NO772106L - PROCEDURES FOR THE PREPARATION OF 1-SUBSTITUTED DERIVATIVES OF DIFENYL-2,2-CYCLOPROPANE - Google Patents

Description

The invention relates to the preparation of 1-substituted derivatives of aminomethyl-1-diphenyl-2,2-cyclopropane as well as their non-toxic, pharmaceutically acceptable acid addition salts.

The new compounds produced according to the invention correspond to formula (I):

where n is 1, 2 or 3, and is individually lower alkyl or lower hydroxyalkyl or can together form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic ring which may optionally contain another heteroatom. The designation " lower alkyl" denotes a radical with 1-4 carbon atoms, straight-chain. or branched. The hydroxyalkyl radical is usually the 3-hydroxyethyl radical.

The heterocyclic ring formed by and together

with the nitrogen atom to which they are attached is preferably a 6-membered heterocyclic ring selected from the following: piperidino, morpholino, piperazino or N-(lower alkyl)-piperazino.

The compounds I can form addition salts with acids. Production of these salts is also covered by the invention.

In the method according to the invention,

in a first step a compound of formula:

where n = 1, 2 or 3, X means a chlorine or bromine atom, with amino-

methyl-1-diphenyl-2,2-cyclopropane in practically equimolar amounts, in an inert organic solvent, e.g. benzene, toluene or tetrahydrofuran, in the presence of a hydrogen acid acceptor formed during the course of the reaction, in particular triethylamine, to obtain a compound of formula (II):

where X and n have the meanings given above.

In another step, a compound (II) is reacted with an amine:

where and R 2 have the above meaning, in practically equimolar amounts, to obtain the compound corresponding to formula (I). The reaction is carried out in the presence of a hydrogen acid acceptor which is formed during the course of the reaction and which can advantageously be an excess of amine

or triethylamine.

The compounds (I) have pharmacological properties which make them valuable in therapy. They are particularly active on the cardiovascular system.

The following examples, which are not limiting, are given to illustrate the invention.

Example 1

Chloroacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane

0.1 mol of aminomethyl-1-diphenyl-2,2-cyclopropane, 0.11 mol of triethylamine and 150 cm 3 of anhydrous benzene are mixed under agitation.

To the thus obtained solution is added drop by drop, over the course of approx. 1 hour, a solution of 0.1 mol of chloroacetic acid chloride 3

in 50 cm of aqueous benzene.

When the thermal effect is over, the mixture is allowed to stand for 2 hours at ambient temperature. It is taken up with 300 cm3

3

water, decanted, the organic phase is washed with 100 cm of water, decanted, dried over magnesium sulfate, and the benzene is evaporated under vacuum, so that 28 g of chloroacetamide from aminomethyl-1-diphenyl-2,2-cyclopropane are obtained in the form of a thick oil which is used as is for the following operations.

Example 2

ff- chloro<p>ro<p>ionamide of aminoethyl- l- diphenyl- 2, 2- cyclopropane

(Formula (II), n = 2, X = Cl)

The procedure from example 1 is repeated, but starting from 0.1 mol of $-chloropropionic acid chloride, to obtain 29 g of a/3-chloropropionamide.d of aminomethyl-1-diphenyl-2,2-cyclopropane in the form of a thick oil which is used as it is for the following operations.

Example 3

Diethylaminoacetamide of aminomethyl-l-diphenyl-2,2-cyclopropane, in the form of oxalate

To 0.05 mol of chloroacetamide prepared as stated in example 1, in 30 cm 3 of triethylamine, 0.05 mol of diethylamine x 10 cm 3 of triethylamine is added dropwise while stirring.

When the thermal effect has occurred, it is boiled under reflux for 1 hour, the excess of triethylamine is distilled off, the residue is taken up with 150 cm 3 of water, extracted with ether, dried over magnesium sulphate and the ether evaporated under vacuum.

Preparation of the oxalate.

