JP3252485B2 - Tricyclic triazolo derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 3-ring useful as an anti-inflammatory or anti-allergic agent, which strongly antagonizes the action of PAF (platelet activating factor; hereinafter referred to as PAF) and has an antihistamine action. The present invention relates to a triazolo derivative.

[0002]

2. Description of the Related Art Platelet activating factor (PAF-Platelet A)
ctivating Factor—hereinafter, referred to as PAF) has received a great deal of attention in recent years, and recently its association with various diseases has been clarified. That is, PAF is inflammation, allergic disease, anaphylactic shock, pulmonary shock, DIC, endotoxin shock, myocardial disease,
It is presumed to be involved in asthma, pulmonary edema, gastrointestinal ulcer, nephritis, hepatitis, and rejection during organ transplantation.
[Hyundai Chemical Special Edition 17, Platelet Activating Factor-Biochemistry / Physiology /
Pathology-, edited by Keizo Waku and Keizo Inoue, Tokyo Chemical Doujinshi 1989]. Therefore, compounds that antagonize the action of PAF are expected to have a therapeutic effect on the above-mentioned diseases or other diseases where it is desirable to antagonize PAF.

[0003] In fact, administration of a PAF antagonist suppressed the Alsace reaction in mice, which is an inflammatory response model, indicating that PAF is involved in the inflammatory response (Jpn. J. Pharmacol., 46 , 55P (1988)) On the other hand, among allergic diseases among PAF-related diseases, chemical mediators such as histamine and leukotriene besides PAF result from antigen-antibody reaction.
It is known to be released from various cells. Therefore, a compound having both a PAF antagonistic action and an antihistamine action can be expected to have a more effective antiallergic action than the PAF antagonist alone or the antihistamine alone.

At present, thienotriazolo-1,4-diazepine compounds are known as anti-PAF agents. (JP-A-61-176591, JP-A-2-256681, JP-A-2-256682) As the compound having both an antihistamine action and a PAF antagonistic action, only a benzocycloheptapyridine compound is known. It is. (EP 270818) On the other hand, 4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline compounds are not known in the literature and, of course, a description of their pharmacological actions is given. Not at all.

[0005]

SUMMARY OF THE INVENTION A New and Useful Anti-PA
Agent F is expected and expected to have preventive and therapeutic effects on a wide range of diseases. Further, anti-allergic drugs having an antihistamine action in addition to an anti-PAF action are expected and required for the prevention and treatment of allergic and inflammatory diseases.

The present invention has a PAF antagonistic action, has an antihistamine action, and has anti-inflammatory agents, anti-allergic agents, anti-P
An object of the present invention is to provide a novel tricyclic triazolo derivative useful as an AF agent and a pharmacologically acceptable salt thereof.

[0007]

The present invention relates to a compound of the formula (I)

Embedded image [Wherein, R ¹ represents hydrogen, lower alkyl, substituted or unsubstituted aryl, R ² and R ³ represent hydrogen, lower alkyl, lower alkoxy or halogen, respectively, R ⁴ , R ⁵
Represents hydrogen and lower alkyl, respectively, and A has 1 to 1 carbon atoms.
5 represents a saturated or unsaturated linear or branched alkylene (which may contain a hetero atom). Q
Is a substituent (a) or (b) shown in the figure below

Embedded image (In m, m represents 0 to 2, n represents 1 to 3, ...
Represents a single bond or a double bond, Y represents N or C, and Z represents C (B) Ar ¹ Ar ² (B is hydrogen, hydroxy,
Or lower alkoxy, Ar ¹ and Ar ² are each
Hydrogen, representing substituted or unsubstituted aryl), CAR
¹ Ar ² (Ar ¹ and Ar ² are the same as above), O-CHAr ¹
Ar ² (Ar ¹ and Ar ² are the same as above) . )
You. Provided that when Q is location substituent of (a), R ¹ is a substituted or unsubstituted location
Represents a substituted aryl. It is to provide a tricyclic triazolo derivative or a pharmacologically acceptable salt thereof represented by.

In the definitions of the above symbols, halogen is fluorine,
In the chlorine, bromine and iodine, the alkyl moiety in lower alkyl and lower alkoxy is a straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, t-
It means butyl, n-pentyl and the like. Among these, preferred groups include methyl and ethyl. In the definition of A, the linear or branched saturated or unsaturated alkylene having 1 to 5 carbon atoms means, for example, methylene, ethylene, propylene or the following structure.

