Substituted 3-(benzylamino)piperidine derivatives and their use as therapeutic agents

• US 6,214,846 B1
• Filed: 12/09/1999
• Issued: 04/10/2001
• Est. Priority Date: 06/27/1997
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Inventors: Elliott, Jason Matthew
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/445,664
• Time in Patent Office: 488 Days
• Field of Search: 514/314, 514/329, 514/331, 546/223
• US Class Current: 514/331
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

The present invention relates to compounds of formula (I), wherein R¹ represents a fluoroC_1-2alkoxy group; and R² represents a hydrogen or halogen atom or a C_1-4alkyl, C_1-4alkoxy, fluoroC_1-4alkyl or fluoroC_1-4alkoxy group; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.

Claims

1. A compound of the formula (I):

wherein

R¹ represents a fluoroC_1-2alkoxy group; and

R² represents a hydrogen or halogen atom or a C_1-4alkyl, C_1-4alkoxy, fluoroC_1-4alkyl or fluoroC_1-4alkoxy group;

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R¹ represents OCF₃, OCHF₂, OCH₂F or OCH₂CF₃.

3. A compound as claimed in claim 1 wherein R² represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or trifluoromethoxy group.

4. A compound as claimed in claim 1 of formula (Ia)

or a salt thereof.

5. The compound as claimed in claim 4 in the form of a pharmaceutically acceptable acid addition salt.

6. A compound as claimed in claim 1 in the form of its (2S,3S) stereoisomer.

8. A pharmaceutical composition comprising a therepeutically effective amount of a compound as claimed in claim 1, together with at least one pharmaceutically acceptable carrier or excipient.

9. A process for the preparation of a compound as claimed in claim 1 which comprises:

(A) reacting a compound of formula (II) with a compound of formula (III) in the presence of a reducing agent;

wherein R¹ and R² are as defined in claim 1, and R^a is a hydrogen atom or a nitrogen protecting group;

or

(B) reacting a compound of formula (IV) with a compound of formula (V);

 

wherein R¹ and R² are as defined in claim 1, R^a is a hydrogen atom or a nitrogen protecting group, and one of R³⁰ and R³¹ represents a leaving group and the other of R³⁰ and R³¹ represents NH₂;

in the presence of a base;

or

(C) reacting a compound of formula (VI)

with lithium naphthalenide in tetrahydrofuran;

each process being followed, where necessary, by the removal of any protecting group where present;

and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer;

and/or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof.

7. A compound which is selected from:

N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;

(2S,3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;

N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-(4-fluorophenyl)piperidin-3-amine;

or a pharmaceutically acceptable salt thereof.