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  Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredientUSPTO Application #: 20060287304Title: Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient Abstract: (wherein all symbols are as defined in the specification) and salt thereof, and peroxisome proliferator activated receptor regulator comprising thereof as active ingredient. Because a compound of formula (I) have an activity of regulating peroxisome proliferator activated receptor regulator, the compound of formula (I) is useful as a hypoglycemic agent, a hypolipidemic agent, a preventive and/or treatment agent for diseases associating metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipemia, atherosclerosis, hypertension, circulatory diseases, overeating, coronary heart diseases, etc., an HDL cholesterol-elevating agent, an LDL cholesterol and/or VLDL cholesterol-lowering agent and a drug for relief from risk factors of diabetes or syndrome X. A compound of formula (I) (end of abstract) Agent: Sughrue Mion, PLLC - Washington, DC, US Inventors: Hisao Tajima, Yoshisuke Nakayama, Daikichi Fukushima USPTO Applicaton #: 20060287304 - Class: 514227500 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Sulfur As Ring Members, 1,4-thiazines The Patent Description & Claims data below is from USPTO Patent Application 20060287304. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to dihydronaphthalene derivative compounds. [0002] More specifically, the present invention relates to [0003] (1) dihydronaphthalene derivatives compounds represented by formula (I) [0004] (wherein all symbols have the same meanings as described below), or nontoxic salts thereof, [0005] (2) a process for preparing thereof, and [0006] (3) an agent comprising thereof as an active ingredient. BACKGROUND ART [0007] Recently in the study of transcription factors concerned with marker genes expression in adipocytes differentiation, peroxisome proliferator activated receptor (abbreviated as PPAR hereinafter), which is one of intranuclear receptors, has been focused. cDNAs of PPAR were cloned from various kinds of animals, and plural isoform genes were found, particularly in mammals three types of isoforms (.alpha., .delta., .gamma.) are known (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression., 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology., 6, 1634 (1992)). PPAR .gamma. isoform is predominantly expressed in adipose tissues, immune cells, adrenal gland, spleen, small intestine. PPAR .alpha. isoform is mainly expressed in adipose tissue, liver, retina, and PPAR .delta. isoform is widely expressed without specificity for tissue (see Endocrinology., 137, 354 (1996)). [0008] On the other hand, the following thiazolidine derivatives are known as agents for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and are hypoglycemic agents which are used for the improvement of hyperglycemia in the patients suffering from diabetes. They are also effective for the improvement of hyperinsulinemia, glucose tolerance and decrease of serum lipid and therefore they are thought to be considerably hopeful as agents for the treatment of insulin resistance. [0009] One of the target proteins in the cells of these thiazolidine derivatives is exactly PPAR .gamma. and it is resolved that they enhance the transcription activity of PPAR .gamma. (see Endocrinology., 137, 4189 (1996); Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953 (1995)). Therefore, a PPAR .gamma. activator (agonist) which enhances its transcription activity is thought to be hopeful as a hypoglycemic agent and/or a hypolipidemic agent. Furthermore, since a PPAR .gamma. agonist is known to promote the expression of PPAR .gamma. protein itself (Genes & Development., 10, 974 (1996)), an agent which increases the expression of PPAR .gamma. protein itself as well as PPAR .gamma. activating agent is also thought to be clinically useful. [0010] PPAR .gamma.is related to adipocytes differentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803 (1995)). It is known that thiazolidine derivatives which activate this receptor promote adipocytes differentiation. Recently it was reported that thiazolidine derivatives