PHARMACEUTICAL COMPOSITION COMPRISING A 5-AROYL-1-C1-5 ALKYL-PYRROLE-2-ACETIC ACID COMPOUND AND ACETAMINOPHEN OR ACETYLSALICYLIC ACID

Abstract: The invention relates to a pharmaceutical composition comprising a 5-aroyl-1-lower alkyl-pyrrol-2-acetic acid com­ pound and acetaminophen and/or acetylsalicylic acid having a greater efficacy in the suppression of inflammation and arthritic degenerations. The 5-aroyl-1-lower alkyl-pyrrole-2-­ acetic acid compound has the formula wherein R is -CN, -COOH, -COOalk., CONH₂, -CONHalk, and CON; R₁ is alk.; R is H, alk.; R is H, alk., Cl, Br; and Ar is a possibly substituted phenyl group.

Description: Pharmaceutical Composition Comprising a 5-Aroyl-1-lowerdkyl pyrrole-2-acetic Acid Compound and Acetaminophen and/or Aspirin (R) The invention relates to a pharmaceutical composition comprising a 5-aroyl-1-loweralkyl-pyrrole-2-acetic acid compound and acetaminophen and/or Aspirin(R). Within the past few years, a new class of non-hormonal antiinflammatory agents, namely, certain 5-aroyl-1-loweralkylpyrrole-2-acetic acid derivatives, have been reported. Due to their anti-inflammatory activity, such derivatives are indicated for the inflammation and pain associated with arthritic diseases, e.g., rheumatoid arthritis, osteoarthritis and the like. It has now been found that such derivatives, when combined with two well-known analgesics, acetaminophen and/or Aspirin (R) have greater efficacy in the suppression of inflammation and arthritic degenerations than when administered alone. The 5-aroyi-1 -loweralkyl-pyrrole-2-acetic acid derivatives to be empoyed in this invention are those encompassed within the following structural formula EMI1.1 wherein: R is a member selected from the group consisting of CN, H COO(loweralkyl), CONH2, CONH(loweralkyl) and CON(lower alkyl)2; R1 is loweralkyl; R2 is a member selected from the group consisting of hydrogen and loweralkyl; R3 is a member selected from the group consisting of htiogen, loweralkyl, chloro and bromo, provided that when said R3 is chloro or bromo, then said R is COOH; and Ar is a member selected from the group consisting of phenyl, trifluoromethyiphenyl, methylthiophenyl and phenyl sub stituted with one to three substituents each selected from the group consisting of loweralkyl, loweralkoxy and halo; with the proviso that when R3is hydrogen, then Ar is other than loweralkylphenyl, and the non-toxic, therapeutically acceptable salts of the foregoing acids, i.e., when R is COOH, such as are obtained from appropriate organic or inorganic bases. As used herein, "loweralkyl11 and "loweralkoxy" may be straight or branch chained saturated hydrocarbons having from 1 to 5 carbon atoms, such as for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like alkyls, and, respectively, the corresponding alkoxys such as, methoxy, ethoxy, propoxy, isopropoxy, etc.; and "halo" represents chloro, fluoro, bromo and iodo. The anti-inflammatory compounds of formula (I) are described in U.S. Patent No 3f 752,826. The preferred compounds of formula (I) for the novel combinations of this invention are those embraced by the formula: EMI3.1 wherein: R' is a member selected from the group consisting of COOH and cDO(loweralkyl); '' is a member selected from the group consisting of hydrogen and methyl; is is a member selected from the group consisting of metal, ethyl, chloro and bromo, provided that when said R''' is chloro or bromo, then said R' is COOH; and Arl is a member selected from the group consisting of phenyl, methylthiophenyl, loweralkylphenyl, loweralkoxyphenyl and halophenyl; and the alkali metal salts of the foregoing acids, i.e., when R' is COOH. The more preferred compounds of formula (II) for the novel combinations of this invention are those wherein the substituted phenyls within the term "Ar", are para-sLtstituted. One of the most preferred compounds.is 1,4-dimethyl-5-p- chlorobenzoyl-pyrrole-2-acetic acid, generically known as "ZOMEPIRAC" [see J. Med. (hem., 14, 646 (1971); J. Med.Chem, 16, 172 (1973); and J. Pharmcol. Exptl. Ther., 185, 127 (1973)]. When one component of a combination is known to possess a certain pharmacological property and such