`
`© Copyright 1984 by the American Chemical Society
`
`Volume 27, Number 11
`
`November 1984
`
`Antiinflammatory Agents. 3.1 Synthesis and Pharmacological Evaluation of
`2-Amino-3-benzoylphenylacetic Acid and Analogues
`
`David A. Walsh,“1 H. Wayne Moran} Dwight A. Shambles,T Ibrahim M. Uwaydsh,’r William J. Welstead, Jr,l
`Lawrence F. Sancilio,‘ and Warren N. Dannenburg§
`
`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, 1984
`
`A series of substituted derivatives of 2-smino-3-benzoylphenylaoetic acid (mfenac) has been synthesized and evaluated
`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;cl 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-benzoyloxindolss, precursors
`to the desired 2-mino-3-benzoylphenylacetic acids, were
`prepared by two general methods (Schemes l and IV).
`Gassmen’s‘ method for the synthesis of oxindoles. utilizing
`substituted 2-amin«:ulzpenzophenones5 (Table I) as starting
`material, gave the 3-(msthylthioloxindoles 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‘3 of Gassman’s original pro-
`cedure was used due 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 1'? 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 thiomethoxicle to give
`36. The sulfoxide 37 and the sulfone 38 were prepared
`from 36 by using m-chloroperbenzcic acid. The oxindole
`54 could he nitrated in concentrated sulfuric acid with
`potassium nitrate to yield 106. The nitro group was re-
`ducsd 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 Haney 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
`
`v
`
`X
`
`X
`
`”H:
`
`-s on
`. cH,scH.co.c,H. —-‘—-"-——»
`611,9,
`-1o c
`
`Y
`
`X
`
`a
`
`H CO C H
`r
`a
`a
`.
`or
`"H H
`
`.
`
`scs,
`
`o
`
`<—
`
`x
`
`o
`
`”30-
`4—
`
`x
`
`at,»
`
`ca,
`Hco.c,a,
`NH.
`
`v
`
`°
`
`v
`
`°
`
`v
`
`\u‘wn
`
`V
`
`CHchJla
`NH.
`
`_1_ X.Y=H ,amfena:
`
`Scheme 1]
`
`N0:
`
`5'
`
`
`
`ascends, .3
`oz
`
`uNfiHtochHs):fi: 14%06”
`
`.. D
`
`20
`
`1?
`
`genated derivatives were conveniently prepared by a
`procedure described by Lo et 31.3 (Scheme IV). Thus,
`
`(1) For part 2 in this series. see: Walsh, D. A: Shambles, D. A;
`Welstead, W. J., Jr.; Sancilio, L. F. J. Med. Chem. 1932. 25,
`446—51.
`‘
`(2) Welstead. W. J., Jr.; 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.: Stsuffer, H. F.; Turnbull,
`L. B.; Sancilio. L. F. J. Med. Chem. 1979, 22, 1074-9.
`{4) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96,
`5508-17.
`{5} Walsh, D. A. Synthesis 1930, 677-88.
`
`0022—2823/84/1827-1379$01.50f0 © 1934 American Chemical Society
`
`Page 1 of 10
`
`LUPIN EX 1063
`
`LUPIN EX 1063
`
`Page 1 of 10
`
`
`
`1330
`
`Journal of Medicinal Chemistry, l984, Vol. 27, No. 11
`
`Walsh 2: at.
`
`Table I. 2-Aminobenzophenones
`
` 3.Mm..—
`
`X
`
`formula
`% yield
`method of prep”
`mp, °C (501W)
`Y
`no.
`01 N0
`0
`5
`6.4
`87-38 (w)
`3', ’01,
`H
`2
`flange
`27
`6.2
`142—144 (2)
`4’~C,H,
`H
`3
`C.,H,,,CH~JO2
`67
`6.2
`73—75.!) (x)
`4’-CI
`OCH,
`4
`C,,H,213r1~102
`85
`6.2
`68.5-70 (w)
`4’-Br
`OCH,
`5
`0,,H,,FN0
`62
`7.1
`70—715 (77)
`4’-F
`CH3
`s
`C1,,H12BrNO
`13
`7.1
`105.5—107 (w)
`4’-Br
`CH8
`7
`CHI-11.012510
`78
`7.1
`69-71 (x)
`2’,d’-Cl,
`CH,
`8
`ennui-"No
`29
`7.1
`113-4145 (w)
`4’-CH,
`F
`9
`ClaflgBrFNo
`39
`7 1
`96-915 (w)
`4’-Br
`F
`10
`C1,,H8012FN0
`42
`7.1
`60-625 (w)
`2:41.01,
`F
`11
`ClaflgBrCINO
`13
`6.2
`126—1275 (y)
`4’-Br
`Cl
`12
`seen
`.
`d 'wlmclohexme, x I ljgroin, y = 2-propanol, z I 95% ethanol. I'Numbere refer to sections in ref 5 in which methods of preparation are
`
`‘
`
`R
`
`O
`
`5 e
`
`Table II. Bemoyloxindoles
`
`o
`
`N
`’
`H
`
`method
`%
`
`no.
