JPS5936617B2 - carbostyril derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel carbostyril derivatives.

The carbostyril derivative of the present invention is represented by the following general formula (1). [In the formula, R1 is a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 and R4 are each independently a hydrogen atom or a lower alkyl group, X is an oxygen atom, Y is a hydroxyl group, a lower Alkoxy group, carboxyl group, lower alkoxycarbonyl group, cyano group, carbamoyl group in which one lower alkyl group is substituted on the nitrogen atom, phenyl group, or phenyl group having 1 to 2 identical substituents (the substituent is lower 1 is O or 1, and m and n each independently represent O or an integer of 1 to 3.

However, if Y is a phenyl group, l-0 and n+m-0~
Except for case 3. Further, both R1 and R2 are hydrogen atoms, and the side chain must not be (CH2)204)-CONH2.

] In the present invention, the lower alkyl group refers to a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl,
It includes propyl, IsO-propyl, butyl, IsO-butyl, tert-7-ethyl, pentyl, hexyl, etc., and the lower alkoxy group refers to an alkoxy group corresponding to the above-mentioned alkyl group.

The compounds of the present invention have β-adrenergic neuroblocking action, act selectively on β,1-receptors, have a long action time, and have a strong ability to inhibit platelet aggregation, such as therapeutic agents for angina pectoris, arrhythmia, and hypertension. It is useful as

The compounds of the present invention also have peripheral vasodilatory activity. For example, 5-[3-(
2-hydroxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 5-[3-
(2-hydroxy-1-methylethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 5[3-(2-hydroxy-2-methylpropylamino)-2-hydroxy]propoxy-3. 4-dihydrocarbostyryl, 5-[3-(4-carbamoylphenethylamino)-2-hydroxy]propoxy-3,4
-dihydrocarbostyryl, 1-methyl-5-[3-(
3,4-dimethoxyphenethylamino)-2-hydroxy]propoxy 3,4-dihydrocarbostyryl, 5-
[3-(2-phenoxy-1-methylethylamino-2
-Hydroxy]propoxy-3,4-dihydrocarbostyryl, 5-[3-(2-phenoxyethylamino)-
2-Hydroxy]propoxy-3,4-dihydrocarbostyryl, 8-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 5-[3- (2-carpoxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 5-[3-(3-carboxypropylamino)-2-hydroxy]propoxy 3,4-
Dihydrocarbostyryl, 1-methyl-5-[3-(2
-ethoxycarbonylethylamino)-2-hydroxy]propoxy-3,41-dihydrocarbostyryl, 5-
(3-methoxycarbonylmethylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyryl, 1
-Methyl-5-[3-(2-cyanoethylamino)-2
-hydroxy]propoxy-3,4-dihydrocarbostyrinole, 5-(3-cyanomethylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyryl,
1-Methyl-5-[3-(3ethoxy-propylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 1-benzyl-5-(3-methoxymethylamino-2-hydroxy)propoxy- 3,4-dihydrocarbostyryl, 5-[3-(4-methoxycarbonylaminobutyl)-2-dihydroxy]propoxy-3
・4-dihydrocarbostyryl, 6-[3-(3,4-
dimethoxyphenethylamino)2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 6-[3-(
3,4-dimethoxyphenethylamino)-2-hydroxy]propoxy-1-methyl-3,4-dihydrocarbostyryl, 6-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy] Propoxy-1-benzyl-3,4-dihydrocarbostyryl, 6-[3-(1-
Methyl-2-phenoxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 6
-[3-(1-methyl-2-phenoxyethylamino)
-2-hydroxy]propoxy-1-benzyl-3,4
-dihydrocarbostyryl, 6-[3-(1,1-dimethyl-2-phenoxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 6-
[3-(2-hydroxyethylamino)-2-hydroxy]propoxy-1-1-methyl-3,4-dihydrocarbostyryl, 6-[3(2-hydroxy-1-methylethylamino)-2-hydroxy]propoxy -1-benzyl-3,4-dihydrocarbostyryl, 6-[3-(2
Hydroxy-2-methylpropylamino)-2hydroxy]propoxy-3,4-dihydrocarbostyryl, 6
-[3-(4'-carbamoylphenethylamino)-2
-hydroxy]propoxy-3,4-dihydrocarbostyryl, 6-[3(4'-carbamoylphenethylamino)-2-hydroxy]propoxy-1-methyl-3,4
-dihydrocarbostyryl, 6-[3-(4'-carbamoylphenethylamino)-2-hydroxy]furopoxy-1-benzyl-3,4-dihydrocarbostyryl,
6-[3-(2-phenoxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 6-[3-(2-carboxyethylamino)-2-hydroxy]propoxy-3, 4-dihydrocarbostyryl, 6-[3-(3-carboxypropylamino)-2
-hydroxy]propoxy-1-methyl-3,4-dihydrocarbostyryl, 6-[3-(2ethoxycarbonylethylamino)-2-hydroxy]propoxy-1-
Methyl-3,4-dihydrocarbostyryl, 6-[3-
(2-cyanoethylamino)-2-hydroxy]propoxy-1-methyl-3,4-dihydrocarbostyryl, 6
[3-(3-ethoxypropylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 7
-[3-(3,4-dimethoxyphenethylamino)-2
-Hydroxy]propoxy-3,4-dihydrocarbostyryl, 7-[3-(2-phenoxyethylamino)-
2-Hydroxy]propoxy-3,4-dihydrocarbostyryl, 7-[3-(4!1carbamoylphenethylamino)2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 8-[3-(2 -phenoxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl, 8-[3-(4'-carbamoylphenethylamino)-2-hydroxy]propoxy-3
・4-dihydrocarbostyryl, 8-[3-(4'-carbamoylphenethylamino)-2-droxy]propoxy-1-1-methyl-3,4-dihydrocarbostyryl,
8-[3(1-methyl-2-phenoxyethylamino)
2-Hydroxy]propoxy-1-benzyl-3,4-
Dihydrocarbostyryl, 5-[3-(4'-ethoxycarbonylphenethylamino)-2-hydroxy]proxy-3,4-dihydrocarbostyryl, etc.
Furthermore, the present invention also includes pharmaceutically acceptable inorganic or organic acid addition salts of these compounds.

