KR820000197B1 - 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; n = 2-3) useful as heart frequency decreasing and hypotensive agent, were prepd. by reaction of II and III(Z = Cl, Br, I, alkylsulfonyloxy, arylsulfonyloxy). Thus, 0.5 g NaH was added to 3.0 g II(A = -N=C(CH3)-; R2,R3 = CH3O) in 100 ml dimethyleneformamide and heated at 30≰C, 30min. The heated mixt. was added to 8.5 g III(R4 = CH3; R5 = H; R6,R7 = CH3O; Z = Br, n= 3) and heated at 140≰C, 8 hr to give 0.6 g IHCl.

Description

Process for preparing aryl-alkylamine

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

In the above formula

그룹이고, R₁은 수소 또는 탄소수 1－3인 알킬이고, R₂는 탄소수 1－3인 알콕시이고, R₃는 탄소수 1－3인 알콕시 또는 R₂와 함께 메틸렌 디옥시 또는 에틸렌 디옥시 그룹이고, R₄와 R₅는 같거나 또는 다를 수 있으며 수소 또는 탄소 1－3인 알킬이고 또한 R₄는 벤질일 수 있고, R₆는 수소 또는 탄소수 1－3인 알콕시이고, R₇은 탄소수 1－3인 알콕시이거나 또는 R₆와 함께 메틸렌 디옥시 또는 에틸렌 디옥시 그룹이고, n는 2 또는 3인 정수이다.A is a general 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 1-3 carbons, R ₄ may be benzyl, R ₆ is hydrogen or alkoxy having 1-3 carbon atoms, and R ₇ is 1-3 carbon atoms. Alkoxy of 3 or methylene dioxy or ethylene dioxy group with R ₆ and n is an integer of 2 or 3.

Firstly defining groups 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 in particular 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 together with R ₇ and or R ₂ together with R ₃ 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 ethylenedioxy groups R ₄ is hydrogen or methyl group, R ₅ is hydrogen, R ₆ is hydrogen or methoxy at position 3 and R ₇ is methoxy group at position 4 or methylenedioxy or ethylenedi with R ₆ Is an oxy group and n is an integer of 2;

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

The following compound of formula (II) is reacted with an alkylamine of formula (III).

Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , A and n are as described above and Z is a separable group such as chlorine, cancellation or iodine, alkylsulfonyloxy Or allylsulfonyloxy group.

The reaction optionally varies in temperature between 0-150 ° C. as convenient depending on the reactivity of the Z group in a solvent such as acetone, dimethylformamide, dimethylsulfoxide or chlorobenzene, but preferably proceeds at the boiling point of the solvent used. Let's do it. Reaction in the presence of an alcoholate, a hydroxide of an alkali metal, a carbonate of an alkali metal such as potassium carbonate, an amide of an alkali metal or a tertiary organic base such as triethylamine or pyridine or a reaction accelerator such as potassium iodide useful.

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 1-7 atm at a temperature of 25-75 ° 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 carried out at a temperature of 0-50 ° C. in a solvent such as acetone, dimethylformamide or dioxane, optionally in the presence of an inorganic or tertiary organic base by an alkylating agent such as methyl iodide ethyl iodide, isopropyl bromide or dimethyl sulfoxide. Proceed from 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 general formula (II)-(III) to be used as starting materials can be prepared by known methods (see Examples), respectively, known in the literature.

As mentioned above, the novel compounds of general formula (I) and acid addition salts thereof have an effective pharmacological action and, in addition to a moderately lowering blood pressure lowering action, in particular selectively lower 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-dimethoxyphenyl)- 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) -ethylamino]- 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 on 2-5 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 (40 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 electrocardiogram (thoracic induction) from the electrocardiogram (thoracic induction) on the Graso polygraphy of the grass before and after administration, respectively.

The following table shows the results.

