FI78465C - Process for the preparation of therapeutically active beta-oxo-alpha-carbamoylpyrrole propionitriles - Google Patents

Description

73465

Process for the preparation of therapeutically active β-oxo-α-carbamoyl-pyrrolopropionitriles - For the preparation of therapeutically active β-oxo-α-carbamoyl-pyrrolopropionitriles

Finnish patent 71129 describes β-oxo-α-phenylcarbamoyl-pyrrolopropionitriles which are substituted in the 1-position of the pyrrole ring by lower alkyl or phenyl-lower alkyl and have anti-inflammatory, antiarrhythmic and immunopotentiating properties.

The present invention is based on the object of preparing novel compounds which can be used in the treatment of inflammatory diseases, such as rheumatoid arthritis, and in particular osteoarthritis, and which also have analgesic activity.

The object is solved according to the invention by preparing new analgesic, anti-inflammatory, anti-arterial and immunopotentiating β-oxo-α-carbamoyl-pyrrolepropionitrile compounds which are unsubstituted in the 1-position of the pyrrole residue.

The invention relates to a process for the preparation of therapeutically active - (optionally substituted phenylcarbamoyl) -pyrrolepropionitriles which are unsubstituted in the 1-position of the pyrrole ring and which have the formula I

, __ / \

it ”R2 ii - + - R

1 »'J — C0-CH-C0NH-> x * · 3 (i) PV' 'p I LN K4

B

or to prepare tautomeric forms thereof, wherein each of R 1 and R 2 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 carbalkoxy, each of R 3 and R 4 is hydrogen, C 1 -C 4 alkyl , C 1 -C 4 alkoxy, hydroxy, halogen or 2 78465 trifluoromethyl, for the preparation of their salts, their lower alkyl enoethers or lower alkanoyl enol esters.

Very preferred are the formula II

> + mi Y -

B

and tautomeric forms thereof, wherein each of R 1 and R 2 represents hydrogen or (C 4 -C 31 alkyl), and of each of the symbols R 3 and R 4 represents hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl, and their salts, especially their therapeutically useful salts.

Other preferred compounds are those compounds of formula II in which each of R 1 and R 2 represents hydrogen, each of R 3 and R 4 represents hydrogen, alkyl, fluorine, chlorine or trifluoromethyl having up to 4 carbon atoms, or their salts, in particular their therapeutically useful salts.

Very preferred are compounds of formula II, wherein each of R 2 and R 2 represents hydrogen and each of R 3 and R 4 represents hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, or salts thereof, especially therapeutically useful salts, preferably sodium, potassium. , calcium, triethylammonium or tris- (hydroxyethyl) ammonium salts.

Particularly preferred are compounds of formula II in which at least one of the symbols R3 and R4 is other than hydrogen and is in the para-position of the phenyl ring, and their salts, in particular their therapeutically useful salts, preferably sodium, potassium, calcium -, triethylammonium or tris (hydroxyethyl) ammonium salts.

The general definitions used herein have the following meanings in the context of the present invention.

The C 1 -C 4 alkyl group preferably contains 1 to 4 carbon atoms and represents, for example, ethyl, propyl, butyl or, preferably, methyl.

The C1-C4 alkoxy group denotes, for example, ethoxy, propoxy, isopropoxy or, preferably, methoxy.

Halogen is preferably chlorine or fluorine, but may also be bromine or iodine.

The carbalkoxy group preferably denotes carboethoxy or carbomethoxy.

The tautomeric forms of the compounds of formula I may be represented by the corresponding formula of formula Ia

Rr1 is a human enol structure in which the symbols R 1, R 2, R 3 and R 4 have the meanings given above for the compounds of formula I and are in equilibrium with these compounds.

The compounds of formula I which are in equilibrium with their tautomeric forms have an acidic nature. They form lower alkyl enol ethers, lower alkanoyl enol esters and salts as derivatives of the enol tautomeric structure of formula Ia. Salts formed with therapeutically useful bases are derived, for example, from alkali metal, alkaline earth metal, copper or zinc hydroxide, ammonia, mono-, di- or tri- (lower alkyl or hydroxy-lower alkyl) -5 amines, monocyclic amines or alkylenediamines. Such salts are, for example, sodium, potassium, magnesium, ammonium, mono-, di- or tri- (methyl, ethyl or hydroxyethyl) -ammonium, pyrrolidinium, ethylenediammonium or morpholinium salts or their various hydrates. .

