CH620906A5 - Processes for the preparation of new propylenediamines - Google Patents

Description

The invention relates first of all to a process for the preparation of the compounds of formula:

R, HN - CH, 1 /

- ch2 -

CH0 N -

2 I

R „

R „

in which the substituents Ri and R3 are defined as above and R2 represents hydrogen or a benzyl radical, to obtain a diarylacetamide of formula:

'X, X

co— N-CH2— CH2— CH2 NH-R3

R

55

CO- N- Eyelash "CH_- CH.N i II 2

^ 2

R

360

and the compound obtained, when R2 represents a benzyl radical, is subjected to debenzylation.

2. Method according to claim 1, characterized in that the salification of the compounds obtained, of formula I, is carried out by the action of a mineral or organic acid.

3. Process for the preparation of the new compounds of formula I as defined in claim 1, and of their addition salts with in which Xi and X3 represent, simultaneously or distinctly, a lower alkyl radical, a lower alkoxy radical, or a lower alkylthio radical,

X2 and X4 represent, simultaneously or distinctly, a lower alkyl radical,

A and B represent, simultaneously or distinctly, a halogen, a lower alkyl or a lower alkoxy,

n and n 'have the value of zero, one, two or three and, when n is greater than or equal to 1, the residues Xi, X2, X3 and X4 may be hydrogen,

R 1 represents hydrogen or a lower alkyl radical, R 3 represents a lower alkyl radical, a lower alkenyl radical, a lower aralkyl radical or an alkyl radical substituted by a heterocycle having from 3 to 7 carbon atoms, optionally substituted, characterized in what is condensed a diarylacetic acid of formula:

3

620 906

e "X5-w-

COOH I

X,

(II)

the meanings provided previously, or one of its functional derivatives, with a propanediamine of formula:

R1 HH "CH2 * CH2 * CH2 j1 - R3 (, .I>

R-

^ in which the substituents Ri and R3 are defined as above - in which the substituents A, B, Xi, X2, X3, X4, n and n 'keep 10 and R2 represents hydrogen or a benzyl radical,:; to obtain a diarylacetamide of formula:

(B)

laughed

(Year,

CO - N - XH2 - CH2 - CH2 N

R „

in which the substituents Xi, X2, X3, X4, A, B, Ri, R2, R3, n and n 'are defined as above, which is debenzylated, when R2 represents a benzyl radical, by hydrogenolysis or hydrolysis in the medium acid.

If desired, the compound obtained can be salified by adding a mineral or organic acid.

The invention also relates to a process for obtaining the compounds of general formula I, characterized in that a diarylacetic acid of general formula II or one of its functional derivatives is condensed, with a cù-substituted propane amine of formula:

RiNH - CH2 - CH2 - CH2Z

(IV)

in which Z is a cleavable radical chosen from the group of halogens, arylsulfonyloxy, alkylsulfonyloxy, trialcoylsilyloxy and hydroxy radicals, to obtain a diarylacetamide of formula:

X, X „

(B) +

in which the meaning of the substituents A, B, Xi, X2, X3, X4, Ri and Z remains that supplied previously, which is reacted with an amino derivative of formula:

R3NH2

(VI)

in which R3 has the meanings previously supplied, and the desired compound of general formula (I) is obtained.

The methods according to the invention can be carried out advantageously, as follows:

- The functional derivative of diarylacetic acid is a halogenide, such as chloride or bromide; or the anhydride or a mixed anhydride, such as an anhydride with formic acid or acetic acid; or the mixed anhydrides formed in situ by reaction with a dialkoylcarbodiimide or dicyclohexylcarbodi-imide, acetoxyacetylene or carbonyldiimidazole.

- The functional derivative of diarylacetic acid of formula II can be an alkyl or aryl ester such as, for example, a methyl, ethyl, phenyl or nitrophenyl ester.

The condensation is carried out in an inert polar or non-polar solvent, such as an ether, pyridine, dimethylforma-

55

mide, 4-dimethylaminopyridine or hexamethylphosphoro-triamide.

- The hydrogenolysis is carried out in the presence of a catalyst of the platinum family such as, for example, platinum or palladium.

- the co-substituted propaneamine of general formula IV is preferably a p-toluenesulfonyloxy derivative, benzenesulfonyloxy, a chlorinated derivative, a brominated derivative or a methylsulfonyloxy derivative.

- The reaction between the diarylacetamide of general formula V and the amine of general formula VI is carried out in basic medium such as, for example, a trialkylamine, a pyridic base, dimethylformamide or dimethylacetamide.

