4,5-DIARYL-2-(SUBSTITUTED-THIO)-PYRROLES AND THEIR CORRESPONDING SULFOXIDES AND SULFONES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Antiinflammatory 4,5-diaryl-2-(substituted-thio)-pyrroles and their corresponding sulfoxides and sulfones, useful for treating arthritis and related diseases. This application is a continuation-in-part of my copending application Serial No. 972,201, filed December 28, 1978, which is a continuation-in-part of Serial No. 886,337, filed March 13, 1978.

Description: TITLE ANTIINFALAMMATORY 4,5-DIARYL-2 (SUBSTITUTED-THIO) PYRROLES AND THEIR CORRESPONDING SULFOXIDES AND SULFONES Background of the Invention This invention relates to antiinflamatory pyrroles. J. Szmuszkovicz et al. J. Med. Chem., 9 (4), 527-35 (1966) describe synthesis and biological activity of a clinically tested antiinflammatory agent of the formula EMI1.1 Yoshida et al. U.S.P. 3,709,906 disclose 2-alkyl4,5-diphenylpyrrole derivatives which are useful as antiinflaxnmatory agents. There is a continuing need for safe and effective antiinflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling, and pain. Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment. The usefulness of most commercial antiinflammatories is limited because of toxicity and adverse side-effects. stany produce gastric irritation and other effects, such as changes in blood cells and central nervous system. Adreno-cortical steroids produce gastric irritation and suppression of normal adrenal function In addition to antiinflammatory properties, compounds within the scope of this invention have demonstrated analgesic activity in a test procedure. This additional property is desirable in treatment of arthritis or related diseases; however, the compounds which exhibit this property can be employed solely to alleviate pain. Summary of the Invention This invention relates to compounds of formula I, pharmaceutical compositions containing them and methods of use of these compounds to treat arthritis or alleviate pain in mammals. where EMI2.1 R1 = Cl-C4 alkyl, C1-C4 mono- or polyfluoroalkyl or allyl: R2 and R3, independently, = 2-thienyl, 3-pyridyl 3-pyridyl-N EMI3.1 oxide or EMI3.2 Y1 Cl-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, H or (R5)2N; wherein R5 - methyl or ethyl; = H, F or Cl; R4 = H or C1-C3 alkyl; R6 = H, C1-C4 alkyl, allyl, -CH2CH2N(R7)2, EMI3.3 2-tetrahydropyranyl, 2-tetrahydrofuranyl, EMI3.4 EMI3.5 R7 = H, methyl or ethyl; R8 = H or methyl; R9 = C1-C3 alkyl, benzyl, -CH2CH2OCH3, or EMI3.6 R10 = C1-C4 alkyl or benzyl; R11 = methyl or ethyl; X = o or S; Y3 = H, F, C1, Br, C1-C4 alkyl, C1-C4 alkoxy or nitro; n = 0, 1 or 2; provided when Y1 and Y2 both = H, R1 is CF3; or its pharmaceutically suitable addition salt where at least one of R2 or R3 = 3-pyridyl, Y1 = (R5)2N, or R6 = -CH2CH2N (R7)2 Detailed Description of the Invention Preferred Compounds Compounds preferred for their degree of activity, safety and/or ease of synthesis include those where independently: a) R1 = methyl or trifluoromethyl; or b) R1 = methyl and n = 2; or c) R1 = trifluoromethyl and n = O; or d) R2 and R3, independently, are EMI4.1 and preferably Y1 = F, C1, methoxy and more preferably F; Y2 = H; or e) R2 = 3-pyridyl; or f) R4 ;= H; or g) R6 = H; or h) n = 0 or 1 and more preferably for ease of synthesis, n = 0. Compounds of a preferred scope include those where: R1 = methyl or trifluoromethyl; R2 and R3 are EMI4.2 and Yl = F, Cl or methoxy and more preferably F; Y2 = H; R4 = H; R6 = H; and n = 0 or 1 and more preferably for ease of synthesis n = 0. Two examples of compounds preferred for their activity are where R1 = CF3; R2 and R3 both = = = H; EMI5.1 R6 = H; and n = O or 1. Another example of a preferred compound is where R1 = CF3; R2 = 3-pyridyl; R3 C6H5; R4 = H; R6 = H; and n = Q. Synthesis The compounds of this invention can be prepared from 2,3-diarylpyrroles. One method of preparation of 2,3-diarylpyrroles involves reaction of substituted &alpha;-aminodeoxybenzoins with acetylene diesters, followed by hydrolysis and decarboxylation according to the procedure used by J. Szmuszkovicz et al, J. Med. Chem., 9, 527 (1966) and s.S. Patent 3,462,451 for the synthesis of 2,3-bis (4-methoxyphenyl) pyrrole. (Scheme I). Scheme I EMI5.2 Another method of preparation of 2,3-diarylpyrroles is a modification of the procedure of T. Severin and H. Poehlmann, Chem. Ber., 110, 491 (1977), which describes the preparation of monoaryl pyrroles. By using substituted desoxybenzoins, the desired 2,3 diaryipyrroles result (Scheme II). Scheme II EMI6.1 Preparation of 4,5-diaryl-3-aLkylpyrroles can be accomplished by several methods. First, 4,5-diarylpyrrole-3-carboxylate esters, prepared, for instance, by the method of A. M. van Leusen et al., Tet. Letters, 5337 (1972) can be reduced to the 4,5-diaryl-3-methylpyrroles by lithium aluminum hydride [following the general procedure of R. L. Hinman and S. Theodoropulos, J. Orr. Chem., 28, 3052 (1963)l. EMI6.2 Secondly, 4,5-diaryl-3-propylpyrroles can be prepared by the thio-Claisen rearrangement of 2-allylthiopyrroles, followed by Raney nickel reduction [general procedure of K. Teo et al., Can. J. Chem., 56, 221 (1978)1. EMI7.1 Thirdly, 4,5-diaryl-3-alkylpyrroles can be prepared by the general procedure of N. Engel and, W. Steglich, Angew. Chem. Int. Ed. Engl., 17, 676 (1978), from N-allylcarboxamides. EMI7.2 Introduction of an alkylthio functionality is lccomplished in several ways. First, trifluoro iethanesulfenyl chloride reacts directly and nearly uantitatively with diarylpyrroles to give the 2-triluoromethylthio substituted compounds. EMI8.1 Secondly, other alkylthio pyrroles can also be prepared directly by the reaction of an alkanesulfenyl chloride (such as methanesulfenyl chloride) with a 2,3-diarylpyrrole in an inert organic solvent, such as tetrahydrofuran, diethyl ether, or dioxane, at temperatures from -800C to 250C. EMI8.2 