FI71129C - FOERFARANDE FOER FRAMSTAELLNING AV FARMACEUTISKT AKTIVA ALFAKARBAMOYLPYRROLPROPIONITRILER - Google Patents

Abstract

Antiinflammatory and antiarthritic compounds of the formula I <IMAGE> in which Pl denotes a 2- or 3-pyrrolyl radical, which is substituted in the 1-position by lower alkyl or Ph-lower alkyl and is unsubstituted in the three remaining positions or substituted by lower alkyl and/or a carboxyl or carboxy-lower alkoxy group; R represents lower alkyl and Ph denotes phenyl which is unsubstituted or substituted by one to three identical or different substituents from the group comprising lower alkyl, lower alkoxy, lower alkylthio, hydroxyl, halogen, trifluoromethyl, nitro, amino or lower alkanoylamino; these compounds in their enol form, their enol lower alkyl ethers or enol lower alkanoyl esters, or their salts with bases can be obtained, for example, by condensation of compounds of the formulae <IMAGE> in which X denotes lower alkoxy, lower alkanoyloxy or halogen.

Description

ΓΒ1 (11) KUUXLUTUSJULKA, SU n * 129 τ & βφ lJ ΊΊ UTLÄGG N I N G SSKRIFT

C Patent: tty ^ Pn> '' t Γ "% · 7 -'- ν; 'il 1310 ^ ^ (51) K» .ik // int.ci. * C 07 D 207/337 SUOMI-FINLAND (21 ) Patent application Patentansökning 8018A0 (22) Filing date - Ansökningsdag 09 * 06.80 (Fl) (23) Starting date - Giltighctsdag 09 * 06.80 (41) Published public - Blivit offentlig ^ 2.80

National Board of Patents and Registration Date of publication and publication. 1. 08 .86

Patents and registers '' Ansökan utlagd och uti.skriften publicerad (86) Kv. application · Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority 1 1 .06.79 USA (US) 46063 (71) Ciba-Geigy AG, 4002 Basel, Switzerland-Switzerland (CH) (72) Gordon Northrop Walker, Morristown, New Jersey, USA (74) Oy Jalo Ant-Wuorinen Ab (54) Process for the preparation of pharmaceutically active α1-carbarbamoyl-pyrrolepropionols - For the preparation of pharmaceutically active α-carbarbamoyl-pyrrolepropiones

Certainly substituted "cyanoacetic anilides" and related "isooxazolyl carboxylic acid anilides", e.g. those of formula V3 NOC-CONH- · · „<<2

Cfi3NOM \ // * ϋ rC0NH'5 t * 5 Xoy NCH3 x · ^ are BE patents 842,688; 842,689; 849 343; 861,500 or U.S. Patent No. 2,071,129 discloses "non-exogenous, antiphlogistic and analgesic agents".

It has surprisingly been found that the novel pyrrolopropionitriles, in contrast to the said known anilides, offer considerable therapeutic advantages in view of the spectrum of activity and suitability.

This invention relates to a process for the preparation of therapeutically active substituted O-oxo-α-phenylcarbamoyl-pyrrolepropionitriles of general formula (I):

CN H

R —ft 4 I I

r3- · 4-CO-CH-CO-N-Ph (I),

2 Y

R 1 is wherein C 1 -C 4 alkyl, R 2 is hydrogen or C 1 -C 2 alkyl, R 3 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 carbalkoxy, R 4 is hydrogen or C 1 -C 2 alkyl and Ph represents phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or C 1 -C 4 alkyl. ~ C2-alkanoylamino; for the preparation of these compounds in enol form, for the preparation of their eno-C 1 -C 4 alkyl ethers or enol C 1 -C 4 alkanoyl esters or their base salts.

Both said pyrrolyl and phenyl groups are preferably C-unsubstituted. However, they may also be substituted, in particular by one or two, identical or different substituents, which are methyl or ethyl. In addition, the residue Ph may also be substituted by nitroxy, ethoxy, methylthio or ethylthio, hydroxy, halogen, e.g. fluorine, chlorine or bromine, trifluoromethyl, nitro, amino or acetylamino. The pyrrolyl residue may contain carbomethoxy or carboethoxy.

3 71129

The alkyl groups in the 1-position of the pyrrole ring are preferably methyl, but also ethyl, n- or i-propyl or -butyl.

The term "lower" defines the abovementioned or hereinafter mentioned organic residues or compounds as having up to 7, preferably up to 4, in particular 1 or 2 carbon atoms.

The ρ-hydroxy tautomeric compounds of formula (I) are sufficiently acidic for the preparation of said enol C 1 -C 4 alkyl ethers, enol C 1 -C 4 alkanoyl esters or salts with bases, in particular those obtained with bases, which are therapeutically useful. These salts are derived from alkali metal, alkaline earth metal, copper or zinc hydroxide; ammonia, mono-, di- or tri- (lower alkyl or hydroxy-lower alkyl) amines, lower alkyleneamines or lower alkylenediamines. Such salts include, for example, sodium, potassium, magnesium, ammonium, mono-, di- or tri- (methyl, ethyl or hydroxy-ethyl) -ammonium, pyrrolidinium, ethylenediammonium or morpholinium salts or various hydrates thereof.

The compounds of the invention have valuable pharmacological properties, in particular anti-inflammatory and anti-arthritic effects. These can be detected in vitro or in vivo. In the latter, mammals, e.g. rats, cats, guinea pigs or dogs, are preferably used as experimental animals. The compounds of the invention may be administered to animals enterally, preferably orally, parenterally, e.g. subcutaneously or intravenously, or topically, e.g. in the form of aqueous or oily solutions or in the form of suspensions containing starches. The dose used may be about 0.1 to 100 mg / kg / day, preferably about 1 to 50 mg / kg / day, more preferably about 2 to 25 mg / kg / day. The tests selected for said effects are either classical test methods, e.g., carrageenan-paw-edema or adjuvant-arthritis test in rats, synovitis test in dogs, or a test to evaluate redness induced by ultraviolet light or the use of 4 71129 modern test methods. Such are neutral protease inhibition [disclosed in Arthritis Rheum. 17, 47 (1974)] or inhibition of leukocyte chemotaxis [N.Y.Acad. Sci ,. 256, 177 (1975)]. Other methods include reduction of neutrophil adherence [Amer.J.Med. 61, 597 (1976)] or inhibition of prostaglandin synthetase, a test described in Biochem. 10, 2372 (1971).