The compounds according to the invention have valuable pharmacological properties, primarily anti-inflammatory, analgesic (antinosiseptic), antirheumatic, immunopotentiating and antiarthritic effects. These can be demonstrated in in vitro and in vivo experiments. In the latter, mammals, e.g., rats, guinea pigs, or dogs, are preferred test subjects. The compounds of the invention may be administered enterally, preferably orally, parenterally, e.g. subcutaneously or intravenously, or topically, e.g. in the form of solutions in water or oil, or in the form of suspensions containing starch. The dose used may be about 0.1 to 100 mg / kg / day, preferably about 1 to 50 mg / kg / day. The tests selected for said effects are either classical test methods, e.g., the rat carrageenan paw edema or adjuvant arthritis test, the canine Synovitis test or the test for interpreting ultraviolet light-produced erythema, or modern test methods. These include neutral protease inhibition (disclosed in Arthritis Rheum. V7, 47 30 (1947)) or leukocyte chemotaxis inhibition (Ann. N.Y.Acad.

Sci., 256, 177 (1975)). Other methods include reduction of neutrophilic adherence (Amer. J. Med. £ 59, 597 (1976)) or inhibition of prostaglandin synthetase as described in Biochem. _H), 2372 (1971); or phenyl-35 quinone writhing test.

5 7846S

Immunopotentiating effects are observed in BCG-immunized animals in vitro or in vivo.

The improvement in cell-mediated immunity is determined in vitro by measuring the increased chemotaxis of monocytes.

5 Male Charles River rats weighing 250-300 g are immunized by intradermal injection of 0.1 ml of Bacillus Calmette Guerin (BCG) vaccine. After one week, the experimental animals are injected intraperitoneally with 10 ml of 10 sterile 2% rice-starch solution to trigger macrophage accumulation. On day 11 after immunization, animals are sacrificed and peritoneal macrophages are harvested in 20 ml of Gey's buffered saline containing heparin (25 units / ml). The cells are centrifuged for 10 minutes at 1000 rpm, washed with 50 ml of Gey's solution at the same speed and time, and then suspended in Gey's solution containing 0.1% human serum albumin to give a concentration of 2x 106 cells / ml.

_2

Test substances are used to prepare 1 x 10 molar solutions in 20 dimethylacetamide. Subsequent dilutions are made with Gey's solution and these are finally added to the above-mentioned cell -5 -5-6 -7 suspension to achieve suitable final concentrations of 10, 10, 10 and 10 molar. The suspensions are placed in the top of the modified Boyden chemotaxis chambers, keeping said test substances together with the cells. Rat serum activated with Escherichia coli lipopolysaccharide (Difco) (1/10 dilution at pH 7.1) is used as the chemotactic agent. This serum is filled into the lower part of said chambers. The chamber cell-containing portion 30 is separated from the chemotactic solution by an 8 micron cellulose filtration membrane.

6,73465

Three parallel chambers are prepared and incubated for 5 hours at 37 ° C. Cell suspensions that do not contain the test compound are used to control cell progression. After incubation, the filters are removed, fixed and stained with iron hematoxylin according to Weigert.

The four fields on the underside of the filter are examined from microscopic at 320x magnification. The average of the number of neutrophils counted in these four fields is used as an index of chemotactic activity.

The improvement in cell-mediated immunity is measured in vivo in BCG-immunized arthritic rats by measuring the slowing of the hypersensitivity reaction substantially according to Current Therapeutic Research 3j), p. 34 (1981).

Male Charles River rats weighing 325-300 g are sensitized by injecting 250 μg of Mycobacterium tuberculosis (Difco) suspended in Freund's incomplete adjuvant into the base of the right hind paw of each test animal. Animals are immunized intradermally on day 18 after adjuvant injection with 0.1 ml of BCG vaccine. The active ingredient is administered orally in a corn starch suspension. Control animals are treated exclusively with corn starch. All animals are tested on skin 29 by intradermal administration of 10 μg PPD (purified protein derivative) to induce skin reactions. The diameter of the erythema and the curing reaction are measured 24 hours after antigen treatment. A decrease in the diameter of the erythema indicates improved cellular immunity.

The carrageenan paw edema test is performed in rats for anti-30 inflammatory activity as follows:

One hour after oral administration of the active substance, 0.1 ml of carrageenan 7 78465 (18%) is injected into the base of the hind paw. At specified times, the difference in swelling between the treated and undamaged paw is then measured by mercury transfer.

The conventional adjuvant-5 arthritis assay for anti-arthritic activity is performed essentially as described in Proc. Soc. Exp. Biol. Med. 137, 506 (1971).

Phenyl-p-benzoquinone - induced analgesic (antinoseptic) effect Writhing test is performed according to J. Pharmacol Exp. Therap. 125, 237 (1959) in 10 mice.

