Substituted piperidines and methods of use
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Abstract
Selected substituted piperidine compounds are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving activation of the melanocortin receptor. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Citations
24 Claims
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1. A compound of Formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 19, 20, 21, 22, 23, 24)
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2. Compound of claim 1 wherein Y is —
- NH—
or —
CH2—
;
wherein R is selected from a) —
(CH2)n—
C3-8-cycloalkyl,b) aryl c) unsubstituted benzyl, and d) —
(CH2)n-5-6-membered heterocyclyl;
wherein R is substituted at the 2-position of the cycloalkyl, heterocyclyl, benzyl and aryl groups with a radical selected from R4; and
wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 2 additional radicals selected from R4; and
the heterocyclyl group is optionally substituted with 1 to 2 additional radicals selected from R4 and oxo;
wherein R1a, R1b, R1c, R1d, R1e, and R1f are independently selected from R4;
or wherein R1a and R1b or R1d and R1c form oxo;
or wherein R1e and R1c form an C1-4-alkylenyl or C2-4-alkenylenyl bridge;
or wherein R1a, R1b, R1c, and R1d together with the piperazine ring forms an optionally substituted 1,2,3,4-tetrahydro-quinoxalinyl ring;
wherein R2 is selected from a) —
(CH2)n—
C3-8-cycloalkyl,b) —
(CH2)n-aryl,c) —
(CH2)n-4-10-membered heterocyclyl,wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4; and
the heterocyclyl groups are optionally substituted with 1 to 3 groups selected from R4 and oxo;
wherein R3 is independently selected from H, halo, amino, C1-6-haloalkyl, C1-6-alkyl, phenyl, C1-6-haloalkoxy and C1-6-alkoxy;
or wherein R3 is an C2-4-alkenylene bridge;
wherein R4 is selected from H, C1-6-alkyl, —
(CH2)n—
C3-6-cycloalkyl, —
(CH2)n-aryl, —
(CH2)n-4-10-membered heterocyclyl, halo, —
(CH2)n—
OR9, —
NR9SO2R7, —
N(R9)2, —
C(O)NR9R9, —
NR9C(O)R7, —
NR9CO2R7, nitro, cyano, —
(CH2)n—
C(O)R7, —
C(O)OR9, —
(CH2)n—
C(S)R7, —
(CH2)n—
C═
(NR9)R7, —
NR9C═
(NR7)N(R7)2, —
[C(R7)2]pNR9SO2R7, —
[C(R7)2]pNR9C(O)R7, —
[C(R7)2]pN(R9)2, —
SO2N(R9)2, —
S(O)mR7, —
C(R7)2SO2CF3, C1-6-hydroxyalkyl, C1-6-haloalkyl and C1-6-haloalkoxy;
wherein R5 is selected from halo, —
OR9, —
NHSO2R7, —
N(R9)2, cyano, —
COR7, —
]C(R7)2]nN(R9)2, nitro, —
SO2N(R9)2, —
S(O)mR7, C1-6-haloalkyl and C1-6-haloalkoxy;
wherein R6 is selected from phenyl, naphthyl and 6-membered heteroaryl, wherein R6 is optionally substituted with one or more R3;
wherein R7 is selected from H, C1-6-alkyl, —
(CH2)n—
C3-6-cycloalkyl, —
(CH2)n-4-10-membered heterocyclyl, —
(CH2)n-phenyl, amino-C1-6-alkyl, C1-6-alkylamino, C2-6-alkenyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkylcarbonylamino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl and C1-6-alkoxy;
wherein R8 is selected from a) 4-10-membered heterocyclyl, b) amino-C1-6-alkyl, c) amino-C1-6-alkylamino, d) C1-6-alkylamino-C1-6-alkylamino, e) C1-6-alkylamino-C1-6-alkyl, f) arylamino-C1-6-alkyl, g) aryl-C1-6-alkylamino-C1-6-alkyl, h) 4-10-membered heterocyclyl-C1-6-alkylamino-C1-6-alkyl, i) aryl, j) C1-6-alkyl, k) optionally substituted aryl-C1-6-alkyl, l) heterocyclyl-C1-6-alkyl, m) C3-6-cycloalkyl-(CH2)n—
,n) —
OR9o) amino-C1-6-alkoxy, p) N-(4-10-membered heterocyclyl-C1-6-alkyl)amino, q) aryl-C1-6-alkyl where the alkyl portion is substituted with amino, hydroxy or C1-6-alkylamino, and r) 4-10-membered heterocyclyl-C1-6-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C1-6-alkylamino;
wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4;
the heterocyclyl groups are optionally substituted with 1 to 3 groups selected from R4 and oxo; and
the alkyl groups are optionally substituted with 1 to 3 groups selected from R5;