`isomer
`R
`mp, °C ($017“)
`of prep"
`yield
`formula
`18
`4
`song
`235-237 (F)
`A
`52
`CmHmNOgS
`14
`4
`H
`210.5—216 (p)
`c
`76
`01,111,110,
`15
`5
`SCH3
`131-183 (q)
`A
`64
`CmngNOgS
`l6
`5
`H
`204-205 (p)
`c
`73
`(immune2
`17
`6
`H
`209-211 (w)
`F
`so
`01,111,140,
`13
`7
`SCHs
`130 (x)
`A
`80
`CmHIgNOZS
`
`" p = methanol, q = 2-propenol, w = nitromethane, x = toluene, y = ethanol. ”Letters refer to methods of preparation described in the
`Experimental Section.
`
`Scheme III
`
`
`
`m» as.v=s<:H,
`"
`
`NaOCI-I
`_._1,, g.v=ocn,
`
`m-CPBA
`‘—«——+
`
`sax-soon,
`'"
`
`r'n’ cm
`flJ’ISOgCH.
`
`Scheme IV
`
`.
`
`H
`
`cu
`
`sol,
`
`r me"
`
`Y‘H.C|.Br.l
`
`ucs
`OI
`use
`
`
`
`x
`
`H
`
`o
`
`Y
`
`1=H.CI.Er
`
`Mno,
`
`
`
`
`!0_7
`
`ms
`
`indoline was benzoyieted exclusively in the 7-position
`under Friedel—Crefte conditions by a modification of the
`method of S
`ass a et all? The 7-ben—zo l' d l'ne de-
`ug w
`y in o l
`
`(6| Gaeaman, P. G.; van Bergen, T. J.; Gruetzmacher. G. J. Am.
`Chem. Soc. 1973, 95, 6503-9.
`(7) Gasman, 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.
`(3) Lo, Y. 3.; Welsh, D. A.; Welatead. W. J., Jr.; Mays R. P.; Roee,
`E. K; Causey, D. H.; Duncan, FL L. J. Heterocycl. Chem. 1980,
`17, 1663—4.
`
`Page 2 of 10
`
`rivative was halogenated in the 5-position with either
`N-bromosuccinimide 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 substituted indole. Indoles with no halogen
`in the 5-position were halogenated in the 3-position with
`
`(9) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasekwa. K. J. Am.
`Chem. Soc. 1978, 1‘00, 4842—52.
`
`Page 2 of 10
`
`
`
`Antiinflammatory Agents
`E
`
`r .;
`a will“. T7):
`
`E
`.. ,r”
`HWK‘MIP
`1.
`
`Figure I.
`
`either N-bromosuccinimide or N-chlorosuccinimide; 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.
`Oxindoles 37 (if-SOCKS), 38 (sf-3020113), 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 a1.” and they agree with the view“ that the inhibition
`of prostaglsndin 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 Brown12 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 (PGGE) 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 oxygen—orienting 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 benzeyl 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 l 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 antiinflammatory
`potency with the 5-01 (143) group being the least detri-
`mental. Taylor and Salata“ have reported that for the
`tolmetin (1-methyl-5-p-toluoylpyrrole-2-aeetic acid) series,
`substitution of a methyl group ortho to the benzoyl sub-
`stituent increases the inhibition of prostaglandin E2 syn-
`
`
`(10) Behemeier, H.; Bohm, 1-1.; Hagen, V4 Hannig. Es, Henkel, H.
`J.-, Hirschelrnann, 11.; Weasel, U. In “Trends in Inflammation
`Research. 2". Agents and Actions Supplement; Bekemeier, 1-1.,
`Hirschelmann, R., Eds; Birkhaoser Verlag: Basel, 1982; Vol.
`10. DD 17-34.
`(11) Vane. J. R. Agents Actions 1978. s. 430.
`(12) Appleton, R. A.; Brown, K. Prostaglcndins 1979, 18, 29—33.
`(13) Bays. D. E.; Foster, R V.; US. Patent 3 828 093, 1974.
`(14) Taylor, R. J ., Jr.; Saints. J. J. Biochem. Pharmacol. 1076, 25,
`2479-34.
`
`Page 3 of 10
`
`Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`1381
`
`thesis. However, in this series 143 was devoid of antiin-
`flammatory activity of 100 mg/kg in vivo and did not
`inhibit cyclooxygenase at 1 mM.
`Substitution 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
`~ 2’,4’-C12 ~ 2’-Cl, 4’-Br > F ~ SCH3 > H > CH3 ~ CF3
`3' 001-13 ~ CBH5. Derivatives containing a substituent in
`the 3’-position (156 and 163) were less active than i in both
`test systems.
`Compounds that were equipotent to 1 in the acute an-
`tiinflanunatory 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 rain 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 l 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 157, 158, and 182 are being developed as an-
`algesic and antiinflammatory agents.
`
`Experimental Section
`Pharmacology. A. Antiinflammation. 1. Acute antiin-
`flammatory activity was determined in the Evans blue-cana-
`geenan-induced pleural effusion model by a modification of the
`method of Sancilio and Fishman.16 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% carrsgeenan 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
`antiinflarnmatory 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 of 10
`
`
`
`1382 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`Walsh 3: al.
