CA1212944A

CA1212944A - Phenyl-(3-aminopropyl)-ketone derivatives

Info

Publication number: CA1212944A
Application number: CA000439563A
Authority: CA
Inventors: Louis Lafon
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1982-10-26
Filing date: 1983-10-24
Publication date: 1986-10-21
Also published as: FR2534916A1; EP0110748A1; AU556589B2; DK489283D0; FR2534916B1; ATE26712T1; DK156003B; GR79617B; IE56129B1; DK489283A; AU2056883A; JPS5995283A; DK156003C; IE832488L; ES8406069A1; DE3371077D1; ES526736A0; EP0110748B1

Abstract

A B S T R A C T

The present invention relates to new phenyl-(3-amino-propyl)-ketone derivatives, namely (2, 4, 6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone and its addition salts.
The invention also relates to the method for preparing these new derivatives and to their use in therapeutics for the treatment of disorders of the cardiovascular system as vasodilator and bradycardia agents intraveniously and intraduodenially.

Description

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PHE~YL-(3-A~IINOPROPYL)-~ETONE DERIVATIVES

B~CKGROUND OF THE INVENTION

The present invention relates as industrial products to novel derivatives of phenyl-(3-aminopropyl)-ketone, namely (2,4,6-trimethGxyphenyl)-(3-hexamethylene-iminopropyl)-ketone and its addition salts. It relates also to the use in therapeutics and the process of preparing these novel products.
_ It is known that therz has already been described in the past a certain number of deri~atives of the (alkoxy-and hydroxy-phenyl)-(aminoalkyl)-ketone type. See for this purpose French Patents Nos. 1,492,256 and 5636M
and the article of A. BOUCHERLE et al., Chimie Therapeutique 3 (No ~), 256-259, (1968), on the one hand, British Patents No. 1,078,975 and No. 1,115,992, on the other hand, and finally USP No. 3,895,030, on the other hand.
It is known that the above-indicated derivatives of the (alkoxy- and hydroxy-phenyl)-(aminoalkyl~-ketone type have been presented as anti-inflammatory, antalgic, anti~yretic, antispasmodic, tranquilizing agents, peripheral vasodilators or bradycardiac agents.
- Finally it is known, particularly from French Patent ~o. 2 404 003 that there is no structur~-activity relationship within the family of (alkoxy- and hydroxy-phenyl)-(aminoalkyl)-ketones, the pharmacological effects being modified or disappearing according to the nature of the substituents of the pheDyl group, the nature o~
the amino group and ~inally the nature of the alkyl group present between the CO group and the amino group.

GENERAL DESCRIPTION OF THE INVENTION

It has just been found surprisiDgly that (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone, which is included in the family o~ the (alkoxyphenyl)-(3-aminopropyl)-~etones envisaged in the description 294~

of the aforesaid American Patent No. 3,39j,030, without being specifically exemplified, has, with its addition salts, pharmacological properties interesting in thera-peutics and not obvious taking into account the teaching S o~ the prior art.
In particular, it was not obvious from the teaching of American Patent No. 3,895,030 which describes particularly (i1 (2,4,~-trimethoxyphenyl)-(3-pyrrolidino-propyl~-ketone hydrochloride a product marketed under the name "FO~ZYLANE" [International Common Name : BUFLO~IEDIL
HYDROCHLORIDE) and having Code No. LL 16j6~ which is a reference peripheral vasodilator agent, and (ii) (2,4,6-trimethoxyphenyl)-(3-piperidinopropyl)-ketone hydrochloride [Code No. LL 1647~ which is essentially an antispasmodic l; agent, that (2,4,6-trimethoxyphenyl)-(3-hexamethylene-iminopropyl)-ketone hydrochloride ~Code No. CRL 41080 according to the invention is more ef~ective than LL 1656 as a vasodilator and bradycardiac agent, and deYoid o~
antispasmodic effect unlike LL 1647. In brief, there ?O is no structure-activity relRtionship when one passes from the pyrrolidino derivative to the piperidino derivative and then to the hexamethyleneimino derivati~e.
The novel derivatives of phenyl-(3-aminopropyl)-ketone according to the invention are characterized in 25 that they are selected from the group consisting of (i) (2,4,6-trimethoxyphenyl)-{3-hexamethylene-imino-propyl)-ketone which has the developed ~ormula ~C~l3 C~O- ~ -CO~tCH~)3-N 3 (1) ~l3 and, (ii~ its addition salts.
9y addition salts, is meant here, on the one 35 hand, the acid addition salts obtained by the reaction .