Results for dogs (continued)

C 1.00 Intravenous injection

C 2.0 Intravenous injection

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

Formula (I) compounds may also be suitable as tablets, dragees, powders, suspensions, solutions or suppositories suitable for administration in the treatment of circulatory diseases, in particular chronic coronary artery disease, and with other active substances. 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] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -amino-propane-hydrochloride

0.5 g sodium hydride is added to a 3.0 g (13.0 mmol) 4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone solution in 100 ml of dimethylformamide. After heating at 80 ° C. for 30 minutes, 8.5 g (35.2 mmol) of 1- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] in 100 ml of dimethylformamide] Add dropwise addition to the solution of -3-bromopropane. After heating to 140 ° C. for 8 hours, the reaction mixture is cooled, diluted with water and extracted several times with chloroform. The organic layer is dehydrated with sodium sulfate and evaporated to dryness in vacuo. The residue is chromatographed with silica gel (chloroform / methanol = 100/1). The evaporated fraction is then dissolved in acetone and the base is precipitated with hydrochloride. Yield: 0.6 g (10%) Melting point: 110 to 115 ° C

Example 2

2.6 g (4.4 mmol) of 1- [4-methyl-6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3-100 [N-benzyl-N- () in 100 ml of ethanol 0.3 g of palladium / charcoal (10%) is added to a 2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane solution, followed by introducing at 50 캜 and 5 atmospheres. After the hydrogen gas absorption is terminated, the precipitate is filtered off and the filtrate is evaporated in vacuo. A free base is obtained as a yellow oily substance. Yield: 1.8 g (82%)

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

Example 3

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

5.0 g (11.3 mmol) of the compound obtained according to Example 2 is heated to 100 ° C for 1 hour with a mixture of 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formalin. After cooling, 2N-sodium hydroxide is added to the reaction solution, the mixture is adjusted to 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 / ethanol = 100/1) to evaporate the main fraction and precipitate hydrochloride with etheric hydrochloric acid. Melting Point: 110-115 ° C

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

Example 4

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

Similar to Example 2, 1- (6,7-dimethoxy-4 (3H-quinazolinone-2-yl) -3- (N-benzyl- (2- (3,4-dimethoxy-phenyl)-) Ethyl) -amino] -propane is prepared by debenzylating with hydrogen in the presence of palladium / charcoal (10%).

Rf value (chloroform / methanol = 9/1): 0.45 Melting point: 192 to 194 ° C

The following compounds are prepared analogously.

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 degreeC.

1- [4-isopropyl-6,7-dimethoxy-1 (2H) -phthalazinone-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] -propane-hydrochloride. Melting point: 210 to 212 ° C.

1- [6,7-dimethoxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl-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-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-methyl-6,7-ethylenedioxy-1 (2H) -phthalazinone-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-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 | fusing point: 205-208 degreeC.

1- (6,7-dimethoxy-4 (3H) -quinazolin-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 degreeC.

1- (2-methyl-6,7-dimethoxy-4 (3H) -quinazolinone-3-yl) -3- (N-methyl-N- (2- (3,4-dimethoxy-phenyl) -Ethyl) -aminopropane-hydrochloride. Melting point: 125-217 degreeC.

1- (2-methyl-6,7-dimethoxy-4 (3H) -quinazolinone-3-yl) -3- (N- (2- (3,4-dimethoxy-phenyl) -ethyl)- Amino] propanehydro chloride. Melting point: 243-245 degreeC.

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 alkylamine of formula (I) or a salt thereof by reacting a compound of formula (II) with an alkylamine of formula (III).

In the above formula 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, and R ₃ is a methylene dioxy or ethylene deoxy 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 Form a methylene dioxy or ethylene dioxy group together with alkoxy or R ₅ having 1 to 3 carbon atoms, n is an integer of 2 or 3, Z is chlorine, cancelled, or iodine, alkylsulfonyloxy or arylsulfonyloxy It is the same group that can be separated.