`
`Table III. Substituted 7-Benzoyloxindolel
`
`
`
`method
`%
`
`n°~
`X
`Y
`R
`mp. °C (80117“)
`of prepll
`yield
`formula
`21
`5~OCH3
`H
`SCH;
`138-142 (111)
`B
`19
`Cu}!
`0
`22
`5-0611a
`H
`H
`149-152 (111)
`c
`29
`cmuizfiois
`25
`4-01-13
`H
`SCI-I;
`122—124 (11}
`A
`85
`CI7H1,N03$
`24
`4-01-13
`H
`H
`177—130 (11)
`C
`96
`CmHnNOg
`25
`5-CH3
`H
`SCH;
`185-187 (0)
`A
`74
`01-;H15N023
`
`27
`28
`29
`so
`51
`52
`38
`54
`35
`as
`57
`88
`59
`40
`41
`42
`45
`44
`45
`45
`47
`as
`49
`50
`51
`52
`53
`54
`55
`55
`57
`53
`59
`50
`61
`52
`53
`54
`55
`55
`57
`58
`59
`70
`71
`72
`73
`74
`75
`76
`7?
`78
`79
`so
`Bl
`52
`83
`84
`55
`96
`87
`
`5-CH3
`5-CH3
`54“
`5-1?
`5-0]
`5-0]
`5-0]
`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-OCH3
`5-OCH9
`5001-1;
`6‘00
`5-CH
`5-CH
`5-01-12
`5-63;
`50H:
`54311:
`5-01-13
`5-01-13
`5-011:
`5-033
`5-CH3
`5-1?
`5-F
`5-1"
`5-F
`5-1?
`5-1"
`
`H
`H
`H
`H
`H
`H
`H
`H
`4’-OCH,
`4’-SCH
`4’-SOCH3
`4’-SO,CH3
`43-0153
`a011,,
`’-CH,
`2—01-15
`4’-CH3
`440%
`2’-F'
`2’-F
`4’-F
`’-F
`2’-Cl
`2'-Cl
`3’-Cl
`’-Cl
`’-Cl
`(ii-Cl
`4’-Br
`4"-Br
`’-I
`J-CGHE
`’-CgH;
`2',4’-(CH5)3
`2’,"‘(CH3)2
`2’,4’-Clg
`224-013
`3",4’vC12
`3’,4’-C13
`2’-Cl, 4’-Br
`4’-CI
`4’-Cl
`4‘-Br
`’-Br
`4’-SCHg
`41-011,,
`«IR-CH3
`43-1”
`’-F
`4’-Cl
`4’-Cl
`4‘-Br
`’-Br
`any-01,
`224301;
`4’-SCH3
`4’—CH3
`4’-CH3
`’-F'
`4&1?
`4’-Cl
`
`SCHa
`H
`SCH,
`1-1
`SCI-la
`H
`SCI-la
`H
`H
`H
`H
`H
`SCH;
`H
`SCHa
`H
`SCH,
`H
`SCHa
`H
`SCH,
`1-1
`SCI-Is
`H
`SCH.
`H
`SCH,
`H
`SCH;
`1-1
`H
`SCH3
`H
`SCH,
`H
`SCI-Ia
`H
`SCI-L;
`1-1
`H
`SCH;
`H
`SCH.
`H
`H
`SCH,
`H
`SCH,
`H
`SCH,
`1-1
`SCH,
`H
`SCH,
`1-]
`H
`SCH;
`H
`SCHg
`H
`SCH,
`
`162-164 (11}
`176—177 (11)
`157-153 (1)
`1595-1665 (1)
`213-215 (p)
`184—185 (lq)
`1555-1605 (11)
`206-209 (11)
`145-147 (I)
`167—169 (1')
`199~201 (n)
`254—253 (I)
`194-197 (11)
`220-223 (1)
`131—132 (In)
`146-143 (11)
`162—163 (1)
`171-173 (I)
`147-1435 (kl)
`209—210 (1}
`155-167 (5)
`185-157 (11)
`142-144 (1)
`170-472 (1)
`177—1715 {1)
`178-180 (1)
`136—188 (q)
`177 (q)
`252-205 {111:}
`196-198 (0)
`213-214 (1)
`149‘150 (111‘)
`212-215 (ht)
`149—1555 (11)
`176-1715 (II)
`202-204 (a)
`251-256 (ht)
`178—181
`1915—193 (11')
`271-274 (w)
`142—1445 (11)
`1745—176 (11}
`1555-160 (111)
`1805—132 (It)
`175-1715 (kl)
`[60-161 (m)
`1455—150 (111)
`171-1725 (111)
`M2065 (kl)
`1825—184 (1)
`167—171 (kl)
`187—189
`179-1315 (11)
`215—217 (kl)
`211—213
`178-130 (11)
`176-178 (1:)
`1895—1915 (11)
`171—1725 (111)
`195-1955 (In)
`177-135
`
`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
`'I'
`B
`C
`B
`C
`H
`A
`C
`A
`C
`A
`C
`A
`c
`A
`C
`H
`A
`C
`A
`C
`A
`
`80
`95
`66
`82
`47
`25
`57
`30
`51
`70
`92
`89
`56
`so
`61
`33
`77
`92
`55
`60
`53
`72
`55
`79
`85
`83
`33
`93
`58
`61
`58
`66
`93
`75
`70
`5'?
