`
`© Copyright 1984 by the American Chemical Society
`
`Volume 27, Number 11
`
`November 1984
`
`Antiinflammatory Agents. 3.‘ Synthesis and Pharmacological Evaluation of
`2-Amino-3-benzoylphenylacetic Acid and Analogues
`
`David A. Walsh,“ H. Wayne Moran} Dwight A. Shambles,’ Ibrahim M. Uwaydahf‘ William J. Welstead, Jr.,*
`Lawrence F. Sancilio,‘ and Warren N. Dannenburgi
`
`Department of Chemical Research, Department of Pharmacology, and Department of Molecular Biology, A. H. Robins
`Company, P. O. Box 26609, Richmond, Virginia 23261-6609. Received February 13, 1.984
`
`and evaluated
`been
`A series of substituted derivatives of 2-amino-3-benzoylphenylaoetic acid (smfenac)
`for antiinflammatory, analgesic, and cyclooxygenase inhibiting activity. Several derivatives including 157 (4’-chloro),
`158 (4’-bromo), and 182 (5-chloro, 4’-bromo) Were more potent than indomethacin in these assays.
`
`Initial investigations“ into the pharmacological activity
`of derivatives of 2-amino-3-benzoylphenylacetic acid (1,
`amfenac, Scheme 1), a potent analgesic and nonsteroidal
`antiinflammatory drug,” suggested that the potency of 1
`could be increased by the addition of certain substituents
`to the molecule. This article describes the results obtained
`from a comprehensive structure-activity study of ana-
`logues of 1.
`Chemistry. Substituted 7-benzoyloxindoles, precursors
`to the desired 2-amino-3-benzoylphenylacetic acids, were
`prepared by two general methods (Schemes I and IV).
`Gassms.n’s‘ method for the synthesis of oxindoles. utilizing
`substituted 2-aminobenzophenones5 (Table I) as starting
`material, gave the 3-(methylthioloxindoles in good yields
`(Tables II, III) in a one-pot synthetic sequence. Removal
`of the 3-methylthio group with either Raney nickel or tin
`and hydrochloric acid gave the oxindoles (Scheme I). In
`cases where the electron-donating 5-methoxy substituent
`was required, a modification“ of Gassm.an’s original pro-
`cedure was used duc to the instability of the N-chloro-p-
`anisidine intermediate.
`The reaction of 3-aminobenzophenone under the
`standard reaction conditions gave exclusively 4-benzoyl-
`3-(methylthio)oxindole (13) and none of the 6-benzoyl
`isomer (17). Strongly electron withdrawing groups direct
`attack to the more hindered ortho position.’ The synthesis
`of 17 is described in Scheme II.
`Scheme III depicts some miscellaneous synthetic reac-
`tions that gave specific 7-benzoyloxindole derivatives. The
`4'-fluoro group of 48 could be displaced with sodium
`methoxide to give 35 or with sodium thiomethoxide to give
`36. The sulfoxide 37 and the sulfone 38 were prepared
`from 36 by using m-chloroperbenzoic acid. The oxindole
`54 could be nitrated in concentrated sulfuric acid with
`potassium nitrate to yield 106. The nitro group was re-
`duced with iron and acetic acid to give the amine 107.
`Derivatives containing bromine or iodine were some-
`times difficult to prepare by the method outlined in
`Scheme I since these groups could be partially removed
`by the Raney nickel or the tin and hydrochloric acid that
`was used to remove the 3-methylthio group. These halo-
`
`
`‘ Department of Chemical Research.
`‘Department of Pharmacology.
`5Department of Molecular Biology.
`
`Scheme I
`
`”"=
`
`-s on
`cH,scH,co.c,H. —-'——‘'——-—r
`cu,§|,
`-10 e
`
`V
`
`X
`
`H,co,c,H.
`-
`"H H
`cu’
`
`'
`
`Y
`
`scu,
`
`X
`
`CI
`
`.a—
`
`X
`
`0
`
`p-1:9‘
`<———
`
`X
`
`5'
`
`°
`
`Y
`
`°
`
`V
`
`J at,»
`cu-I,
`Hco,c.H,
`NH.
`
`\a0l-I
`
`V
`
`cH,co,Na
`N».
`
`_1_ X.\'=|-I .amfenac
`
`Scheme 1]
`
`no,
`
`5'
`
`
`
`=H[<“-o=c.u.
`0.
`
`.NaCH[CO,C,H,): -‘
`
`,J
`
`Sn
`0 © "
`HCI
`-—r é
`i
`
`20
`
`1:4
`
`genated derivatives were conveniently prepared by a
`procedure described by Lo et al.‘ (Scheme IV). Thus,
`
`(1) For part 2 in this series. see: Walsh, D. A.: Shambles, D. A.;
`Welstesd, w. .I., Jrx, Sancilio, L. F‘. J. Med. Chem. 1932. 25,
`443-51.
`‘
`(2) Welsteed, W. J., J12; Moran, H. W.'. Taylor, C. R.. Jr.: Stauffer,
`H. F., Jr. “Abstracts of Papers”, 170th National Meeting of the
`American Chemical Society, Chicago. IL, Aug 1975; American
`Chemical Society: Washington. DC, 1975; MEDI 16.
`(3) Welstead, W. J., Jr.; Moran, H. W.: Stauffer, H. F.; Turnbull,
`L. B.; Sancilio. L. F. J. Med. Chem. 1979, 22, 1074-9.
`{4} Gsssmsn, P. G.; van Bergen. T. J. J. Am. Chem. Soc. 1974, 96,
`5508-17.
`{5} Welsh, D. A. Synthesis 1930, 677-88.
`
`Page1 of10
`
`
`
`0022-2623/84/1827-1379$01.50jO © 1934 American Chemical Society
`
`LUPIN EX 1063
`
`LUPIN EX 1063
`
`Page 1 of 10
`
`
`
`1330
`
`Journal of Medicinal Chemistry, I984, Vol. 27, No. 11
`
`wash at a;
`
`Table I. 2-Aminobenzophenonee
`
`
`
` _i
`“'3'
`X
`Y
`1119. °C (solv“)
`method of prep”
`% yield
`formula
`H
`2
`3', ‘-01,
`37-33 (w)
`3.4
`5
`H
`3
`4’~CsHa
`142-144 (2)
`6.2
`27 0
`001-11;
`4
`4’-CI
`73-755 (:0
`6.2
`67
`c,.,1-1.,c1No2
`0CHs
`5
`4’-Br
`68.5-70 (w)
`6.2
`35
`cuH,2BrNo2
`CH1
`6
`4’—F
`70-71.5 (w)
`7.1
`62
`c,.,H12rNo
`CH,
`7
`4:-Br
`105.5-107 (w)
`7.1
`13
`C14]-I._2B1-NO
`CHa
`3
`2 .-I’-C12
`69-71 (x)
`7.1
`73
`c1,,Huc12No
`F
`9
`4’-CI-I,
`113~114.5 (w)
`7.1
`29
`c,.H,,1='No
`F
`10
`4’-Br
`95-915 (w)
`7.1
`39
`C13]-IQB1-FN0
`F
`11
`2*,4’.c1,
`so-32.5 (w)
`7.1
`42
`C131-l,Cl2FN0
`
`12 C15}-L_.BrC!N0 Cl 4’-Br 126-1215 (y) 3.2 13
`
`
`
`
`
`eec1-1
`.
