Anticonvulsant Properties of N-Substituted a,a-Diamino Acid Derivatives
`
`l
`I
`I
`I
`I
`I
`
`HAROLD KOHNtx, KAILASH N. SAWHNEYt, DAVID W. ROBERTSON~§, AND J. DAVID lEANDERt
`
`Received April 19, 1993, from the tDepartment of Chemistry, University of Houston, Houston, TX 77204-5641,
`IUffy_ Re_search Laboratories, Eli Ul/y and Company, Ul/y Corporate Center, Indianapolis, IN 46285.
`Accepted for
`pubhcat1on November 24, 1993111
`§Current address: Ugand Pharmaceuticals, 9393 Towne Center Dr., Suite 100,
`•
`San Diego, CA 92121.
`
`Abstract D Recent studies have demonstrated that functionalized
`a,a-diamino acids (1) display excellent activity when evaluated in the
`maximal electroshock seizure (MES) test in mice. The synthesis and
`pharmacological evaluation of 14 select analogues within this series
`of compounds are detailed. Included in this survey were 10 N-acyl
`derivatives in which the basic C(a) N-group in 1 was replaced by a
`neutral N-substituent and four dipeptides where the amino acid fusion
`point was the a-carbon site. N-Acylation of 1 led to decreased
`anticonvulsant activity. The importance of these findings in relation
`to the requirements of the C(a) substituent for anticonvulsant activity
`in 1 are briefly discussed.
`
`~, ,rfl
`N
`I
`1
`RNH-C-C-ff
`I
`I
`H 0
`
`.1
`
`0
`rf
`0
`I
`I
`I
`CH3CNH- CH- CNHCH2Ph
`
`I
`I
`I
`l
`I
`I
`
`Introduction
`
`Recent studies have shown that a,a-diamino acid derivatives
`(1) and related compounds are surprisingly stable and readily
`accessible materials.l-S Moreover, we have demonstrated that
`a-amino, a-hydrazino, and a-N-hydroxylamino adducts display
`excellent anticonvulsant activity when evaluated in the maximal
`electroshock seizure (MES) test in mice.s For example, the
`median effective dose (ED50) values after intraperitoneal injection
`for the a-N-ethylamino (2a) (42.4 mg/kg) and a-N2-(benzyloxy(cid:173)
`carbonyl)hydrazino (2b) (55.6 mg/kg) derivatives approached
`the ED50 of phenobarbital& (21.8 mg/kg), whereas the EDsoS of
`the a-methoxyamino (2c) (6.2 mg/kg) and the a-[(methoxy(cid:173)
`methyl)amino] (2d) (6.7 mg/kg) adducts exceeded the ED50 of
`phenytoin6 (9.5 mg/kg). Both 2c and 2d exhibited these potent
`anticonvulsant effects at doses much lower than those which
`produced neuromotor impairment on the horizontal screen (HS)
`test (46.0 and 50.5 mg/kg were the ED50 doses for 2c and 2d on
`the HS test). 5 These fmdings prompted our investigation of the
`pharmacological activity of the racemic N-substituted a,a(cid:173)
`diamino acid derivatives (2e-r) (Table 1). TheN-acyl derivatives
`(2e-n) were evaluated to determine the effect of conversion of
`thebasicC(a)-aminogroupin2a-dtoaneutralC(a)-carbamate
`(2e, 2f), urea (2g-2i), thiourea (2j, 2k), amide (21, 2n), or suc(cid:173)
`cinimide (2m) substituent on anticonvulsant activity. Also
`included in our study were the unique dipeptides 2o-r, where
`the amino acid fusion point was the a-carbon site.
`
`Experimental Section
`
`Chemical Methods-Melting points were determined with a Thomas(cid:173)
`Hoover melting point apparatus and are uncorrected. Infrared spectra
`(ffi) were run on a Perkin-Elmer 1330 and 283 spectrometers and
`calibrated against the 1601-an-1 band of polystyrene. Absorption values
`are expressed in wavenumbers (cm-1). Proton (lH NMR) and carbon
`(l3(; NMR) nuclear magnetic resonance spectra were taken on Nicolet
`NT-300andGeneralEiectricQE-300NMRinstruments. Chemicalshift.s
`(a)areinpartspermillion(ppm)relativetoMe~iandcouplingconstants
`(Jvalues) are in hertz. Low-resolution mass spectra (MS) were rerorded
`at an ionizing voltage of 70 e V from a Varian MAT CH-5 spectrometer
`attheLillyResearchLabo~tories. MicroiUWyseswereprovidedbythe
`
`• Abstract published in Advance ACS Abstrocts, February 1, 1994.