wherein R8a is selected from a) 5-10-membered heterocyclyl, b) aryl, and c) benzyl;
wherein the aryl and heterocyclyl groups are optionally substituted with 1 to 3 radicals selected from C1-6-alkyl, halo, hydroxyl, alkoxy, amino, alkylamino, cyano, —
NHC(O)R7, —
COR7, C1-6-haloalkyl and C1-6-haloalkoxy;
wherein R9 is selected from H, C1-6-alkyl, alkenyl, C3-6-cycloalkyl-(CH2)n—
, 4-10-membered heterocyclyl-(CH2)n—
, aryl-(CH2)n—
, amino-C1-6-alkyl, C1-6-alkylcarbonylamino-C1-6-alkyl, C3-6-cycloalkylamino-C1-6-alkyl, C3-6-cycloalkyl-C1-6-alkylamino-C1-6-alkyl, 5-6-membered heteroarylamino-C1-6-alkyl, 5-6-membered heteroaryl-C1-6-alkylamino-C1-6-alkyl, arylamino-C1-6-alkyl, aryl-C1-6-alkylamino-C1-6-alkyl, 5-6-membered heteroaryloxy-C1-6-alkyl, 5-6-membered heteroaryl-C1-6-alkyloxy-C1-6-alkyl, aryl-C1-6-alkyloxy-C1-6-alkyl, aryloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, C1-6-hydroxyalkyl and C1-6-alkoxy-C1-6-alkyl;
wherein Ra are independently selected from H and C1-6-alkyl;
wherein k is 1;
wherein m is 0, 1 or 2;
wherein n is 0, 1, 2 or 3; and
wherein p is 1 or 2;
and a pharmaceutically-acceptable salt thereof.
- NH—
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3. Compound of claim 2 wherein Y is —
- NH—
;
wherein R is phenyl ortho substituted with a radical selected from R4 and optionally substituted with a radical selected from R4;
wherein R1a, R1b, R1c, R1d, R1e, and R1f are independently selected from R4;
or wherein R1a and R1b or R1d and R1c form oxo;
wherein R2 is selected from a) —
(CH2)n—
C3-6-cycloalkyl,b) —
(CH2)n-phenyl,c) —
(CH2)n-5-10-membered heterocyclyl, andwherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 radicals selected from R4; and
the heterocyclyl groups are optionally substituted with 1 to 3 radicals selected from R4 and oxo;
wherein R3 is independently selected from H, chloro, bromo, iodo, phenyl, fluoro, amino, C1-2-alkyl, C1-2-haloalkyl, C1-2-haloalkoxy, and C1-2-alkoxy;
wherein R4 is selected from H, C1-2-alkyl, —
(CH2)n—
C5-6-cycloalkyl, —
(CH2)n-phenyl, —
(CH2)n-4-10-membered heterocyclyl, fluoro, chloro, —
(CH2)n—
OR9a, NR9aSO2R7, —
NR9aR9b, —
C(O)NR9aR9b, —
NR9aC(O)R7, cyano, nitro, —
(CH2)n—
C(O)R7, C(O)OR9a, —
(CH2)n—
C(S)R7, —
(CH2)n—
C═
(NR9a)R7, —
NR9aC═
(NR9a)N(R7)2, —
[C(R7)2]pNR9aR9b, —
[CH2]pNR9aSO2R7, —
[CH2]pNR9aC(O)R7, —
SO2NR9aR9b, —
S(O)mR7, —
C(R7)2SO2CF3, C1-2-hydroxyalkyl C1-2-haloalkyl and C1-2-haloalkoxy;
wherein R5 is selected from halo, —
OR9a, —
NR9aR9b, —
[C(R7)2]nNR9aR9b, and —
SO2NR9aR9b;
wherein R6 is naphthyl or phenyl optionally substituted with one or two R3;
wherein R7 is selected from H, C1-4-alkyl, —
(CH2)n—
C3-6-cycloalkyl, —
(CH2)n-4-10-membered heterocyclyl, —
(CH2)n-phenyl, amino-C1-4-alkyl, C1-4-alkylamino, C2-4-alkenyl, C1-4-alkylthio-C1-4-alkyl, C1-4-alkylcarbonylamino-C1-4-alkyl, C1-4-alkylamino-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl and C1-4-alkoxy;
wherein R8 is selected from a) amino-C1-4-alkylamino, b) amino-C1-4-alkyl, c) C1-4-alkylamino-C1-4-alkylamino, d) C1-4-alkylamino-C1-4-alkyl, e) phenyl-C1-4-alkylamino-C1-4-alkyl, f) phenylamino-C1-4-alkyl, g) 4-10-membered heterocyclyl-C1-4-alkylamino-C1-4-alkyl, h) N-(4-10-membered heterocyclyl-C1-4-alkyl)amino, i) C1-4-alkyl, j) C3-6-cycloalkyl-(CH2)n—
,k) aryl-(CH2)n—
,l) 4-10-membered heterocyclyl-(CH2)n—
,m) R9aO—
,n) amino-C1-4-alkoxy, o) phenyl-C1-4-alkyl where the alkyl portion is substituted with amino, hydroxy or C1-4-alkylamino, and p) 4-10-membered heterocyclyl-C1-4-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C1-4-alkylamino;
wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4; and
the heterocyclyl groups are optionally substituted with 1 to 3 groups selected from R4 and oxo;
wherein R9a is selected from H, C1-6-alkyl, C3-6-cycloalkyl-(CH2)n—
, 4-10-membered heterocyclyl-(CH2)n—