Illustrative is the following test method, which leads to appropriate results: Male Charles River rats weighing 250-300 g are immunized by intradermal injection of 0.1 ml of Bacillus Calmetta Guerin (BCG) vaccine. After one week, the experimental animals are injected intraperitoneally with 10 ml of sterile 2% rice-starch solution to trigger macrophage enrichment. Eleven days after immunization, animals are sacrificed and peritoneal macrophages are collected with 20 ml of Gey's buffered saline containing heparin (25 units / ml). The cells are centrifuged for 10 minutes, 1000 rpm, washed again with 50 ml of Gey's solution, centrifuged at the same speed and for the same time, and then suspended in Gey's solution containing 0.1% human serum albumin. (Fraction V, Sigma Co., pH 7.1) so as to achieve a concentration of 2 x 10 6 cells / ml.

1 x 10 -10 molar solutions of the test substances are prepared in dimethylacetamide. Subsequent dilutions are made using Gey's solution and finally these are added to the above cell suspensions to achieve suitable final concentrations of 10 ", 10", 10 "and 10-7 moles. After the suspensions have been introduced into the upper part of the modified Boyden chemotaxis chambers, said test substances remain in contact with the cells.

Rota serum activated with Escherichia coli lipopolysaccharide (Difco) (1/10 dilution, pH 7.1) is used as the chemotactic agent. This serum fills the lower chambers of said chambers. The cell-containing portion of the chamber 5 71129 is separated from the chemotactic solution by a cellulose filter membrane with pores of 8 microns. Three similar chambers are prepared in parallel and incubated for 5 hours at 37 °. Cell suspensions that do not contain any test substance are used to control cell migration. After incubation, the filter is removed, fixed and stained with iron hematoxylin according to Weigert. From the underside of the filter, four fields are examined with a 320-fold magnifying microscope. The index of chemotactic activity is the average of the number of neutrophils counted in each of the four fields. Indomethacin and levamisole are also used as reference compounds in this test method.

Thus, in an adjuvant arthritis test, e.g. 1-methyl-oxo-u-phenylcarbamoyl-2-pyrrolopropionitrile, a typical member of the compounds of the invention, or said enol ethers or enol esters, salts or closely resembling them of formula (I) and (II) The compounds are highly active in rats at oral doses up to less than 2 mg / kg / day. The effect of these compounds on the in vitro chemotactic activity of BCG-immunized macrophages is significant at concentrations even below 10 μm and ja- ** moles, and this is reflected in an increase in the chemotactic response of macrophages. In contrast, indomethacin does not affect macrophage chemotaxis, whereas levamisole, a known immunopotentiator, causes increased migration at final concentrations of 10 "3 - 10 -10 moles.

The above test methods show that the compounds of the invention have a very good anti-inflammatory effect but also a different mechanism of action compared to ordinary non-steroidal anti-inflammatory agents, as they also have similar components of action as levamisole, as shown by the macrophage chemotaxis test. [Levamisole is an antirheumatic drug that affects the disease. (This is shown in "Arthritis and Rheuma- 6 71129 tism", 18, 385 (1975) and "The Lancet", 21.2.1976, p. 393)]. The compounds of the invention, which have both indomethacin-type and levamisole-type activity, are valuable anti-inflammatory and antiarthritic agents, e.g. in the treatment or control of inflammatory arthritis and / or dermatopathogenic conditions. In addition, the new compounds can be used as intermediates in the preparation of other valuable preparations, in particular pharmacologically active preparations.

Experimental report 1. Determination of anti-inflammatory activity in the rat by the carrageenan paw edema test

One hour after oral administration of the compounds, 0.1 ml of carrageenan (1%) is injected into the underside of the second hind paw. The difference in swelling is measured by the displacement of mercury. Anti-inflammatory activity is expressed as the percentage inhibition of carrageenan-induced swelling, measured three hours after administration of the test compound.

Example inhibition% Example inhibition% (100 mg / kg / po) (100 mg / kg / po) 1 36 20/3 25 5 47 20/4 23 12a 35 20/5 44 14 36 20/6 42 15 31 20 / 7 44 16a 48 20/8 26 18a 25 20/9 42 18b 33 20/10 23 19b 43 20/12 11 20/2 46 71129 7 2. Established Adjuvant Arthritis Test

The Established Adjuvant Arthritis Assay was performed according to the methods described by Perper et al. (Proc. Soc. Exp. Biol. & Med., 137; 506, 1971). Test compounds were administered orally to the rat.

Example No.% inhibition of arthritic swelling, dose 12.5 mq / kq p.o._ 3 49 5 64 20/1 34 20/2 41 20/4 43 20/6 53 20/7 29 20/9 41

Particularly preferred are compounds of general formula (II) eβ R3- · «- - CO-CH-CONH- · ^ R5 (II), 'v <v- \ 6

I CN

RI

wherein is C 1 -C 4 alkyl, R 2 is hydrogen or C 1 -C 4 alkyl, R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 2 carbalkoxy, R 4 is hydrogen or C 1 -C 2 alkyl and each of R 5 and R 8 represents C 1 -C 2 alkyl, C 1 -C 2 alkoxy, hydroxy, halogen or trifluoromethyl, or their salts with bases, in particular their therapeutically useful salts with bases.

Further preferred are compounds of formula II wherein R 1 represents alkyl of up to 4 carbon atoms, each of R 2, R 3 and R 4 represents 8 71129 hydrogen and each of R 5 and R 8 represents hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkyl. alkoxy, fluorine, chlorine or trifluoromethyl, or their salts with bases, in particular their therapeutically useful salts with bases.

Particularly preferred are compounds of general formula II, wherein R 1 represents methyl, each of R 2 / R 3 and R 4 represents hydrogen and each of R 5 and R 8 represents hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, or their sodium, potassium -, calcium, triethylammonium or trihydroxyethylammonium salts, one of the symbols R5 and Rg being different from hydrogen is preferably in the para position.