Examples of the invention include the β-oxo-α- (phenylcarbamoyl) -β- (2-pyrrolyl-propionitrile) of Example 1 and the β-oxo-α- (4-chloro-phenyl) -β-pyrrolyl) -propionitrile of Example 2, which guarantee 46 or equivalent

15 63% protection at an oral dose of 100 mg / kg in rats against carrageenan-induced edema 3 hours after administration. Similarly, the β-oxo-α- (2/4-difluorophenylcarbamoyl) -3- (2-pyrrolyl) -propionitrile of Example 3 affords 33% protection at a dose of 25 mg / kg / p.o.

Further, the compounds of the invention, e.g. the above-mentioned compounds of Examples 1, 2 and 3, are active in a conventional adjuvant arthritis test in rats at a dose of 25 mg / kg / p.o. and provide 47, 58 or resp.

55% protection.

The immunopotentiating effect of the compounds of the invention is indicated by the fact that e.g. the above-mentioned compounds of Examples 1 and 2 have a significant effect in a skin test in BCG-immunized adjuvant arthritis rats at a dose of 25 mg / kg / p.o.

8,78465

The compounds of the invention are also active in a cartilage synovial tissue co-culture system, a cartilage degeneration study model. This in turn can lead to their effect on osteoarthritis. The model is formed as follows:

In vitro proteoglycan corrosion of bovine nasal septal cartilage is labeled glycosaminoglycan 35 in vitro. To this end, the cartilage plates are incubated in sulphate-free medium with 35 S-sodium sulphate. 35 S S-labeled cartilage plates are then co-cultured with normal synovial tissue tissue cultures for 4 days on "Multi-Well" tissue culture plates. At the end of this incubation period, the radioactivity is measured in 100 ul of medium. The cartilage plates are then hydrolyzed and the radioactivity in them is determined. From this it can be calculated which part of the ^ S-labeled glycosamino-glycans is transferred to the medium during co-culture; by comparing treated and untreated (= control) cultures, the percentage inhibition of marro degradation can be calculated.

Examples according to the invention are the β-oxo-α- (phenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile according to Example 1, the β-oxo-α- (4-chlorophenylcarbamoyl) -3- (2- pyrrolyl) propionitrile and the β-oxo-α- (2,4-difluorophenylcarbamoyl) -25 β- (2-pyrrolyl) propionitrile of Example 3 which inhibit the degradation of cartilage in the concentration range of about 10 μM to 10 μM .

Due to the above-mentioned advantageous properties, the compounds of the invention can be used as analgesic, anti-inflammatory, antiarthritic and immunopotentiating agents and can be used e.g. for the treatment of various pain conditions and inflammatory diseases, e.g. rheumatoid arthritis and osteoarthritis in mammals.

Comparative test report

9 7346S

A. Compounds compared: A.1. The compounds of this invention __ y * \ 5 · —COCH — CONH- · ^ ^ “Rj Ϊ h '

Compound r3

I (Example 1) H

II (Example 5) p-F

A. Compounds according to reference publication 71 71129 ♦ * —COCH — CON'H- ΐ.

X

tn 3

Compound r3

III (Example 1) H

IV (Example 5) p-F

B. Analgesic (antinociceptive effect)

The analgesic (antinociceptive) effect is tested for phenyl-p-benzoquinone-induced writhing symptoms [Hendershot and Forsaith: J. Pharmacol. Exp. Therap. 125, 237 (1959)]. This method is modified as follows:

Mice (MAG, 18-25 g) first fasted overnight are dosed with the active ingredient dissolved in 0.75% methylcellulose 55 minutes after induction of writhing symptoms. Writhing symptoms are induced by injection i.g. 0.25 ml of a suspension of phenyl-p-benzoquinone (0.02-0.03%) in tragacanth (0.4%). After 5 minutes, counting of writhing-induced irritation movements is started by observation for 10 minutes. The decrease in the frequency of ίο 7 8 4 6 5-induced stimulation movements induced by 0.02% phenyl-p-benzoquinone compared to the control is shown in Tables 1 and 2.

Score:

Table l

Compound Dose Mice Writhing-induced mg / kg number of irritant movements p.o. decrease in% I (FI 841215) 2 8 -26 6 8 _701 20 8 _971 III (FI 71129) 68 +9 20 8 -52 * 60 8 -891 * significant difference compared to control p <0.05 ** significant difference compared to control p <0.01

Table 2

Compound Dose Mice Writhing-induced mg / kg number of irritant movements p.o. decrease in% I (FI 841215) 28 - 8 6 8 -701 20 8 _921 III (FI 71129) 68 - 2 20 8 +34 60 8 -831 significant difference compared to control p <0.01 n 78465 0. 03. The decrease in the frequency of stimulation movements induced by phenyl p-benzoquinone compared to the control is shown in Table 3.

