Diarylcycloalkyl derivatives, process for their preparation and their use as pharmaceuticals
View Patent ↗Diarylcycloalkyl derivatives, process for their preparation and their use as pharmaceuticals The invention relates to diarylcycloalkyl derivatives and to their physiologically acceptable salts, racemates 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 the 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 )-cycloalkanediyl and (C 3 –C 8 )-cycloalkenediyl groups is optionally replaced by oxygen atoms;
Ring B is a) phenyl; or
b) (C 3 –C 8 )-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S;
R1 is a) in the case where ring B is selected from a) above:
SCF 3 , OCF 2 —CHF 2 , O-phenyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , OCF 2 —CF 3 , SCF 3 , OCF 2 —CHF 2 , O-phenyl, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
c) in the case ring B is selected from a) above and R4 is phenyl:
(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R2 is H or CF 3 ;
R4 is a) in the case where ring B is selected from a) above:
phenyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
c) in the case ring B is selected from a) above and R1 is selected from a) above:
(C 1 –C 6 )-alkyl;
R5 is H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R3 is H or (C 1 –C 6 )-alkyl;
X is (C 1 –C 6 )-alkanediyl, wherein one or more carbon atoms in said (C 1 –C 6 )-alkanediyl group are optionally replaced by oxygen atoms;
Y is (C 1 –C 6 )-alkanediyl, wherein one or more carbon atoms in said (C 1 –C 6 )-alkanediyl group are optionally replaced by oxygen atoms;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 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 )-cycloalkanediyl and (C 3 –C 8 )-cycloalkenediyl groups are optionally replaced by oxygen atoms;
Ring B is a) phenyl; or
b) (C 3 –C 8 )-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S;
R1 is a) in the case where ring B is selected from a) above: SCF 3 , OCF 2 —CHF 2 , O-phenyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , OCF 2 —CF 3 , SCF 3 , OCF 2 —CHF 2 , O-phenyl, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
c) in the case where ring B is selected from a) above and R4 is phenyl:
(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R2 is H or CF 3 ;
R4 is a) in the case where ring B is selected from a) above:
phenyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
c) in the case where ring B is selected from a) above and R1 is selected from a) above:
(C 1 –C 6 )-alkyl;
R5 is H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R3 is H or (C 1 –C 6 )-alkyl;
X is CH 2 —O;
Y is (C 1 –C 6 )-alkanediyl, wherein one or more carbon atoms in said (C 1 –C 6 )-alkanediyl group are optionally replaced by oxygen atoms.
3. The compound of claim 2 wherein:
Ring A is (C 3 –C 8 )-cycloalkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom;
Ring B is a) phenyl; or
b ) (C 3 –C 8 )-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S;
R1 is a) in the case where ring B is selected from a) above:
SCF 3 , OCF 2 —CHF 2 , O-phenyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , OCF 2 —CF 3 , SCF 3 , OCF 2 —CHF 3 , O-phenyl, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
c) in the case where ring B is selected from a) above and R4 is phenyl:
(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R2 is H or CF 3 ;
R4 is a) in the case where ring B is selected from a) above:
phenyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
c) in the case where ring B is selected from a) above and R1 is selected from a) above:
(C 1 –C 6 )-alkyl;
R5 is H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R3 is H or (C 1 –C 6 )-alkyl;
X is CH 2 —O;
Y is CH 2 —O.
4. The compound of claim 1 which has the formula Ia
wherein ring A, ring B, R1, R2, R3, R4, R5, X and Y are as defined in claim 1 .
5. The compound of claim 4 wherein:
R3 is H; and
R5 is methyl.
6. The compound of claim 5 wherein:
Ring A is (C 5 –C 7 )-cycloalkanediyl;
Ring B is a) phenyl; or
b) (C 3 –C 8 )-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S;
R1 is a) in the case where ring B is selected from a) above:
SCF 3 , OCF 2 —CHF 2 , O-phenyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , OCF 2 —CF 3 , SCF 3 , OCF 2 —CHF 2 , O-phenyl, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl-O—(C 1 –C 3 )-alkyl;
c) in the case where ring B is selected from a) above and R4 is phenyl:
(C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
R2 is H or CF 3 ;
R4 is a) in the case where ring B is selected from a) above:
phenyl;
b) in the case where ring B is selected from b) above:
H, F, Cl, Br, OH, NO 2 , CF 3 , OCF 3 , (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl;
c) in the case where ring B is selected from a) above and R1 selected from a) above:
(C 1 –C 6 )-alkyl;
R5 is methyl;
R3 is H;
X is CH 2 —O;
Y is CH 2 —O.
7. The compound of claim 6 wherein the central cycloalkanediyl ring is attached 1,3-cis.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 1 .
9. The pharmaceutical composition of claim 6 further comprising at least one additional active ingredient.
10. The pharmaceutical composition of claim 9 wherein said additional active ingredient has favorable effects on metabolic disturbances or disorders.
11. The pharmaceutical composition of claim 9 wherein said additional active ingredient is an antidiabetic.
12. The pharmaceutical composition of claim 9 wherein said additional active ingredient is a lipid modulator.