`d 'W_;;11!010heXme. K I ligroin, y = 2-propanol, z - 95% ethanol. ‘Numbers refer to sections in ref 5 in which methods of preparation are
`
`R
`
`O
`
`N
`H
`
`I
`
`9
`
`5 5
`
`O
`
`Table II. Bemoyloxindoles
`
`
`
`%
`method
`formula
`yield
`of prep‘
`isomer
`no.
`C1§H13N0gS
`52
`A
`4
`18
`c,,1-1.1140,
`73
`C
`2105-216 (13)
`H
`4
`14
`C13H13NO2S
`64
`A
`131-133 (q)
`SCH3
`5
`I5
`C]5H1]N0g
`73
`C
`204-205 (13)
`H
`5
`I6
`CIEHHNO2
`so
`F
`209-211 (w)
`H
`6
`17
`C13H1gN02S
`80
`A
`130 (X)
`SCH3
`7
`13
`
`
`mp. °C (eolv")
`
`R
`
`" p = methanol, q = 2-propenol, W «-1 nitromethene, x = toluene, y = ethanol. “Letters refer to methods of preparation described in the
`Experimental Sectioni
`
`Scheme III
`
`Scheme IV
`
`
`
`!———+'cPBA
`
`soc-H
`
`. -
`37 v
`-*
`
`'
`r_n_-area
`fix-so,cH.
`
`C“
`
`_
`
`H
`
`Bcl,
`men,
`
`"
`
`‘f=H.CI.Br.I
`
`ucs
`":5
`
`’‘
`
`Y
`
`H
`
`o
`
`1=H‘¢'-I-3*
`
`mo.
`
`
`
`
`II)?
`
`mg
`
`indoline was benzoylated exclusively in the 7-position
`under Friede1—Crafta conditions by a modification of the
`9
`_
`_
`.
`.
`_
`method of Sugasawa at al'
`The 7 benmylmdolme de
`{6} Gaeemnn, P. G.; van Bergen, T. J.; Gruetzmaoher. G. J. Am.
`Chem. Soc. 1973, 95, 6508-9.
`(7) Gaseroan, P. G.; Cue, B. W., Jr.; Luh, T. Y. “Abstracts of
`Papers”, 169th National Meeting of the American Chemical
`Society, Philadelphia. PA. April 1975; American Chemical
`Society: Washington, DC, 1975; ORGN 54.
`(8) Lo, Y. 3.; Welsh. D. A.:We1stead. W. J.. J15: Mays R. P.; Rose.
`E. K.; Causey, D. H.; Duncan, FL L. J. Hecerocycl. Chem. 1980,
`17, 1663-4.
`
`rivative was halogenated in the 5-position with either
`N-bromoeuccinimide or N-chloroeuccinimide (Table IV).
`Liquid bromine was also used to introduce a bromine in
`the 5-position. Oxidation with activated manganese di-
`oxide gave the suhetcituted indole. Indoles with no halogen
`in the 5-position were halogenated in the 3-position with
`
`(9) Sugaaawa, T.; Toyoda, T.; Adachi, M.; Sasekwa. K. J. Am.
`Chem. Soc. 1978, 1'00, 4842-52.
`
`Page 2 of10
`
`
`
`Page 2 of 10
`
`
`
`Antiinflammatory Agents
`E
`
`1*: "/.,°
`...Ei"*- T?
`
`°
`
`Figure I.
`
`E
`
`;-‘°’‘' °
`’°
`
`1.
`
`either N-bromosuccinimide or N-chlorosucoinimide; how-_
`ever, indoles bearing a halogen in the 5-position would only
`undergo reaction with N-bromosuccinimide (Table V).
`The 3-haloindoles were hydrolyzed to oxindoles with
`phosphoric acid in either 2-methoxyethanol or acetic acid.
`The substituted oxindoles were hydrolyzed to the am-
`inobenzoylphenylacetic acid sodium salts (Tables VI and
`VII) most conveniently with 3 N sodium hydroxide at
`reflux overnight (Scheme I). In one instance, the 4’-fluoro
`group of 97 was converted to a phenolic hydroxyl (184)
`under the reaction conditions.
`Oxincloles 37 (4’-SOCHS), 38 (4’-S0201-I3), 106 (5-N02),
`and 107 (5-NH2) decomposed under basic hydrolysis con-
`ditions.
`
`Results and Discussion
`
`Table VI lists the acute antiinflammatory activity for
`l and several positional isomers. Only 1 possesses activity
`at 4.0 mg/ kg, a dose at which indomethacin is also active.
`In recent years, there have been various models proposed
`that describe the binding of a nonsteroidal antiinflam-
`matory drug (NSAID) to the cyclooxygenase enzyme.
`Many of these models have been reviewed by Bekemeier
`et al.1° and they agree with the view“ that the inhibition
`of prostaglandin formation by NSAIDs is due to their
`interaction with cyclooxygenase and is responsible for their
`therapeutic utility. One such model was described by
`Appleton and Brown” and is illustrated in Figure 1.
`These investigators concluded that the carboxyl group of
`a NSAID competes with the peroxy group of the precursor
`peroxy radical of the cyclic endoperoxide (PGG2) for the
`same site. In addition, substituents that could occupy a
`position that is equivalent to carbon atom 15 of the peroxy
`radical and could chelate to the oxygemorienting site on
`the enzyme would be favorable to binding. The fit of 1
`in this receptor is excellent. Isomers 138, 189, and 140 do
`not have the benzoyl group ortho to the amino group and
`the possibility of a bidentate chelation with a metal is lost.
`Isomer 141,13 while possessing the ortho arrangement of
`the benzoyl and amino groups, does not have the amino
`group in a favorable position for chelation.
`Derivatives of 1 were tested for their acute antiinflam-
`matory activity and for their ability to inhibit cyclo-
`oxygenase obtained from bovine seminal vesicles (Table
`VII). Addition of a substituent to the ring of 1 containing
`the amino group (142 to 148) decreased antiinflamrnstory
`potency with the 5-Cl (143) group being the least detri-
`mental. Taylor and Salata“ have reported that for the
`tolmetin (1-methyl-5-p-toluoylpyrrole-2-acetic acid) series,
`substitution of a methyl group ortho to the benzoyl sub-
`stituent increases the inhibition of prostaglandin E2 syn-
`
`
`(10) Bekemeier, H.; Bohm, I-1.; Hagen, V.; Hannig. Es, l-Ienkel, H.
