CA1055036A - 3-amino-4-carbamyl-pyrrol derivatives and methods for their preparation - Google Patents

Abstract

Abstract of the Disclosure This invention relates to I
wherein: R is selected from hydrogen, (C1-4) alkyl, benzyl, and halo-sub-stituted benzyl: R1 represents hydrogen, (C1-4) alkyl, phenyl or phenyl sub-stituted with 1 to 3 radicals independently selected from (C1-4) alkyl, (C1-4) alkoxy, benzyloxy, fluoro, chloro, bromo and hydroxy; R2 is a member of the class consisting of hydrogen, (C1-4) alkyl, formyl, (C2-4) aliphatic acyl, benzoyl, carbamyl, phemylcarbamyl, (C1-4) alkylsulfonyl, benzenesul-fonyl, toluenesulfomyl and phenacylsulfonyl; R3 is selected from hydrogen and (C1-4) alkyl; R4 and R5 independently represent hydrogen, or taken together with the adjacent nitrogen atom they can also represent dimethylamino or a 5-6 membered heterocyclic ring containing a further oxygen or nitrogen atom optionally substituted by one to three (C1-4) alkyl radicals or by a phenyl group; R6 represents a (C1-4) alkyl group; R2 and R3 taken together represent (C2-4) alkylidene, benzylidene or halo-substituted benzylidene and pharmaceutically acceptable acid addition salts thereof. It also relates to the preperation of these compounds according to known methods. The com-pound of formula I together with their pharmaceuticaly acceptable acid addition salts display very interesting pharmscological properties: more particul-arly, they are active as antlinflammatories, antipyretics and as prostaglan-din synthetase inhibitors. Furthermore, some of them display also interesting C.N.S. depressant and anti-hypertensive properties and possess a valuable degree of activity on the hydric balance of warm blooded animals. Certain of the internediates used in the preparation are new and form part of the present invention.

Description

~05503~;

The present invention concerns new aminopyrrole derivatives of the following general formula:

R3 \ / R4 N CON

2 ~ ~ R5 '/ ~ 6 the pharmaceutically acceptable acid addition salts thereof, and the process for their preparation. In the above formula I the substituents R through R6 have the following meanings: R is selected from hydrogen, (Cl 4) alkyl, benzyl and halo-substituted benzyl; Rl represents hydrogen, (Cl 4) alkyl, phenyl or phenyl substituted with 1 to 3 radicals independently selected from (Cl 4) alkyl, (Cl 4) alkoxy, benzyloxy, fluoro, chloro, bromo and hydroxy; R2 is a member of the class consisting of hydrogen, (Cl 4) alkyl, formyl, (C2 4) aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (Cl 4) alkylsulfonyl, ben7enesulfonyl, toluenesulfonyl and phenacylsulfonyl; R3 is selected from hydrogen and (Cl 4) alkyl; R4 and R5 independently represent hydrogen, (C2 4) alkyl and substituted phenyl, though not simultaneously hydrogen, or taken together with the adjacent nitrogen atom they can also represent dimethylamino or a 5-6 membered heterocyclic ring which may contain a further oxygen or nitrogen atom and be optionally substituted by one to three (Cl 4) alkyl radicals or by a phenyl group; R6 represents a (Cl 4) alkyl group; R2 and R3 taken together represent (C2 4) alkylidene, benzyl-idene or halo-substituted benzylideneO
In the specification and claims the term "(Cl 4) alkyl" refers to an alkyl radical containing 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertbutyl; the term "(C2 4) alkyl" identifies the same radicals excluding methyl, the term "halo-substituted benzyl" essen-tially identifies a benzyl radical substituted in the aromatic ring with 105S03~;

fluoro, chloro or bromo such as, for instance, p-chlorobenzyl, o-chlorobenzyl, p-fluorobenzyl, o-bromobenzyl and m-bromobenzyl; the term "substituted phenyl" designates phenyl radicals substituted with 1 to 3 groups independently selected from (Cl 4) alkyl, ~Cl 4) alkoxy, fluoro, chloro, bromo, hydroxy, nitro, amino, (C2 4) aliphatic acylamino, carbo (Cl 4) alkoxy, carboxy, carbamyl and trifluoromethyl; the term "(C2 4) aliphatic acyl" refers to an aliphatic acyl radical containing 2 to 4 carbon atom such as acetyl, propionyl, butyryl and isobutyryl; "(Cl 4) alkoxy" identifies alkoxy groups containing 1 to 4 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy; a "(C2 4) alkylidene" radical is essentially identified by ethylidene, propylidene, isopropylidene, butylidene and isobutylidene;
the term "halo-substituted benzylidene" designates a benzylidene radical substituted in the aromatic ring with chloro, fluoro or bromo such as, for instance, o-chlorobenzylidene, m-chlorobenzylidene, p-chlorobenzylidene, p-fluorobenzylidene, o-fluoro~enzylidene, m-bromobenzylidene.
A preferred group of compounds comprises those of formula I wherein R represents hydrogen, benzyl or halo substituted benzyl, Rl is phenyl9 Rz is selected from hydrogen, tCl 4) alkyl, (C2 4) aliphatic acyl and toluene-sulfonyl, R3 may be hydrogen or (Cl 4) alkyl, R4 and R5 independently represent hydrogen, (C2 4) alkyl, phenyl substituted by (Cl 4) alkyl, (C
aliphatic acyl, (Cl 4) alkoxy, halo, carboxy, carbo (Cl 4) alkoxy and trifluoromethyl, though not simultaneously hydrogen or, taken together with the adjacent nitrogen atom, they can also represent dimethylamino, piperidino, morpholino, ~Cl 4) alkyl-piperazino and phenylpiperazino, and R6 is as above defined, and salts therewith of pharmaceutically acceptable acids.
A second preferred group of compounds comprises those of formula I wherein R is hydrogen, Rl is phenyl, R2 is selected from hydrogen, (Cl 4) alkyl, (C2 4~ aliphatic acyl and toluenesulfonyl, R3 may be hydrogsn or (Cl 4) alkyl, R4 and R5 independently represent hydrogen, (C2 4) alkyl, phenyl sub-lOSS~36 stituted by ~Cl 4~ alkyl9 (C2 4) aliphatic acyl, ~Cl_4) alkoxy, halo, carboxy, carbo ~Cl 4) alkoxy and trifluoromethyl, though not simultaneously hydrogen, or, taken together with the adjacent nitrogen atom, they can also represent dimethylamino, piperîdino, morpholino, (Cl 4) alkylpiperazino and phenyl-piperazino, and R6 is as above defined and salts therewith of pharmaceutically acceptable acids.
A further preferred group of compounds comprises those of formula I wherein R, R2 and R3 stand fOr hydrogen, Rl is phenyl, R4 and R5 indepen-dently represent hydrogen, tC2 4~alkyl, phenyl, substituted by (~1 4)alkyl (C2_4) aliphatic acyl, (Cl 4) alkoxy, halo, carboxy, carbo (Cl 4) alkoxy and trifluormethyl, though not simultaneously hydrogen, or taken together with the adjacent nitrogen atom, they can also represen~ dimethylamino, piperidino, morpholino, (Cl 4) alkylpiperazino and phenylpiperazino, and R6 is methyl, and salts therewith of pharmaceutically acceptable acids.
The compounds of the invention are prepared starting from a 3-amino-4-carboxy-pyrrole derivative of formula ~ II