Such inorganic acids include, for example, hydrohalic acids, i.e., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, thiocyanic acid, phosphoric acid, etc., and organic acids include, for example, acetic acid, propionic acid, glycolic acid, etc. , lactic acid, pyruvic acid,
Oxalic acid, malonic acid, conicic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
Examples include mandelic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, and 2-acetoxybenzoic acid. The compound of the present invention is, for example, an epoxycarbostyryl derivative represented by the general formula (wherein R1 is the same as above) and a general formula (wherein R2, R3, R4, X.
Y. n. m and l are the same as above).

The epoxycarbostyryl derivative of general formula (11), which is one of the raw materials of the present invention, is a known compound, and R in the formula,
Examples include a hydrogen atom, a lower alkyl group, and a phenyl lower alkyl group.

In the formula, the position of the 2,3-epoxypropoxy group is the 5th position,
6th, 7th or 8th place is fine. The amines of general formula (e), which are the other raw materials of the present invention, are also known compounds. In the formula, R2 is a hydrogen atom or a lower alkyl group, R3 and R4 are each independently a hydrogen atom or a lower alkyl group, X is an oxygen atom, and Y
Examples include hydroxyl group, lower alkoxy group, carboxyl group,
Lower alkoxycarbonyl group, cyano group, 1 on nitrogen atom
carbamoyl group, phenyl group, or phenyl group having 1 to 2 identical substituents (the substituent is a lower alkoxy group or carbamoyl group)
etc. can be mentioned. l represents O or 1; m and n each independently represent O or an integer from 1 to 3; Typical common amines include hydroxymethylamine, 2-hydroxyethylamine, 2-hydroxy-1-methylethylamine, 3-hydroxybutylamine, methoxymethylamine, 2-ethoxyethylamine, 3ethoxypropylamine, 2-ethoxy-
1-methylethylamine, 4-methoxy-butylamine, 2-carboxyethylamine, 4-carboxybutylamine, 2-ethoxycarbonylethylamine, 4-methoxycarbonylbutylamine, 3-isopropoxypropylamine, 2-cyanoethylamine, 3-cyanobutylamine, 5-cyanopentylamine, 3,4-dimethoxyphenethylamine, p-carbamoylphenethylamine, 2-(4-methoxyphenoxy)ethylamine, phenoxymethylamine, 2-phenoxyethylamine, 2-( 3,5-dimethoxyphenoxy)ethylamine, 2-(p-carbamoylphenoxy)ethylamine, 1-methyl-2-phenoxyethylamine, 1,1-
Dimethyl-2-phenoxyethylamine, 2-(3.4
-dimethoxyphenoxy)ethylamine, 1-methyl-
Examples include 3-(4-methoxyphenoxy)-propylamine.