`
`@ 1994, ATnerican Ch6mlcal Society and
`.• American Pharrnacsutical Association
`
`11 rf = NHC{O)CH2NHC(O)OC!¥'h
`a rf = NHCH~(O)OCH3
`Q rf = NHCH~(O)OCt¥:tfa
`a rf • NHCH~(O)oety>h
`r RZ-'NH~~w
`S rf-N~
`1 rf-Br
`u rf • ~(Ctfah, BF 4-
`X rf • NHC(O)Ctfa
`lilt rf • NHC(O)CF3
`
`Zil ~ = NHCH2CH3
`tl rf = NHNHC~~Ph
`.c rf = NH(OC~
`d rf,.N(C~Ha
`.11. rf • NHC(O)OCHa
`1 rf = NHC(O)OPh
`Q rf = NHC(O)NHCH3
`h rf • NHC(O)NHPh
`i rf • NHC(O)NHS(QVPh
`j rf • NHC(S)NHCH3
`k rf = NHC(S)NHPh
`1 rf .. NHC(O)Ph(2'C~)
`0
`
`mrf·N)
`
`0
`
`Physical Chemistry Department of the Lilly Research Laboratories. All
`compounds gave satisfactory elemental analyses {C, H, N> that were
`within :1:0.4% of theoretical values. Thin-and thick-layer chromatog(cid:173)
`raphy were run on precoated silica gel GHLF microscope slides (2.5 X
`10 em; Analtech No. 21521) or silica gel GHLF (20 X 20 em; Analtech
`11187).
`Chemical Synthesis-General Proeedure for the Synthesis of
`Functionalized Amino Acid Derivatives 2e-k-A tetrahydrofuran
`{THF) solution containing 285 and either the aeylating agent (1.06-LIO
`equiv) and triethylamine (1.20 equiv) or the isocyanate (isothiocyanate)
`(1.(}--1.1 equiv) was heated. The reaction was then filtered to remove
`any salts formed and purified, and the product was recrystallized if
`necessary. The reaction temperatures, times, and recrystallization
`solvents (if appropriate) were as follows: (2e) ~ •c, 2 h, EtOH; (2t)
`45-50 •c, 2 h, MeOH; (2g) 45-50 •c, 2 h, MeOH; (%h) 45--50 •c, 2 h;
`(2i) 50-55 •c, 22 h; {2j) 65 •c, 4 h, EtOH; (2k) 65 •c, 3 h, EtOIL
`Synthesis of 1\t[Acetamido(benzylcarbamoyl)methyl]phthalamic
`Acid (21). To a warm pyridine solution (7.0 mL) containing 2s (0.63
`g, 2.83 mmol) was added phthalic anhydride (0.43 g, 2..87 mmol), and
`the reaction was stirred at 5(H)5 •c (5 h). Pyridine was removed by
`distillation in vacuo and the residue was treated with H:z() (20 mL). The
`aqueousmixturewasextractedwithEtOAe(2X20mL)andthenacidified
`with aqueous 1 N HClsolution. The white solid (0.70 g, 70%) that
`precipitated was filtered, washed withH:z() (10mL},anddried;mp 186-:-
`188 ·c.
`·
`Synthsisof2-Acetamido-N-bellzyl-%-(1\tsuceinimidyl)aeetamlde
`(2m). A cooled (-78 "C) THF solution (150 mL> of %15 {prepared from
`2-acetamido-N-benzyl-2-ethozyaceta:mide7.S(2..00g,8.0mmol)andBBrs
`(2..51 g, 10.05 mmol)} was added slowly into a cooled {-:78 •C) THF.
`suspension (50 mL) of sodium suecinimide (3.06 g, 25.25 mmol). The
`
`IPR2014-01126- Exhibit 1026 p. 1
`
`

`
`reaction mixture was stirred at-78 "C (30 min) and at room temperature
`(90 min), and then treated with a 10% aqueous citric acid solution (50
`mL). The resulting solution was neutralized with a saturated aqueous
`NaHC03 solution, and the reaction mixture extracted with EtOAc (3 X
`100 mL). The combined extracts were dried (Na2S04), and the volatile
`materials were removed by distillation in vacuo. The residue was purified
`by flash column chromatography on Si02 gel (6% MeOH/CHCla) to give
`1.10 g (45%) of 2m; mp 181-183 "C (recrystallized from EtOH).
