Table 42. 13 C NMR Spectral Properties
`l:i-benzylpropionamide
`(ili).a
`
`for
`
`the Polar Analogues
`
`107a-e
`
`of 2-Acetaniido·
`
`0
`
`R
`
`/l--,N~~"-"Ph
`H o
`
`107
`
`No.
`
`R
`
`liib H
`
`Cti3
`
`COCH3
`
`CH
`
`COCH
`
`22.50
`
`169.ooc
`
`42.50
`
`169,60c
`
`CH2
`
`. 42,00
`
`fill.ab
`
`CH3
`
`22,50
`
`169.5
`
`42.00
`
`174.3
`
`42.10
`
`1..01.a'
`
`CN
`
`22.07
`
`162.01
`
`44.22
`
`169.69
`
`42,64
`
`lQlll CONH2
`
`22.48
`
`1 68.5JC
`
`57.28
`
`169,41c
`
`42.22
`
`C1"
`
`C2•C3•
`
`C4•
`
`R
`
`139.30 126. 10d,e
`12s. rod,e
`
`139.70 121. tod,B"
`12S..3od.e
`
`136.36 12s,god,e
`121.11d,&
`
`126.50
`
`126.70
`
`15.80
`
`t28.23
`
`116.45
`
`138.99 121.02d,&
`12a.19d,e-
`
`126.73
`
`166.67
`
`.....
`""' <O
`
`
`l:i-benzylpropionamide
`(ili).a
`
`for
`
`the Polar Analogues
`
`107a-e
`
`of 2-Acetaniido·
`
`0
`
`R
`
`/l--,N~~"-"Ph
`H o
`
`107
`
`No.
`
`R
`
`liib H
`
`Cti3
`
`COCH3
`
`CH
`
`COCH
`
`22.50
`
`169.ooc
`
`42.50
`
`169,60c
`
`CH2
`
`. 42,00
`
`fill.ab
`
`CH3
`
`22,50
`
`169.5
`
`42.00
`
`174.3
`
`42.10
`
`1..01.a'
`
`CN
`
`22.07
`
`162.01
`
`44.22
`
`169.69
`
`42,64
`
`lQlll CONH2
`
`22.48
`
`1 68.5JC
`
`57.28
`
`169,41c
`
`42.22
`
`C1"
`
`C2•C3•
`
`C4•
`
`R
`
`139.30 126. 10d,e
`12s. rod,e
`
`139.70 121. tod,B"
`12S..3od.e
`
`136.36 12s,god,e
`121.11d,&
`
`126.50
`
`126.70
`
`15.80
`
`t28.23
`
`116.45
`
`138.99 121.02d,&
`12a.19d,e-
`
`126.73
`
`166.67
`
`.....
`""' <O
`
`
`
`1.Q1'
`
`COOCH2CH3
`
`22.50
`
`167.41
`
`58.B 1
`
`170.42
`
`43.67
`
`1il<! CHzOH
`
`22.19
`
`169.B6c
`
`S4.B7
`
`1 s9,oac
`
`41.59
`
`lllid CHzOCH3
`
`23.19
`
`169.96°
`
`52.40
`
`169,96c.
`
`43.55
`
`137.45 121.390,g
`12e.so0.•
`
`127.399
`
`13.81 (CH3)
`62.29 (CH2i
`165.19 (CO)
`
`138.90 12s.53d,•
`127.11d.•
`
`128.15
`
`81.30
`
`h
`
`127.4.td.•
`12s.1od.•
`
`127.49
`
`59.08 (CH3)
`71.65 (CH2)
`
`B.The llc NMR '~ra ware !ale.en In OMSO-d5 unless 01herwlse ln.Qicats<l. The number ln each enlry Is
`lhe chemical ahtn va!uo observed ·1n par1s por
`mlflion rela!lve lo ™$· The Information In parentheses In sel&ci cases Is lh• proposed asstgnm&nl. bRef. 103. C Th!s aal ol resonrinces may be In·
`lor6hangeablo, d The close proxlmhy ol
`lhase lwo peaks did not permit lhe ass.lgnmenl ot lhese resonancea. • Thls poakhad approxlmalely
`lw*ce !he·
`ln!onsily of neatby peaks.. I The 13c NMR spoctrum wa$1 lakon In CO.Ct3. g This penk had !!pproxlmalety three times the lnlenslty of nearby poa.ks, h A
`discreie algnal for this· ca1bon resonanco was nol ob1Grvod.
`
`....
`c.n
`0
`
`., ... , .. ,_,;·
`
`
`
`Table 43.
`
`13 C NMR
`
`Spectral Properties
`
`for Oxnzole Derivatives ill and ill.a
`'o~R'
`I \
`'
`'
`RJ.!__N , R
`l
`
`No,
`
`A2
`
`R4
`
`111ll
`
`H
`
`H
`
`Rs
`
`H
`
`C2
`
`C4
`
`--e:5-
`
`R2
`
`R4
`
`Rs
`
`150,60
`
`125.40
`
`138,10
`
`....
`01 _.
`
`ill
`
`CH3
`
`COOCHzCH3
`
`OCH2CH3
`
`tS1.53b
`
`107.30
`
`151.01 13,90
`
`15.00(CH3)
`0~.11{Cll::i)
`
`14.93(CH3)
`64.'"'(CH2)
`
`14.48 (CH3)
`CO,.J.O (Cl !2}
`161.4Sb (CO)
`
`41.69 (CH2)
`126.69 (C4')
`126.94
`(C2" or C3")
`12a.2ad.
`(C2" o~ C,J.")
`139.96 (C1")
`.154.sob(CO)
`
`llle CH3
`
`y
`0
`
`~
`
`~·"
`
`l"
`
`!"
`
`, ..
`
`OCH2CH3
`
`159.42b
`
`104,55
`
`141.74 13.94
`
`
`
`·'·"'""
`
`ill
`
`CH3
`
`. ~•"
`Y~~'" NH2
`0
`
`?''
`
`1eJ.o:1ob
`
`106,37
`
`1'9.<0 13.29
`
`42.S1 {CH2)
`127.10 (C4"}
`127,tl.-ld,o (C2" or C3"}
`120.<!Sd,o {C2" or C3") .
`13a.so 1c1")
`1 ss.ssb ccoi
`
`...