increase fat mass and cause man to gain weight and to become obese (see Lancet., 349, 952 (1997)). Therefore, it is also thought that antagonists which inhibit PPAR .gamma. activity and agents that decrease the expression of PPAR .gamma. protein itself are also clinically applicable. On the other hand, a compound that phosphorylates PPAR .gamma. protein and decreases its activity is reported (Science., 274, 2100 (1996)). This implies that an agent which does not bind on PPAR .gamma. protein as a ligand, but inhibits its activity is also clinically applicable. [0011] From these, PPAR .gamma. activators (agonists) and PPAR .gamma. regulators for its expression that can increase the expression of the protein itself are expected to be useful as hypoglycemic agents, hypolipidemic agents, and agents for prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia, atherosclerosis, hypertension, circulatory diseases and overeating etc. [0012] On the other hand, antagonists that inhibit the transcription activity of PPAR .gamma. or PPAR .gamma. regulators that inhibit the expression of the protein itself are expected to be useful as hypoglycemic agents and agents for prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity and syndrome X etc., hyperlipidemia, atherosclerosis, hypertension and overeating etc. [0013] The following fibrate compound (e.g. chlofibrate) is known as a hypolipidemic agent. [0014] And, it is also resolved that one of the target proteins in the cells of fibrate compounds is PPAR .alpha. (see Nature., 347, 645 (1990); J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)). From these facts, PPAR .alpha. regulators which can be activated by fibrate compounds are thought to have a hypolipidemic effect, and so they are expected to be useful as agents for prevention and/or treatment of hyperlipidemia etc. [0015] Besides, it has been, recently reported that PPAR .alpha. possesses anti-obese activity in the specification of WO 9736579. In addition, it was reported that the elevation of high density lipoprotein (HDL) cholesterol level and the reduction of low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglyceride levels were induced by activation of PPAR .alpha. (J. Lipid Res., 39, 17 (1998)). It was also reported that composition of fatty acids in blood, hypertension and insulin resistance were improved by administration of bezafibrate which is one of fibrate compounds (Diabetes., 46, 348 (1997)). [0016] Therefore, agonists that activate PPAR .alpha. and PPAR .alpha. regulators that promote expression of PPAR .alpha. protein itself are useful as hypolipidemic agents and agents for treatment of hyperlipidemia, and are expected to have HDL cholesterol level-elevating effect, LDL cholesterol and/or VLDL cholesterol levels-lowering effect, inhibition on the progress of atherosclerosis and anti-obese effect. Therefore, they are thought to be hopeful agents for the treatment and/or prevention of diabetes as hypoglycemic agents, for the improvement of hypertension, for the relief from risk factor of syndrome X and for the prevention of occurrence of ischemic coronary diseases. [0017] On the other hand, few reports are found on ligands that activate PPAR .delta. significantly or on biological activities associated with PPAR .delta.. PPAR .delta. is sometimes called PPAR .beta., or it is also called NUC1 in human. Until now, as for activity of PPAR .delta., it is disclosed in the specification of WO 9601430 that hNUC1B (PPAR subtype whose structure is different from that of human NUC1 in one amino acid) inhibited the transcription activities of human PPAR .alpha. and thyroid hormone receptor. Recently in the specification of WO 9728149, it was reported that the compounds, which possessed high affinity to PPAR .delta. protein and which could activate PPAR .delta. significantly (i.e. agonists) were found out and that they had HDL (high density lipoprotein) cholesterol level-elevating activity. Therefore, agonists that can activate PPAR .delta. are expected to have HDL cholesterol level-elevating effect, and so they are expected to be useful for the inhibition on the progress of atherosclerosis and treatment thereof, as hypolipidemic agents and hypoglycemic