Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof

Patent metadata

Field	Value
Publication number	US-10172814-B2
Application number	US-201515537280-A
Country	US
Kind code	B2
Filing date	Dec 16, 2015
Priority date	Dec 18, 2014
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The present invention relates to substituted Pyridyl-cycloalkyl-carboxylic acids of general formula (I), to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular in mammals, such as diseases associated with pains, or for the treatment or prophylaxis of pain syndromes (acute and chronic), inflammatory-induced pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis and adenomyosis as such, cancer as such, and proliferative diseases as such like endometriosis.

First claim

The invention claimed is:

1. A compound of formula (I):

in which:
R 1 represents halogen, C 1 -C 4 -alkyl, or O—(C 1 -C 4 -alkyl), wherein C 1 -C 4 -alkyl and O—(C 1 -C 4 -alkyl) are optionally substituted with 1-5 halogen atoms which are the same or different;
R 2 represents hydrogen, halogen, C 1 -C 4 -alkyl, or O—(C 1 -C 4 -alkyl), wherein C 1 -C 4 -alkyl and O—(C 1 -C 4 -alkyl) are optionally substituted with 1-5 halogen atoms which are the same or different;
X is —C 2 H 4 , —CH 2 —Y—, —CH 2 —CR 6 R 7 —, —CR 6 R 7 —CH 2 —, or 1,2-cyclopropylidene;
R 3 is C 3 -C 6 -cycloalkyl, which is optionally substituted with one or more substituents which are the same or different and either halogen or C 1 -C 4 -alkyl;
R 4a and R 4b represent hydrogen, halogen, C 1 -C 4 -alkyl, —O—(C 1 -C 4 -alkyl), (CH 2 ) n —OH, wherein C 1 -C 4 -alkyl is optionally substituted with one or more substituents which are the same or different and either halogen or C 1 -C 4 -alkyl;
R 5 is pyridine, which is substituted with one or two substituents which are the same or different and selected from the group consisting of halogen, C 1 -C 4 -alkyl, —O—(C 1 -C 4 -alkyl), OH, CN, —CH 2 —OH, —CH 2 —O—(C 1 -C 4 -alkyl), C 3 -C 6 -cycloalkyl, —O—(C 3 -C 6 -cycloalkyl), 3- to 7-membered-heterocycloalkyl-, and —O—(3- to 7-membered-heterocycloalkyl),
wherein said C 1 -C 4 -alkyl and —O—(C 1 -C 4 -alkyl) are optionally substituted with 1-5 halogen atoms which are the same or different;
R 6 and R 7 are different and selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, and C 3 -C 6 -cycloalkyl;
R 8 represents hydrogen or C 1 -C 4 -alkyl;
Y represents O or NR 8 ;
n is 0, 1 or 2;
or a tautomer, an isomer, enantiomer, diastereomer, racemate, an N-oxide, or a salt thereof, or a mixture of same.

2. A compound according to claim 1 , wherein
R 4a is in ortho position in relation to R 5 .

3. A compound according to claim 1 , wherein
R 1 represents an optionally substituted C 1 -C 4 -alkyl.

4. A compound according to claim 1 , wherein
R 2 represents hydrogen or halogen.

5. A compound according to claim 1 , wherein
R 3 represents unsubstituted C 3 -C 6 -cycloalkyl.

6. A compound according to claim 1 , wherein n is 1.

7. A compound according to claim 1 , wherein
R 4a and R 4b represent hydrogen, halogen, or C 1 -C 4 -alkyl.

8. A compound according to claim 1 , wherein
R 4b is in meta position in relation to R 5 .

9. A compound according to claim 1 , wherein
R 5 represents pyridine-3-yl, which is substituted with one or two substituents which are the same or different and selected from the group consisting of halogen, C 1 -C 4 -alkyl, —O—(C 1 -C 4 -alkyl), C 3 -C 6 -cycloalkyl, and —O—(C 3 -C 6 -cycloalkyl).

10. A compound according to claim 1 , wherein
R 5 represents pyridine-3-yl, which is substituted with a halogen.

11. A compound according to claim 10 , wherein R 5 is additionally substituted with C 1 -C 4 -alkyl.

12. A compound according to claim 1 , wherein
R 1 represents unsubstituted C 1 -C 4 -alkyl; and
R 2 represents hydrogen.

13. A compound according to claim 1 , wherein
R 1 represents unsubstituted C 1 -C 4 -alkyl;
R 2 represents hydrogen; and
R 3 represents unsubstitued C 3 -C 6 -cycloalkyl.

14. A compound according to claim 1 , wherein
R 1 represents unsubstituted C 1 -C 4 -alkyl;
R 2 represents hydrogen;
R 3 represents unsubstitued C 3 -C 6 -cycloalkyl; and
R 4a and R 4b both represent hydrogen.

