IE52871B1

IE52871B1 - (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its acid addition salts, use thereof in therapeutics and method for preparing same

Info

Publication number: IE52871B1
Application number: IE742/82A
Authority: IE
Original assignee: Lafon Labor
Priority date: 1981-04-15
Filing date: 1982-03-29
Publication date: 1988-03-30
Also published as: ES8304105A1; DK156002B; EP0063075B1; JPH039112B2; GR75918B; ATE8258T1; DK167782A; EP0063075A1; JPS57181073A; FR2504136A1; ES511431A0; DK156002C; DE3260320D1; CA1183853A; IE820742L; FR2504136B1

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE New derivative belonging to the family of (alkoxy and hydroxy-phenyl)-(3-aminopropyl) ketones, characterized in that it is selected from the group constituted by (i) the (2,6-dimethoxy-4-hydroxyphenyl)- (3-piperidinopropyl)-ketone of formula : (I) see diagramm : EP0063075,P8,F3 and (ii) its addition salts. 1. Claim for the Contracting State : AT Process for the preparation of the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone of developed formula : (I) see diagramm : EP0063075,P9,F2 and its addition salts, characterized in that 1,5-dimethoxy-3-hydroxybenzene of the formula (II) see diagramm : EP0063075,P9,F3 is stoichiometrically reacted with piperidinobutyronitrile of the formula (III) see diagramm : EP0063075,P9,F4 in the presence of AlCl3 and by passing through the reaction medium a HCl gas stream for at least 2 hours, at 10-20 degrees C, then hydrolyzing the ketimine derivative thus formed and which corresponds to the formula (IV) see diagramm : EP0063075,P9,F5

Description

The present invention relates to the (2—6— dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone belonging to the family of the (alkoxy- and hydroxyphenyl) -(3-aminopropyl) -ketones, and to its addition salts It also relates to the use thereof in therapeutics and to their method of preparation.

It is known that a certain number of compounds of the (alkoxy- and hydroxy-phenyl)-.(aminoalkyl)- . ketone type has already been described and proposed in therapeutics in the past. In particular, - French Patent No. 1 492 256, French Patent (BSM) No. 5636M and the article by A. BOOCHERLE et al., Chimie Therapeutigue, 2 (No.4), 256-259 (1968), disclose the (2,4,6-trimethoxyphenyl)-(2-piperidinoethyl)-ketone and (2,4,6-trimethoxyphenyl)-/7-(4-methylpiperidino)ethyl/-ketone, which present essentially anti-inflammatory, antalgic and antipyretic effects? - British Patent No. 1 115 992 discloses the (2,4— dimethoxyphenyl)-(piperidinomethyl)-ketone and (2,4,6trimethoxyphenyl-/—(4-methylpiperidino)-methyl7-ketone, which present essentially antispasmodic and tranquillizing effects? and - British Patent No. 1 325 192 discloses the hydrochloride of (2,4, 6-trihydroxyphenyl)-(3-piperidinopropyl) -ketone (Code No. LL 1647) , which presents essentially antispasmodic effects and which is useful in the treatment of renal colics, and the hydrochloride of (2,4,6-trimethoxyphenyl)-(3-pyrrolidinopropyl)-ketone (Code No. LL 1656), which is a reference peripheral vasodilator agent, which has formed the subject matter of a publication by DEBRAY et al., Therapie, 30, 259266 (1975) and which is marketed in pharmacy under the name of FONZYLANE (Common International Name: HYDROCHLORIDE OF BUFLOMEDIL).

Finally, French Patent No. 2404003 discloses that the replacement of one or more OCHg groups of the LL 1656 mentioned above, by one or more OH groups has unforeseeable consequences as far as the possible peripheral vasodilator properties of the resulting products are concerned. In fact, French Patent No. 2404003 shows that there is no structure-activity relationship in said OCHg/OH replacements while the (2,4,6- trihydroxyphenyl- (3-pyrrolidinopropyl)-ketone and (2, 4-dimethoxy-6-hydroxyphenyl)-(3-pyrrolidinopropyl)ketone are peripheral vasodilator agents as advantageous as the LL 1656, on the contrary, the (2,6-dihydroxy4-methoxyphenyl)- or (2,4-dihydroxy-6-methoxyphenyl)(3-pyrrolidinopropyl)-ketone derivative and the (2,6dimethoxy-4-hydroxyphenyl) - (3-pyrrolidinopropyl)ketone derivative have no peripheral vasodilator effects.

