1 publication Critical patent/WO2006048330A1/en
Publication of WO2006048330A8 publication Critical patent/WO2006048330A8/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
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    • 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
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a novel class of 1 l ⁇ -HSDl inhibitors, including pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds, particularly in the treatment of type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes mellitus (NIDDM), and of conditions that are often associated with this disease, such as metabolic syndrome, obesity and lipid disorders.
  • NIDDM non-insulin dependent diabetes mellitus
  • the present invention also relates to processes for preparing said compounds.
  • Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • hyperglycemia plasma glucose
  • IBDDM insulin-dependent diabetes mellitus
  • type 2 diabetes or noninsulin-dependent diabetes mellitus (NIDDM)
  • NIDDM noninsulin-dependent diabetes mellitus
  • Patients often have hyperinsulinemia plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects); however, these patients have developed insulin resistance, which is a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues.
  • Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for the insulin resistance so that serum glucose levels are not elevated, hi patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance.
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet completely understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, - ? -
  • Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality.
  • Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with type 2 diabetes mellitus are at an especially increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
  • This syndrome is characterized by insulin resistance, abdominal/visceral obesity, hyperinsulinemia, high blood pressure, low HDL, and high VLDL (dyslipidemia).
  • diabetes mellitus e.g. atherosclerosis and coronary heart disease/cardiovascular disease.
  • the metabolic syndrome often starts with continuous weight increase leading to significant visceral obesity.
  • Increased visceral adipose tissue mass which is not only an energy storage organ but also an important endocrine organ secreting hormones and signalling molecules, is believed to be a major source for the development of all the diseases that are summarized as metabolic syndrome especially dyslipidemia, hypertension, insulin resistance and ⁇ -cell dysfunction. Progression of visceral obesity can lead toinsulin resistance causing impaired glucose tolerance and finally type 2 diabetes mellitus.
  • Diabetes, dyslipidemia and hypertension are major risk factors for cardiovascular disease, a main cause for death in western world.
  • Increased 11 ⁇ -HSD 1 activity in adipocytes is believed to be one of the essential factors that are responsible for the increase of visceral adipose tissue mass because overexpression in adipose tissue in mice causes visceral obesity and finally a disease state representing human metabolic syndrome (Masuzaki, H. et al. 2001).Furthermore, increased 11 ⁇ -HSD 1 activity in visceral adipose tissue is found in patients with visceral obesity and/or type 2 diabetes mellitus and in patients with metabolic syndrome.
  • mice On the other hand deletion of 11 ⁇ -HSD 1 activity in mice protects against diet-induced obesity and related diseases like, glucose intolerance, insulin resistance, type 2 diabetes mellitus and metabolic syndrome (Kotelevtsev, Y. et al. 1997; Morton, NM. et al. 2001 and
  • sulfonylureas e. g. tolbutamide and glipizide
  • meglitinide which stimulate the pancreatic ⁇ -cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues.
  • phenformin can induce lactic acidosis and nausea/diarrhea.
  • Metformin has fewer side effects than phenformin and is often prescribed for the treatment of type 2 diabetes.
  • the glitazones are a newer class of compounds with the potential for ameliorating hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor
  • PPARgamma agom ' sm is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Besides these positive effects glitazones promote adipocyte differentiation leading to undesirable weight gain.
  • Newer PPAR agonists that are being developed for treatment of type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha, gamma and delta subtypes.
  • New biochemical approaches that have been recently introduced or are under active development include treatment with alpha-glucosidase inhibitors (e. g. acarbose), protein tyrosine phosphatase-lB (PTP-IB) inhibitors, and inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Inhibition of the expression of PTP-IB by the use of antisense oligonucleotides is also under investigation.
  • alpha-glucosidase inhibitors e. g. acarbose
  • PTP-IB protein tyrosine phosphatase-lB
  • DPP-IV dipeptidyl peptidase-IV
  • Another method of treating type 2 diabetes that has been suggested in the literature is the use of inhibitors of the 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (1 l ⁇ -HSD 1) to reduce the amount of active glucocorticoids in tissues where glucose is metabolized.
  • 1 l ⁇ -HSD 1 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme
  • Mono- and bicyclic thiazole sulfonamides are disclosed in WO-A 01/90090, WO-A 01/90091, WO-A 01/90092, WO-A 01/90093, WO-A 01/90094, WO-A 03/043999 and WO-A 2004/037251.
  • Thiophene and thiadiazole sufonamides are known from WO-A 03/044009 and WO-A 03/044000.
  • compounds containing a triazole moiety are known from WO-A 03/065983 and WO-A 03/104208.
  • Aryl and heteroaryl ketones are known from WO-A 04/011410.
  • 1,4-Disubstituted piperidines are known from WO-A 04/033427 and 2-oxo-ethanesulfonamides are known from WO-A 04/041264.
  • Adamantyl acetamides are known from WO-A 04/056744 and WO-A 04/056745.
  • Amide derivatives are known from WO-A 04/065351.
  • the object of the present invention is to provide a new class of compounds as 1 l ⁇ - HSD 1 inhibitors which may be effective in the treatment of type 2 diabetes, metabolic syndrome and other 1 l ⁇ -HSD 1 modulated diseases.
  • X 1 , X 2 , X 3 , X 4 are independently selected from the group consisting of N; and CR 4 , wherein R 4 is independently H; halogen; CN; C(O)OR 4a ; C(O)N(R 4a R 4b ); OR 4a ; N(R 4a R 4b ); phenyl; C 1-6 alkyl; or C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
  • R 4a , R 4 are independently selected from the group consisting of H; C 1-6 alkyl; and C 3-7 cycloalkyl;
  • R 1 , R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; and halogen, wherein Ci -6 alkyl and C 3-7 cycloalkyl are optionally substituted with halogen;
  • Y is -N(R la )S(O) 2 -; -S(O) 2 N(R 1 Y; or -N(R l3 )S(O) 2 N(R lb )-;
  • A is T; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R , wherein R 5 is independently halogen; CN; COOR 6 ; OR 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 63 ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)N(R 6a R 6b ); N(R 6 )C(CO)OR 6a ; OC(O)N(R 6 R 63 ); or T;
  • a and R la form together with the nitrogen to which they are attached to a heterocycle or heterobicycle, optionally substituted with one or more R 7 which are the same or different;
  • R 6 , R 6a R 6b are independently selected from the group consisting of H; Ci -6 alkyl; and T, wherein Ci -6 alkyl is optionally substituted with one or more halogen, which are the same of different;
  • T is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R 7 , which are the same or different; R 7 is independently halogen; CN; COOR 8 ; OR 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8
  • R 8 , R 8a , R 8b are independently selected from the group consisting of H; T 1 ; and C 1-6 alkyl, wherein Cj -6 alkyl is optionally substituted with one or more R 10 ;
  • R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 11 ;
  • R 11 , R lla , R l lb are independently selected from the group consisting of H; C 1-6 alkyl; and
  • T 1 is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 1 is optionally substituted with one or more
  • R 12 wherein R 12 is independently halogen; CN; COOR 13 ; OR 13 ; C(O)N(R 13 R 133 );
  • N(R 13 )C(0)OR 13a ; OC(O)N(R 13 R 133 ); oxo ( 0), where the ring is at least partially saturated; C(O)R 13 ; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; or heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
  • Z 1 N-R 15 and R 15 , R 3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R ;
  • Z 2 is O; S; or N-R 14 ;
  • R 3 , R 14 are independently selected from the group consisting of H; T 2 ; C 1-6 alkyl, wherein C C 11--66 a allkkyyll i iss o oppttiioonnaallllyy s suubbssttiittuutteedd w wiitthh o onnee o orr m moorree R R 11 , , provided that when one of R 3 and R 14 is H and the other is ethyl, R 17 is other than -COOH;
  • R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R ;
  • R 16 , R 18 , R 19 are independently selected from the group consisting of halogen; CN; COOR 20 ; OR 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ;
  • N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )S(O) 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; OC(O)N(R 20 R 20a );_oxo ( O), where the ring is at least partially saturated; C(O)R 20 ; C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 21 ; R 20 , R 20a , R 20b are independently selected from the group consisting
  • R 17 , R 21 are independently selected from the group consisting of halogen; CN; COOR 22 ; OR 22 ; C(O)R 22 ; C(O)N(R 22 R 22a ); S(O) 2 N(R 22 R 223 ); S(O)N(R 22 R 22a ); S(O) 2 R 22 ; N(R 22 )S(O) 2 N(R 22a R 22b ); SR 22 ; N(R 22 R 22a ); OC(O)R 22 ; N(R 22 )C(O)R 22a ; N(R 22 )SO 2 R 22a ; N(R 22 )S(O)R 22a ; N(R 22 )C(O)N(R 22a R 22b ); N(R 22 )C(O)OR 22a ; OC(O)N(R 22 R 22a ); C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein
  • R 22 , R 22a , R 22 are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more R ;
  • R , R a are independently selected from the group consisting of halogen; CN; COOR ; OR 24 ; C(O)R 24 ; C(O)N(R 24 R 24a ); S(O) 2 N(R 24 R 243 ); S(O)N(R 24 R 24a ); S(O) 2 R 24 ; N(R 24 )S(O) 2 N(R 24a R 24b ); SR 24 ; N(R 24 R 24a ); OC(O)R 24 ; N(R 24 )C(O)R 24a ; N(R 24 )SO 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)N(R 24a R 24b ); N(R 24 )C(O)OR 24a ; OC(O)N(R 24 R 24a ); and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are
  • R 24 , R 24a , R 24b are independently selected from the group consisting of H; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R , when the heterobicycle is unsubstituted or in 3,6 and/or 7 position substituted 1,2,3,4- tetrahydroquinoline and its 4-oxa, thia, aza and/or 8-aza derivatives; and
  • R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 18 , when the heterobicycle is unsubstituted or in 3,6 and/or 7 position substituted 1. ,2,3,4- tetrahydroquinoline and its 4-oxa, thia, aza and/or 8-aza derivatives.
  • a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
  • Alkyl means a straight-chain or branched carbon chain that may contain double or triple bonds. It is generally preferred that alkyl doesn't contain double or triple bonds. Each hydrogen of an alkyl carbon may be replaced by a substituent.
  • -CH 2 -, -CH 2 -CH 2 -, -CH CH-, -CH(CH 3 )-, -C(CH 2 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -CH(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a C 1-4 alkyl carbon may be replaced by a substituent.
  • -CH 2 -, -CH 2 -CH 2 -, -CH CH-, -CH(CH 3 )-, -C(CH 2 )-, - CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -CH(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a C 1-6 alkyl carbon may be replaced by a substituent.
  • C 3-7 cycloalkyl or “C 3-7 cycloalkyl ring” means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples for a heterocycle are furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, tri
  • Heterobicyclyl or “heterobicycle” means a heterocycle which is condensed with phenyl, C 3-7 cycloalkyl or an additional heterocycle to form a bicyclic ring system.
  • Condensed to form a bicyclic ring means that two rings are attached to each other by sharing two ring atoms.
  • heterobicycle examples include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substiruent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.
  • the s ⁇ bstituents A, Y, Z 1 , Z 2 , R 1 to R 3 and X 1 to X 4 of the formula (I) independently have the following meaning.
  • one or more of the substituents A, Y, Z 1 , Z 2 , R 1 to R 3 and X 1 to X 4 can have the preferred or more preferred meanings given below.
  • At most three of X 1 , X 2 , X 3 and X 4 are N; more preferred at most one of X 1 , X 2 , X 3 and X 4 is N.
  • R 4 is F; Cl; Br; CH 3 ; OCH 3 , NH 2 ; or phenyl.
  • Y is -*S(O) 2 -NH-, or -*S(O 2 )-N(CH 3 )- wherein the atom marked with an asterisk is attached to A.
  • A is phenyl, adamantyl; C 3-7 cycloalkyl; heterocyclyl; or C 1-O alkyl, wherein C 1- 6 alkyl is otionally substituted with T. More preferred, A is phenyl; cyclohexyl; thiophenyl; benzothiophenyl; naphthyl; diazolyl; or pyridyl.
  • A is T and T is optionally substituted with up to 3 R 7 , independently being F; Cl; CH 3 ; OCH 3 ; N(CH 3 ) 2 ; T 1 ; OT 1 ; or NHT 1 .
  • T is phenyl, which is optionally substituted with up to three halogens, independently being F; or Cl.
  • A is T and T is heterobicyclyl, more preferred T is decahydroquinoline or tetrahydroisoquinoline, wherein the ring nitrogen is directly linked to the sulphur of the sulphonamide group representing Y.
  • Z 1 0 and Z 2 is -NR 14 .
  • R 14 is H.
  • R 3 is phenyl; benzyl; heterocyclyl; C 3-7 cycloalkyl; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with OC 1-6 alkyl or C 3-7 cycloalkyl.
  • R 3 is T 2 and T 2 is substituted with up to three R 19 , independently being F; Cl; CH 3 ; OCH 3 ; N(CH 3 ) 2 ; COOH; COOCH 3 ; CF 3 ; or C(O)NH 2 .
  • T 2 is phenyl; cyclohexyl; or pyridyl.
  • R 3 , R 14 are independently H or C 1-6 alkyl independently selected from the group consisting of ethyl; isopropyl; n-propyl; n-butyl, wherein C 1-6 alkyl is optionally substituted with N(CH 3 ) 2 ; or N(C 2 Hs) 2 .
  • Z 1 N-R 15 and R 15 , R 3 jointly form a heterocycle.
  • the heterocycle is oxazole; oxadiazole; diazole; or triazole, wherein the heterocycle is optionally substituted with one R 16 being C 1-6 alkyl, optionally substituted with N(CH 3 ) 2 or N(CH 2 CH 3 ) 2 ; C 3-7 cycloalkyl; phenyl; or heterocyclyl.
  • R 16 is methyl; ethyl; iso-propyl; cyclohexyl; phenyl; or piperidinyl.
  • R 3 , R 14 jointly form a heterocycle.
  • the heterocycle is piperazine; morpholine; piperidine; or pyrrolidine, wherein the heterocycle is optionally substituted with methyl.
  • Prodrugs of the compounds of the invention are also within the scope of the present invention.
  • Prodrug means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxy! group is acylated, alkylated, phosphorylated or converted into the borate, e.g.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • compounds of general formula (I) may occur
  • the individual forms like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the present invention provides compounds of general formula (I) as 11 ⁇ -HSDl inhibitors.
  • the biochemical mechanism, where the 11 ⁇ -HSDl enzyme may play a role is described in more detail in WO-A 03/065983 under the paragraph "Biochemical Mechanism” starting on page 18, which paragraph is herewith incorporated by reference.
  • the tissue specific 11 ⁇ -HSD 1 enzyme and its counterpart 11 ⁇ -HSD2 may play a role for the modulation of glucocorticoid concentrations.
  • Glucocorticoids also called corticosteroids
  • Glucocorticoids are steroid hormones that play an important role in mammals, including humans. Control or modulation of glucocorticoid activity is important in regulating physiological processes in a wide range of tissues and organs.
  • 11 ⁇ -HSDl and 11 ⁇ -HSD2 have different cofactor requirements and substrate affinities.
  • the 11 ⁇ - hydroxysteroid dehydrogenase type 2 enzyme (1 l ⁇ -HSD2) is a high affinity enzyme that generally uses NAD + as the preferred cofactor and rapidly dehydrogenates 11 ⁇ -hydroxy- glucocorticoids, such as Cortisol, to 11-keto glucocorticoids, such as cortisone.
  • the ll ⁇ - hydroxysteroid dehydrogenase type 1 enzyme (1 l ⁇ -HSDl) is a low affinity enzyme that generally uses NADP + /NADPH as a cofactor rather than NAD + (Agarwal et al., 1994, J. Biol. Chem., 269: 25959-25962).
  • 1 l ⁇ -HSDl is capable of acting as both a reductase and a dehydrogenase. Therefore, selectivity may play a role with regard to inhibitors of 11 ⁇ -HSDl .
  • 11 ⁇ -HSDl in vivo mainly acts as a reductase, converting 11-ketoglucocorticoids, such as cortisone, to l l ⁇ -hydroxyglucocorticoids, such as Cortisol. Therefore 11 ⁇ -HSDl regulates the intracellular pool of the insulin antagonists 1 l ⁇ -hydroxyglucocorticoids, such as Cortisol in humans, especially in metabolically active tissues such as liver and adipose tissue.
  • increased 11 ⁇ -HSDl activity might be a cause for the development of type 2 diabetes mellitus, metabolic syndrome and related diseases, e. g. obesity, cardiovascular disease and hypertension.
  • MCI mild cognitive impairment
  • S. J. et al. 1998 Seckl, J. R. & Olsson, T. 1995.
  • the hippocampus plays a central role in the formation of long-lasting memories, highly expresses receptors for glucocorticoids in rodents (Reul, J. M. H. M. & de Kloet, E. R. 1985) and humans (Seckl, J. R. et al. 1991), and is particularly sensitive to the deleterious actions of chronic glucocorticoid excess (Landfield, P. W. et al. 1978; Meaney, M. J. et al. 1995).
  • HPA hypothalamic-pituitary-adrenal
  • 1 l ⁇ -HSDs are also expressed in the adult rat brain (Moisan, M.-P. et al. 1990; Lakshmi, V. et al. 1991; Sakai, R. R. et al. 1992) where 1 l ⁇ -HSDl is abundant, but 1 l ⁇ -HSD2 is largely absent (Roland, B. L. et al. 1995).
  • the reaction catalyzed is reduction.
  • glucocorticoids by 1 l ⁇ -HSDl allows intrinsically inert 11-keto steroids to mimic active glucocorticoids in potentiating kainate-induced neurotoxicity (Raj an, V. et al. 1996).
  • Carbenoxolone which inhibits unspecifically both isozymes of 11 ⁇ -HSD in vitro and in vivo (Stewart, P. M. et al. 1990), prevents regeneration of glucocorticoids by 1 l ⁇ -HSDl and thereby protects primary cultures of hippocampal cells from glucocorticoid-mediated exacerbation of excitatory amino acid neurotoxicity (Rajan, V. et al. 1996).
  • HAART Highly active antiretroviral therapy in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma Cortisol is not elevated.
  • adipose tissue of these patients with HAART-associated lipodystrophy ll ⁇ -HSDl mRNA is increased and its concentration is correlated with features of insulin resistance. Therefore highly active antiretroviral therapy (HAART)- associated lipodystrophy might be explained by increased local regeneration of Cortisol from inactive cortisone within adipose tissue, catalyzed by the enzyme 11 ⁇ -HSDl (Sutinen J. et al., Diabetologia Epub 29.09.2004).
  • Glucocorticoids are known to control the proliferation of undifferentiated cells and the differentiation of precursor cells to fully differentiated cells (T.M. Stulnig et al,
  • the activity of 11 ⁇ -HSDl may therefore contribute to the development of cancer cells and the growth of tumours.
  • Glucocorticoid-receptor immunoactivity in the hippocampus was found higher in seizure sensitive compared to seizure-resistant gerbils (LK. Hwang et al, Neurosci Res. 53 (2005), 14-24). Controlling glucocorticoid levels through 1 l ⁇ -HSDl activity may therefore be of therapeutic use for epilepsy.
  • 11 ⁇ -HSDl activity may be of therapeutic use for depression (WO-A 2005/060963; WO-A 2005/047250; WO-A 2005/075471). Accordingly, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, ⁇ -cell dysfunction, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART- associated lipodystrophy or other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 11 ⁇ -HSDl enzyme.
  • the present invention also provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of the onset of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, ⁇ -cell dysfunction, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART-associated lipodystrophy and other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 1 l ⁇ -HSDl enzyme, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other 11 ⁇ -HSD 1 inhibitors.
  • other active ingredients may be DPP-IV inhibitors; insulin sensitizers, e.g. PPAR agonists and biguanides; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; ⁇ -glucosidase inhibitors; glucagon receptor antagonists; GLP-I, GLP-I mimetics, and GLP-I receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents, e.g.
  • HMG-CoA reductase inhibitors sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PPAR ⁇ agonists, PPARoc/ ⁇ dual agonists, inhibitors of cholesterol absorption, acyl CoA: cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR agonists; antiobesity compounds ; ileal bile acid transporter inhibitors; anti-inflammatory agents; or protein tyrosine phosphatase-lB (PTP-IB) inhibitors.
  • Other active ingredients may be anti-hypertensive compounds or compounds for the treatment of cardiovascular diseases, particularly atherosclerosis.
  • the active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as di calcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions, hi all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • TMSCHN 2 Trimethylsilyldiazomethane
  • Available starting materials for the synthesis of preferred embodiments of the invention may be amines of formula (II) and sulfonyl chlorides of the formula (III). They may be purchased from commercially available sources such as Array, Sigma Aldrich, Fluka, ABCR or be synthesized by one skilled in the art.
