Apo ai expression accelerating agent

Abstract

Pharmaceutical compositions for enhancing the expression of apoAI are provided.

Description

FILED OF THE INVENTION

[0001] This invention relates to a pharmaceutical composition for preventing and/or treating arteriosclerotic diseases or blood lipid disorders, and specifically to a pharmaceutical composition for enhancing the expression of apoAI.

BACKGROUND ART

[0002] Cholesterol is well known as a main etiologic factor for arteriosclerosis that causes severe heart diseases. Especially, increased levels of serum low density lipoprotein (LDL) are believed to be a definite risk factor for coronary heart diseases (CHDs). Remedies for decreasing the level of LDL-cholesterol (LDL-C) in plasma by use of statins have been shown to be clinically effective in preventing the onset of CHDs and improving the conditions of CHDs and survivals in patients suffering from hypercholesterolemia. However, about 40% of CHDs patients have a normal level of LDL-C, and are not always cured effectively by remedies for decreasing the level of LDL-C. On the other hand, it has been known that a half of CHDs patients having a normal level of LDL-C shows a lower level of high density lipoprotein (HDL) cholesterol (HDL-C).

[0003] Epidemiological trials in Europe and the U.S. such as Framingham studies and MRFIT (Multiple Risk Factor Intervention Trial) have reported that incidence of coronary heart diseases is higher when the level of HDL-C is lower. Other reports show that patients having only a lower level of HDL-C with normal levels of total cholesterol and triglyceride increased in a risk of arteriosclerosis. Those suggest that a low level of serum HDL-C (less than 35 to 40 mg/dl) should be an independent risk factor of CHD, and the risk of complications in coronary artery diseases rapidly increases.

[0004] HDL plays an important role in reverse cholesterol transport system that is known as a biological mechanism to transfer an excess cholesterol in cells back to liver so as to maintain the level of cholesterol in living bodies normally.

[0005] Lipoproteins such as HDL is mainly comprised of lipids and proteins called apoprotein, and HDL comprises an apoprotein as referred to apolipoprotein AI (hereinafter, made up by apoAI) as a main component.

[0006] Excess free cholesterols (FCs) and phospholipids in peripheral cells are extracted by free apoAI to form lipoproteins called preβ-HDL(s). The excess FCs integrated in the preβ-HDLs are transformed into cholesteryl esters (CEs) by lecithin:cholesterol acyl transferase (LCAT), while the preβ-HDLs increase in their particle size to mature into spherical HDLs (HDL3s). The matured HDLs are classified into diverse subfractions based on the density, and these particles further grow up them to form HDL2(s). CEs are continuously transferred into VLD and LDL by means of cholesteryl ester-transporter protein (CETP). Those lipoproteins that integrate CEs are finally taken into the liver via receptors. During the course, apoAI is regenerated, and again interacts with peripheral cells to repeat the extracting of cholesterols and the regeneration of preβ-HDLs.

[0007] It has been well understood that HDL plays a central role in reverse cholesterol transport system and is a defensive factor of arteriosclerosis. It is expected that agents that promote the HDL functions would be clinically effective as medicaments for treating arteriosclerotic diseases. Accordingly, researches and developments of screening for agents that enhance in the level of HDL in plasma have been conducted via various approaches.

[0008] Among the possible approaches, one of the most likely effective approaches is to enhance the serum level of apoAI, a main component of HDL. Although increased level of HDL does not necessarily correlate with the level of apoAI, it is apparent in view of the role of apoAI in reverse cholesterol transport system that the increased level of apoAI is directly responsible for the promotion of the HDL functions. Actually, it has been shown that the mRNA level of apoAI in liver correlates closely to the levels of apoAI protein and HDL in blood (Dueland S, France D, Wang S L, Trawick J D, and Davis R A, J. Lipid Res. 38:1445-53 (1997), “Cholesterol 7alpha-hydroxylase influences the expression of hepatic apoA-I in two inbred mouse strains displaying different susceptibilities to atherosclerosis and in hepatoma cells.”). Accordingly, it would be believed that the increase in the expression level of apoAI gene could elevate the serum level of apoAI, and consequently improve the HDL functions, leading to the activation of reverse cholesterol transport system. Actually, it has been shown that apoAI-transgenic mice and rabbit pathologic models administered with apoAI exhibit anti-arteriosclerosis activities (Rubin E. M., Krauss R. M., Spangler E. A., Verstuyft J. G., and Clift S. M., Nature 353, 265-267 (1991), “Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI.”; Plump A. S., Scott C. J., Breslow J. L., Proc. Natl. Acad. Sci. USA., 91, 9607-9611 (1994), “Human apolipoprotein A-I gene expression increases high density lipoprotein and suppress atherosclerosis in the apolipoprotein E-deficient mouse.”; Miyazaki A., Sakuma S., Morikawa W., Takiue T., Miake F., Terano T., Sakai M., Hakamata H., Sakamoto Y., et al., Arterioscler. Thromb. Vasc. Biol. 15, 1882-1888 (1995) “Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits.”).

[0009] Taking into account those facts, the inventors of the present application believe that agents that activate apoAI would be candidates for medicaments of blood lipid disorders, arteriosclerotic diseases, and other diverse diseases involving HDL.

[0010] Compounds that elevate HDL are described in WO97/19931, WO97/19932, U.S. Pat. No. 5,599,829, and EP796874, whereas compounds that increase apoAI are described in Japanese Patent Publication (kokai) No. 221959/1993, Japanese Patent Publication (kokai) No. 291094/1996, and WO97/09048. However, those compounds are different from the compounds according to the present invention in terms of their chemical structure.

DISCLOSURE OF THE INVENTION

[0011] The present invention is directed to pharmaceutical compositions for enhancing excellently the expression of apoAI.

[0012] Specifically, the invention provides

[0013] 1) A pharmaceutical composition for enhancing the expression of apoAI, which comprises a compound of formula (I): 2

[0014] in which

[0015] Y1 is O, S or NR1;

[0016] Y2 is CR2 or N;

[0017] Y3 is CR3 or N;

[0018] Y4 is CR4 or N;

[0019] Y5 is CR5 or N;

[0020] R1 is A1, -Z-A2, a hydrogen, a lower alkyl that may be optionally substituted, an acyl that may be optionally substituted, an amino that may be optionally substituted, a lower alkoxycarbonyl that may be optionally substituted, or a carbamoyl that may be optionally substituted;

[0021] R2, R3, R4 and R5 are independently A1, -Z-A2, a hydrogen, a halogen, a hydroxy, a lower alkyl that may be optionally substituted, a lower alkoxy that may be optionally substituted, a nitro, an acyl that may be optionally substituted, an amino that may be optionally substituted, a mercapto, a lower alkylthio that may be optionally substituted, a carboxy, a lower alkoxycarbonyl that may be optionally substituted, or a carbamoyl that may be optionally substituted;

[0022] A1 and A2 are independently a cycloalkyl that may be optionally substituted, an aryl that may be optionally substituted, or a heterocyclic ring that may be optionally substituted;

[0023] -Z- is a single bond, —CR6═CR7—, or —N—, wherein R6 and R7 are independently a hydrogen or a lower alkyl;

[0024] provided that at least one selected from Y1, Y2, Y3, Y4, and Y5 has A1, and any one of the others has -Z-A2; a prodrug thereof, a pharmaceutically acceptable salt or solvate of them;

[0025] 2) The pharmaceutical composition according to above 1), in which the 5-membered ring consisting of Y1, Y2, Y3, Y4, and Y5 has a nucleus selected from a group consisting of 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, and thiophene;

[0026] 3) The pharmaceutical composition according to above (2), in which the 5-membered ring consisting of Y1, Y2, Y3, Y4, and Y5 has a nucleus selected from a group consisting of 1,2,3-triazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, furan, and thiophene;

[0027] 4) The pharmaceutical composition according to any one of above (1) to (3), in which A1 and A2 are independently a phenyl, a pyridyl, a pyrazinyl, a furyl, a thienyl, a thiazolyl, a pyrazolyl, a isoxazolyl, a benzofuryl, or an indolyl, each of which may be optionally substituted;

[0028] 5) The pharmaceutical composition according to above (4), in which A1 and A2 are independently a phenyl that may be optionally substituted by a halogen, a hydroxy, a lower alkyl, a lower alkoxy, a lower alkylthio, an amino that may be optionally substituted by a lower alkyl, a phenyl, a styryl or a heteroaryl; a thiazolyl that may be optionally substituted by a lower alkyl; a pyrazolyl that may be optionally substituted by a lower alkyl; an unsubstituted pyridyl; an unsubstituted indolyl; an unsubstituted benzofuryl; an unsubstituted thienyl; or an unsubstituted furyl;

[0029] 6) The pharmaceutical composition according to any one of above (1) to (5), in which Z is a single bond;

[0030] 7) The pharmaceutical composition according to any one of above (1) to (6), in which Y1 is O, S or NR1, R1 is a lower alkyl that may be optionally substituted, or an amino that may be optionally substituted; and, among Y2, Y3, Y4 and Y5, one or two is (are) independently CA1, one is CA2, and the others are independently CH or N;

[0031] 8) The pharmaceutical composition according to any one of above (1) to (7), which is used for prevention and/or treatment of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases;

[0032] 9) A method of enhancing the expression of apoAI, which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in above (1), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient expected to enhance the expression of apoAI; preferably, the method which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in above (2) to (8), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them;

[0033] 10) A method of treatment and/or prevention of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases, which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in above (1), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient suspected to have blood lipid disorders, arteriosclerotic diseases or coronary artery diseases; preferably, the method which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in above (2) to (8), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them;

[0034] 11) Use of a compound of formula (I) as defined in above (1), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them for the manufacturing a medicament of enhancing the expression of apoAI; preferably, the use of a compound of formula (I) as defined in above (2) to (8), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them;

[0035] 12) Use of a compound of formula (I) as defined in above (1), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them for the manufacturing a medicament of treatment and/or prevention of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases; preferably, the use of a compound of formula (I) as defined in above (2) to (8), a prodrug thereof, a pharmaceutically acceptable salt or solvate of them.

[0036] When a compound according to the invention has two or more substituents: A1, then they may be the same or different each other.

[0037] The term “halogen” as used herein includes fluorine, chlorine, bromine and iodine.

[0038] The term “lower alkyl” as used herein refers to a straight or branched chain alkyl comprising 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, and the like.

[0039] The term “lower alkyl that may be optionally substituted” as used herein includes a lower alkyl, of which any position may be substituted by one or more substituents. The substituent may be a halogen, a hydroxy, a lower alkoxy, an aryl, an acyl, an acyloxy, a carboxy, a lower alkoxycarbonyl, an amino, a lower alkylamino, a nitro, a heteroaryl, and the like.

[0040] Alkyl moiety of “lower alkoxy”, “lower alkylthio” or “lower alkylamino” is similar to the “lower alkyl” as described above.

[0041] Substituent in “lower alkoxy that may be optionally substituted” and “lower alkylthio that may be optionally substituted” is similar to the substituent of “lower alkyl that may be optionally substituted” as described above.

[0042] The term “lower alkylenedioxy” specifically includes methylenedioxy and ethylenedioxy.

[0043] Lower alkyl moiety of “lower alkoxycarbonyl” is similar to the “lower alkyl” as described above, and substituent of “lower alkoxycarbonyl that may be optionally substituted” is similar to the substituent of “lower alkyl that may be optionally substituted” as described above.

[0044] The term “acyl” as used herein includes an aroyl and an aliphatic acyl containing 1 to 7 carbon atoms. Here, “aroyl” refers to a group wherein an aryl or a heteroaryl group is bound to a carbonyl group. Examples of the acyl are formyl, acetyl, propionyl, butyryl, isobutyryl, valery, pivaloyl, hexanoyl, acryloyl, propiolyl, methacryloyl, crotonoyl, benzoyl and the like. Preferably, acetyl and benzoyl are exemplified.

[0045] Substituent of “acyl that may be optionally substituted” is similar to the substituent of the “lower alkyl that may be optionally substituted” as described above. Aroyl may be substituted by a lower alkyl. Acyl may be substituted at one or more positions by such a substituent.

[0046] Acyl moiety of “acyloxy” is similar to the “acyl” as described above.