`J.-, I-Ilrschelmann, R.; Wenzel, U. In “Trends in Inflammation
`Research. 2". Agents and Actions Supplement; Bekemeier, I-1.,
`Hirechelmann,R.,Eds.',Birkl1ailser Verlag: Basel, 1982; Vol.
`10. pp 17-34.
`(11) Vane, J. R. Agents Actions 1978, S, 430.
`(12) Appleton. R. A.; Brown, K. Proscaglandins I979, 18, 29-33.
`(13) Bays. D. E.; Foster, R. V.; US. Patent 3 828 093, I974.
`(14) Taylor. R. J ., Jr.; Salata. J. J. Biochem. Pharmocol. 1976, 25,
`2479-34.
`
`Journal of Medicinal Chemistry, I984, Vol. 27, No. 11
`
`1381
`
`thesis. However, in this series 143 was devoid of antiin-
`flarnmatory activity of 100 mg/kg in vivo and did not
`inhibit cyclooxygenase at 1 mM.
`Subtitution of a group in the benzoyl ring (149-164)
`of 1 had a pronounced effect on both the in vitro and in
`vivo potency.
`In general, the most potent compounds
`contained a halogen in the 4’-position with I ~ Br > Cl
`.. 2g4r-c12 ~ 2’.C1, 4'.B: > F ~ SC]-13 > H > CH3 ~ CF3
`:- 0C1-I3 ~ CBH5. Derivatives containing a substituent in
`the 3’-position (156 and 163) were less active than 1 in both
`test systems.
`Compounds that were equipotent to 1 in the acute an-
`tiinflammatory test system were then screened in a battery
`of test systems to determine antiinflammatory activity in
`a chronic model, analgesic activity, and gastrointestinal
`irritation liability. Table VIII lists the potency of com-
`pounds in relation to that of indomethacin, which has been
`assigned a potency of 1. Analgesic activity in the acetyl-
`choline-induced abdominal constriction model in mice was
`determined twice for each compound: once at a pre-
`treatment time of 20 min that gave an indication of onset
`of action and once at a 5-h pretreatment time that gave
`an indication of duration of action.
`Several compounds listed in Table VIII were very potent
`antiinflammatory and analgesic agents. It is interesting
`to note that compounds containing a metabolically labile
`group such as methyl (170, 171, and 180) and methylthio
`(173 and 179) were relatively less potent in the chronic
`model of inflammation and in the analgesia model (5-h
`pretreatment), suggesting that these compounds were
`rapidly degraded. Compound 173 was the most potent
`cyclooxygenase-inhibiting compound tested (Table VII),
`but its relative potency in the antiinflammatory assay was
`not retained in vivo.
`Compounds that contain a halogen substituent in each
`ring of 1 are among the most potent prostaglandin
`synthetase inhibiting compounds reported to date and are
`very potent in both pharmacological models of inflam-
`mation.
`In order to assess the relative gastrointestinal
`irritation liabilities of these compounds, therapeutic in-
`dexes were computed and are listed in Table IX. The
`acute therapeutic index is defined as the potency (relative
`to indomethacin) in the pleural effusion assay] potency
`(relative to indomethacin) in the gastric toxicity assay, and
`the chronic therapeutic index is defined as the potency
`(relative to indomethacin) in the adjuvant-induced arthritis
`assay/potency (relative to indomethacin) in the intestinal
`toxicity assay. Several compounds have therapeutic in-
`dexes greater than that of indomethacin. As a result,
`compounds I57, 158, and 182 are being developed as an-
`algesic and antiinflammatory agents.
`
`Experimental Section
`Pharmacology. A. Antiinflarnmation. 1. Acute antim-
`flammatory activity was determined in the Evans b1ue-carra-
`geenan-induced pleural effusion model by a modification of the
`method of Sancilio and Fishman.“ Each compound was ad-
`ministered orally at doses of 100 and 4.0 mg/kg to six fasted rats,
`and the 5-h effusive response to the intrapleural injection of 5
`mL of 0.075% Evans blue-0.5% carrageenan type 7 at 37 °C was
`measured. Indornethacin at 4.0 mg,’ kg orally was used for com-
`parison. The data were reported as a percentage decrease in the
`average volume of pleural fluid from that of the control group.
`Compounds that were approximately equipotent to l were further
`tested in a battery of pharmacological test systems to determine
`antiinilammatory potency, analgesic potency, and relative gas-
`trointestinal irritation liability compared with indomethacin
`
`(15) Sancilio, L. F.; Fishman, A. Toxicol. Appl. Pharmacol. 1973,
`26, 575-34.
`
`Page 3 of10
`
`
`
`Page 3 of 10
`
`
`
`1382 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`Wglsh 3; a1_
`
`Tabla III. Substituted 7-Benzoyloxindolel
`
`
`
`R
`SCH,
`H
`SCI-I;
`H
`SCH,
`
`SCH,
`H
`SCH,
`1-1
`SCI-la
`H
`SCI-la
`H
`H
`H
`H
`H
`SCH;
`H
`SCH,
`H
`SCH,
`H
`SCH,
`H
`SCH,
`H
`SCI-I,
`H
`SCH,
`1-1
`SCH,
`H
`SCH,
`1-1
`H
`
`H
`SCH,
`H
`SCH3
`H
`SCI-lg
`1-!
