GB1574046A

GB1574046A - Diarylacetamidopropanes processes for producing them and compositions containing them

Info

Publication number: GB1574046A
Application number: GB5698/77A
Authority: GB
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1976-02-13
Filing date: 1977-02-11
Publication date: 1980-09-03
Also published as: PT66182A; FR2340724A2; IL51425A0; CH620906A5; PT66182B; NL7701509A; JPS52105156A; FR2340724B2; DE2705639A1; AU2222277A; ES455870A1; BE851372A; CA1093582A

Abstract

Compounds of formula: <IMAGE> are prepared from a correspondingly substituted diphenylacetic acid, either by condensation with an amine R1NH-(CH2)3-NR2R3, R2 representing hydrogen or a benzyl group, in which case a debenzylation is then carried out, or by condensation with an amine R1NH-(CH2)3-Z, Z representing certain radicals which can be split off, followed by a reaction with an amine R3NH2. For the meaning of the various symbols, reference will be made to Claim 1. The compounds and their salts have antiarrhythmic properties; they can be used in the treatment of tachycardias or of disorders of the rhythm caused by digitalis.

Description

(54) DIARYLACETAMIDOPROPANES, PROCESSES FOR PRODUCING THEM AND COMPOSITIONS CONTAINING THEM (71) We. SCIENCE UNION ET CIE, SOCIETE FRANCAISE DE RECHER CHE MEDICALE, a French Societe en nom collectif, of 14 rue du Val d'Or, 92150 Suresnes, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to diarylacetamidopropanes, to process for making them and to pharmaceutical compositions containing them.

The present invention provides Nsubstituted propylene diamines of the general formula

in which each of A and B is a halogen atom, a lower alkyl radical (as hereinafter defined), or a lower alkoxy radical; each of X1, X2, X3 and X4 is a hydrogen atom and each of n and n' is an integer from 1 to 3, or each of X1 and X3 is a lower alkyl radical (as hereinafter defined), a lower alkoxy radical or a lower alkylthio radical, each of X2 and X4 is a lower alkyl radical (as hereinafter defined) and each of n and n' is zero or an integer from I to 3 and, in addition, when n is 3 and X1 and X3 are each methoxy, X2 may also be methoxy; R1 is a hydrogen atom or a lower alkyl radical (as hereinafter defined); and R3 is a lower alkyl radical (as hereinafter defined), a lower alkenyl radical, an aryl-(lower alkyl) radical (as hereinafter defined) or a lower alkyl radical (as hereinafter defined) substituted with a saturated heterocycle having from 3 to 7 ring atoms which may itself carry one or more substituents selected from lower alkyl radicals (as hereinafter defined), acyloxylower alkyl radicals (in which the acyl radical is derived from an alkanoic acid having from I to 6 carbon atoms and lower alkyl is as hereinafter defined) and lower alkoxy-lower alkoxy-alkyl radicals.

The term "lower alkyl" is used herein to designate an alkyl radical having from 1 to 6 carbon atoms which may be substituted by a hydroxy, a lower alkoxy or a dialkylamino group. Examples of such alkyl radicals are methyl, ethyl, isopropyl, sec butyl, neo pentyl, tert butyl, n-hexyl, p-hydroxyethyl and diethylaminoethyl radicals.

The term "lower alkoxy" means an alkyloxy radical, the alkyl group of which has from I to 6 carbon atoms, for example ethoxy and isopropoxy radicals.

The term "lower alkenyl" means a hydrocarbon radical containing one or more carbon-carbon double bonds having from 2 to 10 carbon atoms in a straight or branched chain, for example allyl, methylallyl, isopentenyl, dimethylallyl, butenyl and triallylmethyl radicals.

The term "aryl - (lower alkyl)" is used herein to designate a phenyl or substituted phenyl radical bearing a straight or branched chain alkyl radical having from I to 4 carbon atoms. The substituents on the phenyl ring may be one or more halogen atoms, or lower alkoxy or trifluoromethyl radicals, for example benzyl, 3,4 dimethoxybenzyl, 3 - trifluoromethylbenzyl, cr - methylbenzyl, p - chiorobenzyl, phenethyl, phenyl - propyl, or ,B - methylphenethyl radicals.

