2-CARBONYL-3-HYDROXY-ALKENONITRILES, THEIR USE AS ANTI-ARTHRITIC AGENTS AND PROCESSES FOR THEIR PREPARATION

Abstract: There are disclosed 2-carbonyl-3-hydroxy-2- alkenonit­ riles, their use as anti-arthritic agents and processes for their preparation. The active compounds have the formula: wherein n is an integer from 1 to 3 inclusive; M is hydrogen or a pharmaceutically acceptable cation; R₆ is an alkyl group of 1 to 4 carbons; R⁰ is one of the following aromatic groups: (1) the group in which R₁, R₂, R₃, R₄ and R₅ are the same or different and are hydrogen, halogen, alkyl having up to 4 carbons, alkoxy hav­ ing up to 4 carbons, trifluoromethyl or trichloromethyl, with the proviso that when m is the number 0 at least two of R₁, R₂, R₃, R₄ and R₅ must be hydrogen; (2) the thienyl moiety wherein R₇ is hydrogen, an alkyl group of up to 3 carbons, fluorine, chlorine or bromine; X is Ch₂ 0 or S and m is the number 0 or 1, provided that when R⁰ is a thienyl moiety then m is O; and the tautomers of the above compounds.

Description: TITLE: 2-CARBONYL-3-HYDROXY-2-ALKENONITRILES, THEIR USE AS ANTI-ARTHRITIC AGENTS AND PROCESSES FOR THEIR PREPARATION The present invention concerns compounds and compositions useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease, as well as methods and intermediate compounds for preparation thereof, and also methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith. More particularly, the invention is concerned with 2-carbonyl-3-hydroxy2-alkenonitriles. According to the present invention there is provided 2-carbonyl-3-hydroxy-2-alkenonitriles of the formula: EMI1.1 wherein n is an integer from 1 to 3 inclusive; M is hydrogen or a pharmaceutically acceptable cation; R6is an alkyl group of 1 to 4 carbons; Ro is one of the following aromatic groups: : (1) the group EMI1.2 in which R11 R2 R3, Rq and R5 are the same or different and are hydrogen, halogen, alkyl having up to 4 carbons, alkoxy having up to 4 carbons, trifluoroceohyl or trichlpro- methyl, with the proviso that when m is the number 0 at least two of R1, R2, , R4 and R5 must be hydrogen when R6 is methyl and m is the nueber 0 not all of R1, R2, R3, R4 and R5 may be hydrogen; or (2) the thienyl moiety EMI2.1 wherein R7 is hydrogen, an alkyl group of up to 3 carbons, fluorine, chlorine or bromine; X is CH2, O or S and m is the number 0 or 1, provided that when R is a thienyl moiety then m is 0; and the tautomers of the above compounds. Also provided according to the invention is an anti-arthritic composition in dosage unit form useful for meliorating the inflammation and/or the progressive joint deterioration characteristic of arthritic disease in mammals, comprising from about one milligram to about 250 milligrams per kilogram of body weight per dosage unit of a 2-carbonyl-3-hydroxy-2-alkenonitrile of the formula: EMI2.2 wherein n is an integer from 1 to 3 inclusive; M is hydrogen or a pharmaceutically acceptable cation; -R6 is an alkyl group of 1 to 4 carbons; R0 is one of the following aromatic groups: : (1) the group EMI2.3 in which R1, R2, R3, R4 and R5 are the same or different and are hydrogen, halogen, alkyl having up to 4 carbons, alkoxy having up to 4 carbons, trifluoromethyl or trichloromethyl, with the proviso that when m is the number 0 at least two of R1, R2, R3, R4 and R5 must be hydrogen; or (2) the thienyl moiety EMI3.1 wherein R7 is hydrogen, an alkyl group of up to 3 carbons, fluorine, chlorine or bromine; X is CH2, O or S and m is the number 0 or 1, provided that when R" is a thienyl moiety then m is 0; and the tautomers of the above compounds. Further according to the present invention there is provided a method of producing compounds of Formula 1, which comprises: (a) reacting an acetonitrile of the formula: EMI3.2 with a compound of the EMI3.3 wherein R , X, m and R6 are as defined above and R8 is O-Alkyl or N(Alkyl)2 and them hydrolyzing the product produced, and wherein, when R8 is O-Alkyl the resultant product may be treated with a dialkyl amine prior to said hydrilysis; or (b) reacting the metal (Me) enolate salt of an acetonitrile of the formula: EMI3.4 with an acyl halide of the formula: EMI3.5 wherein RO and R6 are as defined above; or (c) reacting an acyl halide of the formula: EMI4.1 halide with a metal (Me) enolate salt of the formula EMI4.2 wherein X is CH2, m is the number 0 or 1, R and R6 are as defined above; or (d) reacting a compound of the formula: EMI4.3 with N,N-dimethylformamide dimethylacetal to-produce an intermediate compound of the formula: EMI4.4 reacting said intermediate with hydroxylamine hydrochloride and treating the resulting reaction mixture with a strong base, wherein R and R6 are as definedabove; or (e) reacting a compound of the formula: R - X - H with a compound of the formula: EMI4.5 in the presence of a proton scavenger such as a, tertiary amine, to form an intermediate of the formula: : EMI4.6 wherein X is O or S and RO and R6 are as defined above, and further treating said intermediate with a proton scavenger such as a tertiary amine or alkoxide, thereby producing the corresponding final product; and (f) if desired, forming pharmaceutically acceptable cation salts. Also provided in accordance with the present invention is a method for preparing an anti-arthritic composition in dosage unit form useful for inhibiting the pro gression of arthritis, meliorating inflamMtion and/or inhibiting progressive joint deterioration in mammals, canpflsing incorporating into a pharmaceutical carrier from about one milligram to about 250 milligrams per kilogram of body weight of a 2-carbonyl3-hydroxy-2-alkenonitrile of the Formula II, hereinabove. The useful pharmaceutically acceptable salts of the compounds of the above structural formula wherein M is hydrogen are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations. Preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, iron and in particular copper are within the scope of the invention. Pharmacologically acceptable amine cations and those derived from primary, secondary, or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, a- or 6-phenyl-- ethylamine, ethylenediamine, diethylenetriamine, and aryliphatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivative thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1, 4-dimethyl piperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, or triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-l-butanol, 2-amino-2-ethyl1,3-propanediol, 2-amino-2-methyl-l-propanol, tris(hydr oxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert amylphenyl) diethanolamine, galactamine, N-methylglucamin-e, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like. Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like. Suitable alkyl and alkoxy groups contemplated by the present invention may be, for example, methyl, ethyl, isopropyl, sec-butyl, methoxy, ethoxy, n-propoxy, isobutoxy, etc., whereas halogen is exemplified by fluoro, chloro and bromo. The compounds of the present invention may exist in other tautomeric forms as follows: EMI6.1 The compounds and compositions of the invention include cis-2-benzoyl-3-hydroxy-2-alkenonitriles and the pharmacologically acceptable cationic salts thereof which may be represented by the following structural formula: EMI7.1 wherein the groups are as above defined. Several procedures exist for the attachment of the acyl fragment to a benzoylacetonitrile side chain. The first involves direct acylation of the benzoylacetonitrile anion (1) with an acyl halide (2) in an appropriate solvent to provide the product (3) as set forth in the following reaction scheme wherein Me is a metal cation as hereinabove defined, X is chloro or fluoro, and R1, R2, R3, R4, R5 and R6 are as hereinabove defined. The enolate anions (1) EMI7.2 are prepared by the treatment of the benzoylacetonitrile with the appropriate base in an inert solvent. This enolate may be generated in situ and acylated with (2) in the same solvent or may be isolated and reacted in a different solvent system. When Me represents sodium where (1) has been generated by treatment of the benzoylacetonitrile with sodium hydride, sodium amide sodium methoxide, etc. and X represents chlorine, yields of (3) are low with undesired side products sometimes predominating. Preferably, the benzoylacetonitrile is dissolved in diethyl ether and one equivalent of thallium (I) ethoxide is added. The stable enolate (1), where Me is thallium, precipitates and may be collected by filtration, dried and stored indefinitely. Suspension of (1) in an inert solvent such as ether, tetrahydrofuran, dioxane, etc. at room temperature and the treatment of same with an acyl fluoride (2-) causes precipitation of thallium (I) fluoride. This is removed by filtration and the product is extracted from the filtrate. Another approach involves addition of the acyl fragment as a hydrolyzable portion to yield (5) wherein R1, R2, R3, R4 and R5 are as hereinabove defined. This may be EMI8.1 performed by treatment of the benzoylacetonitrile (4) with N,N-dimethylacetamide dimethylacetal at low temperature in chloroform, methylene chloride, or even as a neat mixture of reagents. Purification yields the condensed product (5). Alternatively, the benzoylacetonitriie (4) is condensed with a trialkyl orthoester (7) in refluxing acetic anhydride as set forth in the following reaction scheme: EMI9.1 wherein R1, R2, R3, R4, R5 and R6 are as hereinbefore defined, R is alkyl having up to 4 carbon atoms, R' and R" are each hydrogen or alkyl having up to 4 carbon atoms and R' and R" taken together with the associated N(itrogen) is pyrrolidino, piperidino, morpholino, thiomorpholino or Nmethylpiperazino. Evaporation of by-products and excess acetic anhydride in vacuo and purification of the product under anhydrous conditions provides (8). Treatment of (8) with ammonia or a primary or secondary amine at steam bath temperature under pressure in a sealed vessel for 8-12 hours then provides (9). Both of these intermediates (8) and (9) may be hydrolyzed under acidic conditions to provide the desired products (10). A different approach to (10) particularly wherein R6 is methyl or ethyl involves addition of the cyanoacyl fragment to a benzoyl chloride as set forth below wherein the groups are as hereinabove defined. This may be performed by generation of the enolate anion (12) in situ with the 5-alkyl-isoxazole (14) and a base such as sodium hydride or sodium amide and subsequent addition of the benzoyl chloride (11) to affect condensation to provide (13). EMI10.1 Alternatively the a-cyanoenolate (12) may be prepared separately in a similar manner as above and isolated. Addition of this enolate to the appropriate benzoyl chloride in ether, tetrahydrofuran, etc. at room temperature or at reflux provides (13). A less desirable route to (10) involves that set forth below wherein R1, R2, R3, Ro, R5 and R6 are as hereinabove defined. The acylacetophenone (15) is condensed with N,N-dimethylformamide dimethylacetal at reflux either neat or in solution with an inert solvent such as chloroform or carbon tetrachloride to provide the intermediate (16). Treatment of this with hydroxylamine hydrochloride in solvents such as alcohol, dioxane, dimethylformamide or aqueous solutions of the same provides a mixture of products (17) and (18). These are reacted as an unseparated mixture with a strong base such as sodium hydroxide or sodium alkoxide in alcohol and provides the desired product (10) upon acidification. EMI11.1 The compounds and compositions of the invention also include substituted cis-2-[2(or 3)-thenoyl]-3-hydroxy- 2-alkenonitriles and the pharmacologically acceptable cationic salts thereof which may be represented by The following structural formula: EMI11.2 wherein R is a 2-thienyl or 3-thienyl moiety of the formulae: EMI12.1 and the other groups are as defined above Several procedures exist for the attachment of the acyl fragment to a thenoylacetonitrile side chain. The first involves direct acylation of the thenoylacetonitrile anion (1) with an acyl halide (2) in an appropriate solvent to provide the product (3) as set forth in the following reaction scheme wherein Me is a metal cation as hereinabove defined and X is chloro or fluoro: EMI12.2 The enolate anions (1) are prepared by the treatment of the thenoylacetonitrile with the appropriate base in an inert solvent. This enolate may be generated in situ and acylated with (2) in the same solvent or may be isolated and reacted in a different solvent system. When Me represents sodium where (1) has been generated by treatment of the thenoylacetonitrile with sodium hydride, sodium amide, sodium methoxide, etc. and X represents chlorine, yields of (3) are low with undesired side products sometimes predominating. Preferably, the thenoylacetonitrile is dissolved in diethyl ether and one equivalent of thallium (I) ethoxide is added. The stable enolate (1), where Me is thallium, precipitates and may be collected by filtration, dried and stored indefinitely. Suspension of (1) in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane, etc. at room temperature and the treatment of same with an acyl fluoride (2) causes precipitation Of thallium (I) fluoride. This is removed by filtration and the product is extracted from the filtrate. Another approach involves addition of the acyl fragment as a hydrolyzable portion to yield'(5) as set forth in the following reaction scheme wherein R1 is as herein above defined: EMI13.1 This may be performed by treatment of the thenoylacetonitrile (4) with N,N-dimethylacetamide dimethylacetal at low temperature in chloroform, methylene chloride, or even as a neat mixture of reagents. Purification yields the condensed product (5). Hydrolysis of (5) with dilute aqueous mineral acid provides (6). Alternatively, the thenoylacetonitrile (4) is condensed with a trialkyl orthoester (7) in refluxing acetic anhydride as set forth in the following reaction scheme: EMI13.2 wherein alkyl is methyl or ethyl, R' and R" are each hydro gen or alkyl having up to 4 carbon atoms and Rt and R" taken together with the associated N(itrogen) is pyrrolidino, piperidino, morpholino, thiomorpholino or N-methylpiperazino. Evaporation of by-products and excess acetic anhydride in vacuo and purification of the product under anhydrous conditions provides (8). Treatment of (8) with ammonia or a primary or secondary amine- at steam bath temperature under pressure in a sealed vessel for 8-12 hours then provides (9). Both of these intermediates (8) and (9) maybe hydrolyzed under acidic conditions to provide the desired products (10). A different approach to (10) particularly wherein R6 is methyl or ethyl involves addition of the cyanoacyl fragment to a 2(or 3)-thenoyl chldride (11) as set forth below. This may be performed- by generation of the enolate EMI14.1 anion (12) in situ with the 5-alkyl-isoxazole -(14) and a base such as sodium hydride or spdium amide and subsequent addition of the 2(or 3)-thenoyl chloride (11) -to affect condensation to provide (13). Alternatively, the a-cyanoenolate (12) may be prepared separately in a similar¯manner as above and isolated. Addition of thisenolate to the appropriate 2(or 3)-thenoyl chloride in ether, tetrahydrofuran, etc. at room temperature or at reflux provides (13). The compounds and compositions of the invention also include substituted phenyl-alkylidene acetoacetonitriles of the formula: EMI14.2 wherein the groups and symbols are as defined above. The compounds of Formula V, for example, may be prepared according to the following Flowchart A: FLOWCHART A EMI15.1 In accordance with Flowchart A an appropriate phenylacetic acid (1) is refluxed with thionyl chloride for several hours, giving the corresponding phenylacetyl chloride (2), which is reacted with cyanoacetone sodium enolate (3) in a solvent such as tetrahydrofuran for several hours, then after removal of the solvents, the residue in aqueous suspension is acidified and extracted into methylene chloride. Evaporation of this extract gives the products (4) where R1, R2, R3, R, R5, R6 and M are as described above. The compounds and compositions of the invention also include substituted phenyl-2-cyano-2-thioalkenoic acid esters of the formula: EMI15.2 wherein the groups and symbols are as defined above. The compounds of Formula V; for example, may be prepared according to the following Flowchart B: FLOWCHART B EMI16.1 In accordance with Flowchart B, thionyl chloride and sodium carbonate in chloroform are used to convert a 5-alkylisoxazole 4-carboxylic acid (1) to the corresponding 5-alkylisoxazole carbonyl chloride (2) by heating for several hours. The compound (2) is then reacted with a substituted thiophenol (3) and one molar equivalent of triethylaine in ether at reduced temperature for several hours. The resulting alkylthio isoxazolecarboxylic acid-S-phenyl ester (4) is extracted in methylene chloride and rystallized with hexane at reduced temperature. The isoxazole (4) is treated with triethylamine in ether for several hours giving the 2-cyano3-hydroxythio