PYRROLE-2-ACETYLAMINO ACID DERIVATIVES

Abstract: Novel pyrrole-2-acetylamino compounds of the formula (5): and salts thereof, wherein R″ is H, C₁₋₆ alkyl, (CH₂) n ,CO₂H, CH₂CH₂SCH₃, (CH₂)₄NH₂ or (CH₂)₂CONH₂; and n is 1 or 2; and Y is hydrogen and Q is CH₃ or Y is CH₃ and Q is Cl, have utility as anti-inflammatory agents and esters of the compounds of the above formula which are useful as intermediates to make said compounds. When Y is H and Q is CH₃, the compounds have, in lower dosages, the same nonsteroidal anti-­ inflammatory utility as tolmetin and when Y is CH₃ and Q is Cl, the compounds have the same analgesic and anti-­ inflammatory utility as zomepirac but with reduced liability toward gastrointestinal irritation.

Description: PYRROLE-2-ACETYDAMINO ACID DERIVATIVES The present invention comprises novel acylamino acids and their salts of the following formula (5): EMI1.1 wherein R' is as defined below for formulae 4 and 40 and Y is hydrogen and Q is CR3, wherein the acyl group is E1- methyl-5-[4-methylbenzoy)-1H-pyrol-2-yl]-acetyl, having the general formula 4 below, or Y is CH3 and g is chlorine, wherein the acyl group is [5-(4-chlorobenzoyl]- 1.4-dimethyl)-1H-pyrrol-2-yl]-acetyl having the general formula 40 below and also amide esters of said acids of the following formula (6): EMI1.2 Also being defined by the general formulae 3 and 30 below, which are used as intermediates to make the acids of general formula 4 and 40, respectively. Tolmetin (general formula 1 below) is the generic name for the compound: fl-methyl-5-( 4-methylbenzoyl)-lH-pyrrol-2- yl]-acetic acid; which can also be named as l-methyl-5-(4- methylbenzoyl)-lH-pyrrole-2-acetic acid, which has antiinflammatory activity, and which is commercially available as tolmetin sodium dihydrate for use as a nonsteroidal, anti-inflammatory agent. Tolmetin is a safe and effective drug, but is administered at relatively large doses. It has now been unexpectedly found that the potency of tolmetin can be substantially enhanced and the dosage required substantially reduced by means of the novel compounds of the present invention having general formula 4 below, so that the tolmetin is administered in the form of its amide with an amino acid. zomepirac (general formula 10 below) is the generic name for the compound t5-(4-chlorobenzoyl)-l ,4-dimethyl-lH- pyrrol-2-yl]acetic acid which has analgesic and antiinflammatory activity and which is commercially available as zomepirac sodium dihydrate. Although zomepirac is used clinically as an analgesic, its mode of action appears to involve inhibition of prostaglandin biosynthesis. Zomepirac shares with other drugs which inhibit prostagland in biosynthesis the side effect of gastrointestinal irritaticn. It has now been unexpectedly found that the liability of zomepirac toward gastrointestinal irritation can be reduced if zomepirac is administered in the form of its amide with an amino acid. The particular amino acid derivatives of tolmetin and zomepirac are the following: glycine, alanine, methionine, glutamic acid, aspartic acid, lysine, and glutamine, and the resultant compounds of the present invention have yeneral formula 4 and 40 below, and may be in either optically active or racemic form. They may be administered in the form of their free acids or in the form of their pharmaceutically-acceptable salts, for example, as salts of alkali metals, preferably sodium or potassium, or alkaline earth metals, preferably calcium, or salts of organic amines, preferably 2-amino-2-(hydroxymethyl)-1,3propanediol (tromethamine). The amino acid derivatives of tolmetin and zomepirac may be prepared by the following reaction scheme (A) and (B), respectively: EMI3.1 In the above formulae: X = halide (particularly C1 or Br), OCH2CN, or -OCOO alkyl R = H, alkyl, (CH2)nC02R', CH2CH2SCH3, (CH2)4NHCHZ, or (CH2) 2C NH2 n = 1 or 2 R' = alkyl or -benzyl R" = H, alkyl, (CH2)nCO2H, CH2CH2SCH3, (CH2)4NH2, or (CH2) 2CORNY When the term "alkyl" is used, it is intended to include C1-C6 alkyls, which can be straight or branched chain, primary, secondary or tertiary, such as methyl, isopropyl, isobutyl, sec-butyl, hexyl, and the like alkyls. Compounds of type 4 and 40 may be prepared by the illustrated three-step procedures (1 to 4) and ;10 to 40). Tolmetin (1) or zomepirac (10) is first converted to an activated derivative (2) or (20). Three different types of activated derivatives may be used, namely, the acid halide (X = halide), the activated ester (X = OCH2CN), or the mixed carbonic anhydride (X = O-CO-O-alkyl). Preparation of acid halides has been previously described by J. R. Carson in U.S. Patent No. 3,752,826 (1973) The activated ester (X = OCH2CN) may be prepared by reaction of a tolmetin or zomepirac salt with chloroacetonitrile in a dipolar aprotic solvent (such as, for example, DMSO, DMF, acetonitrile or acetone) at 200 to 800C. The mixed anhydrides (X = -oCooalkyl) may be prepared by reaction of a tolmetin or zomepirac salt (for example, triethylammonium or N-methylmorpholinium) with an alkyl chloroformate (for example, ethyl chloroformate or isobutyl chloroformate) in an inert aprotic solvent (such