or an acid addition salt thereof, wherein R, Rl and R6 have the meanings given above, which is reacted with carbonyl chloride to form an intermediate compound of formula o C o H _ N
~CcO

Rl ¦ R6 III

iOS~3~;

wherein R, Rl and R6 are as above defined. This compound is in turn reacted with a molsr excess over the starting compound of formula II of an amine of formula HN / 4 in which R4 and R5 are as above defined, whereby compounds of formula I are obtained in which R2 and R3 are hydrogen and Rl, R4, R5 and R6 have the aforesaid meanings. If compounds of formula I are desired in which R2 and /or R3 are different from hyd~ogen, they are obtained by means of conventional procedures as hereinbelow described.
According to a preferred mode of carrying out the process of the inYention, a molar proportion of the starting compound of formula II is dissolved in an anhydrous inert organic solvent, preferably dioxane or tetrahydrofuran though many other solvents as, for instance, halogenated hydrocarbons, of 1 to 4 carbon atoms can suitably be employed. The resulting solution is heated at abou~ 40-70C, the phosgene is allowed to bubble into this solution for about 1-3 hours. The unreacted phosgene is preferably removed from the reaction ambient by a current of dry nitrogen.
The obtained intermediate of formula III which can be regarded as the anhydride of a 3-(N-carboxamino)-4-pyrrolecarboxylic acid and formally is a 4H,6H-pyrrole [3,4-d] (1,3) oxazine-2(IH), 4-dione derivative, can be isolated and characterized if desired) but can also be employed as a crude product for the subsequent condensation step with the selected amin~ of / ~4 formula HN \
This step is performed by dissolving the anhydride of formula III
in a suitable organic Solvent, which is preferably selected from halogenated hydrocarbons containing from 1 to 4 carbon atoms. The resulting solution is added to the solution containing the amine, or to the amine itself if it is a liquid substance. The amine is employed in a molar proportion corre-sponding to about three-ten times the molar amount of ~he starting material of formula II; suitable solvents of the amine are again halogenatet hydro-carbons containing from 1 to 4 carbon atoms. The addition occurs at room temperature, but the obtained reaction mixture is preferably heated for 105503~

about one to about three hours to 30~40C or, if necessary, even to the boiling temperature to speed up the formation of the desired end products of formula I.
Compounds of formula I are obtained, wherein R2 and R3 represent hydrogen. They are recovered from the reaction mixture following ~echniques which are entirely familiar to a skilled chemist. These techniques comprise removing the solvent from the reaction mixture by evaporation, taking up the residue with a solvent5 evaporating again the solvent and purifying the obtained solid, liquid or oily substance by column chromatography, recryst-allization, fractional distillation, 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 tCl 4)-alkanols, diethylether, water or mixtures thereof.
When substituents R2 and R3 different ~rom hydrogen are desired they are introduced through well known procedures by reacting the compounds of formula I with appropriate reactants.
Thus9 for instance, the reaction with (Cl 4) alkyl halides or (Cl 4) alkylsulfates gives compounds wherein R2 and/or R3 represent (Cl 4) alkyl. Compounds where R2 is a (C2 4) aliphatic acyl radical or benzoyl are obtained by reaction with halides or anhydrides of ~C2 4) aliphatic or benzoic acids, whereas the benzenesulfonyl, toluenesulfonyl, (Cl 4) alkyl-sulfonyl and phenacylsulfonyl groups are conveniently introduced by reaction with benzenesulfonyl, toluenesulfonyl, (Cl 4) alkylsulfonyl or phenacylsulf-onyl halides respectively.
The carbamyl and phenylcarbamyl groups are introduced by reacting the aminopyrrole of formula I wherein R2 and R3 represent hydrogen, with an alkali isocyanate or phenylisocyanate respectively.
The replacement of one of the hydrogen atoms of the amino group at the 3-position by formyl is achieved by contacting a predetermined 3-aminopyrrole with formic acid in substantially equimolecular ratios, whereassubstances where R2 and R3 taken together represent tC2 4) alkylideneJ
benzylidene or halo-substituted benzylidene are easily prepared according to the known reactions for obtaining Schiff's bases from amines and carbonyl compounds .
The sulfonylation of the amino group at the position 3 provides also a useful route for preparing compounds of formula I wherein ~ is hydrogen and R3 is a (Cl 4) alkyl group. Said route consists in tCl 4) alkylating the amine nitrogen of a compound of formula I wherein R2 is benzenesulfonyl, tCl 4) alkylsulfonyl, toluenesulfonyl or phenacylsulfonyl, R3 is hydrogen, according to the usual procedures for alkylating amines.
The group ~ 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, 1970 when R2 is a phe~acylsulfonyl group.
The co~pounds of formula I may be obtained either as free bases or as the corresponding salts of pharmaceutically acceptable acids.
These salts are essentially represented by the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, benzoate, oxalate, acetate, methanesulfonate, cyclohexylsulfonate and analogs. These salts possess the same degree of pharmacological activity of ~he free bases and accordingly are included within the scope of the invention. They are easily obtained by treating a compound of formula I as the free base with a predetermined pharm-aceu~ically acceptable acid. In turn, it is possible to restore the free base from the corresponding acid salt by reaction wi~h at least one equi-molecular amount of a basic agent.
The starting amines of formula HN \ 4 are commercially available products or are prepared through obvious modifi5caticns of commercially avai-lable products.
~ he starting compounds of formula II are prepared through a process which involves as the first step the condensation bet~een an -aminonitrile lOSS036 of formula CN

