LU85246A1 - 2- (AMINOALKYL) ACRYLOPHENONES, THEIR PREPARATION AND THEIR USE - Google Patents

Description

r to V.370186 - DB 33925 2.4845

C 0/1 ^ GRAND-DUCHY OF LUXEMBOURG

3 £ 1 \) of 1.3 jnars 1984. Minister for the Economy and the Middle Classes

Title issued: ........................................ Intellectual Property Service

”MPc | F LUXEMBOURG

Breyet's request for invention I. Request

The ..... society ..... dit.:......SAR,L,.....GALEP.HAR., Industrial zone A ^ rue (1) • du · Mont-de —Templemars, .....- 59139 ..... Noelles les See-fiir * · ...... France ·; · ...... repréeei ..par. Maître Alain ..... RliKAVlNA, lawyer ..... in Luxembourg, ...... lia, boubev-arcK2) -Joseph ...... I l · ·, ...... acting ..... in ..... quality ·· of •• mandata ir-ey ............................ .................................................. ......

deposit (s) this ........... thirteen •• fnans — lÇOO -four — twenty — four ...................... ......... (3) at ....... 15.,. 0.0 .... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning:; · ................................................. .................................................. .........................................-........ ............................. — .................... ...................: .............................. .......: ........ (4) ... "2. =. (. Am i noa lkyl) ..... acr y lophenones, ....... l eur "preparation and ...... their .................................-; .......use"......................................... .................................................. .................................................. .................................................. .....................................

2. the delegation of power, dated -Water foo-, · ...... BefgiqJê 12 • March ..... 1-98-4 -.— 3. description in language ...... .Fr an it is ............................. of the invention in two copies; 4 .......... y.y .............. drawing boards, in two copies; 5. the receipt of the taxes paid to the Registration Office in Luxembourg, 13 nilecfare (nt ^ assuming responsibility for this declaration, that the inventor (s) is (are): ____________________________________________________________________..... .................................................. .................................................. .................................................. ............................. (5) ------------------ ---------------------------------------------------------- --------. see — ei — against .................................... .................................................. ......................................

claims (s) for the above patent application the priority of one (s) application (s) of ______________________________________ yy ._____________________________________________________________________________________________________________ JL ------------------------ ---------------------------------------------------------- --------- (8) in the name of __________________________, y..y .___________________________________________________________________________________________________________________________________________________________________________________________________ (9) elect (elect) for him / her and, if appointed, for his / her proxy, in Luxembourg_____________________________

Ha, boulèvarcî Joseph ΓΠ ............................ ................. ................ ~ ^ requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, - with postponement of this grant to _______ ,, .......... r______________________________months. (11) ^ eighteen ------------------------------ W ÏL · '' H. Deposit Report

The above said patent application has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, dated: / ii y & ma ç 1ή £ οΑ f + *** '5ΡΡ ^ ··· \ | Pr-1 | Minister at hours (^ \ “Jde l'Economie etfees Classes Moyennes, 15.00 ^ j ^ d ^ / 3.yi5 **) Brief Description filed in support of a PATENT INVENTION application in the name of: J La public limited company known as: "GALEPHAR SARL M for: H2- (aminoalkyl) acrylophenoneS, their preparation and their use"

Inventors: Micheline CAZIN Isabelle LESIEUR Daniel LESIEUR Charles LESPAGNOL André DELACOURTE Philippe BAUDIER André BIANCHI

// "-2-

The 2- (aminoalkyl) acrylophenones of the present invention can be present either in the form of the base or in the form of pharmaceutically acceptable salts such as hydrochlorides, hydrobromides, sulfates or salts of organic acids.

The acrylophenones of the present invention are endowed with remarkable therapeutic activities * and have excellent anti-cancer, antiparasitic, antimicrobial, antifungal, hypolipidemic, cholesterol-lowering and anti-aggregating platelet properties.

Two processes for the preparation of the 2- (aminoalkyl) acrylophenone of the present invention have been described below.

Method I: Allows obtaining 2- (aminomethyl) acrylophenone (m = 1) The process consists in reacting an amine of type (11) under! basic or hydrochloride form, formaldehyde and an acetophenone (111) suitably substituted in acetic acid medium. After heating at reflux for a few hours, the reaction mixture is evaporated to dryness and the 2- (aminomethyl) acrylophenone is recrystallized from an appropriate solvent (scheme I).

i R (n> Â? A '

C - CH3 + CH20 + HN

^ B.

(III) (II)

R (n4ÖM

C - C - CH2 - N

B

CH2

Diagram I

/ 7 -1- ί j The present invention relates to new derivatives of 2-acrylophenone, i j their pharmaceutically acceptable salts, their preparation process | as well as the medicines that contain them.

The compounds of the present invention correspond to the general formula (I) i --fein - C - (CH2) m - (I); . There CH2 in which. A and B may or may not be identical and denote a hydrogen atom, a lower alkyl radical, a substituted or unsubstituted phenyl radical, or with the nitrogen atom to which they are linked, a heterocyclic radical such as a radical morpholino, piperazyle, 4-mithylpiperazyle, piperidino, substituted or unsubstituted pyridino.