as THF or methylene chloride) at -50 to -700C. In the second step, amino acid esters (NH2-CHR-CO2R') are acylated by the action of an activated tolmetin or zomepirac derivative (2) or (20) to give amide esters (3) or (30). The amino acid esters may be liberated from their corresponding salts by treatment with an organic tertiary amine such as triethylamine or an inorganic weak base such as an alkali metal bicarbonate or carbonate. Acylations of the amino acid esters using tolmetin or zomepirac acyl halides are carried out in the presence of a hydrogen halide acceptor such as a tertiary amine (e.g., triethylamine) in an inert aprotic solvent at 0 to 80 C. The acylation procedures using the activated esters (X = OCH2CN) are carried out in an inert aprotic solvent (for example, THF or dioxane) at elevated temperature (500 to 1000C), preferably in the presence of a weak organic acid catalyst, such as acetic acid. The amino acid esters are used in excess. The acylation reactions utilizing the mixed anhydride reagents (X = -O-COO-alkyl) are carried out in inert aprotic solvents, preferably in the same solution in which the reagent is prepared. The temperature range for carrying out acylations using mixed anhydrides is o to -75 C. When the amino acid ester being used is a glutamic acid ester, the mixed anhydride route is preferred, and the activated ester route is not use. The conversion of amide esters 3 or 30 to amide acids 4 or 40, respectively, may be carried out by conventional saponification using about one equivalent of an alkali metal hydroxide in aqueous or mixed aqueous organic solution (e.g., ethanol-water) over a temperature of 250 to 1000 C. When R' is benzyl, the generation of 4 m2v be carried out by catalytic debenzylation using hydrogen and a noble metal catalyst (for example, palladium or platinum) in < :n organic solvent such as a lower alkanol or acetic acid. When RÚ is benzyl, the generation of s or 40 may be carried out by treatment with boron tribromide 'in an inert oranic solvent such as methylene chloride. When R is (CK2)4NHCbz in 3, (CbZ = benzyloxycarbonyl) the removal of the CbZ blocking group is carried out by catalytic debenzylation or preferably by treatment with boron tribromide. When R is (CH2)4NRCbZ in 30 the removal of the CbZ blocking group is carried out by treatment with boron tribromide. When R' is tertiary alkyl the conversion of 3 to 4 or 30 to 40 may be carried out by the action of an aprotic acid, for example, by refluxing trifluoroacetic acid. Alternatively, compounds of type 4 or 40 may be prepared by Schotten-Baumann reaction of the acid halide (2 or 20, respectively, X = halide) with the amino acid in the presence of a weak base, preferably sodium or potassium bicarbonate, in aqueous solution as in the following reaction schemes: EMI6.1 The salts of the compounds of general formula 4 and 40 may be prepared by the conventional method of reacting'the acid compounds a and 40, respectively, with the desired base, or by cation exchange. The anti-inflammatory activity of the compounds 4 of the instant invention was measured in the rat adjuvant arthritis test (S. Wong et al., J. Pharmacol. and Exp. Ther. 185, 127 (1973)). Female Wistar/Lewis rats were given an injection of heat-killed Mycobacterium butyricum in light mineral oil. After eleven days, the animals which had developed an arthritic condition were selected and given daily oral doses of test drug for seventeen days. The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension of free acid in 0.05% methyl cellulose (Admin. Form "b"). paw volumes were measured and the percent inhibition of swelling of the noninjected hind paw as compared to controls was calculated for the fourth and seventeenth day after initiation of dosing. The test results are set forth in Table I and are expressed as ED50 (mg/kg/day). TABLE I* Compound Admin. ED50 EDs0 Form (4 days) (17 days) Tolmetin a 47.7 19.8 4, Rlr b H b 24.75 3.10 4, R8 = CH3 b 28.86 9.68 4, R" = (CH2)2SCH3 b 22.07 8.66 4, R" = CH2CO2E a 28.65 7.71 4, R" = (CH2)2C02H a 24.56 7.69 4, R" = (CH2)2CONH2 a 31.1 11.4 4, R" = (CH2)4NH2 a 27.16 *All test compounds were significantly different from Tolmetin, p ( 0.05. In addition to their anti-inflammatory activity, the compounds of Formula 4 were evaluated for their ability to induce gastric ulceration since gastric irritation is the most significant side effect following administration of nonsteroidal anti-inflammatory agents. The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension Or free acid in 0.05% methyl cellulose (Admin. Form "b"). As described by Wong et al., the dose (UD50, mg/kg/day) required to produce 50 percent ulcerogenic response following 4 days of oral dosing with the test drug was deternined. A therapeutic index in respect to gastric ulceration, the "Anti-inflammatory Index" (All) was calculated. UD50 All = ED50 The test results are set forth in Table II. TABLE II* Admin. Compound Form AII Tolmetin a 4.7 4, R" = H b 30.41 4, R" = CH3 b 13.09 4, R" = (CH2)2SCH3 b 25.31 4, R" = CH2CO2H a > 34.89 4, R" = (CH2)2CO2H a > 32.57 4, P" = (CH2)2CONH2 a 43.06 *All test compounds were significantly