CA1050556A - Aminopyrrole derivatives - Google Patents

Abstract

Abstract of the Disclosure New pharmacologically active aminopyrrole derivatives of the general formula I

wherein:
R is selected from hydrogen, (C1-4)alkyl, benzyl and halo-sub-stituted benzyl;
R1 represents hydrogen, (C1-4)alkyl, phenyl or substituted phenyl;
R2 is a member of the class consisting of hydrogen, (C-4)alkyl, formyl, (C2-4)aliphatic acyl, benzoyl, [carbo(C1-4)alkoxy]-(C2-4)aliphatic acyl, carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzone-sulfonyl, (C1-4)alkylsulfonyl, tolenesulfonyl, phenacylsulfonyl;
R3 is selected from hydrogen and (C1-4)alkyl;
R4 represents (C2-4)aliphatic acyl, benzoyl, substituted benzoyl, carbo(C1-4)alkoxy, carboxy, carbamyl, methylcarbaml or phe-nylcarbamyl;
R5 is selected from the group consisting of hydrgen, (C1-4)alkyl carbo(C1-4)alkoxy, [carbo(C1-4)alkoxy]mehyl, trifluoromethyl, carboxy, carbamyl and carbazoyl;

R2 and R3 taken together represent (C2-4)alkylidene, benzylidene, or halo-substituted benzylidene;
R4 and R5 taken together may also represent a group -CO-(CH2)n-, wherein n is an integer selected from 2, 3, and 4;
with the proviso that when R1 and R5 simultaneously represent mothyl and R is hydrogen, one of R2 and R3 must be different from hydrogen and R4 cannot be carbethoxy;
and salts therewith of pharmaceutically acceptable acids.

Description

The present invention is concerned with new aminopyrrole derivatives of ~he following general formula

2 R ~( R

R

and pharmaceutically acceptable salts thereof with acids, wherein R is selected from hydrogen, (Cl 4) alkyl~ benzyl and halo-substituted benzyl;
Rl represents hydrogen, ~Cl 4) alkyl, phenyl and substituted phenyl carrying one to three substituents independently selected from ~Cl 4) alkyl, CCl 4) alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro, R2 is a member of the class consisting of hydrogen, ~Cl 4)alkyl, '! 10 formyl, (C2 4) aliphatic acyl, benzoyl, /carbo~Cl 4) alkoxy7-~C2 4) aliphatic acyl, carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulfonyl ~Cl 4) alkylsulfonyl, toluenesulfonyl, phenacylsulfonyl; R3 is selected from hydrogen and (Cl 4) alkyl; R4 represents ~C2 4) aliphatic acyl, benzoyl, benzoyl carrying one to three substituents:independently selected from fluoro, chloro, bromo and ~Cl 4)alkoxy, carbo ~Cl 4)alkoxy, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl; R5 is selected from the group consisting o hydrogen, ~Cl 4)alkyl, carbo(Cl 4)alkoxy, ~carbo~Cl 4)alkoxy/methyl~ -trifluoromethyl, carboxy, carbamyl and carbazoyl; R2 and R3 taken together represent ~C2 4)alkylidene, benzylidene, or halo-substituted benzylidene;
R4 and R5 taken together may also represent a group -C0-(CH2)n-, wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4 and n is an integer selected from 2, 3 and 4; with the proviso that when Rl and R5 simultaneously represent methyl and R is hydrogen, one of R2 and R3 must be diferent from hydrogen and R4 cannot be carbethoxy; and pharmaceutically acceptable salts thereof with acids~ : :
This invention also relates to a process for preparing a compound :: ~

h~ j - 2 -~, . .

-of the formula \ N R4 1~ ~
N :~

and pharmaceutically acceptable salts thereof with acids wherein R is selected from hydrogen, (Cl 4)alkyl, benzyl and halo-substituted benzyl;
Rl represents hydrogen ~Cl 4)alkyl, phenyl and substituted phenyl carrying one to three substituents independently selected from (Cl ~alkyl, CCl 4)alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro; R2 is a member of the class consis~ing of hydrogen, ~Cl 4)alkyl, formyl, ~C2 4) aliphatic acyl, ben7oyl, /carbo(Cl 4~alkoxy7-~C2 4)aliphatic acyl, carbamyl, ~:.
phenylcarbamyl, thiocarbamyl, phenyl~hiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulfonyl, ~Cl 4)alkylsulfonyl, toluenesulfonyl, phenacylsulfonyl;
.

.;~
:.
;
, . . . .
: .
,.. . .

, ~;,; .
.. . .
. ' ' :' .
., . :. .

::. - .
! :~ "
.' ~. .

' ~ ' ''"''' ~q:i 5~5~
R3 is selected from hydrogen and (Cl ~)alkyl;
R4 represents (C2 ~)aliphatic acyl, benzoyl, benzoyl carrying one to three substituents independently selectcd from fluoro, chloro, bromo a~d (Cl 4)alkoxy, carbo(Cl ~)alkoxy, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl;
R5 is selected from the group consisting of hydrogen, ~Cl 4)alkyl, carbo(Cl ~)alkoxy, ~carbo(Cl ~)alkoxyJmethyl, trifluoromethyl, carboxy, car~amyl and carbazoyl;
R2 and R3 taken together represent (C2 4)alkylidene, benzylidene, or halo-substituted benzylidene;
R4 and R5 taken together may also represent a group -CO-(CH2)n-, wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4 and _ is an integer selected from 2, 3, and 4; with ~he proviso ~hat when Rl and R5 simultaneously represent methyl and R is hydrogen, one of R2 and R3 must be different , from hydrogen and R4 cannot be carbethoxy;
which comprises reacting subs~antially equimolecular amounts of an a-aminoni~rile of the general formula fN
/ Cll II

R NH
1 .
R

or an acid addition salt thereof, wherein R is hydrogen and Rl has the meanings given above, and a compound of the general formula R4 ::
X III
R

wherein R4 and R5 have the above meanings and X represents the groups -C~C- or -CH2-C- wherein the -CH2 portion is linked to the substituent R4, O
and wherein this process step may be followed by one or more of the following steps:
(a) when a c~mpoundof formula I is required in which R2 or R3 or both are ~ -3a-~ ' , . . .

~5~S~6 acyl, alkyl or aryl groups acylating~ alkylating or arylating a corres-ponding compound of formula I in which one or both of R2 and R3 are hydrogen atoms;
~b) when a compound of formula I is required in which R2 is carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl or benzoylthiocarbamyl group reacting a corresponding compound of formula I in which R2 is a hydrogen atom with a cyanate, a thiocyanate, phenylisocyanate, phenyl-isothiocyanate or benzoylisothiocyanate; or (c) when a compound of formula I is required in which R2 and R3 together form an alkylidene, benzylidene or halogen substituted benzylidene group as defined above reacting a corresponding compound of formula I in which R2 and R3 are hydrogen atoms with the appropriate aldehyde or ketone; or (d~ when a compound of formula I is required in which R is alkyl, benzylJ or halogen-substituted benzyl as defined above alkylating, benzylating or halobenzylating a correspond-.Lng compound of formula I in which R is hydrogen, or ~e) when a compound of formula I is required in which R4 is carboxy, carbamyl, methylcarbamyl or phenylcarbamyl, subjecting a corresponding compound of formula I in which R4 is alkoxy to hydrolysîs or reaction with ammonia, methylamine or aniline; or ~f) when a compound of formula I is required in which R5 is carboxy, carbamyl or carbazoyl, subjecting a corresponding compound of fnrmula I ~ .
in which R5 îs alkoxy to hydrolysis or reaction with ammonia or hydrazine, :
and where a base of formula I may be converted into a corresponding : ~.
pharmaceutîcally acceptable acid additîon salt. :
In the specî$icatîon and claims the term "(Cl 4)alky1" re$ers to an alkyl radîcal containing 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl; the term "halo-substituted benzyl"
essentially identifies a benzyl radical substituted în the aromatic ring with ~luoro, chloro or bromo such as, ~or înstance, p-chlorobenzyl, o-chlorobenzyl, p-fluorobenzyl, o-bromobenzyl and m-bromobenzyl; the term ~: -3b-. .

Si5~
"substituted phenyl" designates phenyl radicals suhstituted with 1 to

3 groups independently selected from (Cl 4)alkyl, (Cl 4)alkoxy, ." .~

~ -3c-j 1~50556 I ¦benzyloxy9 fluoro, chloro, bromo, hydroxy and nitro; the term ; ~ -''(C2 4)aliphatic acyl refers to an aliphatic acyl radical containing 2 ~o 4 carbon atoms such as acetyl~ propionyl, butyryl and iso-¦butyryl; "(Cl 4~alkoxy" identifies alkoxy groups containing I
to 4 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, buto-: Ixy, tert-butoxy; the term "substituted benzoyl" refers to a ¦benzoyl radical carrying 1 to 3 substituents independ~ntly selected f~om fluoro, chloro, bromo and ~Cl 4)alkoxy; a "(C2 4~ alkylidene"
~ radical is essentially identifled by ethylidene, propylidene, .~ isopropylidene, butyli~ene and isobutylidene; the term "halo-substi-tuted benzylidene" designa~es a benzylidene radical substituted in the aroma$1c ~ing with chloro, fluoro or bromo such as, for : instance, o-chlorobenzylidene, m-chlorobenzylidene, p-chlorobcnzy- ~ :
- . lidene, p~fluorobenzylidene, o-fluorobenzylidene, m-bromoben7ylide-ne.
When the radicals R4 and R5 taken together reprcsent a group : :
. -CO-tCH2)n- the carbonyl group is connected with th~ carbon atom ~ . of the pyrrole ring which bears ~he substituents R4. .
.- ; A preferred group of compounds of fo~mula I comprises those D ~herein R is hydrogen~ methyl, benzyl or chloro-substituted benzyl, :
: Rl represents hydrogen, phenyl, phenyl substituted with methyl, ~e-thoxy, fluoro or chloro, R2 is selected from hydrogen, acetyl, ¦methyl or methylsulfonyl, R3 is hydrogen or methyl, R4 is acetyl, propionyl, butyryl, isobutyryl, carbomethoxy, carbethoxy, carboxy, j carbamyl or benzoyl, R5 stands for hydrogen, methyl, carbomethoxy, ''': ~
iO7 1 .
, , ,"~ ~ ' I I - j - ~5~556 -~carbamyl OT carboxy, R2 and R3 taken together re~resent benzylidene or chloro-substituted benzylidene, R4 and R5 taken together are the group -CO-(CH2)3- wherein the carbonyl group is connected with the carbon atom of the pyrrole ring bearing the radical ~4, and salts therewith of pharmaceutically acceptable acids.
The method for preparing the compounds of the invention comprises reacting an a-aminonitrile of the general formula ¦ Rl ~H
or an acid addition salt thereof, wherein R is hydrogen and Rl has .
¦¦~he e nin8 glven above, with a compound of the general formula~

\ R5 III

where R4 and R5 have the above significance and X represents a group -C~C- or a group -C112~ herein the -CH~- portion is linked to the substituent R4 . It is obvious to any person who is skilled in the art that substances which have chemical properties similar to those displayed by ~-dicarbonyl compounds or by acetylenecarbonyl compounds may advantageously be employed such as, for instance, substances of for~ula III in which X is -CII=C- hal, wherein hal represents a halogen atom, prefera- I .
bly chlorine and ~he carbon atom bearing the halogen atom is linked to the radical R~. ` .
The starting aminonitriles are prepared following substantially the method described by Steiger in Organic Synthesis, ~' , ' ' . .
, ... .~ , ~507 " ''I I ,.

