CA1126738A - Process for the preparation of phloroglucinol derivatives and their therapeutic applications - Google Patents

Abstract

B R E V E T D 'I N V E N T I O N New phloroglucinol derivatives, their preparation process and their therapeutic application. Invention: Louis LAFON Société Anonyme known as: LABORATOIRE L. LAFON Descriptive abstract: The present invention relates to new phloroglucinol derivatives of formula (I) and their salts. The compounds of formula I and their non-toxic salts are useful in therapy as peripheral vasodilators.

Description

: `-3 ~

The present invention relates to new derivatives phloroglucinol as new industrial products, to the process of preparation desdi ~ s derivatives and their application in therapy It relates more particularly to (2,4,6-trihydroxyphenyl) - (3 ~ pyrroli dinopropyl) -ketone, (2,4-dimethoxy-6-hydroxyphenyl ~ - (3-pyrrolidino-propyl) ketone and their salts.
We know that (2,4,6-trimethoxyphenyl) hydrochloride -(3-pyrrolidinopropyl) -ketone, which was described in the British patent n 1,325,192 and which has the code LL 1656, ast a vasodilator device which is ap ~ sent marketed in therapy under the designation of FONZYIA ~ E1 (international common name: CHLORHYDRATE
BUFLOMEDIL) and whose pharmacological properties have been the subject from a publication: DE ~ RAY et al, Therapia (1975), 30, pages 259-266.
We have just surprisingly found that lS compounds according to the invention (which have a voline structure of that of LL
LL 1656) are less toxic and have a longer service life than LL 1656, while their closest counterparts ~ in terms of the structure (in particular the CRL 40 633 and CRL 40 634 studied below) are devoid of vasodl.lata actlvlté ~ rice.
The new compounds in the invention are charac ~ e-laughed at that they are chosen from the group consisting of:
(a) the (hydroxyphenyl) - (3-pyrrolidinopropyl) -ketones of formula developed: OR

25 RO ~ -CO-CH2-C ~ 2 CH2 ~ (I) OH
wherein R is H or CH3; and (b) their non-toxic salts By salts is meant here the acid addition salts and quaternary ammonium salts. Acid addition salts can be obtained according to a method known per se, for example p ~ r reaction of bssa libra with mineral or organic acida. Among the acids used : ~ -. , ..,.,,. :, i. ~:, ~,::
'' ~

~, '' ~ ''.'`'' `` ',,:, ~ 2 ~ 73 ~

- 2 -for this purpose, we can in particular mention the acids hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, formic, oxalic, malic, fumaric, mal ~ ique, citric, ascorbic, benzoic, glutamic, aspartic, methanesulfonic, paratoluenesulfonic.
Among the quaternary ammonium salts which may be ~
wise, mention may be made of the salts obtained from the free base and of ICH3 and ClCH3. Preferred salts according to the invention are the chlorhyarate, tartrate and citrate.
The compounds of formula I can be pre-trimmed according to a method known per se, for example a of the two methods described in the British patent No. 1,325,192 cited above. According to the invention, recommends to react according to HOUBEN-HOECH phloro-glucinol with 4-pyrrolidino-butyronitrile in a anhydrous solvent (especially diethyl ether, chloro-benzene) in the presence of ZnC12 or AlC13 and a HCl gas flow, according to the diagram:
OR OR

RO ~ + NC- (CH2) 3 ~ 3RO ~ CO (CH2) 3 a OH OH ;

(where R is defined as above), this reaction scheme ~ `
being supplemented if necessary by iso- operations lation and purification.