different from Talmetin, p < 0.05. us s can be seen, in addition to greater potency than tolme- tin, the compounds of Formula 4 also display a more favorable therapeutic index than the parent drug. In common with other nonsteriodal anti-inflammatory agents, compounds of Formula 4 also possess analgesic activity. The compounds of formula 4 may be administered to humans in the same general manner as tolmetin, except that, since the compounds are more potent, the amount of active drug per unit dose will be less, on the order of 25 mg to 200 mg. Analgesic activity of compounds of Formula 40 can be demonstrated using the mouse acetylcholine bromide-induced writhing test described by H.O.J. Collier, L. C. Deneen, C. A. Johnson and C. Schneider in Brit. J. Pharmacol. Chemother. 32, 295 (1968) at doses of about 0.5 to 5 mg/kg, p.o. The anti-inflammatory activity of the compounds 40 of the instant invention was measured using the rat adjuvant arthritis test (S. Wong, J. F. Gardocki and T. P. Pruss, J. Pharmacol. and Exp. Ther. 185, 127 (19731). Female Wistar/Lewis rats were given an injection of heat-killed Mycobacterium butyricum in light mineral oil. After 11. days; the animals which had developed an arthritic condition were selected and given daily oral doses of test drug for 4 days. Paw volumes were measured and the percent inhibition of the noninjected hind paw as compared to controls was calculated. The results (Table III) are expressed as ED50 (mg/kg/day). In addition to their antiinflammatory activity, the compounds of Formula 40 were evaluated for their ability to induce gastric ulceration -since gastric irritation is the most significant side effect following administration of prostaglandin biosynthesis inhibitors. As -described by Wong et al., the dose (UD50 mg/kg/day) required to produce 50 percent ulcerogenic response following 4 days of oral dosing with test drug was determined. The results are shown in Table III. As described by Wong et al., a therapeutic index in respect to gastric ulceration, the eantiinflammatory index (AII)" defined as UD50/ED50 was determined. The results in Table III demonstrate unexpected safety of the compunds of the instant invention. Table III Example Compound** ED50 UD50 AII No. zomepirac 0.51 13.8 27.2 21 40, R" = H 0.61 21.1* 34.4 22(1) 40, R" = CH3 0.67 25.4* 37.6 25 40, R" = (CH2)2CONH2 0.72 33.4* 46.5 22(2) 40, R" = (CH2)2SCH3 0.93 43.7* 46.9 22(3) 40, R" = (CH2)2C02H 0.54 37.0* 68.9* 24 40, R" = (CH2)4NH2 0.64 35.1* 54.8* 22(4) 40, R" = CH2CO2H 0.76 71.0* 93.1* *Significantly different from parent compound p < 0.05 **The compounds were all administered as aqueous solutions of their sodium salts. The compounds of Formula 40 may be administered to hunans in the same general manner as zomepirac in a per unit dose range from about 10 to 100 mg. The following examples are intended to illustrate, but not to limit, the scope of the present invention. EXAMPLE 1 Cyanomethyl [1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetate A 132.9 g (1.76 mole) sample of chloroacetonitrile was added to a suspension of 446.8 g (1.6 mole) of dry sodium ll-methyl-5-(4-methylbenzoyl)-lH-pyrrOl-2-yll-acetate in one liter of DMF. The mixture was heated at 55 C for 4 hours. The reaction was cooled and water was added. The precipitate was collected and air dried to give 436 g of cyanomethyl [1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2 yl]-acetate (92% yield), m.p. 132-50C. EXAMPLE 2 Methyl N-[(1-Methyl-5-(4-methylbenzoyl)]-1H-pyrrol-2-yl acethyl]glycinate A mixture of 5.6 g (0.019 mole) of cyanomethyl ll-methyl- 5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetate, 2.34 g (0.019 mole) of glycine methyl ester hydrochloride, 2.6 ml (0.019 mole) of triethylamine, and 0.2 ml of glacial acetic acid in 15 mi of THF was heated under reflux for 3 hours. A second addition of 1.17 g (0.0095 mole) of glycine methyl ester hydrochloride and 1.3 ml (0.0095 mole) of triethylamine was made. The reaction was heated under reflux for 2 hours. A third addition of 1.17 g of glycine methyl ester hydrochloride and 1.3 ml of triethylamine was made. The reaction was heated under reflux for 1 hour. It was cooled and poured into water. The solid was collected and dried to give 6.0 g of white crystalline methyl N-(il- methyl-5-(4-methylbenzoyl)]-lH-pyrrol-2-yS|-acetyl}- glycinate (97% yield) m.p. 149-150 C. H nmr (CDCl3) 67.7 (d, J=9), 2H; 7.2 (d, 3=9), 1H; 6.7 (d, J=4), lH; 6.3 (m), 1H; 6.15 (d, J=4), Is, 4.0 (m), 2H; 3.9 (s), 3H; 3.71 (s) 3H, 3.68 (s), 2H; 2.4 (s), 3H. EXAMPLE 3 Using the procedure of Example 2, employing the following amino acid ester salts in place of glycine methyl ester hydrochloride, and allowing them to react with cyanomethyl (l-methyl-5-( 4-methylbenzoyl)-lH-pyrrol-2-yl)-acetate in the presence of triethylamine, the respective [1-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl derivatives of the amino acid esters were prepared: Reaction % m.p. Starting Material/Product time (hr.) yield "C Alanine methyl ester hydrochloride/Metbyl N-{[1-methyl-5-94methyl benzoyl)-lH-pyrrol-2-yl] acetyl]-alaninate 4 75 171-2 Methionine methyl ester