~ ~ 105055~

1 22, 13, 1942 and 22, 23, 1942.

The compounds of formula III either are commercially available products or are obtained through obvious modifications of commer-cially available products.
; The reaction generally proceeds with the ormation of an intermediate open chain compound representable by the following general formula IV or its tautomeric iminic form ¦¦ Rl ~ ~ 5 IV

which, if desired, may be isolatecl, purified and characterized by means of common analytical procedures before being cyclized to the end compounds of formula I. However, it may also be used as a raw material for the subsequent cyclization step without affecting the final yields.
The reactants II and III are contacted in substan~ially equi-molecular amounts in the presence of an anhydrous organic solvent which is advantageously selected from benzene, dioxane, tetrahy-drofuran, lower alkanols and analogs. A small amount of p-tolue-nesulfonic acid as the catalyst may be added and the mixture isrefluxed for a time varying from 2 to 28 hours. The intermediate compound of formula IV which forms may be isolated and characte-rized, if desired, or employed as such for the subsequent cycliza-tion stepJ which is carried out in the presence of basic catalystsJ

2~ selected from carbonates, hydroxides, alkoxides, hydrides and amides . ~
Lp. S07 ll - 6 :~L05055~j 1 of the metals of the I and II group of the periodic table of the elements. Also in this case the reaction is carried ou~ in the presence of a solvent which is preferably selected f-rom an-hydrous lower alkanols with a maximum of four carbon atoms. The cyclization may take place at room temperature, but sometimes it is necessary to heat or to reflux ~he reaction mixture, in order to speed up the cyclization reaction which is completed within an in~erval of time ranging from 1 to 30 hours In some instances it has been observed that when X represents a -C-C- moiety, the formation of the aminopyrrole derivatives of ormula I may take place in one reaction step only. In this case, ~he aminonitrile of ~he formula IX or an acid addition salt thereof and the compound of the formula III wherein X is a -C~C- group, are mixed together in substantially equimolecular ratios, in the pre-sence of an organic solven~ as, for instance, an anhydrous~Cl 4)alkanol, chloroform, ~e~rahydrofuran, benzene and analogs and an alkali or alkaline earth metal carbonate or hydroxide as the catalyst~
and the resulting mixture is refluxed for about 3-5 hours.
The final compounds of formula I are recovered from the reaction mixture as the free bases or in form of salts of pharmaceutically acceptable acids, ollowing techniques which are entirely familiar to a skilled chemist.
These techniques comprise removing the solvent from the reaction mixture by e~aporation, taking up the residue witl- a solvent, evaporating again the solvent and purifying the obtained solid, Lp. 50, ~ 7 . ,, . ;

~5~556 1 liquid or oily substance by recrystallization, fractional di-: stillation, or distillation under reduced pressure. If a crystalline solid directly results from the reaction, this is recovered simply by filtration, and, if necessary, purified by recrystallization.
Recrystallization solvents are preferably selected from Cl-C4 lower alkanols, diethyl ether or mixtures thereof.
The above mentioned salts of the compounds of formula I with pharmaceutically acceptable acids are essentially represented by the hydrochloride~ hydrobromide, hydroiodide, sulfate, pho-- 10 sphate, benzoate, oxalate, acetate, methanesulfonate,cyclohexyl-sulfonate and analogs and accorclingly are included within the sco-pe of the invention. They are easily obtained by treating a compound of formula I as ~he free base with a predetermined pharmaceutically acceptable acid. In turn, it is possible to ~5 restore the free base from the corresponding acid salt by reac~ion with at least one equimolecular amount of a basic agent.
Pursuant to the outlined procedurss, compounds of formula I
are obtained, wherein R, R2 and R3 are hydrogen atoms, or their acid addition salts. When sybstituents R2 and R3 different from hydrogen are desired they are introduced through well known pro-cedures by reacting the compounds of formula I with appropriate reactants. Thus for instance, the reaction with a mono-halide of a dicarboxylic acid of 3 to 5 carbon atoms in which the second carboxy group is esterified with a (Cl 4)alkanol affords a compound wherein R2 is /carbo(Cl 4)alkoxy7-(C2 4)aliphatic acyl, Lp. 507 _ _ ,, ' ' : ' .

~L050556 1 whereas the reaction with an alkylating agent, as for instance, mixtures of formic acid and formaldehyde, (Cl ~)alkyl halides or (Cl 4)alkyl sulfates gives compounds wherein R2 rR3 or both represen~ ~Cl 4)alkyl. Compounds where R2 is a (C2 ~) aliphatic ; acyl radical or benzoyl are obtained by reacting a compound of formula I with halides or anhydrides of ~C2 4)aliphatic or benzoic acids~ whereas the benzenesulfonyl, toluencsulfonyl, (Cl 4)alkylsul-fonyl and phenacylsulfonyl derivatives are conveniently prepared by reaction with benzenesulfonyl, toluenesulfonyl, (Cl 4)alkylsulfonyl or phenacylsulfonyl halides respectively.
- The carbamyl and the thiocarbamyl groups as ~ell as their methyl-, phenyl- and benzoyl- analogs are introduced by reacting the aminopyrrole of formula I wherein R2 and R3 represent hydrogen, with the appropriate isocyanate or isothiocyanate compound.
The replacement of one of the hydrogen atoms of the amino group - at the 3-position by formyl is achicved by contacting a predeter-; mined 3-aminopyrrole with formic acid in substantially equimolecu-lar ratios whereas the compounds wherein R2 lS carboxy-phenyl are obtained by reacting a compound of formula I wherein R2 is hydro-gen with a predetermined benzoic acid substituted in the aromatic ring with a halogen atom. Finally, substances where R2 and R3 taken together represent (C2 ~)alkylidene, benzylidene or halo-; substituted benzylidene are easily prepared according to the known reactions for obtaining Schiff's bases from amines and carbonyl 2; compounds.
;i~, __ .
Lp~ 507 _ _ , .

~ 5~ 5~ ~
l The substitution on the ring nitrogen atom generally does not take place under the reac~ion conditions employed for in~rodu-cing the radicals R2 and R3 on the nitrogen atom at the position 3. ~ convenient method for introducing the desired substituents according to formula I on the nuclear nitrogen atom of the pyrro-le ring involves reaction of a predetermined compound of formula I wherein R is hydrogen with a selected (Cl 4)alkyl, benzyl or halo-substituted benzyl halide in the presence of a strong basic agent, preferably an alkali metal or an alkali metal hydride, in an inert organic solvent, such as, for instance~ dimethyl-formamide, under nitrogen atmosphere. The reaction is carried out at room temperature. The desired aminopyrrole substituted at the position 1 is then isolated in good yields -from ~he reaction mixture. It is understandable that under these reaction conditions, when either R2 or R3 or both represent hydrogen in the predetermi-ned compound of the formula I, also these atoms may be replaced by the substituents outlined before. Accordingly, in the obtained compound, also the amino group at the 3-position can contempora-neously be substituted for instance by one or two (Cl 4)-alkyl groups. However, if compounds of formula I wherein R2 and/or R3 are hydrogen which are substituted on the nuclear nitrogen atom are desired, it is necessary to protect the amino group at the 3-position e.g. by reaction with a carbonyl compound or an alkylsulfonyl or benzenesulfonyl halide to prepare the correspond-ing Schiff's base or the alkylsulfonyl or benzenesulfonylamino . _ _ _ _ Lp. 507 , . . , . ,,:
.

lOS~)556 l derivatives respectively. Then the substitution at the l-posi-tion is carried out as outlined above and an acidic hydrolytic cleavage of the protecting group affords the desired compounds wherein R2 and/or R3 represent hydrogen.
Methods involving sulfonylation of the amino groups in the po-sition 3 provide also a useful route for preparing compounds of formula I wherein R is hydrogen, R2 is hydrogen and R3 is a (Cl 4)alkyl group. Said route consists in (Cl 4)alkylating the aminic nitrogen of a compound of formula I wherein R is hydrogen, R2 is benzenesulfonyl, (Cl 4~alkylsulfonyl, toluenesulfonyl or : phenacylsulfonyl, R3 is hydrogen~ according to the usual procedures for alkylating amines. The group R2 as above defined is removed by ` hydrolytic cleavage with acids or according to the method described by J.B. Hendrickson and R. Bergeron, Tetrahedron Letters, page 345, lS 1970.
Also the radicals R4 and R5 may be transformed by known chemi-cal reactions into other ~roups falling within the general meaning given for said substituents. For instance, when a compound of the formula I, wherein either R4 or R5 or both represent a carboxy group is desired, hydrolysis under alkaline or acid conditions of the corresponding mono- or di-carbo(Cl 4)alkoxy derivative gives the desired compound.
The compounds of formula I wherein either R4 or R5 or both re-present carbamyl groups are obtained by saturating with ammonia 2~ an alcoholic solution of the corresponding mono- or di-carbo-_ . _ Lp.507 1l ~ 0 5~ 55~

1 (Cl 4)alkoxy compounds, whereas the compounds where R5 representscarbazoyl are prepared by contacting compounds of formula I
wherein R5 is carbo(Cl 4)alkoxy with hydrazine at room temperature.
Other obvious routes useful for introducing appropriate substituents ; at the desired positions or for modifying a pre-exis~ing radical into another falling within the given meanings, are intended to fall within the scopes of the invention.
The compounds of the invention possess very interesting phar-macological properties: more exactly, they are endowed with remar-; 10 kable antinflammatory and C.N.S. depressant activities.
An aspect of the antinflammatory action was evidenced by meansof the carrageenin induced edema test in rats, which was performed according to the methodology described by C.A. Winter et al., Proc.Soc.Exptl.Biol.Med., 111, 544, 1962. In representative experiments it was found that the compounds of Examples 1, 2, 3, 7, 14, 15, 169 18, 203 21, 23, 27, 34, 82, 47, 50, 52, 59, 70, 71, 74 a), 74 b), 78, 79, 87 caused a per cent decrease of the induced edema varying from about 40 to about 80 when administered ; at dose levels comprised between 1/50 and 1/5 of their LD50 values.

Under the same experimental condi~ions the decrease of the induced edema caused by a widely employed antinflammatory drug as, for instance, phenylbutazone ~4-butyl-1,2-diphenyl-pyrazolidine-3>5-dione) is about 45 per cent, but only when ~he substance is administered at a dosage higher than 1/4 of its LD50. It is to be 2; noted that the toxicities of the aminopyrrole derivatives which ", Lp. 507 , . , . . . _ _ , . ' . : . , ~: ~6~50S~i are the object of the present invention are very low: in fact, apaTt from few exceptions, their LD50 values are always higher than 1000 mg/Kg p.o. in mice, whereas the corresponding LD50 f phenylbutazone is about 390 mg/Kg p.o. Toxicities were determined according to the procedure described by Lichtfield and Wilcoxon, JOPharm.Exp.Ther., 96, 99, 1949.
.