Table 3

Compound Dose Mice Writhing-induced mg / kg number of irritant movements p.o. reduction in% I (FI 841215) 1 16 - 33 5 24 - 78 50 8 -100 III (FI 71129) 5 24 - 28 50 24 - 80 C. Conclusions 1. The results in Table 1 show that the compound I according to the invention at a dose of 6 mg / kg po has a substantially better effect (-70%) than the known compound III at a dose of 20 mg / kg p.o. (-52%) and compound III at the same dose of 6 mg / kg has no effect.

2. The results in Table 2 show a clear superiority of the compound II according to the invention, which compound already at a dose of 6 mg / kg p.o. reduces by 70% the account of irritant movements, while the known compound IV has no effect at all at the same dose.

3. The results in Table 3 show that Compound II of the invention has the same effect at a dose of 5 mg / kg p.o. than the known compound IV at a dose of 50 mg / kg p.o.

The compounds according to the invention are prepared in a manner known per se, e.g. in such a way that 78465 12

a) condensing of formulas III and IV

* - * ^ 3 \ · - · R1 HH R2 (HI) and 't ^ -SC-O (IV) * w \ „Y coch2-cn R4 compounds in which the formulas R1, R2, R3 and R4 have the same meaning as above, or b) a compound of formula VI RHf f-R2 (VI) • ·

^ XCO2H-C00H

or a reactive functional derivative thereof is condensed with an amine of formula VII / -V * 3 HNH-. ((VII) R4 wherein Rx, R2, R3 and R4 are as defined above, or c) a compound of formula IX RHf f-R2 <IX > • · ^ ncooh

or a reactive functional derivative thereof is condensed of formula X.

13 78465 / - / 3 9h2-co — nh— · (* · (x) iN * = * \, wherein, R2> R3 and R4 have the same meaning as above, and the compound of formula I obtained is, if desired, converted into another and / or the resulting enol is optionally converted to an enol lower alkyl ether or enol lower alkanoyl ester, and / or the resulting enol is optionally converted to a base salt or the resulting enol salt to the free enol or base to another salt, and / or the resulting mixture of isomers is separated into individual isomers if desired.

The condensation of process a) in which an isocyanate of formula IV is reacted with a pyrroloylacetonitrile of formula III can be performed according to U.S. Patent No. 4,256,759. In this case, work is carried out in the presence or absence of an inorganic or organic base, e.g. sodium hydride or triethylamine, or in the presence of a polar solvent, e.g. ether, e.g. diethyl ether, ethylene glycol dimethyl ether (glyme) or tetrahydrofuran and / or amide or sulfoxide, e.g. or without this, preferably in the temperature range of 25 to 100 ° C, especially at elevated temperatures, e.g. about 150 ° C, when no base is used.

The above method a) is carried out according to the invention as follows:

Said nitrile is treated with a small molar excess of anhydrous trialempalkylamine, preferably triethylamine, and then a molar equivalent of the appropriate enyl isocyanate (Ph-N = C-O) or a polar solvent thereof, e.g., dimethyl sulfoxide or glycine is added. . The reaction mixture is stirred for about 2-12 hours at room temperature and its volume is reduced by heating at not too high temperatures. The residue is treated with an excess of dilute acid, e.g. 0.1-0.3 normal hydrochloric acid. The crude product obtained is extracted or separated, washed with water, dried, triturated and / or recrystallized from suitable solvents. Such solvents include lower alkanols, lower alkanones, lower alkyl ethers and / or lower alkyl lower alkanoates, e.g. methanol, acetone, diethyl ether and / or ethyl acetate.

The starting materials of the formulas III and IV are known or can be prepared according to methods known per se. Thus, for example, compounds of the formula III can be obtained in Ber. 113, 3675 (1980), Chem. Abstracts 29, 2164 and Ber. 55, 2390 (1922).

In process b) the protecting group on the nitrogen atom of the pyrrole ring is e.g. optionally substituted benzyl, optionally substituted carbobenzyloxy, lower alkanoyl (e.g. acetyl), trifluoroacetyl, di-lower alkylamino (e.g. dimethylamino), tetrahydropyranyl, lower alkoxymethyl (e.g. lower alkoxycarbonyl (e.g. tert-butyloxycarbonyl).