alkenoic acid-S-phenyl ester triethylamine salt (5) which is then acidified in aqueous solution with hydrochloric acid to provide (6) where R1, R2, R3, Rd, R5, R6 are as described above and M is hydrogen. The compounds and compositions of the invention also include substituted phenyl-2-cyano-2-alkenoic acid esters of the formula: EMI17.1 wherein the groups and symbols are as defined above. The compounds of Formula VII, for example, may be prepared according to the following Flowchart C: FLOWCHART C EMI18.1 In accordance with-Flowchart C, the 5-altylisox- azole-4-carboxylic acid (1) H. Yasuda, Yakugaku Zasshi, 79, 836-838 81959); C.A., 53, 21885d] is reacted with thionyl chloride and sodium carbonate in chloroform with heat for several hours producing the corresponding 5-alkylisoxazole carbonyl chloride (2). The compound (2) is then reacted with the appropriate phenol (3) in ether at ice bath temperature with one molar equivalent of triethylamine for several hours giving the 5-alkyl-4-isoxazolecarboxylic acid phenyl ester (4). The ester (4) is treated with triethylamine at ice bath temperature for several hours giving the 2-cyano3- substituted alkenoic acid phenyl ester triethylamine salt (5). The salt (5) is converted to the free ester (6) where R1, R2 R3, R4, R5 and R6 are as described above by treatment in aqueous solution with a mineral acid. This invention further relates to novel substituted 2-benzoyl-3-substituted-2-alkenonitriles which are useful as intermediates for the preparation of certain substituted cis-2-benzoyl- 3-hydroxy-2-alkenonitriles which possess anti-inflammatory activity. According to the invention there is provided substituted 2-benzoyl-3-substituted-2-alkenonitriles of the formula: EMI19.1 wherein Y represents the group OR or the group EMI19.2 wherein R1, R2, R3, R4 and R5 are each individually selected from the group consisting of hydrogen, halogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, trifluoromethyl and trichloromethyl with the proviso that at least two of R1, R2, R3, R4 and R5 must be hydrogen, R6 is alkyl ' having from 1 to 4 carbon atoms; R is alkyl having from 1 to 4 carbon atoms; and R' and R" are each hydrogen or alkyl having from 1 to 4 carbon atoms or R' and R" taken together with the associated nitrogen is pyrrolidino, piperidino, morpholino, thiomorpholino or N-methylpiperazino. Halogen is exemplified by fluoro, chloro and bromo. In an embodiment of the invention Y is OR, all of R1, R2, R3, R4 and R5 are hydrogen and the other groups are as defined in Formula VIII. In another embodiment of the invention in the compounds of Formula VIII, R6 is methyl, Y is OR and R, R1, R2 R3, R4 and R5 are as defined for Formula VIII, but at least one of R1, R2, R3, R4 and R5 is other than hydrogen. The compounds of Formula VIII relate to new organic compounds and, more particularly, to novel substituted 2 benzoyl-3-alkoxy-2-alkenonitrlles (i) and novel substituted 2-benzoyl-3-amino-2-alkenonitriles (ii) which may be represented by the following structural formulae: EMI20.1 wherein the groups are as defined above for Formula VIII. The novel compounds of Formula VIII are obtainable as crystalline materials having characteristic melting points and absorption spectra. They are appreciably soluble in many organic solvents such as lower aikanols, acetone, ethyl acetate, and the like but are generally insoluble in water. The preparation of the novel intermediates of the present invention and their conversion to useful final products is set forth in the following -reaction scheme wherein R1, R2, R3, R4, R5, R6, R, Rt and R" are as hereinbefore defined for Formula VIII. EMI21.1 In accordance with this reaction scheme, an appropriately- substituted benzoylacetonitrile (iii) is condensed with a trialkyl orthoester (iv) in refluxing acetic anhydride-. Evaporation of by-products and excess acetic anhydride in vacuo and purification of the residue under anhydrous conditions provides the corresponding substituted 2-benzoyl-3-alkoxy-2-alkenonitrile (i). Treatment of (i) with ammonia or a primary or secondary amine of the formula: EMI21.2 at steam bath temperature under pressure in a sealed vessel for 8-12 hours then provides the gybstituted 2-benzoyl-3amino-2-alkenonitriles (ii). Both of these intermediates (i) and (ii) may be hydrolyzed under acidic conditions to provide the anti-inflammatory products (v). The compounds (ii) wherein R' and R" are both methyl may also be prepared by treatment of an appropriately substituted benzoylacetonitrile (iii) with N,N-dimethylacetamide dimethylacetal at low temperature in chloroform, methylene chl-orid or even as a neat mixture of reagents. The present invention also relates to isoxazole carboxylic acid phenyl esters which are useful as inter- mediates for the preparation of anti-inflammatory reagents. According to this invention there is provided compounds of the formula: EMI22.1 wherein R1, R2, R3, R4 and R5 are each selected from the group comprising hydrogen, halogen, lower alkyl (C1-C4), lower alkoxy (C1-C4), trifluoromethyl and-trichloromethyl, R6 is lower alkyl (C1-C4); and X-is sulfur or oxygen. These compounds may be treated with triethylamine in ether solution. followed - by acidification to produce compounds of the formula: EMI22.2 wherein R1, R2, R3, R4, R5, R6 and X are as described above for Formula IX, which compounds are active anti-inflammatory agents. In addition, certain of the compounds of the above formula,- namely 5-methy1-4-isoxazolecarboxylic acid, o-meth- oxyphenyl ester and 5-methyl-4-isoxazolecarboxyxlic acid, 2,4,6-trichlorophenyl ester, are active as anti-inflammatory agents. The compounds of Formula IX.may¸be prepared accord- ing to the following Flowchart D: FLOWCHART D EMI23.1 In accordance with Flowchart D a 5-alkylisoxazole-4-carboxylic acid (1) is converted to the corresponding 5-alkylisoxazole carbonyl chloride (2) by treatment with thionyl chloride and sodium carbonate at reflux for several hours. The chloride (2) is then reacted with the substituted phenol or thiophenol (3) in ether with one molar equivalent of triethylamine added. The reaction mixture is filtered, the filtrate evaporated and the residue extracted from methylene chloride to give the product (4), where R1, R2, R3, R4, R5, R6 and X are as described above for Formula IX. The novel compounds of the present invention have been found to be highly useful for meliorating inflammation and inhibiting joint deterioration in mammals when administered in amounts ranging from about one milligram to about 250 mg. per kilogram of body weight per day. A preferred dosage regimen for optimum results would be from about 5 mg. to about 100 mg. per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.35 gm. to about 7.0 gm. of the active ingredient for a subject of about 70 kg. of body weight are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage of this invention is that the active ingredient may be administered in any convenient manner such as by the oral, intravenous, intramuscular, topical, intraarticular, or subcutaneous route The anti-inflammatory activity of the novel compounds of the present invention was established by the following tests. (A) Carrageenin-induced edema in the rat In determining the acute anti-inflammatory activity of the active compounds of the present invention, Royal Hart, Wistar strain rats, ranging in weight from 80 to 90 grams were used. The rats were fasted overnight prior to dosing but had free access to water. The test compounds were administered in aqueous suspension, by gavage, in a volume of 1.7 ml. per 50 grams of rat [corresponds to hydration volume used by Winter, et al., Proc. Soc. Exp. Biol. & Med., 111, 544-547 (1962)). The phologistic agent used was carrageenin prepared as a sterile 18 suspension in 0.9% aqueous sodium chloride for routine testing A volume of 0.05 ml. was injected through a 26 gauge needle into the plantar tissue of the right hind paw. Measurements were made 5 hours after drug administration (4 hours after carrageenin challenge). Volumes of both the normal and carrageenin inflammed feet were determined. The difference between the two measurements is considered to be the increased edema due to the carrageenin ad- ministration. Results are expressed as a C/T efficacy ratio (edema of control animals/edema of treated animals). Table I records the results of this test at the indicated dose level with typical compounds of the present invention and demonstrates the anti-inflammatory effect of these compounds in comparison with known anti-inflammatory agents. TABLE I Dose mg./kg. No. C/T of Body of Edema Compound Weight Rats Ratio Controls - 64 Aspirin 250 32 2.8* Phenylbutazone 250 32 2.3* Indomethacin 250 32 2.9* Cis-2-benzoyl-3-hydroxy-crotononitrile 250 12 2.3* Cis-2- (m-fluorobenzoyl) -3-hydr- oxy-crotononitrile 250 7 1.61* Cis-3-hydroxy-2-E-toluoylcrotononitrile 250 8 1.41* Cis-3-hydroxy-2-(p-anisoyl)- crotononitrile 250 5 1.59* Cis-3-hydroxy-2-(o-anisoyl)crotononitrile 250 8 1.30* Cis-2- (o-fluorobenzoyl) -3-hydr- oxy-crotononitrile 250 8 2.18* Cis-3-hydroxy-2-(&alpha;,&alpha;,&alpha; ;,-trifluoro- -toluoyl)crotononitrile 250 3 1.97* Cis-2-(2-thenoyl) 3-hydroxy92- butenonitrile 250 6 2.04* Cis-2- (3-thenoyl) -3-hydroxy-2- butenonitrile 250 7 2.42* *Statistically significant activity p = < .05 by t test (B) Adjuvant-induced arthritis in the rat The following test shows the activity of the active compounds of this invention against chronic inflammation in adjuvant-induced arthritis which is accompanied by joint destruction. Groups of three Royal Hart, Wistar strain rats weighing 200 + 10 g. each were injected intradermally in the right hind paw with Freund's adjuvant (dried human tubercle bacilli in a mineral oil vehicle) at a dose of 2 mg./kg. of body weight. The test compounds were administered orally in a 1.5% starch vehicle at various doses once daily on days 0 to 13 post challenge. Control rats were treated in a similar manner, but given only starch vehicle. On the 14th and 21St day post challenge the diameter of the injected paw (primary lesion) was measured -by micrometer caliper. The volume of inflamed paws were estimated from these measurements and the effects of each compound are expressed as per cent inhibition of swelling as compared to controls. Table records the results of these tests conducted with representative compounds of- this invention and known anti-inflammatory agents. The active compounds of this invention-suppress the progression of the arthritis and associated joint deterioration. TABLE II The Effect of Anti-Inflammatory Agents on AdJuvant- Induced Arthritis in Rats Number % Inhibition of Oral Dose of Swelling Compound (mg./kg.) Rats Day 14 Day 21 Normal rats Adjuvant Controls - 0 0 Indomethacin 2 57 51* 24* 1 54 46* 19* 0.5 54 40* 20* 0.25 9 30* 4 Aspirin 400 57 73* 43* 200 66 48* 27* 100 63 36* 13 50 21- 23* 3 Phenylbutazone 150 27 75* 44* 75 39 62* 28* 37.5- 39 56* 14 18.8 21 31* 7 Cis-2-(p-fluorobenzoyl)3-hydroxycrotononitrile 25 18 65* 30* Cis-2-(2-chlorobenzoyl)- 3-hydroxycrotononitrile 25 21 58* 15 Cis-2-(o-chlorobenzoyl)- 3-hydroxycrotononitrile 50 9 39* 29 Cis-2- (m-fluorobenzoyl) - 3-hydroxycrotononitrile 50 9 48* 37* Cis-2-(3-chloro-o-toluoyl)-3-hydroxycrotononitrile 50 9 61* 17 Cis-3-hydroxy-2-(&alpha;,&alpha;,&alpha;trifluoro-E-toluoyl)- crotononitrile 25 6 68* * Statistically significant activity p = < .05 by t test. Table II (continued) Number % Inhibition of Oral Dose of Swelling Compound (mg./kg.) Rats Day 14 Day 21 Cis-2-(2-thenoyl)-3hydroxy-2-butenonitrile 50 18 42 6 Cis-2- (3-thenoyl) -3- hydroxy- 2-b uteno- nitrile 50 18 38* Cis-2- (5-chloro-2- thenoyl)-3-hydroxy2-butenonitrile 25 9 49* 31* * Statistically significant activity p = < .05 by t test. Using the same procedure, additional active compounds of the present invention were tested against chronic inflammation in adjuvant-induced arthritis, with observation of the primary lesion. At the same time, the other inflamed sites, such as ears, paws and tail (secondary lesions) were observed and each rat was graded as to degree of inflammation and swelling present. The grading is based on a scale of 0 to 24, where 0 represents a complete absence of induced arthritic nodules and 24 represents the maximum degree of inflammation. The mean grade for each treated group is calculated and the effects of each compound are expressed as per cent inhibition of the control grade. Table III records the results of tests conducted with typical compounds of the present invention and known anti-inflammatory agents. The present active compounds appear to suppress the progression of the arthritis and associated joint deterioration. TABLE II - The Effect of Anti-Inflammatory Agents on Adjuvant Arthritis in Rate % Inhibi- %Inhibition Mean tion of of Control Oral Weight Swelling Grade Dose Dead/- Gain (primary (secondary mg./kg. Treated (grams) lesion) lesion) of body At Day Day Day Day Day Day Compound weight 21 Days 14 21 14 21 14 21 Normal Rats - 8/186 77 112 - - - Adjuvynt Controls - 53/630 36 31 0 0 0 0 Indomethycin 2 8/57 68* 68* 51* 24* 28* 25* 1 9/54 63* 65* 46* 19* 34* 20* 0.5 5/54 53* 51* 40* 20* 25* 17* 0.25 0/9 51 57* 30* 4 22* 4 Aspirin 400 18/57 41 55* 73* 48* 58* 45* 200 10/66 40 44 48* 27* 26* 17* 100 18/63 48 53* 36* 43 19* 8 50 2/21 56* 44 23* 3 12 9 Phenylbutazone 150 2/27 40 50* 75* 44* 54* 31* 75 2/39 51* 50* 62* 28* 27* 15 37.5 5/39 53* 53* 56* 14 18 13 18.8 2/21 50* 45 31 7 4 8 Cis-2-benzoyl-3-hydroxy- 100 5/18 43 41 68* 53* 38* 46* crotononitrile 50 3/36 51* 45* 64* 54* 14 17 25 3/18 37 28 26 14 10 1 4.-(p-Chlorophenyl)-2-(1-hydroxyethelidine)acetonitrile 25 6/21 41 21 68* 17 - 2-Cyano-3-hydroxyorotonic acid, p-chlorophzenyl ester 25 2/18 60 46 45* 0 - * Significantly different from adjuvant controls TABLE III (continued) % Inhibi- %Inhibition Mean tion of of Control Oral Weight Swelling Grade Dose Dead/- Gain (primary (secondary mg./kg. Treated (grams) lesion) lesion) of body At Day Day Day Day Day Day Compound weight 21 Days 14 21 14 21 14 21 2-Cyano-3-hydroxyorotonic acid, 2,3-dichlorophenyl ester 50 11/24 36 32 41* 0 - 2-Cyano-3-hydroxyorotonic acid, o-chlorophenyl ester 50 0/9 25 29 57* 35 - *Significantly different from adjuvant controls Adjuvant-induced experimental polyarthritis is a specific systemic disease of the rat which shares interesting similarities with rheumatoid arthritis. Specifically the histology of the two diseases bears a remarkable resemblence as shown by C.M. Pearson et al., Am. 3. Path. 42, 73 (1963-). EM. Glenn, Am. J. Vet. Res. 27, (116), 339 to966) has classified adjuvant-induced polyarthritis as a crippling and permanent deformity resulting from diffuse connective tissue involvement around certain susceptible joints in the rat. Zahiri et al., Can. Med. Ass. J., 101, 269 (1969) have shown that the fusiform swelling of the distal joints is associated with edema, congestion and synovitis including pannus formation, all of which.precede the ultimate destruction of bone and cartilage. Furthermore, Zahiri et al., indicate that the cartilage destruction in the joint is due to an invasive pannus which originates in the marginal synovium and extends across the articular surface to erode it. When non-steroidal, anti-inflammatory agents such as indomethacin inhibit arthritic paw swelling, which is composed of inflammatory cell infiltrates, they have also been shown to prevent joint and bone deterioration lsee S. Wong et al., J. Pharm. & Exp. Ther. 185, 127 (1973) and G.R. Bobalick et al., Agents and Actions 4, 364 (1974)]. The most pointed reference showing the relationship between arthritis and joint deterioration is an X-Ray analysis of adjuvant arthritis in the rat by Blackham et al., Agents and Actions 7, 145 (1977). In a similar manner, inhibition of the progress-f arthritis in paws of rats treated with the compounds of this invention also lessens associated joint deterioration. (C) Migration inhibitory factor in the guinea pig Rheumatoid arthritis is a chronic inflammatory disease that is characterized by the migration of lymphocytes, macrophages and polymorphonuclear leukocytes to the sites of inflammation. The migration of lymphocytes and macrophages and their multiplication in situ is one reason for the very large increase in size of the normally thin synovial membrane, the membrane that encloses the joint space. The synovial membrane that has been transformed in this manner, slowly grows over the articular surfaces and causes the destruction of the articular cartilage and other connective tissue structures of the joint. One of the mechanisms for the destruction of articular cartilage by the synovium is believed to be through the release of various hydrolytic enzymes by the resident macrophages which have been immobilized and activated by migration inhibitory factor (MIF). Macrophages stimulated by MIF are termed "activated macrophages" and undergo the following changes: (a) increased glucose oxidation, (b) increased ruffling of plasma membrane and increased spreading of cells, (c) synthesis and secretion of neutral proteases, (d) release of preformed lysosomal enzymes, (e) decreased migration from a capillary tube. All these effects are associated with an inflammatory situation and it has been demonstrated that MIF is present in the synovial fluid from patients with rheumatoid arthritis. The mechanisms of cartilage destruction can be pictured as follows: EMI31.1 Although the postulated antigen initiating These destructive events in rheumatoid arthritis has not been discovered, the secretion of MIF by lymphocytes and the secretion of enzymes by macrophages as well as the breakdown of cartilage by macro phage enzymes has been demonstrated. Drugs that can therefore block the release of MIF by lymphocytes or the activation of macrophages by MIF should be clinically effective in retarding the destructive joint damage which occurs in rheumatoid arthritis. Drugs can be tested as MIF inhibitors by using the capillary tube migration assay as follows. Male Hartley guinea pigs, weighing between 300 and 600 grams, are injected intraperitoneally with 25 ml. Marchs 52 Oil (Humble Oil). Three to four days later, the guinea pigs are sacrificed by decapitation, the peritoneium opened, and the exudate aspirated into a separatory funnel after the addition of 50 ml. of cold Hank's solution. This is repeated two times. The oil phase is discarded and the cell suspension is spun down at 1200 r.p.m. for ten. minutes. The cells are resuspended in Hank's solution and spun down at 900 r.p.m. for five minutes This is repeated two times. Viability of the cells is then determined using trypan blue. In all experiments, viability is greater than 90%. The cell concentration is then adjusted to give a 10% packed cell volume by the addition of the appropriate amount of MEM z (Gibco 109) + 15% guinea pig - serum. To the medium is added L-glutamine (2 mM), penicillin (100 Ufml.)