The following table gives a more detailed account of the foregoing mentioned an~inflammatory action.
T A B L E
.' CompoundLD50 mg/KgDose mg/Kg ~ Decrease of the . Example p.o. micep.o._rats induced edema 2 ~ 1000 100 36.5 lS 200 44.3 1 ;' 1000 5 23.4 : 10 32.5 39.0 43.8 100 58.9 200 76.6 3 ~ 1000 100 40.6 200 53.9 14 ~ 1000 5 23.2 31.9 43.5 : 50 50.7 100 69.6 200 75.4 ~ 1000 5 . 23.0 31.1 2; 20 35.1 41.9 Ip. 507 _13 :~05~5i6 . . . . ... ... . ... ~
CompoundLD50 mg/Kg Dose mg/Kg O Decrease of che Examplep.o. mice_ p.o. rats induced edema 100 55.4 2no 67.6 16~ 1000 50 29.6 100 40,8 200 58.3 18>1000 100 35.4 200 47.9 20 500 50 24.3 100 45.9 21>1000 50 24.2 100 37.3 200 44.g 27> 1000 20 29.2 43.1 100 58.5 200 71.0 ~Z>1000 100 41 41 200 56.3 50>1000 20 21.5 38.5 , 100 4g.2 200 69.6 52> 1000 100 24.2 : 20 200 38.7 70> 1000 50 23.9 100 47.9 ; 200 68.2 Lp. 5 07 , . . ~ ' '' ,. , ,, . ~ .
, .. '' ' . , . ;, ,,, ' . .

~ ~ lOSO.56 Compound LD50 mg/Kg Dose mg/~g ~ Decrease of the , Examplep.o. mice ~.o. rats induced edema _ ¦~
71 ~1000 250 23 9 , ; 100 47.
200 69.0 74 a)>1000 100 31.0 200 53.1 ' ' 74 b)~1000 50 11.0 100 34.3 200 52.7 '10 79 >1000 100 38.0 -200 47.6 phenylbutazone 390 50 33 ' 100 45 ,' ~ . , I ~

The compounds of the invention are also endowed with other ,li biological properties which are very desirable in potential antinflammatory substances. They, In fact, possess outstanding antipyretic and analgesic activities, which are respectlvely 3 2, 10 and about 4 times those displayed by acetylsalicylic acid. , ~, ~loreover, the compounds of the invention display a very lot~ i ulcerogenic actlvity which i5 about 5-10 times lesser than the one observed with other known and therapeutically used antinflam- , matory substances e.g. acetylsalicylic acid and ~henylbutazone. -'! Analgesic activity was ev31uated according to L.O.Randall and -J.J0 Selitto, Arch.Int.rharmacodyn., No. 4, C~I, page 4~9, 1957.
'; Antipyretic activity was investigated accordirtg to R.~ ul]cr et . , i . _ _ : __ _ _ ....
~7 _ _ , 15 .' ~ ' 1 al., J~ Pharm.Pharmacol., 9, 128, 1957, whereas the ulcerogenic action was determined according to Thuilliet et al., Chim.
Therap., 39 53, 1968.
As stated above, ~he aminopyrrole derivatives described in the present invention are also active on ~he Central Nervous System:
this characteristic was investigated according to the general method proposed by S. Irwin, Psychopharmacologia (Berl.), 13, 222, 1968. It was found that some of the compounds which showed particularly effective antinflammatory properties as,for instance, lo the compounds of Examples l and 15, were also endowed with a good degree of sedative and myorelaxing activity: this is undoubtedly another very favorable characteristic of the invention compounds, as a certain sedative and myorelaxing effect is use-~ul in patients affected by severe inflammatory diseases.
Some other compounds of the invention display also very interesting ansiolytic properties.
These properties were investigated by means of the "pole climbing avoidance test" in rats, which was performed as described by G. Maffii, J. Pharm.Pharmacol., 11, 129 9 1959~ Representative experiments showed that the compounds of Examples 4, 30 and 46 were particularly effective in inhibiting the secondary condi-tioned response in rats (CR2) at a dosage level which does not affect the primary conditioned response (CR) and tlle unconditioned response (UR~. It is known that the secondary conditioned response is related to an anxious state of the animal and its inhibition , ~

Lp.507 - 16 ~

~ ~ 1050556 `~

1 is directly influenced by the administration of anxiolytic substances.
The results are summarized in the following tablc, in ~hich the toxicity of the compounds tested is also re~orted. The ;; table shows also that meprobamate (2-methyl-2-propyl-1,3-propa-nediol dicarbamate) has considerably lower anxiolytic prope;ties than tlle tested compounds. I
:~ , , . I
T A B L E l ,LO : 7 - . 1 Compound 'LD50 mg/Kg 'Dose mg/Kg' Inhibition of of , ' ~R2 CR UR
Example~ mice ' i.~. mice' Deconditioncd rats/treated rats ` 4 500 30 7/10 3/10 0/10 800 30 4/10 0/1~ 0/10 I; 60 8/10 0/10 0/10 ~6 800 30 4~10 0/10 0/10 meprobamate ~ 500 30 3/10 n/lo o/lo " ' ' , .

While the preferred routes of administration are oral and rectal, parenteral administration can also be employed.
For oral administration, the compounds are compounded into pharmaceutical dosage forms, such as, Çor instance, tablets, capsules, elixirs, solutions and the like. The dosage unit may 2; contain the usual excipients, e.g.~starch, gums, fat~y acids, 507 _ _ 1C~5~556 l alcohols, sugars~ etc~ For rectal administration the compounds are administered in the form of suppositories, admixed with conventional vehicles~ such as, for example, cocoa butter, wax, spermaceti or polyoxyethylene~lycols and their derivatives, The dosage range is from about 0.05 to about 2.00 g. per day, preferably administered in divided dose.
Accordingly the present invention provides a therapeutic composition comprising as the active ingredient a compound of the invention together with a pharmaceutically acceptable carrier.
~ 10 Descri~ion of Preferred Embodiments The following additional descript:lon and examples furtller describe the invention and the manner and process of making and using it to enable the art skilled to make and use the same ahd set forth the best mode contemplated by the inventors of carrying out the invention.
~ ~ ' ~

Example 1 4Acetyl-3-amino-5-methyl-2-phenyl-pyrrole hydrochloride ;` a) A solution of 2 g. (0.015 mole) of 2-amino-2-phenylace-- tonitrile and 1,4 g, (0,014 mole) of acetylacetone in 30 ml. of anhydrous benzene is refLuxed for two hours on an oil bath in the presence of lO0 mg. of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered, then the solvent is evaporated off 2; to give an oily residue whicll is distilled under reduced pressure.

P. 507 _ _ - l 1~ ~ ~ 5 6 1 The obtained intermediate open chain compound boils at 150Ct 0.1 ~mHg.
b) 0.40 Grams of sodium are dissolved in 15 ml. of anhydrous ethanol, then a solution of 2.5 g. of the compound ~repared as in point a) in anhydrous ethanol is added dropwise and the mixturc is allowed to stand at room temperature for four hours. After bubbling dry hydrogen chloride in the ethanol solution, a preci-pitate forms, which is recovered by filtration and recrystallized from ethanol/diethyl ether.
Yield 2.0 g. of the title compound. ~.p. 242C (with decomposition).
; The free base is obtained by extraction with ethyl ace~ate of ~ -~an aqueous solution of the hydrochloride alkalinized with 5~
sodium hydroxide. M.p. 220C (from methanol).
~,: . ' ' , . :' Example 2 `
3-Amino-4-carbethoxy-5-methyl-2-phenyl-pyrrole h~rochloride a~ A solution of 6 g. (0.042 mole) of 2-amino-2-phenyl-acetonitrile and 5 g. t0.042 mole) of ethylacetoacetate in 30 ml.
of anhyd~ous benzene is refluxed for four hourson an oil bath in the presence of 100 mg. of p-~oluenesulfonic acid. After cooling, the reaction mixture is filtered, then the solvent is evaporated of~
to give an oily residue, which is distilled under reduced pressure.
The open chain intermediate compound which is obtained has b.p.
140C/0.05 mmHg.
b) 0.80 Grams of sodium are dissolved in 15 ml. of ~:
P .
507 _ _ ., . , `' 1 ' , ~ 5~D~ ~ 6 anhydrous ethanol, then a solution of 5 g. of the above compound in 35 ml. of anhydrous ethanol is added dropwise and the ~ix~ure is allowed to stand at room temperature for four hours.
Af~er bubbling dry hydrogen chloride in the ethanol solution, a ; precipitate readily forms, which is filtered and recrystallized from a mixture of e~hanol and diethyl ether. Yield 4 g.
M.p.249-252C (from ethanol/ethyl ether).

Examples 3 - 42 lo The following compounds are prepared pursuant to the two steps procedure described in Example 1, starting from the appropriate compounds of formulas II and III and using alkali metal alkoxides or carbonates as the cyclizing basic catalystis. If the open chain intermediate compounds are isolated and characterized, their chemico-physical properties are reported, otherwise it is intended that these intermediates are directly cyclized to the end compounds.

3 - 3-Amino-4-benzo~1-5-methy~-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and benzoylacetone the open chain intermediate compound is obtained melting at 134-X5C (~rom diethyl ether/hexane). The title compound is obtained with 60~o overall yield. M.p. 285-90C (from methanol/
diethyl ether). The free base melts at 203-5C (from methanol~.
~j _ _ .
~p.507 ~ 20 ~

~ 050556 l 4-Starting from 2-amino-2-phenyl-acetonitrile and cyclohexane 1,3 dione the open chain intermediate compound is obtained melting at 138-40C ~from benzene). The title compound is obtained with 58 overall yield. M~po 290-1C. (from ethanol/diethyl ether).

5 - 3-Amino-4-b~-2-pheny~yrrole hydrochloride ~' The open chain intermediate compound melting at 88-90C (~rom hexane) is prepared from 2-amino-2-phenyl-acetonitrile and benzoyl-. lO acetaldehyde. The title compound is obtained with 470 overall ~, yield. M~p. 272-74C (from ethanol).
~1 ~, 6 - 4-Acetyl-3-amino-2-ethyl-S-methyl-pyrrole hydrochloride Starting from 2-amino-butyronitrile and acetylacetone, the open chain intermediate compound is obtained, boiling at 100C/0.02 mml~g. The title product is obtained with 49~ overall yield.
M.p. 245-48C ~from ethanol/diethyl ether). The free base melts at 219-21C (from methanol).
~-.

2 7 _ 3-Amino-4-carbethoxy-2-phenyl-pyrrole hydrochloride The title compound is ob~ained with 450 overall yield from 2-amino-2-phenylacetonitrile and ethyl propynoate. M.p. 244-45"C

(from e'chanol/diethyl ether).

Lp. 507 ,, ,, , " , . ~ .