`H
`SCH,
`H
`SCH,
`H
`H
`
`I-1
`
`H
`SCH,
`1-1
`son,
`H
`SCH,
`1-1
`H
`scl-1,
`H
`SCH3
`H
`SCI-I,
`
`11111. °C (solv")
`138-142 (kl)
`
`122-124 (:1)
`
`185-187 (0)
`
`162-164 (11)
`176-177 (11)
`157-168 (1)
`1595-1665 (1)
`213-214 (11)
`184-185 (lq)
`1585-1605 (11)
`206-209 (11)
`146-147 (I)
`167-169 (1-)
`199-201 (n)
`254-258 (1)
`194-197 (:1)
`220-223 (1)
`131-132 (11)
`146-148 (11)
`162-163 (1)
`171-173 (I)
`147-148.5 (kl)
`209-210 (1)
`165-167 (s)
`185-187 (11)
`142-144 (1)
`170-172 (1)
`177-177.5 (1)
`178-180 (1)
`186-188 (q)
`177 (Q)
`202-205 {nt}
`196-198 (0)
`213-214 (1)
`(Dr)
`212-215 (lat)
`149-1505 (n)
`176-1715 (:1)
`202-204 (0)
`251-256 (M)
`178-181
`1915-193 (11)
`271-2'14 (w)
`142-1445 (11)
`1745-178 (11)
`158.5-160 (nr)
`180.5-182 (lt)
`176-177.5 (kl)
`160-151
`148.5-150 (kl)
`
`204-206.5 (kl)
`1825-184 (1)
`137-171 (kl)
`1a7—1s9
`179-181.5 (n)
`216-217 (kl)
`211-213
`1734-30 (ll)
`176-178 (1:1)
`189.5-191.5 (n)
`171-1725 (111)
`195-1985 (In)
`177-185
`
`method
`of prep‘
`B
`C
`A
`C
`A
`
`A
`C
`A
`C
`A
`D
`A
`C
`G
`H
`I
`J
`A
`C
`A
`C
`A
`C
`A
`D
`A
`D
`A
`D
`A
`C
`A
`C
`A
`T
`T
`A
`C
`A
`C
`A
`C
`A
`C
`T
`B
`C
`B
`C
`H
`A
`C
`A
`C
`A
`C
`A
`C
`A
`0
`H
`A
`C
`A
`C
`A
`
`%
`yield
`19
`29
`85
`
`74
`
`80
`95
`66
`82
`47
`25
`B7
`80
`51
`70
`92
`89
`56
`80
`61
`33
`77
`92
`55
`60
`53
`72
`55
`79
`85
`83
`33
`
`58
`61
`68
`68
`98
`75
`70
`57
`83
`48
`'73
`55
`74
`90
`63
`79
`92
`53
`83
`
`91
`72
`79
`71
`70
`53
`as
`30
`as
`86
`45
`64
`80
`
`formula
`C1-,H1,N0;S
`C1gH1aN0a
`C,-,H,,N0,S
`C1§H13NOg
`C,-,-H1.NOgS
`
`C1-,.H,5NO¢S
`CNHHNO;
`C,.H,,FNO,S
`C1§H;gFNOg
`C15!-InClN03S
`CWHNCINO,
`C19H1gC]N0gS
`C151-ImClNOg
`C1,!-I,-,N0,
`C1,H,,N0gS
`C1
`132N033
`C1,!-I,3NO4S
`C11H1gFgN0gS
`CwH1,F,N0,
`C,-,H1,ND,S
`C;5H19N0g
`C,7H,5N0gS
`C1sHwN0g
`C,5HmF'N02S
`C1,HmF‘N0g
`C131-IHFNOZS
`Cw!-INFNO,
`13131-1,
`INOgS
`C131-I,..;,ClN0¢
`C1g,H1,ClN0gS
`Cu,H,oClNO,
`C1,H,3ClN02S
`C15H1oC1NO§
`C1,H,,BrNO3S
`C,.HmB1-N02
`C151-l,o1N0,
`CggH11NOgS
`C,nHwNO,
`C1,]-L-,N0,;S
`CHHHNO3
`C15H,,Cl,NDgS
`C15HgC1gNO2
`C1,]-IuClgN0;S
`C1.,H,Cl,NO,
`C151-l,BrCl.N02
`C"HuClN0,S
`C1.H,,C1N03
`Cu-I'Iu,B!'NO3
`C151-I,,BrN03
`C17H;5N0gS
`C15H11NOg
`C171-I",N0,
`
`CIEHHFNOQ
`CHHHCINOES
`C1aH12ClN02
`CuHuBrN02S
`C1gHuBlN0g
`C"H.,ClgN02S
`C1aHuCl2N02
`C1oH12FN°23
`C11HuFN0aS
`C1aHuFNO2
`C1,!-I,1F‘gN0,S
`C1sH9F-2N0:
`C1gHl1ClFN0gS
`
`
`
`"°-
`21
`23
`28
`2'‘
`25
`
`X
`5~0Cl-I3
`5-OCH;
`4-C]-I3
`"CH3
`5-CH3
`
`27
`28
`29
`30
`31
`32
`38
`34
`35
`36
`37
`88
`39
`-10
`-11
`42
`-13
`44
`4.5
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`58
`57
`53
`59
`60
`61
`62
`63
`64
`55
`68
`67
`08
`59
`70
`11
`72
`73
`7‘
`75
`76
`77
`73
`79
`so
`31
`B2
`as
`84
`85
`34;
`87
`
`6-CH3
`8-CH3
`6-1‘
`5-1?‘
`5-0]
`5-Cl
`15-01
`(5-0!
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`5-0CHa
`5-OCH;
`5-OCH;
`6-00
`5-CH
`
`5-CH3
`
`5-CH3
`5~CH3
`5.011,
`5-Cl-1,
`5-CH,
`5-CH,
`5-CH,
`5-!’
`5-1?
`5-17‘
`5-1?
`5-1?‘
`5-1‘
`
`Page 4 of10
`
`
`
`Y
`
`H
`H
`H
`H
`H
`
`H
`H
`H
`H
`H
`H
`H
`H
`4’-OCH,
`4’-SCH,
`4’-SUCH;
`4’-S0301-la
`4’-CF;
`4’-CF,
`2’-CH,
`2’—Cl-I,
`4’-CH,
`4’-CH5
`2'-F‘
`2’-F‘
`4’-F
`4’-F
`2’-Cl
`2'-Cl
`3’-C1
`3-01
`4’-Cl
`4'-Cl
`4’-Br
`4’-Br
`4’-I
`4’-cgH5
`4’-CgH;
`234’-(Cl-I5);
`234’-(CH3);
`2’,4’-C1,,
`2’,4-C1,
`324’-C12
`3’,d’—C13
`2’-Cl, 4’-Br
`4’-C1
`4’-Cl
`4‘-Br
`4’-Br
`4’-SCHg
`4'-CH;
`4’-Cl-[3
`4’-F
`4’-F
`4’-Cl
`4*-c1
`4‘-Br
`4’-Br
`234*-C1,
`234‘-Cl,
`4’-SCH:
`4'—C1-[3
`4’-C1-I3
`4’-F‘
`4*-F
`4’-Cl
`
`Page 4 of 10
`
`
`
`Antiinflammatofy Agents
`
`Journal of Medicinal Chemistry, 1984, Vol. 27. No. 11
`
`1383
`
`
`
`
`
`Table III (Continued)
`
`method
`%
`
`xno. fmmulam Y R mp. °C (salvo of prep‘ yield
`
`
`
`
`C
`84
`5.1-1
`-1’-Cl
`H
`137-139 (r)
`C:sH9C1FN02
`5-11
`4’-Br
`SCH,
`197-193 (rt)
`.1
`52
`C1eH11BTFN023
`2:
`5-F
`4’-Br
`H
`196-197 (nt)
`C
`80
`C1sHoB1'FN02
`90
`5.11‘
`2*,4cc1,
`SCH,
`193-200
`A
`44
`C1eH10Cl2FN0eS
`91
`5.11
`224'-C1,
`H
`202-203
`0
`33
`0151']-sC12FNO2
`92
`5.01
`-1*-SCH,
`H
`179-131 (m)
`H
`03
`C1eH12ClN02S
`93
`501
`4*-CH,
`3011,
`197-139 (ml
`A
`43
`C11H1iClNO2S
`9-1
`5-01
`4’-CH,
`1-1
`152-155 1:)
`0
`74
`C1sH12C1N0'.1
`95
`5.01
`or
`3011,
`202-204 (In)
`A
`43
`C...HuClFN02S
`90
`5-01
`as
`H
`222-225 0:)
`0
`04
`C1sH9ClFNO2
`97
`3-01
`4201
`SCH3
`199-202 (no
`A
`35
`C1eH11Cl2N02S
`93
`5-01
`41-01
`H
`190-201
`0
`30
`C15H0Cl2N02
`99
`5-01
`4’-Br
`son,
`203-211 {no
`A
`46
`C1sH11B|'ClN02S
`100
`5-01
`4’-Br
`H
`213-214 (r)
`T
`43
`C1sHeB1’ClN02
`101
`5.01
`4'.1
`H
`218-221 (r)
`T
`43
`CHI-IQCIINO
`103
`5-01
`2-01. 4’-Br
`H
`255-253(ry1
`T
`33
`C,.H9BrC12N0r
`103
`5-Br
`-2.01
`H
`203-209 to
`T
`35
`C1sH9B1'ClN02
`10.1
`5-Br
`423:
`[-1
`206-207 (r)
`T
`41
`CuHaBr2N02
`105
`100
`5.130,
`4'-c1
`1-1
`253-259 (mz)
`K
`75
`0,,H,01N,o,
`
`101
`5-NH,
`4'-01
`H
`230-239 (mt)
`L
`32
`C15l'l11ClN2O2
`“l: = water.
