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US 2004/0023950 A1Published application
N-heterocyclic derivatives as NOS inhibitors
AssigneeSchering Corporation
InventorsDavid D. Davey, Raju Mohan, Gary B. Phillips, Guo Ping Wei, Wei Xu
Life of this patent
Estimating the term…
Abstract
N-Heterocyclic derivatives of the following formula: 1 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.
Claims36
A compound selected from the group consisting of the following formulae:
- 15
- wherein:
- each n is 0 to 2;
- each m is 0 to 4;
- each p is 0 to 2;
- A1 is —O—(CH2)q— (where q is 0 to 3), —(CH2)q—O— (where q is 0 to 3), —N(R6)—(CH2)q— (where q is 0 to 3) or —(CH2)q—N(R6)— (where q is 0 to 3);
- A2 is —(CH2)q—O— (where q is 2 to 3);
- R1 is hydrogen, alkyl, —(CH2)t—C(O)OR7 (where t is 0 to 6), —(CH2)t—C(O)N(R6)R7 (where t is 0 to 6), or —C(O)R7;
- or R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R1 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R2 is independently halo, haloalkyl, alkyl, nitro, —OR6, —C(O)OR6, —C(O)N(R6)R7, —N(R6)R7, —N(R6)C(O)R7, or —N(H)S(O)2R8;
- each R3 is independently hydrogen or alkyl;
- each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl;
- R5 is hydrogen, alkyl, aralkyl, —(CH2)m—C(O)—OR9 (where m is 1 to 4), —(CH2)m—C(O)—N(R9)R10 (where m is 1 to 4), or heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R6 and R7 is independently hydrogen, alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- each R8 is alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R9 is independently hydrogen, alkyl or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- R10 is hydrogen, alkyl, or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R10 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
- or
- a pharmaceutically acceptable salt thereof.
21 more elements
A pharmaceutical composition useful in treating a condition in a mammal resulting from an abnormality in nitric oxide production, which composition comprises a pharmaceutically excipient excipient and a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- 19
- wherein:
- each n is 0 to 2;
- each m is 0 to 4;
- each p is 0 to 2;
- A1 is —O—(CH2)q— (where q is 0 to 3), —(CH2)q—O— (where q is 0 to 3), —N(R6)—(CH2)q— (where q is 0 to 3) or —(CH2)q—N(R6)— (where q is 0 to 3);
- A2 is —(CH2)q—O— (where q is 2 to 3);
- R1 is hydrogen, alkyl, —C(O)N(R6)R7, or —C(O)R7;
- or R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R1 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R2 is independently halo, haloalkyl, alkyl, nitro, —OR6, —C(O)OR6, —C(O)N(R6)R7, —N(R6)R7, —N(R6)C(O)R7, or —N(H)S(O)2R8;
- each R3 is independently hydrogen or alkyl;
- each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl;
- R5 is hydrogen, alkyl, aralkyl, —(CH2)m—C(O)—OR9 (where m is 1 to 4), —(CH2)m—C(O)—N(R9)R10 (where m is 1 to 4), or heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R6 and R7 is independently hydrogen, alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- each R8 is alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R9 is independently hydrogen, alkyl or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- R10 is hydrogen, alkyl, or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R10 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
- or
- a pharmaceutically acceptable salt thereof.
21 more elements
A method of treating a condition in a mammal resulting from an abnormality in nitric oxide production which comprises administering to a mammal having a condition resulting from an abnormality in nitric oxide production a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- 20
- wherein:
- each n is 0 to 2;
- each m is 0 to 4;
- each p is 0 to 2;
- A1 is —(CH2)q— (where q is 0 to 3), —(CH2)q—O— (where q is 0 to 3), —N(R6)—(CH2)q— (where q is 0 to 3) or —(CH2)q—N(R6)— (where q is 0 to 3);
- A2 is —(CH2)q—O— (where q is 2 to 3);
- R1 is hydrogen, alkyl, —C(O)N(R6)R7, or —C(O)R7;
- or R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R1 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R2 is independently halo, haloalkyl, alkyl, nitro, —OR6, —C(O)OR6, —C(O)N(R6)R7, —N(R6)R7, —N(R6)C(O)R7, or —N(H)S(O)2R8;
- each R3 is independently hydrogen or alkyl;
- each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl;
- R5 is hydrogen, alkyl, aralkyl, —(CH2)m—C(O)—OR9 (where m is 1 to 4), —(CH2)m—C(O)—N(R9)R10 (where m is 1 to 4), or heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R6 and R7 is independently hydrogen, alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- each R8 is alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- each R9 is independently hydrogen, alkyl or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- and
- R10 is hydrogen, alkyl, or aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- or R10 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
- as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
- or
- a pharmaceutically acceptable salt thereof.
21 more elements
Dependencies are inferred from the claim text.