The compounds according to the invention are prepared by methods known per se, e.g. by a) combining compounds of the formulas r3-2 ^ O-CH, -CN OC = N-Ph 2 V 2

R 1 wherein R 1, R 2, R 3, R 4 and Ph are as defined above, or b) condensing compounds of the formulas

R

r3- · 4-CO-CH-COX and H-NH-Ph

2 V I

I CN

R 1 wherein X represents lower alkoxy, lower alkanoyloxy or halogen and R 1, R 2, R 3, R 4 and Ph have the same meaning as above, or c) condensing compounds of the formulas 71129 9

Vrt-iu and CH 2-CON-Ph

2 in I I

I CN H

R 1 wherein Y represents lower alkoxycarbonyl, halocarbonyl or cyano and R 1, R 2, R 3, R 4 and Ph have the same meaning as above and the imines obtained are hydrolysed, or d) a compound of formula R 1 - CONH-Ph 2 v - 1

; VH

wherein R 1, R 2, R 3, R 4 and Ph are as defined above, isomerized with a strong base, and the enol obtained is converted, if desired, into an enol C 1 -C 4 alkyl ether or an enol C 1 -C 4 alkanoyl ester, and / or the enol obtained is, if desired, converted into a base. or the resulting enol salt to the free enol or another base salt, and / or the resulting mixture of isomers is separated into the individual isomers, if desired.

The addition of the isocyanate in process a) is preferably carried out according to said BE patents or U.S. Patent 3,905,997, i.e. without an inorganic or organic base or in the presence of an inorganic or organic base, e.g. sodium hydride, or a polar solvent, e.g. an ether such as diethyl ether or tetrahydrofuran. and / or in the presence or absence of an amide or sulfoxide, e.g. dimethylformamide or dimethylsulfoxide, preferably at an elevated temperature, e.g. about 150 °, when no base is used.

The process according to the invention is preferably carried out as follows: A suspension of said nitrile is treated in an aromatic hydrocarbon, e.g. warm toluene, with a small molar excess of anhydrous trialempalkylamine, preferably triethylamine. The molar equivalent of phenyl isocyanate Ph-N = CO or a solution thereof in one of the above-mentioned polar solvents, e.g. dimethyl sulfoxide, is then added. The reaction mixture is stirred for about 2-12 hours at room temperature and its volume is reduced by heating, at a temperature which is not too high, e.g. at a maximum of 100 °. The resulting precipitate is dissolved in an alkanol, e.g. methanol, and the solution is treated with an excess of dilute aqueous acid, e.g. 0.3 N hydrochloric acid. The crude product obtained is separated, washed with water, dried, triturated and / or recrystallized from suitable solvents. Such solvents include lower alkanols, lower alkanones, di-lower alkyl ethers and / or lower alkyl lower alkanoates, e.g. methanol, acetone, diethyl ether and / or acetic acid ethyl ester.

The amination according to process b) is carried out in the usual manner, preferably between room temperature and about 150 °. Work either using equivalent amounts of the compounds involved in the reaction, preferably using an ester, or using an excess of amine, or work in the presence of another base. Such bases include, for example, tertiary amines such as tri-lower alkylamine or pyridine. These are used to neutralize the acid formed when using halide or anhydride starting materials. The alkanol formed in the reaction of the ester starting materials is preferably distilled off together with a solvent, e.g. an aromatic hydrocarbon, e.g. benzene, toluene or xylene.

The condensation of process c) is preferably carried out using alkali metals, their lower alkoxides or in particular hydrides, e.g. sodium hydride, in suitable polar solvents, preferably dimethylformamide or dimethyl sulfoxide. This condensation corresponds to the preparation of the nitrile starting materials mentioned for methods a) and b), which condensation is described in the corresponding examples.

Finally, the isomerization of process d) is carried out in the presence of strong inorganic or organic bases, e.g. alkali metal hydroxides or tri-lower alkyl aralkylammonium hydroxides, e.g. trimethylbenzylammonium hydroxide.

The compounds of formula (I) obtained can be converted into one another in a manner known per se. Thus, for example, the enols obtained can be etherified, preferably with diazoalkanes, or esterified with, for example, lower alkanoic anhydrides. Therapeutically useful salts of said enols can be prepared, for example, with aqueous alkali metal hydroxides, preferably in the presence of an ether or an alcohol as a solvent, e.g. in the presence of lower palkanol. Of the alcoholic solutions, the salts can be precipitated with said ethers, e.g. diethyl ether or tetrahydrofuran. Work at reasonable temperatures, eg below 100 °. The salts obtained can be converted into the free compounds, as mentioned above, by treatment with acids. The nitro group in the residue Ph can also be converted into an amino group, e.g. with catalytically activated hydrogen, such as hydrogen in the presence of a nickel or palladium catalyst. The latter can be acylated either as described above or with lower alkanoic acid halides or lower alkyl esters.

The starting materials are known or, if new, can be prepared according to the methods described for the corresponding compounds, e.g. according to the methods described in connection with the description of the prior art, to the compounds mentioned therein or according to the methods described in the examples.

The starting materials and the final products, which are mixtures of isomers, can be separated into the individual isomers by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography.

The above reactions are carried out according to methods known per se, in the presence or absence of diluents, preferably those which are inert to and soluble in the reagents, catalysts, condensing agents or neutralizing agents, and / or inert atmosphere, cooling, room temperature or elevated temperature. at normal or elevated pressure.

The invention also relates to variants of these processes in which the intermediate obtained at any stage of the process is used as starting material and the missing process steps are carried out, or the process is stopped at any stage, or in which the starting material is formed under reaction conditions, or using a salt or a reactive derivative. in terms of. Said isocyanates can also be prepared starting from the corresponding acid azides and mixed anhydrides starting from the corresponding acids and simple alkanoic anhydrides.

The starting materials used in the process according to the invention are preferably those which give the compounds initially described as being of particular value, in particular the compounds of the formula (I).

The pharmacologically useful compounds of this invention may be used in the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration. Preferably tablets or gelatin capsules are used which contain the active ingredient together with diluents e.g. lactose, dextrose, crude sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants e.g. milk, talc, stearic acid or its salts such as magnesium. or with calcium stearate and / or polyethylene glycol; the tablets also contain binders, e.g. magnesium aluminum silicate, starch pastes, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, a disintegrant, e.g. starch, agar or sodium acid, alginic acid or effervescent mixtures, or adsorbents, colorants, flavors and sweeteners. Formulations for injection are preferably isotonic, aqueous solutions or suspensions, and suppositories or topical lotions are primarily fat emulsions or suspensions. The pharmaceutical preparations may be sterilized and / or may contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations, which may, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. according to customary mixing, granulating or granulating methods, and contain from about 1% to about 75%, in particular from about 1% to about 50%, of active ingredient.

