JPS6112901B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides α-substituted aminoalkanoyl-3,4
- Dihydrocarbostyryl derivatives and acid addition salts thereof. The present invention is a new substance, with the general formula [In the formula, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is a lower alkyl group, R ₃ is a hydrogen atom or a phenyl lower alkyl group, and R ₄ has or does not have a lower alkoxy group as a substituent on the aromatic ring. It represents a phenyl lower alkyl group, a diphenyl lower alkyl group, or a phenoxy lower alkyl group. ] is an α-substituted aminoalkanoyl-3,4-dihydrocarbostyryl derivative. The compound of the present invention is an important intermediate of (1-hydroxy-2-substituted amino)alkylcarbostyryl derivatives that exhibit vasodilatory action and is useful as a vasodilator, and the compound of the present invention itself has platelet aggregation inhibiting action. It is useful as a blood clot preventive drug. In the compound of the above general formula [], the lower alkyl group means a straight chain or branched alkyl group having 1 to 6 carbon atoms, including methyl group, ethyl group, propyl group, isopropyl group, butyl group, and isobutyl group. Examples include sec-butyl group, tert-butyl group, pentyl group, and hexyl group. The number of carbon atoms in each lower alkyl group constituting the phenyl lower alkyl group, the phenyl lower alkyl group with or without a lower alkoxy group as a substituent on the aromatic ring, the diphenyl lower alkyl group, and the phenoxy lower alkyl group also corresponds to the above lower alkyl group. It is similar to that of . Examples of the lower alkoxy group used as the above-mentioned substituent include methoxy group, ethoxy group, propoxy group, isopropoxy group, and butoxy group. Representative compounds of the present invention include 6-(α-
phenethylamino)heptanoyl-3,4-dihydrocarbostyryl, 1-methyl-6-[α-(4
-phenylbutylamino)-γ-methyl]pentanoyl-3,4-dihydrocarbostyryl, 1-
Benzyl-6-[α-(3,3-diphenylpropylamino)-β-methyl]butyryl-3,4-dihydrocarbostyryl, 6-[α-(2-phenoxyethylamino)]pentanoyl-3・4-dihydrocarbostyryl, 1-methyl-6-[α-(1
-Methyl-3-phenylpropylamino)]propionyl-3,4-dihydrocarbostyryl, 6
-[α-(3,4-dimethoxyphenethylamino)]butyryl-3,4-dihydrocarbostyryl, 1-benzyl-6-{α-[1,1-dimethyl-2-(4-methoxyphenyl) )ethylamino]}
Propionyl-3,4-dihydrocarbostyryl, 1-benzyl-6-[α-(N-benzylbenzylamino)]propionyl-3,4-dihydrocarbostyryl, 1-ethyl-6-[α-(1-methyl -2-phenoxyethylamino)]butyryl-3,4-dihydrocarbostyryl, 6-[α-
(4-phenoxybutylamino)]propionyl-
3,4-dihydrocarbostyryl, 6-[α-
Examples include (1,1-dimethyl-4-phenoxybutylamino)]propionyl-3,4-dihydrocarbostyryl. Furthermore, in the present invention, pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or oxalic acid, maleic acid,
Also included are addition salts of organic acids such as succinic acid, malonic acid, acetic acid, salicylic acid, citric acid, and benzoic acid. The compound of the present invention has the general formula [In the formula, R ₁ and R ₂ are the same as above. X represents a halogen atom. ] α-haloalkanoyl-
3,4-dihydrocarbostyryl derivative and general formula [In the formula, R ₃ and R ₄ are the same as above. ] is produced by reacting with an amine represented by: The compound of formula [], which is the starting material of the present invention, is a new compound, and can be produced, for example, as follows. That is, the general formula which is a known compound A 3,4-dihydrocarbostyryl derivative represented by [wherein R ₁ is the same as above] and a general formula that is a known compound [In the formula, R ₂ and X are the same as above. X′ represents a halogen atom. It is produced by reacting with an α-halogenoalkanoyl halide represented by the following formula. This reaction is generally called a Friedel-Crafts reaction, and is carried out in the presence of a Lewis acid. Examples of the Lewis acid used here include anhydrous aluminum chloride and titanium chloride. The amount of Lewis acid to be used may be selected as appropriate, but it is usually used in an amount of 1 to 5 times the mole (preferably 2 to 4 times) of the 3,4-dihydrocarbostyryl derivative represented by the general formula []. In addition, the ratio of the 3,4-dihydrocarbostyryl derivative represented by the general formula [] and α-halogenoalkanoyl halide may be appropriately selected, but the latter is usually used in equal molar to large excess (preferably 1.5 to 5 times the mole) may be used. This reaction can be carried out without a solvent or in a solvent. As the solvent, for example, nitrobenzene, methylene chloride, ethylene chloride, etc. are usually used. The reaction temperature in this reaction is not particularly limited, but is generally room temperature to 120°C (preferably 50 to 80°C).