`83
`48
`'73
`55
`74
`90
`63
`79
`92
`53
`83
`'79
`91
`72
`79
`71
`70
`53
`85
`80
`56
`86
`45
`64
`85
`
`CHHHNOg-S
`0161115110:
`C,.H,,FNO,S
`CMHIOFNOE
`01511130114023
`CmeClNO,
`01911120111058
`ClgH-mclNOg
`Cum-3ND,
`cmHlaNogs
`CHI-[13151093
`013111314043
`CHI-1121191035
`01611101910,
`CHI-[1.51028
`Cal-[195103
`CHHsNOgS
`cmeN
`CHI-[151151023
`CHHIJ‘NOE:
`ClgfluFNOZS
`cwflmmo2
`ClsHlfiINOES
`CHI-110015103
`CwHuClNOZS
`cmecmog
`CHI-1301151028
`CfiflloClNO!
`0151112391023
`CuHmBl'NOg
`CIEHWINOI
`Gun-”“038
`CmeNOg
`CHHHNOES
`CnHuNOz
`ClgH,1Cl,NDgS
`CHI-50121102
`CHHIIClgNOZS
`Owl-LaCIQNO,
`C;,H,BrClN02
`CHHNCINOSS
`CIGHECINOs
`CuHuBrNos
`CmHmBl‘NOa
`CHI-luNogs
`CHI-{11110,
`CHI-[”1102
`CHI-IMFNUES
`CHHuFNOg
`CHHHCINOES
`ClgHuClNOg
`CHI-IMBINOfi
`cwHulatrNo2
`cunlaclgNms
`CmHUClgNog
`Ciel-[131551023
`CHHHFNOgS
`CmHuFNOZ
`CloHquNOzS
`C15H9F2N02
`CIngIClFNOgS
`
`Page 4 of 10
`
`Page 4 of 10
`
`
`
`Antiinflommatory Agents
`
`Journal of Medicinal Chemistry, 1934, Vol. 27, No. 11
`
`1383
`
`
`
`
`
`Table III (Continued)
`_____fl—__________________—.___________.—._.__——.——————-—
`method
`%
`
`Xno. formulaWY R mp, °C (solv“) of prep” yield
`
`
`
`
`C
`8s
`5-F‘
`4’-Cl
`H
`187-189 (r)
`CEHBCIFNOa
`5-F‘
`4’-Br
`SCI-la
`197-198 (rt)
`A
`52
`C,.1{,,Brsno,s
`g:
`5-1?
`41-13:
`1-1
`196—197 (nt)
`0
`so
`0,,H.BrFNO,
`90
`5-1"
`2’,4’—C19
`SCH,
`193—200
`A
`44
`cwmcnsnog
`91
`5-F
`2’, [“012
`H
`207-208
`C
`83
`CHI-IBCIEFNOQ
`92
`5-01
`4’-SCH3
`H
`179-181 (in)
`H
`63
`Owl-1130114028
`93
`5-01
`4’-CH3
`SCHa
`187-189 (m)
`A
`43
`Cnl-IHCINOgS
`94
`5-01
`4"CH3
`H
`152*155 (I)
`C
`74
`CmHuClNOg
`95
`5-01
`4’-F
`SCH,
`202~204 (m)
`A
`43
`CmHuClFNogs
`116
`5-01
`’-F
`H
`222-225 (1:)
`C
`64
`Clgl-IQCIFNOg
`97
`5-01
`4’-Cl
`SCH,
`199-202 (ny)
`A
`35
`C,,H,,Cl,No,s
`93
`am
`41.01
`H
`196-201
`0
`so
`C,,H,CI,N0,
`as
`5-0]
`4’-Br
`SCI-Is
`208—211 (or)
`A
`46
`cmnusrcmom
`100
`5—01
`he:
`H
`213-214 (r)
`T
`43
`Unmarcmo,
`101
`5-01
`in]
`H
`213-221 (r)
`T
`43
`Camelmo
`102
`5-01
`2’-Cl, 4’-Br
`H
`255-253 (1‘)?)
`T
`33
`CHHDBrClgNog
`103
`5-13:
`41-01
`H
`206—209 (r)
`T
`35
`anaerobic,
`101
`5-5:
`4'-Br
`[-1
`206—207 (1')
`T
`41
`Cumermo,
`105
`106
`5N0;
`4‘-Cl
`H
`253-259 (ms)
`K
`75
`015H901N90.
`
`101r
`5-NH,
`4’-Cl
`H
`236—239 (mt)
`L
`32
`Clsl-l,,ClN20,
`“k = water.
`= ethanol, m = ethyl acetate. 11 - 2-propanol, o = acetonitrils, p - methylene chloride, q = toluene, r = benzene, s =
`methanol. t I tetrahydrofuran, w I 2-methoxyethanol, x = acetone, y = pyridine, 2 I dimethyli’ormamide. °Letters refer to methods of
`preparation described in the Experimental Section.
`
`Table IV.
`
`I'2'-Benzoylindoline Derivatives
`
`
`
`method of
`%
`
`no.