`Synthesis of N·(Benzyloxy)-N-[acetamido(benzylcarbamoyl)(cid:173)
`methyl]malondiamide (2n). 4-Methylmorpholine (0.35 g, 3.56 mmol)
`was added to a solution of N-CBZ.glycine (0.74 g, 3.55 mmol) in THF
`(75 mL) at -10 to -15 "C. The solution was stirred (5 min), and then
`isobutyl chloroformate (0.49 g, 3.55 mmol) was added and the mixture
`was stirred for an additional20 min. A cooled (-10 "C) solution of 2s
`(0.79 g, 3.55 mmol) in THF (125 mL) was then added slowly (30 min).
`The reaction mixture was stirred at this temperature (2 h) and then at
`room temperature (2 h). The insoluble materials were flltered, and the
`flltrate was concentrated in vacuo. The residue was triturated with
`EtOAc (20 mL) and the white solid (0.60 g) that remained was flltered,
`washed with H20, and dried to give 2n. The initial insoluble material
`on trituration with H20 gave an additional 0.40 g of2n to give a combined
`yield of 1.00 g (68% ); mp 177-179 "C (recrystallized from EtOH).
`Synthesis of Methyl N-[Acetamido(benzylcarbamoyl)methyl](cid:173)
`glycinate (2o). A methanolic solution (50 mL) containing 2n5 (1.00 g,
`2.85 mmol) and methyl glycinate (prepared from methyl glycinate
`hydrochloride (1.01 g, 8.55 mmol), and NaOMe (0.38 g, 7.10 mmol)) was
`heated to reflux (2 h). The reaction was concentrated in vacuo to give
`an oily residue that was purified by flash column chromatography on
`Si02gel (3% MeOH/CHCla) togive0.60g (72%) of2o;mp 144-146 "C
`(recrystallized from EtOAc).
`Synthesis of Ethyl N-[Acetamido(benzylcarbamoyl)methyl](cid:173)
`glycinate (2p). A methanolic solution (70 mL) containing 2n5 (1.50 g,
`4.28 mmol) and ethyl glycinate [prepared from ethyl glycinate hydro(cid:173)
`chloride (3.10 g, 22.2 mmol) and NaOMe (1.17 g, 21.7 4 mmol)] was heated
`to reflux (2 h). The reaction was concentrated in vacuo to give an oily
`residue that was purified by flash column chromatography on Si02 gel
`(5% MeOH/CHCia> to give 0.60 g (46%) of 2p; mp 125-127 "C
`(recrystallized from EtOAc).
`Synthesis of Benzyl N-[Acetamido(benzylcarbamoyl)methyl](cid:173)
`glycinate (2q). A suspension of benzyl glycinate hydrochloride (5.00
`g, 24.8 mmol) in THF (400 mL) containing EtaN ( 4.90 g, 48.5 mmol) was
`stirred (4 h) at room temperature. The reaction mixture was cooled
`(-78 "C) and then a cooled (-78 "C) THF solution (150 mL) of 2t5
`[prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide7.B (4.00 g,16.0
`mmol) and BBra (1 Min CH2Cl2. 20.0 mL, 20.0 mmol)] was added (30
`min). The reaction mixture was stirred at -78 °C (30 min) and then at
`room temperature (16 h). The insoluble materials were flltered, the
`flltrate was concentrated in vacuo, and the residue was purified by flash
`column chromatrgraphy on Si02 gel (3% MeOH/CHCla) to give 1.56 g
`(26%) of2q as a white solid; mp 133-135 °C (recrystallized from EtOH).
`Synthesis of N-[Acetamido(benzylcarbamoyl)methyl]glycine
`(2r). A solution of methyl N-[acetamido(benzylcarbamoyl)methyl](cid:173)
`glycinate (2o) (0.60 g, 2.05 mmol) and KOH (0.30 g, 5.36 mmol) in 90%
`aqueous EtOH (50 mL) was stirred at room temperature (48 h). The
`volatile materials were then removed in vacuo, and the residue dissolved
`in H20 (10 mL). The aqueous solution was extracted with EtOAc (2 X
`20 mL}, and the aqueous layer was acidified to pH -2.0 with aqueous
`1 N HCL A column containing ion-exchange resin Dowex SOX W 4 was
`prepared using 10% aqueous pyridine. The column was thoroughly
`washed with HaQ. The acidic aqueous reaction solution was added to
`the top of the column, and the column was eluted with H20 (300 mL
`or until the eluate was neutral). The column was then eluted with 10%
`aqueous pyridine (400 mL). The aqueous pyridine fraction was
`concentrated in vacuo to give a white solid, dried in vacuo and then
`triturated with absolute EtOH (7 mL) •. The insoluble materials that
`... remained were filtered and dried togive0.29 g (50%) of2r;mp 124-126
`.·· "Cdec..
