IE42956B1 - 4-amino-3-pyrrole carboxamides - Google Patents

Abstract

1492663 Pyrrolidinecarboxamides GRUPPO LEPETIT SpA 4 Feb 1976 [20 Feb 1975] 7220/75 Heading C2C The invention comprises pyrrolidinecarboxamides of the Formula I wherein R is H, C 1-4 alkyl, benzyl or halobenzyl; R 1 is H, C 1-4 alkyl or phenyl optionally substituted 1 to 3 times by C 1-4 alkyl, C 1-4 alkoxy, benzyloxy, F, Cl, Br and OH; R 2 is H, C 1-4 alkyl, formyl, C 2-4 aliphatic carboxylic acyl, benzoyl, carbamoyl, phenylcarbamoyl, C 1-4 alkyl sulphonyl, benzenesulphonyl, toluenesulphonyl or phenacylsulphonyl; R 3 is H or C 1-4 alkyl; or R 2 and R 3 taken together represent C 2-4 alkylidene, benzylidene or halobenzylidene; R 4 and R 5 are H, C 2-4 alkyl or substituted phenyl, though not simultaneously H, or taken together with the nitrogen atom to which they are attached they may be dimethylamine or a 5-6 membered saturated heterocyclic ring optionally containing a further O or N atom and optionally substituted by 1 to 3 C 1-4 alkyl radicals or by a phenyl radical; R 6 is C 1-4 alkyl, and pharmaceutically acceptable acid addition salts thereof. The compounds are prepared either by reacting the appropriate 1 - R - 2 - R 6 - 5 R 1 - 4 - amino - 3 - pyrrolecarboxylic acids or acid addition salts thereof with phosgene and treating the resulting intermediates with amines of the formula HNR 4 R 5 or by reacting aminonitriles of the formula with compounds of the formula and, if desired, reacting the compounds of Formula I thus obtained in which R 2 and R 3 are both H, with C 1-4 alkyl halides, di(C 1-4 alkyl) sulphates, C 2-4 aliphatic acyl halides or anhydrides, benzoyl halides or anhydrides, benzene sulphenyl halides, C 1-4 alkyl sulphonyl halides, formic acid, alkali metal cyanates, phenyl isocyanate, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, acetone, ethyl methyl ketone, optionally substituted benzaldehydes. The following intermediates are also prepared: 5 - methyl - 7 - phenyl - 4H,6H - pyrrolo[3,4-d]- (1,3)oxazine - 2(1H),4 - dione; N,N - diethyl- 3 - (α - cyanobenzylamino) - crotonamide; 4- amino - 2 - methyl - 5 - phenyl - 3 - pyrrolecarboxylic acid and its hydrochloride and the hydrochloride of its ethyl ester; 3-amino-1-pchlorobenzyl - 2 - methyl - 5 - phenyl - 3 - pyrrole carboxylic acid hydrochloride; ethyl 4-(p-chlorobenzylideneamino) - 2 - methyl - 5 - phenyl- 3-pyrrolecarboxylate and ethyl 1-p-chlorobenzyl - 4 - (p - chlorobenzylideneamino) - 2- methyl - 5 - phenyl - 3 - pyrrolecarboxylate. Pharmaceutical compositions, suitable for oral, parenteral or rectal administration, contain the above compounds or acid addition salts thereof together with pharmaceutically acceptable carriers. The compounds possess antiinflammatory, antipyretic, CNS depressant and anti-hypertensive activities, and are also active as prostaglandin synthetase inhibitors.

Description

The present invention concerns new amino-pyrrole derivatives of the following general formula: the salts therewith of pharmaceutically acceptable acids, and their preparation.

In the above formula I the substituents R to Rg have the following meanings: R is hydrogen, (C^_^) alkyl, benzyl or halo-benzyl; R-j represents hydrogen, (C^_^)alkyl, phenyl or phenyl substituted with 1 to 3 substituents independently selected from (C^^Jalkyl, (C.^) alkoxy, benzyloxy, fluorine, chlorine, bromine and hydroxy; R2 is hydrogen, (Cp^)alkyl, formyl, (C2_4)aliphatic acyl, benzoyl, carbamoyl, phenyl carbamoyl, (C^_^)alkylsulfonyl( benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl; -242956 Rg is hydrogen or (C-]_4)alky1; or R2 and R^ taken together represent (C2_4) alkylidene, benzylidene or halobenzylidene; R4 and Rg independently represent hydrogen, (C2_4)alky1 or substituted phenyl (as hereinafter defined), though not simultaneously hydrogen, or, taken together with the nitrogen atom to which they are attached, may represent dimethyl amino or a 5-6 membered saturated heterocyclic ring optionally containing a further oxygen or nitrogen atom and optionally substituted by one to three (C^_^)alk.yl radicals or by a phenyl group; and Rg represents a (C-j_4) alkyl group.

