Substituted Dibenzo[b,e]thiepinalkanoic Acids
(7)
(8)
(9)
(10) (11)
(12) (13)
(14)
(15) (16) (17) (18) (19) (20)
Bodanszky in “Peptides, Proceedings of the Fifth American Peptide Symposium”, M. Goodman and J. Meienhofer, Ed., Wiley, New York, N.Y., 1977, p 1. V. Mutt and J. E. Jorpes, Biochem. Biophys. Res. Commun., 26, 392 (1967); Eur. J . Biochem., 6, 156 (1968); Proc. Znt. Union Physiol. Sci., 6, 193 (1968); J. W. Jorpes, Gastroenterology, 55, 157 (1968); V. Mutt and 3. E. Jorpes, Biochem. J., 125, 57 (1971). A. Anastasi, V. Erspamer, and R. Endean, Experientia, 23, 699 (1967). For a review on gastrin, cf. J. H. Walsh and M. I. Grossman, N . Engl. J . Med., 292, 1324 (1975). A. Anastasi, L. Bernardi, G. Bertaccini, G. Bosisio, R. decastiglione, V. Erspamer, 0. Goffredo, and M. Impicciatore, Experientia, 24, 771 (1968). (a) M. A. Ondetti, J. Pluleec, E. F. Sabo, J. T. Sheehan, and N. Williams, J . Am. Chem. Soc., 92, 195 (1970); (b) M. A. Ondetti, B. Rubin, S.L. Engel, J. PldEec, and J. T. Sheehan, Dig. Dis., 15, 149 (1970). M. Bodanszky, N. Chaturvedi, D. Hudson, and M. Itoh, J . Org. Chem., 37, 2303 (1972). Y. S.Klausner and M. Bodanszky, J . Org. Chem., 42,147 (1977). H. Yajima, Y. Mori, Y. Kiso, K. Koyama, T. Tobe, M. Setoyama, H. Adachi, T. Kanno, and A. Saito, Chem. Phurm. Bull., 24, 1110 (1976);Y. Mori and H. Yajima, ibid., 24,2781 (1976);Y. Mori, K. Koyama, Y. Kiso, and H. Yajima, ibid., 24,2788 (1976); H. Yajima, Y. Mori, K. Koyama, T. Tobe, M. Setoyama, H. Adachi, T. Kanno, and A. Saito, ibid., 24, 2794 (1976). Migration of the sulfate ester group with the concomitant formation of a tyrosine-3-sulfonic acid derivative was observed by Dr. M. A. Ondetti (personal communication). P. Dreyfuss, J . Med. Chem., 17, 252 (1974). (a) M. Bodanszky and S.Natarajan, J. Org. Chem., 40,2495 (1975); (b) S.Natarajan and M. Bodanszky, ibid., 41, 1269 ( 1976). M. Bodanszky, Ann. N.Y. Acad. Sci., 88, 655 (1960). M. Bergmann and L. Zervas, Ber., 65, 1192 (1932). L. A. Carpino, J. Am. Chem. SOC.,79,98 (1957);F. C. McKay
Journal of Medicinal Chemistry, 1978, Vol. 21, No. 10 1035
(21)
(22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35)
(36) (37) (38) (39) (40) (41)
and N. F. Albertson, ibid., 79,4686 (1957); G. W. Anderson and A. C. McGregor, ibid., 79, 6180 (1957). H. Medzihradszky-Schweiger and K. Medzihradszky, Acta Chim. Acad. Sci. Hung., 50, 339 (1966); H. Medzihradszky-Schweiger, Ann. Uniu. Sci. Budap. Rolando Eotuos Nominatae, Sect. Chim., 13, 35 (1972); H. Medzihradszky-Schweiger, Acta Chim. Acad. Sci. Hung., 76,431 (1973). A closed system was used with DMF containing DIEA (in the concentration present in the reaction mixture) in the gas buret and connecting tube. Hog kidney acylase from Nutritional Biochemicals Corp., Cleveland, Ohio. J. P. Greenstein and M. Winitz, “Chemistry of Amino Acids”, Vol. 2, Wiley, New