The following examples illustrate the invention without limiting the scope thereof. Temperatures are given in degrees Celsius and parts given are by weight. Unless otherwise specified, evaporation of the solvents is performed at atmospheric pressure. Example 1:

To a suspension of 12.9 g of 1-methyl-8-oxo-2-pyrrolopropionitrile in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine are added 10.7 g of phenyl isocyanate while stirring. After the solids have dissolved, the dark red solution is kept for 30 minutes at room temperature, 5 minutes on a steam bath and overnight at room temperature. The mixture is evaporated on a steam bath, the residue is dissolved in methanol and the solution is poured into a mixture of 25 ml of 5N hydrochloric acid and 600 ml of water. The resulting bright yellow crystals are separated, washed with water, triturated with ethanol and recrystallized from about 2200 ml of methanol. 1-Methyl-β-oxo-α-phenylcarbamoyl-2-pyrrole-propionitrile of the formula • - CO - CH - CONH X · is obtained,

if I »mS

I CN

CH3 71129 14 and melting at 174-175 °.

The starting material is prepared as follows: A solution of 28 g of 1-methylpyrrole-2-carboxylic acid in 20 ml of dimethylformamide is added, with stirring and cooling, to a suspension prepared from 12 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended. To 50 ml of dimethylformamide. 30 ml of methyl iodide are then added to the reaction mixture and further stirred at room temperature. At the beginning of the quenching of the exothermic reaction, a further 10 ml of methyl iodide are added. The reaction mixture is allowed to stand overnight, treated with water and extracted with diethyl ether. The extract is washed with aqueous sodium carbonate solution and water, dried and evaporated. An oily 1-methylpyrrole-2-carboxylic acid methyl ester is obtained.

A solution of 28 g of the latter compound in 50 ml of acetonitrile is added, with stirring, to a suspension prepared from 19 g of 50% sodium hydride in mineral oil, washing with petroleum ether and suspending in 50 ml of dimethylformamide. After quenching the exothermic reaction, the mixture is heated on a steam bath for 15 minutes, during which time another vigorous effervescent reaction takes place. The thick reddish brown suspension is further diluted with 50 ml of dimethylformamide and allowed to stand at room temperature overnight. The mixture is then heated on a steam bath again for 5 minutes, after which it is cooled and diluted with water. The aqueous solution is filtered, washed once with diethyl ether and acidified with hydrochloric acid. The crystals obtained are separated, washed with water, dried, triturated with cold ethanol and recrystallized from ethanol.

1-Methyl-6-oxo-2-pyrrolopropionitrile is obtained, melting at 107-109 °.

Example 2: By treating equivalent aqueous solutions of concentrated aqueous solutions of sodium hydroxide, potassium hydroxide or calcium hydroxide with 1-methyl-g-oxo-g-phenylcarbamoyl-2-pyrrole-propionitrile, the mixtures are filtered and the corresponding filtrates are obtained, evaporated to dryness, dried. These do not show any well-defined crystalline properties or melting points, although they can be reprecipitated from an ethanol-containing solution by the addition of diethyl ether. The salts 71 1 29 15 are water-soluble and have the following bands in the infrared spectrum:

Na salt: 4.57; 6.17 and 6.29y? K-salt: 4.58? 6.17 and 6.30y;

Ca salt: 4.55; 6.13 and 6.23μ.

In each case, acidification of the aqueous brine with hydrochloric acid gives the identical free compound (m.p. 174-175 °).

Example 3:

To a suspension of 21.4 g of 1-methyl-S-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile in 100 ml of absolute ethanol is added 11.68 ml of tris-ethanolamine in 25 ml of ethanol and heated until dissolution is complete. happened. The solution is filtered hot, allowed to cool to room temperature while stirring, the resulting suspension is cooled to 10 °, filtered and the residue is washed with 25 ml of cold ethanol. The corresponding tris-hydroxyethyl ammonium salt is obtained, melting at 115-117 °. Example 4:

3.8 g of 1-methyl-8-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile are added to 500 ml of ethereal diazomethane prepared from 10.3 g of N-nitroso-N-methylurea with 35 ml. % aqueous potassium hydroxide solution and dried over potassium hydroxide tablets. When nitrogen evolution ceases, the solution is filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethyl acetate. The corresponding methyl enol ether is obtained, namely 1-methyl-g-methoxy-α-phenylcarbamovyl-2-pyrrolacrylonitrile, melting at 121-122 °.

Example 5:

To a suspension of 4 g of 1-methyl-6-oxo-2-pyrrolopropionitrile in 70 ml of toluene and 3.2 g of triethylamine are added, with stirring, 3.7 g of p-fluorophenyl isocyanate. The mixture is heated on a steam bath until the solids have dissolved and the red-brown solution is left to stand at room temperature overnight. The reaction mixture is evaporated on a steam bath, the residue is dissolved in methanol and the solution is poured into a mixture of 8 ml of 5N hydrochloric acid and 300 ml of water. The precipitated crystals are separated, washed with water, dried, triturated with methanol and recrystallized from ethyl acetate.

16 71129

1-Methyl-g-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 198-199 °.

Example 6:

A mixture of 1.1 g of 1-methyl-g-oxo-α-ethoxycarbonyl-2-pyrrolopropionitrile, 1.1 g of aniline and 60 ml of xylene is refluxed for 4.5 hours. The reaction mixture is allowed to cool overnight and stand at room temperature. The solution is then filtered, evaporated and the residue is recrystallized from methanol. 1-Methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 173-174 °.

The product is identical to the product of Example 1.

The starting material is prepared as follows: To a solution of 10 g of 1-methylpyrrole-2-carboxylic acid in 650 ml of dry diethyl ether and 8.5 g of anhydrous triethylamine is gradually added, with stirring, a solution of 6 ml of thionyl chloride in 50 ml. in diethyl ether. After 30 minutes, the reaction mixture is filtered and the residue is washed with diethyl ether. The filtrate is evaporated to a smaller volume, filtered again and finally evaporated under reduced pressure. The corresponding acid chloride is obtained.

Its solution in 20 ml of ethylene glycol dimethyl ether is slowly added, with stirring and cooling, to a suspension of 7.2 g of 50% sodium hydride in mineral oil (washed with petroleum ether) in 50 ml of dimethylformamide and 20 g of ethyl cyanoacetate. The moderate exothermic reaction is accelerated by heating the mixture briefly in a steam bath. The reaction mixture is allowed to stand overnight, treated with water, acidified with 5N hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue is triturated and recrystallized from diethyl ether. 1-Methyl-g-oxo-α-ethoxycarbonyl-2-pyrrolopropionitrile is obtained, melting at 74-77 °.