.,, ',. ::.:,, `:, ":`. ~:.
:; . ~:
.., - 2a -The compounds of formula I and their salts, especially the hydrochlorides, citra-tes and tartrates, are vaso ~ peripheral ilatants and are useful: ~:
in therapeutics in the treatment of insufficiencies:;
arterial circulatory systems of the limbs t and in particular in the treatment of RAYNAUD syndrome and pressure sores decubitus.
According to the invention, we recommend therapeutic reactions, characterized in that they lO contain, in association with a physiological excipient `
gically acceptable, a pharmaceutically acceptable amount effective of at least one compound chosen from the group consisting of (2, ~, 6-trihydroxyphenyl) - (3 ~ pyrrolidi-nopropyl) -ketone, (2, ~ -dimethoxy-6-hydroxyphenyl) -(3-pyrrolidinopropyl) -ketone and their non-toxic salts.
Other advantages and characteristics of the invention will be better understood from the reading that goes follow nonlimiting preparation examples and results of pharmacological trials.
Table I, given below to facilitate the comprehension of the text, groups the products according to the invention (examples 1 and 2), their counterparts (example-comparison ples 3 to 5) and a reference product already known in therapy (LL 1656).

. ~.

:,, :: `

7 ~ 1 Example 1 ~ 2,4,6-trihydroxyphenyl hydrochloride) - (3-pyrrolidinopropyl) -ketone. OH
HQ $ CO (CH2 3 ~, HCl H

Code No .: CR ~ 40598 In 500 ml of anhydrous diethyl ether dried over CaC12, 38.30 g (0.304 mole ~ of anhydrous phloroglucinol Pt) are dissolved 41.95 g (0.304 ~ ole ~ of 4-pyrrolidino-butyronitrile. Add 7.28 g of zinc chloride and bubbled through the medium r ~ actionnet HCl gaæ
up to ~ saturatlon. We leave one night in contact and add water in the reaction medium.
An aqueous phase and an eth phase are obtained.
The é ~ h ~ rée phase is washed with water and the aqueous phase is then collected.
and the wash water, and refluxing 3U is heated for 1 h the resulting mixture.
We re ~ stiffen, neutralized with sodium bicarbonate, and ~ ilter the bflse.
The base is dissolved in the minimum amount of dimethylformamide while hot and acidifies with 45 ml of 7N hydrochloric thanol. The dimethyl is evaporated.
vacuum formamide without going ~ usqu ~ dryness, we have ~ out of ~ ther p ~ ur facilitate the precipitation of the expected hydrochloride. By recrystallization in the methanol-acetone mixture (1: 1) v / v, we obtain ~ 15 g ~ yield ~
16%) (2,4,6-trihydroxyph ~ nyl) - (3-pyrrolidinopropyl) hydrochloride -ketone.
F = 260C
~% N measurement = 4.52%
Analyze ~ z N bh ~ orique = 4.64%
The pllurity of CRL 40598 is checked by chromatography.
written on a mlnce / el ~ nt layer: CH30H-CH3COCH3-NH40H (50: 50: 2) v / v;
plate: silica gel (Merck1F 254); revelation ~: UV plus Draggendro ~]:
'~
From the free base, we prepare according to the same te ~ hnique citrate e ~ tartratc corresponding ~.

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: ~,:::, -,.,,. :

