Thema: Patent: N-heterocyclic derivatives as NOS inhibitors

United States Patent 6,982,259 - Davey , et al. - January 3, 2006

N-heterocyclic derivatives as NOS inhibitors

Abstract
N-Heterocyclic derivatives of the following formula: ##STR1##
where m, n, p, A1, R1, R2, R3 and R4 are described herein, as well as other N-heterocyclic derivatives, are useful as inhibitors of nitric oxide synthase. Pharmaceutical compositions containing these compounds, methods of using these compounds as inhibitors of nitric oxide synthase and processes for synthesizing these compounds are also described herein.

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What is claimed is:

1. A compound selected from formula (I) ##STR15##

wherein:

n is 0 to 2;

m is 0 to 1;

p is 0 to 2;

A1 is -O-, -CH2O- or -N(R6)-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

or R1 is (1,3-benzodioxol-5- yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy):

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein:

n is 0;

m is 0 to 1;

p is 0 to 2;

A1 is -O- or -CH2O-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocorbonyl, or dialkylaminocarbonyl; and

R8 is hydrogen or alkyl.

3. The compound of claim 2 selected from the group consisting of the following compounds:

3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

(3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

(3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

2-methoxycarbonyl-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

2-carboxy-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; and

2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine.

4. The compound of claim 1 wherein:

n is 0;

m is 0 to 1;

p is 0 to 2;

A1 is -O-; R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodaoxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl.

5. The compound of claim 4, namely, 3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)carbonyl]pyrrolidine.

6. The compound of claim 1 wherein:

n is 1 or 2;

m is 0 to 1;

p is 0 to 2;

A1 is -O-, -CH2-O- or -N(H)-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl.

7. The compound of claim 6 selected from the group consisting of the following compounds:

3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

(3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

(3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodiaxol-5-yl)methyl]piperidine;

3-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; and

3-[(4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1H-azepine.

8. A method of treating congestive heart failure, which method comprises administering to a mammal having congestive heart failure a therapeutically effective amount of a compound selected from the group consisting of the following formula: ##STR16##

wherein:

n is 0 to 2;

m is 0 to 1;

p is 0 to 2;

A1 is -O-,-CH2O- or -N(R6)-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

or R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

each R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound selected from formula (I) ##STR17##

wherein:

n 0 to 2;

m is 0 to 1;

p is 0 to 2;

A1 is -O-, -CH2O- or -N(R6)-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

or R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

each R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl; as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition of claim 9 wherein:

n is 0 ;

m is 0 to 1;

p is 0 to 2;

A1 is -O-, -CH2O-;

R1 is (1,3-benzodioxol-5-yl)alkl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl, and

R6 is hydrogen or alkyl.

11. The phamiaceutical composition of claim 10 wherein the compound is selected from the group consisting of the following compounds:

3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

(3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

(3R)-3-[(4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;

2-methoxycarbonyl-4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol)-5-yl)methyl]pyrrolidine;

2-carboxy-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; and

2-[(4-(imidazol-1-yl)phenoxy]methyl]-1-[(1,3benzodioxol-5-yl)methyl]pyrrolidine.

12. The pharmaceutical composition of claim 9 wherein:

n is 0;

m is 0 to 1;

p is 0 to 2;

A1 is -O-;

R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoolkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl.

13. The pharmaceutical composition of claim 12 wherein the compound is 3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)carbonyl]pyrrolidine.

14. The pharmaceutical composition of claim 9 wherein

n is 1 or 2;

m is 0 to 1;

p is 0 to 2;

A1 is -O-, -CH2-O- or -N(H)-;

R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy);

R2 is halo, haloalkyl, alkyl, or -OR6;

R3 is hydrogen or alkyl;

each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and

R6 is hydrogen or alkyl.

15. The pharmaceutical composition of claim 14 wherein the compound is selected from the group consisting of the following compounds:

3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

(3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

(3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

3-[4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;

3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; and

3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1H-azepine.