IL45368A - Aminopyrrole derivatives - Google Patents

Abstract

1427945 Derivatives of 3-aminopyrrole GRUPPO LEPETIT SpA 25 July 1974 [22 Aug 1973] 39790/73 Heading C2C The invention comprises compounds of formula and their salts with pharmaceutically acceptable acids, wherein R is hydrogen, (C 1-4 )alkyl, benzyl or halo-substituted benzyl; R 1 is hydrogen, (C 1-4 )alkyl, phenyl or phenyl carrying one to three substituents chosen from (C 1-4 )alkyl, (C 1-4 )alkoxy, benzyloxy, fluoro, chloro, bromo, hydroxy and nitro; R 2 is hydrogen, (C 1-4 )alkyl, formyl, (C 2-4 )aliphatic acyl, benzoyl, carbo- (C 1-4 )alkoxy -(C 2-4 )aliphatic acyl, carbamyl, phenylcarbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulphonyl, (C 1-4 )alkylsulphonyl, toluenesulphonyl or phenacylsulphonyl; R 3 is hydrogen or (C 1-4 )alkyl or R 2 and R 3 together are (C 2-4 )alkylidene, benzylidene or halo-substituted benzylidene; R 4 is (C 2-4 )- aliphatic acyl, benzoyl, benzoyl carrying one to three substituents chosen from fluoro, chloro, bromo and (C 1-4 )alkoxy, carbo(C 1-4 )alkoxy, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl and R 5 is hydrogen, (C 1-4 )alkyl, carbo(C 1-4 )alkoxy, carbo (C 1-4 )alkoxy-methyl, trifluoromethyl, carboxy, carbamyl or carbazoyl or R 4 and R 5 together are -CO-(CH 2 ) n -, wherein the carbonyl group is connected to the carbon atom of the pyrrole ring which bears the substituent R 4 and n is 2, 3 or 4, provided that when R 1 =R 5 =Me and R=H, then one of R 2 , R 3 #H and R 4 #CO 2 Et. These compounds are prepared (when R=R 2 =R 3 =H) by reacting RNH-CHR 1 -CN with either R 2 COCH 2 R 4 or R 5 C # CR 4 and cyclizing the thus formed inter-- mediate of formula the products may then be reacted further if desired to convert the 3-NH 2 groups or other functional groups present to different substituent groups and/or replace the 1-H atom by R(#H). Therapeutic compositions having anti-inflammatory antipyretic and analgesic activity, C.N.S. depressant activity, and in some cases sedative and myorelaxing activity, comprise compounds of the above formula, and may be administered orally, parenterally or rectally. [GB1427945A]

Description

NEW AMINOPYRROLE DKKIVATIV S Abstract of the Disclosure New pharmacologically active aminopyrrole derivatives of the general formula hereinI R is selected from hydrogen, (C ^^alk l, benzyl and halo-substituted benzyl? Rj represents hydrogen, (C^^) lk l, phenyl or substituted phenyl as defined hereinafter} g is a member of the olass consisting of hydrogen, (Cj_^)alk l# formyl, (C^^Jalkano l, benzoyl, ^carboiC^^) alkox J7- (^2-4^ alkanoyl, earbamyl, phenylcarbamyl, thioear-bamyl, phenylthiocarbamyl, be^oylthiocarbamyl, carboxyphenyl, benzene-sulfonyl, (Cj ^)alkylsulfonyl, toluenesulfonyl, phenacylsulfonyl; R^ is selected from hydrogen and {j ^)alkyl benzoyl, substituted benzoyl as defined hereinafter, carbo(C^4)alkoxy, carboxy, earbamyl, methylcarbamyl or phenylcarbamyl} is selected from the group consisting of hydrogen, trifluoromethyl, carboxy, earbamyl and carbazolyl} and taken together represent (C2_4)alkylidene, benzylidene or halo-substituted benzylidene; R. and R taken together may also represent a group -C0-(CH_) wherein n is an integer selected from 2, 3, and 4; with the proviso that when R^ and R<_ simultaneously represent methyl and R is hydrogen, one of R^ and must be different from hydrogen and R^ cannot be carbethoxy; and salts therewith of pharmaceutically acceptable acids.

Summary of the Invention The present invention is concerned with new an inopyrrole derivatives of the following general formula R.

R and salts therewith of pharmaceutically acceptable acids, wherein R is selected from hydrogen, (C^ 4)alkyl, benzyl and halo-sub¬ stituted benzyl; represents hydrogen, (C^ ^)alkyl, phenyl or substituted phe¬ nyl, as hereinafter defined.

R2 is a member of the class consisting of hydrogen, (C.^) alkyl , formyl, (C2_4) benzoyl, /carbo(C1_4)alkoxy/-(C2_ alkanoyl ^-i^H^i-r--a-r-y-T-^ carba yl, phenylcarbamyl , thiocarba yl , phenyl- thiocarbamyl , benzoylthiocarba yl , carboxypheny1 , benzenesulfon carbamyl or carboxy, and taken together represent benzylide or chloro-substituted benzylidene, R^ and R<. taken together are t group -CO- (Cl^) .j- wherein the carbonyl group is connected with th carbon atom of the pyrrole ring bearing the radical ^ , and salts therewith of pharmaceutically acceptable acids.

