Pyrimidine derivatives

Details Pyrimidine derivatives Pyrimidine derivatives

2001-11-08

2003-12-02

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S322000, C544S324000, C544S326000, C544S329000, C514S256000, C514S273000

Reexamination Certificate

active

06657060

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with novel pyrimidine derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
R
1
and R
2
are each independently alkyl, cycloalkyl or aralkyl, or one of R
1
and R
2
is hydrogen and the other is alkyl, aminoalkyl or cyclopropyl, or R
1
and R
2
together with the N atom to which they are attached form a 4- to 10-membered heterocylic ring or a 4- to 10-membered heterocylic ring that is substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl, and CONR
5
R
6
;
R
3
is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, hydroxyalkoxy, aralkyl or amino;
R
4
is aryl or heteroaryl, wherein R
4
is not nitro-furyl or nitro-thienyl;
R
5
and R
6
are each independently hydrogen or alkyl;
A
1
is CH or N; A
2
is CH or N; wherein one of the A
1
and A
2
is N and the other is CH;
and pharmaceutically usable salts and esters thereof.
Preferred substituents include where R
3
is alkyl or amino, for example methyl or methylamino. Also preferred is where A
1
is CH and A
2
is N or A
1
is N and A
2
is CH. Other favored compounds are where one of R
1
and R
2
is hydrogen and the other is alkyl, aminoalkyl or cyclopropyl, or R
1
and R
2
together with the N atom to which they are attached form a 4- to 10-membered heterocylic ring or a 4- to 10-membered heterocylic ring that is substituted with one or two substituents independently selected from alkyl, hydroxy, or alkoxy. Examples include where R
1
and R
2
together with the N atom to which they are attached form a pyrrolidine ring, a pyrrolidine ring that is substituted with alkyl, azetidine ring, or an azetidine ring that is substituted with alkyl.
R
4
is favorably phenyl, thienyl, furanyl, pyridinyl, or phenyl that is substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, amino, cyano, haloalkyl, nitro, 2H-tetrazol-5-yl, alkylthio, alkylsulfonyl, benzyloxy, alkoxycarbonyl, hydroxyalkyl, aminosulfonyl, —O—CH
2
—O—.
Specifically provided are compounds of the formula:
wherein the double bond * is an E double bond and R
1
and R
2
are each independently alkyl, cycloalkyl or aralkyl, or one of R
1
and R
2
is hydrogen and the other is alkyl, aminoalkyl or cyclopropyl, or R
1
and R
2
together with the N atom to which they are attached form a 4- to 10-membered heterocylic ring or a 4- to 10-membered heterocylic ring that is substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl, and CONR
5
R
6
;
R
3
is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkoxy,
hydroxyalkoxyalkyl, hydroxyalkoxy, aralkyl or amino;
R
4
is aryl or heteroaryl, wherein R
4
is not nitro-furyl or nitro-thienyl;
R
5
and R
6
are each independently hydrogen or alkyl;
A
1
is CH or N; A
2
is CH or N; wherein one of the A
1
and A
2
is N and the other is CH;
and pharmaceutically usable salts and esters thereof.
The groupings mentioned above are also preferred with the compounds of formula Ia.
Some especially preferred compounds of formula Ia have R
3
as methyl, and R
1
and R
2
together with the N atom to which they are attached form a 4- to 10-membered heterocylic ring, such as a pyrrolidine ring. In these compounds, R
4
can favorably be phenyl that is substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, amino, cyano, haloalkyl, nitro, 2H-tetrazol-5-yl, alkylthio, alkylsulfonyl, benzyloxy, alkoxycarbonyl, hydroxyalkyl, aminosulfonyl, —O—CH
2
—O—.
Other favored compounds of formula Ia have R
4
as thienyl or pyridinyl. Alternatively, R
1
and R
2
together with the N atom to which they are attached form a piperidine ring and R
4
can be phenyl that is substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, amino, cyano, haloalkyl, nitro, 2H-tetrazol-5-yl, alkylthio, alkylsulfonyl, benzyloxy, alkoxycarbonyl, hydroxyalkyl, aminosulfonyl, —O—CH
2
—O—. R
1
and R
2
together with the N atom to which they are attached can also favorably form an azetidine ring that is substituted with alkyl, such as methyl. R
3
can also favorably be methylamino.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention is concerned with compounds of formula I
wherein
R
1
and R
2
are each independently alkyl, cycloalkyl or aralkyl or one of R
1
and R
2
is hydrogen and the other is alkyl, aminoalkyl or cyclopropyl or R
1
and R
2
together with the N atom to which they are attached form a 4- to 10-membered heterocylic ring optionally substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl or CONR
5
R
6
;
R
3
is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, hydroxyalkoxy, aralkyl or amino;
R
4
is aryl or heteroaryl, wherein R
4
is not nitro-furyl or nitro-thienyl;
R
5
and R
6
are each independently hydrogen or alkyl;
A
1
is CH or N; A
2
is CH or N; wherein one of the A
1
and A
2
is N and the other is CH;
and pharmaceutically usable salts and esters thereof
The compounds of formula I and their pharmaceutically usable salts and esters are novel and have valuable pharmacological properties. They are neuropeptide ligands, for example neuropeptide receptor antagonists and in particular, they are selective neuropeptides Y Y5 receptor antagonists.
Neuropetide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis. Therefore compounds that antagonize neuropetide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia.
The current approach is aiming at medical intervention to induce weight loss or prevention of weight gain. This is achieved by interfering with appetite control, which is mediated by the Hypothalamus, an important brain region proven to control food intake. Herein, neuropeptide Y (NPY) has been proven to be one of the strongest central mediators of food intake in several animal species. Increased NPY levels result in profound food intake. Various receptors of neuropeptide Y (NPY) have been described to play a role in appetite control and weight gain. Interference with these receptors is likely to reduce appetite and consequently weight gain. Reduction and long-term maintenance of body weight can also have beneficial consequences on associated risk factors such as arthritis and diabetes.
Accordingly, the compounds of formula I maybe used in the prophylaxis or treatment of arthritis, diabetes and particularly eating disorders and obesity.
The subject invention provides the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the compounds, their pharmaceutically usable salts and esters, the use of the said compounds salts and esters for the prophylaxis and/or therapy of illnesses, especially in the treatment or prophylaxis of arthritis, diabetes and particularly eating disorders such as hyperphagia and particularly obesity, and the use of the compounds,

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