~ ) -of the free base of formula I with inorganic and organic acids, and, on the other hand, ammonium salts. Among the acids usable to salify the bass of formula I, may be mentioned particularly hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, suc-cinic, benzoic, cinnamic, mandelic, citric, malic, tartaric aspartic~ ~lutamic~ methanesul~onic, p-toluenesulfonic acids. Among the compounds enabling ammonium salts to be obtained, may be mentioned particularly ICH3 and ClCH3.
The acid addition salts are the preferred salts, (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride being particularly interesting therapeutic-ally.
The base of formula I may be prepared by a method known in itself by the application of conventional reaction mechanisms. The process which is recommended according to the invention comprises :
a) the reaction of hexamethyleneimine with 4-chloro-butyronitrile, then b) the reaction of 4-hexamethyleneimino-butyronitrile so obtained with 1,3,5-trimethoxybenzene in the presence of a flow of HCl gas at a temperature comprised between 5C and 0C for at least 2h in an anhydrous solvent (particularly selected rrom among the group consisting of benzene, toluene, chlorobenzene and their mixtures), then the -subjection of the ketimine derivative thus obtained to a hydrolysis reaction for at least O.Sh at the reflux temperature of the reaction medium.
Advantageously, the reaction of stage a) ~ill be carried out from 2 moles or hexamethyleneimine for 1 mole of 4-chlorobutyronitrile in the pre~ence of an aromatic hydrocarbon such as benzene or toluene, for at least 4h at the reflux temperature of the reaction medium; and the reaction or stage b) between 4-hexamethyl-eneimi`no-butyronitrile and 1,3,5-trimethoxybenzene will be carried out under stoichiometric conditions in chloro-:
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benzene, the ketimine derivative formed being then hydro-lyzed l~ithout being isolated.
(2,4,6-trimethoxyphenyl)-(3-hexamethyleneimino-propyl)-ketone and its salts are agents useful in the treatment of disorders of the cardiovascular ~ystem;
they act as vasodilator and brady~ardiac agents intraven-ously and intraduodenally. According to the invention, there is recommended a therapeutic composition which is characterized in that it comprises, in association with a physiologically acceptable excipient, at least one compound se~ected from among the group constituted by (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl~-ketone and its non-toxic additior salts. In such a composition, the actiYe ingredient takes part. of course, in a pharmaceutically effective amount.
Other advanta~es and features o~ the invention will be better understood on reading the description which follows (i) of an example of the preparation which i5 in no way limiting but given purely by way of illustra-tion, and (ii) results of pharmacological tests whichhave been carried out.

DESCRIPTIO~ OF PREFERRED EMBODIMENTS

PREPARATIO~
Preparation of (2~4~6-trimethoxyphen~])-(3~hexameth~1ene-____________________ _ ___________ _________________s_ _____ iminopropyl)-ketone hydrochlor~de (Code No. CRL 41 o80).
a) 4-He~amethyleneimino-butyronitrile ___________________________________ Into a solution under reflux of 50 g (~.505 mole) of hexamethyleneimine in 80 ml of ben~ene, are run in 15 min 26.1 g (0.252 mole) of 4-chlorobutyronitrile.
The reflux is continued 4h, the cold reaction medium taken up with diethyl ether, the precipitate removed by filtration and the filtrate taken to dryness. The residue so obtained was purified by distillation under reduced pressure to giYe 29.3 g (yield 70%) of 4-hexamethyl-eneimino-butyronitrile which is in the ~orm of a colorless .~

