Antidepressant azaheterocyclylmethyl derivatives of 7,8-dihydro-6H-5-oxa-1-aza-phenanthrene

• US 20030078268A1
• Filed: 07/24/2002
• Published: 04/24/2003
• Est. Priority Date: 07/25/2001
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Zhao, Rulin, Stack, Gary P., Tran, Megan, Mewshaw, Richard E.
• Granted Patent: US 6,903,110 B2
• Time in Patent Office: Days
• US Class Current: 514/250
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Compounds of the formula

useful for the treatment of such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addition, sexual dysfunction (including premature ejaculation), and related illnesses.

Claims

1. A compound of formula I

2. A compound of claim 1 wherein R¹ is hydrogen, hydroxy, halo, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms.

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

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

5. A compound of claim 1 wherein R¹, R², R³, R⁴ and R⁵ are, independently selected from hydrogen, halogen and cyano.

6. A compound of claim 1 wherein A═

D is —

CH═

CH—

.

7. A compound of claim 1 wherein Z is CR⁸.

8. A compound of claim 7 wherein R⁸ is hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms.

9. A compound of claim 1 in which R¹ is hydrogen, hydroxy, halo, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms;

R² is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;

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

n is an integer 0 or 1; and

A═

D is CR⁹═

CH and R⁹ is H;

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 2 in which R² and R⁶ are hydrogen, and R³, R⁴ and R⁵ are independently selected from hydrogen, halo and cyano, n is 0 and the dotted line represents a double bond;

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 which is the R stereoisomer substantially free of the S stereoisomer.

12. The compound of claim 1 which is 6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 which is (6S)-6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 which is (6R)-6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene or a pharmaceutically acceptable salt thereof.

15. An intermediate of the formula

16. A compound of claim 15 which is:

Toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester;

(6S)-Toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester;

or

(6R)-Toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester.

18. The method of claim 16 wherein the condition is depression.

19. The method of claim 16 wherein the condition is obsessive compulsive disorder, panic attacks, generalized anxiety disorder or social anxiety disorder.

17. 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 such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addition, sexual dysfunction, and related illnesses which comprises providing to the subject suffering from said condition, a therapeutically effective amount of a compound of formula I

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I