`= ethanol, in = ethyl acetate. 11 I 2-propanol, o = acetonitrile, p I methylene chloride. q =-' toluene, I’ = l>eD29I19: 8 ’
`methanol, t : tetmhyd1-ofumn_ w as zmethoxyethanol, x = acetone, 3! = pyridine, 2 I dimethylformamide. °Letters refer to methods of
`preparation described in the Experimental Section.
`
`Table IV. 7-Benzoylindoline Derivatives
`
`
`
`%
`method of
`formula
`yield
`prep‘
`mp, °C (sols-“)
`X
`no.
`C1,H1gClN0
`91
`M
`107-108 (W)
`4’-CI
`H
`103
`C“,HmBrN0
`76
`M
`128-129 (x)
`4’-Br
`H
`109
`C15H1glNO
`85
`M
`l.49‘150 (Y)
`4'-I
`H
`ll.“
`C;5l'lnBrClN0
`55
`M
`120-121 (x)
`2’-Cl. 4’-Br
`H
`lll
`C15H11clgN0
`45
`N
`146-148
`4’-Cl
`CI
`112
`C15HnB1-CIN0
`67
`N
`168-169 (z}
`4’-Br
`C1
`113
`C15H,_1ClIN0
`54
`N
`175 (Z)
`4’-I
`C1
`114
`0,_._.H,,Br01,No
`68
`N
`113-113 (11)
`2201, 4’-Br
`01
`115
`C15HuBrClN0
`49
`P
`157-159 (3)
`4’-Cl
`B1‘
`116
`117 C1gH11BrgN0 Br 4’-Br 16785-168 (z) 0 89
`
`
`
`
`
`
`“W = petroleum ether, 1: I 2-propsnol, 31 I absolute ethanol, 2 = ethyl acetate. "Letters refer to methods of preparation described in the
`Experimental Section.
`
`Y
`
`(Table VIII). Potencies relative to indomethacin were determined
`by regression analysis.
`2. Chronic antiinflammatory activity was determined in the
`adjuvant-induced arthritic rat model of Walz et al.“ using a
`therapeutic rather than a prophylactic dosing regimen as described
`by Sanciiio et aL"
`B. Analgesia. Oral analgesic activity was determined in mice
`by the acetylcholine-induced abdominal constriction assay.”
`Aoetylcholine bromide was administered intraperitoneally 20 min
`or 5 h following oral administration of the test compound.
`Zompirac was used as a standard.
`C. Gastrointestinal Liability. 1. Acute Gastric Toxicity
`(Single Oral Dose). Male fasted rats weighing between 150 and
`200 g were randomly divided into groups ofseven. The compounds
`were dissolved or suspended in 0.5% Tween 30 and administered
`by gevege (10 mLfl1g). Six hours later, the animals were killed
`with chloroform or carbon dioxide. The stomachs were removed,
`washed, and examined for the presence of erosions. On a blind
`
`
`(16) Walz. D. T.; Di Martino. M. J.; Misher, A. J. Pharmocol. Exp.
`Ther. 1971, 178, 223-31.
`(17) Sancilio, L. F.; Reese, D. L.; Cheung, S.;A1phin, R. S. Agents
`Actions 1977, 7, 133-44.
`
`basis, the degree of damage was scored aooording to the following
`system: 1, one to three eroeions <3 mm in diameter; 2, many small
`erosions; 3, two to three eroeions greater than 3 mm in diameter
`or 4-5 mm in length; and 4, four or more large srosions.
`2. Chronic Intestinal Toxicity (Multiple Oral Doses).
`Male and female Sprague—Dawley rats. weighing between 160 and
`200 g, were randomly divided into groups of eight. Excluding the
`weekend, compounds were orally administered on a daily basis
`for 11 days. Twenty-four hours after the last dose, the rats were
`killed with chloroform or carbon dioxide and the intestines were
`examined for the presence of ulcers. The severity of the lesions
`was scored in increments of 10, from 0 for no damage to +40 for
`maximum damage, plus 10 for perforations and/or adhesions, and
`an additional 10 if the animal died. Growth of the animals was
`also monitored during the course of the experiment.
`D. Prostaglandin Synthetase Inhibition. The polarographic
`method used for the determination of the inhibition of cyclo-
`oxygenase obtained from bovine seminal vesicles has been de-
`scribed in detail.‘
`General Procedures. Melting points were determined in open
`capillary tubes in a Thomas-Hoover melting point apparatus and
`are uncorrected; ‘H NMR spectra were obtained in CD013 or
`M9380-d5 with Me,Si as internal standard or in D20 with sodium
`3-(t.rimethylsi1yl)propionate-d4 as internal standard on a Varisn
`
`Page 5 of10
`
`
`
`Page 5 of 10
`
`
`
`1384 Journal of Medicinal Chemistry, 1.984, Vol. 27, No. II
`
`Walsh er al.