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s oil. BP6 7 m Hg = 126C (6-7 mm Hg corresponding approxi-mately to 800-933 p~scals).
b) CRL 4t 080 A current of dry HCl gaz is passed for 2.Sh between -5C and 0C into a solution of 16.8 g (0~10 mole) of 1,3,5-trimethoxybenzene and 16.6 g (0.10 mole) of 4-hexamethyleneimino-butyronitrile in solution in 115 ml of anhydrous chlorobenzene. The suspension is left in the cold between 0C and +4C overnight and the reaction medium is extracted with water. The aqueous phase is take~ to re~lux for lh3 it is made alkaline with concentrated sodium hydroxide and the precipitate extracted with diethyl ether to give 29.8 g of a pale yellow oil. This oil is treated in diethyl ether with hydrochloric ethanol. After puri~ication of the precipitate by crystallization in the mixture ethyl acetate-isopropanol (8:7)v/v, 19.5 ~tyield from stage b is obtained:~2.5~-, global yield: 38.75~o) of CRL 41 o80 in the form of a water-soluble white powder. MPinSt (Kofler~ = 150C.
Belo~Y are summarized the results of the pharmaco-logical tests which were undertaken with CRL 41 080.
I - VASODILATOR PROPERTIES OF CRL 41 o80 , A - EE~IORAL VASODILATOR ACTION INTRAVENOUSLY
Two dogs (average weight 12.4 kg) anesthetized with pentobarbital received CRL 41 o80 intravenously, in perfusion of 6 min, at successive doses of twice 1 mg/kg, then 2 and 4 mg/kg every 60 min. For comparison, these animals received at the end of the test a perfusion of 6 mg/kg I.V. of a known reference product, the aforesaid LL 1656.
It is observed that CRL 41 o80 does not modify the blood pressure nor the heart rate; the -femoral flow rate increases during the period of the perfusion from 1 mg/kg, the effect is reproducible and increases moderately with the dose. LL 1656, at the dose of 6 mg/kg, increases the femoral flow rate l0ss than 1 mg/kg of CRL 41 080.

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B - VA.~ODILATOR ACTION INTRADUODENALLY
_________________________._______ Four dogs (average weight 15.7 kg) anesthetized with nembutal received CRL 41 o80 intraduodenally, at the successive doses of 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg and 5 mg/kg; three of these dogs then received 10 mg/kg of CRL 41 OSO. The blood pressure, the heart rate, the femoral artery flol-~ rate~ the Yertebral artery flow rate, the rectal and skin temperatures were measured.
It was obserYed that CRL 41 o80 distinctly increased the femoral flow rate from the dose of 5 mg/kg;
this effect lasted more than one hour. In addition, it seems that the ~ertebral flow rate was reduced, but this effect was not statistically significant.
C - DURATION 0~ V~SODILATOR ACTION
______________________________ Three dogs (average weight 11.1 kg) received CRL 41 o80 intraduodenally at the dose of 5 mg/kg at two ti~es (period between the two administrations: 90 min~
then 6 mg/~g l.D. of LL 1656 and, 2 hours later, a further administration of 5 mg/kg I.D. of CRL 41 080.
It was observed that CRL 41 080 increased the femoral flow rate at 5 mg/kg I.D.3 this effect was a maximum at 30 min 3 lost hal~ its intensity at 60 ~in and disappeared at 120 min; the other parameters measured were not modified. A second administration of 5 mO/kg of CRL 41 o80 had a more intense effect on the fe~oral flow rate, the effect was a ma~imum at 30 min, then gradual-ly decreased, but was still present at 120 min. An adminis-tration of 6 mg/kg I.D. of LL 1656 resulted in an insrease in the femoral flow rate of average intensity, slow to develop and then the maximum of the effect was obtained at 120 min. This cinetics of action of LL 1656 intraduo-denally is not the usual cinetics (maximum of the effect at 30 or 60 min and gradual disappearance then of the latter); it may be thought that the prior administration of CRL 41 o80 modifi~s the action of LL 1656. An additional dose of S mg/kg I.D. of 41 080 does not further increase the femoral flow rate but results in a hypotension and , -: ~2~