hydrochloride/Methyl N-{ll-methyl-5- (4-nethyl-benzoyl) -lH-pyrrol-2- yl]acetyl]-methioninate 5 71 102-4 N6-Benzyloxycarbonyl-lysine benzyl ester hydrochloride/Benzyl N6-Ben- zyl-oxycarbonyl-N2-I[I-methyl-5-(4- methyl-benzoyl) -lH-pyrrol-2-yl3 acetyl]-lysinate 22 62 138-9 Aspartic acid dimethyl ester hydrochloride/Dimethyl N-{[1-methyl-5 (4-methyl-benzoyl)-1H-pyrrol-2-yl] acethyl]-aspartate 18 65 115-7 Aspartic acid dibenzyl ester ptosylate/Dibenzyl N-{[1-methyl-5 (4-methyl-benzoyl)-1H-pyrrol-2-yl] acetyl )-aspartate 9 48 123-4 EXAMPLE 4 Following the procedure of Example 2, employing the following amino acid esters, causing them to react with cyanomethyl [1-methyl-5-(4-methylbehzoyl)-1H-pyrrol-2-yl] acetate in the presence of triethylamine, the correspond- ing [1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acethyl amino acid esters may be prepared respectively: : Amino Acid Ester Product L-Valine methyl ester Methyl N- ! N-i[l-methyl-5-(4-hethyl- hydrochloride benzoyl)]-1H-pyrrol-2-yl]acetyl] valinate L-Leucine methyl ester Methyl N-{il-methyl-s-(4-methyl- hydrochloride benzoyl) -lH-pyrrol-2-yI - acethyl]-leucinate L-Isoleucine methyl Methyl N-{[1-methyl-5-(4-methyl- ester hydrochloride benzoyl)}-1H-pyrrol-2-yl] acetyl]-isoleucinate EXAMPLE 5 Dimethyl N-[1-Methyl-5-(4-methylbenzoyl)-1R-pyrrol-2-yl] acetylglutamate To, a suspension of 45.10 g (0;152 mole) (l-methyl-5-(4- methylbenzoyl)-1H-pyrrol-2-yl]-acetic acid in 230 ml dry THF was added 16.47 ml (0.15 mole) of N-methylmorpholine. The mixture was cooled to -65 C. A 14 ml (0.152 moles) sample of ethyl chloroformate in 50 ml dry THF was added dropwise to the reaction mixture while maintaining the temperature at -65 C. The mixture was stirred for onehalf hour after the addition was completed. Meanwhile, 40.0 g (0.20 mole) L-glutamic acid dimethyl ester hydrochloride was partitioned between 175 ml of cold 20% potassium carbonate and 310 ml of THF. The ThF was washed with brine, dried over 4A sieves and anhydrous sodium sulfate. (Elapsed time 10 minutes). The L-glutamic acid dimethyl ester solution was added to the reaction mixture as quickly as possible maintaining the temperature at -65 C. It was stirred- an additional 4 hours. The reaction mixture was poured into 3N hydrochloric acid, extracted into chloroform, washed with sodium bicarbonate solution, water, brine and dried over mnhydrous magnesium sulfate. The solvent was removed in vacuo giving a tan solid which upon recrystallization from 2-propanol gave 40.5 g of dimethyl N-j[l-methyl-5-(4- methylbenzoyl)-1H-pyrrol-2-yl]j-acetyl}-glutamate (655 yield), m.p. 109-111 C, nmr: 7.70, d, (J=8), 2H; 7.25, d, (J-8), 2H; 6.68, d, (J=4), 1B; 6.52, m, 1E; 6.15, d, (J=4), 1H; 4.55, m, 1H, 3.95, s, 2H; 3.74, S, 3H; 3.56, 2s, (coincidental), 6H; 2.2, m, 411. -EXAMPLE 6 N- I [1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acethyl ) glycine A solution of 64 ml (0.032 mole) of 0.5 N sodium hydroxide was added dropwise over 2 hours to a refluxing solution of 10.49 g (0.0318 mole) of methyl N-(ll-methyl-5-( 4-methyl- benzoyl]-1H-pyrrol-2-yl]-acetyl]-glycinate in 160 ml of methanol. The methanol was evaporated in vacuo. The solution was added to cold 3N HCl. The solid was collected and air dried. It was recrystallized from 2propanol to give 7.3 g of white crystalline N-[[(1-methyl- 5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl]-glycine (72% yield), m.p. 197-199 C. Anal. Calc'd. for C17H18N2O4: C, 64.96; H, 5.77; Found: C, 64.98; H, 5.84. EXAMPLE 7 Following the procedure of Example 6, employing the N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl3-acetyl} derivatives of the aminoacid methyl esters from Examples III and V in place of methyl N-{[1-methyl-5-(4- methylbenzoyl)-1H-pyrrol-2-yl]-acetyl]-glycinate and employing one equivalent of sodium hydroxide for each saponifiable ester group, the following N-{[1-methyl-5-(4- benzoyl)-lH-pyrrol-2-yl]-acetyl} derivatives of amino acids were prepared respectively: Compound 4 m.p. Yield N-{[1-methyl-5-[4-methyl benzoyl)-lH-pyrrol-2-yl]- acetyl}-alanine CH3 67 181-2 N-{[1-methyl-5-(4-methyl benzoyl)-lH-pyrrol-2-yll- acetyl)-methionine (CH202SCH3 92 162-4 N-{[1-methyl-5-(4-methyljbenzoyl)-1H-pyrrol-2-yl] acetyliglutamic acid (CH2)2CO2H 21 178-80 N{[1-methyl-5-(4-methyl benzoyl)-lH-pyrrol-2-yl]- acethyl}aspartic acid CH2CO2H 52 1900d EXAMPLE 8 Following the procedure of Example 6 and employing the N-{tl-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl} amino acid methyl esters from Example 4, the following products may be obtained respectively: : N{ Il-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-y10-acetyl }- valine N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl]leucine N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}isoleucine EXAMPLE 9 N-{[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl} aspartic acid A solution of 13.3 g (0.024 mole) of dibenzyl N-{[1- methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}aspartate in 150 ml of glacial acetic acid was hydrogenated over 1.3 g of 10% palladium on charcoal for 2-1/4 hours at room temperature under 50 psi of -hydrogen. The solvent was evaporated