The reaction proceeds advantageously at temperatures (°C). In this way, a compound of the general formula [] corresponding to R ₁ and R ₂ of the compound of the general formula [] is obtained. As the compound of formula [] which is the other starting material of the present invention, the compound represented by formula []
All amines corresponding to R ₃ and R ₄ can be used. The reaction between the compound of formula [] and the compound of formula [] may be carried out without a solvent since the amine itself acts as a solvent, or may be carried out in a suitable solvent. The solvent used at this time is not particularly limited as long as it does not participate in the reaction, but lower alcohols such as methanol, ethanol, isopropanol, water, etc. are usually preferably used. The ratio of the compound represented by the general formula [] and the amine of the general formula [] may be selected as appropriate, but when the reaction is carried out without a solvent, the latter is usually used in large excess relative to the former, or in a solvent. In this case, it is preferable to use the latter in an equimolar to three times the molar amount of the former. The reaction temperature in this reaction is not particularly limited, but it generally proceeds advantageously at room temperature to around reflux temperature (preferably 40 to 60°C), and is appropriately selected depending on the type of raw materials, the amount used, etc. After completion of the reaction, the compound of this step is isolated from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. The obtained compound can be further purified, if necessary, using commonly used methods such as fractional recrystallization, column chromatography, thin layer chromatography, etc. Incidentally, the present invention naturally includes optical isomers of the 3,4-dihydrocarbostyryl derivative of the general formula []. Furthermore, a true carbostyryl derivative in which the hydrogen at the 3/4-position of the carbostyryl group of the 3,4-dihydrocarbostyryl derivative of the general formula [] is dehydrogenated can be easily obtained by dehydrogenating the compound of the general formula []. can be obtained. Examples of pharmacological tests conducted on the compounds of the present invention are listed below. <Pharmacological test> The platelet aggregation inhibitory effect was investigated according to the method described in Nature, pages 927-929 (1962). In other words, the platelet aggregation inhibition effect was measured using an AG-type aggregometer (Bryston Manufacturing Company).
Manufacturing Co.). The blood sample collected from the rabbit is a mixture of sodium citrate and whole blood, with a mixing ratio of 1:9 (volume ratio).
It is. The sample was centrifuged at 1000 rpm for 10 minutes to extract platelet rich plasma.
plasma] (hereinafter referred to as "PRP-1"). The obtained PRP-1 was separated and the remaining blood sample was
Further centrifugation is performed at 3000 rpm for 15 minutes to obtain platelet poor plasma (hereinafter referred to as "PDP"). The number of platelets contained in the PRP-1 was determined by the Bretcher-Cronkhite method.
Adenosine diphosphate (ADP) was measured by diluting PRP-1 with PPP.
A sample containing 300,000/ ^mm3 platelets (hereinafter referred to as "PRP-2") was prepared for the induced aggregation test, and also for the collagen-induced aggregation test.
A sample containing 450,000/ ^mm3 platelets (hereinafter referred to as “PRP-
3) was prepared. (1) ADP-induced aggregation inhibition test Add 0.6 ml of PRP-2 prepared above to 0.01 ml of a solution containing the compound to be tested at a predetermined concentration.
ml was added, and the mixture was placed in a constant temperature bath at a temperature of 37°C for 1 minute. Then 0.07 ml of ADP solution was added to the mixture. The permeability of this mixture was measured, and the change in permeability was measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. used in this test
The ADP solution was prepared using Oren-Veronal buffer to a concentration of 7.5×10 ⁻⁵ M. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = c ₁ - _{a 1} / b ₁ - _{a 1} × 100 where a ₁ : Permeability of PRP-2 b ₁ : Permeability of PPP c ₁ : Permeability of PRP-2 mixed with test compound and ADP Let the aggregation rate calculated by the above formula be _B1 . In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is defined as the control aggregation rate _A1 . The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Inhibition rate (%) = A ₁ - B ₁ / A ₁ × 100 (2) Collagen-induced aggregation inhibition test Add 0.6 ml of PRP-3 prepared above to 0.01 ml of a solution containing the compound to be tested at a predetermined concentration.
ml was added, and the mixture was placed in a constant temperature bath at a temperature of 37°C for 1 minute. Next, add 0.07ml of collagen solution to the mixture.