property is increased many-fold, or knozn side-effects are concurrently ;eliminated or reduced, whn said component is combined with one or more other drugs, 'then the net effect of the combination is commonly referred to as "potentiation". It has now been found that a potentiation of the antiinflammatory activity possessed by the above-described 5-anoyl- l-loweralkyl-pyrrole-2-acetic acid derivatives is produced by a combination with Aspiri)or acetaminophen in specified proportions. It has also been found that the latter t v druRs also potentiate the anti-arthritic activity of the former derivatives as evidenced by an increased suppression of bonedegenerative changes. Such unique and surprising potentiatiocs are not merely due to the additive effects of the individual components but, rather, are made possible solely and entirely by the action of the combination itself. It is evident, therefore, that the novel combinations of this invention would find useful applications in alleviating the inflammation, and particularly inflammation, pain and bone degenerative changes associated with arthritic diseases, e.g., rheumatoid arthritis, osteoarthritis and the like. The efficacy.of the novel combination of this invention in inhibiting inflammation and osteogenic degeneration is particularly seen in the adjuvant arthritis test. Although a number of acute antiphlogistic tests have been devised for the study of inflammation and although inflammation is a common feature of these tests and arthritis, every type of inflammation does not lead to articular (joint) tissue damage that is associated with arthritis. The adjuvant arthritis test, a test in which adjuvant arthritis which results both in inflammation and osteogenic changes is induced by Myco bacterium butvricum and in which the effect of the test compounds on each effect can be petermined, is considered to be most useful for evaluation of compounds which may be suitable for the treatment of rheumatoid arthritis and other arthritic diseases. The test procedure, in which the effect on inflammation is determined by paw volume changes and the effect on osteogenic changes is determined by microscopic observation, is described by Wong et al, in J. Pharmacol. Exp.Ther. 185, 127-138, 1973, and is employed in the present deteuttina'- tion of the potentiation of the antiarthritic properties of 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid derivatives by aspirin or acetaminophen. Briefly, in this procedure, adjuvant arthritis is induced in female Wistar, Lewis rats (Charles River Breeding Labora tories Int., Wilmington, Mass.) weighing lB0-l90 gm by a single subcutaneous injection of 0.75 mg Mycobacterium butyricum (Difco) into the left hind paw. The non-injected hind paw remains a normal size for the first seven days. Swelling begins to appear in the non-injected paw of the first rats on Day 8. Using the paw volume determination technique (a technique in which rat paws are dippedin mercuryto the hairline and the volume of displacement determined by a modified Van Arman mercury displacement method as described in the aforementioned paper of Wong et al), the time progress curve of volume changes in the non-injected (contralateral) paw is followed. Since it has been found that whenever an animal shows edema > - 0.25 ml, further increase in the contralateral paw size always follows with swelling developing rapidly during the next two to three days, the 0.25 ml edema is used as criterion of arthritis onset. The mean onset time for 100 rats is found to be 11.6 days with a standard deviation of 1.9 days and the frequency of onset time values distributed normally between Days 8 and 19. Thus, determinations of antiarthritic activity are made in the period Day5L1 to Day 28. It has been found that the progress of adjuvant arthritis can be divided into four phases: Phase I (generally Days 010) is the incubation period, Phase II (generally Days 1118), the time of rapid development of swelling, Phase III (generally Days 19-25), the period of established adjuvant arthritis and Phase IV (generally after 25 Days), the phase of osteogenic changes. For determination of anti-inflammatory properties