`
`t/l
`N
`
`anief~c NMR spectra wore takon lnCDCl3,vnlos! olhorwise lndicalod. The numbor in oach enlry Is Iha chomicol shilt valuo In parts per million rel3·
`intorchangQnblo. e Tho 1:lc NMR -spoc11a was
`tnkon in OMSO·dG. d This se1 ol resoniiices may bo
`tlvG
`to TMS. b This sot o! resonnnces may be
`lnterchal"Qeablo. e Th1s peak had opproximo.loly lwico the inton-sity or noarby poaks.
`·
`
`
`
`153
`
`,.,
`
`'!
`::i
`
`gen atoms at carbons -4 and -5 by an electron - withdrawing and a
`
`electron-donating groups,
`
`respectively,
`
`led
`
`to a pronounced shift in
`
`the resonances of the corresponding carbon atoms. The carbon-4
`from 1..1.fil1., while
`the carbon-5 atom was shifted downfield (11.30 - 13.64
`
`signal moved upfield . (19.03 - 20.85 ppm)
`
`the
`
`resonance
`
`for
`
`ppm)
`from
`that observed in 11.l!Q. This perturbation
`in the 13c NMR
`spectra for ID. ill and lli is attributed to the push-pull resonance
`
`effects exerted by the carbon-5 and carbon-4 substituents.
`
`3.
`
`Pharmacological Evaluation.
`
`The 2-substituted-2-acetamido-N-benzylacetamides 107a-d and
`
`the oxazole derivative 111 prepared
`
`in this study were submitted to
`
`the Eli Lilly Corporation, Indianapolis,
`
`Indiana,
`
`for evaluation of
`
`their
`
`anticonvulsant activity. They were
`
`tested using
`
`the same protocols
`
`described in Chapter r.
`
`Pharmacological data
`
`for these functiona-
`
`lized amino acids are
`
`listed
`
`in Table 44.
`
`Compounds 1 O?a-c did not exhibit significant activity in the
`
`MES seizure
`
`test.
`
`The
`
`lack of anticonvulsant properties of
`
`these
`
`adducts was
`
`in
`
`light of
`
`the pronounced activity of
`
`the
`
`methyl analogue
`
`interesting
`filIB..
`
`A
`
`tentative explanation
`for
`this dichotomy
`first approximation compounds filIB.
`
`In a
`
`of results can be offered.
`
`and 1 O?a-c all contain relatively small substituents.
`
`The primary
`
`difference between
`
`the two sets of compounds
`
`is the presence of
`
`an
`
`electron-donating
`
`(fillli) or an
`
`electron-withdrawing (107a-c)
`
`moiety at the a-carbon. Our previous studies have
`
`indicated
`
`that
`
`
`
`154
`
`Pharmacological Evaluation of
`Table 44.
`2-Acetamido-N-be nzylpropionamide (film). a
`
`the Polar Analogues of
`
`No.
`
`-2.fu!.d
`
`.1Qla
`
`107b
`
`1Qk
`
`j_QZQ
`
`A
`
`CH3
`
`CN
`
`CONH2
`
`COO Et
`
`CH20H
`
`.107
`
`MES,Eosob
`
`rox. ro5oc
`
`51 (46.6 - 58.6)
`
`> 1ooe
`
`> 300
`
`> 300
`
`> 300
`
`> 100, < 300
`
`> 300
`
`> 300
`
`< 300
`
`< 300
`
`arhe compounds were administered intraperitoneally. ED50 and TD50
`values are
`in mg/kg.
`The number
`in
`parentheses
`is the 95 %
`confidence
`interval.
`b Maximal electroshock seizure
`test. CHorizontal
`indicated. d Ref. 104.
`screen
`test
`(neurotoxicity), unless otherwise
`eRotarod ataxia test.
`
`
`
`155
`
`the activity of the drug candidate
`
`in
`
`the MES seizure test
`
`is en(cid:173)
`
`hanced by
`
`the presence
`
`of
`
`electron-donating groups at the
`
`a-carbon.
`
`The negligible activity of 1 OZa.b and Q.. is
`
`in agreement
`
`with this trend.
`
`The
`
`serine
`
`derivative .lil1.d. exhibited only
`
`slight
`
`anticonvulsant activity
`
`in
`
`the MES seizure
`
`test.
`
`The activity of
`
`this
`
`compound
`
`was
`
`considerably
`
`diminished
`
`from
`
`the
`
`corresponding
`
`may
`
`reflect
`
`the
`
`inability of
`
`isomeric methoxy ether fill.a (Table 33).
`.1.Q1d.
`
`to
`
`readily pass
`
`This result
`
`through
`
`the
`
`blood-brain barrier. The more
`
`lipophilic methoxy ether .1.QTu. has not
`
`been evaluated yet. The ·close structural analogy of this compound
`
`with fill.!:2. suggest
`
`that
`
`this adduct may have · good anticonvulsant
`
`activity.
`
`No activity
`
`in the MES seizure
`
`test was observed for
`
`the oxazole derivative 111. The absence of · other pharmacological
`
`data in
`
`this series prohibits any definitive statement concerning
`
`the
`
`significance of this observation.
`
`Experimental Section .GeneralMethods.Syntheses. Melting
`
`points were determined with a Thomas Hoover melting point apparatus and
`
`are uncorrected. Infrared spectra (IR) were run on a Perkin-Elmer 1330
`
`spectrophotometer and are calibrated against the 1605 cm·1 band of
`
`polystyrene. Absorption values are expressed in wavenumbers (cm·1 ).
`
`Proton nuclear magnetic resonances (1 H NMR) and carbon nuclear magnetic
`
`resonances (13c NMR) spectra were taken on a Nicolet NT-300 instrument or
`
`
`
`156
`
`a General Electric QE-300 instrument. Chemical shift are in parts per million
`
`(o values) relative to tetramethylsilane (TMS) and coupling constant (J
`
`Values) are in hertz. Mass spectra were performed at the Eli Lilly
`
`Corporation, Indianapolis, Indiana, or by Dr. John Chinn at the Department of
`
`Chemistry, University of Texas at Austin. Elemental analysis was conducted
`
`at the Eli Lilly Corporation, Indianapolis, Indiana. p-Toluenesulfonic acid,
`
`diethyl 2-acetamidomalonate and diisobutylaluminum
`
`hydride were
`
`purchased from Aldrich Chemical Company, Milwaukee, Wisconsin;
`
`ph.osphorus pentoxide and lithium chloride were obtained from Fisher
`
`Scientific, Pittsburg, Pennsylvania. Tetrahydrofuran was distilled from
`
`Na/benzophenone. All other chemicals were of the highest grade available
`
`and were used without
`
`further purification.
