US 2010/0249161 A1Published application

2- ( 2 -hydroxyphenyl) -quinazolin-4-ones useful for treating obesity and diabetes

OwnerAnders Klarskov Petersen, Preben Houlberg Olesen +3inventors

InventorsAnders Klarskov Petersen, Preben Houlberg Olesen, Lise Brown Christiansen, Holger Claus Hansen, Flemming Elmelund Nielsen

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Abstract

The present invention relates to novel compounds that act as chemical uncouplers. Compounds of the invention are useful, inter alia, in the treatment, including prevention, of obesity, diabetes and a number of diseases or conditions associated therewith.

Claims27

Dependent claims

A compound according to formula I

wherein
m is 0, such that R3 is linked directly to the benzene ring by a bond,
or m is 1 or 2;
X, when present, represents a group
R1 represents C1-8alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl or phenyl, all of which may optionally be further substituted by halogen, C1-8alkyl, C3-8cycloalkyl, C4-8cycloalkenyl or phenyl;
or R1 represents bicyclo-C4-18alkyl or tricyclo-C4-10-alkyl;
wherein said C3-8cycloalkyl, bicyclo-C4-10alkyl, tricyclo-C4-10alkyl or phenyl are optionally substituted with one or more substituents selected among
hydroxy, cyano, nitro, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy,
C1-6haloalkoxy and C1-6haloalkyl;
R2 represents hydrogen, halogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl or C1-6alkoxy;
R4 represents halogen, hydroxy, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl,
C1-6alkoxy or C(═O)—R10;
R8 and R9 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl,
C4-8cycloalkenyl or C1-6alkoxy;
or
R1 and R2 together with the benzene ring, or, with the proviso that m is 0, R2 and R3 together with the benzene ring or R3 and R4 together with the benzene ring form a 9-11-membered bicyclic ring system which may be fully conjugated or partly saturated, and which may optionally be substituted with one or more substituents selected among halogen, hydroxy, nitro, cyano, C1-6alkyl, C1-6-alkenyl, C1-6alkynyl,
C3-8cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy, C1-6haloalkoxy and C1-6-haloalkyl;
R5, R6 and R7 independently represent hydrogen, nitro, cyano, halogen, C1-6alkyl, C1-6alkenyl,
C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6-haloalkyl, —OR19, —NR10R11, —C(O)OR10, —COR10,
—C(O)NR10R11, —SH, —S(O)2NR10R11, —SR11, —S(O)R11, —S(O)2R11, aryl or heteroaryl;
wherein the latter aryl or heteroaryl may optionally be substituted with one or more substituents selected among
C1-6alkyl, halogen, hydroxy and phenyl;
R10 and R11 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl,
C4-8cycloalkenyl or C1-6haloalkyl;
R3 represents hydrogen, amino, nitro, cyano, halogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6-haloalkyl, arylC1-6alkyl, arylC1-6alkenyl, arylC1-6alkynyl, heteroarylC1-6alkyl, heteroarylC1-6-alkenyl, heteroaryl-
C1-6alkynyl, C3-8cycloalkyl, —OR17, —NR17R18, C1-6haloalkyl, —C(O)OR17, —COR17, —C(O)NR17R18, —SH,
—S(O)2NR17R18, —SR17, —S(O)R17, —S(O)2R17, —NH—COR17, —NH—S(O)2R17 or S(═O)(═NH)R17;
or R3 represents aryl or heteroaryl which may optionally be substituted with one, two, three or four substituents independently selected among halogen, cyano, nitro, C1-6alkyl, C1-6alkenyl, C1-6alkynyl,
C3-8cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy, C1-6haloalkoxy, C1-6haloalkyl, C1-6hydroxyalkyl,
C1-6alkaryl, hydroxy, —(CH2)rO R13, —SH, —S(O)pR13, —S(O)pN(R13)(R14), —C(O)O R13, —OC(O)R13,
—C(O)R13, —C(O)N(R13)(R14), —(CH2)rN(R13)C(O)R14, —B(OR13)(OR14), —(CH2)rN(R13)(R14) and phenyl;
wherein said phenyl is optionally substituted with one or more substituents selected among cyano,
nitro, C1-6alkyl, halogen, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6haloalkoxy, —OR15—, —S(O)sR15, —C(O)OR15, —OC(O)R15, —C(O)R15, —C(O)N(R15)(R16), —N(R15)(R16), —(CH2)sN(R15)C(O)R16, —B(OR15)(OR16),
—(CH2)tOR15 and —(CH2)tN(R15)(R16);
R13, R14, R15, R16 and R18 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl,
C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6-aminoalkyl or phenyl, said phenyl optionally being substituted with one or more substituents selected among halogen, cyano, C1-6alkyl,
C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6 haloalkoxy and C1-6hydroxyalkyl;
R17 represents hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl,
C1-6hydroxyalkyl, C1-6-aminoalkyl, arylC1-6alkyl or phenyl, said phenyl optionally being
substituted with one or more substituents selected among halogen, cyano, C1-6alkyl, C1-6alkenyl,
C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6haloalkoxy and C1-6hydroxyalkyl;
or one or more of the substituent pairs R10 and R11, R13 and R14, R15 and R16, and R17 and R18, when attached to the same nitrogen atom, together with said nitrogen atom form a saturated or unsaturated carbocyclic or heterocyclic 3-8-membered ring, optionally substituted with one or more C1-6alkyl substituents;
p and s, independently of each other, are 0, 1 or 2;
r and t, independently of each other, are 0, 1, 2 or 3;
and pharmaceutically acceptable salts, solvates and prodrugs thereof.