two different evaluations are made: (a) the evaluation of paw volume during the Phase II and Phase III periods and, (b) the evaluation of osteogenic (bone) degenration during the Phase IV period. For evaluation of paw volume, adjuvant arthritic rats with early but significant signs of arthritis in the contralateral paw are selected on Day 11 and randomly assigned to the various groups of 10 animals in each group. All test animals are dosed daily (per os) with the test compound, preferably as sodium salt, or in saline for 17 days (Days 11 to 27 inclusive). Control animals are dosed with an equivalent volume of saline. The paw volumes of the non-injected paws are determined initially on Day 11 and again on Days 15, 18, 22, 25, and 28. The paw volumes are then compared with normal paw volumes of adjuvant arthitic rats previously determined from a reference curve relating normal paw volume to body weight. The volume of each individual rat which is greater than the normal volume is utilized in the analysis of the data. Values for drug treated animals are expressed as a percent inhibition of the paw volume change relative to the mean value for saline controls. Data is evaluated statistically and ED50 values with 95 percent confidence limits are calculated. The method for statistical analysis is described in detail in the aforementioned paper of Wong et al. The term "ED50" refers to the dose of drug are quired to produce 50 percent antagonism of the paw volume changes observed in the saline treated adjuvant arthritis controls. Suppression of paw volume changes reflects antiinflammatory and antiarthritic activity of a test drug. For evaluation of bone degenerations, normal and adjuvant arthritic rats are sacrificed under CO2, aftr the paw volume measurements have been completed on Day 28. The hind legs are removed above the knees and skinned and the soft tissues dissected away with care to avoid injury to bone and articular structures. The leg bones are then immersed in 2 percent potassium hydroxide solution for approximately four to five days until the remaining soft tissues becomes properly macerated and/or transparent, and the bones are fully visible. The leg bones are stained with Alizarin Red (0.01 percent in 2 percent KOH) for eight hours, and then processed through increasing concentrations of-glycerol in water (20, 40, 60, 80 and 100 percent) for purposes of clearing the tissues for microscopic observation. The distal end of the tibiae, the tarsals, metatarsals, phalanges, and sesamoids are evaluated under a Stereozoom Microscope (a special type of dissecting microscope, product of Bausch and Lomb). -Osteogenic changes for each bone (in 31 bone categories) in the non-injected hind paw are graded on a scale of from O to 10 (increasing numerical value corresponding to increasing severity of bone degeneration). A total bone degeneration score is'obtained (maximum score/paw = 310 points) and then expressed as a percent score. The mean percent score (95 percent confidence limits) for saline control groups from 26 experiments (184 animals) is found to be 53.4 (50.9-55.9). Percent score values for drug treated animals are expressed as a percent inhibition relative to the mean for the saline control group. Data is evaluated statistically and ED50 values with 95 percent confidence limits are calculated. Employing the above described procedures, potentia- tion of antiarthritic activity of 5-aroyl-l-loweralkyl pyrrole-2-acetic acid derivatives by acetaminophen and aspirin are determined. The application of the above-des- cribed procedure is particularly illustrated with Tolmetin (l-methyl-5-p-toluoyl-pyrrole-2-acetic acid), 1, 4-dimethyl- 5-p-chlorobenzoyl-pyrrole-2-acetic acid and 4-chloro-5-pchlorobenzoyl-l-methyl-pyrrole-2-acetic acid. It is to be understood that the compounds illustrated are not for purposes of limiting the invention thereto but only to show the useful properties of compounds within the scope of Formula I. (In the experiments hereinafter described, the 5-aroyl-l-loweralkyl compounds are employed as sodium salts but are calculated and expressed as free acids.) It should be noted that Tolmetin, as such, has