GB2127809A - Certain beta -oxo- alpha -carbamoyl- pyrrolepropionitriles - Google Patents

Description

1 GB 2 127 809 A 1

SPECIFICATION Certain P-oxo-a-carbamoyi-pyrrolepropionitriles

The present invention concerns new a-(optionally substituted phenylcarbamoyi)pyrrolepropionitriles unsubstituted at the 1 -position of the pyrrole ring, of formula 1 or tautomers thereof CN R 1 i Fy-CO-CH-CON-Ph (1) wherein Py is 2- or 3-pyrroly] unsubstituted at the 1 -position and optionally substituted at one or more of the remaining three positions by lower alkyl and/or by carboxy or lower carbalkoxy and/or by halogen; R is hydrogen or lower alkyl; and Ph is phenyl, unsubstituted or substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, lower alkyisuifinyl, lower alkylsulfonyl, hydroxy, halogen, trifluoromethyl, nitro, amino and lower alkanoylamino; salts, especially pharmaceutically acceptable salts thereof; the lower alkyl enol ethers thereof; or the lower alkanoyl enol esters thereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

More particularly the invention relates to compounds of formula i, or tautomers thereof, wherein 15 Py represents 2- or 3-pyrrolyl unsubstituted at the 1 -position and unsubstituted or substituted at one or more of the remaining three positions by one to three lower alkyl or halogen, by one carboxy or one lower carbalkoxy, or by one or two lower alkyl or halogen in addition to one carboxy or one lower carbalkoxy; R is hydrogen or lower alkyl; Ph is phenyl unsubstituted or substituted by one or two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, nitro, amino and lower alkanoylamino; salts, especially the pharmaceutically acceptable salts thereof; the lower alkyl enol ethers thereof; or the lower alkanoyl enol esters thereof.

Preferred are compounds of formula 1 or tautomers thereof, wherein Py represents 2-pyrrolyl unsubstituted or substituted at one or more of the 3, 4 and 5-positions by one to three lower alkyl groups or by one or two lower alkyl groups in addition to one carboxy or one lower carbalkoxy group at 25 the 3 or 4-positions; Ph is phenyl unsubstituted or substituted by one or two identical or different members selected from lower alkyl, halogen, trifl uorom ethyl, lower alkylthio, hydroxy and lower alkoxy; R is H or lower alkyl; salts, especially pharmaceutically acceptable salts thereof; the lower alkyl enol ethers thereof; or the lower alkanoyl enol esters thereof.

Particularly preferred are the compounds of formula 11 or tautomers thereof R,-f-I-R 2 _QR N CO-CH-CONN 1 3 1 1 H CN wherein each of R, and R, is hydrogen or lower alkyl; and each of R, and R, is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; or a salt, especially a pharmaceutically acceptable salt thereof.

Further preferred are the compounds of formula 11 wherein R, and R, are hydrogen; each of R, and 35 R4 is hydrogen, alkyl with up to 4 carbon atoms, fluoro, chloro or trif 1 uoro methyl; or a salt, especially a pharmaceutically acceptable salt thereof.

Highly preferred are the compounds of formula 11, wherein each of R, and R2 is hydrogen; and each of R, and R, is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; or a salt, especially a pharmaceutically acceptable salt, preferably the sodium, potassium, calcium, triethylammonium or tris- 40 (hydroxyethyl)ammonium salt thereof.

Particularly preferred are the said compounds of formula 11, wherein at least one of R, and R4 is different from hydrogen and is preferably located at the para-position of the phenyl ring, and salts thereof, especially the pharmaceutical ly acceptable salts thereof, preferably the sodium, potassium, calcium, triethylammonium or tris-(hydroxyethyi)ammonium salt thereof.

The general definitions used herein have the following meaning within the scope of the present invention.

The term---lower-referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.

2 GB 2 127 809 A A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example ethoxy, propoxy, isopropoxy or advantageously methoxy; a lower alkylthio group preferably contains 1-4 carbon atoms and represents advantageously methylthio or ethylthio; a lower alkylsulfinyl group preferably contains 1-4 carbon atoms and represents advantageously methyisuifinyl or ethyIsulfinyl: 5 a lower alkylsulfonyl group preferably contains 1-4 carbon atoms and represents advantageously methyisuifonyl or ethyisuifonyl.

Halogen preferably represents chloro or f luoro but may also be bromo or iodo.

Lower alkanoylarnino represents preferably acetylamino or propionylamino.

A lower carbalkoxy group represents preferably carboethoxy or carbomethoxy.

Tautomers of the compounds of formula 1 may be represented by the corresponding enol 10 structure of formula la CN R Py-C=C-C-N-Ph t ' J OH 0 0a) wherein Py, R and Ph have the meaning as previously defined for compounds of formula 1, and are in equilibrium therewith.