Thirdly, introduction of other alkylthio groups is also accomplished in a two step procedure involving substitution by cupric thiocyanate, thiocyanogen or the like to give the 2-thiocyanate derivative, then hydrolysis in the presence of an alkyl halide, e.g., methyl iodide, or fluorinated olef in, e.g., tetrafluoroethylene. EMI9.1 Fourthly, trifluoromethanesulfenyl chloride reacts with 4,5-diarylpyrrole-2-carboxaldehydes and 4,5diarylpyrrole-2-carboxylic acids-to give 4,5-diaryl-2 (trifluoromethylthio)pyrroles directly (with. concomitant loss of carbon monoxide and carbon dioxide respectively). EMI9.2 Oxidation of the 2-alkylthio compounds with suitable oxidizing agents, such as m-chloroperoxybenzoic acid (mClPBA) gives the corresponding sulfoxides and sulfones. EMI10.1 The R6-substituent other than hydrogen of formula I can be introduced by direct alkylation, acylation, or sulfonylation of the compounds of formula I where R6 = H. This reaction can be carried out in the absence or presence of a base, such as potassium carbonate, pyridine, triethylamine, potassium t-butoxide, methyl lithium, dimsyl sodium or the like. The reaction can be run neat, using the reagent as solvent, or in the presence of an inert solvent, including but not limited to dimethylformamide, glyme, THF, pyridine and methylene chloride. The temperature of the reaction can be in the range -780C to the boiling point of the solvent or reagent, if used in excess as the solvent. Examples of alkylating, acylating and sulfonylating agents that can be employed are allyl halides; alkyl halides such as methyl iodide; dimethylaminoethyl chloride; alkoxymethyl halides, such as benzyloxymethyl chloride; acyloxymethyl halides, such as chloromethylpivalate; dihydropyran; ethyl vinyl ether; 2-chlorotetrahydrofuran; alkyl chloroformates, such as ethyl chloroformate; dialkylcarbamoyl chlorides, such as diethylcarbamoyl chloride; dialkylthiocarbamoyl chlorides such as diethylthiocarbamoyl chloride; alkanoic anhydrides and alkanoyl halides, such as acetic anhydride; aroyl halides, such as benzoyl chloride; alkanesulfonyl halides such as methanesulfonyl chloride; arylsulfonyl halides, such as benzenesulfonyl chloride. Preparation of pharmaceutically suitable salt of compounds of formula I can be in accordance with well-known techniques of forming salts. The preparation of these compounds is further illustrated by the following Examples. All parts are by weight and temperatures are in degrees centigrade unless otherwise specified. Preparation 1 2,3-Diphenylpyrrole (Method A) A. Dimethyl 4,5-dipheneylpyrrole-2,3-dicarboxylate In a 2 . RB 3-neck flask with mechanical stirrer and condenser was placed 76.7 g (0.31 mole) of desyl amine hydrochloride LPschorr et al, Chem. Ber., 35, 2740 (1902)], 750 ml methanol, 88 g (0.62 mole) dimethyl acetylenedicarboxylate (freshly distilled) and 61 g (0.75 mole) anhydrous sodium acetate. The mixture was heated at reflux for two hours. Then another 44 g (0.31 mole) of dimethyl acetylenedicarboxylate was added and heating continued another two hours. While the reaction mixture was still at reflux, concentrated hydrochloric acid (¯60 ml, to F8"2) was added dropwise. The mixture was heated at reflux another hour, then poured into 2 ; water containing 200 ml 108 sodium bicarbonate solution. With stirring, more sodium bicarbonate was added until the solution was neutral. The gummy solid which precipitated was collected and washed with water. Trituration of this gummy material with 500 ml of 50% aqueous ethanol gave a tan powdery solid, which was recrystallized from -ss5% aqueous ethanol to give 55.5 g (63%) of white crystals, m.p. 191-2 [Lit. m.p. 185-7 ; J. B. Hendrickson et al, J. Am. Chem. Soc., 86, 107 (1964)]. B. 4,5-Diphenylpyrrole-2,3-dicarboxylic Acid To a mixture of 57.5 g (0.172 mole) of dimethyl 4,5-diphenylpyrrole-2,3-dicarboxylate in 350 ml methanol was added a solution of 71 g (1.78 mole) of sodium hydroxide in 350 ml water. The mixture was heated at reflux for two hours, then cooled in an ice bath. The insoluble white crystals were collected and washed with cold methanol to give the bis sodium salt of the product. The still damp solid was dissolved in 1 scold water and acidified with conc. hydrochloric acid. The precipitated product was collected by filtration, washed with water containing ¯1% hydrochloric acid, then air dried and finally dried in a vacuum oven at 1000 to give 50.0 g (95%) of white solid, m.p. 216-218 (dec., depends on heating rate). C. 2,3-Diphenylpyrrole (Method A) A mixture of 20 g (0.065 mole) of 4,5-diphenylpyrrole-2,3-dicarboxylic acid in 80 ml quinoline was heated at reflux in an oil bath (bath # 230 ) until gas evolution stopped (approx. one-half hour). The reaction mixture was cooled and most of the quinoline was removed by distillation (bp 580 &commat; 0.2 mm). The partially crystalline residue was chromatographed on 300 g Silic AR CC-7, eluting with toluene to give 12 g (85%) of faintly pink 2,3-diphenylpyrrole which could be further purified by recrystallization from ethanol/water or by sublimation ('v1250 &commat; 0.2 mm) to give white solid, m.p. 132-3 . Anal. Calcd. for C16H13N: C, 87.64; H, 5.98; N, 6.39. Found: C, 87.99; H, 5.86; N, ó.SO. Preparation 2 2,3-Diphenylpyrrole (Method B) A. Glyoxal mono(dimethylhydrazone) was prepared by the procedure of T. Severin and H. Poehlmann, Chem. Ber., 110, 491 (1977) to give 36.1 g (80%) of pale yellow liquid, bp 1090 (22 nm); lit. bp 900 (16 mm). B. 4-Dimethylhydrazono-l , 2-diphenyl-2-buten-l-one To a mixture of 19.6 g (0.1 mole) desoxybenzoin and 10 g (0.1 mole) of glyoxal mono(dimethylhydrazone) in 100 ml ethanol was added dropwise a solution of sodium ethoxide prepared by dissolving 2.3 g (0.1 mole) sodium metal in 100 ml ethanol. The mixture was heated at reflux for one-half hour. TLC (90/10, toluene/ethyl acetate) showed a small amount of starting