. the symbols R, which may be the same or different, denote hydrogen, a halogen, a lower alkyl group, a lower alkyl group substituted by 1 to 3 identical or different halogen atoms, a carboxylic, sulfonic acid or an ester of these acids, a substituted or unsubstituted amide, a nitro, hydroxy, lower alkyl ether group such as methoxy, ethoxy, n- or isopropyloxy, a substituted or unsubstituted phenyl or phenoxy group n is the number 1, 2, 3 m is the number 1, 2, 3, 4, 5.

AT

U

1 r "-3-

Method II: allows 2- (aminoalkyl) acrylophenone of general formula (I) to be obtained

The process consists in reacting an aminoalkylphenone (IV) with formaldehyde in acetic acid medium. After bringing the reaction mixture to reflux for a few hours, the solvent is evaporated under vacuum and the 2- (aminoalkyl) acrylophenone is recrystallized from an appropriate solvent (scheme II).

r (n) -C \ l 0 A

- CH2 - (CH2) m - H CL + CH2 ° ^ "B. - (IV) CH2

C- C - (CH2) m- N

II

0 B.

Diagram II

The products of this invention can be administered parenterally, topically or perorally and can be mixed as desired with diluents, solvents, suspending agents, excipients, adhesives, colorants or flavorings for preparing convenient dosage forms.

The examples below are intended to illustrate the preparation of the compounds of the present invention and cannot in any way limit it.

r / ί -4- "

Example 1 2- (4-methyl-1-piperazinylmethyl) acrylophenone dihydrochloride 3 g (0.1 M) of trioxymethylene and 8.65 g (0.05 M) of N-methylpiperazine di hydrochloride are added to 6 g of acetophenone in 20 ml of acetic acid. The mixture is heated at reflux for 3 h. The solvent is removed and the oily yellow residue is dissolved in 50 ml of ethanol.

After removal of the solvent, the residue crystallizes from methanol. 9.5 g of the title product were obtained having the melting point: 231-233 ° C and the characteristics of which are white crystalline powder, very soluble in water, sparingly soluble in alcohol and practically insoluble in l 'acetone.

Elementary analysis s C% H% N% 0% Cl% calculated: 56.79 6.99 8.83 5.04 22.35 found s 56.67 6.92 8.68 5.28 22.04

Example 2 2- (4-mithyl-1-piperazinylmethyl) acrylophenone dichlorhydrate "

Proceeding in the same manner as in Example 1, but starting from 0.05 mole (15.26 g) of 3- (N-iaethyl-piperazinyl) -propiophenone hydrochloride and 0.05 mole (1.5 g ) of formaldehyde in the form of trioxymethylene, 7.9 g of title product were obtained having the melting point: 232 ° C. and in all respects identical to the product of Example 1.

"- -5-

T

By proceeding as in Example 1 or 2, the following products were obtained: b

- 2- (4-methyl — piperazinylmethyl) -acrylophenone dihydrochloride recrystallization solvent: methanol, melting point 231-233 ° C

- 2 (1-morpholinomethyl) -acrylophenone hydrochloride recrystallization solvent: isopropanol / melting point 182-184 ° C.

- 2 (N, N-dimethylaminomethyl) -acrylophenone hydrochloride

recrystallization solvent: acetone, melting point: 158-160 ° C

- 2 (4-methyl-1 -piperazinylmethyl) -p-chloroacrylophenone dihydrochloride

recrystallization solvent s isopropanol, melting point s 215-220 ° C

'ii S - 2- (1-morpholinomethyl) -p-chloroacrylophenone hydrochloride

recrystallization solvent: acetonitrile, melting point: 201-207 ° C

- 2- (N, N-dimethylaminomethyl) -p-chloroacrylophenone hydrochloride

^^ B recrystallization solvent: dioxane, melting point: 176-179 ° C

- 2 (4-methyl-1 -piperazinylmethyl) -p-methoxyacrylophenone hydrochloride

^^^ B recrystallization solvent t ethanol, melting point: 214-224 ° C

- 2- (1-morpholinomethyl) -p-methoxyacrylophenone hydrochloride

recrystallization solvent: isopropanol, melting point: 180-181 ° C

- 2 (N, N-dimethylaminomethyl) -p-methoxyacrylophenone hydrochloride

^^ B recrystallization solvent: dioxane, melting point: 149-153 ° C

- 2 (1-morpholinomethyl) -3 / 4, 5-trimethoxyacrylophenone hydrochloride recrystallization solvent: isopropanol, melting point: 173-177 ° C

^^^ B - 2 (1-morpholinomethyl) -2,3,4-trimethoxyacrylophenone hydrochloride

recrystallization solvent: isopropanol, melting point: 170-175 ° C

// //. . .y.jiT Wi "% -6-

The derivatives of the present invention exhibit remarkable hypoglycemic and cholesterol-lowering activities and can therefore find applications in human medicine.

| This property was demonstrated in the rat using the method using the newt WR 1339 as an inducer of hyperlipemia.

