KR820000198B1 - Process for preparing aryl-alkylamine - Google Patents

Abstract

Title compds. [I; A = -N=C(R1)-(R1 = H, C1-3 alkyl; R2 = C1-3 alkoxy; R3 = C1-3 alkoxy, forming methylenedioxy or ethylenedioxy with R2; R4,R5 = H, C1-3 alkyl; R6 = H, C1-3 alkoxy; R7 = C1-3 alkoxy, forming methylenedioxy or ethylenedioxy with R6; n = 2-3 useful as heart frequency decreasing and hypotensive agent, were prepd. by reaction of II and III. Thus, 0.3 g Pd/C (10%) was added to 3.0 g II(A = -N=C(CH3); R2,R3 = CH3O; n =3) and 2.0 g III(R4 = CH3; R5 = H; R6,R7 = CH3O) in 100 ml C2H5OH and H2 was introduced at 50≰C, 5 atm, 4 hr to give 3.7 g IHCl.

Description

Process for preparing aryl-alkylamine

The present invention relates to a method for preparing aryl-alkylamine of the following general formula (I) and a salt thereof having a function of reducing heart rate and a blood pressure lowering action.

그룹이고, R₁은 수소 또는 탄소수 1 내지 3인 알킬이고, R₂는 탄소수 1 내지 3인 알콕시이고, R₃는 탄소수 1 내지 3인 알콕시 또는 R₂와 함께 메틸렌 디옥시 또는 에틸렌 디옥시 그룹이고, R₄와 R₅는 같거나 또는 다를 수 있으며 수소 또는 탄소 1 내지 3인 알킬이고 또한 R₄는 벤질일 수 있고, R₆는 수소 또는 탄소수 1 내지 3인 알콕시이고, R₇은 탄소수 1 내지 3인 알콕시이거나 또는 R₆와 함께 메틸렌디옥시 또는 에틸렌디옥시 그룹이고, n는 2 또는 3인 정수이다.Wherein A is a structural formula

Is a group, R ₁ is hydrogen or alkyl having 1 to 3 carbon atoms, R ₂ is alkoxy having 1 to 3 carbon atoms, R ₃ is a methylene dioxy or ethylene dioxy group together with alkoxy having 1 to 3 carbon atoms or R ₂ R ₄ and R ₅ may be the same or different and are hydrogen or alkyl having 1 to 3 carbon atoms, R ₄ may be benzyl, R ₆ is hydrogen or alkoxy having 1 to 3 carbon atoms, and R ₇ may be 1 to 3 carbon atoms. Or alkoxy of 3 or a methylenedioxy or ethylenedioxy group with R ₆ and n is an integer of 2 or 3.

First defining a group R ₁ -R ₇ , R ₁ , R ₄ and or R ₅ are in particular hydrogen, methyl, ethyl, propyl or isopropyl groups and R ₄ is a benzyl group and R ₂ , R ₃ , R ₆ and / or R ₇ is methoxy, ethoxy, propoxy or isopropoxy and R ₆ is also hydrogen, and / or R ₆ is with R ₇ and / or R ₂ with R ₃ is methylenedioxy or ethylenedioxy Group.

However, particularly preferred compounds of general formula (I) are those in which R ₁ is a hydrogen, methyl or isopropyl group and R ₂ and R ₃ are methoxy groups at positions 6 and 7, or together are methylene dioxy or ethylene dioxy groups R ₄ is hydrogen or methyl group, R ₅ is hydrogen, R ₆ is hydrogen or methoxy group at position 3 and R ₇ is methoxy group at position 4 or methylenedioxy or ethylene with R ₆ A deoxy group and n is an integer of 2 or 3.

The present invention relates to a method for preparing the novel compound of the general formula (I) by the following method:

In the above formula

R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , A and n are as described above.

Reductive amination of the reaction takes place at a temperature of 0 to 100 ° C., but preferably at a temperature of 20 to 80 ° C. in a solvent such as methanol, ethanol or dioxane with hydrogen at 5 atm hydrogen pressure in the presence of palladium charcoal.