  • A-Y-Cl wherein A is T or C 1-6 alkyl
  • the sulfamide moiety could be introduced using a literature procedure (J. Med. Chem, 1972, 15, 5, 538) starting from key intermediate 1C.
  • nitrile intermediate could be synthesised by reaction of ethyl pyruvate and 4- cyanopyridine, according to literature procedure (Tet. Lett., 1973, 645). It is anticipated that the remainder of the synthesis would utilise methodology already developed for route 1.
  • Ethyl 5-bromonicotinate could be reacted with copper cyanide in order to displace the bromine atom and introduce a nitrile. With the nitrile in hand the methodology for the remainder of the route should follow that of route 1.
  • the HCl salt of 3-aminomethyl-benzoic acid methyl ester 1C was dissolved in saturated sodium hydrogen carbonate and DCM. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were dried (MgSO 4 ) and concentrated in vacuo to liberate the free amine.
  • the final compounds were cleaved from resin with 60% TFA in DCM (2ml, x3) and the resulting solutions were concentrated. Typically the crude mixtures were purified by column chromatography with DCM/ EtOAC (up to 20% EtOAc) as the eluent to give the final compound.
  • 35EE 3-[(l,2,3,4-TetrahydBoisoquinoline-2-sulfonyl)aminomethyl ⁇ -benzoic acid
  • the compound was synthesised using method EE to give title compound 35EE (1.45 g, 100%)
  • LC/MS: 82% MH + , m/z 347, Rt 1.89 mins.
  • 34HH 4- ⁇ [3-((Decahydroisoquinoline-2-sutfonyl)aminomethyl)-benzoylamino]- methyl ⁇ -benzamide
  • the human embryonic kidney cell line HEK 293
  • HEK 293 As source for the respective enzyme the human embryonic kidney cell line, HEK 293, was transfected with the foil length cDNAs for human and mouse 1 l ⁇ -HSD 1 and human ll ⁇ - HSD2 followed by selection of stably expressing clones according to standard procedures.
  • the enzymatic reaction was carried out in the presence of cofactors NAD + (dehydrogenase activity) or NADPH (reductase activity) and the respective steroid substrates.
  • NADPH dehydrogenase activity
  • NADPH reductase activity
  • NADPH reductase activity
  • reaction buffer 20 mM Tris-HCl (pH 7.4), 250 mM sucrose, 100 mM NaCl 5 1 mM MgCl 2 , 1 mM EDTA, 1 mM EGTA, and stored on ice prior to use.
  • reaction mixtures plus compounds in concentrations between 10 pM and 300 ⁇ M were prepared in a total volume of 102 ⁇ l and were incubated for 15 min at 37°C.
  • the compounds exemplified in this invention typically have IC 50 values ⁇ 100 ⁇ M
  • the enzymatic reaction was started by adding 18 ⁇ l whole cell lysates, equivalent to 80.000 cells of the respective HSD overexpressing cell lines. After 60 minutes at 37°C the reaction was stopped by carbenoxolone (Sigma, cat. no C-4790), an inhibitor of all HSD enzymes analysed, in a final concentration of 100 ⁇ M.
  • cortisole or corticosterone were measured in an ELIS A-based assay principle.
  • This cortisol/corticosterone ELISA makes use of a monoclonal antibody specifically binding to cortisol/corticosterone.
  • the detection is competition-based, since Cortisol or corticosterone in a sample compete with Cortisol covalently attached to alkaline phosphatase (AP).
  • AP alkaline phosphatase
  • the amount of alkaline phosphatase bound was detected by a colourimetric measurement, using pNPP as phosphatase substrate.
  • 96well ELISA plates (Falcon, cat. no. BD 353915) were coated with 5 ⁇ g/ml rabbit anti mouse IgG antibody (Sigma, cat. no. M-9637) in PBS overnight at 4°C. After aspiration of this solution the wells were blocked with 200 mM acetate citrate buffer, pH 6.0, 20% FCS and 2% gelatine for one hour at RT. The plates were washed three times (50 mM Tris-HCl, pH 7.8, 0.1% Tween 20) and 100 ⁇ l of samples and standards, Cortisol or corticosterone ranging from 78 nM to 10 ⁇ M, were added. The stocks of Cortisol- AP conjugate (Fitzgerald, cat.
  • mice monoclonal anti-cortisol antibody (Biotrend cat. no. 2330-4879) were diluted 1:1600 or 1:3600, respectively, in 100 mM Tris-HCl , pH 7.7, 10 mM MgCl 2 , 0.1% BSA. 50 ⁇ l of each dilution were added per well. After a incubation of two hours at RT under shaking, plates were washed three times (50 mM Tris-HCl, pH 7.8, 0.1% Tween 20).
  • the compounds exemplified in this invention show no activity against the 1 l ⁇ -HSD-2 enzyme.
  • 30.000 1 l ⁇ -HSDl stably expressing HEK293 cells were seeded per 96 well in 100 ⁇ l culture medium (DMEM, 10% FCS and 600 ⁇ g/ml G418). After overnight incubation at 37°C and 5% CO 2 ll ⁇ -HSD inhibitors in final concentrations between 10 pM and 300 ⁇ M, 3 ⁇ M cortisone and 20 mM HEPES were added to the culture medium. All components, i.e. inhibitors, steroid substrate and HEPES were pre-diluted in DMEM prior to use.
  • Cortisol concentrations were carried out with a commercially available Cortisol ELISA (Assay Designs, cat. no. 901071) according to the recommended protocol.
  • concentrations of Cortisol were calculated with SoftmaxPro software (Molecular Devices), the inhibitory potency of 11 ⁇ - HSD inhibitors was determined by IC50 calculation with Prism 4.0 software (GraphPad).
  • the compounds exemplified in this invention typically have IC 50 values ⁇ 50 ⁇ M.
  • DMEM/Nutrient Mix F 12 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 17 ⁇ M biotin, 33 ⁇ M pantothenate, 10% none heat inactivated fetal calf serum
  • Differentiation was initiated by medium change to 100 ⁇ l differentiation medium (DMEM/Nutrient Mix F 12, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 17 ⁇ M biotin, 33 ⁇ M pantothenate, 0.01 mg/ml transferrin, 100 nM hydrocortisone, 20 nM human insulin, 0.2 nM T3, 25 nM dexamethasone, 250 ⁇ M IBMX, 3 ⁇ M rosiglitazone).
  • DMEM/Nutrient Mix F 12 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 17 ⁇ M biotin, 33 ⁇ M pantothenate, 0.01 mg/ml transferrin, 100 nM hydrocortisone, 20 nM human insulin, 0.2 nM T3, 25 nM dexamethasone, 250 ⁇ M IBMX, 3 ⁇ M rosiglitazone.
  • the medium was changed to post-differentiation medium (DMEM/Nutrient Mix F 12, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 17 ⁇ M biotin, 33 ⁇ M pantothenate, 0.01 mg/ml transferrin, 100 nM hydrocortisone, 20 nM human insulin, 0.2 nM T3).
  • the assay was performed with differentiated adipocytes between day 11 and day 15 of differentiation in assay medium (DMEM/Nutrient Mix F 12, 17 ⁇ M biotin, 33 ⁇ M pantothenate, 0.01 mg/ml transferrin, 20 nM human insulin, 0.2 nM T3, 0.5 ⁇ M cortisone).
  • the procedures for incubation with compound, determination of Cortisol concentrations and data analysis were performed identically to the cellular assay with HEK293 cells described above.
  • the compounds exemplified in this invention typically have IC 5 0 values ⁇ 50 ⁇ M.

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Abstract

The invention relates to compounds of formula (I) wherein A, Y, Z1, Z2, R1 to R3 and X1 to X4 have the meaning as cited in the description and the claims. For example A is 4'-fluorobiphen-4-yl; Y is -S(O)2NH-; R1, R2 are H; X1, X2, X4 are CH; X3 is C-F; Z' is =0; and Z2-R3 is N(CH2CH3)2 . Said compounds are useful as 11ß-HSD1 inhibitors. The invention also relates to the preparation of such compounds as well as the production and use as medicament.

Description

11BETA-HSD1 INHIBITORS
The present invention relates to a novel class of 1 lβ-HSDl inhibitors, including pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds, particularly in the treatment of type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes mellitus (NIDDM), and of conditions that are often associated with this disease, such as metabolic syndrome, obesity and lipid disorders. The present invention also relates to processes for preparing said compounds.
Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes, hi type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body. Patients often have hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects); however, these patients have developed insulin resistance, which is a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for the insulin resistance so that serum glucose levels are not elevated, hi patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet completely understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, - ? -
oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver (gluconeogenesis and glycogenosis).
Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with type 2 diabetes mellitus are at an especially increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus and metabolic syndrome.
Many patients who have insulin resistance but have not developed type 2 diabetes are at a risk of developing at least several symptoms selected from a group of symptoms that are often referred to as syndrome X, or the metabolic syndrome.
This syndrome is characterized by insulin resistance, abdominal/visceral obesity, hyperinsulinemia, high blood pressure, low HDL, and high VLDL (dyslipidemia). These patients, whether or not they develop overt diabetes mellitus, are at increased risk of the microvascular and microvascular complications of type 2 diabetes listed above (e. g. atherosclerosis and coronary heart disease/cardiovascular disease). The metabolic syndrome often starts with continuous weight increase leading to significant visceral obesity. Increased visceral adipose tissue mass, which is not only an energy storage organ but also an important endocrine organ secreting hormones and signalling molecules, is believed to be a major source for the development of all the diseases that are summarized as metabolic syndrome especially dyslipidemia, hypertension, insulin resistance and β-cell dysfunction. Progression of visceral obesity can lead toinsulin resistance causing impaired glucose tolerance and finally type 2 diabetes mellitus.
Diabetes, dyslipidemia and hypertension are major risk factors for cardiovascular disease, a main cause for death in western world.
Increased 11 β-HSD 1 activity in adipocytes is believed to be one of the essential factors that are responsible for the increase of visceral adipose tissue mass because overexpression in adipose tissue in mice causes visceral obesity and finally a disease state representing human metabolic syndrome (Masuzaki, H. et al. 2001).Furthermore, increased 11 β-HSD 1 activity in visceral adipose tissue is found in patients with visceral obesity and/or type 2 diabetes mellitus and in patients with metabolic syndrome. On the other hand deletion of 11 β-HSD 1 activity in mice protects against diet-induced obesity and related diseases like, glucose intolerance, insulin resistance, type 2 diabetes mellitus and metabolic syndrome (Kotelevtsev, Y. et al. 1997; Morton, NM. et al. 2001 and
2004) and ameliorates age-related learning impairments in addition (Yau, JLW. et al.
2001).
The available treatments for type 2 diabetes have not changed substantially in many years, and these treatments have recognized limitations.
Physical exercise and reductions in dietary intake of calories often dramatically improve the diabetic condition, but compliance with this treatment is very poor because of well- entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of sugar and saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e. g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic β-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues.
However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. - A -
However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of type 2 diabetes.
The glitazones (i. e. 5-benzylthiazolidine-2,4-diones) are a newer class of compounds with the potential for ameliorating hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor
(PPAR) gamma subtype. PPARgamma agom'sm is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Besides these positive effects glitazones promote adipocyte differentiation leading to undesirable weight gain. Newer PPAR agonists that are being developed for treatment of type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha, gamma and delta subtypes.
There is a continuing need for new methods of treating the disease.
New biochemical approaches that have been recently introduced or are under active development include treatment with alpha-glucosidase inhibitors (e. g. acarbose), protein tyrosine phosphatase-lB (PTP-IB) inhibitors, and inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Inhibition of the expression of PTP-IB by the use of antisense oligonucleotides is also under investigation.
Another method of treating type 2 diabetes that has been suggested in the literature is the use of inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 enzyme (1 lβ-HSD 1) to reduce the amount of active glucocorticoids in tissues where glucose is metabolized.
Mono- and bicyclic thiazole sulfonamides are disclosed in WO-A 01/90090, WO-A 01/90091, WO-A 01/90092, WO-A 01/90093, WO-A 01/90094, WO-A 03/043999 and WO-A 2004/037251. Thiophene and thiadiazole sufonamides are known from WO-A 03/044009 and WO-A 03/044000. Additionally compounds containing a triazole moiety are known from WO-A 03/065983 and WO-A 03/104208.
Aryl and heteroaryl ketones are known from WO-A 04/011410. 1,4-Disubstituted piperidines are known from WO-A 04/033427 and 2-oxo-ethanesulfonamides are known from WO-A 04/041264. Adamantyl acetamides are known from WO-A 04/056744 and WO-A 04/056745. Amide derivatives are known from WO-A 04/065351.
Compounds with similar structure but related to a different technical field are known from WO 03/078398, R. Ziessel et al, Synthesis 14 (2003), 2145-2154) and Y.A. Aizina et al, Russian Journal of Organic Chemisty 38 (2002), 235-238.
Thus, the object of the present invention is to provide a new class of compounds as 1 lβ- HSD 1 inhibitors which may be effective in the treatment of type 2 diabetes, metabolic syndrome and other 1 lβ-HSD 1 modulated diseases.
Accordingly, the present invention provides compounds of formula (I)
Figure imgf000006_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X1, X2, X3, X4 are independently selected from the group consisting of N; and CR4, wherein R4 is independently H; halogen; CN; C(O)OR4a; C(O)N(R4aR4b); OR4a; N(R4aR4b); phenyl; C1-6 alkyl; or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R4a, R4 are independently selected from the group consisting of H; C1-6 alkyl; and C3-7 cycloalkyl; R1, R2 are independently selected from the group consisting of H; C1-6 alkyl; C3-7 cycloalkyl; and halogen, wherein Ci-6 alkyl and C3-7 cycloalkyl are optionally substituted with halogen;
Optionally R1, R2 are combined to form oxo (=O);
Y is -N(Rla)S(O)2-; -S(O)2N(R1Y; or -N(Rl3)S(O)2N(Rlb)-;
A is T; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R , wherein R5 is independently halogen; CN; COOR6; OR6; C(O)N(R6R6a); S(O)2N(R6R63); S(O)N(R6R6a); S(O)2R6; N(R6)S(O)2N(R6aR6b); SR6; N(R6R6a); OC(O)R6; N(R6)C(O)R6a; N(R6)S(O)2R6a; N(R6)S(O)R6a; N(R6)C(O)N(R6aR6b); N(R6)C(CO)OR6a; OC(O)N(R6R63); or T;
Rla, Rlb are independently selected from the group consisting of H; allyl; benzyl; CH2- C(O)NH2; CH2-COOH; CH2-C(O)O-Ci-6 alkyl; C1-6 alkyl; and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more Rlc, wherein R c is independently halogen; C1-6 alkyl; -CH=CH2; phenyl; C(O)NH2; COOH; C(O)O-Ci-6 alkyl or C3-7 cycloalkyl;
Optionally A and Rla form together with the nitrogen to which they are attached to a heterocycle or heterobicycle, optionally substituted with one or more R7 which are the same or different;
R6, R6a R6b are independently selected from the group consisting of H; Ci-6 alkyl; and T, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R7, which are the same or different; R7 is independently halogen; CN; COOR8; OR8; C(O)N(R8R8a); S(O)2N(R8R8a); S(O)N(R8R8a); S(O)2R8; N(R8)S(O)2N(R8aR8b); SR8; N(R8R8a); OC(O)R8; N(R8)C(O)R8a; N(R8)S(O)2R8a; N(R8)S(O)R8a; N(R8)C(O)N(R8aR8b); N(R8)C(O)OR8a; OC(O)N(R8R8a); oxo (=0), where the ring is at least partially saturated; C(O)R8; T1; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R ;
R8, R8a, R8b are independently selected from the group consisting of H; T1; and C1-6 alkyl, wherein Cj-6 alkyl is optionally substituted with one or more R10;
R9, R10 are independently selected from the group consisting of halogen; CN; COOR11;
OR11; C(O)R11; C(O)N(R11R11'); S(O)2N(R11R112); S(O)N(R11R113); S(O)2R11;
N(Rπ)S(0)2N(RllaRl lb); SR11; N(RπRl la); OC(O)R11; N(R1 ^C(O)R113; N(R1 ^SO2R113;
N(R1 ^S(O)R113; N(R1 ^C(O)N(R113R1 lb); N(R1 ^C(O)OR113; OC(O)N(R11R113); and T1;
R11, Rlla, Rl lb are independently selected from the group consisting of H; C1-6 alkyl; and
T1;
T1 is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T1 is optionally substituted with one or more
R12, wherein R12 is independently halogen; CN; COOR13; OR13; C(O)N(R13R133);
S(O)2N(R13R133); S(O)N(R13R133); S(O)2R13; N(R13)S(O)2N(R13aR13b); SR13; N(R13R133);
OC(O)R13; N(R13)C(O)R13a; N(R13)S(O)2R13a;N(R13)S(O)R13a; N(R13)C(O)N(R13aR13b);
N(R13)C(0)OR13a; OC(O)N(R13R133); oxo (=0), where the ring is at least partially saturated; C(O)R13; C1-6 alkyl; phenyl; C3-7 cycloalkyl; or heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H; Ci-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different; Z1 is =0 or =S;
Optionally Z1 is =N-R15 and R15, R3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R ;
Z2 is O; S; or N-R14;
R3, R14 are independently selected from the group consisting of H; T2; C1-6 alkyl, wherein C C11--66 a allkkyyll i iss o oppttiioonnaallllyy s suubbssttiittuutteedd w wiitthh o onnee o orr m moorree R R11 , , provided that when one of R3 and R14 is H and the other is ethyl, R17 is other than -COOH;
Optionally R3, R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R ;
T2 is C3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T2 is optionally substituted with one or more R19; provided that when A is phenyl; Y is -S(O)2NH-, wherein the sulfur is attached to A; R1, R2 are H; X1, X3, X4 are CH; X2 is C-R4, wherein R4 is OCH3; Z1 is =0; and Z2 is NH, T2 is other than unsubstituted phenyl;
R16, R18, R19 are independently selected from the group consisting of halogen; CN; COOR20; OR20; C(O)N(R20R20a); S(O)2N(R20R20a); S(O)N(R20R20a); S(O)2R20;
N(R20)S(O)2N(R20aR20b); SR20; N(R20R20a); OC(O)R20; N(R20)C(O)R20a; N(R20)S(O)2R20a; N(R20)S(O)R20a; N(R20)C(O)N(R20aR20b); N(R20)C(O)OR20a; OC(O)N(R20R20a);_oxo (=O), where the ring is at least partially saturated; C(O)R20; C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R21 ; R20, R20a, R20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R17, R21 are independently selected from the group consisting of halogen; CN; COOR22; OR22; C(O)R22; C(O)N(R22R22a); S(O)2N(R22R223); S(O)N(R22R22a); S(O)2R22; N(R22)S(O)2N(R22aR22b); SR22; N(R22R22a); OC(O)R22; N(R22)C(O)R22a; N(R22)SO2R22a; N(R22)S(O)R22a; N(R22)C(O)N(R22aR22b); N(R22)C(O)OR22a; OC(O)N(R22R22a); C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R23;
R22, R22a, R22 are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more R ;
R , R a are independently selected from the group consisting of halogen; CN; COOR ; OR24; C(O)R24; C(O)N(R24R24a); S(O)2N(R24R243); S(O)N(R24R24a); S(O)2R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R24a); OC(O)R24; N(R24)C(O)R24a; N(R24)SO2R24a; N(R24)S(O)R24a; N(R24)C(O)N(R24aR24b); N(R24)C(O)OR24a; OC(O)N(R24R24a); and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
With regard to compounds of formula (I) according to the present invention as such it is preferred that the following compounds are excluded:
• Compounds where Z1 is =N-R15 and R15, R3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 16 , when the heterocycle is
Figure imgf000011_0001
Compounds, where R3, R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R , when the heterobicycle is unsubstituted or in 3,6 and/or 7 position substituted 1,2,3,4- tetrahydroquinoline and its 4-oxa, thia, aza and/or 8-aza derivatives; and
• N-[l-(3-aminocarbonyl-4-hydroxyphenyl)-2,2,2-trichloroethyl]-4- chlorobenzenesulfonamide.
With regard to compounds of formula (I) according to the present invention for use as a medicament and as only active ingredient of a pharmaceutical composition it is preferred that the following compounds are excluded:
• Compounds, where R3, R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R18, when the heterobicycle is unsubstituted or in 3,6 and/or 7 position substituted 1. ,2,3,4- tetrahydroquinoline and its 4-oxa, thia, aza and/or 8-aza derivatives. In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
Within the meaning of the present invention the terms are used as follows:
"Alkyl" means a straight-chain or branched carbon chain that may contain double or triple bonds. It is generally preferred that alkyl doesn't contain double or triple bonds. Each hydrogen of an alkyl carbon may be replaced by a substituent.
