J.Med. Chem. 1985,28, 1037-1049
1037
Synthesis and Antiinflammatory and Analgesic Activity of 5-Aroyl-1,2-dihydro-3H-pyrrolo[ 1,293 ]pyrrole-1-carboxylic Acids and Related Compounds' Joseph M. Muchowski,*+Stefan H. Unger,*t Jack Ackrell,? Paul Cheung,+Gary F. Cooper,? James Cook,? Pascuale Gallegra,? Otto Halpern,' Richard Koehler,? Arthur F. Kluge,? Albert R. Van Horn,? Yulia Antonio,' Humberto Carpio,' Fidencio Franco) Edvige Galeazzi,t Irene Garcia,' Robert Greenhouse,$ Angel Guzmb,* Jose Iriarte,t Alicia Leon,' Angeles Pefia,* Virginia Per&,' David ValdBz,' Neil Ackerman,l Silveria A. Ballaron,s D. V. Krishna Murthy,%Joseph R. Rovito,%Albert J. Tomolonis,l John M. Young,s and Wendel H. Rooks 11s Syntex Research, Institute of Organic Chemistry, Palo Alto, California 94304, Syntex, S.A. Diuisidn de Investigaci6n, Apartado Postal 10-820, Mgxico 10, D.F., Mexico, and Syntex Research, Institute of Biological Sciences, Palo Alto, California 94304. Received April 2, 1984
5-Acyl-l,2-dihydro-3H-pyrrolo[ 1,2-a]pyrrole-l-carboxylicacids and the homologous pyridine and azepine derivatives were synthesized and assayed for antiinflammatory and analgesic activity. 5-Benzoyl-l,2-dihydro-3H-pyrrolo[ 1,2-a]pyrrole-l-carboxylicacid (62) and the corresponding p-methoxy compound 74 were selected for evaluation as analgesic agents in humans on the basis of their high potency in the mouse phenylquinone writhing assay as well as on their minimal liability to elicit gastrointestinal erosion in rata on chronic administration. Extensive quantitative structureactivity relationship (QSAR)studies of the benzoylpyrrolopyrrolecarboxylicacids have demonstrated that the analgesic (mouse writhing) and antiinflammatory (rat carrageenan paw) potencies of these compounds are satisfactorily correlated with the steric and hydrogen-bonding properties of the benzoyl substituent(s). The 4vinylbenzoyl compound 95, which was correctly predicted to be highly active in both assays on this basis, is undergoing advanced pharmacological evaluation in animals as a potential antiinflammatory agent.
In the early part of the last decade, a wide ranging program was initiated in these laboratoires, the objective of which was to develop new high-potency nonsteroidal antiinflammatory agents that elicited fewer side effects than those in use (e.g., indomethacin). Tolmetin (I) and zomepirac (11)are two pyrroleacetic acid derivatives that now enjoy a modicum of success in the treatment of rheumatoid arthritis2 and pain.3 These compounds were chosen as one class of arylacetic acids, among others,& that was of interest as a starting point for structural modifications. In this connection, it was reported by Carson and Wong' that methylation of zomepirac in the acetic acid side chain, as in 111, markedly increased the antiinflammatory potency as measured by the rat paw kaolin edema assay. It was therefore not illogical to expect that the rigid bicyclic framework that would result from the inclusion of the carbon atoms corresponding to the N- and C-methyl groups of I11 in a cyclic system (Le., IV) might be associated with an increase in antiinflammatory potency. This paper describes the synthesis, pharmacological evaluation, and structure-activity relationships of various 5-acyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acids (IV, n = 1) and the homologous six-membered (IV, n = 2) and seven-membered (IV, n = 3) analogues thereof.8 Many members of the 5-benzoyl pyrrolopyrrole series of compounds show high antiinflammatory and/or analgesic activity in animal models. Two of these [62 (assigned the generic name "ketorolac") and 74 (assigned the generic name " a n i r o l a ~ " ) ] ~are J ~ currently undergoing clinical evaluation in man as analgesic agents," and a third (95) is being subjected to advanced pharmacological study in various animal species. Chemistry. With very few exceptions (see below), the carboxylic acids IV were prepared by alkaline hydrolysis of the corresponding esters VI or the nitriles VI1 (Scheme I, Tables I and 11), which in turn were obtained by acylation of the appropriate parent bicyclic systems V and VII.12 The acylation of the esters V was effected with either the Vilsmeier-Haack reagent derived from an NJVInstitute of Organic Chemistry. S.A. Divisibn de Investigacibn. f Institute of Biological Sciences.