The same product is obtained by acylation with mixed anhydride, i. using an equivalent amount of chloroformic acid ethyl ester instead of thionyl chloride in the above reaction step.

17 71129

Example 7: * *

A mixture of 5.7 g of 1-methyl-3-oxo-α-ethoxycarbonyl-2-pyrrolopropionitrile, 3.6 g of p-aminophenol and 300 ml of xylene is refluxed for 2 hours and filtered hot. The filtrate is cooled, the crystals obtained are separated and recrystallized from methanol. 1-Methyl-β-oxo-g- (p-hydroxyphenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 182-184 °.

Example 8;

To a solution of 4 g of phenylcarbamoylacetonitrile in 50 ml of dimethylformamide is added, under stirring, 28 g of potassium tert-butoxide under a nitrogen atmosphere. After 2 hours, the resulting suspension is cooled to 5 ° and 4 g of 1-methyl-pyrrole-2-carboxylic acid chloride are added over 10 minutes (U.S. Patent 3,551,571). The reaction mixture is stirred for 18 hours at room temperature, poured into 300 ml of ice water and the precipitate obtained is filtered off. This is washed with water, dried and recrystallized from ethanol. 1-Methyl-8-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 172-174 °. The product is identical to the product of Example 1.

The starting material is prepared as follows: To a mixture of 42.53 g of cyanoacetic acid, 46.56 g of aniline and 500 ml of acetonitrile is added, under stirring, a solution of 113.7 g of N, N-dicyclohexylcarbodiimide under nitrogen for 30 minutes while stirring. In 500 ml of acetonitrile. After 3 hours, the suspension obtained is filtered, the residue is washed with 200 ml of acetonitrile and the filtrate is evaporated. The residue is triturated with 500 ml of diethyl ether and 50 ml of acetic acid ethyl ester, filtered and dried. Phenylcarbamoylacetonitrile is obtained, melting at 200-202 °.

Example 9:

To a suspension of 1.135 g of 1-methyl-β-oxo-2-pyrrole-propionitrile in 17,000 ml of dry toluene is added, under a nitrogen atmosphere, with stirring, first 913 g of anhydrous triethylamine and then 913 g of phenyl isocyanate. The resulting dark brown solution is stirred overnight at room temperature and then evaporated at 60-70 ° / 10 mmHg. The residue is dissolved in 1400 ml of methanol and the solution is treated with 1400 ml of 6N hydrochloric acid in 4200 ml of water. The suspension is cooled to 15-20 ° in 20 minutes, filtered and the residue is washed twice with 1800 ml of water, twice with 1000 ml of isopropanol and 13 times with 1000 ml of diethyl ether.

18 71129

The crude residue is dried at 60 ° and 5 mmHg to constant weight.

1960 g of this residue are dissolved in 44,400 ml of methylene chloride at room temperature. The solution is treated with 400 g of activated carbon, filtered and the filtrate is evaporated. The residue is triturated with 12,000 ml of anhydrous ethanol, the suspension is filtered at 20 °, washed four times with 1000 ml of anhydrous ethanol and dried at 60 ° and 5 mmHg. 1-Methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 172-174 °. The product is identical to the products of Examples 1, 6 or 8.

1801 g of the latter compound are suspended in 10,500 ml of anhydrous ethanol and 1108 g of triethanolamine are added. The mixture is stirred and heated until the solid has dissolved and then slowly cooled to 20 ° C. The precipitate obtained is filtered off, washed twice with 1000 ml of cold anhydrous ethanol and dried at 45 ° and 0.1 mmHg. The corresponding tris-hydroxyethylammonium salt is obtained, melting at 115-117 °. The salt is identical to the product of Example 3.

The starting material is prepared as follows: A solution of 1325 g of 1-methylpyrrole-2-carboxylic acid in 2400 ml of dimethylformamide is added, under a nitrogen atmosphere, with stirring and ice-cooling, to a suspension of 568.5 g of 50% sodium hydride in mineral oil and 2400 ml of dimethylformamide. Then, while stirring at a temperature below 88 °, 1000 ml of dimethylformamide and then 4316 g of methyl iodide are added to the reaction mixture. Stirring is continued overnight at room temperature, then the mixture is cooled to 10 ° and 10,600 ml of water are added. The mixture is extracted three times with 5,300 ml of diethyl ether, the extract is washed with 5,300 ml of 10% aqueous sodium carbonate solution and 5,300 ml of water, dried and evaporated. An oily 1-methylpyrrole-2-carboxylic acid methyl ester is obtained.

A solution of 1604 g of the latter compound in 2650 ml of acetonitrile is rapidly added to a suspension of 1017 g of 50% sodium hydride in mineral oil and 2650 ml of dimethylformamide, while stirring under a nitrogen atmosphere. The mixture is heated at 8 ° for 2 hours and then cooled to 10 °, finally 25 400 ml of water are added over 15 minutes. The mixture is washed three times with 9,000 ml of diethyl

II

19 71129 ether, stirred for 45 minutes at 10 mmHg to remove diethyl ether and acidified with 6,400 ml of 6N hydrochloric acid. The crystals obtained are separated, washed four times with 2,400 ml of water and once with 2,400 ml of isopropanol and dried at 60 ° and 5 mmHg. 1-Methyl-β-oxo-2-pyrrolopropionitrile is obtained, melting at 106-108 °.

Example 1Q:

To a filtered solution of 4.4 g of 2,6-dichlorophenyl isocyanate in 30 ml of toluene are added 2.5 g of 1-methyl-β-oxo-2-pyrrolopropionitrile and 2.1 g of triethylamine with stirring. The mixture is allowed to stand at room temperature overnight and then filtered. The solid is washed with toluene and diethyl ether, dissolved in 50 ml of methanol and the solution is poured into a mixture of 6 ml of 5N hydrochloric acid and 300 ml of water. The crystals obtained are separated, washed with water, dried, triturated with ethanol and recrystallized from methanol. 1-Methyl-β-oxo-α- (2,6-dichlorophenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 196-199 °. Example 11:

A suspension of 2 g of 1-methyl-β-oxo-2-pyrrolopropionitrile in 50 ml of toluene and 1.6 g of triethylamine is treated with 2.1 g of p-methoxyphenyl isocyanate. The mixture is gently heated until the solid has dissolved and allowed to stand overnight at room temperature. It is then evaporated, the residue is dissolved in methanol and 10 ml of 10% aqueous sodium hydroxide solution and 250 ml of water are added. The alkaline solution is filtered, acidified with 5N hydrochloric acid and the precipitate obtained is separated. The precipitate is washed with water, dried and triturated with a warm mixture of methanol and ethyl acetate and recrystallized from ethyl acetate. 1-Methyl-β-oxo-α- (p-methoxyphenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 192-193 °.