42 more elements

A compound selected from the group consisting of:

2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-Bromo-5-tert-butyl-6-hydroxy-2-methyl-phenyl)-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-6-fluoro-3H-quinazolin-4-one;
2-(-3-tert-Butyl-5-fluoro-2-hydroxy-6-methyl-phenyl)-6-fluoro-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-fluoro-2-hydroxy-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-Bromo-5-tert-butyl-6-hydroxy-2-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
5-tert-Butyl-4-hydroxy-2-methyl-3-(4-oxo-6-trifluoromethanesulfonyl-3,4-dihydro-quinazolin-2-yl)-benzonitrile;
N-[5-tert-Butyl-4-hydroxy-2-methyl-3-(4-oxo-6-trifluoromethanesulfonyl-3,4-dihydro-quinazolin-2-yl)-phenyl]-methanesulfonamide;
2-(3-tert-Butyl-2-hydroxy-6-methyl-5-trifluoromethylsulfanyl-phenyl)-6-trifluoromethane-sulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-chloro-6-ethyl-2-hydroxy-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-2-hydroxy-6-methyl-5-methylsulfanyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-2-hydroxy-5-methanesulfinyl-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
(R)-2-(3-tert-Butyl-2-hydroxy-5-methanesulfinyl-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
(S)-2-(3-tert-Butyl-2-hydroxy-5-methanesulfinyl-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-2-hydroxy-5-methanesulfonyl-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-6-ethyl-2-hydroxy-5-methanesulfinyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-fluoro-2-hydroxy-6-methyl-phenyl)-6-methanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-chloro-2-hydroxy-6-methyl-phenyl)-6-methanesulfonyl-3H-quinazolin-4-one;
N-[5-tert-Butyl-4-hydroxy-2-methyl-3-(4-oxo-6-trifluoromethanesulfonyl-3,4-dihydro-quinazolin-2-yl)-phenyl]-methanesulfonamide;
2-(3-tert-Butyl-2-hydroxy-6-isopropyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-fluoro-2-hydroxy-6-methyl-phenyl)-8-chloro-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-2-hydroxy-6-methyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
2-(3-tert-Butyl-5-bromo-2-hydroxy-6-isopropyl-phenyl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one;
and
2-(6-tert-Butyl-5-hydroxy-2,3-dihydro-benzofuran-4-yl)-6-trifluoromethanesulfonyl-3H-quinazolin-4-one.