, and phenyl-(CH2)n—
;
wherein R9b is selected from H, C1-6-alkyl, C2-6-alkenyl, C3-6-cycloalkyl-(CH2)n—
, 4-10-membered heterocyclyl-(CH2)n—
, phenyl-(CH2)n—
, amino-C1-6-alkyl, C1-6-alkylcarbonylamino-C1-6-alkyl, C3-6-cycloalkylamino-C1-6-alkyl, C3-6-cycloalkyl-C1-6-alkylamino-C1-6-alkyl, 5-6-membered heteroarylamino-C1-6-alkyl, 5-6-membered heteroaryl-C1-6-alkylamino-C1-6-alkyl, phenylamino-C1-6-alkyl, phenyl-C1-6-alkylamino-C1-6-alkyl, 5-6-membered heteroaryloxy-C1-6-alkyl, 5-6-membered heteroaryl-C1-6-alkyloxy-C1-6-alkyl, phenyl-C1-6-alkyloxy-C1-6-alkyl, phenyloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, C1-6-hydroxyalkyl and C1-6-alkoxy-C1-6-alkyl;
wherein Ra are independently H or methyl;
wherein k is 1;
wherein m is 0, 1 or 2;
wherein n is 0, 1, 2 or 3;
wherein p is 1 or 2; and
wherein q is 1;
and a pharmaceutically-acceptable salt thereof.
- NH—
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4. Compound of claim 3 wherein R is
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5. Compound of claim 4 wherein R is
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6. Compound of claim 3 wherein R is
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7. Compound of claim 6 wherein R8 is
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8. Compound of claim 7 wherein R8 is
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9. Compound of claim 1 and pharmaceutically acceptable salts thereof selected from
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-{(1R)-2-[4-(2-methoxyphenyl)-piperidyl]-2-oxo-1-benzylethyl}carboxamide; -
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S)-1-methylpyrrolidin-2-yl)carboxamide N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S,1R)-3-aminocyclopentyl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((1S,3R)-3-aminocyclopentyl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl](5-oxopyrrolidin-2-yl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]azetidin-3-ylcarboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]-2-(4-piperidyl)acetamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S,3R)-3-phenylpyrrolidin-2-yl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S)pyrrolidin-2-yl)carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-1-[(4-cChlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]azetidin-3-ylcarboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)phenyl]-piperidyl)ethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(hydroxyethyl)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-2-(4-{2-[(2-aminoethyl)(methylsulfonyl)amino]-phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(3-methyl-2-oxo(4-imidazolinyl))phenyl]piperidyl}-2-oxoethyl)carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]piperidyl}ethyl)carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl}ethyl)azetidin-3-ylcarboxamide;
tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-{[(2-cyanophenyl)sulfonyl]amino}-phenyl)piperidyl]-2-oxoethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl)piperidyl]ethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(methoxycarbonylamino)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)amino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide; and
N-[(1R)-2-(4-{2-[(2-aminoethyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide.
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19. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound as in claim 1.
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20. A method of treating obesity in a subject, said method comprising administering an effective amount of a compound of claim 1.
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21. A method of treating diabetes mellitus in a subject, said method comprising administering an effective amount of a compound of claim 1.