The compound of formula (I) wherein R ₄ is benzyl may be debenzylated if necessary, or the compound of formula (I) wherein R ₄ is hydrogen thus obtained may be converted to the corresponding compound of formula (I) by alkylation method. You can switch.

The debenzylation reaction is preferably carried out at a hydrogen pressure of 1 to 7 atmospheres at a temperature of 25 to 75 DEG C by a catalytic hydrogenation reaction using hydrogen in ethanol or ethyl acetate solvent in the presence of a palladium charcoal catalyst.

The alkylation reaction is then from 0 to 50 ° C. in a solvent such as acetone, dimethyl formamide or dioxane, optionally in the presence of inorganic or tertiary organic salts by alkylating agents such as methyl iodide / ethyl iodide, isopropyl bromide or dimethyl sulfoxide. Proceed at the temperature of. However, the methylation reaction is preferably carried out at the boiling point of formaldehyde formic acid and the mixture.

Furthermore, the obtained general formula (I) compound can be converted into a pharmaceutically nontoxic salt with inorganic or organic acid, if necessary. Suitable acids include hydrochloric acid, phosphoric acid, hydrochloric acid, sulfuric acid, lactic acid, tartaric acid, or maleic acid.

Compounds of the general formulas (II) and (III) used as starting materials can be reconstituted by known methods known in the literature (see Examples).

As mentioned above, the novel compounds of general formula (I) and acid addition salts thereof have an effective pharmacological action and, in addition to the alleviated blood pressure lowering action, have a particularly selective action of lowering the heart rate.

For example, the following compounds are used in tests on physiology.

A = 1- [4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-methoxyphenyl ) -Ethyl-amino] -propane-hydrochloride

B = 1- [4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (4-methoxyphenyl)- Ethyl) -amino] -propane-hydrochloride

C = 1- [4-isopropyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy Phenyl) -ethyl) -amino] -propane-hydrochloride

D = 1- [6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (4-methoxyphenyl) -ethyl-amino] Propane-hydrochloride

E = 1- [4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxyphenyl ) -Ethyl-amino-ethane-hydrochloride

The effect of the compound on heart rate is demonstrated by testing two to five cats or dogs regardless of gender. The average weight of a cat is 2.5 to 3.5 kg and a dog is 18 to 28 kg. Test animals are anesthetized with embutal (30 mg / kg intraperitoneal injection) and chloralose-urethane (10 mg / ml chloralose-200 mg / ml urethane, if necessary). The test substance is dissolved in a solvent and injected into the vein or duodenum.

Heart rate is measured by electrocardiography (thoracic induction) from the electrocardiogram (thoracic induction) on the Grass- polygraphy before and after administration, respectively.

The following table shows the results.

In addition, all test doses used in the test are very well tolerated and have no other adverse effects. For example, in mice of Test A, LD ₅₀ is 63 mg / kg (intravenous injection) when observed for 14 days.

The compound of formula (I) may also be a tablet, dragee, powder, suspension, solution or suppository suitable for administration in combination with other active substances and suitable for the treatment of circulatory diseases, especially chronic coronary artery disease. The disposable amount is preferably 50 to 250 mg.

The following examples illustrate the invention.

Example 1

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -2- [N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] -propane-hydrochloride 3.0 g (11.3 mmol) of 4-methyl-3- (6,7-dimethoxy-1 (2H) -phthalazinone-2-yl) -propion aldehyde in 2.0 ml of ethanol 0.3 g of palladium charcoal (10%) is added to g (11.3 mmol) of 3,4-dimethoxy-phenylethyl amine solution, and hydrogen gas is introduced at 50 캜 and 5 atmospheres over 4 hours. After the hydrogen absorption is completed, the catalyst is filtered off. The filtrate is evaporated in vacuo to give a viscous yellow oil.