Four hours after the I.V. injection into the rats of 175 mg of Triton WR 1339 per kg of body weight, they are injected intraperitoneally with either physiological saline (controls) or the substance to be studied. The rats are sacrificed 24 hours after injection of the triton WR 1339 and the plasmas collected for the assays (results: Table I) of the triglycerides and the cholesterol.

Table I (see next page)

These results show a decrease in triglyceridemia from 36.5% to 47% and in cholesterolemia from 48% to 57.5%.

The anti-platelet aggregating properties of the acrylophenones of the present invention have been demonstrated by means of adenosine triphosphate chosen as an agent inducing platelet aggregation.

The effective doses reducing the aggregation of platelets by 50% (D.E.50) have been determined (Table 2). These results show that the substances act at doses of the micromolar order.

Table 2

Anti-aggregating activity in platelets (D.E.50)

Acrylophenone ED50 mole / l 2 (4-methyl-1-piperazinylmethyl) acrylophenone hydrochloride 2,323.10-6 2 (1-morpholinomethyl) acrylophenone hydrochloride 1,939.10-6 2 (K, N-dimethylaminomethyl) acrylophenone hydrochloride 1,130.10-6 r -7- i -1; -ο — i --- 1 II 0) -hiiii ο giii GI MD ii IIG 'HI!

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Claims (17)

1. As a new industrial product, the 2-acrylophenones corresponding to the formula (I) R (n) -i + -)] O CH2 A ^ X \ l! H c - C - (CH2) m - N (I) VNSs> B 3ê in which. A and B can be identical or not and denote a hydrogen atom, a lower alkyl radical, a substituted or unsubstituted phenyl radical, or with the nitrogen atom to which they are linked, a heterocyclic radical such as a morpholino radical , piperazyle, 4-methylpipirazyle, piperidino, pyridino substituted or not * • the symbols R, which can be identical or different indicate hydrogen, halogen, a lower alkyl group, a lower alkyl group substituted by 1 to 3 atoms of identical or different halogens, a carboxylic, sulfonic acid or an ester of these acids, a substituted or unsubstituted amide, a nitro, hydroxy, lower alkyl ether group such as methoxy, ethoxy, n- or isopropyloxy, a group phenyl or substituted or unsubstituted phenoxy n is the number 1,2,3 a »m is the number 1,2,3,4,5. 2. 2 (1-morpholinomethyl) -acrylophenone 3 * La 2 (N, N-dimethylaminomethyl) -acrylophenone 4. La 2 (4-methyl-1 -piperazinylmethyl} -p-chloroacrylophenone 5. 2- {1 * -morpholinomethyl) -p-chloroacrylophenone /// -9- c 6. 2- (N, N-dimethylaminomethyl) -p-chloroacrylophenone 7. 2- (4-methyl-1-piperazinylmethyl) -p-methoxyacrylophenone 8. 2- {1-morpholinomethyl) -p-methoxyacrylophenone 9. 2- {N, N-dimethylaminomethyl) -p-methoxyacrylophenone " 10. 2- (1-morpholinomethyl) -3,4,5-trimethoxyacrylophenone 11. 2- (1-morpholinomethyl) -2,3,4-trimethoxyacrylophenone 12. 2- (4-inethyl-1 -piperazinylmethyl) acrylophenone 13. The non-toxic, pharmaceutically acceptable salts of the compounds according to any one of claims 1 to 12. 14. The acid salts of the compounds according to any one of claims 1 to 13 such as the hydrochlorides, hydrobromides, iodhydrates, sulfates or carboxylates. 15. Process for the preparation of the 2 acrylophenones according to any one of claims 1 to 14, characterized in that an amine of type A-NH-B is reacted. in the form of a base or a salt with an acetophenone of type ", (II) in the presence of formaldehyde in an acetic acid medium, the values of the symbols A, B, R, n are as defined in claim 1. Rin, Ê) k '(II) XC -CH3. 16. Process for the preparation of the 2 acrylophenones according to any one of claims 1 to 14, characterized in that formaldehyde is reacted with an aminoalkylphenone of type (III) in the form of the base or of salt in acetic acid medium, the values of A, B, R, n, m are as defined in claim 1. R (n) ^ If A - (CH2) m- N CT (HD ^ B. r * /// / "-10- 17. Pharmaceutical composition comprising, as active product, at least one acrylophenone according to any one of claims 1 to 14, combined with at least one suitable excipient and / or at least one other therapeutic agent. * Drawings: _______ / L. plates M pages of which ........ A ...... cover page ........ Ίτ ... description pages. at . r r ··; vs claim - / r - 'description Luxembourg b 13 j-CRS 1984 The representative: Me Alain Ru / Ærd, wc / jmm ^ 1 V t