In this specification the term (C^^Jalkyl refers to an alkyl radical containing 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl andieri.-butyl; the term “(C2_4)alkyl identifies the same radicals excluding methyl, the term 'halobenzyl' designates a benzyl radical substituted in the aromatic ring with flourine, chlorine or bromine such as, p-chlorobenzyl, o-chlorobenzyl, p-fluorobenzyl, o-bromobenzyl, and m-bromobenzyl; the term “substituted phenyl designates phenyl radicals substituted with 1 to 3 radicals independently selected from (C-|_4)alkyl, (C^^Jalkoxy, fluorine, chlorine, bromine, hydroxy, nitro, amino, (C2_4)aliphatic carboxylic acylami no, (C^_4 alkoxy) carbonyl, carboxy, carbamoyl and trifluoromethyl; the term (C2_4)aliphatic acyl refers to an aliphatic carboxylic acyl radical containing 2 to 4 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl; (C^_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 for example ethylidene, propylidene; isopropylidene, butylidene and isobutylidene; the term halobenzylidene designates a benzylidene radical substituted in the aromatic ring with for example chlorine, fluorine or bromine such as o-chlorobenzylidene, m-chlorobenzylidene, p-chlorobenzylidene, p-fluorobenzylidene, o-fluorobenzylidene and m-bromobenzylidene, A preferred group of compounds comprises those of formula I wherein R represents hydrogen, benzyl or halobenzyl, R·] is phenyl, R2 is hydrogen, (<η_4) alkyl, (C2_4)aliphatic acyl or toluenesulfonyl, R3 is hydrogen or (C.j_4)alkyl, R4 and Rg independently represent hydrogen, (C2_4)alkyl, phenyl substituted by (C1_4)alkyl, (C2_4)aliphatic acyl, (C-].4) alkoxy, halogen, carboxy, (C-^alkoxy) -39S6 carbonyl or trifluormethyl, though not simultaneosuly hydrogen, or and Rg together with the nitrogen atom to which they are attached may also represent dimethylamino, piperidino, morpholino, 4 - ^(C^_4)-alky^ piperazone and 4phenylpiperazino, and Rg is above defined, and salts therewith of pharmaceutically acceptable acids. A second preferred group of compounds comprises those of formula I wherein R is hydrogen, R^ is phenyl, Rg is hydrogen, (C^_4)alkyl, (Cg ^)-aliphatic acyl or toluenesulfonyl, Rg is hydrogen or (C^_4)alkyl, and Rg independently represent hydrogen, (Cg_4)alkyl, phenyl substituted by (C-]_4) alkyl, (Cg^)aliphatic acyl, (C-j_4)alkoxy, halogen, carboxy, (C^_4 alkoxy) carbonyl or trifluoromethyl, though not simultaneously hydrogen, or, taken together with the nitrogen atom to which they are attached, they may also represent dimethylamino, piperidino, mPrpholino,|4- (C^_4)-alkyl] piperazino and 4-£henyTpiperazino, and Rg is as .above defined and salts therewith of pharmaceutically acceptable acids.

A further preferred group of compounds comprises those of formula I Wherein R, Rg and Rg stand for hydrogen, R-j is phenyl, R^ and Rg independently represent hydrogen, (Cg_4)alkyl, phenyl substituted by (C-j_4)-alkyl, (Cg_4) aliphatic acyl, (C-|_4)alkoxy, halogen, carboxy, [(C^_4)alkox^ carbonyl}trifluoromethyl, though not simultaneously hydrogen, or, taken together with the nitrogen atom to which they are attached they may also represent dimethylamino, piperidino, morpholino, 4- Qc^)alkyl] piperazino and 4-phenylpiperazino, and Rg is methyl, and salts therewith of pharmaceutically acceptable acids.

The compounds of the invention in which Rg and Rg are hydrogen are prepared starting from a 4-amino-3-pyrrole carboxylic acid of formula H2\ COOH II -4429s6 or an acid addition salt thereof, wherein R, R-, and Rg have the meanings given above, which is reacted with phosgene to form an intermediate compound of formula wherein R, R-j and Rg are as above defined. This compound is in turn reacted with 5 a molar excess over the starting compound of formula II of an amine of formula in which R^ and Rg are as above defined, whereby compounds of formula I are obtained in which R2 and Rg are hydrogen and Rp Rp Rg and Rg have the aforesaid meanings.

If compounds of formula I are desired in which R2 and/or R, are different from hydrogen, they are obtained by means of conventional procedures as hereinbelow described. Compounds of formula II are the subject of our Patent No. 40290.

According to a preferred mode of carrying out the process of the invention, a molar pronortion 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 40-70°C, the phosgene is allowed to bubble into this solution for 1-3 hours. The unreacted phosgene is preferably removed from the reaction ambient by a current of dry nitrogen. -556 The obtained intermediate of formula III which can be regarded as the anhydride of a 4 - (N - carboxamino) -3- pyrrol ecarboxylic acid and formally is a 4#, 6 -H pyrrole β,4-d] (1,3)oxazine-2(l/z), 3- dione derivative, can be isolated and characterized if desired, but can also be employed as a raw product for the subsequent condensation step with the selected amine of formula This step is performed by dissolving the anhydride of formula III is a suitable organic solvent, which in 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 employed in a molar proportion corresponding to three-ten times the tolar amount of the starting material of formula II; suitable solvents of the amine are again halogenated hydrocarbons containing from 1 to 4 carbon atoms.