The method for preparing the compounds of the invention comprises reacting an a -a inonitrile of the general formula CN I CH II R. NH R or an acid addition salt thereof, wherein R is hydrogen and R^ ha the meaning given above, with a compound of the general formula: where R. and R have the above significance and X represents a group -C≤C- or a group -CH.-ζ- wherein the -CH_- portion L d L is linked to the substituent R. . It is obvious to any person who is skilled in the art that substances which have chemical properties similar to those displayed by β-dicarbonyl compounds or by acetylenecarbonyl compounds may advantageously be employed such as, for instance, substances of formula III in whic I X is -CH=C— hal, wherein hal represents a halogen atom, prefera¬ bly chlorine and the carbon atom bearing the halogen atom is linked to the radical R,..

The starting aminonitriles are prepared following substantiall the method described by Steiger in Organic Synthesis, 22, 13, 1942 and 22, 23, 1942.

The compounds of formula III either are commercially available products or are obtained through obvious modifications of commercially available products.

The reaction generally proceeds with the formation of an intermediate open chain compound representable by the following general formula IV or its tautomeric i inic form which, if desired, ma , 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 substantially 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 is refluxed for a time varying from 2 to 28 hours. The intermediate compound of formula IV which forms may be isolated and characterized, if desired, or employed as such for the subsequent cyclization step, which is carried out in the presence of basic catalysts, selected from carbonates, hydroxides, alkoxides, hydrides and amide of the metals of the I and II group of the periodic table of the elements. Also in this case the reaction is carried out in the presence iOf a solvent which is preferably selected from anhydrous 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 the reaction mixture, in order to speed up the cyclization reaction which is completed within an interval 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 formula I may take place in one reaction step only. In this case, the aminonitrile of the formula II 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 presence of an organic solvent as, for instance, an anhydrous (C^_^ ) alkanol , chloroform, tetrahydrofuran , benzene and analogs and an alkali or alkaline earth metal carbonate or hydroxide as the cataly 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, following techniques 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 solvent, evaporating again the solvent and purifying the obtained solid, liquid or oily substance by recrystallization, fractional di¬ stillation, or distillation under reduced pressure. If a crystalli solid directly results from the reaction, this is recovered simply by filtration, and, if necessary, purified by recrystallization.

Recrystallization solvents are preferably selected from C^-C^ 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¬ sphate, benzoate, oxalate, acetate, methanesulfonate,cyclohexyl- sulfonate and analogs and accordingly are included within the sco¬ pe of the invention. They are easily obtained by treating a compound of formula I as the free base with a predetermined pharmaceutically acceptable acid. In turn, it is possible to restore the free base from the corresponding acid salt by reaction jwith at least one equimolecular amount of a basic agent.

Pursuant to the outlined procedures, compounds of formula I are obtained, wherein R, R^ and ^ are hydrogen atoms, or their u acid addition salts. When sybstituents R2 and 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 (-C ^)alkanol affords a alkanoyl compound wherein R? is /carbo _ . ) alkoxy - (C .) atipha*5¾=¾¾yl=,== whereas the reaction with an alkylating agent, as for instance, mixtures of formic acid and formaldehyde, (C^_^)alkyl halides or (C1_^)alkyl sulfates gives compounds wherein orR3 or both alkanoyl represent (C^_^) alkyl . Compounds where R2 is a (C2 ) aliphatie aeyi radical or benzoyl are obtained by reacting a compound of alkanoic formula I with halides or anhydrides of (C2_^) akLpkatte or benzoic acids, whereas the benzenesulfonyl , toluenesulfonyl, (C^ ^)alkylsu fonyl and phenacylsulfonyl derivatives are conveniently prepared b reaction with benzenesulfonyl, toluenesulfonyl, (C^ alkylsulfony or phenacylsulfonyl halides respectively.

The carba yl and the thiocarbamyl groups as well as their methyl-, phenyl- and benzoyl- analogs are introduced by reacting the aminopyrrole of formula I wherein and 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 achieved by contacting a predetermined 3-aminopyrrole with formic acid in substantially equimolecu-lar ratios whereas the compounds wherein is carboxy-phenyl are obtained by reacting a compound of formula I wherein ^s hydrogen with a predetermined benzoic acid substituted in the aromatic ring with a halogen atom. Finally, substances where anc* ^3 taken together represent (C^ alkylidene , benzylidene or halo-substituted benzylidene are easily prepared according to the known reactions for obtaining Schiff's bases from amines and carbo compounds .