York, N.Y., 1961, p 1053. M. Itoh, D. Hayiwara, and T. Kamiya, Tetrahedron Lett., 4393 (1975). H. C. Reitz, R. E. Ferrel, H. Fraenkel-Conrat, and H. S. Olscott, J . Am. Chem. Soc., 68, 1024 (1946); cf. also ref l l a . S. Ljungberg, Acta Pharm. Suec., 6, 599 (1969). J. D. Gardner, Annu. Rev. Physiol., in press. W. Konig and R. Geiger, Chem. Ber., 103, 788 (1970). T. A. Hylton, G. Preston, and B. Weinstein, J . Org. Chem., 31, 3400 (1966). J. M. Davey, A. H. Laird, and J. S. Morley, J . Chem. SOC. C , 555 (1966). F. Marchiori, R. Rocchi, and E. Scoffone, Ric. Sci. Rend., A2, 647 (1962). M. Wilchek and A. Patchornik, J . Org. Chem., 28, 1874 (1963). M. Bodanszky, Acta Chim. Hung., 10, 335 (1957). E. Scoffone, R. Rocchi, E. Vidali, V. Scatturin, and I. Marchiori, Gazz. Chim. Ztal., 94, 743 (1964). M. Bodanszky and N. Chandramouli, unpublished work. L. Berlinguet and R. Gaudry, J. Biol. Chem., 198,765 (1952). J. D. Gardner and M. J. Jackson, J. Physiol., 270,439 (1977). M. Ceska, K. Birath, and B. Brown, Clin. Chim. Acta, 26, 437 (1969). M. Ceska, B. Brown, and K. Birath, Clin. Chim. Acta, 26, 445 (1969). V. Mutt, Clin. Endocrinol., 5, 175s (1976).
Synthesis and Antiinflammatory Activity of 6,1l-Dihydro-ll-oxodibenzo[ b,e]thiepinalkanoic Acids and Related Compounds’ J a c k Ackrell,* Yulia Antonio, Fidencio Franco, Rosita Landeros, Alicia Leon, Joseph
M. Muchowski,*
Research Laboratories, Syntex, S.A., Apartado Postal 10-820, Mexico 10, D.F. Michael L. M a d d o x , P e t e r H. Nelson, Wendell H. Rooks, Adolph P. Roszkowski, and Marshall
B. Wallach
Syntex Research, Institutes o f Biological Sciences, Organic Chemistry, and Pharmacology and Metabolism, Palo Alto, California 94304. Received April 24, 1978 Acetic acid derivatives of tricyclic systems, such as 6,11-dihydro-ll-oxodibenzo[ b,e]thiepin, 4,10-dihydro-4-oxothieno[2,3-c][ llbenzothiepin, dibenzo[b,flthiepin, dibenz[b,floxepin, etc., were synthesized and assayed for antiacid (52), was chosen inflammatory activity. One of the compounds, 6,11-dihydro-ll-oxodibenzo[b,e]thiepin-3-acetic for evaluation in man on the basis of high antiinflammatory activity in both short- and long-term animal assays and a low gastric irritation liability in rats and dogs. During t h e past 15 years a very large n u m b e r of nonsteroidal antiinflmmatory agents, principally aryl- and h e t e r o a r y l a c e t i c a n d -propionic a c i d s , h a v e been synthesized2with t h e aim of finding substances with fewer
side effects (especially gastric irritation) than phenylbutazone and indomethacin. Of the numerous compounds synthesized, only a few, including i b ~ p r o f e nk, ~ et~profen,~ naproxen: and tolmetin? have m e t m o s t of the above
0022-2623/78/1821-1035$01.00/00 1978 American Chemical Society
1036 Journal of Medicinal Chernistrj, 1978, Vol 21, N u 10
Achrell, Muchowski, et al.