[0009]

Embedded image The aryl represented by Ar ¹ and Ar ² in the definition of Z and the aryl in the definition of R ¹ are aryl having 6 to 10 carbon atoms such as phenyl and naphthyl, and include 2-pyridyl,
Aromatic heterocycles such as 3-pyridyl, 2-pyrimidyl, 2-thienyl and 2-furyl are also included. The substituent in each group in the above definition means the same or different substituent to an aromatic ring having 1 to 3 substituents, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogen, Alkyl halide,
It means a group selected from alkylamino and nitro. Therefore, substituted aryl means 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 5-methyl-2-thienyl, 2,3 -Means dichlorophenyl, 3,4,5-trimethoxyphenyl and the like.

The pharmacologically acceptable salts of the compound represented by the formula (I) include hydrochloride, hydrobromide, sulfate,
Borates, inorganic salts such as phosphates, acetates, maleates, fumarate, tartrate, succinate, malate, organic acid salts such as paratoluenesulfonate, lysine, glycine, Amino acid addition salts such as phenylalanine.

When the compounds of the present invention have one or more asymmetric carbon atoms, they may exist as racemates, diastereoisomers and individual optical isomers, and the present invention includes all of them. I do.

Hereinafter, a method for producing the compound represented by the formula (I) will be described. However, the production method of each compound is not limited to them, and in various production methods, reaction conditions are appropriately selected from those described below.

The compound represented by the formula (I) of the present invention can be synthesized by using the compound represented by the formula (II) as a starting material by the following method.

That is, the formula (II)

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as defined above, to a compound of the formula (III)

Embedded image (Wherein X represents a halogen, and A and Q have the same meanings as described above) by reacting the compound represented by the formula (I)
Can be produced. For the reaction, a solvent inert to the reaction (dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, etc.)
Medium, inorganic bases (sodium hydride, calcium hydride,
In the presence of sodium amide, potassium hydroxide, potassium t-butoxy, etc.) or an organic base (pyridine, triethylamine, etc.) at 0 ° C. to the reflux temperature of the solvent used.
Progress in minutes to 5 hours.

Next, a method for producing the compound used as a raw material in the above reaction will be described.

The compound represented by the formula (II) can be produced by the following reaction steps.

That is, the formula (IV)

Embedded image (Wherein R ² and R ³ have the same meanings as described above) by converting a compound represented by the formula (V) X—CR ⁴ R ⁵ —CO—E (V) (where E is a halogen, hydroxy, Or lower alkoxy, X represents a halogen, and R ⁴ and R ⁵ have the same meanings as defined above.

Embedded image (Wherein, R ² , R ³ , R ⁴ , and R ⁵ are as defined above)
Can be obtained. The reaction proceeds in an inert solvent (tetrahydrofuran, ethanol, 2-butanone, benzene, toluene, etc.) at 0 ° C. to the reflux temperature of the solvent used for 5 minutes to 24 hours. Equation (V
The compound represented by I) is converted to phosphorus pentasulfide, Lawesso
(VII) by reacting a sulfurizing agent such as n reagent (registered trademark).

Embedded image (Wherein, R ² , R ³ , R ⁴ , and R ⁵ are as defined above)
Can be obtained. The reaction is usually carried out in a solvent inert to the reaction (pyridine, acetonitrile, toluene, xylene, tetrahydrofuran, chloroform, dioxane, diethyl ether, diglyme, etc.).
Proceeding at ~ 100 ° C for 1 minute to 5 hours.

The compound represented by the formula (VII) is added to the compound represented by the formula (VI)
II) A compound represented by R ¹ CONHNH 2 (VIII) (wherein R ¹ is as defined above) is reacted with a solvent inert to the reaction (xylene, n-butanol, n-butanol).
The compound represented by the formula (II) can be obtained by reacting in a solvent such as hexanole, acetonitrile, or cyclohexanol at 50 ° C. for 30 minutes to 6 hours at the boiling point of the solvent used.

The compound represented by the formula (III) has the formula (I)
X) or formula (X)

Embedded image (Wherein m, n, Y, Z, ... are as defined above) and a compound represented by the formula (XI) X-AX ₁ (XI) (where X and X ₁ are the same or different. Represents a halogen, A is as defined above) and a solvent inert to the reaction (dimethylformamide, dimethylacetamide, 2-
Butanone, ethanol, n-butanol, tetrahydrofuran, dichloromethane, etc., or a mixed solvent thereof)
Medium, it can be carried out at 0 ° C. to 150 ° C. for 10 minutes to 1 week. Further, it is preferable to add an organic base such as triethylamine and pyridine, for example, an inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium hydride and potassium acetate as a catalyst.

The thus-obtained compound represented by the formula (I) can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography. The compound represented by the formula (I) can be converted into the above-mentioned pharmacologically acceptable salt by treating it with an inorganic acid, an organic acid or an amino acid by a conventional method.

When the compound of the present invention has an asymmetric carbon atom, it is usually obtained as a racemic form. The racemate can be separated into optical isomers by a conventional method. Such optical isomers can also be produced by using an optically active compound as a starting material. If diastereoisomers are present, the individual diastereoisomers can be purified by fractional recrystallization or chromatography.

In the process for producing the compound represented by the formula (I) and an intermediate thereof, the compound used in the reaction may be an inorganic acid salt such as a hydrochloride, a sulfate, etc. It may be used in the form of a salt such as an organic acid salt such as an acid salt.

The compound represented by the formula (I) of the present invention or a salt thereof has an anti-PAF action and an antihistamine action, and is used for inflammatory, allergic diseases (such as bronchial asthma and psoriasis), PA
Diseases caused by F (eg, thrombosis, stroke, myocardial infarction, angina, thrombophlebitis, nephritis, diabetic nephropathy, endotoxin shock, endovascular coagulation caused by endotoxin, anaphylactic shock, hemorrhagic) Cardiovascular disorders such as shock, gastrointestinal disorders such as gastric ulcer, pneumonia, rejection due to increased PAF production during organ transplantation, organ failure during organ surgery, etc., and diseases in which PAF antagonists are effective (high endothelinosis) Etc.) are useful as preventive and therapeutic agents.

The compound represented by the formula (I) and an acid addition salt thereof can be orally or parenterally administered to mammals as a powder or as a pharmaceutical composition in a suitable dosage form. it can.

Specific examples of the dosage form for oral administration include tablets, pills, powders, capsules, granules, syrups, emulsions and suspensions. Such dosage forms are produced by a method known per se and contain carriers or excipients usually used in the field of pharmaceuticals. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.

Examples of dosage forms for parenteral administration include ointments, injections, poultices, liniments, inhalants, suppositories, and the like.
Transdermal inhalants and the like. The injection is prepared by a method known per se, for example, by dissolving, suspending or emulsifying the compound represented by the formula (I) or a salt thereof in a sterile aqueous or oily liquid commonly used for injections. An aqueous solution for injection includes physiological saline and glucose solution, and an oily liquid includes sesame oil, soybean oil and the like, and may each be used in combination with a solubilizing agent. Suppositories to be used for enteral administration are prepared by a method known per se, for example, by mixing a compound represented by the formula (I) or a salt thereof with a usual base for suppositories and molding.

The effective dose and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof will depend on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. But usually 0.1 per adult per day
10001000 mg, preferably 1-200 mg, can be administered in one or several divided doses.

Each of the above-mentioned dosage forms may contain an active ingredient for other treatments as long as an undesirable interaction is not caused by compounding with the compound represented by the formula (I) or a salt thereof. For example, steroids, non-steroidal anti-inflammatory drugs, lipoxygenase inhibitors, leukotriene antagonists,
Examples include bronchodilators, thromboxane synthesis inhibitors, thromboxane antagonists, histamine release inhibitors, serotonin antagonists, adenosine receptor antagonists, adrenergic β receptor antagonists, immunosuppressants, immunomodulators, and the like.

Examples of the composition of tablets using the compound of the present invention are shown below.

Formulation Example Tablet A tablet having the following composition is prepared by a conventional method .

Compound of Example 9 20 mg Lactose 80 mg Maize starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye trace amount

[0032]

EXAMPLES The effects of the present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 1,2-dihydroquinoxaline-3 (4H) -thione

Embedded image Diglyme 28 in 52 g of 1,2-dihydro-3-hydroxyquinoxaline, 47 g of phosphorus pentasulfide and 59 g of sodium hydrogen carbonate
0 ml was added, and the mixture was stirred at 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, 500 ml of water was added, and the crystals were filtered and washed to obtain 47 g of the title compound as yellow-green crystals. Recrystallization from benzene gave the title compound.