The condensation according to process b) is carried out according to U.S. Patent 4,256,759, preferably at a temperature between room temperature and 150 ° C, with equivalent amounts of reagent (when using a reactive ester) or to neutralize the acid formed with an excess of amine or another base, e.g. in the presence of an amine such as tri-lower alkylamine or pyridine (when halide or anhydride is used). The lower alkanol formed in the reaction with said esters is preferably distilled off together with the diluent. Such substances are, for example, aromatic hydrocarbons, e.g. benzene, toluene or xylene. If a free carboxylic acid is used in the condensation, this is preferably carried out in the presence of a condensing agent, e.g. a disubstituted carbodiimide such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole or diethylphosphorocyanidate (diethylphosphoryl cyanide).

The starting materials of the formula VI can be prepared, for example, by reacting a compound of the formula III with a carbonic acid derivative, e.g. ethyl chloroformate. An ethyl ester of formula VI is obtained which can be converted into a compound of formula VI or another derivative thereof according to methods known per se.

The condensation according to process c), when the starting material is a reactive functional derivative of a compound of formula IX, is preferably carried out with a metallating agent, e.g. an alkali metal, metal alkoxide or hydride such as sodium hydride, potassium tert-butoxide, thallium I- in the presence of ethoxide or under phase transfer conditions, in polar solvents, e.g. 1,2-dimethoxyethane, dimethylformamide or dimethylsulfoxide, at temperatures of about 0-100 ° C, preferably 25-50 ° C.

Reactive functional derivatives of the carboxylic acids of the formulas VI, IX and XII are, for example, anhyrides, in particular mixed anhydrides, acid halides, acid azides, lower alkyl esters or activated esters. The mixed anhydrides are preferably anhydrides of a lower alkyl (ethyl, isobutyl) hemiester of povalic acid or carbonic acid. Acid halides are, for example, chlorides or bromides. Activated esters are, for example, succinimido, phthalimido or 4-nitrophenyl ester. Lower alkyl esters are, for example, methyl or ethyl ester.

78465 16

With a compound of formulas VI, IX and XII, according to the above methods, it can be carried out in the presence of a condensing agent, e.g. diethyl phosphorocyanidate, in the presence of a base, e.g. triethylamine, in a polar solvent, e.g. dimethylformamide or methylene chloride.

The compounds of the formula I obtained can be converted into one another in a manner known per se. The enols thus obtained, for example, can be preferably etherified 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 alcohol used as a solvent, e.g. a lower alkanol. Salts can be precipitated from alcoholic solutions with said ethers, e.g. diethyl ether or tetrahydrofuran. Work at reasonable temperatures, eg below 100 ° C. The resulting salts can be converted, as mentioned above, by treatment with acids or bases to the free compounds. These or other salts can also be used to purify the resulting compounds. Due to the close relationship between the new compounds in free form and those in the form of their salts, free compounds and salts are to be understood above and below as meaning and, where appropriate, possibly also the corresponding salts or free compounds.

The starting materials are known or, if new, can be prepared by methods known per se, e.g. as indicated in the referenced literature or examples.

17 78465

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

The invention also relates to variations of the present process 10 according to which an intermediate obtained in a step of the process is used as starting material and the remaining steps of the process are carried out, or the process is cut off in a step, or in which the starting material is formed under reaction conditions or in the form of said enols, a salt or a reactive derivative, preferably an alkali metal or trialkylammonium salt. The process according to the present invention preferably uses starting materials which lead to the compounds initially described as being of high value.

The invention also relates to novel intermediates and methods for their preparation.

Depending on the choice of starting materials and methods, new compounds are obtained in the form of isomers, tautomers or mixtures thereof, provided that they are possible.

The compounds and their salts can also be obtained in the form of their hydrates or they can contain other solvents used for crystallization.

The pharmacologically acceptable compounds of the present invention are used in the preparation of pharmaceutical preparations containing an effective amount of 18,784,65 active ingredients together or in admixture with carriers suitable for enteral, parenteral or topical use. Preferably tablets or gelatin capsules are used which contain the active ingredient together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or its with salts, e.g. magnesium or calcium stearate and / or polyethylene glycol; the tablets likewise contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, e.g. starch, agar or agar, agar, algin, adsorbents, colorants, flavors and sweeteners. Formulations for injection are preferably isotonic aqueous solutions or suspensions, and suppositories or topical liquid creams are primarily fat emulsions or suspensions. The pharmaceutical preparations 20 may be sterilized and / or may contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, if desired containing other pharmacologically valuable substances, are prepared in a manner known per se, e.g. according to conventional mixing, granulating and granulating methods, and contain from about 1 to about 75%, in particular from about 1 to about 50%. active substance. Single doses of mammals weighing about 50 to 70 kg may contain about 10 to 200 mg of active ingredient.