"C1-4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, -CH=CH2, -C≡CH, n-propyl, isopropyl, -CH=CH-CH3, -CH2- CH=CH2, n-butyl, isobutyl, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, sec-butyl tert-butyl, or e.g. -CH2-, -CH2-CH2-, -CH=CH-, -CH(CH3)-, -C(CH2)-, -CH2-CH2-CH2-, -CH(C2H5)-, -CH(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-4 alkyl carbon may be replaced by a substituent.
"C1-6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C1-4 alkyl, methyl, ethyl, -CH=CH2, -C≡CH, n-propyl, isopropyl, -CH=CH-CH3, -CH2-CH=CH2, n-butyl, isobutyl, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, sec-butyl; tert- butyl, n-pentane, n-hexane, or e.g. -CH2-, -CH2-CH2-, -CH=CH-, -CH(CH3)-, -C(CH2)-, - CH2-CH2-CH2-, -CH(C2H5)-, -CH(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-6 alkyl carbon may be replaced by a substituent.
"C3-7 cycloalkyl" or "C3-7 cycloalkyl ring" means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.
"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro. "Heterocyclyl" or "heterocycle" means a cyclopentane, cyclohexane or cycloheptane ring that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one carbon atom up to 4 carbon atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a heterocycle are furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, azepine or homopiperazine. "Heterocycle" means also azetidine.
"Heterobicyclyl" or "heterobicycle" means a heterocycle which is condensed with phenyl, C3-7 cycloalkyl or an additional heterocycle to form a bicyclic ring system. "Condensed" to form a bicyclic ring means that two rings are attached to each other by sharing two ring atoms. Examples for a heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substiruent definitions being a subject of the present invention. With respect to all preferred compounds of the formulas (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts. In preferred embodiments of the present invention, the sύbstituents A, Y, Z1, Z2, R1 to R3 and X1 to X4 of the formula (I) independently have the following meaning. Hence, one or more of the substituents A, Y, Z1, Z2, R1 to R3 and X1 to X4 can have the preferred or more preferred meanings given below.
Preferably, at most three of X1, X2, X3 and X4 are N; more preferred at most one of X1, X2, X3 and X4 is N.
Preferably, R1 and R2 are H or combined to form =O.
Preferably, R4 is F; Cl; Br; CH3; OCH3, NH2; or phenyl.
Preferably, Y is -*S(O)2-NH-, or -*S(O2)-N(CH3)- wherein the atom marked with an asterisk is attached to A.
Preferably, A is phenyl, adamantyl; C3-7 cycloalkyl; heterocyclyl; or C1-O alkyl, wherein C1- 6 alkyl is otionally substituted with T. More preferred, A is phenyl; cyclohexyl; thiophenyl; benzothiophenyl; naphthyl; diazolyl; or pyridyl.
It is also preferred, that A is T and T is optionally substituted with up to 3 R7, independently being F; Cl; CH3; OCH3; N(CH3)2; T1; OT1; or NHT1.
Preferably, T is phenyl, which is optionally substituted with up to three halogens, independently being F; or Cl.
It is also preferred that A is T and T is heterobicyclyl, more preferred T is decahydroquinoline or tetrahydroisoquinoline, wherein the ring nitrogen is directly linked to the sulphur of the sulphonamide group representing Y.
Preferably, Z1 is =0 and Z2 is -NR14.
Preferably, R14 is H. Preferably, R3 is phenyl; benzyl; heterocyclyl; C3-7 cycloalkyl; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with OC1-6 alkyl or C3-7 cycloalkyl.
It is also preferred, that R3 is T2 and T2 is substituted with up to three R19, independently being F; Cl; CH3; OCH3; N(CH3)2; COOH; COOCH3; CF3; or C(O)NH2.
Preferably, T2 is phenyl; cyclohexyl; or pyridyl.
Preferably, R3, R14 are independently H or C1-6 alkyl independently selected from the group consisting of ethyl; isopropyl; n-propyl; n-butyl, wherein C1-6 alkyl is optionally substituted with N(CH3)2; or N(C2Hs)2.
It is also preferred, that Z1 is =N-R15 and R15, R3 jointly form a heterocycle. Preferably, the heterocycle is oxazole; oxadiazole; diazole; or triazole, wherein the heterocycle is optionally substituted with one R16 being C1-6 alkyl, optionally substituted with N(CH3 )2 or N(CH2CH3)2; C3-7 cycloalkyl; phenyl; or heterocyclyl.
More preferred, R16 is methyl; ethyl; iso-propyl; cyclohexyl; phenyl; or piperidinyl.
It is also preferred, that R3, R14 jointly form a heterocycle. Preferably the heterocycle is piperazine; morpholine; piperidine; or pyrrolidine, wherein the heterocycle is optionally substituted with methyl.
Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.
Prodrugs of the compounds of the invention are also within the scope of the present invention.
"Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxy! group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods.
Metabolites of compounds of formula (I) are also within the scope of the present invention.
Where tautomerism, like e.g. keto-enol tautomerism, of compounds of general formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.
If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
The present invention provides compounds of general formula (I) as 11 β-HSDl inhibitors. The biochemical mechanism, where the 11 β-HSDl enzyme may play a role is described in more detail in WO-A 03/065983 under the paragraph "Biochemical Mechanism" starting on page 18, which paragraph is herewith incorporated by reference.
Accordingly, the tissue specific 11 β-HSD 1 enzyme and its counterpart 11 β-HSD2 may play a role for the modulation of glucocorticoid concentrations. Glucocorticoids (also called corticosteroids) are steroid hormones that play an important role in mammals, including humans. Control or modulation of glucocorticoid activity is important in regulating physiological processes in a wide range of tissues and organs. 11 β-HSDl and 11 β-HSD2 have different cofactor requirements and substrate affinities. The 11 β- hydroxysteroid dehydrogenase type 2 enzyme (1 lβ-HSD2) is a high affinity enzyme that generally uses NAD+ as the preferred cofactor and rapidly dehydrogenates 11 β-hydroxy- glucocorticoids, such as Cortisol, to 11-keto glucocorticoids, such as cortisone. The llβ- hydroxysteroid dehydrogenase type 1 enzyme (1 lβ-HSDl) is a low affinity enzyme that generally uses NADP+/NADPH as a cofactor rather than NAD+ (Agarwal et al., 1994, J. Biol. Chem., 269: 25959-25962). In vitro studies have shown that 1 lβ-HSDl is capable of acting as both a reductase and a dehydrogenase. Therefore, selectivity may play a role with regard to inhibitors of 11 β-HSDl . However, 11 β-HSDl in vivo mainly acts as a reductase, converting 11-ketoglucocorticoids, such as cortisone, to l lβ-hydroxyglucocorticoids, such as Cortisol. Therefore 11 β-HSDl regulates the intracellular pool of the insulin antagonists 1 lβ-hydroxyglucocorticoids, such as Cortisol in humans, especially in metabolically active tissues such as liver and adipose tissue. Hence, increased 11 β-HSDl activity might be a cause for the development of type 2 diabetes mellitus, metabolic syndrome and related diseases, e. g. obesity, cardiovascular disease and hypertension.
1 lβ-HSDl enzyme related or modulated diseases are also described in more detail in WO- A 03/065983 under the paragraph "Utilities" starting on page 20, which paragraph is herewith incorporated by reference.
Another disease related to the 1 lβ-HSDl enzyme is Alzheimer's disease and its inherent mild cognitive impairment (MCI) that is a common feature of aging but is, at present, untreatable (Ritchie, K. & Touchon, J. 2000). MCI and Alzheimer's disease are associated with a poor quality of life and loss of independence in older people and results in huge socioeconomic costs (Fillit, H. et al. 2002). In aged animals and humans, interindividual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure (Lupien, S. J. et al. 1998; Seckl, J. R. & Olsson, T. 1995). The hippocampus plays a central role in the formation of long-lasting memories, highly expresses receptors for glucocorticoids in rodents (Reul, J. M. H. M. & de Kloet, E. R. 1985) and humans (Seckl, J. R. et al. 1991), and is particularly sensitive to the deleterious actions of chronic glucocorticoid excess (Landfield, P. W. et al. 1978; Meaney, M. J. et al. 1995). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis with resultant chronically increased exposure of the hippocampus to elevated glucocorticoid levels has been hypothesized to contribute to the decline in cognitive function with aging, through the detrimental effects of glucocorticoids on hippocampal neurons (McEwen, B. S. & Sapolsky, R. M. 1995; McEwen, B. S. 1999). In human populations, including those with Alzheimer's disease and normal aging, higher Cortisol levels have been associated with poorer memory and hippocampal shrinkage/neuronal loss (Lupien, S. J. et al. 1998;
Newcomer, J. W. et al. 1994; de Leon, M. J. et al. 1988). 1 lβ-HSDs are also expressed in the adult rat brain (Moisan, M.-P. et al. 1990; Lakshmi, V. et al. 1991; Sakai, R. R. et al. 1992) where 1 lβ-HSDl is abundant, but 1 lβ-HSD2 is largely absent (Roland, B. L. et al. 1995). In intact rat hippocampal cells in primary culture, which express solely the 11 β- HSDl isozyme, the reaction catalyzed is reduction. Such reactivation of glucocorticoids by 1 lβ-HSDl allows intrinsically inert 11-keto steroids to mimic active glucocorticoids in potentiating kainate-induced neurotoxicity (Raj an, V. et al. 1996). Carbenoxolone, which inhibits unspecifically both isozymes of 11 β-HSD in vitro and in vivo (Stewart, P. M. et al. 1990), prevents regeneration of glucocorticoids by 1 lβ-HSDl and thereby protects primary cultures of hippocampal cells from glucocorticoid-mediated exacerbation of excitatory amino acid neurotoxicity (Rajan, V. et al. 1996). Regeneration of glucocorticoids by 1 lβ-HSDl within neurons seems important in vivo because 11 β-HSD 1 knockout mice are protected from glucocorticoid-associated hippocampal dysfunction with aging (Yau, J. L. W. et al. 2001). Therefore specific inhibition of 1 lβ-HSDl might additionally protect against age-dependent cognitive impairment. Furthermore, administration of the 11 β-HSD inhibitor carbenoxolone improved verbal fluency in healthy elderly men and improved verbal memory in patients with type 2 diabetes (Sandeep T. C. et al. 2004).
Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma Cortisol is not elevated. In adipose tissue of these patients with HAART-associated lipodystrophy, llβ-HSDl mRNA is increased and its concentration is correlated with features of insulin resistance. Therefore highly active antiretroviral therapy (HAART)- associated lipodystrophy might be explained by increased local regeneration of Cortisol from inactive cortisone within adipose tissue, catalyzed by the enzyme 11 β-HSDl (Sutinen J. et al., Diabetologia Epub 29.09.2004).
1 lβ-HSDl is expressed in both osteoclasts and osteoclasts (J.W. Tomlinson, Minerva Endocrinol VoI 30(2005), 37-46). Sine its activity increases with age in primary cultures of osteoblasts, a role in the pathogenesis of age related bone loss (osteoporosis) is likely (M.S. Cooper et al, J Bone Miner Res Voll7(2002), 979-86).
Glucocorticoids are known to control the proliferation of undifferentiated cells and the differentiation of precursor cells to fully differentiated cells (T.M. Stulnig et al,
Diabetologica 47 (2004), 1-11. The activity of 11 β-HSDl may therefore contribute to the development of cancer cells and the growth of tumours.
Abnormal corticosteroid levels enhance the vulnerability of specific hippocampal neurons. Glucocorticoid-receptor immunoactivity in the hippocampus was found higher in seizure sensitive compared to seizure-resistant gerbils (LK. Hwang et al, Neurosci Res. 53 (2005), 14-24). Controlling glucocorticoid levels through 1 lβ-HSDl activity may therefore be of therapeutic use for epilepsy.
It is also believed that 11 β-HSDl activity may be of therapeutic use for depression (WO-A 2005/060963; WO-A 2005/047250; WO-A 2005/075471). Accordingly, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.
Furthermore, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, β-cell dysfunction, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART- associated lipodystrophy or other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 11 β-HSDl enzyme.
The present invention also provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of the onset of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, β-cell dysfunction, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART-associated lipodystrophy and other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 1 lβ-HSDl enzyme, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
The present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other 11 β-HSD 1 inhibitors.
Other active ingredients are disclosed, e.g., in WO-A 03/065983 under the paragraph "Combination Therapy" starting on page 27, which paragraph is herewith incorporated by reference.
Accordingly, other active ingredients may be DPP-IV inhibitors; insulin sensitizers, e.g. PPAR agonists and biguanides; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; α-glucosidase inhibitors; glucagon receptor antagonists; GLP-I, GLP-I mimetics, and GLP-I receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents, e.g. HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PPARγ agonists, PPARoc/γ dual agonists, inhibitors of cholesterol absorption, acyl CoA: cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR agonists; antiobesity compounds ; ileal bile acid transporter inhibitors; anti-inflammatory agents; or protein tyrosine phosphatase-lB (PTP-IB) inhibitors. Other active ingredients may be anti-hypertensive compounds or compounds for the treatment of cardiovascular diseases, particularly atherosclerosis.
The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as di calcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions, hi all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or preventing diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of formula (I) are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
Some abbreviations that may appear in this application are as follows.
Abbreviations
Designation
Boc 'Butoxycarbonyl
Boc2O Di-te/t-butyl-di carbonate nBuLi «-Butyl lithium
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMAP Dimethylaminopyridine
DMF N,7V-Dimethylformamide
DPPA Diphenyl phosphoryl azide
EDC 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAc Ethyl acetate
EtOH Ethanol
FMPE 2-(4-Formyl-3 -methoxphenoxy)ethyl polystyrene
HOBt 1 -Hydroxybenzotriazole
MeOH Methanol
STAB Sodium triacetoxyborohydride
TBTU 2-( lH-Benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluoroborate
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TMOF Trimethylorthoformate
TMSCHN2 (Trimethylsilyl)diazomethane Available starting materials for the synthesis of preferred embodiments of the invention may be amines of formula (II) and sulfonyl chlorides of the formula (III). They may be purchased from commercially available sources such as Array, Sigma Aldrich, Fluka, ABCR or be synthesized by one skilled in the art.
hi general preferred compounds of the formula (I)
Figure imgf000027_0001
wherein the variables have the above described meanings may be prepared by reducing a compound of formula (II)
Figure imgf000027_0002
and coupling the resulting amine (III)
Figure imgf000027_0003
with A-Y-Cl, wherein A is T or C1-6 alkyl; or
with A-H and SO2Cl2, wherein A is T-N(Rlc)-. More specific routes to prepare preferred embodiments of compounds of the present invention are outlined in schemes A to I.
Exemplified conditions for a reaction according to scheme A are given in the experimental section - Route 1
TMSCHN2
Figure imgf000028_0001
Figure imgf000028_0002
1. H2, Pd/C, BoC2O 2. HCI/ Dioxane
3 A-SO2CI
HOBt
Figure imgf000028_0004
Figure imgf000028_0003
Scheme A
An alternative route to these compounds is being investigated using solid phase reagents (J. Comb. Chem.2000, 2, 66-1 A, Tetrahedron Lett. 2002, 43, 4741-4745). Key intermediate 1C (prepared as described in route 1) is loaded onto a benzaldehyde resin before the remainder of the chemistry is carried out (scheme B).
Figure imgf000029_0001
1. HCI/ Dioxaπe 2. AMEBA 2
A-SO2CI
HOBt
Figure imgf000029_0003
Figure imgf000029_0002
Scheme B
Exemplified conditions for a reaction according to scheme C are given in the experimental section (where R4= F) - Route 2
Figure imgf000029_0004
DCM
HOBt
Figure imgf000029_0006
Figure imgf000029_0005
Scheme C
The sulfamide moiety could be introduced using a literature procedure (J. Med. Chem, 1972, 15, 5, 538) starting from key intermediate 1C.
Figure imgf000030_0001
HOBt
Figure imgf000030_0002
Scheme D
The synthesis of oxadiazoles from the carboxylic acid and amidoximes is described in Tetrahedron Lett. 2001, 42, 1495-1498 and J. Org. Chem. 2003, 68, 7316-7321. The carboxylic acid precursor would be prepared by route 1
Figure imgf000030_0003
Scheme E
Pyridyl Replacements for the Benzyl (Central) Ring
Three series of compounds are described below in which the nitrogen occupies a different position in the central ring.
Series 1
The key nitrile intermediate could be synthesised by reaction of ethyl pyruvate and 4- cyanopyridine, according to literature procedure (Tet. Lett., 1973, 645). It is anticipated that the remainder of the synthesis would utilise methodology already developed for route 1.
Figure imgf000031_0001
1. H2, Pd/C, Boc^O
2. HCI
3. A-SO2Cl
Figure imgf000031_0002
Scheme F
Series 2
Ethyl 5-bromonicotinate could be reacted with copper cyanide in order to displace the bromine atom and introduce a nitrile. With the nitrile in hand the methodology for the remainder of the route should follow that of route 1.
Figure imgf000031_0003
1. H2, Pd/C, BoC2O
2 HC!
3 A-SO2CI
HOB
Figure imgf000031_0005
Figure imgf000031_0004
Scheme G Series 3
The route for the synthesis of these compounds could be synthesised using the same conditions as for series 2 except that the starting material would be ethyl 2- bromoisonicotinate. Subsequent steps should follow route 1.
Figure imgf000032_0001
1. H2, Pd/C, BoC2O
2. HCI
3. A-SO2CI
HOBt
Figure imgf000032_0003
Figure imgf000032_0002
Scheme H
Pyrimidinyl Replacement for the Benzyl (Central) Ring
The route to the key intermediate in this synthesis will involve a cyanide displacement of the 4-chloro substituent (Bioorg. Med. Chem. Lett. 1999, 9, 1973-1978), subsequent hydrolysis and methyl ester formation will give the desired functionality. In the course of the hydrolysis the 2-chloro substituent may be also hydrolysed which would be reintroduced using POCl3 followed by a second displacement with sodium cyanide. The remainder of the route will then use the same methodology as that described for route 1.
Figure imgf000033_0001
HOBt
Figure imgf000033_0003
Figure imgf000033_0002
Scheme I
Examples
Example 1: Preparation of 3-[(3-Chloro-2-methylbenzene sulfonylamino)-methyl]-iV, JV-diethylbenzamide (Route 1)
Figure imgf000033_0004
IA. 3-Cyano-benzoic acid methyl ester To a solution of 3-cyanobenzoic acid (7.35 g, 50 mmol) in DCM/ MeOH (80 ml/ 20 ml) is added trimethylsilyldiazomethane (2M solution in ether; 1 eq, 50 mmol) and the mixture is stirred for 1 h. Acetic acid is added dropwise until the yellow colour disappeared. The solvents are then removed in vacuo. The residue is dissolved in DCM and washed with water. The organic phase is dried (MgSO4) and concentrated in vacuo to give the title compound (5 g, 62%) LC/MS: 93% MH+, m/z not ionised, Rt = 1.14 mins. IB. 3-(tert-Butoxycarbonylamino-methyl) benzoic acid methyl ester To a solution of title compound IA, 3-cyano-benzoic acid methyl ester, (5.80 g, 36.0 mmol) in ethyl acetate (25 ml) in a 500ml pressure bomb is added di-tert-butyl-dicarbonate (1.2 eq, 43.2 mmol) and 10% palladium on carbon (580 mg) the vessel is charged with hydrogen at 5 arm and left to stir overnight. The vessel is recharged with hydrogen and left to stir for a further 5 h. The mixture is filtered through celite, the filtrate is concentrated in vacuo to give the title compound (10.01 g, >100% starting material remaining). LC/MS: >75% MH+, m/z not ionised, Rt = 1.36 mins.
1 C. 3-Λminomethyl-benzoic acid methyl ester
To a solution of title compound IB, 3-(te/^butoxycarbonylamino-methyl) benzoic acid methyl ester, (4 g, 15.1 mmol) in DCM (40 ml) is added 4M HCl in dioxane (4 eq, 60.4 mmol) and the mixture is stirred at room temperature for 4.5 h. The solvents are removed in vacuo. The residue is redissolved in DCM and carbonate resin is added and the mixture is stirred at room temperature overnight. The mixture is filtered and the solvent is removed in vacuo to give the title compound which is used without purification. LC/MS: 86% MH+, m/z 166, Rt = 0.69 mins.