The heterocycle which may be a substituent on the lower alkyl radical R3 is preferably a nitrogen - containing heterocycle, for example pyrrolidine, piperidine or hexamethylene - imine. It may include another heteroatom such as oxygen, sulphur or nitrogen. Examples of such bi - heterocyclic structures are oxazolidine, morpholine, thiazolidine, thiamorpholine, piperazine and homomcr- pholine. These heterocyclic structures may be substituted with one or more lower alkyl, acyloxy - lower alkyl or lower alkoxy lower alkoxy - allyl radicals.Preferred heterocycles are N- A- - hydroxyethyl- piperazine, N - /3 - acetoxyethylpiperazine, N - ethylpiperazine, N - A - ethoxy - /3 - ethoxy - ethyl piperazine, 3 methylpiperazine and 3,5 - dimethylpiperazine.

The compounds of general formula I are basic and they can be salified by adding a mineral or organic acid, preferably a physiologically tolerable acid.

The organic acid may be a carboxylic, sulphonic or phosphoric acid. Examples of acid addition salt are the hydrochloride, hydrobromide, sulphate, phosphate, nitrate, acetate, pripionate, laurate, benzoate, salicylate, cinnamate, lactate, maleate, fumarate, pyruvate, glutamate, oxalate, methane sulphonate, isethionate, benzene sulphonate, glucose - 1 - phosphate and embonate.

Preferred compounds according to the present invention are those of the formula

in which R1 and R3 have the meanings given above, and especially - - Ibis - (2,6 - dimethylphenyl) acetamido]- 3 - ethylaminopropane: I-Ibis- - Ibis - (2,6 - dimethylphenyl) acetamido] - 3 - tert. butylamino propane and its methanesulphonate; - - Ibis - (2,6 - dimethylphenyl) acetamidoi - 3 - (2 - phenypropylamino) propane and its hydrochloride: and - - [bis - (2,6 - dimethylphenyl) acetamido]- 3 - isopropylaminopropane and its hydrochloride.

The compounds of the present invention have interesting pharmacological properties, namely anti - arrythmic properties. In addition, they have no neurodepressant activity, they do not exert any anti - convulsant activity and they do not decrease the mean arterial pressure.

Due to their very specific activity, they find a use in human and veterinary medicine for treating tachycardia or the irregularities of the cardiac rhythm resulting from cardiac intoxication of the digitalic type.

The present invention therefore provides pharmaceutical compositions comprising as active ingredient a compound of the general formula I or a physiologically tolerable acid addition salt thereof in admixture or conjunction with a pharmaceutically suitable carrier.

These compositions may be in a form suitable for parenteral, oral, sublingual or rectal adminstration, and may include another active ingredient which has a similar, complementary or synergistic action.

The useful posology of the compounds varies broadly depending on the age and weight of the patient to be treated and the severity of the disease. It ranges from 50 to 200 mg per unit dosage and from 100 to 600 mg per day in man, generally by oral administration.

The pharmaceutical compositions are most suitably in the form of a tablets, such as coated tablets or sublingual tablets, dragees, soft gelatine capsules, granulates, injectable solutions or suspensions packed in ampoules, phials or multi-dose flasks, or suppositories.

The present invention also provides a process for preparing the compounds of general formula I which comprises reacting a diarylacetic acid of the general formula

in which A, B, X1, X2, X3, X4, n and n' have the meanings given above, or a functional derivative thereof, with a diamine of the general formula

in which R1 and R3 have the meanings given above. and R2 is a hydrogen atom or a benzyl radical, to produce a diarylacetamide of the general formula

and, when R2 is a benzyl radical, hydrolysing this compoound in an acid medium or hydrogenolysing this compound in the presence of a catalyst to produce a compound of general formula I.

The present invention also provides a process for preparing the compounds of the general formula I which comprises condensing a diarylacetic acid of the general formula II or a functional derivative thereof, with a w-substituted propylamine of the general formula R1 NH-CH2-CH2-CH2 Z IV in which Z is a hydrogen atom, a hydroxy group, an aryl - sulphonyloxy radical, or an alkylsulponyloxy or trialkyl silyloxy radical in which the alkyl radicals have from I to 6 carbon atoms, and R1 has the meaning given above to produce a diarylacetamide of the general formula

and the reacting the latter with an amine of the general formula R,--NH, VI in which R3 has the meaning given above, to produce a compound of the general formula I.