The following examples illustrate the invention and are not intended to limit the invention. Temperatures are given in degrees Celsius and parts are by weight. Unless otherwise specified, evaporation of the solvents is performed under reduced pressure, preferably at about 15 to 100 mm Hg.

Example 1:

A solution of 3.1 g of pyrroloylacetonitrile in 25 ml of 5 Glyme (ethylene glycol dimethyl ether) and 2.7 g of anhydrous triethylamine is treated with 3.0 g of phenyl isocyanate. After a moderately exothermic reaction, the reaction mixture is allowed to stand overnight. Most of the solvent is evaporated off and the residue is taken up in water and 10 ml of 10% sodium hydroxide solution. The aqueous alkaline solution is washed with ethyl acetate and acidified with 6N hydrochloric acid. The product is separated, washed with water, dried and recrystallized from ethanol. G-Oxo-α- (phenylcarbamoyl) -β-15 (2-pyrrolyl) -propionitrile is obtained, melting at 207-209 ° C.

This is a compound of formula II wherein hydrogen is indicated.

The starting material is prepared as follows:

Dry hydrogen chloride is introduced for 20 minutes into an ice-cooled solution of 30 g of pyrrole and 30 g of malonic acid nitrile in 800 ml of dry ether. The reaction mixture is allowed to stand for a few hours and the solution is filtered. 65 g of an orange-brown, water-soluble solid are obtained. A solution of 50 g of this intermediate (enamine-25-nitrile hydrochloride) in 600 ml of water is coated with 400 ml of ethyl acetate and stirred for 2.5 hours at room temperature. The organic layer is separated, dried over magnesium sulfate and evaporated. Crystals are obtained which melt at 77-79 °. Another amount of this product is obtained by heating the aqueous layer on a steam bath for 30 minutes and extracting with ethyl acetate. Recrystallization from water affords 20,78465 2-pyrroloylpropionitrile, m.p. 79-81 °.

Example 2;

To a solution of 6.7 g of 2-pyrroloylacetonitrile in 25 ml of Glyme and 5.5 g of triethylamine is added a solution of 8.6 g of 4-chlorophenyl isocyanate in 25 ml of Glyme. After the exothermic reaction, the mixture is allowed to stand overnight. A portion of the solvent is evaporated off and the cooled residue is poured into a solution of 10 ml of 6N hydrochloric acid in 250 ml of water. Add a little 10 methanol to the mixture and separate the crude material. It is dissolved in dilute sodium hydroxide solution, treated with activated carbon, filtered and acidified with 6N hydrochloric acid. The reprecipitated product is separated off, washed with water and triturated with methanol. 15 Sp. 219-221 °. Recrystallization from methanol gives β-oxo-α- (4-chlorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile, m.p. 223-225 °.

Example 3;

By reacting 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of triethylamine (2.0 g) in 25 ml of glyme and isolating according to the above examples, then triturating with ethanol and recrystallization from ethanol gives β-oxo-α- (2,4-difluorophenylcarbamoyl) -β-25 (2-pyrrolyl) -propionitrile, m.p. 169-171 °.

Example 4;

By reacting 2.0 g of 2-pyrroloylacetonitrile with 3.0 g of 3- (trifluoromethyl) phenyl isocyanate in the presence of triethylamine (1.8 g) in 25 ml of Glyme 30 according to the above examples and recrystallizing 21,73465 crude products from methanol β-oxo-α- (3-trifluoromethyl-phenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile is obtained, m.p. 210-212 °.

Example 5: By reacting 2.4 g of 2-pyrroloylacetonitrile with 2.5 g of 4-fluorophenyl isocyanate in the presence of triethylamine (2.2 g) in 25 ml of Glyme according to the above examples, precipitating once more from dilute sodium hydroxide solution hydrochloric acid and recrystallization from methanol gives β-oxo-α- (4-fluorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile, m.p. 233-234 °.

Example 6:

By reacting 2.7 g of 2-pyrroloylpropionitrile with 3.8 g of 3-chloro-4-fluorophenyl isocyanate in the presence of triethylamine (2.4 g) in 25 ml of Glyme and finalizing according to the above examples and recrystallizing Acetic acid ethyl ester gives β-oxo-α- (3-chloro-4-fluorophenylcarbamoyl) -8- (2-pyrro-20-yl) -propionitrile, which melts with decomposition at 257-258 °.

Example 7:

A solution of 2.1 g of 2-pyrroloylacetonitrile in 15 ml of Glyme and 1.8 g of triethylamine is treated according to the above examples with a solution of 3 g of 2,4-di-25-chlorophenyl isocyanate in 15 ml of Glyme. After a weakly exothermic reaction, a thick crystal suspension is obtained.