It has been unexpectedly found that the (2,6dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts are, as peripheral vasodilator agents, (i) more efficient than the similar products of the piperidino type and (ii) at least as advantageous as the LL 1656 mentioned above.

According to the invention there is provided a derivative belonging to the family of the (alkoxyand hydroxy-phenyl)-(3-aminopropyl)-ketones which is selected from (i) the (2,6-dimethoxy-4-hydroxyphenyl)-(3piperidino-propyl)-ketone of formula: and (ii) its addition salts.

Addition salts are understood here to mean S3871 the acid addition salts (obtained by reaction of the free base of formula (I) with a mineral or organic acid) and the ammonium salts. Among the acids which may be used for salifying the base of formula (I), particular mention may be made of hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, lactic, malic, tartaric, aspartic, p-toluenesulfonic and methanesulfonic acids. Among the compounds enabling ammonium salts to be obtained, particular mention may be made of ICHg and ClCHg. The acid addition salts are generally preferred to the ammonium salts.

The preferred product according to the invention is the hydrochloride of (2,6-dlmethoxy-4-hydroxy15 phenyl)-(3-piperidinopropyl)-ketone.

The free base of formula (I) may be prepared according to a method, knovzn per se, by application of conventional reaction mechanisms. The method according to the invention consists in stoichiometrical20 ly reacting the l,5-dimethoxy-3-hydroxy-benzene of formula: HO '/ \\ OCH(II) OCH, with the piperidinobutyronitrile of formula: NC-(CH2)3-N in the presence of AlClg, passing a HC1 gas stream through the reaction medium for at least 2 hours at a temperature of 10-20°C and then hydrolyzing the ketimine derivative thus formed and which corresponds to the formula: (III) 53871 OCH HO c(=nh)-(ch2)3-n (IV) to obtain the compound of formula (I).

In this method, the reaction of II with III is advantageously carried out in chlorobenzene, using 1 mole of II, 1 mole of III and 1 mole of AlClg. It is not necessary to isolate the ketimine derivative IV: hydrolysis thereof is effected directly in the reaction medium resulting from the reaction of II with III by introducing ice into said reaction medium. The resultant aqueous phase is collected by decantation, then subjected to boiling for at least 30 mins. in the presence of carbon black.

According to the invention, a therapeutic composition is also provided, which is particularly useful in the treatment of vascular diseases, in particular the treatment of eschars, and which contains, in association with a physiologically acceptable excipient, the free base of formula (I) or one of its non-toxic addition salts. Of course, such a therapeutic composition will include a pharmaceutically effective amount of the peripheral vasodilator-active ingredient.

Other advantages and characteristics of the invention will be more readily understood on reading the following Examples of preparation given solely by way of non-limiting illustration.

Preparation I Preparation of the hydrochloride of (2,6-dimethoxy-4hydroxyphenyl)-(3-piperidinopropyl)-ketone (Example 1; Code No. CRL 40746) .8 g (0.2 mole) of 1,5-dimethoxy-3-hydroxybenzene, 34 g (0.2 mole) of piperidinobutyronitrile and 200 ml of chlorobenzene are introduced into a threenecked flask provided with stirring means; 28 g (0.2 mole) of aluminium chloride are then added slowly, then, maintaining the temperature between 14 and 20°C, an anhydrous HCl gas stream is passed through the resultant reaction medium, with stirring, for 4.25 hrs. It is left to stand at 4°C for 20 hours then thrown on ice (to hydrolyze the ketimine hydrochloride which has formed) and the lower aqueous phase is decanted and boiled in the presence of CXA black for 1 hour. It is filtered hot and the mother liquor is cooled. A crystallized product and an oil are obtained. (After isolation and treatment, the oil will give the CRL 40747 (cf. Preparation II hereinbelow).) The crystallized product is filtered, washed on the filter with ice water to free it of the oil which accompanies it. By recrystallization in water, a crystallized hydrate is obtained, yellow in colour, which, after trituration in ethanol, gives 21 g (yield 31%) of CRL 40746 in the form of a white crystalline powder, soluble in water. Inst.m.p.=214-215°C (with decomposi25 tion).