"QJy
c
0 CH3
I
CH3
R
11, R = H
ID. R = C H 3
IV
62, X = H 74, X s C H 3 95, X . C H 2 = C H
dimethylcarboxamide and phosphorus oxychloride in boiling 1,2-dichloroethane' or with a carboxylic acid Contribution No. 647 from the Syntex Institute of Organic Chemistry. Berkowitz, S. A.; Bernhard, G.; Bilka, P. J.; Marchesano, J. M.; Rosenthal, M.; Wortham. G. F. Curr. Ther. Res. 1974,16,442. "Zomepirac: A New Non-Narcotic Analgesic"; Proceedings of the Symposium on Zomepirac; Atlanta, GA, 1979: J. Clin. Pharmacol. 1980, 20, 213. Dunn, J. P.; Green, D. M.; Nelson, P. H.; Rooks, W. H.; Tomolonis, A.; Untch, K. G. J.Med. Chem. 1977, 20, 1557. Ackrell, J.; Antonio, Y.; Franco, F.; Landeros, R.; Leon, A,; Muchowski, J. M.; Maddox, M. L.; Nelson, P. H.; Rooks, W. H.; Roszkowski, A. P.; Wallach, M. B. J.Med. Chem. 1978,21, 1035. Dunn, J. P.; Muchowski, J. M.; Nelson, P. H. J. Med. Chem. 1981, 24, 1097. Carson. J. R.: Wone. S. J. Med. Chem. 1973. 16. 172. Muchowski, J. M.; kluge, A. F. U.S. Patent 4 089 969, 1978; U S . Patent 4232038, 1980; Chem. Abstr. 1981, 94, 103156a. Muchowski, J. M.; Greenhouse, R. US.Patent 4 347 187,1982. A detailed account of the animal pharmacology of 5-benzoylacid (62) has 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic recently been published. Rooks, W. H.; Tomolonis, A. J.; Maloney, P. J.; Wallach, M. B.; Schuler, M. E. Agents Actions 1982, 12, 684. Syntheses different from those described herein have been reported for several of the 5-benzoylpyrrolopyrrolecarboxylic acids. Franco, F.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982,47, 1682.
0022-2623/85/1828-1037$01.50/00 1985 American Chemical Society
1038 Journal of Medicinal Chemistry, 1985, Vol. 28, No. 8
Muchowski et al.
Table I. Acyl-l,2-dihydro-3H-pyrrolo[1,2-alpyrrolecarboxylic Esters and Nitriles and Homologous Pyridine and Azepine Analogues
A
0
C
D
no. 1
system X A H A 2-CH3 A 3-CH3 A 4-CH3 A 3-F A 4-F A 241 A 3-C1 A 4-C1 A 4-Br A 2-1 3-OCH3 A A 4-OCH3 A 3-OEt 4-OEt A A 4-0-i-Pr A 4-OCHzCH4Hz A 4-OCHZC=CH 2-CH3C02 B A 3-CH3C02 A 4-CH3C02 A 4-CH3S A 4-CH3SO B 4-CHSS 4-CH3S02 B A A 4-NO2 A 3-"2 A 3-i-C3H7CONH A 4-NH2 A 4-N3 A 3-CN A 4-CN 3-CF3 A A 4-CF3 A 4-CH3CO A 4-CH,=CH A 4-CHzC A 2,6-F2 A 2,4-F2 A 2,4-C& A 3,4-OCHzO A F5 A 4-CeH5 C C
n
R
R'
acylation methoda A A A A A A A A A B B A A A A A B B D C C C
rctn time, h 24 168 78
%
yield mp, "C recrystn solvent* emp formula anal.' 1 i-Pr 85 oil d C18H19N03 e 2 1 i-Pr 37 oil f C19H21N03 g 3 1 i-Pr 90 oil h C19H21N03 g 4 1 i-Pr 8 66 oil 1 C19H21N03 g 1 i-Pr 11 5 66 oil j C18H18FN03 6 1 i-Pr 34 98 72-72.5 CH2C12-hex C18H18FN03 C, H, F 7 1 i-Pr 150 19 oil 1 Ci8H18ClNO3 m 8 1 i-Pr 70 oil 27 C18H18C1N03 m 1 9 4C-70 79-91 1 i-Pr 80.5-81 CH2C12-MeOH C18H18ClN03 C, H, C1, N 10 1 CH3 85 20 82-84 C16H14BrN0, C, H, Br, N acet-hex 11 1 CH3 1.5 79 174-175 acet-hex C16HiiIN03 c, H, N 1 i-Pr 12 66 12 oil i C19HZ1N04 13 1 i-Pr 65 100 oil h C19HZIN04 n 14 1 i-Pr 19 45 50-51 eth-hex C2oH23N04 C, H, N 22 1 i-Pr 52 94-95 15 CH,Cl,-MeOH