3 ~

Example 2 (2,4-Dimethoxy-6-hydroxyph ~ nyl) - (3-pyrrolidino-) hydrochloride propyl) -ketone.
JC
S H3CO ~ C- (CH2 ~ 3-N ~, HCl OH
Code number: CRL 40 635 In a 2 liter three-necked flask, dissolve 69 g (0.5 mole) of 4-pyrrolidino-butyronitrile in 0.5 liters of chlorobenz ~ na is added slowly 67 g (0.5 mole) of AlC13 then 77 g (0.5 mole) of 3,5-dim ~ thoxy-ph ~ nol. A current of HCl gas is then passed through the reaction medium.
tlonnel (maintained at 25-30C) for 2 h (duration necessary to saturate the reaction medium), then leave to repwer at room temperature (15-20C) overnight, 0.5 liter of water is slowly added ~ for hydro-lyse the c ~ timine which has formed) and cante the aqueous phase which is collects, the aqueous phflse is brought to reflux for 1 h. We cool and a precipitate P is formed which is removed by filtration (the pr ~ ci-pit ~ P, which consists mainly of the isom ~ re 2,6-dim ~ thoxy-4-kydroxyphenényle, will be isolated as indicated ~ Example 5 comparati ~), Lefiltrat is extracted with chloroform and the chloroform solution e ~ t eva-dry porous under reduced pressure Dissolve the ~ vaporization ~ residue in the minimum amount of water and the free base is formed by sodium bicarbonate.
The insoluble material is filtered and the base is extracted with chloro ~ elm. The new solu-tion chloroformlque is evaporated ~ e ~ dry 90US reduced prassion. The oils as well obtained ast taken up with isopropanol and barbotex HCl gas ~ usqul ~ p} l 2, The expected hydrochloride cxistallise, By filtration, we obtains 2S g (yield: 15 V / o) of hydrochloride (2,4-dil ~ thoxy-6-hydroxy-phenyl) - (3-pyrrolidinopropyl) -c ~ tona F = 170C ~ `
(% Cl measured ~ = 10.68 V / ~
Analysis (% Cl theoretical = 10.74%
From the free base, we prepare according to the same technical citrate e ~ tartrate corresponding. 5 Example 3 ~ comparison) T2,4,6-trihydxoxyph ~ nyl) - (3-diethylaminopropyl) ketone hydrochloride Code: CRL`40 624 From 12.6 g of phloroglucinol (0.10 mole), 7 ~

14.0 g of 4-diethylamino-butyronitrile (0.10 mole), 2.4 g of ZnC12 and 125 ml of diethyll ether, we obtain (by proceeding as indicated in Example 1) 8 g (reIldement: 27/0) of chlo ~ hydrate of (2,4,6-trihydroxy-phenyl) - (3-diethylaminopropyl) -ketone.
5 F = 260C
(% Cl measured = 11.46 V / o Analysis (v / Cl- theoretical = 11.59%
Note:
The Scream. 40,624 is hardly soluble in water and 10 physiological saline ~ room temperature; at 60C, its solubility in physiological saline (water containing 4 to 9 g / l NaCl) is lower at 6 g / l. Tartrate and citrate are no more soluble than chlorine.
hydra ~ e.
Example 4 (comparative) lS (2,6-dihydroxy-4-methoxyphenyl) hydrochloride ~ (3-pyrrolidLnopro-pyl) -c ~ tone or hydrochloride of (2,4-dihydroxy ~ 6-methoxyphenyl) - (3-pyrrolidinopropyl) -ketone Code number: CRL 40 633 In a 2 liter three-necked flask, dissolve 69 g (0.5 mole) 20 of 4-pyrrolidino-butyronitrile in 1 liter of diethyl ether, and added 13.6 g ~ 0.1 mole) of ZnC12 then 70 g (0.5 mole) of 1,3-dihydroxy-5-methoxy-benzene. We must then pass a current of ~ Cl gas pendan ~
2.5 h in the reaction medium maintanu ~ 25-30C, pUi8 is left in contac ~ pendan ~ one night. Evaporated ~ dry under reduced pressure, resumes 25 the evaporation residue with 1 liter of water, brings to reflux for 1 h then cools. The product crystallizes and is isolated by filtration and then recrystallized.
tallization in methanol-water mixture (3: 1) v / v. We obtain 69 g ( ment: 44%) of CRL 40 633).
F = 270C
(~ / 3 Cl measured = 11.35 ~ / 0 Analysis (7 Cl- th ~ orique ~ 11,22%
~ marks:
I) Due to the absence of vasodilator activity device of the CRL 40 633, determining the exact position of the 35 methoxy group was not performed ~; it may also be that both ison ~ èreæ are present in the isolated product.
2) CRL 40 633 is hardly soluble in water and physiological saline at room temperature; ~ 60C, its maximum solubility :::, :: - -, ~; ::;::. :. ::. :
,.:,. . :: ~ ::