desoxybenzoin, so 2.0 g (0.02 mole) of additional glyoxal mono(dimethylhydrazone) was added. Heating was continued another two hours. TLC at this time showed no starting material, and two clean close yellow product spots (isomers). The mixture was poured into 1 2 ice water then extracted with methylene chloride. The organic extracts were dried and concentrated on a rotary evaporator to give 28.7 g (100%) of yellow oil. The NMR showed the presence of two major N(CH3)2 containing materials (product isomers). The crude oil crystallized from isopropanol to give one pure isomer of product, 13.4 g (488), pale yellow crystals, m.p. 131-2". Anal. Calcd. for C18Hl8N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.44; H, 6.46; N, 10.17. C. 2,3-Diphenylpyrrole (Method B) A mixture of 3.1 g (0.011 mole) of 4-dimethylhydrazono-l, 2-diphenyl-2-buten-l-one, 11.2 g (.0.064 mole) sodium hydrosulfite in 75 ml ethanol and 37.5 ml water was heated at reflux for three hours. The mixture was cooled and poured into 300 ml ice water. The white crystalline produce was collected, washed with water and air dried to give 1.9 g (79%), m.p. 130-1 , identical to product obtained via the decarboxylation, Method A. Preparation 3 4, 5-Diphenyl-3-methylpyrrole A. Ethyl 4,5-diphenylpyrrole-3-carboxylate was prepared by a procedure similar to that used by A. M. van Leusen et al., Tet. Letters, 5337 (1972) for the preparation of the methyl ester. The ethyl ester was obtained as a white solid, m.p. 207-208,50 (methyl cyclohexane/toluene). Anal. Calcd. for ClgHl7NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 77.92; H, 5.87; 77.90 5.88 N, 4.60. 4.62 B. 4,5-Diphenyl-3-methylpyrrole To a stirred slurry of 0.76 g (20 m moles) of lithium aluminum hydride in 25 ml. THF was added dropwise a solution of 0.58 g (2 m moles) of ethyl 4,5-diphenylpyrrole-3-carboxylate in 5 ml THF. The mixture was heated at reflux overnight. After cooling, 0.8 ml water, 2.4 ml 15% sodium hydroxide solution and 0.8 ml water were added dropwise. The solids were removed by filtration and the filtrate concentrated by rotary evaporation. The crystaline residue was purified by chromatography on 50 g Silic AR CC-7, eluting with hexane/toluene (90/10) to give 0.25 g of product, m.p. 163-40. Anal. Calcd. for C17H15N: C, 87.51; H, 6.48; N, 6.00. Found: C, 87.77; H, 6.60; N, 5.89. Preparation 4 4,5-Bis(4-chlorophenyl)-3-propylpyrrole A. 2-Acetylthio-3-allyl-4,5-bis(4-chlorophenyl)pyrrole A solution of 3.6 g (0.01 mole) of 2-allylthio4,5-bis(4-chlorophenyl)pyrrole in 20 ml acetic anhydride was added dropwise to 20 ml quinoline preheated at 1700. The mixture was kept at 1700 an additional 45 minutes, then cooled. Most of the acetic acid, acetic anhydride and quinoline were removed by distillation under reduced pressure. The residue was chromatographed on 125 g of Silic AR CC-7, eluting with toluene, to give, after recrystallization from hexane/methyl cyclohexane, 2.7 g of white product, m.p. 131-20. Anal. Calcd. for C21Hl7Cl2NOS: C, 62.69; H, 4.26; N, 3.48. Found: C, 62.48; H, 4.47; N, 3.57. B. 4,5-Bis(4-chlorophenyl)-3-propylpyrrole A mixture of 5 g Raney nickel, 0.8 g (2 m moles) of 2-acetylthio-3-allyl-4,5-bis (4-chlorophenyl)pyrrole and 50 ml acetone was heated at reflux under nitrogen for two hours. The mixture was diluted with ethanol and the catalyst was removed by filtration. The filtrate was concentrated by rotary evaporation. The residue was purified by chromatography on 50 g Silic ARCC-7, eluting with hexane/toluene (90/10), to give 0.15 g of white crystals, m.p. 90-930. Mass spectrum calcd. for C19H17NC12: 329.0738. Found: 329.0759 Other 2,3-diarylpyrroles prepared by these procedures are given in Table I. Table I 2,3-Diarylpyrroles EMI16.1 Preparation Ar Ar m.p. 5 4-CH3OC6H4 4-CH3OC6H4 oil 6 4-FC6H4 4-FC6H4 119.5-120.5 7 4-ClC6H4 4-ClC6H4 124-7 8 4-FC H 4-C H OC H 118-118.5 9 4-C1C6H4 4-FC H 102-4 10 4-FC6H4 4-C1C6H4 116-118 11 4-FC6H4 4-CH30C6H4 117-118 12 4-ClC6H4 4-CH3OC6H4 105-110 13 4-FC6H4 C6H5 137-8 14 4-ClC6H4 C6H5 124-6 15 4 CH3C6H4 4 CH3C6H4 128-9 16 3-FC6H4 3-FC6H4 90-90.5 17 C6H5 3,4-diClC6H3 112-113 18 2-FC6H4 2-FC6H4 131-132.5 19 C6H5 3-piridyl 190-192 20 4-CH3OC6H4 2-thienyl 65-66.5 Example 1 4,5-Diphenyl-2-(trifluoromethylthio)pyrrole In glassware flamed out, under nitrogen, and fitted with a dry ice condenser, were placed 11 g (0.05 mole) 2,3-diphenylpyrrole, 6.4 g (0.06 mole) anhydrous sodium carbonate and 200 ml ether. The mixture was chilIed to -30 and 7.6 g (0.055 mole) trifluoromethanesulfenyl chloride was added as a gas from a tared trap. The reaction was stirred at -30 one-half hour, then allowed to warm to room temperature for two hours. The inorganic salts were removed by filtration and the ether filtrate was concentrated. The residue was chromatographed on 300 g Silic AR CC-7 eluding with hexane containing 5-10% toluene. The produce was obtained as a white solid, 15.4 g (96%), m.p. 58-9 . Anal. Calcd. for C17H12F3NS: C, 63.94; H, 3.79; N, 4.39. Found: C, 63.66; H, 3.87; N, 4.34. Example 2 4,5-Bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole Method A Following the procedure of Example 1, reaction of 2,3-bis(4-methoxyphenyl)pyrrole with trifluoromethanesulfenyl chloride gave 4,5-bis(4-methoxyphenyl)-2 (trifluoromethylthio)pyrrole as a white solid, m.p. 114-115 . Anal. Calcd. for ClgHl6F3NO2S: C, 60.14; H, 4.25; N, 3.69 Found: C, 60.24; H, 4.29; 60.32 4.20; N, 3.67. 