`· PharmaeologicalEvalnation-All tests were performed with male
`, ., . CF~1 mice from Charles River Breeding Laboratories (Portage, Ml). All
`· · ' cOmpounds were dissolved in 30% poly( ethylene glycol) 400 and
`·
`· administered in an injection volume ofl mL/100g ofbodyweight.Initial
`;/ . ·. anticonvulsant evaluation of :e-:r was conducted with two dose levels
`·• (30,100mg/kg}adminiSteredintraperitoneally. Four mice at each dose
`·· level were tested at0.5,1, and 4 h after administration, unless otherwise
`£;·:·intliiea·te.din ':['able 1, to determine if there was protection against MES
`
`._ ··';'
`
`Table 1-Physlcal and Pharmacological Data In Mice for
`NSubstHuted a,a-Diamlno Acid Derlvatlves-
`o
`fi!
`0
`II
`I
`II
`CH3CNH- CH- CNHCH2Ph
`
`No.
`
`R2
`
`mpb
`
`MEScED50
`
`NHC(O)OCH3
`
`202-204
`
`NHC(O)OPh
`NHC{O)NHCH3
`NHC{O)NHPh
`NHC(O)NHS(02)Ph
`NHC{S)NHCH3
`NHC{S)NHPh
`NHC(O)Ph(2' -C02H)
`
`201-203
`229-230
`242-244
`188-191
`162-163
`196-197
`186-188
`181-183
`
`NC(O)CH2CH2C(O)
`NHC{O)CH2NHC(O)OCH2Ph 177-179
`144-146
`NHCH2C(O)OCH3
`125-127
`NHCH2C(O)OCH2CH3
`133-135
`NHCH2C(O)OCH~h
`124-126
`+NH~H2C02-
`
`2e
`
`2f
`2g
`2h
`21
`21
`2k
`21
`2m
`
`2n
`2o
`2p
`2q
`2r
`phenytoin'
`
`phenobarbital'
`
`valproate'
`
`48.0
`(37.7-56.7)
`>100
`>100
`>100
`>100
`>100d
`>100d
`>100
`>100
`
`"'30"
`>100
`>100
`>100
`>10Qd
`9.5
`(8.1-10.4)
`21.8
`(15.0-22.5)
`272
`(247-338)
`
`8 The compounds were administered intraperitoneally. ED50 values
`are in milligrams per kilogam. Numbers in parentheses are 95%
`confidence intervals. A dose-response curve was generated for all
`compounds that displayed sufficient activity. The dose-effect data
`for these compounds were obtained at 0.5 h ("time of peak effect").
`b Melting points (0 C) are uncorrected. c MES =maximal electroshock
`seizure test. All compounds were suspended in 30% PEG. d The
`compound was tested only at 0.5 and 1 h due to insufficient supply
`of sample. "Unable to definitively define an E050 value and confidence
`limits because of insufficient supply of sample. 'Reference 6.
`
`MES seizures were elicited by electrical current (ac, 60 cps, 50 mA,
`0.2 s) applied via corneal electrodes. A drop of 0.9% saline was instilled
`on each eye prior to application of the electrodes to ensure electrical
`contact. Abolition of the hind limb tonic extension component of the
`seizure was deimed as protection in the MES test. This is the identical
`protocol used by the Antiepileptic Drug Development Program of the
`Epilepsy Branch of NlNCDS, NIH.6.9
`After the time of peak anticonvulsant activity and the approximate
`dose range were determined, a dose-response curve was generated at
`the time of peak activity with at least three or four doses and 1o-12 mice
`per dose. TheMES EDso is the calculated dose required to protect 50%
`of the mice in the MES test. For those compounds with significant
`anticonvulsant activity, the doses that caused neuromotor impairment
`on the horizontal screen (HS) test also were determined. to Previously
`trainedmiceweredosedwiththecompoundandthenplacedindividually
`on top of a square (13 X 13 em) wire screen which was mounted on a
`vertical rod. The rod was rotated 180°, and the number of mice that
`returned to the top of the screen in one minute were counted.