~ 673 ~ 3 . ~ ~

male in physiological saline (water containing 4 to 9 g / l NaCl) is of 10 g / l. Tartrate and citrate are no more soluble than chlor hydrate, ~ (comparison) (2,6 ~ dimethoxy-4-hydroxyphenyl) - (3-pyr} olidinopro hydrochloride ~
pyl) -ketone Code number: CRL 40 634 The precipitate P obtained ~ exernple 2 and recrystallized in the acetone-ethanol mixture (1: 1) v / v gives 49.5 g (yield: 30%) 10 (2,6-dimethoxy-4-hydroxyphenyl) hydrochloride - (3-pyrrolidinopropyl ~ -ketone, F = 177C
(% Cl measured = 10.72%
Analyzes ~ (% Cl- th ~ orique = 10,74%
15 Note:
The position of the 4-hydroxy group of CRL 40 ~ 34 from mame that that of the 6-hydroxy group of CRL 40 635 tproduct of example 2) is determined by analysis, We summarized cl ~ after the results of the tests which 20 was undertaken with the products of examples 1 (CRL 40 598) and 2 (CRL 40 635), the products of Comparative Examples 3 (CRL 40 624),

4 (CRL 40 633) and S (CRL 40 634) and a reference product known as as a peripheral vasodilator (LL 1656), 1) Acute toxicity Orally in male mice (pxoducts ~ test ~ both administered in aqueous solution, DL-50 are sui ~
touts:
CRL 40 598 ~ DL-50 = 1400 + 112 mg / kg CRL 40 635: DL-SO = 880-1 76 mg / kg LL 1656: LD 50 = 280 + 25 mg / kg 2) A ~. ~ Vlté vasodilatrice Vasodilator activity has been studied in dogs male anesthetized with nembutal (6 animals per dose and per product). Professionals-tests to be compared are administered in solution in physiological saline 35 under a volum2 of 6 ml / animal intravenously (infusion of 1 ml / minute [6 ~ 9 ml / animal with infusion of 1 ~ 5 ~ 2 ml / minute for CRL 40 624, due to its low solubility] and in a volume dq 10 ml / animal by lntraduodenal route (the solutions of CRL 40 633 being 1, 1, '' 1 ~, ; ','',.''"";"~'''':.
'~'. "'` .: ":'::. . . ' ~ ~ 673 ~

preserved in a bain-marie). Compared to witnesses (the same animals do not receiving only physiological serum), we measure three parameters:
mean blood pressure (expressed in min ~ lg), heart rate (expressed in beatslminute) and femoral arterial flow (expressed in ml / minute). The variations of these parameters expressed in percentages, by report to the witnesses, are given in tables ~ II (administration intravenous) and III (intraduod ~ nala administration) below.
Peripheral vasodilation is characterized here by an increase in arterial flow f ~ moral, the other two parameters (mean blood pressure and heart rate) are dolmated for illustrate the COORDINATION of products in the body We say, according to these operating conditions, that a product is a vasodi-peripheral latator if the d ~ bit art ~ femoral riel increases by at least 30 / O
by intravenous administration, on the one hand, and by intravenous administration duodenal, on the other hand Intravenously (see Table II), the anesthetized dog is observed to have slightly increased CRL 40 598 and CRL 40 635.
rement the average blood pressure, that they are practical ~ ent without effect on the cardiac frequency and that they increase the flow much more art ~ riel f ~ moral than the LL 1656. We also note that the vasodilata-caused by CRL 40 598 and CRL 40 635 takes about 10 minutes for all the doses tested, this duration being greater than that of the LL 1656 ~ Table II also shows that the products of the examples Comparative (CRL 40 624, CRL 40 633 and CRL 40 634) generally do not of vasodilata effect and that this effect, if it manifests itself (at the dose of 3 mg / kg for CRL 40 634 and at a dose of 6 mg / kg for CRL 40 624) is fleeting or short-lived.
Intraduodenally che ~ the dog anesthesia, the LL 1656 has been administered in doses corresponding to 1/40 respectively, 30 1/20 and l / lOe of ~ L-50 in mice by the oral route and CRL 40 598 and 40,635 were administered at relatively lower doses corresponding to the 1/70 of the DL-50 for 13 first and to the 1/44 of the DL-50 for the second We note that, after intraduodenal administration, the duration of ef ~ and peripheral vasodilator in CRL 40 598 and CRL 40 635 is longer than that of LL 1656, the kinetics of the effect ~ asodila-the following:
- for LL 1656, the appearance of the effect ~ occurs