`
`Table V.
`
`‘T-Benzoylindole Derivatives
`
`
`
`method
`
`%
`
`c,,Hmc1No
`69
`Q
`149~151 (p)
`H
`4’-C1
`H
`113
`c._,H.,C1,,No
`45
`R
`192-193 (1))
`Cl
`4:-cl
`H
`119
`c,,HmB.No
`35
`Q
`161-163 (p)
`1-1
`4’-Br
`H
`129
`C151-1,13,-cmo
`as
`R
`193-194 (p)
`Cl
`4’-Br
`H
`121
`cw]-110]N0
`97
`Q
`175-176 (q)
`H
`4 -I
`H
`122
`Cu,H9ClIN0
`31
`R
`179-139 (q)
`Cl
`4'-I
`H
`123
`C,.H.Brc1No
`93
`Q
`144-146 (w)
`H
`2ac1, 4’-Br
`H
`124
`C151-lgBrCl,NO
`98
`R
`155-157 (w)
`Cl
`2’-Cl, 4’-Br
`H
`125
`c.,H.cI,No
`39
`Q
`170-171 (M
`H
`4’-CI
`CI
`123
`C151-I,B:rC12N0
`58
`S
`220-221 {pl
`Br
`4’-Cl
`Cl
`12?
`C15H,BrClNO
`98
`Q
`183.5485 (11)
`H
`4’-Br
`C]
`128
`C,,H.B:,c1N0
`95
`S
`224-226 ((1)
`Br
`4’-Br
`Cl
`129
`our-I,c1INo
`92
`Q
`171-173 (x)
`H
`4’-I
`Cl
`130
`c],H,,13;c1mo
`34
`S
`223-224 (:1)
`Br
`4’-I
`C1
`131
`Cu,HgBrCl,NO
`99
`Q
`134-135 (at)
`1-!
`2’-C1, -I’-Br
`C1
`132
`Cu.,H1-,Br2Cl,N0
`99
`S
`162-1625 (x)
`Br
`2’-Cl. 4’-Br
`Cl
`133
`c,,H,Brc1N0
`79
`Q
`133-184 (qy)
`H
`4’-Cl
`Br
`134
`C15H9BTgClNO
`97
`S
`215-217 (p)
`Br
`4’-Cl
`Br
`135
`C1,]-l9Br,NO
`190
`Q
`291-202.5 (p)
`H
`4’-Br
`Br
`1313
`4'-BrBr137 C151-I,3Br,N0 Br 226-228 (pz) S B1
`
`
`
`
`
`
`
`‘p = ethyl acetate, :21 - benzene, w = 2-propane], x = absolute ethanol, 3; = cyclohexane. 2 at tetrahydrofuran. "Letters refer to methods
`of preparation described in the Experimental Section.
`
`Table VI. Oral Antiinfiammatory Activity in the 5-h Evans Blue-Carrageenan Pleural Effusion Assay for Aminobenzoylphenylacetic
`Acids
`
`cHgCD3R
`
`3 NH;
`
`
`
`mp, “C (aolv")
`
`% change in av
`vol of
`pleural fluid, dose
`(walks)
`indob
`compel
`%
`(4.0)
`(4.0)
`formula
`yield
`R
`PhC[=0}
`NH,
`no.
`'33
`'26
`C1§H13NN803'Hg0
`80
`N3
`3
`2
`1
`-31
`--2‘
`C151-lmNNa0,-D.5H20"
`65
`244-245 (2)
`Na
`4
`2
`138
`-43
`11‘
`C151-l;‘.,N0_-3
`85
`I50-151 (wx)
`H
`5
`2
`139
`-35
`-2‘
`c[5H1gNN8O3'Hg0
`51
`254.5-256 {Will
`Na
`8
`2
`140
`-31
`-4‘
`C151-IHNO5
`52
`133-134 (2)
`1-1
`3
`4
`141'
`‘w = water, 1 % ethanol, gr I 2-propanol, z I benzene. °Indomethacin. ‘C: calcd, 62.94; found, 62.45. ‘Not significantly different from
`control group at p < 0.05, as determined by the Dunnett’s t test. ‘Reference 16.
`mixture was allowed to warm to ambient temperature and 400
`mL of 3 N hydrochloric acid was added. The mixture was heated
`at reflux with vigorous stirring for 2 h. The organic phase was
`separated and concentrated and the residue was recrystallized
`from 95% ethanol togive 38.0; (55%) of 49 as paleyellow needles,
`mp 142-144 °C. Anal.
`(Cw!-l13ClN02S) C, H, N.
`Method B.
`'7-(4-Chlorobenzoylyl,3-dihydro~fi-methoxy-
`3-(methylthio)-2H-indol-2-one (67). To a solution of 4.0 mL
`(0.088 mol) of chlorine in 200 mL of methylene chloride (CHgC1g)
`cooled to -70 °C was added dropwise a solution of 11.3 g (0.088
`mol) of ethyl lmethylthiolacetate in 30 mL of CHgCl.g, while the
`temperature was maintained below-65 °C. After 5 min, a solution
`of 53 g (0.2 mol) of 4 in 100 mL of CI-I201; was added dropwise
`over a 30-min period. The mixture was stirred at -70 “C for 1.5
`h and 18 g (0.18 mol) of triethylamine was added. The mixture
`was stirred for 1 h at-70 °C and then allowed to warm to ambient
`temperature. The miszture was treated with 30 ml. ofconcesntrated
`hydrochloric acid and stirred for 1 h. The mixture was filtered
`
`A-60, a Vsrien EM-360L, or a Varisn FT-80A spectrometer; mass
`spectra were determined on a Varisn MAT-44 or on a Hitachi
`Perkin-Elmer RMU-6H mass spectrometer; IR spectra were run
`as KBr pellets on a Beckman IE8 or on a Perkin-Elmer 297 IR
`spectrophotometer; analytical results for compounds followed by
`elemental symbols are within ¢0.4% of theory and were deter-
`mined on 9. Perkin-Elmer Model 240 CHN analyzer. Spectral
`data for all reported compounds were consistent with assigned
`structures. Indomethacin was obtained from Merck and Co., Inc.
`and zompirac was obtained from McNeil Pharmaceutical.