[0047] The term “amino that may be optionally substituted” as used herein refers to an unsubstituted, mono-substituted, or di-substituted amino. Examples of the substituents include the substituents of the “lower alkyl that may be optionally substituted” as described above, and a lower alkyl. Preferably, an unsubstituted amino, a lower alkylamino, a di-lower alkylamino, a benzylamino, and an acylamino are exemplified.

[0048] Substituent of “carbamonyl that may be optionally substituted” is similar to the substituent of the “lower alkyl that may be optionally substituted” as described above. Preferably, an unsubstituted carbamoyl and a di-lower alkylcarbamoyl are exemplified.

[0049] The term “cycloalkyl” as used herein refers to an aliphatic cyclic carbon ring group containing 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. This includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like.

[0050] Substituent of “cycloalkyl that may be optionally substituted” is similar to the substituent of the “lower alkyl that may be optionally substituted” as described above.

[0051] The term “aryl” as used herein includes, for example, phenyl, naphthyl, indanyl, indenyl, and anthryl. Phenyl and naphthyl are preferable, and phenyl is most preferable.

[0052] The term “heteroaryl” as used herein refers to a monocyclic and bicyclic aromatic heterocyclic ring group containing one or more hetero atoms selected from the group consisting of N, S and O within its ring. Examples of the heteroaryl include a monocyclic group, e.g., pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, and the like; as well as a bicyclic ring group, e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopiridazinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, pteridinyl, naphthylidinyl, pyrazinopyridazinyl, and the like. Preferably, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, benzoxazolyl, benzofuryl, benzothienyl, and the like.

[0053] The term “heterocyclic ring” refers to the “heteroaryl” as described above, as well as a monocyclic or bicyclic non-aromatic ring group containing one or more hetero atoms selected from the group consisting of N, S and O within its ring. Examples of the non-aromatic heterocyclic ring include a monocyclic group dioxanyl, dioxazinyl, dioxolanyl, dioxolyl, dithiazinyl, imidazolidinyl, imidazolinyl, morpholyl, morpholino, oxazinyl, oxadiazyl, furazanyl, oxathianyl, oxathiazinyl, oxathiolanyl, oxazolidinyl, oxazolinyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiadiazolidinyl, thianyl, thiazinyl, thiadiazinyl, thiiranyl, thioranyl, and the like; as well as a bicyclic group chromanyl, 2H-chromenyl, coumarinyl, coumaranonyl, 1,3-dioxaindanyl, indolinyl, isoindolinyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 6,7-dihydro-5H-[1]-pyrimidinyl, benzothiazinyl, tetrahydroquinoxalyl, cyclo-pentenopyridinyl, 4,5,6,7-tetrahydro-1H-indolyl, 4-oxochromenyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl and pyrrolidinyl, and the like.

[0054] Substituents of “aryl that may be optionally substituted” and “heterocyclic ring that may be optionally substituted” in A1 and A2 include a halogen; a hydroxy; a lower alkyl optionally substituted by a halogen, a hydroxy or a lower alkoxy; a lower alkoxy optionally substituted by a halogen, a hydroxy, a carboxy or a lower alkoxycarbonyl; a lower alkenyl optionally substituted by a halogen, a hydroxy, a carboxy, a lower alkoxycarbonyl or a phenyl; a lower alkenyloxy optionally substituted by a halogen or a hydroxy; a mercapto; a lower alkylthio; a cycloalkyl optionally substituted by a halogen, a hydroxy or a lower alkyl; an acyl optionally substituted by a lower alkyl; an acyloxy; a carboxy; a lower alkoxycarbonyl; a lower alkenyloxycarbonyl; an amino optionally substituted by a lower alkyl or an acyl; a hydrazino; a carbamoyl optionally substituted by a lower alkyl; a lower alkylsulfonyl; a nitro; a cyano; an aryl optionally substituted by a halogen, a hydroxy, a lower alkyl or a lower alkoxy; a heterocyclic ring; a phenoxy optionally substituted by a halogen, a hydroxy or a lower alkyl; a monocyclic heteroaryloxy; a phenylamino optionally substituted by a halogen, a hydroxy or a lower alkyl; an oxo; and a lower alkylenedioxy; and the like. Such the substituents may be bound at one or more arbitrary positions.

[0055] The compounds according to the invention include pharmaceutically acceptable, producible salts. Examples of the “pharmaceutically acceptable salts” include a salt with an inorganic acid e.g. those with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or the like; a salt with an organic acid e.g. those with p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, citric acid, or the like; a salt with an organic base e.g. ammonium, trimethylammonium, triethylammonium, or the like; a salt with an alkaline metal e.g. sodium or potassium, or the like; a quaternary salt with alkyl halide e.g., methyl iodide, ethyl iodide or the like; and a salt with an alkaline earth metal e.g., calcium or magnesium, or the like.

[0056] The compounds according to the invention may form solvates as coordinated with a suitable organic solvent and/or water. Hydrates are preferable.

[0057] The compounds according to the invention also include prodrugs. In the context of the invention, a “prodrug” is a derivative of a compound according to the invention comprising a chemically or metabolically cleavable group. In the course of metabolism in the body, a prodrug shows a pharmacological activity as a result of conversion to the compounds according to the invention. Method for selecting and producing suitable prodrug derivatives are described in, e.g. “Design of Prodrugs, Elsevier, Amsterdam (1985)”.

[0058] Prodrugs of a compound according to the invention having a carboxy are exemplified by an ester derivative produced by condensing the carboxy group with a suitable alcohol, e.g., COORA wherein RA is a lower alkyl, a lower alkenyl or an aryl, each of which may be optionally substituted in which the substituent may be a hydroxy, an acyloxy, a carboxy, a sulfonic acid, an amino, a lower alkylamino, or the like; and alternatively by an amide derivative produced by reacting the carboxy and a suitable amine, e.g., CONRBRC wherein RB is a hydrogen, a lower alkyl, or the like; and RC is a hydrogen, a lower alkyl, an amino, a hydroxy, or the like.

[0059] Prodrugs of a compound according to the invention having a hydroxy are exemplified by an acyloxy derivative produced by reacting the hydroxy group and a suitable acyl halide or a suitable acid anhydride, e.g., —OCORA wherein RA is as defined above.

[0060] Prodrugs of a compound according to the invention having an amino are exemplified by an amide derivative produced by reacting the amino group and a suitable acid halide or a suitable mixed anhydride compound, e.g., NHCORA, and NHCOORA wherein RA is as defined above.

[0061] When compound (I) according to the invention has an asymmetric carbon atom, then the invention encompasses a racemic mixture, both of enantiomers, and all of diastereomers. When compound (I) according to the invention has a double bond, the invention may include both of geometric isomers resulting from possible arrangements of its substituents.

[0062] Although all of the compounds according to the invention have an activity for enhancing the expression of apoAI, the following compounds that comprise one group: A1 and one group: A2 can be listed as preferable compounds.

[0063] Compounds of formula (I):

[0064] (1) wherein the 5-membered ring consisting of Y, Y2, Y3, Y4 and Y5 is:

[0065] 1,2,3-triazole having one of A1 and A2 at position 1 and the other at position 4 (hereinafter Y-1);

[0066] 1,2,4-oxadiazole having one of A1 and A2 at position 3 and the other at position 5 (hereinafter Y-2);

[0067] 1,2,4-triazole having one of A1 and A2 at position 3 and the other at position 5 (hereinafter Y-3);

[0068] 1,3,4-oxadiazole having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-4);

[0069] 1,2,4-thiadiazole having one of A1 and A2 at position 3 and the other at position 5 (hereinafter Y-5);

[0070] 1,3,4-thiadiazole having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-6);

[0071] furan having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-7);

[0072] isoxazole having one of A1 and A2 at position 3 and the other at position 5 (hereinafter Y-8);

[0073] oxazole having one of A1 and A2 at position 2 and the other at position 4 (hereinafter Y-9);

[0074] oxazole having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-10);

[0075] pyrazole having one of A1 and A2 at position 3 and the other at position 5 (hereinafter Y-11);

[0076] tetrazole having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-12);

[0077] thiazole having one of A1 and A2 at position 2 and the other at position 4 (hereinafter Y-13);

[0078] thiazole having one of A1 and A2 at position 2 and the other at position 5 (hereinafter Y-14); or

[0079] 1,2,4-triazole having one of A1 and A2 at position 1 and the other at position 3 (hereinafter Y-15); and

[0080] (2) wherein A1 and A2 are defined as follows:

[0081] A1 or A2 is a phenyl that may be optionally substituted by one or more substituents selected from the group consisting of a hydroxy, a lower alkoxy, a lower alkyl, a lower thioalkyl, an amino optionally substituted by a lower alkyl, a halogen, a phenyl and a thiadiazolyl (hereinafter A1 or A2 is regarded as A-1);

[0082] A1 or A2 is a furyl, thiazolyl, thienyl or pyrazolyl, each of which may be optionally substituted by one of more substituents selected from the group consisting of a lower alkyl optionally substituted by a halogen, a lower alkylsulfonyl, a lower alkylcarbamoyl, a nitro, a phenyl, a benzoyl, and a thienyl (hereinafter A1 or A2 is regarded as A-2);

[0083] A1 or A2 is a pyridyl that may be optionally substituted by a halogen (hereinafter A1 or A2 is regarded as A-3);

[0084] A1 or A2 is a benzofuryl or a indolyl (hereinafter A1 or A2 is regarded as A-4);

[0085] Both A1 and A2 are A-1 (hereinafter A1 and A2 are regarded as A-5);

[0086] One of A1 and A2 is A-1 and the other is A-2 (hereinafter A1 and A2 are regarded as A-6);

[0087] One of A1 and A2 is A-1 and the other is A-3 (hereinafter A1 and A2 are regarded as A-7);

[0088] One of A1 and A2 is A-1 and the other is A-4 (hereinafter A1 and A2 are regarded as A-8);

[0089] Both of A1 and A2 are A-2 (hereinafter A1 and A2 are regarded as A-9);

[0090] One of A1 and A2 is A-2 and the other is A-3 (hereinafter A1 and A2 are regarded as A-10); and

[0091] (3) wherein Z is defined as follows:

[0092] Z is a single bond; or

[0093] Z is —N— or —HC═CH—.

[0094] More preferable compounds having one group: A1 and one group: A2 are those of formula (I) wherein Z is a single bond; and a combination of the 5-membered ring comprising Y1, Y2, Y3, Y4 and Y5, and A1 and A2, i.e., (Y, A) is as follows:

[0095] (Y-1, A-5), (Y-2, A-5), (Y-3, A-5), (Y-4, A-5), (Y-5, A-5), (Y-6, A-5), (Y-7, A-5), (Y-8, A-5), (Y-9, A-5), (Y-10, A-5), (Y-11, A-5), (Y-12, A-5), (Y-13, A-5), (Y-14, A-5), (Y-1, A-6), (Y-2, A-6), (Y-3, A-6), (Y-4, A-6), (Y-6, A-6), (Y-7, A-6), (Y-8, A-6), (Y-9, A-6), (Y-10, A-6), (Y-11, A-6), (Y-12, A-6), (Y-13, A-6), (Y-14, A-6), (Y-1, A-7), (Y-2, A-7), (Y-3, A-7), (Y-4, A-7), (Y-5, A-7), (Y-6, A-7), (Y-7, A-7), (Y-8, A-7), (Y-9, A-7), (Y-10, A-7), (Y-11, A-7), (Y-12, A-7), (Y-13, A-7), (Y-14, A-7), (Y-1, A-8), (Y-2, A-8), (Y-3, A-8), (Y-4, A-8), (Y-5, A-8), (Y-6, A-8), (Y-7, A-8), (Y-8, A-8), (Y-9, A-8), (Y-10, A-8), (Y-11, A-8), (Y-12, A-8), (Y-13, A-8), (Y-14, A-8), (Y-1, A-9), (Y-2, A-9), (Y-3, A-9), (Y-4, A-9), (Y-5, A-9), (Y-6, A-9), (Y-7, A-9), (Y-8, A-9), (Y-9, A-9), (Y-10, A-9), (Y-11, A-9), (Y-12, A-9), (Y-13, A-9), (Y-14, A-9), (Y-1, A-10), (Y-2, A-10), (Y-3, A-10), (Y-4, A-10), (Y-5, A-10), (Y-6, A-10), (Y-7, A-10), (Y-8, A-10), (Y-9, A-10), (Y-10, A-10), (Y-11, A-10), (Y-12, A-10), (Y-13, A-10) or (Y-14, A-10).

