KR790001498B1 - Process for the preparation of isoquinolin derivatives - Google Patents

Abstract

Isoquinoline derivs. and their acid salts (I; R' = H, halogen, methoxy, methymercapto, R2 = H, methoxy, A = piperazine derivs., methoxyphenyl derivs.) with therapeutic effect of bradycardia, arrhythmia, and hypertension were manufd. Dicarboxylates were reacted with alkylamines at 50-250≰C in glycol as a solvent, and acid salts were given with mineral acids or org. acids. The compds I were formulated as oral doses and suppositories in signle administration of 25-200mg.

Description

Method for preparing isoquinoline derivative

The present invention relates to a novel isoquinoline derivative represented by general formula (I) and a method for producing acid addition salts thereof.

In formula, R <_1> represents hydrogen or a halogen element, a methoxy or methyl mer capto group, R <_2> represents a hydrogen or a methoxy group, n represents the number of 2 or 3, A represents the following general formula (a) (B) is shown.

The novel compound of general formula (I) can be produced by reacting a compound of general formula (III), a compound of dicarboxylic acid of general formula (IIa) with a compound of general formula.

The reaction is preferably carried out at a melting temperature of 50-250 ° C. in the presence of a solvent such as glycol. In particular, when the compound of general formula (III) is used as an acid addition salt, it is preferable to use an adduct of a base such as potassium, tert-butoxide.

Wherein R ₁ and R ₂ and n and A have the same meanings as described above and B represents oxygen or an optionally substituted amino group.

The compound of general formula (I) is a base and forms an addition salt with an acid. Acids suitable for salt formation include mines such as hydrochloric acid, brittle acid, oxane, boric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, P- Organic acids such as hydroxybenzoic acid, P-aminobenzoic acid, salicylic acid, acetylsalicylic acid, phthalic acid, terephthalic acid, ascolic acid, methanesulfonic acid, ethanephosphonic acid.

The acid addition salts as well as the novel compounds of general formula (I) show useful activity for treatment. They are especially hypothermic in addition to bradycardia, antiarrhythmic and sedation.

The compounds tested for hypotensive effects are as follows.

A = 1- [4,4-dimethyl-1,3-dioxo- (2H, 4H L isoquinolin-2-) yl] -2- [4- (2-methoxy-phenyl) -piperazine-1 -Yl] ethane-dihydrochloride

B = 1- [4,4-dimethyl-7-methoxy-1, 3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy- Phenyl) -ethylamine] propane-hydrochloride

Hypoglycemic effects were measured for 2-4 female and female mongrel dogs weighing 14-23 kg with Chlorose-Urethane-Nembutal Anesthetics (54 + 270 + 10 mg / Hg i.v). The test drug was injected intravenously in the form of an aqueous solution.

Arterial blood pressure was measured as the value shown in the glass-polygraph with Statan-sphygmomanometer P230b.

The following table shows the measurement results.

Rapid toxicity of the compound was tested in mice administered orally (14 days observation). LD ₅₀ was measured from the percentage of animals that died within the observation period following administration of various doses.

For medicine, the compound of general formula (I) can be converted into a herbal composition such as tablets, dragees, powders and suppositories by appropriately mixing with other active ingredients. Single dose is 20-300mg, suitable dose is 25-200mg.

The method of the present invention is further described through the following examples.

Example 1

1- [4,4-Dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- (4-phenyl-pyrazin-1-yl) -ethane-dihydrochloride

18 g of 1,2,3,4-tetrahydro-4,4-dimethyl-isoquinoline-dione- (1,3) and 2- (4-phenyl-piperazine-1- using a device with a water rectification filter 20.5 g of 1) -ethylamine was refluxed in the presence of 150 ml of xylene for 12 hours, then the solvent was removed, the residue was taken up in ethyl and the dihydrochloride was precipitated with etheric hydrochloric acid. Recrystallize from ethanol.

Melting point: 193-205 ℃ (decomposition)

Example 2

1- [4,4-Dimethyl-7-chloro-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- (4-phenyl-piperazin-1-yl) -ethane Hydrochloride

From 1,2,3,4-tetrahydro-7-chloro-4,4-dimethyl-isoquinoline-dione- (1,3) and 2- (4-phenyl-piperazin-1-yl) -ethylamine Prepared in the same manner as in Example 1.

Recrystallization point with isopropanol: 231-232 ℃

Example 3

1- [4,4-Dimethyl-7-methoxy-1, 3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- (4-phenyl-piperazin-1-yl)- Ethane-hydrochloride

1,2,3,4-tetrahydro-7-methoxy-4,4-dimethyl-isoquinoline-dione- (1,3) and 2- (4-phenyl-piperazine-1 using glycol as flux Prepared in the same manner as in Example 1 from -yl) -ethylamine.

Recrystallization point with isopropanol: 215-218 ℃

Example 4

1- [4,4-Dimethyl-7-fluor-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- (4-phenyl-piperazin-1-yl) -ethane Hydrochloride

From 1,2,3,4-tetrahydro-7-fluor-4,4-dimethyl-isoquinoline-dione- (1,3) and 2- (4-phenyl-piperazin-1-yl) -ethylamine Prepared in the same manner as in Example 3.

Recrystallization with isopropanol: melting point 200-203 ℃

Example 5

1- [4,4-dimethyl-6,7-dimethoxy-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- (4-2-methoxy-phenyl-pipe Razin-1-yl] -ethane-hydrochloride

1,2,3,4-tetrahydro-6,7-dimethoxy-4,4-dimethyl-isoquinoline-dione- (1,3) and 2- (4- (2-methoxy-phenyl) -pipe Prepared in the same manner as in Example 1 from razin-1-yl) -ethylamine.