The reaction between the epoxycarbostyryl derivative of the general formula 01'P) and the amines of the general formula ◇ can be carried out without a solvent, but it can also be advantageously carried out in a solvent.

Solvents used include methanol, ethanol, Is
Alcohols such as O-propanol, butanol, tert-butanol, tetrahydrofuran, dioxane,
Ethers such as ethylene glycol dimethyl ether, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, benzene, toluene,
Aromatic hydrocarbons such as xylene, acetonitrile, N-
Commonly used polar solvents include N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and the like. In the reaction of the present invention, the amines are used in equimolar to large excess amounts relative to the epoxycarbostyryl derivative, but it is generally preferred to use equimolar to twice the molar amount.

The reaction proceeds smoothly in a temperature range from room temperature to around the boiling point of the solvent, but it is generally advantageous to carry out the reaction at a temperature of 50 to 80°C. The compound of the present invention can be easily isolated from the reaction system by a commonly known method.

For example, the reaction product is subjected to operations such as concentration and extraction under reduced pressure, and the desired product can be easily obtained from the resulting residue by conventional methods such as recrystallization and column chromatography. In addition, the present invention naturally includes optical isomers and geometric isomers of the compound represented by the general formula (0).Also, the compound represented by the general formula By using an authentic carbostyryl derivative as a raw material or by dehydrogenating the obtained compound of general formula (1)7), the hydrogens at the 3 and 41 positions in the compound of general formula 0') f) can be easily converted. Dehydrogenated genuine carbostyril derivatives can be obtained. Examples are described below to explain the present invention in more detail, but the present invention is not limited thereto.

Reference Example 1 5-(2,3-epoxy)propoxy-3,4-dihydrocarbostyryl 2.27 and 3,4-dimethoxyphenethylamine 2.2f! was added to 100 ml of ethanol and stirred under reflux for 4.5 hours.

After the reaction with Xr is completed, the solvent is distilled off under reduced pressure, and 200 ml of benzene is added to the residue to remove insoluble matter when hot.

After cooling the solution, the precipitated crystals were collected and recrystallized from benzene to give colorless needle-like crystals of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy]propoxy-13. 4
-dihydrocarbostyril 3.27 are obtained. Mp78-
80°C Example 1 8.8 y of 5-(2,3-epoxy)propoxy-3,4 dihydrocarbostyryl and 2.67 y of 2-hydroxyethylamine were added to 400 ml of ethanol, and the mixture was refluxed and stirred for 3.5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was added with 1-
Add 100 ml of N aqueous hydrochloric acid solution to remove insoluble materials.
After adding 5% caustic soda aqueous solution to the filtrate and adjusting the pH to 9, the precipitated crystals were collected and recrystallized from ethanol to give colorless needle-like crystals of 5-[3-(2-hydroxyethylamino)-
7.57% of 2-hydroxy]propoxy-3,4-dihydrocarbostyryl is obtained. Mpl46-147°C Examples 2 to 11 Epoxycarbostyryl specified by Table 1 below?
A corresponding target compound was obtained in the same manner as in Reference Example 1, except that the derivatives and amines were used as raw materials.

The crystal form and melting point of the obtained compound are also shown in Table 1. Example 12 0.57 1 nor of 5-[3-(2-hydroxyethylamino)-2-hydroxy]propoxy-13,4-dihydrocarbosti was added to 5 ml of methanol, and then 0.57 ml of oxalic acid was added.
Add a solution of 37 dissolved in 5me methanol and leave for 10 minutes.

Add 200ml of acetone to the reaction solution and collect the precipitated crystals.
Recrystallization from methanol-acetone gives colorless needle-like crystals of 5-
0.57 of [3-(2-hydroxyethylamino)-2-hydroxy]propoxy-13,4-dihydrocarbostyryl oxalate is obtained. Mpl9l-193℃ (decomposition) Example 13 1-Methyl-5-(2,3-epoxy)propoxy-3
・Add 4.67 4-dihydrocarbostyryl and 1.57 2-cyanoethylamine to 100 ml of ethanol,
Stirring is carried out for 4.5 hours under reflux.