[0096] Some illustrative examples of compound (I) according to the invention are shown in Tables below.

TABLE 1
Compound	Publications or					M.p (° C.)
No.	Manufactures	year,	Vol.,	Page	Structure	or MS
123TA14-1	Organic Synthesis	1963	4	380	3	169-171
123TA14-2	J. Am. Chem. Soc. (Maybridge)	1964	86	2213	4
123TA15-1	J. Prakt. Chem	1966	33	199	5	124
123TA15-2	Zh. Org. Khim	1967	3	968	6	112-113
123TA15-3	Maybridge				7
123TA24-1	Helv. Chim. Acta	1991	74	501	8	140-142
123TA24-2	J. Chem. Soc. (C)	1968		2097	9	101
123TA24-3	J. Chem. Soc. (C)	1968		2097	10	40
123TA24-4	J. Chem. Soc. (C)	1968		2097	11	164
123TA45-1	Tetrahedron Lett.	1993	34	1055	12	130-131
123TA45-2	Tetrahedron Lett.	1993	34	1055	13	139-140
123TA45-3	J. Org. Chem.	1987	52	375	14	126-8

[0097]

TABLE 2
123TA45-4	J. Heterocycl. Chem.	1996	33	911	15	246-247
123TA45-5	J. Chem. Soc.	1988		2917	16	oil
123TA45-6	J. Chem. Soc.	1988		2917	17	187-8
123TA45-1	Heterocycles	1990	31	1669	18	161-163
123TD45-1	J. Med. Chem.	1985	28	442	19	81.5-82.5
123TD46-2	J. Med. Chem.	1985	28	442	20	56.5-58
123TD45-3	J. Med. Chem.	1985	28	442	21	84-86
123TD45-4	J. Med. Chem.	1985	28	442	22	117-119
123TD45-5	J. Med. Chem.	1985	28	442	23	107-109
123TD45-6	Maybridge				24	92-94
124OD35-1	Tetrahedron Lett.	1996	37	6627	25	no data
124OD35-2	Synthesis	1983	6	483	26	107-109
124OD35-3	Maybridge				27

[0098]

TABLE 3
124OD35-4	Maybridge				28
124OD35-5	Maybridge				29
124OD35-6	Maybridge				30	121-122
124OD35-7	Maybridge				31
124OD85-8	J. Heterocycl. Chem.	1983	20	1693	32	125-127
124OD35-9	Heterocycles	1996	43	1021	33	114-115
124OD35-10	Maybridge				34
124OD35-11	Arch. Pharm	1994	327	389	35	127-129
124OD35-12					36	97-98
124OD35-13	BIONET				37
124OD35-14	Maybridge				38
124OD35-15	Maybridge				39
124TA13-1	Tetrahedron Lett.	1985	26	5655	40	88-89
124TA13-2	Synthesis	1993		59	41	198-200
124TA13-3	Syntec				42
124TA13-4	Maybridge				43

[0099]

TABLE 4
124TA13-5	J. Chem. Soc.	1970		1515	44	175-6
124TA13-6	J. Chem. Soc.	1970		1515	45	199-200
124TA13-7	J. Chem. Soc.	1994		3563	46	139- 149dec
124TA13-8	J. Chem. Soc.	1994		3563	47	93-94
124TA13-9	Maybridge				48
124TA15-1	Synthesis	1986		772	49	126-127
124TA15-2	Maybridge				50
124TA15-3	Salor				51
124TA15-4	Maybridge				52
124TA15-5	Maybridge				53
124TA15-6	J. Heterocycl. Chem.	1983	20	1693	54	125-127
124TA15-7	J. Heterocycl. Chem.	1983	20	1693	55	141-143

[0100]

TABLE 5
124TA15-8	Chem. Pharm. Bull	1997	45	987	56	189-190
124TA15-9	Chem. Pharm. Bull	1997	45	987	57	263-264
124TA34-1	J. Heterocycl. Chem.	1976	16	561	58	252-253
124TA34-2	J. Heterocycl. Chem.	1976	16	561	59	199-200
124TA34-3	J. Heterocycl. Chem.	1976	16	561	60	185
124TA34-4	J. Heterocycl. Chem.	1992	29	1101	61	282
124TA34-5	J. Heterocycl. Chem.	1992	29	1101	62	201
124TA34-6	Bull. Chem. Soc. Jpn	1984	57	544	63	139-140
124TA34-7	Bull. Chem. Soc. Jpn	1984	57	544	64	149-151
124TA34-8	Bull. Chem. Soc. Jpn	1984	57	544	65	121-2
124TA34-9	Bull. Chem. Soc. Jpn	1984	57	544	66	189-190
124TA34-10	Bull. Chem. Soc. Jpn	1984	57	544	67	165-6
124TA34-11	Bull. Chem. Soc. Jpn	1984	57	544	68	192-194

[0101]

TABLE 6
124TA34-12	Bull. Chem. Soc. Jpn	1984	57	544	69	184-6
124TA34-13	Bull. Chem. Soc. Jpn	1984	57	544	70	174-175
124TA35-1	J. Org. Chem.	1996	61	8397	71	192-195
124TA35-2	J. Med. Chem.	1983	26	1187	72	191-192
124TA35-3	J. Med. Chem.	1983	26	1187	73	152-3
124TA35-4	J. Med. Chem.	1983	26	1187	74	112-4
124TA35-5	J. Med. Chem.	1983	26	1187	75	127-130
124TA35-6	J. Med. Chem.	1983	26	1187	76	100-102
124TA35-7	J. Med. Chem.	1983	26	1187	77	144-6
124TA35-8	J. Med. Chem.	1983	26	1187	78	155-7
124TA35-9	J. Med. Chem.	1991	34	281	79	144-7
124TA35-10	J. Med. Chem.	1991	34	281	80	196-9
124TA35-11	J. Heterocycl. Chem.	1983	20	1693	81	224-226
124TA35-12	J. Heterocycl. Chem.	1991	28	1197	82	171-171.5
124TA35-13	Maybridge				83
124TA35-14	Bull. Chem. Soc. Jpn	1983	56	545	84	79-81

[0102]

TABLE 7
124TA35-15	Acta. Chem. Scand	1991	45	609	85	81-82
124TA35-16	Acta. Chem. Scand	1991	45	609	86	74-75
124TA35-17					87	169-170
124TD35-1	Chem. Commun.	1984		1386	88	55-57
124TD35-2	Bull. Chem. Soc. Jpn	1985	58	995	89	91-91.5
124TD35-3	Bull. Chem. Soc. Jpn	1985	58	995	90	139-139.5
124TD35-4	Bull. Chem. Soc. Jpn	1985	58	995	91	161.5-2.5
124TD35-5	Bull. Chem. Soc. Jpn	1985	58	995	92	180-180.5
124TD35-6	Salor				93
125TD34-1	J. Heterocycl. Chem.	1992	27	1861	72-73
134OD25-2	Tokyo Kase Kogyo				94
134OD25-3	Maybridge				95
134OD26-4	Maybridge				96
134OD25-5	Maybridge				97
134OD25-6	Lancaster				98
134OD25-7	Fluka				99
134OD25-8	Aldrich				100

[0103]

TABLE 8
134OD25-13	101	202-203
134OD25-14	102	120-122
134OD25-15	103	135-140
134OD25-16	104	131-132.5
134OD25-17	105	169-170.5
134OD25-18	106	142-143
134OD25-19	107	170-172
134OD25-20	108	146.5-148
134OD25-21	109	154-156
134OD25-22	110	223-224
134OD25-23	111	131-132
134OD25-24	112	258-260
134OD25-25	113	121-124
134OD25-26	114	108-109
134OD25-27	115	261-263

[0104]

TABLE 9
134OD25-28	116	148-149
134OD25-29	117	164-165.5
134OD25-30	118	88-89
134OD25-31	119	228-229
134OD25-32	120	70-71
134OD25-33	121	65-67
134OD25-34	122	95-97
134OD25-35	123	118-120
134OD25-36	124	120.5-122
134OD25-37	125	94-95.5
134OD25-38	126	101-102
134OD25-39	127	234-236
134OD25-40	128	82-83
134OD25-41	129	160-164
134OD25-42	130	103-105
134OD25-43	131	118-119
134OD25-44	132	140-142
134OD25-45	133	126-127

[0105]

TABLE 10
134OD25-46				134	127-128
134OD25-47				135	176-478
134OD25-48				136	122-124
134OD25-49				137	165-167
134OD25-50				138	111-113
134TD25-1				139	117-119
134TD25-2				140	75.5-76.5
134TD25-3				141	90-91
134TD25-4				142	66-67
134TD25-5				143	111-113
134TD25-6				144	61-62.5
F23-1	Synth. Lett	1991	869	145	no mp
F23-2	Synth. Lett	1991	869	146	no mp
F23-3	Maybridge			147
F24-1	Synthesis	1981	625	148	109-110
F24-2	Synthesis	1983	49	149	175

[0106]

TABLE 11
F24-3	Synthesis	1983		49	150	133
F24-4	Maybridge				151
F24-5	Maybridge				152
F24-6	Maybridge				153
F24-7	Chem. Commun.	1968		33	154	129-130
F25-1	Synthesis	1984	7	593	155	195-196
F25-2	Synthesis	1984	7	593	156	167-168
F25-3	Synthesis	1984	7	593	157	210 dec
F25-4	Synthesis	1987		1022	158	97-98
F25-5	Synthesis	1996		388	159	54-55.5
F25-6	J. Chem. Soc.	1997		477	160	91-92
F25 7	J. Chem. Soc.	1997		477	161	105-107
F25-8	J. Chem. Soc.	1997		477	162	85-86
F25-9	Chem. Pharm. Bull	1996	44	448	163	117-118
F25-10	Lancaster				164	82-84
F25-11	Maybridge				165

[0107]

TABLE 12
F25-12	Maybridge				166
F34-1	Tetrahedron	1994	50	9583	167	107-111
F34-2	Tetrahedron	1994	50	9583	168	133-134
F34-3	Chem. Commun.	1992	11	656	169	105-7
IM12-1	Salor				170
IM12-2	Salor				171
IM12-3	Salor				172
IM12-4	Salor				173
IM12-5	J. Chem. Soc.	1991		2821	174	220-221
IM12-6	Heterocycles	1995	41	1617	175
IM12-7	Chem. Pharm. Bull	1997	45	987	176	oil
IM12-8	Chem. Pharm. Bull	1997	45	987	177	210-211

[0108]

TABLE 13
IM12-9	Chem. Commun.	1984		430	178	105
IM12-10	Chem. Ber	1989	122	1983	179	208
IM14-1	Maybridge				180
IM14-2	J. Org. Chem.	1964	29	153	181	187-192 dec
IM14-3	J. Org. Chem.	1964	29	153	182	195-210 dec
IM14-4	J. Heterocycl. Chem.	1978	15	1543	183
IM14-5	J. Heterocycl. Chem.	1978	15	1543	184
IM15-1	Synthesis	1990		781	185	153-165
IM15-2	J. Org. Chem.	1977	42	1153	186	154-155
IM15-3	J. Org. Chem.	1977	42	1153	187	97-98
IM15-4	J. Org. Chem.	1977	42	1153	188	154-5
IM15-5	J. Org. Chem.	1977	42	1153	189	164-5

[0109]

TABLE 14
IM15-6	Maybridge				190
IM15-7	J. Chem. Soc.	1992		147	191	173-175
IM24-1	J. Org. Chem.	1993	58	7092	192	62-64
IM24-2	J. Org. Chem.	1997	62	3480	193	182-183
IM24-3	J. Org. Chem.	1997	62	3480	194	200-201.5
IM24-4	Heterocycles	1994	38	575	195	88-94
IM24-5	Heterocycles	1994	38	575	196	291 dec
IM24-6	Bull. Soc. Chim. Belg	1986	95	1073	197	116
IM24-7	Chem. Ber	1896	29	2097	198
IM45-1	J. Chem. Soc.	1980		244	199	156-157
IM45-2	J. Chem. Soc.	1980		244	200	172-3
IM45-3	J. Chem. Soc.	1980		244	201	134-5
IM45-4	J. Chem. Soc.	1980		244	202	162-3

[0110]