Recrystallized from ethanol: Melting point: 264-265 ℃

Example 6

1- [4,4-dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- (4-pyridyl- (2))-piperazin-1-yl) Propane-dihydrochloride

From 1,2,3,4-tetrahydro-4,4-dimethyl-isoquinolin-dione (1,3) and-[4- (pyridyl- (2)) piperazin-1-yl] -propylamine Prepared in the same manner as in Example 1.

Precipitate from toluene with etheric hydrochloric acid and recrystallize with acetone.

Melting Point of Dihydrochloride: 176-178 ℃

Example 7

1- [4,4-dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -2- [4- (2-methoxyphenyl) -piperazin-1-yl) Ethane-dihydrochloride

1,2,3,4-tetrahydro-4,4-dimethyl-isoquinolin-dione- (1,3) and 2- [4- (2-methoxyphenyl) -piperazin-1-yl] ethylamine Was prepared in a similar manner to Example 1 using as a starting material.

Ethylene hydrochloric acid is used to precipitate the dihydrochloride directly from the toluene solution.

Melting Point: 215-217 ℃

Example 8

1- [4,4-dimethyl-7-methoxy-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy-phenyl) -Ethylamino] -propane-hydrochloride

a) 2- [2- (3,4-dimethoxy-phenyl) -ethylamino] -1-cyano-ethane

A solution in which 54.5 g of 2- (3,4-dimethoxy-phenyl) -ethylamine was dissolved in 100 ml of methanol was added dropwise at 50 ° C to a solution in which 16.2 g of acrylonitrile was dissolved in 50 ml of methanol. Stir for 1 h.

The solvent is evaporated to treat the crude product in the following process.

b) 1- [2- (3,4-dimethoxy-phenyl) -ethylamino] -3-aminopropane

The crude product (70.3 g) obtained in Example a was dissolved in 1.3 L of methanolic ammonia solution and then hydrogenated under Rayne-Nickel catalyst in a high pressure reactor at 80 ° C. and 50 atm.

Boiling Point, 1mm = 168-173 ℃

c) 1- [4,4-dimethyl-7-methoxy-1, 3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy- Phenyl) -ethylamino] -propane-hydrochloride

13.2 g of 4,4-dimethyl-7-methoxy-1,2,3,4-tetrahydro-isoquinoline-dione- (1,3) and 1- [2- (in a device equipped with a water rectifying funnel 14.3 g of 3,4-dimethoxy-phenyl) -ethylamino] -3-amino-propane is boiled in the presence of 250 ml of toluene for 5 hours. After cooling, the hydrochloride is crystallized with etheric hydrochloric acid and the oily product is recrystallized from ethanol.

Melting Point: 191-193 ℃

Example 9

1- [4,4-dimethyl-6,7-dimethoxy-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy- Phenyl) -ethylamino] -propane-hydrochloride

4,4-dimethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-dione- (1,3) and 1- [2- (3,4-dimethoxy as starting materials Prepared analogously to Example 8 using -phenyl) -ethylamino] -3-amino-propane.

Recrystallization from ethyl acetate: Melting point: 98-101 ℃

Example 10

1- [4,4-dimethyl-6,7-dimethoxy-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [methyl- (2- (3,4- Dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

4,4-dimethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-dione- (1,3) and 1- [N-methyl-2- (3,4-dimethic Prepared in the same manner as in Example 8 from oxyphenyl) -ethylamino] -3-amino-propane.

Melting Point: 167-168 ℃

Example 11

1- [4,4-Dimethyl-7-methylmercapto-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy-phenyl ) -Ethylamino] -propane-hydrochloride

4,4-dimethyl-7-mercapto-1,2,3,4-tetrahydro-isoquinoline-dione- (1,3) and 1- [2- (3,4-dimethoxy-phenyl as starting materials Prepared similarly to Example 8 using) -ethylamino] -3-amino-propane.

Melting Point: 133-135 ℃

Example 12

1- [4,4-dimethyl-7-chloro-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl] -3- [2- (3,4-dimethoxy-phenyl)- Ethylamino] -propane-hydrochloride

4,4-dimethyl-7-chloro-1,2,3,4-tetrahydro-isoquinoline-dione- (1,3) and 1- [2-3,4-dimethoxy-phenyl)-as starting materials Prepared similarly to Example 8 using ethylamino] -3-amino-propane.

Recrystallized from ethanol: Melting point: 222-226 ℃

Claims (1)

Isoquinoline derivatives of formula (I) characterized by reacting a compound of formula (II) or a compound of dicarboxylic acid of formula (IIa) with an amine of formula (III) or an acid addition salt thereof The manufacturing method of the acid addition salt.

In the formula, R ₁ represents hydrogen, a halogen element, a methoxy or methyl mercapto group, R ₂ represents hydrogen or a methoxy group, n represents a number of 2 or 3, A represents the following general formula (a) or (b).

In the formula (a) or (b), R ₃ represents hydrogen or a methyl group R ₄ represents a pyridyl group optionally substituted by a methyl group, a phenyl group or an unsubstituted phenyl group, a prefluoromethyl group, one or two methyl, ethyl or methoxy groups substituted by chlorine, R ₅ and R ₆ may be the same or different and they represent hydrogen or a methoxy group. B represents oxygen or an optionally substituted amino group.