- and streptomycin (100yg/ml). Capillary tubes (1.1-1.5 x 75 mm, Clay Adams) are filled with cells by capillary action and sealed at one end with a small plug of paraffin. Capillary tubes are centrifuged at 700-800 r.p.m. for five minutes to get approximately 4-5 mm of packed cells at the closed end. The tubes are cut at the cell-fluid interface. Two packed capillary tubes are then transferred to each chamber of the Lexy culture dish (Mini Lab Co. LLC-4002, Quebec, Canada). The capillaries are held in place using a small amount of silicone grease (Dow Corning) and a cover glass then placed on top of the chamber, making a seal between the cover glass and the chamber using paraffin wax. Chambers are then filled with medium or in medium in which antigen (PPD) or antigen + drug are dissolved by filling the chamber through the passages. After the addi tion of medium, the passages are sealed off using silicone. The cells are then incubated at 370C. for 24 hours. To determine the area of cell migration out of the capillary tube onto the chamber surface, the chambers are projected onto a microscope screen, the area traced onto paper, and then measured using a planimeter. The antigen, PPD, inhibits the migration of macrophages by approximately 50%. Drugs that reverse this inhibition by greater than 15% are considered active. Table IV lists the results of this direct MIF assay at the indicated dose level with typical compounds of the present invention. TABLE IV The Effect of Anti-Inflammatory Agents on Migration Inhibi tory Factor &num;Actives** Compound Dose % Reversal* Total Tests Cis-2- (-fluorobenzoyl -5 3-hydroxycrotononitrile 5 x 10 M 48 4/4 Cis-2- (-bromobenzoyl)- 3-hydroxycrotononitrile 10 g./ml. 25 2/3 Cis-2-(o-anisoyl)-3- -3- hydroxycrotononitrile 5 x 10 M 18 4/5 Cis-2-(3-chloro-o-tolu oyl) - 3-hydroxycrotono- -5 nitrile 5 x 10 M 16 3/5 *Per Cent reversal of inhibition = c-b wherein a = a-b cells with no addition, b = cells + antigen, and c = cells + antigen + drug. **Ratio is the number of tests wherein the per cent reversal of inhibition > 15%e (D) Ultraviolet-induced erythema in guinea pigs Another method of determin ng a drug effect on conditions which result in inflammation is by measuring the. effect on ultraviolet induced erythema in guinea pigs. Albino guinea pigs were depilitated on their flanks, the evening before testing, with a standard mixture of barium sulfide and gum acacia. On the morning of the test, groups of four guinea pigs were dosed by gavage one hour prior (-1 hour) to ultraviolet exposure. At 0 hour they were restrained in a plastic container which allows exposure of 3 circular spots. They were then exposed to ultraviolet irradiation from a "Hanovia" Kromayer lamp, model 10, for 60 seconds. At one and four hours, the degree of erythema for each of the three sites was assessed according to the following scoring system: 0 = no erythema, 0.5.-- incomplete circle or faint erythema, and 1,0 = complete circle of distinct erythema. Thus, the maximum score for each animal was 3.0. The following Table V summarizes the results of this test with a typical compound of the present invention and other drugs known to have a beneficial antiinflammatory effect in suppressing ultra-violet induced erythema in warm blooded animals. TABEL V - The Effect of Anti-Inflammatory Agents on Development of erythema in Giunea Pigs (pooled data) Dose mg./kg. of body Soore (avg.) Oral Treatement weight 1 hour 4 hours Number Decision Control - 2.1 2.8 384 Aspirin 250 0.1 1.2 88 A 125 0.1 2.0 16 A 62.5 0.8 2.0 11 A 31.3 1.2 2.3 12 Phenylbutazone 250 0 0.5 60 A 125 0.1 1.1 16 A 62.5 0.3 0.9 12 A 31.3 0.4 1.7 12 A 15.6 0.4 2.3 8 A 7.8 1.1 2.9 8 Indomethycin 250 0 1.0 20 A 125 0 1.3 12 A 62.5 0 1.3 8 A 31.3 0.1 1.9 8 A 15.6 0 2.0 8 A 7.8 0.6 2.3 8 A 3.9 1.2 2.9 8 Cis-2-benzoyl-3-hydroxy-crotono- 125 0 1.3 8 A nitrile 62.5 0.8 2.4 4 A 31.3 0.8 2.3 4 A 15.6 2.3 2.5 4 A - Statistically significant activity - p = < .05 by t test. (E) Synovium-cartilage Test Compounds of the invention have been tested by the synovium-cartilage test which is a modification of the method described by Dumonde, D.C. and Glynn, L.E., The Production of Arthritis in Rabbits by an Immunological Reaction to Fibrin, Brit. J Exp. Pathos*, 43, 373 (1962). Male, New Zealand rabbits, weighing 1.6-3.0 kg were used. The rabbits were housed in individual cages and given food and water ad libitum. The rabbits were sensitized to bovine serum albumin (BSA) by injection of 20 mg./kg. BSA in complete Freund's adjuvant The emulsion was injected subcutaneously into multiple sites on the back. Total injection volume equaled one mg./kg. of body weight. Between 18 and 21 days following immunization, the rabbits were challenged with an intra-articular injection of 5 mg. BSA into the right knee joint. Unanesthetized animals were restrained on their backs, and a 20-gauge, one-inch needle, with a 5 ml. syringe, was introduced into the joint and synovial fluid aspirated to determine that the synovium had been penetrated. The needle was then left in place for injection of the antigen. A0.5 ml. portion of 10 mg./ml. BSA in sterile saline was injected into the synovial sac The rabbits received an additional five intra-articular inJections of 5 mg BSA into the right knee at intervals of 12-16 clays. Following the sixth injection the rabbits-were sacrificed by an intracardiac injection of 5 ml. of a saturated solution of potassium chloride. -The right knee was shaved. A longitudinal incision was made over the patellar ligament and the skin reflected under sterile conditions. The patellar ligament was cut transversely and reflected. Fascia and capsular tissue were trimmed from the lateral and medial aspects of the knee exposing the synovial membrane. The membrane was grasped with forceps, stretched laterally and then excised in -a single piece on each side of the knee. The infrapatellar fat pad was removed and the joint space widened by cutting the anterior attachments of the menisci and severing the collateral cruciate ligaments. The femur and tibia were then separated and the menisci excised along with sufficient amounts of synovial tissue from the popliteal area adhering to the menisci. The tissues were immediately placed in a sterile Petri dish containing tissue culture medium composed of AEM (Earle's salts) without sodium bicarbonate, with 25 mM Hepes buffer,.pH adjusted to 7.34-7.37, and antibiotics (streptomycin and neomycin, 100 units/ml.). Ten per cent normal rabbit serum (NRS) was added. The tissues were rinsed three times in fresh medium plus 10% NRS, then cut into pieces of 20-30 mg. Articular cartilage was obtained from the knees of normal, young rabbits, weighing 1.0 to 1.5 kg. The knees were shaved, the rabbits sacrificed and the joint exposed as described above. Synovial tissue and the infrapatellar fat pad were removed. Ligaments were severed and the menisci excised. Femur and tibia were then separated and articular cartilage was cut from supracondylar lines, patellar surface and femoral condyles. Due to curvature of the bone, these pieces were not more than 6-7 mg. each. No cartilage was taken from the tibia. The cartilage was placed in a sterile Petri dish containing tissue culture medium plus 10% NRS and rinsed three times wth fresh medium t 10% NRS. The cartilage was then cut into 1-2 mg. pieces and stored at -70 C. A 10 mg portion of the test ccOnpound was dissolved or suspended in absolute ethanol. Ten ul. were then transferred to the complete tissue culture medium. The final concentration of test compound was then 10 mcg./ml. and the vehicle 001%. Tissue culture medium was added to 12 x 75 mm clear plastic culture tubes containing one piece of normal articular cartilage. A piece of arthritic synovial tissue was then added to all tubes except those tubes in which cartilage was incubated alone. All tubes were then incubated at 370C. for 48 hours with constant rotation in a roller drum at 0.2 rpm. After 48 hours the cartilage was removed, hydrolyzed and assayed for hexoseamine and hydroxyproline. Hexoseamine to hydroxyproline ratios were calculated for the three groups: 1. Cartilage alone 2. Cartilage + synovium 3. Cartilage + synovium + test compound. Cartilage hexoseamine decreases when it is cultured in the presence of synovium but remains constant when cultured alone. Hydroxyproline remains constant in all groups and the amount assayed is a measure of the size of the incubated cartilage. Therefore, the hexoseamine/hydroxyproline ratio decreases in the cartilage + synovium group relative to the cartilage alone group. The decrease is approximately 508 a If a compound prevents the decrease in the hexoseamine/hydroxyproline ratio by greater than 50% it is retested. A compound is considered active if it averages greater than 50% suppression of breakdown in three separate tests. The following Table VI gives the results of this test with compounds of the present invention. These compounds are indicated to be active when tested by the above procedure. TABLE VI No. of Mean % Compound Tests Inhibition 2-Cyano-3-hydroxyctotonic acid, - methoxyphenyl ester 4 58.38 2-Cyano-3-hydroxycrotonic acid, - tolyl ester 3 50.34 2-Cyano-3-hydroxycrotonic acid, omethoxyphenyl ester 3 49.30 2-Cyano-3-hydroxycrotonic acid, ofluorophenyl ester 3 52.34 2-Cyano- 3-hydroxythiocrotonic acid S-phenyl ester 3 105.77 5-Methyl-4-isoxazolecarboxylic acid, o-methoxyphenyl ester 3 86.67 S-Methyl-4-isoxazolecarboxylic acid, 2,4,6-trichlorophenyl ester 3 63.80 Compositions according to the present invention having the desired clarity, stability and adaptability for parenteral and intra-articular use are obtained by dissolving from 0,108 to 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normaily liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500. Although the amount of active compound dissolved in the above vehicle may vary from 0.10% to 10.0% by weight, it is preferred that the amount of active compound employed be from about 3.0% to about 9.0% by weight Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having an average molecular weight of from about 200 to about 400. In addition to the active compound, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for these purposes are, for example, myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, benzalkonium chloride, phenethyl alcohol, chloro phenyl-a-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter it is also convenient to employ antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0.05 to about 0.2% concentrations of antioxidant are employed. For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.50 mg./ml. of the finished compositions. The active compounds of the invention are equally adapted to intravenous administration when diluted with water or diluents employed in intravenous therapy such as isotonic glucose in appropriate quantities. For intravenous use, initial concentrations down to about 0.05 to 0.25 mg./ml. of active compound are satisfactory. The active compounds of the present invention -may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of tablets troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such ccrnpositlons and preparations should contain at least 0.1t of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60 of the weight of the unit. The amount of active ingredient in such Xherapeuticaily useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 250 milligrams of active compound. The tablets, troches, pulls, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermlnt, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in audition to materials of the above type, a liquid carrier such as a fatty oil, Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. The invention will be described in greater detail in conjunction with the following specific Examples. EXAMPLE 1 3-Dimethylamino-2-(p-fluorobenzoyl)crotononitrile To a solution of 1.6 g. of -fluorobenzoylaceto- nitrile [Pihl et al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Univ., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -100C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10 C. for 2 hours and then evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through Magnesol#. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product. EXAMPLE 2 Cis-2-(p-fluorbenzoyl)-3-hydroxycrotononitrile To a solution of 6.7 g. of p-fluorobenzoylaceto- nitrile in 100 ml. of chloroform, cooled to O c., is added 7 ml. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred in an ice bath for 2 hours and then at room temperature for 16 hours. The solution is evaporated in vacuo to an oil. This oil is dissolved in chloroform, filtered through Magnesol# and then evaporated to an oil. This oil is dissolved in 100 ml. of methanol and 20 ml. of IN hydrochloric acid is added. The reaction mixture is heated on a steam bath for 25 minutes, cooled and the precipitate is collected, The solid is recrystallized from 50 ml. of cyclohexane, giving the desired product. EXAMPLE 3 3, 4-Difluoroacetophenone Dry aluminum chloride (26 g., 0.19 mole) is added to a 250 ml. three-neck flask under argon and the flask is cooled in ice. Acetyl chloride (14 ml., O.19 mole) is then added dropwise, followed by 20 g. (0.18 mole of o-difluorobenzene. The ice bath is removed and the reaction is slowly warmed and eventually held at 1000 for 3.5 hours. The hot reaction solution is then poured onto ice and extracted with ether. The organic extracts are washed with aqueous sodium bicarbonate and evaporated. The dark residue (23 g.) is distilled at 39 /0.1 mm to provide 20 g. (73%) of colorless 3,4-difluoroacetophenone (mp. ca. 20 C). Similarly prepared is 2,5-difluoroacetophenone. EXAMPLE 4 3, 4-Difluorophenacyl bromide To a solution of 10.1 g. (0.065 mole) of 3,4-difluoroacetophenone in 100 ml. of glacial acetic acid was added 3.4 ml. (0.065 mole) of bromine dropwise. When the addition was complete the solution was stirred for 0.5 hr. and then stripped to dryness under reduced pressure. The residue was dissolved in chloroform and washed with aqueous sodium bicarbonate. Evaporation of the organic phase provided 14.8 g. (97%) of colorless liquid product. Similarly prepared were 2,4-dichlorophenacyl bromide, o-ethylphenacyl bromide, p-isopropylphenacyl bromide, m-isobutylphenacyl bromide, 3,4-dimethylphenacyl bromide, m-ethoxyphenacyl bromide, p-isopropoxyphenacyl bromide, 3,4-diethoxyphenacyl bromide, and 2,5-difluorophenacyl bromide. EXAMPLE 5 3,4Difl.uorobenzoylacetonitrile A solution of 13.2 g. (0.056 mole) of 3,4-difluorophenacyl bromide was dissolved in 100 ml. of ethanol and cooled to 50C. in ice. A solution of 7.6 g. (0.16 mole) of sodium cyanide in 40 ml. of water was added dropwise over 0.5 hr. and the reaction is stirred for an additional one hour. At that time, the mixture was diluted with 100 ml. of water and filtered through Celite&commat;. Acidif cation of the filtrate gave a cloudy mixture which was extracted with methylene chloride. The organic phase was dried, filtered through Magnesol# and evaporates. Re- crystallization of the residue from carbon tetrachloride provides 5.3 g. (52%) of colorless solid, m.p. 74-75 C. Similarly prepared were 2, 4-dichlorobenzoylacetonitrile, o-ethylbenzoylacetonitrile, -isopropylbenzoylacetonitrile, m-isobutylbenzoylacetonitrile, 3,4-dimethylbenzoylaceto nitrile, m-ethoxybenzoylacetonitrile, p-isopropoxybenzoylacetonitrile, ,3,4-diethoxybenzoylacetonitrile, and 2, 5-di- fluorobenzoylacetonitrile. EXAMPLE 6p-Fluorobenzoylacetonitrile, thalium (I) salt A suspension of 10 g. of p-fluorobenzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (I) ethoxide is slowly added. The resulting reaction mixture is-stirred for one hour at room temperature and then filtered. The collected precipitate is washed with diethyl ether and air dried whereby there is obtained 23.7 g. (998 yield) of the thallium (I) salt of p-fluorobenzoylacetonitrile which may be stored at room temperature. In a similar manner, the thallium (I) salts tabulated below were prepared. Example No. Thallium (I) salts 7 m-Chlorobenzoylacetonitrile, thallium (I) salt 8 p-Bromobenzoylacetonitrile, thallium (I) salt 9 o-Bromobenzoylacetonitrile, thallium (I) salt 10 2,4-Dichlorobenzoylacetonitrile, thallium (I) salt 11 3,4-Difluorobenzoylacetonitrile, thallium (I) salt 12 o-Ethylbenzoylacetonitrile, thallium (I) salt 13 p-Isopropylbenzoylacetonitrile, thallium (I) salt 14 m-Isobutylbenzoylacetonitrile, thallium { alt 15 3,4-Dimethylbenzoylacetonitrile, thallium (I) salt 16 m-Ethoxybenzoylaceton-itrile, thallium (I) salt 17 p-Isopropoxybenzoylacetonitrile, thallium (I) salt 18 3,4-Diethoxybenzoylacetonitrile, thallium (I) salt EXAMPLE 19 Cis-2-(p-fluorobenzyol)-3-hydroxycrotononitrile To a suspension of 2.