been excluded from the scope of the presently claimed invention, but the following data concerning Tolmetin are included merely as illustrative of those obtained according to the procedures described herein. Potentiation of Antiarthritic Activity of Tolmetin (l-methyl-5-p-toluoyl-pyrrole-2 acetic acid) by Acetaminophen I. Paw Volume Studies. Determinations of ED50 are made of tolmetin, acetaminophen and a combination of acetaminophen with varying dosages of tolmetin. The ER50 for tolmetin on the 28th day, and 95 percent confidence limits (C.L.) are 26.4 (Z2.3-29.6) mg/kg/day. The Ed50 for acetaminophen and its 95 percent C.L., evaluated under the same conditions, are 576 (504-698)mg/kg/day. The minimum effective dose (MED ) for acetaminophen is found to be 320 mg/kg/day. The results (ED50 values) obtained when acetaminophen at 200 mg/kg/day is combined with tolmetin is seen in Table I. MED is the dose drug which will produce a statistically signaficant difference (p < 0,05) from saline treated controls according to Dunnett's procedure described in Wong et al. For these experiments the mean (# Standerd Error) for Dunnett's significant difference (DSD) is 23,8 # 3,2 percent inhibition. TABLE I ED5 Values and 95 Percent C.L. (mg/kg/day) Day of Tolmetin Tolmetin Evaluation Only +Acetaminophen 15 42.1 11.7 (36.7-47.3) (9.69-12.7) 18 40.6 6.75 (32.9-48.0) (4.82-7.23) 22 32.4 7.73 (26.9-37.3) (5.88-8.41) 25 29.5 2.09 (20.0-40.1) ( - ) 28 26.4 1.98 (22.3-29.6) (1.44-2.11) The decrease in the ED50 for tolmetin to 1.98 (1.442.11) mg/kg/day shows a 13.3 fold increase in relative potency for t.olmetin indicating potentiation by acetaminophen. It is immediately obvious that the 95 percent C.L. of the ED50 values for the various days evaluated with and without acetaminopehn do n':'t overlap and therefore are significantly different. When various doses of acetaminophen (50, 200 and 800 mg/kg/day) ere combined with tolmetin, the ED50 values for tolmetin are found to decrease with increasing dose of acetaminophen as seen in Table II. TABLE II Treatment Percent Inhibition of Paw Volume # S.E. Dose of Dose of Acetaminophen (mg/kg/day) Tolmetin (mg/kg/day) 0 50 200 800 0 0 0 27.2 + 15.5 67.8 + 5.7 7.5 37.8 +8.8 34.0 + 6.9 58.9 + 5.4 76.3 + 3.8 30.0 49.3 + 9.7 50.7 + 6.4 74.0 + 3.4 82.7 t 4.5 120.0 78.4 + 3.0 75.0 t 5.5 82.4 + 6.4 79.4 # ED50 values of Tolmetin 32 28 3.3 0.6 The data is evaluated by analysis of variance (as set forth in Wong et al, supra) for a 4 x 5 factorial complete block design, with days representing the block. Comparison of means are carried out using Dunnett's pro cedure at the 5 percent special protection level. The ED50 values for tolmetin, when combined with acetaminophen at 200 and 800 mg/kg/day, are significantly different from that of tolmetin administered without acetaminophen or tolmetin plus acetaminophen at 50 mg/kg/day. Regression analysis shows that the decrease in the requirement for tolmetin produced by acetaminophen is linearly related to the logarithmic dose of acetaminophen. The regression coefficient (slope of the dose-response curve) and its 95 percent CL. are 23.4 (13.6-33.3). The dose of acetaminophen required to suppress the tolmetin ED50 by 50 percent is found to be 35.3 (13.4-81.3) mg/kg/day. Since this dose of acetaminophen when ad ministered alone, has no significant effect in the adjuvant arthritis test, acetaminophen given with tolmetin is potentiating the anti-inflammatory activity of tolmetin. Bone Degeneration Studies. A number of studies have shown tolmetin to be effective against the osteogenic changes which occur in the adjuvant arthritic rat. The results obtained when various doses of acetaminophen are combined with various doses of tolmetin and the ED50 values determined, the ED50 values of tolmetin are found to decrease with increasing dose of acetaminophen as seen in Table III. TABLE III Treatment Percent Inhibition of Bone Degeneration # S.E. Dose of Dose of Acetaminophen (mg/kg/day) Tolmetin (mg/kg/day) 0 50 200 800 0 0 0 12,6#6,5 32,9#3,4 7,5 18,6#6,9 13,6#4,4 32,8#4,6 39,2#4,0 30,0 26,3#3,7 18,1#6,7 40,3#3,6 69,5#5,7 120,0 5 + 6.4 48.5 + 7.9 61.7 - 3,0 (0,9 @ 2,9 EDf values (mg/kg/day) 110.5 130 41.4 12.4 When similar data from several experiments showing tolmetin alone to be effective against osteogenic change are pooled and the results analyzed the following values are obtained. The regression coefficient of the dose response curve, for osteogenic change and its 95 percent C. L. are 28.9 (27.6-30.2). The ED50 for tolmetin and 95 percent C.L. are 89.7 (82.1 -10.2) mg/kg/day. The for for acetaminophen and its 95 percent C,L. are 1673 (1563-2008) mg/kg/day with a regression coefficient and 95 percent C.L. 32.3 (31.0-33.6). When acetaminophen at 200 mg/kg/day is combined with tolmetin, the ED50 for tolmetin is decreased to 41.4 (29.8-55.3) mg/kg/day, representing a 2.8 (1.8-4.6) fold increase in the potency of tolmetin against bone degenerative changes. Since the response to acetaminophen alone at 200 mg/kg/day is 12.6 + 6.5 percent inhibition - Standard Error and not significantly different from controls (Dunnett's Significant Difference (DSD) = 22.7 percent), the results show that acetaminophen significantly potentiates the antiarthritic activity of tolmetin. Potentiation of Antiarthritic Activity of Tolmetin by Aspirin I. Paw Volume Studies. Using the method previously described, determinations of ED50 are made of various dosages of aspirin and various dosages of tolmetin. The results seen in Table IV show that the ED50 values for tolmetin are found to decrease with increasing dose of Aspirin(R) TABLE IV Percent Inhibition # S. E. (Day 28) (R) Dose of Aspirin (mg/kg/day) Dose of Tolmetin (mg/kg/day) 0 25 75 100 150 300 0 15.2 # 12.6 39.6 # 3.6 28.3 # 8.2 34.2 # 6.0 66.2 # 6.3 5.6 30.5 # 5.1 36.7 # 7.2 46.4 # 6.8 70.3 # 6.4 11.1 34.5 # 8.0 41.5 # 5.2 53.9 # 6.5 16.7 58.4 # 8.1 42.6 # 5.9 63.1 # 5.4 72.2 # 6.5 33.3 50.8 # 8.4 41.4 # 7.9 45.7 # 5.0 50 62.6 # 2.7 60.4 # 6.9 61.5 # 4.3 75.1 # 4.4 100 66.4 # 3.9 75.2 # 7.7 69.2 # 4.2 ED50 mg/kg 32.0 29.2 23.1 13.5 6.04 < 0.001 When data from several similar experiments are pooled and the results analyzed, the following values are obtained. The ED50 for aspirin and its 95 percent C.L. are found to be 322 (299-545)mg/kg/day. Aspirin alone shows a 16.4 - 11.4 percent inhibition at 25 mg/kg/day and a 28.3 + 8.2 percent inhibition at 100 mg/kg/day. Both of these responses are not significantly different from the saline control (DSD = 30.8 percent). When aspirin at 25 mg/kg/day is combined with tolmetin (5.6 to 100 mg/kg/ day), the ED50 for tolmetin is decreased from 26.4 (22.3 29.6) mg/kg/day to 18.5 412.3 - 24.7) mg/kg/day. When aspirin at 100 mg/kg/day is combined with varying doses of tolmetin, the ED50 of tolmetin decreases to 8.0 (6.2 9.8). Analysis of the results indicates that ED50 values for tolmetin, when combined with aspirin at 150 and 300 mg/ kg/day, are significantly different from that of tolmetin administered without Aspirin, or tolmetin plus aspirin at 75 mg/kg/day. Regression analysis shows that the decrease in the requirement for tolmetin produced by aspirin is linearly related to the logarithmic dose of aspirin. The regression coefficient and its 95 percent C.L. are 25.1 (17.8 - 32.5). ct) The dose of Aspirin required to suppress the tolmetin ED50 by 50 percent is found to be 83.6 (60.5 (a) 101) mg/kg/day. This dose of Aspirin, when administered alone, has no significant effect in the adjuvant arthritis test. Therefore Aspirin given in combination with tolmetin will potentiate the anti-inflammatory activity of tolmetin. II. Bone degeneration Studies. The results obtained when various doses of aspirin are combined with various doses of tolmetin, and the ED50 values of tolmetin determined, it is found that the ED50 values of tolmetin are found to decrease with increasing dose of acetaminophen as seen in Tables V and VI. TABLE V Percent Inhibition + S. E. Dose of Dose of Aspirin (mg/kg/day) Tolmetin (mg/kg/day) 0 25 100 0 20.1 + 5.2 22.9 + 11.0 11.1 28.7 # 7.7 23.4 + 2.5 39.9 + 8.9 33.3 33.4 + 3.9 31.7:+ 4.6 33.7 # 7.0 100 54.2 # 1.9 60.2 # 4.1 54.6 # 3.9 ED50 (mg/kg) 89.7 68:1 47.6 TABLE VI Percent Inhibition -+ S. E. Dose of Dose of Aspirin (mg/kg/day) Tolmetin (mg/kg/day) 0 75 150 300 o 29.5 + 5.6 22.9 # 3.1 59.9 # 5.4 5.6 26.6 + 7.0 