`
`ResuHs and Discussion
`
`Chemistry-Several preparative routes were utilized for the
`construction of the targeted compounds. In most cases, 2-ac·
`etamido-N-benzyl-2-aminoacetamideS (2s) served as the starting
`material Treatment of 2s With the appropriate chloroformate,
`isocyanate, isothiocyanate, or anhydride, or use of the mixed
`anhydride protocol advanced for peptide synthesis, u led to the
`preparation of the N-acyl substituted adducts 2e-l and 2n.
`.Correspondingly, the preformed a-bromo derivatiVeS: 2t. was
`
`IPR2014-01126- Exhibit 1026 p. 2
`
`

`
`Table 2-Key Spectral Properties of ~ubstHuted a,a-Diamlno
`Acid Derivatives
`
`R2 0
`0
`I
`•
`u
`CH3CNH-CH-CNHCH~h
`a
`
`1HNMRI>
`
`13C NMRC
`
`No.
`
`IR•
`
`CaH
`
`CH2Ph
`
`2e 1650
`1630, 1700
`2f
`2g 1630
`2h 1600 (br)
`1630 (br)
`21
`1620
`21
`2k 1620
`1620 (br)
`21
`2m 1620 (br)
`2n 1640 (br)
`2o 1610,1710
`2p 1600, 1710
`2q 1620, 1710
`2r 1630
`
`5.56 (t, 7.8) 4.27 (d, 5.6)
`5.66 (t, 7.6) 4.29-4.35 (m)
`5.59 (t, 7.8) 4.26 (d, 5.8)
`57.92 157.30
`5.67 (t, 7.6) 4.30 (d. 5.9)
`57.59 153.98
`5.47 (t, 7.7) 4.24 (d, 5.7)
`57.14 150.36
`6.10 (br, s) 4.27 (d, 5.8)
`61.33 -II
`5.24 (t, 6.9) 4.32 (d. 5.8)
`61.18 180.02
`5.92 (t, 7.2) 4.36 (d. 6.0)
`57.44 _Jt
`6.31 (d, 9.0) 4.23-4.36 (m) 55.19 176.33
`5.79 (t, 7.7) 4.28 (d. 5.8)
`56.77 167.86
`5.00 (t, 7.8) 4.28 (d. 6.0)
`63.98 46.09
`5.01 (t, 8.2) 4.28 (d, 5.8)
`63.96 46.22
`5.02 (t, 8.2) 4.27 (d. 6.1)
`63.94 46.22
`4.98 (d. 8.2) 4.29 (d. 5.7)
`64.08 47.48
`
`CaH CaNRC
`58.57 __.
`58.69 _,
`
`MSd
`
`279
`341
`279
`340
`405
`294
`356
`370
`3041
`413
`294
`342
`370
`-1
`
`• Infrared spectra were taken with KBr discs and values are reported
`in cnr 1• b All spectra were recorded with DMSO-de. The number in
`each entry is the chemical shift value (~) observed in ppm relative to
`DMSO-!fe, followed by the multiplicity of the signal and the coupDng
`constant in hertz. 1H NMR spectra were recorded at 300 MHz. c 13C
`NMR spectra were obtained at 75 MHz and the values referenced to
`DMSO-c:fe. d All spectra were recorded using FD-MS unless otherwise
`indicated. Molecular ions reported refer to either M+ or W + 1 ions.
`• The carbamate carbonyl carbon resonance was not detected. The
`attached NHC(O)O~ signal was observed at o 51.46. 'The carbamate
`carbonyl carbon resonance was not detected. The attached
`NHC(O)CeH5 signals were observed at o 121.70, 125.18, 129.30, and
`150.91. gThe thiocarbonyl carbon resonance was not detected. The
`attached NHC(S)NHQ-13 signal was observed at o 30.92. h The amide
`carbonyl resonance could not be readily assigned. Signals corre(cid:173)
`sponding to four carbonyl peaks were observed at o 167.85, 167.93,
`168.48, and 169.47. 'Value refers toW+ 1 ion observed by FAB(cid:173)
`MS. I Spectrum was not taken.
`
`employed as the immediate precursor for 2m and 2q, while
`2-acetamido-N-benzyl-2-(trimethylammonio)acetamide tetraflu(cid:173)
`oroborateS (2u) was utilized for the synthesis of2o and 2p. Finally,
`alkaline hydrolysis of 2o, followed by neutralization of the
`dipeptide by passage through an ion-exchange resin yielded 2r.
