Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-21
2002-06-04
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S323000, C514S411000, C546S175000, C546S200000, C548S444000
Reexamination Certificate
active
06399631
ABSTRACT:
FIELD OF THE INVENTION
This invention describes a series of carbazole NPY-5 antagonists which bind potently to the NPY-5 receptor and decrease food intake in animal models that are useful in the treatment of obesity, feeding disorders, as well as other neurological diseases related to NPY activity.
BACKGROUND OF THE INVENTION
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 these 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) have utility in a number of feeding disorders, including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorders including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well other indications for treatment where blockade of NPY activity is beneficial.
A number of NPY-5 receptor antagonist patents have been published. Four patents from Banyu; WO 9827063 [Fukami, Takehiro; Fukuroda, Takahiro; Kanatani, Akio; Ihara, Masaki. Preparation of aminopyrazole derivatives for the treatment of bulimia, obesity, and diabetes. PCT Int. Appl., 38 pp.]; WO 9825907 [Fukami, Takehiro; Fukuroda, Takahiro; Kanatani, Akio; Ihara, Masaki. Preparation of pyrazole derivatives for the treatment of bulimia, obesity, and diabetes. PCT Int. Appl., 63 pp.]; WO 9824768 [Fukami, Takehiro; Fukuroda, Takahiro; Kanatani, Akio; Ihara, Masaki. Preparation of urea moiety-containing pyrazole derivatives as neuropeptide Y antagonists. PCT Int. Appl., 36 pp.]; and WO 9825908 [Fukami, Takehiro; Fukuroda, Takahiro; Kanatani, Akio; Ihara, Masaki. Preparation of novel aminopyrazole derivatives as neuropeptide Y antagonists. PCT Int. Appl., 30 pp.] describe a series of aminopyrazole compounds with potent NPY-5 binding. Novartis has also described a series of Heinrich; Schmidlin, Tibur; Rigollier, Pascal; Yamaguchi, Yasuchika; Tintelnot-Blomley, Marina; Schilling, Walter; Criscione, Leoluca; Stutz, Stefan. Quinazoline derivatives useful as antagonists of NPY receptor subtype Y5. PCT Int. Appl. No. 110 pp.], WO 9720820 [Rueger, Heinrich; Schmidlin, Tibur; Rigollier, Pascal; Yamaguchi, Yasuchika; Tintelnot-Blomley, Marina; Schilling, Walter; Criscione, Leoluca. Quinazoline derivatives useful as antagonists of NPY receptor subtype Y5. PCT Int. Appl. No. 94 pp.], as well as quinazoline-2,4-diazirine NPY-5 antagonists WO 9720822 [Rueger, Heinrich; Schmidlin, Tibur; Rigollier, Pascal; Yamaguchi, Yasuchika; Tintelnot-Blomley, Marina; Schilling, Walter; Criscione, Leoluca. Quinazoline-2,4-diazirines as NPY receptor antagonists. PCT Int. Appl., 154 pp.] and 2-aminoquinazolines WO 9720823 [Rueger, Heinrich; Schmidlin, Tibur; Rigollier, Pascal; Yamaguchi, Yasuchika; Tintelnot-Blomley, Marina; Schilling, Walter; Criscione, Leoluca; Mah, Robert. Preparation of 2-aminoquinazolines as neuropeptide Y subtype Y5 receptor antagonists. PCT Int. Appl., 166 pp.]. Synaptic WO 9746250 [Gerald, Christophe P. G.; Weinshank, Richard L.; Walker, Mary W.; Branchek, Theresa. Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor. PCT Int. Appl. No. 272 pp] also describes a series of quinazoline NPY-5 antagonists, and WO 9719682 [Islam, Imadul; Dhanoa, Daljit S.; Finn, John M.; Du, Ping; Gluchowski, Charles; Jeon, Yoon T. Preparation of aryl sulfonamide and sulfamide derivatives which bind selectively to the human Y5 receptor. PCT Int. Appl. No. 171 pp.] reports on aryl sulfonamide and sulfamide NPY-5 compounds. Recently, Bayer revealed a series of amide compounds with NPY-5 binding affinity; WO 9835944 [Connell, R. D.; Lease, T. G.; Ladouceur, G. H.; Osterhout, M. H.; Amides as NPY5 Receptor Antagonists. PCT Int. Appl. No. 64 pp.] and WO 9835957 [Connell, R. D.; Lease, T. G.; Ladouceur, G. H.; Osterhout, M. H.; Amide Derivatives as selective Neuropeptide Y Receptor Antagonists. PCT Int. Appl. No. 66 pp.]. Banyu patent WO 9840356 [Preparation and formulation of aminopyridine derivatives as neuropeptide Y receptor antagonists. Fukami, Takehiro; Okamoto, Osamu; Fukuroda, Takahiro; Kanatani, Akio; Ihara, Masaki. (Banyu Pharmaceutical Co., Ltd., Japan). PCT Int. Appl., 78 pp. CODEN: PIXXD2. WO 9840356 A1 980917] covers substituted pyridines as NPY-5 ligands, exemplified by (E)-2-methyl4-pyrrolidino-6-[2-(3-trifluoromethylphenyl)vinyl]pyridine, which in an in vitro test for neuropeptide Y receptor antagonism showed an IC50 of 4.1 nM. However, to date no carbazole NPY-5 receptor antagonists have been described in the scientific or patent literature.
A number of acylated 3-aminocarbazoles are described in the literature. WO 9801417 [Preparation of aryloxyalkylamines, heteroaryloxyalkylamines and their analogs as calcium receptor-active compounds; Sakai, Teruyuki; Takami, Atsuya; Suzuki, Rika, Kirin Beer K. K., Japan; NPS Pharmaceuticals, Inc.; Sakai, Teruyuki; Takami, Atsuya; Suzuki, Rika. PCT Int. Appl., 430 pp.] includes carbazoles of the type shown below.
U.S. Pat. No. 4,703,107 A (abandoned) [Preparation and testing of water-soluble polyhydroxyacylpeptide derivatives of drugs and enzyme inhibitors; Monsigny, Michel; Mayer, Roger; Centre National de la Recherche Scientifique, Fr.; U.S., 10 pp. Cont.-in-part of U.S. Ser. No. 610,112] describes a number of amino acid and peptide carbazole amides. Patents GB 2000800 [Pigments for coloring hydrophobic and hydrophilic materials; Dietz, Erwin; Fuchs, Otto; Gutbrod, Robert; Kroh, Adolf; Maikowski, Michael; Hoechst A.-G., Fed. Rep. Ger.; Brit. UK Pat. Appl., 11 pp.] and JP 54017932 [Pigment compositions; PATENT ASSIGNEE(S): Hoechst A.-G., Fed. Rep. Ger.; SOURCE: Jpn. Kokai Tokkyo Koho, 15 pp.] report on long alkyl chain (C9 or longer) carbazole amides at the 3-position, such as the compound shown below.
In addition, Japanese patent JP 07053950 [Organic electroluminescent device materials and organic electroluminescent devices with them. Enokida, Toshio; Ogawa, Tadashi. (Toyo Ink Mfg Co, Japan). Jpn. Kokai Tokkyo Koho, 13 pp.] claims compounds of the type below where G1 can be NR9 and G8 is acylamino.
Also, U.S. Pat. No. 4,111,850 [Organic photoconductors; Kwalwasser, William David; AMP Inc., USA; U.S., 12 pp.], claims 3-(acetylamino)-N-ethylcarbazole [6954-68-3] useful as photoconductors, and JP 48091196 [Polyamides containing carbazole rings; Tazuke, Shigeo; Hayashi, Yoshio; Ono, Hisatake; Noguchi, Yasuhiro; Fuji Photo Film Co., Ltd.; Japan. Kokai.] covers carbazole ring-containing polyamides. Also, a Yamanouchi Pharmaceutical Co patent [Ohta, Mitsuaki; Koide, Tokuo; Suzuki, Takeshi; Matsuhisa, Akira; Miyata, Keiji; Ohmori, Junya; Yanagisawa, Isao. Preparation of tetrahydrobenzimidazoles as 5-HT3 receptor antagonists. Eur. Pat. EP 381422] describes a number of tetrahydrobenzimidazoles as 5-HT
3
receptor antagonists as exemplified by the formula below.
Also, Neurogen patent WO 9806717 [Yuan, Jun; Wasley, Jan William Francis. Preparation of N-[4-(4-phenylpiperazin-1-yl)butyl]-substituted fused indolecarboxamides as dopamine receptor subtype specific ligands] describes a series of 9H-carbazole-3-carboxamide analogs of the general formula below as dopamine receptor ligands.
A journal publication by A. Dlugosz [Synthesis and cytotoxicity of the three-membered aromatic pyrimidine derivatives. Dlugosz, Anna. Department of Toxico
Elliott Richard L.
Griffith David A.
Hammond Marlys
Benson Gregg C.
Kleiman Gabriel L.
Pfizer Inc.
Richardson Peter C.
Solola T. A.
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