US 2009/0221663 A1Published application

Pyrazole derivatives as 11-beta-hsd1 inhibitors

AssigneeAstraZeneca AB

InventorsMartin John Packer, James Stewart Scott, Andrew Stocker, Paul Robert Owen Whittamore

Life of this patent

Estimating the term…

Abstract

A compound of Formula (I): and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described.

Claims14

Dependent claims

A compound of the Formula (1) or a pharmaceutically-acceptable salt thereof:
wherein:
Q is O, S or a single bond;
R1 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, heterocyclyl, arylC1-3alkyl, heteroarylC1-3alkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl or C3-7cycloalkylC2-3alkynyl, [each of which is optionally substituted by 1, 2 or 3 substituents independently selected from C1-3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C1-3alkoxy, C1-3alkylS(O)n— (wherein n is 0, 1, 2 or 3), R5CON(R5′)—, (R5′)(R5″)NC(O)—, R5′OC(O)O—, R5′OC(O)—, (R5′)(R5″)NC(O)N(R5′″)—, R5SO2N(R5″)—, and (R5′)(R5″)NSO2— (wherein R5 is C1-3alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxyl, halo or cyano;
and
R5′ and R5″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-3alkoxy, carboxy and cyano or R5′ and R5″ together with the nitrogen atom to which they are attached form a 4-7 membered saturated ring)];
R2 is selected from heterocyclyl, C3-7cycloalkyl(CH2)m—, and C6-12polycycloalkyl(CH12)m— (wherein m is 0, 1 or 2 and the rings are optionally substituted by 1, 2 or 3 substituents independently selected from R6);
R3 is selected from hydrogen, C1-4alkyl C3-5cycloalkyl and C3-5cycloalkylmethyl (each of which is optionally substituted by 1, 2 or 3 fluoro atoms);
R2 and R3 together with the nitrogen atom to which they are attached form a saturated mono, bicyclic or bridged ring system optionally containing 1 or 2 additional ring heteroatoms selected from nitrogen, oxygen and sulphur and which is optionally fused to a saturated, partially saturated or unsaturated monocyclic ring wherein the resulting ring system is optionally substituted by 1, 2, or 3 substituents independently selected from R7;
R6 and R7 are independently selected from hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R9, R9O—, R9CO—, R9C(O)O—, R9CON(R9′)—, (R9′)(R9″)NC(O)—, (R9′)(R9″)N—, R9S(O)a— wherein a is 0 to 2, R9′OC(O)—, (R9′)(R9″)NSO2—, R9SO2N(R9″)—, (R9′)(R9″)NC(O)N(R9′″)—, phenyl and heteroaryl [wherein the phenyl and heteroaryl groups are optionally fused to a phenyl, heteroaryl or a saturated or partially-saturated 5- or 6-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur and the resulting ring system is optionally substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo, C1-4alkoxy, C1-4alkoxyC1-4alkyl, amino, N—C1-4alkylamino, di-N,N—(C1-4alkyl)amino, N—C1-4alkylcarbamoyl, di-N,N—(C1-4alkyl)carbamoyl, C1-4alkylS(O)r—, C1-4alkylS(O)rC1-4alkyl (wherein r is 0, 1 or 2)];
R9 is independently selected from C1-3alkyl optionally substituted by hydroxyl, halo, C1-4alkoxy, carboxy or cyano;
R9′, R9″ and R9′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2, or 3 substituents independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano);
A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring being optionally substituted on ring carbon atoms by 1, 2 or 3 R10 groups and on an available ring nitrogen in a heteroaryl group by R11);
R10 is independently selected from C1-4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo, C1-4alkoxy, C1-4alkoxyC1-4alkyl, amino, N—C1-4alkylamino, di-N,N—(C1-4alkyl)amino, N—C1-4alkylcarbamoyl, di-N,N—(C1-4alkyl)carbamoyl, C1-4alkylS(O)s—, C1-4alkylS(O)sC1-4alkyl (wherein s is 0, 1 or 2)];
R11 is independently C1-3alkyl optionally substituted by 1, 2 or 3 fluoro atoms;
X is a direct bond, C3-4cycloalkandiyl, C3-4cycloalkanylidene, —C(R12)(R13)—, C(R12)(R13)C(R14)(R15)—, —CH2O— or —CH2S(O)t— (wherein t is 0, 1 or 2):
Y is a direct bond, C3-4cycloalkandiyl, C3-4cycloalkanylidene, —C(R16)(R17)— or —C(R18)(R19)C(R20)(R21)—;
wherein R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from hydrogen and methyl.

15 more elements

A compound according to claim 1 selected from:
4-[4-[[(1S,3R)-5-hydroxy-2-adamantyl]carbamoyl]-5-propylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoic acid;
4-[4-(cyclohexylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;
4-[4-(1-adamantylcarbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;
4-[4-(cyclohexyl-methyl-carbamoyl)-5-cyclopropyl-pyrazol-1-yl]benzoic acid;
4-[5-cyclopropyl-4-[(4-hydroxy-1-adamantyl)carbamoyl]pyrazol-1-yl]benzoic acid;
2-[4-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic acid;
2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic acid;
4-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic acid;
3-(4-cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic acid;
3-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoic acid;
4-[4-(adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-ylmethyl]-benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-(1-methylcyclopropyl)pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-ethylpyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-propan-2-ylpyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-cyclobutylpyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoic acid;
4-(5-tert-butyl-4-(cyclohexylcarbamoyl)-1H-pyrazol-1-yl)benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(1-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[5-cyclohexylsulfanyl-4-[(5-hydroxy-2-adamantyl)carbamoyl]pyrazol-1-yl]benzoic acid;
4-[5-cyclohexylsulfanyl-4-[[5-(difluoromethoxy)-adamantyl]carbamoyl]pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoic acid;
methyl 4-[4-(1-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate;
methyl 4-[5-cyclopentylsulfanyl-4-[[(1R,3S)-5-hydroxy-2-adamantyl]carbamoyl]pyrazol 1-yl]benzoate;
4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoic acid;
4-[4-(cyclohexylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-methylsulfanyl-pyrazol-1-yl]benzoic acid;
4-[4-(5-methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-2-methoxy-benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoic acid;
4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoic acid;
and
4-[4-(adamantan-2-ylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid;
and pharmaceutically-acceptable salts thereof.

