Therapeutic uses of di-aryl acid derivatives
First Claim
Patent Images
1. A compound of formula (I) wherein:
-
is oxazolyl or quinolinyl, which are optionally substituted by one or more ring system substituents;
is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z;
A is B and E are a chemical bond;
a is 1;
b is 0 or 1;
c is 0;
d is 0;
g is 1-5;
R1, R2, R3 and R4 are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents;
Z is R21O2C—
, R21OC—
, —
CN, R21O2SHNCO—
, R21O2SHN—
, (R21)2NCO—
or R21O—
;
R21 is independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aryl, which is optionally substituted by one or more ring system substituents, cycloalkyl, which is optionally substituted by one or more ring system substituents, or aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents;
R15, R16 are independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents;
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof,whereinalkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms;
aryl is an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms;
a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and
an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl.
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Abstract
The use of diaryl acid derivatives of formula (I)
or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof, wherein the variables shown are defined in the disclosure, and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.
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Citations
42 Claims
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1. A compound of formula (I)
wherein: -
is oxazolyl or quinolinyl, which are optionally substituted by one or more ring system substituents;
is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z; A is B and E are a chemical bond; a is 1;
b is 0 or 1;
c is 0; d is 0; g is 1-5;
R1, R2, R3 and R4 are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents;
Z is R21O2C—
, R21OC—
, —
CN, R21O2SHNCO—
, R21O2SHN—
, (R21)2NCO—
or R21O—
;
R21 is independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aryl, which is optionally substituted by one or more ring system substituents, cycloalkyl, which is optionally substituted by one or more ring system substituents, or aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents;
R15, R16 are independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents;
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof, wherein alkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms;
aryl is an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms;
a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and
an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; - or 2-substituted-oxazol4-yl or 2,5 disubstituted-oxazol4-yl;
4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl;
wherein an indicated substituent is a ring system substituent.
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6. A compound as claimed in claim 1, wherein the compound is 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic acid.
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7. A compound as claimed in claim 1, which is of formula
wherein b=0; -
R1, R2, R3, R4 are hydrogen R15, R16 are hydrogen;
g=2, 3, 4 or 5;
Z is R21O2C—
, R21OC—
, or R21O—
;
R′
is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy or unsubstituted aralkyloxy; and
R″
is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy, ora pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof .
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8. A compound according to claim 7, wherein Z is —
- CO2H.
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9. A compound according to claim 7, wherein R′
- is hydrogen; and
R″
is lower alkyl of 1 to about 4 carbon atoms.
- is hydrogen; and
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10. A compound according to claim 7, wherein
is 2-substituted-oxazol-4-yl, wherein the substituent is a ring system substituent. -
11. A compound according to claim 1, wherein the compound is
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12. A compound according to claim 1, wherein the compound is
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13. A compound according to claim 1 , wherein the compound is
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14. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
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15. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound wherein the disorder is associated with a physiological detrimental blood level of insulin, glucose, free fatty acids, or triglycerides.
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16. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperglycemia.
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17. The method according to claim 16, wherein the hyperglycemia is diabetes.
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18. The method according to claim 16, wherein the hyperglycemia is A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is Type II diabetes.
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19. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperinsulinism.
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20. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is insulin resistance.
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21. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is a cardiovascular condition.
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22. The method according to claim 21, wherein the cardiovascular condition is atherosclerosis.
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23. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperlipidemia.
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24. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hypertension.
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25. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is an eating disorder.
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26. A compound of formula (I)
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36. A compound, wherein the compound is
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.
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38. A compound, wherein the compound is
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.
Specification