Preparation II Preparation of the hydrochloride of (2,4-dimethoxy-6hydroxyphenyl)-(3-piperidinopropyl)-ketone' ocfl h3co co-(ch2)3-n • HCl OH (conparative Ex.CPl,Code No.CRL 40747) The oil which decants in Preparation I hereinabove, after hydrolysis of the kotimine hydrochloride IV and then boiling of the aqueous phase in the presence of carbon black, is extracted with chloroform.

The chloroform phase is dried over NagSO^ in the presence of carbon black. The solvent is evaporated and a rough powder , yellow in colour, is obtained, which is recrystallized from the isopropanol-water mixture (100:2) v/v. 18.2 g (yield 26.6%) of CRL 40 747 is obtained, in the form of a crystalline powder, pale cream in colour, very soluble in water. Inst.m.p.=181-183°C (with decomposition) .

Part of the results of the tests undertaken on animals have been summarized hereinafter, and more par15 ticularly those of the comparative tests relative to the products mentioned in Table I hereinafter, namely CRL 40 746 (Example 1), its structural analogues (CP1-CP6) and a reference peripheral vasodilator product which is LL 1656 (CP7) mentioned above.

The peripheral vasodilator properties were studied in the male dog anaesthetized with nembutal (6 animals per dose and per product). The products to be compared are administered in solution in physiological serum in a volume of 6 ml/animal by the intravenous route (perfusion of 1 ml/min) and in a volume of 10 ml/ animal by the intraduodenal route. With respect to the controls (the same animals receiving only the physiological serum), three parameters are measured: the average arterial pressure (expressed in ram Hg; 1 mm Hg corresponds to 1.333224 x 10 Pa), the cardiac frequency (expressed in beats/minute) and the flow rate of the femoral artery (expressed in ml/min). The variations of these parameters expressed in percentages, with respect to the controls ,are given in Tables II (intravenous administration) and III (intraduodenal administration) hereinafter.

Peripheral vasodilation is represented under these circumstances by an increase in the flow rate of the femoral artery. According to the present conditions of operation, a product is said to be a peripheral vasodilator agent if the flow rate of the femoral artery increases by at least 30% by intravenous administration, on the one hand, and by intraduodenal adminstration on the other hand, without the variation in the arterial pressure being greater than +10% or less than -10%.

The results of Tables II and III hereinafter demonstrate the interest of CRL 40746 as peripheral vasodilator. In fact, this product is, on the one hand, as active as the reference product CP7 (LL 1656) and, on the other hand, more effective than its analogues of the piperidino type such as, in particular, its isomer CPI (CRL 40747) and its homologue CP2 (LL 1647) which presents a trihydroxylated phenyl group.

More precisely, the CRL 40746 according to the invention, administered by I.V route and by I.D. route increases the flow rate of the femoral artery (variation always greater than +30%), whilst its isomer CPI is (i) very weakly vasodilatory by the I.V. route (variation always less than + 30%, but of the order of +20 to +22%) and (ii) has hardly any vasodilator effect by the I.D. route (it has, rathermore, an antihypertensive effect as it reduces the arterial pressure by more than 10%), and its trihydroxylated homologue CP2 which is vasodilatory by the I.V. route (from the dose of 5 mg/kg as indicated in British Patent No. 1 325 192 mentioned above), has virtually no vasodilator effect by the I.D. route (variation of the flow rate of the fanoral artery by I.D. route of +17% with antihypertensive effect).