and a bradycardia. In these dogs, the CRL 41 080 does not diminish the vertebral flow rate.
D - CO~CLUSI0~
__________ Results of the tests summarized above establish that CRL 41 080 is a peripheral vasodilator (particularly a femoral vasodilator) and a particularly interesting bradycardiac agent. CRL 41 o80 is more active as a ~aso-dilator than LL 1656, its pyrrolidino homolog, and does not have the antispasmodic properties of its piperidino homolo~.
II - CO~IPARATIVE TESTS
There are colleoted in Tables I and II below the results of the additional tests which were under-taken to compare the CRL 41 o80 sccording to the invention with its pyrroli~ino (LL 16~6) and piperidino (LL 1647) homologs described in USP No. 3,895,030 mentioned above.
Table I relates to the toxicity in the male mouse, on the one hand, and the minimum dose inducing in the anesthetized dog a distinct femoral vasodila~or effeet, on the other hand. The LD-50 I.V. was determined on batches of 10 male mice; the minimum vasodilator dose was determined on a batch of S dogs serving as controls with respect to themselves and each receiving a doae of the product to be tested every 2.5 hours.
Table II relates to the variations in the arte-rial blood pressures (systolic, diastolic, dif~erential and average~, the heart rate and the femoral artery blood flow. These Yariations were determined intravenously on the same aforementioned batch o~ 5 anesthetized dogs.
In the course of clinieal assays, good results in ~an were obtained by ad~inistering CRL 41 080 orally ~three capsules daily each containing 100 mg of aotive ingredient) and by injection (I~Vo route or I.M. route, one ~mpoule of 5 ml per day containing 40 mg of aotive principle in a physiological sallne ~olution).

~ 294~

TABLE I

minimum dose inducing Product LD-50 I.V. in the anesthetized mouse dog a Pemoral vaso-dilator effect I~Va I.D.
. . .
CRL 41 o80 (a) 96 + 3 mg/kg 1 mg/kg 5 ~g/~
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LL 1656 (b)(c) 60 + 2.2 mg/kg5 mg/kg 6 mglkg :.
LL ~6~47 (c) 68 + 4 mg/kg 5 mg/kg (d) , - . ~ . - .
Notes (a) product according to the invention (b) re~erence peripheral vasodilator -(c~ descri~ed in USP No. 3,895jO30 (d) no vasodilator effect I.D.
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Claims

The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:

1. A method for preparing (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone in which 4-hexamethyleneimino-butyronitrile is formed, its ketimine derivative is obtained by reaction with 1,3,5-trimenthoxybenzene, and said ketimine derivative is hydrolyzed, said method comprising a) reacting 2 mols of hexamethyleneimine with 1 mol of 4-chlorobutyronitrile, in the presence of an aromatic solvent selected from the group consisting of benzene and toluene, for at least 4h at the reflux temperature of the reaction medium, then b) reacting 1 mole of 4-hexamethyleneimino-butyronitrile thus obtained with 1 mol of 1,3,5-trimethoxybenzene in the presence of HC1 gas stream, at a temperature comprised between -5°C and 0°C, for at least 2h, in an anhydrous solvent selected from the group consisting of benzene, toluene, chlorobenzene and mixtures thereof, then hydrolyzing the corresponding ketimine derivative thus obtained for at least 0.5 h at the reflux temperature of the reaction medium.

2. (2,4,6-trimethoxyphenyl)-(3-hexmethylenimino-propyl)-ketone when produced by the method of claim 1, and addition salts thereof.

3. A pharmaceutically effective amount of a phenyl-(3-aminopropyl)-ketone derivative which is selected from the group consisting of the (2,4,6-trimethoxyphenyl)-(3-hexamethylene-iminopropyl)-ketone and its non-toxic addition salts when produced by the method of claim 1.

4 A method for preparing (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride comprising a) reacting 2 mols of hexamethyleneimine with 1 mol of 4-chlorobutyronitrile, in the presence of an aromatic solvent selected from the group consisting of benzene and toluene, for at least 4h at the reflux temperature of the reaction medium, then b) reacting 1 mole of 4-hexamethyleneimino-butryronitrile thus obtained with 1 mol of 1,3,5-trimethoxybenzene in the presence of HC1 gas stream, at a temperature comprised between -5°C and 0°C, for at least 2h, in an anhydrous solvent selected from the group consisting of benzene, toluene, chlorobenzene and mixtures thereof, then hydrolyzing the corresponding ketimine derivative thus obtained for at least 0.5h at the reflux temperature of the reaction medium, and then c) reacting the product of step b) with hydrochloric acid.

5. (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride when produced by the method of claim 4.

6. A pharmaceutically effective amount (2,4,5-trimethoxy-phenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride when produced by the method of claim 4.