`
`The
`
`reaction with
`
`diisobutylaluminum hydride was run under anhydrous conditions.
`
`In this
`
`case all glassware was flame dried under N2, the solid starting material was
`dried in vacuo immediately prior to use, and the reaction was conducted
`
`under positive pressure of N2. Preparative flash column chromatographies
`were run using Merck silica gel, grade 60, 230-240 mesh, GOA from Aldrich
`
`Chemical Company, Milwaukee, Wisconsin.
`
`Preparation of 2-Acetamldo-N:-benzyl-2-cyanoacetamide
`
`(107a). Benzylamine (.e.3_) (4.72 g, 4.78 ml, 44.0 mmol) was added in one
`
`portion to a suspension of ethyl acetamidocyanoacetate (lll.8.) (4.90 g, 28.8
`
`mmol) in ethanol (75 ml). The mixture was stirred at room temperature (18 h)
`
`and the resulting suspension was evaporated invacuo. The residue was
`
`recrystallized (tetrahydrofuran/petroleum ether (35-60 °0)) to give 4.26 g
`
`(64%) of the desired product as white crystals: Rt 0.25 (95:5
`
`
`
`157
`
`chloroform/methanol); mp: 179-160 °C; 1H NMR (300 MHz, DMSO-d6) Ii
`1.94 (s, CH3), 4.33 (d, J = 6.0 Hz, CH2), 5.59 (d, J = 6.1 Hz, CH), 7.20-7.36
`(m. Ph), 8.66 (t. J = 6.0 Hz. NH). 9.09 (d, J = 6.1 Hz, NH): 13c NMR (75 MHz,
`
`DMSO-d5) 22.07 (CH3), 42.64 (CH2), 44.22 (CH), 116.45 (CN), 126.90
`
`(2C2" or 2C3u), 127.11 (2C2" or 2C3"), 126.23 (C4u), 136.36 (C1"),
`
`162.61 (CH3CO), 169.69 (NHCO) ppm; IR (KBr) 3200, 3040, 1620 (br), 1565
`(br), 1505 (br), 1360, 1260, 1210, 1030, 990 (br), 690, 725, 690, 560 cm-1;
`
`mass spectrum, m/e (relative intensity) 231 (4), 215 (1), 204 (2), 190 (4), 172
`
`(17), 146 (1 ), 129 (6), 106 (20). 98 (42), 91 (100), 77 (19), 65 (29).
`
`Anal. Calcd for C12H13N302: C,62.33; H 5. 67; N, 16.17. Found: C,
`62.60; H, 5.65; N, 17.99.
`
`Preparation of 2·Acetamldo-N.-benzylmalonamlde (107b).
`
`2-Acetamido-N-benzyl-2-cyanoacetamide (.1.QZa) (2.00 g, 6.65 mmol) and
`
`concentrated aqueous HCI (4.20 g, 4 ml, 34.6 nimol) were combined and
`
`stirred at 40 °C (15 min). The resulting suspension was filtered and the white
`
`solid was triturated with chloroform (20 ml, 5 min), filtered, and then
`
`dissolved in 4:1 n-butanol/H20 (150 ml). The organic phase was
`
`concentrated to a small volume i.uvacuo, and then hexanes were added and
`
`the resulting solution was refrigerated (-16 °C) overnight to yield after filtration
`
`1.20 g (55%) of the desired compound as a white solid: R1 0.18 (95:5
`chloroform/methanol); mp 191-192°C;1H NMR (300 MHz, DMSO-ds) o 1.92
`(s, CH3), 4.31 (d, J = 5.7 Hz, CH2), 4.92 (d, J = 7.8 Hz, CH), 7.20-7.34 (m,
`Ph), 7.36 (s, NHH'), 7.50 (s, NHH'), 8.10 (d, J = 7.6 Hz, NH), 8.60 (t, J=5.7
`
`Hz, NH); 13c (75 MHz, DMSO-d5) 22.46 (CH3). 42.22 (CH2). 57.28 (CH),
`
`126.73 (C4"), 127.02 (2C2" or 2C3u). 126.19 (2C2" or 2C3"). 138.99
`
`
`
`: ..
`
`158
`
`(C1u), 166.87 (CONH2). 168.53 (COCH3), 169.41 (CONH) ppm; IR (KBr)
`
`3370, 3300, 3160, 2905, 1665 (br), 1635 (br), 1520, 1480, 1390, 1260, 1050,
`
`730, 690, 665, 600 cm-1; mass spectrum, m/e (relative intensity) 249 (6), 232
`
`(3), 206 (5), 190(13),163 (6), 146 (8), 116 (70), 99 (92), 91 (100), 73 (95), 66
`
`(46); high resolution mass spectrum, calcd for c 12H15N302 249.11134,
`found 249.11101.
`
`Preparation of Ethyl 2-Acetamido·N.·benzylmalonamate
`
`(107c). To an ethanolic suspension(400ml) of 2-acetamido·fi-benzyl-
`
`2-benzyl-2-cyanoacetamide (lfil.a) (4.00 g, 17.2 mmol), was added
`
`p-toluenesulfonic acid (3.26 g, 17.2 mmol). The mixture was heated to reflux
`
`(9 h) and then stirred at room temperature (12 h). The resulting suspension
`was concentrated in vacuo and the residue dissolved in a 2:1 mixture of ethyl
`
`acetate and H20 (300 ml), the organic layer was separated and the aqueous
`
`layer extracted with ethyl acetate (200 ml). The organic layers were
`
`combined, washed with aqueous 10% NaHC03 (100 ml), dried (Na2S04)
`
`and evaporated in.vacuo. The white residue was recrystallized (75:25
`
`ethanol/H20) to yield 1.34 g (45%) of the desired product as slightly beige
`
`crystals: Rt 0.43 (95:5 chloroform/methanol); mp 142-143 °C; 1H. NMR (300
`MHz, CDCl3) o 1.22 (t, J = 7.2 Hz, CH3CH2). 2.02 (s, CH3), 4.21 (q, J = 7.2
`Hz, CH3CH2). 4.35 (dd, J = 5.4 Hz, J =14.7 Hz, NHCHH'), 4.50 (dd, J = 6.3
`
`Hz, J= 14.7 Hz, NHCHH'), 5.18 (d, J= 7.2 Hz, CH), 7.01 (d, J= 7.2 Hz, NH),
`
`7.20-7.33 (m. Ph, NH); 13c NMR (75 MHz, CDCl3) 13.81 (CH3CH2). 22.50
`
`(CH3CO), 43.67 (CH2NH), 56.81 (CH), 62.29 (CH3CH2). 127.39 (2C2" or
`
`2C3", C4"), 128.50 (2C2" or 2C3"), 137.45 (C1"), 165.19 (COCH 3),
`167.41 (COOCH 3), 170.42 (CONH) ppm; IR (KBr) 3250, 1750, 1625 (br),
`
`
`
`159
`
`1525 {br), 1365, 1300, 1230, 1180, 1140, 1080, 101 O, 895, 730, 680, 600
`
`cm-1; mass spectrum, m/e {relative intensity) 278 (6), 259 (8), 219 (5), 163
`
`'i. .