CmHZ3NO4 C, H, N 16 1 i-Pr 24 93 oil 0 C21H25N04 P 17 1 CH3 72 679 105-107 acet-hex CigHigN04 C, H, N 50 58' 1 CH3 121-122 18 acet-hex CigH17N04 C, H, N 1 40 20 oil 19 d C17H14N203 20 1 CH3 30 60-73 oil t C18H17N05 m 21 1 CH3 45 70" 90.5-91 CH2Cl,-MeOH CI8Hl7NO5 C, H, N 22 1 CH3 63 80' 77-78 CHZClz-eth C17H17N03S C, H, N 1 CH3 V 1 23 76w 113-114 CH2C12-eth CI7Hl7NO4S C, H, N 24 1 E 168 25' 113-113.5 CHzC12-eth C16H14N203S C, H, N 1 X 1.5 94 183-184 25 CHzC12-eth CI6Hl4N2o3S C, H, N 26 1 CH3 C 20 61-76' 124-125 CHzCl2-MeOH CI6Hl4N2o5 C, H, N C 68 51Y 118-120 27 1 CH3 acet-hex Ci6HiclN205 C, H, N 1 CH3 z 0.5 96 78-79 28 MeOH-EtOAc CI6Hl6N2o3 C, H, N 40-46" 134-135 1 CH3 b' 0.5 29 MeOH-HzO C20H22N205 C, H, N 1 CH3 C' 0.5 76 109-111 30 acet-hex Ci6H16Nz03 c, H, N b' 0.5 70 90-92 1 CH3 31 CHzClz-MeOH Cl5Hl2N4O3 C, H, N 70 1 CH3 C 23 101.5-102 CH2C12-eth 32 Cl7Hl4N2O3 C, H, N 59 112-113 1 CH3 C 15 33 CH2C12-ether CI7Hl4N2O3 C, H, N C 41 98 oil 1 CH3 34 C17H14F3N03 0 1 CH3 B 1 74" 73-75 35 acet-hex C I ~ H I ~ F ~ NC,OH,~ F, N 44y 1 CH3 B 20 114-116 36 acet-hex Ci8H17N04 C, H, N 36p 99-100 1 CH3 B 6 37 MeOH Ci&iW3 C, H, N 4v 1 CH3 B 12 113-114 38 acet-hex CiaHiJ'J03 C, H, N 83"' 1 CH3 C 64 84-84.5 39 CH2C12-eth C16H13FZN03 C, H, F, N 826' 81-81.5 1 CH3 C 67 40 CH2C12-MeOH Cl6Hl3F2NO3 C, H, F, N 41 1 CH3 C 22 81 oil U CI~H~~CI~ h' N O ~ 42 1 CH3 B 42 52f 98-100 acet-hex C17HibN05 C, H, N 43 1 CH3 B 1 93" 103-105 CH2Cl2-MeOH CI6H10F5No3 C, H, F, N 1 i-Pr A 20 50° 121-123 CH2C12-hex CZ4H2,NO3 C, H, N 44 45 i-Pr P-napthyl A 15 88 oil 0 CzzHziN03 J' 46 i-Pr cyclobutyl A 5 88 54-55 eth-hex Ci~H2iN03 C, H, N 47 c i-Pr tert-butyl A 96 25 oil d C16H23N03 k' 48 C i-Pr benzyl A 5 70 oil 0 C19H21N03 g 49 D H C 24 89 oil 1' C16H15N03 m' 50 D C1 C 40 86" 74.5-75.5 eth-EtOAc CI6Hl4C1NO3 C, H, C1, N 51 B H 2 D 24 65y 100-102 acet-hex C I G H ~ ~ N ~ OC, H, N 52 B 4-CH3 2 D 48 25"' 92-94 MeOH Ci7Hi~N20 C, H, N 53 A 4-F 2 CH3 C 20 52O' 78-79 acet-hex Ci7Hi~FN03 C, H, N 54 B 3-C1 2 D 50 53'" 113-115 acet-hex C ~ G H ~ ~ C C, ~ NH,~C1, ON 2 D 66 62O' 102-104 MeOH 55 B 4-C1 C16H13ClN2O C, H, C1, N D 48 26"' 112-113 acet-hex C17Hie.N20z c, H, N 4-CH30 2 56 B D 24 24"' 118-119 acet-hex C17HieN20S c, H, N 4-CH3S 2 57 B acet Ci7Hi~N203S c, H, N 4-CH3S02 2 58 B P' 1 74 199-201 3 CH3 C 44 50'' 98-99 acet-hex Ci~HigN03 C, H, N 59 A H 68q' 78-80 acet-hex Cis"aFN03 C, H, F, N 3 CH3 C 24 60 A 4-F 57q' 96-98 MeOH CigHnN03S C, H, N 3 CH3 A 68 61 A 4-CH,S "Acylation methods: A, Vilsmeier-Haack reaction; B, acid chloride and methyl ester in boiling xylene; C, acid chloride and methyl ester in boiling toluene; D, acid chloride and nitrile in boiling xylene; E, acid chloride and nitrile in boiling toluene; see Experimental Section. *hex = hexane; acet = acetone; eth = ether. e Elements shown analysed correctly to within &0.4% of the calculated values. Purified by TLC; EtOAc-CH2C12 (397). e MS M+ 297. (Purified by TLC; EtOAc-CH2C12 (298). BMS M+ 311. hPurified by TLC; EtOAc-CH2C12(1.5:98.5). 'Purified by column chromatography on silica gel; EtOAc-hexane (1:3), 'Purified by column chromatography on silica gel; EtOAc-hexane (6:94). kMS M* 315. 'Purified by TLC; d l