",CH ~ V
or an acid salt thereof wherein Rl has the meaning given above tthe compounds of formula V are prepared according to the method described by Steiger in Organic Synthesis, ~ 13, 1942 and 22, 23, 1942) and a ~ ketoester of formula I 2 Coo-~cl-4) alky CO~

wherein R6 has the meaning gi~en aboYe. The intermediate ~-aminopyrrole which forms, of formula 2 ~ COO-(Cl 4) alkyl Rl N R6 VII

is subjected to basic hydrolysis, by means of 10% of aqueous lithium hydroxide, to obtain starting compounds of formula II wherein Rl and R6 are as above defined and R stand for hydrogen. If starting materials of formula II are desired, wherein R is ~Cl 4) alkyl, benzyl or halo-substituted benzyl, the above aminester of formula VII is transformed by mea~s of a predetermined carbonyl compounds according to common procedures into the corresponding Schiff's base of formula R7 = N COO-(Cl 4) alkyl Rl N R6 VIII

wherein R7 is a diYalent radical deriving from the employed carbonyl compound . such as, for instance, benzylidene, p-chlorobenzylidene, butylidene, iso-propylidene ~th~lide~e.~nd analogs. This substance is subsequently reacted ~0~503~;
in an anhydrous medium at about 0-5C with sodium hydride and with a (Cl 4) slkyl-,benzyl- or halo-substituted benzyl halide, thus obtaining a compound of formula:
7 N ~ _ _ ~ COO-(Cl 4) alkyl N IX
R

wherein Rl and R6 are as above defined and R stands for (Cl 4) alkyl, benzyl or halo-substituted benzyl. The obtained product of formula IX, which, if desired, may be isolatad and characterized, i5 subjected to acid hydrolysis to the corresponding starting substances of formula II.

A number of compounds of the invention, namely those where R, R2 and R3 represent hydrogen atoms, can advantageously be prepared through an alternative process which comprises reacting the above ~ -aminonitrile of formula V
CN

C~l / \ V
Rl NH2 or an acid salt thereof with a ~ -ketoamide of general formula CH2-CON \ 4 X

C--R

wherein R4, R5 and R6 h ~e the meanings previously reported.
The ~ -ketoamides of formula X are prepared through common procedures, as for instance, those described by Williams and Krynitsky, Organic Synthesis, 21, 4, 1941 and by Kaslow and Cookp Jour. Am. Chem. Soc., 67, 1969, 1945, starting from diketenes of formula ~OS'~03~;

R'6-CH-C-O=C XI

R'6--CHGC--O
in which R'6 is an alkyl from 1 to 3 carbon atoms, and amines of formula HN ~ . The compounds of formula XI are known products and are reported by Wa~ er and Zook in Synthetyc Organic Chemist~y, page 409, John Wiley and Sons, Inc" New York, 1965.
The reaction between compounds V and X generally proceeds with the formation of an intermediate open chain compound representable by the following general formula XII or its tautomeric iminic form CN CON
~ ~ \ R5 Rl N R6 which may be isolated, purified and characterized, but is generally used as a crude material for the subsequent cyclization step.
The reactants V and X are contacted in substantially equimolecul-ar amounts in the presence of an anhydrous organic solvent which is advantage-ously selected from benzene, dioxane, tetrahydrofuran and analogs.
A small amount of p-toluenesulfonic acid or molecular sieves, acting as the catalysts and waterblocking agents, is added to the reaction mixture, which is kept for about 2-28 hours at a temperature varying from room temperature to the reflux temperature.
The subsequent cycli~ation step is carried out in the presence of basic agents selected from alkali carbonates, hydroxides, alkoxides, hydrides or amides and in the presence of a solvent, which is preferably selected from anhydrous lower alkanols with a maximum of four carbon atoms.

~05503~;

The cyclization may take place at room temperature, but sometimes it is necessary to apply a gentle heating or to reflux the reaction mix~ure, in order to speed up this step, which is completed within an interval of time ranging from 1-30 hours.
The so obtained compounds of formula I, wherein R, R2 and R3 stand for hydrogen, are recovered as free bases or as the above mentioned salts of pharmaceutically acceptable acids through known methods as hereinbefore described, and may undergo the previously outlined chemical transformations for introducing the substituents R2 and/or R3, when one of them or both are desired to be different from hydrogen. Accordingly, compounds of formula I
can be obtained wherein Rl, R4, R5 and R6 are as above defined, R represents hydrogen atom and ~ and R3 are as above defined, as the free bases or as the already mentioned salts of pharmaceutically acceptable acids.
The compounds of the invention display ~ery interesting pharma-cological properties: more particularly, they are active as antiinflammatories, antipyretics and as prostaglandin synthetase inhibitors. Furthermore, some of them display also interesting C.N.S. depressant and anti-hypertensive properties and possess a valuable degree of activity on the hydric balance of warm blooded animals, The antiinflammatory activity has been investigated through the "carrageenin induced edema" test in rats, which was performed following sub-stantially the operative scheme proposed by C.A. Winter et al. in Proc. Soc.
Expl. Biol. Med., 111, 544 1962.
Representative experiments have shown that the compounds of Examples

3, 4, 5 and 11 are particularly active in this test i.e., they cause a percent decrease of the induced edema significantly higher than 30 when tested at dose level very far from the lethal dose i.e., at about 1/5 of the Said LD50 Yalues are very favorable in that they are generally higher than 500 mg/kg p.o. in mice.

lOS5036 The following table gives a more detailed account of the foregoing mentioned ant}~inflammatory activity:
Table CompoundLD50 mgfkgDose mg/kg % Decrease of the of Examplep.o. micep.o rats induced edema ..... _ _ _ 3 1000 50 16.9 100 30.0 200 45.9

4 1000 50 26.1 100 30.4 200 35.2 ~000 50 17.4 100 27.7 200 52.1 11 500 20 20.0 28.0 100 35.2 . _ . . .. _ . . _ The compounds of the invention may be administered by various routes.
While the preferred routes of administration are oral and rectal, parenteral administration can also be employed.

For oral administration, the compounds are compounded into pharma-ceutical dosage forms, such as, for instance, tablets, capsules9 elixirs, solutions and the like. The dosage unit may contain the usual excipien~s, e.g. starch, gums, fatty acids, alcohols, sugars, etc., For rectal administrat-ion the compounds are administered in the form of suppositories, admixed with conventional vehicles, such as, for instance, cocoa butter, wax, spermaceti or polyoxyethyleneglycols and their derivatives.
The dosage range is from about 0.05 to about 2.00 g. per day, preferably adminis$ered 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.