`Key spectral data (i.e., ffi, tH NMR, l:JC NMR, MS) observed
`for 2e-r are recorded in Table 2 and were consistent with both
`the proposed structures and previously reported trends.5
`Pharmacological Evaluation-The N-substituted a,a-di(cid:173)
`amino acid derivatives 2e-r were tested for anticonvulsant
`activity by using the procedures described by Krall et al.,9 which
`have become standard testing procedures for the Antiepileptic
`Drug Development Program of the Epilepsy Branch of the
`National Institutes of Health. All compounds were administered
`intraperitoneally (ip) to mice. Table llists the median effective
`dose (ED50) values required to prevent seizures in theMES test
`by racemic 2.. Inspection of the results revealed several important
`observations. First, most of the N-acyl substituted derivatives
`(2e-n) evaluated were inactive in theMES test at doses of 100
`mg/kg or less, and all were significantly less potent than 2c and
`2d. Only 2e and 2n displayed noticeable activity. One note(cid:173)
`worthy difference about the anticonvulsant effect of 2n is that
`it also produced neuromotor impairment on the HS test at the·
`same doses that blockedMES seizures. Thus. this anticonvulsant
`effect is qualitatively different than that previously seen with
`2c and 2d.5 These findings were of interest since the N-acyl
`
`derivatives 2e-n, unlike 2a-d, are not protonated at physiological
`pH values, thereby demonstrating that replacement of the basic
`C(a)-amino group in functionalized amino acids 2a-d by the
`neutral C(a) N-substituents in 2e-n did not lead to improved
`anticonvulsant activity. This observation was consistent with
`results previously obtained for two other N-acyl derivatives, 2,2-
`diacetamido-N-benzylacetamide (2v) and 2-acetamido-N-benzyl-
`2-(trifluoroacetamido)acetamide (2w).5 Both 2v and 2w did
`not prevent maximal electroshock seizures at doses of 100 mg
`or less. Of the two active N-acyl derivatives, 2n can also be
`viewed as a functionalized dipeptide as well as an N-acyl a,a(cid:173)
`diamino acid adduct. Previously, we prepared and evaluated
`functionalized dipeptides 3 and 4.11 These compounds differed
`
`w TH3 w w
`
`CH3CNH-cH-CNHCH~NHCH~h
`
`w w TH3 w
`
`CHaCNHCH2CNH-cH -CNHCH~h
`
`from 2o-r in that the two amino acid units were joined through
`an amide bond. Both 3 and 4 were inactive in both the maximal
`electroshock and subcutaneous pentylenetetrazole seizure test;s6.9
`when administered to mice at dose levels up to and including
`600 mg/kg.12
`
`Conclusions
`
`The composite data indicated that most structural modifi(cid:173)
`cations at the a-amino site in functionalized a,a-diamino acids
`led to a decrease in the anticonvulsant activity after intraperi(cid:173)
`toneal administration to mice when compared to the simple
`N-ethylamino adduct 2a,s while none of the compounds ap(cid:173)
`proached the superior activity observed for the N-hydroxylamino
`derivatives 2c and 2d. 5 These results documented that excellent
`protection against MES-induced sei2ures by 1 can be achieved
`by incorporation of a basic C(a)-amino substituent.
`
`References and Notes
`
`1. Katritzky, A. R; Urogdi, L.; Mayence, A. J. Chem. Soc .. Chem.
`Commun. 1989,337-338.
`2. Katritzky, A. R; Urogdi, L.; Mayence, A. J. Org. Chem. 1990, 55,
`2206-2214.
`.
`3. Bock, M.G.; DiPardo, R M.; Freidinger, R M.J. Org. Chem.l986,
`51, 3718-3720.
`4. Fischer, B.; Hassner, A. J. Org. Chem. 1990, 55, 5225-5229.
`5. Kohn, H.; Sawhney, K. N.; LeGall, P.; Robertson, D. W.; Leander,
`J. D. J. Med. Chem. 1991, 34, 2444-2452.
`6. Porter, R J.; Cereghin?, J. J.; G~dding, G. D.; Hessie, ~· J.;
`Kupferberg, H. J.; Scovllle, B.; White, B. G. Cleveland Clin. Q.
`1984, 51, 293-305.
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`Acknowledgments
`
`We thank Dr. Dennis Zimmerman, Dennis Thompson, and H. Lawson
`(Lilly Research Laboratories) for theiussistance. · ·
`·
`
`Jct.mal of Pbsrmaceutlcal S<:/enCBIJ/6t1·
`VoL 83. No. .s. May .1994
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`IPR2014-01126- Exhibit 1026 p. 3