After the reaction is completed, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wako C-20
0, eluent chloroform). The syrup obtained by distilling off the solvent in the eluted portion is dissolved in 40 ml of acetone, and then a solution of 2.07 ml of oxalic acid dissolved in 200 ml of acetone is added to collect the precipitated crystals. The crude crystals were recrystallized from methanol to give colorless needle-like crystals of 1-methyl-5-[3-
(2-cyanoethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl oxalate 4.07
get. Mpl9l - 193℃ (decomposition) Example 14 8-(2,3-epoxy)propoxy-13,4-dihydrocarbostyryl 2.27 and 3,4-dimethoxyphenethylamine 2.17 were added to 100 ml of ethanol and refluxed. React for 5 hours while stirring.

After the reaction was completed, the solvent was distilled off under reduced pressure, and 20% of benzene was added to the residue.
Add 0me and remove insoluble matter when heated. After cooling the slurry, the precipitate is collected and recrystallized from benzene. When the precipitate is dissolved in ethanol, hydrochloric acid gas is introduced to collect the precipitate, and recrystallized with ethanol, a colorless amorphous crystal of 8-[3-
(3,4-dimethoxyphenethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl hydrochloride is obtained. Mpll8-12 "C Examples 15 to 32 Same as Example 14 except that the epoxycarbostyryl derivatives and amines specified in Table 2 below were used as raw materials, and hydrochloric acid gas or oxalic acid was used to produce the addition salt. The corresponding target compound was obtained.

The crystal form and melting point of the obtained compound are also shown in Table 2. Hereinafter, pharmacological tests of the compounds of the present invention will be described.

[Pharmacological test-1] An adult male dog (body weight 10-16k9) is anesthetized by intravenously administering 30W1f7/Kg of pentobarbital sodium salt, and a cannula is inserted into the trachea.

Heparin is administered intravenously at a level of 1000 units to avoid blood clotting. A cannula is then inserted into the right femoral artery. During the experiment, 20m1/K9, 18r. p.
m. Artificial respiration was performed at a rate of

Blood pressure is measured by Pressu
retranducer,. MDU-0.5 type, N
ippOnKOdenCO. The heart rate was measured using an instantaneous heart rate tachometer (2130 type, Sa
neiSOkkiCO. Blood pressure was determined from the pulse wave using a commercially available product. Air resistance (AR) was calculated using the Konjett-R'6ss1er method (K6nze
llH. &RδSslerR. , ゝゞVersuchs
anOrdnugzuUntersuchunande
rBrOnchialMOskOlatur″Aach
．． Exp. Path. , Pharmak, 195, 7
1-74, 27-40 (1940), low pressure type Pledger 1 Transuser 1 (LP-0.1, N
ippOnKOdenCO. (manufactured by). The blood pressure and heart rate mentioned above were recorded on a polygraph (8S
28 types, manufactured by SaneiSOkki).

During the experiment, 3η/Kg of gallamine was intravenously administered every hour to avoid air resistance fluctuations. The β-adrenergic agonist/blocking effect of the test compound was that of isoprenaline 1μ7/K9.
antagonistic effect (inhibition %) on the suppression of diastolic blood pressure and increase in heart rate induced by intravenous administration of histamine (5μ7/I<9) on isoprenaline, which suppresses the increase in air resistance induced by intravenous administration of Antagonism (
% inhibition). In this case, histamine was administered 45 seconds after isoprenaline administration. The test compound was administered intravenously at 300 μ7/Kg, and the β-adrenergic blocking effect was measured 10 minutes later. The results are shown in Table 3. [Pharmacological Test-2] A pharmacological test was conducted according to the principle described in Natya I, pp. 927-929 (1962).

That is, the platelet aggregation inhibiting effect was measured using a platelet aggregation meter [PlateletA Reg] manufactured by Niko Bioscience Co., Ltd.
atiOnTracerMOdelPTA-6M]. A blood sample obtained by adding 3.8% trisodium citrate solution [the mixing ratio of trisodium citrate solution and blood is 1:9 (volume ratio)] to blood collected from a rabbit was centrifuged using a swing-type rotor. Centrifugation was performed in a separator at room temperature at 200 f for 10 minutes.

