Pyridyl derivatives and their use as therapeutic agents

• US 8,383,628 B2
• Filed: 06/15/2010
• Issued: 02/26/2013
• Est. Priority Date: 07/29/2003
• Status: Expired due to Fees

• Current Assignee: Xenon Pharmaceuticals Inc.
• Original Assignee: Xenon Pharmaceuticals Inc.
• Inventors: Abreo, Melwyn, Harvey, Daniel F., Kondratenko, Mikhail A., Li, Wenbao, Kamboj, Rajender, Kodumuru, Vishnumurthy, Winther, Michael D., Gschwend, Heinz W., Chakka, Nagasree, Liu, Shifeng, Sviridov, Serguei, Sun, Shaoyi
• Primary Examiner(s): JARRELL, NOBLE E
• Application Number:
  US12/816,076
• Publication Number:
  US 20100305138A1
• Time in Patent Office: 987 Days
• Field of Search: None
• US Class Current: 514/253.01
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings

Abstract

Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I):

• • wherein W, V, x, y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^7a, R⁸, R^8a, R⁹, R^9a, R¹⁰ and R^10a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Claims

1. A compound of formula (III):

2. The compound of claim 1 wherein:

x and y are each 1;

V_a is —

C(O)—

;

R¹ is hydrogen or C₁-C₆alkyl;

R² is selected from the group consisting of C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂hydroxyalkyl, C₂-C₁₂hydroxyalkenyl, C₁-C₆alkoxy, C₃-C₁₂alkoxyalkyl, C₃-C₁₂cycloalkyl, C₄-C₁₂cycloalkylalkyl, aryl, C₇-C₁₉aralkyl, C₃-C₁₂ heterocyclyl, C₃-C₁₂heterocyclylalkyl, C₁-C₁₂heteroaryl and C₃-C₁₂heteroarylalkyl;

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C₁-C₆alkyl, C₁-C₆trihaloalkyl, C₁-C₆trihaloalkoxy, C₁-C₆alkylsulfonyl, —

N(R¹²)₂, —

OC(O)R¹², —

C(O)OR¹², —

S(O)₂N(R¹²)₂, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl;

R⁴, R⁵ and R⁶ are each hydrogen;

R⁷, R^7a, R⁸, R^8a, R⁹, R^9a, R¹⁰, and R^10a are each hydrogen; and

each R¹² is independently selected from hydrogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, aryl or aralkyl.

3. The compound of claim 2 wherein:

R² is C₁-C₁₂alkyl or C₂-C₁₂alkenyl; and

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆trihaloalkyl and C₁-C₆trihaloalkoxy.

4. The compound of claim 3 selected from the group consisting of the following:

Pentane-1-sulfonic acid {5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-amide; and

Hexane-1-sulfonic acid {5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-amide.

5. The compound of claim 2 wherein:

R² is C₇-C₁₂aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₃alkyl and C₁-C₆trihaloalkyl; and

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆trihaloalkyl and C₁-C₆trihaloalkoxy.

6. The compound of claim 5, namely, 3-Phenyl-propane-1-sulfonic acid {5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-amide.

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (III):

8. A compound of formula (IV):

9. The compound of claim 8 wherein:

x and y are each 1;

V_a is —

C(O)—

;

each R¹ is independently hydrogen or C₁-C₆alkyl;

R² is selected from the group consisting of C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂hydroxyalkyl, C₂-C₁₂hydroxyalkenyl, C₃-C₁₂alkoxyalkyl, C₃-C₁₂cycloalkyl, C₄-C₁₂cycloalkylalkyl, aryl, C₇-C₁₉aralkyl, C₃-C₁₂ heterocyclyl, C₃-C₁₂heterocyclylalkyl, C₁-C₁₂heteroaryl and C₃-C₁₂heteroarylalkyl;

R³ is selected from the group consisting of C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂hydroxyalkyl, C₂-C₁₂hydroxyalkenyl, C₂-C₁₂alkoxyalkyl, C₃-C₁₂cycloalkyl, C₄-C₁₂cycloalkylalkyl, aryl, C₇-C₁₉aralkyl, C₃-C₁₂heterocyclyl, C₃-C₁₂heterocyclylalkyl, C₁-C₁₂heteroaryl and C₃-C₁₂heteroarylalkyl;

R⁴, R⁵ and R⁶ are each hydrogen; and

R⁷, R^7a, R⁸, R^8a, R⁹, R^9a, R¹⁰, and R^10a are each hydrogen.

10. The compound of claim 9 wherein:

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C₁-C₆alkyl, C₁-C₆trihaloalkyl, C₁-C₆trihaloalkoxy, C₁-C₆alkylsulfonyl, —

N(R¹²)₂, —

OC(O)R¹², —

C(O)OR¹², —

S(O)₂N(R¹²)₂, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and

each R¹² is independently selected from hydrogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, aryl or aralkyl.

11. The compound of claim 10 wherein:

R² is C₁-C₁₂alkyl or C₂-C₁₂alkenyl; and

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆trihaloalkyl and C₁-C₆trihaloalkoxy.

12. The compound of claim 11 selected from the group consisting of the following:

1-(3-Methyl-butyl)-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea;

1-Pentyl-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea; and

1-Butyl-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea.

13. The compound of claim 10 wherein:

R² is C₇-C₁₂aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₃alkyl and C₁-C₆trihaloalkyl; and

R³ is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆trihaloalkyl and C₁-C₆trihaloalkoxy.

14. The compound of claim 13 selected from the group consisting of the following:

1-[3-(4-Fluoro-phenyl)-propyl]-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea;

1-Phenethyl-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea; and

1-Benzyl-3-{5-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridin-2-yl}-urea.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (IV):