- The amine of general formula VI is preferably pyrro-lidylmethylamine, N-ethylpyrrolidylmethylamine, N-methyl-piperazinylethylamine, N-hydroxyethylpiperazinylethylamine, N-methylpiperidinylethylamine or morpholylethylamine.

The compounds of general formula I or of formula I 'are basic compounds which can be salified. The salts of these compounds result from the addition of a mineral or organic, carboxylic, sulfonic or phosphoric acid, preferably a therapeutically compatible acid.

The term lower alkyl designates here and in the following a hydrocarbon radical optionally substituted by a hydroxy or a lower alkoxy or a dialkoylamino, having from 1 to 6 carbon atoms, linear or branched such as, for example, methyl, ethyl, isopropyl, secbutyl, neopentyl, terbutyl, hexyl, B-hydroxyethyl or diethylaminoethyl.

The term lower alkoxy denotes an alkyloxy radical where the alkyl radical is defined as above, as ethoxy or isopropoxy.

The term lower alkenyl denotes a mono- or polyunsaturated hydrocarbon radical having from 2 to 10 carbon atoms in a straight or branched chain such as, for example, allyl, methallyl, isopentenyl, dimethylallyl, butenyl or triallylmethyl.

The term lower arylalkyl designates a phenyl radical optionally mono- or polysubstituted on the nucleus by a halogen, a lower alkoxy or a trifluoromethyl, carrying a hydrocarbon chain having from 1 to 4 carbon atoms in the right or branched as, for example, benzyl, dimethoxy-benzyl, trifluoromethylbenzyl, oc-methylbenzyl, p-chloro-benzyl, phenylethyl, phenylpropyl or p-methylphenylethyl.

The heterocycle having from 3 to 7 members can be a nitrogen heterocycle such as Pyrrolidine, piperidine or hexamethyleneimine. It can also include another heteroatom such as a nitrogen, oxygen or sulfur atom. Examples of such cyclic structures are in particular oxazolidine, morpholine,

620 906

4

thiazolidine, thiamorpholine, piperazine or homomorpholine. These heterocycles can also contain one or more alkyl substituents.

Among these heterocycles, mention may in particular be made of N-hydroxyethylpiperazine, N-acetoxyethylpiperazine, N-ethylpiperazine or p-ethoxy p-ethoxyethylpiperazine, 3-methylpiperidine and 3,5-dimethylpiperidine.

The salification of the compounds of general formula I is carried out by addition of a mineral acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric acid; or by addition of an organic acid, such as acetic, propionic, lauric, benzoic, salicylic, cinnamic, lactic, maleic, fumaric, pyruvic, glutamic, oxalic, methanesulfonic, isethionic, benzenesulfonic, phosphoric-1 or phosphoic acid .

Certain basic derivatives of diphenyl acetamide were already known, the benzene rings of which do not carry any substituent. This is the case, in particular, for N- (3-diethyl-aminopropyl) diphenylacetamide hydrochloride, known under the name of Arpenal and endowed with antiarrhythmic properties [“Unlisted Drugs” 11 (1979), 539], and the hydrochloride of N- (3-isopropylaminopropyl) diphenyl-acetamide which also has antiarrhythmic properties [“Unlisted Drugs” 12 (1960), 38s].

The compounds of general formula I are endowed with interesting pharmacological properties, in particular antiarrhythmics. They do not have a neurosuppressive effect. They have no anti-convulsant effect. They do not lower blood pressure.

Among the compounds of general formula I, mention may be made, as preferred compounds, of the compounds of general formula I '

in which Ri and R3 have the same meanings as those provided above and more particularly

- N - [(2,6-2 ', 6'-tetramethyldiphenyl) acetyl] 3-N'-ethyl-aminopropylamine,

- N - [(2,6-2 ', 6'-tetramethyldiphenyl) acetyl] 3-N'terbutyl-aminopropylamine and its methanesulfonate,

- N - [(2,6-2 ', 6'-tetramethyldiphenyl) acetyl] 3-N- (2-phenyl-propyl) aminopropylamine and its hydrochloride,

- N - [(2,6-2 ', 6'-tetramethyldiphenyl) acetyl] 3-N'-isopropyl-aminopropylamine.

The compounds obtained according to the process of the invention can find a use in therapeutics, in particular in tachycardias or disorders of the cardiac rhythm consecutive to an intoxication of the digital type. They can be used for this purpose in the form of pharmaceutical compositions, suitable for parenteral, buccal, sublingual or rectal use, containing at least one compound of general formula I or one of its salts with a mineral or organic acid, in association with an inert, non-toxic, pharmaceutically acceptable excipient.

