CA1175425A - Derivatives of pyrrole for protecting the myocardium, having an antiarrhthymic activity and an activity as blood platelet anti-aggregant, process for preparation thereof and drugs containing same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to new derivatives of pyrrole of formula:
(I) in which:
-R1 represents an atom of hydrogen, a lower alkyl group, a phenyl radical or a pyridyl-2 radical, -R2 represents an atom of hydrogen or a lower alkyl radical -R3 and R4 represent a lower alkyl or cycloalkyl radical or the radical is a heterocyclic amine radical, and - n is equal to 2 or 3;
the invention concerns drugs having an antiarrhythmic activ-ty abd ab activity as blood platelet anti-aggregant, containing said derivatives.

Description

The pre~ent lnvention relates, as new industrial products, to derlvatives of pyrrole, as well as to the methods for preparing them and appllcation thereto in therapeutics.

The novel compounds according to the lnventlon correspond to the ~eneral formula:

Rl / R3 4 1 (CH2)n N ~ (I~
A
CONHz in whlch:

- Rl represents an atom of hydrogen, a lower alkyl group, a phenyl radlcal or a pyrityl-2 radical;
- R2 designates an atom of hydrogen or a lower alkyl radlcal;
- R3 and R4, whlch are ldentlcal or dlfferent, eachRrepre~ent a l~er alkyl or cycloalkyl radical or the group - N ~ R designab~
a cyclic amlne radical comprislng 1 or 2 cycles an~ being able to pos~ess a second heteroatom and comprise substi-tuents; and - n 19 equal to 2 or 3.

1 175~2S

,R3 When the group - N R i9 a cyclic amlne radical, the ~ollowing may be mentloned among said amines:
pyrrolidine, piperidine, dimethyl-2, 6 piperidine, morpholine, piperazine and the radical /
_ N N
~/

In the present lnvention, lower alkyl group designates ~traight or branched alkyl groups having from l to 6 atoms of carbon.

The compounds (I) yLeld soluble salts with thc 10 mineral or organic acids. These salts, with the pharmaceu-tlcally acceptable acids, form an integral part of thc inven-tion.

Accordlng to the nature of the substituent Rl, the compounds ~I) may be obtalned by one of the following 15 methods:

When Rl designates hydrogen, ehe compound~
(I) may be obtained according to two ~o ocesses.

~ ~ ~ 3 75~25 1 ~
--3.--Method Al The different steps of the process are lndlcated in the followlng reaction dlagram:

/ / R3 ~ R3 C:H3CONH C (C~2)n~N - > H2N--~(C~12)n-N
4 COO~ 4 ~ 3 ~R3 > H2N --C}~ (CH2)2 N~ R H2N--CH--(CH2~2-N

~=\ H /R3-? ¦ N--C--(CH2)n-N (I) (Rl - H) ~ R2 CONH2 4 The compound 1 is prepared by alkylation according to the known processes of ethyl aoetamidomalonate. By sapo-nification of the compound 1 ln an alkaline medium, the corre~-ponding malonic acid is obtained which easily decarboxlates by heating in an acid medium to yield the substituted butyric ~cid

2. The lat~er is esterified by a known proces~ into methyl ester

3. The ester 3 is converted lnto the corresp~n ding amide 4 by actlon of ammonla accordlng to a known proces~. Finally, the amlde 4 iB converted into compound (I) by heating wlth a y-diketone R2C-CH2CH2C-R2 ln the acetic acld.
O O

~ 175425 ~ -

-4 -In the partlcular case of R2 = H, compound (I) may be obtained by heating the amide 4 with dimethoxy-2, 5 tetrahydrofuran in absolute alcohol in the presence of acetlc acid.
Method A
The different step~ of the process are indicated ln the following reaction diagram:

Br--(CH2)1,-CH --- COOCH3, HCl ) [~ , ( 2)n Br C _ (CN2)~ C-- (C~12)n-1{~
.c< COOC~3 4 CONH2 4 7 tI) (Rl ~ H) The hydrochloride of methyl amino-2 bromo-4 butyrate 5 CTetrahedron, 25, 5971-81, (1969) ~ is converted into corresponding pyrrolic derivatlve 6 either by action of a ~-diketone or by action of the dimethoxy-2, 5 furan, as indicated ln method Al.
,R3 By action of an amlne HN~ on 6 in solution lS in an inert solvent, such as benzene or toluene, the compound 7 is obtained which, by amidification by ammonia, leads to the products (I), (Rl = E~).
Method B
When Rl repre~ent~ a phenyl group or a pyridyl-2 1 ~75425 group, the compounds (I) are obtained according to the~llowing reaction diagram from a product 8, RlC~H-A, in which R

designates a phenyl or pyridyl-2 group and A designates a group derived from the acid function, namely a nitrile group -C--N or an ester group -C00-Alk (Alk represents a methyl or ethyl group). ~~ R
l -=~ Rl Rl--CH--A ~\N--CH--A
N'{2 = ~

--C-- (CR2) -~> L~cl_ (CH ) /3 A 4 \ CONH2 R4 (I) (Rl = phenyl or pyridyl-2~ -As in the methods Al and A2, the amino compound 8 is converted into the corresponding pyrrolic compound 9 by 10 action of a r-diketone or by action of the dimethoxy-2, 5 tetrahydrofuran.
R3~
The compound 9 is alkylated by~ N-(CH2) -Hal (Hal designating a halogen) in an inert solvent such as toluene and in the presence of a base such as sodium hydride and yields 15 compound 10. In the latter, the group A is converted into an amide group. When A represents a nitrile group, the latter is hydrolysed for example by heating with sodium hydroxide in dilute alcoholic solution. When A designates an ester group, the latter i9 converted into amide by action of ammonia or, in the 20 case of voluminous amines, by action of the complex salt formed by the aluminium hydride and the ammonia in the tetra-hydrofuran.

~ 175425 Method C
When Rl is an alkyl group, the different steps of the synthosls are shown in the following reaction diagram:
N~C ~C R3 Rl--C~--COOC2H5 ~ ~lC-- (CH2)n N~R
C00~2~5 C Z 5 ~--c-- (c3z),-x_ i3 ` 14 .. ...

C~ (cX2)n-N~R4 (I) (Rl = alkyl ) The starting protuct 11 ls an oC -isocyanoester.
The products of this type are known or may be prepared accor-ding to known processes, partlcularly by action of the pho~gene on the corresponding o~-formylaminoester compound~.
,R3 Compound 11 is alkylated by Hal-tCH2)n-N ~ in a suitable solvent ant in the pre~ence of an alkaline agent to lead to compound 12. The latter treated by an acid in organic olution leads to the amine L3. The latter is converted into pyrrolic derivative ~ as has been indicated pre~iously.

Finally, the ester function is converted into amlde by action of ammonia or, preferably, by using the complox ~alt formed by the hydrite of lithlum-aluminium and ammonla in thc tetrahydrofuran.

3~ ~175425 The following non-limiting examples are given by way of illustration for the preparation of the compounds (I).

Method A
___----------1 (Dimethyl-2, 5 pyrrolyl-1)-2 diisopropylamino-4 butyrarnide (C M 77 53 ) ~;~3:
(I) Rl = H; R2 = CH3; R3 = R4 = CH~CH

1) Amino-2 diisopropylamino-4 burytic acid __________ __________________ _______ The mixture of 17. 3 g of ethyl (diisopropylamino-2 ethyl)-2 acetamidomalonate and 4. 4 g of sodium hydroxide ln 300 ml of water and 150 ml of ethanol at 96 is refluxed for 3 hours. The mixture is evaporated to dryness and the residue is taken up in 200 ml of 2N hydrochloric acid; the mixture is refluxed for 5 hours.