~ S~ 6 1 8 - a Amino-4-benzoyl-5-carbethoxy-2-phenyl-pyrrole hydrochloride The title compound is obtained with 48~o overall yield from 2-amino-2-phenyl-acetonitrile and benzoyl piruvic acid ethyl ester. M~po 218-9C (from ethanol/diethyl ether).
''' ~

9 - 4-Acetyl-3-amino-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and acetylacetalde-hyde the open chain intermediate compound is obtained, boiling at 140~C/0.05 mmllg. The title compound is obtained with an lo overall yield of 56%. It does not melt up to 335C.
:~

10 - 4-Acetyl-3-amino-2-(p-methoxyphenyl)-~rrole Starting from 2-amino-2-(p-methoxyphenyl)-acetonitrile and acetylacetaldehyde~ the open chain intermediate product is lj prepared, boiling at 180C/0.03 mmllg. Overall yield of the ti-tle compound: 44 ~. M.p. 198-200C (from diethyl ether).
, , . ',.
11- =}~=~ "
Starting from aminoacetonitrile and benzoylacetone the open chain intermediate compound is obtained , melting at 111-12C
(from diethyl ether). Overall yield of the title compound: 52%.

M.p. 225-270C (from ethanol/diethyl ether).

12 - 4-Acetyl-3-amino-S-methyl-pyrrole hydrochloride _~ Starting from aminoacetonitrile and acetylacetone the open l~. 507 ~ _ .'';
.,,, . - . . . .. , : .
,'~ " ' ,, , - .,. . ~

~55~
chain intermediate compound is obtained, melting at 106-8C
(from diethyl ether). The title substance is obtained with 64 overall yield. M.p. 211-12C (from ethanol).

13 - 3-Amino-4-carbethoxy-5-carbethoxymethyl-2-phenyl-pyrrole hydrochloride The ~itle compound is obtained with 42~ overall yield from 2-amino~2-phenyl-acetonitrile and 1,3-dicarbethoxyacetone.
M.p. 232-36C (from diethyl ether/ethanol~.

14 - 4-Acetyl-3-amino-5-methyl-2-(p-tolyl)-py~role The title compound is obtained with 94% overall yield from 2-amino-2-(p-tolyl)-acetonitrile and acetylacetone. M.p. 232-4C
(from ethanol/diethyl ether).

;
.' 15 ~ 4-Acetyl-3-amillo-2 - 5p-methoxyphellyl) -S-methyl-p The title compound is prepared with 92~o overall yield from 2-amino-2-~p~methoxyphenyl)-acetonitrile and acetylacetone.
M.p. 222-23C (from ethanol).

~0 16 - 3-Amino-4-carbethoxy-5-methyl-Z-(p-tolyl~pyrrole hydrochloride Starting from 2-amino-2-(p-tolyl)-acetonitrile and ethyl aceto-acetate the open chain intermediate cnmpound~ boiling at 160C/

0.05 mmHg is obtained. Overall yield of the title product: 88%.

, M.p. 266-68C (from methanol).
, I~, 5~)7 .. . . ..
" : , . " , 17 - 3-Amino-4-carbethox~-2-phenyl-5-trifluoromethyl-pyrrole hydrochloride The title compound is obtained with 52% overall yield from 2-amino-2-phenylacetonitrile and trifluoroacetyl ethyl acetate. M.p.
203-5C. (from ethanol).

18 - 4-AcetYl-3-amino-2-(~-fluorophenyl)-5-methyl-pyrrole Starting from 2-amino-2-(p-fluorophenyl)-acetonitrile and acetylace~one, ~he open chain intermediate compound is obtained. Bop~
150C/0.3 mmHg. Overall yield of the title compound: 47%. M.p. 211-12C
(from ethanol).
.. ", .
~ 10 19 - 3-Amino-4-carbethoxy-2-(~-fluoropheny~)-5-me~yl-~yrrole hydrochloride '~ The open chain intermediate compound is obtained from 2-amino-2-~p-fluorophenyl)-acetonitrile and ethyl acetoacetate. B.p. 220C/0.2 mmHg.
The title produc~ is obtained with 53% overall yield. M,p. 258-60C
cfrom ethanol/diethyl ether).
--20 - ~ hydrochloride ` The open chain intermediate compound is obtained from amino--~ acetonitrile and ethyl acetoacetate. M.p. 90-98C (from methanol). The title compound is obtained with 44% overall yield. M.p. 211-14C (from methanol).
.,~
.~
'.
'' , . .
' ', .'', ~

t, , , , . , , , , ', . . .

~ 1 ~1.050556 1 21 - 3-Amino-4-isobutyryl-5-methyl-2-phenyl-~yrrole The open chain intermediate compound is obtained from 2-amino-2 phenyl-acetonitrile and S methyl-hexane-2,4-dione. B.p.

150C/0.3 mm~lg. Overall yield of the title compound: 64~. ~l p.

180-83C (from me~hanol/diethyl ether).

22 - 3-Amino-5-methyl-2-phenyl-4-pro~l_ yl-pyrrole Starting from 2-amino-2-phenyl-ace~onitrile and hexane-2,4-dione the open chain intermediate co~pound is obtained. B.p.

- lO 160C/0.3 mmHg. The title product is obtained with an overall y;eld of 53~0 ~.p. 166-68C (from methanol).
~" ~
23 -- 4-Acetyl-3-amino-5-methyl-2-(m-tolyl)-pyrrole Starting from 2~amino-2-(m-tolyl)-acetonitrile and acetylaceto-ne, the open chain intermediate compound is obtained. B.p.
170C/0.02 mm~g.
The title compound is obtained ~;th S9~-overall yield. ~.p. 195-7~C.
;
~from ethanol).

~s' 24 - 4-Acetyl-3-a _no-2-eth~-5-methyl-pyrrole hydrochloride The title compound is obtained with 73~ overall yield from 2-amino-butyronitrile an~d acetylacetone. ~.p. 245-48C

(from methanol).
'.

; 25 - 3-~mino-4-(p- ~ hyl-2-phenyl-pyrrole _.
p.5~7 ~ 25 i5~
The title compound is obtained wi~h 43% overall yield from 2-amino-2-phenyl-acetonitrile and (p-methoxybenzoyl)-acetone. M,p. 219-21C.
(from ethanol).

26 - 4-Acetyl-3-amino_2-(p-benzyl ~
The title compound is obtained with 51% overall yield from 2-amino-2-(p-benzyloxyphenyl)-acetonitrile and acetylacetone. M.p. 245-50C (from ethanol).

27 ~ ~
The title compound is obtained with 67% overall yield starting 10 from 2-amino-2-(p-chlorophenyl)-acetonitrile and acetylacetone. M.p. 205-8C ~from ethanol).

~' 28 - 3-Am no-4-carbethoxy-2-~p-methoxy~heny~-5-methyl-p~rrole hydrochloride The title compound is obtained wi.th 44% overall yield from 2-amino-2-(p-methoxyphenyl)-acetonitrile and ethyl acetoacetate. M.p. 234-36C (from methanol).

29 - 3-Amino-4-benz~yl-2-(p-fl or~ enyl)-5-methyl-p~rrole Starting from 2-amino-2-(p-fluorophenyl~-acetonitrile and benzoyl acetone ~he open chain intermediate compound is obtained. B.p.
120C/0.2 mmHg. The title compound is obt ~ned with 66% overall yield.
M.p, 209-lO~C (from ethanol/diethyl ether).
.,. . ' " ~
;. .. .
' .: :
.,~ ' ~.

, ' '' ' . 'A~, JJ .

' i ', ; ' .:
" ,: . .

~050556 1 30 - 4-Acetyl 3-amino-2-(o-tol~1)-5-methyl-pyrrole Starting from 2-amino-2-(o-tolyl)-acetonitrile and ace~ylace-tone, the open chain intermediate compound is obtained. B.p.
120C/0~2 mmHg. The title compound is obtained with 77~ overall ...
; yield. M.p. 258C (from methanol).

31 - 3-Amino-4-carbomethoxy-5-carbomethoxymethyl-2-phenyl-pyrrole hydrochloride The title product is obtained with 4840 overall yield starting lo from 2-amino-2-phenyl-acetonitrile and 1,3-dicarbomethoxy-acetone.
; M,p. 210-13C. (from methanol), ,~ 32 - 3-Amino-5-methyl-4-methylcarbamyl-2-phenyl-pyrrole hydrochlo-ride The title compound is obtained ~ith 55~ overall yield starting ~rom 2-amino-2-phenyl-acetonitrile anda-ace~yl-N-methyl-acetamide, M.p. 247-50C (from ethanol).
'~

33 - 3 Amino-4-to-chlorobenzoyl)-5-methyl-2-phenyl-pyrrole ~o The title compound is obtained with 51~ overall yield~ starting ; from 2-amino-2-phenyl-acetonitrile and o-chlorobenzoyl-acetone.
M.p. 214-16C ~from ethanol).
' _, _ _ , 507 27 .-. .

34 - 3-Amino-4-carbamyl-5-methyl-2-phenyl-pyrrole hydrochloride 1Starting from Z-amino-2-phenyl-acetonitrile and a-acetylace-tamide the open chain intermediate compound is obtained. ~.p.
128-30C (from diethyl ether). The title product is obtained with 49~ overall yield~ ~I.p. 307-9C (from methanol).
;
35 ~ enyl-5-pr_ryl-pyrrole hydrochloride The ~itle compound is obtained with 60% overall yield~ starting from 2-amino-2-phenyl-acetonitrile and nonane-4,6-dione.
M.p. 228-30C with decomposition (from methanol/diethyl ether).
~ 10 36 - 3-Amlno-4-butyryl-S methyl-2-phenyl-pyrrole hydrochloride The title compound is obtained with 48~o yield from 2-amino-2-phenyl-acetonitrile and heptane-2,4-dione. ~I.p.240-45C l.ith decomposition (from methanol/diethyl ether).
.

: :

37 - 3-Amino-4,5-dicarbomethoxy-2-(p-chloro~henyl)-pyrrole hydrochlo-ride --Starting from 2-amino-2-(p-chlorophenyl)-acetonitrile and dicar-bomethoxyacctylene the open chain intermediate compound is obtained . ~I.p. 74-76C (from diethyl ether).
The title compound is obtained ~ h 48~o overall yield. M.p. 216-~C
tfrom methanol/dietllyl ether~.
;' . " :
.
_; 38 - 3-Amino-4,5-dicarbomethoxy-~-tp-tolyl)-pyrrole_hydrochlorl~e ' 507 _ _ 2~
" . ', . ' , `''~
,~ . .
. " . . ~ . . ' :, ' . . , ! ' ,-1 : ~05~S5`~
Starting from 2-amino-2~(p-tolyl)-acetonitrile and dicarbo-methoxy-acetylene the open chain intermediate compound is obtai-ned. ~.p. 76-77C (from diethyl ether/hexane).
The title compound is obtained with 70~ overall yicld. M.p. 193-; 96~C (from methanol/diethyl ether).
',.
39 - 3-Amino-4 5-dicarbethoxv-2-~henYl-~Yrrole hYdrochloride . .
S~artin~ from 2-amino-2-phenyl-acetonitrile and clic~rbethoxy acetylene~ the open chain intermediate compound is obtained.

B.p. 140/0.03 mm~lg. The title compound is obtained ~ith 78~

; overall yield. ~l~p. 193-96C~(from ethanol/dicthyl ether). ~-~ . ~ .

40 - 3-Amino-4,5-d_carbomethoxy-2~ methoxyphenyl)-p~rrole hy-- drochloride ;~ ~ Starting from 2-amino-2-tp-methoxyphenyl)-acetonitrile and dicarbomethoxyacetylene, the open chain intermediate compound ~ is obtained. M.p. 86-88~C (from hexane). The title compound is ., obtained with 63i overall yield. M.p. 195-97C (from methanol/
diethyl cther).