Journal of Medicinal Chemistry, 1985, Vol. 28, No. 8 1039
3H-Pyrrolo[l,2-a]pyrrole-l-carboxylic Acids
Footnotes to Table Z (Continued) EtOAc-CH2C12(2.597.5)."MS Mt 333,331. "MS Mt 327. "Purified by column chromatography on silica gel; EtOAc-hexane (1:l).PMS Mt 355. qPurified by column chromatography on Activity 11 neutral alumina; EtOAc-hexane (1:9). 'Purified by column chromatography on Activity 11 neutral alumina; EtOAc-hexane (1:4),'MS Mt 294. "Purified by TLC; EtOAc-hexane (3:7). "Purified by column chromatography on silica gel; EtOAc-hexane (23). "Peracid oxidation of 22; see Experimental Section. "'Purified by column chromatography on silica gel; EtOAc. *Peracid oxidation of 24; see Experimental Section. YPurified by column chromatography on silica gel; CH2C12. 'Catalytic hydrogenation of 26; see Experimental Section. "'Purified by TLC; EtOAc-hexane (1:l)."See Experimental Section. "Catalytic hydrogenation of 27;see Experimental Section. d'MSMt 337. "Purified by column chromatography on Florisil; EtOAc-hexane (595). PPurified by column chromatography on Activity 11 neutral alumina; EtOAc-hexane (5:95). #Purified by column chromatography on silica gel; EtOAc-hexane (3:7). h'MS Mt 339,337. 'Purified by column chromatography on silica gel; EtOAc-hexane (595).f MS Mt 347. VMS Mt 277. l'PuriAed by TLC; EtOAc-hexane (1:4)."'MS Mt 269. "'Purified by TLC; CH2C12.dPurified by TLC; EtOAc-hexane (1:3).f Peracid oxidation of 57; see Experimental Section. @Purifiedby column chromatography on silica gel; EtOAc-hexane (1:9). Scheme I
VI
'
//
VI1
IV
VI11 n = 1 , 2 , 3 ; R'=CH3, i - P r
chloride in an inert high-boiling solvent at reflux temperature in the absence of a catalyst13(methods A-C, see Experimental Section). The latter technique was also utilized to acylate the nitriles VI1 (methods D and E). There are several noteworthy features of each acylation process. Thus, the Vilsmeier-Haack reaction was particularly efficient for the acylation of the esters V with nonhindered NJV-dimethylcarboxamides (Table I, method A). When moderately hindered amides were used, low product yields resulted even after exceedingly long reaction times (e.g., N,N-dimethyl-2-chlorobenzamide, 19% after 150 h; NJV-dimethylpivalamide, 25% after 96 h; Table I, 7 and 47). With an even more sterically encumbered system, such as N,N-dimethyl-2,6-difluorobenzamide, acylation did not occur at all. Another problem was encountered when Vilsmeier-Haack acylations were effected on the pyrroloazepine system V ( n = 3, R' = CH,). The initially formed 3-acylated product underwent facile acid catalyzed rearrangement14to the more thermodynamically stable 2-acylated compound. Indeed, with N,N-dimethyl-4-fluorobenzamide, 121 was the only product isolated. In contrast to the Vilsmeier-Haack process, the noncatalyzed acylation with acid