After cooling, the mixture is neutralised to pH 7 by the addition of a solution of ~odium hydroxide. The mixture is evaporated to dryness and the residue is taken up in chloro-form. The insoluble sodlum chloride is filtered, the solution is dried over sodium sulfate and is evaporated to dryness.

The residue constituted by a brownish solid (11. 3 g) i8 used as such f or the following operation.
2) Methyl amino-2 diisopro~ylamino-4 butyrate ____ _________________ ___________ ____ 22 g of thionyl chloride are added to 30 ml of methanol, with cooling, 50 as to maintain the temperature be~w -5C, then 37 7 g of the acid obtained hereinabove are added in portions, always malntaining the temperature lower than -5C.
When the addition is finished, the temperature is allowed to return to ambient temperature, then the mixture is heated for 2 hours at 40~C. The methanol is evaporated and the residue i8 taken up in the minlmum of water; 500 ml of ether are added and, with stirring, the aqueouo phase 18 saturated with potas-sium carbonate. The ethereal phaso ls ~eparated and the aqueou~ phase 19 re-extracted wlth ether. The ethereal ex-tracts are combined, drled over sodium sulfate and evaporated to dryne s 9 .

A yellow liquld remain~ (13 g) u~et as such for the following operation.
3)~n~ino-2 diisopro~ y~mino-4 butyramide ___________. __ _ ___________ _______ In an autoclave cooled by ai~ ice bath, the solution 10 of 3 g of the preceding ester i~ placed in 20 ml of ab301ute ethanol and a current of ?mmonla 1~ bubbled thorein for 1 hour.
The autoclave ia clo~ed and heated at 150C for 36 hours.

The alcohol 111 evaporatet and the residue i9 taken u~ in water and chloroform. The organic phase is ~eparatet 15 and washed with water. The aqueou~ phases are evaporated to dryness and the residue i~ extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate and evaporated to dryne~.

A coloured liquid remains (1. 54 g) used without 20 purification for the following operation.

4) CM 7753 ________ The previously obtained oil (1. 54 g) and 0. 98 g of hexanedione-2, 5 is dissolved ln 40 ml of acetic acid and the mixture i8 heated at lOO-C for 3 hours. The 301vent iB evapora-25 ted then alkallnized with diluted 30dium hydroxi de . It is extrac-ted wlth ether, the ethereal phase is dried over sodium sulfaee and evaporated to dryness. A blactcish, viscous liquid is obtai~
which 19 chro matographed over an alumina column, eluting by the 70:30 (vol/vol) mixture of hexane-cthyl acetate.
A yellowish solid (1 g) {~ obtained which is recrystal-.

1 17~425 ~.

llsed in isopropylic ether. Finally, colourless crystal~ are obtained; m.p. 71-72C.

Method A
2 (Dimethyl-Z, S pyrrolyl)-l (diaza-l, 4 bicyclo~4, 3, O)-nonvl-4)-4 butvram}de (CM 40018) (I) Rl = H; R2 = CH3; -N~ 3 = N N-; n=2 1) methyl (dlmethyl-2, 5 pyrrolyl-l)-2 bromo-4 butyrate ____ __ _ __ ___________ ____ ____________ ____ The mixture of 30 g of hydrochloride of methyl amino-2 bromo-4 butyrate, 17. 7 g of hexanedione-2, 5 and lQ 6 g of anhydrous sodium acetate in 500 ml of acetic acid is heated at 100C for 3 hours. The acetlc asid is evaporated in vacuo, then the residue is taken up with water and ether. The ethereal layer is separated and wa~hed successively with water, with a solution of sodium bicarbonate and again with water. The solution is dried over sodium ~ulfate, then the solvent is evaporated to dry^
ness.