`
`(12), 145 (93), 117 (5), 104 (77), 99 (100), 74 (53), 66 (44).
`AnaL Calcd for c14H18N204: C, 60.42; H, 6.52; N, 10.07. Found: C,
`60.64; H, 6.48; N, 10.19.
`
`Preparation of 2-acetamldo-N_-benzylhydracrylamlde
`
`(107d). Ethyl 2-acetamido-N-benzylmalonamate (iQl.c.) (2 17 g, 7.8 ml)
`
`was dissolved in anhydrous tetrahydrofuran (50 ml). To this solution dry
`
`UC! (0.66 g, 15.6 mmol), NaBH4 (0.59 g, 15.6 mmol) and ethyl alcohol (30
`ml) were successively added. The mixt1Jre was stirred at room temperature
`
`(15 h), cooled {O °C) and then made acidic (pH 4) by the addition of a 5%
`
`aqueous solution of citric acid (ca. 14 ml). The suspension was concentrated
`in vacuo, and then H20 (20 ml) was added, and the resulting ·solution was
`
`extracted with ethyl acetate (3 x 25 ml). The organic layers were combined,
`dried (NaS04), and evaporated in vacuo to give a colorless oil (1.52 g) which
`was crystallized with hexanes. The desired product was further purified by
`
`recrystallization from acetonitrile to yield 1.21 g (66%) of 1.Q.M as white
`
`crytals: Rf 0.20 (95:5 chloroform/ethanol); mp 201-203 °C; 1H NMR (300
`MHz, DMSO-d5) o 1.88 (s, CH3), 3.59 (dd, J = 5.7Hz, J = 5.7 Hz, CH20),
`4.19-4.35 (m, CH2NH, CH), 4.92 {t, J= 5.7 Hz, OH), 7.10-7.40 {m, Ph), 7.94
`{d, J = 5.7 Hz, NHCH), 8.38 (t, J = 5.7 Hz, NHCH2); 13c NMR (75 MHz,
`
`DMSO-d5) 22.19 {CH3). 41 .58 (CH2NH), 54.87 (CH), 61.30 (CH20H),
`
`126.15 (C4 u), 126.53 (2 C2" or 2 C3•o}, 127.71 {2 C:z• or 2 C3•o}, 138.90
`(C1 .. ), 169.08 (CH3CO), 169.86 {CHCO) ppm; IR {KBr) 3220 (br), 1605 (sh),
`1530 (br), 1375, 1280, 1230, 1045, 895, 725, 690, 570 cm·1; mass spectrum,
`
`;_~
`
`
`
`160
`
`m/e (relative fritensity) 237 (48), 219 (4), 206 (10), 193 (5), 177 (37), 163
`
`(21), 146 (11), 130(76),106 (100), 91 (100).
`Anal. Calcd for C12H15N2o3: C, 61.26; H, 6.43; N, 11.91. Found: C,
`61.06; H, 6.72; N, 11'78.
`
`Preparation of 2-Acetamido-N:-benzyl-3-methoxyproplon(cid:173)
`
`amlde (107e). To a
`
`tetrahydrofuran (ca. 20 ml) suspension of
`
`2-acetamido- N.-benzylhydracrylamide (1.!l.lli) (150 mg, 0.63 mmol) was
`
`added 3-methyl-p-tolyltriazene (.11.Q.) (210 mg, 1.41 mmol), and the resulting
`
`mixture was stirred at reflux (4 d). The suspension was then tittered and the
`
`filtrate evaporated lD_ vacuo. The residue was purified by column
`
`chromatography (100% chloroform, then 97:3 chloroform/methanol) to give 7
`
`light yellow solid: Rf 0.30 (97:3
`mg (4%) of the desired product as a
`chloroform/methanol); mp 109-112 °c; 1NMR (300 MHz, CDCl3 ) o 2.02
`(s,CH 3). 3.31 (s, CH30), 3.30-3.45 (m, CHH'0),3.70-3.85 (m, CHH'O),
`4.39-4.42 (m, CH2NH), 4.48 (dt, J =4.2 Hz, J =7.2 Hz, CH), 6.46-6.56 (br d, J
`
`=4.2 Hz, NHCH), 6.80-6.90 (br s, NHCH2). 7.20-7.36 (m, Ph); 13c NMR (75.
`
`MHz, CDCl3) 23.19 (CH3CO), 43.55 (CH2NH), 52.40 (CH), 59.06 (CH30),
`
`71.65 (CH20), 127.44 (2 C2" or 2 C3u). 127.49 (C4u), 128.70 (2 C2" or 2
`
`C3u), 169.96 (COCH3, CONH) ppm. [The C1" was not detected].
`
`IR (KBr)
`
`3240, 1610, 1525, 1150, 1085, 720, 690 cm·1.
`
`Acid
`
`f:!...-benzylamlde
`
`Preparation of 5-Ethoxy-2-methyloxazole-4-carboxylic
`(11JJ. To a solution of
`N-benzylmalonamate (1.QZQ) (1.35 g, 4.85 mmol) in chloroform (15 ml) was
`added P.2o5 (6.88 g, 48.5 mmol) and the resulting suspension was heated to
`reflux (8 h). The reaction mixture was carefully neutralized (10% aqueous
`
`2-acetamido(cid:173)
`
`
`
`161
`
`KOH) and then extracted with dichloromethane (4 x 100 ml). The organic
`fractions were combined, dried (Na2so4) and concentrated in vacuo to yield
`a beige residue which was recrystallized (4:2 tetrahydrofuran/hexanes) to
`
`give 1.22 g (97%) of the desired product as white crystals: Rt 0.85 (95 : 5
`chloroform/methanol); mp 111 - 113 °C; 1 H NMR (300 MHz, DMSO-d6) o
`1.33 (t, .J = 8.3 Hz, CH3CH2). 2.33 (s, CH3), 4.25 (q, J = 8.3 Hz, CH2CH3),
`4.50 (d, J= 6.9 H, CH2Ph), 7.15-7.35 (m, Ph, 2NH); 13c NMR (75 MHz,
`
`DMSO-d6) 13.94 (CH3), 14.83 (CH3CH2). 41.69 (CH2Ph), 64.44 (CH2CH3).