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22. A method of treating disorders related to activation of a G-protein coupled receptor, in a mammal, said method comprising administering an effective amount of a compound of claim 1.
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23. The method of claim 22 wherein the receptor is a melanocortin receptor.
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24. The method of claim 23 wherein the melanocortin receptor is MC4R.
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2. Compound of claim 1 wherein Y is —
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10. A compound of formula II
- View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
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11. Compound of claim 10 wherein R10 is H;
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wherein R13a is selected from H, bromo, chloro, phenyl, trifluoromethyl and methoxy;
wherein R13b is H;
wherein R15 is selected from H and C1-2-haloalkyl wherein R16 is selected from a) 4-6 membered saturated heterocyclyl, b) 10 membered partially unsaturated heterocyclyl, c) 5-10 membered heteroaryl, d) C1-3-aminoalkyl, e) C1-3-aminoalkylamino, f) C1-3-alkylamino-C1-3-alkylamino, g) C1-3-alkylamino-C1-3-alkyl, h) phenylamino-C1-3-alkyl, i) phenyl-C1-4-alkylamino-C1-3-alkyl, j) heterocyclyl-C1-3-alkylamino-C1-3-alkyl, k) phenyl, naphthyl or tetrahydronaphthyl, provided R16 is not 2-methoxyphenyl, 2-phenoxyphenyl or 2-phenylaminophenyl, l) C1-3-alkyl, m) phenyl-C1-2-alkyl, n) 5-10-membered saturated or partially unsaturated heterocyclylmethyl, o) 5-6 membered heteroaryl-C1-4-alkyl, p) optionally substituted C5-6-cycloalkyl, q) C1-3-aminoalkoxy, r) [5- or 6-membered heterocyclyl]-C1-3-alkoxy, s) N-(5-10-membered heterocyclyl-C1-3-alkyl)amino, t) phenyl-C1-2-alkyl where the alkyl portion is substituted with amino, hydroxy or C1-3-alkylamino, and u) 5- or 6-membered heterocyclyl-C1-3-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C1-3-alkylamino;
wherein R17 is selected from H, C1-3-alkyl, —
(CH2)n—
C3-6-cycloalkyl, and —
(CH2)n-phenyl;
wherein R19 is selected from H, R23SO2—
, C1-6-alkyl, amino-C1-3-alkyl, C1-6-alkylamino-C1-3-alkyl, C3-5-cycloalkylamino-C1-3-alkyl, C3-5-cycloalkyl-C1-3-alkylamino-C1-3-alkyl, C1-3-alkylthio-C1-3-alkyl, C1-3-alkoxy-C1-3-alkyl, heteroarylamino-C1-3-alkyl, 5-6 membered heteroaryl-C1-3-alkylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, phenyl-C1-3-alkylamino-C1-3-alkyl, 5-6 membered heteroaryloxy-C1-3-alkyl, phenyloxy-C1-3-alkyl, hydroxy-C1-3-alkyl, phenyl-C1-3-alkoxy-C1-3-alkyl, C1-6-alkylcarbonyl, C1-3-alkoxycarbonyl, C1-3-alkoxy-C1-3-alkylcarbonyl, C1-3-alkylaminocarbonyl, C3-6-cycloalkylcarbonyl, C3-6-cycloalkyl-C1-3-alkylcarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, 5- or 6-membered heteroaryl-C1-3-alkylcarbonyl, 5- or 6-membered heteroarylcarbonyl and —
(CH2)n—
C3-5-cycloalkyl optionally substituted with C1-2-alkoxycarbonyl;
wherein R20 is selected from H, C1-7-alkyl, —
(CH2)n—
C5-6-cycloalkyl, —
(CH2)n-5-6-membered heterocyclyl, C1-3-alkylsulfonyl, amino-C1-3-alkyl and —
(CH2)n-phenyl;
alternatively R19 and R20 together with the nitrogen atom form a 4-7 membered heterocyclic ring;
wherein R21 is selected from H, C1-3-alkyl, C2-3-alkenyl, C1-3-alkylthio-C1-3-alkyl, C1-3-alkylcarbonylamino-C1-3-alkyl, amino-C1-3-alkyl, —
(CH2)n-[5- or 6-membered heterocyclyl], —
(CH2)n—
C5-6-cycloalkyl, and —
(CH2)n-phenyl;
wherein R22 is selected from H, C1-3-alkyl, —
(CH2)n—
C4-6-cycloalkyl, —
(CH2)n-[5- or 6-membered heterocyclyl] and —
(CH2)n-phenyl;
alternatively R21 and R22 together with the amide nitrogen atom form a 5-6 membered heterocyclic ring; and
wherein R23 is selected from H, C1-3-alkyl, —
(CH2)n—
C4-6-cycloalkyl, —
(CH2)n-[5- or 6-membered heterocyclyl] and —
(CH2)n-phenyl;
wherein phenyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from C1-2-haloalkyl, C1-2-alkyl, —
(CH2)n—
C4-6-cycloalkyl, chloro, fluoro, —
OR17, —
NR17SO2R17, N(R17)2, cyano, —
COR17, —
C(R17)2N(R17)2, nitro, —
SO2N(R17)2, —
S(O)mR17, and C1-2-haloalkoxy;
and pharmaceutically-acceptable salts thereof.
