Quinoline derivatives

Details Quinoline derivatives Quinoline derivatives

2002-05-20

2004-11-16

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S176000, C546S179000

Reexamination Certificate

active

06818767

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with novel quinoline derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
SUMMARY OF THE INVENTION
The subject invention provides compounds of formula:
wherein:
R
1
is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH
2
—SO
2
—, monoalkylamino-SO
2
—, dialkylamino-SO
2
—, alkyl-SO
2
—, aryl, NH
2
-alkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aryl-SO
2
—O-alkyl, cycloalkyl, or cycloalkylalkyl;
R
2
is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy, arylamino, heteroarylamino, NH
2
—, monoalkylamino, dialkylamino, heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy, or heteroarylalkoxy;
R
3
is hydrogen, alkyl, NH
2
—, monoalkylamino, dialkylamino, or alkoxy;
R
4
is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH
2
—, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO
2
—, or aryl-SO
2
—;
R
5
is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH
2
—, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO
2
—, or aryl-SO
2
—;
A is a 5- to 10-membered mono- or bicyclic saturated heterocyclic ring comprising the nitrogen atom which is attached to the quinoline ring or a 5- to 10-membered mono- or bicyclic saturated heterocyclic ring comprising the nitrogen atom which is attached to the quinoline ring, which is substituted by one or two further heteroatoms which are independently selected from the group consisting or oxygen, sulfur and nitrogen;
and pharmaceutically acceptable salts or esters thereof.
A preferred embodiment is where R
1
is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH
2
—SO
2
—, monoalkylamino-SO
2
—, dialkylamino-SO
2
—, or alkyl-SO
2
—; R
4
is hydrogen, alkyl, alkoxy, hydroxy, NH
2
—, monoalkylamino, dialkylamino, acetylamino, or cyano; R
5
is hydrogen; and A is a saturated ring consisting of the nitrogen atom which is attached to the quinoline ring and a —(CH
2
)
n
— moiety with n being 4, 5, or 6. Preferred compounds are where R
1
is hydrogen, cycloalkylalkyl, aralkyl, or heteroarylalkyl. Further preferred compounds are where R
1
is hydrogen, aralkyl or heteroarylalkyl, favorably hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen. Especially preferred is where R
1
is hydrogen, cyclopropylmethyl, (methoxyphenyl) methyl, (cyanophenyl) methyl, (chlorophenyl) methyl, pyridinylmethyl, chloropyridinylmethyl, or fluoropyridinylmethyl.
Favored groups of compounds are where R
2
is hydrogen, alkyl or halogen. Especially preferred is where R
2
is hydrogen, butyl, fluoro, chloro or bromo.
R
3
is favorably hydrogen, alkyl, or NH
2
—. Methyl is a preferred alkyl group.
R
4
is favorably hydrogen, alkoxy, alkoxyalkyl, hydroxyalkyl or hydroxy. A is preferably a pyrrolidinyl or azepanyl ring, with the pyrrolidinyl ring being favored.
The subject invention also provides compounds of formula:
wherein:
R
1′
is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen;
R
2′
is is hydrogen, alkyl or halogen;
R
3′
is hydrogen or alkyl;
A′ is selected from the group consisting of pyrrolidinyl, pyrrolidinyl substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl, and azepanyl;
and pharmaceutically acceptable salts and esters thereof.
Some favored compounds are where R
3′
is hydrogen or methyl, A′ is pyrrolidinyl, R
2′
is alkyl, such as butyl, and R
1′
is hydrogen, e.g. 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptable salt or ester thereof R
1′
may also be (cyanophenyl)methyl, e.g. 4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salt or ester thereof
Other favored compounds are where R
3′
is methyl, A′ is azepanyl, R
2′
is hydrogen, and R
1′
is pyridinylmethyl, e.g. 4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline or a pharmaceutically acceptable salt or ester thereof. R
1′
may also be (cyanophenyl)methy, e.g. 4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or 3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salts or esters thereof.
Preferred compounds include those where A′ is pyrrolidinyl or pyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl. A favored group is where A′ is pyrrolidinyl, R
2′
is hydrogen or halogen. R
1′
can favorably-be hydrogen, phenylalkyl wherein the phenyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen. When R
1′
is hydrogen, 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptable salt or ester thereof is favored. When R
1′
is (methoxyphenyl)methyl, 7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof is favored. When R
1′
is (cyanophenyl)methyl, 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl) -benzonitrile and 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile, as well as pharmaceutically acceptable salts and esters thereof are favored. Where R
1′
is (chlorophenyl)methyl, 7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and 7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline, as well as pharmaceutically acceptable salts and esters thereof are preferred. R
1′
is (chloropyridinyl)methyl, 7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are favored. When R
2′
is halogen, such as fluoro, and R
1′
is (cyanophenyl)methyl, the comopund 4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)benzonitrile and pharmaceutically acceptable salts and esters thereof are preferred. Likewise, when R
1′
is (fluoropyridinyl)methyl, 6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are preferred and when R′ is (chloropyridinyl)methyl, 7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are preferred.
Preferred compounds also include those where A′ is pyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl. When A′ is pyrrolidinyl which is substituted by hydroxy, R
1′
is (cyanophenyl)methyl, and R
2′
is hydrogen, the compounds (S) and (R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile and pharmaceutically acceptable salts and esters thereof are favored. When A′ is pyrrolidinyl which is substituted by alkyloxy, such as methox

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