The substitution on the ring nitrogen atom generally does not take place under the reaction conditions employed for introducing the radicals and on the nitrogen atom at the position 3. A convenient method for introducing the desired substituents according to formula I on the nuclear nitrogen atom of the pyrrole ring involves reaction of a predetermined compound of formula I wherein R is hydrogen with a selected (C^_^) alky1, 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 the reaction mixture. It is understandable that under these reaction condition when either or 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 contemporaneously be substituted for instance by one or two (C^_^)-alkyl groups. However, if compounds of formula I wherein R^ and/or R^ 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 si- tic nds pos of the rogen, or ocedure oved by escribe age 345 chemi¬ ompound a xy th reonia bo- Compound LD50 mg/Kg Dose mg/Kg % Decrease of the of Exam le p.o. mice p.o. rats induced edema 71 >1000 20 23.9 50 35.2 100 47.9 200 69.0 74 a) >1000 100 31.0 200 53.1 74 b) >1000 50 11.0 100 34.3 200 52.7 79 >1000 100 38.0 200 47.6 phenylbutazone 390 50 33 100 45 The compounds of the invention are also endowed with other biological properties which are very desirable in potential antinflammatory substances. They, in fact, possess outstanding antipyretic and analgesic activities, which are respectively 2, 10 and about 4 times those displayed by acetylsalicy lie acid.

Moreover, the compounds of the invention display a very low ulcerogenic activity which is about 5-10 times lesser than the one observed with other known and therapeutically used antinflam- matory substances e.g. acetylsalicylic acid and phenylbutazone.

Analgesic activity was evaluated according to L.O.Randall and J.J. Selitto, Arch.Int .Pharmacodyn. , No. 4, CXI, page 409, 1957.

Antipyretic activity was investigated according to R.H. Ruller et al., J. Pharm.Pharmacol . , 9, 128, 1957, whereas the ulcerogenic action was determined according to Thuilliet et al., Chim.

Therap. , 3, 53 , 1968.

As stated above, the aminopyrrole derivatives described in the present invention are also active on the 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, the compounds of Examples 1 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 useful in patients affected by severe inflammatory diseases.

Some other compounds of the invention display also very interestin 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 . , Π.» 129, 1959. Representative experiments showed that the compounds of Examples 4, 30 and 46 were particularly effective in inhibiting the secondary conditioned response in rats (CR2) at a dosage level which does not affect the primary conditioned response (CR) and the unconditioned response (UR) . It is known that the secondary conditioned response is related to an anxious state of the animal and its inhibition s. the d ce - f the the ff ure.

The obtained intermediate open chain compound boils at 150°C/ 0.1 mmHg. b) 0.40 Grams of sodium are dissolved in 15 ml. of anhydrou ethanol, then a solution of 2.5 g. of the compound prepared as in point a) in 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 forms, which is recovered by filtration and recrystallized from ethanol/diethyl ether.

Yield 2.0 g. of the title compound. M.p. 242°C (with decomposition) The free base is obtained by extraction with ethyl acetate of an aqueous solution of the hydrochloride alkalinized with 5¾ sodium hydroxide. M.p. 220°C (from methanol).

Example 2 3-Amino-4-carbethoxy-5-methyl-2-phenyl-pyrrole hydrochloride 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 hourson an oil bath in the presence of 100 mg. of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered, then the solvent is evaporated o to give an oily residue, which is distilled under reduced pressure. The open chain intermediate compound which is obtained has b.p. 140°C/0.05 mmHg. 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 recrystalli zed from a mixture of ethanol and diethyl ether. Yield 4 g.

M.p.249-252°C (from ethanol/ethyl ether).

Examples 3 - 42 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-benzoyl-5-methyl-2 -phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and benzoylacetone the open chain intermediate compound is obtained melting at 134-35eC (from diethyl ether/hexane) . The title compound is obtained with 60% overall yield. M.p. 285-90°C (from methanol/ diethyl ether). The free base melts at 203-5°C (from methanol). 4 - 3-Amino-6 ,7-dihydro-2-phenyl-indole-4 (5H) -one hydrochloride Starting from 2-amino-2-phen 1-acetoni trile and cyclohexane 1,3 dione the open chain intermediate compound is obtained melting at 138-40°C (from benzene). The title compound is obtained with 58 overall yield. M.p. 290-l°C. (from ethanol/diethy1 ether). 5 - 3-Amino-4-benzoyl-2-phenyl-pyrrole hydrochloride The open chain intermediate :ompound melting at 88-90°C (from hexane) is prepared from 2-aminc-2-phenyl-acetonitrile and benzoyl acetaldehyde . The title compound is obtained with 47% overall yield. M.p. 272-74°C (from ethancl) . 6 - 4-Acetyl-3-amino-2-ethyl-5 -melhyl-pyrrole hydrochloride Starting from 2-amino-butyronit-ile and acetylacetone , the open chain intermediate compound is obtdned, boiling at 100°C/0.02 mrnllg. The title product is obtainedwith 49% overall yield.