-2 go of p-fluorobenzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml. of acetyl fluoride with stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added1 followed by 2 ml. more after twelve hours. Twelve hours later, the precipitated thallium (I) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the cis-2-(p-fluorobenzoyl)- 3-hydroxycrotononitrile. EXAMPLE 20 Cis-2- (p-bromobenzoyl) -3-hydroxy-2-pentenonitrile A suspension of 5.0 g. of p-bromobenzoylacetonitrile, thallium salt in 30 ml. of tetrahydrofuran is treated with an excess of propionyl fluoride. After 15 hours, the precipitate is filtered off and the filtrate is stripped to dryness. The residue is dissolved in chloroform and extracted with aqueous sodium bicarbonate. The aqueous phase is acidified and the product is extracted with chloroform. The title compound is obtained after column chromatography. In a similar manner the acid fluorides listed below were reacted with the appropriately substituted benzoylacetonitrile thallium salts to provide the compounds tabulated below. Example Thallium Salt No. Product Acid Fluoride from Example No. 21 Cis-2-(m-chlorobenz- Butyryl 7 oyl) -3-hydroxy-2- Fluoride hexenonitrile 22 Cs-2-(p-bromobenz- Propionyl 8 oyl)-3-hydroxy-2- Fluoride pentenonitrile 23 Cis-2-(o-bromobenz- Isobutyryl 9 oyl)-3-hydroxy-4- Fluoride methyl-2-penteno nitrile 24 Cis-2-(2,4-dichloro- Valeryl 10 benzoyl) -3-hydroxy- Fluoride 2-heptenonitrile 25 Cis-2-(3,4-difluoro- Isovaleryl 11 benzoyl)-3-hydroxy- Fluoride 5-methyl-2-hexeno nitrile 26 Cis-2-(o-ethylbenz- 2-Methylbutyr- 12 oyl)-3-hydroxy-4 yl Fluoride methyl-2-hexeno- nitrile Example Thallium Salt No. Product Acid Fluoride from Example No. 27 Cis-2-(p-isopropyl- Pivalyl 13 benzoyl) -3-hydroxy- Fluoride 4, 4-dimethyl-2- pentenonitrile 28 Cis-2-(m-isobutyl- Propionyl 14 benzoyl) -7hydroxy- Fluoride 2-pentenonitrile 29 Cis-2-(3,4-dimethy- Butyryl 15 ylbenzoyl) -3-hydr- Fluoride oxy-hexenonitrile 30 Cis-2-(m-ethoxy- Isobutyryl 16 benzoyl) -3-hydroxy- Fluoride 4-methyl-2-penteno nitrile 31 Cis-2-(p-is6prop- Valeryl 17 oxybenzoyl)-3-hydr- Fluoride oxy-2-hepteno nitrile 32 Cis-2-(3,4-dieth- Isovaleryl 18 oxybenzoyl)-3-hydr- Fluoride oxy-5-meEhyl-2- hexenonitrile EXAMPLE 33 Cis-2- (E-ehl.orobenzoyll-3-hydroxycrotonitrile To a mixture of 68.5 g. of p-chlorobenzonitrile and 24.0 g. of sodium hydride (50% in mineral oil) in 250 ml. of ether is added, 26.1 ml. of acetonitrile and 2 ml. of isopropanol. The mixture is stirred and refluxed on a steam bath for 6 hours and then stirred overnight at room temperature. A 5 ml. portion of methanol and 250 ml. of water are added. The ether is boiled away on a steam bath and the mixture is filtered. The solid is dissolved in warm ethyl acetate and filtered. The filtrate is evaporated to a solid giving ss-amino-4-chlorocinnamonitrile. A 94.68 g. portion of 6-amino-4-chlorocinnamo- nitrile is suspended in 250 ml. of water. A 50 ml. portion of concentrated hydrochloric acid is added and the mixture is stirred overnight. The solid is collected and stirred for 4 hours in a mixture of 250 ml. of water, 250 ml. of ethanol and 50 ml. of concentrated hydrochloric acid. The reaction mixture is evaporated and the solid is taken up in methylene chloride and passed through Magnesol z The filtrate is evaporated on a steam bath with the addition of hexanes giving crystals of -chlorobenzoylacetonitrile. A 9.0 g. portion of p-chlorobenzoylacetonitrile in 100 ml. of chloroform is reacted with 10 ml. of N,N-dimethylacetamide dimethylacetal as described in Example 2, giving the desired product. EXAMPLE 34 Cis-2- (o-chlorobenzoyl) - 3-hydroxycrotonnitrile A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged 5.75 ml. of acetonitrile in 10 ml. of ether are added. The reaction is cooled in a dry ice-acetone bath and 13.3 g. of 2-chlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol #. The filtrate is evaporated with the addition of hexanes giving ss-amino-2-chloro- cinnamonitrile as a white crystalline solid. A 45 ml. portion of 1N hydrochloric acid is added to the S-amino-2-chlorocinnamonitrile and the reaction is stirred overnight. The solid is collected, washed with water, dried, taken up in methylene chloride and passed through Magnesol The filtrate is evaporated on a steam bath with the addition of hexanes giving o-chlorobenzc"t- acetonitrile as a white crystalline solid. A 4.4 g. portion of o-chlorobenzoylacetonitrile in 50 ml. of chloroform is reacted with 5 ml. of N,N-di- methylacetamide dimethylacetal as described in Example 2, giving the desired product. EXAMPLE 35 Cis-2- (m- fluorobenzoyl) - 3-hydroxycrotononitrile To a solution of 4.7 g. of m-fluorobenzoylaceto- nitrile [Pihl, et al., Reakts. Sposabnost. Org. Soedin. Tartu. Gos. Uni°, 5 (1), 27 (1968)3 in 50 ml. of chloroform, cooled in an ice bath, is added 5 ml. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at OOC, for 2 hours then at room temperature for 16 hours. The solution is evaporated in vacuo to an oil. The oil is dissolved in 50 ml. of methanol and 15 ml. of 1N hydrochloric acid is added. The reaction mixture is heated on a steam bath for 30 minutes and then evaporated in vacuo to an oil. This oil is added to 75 ml. of benzene and extracted three times with a saturated solution of sodium-bicarbonate. The combined aqueous phase is washed with benzene, acidified with concentrated hydrochloric acid and the precipitate is collected and recrystallized from isopropanol with charcoal treatment giving the desired product. EXAMPLE 36 Cis-2- (o-fluorobenzoyl) -3-hydroxycrotononitrile A 9.8 g. portion of o-fluorobenzoylacetonitrile [Dorsch et al., J.A.C.S. 54, 2960 (1932)) in 100 ml. of chloroform is cooled in an ice-water bath. A 10 ml. portion of N,N-dimethylacetamide dimethylacetal is added and the mixture is stirred in an ice bath for 2 hours and then at room temperature overnight. The mixture is evaporated to an oil, dissolved in 50 ml. of methanol, acidified with 20 ml. of 1N hydrochloric acid, heated on a steam bath for 1/2 hour and evaporated to an oil. A 100 ml. portion of chloroform and 100 ml. of saturated aqueous sodium bicarbonate solution are added. The mixture is shaken and the organic phase is again extracted with saturated aqueous sodium bicarbonate solution. The aqueous phases are washed with chloroform, acidified with concentrated hydrochloric acid and the solid is collected, washed with water and recrystallized from hot isopropanol with charcoal treatment giving the desired product. EXAMPLE 37 C2s-2-(3-chloro-o-toluýl)-3-hydroxycrotononitrile A 45.0 g. portion of potassium tertiary butoxide is added to 700 ml. of ether and then cooled in an ice-salt bath. To this is added, over 15 minutes, a mixture of 60.0 g. of 3-chloro-2-methylbenzonitrile and 22.0 ml. of acetonitrile in 300 ml. of ether. The mixture is stirred in the ice bath for 1/2 hour, allowed to warm to room temperature and then stirred for one hour. This mixture is poured into one liter of water and the layers are separated. The aqueous phase is extracted with ether and the ether layers are combined, washed four times with water and dried over magnesium sulfate. The crystals which form on evaporation are collected and recrystallized from 200 ml. of hot benzene giving 16.0 g. of S-amino-3-chloro-2-methylcinnamo- nitrile. An 11.0 g. portion of the above product is added to 150 ml. of methanol and heated to solution on a steam bath. A 50 ml. portion of 1N hydrochloric acid is added and the mixture is heated on the steam bath for 3 hours. The mixture is cooled, 30 ml. of water are added, the precipitate is collected and air dried. This solid is recrystallized from 80 ml. of hot methanol with charcoal treatment giving 7.8 g. of 3-chloro-2-methylbenzoylaceto- nitrile. A 5.4 g. portion of the above ketone in 75 ml. of chloroform is reacted with 60 ml. of N,N-dimethylacetamide dimethylacetal as described in Example 2, to give The desired product. EXAMPLE 38 Cis-3-hydroxy-2- (p- to luoyl)crotonitrile To a solution of 10 g. of a-bromo-p-methy) acetophenone in 50 ml. of ethanol in an ice bath is added dropwise a solution of 6.4 g. of sodium cyanide in 30 ml. of water, at a rate so that the temperature is maintained at 250-300C. The mixture is then stirred at room temperature for 2 hours, drowned in 600 ml. of water and filtered through Celite #. The filtrate is acidified to pH 5 with acetic acid, allowed to stand 10 minutes and then filtered. The solid is dissolved in 100 ml. of boiling benzene, magnesium sulfate is, akeled together with charcoal and the mixture is filtered.(1 400 ml. portion of hexane is added to the filtrate and the mixture is cooled giving 3.0 g. of p-methylbenzoylaceton'trile. A 2.6 g. partion of p-methylbenzoylacetonitrile in 30 ml. of chloroform is cooled in an ice bath. A 3 ml. portion of N,N-dimethylacetamide dimethylacetal is added and the nixture is allowed tio stand in an ice bath for 2 hours and then at room temperature for 48 hours. The mixture is evaporated to an oil which is dissolved in 20 ml. of methanol. A 3 ml. portion of lN hydrochloric acid is added and the mixture is heated on a steam bath for 1/2 hour and evaporated to a dark oil. This oil is dissolved in 75 ml. of benzene and extracted with three 50 ml. portions of saturated aqueous sodium bicarbonate. The combined aqueous phases are washed with benzene and acidified with concentrated hydrochloric acid. The precipitate is collected and recrystallized from 20 ml. of hot isopropanol with charcoal treatment, giving the desired product. EXAMPLE 39 Cis- 3-hydroxy-2-(o-anisoyl)-crotononitrile A 10.0 g. portion of a-bromo-o-methoxyaceto- phenone is suspended in 50 ml. of ethanol. A solution of 6.4 g. of sodium cyanide in 30 ml. of water is added as described in Example 38. Following the procedure of Example 38, there is obtained o-methoxybenzoylacetonitrile. A 3.1 g. portion of o-methoxybenzoylacetonitrile is added to 50 ml. of chloroform cooled in an ice bath. A 3.5 ml. portion of dimethylacetamide dimethylacetal is added and the mixture is stirred in an ice bath for 2 hours and then at room temperature overnight The mixture is evaporated to an oil which is dissolved in 25 ml. of methanol. A 5 ml. portion of 1N hydrochloric acid is added and the mixture is heated on a steam bath for 1/2 hour and then evaporated to an oil. This oil is dissolved in 50 ml. of benzene. A 50 ml. portion of saturated aqueous sodium bicarbonate solution is added forming two layers. The benzene layer is extracted with two 50 ml portions of saturated aqueous sodium bicarbonate solution. The aqueous phases are combined, washed twice with 50 ml. df benzene and acidified with concentrated hydrochloric acid. The solid is collected, washed with water and recrystallized from hot isopropanol, with charcoal treatment, giving the desired product., EXAMPLE 40 Cis-3-hydroxy-2-(p-methoxybenzoyl)crotononitrile A 25.0 g. portion of a-bromo-p-methoxyaceto- phenone is suspended in 125 ml. of ethanol. A solution of 16.0 g. of sodium cyanide in 75 ml. of water is added, using an ice-water bath to-keep the temperature at 25 -30 C. The mixture is stirred for 45 minutes at room temperature. A total of 1.2 liters of water is added in 200 ml. incre ments with filtration through Celite # until no more pre- cipitate forms. The filtrate is acidified to pH 5 with acetic acid. The solid is collected, washed with water, dried and recrystallized from benzene giving p-methoxybenz- oylacetonitrile. A 4.7 g. portion of p-methoxybenzoylacetonitrile is added to 50 ml. of chloroform, cooled in an ice bath. A 5 ml. portion of N,N-dimethylacetamide dimethylacetal is added and the mixture is stirred in an ice bath for 2 hours and then at room temperature overnight. The mixture is evaporated to an oil which is dissolved in 25 ml. of methanol. A 5 ml. portion of 1N hydrochloric acid is added, the mixture is heated on a steam bath for 1/2 hour and then evaporat ed to an ol, A 70 ml. portion of saturated aqueous sodium bicarbonate solution and 70 ml. of benzene are added and the mixture separates into two layers. The benzene layer is extracted twice with saturated aqueous sodium bicarbonate solution The aqueous phases are combined, washed twice with benzene, acidified with 12N hydrochloric acid and the solid is collected. This solid is recrystallized from 50 ml. of hot isopropanol with charcoal treatment giving the desired product. EXAMPLE 41 Cise-3-hydroxy-2-(&alpha;,&alpha;,&alpha;trifluoro-p-toluoyl)crotonitrile An 8.0 g. portion of diisopropylamine in 100 ml. of ether is cooled to OOC. under argon. A solution-of 31.5 ml. of 2.5M n-butyllithium in hexane is added dropwise-and the reaction is further cooled to-100C. A 5.94 -g. portion of 5-methylisoxazole is then added dropwise and the mixture is stirred for 1/2 hour A 15.0 g. portion of -trifluoro- methylbenzoylchloride is added while the reaction is held at O:C. The mixture is allowed to warm to room temperature and stand for 18 hours. The reaction is quenched-with water, acidified with dilute hydrochloric acid and extracted with ether. The ether phase is treated with aqueous sodium carbonate producing three phases. The dark middle phase is isolated, acidified and extracted with chloroform. The extract is dried7 filtered and evaporated. The residue is recrystallized from ethanol-hexane giving the desired compound. EXAMPLE 42 Cyanoacetone, sodium salt A solution of 0.174 mole of sodium ethoxide is prepared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 15 ml. (0.184 mole) of 5-methylisoxazole is then added dropwise as a -colorless precipitate forms When the addition is complete, the mixture is cooled in an ice bath and then filtered. The precipitate is collected, and washed with hexane, yielding 14.0 g. of colorless product. EXAMPLE 43 Cis-3-hydroxy'-2- (a ,a 1a-trifluoro-m-toluoyl) -crotononitrile A mixture of 5.0 g. (48 mmole) of cyanoacetone, sodium salt in 20 ml of tetrahydrofuran is stirred at room temperature as a solution of 3.3 g. (16 mmole) of m-trifluoromethylbenzoyl chloride in 5 ml. of t-e-trahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then evaporated. The residue is acidified and extracted with chloroform Evaporation of the organic phase provides 4.5 g. of an orange solid which is recrystallized from chloroform to provide 2.4 g. of the title compound. EXAMPLE 44 l-Cyano-2-butanone, sodium salt A solution of 0.174 moles of sodium ethoxide is prepared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 5-ethylisoxazole (17.9 g., 0.185 mole) is then added. The reaction is stirred for one hour as a colorless precipitate forms. The mixture is cooled in an ice bath and filtered. The precipitate is washed with hexane and air dried, yielding the title compound. EXAMPLE 45 Cis-2- (p-bromoben zoyl) - 3-hydroxy-2-pentenonitrile A mixture of 3.0 g. (25 mmole) of l-cyano-2butanone, sodium salt in 20 ml. of tetrahydrofuran is stirred as a solution of (8.6 mmole) of p-bromobenzoyl chloride in 6 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 3 hours, then cooled and the solvent evaporated. The residue is acidified and extracted with chloroform. The organic phase is extracted twice with aqueous sodium bicarbonate which in turn is acidified and extracted again with chloroform. The organic phase is dried and evaporated to yield the title compound. EXAMPLE 46 Cis-2- ( , a, a-trichloro-p-toluoyl) -3-hydroxy-crotononitrile In the manner described in Example 41, reaction of 5-methylisoxazole with p-trichloromethylbenzoyl chloride provides the corresponding eis-2- trichloromethylbenzoyl)-3- hydroxy-crotononitrile. EXAMPLE 47 Preparation of 50 mg. Tablets Per Tablet Per 10,099 Tablets 0.050 gm. One of the active compounds 500 gm. listed below 0.080 gm. Lactose 800 gm. 0.010 gm. Corn Starch (for Mix) 100 gm. 0.008 gm. Corn Starch (for paste) 75 gm. 0.148 gm. 1475 gm. 0.002 gm. Magnesium Stearate (1%) 15 gm. 0.150 gm. 1490 gm. Active compounds for above preparation: Cis-2-(p-fluorobenzyol)-3-hydroxycrotononitrile Cis-2-benzoyl- 3-hydroxycrotononitrile Cis-2-(S-fluoro-2-thenoyl-3-hydroxycroto The active compound, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. 