in vacuo. The residue was recrystallized from ethanol-water to give 8.4 g of a gummy red solid. The solid was placed in the thimble of a Soxhlet extractor and continuously extracted with moist ether. The solid was collected from the extract and dried. There was obtained 5.1 g of pink N-{Il-methyl-s-(4-methyl benzoyl)-lH pyrrol-2-yll-acetyl}-aspartic acid (63% yield), m.p. 158-60. Anal. Calcd. for C19H20N2O6 : C, 61.28; H, 5.41; N, 7.52 Found: C, 61.18; H, 5.45; N, 7.52 EXAMPLE 10 N2-j ll-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl)-acetyl 1- lysine hydrate (2:1) A 17.2 g (0.028 mole) sample of N6-benzyloxycarbonyl Nê-{[1-methyl-5-(4-methylbenzoyl[}-1H-pyrrol-2-yl]-acetyl} lysine benzyl ester was dissolved in 170 ml of methylene chloride and the solution cooled to -700C in a dry ice bath under a nitrogen atmosphere. Then 227 ml of 1 Molar boron tribromide solution in methylene chloride was added dropwise, keeping the temperature of the reaction mixture below -50 C. The reaction was mechanically stirred for 3 hours at -50 C, then allowed to warm to 220C over a onehour period. Water was then added dropwise with vigorous stirring. The methylene chloride was evaporated in vacuo, and the aqueous mixture basified to pH 12 with sodium hydroxide solution, then treated with 3N hydrochloric acid to pH 7.5. The solid precipitate was filtered cold, then dried using an evaporating dish. The solid residue was washed several times with hot acetonitrile, then recrystallized from ethanol-water to give Nê-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl}-lysine hydrate (2:1), m.p. 231-233 C d as a light tan solid; the yield was 10% of theoretical. nmr (CD3OD/D2O): 67.9-7.0 (q, 4H, J-14 Hz); 6.8-6.6 (d, 1H, J=4Hz); 6.3-6.1 (d, 1H, J-4Hz); 3.85 (s, 3O; 3.75 (s, 2H); 3.4-3.15 (m, 1H); 3.1-2.6 (m, 2H); 2.4 (2, 3H); 2.11.0 (m, 6H). EXAMPLE 11 N2-I Il-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yli-acetyl } glutamine A 20 g sample (0.073 mole) of [l-methyl-5-(4-methyl- benzoyl)-lH-pyrrol-2-yl]-acetyl chloride was added to a solution of 11.5 g (0.079 mole) of glutamine and 29.3 g (r).32 mole) of- sodium bicarbonate in 300 ml of water. The solution was stirred for 3 hours. The solid was filtered and discarded. The filtrate was acidified with 3N HCl. The solid was filtered and washed with water. The solid was dissolved in acetone-water (50:50), treated with charcoal and the solvent evaporated in vacuo. The solid was extracted with boiling acetone to give 4.3 g of white crystalline Nê-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2 yl]-acetyl} glutanine hydrate (10:1) m.p. 194-6 , yield 15.4%. Anal. calcd. for C20H23N3o50.l H2O: C, 62.04; H, 6.4; H2O, 0.46 Found: C, 62.08; H, 6.01; H2O, 0.29 EXAMPLE 12 Methyl N={[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl)-glycinate A solution of 14.0 g (0.139 mole) of triethylamine in 350 ml of ethanol free chloroform was added to a suspension of 8.3 g (0.066 mole) of glycine methyl ester hydrochloride in 500 ml of chloroform. The mixture was cooled to 0 and a solution of 16.83 g (0.061 mole) of [1-methyl- 5-(4-methylbenzyl)-1H-pyrrol-2-yl)-acethyl chloride in 300 ml of chloroform added. The mixture was stirred at room temperature for 90 minutes. The solution was then washed successively with dilute HC1, sodium bicarbonate solution, water and brine. The solution was dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The solid was dissolved in chloroform-ethyl acetate and filtered through silica gel. The solvent was evaporated and the residue recrystallized twice from ethyl acetate to give 14.9 g (68% yield) of methyl N-((l-methyl- 5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glycinate, m.p. 149-150 C. EXAMPLE 13 Salts of N-{[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl]-glycine (A) A solution of 361 g (1.1 mole) of methyl N-{[1- methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl}-acetyl]jglycinate in 2 1 of ethanol and 220 ml 5N NaOH was heated under reflux for 45 minutes. The mixture was cooled and the solid collected and dried to give 303 g of sodium N f !1-methyl-5-(4-methylbenzoyl-lH-pyrrol-2-yli-acetyl 1- glycinate, m.p. 281-284 C (d). (3) A solution from 12 g (0.038 mole) of N-{[1-methyl-5- 94-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glycine and 4.6 g of 2-amino-2-(hydroxymethyl-1,3-propanediol in 300 ml 2-propanol was concentrated in vacuo and the solid collected and dried. There was obtained 6.0 g of 2ammonium-2-(hydroxymethyl)-1,3 propanediol N-{[1-methyl-5 (4-methylbenzoyl)-lH-pyrrol-2-yll-acetyl}-glycinate hydrate 1:1.65, m.p. 68-73 C. (C) To a solution of 6.73 g of 2-ammonium-2-(hydroxymethyl)-1,3-propanediol N-{[1-methyl-5-(methylbenzoyl)-1Hpyrrol-2-yl]-acetyl}-glycinate in 50 ml of water was added a saturated solution of 22.64 g of CaCl2 in water. The solid was collected, washed with water and air dried to give calcium N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2 yl]-acetyl}-glycinate hydrate [1:0.5:1.6], m.p. 267-2700C (d). EXAMPLE 14 Following the procedures of the foregoing Example 13 and substituting the appropriate N-[1-methyl-5-(4-methyl- henzoyl)-1H-pyrrol-2-yl]-acetyl