The addition occurs at room temperature, but the obtained reaction mixture is areferably heated for one to three hours to 30-40°C 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, rhey are recovered from the reaction mixture following techniques which are antirely familiar to a skilled chemist. These techniques comprise removing the solvent from the reaction mixture by evaporation, taking up the residue with a solvent, evaporating again the solvent and purifying the obtained solid, liquid or )ily Substance by column chromatography, recrystallization, fractional distillation, >r distillation under reduced pressure. If a crystalline solid directly results ?rom the reaction, this is recovered simply by filtration, and, if necessary, lurified by recrystallization.

Recrystallization solvents are preferably selected from (C^_^)-alkanols, -642956 diethyl ether, water or mixtures thereof. When substituents Rg and Rg different from hydrogen are desired they are introduced through well known procedures by reacting the compounds of formula I with appropriate reactants. Thus, for instance, the reaction with (C1_4)alkyl halides or di(C^ alkyl sulfates gives compounds wherein Rg and/or Rg represent (0^^,)alkyl. Compounds where Rg is a (Cg_4)aliphatic acyl radical or benzoyl are obtained by reaction with halides or anhydrides of (Cg_4)aliphatic or benzoic acids, whereas the benzenesulfonyl, toluenesulfonyl (C-^alkylsulfonyl or phenacyl sulfonyl groups are conveniently introduced by reaction with benzenesulfonyl, toluenesulfonyl, (C^_^)alkylsulfonyl or phenacyl sulfonyl halides respectively.

The carbamoyl and phenylcarbamoyl group ate introduced by reacting the aminopyrrole of formula I wherein Rg and Rg represent hydrogen, with an alkali metal isocyanate or phenyl isocyanate respectively.

The replacement of one of the hydrogen atoms of the amino group at the 4position by formyl is achieved by contacting an appropriate 4-ami nopyrrole with formic acid in substantially equimolecular ratios, whereas substances where Rg and Rg taken together represent (Cg_^)alkylidene, benzylidene or halobenzylidine are easily prepared according to the known reactions for obtaining Schiff's bases from amines and the appropriate carbonyl compounds i.e. acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, acetone, ethyl methyl ketone, benzaldehyde and benzaldehyde substituted by halogen.

The sulfonylation of the amino group at the position 4 provides also a useful route for preparing compounds of formula I wherein Rg is hydrogen and Rg is a (c-|_4)alkyl group. Said route consists in (C^_4)alkylating the amino nitrogen of a compound of formula I wherein Rg is benzenesulfonyl, (C^) alkylsulfonyl, toluenesulfonyl or phenacylsulfonyl, Rg is hydrogen, according to the usual procedures for alkylating amines. The group Rg as above defined is removed by hydrolysis with acids or according to the method described by J.B. Hendrickson and R. Bergeron, Tetrahedron Letters, page 345, 1970 when Rg is a phenacylsulfonyl group.

The compounds of formula I may be obtained either as free bases or as the corresponding salts of pharmaceutically acceptable acids. -7These salts are for example represented by the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, benzoate, oxalate, acetate, methanesulfonate and eyclohexylsulfonate. These salts possess the same degree of pharmacological activity of the 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 an appropriate pharmaceutically acceptable acid. In turn, it is possible to re-obtain the free base from the corresponding acid salt by reaction with at least one equilmolecular amount of a base.

The starting amines of formula are commercially available products or are prepared through obvious modifications of commercially available products.

The starting compounds of formula II are prepared through a process which involves as the first step the condensation between an α-aminoitrile of formula CN ./ \.. or an acid salt thereof, wherein has the meaning given abobe (the compounds of formula V are prepared according to the method described by Steiger in Organic Synthesis, 22, 13, 1942 and 22, 23, 1942) and a e-ketoester of formula CH2_ COO_(C·,-^alkyl J° 'n wherein Rg has the meaning given above. The intermediate alkyl 4 - amino - 3 VI -8VII 4S9 36 pyrrole carboxylate which forms, of formula h2^ -C00-(C-|_4)alkyl is subjected to basic hydrolysis, by means of 10% w/v aqueous lithium hydroxide, to obtain starting compounds of formula II wherein and Rg are as above defined and R stands for hydrogen. If starting materials of formula II are desired, wherein R is (C^^Jalkyl, benzyl or balobenzyl, the above aminoester of formula VII is transformed by means of an appropriate carbonyl compound according to common procedures into the corresponding Schiff's base of formula R?=N· /00-((^ _4)alkyl VIII wherein R? is a divalent radical derived from the carbonyl compound such as, benzylidene, p-thlorobenzylidene, butylidene, isopropylidene and ethylidene. This substance is subsequently reacted in an anhydrous medium at 0-5°C with sodium hydride and with a (C^4)alkyl, benzyl or halobenzyl halide, thus obtaining a compound of formula: R7sl\_^COO-fC^alkyl wherein R^ and Rg are as above defined and R stands for alkyl, benzyl or halobenzyl. The obtained product of formula IX, which, if desired, may be isolated and characterized, is subjected to acid hydrolysis to the corresponding -95 56 ‘ starting substances of formula II.

A number of compounds of the invention, namely those where R, R,, and R3 •epresent hydrogen atoms, can advantageously be prepared through an alternative irocess which comprises reacting the above «-aminonitrile of formula V ir an acid salt thereof, nth a β-ketoamide of general formula CH„ C0N<< .

CO /here R^, Rg and Rg have the meanings previously reported.