8 hand screen and dried at 1200F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine. EXAMPLE 48 Preparation of Oral Suspension Ingredient Amount One of the active compounds listed below 500 mg Sorbitol solution 5708 N.F.) 40 ml-. Sodium benzoate 150 mg. Saccharin 10 Red dye 10 mg.- Cherry flavor 50 mg. Distilled water qs ad 100 ml. Active compounds for above preparation: Cis-2-(p-bromobenzyol)-3-hydroxy-2-pentenonitrile Cis-2-benzoyl- 3-hydroxy-2-pentenonitrile 5 2-(5-fluoro-3-thenoyl)-3 hydroxy-2-pentenonitrile, The sorbitol solution is added to 40 ml. of distilled water and the active compound is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. of the active compound. EXAMPLE 49 Preparation of Parenteral Solution In a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is suspended 20.0 grams of one of the below-listed active compounds with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid and the volume is made up to 1000 ml. with water for injection. The formulation is sterilized, filled into 5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg. of drug) and sealed under nitrogen. Active compounds for the above preparation: Cis-3-hydroxy-2- (a ,a ,a-trifluoro-p-toluoyl) crotononitrile Cis-2-benzoyl-3-hydroxy-2-hexenonitrile Cis-3-hydroxy-2- (S-bromo-2-thenoyl) crotononitrile. EXAMPLE 50 Preparation of Topical Cream Ingredient Amount One of the active compounds listed below 1.0% Ethoxylated stearyl alcohol 10.0% Benzyl alcohol 0.9% Is propyl palmitate 5.0% Sorbitol solution (USP) 5.0% Glycerin 5.08 Lactic acid qs to pH 4.0-5.0 Water qs ad 100.08 Active compounds for the above preparation: Cis-2- (2-methyl-4-isopropoxybenzoyl)-3-hydroxy-4-methyl 2-pentenonitrile Cis-2-benzoyl- 3-hydroxy-4-methyi-2-pentenonitrile Cis-,2- (5-bromo- 3-thenoyl) -3-hydroxy-4-methyl-2-penteno- nitrile. The ethoxylated stearyl alcohol and isopropyl palmitate are heated to liquefying temperature. About 95% of the total volume of water is placed in a separate container followed by the glycerin and sorbitol solution. This aqueous mixture is brought to a boil and then cooled to 600- 750C. The active compound is added to the wax phase and the mixture is stirred until a clear solution is obtained. The benzyl alcohol is added and dissolved in the wax phase. The water phase is passed through a screen into the wax phase while maintaining agitation. Both phases are kept at about the same temperature during transfer. The mixture is cooled while agitation is continued. At a temperature of 50 -55 C. the balance of the water is added. The pH is adjusted to 4.0-5.0 with lactic acid. The batch is cooled with minimum agitation until the cream sets in its final form. EXAMPLE 51 Preparation of Intra-articular Product Ingredient Amount One of the active compounds listed below 2-20 mg. NaC1 (physiological saline) 0.9% Benzyl alcohol N.F. 0.9% Sodium carboxymethylcellulose 1-5% pH adjusted to 5.0-7.5 Water for injection qs ad 100% Active compounds for the above preparation: Cis-2-(2-methoxy-4-trifluoromethylbenzoyl)-3-hydroxy-2 heptenonitrile Cis-2-benzoyl- 3-hydroxy-2-heptenonitrile Cis-2- (S-chloro-3-thenoyl) -3-hydroxy-2-heptenonitrile. EXAMPLE 52 Preparation of Injectable Depo Suspension Ingredient % W/V One of the active compounds listed below 0.05--5 Polysorbate 80 USP 0.2 Polyethylene glycol 4000 USP 3.0 Sodium chloride USP 0.8 Benzyl alcohol N.F 0.9 HC1 to pH 6-8 gs Water for injection qs ad leo0.0 Active compounds for the above preparation: Cis-2-(3,4-difluorobenzoyl)-3 hadroxy-4,4-dimethyl-2 pentenonitrile Cis-2-benzyol-3-hydroxy-4,4-dimethyl-2-pentenonitrile. EXAMPLE 53 2,5-Dichloro-ss-aminocinnamonitrile To a dry 250 ml. three-neck flask is added 30 ml. of hexane under argon, followed by 2.2g.. (46 mmole) of 50% sodium hydride in oil. The mixture is stirred for 5 minutes, the hexane is siphoned off and replaced by 30 ml. of ether. A solution of 7.0 g. (41 mmole) of 2,5-dichlorobenzonitrile, 2.4 ml. (46 mmole) of acetonitrile and 0.4 ml. (4 mmole) of t-butanol diluted to 45 ml. with ether is then added dropwise to the stirred sodium hydride mixture. When the addition is complete, the mixture is heated to reflux overnight. After 24 hours, 40 ml. of water is cautiously added and the ether phase is separated. This solution is dried and evaporated to yield 6.4 g. of off-white solid. This residue is dissolved in chloroform, filtered through a Magnesol pad and the filtrate is concentrated on the steam bath and diluted with hexane. Upon cooling, 5.0 g. of colorless product precipitated. Similarly prepared is 3,5-dimethoxy-ss-aminocinnamo- nitrile; 3,4,5-trimethoxy-B-aminocinnamonitrile; and 2,4,6 trimethyl- -aminocinnamonitrile. EXAMPLE 54 2, S-Dichlorobenzoylacetonitrile A two-phase mixture of 5.0 g. of 2,5-dichloro-ss- aminocinnamonitrile, 50 ml. of chloroform, and 30 ml. of 3N aqueous hydrochloric acid is stirred overnight at 250C. After 15 hours the layers are separated and the chloroform phase is dried over sodium sulfate, and filtered through a pad of Magnesol #. The product is crystallized directly from the filtrate to provide 4.3 g. of colorless solid. Similarly prepared is 3,5-dimethoxybenzoylacetonitrile; 3,4 ,5-trimethoxybenzoylacetonitrile and 2,4,6-trimethylbenzoylacetonitrile. EXAMPLE 55 Cis-2- (3, 4-difluorobenzoyl) -3-hydroxycrotononitrile A solution of 10.2 g. of 3,4-difluorobenzoylacetonitrile, 9.2 g. of-triethyl orthoacetate and 20 ml.- of acetic anhydride is heated on a steam bath for 0.5 hour and then poured into 200 ml. of water which is then heated on the steam bath for 2 hours. On cooling, the solid is filtered and then dissolved in methylene chloride This solution is extracted with two portions of aqueous sodium bicarbonate and the aqueous extracts are combined and acidified with concentrated hydrochloric acid. -The precipitate is extracted into methylene chloride, passed through a pad of Magnesol heated and diluted with hexane. Upon cooling, colorless crystals result, yielding the title compound, m.p. 51 -54 C. Similarly prepared are cis-2- (2, 5-difluorobenzoyl) - 3-hydroxycrotononitrile, cis-2-(3,4, 5-trimethoxybenzo-yl)-3- hydroxycrotononitrile, cis-2- (2,4, 6-trimethylbenzoyl) -3- hydroxycrotononitrile, and cis- 2- (2, 5-dichlorobenzoyl) - 3- hydroxycrotononitrile. EXAMPLE 56 2-(Pentafluorobenzoyl)-3-hydrxycrotononitrile A mixture of 6.8 g. of cyanoacetone, sodium salt in 70 ml. of dry tetrahydrofuran is cooled in ice and 50 g. of pentafluorobenzoylchloride diluted to 10 ml. with tetrahydrofuran is added dropwise. The reaction is stirred overnight and then the solvent is evaporated. The residue is acidified and extracted into chloroform. This chloroform phase is then extracted with aqueous sodium bicarbonate which in turn is acidified and the colorless precipitate is again extracted with chloroform. Upon evaporation of the solvent, a yellow semi-solid results which is recrystallized from ethyl ether (-78 C.) to afford off-white crystals, m.p. 620-630C. Similarly prepared is 2--(2-chloro-6-fluorobenzoyl) - 3-hydroxycrotononitrile. EXAMPLE 57 Cis-2-(p-fluorobenzoyl)-3-hydroxycrotonitrile A mixture of 1.0 g. (9.5 mmole) of cyanoacetone, sodium salt in 20 ml. of tetrahydrofuran is stirred in room temperature as a solution of 0.37 ml. (3.2 mmole) of -fluorobenzoyl chloride in 5 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then evaporated. The residue is acidified and extracted with diethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallized on standing to provide the title compound. EXAMPLE 58 2-p-Fluorobezoyl)-3-methoxycrotonitrile A solution containing 55.8 g. (0.34 mole) of - fluorobenzoylacetonitrile, 41 g. (0.34 mole) of trimethyl orthoacetate, and 90 g. (0.88 mole) of acetic anhydride is heated to reflux for 5 hours. The excess solvent and volatile by-products are then removed by vacuum distillation and the residue is recrystallized from diethyl ether. Alternatively, the distillation residue may be distilled over on a Kugelrohr apparatus at 1600C./0.25 mm. to provide a viscous oil which may be crystallized from diethyl ether to provide the pure title compound. EXAMPLE 59 Cis-2-(p-fluorbenzyol)-3-hydroxycrotonitrile A solution of 5 g. of cis-2-(E-fluosobenzoyl)- 3-methoxycrotononitrile in 50 ml. of ethanol is treated with 25 ml. of 3N aqueous hydrochloric acid at room temperature for one hour. The solvent is evaporated, the residue diluted with water, and the product is extracted with chloroform. The organic phase is separated, dried, filtered and evaporated to provide the title compound. EXAMPLE 60 2- (Dimethylaminomethylene) -2- (fluorophenyl) -butane- 1, 3-dione A solution of 15 g. of p-fluorobenzoylacetone in 35 ml. of N,N-dimethylformamide dimethylacetal is heated on a steam bath and the volatile by-product (methanol) is distilled out. When the theoretical amount of methanol been collected, the reaction mixture is pumped dry, then the product is collected by distillatlon from the reaction pot at 1500C./0.025 mm. Crystalline product (19.5 g. 97% yield) is thus obtained upon cooling of the distillate. EXAMPLE 61 4-Acetyl-5-(p-fluorophenyl)isoxazole and 4-(p-fluorobenzyol)-5-methylisoxazole To a solution of 12.8 g. of 2-(dimethylaminomethyl- ene)-1-(p-fluorophenyl)butane-1,3-dione in 130 ml. of THF is added 4.10 g. of hydroxylamine hydrochloride, followed by 40 ml. of water. The reaction is heated to reflux for 2- hours, then cooled and the solvent is evaporated. The residue is partitioned between ether and water and the organic layer is separated and evaporated. The residue-ls distilled at 100-110 C./o.25 mm. to provide 9.0 g-. of an oily mixture of approximated equal amounts of 4-(p-fluorophenyl)isoxazole azole and 4-acetyl-5-(p-fluorophenyl)isoxazole EXAMPLE 62 Cis-2-(p-fluorobenzoyl)-3-hyrdroxycrotononitrile A solution of 1.65 g. of a mixture of A-acetyl- 5-(p-fluorphenyl)isoxazole and 4-(p-fluorobenzoyl)-5-methylisoxazole in equal amounts is dissolved in 7 ml. of methanol and treated with 5 ml. of 10% aqueous sodium hydroxide. The solution is heated on a steam bath for 15 minutes then cooled, acidified with IN aqueous-HCl and extracted with ether. Vapor ation of the ether provides 1.55 g. of product. Recrystallization from iso-propanol provides 1.0 g. (66%) of cis-2-(pfluorobenzoyl)-3-hydroxycrotonitrile. EXAMPLE-63 3-Amino-2- (p-fluorobenzoyl) crotononitrile Approximately 50 ml. of liquid ammonia is condensed in a three-neck flask cooled to -78 in a dry ice-acetone bath. To this is added 200 mg. of sodium metal, followed by 100 mg of ferric chloride hexahydrate. When the blue color had¯ vanished, 6.2 g. of 2-(p-fluorobenzoyl)-3-methoxycrotono- nitrile is added After stirring for one hour, the reaction is allowed to warm and the solvent evaporate. The residue is dissolved in hot ethyl acetate and filtered through Celitet. The filtrate is concentrated on the steam bath and diluted with hexane. Upon cooling, the crystalline product precipitates, is filtered and dried. EXAMPLE 64 2-(p-Fluorobenzoyl)-3-methylaminocrotononitrile In the glass liner of a stainless steel bomb cooled to -78 is condensed 10 ml. of methylamine. To this is added 0.5 ml. of 2M n-butyllithium (in hexane), followed by 5.0 g. of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile. The bomb is sealed and heated on a steam bath overnight. The bomb is then cooled, opened and the contents evaporated. The residue is dissolved in chloroform, passed through a Magnesol Q pad and the filtrate is evaporated. The residue is recrystallized from chloroformhexane yielding the title compound. EXAMPLE 65 2-(p-Fluorobenzoyl)-3-butylaminocrotononitrile A sample of 2.5 g. of 2-(p-fluorobenzoyl)-3-methoxy crotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200 C./0.1 mm. to obtain the yellow oily product. Example 66 2-(p.-Fluorobenzoyl)-3-dimethylaminocrotononitrile To a solution of 14.5 g. (0.10 m) of Cp-fluoro- benzoyl)acetonitrile in 100 ml. of chloroform, cooled in an ice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide dimethylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol R. The filtrate was evaporated and the oil thus obtained was dissolved in .50 ml. benzene to which petroleum ether- was added until the solution became cloudy. The precipitate which formedupon cooling was collected. The solid was recrystallized twice from benzene-petroleum ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 90 -92 C. EXAMPLE 67 2-(p-fluorobenzoyl)-3-hydroxycrotonitrile A solution of l-.35 g-. (0.006 ml) of 2-(p-fluoro benzoyl)-3-dimethylaminocrotononitrile in a mixture of 15 ml. methanol and 8 ml. of 1N HC1 was heated on the steam bath in an open beaker for 45 minutes. Upon cooling in; an ice bath, a solid formed, was collected, and then recrystallized from cyclbhexane-petroleum ether with charcoal treatment, giving 0.7 g. (64%) of light pinkish crystals7 m.p. 650-670C. EXAMPLE 68 2-(P-Fluorobenzoyl)-3-methoxy-2-pentenonitrile A solution containing 30 g. -of (p-fluorobenzoyl)- acetonitrile, 36.4 g. of trimethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 130 for 3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The chloro form solution is passed quickly through Magnesol# and con- centrated, then cooled to produce the title-product. EXAMPLE 69 2-(p-Fluorobenzoyl)-3-hydroxy-2-pentenonitrile A two-phase mixture of 5.0 g. 2-(p-fluorobenzoyl)3-methoxy-2-pentenonitrile in 50 ml. of chloroform is stirred with a 50 ml. solution of aqueous 1N hydrochlorìc-acid. After 24 hours, the organic phase is separated and evaporated. The residue is recrystallized from chloroform to yield the title compound. EXAMPLE 70 2-(p-Fluorobenzoyl)-3-N-piperidylcrotononitrile To a solution of 5.0 g. of 2-(p-fluorobenzoyl)-3- methoxycrotononitrile in 50 ml. of dry tetrahydrofuran is added 5 ml. of piperidine. The reaction is heated to reflux for 2 hours, cooled and evaporated in vacuo. he residue is recrystallized from chloroform/hexane to provide the crystalline title compound. EXAMPLE 71 2- (p-Fluorobenzoyl) -3-diethylaminocrotononitrile A volume of 10 ml. of diethylamine is condensed in a glass tube at -78 C. A sample of 5 g. of 2-(p-fluorobenzoyl) 5-methoxycrotononitrìle is added, the tube is sealed in stainless steel bomb and heated on a steam bath overnight. The bomb is then cooled, opened, and the contents evaporated. The residue was recrystallized from chloroform to provide the title compound. EXAMPLE 72 2- (p-Fluorobenzoyl) -3-hydroxycrotononitrile, sodium salt A solution of 5.0 g. of 2-(p-fluorobenzoyl)-3- hydroxycrotononitrile in 30 ml. of dry tetrahydrgfuran is added dropwise to a stirred suspension of sodium hydride (1.0 g.) in 30 ml. of dry tetrahydrofuran. After the addition is complete, the reaction mixture is stirred for 2 hours and the resulting orange solution is poured into diethyl ether. A colorless solid precipitates which is filtered a-nd dried to provide the title compound. EXAMPLE 73 2- (p-Fluorobenzoyl) -3-hydroxycrotononitrile, triethyl ammonium salt A solution of 1.3 ml. of triethyl amine in 10 ml. of diethyl ether is added dropwise to a solution of 1.5 g. of 2-(p-fluorobenzoyl)-3-hydroxycrotononitrile in 20 ml. of diethyl ether. After stirring for 1 hour, a yellow oil separated which crystallizes upon evaporation of the solvent. The product was filtered, washed with ether and dried, providing the title compound. EXAMPLE 74 Benzoylacetonitrile, thallium (I) salt A suspension of 10 g. of benzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (z) ethoxide is slowly added. The resulting reaction mixture is stirred for one hour at room temperature and then filtered. The collected precipi tate is washed with diethyl ether and air dried-whereby there is obtained 23.7 g. (998 yield) of the thallium (I) salt of benzoylacetonitrile which may be stored indefinitely at room temperature. EXAMPLE 75 Cis-2-benzoyl-3-hydroxycrotononitrile To a suspension of 2.2 g.-of benzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml. of acetyl fluoride with¯stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added, followed by 2 ml. more after twelve hours. Twelve-hours later, the precipitated thallium CT) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the cis.