chlorides was generally applicable. The required products were usually obtained in good yields even with sterically hindered acid halides (e.g., compounds 39 and 41;Table I) and acid-promoted acyl group migration was not a problem. (11) The initial results from clinical evaluation of 62 indicate that this compound (10mg, oral) is equivalent to morphine sulfate (10 mg, intramuscular) for the relief of moderate to severe postoperative pain (Yee, J.; Brown, C. R.; Sevelius, H.; Wild, V. Clin. Pharmacol. Ther. 1984,35,285) and is more efficacious than aspirin (650mg, oral) in the aleviation of moderate or severe postpartum uterine cramps (Bloomfield, S. S.; Mitchell, J.; Cissell, G.; Barden, T. P. Zbid. 1984, 85, 228). (12) Carpio, H.; Galeazzi, E.; Greenhouse, R.; G m h , A,; Velarde, E.; Antonio, Y.; Franco, F.; Leon, A.; PBrez, V.; Salas, R.; ValdBs, D.; Ackrell, J.; Cho, D.; Gallerga, P.; Halpern, 0.; Koehler, R.; Maddox, M. L.; Muchowski, J. M.; Prince, A,; Tegg, D.; Thurber, T. C.; Van Horn, A. R.; Wren, D. Can. J. Chem. 1982,60,2295. (13) Carson, J. R.U.S.Patent 3 998 844, 1976. (14) Carson, J. R.; Davis, N. M. J. Org. Chem. 1981,46, 839.
The use of the bicyclic systems V and VI1 was also associated with advantages and disadvantages. Thus, the esters V were readily acylated by either of the above processes, but, in general, these compounds required storage at 0 OC or less, in the absence of light and acids, if appreciable decomposition was to be avoided. While the bicyclic nitriles VI1 were stable solids, the rate of acylation thereof was considerably less than that observed for the esters. This rate retardation is consistent with the greater inductive effect of the nitrile moiety (a, = 0.56) vs. that of an alkoxycarbonyl group (e.g., a, = 0.37 for C02CH3).15 Methyl 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-2carboxylate (125),the precursor of carboxylic acids 107 and 108,isomeric with 62 and 70,was prepared by catalytic reduction (Rh/A1203or Pd/CaC03) of the mixture of 123 and 124 obtained from the sodium methoxide promoted cyclization of the aldehyde 122.16 The more polar, less abundant pyrrole 126 was separated from 125 by preparative TLC (see Experimental Section). 0
121
123
122
95
94
C02R
126
127. R = i - P r 128. R = H
The 1-methyl analogue 128 of 62 was prepared by alkylation of the sodium salt of the ester l with methyl iodide and subsequent hydrolysis of the product thus obtained with potassium carbonate.
General Discussion The antiinflammatory and analgesic activities of the compounds listed in Table I11 were first determined by using the carrageenan rat paw edema and mouse phenylquinone writhing assays, respectively (see Experimental Section). From these data it is obvious that particularly high analgesic and antiinflammatory activities reside in (15) Hanech, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lein, E. J. J.Med. Chem. 1973,16,1207. (16) Schnekenburger, J.; Vollhardt, H. Arch. Pharm. (Weinheim, Ger.) 1977,310, 186.