~O
41 - 3-Amino-4?5-dicarbomethoxy-~-ethyI-pyrrole hydrochloride The title product is`obtained with 66~ overall yleld from 2-amino-butyronitrile and dicarbomethoxyacetylene. M.p. 209,10C
t~rom diethyl ether/methanol).
', ..;
~ ~ ' ., . 507 _ _ '`,'' ,~
, :.

105055~;
~Z - 3-Ami no 4, 5 -dic arb ome thoxy- 2 -pheny 1 -pyrrole hydroch lor i de The title subs~ance is obtained with 39~0 overall yield from 2-amino-2-phenyl-acetonitrile and dicarbomethoxyacc~ylene.
M.p. 205-7C (from methanol/diethyl ether).
; rhe free base melts at 142-43C (from dietl-yl ether).
'''-' Example 43

4-Acety~-3-(2-caTbethoxyacetylamino~-5-methyl-2-~henyl-~yrrole lS Grams (0.0748 mole) of the compound of Example 1 are dissolved in 300 ml. of chloroform. A saturated solution of sodium bicarbonate is added, then 14 gO (0.0933 mole) of malonic acid ethyl ester chloride are added dropwise and the .
~- mixture is vigorously stirred for 2 hours at room te~perature.
The solution is concentrated to dryness, the residue is taken up l; with diethyl ether and filtered.
Upon recrystallization from acetone/hexane 13.5 g. of the .- .
title compound are obtained. ~.p. 178-80C.
','': ' ' ~ . .
F~xamples 44-45 ~0 According to the procédure described in Example 43, the following compounds are prepared:
, ~ 44~
,,, . . . pyrrole froM the compound of Exam~le 2 and malonic acid ethyl ester chloride ; Yield 86~. M.p~ 156-58C (from acetone).
, ; ~ 507 - 30 ~

, . :' ' , ' '' ,'.' ' ' ' . ' ' , ' 1 ~055)556 1 ~5 - 4-Acetyl-3-benzoylamino-S-methyl-2 phenyl-pyrrole from the compound of Example 1 and benzoylchlori~e. Yield 79~.
I p. 3~1-303C (from ethanol/water).

,.
; Examples 46-50 Starting from acetic anhydride and a predetermined a~ino-pyrrole derivative in the presence of pyridine and substantially operating as described by. E.E. ~oyals, Advanced Organic Ci-emistry, pages 616-617, New York, Prentice llall Inc., 19549 for acylating 1() amines, tlle Eollowing compounds are prepared:

46 - 3-Acetylamino-4-carbe-h~ LL -2-phenyl-~yrrole, by using the compound of Example 2 as the aminopyrrole reaction partner. Yield 8940~ p~ 213-15C (from ethanol).
~:
1; 47 - 3-Acetylamino-4-~enzoyl-5-met~ 3~ by using the compoun~
of Fxample 11 as the aminopyrrole reaction partner.
Yield 864. M.p. 182-3C tfrom ethylacetate/water).
'':. . ~ .
';,''' . , ~ 48 - 4-Acetvl-3-acetYlamino-5-methYl-Pyrrole , _ L . ~
by using the compound of E.xample 12 as the aminopyrrole reaction ; partner. Yield 72~. M.p. 206-8C (from methanol).
'' ~ 49 - 4-Acet ~-3-acetylamino-5-methyl-2-phenyl-pyrrole, ; by using the compound of Example I as the aminopyrrole reaction _; partner. Yield 801. M.p. 215-17C (from acetone/hexane).

. ._ _ ` Lp 507 ':' . ~
.
' ' .. . " . ' ~ ':

50 - ~
by using the compound of Example 20 as the aminopyrrole reaction partner YielcL 90%. M.p. 165-60C ~from ethyl acetate).

Example 51 4-Acetyl-3-~ 5-methyl-2-phenyl pyrrole 6 Grams (0.0332 mole) of the compound of ~he Example 1 are suspended in 100 ml~ of aqueous 10% sodium hydroxide, then 20 ml .0154 mole) of benzenesulfonyl chloride are added at 5C under ~- stirring. The oily precipitate which forms is separated from the aqueous ::
~ 10 layer~ dissolved in ethyl acetate and taken up three times with aqueous - 10% sodium hydroxide. The alkaline aqueous layers are joined together, and the resulting solution is brought to pH 2.5 by means of aqueous 10% hydrochloric acid. A precipitate forms, which is collected and recrystallized from aqueous ethanol. Yield 6.7 g. M.p. 170-73C.

Example 52 4-Acet~-3-methanesulfonamido-5 meth~2-~ nyl pyrrole To a solution of 5 g. (0.0278 mole) of the compound of ~`
.. . .
;~ ; Example 1 in 40 ml. of pyridin, 2.6 g. (0.0228 mole) of methanesulfonyl ,, ~ , ~ chloride are added under stirring at 0C. Stirring is continued for an ~ 20 hour, then the solution is allowed to stand overnight at 0C. The reaction ~ mixture is poured in~o aqueous 10% hydrochloric acid and the precipitate which forms is collected and :,...
''',','~
:

', ~,~
" .

, . ~, ::
' 10~i05S6 1 recrystallized from aqueous ethanol. Yield 4.1 g. M.p. 172-75C.

Examples 53-56 Pursuant to the method described in F,xample 52 the following compounds are prepared:
53 - 4-Carbethoxy-3-methanesulfonamido-5-methyl-2-phen~l-pyrrole from the compound of Example 2 and methanesulfonyl chloride.
Yield 83%. ~I.p. 173-74C (from aqueous e~hanol).

54 - 4,5-Dicarbomethoxy-3-methanesulfonamido-2-phenyl-pyrrole from the compound of Example 42 and methanesulfonyl chloride.
Yield 77~0. M.p. 158-60DC (from aqueous ethanol).
-:~
, 55 - 4-Acetyl-5-methy1-3-phenacylsulfonamido-2-phenyl-pyrrole from the compound of Example 1 and phenacylsulfonyl chloride.

Yield 89~o. M.p. 201-3C (from acetone/hexane).
:: :
56 - ~

from the compound of Example 3 and p-toluenesulfonyl chloride.

Yield 83~ p. 230-33C (from ethanol/water).

Example 57 4-Acetyl-5-methyl-3-(N-methyl~henacylsulfonamido~-2-phenyl-pyrrole A mixture of 5.0 g. (0.0126 mole) of the compound of Example 2~ 55, 5.0 g. of potassium carbonate and 15 ml. (0.159 mole) of . _ _ .
Lp,507 : .
. . .
: . . .
.

-1;

~ ~ 5~ S~ 6 1 dimethylsulfate in 400 ml. of acetone is refluxed for 35 hours.
The reaction mixture is then concentrated to small volume and upon adding 400 ml. of water a product precipitates which is recovered by filtration and recrystallized from hexane. Yield ; 4.5 g of the title compound. M.p. 195-97C.
.

F.xamples 58-60 Pursuant to the alkylation procedure described in Example 57, the following compounds are prepared:
; 1~ 58 - 4-Acetyl-S-methyl-3-(N-methylbenzenesulfonamido~-2-phenyl-pyrrole from the compound of Example 51 and dimethylsulfate. Yield 72~. ~I.p. 247-49C (from acetone/water).
':

59 - 4-Acetyl-3 dimethylamino-S-m_thyl-2-phenyl-pyrrole :`
l; from the compound of Example 1 and dimethylsulfate. Yield 68~.

M.p, 153-5~C ~from chloroform).
.
60 - 4-Benzoyl-3-(N~ethyl-p-toluenesulfonamido)-5-methyl-2-phenyl-pyrrole "., 0 from the compound of Example 56 and diethylsulfate. Yield 67~. M.p. 224-25C (from ethanol).
"

Example 61 4-Benzoyl-3-isopropylamino-5-methyl-2-phenyl-pyrrole _, The title compound is prepared by reacting equimolecular amounts ~, 507 . ... . . ..
.. . . . . .
: , ' ' ' ~, 1 of the compound of Example 3 and isopropyl bromide at room tempe-rature. Yield 31~o Mop~ 132-36C tfrom hexane).

Example 62 4~5-Dicarbomethoxy-2-phenyl-3-ureido-p~rrole To a solution of 5 g. of the compound of Example 42 in 50 ml. of acetic acid, a solution of 13 g. of sodium cyana~e in 20 ml. of water is added under stirringat room temperature.
The solution is allowed to stand or about one hour at 0C. The lo product which crystallizes is recovered by filtration and re-crystallized from methanol. Yield 5.1 g., m.p. 246-8C.
~:
'; Examples 63-67 The compounds of the following examples are prepared substan-tially according to ~he same procedure outlined in Example 62:
63 - 4~Acetyl-5-methyl-2-phenyl-3-ureido-pyrrole :~
from the compound of Example 1 and sodium cyanate. Yield 84~.
M.p. 234-38C (from acetone/hexane).

~o 64 - 4-Carbethoxy-5-meth~1-2-phenyl-3-ureido-pyrrole from the compound of the Example 2 and sodium cyanate. Yield 66~.
M.p. 217-19C tfrom ethanol).
,:' 65 - 4-Carbethoxy-5-meth 1-2- hen 1-3-(3- hen lureido)- rrole , Y_ ~ .,. Y , P. .Y... ,_... _~ -; from the compound of Example 2 and phenyisocyanate. Yield 70~.

. 507 ~.~5 ~
., .,, "
;. ' ,.... : '. . . . . .

~ LILD5~D ~35i~6 l~l~po 224-26C (from methanol/wa~cer).

66 4-Acetyl-5-methyl-2-phenyl-3-(3-phenylureido)-pyrrole from the compound of Example 1 and phenylisocyanate. Yield 62~o.
M.p. 256-57C (f~om acetone).
:
67 - 4-Acetyl-3-(3-~enzoylthioureido~-5-methyl-2-phenyl-pyrrole from the compound of Example 1 and benzoylisothiocyanate. Yield 691~. M.p. 228-30C (from ethanol/water).

.' 10 Example 68 4-Acetyl-3-formamido-2-~p-methoxyphenyl)-5-methyl-pyrrole

5 Grams (0.0206 mole) of the compound of Example 15 are dissolved in 50 ml. of 85~ formic acid and the resulting solu-l; tion is refluxed for 15-20 mlnutes. Then the reaction mixture is cooled and poured into ice-water. The precipitate which fo~ms is recovered by filtration and recrystallized from methanol.
Yield 2.5 g. of the title compound. M.p. 210-11C.
~:

Example 69 4-Carbethoxy-3-formamldo-5-methyl-2-phen,~l-pyrrole This compound is prepared as described in the foregoing example, starting from the compound of Example 2. Yield 83~.
M.p. 180-82C (from ethanol/water).
', L~). 507 36 . : , , : .

, . .
': , ~ ' . . , ~, :
. " .. . . . . ..
, . : . .: , ~ , . .