`
`104.55 (C4), 126.68 (C4u), 126.94 (2C2• or 2 C3"), 128.28 (2C2" or 2C3"),
`
`139.96 (Cr·), 141.74 (C5). 154 .. 50 (C2 or CONH), 159.42 (C2 or CONH)
`
`ppm; IR (KBr) 3300, 2900, 1620 (br), 1585, 1570, 1540, 1430 (br), 1380,
`
`1350, 1300, 1175, 1085, 900, 720 cm·1; mass spectrum, m/e (relative
`
`intensity) 260 (48), 215 (12), 173 (7), 126 (6), 106 (6), 91 (100).
`
`Anal. Calcd for C14H13N203: C, 64.11; ·H, 6.92; N, 10.68. Found: C,
`
`64.38; H, 6.74; N, 10.76.
`
`Preparation of 5-Amlno-2-methyloxazole-4-carboxylic
`
`Acid
`
`li_-benzylamide
`
`(1_W.To a chilled solution (-5 °C) of
`
`2-acetamido-N- benzyl-2-cyanoacetamide (1.Q.Ia) (0.50 g, 2.16 mmol) in
`
`anhydrous tetrahydrofuran (40 ml) was slowly added (7 min) a 25% solution
`
`of diisobutylaluminum hydride (0.92 g, 6.48 mmol) in toluene . The solution
`
`was stirred at -5 to O °C for 15 min, and then at room temperature (50 h), and
`
`finally at reflux (96 h). A saturated aqueous solution of NH4CI (50 ml) was
`then added to the reaction, followed by a 5% aqueous solution of H2so4 (20
`ml). The mixture was then extracted with ethyl acetate (3 x 60 ml). The
`organic layers were combined, dried (Na2S04) and evaporated to dryness in
`
`
`
`162
`
`vacuo. The residue. was purified by flash chromatography (95:5
`
`chloroform/methanol) to yield 0.20 g (37%) of the product as a pale yellow
`solid: Rt 0.58 (95:5 chloroform/methanol); mp 108-110 °C; 1 H NMR (300
`MHz, CDCl3) o 2.28 (s, CH3), 4.54 (d, J = 5.0 Hz, CH2), 5.20-5.35 (br s,
`NH2). 6.60-6.80 (br s, NH), 7.20-7.50 (m, Ph); 13c NMR (75 MHz, DMSO-d5)
`
`13.29 (CH3), 42.51 (CH2). 106.37 (C4), 127.10 (C4"),. 127.44 (2C2" or
`
`2C3u), 128.45 (2C2" or 2C3 .. ). 138.50 (C1"), 149.40 (C2). 156.65 (CO),
`163.40 (C5) ppm: IR (KBr) 3360, 3240, 3230, 1605 (br). 1510 (br), 1220,
`121 o, 1090, 890, 730, 690 cm·1: mass spectrum, m/e (relative intensity) 231 ·
`
`(21 ), 106 (63), 98 (18), 91 (100); high resolution mass spectrum, calcd
`
`forC12H13N302 231.10078, found 231.10107.
`
`Pharmacology.The compounds prepared in this study were tested for.
`
`anticonvulsant activity using male albino mice (CF-1 strain, 18-25 g, Charles
`
`River, Wilmington, MAJ.The drug candidates were intraperitoneally
`
`administered to the animals in 30% polyethylene glycol 400 or 5%
`
`acacia/water prior to the tests. Maximal electroshock seizures (MES) were
`
`elicited with a 60-cycle alternating current of 50 mA intensity (approximately 6
`
`times that was necessary to elicit minimal electroshock seizures) delivered for
`
`0.2 s via corneal electrodes. A drop of 0.9%saline solution was instilled in the
`
`eyes of the animal prior to application of the electrodes so as to prevent the
`
`death of the animal. Protection in this test was defined as the abolition of the
`
`hind limb tonic extension component of the seizure. In this initial test, the
`
`compound to be evaluated was administered at three dosages (300, 100, 30
`
`mg/kg), with four mice at a dose, and maximal electroshock seizures were
`
`elicited at 0.5, 1, 2, 3 and 4 hr post-treatment to determine the approximate
`
`
`
`163
`
`. time of peak .effect (TPE). Compounds demonstrating significant
`
`.· anticohvulsant activity were then retested at the estimated TPE using at least
`
`four doses, with twelve mice at a dose, and the ED 50 was calculated. The
`
`neurologic toxicity was evaluated by the horizontal screen (HS) test.
`
`Previously trained mice were dosed with the compounds and placed
`
`individually on top of a square (13 x13 cm) wire screen (No. 4 mesh) which
`
`was mounted on a metal rod. The rod was rotated 180°, and the number of
`
`mice that returned to the top of the screen within ·one minute was determined.
`
`This measurement was performed at the estimated TPE, using at least four
`
`doses, with twelve mice at a dose, and the TD 50 was calculated.
`
`
`
`164
`
`GENERAL CONCLUSIONS
`
`The synthesis and pharmacological properties of
`
`the new
`
`functionalized amino acids analogues of u-acetamido-N-benzylphenyl(cid:173)
`
`acetamide (filll2) and 2-acetamido-N-benzylpropionamide (filli!.) revealed
`
`several
`
`notable
`
`findings.
`
`First,
`
`the use of amidoalkylation
`
`procedures provided a straightforward and
`
`reliable method to
`
`intro(cid:173)
`
`duce an electron
`
`rich heteroaromatic substituent at
`
`the a-carbon
`
`in the amino acid derivatives.
`
`In particular,
`
`the employed condi-
`
`tions
`
`(boron
`
`trifluoride · etherate, ether) permitted
`
`the synthesis of
`
`both
`
`2-acetamido-N-benzyl-2-pyrroleacetamide (lill.Q), 2-acetamido-N-
`
`benzyl-3-indoleacetamide (2.ag_) and 2-acetamido- N-benzyl-2-benzofurana-
`
`in
`results
`unaware of any previous
`We are
`cetamide
`(.Qfil).
`the acid sensitive unsubstituted heterocycles, pyrrole fill ,
`which
`benzofuran as and
`transformations. We suspect
`in amidoalkylation
`
`indole (l2), have been successfully employed
`
`that optimization of
`
`the general reaction conditions will not only provide higher yields
`
`but permit
`
`the use of less reactive heteroaromatic compounds
`
`in
`
`this
`
`procedure.