1040 Journal of Medicinal Chemistry, 1985, Vol. 28,No. 8
Muchowski et al.
Table 11. Acyl-1,2-dihydro-3H-pyrrolo[ 1,2-a]pyrrolecarboxylic Acids and Homologous Pyridine and Azepine Analogues
A
C rctn time, h 0.5 0.4 0.5 0.5
hydro1 % methoda yield mp, "C recryst solventb emp formula analaC H A 64 160-161 EtOAc-eth CEH13N03 C, H, N 2-CH3 A 95 161-163d CzsH3~Nz03~ C, H, Nd CH2ClZ-ethd 3-CH3 A 95 144-145 CH2ClZ-eth C16H15N03 C, H, N 4-CH3 A 95 182-183 EtOAc-hex C16H15N03 C, H, N 3-F A 1 85 150-152 EtOAc-hex C15H12FN03 C, H, N 4-F A 0.33 63 179.5-180.5 EtOAc-CH,Cl,-eth CI5Hl2FNO3 C, H, N 2-C1 A 0.33 85 173-175d CH2C12-ethd C27H35C1N203dzP C, H, Ndbe 341 A 0.5 52 180-181 EtOAc-eth C15H12ClN03 C, H, C1, N 4-C1 A 0.33 61 201.5-202.5 EtOAc-eth Cl5Hl2C1NO3 C, H, N 4-Br A 0.5 50 180-182 Cl5HlZBrNO3 C, H, Br, N acet-hex 2-1 A 1.5 79 174-175 acet-hex C I E ~ ~ Z I N O B C, H, N 3-OCH3 A 1 61 168-170 EtOAc-hex C16H15N04 C, H, N 4-OCH3 A 0.33 85 187-187.5 MeOH-CH2C12-eth Cl6Hl6No4 C, H, N 3-OC&j A 0.25 79 155-156 EtOAc-eth C17H17N04 C, H, N 4-OCzH5 A 0.5 76 169.5-170 EtOAc-eth C17H17N04 C, H, N 4-0-i-Pr A 0.25 59 157-158 EtOAc-eth C18H19N04 C, H, N 4-OCHZCH=CHz A 0.5 90 112-113 acet-hex C18H17N04 C, H, N 4-OCHzC=CH 1 A 0.5 79 185-187 EtOAc C18H15N04 C, H, N 80 2-OH 1 B 18 40 160-161 EtOAc-eth C15H13N04 c , H, N 81 3-OH 1 c 3 49 190-191 EtOAc-eth C15H13N04 C, H, N 82 4-OH 1 c 1.5 47 191-192 MeOH-EtOAc-eth C15H13N04 C, H, N 4-CH3S 1 A 0.25 83 70 156-157 EtOAc-eth Ci6HibN03S C, H, N 4-SOCH3 1 A 0.25 84 71 214-214.5 MeOH C16H15N04S C, H, N 4-SOZCH3 1 B 85 6 35 211-212 EtOAc-eth C16H15N05S C, H, Nf 86 %NO2 1 c 3 39 221-222 EtOAeCH2C12 C15H12Nz05 C, H, N 4-NO2 1 D 20 87 IO0 189-191 aCet-C&& C15H12N205 C, H, N 3-NHCOCH(CH3)2 1 C 1 51 187-188 88 CigHzoNz04 C, H, Ng EtOAc-eth 89 4-N3 1 c 2 54 167-169 EtOAc-hex Ci5HizN403 C, H, N 3-CN 1 c 1.5 77 193-194 90 Cl6HI2N2o3 C, H, Nh3' MeOH-EtOAc 91 4-CN 1 c 1.5 54 198.5-199.5 MeOH Ci8izNz03 C, H, N 92 3-CF3 1 A 0.25 50 185-186 EtOAc-hex C16H12F3N03 C, H, F, N 93 4-CF3 1 A 0.5 80 187-188 acet-hex Ci~HizF3N03 C, H, F, N 4-COCH3 1 A 1 72 155-156 94 acet-hex C17H15N04 C, H, N 1 E 5 95 4-CH=CHZ 88 155-157 acet-hex C17H15N03 C, H, N 1 E 2 96 4-C=CH 93 161-162 C17H13N02 C, H, N' acet 0.25 2,6-F2 1 A 71 165-166.5 97 EtOAc-eth-hex CI5HllF2NO3 C, H, F, N 1 c 1.5 53 154-155 98 2,4-F2 EtOAc-eth C15HllFZNO3 C, H, F, N 0.25 39 150-151 2,4-C12 1 A 99 C,,H11C12NO3 C, H, C1, N EtOAc-eth 100 3,4-OCHzO 1 A 0.5 98 166-168 EtOAc-hex C16H13N05 C, H, N 48 80 128-130 F5 1 F C15HaF5N03 C, H, F, Nb eth-hex 101 