The β-ketoamides of formula X are prepared through common procedures, as for nstance, those described by Williams and Krynitsky, Organic Synthesis, 21, 4, 941 and by Kaslow and Cook, Jour. Am. Chem. Soc.,/??, 1969, 1945, starting from n's-ketenes of formula R‘ R'6~CH CH—c X =0 b XI n which Rg 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 Wagner nd Zook in Synthetic Organic Chemistry, page 409, John Wiley and Sons, Inc., ew York, 1965.

The reaction between compounds V and X generally proceeds with the formation f an intermediate open chain compound representable by the following general -1042956 formula XII or its tautomeric iminic form which may be isolated, purified and characterized, but is generally used as a raw material for the subsequent cyclization step.

The reactants V and X are contacted in substantially equimolecular amounts in the presence of an anhydrous organic solvent which is advantageously selected from benzene, dioxane and tetrahydrofuran.

A small amount of p-toluenesulfonic acid or molecular sieves, acting as catalyst and dehydrating agent, is added to the reaction mixture, which is kept for 2-28 hours at a temperature varying from room temperature to the reflux temperature.

The subsequent cyclization step is carried out in the presence of a base selected from alkali metal carbonates, hydroxides, alkoxides, hydrides or amides and preferably in the presence of a solvent, which is preferably selected from anhydrous alkanols with a maximum of four carbon atoms. The base is preferably used in a slight excess (in molar terms) with respect to the d-aminonitrile initially employed.

The cyclization may take place at room temperature, hut sometimes it is necessary to apply a gentle heating or to reflux the reaction mixture, 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, Rg and Rg 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 Rg and/or Rg, when one of them or both are desired to be different from hydrogen. Accordingly, compounds of formula I can be -11956 obtained wherein R-p R^, Rg and Rg are as above defined, R represents hydrogen atom and R2 and Rg are as above defined, as the free bases or as the already mentioned salts of pharmaceutically acceptable acids.

The compounds of the invention display very interesting pharmacological properties: more particularly, they are active as anti-inflammatories, 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 carrageenih induced edema test in rats, which was performed following substantially the sperative scheme proposed by C.A. Winter et at. in Proc. Soc. Expl. Biol. Med., 7W, 544 1962. Representative experiments have shown that the compounds of xamples 3, 4, 5 and 11 are particularly active in this test i.e., they cause percent decrease of the induced edema significantly higher than 30 when tested t dose level very far from the lethal dose i.e., at about 1/5 of the LD-θ. lid LDg0 values are very favorable in that they are generally higher than 500 j/kg p.o. in mice.

The following Table gives a more detailed account of the foregoing mentioned itiinflammatory activity. -1242SoS TABLE Compound LDg0 mg/kg Dose mg/kg 50 Decrease of the of Example p.o. mice p.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 5 1000 50 17.4 100 27.7 200 52.1 11 500 20 20.0 50 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 pharmaceutical dosage forms, such as, for instance, tablets, capsules, elixirs and solutions. The dosage unit may contain the usual excipients, e.g. starch, gums, fatty acids, alcohols and sugars. For rectal administration the compounds are administered in the form of suppositories, admixed with conventional vehicles, such as cocoa butter, wax, spermaceti or polyoxyethyleneglycols and their derivatives. The dosage range is from 0.05 to 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.

The invention is illustrated by the following Examples.

EXAMPLE 1. ιέ 3 - Amino - ν,ν - diethyl - 2 - methyl - 5-phenyl - 3 - pyrrole carboxamide hydro-13iloride.

Phosgene is bubbled for about too hours in a solution of 12.0 g. (0.0566 mole) ' 4 - amino - 2 - methyl - 5 - phenyl - 3-pyrrole - carboxylic acid in 600 ml. : anhydrous dioxane, keeping the reaction solution under vigorous stirring at out 55°C. The untracted phosgene is removed from the reaction ambient by means a current of dry nitrogen, the reaction solution is cooled to room temperature d the solid obtained is recovered by filtration and washed with hexane. Yield 3 g. of the intermediate anhydride of formula III wherein R is hydrogen, R^ is enyl and Rg is methyl, namely 5 - methyl- 7 - phenyl - 4//,6//- pyrrolo β,4 - dj ,3)-oxazine-2(l//), 4-dione. M.p. 248-49°C.

B). A solution of 7.0 g. (0.029 mole) of the compound obtained under point A) 100 ml. of chloroform is added dropwise to 30 ml. (0.29 mole) of diethylamine room temperature. After refluxing for about too hours the reaction mixture evaporated to dryness and the obtained residue is taken up with 40 ml, of ethyl ether. The etheral solution is first washed with water, then with ueous sodium bicarbonate and is finally separated from the aqueous phase.

The title compound is obtained by bubbling gaseous hydrogen chloride in the heral solution. Yield 2.0 g. M.p. 212-14°C (from ethanol/diethyl ether).

Examples 2-18.

The following compounds have been prepared pursuant to the same procedure of e foregoing example, starting from 4 - amino - 2 - methyl - 5 - phenyl - 3 rrole carboxylic acid hydrochloride and a selected amine of formula Λ HN - Amino - N - ethyl - 2 - methyl- 5 - phenyl - 3 - pyrrol ecarboxamide hydroloride. Yield 35%. M.p. 261-63°C (from ethanol/water).