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12. Compound of claim 11 wherein R13a is selected from H, bromo, phenyl and chloro;
-
wherein R14 is selected from trifluoromethyl, 2-hydroxyethyl, 1-hydroxyethyl, R19R20N—
, R19R20N—
C1-2-alkyl and (R21R22N—
)(O═
)C—
;
wherein R15 is H or trifluoromethyl;
wherein R17 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenylpropyl, phenylethyl, benzyl and phenyl;
wherein R19 is selected from H, R23SO2—
, methyl, ethyl, propyl, isopropyl, isopentyl, 3-ethylbutyl, hydroxymethyl, hydroxyethyl, cyclopropylmethyl, 1-(ethoxycarbonyl)cycloprop-2-ylmethyl, R23SO2—
, aminomethyl, aminoethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, diisobutylaminoethyl, di-(tert-butylmethyl)aminoethyl, di-(3-ethylbutyl)aminoethyl, di(cyclohexylmethyl)aminoethyl, furylmethylaminoethyl, thienylmethylaminoethyl, benzylaminoethyl, di(furylmethyl)aminoethyl, di(cyclopropylmethyl)aminoethyl, di(thienylmethyl)aminoethyl, di(benzyl)aminoethyl, phenylmethoxyethyl, pyridyloxymethyl, methylthiopropyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, cyclopentylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclohexylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, ethoxycarbonyl, propoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, optionally substituted thienylmethylcarbonyl, optionally substituted benzylcarbonyl, optionally substituted phenylethylcarbonyl, optionally substituted phenylcarbonyl and optionally substituted pyridylcarbonyl;
wherein R20 is selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclohexyl, methylsulfonyl, aminoethyl, optionally substituted phenyl, optionally substituted imidazolyl, optionally substituted imidazolylmethyl, optionally substituted thienylmethyl, optionally substituted furylmethyl, optionally substituted pyrrolidinylmethyl, optionally substituted pyridylmethyl, optionally substituted thienylmethyl, optionally substituted benzyl, optionally substituted phenylethyl and optionally substituted phenylpropyl;
alternatively R19 and R20 together with the nitrogen atom form a heterocyclic ring selected from triazolyl, tetrazolyl, 2-pyridone, oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4,5-dihydro-2-oxo-oxazolyl, 1,1-dioxo-isothiazolidin-2-yl, 2-oxo-imidazolin-1-yl, 3-methyl-2-oxo-imidazolin-1-yl, piperidinyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl, piperazinyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl, imidazolyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl, and pyrrolidinyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl;
wherein R21 is selected from H, methyl, ethyl, propyl, isopropyl, allyl, methylthioethyl, methylthiomethyl, methylcarbonylaminoethyl, methylcarbonylaminomethyl, aminomethyl, aminoethyl, 1-methylpyrrolidinylethyl, piperidinylethyl, pyridyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, 4-chlorophenylmethyl, 4-phenoxyphenylethyl, benzyl and phenylethyl;
wherein R22 is H or methyl;
alternatively R21 and R22 together form a ring selected from pyrrolidinyl, morpholino, piperidinyl, piperazinyl, 4-acetylpiperazinyl and 4-methylpiperazinyl; and
wherein R23 is selected from H, methyl, ethyl, propyl, optionally substituted thienyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenylethyl and optionally substituted phenylpropyl;
wherein phenyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from trifluoromethyl, methyl, nitro, cyano, chloro, methoxy, phenyloxy, acetyl, amino, dimethylamino and aminomethyl;
and pharmaceutically-acceptable salts thereof.