Table I . Substituted Phthalic Acids and Derivatives
R3 R2-X
no.
R'
R:
X
R'
m p or bp % (mm), " C yield
recrystn solvent'
emP formula
analysesb
-
1' 7H160,S C 6-COOCH, oil 84 6-COOH 138-139 8 2 CHC1, Cl,Hl,O,S C, H 2 C,,H,,Cl,O,S C, H, C1 6-COC1 37-38 79 hex 3 c1 5-COOCH(CH3), oil 90 C14H,,N06 c, H 4 (CH,),CHO 91 pen c, 1 H?,O,S c, H, s 5-COOCH(CH3), 70-71 5 (CH,),CHO 299-300 5-COOH 9 2 i-PrOH C15H1204S c, H 6 HO 7 c1 5-COC1 158 72 hex C1~H10C1202S 73-74 4-COOCH, C17H1604S c , H, s 90 C6H6 8 CH,O C,,H,,04S e 4-COOCH(CH3), 105-107 80 C,H,-eth 9 (CH,),CHO 298-300 4-COOH 90 EtOH Cl ,HI 20,s c, H, s 1 0 HO Cl,Hl,C1,O,S d 99-100 4-COC1 90 C,H,-hex 11 c1 70-70.5 3-COOCH, 1' T H 1 64'' c, H 6 5 MeOH 1 2 CH,O 160-162 S 3-CO C,,H,,O,S C, H 8 4 C6H6 13 0 CH, 5-COOH 272-273 80 MeOH C,,H,,O,S C, H 1 4 HO C6H5S CH, 5-COC1 70 90 C,H,-hex C,,H,,Cl,O,S d 15 C1 C6HSS 5-COOCH(CH3), 57-58 88 MeOH-H,O C,,H,,O,S, C, H 16 (CH,),CHO C,H,SCH2 S 5-COOH 1 7 HO C4H,SCH, S 280-282 97 MeOH Cl,Hl,O,S, c, H 18 c1 C,H,SCH, S 5-COC1 80-81 90 CH,Cl,-hex C, ,H,Cl,O,S, f 1 9 CH,O C,H5 S 5-COOCH3 57-59 80 hex Cl,Hl,O,S C, H, S 4-COOCH3 C16H1404S c, H, s C6H5 S 65-67 90 eth-hex 20 CH,O 4-COOCH, C6H\ 0 C, ,HI 4 0 5 g 170(2) 72 21 CH,O MS Elements shown analyzed to within i 0 . 3 % of the calculated values. eth = ether; pen = pentane; hex = hexane, M' 316. MS M' 326, 324. e MS M' 372. f MS M' 288, 286, 284. MS M' 286.