It is allowed to stand overnight, diluted with dry ether and filtered. The triethylammonium salt of β-oxo-α- (2,4-dichlorophenylcarbamoyl) -β- (2-pyrrolyl) -30 propionitrile in the form of an enol structure is obtained, m.p. 180-182 ° 78465 (dispersed).

A solution of the above triethylammonium salt in methanol is added to a solution of 4 ml of 6N hydrochloric acid in 250 ml of water. The free enol product is separated, washed with water and triturated with methanol, m.p. 219-221 °. Recrystallization from ethyl acetate gives β-oxo-α- (2,4-dichlorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile, m.p. 222-223 °.

Example 8: A mixture of 1.1 g of β-oxo-α-ethoxycarbonyl-β- (2-pyrrolyl) -propionitrile, 1.5 g of 4-fluoroaniline and 60 ml of xylene is refluxed for 4.5 hours. The mixture is allowed to stand and cool overnight, filtered, the solution evaporated and the product purified. The β-oxo-α- (4-fluorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile of Example 15 is obtained.

The starting material is prepared as follows: a) A solution of 2.22 g of 2-pyrrolecarboxylic acid, 8.4 ml of anhydrous triethylamine and 2.1 ml of cyanoacetic acid-ethyl ester in a sufficient amount of dimethylformamide is stirred, treated at room temperature with 2.9 g: 11a diethyl phosphorocyanidate and allowed to stand for 1.3 hours. The solution is cooled in an ice bath, treated with 50 ml of water, filtered and acidified with 6N hydrochloric acid. The precipitate obtained is separated, washed with water, dried and recrystallized from ether. 8-Oxo-α-ethoxycarbonyl-3- (2-pyrrolyl) -propionitrile is obtained, m.p. 138-139 °.

23 73465 b) 2-Pyrroloylacetonitrile is treated in the presence of triethylamine in ethylene glycol dimethyl ether with chloroformic acid ethyl ester at 50 ° C overnight and the product is purified. 8-Oxo-α-ethoxycarbonyl-B- (2-pyrrolyl) -propionitrile is obtained.

Example 9:

The following compounds of formula I can also be prepared according to the methods set forth in the above examples: N: Ο Εχ, 1 * 2 1 * 3 / R 4 9/1 H 4 -methoxy 9/3 H 4-hydroxy 9/5 3,5-dimethyl 2,4-Difluoro 9/6 3,5-dimethyl-4-carboethoxy 4-chloro 9/7 H 4-trifluoromethyl 9/8_H_4-methyl_

The pyrrole starting materials of Examples 9/5 and 9/6 are disclosed in Ber. 113 (1980), Chem. Abstr. 29, 2164 or resp. Ber. 55, 2390 (1922).

Example 10: Treatment of B-oxo-α- (2-phenylcarbamoyl) -8- (2-pyrrole-24,78465yl) -propionitrile with an equivalent amount of a concentrated aqueous or alcoholic solution of sodium, potassium or calcium hydroxide or ethoxide and evaporation the sodium, potassium or calcium salt of the corresponding compound of the tautomeric form of formula Ia is obtained to dryness, in which Py represents 2-pyrrolyl, Ph represents phenyl and R represents hydrogen.

In a similar manner, triethyl-ammonium and tris- (hydroxyethyl) -ammonium salts are prepared in equivalent amounts with triethylamine or tri- (hydroxyethyl) -amine.

Example 11: To 500 ml of ethereal diazomethane (prepared starting from 10.3 g of N-nitroso-N-methyl urea with 35 ml of 45% aqueous potassium hydroxide solution 15 and dried over potassium hydroxide tablets) is added 3 .9 g of 3-oxo-α- (phenylcarbamoyl) -3- (2-pyrrolyl) -propionitrile. When the evolution of nitrogen has ceased, the solution is filtered and evaporated. After purification, the corresponding methyl enol ether is obtained, i.e. β-methoxy-α- (phenylcarbamoyl) -20 3 '(2-pyrrolyl) -acrylonitrile.

Example 12:

To a solution of 1.6 g of cyanoacetanilide in 10 ml of dimethylformamide is added 3.4 g of potassium tert-butoxide. The stirred and cooled suspension is treated with 1.1 g of pyrrole-2-carboxylic acid in 6 ml of dimethylformamide and 1.4 ml of diethyl phosphorocyanidate (DEPC). The deep-red solution is kept in a closed container for half an hour. The reaction mixture is then treated with 80 ml of ice-cold water, filtered to remove unreacted cyanoacetanilide and acidified with 6N hydrochloric acid.