The useful dosage may vary according to the age and weight of the subject and the severity of the therapeutic indication. It ranges in particular between 50 and 200 mg per dose and 100 and 600 mg / day in adults, mainly by the oral route.

Among the pharmaceutical forms, mention may be made, by way of example, of naked or coated tablets, dragees, capsules, granules, solutions or suspensions for injection in multidose ampoules or vials, sublingual tablets and suppositories.

The pharmaceutical forms are obtained by the usual methods in pharmacotechnology, in particular by dissolution, suspension or mixture with a solvent or an excipient suitable for the intended route of administration.

The following examples illustrate the invention.

Example 1:

10 3-N (2,6-2 ', 6'-tetramethyldiphenylacetyl) l-terbutylamino-

propylamine.

3.9 g of N-ter-butylpropanediamine dissolved in 20 ml of ether and 4.2 ml of triethylamine are introduced into a three-tube flask and the mixture is cooled to below 10 °. Then added with stirring and maintaining the temperature at + 10 ° by external cooling, a solution of 8.6 g of acid chloride (2.6-2 ', 6'-tetramethyldiphenyl) acetic in 90 ml of ether. Stirring is continued for approximately 5 hours. 37.15 ml of a 2N sodium hydroxide solution are then added and the mixture is left in contact with stirring for 2 h. A light precipitate is separated and then the ethereal phase is decanted. It is washed with water and then with 2N sodium hydroxide, then twice with water, dried over magnesium sulphate, filtered and evaporated to dryness. A dry residue weighing 9.6 g is thus obtained which is taken up in isopropyl ether. By concentration the product crystallizes from isopropyl ether. The precipitate is filtered off, washed with a little ice-cold isopropyl ether and then dried to constant weight, the yield is 6.1 g.

The product is purified by passage in the form of methane sul-fonate then alkalization.

30

3-N (2,6-2 ', 6'-tetramethyldiphenylacetyl) 1-terbutylamino-propylamine precipitates. Separated by filtration, wrung, washed with water and dried at constant weight.

The yield of pure product is 5.6 g. The 3-N (2,6-2 ', 6'-tetramethyldiphenylacetyl) 1-terbutylamino-propylamine melts at 144 °.

Example 2:

3-N [(2,6-2 ', 6'-tetramethyldìphenyl) acetyl] 1-isopropy laminosa propylamine and its hydrochloride.

By operating as in Example 1 starting from 3.8 g of N-iso-propylpropylenediamine and 8.6 g of 2,6-2 ', 6'-tetramethyldiphenylacetic acid chloride, 7.7 g are obtained. N [(2,6-2 ', 6'-tetra-methyldiphenyl) acetyl] 3-isopropylaminopropylamine which is purified by conversion to the hydrochloride. By recrystallization from acetonitrile, 5.5 g of N - [(2,6-2 ', 6'-tetra-methyldiphenyl) acetyl] 3-isopropylaminopropylamine hydrochloride, melting at 220-222 °, are obtained.

n / a Example 3:

3-N [(2,6-2 ', 6'-tetramethyldiphenyljacetyl] (2-phenylpropyl-

amino) propylamine and its hydrochloride.

By operating as in Example 1, starting from 8.6 g of 5S chloride of 2,6-2 ', 6'-tetramethyldiphenylacetic acid and of 5.75 g of N (2-phenylpropyl) propylenediamine, 13.9 g of N - [(2,6-2 ', 6'-tetramethyldiphenylacetyl] 1 - (2-phenylpropylamino) propylamine which is converted into its hydrochloride after crystallization of the ether, which melts at 220 °.

60 Example 4:

3-N [(2,6-2 ', 6'-tetramethyldiphenyl) acetyl} 1-ethylaminopropyl-

aminopropy lamin.

By operating as in Example 1, starting with 8.6 g of chloride 2, 6-2-2 ', 6'-tetramethyldiphenylacetic acid and 3.9 g of 3-ethyl-aminopropylamine, 7.7 g are obtained. of 3-N (2.6-2 ', 6'-tetramethyl-diphenyl) acetyl] l-ethylaminopropylamine which melts at 116 ° after recrystallization from cyclohexane.

5

620 906

Example 5:

In the same way, starting from bis (2,4-diterbutyl-6-isopropylphenyl) acetic acid and N-isopropylpropylenediamine, 3-N- [bis (2,4-diterbutyl 6-isopropylphenyl) acetyl] is obtained. -3-isopropylaminopropylamine. 5

Likewise, starting from ethyl 4,4-difluorodiphenylacetate and N-isopropylpropylenediamine, 3-N [4,4'-difluorodiphenylacetyl] 3-isopropylaminopropylamine is obtained.