15. A compound according to claim 1 , wherein
R 1 represents unsubstituted C 1 -C 4 -alkyl;
R 2 represents hydrogen;
R 3 represents unsubstitued C 3 -C 6 -cycloalkyl;
R 4a and R 4b both represent hydrogen; and
R 5 represents pyridine-3-yl, which is substituted with one halogen.

16. A compound according to claim 1 , which is selected from the group consisting of:
1) (R/S) 3-{3-[(Cyclopentyl{4-[5-(trifluormethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 1);
2) (−) 3-{3-[(Cyclopentyl{4-[5-(trifluormethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 2);
3) (+) 3-{3-[(Cyclopentyl{4-[5-(trifluormethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 3);
4) (R/S) 3-{3-[(Cyclopentyl{4-[6-(trifluormethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 4);
5) (−) 3-{3-[(Cyclopentyl{4-[6-(trifluormethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 5);
6) (R/S) 3-[3-({Cyclopentyl[4-(5-fluorpyridin-3-yl)phenyl]acetyl}amino)-2methylphenyl]propanoic acid (Example 6);
7) (R/S) 3-[3-({[4-(6-Cyanpyridin-3-yl)phenyl](cyclopentyl)acetyl}-amino)-2-methylphenyl]propanoic acid (Example 7);
8) (R/S) 3-[3-({Cyclopentyl[4-(5-ethoxypyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 8);
9) (R/S) 3-{3-[(Cyclopentyl{4-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-phenyl}acetyl)amino]-2-methylphenyl}propanoic acid (Example 9);
10) (R/S) 3-{3-[(Cyclopentyl{4-[5-(methoxymethyl)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 10);
11) (R/S) 3-[3-({Cyclopentyl[4-(5-methoxypyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 11);
12) (R/S) 3-[3-({Cyclopentyl[4-(4-methylpyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 12);
13) (R/S) 3-[3-({Cyclopentyl[4-(5-ethylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]propanoic acid (Example 13);
14) 3-[3-({Cyclopentyl[4-(5-cyclopropylpyridin-3-yl)phenyl]acetyl}amino)-2-methylphenyl]propanoic acid (Example 14);
15) (R/S) 3-{3-[(Cyclopentyl{4-[5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}acetyl)amino]-2-methylphenyl}propanoic acid (Example 15);
16) (R/S) 3-[3-({[4-(5-Chlorpyridin-3-yl)phenyl](cyclopentyl)acetyl}-amino)-2-methylphenyl]propanoic acid (Example 16);
17) (−) (R) 3-[3-({[4-(5-Chloropyridin-3-yl)phenyl](cyclopentyl)acetyl}-amino)-2-methylphenyl]propanoic acid (Example 17);
18) (R/S) 3-[3-({Cyclopentyl[4-(6-methoxypyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 18);
19) (R/S) 3-[3-({Cyclopentyl[4-(6-fluoropyridin-3-yl)-phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 19);
20) (R/S) 3-[3-({Cyclopentyl[4-(2-methoxypyridin-3-yl)-phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 20);
21) (R/S) 3-[3-({Cyclopentyl[4-(5-methylpyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 21);
22) (R/S) 3-[3-({Cyclopentyl[4-(6-methylpyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 22);
23) (R/S) 3-[3-acyclopentyl[4-(2-fluoropyridin-3-yl)phenyl]acetyl}-amino)-2-methyl-phenyl]propanoic acid (Example 23);
24) (R/S) 3-[3-({[4-(5-Chloro-6-methylpyridin-3-yl)phenyl](cyclopentyl)-acetyl}amino)-2-methylphenyl]propanoic acid (Example 24);
25) (+) (S) 3-[3-({[4-(5-Chloro-6-methylpyridin-3-yl)phenyl](cyclo-pentyl)-acetyl}amino)-2-methylphenyl]propanoic acid (Example 25);
26) (−) (R) 3-[3-({[4-(5-Chloro-6-methylpyridin-3-yl)phenyl](cyclopentyl)-acetyl}amino)-2-methylphenyl]propanoic acid (Example 26);
27) (R/S) 3-[3-({Cyclopentyl[4-(5,6-dimethylpyridin-3-yl)phenyl]acetyl}-amino)-2-methylphenyl]propanoic acid (Example 27);
28) (R/S) 3-{3-[(Cyclopentyl{4-[5-(difluoromethoxy)pyridin-3-yl]phenyl}-acetyl)amino]-2-methylphenyl}propanoic acid (Example 28);
29) (R/S) 3-{3-[(Cyclop

Assignees

• Bayer Pharma AG

Inventors

• Bräuer Nico
• Nagel Jens
• Irlbacher Horst
• Rotgeri Andrea
• Schwede Wolfgang
• Dahllöf Henrik
• Koppitz Marcus
• Peters Michaele
• Godinho-Coelho Anne-Marie

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/61 Primary

  Halogen atoms or nitro radicals · CPC title

• C07D213/56

  Amides · CPC title

• C07D213/84 Primary

  Nitriles · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title