The following additional description and examples further describe the invention and the manner and process of making and using it to enable the art skilled to make and use the same and set forth the best mode con-templated by the inventors of carrying out the inYention.
Example 1 3-Amino-4-diethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride A) Phosgene (Carbonyl chloride) is bubbled for about two hours in a solution of 12.0 g. (0.0556 mole) of 3-amino-4-carboxy-5-methyl-2-phenyl-pyrrole in 600 ml. of anhydrous dioxane, keeping the reaction solution under vigorous stirring at about 55C. The unreacted carbonyl chloride is removed from the reaction ambient by means of a current of dry nitrogen, the reaction solution is cooled to room temperature and the obtained solid is recovered by filtration and washed with hexane. Yield 7.3 g. of the intermediate an-hydride of formula III wherein R is hydrogen~ Rl is phenyl and R6 is methyl, namely 5-methyl-7-phenyl-4H, 6H-pyrrolo [3,4-d] (1,3) oxazine- 2(IH), 4-diGne.
M.p. 247-49C.
B) A solution of 7.0 g. ~0.029 mole) of the compound obtained under point A) in 100 ml. of chloroform is added dropwise to 30 ml. ~0.29 mole) of diethylamine at room temperature. After refluxing for about two hours the reaction mixture is e~aporated to dryness and the obtained residue is taken up with 40 ml. of diethylether. The ether solution is first washed with water, then with aqueous sodium bicarbonate and is finally separated from the aqueous phase.
The title compound is obtained by bubbling gaseous hydrogen chloride in the ether solution. Yield 2.0 g. M.p. 212-14C tfrom ethanol/diethylether).
Example 2-18 The following compounds ha~e been prepared pursuant to the same procedure of the foregoing example, starting from 3-amino-4-carboxy-5-methyl-2-phenyl-pyrrole hydrochloride and a selected amine of formula HN < 4 2) 3-Amino-4-ethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride. 5 1~55 0 3 ~
Yield 35%. M.p. 261-63C (~rOm 4ThQnol /water).
3) 3-Amino-4-isopropylcarbamyl-5-methyl-2-phenyl-pyrrole. Yield 33%. M.p 197-98C (from methanol).
4) 3-A no-4-(p-chloro~ enylcarbamyl)-5-methyl-2-phenyl-pyrrole hydrochloride.
Yield 40%. M.p. 231-33C ~from methanol/water).

5) 3-Amino-5-methyl-2-phenyl-4-(p-tolylcarbamyl)-pyrrole hydrochloride.

_ . _ _ _ . _ .
Yield 52%. M.p. 250C (with decomposition).

6) 3-Amino-4-~p-anisylcarbamyl)-5-methyl-2-phenyl-pyrrole .
Yield 43%. M.p. 190-92C (from ethanol).

7) 3-Amino-4-f~ carbethoxyphenylcarbamyl)-5-methyl-2-phenyl-pyrTole.
Yield 61%. M.p. 217-19C (from ethanol).

8) 3-Amino-4-(~-carboxyphenylcarbamyl)-5-methyl-2-phenyl-pyrrole.

Yield 37%. M.p. 200-10C (from methanol/water).

9) ~ dinocarbonyl-p-yrrole hydrochloride.

Yield 50%. M.p. 245-49C (from methanol/water).

10) 3-Amino-5-methyl-4-(4-methyl-l-Riperazinylcarbonyl)-2-phenyl-pyrrole.

Yield 46%. M.p. 104-106C (from ethanol)

11) 3-Amino-5-methyl-2-phenyl-4-(4-phenyl-1-piperazinylcarbonyl)-pyrrole hydrochloride. Yield 44%. M.p. 220-22C (from ethanol/ water), The free base melts at 154-56C (from methanol).

12) 3-Amino-4-(o-chlorophenylcarbamyl)-5-methyl-2-phenyl-pyrrole hydrochloride.
.
Yield 47%. M.p. 268-72C (from methanol/water)

13) 3-Amino-5-methyl-4-morpholinocarbonyl-2-phenyl-pyrrole hydrochloride Yield 81%. M.p. 236-38C (from methanol/water).

14) 3-Amino-4-( -ethylphenylcarbamyl)-5-me ~ rochloride.
. ~ . ...
Yield 62%. M.p. 250-52C (from ethanol/ether).

15) ~ yrrole/

Yield 80%. M.p. 234-237C tfrom dimethylformamide).

A 16) 3-Amino-5-methyl-2-phenyl-4-(m-trifluoromethy~caTballlyl~-pyrrole~

30 Yield 46~. M.p. 150-51C. (from ethanol/water).

17) 3-AminO-5-m hyl-2-phenyl-4-~o-tolyl)-pyrrole.
Yield 33~ M.p. 218C (from ethanol/water).
18) 3-Amino-5-methyl-2-phenyl-4-(m-tolyl)-pyrrole, Yield 31% M,p, 171-73C (from ethanol/water), Example 19 . _ 3-Amino-~p-chlorobenzyl)-5- ~ nyl-pyrrole hydrochloride, from 3-amino-4-carboxy-1-(p-chlorobenzyl)-5-methyl-2-phenyl-pyrrole hydrochloride and piperidine,according to the procedure of Example 1, Yield 44%, M,p, 195-97C (from methanol/water), The corresponding intermediate compound of formula III has not been isolated in this case, Example 20 4-Ethylcarbamyl-5-methyl-2-~henyl-3-~p-toluenesulfonamido) _yrrole A solution of 5,0 g. (0,018 mole) of the compound of Example 2, 3.4 g. (0,018 mole) of p-toluenesulfonylchloride and 1,8 g, of triethylamine in 250 ml, of pyridine is stirred at room temperature for about 15 minutes and is subsequently allowed to stand overnight at about 5C. The reaction mixture is then poured into 250 ml, of aqueous hydrochloric acid and crushed ice and the resulting solution is extracted with ethyl acetate.

The precipitate which forms upon chilling is recrystallized from ethanol/water, Yield 2,0 g, of the title compound. M,p. 219-21C, Example 21 3-Acetylam no-5-methyl-2-~henyl-4-piperidinocarbonyl-~yrrole hydrochloride 5,0 Grams ~0,016 mole) of the compound of Example 9 are dissolved in 250 ml, of pyridine and the resulting mixture is added with 25 ml. of acetic anhydride, After standing for about 90 minutes at room temperature, the whole is poured into 250 ml, of 10% aqueous hydrochloric acid, The obtained solid is recovered by filtration and recrystallization from ethanol.
Yield 2,5 g, of the title compound, M,p, 289-90C, Example 22-25 The following compounds have been prepared pursuant to the same lOS503~;

procedure of the foregoing Example.