added. The permeability of this mixture was measured, and the change in permeability was measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. In this test, collagen was ground by adding 5 ml of Oren-Veronal buffer (PH7.35) to 100 mg of collagen, and the resulting supernatant was used. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = c ₂ - _{a 2} / b ₂ - _{a 2} × 100 where a ₂ : Permeability of PRP-3 b ₂ : Permeability of PPP c ₂ : PRP mixed with test compound and collagen
Transmittance of -3 Let the aggregation rate calculated by the above formula be _B2 . In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is defined as the control aggregation rate _A2 . The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Rejection rate (%) = A ₂ - B ₂ /A ₂ ×100 For the compounds of the present invention obtained in each example described later,
The results of determining the usage concentration (IC ₅₀ ) of each test compound at which the inhibition rate (%) determined above is 50% are determined in the following 1.
Shown in the table.

[Table] It is clear from Table 1 above that all of the compounds of the present invention have excellent platelet aggregation inhibiting activity. Reference Examples and Examples will be described below to explain the present invention in more detail, but the present invention is not limited thereto. Reference Example 1 140 g of α-bromopropionyl bromide and 87 g of AlCl ₃ were added to 250 ml of CS ₂ , stirred, and then refluxed to dissolve. A solution in which 20 g of N-methyl-3,4-dihydrocarbostyryl was suspended in 50 ml of CS _2. Drop in small portions over 15 minutes. After dropping, stir and reflux.
After 1.5 hours, CS ₂ was distilled off from the reaction solution under reduced pressure.
The concentrated residue was poured into ice-water and extracted with CHCl ₃ .
The CHCl ₃ layer was washed with water, dried over Na ₂ SO ₄ and concentrated. The residue was recrystallized from ligroin to give N-methyl-6-
α-bromopropionyl-3,4-dihydrocarbostyryl is obtained. Yield 24 g (yield 65%), colorless needle crystals, mp 84-86°C NMR δ ^ppm _CDCl3 : 1.9 ^d (3H, CH- _CH3 ) 2.6-3.3 ^m (4H, _CH2 of _C3 , _C4 ) 3.4 ^s (3H, N-C H ₃ ) 5.3 ^q (1H, C H -CH ₃ ) 7.15 ^d (1H, H of C ₈ ) 7.8-8.2 ^m (2H, 2H, H of C ₅ , C ₇ ) Reference Example 2 In the same manner as Reference Example 1, 6-(α-
Bromopropionyl)-3,4-dihydrocarbostyryl (mp 192-193°C) is obtained. Example 1 11 g of β-(3,4-dimethoxy)phenylethylamine was added to 50 ml of DMF, and while stirring at 40 to 50°C, a small amount of 50 ml of DMF solution containing 6 g of 6-α-chloropropionyl-3,4-dihydrocarbostyryl was added. Drop one by one. The dropwise addition took 1 hour, and after stirring for another 1 hour at the same temperature, the reaction solution was poured into about 500 ml of saturated NaCl water and extracted with CHCl ₃ . Water and saturate ₃ layers of CHCl
NaHCO ₃ water, washed with water and dried with Na ₂ SO ₄ HCl/
Add EtOH solution to acidify and concentrate. The residue was recrystallized from ethanol to give colorless powdery crystals of 6-
2.6 g of [2-β-(3,4-dimethoxy)phenylethylamino]propionyl-3,4-dihydrocarbostyryl hydrochloride is obtained. Yield 24.5%, melting point
242-245℃ (decomposition). Example 2 12.8 g of 6-α-bromo-propionyl-3,4-dihydrocarbostyryl and 16.5 g of 2-phenoxy-tert-butylamine were added to 150 ml of ethanol and refluxed with stirring for 15 hours. Reaction liquid approx. 100
Concentrate to ml, acidify with 47% HBr and let cool to precipitate crystals. The precipitated crystals were collected, washed with a small amount of ethanol, and recrystallized from water to give pale yellow crystals of 6-
[α-(2-phenoxy)-tert-butylamino]
9.8 g of propionyl-3,4-dihydrocarbostyryl hydrochloride are obtained. Yield 48.6%, mp272~274℃
(Decomposition) Examples 3 to 8 Examples 3 to 7 were conducted according to Example 1, and Example 8 was conducted according to Example 2 to obtain the following compounds.

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【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is a lower alkyl group, R ₃ is a hydrogen atom or a phenyl lower alkyl group, and R ₄ has or does not have a lower alkoxy group as a substituent on the aromatic ring. It represents a phenyl lower alkyl group, a diphenyl lower alkyl group, or a phenoxy lower alkyl group. ] α-Substituted aminoalkanoyl-3 represented by
4-dihydrocarbostyryl derivatives and acid addition salts thereof.