- Amino - N - isopropyl - 2 - methyl- 5 - phenyl - 3 - pyrrolecarboxamide. ;ld 33%. M.p. 197-98°C (from methanol).

- Amino - 4' - chloro - 2 - methyl- 5 - phenyl - 3 - pyrrolecarboxaniTide -1442956 hydrochloride. Yield 40%. M.p. 231-33°C (from methanol/water). } 4 - Amino - 2,4'- dimethyl - 5- phenyl - 3 - pyrrolecarboxanilide hydrochloride. Yield 52%. M.p. 250°C (with decomposition). ) 4 - Amino - 2 - methyl - 5 - phenyl- 3 - pyrrolecarbox -«-anisidide. Yield 5 43%. M.p. 190-92°C (from ethanol). 7) 4 - Amino - 4' - ethoxycarbonyl - 2- methyl - 5 - phenyl -3-pyrrolecarboxanilide. Yield 61%. M.p. 217-19°C (from ethanol). 8) 4 - Amino 4' - carboxy - 2 - methyl- 5 - phenyl - 3 - pyrrolecarboxanilide. Yield 37%. M.p. 200-10°C (from methanol/water). 9) 3 - Amino - 5 - methyl - 2 - phenyl- 4 - piperi di nocarbonyl pyrrole hydrochloride. Yield 50%. M.p. 245-49°C (from methanol/water). ) 3 - Amino - 5 - methyl -4-(4- methyl - 1 - piperazinylcarbonyl)- 2 - phenylpyrrole. Yield 46%. M.p. 104-106°C (from ethanol). 11) 3 - Amino - 5 - methyl - 2 - phenyl- 4-(4- phenyl - 1 - pi perazinyl carbonyl) pyrrole hydrochloride. Yield 44%. M.p. 220-22°C (from ethanol/water). The free base melts at 154-56°C (from methanol). 12) 4 - Amino - 2' - chloro - 2 - methyl- 5 - phenyl - 3 - pyrrolecarboxanilide hydrochloride. Yield 47%. M.p. 268-72°C (from methanol/water). 13) 3 - Amino - 5 - methyl - 4 - morpholinocarbonyl - 2 - phenyl pyrrole hydro20 chloride. Yield 81%. M.p. 236-38°C (from methanol/water). 14) 4 - Amino - 4' - ethyl - 2 - methyl- 5 - phenyl - 3 - pyrrolecarboxanilide hydrochloride. Yield 62%. M.p. 250-52°C (from ethanol/ether). , 15) 4' - Acetyl - 4 - amino - 2 - methyl- 5-phenyl - 3 - pyrrolecarboxanilide.

Yield 80%. M.p. 234-237°C (from dimethylformamide). 16) 4 - Amino - 2 - methyl - 5- phenyl- 3' - trifluoromethyl - 3 - pyrrolecarboxanilide. Yield 46%. M.p. 150-51°C. (from ethanol/water). 17) 4 - Amino - 2,2' - dimethyl - 5- phenyl - 3- pyrrolecarboxanilide. Yield 33%. M.p. 218°C (from ethanol/water). 18) 4 - Amino - 2,3' - dimethyl - 5- phenyl - 3 - pyrrolecarboxanilide. Yield 31%. M.p. 171-73°C (from ethanol/water). -1556 Example 19. i - Amino - 1 - (p - chororbenzyl) - 5 - methyl - 2 - phenyl - 4 - piperidi nocarbonyl pyrrole hydrochloride.

From 4 - amino - 1 > (p - chlorobenzyl)-2 - methyl - 5 - phenyl - 3 - pyrrole:arboxylic acid hydrochloride and piperidine, according to the procedure of Example 1. Yield 44%. M.p. 195-97°C (from methanol/water). The corresponding ntermediate compound of formula III has not been isolated in this case.

Example 20.

I - Ethyl - 2 - methyl - 5 - phenyl - 4- (p -toluenesulfonanrido) - 3 - pyrrolecarboxamide.

A solution of 5.0 g. (0.018 mole) of the compound of Example 2, 3.4 g. (0.018 rale) of p- toluenesulfonyl chloride and 1.8 g. of triethyl amine in 250 ml. f pyridine is stirred at room temperature for about 15 minutes and is Subsequently llowed to stand overnight at about 5°C. The reaction mixture is then poured nto 250 ml. of aqueous hydrochloric acid and crushed ice and the resulting olution is extracted with ethyl acetate. The precipitate which forms upon hilling is recrystallized from ethanol/water. Yield 2.0 g. of the title ompound. M.p. 219-21°C.

Example 21.

- Acetylamino - 5 - methyl - 2 - phenyl- 4 - piperidinocarbonyl pyrrole hydrochloride. .0 Grams (0.016 mole) of the compound of Example 9 are dissolved in 250 ml. f pyridine and the resulting mixture is added with 25 ml of acetic anhydride, fter standing for about 90 minutes at room temperature, the whole is poured nto 250 ml. of 105! aqueous hydrochloric acid. The obtained solid is recovered y filtration and recrystallization from ethanol. Yield 2.5 g. of the title ompound. M.p. 289-90°C.