The residue is chromatographed over a silica column eluting with the 9:1 (vol/vol) pentane-ethyl acetate mixture.
By evaporation, a crystallised solid iB obtained which is washed with petroleum ether. Weight: 15.1 g; m.p. 79~C.
2) Methyl (dimethyl-2, 5 pyrrolyl-1)-2 (diaza-l, 4 bicyclo-C4. 3. Ol-nonyl-4)-4 butyrate _______ _, __________ ___________________________ The mixture of 11 g of the ester obtained hereinabove `~ and 10.1 g of dlaza-l, 4 bicyclo-C4. 3. Oj-nonane in 150 ml of toluene is refluxed for 48 hours. After cooling, the organic solution is washed with water, dr~ed over sodium sulfate and the solvent is evaporated to dryness in vacuo.
The residue is chromatographed over an alumina 30 column, eluting with the 95:5 (vol/vol) pentane-ethyl acetate mixture, --` ` 1 175425 An oil (9 g) i~ obtained, used as such for the follo-wing operation.
3) CM 40018 _ _ _ _ _ _ _ _ In the suspension of lo 71 g of lithium-aluminium

5 hydride in 100 ml of anhydrous tetrahydrofuran, a current of dry ammonia gas i3 bubbled until the end of precipitation. The ~olution of 3.19 g of the ester obtained in the preceding para-graph in 40 ml of tetrahydrofuran is then added with stirring, then the mixture i8 heated at 55-60C for 3 hours 30 minute~.
10 The mixture is cooled by an ice bath and hydrolysed by a 40%
sodium hydroxide solution. It is filtered and the solvent is evaporated to dryness. The residue is taken up in chloroform and water. The organic phase is separated and the aqueous phase is again extracted with chloroform. The organic extracts are 15 combined and dried over sodium sulfate. The solvent is eva-porated to dryness.

The solid residue is recrystallised in ethyl acetate (1. 7 g); m. p. 166 -167 C.

20 Method B
_ _ _ _ _ _ _ _ _ Phenyl-2 (pyrrolyl-1)-2 diisopropylamino-4 butyramide (CM 7611) (I) Rl~; R2=H; R3 = R4 -~ -CH ~
n=2 3 1) Phenyl-2 (pyrrolyl-1)-2 acetonitrile The mixture of 16, 85 g of hydrochloride of arnino_2 phenyl-2 acetonitrile, 8. 2 g of molten sodium acetate and 26. 4g of dimethoxy-2. 5 tetrahydrofuran in 200 ml of acetic acid is heated at 100C for 2 hours. The acetic ~cid is then cvaporated ln vacuo to dryness and the residue is taken up in ether. The 30 precipitated solid is dried without heat, then the ethereal solu-~ ~1754~ ~

tion is washed with water. The ethereal solution i8 dried over sodium ~ulfate and the ether is evaporated to drynes~.

The residue i~ distilled under a high vacuum,b- P/
0. 03 mm of mercury; 108-112C. The distillate crystallises;
it is recrystallised in hexane; weight: 8 g; m. p. 51C.

2) Phenyl-2 (pyrrolyl-1)-2 dilsopropylamino-4 butyronitrile __________ _____________________________ The mixture of 5.16 g of the ~itrile obtained pre-viously, 1 3 g of sodium amide and 5.1 g of chloro-1 diisopro-10 pylamino-2 ethane in 150 ml of toluene is heated to reflux for 2 hours. After cooling, the organic solution is extracted with a dilute solution of h~rdrochloric acid. The acid aqueous phase is separated, is alkalinised with sodium hydroxide and extrad~d with ether. The ethereal ~olution is dried and the solvent is 15 evaporated to dryness. The residuç is chromatographed over a silica column, eluting by the 8:2 (vol/volJ hexane-ethyl acetate mixture .

6. 35 g of the expected product is obtained, used as such for the foilowing operation.
3) CM 7611 _ _ _ _ _ _ _ The solution of 6. 07 g of the nitri le obtained pre-viously and 22. 5 g of potash in 180 ml of 96 ethanol and 45 ml of water is heated to reflux for 5 hours.