1
CH,O HO
C6H5CH2 C6H,CH, C,HSCH, 0, C6HjCH, C6HjCH, C,H5CH2 C,H,CH, C6HSCH, C6H,CHI C,H,CH, C,H,CH2 C,H,CH,
S S S N S S S S S S S S
Scheme I requirements and reached the marketplace as well. Recently Ueno et al.' and McFadden and co-workers8 reported on the synthesis and antiinflammatory activity of several 6,ll-dihydro-11-oxodibenz[b,e]oxepins bearing acetic or propionic acid entities at carbons 1,' 2,i,s or 3.8 In this paper we describe the synthesis and some of the pharmacological properties of the isoelectronic 6,ll-diI hydro-11-oxodibenzo[b,e]thiepinacetic acids.g The structure-activity relationships of the above compounds are discussed and compared with the isomeric 10,ll-dihydro-10-oxodibenzo[b,flthiepinaceticacids as well as with alkanoic acids in the lO,ll-dihydro-lO-oxodibenz[b,floxepin, 4,10-dihydro-4-oxothieno[2,3-c] [ llbenzothiepin, l0,ll-dihydrodibenzo[b,flthiepin, l0,ll-dihydrodibenz[b,floxepin, dibenzo[b,flthiepin, and dibenz[b,floxepin series. Based on the high degree of antiinflammatory IIIa, R = C1 b, R - OH activity and a low incidence of side effects in animals, c, R = CHN, 6.11-dihydro-ll-oxodibenzo[ b,e]thiepin-3-acetic acid (52) d, R
H
=
IIa, R = OR b, R = OH c, R = C1
HCOOH R
IVa, R = H b, R = CH,
CCH,N,
Scheme I1
52
was selected for evaluation in man. [Compound 52 has been assigned the generic name "tiopinac".] Chemistry. The 6,ll-dihydro-11-0xodibenzo [ b , e ]thiepinacetic acids were synthesized in the manner shown in Schemes 1-111. Thus, the reaction of the appropriate dialkyl nitrobenzenedicarboxylates I with sodium benzyl mercaptide in dimethylformamide solution, at -30 "C to room temperature, gave the corresponding sulfides IIa in 65-9170 yields (see Table I). Although the nucleophilic displacement of aromatic nitro groups no longer can be considered as unusual,1° both the generality (see also below) and the ease with which the substitutions described herein took place, even with hindered substrates (e.g.,
12
13
V
dimethyl !&nitroisophthalate), are remarkable. T h e proclivity of these compounds to undergo displacement of nitrite ion clearly must be a reflection of the combined effect of three strongly electron-attracting groups on the
Journal of Medicinal Chemistry, 1978, Vol. 21, No. 10 1037
Substituted Dibenzo[b,e]thiepinalkanoic Acids Table 11. Precursors of Dibenzo[ b,f]heteropins
6
X
no.
Y
mp or !p
R
(mm), C
%
yield
recrystn solvent?'
83-84 90 eth-hex 5-CH,OH HO 22 s 68-69 88 C,H, 4-CH,OH HO 23 S 73.5-74 4-CH,OH 90 C,H, HO 24 0 45-46 5-CH2Cl 90 eth-hex c1 25 S 92 4-CH2Cl 168 (0.1) c1 26 S 95 4-CH2C1 oil c1 27 0 167-168 5-CH2COOH 54 MeOH-H,O COOH 28 s 176-18 0 4-CH,COOH 60 MeOH-H,O COOH 29 S 161-162 4-CH2COOH 80 MeOH-H,O COOH 30 0 Elements shown analyzed t o within iO.3%of the a See Table I for key t o abbreviations. 270, 268, 266. Scheme I11
4
0
+
as,, -
0
R
g-0S
0
1 4 , R = OH 15, R = C1
hw-d_b4, S
O
41
R'
S
2
VI
monocyclic aromatic systems. With the exception of dimethyl 3-benzylthiophthalate (12), the diesters IIa were saponified and the dicarboxylic acids IIb, thus obtained, were converted into the acid chlorides IIc with thionyl chloride. The cyclization of these substances to the 6,ll-dihydro-11-oxodibenzo[b,e]thiepincarbonyl chlorides IIIa (see Table 111) was effected with the aluminum chloride-nitromethane complex" in dichloromethane solution. The carboxylic acid chlorides IIIa were transformed into the acetic and propionic acid derivatives IVa and IVb (see Table IV) by means of the Arndt-Eistert extension reaction. To essay the synthesis of the 6,11-dihydro-ll-oxodibenzo[b,e]thiepin-1-aceticacids, 3-benzylthiophthalic anhydride (13) was