`
`Second,
`
`all
`
`five-membered
`
`ring
`
`heteroaromatic
`
`analogues of §.§Q proved highly active
`
`in
`
`the MES seizure
`
`test.
`
`Significantly,
`
`the
`
`furan-(2.9_a) and pyrrole-(2.9.b) adducts
`
`exhibited
`
`activities similar
`
`to
`
`those of phenytoin ~ and diazepam
`
`l21k)
`
`,
`. ~·
`
`under
`
`comparable
`
`that
`
`the
`
`D-enantiomers of
`
`than
`
`the corresponding
`
`conditions.
`The
`recent
`finding
`.fillli were more active and
`fill.a and
`toxic
`less
`racemates6B suggests that the D-enanliomer.
`
`
`
`165
`
`of each of
`
`these compounds (fill.£ and
`
`.Qfil;)_) may display even
`
`improved
`
`pharmacological
`
`properties.
`
`Third,
`
`the composite
`
`biological
`
`data
`
`suggests
`
`that
`
`stringent
`
`electronic and
`
`steric
`
`requirements exist for maximal activities. Moreover this study supports
`
`the
`
`notion
`
`that
`
`the
`
`a-carbon
`
`substituent
`
`interacts with an
`
`electrophilic site on
`
`the
`
`receptor.
`
`This
`
`scenario
`
`for biological
`
`activity can be tested.
`
`We suggest
`
`that
`
`replacement of the ring
`
`hydrogen atoms in
`
`the
`
`furan (fill.£) and pyrrole (filth) adducts by
`
`small electron-donating groups may be accompanied by an
`
`increase
`
`in anticonvulsant activity
`
`in
`
`the MES seizure
`
`test.
`
`Furthermore,
`
`we speculate
`
`that
`
`the 0-vinyl and 0-ethynyl adducts (120a-d) may
`
`be active
`
`in
`
`this biological screen.
`
`Fourth,
`
`the
`
`importance of
`
`the
`
`location of
`
`the
`
`heteroatom on
`
`the
`
`a.-substituent
`
`in
`
`the
`
`monocyclic derivatives
`
`fillg_ and filtb. has not been adequately
`
`addressed. This information should be accessible by comparing
`
`the
`
`biological data of 120e-g with those already obtained for the
`
`furan
`
`derivative 69a .
`
`the
`
`pyrrole
`
`adduct
`
`fillQ
`
`and
`
`the
`
`two
`
`thienyl
`
`compounds filk and filill.
`
`0
`
`R
`
`~~~'-./Ph
`
`~: R = OCH=cH,
`~: R = CHpCH=CH,
`~=R:OC=oCH
`ft: R = CH,oc:cH
`
`120
`
`-
`
`e:R: n
`~=R=Q
`
`'(N)l
`l
`
`H
`
`
`
`REFERENCES
`
`Wilder, B.J.; Bruni, J. Seizure Disorders: A Pharmacological
`Approach to Treatment; Raven Press: New York, 1981.
`
`Hauser, W.A.; Kurland, L.T. Epilepsia . 1975, 16, 1-66.
`
`Sprinks, A.; Waring, W.S. Progress
`1963, 3, 261 - 331.
`
`in Medicinal Chemistry
`
`Swinyard, E.A. Adv. Neurol. 1980, 27, 1 - 9.
`
`Vida, J.A. Anticonvulsants, Medicinal Chemistry, A Series of
`Monograph; Academic Press: New York, 1977; vol. · 15.
`
`Peters, A. Adv. Neurol. 1980, 27, 21 - 48.
`
`Scheibe!, A.B. Adv. · Neurol. 1980, 27, 49 - 61.
`
`Lux, H.D. Adv. Neurol. 1980, 27, 63 - 83.
`
`Ebersole, J.S.; Levine, R.A.
`266.
`
`J. Neurophysiol. 1975, 38, 250 -
`
`Delgado - Escueta, V. A. Adv. Neurol. 1980, 27, 85 -126.
`
`Prince, D.A. Exp. Neurol. 1968, 27, 155 - 167.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12. Westrum, J.; White, L.; Ward, A.J. Neurosurg. 1964, 21, · 1033 -
`1046.
`
`13. Woodbury, J.W. Basic Mechanism of
`brown: Boston, 1969.
`
`the Epilepsies;
`
`Little
`
`14.
`
`15.
`
`Somjen, G.G. Adv. Neuro/. 1980, 27, 155 - 167.
`
`Ogata, N.; Hori, N.; Katsuda, N. Exp. Neurol. 1974, 36,
`
`337 - 345.
`
`166
`
`
`
`167
`
`16.
`
`17.
`
`18.
`
`Ogata, N.; Hori, N.; Katsuda, N. Brain Res. 1976, 110, 371 -
`375.
`
`Meldrum, B.S.; Porter, R.J. Current Problems in Epl1epsy
`- New Anticonvulsant Dnigs; Jahr Libbey: London, 1986.
`
`Schlesinger, K.; Boggan, W.; Freedman, D.X. Ufe Sci. 1968,
`7. 437 - 444.
`
`19.
`
`Stone. W.E. Am. J. Phys. Med. 1957, 36, 222 - 227.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`Kilian, M.; Frey, H.H. Neuropharmacol. 1973, 12, 681 - 692.
`
`Crill, W.E. Adv. Neural. 1980, 27, 169 -183.
`
`Gastaut, H. Epilepsia 1970, 102 - 113.
`
`Penry, J.K. Adv. Neural. 1975, 11, 132-151.
`
`Purpura, D.P.; Penry, J.K.; Tower, D.B.;
`R.D. Experimental Models of Epilepsy.
`Laboratoiy Worker; Raven Press: New
`
`Woodbury, D.M.; Walter,
`A Manual for the
`York, 1972.
`
`Woodbury, D.M. Adv. Neural. 1980, 27, 249 - 303.
`
`Woodbury, D.M.; Penry, J.K.; Pippenger, C.E. Antiepileptic
`Drugs, 2nd ed.; Raven Press: New York, 1982.
`
`Toman, J.E.P.; Goodman, LS. Proc. Assoc. Res. Nerv. Ment.
`Dis. 1946, 26, 141 - 163.
`
`Goodman, LS.; Toman, J.E.P.; Swinyard, E.A. Arch. Int. Phar(cid:173)
`macodyn. Ther. 1949, 78, 144 - 162.