The evaporation residue is dissolved in 80 cm3 of acetone and, with agitation, a solution of 0.05 mol of oxalic acid in 80 cm3 of acetone is added. This is allowed to rest for 3 hours, after which it is filtered, washed with acetone and dried to obtain 15 g of the oxalate of the diethylaminoacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane which melts at 147°C.

Example 4

Morpholinoacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of diethylamine is replaced by 0.05 mol of morpholine.

the evaporation residue is recrystallized in the ether/pentane 30/70 mixture so that 9 g of morpholinoacetamide of aminomethyl-1-diphenyl-2, 2-cyclopropane, m.p. 98°.

Example 5

Piperjdinoacetamide of aminomethyl-1-diphenyl-2,2- cyclopropane in the form of oxalate

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of diethylamine is replaced by 0.05 mol of piperidine.

Preparation of the oxalate.

The evaporation residue is taken up with 100 cm 3 of ethyl acetate. To the solution thus obtained, a solution of 0.05 mol of oxalic acid in 80 cm 3 of ethyl acetate is added while stirring. This is left to rest

for 3 hours, filter, wash with ethyl acetate and dry to obtain 13 g of oxalate of piperidinoacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane, m.p. 144°C.

Example 6

N-methylpiperazinoacetamide, of aminomethyl-l-diphenyl-2,2-cyclopropane

in the form of dimaleate

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of diethylamine is substituted

with 0.05 mol of N-methylpiperazine.

Preparation of dimaleate

The evaporation residue is taken up with 80 cm^ of isopropanol. A solution of 0.1 mol of maleic acid in 100 cm 3 of isopropanol is added to the solution thus obtained while stirring. This is left to stir for 3 hours, filtered, washed with ethyl acetate and dried to obtain 15 g of the dimaleate of N-methylpiperazineacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane, m.p. 160°C.

Example 7

N-methyl-N-hydroxyethylaminoacetamide of aminomethyl-l-diphenyl-2,2-cyclopropane in the form of oxalate

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of diethylamine is replaced by 0.05 mol of N-methylethanolamine.

Preparation of the dksalat

The evaporation residue is dissolved x 80 cm 3 acetone, a solution of 0.05 mol oxalic acid x 60 cm 3 acetone is added while stirring to the solution thus obtained, this is allowed to rest for 3 hours, filtered, washed with acetone and dried to obtain 14.3 g oxalate of N-methyl-N-hydroxyethylaminoacetamide of aminomethyl-1-diphenyl-2, 2-cyclopropane, m.p. 112°C.

Example 8

Bis-hydroxyethylaminoacetamide of aminomethyl-1-diphenyl-2,2- cyclopropane in the form of oxalate

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of diethylamine is replaced by 0.05 mol of diethanolamine.

Preparation of the oxalate

The evaporation residue is taken up with 80 cm 3 of acetone. To the solution thus obtained, 0.05 mol is added while stirring

oxalic acid in 60 cm 3 :acetone. This is allowed to stand for 3 hours, filtered, washed with acetone, dried and gives 6 g of oxalate of bis-hydroxyethylaminoacetamide of aminomethyl-1-diphenyl-2,2-cyclopropane, m.p. 120°C (paste-like melt).

Example 9

ff- dimethylaminopropionamide of aminomethyl-l- diphenyl- 2, 2- cyclopropane in the form of oxalate

The procedure is identical to that stated in example 3, with the exception that 0.05 mol of chloroacetamide is replaced by 0.05 mol of /3-chloropropionamide prepared as stated in example 2, and that 0.05 mol of diethylamine is replaced by 0.05 mol of dimethylamine.

Preparation of the oxalate

The evaporation residue is taken up with 80 cm 3 of isopropanol. A solution of 0.05 mol of oxalic acid in 60 cm 3 of isopropanol is added to the solution thus obtained while stirring. This is allowed to agitate for 3 hours, filtered, washed with isopropanol and dried to obtain 12 g of oxalate of /3-dimethylaminopropionamide of aminomethyl-1-diphenyl-2,2-cyclopropane, m.p. 172°C.