`x
`Y
`mp, °C (solv‘)
`prep‘
`yield
`formula
`41-01
`103
`H
`107—108 (w)
`M
`91
`0,,H1201No
`as:
`100
`H
`128—129 (x)
`M
`76
`0,,H,,Brno
`4&1
`11.0
`H
`149—150 (3")
`M
`85
`CmHmINO
`2’«Cl. 4’-Br
`111
`H
`120-121 (K)
`M
`55
`CwHHBrClNO
`4’-Cl
`112
`CI
`146—148 ()1)
`N
`45
`Owl-111013140
`4’-Br
`113
`01
`168469 (2}
`N
`67
`CIEHnBrCINO
`4&1
`114
`Cl
`175 (z)
`N
`54
`C,,H,,C1INO
`2201, 41-13:
`115
`Cl
`113—113 (11)
`N
`as
`cmflmercwo
`“-01
`116
`Br
`157—159 (2)
`P
`49
`c,,n,,BrCINO
`117 CHI-luBrgNO Br 4’-Br 1615—168 (z) 0 89
`
`
`
`
`
`
`aw = petroleum ether, :1: I 2-propancl, y - absolute ethanol, z = ethyl acetate. Hatters refer to methods of preparation described in the
`Experimental Section.
`
`(Table VH1). Potencies relative to indomethacin were determined
`by regression analysis.
`2. Chronic antiinflammatory activity was determined in the
`adjuvant-induced arthritic rat model of Wei: et a1.16 using a
`therapeutic rather than a prophylactic dosing regimen as described
`by Sancilio et aL"
`B. Analgesia. Oral analgesic activity was determined in mice
`by the acetylcholine-induced abdominal constriction assay.”
`Acetylcholine bromide was administered mtrsper-itcneelly 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 80 and administered
`by gevege (10 mL/kg). 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. Pharmacol. Exp.
`Ther. 1971, 178, 223-31.
`(17) Sancilio, L. F.; Reese, D. 1...; Cheung, 8.; Alphin, R. S. Agents
`Actions 1977, 7, 133—44.
`
`basis, the degree of damage was scored according to the following
`system: 1, one to three erosions <3 mm in diameter; 2, many small
`erasions; 3, two to three erosions greater than 3 mm in diameter
`or 4—5 mm in length; and 4, four or more large erosions.
`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-t‘our 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 sdhesions, and
`an additional 10 if the animal died. Growth of the animals was
`also monitored during the course of the experiment.
`D. Prostaglaadin 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.1
`General Procedures. Melting points were determined in open
`capillary tubes in a Thomas-Hoover melting point apparatus and
`are uncorrected; 1[-1 NMR spectra were obtained in CD013 or
`MefiO-dfi with Mefii as internal standard or in D20 with sodium
`3-(trimethylsilyl)propionste-d, as internal standard on a Varien
`
`Page 5 of 10
`
`Page 5 of 10
`
`
`
`1384 Journal of Medicinal Chemistry. 1984, Vol. 27, No. 11
`
`Walsh at al.
`
`Table V. T-Benzoylindole Derivatives
`
`
`
`Y
`
`%
`method
`formula
`yield
`of prep“
`mp. °C (solv‘)
`R
`X
`110.
`C 1-1 ClNO
`69
`Q
`149451 (p)
`1-1
`4’-Cl
`1-1
`113
`ciinihlguo
`45
`a
`192-193 (p)
`01
`41-01
`1-1
`119
`ClgHmBINO
`35
`Q
`161-163 (D)
`H
`4’-Br
`H
`120
`ClfiHgBrClNO
`a:
`a
`193-194 (p)
`Cl
`4’-Br
`H
`121
`owl-1.01m
`97
`Q
`175-171; (q)
`H
`421
`1-1
`122
`CwH9ClINO
`81
`R
`179-130 (q)
`Cl
`4“]
`H
`123
`classrcmo
`93
`Q
`144—143 (w)
`H
`and, 4’-Br
`1-1
`124
`CngBrClgNO
`93
`R
`155—157 (w)
`Cl
`2201, 4’-Br
`1-1
`125
`ClfichlzNO
`89
`Q
`170-171 (w)
`H
`’«Cl
`CI
`123
`CHI-1331013510
`58
`S
`220-221 {13)
`Br
`4’-Cl
`Cl
`12?
`C15H931C1N0
`98
`Q
`1835—185 (p)
`H
`’-Br
`Cl
`128
`CHHBBraClNO
`85
`S
`224-226 (q)
`Br
`4’-Br
`CI
`129
`CquCllNO
`92
`Q
`171-173 (I)
`H
`4’4
`Cl
`130
`Owl-lsBrcllNO
`34
`S
`223-224 (q)
`Br
`4’4
`C1
`131
`CngBrClgNO
`99
`Q
`134—135 (1:)
`1-1
`’-Cl, r-Br
`Cl
`132
`ownsrzclmo
`99
`S
`152-1625 (x)
`Br
`21-01, 41-13:
`CI
`133
`ClgHsBrClNO
`79
`Q
`133—134 (qy)
`H
`4cm
`Br
`134
`Clsl'lgBrEClNO
`97
`S
`215-217 (D)
`Br
`4’-Cl
`Br
`135
`0151193er0
`100
`Q
`sol-202.5 (p)
`H
`4am
`Br
`1313
`4’-BrBr137 ClngaBraNO Br 226-228 (p2) S BI
`
`
`
`
`
`
`
`“p a ethyl acetate, q - benzene, w = 2-propanol, x = absolute ethanol, 3; = cyclohexane. z a tetrahydrofuran. I'Letters refer to methods
`of preparation described in the Experimental Section.
`
`Table VI. Oral Antiinflammatory Activity in the 5-h Evans Blue-Carrageenan Pleural Effusion Assay for Aminobenzoylphenylacetic
`Acids
`
`CH2C03R
`
`
`
`3 NHz
`
`% change in av
`vol of
`.pleural fluid. dose
`(walks)
`%
`compd
`indoi'
`
`no.
`NH;
`PhC[=0)
`R
`mp, °C (solv‘)
`yield
`formula
`(4.0)
`(4.0)
`l
`2
`3
`N3
`248—252 (W1)
`80
`CHHHNNROfHQO
`‘26
`'33
`138
`2
`4
`Na
`244—245 (3:)
`65
`CmeNNaog-Dfil-IQO"
`-2‘
`-31
`139
`2
`5
`H
`150-151 (wx)
`85
`Owl-ImNOa
`11"
`43
`140
`2
`8
`Na
`254.5—256 {wyl
`51
`ClgHuNNaO‘gvHQO
`—2"
`—35
`141'
`4
`3
`1-1
`133—134 (2)
`52
`CHI-113N013
`-4“
`-31
`“w = water, I 9 ethanol, 3; - 2-propanol, z - benzene. bIndot'flethacin. ‘C: calcd, 62.94; found, 62.45. J Not significantly different from
`control group at p < 0.05, as determined by the Dunnett’s t test.
`'Refereuce 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 38.0g (55%) of 49 as paleyellow needles,
`mp 142-144 °C. Anal.
`(CwHIQClNOZS) C, H, N.
`Method B. 7-(4-Chlorobenzoyl)-lfi-dlhydrmfi-methoxy-
`3-(mathylthio)—2H-indol-2—one (67). To a solution of 4.0 mL
`(0.088 mol) of chlorine in 200 mL of methylene chloride (CH-‘01,)
`cooled to —70 °C was added dropwise a solution of 11.3 g (0.038
`mol) of ethyl (methylthiolacetate in 30 mL of CHQClz, 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 01-12012 was added dropwise
`over a 30-min period The mixture was stirred at —70 0C for 15
`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 nurture was treated with 30 mL ofconoemtrated
`hydrochloric acid and stirred for 1 h. The mixture was filtered
`
`A60, a Varian RIM-3601., or a Varian F'P-SOA spectrometer; mass
`spectra were determined on a Varian MAT-44 or on a Hitachi
`Perkin-Elmer EMU-6H mass spectrometer; IR spectra were run
`as KBr pellets on a Beckman [BS or on a Perkin—Euner 297 IR
`spectrophotometer; analytical results for compounds followed by
`elemental symbols are within $0.490 of theory and were deter-
`mined on a 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 mmpirac was obtained from McNeil Pharmaceutical.
`Method A. 7-(2-Chlorohenzoyl)- lfi-dihydro-S-(methyl-
`thio)-ZH-lndol-2—one (49). A solution of 50 g (0. 216 11101) of
`2’vchloro-2-aminobensopl'lenone‘s in 800 mL of methylene chloride
`was cooled to -70 °C and 30.5 g (0.227 moll of ethyl (methyl-
`thiolacetate 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 of 10
`
`Page 6 of 10
`
`
`
`Antiinflammatory Agents
`
`Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`1385
`
`Table VII. Oral Antiinflamrnatory Activity in the 5-h Evans Blue-Carrageenan Pleural Elfusion Assay and Cyclooxygenase Inhibition
`Data for Substituted 2-Amino-3-benmylpheny1acetic Acids
`
`'
`
`cnzcozuu
`
` “Hg
`
`WWW—WH—
`% change in av
`vol of pleural fluid
`
`no.
`
`X
`
`Y
`
`M indoc dose, cyclooxygenase
`%
`100
`4.0
`0.16 4.0 rug/kg inhib: 105°, 11M
`formulab
`yield
`mp, °C [8010“)
`'35 ‘26 "136
`'33
`0.2
`CmNmNNflOg‘HgO
`30
`248-252 (13:1)
`H
`H
`1
`~18
`48‘
`5.4
`80 ClgfluNNsO‘olfiHzo
`265
`5-001-13 H
`112
`"1‘
`~38
`>1000
`86 CleMNaoaflflfif-Igo
`206-207 (w)
`4—01-13
`H
`143
`-11“I
`-25
`11
`58
`C19H14NNs03-0.5H30
`252 (w)
`5-CH3
`H
`144
`2‘i
`-38
`3
`69
`le-IuNNaOr025I-120
`235-238 (w)
`6-01-19 H
`145
`-9‘*
`-20
`0.2
`41 CmHuFNNaoa-Ojl-Igo
`253 (po)
`5-F
`H
`145
`41"
`-35
`3'7
`57
`CwflllClNNaOVOBSI-IQO
`229-231 (00)
`4-01
`1-1
`147
`-17
`-35
`1
`82 CldillClNNaOa
`260 (qw)
`5-01
`H
`148
`—10‘t
`-35
`58
`29 CmHI‘NNsO4-05H30
`230—232 (:0
`H
`45001-13
`149
`‘21
`'30
`0.1
`83
`CmHuNNEOSS'HQO
`244—247 (pq)
`H
`"SCHg
`150
`-24
`-38
`1
`65
`C15H11F3NNa03'ossflgo
`265 (qw)
`H
`4’-CF3
`151
`-32 —13d
`-25
`1
`71
`CmHHNNaOa'025HgO
`258-272 (w)
`H
`2’-CH3
`152
`'17
`‘33
`0.3
`51
`CmHuNNflOa
`264 (PC!)