22) 3-Acetylamino-4-t -ethylphenylcarbamyl)-5-methyl-2-phenyl-Ryrrole from P
the compound of Example 14 and acetic anhydride. Yield 67%. M.p. 230 ~decomposition); (from methanol/water).
23) 3~Acetylamino-4-isopropylcarbamyl-5-methyl-2-phenYl-pyrrole from the compound of Example 3 and acetic anhydride. Yield 71%. M.p. 275C (from methanol/water).
24) 3-Acetylamino-4-(o chlorophenylcarbamyl)-5-methyl-2-phenyl-pyrrole?
from the compound of Example 12 and acetic anhydride Yield 56~ M.p. 255-257C
(from ethanol).
25) 5-Methyl-2-phenyl-3-propionylamino-4-(o-tolycarbamyl)-pyrrole, from the compound of Example 17 and propionic anhydride. Yield 60% M.p. 254C
(from acetone/water) Exampie ?6 3-Dimeth~lamino-5-methyl-2-phenyl-4-piperidinocarbonyl-pyrrole -A solution of 5.0 g. (0.016 mole) of the compound of Example 9 in 70 ml. of methanol and 20 ml. of water is added with 5 ml. of dimethylsulfate and 15.0 g. of potassium carbonate. The resulting mixture is refluxed for about four hours, then is poured into water and the obtained solid is recovered by filtration.
Yield 2,8 g. of the title compound. M.p.207-9 C. (from acetone).
Example 27 l-(p-Chlorobenzyl)--3-dimethylamino-5-methyl-2-phenyl-4-pi~eridinocarbonyl-. . _ pyrrole from the compound of Example 19 and dimethylsulfate, according toths procedure of the foregoing Example. Yield 42%. M.p. 199-201C (from ethanol/diethyl ether).
Typical compounds of formula I which can be prepared according to the procedure described in the foregoing Examples are lOSS03~
R3~ / R4 R / ~ CON \ R5 Rl I R6 Exam- ~ Rl R2 R3 R4 R5 R6 28 1~ _ H ~ CONH~ CH3 29 H ~ H I H H ~ NO2 CH3 H ~ H ¦ H H ~NH2 CH3 31 H ~3 H H H ~NHCOCH3 CH3 32 H~ OCH3 H H H C2H5 3 33 H~ OCH3 H H C2H5 C2H5 CH3 34 H~ OCH3 H H H CH~CHH3 CH3 H~ OCH3 H H H ~Cl CH3 36 H~ OCH3 H H ~Q2 CH2 ~ ~3 CH3 37 H~ CH3 H H C3H7 C3 7 C~H5 38 H- ~ C4Hg H H C2H5 ~ CH3 39 H~3 H H H ~CF3 l CH3

16 1(3SS~36 40 H ~3 H CF3 41~ H ~3 H H CH3 ~ CH3 CH3 43 H ~ H H CH ~CH3 3 44 I H ~3 H HCzH5 C2H5 C2H5 H OC2115 H ~ 2 OE 2 ~ C2H5 46 H C4Hg H H

47 H ~3 OE3 CH3C2H5Cl C2HS OEH3 48 H ~ [~ CH3 H ~ C2 5 49 CH3 ~ 4 9 2 H CH~CH3 C3H7 50 C2H5 1~3 NH2C HC2H5 C2H5 CH3 ~ H H F ~ Cl C4Hg

17 ~05503f~

C2HS H ~i C113 53 ~ ~ C2H5 C2H5 H C2H5 CH3 CH2 OC~3 54 Cl [~3 H C2H5C2H5 3 C4Hg C2H5 CH3CO CH3 H ~ C2H5 56 C4Hg ~ C2 5 H C2 5C2H5 ~ CH3 57 C4Hg ~ H H H C2H5 CH3 58 , ~ ` ~ H H C2H5 C2HS CH3 59 Cl 4~ 2 5 H ~ ~ H C2HS ~ H3 61 OH¦ CH3/CH H H 2HS CH3 62 ~ CH2 ~3 C2H5 CH3 CH3 63 H OCH3~ / ~ C2 5 64 CH3 ~ Cl CH3 H H ~3 CH3 H ~3 ~ C2 5 3 66 H ~3OCH3 CH3~C= H C2 5 CH3 67 H ~ Br~3CH= H C2 5 CH3 68 H ~3~ Cl ~ CH= H C2H5 CH3 69 H ~ CI~CH= H C2H5 CH

~05503t;

The compound of Example 1 can also be prepared according to the alternative procedure described in the following Example.
Example 70 3-Amino-4-diethylcarb~nyl-5-methyl-2-phenyl-pyrrole hydrochloride.

_ A solution of 42.0 g. (0.318 mole) of 2-amino-2-phenyl acetonitrile9 50.0 g. t0.318 mole) of ~-ace~yl-N, N-diethylacetamide and 2.1 g. of p-toluenesulfonic acid in 700 ml. of benzene is refluxed for seven hours under nitrogen atmosphere and then is allowed to stand overnight at room temperature. After distilling off the benzene at atmospheric pressure, the obtained residue ls taken up with diethyl ether, the resulting solution is filtered from any insoluble and is subsequently brought to dryness. 95.0 Grams of a residue are obtained, corresponding to the intermediate compound of formula XII in which Rl is phenyl, R4 and R5 are ethyl, R6 is methyl.
It is used as such for the subsequent cyclization step.
B) 14.0 Grams of sodium are dissolved in 360 ml, of ethanol and the resulting solution is added with a solution of 95.0 g. of the crude compound prepared unter A) in 360 ml. of ethanol.
After stirring for S hours and standing overnight at room tem-perature, the reaction mixture is concentrated to small volume by evaporat-ing the ethanol an~ is subsequently added with 300 ml. of a mixture of aqueous 10~ hydrochloric acid and diethyl ether. The obtained precipitate is recovered by filtration and recrystallized from ethanol/diethyl ether.
Yleld 67.0 g. of the title compound. M.p. 212-14C.
The compounds of Examples 2-18, 28-46, and 63 can be prepared substantially following the method described in the foregoing Example.