Example 10

ff-piperidinopropionamide of aminomethyl-l-diphenyl-2,2-cyclopropane in the form of chlorohydrate

The procedure is identical to that indicated in example 3, with the exception that 0.05 mol of chloroacetamide is replaced by 0.05 mol of ^-chloropropionamide prepared as indicated in example 2, and that 0.05 mol of diethylamine is replaced by 0 .05 mol of piperidine.

Preparation of the chloral hydrate

The evaporation residue is dissolved in 150 cm 3 of isopropanol.

To the solution thus obtained, ether chloride is added while stirring until pH = 1. This is allowed to stand for 3 hours, filtered, washed with isopropanol and dried to obtain 14 g of chlorohydrate of /3-piperidinopropionamide of aminomethyl-1-diphenyl-2, 2-cyclopropane, m.p. 195°C.

The pharmacological activity of the new 1-substituted derivatives of diphenyl-2,2-cyclopropane is illustrated in the following.

Cardiac haemodynamics in the dog

In Trial protocol

Dogs of mixed litters, of one or the other sex, anesthetized with sodium mebubarbital, are artificially ventilated using a pump of the Pesty RPP type.

One measures:

- the pressure in the carotid artery using a Statham P 23 Db meter, - the heart rate based on the systolic pressure signal, - the flow in the ascending aorta and the flow in the circumflex coronary artery using an electromagnetic sensor and amplifier of the Statham SP 2200 type .

All parameters are recorded on DynographBeckmån.

One calculates:

- the mean arterial pressure (PA m in mmHg) : diastolic pressure + 0.43 (systolic pressure diastolic pressure),

- the work in the left ventricle (WVG in kgm/mn):

1055 flow in the aorta (l/mn), x PA m x 13.6 x ^' qqq - the vascular resistance in the coronary artery (mm Hg/ml/mn) = PA m (mm Hg)/flow in the coronary artery (ml), - the flow in the coronary artery at stroke (ml) flow in the coronary artery/heart rhythm, - the flow in the coronary artery at work unit (ml/kg): flow in the coronary artery/work in the left ventricle.

The injections are given intravenously in the mother's vein. The doses are expressed as base.

II - Results

The following table shows, for each dog, the results obtained in percentage of variation in relation to the value before the injection, for the products from the different examples. For the various cardiovascular parameters, the variations are expressed at the peak of vasodilation in the coronary artery and at the peak of hypotension.

In conclusion, the described products have vasodilating properties in the coronary arteries. They otherwise reduce the vascular resistances and the afterload of the heart. They can therefore be used therapeutically in the treatment of angina pectoris and vascular difficulties, in the form of gelled capsules dosed with 50-200 mg, drops with a concentration of 10 mg per ml and ampoules dosed with 100 mg per ampoule, for intravenous and intramuscular injection.

Claims (1)

Process for the preparation of 1-substituted derivatives of aminomethyl-1-diphenyl-2,2-cyclopropane of formula: where: n is 1, 2 or 3; and R^ is individually a lower alkyl radical or lower hydroxyalkyl radical, orR^ and R^ may together, and together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the following: piperidino, morpholino, piperazino or N-(lower alkyl)-piperazino, the term "lower alkyl" meaning a radical of 1-4 carbon atoms, as well as non-toxic, pharmaceutically acceptable acid addition salts of these derivatives, characterized in that: • in a first step, a compound of formula is converted: where n is 1, 2 or 3, X is a chlorine or bromine atom, with aminomethyl-1-diphenyl-2,2-cyclopropane in amounts that are practically equimolar, in an inert organic solvent, in the presence of a hydrogen acid acceptor which is formed during the course of the reaction, to obtain a compound of formula: and, in a second step, reacting compound II with an amine: in practically molar amounts, in the presence of a hydrogen acid acceptor which is formed during the course of the reaction, to obtain the compound of formula I which is separated, and that the compound of formula I is optionally converted in a manner known per se into a non- toxic, pharmaceutically acceptable acid addition salt.