M.p. 245-48°C (from ethanol/diethy1 ther) , The free base melts at 219-21°C (from methanol). 7 - 3-Amino-4-carbethoxy-2-phenyl-pyrrole hydiochloride The title compound is obtained with 451 ovenll yield from 2-amino-2-phenylacetonitrile and ethyl propynoat.. M.p. 244-45°C (from ethanol/diethyl ether) . 8 - 5-Amino-4-benzoyl-5-carbethoxy-2-phenyl-pyrrole hydrochloride The title compound is obtained with 48% overall yield from 2-amino-2-phenyl-acetonitrile and benzoyl piruvic acid ethyl ester. M.p. 218-9°C (from ethanol/diethyl ether) . 9 - 4-Acetyl-3-amino-2-pheny1-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 mmHg. The title compound is obtained with an overall yield of 56%. It does not melt up to 335°C. 10 - 4-Acetyl-3-amino-2- (p-methoxyphenyl) -pyrrole Starting from 2-amino-2- (p-methoxyphenyl) -acetonitrile and acetylacetaldehyde, the open chain intermediate product is prepared, boiling at 180°C/O.O3 mmHg. Overall yield of the title compound: 44 %. M.p. 198-200°C (from diethyl ether). 11 - 3-Amino-4-benzoyl-5-methy1-pyrrole hydrochloride Starting from aminoacetonitrile and benzoylacetone the open chain intermediate compound is obtained , melting at 111-12°C (from diethyl ether). Overall yield of the title compound: 52%. M.p. 225-270°C (from ethanol/diethy1 ether). 12 - 4-Acetyl-3-amino- 5-meth l-pyrrole hydrochloride Starting from aminoacetonitrile and acetylacetone the open chain intermediate compound is obtained, melting at 106-8°C (from diethyl ether) . The title substance is obtained with 641 overall yield. M.p. 211-12°C (from ethanol). 13 - 3-Amino-4-carbethoxy-5 -carbethoxymethy1-2-phenyl-pyrrole hydrochloride The title compound is obtained with 42% overall yield from 2-amino-2-phenyl-acetonitrile and 1 , 3-dicarbethoxyacetone.

M.p. 232-36°C (from diethyl ether/ethanol) . 14 - 4-Acetyl-3-amino-5-methy1-2- (p-tolyl) -pyrrole The title compound is obtained with 941 overall yield from 2-amino-2- (p-tolyl) -acetonitrile and acetylacetone . M.p. 232-4°C (from ethanol/diethyl ether). 15 - 4-Acetyl-3-amino-2- (p-methoxyphenyl) -5-methyl-pyrrole The title compound is prepared with 92% overall yield from 2-amino-2- (p-methoxyphenyl) -acetonitrile and acetylacetone.

M.p. 222-23°C (from ethanol). 16 - 3-Amino-4-carbethoxy-5-methyl-2- (p-tolyl) -pyrrole hydrochlori Starting from 2-amino-2- (p-tolyl) -acetonitrile and ethyl aceto- acetate the open chain intermediate compound, boiling at 160°C/ 0.05 mmHg is obtained. Overall yield of the title product: 881. M.p. 266-68°C (from methanol) . 17 - 3-Amino-4-carbethoxy-2-phenyl-5-trifluoromethy1-pyrrole hydrochloride The title compound is obtained with S2% overall yield from 2-amino-2-phenylacetonitrile and trifluoroacety1 ethyl acetate. M.p. 203-5°C. (from ethanol) . 18 - 4-Acetyl-3-amino-2- (p- luorophenyl) -5-methy1-pyrrole Starting from 2-amino-2- (p-fluorophenyl) -acetonitrile and acetylacetone, the open chain intermediate compound is obtained. B.p. 150°C/0.3 mmHg. Overall yield of the title compound: 47%.

M.p. 211-12°C (from ethanol). 19 - 3-Amino-4-carbethoxy- 2- (p-fluorophenyl) -5-methy1-pyrrole hydrochloride The open chain intermediate compound is obtained from 2-amino- 2- (p-fluorophenyl) -acetonitrile and ethyl acetoacetate. B.p. 220°C/ 0.2 mmHg. The title product is obtained with 53% overall yield. M.p. 258-60°C (from ethanol/diethy1 ether). 20 - 3-Amino-4-carbethoxy-5-methy1-pyrrole hydrochloride The open chain intermediate compound is obtained from amino- acetonitrile and ethyl acetoacetate .M.p . 90-98°C (from methanol). The title compound is obtained with 44¾ overall yield.

M.p. 211-14°C (from methanol). 21 - 3-Amino-4-isobutyr l-5-methyl-2-pheny1-pyrrole The open chain intermediate compound is obtained from 2-amino-2-phenyl-acetonitrile and 5 -methyl-hexane-2 , 4-dione . B.p. 150°C/0.3 mmHg. Overall yield of the title compound: 64%. M.p. 180-83°C (from methanol/diethyl ether) . 22 - 3-Amino-5-methy1-2 -phenyl-4 -pro ionyl-pyrrole Starting from 2-amino-2-phenyl-acetonitrile and hexane-2,4-dione the open chain intermediate compound is obtained. B.p. 160°C/0.3 mmHg. The title product is obtained with an overall yield of 531. M.p. 166-68°C (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. 170°C/0.02 mmHg.

The title compound is obtained with 591 overall yield. M.p. 195-7°C (from ethanol) . 24 - 4-Acetyl-3-amino-2 -ethyl-5-methyl-pyrrole hydrochloride The title compound is obtained with 73¾ overall yield from 2-amino-butyronitrile and acetylacetone. M.p. 245-48°C (from methanol) . 25 - 3-Amino-4- (p-methoxybenzoy1) -5-methyl-2-phenyl-pyrrole The title compound is obtained with 431 overall yield from 2-amino-2-phenyl-acetonitrile and (p-methoxybenzoy1) -acetone .

