Antidepressant azaheterocyclylmethyl derivatives of 2,3-dihydro-1,4-benzodioxan

• US 20020193400A1
• Filed: 04/23/2002
• Published: 12/19/2002
• Est. Priority Date: 04/24/2001
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Cliffe, Ian A., Stack, Gary P., Mewshaw, Richard E., Husbands, George E.M.
• Granted Patent: US 6,559,169 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Compounds of the formula

useful for the treatment of depression and other conditions such as obsessive compulsive disorder, panic attacks, generalized anxiety disorder, sexual dysfunction, eating disorders, addictive disorders caused by ethanol or cocaine abuse and related illnesses.

Claims

1. A compound of formula I

2. A compound of claim 1 wherein R¹ is hydrogen, halo, cyano, carboxamido, trifluoromethyl, amino, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms.

3. A compound of claim 1 wherein R² is hydrogen, halo, cyano, carboxamido, trifluoromethyl, amino, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms.

4. A compound of claim 1 wherein one of R¹ and R² is hydrogen and the other one of R¹ and R² is hydrogen, amino, alkoxy, halogen, or carboxamido.

5. A compound of claim 4 wherein R¹ is alkoxy of one to six carbon atoms and is attached to position 8 of the benzodioxan moiety.

6. A compound of claim 1 wherein R³, R⁴ and R⁵ are independently selected from hydrogen, halo, cyano, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms.

7. A compound of claim 1 wherein n is 0 or 1.

8. A compound of claim 1 in which R¹ and R² are, independently, hydrogen, halo, cyano, carboxamido, trifluoromethyl, amino, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;

R³, R⁴ and R⁵ are independently selected from hydrogen, halo, cyano, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms;

n is an integer 0 or 1;

or a pharmaceutically acceptable salt thereof.

9. A compound of claim 8 wherein X is CR⁷ and R⁷ is hydrogen, halo, cyano, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms.

10. A compound of claim 1 in which R¹ is alkoxy of one to six carbon atoms and is attached to position 8 of the benzodioxan moiety, R² and R⁴ are hydrogen, R³, R⁴ and R⁵ are independently selected from hydrogen, halo and cyano, X is CR⁷, R⁷ is hydrogen, halo, cyano, n is 0 and the dotted line represents a double bond;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 which 5-methoxy-3-[4-[1,2,3,6-tetrahydro-1-[2-(2,3-dihydro[1,4]benzodioxinyl)]methyl]pyridinyl]indole or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 which is 5-fluoro-3-[4-[1,2,3,6-tetrahydro-1-[2-(2,3-dihydro[1,4]benzodioxinyl)]methyl]pyridinyl]indole or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 which is 3-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-7-ylamine or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 which is 2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ylamine or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 which 3-[1-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 which 2-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ylamine or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 which 3-[1-(8-methoxy-2,3-dihydro-benzo-[1,4]dioxin-2-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 which 3-[1-(8-methoxy-2,3-dihydro-benzo[1,4]-dioxin-2-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 which 6-fluoro-3-[1-(8-methoxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 which is 3-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 which is 3-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 which is 3-(1-{[8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 which is 3-(1-{[7-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 which is 5-fluoro-3-[1-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole or a pharmaceutically acceptable salt thereof.

26. The method of claim 25 wherein the condition is depression.

27. The method of claim 25 wherein the condition is obsessive compulsive disorder, panic attacks, generalized anxiety disorder or social anxiety disorder.

28. The method of claim 25 wherein the subject is a human.

25. A method of treating a subject suffering from a condition selected from the group consisting of depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol addiction, and sexual dysfunction, which comprises providing to the subject suffering from said condition, a therapeutically effective amount of a compound of formula I

29. A pharmaceutical composition comprising a compound of the formula I