The compounds of formula 1, being in equilibrium with their respective tautomers, have acidic properties and form, as derivatives of the enolic tautomeric structure of formula]a, lower alkyl enol ethers, lower alkanoyl enol esters, or salts thereof. Salts formed with pharmaceutically acceptable bases, such as alkali metal, alkaline earth metal, copper or zinc hydroxides, ammonia, mono-, di- or tri lower (alkyl or hydroxya 1 kyi)a mines, monocyclic amines or alkyienediamines, are e.g. sodium, potassium, magnesium, ammonium, mono-, di- or tri-(methyi, ethyl or hydroxyethy0ammonium, pyrrolidinium, ethylenediammonium or morpholinium salts; or various hydrates thereof.

The compounds of the invention exhibit valuable pharmacological properties, primarily antiinflammatory, antirheumatic, immunopotentiating and antiarthritic activity. These can be demonstrated by in-vitro or in-vivo tests, using for the latter advantageously mammals, such as rats, guinea pigs or dogs, as test objects. The compounds of the invention can be administered to the animals either enterally, preferably orally, parenterally, e.g. subcutaneously or intravenously, or topically, for example, in the form of aqueous or oily solutions or starchy suspensions. The applied dosage may range between about 0.1 and 100 mg/kg/day, preferably between about 1 and 50 mg/kg/day. The tests chosen are among the classical assay methods for said activities, such as the carrageenin paw-edema, or adjuvant arthritis test in rats, the canine synovitis or ultraviolet erythema 30 assays, or more recent tests, such as neutral protease inhibition [described in Arthritis Rheum. 17, 47 (1 974)l or inhibition of leukocyte chemotaxis [described in Ann. N.Y. Acad. Sci., 256,177 (1975)1; or decrease of neutrophil adherence [described in Amer. J. Med. 61, 597 (1976)1; or inhibition of prostaglandin synthetase [described in Biochem. 10, 2372 (1971)1.

Immunopotentiating effects are determined in BCG-immunized animals invitro and invivo. 35 Enhancement of cell-mediated immunity is determined in-vitro as follows by treatment of increased chemotaxis of monocytes:

Male Charles River rats, weighing 250-300 g are immunized by intradermal injections of 0.1 mi Bacillus Calmette Guerin (BCG) vaccine. One week later, the animals are injected with 10 mi of a sterile 2% rice starch solution intraperitoneally, to induce the accumulation of macrophages. On day 11 after 40 immunization, the animals are sacrificed and peritoneal macrophages collected with 20 mi of Gey's buffered salt solution containing heparin (25 units/m]). The harvested cells are centrifuged at 1000 RPM for 10 minutes, washed with 50 mi more of Gey's solution at the same speed and time, and then they are resuspended in Gey's solution containing 0. 1 % human serum albumin to yield a concentration of 2 x 10' cells/mi.

The test substances are dissolved in dimethylacetamide to yield a 1 X 1 02M solution.

Subsequent dilutions are made with Gey's solution, and they are finally added to the above cell suspension to yield the appropriate final concentrations of 10', 10-1, 10- 1 and 1 O'lVI. Said substances remain with the cells after the suspensions are distributed over the upper compartment of the modified Boyden chemotaxis chambers. Escherichia coli lipopolysaccharide (Difco) activated rat 50 serum 0/10 dilution at PH=7. 1) is used as the chemotactic agent and placed in the lower compartment of said chambers. The cell compartment of the chamber is separated from the chemotactic solution by a 8 micron pore size cellulose filter membrane, the chambers are set up in triplicate and incubated for 5 hours at 371C. Cell suspensions alone, without test compound, serve as controls for cell-migration. After incubation, the filters are removed, fixed and stained with Weigert's iron hematoxylin, and four fields of the lower surface of the filter are examined microscopically at a magnification of 320. The average of the number of neutrophils counted in those four fields is used as an index of chemotactic activity.

The enhancement of cell-mediated immunity is determined in-vivo in the BCG-immunized 3 GB 2 127 809 A 3 arthritic rat by measurement of delayed hype rsensitivity reaction essentially as described in Current Therapeutic Research 30, S34 (1981).

Charles River male rats weighing 325-400 g are sensitized by intradermai injection into the right hind foot pad with 250 Ag per animal of Mycobacterium tuberculosis (Difco) emulsified in Freund's incomplete adjuvant. Animal are immunized with 0. 1 mi of BW vaccine intradermally on day 18 after adjuvant injection. Corn starch suspensions of drugs are administered orally. Control animals are dosed with comstarch vehicle only. All animals are skin-tested with 10 Aq PPD (purified protein derivative) intradermally on day 29 to elicit skin reactions. The diameter of the erythema and induration reaction is measured 24 hours after antigen challenge. An increase in the diameter of the erythema is indicative of enhanced cellular immunity.

