Vet.
`
`DateS
`Not to
`
`]ourrtal of
`MEDICINAL AND
`PHARMACEUTICAL CHEMISTRY
`
`f'
`
`Volume 5,
`1962
`
`ALFHED BUHUEH, EDITOH
`
`EDITORIAL ADVISOBY B011llD
`
`JULIUS AXELROD
`
`E. E. CAMPAIGNE
`
`DAVID PRE::>SMAN
`
`ARNOLD H. BECKE'l'T
`
`JACKSON P. ENGLI:::iH
`
`HENRY RAPOPOR1'
`
`BERNARD BELLEAU
`
`KENNE1'H E. HAMLIN
`
`EDWARD E. ~MI:::iSMAN
`
`BEH.NARD B. BRODIE
`
`H. F. HAH.DMAN
`
`J. J. BURNS
`
`RoY HERTz
`
`c. CHES'l'ER ~'l'OCK
`
`E. c. TAYWR
`
`EAS'l'ON, PA.
`
`MAcK PRINTING CoMPANY
`1962
`
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`

`
`Journal of
`IVIEDICINAL AND PHARMACEUTICAL
`CHEMISTRY
`
`Volume 5, Number 1
`
`© Copyright 1962 by the
`American Chemical Society
`
`January 6, 1962
`
`Potential Anticancer Agents. 1 LXIL
`The Rei a tionship of Chemical Structure to
`Antileukemic Activity with Analogs of l-Methyl-3-
`nitro-l-nitrosoguanidine (NSC-9369). II
`
`KAR.EN A. HYDE, EDWARD AcToN, W. A. SKINNER,
`LEON GooDMAN, .JosEPH GREENBERG, AND B. R. BAKER
`
`Life Sciences Division, Stanford Research Instit1de, ~Menlo Park, California
`
`Received May 29, 1961
`
`In a continued investigation of the relationship of structure to antileukemic
`activity of 1-methyl-3-nitro-1-nitrosoguanidine
`(NSC-9369), an aclclitional
`eight nitroso amides bearing an N-(2-substituted ethyl) group were synthesized
`and evaluated against Leukemia L-1210. The most effective analog was found
`to be 1-(2-chloroethyl)-1-nitrosourea (NSC-47547).
`
`The first paper 2 on analogf3 of 1-methyl-3-nitro-1-nitrosoguanidine
`(I) (NSC-9369) 3 described Phases I and II of the structure-activity
`study. It was clear that the 2-chloroethyl analog (II) and the 2-hro(cid:173)
`moethyl analog (III) were superior to the originally discovered lead
`(I).
`In this first paper were also posed the following questions:
`Are other 2-substituted ethyl analogs even more effective than II
`(1) This program is carried out under the auspices of the Cancer Chemotherapy National
`Service Center, National Cancer Institute, National Institutes of Health, Public Health Service,
`Contract No. SA-43-ph-1892. The opinions expressed in this paper are those of the authors and
`are not necessarily those of the Cancer Chemotherapy National Service Center. For the preced(cid:173)
`ing paper in this series, see E. J. Reist, J. H. Osiecki, L. Goodman, and B. R. Baker, .J. A.m.
`Chem. Soc., 83, 2208 (1961).
`(2) W. A. Skinner, H. F. Gram, M. 0. Greene, .J. Greenberg and B. R. Baker, J. J1ed. Pharm.
`Chem., 2, 299 (1960).
`(3) The NSC accession numbers used in this paper were assigned by the Cancer Chemo(cid:173)
`therapy National Service Center.
`
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`
`Penetration of Brain and Brain Tumor by Aromatic
`Compounds as a Function of Molecular
`2
`Suhstituents. 111 1
`
`•
`
`A. H. SoLoWAY, B. WHITMAN, AND J. R. MESSER
`
`Neurosurgical Serm·ce of the Massachusetts General Hospital and the Harvard
`~Medical School, Boston, ~Mass.