20.7 + 3.0 25.6 # 4.7 50.4 + 16.7 27.5 + 4.9 27.5 # 4.9 42.5 #10.9 52.4 + 7.8 fo.o 34.9 t 2.7 34.9 # 2.7 43.4 + 6.6 71.0 + 2.5 89.7 54.0 35 7.2 When data from several experiments are pooled and the results analyzed, the following values are obtained. The ED50 for Aspirin and its 95 percent C.L. for suppression of osteogenic changes in adjuvant arthritis has been shown to be 382 (367-464) mg/kg/day with a regression coefficient + 95 percent C.L. 33.4 (32.1 34.6). When Aspirin at 25 mg/kg/day is combined with varying doses of tolmetin, the ED50 for tolmetin alone 110 (96.7 - 139) mg/kg/day is decreased to 68.1 (55.9 105) mg/kg/day. When Aspirin at 100 mg/kg/day is combined with varying doses of tolmetin, the ED50 is further decreased to 47.6 (15.0 - 62.6) mg/kg/day. (R) Since the response to Aspirin alone at 25 and 100 mg/kg/ day are 15.2 - 12.6 and 28.3 + 8.2 percent inhibition -+ S.E. respectively, and not significantly different from controls (DSD = 30.8%), aspirin has potentiated the antiarthritic activity of tolmetin. Potentiation of Anti-Inflammatory Activity of Other Compounds of Formula I Using the paw volume technique previously described, the effect of acetaminophen and/or aspirin on other 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid compound are determined. Table VII shows the results obtained when l,4-dimethyl-5-p-chlorobenzoyl-pyrrole-2-acetic acid alone, acetaminophen alone and the combinations of the two agents are administered in various doses. The ED50 values for each case are indicated. EMI17.1 <tb> ThHE±-VII <tb> I <SEP> <SEP> < <SEP> Percent <SEP> Inhibition <SEP> * <tb> <SEP> u <SEP> I <SEP> Percent <SEP> Inhibition <SEP> 0 <tb> o <SEP> bl-l <tb> tn <SEP> I <SEP> W¯ <tb> <SEP> s <SEP> 200 <SEP> 200 <tb> <SEP> . <tb> <SEP> o <SEP> 2.7 <SEP> +17.4 <SEP> 6.6 <SEP> t <SEP> 11.4 <SEP> 31.6 <SEP> t <SEP> 6.1 <tb> <SEP> o,ii <SEP> 27.4 <SEP> + <SEP> 10.1 <SEP> 35.3 <SEP> + <SEP> 8.9 <SEP> 39.1 <SEP> + <SEP> 12.3 <SEP> 61.2 <SEP> F <SEP> 3.2 <tb> <SEP> 0.3345.0 <SEP> +- <SEP> 6.o <SEP> 48.3 <SEP> t <SEP> 7.0 <SEP> 57.8 <SEP> + <SEP> 2.8 <SEP> sub.4 <SEP> + <SEP> 4.3 <tb> <SEP> l.o <SEP> 68.o <SEP> + <SEP> 7.8 <SEP> 74.9 <SEP> + <SEP> 6.2 <SEP> 70.0 <SEP> + <SEP> 3.8 <SEP> 84.5 <SEP> + <SEP> 5.3 <tb> EDso(mg/}) <SEP> 0.40 <SEP> 0.36 <SEP> 0.21 <SEP> 0.04 <tb> Table VIII shows the results obtained when 1,4dimethyl-5-p-chlorobenzoyl-pyrrole-2-acetic acid alone, aspirin alone-and the combinations of the two agents are administered in various doses. TAB VIII Dose of 1,4-Dimethyl-5-p- Percent Inhibition # S.E. (Day 28) chlorobenzoylpyrrole-2- Dose of Aspirin (mg/kg/day) acetic acid (mg/kg/day) 0 75 150 300 0 4.1 # 14.4 33.2 # 7.6 28.9 # 9.4 0.125 17.5 # 7 .5 17.3 # 3.4 23.6 # 9.0 51.0 # 5.2 0.5 43.8 # 11.8 45.6 # 12,3 48.6 # 9.4 48.9 # 8.3 2.0. 68.2 t 5.3 67.9 + 6.3 73.5 I 5.5 64.3 +5.0 ED50(mg/kg) 0.728 0.712 0.541 0.283 Table IX shows the results obtained when 4chloro-5-p-chlorobenzoyl-l-methyl-pyrrole-2-acetic acid alone, acetaminophen alone and the combination of the two agents are administered in various doses. TABLE IX Dose of 1,4-Dimethyl-5-p- Percent Inhibition # S.E. (Day 28) chlorobenzoyl pyrrole-2- Dose of Acetaminophen (mg/kg/day) acetic acid (mg/kg/day) 0 50 200 800 0 7.6 # 6.1 29.0 # 12.8 75.3 # 3.9 0.02 18.6 # 11.7 41.2 # 11.7 48.7 # 5.4 80.5 # 3.6 0.06 61.3 # 5.3 58.1 # 9.1 75.0 # 2.3 91.1 # 7.2 0.18 78.9 # 8.7 84.0 # 5.7 87.6 # 6.1 88.2 # 5.8 ED50 (mg/kg) 0.054 0.032 0.019 < 0.001 The foregoing results illustrate the potentiation of the anti-inflammatory and antiarthritic properties of 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid derivatives acetaminophen and aspiring The properties are utilized in the methods and compositions of the present invention. The process of the present invention, namely, a method of inhibiting inflammation and osteogenic degeneration, comprises orally administering to subjects with inflammation and/or osteogenic degeneration, an in inflammation and/or osteogenic degeneration inhibiting amount of a 5-aroyl-1-loweralkyl-pyrrole-2-acetic derivative of Formula I or its pharmaceutically acceptable salt as primary active agent together with a potentiating