aminoacid derivative the following salts may be obtained: sodium N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl i-alaninate Sodium N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]- B acetyl]-lysinate 2-Ammonium-2-(hydroxymethyl)-1,3-propanediol N-{[1-methyl 5- ( 4-methylbenzoyl) -lH-pyrrol-2-yl) -acetyl i-methioninate Calcium N{1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl]-aspartate [1: :1] Example 15 Cyanomethyl [5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2 yl) -acetate A 21 ml (0.33 mole) sample of chloroacetonitrile was added to a suspension of 100 g (0.28 mole) sodium (5-(4-chloro- benzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetate in 1.3 1 DMSO. Th reaction mixture was stirred for 5 hours. The reaction mixture was poured into water. The precipitate was collected, taken up in methylene chloride, washed with sodium bicarbonate solution, and dried over anhydrous potassium carbonate. The methylene chloride was stripped off in vacuo giving a yellow solid which upon recrystallization from toluene yielded 74.6 g of cyanomethyl [5-(4- chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl] acetate (80% yiedl), m.p. 133-136 C. Example 16 Methyl N-{[5(4-chlorobenzoyl]-1,4-dimethyl-1H-pyrrol-2-yl] acetyl)alaninate A solution of 10.0 9 (0.03 mole) of cyanomethyl [5-(4chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetate, 1.6 g (0.015 mole) of alanine methyl ester hydrochloride, 0.3 ml of glacial acetic acid, and 2.1 ml (0.015 mole) triethylamine in 40 ml of THF was heated under reflux for 3-1/2 hours. A second addition of 1.6 g of alanine methyl ester hydrochloride and 2.1 ml of triethylamine was made. The mixture was heated under reflux for 2 hours. A fourth addition of 2.0 g (0.018 mole) of triethylamine was made. The mixture was heated under reflux for 16 hours. The reaction was partitioned between chloroform and dilute hydrochloric acid. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized from acetonitrile to give 9.6 g of methyl N-{15- (4-chlorobenzoyl)-1,4-dimethyl-lH-pyrrol-2-yl) acetyl )- alaninate, m.p. 163-165"C (85% yield). Example 17 Using the pro¯dure of Example 16, employing the following amino acid ester salts in place of alanine methyl ester hydrochloride znd allowing them to react with cyanomethyl [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetate in the presence of triethylamine, the respective t5-(4- chlorobenzoyl-1,4-dimethyl-lH-pyrrol-2-yl]acetyl derivatives of the amino acid esters were prepared: Starting Material Product Reaction % m.p. (Molar equívalents) time Yield 0C (hours) Methionine methyl Methyl N-{[5-(4- 49 78 125-6 ester hydro- chlorobenzoyl)-l,4 chloride dimethyl-lH-pyrrol- (2) 2-yl]-acethyl] methioninate Aspartic acid Dimethyl N-{[5- 7 60 160-161 dimethyl ester (4-chlorobeflzoyl)- hydrochloride I ,4-dimethyl-lH- (1 5) pyrrol-2-yl] -acetyl } aspartate N6-(benzyloxy- Benzyl N6-benzyloxy- 22 50 103-104 carbonyl) lysine carbonyl-N2{ [5-(4benzyl ester chlorobenzoyl)-l,4- hydrochloride dimethyl-lH-pyrrol 2-yl)-acethyl}lysinate Example 18 Using the procedure of Example 16, employing the following amino acid esters in place of alanine methyl ester, and causing them to react with cyanomethyl [5-(4-chloro- benzoyl)-1,4-dimethyl-1Hpyrrol-2-yl]-acetate in the presence of triethylamine, the corresponding [5-(4-chloro- benzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]j-acetyl amin o acid esters may be prepared respectively: Amino Acid Ester Product L-valine methyl ester Methyl N-([5-(4-chlorobenzoyl)- hydrochloride 1,4-dimethyl-1H-pyrrol-2-yl]j acetyl]-valinate L-leucine methyl ester Methyl N-([5-( 4-chlorobenzoyl)- hydrochloride 1 ,4-dimethyl-lH-pyrrol-2-yl]- acetyl}-leucinate L-isoleucine methyl Methyl N-{[5-(4-chlorobenzoyl)- ester hydrochloride 1,4-dimethyl-lH-pyrrol-2-yi]- acetyl}-isoleucinate Example 19 Dimethyl N{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2yl[}-acethyl-glutamate To a suspension of 30.45 g (.098 mole) [5-(4-chloro- benzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetic acid in 120 ml dry THF was added 1.4 ml (.098 mole) of N-methylnorpholine. The mixture was cooled to -65 C. A 10 ml (.098 mole) sample of ethyl chloroformate in 50 ml of dry TEF was added dropwise to the reaction mixture maintaining the temperature at -65 C. The mixture was stirred for 1/2 @2 hour after the addition was completed. suen, 32.32 g (.15 mole) of L-glutamic acid dimethyl ester hydrochloride was partitioned between 150 ml of 20% potassium carbonate and 275 ml tetrahydroforan. The tetrahydroforan layer was separated and dried over 4A molecular sieves and anhydrous sodium sulfate. The resulting L-glutamic acid dimethyl ester solution was added to the reaction mixture as quickly as possible maintaining the temperature at -650C. It was allowed to stir for 3-1/2 hours at -650C then warmed to room temperature and stirred overnight. The reaction mixture was poured into 3N hydrochloric acid, extracted into chloroform, washed with sodium bicarbonate solution, water, brine and dried over anhydrous sodium sulfate. The chloroform was evaporated in vacuo giving a yellow solid, dimethyl N{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2 yl]acetyl)-glutamate (45.7%) m.p. 129-130.5 C. Example 20 Methyl N{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2yl]-acetyl}-glycinate A 22.6 ml (0.16 mole) sample of triethylamine was added to a suspension of 6.78 g (0.054 mole) of glycine methyl ester hydrochloride in 200 ml of spectral grade chloroform The mixture was cooled to 0 C and a solution of 16.8 g (0.54 mole) of 15-(4-chlorobenzoyl)-1,4-dimethyl- lH-pyrrol-2-y13-acetyl chloride in 80 ml of chloroform was added slowly. The mixture was stirred at room temperature overnight. The solution was washed successively with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized successively from methanol and acetonitrile to -ve 9.2 g (47% yield) of crystalline methyl N-{[5-(4chlorobenzoyl)-1,4-di- methyl-1H-pyrrol-2-yl]-acetyl)-glycnate m.p. 198-201 C. Example 21 N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-lH-pyrrol-2-yl?- acetyl }-glycine To a solution of 8.55 g (0.0236 mole) of methyl N-([5-(4- chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}glycinate in 50 ml of refluxing methanol was added 49.2 ml of 0.5 normal sodium hydroxide. The solution was heated under reflux for 30 minutes. The mixture was poured into dilute hydrochloric acid. The precipitate was collected and dried. It was recrystallized successively from ethanol and rethanol to give 6.2 g (75% yield) of white crystalline N-{[5-(4-chlorobenzoyl)-1,4-dimetyl-1Hpyrrol-2-yl]-acetyl}-glycine, m.p. 206-208 C. Anal. Calc'd for C17H17ClN204: C, 58.54; H, 4.91 Found: C, 58.42; H, 5.03 Example 22 Using the procedure of Example 21, employing the N-[5-(4chlorobenzoyl]-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl derivatives of the amino acid methyl esters from Examples 16, 17 and 19 in place of methyl N-{15-(4-chlorobenzoyl)- 1,4-dimethyl-1H-pyrrol-2-yl]-glycinate and employing one equivalent of sium hydroxide for each saponifiable ester group, the following N-[5-( $-chlorobenzoyl)-l r4-dimethyl- 1H-pyrrol-2-yl]-acetyl derivatives of amino acids were prepared respectively. Yield m.p. "C N-{[5-(4-chlorobenzoyl)-1,4-dimethyl1H-pyrrol-2-yl]-acetyl}-alanine 56 222-223 N-{[5-(4-chlorobenzoyl)-1,4-dimethyl- 60 184-185 1H-pyrrol-2-yl]-acetyl}-methionine N-{[5-(4-chlorobenzoyl)-1,4-dimethyl- 11 194-196 1H-pyrrol-2-yl]-acetyl}-glutamic acid N-{[5-(4-chlorobenzoyl)-1,4-dimethyl- 42 219-220 1H-pyrrol-2-yl]-acetyl}-aspartic acid Example 23 Using the procedure or Example 21 and employing the N-15 (4-chlorobenzoyl)-l,4-dinethyl-lH-pyrrol-2-ylJ-Åacetyl amino acid methyl esters from Example 18, the following products may be obtained respectively: : N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl] acetyl -valine N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl] acetyl i- leucine N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl] acetyl}-isoleucine Example 24 N2-15-(4-chlorobenzoyl) 1,4-dimethyl-1H-pyrrol-2-yl] acetyl i-lysine-hydrate (5:8) A solution of 3.7 g (5.7 mmoles) of benzyl N6-benzyloxy- carbonyl-N2-{[5-(4-chlorobenzoyl)-l4-dimethyl-lH-pyrr 2-yl]-acetyl}-lysinate in 75 ml of methylene chloride was cooled at -70 . A solution of 35.7 ml of lM boron tribromide in methylene chloride was added in portions and the mixture stirred at -700 for 3 hours. The reaction was allowed to warm to room temperature over one hour. Water was added. The aqueous layer was adjusted to pH 7.5 by the addition of ls NaOH solution. The precipitated solid was collected and recrystallized from ethanol-water (2:1) to give 1.5 g (508 yield) of N2-115-( 4-chlorobenzoyl)-l ,4- dimethyl-lH-pyrrol-2-yl]-acetyl}-lysine hydrate (5:8) m.p. 252-253 C Anal. Calc'd for C21H26ClN3O4 : C, 56.19;' H, 6.20; N, 9.36 Found: C, 55.97; H, 6.59; N, 9.07 Example 25 N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1Hpyrrol-2-yl]acetyl}-glutamine A solution of 30.5 g (0.1 mole) of [5-(4-chlorobenzoyl) 1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 150 ml of dioxane was added slowly at 0-50C to a suspension of 5.88 g (0.15 mole) of magnesium oxide and 14.3 g (0.1 mole) of L-glutamine in 300 ml of water. The result ing yellow suspension was stirred at room temperature for 64 hours. The mixture was acidified with 1N hydrochloric acid and cooled. The precipitate was collected, washed with water and air dried. It was recrystallized three times froze 2-propanol to give 10.8 g of light tan solid which was subjected to chromatography on silica gel. The column was eluted with chloroform:acetic acid:methanol (95:05:4.5). The major compound bearing fraction was concentrated to dryness and the residue recrystallized from acetone, water (2:1) to give 4.5 g (10% yield) of pale yellow crystalline N-ijS-(4-chlorobenzoyl)-1,4- dimethyl-1H-pyrrol-2-yl]-acetyl}-glutamine, hydrate (1:1), m.p. 186-188 C. Anal. Calc'd for C20H22ClN2O5.H2O: C, 54.86; H, 5.52; H2O, 4.11 Found: C, 5.75; H, 5.42; H2O 4.30 EXAMPLE 26 Salts of N-{[5-(4-Clorobenzoyl)-1,4-dimethyl-1H-pyrrol-2 yl -acetyl i-aminoacids (A) By treating the acylamino acid from Example 21 with 5N NaOH and filtering the solid, the following sodium salt may be obtained: Sodium