PREPARATION OF THE STARTING AMINO ACIDS OF FO~MULA II

,, .. ... . _ A) 3-Amino-4-carboxy-5-methyl-2-phenyl-pyrrole.
a) A solution of 6 g. (0.042 mole) of 2-amino-2-phenyl-acetonitrile and 5 g. (0.042 mole) of ethylacetoacetate in 30 ml. of anhydrous benzene is refluxed for four hours on an oil bath in the presence of 100 mg. of p-~LI )S503~i toluenesulfonic acid. Af~er cooling, the reaction mixture is filtered, then the solvent is evaporated off to give an oily residue, which is distilled under reduced pressure. B. p. 140C /0.05.
b) 0.80 Grams of sodium are dissolYed in 15 ml. of anhydrous ethanol, then a solution of 5 g. of the above compound in 35 ml. of anhydrous ethanol is added dropwise and the mixture is allowed to stand at room temperature for ~ous hours.
After bubbling dry hydrogen chloride in the ethanol solu~ion, a precipitate readily forms, which is filtered and recrystallized from a ~ixture of ethanol and diethyl ether. Yield 4 g. of 3-amino-4-carbethoxy-5-methyl-2 phenyl-pyrrole hydrochloride. M.p. 249-252C (from ethanol/ethyl ether).
A solution of 4 g. (0.0143 mole) of the compound prepared under b) in 60 ml. of dimethylsulfoxide is added with a solution of 6 g. of lithium hydroxide monohydride in 90 ml. of water and the resulting mix~ure is heated at about 80-85C for 3-4 hours.
After chilling, pouring into 160 ml. of ice water and adjusting the pH to 7, the solution is four time extracted each time with 60 ml. of ethylacetate. The organic extracts are collected and dried over sodium sulfate, then the solvent is evaporated off in vacuo. 2.58 Grams of an oily residue are obtained, which are taken up with chloroform, from which a solid crystallizes upon cooling. Yield 1.3 g. of the title compound.
M.p. 153-54C. The hydrochloride melts at 200-200.5C dec. (from water).
B) 3-Amino-4-carboxy-1-p-chlorobenzyl-5-methyl-2-phenyl-~yrrole hydrochloride.3-Amino-4-carbemoxy-5-methyl-2-phenyl-pyrrole hydrochloride, .
prepared as under point b) of the previous example is reacted with p-chlorobenzaldehyde according to the known procedures for preparing Schiff's bases from amine and carbonyl compounds. The so formed 4-carbethoxy-3-(p-chlorobenzylîdenea~ino)-5-methyl-2-phenyl-pyrrole (M.p 180-82C, from ethanol/water) is reacted in a strong alkaline medium with p-chlorobenzyl ~C)55036 chloride, according to the usual procedures for introducing a substituent into the nitrogen atom of a pyrrole nucleus.
The obtained 4-carbethoxy-1-(p-chlorobenzyl)-3-(p-chlorobenzylid-eneamino)-5-methyl-2-phenyl-pyrrole is not isolated and is hydrolyzed under acidic conditions to give the title compound M.p. 170-171C tfrom methanol/
ethcr).

Claims (28)

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

1. A process for the preparation of a compound of the 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 phenyl sub-stituted with 1 to 3 radicals independently selected from (C1-4) alkyl, (C1-4)alkoxy, benzyloxy, fluoro, chloro, bromo and hydroxy; R2 is a member of the class consisting of hydrogen, (C1-4)alkyl, formyl, (C2-4)aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (C1-4)alkylsulfonyl, benzenesulfonyl, toluenesulfonyl and phenacylsulfonyl; R3 is selected from hydrogen and (C1-4)alkyl; R4 and R5 independently represent hydrogen, (C2-4)alkyl and substituted phenyl, though not simultaneously hydrogen, or taken together with the adjacent nitrogen atom they can also represent dimethylamino or a 5-6 mem-bered heterocyclic ring which may contain a further oxygen or nitrogen atom and be optionally substituted by one to three (C1-4)alkyl radicals or by a phenyl group; R6 represents a (C1-4)alkyl group; R2 and R3 taken together re-present (C2-4)alkylidene, benzylidene or halo-substituted benzylidene and pharmaceutically acceptable acid addition salts thereof which comprises either;
(a) reacting a compound of the formula II

wherein R, R1 and R6 are as defined above, or an acid addition salt thereof, with phosgene and reacting the intermediate so formed with an excess of an amine of the formula:

IV

wherein R4 and R5 are as defined above, to produce a compound of formula I in which R2 and R3 are hydrogen atoms; or (b) reacting an .alpha.-aminonitrile of the formula:

V

wherein R1 is as defined above, with a compound of the formula wherein R4, R5 and R6 are as defined above under anhydrous conditions, to produce a compound of formula I in which R, R2 and R3 are hydrogen atoms; and when the radicals R2 or R3 or both, as defined above, are desired to be dif-ferent from hydrogen, they are introduced by common alkylation, acylation in-cluding sulfonylation, carbamylation and formylation, Schiff base formation procedures, which include reaction with (C1-4)alkyl halides, (C14)alkyl sul-fates, (C2-4)aliphatic acyl halides or anhydrides, benzoyl halides or anhy-drides, benzenesulfonyl halides, (C1-4)alkylsulfonyl halides, toluenesulfonyl halides, phenacylsulfonyl halides, formic acid, alkali metal cyanates, phenyl-isocyanate, (C2-4)aliphatic aldehydes, (C3-4)aliphatic ketones, benzaldehyde, benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally by removing the (C1-4)alkylsulfonyl, benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl groups by hydrolysis; and when a compound of formula I is desired in the form of a pharmaceutically acceptable acid addition salt treat-ing the free base of formula I with an acid having a pharmaceutically accept-able anion and when a free base of formula I can be liberated from a corres-ponding acid addition salt by treatment with an alkali,

2. A process according to claim 1 for preparing compounds of the formula:

and pharmaceutically acceptable acid addition salts thereof, wherein the sub-stituents R through R6 are defined as in claim 1, which comprises reacting a compound of formula I I

wherein R, R1 and R6 are defined as claim 1, or an acid addition salt thereof, with phosgene (carbonyl chloride) for about one to about three hours in an inert organic solvent, at a temperature comprised between about 40 and about 70°C, subsequently adding from about three to about ten molar equivalents of an amine of formula wherein R4 and R5 are defined as in claim 1, keep-ing the reaction mixture between room temperature and the boiling temperature of the reaction mixture for about one to about three hours, said process being further characterized in that:
a) when the radicals R2 and R3 or both, as defined above, are desir-ed to be different from hydrogen, they are introduced by common alkylation, acylation including sulfonylation, carbamylation and formylation, Schiff base formation procedures, which include reaction with (C1-4)alkyl halides, (C1-4) alkyl sulfates, (C2-4)aliphatic acyl halides or anhydrides, benzoyl halides or anhydrides, benzenesulfonyl halides, (C1-4)alkylsulfonyl halides, toluene-sulfonyl halides, phenacylsulfonyl halides, formic acid, alkali metal cyanates, phenylisocyanate, (C2-4)aliphatic aldehydes, (C3-4)aliphatic ketones, benz-aldehyde, benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally by removing the (C1-4)alkylsulfonyl, benzenesulfonyl, toluene-sulfonyl or phenacylsulfonyl groups by hydrolysis;
b) when a compound of formula I is desired in the form of a pharma-ceutically acceptable acid addition salt, the corresponding free base is treat-ed with the appropriate acid, and, if desired, a free base may be obtained from the corresponding salt by treatment with alkali.