In a similar manner there is also prepared 1-methyl-β-oxo-α- (p-methylthio-phenylcarbamoyl) -2-pyrrolopropionitrile, m.p. 167-168 °.

Example 1 2:

A solution of 4.9 g of 1-methyl-O-oxo-2-pyrrolopropionitrile in 50 ml of toluene, 5 ml of dimethyl sulphoxide and 4 g of 20 71 129 triethylamine is treated with a solution of 5.7 g of p-nitrophenyl isocyanate in as little toluene as possible, while stirring. The reaction mixture is allowed to stand overnight, evaporated and the residue is dissolved in methanol. The solution is filtered, diluted with water and 6 ml of triethylamine, washed with ethyl acetate and the washings are extracted once with 5% aqueous sodium hydroxide solution. The combined aqueous solutions are acidified with 5N hydrochloric acid and the resulting precipitate is separated. This is washed with water, triturated with methanol-ethanol and recrystallized from dimethylformamide. 1-Methyl-β-oxo-α- (p-nitro-phenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 245-250 °, with decomposition.

A solution of 2 g of the latter compound in 220 ml of ethanol and 2 ml of triethylamine is hydrogenated with 0.5 g of 10% palladium on carbon under 3.5 atmospheres and at room temperature for 50 minutes. The filtered solution is evaporated, the residue is dissolved in water, 1 ml of triethylamine are added and the solution is washed with ethyl acetate and diethyl ether. It is acidified with 5N hydrochloric acid, the precipitate is separated off, washed with water, dried and recrystallized from aqueous methanol. 1-Methyl-β-oxo-α- (p-amino-phenylcarbamoyl) -2-pyrrolopropionitrile is obtained, melting at 193-195 °, with decomposition.

Dissolve 0.5 g of the latter compound in 10 ml of acetic anhydride, boil the solution for 10 minutes at reflux and evaporate. The residue is triturated with diethyl ether and recrystallized from methanol-ethyl acetate. 1-Methyl-β-acetoxy-α- (p-acetylamino-phenylcarbamoyl) -2-pyrrolacrylonitrile is obtained, melting at 178-179 °.

Example 1 3:

A mixture of 2.1 g of 1-ethyl-β-oxo-2-pyrrolopropionitrile, 25 ml of toluene and 1.6 g of triethylamine is treated, with stirring, with 1.6 g of phenyl isocyanate. The mixture is allowed to stand overnight at room temperature, then evaporated and dissolved in methanol. The solution is poured into 300 ml of water containing 5 ml of 5N hydrochloric acid, the precipitate is separated and dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, the filtrate is re-acidified, the solid is separated, washed with water, dried and recrystallized from ethanol. 1-Ethyl-3-oxo-α-phenyl-carbamoyl-2-pyrrolopropionitrile is obtained, melting at 144-145.

The starting material is prepared as follows: A suspension of 9.1 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended in 50 ml of dimethylformamide, is gradually added together with 20 g of pyrrole-2-carboxylic acid methyl ester to 50 ml. dimethylformamide while stirring and cooling on ice. After dissolution, 25 ml of ethyl bromide are added and the reaction mixture is warmed slightly to initiate an exothermic reaction. When this subsides, an additional 5 mL of ethyl bromide is added and the mixture is allowed to stand overnight. It is treated with water and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated. An oily 1-ethylpyrrole-2-carboxylic acid methyl ester is obtained.

A solution of 10 g of the latter compound in 25 ml of acetonitrile and 25 ml of dimethylformamide is added to a suspension of 5.5 g of 50% sodium hydride (washed with petroleum ether) in 15 ml of dimethylformamide and the mixture is heated on a steam bath for 15 minutes. while confusing. The mixture is allowed to stand overnight, water is added, filtered and acidified with 5N hydrochloric acid. The precipitate is separated, washed with water and recrystallized from ethanol. 1-Ethyl-6-oxo-2-pyrrolopropionitrile is obtained, melting at 77-79 °. Example 1 '4:

To a solution of 2.5 g of 1-isobutyl-β-oxo-2-pyrrole-propionitrile in 30 ml of toluene and 1.6 g of triethylamine are added, with stirring, 1.6 g of phenyl isocyanate.

The mixture is allowed to stand overnight, filtered and the residue is dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, acidified with 5N hydrochloric acid and extracted with a mixture of diethyl ether and ethyl acetate. The organic extract is washed with water, dried and evaporated. The residue is triturated with ethanol and recrystallized from methanol. 1-Isobutyl-3-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 134-136 °.

The starting material is prepared as follows: 13 g of pyrrole-22 71 1 29 2-carboxylic acid methyl ester are added, with stirring, to a suspension of 5.5 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended in 70 ml of dimethylformamide. 40 g of isobutyl bromide are then added to the mixture and it is heated on a steam bath for 10 minutes, while stirring. The reaction mixture is allowed to stand overnight, then treated with water and extracted with diethyl ether. The extract is washed with water, dried and evaporated. An oily 1-isobutylpyrrole-2-carboxylic acid methyl ester is obtained.

A solution of 10 g of the latter compound in 15 ml of acetonitrile is added, with stirring, to a suspension of 5 g of 50% sodium hydride in mineral oil, washing with petroleum ether and suspending in 25 ml of dimethylformamide. After the effervescent reaction has subsided, the mixture is heated on a steam bath for 30 minutes. During this time, sodium hydride is consumed. The mixture is allowed to stand at room temperature overnight, water is added and the mixture is acidified with 5N hydrochloric acid. The mixture is extracted with diethyl ether, the extract is washed with water, dried and evaporated. Oily 1-isobutyl-β-oxo-2-pyrrolopropionitrile is obtained.

Example X5;

To a solution of 1.6 g of 1,3,5-trimethyl-4-ethoxycarbonyl-3-oxo-2-pyrrolopropionitrile in 30 ml of dry toluene and 0.8 g of anhydrous triethylamine are added, with stirring, 0.8 g phenyl isocyanate. The mixture is heated on a steam bath for 10 minutes and allowed to stand at room temperature overnight. The mixture is then evaporated, the residue is dissolved in methanol and treated with 2 ml of 5N hydrochloric acid and 200 ml of water. The resulting crystals are separated, washed with water, triturated with a mixture of methanol and ethanol, and recrystallized from methanol. 1,3,5-Trimethyl-4-ethoxycarbonyl-8-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 164-166 °.