The carrageenin paw-edema assay for antiinflammatory activity is carried out in rats as follows:

One hour after compounds are administered orally, 0. 1 mi of carrageenin (1 %) is injected into plantar area of one hind paw. Difference of swelling is measured between contralateral and injected paw by means of mercury displacement at designated times.

is The established adjuvant arthritis test for anti-arthritic activity is performed essentially as 15 described in Proc. Soc. Exp. Biol. Med. 137, 506 (1971).

Illustrative of the invention, P-oxo-a-(phenylcarbamoyl)-P-(2pyrrolyi)propionitrile of example 1 and P-oxo-a-(4-chlorophenyl)-P-(2-pyrroiiyl)propionitrile of example 2 both at a dose of 100 mg/kg/p.o. afford protection against carrageenin-induced edema in rats measured 3 hours after administration by 46 and 63% respectively. Similarly, P-oxo-a-(2,4- difluorophenylcarbamoyi)-P-(2pyrrolyl)propionitrile of example 3 at a dose of 25 mg/kg/p.o. affords 33% protection.

Furthermore the compounds of the invention, e.g. said above compounds of examples 1, 2 and 3 are active in the established adjuvant arthritis test in the rat at a dose of 25 mg/kg/p.o. (47%, 58% and 55% protection respectively).

Indicative of the immunopotentiating activity of the compounds of this invention, said compounds of examples 1 and 2 exhibit significant activity in the skin test in the BCG-immunized adjuvant arthritic rat at a dose of 25 mg/kg/p.o.

The compounds of the invention are also active in the cartilage-synovium co-culture model of cartilage matrix degradation, indicative of their effectiveness in osteoarthritis. The screen is carried out as follows:

The proteoglycan matrix of bovine nasal septum cartilage is labeled invitro by incorporation of S into glycosaminoglycan. Cartilage slices are incubated overnight in a suffate-free medium containing S-sodium sulfate. 'IS-Labeled cartilage slices are co-cultured with normal synovium explants in multiwell tissue culture plates. After 4 days incubation a 100 AI aliquot of medium is counted. Cartilage slices are hydrolyzed and a 100 pi aliquot of cartilage hydrolysate is counted. The 35 percent 35S released into the medium is determined and the percent inhibition of matrix degradation is calculated.

Illustrative of the invention, p-oxo-a-(phenylcarbamoyl)-P-(2-pyrroiyl)propionitrile of example 1, p-oxo-a-(4-chlorophenylcarbamoyi)-P-(2-pyrroiyi)-propionitrile of example 2 and P-oxo-a-(2,4- difluorophenylcarbamoyl)-P-(2-pyrroiyi)-propionitrile of example 3 inhibit cartilage matrix degradation 40 in-vitro at a concentration range of about 10-7 M to 10-5 M.

The aforementioned advantageous properties render the compounds of the invention useful as antfinflammatory, antiarthritic and immunopotentiating agents especially for the treatment and amelioration of e.g. inflammatory disorders, such as rheumatoid arthritis and osetoarthritis in mammals, including man.

The compounds of formula 1 are prepared according to conventional methods, for example, by a) condensing the compound of the formulae Ill and IV Py-COCH,-Cl\1 (111) and Ph-N=C=O OV) and, if desired, N-substituting a resulting compound with a reactive ester of ROH, wherein Py, Ph and R 50 have meaning as previously defined; or b) removing the group Z from a compound of the formula V CN R 1 1 Z-Py-CO-CH-CON-Ph (V) wherein Py, R and Ph have meaning as described above, and Z is a protecting group on the pyrrole nitrogen; or c) condensing a compound of formula VI Py-COCH-COOH 1 UN (V1) - 4 GB 2 127 809 A 4 or a reactive functional derivative thereof, with an amine of the formula R-NH-Ph MO, wherein Py, R and Ph are as defined above; or d) ring opening a compound of the formula Vill R 1 PY ON-Ph (VII0 O"N wherein Py, R, Ph have meaning as described; or e) condensing a compound of formula IX or a reactive functional derivative thereof, with a compound of formula X Py-COOH OX) wherein Py, R, Ph have meaning as described above; f) reacting ammonia or salt thereof with a compound of formula XI CN 1 R i Y-CO-dH-CO-N-Ph CH,-CO-N-Ph (X) i M R (M) wherein R and Ph have the meaning as described above, and Y represents unsubstituted or substituted 2,5-di-(ioweralkoxy or halo)-2-tetrahydrofuranyi; and, if desired, converting any resulting product of formula 1 into another compound of the invention, and/or, if desired, converting any resulting enol into a lower alkyl enol ether or a lower alkanoyl enol ester, and/or, if desired, converting any resulting enol 15 into a salt with a base, or a resulting enol salt into the free enoi or into another salt with a base, and/or, if desired, resolving a mixture of isomers obtained into the single isomers.