ID. 3-[(3-Chloro-2-methylbenzene sulfonylamino)-methylj -benzoic acid methyl ester To a solution of title compound 1C, 3-aminomethyl-benzoic acid methyl ester, (1 g, 6.06 mmol) and 3-chloro-2-methylphenylsulfonyl chloride (1.1 eq, 6.66 mmol) in DCM (30 ml) is added pyridine (3 eq, 18.18 mmol). The mixture is allowed to stir at room temperature for 16 h. The solvent is removed in vacuo. The residue is redissolved in DCM and is washed with water. The organic layer is acidified with IM HCl and washed with DCM. The aqueous phase is basified with IM NaOH solution and extracted with DCM. The organic phases are dried (Na2SO4) and concentrated in vacuo to give the title compound (1.33 g, 62%). LC/MS: 55% MH+, m/z 354, Rt = 1.49 mins.
IE. 3-[(3-Chloro-2-methylbenzene sulfonylamino) -methyl] -benzoic acid
To a solution of title compound ID, 3-[(3-chloro-2-methylbenzene sulfonylamino)- methyl] -benzoic acid methyl ester, (1.13 g, 3.2 mmol) in THF/ MeOH (3:2 50 ml) is 005/011933
- 34 -
added lithium hydroxide (5 eq, 16.06 mmol) and the mixture is heated to 5O0C for 32 h. After cooling, the solvents are removed in vacuo. The residue is dissolved in ethyl acetate and water. The aqueous phase is washed with ethyl acetate. The aqueous phase is acidified with 2M HCl and re-extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated in vacuo to give the title compound (0.91 g, 83%).
IF. 3-[(3-Chloro-2-methyl-benzene sulfonylamino)-methyl] - N, N-diethylbenzamide To a solution of title compound IE, 3-[(3-chloro-2-methylbenzene sulfonylamino)- methyl] -benzoic acid, (0.6 g, 1.77 mmol) in THF (9 ml) is added thionyl chloride (4 eq, 7.07 mmol) and a few drops of DMF, the mixture is left to stir at room temperature. After completion the reaction mixture is concentrated in vacuo. Diethylamine (1 eq, 0.42 mmol) is dissolved in DCM (2 ml) and a solution of the acid chloride (150 mg, 0.42 mmol) in DCM (3 ml) is added and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The crude product is purified by column chromatography with DCM/ MeOH (gradient 0-2%) as the eluent to give the title compound (77.6 mg, 47%). LC/MS: 94% MH+, m/z 395, Rt = 1.41 mins.
Example 2: Preparation of iV, iV-Diethyl-3-fluoro-5-[(4'-fluoro-biphenyl-4- sulfonylamino)-methyl]-benzamide (Route 2)
Figure imgf000035_0001
2A. S-Bromo-5-fluorohenzoic acid methyl ester To a solution of 3-bromo-5-fluorobenzoic acid (2 g, 9.13 mmol) in DCM/ MeOH (20 ml/ 5 ml) is added trimethylsilyldiazomethane (2M solution in ether; 1 eq, 9.13 mmol) and the mixture is stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents are then removed in vacuo. The residue is dissolved in DCM and washed with K2CO3. The organic phase is dried (MgSO4) and concentrated in vacuo to give the title compound (1.5 g, 71%) LC/MS: 91% MH+, m/z not ionised, Rt = 1.55 mins.
2B. 3-Cyano-5-fluorobenzoic acid methyl ester
To a solution of title compound 2A, 3-bromo-5-fluorobenzoic acid methyl ester, (1 g, 3 mmol) in degassed DMF (5 ml) in a schlenk tube is added copper cyanide (1.1 eq, 3.3 mmol). The mixture is heated to 16O0C for 18 h. After cooling the reaction mixture is poured into IM K2CO3 and ethyl acetate. To improve separation NH4OH solution (5 ml) is added and the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography with DCM/ MeOH (99:1) as the eluent to give the title compound (0.47 g, 60%) LC/MS: 100% MH+, m/z not ionised, Rt = 1.24 mins.
2C. 3-(tert-Butoxycarbonylamino-methyl)-5-fluoro-benzoic acid methyl ester
To a solution of title compound 2B, 3-cyano-5-fluorobenzoic acid methyl ester, (0.8 g, 4.47 mmol) in ethyl acetate (20 ml) is added di-te/t-butyl-dicarbonate (1.2 eq, 5.36 mmol) and 10% palladium on carbon (0.1 eq) the vessel is charged with hydrogen and left to stir overnight. The vessel is recharged with hydrogen and left to stir for a further 5 h. The mixture is filtered through celite, the filtrate is concentrated in vacuo. The crude product is purified by column chromatography with heptane/ ethyl acetate (85:15) to give the title compound (0.41 g, 32%). LC/MS: 94% MH+, m/z not ionised, Rt = 1.43 mins.
2D. 3-Aminomethyl-5-fluoro-benzoic acid methyl ester To a solution of title compound 2C, 3-(tert-butoxycarbonylamino-methyl)-5-fluoro- benzoic acid methyl ester, (0.41 g, 1.45 mmol) in DCM (10 ml) is added 4M HCl in dioxane (4 eq, 5.65 mmol) and the mixture is stirred at room temperature for 4.5 h. The solvents are removed in vacuo. The residue is redissolved in DCM and carbonate resin is added and the mixture is stirred at room temperature overnight. The mixture is filtered and the solvent is removed in vacuo to give the title compound (0.25 g, 94%). LC/MS: 48% MH+, m/z 184, Rt = 0.76 mins. 2E. 3-Fluoro-5-[(4'-fluoro-biphenyl-4-sulfonylamino)-methyl] benzoic acid methyl ester
To a solution of title compound 2D, S-airώiomemyl-5-fluoro-berizoic acid methyl ester, (0.25 g, 1.37 mmol) and 4-fluorobiphenylsulfonyl chloride (1.0 eq, 1.37 mmol) in DCM (10 ml) is added DMAP (1.1 eq, 1.50 mmol). The mixture is allowed to stir at room temperature for 16 h. The solvent is removed in vacuo to give the title compound (0.57 g, 100%). LC/MS: 48% MH+, m/z 418, Rt = 1.57 rains.
2F. 3-Fluoro-5-[(4 '-fluoro-biphenyl-4-sulfonylamino)-methyl] benzoic acid To a solution of title compound 2E, 3-fluoro-5-[(4'-fluoro-biphenyl-4-sulfonylamino)- methyl] benzoic acid methyl ester, (0.57 g, 1.37 mmol) in THF/ H2O (2:1 5ml:2.5 ml) is added lithium hydroxide (2 eq, 2.73 mmol) and the mixture is stirred at room temperature for 5 h. The solvents are removed in vacuo. The residue is dissolved in DCM and water.
The aqueous phase is washed with DCM. The aqueous phase is acidified with IM HCl to pH= 4 and re-extracted with DCM. A solid precipitates from the DCM phase which is collected by filtration to give the title compound (0.16 g, 29%). LC/MS: 100% MH+, m/z
404, Rt= 1.40 mins.
2G. N, N-Diethyl-3-fluoro-5-[(4 '-fluoro-biphenyl-4-sulfonylamino)-methyl]-benzamide To a solution of title compound 2F, 3-fluoro-5-[(4'-fluoro-biphenyl-4-sulfonylamino)- methyl] benzoic acid, (0.08 g, 0.19 mmol) in DCM (2 ml) is added EDC (1 eq, 0.19 mmol) and HOBt (1 eq, 0.19 mmol). Diethylamine (1 eq, 0.19 mmol) is added and the mixture is stirred at room temperature for 18 h. The solvent is removed in vacuo. The crude product is purified by column chromatography with DCM/ MeOH (gradient 0.5-1%) as the eluent to give the title compound (22 mg, 25%). LC/MS: 100% MH+, m/z 459, Rt = 1.52 mins.
Example 3
Synthesis of 3-Aminomethyl-benzoic acid methyl ester - Intermediate 1 C. TMSCHN2, MeOH, DCM
Figure imgf000038_0001
Figure imgf000038_0002
1A
1. H2, Pd/C, BoC2O 2. HCI/ Dioxane
Figure imgf000038_0003
1C
Scheme 1
IA. 3-Cyano-benzoic acid methyl ester
To a solution of 3-cyanobenzoic acid (7.35 g, 50 mmol) in DCM/ MeOH (80 ml/ 20 ml) was added trimethylsilyldiazomethane (2M solution in ether; 1 eq) and the mixture was stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents were then removed in vacuo. The residue was dissolved in DCM and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (5 g, 62%) LC/MS: 93% MH+, m/z not ionised, Rt = 1.14 mins.
IB. 3-(te?t-Butoxycarbonylaminomethyl) benzoic acid methyl ester
To a solution of title compound IA, 3-cyano-benzoic acid methyl ester, (5.80 g, 36.0 mmol) in ethyl acetate (25 ml) in a 500ml pressure bomb was added di-tert-butyl- dicarbonate (1.2 eq) and 10% palladium on carbon (580 mg) and the vessel was charged with hydrogen at 5 arm and stirred overnight. The vessel was recharged with hydrogen and stirred for a further 5 h. The mixture was filtered through celite, the filtrate was concentrated in vacuo to give the title compound (10.01 g, >100% starting material remaining). LC/MS: >75% MH+, m/z not ionised, Rt = 1.36 mins. IC. 3-Aminomethyl-benzoic acid methyl ester
To a solution of title compound IB, 3-(te7t-butoxycarbonylaimnomethyl) benzoic acid methyl ester, (4 g, 15.1 mmol) in DCM (40 ml) was added 4M HCl in dioxane (4 eq) and the mixture was stirred at room temperature for 4.5 h. The solvents were removed in vacuo. The residue was redissolved in DCM and carbonate resin was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was removed in vacuo to give the title compound which was used without purification. LC/MS: 86% MH+, m/z 166, Rt = 0.69 mins.
Synthetic Route 1 - Solution Phase Synthesis
ASO2Cl, Pyridine
Figure imgf000039_0002
Figure imgf000039_0001
H2O
Figure imgf000039_0003
Scheme 2
Method D - Sulfonamide formation.
To a solution of 3-aminomethyl-benzoic acid methyl ester 1C (6.06 mmol) and sulfonyl chloride (1.2 eq) in DCM (30 ml) was added pyridine (20 eq) and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was redissolved in DCM and was washed with water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by column chromatography with DCM/ EtOAc as the eluent to give the title compound. Method E - Saponification.
To a solution of title intermediate D (3.2 mmol) in THF/ H2O (3:2 50 ml) was added lithium hydroxide (2 eq) and the mixture was heated to 5O0C for 5 h. After cooling, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate and water. The aqueous phase was acidified to pH=2 with IM HCl and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound.
Method F - Amide Formation.
To a solution of title intermediate E (1.77 mmol) in THF (9 ml) was added thionyl chloride (4 eq) and a few drops of DMF, the mixture was stirred at room temperature. After completion the reaction mixture was concentrated in vacuo. The amine (1 eq) was dissolved in DCM (2 ml) and a solution of the acid chloride (0.42 mmol) in DCM (3 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Method G - Amide Formation.
To a solution of title intermediate E (0.45 mmol) in DMF/ DCM (1 :2, 4.5 ml) was added HBTU (1.2 eq) and HOBt (1.2 eq) and the mixture was stirred at room temperature for 10 mins. The amine (1.2 eq) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Method H - Amide Formation.
To a solution of title intermediate E (0.45 mmol) in DMF/ DCM (1 :2, 4.5 ml) was added HBTU (1.2 eq) and HOBt (1.2 eq) and the mixture was stirred at room temperature for 10 mins. The HCl salt of the amine (1.2 eq) and DIPEA (1.2 eq) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Compounds synthesised by route 1 are detailed below:
ID. 3-[(Biphenyl-4-sulfonylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method D to give title compound ID (3.21 g, 32%) LC/MS: 98% MH+, m/z 382, Rt = 1.56 mins.
IE. 3- [(Biphenyl-4-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using method E to give title compound IE (3.67 g, 100%) LC/MS: 100% MH+, m/z 368, Rt = 1.40 mins.
IFl. 3-[(Biphenyl-4-sulfonylamino)-methyl]-N,iV-diethyl-beiizaniide
The compound was synthesised using method F to give title compound IFl (10.5 mg, 6%) LC/MS: 100% MH+, m/z 423, Rt = 1.51 mins.
1F2. Biphenyl-4-sulfonic acid 3-(morpholine-4-carbonyl)-benzylamide
The compound was synthesised using method F to give title compound 1F2 (15.8 mg, 9%) LC/MS: 96% MH+, m/z 437, Rt = 1.36 mins.
1F3. Biphenyl-4-sulfonic acid 3-(4-methyl-piperazine-l-carbonyl)-benzylamide
The compound was synthesised using method F to give title compound 1F3 (15.7 mg, 8%) LC/MS: 100% MH+, m/z 450, Rt = 1.17 mins.
2D. 3- [(3-Chloro-2-methyl-benzenesulfonylamino)-methyl] -benzoic acid methyl ester
The compound was synthesised using method D to give title compound 2D (0.34 g, 38%) LC/MS: 96% MH+, m/z 354, Rt = 1.55 mins. 2E. 3-[(3-Chloro-2-methyl-benzenesulfonylamino)-methyl]-benzoic acid
The compound was synthesised using method E to give title compound 2E (0.14 g, 100%) LC/MS: 84% MH+, m/z 340, Rt = 1.35 mins.
2Fl. 3-[(3-CUoro-2-methyl-benzenesulfonylamino)-methyl]-iV,iV-diethyl-benzamide
The compound was synthesised using method F to give title compound 2Fl (10.7 mg, 6%) LC/MS: 94% MH+, m/z 395, Rt = 1.41 mins.
2G2. 3-[(3-Chloro-2-methyl-benzenesulfonylamino)-methyl]-iV-(4-trifluoromethyl- benzyl)-benzamide
The compound was synthesised using method F to give title compound 2G2 (34.4 mg, 34%) LC/MS: 96% MH+, m/z 497, Rt = 2.41 mins.
2G3. 4-({3-[(3-Chloro-2-methyl-benzenesulfonylamino)-methyI]-benzoylamino}- methyl)-benzoic acid methyl ester
The compound was synthesised using method G to give title compound 2G3 (105.5 mg, 100%) LC/MS: 65% MH+, m/z 486, Rt = 2.13 mins.
3D. 3-[(Naphthalene-2-sulfonylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method D to give title compound 3D (1.93 g, 42%) LC/MS: 90% MH+, m/z 356, Rt - 1.47 mins.
4D. 3-[(Benzo[b]thiophene-2-sulfonylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method D to give title compound 4D (1.5 g, 41%) LC/MS: 95% MH+, m/z 362, Rt = 1.54 mins.
5D. 3-[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method D to give title compound 5D (2.7 g, 44%) LC/MS: 86% MH+, m/z not ionised, Rt = 1.68 mins. 5E. 3-[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-methyl]-beii2oic acid
The compound was synthesised using method E to give title compound 5E (1.4 g, >100%) LC/MS: 76% MH+, m/z 396, Rt = 1.50 mins.
5Gl. 3-[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-methyl]-iV,7V- diethyl-benzamide
The compound was synthesised using metihod G to give title compound 5Gl (23 mg, 40%) LC/MS: 100% MH+, m/z 451, Rt = 2.35 mins.
5G2. 3-[(5-Chloro-3-methyl-benzo[b]tbJophene-2-sulfonylamino)-methyl]-iV- cyclohexyl-benzamide
The compound was synthesised using method G to give title compound 5G2 (22 mg, 37%) LC/MS: 82% MH+, m/z 477, Rt = 2.47 mins
5G3. 4-({3-[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-methyl]- benzoylamino}-methyl)-benzoic acid methyl ester
The compound was synthesised using method G to give title compound 5G3 (22 mg, 32%) LC/MS: 98% MH+, m/z 543, Rt = 2.38 mins
Synthetic Route 2
Figure imgf000043_0001
HOBt
Figure imgf000043_0002
Scheme 3 Method I - 3-[(4-Bromo-benzenesulfonylamino)-methyl]-benzoic acid methyl ester
To a solution of title intermediate 1C (3 g, 14.88 rnmol) and 4-bromophenylsulfonyl chloride (1.2 eq) in DCM (120 ml) was added pyridine (20 eq) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the residue was redissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by column chromatography with DCM as the eluent to give the title compound (2.51 g, 44%). LC/MS: 85% MH+, m/z 386, Rt = 1.52 mins.
Method J - Suzuki reaction.
A solution of the sulfonamide intermediate 1 (110 mg, 0.29 mmol) and the boronic acid (1.5 eq) in toluene/ EtOH (2:1; 2 ml: 1 ml) was degassed under argon. Pd(PPh3)4 (0.1 eq) and potassium carbonate (1.5 eq) were added and the mixture was degassed under argon and the mixture was heated to 950C for 16 h. After cooling the mixture was filtered through celite and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound.
Method E - Saponification.
As detailed in synthetic route 1 to give intermediate E.
Method G - Amide Formation.
As detailed in synthetic route 1 to give compound G.
Compounds synthesised by route 2 are detailed below:
6J. 3-[(4'-Cyano-biphenyl-4-sulfonylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method J to give title compound 6 J (0.76 g, 31%) LC/MS: 60% MH+, m/z 407, Rt = 2.16 mins.
6E. 3-[(4'-Cyano-biphenyl-4-sulfonylamino)-methyl]-benzoic acid The compound was synthesised using method E to give title compound 6E (0.24 g, 68%) MS: m/z 392
6Gl. 3-[(4'-Cyano-biphenyl-4-sutfonylamiiio)-methyl]-iV,iV-diethyl-benzamide
The compound was synthesised using method G to give title compound 6Gl (24 mg, 42%) LC/MS : 100% MH+, m/z 448, Rt = 2.20 mins.
6G2. 3-[(4'-Cyano-biphenyl-4-suIfonylamino)-methyl]-iV-cyclohexyl-benzamide
The compound was synthesised using method G to give title compound 6G2 (24 mg, 40%) LC/MS: 100% MH+, m/z 474, Rt = 2.30 mins.
6G3. 3-[(4'-Cyano-biphenyl-4-sulfonylanώio)-methyl]-ΛLcyclohexylmethyl- benzamide
The compound was synthesised using method G to give title compound 6G3 (31 mg, 50%) LC/MS: 100% MH+, m/z 488, Rt = 2.39 mins.
6G4. 4-({3-[(4'-Cyano-biphenyl-4-sulfonylamino)-methyl]-benzoylamiπιo}-methyl)- benzoic acid
The compound was synthesised using method G to give title compound 6G4 (24 mg, 36%) LC/MS: 88% MH+, m/z 526, Rt = 2.06 mins.
Synthetic Route 3 - Solid Phase Synthesis
Figure imgf000045_0001
Scheme 4
Method K- Resin Loading
The HCl salt of 3-aminomethyl-benzoic acid methyl ester 1C was dissolved in saturated sodium hydrogen carbonate and DCM. The phases were separated and the aqueous phase was extracted with DCM. The organic phases were dried (MgSO4) and concentrated in vacuo to liberate the free amine.
A solution of 3-aminomethyl-benzoic acid methyl ester 1C (9.1 mmol, 1.5 eq), FMPE resin (1 eq) and acetic acid (1 eq) in THF (50 ml) and TMOF (5 ml) was shaken at room temperature for 45 min. STAB (1.5 eq) was added and the mixture was shaken at room temperature overnight. The resin was filtered and washed with MeOH, water, DMF, [MeOH, DCM] x2 and the resin was dried in vacuo.
Method L- Sulfonamide Formation
To a suspension of resin loaded 3-aminomethyl-benzoic acid methyl ester K (0.13 mmol) in DCM (4 ml) and pyridine (10 eq) was added the sulfonyl chloride (1.5 eq) and the mixture was shaken at room temperature overnight. A small sample of resin was washed with DMF, MeOH, DCM and stained with chloranil to determine the presence of free NH. On completion the resin was filtered and washed with DCM, MeOH, [DMF, DCM, MeOH] x3, DCM, MeOH and the resin was dried in vacuo.
Method M- Saponification
To a suspension of resin L (0.65 mmol) in 1,4-dioxane (20 ml) was added IM lithium hydroxide (20 eq) and the mixture was shaken at 5O0C overnight. A small sample of resin was cleaved with 60% TFA/ DCM and analysed by LCMS. On completion the resin was filtered and washed with [water, DMF] x2, [DCM, MeOH] x3 and the resin was dried in vacuo.