M.p. 219-21°C. (from ethanol) . 26 - 4-Acetyl-3-amino-2- (p-benzyloxypheny1) -5-methyl-pyrrole The title compound is obtained with 51% overall yield from 2-amino-2- (p-benzyloxyphenyl) -acetonitrile and acetylacetone. M.p. 245-50°C (from ethanol). 27 - 4-Acetyl-3-amino-2- (p-chlorophenyl) -5-methyl-pyrrole The title compound is obtained with 671 overall yield starting from 2-amino-2- (p-chlorophenyl) -acetonitrile and acetylacetone. M.p. 205-8°C (from ethanol) . 28 - 3-Amino-4 -carbethoxy-2- (p-methoxyphenyl) -5-methyl-pyrrole hydrochloride The title compound is obtained with 441 overall yield from 2-amino-2- (p-methoxyphenyl) -acetoni trile and ethyl acetoacetate. M.p. 234-36°C (from methanol). 29 - 3-Amino-4-benzoy1-2- (p-fluorophenyl) -5-methyl-pyrrole Starting from 2-amino-2- (p-fluorophenyl) -acetonitrile and benzoyl acetone the open chain intermediate compound is obtained. B.p. 120°C/0.2 mmHg. The title compound is obtained with 66¾ overall yield. M.p. 209-10°C (from ethanol/diethy1 ether). 34 - 3-Amino-4-carbamy1-5-methyl-2-phenyl-pyrrole hydrochloric! Starting from 2-amino-2-phenyl-acetonitrile and a-acetylace-tamide the open chain intermediate compound is obtained. M.p. 128-30°C (from diethyl ether). The title product is obtained with 49% overall yield. M.p. 307-9°C (from methanol). 35 - 3-Amino-4-butyryl-2-phenyl-5-propyl-pyrrole hydrochloride The title compound is obtained with 60% overall yield, starting from 2-amino-2-phenyl-acetonitrile and nonane-4 ,6-dione .

M.p. 228-30°C with decomposition (from methanol/diethyl ether). 36 - 3-Amino-4-butyryl-5-methyl-2-phenyl-pyrrole hydrochloride The title compound is obtained with 48% yield from 2-amino- 2-phenyl-acetonitrile and heptane-2 , 4-dione . M.p.240-45°C with decomposition (from methanol/diethyl ether). 37 - 3-Amino-4 ,5-(dicarbomethoxy)-2- (p-chlorophenyl) -pyrrole hydroch ride Starting from 2-amino-2- (p-chlorophenyl) -acetonitrile and dicar bomethoxyacetylene the open chain intermediate compound is obtained . M.p. 74-76°C (from diethyl ether).

The title compound is obtained with 48% overall yield. M.p. 216-8° (from methanol/diethyl ether) . 38 - 3-Amino-4 ,5-(ticarbomethoxy)-2- (p-tolyl) -pyrrole hydrochloride Starting from 2-amino-2-(p-tolyl) -acetonitrile and dicarbo-methoxy-acetylene the open chain intermediate compound is obtained. M.p. 76-77°C (from diethyl ether/hexane) .

The title compound is obtained with 70$ overall yield. M.p. 193-96°C (from methanol/diethyl ether) . 39 - 3-Amino-4 , 5-dicarbethoxy)-2-phenyl-pyrrole hydrochloride Starting from 2-amino-2-phenyl-acetonitrile and dicarbethoxy acetylene, the open chain intermediate compound is obtained. B.p. 140/0.03 mmHg. The title compound is obtained with 78$ overall yield. M.p. 193-96 C (from ethanol/diethy1 ether). 40 - 3-Amino-4 ,5-(dicarbomethoxy)-2- (p-methoxyphenyl) -pyrrole hydrochloride Starting from 2-amino-2- (p-methoxyphenyl) -acetonitrile and dicarbomethoxyacetylene, the open chain intermediate compound is obtained. M.p. 86-88°C (from hexane) . The title compound is obtained with 63$ overall yield. M.p. 195-97°C (from methanol/ diethyl ether) . 41 - 3-Amino-4,5 -(dicarbomethoxy)-2-ethyl-pyrrole hydrochloride The title product is obtained with 66$ overall yield from 2-amino-butyronitrile and dicarbomethoxyacetylene. M.p. 209-10°C (from diethyl ether/methanol) . 9 45 - 4-Acetyl-3-benzoylamino-5 -meth 1-2-phenyl-pyrrole from the compound of Example 1 and benzoylchloride . Yield 79%. M.p. 301-303°C (from ethanol/water) .

Examples 46-50 Starting from acetic anhydride and a predetermined aminopyrrole derivative in the presence of pyridine and substantially operating as described by. E.E. Royals, Advanced Organic Chemistr pages 616-617, New York, Prentice Hall Inc., 1954, for acylating amines, the following compounds are prepared: 46 - 3-Acetylamino-4-carbethoxy-5-meth l-2-phenyl-pyrrole , by using the compound of Example 2 as the aminopyrrole reaction partner. Yield 89 % . M.p. 213-15°C (from ethanol) . 47 - 3-Acetylamino-4-benzoyl-5-methyl-pyrrole , by using the compo of Example 11 as the aminopyrrole reaction partner.