Preferred features of the processes according to the present invention are as follows: - the functional derivative of the diarylacetic acid of the general formula II may be a halide, for example the chloride or the bromide: the anhydride or a mixed anhydride, for example the mixed anhydride with formic acid or acetic acid: or an alkyl ester or an aryl ester, for example a methyl, ethyl, phenyl or nitrophenyl ester; - the functional derivative of the diaryl acetic acid of the general formula II may be formed "in situ" by reacting the diaryl acetic acid with a dialkyl or a dicycloalkyl carbodiimide or carbonyl diimidazole; - condensation is carried out in an inert polar or non-polar solvent, for example in ether, pyridine, dimethylformamide, 4 dimethylaminopyridine, or hexamethyl phosphoramide; - hydrogenolysis is carried out in the presence of a catalyst based on a metal of the platinum family, for example palladium or platinum;; - the co-substituted propylamine of the general formula IV is a toluenesulphonyloxy derivative, a benzenesulphonyloxy derivative, a chloroderivative, a bromo derivative or a methanesulphonyloxy derivative; - the reaction between the diarylacetamide of the general formula V and the amine of the general formula VI is carried out in a basic medium, for example a trialkylamine, a pyridine base, dimethylformamide or dimethylacetamide;; -- the amine of the general formula VI is a lower alkylamine (in which lower alkyl is as herein defined), the lower alkyl group of which is substituted with a heterocycle, for example pyrrolidimylmethylamine, N - ethyl -pyrrolidimylmethylamine, N - methyl piperazinylethylamine, N - /3 - hydroxy- ethyl piperazinylethylamine, N - methyl piperidinylethylamine and morpholinylethylamine.

The following Examples illustrate the invention.

Example I.

- - [bis - (2,6 - dimethylphenyl) - acetamido] - 3 - tert.butylaminopropane Into a three-neck flask, there are successively placed 3.9 g of 1 - tert.butylamino - 3 - amino propane in 20 ml diethyl ether and 4.2 ml triethylamine.

The mixture is cooled below 10"C and a solution of bis - (2,6 - dimethylphenyl) acetyl chloride in 90 ml diethyl ether is added dropwise while stirring and maintaining the temperature of the reaction mixture at 100C. When the addition is complete, stirring is maintained for 5 hours.

A solution of 2N sodium hydroxide is then added and the mixture is stirred for a further 2 hours. A small amount of insoluble matter is separated, then the ether phase is decanted off. The etherous phase is washed with water, with aqueous sodium hydroxide and then twice with water. The organic phase is then dried over magnesium sulphate, filtered and evaporated to dryness.

The dry residue weighs 9.6 g. It is taken up in isopropyl ether from which it recrystallizes.

The crystals are separated, washed with a few ml of cooled isopropyl ether and dried to constant weight. The yields amounts to 6.1 g. The pure compound is converted into its methanesulphonate then basified. 1 - [bis - (2,6 - dimethylphenyl) - acetamido] 3 - tert.butylamino propane precipitates.

The precipitate is separated by suction filtration, dried, washed with water and dried to constant weight. The yield of pure product amounts to 5.6 g. The ptire compound melts at 144 C.

Example II.

- - [bis - (2,6 - dimethylphenyl) - acetamido] - 3 - isopropylamino propane and its hydrochloride Using the procedure described in Example I and starting from 3.8 g 1 - isopropylamino - 3 - aminopropane and 8.6 g of bis - (2,6 - dimethylphenyl) - acetyl chloride, there are obtained 7.7 g of 1 [bis - (2,6 - dimethylphenyl) - acetamido] 3 - isopropylaminopropane which is purified by conversion into its hydrochloride.

By recrystallizing the hydrochloride from acetonitrile, there are obtained 5.5 g of 1 [bis - (2,6 - dimethylphenyl) - acetamido] 3 - isopropylaminopropane hydrochloride which melts at 220-222 C.

Example III.

I - [his - - (2,6 - dimethylphenyl) - acetamido] - 3 - (2 - phenylpropylamino) - propane and its hydrochloride Using the procedure described in Example I but using as starting material 5.75 g of 1 - (2 - phenylpropylamino)- 3 aminopropane, there are obtained 13.9 g of I - Ibis - - (2,6 - dimethylphenyl) - acetamido] - 3 - (2 - phenylpropylamino) - propane. This is converted into the hydrochloride. After recrystallizing the latter from diethyl ether, it melts at 2200 C.