Method N- Amide Formation
To a suspension of resin M (0.24 mmol) in DMF (5 ml) was added HBTU (5 eq) and
HOBt (5 eq) and the mixture was left to shake at room temperature for 10 mins. The amine (5 eq) was added and the mixture was shaken at room temperature overnight. A small sample of the resin was cleaved using 40% TFA in DCM and analysed by LCMS. If reactions were incomplete a further 5 eqs of HBTU, HOBt and amine were added and shaking continued for a further 24 hr. Once the reactions were complete the resin was filtered and washed with DMF, 5% Na2CO3 (aq), H2O, H2O/ acetone, MeOH, DCM, MeOH, DCM, MeOH. The final compounds were cleaved from resin with 60% TFA in DCM (2ml, x3) and the resulting solutions were concentrated. Typically the crude mixtures were purified by column chromatography with DCM/ EtOAC (up to 20% EtOAc) as the eluent to give the final compound.
Compounds synthesised using route 3 are detailed below: 7M. PS- 3- [(Biphenyl-4-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 7M.
7Nl. Biphenyl-4-sulfonic acid 3-(piperidine-l-carbonyl)-benzylamide
The compound was synthesised using method N to give title compound 7Nl (2.3 mg, 4%) LCMS: 100% MH+, m/z 435, Rt = 1.55 mins.
7N2. 7V-Benzyl-3- [(biphenyl-4-sulf onylamino)-methyl] -benzamide
The compound was synthesised using method N to give title compound 7N2 (1.9 mg, 3%) LCMS: 100% MH+, m/z 457, Rt = 1.73 mins.
7N3. 3- [(Biphenyl-4-sulf onylamino)-methyl] -7V-methyl-benzamide
The compound was synthesised using method N to give title compound 7N3 (0.9 mg, 1%) LCMS: 100% MH+, m/z 381, Rt = 1.45 mins.
7N4. 3-[(Biphenyl-4-sulfonylamino)-methyl]-iV-(3-methoxy-propyl)-benzamide
The compound was synthesised using method N to give title compound 7N4 (5.8 mg, 7%) LCMS: 100% MH+, m/z 439, Rt = 1.38 mins.
7N5. 3-[(Biphenyl-4-sulfonylamino)-niethyI]-iV-cyclohexyl-benzamide
The compound was synthesised using method N to give title compound 7N5 (7 mg, 9%) LCMS: 100% MH+, m/z 449, Rt = 1.57 mins.
7N6. 3-[(Biphenyl-4-sulfonylamino)-methyl]-N-cyclohexylmethyl-benzamide
The compound was synthesised using method N to give title compound 7N6 (2.6 mg, 3%) LCMS: 100% MH+, m/z 463, Rt = 1.69 mins.
7N7. 3-[(Biphenyl-4-sulfonylamino)-methyl]-iV-Jp-tolyl-benzamide
The compound was synthesised using method N to give title compound 7N7 (5.8 mg, 7%) LCMS: 95% MH+, m/z 457, Rt = 2.21 mins. 7N8. 4-({3-[(Biphenyl-4-sulfonylamino)-methyl]-benzoylamino}-methyl)-beiizoic acid
The compound was synfhesised using method N to give title compound 7N8 (3.9 mg, 4%) LC/MS: 95% MH+, m/z 501, Rt = 1.45 mins.
7N9. 3-[(Biphenyl-4-sulfonylamino)-methyl]-iV,iV-dimethyl-benzamide
The compound was synthesised using method N to give title compound 7N9 (7.7 mg, 10%) LC/MS: 100% MH+, m/z 395, Rt = 1.47 mins.
7N10. Biphenyl-4-sulfonic acid 3-(pyrroIidine-l-carbonyl)-benzylamide
The compound was synthesised using method N to give title compound 7N10 (10.6 mg, 13%) LC/MS: 100% MH+, m/z 421, Rt = 2.04 mins.
8M. PS- 3-[(3-Chloro-2-methyl-benzenesulfonylamiiio)-methyl]-beiizoic acid
The compound was synthesised using methods L and M to give title compound 8M. LC/MS: 91% MH+, m/z 340, Rt = 1.31 mins.
8Nl. 3-[(3-Chloro-2-methyl-benzenesulfonylamino)-methyl]-iV-cyclohexyl- benzamide
The compound was synthesised using method N to give title compound 8Nl (10.6 mg, 13%) LC/MS: 95% MH+, m/z 421, Rt = 2.11 mins.
8N2. 3-[(3-Chloro-2-methyl-benzenesulfonylamino)-methyl]-iV-cycIohexylinethyl- benzamide
The compound was synthesised using method N to give title compound 8N2 (6.7 mg, 8%) LC/MS: 100% MH+, m/z 435, Rt = 2.43 mins.
9M. PS- 3- [(Benzo[b]thiophene-2-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 9M. LC/MS: 35% MH+, m/z 348, Rt = 1.32 mins. 9Nl . 3- [(Benzo [b] thiophene-2-sulf onylamino)-methyl] -iV,N-diethyl-benzamide
The compound was synthesised using method N to give title compound 9Nl (2.2 mg, 3%) LC/MS: 100% MH+, m/z 403, Rt = 2.03 mins.
9N2. Benzo [b] thiophene-2-sulf onic acid 3-(4-methyl-piperazine-l-carbonyl)- benzylamide
The compound was synthesised using method N to give title compound 9N2 (6.4 mg, 8%) LC/MS: 100% MH+, m/z 430, Rt = 1.74 mins.
9N3. 3- [(Benzo [b] thiophene-2-sulf onylamino)-methyl] -iV-cyclohexyl-benzamide
The compound was synthesised using method N to give title compound 9N3 (10.8 mg, 13%) LC/MS: 100% MH+, m/z 429, Rt = 2.12 mins.
9N4. 3- [(Benzo [b] thiophene-2-sulf onylamino)-methyl] -iV-cyclohexylmethyl- benzamide
The compound was synthesised using method N to give title compound 9N4 (9.7 mg, 11%) LC/MS: 100% MH+, m/z 443, Rt = 2.18 mins.
1OM. PS- 3- [(Toluene-4-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 1OM. LC/MS: 79% MH+, m/z 306, Rt = 1.21 mins.
10Nl. iV,N-Diethyl-3-[(toluene-4-sulfonylamino)-methyl]-benzamide
The compound was synthesised using method N to give title compound 10Nl (9.8 mg, 14%) LC/MS: 97% MH+, m/z 361, Rt = 1.32 mins.
HM. PS- 3-[(4-Methoxy-benzenesulfonylamino)-methyl]-benzoic acid
The compound was synthesised using methods L and M to give title compound HM. LC/MS: 82% MH+, m/z 322, Rt = 1.16 mins.
1 IN 1. JV,iV-Diethyl-3- [(4-methoxy-benzenesulf onylamino)-methyl] -benzamide The compound was synthesised using method N to give title compound 1 INl (4.6 mg, 6%) LC/MS: 100% MH+, m/z 377, Rt = 1.27 mins.
11N2. 4-Methoxy-N-[3-(morpholine-4-carbonyl)-benzyl]-benzenesulf onamide
The compound was synthesised using method N to give title compound 11N2 (6.4 mg, 12%) LC/MS: 100% MH+, m/z 391, Rt = 1.12 mins.
12M. PS- 3-[(4-Chloro-benzenesulfonylamino)-methyl]-benzoic acid
The compound was synthesised using methods L and M to give title compound 12M. LC/MS: 98% MH+, m/z 326, Rt = 1.25 mins.
12Nl. 3- [(4-Chloro-benzenesulf onylamino)-methyl] -JV,iV-diethyl-benzamide
The compound was synthesised using method N to give title compound 12Nl (15.4 mg, 20%) LC/MS: 100% MH+, m/z 381, Rt = 1.35 mins.
13M. PS- 3- [(Thiophene-2-sutfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 13 M. LC/MS: 86% MH+, m/z 298, Rt =1.12 mins.
13Nl. Λr,iV-Dietb.yl-3-[(thiophene-2-sulfonylami-io)-inethyl]-beiizamide
The compound was synthesised using method N to give title compound 13Nl (14.9 mg, 21%) LC/MS: 100% MH+, m/z 353, Rt = 1.24 mins.
14M. PS- 3- [(3-Chloro-benzenesulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 14M. LC/MS : 96% MH+, m/z 326, Rt = 1.27 mins.
14Nl. 3-[(3-Chloro-benzenesulfonylamino)-methyI]-Λr,iV-diethyl-benzamide
The compound was synthesised using method N to give title compound 14Nl (11.4 mg, 23%) LC/MS: 100% MH+, m/z 381, Rt = 1.98 mins. 15M. PS- 3-[(Toluene-3-sulfonylamino)-methyl]-benzoic acid
The compound was synthesised using methods L and M to give title compound 15M. LC/MS: 97% MH+, m/z 306, Rt = 1.23 mins.
15Nl. Λr,Λr-Diethyl-3-[(toluene-3-sulfonylamino)-methyl]-benzaniide
The compound was synthesised using method N to give title compound 15Nl (11.7 mg, 24%) LC/MS: 100% MH+, m/z 361, Rt = 1.94 mins.
16M. PS- 3- [(3-Methoxy-benzenesulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 16M. LC/MS: 93% MH+, m/z 322, Rt = 1.20 mins.
16Nl. iV,Λr-Diethyl-3-[(3-methoxy-benzenesulfonylamino)-methyl]-benzamide
The compound was synthesised using method N to give title compound 16Nl (12.8 mg, 26%) LC/MS: 100% MH+, m/z 377, Rt = 1.90 mins.
17M. PS- 3-(Benzenesulfonylamino-methyI)-benzoic acid
The compound was synthesised using methods L and M to give title compound 17M. LC/MS : 98% MH+, m/z 292, Rt = 1.16 mins.
17Nl. 3-(Benzenesulfonylamino-methyl)-iV,iV-diethyl-benzamide
The compound was synthesised using method N to give title compound 17Nl (9.9 mg, 14%) LC/MS: 97% MH+, m/z 347, Rt = 1.88 mins.
18M. PS- 3- [(Naphthalene-2-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 18M. LC/MS: 100% MH+, m/z 342, Rt = 1.31 mins.
18Nl. iV,iV-Diethyl-3-[(naphthalene-2-sulfonylaniino)-methyl]-benzamide The compound was synthesised using method N to give title compound 18Nl (14.6 mg, 22%) LC/MS: 100% MH+, m/z 397, Rt = 2.03 mins.
18N2. Naphthalene-2-sulfonic acid 3-(morpholine-4-carbonyl)-benzylamide
The compound was synthesised using method N to give title compound 18N2 (4.4 mg, 6%) LC/MS: 100% MH+, m/z 411, Rt = 1.89 mins.
18N3. iV-Cyclohexyl-3-[(naphthalene-2-sulfonylamino)-methyl]-benzamide
The compound was synthesised using method N to give title compound 18N3 (30 mg, 28%) LC/MS: 88% MH+, m/z 423, Rt = 2.28 mins.
18N4. Λr-Cyclohexylmethyl-3-[(naphthalene-2-sulfonylamino)-methyl]-benzainide
The compound was synthesised using method N to give title compound 18N4 (48 mg, 44%) LC/MS: 94% MH+, m/z 437, Rt = 2.36 mins.
18N5. 4-({3-[(Naphthalene-2-sulfonylamino)-methyl]-benzoylamino}-methyl)-benzoic acid
The compound was synthesised using method N to give title compound 18N5 (26 mg, 22%) LC/MS: 90% MH+, m/z 475, Rt = 2.02 mins.
18N6. 3- [(Naphthalene-2-sulf onylamiHθ)-methyl] -iV-p-tolyl-benzamide
The compound was synthesised using method N to give title compound 18N6 (20 mg, 19%) LC/MS: 95% MH+, m/z 431, Rt = 2.33 mins.
19M. PS- 3- [(Naphthalene-l-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 19M. LC/MS: 100% MH+, m/z 342, Rt = 1.28 mins.
19Nl. N,iV-Diethyl-3-[(naphthalene-l-sulfonylamiiio)-methyl]-ben2amide
The compound was synthesised using method N to give title compound 19Nl (17.5 mg, 26%) LC/MS: 100% MH+, m/z 397, Rt = 2.00 mins. 19N2. Naphthalene-1-sulfonic acid 3-(morphoIine-4-carbonyl)-benzylamide
The compound was synthesised using method N to give title compound 19N2 (15.7 mg, 23%) LC/MS: 100% MH+, m/z 4115 Rt = 1.86 mins.
2OM. PS- 3- [(4-Phenoxy-benzenesulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 2OM.
20Nl. 7V,ΛLDiethyl-3-[(4-phenoxyΦenzenesulfonylamino)-methyl]-benzamide
The compound was synthesised using method N to give title compound 20Nl (11.9 mg, 20%) LC/MS: 100% MH+, m/z 439, Rt = 1.49 mins.
20N2. iV-[3-(Morpholine-4-carbonyI)-benzyl]-4-phenoxy-benzenesulfonamide
The compound was synthesised using method N to give title compound 20N2 (9.1 mg, 15%) LC/MS: 100% MH+, m/z 453, Rt = 1.98 mins.
2 IM. PS- 3- [(6-Phenoxy-pyridine-3-sulfonylamino)-methyl] -benzoic acid
The compound was synthesised using methods L and M to give title compound 21M
21Nl. iV,iV-Diethyl-3-[(6-phenoxy-pyridine-3-sulfonylamino)-methyI]-benzamide
The compound was synthesised using method N to give title compound 21Nl (9.2 mg, 16%) LC/MS: 100% MH+, m/z 440, Rt = 1.40 mins.
21N2. 6-Phenoxy-pyridine-3-sulfonic acid 3-(morpholine-4-carbonyl)-benzylamide
The compound was synthesised using method N to give title compound 21N2 (10.1 mg, 17%) LC/MS: 100% MH+, m/z 454, Rt = 1.28 mins.
22M. PS- 3-[(4-Phenylamino-benzenesulfonylamino)-methyl]-benzoic acid
The compound was synthesised using methods L and M to give title compound 22M
22Nl. iV,iV-Diethyl-3-[(4-phenylamino-benzenesulfonylamino)-methyl]-benzamide The compound was synthesised using method N to give title compound 22Nl (12.4 mg, 21%) LC/MS: 100% MH+, m/z 438, Rt = 1.47 mins.
22N2. iV-[3-(MorphoIine-4-carbonyl)-benzyl]-4φhenylamino-benzenesulfonamide
The compound was synthesised using method N to give title compound 22N2 (6.8 mg, 11 %) LC/MS : 100% MH+, m/z 452, Rt = 1.29 mins.
Synthetic Route 4
ASO2CI, pyridine
Figure imgf000055_0002
Figure imgf000055_0001
1. NaH1 MeI1 THF 2. LiOH, THF/ H2O
HOBt
Figure imgf000055_0004
Figure imgf000055_0003
Scheme 5
Method O - N-methylation
A solution of title intermediate D (4.2 mmol) in THF (50 ml) was added to a suspension of NaH (1.5 eq) in THF (30 ml) at O0C and the mixture was stirred for 1.5 hr. Methyl iodide (2 eq) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (40 ml) and the THF was removed in vacuo. The residue was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compounds. The 7V-methylation reaction gave mixtures of N-methylated methyl ester and carboxylic acid which were saponified without further purification.
Method E - Saponification.
As detailed in synthetic route 1 to give intermediate E.
Method G - Amide Formation.
As detailed in synthetic route 1 to give compound G.
Compounds synthesised by route 4 are detailed below:
23O. 3-{[(Biphenyl-4-sulfonyl)-methyl-amrno]-methyl}-benzoic acid methyl ester
The compound was synthesised from intermediate ID using method O to give title compound 230 (0.52 g, 100%, mixture of ester and acid) LC/MS: 6% ester:82% acid MH+, m/z 395, Rt = 1.71 mins.
23E. 3-{[(Biphenyl-4-sulfonyI)-methyl-amino]-methyl}-benzoic acid
The compound was synthesised using method E to give title compound 23E (0.49 g, 97%) LC/MS: 95% MH+, m/z 382, Rt = 1.65 mins.
23Gl. Biphenyl-4-sulfonic acid methyl-[3-(morpholme-4-carbonyl)-benzyl]-amide
The compound was synthesised using method G to give title compound 23Gl (16.9 mg, 14%) LG/MS: 100% MH+, m/z 451, Rt = 2.07 mins.
24O. 3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-amino]-methyl}-benzoic acid methyl ester The compound was synthesised from intermediate 2D using method O to give title compound 24O (2.1 g, >100%, mixture of ester and acid ) LC/MS: 15% ester:74% acid MH+, m/z 368, Rt = 1.65 mins.
24E. 3-{[(3-Chloro-2-methyl-benzenesulfonyI)-methyl-amino]-methyl}-benzoic acid
The compound was synthesised using method E to give title compound 24E (1.39 g, 93%) LC/MS: 89% MH+, m/z 354, Rt = 1.52 mins.
24Gl. 3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-amino]-methyl}-iV,iV-diethyl- benzamide
The compound was synthesised using method G to give title compound 24Gl (12 mg, 10%) LC/MS : 100% MH+, m/z 409, Rt = 1.63 mins.
24G2. 3-Chloro-2^V-dimethyl-iV-[3-(4-methyl-piperazine-l-carboiiyl)-beii2yl]- benzenesulfonamide
The compound was synthesised using method G to give title compound 24G2 (41 mg, 33%) LC/MS: 96% MH+, m/z 436, Rt = 1.31 mins.
24G3. 3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-amino]-methyl}-iV- cyclohexylmethyl-benzamide
The compound was synthesised using method G to give title compound 24G3 (26 mg, 41%) LC/MS: 96% MH+, m/z 449, Rt = 4.40 mins.
24G4. 4-[(3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-ainino]-inethyl}- benzoylamino)-methyl] -benzoic acid
The compound was synthesised using method G to give title compound 24G4 (40 mg, 58%) LC/MS: 91% MH+, m/z 487, Rt = 2.19 mins.
24G5. 3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-amino]-methyl}-iV- cyclohexyl-benzamide The compound was synthesised using method G to give title compound 24G5 (25 mg, 41%) LC/MS: 90% MH+, m/z 435, Rt = 4.25 mins.
24G6. 4-[(3-{[(3-Chloro-2-methyl-benzenesulfonyI)-methyl-amino]-methyl}- benzoylamino)-methyl]-benzoic acid methyl ester
The compound was synthesised using method G to give title compound 24G6 (30 mg, 42%) LC/MS: 96% MH+, m/z 501, Rt = 3.45 mins.
25O. S-IICBenzofbJthiophene-l-sulfony^-methyl-aminol-methyll-benzoic acid methyl ester
The compound was synthesised from intermediate 4D using method O to give title compound 250 (0.21 g, 100%) LC/MS: 88% MH+, m/z 376, Rt = 1.65 mins.
25E. 3-{[(Benzo[b]thiophene-2-sulfonyI)-methyl-amino]-methyl}-benzoic acid
The compound was synthesised using method E to give title compound 25E (0.2 g, 100%) LC/MS: 97% MH+, m/z 362, Rt = 1.47 mins.
25Gl. 3-{[(Benzo[b]tbiophene-2-sulfonyl)-methyl-amino]-methyl}-iV,iV-diethyl- benzamide
The compound was synthesised using method G to give title compound 25Gl (93.6 mg, 41%) LC/MS: 95% MH+, m/z 417, Rt = 2.15 mins.
25G2. 3-{[(TBenzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}-Λr-cyclohexyl- benzamide
The compound was synthesised using method G to give title compound 25G2 (24 mg, 39%) LC/MS: 95% MH+, m/z 443, Rt = 3.52 mins.
25G3. 3-{[(Benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}-iV- cyclohexylmethyl-benzamide
The compound was synthesised using method G to give title compound 25 G3 (25 mg, 40%) LC/MS: 89% MH+, m/z 457, Rt = 3.88 mins. 25G4. 3-{[(Benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}-iV-(4- trifluoromethyl-benzyl)-benzamide
The compound was synthesised using method G to give title compound 25G4 (24 mg, 33%) LC/MS: 97% MH+, m/z 519, Rt = 3.99 mins.
25G5. 4-[(3-{[(Benzo[b]tMophene-2-sulfonyl)-methyl-amiiio]-inethyl}-benzoylamino)- methyl]-benzoicacid methyl ester
The compound was synthesised using method G to give title compound 25G5 (26mg, 37%) LC/MS: 96% MH+, m/z 509, Rt = 2.95 mins.
25G6. 4-[(3-{[(Benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}-benzoylanjiBθ)- methyl] -benzoic acid
The compound was synthesised using method G to give title compound 25 G6 (43 mg, 63%) LC/MS: 93% MH+, m/z 494, Rt = 1.90 mins.