Example 22-25 The following compounds have been prepared pursuant to the same procedure of he foregoing Example. 2) 4 - Acetylamino - 4' - ethyl - 2- methyl - 5 - phenyl - 3 - pyrrolecarboxan -164395C Hide, from the compound of Example 14 and acetic anhydride. Yield 67*/.

M.p, 230° (decomposition); (from methanol/water).. 23) 4 - Acetylamino - N - isopropyl - 2- methyl - 5 - phenyl - 3 - pyrrol ecarboxamide, from the compound of Example 3 and acetic anhydride. Yield 71*/. M.p. 275°C (from methanol/water). 24) 4 - Acetylamino - 2‘ - chloro - 2- methyl - 5 - phenyl - 3 - pyrrolecarboxanilide, from the compound of Example 12 and acetic anhydride. Yield 56%..

M.p. 255-257°C (from ethanol). ) 2 - Methyl - 5 - phenyl - 4 - propionyl amino - 3 - pyrrol ecarbox toluidide, from the compound of Example 17 and propionic anhydride. Yield 60%.

Mp. 254°C (from acetone/water).

Example 26.

- Dimethyl amino - 5 - methyl - 2 - phenyl - 4-piperi di nocarbonyl pyrrole.

A solution of 5.0 g. (0.016 mole) of compound of Example 9 in 70 ml. of methanol and 20 ml. of water is added with 5 ml. of dimethyl sulfate 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. - (p - Chlorobenzyl )-3- dimethyl ami no- 5 - methyl - 2 - phenyl - 4 - piperidinocarbonylpyrrole, from the compound of Example 19 and dimethyl sulfate, acccording to the procedure of the foregoing Example. Yield 42%. M.p. 199-201°C (from ethanol/diethyl ether).

Typical compounds of formula I which can be prepared according to the procedure described in the foregoing Examples are -184 2 9 5 3 19' CO χ ο r-» © m in in X X X CM CM CM ο ο o co x o co x o σι X «do ι £ χ/ r tn x CM O x co o o o Lj Li X X CM «sf· CO ς± in «ύ* «3UO 3· · 429 26 •21 9S6 in ΣΕ CM Ο co\ ΣΕ Ο CO ΣΕ Ο CO X Ο Η) ΣΕ CM Ο © ΣΕ CM Ο © ΣΕ CM Ο X © X CM Ο X © X CM Ο X ΠΣ CO ΣΕ Ο X X X X X Ο <_> CO X ο © X CM Ο X X CH0 \ CH ~ co co X X CJ Ο «3· Ο ι· <4* V κ ΣΕ Ο ΣΕ -22· 23 56 23· The compound of Example 1 can also be prepared according to the alternative rocedure described tin the following Example. ι Example 68.

- Amino - - diethyl - 2 - methyl - 5- phenyl - 3 - pyrrol ecarboxamide hydrochloride.

A solution of 42.0 g. (0.318 mole) of 2 - amino - 2 - phenylacetonitrile, ).0 g. (0.318 mole) of 2 - acetyl - ν,ν - diethylacetamide and 2.1 g. of p jluenesulfonic acid in 700 ml. of benzene is refluxed for seven hours under itrogen atmosphere and then is allowed to stand overnight at room temperature, rter distilling off the benzene at atmospheric pressure, the obtained residue ; taken up with diethyl ether, the resulting solution is filtered from any isoluble and is subsequently, brought to dryness. 95.0 Grams of a residue are jtained, corresponding to the intermediate compound of formula XII in which R-j ; phenyl, R^ and Rg are ethyl, Rg is methyl. It is used as such for the subselent cyclization step. ι 14.0 Grams of sodium are dissolved in 360 ml. of ethanol and the resulting ilution is added with a solution of 95.0 g. of the crude compound prepared under ι in 360 ml. of ethanol. After stirring for 5 hours and standing overnight at )om temperature, the reaction mixture is concentrated to small volume by 'aporating the ethanol and is subsequently added with 300 ml. of a mixture of lueous 10% hydrochloric acid and diethyl ether. The obtained precipitate is •covered by filtration and recrystallized from ethanol/diethyl ether. Yield ’.0 g. of the title compound. M.p. 212-14°C.

The compounds of Examples 2-18, 28-46, and 62 can be prepared substantially •llowing the method described in the foregoing Example. eparation of the Starting Amino Acids of Formula II.

A) 4.- Amino - 2 - methyl - 5 - phenyl- 3-pyrrole carboxylic acid. a) A solution of 6 g. (0.042 mole) of 2 - amino - 2 - phenylacetonitrile and g. (0.042 mole) of ethyl acetoacetate in 30 ml. of anhydrous benzene is refluxed ir four hours on an oil bath in the presence of 100 mg. of p-toluenesulfonic acid ter cooling, the reaction mixture is filtered, then the solvent is evaporated -2442956 off to give an oily residue, which is distilled under reduced pressure.

B.p. 140°C/0.05. b) 0.80 Grams of sodium are dissolved 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 four hours.

After bubbling dry hydrogen chloride in the ethanol solution, a precipitate readily forms, which is filtered and recrystallized from a mixture of ethanol and diethyl ether. Yield 4 g. of ethyl 4 - amino - 2 - methyl - 5- phenyl -3pyrrolecarboxylate hydrochloride. M.p. 249-252°C (from ethanol/ethyl ether).

