Substituted aminotetralines

• US 8,263,656 B2
• Filed: 08/13/2009
• Issued: 09/11/2012
• Est. Priority Date: 08/15/2008
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Firooznia, Fariborz, Gillespie, Paul, Goodnow, Robert Alan Jr., Lin, Tai-An, Sidduri, Achyutharao, So, Sung-Sau, Tan, Jenny
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US12/540,839
• Publication Number:
  US 20100041713A1
• Time in Patent Office: 1,125 Days
• Field of Search: None
• US Class Current: 514/562
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 311/20 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/14 having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 213/34 to which a second hetero atom is attached

Abstract

The invention is concerned with the compounds of formula I:

and pharmaceutically acceptable salts and esters thereof, wherein R¹-R⁴ are defined in the detailed description and claims. In addition, the present invention relates to methods of manufacturing and using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds of formula I are antagonists at the CRTH2 receptor and may be useful in treating diseases and disorders associated with that receptor such as asthma.

Claims

1. A compound of formula I:

2. A compound of claim 1 wherein R³ is hydrogen.

3. A compound of claim 1 wherein R³ is methyl.

4. A compound of claim 1 wherein R⁴ is phenyl substituted by two substituents independently selected from the group consisting of:

(1) halogen, and (2) lower alkyl optionally substituted by halogen.

5. A compound of claim 1 wherein R⁴ is phenyl substituted by two substituents independently selected from the group consisting of:

(1) fluoro;

(2) chloro;

(3) bromo;

(4) lower alkyl

(5) lower alkanoyl;

(6) lower alkylsulfanyl, lower alkylsulfinyl, or lower alkylsulfonyl;

(7) lower cycloalkylsulfanyl, lower cycloalkylsulfinyl, or lower cycloalkylsulfonyl;

(8) trifluoromethyl, difluoromethyl, or fluoromethyl; and

(9) 1,1-difluoroethyl.

6. A compound of claim 1 wherein R⁴ is phenyl substituted by two substituents independently selected from the group consisting of:

(1) fluoro;

(2) chloro;

(3) bromo;

(4) methyl;

(5) ethyl;

(6) propyl or isopropyl;

(7) butyl, sec-butyl, or tert-butyl;

(8) trifluoromethyl, difluoromethyl, or fluoromethyl; and

(9) 1,1-difluoroethyl.

7. A compound of claim 1 wherein R⁴ is phenyl substituted by two substituents independently selected from the group consisting of:

(1) fluoro;

(2) chloro;

(3) bromo; and

(4) trifluoromethyl.

8. A compound of claim 1 wherein R⁴ is pyridine substituted by one substituent selected from the group consisting of:

(1) halogen;

(2) lower alkyl optionally substituted by halogen; and

(3) phenyl or pyridine, wherein said phenyl or pyridine is optionally substituted by lower alkyl.

9. A compound of claim 1 wherein R⁴ is pyridine substituted by phenyl wherein said phenyl is optionally substituted by lower alkyl.

10. A compound of claim 1 wherein R¹ is hydrogen, fluoro, chloro, bromo, methoxy, or phenyl and R² is hydrogen, fluoro, chloro, methyl, ethyl, propyl, or isopropyl;

with the proviso that R¹ and R² are not both hydrogen.

11. A compound of claim 1 wherein R¹ is hydrogen, fluoro, chloro, or bromo and R² is hydrogen, fluoro, chloro, or methyl, ethyl, or isopropyl;

with the proviso that R¹ and R² are not both hydrogen.

12. A compound of claim 1 wherein at least one of R¹ or R² is fluoro, chloro, or bromo.

13. A compound of claim 1 wherein R¹ is fluoro or chloro.

14. A compound of claim 1 wherein R⁴ is phenyl substituted by two substituents at positions 3 and 5 on the phenyl ring where such positions are indicated below in formula IC:

15. A compound of claim 14 wherein R¹ is fluoro or chloro;

R² is hydrogen or fluoro;

R³ is hydrogen; and

the phenyl ring is substituted at positions 3 and 5 as indicated in formula IC with substituents independently selected from the group consisting of fluoro, bromo, or trifluoromethyl.

16. A compound of claim 14 wherein R¹ is fluoro or chloro;

R² is hydrogen or fluoro;

R³ is hydrogen; and

the phenyl ring is substituted at positions 3 and 5 with trifluoromethyl.