agent selected from the group consisting of aspirin and acetaminophen. The active agents may be administered with or without carrier in the amounts hereinafter set forth. A preferred method of administration is by the use of the novel compositions in unit dosage form as subsequently described. The operative ranges of the combination of 5-aroyll-loweralkyl-pyrrole-2-acetic acid derivative and acetaminophen or aspirin depends to some extent on whether the potentiating agent is acetaminophen or Aspirin. Generally when acetaminophen is the potentiating agent, from about 50 to 800 mg/kg of acetaminophen is employed together with from about 0.001 to 100 mg/kg of the 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid compound, and preferably from 100 to 400 mg/kg of acetaminophen with from 0.1 to 50 mg/kg of the 5-.aroyl-l-loweralkyl- pyrrole-2-acetic aid compound. When aspirin is the potentiating agent, from about 50 to 300 mg/kg of aspirin is employed with from 0.001 to 100 mg/kg of the 5-aroyl-l-loweralkyl-2-acetic acid compound, and preferably from 100 to 150 mg/kg of Aspirin with from 0.0l to 50 mg/kg of the 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid compound. The outstanding properties are most effectively utilized by use of the novel pharmaceutical compositions of the present invention To prepare the pharmaceutical compositions of this invention, a 5-aroyl-l-loweralkylpyrrole-2-acetic acid compound and a potentiating agent selected from the group consisting of Aspirin and acetaminophen are intimately admixed with a pharmaceutically acceptable carrier suitable for oral administration. By the expression "5-aroyl-l-loweralkyl-pyrrole-2- acetic acid compound" as employed above and in the claims is meant not only the compounds defied by Formulas I and = 7-buv he-pharm ceuticatly acceptable salts thereof. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employer, such as for example, water, glycols, oils, alcohols and the like for oral liquid preparations such as suspensions, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like for powders, capsules and tablets.. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are employed. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. The term dosage unit form" as used in the specification and claims herein refers to physically discrete untis suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets, capsules, pills, powder packets, wafers, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. A dosage unit generally will contain from about 0.1 to 1000 mg of a 5-aroyl-l-loweralkyl-pyrrole-2acetic acid compound as primary active ingredients together with from about 150 to 1000 mg of aspirin or from about 150 to 2000 mg of acetaminophen. The preferred dosage unit is from about 0.2 to 500 mg of a 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid compound together with from about 325 to 500 mg of aspirin or from about 325 to 1000 mg of acetaminophen. The following examples are given to illustrate the novel compositions and are not to be construed as limiting the invention in spirit or in scope. EXAMPLE I 1000 hard gelatin capsules, each containing 4.6 milligrams of 5-p-chlorobenzoyl-l,4-dimethyl-pyrrole-2acetic acid as primary active ingredient and 325 milligrams of acetaminophen as potentiating agent are prepared from the following formulation: Grams 5-p-Chlorobenzoyl-l,4-dimethyl-pyrrole2-acetic acid 4.6 Acetaminophen 325 Starch 250 Lactose 750 Talc 250 Calcium stearate 10 A uniform mixture of the ingredients is prepared by blending and filled into two-piece hard gelatin capsules. The capsules are suitable to be used for providing satisfactory inhibition of inflammation upon administration to subjects with articular inflammation. EXAMPLE II Gelatin capsules are prepared as described in Example I except that in the formulation, 5.2 grams of potassium 5-p-chlorobenzoyl-l, 4-dimethyl-pyrrole-2- acetate is employed as the primary active ingredient and 325 grams of aspirin is substituted as the potentiating agent, thus providing capsules each containing 5.2 mg of potassium 5-p-chlorobenzoyl-1, 4-dimethyl-pyrrole-2- acetate and 325 milligrams of aspirin.