3.71 Method B (a) 4, 5-Bis (4-methoxyphenyl) pyrrole-2-carboxaldehyde To 25 ml DMF at 0 was added dropwise with stirring 30 g of phosphorous oxychloride. The mixture was stirred for 15 minutes at room temperature, then a solution of 5.6 g (0.02 mole) of 2,3-bis(4-methoxyphenyl)pyrrole in 40 ml DMF was added dropwise with cooling in an ice bath. The mixture was then heated at 70-80 for one hour, then cooled. Aqueous sodium hydroxide (50%) was added until the mixture was basic. The reaction mixture was then heated again at 700 for 15 minutes. The cooled reaction mixture was poured into ice water. The precipitated material was collected and purified by chromatography on 600 g Silic AR CC-7 (eluting with toluene containing 1-28 ethyl acetate) to give 3.4 g (55%) of product, m.p. 165-6 (methylcyclohexane/ toluene). Anal. Calcd. for C19H17NO3: C, 74.25;' H, 5.58; N, 4.56. Found: C, 74.46; H, 5.43; N, 4.44. (b) 4,5-Bis(4-methoxyphenyl)-2-(trifluoromethylthio) pyrrole To a stirred mixture of 1.5 g (5 m mole) of 4,5 bis (4-methoxyphenyl) pyrrole-2-carboxaldehyde and 1.3 g sodium carbonate in 10 ml ether/l0 ml THF at -78 was added 0.8 g of trifluoromethanesulfenyl chloride. The mixture was allowed to warm to room temperature with a dry-ice condenser attached to keep the trifluoromethanesulfenyl chloride from escaping. Excess trifluoromethanesulfenyl chloride was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate concentrated by rotary evaporation. The residue was purified by chromatography on 300 g Silic ARCC-7, eluting with toluene, to give 0.75 g (39%) of product, identical to that obtained by Method A. Method C (a) 4, 5-Bis (4-methoxyphenyl) -2- (trifluoroacetyl) pyrrole To a stirred solution of 2.5 g trifluoroacetic anhydride in 30 ml ether at 0 was added dropwise a solution of 2.8 g (0.01 mole) of 2,3-bis(4-methoxyphenyl)pyrrole and 1.5 g of dimethyl aniline in 20 ml ether. The mixture was stirred one hour at 00, then diluted with more ether and washed with water, 1N hydrochloric acid, then water again. The organic layer was dried and concentrated. The residue was purified by chromatography in Silic ARCC-7 (300 g, eluted by toluene), followed by recrystallization from methylcyclohexane to give 2.2 g (59%) of pale yellow crystals, m.p. 185-186.5 . Anal. Calcd. for C20z16F3N 3 C, 64.00; H, 4.30; N, 3.73. round: C, 64.35; H, 4.41; 64.03 4.22 N, 3.61. 3.70 (b) 4,5-Bis(4-methoxyphenyl)pyrrole-2-carboxylic acid To a refluxing solution of 1.9 g (5 m moles) of 4,5-bis(4-methoxyphenyl)-2-(trifluoroacetyl)pyrrole in 20 ml ethanol was added a solution of 2 g sodium hydroxide in 20 ml water. The mixture was heated at reflux 3 1/2 hours then cooled and diluted with water. The aqueous solution was extracted with methylene chloride. The aqueous layer gave only 0.1 g of acid product upon acidification with hydrochloric acid. The methylene chloride solution of the sodium salt of the acid was acidified by shaking with IN hydrochloric acid. The methylene chloride layer was then dried and concentrated to give another 1.1 g of acid product. The combined product was recrystallized from ethanol/water to give 1.2 g (75%) of white product, m.p. 204-5 . Anal. Calcd. for ClgHl7NO4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.38; H, 5.35; N, 4.44. (c) 4,5-Bis(4-methoxyphenyl)-2-(trifluoroacetyl)pyrrole thio)pyrrole To a solution of 0.3 g (1 m mole) of 4,5-bis(4 methoxyphenyl)pyrrole-2-carboxylic acid in 5 ml ether/5 ml THF at -780 was added as a gas 0.3 g of trifluoromethanesulfenyl chloride. After 15 minutes, TLC showed no evidence of reaction, so a large excess of trifluoromethanesulfenyl-chloride was added and the mixture was allowed to warm slowly to room temperature overnight, with a dry ice condenser attached for the first few hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on 100 g Silic AR CC-7 to give after recrystallization from hexane 0.15 g (40%) of 4,5bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole, identical to material obtained by Method A. Other 4, 5-diaryl-2- (trifluoromethylthio) pyrroles prepared by the procedures of Examples 1 and 2A are given in Table II. Table II 4,5-Diaryl-2-(trifluoromethylthio)pyrroles EMI21.1 Example Ar Ar' R4 m.p. 3 4-FC6H4 4-FC6H4 H 106-107.5 4 4-ClC6H4 4-ClC6H4 H 95-96.5 5 4-FC6H4 4-C2H50C6H4 H 83-84 6 4-ClC6H4 4-FC6H4 H 103-4 7 4-FC6H4 4-ClC6H4 H 90-1 8 4-FC6H4 4-CH3OC6H4 H 122-3 9 4-ClC6H4 4-CH3OC6H4 H 115-116.5 10 4-FC6H4 C6H5 H 78-9 11 4-ClCH4 C6H5 H 98-9 12 4-CH3C6H4 4-CH3C6H4 H 79-80 13 3-FC6H4 3-FC 6H4 H 74-5 14 4-ClC6H4 4-CLC6H4 CH3CH2CH2 99-100 15 C6H5 C6H5 CH3 79-81 16 C6H5 3,4-diClC6H3 H 82-82.5 16a C6H5 3-pyridyl H 196-197 16b 4-CH3OCH6H4 2-thienyl H 73-74 Preparation 21 4,5-Diphenyl-2-(thiocyanato)pyrrole To a mixture of 11 g (0.05 mole) of 2,3-diphenylpyrrole in 150 ml methanol at room temperature was added in portions 18 g (#0.1 mole)cupric thiocyanate. After stirring at room temperature for three hours, TLC indicated approximately 50% starting material was left (no change from two hours), so another 18 g (0.1 mole) cupric thiocyanate was added. After another hour, TLC indicated no starting material. The inorganic material was removed by filtration and the methanol filtrate was concentrated. This residue was taken up in methylene chloride, washed with water, then dried and concentrated. The residue was chromatographed on 300 g Silic AR CC-7, eluting with toluene to give 11.3 (82%), m.p. 139-140 (methylcyclohexane). Anal. Calcd. for C17H12N2S: C, 73.39; H, 4.38; N, 10.14. Found: C, 73.90; H, 4.49; N, 10.31. Other 4,5-diaryl-2-(thiocyanato)pyrroles prepared in this manner are given in Table III. Table III 4,5-Diaryl-2-(thiocyanato)pyrroles EMI22.1 Preparation Ar Ar m.p. 22 4-CH3OCH6H4 4-CH3OC6H4 oil 23 4-FC6H4 4-C2H5OC6H4 129-131 24 4-C1C6H4 4-C1C6H4 168-9 25 4-FC6H4 4-FC6H4 164-165.5 26 4-C1C6H4 4-FC6H4 150-1 25 4-FC6H4 4-C1C6H4 174-5 28 4-FC6H4 4-CH3OC6H4 148-9 29 4-C1C6H4 4-CH3OC6H4 173-4 30 4-FC6H4 C6H5 175-6 31 5-CöC6H4 C6H5 162-162.5 32 4-CH3C6H4 4-CH C H 161-2 Example 17 4,5-DiphenZl-2-(methylthlo)pyrrole To a mixture of 1.4 g (0.005 mole) 2,3-diphenyl-5thiocyanatopyrrole, 0.85 5 (0.006 mole) methyl iodide in 10 ml methanol was added dropwise at 0 a solution of 0.8 g (-0.012 mole, 85%) potassium hydroxide in 5 ml water + 5 ml methanol. The mixture was allowed to warm to room temperature, then was poured into 100 ml ice water and