Example IV.

- - Ibis - (2,6 - dimethylphenyl) - acetamido] - 3 - ethylaminopropane Using the procedure described in Example I but starting from 3.9 g of 1 ethylamino - 3 - aminopropane, there are obtained 7.7 g of I - [bis - (2,6 - dimethylphenyl) - acetamido] - 3 - ethylaminopropane. After having been recrystallized from cyclohexane, it melts at 116"C.

Example V Using the same procedure but starting from bis - (2,4 - ditertbutyl - 6 - isopropylphenyl) - acetyl chloride and I - isopropylamino - 3 - aminopropane, there is obtained 1 - Ibis - 2,4 - ditertbutyl - 6 isopropylphenyl) - acetyl] - 3 - isopropylaminopropane.

Similarly, starting from ethyl 4,4' difluorodiphenylacetate and 1 - isopropylamino - 3 - aminopropane, there is obtained - - [bis - (4 - fluorophenyl) - acetamido]- 3 - isopropylaminopropane.

Similarly, starting from 3',5' - dichloro 2,2',4,-6' - tetramethoxy - 4',6 - dimethyldiphenylacetyl chloride (obtained from 3',5' - dichloro - 2,2',6' - trihydroxy - 4 methoxy 4',6 - dimethylbenzophenone as described by Azfal and coworkers J. Chem.

Soc. 1969 (section C) 1721) and 1 - tert.butylamino - 3 - aminopropane, there is obtained 1 - (3',5' - dichloro - 2,2',4,6' tetramethoxy - 4',6 - dimethyldiphenylacetamido) - 3 - tert.butylaminopropane.

Example VI.

Pharmacological tests.

(1) actute toxicity The acute toxicity of the compounds of the invention has been determined on batches of male mice (Rockland strain) weighing about 20 g to which the compound to be tested is administered intraperitoneally or orally in an aqueous vehicle in increasing doses. The animals are kept under survey and the deaths, if any, are recorded. The average lethal dose is calculated graphically.

Depending on the product, the average lethal dose (LDso) ranges from 50 to 100 mg/kg intraperitoneally and from 500 to 1000 mg/kg orally.

(2) neurological activity Doses of 25 mg/kg intraperitoneally in mice induce only a slight decrease in motility.

Doses of 50 mg/kg intraperitoneally induce a decrease in motility then belated lethality.

These symptoms are weak and occur only at sublethal doses.

Further, the compounds of the invention have no protective effect against convulsions caused by electroshock or injections of pentamethylene tetrazole.

(3) cardio-regulating effect The cardio-regulating effect has been determined on batches of dogs previously anesthetized with 30 mg/kg of pentobarbital, injected intravenously. Ouabain is then injected intravenously at a dose of 0.5 mg/kg. Every 15 minutes, a further injection of 0.01 mg'kg of ouabain is made until permanent ventricular tachycardia occurs for at least 15 minutes as shown by recording the electrocardiogram in derivation D2.

The total dose required for producing the occurance of such tachycardia is on average about 0.07 mg/kg.

The compounds to be tested are injected intravenously at doses ranging from 0.5 to 5 mg/kg depending on the compound. The minimum dose required to restore the cardiac rhythm and cause a return to a normal sinusoidal rhythm is thus determined.

In general, the minimum effective dose is 2 mg/kg. For the most active compounds, it is I mg/kg. The duration usually ranges from 10 to 90 minutes or more.

At the tested doses, the compounds do not exert any effect on the arterial pressure.

WHAT WE CLAIM IS: 1. A compound of the general formula

in which each of A and B is a halogen atom, a lower alkyl radical (as herein defined), or a lower alkoxy radical; each of Xt, X2, X3 and X4 is a hydrogen atom and each of n and n' is an integer from I to 3, or each of X1 and X3 is a lower alkyl radical (as hereinafter defined), a lower alkoxy radical or a lower alkylthio radical, each of X2 and X4 is a lower alkyl radical (as hereinafter defined) and each of n and n' is zero or an integer from 1 to 3 and, in addition, when n is 3 and X, and X3 are each methoxy, X2 may also be methoxy; R, is a hydrogen atom or a lower alkyl radical (as hereinafter defined); and radical (as herein defined); and R3 is a lower alkyl radical (as herein defined), a lower alkenyl radical, an aryl (lower alkyl) radical as herein defined) or a lower alkyl radical (as herein defined) substituted with a saturated heterocycle having from 3 to 7 ring atoms which may itself carry one or more substituents selected from lower alkyl radicals (as herein defined), acyloxy-lower alkyl radicals (in which the acyl radical is derived from an alkanoic acid having from I to 6 carbon atoms and lower alkyl is as herein defined) and lower alkoxy-lower alkoxy-alkyl radicals.

in which R, and R3 have the meanings specified in claim 1.