Yield 86%. M.p. 182-3°C (from ethylacetate/water) . 48 - 4-Acetyl-3-acetylamino-5-methyl-pyrrole , by using the compound of Example 12 as the aminopyrrole reaction partner. Yield 72%. M.p. 206-8°C (from methanol). 49 - 4-Acetyl-3-acetylamino-5-methyl-2-phenyl-pyrrole , by using the compound of Example 1 as the aminopyrrole reaction partner. Yield 80%. M.p. 215-17°C (from acetone/hexane) . 50 - 3-Acetylamino-4-carbethoxy-5 -meth l-pyrrole , by using the compound of Example 20 as the aminopyrrole reaction partner. Yield 90%. M.p. 165-60°C (from ethyl acetate).

Example 51 4-Acetyl-3-benzenesulfonamido-5-methyl-2-phenyl pyrrole 6 Grams (0.0332 mole) of the compound of the Example 1 are suspended in 100 ml. of aqueous 10% sodium hydroxide, then 20 (0.0154 mole) of benzenesulfonyl chloride are added at 5°C under stirring. The oily precipitate which forms is separated from the aqueous 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 recrys tallized from aqueous ethanol. Yield 6.7 g. M.p. 170-73°C.

Example 52 4-Acetyl-3-methanesul fonamido-5 -methyl-2 -phenyl 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 methane-sulfonyl chloride are added under stirring at 0°C. Stirring is continued for an hour, then the solution is allowed to stand overnight at 0°C. The reaction mixture is poured into aqueous 101 hydrochloric acid and the precipitate which forms is collected and recrystallized from aqueous ethanol. Yield 4.1 g. M.p. 172-75°C.

Examples 53-56 Pursuant to the method described in Example 52 the following compounds are prepared: 53 - 4-Carbethoxy-3-methanesulfonamido- 5-methy1-2 -phenyl-pyrrole from the compound of Example 2 and methanesulfony1 chloride.

Yield 831. M.p. 173-74°C (from aqueous ethanol). 54 - 4, 5-(Dicarbomethoxy)-3-methanesulfonamido-2-phenyl-pyrrole from the compound of Example 42 and methanesulfonyl chloride.

Yield 77 % . M.p. 158-60°C (from aqueous ethanol). 55 - 4-Acetyl-5-methy1-3-phenacylsulfonamido-2 -phenyl-pyrrole from the compound of Example 1 and phenacylsulfonyl chloride.

Yield 89¾. M.p. 201-3°C (from acetone/hexane) . 56 - 4-Benzoyl-5-methy 1-2-phenyl-3- (p-toluenesul fonamido) -pyrrole from the compound of Example 3 and p-toluenesulfonyl chloride. Yield 831. M.p. 230-33°C (from ethanol/water) .

Example 57 4-Acetyl-5-methy1-3- (N-methylphenacylsulfonamido) -2-phenyl-pyrrole A mixture of 5.0 g. (0.0126 mole) of the compound of Example 55, 5.0 g. of potassium carbonate and 15 ml. (0.159 mole) of 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. 195-97°C.

Examples 58-60 Pursuant to the alkylat ion procedure described in Example 57, the following compounds are prepared: 58 - 4-Acetyl-5-methyl-3- (N-methylbenzenesulfonamido) -2-phenyl-pyrro from the compound of Example 51 and dimethylsulfate . Yield 721. M.p. 247-49°C (from acetone/water). 59 - 4-Acetyl-3-(dimethyl)amino-5 -methyl-2-phenyl-pyrrole from the compound of Example 1 and dimethylsulfate. Yield 681.

M.p. 153-5°C (from chloroform) . 60 - 4-Benzoyl-3- (N-ethyl-p-toluenesulfonamido) -5-methy1-2-phenyl- pyrrole from the compound of Example 56 and diethylsulfate . Yield 67%. M.p. 224-25°C (from ethanol) .

Example 61 4-Benzoyl-3-isopropylamino-5-methyl- 2-phenyl-pyrrole The title compound is prepared by reacting equimolecular amounts of the compound of Example 3 and isopropyl bromide at room temperature. Yield 31%. M.p. 132-36°C (from hexane) .

Example 62 4 , 5-(Dicarbomethoxy-2-phenyl-3-ureido-pyrrole 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 cyanate in 20 ml. of water is added under stirringat room temperature.

The solution is allowed to stand for about one hour at 0°C. The 10 product which crystallizes is recovered by filtration and re- crystallized from methanol. Yield 5.1 g., m.p. 246-8eC.

Examples 63-67 The compounds of the following examples are prepared substantially according to the same procedure outlined in Example 62: 63 - 4-Acetyl-5-methy1-2-phenyl-3-ureido-pyrrole from the compound of Example 1 and sodium cyanate. Yield 84%.