neutralized with hydrochloric acid. The aqueous mixture was extracted with methylene chloride, and the extracts dried and concentrated. The residue was chromatographed on 50 g Silic AR CC-7, eluting with toluene to give 1.2 g (90%) yellow oil. Example 18 4,5-Bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio) pyrrole A mixture of 3.1 g (0.01 mole) of 4,5-bis(4-fluoro phenyl)-2-(thiocyanato)pyrrole,10 ml water and 100 ml methanol was placed in a pressure vessel and frozen in dry ice. Then 2.0 g of potassium hydroxide was added. The pressure vessel was evacuated and purged with nitrogen. Then 2.5 g of tetrafluoroethylene was added and the pressure vessel sealed. The mixture was allowed to warm to room temperature and was shaken overnight. The pressure vessel was vented and the contents rinsed out with methanol. The mixture was diluted with water and saturated sodium chloride solution, then extracted with methylene chloride. The organic layers were combined, dried and concentrated by rotary evaporation. The residue was chromatographed on 300 g Silic AR CC-7 eluting with mixtures of hexane and toluene to give, after recrystallization from hexane or ethanol/water 1.8 g of product, m.p. 70.5-710, Anal. Calcd. for C18H11F6NS: C, 55.82; H, 2.86; N, 3.62. Found: C, 55.78; H, 3.08; N, 3.48. Other 4,5-diaryl-2-(alkylthio)pyrroles prepared in this manner are given in Table IV. Table IV 4,5-Diaryl-2-(alkylthio)pyrroles EMI24.1 Example Ar Ar' R1 m.p. 19 4-CH3OC6H4 4-CH3OC6H4 CH3 164-5 20 4-CH3OC6H4 4-CH3OC6H4 CH3CH2 82-3 21 4-ClC6H4 4-ClC6H4 CH3 139-141 22 4-FC6H4 4-C2H5OC6H4 CH3 119.5-120.5! 23 4-CLC6H4 4-ClC6H4 CHF2CF2 oil 24 4-FC6H4 4-FC6H4 CH3 88-88.5 25 4-ClC6H4 4-CLC6H4 CH3CH2 oil 26 4-C1C6H4 4-FC6H4 CH3 112-112.5 27 4-FC6H4 4-ClC6H4 CH3 102-102.5 28 4-FC6H4 4-CH3OC6H4 CH3 103-5 29 4-C1C6H4 4-CH3OC6H4 CH3 149-151 30 4-FC6H4 C6H5 CH3 97-8 31 4-ClC6H4 C6H5 CH3 124-124.5 32 4-CH3C6H4 4-CH3C6H4 CH3 117-118 33 4-CLC6H4 4-ClC6H4 CH=CHCH2 oil Examples 34, 35 4,5-Diphenyl-2-(trifluoromethylsulfonyl and sulfinyl)pyrrole To a solution of 9.6 g (0.03 mole) 4,5-diphenyl-2 (trifluoromethylthio)pyrrole in 100 ml methylene chloride at roan temperature was added dropwise a solution of 12 g (# 0.06 mole, #85%) m-chloroperoxybenzoic acid in 130 ml methylene chloride. After two hours, TLC (toluene/ ethyl acetate, 90/10) showed a trace of sulfide and major amounts of sulfoxide and sulfone. Since a potassium iodide-starch test was negative, an additional 1 g (NO.005 mole) of peracid was added and stirring continued for another two hours (KI-starch test negative, TLC no sulfide left). The mixture was washed twice with 10% sodium bicarbonate, once with water, then dried and concentrated. The residue was chromatographed on #1 kg Silic AR CC-7. Eluted with toluene was the sulfone, 2.2 g (22%), m.p. 159-160 (methyl cyclohexane), example 34. Anal. Calcd. for C17H12F3NO2S: C, 58.12; H, 3.44; N, 3.99. Found: C, 58.25; H, 3.60; N, 4.39. Eluted with toluene/ethyl acetate (95/5) was the sulfoxide, 0.9 g (98), m.p. 125-6 (ethanol/water), example 35. Anal. Calcd. for C17H12F3NOS: C, 60,89; H, 3.61; N, 4.18. Found: C, 60.99, 61.37; H, 3.45, 4.12; N, 3.94, 4.00. Other 4,5 -diaryl-2-(alkylsulfinyl and sulfonyl)pyrroles prepared in this manner are given in Table V. Table V 4,5-Diaryl-2-(alkylsulfonyl or sulfinyl)pyrroles EMI26.1 Example Ar Ar' R1 n m.p. 36 4-CH3OC6H4 4-CH3OC6H4 CF3 2 203-204.5 37 4-CH3OC6H4 4-CH3OC6H4 CH3 2 142-142.5 38 4-CH30C6H4 4-CH3oC6H4 CH3CH2 2 136-136.5 39 4-FC6H4 4-FC6H4 CF3 2 154-5 40 4-FC6H4 4-FC6H4 CF3 1 128-9 41 4-ClC6H4 4-ClC6H4 CF3 2 133-5 42 4-ClC6H4 4-CLC6H4 CF3 1 175-176.5 43 4-FC6H4 4-C2H5OC6H4 CF3 2 131-2 44 4-FC6H4 4-C2H5OC6H4 CF3 1 166-9 45 4-C1C6H4 4-C1C6H4 CH3 2 186-8 46 4-FC6H4 4-C2H5OC6H4 CH3 2 149-150 47 4-FC6H4 4-FC6H4 CH3 2 185-6 48 4-ClC6H4 4-ClC6H4 CH3CH2 2 185-185.5 49 4-ClC6H4 4-FC6H4 CH3 2 212-212.5 50 4-FC6H4 4-ClC6H4 CH3 2 188-9 51 4-FC6H4 4-CH3OC6H4 CH3 2 182-3 52 4-ClC6H4 4-CH3OC6H4 CH3 2 211-212 53 4-FC6H4 C6H5 CH3 2 183-183.5 54 4-ClC6H4 C6H5 CH3 2 198-9 55 4-CH3C6H4 4-CH3C6H4 CH3 2 212-213 Table VI illustrates other compounds that can be prepared by the procedures previously described. Table VI EMI27.1 R1 R2 R3 R4 n -CH2CH=CH2 4-FC6H4 4-FC6H4 H 0 -CH2CH2CH2CH3 4-CH3OC6H4 4-CH3OC6H4 H 2 -CHF2 4-FC6H4 4-FC6H4 H 0 -CF2CF3 4-FC6H4 4-FC6H4 H 0 -CF3 4-ClC6H4 4-FC6H4 H 2 -CH3 4-FC6H4 4-CH3OC6H4 H 2 -CF3 4-ClC6H4 4-CH3OC6H4 H 0 -CF3 C6H5 4-CH3OC6H4 H 0 -CF3 2-FC6H4 2-FC6H4 H 0 -CF3 C6H5 3,4-diClC6H3 H 2 -CF3 4-FC6F4 4-(CH3)2NC6H4 H 0 -CF3 4-FC6H4 4-BrC6H4 H 0 -CF3 4-FC6H4 4-FC6H4 CH3 0 -CF3 4-FC6H4 4-CH3CH2CH2CH2C6H4 H 0 -CF3 4-FC6H4 4-CH3CH2CH2CH2OC6H4 H 0 -CF3 4-FC6H4 4-FC6H4 CH3CH2CH2 O -CF3 4-FC6H4 4-(C2H5)2NC6H4 H 0 -CH2CH2CH2F 4-FC6H4 4-FC6H4 H 0 Example 56 1-Acetyl-4,5-bis(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole A mixture of 1.8 g. of 4,5-bis (: :4-fluorophenyl)- 2-(trifluoromethylthiolpyrrole and 25 ml, of acetic anhydride was heated at reflux with stirring under nitrogen for 2 days and then concentrated under vacuum. The residue was purified by chromatography on Silic AR CC-7 Celuting with hexane and then hexane/ toluene) to give 40Q mg. of a colorless solid product. Recrystallization from athanol/H2O gave an analytical sample, m.p. 75-76 C. Anal. Calcd. for ClgH12F5NOS: C, 57.43; H. 3.04; N, 3.52; Found: C, 57.05, H, 3.15; N, 3.51. Example 57 1-Methyl-4, 5-bis (A-f luorophenyl) -2- (trifluoromethylthio) - pyrrole A sodium hydride dispersion (0.45 g.; 9 mmoles) was reacted with 30 ml. of DMSO under nitrogen with stirring. After gas evolution had ceased, a solution of 2.13 g. (6 mmoles) of 4,5-bis(4-fluorophenyl)-2 (trifluoromethylthio)pyrrole in 6 ml. of DMSO was added dropwise at room temperature. After stirring at room temperature for 15 minutes, 2.1 g. (15 mmoles) of methyl iodide was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was then poured into water and the product