`Method A. 7-(2-Chlo1-obensoyl)-l.3-dihydro-3-(methyl-
`tllio)-2H-lndol-2—one (49). A solution of 50 g (0.216 mol) of
`2’-chloro-2-eminobenzophenoneb in 800 mL of methylene chloride
`was cooled to -70 “C and 30.5 g (0.227 moll or ethyl (methyl-
`thiohcetate was added. The cold mixture was stirred vigorously
`while 26.0 g (0.227 mol) of 95% tert-butyl hypochlorite (Frinton
`Labs) was added dropwise. The mixture was stirred at -70 ‘C
`for 1 h and then 25 g (0.25 mol} of triethylamine was added. The
`
`Page 6 of10
`
`
`
`Page 6 of 10
`
`
`
`Anm-nflammawry Agents
`
`Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`1385
`
`Table VII Oral Antiinflanimatory Activity in the 5-h Evans B1ue—Cerrageenan Pleural Effusion Assay and Cyclooxygenase Inhibition
`Data for Substituted 2-Amino-3-benzoylphenylacetic Acids
`
`'
`
`CH2C0gNfl
`
` NH;
`
`
`% change in av
`vol of pleural fluid
`
`no.
`
`X
`
`Y
`
`mp, °C [sclv“)
`
`1
`142
`143
`144
`14.5
`146
`147
`143
`149
`
`151
`152
`
`265
`206-207 (W)
`252 (w)
`235-233 on
`253 (pq)
`229-231 (ml
`260 (qw)
`230-232 (cg)
`
`265 (qw)
`266-272 (w)
`
`65
`71
`51
`
`-32
`
`-37
`-36
`-33
`-33
`-47
`-35
`-38
`-39
`-43
`
`-49
`-42
`
`-28
`-46
`-43
`-44
`
`0‘
`
`-16
`-27
`-1'7
`
`-16
`
`0*‘
`
`-15“
`
`-18
`
`indo° dose, cyclooxygenase
`d°3°' mg/kg
`%
`100
`4.0
`0.16 4.0 mg/kg inhib: lC5o. FM
`formula”
`yield
`'35 ‘26 "136
`'33
`C15N1qNN803'Hg0
`30
`H
`H
`5.4
`J -18‘
`-48‘
`80 C1,H“NNs0.-1.5H,0
`5-OCI-I3 H
`>1000
`-13
`-Id
`-38
`36
`Cml-IuNNa03~0.25H;O
`4-CH3
`1-1
`11
`-35 -11¢
`-25
`as
`C1eH14NN50s'0-5H20
`was
`H
`3
`-39
`2
`-38
`69
`Ciel-IuNN80s*9-25320
`ecu.
`1-1
`0.2
`-33
`-9:
`-20
`41
`C151-IuFNNa0,-0.5]-120
`5-F
`H
`3'?
`-45
`-4
`-35
`57
`C15l'IuClNNa03~0.25l-I;O
`4-01
`1-1
`1
`-17
`-35
`82 CwHnClNNa0a
`5-c1
`H
`68
`-10"
`-35
`29
`C1.;H1¢NNaO4-0.51-[,0
`H
`4‘-OCH,
`0.1
`-21
`'30
`C1aH;4NN&03S'Hg0
`H
`4"SCH3
`1
`-24
`-33
`C-,¢,HuF3NNa03-0.5H2O
`H
`4’-CF3
`1
`-13‘
`-25
`C131-I“NNaO3-0.25H;0
`H
`2’-CH,
`0.3
`-17
`‘33
`C1gH1‘NNflO3
`H
`4}-CH3
`0.9
`"36
`'35
`C1,-,H“FNNa03
`260
`H
`‘\’-F
`15‘
`0.3
`-42 -22
`-83
`C,5HnClNNaO3-H30
`64
`260
`H
`2’-Cl
`155
`>1000
`-35
`-15
`-33
`C1,,HnClNNa0a-0.5H20
`18
`>250 (D03
`H
`3’-Cl
`156
`0.3
`-38
`-29
`-33
`C15H11C]NNflo3‘0.75HgO
`6'?
`265 (p)
`H
`4’-C1
`157
`0.08
`-43
`-41
`C151-l,,BrNNa03
`54
`285 (pq)
`H
`4’-Br
`158
`0.07
`-31
`-82
`-44
`C15HuINNa03-0.251-I20
`55
`280-282 {war}
`H
`4’-I
`159
`0.08
`-14‘ -15"
`-36
`CnH1,NNaO3»0.25H30
`25
`246-247 (13)
`H
`4’-Cull.
`160
`0.1
`-38
`-3°’
`-40
`C,-,H15NNa03
`91
`240
`H
`224’-(CH3);
`161
`0.6
`-41
`-3'?
`-33
`C1,,HmCl,NNa03-0.51-I20
`62
`$35-240 tpx)
`H
`2’,4’-Cl;
`162
`50
`-10‘
`-30
`C,,HmCl,NNaO9-1.75H-,0
`13
`‘Z60-265 (pqx)
`H
`3’,4'-Cl,
`163
`0.05
`-26
`-32
`C1_;,H1oBrClNNe03-0.51-I20
`72
`125-130 (pw)
`H
`2’-Cl, 4’ Br
`16-!
`12
`-26
`-37
`CmH,gClNI~Ia04-0.251-L0
`47
`215-220 (W)
`5—OC1-I3
`4’—Cl
`165
`0.9
`-28
`-25
`C1e,H1,BrNNaO.
`44
`245-250(13)
`5-OCI-I3 4’-Br
`166
`30
`-12‘
`-42
`C17H17N0J
`45
`118-120
`5-CH3
`4’-Cl-la
`167
`0.4
`-26
`-42
`C1-,H1,NNeO5S~2H,0
`37
`225-260 (13)
`5-CH,
`4’-SC]-I5
`168
`17 '
`0‘
`-42
`CmH,_,F'NNa0,-H90
`17
`140-160 (per)
`501-13
`4’-F
`169
`0.7
`-32
`-35
`C,.;Hl3ClNNa03
`13
`262 (p)
`5~CH3
`4’-Cl
`170
`0.7
`-31
`-36
`C131-l,_;,BrNNs05
`41
`267-270 (wy)
`5-CH3
`4’-Br
`171
`1
`-24
`-45
`C1,!-lu;Cl,NNa05»0.5I-I20
`65
`185-188
`5-Cl-I5
`2’,4'-Cl;
`172
`0.008
`-28
`-33
`C131-I”FNl~laO9S-0.25H._.0
`75
`241-244
`5-13‘
`4’-SCH,
`173
`0.07
`-32
`-36
`C;.;H13F‘NNaO3~0.25H30
`32
`239-244 (W)
`5-F
`4’-Cl-I3
`174
`0.2
`«-42
`-40
`C,5l-I,.,F,NNaO3
`35
`244-246 (w)
`5-1?
`4’-F
`175
`0.1
`-37
`-34
`48 C15HmClFNNa03.0.25H;0
`237-240 (pqw)
`51-‘
`4’-Cl
`176
`0.04
`-28
`-25
`70
`C151-[,;,BrFNNa03-H30
`244-247 (13)
`5-1?