43 more elements

Facts

Application: 12/259,562Filed 28 Oct 2008
Priority: 12 Feb 2007
Published: 3 Sep 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 231/18
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,…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/889,336Us provisional application · filed 12 Feb 2007
Application60/985,735Us provisional application · filed 6 Nov 2007
Application12/259,562Continuation
US 7,816,391 B2Related patent
US 2009/0221663 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the Formula (1) or a pharmaceutically-acceptable salt thereof:
wherein:
Q is O, S or a single bond;
R1 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, heterocyclyl, arylC1-3alkyl, heteroarylC1-3alkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl or C3-7cycloalkylC2-3alkynyl, [each of which is optionally substituted by 1, 2 or 3 substituents independently selected from C1-3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C1-3alkoxy, C1-3alkylS(O)n— (wherein n is 0, 1, 2 or 3), R5CON(R5′)—, (R5′)(R5″)NC(O)—, R5′OC(O)O—, R5′OC(O)—, (R5′)(R5″)NC(O)N(R5′″)—, R5SO2N(R5″)—, and (R5′)(R5″)NSO2— (wherein R5 is C1-3alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxyl, halo or cyano;
and
R5′ and R5″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-3alkoxy, carboxy and cyano or R5′ and R5″ together with the nitrogen atom to which they are attached form a 4-7 membered saturated ring)];
R2 is selected from heterocyclyl, C3-7cycloalkyl(CH2)m—, and C6-12polycycloalkyl(CH12)m— (wherein m is 0, 1 or 2 and the rings are optionally substituted by 1, 2 or 3 substituents independently selected from R6);
R3 is selected from hydrogen, C1-4alkyl C3-5cycloalkyl and C3-5cycloalkylmethyl (each of which is optionally substituted by 1, 2 or 3 fluoro atoms);
R2 and R3 together with the nitrogen atom to which they are attached form a saturated mono, bicyclic or bridged ring system optionally containing 1 or 2 additional ring heteroatoms selected from nitrogen, oxygen and sulphur and which is optionally fused to a saturated, partially saturated or unsaturated monocyclic ring wherein the resulting ring system is optionally substituted by 1, 2, or 3 substituents independently selected from R7;
R6 and R7 are independently selected from hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R9, R9O—, R9CO—, R9C(O)O—, R9CON(R9′)—, (R9′)(R9″)NC(O)—, (R9′)(R9″)N—, R9S(O)a— wherein a is 0 to 2, R9′OC(O)—, (R9′)(R9″)NSO2—, R9SO2N(R9″)—, (R9′)(R9″)NC(O)N(R9′″)—, phenyl and heteroaryl [wherein the phenyl and heteroaryl groups are optionally fused to a phenyl, heteroaryl or a saturated or partially-saturated 5- or 6-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur and the resulting ring system is optionally substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo, C1-4alkoxy, C1-4alkoxyC1-4alkyl, amino, N—C1-4alkylamino, di-N,N—(C1-4alkyl)amino, N—C1-4alkylcarbamoyl, di-N,N—(C1-4alkyl)carbamoyl, C1-4alkylS(O)r—, C1-4alkylS(O)rC1-4alkyl (wherein r is 0, 1 or 2)];
R9 is independently selected from C1-3alkyl optionally substituted by hydroxyl, halo, C1-4alkoxy, carboxy or cyano;
R9′, R9″ and R9′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2, or 3 substituents independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano);
A is a phenyl or heteroaryl ring (the phenyl or heteroaryl ring being optionally substituted on ring carbon atoms by 1, 2 or 3 R10 groups and on an available ring nitrogen in a heteroaryl group by R11);
R10 is independently selected from C1-4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo, C1-4alkoxy, C1-4alkoxyC1-4alkyl, amino, N—C1-4alkylamino, di-N,N—(C1-4alkyl)amino, N—C1-4alkylcarbamoyl, di-N,N—(C1-4alkyl)carbamoyl, C1-4alkylS(O)s—, C1-4alkylS(O)sC1-4alkyl (wherein s is 0, 1 or 2)];
R11 is independently C1-3alkyl optionally substituted by 1, 2 or 3 fluoro atoms;
X is a direct bond, C3-4cycloalkandiyl, C3-4cycloalkanylidene, —C(R12)(R13)—, C(R12)(R13)C(R14)(R15)—, —CH2O— or —CH2S(O)t— (wherein t is 0, 1 or 2):
Y is a direct bond, C3-4cycloalkandiyl, C3-4cycloalkanylidene, —C(R16)(R17)— or —C(R18)(R19)C(R20)(R21)—;
wherein R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from hydrogen and methyl.

15 more elements

Facts

Application

12/259,562Filed 28 Oct 2008

Priority

12 Feb 2007

Published

3 Sep 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 231/18
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,…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics