Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-19
2004-03-30
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228800, C514S231500, C514S323000, C514S339000, C514S385000, C514S383000, C514S254080, C544S142000, C544S360000, C544S333000, C544S061000, C544S372000, C546S200000, C546S267000, C548S449000, C548S311400, C548S266400, C548S146000, C540S602000
Reexamination Certificate
active
06713473
ABSTRACT:
TECHINCAL FIELD
The present invention relates to a tricyclic compound useful in the pharmaceutical field and a medicament comprising the compound as an active ingredient.
BACKGROUND ART
Neuropeptide Y (hereinafter occasionally abbreviated as “NPY” in the specification) is a peptide consisting of 36 amino acid residues, and first isolated from swine brain by Tachimoto et al. in 1982 [Nature, 296, p.659 (1982)]. NPY was revealed to be classified into the pancreatic polypeptides (PP) family based on the homology of primary amino acid sequence. As polypeptides belonging to this family, pancreatic polypeptides (PP) produced in pancreatic endocrine system cells and peptides YY (PYY) produced in endocrine system cells of the digestive tract are known. All of these peptides of the PP family consist of 36 amino acid residues and a carboxy terminal (C-terminal) sequence consisting of several amino acid residues is well conserved among them. In particular, in all of the polypeptides, the C-terminal amino acid (36th amino acid: Y36) is tyrosine. For this reason, receptors for the peptides of the PP family are referred to as Y-type receptors. It has also found that the Y type receptors are seven transmembrane-type receptors conjugated with G protein.
NPY is widely distributed over the central nervous system and the peripheral nervous system, and it bears various functions in living bodies as one of the peptides existing in the nervous systems in largest amounts. For example, NPY is involved in control of blood pressure, control of ingestion behavior, control of intestinal function, control of circadian rhythm, suppressive control of insulin secretion, suppression of secretion of hormones such as prolactin, lutenizing hormone, adrenocorticotropic hormone, gonadotropin releasing hormone and vasopressin, and the like. It is known that, when NPY is continuously administered into a ventricle, obesity and insulin resistance are induced based on these actions. NPY is also involved in control of emotion, functions of the central autonomic nervous system and the like.
Furthermore, NPY coexists with norepinephrine at terminals of sympathetic nerves, and is involved in tonicity of sympathetic nerves. It is known that peripheral administration of NPY causes vasoconstriction and enhances actions of other vasoconstrictors such as norepinephrine [International Journal of Obesity], 19, p.517 (1995); Endocrinology, 133, p.1753 (1993); British Journal of Pharmacology, 95, p.419 (1998)].
The function of NPY is expressed when it binds to a Y-type receptor for NPY which exists in the central or peripheral nervous system. As the NPY receptor, at least six kinds of subtypes have been recognized so far, and genes encoding the receptors have been isolated except for Y3. Y1 is the first cloned receptor [FEBS Letter, 271, p.81 (1990)], and the receptor mainly distributes in vessels in the peripheral system and is involved in vasoconstriction (increase of blood pressure). In the central system, the receptor mainly distributes in cerebral cortex, thalamus and amygdaloid corpus, and it is considered that anxiety action is expressed in amygdaloid corpus through the Y1 receptor.
Y2 receptor was first classified as a pharmacologically different receptor from the Y1 receptor, and its existence was clarified by isolation of its gene [J. Biol. Chem., 270, p.22661 (1995)]. The expression site of this receptor is mainly brain. The receptor is localized in, in particular, cerebral cortex, hippocampus, amygdaloid corpus and the like, whilst the receptor has not been found in cerebellum or spinal marrow. Y3 receptor has been pharmacologically classified, however, its gene has not yet been isolated. Y4 receptor was found by using human Y1 receptor cDNA as probe, and its gene was isolated [J. Biol. Chem., 270, p.26762 (1995)]. Its expression is specifically limited to prostate, colon, pancreas and small intestine, and the receptor has not found in brain, kidney, lung, heart, spleen and the like.
It has long been suggested that other NPY receptor subtype may exist in hypothalamus, which has ligand affinity similar to that of the Y1 receptor and controls ingestion behavior, and Gerald et al. successfully cloned Y5 receptor that controlled ingestion from a rat hypothalamus cDNA library [Nature, 382, p.168 (1996)]. The Y5 receptor has low homology of 35% or less to the other NPY receptors. Its expression site is limited to cerebral hypothalamus, and the receptor is mostly involved in control of ingestion. Y6 receptor is found only in mouse, and the receptor does not function in human as its gene is a pseudogene.
A substance that has affinity for these Y-type receptors and acts as an agonist or antagonist for the receptors can control expression of actions of NPY. A substance having such properties is expected to be useful in prophylactic or therapeutic treatment of various kinds of diseases in which NPY is involved, for example, cardiovascular diseases such as hypertension, kidney diseases, heart diseases and vascular spasm, central system diseases such as hyperphagia, melancholia, epilepsy and dementia, metabolic diseases such as obesity, diabetes mellitus, hyperlipidemia and hormone abnormality, inappetence of cancer patients, glaucoma and the like [Trends in Pharmacological Sciences], 15, p.153 (1994)].
In particular, it is expected that a substance that has selective affinity to the Y5 receptor (also referred to as “NPY/Y5 receptor” hereinafter in the specification) among the NPY receptors is useful for prophylatic and/or therapeutic treatment of diseases in which the NPY/Y5 receptor is involved, and can be used without a risk of side effects of enhancing or antagonizing other Y-type receptors. Since the Y5 receptor is mostly involved in the control of ingestion, it is considered that the substance can be used as an ingestion controlling agent for hyperphagia and inappetence of cancer patients, for example, and can also be used for prophylactic or therapeutic treatment of central system diseases such as melancholia, epilepsy and dementia, metabolic diseases such as obesity, diabetes mellitus, hyperlipidemia and hormone abnormality and the like.
The gene coding for the NPY/Y5 receptor and applications thereof are disclosed in U.S. Pat. No. 5,602,024, International Patent Publication WO96/16542 and WO97/46250. However, these publications do not specifically disclose nor suggest the compounds of the present invention.
As antagonists against the NPY/Y5 receptor, aryl sulfonamide and sulfamide derivatives are disclosed in WO97/19682, quinazoline derivatives are disclosed in WO97/20820, WO97/20821, WO97/20822 and WO97/20823, amide derivatives are disclosed in WO98/35944 and WO98/35957, aminopyridine derivatives are disclosed in WO98/40356, pyrazole derivatives are disclosed in WO98/24768, WO98/25907, WO98/25908 and WO98/27063, xanthene derivatives are disclosed in WO98/47505 and the like. However, these publications do not specifically disclose nor suggest the compounds of the present invention. WO99/27965 discloses that NPY/Y5 receptor antagonists are useful for prophylactic or therapeutic treatment of hypercholesterolemia, hyperlipidemia or arteriosclerosis.
Compounds which structurally relates to the compounds represented by the general formula (I) or the general formula (IV) of the present invention are described in European Patent Publication EP882726, WO98/01417, WO97/40017, Japanese Patent Unexamined Publication (Kokai) Nos. 8-301846, 54-017932, 48-054061, WO95/04720, Canadian Patent No. 1,299,577, WO92/15590, WO98/06717, WO94/14773, U.S. Pat. No. 3,932,456. However, these publications do not disclose NPY antagonism of the respective disclosed compounds, and do not specifically disclose nor suggest the compounds newly provided by the inventor of the present invention.
Compounds which structurally relates to the compounds represented by the general formula (XXI) of the present invention are described in WO98/11895, WO98/06402, EP 749 962, U.S. Pat. Nos
Aoki Kozo
Asai Kenji
Ikegawa Akihiko
Kakui Nobukazu
Masuda Naomi
Greenblum & Bernstein P.L.C.
Meiji Seika Kaisha Ltd.
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