E~a~pl~ 70 A ~olution of S.O g. (0.0234 mole) of the compound of Example 1 in 200 ml. of ethanol is added to a solution of S.0 g. (0.0358 ; mole) of p-chlorobenzaldehyde in 100 ml. of ethanol at 45-SO~C, then the resulting mixture is refluxed for about four hours.
After cooling~ thc reaction mixture is poured into 1200 ml. of water saturated ~ith sodium chloride. A precipitate forms, ~hich is recovored by filtration and recrystallized from ethanol/water.
;; lo Yield 9.5 g. of the title compound. M.p. 214-15C.
':`' Examples 71~73 The ollowing compounds have been prepared according to the ~ procedure describedin Example Y0.
'`" 1,; 11 - 4-Acetyl-3-benzylideneamino-5-methyl-2-Phenyl-Pyrrole from the compound of Example 1 and benzaldehyde- Yield 87~o~
M.p. 173-76C (from methanol).
., . .

..-72 ~ 4-Carbamyl-3-iso~ropylideneamino-5-met~y1-2-~henyl-pyrrole ~0 from the compound of Example 34 and acetone. Yield 82~.
M.p. 221-23C tfrom ethanol/hexane).
,`
73 - 3-Benz~ deneamino-4~5-dicarbomethoxy-2-phenyl-p~rrole rom the compound of Example 42 and benzaldehyde. Yield 78~.
_; M,p. 218-20C (from m~thanol).
..;, . .
>,507 . _37 _ .. . . .. .. . .. . ... . ... ... ....

10505~6 Eximple 74 4-Acetyl-3-amino-1,5-dimeth~1-2-~henyl-pyrrole a) A solution of 1.4 g. (0.00467 mole) of the compound of Example 71 in 25 ml. of dimethylformamide is added dropwise to a cool suspension of sodium hydride in 10 ml. of dimethylfor-mamide. The resulting mixture is stirred at about 0-5C for 15 minutes, then 1 ml. of methyl iodide (0.0161 mole) is added.
Stirring is continued for 30 minutes at about 0C and for 30 minutes at room temperature D then 150 ml. of water are added to ;`' 10 the reaction mixture, which is subsequently extracted with diethyl ether. The organic phase is separated and the solvent is evaporated off. The resulting residue tl.2 g.) is recrystallized from isopropanol/water. M.p. 136-38C. It is the 4-acetyl-3-benzylidenea-mino-l,S-dimethyl-2-phenyl-pyrrole.
b) 1.0 Gram (0.00316 mole) of the compound prepared under a) are dissolved in 30 ml. of 10~ aqueous hydrochloric acid and the resulting solution is heated at 80-90C for about 2 hours. Upon cooling and neutralization with sodium hydroxide a precipitate forms 9 which is recrystallized from ethanol/water.

~0 Yield 0.8 g. of the title compound. M.p. 124-26C.
The corresponding hydrochloride melts at 208-9C (from e~hanol/
diethyl ether).
, .',',.
" _;
,' Li~,507 - 3~ -, 1~ 5~ ~5 ~
1 Example 75 ~-Acetyl-3-amino-l-ethyl-5-methyl-2-phenyl-pyrrole By operating as under point a) of Example 74 and starting from the compound of Example 71 and ethyl iodide, the 4-acetyl-3-benzylideneamino-l-ethyl-S-m0thyl-2-phenyl-pyrrole is obtained.
- M~po 139-41C (from isopropanol/water).
This compound is hydrolized as under point b) of Example 74.
Overall yield of the title compound: 54~. M~p. 107-8C (from ethanol).
~'~ 1() Example 76 4-Acetyl-3-amino-5-methyl-2-~enyl-1-propyl-pyrrole 3 Starting from the compound of Example 71 and propyl iodide, ;- and operating as under point a) of Example 74 the 4-acetyl-3-l; benzylideneamino-5-methyl-2-phenyl-1-propyl-pyrrole as an oily subs~ance is obtained. This compound is hydrolized as under point b) of F,xample 74, Yield of the title compound: 50~0. M.p.
113-15C (from ethanol).
'.~' ` 20 Example 77 4-Acetyl-3-amino~ p-chlorobenzyl)-5-methyl-2-phenyl pyrrole ~,, The 4-acetyl~3-benzylideneamino-1 (p-chlorobenzyl)-5-methyl-,A~ 2-phenyl-pyrrole is prepared from the compound of Example 71 and p-chlorobenzyl chloride, by operating as under '; point a) of Example 74. M.p. 136-37C (from ethanol/water). This ., . ..

_ 39 _ :, , .

5~ 5~ ~
compound is hydrolized as under point b) of Example 74. Yield of the ~itle compound 58~. M.p. 164-66C (from ethanol/water).

Example 78 4-Acetyl-l-(o-chlorobenzyl)-5-methyl-3-dimethylamino-2-phenyl-~rrole ~` The title compound is prepared in a 67~o yield by starting from the compound of Example 59 and o-chlorobenzyl chloride, ~ and operating as under point a) of Example 74. M.p. 103-5C
; 10 (from isopropanol).
:,~

` Example 79 4-Acetyl~ chlorobenzyl)-5-methyl-3-dimethylamino-2-phenyl-: pyrrole l; The title compound is ob~ained in a 52% yleld, starting from the compound of Example 59 and p-chlorobenzyl chloride, by operating as under point a) of Example 74. M.p. 118-19C (from hexane).

Example 80 4-Carbeth ~ N-methyl-methanesulfonam_ ol~l,5-dimethyl-2-phenyl-pyrrole Starting from the compound of ~xample 53 and me~hyl iodide, according to the procedure of point a~ of Example 74 ~ the title ~,; compound is obtained with 71~o yield. M.p. 138-40C (from , Lp. 507 _~_ . ,.. , , ~. ,' .

~ ss~
ethanol/acetone)0 Example 81 4-Acetyl-3-to-carboxy~henyl)amino-5-methyl-2-phenyl-py~rrole A suspension of 2 gO (0.00934 mole) of the compound of Example l, 1.87 g. (0.00934 mole) of o-bromobenzoic acid, 2 g. of sodium acetate and 0.5 g. of copper powder in 150 ml. of water is ; refluxed for 4 hours. After cooling, the mixture is allowed to stand overnight. A precipitate forms, which is l() recovered by filtration and recrystallized from aqueous methanol.
Yield o~ the tltle product: l.S g, M.p. 260-62C.
,,., Example 82 3-Amino S-carbamyl-4-carbomethoxy-2-phenyl pyrrole L; A solution of S g, (0.0161 mole~ of the compound of Example 42 is saturated with gaseous ammonia, ~hen i~ is allowed to stand for two days. A product crystallizes which is recovered by filtration. Yield 2.8 g. ~I,p. 177-79C
(from methanol/water).

., Example 83 3-Amino-4 5-dicarboxy-2-pheny~ rrole .. .~
A solution of 15 g. tO.0545 mole)of the compound of Example ; 42 in Z00 ml. o methanol is added with 90 ml. of aqueous 10 ''; lithium hydroxide and re~luxed for 20 minutes under stirring.

... ......

,,: ", , , :,,.." ,, ''','''.' .''.'":; '.,' , , .

:, ., ,: . .. , , . . . ., , .. , ... ; . . .. . . . .

~ s~
1 Then the solution is poured into water and the mixture is acidified with aqueous 10~ hydrochloric acid. The title compound precipi~ates, which is recovered by filtration and recrystallized from dime-thylforma~ide/ethyl ether. Yield 12.5 g. ~I.p. 191-94C (The compound ; contains one molecule of water of crrstallization) .

Example 84 3-Amino-5-carboxy~4-carbomethoxy-2-phenyl-pyr ole A solution of 10 g. ~0.0322 mole) of the compound of the Example 42 in 150 ml. of methanol and 30 ml. of aqueous 10%
sodium hydroxide is refluxed for 3 hours. The methanol is evaporated off and the resulting solution is brought to pH 7 with aqueous 10~ hydrochloric acid. A product separates which is filtered~
dissolved in aqueous sodium bic,arbonate and then neutralized by 1~ adding aqueous 10 ~ hydrochloric acid. Yield 5 gO M.p. 206-207C.
..'' Example 85 3-Amino-4-carboxy-5-carbomethoxY-2-phenYl-~Yrrole . ..
2 Grams (0.00644 mole) of the compound of Example 42 are dissolved in 20 ml. of concentrated sulfuric acid and the solution is allowed to stand at room temperature for about 35 minutes.
Then it is poured into ice-water and the resulting mixture is brought to neutrality by means of aqueous 10~ sodium hydroxide.
A product separates, which is recovered by filtration and '; recrystallized from aqueous methanol. Yield 0.5 g. ~.p. 218-19C.

I p~ 507 ., .. :, ~

:~,, , , . :
. .

~ s~
1Examples 86-88 According to the hydrolysis procedure described in Example 85, the following compounds have been prepared:
86 - 4-Carboxy-3-(2-carbethoxyacetylaminol-5-methyl-2-phenyl-pyrrole ;The compound is obtained ~lith 64~ yield starting from the compound of Example 44. ~I.p. 92-98C (from ethanol).

87 - 3-Acetylamino-4-carboxy-5-methyl-2-phenyl-pyrrole The compound is obtained with 49~ yield starting from the lOcompound of Example 46. ~.p. 258-60C (from ethanol/water).

88 - 4-Carboxy-3-methanesulfonamido-S-methyl-2-phenyl-pyrrole The compound is obtalned with a 54~ yield from the compound of Example 53. M.p. 269-71C (from acetone/water).

l;
Example 89 3-Amino-5-carbazoyl-4-carbomethoxy-2-phenyl pyrrole Five grams (0~0161 mole) of ~he compound of Example 42 are dissolved in 60 ml. of methanol and I.3 g. of pyridine are added.

The solution is then added with 25 ml. of hydrazine in 20 ml. of water and kept at the room temperature for 15 minutes.
The product which crystallizes is recovered on filter and recrystallized from methanol. Yield 3 g., m.p. 166-7C.

Lp.507_ 43 _ "

lOSOSb6 1 Example 90 ~-Acetyl-3-amino-5-methyl-2- ~ hYdroxyphenyl,)-Pyrrole ; The title compound is prepared starting from the compound of Example 15, following substantially the procedure described by R.L. Burwell, Chem.Rev., 54, 628, 1954 for the hydrolyzing 0-alkylphenols. Yield 71~. M.p. 273-74C (from ethanol/water).
' Example 91 1~ 3-Amino~5-methyl-2~ en~1-4-~henylcarbamyl-pyrrole ., This compound is prepared according to the procedure described for Examples 1-42 3 starting from 2-amino-2-phenyl-acetonitrile and -acetyl-N-phenyl-acetamide, cmd is obtained with a 73% overall yield. M.p. 271-73CC (from ethanol).