After collecting platelet-rich plasma from the supernatant part of the separated blood, the precipitate part was further centrifuged for 15 minutes, and the supernatant part was collected to obtain platelet-free plasma (PlateletPOOrPlasma). (hereinafter abbreviated as "PPP") was obtained. 3.3 μl of the platelet-rich plasma was diluted with 10 ml of commercially available physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd., Japanese Pharmacopoeia physiological saline), and the number of platelets in this mixture was measured using a Coulter counter (Coutt).
erElectrOnicslIncHieleah.
The platelet concentration of the same plasma is calculated, and the platelet concentration of the same plasma is appropriately diluted with PPP to obtain platelet-rich plasma (Platelet-rich plasma) with a constant platelet count (500,000/M7i).
LetrichPlasma (hereinafter abbreviated as "PRP") was obtained. PRP and PPP prepared as above
was used as the material for the following tests. A solution containing the compound to be tested at a predetermined concentration (the solvent is described separately) or as a blank test, 20 μl of the solvent alone and PRP (:!) 0
．． After putting 2 m2 into the glass cuvette of the platelet aggregometer and mixing thoroughly and inserting the iron rotor, this cuvette was inserted into the cuvette insertion part of the platelet aggregometer (the cuvette was kept at 37°C and the added iron rotor was heated by electromagnetic induction). (This allows rotation at a constant speed to be applied.) Three minutes after the insertion, 20 μl of adenosine diphosphate (hereinafter abbreviated as "ADP") solution or collagen suspension was injected into the inner liquid of the cuvette using a microsyringe to induce platelet aggregation. ADP is 75μM using Sigma.
A physiological saline solution was prepared, stored frozen at -20°C, and thawed before use for testing (the ADP solution once thawed was not reused). Collagen suspension is COllagenr
agentHOlm(HORMON-CHEMIEM
UNCHENGMBH) was used and diluted to 200tt7/ml with physiological saline before use and used for the test. The platelet aggregation inhibition effect was expressed as the inhibition rate relative to the aggregation rate of platelet aggregation in a blank test.

Here, the aggregation rate and inhibition rate were calculated according to the following formula. a - Permeability of PRP containing test compound solution (or only its solvent) b - Permeability of PPP c = PRP containing test compound solution (or only its solvent)
Maximum permeability A of the mixture after addition of ADP solution or collagen suspension to B = aggregation rate B of blank test - aggregation rate results obtained for PRP containing the test compound are shown in Table 4.

The following compounds were used as test compounds. <Test compound polishing> 11-Methyl-6-{3-[(1-methyl-2-phenoxyethyl)amino]-2-hydroxy}propoxy-3,4-dihydrocarbostyryl 5-{3-[ 2-(4
-methoxyphenoxy)ethyl]-2-hydroxy}propoxy-3,4-dihydrocarbostyryl-1-methyl-5-{3-[2-(4-carbamoylphenoxy)ethyl]-2-hydroxy}propoxy -3,4-dihydrocarbostyryl 5-{3-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxy}propoxy-3,4-dihydrocarbostyryl 5-[3-(2
-carboxyethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl-1-methy)-5-[3-(2-cyanoethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl oxalate 1-benzyl-5-[3-(3,4-dimethoxy-β
-phenethylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl hydrochloride 1-methyl-5
-[3-(3-methoxypropylamino)-2-hydroxy]propoxy-3,4-dihydrocarbostyryl oxalate 5-[3-(2-ethoxycarbonylethylamino)-2-hydroxy]propoxy-3,4- Dihydrocarbostyryl oxalate 5-[3-(2-N-ethylaminocarbonylethyl)-2-hydroxy]propoxy-3
・4-dihydrocarbostyryl hydrochloride (comparison) 5-(3-isopropylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyryl hydrochloride (comparison) 5-(3-benzylamino-2-hydroxy)propoxy -3,4-dihydrocarbostirinore In the table, HRl represents heart rate, DBP2 represents diastolic blood pressure, and AR3 represents air resistance.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. independently a hydrogen atom or a lower alkyl group, X is an oxygen atom, Y is a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group,
a cyano group, a carbamoyl group in which one lower alkyl group is substituted on the nitrogen atom, a phenyl group, or a phenyl group having 1 to 2 identical substituents (the substituent is a lower alkoxy group or a carbamoyl group), l is 0 or 1, m and n
each independently represents 0 or an integer from 1 to 3. However, when Y is a phenyl group, l=0 and n+m=0~
Except for case 3. In addition, if R_1 and R_2 are both hydrogen atoms, and the side chain ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is substituted at the 5th position, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ in the side chain is ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼. ] Carbostyryl derivatives and salts thereof.