4-CeH5 1 A 0.25 102 64 202.5-203.5 EtOAc-eth C21H17N03 C, H, N P-naphthyl 1 A 0.25 103 80 179-180 EtOAc C19H15N03 C, H, N cyclobutyl 1 A 0.4 78 152-153 104 CH2C12-eth-hex C13H15N03 C, H, N 0.6 tert-butyl 1 A 7 1 175-175.5 105 CH2Clz-hex C13H17N03 C, H, N 0.25 66 142-144 benzyl 1 A 106 C16H15N03 C, H, N' EtOAc-eth 107 H C 0.5 99 125.5-126.5 hex C15H13N03 C, H, N 108 c c1 C 0.5 90 171.5-172.5 EtOAc C15H1zClN03 C, H, C1, N 2 G 3 62 168-169 109 A H EtOAc-eth C16H15N03 C, H, N 1 46 146-147 110 A 4-CH3 2 G acet-hex C17H17N03 C, H, N 2 70 161-162 111 A 4-F 2 A acet C16Hi4FN03 C, H, F, N 112 A 3-C1 2 B 10 61 145-147 C16H14ClN03 C, H, C1, N EtOAc 113 A 4-C1 2 G 2 54 153-155 EtOAc-hex C ~ G H ~ ~ C ~ N OC, ~ "H, ' N" 4-OCHS 2 G 1 61 156-157 114 A acet-hex C17H17N04 C, H, N 115 A 4-SCHa 2 G 2.5 55 174-175 CHzC12-MeOH CI7Hl7NO3S C, H, N 4-SOCHS 2 k 18 116 A 60 201-202 CH2Clz-MeOH C1,H17N04S C, H, N 4-SOzCH3 2 G 2.5 117 A 35 179-180 acet-eth C17Hi7N05S C, H, N 118 A H 73 163-165 3 A 2 EtOAc-Hex C17H17N03 C, H, N 119 A 4-F 3 A 1 80 142-144 acet-hex Ci7Hi6FN03 C, H, F, N 3 A 1 60 165-167 120 A 4-SCH3 acet-hex Ci8HigN03S C, H, N Hydrolysis methods: A, KzCOs/aqueous methanol on esters; B, KOH/aqueous ethanol on nitriles; C, KOH/aqueous methanol on esters; D, DBN/THF; E, NaOH/aqueoua methanol on esters; F, TsOH/HCOOH; G, KOH/aqueous ethylene glycol on nitriles. bSee Table 1 for key to abbreviations. 'Elements shown analyzed correctly to within 4~0.4% of the calculated values except where indicated otherwise. dRefers to dicyclohexylammonium salt. eAnal. Calcd for CnH&1NzO3.0.25Hz0. fCalcd C, 57.64; found C, 56.39. gCalcd C, 67.03; N, 8.23; found C, 66.40; N, 7.77. hCalcd C, 68.56; N, 10.00; found C, 67.01; N, 8.85. i r n / e 280.0841 (calcd for C16H12N203:280.0848). 'Anal. Calcd for C17H13N03.0.1H20.kCalcd F, 27.51; found F, 26.96. 'Calcd C, 71.36; found C, 70.86. "'Anal. Calcd for C16H14C1N03.0.25H20. no. 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79
system A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A B B B B C
R
n 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
3H-Pyrrolo[l,2-a]pyrrole-l-carboxylic Acids
Journal of Medicinal Chemistry, 1985, Vol. 28, No. 8 1041
Table 111. Historical Antiinflammatory and Analgesic Activities of Acyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrolecarboxylic Acids and Homologous Pyridine and Azepine Analogues rat paw assay, mouse writhing rat paw assay mouse writhing no. phenylbutazone = 1" assay, aspirin = Ib no. phenylbutazone = 1 assay, aspirin = 1