5 minutes after administration7 this effect reaches its maximum in 15 minutes nutes and its maximum duration is 60 to 90 minutes;
,::

. ........................ ~. ,.,,. ::: ~::. . i,.:,. . ,::
.: ..: -. . ~ ~

- for CRL 40 598, the appearance of the vaso-dilator is slower because it occurs around 30 minutes after injection, this effect reaches its maximum 2 ~ 4 hours after injection and its maximum duration is 5 hours;
- for CRL 40 635, the vasodilator effect begins 20 minutes after the injection, reaches its maximum in 30 to 60 minutes and lasts more than 2 hours.
The results in Table III show that, by flight intraduodenal, CRL 40 598, CRL 40 635 and LL 1656 are active, so that the other products (CRL 40 624, CRL 40 633 and CRL 40 634) are provided with vasodilating activity because the variation of arterial d ~ bit femoral they cause is very weak. Furthermore, we observe that CRL 40 598 and CRL 40 635 do not cause any change in the their t ~ guments (ear, tongue, leg pads) even at most Eort de la vasodilata; tion In conclusion, all of the comparative results which have been undertaken highlights that:
(a) the products according to the invention are agents peripheral vasodilators as interesting in therapy as reference product, LL 1656, and il9 differ from it by lower toxicity and a more peripheral vasodilator effect long lasting; e ~ ~
(b) the compounds of the comparative examples, which are from the point of view of the structure very close to the compounds according to the invention 2S tion, are devoid of peripheral vasodilator activity.
3) Activity an ~ ia ~ reg ~ te ~ It has also been found that the compounds s210n the invention have a beneficial effect antiagr ~ glove platelets san-~ uines Thus, CRL 40 598 modifies blood platelet aggregation according to the AD P (adenosine diphosphate) test ~ the dose of 50 mg / kg / day for 4 ~ bears in rats (average inhibition of 44%).
4) Clinical trials Clinical trials undertaken with the compounds according to the invention have given good results in humans in the treatment medical elements where vasodilation of blood vessels is sought. Thus, CRL 40 598, administered (i) SOU5 in the form of tablets or capsules (each containing 100 mg to 200 mg of CRL 40 598), at a rate of 2 ~
3 tablets or capsules ~ per day, effectively treated the disease ","", ,,:, ~.." ~., i:. . ~ :. . .:

, Raynaud e ~ (ii) intravenously (injectable ampoule containing 50 mg ~ 100 mg CRL 40 598), ~ 2 to 3 injections per day, a allowed cerebral vasodilator treatment.

`~ 10 BOARD
A-CO ~ 2) 3-B, HCl ~ _ _ ~
Product N of code AB F.
_ _ _ _ _ ~ _ . ~ 0 ~ 1 (a ~ CRL 40598 HO ~ pyrrolidino 260C

OCH3 _ _, Example 2 CRL 40635 H3CO ~ pyrrolidino 170C

_ _ _ OH ~ _. :
Example 3 CRL 40624 HO ~ N (C ~ H5) ~ 260C
(comparative ~ OH _ ~ 3CO ~

Example 4 CRL 40633 or pyrrolidino 270C
(comparison3 (b) (c) ~ ~ ~ 1 3 _ .OCH3 ~.
Example. 5 HO 4 ~
(comparison) CRL 40634 ~ pyrrolidino 177C
(b) (d ~ ~ CH3 ___ ~ _ ~ OC ~ 3 _ _ FONZYLANE LL I 656 H3CO ~ pyrrolldino 192C
(Reference): OCH.
3 _ _.
~ otes: ta) active product as a ~ vasicilator (bj inactive product as a peripheral vasodilator tc) this product whose structure has not been determined ~ e could ~ be a mixture of the two ~ somers (d) isomer of the product of e ~ example 2 .