subjected to a varieity of Friedel-Crafts conditions. In no case was cyclization to the tricyclic carboxylic acid V (Scheme 11) observed. The 6,11-dihydro-ll-oxodibenzo[ b,e]thiepin-8-alkanoic acids VI (Scheme 111) were prepared in a manner slightly different from that shown in Scheme I. Phthalide-4carboxylic acid, upon treatment with potassium thiophenolate in boiling dimethylformamide, gave the dicarboxylic acid 14 in 80% yield. Cyclization to 41 was accomplished by heating the diacid chloride 15 in polyphosphoric acid'* a t 110-115 "C. The thiepin 4 1 was subsequently transformed into VI using the Arndt-Eistert procedure. Members of the 4,10-dihydro-4-oxothieno[2,3-c] [1]benzothiepin-7-acetic acid series (e.g., 70, Table IV)'* were
emP formula C,,Hl,O,S Cl,Hl,O,S
analysed
c, H
C, H c,H C,,Hl,C1,S C, H, C1 c 14H1ZC12S c, H, s Cl,Hl,C120 c Cl,Hl,O,S c, H Cl,Hl,04S c, H Cl,Hl,O, c, H MS M' calculated values. C14H1403
synthesized in a manner analogous to that shown in Scheme I commencing with diisopropyl 3-nitroterephthalate (4) (Table I) and sodium 2-thienylmethanethiolate. The l0,11-dihydro-ll-oxodibenzo[b,e] thiepins bearing the alkanoic acid side chain at C-3 were found to be especially potent antiinflammatory agents (see below) and, therefore, the effect of slight structural modifications upon the activity of these substances was investigated. For example, reduction of the acetic acid 52 (Table IV) with sodium borohydride or with amalgamated zinc and hydrochloric acid gave the alcohol 59 or the deoxy compound 61, respectively. In addition, the sulfoxide 62 and the sulfone 63 were obtained by oxidation of 52 with 1 or 2 equiv of rn-chloroperbenzoic acid. Lastly, the butyric acid derivative 58 was prepared by alkylation of the sodium salt of the ester 51 with diethyl sulfate. The resolution of dl-2-(6,11-dihydro-ll-oxodibenzo[b,e]thiepin-3-yl)propionicacid (53) was effected by chromatographic separation of the diastereomeric 1phenethylamides. Cleavage of the less polar l-phenethylamide with a mixture of concentrated hydrochloric acid and acetic acid gave the d-propionic acid 56. Nitrosation of the more polar amide and subsequent rearrangement of the N-nitroso compound in hot benzene solution gave the phenethyl ester of the 1 acid from which the free 1 acid 55 was obtained upon treatment with trifluoroacetic acid. The dibenzothiepin- and dibenzoxepinacetic acids of the [b,fl series were prepared using the route shown in Scheme IV. Displacement of nitrite ion from the appropriate nitro diesters with sodium phenolate or thiophenolate gave the esters VI1 (Table I) which were converted into the diols VIIIa (Table 11) by reduction with lithium aluminum hydride. The dichlorides VIIIb, derived from VIIIa and thionyl chloride, were treated with potassium cyanide in dimethyl sulfoxide to give the dinitriles VIIIc which were subsequently hydrolyzed to the diacetic acids IXa by means of a hot mixture of acetic and phosphoric (85%) acids. The diacid chlorides IXb, prepared from IXa by treatment with oxalyl chloride, were cyclized in a manner analogous to that described for IIc. In some cases it was more convenient to isolate the methyl esters Xc rather than the carboxylic acids Xb (Table IV). Reduction of the ketones Xc with sodium borohydride gave the alcohols XI which were readily dehydrated by treatment with a trace of perchloric acid in boiling tetrahydrofuran. Hydrolysis of XIIa gave the acids XIIb (Scheme IV). The l0,ll-dihydro compounds 76 and 92 were prepared by the Clemmenson reduction of 73 and 89
1038 Journal of Medicinal Chemistry, 1978, Vol. 21, No. 10
Ackrell, Muchowski, et al.