M.p. 234-38°C (from acetone/hexane) . ίθ 64 - 4-Carbethoxy-5 -methy1-2 -phenyl-3-ureido-pyrrole from the compound of the Example 2 and sodium cyanate. Yield 66% M.p. 217-19°C (from ethanol) . 65 - 4-Carbethoxy-5-methyl-2-phenyl-3- (3-phenylureido) -pyrrole - ·> from the compound of Example 2 and phenyisocyanate . Yield 70%.

M.p. 224-26°C (from methanol/water) . 66 - 4-Acetyl-5-methyl-2-phenyl-3- (3-phenylureido) -pyrrole from the compound of Example 1 and phenylisocyanate . Yield 62¾ . M.p. 256-57°C (from acetone). 67 - 4-Acetyl-3- (3-benzoylthioureido) -5-methyl-2-phenyl-pyrrole from the compound of Example 1 and benzoylisothiocyanate. Yield 69%. M.p. 228-30°C (from ethanol/water) .

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 85¾ formic acid and the resulting solution is refluxed for 15-20 minutes. Then the reaction mixture is cooled and poured into ice-water. The precipitate which forms is recovered by filtration and recrys tallized from methanol. Yield 2.5 g. of the title compound. M.p. 210-11°C.

Example 69 4-Carbethoxy-3-formamido-5-methy1-2-pheny1-pyrrole This compound is prepared as described in the foregoing example, starting from the compound of Example 2. Yield 831 M.p. 180-82°C (from ethanol/water).

Example 70 4-Acetyl-3- (p-chlorobenzylideneamino) -5-meth l-2-phenyl-pyrrole A solution of 5.0 g. (0.0234 mole) of the compound of Example 1 in 200 ml. of ethanol is added to a solution of 5.0 g. (0.0358 mole) of p-chlorobenzaldehyde in 100 ml. of ethanol at 45-50°C, then the resulting mixture is refluxed for about four hours.

After cooling, the reaction mixture is poured into 1200 ml. of water saturated with sodium chloride. A precipitate forms, which is recovered by filtration and recrystallized from ethanol/water. Yield 9.5 g. of the title compound. M.p. 214-15°C.

Examples 71-73 The following compounds have been prepared according to the procedure described n Example 70. 71 - 4-Acetyl-3-(benzylideneamino)-5-methy1-2-phenyl-pyrrole from the compound of Example 1 and benzaldehyde . Yield 87%.

M.p. 173-76°C (from methanol). 72 - 4-Carbamy1-3-dsopropylideneamino)-5-methy1-2-phenyl-pyrrole from the compound of Example 34 and acetone. Yield 82 %.

M.p. 221-23°C (from ethanol/hexane) . 73 - 3-(Benzylideneamino)4 , 5-fcicarbomethoxy)-2-phenyl-pyrrole from the compound of Example 42 and benzaldehyde. Yield 78 % .

M.p. 218-20°C (from methanol) .

Example 74 4-Acetyl- 3-amino-l, 5-faimethyl)- 2-phenyl-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 0-5°C for 15 minutes, then 1 ml. of methyl iodide (0.0161 mole) is added.

Stirring is continued for 30 minutes at about 0°C and for 30 minutes at room temperature, then 150 ml. of water are added to the reaction mixture, which is subsequently extracted with diethy ether. The organic phase is separated and the solvent is evaporat off. The resulting residue (1.2 g.) is recrystalli zed from isopropanol/water . M.p. 136-38°C. It is the 4-acetyl-3-benzyliden mino-1, 5-dimeth l-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 80-90°C for about 2 hours. Upon cooling and neutralization with sodium hydroxide a precipitate forms, which is recrystallized from ethanol/water . Yield 0.8 g. of the title compound. M.p. 124-26°C.

The corresponding hydrochloride melts at 208-9° C (from ethanol/ diethyl ether) .

Example 75 [ -Acetyl-3-amino- 1-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-5-methyl-2-phenyl-pyrrole is obtained. M.p. 139-41°C (from isopropanol/ ater) .

This compound is hydrolized as under point b) of Example 74.

Overall yield of the title compound: 54%. M.p. 107-8°C (from ethanol) .

Example 76 4-Acetyl-3-amino-5 -methyl-2-phenyl-1-propyl- yrrole Starting from the compound of Example 71 and propyl iodide, and operating as under point a) of Example 74 the 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-l-propyl-pyrrole as an oily substance is obtained. This compound is hydrolized as under point b) of Example 74. Yield of the title compound: 50%. M.p. 113-15°C (from ethanol).

Example 77 4-Acetyl-3-amino-l- (p-chlorobenzyl) -5 -methy1-2-phenyl pyrrole The 4-acetyl-3-benzylideneamino-l- (p-chlorobenzyl) -5-methy1-2-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. 136-37°C (from ethanol/water) . This ethanol/acetone) .

Example 81 4-Acetyl-3- (o-carboxypheny1) amino-5 -methyl-2-phenyl-pyrrole A suspension of 2 g. (0.00934 mole) of the compound of E,:ampl 1, 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 recovered by filtration and recrystallized from aqueous methanol Yield of the title product: 1.5 g. M.p. 260-62°C.