he TABLE II
Variation of parameters after administration intravenous che ~ ch ~ e ~ anesthesia Product Dose Variations year ~ / 0 mg / kg Pressure Flow rate Frequency arterial riel femoral heart _. _ _ ____ _ _ CRL 40598 1.5 - ~ 9 ~ 56 (a) ~ 3 CRL 40635 1.5 +3 ~ 38 (a) ~ 2 CRL 40624 1.5 -5 +3 -5 CRL 40633 1.5. 0 ~ 5 +1 CRL 40634 1.5 ~ 2 +10 0 LL 1656 1.5 0 ~ 33 (b) +5 _ _ __ _.
CRL 40598 3- - ~ 10 +63 (a) 0 ~ RL 40635 3 +5 +40 (a) ~ 1 CRL 40624 3 -7 +1 -6 CRL 40633 3 +1 - ~ 8 -2 CRL 40634 3 -1 +30 (c) 0 LL 1656 3 -2 - ~ 36 tb) +6:
_. _.I _ _ _ _ _ _ _ CRL 40598 6 - ~ 4 +63 (a) ~ 3 CRL 40635 6 - ~ 2 ~ 44 ~ a) +1:
CRL 40624 6 -10 +26 (d) -8 CRL 40633 6 +2 +7 +1 CRL 40634 6. - ~ 1 +7 +2 LL 1656 6 -2 +39 (b) 0 . - _ _.

Notes:
~ a) duration of the effect: 10 mlnutes (b) duration of the effect: 5 minutes (c) duration of effect: 3 mlnutes (d) duration of effect: 1 minute ",: - ,, ,,, -, :,, ~:

TABLE III

Variation of parameters for administration intraduodénale_chez le chien a ~ esth ~ sié ::

__ ~
Product Dose Variations in% ~:
mg / kg. _ _ _ ~ _ . Pressure Flow rate - Fr ~ than ~ ce arterial riel femoral heart ~:
__ ~ ~ _ ~

LL 1656 7 ~ 2 +44 +7 LI. 1656 14 -3.5 +73 ~ 4.5 ~:
L1 1656 28 -4.5 - ~ 100 ~ 6 CRL 40598 20 _ ~ ~ 60 _ ~
CRL 40624 ~ 0 - O ~ 2 ~ 1.
CRL 40633 20. ~ 1 ~ 3 ~ 2:
CRL 40634 20 -1 ~ 5 -1 ~
CR2 40635. _ _ _ +60 _ __ ..

Claims (6)

The realizations of the invention on the subject of-which an exclusive property right or privilege is claimed, are defined as follows: 1. Process for the preparation of a derivative of phloroglucinol corresponding to the general formula:

I
in which R is H or CH3 and its salts, says so process being characterized in that one reacts a consists of formula:

where R is as defined previously, with 4-pyrroli-dino-butyronitrile of the formula:

in an anhydrous solvent in the presence of ZnCl2 or AlCl3. 2. Method according to claim 1, character-laughed at by reacting phloroglucinol with 4-pyrrolidino-butyronitrile in a solvent and that one isolates (2,4,6-trihydroxy) - (3-pyrrolidinopropyl) -ketone. 3. Method according to claim 1, character-laughed at by reacting 4-pyrrolidino-butyro-nitrile with 3,5-dimethoxyphenol and that we isolate the (2,4-dimethoxy-6-hydroxyphenyl) -3- (pyrrolidinopropyl) -ketone. 4. A derivative of phloroglucinol responding to the general formula:

in which R is H or CH3 and its salts, when prepared by the process of claim 1 or by a equivalent chemical process. 5. La (2,4,6-trihydroxy) - (3-pyrrolidino-propyl) -ketone, when prepared by the process of claim 2 or by an equivalent chemical process. 6. La (2,4-dimethoxy-6-hydroxyphenyl) -3-(pyrrolidinopropyl) -ketone, when prepared by the process of claim 3 or by a chemical process equivalent.