After evaporatlon ~f the alcohol, the residue is tal¢n up in water and chloroform. The organic phase is separated, i9 dried over sodium sulfate and the solvent is evaporated to dryness. The residue is chromatographed over an alumina column . By eluting with the 8-Z ~vol/vol) hexane-ethyl acetate mixture, an impurity is eliminated then, with the 1:1 (vol/vol) mixture of hexane-ethyl acetate, the expected product is eluted.

175~25 By recrystallisation in i~opropyl ether, colourle~s crystals are obtained (4. 5g), m. p. 103-104C.

Me____B_ (Pyridyl-2)-2tpyrrolyl-1)-2 diisopropylamino-4 butvramide (CM 7954) (I) Rl =(~N; R2 = H; R3 = R4 = -CH ~ 3;
n= 2 1) Ethyl (pyridyl-2)-2 (pyrrolyl-1)-2 acetate The mixture of 22 g of amino-2 (pyridyl-2)-2 acetate of ethyl and 32:3 g of dimethoxy-2, 5 tetrahydrofuran in 300 ml of absolute ethanol and 150 ml of acetic acid, i8 heated to reflux for 3 hours.

The solvent6 are evaporated to dryness in vacuo and the residue is taken up in an aqueous solution of sodium bicar-bonate. The solution is extracted with ether and - is dried over sodium sulfate. The solvent Is evaporated to dryness and the residue i9 distilled under reduced pressure;h p./0. 01 mmHg: 115 -12 2 C .
The distillate crystallises; m.p. 75-76C; weight:
11.3 g.
2) ~Sthyl (pyridyl-2)-2 (pyrrolyl-1)-2 diisopropylamino-4 butyrate ___ ______ _____________________________________ The mixture of 15. 65 g of the preceding ester, 3, 57 g of sodium hydride and 12. 4 g of chloro-l diisopropyl -amino-2 ethane in 500 ml of anhydrous toluene is heated at 100C in an atmosphere of nitrogen, for 1 hour 30 minutes.
After cooling, the solution is washed with water, dried over sodium sulfate and the solvent is evaporated to dry-ness Chromatography is carried out over an alumina column.
By eluting with the 95:5 (vol/vol1 pentane-ethyl acetate mixture, --" 1 175425 17. 8 g of the expected product is obtained; m. p. 45-47C.
3) CM ?954 _ _ _ _ _ _ In the suspen~ion of 1.14 g of touble hydride of lithium-aluminLum ln 60 ml of anhydrous tetrahydrofuranJ
a stream of dry ammonla ls bubbled untll the complex had finlshed precipitating. The solution of 7.14 g of the ester ob-tained herelnabove i9 added in 40 ml of tetrahydrofuran and the mixture is left, with stirrlng, at ambient temperature for 24 hours.

Hydrolysis i~ carriet out by addition of 40% solu-tion of ~odium hydroxide, the in!~oluble matter is filtered and the tetrahydrofuran i9 evaporated to drynes~. The residue is taken up in ether, the organlc solution is washed with water, dried over sodium sulfate and ev~porated to dryness. The residue is recrystallised ln lsopropylic ether.

Colourless crystals are obtained (3. 35 g); m. p. 128-129C.

Method_C_ Methyl-2 (pyrrolyl-1)-2 diisopropylamino-4 butyramide (CM 40019) ,CH 3 (I) Rl = CH3; R2 = H; R3 = R4 CH~cH

1) ethyl isocyano-2 methyl-2 dilsopropylamino-4 butyrate 14. 54 g of ethyl isocyano-2 propionate and 19. 75 g of chloro-l diisopropylamino-2 ethane are dissolved in 300 ml 25 of anhydrous ether and 120 ml of dimethylsulfoxide. Cooling i~ effected with an ice bath and a suspension of 5. 73 g of 55-60%
sodium hydride in 90 ml of anhydrou3 ether is added by frac-tions. The addition terminated, the mixture is refluxed for 2 hours. After cooling, the reaction mixture is poured in 300 ml 30 of glacial water. The organic phase i~ decanted and the aqueous phase is extracted three times wlth ether. The organic extracts ~ ~754~5 are combined and washed with water. Drying ls effected over sodium sulfate and the solYent i8 evaporat ed to dryne~s.