`H
`4"CH3
`153
`—36
`-35
`0.9
`35 CEHHFNNaoa
`260 (W1)
`H
`4’-F
`154
`'42 ‘22
`‘33
`0.3
`64
`C15H11C1NNa03-H20
`230
`H
`2"01
`155
`-35
`-15
`—33
`>1000
`18
`CwHIIClNNaOa-Ofiligo
`>250 (pq)
`H
`3’-CI
`155
`—38
`-29 —16
`~33
`0.3
`67 ClencmNsOgOJH-IZO
`265 (p)
`H
`4’-Cl
`157
`-43
`.27
`«41
`0.08
`54 CmHHBrNNeoa
`285 (pq)
`H
`4’-Br
`158
`«~44 —3‘1
`’1'?
`—32
`0.07
`55
`0151111INN303-025H20
`280—282 {was}
`H
`’-I
`150
`4.4“ ~15“
`—36
`0.08
`25 CnHmNNaosflflfii-Igfl
`240-247(13)
`H
`4’-CuH,
`160
`-38
`~3“
`-40
`0.1
`91
`CHI-115100503
`240
`H
`2’,4’-(CHa)z
`151
`-41
`~37 —16
`-33
`0.6
`62
`ClafllnClzNNaOa-Ojl-Igo
`235—240 (pin)
`H
`2’,4’-Clg
`162
`-10d
`-30
`50
`18
`CwHIOClENNaOa-IJEHEO
`260-265 (pqx)
`H
`KAY-Cl;
`153
`-3'7 —25
`—32
`0.05
`'12 CHHIOBICINNsog-Ojflgo
`125-130 (pw)
`H
`2’-Cl, 4’-Br
`164
`-36
`-26
`-37
`12
`4'?
`Cmi-llgClNNaoi-025H30
`215-220 (w)
`5—OCH3 4’—Cl
`165
`-33
`-28
`—25
`0.9
`44 CISHuBrNNaO.
`245—250(13)
`5-OCH3 4’-Br
`165
`-33 42‘
`—42
`30
`45
`cur-11,10);
`113-120
`5-0113
`4201-1,
`161'
`.47
`-26
`—42
`0.4
`37
`CHHNNNsOaSEI-IEO
`225-260 (13}
`5-0113
`4’-SCH5
`168
`-35
`0"
`~42
`17 '
`1'? CmeFNNaOS-Hgo
`140-160 (pw)
`5-CH3
`4’-F
`159
`-38
`-32
`~35
`0.7
`18
`CIEHBCINNaog
`262 (p)
`5-CH3
`’-Cl
`170
`.39 -31
`-36
`0.7
`41
`ClelimBrNNaOS
`267-270 (wy)
`5-01-13
`4’-Br
`171
`-43
`-24
`-45
`1
`65
`Clai-llgClgNNeOyO51-120
`185-188
`5-01-15
`2’,4'-Clg
`172
`-28
`-33
`0.008
`75
`ClaHHFNNaOQS-025H20
`241—244
`5-1?
`£801],
`173
`«19 —32
`-36
`0.07
`32
`CmHlsF‘NNaOyD25H30
`239—244 (w)
`5-F
`$01-13
`174
`42 «~42
`~40
`0.2
`35
`cwlormmo,
`244-246 (w)
`5-F
`4’-F
`175
`—37
`~34
`0.1
`48
`C15HmClFNN803.0.25H20
`237-240 (pow)
`5-1"
`4’-Cl
`175
`-28
`-25
`0.04
`-28
`70
`CISH‘OBTFNNan'HgO
`244—247 (1:)
`5-F
`4’-Br
`177
`68 CHI-RCIJNNaOa-Oficaflso‘ —46 —41
`—45
`0.1
`215-217 {w}
`5-F
`2915013
`178
`39
`CmHIgClNNaOaS‘OflfiHgO
`—43 —43
`-40
`0.02
`259-280 (w)
`5-01
`4’-SCH3
`179
`23 CiusCINNaOa-025H20
`—44 —35
`—40
`0.02
`259-260 (w)
`5-01
`4’-CH3
`180
`43
`CIEHIOCISNNsoa-025H20
`-41 —18
`-32
`0.3
`>260 (qw)
`5-01
`'-C]
`181
`--38
`40 CmeBrClNNsOS
`-41
`~40
`0.02
`264—206 (p)
`5-01
`4’-Br
`182
`-38
`36
`Clsl-IIOCIINNaOQ-Oéflgo
`-35
`~33
`0.03
`275-278 (1))
`5-01
`’-I
`183
`-21
`47
`CHH11C1N04-035H20
`-3'*
`~40
`30
`87-89
`5-01
`d’—OH
`184
`-37
`09
`CisHeBrClzNNsOB-Hgo
`-25
`—38
`0.05
`125-130 (w)
`5-Cl
`2’-Cl, 4'—Br
`185
`—42
`58 CmeBrCINNaOa-O.5H20
`-26
`—40
`0.6
`270-275 (p)
`5-13:
`4’-CI
`185
`~34
`74
`CwH1gBl'3NN303‘0.5H20
`-30
`~33
`0.8
`268—269 ([9)
`E-Br
`4’-Br
`187
`—7“
`. —33
`indometh-
`1
`acln
`
`43"
`—35
`~39
`-33
`415
`
`0‘
`
`0d
`
`-15d
`
`“p - water, q = absolute ethanol, w - 2-propanol, x -= isopropyl ether, y = methanol. ”All compounds were analyzed for C, H, and N and
`results agreed to $0.495 of theoretical values. cIndornetlnacin. ‘ Not significantly different from control group at p < 0.05, as determined by
`the Dunnett‘s t test.
