IP Library › Granted Patent US 8,227,481

Granted Patent B2

US 8,227,481 · App. 13/151,946 · Granted Jul 24, 2012

Substituted piperidine spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof

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Quick Facts

Patent No.: US 8,227,481
App. No.: 13/151,946
Granted: Jul 24, 2012
Kind: B2

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Abstract

The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). wherein R 1 , R 2 , R 3 , m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor are disclosed.

Claims (128)

1. A compound of formula (I):

wherein

m is 1 or 2;

n is 1 or 2;

p is 1 or 2;

R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , or (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl;

R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ; and

R 3 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 6 )alkyloxycarbonyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heterocycloalkyl(C 1 -C 6 )alkyl, substituted or unsubstituted 5- or 6-membered ring heteroaryl(C 1 -C 6 )alkyl, substituted or unsubstituted benzyl, (C 1 -C 4 )alkoxymethylcarbonyl, substituted or unsubstituted (C 3 -C 7 )cycloalkanecarbonyl, substituted or unsubstituted benzylcarbonyl, substituted or unsubstituted (C 6 -C 10 )arylcarbonyl, substituted or unsubstituted 5 or 6-membered ring heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl, substituted or unsubstituted benzenesulfonyl, wherein the substituents are selected from halogen, trifluoromethoxy, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl and CF 3 ;

or a salt, enantiomer or diastereomer thereof.

2. The compound according to claim 1 , wherein

n, p, and m are 1;

R 1 is methyl, ethyl, isopropyl, n-propyl or methoxymethyl;

R 2 is hydrogen, fluorine, chlorine, methyl, ethyl or CF 3 ; and

R 3 is hydrogen, methoxyethylcarbonyl, tert-butyloxycarbonyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl, cyclopentane-carbonyl, cyclohexanecarbonyl, trifluoromethoxybenzoyl, fluorobenzoyl, benzyl-carbonyl, naphthylcarbonyl, benzenesulfonyl, fluorobenzene sulfonyl or methoxybenzenesulfonyl;

or a salt, enantiomer or diastereomer thereof.

3. The compound according to claim 1 , wherein

n is 2 and m is 1; or

n is 1 and m is 2;

p is 1 or 2;

R 1 is methyl or ethyl;

R 2 is hydrogen, fluorine, chlorine, methyl, ethyl or CF 3 ; and

R 3 is hydrogen, isopropyl, tert-butyloxycarbonyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl, tetrahydropyranylmethyl, cyclopentane carbonyl, cyclohexane carbonyl, tetrahydropyran carbonyl, benzoyl, trifluoromethoxybenzoyl, fluorobenzoyl, benzyl carbonyl, naphthyl carbonyl, pyridine carbonyl or furan carbonyl;

or a salt, enantiomer or diastereomer thereof.

4. The compound of claim 1 selected from the group consisting of:

2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;

2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;

4-{[2-fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylic acid tert-butyl ester;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl]-piperidin-1′-yl)-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-t-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

8-benzenesulfonyl-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-(4-methoxy-benzenesulfonyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

3-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

3-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(pyridine-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;

9-(furan-3-carbonyl)-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-(4-fluoro-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexanecarbonyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;

9-isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;

9-benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-(4-fluoro-benzoyl)-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclohexanecarbonyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-(4-fluoro-benzenesulfonyl)-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentanecarbonyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclohexylmethyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{2-fluoro-4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one;

8-(2-methoxy-acetyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(naphthalene-2-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;

8-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-(furan-3-carbonyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one; and

2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

or a salt thereof.

5. The compound of claim 1 selected from the group consisting of: