JPS6242901B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel 4 represented by the following formula []
- Phenylphthalazine derivatives and pharmaceutically acceptable salts thereof. (In the formula, group, an alkylcarbonyl group having a total of 2 to 4 carbon atoms, a hydroxyl group, a trifluoromethyl group, and n is 1
is an integer of ~3, and when n is 2 or more, R may be the same or different. ) Background (prior art) As 4-phenylphthalazine derivatives similar to the compound of the present invention, 1-anilino-4-phenylphthalazine [Ber., 38 , 3923 (1905)], 1-phenoxy-4-phenyl Phthalazine [Pharmaceutical Journal, 88 , 83
(1968)], 1-[2-(2-methylallyl)phenoxy]-4-phenylphthalazine, 1-(2-
Allylphenoxy)-4-phenylphthalazine [Chem.Pharm.Bull., 24 1581-1595 (1976)] is already known. However, it is only described as a synthetic intermediate, and its usefulness has not been investigated. Also, 1-[2-(2-methylallyl)phenoxy]-4-phenylphthalazine, 1-(2
-Allylphenoxy)-4-phenyl phthalazine has a double bond in the substituent, so it is susceptible to structural changes due to ring-closing reactions and the like. On the other hand, 1-alkylamino-4-phenylphthalazine derivatives, 1-alkyloxy-4-phenylphthalazine derivatives [J.Med.Chem. 12 555
(1969)], and 1-(piperazin-1-yl)
-4-Phenylphthalazine derivatives [Special Publication 1977-
No. 39944] was being studied as an anti-inflammatory agent. However, these documents do not mention 1-anilino derivatives and 1-phenoxy derivatives. Summary of the Invention The present inventors succeeded in synthesizing a novel compound represented by the formula [ ] that has not been described in any literature, and through further research, confirmed that these compounds have a strong platelet aggregation inhibiting effect. Therefore, the compounds of the present invention are considered to be applicable to the prevention and treatment of thrombotic thrombosis, active infarction, myocardial infarction, and arteriosclerotic diseases, which are diseases induced by enhanced platelet aggregation. That is, an object of the present invention is to provide a novel compound represented by the formula [ ] that has a stable and strong platelet aggregation inhibitory effect. Specific description of the invention (1) Compound of the present invention The compound of the present invention is represented by the following formula [], (In the formula, X represents NH or O, R is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms,
5 alkoxy group, halogen atom, total carbon number 2~
5 alkoxycarbonyl group, carboxyl group,
Represents a cyano group, an alkylcarbonyl group having a total of 2 to 4 carbon atoms, a hydroxyl group, or a trifluoromethyl group, where n is an integer of 1 to 3, and when n is 2 or more, R may be the same or different. good. ) The alkyl group represented by R in formula [] is, for example, methyl, ethyl, propyl, isopropyl, n
-butyl, t-butyl, etc., alkoxy groups include, for example, methoxy, ethoxy, propoxy, butoxy, etc., halogens include fluorine, chlorine, bromine, and iodine, and alkoxycarbonyl groups include, for example, methoxycarbonyl, Ethoxycarbonyl, etc., and the alkylcarbonyl group is, for example, acetyl, propionyl, etc. Furthermore, since the compound represented by the formula [] has a basic nitrogen atom, it can form a salt with a pharmaceutically acceptable acid. For example, hydrogen chloride,
Mineral acids such as sulfuric acid, hydrobromic acid, phosphoric acid, or methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid, maleic acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, etc. There is salt. Next, specific examples of the compound represented by the formula [] will be shown. Compound number Compound name (1) 1-(4-methylanilino)-4-phenylphthalazine (2) 1-(3-methylanilino)-4-phenylphthalazine (3) 1-(2-methylanilino) -4-phenylphthalazine (4) 1-(4-ethylanilino)-4-phenylphthalazine (5) 1-(2-ethylanilino)-4-phenylphthalazine (6) 1-(4-n -butylanilino)-4
-Phenylphthalazine (7) 1-(3-n-butylanilino)-4
-Phenylphthalazine (8) 1-(4-t-butylanilino)-4
-Phenylphthalazine (9) 1-(4-methoxyanilino)-4-
Phenylphthalazine (10) 1-(3-methoxyanilino)-4-
Phenylphthalazine (11) 1-(3-propoxyanilino)-4
-Phenylphthalazine (12) 1-(4-n-butoxyanilino)-
4-Phenylphthalazine (13) 1-(4-fluoroanilino)-4
-Phenylphthalazine (14) 1-(3-fluoroanilino)-4
-Phenylphthalazine (15) 1-(2-fluoroanilino)-4
-Phenylphthalazine (16) 1-(4-chloroanilino)-4-
Phenylphthalazine (17) 1-(3-chloroanilino)-4-
Phenylphthalazine (18) 1-(2-chloroanilino)-4-
Phenylphthalazine (19) 1-(4-bromoanilino)-4-
Phenylphthalazine (20) 1-(3-bromoanilino)-4-
Phenylphthalazine (21) 1-(4-iodoanilino)-4-
Phenylphthalazine (22) 1-(3-iodoanilino)-4-
Phenylphthalazine (23) 1-(4-ethoxycarbonylanilino)-4-phenylphthalazine (24) 1-(4-carboxylanilino)
-4-Phenylphthalazine (25) 1-(4-cyanoanilino)-4-
Phenylphthalazine (26) 1-(4-acetylanilino)-4
-Phenylphthalazine (27) 1-(4-trifluoromethylanilino)-4-phenylphthalazine (28) 1-(3-trifluoromethylanilino)-4-phenylphthalazine (29) 1-(2-trifluoromethylanilino)-4-phenylphthalazine (30) 1-(3-hydroxyanilino)-
4-Phenylphthalazine (31) 1-(2,3-dimethylanilino)
-4-Phenylphthalazine (32) 1-(2,4-dimethylanilino)
-4-Phenylphthalazine (33) 1-(2,5-dimethylanilino)
-4-Phenylphthalazine (34) 1-(3,4-dimethylanilino)
-4-Phenylphthalazine (35) 1-(2,5-diethylanilino)
-4-Phenylphthalazine (36) 1-(2,5-dipropylanilino)-4-phenylphthalazine (37) 1-(2,5-dimethoxyanilino)-4-phenylphthalazine (38) 1-(3,4-dimethoxyanilino)-4-phenylphthalazine (39) 1-(2,5-dichloroanilino)
-4-Phenylphthalazine (40) 1-(3,4-dichloroanilino)
-4-Phenylphthalazine (41) 1-(2,5-difluoroanilino)-4-phenylphthalazine (42) 1-(3-chloro-4-methylanilino)-4-phenylphthalazine ( 43) 1-(2-methyl-3-chloroanilino)-4-phenylphthalazine (44) 1-(2-methyl-4-chloroanilino)phenylphthalazine (45) 1-(3-methyl-4- chloroanilino)-4-phenylphthalazine (46) 1-(3-fluoro-4-methylanilino)-4-phenylphthalazine (47) 1-(2-methoxy-5-methylanilino)-4-phenylphthalazine Radin (48) 1-(2-methoxy-4-chloroanilino)-4-phenylphthalazine (49) 1-(2-methyl-5-trifluoromethylanilino)-4-phenylphthalazine (50) 1-(2-Methoxy-5-trifluoromethylanilino)-4-phenylphthalazine (51) 1-(2,4,6-trimethylanilino)-4-phenylphthalazine (52) 1- (3,4,5-trimethoxyanilino)-4-phenylphthalazine (53) 1-(4-methylphenoxy)-4
-Phenylphthalazine (54) 1-(3-methylphenoxy)-4
-Phenylphthalazine (55) 1-(2-methylphenoxy)-4
-Phenylphthalazine (56) 1-(4-ethylphenoxy)-4
-Phenylphthalazine (57) 1-(2-ethylphenoxy)-4
-Phenylphthalazine (58) 1-(4-n-butylphenoxy)
-4-Phenylphthalazine (59) 1-(3-n-butylphenoxy)
-4-Phenylphthalazine (60) 1-(4-t-butylphenoxy)
-4-Phenylphthalazine (61) 1-(4-methoxyphenoxy)-
4-Phenylphthalazine (62) 1-(3-methoxyphenoxy)-
4-Phenylphthalazine (63) 1-(3-propoxyphenoxy)
-4-Phenylphthalazine (64) 1-(3-butoxyphenoxy)-
4-Phenylphthalazine (65) 1-(4-fluorophenoxy)-
4-Phenylphthalazine (66) 1-(3-fluorophenoxy)-
4-Phenylphthalazine (67) 1-(4-chlorophenoxy)-4
-Phenylphthalazine (68) 1-(3-chlorophenoxy)-4
-Phenylphthalazine (69) 1-(2-chlorophenoxy)-4
-Phenylphthalazine (70) 1-(4-bromophenoxy)-4
-Phenylphthalazine (71) 1-(3-bromophenoxy)-4
-Phenylphthalazine (72) 1-(3-iodophenoxy)-4
-Phenylphthalazine (73) 1-(4-Ethoxycarbonylphenoxy)-4-Phenylphthalazine (74) 1-(4-Carboxylphenoxy)-4-Phenylphthalazine (75) 1 -(4-dianophenoxy)-4
-Phenylphthalazine (76) 1-(4-acetylphenoxy)-
4-Phenylphthalazine (77) 1-(4-trifluoromethylphenoxy)-4-phenylphthalazine (78) 1-(3-trifluoromethylphenoxy)-4-phenylphthalazine (79) 1-(3-hydroxyphenoxy)
-4-Phenylphthalazine (80) 1-(2,3-dimethylphenoxy)-4-phenylphthalazine (81) 1-(2,5-dimethylphenoxy)-4-phenylphthalazine Radin (82) 1-(2,5-diethylphenoxy)-4-phenylphthalazine (83) 1-(2,5-dipropylphenoxy)-4-phenylphthalazine (84) 1 -(2,5-dimethoxyphenoxy)-4-phenylphthalazine (85) 1-(3,4-dimethoxyphenoxy)-4-phenylphthalazine (86) 1-(2,5- Dichlorophenoxy)-4-phenylphthalazine (87) 1-(2,6-dichlorophenoxy)-4-phenylphthalazine (88) 1-(2,5-difluorophenoxy)- 4-Phenylphthalazine (89) 1-(3-chloro-4-methylphenoxy)-4-phenylphthalazine (90) 1-(3-methyl-4-chlorophenoxy)-4-phenylphthalazine (91) 1-(3-fluoro-4-methylphenoxy)-4-phenylphthalazine (92) 1-(2-methoxy-4-chlorophenoxy)-4-phenylphthalazine (93) 1-( 2-Methoxy-5-methylphenoxy)-4-phenylphthalazine (94) 1-(2-methyl-4-trifluoromethylphenoxy)-4-phenylphthalazine (95) 1-(2,4 , 6-trimethylphenoxy)-4-phenylphthalazine (2) Synthesis of the compound of the present invention The compound of formula [] can be produced by any convenient method, but the preferred method is shown below. . (In the formula, X' represents -NH ₂ or OH.R,
(n, and Below, a 4-phenylphthalazine derivative represented by the formula [] is synthesized by reacting with a benzene derivative represented by the general formula []. The starting material, 1-chloro-4-phenylphthalazine, was synthesized by the method described in Pharmaceutical Journal 86 576 (1966). As the benzene derivative [] to be reacted, substituted aniline or substituted phenol derivatives suitable for the purpose were used. The reaction temperature is -20° to 250°C, preferably -10° to
The temperature is preferably 180°C, and the reaction time is preferably 5 minutes to 24 hours, preferably 10 minutes to 10 hours. When using a catalyst, an organic base such as ammonia, triethylamine, piperidine, pyridine, etc.
Or NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ ,
The molar ratio of an inorganic base such as NaOH, KOH, NaH, _NaNH2, etc. to the compound [] is 0.5 to 5, preferably 1.
-3 use, or a molar ratio of metals such as copper, magnesium, cadmium, sodium, potassium, etc. to the compound [] is 0.001-2, preferably 0.01-2
1.5 is recommended. When using a solvent, ethers such as ethyl ether, tetrahydrofuran and dioxane, halogenated alkanes such as chloroform and methylene chloride, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, Amides such as dimethylformamide and dimethylacetamide, dimethyl sulfoxide, etc. in a weight ratio of 1 to 100 to the compound []
Use twice. The amount of compound [] to be used is 0.5 to 30, preferably 1 to 20, in molar ratio to compound []. After the reaction is complete, pour it into a large excess of water, or dissolve it directly in a solvent such as chloroform to neutralize it, and if necessary, collect the precipitated crystals after concentration.
Alternatively, if it does not precipitate, it is extracted with a suitable solvent such as chloroform, and then purified by conventional methods such as recrystallization and chromatography. (3) Examples Example 1 Synthesis of 1-(4methylanilino)-4-phenylphthalazine [Compound number (1)] 2.41 g of 1-chloro-4-phenylphthalazine and 5.35 g of P-toluidine copper 70 mg of powder was added, and the reaction temperature was maintained at 100°C and heated and stirred for 1 hour. After cooling,
After adding a large excess of chloroform to the reaction solution, insoluble matter was removed, the mixture was washed successively with a 5% NaOH aqueous solution and water, the organic layer was dried and concentrated, and the residue was recrystallized from ethanol. 910 mg (yield 29%) of pale yellow crystals were obtained. mp 185-186°C IR 1630cm ^-1 , 1510cm ^-1 , 1410cm ^-1 MS 310 (M ⁺ -1) Examples 2-30 The compounds shown in Table 1 were synthesized in the same manner as in Example 1.

【table】

[Table] Example 31 Synthesis of 1-(2-methylphenoxy)-4-phenylphthalazine [Compound number (55)] Add 5.40 g of 0-cresol and 360 mg of KOH to 1.20 g of 1-chloro-4-phenylphthalazine. The mixture was heated and stirred for 2 hours while maintaining the reaction temperature at 100°C. The reaction mixture was poured into 12 ml of an aqueous solution containing 3.6 g of KOH, and the precipitated crystals were collected. The crude crystals were dissolved in CHCl ₃ , washed with water, dried and concentrated, and the residue was recrystallized from ethanol-n-hexane to obtain 725 mg (yield: 46%) of white crystals. mp 136.5～137.5℃ IR 1490cm ^-1 , 1385cm ^-1 , 1230cm ^-1 , 1190cm
^-1 , 790 cm ^-1 , 750 cm ^-1 MS 312 (M ⁺ ) Examples 32 to 44 The compounds shown in Table 2 were synthesized in the same manner as in Example 31.

【table】

[Table] (4) Drug efficacy test Rabbit arterial blood was centrifuged to obtain platelet rich plasma, 5 μl of drug solution was added to 250 μl of the plasma, incubated for 2 minutes, and 3 μg of collagen was added as a platelet aggregation inducer. , changes in platelet aggregation were measured using a Kagligometer.
Observations were recorded for minutes. The platelet aggregation inhibition rate was calculated using the following formula. Inhibition rate = Tc - Ts / Tc x 100 Tc: Degree of aggregation when only solvent is added Ts: Degree of aggregation when drug solution is added Table 3 shows the inhibition rate at each molar concentration of the compound. As a result, it was found that among these compounds, anilinophthalazine derivatives tend to be generally more potent than phenoxyphthalazine derivatives.

【table】

【table】

[Table] (5) Safety All of the compounds of the present invention had very low toxicity, with an LD ₅₀ of 5000 mg/Kg or more when administered orally to mice.

Claims (1)

[Claims] 1. A 4-phenylphthalazine derivative represented by the following general formula or a pharmaceutically acceptable salt thereof (In the formula, group, an alkylcarbonyl group having a total of 2 to 4 carbon atoms, a hydroxyl group, a trifluoromethyl group, and n is 1
is an integer of ~3, and when n is 2 or more, R may be the same or different. )