`‘Amfenac. 1, used as the referenoe standard.
`*‘ Characterized as the acid. ‘0.5 mol of 2-propanol present by NMR.
`to remove H-ICI, 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-
`propanol to give 22.5 g (74%) of 37 as off-white needles, mp
`1420—1445 °C. Anal. (CnHuClNOasl G. H, N.
`Method 0. 7-Benaoy1-8-chloro-1,8-dihydro-2EI-indol-2-ono
`(34). A 200-3 sample of a commie] (Grace, No. 28) Honey nickel
`preparation was Washed thrice with water, with dilute acetic acid
`until neutral, and thrioe with itetrahydrofinsn. The Raney nickel
`slurry was added cautiously to a solution of 24.7 g (0.078 mol)
`
`of 33 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 34 as a white powder, mp 200-209 °C. Anal.
`(CHI-110011402) C, H. N.
`Method D. 7-(z-Fluorohenzoyl)-1,3-dihydro-2H-indol-2-
`one (46). A mixture of 30 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 of 10
`
`Page 7 of 10
`
`
`
`1386 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
`
`Welsh et al.
`
`Table V111. Pharmacological Potency Relative to lndomethacin of Substituted 2-Amino-3~benzoylphenylscetic Acids
`CHzCOaNO
`
`"Hz
`
`
`
`
`chronic
`analgesia
`pleural
`gastric
`adjuvant
`intestinal M
`
`compd
`X
`Y
`effusion
`toxicity
`arthritis
`toxicity
`20 min
`5 h
`inclo‘I
`1
`1
`1
`1
`0.22
`0.22
`corn"
`0.73
`0.25
`0.67
`0.63
`0.21
`0.59
`H
`1
`0.7
`0.7
`1.1
`0.4
`0.1 1
`> 3.0
`H
`H
`157
`3.8‘
`0.9
`2.2‘
`1.4
`0.10
`0.93
`4’-C1
`H
`158
`7.5”
`1.4
`5.8”
`1.8“
`0.07
`0.13
`4’-Br
`H
`159
`6.9‘
`5.3‘
`3.1.c
`3.30
`0.13
`0.18
`’-I
`H
`162
`5.3‘
`1.0
`4.2‘
`0.63
`0.21
`>03
`2’,4’-Clg
`H
`164
`1.6
`5.6“
`7.4”
`1.6‘
`0.12
`1.6
`2'-Cl, 4’-Br
`5-CH3
`170
`1.7
`0.27c
`0.63
`0.4“
`0.78
`0.65
`4’—Cl
`5—01-13
`171
`2.8‘
`1.2
`1.0
`1.1
`0.72
`0.70
`4’—Br
`5-1“
`173
`0.4‘
`e
`0.03c
`e
`0.10
`> 1.0
`43501-13
`5-F
`175
`1.4‘
`0.37‘
`0.01‘
`e
`0.71
`e
`4’-F
`5-F
`176
`3.6‘
`1.1
`1.9
`0.5‘
`0.28
`1.4
`4’-Cl
`5-F
`177
`8.4"
`1.7
`2.2
`1.9“I
`0.18
`0.29
`4’-Br
`5-F
`178
`1.2
`1.0
`0.13r
`e
`0.10
`0.65
`2’,4’-Cl,
`5-01
`179
`1.8
`0.9
`0.1‘
`e
`0.10
`1.9
`4’-SCH3
`5-01
`180
`1.6“
`0.7
`0.1‘
`e
`0.10
`0.43
`“301-13
`5-Cl
`18].
`4.6‘
`1.2
`1.7
`1.2
`0.23
`0.31
`4’-Cl
`5-01
`182
`15°
`1.5“
`4.6‘
`2.9c
`0.05
`0.13
`4’-Br
`5-Cl
`183
`3.8
`3.5°
`5.5‘
`2.2‘=
`0.24
`0.24
`4’-1
`5-01
`185
`4.9"
`1.2
`2.5
`3.3‘
`0.66
`0.19
`2’-Cl, 4’-Br
`5-Br
`137
`4.2!
`1.1
`2.5
`1.0
`>032
`0.2
`4’-Br
`"Indometh