IP Library › Granted Patent US 8,008,331

Granted Patent B2

US 8,008,331 · App. 11/950,948 · Granted Aug 30, 2011

Benzothiazol-2-one derivatives as lipase and phospholipase inhibitors

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Quick Facts

Patent No.: US 8,008,331
App. No.: 11/950,948
Granted: Aug 30, 2011
Kind: B2

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Abstract

The invention relates to benzothiazol-2-one derivatives of general formula (I) with the meanings indicated in the description, the pharmaceutically usable salts thereof, and the use thereof as medicinal substances.

Claims (104)

1. A compound of the formula I

wherein:

R1 is (C 5 -C 16 )-alkyl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 4 )-alkylene-(C 4 -C 12 )-cycloalkyl, (C 8 -C 14 )-bicycle, where aryl, cycloalkyl or bicycle may be substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (C 1 -C 6 )-alkylsulfonyl or aminosulfonyl;

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and chosen from hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, CO—OR7, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

R6 is hydrogen, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

R9, R10 are either identical or different and selected from hydrogen, (C 1 -C 6 )-alkyl, (C 6 -C 10 )-aryl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 4 )-alkylene-(C 3 -C 12 )-cycloalkyl or (C 8 -C 14 )-bicycle;

or a tautomer or a physiologically tolerated salt thereof.

2. The compound of the general formula I as claimed in claim 1 , wherein

R1 is (C 6 -C 12 )-alkyl, (C 1 -C 3 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 3 )-alkylene-(C 4 -C 12 )-cycloalkyl, (C 4 -C 12 )-bicycle, where aryl, cycloalkyl or bicycle is optionally substituted one or more times by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy, hydroxy, amino, (C 1 -C 6 )-alkylamino or trifluoromethyl;

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and selected from hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, amino, COOR7, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, (C 1 -C 6 )-alkylcarbonyl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

R6 is hydrogen, hydroxy, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylamino carbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl, (C 6 -C 10 )-aryl or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

R9, R10 are either identical or different and selected from hydrogen, (C 1 -C 6 )-alkyl, (C 6 -C 10 )-aryl or (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl.

3. The compound of the general formula I as claimed in claim 1 , wherein

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and selected from hydrogen, (C 1 -C 6 )-alkyl, hydroxy, amino, COOR7, (C 1 -C 6 )-alkylsulfonyl, aminosulfonyl, pentafluorosulfanyl, (C 1 -C 6 )-alkylcarbonyl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

R6 is hydrogen, hydroxy, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, mono-(C 1 -C 6 )-alkylamino carbonyl, di-(C 2 -C 8 )-alkylaminocarbonyl or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is (C 1 -C 6 )-alkyl;

R7 is hydrogen or (C 1 -C 6 )-alkyl;

and

R9, R10 are either identical or different and selected from hydrogen or (C 1 -C 6 )-alkyl.

4. The compound of the formula I as claimed in claim 1 , wherein

R1 is (C 6 -C 12 )-alkyl, benzyl, (C 1 -C 2 )-alkylene-(C 4 -C 12 )-cycloalkyl, (C 8 -C 14 )-bicycle, where benzyl, cycloalkyl or bicycle may be substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy or trifluoromethyl; and

R2 is hydrogen.

5. The compound of the formula I as claimed in claim 1 , in which

R1 is (C 6 -C 12 )-alkyl, benzyl or (C 8 -C 14 )-bicycyl, where benzyl or bicycyl is optionally substituted by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy or trifluoromethyl;

R2 is hydrogen;

R3 is hydrogen;

R4, R5 are either identical or different and selected from hydrogen, hydroxy, (C 1 -C 6 )-alkyl, or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy; and

R6 is hydrogen.

6. The compound of the formula I as claimed in claim 1 , wherein

R1 is (C 6 -C 12 )-alkyl or benzyl, where benzyl is optionally substituted by methyl;

R2 is hydrogen;

R3 is hydrogen;

R4, R5 are hydrogen; and

R6 is hydrogen.

7. The compound of the formula I as claimed in claim 1 , wherein

R3, R6 are hydrogen and R4 or R5 are not hydrogen.

8. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 2 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 3 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 4 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 5 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 6 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 7 or a pharmaceutically acceptable salt thereof or a tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

15. A method for the treatment of insulin resistance in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I

wherein:

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and chosen from hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, CO—OR7, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—-NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

R9, R10 are either identical or different and selected from hydrogen, (C 1 -C 6 )-alkyl, —(C 6 -C 10 )-aryl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl, (C 1 -C 4 )-alkylene-(C 3 -C 12 )-cycloalkyl or (C 8 -C 14 )-bicycle; or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of dyslipidemias in a patient, which comprises administering to said patient a therapeutically effective amount of a compound of formula I

wherein:

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and chosen from hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, CO—OR7, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

17. The method for the treatment of insulin resistance in a patient according to claim 15 , which comprises administering to said patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and in combination with at least one other active ingredient.

18. A process for preparing a compound of the general formula I,

wherein:

R2 is hydrogen or (C 1 -C 6 )-alkyl;

R3 is hydrogen;

R4, R5 are either identical or different and chosen from hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, CO—OR7, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

a) acylating benzothiazol-2-one of the formula II with carbamoyl chloride of the formula III;

b) in two stages reacting first benzothiazol-2-one of the formula II with phosgene or its equivalents chosen from trichloromethyl chlorocarbonate, ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and in a second step with an amine of the formula IV,

19. A process for preparing a compound of the general formula I

wherein:

R2 is hydrogen;

R3 is hydrogen;

R4, R5 are either identical or different and chosen from hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 3 )-alkyloxy-(C 1 -C 3 )-alkylene, hydroxy, (C 1 -C 6 )-alkylmercapto, amino, (C 1 -C 6 )-alkylamino, di-(C 2 -C 12 )-alkylamino, (C 1 -C 6 )-alkylcarbonyl, CO—OR7, trifluoromethyl, (C 1 -C 6 )-alkylsulfonyl, (C 1 -C 6 )-alkylsulfinyl, aminosulfonyl, pentafluorosulfanyl, (C 6 -C 10 )-aryl, CO—NR9R10, O—CO—NR9R10, O—CO—(C 1 -C 6 )-alkylene-CO—O—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-alkylene-CO—OH, O—CO—(C 1 -C 6 )-alkylene-CO—NR9R10 or unsubstituted or mono- or poly-F-substituted (C 1 -C 6 )-alkyloxy;

with the proviso that not more than one of the substituents R4 and R5 is halogen, trifluoromethyl or (C 1 -C 6 )-alkyl;

R7 is hydrogen, (C 1 -C 6 )-alkyl or benzyl;

and

Assignments (2)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

Reel/Frame 028413/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2008

From: ZOLLER, GERHARD; PETRY, STEFAN; MULLER, GUNTER; HEUER, HUBERT; TENNAGELS, NORBERT

To: SANOFI-AVENTIS

Reel/Frame 020678/0619 →