Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-08-21
2003-11-18
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...
C540S600000, C514S217060, C514S252160, C514S259300
Reexamination Certificate
active
06649759
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates to the use of substituted pyrazolo pyrimidines and pyrazolo triazines which selectively bind to mammalian neuropeptide receptors. It further relates to the use of these compounds and compositions containing these compounds in treating conditions related to an excess of neuropeptide Y.
2. Description of the Related Art
Neuropeptide Y (NPY), a 36 amino acid peptide neurotransmitter, is a member of the pancreatic polypeptide class of neurotransmitters
eurohormones which has been shown to be present in both the periphery and central nervous system. NPY is one of the most potent orexogenic agents known and has been shown to play a major role in the regulation of food intake in animals, including humans. At least 6 NPY receptor subclasses have been identified and cloned to date, with two of the subclasses, NPY-1 and NPY-5, thought to be the most important receptor subtypes modulating food intake and energy expenditure. Hence, agents capable of blocking NPY binding at these receptor subtype(s) should have utility in a number of feeding disorders, including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorder including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well as other indications for treatment where blockade of NPY activity is beneficial.
Grundemar and Hakanson.
TiPS,
May 1994 [Vol. 15], 153-159, state that, in animals, neuropeptide Y is a powerful stimulus of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y (NPY) are associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
EP0759441 and U.S. Pat. No. 5,576,337 report that physiological disorders related to an excess of neuropeptide Y include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and sugery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemmorrhage, depression, anxiety, schizophrenia, and dementia;
conditions related to pain or nociception;
diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as anorexia and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
A patent application WO 9535298 entitled “Preparation and formulation of pyrazolopyrimidine derivatives as analgesics” [Shoji, Yasuo; Inoue, Makoto; Okamura, Takashi; Hashimoto, Kinji; Ohara, Masayuki; Yasuda, Tsuneo. (Otsuka Pharmaceutical Factory, Inc., Japan). PCT Int. Appl. 89 pp.] as well as JP 10101672 [Adenosine reinforcement agents. Moritoki, Hideki; Iwamoto, Takeshi; Yasuda, Tsuneo. (Otsuka Pharmaceutical Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho 22 pp.] and JP 10101671 [Nitrogen monooxide synthase inhibitors. Moritoki, Hideki; Iwamoto, Takeshi; Yasuda, Tsuneo; 25 pp.]claim a series of aminopyrazolopyrimidines of the formula
where R
1
represents hydrogen, lower alkyl, cycloalkyl, thienyl, furyl, lower alkenyl or phenyl; R
2
represents naphthyl, cycloalkyl, furyl, thienyl, pyridyl, phenoxy or phenyl; R
3
represents hydrogen, Ph or lower alkyl; R
4
represents hydrogen, lower alkyl, lower alkoxycarbonyl, phenyl-substituted lower alkyl, Ph or halogen; R
5
represents hydrogen or lower alkyl; R
6
represents hydrogen, lower alkyl, phenyl-substituted lower alkyl or benzoyl; Q represents carbonyl or sulfonyl; A represents a single bond, lower alkylene or lower alkenylene; and n represents 0 or 1.
WO 9218504 [Preparation of pyrazolo[1,5-a]pyrimidine derivatives antiinflammatory agents. Inoue, Makoto; Hashimoto, Kinji; Kuwahara, Toshiko; Sugimoto, Yukio; Uesako, Takuji; Funato, Toshiaki. 48 pp.] and JP 03204877 [Preparation of pyrazolo[1,5-a]pyrimidine derivatives as drugs. Inoue, Makoto; Hashimoto, Kinji.; 10 pp.] describe compounds of the formula:
where R
1
—R
4
may be hydrogen, carboxyl, lower alkoxycarbonyl, phenyl, or lower alkyl or cycloalkyl which may be each substituted with hydroxy, carboxyl or lower alkoxycarbonyl, or alternatively R
1
and R
2
may combined together to form lower alkylene; R
5
represents —SR
6
or —NR
7
R
8
; and R
7
and R
8
represent each hydrogen or phenyl which may be substituted with one to three groups, or R
7
and R
8
may be combined to form, together with the nitrogen atom to which they are bound, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, or 1-piperazinyl which may be substituted with hydroxy-lower alkyl or diphenyl-lower alkyl.
The patent WO 9635690 A1 [Pyrazolo[1,5-a]pyrimidines, process for preparing them, and their use as as pesticides and fungicides. Benoit, Remy; Grote, Thomas; Bayer, Herbert; Mueller, Bernd; Oberdorf, Klaus; Sauter, Hubert; Ammermann, Eberhard; Lorenz, Gisela; Strathmann, Siegfried). 115 pp.] covers compound of the general structure below where n=0 or 1; Y═O, S, NH
2
, OCH
2
, SCH
2
, NH
2
CH
2
, CH
2
O, CH
2
S, CH
2
NH
2
, CH
2
CH
2
, CH
2
:Rb, or C.tplbond.C; and R′═C(:CHOMe)CO
2
Me, C(:CHOMe)CONHMe, C(:NOMe)CO
2
Me, C(:NOCH
3
)CONHMe, C(:NOMe)CONH
2
, C(:NOMe)CO
2
H, C(:CHMe)CO
2
Me, C(:CHEt)CO
2
Me, C(:CHOMe)COMe, C(:NOMe)COMe, C(:NOMe)COEt, N(OMe)CO
2
Me, N(Me)CO
2
Me, N(Et)CO
2
Me, C(:NOMe)R where R=2-oxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl.
Patents EP 347252 [Preparation of triazolo- and pyrazolopyrrolopyrimidines, their use in cacexia treatment, and formulations containing them. Takiguchi, Yo; Ohsumi, Jun; Shimoji, Yasuo; Sasagawa, Kazuhiko. (Sankyo Co., Ltd., Japan) 45 pp] and EP 508549 [New triazolo-pyrimidine and pyrazolo-pyrimidine derivs. for treating cachexia, e.g. 8-benzyl-7,8-dihydro-5-methyl-6H-pyrazole-(1,5A)-pyrrolo-(3,2E)-pyrimidine. Ohsumi, J; Sasagawa, K; Shimoji, Y; Takiguchi, Y. (Sankyo Co., Ltd., Japan) 39 pp] describe compounds of the formula below where Y can be N or CR
2
and R
1
can be, among other things, substituted alkyl or aryl; R
2
is H or halogen; R
3
is alkyl or cycloalkyl; R
4
and R
5
is hydrogen (when dashed line represent single bond) or hydrogen or halogen (when dashed line represents double bond) and R
6
is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or alkaryl.
Likewise, EP 369145 [Preparation of pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidines as cardiovascular agents and bronchodilators. Tsujitani, Michihiko; Kishii, Kenichi; Inazu, Masato; Morimoto, Toshihiro; Motoki, Yoshiaki; Matsuo, Ichiro. (Pola Chemical Industries, Inc., Japan). 20 pp.] covers structures of the type I below where R
1
and R
2
can be, among other things, H, alkyl, cycloalkyl, phenyl, or a heterocyclic group and R
3
is H or CN.
SUMMARY OF THE INVENTION
This invention provides compounds of the formula:
Wherein: A is —CH═; or —N═; or —CR═; X is
R
1
is phenyl, thienyl or pyridyl each optionally substituted with one to three substituents selected from halogen, —OCF
3
, NO
2
Elliott Richard L.
Oliver, III Robert M.
Benson Gregg C.
Musser Arlene K.
Pfizer Inc.
Raymond Richard L.
Richardson Peter C.
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