The reYidue i8 distilled under reduced pressure;
B. p. / 0. 7 mmHg: 102-106~C; welght: 16 g.
2) Ethyl amino-2 methyl-2 dliso~ropylamino-4 butyrate .__________ _____ ________ ___ __________ _ __ In 60 ml of absolute ethanol to which 1 57 g of water is adted, hydrogen chloride is bubbled up to saturation.

The solution i8 cooled below -lO~C and 16 g of the isocyanate obtained previously dissolved in 18 ml of absolute ethanol are added, then the temperature is allowed to ri~e progressively up to ambient temperature and the mixture is left to stand for 20 hour3 at this temperature. The solvent i8 evaporated to dryness in vacuo and the residue i9 taken up in ether. The ethereal ~olution i8 washed wlth a saturated solu-tion of potassium bicarbonate in water. The aqueous phase i9 s eparated and extracted with ether. The ethen~l extracts are combined, dried over potassium carbonate and the solvent i~
evaporated to dryness.

An oil remains (14. 75 g) used as such for the follo-wing operation.
3) Ethyl methyl-2 (pyrrolyl-1)-2 diisopropylamino-4 butyrate ______ __ _ _ _ __ _ ______________________ ____ The mlxture of 2 g of the aminoester obtained here-inabove and 2.17 g of dimethoxy-2, 5 tetrahydrofuran in 30 ml of absolute ethanol and 15 ml of acetic acid is heated to reflux for 18 hours. The solvents are evaporated to dryness in vacuo and the residue is taken up in ether. The ethereal solution is washed with water, then with an aqueous ~olution of sodium bi-carbonate and again with water. The substance is dried over sodium sulfate and the solvent i8 evaporated to dryness. Ch~
matography is carried out on an alumina column.
By eluting with the 98:2 (vol/vol) pentane-ethyl acetate mix--` : I t 75425 ture, 1.1 g of the expectcd product i8 obtained.
4) CM 40019 _ _ _ _ _ _ _ _ The modu~ operandi ~8 a8 indlcated in Example 4, paragraph 3, u~lng the ester propared prevlou~ly and reduclng the duratiorl o reactlon to 1 hour instead of 24 hour~.

By thc same treatment, the expected amlde i3 obtalned .vlth a yield of 60%;m. p. 79 - 80 C (~etroleum ether (b. p. 40-65-C) ~.

EXAMPLES 6 to 11 By operatlng accordlng to E:~camples 1 to 5, but by varying the reagent~, the products fihown in Table I
hereinbelow are obtalned.

For each of the products (I), the code number, the nature of the sub~tltu ento, the method of preparatlon used 15 and finally the melting point and crysta1lisation solvent, are indicated.
T A B L ~
m~O ( CNdOe Rl R R3 ll R4 M~thod talli ation . . _ .
I 7640 ~'-C113 2 -Cll - c~3 ¦_C~CII ~ role~m eth;rl ¦ 40017 ~ -CH3 2 N 3 A2 1 l24-l25(et)hyl ¦ 40002 HCH8 2 C2H5 C2Hs, A1 li 88~89(i,~,opro_ 7921, HH 1 2 ~-CH~CH -CH~c~3 Al 68-69 (hexane) ¦. ! . -i~olated ~n i I the form of 40020 H -C2H5 I 2 1 " I n Al hydrochloride ! , , I 122-124 Sm~-thyle thyke~ne --\ t T A B L E I (cont. ) Code ¦ Rl I R2 1 ~ ¦ R3 ~ R4 ~ nLp. C (crys-No. tallisation ~ol . ._ . _. . ----___ .___ ~ i so~a~ eZrln the . ~CH !~ 3 ~ 3 ~ form of 40021 -CH -CH~ 3 11 2 ~ c~ C hydrochloride 1 2C~13 . 3 ~ 184-186 (iso-I propanDl) iH3C isolated inl~
40105 H -CH3 2 ,Nrp 11 Al form of tosy-! i j I ~isopropanol) ! j H3C I i ' I I isolated in th~
. . I ~ ~CH~I i form of fu-40169 H -CH3 2 ~ 3C~ C 1 Al ! ma~atel65-166 l H~ I (ethanol) , . , ! .