3. A process according to claim 1 for preparing compounds of the formula:
Ia and pharmaceutically acceptable acid addition salts thereof, wherein the sub-stituents R1 through R6 are as defined in claim 1, which comprises reacting an .alpha.-aminonitrile of formula V

with a molar equivalent of a compound of formula X

wherein R1, R4, R5 and R6 are as defined in claim 1, in the presence of an anhydrous organic solvent, in the further presence of a catalytic amount of p-toluenesulfonic acid, for two or twenty-eight hours, at a temperature compris-ed between the room temperature and the reflux mixture temperature, subsequen-tly adding a slight molar excess over the starting .alpha.-aminonitrile of a basic condensing agent selected from alkali carbonates, hydroxides, alkoxides, hy-drides or amides, keeping the obtained reaction mixture for one to thirty hours at a temperature varying from room temperature to the boiling temperature of the reaction mixture, said process being further characterized in that:
a) when radicals R2 or R3 or both, as defined in claim 1, are desir-ed to be different from hydrogen, they are introduced by common alkylation, acylation, sulfonylation, carbamylation, formylation, Schiff's bases formation procedures which include reaction with (C1-4)alkyl halides, (C1-4)alkyl sulfates, (C2-4)aliphatic acyl halides or anhydrides, benzoyl halides or an-hydrides, benzenesulfonyl halides, (C1-4)alkylsulfonyl halides, toluenesul-fonyl halides, phenacylsulfonyl halides, formic acid, alkali metal cyanates, phenylisocyanate, (C2-4)aliphatic aldehydes, (C3-4)aliphatic ketones, benz-aldehyde, benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally by removing the (C1-4)alkylsulfonyl, benzenesulfonyl, toluene-sulfonyl or phenacylsulfonyl groups by hydrolysis;
b) when a compound of formula I is desired in the form of a pharma-ceutically acceptable acid addition salt, the corresponding free base is treated with the appropriate acid, and, if desired, a free base may be obtain-ed from the corresponding salt by treatment with alkali.

4. A process according to claim 1 for the preparation of compounds of formula I in which R2 and R3 are hydrogen atoms which comprises reacting a compound of formula II as defined in claim 1 with phosgene and reacting the intermediate so obtained with an excess of an amine of formula IV as defined in claim 1.

5. A process according to claim 4 in which the reaction with phos-gene is effected in an inert solvent at about 40° to about 70°C for about one to three hours.

6. A process according to claim 4 or 5 in which the reaction with phosgene is followed by reacting the intermediate so formed with about 3 to about 10 molar equivalents of the amine of formula IV at a temperature from about room temperature and the boiling point of the reaction mixture for about one to about three hours.

7. A process according to claim 1 for the preparation of compounds of the formula I where R, R2 and R3 are hydrogen atoms, which comprises react-ing an .alpha.-aminonitrile of formula V so defined in claim 1 with a compound of the formula X as defined in claim 1 under anhydrous conditions.

8. A process according to claim 7 in which a molar equivalent of the compound of formula X is used and the reaction is carried out in an anhydrous inert solvent, in the presence of a catalytic amount of p-toluenesulfonic acid.

9. A process according to claim 8 in which the reaction is effected for 2 to 28 hours at a temperature between room temperature and about the reflux temperature of the reaction mixture.

10. A process according to claim 7, 8 or 9 in which there is subse-quently added a slight molar excess over the starting .alpha.-aminonitrile of a basic condensing agent selected from alkali metal carbonates, hydroxides, alkoxides, hydrides or amides and the resulting reaction mixture is maintained for one to thirty hours at a temperature varying from room temperature to the boiling point of the reaction mixture.

11. Compounds of formula wherein: R is selected from hydrogen, (C1-4)alkyl, benzyl, and halo-sub-stituted benzyl; R1 represents hydrogen, (C1-4)alkyl, phenyl or phenyl substi-tuted with 1 to 3 radicals independently selected from (C1-4)alkyl, (C1-4) alkoxy, benzyloxy, fluoro, chloro, bromo and hydroxy; R2 is a member of the class consisting of hydrogen, (C1-4)alkyl, formyl, (C2-4)aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (C1-4)alkylsulfonyl, benzenesulfonyl, toluenesulfonyl and phenacylsulfonyl; R3 is selected from hydrogen and (C1-4)alkyl; R4 and R5 independently represent hydrogen, (C2-4)alkyl and substituted phenyl, though not simultaneously hydrogen, or taken together with the adjacent nitrogen atom they can also represent dimethylamino or a 5-6 membered heterocyclic ring which may contain a further oxygen or nitrogen atom and be optionally substituted by one to three (C1-4)alkyl radicals or by a phenyl group; R6 represents a (C1-4)alkyl group; R2 and R3 taken together represent (C2-4) alkylidene, benzylidene or halo-substituted benzylidene and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1, 2 or 3 or by an obvious chemical equivalent thereof.

12. A process according to claim 1 wherein: R represents hydrogen, benzyl or halo-substituted benzyl; R1 is phenyl; R2 is selected from hydro-gen, (C1-4)alkyl, (C2-4)aliphatic acyl, toluenesulfonyl; R3 may be hydrogen or (C1-4)alkyl; R4 and R5 independently represent hydrogen, (C2-4)alkyl, phenyl substituted by (C1-4)alkyl, (C2-4)aliphatic acyl, (C1-4)alkoxy, halo, carboxy, carbo(C1-4)alkoxy and trifluoromethyl, though not simultaneously hydrogen, or taken together with the adjacent nitrogen atom, they can also represent dimethylamino, piperidino, morpholino, (C1-4)alkylpiperazino and phenylpiperazino; R6 is a (C1-4)alkyl group.

