Propanolaminomethyltetralines, their preparation and pharmaceutical composition comprising same

• US 7,115,780 B2
• Filed: 12/02/2002
• Issued: 10/03/2006
• Est. Priority Date: 12/05/2001
• Status: Expired due to Fees

• Current Assignee: Sanofi-Aventis (Sanofi-Synthélabo SA)
• Original Assignee: Sanofi-Aventis (Sanofi-Synthélabo SA)
• Inventors: Cecchi, Roberto, Viviani, Nunzia, Barzaghi, Laura
• Primary Examiner(s): DAVIS, BRIAN J
• Application Number:
  US10/497,379
• Publication Number:
  US 20050054641A1
• Time in Patent Office: 1,401 Days
• Field of Search: None
• US Class Current: 564/308
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Abstract

The invention concerns compounds of formula (I), wherein A is a group of formula (a) or (b), wherein: R represents a hydrogen or halogen atom, a —S(O)_z(C₁–C₄)Alk wherein z is 0, 1 or 2, a —NHSO₂(C₁–C₄)Alk, —SO₂NH(C₁–C₄)Alk, —NHSO₂—(C₁–C₄)Alk-phenyl or —NHSO₂-phenyl group, said phenyl capable of bearing a halogen atom, a (C₁–C₄)Alk group or a (C₁–C₆)alkoxy group; R₁ represents a hydrogen atom or a —(C₁–C₄)Alk, —CO(C₁–C₄)Alk, —(C₁–C₄)Alk-phenyl or —CO-phenyl group, said phenyl capable of bearing a halogen atom or a —(C₁–C₄)Alk or (C₁–C₆)alkoxy group; R₂ is a hydrogen atom, a —SO₂(C₁–C₄)Alk, —SO₂—(C₁–C₄)Alk-phenyl, —SO₂-phenyl group, or a —(C₁–C₄)Alk group; X completes a saturated or unsaturated cycle of 5 to 8 atoms, capable of bearing one or two —(C₁–C₄)Alk groups and/or two carbonyl groups; R₃ and R′₃ represent each independently a hydrogen or halogen atom, a —(C₁–C₆)Alk, hydroxy, —CN, —(C₁–C₆)alkoxy, —COR₄ or Y—CR₈R₉—COR₄ group; Y represents O or CH₂; R₄ represents a hydroxy, (C₁–C₆)alkoxy or —NR₅R₆ group; R₅ and R₆ independently represent a hydrogen atom, a —(C₁–C₄)Alk, group, aryl or heteroaryl optionally substituted by a R₇ group, aralkyl or heteroaralkyl optionally substituted by a R₇ group; or R₅ and R₆, with the nitrogen atom which bears them, form a saturated or unsaturated cycle of 5 to 7 atoms optionally substituted by a R₇ group; and R₇ represents a hydrogen or halogen atom, a hydroxy, —(C₁–C₄)Alk, —(C₁–C₆)alkoxy, —NH(C₁–C₄)Alk, —N(C₁–C₄)Alk₂, —COO(C₁–C₄)Alk, aralkyl or heteroaryl group; R₈ and R₉ independently represent a hydrogen atom or a —(C₁–C₄)Alk group; their salts or solvates, the pharmaceutical compositions containing them, a method for preparing them and synthesis intermediates

Claims

1. A compound of formula (I):

2. A compound according to claim 1 wherein the configuration of the carbon of the propanolamine carrying the OH group is (S).

3. A compound according to claim 1 wherein A is a group of formula (a).

4. A compound according to claim 3 wherein R is an —

NHSO₂(C₁–

C₄)alk group.

5. A compound according to claim 4 wherein R₁ is a hydrogen atom.

6. A compound according to claim 1 wherein R₃ and/or R′

₃ are a hydrogen atom, a hydroxyl, —

(C₁–

C₆)alkoxy or —

Y—

CR₈R₉—

COOCH₂—

CH₃ group.

8. A process for preparing a compound according to claim 1 which comprises reacting a compound of formula (II)

9. A compound according to claim 2 wherein A is a group of formula (a).

10. A compound according to claim 9 wherein R is an —

NHSO₂(C₁–

C₄)alk group.

11. A compound according to claim 10 wherein R₁ is a hydrogen atom.

12. A compound according to claim 2 wherein R₃ and/or R′

₃ are a hydrogen atom, a hydroxyl, —

(C₁–

C₆)alkoxy or —

Y—

CR₈R₉—

COOCH₂—

CH₃ group.

13. A compound according to claim 3 wherein R₃ and/or R′

₃ are a hydrogen atom, a hydroxyl, —

(C₁–

C₆)alkoxy or —

Y—

CR₈R₉—

COOCH₂—

CH₃ group.

14. A compound according to claim 4 wherein R₃ and/or R′

₃ are a hydrogen atom, a hydroxyl, —

(C₁–

C₆)alkoxy or —

Y—

CR₈R₉—

COOCH₂—

CH₃ group.

15. A compound according to claim 5 wherein R₃ and/or R′

₃ are a hydrogen atom, a hydroxyl, —

(C₁–

C₆)alkoxy or —

Y—

CR₈R₉—

COOCH₂—

CH₃ group.

16. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound according to claim 11 together with a pharmaceutically acceptable excipient.

19. A pharmaceutical composition comprising a compound according to claim 15 together with a pharmaceutically acceptable excipient.

20. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1.

22. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 11.

23. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 15.

7. A compound selected from the group consisting of:

N-[2-Benzyloxy-5-({(2S)-2-hydroxy-3-[(1,2,3,4-tetrahydro-2-naphthalenylmethyl)amino]-propyl}oxy)phenyl]methane sulfonamide;

N-[2-Hydroxy-5-({(2S)-2-hydroxy-3-[(1,2,3,4-tetrahydro-2-naphthalenylmethyl)amino]propyl}oxy)phenyl]methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methane sulfonamide;

N-(2-Benzyloxy-5-{[(2S)-2-hydroxy-3-({[(2R)-6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl}amino)propyl]oxy}phenyl)methanesulfonamide;

N-(2-Hydroxy-5-{[(2S)-2-hydroxy-3-({[(2R)-6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl}amino)propyl]oxy}phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(6-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(6-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methane sulfonamide;

(2S)-1-[4-Benzyloxyphenoxy]-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}-2-propanol;

4-[((2S)-2-Hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenol;

Ethyl [(6-{[((2S)-3-{4-benzyloxy-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]methyl}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]acetate;

Ethyl [(6-{[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]-phenoxy}propyl)amino]methyl}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]acetate;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-[2-Benzyloxy-5-({(2S)-3-[(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-7-ylmethyl)amino]-2-hydroxypropyl}oxy)phenyl]methanesulfonamide;

N-[5-({(2S)-3-[(2,3,6,7,8,9-Hexahydronaphtho[2,3-b][1,4]dioxin-7-ylmethyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;

N-{2-Benzyloxy-5-[((2S)-3-{[(6,7-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-amino}-2-hydroxypropyl)oxy]phenyl}methanesulfonamide; and

N-{5-[((2S)-3-{[(6,7-Dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamide;

or a salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 7 together with a pharmaceutically acceptable excipient.

21. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 7.