40176 I H I-CH3 12 ~ -CH2C112CH3 ¦ -CU2cH2c~3l A~ thla~fed in f ¦ ! I ¦ hyarochloridei , , . I 198-199 (iso-l I ~ ¦ C113 CH3 i propanol) 3 401~8 I H I-CH3, 21 -c~-cH2cH3~CH-C~2cH3 Al ¦ i80lated in~
; . I rate, 147-148 !j . ¦ (acetone~ j l ,CH3~CH3 !
3 40201 H I-CH3 ~ 3 -CH .-CH~ ! Al i 80-81 t~sopro, . ' C 3 CH3 3 I pylic ether) ~.i . ~ I
, 40261 H -CH3 1 2 ¦ ~0 ~0 1 tane) Tho products of the invention have been studed in animal pharmacology and in particular with a view to demon-~tratlng their properties.
Arrhythmic properties Pr0tocol _ _ _ _ _ _ _ _ The anti-arrythmic power of these molecule~i was assessed on an animal model of ventricular arrythmia.

Mongrel dogs are anae~thesized then ~ubjectcd to the po~itlonlng, by retr~grado catheterlsm, of a metal spir~
In the coronary bed. At the same tlme, a mlcro-emltter 5 {requency modulator ls fixed to the animal's back and connected to two precordial electrodes.

The anlmal returned to its box then shows a pro-gressive thrombosis of the anterior interventricular artery.
Thus a localised, transmural myocardial infarction i9 consti-10 tuted, generating an abnormal, but repetitive electrical activity:ventr}cular tachycardia.

In this state, the drugs are administered per os (P. O. ) and the telemetered cystem enables the development of tho arrythmia to be followed in real time.

The sinusal systolic complexes and pathologies are permanently counted by electronic processe~.

Thus, the quality and duration of action of the pro-duct may be quantlfied.
Results _ _ _ _ _ _ _ The results concerning variou~ products are shown ln Table II hereinbelow.

The activity of the tested products on the ventrlcular tachycardla ls expressed either by the re-establishment of the sinu~al rhythm, or by a considerable improvement in the ratio:
s~umber of abnormal complexe~
number of sinusal complexes .

~ 175425 T A B L E II

Producto Do~e,mg/kg Number - Effect on the ventr}cu CM No.P. O of animal~ lar tachycardia CM 761150 3 Sinusal rhythm or improvement between 70-90% from 3 or 4 hours CM 775350 4 Sinu~al rhythm or 9 0 % improvement from 1 1/2 hrs to 5 hours CM 764050 1 Sinuaal rhythm or - 90% ~mprovement for 90 minutes 15 Activit~ a~ blood platslet anti-a~f~reeant Experimental protocol ___ ____ _______ In vitro and ex vivo studie~ of the anti-aggregant activity were made according to Born's turbidiuretic technique.

The in vitro stud}e~ were made on platelet-rich 20 plasma (PRP) prepared from human venou~ blood.

The trarlous solutlons of the products to be tested were prepared extempo~aneously. The CM 7753, 7611, 7640, 7921, 7954, 40018, 40020 were dissolved a~ a concentration of 2 x 10 M in acetone.