25G7. 3-{[(Benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}-Λ':p-tolyl- benzamide
The compound was synthesised using method G to give title compound 25G7 (28 mg, 45%) LC/MS: 97% MH+, m/z 451, Rt = 3.82 mins.
260. 3-{[Methyl-(naphthalene-2-sulfonyI)-amino]-methyl}-benzoic acid methyl ester
The compound was synthesised from intermediate 3D using method O to give title compound 26O (1.99 g, 100%) LC/MS: 46% ester: 46% acid MH+, m/z 370, Rt = 1.68 mins.
26E. S-lpVTethyl-^aphthalene-Z-sulfonylJ-aminol-methy^-benzoic acid
The compound was synthesised using method E to give title compound 26E (1.75 g, 92%) LC/MS: 90% MH+, m/z 356, Rt = 1.48 mins.
26Gl. iV,iV-Diethyl-3-{[methyl-(naphthalene-2-sulfonyl)-amJuio]-methyl}-benzainide The compound was synthesised using method G to give title compound 26Gl (28 mg, 49%) LC/MS: 94% MH+, m/z 411, Rt = 2.55 mins.
26G2. iV-Cyclohexyl-3-{[methyl-(naphthalene-2-sulfonyI)-amino]-methyl}-benzamide
The compound was synthesised using method G to give title compound 26G2 (27 mg, 44%) LC/MS: 94% MH+, m/z 437, Rt = 3.41 mins.
26G3. iV-Cyclohexylmethyl-3- { [methyl-(naphthalene-2-sulf onyl)-amino] -methyl}- benzamide
The compound was synthesised using method G to give title compound 26G3 (26 mg, 41%) LC/MS: 95% MH+, m/z 451, Rt = 4.14 mins.
26G4. 3- { [Methyl-(naphthalene-2-sulf onyl)- amino] -methyl}-iV-(4-trifluor omethyl- benzyl)-benzamide
The compound was synthesised using method G to give title compound 26G4 (28 mg, 39%) LC/MS: 98% MH+, m/z 513, Rt = 3.85 mins.
26G5. 4-[(3- { [Methyl-(naphthalene-2-sulf onyl)-amino] -methyl}-benzoylamino)- methyl] -benzoic acid methyl ester
The compound was synthesised using method G to give title compound 26G5 (26 mg, 37%) LC/MS: 95% MH+, m/z 503, Rt = 2.87 mins.
26G6. 3-{[Methyl-(naphthalene-2-sulfonyI)-an-ino]-methyl}-Λr-Jp-tolyl-benzamide
The compound was synthesised using method G to give title compound 26G6 (21 mg, 34%) LC/MS: 97% MH+, m/z 445, Rt = 2.49 mins.
27O. 3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-am)Lno]-methyI}- benzoic acid methyl ester
The compound was synthesised from intermediate 5D using method O to give title compound 270 (0.28 g, 73%) MS: m/z 423. 27E. 3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}- benzoic acid
The compound was synthesised using method E to give title compound 27E (0.2 g, 87%) MS: m/z 409.
27Gl. 3-{[(5-Chloro-3-metb.yl-benzo[b]tbiophene-2-sulfonyI)-methyl-amino]-methyl}- NjiV-diethyl-benzamide
The compound was synthesised using method G to give title compound 27Gl (17mg, 30%) LC/MS: 100% MH+, m/z 465, Rt = 2.52 mins.
27G2. 3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-amino]-methyl}- iV-cyclohexyl-benzamide
The compound was synthesised using method G to give title compound 27G2 (19mg, 32%) LC/MS: 96% MH+, m/z 491, Rt = 2.63 mins.
27G3. S-JtCS-Chloro-S-methyl-benzoIbjthiophene-Z-sulfony^-methyl-aminol-methyl}- JV-cyclohexylmethyl-benzamide
The compound was synthesised using method G to give title compound 27G3 (40 mg, 65%) LC/MS: 99% MH+, m/z 505, Rt = 2.71 mins.
27G4. 3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyI)-methyl-amino]-methyl}- iV-(4-trifluoromethyl-benzyl)-benzamide
The compound was synthesised using method G to give title compound 27G4 (30 mg, 43%) LC/MS: 100% MH+, m/z 567, Rt = 2.67 mins.
27G5. 4-[(3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-amino]- methyl}-benzoylamino)-methyl] -benzoic acid methyl ester
The compound was synthesised using method G to give title compound 27G5 (24 mg, 35%) LC/MS: 94% MH+, m/z 557, Rt = 2.55 mins. 27G6. 4-[(3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-amino]- methyl}-benzoylamino)-methyl] -benzoic acid
The compound was synthesised using method G to give title compound 27G6 (25 mg, 38%) LCMS: 91% MH+, m/z 543, Rt = 2.36 mins.
Synthetic Route 5
Figure imgf000062_0001
DCM
HOBt
Figure imgf000062_0003
Figure imgf000062_0002
Scheme 6
Method P - 3-Bromo-5-fluorobenzoic acid methyl ester
To a solution of 3-bromo-5-fluorobenzoic acid (2 g, 9.13 mmol) in DCM/ MeOH (20 ml/ 5 ml) was added trimethylsilyldiazomethane (2M solution in ether; 1 eq) and the mixture was stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents were removed in vacuo and the residue was dissolved in DCM and washed with K2CO3. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (1.5 g, 71%) LC/MS: 91% MH+, m/z not ionised, Rt = 1.55 mins. Method Q - 3-Cyano-5-fluorobenzoic acid methyl ester
To a solution of title compound P, 3-bromo-5-fluorobenzoic acid methyl ester, (1 g, 3 mmol) in degassed DMF (5 ml) in a schlenk tube was added copper cyanide (1.1 eq) and the mixture was heated to 16O0C for 18 h. After cooling the reaction mixture was poured into IM K2CO3 and ethyl acetate. To improve separation NH4OH solution (5 ml) was added and the aqueous phase re-extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography with DCM/ MeOH (99:1) as the eluent to give the title compound (0.47 g, 60%) LC/MS: 100% MH+, m/z not ionised, Rt = 1.24 mins.
Method R - 3-(tert-Butoxycarbonylamino-methyl)-5-fluoro-benzoic acid methyl ester
To a solution of title intermediate Q, 3-cyano-5-fluorobenzoic acid methyl ester, (0.8 g, 4.47 mmol) in ethyl acetate (20 ml) was added di-tert-butyl-dicarbonate (1.2 eq) and 10% palladium on carbon (0.1 eq) the vessel was charged with hydrogen and the mixture was stirred overnight. The vessel was recharged with hydrogen and stirred for a further 5 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography with heptane/ ethyl acetate (85:15) to give the title compound (0.41 g, 32%). LC/MS: 94% MH+, m/z not ionised, Rt = 1.43 mins.
Method S - 3-Aminomethyl-5-fluoro-benzoic acid methyl ester
To a solution of title intermediate R, 3-(tert-butoxycarbonylamino-methyl)-5-fluoro- benzoic acid methyl ester, (0.41 g, 1.45 mmol) in DCM (10 ml) was added 4M HCl in dioxane (4 eq) and the mixture was stirred at room temperature for 4.5 h. The solvents were removed in vacuo. The residue was redissolved in DCM and carbonate resin added and the mixture stirred at room temperature overnight. The mixture was filtered and the solvent removed in vacuo to give the title compound (0.25 g, 94%). LC/MS: 48% MH+, m/z 184, Rt = 0.76 mins. Method T - Sulfonamide formation
To a solution of title intermediate S, 3-aminometliyl-5-fluoro-benzoic acid methyl ester, (1.37 mmol) and the sulfonyl chloride (1.0 eq) in DCM (10 ml) was added DMAP (1.1 eq, 1.50 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to give the title compound.
Method U - Saponification
To a solution of title intermediate T (1.37 mmol) in THF/ H2O (2:1 5ml:2.5 ml) was added lithium hydroxide (2 eq) and the mixture is stirred at room temperature for 5 h. The solvents were removed in vacuo and the residue was dissolved in DCM and water. The aqueous phase was washed with DCM and then acidified with IM HCl to pH= 4 and re- extracted with DCM. The solid which precipitated from the DCM phase was collected by filtration to give the title compound.
Method V - Amide formation
To a solution of title intermediate U (0.19 mmol) in DCM (2 ml) was added EDC (1 eq) and HOBt (1 eq). The amine (1 eq) was added and the mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Compounds synthesised by route 5 are detailed below:
28T. 3-Fluoro-5-[(4'-fluoro-biphenyl-4-sulfonylamino)-methyl]-benzoic acid methyl ester The compound was synthesised using method T to give title compound 28T(0.57 g, 100%) LC/MS: 83% MH+, m/z 418, Rt = 1.57 mins.
28U. 3-Fluoro-5-[(4'-fluoro-biphenyl-4-sulfonylamiiio)-methyI]-benzoic acid
The compound was synthesised using method U to give title compound 28U (50 mg, 9%) LC/MS : 100% MH+, m/z 404, Rt = 1.41 mins.
28 Vl . i\yV-Diethyl-3-fluoro-5- [(4 '-fluoro-biphenyl-4-sulf onylamino)-methyl] - benzamide
The compound was synthesised using method V to give title compound 28Vl (14.7 mg, 15%) LC/MS: 100% MH+, m/z 459, Rt = 1.52 mins.
28 V2. 4'-Fluoro-biphenyl-4-sulfonic acid 3-fluoro-5-(morphoIine-4-carbonyl)- benzylamide
The compound was synthesised using method V to give title compound 28 V2 (10.7 mg, 12%) LC/MS: 100% MH+, m/z 473, Rt = 1.4 mins.
29T. 3-[(Biphenyl-4-sulfonylamino)-methyl]-5-fluoro-benzoic acid methyl ester
The compound was synthesised using method T to give title compound 29T (0.37 g, 35%) LC/MS: 100% MH+, m/z 400, Rt = 1.6 mins.
29U. 3-[(Biphenyl-4-sulfonylamino)-methyl]-5-fluoro-benzoic acid
The compound was synthesised using method U to give title compound 29U (0.33 g, 99%) LC/MS: 100% MH+, m/z 386, Rt = 1.43 mins.
29Vl. 3-[(Biphenyl-4-sulfonylamino)-methyl]-iV,iV-dietb.yl-5-fluoro-benzamide
The compound was synthesised using method V to give title compound 29Vl (47.8 mg, 39%) LC/MS: 100% MH+, m/z 441, Rt = 1.52 mins.
29V2. Biphenyl-4-sulfonic acid 3-fluoro-5-(morphoIine-4-carbonyI)-benzylamide The compound was synthesised using method V to give title compound 29V2 (7.8 mg, 6%) LC/MS: 100% MH+, m/z 455, Rt = 1.39 mins.
29V3. Biphenyl-4-sulfonic acid 3-fluoro-5-(4-methyI-piperazine-l-carbonyI)- benzylamide
The compound was synthesised using method V to give title compound 29V3 (31 mg, 23%) LC/MS: 100% MH+, m/z 468, Rt = 1.22 mins.
Synthetic Route 6.
Figure imgf000066_0001
TEA, DMF
Figure imgf000066_0003
Figure imgf000066_0002
Scheme 7
Method W - 2-Cyano-isonicotinic acid ethyl ester.
35% wt aq hydrogen peroxide (3 eq) was added dropwise to ethyl pyruvate (4.5 eq) at - 10°C.The resulting solution was added to a solution of 2-cyanopyridine (20 g, 192.1 mmol), cone, sulphuric acid (3 eq) and iron (II) sulphate heptahydrate (3 eq) in DCM/ H2O (1 : 1.6; 100 ml: 160 ml) at -50C and the mixture was stirred for 1 h. The reaction mixture was poured into ice water (300 ml) and the two phases were separated. The aqueous phase was extracted with DCM and the combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by dry flash chromatography with cyclohexane/ EtOAc (9:1) as the eluent to give the title compound (3.46 g, 10%). LC/MS: 100% MH+, m/z 177, Rt = 1.17 mins.
Method X - 2-(te7-t-Butoxycarbonylamino-methyl)-isonicotinic acid ethyl ester
To a solution of title intermediate W, 2-cyano-isonicotinic acid ethyl ester, (25 mmol) in ethanol (500 ml) was added di-fert-butyl-dicarbonate (1.2 eq) and 10% palladium on carbon (900 mg), the vessel was charged with hydrogen and stirred at room temperature for 3 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo.
The crude residue was purified by column chromatography with cyclohexane/ EtOAc (4:1) as the eluent to give the title compound (3.85 g, 55%). LC/MS: 95% MH+, m/z 281, Rt = 1.18 mins.
Method Y - 2-Aminomethyl-isonicotinic acid ethyl ester
To a solution of title intermediate X, 2-(tert-butoxycarbonylamino-methyl)-isonicotinic acid ethyl ester, (13.7 mmol) in DCM (35 ml) was added 4M HCl in dioxane (5.6 eq) and the mixture was stirred at room temperature for 4 h. The solvents were removed in vacuo to give the HCl salt of the title compound which was used without purification (3.28 g, >100%). LC/MS: 100% MH+, m/z 181, Rt = 0.77 mins.
Method Z - Sulfonamide formation
To a solution of intermediate Y, 2-aminomethyl-isonicotinic acid ethyl ester (3.16 mmol) and the sulfonyl chloride (1.05 eq) in DCM (15 ml) was added DIPEA (3.5 eq) and the mixture was stirred at room temperature for 1 h. The reaction mixture was washed with IM NaOH solution and the organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Method AA - Saponification.
To a solution of intermediate Z (3.28 mmol) in THF/ H2O (3 :2 50 ml) was added lithium hydroxide (8 eq) and the mixture was stirred at room temperature for 2 h. The solvents were removed in vacuo and the residue was suspended in ethyl acetate and washed with IM HCl. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound.
Method BB - Amide Formation.
To a solution of intermediate AA (0.23 mmol) and TEA (3 eq) in DMF (2 ml) was added the amine (2 eq) and DPPA (4 eq) and the mixture was stirred at room temperature for 1 h. The reaction mixture was basified with 15% NaOH (1 ml) and extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude mixture was triturated with DCM, the solid impurity removed by filtration and the filtrate was concentrated in vacuo to give the title compound.
Compounds synthesised by route 6 are detailed below:
3OZ. 2-[(Biphenyl-4-sulfonylamino)-methyl]-isonicotinic acid ethyl ester
The compound was synthesised using method Z to give title compound 3OZ (1.3 g, 99%) LC/MS: 95% MH+, m/z 397, Rt = 1.47 mins.
30AA. 2-[(Biphenyl-4-sulfonylamino)-methyl]-isonicotinic acid
The compound was synthesised using method AA to give title compound 30AA (1.27 g, 88%) LC/MS: m/z 369, Rt = 1.2 mins, purity could not be determined due to poor solubility; NMR confirmed purity >90%.
30BB1. 2-[(Biphenyl-4-sulfonylamino)-methyl]-N,iV-diethyl-isonicotinamide
The compound was synthesised using method BB to give title compound 3 OBBl (24.1 mg, 25%) LC/MS : 100% MH+, m/z 424, Rt = 1.9 mins.
30BB2. Biphenyl-4-sulfonic acid [4-(morphoIine-4-carbonyl)-pyridin-2-ylmethyI]- amide
The compound was synthesised using method BB to give title compound 30BB2 (50.9 mg, 51%) LC/MS: 100% MH+, m/z 438, Rt = 1.63 mins. 30BB3. Biphenyl-4-sulfonic acid [4-(4-methyl-piperazine-l-carbonyI)-pyridin-2- ylmethyl]-amide
The compound was synthesised using method BB to give title compound 30BB3 (45.2 mg, 44%) LC/MS: 100% MH+, m/z 451, Rt = 1.68 mins.
Synthetic Route 7
Figure imgf000069_0001
Scheme 8
Method CC- Oxazolidinone Formation
Chloroethanol (1 eq) was added dropwise to chlorosulfonyl isocyanate (1 eq) in DCM (30 ml) at O0C and the mixture was stirred for 1 h. A solution of 3-aminornethyl-benzoic acid methyl ester. HCl 1C (14.88 mmol) and rriethylamine (3 eq) in DCM (30 ml) was added dropwise maintaining the temperature between 0-50C. The reaction was stirred at room temperature for 3 days. The reaction was quenched with 1 M HCl and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography with DCM/ MeOH (98:2) as the eluent to give the title compound (2.59 g, 50%). LC/MS: 90% MH+, m/z 315, Rt - 1.14 mins.
Method DD- Sulfamide formation To a solution of the oxazolidinone intermediate CC (1.59 mmol) and triethylamine (1 eq) in acetonitrile (2 ml) was added a solution of the amine (1 eq) in acetonitrile (ImI) and the mixture was heated to 8O0C for 4 h. After cooling, the reaction mixture was concentrated in vacuo. The crude reaction mixtures were purified by column chromatography with DCM/ MeOH as the eluent to give the title compound.
Method EE - Saponification.
To a solution of intermediate DD (1.48 mmol) in THF/ MeOH (3:2 15 ml) was added lithium hydroxide (8 eq) and the mixture was stirred at room temperature for 3.5 days. The solvents were removed in vacuo and the residue was dissolved in DCM. The organic phase was washed with IM HCl and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound.
Method FF- Amide Formation
To a solution of intermediate EE (0.22 mmol) and triethylamine (3 eq) in DMF (2 ml) was added the amine (2 eq) and DPPA (2.5 eq). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was basifed with 15% NaOH (1 ml) and the mixture was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in DCM and filtered (white solid removed) and the filtrate was concentrated in vacuo. The crude mixture was purified either by semi-prep HPLC or column chromatography with DCM/ EtOAc as the eluent to give the title compound.
Amide formations also carried out as detailed in synthetic route 1 methods G, H and V.
Compounds synthesised using route 7 are detailed below:
31DD. 3-[(Biphenyl-4-aminosulfonyl)aminomethyl]-benzoic acid methyl ester
The compound was synthesised using method DD to give title compound 31DD (0.18 g, 33%) LC/MS: 100% MH+, m/z 397, Rt = 1.53 mins. 31EE. 3-[(Biphenyl-4-aminosulfonyI)aminomethyl]-benzoic acid
The compound was synthesised using method EE to give title compound 31EE (0.17 g, 98%) LC/MS: 100% MH+, m/z 383, Rt = 1.21 mins.
31 Vl . 3- [(Biphenyl-4-aminosulf onyl)aminomethyl] -iV,iV-diethyl-benzamide
The compound was synthesised using method V to give title compound 3 IVl (4.7 mg, 8%) LC/MS: 100% MH+, m/z 438, Rt = 2.07 mins.
32DD. 3-[(Biphenyl-3-aminosulfonyI)aminomethyl]-benzoic acid methyl ester
The compound was synthesised using method DD to give title compound 32DD (0.59 g, 93%) LC/MS: 100% MH+, m/z 397, Rt = 1.51 mins.
32EE. 3-[(Biphenyl-3-aminosulfonyl)aminomethyl]-benzoic acid
The compound was synthesised using method EE to give title compound 32EE (0.39 g, 69%) LC/MS: 100% MH+, m/z 383, Rt = 1.37 mins.
32FF1. 3- [(Biphenyl-3-aminosulf onyl)aminomethyl] -JV,iV-diethyI-benzamide
The compound was synthesised using method FF to give title compound 32FF 1 (50.7 mg, 53%) LC/MS: 100% MH+, m/z 438, Rt = 2.07 mins.
33DD. 3-[(Adamantane-2-aminosulfonyl)aminomethyl]-benzoic acid methyl ester
The compound was synthesised using method DD to give title compound 33DD (0.43 g, 71%) LC/MS: 100% MH+, m/z 379, Rt = 1.57 mins.
33EE. 3-[(Adamantane-2-aminosulfonyl)aminomethyl]-benzoic acid
The compound was synthesised using method EE to give title compound 33EE (0.8 g, 100%) LC/MS: 100% MH+, m/z 365, Rt = 1.39 mins.
33FF1. 3- [(Adamantane-2-aminosulf onyl) aminomethyl] -iV, JV-diethyl-benzamide The compound was synthesised using method FF to give title compound 33FF1 (28.1 mg, 24%) LC/MS: 100% MH+, m/z 420, Rt = 1.55 mins.
34DD. S-tCDecahydroisoquinoline-Z-sulfony^amiiiomethyll-benzoic acid methyl ester
The compound was synthesised using method DD to give title compound 34DD (0.47 g, 81 %) LC/MS : 100% MH+, m/z 367, Rt = 1.64 mins.
34EE. S-Iφecahydroisoquinoline-l-sulfony^aminomethyll-benzoic acid
The compound was synthesised using method EE to give title compound 34EE (0.24 g, 53%) LC/MS: 100% MH+, m/z 353, Rt = 1.44 mins.