-2-benzoyl-3-hydroxycrotononitrile which has been described by Musante, Eazz. Chim. Ital. 69, 523 Cl-939). EXAMPLE 76 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile To a suspension of 5 g. of benzoylacetonitrile, thallium (I) salt in 50 ml. of diethyl ether is added a solution of 5 g. of propionyl fluoride in 10 ml. of diethyl ether with stirring at room temperature. After 12 hours, the reaction mixture is filtered and the filtrate evaporated and then pumped dry on a vacuum pump for one-hour. The residue is then treated with chloroform and filtered and the solid collected provides the title compound. EXAMPLE 77 Cis-2-benzoyl-3-hydroxy-2-hexenonitrile The procedure of Example 75 is repeated substituting an equimolecular amount of butyryl fluoride for the acetyl fluoride employed in that example. There is thus-obtained the cis-2-benzoyl-3-hydroxy-2-hexenonitrile after purification by column chromatography. EXAMPLE 78 Cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile By replacing the acetyl fluoride employed in Example 75 with an equimolar amount of isobutyryl fluoride, there is obtained the corresponding cis-2-benzoyl-3-hydroxy-4-methyl2-pentenonitrile after purification by column chromatography. EXAMPLE 79 Cis-2-benzoyl-3-hydroxy-2-heptenonitrile The general procedure of Example 75 is repeated but replacing the acetyl fluoride employed in that Example with an equivalent amount of valeryl fluoride whereby there is obtained the cis-2-benzoyl-3-hydroxy-2-heptenonitrile after purification by column chromatography. EXAMPLE 80 2-Methylbutyryl fluoride A sample of 2-methylbutyryl chloride in dimethylformamide is treated with a threefold excess of sodium fluoride. The temperature is raised and the pure acid fluoride is collected by distillation from the reaction mixture. EXAMPLE 81 cis-2-benzoyl-3-hydroxy-4-methyl-2-hexenonitrile Following the general procedure of Example 76, benzoylacetonitrile, thallium (I) salt is treated with 2 methylbutyryl fluoride to give the cis-2-benzoyl-3-hydroxy4-methyl-2-hexenonitrile after purification by column chromatography. EXAMPLE 82 Cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile Treatment of benzoylacetonitrile, thallium (I) salt with isovaleryl fluoride by the procedure described in Example 76 is productive of the cs-2-benzoyl-3-hydroxy-5- methyl-2-hexenonitrile after purification by column chromatography. EXAMPLE 83 Cis-2-benzoyl-3-hydroxy-4 ,4-dimethyl-2-pentenonitrile In the manner described in Example 76, reaction of benzoylacetonitrile, thallium (I) salt with pivalyl fluoride provides the corresponding cis-2-benzoyl-3-hydroxy 4,4-dimethyl-2-pentenonitrile after purification by column chromatography. EXAMPLE 84 Cis-2-benzoyl-3-hydroxycrotononitrile, sodium salt A calculated concentration of sodium hydroxide in water is prepared and an excess of cis-2-benzoyl-3-hydroxy crotononitrile is added and stirred for half -an hour. The mixture is filtered and the filtrate is evaporated. The gummy residue is dissolved in dry acetone and again evaporat ed, providing the title compound. EXAMPLE 85 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile, triethylammonium salt A sample of cis-2-benzyol-3-hydroxy-2-penteno- nitrile is dissolved in dry diethyl ether and an equivalent amount of triethylamine is added dropwise. The mixture is cooled in ice and the precipitate is removed by flltration to provide the title compound. EXAMPLE 86 Cis-2-benzoyl-3-hydroxycrotononitrile, copper (II) salt A weighed sample cis-2-benzoyl-3-hydroxy- crotononitrile is dissolved in a dilute solution of ammonium hydroxide and an equivalent quantity 6f cupric sulfate in water is added. The blue solution is heated on a steam bath for 3 hours and cooled. The precipitate removed by fil tration and washed with water to yield the title compound. EXAMPLE 87 Cis-2-benzoyl-3-hydroxycrotononitrile A mixture of 1.0 g. (9,5 mmole) of cyanoacetone, sodium salt in 20 ml. of tetrahydrozuran is stirred at room temperature as a solution of 0.37 ml. (3.2 mmole) of benzoyl chloride in 5 ml. of tetrahydroùran is added. The reaction is heated to reflux for 2 hours and the solvent is then evaporated. The residue is acidified and extracted with di ethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallizes on standing to provide the title compound. EXAMPLE 88 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile The procedure of Example 45 is repeated but the p- bromobenzoyl chloride is replaced by 0.9 g. (8.6 mmole) of benzoyl chloride, and there is obtained the title compound. EXAMPLE 89 2-(p-Fluorobenzoyl)-3-ethoxycrotononitrile A solution of 16.3 g. of -fluorobenzoylaceto- nitrile and 18.3 ml. of triethyl orthoacetate in 35 ml. of acetic anhydride is heated on a steam bath for 2.5 hours. The solvents are removed in vacuo and the residue is distilled at 1650-1670C.,/300 ij. Upon cooling, this distillate solidifies and is recrystallized from methylene chloride/hexane to give the desired 2-(2-fluorobenzoyl)-3-ethoxy- crotononitrile, m.p. 770/890C. EXAMPLE 90 2-Benzoyl-3-methylaminocrotononitrile In the glass liner of a stainless steel bomb cooled to -78 is condensed 10 ml. of methylamine. To this is added 0.5 ml. of 2M n-butyllithium (in hexane), followed by 5.0 g. of 2-benzoyl-3-methoxycrotononitrile. The bomb is sealed and heated on a steam bath overnight. The bomb is then cooled, opened and the contents evaporated. The residue is dissolved in chloroform, passed through a Magnesol# pad and the filtrate is evaporated. The residue is recrystallized from chloroform-hexane yielding the title compound. EXAMPLE 91 2-Benzoyl-3-butylaminocrotononitrile A sample of 2.5 g. of 2-benzoyl-3-methoxycrotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200 C./0.1 mm. to obtain the yellow oily product. EXAMPLE 92 2-Benzoyl-3-dimethylaminocrotononitrile To a solution of 14.5 g. (0.10 m) of benzoylacetonitrile in 100 ml. of chloroform, cooled in anice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide di- methylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol t. The filtrate was evaporated and the oil thus obtained was dissolved in -50 ml. benzene to which petroleum ether was added until the solution became cloudy. The precipitate which formed upon cooling was collected. The solid was recrystallized twice from benzene petroleum ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 1050-l060C. EXAMPLE 93 Cis-2-benzoyl-3-hxdroxycrotononitrile A solution of 1.35 g. (.006 m) of 2-benzoyl-3dimethylaminocrotononitrile in a mixture of 15 ml. methanol and 8 ml. of 1N HCI was heated on the steam bath in an open beaker for 45 minutes. Upon cooling in an ice bath, a solid formed, was collected and then recrystallized from -c-yclohexane-petroleum ether with-charcoal treatment, giving 0.7 g. (648) light pinkish crystals, m.p. 710-730C. EXAMPLE 94 2-Benzoyl-3-methoxy-2-pentenonitrile A solution containing 30 g. of benzoylaceto- nitrile, 36.4 g. of triethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 1300 for-3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The cloroform solution is passed quickly through Magnesol # and concentrated, then cooled to produce the title product. Similarly prepared is 2-benzoyl-3-methoxy-2-hexenonitrile ans 2-benzoyl-3-methoxy2-heptenonitrile. EXAMPLE 95 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile A two-phase mixture of 5.0 g. 2-benzoyl-3-methoxy2-pentenonitrile in 50 ml. of chloroform is stirred with a 50 ml. solution of aqueous 1N hydrochloric acid. After 24 hours, the organic phase is separated and evaporated. The residue is recrystallized from chloroform to yield the title compound. Similarly, cis-2-benzoyl-3-hydroxy-2-hexeno- nitrile is prepared from 2-benzoyl-3-methoxy-2-hexeno- nitrile and cis-2-benzoyl-3-hydroxy-2-heptenonitrile is prepared from 2-benzoyl-3-methoxy-2-heptenonitrile. EXAMPLE 96 2-Benzoyl- 3-N-piperidylcrotononitri le To a solution of 5.0 g. of 2-benzoyl-3-methoxycrotononitrile in 50 ml. of dry tetrahydrofuran is added 5 ml. of piperidine. The reaction is heated to reflux for 2 hours, cooled and evaporated in vacuo. The residue is recrystallized from chloroform/hexane to provide the crystalline title compound. Similarly prepared are 2-benzoyl-3-N-piperidylcrotononitrile, 2-benzoyl-3-N-pyrazoylcrotononitrile and 2-benzoyl-3-N-piperazylcrotononitrile. EXAMPLE 97 2-Benzoyl-3-dimethylaminocrotononitrile A volume of 10 ml. of diethylamine is condensed in a glass tube at -780C. A sample of 5 g. of 2-benzoyl-5methoxycrotononitrile is added, the tube is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then cooled, opened, and the contents evaporated. The residue was recrystallized from chloroform to provide the title compound. Similarly prepared were 2-benzoyl-3-diethylaminocrotononitrile and 2-benzoyl- 3-di-isopropylaminocrotono- nitrile. EXAMPLE 98 2-(E-Fluorobenzoyl)-3-dìmethylaminocrotononitrile Dimethylamine is bubbled into a solution of 2- fluorobenzoyl)-3-ethoxycrotononitrile in 50 ml. of diethyl ether for 15 minutes. After stirring at room temperature for one hour, the reaction mixture is allowed to¯evaporate to dryness and the resulting solid -is recrystallized from methylene chloride/hexane to give 2-(p-fluorobenzoyl)-3- dimethylaminocrotononitrile, m.p. 650-670C. EXAMPLE 99 Cis-2-(5-chloro-o-toluoyl)-3-hydroxycrotononitrile The procedure of Example 37 is repeated but the 3-chloro-2-methylbenzonitrile is replaced by the same amount of 5-chloro-2-methylbenzonitrile, and there is obtained the title compound. EXAMPLE 100 Cis-2-2,4-dichlorobenzoyl)-3-hydroxycrotononitrile The -procedure of Example 34 is repeated, but the 2-chlorobenzonitrile is replaced by 16.6 g. of 2,4-dichlorobenzonitrile, and there is obtained the title compound. EXAMPLE 101 Cis-2-(2-thenoyl)-3-hydroxycrotononitrile A 67 ml. portion of ethyl 2-thiophenecarboxylate is added to 56 g. of potassium t-butoxide (exothermic). After cooling, 33 ml. of acetonitrile-is added and the mixture is stirred and heated on a steam bath-for 1.5 hours. A 250 ml. portion of water is added followed by 200 ml. of methylene chloride. The mixture is stirred overnight. The aqueouslayer is separated and combined with 42 ml.-of concentrated hydrochloric acid. This mixture is extracted with 300 ml. of methylene chloride followed by two 100 ml. portions of methylene chloride. The combined extracts are then washed with 200 ml. followed by 100 ml. of 10% sodium bicarbonate. The extracts are dried over sodium sulfate and passed through Magnesol #. The filtrate is combined with hexanes and evaporated giving crystals of ss-oxo-2-thiophenepriopionitrile. A 10.0 g. portion of ss-oxo-2-thiophenepropionitrzle in 100 ml. of chloroform is reacted with 10 ml. of N,N-di- methylacetamide dimethylacetal in an ice bath. -The mixture is stirred in an ice bath for 2 hours and then at room temperature overnight. The mixture is evaporated to an oil which is dissolved in 50 ml. of methanol. A 15 ml. portion of lN hydrochloric acid is added and the mixture is heated on a steam bath for 1/2 hour. Evaporation produces an oil which is combined with 75 ml. of benzene and 75 ml. of saturated aqueous sodium bicarbonate and mixed. The aqueous phase is saved. The organic phase is washed three times with saturated aqueous sodium bicarbonate. The aqueous phases are combined, washed twice with 100 ml. of benzene, and acidified with concentrated hydrochloric acid and the solid is collected. This solid is dried, dissolved in 50 ml. of hot isopropanol, treated with charcoal and cooled giving the desired product as a solid, m.p. 1060-1080C. EXAMPLE 102 Cis-2- (3-thenoyl) -3-hydroxycrotononitrile A 50 ml. portion of quinoline is added to a mixture of 35 g. of cuprous cyanide and 50 g. of 3-bromothiophene. The mixture is warmed slowly with stirring until a solution forms and then heated at 1900C. for one hour. The mixture is poured into water, 200 ml. of concentrated ammonium hydroxide is added and the solid residue is extracted five times with diethyl ether. The combined ether extracts are dried, treated with charcoal, filtered and evaporated to a brown liquid. This liquid is distilled, collecting four fractions which are combined, dissolved in diethyl ether, washed twice with 4N hydrochloric acid, water and saturated sodium chloride solution, dried and evaporated giving 27.7 g. of 3-cyanothiophene. A 113 g. portion of potassium t-butoxide is added to 800 ml. of diethyl ether. To this is added a mixture of 110.6 g. of 3-cyanothiophene and 54 ml. of acetonitrile in 350 ml. of ether. The reaction mixture is stirred in an icesalt bath, more ether is added and the mixture is shaken vigorously. After standing for one hour at room temperature the mixture is poured into one liter of water. The layers are separated. The aqueous phase is extracted with diethyl ether. The ether phases are combined, washed with water and evaporated. The residue is dissolved in benzene, dried over magnesium sulfate and evaporated. To the- residue is added -200 ml. benzene and some petroleum ether. The mixture is cooled and the precipitate is collected and saved. The mother liquor is filtered through Magnesolt0, evaporated and petroleum ether is added. Cooling produces a precipitate which is collected, dissolved in hot benzene, treated with charcoal and cooled giving a precipitate which is collected and combined with the first precipitate. The combined precipitates are recrystallized twice from hot benzene and charcoal giving 29.6 g. of B-amino-3-thiopheeacrylonitrile. A 2.5 g. portion of the ss-amino-3-thiopheneacrylo- nitrile is combined with 20 ml. of IN hydrochloric acid and sufficient methanol to produce solution. The mixture is stirred at room temperature for 1/2 hour, evaporated to 1/2 volume, cooled and the precipitate is collected. This solid is recrystallized with charcoal treatment from 30 ml. of hot isopropanol giving 2.4 g. of ss-oxo-3-thiophenepropionitrile. A 1.5 -g. portion of S-oxo-3-thìophenepropionitrile in 25 ml. of chloroform is reacted with 1.5 ml. of N,N-dimethylacetamide dimethylacetal as described in Example 101, giving the desired product as a solid7 m.p. 740-760C. EXAMPLE 103 Cis-2-(5-chloro-2-thenoyl)-3-hydroxycrotononitrile A 50 g. portion of 5-chloro-2-thiophenecarbox aldehydet 27.6 g. of hydroxylamine hydrochloridet 43.1 g. of sodium formate and 500 ml. of formic acid are reacted to produce 5-chloro-2-cyanothiophene. A mixture of 32.4 g. of potassium t-butoxide in 600 ml. of toluene is cooled in an ice bath. A solution of 37.9 g. of 5-chloro-2-cyanothiophene and 21.0-ml. of aceto- nitrile diluted to 150 ml. with toluene is added ¯ dropwise, with rapid stirring over a one hour period. The mixture is stirred at room temperature overnight. One liter of water is added. The mixture is stirred for 1/2 hour. The aqueous layer is extracted with three 250 ml. portions of diethyl ether which are 'combined, dried over magnesium sulfate and concentrated almost to dryness. The residue is dissolved in a minimum of hot toluene, treated with charcoal and cooled. Petroleum ether is added, the mixture is chilled and the precipitate is collected as crystals of ss-amino- 5-chloro-2-thiopheneacrylonitrile. A 9.2 g. portion of ss-amino-5-chloro-2-thio- pheneacrylonitrile is dissolved in 100 ml. of methanol. A 50 ml. portion of 1N hydrochloric acid is added and the mixture is stirred at room temperature for 3 hours. The precipitate is collected giving 5-chloro-B-oxo-2-thio- phenepropionitrile. A 9.8 g. portion of 5-chloro-B-oxo-2-thio- phenepropionitrile in 75 ml. of chloroform is reacted with 9.0 ml. of N,N-dimethylacetamide dimethylacetal as described in Example 101 giving the desired product, m.p. 1030-1050C. EXAMPLE 104 6-Oxo-2-thiophenepropionitrile, thallium (I) salt A solution of 10 g. of ss-oxo-2-thiophene- propionitrile in 150 ml. of diethyl ether is stirred at 250C. while 17.2 g. of neat thallium (I) ethoxide is added dropwise. The mixture is stirred as a colorless precipitate forms. After one hour, the mixture is filtered and the precipitate is washed with diethyl ether. Upon air-drying, 21.3 g. of colorless thallium (I) salt is obtained. Similarly prepared are the thallium (I) salts of 8-oxo-3-thiophenepropionitrile and 5-chloro-B-oxo-2- thiophenepropionitrile. EXAMPLE 105 Cis-2- (2-thenoyl) -3-hydroxycrotononitrile A suspension of 5.5 g. of 8-oxo-2-thiophenepropio- nitrile, thallium (I) salt in 50 ml. of tetrahydrofuran is stirred at room temperature as acetyl fluoride is bubbled through. After 3 hours, the gas flow is stopped, the reaction vessel is stoppered and the mixture is allowed to stand over-¯ night. After 24 hours, the mixture is filtered and the filtrate is evaporated to dryness. Recrystallization of the residue from chloroformZhexane provides the title compound. Similarly prepared are cis-2-- ( 3-thenoyl) -3-hydroxy- crotononitrile and cis-2- (5-chloro-2-thenoyl)-3-hydroxy- crotononitrile. EXAMPLE 106 Cis-2- (2-thenoyl) -3-hydroxycrotononitrile A solution of 10 g. of B-oxo-2-thiophenepropio- nitrile, 10.7 g. of triethyl orthoacetate and 20 ml. of acetic anhydride is heated on-a steam bath for 12 hours, then cooled and the excess acetic anhydride is evaporated under reduced pressure. The residue is treated with 50 ml. of ethanol and 50 ml. of 1N aqueous hydrochloric acid. After one hour, the solution is diluted with water and the product extracted