25 78 465

The precipitate obtained is separated off, washed with water and dried. The crude product is dissolved in ethyl acetate, the solution is filtered and evaporated to dryness. The product obtained is recrystallized from ethanol-ether. 6-Oxo-α- (phenylcarbamoyl) -6- (2-pyrrolyl) -propionitrile is obtained. The product is identical to the product of Example 1.

Example 13:

Protection in a conventional adjuvant arthritis test performed essentially as described in Proc.Soc.Exp.Biol.Med. 137, 506 (1971) is as follows:

Example_% - change compared to control 1 - 47 2 - 58 3 - 55 4 - 59 5 - 59 7_- 42_

Example 14;

The analgesic (antinosiseptic) effect is tested in phenyl-p-benzoquinone-induced Writhing syndrome (Hendershot and Forsaith: J.Pharmacol.Exp.Therap. 125, 237 (1959)). This method was modified as follows:

Mice fasted overnight are administered the active ingredient dissolved in 0.75% methylcellulose at doses of 1-50 mg / kg p.o. 55 minutes after Writhing-synd-Rome induction. Writhing syndrome is induced i.g. injection containing 0.25 ml of a suspension of phenyl-p-benzoquinone (0.03%) in tragacanth (0.4%). 1 minute thereafter, the counting of Writhing-induced stimulation movements begins in the observation over a period of 10 minutes.

Claims (4)

26 78465 The antinociceptive EDgg value of a test compound is the dose that reduces the frequency of induced stimuli by 50% compared to the control. A process for the preparation of therapeutically active Y 1, A, H β-oxo-α-carbamoylpyrrolepropionitriles of formula I or tautomeric forms thereof, wherein each of R 1 and R 2 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 carbalkoxy , each of R 3 and R 4 is hydrogen, C 1-4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or trifluoromethyl, for the preparation of their salts, their lower alkyl enol ethers or lower alkanoyl enol esters, characterized in that a ) is condensed of formula III and IV »* R Rl- | Compounds of R2 (III) and y - \ - N = cO (IV) Y \ / · * · COCH2 “CN R4, in which R1 # R2, R3 and R4 have the same meaning as above, or 27 78465 b) of formula VI The compound of the formula “Hf f - R2 (VI) ^ nco ^ h-cooh or a reactive functional derivative thereof is condensed with an amine of the formula vil / '' s / * 3 HNH- · '* · (VII) * 4 wherein R ^ , R 2, R 3 and R 4 have the same meaning as above, or c) a compound of formula IX “H1 II · R 2 <>> • · ncooh or a reactive functional derivative thereof is condensed of the formula X / -y * 3 CH 2 -CO-NH With a compound of formula (X) 6N * = R / 4, wherein R1 # R2, R3 and R4 are as defined above, and the compound of formula I obtained is, if desired, converted into another compound of the invention, and / or the enol obtained is converted into if desired to an enol lower alkyl ether or an enol lower alkanoyl ester, and / or the enol obtained is converted, if desired, into a base salt or the enol salt obtained into the free enol or with a base to a second salt, and / or the resulting mixture of isomers is separated into the individual isomers, if desired. Process according to Claim 1, characterized in that β-oxo-α- (phenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile or a salt thereof is prepared. Process according to Claim 1, characterized in that S-oxo -? - (4-chlorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile or a salt thereof is prepared. Process according to Claim 1, characterized in that O-oxo-α- (4-fluorophenylcarbamoyl) -β- (2-pyrrolyl) -propionitrile or a salt thereof is prepared. For the preparation of the therapeutic network B-oxo-α-carbamoylpyrrolproplonitrile with the formula I Rlt tXo-CH-COHH-'i (I) Y i, H or a tautomeric former, in which the formula E1 and R2 are used, C1 -C 4 -alkyl or C 1-4 -carboalkoxy, represented by the symbols R 3 and R 4, C 1 -C 4 -81-yl, C 1 -C 4 -alkoxy, hydroxy, halogen or trifluoromethyl, derivative, derivative enoletrar eller lägalkanoyl-enol-estrar, kännetecknat därav, att 29 7346 5 a) föreningarna med formlerna III och IV • - · R- RlHi I R2 (III) och -¾ WC-o (IV) \ / * \ x · * · Y COCH2-CN r4 is a single form of R1 # R2, R3 and R4 in the form of a quaternary, capacitor, or b) and for the formulation of VI VI — if IK (vi> • ♦ ^ CO ^ H-COOH or with a reaction function) a derivative of a condenser with an amine of formula VII HNH- · '* · (VII) \ varies R1, R2, R3 and R4 in the form of a ring as defined above, or c) a compound of formula IX • - · R1 — If f “R2 ( IX) • · Y XCOOH or react The ionic function of the condenser is derived from the condenser of formula X.