-
-
13. Compound of claim 12 wherein R14 is selected from N-pyrrolidinylcarbonyl, N-morpholinocarbonyl, N-piperidinylethylaminocarbonyl, benzylaminocarbonyl, N-methyl-N-benzylaminocarbonyl, aminoethylaminocarbonyl, pyridylaminocarbonyl, methylthioethylaminocarbonyl, methylcarbonylaminoethylaminocarbonyl, 1-methylpyrrolidinylethylaminocarbonyl, phenethylaminocarbonyl, phenylaminocarbonyl, cyclohexylmethylaminocarbonyl, N-methyl-N-phenethylaminocarbonyl, N,N-dimethylaminocarbonyl, 4-chlorophenylmethylaminocarbonyl, phenoxyphenethylaminocarbonyl, allylaminocarbonyl, 4-methylpiperazinylcarbonyl, 4-acetylpiperazinylcarbonyl, isopropylaminocarbonyl,
1-(N-cyclopropylmethylamino)ethyl, 1-(N-methyl-N-methylcarbonylamino)ethyl, 1-(N-isopropylamino)ethyl, 1-(N-isobutyl-N-methylamino)ethyl, N-cyclopropylmethyl-N-propylaminomethyl, N,N-dicyclopropylmethylaminomethyl, 1-(N-propyl-N-methylamino)ethyl, 1-(N-methyl-N-methylsulfonylamino)ethyl, triazolylmethyl, imidazol-1-ylmethyl, 2-isopropylimidazol-1-yl-methyl, 2-propylimidazol-1-yl-methyl, 2-oxo-pyrid-1-yl-methyl, 3-pyridyl-oxymethyl, 2-methylimidazol-1-yl-methyl, tetrazolylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, 2-oxo-pyrrolidin-1-yl-methyl, 2-oxo-piperidin-1-yl-methyl, 4,5-dihydro-2-oxo-oxazol-3-yl-methyl, pyrrolidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, piperazin-1-yl-methyl, 4-methylpiperazin-1-yl-methyl, piperidin-1-yl-methyl, 1-(N-ethyl-N-methylamino)ethyl, 1-(N,N-dipropylamino)ethyl, 1-(N,N-diisopropylamino)ethyl, 1-(N-(1-ethoxycarbonyl)cycloprop-2-ylmethyl-N-methylamino)ethyl, 1-(N-(2-methylbutyl)-N-methylamino)ethyl, 1-(N-(4-methylcarbonylaminophenyl)methyl-N-methylamino)ethyl, 1-(N-methylamino)ethyl, 1-(N,N-dimethylamino)ethyl, N,N-dimethylaminomethyl, N-cyclopropylmethyl-N-methylsulfonylaminomethyl, 1-(N-(3-thienyl)methyl-N-methylamino)ethyl, 1-(N-phenylmethoxyethyl-N-methylamino)ethyl, 1-(N-(2-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-(4-pyridyl)methyl-N-methylamino)ethyl, 1-(N-(2-pyrrolidinyl)methyl-N-methylamino)ethyl, 1-(N-(3-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-(4-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-benzyl-N-methylamino)ethyl, 1-(N-methyl-N-aminoethylamino)ethyl, 1-(N-cyclohexylmethyl-N-methylamino)ethyl, N,N-dimethylaminomethyl, N-(1-hydroxyethyl)-N-methylaminomethyl, N-(1-hydroxyethyl)-N-methylaminomethyl, N-propyl-N-methylsulfonylamino, N-(methylsulfonyl)-N-propylamino, N-(methylsulfonyl)-N-cyclopropylmethylamino, N-(methylsulfonyl)-N-aminoethylamino, N-(methylsulfonyl)-N-(N′ - ,N′
-dimethylaminoethyl)amino, N-(N′
,N′
-diethylaminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-dipropylaminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-diisobutylaminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di-tert-butylmethylaminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(3-ethylbutyl)aminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(cyclopropylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(cyclohexylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(2-furylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(3-thienylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′