The condensation according to process a) of the isocyanate of formula IV with the pyrroloylacetonitrile of formula Ill may be carried out according to U.S. patent 4,256,759, i.e., in the absence or presence of an inorganic or organic base, such as sodium hydride or triethylamine or in the 20 presence or absence of a polar solvent, such as an ether, e.g. diethyl ether, ethylene glycol dimethyl ether (glyme) or tetra hydrofu ran, and/or an amide or sulfoxide, e.g. dimethylformamide or dimethyl sulfoxide; preferably at a temperature range of 251 to 1 OOIC; advantageously at elevated temperatures, e.g. at about 1501 if no base is used.

The above-cited process a) according to the invention is generally performed thus: said nitrile is treated with a slight molar excess of an anhydrous tri-lower alkylamine, preferably triethylamine, and then a molar equivalent of the appropriate phenyl isocyanate (Ph-N=C0) is added, or a solution thereof in the polar solvents mentioned above, e.g. di methyl su Ifoxide or glyme. After stirring for about 2-24 hours at room temperature, the reaction mixture is reduced in volume by evaporation without excessive warming. The residue is treated with an excess of dilute aqueous acid, e.g. 0. 1 -0.3 N hydrochloric acid and the crude products are extracted or collected, washed with water, dried, triturated and/or recrystallized from appropriate solvents, such as lower alkanols, alkanones, dialkyl ethers and/or alkyl alkanoates, e.g. methanol, acetone, diethyl ether and/or ethyl acetate.

The starting materials of formulae 111 and IV are either known or are prepared according to methods well-known to the art, e.g. for compounds of formula Ill as described in Ber. 113, 3675 35 (1980), Chem. Abstracts 29, 2164 and Ber. 55, 2390 (1922).

In the process b) a protecting group on the pyrrole nitrogen is for example optionally substituted benzyi, optionally substituted carbobenzyloxy, lower alkanoyl (such as acetyl), trifluoroacetyl, di-lower alkylamino (such as dimethylamino), tetra hydropyra nyl, lower aikyloxymethyl (such as methoxymethyl), or lower alkoxycarbonyl (such as t-butyloxycarbonVI).

Process b) involving the removal of group Z is carried out by methods well-known to the art, e.g. 1) by hydrogenolysis when Z represents optionally substituted benzy] or carbobenzyloxy, e.g. with hydrogen in the presence of a hydrogenation catalyst; 2) by hydrolysis, preferably in the presence of e.g. a mineral acid or by ion exchange according to J. Am. Chem. Soc. 101, 6789 (1979), when Z represents optionally substituted carbobenzyloxy, lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl, 45 lower alkoxymethyl, or tetra hydropyra nyl; 3) by oxlidative cleavage, when Z represents dialkylamino, with chromium (11) acetate according to J. Org. Chem. 46, 3760 (1981).

The starting materials of formula V are prepared by e.g. condensing an acid of formula XII, GB 2 127 809 A 5 CN 1 Z-Py-CO-UH-COOH (X11) or a reactive functional derivative thereof, wherein Z and Py are as defined above, with an amine of the formula R-NH-Ph (VII).

The condensation is carried out according to U.S. patent No. 4,256,759 advantageously between room temperature and about 1500, either with equivalent amounts of the reactants (when a reactive ester is used), or with an excess of the amine, or in the presence of another base, such as a tertiary amine, e.g. a tri- lower alkyl-amine or pyridine (when a halide or anhydride is used) in order to neutralize the generated acid. The lower alkanol, generated in the reaction with said esters, is preferably distilled off together with a diluent, such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene. The condensation using a free carboxylic acid is preferably carried out in the presence of a condensing 10 agent, e.g. a disubstituted carbodiimide, such as dicyclohexylcarbodiimide, 1, 1'-carbonyidiimidazole or diethyl phosphorocyanidate (diethylphosphoryl cyanide).

Said starting materials of formula V may also be prepared according to other methods as described in U.S. patent 4,256,759.

The condensation of process c) is carried out similarly to methods described above for the preparation of compounds of formula V.

The starting materials of formula VI are prepared e.g. by reacting a compound of formula Ill with a derivative of carbonic acid, e.g. ethyl chloroformate, to give e.g. the corresponding ethyl ester of a compound of formula VI, which in turn may be converted to a compound of formula VI, or another reactive functional derivative thereof, by conventional means.

The ring opening reaction according to process cl), a reaction known to the art as described in J.

Am. Chem. Soc. 35, 959 (1913), 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 isoxazole starting materials of formula Vill are also prepared by procedures well-known to 25 the art, e.g. as disclosed in J. Am. Chem. Soc. 35, 959 (1913).

