Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-26
2004-02-03
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S194000
Reexamination Certificate
active
06686381
ABSTRACT:
BACKGROUND OF THE INVENTION
Neuropeptide 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 neuropeptide 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 con associated risk factors such as arthritis, cardiovascular diseases, diabetes and renal failure.
SUMMARY OF THE INVENTION
The invention provides compounds of formula I and pharmaceutically acceptable salts and esters thereof
wherein
R
1
is aryl or heteroaryl;
R
2
is hydrogen, alkyl or cycloalkyl;
R
3
is hydrogen, alkyl or cycloalkyl;
R
4
is hydrogen, alkyl or cycloalkyl;
R
5
is alkyl, cycloalkyl, aryl, heteroaryl;
R
6
is hydrogen, alkyl or cycloalkyl;
A is —C(O)—; —S(O)
2
—; —N(R
6
)—C(O)— or —O—C(O)—;
n is 2 to 6; and
m is zero to 2.
The compounds of formula I and their pharmaceutically acceptable salts and esters are neuropeptide ligands, for example, neuropeptide receptor antagonists and in particular, they are selective neuropeptides Y Y5 receptor antagonists.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with novel thiazole derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
The invention provides compounds of formula I and pharmaceutically acceptable salts and esters thereof
wherein
R
1
is aryl or heteroaryl;
R
2
is hydrogen, alkyl or cycloalkyl;
R
3
is hydrogen, alkyl or cycloalkyl;
R
4
is hydrogen, alkyl or cycloalkyl;
R
5
is alkyl, cycloalkyl, aryl, heteroaryl;
R
6
is hydrogen, alkyl or cycloalkyl;
A is —C(O)—; —S(O)
2
—; —N(R
6
)—C(O)— or —O—C(O)—;
n is 2 to 6; and
m is zero to 2.
The compounds of formula I and their pharmaceutically acceptable salts and esters are neuropeptide ligands, for example, neuropeptide receptor antagonists and in particular, they are selective neuropeptides Y Y5 receptor antagonists.
The compounds of formula I, their salts and esters can be used in the prophylaxis or treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
Objects of the present invention are 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 comprising the said compounds, their pharmaceutically acceptable 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, cardiovascular diseases, diabetes, renal failure and particularly eating disorders such as hyperphagia and particularly obesity, and th e use of the said compounds, salts and esters for the production of medicaments for the treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched C
1
-C
8
alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl, and most preferred methyl.
The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C
3
-C
8
cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl and cyclopentyl.
The term “alkoxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, preferably methoxy and ethoxy, and most preferred methoxy.
The term “aryl”, alone or in combination, signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more, preferably one to three substituents each independently selected from halogen, haloalkyl, amino, alkyl, alkoxy, aryloxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, and haloalkoxy. Preferred substituents of aryl, preferably phenyl, are independently selected from halogen, trifluoromethyl, alkyl, alkoxy and haloalkoxy.
The term “aralkyl”, alone or in combination, signifies an alkyl or cycloalkyl group as previously defined, preferably an alkyl group in which one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl, benzyl substituted with hydroxy, alkoxy or halogen, preferably fluorine.
The term “heteroaryl”, alone or in combination, signifies an aromatic 5- or 6-membered ring comprising 1 to 3 atoms independently selected from nitrogen, oxygen or sulfur. Optionally, the heteroaryl ring can be substituted on one or more carbon atoms with at least one substituent selected from halogen, alkyl, alkoxy and cyano. Examples of heteroaryl rings include furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl or pyrazinyl, thienyl, isoxazolyl, oxazolyl, thiazolyl and pyrrolyl. Preferred heteroaryl rings are pyridinyl, thiophenyl and pyrazinyl which are optionally substituted with alkyl.
The term “amino”, alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substituents together forming a ring, such as, for example, —NH
2
, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino and particularly preferred primary amino.
The term “halogen”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine and particularly chlorine.
The term “haloalkyl”, alone or in combination, signifies an alkyl group as previously defined, wherein one or several hydrogen atoms, preferably one to three hydrogen atoms have/has been replaced by halogen. Examples of haloalkyl groups are trifluoromethyl, pentafluoroethyl and trichloromethyl. Preferred examples are trifluoromethyl and difluoromethyl. Most preferred is trifluoromethyl.
The term “haloalkoxy”, alone or in
Mattei Patrizio
Neidhart Werner
Nettekoven Matthias Heinrich
Pflieger Philippe
Taylor Sven
Ebel Eileen M.
Gerstl Robert
Hoffmann-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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