COMPOUNDS AND METHODS FOR THE TREATMENT OF GASTROINTESTINAL AND CENTRAL NERVOUS SYSTEM DISORDERS

• US 20080085915A1
• Filed: 06/20/2007
• Published: 04/10/2008
• Est. Priority Date: 06/23/2006
• Status: Abandoned Application

• Current Assignee: ARYx Therapeutics, Inc.
• Original Assignee: ARYx Therapeutics, Inc.
• Inventors: Rubens, Courtney, Becker, Cyrus
• Application Number:
  US11/765,554
• Publication Number:
  US 20080085915A1
• Time in Patent Office: Days
• US Class Current: 514/305
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

The subject invention provides stereoisomeric compounds of formula (X): wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.

Claims

1. A compound of the formula:

2. A compound according to claim 1, wherein

R₁ is chloro.

3. A compound according to claim 1, wherein

R₂ is amino.

4. A compound according to claim 1, wherein

R₃ is methoxy.

5. A compound according to claim 1, wherein

R₄ is H.

6. A compound according to claim 1, wherein

R₁ is chloro;

R₂ is amino;

R₃ is methoxy;

R₄ is H, and R₁, R₂, and R₃ have the following orientation on the phenyl ring;

7. A Compound according to claim 6, wherein

L is —

(C₁-C₄ alkyl)-NR₉—

(C₁-C₄ alkyl)-, —

(C₁-C₄ alkyl)-C(O)NR₉—

, or —

(C₁-C₄ alkyl)-.

8. A compound according to claim 7, having the formula:

9. A compound according to claim 8, wherein

the bonds at positions 3 and 4 of the piperidinyl ring are cis to each other.

10. A compound according to claim 9, wherein

R₁₇ is attached at the para position, relative to the point of attachment of the L group.

11. A compound according to claim 10, wherein

L is —

(C₁-C₃ alkyl)-NR₉—

(C₁-C₃ alkyl)-;

R₁₀ is H, C₁-C₄ alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, —

C(O)NH₂, or piperidinyl optionally substituted with C₁-C₃ alkyl;

R₁₇ is OH, —

O—

C₂-C₄ alkanoyl, —

CO₂R₁₀, or —

(C₁-C₄ alkyl)-CO₂R₁₀; and

R₁₈ is H.

12. A compound according to claim 11, having the formula:

13. A compound according to claim 10, wherein

L, is —

(C₁-C₃ alkyl)-C(O)NR₉—

;

R₁₀ is H, C₁-C₄ alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, —

C(O)NH₂, or piperidinyl optionally substituted with C₁-C₃ alkyl;

R₁₇ is OH, —

O—

C₂-C₄ alkanoyl, —

CO₂R₁₀, or —

(C₁-C₄ alkyl)-CO₂R₁₀; and

R₁₈ is H.

14. A compound according to claim 13, having the formula:

15. A compound according to claim 10, wherein

L is —

(C₁-C₃ alkyl)-;

R₁₀ is H, C₁-C₄ alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, —

C(O)NH₂, or piperidinyl optionally substituted with C₁-C₃ alkyl;

R₁₇ is OH, —

O—

C₂-C₄ alkanoyl, —

CO₂R₁₀ or —

(C₁-C₄ alkyl)-CO₂R₁₀; and

R₁₈ is H.

16. A compound according to claim 15, having the formula:

17. A compound according to claim 10, wherein

L, is —

(C₁-C₄ alkyl)-NR₉C(O)—

;

R₁₀ is H, C₁-C₄ alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, —

C(O)NH₂, or piperidinyl optionally substituted with C₁-C₃ alkyl;

R₁₇ is OH, —

O—

C₂-C₄ alkanoyl, —

CO₂R₁₀, or —

(C₁-C₄ alkyl)-CO₂R₁₀; and

R₁₈ is H.

18. A compound according to claim 17, having the formula:

19. A compound according to claim 1, that is

2-(pyrrolidin-1-yl)ethyl 4-(((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl)(methyl)amino)methyl)benzoate;

1-methylpiperidin-4-yl 4-(((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl)(methyl)amino)methyl)benzoate;

2-morpholinoethyl 4-(((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl)(methyl)amino)methyl)benzoate;

4-((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethylamino)methyl)benzoic acid;

3-hydroxypropyl 4-((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethylamino)methyl)benzoate;

piperidin-4-yl 4-((2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethylamino)methyl)benzoate;

4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethylcarbamoyl)benzoic acid;

piperidin-4-yl 4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethylcarbamoyl)benzoate;

2-(4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl)acetic acid;

ethyl 2-(4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl)acetate;

1-methylpiperidin-4-yl 2-(4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl)acetate;

3-hydroxypropyl 2-(4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl)acetate;

quinuclidin-3-yl 2-(4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl)acetate;

4-amino-5-chloro-N-((3S,4R)-1-(2-(4-hydroxyphenylamino)-2-oxoethyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamide;

4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)phenyl acetate;

4-(3-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)propyl)benzoic acid;

2-morpholinoethyl 4-(3-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)propyl)benzoate;

2-(pyrrolidin-1-yl)ethyl 4-(3-((3S,4R)-4-(4 amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)propyl)benzoate;

1-methylpiperidin-4-yl 4-(3-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)propyl)benzoate;

2-hydroxyethyl 4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)benzoate;

2-amino-2-oxoethyl 4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido) 3-methoxypiperidin-1-yl)acetamido)benzoate;

2-(piperazin-1-yl)ethyl 4-(2-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)acetamido)benzoate;

or pharmaceutically acceptable salts thereof.

20. A composition comprising a compound or pharmaceutically acceptable salt of claim 1 and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

21. A method of treating emesis, dyspepsia, gastroparesis, constipation, intestinal pseudo-obstruction, gastroesophageal reflux, or post-operative ileus, the method comprising administering a compound or salt according to claim 1 to a patient in need of such treatment.

22. A method according to claim 21, wherein the compound or salt is administered intra venously.