N-ilS-(4-chlorobenzoyl)-1,4- dimethyl-1H-pyrrol-2-yl]-acetyl}-glycinate. The alkali metal salts of the acids from Examples 22-25 may be obtained in a similar manner. (B) By treating the acylamino acids from Example 2 with 2-amino-2-(hydroxymethyl)-1,3-propanediol in alcoholic solution and concentrating the solution, the following tromethamine salt may be prepared: 2-ammonium-2hydroxmehtyl-1,3-pyopanediol N-{[5-(4-chlorobenzoyl)-1,4 dimethyl-1H-pyrrol-2-yl]-acetyl)-alanina The tromethamine salts of the acids from Examples 22-25 may be obtained in a similar manner. (C) By dissolving the acylamino acids form Example 21 in one equivalent of agueous tromethamine and adding agueous calcium chloride solution, the following calcium salt may be obtained : calcium N-{[5-(4-chlorobenzoyl)-1,4dimethyl-1H-pyrrol-2-yl]-acetyl}-methioninate [1:2].The calcium salts of the acids from Examples 22-25 may be obtained in a similar manner, The compounds of the present invention may be formulated for use as anti-inflammatory agents in any of the commonly used torms, such as, tablets, capsules, or syrups; by admixing them with any of the commonly used pharmaceutîcal carriers.

Claims: CLAIMS 1. A pyrrole-2-acetylamino acid compound of the following Formula (5): EMI30.1 or a pharmaceutically acceptable salt thereof, wherein R" is H, C16 alkyl, (CH2)nCO2H, CH2CH2SCH3, (CH2)4NH2 or (CH2)2CONH2; n is I or 2; and Y is hydrogen and Q is CH3 or Y is CH3 and Q is C1. 2. A compound according to Claim 1, wherein Y is hydrogen and Q is CH3. 3. A compound according to Claim 2, which is: N-{tl-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yll-acetyl}- glycine; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}alanine; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}methionine; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}aspartic acid; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}glutamic acid; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl} g lutamine; N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}lysine; or sodium N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl] acetyl]-glycinate. 4. A compound of Claim 3, which is sodium N-Ill-methyl-s- (4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glycinate. 5. A compound according to Claim 1, wherein v is CH3 and Q is Cl. 6. A compound according to Claim 5, which is N-{[5-(4- chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl-acetyl}aspartic acid. 7. An amide ester compounds of the following formula (6): EMI31.1 R is GH, C1-6 alkyl, (CH2)n CO2R', CH2CH2SCH3, (CH2)4NHCbZ, or (CH2)2CONH2; n is 1 or 2; R' is C1-C6 alkyl or benzyl; and Y is hydrogen and Q is CH3 or Y is CH3 and Q is Cl. 8. An ester according to Claim 7, wherein Y is hydrogen and Q is CH3. 9. A compound according to Claim 8, which is: methyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2yl]acetyl}glycinate; methyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2 yll acetyl-aIaninate; methyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2yl]acetyl}-methioninate, benzyl N6-benzyloxycarbonyl-Nê-{[1-methyl-5-(4methylbenzoyl)-1H-pyrrol-2-yl}acetyl}-lysinate; dimethyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2yl]acetyl}-asparatte; dibenzyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2 yl acetyl 1-aspartate; or dimethyl N-{[1-methyl-5-[4-methylbenzoyl)]-1H-pyrrol-2yl]acetyl}-glutamate. 10. A compound according to Claim 9, which is methyl N-{[5-(4-chlorobenzoyl)1,4-dimethyl-1H-pyrrol-2-yl]acetyl}-methioninate. 11. An ester according to Claim 7, wherein Y is CH3 and Q is Cl. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 in admixture with a pharmaceutica]'y acceptable carrier. 13. A compound according to any one of claims 1 to 5 or a composition according to claim 12 for use as an anti-inflammatory agent. 14. A method of producing a compound according to any one of claims 1 to 5, comprising hydrolysing an appropriate amide ester according to any one of claims 7 to 11. 15. A method of producing an amide ester according to any one of claims 7 to 11, which comprises activating a compound of formula (50) EMI33.1 to form a compound of formula (51) EMI33.2 acylating the compound of formula (51) with a compoud of formula (52) EMI33.3 wherein X is halide, -OCH2-CN, or -OCOO-C1-C6 alkyl, and Q,Y, R and R' are selected appropriately from the definitions given above to produce the desired amide ester. 16. A method according to claim 14 > wherein the amide ester is prepared by the method of claim 15. 17. A method of producing a compound according to any one of claims 1 to 5, comprising reacting a compound of formula (60) EMI34.1 with a compound of formula (61) EMI34.2 by a Schotten - Baumam reaction, wherein Q,Y, X and Rf' are selected appropriately from the definitions given above to produce the desired compound. 18. A method of producing a composition according to claim 12, comprising mixing a compound according to any one of claims 1 to 5 with a pharmaceutically acceptable carrier.

Inventors: CARSON, JOHN ROBERT, MIGDALOF, BRUCE HOWARD
Applicants: MCNEILAB, INC.
Application year: 1984
Main classification: C07D207
IPC codes: C07D207