Table 111. Tricyclic Carboxylic Acids and Related Compounds
B
A
emp yield formula analysesb no. system substituent mP,"C 31 A 2-coc1 164 81 C,H,-hex C,,H,ClO,S C 32 A 2-COOH 250- 25 2 1' SH1003S C,H S 88 EtOH 33 A 2-COCHN, 149-150 1' 6H10N,02S H; Ch 76 C6H6 34 A 3-COC1 119-120 60 CH2C1,-eth C,,H,ClO,S C 35 A 3-COOH 225-226 95 MeOH C15H1003S c, H 36 A 3-COCHN, 153 1 ON,' 2' H, N ; Ce 72 C6H6 37 A 3-COCCH,N2 127 73 eth CI,HlZN,O,S f 38 A 4-COC1 149-150 C,,H,ClO,S C, H, C1 90 C6H6 39 A 4-COCHN, 112-113 90 CH,Cl,-eth C16H10N202S c, H, N 40 A 8-coc1 80 eth-hex C,,H,ClO,S C 70 41 A 8-COOH 275-276 80 MeOH-H,O 'I S3H l' 0 c, H 42 A 8-COCHN, 142-143 70 C,H,-hex C16H10N202S c, H 43 A 8-COCCH3N, 125-126 61 eth-hex C17HlZN,OZS f 60 1' 3H,C102S2 h 44 B 7-COC1 g 45 B 7-COOH 222-223 C13H803S2 H; Ci 87 MeOH 46 B 7-COOCH3 122-1 23 67 MeOH C14H1003SZ c, H 47 B 7-COCHN2 149 50 eth C,4H*N,O,S, c, H, N 48 B 7-COCCH3N, 108 86 eth CI,HlON,O,S, C, H, N Elements shown analyzed correctly t o within +0.4% of calculated values unless a See Table I for key to abbreviations, stated otherwise. M S M' 290, 288. C : calcd, 65.33; found, 65.78. e C: calcd, 65.33; found, 65.79. MS M' 308. Amorphous solid. MS M+ 294, 296. ' C: calcd, 56.23; found. 59.03. %
Scheme IV
recrystn solventa
oxidized with the appropriate quantity of m-chloroperbenzoic acid. Finally, the ester groups were removed by hydrolysis to the acids. The unsaturated sulfone 80 was prepared via the alcohol XI using procedures analogous to those described above. Structure-Activity Relationships, The antiinflammatory and analgetic activity of the compounds listed in Table V was measured using the carrageenan paw edema and the phenylquinone writhing assay, respectively (see the Experimental Section). The compounds which were the most active as antiinflammatory agents were those in which the side chain was at a non-peri meta position with respect to the two atom unit spanning the lateral aryl moieties (e.g., 52 and 76). Furthermore, antiinflammatory agents of exceptional potency resulted when the single atom bridge of the central seven-membered ring was a carbonyl group (e.g., 52 and 70) or a divalent sulfur moiety (75 and 76). Alteration of the nature of this portion of the molecule resulted in a substantial diminution in activity as exemplified by the reduced analogues 59 and 61 of 52 and the sulfoxide 79 and sulfone 80 analogues of 76. It is also evident that the character of the two-atom bridge has a considerable effect on the activity, especially in the diaryl[ b,e]thiepinone series. For example, neither the sulfoxide 62 nor the sulfone 63 possessed appreciable antiinflammatory activity. The most surprising observation, however, was that translocation of the sulfur atom and the methylene group, of the central ring, from that found in 52 to that present in 67 caused a 40-fold decrease in activity. This suggests that the sulfide