In a similar manner, 1,3,5-trimethyl-4-ethoxycarbonyl-8-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolopropionitrile, m.p. 178-179 °, and 1,3,5-trimethyl-4-ethoxycarbonyl-g-oxo-α- (p-chlorophenylcarbamoyl) -2-pyrrole-propionitrile, m.p. 238-241 ° (with decomposition).

23 71 1 29 The starting material is prepared as follows: To a suspension of 3.6 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and 50 ml of dimethylformamide are added portionwise, with stirring, 16 g of 3,5-dimethylpyrrole-2.4 -dicarboxylic acid diethyl ester in 25 ml of dimethylformamide. After consumption of sodium hydride, 40 ml of methyl iodide are added and the mixture is allowed to stand overnight at room temperature. The mixture is then treated with water, the solid obtained is separated off and, in order to remove excess methyl iodide, air-dried. The solid is washed with water, dried and recrystallized from ethanol. 1,3,5-Trimethyl-pyrrole-2,4-dicarboxylic acid diethyl ester is obtained.

A solution of 13.9 g of the latter compound in 30 ml of acetonitrile and 30 ml of dimethylformamide is added, with stirring, to a suspension of 5.5 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and suspended in 60 ml of dimethylformamide. The mixture is heated on a steam bath for 15 minutes and the resulting solution is allowed to stand overnight. The mixture is then treated with water, the aqueous solution is filtered and acidified with 5N hydrochloric acid. The precipitate is separated, washed with water, triturated with ethanol and recrystallized from ethanol. 1,3,5-Trimethyl-4-ethoxycarbonyl-β-oxo-2-pyrrolopropionitrile is obtained, melting at 105-107 °.

Example 16;

A solution of 0.3 g of 5- (1-methyl-2-pyrrolyl) -4-phenylcarbamoyloxazole in 10 ml of a 5% aqueous sodium hydroxide solution in as little ethanol as possible is heated on a steam bath for 5 minutes. The solution is then filtered and acidified with 5N hydrochloric acid. The resulting crystals are separated, washed with water and triturated with methanol. 1-Methyl-g-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 170-172 °. The product is identical to the product of Example 1.6, 8 or 9.

The starting material is prepared as follows: To a solution of 17 g of 1-methylpyrrole in 400 ml of 1,2-dichloroethane is added portionwise, with stirring and cooling at 10-15 °, first 28 g of anhydrous aluminum chloride. 27 g of malonic acid ethyl ester chloride in 50 ml of dichloroethane are then added in such portions that the temperature is maintained at 10-15 °. The mixture 24 71 129 is stirred for 3.5 hours and then allowed to slowly rise to 32 °. The reaction mixture is allowed to stand at room temperature overnight, treated with water and shaken. The organic layer is separated, washed twice with water, dried and evaporated. The residual dark brown oil is distilled and the fractions boiling at 105-122 ° and 0.25 mmHg are collected. 1-Methyl-6-oxo-2-pyrrolopropionic acid ethyl ester is obtained.

A mixture of 3.6 g of the latter compound and 3.9 g of N, N'-diphenylformamide is heated at 145-165 ° for 2.5 hours. The resulting, crumbly, glassy mass is ground, triturated with diethyl ether and recrystallized from ethanol-acetic acid ethyl ester. 1-Methyl-β-oxo-α-anilino-methylene-2-pyrrolopropionic anilide is obtained, melting at 178-180 °.

A mixture of 1.4 g of the latter compound, 1.1 g of hydroxylamine hydrochloride, 1.2 g of pyridine and 150 ml of ethanol is refluxed for 7 hours. The reaction mixture is allowed to stand overnight, filtered, evaporated and the residue is treated with water. The resulting orange oil crystallizes on standing. The precipitate is separated, washed with water and recrystallized from ethanol. 5- (1-Methyl-2-pyrrolyl) -4-phenylcarbamoyl-isoxazole is obtained, melting at 100-103 °.

Example 17;

To a suspension of 1 g of 1,3,5-trimethyl-β-oxo-2-pyrrolopropionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triethylamine are added, while stirring, 0.75 g of phenyl isocyanate. The mixture is heated on a steam bath for 5 minutes and allowed to stand at room temperature overnight. Filter, dissolve the residue in methanol and acidify the solution with 1N hydrochloric acid. The resulting precipitate is separated, dissolved in 1N aqueous sodium hydroxide solution, reprecipitated with 5N hydrochloric acid and washed with water. 1,3,5-Trimethyl-8-oxo-α-phenylcarbamoyl-2-pyrrolopropionitrile is obtained, melting at 172-174 °.

The starting material is prepared as follows: A mixture of 11.9 g of 1,3,5-trimethylpyrrole-2,5-dicarboxylic acid diethyl ester and 50 ml of concentrated sulfuric acid is heated on a steam bath for one hour. The resulting solution is poured onto ice, the precipitate is separated and washed with water. It is then dissolved in aqueous sodium carbonate solution, the solution is filtered and the filtrate is acidified with 5N hydrochloric acid. The precipitate obtained is separated, washed with water, dried and recrystallized from ethanol. 1,3,5-Trimethyl-2-carbethoxypyrrole-4-carboxylic acid is obtained, melting at 797-198 °, with decomposition.

7.5 g of the latter compound are heated under reflux for 15 minutes at 235-240 ° and then cooled. The residue is dissolved in petroleum ether, the solution is filtered and evaporated. 1,3,5-Trimethyl-pyrrole-2-carboxylic acid ethyl ester is obtained, melting at 38-40 °. (The product is described in U.S. Patent 2,479,972 with a boiling point of 102-108 ° / 3-4 mmHg.).

A solution of 4 g of the latter compound in 10 ml of acetonitrile is added, with stirring, to a suspension of 2 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and suspended in 15 ml of dimethylformoform. The mixture is heated on a steam bath for 25 minutes and allowed to stand for 3 hours at room temperature. Water is added to the mixture, the aqueous solution is extracted with diethyl ether and acidified with 5N hydrochloric acid. The crystals are separated, washed with water, dried and recrystallized from ethanol while adding activated carbon. 1,3,5-Trimethyl-β-oxo-2-pyrrolopropionitrile is obtained, melting at 106-107 °.

