CA1183853A

CA1183853A - (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)- keton and its acid salts, use thereof in therapeutics and method for preparing same

Info

Publication number: CA1183853A
Application number: CA000400489A
Authority: CA
Inventors: Louis Lafon
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1981-04-15
Filing date: 1982-04-05
Publication date: 1985-03-12
Also published as: EP0063075B1; JPS57181073A; DK156002C; DK156002B; JPH039112B2; ATE8258T1; IE52871B1; ES8304105A1; IE820742L; DK167782A; GR75918B; FR2504136A1; DE3260320D1; ES511431A0; FR2504136B1; EP0063075A1

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates, as new indus-trial products, to the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts.
These products are useful in therapeutics as peripheral vasodilator agents, particularly in the treatment of eschars.

Description

~3~1~3 The present inven-tion relates, as new indus-trial products belon~in~ to the f~nily of the (alkoxy~
and hydroxy--phenyl)-(3-~ninopropyl-ketones, to the (2,6-dimethoxy-4-hydroxy-phenyl)-~3-piperidinopropyl)-ketone and to its addition salts~ It also relates tothe use thereof in therapeutics and to their method for preparation.
It is known that a certain number of com-pounds of the (alkoxy- and hydroxy phenyl)~(aminoalkyl)-10 ketone type has already been described and proposed intherapeutics in the past. In particular, - Freneh Patent No. l 492 256, French Patent (BSM) No.
5636~ and the article by ~. BOUCHERLE et al, Chimie ~ peutique, _ (No.4), 255-259 (1968), disclose the ~2,4,6-trimethoxyphenyl)-(2-piperidinoethyl)-ketone and (2~4,6-trimethoxyphenyl)-~2-(4-methylpiperidino)-ethyl/-ketone, whlch present essentially anti-inflam-matory, antalgic and antipyretic effects;
- British Patent No. 1 115 992 discloses the (2,4-20 dimethoxyphenyl~--(piperidinomethy].)-ketone and ~2,4,6-trimethoxyphenyl-/ (4-methylpiperidino)-methyl7-ketone, which present essentially antispasmodic and tranquilli-zing ef~ects; and - British Patent No. 1 325 192 discloses the hydro-chloride o~ (2,4-6-trihydroxyphenyl)-(3-piperidino-propyl)-ketone (Code No. LL 1647~ , which presents essentially antispasmodic effects and which is useful in the treatment of renal colics, and the hydrochloride o~
(2,4l6-trimethoxyphenyl)-(3-pyrrolidinopropyl)-ketone (Code No~ L~ 1656), which is a reference peripheral vasodllator a~ent, which has formed the subject matter of a publlcation by DEBRAY et al., Th~rapie, 30, 259-266 (1975~ and which is marketed in the pharmacy under khe name o:E FONZ~LANE (Common In-ternational Name: HYDRO-C~LORIDE OF BUFLQ~DIL).
Finally, French Patent No. 78 26464 discloses 3l3~3 -that the replacement of one or more OCH3 groups of the L,L 1656 mentioned above, by one or moxe OH groups has unforeseeable consequences as far as the possible peri-pheral vasodilator properties of the resulting products are concerned. In fact, French ~atent No. 78 26464 shows that there is no structure-activity relationship in said OCH3/OH replacement: if the (2,4,6- tri-Iydro~- phen~ (3-pyrrolidinopropyl)-ketone and (2, 4-dimethoxy-6-hydroxyphenyl)-(3-pyrrolidinopropyl)-10 ketone are peripheral vasodilator agents as advantageousas the LL I656, on the contrary, the (2,6-dihydroxy-4-methoxyphenyl)- or (2,4-dihydroxy-6-methoxyphenyl)-(3-pyrrolidinopropyl)-ketone derivative and the (2,6-dimethoxy-4-hydroxy-phenyl)-(3-pyrrolidinopropyl)-15 ketone derivative have no peripheral vasodilator effects.
It has been unexpectedly found that the (2,6-dimethoxy-4-hyclroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts are, as peripheral vasodilator agents, (i) more efficient than the similar products 20 of the piperidino type and (ii) at least as advantageous as the LL 1656 mentioned above.
A novel derivative belonging to the family of the (alkoxy- and hydroxy-phenyl)-(3-aminopropyl)-ketones according to the invention is characterised in that it is selected from the ~roup constituted by (i) the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidino-propyl)-ke~one of formula:

HO~ CO-(CH2)3-N ~ (I) O~H3 and (ii) its addition salts.
30Addition salts are understood here to mean ~3~353 the acid addition salts (obtained by reaction of the Eree base of formula (I) with a mineral or oryanic acid) and the ammoni~m 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, iuma~ic, maleic, succinic, benzoic, cinnamic, mandelic, citric, lactic, malic, tar-tric, aspartic, p-toluenesulfonic and methanesulfonic acids. Among the compounds enabling ammonium salts to be lO obtained, particular mention may be made of IC~13 and ClCH3. The acid addition salts are generally preferred to the ammonium salts.
The preferred product according to the inven-- tion is the hydrochloride of (2,6-dimethoxy-4-hydroxy-phenyl)-(3-piperidinopropyl)-ketone.
The free base of formula (I) may be prepared according to a method, known per se, by application of conventional reaction mechanisms. ~he method proposed according to the lnvention consists in stoichiometrical-ly reacting the l,5-dimethoxy-3-hydroxy-benzene of formula:
~ OCH3 HO ~

with ths piperidinobutyronitrile of formula:
( 2)3 N ~ (III) i.n the presence oE AlCl3 and by passing a HCl ~as stream through the reaction medium for at least 2 hours at a temperature of 10-20C, then in hydrolyzing the ketimine derivative thus Pormed and which corresponds to the ~ormula:

HO ~ C-(=NH)-(CH2)3-N ~ (IV) to ob-tain the compound of formula (I).
In this method, the reac-tion of II with III
is ad~antageously carried out in chlorobenzene, using 1 mole of II, 1 mole of III and 1 mole of AlC13~ It is not necessary to isolate the ketimine derivative IV:
hydrolysis thereof is effected directly in the reac-tion medium resulting rom the reaction of II with III
by introducing ice into said reaction medium. The resultant aqueous phase is collected by decantation, thensub;ected to boiling for at least 30 mins. in the presence of carbon black.
According to the invention, a therapeutical composition is also proposed, which is particularly useful in the trea~nent of vascular diseases, in parti-cular the treatment of eschars, and which is charac-terised in that it contains, in association w~th a physiologically acceptable excipient, the free base of formula (I) or one of its non-toxic addition salts. Of 2Q course, such a therapeut~cal compositicn will include a pharmaceutically effective 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.
reparation I
Obtaining of the hydrochloride of (2,6-dimethoxy-4-hydrox~pheily~ 3 piperi i_opropyl)-ketone 3~3~3 ~OC~13 HO~ CO-(CH2)3-N ~ , HCl (Example l; Code No. CRL 40746) 30.8 g (0.2 mole) oE 1,5-dimethoxy-3-hydroxy~
benzene, 34 g (0.2 mole) of piperidinobu-tyronitrile - 5 and 200 ml of chloro~enzene are in-troduced into a three-necked flask provided with stirring means; 28 c~ (0.2 mole) of aluminium chloride are then added slowly, then, maintaining the temperature between 14 and 20C, an anhydrous HC1 gas stream is passed through the resultant 10 reaction medium, with stirring, Eor 4.25 hrs. It is-left to stand at 4C for 20 hours then thrown on ice (to hy~rolyze -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 ~other 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 over 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, a~ter trtturation in ethanol, gives 21 g (yield 31~) of CRL 40746 in the form o~ a white crystalline powder, soluble in water. Inst.m.p.=214-215C (wi-th decomposi-tion)Preparation II
-Obtainin~ of the hydrochloride oE (2,4-dimeth_ XY-6~-hyc1roxyphe,1yl)-(3-plperidinopropyl1-ketone 113CO - ~ - CO-(CH2)3-N ~ , HCl OH (comparative Ex.CPl,Code No.CRL 40747) 5~

The oil which decants in preparation I herein-above, after hydrolysis of -the keti~,ine hydrochloride IV
then bo ilin~ of th~ a~ueous phase in the presence of carbon black, is extracted with chloroform.
The chloroform phase ls dried over Na2S04 in the pre-sence of carbon black. ~he solvent is evaporated and a rough po~der , 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, 10 in the form of a crystalline powder, pale cream in colour, very soluble in ~ater. Inst.m.p.=131-183C (~ith decom-position).
Part of the results of the tests undertaken on animals have been summarized hereinafter, and more par-15 ticularly those of the comparative tests relative to the products mentioned in Table I hereinafter, namely CRL
40 746 (Example 1), its structural analogues (CPl-CP6) and a reference peripheral vasodilator product which is LI. 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 adminis-~red in solution in physiological serum i~ 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 intrad~odenal route. With respect to the con-trols (the same animals receiving only the physio-logical serum), three pararneters are measured: the average arterial pressure (expressed in mm Hg; 1 mm Hg corresponds ko 1.333224 x 102 Pa), the cardiac frequen~
cy (expressed in beats/minu-te) and the Elow rate of the femoral artery (expressed in ml/min). The variations of these pararneters expressed in percen-tages, with respect to the controls are given in Tables II (intravenous administration) and III (intraduodenal administration) her~inafte:r.