A solution of 4 g. (0.0143 mole) of the compound prepared under b) in 60 ml. of dimethyl sulfoxide is added with a solution of 6 g. of lithium hydroxide monohydrate in 90 ml. of water and the resulting mixture is heated at 80-85°C 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 off fa vaouo· 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. 153-54°C. The hydrochloride melts at 200-200.5°C dec. (from water).

B) 3 - Amino - 1 - p - chlorobenzyl - 2- methyl - 5 - phenyl - 3 - pyrrolecarboxylic acid hydrochloride. Ethyl 4 - amino - 2- methyl - 5 - phenyl - 3 pyrrolecarboxyl ate hydrochloride, prepared as under b) above is reacted with Pchlorobenzaldehyde according to the known procedures for preparing Schiff's bases from amine and carbonyl compounds. The so formed ethyl - 4 - (p - chlorobenzylideneamino) - 2 - methyl - 5 - phenyl- 3 - pyrrolecarboxylate (M.p. 180-82°C, from ethanol/water) is reacted in a strong alkaline medium with p-chlorobenzyl chloride, according to the usual procedures for introducing a substituent into the nitrogen atom of a pyrrole nucleus.

The obtained ethyl 1 - (p - chlorobenzyl)- 4 - ( p- chlorobenzylideneamino) - 2- methyl - 5 - phenyl - 3 - pyrrolecarboxylate is not isolated and is hydrolized under acidic conditions to give the title compound. M.p. 170-171°C (from methanol diethyl ether).

Claims (14)

1. Compounds of formula / ,C0 ‘5 R. «-'ll, ‘6 wherein: R is hydrogen, (C^_^)alkyl, benzyl or halobenzyl; R-j represents hydrogen, (C-|_ 4 )alkyl, phenyl nr phenyl substituted with 1 to 3 substituents independently selected from (C-|_ 4 )alkyl, (C·^)alkoxy, benzyloxy, fluorine, chlorine, bromine and hydroxy; R 2 is hydrogen, (C-j_^)alkyl, formyl, (Cg^) aliphatic acyl, benzoyl, carbamoyl, phenyl carbamoyl, (C^_^)alkyl sulfonyl, benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl; Rg is hydrogen or (C^^Jalkyl; or and Rg taken together represent Cg_ 4 alkylidene, benzylidene or halobenzylidene, R^ and Rg independently represent hydrogen; (Cg_^)alkyl or substituted phenyl (as hereinbefore defined), though not simultaneously hydrogen, or taken together with‘the nitrogen atom to which they are Attached, they may represent dimethylamino or a 5-6 membered saturated heterocyclic ring, optionally containing a further oxygen or nitrogen atom and optionally substituted by one to three (C-[_ 4 )alkyl radicals or by a phenyl group; and Rg represents a (C-j_^)al kyl group; and salts therewith of pharmaceutically acceptable acids.

2. A compound as in claim 1 wherein: R represents hydrogen, behzyl or halobenzyl; R-j is phenyl; Rg is hydrogen or (C^_ 4 )alkyl, (Cg^) aliphatic acyl, or toluenesulfonyl; -2642955 R o is hydrogen or (C-, .) alkylR 4 and R 5 independently represent hydrogen, {Cg_ 4 )a1kyl, phenyl substituted b X ( c i-4) al kyl, (Cg_ 4 )aliphatic acyl, (C 1 _ 4 )-alkoxy, halogen, carboxy, alkoxy - carbonyl and tirfluoromethyl, though not simultaneosuly hydrogen, or taken together with the nitrogen atom to which they are attached, they can also represent dimethyl ami no, pi peridi no, morpholino, 4 - oiperazino or 4-phenylpiperazino; and Rg is (C-j_ 4 )alkyl group. and salts therewith of pharmaceutically acceptable acids.

3. A compound as in claim 2, wherein: R is hydrogen; R-| is phenyl; Rg is hydrogen, (C-j_ 4 )alkyl, (Cg_ 4 )aliphatic acyl or toluenesulfonyl; Rg is hydrogen or (C^_ 4 )alkyl; R 4 and Rg independently represent hydrogen, (Cg_ 4 )alkyl, phenyl substituted by (C 1 _ 4 )alkyl, (Cg_ 4 )aliphatic acyl, (C^ 4 )-alkoxy, halogen, carboxy, j2i C 1- 4 ) alkoxy|- carbonyl and tri fluoromethyl, though not simultaneously hydrogen or, taken together with the nitrogen atom to which they are attached, they can also represent dimethyl ami no, pi peri di no, morpholino, 4 - Qc^_ 4 )- alkyljpiperazino and 4-phenylpiperazino; and R 6 is · and salts therewith of pharmaceutically acceptable acids. 4. A compound as in claim 2 wherein: R, Rg and Rg stand for hydrogen; R-] is phenyl; R 4 and Rg independently represent hydrogen, (Cg_ 4 )alkyl, phenyl substituted by (C 1 _ 4 )-alkyl, (Cg_ 4 )aliphatic acyl, (C-j_ 4 )alkoxy, halogen, carboxy, Q(C 1 _ 4 ) alkoxyjcarbonyl and trifluoromethyl, though not simultaneosuly hydrogen or, taken together with the nitrogen atom to which they are attached, they can also represent di methyl ami no, piperidino, morpholino, 4 - £jC-|_ 4 )alkyljp1perazino and 4-phenylpiperazino; and -27Rg is (C-,_ 4 )alkyl. and salts therewith of pharmaceutically acceptable acids.