13. A process according to claim 1, 2 or 3, wherein: R is hydrogen;
R1 is phenyl; R2 is selected from hydrogen, (C1-4)alkyl, (C2-4)aliphatic acyl and toluenesulfonyl; R3 may be hydrogen or (C1-4)alkyl; R4 and R5 in-dependently represent hydrogen, (C2-4)alkyl, phenyl substituted by (C1-4) alkyl, (C2-4)aliphatic acyl, (C1-4)alkoxy, halo, carboxy, carbo(C1-4)alkoxy and trifluoromethyl, though not simultaneously hydrogen or, taken together with the adjacent nitrogen atom, they can also represent dimethylamino, piperidino, morpholino, (C1-4)alkylpiperazino and phenylpiperazino; R6 is (C1-4)alkyl.

14. A process according to claim 1, 2 or 3 wherein: R, R2 and R3 stand for hydrogen; Rl is phenyl; R4 and R5 independently represent hydro-gen, (C2 4)alkyl, phenyl substituted by (Cl 4)alkyl, (C2 4)aliphatic acyl, (Cl 4)alkoxy, halo, carboxy, carbo(Cl 4)alkoxy and trifluoromethyl, though not simultaneously hydrogen or, taken together with the adjacent nitrogen atom, they can also represent dimethylamino, piperidino, morpholino, (Cl 4)alkyl-piperazino and phenylpiperazino; R6 is methyl.

15. A process according to claim 1 wherein R, R2, R3 and R5 are hydrogen atoms, Rl is phenyl, R4 is isopropyl and R6 is methyl.

16. A process according ~o claim 1 in which 3-amino-4-isopropyl-carbamyl-5-methyl-2-phenylpyrrole is prepared by either:-(a) reacting 3-amino-4-carboxy-5-methyl-2-phenylpyrrole with phosgene and treating the intermediate 5-methyl-7-phenyl-4H,6H-pyrrole[3,4-d](1,3)-oxazine-2(1H),4-dione so obtained with isopropylamine; or (b) reacting 2-amino-2-phenylacetonitrile with ~-acetyl-N-isopropyl-acetamide and reacting the intermediate so obtained with sodium ethoxide.

17. 3-Amino-4-isopropylcarbamyl-5-methyl-2-phenylpyrrole whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

18. A process according to claim 1 in which R, R2, R3 and R5 are hy-drogen atoms, R4 is p-chlorophenyl, Rl is phenyl and R6 is methyl.

19. A process according to claim 1 in which 3-amino-4(p-chlorophenyl-carbamyl)-5-methyl-2-phenylpyrrole and its hydrochloride are prepared by either:-(a) reacting 3-amino-4-carboxy-5-methyl-2-phenylpyrrole with phosgene and treating the intermediate 5-methyl-7-phenyl-4ll,6H-pyrrole[3,4-d](1,3)-oxazine-2(1H),4-dione so obtained with p-chloroaniline; or (b) reacting 2-amino-2-phenylacetonitrile with ~-acetyl-N-(p-chloro-phenyl)acetamide and reacting the intermediate so obtained with sodium ethoxide, and when the corresponding hydrochloride is required reacting the base so obtained with hydrogen chloride.

20. 3-Amino-4-(p-chlorophenylcarbamyl)-5-methyl-2-phenylpyrrole and its hydrochloride whenever prepared by the process of claim 19 or by an ob-vious chemical equivalent thereof.

21. A process according to claim 1 in which R, R2, R3 and R5 are hydrogen atoms, R4 is p-tolyl, R1 is phenyl and R6 is methyl.

22. A process according to claim 1 in which 3-amino-5-methyl-2-phenyl-4-(p-tolylcarbamyl)pyrrole is prepared by either:-(a) reacting 3-amino-4-carboxy-5-methyl-2-phenylpyrrole with phosgene and treating the intermediate 5-methyl-7-phenyl-4H,6H-pyrrole[3,4-d](1,3)-oxazine-2(1H), 4-dione so obtained with p-toluidine; or (b) reacting 2-amino-2-phenylacetonitrile with .alpha.-acetyl-N-(p-tolyl) acetamide and reacting the intermediate so obtained with sodium ethoxide.

23. 3-Amino-5-methyl-2-phenyl-4-(p-tolylcarbamyl)-pyrrole whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

24. A process according to claim 1 in which R, R2 and R3 are hydro-gen atoms, R1 is phenyl, R6 is methyl and the group is a 4-phenyl-piperazin-l-yl group.

25. A process according to claim 1 in which 3-amino-5-methyl-2-phenyl-4-(4-phenyl-piperazin-1-yl-carbonyl)pyrrole and its hydrochloride are prepared by either:-(a) reacting 3-amino-4-carboxy-5-methyl-2-phenylpyrrole with phosgene and treating the intermediate 5-methyl-7-phenyl-4H,6H-pyrrole[3,4-d](1,3)-oxazine-2(1H),4-dione so obtained with 4-phenylpiperazine; or (b) reacting 2-amino-2-phenylacetonitrile with .alpha.-acetyl-N-(4-phenyl-piperazin-l-yl)acetamide and reacting the intermediate so obtained with sodium ethoxide, and when the corresponding hydrochloride is required reacting the base so obtained with hydrogen chloride.

26. 3-Amino-5-methyl-2-phenyl-4-(4-phenyl-1-piperazinylcarbonyl)-pyrrole and its hydrochloride whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

27. A compound of the formula:- ( IIa) wherein Q is a hydrogen atom or a C1-4 ethyl group and R, R1 and R6 are as defined in claim 1.

28. A process for the preparation of the compounds of formula IIa as defined in claim 27 which comprises reacting an .alpha.-aminonitrile of the formula V:- wherein Rl is as defined in claim 27, or an acid addition salt thereof, with a .beta.-ketoester of the formula VI:- VI

wherein R6 is as defined in claim 27, to produce a compound of formula IIa in which Q is Cl 4alkyl and R is a hydrogen atom; when a corresponding 4-carboxy-lic acid is required hydrolysis the ester so obtained; and when a compound of formula IIa is required in which R is other than hydrogen, subjecting the corresponding N-unsubstituted compound to the additional step of alkylation, benzylation or halobenzylation or reacting it with appropriate carbonyl com-pound and reducing the corresponding N-alkylidene, benzylidene or halobenzyli-dene compound so produced.