Cycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
View Patent ↗The invention relates to arylcycloalkyl-substituted derivatives and to their physiologically acceptable salts and physiologically functional derivatives. What is described are compounds of the formula I, in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparation. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistence is involved.
1. A compound of formula I:
wherein
Ring A is (C 3 –C 8 )-cycloalkanediyl or (C 3 –C 8 )-cycloalkenediyl, wherein one or more carbon atoms in said (C 3 –C 8 )-cycloalkane- and (C 3 –C 8 )-cycloalkenediyl groups may be replaced by oxygen atoms;
R1, R2 are each independently H, (C 1 –C 6 )-alkyl, (C 3 –C 8 )-cycloalkyl or (C 6 –C 10 )-aryl;
R3 is (C 3 –C 6 )-cycloalkyl or (C 1 –C 12 )-alkyl, each of which is optionally substituted by (C 6 –C 10 )-aryl, (C 5 –C 6 )-heteroaryl or (C 3 –C 6 )-cycloalkyl, and wherein said (C 6 –C 10 )-aryl, (C 5 –C 6 )-heteroaryl and (C 3 –C 6 )-cycloalkyl substituents are themselves optionally substituted by (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkoxy, Cl, Br, I, CO—(C 1 –C 6 )-alkyl, CO—O(C 1 –C 6 )-alkyl, CO—NH(C 1 –C 6 )-alkyl or CO—N((C 1 –C 6 )-alkyl) 2 ;
X is (C 1 –C 6 )-alkanediyl, wherein one or more carbon atoms therein are optionally replaced by oxygen atoms;
Y 1 is CO or a bond;
Y 2 is NH or (C 1 –C 12 )-alkanediyl wherein one or more carbon atoms therein are optionally replaced by oxygen atoms;
R4 is (C 1 –C 8 )-alkyl;
R5 is H or (C 1 –C 6 )-alkyl;
R6 is H;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein:
Ring A is (C 3 –C 8 )-cycloalkane-1,3-diyl;
R1, R2 are each independently H, (C 1 –C 6 )-alkyl, (C 3 –C 8 )-cycloalkyl or (C 6 –C 10 )-aryl;
R3 is (C 1 –C 12 )-cycloalkyl optionally substituted by phenyl, wherein said phenyl substituent is optionally substituted by (C 1 –C 6 )-alkyl;
X is (C 1 –C 6 )-alkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom;
Y 1 is CO or a bond;
Y 2 is NH or (C 1 –C 6 )-alkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom;
R4 is (C 1 –C 8 )-alkyl;
R5 is H or (C 1 –C 6 )-alkyl; and
R6 is H.
3. The compound of claim 2 wherein:
Ring A is cyclohexane-1,3-diyl;
R1, R2 are each independently H, (C 1 –C 6 )-alkyl, (C 3 –C 8 )-cycloalkyl or phenyl;
R3 is (C 1 –C 12 )-alkyl optionally substituted by phenyl, wherein said phenyl substituent is optionally substituted by methyl;
X is (C 1 –C 6 )-alkanediyl wherein the carbon atom adjacent to ring A is optionally replaced by an oxygen atom;
Y 1 is CO or a bond;
Y 2 is NH or (C 1 –C 6 )-alkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom;
R4 is (C 1 –C 8 )-alkyl;
R5 is H or (C 1 –C 4 )-alkyl; and
R6 is H.
4. The compound of claim 3 wherein:
Ring A is cyclohexane-1,3-diyl;
R1 is H;
R2 is (C 1 –C 6 )-alkyl, (C 3 –C 8 )-cycloalkyl or phenyl;
R3 is (C 1 –C 8 )-alkyl optionally substituted by phenyl, wherein said phenyl substitutent is optionally substituted by methyl;
X is CH 2 CH 2 O;
Y 1 is CO or a bond;
Y 2 is NH or (C 1 –C 4 )-alkanediyl;
R4 is (C 1 –C 6 )-alkyl;
R5 is H or (C 1 –C 4 )-alkyl; and
R6 is H.
5. The compound of claim 4 , wherein the bond X-ring A-Y 1 is cis-configured.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 1 .
7. The pharmaceutical composition of claim 6 further comprising at least one additional active ingredient.
8. The pharmaceutical composition of claim 7 wherein said additional active ingredient has favorable effects on metabolic disturbances or disorders.
9. The pharmaceutical composition of claim 7 wherein said additional active ingredient is an antidiabetic.
10. The pharmaceutical composition of claim 7 wherein said additional active ingredient is a lipid modulator.
11. A method of treating disorders of insulin resistence comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
12. A method of treating diabetes mellitus and squelae associated therewith comprising administering to a patient in need thereof a therapeutically affective amount of compound of formula 1.
13. A method of treating dyslipidemia and squelae associated therewith comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
14. A method of treating disorders of insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 in combination with at least one further active compound.