`4’-Br
`177
`0.1
`-41
`-45
`68
`C151-I.,Cl._.FNNaO5-0.5C5I1l3O"
`215-217 {w}
`5-!‘
`224’-C13
`I78
`0.02
`-43
`-40
`39
`C1sH]gC]NN&03S‘0.75HgO
`259-260 (ea)
`5-Cl
`4’-SCH
`179
`0.02
`-35
`-40
`23
`C1aHwCINN80f0-25HgO
`259-260 (w)
`5-13]
`4’-CH,
`180
`0.3
`-41
`-32
`43 C,5HmCl,NNa03-0.25H,O
`>260 (qw)
`5-81
`4'-C]
`181
`0.02
`-41
`-40
`-38
`40
`Cu,H1.,BrClNNa03
`264-266 (p)
`5-01
`4’-Br
`182
`0.03
`-35
`-33
`-38
`36
`C15H1oClINN&0g'o.5Hg0
`275-278 (1))
`5-01
`’-
`183
`30
`-3"
`-40
`-21
`47
`C351-IuClNO¢-0.751-I20
`67-89
`5-01
`-1’-OH
`164
`0.05
`-25
`-36
`-37
`69
`C15H7BlClgNNB03'Hg0
`125-130 (w)
`5-Cl
`2’-Cl, 4’-Br
`185
`0.6
`-26
`-40
`-42
`58
`C,5HmBrClNNaO,-0.51-I20
`270-275 (pl
`5-13:
`4’-Cl
`186
`0.8
`-30
`-33
`-34
`74
`0wHmBr,NNa03-0.5H2O
`268-269 (pl
`5-81‘
`4’-Br
`187
`ac n
`indo;neth-
`.
`-33
`1
`-7‘
`“p I Water, q -= absolute ethanol, w - 2-propane}, it -= isopropyl ether, y = methanol. *’AIl compounds were analyzed for C, H, and N and
`results agreed to d:0.4% of theoretical values. °Indomethacin.
`‘‘ Not significantly different from control group at p < 0.05, as determined by
`the Dunnett‘s t test.
`‘Amfsnac. 1, used as the reference standard. ‘Characterized as the acid. 10.5 mol of 2-propanol present by NMR.
`to remove 4-I-[C1, and the filtrate was washed with water. The
`organic solution was concentrated under reduced pressure, and
`the light brown crystalline residue was recrystallized from 2-
`propenol to give 22.5 g (74%) of 67 as off-white needles, mp
`142.0-144.5 °C. Anal.
`(CnH1,.ClN0;,.S) C_, H, N.
`Method C. 7-Benmyl-6-chlorm1,8-dihydro-2H-indol-2-one
`(34). A 200-; sample of a commercial (Grace, No. 28) Harley nickel
`preparation was washed thrice with water, with dilute acetic acid
`until neutral, and thrice with itetrahydrofursn. The Raney nickel
`slurry was added cautiously to a solution of 24.7 g (0.078 mol)
`
`of 38 in 400 mL of tetrahydrofumn and the mixture was me-
`chanically stirred for 10 min. The mixture was filtered and the
`filtrate was concentrated under reduced pressure to give a solid
`residue. The solid was recrystallized from 2-propanol to yield
`16.9 g (80%) of 84 as a white powder, mp 206-209 °C. Anal.
`(C15H1oClN02) C, H.
`Method D. 7-(2-Fluorohenzoyl}1,3-dihydro-2H-indol-2
`one (46). A mixture of 60 g (0.2 mol} of 45 and 60 g (0.5 mol)
`of tin powder in 1 L of 95% ethanol was heated to reflux and 150
`mL of concentrated hydrochloric acid was added. Heating was
`
`Page 7 of10
`
`
`
`Page 7 of 10
`
`
`
`1386 Journal of Medicinal Chemistry, 1984, Vol. 27, Na. 11
`
`Wags}; at (1;
`
`Table V111. Pharmacological Potency Relative to Indomethacin of Substituted 2-Amino-3-benzoylphenylscetic Acids
`CH-2C0-aNd
`
`NH;
`
`
`
`Y
`
`X
`
`analgesia
`chronic
`EDW m3!']'‘3
`intestinal
`adjuvant
`gastric
`pleural
`20 min
`5 h
`toxicity
`arthritis
`toxicity
`effusion
`1301311961
`0.22
`0.22
`1
`1
`1
`1
`indo“
`0.21
`0.59
`0.133
`0.67
`0.25
`0.73
`earn”
`0.1 1
`> 3.0
`0.4
`1.1
`0.7
`0.7
`H
`H
`1
`0.10
`0.93
`1.4
`2.2‘
`0.9
`3.8‘
`4’-Cl
`H
`157
`0.07
`0.13
`1.8‘
`5.8‘
`1.4
`7.5‘
`45131‘
`H
`158
`0.13
`0.18
`3.3‘
`3.1‘
`5.3‘
`6.9‘
`’-I
`H
`159
`0.21
`>03
`0.6‘
`-12°
`1.0
`5.3°
`234’-C1,
`H
`I62
`0.12
`1.6
`1.6‘
`7.4‘
`5.6‘
`1.6
`2'-Cl, 4’-Br
`H
`104
`0.78
`0.65
`0.4‘
`0.63
`0.27‘
`1.7
`4’—Cl
`5-CH3
`170
`0.72
`0.70
`1.1
`1.0
`1.2
`2.8‘
`4-’—Br
`5—CH3
`171
`0.10
`> 1.0
`e
`0.03‘
`e
`0.4‘
`4'—SCH3
`5-11‘
`173
`0.71
`e
`e
`0.01‘
`0.37‘
`1.4‘
`4'-F
`5-17
`175
`0.28
`1.4
`0.5‘
`1.9
`1.1
`3.6‘
`4’-Cl
`5-17
`176
`0.13
`0.29
`1.9‘
`2.2
`1.7
`8.4‘
`4'-Br
`5-F
`177
`0.10
`0.65
`9
`0.13’
`1.0
`1.2
`2’,4’-Cl,
`5-F
`178
`0.10
`1.9
`e
`0.1‘
`0.9
`1.8
`4’-SCH;
`5-Cl
`179
`0.10
`0.43
`e
`0.1‘
`0.7
`1.6‘
`4’-CH3
`5-Cl
`180
`0.23
`0.31
`1.2
`1.7
`1.2
`4.6‘
`4’-Cl
`5-Cl
`131
`0.05
`0.13
`2.9‘
`4.6‘
`1.5‘
`15‘
`4’-Br
`5-13]
`182
`0.24
`0.24
`2.2‘
`5.5‘
`3.5‘
`3.8
`4’-I
`5-Cl
`183
`0.66
`0.19
`3.3‘
`2.5
`1.2
`4.9‘
`2’-Cl, 4’-Br
`5-131
`[85
`>032
`0.2
`1.0
`2.5
`