`
`Penry, J.K.; White, B.G.; Kupferberg, H.J.;
`(a) Krall, R.L;
`Swinyard, E.A. Epilepsia 1978, 19, 404- 428.
`(b) Coughenour, LL; Mclean, J.R.; Parker, R.B. Pharm. Bio(cid:173)
`chem. Behavior 1977, 6, 351 - 353.
`
`30.
`
`Putnam, T.J.; Merritt, M.H. Science .1937, 85, 525- 526.
`
`i-
`
`
`
`168
`
`Toman, J.E.P.; Everett, G.M.; Richards, R.K. Tex. Rep. Biol.
`Med. 1952, 10, 96 - 104.
`
`Swinyard, E.A.
`
`J. Am. Pharm. Assoc. 1949, 38, 201 - 204.
`
`Chapman, A.G.; Croucher, M.J.; Meldrum, B.S. Arzneim.
`1984, .34, 1261 - 1264.
`Forsch.
`
`Marescaux, C.; Micheletti, G.; Vergnes, M.; Depaulis, A.; Rum(cid:173)
`back, L.; Warter, J.M. Epilepsia 1984, 25, 326 - 331.
`
`Killiam, K.J.; Naquet, R.; Bert, J. Epilepsia 1966, 7, 215-219.
`
`Foye. W.O. Principles of Medicinal Chemistry; Lea and Feb(cid:173)
`iger: Philadelphia, 1981.
`
`Peterman, M.G.
`
`J.A.M.A. 1948, 138, 1012- 1019.
`
`Chen, G.; Portman, R.
`54 - 61.
`
`J. Pharmacol. Exp. Ther. 1951, 103,
`
`Richards, R.K.; Everett, G.M.
`
`Fed. Proc. 1944, 3, 39.
`
`Lennox, W.G.
`
`J.A.M.A. 1945, 129, 1069 - 1074.
`
`Everett, G.M.; Richards, R.K. J. Phann. Exp. Ther. 1944, 81,
`402 - 407.
`
`Bogne, J.Y. Br. J. Pharmacol. 1953, 8, 230 - 236.
`
`Handley, R.; Stewart, A.S.R.
`
`Lancet 1952, 1, 742- 744.
`
`Krall, R.L.; Penry, J.K.; Kupferberg, H.J.; Swinyard, E.A.
`Epilepsia 1978, 19, 393 - 403.
`
`Swinyard, E.A.; Castellion, A.W.
`1966, 151, 369 - 375.
`
`J. Pharmaco/. Exp. Ther.
`
`Theobald, W.; Kunz, H.A. Arzneim . Forsch. 1963, 13, 122 .-
`
`
`
`169
`
`125.
`
`47.
`
`48.
`
`Meunier, H.; Carraz, G.; Meunier, Y.; Eymard, P.; Aimard, M.
`Therapie 1963, 18, 435 - 438.
`
`Nardi, D.; Tajana, A.; Leonardi, A.; Pennini, R.; Portiali, F.;
`J. Med. Chem. 1981, 24, 727 -
`Magistratti, M.J.; Subissi, A.
`731.
`
`49. Walker, K.A.M.; Wallach, M.B.; Hirschfeld, D.R.
`1981. 24, 67 - 74.
`
`J. Med. Chem.
`
`50.
`
`51.
`
`52.
`
`53.
`
`54.
`
`55.
`
`56.
`
`57.
`
`58.
`
`59.
`
`Evans, R.H.; Francis, A.A.; Jones, A.W.; Smith, D.A.S.; Wat-
`Brit J. PharmacoL 1982, 75, 65 - 75.
`kins, J.C.
`
`Lippert, B.; Metcalf, B.W.; Jung, M.J.; Casara, P. Eur. J. Bio(cid:173)
`chem. 1977, 74, 441 - 445.
`
`Uno, H.; Kurokawa, M.; Natsuka, K.; Yamato, Y.; Nishimura, H.
`1976, 24, 632 - 643.
`Chem. Pharm. Bull.
`
`Uno, H.; Kurokawa, M. Chem. Pharm. Bull. 1978, 26, 312-
`313.
`
`Uno, H.; Kurokawa, M.
`
`J. Med. Chem. 1979, 22, 180-183.
`
`Yokoyama, N.; Ritter, B.; Neubert, A.D. J. Med. Chem. 1982,
`25, 337 - 339.
`
`Braestrup, C.; Nielsen, M.; Olsen, C.E. Proc. Natl. Acad. Sci.
`1980, 77, 2288 - 2292.
`
`Braestrup, C.; Schmiechen, R.; Neef, G.; Nielsen, M.; Petersen,
`E.N.
`Science 1982, 216, 1241 -1243.
`
`Neef, G.; Eder, U.; Huth, A.; Rahtz, D.; Schmiechen. R.;
`Seialman, D.
`Heterocycle 1983, 20, 1295 - 1313.
`
`Hallot, A.; Brodin, R.; Merlier, J.; Brochard, J.; Chambon, J.P.;
`J. Med. Chem. 1986, 29, 369 - 375.
`Biziere, K.
`
`~---------------·
`
`
`
`170
`
`60.
`
`61.
`
`62.
`
`63.
`
`64.
`
`65.
`
`66.
`
`67.
`
`68.
`
`69.
`
`70.
`
`71.
`
`72.
`
`73.
`
`74.
`
`Desmedt, L.K.C.; Niemegeers, C.J.E.; Janssen, P.A.J. Arzneim.
`Forsch. 1975, 1408- 1413.
`
`Dagani, R. Chem. Eng. News 1986, Sept. 23 - 25.
`
`Ferendelli, J.A.; Kupferberg, H.J. Adv. Neurol. 1980, 27,
`587 - 596.
`
`Godin, Y.; Heiner, L.; Mark,. J~; Mande.I, P.
`1969, 16, 869 - 873.
`
`J. Neurochem.
`
`Saad, S.F.; El Masry, AM.; Scott, P.M. Eur. J. Pharmacol.
`1972, 17, 386 - 392.
`
`Sawaya, M.C.B.; Horton, R.N.; Meldrum, B.S. Epilepsia 1975,
`16, 649 - 655.
`
`Camerman, A.; Camerman. N. Science 1970, 168, 1457 - 1458.
`
`Camerman, A.; Camerman, N. Adv. Neurol. 1980, 27, 223 -
`232.
`
`Conley, J.D.; Kohn, H;
`
`J. Med. Chem. 1987, 30, 568 - 574.
`
`Callery, P.S.; Geelhaar, L.A.; Nayar, M.S.B.; Stogniew, M.;
`Rao, K.G.
`J. Neurochem. 1982, 38, 1063-1067.
`
`Meldrum, B.S.; Chapman, A.G. Neural. Neurobio/.
`625 - 641.
`
`1983, 7,
`
`Mac Bean, R.P.J. Nature 1981, 291, 593 - 595.
`
`De Freudis, F.V.; Mandel, P.
`Chichester, 1981.
`
`Amino Acid Transmitters; Wiley:
`
`Spero, L.
`
`Lancet 1982, 1319 - 1322.
`
`Meldrum, B.S.; Croucher, M.J.; Czuczwar, J.F.; Collins. K.;
`Curry, K.;
`Joseph, M.; Stone, T.W. Neuroscience 1983, 9,
`
`,-l
`
`' -
`
`~
`
`-\
`
`•.
`
`'
`
`
`
`1.71
`
`925. 930.
`
`75.
`
`76.
`
`77.
`
`78.
`
`79.
`
`80.
`
`81.
`
`82.
`
`83.
`
`84.
`
`85 .
`
`86.
`
`87.
`
`Croucher, M.J.; Meldrum, B.S.; Collins, J.F. Neuropharmaco!ogy
`1984, 23, 467. 472.
`
`Davies, J.; Evans, R.H.; Francis, A.A.; Jones, A.W., Walkins,
`J.C. J. Neurochem. 1981, 36, 1305 • 1307.
`
`Collins, J.F.; Dixon, A.J. : De Sarrov, G.; Chapman, A.G.; Hart,
`G.P.; Meldrum, B.S. Neurosci. Lett.
`1984, 51, 371 • 376 ..
`
`Perkins, M.N.; Stone, T.W. Brain Res. 1982, 247, 184-187.
`
`Foster, A.C.; Vezzani, A.; French, E.D.; Schwarcz, R. Neurosci.
`Lett 1984, 478, 273 · 278.
`
`Peet, M.J.; Leah, J.D.; Curtis, D.R.
`83. 95 .
`
`Brain Res. 1983, 266,
`
`Jones, A.W.; Smith, D.A.S.; Watkins, J.C. Neuroscience 1981,
`13, 573. 578.
`
`Stone, T.W.; Perkins, M.N.; Collins, J.F.; Curry, K. Neuro(cid:173)
`science 1981, 6, 2249 - 2252.
`
`Croucher, M.J.; Collins, J.F.; Meldrum, B.S.
`216, 899-901.
`
`Science 1982,
`
`Turski, L.; Meldrum. M.N.; Jones, A.W.; Watkins, J.C. Eur. J.
`Pharmaco!. 1985, 111, 279- 283.
`
`Croucher, M.J.; Meldrum, B.S.; Jones, A.W.; Watkins, J.C. Brain
`Res 1984, 322, 111 -118.
`
`Turski, L.; Meldrum, B.S.; Collins, J.F.
`336, 162 - 166.
`
`Brain Res. 1985,
`
`Christophe, J.; Kurzner, R.; Ngoc Diem, N.; Damien, C.; Chat-
`elain, P.; Giller, L.
`Life Sci. 1983, 33, 533 - 541.
`
`. ~:
`
`. ~-·
`
`,.
`
`f-
`•
`. '\:
`. -1
`
`fr
`;
`
`
`
`172
`
`88.
`
`89.
`
`90.
`
`Krosgaard-Larsen, P.; Scheel-Kruger, P.; Kofod, H. GABA(cid:173)
`Neurotransmittf]rs; Munksgaard: Copenhagen, 1979.
`
`Galzigna, L.; Garbin, L.; Bianchi, M.; Marzotto, A. Arch.
`i 978, 235, 73 - 85.
`Pharmacodyn.
`
`Int.
`
`Tunicliff, G.; Ngo, T.T.; Barbeau, A. Experientia 1977, 33,
`20-22.
`
`91.. .
`
`Johnston, G.A.R.; Krosgaard-Larsen, P.; Stephenson, A.L.;
`Twitchin, B.
`J. Neurochem. 1976, 26, 1029 - 1032.
`
`92.
`
`93.
`
`94.
`
`95.
`
`96.
`
`97.
`
`98.
`
`99.
`
`Johnston, G.A.R.; Krosgaard-Larsen, P.; Stephenson, A.L.;
`Nature 1975, 258, 627 '628.
`
`Krosgaard-Larsen, P.; Johnston, G.A.R.; Lodge, D.; Curtis, D.R.
`Nature 1977, 268, 53 - 55.
`
`Ronquist, G.; Agren, G.; Ponten, J.; Westermark, B.
`1976, 89, 433 - 439.
`Physiol.
`
`J. Cell
`
`Scheechter, P.J.; Traner, Y.; Yung, M.J.; Sjoerdsma, A.
`Pharmacol. Exp. Ther. 1977, 201, 606 - 612.
`
`J .
`
`Scheechter. P.J.; Traner, Y.; Yung, M.J.; Bohlen, P. Eur. J.
`Pharmaco/. 1977, 45, 319 - 328.
`
`Lippert, B.; Metcalf, B.W.; Jung, M.J.; Casara, P. Eur. J.
`Biochem. 1977, 74, 441 - 445.
`
`Brennan, M.J.W.; Cantril!, R.C. Nature 1979, 280, 514 - 515.
`
`Johnston, G.A.R.; Curtis, D.R.; Beart, P.M.; Game, C.J.A.;
`McCulloch, R.M.; Twitchin, B.
`J. Neurochem. 1975, 24,
`157 - 160.
`
`100. Thorne, D.E. U.S. Patent 3,657,341, granted April 18, 1972.
`Chem. Abst. 1972, 72, P 55885j.
`
`!
`i· •
`
`t
`i
`
`I\
`.'$,
`1-:
`1:·
`
`' ..
`
`
`
`173
`
`101. Takahashi, T.; Ogiu, K.; Fujimura, H.; Satoda, I.; Fukui, T.;
`Yamamoto, Y. Swiss Patent 393,355, granted October 30,
`1965. Chem. Abst.1966, 59, P 8660h.
`
`102. Cortes, S.; Liao, Z.K.; Watson, D.; Kohn, H. J. Med. Chem.
`1985, 28, 601 - 606.
`
`103. Conley, J. D. Thesis, University of Houston - University Park,
`Houston, 1986.
`
`104. Kohn, H.; Conley, J.D. (Unpublished results).
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
