ANTIDEPRESSANT HETEROARYL DERIVATIVES OF HETEROCYCLE-FUSED BENZODIOXANS

• US 20090042874A1
• Filed: 05/29/2008
• Published: 02/12/2009
• Est. Priority Date: 05/30/2007
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Mogish, Juliann, Nikitenko, Antonina, Evrard, Deborah, Hatzenbuhler, Nicole T., Zhou, Ping, Failli, Amedeo A., Li, Yanfang, Gunawan, Iwan S.
• Application Number:
  US12/128,930
• Publication Number:
  US 20090042874A1
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: C07D 491/12 in which the condensed system contains three hetero rings

Abstract

The invention provides compounds of the Formula:

that are useful for the treatment of 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, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

Claims

1. A compound having the Formula I:

or pharmaceutically-acceptable salt thereof;

wherein;

G is a carbon atom having a hydrogen atom attached thereto, wherein the carbon atom can have either the R or S configuration;

R₁ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;

the group X—

Y₁ is —

N═

C(R₂)—

C(R₃)═

N—

, —

N═

C(R₂)—

C(R₄)═

CH—

, —

N═

C(R₂)—

N═

CH—

, or —

N═

C(R₂)—

O—

;

R₂ and R₃ are, independently, hydrogen, hydroxy, C_1-12 alkoxy, halo, C_1-6 alkyl, amino, or mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms;

R₄ is hydrogen or C_1-6 alkyl;

A is -Q₁-Q₂-;

Q₁ is —

N(R₈)—

,

wherein;

J is NH;

k is 0 or 1;

L₁ is N, or CH;

L₂is N or CH;

R₆ is hydrogen or C_1-12 alkyl;

R₈ is hydrogen, C_1-12 alkyl C_4-20 alkylcycloalkyl, or C_3-8 cycloalkyl;

n is 1, 2 or 3;

y is 1 or 2, provided that when y is 2, n is 1;

provided that when k is 1, then L₁ is CH;

Q₂ has the Formula III or IV;

wherein;

each R_6a and each R_6b is independently hydrogen or C_1-12 alkyl;

each R₇ is independently hydrogen or C_1-12 alkyl;

X₁ is O, NH or —

(CH₂)_v—

where v is 1, 2, 3 or 4;

r is 0, 1, 2, 3 or 4;

s is 0 or 1;

t is 0, 1, 2 or 3;

provided that when when Q₂ has the Formula IV where X₁ is O or (CH₂)_v then Q₁ is N(R₈);

B has the Formula;

wherein;

R₁₀ is hydrogen, C_1-12 alkyl or C_4-20 alkylcycloalkyl, (CH₂)x-cycloalkyl;

L₃ is —

C(═

W′

)—

or CH₂;

W′

is O or S;

W is O, CH₂ or

Z is O, CH₂ S or SO₂;

R₁₁ is hydrogen, C_1-12alkyl, cyano or halogen;

provided that Z and W are not both O; and

provided that W is not O when Z is S or SO₂.

2. A compound, or pharmaceutically acceptable salt thereof, -or pharmaceutically acceptable salt thereof, according to claim 1, wherein:

—

X—

Y₁—

is —

N═

C(R₂)—

C(R₄)═

CH—

;

R₁ is hydrogen;

—

X—

Y₁—

is —

N═

C(R₂)—

C(R₄)═

CH—

;

R₂ is hydrogen or C_1-4 alkyl;

R₄ is hydrogen or C_1-4 alkyl;

A is Q₁-Q_2, where

Q₁ is —

N(R₈)—

,

where R₈ is hydrogen or C_1-4 alkyl;

Q₂ is —

O—

, or —

(CH₂)_v—

where v is 1 or 2;

B is

where

R₁₀ is hydrogen or C_1-4 alkyl;

L₃ is C=O;

W is CH₂;

Z is C or O; and

R₁₁ is hydrogen or halogen.

3. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, according to claim 2, wherein Q1 is N(R8).

4. A compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein

Q₁ is

where J is NH, k is 1.

5. A compound or pharmaceutically acceptable salt thereof, of claim 4, wherein L₁ is CH, y is 1, L₂ is N, R₆ is H, and n is 2.