TABLE 15
IM45-5	J. Chem. Soc.	1980		244	203	144-5
IM45-6	J. Chem. Soc.	1980		244	204	138-9
IM45-7	J. Chem. Soc.	1980		244	205	94-95
IM45-8	J. Chem. Soc.	1980		244	206	196-7
IM45-9	Heterocycles	1990	31	2187	207	177.5-179.5
IM45-10	Heterocycles	1990	31	2187	208	132-133.5
IM45-11	Helv. Chim. Acta	1978	61	286	209	241.5-242.5
IM45-12	Helv. Chim. Acta	1978	61	286	210	275-277
IM45-13	Chem. Pharm. Bull	1991	39	651	211	195-196
IM45-14	Chem. Pharm. Bull	1991	39	651	212	201.5-204
IM45-15	Chem. Pharm. Bull	1991	39	651	213	182-185
IM45-16					214	228-230

[0111]

TABLE 16
IT34-1	Chem. Commun.	1970		386	215	82-83.5
IT35-1	Chem. Lett.	1984		1691	216	80-81
IT35-2	Chem. Lett.	1984		1691	217
IT35-3	Chem. Lett.	1984		1691	218
IT45-1	Maybridge				219
IT45-2	Maybridge				220
IT45-3	J. Chem. Soc.	1972		1432	221	245-7
IX34-1	Synthetic Lett.	1996		695	222	160
IX34-2	Synthetic Lett.	1996		695	223
IX34-3	Synthetic Lett.	1996		695	224
IX34-4	Maybridge				225
IX34-5	Maybridge				226
IX34-6	J. Heterocycl. Chem.	1990	27	2097	227	143-145
IX35-1	Synthesis	1992		1205	228	140-142

[0112]

TABLE 17
IX35-2	Synthesis	1992		1205	229	124-126
IX35-3	Synthesis	1992		1205	230	122-128
IX35-4	Organic Synthesis	1988	6	278	231	175-176
IX35-5	J. Org. Chem.	1983	48	4590	232	177-8
IX35-6	Acta. Chem. Scand.	1994	48	61	233	235-238
IX35-7	Acta. Chem. Scand.	1994	48	61	234	269-270
IX35-8					165-166
IX35-9					235	36-37
IX35-10					236	47-48
IX35-11					237	80-81
IX35-12					238	78-78.5
IX35-13					239	129.5-130.5
IX35-14					240	59-60
IX45-1	Maybridge				241
IX45-2	Maybridge				242
IX45-3	J. Org. Chem.	1995	60	6637	243	86-87

[0113]

TABLE 18
IX45-4	J. Org. Chem.	1996	61	5435	244	68-70
IX45-5	J. Org. Chem.	1996	61	5485	245	126-128
IX45-6	J. Org. Chem.	1996	61	5435	246	82-84
IX45-7	J. Org. Chem.	1996	61	5435	247	52-54
OX24-1	Tetrahedron	1996	52	10131	248	123-4
OX24-2	Tetrahedron	1996	52	10131	249	114-5
OX24-3	Tetrahedron	1996	52	10131	250	98-99
OX24-4	J. Org. Chem.	1996	61	3749	251	94-95
OX24-5	J. Org. Chem.	1996	61	4623	252	97.5-99
OX24-6	J. Org. Chem.	1996	61	4623	253	131-132
OX24-7	Salor				254
OX24-8	Tokyo Kase Kogyo				255	105
OX25-1	J. Heterocycl. Chem.	1975	12	263	256	72-74
OX25-2					257	88-90
OX25-3					258
OX45-1	Salor				259

[0114]

TABLE 19
OX45-2	J. Med. Chem.	1968	11	1092	260	167-8
OX45-3	J. Med. Chem.	1968	11	1092	261	140-141
OX45-4	J. Med. Chem.	1968	11	1092	262	77-79
OX45-5	J. Heterocycl. Chem.	1975	12	263	263	22-24
OX45-6	Maybridge				264
OX45-7	Maybridge				265
P12-1	J. Chem. Soc. Perkin Trans 1	1990		2995	266	119-120
P12-2	Eur. J. Med. Chem.	1992	27	70	267	131-133
P12-3	Eur. J. Med. Chem.	1992	27	70	268	140-142
P12-4	Heterocycles	1994	37	1549	269	134
P12-5	Heterocycles	1994	37	1549	270	104
P12-6	Synthesis	1995		1315	271	80-82
P12-7	Synthesis	1995		1315	272	oil
P12-8	Synthesis	1995		1315	273	74-76

[0115]

TABLE 20
P12-9	J. Chem. Soc.	1996		1617	274	152-154
P13-1	Tetrahedron Lett	1996	37	4099	275	122-128
P13-2	Tetrahedron Lett	1996	37	4099	276	41-42
P23-1	Tetrahedron	1995	51	13271	277	215-6
P23-2	SALOR				278
P23-3	J. Org. Ohem.	1994	59	4551	279	oil
P23-4	J. Org. Chem.	1994	59	4551	280	124-125
P23-5	J. Org. Chem.	1995	60	6637	281	139-140
P23-6	J. Chem. Soc.	1997		1851	282	131-2
P23-7	Bull. Chem. Soc. Jpn	1995	68	2735	283	143.5-4.5
P24-1	Organic Synthesis	1955	3	358	284	174-176
P24-2	J. Org. Chem.	1978	43	3370	285	196-196.5
P24-3	J. Chem. Soc.	1997		1851	286	131-2
P24-4	Maybridge				287

[0116]

TABLE 21
P25-1	Salor				288
P25-2	MENAI				289
P25-3	J. Org. Chem.	1978	43	3370	290	138-139
P25-4	J. Org. Chem.	1984	49	4780	291	126-7
P25-5	J. Org. Chem.	1996	61	1180	292	215-216
P25-6	Heterocycles	1986	24	2437	293	139-140
P25-7	Heterocycles	1986	24	2437	294	150-151
P25-8	Heterocycles	1986	24	2437	295	156-157
P25-9	Bull. Chem. Soc. Jpn	1990	63	3595	296	105-107
P34-1	Salor				297
P34-2	J. Org. Chem.	1992	57	2245	298	92-95
P34-3	J. Org. Chem.	1995	60	6637	299	169-171
P34-4	Heterocycles	1987	26	3197	300	125-128
P34-5	DP00653 (Maybridge)				301
P34-6	Chem. Commun.	1997		207	302	158-9

[0117]

TABLE 22
PZ13-1	Synthesis	1991		1153	303	76-79
PZ13-2	Maybridge				304
PZ13-3	J. Org. Chem.	1996	61	2763	305	oil
PZ13-4	J. Heterocycl. Chem.	1993	30	365	306	90-91
PZ13-5	J. Heterocycl. Chem.	1993	30	365	307	98-99
PZ13-6	J. Heterocycl. Chem.	1993	30	365	308	336, 335, 301, 123, 118, 77
PZ13-7	Heterocycles	1992	33	813	309	81-83
PZ13-8	Chem. Pharm. Bull	1997	45	987	310	100-102
PZ13-9	Can. J. Chem	1997	75	913	311	102.5-105
PZ13-10	J. Heterocycl. Chem.	1990	27	1847	312	225
PZ14-1	J. Heterocycl. Chem.	1993	30	365	313	318, 303, 78, 77
PZ14-2	J. Heterocycl. Chem.	1993	30	365	314	334, 319, 104, 77
PZ14-3	Heterocycles	1992	33	813	315	95-97
PZ14-4	Maybridge				316
PZ14-5	Maybridge				317
PZ14-6	Maybridge				318

[0118]

TABLE 23
PZ14-7	Maybridge				319
PZ15-1	Tetrahedron	1994	50	12727	320	oil
PZ15-2	Synthesis	1997		337	321	102-104
PZ15-3	Synthesis	1997		337	322	110-112
PZ15-4	Synthesis	1997		337	323	108-110
PZ15-5	Synthesis	1997		337	324	106-108
PZ15-6	J. Org. Chem.	1988	53	1973	325	oil
PZ15-7	J. Org. Chem.	1988	53	1973	326	99-100
PZ15-8	Chem. Pharm. Bull	1997	45	987	327	194-196
PZ15-9	Chem. Pharm. Bull	1997	45	987	328	153-154
PZ15-10	Bull. Chem. Soc. Jpn	1973	46	947	329	121
PZ34-1	Tetrahedron	1996	52	4383	330	188
PZ34-2	Peakdale				331
PZ34-3	Peakdale				332

[0119]

TABLE 24
PZ34-4	J. Org. Chem.	1978	43	3370	333	259-261
PZ34-5	J. Chem. Soc.	1991		329	334	126-7
PZ34-6	Bull. Soc. Chim. Belg	1986	95	1073	335
PZ34-7	BIONET				336
PZ35-1	J. Chem. Soc.	1994		2533	337	158-160
PZ35-2	J. Chem. Soc.	1994		2533	338	oil
PZ35-3	Can. J. Chem	1980	58	494	339	59-60
PZ35-4					340	107-108
PZ35-5	Tokyo Kase Kogyo				341
PZ35-6	Lancaster				342	199-200
PZ35-7					343
PZ45-1	Bull. Chem. Soc. Jpn.	1992	65	698	344	116-117
T23-1	J. Heterocycl. Chem.	1996	33	687	345	120-121
T23-2	Heterocycles	1996	43	2747	346	132-134
T23-3	Bull. Chem. Soc Jpn	1994	67	2187	347	67-68

[0120]

TABLE 25
T23-4	Maybridge				348
T24-1	Maybridge				349
T24-2	Maybridge				350
T24-3	Bull. Chem. Soc. Jpn	1994	67	2187	351	159-161
T24-4	Bull. Chem. Soc Jpn	1994	67	2187	352	74-76
T25-1	Tetrahedron	1996	52	12677	353	225-226
T25-2	Tetrahedron	1996	52	12677	354	164
T25-3	Maybridge				355
T25-4	Maybridge				356
T25-5	Maybridge				357
T25-6	J. Org. Chem.	1992	57	1722	358	148-9
T25-7	J. Org. Chem.	1992	57	1722	359	161-2
T25-8	Heterocycles	1994	39	819	360	141
T25-9	Heterocycles	1994	39	819	361	140
T25-10	ALDRICH				362
T25-11					363	60-61
T25-12					364	82-83

[0121]

TABLE 26
T34-1	Maybridge				365
T34-2	J. Org. Chem.	1997	62	1940	366	115-116
T34-3	J. Org. Chem.	1997	62	1940	367	oil
T34-4	J. Org. Chem.	1997	62	1940	368	104-106
TZ-1	Maybridge				369
TZ-2					370	139-141
TZ-3					371	102-103
TZ-4					372	161-163
TZ-5					373	101-102
TZ-6					374	118-119
TZ-7					375	101-101.5
TZ24-1	Heterocycles	1991	32	2127	376	130-131
TZ24-2	Chem. Lett.	1984		1691	377	92.5-93.5
TZ24-3	Maybridge				378
TZ24-4					379	148-150
TZ24-5					380	98.5-100
TZ24-6					381	77-78

[0122]

TABLE 27
TZ24-7		382	65-68
TZ24-8		383	200-201
TZ24-9		384	130-131
TZ24-10		385
TZ24-11		386	111-112
TZ24-12		387	125.5-126.5
TZ24-13		388	160-162
TZ24-14		389	121-123
TZ24-15		390	66.5-67.5
TZ24-16		391	80.5-82
TZ24-17		392	111-113
TZ24-18		393	186-188
TZ24-19		394	156-157
TZ24-20		395	178-180
TZ25-1	Maybridge	396
TZ25-2		397	131-132
TZ25-3	BIONET	398
TZ25-4	BIONET	399
TZ25-5	BIONET	400

[0123]

TABLE 28
TZ25-6					401	61-62
TZ25-7					402
TZ25-8	Synthesis	1994		1467	403	65-66.5
TZ25-9	Maybridge				404
TZ25-10	Maybridge				405
TZ25-11	Maybridge				406
TZ26-12	J. Med. Chem.	1991	34	2158	407	280 dec
TZ25-13	J. Med. Chem.	1991	34	2158	408	273-6
TZ25-14	J. Med. Chem.	1991	34	2158	409	218-220
TZ45-1	Salor				410
TZ45-2	J. Med. Chem.	1994	37	1189	411	146-8
TZ45-3	J. Med. Chem.	1994	37	1189	412	204-6
TZ45-4	Heterocycles	1991	32	2127	413	oil
TZ45-5	Heterocycles	1991	32	2127	414	91-92
TZ45-6	Maybridge				415

