Patent EA-005274-B1 (EA)
Title: Inhibitors of 11-beta-hydroxy steroid dehydrogenase type
Inventor: BARF TJEERD
IPC: C07D277/28
Filed: 2001-05-22
Abstract: 1. A compound of the formula (I): wherein T is phenyl, naphthyl, or heteroaryl ring, which means a monocyclic, bi-or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium, phenyl-C2-alkenyl ring or naphthyl-C2-alkenyl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, phenyl, naphthyl, heteroaryl, which means a monocyclic, bi-or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium, a heterocyclic ring, which means unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium; optionally halogenated C1-6-alkyl, optionally halogenated C1-6-alkoxy, C1-6-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted by a group consisting of C1-6-acyl, C1-6-alkenyl, C1-6-(cyclo)alkyl, phenyl, naphthyl, pyridylmethyl, or heterocyclic rings, e. g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with C1-6-alkyl; amide which is optionally mono- or di-substituted by a group consisting of C1-6-acyl, C1-6-alkenyl, C1-6-(cyclo)alkyl, phenyl, naphthyl, pyridylmethyl, or heterocyclic rings, e. g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with C1-6-alkyl; phenyloxy, naphthyloxy, phenylsulfonyl, naphthylsulfonyl, phenyl amino, naphthylamino, wherein phenyl, naphthyl, heteroaryl, phenyloxy and naphthyloxy residues and heterocyclic rings can further be optionally substituted in one or more positions independently of each other by C1-6-acyl, C1-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C1-6-alkyl, optionally halogenated C1-6-alkoxy, amide which is optionally mono- or di-substituted by a group consisting of C1-6-acyl, C1-6-alkenyl, C1-6-(cyclo)alkyl, phenyl, naphthyl, pyridylmethyl, or heterocyclic rings, e. g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with C1-6-alkyl; (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); with the proviso that when R<1> is H, X is CH2, Y is CO, R<2> is EtO and B is H, then T is not 2,4-dichloro-5-methylphenyl, 4-chlorophenyl, 4-chloro-2,5-dimethylphenyl, 2,4-difluorophenyl, 3-nitrophenyl and phenyl; R<1> is hydrogen or C1-6-alkyl; X is CH2 or CO; Y is CH2, CO or a single bond; B is hydrogen or C1-6-alkyl; R<2> is selected from C1-6-alkyl, azido, phenylthio, naphthylthio, heteroarylthio, where heteroarylis as defined above, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4-morpholinolinylmethylene, Ci-6-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR<3>R<4>, wherein R<3> and R<4> are each independently selected from hydrogen, C1-6-alkyl, optionally halogenated C1-6-alkylsulfonyl, C1-6-alkoxy, 2-methoxyethyl, 2hydroxyethyl, 1-methylimidazolylsulfonyl, C1-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, phenyl, naphthyl, optionally halogenated phenyl sulfonyl, optionally halogenated naphthylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbothoxypiperidyl, or C1-6-alkyl substituted with one or more phenyl, naphthyl or heteroaryl, where heteroaryl is as defined above, or NR<3>R<4> represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-dioxidothiomorpholine, 2-(3,4-dihydro-2(1H) isoquinolinyl), (1S,4S)-2-oxa-5-azabicyclo[2.2.1] hept-5-yl, which heterocyclic systems can be optionally substituted by C1-6-alkyl, C1-6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR<3>R<4>, wherein R<3> and R<4> are each independently selected from hydrogen, C1-6-alkyl or form together morpholinyl; R<5>O, wherein R<5> is hydrogen, optionally halogenated C1-6-alkyl, phenyl, naphthyl or heteroaryl, where heteroaryl is as defined above, C1-6-acyl, C1-6-alkylsulfonyl, phenylcarbonyl, naphthylcarbonyl, heteroarylcarbonyl, where heteroaryl is as defined above, 2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof. 2. A compound according to claim 1, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2-naphthyl; (E)-2-phenylethenyl; 8-quinolinyl; thienyl substituted with one or more of(benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloio-2-cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or with the proviso that when R<1> is H, X is CH2, Y is CO, R<2> is EtO and B is H, then T is not 2,4-dichloro-5-methylphenyl, 4-chlorophenyl, 4-chloro-2,5-dimethylphenyl, 2,4-difluorophenyl, 3-nitrophenyl and phenyl; R<1> is hydrogen or methyl; X is CH2 or CO; Y is CH2, CO or a single bond; B is hydrogen or methyl; R<2> is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinyl-methylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR<3>R<4>, wherein R<3> and R<4> are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR<3>R<4> represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidinyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl; OCONR<3>R<4>, wherein R<3> and R<4> are each independently selected from ethyl, hydrogen or form together morpholinyl; R<5>O, wherein R<5> is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl. 3. A compound of claim 1-2 selected from the group consisting of: Ethyl 2-(2-(((4-methylphenyl)sulfonyl)amino)-1,3-thiazol-4-yl)acetate, Ethyl 2-(2-{[(2,5-dichloro-3-thienyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2-chlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl 2-{2-[([1,1'-biphenyl]-4-ylsulfonyl)amino]-1,3-thiazol-4-yl}acetate, Ethyl 2-(2-{[(3-bromophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(4-nitrophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(4-memoxyphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(3-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(3-chlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(4-fluorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(3-fluorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(4-isopropylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl [2-({[3-({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}amino)-1,3-thiazol-4-yl]acetate, Ethyl [2-({[4-({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}amino)-1,3-thiazol-4-yl]acetate, Ethyl (2-{[(2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl [2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-4-yl]acetate, Ethyl [2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-4-yl]acetate, Ethyl [2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-4-yl] acetate, Ethyl 2-(2-{[(4-bromophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2-nitrophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2,4-dichlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl (2-{[(3,5-dichlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate, Ethyl [2-({[4-(3-chloro-2-cyanophenoxy)phenyl]su