17. A compound of claim 1 which is an (R)-enantiomer as depicted in formula IA:

18. A compound of claim 1 selected from the group consisting of:

[(R)-5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2,3-dichloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-isopropyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-methyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-ethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-methyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid; and

[3-Chloro-5-(2,5-dichloro-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

19. A compound of claim 1 selected from the group consisting of:

[3-Chloro-5-(2,4-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2,3-dichloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[3-Chloro-5-(2,5-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[3-Chloro-5-(2,4-dichloro-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[3-Chloro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-Tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-3-Chloro-5-(2,4-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-bromo-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid; and

[(R)-5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-bromo-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

20. A compound of claim 1 selected from the group consisting of:

[3-Chloro-2-fluoro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-methoxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-3-phenyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-5-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[2,3-Difluoro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[3-Fluoro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid; and

[5-(2,4-Dichloro-benzenesulfonylamino)-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

21. A compound of claim 1 selected from the group consisting of:

[5-(2,4-Dichloro-benzenesulfonylamino)-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(2,5-Dichloro-benzenesulfonylamino)-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(2,5-Dichloro-benzenesulfonylamino)-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

{2,3-Difluoro-5-[5-(3-isopropyl-phenyl)-pyridine-2-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Fluoro-5-[5-(3-isopropyl-phenyl)-pyridine-2-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Chloro-5-[5-(3-isopropyl-phenyl)-pyridine-2-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

[(R)-3-Bromo-5-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-3-Chloro-2-fluoro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid; and

[(R)-3-Chloro-5-(2,4-dichloro-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

22. A compound of claim 1 selected from the group consisting of:

[(R)-3-Chloro-5-(3-fluoro-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-5-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-3-Chloro-5-(2,5-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

{3-Chloro-2-fluoro-5-[5-(3-isopropyl-phenyl)-pyridine-2-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

[5-(2,5-Dichloro-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[5-(2,4-Dichloro-benzenesulfonylamino)-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

{2-Fluoro-5-[5-(3-isopropyl-phenyl)-pyridine-2-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

[(R)-3-Bromo-5-(2,5-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

[(R)-3-Bromo-5-(2,4-dichloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid; and

[5-(3,5-Bis-methanesulfonyl-benzenesulfonylamino)-3-bromo-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

23. A compound of claim 1 selected from the group consisting of:

[5-(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-2-methyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-2-ethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{(R)-5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Chloro-5-[(2,4-dichloro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-2,3-dichloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-chloro-2-methyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Chloro-5-[(2,5-dichloro-benzenesulfonyl)-methyl-amino]-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid; and

{3-Chloro-5-[(2,5-dichloro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

24. A compound of claim 1 selected from the group consisting of:

{3-Chloro-5-[(2,4-dichloro-benzenesulfonyl)-methyl-amino]-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3-Bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3-Bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-chloro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Chloro-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Chloro-2-fluoro-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(2,4-Dichloro-benzenesulfonyl)-methyl-amino]-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3,5-Bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(2,4-Dichloro-benzenesulfonyl)-methyl-amino]-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(2,5-Dichloro-benzenesulfonyl)-methyl-amino]-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid; and

{5-[(3-Bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

25. A compound of claim 1 selected from the group consisting of:

{5-[(2,5-Dichloro-benzenesulfonyl)-methyl-amino]-2,3-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(3-Bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{3-Fluoro-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{2,3-Difluoro-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

(2,3-Difluoro-5-{[5-(3-isopropyl-phenyl)-pyridine-2-sulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid;

(3-Fluoro-5-{[5-(3-isopropyl-phenyl)-pyridine-2-sulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid;

(3-Chloro-5-{[5-(3-isopropyl-phenyl)-pyridine-2-sulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid;

(3-Chloro-2-fluoro-5-{[5-(3-isopropyl-phenyl)-pyridine-2-sulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid;

{5-[(2,5-Dichloro-benzenesulfonyl)-methyl-amino]-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid;

{5-[(2,4-Dichloro-benzenesulfonyl)-methyl-amino]-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid; and

(2-Fluoro-5-{[5-(3-isopropyl-phenyl)-pyridine-2-sulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid;

or a pharmaceutically acceptable salt or ester thereof.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.