[0124] In the Tables, preferable compounds are 123TA14-2, 123TD45-6, 124OD35-12, 124OD35-13, 124OD35-14, 124OD35-15, 124TA35-17, 124TD35-6, 134OD25-9, 134OD25-10, 134OD25-11, 134OD25-12, 134OD25-13, 134OD25-14, 134OD25-15, 134OD25-16, 134OD25-17, 134OD25-18, 134OD25-19, 134OD25-20, 134OD25-21, 134OD25-22, 134OD25-23, 134OD25-24, 134OD25-25, 134OD25-26, 134OD25-27, 134OD25-28, 134OD25-29, 134OD25-30, 134OD25-31, 134OD25-32, 134OD25-33, 134OD25-34, 134OD25-35, 134OD25-36, 134OD25-37, 134OD25-38, 134OD25-39, 134OD25-40, 134OD25-41, 134OD25-42, 134OD25-43, 134OD25-44, 134OD25-45, 134OD25-46, 134OD25-47, 134OD25-48, 134OD25-49, 134OD25-50, 134TD25-2, 134TD25-3, 134TD25-4, 134TD25-5, 134TD25-6, F25-10, IM45-12, IM45-16, IX35-1, IX35-8, IX35-9, OX24-5, OX24-7, OX24-8, OX25-1, OX25-2, PZ35-4, PZ35-5, PZ35-6, T25-1, TZ-1, TZ-2, TZ-3, TZ-4, TZ-5, TZ-6, TZ-7, TZ24-2, TZ24-3, TZ24-4, TZ24-5, TZ24-6, TZ24-7, TZ24-8, TZ24-9, TZ24-11, TZ24-12, TZ24-13, TZ24-14, TZ24-15, TZ24-16, TZ24-17, TZ24-18, TZ24-19, TZ24-20, TZ25-2, and TZ25-6.

[0125] More preferable compounds are 123TA14-2, 124OD35-12, 124OD35-13, 124OD35-14, 124OD35-15, 124TA35-17, 124TD35-6, 134OD25-9, 134OD25-10, 134OD25-11, 134OD25-12, 134OD25-13, 134OD25-14, 134OD25-15, 134OD25-16, 134OD25-17, 134OD25-19, 134OD25-20, 134OD25-23, 134OD25-25, 134OD25-27, 134OD25-28, 134OD25-30, 134OD25-32, 134OD25-33, 134OD25-34, 134OD25-35, 134OD25-36, 134OD25-37, 134OD25-38, 134OD25-40, 134OD25-41, 134OD25-42, 134OD25-43, 134OD25-46, 134OD25-49, 134TD25-1, 134TD25-2, 134TD25-4, 134TD25-5, 134TD25-6, F25-10, IX35-1, IX35-12, IX35-13, IX35-8, IX35-9, OX24-5, OX24-7, OX24-8, OX25-1, OX25-2, PZ35-4, PZ35-5, PZ35-6, TZ-1, TZ-2, TZ-3, TZ-4, TZ-5, TZ-6, TZ-7, TZ24-2, TZ24-3, TZ24-5, TZ24-6, TZ24-7, TZ24-9, TZ24-11, TZ24-12, TZ24-13, TZ24-14, TZ24-16, TZ25-2, and TZ25-6.

[0126] Even more preferable compounds are 123TA14-2, 124OD35-12, 124OD35-15, 124OD35-13, 124TD35-6, 134OD25-9, 134OD25-10, 134OD25-11, 134OD25-15, 134OD25-14, 134OD25-23, 134OD25-28, 134OD25-27, 134OD25-32, 134OD25-40, 134OD25-46, 134TD25-1, 134TD25-4, 134TD25-5, F25-10, IX35-1, IX35-8, IX35-9, IX35-13, OX24-5, OX24-8, PZ35-4, PZ35-5, TZ-1, TZ-2, TZ-3, TZ-4, TZ-7, TZ24-3, TZ24-6, and TZ24-11.

BEST MODE FOR CARRYING OUT THE INVENTION

[0127] The compound (I) according to the invention can be synthesized as follows. They can be synthesized by the method described in the literatures given in Tables 1 to 28 or are commercially available. Otherwise, they may be synthesized by the following processes.

[0128] 1) Synthesis of Pyrazole Derivatives (PZ35) 416

[0129] in which the symbols are as defined above.

[0130] Pyrazole derivative (PZ35) is prepared by heating 1,3-diketone (1) and hydrazine in a solvent. Alcohol may be used as a solvent, and the reaction may be conducted at a temperature between room temperature and a reflux temperature of the solvent.

[0131] 2) Synthesis of Oxazole Derivatives (OX25) 417

[0132] in which Hal is a halogen and the other symbols are as defined above.

[0133] Chloroacetophenone (2) is converted to aminoacetophenone (4) by the method of e.g. Synthesis, 112 (1990) or Tetrahedron Lett., 30, 5285 (1989). Compound (4) is acylated with acid halide and treated with phosphorus oxychloride, polyphosphoric acid, phosphorus trichloride, dimethyldichlorosilane, or the like in the absence or presence of a solvent, e.g., acetonitrile, dimethylformamide, toluene, or the like at a temperature between room temperature and reflux temperature of the solvent to give a cyclized product, oxazole (OX25).

[0134] 3) Synthesis of Thiazole Derivatives (TZ24) 418

[0135] in which X is a halogen or toluenesulfonyloxy (hereinafter referred to OTs), and the other symbols are as defined above.

[0136] According to the method of e.g. J. Heterocycl. Chem., 28, 673 (1991), 2-halo-acetophenone (2) (e.g., 2-bromoacetophenone) is treated with thioamide (7) in a solvent e.g. alcohol, dimethylformamide, or the like, at a temperature between room temperature and reflux temperature of the solvent to give a thiazole derivative (TZ24) having A1 and A2 at positions 2 and 4, respectively.

[0137] Alternatively, acetophenone is converted to a corresponding tosylate (2: X═OTs) by the method of e.g. Synth. Commun., 28, 2371 (1998), which is then treated with thioamide (7) in a solvent e.g. dichloromethane, methanol, ethanol, or the like at a temperature between room temperature and reflux temperature of the solvent to give the same. 419

[0138] in which the symbols are as defined above.

[0139] According to the method of e.g. Collect. Czech. Chem, 58, 2720 (1993), ketoamide (6) is treated with Lawson reagent in a solvent e.g. benzene, toluene, xylene, dioxane, or the like at a temperature between room temperature and reflux temperature of the reaction solvent to give a thiazole derivative (TZ25) having A1 and A2 at positions 2 and 5, respectively.

[0140] 4) Synthesis of 1,2,4-oxadiazole Derivatives (124OD35) 420

[0141] in which the symbols are as defined above.

[0142] According to the method of e.g. Tetrahedron 46, 3941 (1990), amidoxime (9) is treated with nitrile (8) in the presence of zinc chloride in a solvent e.g. ethyl acetate, butyl acetate, or the like at a temperature between room temperature and reflux temperature of the solvent to give 1,2,4-oxadiazole (124OD35).

[0143] 5) Synthesis of 1,3,4-oxadiazole Derivatives (134OD25) 421

[0144] in which Hal is a halogen, n is 0 or 1, and the other symbols are as defined above.

(10→5→11→134OD25)   [Method A]

[0145] According to the method of, e.g. J. Org. Chem., 58, 2628 (1993), compound (134OD25) can be synthesized.

[0146] Step 1: When the starting material is carboxylic acid, it is converted into acid halide (5) using thionyl chloride, oxalyl chloride, or the like.

[0147] Step 2: A reaction of acid halide (5) and hydrazine monohydrate in the dichloromethane solvent at a temperature between ice cooling and reflux temperature of the solvent gives intermediate 1,2-bisbenzoylhydrazine (11).

[0148] Step 3: The intermediate (11) is cyclized with phosphorus oxychloride, polyphosphoric acid, phosphorus trichloride, dimethyldichlorosilane or the like in the absence or presence of a solvent, e.g., acetonitrile, dimethylformamide, toluene or the like at a temperature between room temperature and 150° C. to give 1,3,4-oxadiazole 134OD25.

(12+□13→14→134OD25)   [Method B]

[0149] Method B follows the method of e.g. Synthesis, 946 (1979). In the presence of a base, phenyltrichloromethane (12) and hydrazide (13) are heated under reflux in alcohol solvent to give 134OD25.

[0150] In this reaction, the base may be sodium carbonate, pyridine, or the like, and the solvent may be alcohol, e.g. methanol, ethanol, or the like.

[0151] When the uncyclized intermediate (14) remains, it can be converted into 134OD25 e.g. by heating with an acid catalyst e.g. p-toluenesulfonic acid in a solvent e.g. dimethylformamide at 130° C.

(15+□16 or 17→134OD25)   [Method C]

[0152] According to the method of e.g. J. Gen. Chem. USSR., 1125 (1992), tetrazole (15) and acid chloride (16) or acid anhydride (17) are heated at a temperature between 50 to 150° C. in the absence or presence of a solvent, e.g., acetonitrile, dimethylformamide, pyridine, toluene, or the like to synthesize 134OD25. The starting tetrazole (15) is commercially available or produced by the method of e.g. J.Org.Chem., 58, 4139 (1993).

(13+16→18→134OD25)   [Method D]

[0153] The intermediate (18) is obtained by the method of e.g. Khim Geterotsikl. Soedin., 333 (1996). The cyclization of (18) is carried out as in Step 3 of method A.

[0154] 6) Synthesis of 1,2,4-triazole Derivatives (124TA35) 422

[0155] in which the symbols are as defined above.

[0156] In a sealed tube, 1,3,4-oxadiazole (134OD25) and thiourea in tetrahydrofuran solvent are heated at 100 to 150° C. to give 124TA35.

[0157] 7) Synthesis of 1,3,4-thiadiazole Derivatives 134TD25 423

[0158] in which Hal is a halogen and the other symbols are as defined above.

(5□+19→18→134TD25)   [Method A]

[0159] The intermediate (18) is treated with phosphorus pentasulfide by the method of e.g. J. Prakt. Chem., 322, 933 (1980) to give 1,3,4-thiadiazole (134TD25).

(13□+20→21→22+23→134TD25)   [Method B]

[0160] According to the method of e.g. J. Chem. Soc. C, 1986 (1971) or J. Chem. Soc. Perkin Trans1, 9, 1987 (1982), the intermediate (22) is prepared. This is then cyclized with thioamide (23) to give 1,3,4-thiadiazole (134TD25).

[0161] 8) Synthesis of Isoxazole Derivatives (IX35) 424

[0162] in which R is a lower alkyl and the other symbols are as defined above.

[0163] As described in e.g. Organic Synthesis Col. Vol. 6, 278 (1988), oxime (24) (prepared conventionally from the corresponding ketone) is treated with n-butyllitium in THF under ice cooling to form dianion. This is condensed with ester (25), followed by acid treatment to give isoxazole (IX35).

[0164] Pharmaceutical compositions of the invention (which enhance the expression of apoAI) activate a reverse cholesterol transport activity of HDL, an anti-inflammatory activity and an anti-coagulant activity, or the like. As a result, the compositions are useful for preventing and/or treating blood lipid disorders, arteriosclerotic diseases and coronary artery diseases caused by decreased level of HDL in plasma, as well as various cardiovascular diseases concomitant with them. “Blood lipid disorders” specifically include conditions of lowered level of serum HDL, hypercholesteremia, hypertriglyceridemia, or the like; “arteriosclerotic diseases” specifically include arteriosclerosis, or the like; “coronary artery diseases” specifically include myocardial infarction, ischaemic heart diseases, cardiac incompetence, or the like. “Various cardiovascular diseases concomitant with the above diseases” to be treated with the pharmaceutical compositions of the invention include hyperuricemia, corneal opacity, cerebrovascular disease, hereditary HDL deficiencies (Tangier disease, fish-eye disease), or the like.

[0165] The compositions of the invention may be administered orally or parenterally. For oral routes, the compositions may be formulated conventionally into usual dosage forms such as tablets, tablets, granules, powders, capsules, pills, solutions, syrups, buccals, sublinguals, or the like before administration. For parenteral administration, the compositions may be conventionally formulated into usual dosage forms such as injections, e.g., intramuscular or intravenous injections, suppositories; transdermal patches, inhalation, or the like.