extracted into ether. The combined ether extracts were washed 3 times with water and, after drying, evaporated to afford 2.3 g of crystals. The crystals above were combined with 700 mg. of product from a previous run and purified by chromatography on Silic AR CC-7 (eluting with hexane) to give 2.4 g. of product, m.p. 76-770C (ethanol/water). Anal. Calcd. forC18H12F2NS: C, 58.53; H, 3.27; N, 3.79; Found: C, 58.76; H, 3.48; N, 3.77. Example 58 l-Ethoxycarbonyl-4, 5-his (4-fluorophenyl) -2-(trifluoro- methylthio)pyrrole A mixture of 700 mg. (2 mmoles) of 4,5-bis(4fluorophenyl)-2-(trilfluoromethylthio)pyrrole and 330 mg. (3 mmoles) of potassium tert-butoxide in 20 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 700 mg. (6 mmoles)of ethyl chloroformate in 15 ml. of toluene was then added dropwise and the reaction mixture stirred at room temperature for several hours. The mixture was poured onto an aqueous sodium bicarbonate solution and the product extracted into methylene chloride. The combined organic layers were dried and concentrated to give 800 mg. of a viscous oil. The oil was purified by chromatography on Silic AR CC-7 (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to give 400 mg. of product as colorless crystals, m.p. 54-54.50C. Anal. Calcd. for C20H14F5NO2S: C, 56.21; H, 3.30; N, 3.28; Found: C, 56.46; H, 3.43; N, 3.16 Example 59 l-BenzOyl-4,5-bis(4-fluorophenyl)-2-(trifluoromethyl- thio)pyrrole A mixture of 2.1 g. (6 mmoles) of 4,5-bis- (4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 1.3 g. (12mmoles) of potassium tert-butoxide in 60 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 1.7 g. of benzoyl chloride in 15 ml. of toluene was then added and the reaction mixture stirred overnight at room temperature. The mixture was diluted with methylene chloride, which was washed with 10% aqueous sodium bicarbonate solution, dried and evaporated. The residue was purified by chromatography on Fisher 100-200 mesh silica gel (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to afford 1.8 g. of colorless crystals, m.p, lQ5,5.lQ6 C. Anal. Calcd. for C24H14F5NOS: C, 62.74; H, 3.07; N, 3.Q5; wound: C, 62.83; H, 3.22; N, 2.90. Example 60 l-Benzenesulfonyl-4,5-bis(4-fluorophenyl)-2-trifluoro methylthio)pyrrole Using the procedure described in Example 58, 700 mg. (2 mmoles) of 4,5-bis (4-fluorophenyl) -2 ttrifluoromethylthio)pyrrole was reacted with 530 mg. (3 mmoles) of benzenesulfonyl chloride. The crude reaction product was purified by chromatography on Fisher 100-200 mesh silica gel (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from hexane to give 250 mg. of colorless crystals, m.p. 133-133.50C. Anal. Calcd. for C23H14F5N02S2: C, 55.75; H, 2.85; N, 2.83; Found: C, 55.46; H, 2.88; N, 2.98. Table VIA illustrates other compounds that can be prepared by the procedures previously described. TABLE VIA EMI31.1 R1 R2 R3 R4 R6 n CH2CH=CH2 4-FCH4 4-FC6H4 H (CH2)3CH3 0 (CH2)2CH3 4-CH3OC6H4 4-FC6H4 CH3 CH2CH=CH2 1 CHF2 4-FC6H4 4-ClC6H4 H (CH2)2N(CH3)2 2 CH3 4-FC6H4 3,4-diClC6H4 H CH2OCH2 0 CF3 4-FC6H4 4-BrC6H4 H CH3OCH2 0 CF3 3-pyridyl 4-FC6H4 H CH3CH2OCH 0 CH3 CF3 4-FC6H4 4-ClC6H4 CH3(CH2) n-C3H7OCH2 2 CF3 4-ClC6H4 4-FC6H4 H CH2OCCH2# 0 CH2CF3 2-thienyl 4-CH3CH2OC6H4 H CH2OCC(CH3)3 0 0 CH2CH3 4-FC6H4 4-FC6H4 H 2-tetrahydro- 0 pyranyl CH2CF3 3-CH3C6H4 3-CH3C6H4 H 2-tetrahydro- 2 furyl (CH2)2CH3 3-piridyl 2-FC6H4 CH3 COCH3 1 N-oxide # O CF3 4-CH3OC6H4 4-FC6H4 H 1 o CF3 4-FC6H4 4-N(CH3)2C6H4 H COCH2# 0 (CH2)2Ch2F 3,4-diClC6H3 4-FC6H4 H CCH3 1 0 CF3 4-FC6H4 3-BrC6H4 H C(CH2)2CH3 2 0 CF3 4-FC6H4 2-ClC6H4 H C-CH2# 0 0 CH2CF3 4-FC6H4 2-CH3OC6H4 CH3 C6H3CO 0 CF3 4-pyridyl 4-FC6H4 H 4-FC6H4CO 0 CH3 4-FC6H4 2-FC6H4 H 3-CH3C6H4CO 0 CF3 4-CH3OC6H4 4-FC6H4 H 2-CH3OC6H4CO 2 (TABLE VIA CONTINUED) R1 R2 R3 -4 -6 n CH2CH3 4-FC6H4 3-ClC6H4 H 4-NO2C6H4CO 1 CH2CF3 4-FC6H4 3,4-diClC6H3 H C6H5SO2 0 CF34- 4-FC6H4 4-FC6H4 CH3CH2 4-ClC6H4SO2 0 CH3 2-thienyl 4-F-3-CH3OC6H3 H 2-CH3CH2C6H4SO2 2 CF3 4-ClC6H4 4-FC6H4 H 3-CH3(CH2)2OC6H4SO2 0 CF3 3-pyridy1- 3-FC H H 3-NO2C6H4SO2 2 N-oxide CF3 4-FC6H4 4-BrC6H4 H CH3SO2 1 CH2CH=CH2 4-FC6H4 4-CH3OC6H4 H CH3(CH2)SO2 0 CH3 2-Br-C6H4 2-BrC6H4 CH3 CN(CH3)2 2 0 CH2F 4-FC6H4 3-FC6H4 H n-C4H9SO2- 0 CF3 4-FC6H4 4-FC6H4 H CN(CH2CH3)2 1 S CF3 4-FC6H4 4-F6H4 H CH3 2 CF3 3,4-diFC6H3 4-FC6H4 H COCH3 0 (CH2)3CH2F 4-CH3(CH2)3C6H4 4-CH3(CH2)3- H CH2OCH2CH2OCH3 0 OC6H4 CF3 4-FC6H4 3-Cl-4FC6H3 H CHOCCH3 1 0 CH3 3-ClC6H4 4-FC6H4 H 0CH2CO 0 CF3 2-BrC6H4 3-ClC6H4 H CH3(CH2)3CO 0 CF3 4-CH3CH2OC6H4 2-CR C H H 4-Cl-C6H6CO 1 CH2CH=CH2 4FC6H4 4-FC6H4 H 4-FC6H4SO2 0 Dosaae Forms The anti-arthritic agents and analgesic agents of this invention can be administered to treat arthritis or alleviate pain by any means that produces contact of the active agent with the agents site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be about 0.05 to 40 milligrams per kilogran of body weight. Ordinarily 0.1 to 20, and preferably 0.2 to 10 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results. Dosage forms (compositions) suitable for internal administration contain from about 5 milligrams to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5 95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenterally, in sterile liquid dosage forms. Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tables. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of. hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E. W. Martin, a standard reference text in this field. Useful pharmaceutical dosage-forms for administra- tion of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 50 milligrams of powdered active ingredient, 110 milligrams of lactose, 32 milligrams of talc, and 8 milligrams magnesium stearate. Capsules A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 milligrams of the active ingredient. The capsules are washed in petroleum ether and dried. Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 50 milligrams of active ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, 7 milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Pharmaceutical Utility A procedure for detecting and comparing the antiinflammatory activity of compounds in this series and standard drugs for which there is a good correlation with human efficacy is the adjuvant-induced arthritis test in rats. A procedure for detecting and comparing the analgesic activity of compounds in this series and standard drugs for which there is a good correlation with human efficacy is the phenylquinone writhing test. The test procedures employed for determining anti in lammatory and analgesic activity are described below with test data included in Tables VII and VIII. EsWablished Adjuvant-Induced Arthritis in Rats Charles River Lewis male rats (130-150 grams) are injected subcutaneously in plantar area of the right hind paw with 0.1 ml of adjuvant (Difco heat-killed, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 20 Non-arthritic controls are injected with mineral oil. The animals are held for 2 weeks to allow development of arthritis. Paw volumes (uninjected, left hind paw) are measured and the adjuvant injected rats are culled and distributed to treatment groups of 10 of equal disease severity. Non-arthritic controls are distributed to 2 groups of 10. The rats are given oral doses of compound or PVA-Acacia (Polyvinyl Alcohol 1%, Gum Acacia, U.S.P. 5%, Methylparaben 0.5%) (10 ml/kg) by gavage on that day and on the 6. following days. One day after the last dose the paw volumes (uninjected, left hind paw) are measured using a Ugo Basile Volume Differential Meter Model 7101. Arthritic Control Treatment Group Mean Paw Volume (ml) - ¯ Mean Paw Volume (ml) x 100 = Arthritic Control - Non-Arthritic Control Mean Paw Volume (ml) Mean Paw Volume (ml) * Decrease from Control Mean Paw Volume. Dose-response regression lines of the % decrease are plotted on semi-log paper by visual fit and the ED50% decrease from control paw volume is determined by inspection. Phenylquinone Writhing Test The phenylquinone writhing test, modified from Siegmund, et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957), was employed. A test compound suspended in lZ methylcellulose was given orally to fasted (17-21 hours) female white mice, 5-20 animals per double blind test. Aqueous (0.019 phenyl--benzoquinone) phenylquinone was injected intraperitoneally at 24 minutes later using 0.20 ml per mouse. Commencing at 30 minutes after the oral administration of the test con- wound, the mice were observed for 10 minutes for a characteristic stretching or writhing syndrome which is indicative of pain induced by phenylquinone. The effective analgesic dose for 50% of the mice (ED50) was calculated by the moving average method of Thompson, W. R., Bact. Rev. 11, 115-145 (1947). Table VII Biological Activity EMI38.1 Adjuvantl Arthritis Analgesic #50 #50 Example Ar Ar' R1 n (mg/kg) (mg/kg) 1 C6H5 C6H5 CF3 0 (36%/25) > 135 2 4-CH3OC6H4 4-CH3OC6H4 CF3 0 1.7 30 3 4-FC6H4 4-FC6H4 CF3 0 1.5 > 135 4 4-ClC6H4 4-ClC6H4 CF3 0 2.8 > 130 5 4-FC6H4 4-C2H50C6H4 CF3 0 (19%/27) > 130 6 4-C1C6H4 4-FC6H4 CF3 0 2.0 > 108 7 4-FC6H4 4-ClC6H4 CF3 0 1.1 > 108 8 4-FC6H4 4-CH3OC6H4 CF3 0 30 26 9 4-C1C6H4 4-CH3OC6H4 CF3 0 6.0 > 108 10 4-FC6H4 C6H5 CF3 0 (22%/27) > 108 11 4-ClC6R4 C6H5 CF3 0 25 > 108 12 4-CH3C6H4 4-CR3C6H4 CF3 0 25 < 108 13 3-FC6H4 3-FC6H4 CF3 0 (33%/27) > 108 16 C6H5 3,4-diC1C6R3 CF3 0 2.5 > 108 18 4-FC6H4 4-FC6H4 CHF2CF2 0 4.0 > 108 19 4-CH3OC6H4 4-CH3OC6H4 CH3 0 5.0 > 130 21 4-C1C6H4 4-ClC6H4 CH3 0 10 > 108 23 4-ClC6H4 4-ClC6H4 CHF2CF2 0 (36%/9) > 108 24 4-FC6H4 4-FC6H4 CH3 0 (19%/27) > 108 26 4-ClC6H4 4-FC6H4 CH3 0 20 > 108 27 4-FC6H4 4-ClC6H4 CH3 0 25 > 108 28 4-FC6H4 4-CH3OC6H4 CH3 0 37 78 ÚValues in parenthesis represent the percent reduction in paw volume at the indicated dose. Table VII (continued) Biological Activity Adjuvant, Arthritis Analgesic ED50 ED50 Example Ar Ar' R1 n (mg/kg) (mg/kg) 29 4-ClC6H4 4-CH3OC6H4 CH3 0 23 63 31 4-ClC6H4 C6H5 CH3 0 (22%/45) > 108 32 4-CH3C6H4 4-CH3C6H4 CH3 0 50 > 135 34 C6H5 C6H5 CF3 2 (46%/25) 15 -- 35 C6H5 C6H5 CF3 1 (31%/25) 30 36 4-CH3OC6H4 4-CH3OC6H4 CF3 2 (36%/9) 78 37 4-CH3OC6H4 4-CH3OC6H4 CH3 2 1.0 16 38 4-CH3OC6H4 4-CH3OC6H4 CH3CH2 2 9 19 39 4-FC6H4 4-FC6H4 CF3 2 1.4 > 135 40 4-FC6H4 4-FC6H4 CF3 1 1.0 > 135 41 4-ClC6H4 4-ClC6H4 CF3 2 1.7 < 130 42 4-ClC6H4 4-ClC6H4 CF3 1 2.7 > 135 43 4-FC6H4 4-C2H5OC6H4 CF3 2 16 > 130 44 4-FC6H4 4-C2H5OC6H4 CF3 1 (14%/9) > 130 45 4-ClC6H4 4-ClC6H4 CF3 2 1.5 > 108 46 4-FC6H4 4-C2H5OC6H4 CF3 2 (34%/25) > 108 47 4-FC6H4 4-FC6H4 CH3 2 (25%/27) > 108 48 4-ClC6H4 4-ClC6H4 CH3CH2 2 (23%/27) > 108 49 4-C1C6H4 4-FC6H4 CH3 2 27 > 135 50 4-FC6H4 4-ClC6H4 CH3 2 50 38 51 4-FC6H4 4-CH3OC6H4 CH3 2 (34%/27) 18 52 4-C1C6H4 4-CH3OC6H4 CH3 2 13 38 54 4-C1C6H4 C6H5 CH3 2 (23X/27) > 108 55 4-CH3C6H4 4-CH3C6H4 CH3 2 90 < 108 Table VIII Biological Activity EMI40.1 Adjwant Analgesic Example Ar Ar' R1 n R4 R6 Arthritis ED50 ED 16a C H 3-pyridyl CF3 0 H H 1.4 > 108 16b 4-CH3OC6H4 2-thienyl CF3 0 H H ¯100 78 57 4-FC6H4 4-FC6H4 CF3 0 H CH3 78%(5.0) 56 4-FC6H4 4-FC6H4 CF3 0 H C(O)CH3 63%(1.0) 59 4-FC6H4 4-FC6H4 CF3 0 H C(O)C6H5 (58%/1.0) 60 4-FC6H4 4-FC6H4 CF3 0 H CO2C6H5 (37%/9.0) 38 4-FC6H4 4-FC6H4 CF3 0 H COOC2H5 - 15 C6H5 C6H5 CF3 O CH3 H 7.5 ? 108 "Consisting essentially of" is intended to have its customary meaning: namely, that all specified materials and conditions are very important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