, '~ l;
Example 92 3-A no-4~5-dicarbomethoxy-2-~henyl~pyrrole hydrochloride To a solution of 9.5 g. (0.0565 mole) of 2-amino-2-phenyl-acetonitrile hydrochloride in 90 ml. of anhydrous methanol, 9.0 g.

of potassium carbonate are added and the resulting mixture is stirred for 15 minutes. Then s.n g. (0.0630 mole) of 1,2-dicarbo-methoxy acetylene are added and the mixture is refluxed for three hours and a half. After evaporation of the solvent, the residue is taken up with ethyl acetate and extracted three times ~; with aqueous lO~o hydrochlorid acid. The hydrochloric solution is . . ... . . . . . . ... _ p, 507 _ 44 _ ,:, " ' ~': ,'', , :IOS0556 1 neutralized with aqueous 105 sodium hydroxide and extracted again with ethyl acetate. After evaporation of the solvent a solid is obtained~ which is recrystallized from a mixture of methanol and diethyl ether saturated with hydrogen cloride. Yield of ~he title compound 5 g. M.p. 205-7C The free base melts at 142-43C
; (from die~hyl ether).
~., By following the procedure described in this example are prepared also the compounds of examples 7, 37, 38, 39, 40 and 41.
-' ; Example 93 -2-phenyl-pyrrole 1.5 Grams (0.00366 mole)of the compound o Example 57 are suspended in 100 ml. of acetic ,acid and 5 ml. of concentrated hydrochloric acid at room temperature, then 1.1 g. of zinc powder are added in small portions. The resulting mixture is stirred for two hours at room temperature, the zinc is eliminated ,, by filtration and the filtrate is twice extracted with 200 ml.

of ethyl acetate. After evaporation of th ethyl acetate, a ,' residue is obtained, which is taken up with diethyl ether and " ~iltered. Yield of the title compound: 0.3 g. M.p. 174-76C.
'', . '.

, Example 94 3gy ~3-~hyl~ ino-5-meth 1-2- henYl- rrole ~' ~' ' _. ~C ~
r:
Lp.507 ~ - 45 -:,, . ....

.. ~ ' , ' ' .
. .

I ~ ~050556 1 This compound is ob~ained with 443 yield from the compound of Example 60, following the method described in the Example 93.
M.p. 178-80C (from ethanol/water).

,~
` 5 ~ Example 95 .;~ 3-Acetylamino-4-benzoyl-5-methyl-2-phenyl-pyrrole : Following the method described in Example 43, starting from the compQund of Example 3 and acetylchloride the title compound is obtained with 87~ yield. M.p. 140-42C (from ethanol/water).

~"''`':
.~
;~'',.'`.~ :
`~:
~ 15 ' .'~', ,.;~,~ , ,~ :
'';
'~' ; 1, `. 20 '~
.,,, ~` 2;
_ _ Lp.

Claims (64)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula I

and pharmaceutically acceptable salts thereof with acids wherein R is selected from hydrogen, (C1-4)alkyl, benzyl and halo-substituted benzyl;
R1 represents hydrogen (C1-4)alkyl, phenyl and substituted phenyl carrying one to three substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro;
R2 is a member of the class consisting of hydrogen, (C1-4)alkyl, formyl, (C2-4)aliphatic acyl, benzoyl, [carbo(C1-4)alkoxy]-(C2-4)aliphatic acyl, carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulfonyl, (C1-4)alkyl-sulfonyl, toluenesulfonyl, phenacylsulfonyl;
R3 is selected from hydrogen and (C1-4)alkyl;
R4 represents (C2-4)aliphatic acyl, benzoyl, benzoyl carrying one to three substituents independently selected from fluoro, chloro, bromo and (C1-4)alkoxy, carbo(C1-4)alkoxy, carboxy, carbamyl, methyl-carbamyl or phenylcarbamyl;
R5 is selected from the group consisting of hydrogen, (C1-4)alkyl, carbo(C1-4)alkoxy, [carbo(C1-4)alkoxy]methyl, trifluoromethyl, carboxy, carbamyl and carbazoyl;
R2 and R3 taken together represent (C2-4)alkylidene, benzylidene, or halo-substituted benzylidene;
R4 and R5 taken together may also represent a group -CO-(CH2)n-, wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4 and n is an integer selected from 2, 3, and 4; with the proviso that when R1 and R5 simultaneously represent methyl and R is hydrogen, one of R2 and R3 must be different from hydrogen and R4 cannot be carbethoxy;
which comprises reacting substantially equimolecular amounts of an .alpha.-aminonitrile of the general formula II

or an acid addition salt thereof, wherein R is hydrogen and R1 has the meanings given above, and a compound of the general formula III
wherein R4 and R5 have the above meanings and X represents the groups -C?C- or -CM2-?- wherein the -CH2 portion is linked to the substituent R4, and wherein this process step may be followed by one or more of the following steps:
(a) when a compound of formula I is required in which R2 or R3 or both are acyl, alkyl or aryl groups acylating, alkylating or arylating a correspond-ing compound of formula I in which one or both of R2 and R3 are hydrogen atoms;
(b) when a compound of formula I is required in which R2 is carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl or benzoylthiocarbamyl group reacting a corresponding compound of formula I in which R2 is a hydrogen atom with a cyanate, a thiocyanate, phenylisocyanate, phenyl-isothiocyanate or benzoylisothiocyanate; or (c) when a compound of formula I is required in which R2 and R3 together form an alkylidene, benzylidene or halogen substituted benzylidene group as defined above reacting a corresponding compound of formula I in which R2 and R3 are hydrogen atoms with the appropriate aldehyde or ketone; or (d) when a compound of formula I is required in which R is alkyl, benzyl, or halogen-substituted benzyl as defined above alkylating, benzylating or halo-benzylating a corresponding compound of formula I in which R is hydrogen, or (e) when a compound of formula I is required in which R4 is carboxy, carba-myl, methylcarbamyl or phenylcarbamyl, subjecting a corresponding compound of formula I in which R4 is alkoxy to hydrolysis or reaction with ammonia, methylamine or aniline; or (f) when a compound of formula I is required in which R5 is carboxy, carbamyl or carbazoyl, subjecting a corresponding compound of formula I in which R5 is alkoxy to hydrolysis or reaction with ammonia or hydrazine, and where a base of formula I may be converted into a corresponding pharmaceuti-cally acceptable acid addition salt.

2. A process according to claim 1 in which the reaction of the compounds of formulae II and III is effected by an inert organic solvent at a tempera-ture ranging from room temperature to the reflux temperature of the reaction mixture.

3. A process according to claim 1 in which a compound of formula I
obtained in which R2 and R3 together form an alkylidene, benzylidene or halogen substituted benzylidene is hydrolysed.

4. A process according to claim 1 in which a compound of formula I
obtained in which R1 is alkoxyphenyl or benzyloxyphenyl is hydrolysed or reduced.

5. A process according to claim 1 in which a compound of formula I in which R3 is an acyl group is hydrolysed.

6. A process according to claim 1 in which X is. -CH2-CO- or -C?C-, R
is hydrogen, methyl, ethyl, propyl, O-chlorobenzyl or p-chlorobenzyl, R1 is hydrogen, phenyl, ethyl, methylphenyl, p-methoxyphenyl, p-benzyloxy-phenyl, p-fluorophenyl, p-chlorophenyl or p-hydroxyphenyl, R2 is hydrogen, methyl ethyl, isopropyl, formyl acetyl, benzoyl, benzenesulfonyl, methane-sulfonyl, p-toluenesulfonyl, phenacylsulfonyl, carbamyl, phenylcarbamyl, benzoylthiocarbamyl, carboxyphenyl, ethoxycarboxylacetyl, R3 is hydrogen, methyl or ethyl, or R2 and R3 together form an isopropylidene, benzylidene or p-chlorobenzylidene group, R4 is acetyl, propionyl, butyryl, isobutyryl, benzoyl, p-methoxybenzoyl, o-chlorobenzoyl, ethoxycarbonyl, methoxycarbonyl, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl, or R5 is hydrogen, methyl, propyl, ethoxycarbonyl, methoxycarbonyl, ethoxycarbonylmethyl, methoxycarbonylmethyl, trifluoromethyl, carboxy, carbamyl or carbazoyl, or R4 and R5 together form a -(CH2)3-CO- grouping.

7. A process according to claim 1 for preparing compounds of formula I
wherein R is hydrogen;
R1 represents hydrogen, (C1-4)alkyl, phenyl and phenyl carrying one to three substituents independently selected from (C1-4) alkyl, (C1-4) alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro;
R2 and R3 are hydrogen;
R4 represents (C2-4)aliphatic acyl, benzoyl, benzoyl carrying one to three substituents independently selected from fluoro, chloro, bromo and (C1-4)alkoxy, carbo(C1-4)alkoxy, carbamyl, methylcarbamyl, phenylcarbamyl;
R5 is selected from the group consisting of hydrogen, (C1-4)alkyl, carbo(C1-4)alkoxy, [carbo(C1-4)alkoxy] methyl and trifluoromethyl;
R4 and R5 taken together represent a group -CO-(CH2)n- wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4 and n is an integer selected from 2, 3 and 4;
with the proviso that when R1 and R5 simultaneously represent methyl and R is hydrogen, R4 cannot be carbethoxy;
which comprises reacting substantially equimolecular amounts of an .alpha.-aminonitrile of the general formula II

or an acid addition salt thereof, wherein R is hydrogen and R1 has the meanings given above, and a compound of the general formula III

wherein R4 and R5 have the above meanings and X represents the groups -C?C- or -CH2-?- wherein the -CH2 portion is linked to the substituent R4 in an inert organic solvent at a temperature ranging from room temperature to the reflux temperature of the reaction mixture.

8. A process as in claim 1 which comprises reacting substantially equimolecular amounts of an .alpha.-aminonitrile of the general formula II

or an acid addition salt thereof, wherein R is hydrogen and R1 has the same meaning given in claim 1, and a compound of the general formula III
wherein R4 and R5 have the meanings given in claim 1 and X represents the groups -C?C- or -CH2-?- wherein the CH2 portion is linked to the substituent R4, in an organic solvent selected from benzene, dioxane, tetrahydrofuran and (C1-4)alkanols, in the presence of an acidic catalyst for one to twenty-eight hours at a temperature varying from room temperature and the reflux temperature of the reaction mixture, subsequently adding a basic condensing agent selected from amides, hydroxides, alkoxides, carbonates or hydrides of alkali or alkaline earth metals, keeping the obtained reaction mixture for one to thirty hours at a temperature varying from room temperature and the boiling temperature of the reaction mixture.

9. A process as in claim 1, which comprises refluxing from two to four hours substantially equimolecular amounts of an .alpha.-aminonitrile of formula II

or an acid addition salt thereof, wherein R is hydrogen and R1 has the same meaning given in claim 1 and a compound of formula wherein R4 and R5 have the meaning given in claim 1 and X is the group -C?C- in an inert solvent selected from benzene, dioxane, tetrahydrofuran and (C1-4)alkanols, in the presence of a basic condensing agent selected from hydroxides, carbonates of alkali or alkaline earth metals.