with methylene chloride. The organic phase is washed with three portions of aqueous sodium bicarbonate which are combined, acidified, and extracted with'methylene chloride. This organic phase is dried and evaporated. The crude residue is recrystallized from chloroform/hexane to provide the title compound. Similarly, cis-2-(2-thenoyl)-3-hydroxy-2-pentenonitrile is prepared from $-oxo-2-thiophenepropionitrile and triethylorthopropionate EXAMPLE 107 Cis-2-(3-thenoyl)-3-hydroxycrotononitrile A neat sample of 20.0 g. of 3-thiophenecarboxylic acid was added dropwise to 50 ml. of thionyl chloride. The solution was stirred at room temperature overnight and the excess thionyl chloride was then evaporated under reduced pressure. The residue was vacuum distilled to provide 21.2 g. of 3-thiophenecarboxylic acid chloride. A mixture of I9.0 g. of cyanoacetone, sodium salt in 200 ml. of dry tetrahydrofuran is stirred while 10.0 g. of 3-thiophenecarboxylic acid chloride in 75 ml. of =tetra- hydrofuran is added dropwise. The reaction mixture is stirred overnight and then most of the solvent is evaporated under reduced pressure. The residue is acidified and extracted with chloroform. The organic phase is washed three times with aqueous sodium bicarbonate and the combined basic washes are acidified. The resulting mixture is extracted with methylene chloride. Evaporation of the organic layer and recrystallization of the residue provides the title compound. EXAMPLE 108 Cis-2-(3-thenoyl)-3-hydroxycrotononitrile An 8.0 g. portion of diisopropylamine in 100 ml. of diethyl ether is cooled to OOC. under argon. A solution of 31.5 ml. of 2.5M n-butyllithium in hexane is added dropwise and the reaction is further cooled to -100C. A 5.94 g. portion of 5-methylisoxazole is then added dropwise and the mixture is stirred for 1/2 hour. A 10.5 g. portion of 3thiophenecarboxylic acid chloride is added while the reaction is held at OOC. The mixture is allowed to warm to room temperature and stand for 18 hours. The reaction is quenched with water, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform phase is extracted three times with aqueous sodium bicarbonate and the combined aqueous extracts are acidified and washed three times with chloroform. The organic extract is dried, filtered and evaporated. The residue is recrystallized from ethanolhexane giving the desired compound. EXAMPLE 109 Cis-2-(5-methyl-3-thenoyl)-3-hydroxy-2-hexenonitrile The general procedure of Example 106 is repeated but replacing the B-oxo-2-thiophenepropionitrile and triethyl orthoacetate employed in that Example with equivalent amounts of 5-methyl-ss-oxo-3-thiophenepropionitrile and triethyl orthobutyrate whereby there is obtained the title compound in equally good yield. EXAMPLE 110 5-Methyl-2-thiophene carbonyl chloride Heating 100 g. of 5-methyl-2-thiophenecarboxylic acid in 130 ml. of thionyl chloride at 1000C. for 1-1/2 hours followed by distillation gave 112.26 -g. (99.3%) of 5methyl-2-thiophene carbonyl chloride, which boiled at 108 -110 C.(13 mm. EXAMPLE 111 Cis-2- (5-methyl-2-thenoyl) - 3-hydroxycrotononitrile A mixture of 0.05 mole (8.03 g.) of 5-methyl-2thiophenecarbonyl chloride and 0.15 mole (15.76 g.) of cyanoacetone sodium enolate in 100 ml. of tetrahydrofuran was stirred for 3 hours. After removal of the tetrahydrofuran in vacuo, the residue was slurried with water, acidified with hydrochloric acid, and extracted into methylene chloride. The methylene chloride extracts were, in turn, extracted with two 50 ml. portions of saturated sodium bicarbonate. The combined bicarbonate extracts were treated with Darco# and acidified to give, after recrystallization from isopropanol, 5.19 g. (50%) of the desired product as a light yellow crystalline solid melting at 710-730C. EXAMPLE 112 4-(E-Chlorophenyl)-2-(1-hydroxyethylidene)acetoacetonitrile A 54 g. portion of sodium methoxide in 250 ml. of methanol is cooled and stirred in an ice bath while 82 ml. (83.5 g.) of 5-methyl isoxazole is added dropwise. After addition is complete the reaction is cooled in ice and the solid is filtered, washed with ether and dried giving 57.18 g. of cyanoacetone sodium enolate. A 100 ml. portion of thionyl chloride is added to 51 g. of p-chlorophenylacetic acid and the mixture is refluxed on a steam bath for 3 hours. The thionyl chloride is removed on a rotary evaporator and the resulting oil is distilled under a water aspirator at 12 mm. giving 51.41 g. of -chlorophenylacetyl chloride as a pink liquid. A 9.45 g. portion of p-chlorophenylacetyl chloride followed by 50 ml. of tetrahydrofuran is added to a mixture of 15.76 g. of cyanoacetone sodium enolate in 50 ml. of -tetrahydrofuran. The mixture is stirred overnight, then the solvent is removed on a rotary evaporator. The solid is taken up in 100 ml. of water, acidified with concentrated hydrochloric acid and extracted with three 100 ml. portions of methylene chloride. The extracts are combined and extracted with three 100 ml. portions of saturated aqueous sodium bicarbonate. These extracts are combined and acidified with 12N hydrochloric acid, giving an oil. This mixture is extracted with methylene chloride. The extract is dried over magnesium sulfate, filtered through diatomaceous earth and reduced in volume on a steam bath giving the desired product as an oil which crystallizes on standing and after recrystallization from hexanes, then aqueous ethanol has a m.p. 50¯53 C. Following the general procedure of Example 112, other representative compounds of this invention, such as those found in Table VII, may be prepared. TABLE VII EMI78.1 R3#CH2-C-OH <SEP> + <SEP> R3#CH2-C-Cl <SEP> + <SEP> R6#CN <SEP> + <SEP> R3#M+n <tb> <SEP> (1) <SEP> (2) <SEP> (3) <SEP> (4) <tb> <SEP> Cyanoacetone <SEP> Phenyl <tb> <SEP> Phenyl <SEP> Phenyl <SEP> Sodium <SEP> Hydroxyethylidene <SEP> m.p. <tb> Example <SEP> Acetic <SEP> Acid <SEP> Acetyl <SEP> Chloride <SEP> Enolate <SEP> Acetoacetonitrile <SEP> 0 C. <tb> 113 <SEP> R1, <SEP> R3, <SEP> $4, <SEP> R5=H <SEP> R1, <SEP> R3, <SEP> R4, <SEP> R5=H <SEP> R6=CH3 <SEP> R1, <SEP> R3, <SEP> R4, <SEP> R5, <SEP> M=H <SEP> 60-62 <tb> <SEP> R2=Cl <SEP> R2=Cl <SEP> R6=CH3; <SEP> R2=Cl <tb> 114 <SEP> R1, <SEP> R2, <SEP> R4, <SEP> R5=H <SEP> R1, <SEP> R2, <SEP> R4, <SEP> R5=H <SEP> R6=CH3 <SEP> R1, <SEP> R2, <SEP> R4, <SEP> R5, <SEP> M=H <SEP> 57-59 <tb> <SEP> R3=F <SEP> R3=F <SEP> R6=CH3 <tb> <SEP> R3=F <tb> 115 <SEP> R2, <SEP> R4, <SEP> R5=H <SEP> R2, <SEP> R4, <SEP> R5=H <SEP> R6=CH3 <SEP> R2, <SEP> R4, <SEP> R5, <SEP> M=H <SEP> 113-117* <tb> <SEP> R1, <SEP> R3=Cl <SEP> R1, <SEP> R3=Cl <SEP> R6=CH3 <tb> <SEP> R1, <SEP> R3=Cl <tb> *Final product recrystallized from isopropanol. TABLE VII (continued) Cyanoacetone Phenyl Phenyl Phenyl Sodium Hydroxyethylidene m.p. Example Acetic Acid Acetyl Chloride Enolate Acetoacetonitrile 0 C. 116 R1, R4, R5=H R1, R4, R5=H R6=CH3 R1, R4, R5, M=H 85-87* R2, R3=Cl R2, R3=Cl R6=CH3 R2, R3=Cl 117 R2, R3, R4, R5=H R2, R3, R4, R5=H R6=CH3 R2, R3, R4, R5, M=H 61-64* R1=F R1=F R6=CH3 R1=F 118 R1, R3, R4, R5=H R1, R3, R4, R5=H R6=CH3 R2, R3, R4, R5, M=H 43-45 R2=F R2=F R6=CH3, R2=F 119 R2, R3, R4=H R2, R3, R4=H R6=CH3 R2, R3, R4, M=H 123-124* R1, R5=Cl R1, R5=Cl R6=CH3 R1, R5=Cl * Final product recrystallized from isopropanol. EXAMPLE 120 2-Cyano-3-hydroxythiocrotonic acid-S-pheny-l ester A 72 ml. portion of thionyl chloride is added dropwise to a mixture of 70.24 g. of 5-methylisoxazole-4- carboxylic acid [. Yasuda, Yakugaku Zasshi, 79, 836-838 (1959); CA. 537 21885d] and 64.44 g. of sodium carbonate in 250 ml. of chloroform. The mixture is heated gently on a steam bath for 4 hours, then the solid is filtered and the filtrate is evaporated to an oil. This oil is distilled at 4.5 mm. and the material boiling at 68-70 C. is collected, giving 65.23 g. of 5-methylisoxazole-4-carbonyl chloride. A mixture of 10.27 ml. (11.02 g.)- of thiophenol and 11.15 ml. (14.6 g.) of 5-methylisoxazole-4-carbonyl chloride in 50 ml. of ether is cooled in an ice bath. -A 14 ml. portion of triethylamine is diluted to 50 ml. with ether and added dropwise. -The mixture is stirred for 2 hours and the solid is filtered and washed with ether. The filtrate is evaporated to an oil which crystallizes, is taken up in methylene chloride and filtered through diatomaceous earth. The filtrate is concentrsted on a steam bath with the addition of hexanes, giving an oil. Cooling crystallizes this oil giving 16.65 -g. of 5 methylthio-4isoxazolecarboxylic acid-S-phenyl ester as a white crystalline solid. An 8 ml. portion of triethylamine in 50 ml. of ether is cooled in an ice bath and mixture of 11.91 g. of 5-methylthio-4-isoxazolecarboxylic acid-S-phenyl ester in 60 ml. of ether is added dropwise. The reaction is stirred overnight and the solid is filtered, giving 15.15 g. of 2cyano-3-hydroxythiocrotonic acid-S-phenyl ester with triethylamine as a white'crystalline solid. A 10.17 g. portion of this triethylamine salt is dissolved in 100 ml. of water and 2.64 ml. of concentrated hydrochloric acid is added, giving an oil which solidifies. The solid is filtered ed and dried, giving. the desired product, m.p. 106-1080C. EXAMPLE 121 2-Cyano-3-hydroxythiocrotonic acid-S-(E-chlorophenyl)ester A 14.46 g. portion of E-chlorothiophenol and 11.15 ml. (14.6 g.) of 5-methylisoxazole-4-carbonyl chloride in 50 ml. of ether is cooled in an ice bath and a solution of 14 ml. of triethylamine in 50 ml. of ether is added dropwise. The mixture is stirred for 3 hours and then diluted with ether. The solid is filtered and washed with ether. The combined filtrate and washing is evaporated to a solid which is taken up in methylene chloride, filtered and evaporated on a steam bath with the addition of hexanes giving an oil which crystallizes on cooling, giving 5-methylthio-4-isoxazolecarboxylic acid-S chlorophenyl)ester as a white crystalline solid. A 17.60 g. portion of the above isoxazole is slurried with 100 ml. of ether and cooled in an ice bath. A solution of 15 ml. of triethylamine in 50 ml. of ether is added dropwise and the reaction is stirred overnight. The solid is filtered and dried, giving 23.61 g. of 2-cyano-3hydroxythiocrotonic acid-S-(p-chlorophenyl)ester triethylamine salt as a white crystalline solid. A 9.17 g. portion of the above salt is taken up in 50 ml. of water and filtered. A 2.4 ml. portion of concentrated hydrochloric acid is added to the filtrate and the reaction is stirred for 2 hours. The solid is filtered and dried giving 6.10 g. of the desired product as a white crystalline solid, m.p. 91-94 C. Following the general procedure of Examples 120 and 121, other representative compounds of this invention, such as those found in Table VIII, may be made. TABLE VIII EMI82.1 TABLE VIII (continued) 2-Cyano-3 hydroxy crotonic 2-Cyano-3 Alkylthio Acid Phen- hydroxy Alkyl Alkyl Isoxazole yl Ester crotonic Isoxazole Isoxazole Thio- Phenyl Triethyl- Acid Phenyl Acid Chloride phenol Ester Amine Salt Ester m.p. Method Example (1) (2) (3) (4) (5) (6) C. of 122 R6=CH3 R6=CH3 R1, R2, R1, R2, R1, R2, R1, R2, 74-80 Example R4, R5=H R4, R5=H R4, R5=H R4, R5, M=H R3=CH3 R3=CH3 R3=CH3 R3=CH3 R6=CH3 R6=CH3 R6=CH3 123 R6=CH3 R6=CH3 R1, R2 R1, R2 R1, R2 R1, R2 105-110 Example R4, R5=H R4, R5=H R4, R5=H R4, R5, M=H 121 R3=F R3=F R3=F R3=F R6=CH3 R6=CH3 R6CH3 124 R6=CH3 R6=CH3 R1-R3, R1-R3, R1-R3, R1-R3, 57-61 Example R5=H R5=H R5=H R5, M=H 120 R4=CH3 R4, R6=CH3 R4, R6=CH3 R4, R6=CH3 125 R6=CH3 R6=CH3 R1-R3, R1-R3, R1-R3, R1-R3, 93-94 Example R5=H R5=H R5=H R5, M=H 121 R4=Cl R4=Cl R4=Cl R4=Cl R6=CH3 R6=CH3 R6=CH3 TABLE VIII (continued) 2-Cyano-3 hydroxy crotonic 2-Cyano-3 Alkylthio Acid Phen- hydroxy Alkyl Alkyl Isoxazole yl Ester crotonic Isoxazole Isoxazole Thio- Phenyl Triethyl- Acid Phenyl Acid Chloride phenol Ester Amine Salt Ester m.p. Method Example (1) (2) (3) (4) (5) (6) C. of 126 R6=CH3 R6=CH3 R2-R5=H R2-R5=H R2-R5=H R2-R5, M=H 73-74 Example R1=Cl R1=Cl R1=Cl R1=Cl 121 R6=CH3 R6=CH3 R6=CH3 127 R6=CH3 R6=CH3 R2-R5=H R2-R5=H R2-R5=H R2-R5, M=H 131-134 Example R1=CH3O R1=CH3O R1CH3O R1=CH3O 121 R6=CH3 R6=CH3 R6=CH3 128 R6=CH3 R6=CH3 R1-R3, R1-R3, R1-R3 R1-R3 61-67 Example R5=H R5=H R5=H R5, M=H 121 R4=CH3O R4=CH3O R4=CH3O R6=CH3 R6=CH3 R6=CH3 129 R6=CH3 R6=CH3 R2-R5=H R2-R5=H R2-R5=H R2-R5, M=H 51-54 Example R1, R1, R5=CH3 R1, R6=CH3 R1, R6=CH3 120 R6=CH3 TABLE VIII (continued) 2-Cyano-3 hydroxy crotonic 2-Cyano-3 Alkylthio Acid Phen- hydroxy Alkyl Alkyl Isoxazole yl Ester crotonic Isoxazole Isoxazole Thio- Phenyl Triethyl- Acid Phenyl Acid Chloride phenol Ester Amine Salt Ester m.p. Method Example (1) (2) (3) (4) (5) (6) C. of 130 R6=CH3 R6=CH3 R1, R2, R1, R2, R1, R2, R1, R2, Example R4, R5=H R4, R5=H R4, R5=H R4, R5, M=H 120 R3=CF3 R3=CF3 R3=CF3 R3=CF3 R6=CH3 R6=CH3 R3=CH3 R3=CH3 131 R6=CH3 R6=CH3 R1-R3, R1-R3, R1-R3, R1-R3, Example R5=H R5=H R5=H R5, M=H 120 R4=CF3 R4=CF3 R4=CF3 R4=CF3 R6=CH3 R6=CH3 R6=CH3 R6=CH3 132 R6=CH3 R6=CH3 R1-R3, R1-R3, R1-R3, R1-R3, Example R5=H R5=H R5=H R5, M=H 120 R4Br R4Br R4Br R4Br R6=CH3 R6=CH3 R6=CH3 R6=CH3 EXAMPLE 133 2-Cyano-3-hydroxycrotonic acid, p-chlorophenyl ester A 130 ml. portion of thionyl chloride is added slowly to a mixture of 63.67 g. of 5-methylisoxazole-4-carb oxylic acid [H. Yasuda, Yakugaku Zasshi, 79, 836-838 (1959); C.A., 53, 21885d] and 58.4 g. of sodium carbonate in 250 ml. of chloroform. The mixture is heated on steam bath for 2 hours, filtered and the solvents are removed from the filtrate by evaporation. Two portions of chloroform are successively added to the -residue and removed by evaporation. The resulting oil is distilled at 1-2 mm and the material boiling at 66-680C. is collected, giving 64.48 g. of 5-methylisoxazole carbonyl chloride. A mixture of 12.86 g. of p-chlorophenol and 11.5 ml. (14.6 g.) of 5-methylisoxazole carbonyl chloride in 100 ml. of ether is cooled in an ice bath. A 14 ml. portion of triethylamine in 50 ml. of ether is added dropwise. The mixture is stirred for one hour and then filtered. The filtrate is evaporated to an oil which is distillled. The fraction boiling at 132-137 C. is collected, giving 14.85 g. of 5-methyl-4-isoxazolecarboxylic acid, E-chlorqphenyl ester-. An 8 ml. portion of triethylamine in 50 ml. of ether is cooled in an ice bath. A 10.15 g. portion of 5methyl-4-isoxazolecarboxylic acid, 2-chlorophenyl ester in 50 ml. of ether is added dropwise and-then stirred overnight. The resulting solid is filtered and- washed with ether, giving 12.-41 g. of 2-cyano-3-hydroxycrotonic acid, - chlorophenyl ester triethylamine salt as a white crystalline solid. A 9.03 g. portion of the above salt is taken up in water, filtered and cooled. A 2.3 ml. portion of concentrated hydrochloric acid is added giving 6.33 g. of the desired product as crystals, mp. 97-1000C. EXAMPLE 134 2-Cyano-3-hydroxycrotonic acid, 2, 3-dichlorophenyl ester A 16.3 g. portion of 2,3-dichlorophenol and 11.15 ml. (14.6 g} of 5-methylisoxazole carbonyl-chloride in 50 ml. of ether is cooled in an ice bath and a solution of 14 ml. of triethylamine is added dropwise. The mixture is stirred for 3 hours and the solid is filtered and washed with ether. The combined filtrate and wash is evaporated to an oil on a steam bath. This oil is taken up in methylene chloride, filtered through diatomaceous earth and the filtrate evaporated on a steam bath with the addition of hexanes to about 50 ml. Cooling gives 24.02 g. of 5-methyl-4-isoxazolecarboxylic acid, 2,3-dichlorophenyl ester as a tan crystalline solid. A 17.95 g. portion of the above isoxazole is slurried in 100 ml. of ether and cooled in an ice bath. A solution of 12 ml. of triethylamine in 50 ml. of ether is added dropwise and the reaction is stirred overnight. The solid is recovered by filtration and dried, giving 22.92 g. of 2-cyano-3-hydroxycrotonic acid, 2, 3-dichlorophenyl ester, triethylamine salt as a light tan crystalline solid. An 11.88 g. portion of the above salt is slurried in 100 ml. of water and acidified with 2.65 ml. of concentrated hydrochloric acid. The mixture is stirred for several hours and the solid is filtered and dried, giving 8.52 g. of The desired product, mp. 142-146QC. Following the general procedure of Examples 133 and 134 other representative compounds of this invention, such as those found in Table IX, may be made. TABLE IX EMI88.1 Alkylis- Alkylis- 2-Cyano Alk Alkylis- oxazole oxazole enoic Acid 2-Cyano oxazole Chloride carboxylic Phenyl Ester Alkenoic Acid (1) (2) Phenol Phenyl Triethylamine Acid Phenyl m.p. Method Example R6= R6= (3) Ester (4) Salt (5) Ester (6) C. of 135 CH3 CH3 R1-R4=H R1-R4=H M=H M=H 88-92 Example R5=Cl R5=Cl R1-R4=H R1-R4=H 133 R5=Cl R5=Cl 136 CH3 CH3 R1, R2, R1, R2, M=H - 112-115 Example R4, R5= R4, R5= R1, R2, R4, 134 H H R5=H R3=CH3O R3=CH3O R3=CH3O 137 CH3 CH3 R1, R2, R1, R2, M=H - 127-130 Example R4, R5=H R4, R5=H R1, R2, R4, 133 R3=CH3 R3=CH3 R5=H, R3=CH3 TABLE IX (continued) Alkylis- Alkylis- 2-Cyano Alk Alkylis- oxazole oxazole enoic Acid 2-Cyano oxazole Chloride carboxylic Phenyl Ester Alkenoic Acid (1) (2) Phenol Phenyl Triethylamine Acid Phenyl m.p. Method Example R6= R6= (3) Ester (4) Salt (5) Ester (6) C. of 138 