group of 52 serves more than just a passive space occupying role at the receptor level and that the sulfur atom-carboxylic acid moiety distance is related to high activity. For the dibenzo[ b,e]thiepinones, this distance most closely approaches the apparent optimum when the acetic acid side chain is at C-3. A similar situation prevails for the isoelectronic dibenz[b,e]oxepinones where it has been reported' that the 3-acetic acids are approximately twice as potent as the 2-acetic acids. These latter
cXJ&co2R VI1
-
WX>CH2Y
VIIIa, Y = OH b, Y = C1 c, Y = CN
IXa, R = OH b, R = C1
Xa, R = C1 b, R = OH c, R = OCH,
&H$OR
-
X
XI
mH$o*R X
XIIa, R = CH, b, R = H
while 87 was obtained from 86 by catalytic reduction. The sulfoxide 79 and the sulfone 82 were prepared from the acid 76 which was esterified (diazomethane) and then
Journal of Medicinal Chemistry, 1978, Vol. 21, No. 10 1039
Substituted Dibenzo[b,e]thiepinalkanoic Acids Table IV. Tricyclic Acetic Acids and Esters
C
A
sysno. tem - substituent 49 A 2-CH,COOCH3 A 2-CH,COOH 50 51 A 3-CH,COOCH3 52 A 3-CH2COOH 53 A (+ )-3-CHCH3COOH 54d A ( + )-3-CHCH,COOH 55d A (-)-3-CHCH3COOH 56d A (+ )-3-CHCH3COOH A 3-CHC ,H CO ,CH , 57 58d A 3-CHC,H ,COOH 59 A 3-CH2COOH 60 A 3-CH,COOCH, 61 A 3-CH2COOH 62 A 3-CH2COOH 63 A 3-CH2COOH 64 A 4-CH,COOCH3 65 A 4-CH2COOH 66 A 8-CH,COOCH, 67 A 8-CHiCOOH . 68d A 8-CHCH,COOH 69 B 7-CH,COOCH2 70 B 7-CHiCOOH 71 B 7-CHCH,COOH C 2-CH,COOCH3 72 C 2-CH,COOH 73 74 C 2-CH,COOCH3 75 C 2-CH2COOH 76 C 2-CH2COOH 77d C 2-CHCH,COOH 78 C 2-CH2COOCH3 79 C 2-CH2COOH 80 C 2-CH2COOH 81 C 2-CH,COOCH, 82 C 2-CH,COOH 83 C 2-CH,COOCH3 84 C 2-CH,COOH 85 C P-CH,COOCH, 86 C 2-CH2COOH 87 C 2-CH ,COO H 88 C 3-CH2COOCH, 89 C 3-CH2COOH 90 C 3-CH2COOCH, 91 C 3-CH2COOH 92 C 3-CH2COOH ~
B
%
Y
X
co co co co co co co co co co
yield
recrystn solvent"
emP formula
analysesb
61 eth 100 C17H1403S 160-1 6 1' 90 C6H,Cl 2 3'' 90 eth 100-101 S C , ,HI4O,S S 83 C6H6 155-156 C16H1203S eth-hex 114.5-115.5 6 5 S c,,HI40 3s 90 C6H6 164-1 6 5 S C29H37N03S 161-163 S C29H37N03S C6H6 167-168 S C29H3,N03S C6H6 73 eth 71-73 S C19H1803S 90 C,H, 152-15 3 S C,OH3,NO3S 90 acet-C6H6 27 9- 2 80 CHOH S 1' g H 1 43' 52 MeOH 89-90 S c l 7H1602S CH, 87 MeOH 218-219 S C16H1402S CH, 93 EtOH so 185 co C16H1404S 88 HOAc 215-216 co C16H140SS SO 2 77 MeOH S 87-88 co C17H1403S 67 MeOH 172 S co C16H1203S 90 MeOH 113-114 S co Cl,H14O,S 95 H,O S 166-167 co 1' g H 1 23'' 36 MeOH S 206-207 co C29H37N03S 50 MeOH 122-123 C1SH1203S2 70 MeOH 179-180 C14H1003S2 40 eth-hex 112-113 C15H1203S2 45 C6H6-hex 82 S co c l ,H1'103S 177-179 53 C,HsCl co S C16H1203S 67 C,H,-hex 100-101 S CH Cl,Hl4O2S 91 eth 144 S CH C16H1202S 80 eth 104 S 1' g H 1 42'' 1 42- 1 4 3 33 C,H6 S C29H43N02S 89 C6H6-hex so 115 1' 63' 78 CH,Cl,-hex so 169-170 C16H1403S 86.5 EtOAc-hex CI,HlZO,S 162-163 SO, 73 CHC13-hex 103- 1 0 5 1 6 4' SO, 89 C,H, C ." , .HI..O,S . . so2 161-162 oil 45 0 Cl,Hl,O, 85 EtOAc-hex co 0 136-137 C16H1204 70 hex CH 0 76-77 cl TH1 4 3' 98 DME-hex 187-188 0 CH 1' 6H1203 85 C,H,-hex 127- 128 c l g H 1 4O3 CH, 0 CH, 107- 108 co 60 C6H6 C17H1403S CH2 S 192-193 56 CH,C12-eth co CH, S C16H1203S 25 CH S oil CH' 1' 7H1402S 95 MeOH S 138-140 CH CH C16H1202S 133-134 50 C6H6 CH2 S C16H1402S CH, Elements indicated analyzed to within t 0 . 