The condensation according to process e), when the starting material is a reactive functional derivative of a compound of formula IX, is advantageously performed in the presence of metallizing agents such as alkali metals, metal alkoxides or hydrides, e.g. sodium hydride, potassium t-butoxide, thallous ethoxide, or under phase transfer conditions, in polar solvents e.g. 1,2-dimethoxyethane, 30 dimethylformamide, dimethyl sulfoxide, at temperatures ranging from about 00 to 1000, preferably at 251 to 501C.

Reactive functional derivatives of the carboxylic acids of formulae VI, IX and XII are for example anhydrides, especially mixed anhydrides, acid halides, the acid azide, lower alkyl esters and activated esters thereof. Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) 35 hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters are for example succinimido, phthalimido or 4-nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.

The condensation of a free carboxylic acid of formulae VI,]X and XII with a compound of formula V11 orX, according to the above processes, maybe carried out in the presence of a condensing agent, 40 e.g. diethyl phosphorocyanidate, in the presence of a base, e.g. triethylamine, in an inert polar solvent, e. g. dimethylformamide or methylene chloride.

The reaction according to process f) preferably involves the reaction of ammonium acetate with a compound of formula X1a X X GN R (X1a) 45 no 1 1 CO-CH-CON-Ph wherein R and Ph have the meaning as previously described above, X represents lower alkoxy or halogen, e.g, methoxy, ethoxy or chloro, advantageously carried out in glacial acetic acid at elevated temperature, according to methodology well-known in the art, e.g. as described in Acta Chimica Scandinavica 6, 862-874 (1952).

The compounds of formula 1, so obtained, can be converted into each other according to methods 50 known per se. Thus, for example, resulting compounds (as enols) can be etherified, e.g. with lower diazoalkanes, or esterified, e.g. with lower alkanoic anhydrides; or converted into salts with said pharmaceutically acceptable bases, e.g. an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts maybe precipitated with said ethers, e.g. diethyl ether ortetrahydrofuran, at moderate 6 GB 2 127 809 A 6 temperatures, e.g. below 1 001C. Resulting salts may be converted into the free compounds by treatment with acids or bases. These or other salts can also be used for purification of the compounds obtained. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended provided such is possible or appropriate.

The starting materials used are known, or if new, can be prepared according to the methods known per se, for example as described in the references cited or as illustrated by the examples herein.

The above reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or neutralization agents and/or inert atmospheres, at low temperatures, room temperature or elevated 10 temperatures, at atmospheric or superatmospheric pressure.

The invention also comprises any modification of the above processes, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salts or reactive derivatives, preferably 15 alkali metal or trialkylammonium salts of said enols. In said processes of the invention those starting materials are advantageously selected, which yield the above-described preferred embodiments of the invention.

The invention also relates to novel intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the new compounds may be in the 20 form of one isomer, tautomer or mixtures thereof, provided such are possible.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for the crystallization.

The pharmacologically applicable compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with 25 excipients suitable for either enteral, parenteral or topical application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; and lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose 30 and/or polyvinyl pyrrol idone; if desired, disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories or topical lotions are advantageously made from fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for 35 regulating the osmotic pressure and/or buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. A unit dosage for a mammal of about 50 to 70 kg may contain between about 10 to 200 mg of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures throughout are given in degrees Centigrade and all parts where given are parts by weight. If not otherwise stated, evaporations are carried out under reduced pressure, preferably between about 15 and 100 mm Hg.

Example 1

A solution of 3.1 g of 2-pyrroloylacetonitrile in 25 mi of glyme (ethylene glycol dimethyl ether) and 2.7 9 of anhydrous triethylamine is treated with 3.0 g of phenyl isocyanate. After the moderately exothermic reaction, the mixture is let stand overnight. Most of the solvent is evaporated and the residue is treated with water and 12 mi of 10% sodium hydroxide solution. The aqueous, alkaline solution is washed with ethyl acetate and acidified with 6N hydrochloric acid. The product is collected, 50 washed with water, dried and recrystallized from ethanol, to give P-oxo-a(phenylcarbamoyi)-P-(2 pyrrolyl)-propionitrile, m.p. 207-2091, the compound of formula 11, wherein R, to R, are hydrogen.

The starting material is prepared as follows:

Into an ice-chilled solution of 30 9 of pyrrole and 30 g of malononitrile in 800 mi of dry ether is passed dry hydrogen chloride for 20 minutes. After standing several hours the suspension is filtered to give 65 g of orange-brown, water-soluble solid. The solution of 50 g of this intermediate (the enamine nitrile hydrochloride) in 600 mi of water is covered with 400 mi of ethyl acetate and stirred for 2-,L hours at room temperature. The organic layer is separated, dried over magnesium sulfate and evaporated to give crystals, m.p. 77-790; additional product is obtained by warming the aqueous layer on steam cone for -L hour and extracting with ethyl acetate. Recrystailization from water gives 2- 60 2 pyrroloylacetonitrile, m.p. 79-81 0 Example 2 To the solution of 6.7 g of2-pyrroloylacetonitrile in 25 mi of glyme and 5.5 9 of triethylamine is 7 GB 2 127 809 A added a solution of 8.6 9 of 4-chlorophenyl isocyanate in 25 mi of glyme. After the exothermic reaction, the mixture is let stand overnight. Part of the solvent is evaporated and the cooled residue is poured into a solution of 10 mi of 6N hydrochloric acid in 250 mi of water. After the addition of some methanol, the crude material is collected. It is dissolved in dilute sodium hydroxide solution, the solution is treated with charcoal, filtered, and acidified with 6N hydrochloric acid. The reprecipitated product is collected, washed with water, and triturated with methanol to give solid, m.p. 219-221 1. Recrystallization from methanol gives P-oxo-a-(4-chlorophenylcarbamoyl)-P-(2-pyrroiyi)- propionitrile, m.p. 223-2251.

Example 3

Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4difluorophenyl isocyanate in the 10 presence of 2.0 g triethylamine in 25 mi of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives P- oxo-a-(2,4 difluorophenylcarbamoyi)-P-(2-pyrrolyi)-propionitrile, m.p. 169-171 ' Example 4

Reaction of 2.0 g of 2-pyrroloylacetonitrile with 3.0 g of 3(trifluoromethyl)-phenyl isocyanate in 15 the presence of 1.8 g of triethylamine in 25 mi of glyme similarly to the previous examples and recrystallization of the crude product from methanol gives P-oxo-ce-(3 trifluoromethylphenylearbamoyl)-P-(2-pyrrolyi)-propionitrile, m.p. 2102121.

Example 5

Reaction of 2.4 g of 2-pyrroloylacetonitrile with 2.5 g of 4-fluorophenyl isocyanate in the 20 presence of 2.2 9 of triethylamine in 25 mI of glyme, similarly to preceding examples, reprecipitation from dilute sodium hydroxide solution with hydrochloric acid, and recrystallization from methanol, gives P-oxo-a-(4-fluorophenylcarbamoyl)-P-(2-pyrrolyl)-propionitrile, m.p. 233-2340.

Example 6

Reaction of 2.7 g of 2-pyrroloylacetonitrile with 3.8 g of 3-chloro-4fluorophenyl isocyanate in 25 the presence of 2.4 g of triethylamine in 25 mi of glyme and workup similarly to the preceding examples gives after recrystallization from ethyl acetate, P-oxo-a-(3chloro-4-fluorophenylearbamoyi)- P-(2-pyrroiyl)-propionitrile, m.p. 257-2580 (decomposition).

Example 7

A solution of 2.1 g of 2-pyrroloylacetonitrile in 15 mi of glyme and 1.8 g of triethylamine is 30 treated with a solution of 3 9 of 2,4-dichlorophenyl isocyanate in 15 mi of glyme similarly to the preceding examples. Mildly exothermic reaction results in formation of a thick suspension of crystals.

After standing overnight, dilution with dry ether and filtration gives the triethylammonium salt of P-OXO a-(2,4-dichlorophenylcarbamoyi)-P-(2-pyrrolyl)-propionitrile, m.p. 180-1 82cl (decomposition), in form of the enol structure as represented by formula]a, wherein Py is 2- pyrrolyl, R is hydrogen and Ph 35 is 2,4-dichlorophenyi.

A solution of the above triethyiammonium salt in methanol is added to a solution of 4 mi of 6N hydrochloric acid in 250 mi of water. The free enolic product is collected, washed with water and triturated with methanol to give crystals, m.p. 219-2210. Recrystallization from ethyl acetate gives oxo-a-(2,4-dichlorophenylearbamoyi)-P-(2-pyrroiyl)-propionitrile, m.p. 222-223'.

Example 8

A mixture of 1.1 9 of P-oxo-a-ethoxycarbonyl-P-2-(pyrroiyl)-propionitrile, 1.5 g of 4-fluoroaniline and 60 mi of xylene, is fluxed for 41 hours. After standing and cooling to room temperature overnight, 2 the solution is filtered, evaporated and the residue is purified to yield P-oxo-a-(4fluorophenylearbamoyl)-P-(2-pyrrolyl)-propionitrile of example 5.

The starting material is prepared as follows:

a) A solution of 2.22 g of 2-pyrrolecarboxylic acid, 8.4 mi of anhydrous triethylamine and 2.1 mi of ethyl cyanoacetate in a sufficient amount of dimethylformamide so as to obtain a solution, is stirred, treated with 2.9 mi of diethyl phosphorocyanidate at room temperature, and allowed to stand for 1.3 hours. The solution is cooled in an ice-bath, treated with 50 mi of water, filtered and acidified with 6N 50 hydrochloric acid. The resulting precipitate is collected, washed with water, dried and recrystallized from ether to give P-oxo-(x-ethoxycarbonyi-p-(2-pyrroiyl)-propionitrile, m.p. 138-1391.

b) 2-Pyrroloylacetonitrile is treated in the presence of triethylamine in ethylene glycol dimethyl ether at 501 overnight with ethyl chloroformate, and the product is purified to give P-oxo-aethoxycarbonyl-p-(2-pyrroiyl)-propionitrile.