6. A compound or pharmaceutically acceptable salt thereof, of claim 5, wherein r, s, and t of Q₂ are each 0.

7. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, of claim 2, wherein

Q1 is

8. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, according to claim 7, wherein Q₂ is —

O—

.

9. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, according to claim 7, wherein Q₂ is —

CH2—

.

10. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, according to claim 2, wherein

Q1 is

11. A compound, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, according to claim 10, wherein Q2 is —

O—

.

12. A compound, or pharmaceutically acceptable salt thereof, according to claim 10, wherein Q2 is —

(CH2)_v—

where v is 1 or 2.

13. A compound, or pharmaceutically acceptable salt thereof, according to claim 2, wherein

Q1 is

14. A compound, or pharmaceutically acceptable salt thereof, of claim 13, wherein Q2 is —

O—

.

15. A compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein

Q1 is

16. A compound, or pharmaceutically acceptable salt thereof, of claim 15, wherein Q2 is —

CH2—

.

17. The compound of claim 1, wherein Z is O;

W is CH₂; and

L₃ is —

C(═

W′

)—

wherein W′

is O.

18. The compound of claim 1, wherein Z is O;

W is CH₂;

L₃ is —

C(═

W′

)—

wherein W′

is O; and

R₁₀ is hydrogen or C_1-6 alkyl.

19. The compound of claim 1, wherein the group X—

Y₁ is —

N═

C(R₂)—

C(R₃)═

N—

.

20. The compound of claim 1, wherein the group X—

Y₁ is —

N═

C(R₂)—

C(R₄)═

CH—

.

21. The compound of claim 1, wherein the group X—

Y₁ is —

N═

C(R₂)—

N═

CH—

.

22. The compound of claim 1, wherein the group X—

Y₁ is —

N═

C(R₂)—

O—

.

23. The compound of claim 20, wherein Z is O;

W is CH₂;

L₃ is —

C(═

W′

)—

wherein W′

is O.

24. The compound of claim 23, wherein R₁₀ is hydrogen or C_1-6 alkyl;

R₁₁ is hydrogen;

R₂ is methyl; and

R₄ is hydrogen.

25. The compound of claim 23, wherein Q₁ has the Formula II;

and Q₂ has the Formula III.

26. The compound of claim 23, wherein Q₁ is —

N(R₈)—

.

27. The compound of claim 26, wherein Q₂ has the Formula IV, wherein X₁ is O or CH₂.

28. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 2, 3, or 4;

s is 1;

X₁ is NH; and

t is 1.

29. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 3;

s is 1;

X₁ is O; and

t is 0.

30. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 2;

s is 1;

X₁ is O; and

t is 0.

31. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 3;

s is 0; and

t is 0.

32. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 2, 3 or 4;

s is 0; and

t is 0.

33. The compound of claim 26, wherein Q₂ has the Formula III, wherein r is 3 or 4;

s is 1;

X₁ is O; and

t is 0.

34. The compound of claim 25, wherein Q₁ has the Formula:

35. The compound of claim 34, wherein Q₂ is O, CH₂ or CH₂CH₂.

36. The compound of claim 35, wherein R₁₀ is hydrogen or C_1-6 alkyl.

37. The compound of claim 36, wherein R₂ is methyl, and R₄ is hydrogen.

38. The compound of claim 25, wherein Q₁ has the formula:

39. The compound of claim 38, wherein Q₂ is O, CH₂ or CH₂CH₂.

40. The compound of claim 25, wherein Q₁ has the formula:

41. The compound of claim 40, wherein Q₂ is O, CH₂ or CH₂CH₂.

42. The compound of claim 1, wherein the carbon atom of said G has the S configuration.

43. The compound of claim 42, wherein said compound is substantially free of the R enantiomer of said compound.

44. The compound of claim 1, having one of the following Formulas:

or a pharmaceuticall acceptable salt thereof.

45. A method of treating a subject suffering from a condition selected from 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, comprising the step of:

administering to said subject suffering from said condition, a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition, comprising:

an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier or excipient.