[0166] A therapeutically effective amount of a compound according to the invention may be admixed with various suitable pharmaceutical additives such as excipient, binding agent, wetting agent, disintegrating agent, lubricant, diluent, or the like to give pharmaceutical compositions, if necessary. In the case of injections, the ingredients are sterilized together with a suitable carrier to formulate the composition.

[0167] More specifically, the excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose, or the like; the binding agents include methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatine, polyvinyl pyrrolidone, or the like; the disintegrating agents include carboxymethylcellulose, sodium carboxymethyl cellulose, starch, sodium alginate, algae powder, sodium lauryl sulfate, or the like; the lubricants include talc, magnesium stearate or Macrogol, or the like. Base materials of the suppository may be for example cacao butter, Macrogol, methylcellulose, or the like. Solutions, emulsions or suspensions for injection may comprise a solubilizing agent, a suspending agent, an emulsifying agent, a stabilizing agent, a preserving agent, an isotonic agent, or the like as usually used. Compositions for oral administration may comprise a flavoring agent, an aromatic agent, or the like.

[0168] Dose or therapeutically effective amount of the compounds according to the invention for enhancing the expression of apoAI is preferably determined considering age and body weight of patients, sort and severity of diseases to be treated, route of administration, or the like. In the case of oral administration to an adult, the dose range is usually 1 to 100 mg/kg/day, preferably 5 to 30 mg/kg/day. In the case of parenteral administration, the dose differs largely depending on the route of administration, but the dose range is usually 0.1 to 10 mg/kg/day, preferably 1 to 5 mg/kg/day. The dosage unit may be administered to a subject once or several times per day.

EXAMPLES

[0169] Following references and examples are presented for purpose of further illustration of the invention, and they are not intended to limit the scope of the invention in any respect.

Reference 1

2-Amino-3′-methoxyacetophenone hydrochloride (4-1)

[0170] 425

[0171] A suspension of 2-brom-3′-methoxyacetophenone (2.291 g, 10.00 mmol), and sodium diformylimide (1.102 g, 11.60 mmol) in acetonitrile (5 mL) was stirred for 2 hours at room temperature and further stirred at 60° C. for 2 hours. Insoluble material in the reaction mixture was removed by filtration and the filtrate was concentrated in vacuo. Without purification, the residue was treated with 5% hydrochloric acid-ethanol (25 mL), and the mixture was allowed to stand for 24 hours at room temperature. After evaporation of the solvent from the reaction mixture in vacuo, the resulting crystals were separated and washed successively with isopropyl ether and ethyl acetate to give crude crystals 4-1 (1.869 g, 92.7%).

[0172] NMR (DMSO, d-6): 3.85 (3H, s), 4.59 (2H, s), 7.27-7.35 (1H, m), 7.45-7.56 (2H, m), 7.58-7.65 (1H, m), 8.42 (3H, br).

Reference 2

3-Furoyl chloride (5-1)

[0173] 426

[0174] A mixture of furan-3-carboxylic acid (11.21 g, 10.0 mmol ) and thionyl chloride (14.5 mL, 20.0 mmol) was stirred at 40° C. for 2 hours 30 minutes. The reaction product was purified by distillation under reduced pressure to give 3-furoyl chloride 5-1 (11.89 g, 91.0%) as colorless crystals (Caution: compound 5-1 is a potent irritant). b.p. 68-72° C. (3325 Pa)

Reference 3

N-(3′-Methoxyphenacyl)-3-furoylamide (6-1)

[0175] 427

[0176] To a solution of compound 4-1 (1.008 g, 5.00 mmol) in pyridine (4 mL) was added 5-1 (0.685 g, 5.25 mmol) dropwise under ice cooling. The mixture was stirred at the same temperature for 3 hours and then at room temperature for 2 hours. After the solvent was evaporated in vacuo, ice and aqueous saturated sodium hydrogen carbonate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The resulting crude crystals were recrystallized from ethyl acetate-hexane to give pale yellow prisms 6-1 (970 mg, 74.8%).

[0177] m.p. 86-88° C. Elemental analysis: Calculated for C14H13NO4-0.1H2O: C, 64.41; H, 5.10; N, 5.37: Found: C, 64.50; H, 4.99; N, 5.45. NMR (CDCl3): 3.88 (3H, s), 4.90 (2H, d, J=4.2), 6.73 (1H, dd, J=0.9 and 2.1), 6.90 (1H, br), 7.15-7.22 (1H, m), 7.43 (1H, t, J=7.8), 7.48 (1H, t, J=1.8), 7.53 (1H, t, J=1.8), 7.61 (1H, d, J=7.5), 8.00-8.05 (1H, m).

Reference 4

2-Furoyl-(3-methoxybenzylidene)hydrazide (21-1)

[0178] 428

[0179] To a solution of 2-furoylhydrazide (2.522 g, 20.00 mmol) in ethanol (20 mL) was added dropwise m-anisaldehyde (2.43 mL, 19.97 mmol) at room temperature. After the mixture was stirred for 4 hours, it was allowed to stand overnight. The crystals precipitated from the reaction mixture were collected and washed with 95% ethanol to give colorless prisms 21-1 (4.436 g, 90.8%).

[0180] m.p. 156-157° C. Elemental analysis: Calculated for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47: Found: C, 63.69; H, 4.98; N, 11.41. NMR (CDCl3): 3.87 (3H, s), 6.58 (1H, dd, J=1.5 and 3.3), 6.94-7.01 (1H, m), 7.24-7.44 (4H, m) 7.47-7.57 (1H, m), 8.24 (1H, s), 9.39 (1H, br).

Reference 5

3-Acetamidobenzonitrile

[0181] 429

[0182] To 3-aminobenzonitrile (2.50, 21.16 mmol) was added acetic anhydride (10 mL, 105.98 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The remaining reagent was evaporated in vacuo. To the residue was added saturated aqueous sodium hydrogen carbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with isopropyl ether to give pale brown crystals (3.266 g, 96.3%).

[0183] m.p. 120-123° C. Elemental analysis: Calculated for C9H8N2O: C, 67.49; H, 5.03; N, 17.49: Found: C, 67.47; H, 5.01; N, 17.57. NMR (CDCl3): 2.21 (3H, s), 7.35-7.47 (3H, m), 7.67-7.75 (1H, m), 7.92 (1H, br).

Reference 6

N-[3-(5-Tetrazolylphenyl)]-acetamide (15-1)

[0184] 430

[0185] To a solution of 3-acetamidobenzonitrile (2.883 g, 18.00 mmol) in toluene (36 mL) were added trimethylsilyl azide (4.8 mL, 36.16 mmol) and di-n-butyltin oxide (0.448 g, 1.80 mmol), and the mixture was heated under reflux for 16 hours. The solvent was evaporated in vacuo, the residue was mixed with methanol, and the mixture was evaporated again in vacuo. The residue was extracted with saturated aqueous sodium hydrogen carbonate (1.81 g, 21.55 mmol) and the aqueous layer was washed with ethyl acetate. The alkaline aqueous solution was acidified with hydrochloric acid. The precipitated crystals were collected by filtration and washed with ethanol to give compound 15-1 (2.033 g, 55.6%).

[0186] m.p. 250-260° C. (dec). Elemental analysis: Calculated for C9H9N5O: C, 53.20; H, 4.46; N, 34.46: Found: C, 53.25; H, 4.40; N, 33.52 NMR (DMSO, d-6): 2.09 (3H, s), 5.20 (1H, t, J=7.8), 7.62-7.78 (2H, m), 8.39 (1H, t, J=1.8), 10.20 (1H, s).

Reference 7

1,2-Bis(3-methylphenyl)hydrazine (11-1)

[0187] 431

[0188] m-Toluic acid (10.89 g, 80.0 mmol) was treated with thionyl chloride (18.0 mL, 248.1 mmol) at 40° C. for 3 hours. Excess thionyl chloride was evaporated in vacuo. To a solution of crude m-toluic acid chloride in dry dichloromethane (44 mL) was added dropwise hydrazine monohydrate (11.5 mL, 237.08 mmol) at room temperature over 1 hour 30 minutes, and the mixture was stirred for 1 hour. The reaction mixture was added to water, and precipitated crystals were collected by filtration and washed with water and methanol to give colorless powdery crystals 11-1 (10.06 g, 93.8%).

[0189] m.p. 220-223° C. Elemental analysis: Calculated for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44: Found: C, 71.27; H, 5.77; N, 10.61 NMR (DMSO, d-6): 2.39 (6H, s), 7.37-7.45 (4H, m), 7.68-7.78 (4H, m), 10.29 (2H, br)

Reference 8

[(3-furoyl)-(3-methoxybenzoyl)]hydrazine (18-1)

[0190] 432

[0191] To a solution of m-anisic acid hydrazide (1.255 g, 7.552 mmol) in pyridine (4 mL) was added compound 5-1 (1.035 g, 7.929 mmol) dropwise under ice cooling and the mixture was stirred at the same temperature for 4 hours, and then for 12 hours at room temperature. The solvent was evaporated in vacuo and precipitated crystals were washed with ethyl acetate and then isopropyl ether, and recrystallized from isopropanol to give colorless needles 18-1 (1.578 g, 80.3%).

[0192] m.p. 211-212° C. Elemental analysis: Calculated for C13H12N2O4-0.5H2O: C, 57.99; H, 4.87; N, 10,40; Found :C, 57, 79; H, 4.83; N, 10.61. NMR (DMSO, d-6): 3.82 (3H, s), 6.93 (1H, d, J=1.8), 7.11-7.23 (1H, m), 7.38-7.56 (3H, m), 7.80 (1H, d, J=1.8), 8.30 (1H, d, J=0.9), 10.23 (1H, br), 10.42 (1H, br).

Reference 9

1-(3-Methoxyphenyl)ethanone oxime (24-1)

[0193] A mixture of 3-methoxyacetophenone (10 g), hydroxylamine hydrochloride (5.1 g), aqueous 4M-sodium hydroxide (18 mL), water (30 mL) and ethanol (50 mL) was heated at reflux for 2 hours. The solvent was removed in vacuo and resulting aqueous layer was extracted with ether. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo. Resulting oily substance was azeotropically dried two times with toluene and the residue was used in following steps without further purification.

Example 1

3,5-Di(4-methoxyphenyl)-1-methylpyrazole (PZ35-4)

[0194] 433

[0195] To a solution of 1,3-bis(4-methoxyphenyl)-1,3-propanedione (14.2 g, 5.0 mmol) in ethanol (10 mL) were added sodium hydrogen carbonate (1.68 g, 20.0 mmol) and methyl hydrazine sulfate (1.44 g, 10.0 mmol), and the mixture was heated at reflux for 3 hours. The solvent was evaporated in vacuo from the reaction mixture and residue was dissolved in chloroform. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was recrystallized from methanol to give colorless prisms PZ35-4 (1.42 g, 96.6%).

[0196] m.p. 107-108° C.

Example 2

2-(3-Furyl)-5-(3-methoxyphenyl)oxazole (OX25-2)

[0197] 434

[0198] A suspension of compound 6-1 (778 mg, 3.00 mmol) in phosphorus oxychloride (7.8 mL, 83.68 mmol) was stirred at 100° C. for 1 hour. Phosphorus oxychloride was removed in vacuo. The residue was mixed with ice, and the mixture was neutralized with aqueous concentrated ammonia, and extracted with ethyl acetate. The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexane=1:3) followed by recrystallization from isopropyl ether to give pale yellow prisms OX25-2 (662 mg, 85.9%).

[0199] m.p. 88-90° C.

Example 3

2-(4-Methoxyphenyl)-4-phenylthiazole (TZ24-5)

[0200] 435

[0201] A suspension of α-bromoacetophenone (3.981 g, 20.00 mmol), 4-methoxythiobenzamide (3.345 g; 20.00 mmol) and dry ethanol (40 mL) was stirred at 50° C. for 2 hours. The solvent was evaporated in vacuo, the residue was mixed with ice, and the mixture was made weakly basic with 4N-sodium hydroxide and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (chloroform), and recrystallization from ethyl acetate-hexane gave pale yellow prisms TZ24-5 (4.786 g, 89.5%).

[0202] m.p. 98.5-100° C.