Yield: 3.7 (67%)

Rf value (chloroform / methanol = 9/1): 0.4

Example 2

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] -propanechloride

5.0 g (11.3 mmol) 1- [4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N- (2- (3,4-dimethoxy -Phenyl) -ethyl) -amino-protanol A mixture of 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formalin was heated to 100 ° C for 1 hour and then semi-cooled. The solution is added with alkali and extracted with chloroform. The chloroform layer is washed with water, dehydrated and evaporated in vacuo. The obtained residue is then chromatographed with silica gel (chloroform / methanol = 100/1) to evaporate the main fraction and precipitate hydrochloride with etheric hydrochloric acid. Melting Point: 100-115 ° C

In a similar manner the following compounds are obtained.

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -2- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] ethane-hydrochloride. Melting Point: 204-205 ° C

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-ethyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] propane-hydrochloride. Melting Point: 110-115 ° C

1- [4-Isopropyl-6,7-dimethoxy-1 (2H) -phthalazinon-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl ) -Ethyl) -amino] propane-hydrochloride. Melting Point: 179 to 180 ° C

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (4-methoxy-phenyl) -ethyl ) -Amino] -propanehydrochloride. Melting Point: 210 to 212 ° C

1- [6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -amino] propane Hydrochloride Melting point: 200 ° C

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-benzyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] propane

Rf value: 0.9 (chloroform / methanol = 9: 1).

1- [4-Methyl-6,7-ethylenedioxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dioxy-phenyl ) -Ethyl) -amino] propane

Rf value: 0.7 (chloroform / methanol = 9: 1).

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-methylenedioxy-phenyl ) -Ethyl) -amino] -propane

Rf value: 0.45 (chloroform / methanol = 9: 1)

1- [4-Methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] propane

Rf value: 0.4 (chloroform / methanol = 9: 1)

1- (4,7-Dimethoxy-4 (3H) -quinazolinone-3-yl) -2- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl-amino ] -Ethane-hydrochloride Melting point: 205-208 ° C.

1- (6,7-Dimethoxy-4 (3H) -quinazolinone-3-yl) -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] propane

Rf value: 0.4 (chloroform / methanol = 9: 1)

1- (6,7-Dimethoxy-4 (3H) -quinazolinone-3-yl) -3- [N-benzyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] propane

Rf value: 0.75 (chloroform / methanol = 9: 1)

1- (6,7-Dimethoxy-4 (3H) -quinazolinone-3-yl) -3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] propane- Hydrochloride. Melting Point: 192-194 ° C

1- (2-Methyl-6,7-dimethoxy-4 (3H) -quinazolinone-3-yl) -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] propane-hydrochloride. Melting Point: 215-217 ° C

1- (2-Methyl-6,7-dimethoxy-4 (3H) -quinazolinone-3-yl) -3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] propane-hydrochloride. Melting Point: 243-245 ° C

1- (2-Methyl-6,7-dimethoxy-4 (3H) -quinazolinone-3-yl) -2- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino] ethane-hydrochloride. Melting Point: 237-239 ° C

Claims (1)

A process for preparing an aryl-alkyl of formula (I) or a salt thereof by reacting an aldehyde of formula (II) with an amine of formula (III).

Wherein A is a general formula

Is a group, R ₁ is hydrogen or alkyl having 1 to 3 carbon atoms, R ₂ is an alkoxy group having 1 to 3 carbon atoms, R ₃ is a methylene dioxy or ethylenedioxy group together with alkoxy or R ₂ having 1 to 3 carbon atoms R ₄ and R ₅ may be the same or different and hydrogen or an alkyl group having 1 to 3 carbon atoms or R ₄ is also a benzyl group, R ₆ is hydrogen or an alkoxy group having 1 to 3 carbon atoms, and R ₇ is Together with alkoxy or R ₆ having 1 to 3 carbon atoms form a methylene dioxy or ethylene dioxy group, n is an integer of 2 or 3.