4 % of the calcua acet = acetone; for key t o other abbreviations see Table I. The data in this row refer t o the dicyclohexylammonium lated values unless stated otherwise. ' Lit.9a m p 163-165 "C. C: calcd, 71.63; found, 71.28. salt. e C: calcd, 72.62; found, 73.05. MS M' 282. S S
compounds are, however, still highly active, and this presumably is a reflection of the shorter nature of the'C-0 bond in the two-atom bridge. The above activity differences may also be related to the conformation of the central seven-membered ring. Indeed, the presence or absence of an heteroatom in the two-atom bridge has a marked effect on the NMR chemical shifts for these compounds. Thus of H-1 (HA)and H-10 (HB) in the dibenzo[b,e]thiepinones H-1 was found at lower and for the H-10 at higher field than that (6 7.85) ~alculated'~ analogous protons in a hypothetical, similarly substituted benzophenone (see Table VI). The deshielding of H-1 and the shielding of H-10 are most consistent with a twist boat conformation for the seven-membered ring. When the sulfur atom was replaced by an oxygen atom or an sp2 carbon,15 the chemical shift difference between the hy-
Y
"
drogens peri to the carbonyl group progressively diminished, indicative of an increasing conformational symmetry. The analgetic activities of the compounds listed in Table V, in general, were approximately parallel to their antiinflammatory activities. There were, however, several cases (e.g., 53 and 71) for which the analgetic potency would not have been correctly predicted on the basis of this parallelism. The antiinflammatory activity of compound 52 was conspicuously superior to that found for the other diarylheteropinacetic acids. The corresponding propionic acid 53 was almost three times as active as 52, with most of the activity residing in the dextrorotatory enantiomer 56. In contrast, the methyl compound 58 was only one-half as active as the acetic acid. The heterocyclic alkanoic acids 70 and 71 were much less active (ca. one-tenth) than the
1040 Journal of Medicinal Chemistry, 1978, Vol. 21, No. 10
Table V. Antiinflammatory and Analgesic Activities of Diarylheteropinalkanoic Acids
no
d , 1, or d l
rat paw assay, phenyl- mouse writhing butazone = 1 assay, aspirin = 1
50 52 53 55 56 58d 59 61 62 63 65 67 68 70 71 73 75 76 77 79 80 82 84 86 87 89 91 92
0.3 (96)a 1.5 ( 4 0 ) b 40 ( 3 8 4 ) 14 (70) dl 115 ( 1 9 2 ) 20 ( 7 4 ) 1 < 4 (72) NF d 206 ( 7 2 ) NT dl 20 ( 3 6 ) 4 (24) dl < 1 (18) < 0 . 3 (8) 1.0( 3 2 ) 2 (24) dl 0.5 ( 4 8 ) G 0 . 5 (10) < 0.2 (12) 0.2 ( 8 )