In clinical trials, the CRL 40746 has given good results in human beings in the treatment of eschars. 53871 < o c T3 •H M Cl O. H Q, 0 o c β ·«« Ή T3 -3 Ή ·* u b *J J G- fl. Ο Ο Ο ·Η Ο ·Η e e e a. e o· •►4 ·ι-1 >r4 r>4 F*C Ό Ό Ό >» Ό 5> •Η Ή ·Κ Λ ,p* £ Μ U M u M U ς) O CJ QJ Cl 0) Cu o. ο. B a. £ Ή pyrrolidino e fO Μ Π Ο Ν H r4 CO CO « ^co υ o co cO cn g 3 § S 53 S © o o CO 5 o CN (4 32 O fO co co co co g S g g S g o o o o o r*i & cn as υ o co CO <0 co CO g 8 g δ g g o o o o © ¢0 s o Code No. o r> O NT Is r* «0 m o fH J J Product r-i Z-\ r*. Λ *-> **» Π J3 U U O’ Ό ' 5S SO %> (X 04 04 04 04 St ο ο u o q a S’ r-. 04 a <0 CO kO in CD ci in cn Ox 04 O' ~ σ» 04 m οί ν' CN M* — co — i—i <8 table_I I Variation of the parameters after intravenous administration in the anaesthetized dog Product Code No. Dose mg/kg Variations in 7. Arterial pressure Flow rate of fsroral artery Cardiac frequency Example 1 CRL 40746 1.5 + 2 + 34 + 2 CPI CRL 40747 1.5 + 2 + 20 + 5 CP2 LL 1647 1.5 + 1 + 10 - 2 CP3 - 1,5 + 3 + 8 - 1 CP4 - 1,5 _ 2 + 3 - 2 CP5 - 1,5 - 1 - 5 + 1 CP6 - 1.5 + 1 + 7 + 3 CP7 LL 1656 1,5 0 + 33 + 5 Example 1 CRL 40746 3 + 5 + 35 + 3 CPI CRL 40747 3 - 12 + 22 - 2 CP2 LL 1647 3 + 1 + 18 + 3 CP3 - 3 - 2 + 8 - 6 CPA - 3 - 5 + 2 + 1 CP5 3 - 8 - 8 . + 3 CP6 - 3 - 1 + 5 - 2 CP7 LL 1656 3 - 2 + 36 + 6 Example 1 CRL 40746 6 + 5 + 41 + 3 CPI CRL 40747 6 - 18 + -22 - 15 CP2 LL 1647 6 + 2 + 34 + 3 CP3 - 6 + 5 + 3 - 1 CP4 - 6 + 1 + 2 - 1 CP5 - 6 - 2 - 3 + 2 CP6 - 6 - 8 + 2 + 1 CP7 LL 1656 6 - 2 + 39 0 TABLE_III Variation of the parameters after intraduodenal administration in the anaesthetized dog Product Code No. Dose mg/kg Variations in 7. Arterial pressure Flow rate of femoral artery Cardiac frequency Ex-uiiple 1 CRL 40746 20 . 2 + 83 - 5 CPi CRL 40747 20 - 15 + 10 - 2 CP2 LL 1647 20 - 12 + 17 - 1 CP3 - 20 - 8 - 5 - 2 CPA - 20 - i - 2 + 3 CP5 - 20 0 +' 2 + 1 CP6 - 20 + 6 + 1 + 4 CP7 LL 1656 20 - 4 + 84 + 5 S2871

Claims

1. 12,6-Dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)ketone of formulaί 5 or an addition salt thereof,

2. (2,6-Dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)ketone hydrochloride.

3. A method for preparing (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone which comprises stoi- with piperidinobutyronitrile of the formula NC - (CH 2 ) 3 - N (III) 15 in the presence of AlCl^, passing through the reaction medium a HCl gas stream for at least 2 hours at 10-20°C and then hydrolyzing the ketimine derivative thus formed and which corresponds to the formula 5*871 C(=NH) - (CH 2 ) 3 - (IV)

4. A therapeutic composition comprising, in association with a physiologically acceptable excipient, an active ingredient selected from (2,6-dimethoxy-4-hydroxyphenyl)5 (3-piperidinopropyl)-ketone and its addition salts.

5. A compound as claimed in Claim 1 or 2 or a therapeutic composition as claimed in Claim 4 for use as a peripheral vasodilator.

6. (2,6-Dimethoxy-4-hydroxyphenyl)- (piperidinopropyl)10 ketone of the formula I given in Claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified.

7. A method for preparing (2,6-dimethoxy-4-hydroxyphenyl)(3-piperidinopropyl)-ketone of the formula I given in 15 Claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified.

8. (2,6-Dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)ketone of the formula I given in Claim 1 or an addition salt thereof, whenever prepared by a method claimed in a 20 preceding claim.

9. A therapeutic composition according to Claim 4 substantially as hereinbefore described.