agents, for the treatment of hyperlipidemia, as hypoglycemic agents, for the treatment of diabetes, for the relief from risk factor of syndrome X, and for the prevention of occurrence of ischemic coronary diseases. [0018] For example, the specification of WO9828254 discloses that a compound represented by formula (A) [0019] (wherein, A.sup.A is optionally substituted aryl or heterocyclic ring, X.sup.1A is bond, O atom, etc., Y.sup.1A is optionally substituted C1-8 alkylene, X.sup.2A is bond, O atom, etc., W is optionally substituted naphthalene, etc., B.sup.A is carboxyl, etc., X.sup.3A is O atom, etc., R.sup.3A is optionally substituted C1-8 alkyl, etc., nA is integer of 1-4.) [0020] or a salt thereof has a hypoglycemic activity and a hypolipidemic activity (necessary parts were extracted from the description of groups). [0021] The specification of WO9911255 disclose that a compound of represented by formula (B) [0022] (wherein, R.sup.1B is C1-8 alkyl, etc., R.sup.2B is --COOR.sup.3B (in which R.sup.3B is hydrogen, or C1-4 alkyl.), A.sup.B is C1-8 alkylene, etc., G.sup.B is carbocyclic ring, or hetero ring (the above carbocyclic ring and hetero ring is optionally substituted by C1-8 alkyl, etc.), E.sup.1B is C1-8 alkylene, etc., E.sup.2B is --O--, etc., E.sup.3B is bond, etc., CyC.sup.1B is saturated, partially saturated or unsaturated carbocyclic ring, etc.) or a salt thereof has a modulating activity of peroxisome proliferator activated receptor (necessary parts were extracted from the description of groups). [0023] Also, in Example 3(35) in the above specification, the compound of formula (B-1) is disclosed. DISCLOSURE OF THE INVENTION [0024] In order to find a compound having a PPAR modulating activity, the present inventors have conducted intensive studies and found, as a result, that the objects can be accomplished by the compound represented by formula (I), and thus the present invention has been accomplished. [0025] The present invention relates to [0026] (1) A dihydronaphthalene derivative compound represented by formula (I) [0027] (wherein X represents (1) bond, or (2)C1-4 alkylene, [0028] Y represents (1) --O--, or (2) --S--, [0029] Z represents C1-4 alkylene, [0030] A represents (1) --O--, or (2) --S--, [0031] R.sup.1 represents (1) COOR.sup.5, (2) CONH.sub.2, (3) CONHOH, (4) CH.sub.2OH, (5) CHO, [0032] (6) 1H-tetrazol-5-yl, or (7) 3,5-dioxoisooxazolin-4-yl, [0033] R.sup.5 represents (1) hydrogen, or (2) C1-8 alkyl, [0034] R.sup.2 and R.sup.3 each independently represents (1) hydrogen, (2) C1-8 alkyl, (3) C1-8 alkoxy, or (4) C1-8 alkoxy substituted by a phenyl, [0035] R.sup.4 represents (1) hydrogen, or (2) C1-8 alkyl, [0036] D represents D.sup.1, D.sup.2, or D.sup.3, [0037] D.sup.1 represents [0038] ring1 represents partially or fully optionally saturated C3-10 mono- or bi-carbocyclic aryl, [0039] D2 represents [0040] ring2 represents partially or fully optionally saturated 3-10 membered mono- or bi-heterocyclic aryl containing 1-4 hetero atom(s) selected from oxygen, nitrogen or sulfur atom, [0041] D.sup.3 represents C1-8 alkyl, [0042] R.sup.6 represents (1) hydrogen, (2) C1-8 alkyl, (3) nitro, (4) NR.sup.7R.sup.8, (5) halogen, (6) C1-8 alkoxy, (i) C1-8 alkylthio, (8) CF.sub.3, (9) CF.sub.3O, (10) partially or fully optionally saturated C3-10 mono- or bi-carbocyclic aryl, or (11) partially or fully optionally saturated 3-10 membered mono- or bi-heterocyclic aryl containing 1-4 hetero atom(s) selected from oxygen, nitrogen or sulfur atom, R.sup.7 and R.sup.8 each independently represents (1) hydrogen atom, or (2) C1-alkyl, m represents 1-3.) [0043] or a nontoxic salt thereof, [0044] (2) a process for preparing thereof, and [0045] (3) an agent comprising thereof as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION [0046] In the specification, the C1-8 alkyl group includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups, and isomers thereof. [0047] In the specification, the C1-4 alkylene group includes methylene, ethylene, trimethylene, and tetramethylene groups, and isomers thereof. Continue reading... Full patent description for Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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