Likewise, starting from (3 ', 5'-dichloro I0 2,2', 6 ', 4-tetramethoxy 4', 6-dimethyldiphenyl) acetic acid - obtained from 3'5'- dichloro 2,2 ', 6'-trihydroxy 4-methoxy 4', 6-dimethylbenzophenone described by M. Afzal et al. "J. Chem. Soc. ”, 1969 (section C) 1721 - and from N-terbutylpropylene diamine, 3-N [(3 ', 5'-dichloro 2,2', 6 ', 4-tetramethoxy 15 4', is obtained, 6-dimethyldiphenyl) acetyl] 1 -terbutylpropylenediamine.

Pharmacological study of the compounds of formula I.

1) toxicological study

The acute toxicity of the compounds was determined on batches of Rockland strain mice weighing approximately 20 g to which the test compound is administered in increasing doses by the intraperitoneal route or by the oral route in suspension in an aqueous solvent. After 8 days of observation during which the dead are counted, the average lethal dose is calculated graphically. 25

Depending on the product, the average lethal dose ranges from 50 to 100 mg intraperitoneally and between 500 mg and 1 g / kg by oral route.

2) search for neurological activity

Doses of 25 mg / kg intraperitoneally in mice lead to a slight decrease in motor skills.

Doses of 50 mg / kg lead to lower motor skills, then delayed mortality. These symptoms are mild and only appear in sublethal doses.

The compounds of formula I have no protective effect on convulsions caused by electroshock or cardiazol.

3) cardio-regulating action

The cardio-regulating activity was tested on batches of dogs anesthetized with 30 mg / kg of pentobarbital administered intravenously. The D2 lead electrocardiogram is recorded. Ouabain is then injected intravenously at a dose of 0.05 mg / kg. A new dose of 0.010 mg / kg is injected every 15 min until a stable ventricular tachycardia appears for at least 15 min. The average total dose necessary for the appearance of this tachycardia is generally of the order of 0.070 mg / kg.

The test substances are injected intravenously at variable doses depending on the batches of dogs, ranging from 0.5 to 5 mg / kg.

We can thus determine the dose of product studied which causes a definitive return to a normal sinus rhythm.

This dose is generally 2 mg / kg. For some products, it is even 1 mg / kg. The persistence of the effect varies according to the products and according to the doses from 10 to 90 minutes and more.

At the doses tested, the compounds of formula I have no effect on blood pressure.

R

Claims (2)

620 906 2 CLAIMS 1. Process for the preparation of the new compounds of formula: (I) acids, characterized in that a diaryl-acetic acid of formula II as defined in claim 1 or one of its functional derivatives is condensed with an ca-substituted propane amine of formula: R1NH-CH2-CH2-CH2Z (IV) in which Z represents a cleavable radical chosen from halogens, arylsulfonyloxy, alkylsulfonyloxy, trialcoyl-silyloxy and hydroxy radicals, to obtain a diarylacetamide of formula: X, X CO — N- -ch ^ -ch2— ch2 nh — r3 R 1 in which Xi and X3 represent, simultaneously or distinctly, a lower alkyl radical, a lower alkoxy radical, or a lower alkylthio radical, X2 and X4 represent, simultaneously or distinctly, a lower alkyl radical, A and B represent, simultaneously or distinctly, a halogen, a lower alkyl or a lower alkoxy, n and n 'have the value of zero, one, two or three and, when n is greater than or equal to 1, the residues Xi, X2, X3 and X4 may be hydrogen, Ri represents hydrogen or lower alkyl, R3 represents a lower alkyl, a lower alkenyl, a lower aryl-coyl or an alkyl substituted by a heterocycle having from 3 to 7 carbon atoms and optionally substituted, and their addition salts with acids, characterized in that l '' a diarylacetic acid of formula: in which the symbols have the meanings given above, and the compound obtained is reacted with an amino derivative of formula: R3NH2 (VI) In which R3 has the meaning given above. 4. Method according to claim 3, characterized in that one carries out the salification of the compounds obtained, of formula I, by the action of a mineral or organic acid. 30 (II) COOH in which the symbols have the meanings given above, or one of its functional derivatives, with a propane diamine of formula: The present invention relates to processes for the preparation of new nitrogen-substituted propylenediamines with a diarylacetic acid.