Example 9

By procedures analogous to those described in the preceding examples the following compounds of formula 1 can be prepared.

8 GB 2 127 809 A- 8_ No. PY R Ph 9/1 2-pyrrolyl H 4-methoxyphenyl 9/2 2-pyrrolyl H 4-methyithiophenyl 9/3 2-pyrroly] H 4-hydroxyphenV1 9/4 2,5-dimethyi-3-pyrrolyl H 4-chlorophenyl 5 9/5 3,5-di m ethyl-2-pyrro lyl H 2,4-difluorophenyl 9/6 3,5-di m ethyl-4-ca rboeth oxy- H 4-chlorophenyl 2-pyrrolyl 9/7 2-pyrrolyl H 4-trifluoromethylphenyl 9/8 2-pyrroly] H 4-tolyl 10 9/9 2-pyrrolyl CH, phenyl The pyrrole starting materials for examples 9/4, 9/5 and 9/6 are described in Ber. 113, 3675 (1980), Chem. Abstr. 29, 2164, and Ber. 55, 2390 (1922) respectively.

Example 10

Treatment of P-oxo-a-(2-phenylcarbamoyi)-P-(2-pyrrolyi)-propionitrile with an equivalent 15 amount of a concentrated aqueous or alcoholic solution of sodium, potassium or calcium hydroxide or ethoxide and evaporating to dryness, yields the corresponding sodium, potassium or calcium salt of the compound in tautomeric form of formula la, wherein Py is 2-pyrrolyl, Ph is phenyl and R is hydrogen.

Similarly prepared with an equivalent amount of triethylamine or tri(hydroxyethyi)-amine are the triethylammonium and tris-(hydroxyethyi)-ammonium salts respectively.

Example 11

To 500 mi of ethereal diazomethane, generated from 10.3 g of N -n itrosoWrn ethyl urea with 35 mi of 45% aqueous potassium hydroxide and dried over potassium hydroxide pellets, are added 3.9 g of P-oxo-a-(phenylcarbamoyi)-P-(2-pyrroiyi)-propionitrile. After the nitrogen evolution ceases, the solution is filtered and evaporated. Purification yields the corresponding methyl enoi ether, i.e. the 25 methoxy-a-(phenylcarbamoyi)-P-(2-pyrroiyi)-acrylonitrile.

Example 12

To the solution of 1.6 g of cyanoacetanilide in 10 mi of dimethyiformamide is added 3.4 g of potassium t-butoxide. The stirred, cooled suspension is treated with 1.1 g of pyrrole-2-carboxylic acid in 6 mi of dimethylformamide and 1.4 mi of diethyl phosphorocyanidate (DEPC). The deep-red solution 30 is stoppered and allowed to react for I hour. The reaction mixture is treated with 80 mi of ice-cold 2 water, and filtered to remove unrea eted cyanoacetanilide and acidified with 6N hydrochloric acid. The resulting precipitate is collected, washed with water and dried. The crude product is dissolved in ethyl acetate, the ethyl acetate solution is filtered and evaporated to dryness. The resulting product is recrystallized from ethanol-etherto yield P-oxo-a-(phenylcarbamoyi)-P-(2pyrroiyl)-propionitrile 35 identical to the product of example 1.

Example 13

Protection in the established adjuvant arthritis test at a dose of 25 mg/kg/p.o. essentially according to Proc. Soc. Exp. Biol. Med. 137, 506 (1971).

Example % Change from control 40 1 -47% 2 -58% 3 -55% 4 -59% 5 -59% 45 7 -42% Example 14

Preparation of 1.000 capsules each containing 25 mg of the active ingredient:

Formula P-Oxo-(Y-(4-fluorophenylcarbamoyl)-P-(2- 25.0 g 50 pyrroiyi)-propionitrile Lactose 207.0 g Modified starch 80.0 g Magnesium stearate 3.0 g 4 1 9 GB 2 127 809 A Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogeneous. No. 2 hard gelatin capsules are filled with 315 mg of said mixture each, 5 using a capsule filling machine.

Analogously capsules are prepared, containing 10-200 mg of the other compounds disclosed and illustrated herein.

Example 15

Preparation of 10,000 tablets each containing 100 mg of the active ingredient:

Formula 10 P-Oxo-a-(2,4-difluorophenylcarbamoyi)-P-(2pyrrolyl)-propionitrile Lactose Corn starch Polyethylene glycol 6.000 Talcum powder Magnesium stearate Purified water 1,000.009 2,53 5.00 g 125.00 g 150.00 g 150.00 g 40.00 g q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, 20 lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 mi of water and the suspension added to the boiling solution of the polyethylene glycol in 260 m] of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 351, broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches uppers 25 bisected.

