IP Library › Granted Patent US 8,435,977

Granted Patent B2

US 8,435,977 · App. 12/765,675 · Granted May 7, 2013

Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

Inventors: Chris Flores (Spring House, PA); Marina Nelen (Spring House, PA); Erica Nulton (Spring House, PA); Stephen Prouty (Philadelphia, PA); Matthew Todd (Spring House, PA); Sui-Po Zhang (Radnor, PA)

Assignee: Janssen Pharmaceutica, NV

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Quick Facts

Patent No.: US 8,435,977
App. No.: 12/765,675
Granted: May 7, 2013
Kind: B2

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Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the inhibition of MGL, including pain. Such compounds are represented by Formula (I) as follows: wherein R 1 , W and are defined herein.

Claims (230)

1. A method of treating or ameliorating a disease, syndrome, condition or disorder that is affected by the inhibition of MGL, wherein the disease, syndrome, condition or disorder is selected from the group consisting of pain, inflammatory pain, and neuropathic pain, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)

selected from the group consisting of

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is 4-methylphenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-methoxyphenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is isobutyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is cyclopentylmethyl, and R 3 is methyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is cyclohexylmethyl, and R 3 is hydrogen;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 2-methoxyphenylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is n-propyl, and R 3 is methyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is t-butyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-methoxyphenyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is isobutyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is CH, R 1 is 4-fluoro,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is t-butyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —NH—C(R 2 )—C(R 3 )—, R 2 is 4-methylphenyl and R 3 is methoxy-methyl-carbonyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 ), R 2 is n-propyl and R 3 is cyclohexylmethyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

2. A method as in claim 1 , wherein the compound of formula (I) is selected form the group consisting of

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is 4-methylphenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-methoxyphenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is isobutyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is cyclopentylmethyl, and R 3 is methyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is cyclohexylmethyl, and R 3 is hydrogen;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 2-methoxyphenylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is n-propyl, and R 3 is methyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

3. A method as in claim 1 , wherein the compound of formula (I) is selected form the group consisting of

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is 4-methylphenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-methoxyphenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 ), R 2 is n-propyl and R 3 is cyclohexylmethyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

4. A method as in claim 1 , wherein the compound of formula (I) is selected form the group consisting of

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-methoxyphenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenoxymethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is cyclopentylmethyl, and R 3 is methyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenyl, and R 3 is isobutyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-methoxyphenyl;

a compound wherein W is CH, R 1 is 2-methoxy,

X—Y—Z is —CH—C(R 2 )—N(R 3 )—, R 2 is phenylmethyl, and R 3 is cyclohexylmethyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —NH—C(R 2 )—C(R 3 )—, R 2 is 4-methylphenyl and R 3 is methoxy-methyl-carbonyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —CH—C(R 2 )—N(R 3 ), R 2 is n-propyl and R 3 is cyclohexylmethyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

5. A method as in claim 1 , wherein the compound of formula (I) is selected form the group consisting of

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 3-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is 4-fluorophenyl;

a compound wherein W is N, R 1 is H,

X—Y—Z is —O—C(R 2 )═N—, and R 2 is t-butyl;

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.

6. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is pain.

7. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is inflammatory pain.

8. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is visceral pain.

9. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is neuropathic pain.

10. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is neuropathic cold allodynia.

11. A method as in claim 1 , wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is selected from the group consisting of inflammatory pain and neuropathic pain.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 13, 2011

From: FLORES, CHRISTOPHER M.; NELEN, MARINA I.; NULTON, ERICA L.; PROUTY, STEPHEN M.; ZHANG, SUI-PO; TODD, MATTHEW

To: JANSSEN PHARMACEUTICA NV

Reel/Frame 027056/0185 →

Continuity (3)

Provisional Application 61171661 · Apr 22, 2009

Provisional Application 61171660 · Apr 22, 2009

Related Publication 20100324016A1 · Dec 23, 2010