Example 4

4-(2-Furyl)-2-(4-methoxyphenyl)thiazole (TZ24-6)

[0203] 436

[0204] A suspension of 2-acetylfuran (0.661 g, 6.00 mmol) and hydroxy(tosyloxy)iodo-benzene (Koser's Reagent, 2.35 g, 6.00 mmol) in dry dichloromethane (12 mL) was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo. To the residue were added 4-methoxythiobenzamide (1.00 g, 6.00 mmol) and dry ethanol (24 mL), and the mixture was heated at reflux for 4 hours. The solvent was evaporated in vacuo, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (toluene) to give crude crystals, which were recrystallized from isopropyl ether-hexane giving TZ24-6 as pale brown crystals (668 mg, 43.4%).

[0205] mp. 77-78° C.

Example 5

2-(3-Furyl)-5-(3-methoxyphenyl)thiazole (TZ25-6)

[0206] 437

[0207] A suspension of compound 6-1 (1.063 g, 4.00 mmol) and Lawson reagent (2.10 g, 5.19 mmol) in dry xylene (20 mL) was heated under reflux for 1 hour 30 minutes. The reaction mixture was mixed with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on neutral alumina followed by silica gel eluted with ethyl acetate-hexane (1:4). Recrystallization from isopropyl ether gave TZ25-6 as pale brown prisms (681 mg, 66.1%).

[0208] m.p. 61-62° C.

Example 6

5-(4-Methoxyphenyl)-3-phenyl-1,2,4-oxadiazole (124OD35-12)

[0209] 438

[0210] To a suspension of benzamidoxime (9.04 g, 66.40 mmol), zinc chloride (27.15 g, 199.22 mmol) and butyl acetate (68 mL) were added anisnitrile 8-1 (8.84 g, 66.39 mmol) and hydrogen chloride-ethyl acetate solution (4M, 17.1 mL, 68.40 mmol), and the mixture was heated under reflux at 130° C. for 3 hours. The reaction mixture was mixed with ice and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was subjected to silica gel chromatography and the fractions were eluted with ethyl acetate-hexane (1:9) to give 124OD35-12. This was recrystallized from isopropyl ether to give colorless prisms (3.779 g, 22.6%).

[0211] m.p. 97-98° C.

Example 7

2,5-Bis (3-tolyl)-1,3,4-oxadiazole (134OD25-40)

[0212] 439

[0213] A mixture of compound 11-1 (5.37 g, 20.01 mmol) and phosphorus oxychloride (18.7 mL, 200.6 mmol) was stirred at 130° C. for 30 minutes. After evaporating phosphorus oxychloride in vacuo, the residue was mixed with ice, neutralized with aqueous ammonia, and the mixture was extracted with chloroform. The chloroform layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (chloroform) and then recrystallized from ethyl acetate-hexane to give colorless prisms 134OD25-40 (2.996 g, 59.8%).

[0214] m.p. 82-83° C.

Example 8

2-(2-Pyridyl)-5-phenyl-1,3,4-oxadiazole (134OD25-46)

[0215] 440

[0216] A suspension of phenyltrichloromethane (7.82 g, 40.00 mmol),α-picolininic acid hydrazide (5.48 g, 39.96 mmol) and sodium carbonate (4.02 g, 37.93 mmol) in dry ethanol (100 mL) was heated at reflux for 6 hours. After filtrating inorganic material off from the reaction mixture, the solvent was evaporated in vacuo. The residue was added to an aqueous saturated sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo.

[0217] The crude intermediate were stirred with p-toluenesulfonic acid hydrate (0.761 g, 4.00 mmol) in dry dimethylformamide (20 mL) at 130° C. for 2 hours. The reaction mixture was added to an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by chromatography over neutral alumina and then silica gel (hexane-chloroform=1:4). Recrystallization from ethyl acetate-hexane gave 134OD25-46 as colorless prisms (3.036 g, 36.1%).

[0218] m.p. 127-128° C.

Example 9

2-(4-Dimethylaminophenyl)-5-phenyl-1,3,4-oxadiazole (134OD25-15)

[0219] 441

[0220] To a suspension of 4-dimethylaminophenylcarboxylic acid (1.652 g, 10.00 mmol), dry dimethylformamide (0.039 mL, 0.05 mmol) and dry dichloromethane (5 mL) was dropwise added oxalyl chloride (1.05 mL, 12.04 mmol) at room temperature over 10 minutes. The mixture was stirred for 1 hour, and the solvent was evaporated in vacuo. To the reaction product were added dry pyridine (0.81 mL, 10.01 mmol), dry acetonitrile (5 mL) and 5-phenyltetrazole (1.462 g, 10.00 mmol) and the mixture was heated under reflux for 2 hours 30 minutes. The reaction mixture was added to an aqueous saturated sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate-chloroform (1:15) and recrystallization from ethyl acetate-hexane gave 134OD25-15 as pale yellow prisms (422 mg, 15.9%).

[0221] m.p. 135-140° C.

Example 10

2-[2-(2-Furyl)vinyl]-5-[1,3,4]-oxadiazole (134OD25-23)

[0222] 442

[0223] A suspension of 3-(2-furyl)acrylic acid (1.381 g, 10.00 mmol), thionyl chloride (0.80 mL, 11.03 mmol), dimethylformamide (0.039 mL, 0.50 mmol) and acetonitrile (1.4 mL) was stirred at room temperature for 3 hours. The product was immediately mixed with 5-phenyltetrazole (1.462 g, 10.00 mmol), and the mixture was stirred at room temperature for 1 hour and at 100° C. for 3 hours. The reaction mixture was added to an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexane=1:3) and recrystallization from 95% ethanol gave pale yellow prisms 134OD25-23 (653 mg, 27.4%).

[0224] m.p. 131-132° C.

Example 11

2-(3-Furyl)-5-(3-methoxyphenyl)-[1,3,4]-oxadiazole (134OD25-32)

[0225] 443

[0226] A suspension of compound 18-1 (5.04 g, 19.37 mmol) and phosphorus oxychloride (18.0 mL, 193.11 m mmol) was stirred at 100° C. for 1 hour 30 minutes. After removal of phosphorus oxychloride in vacuo, the residue was added to ice, neutralized with aqueous concentrated ammonia, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography and compound 134OD25-32 was obtained with ethyl acetate-hexane (1:3). The resulting crude crystals were recrystallized from isopropyl ether to give compound 134OD25-32 as colorless prisms (4.34 g, 92.5%).

[0227] m.p. 70-71° C.

Example 12

3-(3-Furyl)-5-(3-methoxyphenyl)-[1,2,4]-triazole (124TA35-17)

[0228] 444

[0229] A suspension of compound 134OD25-32 (1.211 mg, 5.00 mmol) and thiourea (1.00 g, 13.14 mmol) in tetrahydrofuran (5 mL) was heated at 150° C. for 24 hours in a sealed tube. The reaction mixture was added to an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography. Elution with ethyl acetate-hexane (1:1) followed by recrystallization from ethyl acetate gave 124TA35-17 (471 mg, 39.1%).

[0230] m.p. 169-171° C.

Example 13

2-(3-Furyl)-5-(3-methoxyphenyl)-[1,3,4]-thiadiazole (134TD25-2)

[0231] 445

[0232] A suspension of compound 18-1 (1.562 g, 6.00 mmol) and phosphorus pentasulfide (1.80 g, 8.10 mmol) in dry pyridine (12 mL) was stirred at 100° C. for 9 hours. After the solvent was removed in vacuo, the residue was mixed with ice, made weakly alkaline with 4M-sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography and eluted with ethyl acetate. The eluent (2.529 g) still contained an uncyclized intermediate, which was mixed with p-toluenesulfonic acid hydrate (0.395 g, 2.08 mmol) and dry toluene (25 mL), and the mixture was heated under reflux for 30 minutes. The reaction mixture was added to an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexane=1:3) and recrystallization from 95% ethanol gave compound 134TD25-2 (0.820 g, 52.9%).

[0233] m.p. 75.5-76.5° C.

Example 14

2-(2-Furyl)-5-p-tolyl-[1,3,4]-thiadiazole (134TD25-5)

[0234] 446

[0235] A suspension of compound 21-1 (2.931 g, 12.00 mmol) and thionyl chloride (1.04 mL, 14.34 mmol) in benzene (12 mL) was heated under reflux for 6 hours. The solvent was evaporated in vacuo, and the residue was treated with hot petroleum ether. Only the soluble portion was taken up and the solvent was evaporated in vacuo. The resulting crude product (1.521 g) and 4-methylthiobenzamide (0.875 g, 5.786 mmol) were dissolved in dry ethanol (20 mL) and the solution was stirred at room temperature for 30 hours. The solvent was removed in vacuo from reaction mixture. The residue was purified by silica gel chromatography (ethyl acetate-hexane=1:5) and recrystallization from 95% ethanol gave compound 134TD25-5 (670 mg, 23.0%).

[0236] m.p. 111-113° C.

Example 15

5-(Furan-3-yl)-3-(3-methoxyphenyl)-isoxazole (IX35-9)

[0237] 447

[0238] To a solution of 1-(3-methoxyphenyl)ethanone oxime (1.65 g, 0.01 mol) in THF (55 mL) was added dropwise a solution of n-butyllithium (1.6M-in hexane, 14 mL) under ice cooling. After stirring at the same temperature for 30 minutes, a solution of ethyl furan-3-carboxylate (0.7 g, 5 mmol) in THF (10 mL) was added slowly. After stirring for 1 hour at ice bath temperature, 5N-hydrochloric acid (18 mL) was added in one portion, and the mixture was heated at reflux for 1 hour. After cooling, the reaction mixture was poured into ice, made alkaline with sodium hydrogen carbonate, and extracted with ether. The reaction product was purified by silica gel chromatography (82 g, ethyl acetate-hexane=1:4) to give a mixture mainly containing compound IX35-9. This mixture was again purified by silica gel chromatography (90 g, toluene) to give colorless crystals (480 mg), which were further recrystallized from acetone-hexane to obtain IX35-9 as colorless crystals.

[0239] m.p. 36-37° C.

[0240] Other compounds (I) were synthesized in a similar manner. Their physiological constants are listed below:

TABLE 29
				Elemental
		Molecular	Elemental analysis	analysis
Compounds	m.p (° C.)	formula	(Calculated)	(Found)	NMR
124OD35-12	96-96.5	C15H12N2O2	C, 71.42; H, 4.79; N,	C, 71.40; H, 4.81;	CDCl3) 3.91(3H, s), 7.04(2H, d, J=8.7), 7.45-7.55(3H, m),
			11.10	N, 11.21	8.11-8.21(2H, m), 8.17(2H, d, J=8.7)
134OD25-14	120-122	C15H12N2OS	C, 67.14; H, 4.51; N,	C, 67.28; H, 4.48;	CDCl3) 2.55(3H, s), 7.36(2H, d, J=8.4), 7.49-7.59(3H, m),
			10.44; S, 11.95	N, 10.48; S,	8.04(2H, d, J=8.4), 8.10-8.18(2H, m)
				12.09
134OD25-15	135-140	C16H15N3O	C, 72.43; H, 5.70; N,	C, 72.20; H, 5.76;	CDCl3) 3.06(3H, s), 3.07(3H, s), 6.77(2H, d, J=9.0), 7.47-7.56
			15.84	N, 15.49	7.56(3H, m), 7.99(2H, d, J=9.0), 8.08-8.16(2H, m)
134OD25-23	127-130	C14H10N2O2	C, 70.58; H, 4.23; N,	C, 70.50; H, 4.18;	CDCl3) 6.50(1H, dd, J=2.1 and 3.3), 6.63(1H, d, J=3.3),
			11.76	N, 11.80	6.98(1H, d, J=16.2), 7.40(1H, d, J=16.2), 7.46-7.60(4H, m),
					8.05-8.17(2H, m)
134OD25-27	261-263	C16H11N3O	C, 73.55; H, 4.24; N,	C, 73.46; H, 4.18;	CDCl3) 7.08-7.18(1H, m), 7.25-7.33(1H, m), 7.34(1H, s),
			16.08	N, 16.08	7.52(1H, dd, J=1.2 and 8.4), 7.61-7.75(4H, m), 8.10-8.20(
					2H, m), 12.32(1H, s)
134OD25-28	148-149	C16H10N2O2	C, 73.27; H, 3.84; N,	C, 73.32; H, 3.84;	CDCl3) 7.31-7.76(8H, m), 8.14-8.21(2H, m)
			10.68	N, 10.74
134OD25-32	70-71	C13H10N2O3	C, 64.46; H, 4.16; N,	C, 61.45; H, 4.15;	CDCl3) 3.90(3H, s), 6.99(1H, dd, J=0.9 and 2.1), 7.06-7.13
			11.56	N, 11.73	3(1H, m), 7.43(1H, t, J=7.8), 7.57(1H, t, J=1.8), 7.61-7.72
					(2H, m), 8.17(1H, dd, J=0.9 and 1.5)
134OD25-40	82-83	C16H14N2O	C, 76.78; H, 5.64; N,	C, 76.97; H, 5.44;	CDCl3) 2.46(6H, s), 7.33-7.47(4H, m), 7.91-8.01(4H, m)
			11.19	N, 11.23
134OD25-46	121-124	C13H9N3O	C, 69.95; H, 4.06; N,	C, 70.15; H, 4.10;	CDCl3) 7.45-7.59(4H, m), 7.86-7.96(1H, m) 8.19-8.26(2H,
			18.82	N, 18.76	m), 8.33(1H, d, J=7.8), 8.83(1H, d, J=4.2)
134TD25-2	75.5-76.5	C13H10N2O	C, 60.45; H, 3.90; N,	C, 60.28; H, 4.18;	CDCl3) 3.90(3H, s), 6.96(1H, dd, J=0.9 and 1.8), 7.01-7.08
		2S	10.85; S, 12.41	N, 10.92 S, 12.29	(1H, m), 7.39(1H, t, J=8.1), 7.46-7.53(1H, m), 7.55(1H, t,
					J=1.8), 7.58-7.62(1H, m), 8.06(1H, d, J=0.9)
134TD25-5	110-113	C13H10N2OS	C, 64.44; H, 4.16; N,	C, 64.48; H, 4.24;	CDCl3) 2.43(3H, s), 6.60(1H, dd, J=1.8 and 3.3), 7.19-7.23
			11.56; s, 13.23	N, 11.55 S, 13.27	(1H, m), 7.30(2H, d, J=8.1), 7.59-7.63(1H, m), 7.89(2H,
					d, J=8.1)