,N′
-di(benzyl)aminoethyl)-N-methylsulfonylamino, N-(methylsulfonyl)-N-isobutylamino, N-(methylsulfonyl)-N-methylamino, N-(methylsulfonyl)-N-phenethylamino, N-(methylsulfonyl)amino, N-(benzylsulfonyl)amino, N-(propylsulfonyl)amino, N-(phenylsulfonyl)amino, N-(methylsulfonyl)-N-phenylpropylamino, thienylsulfonylamino, (2-nitrophenyl)methylsulfonylamino, (2,4,6-trimethylphenyl)sulfonylamino, (2-cyanophenyl)sulfonylamino,N-methoxymethylcarbonyl-N-cyclopropylmethylamino, N-methylcarbonyl-N-cyclopropylmethylamino, N-phenylcarbonyl-N-cyclopropylmethylamino, N-(3-methoxyphenylcarbonyl-N-cyclopropylmethylamino, N-benzylcarbonyl-N-cyclopropylmethylamino, N-cyclohexylcarbonyl-N-cyclopropylmethylamino, N-thienylmethylcarbonyl-N-cyclopropylmethylamino, N-phenylethyl-N-cyclopropylmethylamino, N-(2-imidazolyl)-N-cyclopropylmethylamino, N-(4-methyl-5-imidazolyl)-N-cyclopropylmethylamino, N-(4-methyl-5-imidazolylmethyl)-N-cyclopropylmethylamino, N-(4-imidazolylmethyl)-N-cyclopropylmethylamino, N-(5-imidazolylmethyl)-N-cyclopropylmethylamino, N-(2-thienylmethyl)-N-cyclopropylmethylamino, N-(3-thienylmethyl)-N-cyclopropylmethylamino, N-(3-furylmethyl)-N-cyclopropylmethylamino, N-(4-imidazolyl)-N-cyclopropylmethylamino, N-cyclopentylcarbonyl-N-cyclopropylmethylamino, N-cyclohexylcarbonyl-N-cyclopropylmethylamino, N-methylthiopropyl-N-cyclopropylmethylamino, N-ethylcarbonyl-N-cyclopropylmethylamino, N-isopropylcarbonyl-N-cyclopropylmethylamino, N-isobutylcarbonyl-N-cyclopropylmethylamino, N-ethyl-N-cyclopropylmethylamino, N-isobutyl-N-cyclopropylmethylamino, N-cyclopropylcarbonyl-N-cyclopropylmethylamino, N,N-di(cyclopropylmethyl)amino, N-methoxymethylcarbonyl-N-aminoethylamino, N-ethylcarbonyl-N-aminoethylamino, N-isopropylcarbonyl-N-aminoethylamino, N-isobutylcarbonyl-N-aminoethylamino, N-tert-butylcarbonyl-N-aminoethylamino, N-propylcarbonyl-N-aminoethylamino, N-pentylcarbonyl-N-aminoethylamino, N-ethyl-N-aminoethylamino, N-propyl-N-aminoethylamino, N-cyclopropyl-N-aminoethylamino,N-cyclopropylmethyl-N-aminoethylamino, N-cyclobutylmethyl-N-aminoethylamino, N-butyl-N-aminoethylamino, N-pentyl-N-aminoethylamino, N-hexyl-N-aminoethylamino, N-heptyl-N-aminoethylamino, N-(3-ethylbutyl)-N-aminoethylamino, N-cyclohexylcarbonyl-N-aminoethylamino, N-phenylcarbonyl-N-aminoethylamino, N-(3-methoxyphenyl)carbonyl-N-aminoethylamino, N-benzylcarbonyl-N-aminoethylamino, N-phenylethylcarbonyl-N-aminoethylamino, N-pyridylcarbonyl-N-aminoethylamino, N-thienylmethyl-N-aminoethylamino, aminoethylamino, pyridylcarbonylamino, N-cyclopropylmethylamino, methylcarbonylamino, methoxycarbonylamino, trifluoromethyl, 2-hydroxyethyl, 1-hydroxyethyl, methylaminocarbonylamino, 1,1-dioxo-isothiazolidin-2-yl, 2-oxo-imidazolin-1-yl and 3-methyl-2-oxo-imidazolin-1-yl;
and pharmaceutically-acceptable salts thereof.