Claims: What is claimed is: 1. A compound of the formula EMI42.1 where R1 = C1-C4 alkyl, C -C mono- or polyfluoroalkyl or allyl; R2 and R3, independently, = 2-thienyl, 3-pyridyl, 3-pyridyl-N-oxide or EMI42.2 Y1 = C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, H or (R5)2N; wherein R5 = methyl or ethyl; Y2 = H, F or Cl; R4 = H or C1-C3 alkyl; R6 = H, C1-C4 alkyl, allyl, -CH2CH2N(R7)2, EMI43.1 2-tetrahydropyranyl, 2-tetrahydrofuranyl, EMI43.2 EMI43.3 C1-C4 alkylsulfonyl, or EMI43.4 R7 = H, methyl or ethyl; R8 = H or methyl; R9 = C1-C3 alkyl, benzyl, -CH2CH2OCH3, or 0 -CR10; R10 = C1-C4 alkyl or benzyl; R11 = methyl or ethyl; X = O or S; Y3 = lI, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy or nitro; and n = 0, 1 or 2; provided that when Y1 and y2 both = H, R1 is CF3; or its pharmaceutically suitable addition salt where at least one of R2 or R3 = 3-pyridyl, Y1 = (R5)2N, or R6 = -CH2CH2N(R7)2. 2. A compound of Claim 1 where R1 = methyl or trifluoromethyl. 3. A compound of Claim 2 where R1 = methyl and n = 2. 4. A compound of Claim 2 where R1 = trifluoromethyl and n = 0. 5. A compound of Claim 1 where R2 and R3, independently are EMI43.5 6. A compound of Claim 5 where Y1 = F, C1 or methoxy. 7. A compound of Claim 6 where v F. 8. A compound of Claim 5 where Y2 = H. 9. A compound of Claim 1 where R2 = 3-pyridyl. 10. A compound of Claim 1 where R6 = H. 11. A compound of Claim 1 where n = 0 or 1. 12. A compound of Claim 11 where n = 0. 13. A compound of Claim 5 where R1 = methyl or trifluoromethyl; R4 = H; R6 = H; n = 0 or 1; Y1 - F, Cl, or methoxy; and Y2 = H. 14. A compound of Claim 13 where Y1 = F. 15. A compound of Claim 13 where n = 0. 16. A compound of Claim 1 where R4 = H. 17. A compound of Claim 10 where R2 and R3, independently, are EMI44.1 18. A compound of Claim 10 where R2 = 3-pyridyl. 19. A compound of Claim 1 where R1 = CF3; R2 and R3 both R4 = H; EMI45.1 R6 = H; and n = 0 or 1. 20. The compound of Claim 1 where R1 = CF R2 = 3-pyridyl; R3 =C6H5; R4 = H; R6 = H; and n = 0. 21. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 1. 22. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 2. 23. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 3. 24. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 4. 25. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective, antiinflammatory amount of a compound of Claim 5. 26. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 6. 27. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 7. 28. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 8. 29. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective anti inflammatory amount of a compound of Claim 9. 30. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective anti inflammatory amount of a compound of Claim 10. 31. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective anti inflammatory amount of a compound of Claim 11. 32. A pharmaceutical composition consisting essentially oe a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 12. 33. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 13. 34. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 14. 35. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 15. 36. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 16. 37. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 17. 38. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 18. 39. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 19. 40. A pharmaceutical composition consisting essentially of a suitable pharmaceutical carrier and an effective antiinflammatory amount of a compound of Claim 20. 41. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim l. 42. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 2. 43. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 3. 44. A method of treating arthritis in a mammal which comprises administering to the mammal an anti arthritic amount of a compound of Claim 4. 45. A method of treating arthritis in a mammal which comprises administering to the mammal an anti arthritic amount of a compound of Claim 5. 46. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 6. 47. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 7. 48. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 8. 49. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 9. 50. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 10. 51. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 11. 52. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 12. '3. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount'of a compound of Claim 13. 54. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 14. 55. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 15. 56. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 16. 57. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 17. 58. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 18. 59. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 19. 60. A method of treating arthritis in a mammal which comprises administering to the mammal an antiarthritic amount of a compound of Claim 20. 61. A process for preparing a compound of Claim 1 which comprises: (a) contacting a compound of the formula EMI49.1 where R2, R3 and R4 are as previously defined with a sulfenyl chloride, RlSCl where R1 is as previously defined; and optionally, (b) contacting the product of step (a) with a suitable oxidizing agent; (c) optionally alkylating, acylating or sulfonylating the product of (a) or (b); and (d) optionally converting the product of (a), (bL or .(c) into a pharmaceutically suitable salt. 62. A process for preparing a compound of Claim 1 which comprises: (a) contacting a compound of the formula EMI50.1 where R2, R3 and R4 are as previously defined with an alkyl halides, R1X, where R1 is as previously defined, or fluorinated olefin, in the presence of suitable inorganic base; and, optionally, (b) contacting the product of step (a) with a suitable oxidizing agent; (c) optionally alkylating, acylating or sulfonyl ating the product of (a) or (b); and (d) optionally converting the product of (a),(b)or (c) into a pharmaceutically suitable salt.

Inventors: CHERKOFSKY, SAUL CARL
Applicants: E.I. DU PONT DE NEMOURS AND COMPANY
Application year: 1979
Main classification: C07D207
IPC codes: A61K31, C07D409, A61P29, C07D207, C07D401, C07B35