3. An acid addition salt of a compound according to claim 1 with a mineral or orgnic acid.

4. An acid addition salt according to claim 3 which is physiologically tolerable.

5. 1 - [bis - (2,6 - dimethylphenyl) acetamido] - 3 - ethylaminopropane.

6. 1 - [Bis - - (2,6 - dimethylphenyl) acetamido] - 3 - tert.butylamino propane an its methanesulphonate.

7. I - [Bis - (2,6 - dimethylphenyl)acetamido] - 3 - (2 - phenylpropylamino) - propane and its hydrochloride.

8. 1 - [Bis - (2,6 - dimethylphenyl) acetamido] - 3 - isopropyl - amino propane and its hydrochloride.

9. A process for preparing a compound according to claim 1 which comprises reacting a diarylacetic acid of the general formula

in which X1, X2, X3, X4, A, B, n and n' have the meanings specified in claim 1, with a diamine of the general formula

in which R1 and R3 have the meanings specified in claim I and R2 is a hydrogen atom or a benzyl radical, to produce a diarylacetamide of the general formula

and, when R2 is a benzyl radical, hydrolysing this compound in an acid medium or hydrogenolysing this compound in the presence of a catalyst.

10. A process for preparing a compound according to claim l, which comprises condensing an diarylacetic acid as specified in claim 9 or a functional derivative thereof,

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. The compounds to be tested are injected intravenously at doses ranging from 0.5 to 5 mg/kg depending on the compound. The minimum dose required to restore the cardiac rhythm and cause a return to a normal sinusoidal rhythm is thus determined. In general, the minimum effective dose is 2 mg/kg. For the most active compounds, it is I mg/kg. The duration usually ranges from 10 to 90 minutes or more. At the tested doses, the compounds do not exert any effect on the arterial pressure. WHAT WE CLAIM IS:

1. A compound of the general formula

in which R, and R3 have the meanings specified in claim 1.

5. 1 - [bis - (2,6 - dimethylphenyl) acetamido] - 3 - ethylaminopropane.

with a co-substituted propylamine of the general formula R1 NH-CH2-CH2CH2 Z in which R1 has the meaning specified in claim I and Z is a halogen atom, a hydroxy group, an aryl sulphonyloxy radical, or an alkyl sulphonyloxy or trialkyl silyloxy radical in which the alkyl radicals have from 1 to 6 carbon atoms, to produce a diarylacetamide of the general formula

and reacting the latter with an amine of the general formula R3-NH2 in which R3 has the meaning specified in claim 1.

I I. A process according to claim 9 or claim 10 carried out substantially as described in any one of Examples I to V herein.

12. A compoud according to claim 1 whenever obtained by a process according to any one of claims 8 to 11.

13. A pharmaceutical composition comprising as active ingredient a compound according to claim I or a physiologically tolerable acid addition salt thereof in admixture or conjunction with a pharmaceutically suitable carrier.

14. A pharmaceutical composition according to claim 13, which contains the active ingredient in an amount of from 50 to 200 mg per unit dosage.

15. A pharmaceutical composition according to claim 13 or claim 14 in a form suitable for parenteral, oral, sublingual or rectal administration.

16. A pharmaceutical composition according to any one of claims 13 to 15 in which the active ingredient is a compound according to claim 2.

17. A pharmaceutical composition according to any one of claims 13 to 15, in which the active ingredient is a compound according to claim 4.

18. A pharmaceutical composition according to any one of claims 13 to 15, in which the active ingredient is the compound according to claim 5.

19. A pharmaceutical composition according to any one of claims 13 to 15, in which the active ingredient is a compound according to claim 6.

20. A pharmaceutical composition according to any one of claims 13 to 15, in which the active ingredient is a compound according to claim 7.

21. A pharmaceutical composition according to any one of claims 13 to 15, in which the active ingredient is a compound according to claim 8.