Note: Descriptions are shown in the official language in which they were submitted.
~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
--2--
-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:
I OCH3
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 ~
OCH3
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:
IOCH3
HO ~ C-(=NH)-(CH2)3-N ~ (IV)
OCH3
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
--5--
~OC~13
HO~ CO-(CH2)3-N ~ , HCl
OCH3
(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
IOC113
113CO - ~ - CO-(CH2)3-N ~ , HCl
OH (comparative Ex.CPl,Code No.CRL 40747)
5~
--6--
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.
353
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.
3~
~' o o __ _ ,
~ ,c C C
¢ o C~ o o , o .~ ,
U ~,J~ O ~D
cl CJ ;) ;) ~ Cl a 1~ U~
C~. Cl. ~ ,C~ h
Cl~ t~.Q. ~ ~ ~ ~ c~. cn ~.o Cn
._ ._ . _ , ~Icr.
ti C ___, __ ~~ t~ 1 ri Z Z '
~ ¢~ _ ~r~ O ~ O ~ ~ a 5
u '5 ~i 5 O ~ O ~ ~ I W555 ',
rl _ O 5 0 ~ ~ 5'5~5
0 O ~ r~ I I I I u~ ~ D, g
cu ~ _ _ (~
Ca'' ~10 5 ~ _ _ _ ~
3~3
T A B L E _I I
t~ariatit)n_r)t C i~` L~ IE~S . ftel ~llt~a~/ellCLI~:;
~ I r . i ~, t :L ~. ~ i r? r 1 i I I t I: r ~ s ~ l i Z F G Ci O C
_~ ~ Variations in ~
Prod-lct CC~de No. Dose 7~rtr ria~ I 11G~ Iai.~ Of cardi Ic
~, r ~ e e ~ r e ~f enl o ~ .,1 a r te ~y f r r- q ~ rl r: y ¦
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
Variation r~f ~ e ;~lrc~ &tarr .~ter intr~duod~nal
~,di~ c l . c:-~Jan in t~le ùn~,r ~ eti~ .a~,
_ -- - ----L ~ aria-tions in ~/0 - ' ~~
Prod uc t r r~ c~ e ~O . D os e _ _
m,/!;g Artr-eL-ial. t`lG~ ra-lC af CaIoiac
_ ~- r ~ C ~ I ) r ;- I ~ 1 u ~ r ~ r ~ r ~ C ~rr
Ex ,mp1e 1 CRL 40746 20 ~ ~ 83 _ 5
CPl CRL 40747 20 - 15 ~ 10 - 2
CP2 LL 1647 2 0 - 12 + 17 - 1
CP3 _ 20 - 8 - 5 - 2
CP4 _ 20 - 1 - 2 + 3
CP5 _ 20 0 ~ 2 ~ 1
CP6 _ 20 + 6 + 1 ~4
CP 7 LL 16 5 6 2 0 __ + 84 ~k 5