Mp: 120-123 ° C. IR (KBr) cm -1: 3250, 3180, 3100, 2970, 1562, 1510, 1307 1H NMR (CDCl3) δ: 9.75 (1H, brs), 7.12-6.64 (4H, m ), 4.33
(2H, s)

Example 2 4,5-Dihydro-1-methyl [1,2,4] triazolo [4,3-a] quinoxaline

Embedded image To 62 g of the compound of Example 1 and 56 g of acetohydrazide were added 750 ml of n-butanol, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with dichloromethane. After washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropanol to obtain 49 g of the title compound as pale brown needles.

Mp: 173-174 ° C IR (KBr) cm -1: 3230,1562,1510,1499,1431 1H NMR (CDCl3) δ: 7.50-6.82 (4H, m), 4.58 (2H, d, J = 1.8 ),
4.18 (1H, brs), 2.78 (3H, s) MS: 186 (M +)

Example 3 4,5-dihydro-1-phenyl [1,2,4] triazolo [4,3-a]
Quinoxaline

Embedded image The title compound was obtained as light brown needle-like crystals in the same manner as in Example 1 except that benzoylhydrazine was used instead of acetohydrazide.

Mp: 136-141 ° C IR (KBr) cm -1: 1618,1510, 1468, 1423, 756, 704 1H NMR (CDCl3) δ: 7.7-7.4 (5H, m), 7.2-6.5 (4H, m), 4.65
(2H, s), 4.2-4.0 (1H.brs) MS: 248 (M +)

Example 4 4,5-Dihydro-1- (2-furyl) [1,2,4] triazolo [4,3-
a] Quinoxaline

Embedded image The title compound was obtained as light brown needle-like crystals in the same manner as in Example 1 except that 2-furancarboxylic acid hydrazide was used instead of acetohydrazide.

Mp: 161 to 162 ° C. IR (KBr) cm −1: 1613, 1508, 1460, 1427, 1321, 1288, 1168,
745 1H NMR (CDCl3) δ: 7.64 (1H, dd, J = 2,1), 7.3-6.6 (6H, m),
4.66 (2H, d, J = 2), 4.13 (1H, brs) MS: 238 (M +)

Example 5 4,5-Dihydro-1- (2-thienyl) [1,2,4] triazolo [4,3
-a] Quinoxaline

Embedded image The title compound was obtained as pale brown needles in the same manner as in Example 1 except that 2-thiophenecarboxylic acid hydrazide was used instead of acetohydrazide.

Mp: 198-199 ° C. IR (KBr) cm -1: 1618,1506,1437,1319,1284,746,708 1H NMR (CDCl3) δ: 7.57 (1H, dd, J = 5,1), 7.38 (1H , dd, J = 4,
1), 7.3-6.6 (5H, m), 4.64 (2H, d, J = 2), 4.14 (1H, brs) MS: 254 (M +)

Example 6 1- (3-chloropropyl) -4- (diphenylmethylene) piperidine

Embedded image 4.03 g of 4- (diphenylmethylene) piperidine, 1-bromo
-3-Chloropropane 6.37g in toluene 20ml, 25% sodium hydroxide 10ml, tetrabutylammonium hydrogen sulfate 0.
27 g was added and the mixture was stirred at room temperature for 10 hours. After extraction with ethyl acetate, the mixture was washed with water and dried. After evaporating the solvent, the residue was recrystallized from cyclohexane to obtain 3.67 g of the title compound as colorless crystals.

Mp: 73-73.5 ° C. IR (KBr) cm −1: 2922,2772,1491,1441,1377,1296,1122,
996,760,702 1H NMR (CDCl3) δ: 7.3-7.0 (10H, m), 3.60 (2H, t, J = 7), 2.6
-2.4 (6H, m), 2.4-2.3 (4H, m), 1.96 (2H, quint, J = 7)

In the following Examples 7 and 8, the same procedure as in Example 6 was carried out to obtain the title compound. Example 7 8- (3-chloropropyl) -3- (diphenylmethylene) -8-azabicyclo [3.2.1] octane

Embedded image Light brown oil IR (neat) cm-1: 2940,1493,1441,760,708 1H NMR (CDCl3) δ: 7.5-7.0 (10H, m), 3.66 (2H, t, J = 6), 3.2
0 (2H, m), 2.58 (2H, t, J = 7), 2.4-2.0 (4H, m), 2.2-1.6 (6H, m)

Example 8 8- (3-chloropropyl) -3- (diphenylmethoxy) -8-azabicyclo [3.2.1] octane

Embedded image Colorless oil IR (neat) cm-1: 2942,1060,743,704 1H NMR (CDCl3) δ: 7.4-7.1 (10H, m), 5.40 (1H, s), 3.7-3.5
(3H, m), 3.14 (2H, m), 2.47 (2H, t, J = 7), 2.2-1.7 (10H, m)

Example 9 4,5-dihydro-1-methyl-5- [3- [3- (diphenylmethylene) -8-azabicyclo [3.2.1] octan-8-yl] propyl] [1,2, 4] Triazolo [4,3-a] quinoxaline

Embedded image 1.28 g of the compound of Example 2 and 2.43 g of the compound of Example 7 were dissolved in 30 ml of dimethylformamide and cooled to -20 ° C.
After dropping 8 ml of a dimethylformamide solution (1M) of t-BuOK, the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to obtain 1.64 g of the title compound as a pale yellow amorphous.

IR (KBr) cm -1: 2944,1560,1502,1475,143
1,756,704 1H NMR (CDCl3) δ: 7.45 (1H, dd, J = 6.4,1.5), 7.32-7.25 (3
H, m), 7.24-7.10 (8H, m), 7.03 (1H, dd, J = 6.8,1.5), 6.89 (1
H, t, J = 6.8), 4.45 (2H, s), 3.48 (2H, t, J = 6.8), 3.22 (2H, b
r), 2.77 (3H, s), 2.55-2.40 (4H, m), 2.30-2.23 (2H, m), 1.92
-1.75 (6H, m), MS: 501 (M +) Elemental analysis: C33H35N5 Calculated: C, 79.01; H, 7.03; N, 13.96 Found: C, 78.87; H, 6.99; N, 13.85

In the following Examples 10 to 13, the same operation as in Example 9 was carried out to obtain the title compound. Example 10 4,5-dihydro-1-methyl-5- [3- [3- (diphenylmethoxy) -8-azabicyclo [3.2.1] octan-8-yl] propyl] [1,2,4] triazolo [4,3-a] quinoxaline

Embedded image Pale yellow amorphous IR (KBr) cm -1: 2938,1557,1504,1431,1052,745,702 1H NMR (CDCl3) δ: 7.44 (1H, dd, J = 6.8,1.5), 7.36-7.17 (1
1H, m), 7.00 (1H, dd, J = 7.3,1.0), 6.88 (1H, td, J = 7.8,1.0),
5.41 (1H, s), 4.43 (2H, s), 3.61 (1H, br), 3.43 (2H, t, J = 7.
3), 3.17 (1H, br), 2.77 (3H, s), 2.41 (2H, br), 2.17 (2H, br),
2.00-1.70 (10H, m) MS: 519 (M +) Elemental analysis: C33H37N5O Calculated: C, 76.27; H, 7.18; N, 13.48 Found: C, 76.21; H, 7.26; N, 13.35

Example 11 4,5-Dihydro-1-phenyl-5- [3- [4- (diphenylmethylene) piperidin-1-yl] propyl] [1,2,4] triazolo
[4,3-a] quinoxaline

Embedded image Pale yellow amorphous IR (KBr) cm -1: 2954,2810,1499,1479,1464,1446,1427,
762,700 1H NMR (CDCl3) δ: 7.7-7.4 (6H, m), 7.28 (4H, m), 7.2-7.1
(7H, m), 6.98 (1H, d, J = 8.4), 6.90 (1H, td, J = 7.9,1.0), 4.49
(2H, s), 3.44 (2H, t, J = 7.3), 2.55 (4H, brs), 2.44 (6H, m), 1.
86 (2H, quint, J = 7.0) MS: 537 (M +) Elemental analysis: C36H35N5 Calculated: C, 80.41; H, 6.56; N, 13.02 Found: C, 80.24; H, 6.68; N, 12.96

Example 12 4,5-Dihydro-1- (2-furyl) -5- [3- [4- (diphenylmethylene) piperidin-1-yl] propyl] [1,2,4] triazolo [4 , 3-a] Quinoxaline

Embedded image Pale yellow amorphous IR (KBr) cm -1: 2954,2808,1499,1479,1444,1424,748,7
02 1H NMR (CDCl3) δ: 7.64 (1H, dd, J = 2.0, 1.1), 7.4-6.9 (14
H, m), 6.80 (1H, dd, J = 8.4,1.2), 6.62 (1H, dd, J = 1.8,1.5),
4.50 (2H, s), 3.43 (2H, t, J = 7.3), 2.53 (4H, brs), 2.44 (6H,
m), 1.86 (2H, quint, J = 7.0) MS: 527 (M +) Elemental analysis: C34H33N5 O Calculated: C, 77.39; H, 6.30; N, 13.27 Found: C, 77.46; H, 6.17; N, 13.21

Example 13 4,5-dihydro-1- (2-thienyl) -5- [3- [4- (diphenylmethylene) piperidin-1-yl] propyl] [1,2,4] triazolo [4 , 3-a] Quinoxaline

Embedded image Pale yellow amorphous IR (KBr) cm -1: 2952,2810,1499,1468,1435,750,704 1H NMR (CDCl3) δ: 7.56 (1H, dd, J = 5.1,1.1), 7.37 (1H, dd,
J = 6.3,1.1), 7.3-7.1 (13H, m), 6.98 (1H, d, J = 8.4), 6.90 (1
H, td, J = 7.9,1.0), 4.48 (2H, s), 3.43 (2H, t, J = 7.3), 2.55 (4
H, brs), 2.41 (6H, m), 1.90 (2H, quint, J = 7.0) MS: 543 (M +) Elemental analysis: C34H33N5 S Calculated: C, 75.11; H, 6.12; N, 12.88; S , 5.90 found: C, 75.06; H, 5.97; N, 12.95; S, 6.18.

[0053]

Industrial Applicability The tricyclic triazolo derivative of the present invention represented by the formula (I) or a salt thereof exhibits an anti-PAF action and an antihistamine action, and has inflammatory and allergic diseases (such as bronchial asthma and psoriasis). Diseases caused by PAF (eg, thrombosis, stroke, myocardial infarction, angina, thrombophlebitis, nephritis,
With circulatory disorders such as diabetic nephropathy, endotoxin shock, intravascular blood coagulation syndrome caused by endotoxin, anaphylactic shock, hemorrhagic shock, gastrointestinal diseases such as gastric ulcer, pneumonia, and increased PAF production during organ transplantation Rejection, organ failure during organ surgery),
PAF antagonists are effectively used as preventive and therapeutic agents for effective diseases (such as hyperendothelinosis).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/55 A61K 31/55 A61P 1/04 A61P 1/04 1/16 1/16 7/02 7/02 9/02 9 / 02 11/00 11/00 11/06 11/06 13/12 13/12 29/00 29/00 37/06 37/06 37/08 37/08 43/00 113 43/00 113 (58) Survey Field (Int. Cl. ⁷ , DB name) C07D 487/04 145 C07D 487/08 C07D 519/00 311 A61K 31/4985 A61K 31/4995 A61K 31/55 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula (I) [Wherein, R ¹ represents hydrogen, lower alkyl, substituted or unsubstituted aryl, R ² and R ³ represent hydrogen, lower alkyl, lower alkoxy or halogen, respectively, R ⁴ , R ⁵
Represents hydrogen and lower alkyl, respectively, and A has 1 to 1 carbon atoms.
5 represents a saturated or unsaturated straight-chain or branched alkylene (which may contain a hetero atom);
Substituents shown below in (a) or (b) ## STR2 ## (In m, m represents 0 to 2, n represents 1 to 3, ...
Represents a single bond or a double bond, Y represents N or C, and Z represents C (B) Ar ¹ Ar ² (B is hydrogen, hydroxy,
Or lower alkoxy, Ar ¹ and Ar ² are each
Hydrogen, representing substituted or unsubstituted aryl), CAR
¹ Ar ² (Ar ¹ and Ar ² are the same as above), O-CHAr ¹
Ar ² (Ar ¹ and Ar ² are the same as above) . )
You. However, when Q is a substituent (a), R ¹ is substituted or unsubstituted.
Represents a substituted aryl. Tricyclic triazolo derivative or a pharmacologically acceptable salt thereof represented by.