Example 82 3-Amino-5-carbamyl-4-carbomethoxy-2-phenyl-pyrrole A solution of 5 g. (0.0161 mole) of the compound of Example 42 is saturated with gaseous ammonia, then it is allowed to stand for two days. A product crystallizes which is recovered by filtration. Yield 2.8 g. M.p. 177-79°C (from methanol/water) .

Example 83 3-Amino-4 , 5-dicarboxy)-2-phenyl-pyrrole A solution of 15 g. (0.0545 mole)of the compound of Example 42 in 200 ml. of methanol is added with 90 ml. of aqueous 10¾ lithium hydroxide and refluxed for 20 minutes under stirring.

Then the solution is poured into water and the mixture is acidifie with aqueous 101 hydrochloric acid. The title compound precipitate which is recovered by filtration and recrystallized from dime- thylformamide/ethyl ether. Yield 12.5 g. M.p. 191-94°C (The compou contains one molecule of water of crystallization) .

Example 84 3-Amino-5-carboxy-4-carbomethoxy-2-phenyl-pyrrole 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 evaporat off and the resulting solution is brought to pH 7 with aqueous 101 hydrochloric acid. A product separates which is filtered, dissolved in aqueous sodium bicarbonate and then neutralized by adding aqueous 10 % hydrochloric acid. Yield 5 g. M.p. 206-207°C.

Example 85 3-Amino-4-carboxy-5-carbomethoxy-2-phenyl-pyrrole 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. M.p. 218-19°C.

Examples 86-88 According to the hydrolysis procedure described in Example 85, the following compounds have been prepared: 86 - 4-Carboxy-3- (2-carbethoxyacetylamino) -5-methy1-2 -phenyl-pyrro The compound is obtained with 641 yield starting from the compound of Example 44. .p. 92-98°C (from ethanol) . 87 - 3-Acetylamino-4-carboxy-5-methyl-2-phenyl-pyrrole The compound is obtained with 49% yield starting from the compound of Example 46. M.p. 258-60°C (from ethanol/water) . 88 - 4-Carboxy-3-methanesulfonamido-5-methy1-2-phenyl-pyrrole The compound is obtained with a 54 % yield from the compound of Example 53. M.p. 269-71°C (from acetone/water).

Example 89 3-Amino-5-carbazoyl-4-carbomethoxy-2-phenyl pyrrole Five grams (0.0161 mole) of the compound of Example 42 are dissolved in 60 ml. of methanol and 1.3 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. 166-7°C. neutralized with aqueous 10% sodium hydroxide and extracted again with ethyl acetate. After evaporation of the solvent a solid is obtained, which is recrys tallized from a mixture of methanol and diethyl ether saturated with hydrogen cloride. Yield of the tit compound 5 g. M.p. 205-7°C The free base melts at 142-43eC (from diethyl 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 4-Acetyl-5-methyl-3-methylamino-2-phenyl-pyrrole 1.5 Grams (0.00366 mole)of the compound of 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 filtered. Yield of the title compound: 0.3 g. M.p. 174-76°C.

Example 94 4-Benzoyl-3-ethylamino-5-methyl-2-phenyl-pyrrole This compound is obtained with 441 yield from the compound of Example 60, following the method described in the Example 93. M.p. 178-80°C (from ethanol/water) .

Example 95 3-Acetylamino-4-benzoyl-5 -methyl- 2-pheny1-pyrrole Following the method described in Example 43, starting from the compound of Example 3 and acetylchloride the title compound is obtained with 871 yield. M.p. 140-42eC (from ethanol/water).

Claims (1)

1. , ne fr ts * reaction mixture, for one to sixty hours, whereby a compound of formula I is obtained, wherein R, and are hydrogen, said process being further characterized in that: a) when radicals R^ or R^ or both, as defined above, are desired to be different from hydrogen, they are introduced by common alkylation, acylation, sulfonylation , carbamylation, thio- carbamylation, formylation, arylation, Schiff's bases formation procedures, which include reaction with (C^ ^)alkyl halides, di- (C.._^)alkyl sulfates, mixtures of formic acid and formaldehyde, mono halides of (Cj_,.)dicarboxylic acids in which the second alkanoyl carboxy group is esterified with a alkanol , (C2 4 ) »e)tfc halides or anhydrides, benzoyl halides or anhydrides, benze- nesulfonyl halides, (C^, alkylsulfonyl halides, toluenesulfonyl halides, phenacylsulfonyl halides, formic acid, alkali metal cyana- tes or thiocyanates, phenylisocyanate, phenylisothiocyanate, benzo isothiocyanate, benzoic acid substituted in the aromatic ring with a halogen atom, (C2_4)aliphatic aldehydes, (c3_4) liphatic ketones, enzaldehyde, benzaldehyde substituted in the aromatic ring by halogen atoms, and optionally by removing the (C^ alkylsulfonyl , benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl groups by hydrolysis ; b) when a compound of formula I is desired, is carbo xy or carbamyl and R^ is carboxy, carbamyl or carbazoyl, a compoun of formula I wherein or ^ or both are carbo(C^ ^)alkoxy is subjected to basic or acidic hydrolysis or is reacted with al as