47. A method comprising the step of:

a) reacting a compound of Formula S1;

wherein;

G is a carbon atom having a hydrogen atom attached thereto, wherein the carbon atom can have either the R or S configuration;

R is a an appropriately substituted phenyl moiety;

R₁ is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;

the group X—

Y₁ is —

N═

C(R₂)—

C(R₃)═

N—

, —

N═

C(R₂)—

C(R₄)═

CH—

, —

N═

C(R₂)—

N═

CH—

, or —

N═

C(R₂)—

O—

;

R₂ and R₃ are, independently, hydrogen, halo, C_1-6 alkyl, amino, or mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms;

R₄ is hydrogen or C_1-6 alkyl;

with a compound of Formula S2;

wherein;

R₁₀ is hydrogen, C_1-12 alkyl or (CH₂)_xcycloalkyl), where x is 4-20;

L₃ is —

C(═

W′

)—

or CH₂;

W′

is O or S;

W is O CH₂ or

Z is O CH₂ S, or SO₂;

R₁₁ is hydrogen, C_1-12alkyl, cyano or halogen;

provided that Z and W are not both O; and

provided that W is not O when Z is S or SO₂;

for a time and under conditions effective to form a compound of Formula S3;

48. A method comprising the step of:

a) reacting a compound of Formula S10;

wherein;

G is a carbon atom having a hydrogen atom attached thereto, wherein the carbon atom can have either the R or S configuration;

R₁ is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;

the group X—

Y₁ is —

N═

C(R₂)—

C(R₃)═

N—

, —

N═

C(R₂)—

C(R₄)═

CH—

, —

N═

C(R₂)—

N═

CH—

, or —

N═

C(R₂)—

O—

;

R₂ and R₃ are, independently, hydrogen, halo, C_1-6 alkyl, amino, or mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms;

R₄ is hydrogen or C_1-6 alkyl;

with a compound of Formula S11;

wherein;

R₁₀ is hydrogen, C_1-12 alkyl or C_4-20 alkylcycloalkyl;

L₃ is —

C(═

W′

)—

or CH₂;

W′

is O or S;

W is O, CH₂ or

Z is O, CH₂ S or SO₂;

R₁₁ is hydrogen, C_1-12alkyl, cyano or halogen;

provided that Z and W are not both O; and

provided that W is not O when Z is S or SO₂;

for a time and under conditions effective to form a compound of Formula S12;

49. A method of preparing a compound of formula I

or pharmaceutically-acceptable salt thereof;

wherein;

G is a carbon atom having a hydrogen atom attached thereto, wherein the carbon atom can have either the R or S configuration;

R₁ is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;

the group X—

Y₁ is —

N═

C(R₂)—

C(R₃)═

N—

, —

N═

C(R₂)—

C(R₄)═

CH—

, —

N═

C(R₂)—

N═

CH—

, or —

N═

C(R₂)—

O—

;

R₂ and R₃ are, independently, hydrogen, hydroxy, C_1-12 alkoxy, halo, C_1-6 alkyl, amino, or mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms;

R₄ is hydrogen or C_1-6 alkyl;

A is -Q₁-Q₂-;

Q₁ is a group of Formula II;

wherein;

J is NH;

k is 1;

L₁ is CH;

L₂ is N;

R₆ is hydrogen;

R₈ is hydrogen, C_1-12 alkyl C_4-20 alkylcycloalkyl, or C_3-8 cycloalkyl;

n is 2;

y is 1;

Q₂ has the Formula III

wherein;

each R_6a and each R_6b is independently hydrogen or C_1-12 alkyl;

each R₇ is independently hydrogen or C_1-12 alkyl;

X₁ is O, NH or —

(CH₂)_v—

where v is 1, 2, 3 or 4;

r is 0;

s is 0;

t is 0;

provided that when when Q₂ has the Formula IV where X₁ is O or (CH₂)_v then Q₁ is N(R₈);

B has the Formula;

wherein;

R₁₀ is hydrogen, C_1-12 alkyl or C_4-20 alkylcycloalkyl, (CH₂)_x-cycloalkyl;

L₃ is —

C(═

W′

)—

or CH₂;

W′

is O or S;

W is O, CH₂ or

Z is O, CH₂ S or SO₂;

R₁₁ is hydrogen, C_1-12alkyl, cyano or halogen;

provided that Z and W are not both O; and

provided that W is not O when Z is S or SO₂;

comprising the steps of;

treating the resultant product with acid to yield

performing reductive amination with a compound of formula

to produce a compound of formula I.