10. A compound of the formula I

wherein:

R is selected from hydrogen, (C1-4)alkyl, benzyl and halo-substituted benzyl;
R1 represents hydrogen, (C1-4), phenyl and substituted phenyl carrying one to three substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro, R2 is a member of the class consisting of hydrogen, (C1-4)alkyl, formyl, (C2-4)aliphatic acyl, benzoyl, [carbo(C1-4)alkoxy]-(C2-4)aliphatic acyl, carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulfonyl, (C1-4)alkyl-sulfonyl, toluenesulfonyl, phenacylsulfonyl;
R3 is selected from hydrogen and (C1-4)alkyl;
R4 represents (C2-4)aliphatic acyl, benzoyl, benzoyl carrying one to three substituents independently selected from fluoro, chloro, bromo and (C1-4)alkoxy, carbo(C1-4)alkoxy, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl;
R5 is selected from the group consisting of hydrogen (C1-4)alkyl, carbo(C1-4)alkoxy, [carbo(C1-4)alkoxy]methyl, trifluoromethyl, carboxy, carbamyl and carbazoyl;
R2 and R3 taken together represent (C2-4)alkylidene, benzylidene, or or halo-substituted benzylidene;
R4 and R5 taken together may also represent a group -CO-(CH2)n-, wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4 and n is an integer selected from 2, 3, and 4;
with the proviso that when R1 and R5 simultaneously represent methyl and R is hydrogen, one of R2 and R3 must be different from hydrogen and R4 cannot be carbethoxy;
and pharmaceutically acceptable salts thereof with acids, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein R is hydrogen; R1 represents hydrogen, phenyl or phenyl carrying one to three substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, fluoro and chloro; R2 and R3 each represents hydrogen; R4 is selected from (C2-4)aliphatic acyl, benzoyl, carbo(C1-4)alkoxy carbamyl; R5 is selected from hydrogen, (C1-4)alkyl and carbo (C1-4)alkoxy; R4 and R5 taken together represent a group -CO-(CH2)3-wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R4, and salts therewith of pharmaceutically acceptable acids.

12. A compound of the formula I given in claim 1 or a pharmaceutically acceptable acid addition salt thereof, wherein A, R, R1, R2, R3, R4 and R5 are as defined in claim 6 whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

13. A process according to claim 1 in which A is -CO-CH2- R1, R2 and R3 are hydrogen atoms, R1 is phenyl, R4 is acetyl and R5 is methyl.

14. A process according to claim 1 in which 4-acetyl-3-amino-5-methyl-2-phenylpyrrole and its hydrochloride are prepared by reacting 2-amino-2-phenylacetonitrile with acetylacetone and cyclizing the open chain intermediate compound so formed, ancl when the hydrochloride is required reacting the resulting basewith hydrogen chloride.

15. 4-Acetyl-3-amino-5-methyl-2-phenylpyrrole and its hydrochloride, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

16. A process according to claim 1 in which A is -CO-CH2-, R, R2 and R3 are hydrogen atoms, R1 is phenyl, R4 is benzoyl and R5 is methyl.

17. A process according to claim 1 in which 3-amino-4-benzoyl-5-methyl-2-phenylpyrrole and its hydrochloride are prepared by reacting 2-amino-2-phenylacetonitrile with benzoylacetone and cyclizing the open chain intermediate compound so formed, and when the hydrochloride is required reacting the resulting base with hydrogen chloride.

18. 3-Amino-4-benzoyl-5-methyl-2-phenylpyrrole and its hydrochloride whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. A process according to claim 1 in which R, R2 and R3 are hydrogen atoms, R1 is p-tolyl, R4 is acetyl, R5 is methyl and A is -CO-CH2-.

20. A process according to claim 1 in which 4-acetyl-3-amino-5-methyl-2-(p-tolyl)pyrrole is prepared by reacting 2-amino-2-(p-tolyl)-acetonitrile with acetylacetone and cyclizing the open chain intermediate so formed.

21. 4-Acetyl-3-amino-5-methyl-2-(p-tolyl)pyrrole whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

22. A process according to claim 1 in which A is -CO-CH2-R, R2 and R3 are hydrogen atoms, R1 is p-methoxyphenyll R4 is acetyl and R5 is methyl.

23. A process according to claim 1 in which 4-acetyl-3-amino-2(p-methoxyphenyl)-5-methylpyrrole is prepared by reacting 2-amino-2-(p-methoxyphenyl)acetonitrile with acetylacetone and cyclizing the open chain intermediate so formed.

24. 4-Acetyl-3-amino-2-(p-methoxyphenyl)-5-methylpyrrole whenever prepared by the process of claim 23 by an obvious chemical equivalent thereof.

25. A process according to claim 1 in which A is -CO-CH2-, R, R2 and R3 are hydrogen atoms, R1 is p-tolyl, R4 is ethoxycarbonyl and R5 is methyl.

26. A process according to claim 1 in which 3-amino-4-carbethoxy-5-methyl-2-(p-tolyl)pyrrole and its hydrochloride which comprises reacting 2-amino-2-(p-tolyl)acetonitrile with ethyl acetoacetate and cyclizing the open chain intermediate compound so formed, and when the hydrochloride is required reacting the resulting base with hydrogen chloride.

27. 3-Amino-4-carbethoxy-5-methyl-2-(p-tolyl)pyrrole and its hydrochloride whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.

28. A process according to claim 1 in which A is -CO-CH2-, R, R2 and R3 are hydrogen atoms, R1 is p-fluorophenyl, R4 is acetyl and R5 is methyl.

29. A process according to claim 1 in which 4-acetyl-3-amino-2-(p-fluorophenyl)-5-methylpyrrole is prepared by reacting 2-amino-2-(p-fluorophenyl)acetonitrile with acetylacetone and cyclizing the open chain intermediate so formed.

30. 4-Acetyl-3-amino-2-(p-fluorophenyl)-5-methylpyrrole whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

31. A process according to claim 1 in which A is -CO-CH2-, R, R2 and R3 are hydrogen atoms, R1 is phenyl, R4 is isobutyryl and R5 is methyl.

32. A process according to claim 1 in which 3-amino-4-isobutyryl-5-methyl-2-phenylpyrrole is prepared by reacting 2-amino-2-phenylacetoni-trile with 5-methyl-hexane-2,4-dione and cyclizing the open chain intermediate compound so formed.

33. 3-Amino-4-isobutyryl-5-methyl-2-phenylpyrrole whenever prepared by the process of claim 32 or by an obvious chemical equivalent thereof.

34. A process according to claim 1 in which A is -CO-CH2-, R, R2 and R3 are hydrogen atoms, R1 is p-chlorophenyl, R4 is acetyl and R5 is methyl.

35. A process according to claim 1 in which 4-acetyl-3-amino-2-(p-chlorophenyl)-5-methylpyrrole is prepared by reacting 2-amino-2-(p-chlorophenyl)-acetonitrile with acetylacetone and cyclizing the open chain intermediate compound so formed.

36. 4-Acetyl-3-amino-2-(p-chlorophenyl)-5-methylpyrrole whenever prepared by the process of claim 35 or by an obvious chemical equivalent thereof.

37. A process according to claim 1 in which R, R2 and R3 are hydrogen atoms, R1 is phenyl, R4 is methoxycarbonyl, R5 is carbamyl and A is -C?C-.

38. A process according to claim 1(f) in which 3-amino-5-carbamyl-4-carbomethoxy-2-phenylpyrrole is prepared by reacting 3-amino-4,5-di(carbomethoxy)-2-phenylpyrrole with ammonia.

39. A process according to claim 38 in which the starting material is prepared by reacting 2-amino-2-phenylacetonitrile with di(carbomethoxy) acetylene.

40. 3-Amino-5-carbamyl-4-carbomethoxy-2-phenylpyrrole whenever prepared by the process of claim 38 or 39 or by an obvious chemical equivalent thereof.

41. A process according to claim 1 in which A is -CO-CH2-, R, R1 and R3 are hydrogen atoms, R2 is acetyl, R4 is ethoxycarbonyl and R5 is methyl.

42. A process according to claim 1(a) in which 3-acetyl-amino-4-carbethoxy-5-methylpyrrole is prepared by acetylating 3-amino-4-carbethoxy-5-methylpyrrole.

43. A process according to claim 42 in which the starting material is prepared by reacting amino acetonitrile with ethylacetoacetate and cyclizing the open chain intermediate so formed.

43. 3-Acetylamino-4-carbethoxy-5-methylpyrrole whenever prepared by the process of claim 42 or 43 or by an obvious chemical equivalent thereof.

57

45. A process according to claim 1 in which A is -CO-CH2-, R is hydrogen, R1 is phenyl, R2 and R3 together form a p-chlorobenzylidene group, R4 is acetyl and R5 is methyl.

46. A process according to claim 1(c) in which 4-acetyl-3-(p-chlorobenzylideneamino)-5-methyl-2-phenylpyrrole is prepared by reacting 4-acetyl-3-amino-5-methyl-2-phenylpyrrole with p-chlorobenzaldehyde.

47. A process according to claim 46 in which the starting material is prepared by reacting 2-amino-2-phenylacetonitrile with acetylacetone and cyclizing the open chain intermediate compound so formed.

48. 4-Acetyl-3-(p-chlorobenzylideneamino)-5-methyl-2-phenylpyrrole whenever prepared by the process of claim 46 or 47 or by an obvious chemical equivalent thereof.

49. A process according to claim 1 in which A is -CO-CH2-, R is hydrogen, R1 is phenyl, R2 and R3 together form a benzylidene group, R4 is acetyl and R5 is methyl.

50. A process according to claim 1(c) in which 4-acetyl-3-benzylideneamino-5 methyl-2-phenylpyrrole is prepared by reacting 4-acetyl-3-amino-5-methyl-2-phenylpyrrole with benzaldehyde.

51. A process according to claim 50 in which the starting material is prepared by reacting 2-amino-2-phenylacetonitrile with acetylacetone and cyclizing the open chain intermediate compound so formed.

52. 4-Acetyl-3-benzylideneamino-5-methyl-2-phenylpyrrole whenever prepared by the process of claim 50 or 51 or by an obvious chemical equivalent thereof.

53. A process according to claim 1 in which A is -CO-CH2-, R and R5 are methyl groups, R1 is phenyl, R2 and R3 together form a benzylidene group and R4 is acetyl.

54. A process according to claim 1(d) in which 4-acetyl-3-benzyli-deneamino-1,5-dimethyl-2-phenylpyrrole is prepared by methylating 4-acetyl-3-benzylideneamino-5-methyl-2-phenylpyrrole.

55. A process according to claim 54 in which the starting material is prepared by reacting 4-acetyl-3-amino-5-methyl-2-phenylpyrrole with benzaldehyde.

56. 4-Acetyl-3-benzylideneamino-1,5-dimethyl-2-phenylpyrrole whenever prepared by the process of claim 54 or 55 or by an obvious chemical equivalent thereof.

57. A process according to claim 1 in which A is -CO-CH2-, R and R5 are methyl groups, R1 is phenyl, R2 and R3 are hydrogen atoms and R4 is acetyl.

58. A process according to claim 54 in which the product obtained is hydrolysed.

59. 4-Acetyl-3-amino-1,5-dimethyl-2-phenylpyrrole whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.

60. A process according to claim 1 in which A is -CO-CH2-, R is p-chlorobenzyl, R1 is phenyl, R2, R3 and R5 are methyl groups and R4 is acetyl.

61. A process according to claim 1(d) in which 4-acetyl-1-(p-chlorobenzyl)-3-dimethylamino-5-methyl-2-phenylpyrrole is prepared by p-chlorobenzylating 4-acetyl-3-dimethylamino-5-methyl-2-phenylpyrrole.

62. A process according to claim 61 in which the starting material is prepared by methylating 4-acetyl-3-amino-5-methyl-2-phenylpyrrole.

63. A process according to claim 62 in which the starting material is prepared by reacting 2-amino-2-phenylacetonitrile with acetylacetone and cyclizing the open chain intermediate compound so formed.

64. 4-Acetyl-1(p-chlorobenzyl)-5-methyl-3-dimethylamino-2-phenyl-pyrrole whenever prepared by the process of claim 61, 62 or 63, or by an obvious chemical equivalent thereof.