22 more elements

A pharmaceutical composition comprising a compound according to formula I

wherein
m is 0, such that R3 is linked directly to the benzene ring by a bond, or m is 1 or 2;
X, when present, represents a group
R1 represents C1-8alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl or phenyl, all of which may optionally be further substituted by halogen, C1-8 alkyl, C3-8cycloalkyl, C4-8cycloalkenyl or phenyl;
or R1 represents bicyclo-C4-10alkyl or tricyclo-C4-10-alkyl;
wherein said C3-8cycloalkyl, bicyclo-C4-10alkyl, tricyclo-C4-10-alkyl or phenyl are optionally substituted with one or more substituents selected among
hydroxy, cyano, nitro, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy,
C1-6haloalkoxy and C1-6haloalkyl;
R2 represents hydrogen, halogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl or C1-6alkoxy;
R4 represents halogen, hydroxy, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl, C4-8cycloalkenyl,
C1-6alkoxy or C(═O)—R10;
R8 and R9 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl,
C4-8cycloalkenyl or C1-6alkoxy;
or
R1 and R2 together with the benzene ring, or, with the proviso that m is 0, R2 and R3 together with the benzene ring or R3 and R4 together with the benzene ring form a 9-11-membered bicyclic ring system which may be fully conjugated or partly saturated, and which may optionally be substituted with one or more substituents selected among halogen, hydroxy, nitro, cyano, C1-6alkyl, C1-6-alkenyl, C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy, C1-6haloalkoxy and C1-6-haloalkyl;
R5, R6 and R7 independently represent hydrogen, nitro, cyano, halogen, C1-6alkyl, C1-6alkenyl,
C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6-haloalkyl, —OR10, NR10R11, —C(O)OR10, —COR10,
—CONR10R11, —SH, —S(O)2NR10R11, —SR11, —S(O)R11—S(O)2R11, aryl or heteroaryl;
wherein the latter aryl or heteroaryl may optionally be substituted with one or more substituents selected among
C1-6alkyl, halogen, hydroxy and phenyl;
R10 and R11 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8-cycloalkyl,
C4-8cycloalkenyl or C1-6haloalkyl;
R3 represents hydrogen, amino, nitro, cyano, halogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6haloalkyl, aryl C1-6alkyl, arylC1-6alkenyl, aryl C1-6alkynyl, heteroarylC1-6alkyl, heteroarylC1-6-alkenyl, heteroaryl-
C1-6alkynyl, C3-8cycloalkyl, —OR17, —NR17R18, C1-6haloalkyl, —C(O)OR17, —COR17, —C(O)NR17R18, —SH,
—S(O)2NR17R18, —SR17, —S(O)R17, —S(O)2R17, —NH—COR17, —NH—S(O)2R17 or S(═O)(═NH)R17;
or R3 represents aryl or heteroaryl which may optionally be substituted with one, two, three or four substituents independently selected among halogen, cyano, nitro, C1-6alkyl, C1-6alkenyl, C1-6alkynyl,
C3-8cycloalkyl, C4-8cycloalkenyl, C1-6alkoxy, C1-6haloalkoxy, C1-6haloalkyl, C1-6hydroxyalkyl,
C1-6alkylaryl, hydroxy, —(CH2)rOR13, —SH, —S(O)pR13, —S(O)pN(R13)(R14), —C(O)O R13, —OC(O)R13, —C(O)R13, —C(O)N(R13)(R14), —(CH2)rN(R13)C(O)R14, —B(OR13)(OR14), —(CH2)rN(R13)(R14) and phenyl;
wherein said phenyl is optionally substituted with one or more substituents selected among cyano,
nitro, C1-6alkyl, halogen, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6haloalkoxy, —OR15—, —S(O)sR15, —C(O)OR15, —OC(O)R15, —C(O)R15, —C(O)N(R15)(R16), —N(R15)(R16), —(CH2)sN(R15)C(O)R16, —B(OR15)(OR16),
—(CH2)tOR15 and —(CH2)tN(R15)(R16);
R13, R14, R15, R16 and R18 independently represent hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl,
C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6-aminoalkyl or phenyl, said phenyl optionally being substituted with one or more substituents selected among halogen, cyano, C1-6alkyl,
C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6haloalkoxy and C1-6hydroxyalkyl;
R17 represents hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloakyl, C4-8cycloalkenyl,
C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, arylC1-6alkyl or phenyl, said phenyl optionally being
substituted with one or more substituents selected among halogen, cyano, C1-6alkyl, C1-6alkenyl,
C1-6alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, C1-6haloalkyl, C1-6haloalkoxy and C1-6hydroxyalkyl;
or one or more of the substituent pairs R10 and R11, R13 and R14, R15 and R16, and R17 and R18, when attached to the same nitrogen atom, together with said nitrogen atom form a saturated or unsaturated carbocyclic or heterocyclic 3-8-membered ring, optionally substituted with one or more C1-6alkyl substituents;
p and s, independently of each other, are 0, 1 or 2;
r and t, independently of each other, are 0, 1, 2 or 3;
and pharmaceutically acceptable salts, solvates and prodrugs thereof;
and
a pharmaceutically acceptable carrier or diluent.

41 more elements

Dependencies are inferred from the claim text.

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