34FFl. iV,iV-Diethyl-3-[(decahydroisoquinoline-2-sulfonyI)aminomethyl]-benzamide
The compound was synthesised using method FF to give title compound 34FF 1 (28 mg, 29%) LC/MS: 100% MH+, m/z 408, Rt = 2.16 mins.
34G2. iV-Cyclohexyl-3-[(decahydroisoquinoline-2-sulfonyl)aminomethyl]-benzamide
The compound was synthesised using method G to give title compound 34G2 (65.6 mg, 84%) LC/MS: 98% MH+, m/z 434, Rt = 2.49 mins.
34H3. 4-{[3-((Pecahydroisoquinoline-2-sulfonyl)aminomethyI)-benzoylamiiio]- methyl}-benzoic acid methyl ester
The compound was synthesised using method H to give title compound 34H3 (42.4 mg, 6%) LC/MS: 100% MH+, m/z 500, Rt = 2.38 mins.
35DD. 3-[(l,2,3,4-Tetrahydroisoqumolme-2-sulfonyl)aniiiiomethyl]-benzoic acid methyl ester
The compound was synthesised using method DD to give title compound 35DD (1.28 g, 50%) LC/MS: 90% MH+, m/z 361, Rt = 2.13 mins.
35EE. 3-[(l,2,3,4-TetrahydBoisoquinoline-2-sulfonyl)aminomethyl}-benzoic acid The compound was synthesised using method EE to give title compound 35EE (1.45 g, 100%) LC/MS: 82% MH+, m/z 347, Rt = 1.89 mins.
35Gl. N,N-Diethyl-3-[(l,2,3,4-tetrahydroisoquinoline-2-sulfonyl)aminomethyl]- benzamide
The compound was synthesised using method G to give title compound 35Gl (25 mg, 22%) LC/MS: 100% MH+, m/z 402, Rt = 2.18 mins.
35G2. iV-Cyclohexyl-3-[(l,2,3,4-tetrahydroisoquinoline-2-sulfonyl)aminomethyl]- benzamide
The compound was synthesised using method G to give title compound 3652 (21 mg, 17%) LC/MS: 93% MH+, m/z 428, Rt = 2.28 mins.
35G3. N-Cyclohexylmethyl-3-[(l,2,3,4-tetrahydroisoquinoline-2- sulfonyl)aminomethyl]-benzamide
The compound was synthesised using method G to give title compound 35G3 (26 mg, 20%) LC/MS: 97% MH+, m/z 442, Rt = 2.37 mins.
35H4. 4-{[3-((l,2,3,4-TetrahydroisoquinoIine-2-sulfonyl)aminomethyl)- benzoylamino]-methyl}-benzoic acid methyl ester
The compound was synthesised using method H to give title compound 35H4 (0.45 g, 79%) LC/MS: 92% MH+, m/z 494, Rt = 2.23 mins.
Synthetic Route 8
Figure imgf000074_0001
Figure imgf000074_0002
Scheme 9
Method GG - Saponification.
To a solution of the intermediate ester (0.05 mmol) in THF/ H2O (2:1 1.5 ml) was added lithium hydroxide (5 eq) and the mixture was stirred at room temperature for 24hr. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate and water. The aqueous phase was acidified to pH=2 with IM HCl and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound.
Compounds synthesised using route 8 are detailed below:
34GG. 4-{[3-((Decahydroisoquinoline-2-sulfonyl)aminomethyl)-benzoylamino]- methyl}-benzoic acid
The compound was synthesised from intermediate 34H3 using method GG to give title compound 34GG (125 mg, 43%) LC/MS: 100% MH+, m/z 486, Rt = 2.16 mins.
35GG. 4-{[3-((l,2,3,4-tetrahydroisoquύioliiie-2-suIfonyl)amiiiomethyl)- benzoylamino]-methyl}-benzoic acid
The compound was synthesised from intermediate 35H4using method GG to give title compound 35GG (56 mg, 30%) LC/MS: 100% MH+, m/z 480, Rt = 2.02 mins.
Synthetic Route 9
Figure imgf000075_0001
Figure imgf000075_0002
Scheme 10
Method HH - Carboxamide Formation.
A solution of the intermediate ester (0.01 mmol) in ammonium hydroxide (28% v/w, 2 ml) was heated to 8O0C in a sealed tube overnight. After cooling the mixture was concentrated in vacuo. The crude material was purified by column chromatography with DCM/ MeOH (up to 5% MeOH) as the eluent to give the title compound.
Method II — Carboxamide Formation.
To a solution of the intermediate ester (0.01 mmol) in THF/ H2O (1:1, 2 ml) was added lithium hydroxide (2.5 eq) and the mixture heated to 8O0C for 3 h. After cooling, the mixture was acidified to pH=4 with IM HCl and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the carboxylic acid.
To a solution of the carboxylic acid (0.01 mmol) in THF (2 ml) at -150C was added methyl chloroformate (1.2 eq) and TEA (1.5 eq) and the mixture was allowed to warm to room temperature for 15 min. The reaction was cooled to O0C and gaseous ammonia was bubbled through the solution for 10 min. The mixture was allowed to warm to room temperature and was concentrated in vacuo. The crude product was purified by column chromatography with DCM/ MeOH as the eluent to give the title compound. Compounds synthesised using route 9 are detailed below:
2HH. 4-({3- [(3-Chloro-2-methyl-benzenesulf onylamino)-methyl] -benzoylamino}- methyl)-benzamide
The compound was synthesised from intermediate 2G3 using method HH to give title compound 2HH (4 mg, 4%) LC/MS: 96% MH+, m/z 472, Rt = 1.90 mins.
2411. 4-[(3-{[(3-Chloro-2-methyl-benzenesulfonyl)-methyl-amino]-methyl}- benzoylamino)-methyl] -benzamide
The compound was synthesised from intermediate 24G6 using method HH to give title compound 2411 (25 mg, 52%) LC/MS: 100% MH+, m/z 486, Rt = 2.07 mins.
2511. 4-[(3-{[(Benzo[b]tMophene-2-sulfonyl)-methyl-amino]-methyl}-benzoylamino)- methyl]-benzamide
The compound was synthesised from intermediate 25G5 using method HH to give title compound 2511 (28 mg, 57%) LC/MS: 98% MH+, m/z 494, Rt = 2.10 mins.
2611. 4- [(3- { [Methyl-(naphthalene-2-sulf onyl)-amino] -methyl}-benzoylamino)- methyl] -benzoic acid
The compound was synthesised from intermediate 26G5 using method HH to give title compound 2611 (33 mg, 68%) LC/MS: 94% MH+, m/z 488, Rt = 2.07 mins.
2711. 4-[(3-{[(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-methyl-amino]- methyl}-benzoylamino)-methyl]-benzamide
The compound was synthesised from intermediate 27G5 using method HH to give title compound 2711 (20 mg, 41%) LC/MS: 97% MH+, m/z 542, Rt = 2.27 mins.
34HH. 4-{[3-((Decahydroisoquinoline-2-sutfonyl)aminomethyl)-benzoylamino]- methyl}-benzamide The compound was synthesised from intermediate 34H3 using method HH to give title compound 34HH (57 mg, 20%) LC/MS: 100% MH+, m/z 485, Rt = 2.04 mins.
35HH. 4-{[3-((l,2,3,4-tetrahydroisoquinoIine-2-sulfonyl)aminomethyl)~ benzoylamino] -methyl}-benzamide
The compound was synthesised from intermediate 35H4 using method HH to give title compound 35HH (13 mg, 7%) LC/MS: 100% MH+, m/z 479, Rt = 1.90 mins.
Synthetic Route 10
Figure imgf000077_0001
Scheme 11
Method JJ - Acylsulfonamide Formation.
To a solution of mono-methyl isophthalate (0.8 g, 4.44 mmol, 1.2 eq) in DCM/ DMF (3:1, 16 ml) was added EDC (1.2 eq), DMAP (1.2 eq) and the sulfonamide (1 eq) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in DCM. The organic phase was washed with water and IM NaOH, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography with DCM/ MeOH (+ 1% AcOH) as the eluent to give the title compound.
36JJ. 3-(3-Chloro-2-methyl-benzenesulfonylaminocarbonyl)-benzoic acid methyl ester
The compound was synthesised using method JJ to give title compound 36JJ (1.10 g, 76%) LC/MS: 94% MH+, m/z 368, Rt = 2.06 mins.
37JJ. 3-(2,4,6-Trichloro-benzenesulfonylaminocarbonyI)-benzoic acid methyl ester The compound was synthesised using method JJ to give title compound 37JJ (0.89 g, 57%) LC/MS: 100% MH+, m/z 422, Rt = 2.12 mins.
Example 4: 11 β-HSD Assays
Biochemical assays monitoring the mouse llβ-HSD type 1 reductase, human llβ- HSD type 2 dehydrogenase, human llβ-HSD type 1 reductase and dehydrogenase activity
As source for the respective enzyme the human embryonic kidney cell line, HEK 293, was transfected with the foil length cDNAs for human and mouse 1 lβ-HSD 1 and human llβ- HSD2 followed by selection of stably expressing clones according to standard procedures.
Whole cell lysates of 1 lβ-HSD cell lines were prepared by growing of cells in 15 cm dishes in culture medium (DMEM, 10% FCS and 600 μg/ml G418) until 70% confiuency. To force expression of 1 lβ-HSD, cells were incubated overnight with 1.5 mM sodium butyrate (Aldrich, cat. no. 30,341-0), ahistone deacetylase inhibitor. Cells were then harvested by addition of 2 ml PBS with 2.5 mM EDTA per 15 cm dish for 5 to 10 min at RT. Cell suspensions were combined and after centrifugation by lOOOg for 5 min the cell pellet was homogenized in 20 mM potassium phosphate buffer, pH 7.4, 5 mM EDTA, 250 mM sucrose (1.5 ml per cell pellet of five 15 cm dishes) using a Ultra Turrax Homogenizer. The whole cell lysate was frozen in liquid nitrogen and stored at -8O0C in aliquots suitable for single use.
The enzymatic reaction was carried out in the presence of cofactors NAD+ (dehydrogenase activity) or NADPH (reductase activity) and the respective steroid substrates. In order to maintain an excess of the co factor NADPH, NADPH was regenerated by adding glucose- 6-phosphate (G6P) and G6P-dehydrogenase in non-limiting concentrations to the llβ- HSDl reductase enzymatic reaction. All assay components and compounds were diluted in reaction buffer, 20 mM Tris-HCl (pH 7.4), 250 mM sucrose, 100 mM NaCl5 1 mM MgCl2, 1 mM EDTA, 1 mM EGTA, and stored on ice prior to use.
The following reaction mixtures plus compounds in concentrations between 10 pM and 300 μM were prepared in a total volume of 102 μl and were incubated for 15 min at 37°C.
Human and mouse 1 lβ-HSD type 1 reductase activity:
100 μM NADPH (AppliChem, cat. no. Al 395,0500), 10 mM glucose-6-phosphate (Sigma cat. no. G-7879), 0.37 U/ml glucose-6-phosphate-dehydrogenase (Fluka, cat. no 49275) and 3 μM 11-dehydrocorticosterone (Research Plus, cat. no. 3306-16) or 3 μM cortisone (Sigma, cat. no. C-2755) for mouse and human enzyme, respectively.
The compounds exemplified in this invention typically have IC50 values < 100 μM
Human 1 lβ-HSD type 1 and type 2 dehydrogenase activity:
500 μM NAD+ (Applichem, cat. no. Al 124,0001) and 3 μM Cortisol (Sigma, cat. no H- 0888).
The enzymatic reaction was started by adding 18 μl whole cell lysates, equivalent to 80.000 cells of the respective HSD overexpressing cell lines. After 60 minutes at 37°C the reaction was stopped by carbenoxolone (Sigma, cat. no C-4790), an inhibitor of all HSD enzymes analysed, in a final concentration of 100 μM.
To determine the extent of the enzymatic reactions, cortisole or corticosterone were measured in an ELIS A-based assay principle. This cortisol/corticosterone ELISA makes use of a monoclonal antibody specifically binding to cortisol/corticosterone. The detection is competition-based, since Cortisol or corticosterone in a sample compete with Cortisol covalently attached to alkaline phosphatase (AP). The amount of alkaline phosphatase bound, was detected by a colourimetric measurement, using pNPP as phosphatase substrate.
96well ELISA plates (Falcon, cat. no. BD 353915) were coated with 5 μg/ml rabbit anti mouse IgG antibody (Sigma, cat. no. M-9637) in PBS overnight at 4°C. After aspiration of this solution the wells were blocked with 200 mM acetate citrate buffer, pH 6.0, 20% FCS and 2% gelatine for one hour at RT. The plates were washed three times (50 mM Tris-HCl, pH 7.8, 0.1% Tween 20) and 100 μl of samples and standards, Cortisol or corticosterone ranging from 78 nM to 10 μM, were added. The stocks of Cortisol- AP conjugate (Fitzgerald, cat. no. 65-IC07) and mouse monoclonal anti-cortisol antibody (Biotrend cat. no. 2330-4879) were diluted 1:1600 or 1:3600, respectively, in 100 mM Tris-HCl , pH 7.7, 10 mM MgCl2, 0.1% BSA. 50 μl of each dilution were added per well. After a incubation of two hours at RT under shaking, plates were washed three times (50 mM Tris-HCl, pH 7.8, 0.1% Tween 20).
For detection, 200 μl of 25 mM Glycin, pH 10.3, 10 mM pNPP (Fluka, cat. no. 71768), 1 mM ZnSO4 and 1 mM MgSO4, were added and incubated for two hours at RT under shaking. Colourimetric measurement was performed in a microplate reader at 405 nm (Versamax, Molecular Devices). The concentrations of Cortisol or corticosterone were calculated with SoftmaxPro software (Molecular Devices) relative to standard values. The inhibitory potency of 11 β-HSD inhibitors was determined by IC50 calculation with Prism 4.0 software (GraphPad).
The compounds exemplified in this invention show no activity against the 1 lβ-HSD-2 enzyme.
Cell-based assay with human llβ-HSD type 1 stably expressing HEK293 cells
30.000 1 lβ-HSDl stably expressing HEK293 cells were seeded per 96 well in 100 μl culture medium (DMEM, 10% FCS and 600 μg/ml G418). After overnight incubation at 37°C and 5% CO2 llβ-HSD inhibitors in final concentrations between 10 pM and 300 μM, 3 μM cortisone and 20 mM HEPES were added to the culture medium. All components, i.e. inhibitors, steroid substrate and HEPES were pre-diluted in DMEM prior to use. After incubation of 4 h at 370C the culture medium was diluted 1 :10 in 100 mM Tris-HCl, pH 7.7, 10 mM MgCl2 and 0.1% BSA. The determination of Cortisol concentrations was carried out with a commercially available Cortisol ELISA (Assay Designs, cat. no. 901071) according to the recommended protocol. The concentrations of Cortisol were calculated with SoftmaxPro software (Molecular Devices), the inhibitory potency of 11 β- HSD inhibitors was determined by IC50 calculation with Prism 4.0 software (GraphPad).
The compounds exemplified in this invention typically have IC50 values < 50 μM.
Cell-based assay with a human adipocyte cell line, endogenously expressing llβ- HSDl
Human SGBS preadipocytes were differentiated to mature adipocytes as described by Wabitsch et. al. (Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H.: Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord. 2001 Jan;25(l):8-15). 3500 cells were seeded per 96 well and cultured for 3 days in 200 μl culture medium
(DMEM/Nutrient Mix F 12, 100 U/ml penicillin, 100 μg/ml streptomycin, 17 μM biotin, 33 μM pantothenate, 10% none heat inactivated fetal calf serum) until confluence (day 0). Differentiation was initiated by medium change to 100 μl differentiation medium (DMEM/Nutrient Mix F 12, 100 U/ml penicillin, 100 μg/ml streptomycin, 17 μM biotin, 33 μM pantothenate, 0.01 mg/ml transferrin, 100 nM hydrocortisone, 20 nM human insulin, 0.2 nM T3, 25 nM dexamethasone, 250 μM IBMX, 3 μM rosiglitazone). On day 4 of differentiation, the medium was changed to post-differentiation medium (DMEM/Nutrient Mix F 12, 100 U/ml penicillin, 100 μg/ml streptomycin, 17 μM biotin, 33 μM pantothenate, 0.01 mg/ml transferrin, 100 nM hydrocortisone, 20 nM human insulin, 0.2 nM T3). The assay was performed with differentiated adipocytes between day 11 and day 15 of differentiation in assay medium (DMEM/Nutrient Mix F 12, 17 μM biotin, 33 μM pantothenate, 0.01 mg/ml transferrin, 20 nM human insulin, 0.2 nM T3, 0.5 μM cortisone). The procedures for incubation with compound, determination of Cortisol concentrations and data analysis were performed identically to the cellular assay with HEK293 cells described above.
The compounds exemplified in this invention typically have IC50 values < 50 μM.

Claims

Claims
1. A compound of formula (I)
Figure imgf000083_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X1, X2, X3, X4 are independently selected from the group consisting of N; and CR4, wherein R4 is independently H; halogen; CN; C(O)OR4a; C(O)N(R4aR4b); OR4a; N(R4aR4b); phenyl; C1-6 alkyl; or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R4a, R4b are independently selected from the group consisting of H; C1-6 alkyl; and C3-7 cycloalkyl;
R1, R2 are independently selected from the group consisting of H; C1-6 alkyl; C3-7 cycloalkyl; and halogen, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with halogen;
Optionally R1, R2 are combined to form oxo (=0);
Y is -N(Rla)S(O)2-; -S(O)2N(R1Y; or -N(Rla)S(O)2N(Rlb)-;
A is T; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R5, wherein R5 is independently halogen; CN; COOR6; OR6; C(O)N(R6R6a); S(O)2N(R6R62); S(O)N(R6R6a); S(O)2R6; N(R6)S(O)2N(R6aR6b); SR6; N(R6R6a); OC(O)R6; N(R6)C(O)R6a; N(R6)S(O)2R6a; N(R6)S(O)R6a; N(R6)C(O)N(R6aR6b); N(R6)C(CO)OR6a; OC(O)N(R6R6a); or T;
Rla, Rlb are independently selected from the group consisting of H; allyl; benzyl;
CH2-C(O)NH2; CH2-COOH; CH2-C(O)O-C1-6 alkyl; C1-6 alkyl; and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more Rlc, wherein Rlc is independently halogen; C1-6 alkyl; -CH=CH2; phenyl; C(O)NH2; COOH; C(O)O-C1-6 alkyl or C3-7 cycloalkyl;
Optionally A and Rla form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R , which are the same or different;
R6, R6a R are independently selected from the group consisting of H; C1-6 alkyl; and T, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R7, which are the same or different;
R7 is independently halogen; CN; COOR8; OR8; C(O)N(R8R8a); S(O)2N(R8R8a); S(O)N(R8R8a); S(O)2R8; N(R8)S(O)2N(R8aR8b); SR8; N(R8R8a); OC(O)R8; N(R8)C(O)R8a; N(R8)S(O)2R8a; N(R8)S(O)R8a; N(R8)C(O)N(R8aR8b);
N(R8)C(O)OR8a; OC(O)N(R8R8a); oxo (=0), where the ring is at least partially saturated; C(O)R8; T1; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R9;
R , R , R are independently selected from the group consisting of H; T ; and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R10; R9, R10 axe independently selected from the group consisting of halogen; CN; COOR11; OR11; C(O)R11; C(O)N(R11 R1 la); S(O)2N(R11R113); S (O)N(R11 R1 la); S(O)2R11; N(R1 ^S(O)2N(R1 laRllb); SR11; N(RπRlla); OC(O)R11; N(R1 ^C(O)R113; N(R1 ^SO2R113; N(R1 ^S(O)R113; N(R1 ^C(O)N(R113R1115); N(R1 ^C(O)OR113; OC(O)N(R11R113); and T1;
R11, Rl la, Rl lb are independently selected from the group consisting of H; Ci-6 alkyl; and T1;
T1 is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T1 is optionally substituted with one or more R12, wherein R12 is independently halogen; CN; COOR13; OR13;
C(O)N(R13R133); S(O)2N(R13R133); S(O)N(R13R13a); S(O)2R13;
N(R13)S(O)2N(R13aR13b); SR13; N(R13R133); OC(O)R13; N(R13)C(O)R13a; N(R13)S(O)2R13a;N(R13)S(O)R13a; N(R13)C(O)N(R13aR13b); N(R13)C(O)OR13a;
OC(O)N(R13R13a); oxo (=0), where the ring is at least partially saturated; C(O)R13;
C1-6 alkyl; phenyl; C3-7 cycloalkyl; or heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H; C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z1 is =O or =S;
Optionally Z1 is =N-R15 and R15, R3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R16, provided that the heterocycle is other than
Figure imgf000086_0001
Z2 is O; S; or N-R14;
R3, R14 are independently selected from the group consisting of H; T2; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R17, provided that when one of R3 and R14 is H and the other is ethyl, R17 is other than -COOH;
Optionally R3, R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R18, provided that the heterobicycle is other than unsύbstituted or in 3,6 and/or 7 position substituted 1,2,3,4- tetrahydroquinoline and its 4-oxa, -thia, -aza and/or 8-aza derivatives;
T2 is C3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T2 is optionally substituted with one or more R19; provided that when A is phenyl; Y is -S(O)2NH-, wherein the sulfur is attached to A; R1, R2 are H; X1, X3, X4 are CH; X2 is C-R4, wherein R4 is OCH3; Z1 is =0; and Z2 is NH, T2 is other than unsύbstituted phenyl;
R16, R18, R19 are independently selected from the group consisting of halogen; CN; COOR20; OR20; C(O)N(R20R20a); S(O)2N(R20R203); S(O)N(R20R20a); S(O)2R20; N(R20)S(O)2N(R20aR20b); SR20; N(R20R20a); OC(O)R20; N(R20)C(O)R20a; N(R20)S(O)2R20a; N(R20)S(O)R20a; N(R20)C(O)N(R20aR20b); N(R20)C(O)OR20a; OC(O)N(R20R20a); oxo (=0), where the ring is at least partially saturated; C(O)R20; C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R21;
R20, R20a, R20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R17, R21 are independently selected from the group consisting of halogen; CN; COOR22; OR22; C(O)R22; C(O)N(R22R22a); S(O)2N(R22R22a); S(O)N(R22R22a);
S(O)2R22; N(R22)S(O)2N(R22aR22b); SR22; N(R22R22a); OC(O)R22; N(R22)C(O)R22a;
N(R22)SO2R22a; N(R22)S(O)R22a; N(R22)C(O)N(R22aR22b); N(R22)C(O)OR22a;
OC(O)N(R22R22a); C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-
6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R23;
R , R , R are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more R23a;
R23, R23a are independently selected from the group consisting of halogen; CN;
COOR24; OR24; C(O)R24; C(O)N(R24R243); S(O)2N(R24R24a); S(O)N(R24R24a);
S(O)2R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R24a); OC(O)R24; N(R24)C(O)R24a;
N(R24)SO2R24a; N(R24)S(O)R24a; N(R24)C(O)N(R24aR24b); N(R24)C(O)OR24a; OC(O)N(R24R242); and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different, provided that the compound of formula (I) is other than N-[l-(3-aminocarbonyl-4- hydroxyphenyl)-2,2,2-tricnloroethyl]-4-chlorobenzenesulfonarnide.
2. A compound according to claim 1, wherein at most one of X1, X2, X3 and X4 are N.
3. A compound according to claim 1 or 2, wherein R1 and R2 are H or combined to form
=0.
4. A compound according to any of claims 1 to 3, wherein R4 is F; Cl; Br; CH3; OCH3, NH2; or phenyl.
5. A compound according to any of claims 1 to 4, wherein Y is -*S(O)2-NH- or -*S(O)2- N(CH3)- wherein the atom marked with an asterisk is attached to A.
6. A compound according to any of claims 1 to 5, wherein A is phenyl, adamantyl; C3-7 cycloalkyl; heterocyclyl; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with T.
7. A compound according to claim 6, wherein A is phenyl; cyclohexyl; thiophenyl; benzothiophenyl; naphthyl; diazolyl; or pyridyl.
8. A compound according to any of claims 1 to 7, wherein A is T and T is optionally substituted with up to 3 R7, independently being F; Cl; CH3; OCH3; N(CH3)2; T1; OT1; or NHT1.
9. A compound according to claim 8, wherein T1 is phenyl, which is optionally substituted with up to three halogens, independently being F; and Cl.
10. A compound according to any of claims 1 to 9, wherein A is T and T is heterobicyclyl.
11. A compound according to claim 10, wherein heterobicyclyl is decahydroquinoline or tetrahydroisoquinoline and wherein the ring nitrogen is directly linked to the sulphur of the sulphonamide group representing Y.
12. A compound according to any of claims 1 to 11, wherein Z1 is =O and Z2 is
-NR14.
13. A compound according to any of claims 1 to 12, wherein R14 is H.
14. A compound according to any of claims 1 to 13, wherein R3 is phenyl; benzyl; heterocyclyl; C3-7 cycloalkyl; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with 0-C1-6 alkyl or C3-7 cycloalkyl.
15. A compound according to any of claims 1 to 14, wherein R3 is T2 and T2 is substituted with up to three R19, independently being F; Cl; CH3; OCH3; N(CH3)2; C(O)OH;
C(O)OCH3; CF3; or C(O)NH2.
16. A compound according to claim 15, wherein T2 is phenyl; cyclohexyl; or pyridyl.
17. A compound according to any of claims 1 to 16, wherein R3, R14 are independently H or C1-6 alkyl, independently being ethyl; isopropyl; n-propyl; n-butyl, wherein C1-6 alkyl is optionally substituted with N(CH3 )2; or N(C2Hs)2.
18. A compound according to any of claims 1 to 17, wherein Z1 is =N-R15 and R15, R3 jointly form a heterocycle.
19. A compound according to claim 18, wherein the heterocycle is oxazole;_oxadiazole; diazole; or triazole, wherein the heterocycle is optionally substituted with one R16 being C1-6 alkyl, optionally substituted with N(CH3)2 or N(CH2CH3)2; C3-7 cycloalkyl; phenyl; or heterocyclyl.
20. A compound according to claim 19, wherein R16 is methyl; ethyl; iso-propyl; cyclohexyl; phenyl; or piperidinyl.
21. A compound according to any of claims 1 to 20, wherein R3, R14 jointly form a heterocycle.
22. A compound according to claim 21, wherein the heterocycle is piperazine; morpholine; piperidine; or pyrrolidine, and wherein the heterocycle is optionally substituted with methyl.
23. A compound of formula (I)
Figure imgf000090_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X1, X2, X3, X4 are independently selected from the group consisting of N; and CR4, wherein R4 is independently H; halogen; CN; C(O)OR4a; C(O)N(R4aR4b); OR4a; N(R4aR4b); phenyl; C1-6 alkyl; or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R4a, R4b are independently selected from the group consisting of H; C1-6 alkyl; and
C3-7 cycloalkyl;
R , R are independently selected from the group consisting of H; C1-6 alkyl; C3-7 cycloalkyl; and halogen, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with halogen; Optionally R1, R2 are combined to form oxo (=0);
Y is -N(R1^S(O)2-; -S(O)2N(Rlb)-; or -N(Rla)S(O)2N(Rlb)-;
A is T; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R5, wherein R5 is independently halogen; CN; COOR6; OR6; C(O)N(R6R6a); S(O)2N(R6R63); S(O)N(R6R6a); S(O)2R6; N(R6)S(O)2N(R6aR6b); SR6; N(R6R6a); OC(O)R6; N(R6)C(O)R6a; N(R6)S(O)2R6a; N(R6)S(O)R6a; N(R6)C(O)N(R6aR6b); N(R6)C(CO)OR6a; OC(O)N(R6R6a); or T;
Rla, Rlb are independently selected from the group consisting of H; allyl; benzyl; CH2-C(O)NH2; CH2-COOH; CH2-C(O)O-C1-6 alkyl; C1-6 alkyl; and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more Rlc, wherein Rlc is independently halogen; C1-6 alkyl; -CH=CH2; phenyl; C(O)NH2;
COOH; C(O)O-C1-6 alkyl or C3-7 cycloalkyl;
Optionally A and Rla form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R7, which are the same or different;
R6, R6a R6b are independently selected from the group consisting of H; C1-6 alkyl; and T, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R7, which are the same or different;
R7 is independently halogen; CN; COOR8; OR8; C(O)N(R8R83); S(O)2N(R8R83);
S(O)N(R8R83); S(O)2R8; N(R8)S(O)2N(RSaR8b); SR8; N(R8R83); OC(O)R8; N(R8)C(O)R8a; N(R8)S(O)2R8a; N(R8)S(O)R8a; N(R8)C(O)N(R8aR8b); N(R8)C(O)OR8a; OC(O)N(R8R83); oxo (=O), where the ring is at least partially s saattuurraatteedd;; C C((OO))PR ; T ; or Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more R9;
R8, R8a, R8b are independently selected from the group consisting of H; T1; and Ci-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R10;
R9, R10 are independently selected from the group consisting of halogen; CN; COOR11; OR11; C(O)R11; C(O)N(R11 R11 a); S(O)2N(R11R113); S(O)N(R11R1 la); S(O)2R11; N(R1 ^S(O)2N(R113R1115); SR11; N(R11R113); OC(O)R11; N(R1 ^C(O)R113;
N(R1 ^SO2R113; N(R1 ^S(O)R113; N(R11JC(O)N(R118R1 lb); N(R11JC(O)OR113; OC(O)N(R11R113); and T1;
R11, Rlla, Rllb are independently selected from the group consisting of H; C1-6 alkyl; and T1;
T1 is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T1 is optionally substituted with one or more R12, wherein R12 is independently halogen; CN; COOR13; OR13; C(O)N(R13R133); S(O)2N(R13R133); S(O)N(R13R133); S(O)2R13;
N(R13)S(O)2N(R13aR13b); SR13; N(R13R13a); OC(O)R13; N(R13)C(O)R13a;
N(R13)S(O)2R133;N(R13)S(O)R13a; N(R13)C(O)N(R13aR13b); N(R13)C(O)OR133;
OC(O)N(R13R133); oxo (=0), where the ring is at least partially saturated; C(O)R13;
C1-6 alkyl; phenyl; C3-7 cycloalkyl; or heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H; C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different; Z1 Is =O Or =S;
Optionally Z1 is =N-R15 and R15, R3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R1 ;
Z2 is O; S; or N-R14;
R3, R14 are independently selected from the group consisting of H; T2; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R17, provided that when one of R3 and R14 is H and the other is ethyl, R17 is other than -COOH;
Optionally R , R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R18, provided that the heterobicycle is other than unsubstituted or in 3,6 and/or 7 position substituted 1,2,3,4- tetrahydroquinoline and its 4-oxa, -thia, -aza and/or 8-aza derivatives;
T2 is C3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T2 is optionally substituted with one or more R19; provided that when A is phenyl; Y is -S(O)2NH-, wherein the sulfur is attached to A; R1, R2 are H; X1, X3, X4 are CH; X2 is C-R4, wherein R4 is OCH3; Z1 is =O; and Z2 is NH, T2 is other than unsubstituted phenyl;
R16, R18, R19 are independently selected from the group consisting of halogen; CN;
COOR20; OR20; C(O)N(R20R20a); S(O)2N(R20R203); S(O)N(R20R20a); S(O)2R20;
N(R20)S(O)2N(R20aR20b); SR20; N(R20R20a); OC(O)R20; N(R20)C(O)R20a;
N(R20)S(O)2R20a; N(R20)S(O)R20a; N(R20)C(O)N(R20aR20b); N(R20)C(O)OR20a;
OC(O)N(R20R20a); oxo (=0), where the ring is at least partially saturated; C(O)R20; C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R21; R20, R2Oa, R2Ob are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R , R are independently selected from the group consisting of halogen; CN; COOR22; OR22; C(O)R22; C(O)N(R22R22a); S(O)2N(R22R223); S(O)N(R22R22a); S(O)2R22; N(R22)S(O)2N(R22aR22b); SR22; N(R22R22a); OC(O)R22; N(R22)C(O)R22a; N(R22)SO2R22a; N(R22)S(O)R22a; N(R22)C(O)N(R22aR22b); N(R22)C(O)OR22a; OC(O)N(R22R223); C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1- 6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R23;
R , R , R are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more R23a;
R23, R23a are independently selected from the group consisting of halogen; CN; COOR24; OR24; C(O)R24; C(O)N(R24R24a); S(O)2N(R24R243); S(O)N(R24R243); S(O)2R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R243); OC(O)R24; N(R24)C(O)R24a;
N(R24)SO2R24a; N(R24)S(O)R24a; N(R24)C(O)N(R24aR24b); N(R24)C(O)OR24a; OC(O)N(R24R243); and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different,
for use as a medicament.
24. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as defined in claim 23 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
25. Use of a compound of formula (I)
Figure imgf000095_0001
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X1, X2, X3, X4 are independently selected from the group consisting of N; and CR4, wherein R4 is independently H; halogen; CN; C(O)OR4a; C(O)N(R4aR4b); OR4a; N(R4aR4b); phenyl; C1-6 alkyl; or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R a, R are independently selected from the group consisting of H; C1-6 alkyl; and C3-7 cycloalkyl;
R1, R2 are independently selected from the group consisting of H; C1-6 alkyl; C3-7 cycloalkyl; and halogen, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with halogen;
Optionally R1, R2 are combined to form oxo (=O);
Y is -N(Rla)S(O)2-; -S(O)2N(Rlb)-; or -N(Rla)S(O)2N(Rlb)-;
A is T; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R5, wherein R5 is independently halogen; CN; COOR6; OR6; C(O)N(R6R6a); S(O)2N(R6R62); S(O)N(R6R6a); S(O)2R6; N(R6)S(O)2N(R6aR6b); SR6; N(R6R6a); OC(O)R6; N(R6)C(O)R6a; N(R6)S(O)2R6a; N(R6)S(O)R6a; N(R6)C(O)N(R6aR6b); N(R6)C(CO)OR6a; OC(O)N(R6R6a); or T;
Rla, Rlb are independently selected from the group consisting of H; allyl; benzyl;
CH2-C(O)NH2; CH2-COOH; CH2-C(O)O-C1-6 alkyl; Ci-6 alkyl; and C3-7 cycloalkyl, wherein Ci-6 alkyl and C3-7 cycloalkyl are optionally substituted with one or more Rlc, wherein Rlc is independently halogen; C1-6 alkyl; -CH=CH2; phenyl; C(O)NH2; COOH; C(O)O-Ci-6 alkyl or C3-7 cycloalkyl;
Optionally A and Rla form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R7, which are the same or different;
R , R a R are independently selected from the group consisting of H; C1-6 alkyl; and T, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R7, which are the same or different;
R7 is independently halogen; CN; COOR8; OR8; C(O)N(R8R8a); S(O)2N(R8R83); S(O)N(R8R83); S(O)2R8; N(R8)S(O)2N(R8aR8b); SR8; N(R8R8a); OC(O)R8; N(R8)C(O)R8a; N(R8)S(O)2R8a; N(R8)S(O)R8a; N(R8)C(O)N(R8aR8b);
N(R8)C(O)OR8a; OC(O)N(R8R8a); oxo (=O), where the ring is at least partially saturated; C(O)R ; T ; or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R9;
R8, R8a, R8b are independently selected from the group consisting of H; T1; and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R10; R9, R10 are independently selected from the group consisting of halogen; CN; COOR11; OR11; C(O)R11; C(O)N(R11R113); S(O)2N(R11R1 la); S(O)N(R11R113); S(O)2R11; N(Rn)S(0)2N(RllaRl lb); SR11; N(RπRl la); OC(O)R11; N(R1^C(O)R1 la; N(R1 ^SO2R113; N(Rπ)S(O)Rlla; N(Rn)C(0)N(RllaRllb); N(R1 ^C(O)OR113; OC(O)N(R11R113); and T1;
R11, Rl la, Rllb are independently selected from the group consisting of H; C1-6 alkyl; and T1;
T1 is C3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T1 is optionally substituted with one or more R12, wherein R12 is independently halogen; CN; COOR13; OR13;
C(O)N(R13R133); S(O)2N(R13R133); S(O)N(R13R133); S(O)2R13;
N(R13)S(O)2N(R13aR13b); SR13; N(R13R133); OC(O)R13; N(R13)C(O)R13a; N(R13)S(O)2R13a;N(R13)S(O)R13a; N(R13)C(O)N(R13aR13b); N(R13)C(O)OR13a;
OC(O)N(R13R133); oxo (=O), where the ring is at least partially saturated; C(O)R13;
C1-6 alkyl; phenyl; C3-7 cycloalkyl; or heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H; C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl, wherein C1-6 alkyl; phenyl; C3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z1 Is =O Or =S;
Optionally Z1 is =N-R15 and R15, R3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R16;
Z2 is O; S; or N-R14; R3, R14 are independently selected from the group consisting of H; T2; C1-6alkyl, wherein C1-6 alkyl is optionally substituted with one or more R , provided that when one of R3 and R14 is H and the other is ethyl, R17 is other than -COOH;
Optionally R3, R14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R ;
T2 is C3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T2 is optionally substituted with one or more R19; provided that when A is phenyl; Y is -S(O)2NH-, wherein the sulfur is attached to A; R1, R2 are H; X1, X3, X4 are CH; X2 is C-R4, wherein R4 is
OCH3; Z1 is =0; and Z2 is NH, T2 is other than unsubstituted phenyl;
R16, R18, R19 are independently selected from the group consisting of halogen; CN;
COOR20; OR20; C(O)N(R20R20a); S(O)2N(R20R203); S(O)N(R20R20a); S(O)2R20;
N(R20)S(O)2N(R20aR20b); SR20; N(R20R20a); OC(O)R20; N(R20)C(O)R20a;
N(R20)S(O)2R20a; N(R20)S(O)R20a; N(R20)C(O)N(R20aR20b); N(R20)C(O)OR20a; OC(O)N(R20R203); oxo (=0), where the ring is at least partially saturated; C(O)R20;
C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R21;
R20, R20a, R20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R17, R21 are independently selected from the group consisting of halogen; CN; COOR22; OR22; C(O)R22; C(O)N(R22R223); S(O)2N(R22R223); S(O)N(R22R22a);
S(O)2R22; N(R22)S(O)2N(R22aR22b); SR22; N(R22R22a); OC(O)R22; N(R22)C(O)R22a; N(R22)SO2R22a; N(R22)S(O)R22a; N(R22)C(O)N(R22aR22b); N(R22)C(O)OR22a; OC(O)N(R22R223); C1-6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl, wherein C1. 6 alkyl; phenyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more R23;
R , R , R are independently selected from the group consisting of H; phenyl; heterocyclyl; C3-7 cycloalkyl and C1-6 alkyl, wherein phenyl; heterocyclyl; C3-7 cycloalkyl; and C1-6 alkyl are optionally substituted with one or more R23a;
R23, R23a are independently selected from the group consisting of halogen; CN; COOR24; OR24; C(O)R24; C(O)N(R24R24a); S(O)2N(R24R243); S(O)N(R24R243);
S(O)2R24; N(R24)S(O)2N(R24aR24b); SR24; N(R24R243); OC(O)R24; N(R24)C(O)R24a;
N(R24)SO2R24a; N(R24)S(O)R24a; N(R24)C(O)N(R24aR24b); N(R24)C(O)OR24a;
OC(O)N(R24R243); and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R24, R24a, R24b are independently selected from the group consisting of H; C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different,
for the manufacture of a medicament for the treatment or prophylaxis of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART-associated lipodystrophy or other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 1 lβ-HSDl enzyme.
26. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as defined in claim 25 together with a pharmaceutically acceptable carrier, further comprising one or more additional compounds or pharmaceutically acceptable salts thereof selected from the group consisting of compounds as defined in claim 25 and not being the first compound; other 1 lβ-HSDl inhibitors; DPP-FV inhibitors; insulin sensitizers, e.g. PPAR agonists and biguanides; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; α- glucosidase inhibitors; glucagon receptor antagonists; GLP-I, GLP-I mimetics, and
GLP-I receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents, e.g. HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PP ARγ agonists, PPARα/γ dual agonists, inhibitors of cholesterol absorption, acyl CoA: cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR agonists; antiobesity compounds ; ileal bile acid transporter inhibitors; anti-inflammatory agents; and protein tyrosine phosphatase-lB (PTP-IB) inhibitors; anti-hypertensive compounds; and compounds for the treatment of cardiovascular diseases, particularly atherosclerosis.
27. A method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of the onset of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART-associated lipodystrophy and other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 11 β-HSD 1 enzyme, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound as defined in claim 25 or a pharmaceutically acceptable salt thereof.
28. A process for the preparation of a compound as defined in claim 25, comprising the steps of Reducing a compound of formula (II)
Figure imgf000101_0001
Coupling the resulting amine (III)
Figure imgf000101_0002
with A-Y-Cl, wherein A is T or C1-6 alkyl; or
with A-H and SO2Cl2, wherein A is T-N(R I1C0)N-.
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