In a similar manner, 1,3,5-trimethyl-β-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolopropionitrile is obtained, which is recrystallized from methanol-ethanol (1: 1) and then melts at 184-186 °. .

Example 18;

A suspension of 1 g of 1,2,5-trimethyl-8-oxo-3-pyrrole-propionitrile in 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenyl isocyanate and heated on a steam bath for 5 minutes. until the solid is dissolved. The mixture is allowed to stand overnight, the precipitate obtained is separated, dissolved in methanol and the solution is added to a mixture of 3 ml of 5N hydrochloric acid and 250 ml of water. The crude product is separated, washed with water, dissolved in 5% aqueous sodium hydroxide solution, filtered and the alkaline filtrate is acidified with 5N hydrochloric acid. The precipitate is separated, washed with water, air-dried and recrystallized from ethanol. 1,2,5-Trimethyl-β-oxo-α-phenylcarbamoyl-3-pyrrolopropionitrile is obtained, melting at 158-160 °.

In a similar manner, crude 1,2,5-trimethyl-8-oxo-α- (p-fluorophenylcarbamoyl) -3-pyrrolopropionitrile is obtained.

It is dissolved in aqueous sodium hydrogencarbonate solution, precipitated with 5N hydrochloric acid and recrystallized from ethanol. Mp 171-172 °.

The starting material is prepared as follows: A solution of 7.6 g of 1,2,5-trimethylpyrrole-3-carboxylic acid ethyl ester (Ber. 56, 2374 (1923), melting point 65-66 ° after recrystallization from methanol) in 20 ml of acetonitrile, is added to a suspension of 4 g of 50% sodium hydride in mineral oil and 11 ml of dimethylformamide. The mixture is heated on a steam bath for 20 minutes while stirring and the resulting suspension is allowed to cool to room temperature within 90 minutes. The suspension is poured into 200 ml of ice water, the alkaline aqueous solution is filtered and the filtrate is acidified under ice-cooling with 18% hydrochloric acid. The precipitate is separated, washed with water and air-dried, triturated with diethyl ether and recrystallized from methanol. 1,2,5-Trimethyl-β-oxo-3-pyrrole-propionitrile is obtained, melting at 140-141 °.

Example 19: Starting from equivalent amounts of the corresponding starting materials, according to the above examples, in particular Examples 1, 4, 8 and 9, the following compounds of formula (II) are also prepared in which R 2 = R 3 = R 4 = H · iNo. [R. ΪΓ Z '' recrystallized j 1 4 5 re-sul.p.

“| CH 2 -CH 3 6-CH 3 1 of ethanol 170-171 2 J CH 3 -F H of ethyl acetate 191-192 3 | CH3-C1H ethyl acetate 192-193 4 ch3 4-C1 H from ethyl acetate 205-207: 5 ί CH 3-CF H! from methanol 185-186 6 l CH_ 2-F 4-F from methanol 136-138 j

! 3 I

S 7 CH 4 -F 3 -Cl, from ethyl acetate 215-216 '3 I: I 8 CH 3 2 -Cl I 4-Cl! from ethyl acetate 160 to 162 I g CH 3 -Cl 4 -Cl! dimethylformamide 217-219 3 j! J10 j | 4-F H of methanol 156-157 ill C, H, 4-Cl H: ethanol from 160-161 i

t 3 I I

S12 l-butyl 4-F H from methanol 162-163 L

Claims (2)

27 71 1 29 Claim; Process for the preparation of therapeutically active substituted 3-oxo-α-phenylcarbamoyl-pyrrolopropionitriles of general formula (I) of CN H R - fl- / 4 * 1 R> \ 4-CO-CH-CON-Ph (I), 2 R 1 is wherein R 1 is C 1 -C 2 alkyl, R 2 is hydrogen or C 1 -C 2 alkyl, R 3 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 carbalkoxy, R 4 is hydrogen or C 1 -C 2 alkyl; alkyl and Ph represent phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from C1-C2-alkyl, C1-C2-alkoxy, C1-C2-alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or C1-C2-alkyl; C2-alkanoylamino; for the preparation of these compounds in the enol form, for the preparation of their eno-C 1 -C 4 alkyl ethers or their enol-C 1 -C 4 alkanoyl esters or their base salts, characterized in that a) compounds of the formulas r - -A and 4-CO-CH, -CN and OC = N-Ph h 1, / 2 R 1 where R 1, R 2, R 3, R 4 and Ph have the same meaning as above, or b) condensing compounds of the formulas 28 71129 ^ O-CH-COX and H-NH-Ph 2. I f CN R1 wherein X represents lower alkoxy, lower alkanoyloxy or halogen and R1, R2, R3, R4 and Ph have the same meaning as above and / or c) condensing the compounds, of the formulas R, -fl-L · ·, 1 '5 «CH2“ CON-Ph 2. II 1 CN H R 1 wherein Y represents lower alkoxycarbonyl, halocarbonyl or cyano and R 1, R 2 / R 3, R 4 and Ph have the same meaning as above and the resulting imine is hydrolysed, or d) a compound of formula! - CONH-Ph 2 V 'fi \ ./ H * 1 wherein R 1, R 2, R 3, R 4 and Ph have the same meaning as above, isomerized with a strong base »and the enol obtained is converted, if desired, into an enol C 1 -C 4 alkyl ether or an enol C 1 -C 4 alkanoyl ester and / or, if desired, the enol obtained is converted with the base into the salt tri s · -enol salt to the free enol or the second base salt, and / or the mixture of isomers obtained is, if desired, separated into the individual isomers. 11 71129 29 Patentkrav? For the preparation of a therapeutically active substituent 3-0x0 - «- phenylcarbamoyl-pyrrolpropionitrile with the formula (I) CN H R 2 Y R 1 is flash C 1 -C 4 alkyl, R 2 is C 1 -C 2 alkyl, R 3 is C 1 -C 2 alkyl or C 1 -C 2 carbalkoxy, R 4 is C 1 -C 2 alkyl and Phenyl is phenyl substituted with 1 or 2 substituents 1, 2 or 2, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or C 1 -C 2 alkanoylamino; in the case of an enol form, an enol-C1-C4-alkyl ether or an enol-C1-C4-alkanoyl ester or an ester having a base, the same as in the form, 4-CO-CH, -CN and OC = N-Ph 2 V 2 Ri i vilka R ^, R2, R3, R4 och and Ph betecknar decamma som ovan, förenas, eller b) föreningarna med formlerna