CH3 CH3 R1=CH3O R1=CH3O M=H - 86-88 Example R2-R5=H R2-R5=H R1=CH3O 134 R2-R5=H 139 CH3 CH3 R1-R4=H R1-R4=H M=H M=H 94-97 Example R5=F R5=F R1-R4=H R1-R4=H 133 R5=F R5=F 140 CH3 CH3 R2, R3, R2, R3, R2, R3, R4, R2, R3, R4, 101-105 Example R4, R5= R4, R5=H R5, M=H R5, M=H 134 H R1=CH3O R1=CH3O R1=CH3O R1=CH3O 141 CH3 CH3 R1, R2, R1, R2, R1, R2, R5, R1, R2, R5, 115-121 Example R5=H R5=H M=H M=H 134 R3, R4=Cl R3, R4=Cl R3, R4=Cl R3, R4=Cl 142 CH3 CH3 R1, R2, R1, R2, R1, R2, R4, R1, R2, R4, 93-95 Example R4, R5=H R4, R5=H R5, M=H R5, M=H 133 R3=F R3=F R3=F R3=F TABLE IX (continued) Alkylis- Alkylis- 2-Cyano Alk Alkylis- oxazole oxazole enoic Acid 2-Cyano oxazole Chloride carboxylic Phenyl Ester Alkenoic Acid (1) (2) Phenol Phenyl Triethylamine Acid Phenyl m.p. Method Example R6= R6= (3) Ester (4) Salt (5) Ester (6) C. of 143 CH3 CH3 R1, R4, R1, R4, R1, R4, R5, R1, R4, R5, 112-115 Example R5=H R5=H M=H M=H 134 R2, R3= R2, R3= R2, R3=CH3O R2, R3=CH3O CH3O CH3O 144 CH3 CH3 R1, R2, R1, R2, R1, R2, R4, R1, R2, R4, 115-120 Example R4, R5=H R4, R5=H R5, M=H R5, M=H 133 R3=Br R3=Br R3=Br R3=Br 145 CH3 CH3 R2, R3, R2, R3, R2, R3, R4, R2, R3, R4, 93-97 Example R4, R5=H R4, R5=H R5, M=H R5, M=H 133 R1=Br R1=Br R1=Br R1=Br 146 CH3 CH3 R1, R3, R1, R3, R1, R3, R4, R1, R3, R4, 104-108 Example R4, R5=H R4, R5=H R4, M=H R5, M=H 133 R2=Br R2=Br R2=Br R2=Br 147 CH3 CH3 R1, R2, R1, R2, R1, R2, R3, R1, R2, R3, 74-78 Example R3, R4, R3, R4, R4, R5, M=H R4, R5, M=H 133 R5=H R5=H EXAMPLE 148 5-Methyl-4-isoxazolecarboxylic acid, o-methoxyphenyl ester A 186 ml. por-tn of thionylchloride is added dropwise to a solution of IS 67 g, of 5-methylisoxazole-4-carboxylic acid [H. Yasuda, Takugaku Zasshi, 79, 836-838 (1959); C.A., 53, 21885d] and lE g. of sodium carbonate in 500 ml. of chloroform. The reaction is refluxed gently on a steam bath for 4 hours and the stirred at room temperature overnight. The mixture is filtered and the filtrate is evaporated to an oil which is distilled at 3.5 mm. The product, 5-methylisoxazole carbonyl chloride is recovered from the fraction boiling at 61 C. (3.5 mm.), yield 183.43 g. A mixture of --45.5 g. of 5-methylisoxazole carbonyl chloride and 124.1 g. of o-methoxyphenol in 50 ml. of ether is cooled in an ice bath. A 14 ml. portion of triethylamine in 50 ml. of ether is added dropwise. The mixture is stirred for 2 ho-ars, filtered and washed with ether. The combined filtrate and wash is evaporated. The residue is taken up in methylene chloride, filtered through diatomaceous earth and evaporated on a steam bath, with the addition of hexanes, to an oil. Cooling the oil gives the desired product as 4.47 g. of a white crystalline solid, m.p. 108-111 C. Following the general procedure of Example 148, other representative compounds of this invention, such as those found in Table X, may be made. TABLE X EMI92.1 Table X (cont'd) Isoxazole Isoxazole Carbonyl Phenyl Isoxazole Carboxylic Chloride Deriva- Phenyl M.P. Example Acid (1) (2) tive (3) Ester (4) C. 149 R6=CH3 R6=CH3 R2, R4=H R2, R4=H 85-87 R1, R3 R1, R3 R5=Cl R5=Cl X=O X=O R6=CH3 150 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R4, R5=H R4, R5=H R3=F R3=F X=O X=O R6=CH3 151 Rç=CH3 R6=CH3 R1, R2, R1, R2 62-69 R4, R5=H R41 R5=H R3=CH3O R3=CH3O X=O X=O R6=CH3 152 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R3, R5=H R3, R5=H R4=CF3 R4=CF3 X=O X=O R6=CH3 153 R6=CH3 R6=CH3 R1, R2, R1, R2 Oil R4, R5=H R4, R5=H R3=C1 R3=Cl X=O X=O R6=CH3 154 R6=CH3 R6=CH3 R1-R4=H R1-R4=H Oil R5=CF3 R5=CF3 X=O X=O R6=CH3 Table X (cont'd) Isoxazole Isoxazole Carbonyl Phenyl Isoxazole Carboxylic Chloride Deriva- -Phenyl M.P. Example Acid (1) (2) tive (3) Ester (4) C. 155 R6=CH3 R6=CH3 R1, R3, R1, R3, Oil R4, R5=H R4, R5=H R2=CH3O R2=CH3O X=O X=O R6=CH3 156 R6=CH3 R6=CH3 R1-R4=H R1-R4=H 71-76 R5=Cl R5=Cl X-O X-O R6=CH3 157 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R4, R5=H R4, R5=H R3=CH3 R3, R6=CH3 X=O X=O 158 R6=CH3 R6=CH3 R1-R4=H R1-R4=H Oil R5=CH3 R5, R6=CH3 X=O X=O 159 R6=CH3 -R6=CH3 R1, R2, R1, R2, 38-39 R3, R5=H R3, R5=H R4=C1 R4=C1 X=O X=O R6=CH3 160 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R5=H R5=H R3=Cl R3=Cl R4=CH3 R4, R6=CH3 X=O X=O 161 R6=CH3 R6=CH3 R1, R2, R1, R2, 91-92 R4=H R4=H R3, R5=Cl R3, R5=Cl X=O X=O R6=CH3 Table X (cont'd) Isoxazole Isoxazole Carbonyl Phenyl Isoxazole Carboxylic Chloride Deriva- Phenyl M.P. Example Acid (1) (2) tive (3) Ester (4) OC. 162 R6=CH3 R6=CH3 R2-R4=H R2-R4=H 96-101 R1, R5=C1 R1, R5=Cl X=O X=O R6CH3 163 R6=CH3 R6=CH3 R1, R2, R1, R2 86-93 R5=H R5=H R3, R4=Cl R3, R4=C1 X=O X=O R6=CH3 164 R6=CH3 R6=CH3 R1-R3=H R1-R3=H 88-91 R4, R5=Cl R4, R5=C1 X=O X=O R6=CH3 165 R6=CH3 R6=CH3 R1, R2, R1, R2 Oil R3, R5=H R3, R5=H R5=CH3 R4, R6=CH3 X=O X=O 166 R6=CH3 R6=CH3 R1-R4=H R1-R4=H 58-65 R5=F R5=F X=O X=O R6=CH3 167 R6=CH3 R6=CH3 R1, R3, R1, R3, 76-78 R5=H R5=H R2, R4=CF3 R2, R4=CF3 X=O X=O R6=CH3 168 R6=CH3 R6=CH3 R1, R4, R1, R4, 75-79 R5=H, R2, R5=H, R2, R3=CH30 R3=CH30 X=O X=O, R6=CH3 Table X (cont'd) Isoxazole Isoxazole Carbonyl Phenyl Isoxazole Carboxylic Chloride Deriva- Phenyl M.P. Example Acid -(1) (2) tive (3) Ester (4) C. 169 Rs=CH3 R6=CH3 R1, R2, R1, R2, Oil R4, R5=H R4, R5=H R3=Br R3=Br X=O X=O R6=CH3 170 R6=CH3 R6=CH3 R2-R5=H R2-R5=H 65-68 R1=Br Rl=Br X=O X=O R6=CH3 171 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R3, R5=H R3, R5=H R4=Br R4=Br X=O X=O R6=CH3 172 R6=CH3 R6=CH3 R1-R5=H R1-R5=H X=S R6=CH3 173 R6=CH3 R6=CH3 R1, R2, R1, R2, 90-92 R4, R5=H R4, R5=H R3=Cl R3=Cl X=S X=S R6=CH3 174 R6=CH3 R6=CH3 R1, R2, R1, R2, 41-44 R4, R5=H R4, 2 R3=CH3 R3, R6=CH3 X=S X=S 175 R6=CH3 R6=CH3 R1, R2, R1, R2, Ro, 66-70 R4, R5=H R5=H, R3=F R3=F, X=S X=S, R6=CH3 Table X (cont'd) Isoxazole Isoxazole Carbonyl Phenyl Isoxazole Carboxylic Chloride Deriva- Phenyl M.P. Example Acid (1) (2) tive (3) Ester (4) OC. 176 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R3, R5=H R3, R5=H R4=CH3 R4, R6=CH3 X=S X=S 177 R6=CH3 R6=CH3 R1, R2, R1, R2, Oil R3, R5=H R3, R5=H R4=Cl R4=Cl X=S X=S, R6=CH3 178 R6=CH3 R6=CH3 R1-R4=H R1-R4=H 83-87 R5=C1 R5=Cl X=S X=S R6=CH3 179 R6=CH3 R6=CH3 R1-R4=H R1-R4=H 69-72 R5=CH3O R5=CH3O X=S X=S R6=CH3 180 R6=CH3 R6=CH3 R1, R3, R1, R3, Oil R4, R5=H R4, R5 H R2=CH3O R2=CH3O X=S X=S R6=CH3 181 R6=CH3 R6=CH3 R2-R5=H R2-R5=H 61-64 R1=CH3 R1, R6=CH3 X=S X=S

Claims: CLAIMS: 1. 2-Carbonyl-3-hydroxy-2-alkenonitriles of the formula: EMI98.1 wherein n is- an integer from 1 to 3 inclusive; M is hydrogen or a pharmaceutically acceptable cation; R6 is an alkyl group of 1 to 4 carbons; RO is one of the following aromatic groups: (1) the group EMI98.2 in which R1, R2, R3, R4 and R5 are the same or different and are hydrogen, halogen, alkyl having up to 4 carbons, alkoxy having up to 4 carbons, trifluoromethyl or trichloromethyl, with the proviso that when m is the number O at least two of R1, R2, R3, R4 and R5 must be hydrogen but when R6 is methyl and m is the number 0 not all of R1, h , R3, R4 and R5 may be hydrogen; or (2) the thienyl moiety EMI98.3 wherein R7 is hydrogen, an alkyl group of up to 3 carbons, fluorine, chlorine or bromine; X is CH2, 9 or S and m is the number 0 or 1, provided that when RO is a thienyl moiety then m is 0; and the tautomers of the above compounds. 2. A compound according to claim 1, wherein RO is the group: EMI99.1 wherein R1, R2 R3, R4 and R5 are as defined; and m is the number 0. 3. A compound according to claim 2, wherein one of the radicals R1, R2, R3, R4 and R5 is bromo, chloro, fluoro, trifluoromethyl, methyl or methoxy and the remaining of said radicals are hydrogen; or R1 is methyl, R3 is chloro and R2, R4 and R5 are each hydrogen. 4. A compound according to claim 1, wherein RO is a thienyl moiety and m is the number 0. 5. A compound according to claim 4, wherein R7 is hydrogen, chloro, fluoro, methyl or isopropyl. 6. A compound according to claim 1, wherein R is the group EMI99.2 wherein R1, R2, R3, R4 and R5 are as defined; X is CH2 and m is the number 1. 7. A compound according to claim 6, wherein one or two of the radicals R1, R2, R3, R4 and R5 is chloro and the remaining of said radicals are hydrogen; or one of said radicals is fluoro and the remaining of said radicals are hydrogen. 8. A compound according to claim:l, wherein R is the group: EMI100.1 wherein R1, R2, R3, R4 and R5 are as defined; X is S and m is the number 1. 9. A compound according to claim 8, wherein one of the radicals R1, R2, R3, R4 and R5 is bromo, chloro, fluoro, trifluoromethyl, methyl or methoxy and the remaining of said radicals are hydrogen; or all of said radicals are hydrogen. 10. A compound according to clam 1, wherein R is the group: EMI100.2 wherein R1, R2, R3, R4 and R5 are as defined; X is 0 and m is the number 1. 11. A compound according to claim 10, wherein one of the radicals R1, R2, R3, R4 and R5 is bromo, chloro, fluoro, methyl or methoxy and the remaining of said radicals are hydrogen; or two of said radicals are chldro, the remaining being hydrogen; or two of said radicals are methoxy, the remaining being hydrogen; or all of said radicals are hydrogen. 12. A compound according to any one of the preceding claims, wherein R6 is methyl. 13. A compound according to any one of the. preceding claims7 wherein M is hydrogen, sodium or triethylammonium and n is 1, or M is cupric and n- is 2. 14. Substituted 2-benzoyl-3-substituted-2-alkenonitriles, useful for preparing oounds of claim 1 and of Formulas I and II herein, of the formula: EMI101.1 wherein Y represents the group OR or the group EMI101.2 R1, R2, R3, R4 and R5 are each individually selected from hydrogen, halogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, trifluoromethyl or trichloromethyl with the proviso that at least two of R1, R2, R3, R4 and R5 must be hydrogen, R6 is alkyl having from 1 to 4 carbon atoms; R is alkyl having from 1 to 4 carbon atoms; and R' and R" are each hydrogen or alkyl having from 1 to 4 carbon atoms or R' and R" taken together with the associated nitrogen is pyrrolidino, piperidino, morpholino, thiomorpholino or N-methylpiperazino. 15. A compound according to claim 14, wherein Y is EMI101.3 and all of R1, R2, R3, R4 and R5 are hydrogen. 16. A compound according to claim 14, wherein Y is OR and all of R1, R2, R3, R4 and R5 are hydrogen. 17. A compound according to claim 14, wherein R6 is methyl, Y is OR and at least one of R1, R2, R3, R4 and R5 is other than hydrogen. 18. A compound according to claim 14, wherein Y is OR wherein R is methyl or ethyl, and three of the radicals R1, R2, R3, R4 and R5 are methoxy and the remaining of said radicals are hydrogen; or one of said radicals is fluoro, bromo, trifluoromethyl or chloro, the remaining being hydrogen; and R6 is methyl or ethyl. 19. A compound according to claim 14, wherein Y is EMI101.4 wherein R and R" are each methyl, ethyl, n-butyl or hydrogen, or taken together are piperidyl, and three of the radicals R1, R2, R3, R4 and R5 are methoxy and the- remaining..df said radicals are hydrogen; or one of sa-id radicals is methyl, another is chloro and the remaining-being hydrogen; or two of said radicals are fluoro, the remaining being hydrogen; or one of said radicals is fluoro or chloro, the remaining being hydrogen; and R6 is methyl or ethyl. 20. A compound useful for preparing compounds of claim 1, of the formula:. wherein EMI102.1 drogen, halogen, lower alkyl (C1-C4), lower alkoxy (C1-C4), trifluoromethyl or tri ch-loromethyl; R6 is lower alkyl tcl-c4); and X is sulfur or oxygen. 21. A compound according to claim 20, wherein R6 is methyl, X is 0 and three of the radicals R1, R2, R3, R4 and R5 are chloro, -the remaining of said ,radicals ¯ being hydrogen; or two of said radicals are both chloro, both methoxy or both trifluoromethyl, the remaining being hydrogen or one of said radicals is chloro, another is methyl and the remaining are hydrogen; or one ofsaid radical-s is bromo, chloro, fluoro, methyl, methoxy or trifluoromethyl and the remaining are hydrogen. 22. A compound according to clair-20-, -wherein R6 is methyl, X is S and one of the radicals R1, R2, R3, R4 and R5 is chloro, fluoro, methyl or methoxy, and the remaining of said radicals are hydrogen; or all -of said radicals are hydrogen. 23. An anti-arthritic composition useful in -inhibiting the progression of arthritis, meliorating inflammation and/or inhibiting progressive joint deterioration in mammels, comprising a pharmaceutically acceptable carrier or diluent and a 2-carbonyl-3-hydroxy-2.-alkenonitrile. of the formula: EMI102.2 wherein n is an integer from 1 to 3 inclusive; M is hydrogen or a pharmaceutically acceptable cation; R6 is an alkyl group of 1 to 4 carbons; RO is one of the following aromatic groups: : (1) the group EMI103.1 in which R1, R2, R3, R4 and R5 are the same or different and are hydrogen, halogen, alkyl having up to 4 carbons, alkoxy having up to 4 carbons, trifluoromethyl or trichloromethyl, with the proviso that when m is the number O at least two of R1, R2, R3, R4 and R5 must be hydrogen; or (2) the thienyl moiety EMI103.2 wherein R7 is hydrogen, an alkyl group of up to 3 carbons, fluorine, chlorine or bromine; X is CH2, O or S and mis the number 0 or 1, provided that when R is a thienyl moiety then m is 0; and the tautomers of the above compounds. 24. A composition according to claim 23, wherein said 2-carbonyl-3-hydroxy-2-alkenonitrile is as defined in any one of claims 2 to 13. 25. A composition according to claim 23, wherein RO is the group: EMI103.3 in which R1, R2, R3, R4 and R5 are hydrogen; m is the number 0; and R6 is'methyl. 26. A composition according to any of Claims 23-25, in dosage unit form comprising from about 1-250 mg. per kg. of body weight per dosage unit of active compound. 27. A method for preparing an anti-arthritic compos- ition useful for inhibiting the progression of arthritis, meliorating inflammation and/or inhibiting progressive joint deterioration in mammals, comprising incorporating into a pharmaceutical carrier or diluent of a 2-carbonyl-3-hydroxy- 2-alkenonitrile of the Formula II as defined in any of claims 23 to 25. 28. A method of producing compounds of Formula. 1, as defined in Claim 1, which comprises: (a) reacting an acetonitrile of the formula: EMI104.1 with a compound of the formula: EMI104.2 wherein R , X, m and R6 are as defined above andR8 is-O-Alkyl or N(Alkyl)2 and then hydrolyzing the product produced, and wherein, when R8 is O-Alkyl the resultant product may be treated with ammonia or a primary or secondary amine prior to said hydrolysis; or (b) reacting the metal (Me) enolate salt of an acetonitrile of the formula: EMI104.3 with an acyl halide of the formula: EMI104.4 wherein R and R6 are as defined above; or (c) reacting an acyl halide of the formula: EMI105.1 with a metal (Me) nolate salt of the formula: EMI105.2 wherein X is CH2, m is the number 0 or 1, RO and R are as defined above; or (d) reacting a compound of the formula: EMI105.3 with N,N-dimethylformamide dimethylacetal to produce an intermediate compound of the formula: EMI105.4 reacting said intermediate with hydroxylamine hydrochloride and treating the resulting reaction mixture with a strong base, wherein RO and R6 are as defined above; or (e) reacting a compound of the formula: RO - X - H with a compound of the formula: EMI105.5 in the presence of a proton scavenger such as a tertiary amine, to form an intermediate Of the formula: EMI105.6 wherein X is O or S and RO and R6 are as defined above, and further treating said intermediate with a proton scavenger such as a tertiary amine or alkoxide, thereby producing the corresponding final product; and (f) if desired, forming pharmaceutically acceptable cation salts. 29. A method according to claim 28, wherein compounds are produced in accordance with the definitions in any one of claims 2 to 13. 30. A method of producing compounds of Formula VIII as claimed in claim 14, which comprises reacting an acetonitrile of. The formula: EMI106.1 with a compound of the formula: R6, C(9R)3 wherein R, R1, R2, R31 R4, R5, and R6 are as defined in Formula VIII, to produce a compound of Formula VIII in which Y is OR; and where desired, treating the compound where Y is OR with ammonia or a primary or secondary amine, thereby producing a compound of Formula VIII in which Y is the group EMI106.2 wherein R' and R" are as defined in Formula VIII. 31 A method of producing compounds of Formula IX as claimed in claim 20, which comprises reacting a compound of the formula: EMI106.3 with a compound of the formula: EMI106.4 in the presence of a proton scavenger such as-a carbonate, bicarbonate or tertiary amine, wherein X and R1, R2, R3, R4 and R5 are as defined in Formula IX. 32. A 2-carbonyl-3-hydroxy-2-alkenonitrile of the Formula II as defined in any one of Claims 23-25 for use in inhibiting the progression of arthritis, meliorating inflammation and/or inhibiting progressive joint deterioration in mammals.

Inventors: HANIFIN, JOHN WILLIAM, JR., RIDGE, DAVID NELSON
Applicants: AMERICAN CYANAMID COMPANY
Application year: 1979
Main classification: C07C121
IPC codes: C07D261, C07C327, C07C67, C07C255, C07D333, C07C253, C07D295, C07C325, C07F5, A61K31