Analogously tablets are prepared, containing 10-200 mg of one of the other compounds illustrated by the previous examples.

Claims (16)

Claims

1. A compound of the general formula 1 or a tautomer therof CN R 1 1 Py-CO-CH-CON-Ph (1) wherein Py is 2- or 3-pyrrolyl unsubstituted at the 1 -position and optionally substituted at one or more of the remaining three positions by lower alkyl and/or by carboxy or lower carbalkoxy and/or by halogen; R is hydrogen or lower alkyl; and Ph is phenyl, unsubstituted or substituted by one to three 35 identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, hydroxy, halogen, trifluoromethyl, nitro, amino and lower a[kanoylamino; the lower alkyl enol ethers thereof; or the lower alkanoyl enol esters thereof.

2. A compound of the general formula R, -F-t- R 2 _QR N CO-CH-CONH 1 3 1 1 R H W 4 wherein each of R, and R2 is hydrogen or lower alkyl; and each of R3 and R, is hydrogen, lower alky], 40 lower alkoxy, hydroxy, halogen or trifluoromethyl.

3. -Oxo-a-(phenylcarbamoyi)-P-(2-pyrroiyl)-propionitrile.

4. -Oxo-a-(4-chlorophenylcarbamoyi)-P-(2-pyrroiyi)-propionitrile.

5. -Oxo-a-(2,4-difluorophenylcarbamoyl)-P-(2-pyrrolyl)-propionitrile.

6. 3-Oxo-a-(3-trifluoromethylphenylcarbamoyi)--(2-pyrroiyl)-propionitrile.

7. 3-Oxo-a-(4-fluorophenylcarbamoyl)-P-(2-pyrrolyi)-propionitrile.

8. 3-Oxo-.i-(3-chloro-4-fluorophenylcarbamoyi)-P-(2-pyrroiyi)propionitrile.

9. 3-Oxo-a-(2,4-dichlorophenylcarbamoyl)--(2-pyrroiyi)-propionitrile.

GB 2 127 809 A

10 10. A salt of the tautomeric form of a compound as claimed in any one of claims 1 to 9, derived from a base.

11. A pharmaceutically acceptable salt of the tautomeric form of a compound as claimed in any one of claims 1 to 9, derived from a base.

12. A pharmaceutical preparation comprising a compound as claimed in any one of claims 1 to 9 5 and 11 in admixture or conjunction with a pharmaceutically suitable carrier.

13. Process for the manufacture of a compound of the formula 1 claimed in claim 1, in which formula all the symbols have the meanings given in claim 1, salts thereof; the lower alkyl enol ethers thereof; or the lower alkanoyl enol esters thereof, which consist in a) condensing the compounds of the formulae Ill and IV Py-COCH2-M (111) and Ph-N=C=0 OV) and, if desired, N-substituting a resulting compound with a reactive ester of ROH, wherein Py, Ph and R have meaning as previously defined; or b) removing the group Z from a compound of the formula V M R 1 1 Z-Py-CO-CH-CON-Ph (V) 15 wherein Py, R and Ph have meaning as described above, and Z is a protecting group on the pyrrole nitrogen; or c) condensing a compound of formula V] Py-COCH-COOH 1 uN (V0 or a reactive functional derivative thereof, with an amine of the formula R-NH-Ph (VII), wherein Py, 20 R and Ph are as defined above; or d) ring opening a compound of the formula Vill R 1 HY ON-Ph (VIII) 01, N:r wherein Py, R, Ph have meaning as described; or e) condensing a compound of formula IX or a reactive functional derivative thereof, with a 25 compound of formula X Py-COOH (1x) wherein Py, R, Ph have meaning as described above; f) reacting ammonia or salt thereof with a compound of formula XI M R 1 CH,-CO-N-Ph (X) 1 i LN R Y-CO-CH-CO-N-Ph (Xl) 30 wherein R and Ph have the meaning as described above, and Y represents unsubstituted or substituted 2,5-di-(loweralkoxy or halo)-2- tetrahydrofuranyi; and, if desired, converting any resulting product of formula 1 into another compound of the invention, and/or, if desired, converting any resulting enol into a lower alkyl enol ether or a lower alkanoyl enol ester, and/or, if desired, converting any resulting enol into a salt with abase, or a resulting enol salt into the free enol or into another salt with abase, and/or, 35 if desired, resolving a mixture of isomers obtained into the single isomers.

14. The compounds prepared according to claim 13.

11 GB 2 127 809 A 11

15. A compound according to claim 1 substantially as hereinbefore described with reference to any one of Examples 1 to 12.

16. A pharmaceutical composition substantially as hereinbefore described with reference to Example 14 or 15.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.