1-PHENETHYLPIPERIDINE DERIVATIVES AND THEIR USE AS OPIOID RECEPTOR LIGANDS

• US 20100234427A1
• Filed: 02/13/2007
• Published: 09/16/2010
• Est. Priority Date: 02/17/2006
• Status: Abandoned Application

• Current Assignee: Neurosearch AS
• Original Assignee: Neurosearch AS
• Inventors: Peters, Dan, Munro, Gordon, Redrobe, John Paul, Nielsen, Elsebet Østergaard, Eriksen, Birgitte L.
• Application Number:
  US12/161,309
• Publication Number:
  US 20100234427A1
• Time in Patent Office: Days
• US Class Current: 514/330
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: C07D 211/26 : with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links

Abstract

This invention relates to novel 1-phenethylpiperidine derivatives useful as opioid receptor ligands. More specifically, the invention provides compounds useful as μ opioid receptor ligands.

In other aspects the invention relates to the use of these compounds in a method for therapy, such as for the treatment of pain, and to pharmaceutical compositions comprising the compounds of the invention.

Claims

1. A compound of Formula I:

any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof;

wherein

n is 1 or 2;

R^a represents hydrogen, alkyl or R^d;

which alkyl is optionally substituted with one or more substituents independently selected from the group consisting of;

halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cyclo alkyl, cycloalkylalkyl, alkenyl and alkynyl;

R^b represents R^e or —

CH₂—

R^e;

R^c represents R^f, —

CH═

CH—

R^f or —

CH═

CH₂; and

R^d, R^e and R^f independent of each other represent an aryl group;

which aryl group is optionally substituted with one or more substituents independently selected from the group consisting of;

halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —

NR′

R″

, —

(C═

O)NR′

R″

or —

NR′

(C═

O)R″

;

wherein R′ and

R″

independent of each other are hydrogen or alkyl.

2. The compound according to claim 1 being a compound of formula II:

any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof;

wherein

R^a represents hydrogen, alkyl or R^d;

which alkyl is optionally substituted with one or more substituents independently selected from the group consisting of;

halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; and

R^b, R^c and R^d independent of each other represent an aryl group;

which aryl group is optionally substituted with one or more substituents independently selected from the group consisting of;

halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —

NR′

R″

, —

(C═

O)NR′

R″

or —

NR′

(C═

O)R″

;

wherein R′ and

R″

independent of each other are hydrogen or alkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^a represents alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^b represents an optionally substituted phenyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^c represents an optionally substituted phenyl.

6. A compound of claim 1 which is

N-(4-Chloro-phenyl)-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-(3-Methoxy-phenyl)-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-Benzo[1,3]dioxol-5-yl-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-Benzo[1,3]dioxol-5-yl-N-{1-[2-(4-chloro-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-(4-Methoxy-phenyl)-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-{1-[2-(4-Chloro-phenyl)-ethyl]-piperidin-4-ylmethyl}-N-(4-methoxy-phenyl)-propionamide;

N-{1-[2-(4-Chloro-phenyl)-ethyl]-piperidin-4-ylmethyl}-N-(3-methoxy-phenyl)-propionamide;

N-(1-But-3-enyl-piperidin-4-ylmethyl)-N-phenyl-propionamide;

N-Phenyl-N-[1-((E)-3-phenyl-allyl)-piperidin-4-ylmethyl]-propionamide;

N-{1-[2-(4-Fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-N-phenyl-propionamide;

N-{1-[2-(3-Fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-N-phenyl-propionamide;

N-(4-Fluoro-phenyl)-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-(4-Fluoro-phenyl)-N-{1-[2-(3-fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-(4-Fluoro-phenyl)-N-{1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-(4-Fluoro-phenyl)-N-{1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-(3-Fluoro-phenyl)-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-(3-Fluoro-phenyl)-N-{1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-(3-Fluoro-phenyl)-N-{1-[2-(3-fluoro-phenyl)-ethyl]-piperidin-4-ylmethyl}-propionamide;

N-Benzyl-N-(1-phenethyl-piperidin-4-ylmethyl)-propionamide;

N-(1-Phenethyl-piperidin-4-ylmethyl)-N-phenyl-acetamide;

N-(1-Phenethyl-piperidin-4-yl-methyl)-N-phenyl-propionamide;

N-(1-Benzyl-piperidin-4-ylmethyl)-N-phenyl-propionamide;

N-[1-(4-Chloro-benzyl)-piperidin-4-ylmethyl]-N-phenyl-propionamide;

N-{1-[2-(4-Chloro-phenyl)-ethyl]-piperidin-4-ylmethyl}-N-phenyl-propionamide;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.

9. The method according to claim 10, wherein the disease, disorder or condition responsive to modulation of the opioid receptor is pain, postoperative pain, chronic pain, cancer pain, neuropathic pain, pain during labour and delivery, migraine, drug addiction, heroin addiction, cocaine addiction, alcoholism, irritable bowel syndrome, constipation, nausea, vomiting, pruritic dermatoses, allergic dermatitis, atopy, eating disorders, opiate overdoses, depression, smoking, sexual dysfunction, shock, stroke, spinal damage, head trauma, diarrhoea, urinary incontinence and inflammatory reactions.

10. A method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to responsive to modulation of the opioid receptor, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound according to claim 1, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

8. (canceled)