[0241]

TABLE 30
IX35-8	165-166	C17H15NO3	C, 72.58; H, 5.37; N, 4.98	C, 72.12; H, 5.31;	CDCl3) 3.87(6H, s), 6.66(1H, s), 7.00(4H, d, J=9.0), 7.77
				N, 5.17	(2H, d, J=9.0), 7.80(2H, d, J=9.0)
OX25-2	88-90	C14H11NO3	C, 69.70; H, 4.60; N,	C, 69.25; H, 4.55;	CDCl3) 3.88(3H, s), 6.85-6.95(2H, m), 7.18-7.24(1H, m),
			5.81	N, 6.08	7.27-7.36(2H, m), 7.37(1H, s), 7.52(1H, t, J=1.8), 8.10(1H,
					d, J=0.6)
PZ35-4	107-108	C18H18N2O2	C, 73.45; H, 6.16; N,	C, 73.39; H, 6.30;	CDCl3) 3.84(3H, s), 3.87(3H, s), 3.89(3H, s), 6.48(1H, s),
			9.52	N, 9.70	6.94(2H, d, J=9.0), 7.00(2H, d, J=8.8), 7.39(2H, d, J=8.8),
					7.75(2H, d, J=9.0)
TZ-2	139-141	C14H11N4Cl	C, 62.11; H, 4.09; N,	C, 62.00; H, 4.15;	CDCl3) 2.44(3H, s), 7.33(2H, d, J=7.8), 7.55(2H, d, J=9.0),
			20.69; Cl; 13.09	N, 20.83; Cl,	8.13(2H, d, J=7.8), 8.16(2H, d, J=9.0)
				12.98
TZ-3	102-103	C14H12N4	C, 71.17; H, 5.12; N,	C, 71.29; H, 5.13;	CDCl3) 2.45(3H, s), 7.37(2H, d, J=8.7), 7.46-7.58(3H, m),
			23.71	N, 23.87	8.07(2H, d, J=8.7), 8.22-8.29(2H, m)
TZ-4	161-163	C13H8N4Cl2	C, 53.63; H, 2.77; N,	C, 53.58; H, 2.80;	CDCl3) 7.51(2H, d, J=8.7), 7.56(2H, d, J=8.7), 8.15(2H, d,
			19.24; Cl, 24.35	N, 18.55; Cl,	J=8.7), 8.18(2H, d, J=8.7)
				23.36
TZ-7	101-101.5	C14H12N4O	C, 66.65; H, 4.79; N,	C, 66.72; H, 4.73;	CDCl3) 3.90(3H, s), 7.07(2H, d, J=9.0), 7.48-7.57(3H, m),
			22.21	N, 22.22	8.11(2H, d, J=9.0), 8.22-8.28(2H, m)
TZ25-6	59.5-60.5	C14H11NO2S	C, 65.35; H, 4.31; N,	C, 65.33; H, 4.26;	CDCl3) 3.87(3H, s), 6.85-6.93(1H, m), 6.86(1H, dd, J=0.9
			5.44; S, 12.46	N, 5.50; S, 12.35	and 1.8), 7.10(1H, t, J=2.4), 7.13-7.20(1H, m), 7.33(1H, t,
					J=7.8), 7.50(1H, t, J=1.5), 7.94(1H, s), 8.01(1H, dd, J=0.9
					and 1.5)
TZ24-	111-112	C15H12N2OS	C, 67.15; H, 4.51; N,	C, 67.15; H, 4.35;	CDCl3) 3.88(3H, s), 6.98(2H, d, J=9.0), 7.22-7.26(1H, m),
11			10.44; S, 11.95	N, 10.29; S,	7.77-7.83(1H, m), 7.97-8.04(3H, m), 8.26(1H, d, J=8.1),
				11.78	8.62-8.64(1H, m)
TZ24-6	77-78	C14H11NO2S			CDCl3) 3.87(3H, s), 6.50(1H, dd, J=1.8 and 3.3), 6.87(1H,
					d, J=3.3), 6.96(2H, d, J=9.0), 7.35(1H, s), 7.46(1H, m),
					7.95(2H, d, J=9.0)

[0242] Experiment 1

[0243] Activity to Enhance the Production of Human apoAI

[0244] The promoter region of the gene encoding human apoAI was isolated and ligated upstream the structure gene of firefly luciferase to construct a reporter plasmid. The reporter plasmid and a marker plasmid conferring the neomycin resistance were co-infected to cell lines derived from human hepatoma, HepG2 cells, and the cell lines were incubated in a selection medium comprising DMEM medium containing 10% fetal calf serum supplemented with G418 (Final concentration: 0.7 mg/mL, Gibco) to give established strains that stably express the reporter molecule. The strains were seeded to a 96-well culture plates at a density of 50,000 cells per well, and incubated for 48 hours at 37° C. under 5% carbon dioxide. Then, a solution of the compounds according to the invention in DMSO was added to the wells at a final concentration of 0 to 10 μg/mL. After further incubation for 24 hours, the cells were added with a luciferase assay reagent (Piccagene LT 7.5 registered trade mark, Toyo Ink, KK), and the luciferase activity was determined using a luminometer (MicroBetaTM TRILUX, 1 sec/well, Wallac). The concentration of the compounds, which intensified the luciferase activity twice compared to that of control (DMSO without any compound of the invention added) was set as the minimal effective dose (MED). The results are shown in Table 31.

TABLE 31
Compound   MED (μM)
123TA14-2  0.59
124OD35-12 0.07
124OD35-15 0.18
124OD35-13 0.7
124TD35-6  0.93
134OD25-9  0.22
134OD25-10 0.91
134OD25-11 0.74
134OD25-15 0.27
134OD25-14 0.56
134OD25-23 0.82
134OD25-28 1.1
134OD25-27 2.4
134OD25-32 2.8
134OD25-34 1.5
134OD25-40 0.17
134OD25-46 0.37
134TD25-1  0.89
134TD25-4  0.58
134TD25-5  0.98
F25-10     2.5
IX35-1     0.75
IX35-8     0.5
IX35-9     0.53
OX24-5     0.32
OX24-8     2.9
PZ35-4     0.41
PZ35-5     1.5
TZ-1       0.33
TZ-2       0.42
TZ-3       0.2
TZ-4       0.53
TZ-7       0.22
TZ24-3     0.45
TZ24-5     3.7
TZ24-6     1.2
TZ24-11    1.2

[0245] Table 31 shows that the compounds according to the invention can promote the function of the gene encoding human apoAI, thus indicating enhancement of the expression of apoAI.

Formulation 1 tablets
compound (134OD25-32) 15 mg
starch                15 mg
lactose               15 mg
crystalline cellulose 19 mg
polyvinyl alcohol     3 mg
distilled water       30 mL
calcium stearate      3 mg

[0246] The ingredients other than calcium stearate were mixed uniformly, powdered, granulated, and dried to give granules of a suitable size. Then the calcium stearate was added and the materials were compressed to give a tablet formulation.

Formulation 2 Capsules
compound (134OD25-40) 10 mg
magnesium stearate    10 mg
lactose               80 mg

[0247] The ingredients were homogeneously mixed to give powder or fine particles to give a powder formulation. This was filled in capsules to give a capsule formulation.

Formulation 3 Granules
compound (124OD35-12) 30 g
lactose               265 g
magnesium stearate    5 g

[0248] The ingredients were mixed thoroughly, compressed, powdered, granulated and sieved to give a granule formulation.

Industrial Applicability

[0249] As is apparent from the experiment as described above, the compounds according to the invention have an activity for enhancing the expression of apoAI. Thus, the compounds according to the invention are very useful as pharmaceutical compositions for preventing and/or treating blood lipid disorders, arteriosclerotic diseases, or coronary artery diseases.

Claims

1. A pharmaceutical composition for enhancing the expression of apoAI, which comprises a compound of formula (I):

2. The pharmaceutical composition according to claim 1, in which the 5-membered ring consisting of Y1, Y2, Y3, Y4, and Y5 has a nucleus selected from a group consisting of 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan and thiophene.

3. The pharmaceutical composition according to claim 2, in which the 5-membered ring consisting of Y1, Y2, Y3, Y4, and Y5 has a nucleus selected from a group consisting of 1,2,3-triazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, furan, and thiophene.

4. The pharmaceutical composition according to any one of claims 1 to 3, in which A1 and A2 are independently a phenyl, a pyridyl, a pyrazinyl, a furyl, a thienyl, a thiazolyl, a pyrazolyl, a isoxazolyl, a benzofuryl, or an indolyl, each of which may be optionally substituted.

5. The pharmaceutical composition according to claim 4, in which A1 and A2 are independently a phenyl that may be optionally substituted by a halogen, a hydroxy, a lower alkyl, a lower alkoxy, a lower alkylthio, an amino that may be optionally substituted by a lower alkyl, a phenyl, a styryl or a heteroaryl; a thiazolyl that may be optionally substituted by a lower alkyl; a pyrazolyl that may be optionally substituted by a lower alkyl; an unsubstituted pyridyl; an unsubstituted indolyl; an unsubstituted benzofuryl; an unsubstituted thienyl; or an unsubstituted furyl.

6. The pharmaceutical composition according to any one of claims 1 to 5, in which Z is a single bond.

7. The pharmaceutical composition according to any one of claims 1 to 6, in which Y1 is O, S or NR1, R1 is a lower alkyl that may be optionally substituted, or an amino that may be optionally substituted; and, among Y2, Y3, Y4 and Y5, one or two is (are) independently CA1, one is CA2, and the others are independently CH or N.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is used for prevention and/or treatment of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases.

9. A method of enhancing the expression of apoAI, which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in claim 1, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient expected to enhance the expression of apoAI.

10. A method of treatment and/or prevention of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases, which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in claim 1, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient suspected to have blood lipid disorders, arteriosclerotic diseases or coronary artery diseases.

11. Use of a compound of formula (I) as defined in claim 1, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them for the manufacturing a medicament of enhancing the expression of apoAI.

12. Use of a compound of formula (I) as defined in claim 1, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them for the manufacturing a medicament of treatment and/or prevention of blood lipid disorders, arteriosclerotic diseases or coronary artery diseases.