4. A compound as in claim 2 wherein: R, Rg and Rg stand for hydrogen; R 1 is phenyl; R^ and Rg independently represent hydrogen, (C 2 _ 4 )alkyl, phenyl substituted by (C 14 )- alkyl, (Cg_ 4 )aliphatic acyl, (C-]_ 4 )alkoxy, halogen, carboxy, (C 14 ) alkoxy carbonyl and trifluoromethyl, though not simultaneously hydrogen or, taken together with the nitrogen atom to which they are attached, they can also represent di methyl amino, pi peri di no, morpholino, 4- (C-j_ 4 )alkyl piperazine and 4-phenylpiperazino; and Rg is methyl; and salts therewith of pharmaceutically acceptable acids.

5. 4-Amino-N -isopropyl - 2 - methyl- 5-phenyl-3-pyrrolecarboxamide.

6. 4 - Amino - 4' - chloro - 2 - methyl-5-phenyl-3-pyrrolecarboxanilide hydrochloride.

7. 4 - Amino - 2,3' - dimethyl - 5 -phenyl-3-pyrrolecarboxanilide.

8. 3 - Amino - 5 - methyl - 2 - phenyl -4-(4- phenyl - 1 - piperazinylcarbonyl) pyrrole hydrochloride.

9. Compounds according to claim 1 in which R is hydrogen.

10. A process for preparing compounds of formula R and salts therewith of pharmaceutically acceptable acids, wherein the substituents R to Rg are defined as in claim 1, which comprises reacting a compound of formula · -2842856 II COOH wherein R, R^ and Rg are defined as claim 1, or an acid addition salt thereof, with phosgene for one to three hours in an inert organic solvent, at a temperature between 40 and 70°C, subsequently adding from three to ten molar equivalences 5 of an amine of formula HN wherein R^ and Rg are defined as in claim 1, keeping the reaction mixture between room temperature and the boiling temperature of the reaction mixture for one to three hours, said process being further characterized in that: a) when the radicals Rg or Rg or both, as defined above, are desired to be different from hydrogen, they are introduced by reaction with (C^_ 4 )alkyl halides, di(C.]_ 4 )alkyl sulfates, (Cg_ 4 )aliphatic acyl halides or anhydrides, benzoyl halides or anhydrides, benzenesulfonyl halides, (C^_ 4 )alkylsulfonyl halides, toluenesulfonyl halides, phenacyl sulfonyl halides, formic acid, alkali metal cyanates, phenyl isocyanate, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, acetone, ethyl methyl ketone, benzaldehyde, or benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally removing the (C^_ 4 )alkyl sulfonyl, benzenesulfonyl, toluenesulfonyl or phenacyl sulfonyl groups by hydrolysis; b) when a compound of formula I is desired in the form of a salt with a pharmaceutically acceptable acid, the corresponding free base is treated with a pharmaceuitcally acceptable acid, and, if desired, a free base may be obtained from the corresponding acid addition salt by treatment with a base. -29429 ί> 6 Π. A process for preparing compounds of formula: K 3\ / N \ ^CON \, r; n J Λ. and salts therewith of pharmaceutically acceptable acids, wherein the substituents R-j to Rg are as defined in claim 1, which comprises reacting an α-anri nonitrile of formula CN NH 2 with a molar equivalient of a compound of formula CHACON CO \, wherein Rp R^, Rg and Rg are as defined in claim 1, in the presence of an anhydrous organic solvent, in the further presence of a catalytic amount of ptoluenesulfonic aicd, for two to twenty eight hours, at a temperature between room temperature and the reflux mixture temperature, subsequently adding a base selected from alkali metal carbonates, hydroxides, alkoxides, hydrides 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 R 2 and Rg or both, as defined above, are desired to be different from hydrogen, they are introduced by reaction with (C-j_ 4 )alkyl -3042956 halides, di(C^_ 4 )a1kyl sulfates, (C 2 _^)aliphatic acyl halides or anhydrides, benzoyl halides or anhydrides, benzenesulfonyl halides, alkyl sulfonyl halides, toluenesuifonyl halides, phenacylsulfonyl halides, formic acid, alkali metal cyanates, phenyl isocyanate acetaldehyde,propionaldehyde, butyraldehyde, 5 isobutyraldehyde, acetone, ethyl methyl ketone, benzaldehyde or benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally by removing the ( c -j_ 4 )alkylsulfonyl, benzenesulfonyl, toluenesuifonyl or phenacylsulfonyl groups by hydrolysis; b) when a compound of formula I is desired in the form of a salt with a 10 pharmaceuitcally acceptable acid, the corresponding free base is treated with a pharmaceutically acceptable acid, and, if desired, a free base may be obtained from the corresponding acid addition salt by treatment with a base.

11. 12. A process, substantially as hereinbefore described, for the preparation of a compound according to claim 1. 15

12. 13. A compound according to claim 1 when prepared by a prBcess according to any of claims 10 to 12.

13.

14. A pharmaceutical composition comprising a compound according to any of claims 1 to 9 and 13 together with a pharmaceutically acceptable carrier.