Claims: WHAT IS CLAIMED IS: 1. A pharmaceutical composition comprising an effective inflammation and osteogenic degeneration inhibiting amount of (1) a 5-aroyl-l-loweralkyl-pyrrole-2-acetic acid compound as primary active agent, said compound being selected from (a) those having the formula EMI24.1 wherein: R is a member selected from the group consisting of CN, COOH, cOo(loweralkyl), CONH2, CONH (loweralkyl) and CON(loweralkyl) R1 is loweralkyl; R2 is a member selected from the group consisting of hydrogen and loweralkyli R3 is a member selected from the group consisting of hydrogen, loweralkyl, chloro and bromo, provided that-when said R3 is chloro or bromo, then said R is COOH; and Ar is a member selected from the group consisting of phenyl, trifluoromethylphenyl, methylthio phenyl and phenyl substituted with one to three substituents each selected from the group con sisting of loweralkyl, loweralkoxy and halo; with the proviso that when R3 is hydrogen, then Ar is other than lower alkyiphenyl; and (b) the non-toxic therapeutically acceptable salts of the foregoing acids, namely, acids when R is (1) from about 0.1 to 1000 mg of a 5-aroyl-l-loweralkyl pyrrole-2-acetic acid compounds as primary active agent, said 5-aroyl-l-loweralkyl-prrole-2-acetic acid compound having the formula EMI25.1 wherein: : R' is a member selected from the group consisting of COOR, COO(loweralkyl), and COO(alkali metal); R' is a member selected from the group consisting of hydrogen and methyl; R''' is a member selected from the group consisting of methyl, ethyl, chloro and bromo, provided.that when said R''' is chloro or bromo, then said B' is COOH; and Arl is a member selected from the group consisting of phenyl, methylthiophenyl, loweralkylphenyl, lower alkoxyphenyl and halophenyl; and (2) from about 150 to l000 mg of aspirin or from about 150 to 2000 mg of acetaminophen, as a potentiating agent wherein said primary and potentiating agents are in admixture with a pharmaceutically acceptable carrier. 8. A pharmaceutical composition suitable for inhibiting inflammation and osteogenic degeneration in dosage unit form comprising per dogage unit (1) from about 0.2 to 500 mg of a 5-aroyl-1-loweralkyl pyrrole-2-acetic acid compound as primary active agent, said 5-aroyl-1-loweralkyl-pyrrole-2-acetic compound having the structure EMI26.1 wherein: R' is a member selected from the group consisting of COOH, COO(loweralkyl), and COO(alkali metal); R'' is a member selected from the group consisting of hydrogen and.methyl; ''' is a member selected from the group consisting of methyl, ethyl chloro and bromo, provided that when said R''' is chloro qr bromo, then said R' is COOH; and Ar1 is a member selected from the group consisting of phenyl, methylthiophenyl, loweralkylphenyl, loweralkoxyphenyl and thalophenyl; and (2) from about 325 to 500 mg of aspirin or from about 325 to 1000 mg of acetaminophen as a potentiating agent wherein said primary and potentiating agents are in admixture with a atpharmAceutically acceptable carrier. 9. A method of inhibiting inflammation and osteogenic degeneration comprising orally administering a composition sufficient to provide (1) from about 0.001 to 100 mg/kg of body weight of a 5-aroyl-1-loweralkyl-pyrrole-2-acetic acid compound as primary inflammation and osteogenic degeneration inhibiting compound, said 5-aroyl-l-loweralkyl pyrrole-2-acetic acid compound being selected from (a) those having the formula EMI27.1 wherein: : R is a member selected from the group consisting of CN, COOK, COO(loweralkyl), CONH2, CONH(loweralkyl) and CON(loweralkyl)i; Rl is loweralkyl; R2 is a member selected from the group consisting of hydrogen and loweralkyl; R3 is a member selected from the group consisting of hydrogen, loweralkyl, chloro and bromo, provided that when said R3 is chloro or bromo, then said R is COOH; and Ar is a member selected from the group consisting of phenyl, trifiuoromethylphenyl, methylthio phenyl and phenyl substituted with one to three substituents each selected from the group consisting of loweralkyl, loweralkoxy and halo; with the proviso that when R3 is hydrogen, then Ar is other than loweralkylphenyl, and (b) the non-toxic therapeutically acceptable¯salts of the foregoing acids, namely, when R is COOH; and (2) from about 50 to 800 mg/kg of body weight of acetaminophen or from about 50 to 300 mg/kg of body (i) weight of Aspirin as potentiating agent. 10. A method of inhibiting inflammation and osteogenic degeneration comprising orally administering a composition sufficient to provide (l) from 0.01 to 50 mg/kg of body weight of a 5-aroyl l-loweralkyl-pyrrole-2-acetic acid compound having the structure EMI28.1 wherein: R' is a member selected from the group consisting of COOH, C00(lowralkyl) and C00(alkali metal) R'' is a member selected from the group consisting of hydrogen and methyl; R''' is a member selected from the group consisting of methyl, ethyl, chloro and bromo, provided that when said R''' is chloro or bromo, then said R' is COOH; and Ar is a member selected from the group consisting of phenyl, methylthiophenyl, loweralkylphenyl, loweralkoxyphenyl and halophenyl; and (2) from about 100 to 400 mg/kg of body weight of acetaminophen or from about 100 to 150 mg/kg of body weight of aspirin as potentiating agent.

Inventors: WONG, STEWART
Applicants: MCNEILAB, INC.
Application year: 1978
Main classification: A61K31
IPC codes: A61K31