Peripheral vasodilation ls translated under these circumstances by an increase in the flow rate of the femoral artery. Accord:ing to the present conditions of operation, a product is said to be a peripheral vasodilator agent if the flow rate o~
the femoral artery increases by at least 30% by intra venous administration, on the one hand, and by intra-duodenal adminstration on the other hand, without the variation in the arterial pressure bein~ greater 10 than -~10 or less than -10~.
The res~lts of Tables II and III hereinafter demonstrate the interest of CRL 40746 as perip~ral vaso-dilator. 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 CPl (CRL 40747) and its homolo~ue CP2 (LL 1647) which p~sents a trihydroxylated phenyl' group.
More precisely, the CRL 40746 according to 20 the invent~on, administered by IV route and by ID route increases the flow rate of the femoral artery (varia-tion always greater than +30~), whilst its isomer CPl is (i) very weakly va'sodilato~ by the IV route (varla-tion always less than + 30~, but of the order of +20 to ~22~) and (ii) has hardly any vasodilator effect by ID route (it hasl rathermore, an antihypertensive eff~ct as it reduces the arterial pressure by more than 10~), and its trihydroxylated homologue CP2 which is vasodilator by IV route (from the dose of ~ mg/kg as indicated in British Paten-t No. 1 325 192 mentioned above), has virtually no vasodilator effect by ID route (variation of the flow rate of the ~'emoral artery by ID route -~17% with antihypertensive effect~
In cllnic, the C~L 40746 has given good re-sul-ts in human beings in the treatment of eschars.

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Ex~p1s 1CP~L 40746 1,5 + ' + 3'. ~ 2 CP1 CRL 40747 1, S + 2 -r 20 + 5 CP2 I.L, 1647 1,5 + 1 + 10 - 2 CP3 _ 1~5 + 3 + i3 - 1 CP4 _ 1,5 - 2 ~ 3 - 2 CP5 _ 1,5 - 1 - 5 + 1 CP6 _ 1~5 + 1 + 7 + 3 . L-L 1656 1,5 + 33 _ _ Examp1~ 1 CRL 40746 3 + 5 + 35 + 3 CP1CRl. 40747 3 - 12 + 22 ~ 2 CP2 LL 1647 3 + 1 -~ 18 + 3 CP3 _ 3 - 2 -t 8 - 6 CP4 _ 3 - 5 + 2 +1 CP5 _ 3 _ ~ - 8 ~ 3 CP6 _ 3 ~ 1 + 5 ~ 2 .
CP7 LL 1656 3 - 2 + 36 + 6 . _ .
Example 1 CRL 40746 6 t 5 + 41 + 3 CP1 CRL 40747 6 - 18 + 22 ~ 15 CP2 LL 1647 6 + ~ + 34 + 3 CP3 _ 6 + 5 + 3 - 1 CP4 _ 6 + 1 -1- 2 ~ 1 CPS _ 6 ~ 2 - 3 -~ 2 CP6 _ 6 ~ 8 + 2 + 1 CP7 LL 165fi 6 - 2 + 39 ~_ 3~ii3 T A B L E _ I I I
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Claims

The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:
l. A method for preparing 2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts which comprises stoichiometrically reacting 1,5-dimethoxy-3-hydroxybenzene of the formula:

with piperidinobutyronitrile of the formula in the presence of AlCl3 and by passing through the reaction medium a HCl gas stream for at least 2 hours, at 10-20°C, then hydrolyzing the ketimine derivative thus formed and which corresponds to the formula and if desired converting the product to an addition salt.
2. A method according to claim 1 including converting the product with hydrochlorine and to the hydrochloride addition salt.
3. (2,6-dimethoxy-4-hydroxyphenyl)-(3-piper-idinopropyl)- ketone and its addition salts, when prepared by the process of claim 1 or any obvious chemical equivalent thereof.
4. (2,6-dimethoxy-4-hydroxyphenyl)-(3-piper-idinopropyl)-ketone hydrochloride, when prepared by the process of claim 2 or any obvious chemical equivalent thereof.