2 x 10 3 M aqueous ~olutions were prepared for the CM 40169, 40178, 2 ~CIl of the acetone solutions of the products or 40 ~1 of the aqueouY solution3 are incubated for 10 minute~
at 37C with, regpectively, 388 and 350~1 of PRP. After this period of incubation, 10~ 1 of the solution of collagen at 40~ug~n1 are added For controlg, 2~4~1 of acetone or 40 ~1 of distilled water are u~ed.

1175425 ~ .
.

The ex vivo studies in the baboon were made solely on the antl-aggregant activity Of the CM 7753. In this casc, tho CM 7753 is administered orally at a rate Of 50 mg/kg/day for a period of 5 days.

Blood sampleq fOr analysing the platelet aggregatlon were made before the product was administered, 2 hours after administration of 50 rng~kg on day 1 and 2 hours after the last administration of day 5.

Platelet aggregation was quantified by the graphic determination of the maximum amplitude Of aggregation (MA).

The results are expressed in % Of inhibition of this parameter calculated with respect to the control (100% aggre-gation) .
Results _ _ _ _ _ _ _ In vitro study From the products studied, two proved particularly active wlth respect to the platelet aggregation induced by the collagen. These are CM 7640 and CM 7611 ~IC50 approximately situated at 30 ~M).

The products CM 7753 and 7954 inhiblt at 50% the platelet aggregation at a concentration close to 100 ~M. Other products, CM 40018, 40020, 40169, 40178 and 7921 inhibit the phenomenon Of aggregation less strongly (20 to 30% inhibition at a concentration Of 100~M).
ER vivo studv Studied under ex vivo conditions, the CM 7753 particularly inhibits the platelet aggregation induced by the collagen.
In four baboons used in the study, 100% of inhibition was obtained after 5 days of treatment at the dose Of 50 mg/}cg/

day. Al~ anti-aggr~gant activity of lesser importance is also observed with respect to ADP.

These results show that the products according to the invention are endowed with a strong activity on experl-5 mental arr~,ythmia and present a considerable blood plateletanti-aggregant activity. Consequently, the products (I) may be used in human therapeutics as protectors of the myocardium for correcting disorders in the ventricular rhythm of ischaemic origin as well as disorders in platelet aggregation.

The products may be presented in galenic forms of administration to be taken orally (tablets, capsules, ~tc. . . ) and parenterally (injectable ampoules).

The dose necessary for a platelet anti-aggregant activity or for restoring the sinusal rhythm in human being~ is l~ct~,een about 50 and 150 mg by the I. V. route andabout 400 and 800 mg by t~e oral route, per day.

By way of example, the following galonic pre-paration i8 indicated:
T blets CM 7753 0. Z00 g Microcrystalline cegubse 0.140 g Lactose 0. 140 g Magnesium stearate 0. 020 g

Claims (2)

The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:

1. A process for the preparation of derivatives of pyrrole of formula (I) in which:
-R1 represents a phenyl radical or a pyridyl-2 radical, -R2 represents an atom of hydrogen or a lower alkyl radical -R3 and R4, which are identical or different, each represent a lower alkyl or cycloalkyl radical, or the group designates a cyclic amine radical comprising 1 or 2 cycles and being able to possess a second heteroatom and comprise substituents, and -n is equal to 2 or 3 as well as the salts of these derivatives with the minerals or organic acids, the process comprising converting a compound of formula in which A is a nitrile group -C?N or an ester group -COO-alkyl with a ?-diketon of formula or dimethoxy-2, 5 tetrahydrofuran;
reacting the compound obtained with an amine derivative of formula:

(Hal being in halogen atoms) and then converting group A into an amide group.

2. A pyrrole derivative of formula (I) as defined in claim 1 when produced by the process of claim 1 or any obvious chemical equivalent thereof.