- ,N′
-
14. Compound of claim 12 wherein R12 is selected from
-
15. Compound of claim 14 wherein R16 is selected from N-(piperidylmethyl)amino, aminopropylamino, aminomethyl, aminoethyl, aminopropyl, N-methylaminomethyl, N-(4-chlorophenyl)aminoethyl, N-methylaminoethyl, N,N-dimethylaminoethyl, 2-aminoethyl, aminopropoxy, pyrrolidinylmethoxy, N-methylaminoethylamino, 3-aminocyclopentyl, 4-aminocyclohexyl, 1-aminocyclohexyl, 2-indolyl, octahydro-indolyl, 1-methylindol-2-yl, 3-pyridyl, 2-pyridyl, N-methylbenzopyrrolyl, 5-benzopyrrolyl, 2-benzofuran, benzodioxolyl, 2-benzothienyl, 4-imidazolylmethyl, 3-azetidinyl optionally
N-substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclohexylmethyl and benzyl, 6-quinolyl, 2-quinolyl, 3-isoquinolyl, tetrahydroisoquinolyl, N-methylpyrrolidin-2-yl, pyrrolidin-2-yl, 5-oxopyrrolidin-2-yl, 3-phenylpyrrolidin-2-yl, (1-methyl-5-oxo-2-(pyridin-3-yl)-pyrrolidin-3-yl)methyl, thienyl, 4-piperidyl, 4-piperidylmethyl, N-methyl-4-piperidyl, N-methyl-2-piperidyl, N-ethyl-4-piperidyl, N-isobutyl-4-piperidyl, 3-piperidyl, 3-(aminomethyl)phenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-aminophenyl, 3-aminophenyl, isopropyl, 4-chlorophenylmethyl, benzyl, phenyl-2-hydroxyethyl, 1-(amino)benzyl, 2-(1,2,3,4-tetrahydronapthyl, naphthyl, (2-benzylamino)ethyl, imidazol-4-yl-(1-amino)ethyl, phenyl-1-(methylamino)ethyl and phenyl-1-(amino)ethyl; and pharmaceutically-acceptable salts thereof.
-
16. Compound of claim 15 and pharmaceutically acceptable salts thereof selected from
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S)-1-methylpyrrolidin-2-yl)carboxamide N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S,1R)-3-aminocyclopentyl)carboxamide; -
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((1S,3R)-3-aminocyclopentyl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl](5-oxopyrrolidin-2-yl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]azetidin-3-ylcarboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]-2-(4-piperidyl)acetamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S,3R)-3-phenylpyrrolidin-2-yl)carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S)pyrrolidin-2-yl)carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-}2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-1-[(4-cChlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]azetidin-3-ylcarboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)phenyl]-piperidyl}ethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(hydroxyethyl)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-2-(4-{2-[(2-aminoethyl)(methylsulfonyl)amino]-phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(3-methyl-2-oxo(4-imidazolinyl))phenyl]piperidyl}-2-oxoethyl)carboxamide;
((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]piperidyl}ethyl)carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl}ethyl)azetidin-3-ylcarboxamide;
tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;
N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-{[(2-cyanophenyl)sulfonyl]amino}-phenyl)piperidyl]-2-oxoethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl)piperidyl]ethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[((1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(methoxycarbonylamino)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;
N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)amino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide; and
N-[(1R)-2-(4-{2-[(2-aminoethyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide.
-
-
17. Compound of claim 12 wherein R12 is selected from optionally substituted benzyl, and optionally substituted 5-10-membered heteroaryl;
- and wherein R13a and R13b are independently H or chloro.
-
18. Compound of claim 17 wherein R12 is selected from oxazolo[5,4-b]pyridin-2-yl, oxazolo[4,5-b]pyridin-2-yl, 4-chlorobenzyl, benzoxazol-2-yl and benzyl.
-
11. Compound of claim 10 wherein R10 is H;
Specification
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Current AssigneeAmgen Inc.
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Original AssigneeAmgen Inc.
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InventorsNorman, Mark H., Xi, Ning, Xu, Shimin, Kelly, Michael G., Croghan, Michael, Fotsch, Christopher H., Doherty, Elizabeth M., Tamayo, Nuria, Smith, Duncan M.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/217.03
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CPC Class CodesA61K 38/00 Medicinal preparations cont...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 13/12 of the kidneysA61P 15/10 for impotenceA61P 17/00 Drugs for dermatological di...A61P 17/10 Anti-acne agentsA61P 19/02 for joint disorders, e.g. a...A61P 25/04 Centrally acting analgesics...A61P 25/18 Antipsychotics, i.e. neurol...A61P 25/20 Hypnotics; SedativesA61P 25/22 AnxiolyticsA61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 25/30 for treating abuse or depen...A61P 29/00 Non-central analgesic, anti...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/06 AntihyperlipidemicsA61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 : Antineoplastic agentsA61P 37/02 : ImmunomodulatorsA61P 43/00 : Drugs for specific purposes...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesC07D 211/28 : to which a second hetero at...C07D 211/34 : with hydrocarbon radicals, ...C07D 401/12 : linked by a chain containin...C07D 401/14 : containing three or more he...C07K 5/06139 : with the first amino acid b...C07K 5/06191 : containing heteroatoms diff...