`
`Received June 15, 1961; Revised llfanuscript Received October 11, 1961
`
`To a great extent there is a correlation between high aqueous/lipid solvent
`partition coefficients of a series of substituted aromatic boronic acids and the high
`tumor /brain ratios of these compounds in mice with subcutaneously transplanted
`gliomas. There are, however, exceptions to this observation and the mecha(cid:173)
`nism of transport into the central nervous system of compounds with low lipid
`solubility remains obscure. The position of groups on an aromatic nucleus is of
`importance in determining the degree of penetration of brain. An attempt is
`made to correlate chemical and physical properties with biologic attributes.
`
`An understanding of the types of compounds which will penetrate
`brain tumors but not the brain is essential in the treatment of such
`neoplasms by neutron capture .irradiation3 and by chemotherapy. 4
`Previous studies5•6 have shown a definite correlation between brain
`tumor/brain ratio of various substituted benzeneboronic acids in
`C3H mice and their lipid solubility. A histologically-reproducible
`tumor, such as this ependymoma, was used throughout. By compar(cid:173)
`ing the amount of a compound in this tissue with the amount in
`normal brain, the necessity of maintaining a constant blood level,
`in order to ascertain the permeation of the brain, becomes unneces(cid:173)
`sary.
`In this way both tissues are subjected to the same fluctuation
`in blood concentration and the ratio becomes a true measure of the
`
`(1) This research was supported by a grant from the U.S. Atomic Energy Commission under
`contract No. AT (30-1)-1093 and from the National Cancer Institute, United States Public
`Health Service Grant No. C-3174.
`(2) For Papers I and II: see references 5 and 6.
`(3) W. H. Sweet, A. H. Soloway, and G .. L. Brownell, Acta Union Int. Contl'e le Cancer, 16,
`1216 (1960).
`(4) V. H. Mark, R. N. Kjellberg, R. G. Ojemann, and A. H. Soloway, Neul'ol., 10, 772
`(1960).
`(5) A. H. Soloway, Science, 128, 1572 (1958).
`(6) A. H. Soloway, B. Whitman, and J. R. Messer, J. Pha!'macol. Exptl. Themp., 129, 310
`(1960).
`
`<
`
`191
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`
`192
`
`A. H. SOLOWAY, B. WHITMAN AND J. R. MESSER
`
`Vol. 5
`
`permeability of brain relative to this tissue by the compound under
`such conditions.
`Substances with a high lipid solubility invariably penetrated the
`brain readily, were toxic, and gave poor tumor/brain ratios as meas(cid:173)
`ured by their boron content. Only among those substances with low
`lipid solubility were compounds obtained whose ability to penetrate
`the central nervous system was restricted. Many of these hydro(cid:173)
`philic ones were relatively non-toxic and some did give high tumor/
`brain boron ratios. 7 However, two groups of compounds with low
`lipid solubility gave poor ratios. These were the amines, with the
`exception of those containing a carboxylic acid function, and the phe(cid:173)
`nols. Such substances penetrated the brain nearly as well as the
`tumor and were quite toxic.
`The purpose of this investigation in part was to determine whether
`the amines were an exception to the assumption that lipid solubility
`of a compound is one of the main factors in determining its ability
`to penetrate the central nervous system. Additional information
`was also sought relating to the effect produced by groups in an aroma(cid:173)
`tic compound upon its ability to penetrate the brain.
`In particular,
`are position isomers handled in the same or in a different manner
`by the central nervous system? Such information would permit a
`correlation between the physical and chemical properties of drugs \Vith
`their biological qualities.
`
`Experimental Methods
`
`The method for determining lipid solubility is essentially the same
`as previously described. 6 Approximately 10 mg. of each substance
`was distributed between 25 ml. of a phosphate-buffered aqueous me(cid:173)
`dium of pH 7.2 and 25 ml. of a lipid solvent, chloroform or benzene.
`The mixing was carried out in a separatory funnel and the layers were
`separated. Aliquots of each phase then were analyzed for boron con(cid:173)
`tent. 8 The values in Table I are listed in JJ.g. of boron per ml. of each
`solution.
`To determine tumor/brain ratios, C3H mice bearing subcutane-
`
`(7) A. H. Soloway, R. W. Wright, and J. R. Messer, J. PhaTmacol. Exptl. Therap., 134, 117
`(196,1).
`(8) G. H. Ellis, E. G. Zook, and 0. Baudisch, Anal. Chem., 21, 1345 (1949).
`
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`
`Jan. 1962
`
`ARoMATIC CoMPOUNDS IN BRAIN TuMoR PENETRATION
`
`193
`
`TABLE I
`
`AQuEous/LIPID SoLVENT PARTITION CoEFFICIENTS
`
`o-B(OH)2
`
`Aqueous/
`chloro-
`Chloro-
`Aqueous;
`form
`benzene Aqueousa
`Aqueousa Benzenea
`forma
`4-Clb
`10.8
`6.9
`5.2
`11.8
`1
`1
`4-Hb
`6.0
`14.4
`23.6
`2.3
`6
`4
`10
`2.2
`29
`22.0
`20.9
`3-N02-4-NH2c
`0.73
`15
`15.4
`29.2
`67
`3-NH2-4-CHi
`.23
`1.9
`4-COOHb
`73
`0.32
`23.3
`67
`.17
`11.4
`25.4
`67
`170
`.38
`23.5
`3-N02-5-NH2c
`.14
`25.2
`.15
`22.8
`170
`>200
`2-N02-4-NH2c
`.10
`29.8
`.44
`68
`. 3-NH2b
`.06
`12.4
`>200
`>200
`29.0
`>200
`26.0
`3,5-(NH2){
`0
`0
`>200
`30.0
`0.04
`>200
`25.2
`2-CHa-3,5-(NH2)2c
`0
`a Values listed are in J.Lg. of boron/mi.
`b For aqueous/benzene values, see
`ref. 6.
`c The authors wish to thank Dr. Kurt Torssell of the Biokemiska Institutet
`in Stockholm, who very kindly supplied us with these compounds.
`
`ously transplanted gliomas 9 were used. Fresh tumor tissue was
`ground in normal saline and a cellular suspension was injected in the
`region of the left scapula in 6-to 8-week old C3H mice. Within 7
`to 10 days the tumors were large enough for use. Solutions of the
`compounds were prepared and injected intraperitoneally into the
`tumor mice. The animals were sacrificed at fixed time intervals
`after injection to obtain biopsy specimens for boron analysis. The
`boron tissue concentrations are recorded in Table II.
`
`Results and Discussion
`
`The aqueous/benzene and aqueous/ chloroform partition coeffi(cid:173)
`cients of several mono- and disubstituted aromatic boronic acids
`are recorded in Table I. The group includes 3-amino-4-methyl(cid:173)
`benzeneboronic acid, m-aminobenzeneboronic acid, 3,5-diaminoben(cid:173)
`zeneboronic acid and 3,5-diamino-2-methylbenzeneboronic acid.
`The last three compounds have high values for their aqueous/lipid
`solvent coefficients in contrast with the low values for benzeneboronic
`acid and p-chlorobenzeneboronic acid. The coefficients for these
`amines are comparable to those observed with p-carboxybenzene(cid:173)
`boronic acid. On this basis, were low lipid solubility the sole re.:..
`
`(9) The authors are greatly indebted to Dr. D. JVI. Perese of the Department of Neurosurgery
`at the Roswell Park :Memorial Institute in Buffalo, N. Y., for supplying us with the original
`subcutaneously-grown ependymoma.
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`
`1!)4
`
`A. H. SoL0WAY, B. \VurrJVIAN AND J. R. MEssER
`
`Vol. 5
`
`o-B(OH)2
`
`3-NOz-4-NH2
`
`3-N02-5-NHz
`
`2-N02-4-NHz
`
`TABLE II
`TuMoR/BRAIN BoRoN LoCALIZATION FACToRsa
`Time
`of sacri-
`Localization
`ficed
`Doseb
`Brainc
`Tumor
`factor6
`15
`12.8
`7.0
`35
`0.5
`30
`15.0
`8.5
`35
`0.6
`18.7
`12.0
`30
`70
`0.6
`15
`4.9
`9.0
`35
`1.8
`16.7
`30
`35
`7.9
`2.1
`10.6
`34.0
`30
`70
`3.2
`24.4
`15
`35
`8.8
`2.8
`26.9
`11.8
`15
`70
`2.3
`140
`30
`22.0
`48.8
`2.4
`15
`1.8
`13.4
`35
`7.5
`30
`2.9
`21.7
`35
`7.5
`38.4
`30
`140
`5.3
`7.5
`15
`3.9
`18.8
`35
`4.8
`30
`3.7
`17.8
`35
`4.8
`4.0
`30
`30.6
`70
`7.7
`a The tumor and brain concentrations are tissue averages of one or two mice.
`b Dose in p.g. of boron/g. of mouse.
`c Concentrations are in Jtg. of boron per g.
`of tissue. a Time is in min.
`e Localization factor is the tumor /brain boron ratio.
`
`3,5-(NH2)2
`
`2-CHs-3,5-(NH2)2
`
`quirement for a compound in order to achieve a high tumor-to(cid:173)
`brain ratio, it may be anticipated that all these compounds would be
`restricted in their penetration of normal brain but not brain tumor.
`As shown in Table II and in previous work6 this is not completely
`the case. Those compounds containing a single amino function,
`such as m-aminobenzeneboronic acid, penetrate normal brain as
`readily as tumor at the times in which they were examined. 10 Also
`these compounds were more toxic to the central nervous system in
`comparable doses, than those substances which showed a high tumor/
`brain ratio.
`Introduction of a second amino function, however, markedly in(cid:173)
`creased the tumor/brain boron ratio relative to the monoamines and
`appreciably lowered the toxicity of these compounds. Thus, it
`would appear that the transport of the diamines into the central
`nervous system may be related to their lipid solubility but the en(cid:173)
`trance of compounds such as m-aminobenzeneboronic acid may in(cid:173)
`volve a mechanism which is independent of this property.
`
`(10) The tumor/brain boron ratios for monoamines, 3-amino-4-methylberizeneboronic acid
`and m-aminobenzeneboronic acid have been reported in Paper II and ranged from 0.9-1.2.
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`
`,Jan. 1962
`
`ARoMATIC CoMPOUNDS IN BRAIN TuMoR PENETRATION
`
`195
`
`Some workers11 •12 have suggested that the affinity of a compound
`for certain cellular components may be a contributing factor in its
`concentration and penetration of the central nervous system. It
`is conceivable that certain functional groups such as amino and hy(cid:173)
`droxyl moieties can interact with cellular binding sites, become
`fixed in the cell and, as a result, no longer be freely diffusible. Since
`these sites may have specific requirements for adsorption, the arrange(cid:173)
`ment of the substituent groups may be important.
`To contribute information about the effect of the group position
`on an aromatic nucleus and its penetration of the central nervous sys(cid:173)
`tem, three nitroaminobenzeneboronic acids were partitioned between
`an aqueous and a lipid solvent and were then examined in C3H mice
`bearing gliomas. These
`isomers are the 4-amino-2-nitro-,
`the
`5-amino-3-nitro- and 4-amino-3-nitrobenzeneboronic acids. Of these
`compounds the o-nitroaniline derivative has distribution coefficients
`of less than 30 while the others have values in excess of 67. This
`higher lipid solubility of 4-amino-3-nitrobenzeneboronic acid may ac(cid:173)
`count for the fact that it penetrates brain readily and gives tumor/
`brain boron ratios of approximately 0.5, while the two other isomers
`have localization factors ranging from 1.8 to 3.2 as shown in Table
`II. The physical and chemi_cal properties of compounds with certain
`groups in an ortho position are known to be different from other posi(cid:173)
`tion isomers, especially with regard to their greater solubility in non(cid:173)
`aqueous solvents. The theory that this difference is due to intra(cid:173)
`molecular hydrogen bonding with the formation of cyclic structures
`It would appear that such com(cid:173)
`is supported by spectral evidence. 13
`pounds, exemplified by 4-amino-3-nitrobenzeneboronic acid, do show
`an increased permeability of the brain relative to the other isomers.
`This may be due to its higher lipid solubility but it is also conceivable
`that the vicinal position of these groups may result in a greater bind(cid:173)
`ing potential.
`In conclusion, it can be stated that lipid solubility is undoubtedly
`an important factor in the penetrat!on of the brain by a drug. How(cid:173)
`ever, there must be other mechanisms involved to account for the
`
`(11) B. B. Brodie, L. C. Mark, E. M. Papper, P. A. Lief, E. Berstein, and E. A. Rovenstine,
`J. Pharmacol. Exptl. Therap., 98, 85 (1950).
`(12) S. E. Mayer, R. P. Maickel and B. B. Brodie, J. Pharmacol. Exptl. Therap., 127, 205
`(1959).
`(13) L. G. Bellamy, "The Infra-red Spectra of Complex Molecules," John Wiley and Sons,
`New York. N.Y., 1954.
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`
`196
`
`A. S. YARD AND H. McKENNis
`
`Vol. 5
`
`ready permeation of the central nervous system by certain com(cid:173)
`It would seem important to deter(cid:173)
`pounds with low lipid solubility.
`mine in which cellular fraction, if any, the drug is fixed and the degree
`of stability of any drug-cellular substituent bonds.
`Acknowledgment.-The authors are greatly indebted to Dr.
`William H. Sweet, Associate Professor in Surgery at the Harvard
`Medical School and Chief of Neurosurgery at the Massachusetts
`General Hospital, for his kind interest and encouragement of this
`investigation. Technical assistance of Miss Winnie Crane, Mrs.
`Cynthia Provost, and Mrs. Mary Lee Bossert is gratefully acknowl(cid:173)
`edged.
`
`Aspects of the Metabolisin of Isoniazid and
`Acetylisoniazid in the Human and the Dog 1
`2
`
`•
`
`ALLEN S. YARD AND HERBERT lVIcKENNis, JR.
`
`Department of Pharmacology, ll1edical College of Virginia, Richmond, lla.
`
`Received July 28, 1961
`
`After administration of 1-acetyl-2-isonicotinylhydrazine, a known metabolite
`of isonicotinylhydrazine, an adult male excreted 1,2-diacetylhydrazine.
`In
`contrast, the dog, following administration of 1-acetyl-2-isonicotinylhydrazine,
`excreted acetylhydrazine.
`In view of the foregoing and previous data indicating
`the inability of the dog to form 1,2-diacetylhydrazine from hydrazine or acetyl(cid:173)
`hydrazine, it is concluded that the metabolism of isoniazid in man and other
`species such as the rabbit involves the route: isonicotinylhydrazine -
`1-acetyl-
`2-isonicotinylhydrazine -
`acetylhydrazine -
`1,2-diacetylhydrazine.
`
`The metabolism of isonicotinylhydrazine (isoniazid) to yield 1-acet(cid:173)
`yl-2-isonicotinylhydrazine (acetylisoniazid) has been recorded for
`
`(1) Aided by grants from the American Medical Association and the National Institutes of
`Health, U. S. Public Service (R G-5337).
`(2) Presented in part at the Southeastern Regional Meeting of the American Chemical So(cid:173)
`ciety, Richmond, Virginia, November 5, 1959; 48th Annual Meeting of the American Society
`for Pharmacology and Experimental Therapeutics, Philadelphia, Pennsylvania, April 18,
`1958; and the Fall :Meeting of the American Society for Pharmacology and Experimental Thera(cid:173)
`peutics, French Lick, Indiana, August 8-10, 1956.
`
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`
`AUTHOR INDEX~ Vol. 5~ 1962
`AcToN, E. See Hyde, K. A., 1
`ADAMS, A. C. See O'Neal, J. B., 617
`AFoNso, A. See Sih, C. J., 629
`AINSWORTH, c., EASTON, N. R., LIVEZEY, M., l\10RRISON, D. E., AND GIBSON,
`W. R. The anticonvulsant activity of 1,2,4-triazoles, 383
`ALLEN, W. S., KissMAN, H. M., MAUER, S., RINGLER, I., AND \VEiss, M. J.
`Certain steroid ketals and their biological activity, 133
`ANDERSON, E. L. See Zirkle, C. L., 341
`ANDERSON, F. E., KAMINSKY, D., DUBNICK, B., KLUTCHKO, s. R., CETENKO,
`W. A., GYLYS, J., AND HART, J. A. Chemistry and pharmacology of mono(cid:173)
`amine oxidase inhibitors: hydrazine derivatives, 221
`ARCHER, S., LANDS, A. M., AND LEWIS, T. R.
`Isomeric 2-acetoxytropine methi(cid:173)
`odides, 423
`ARCHER, S. See Wylie, D. W., 932
`ARNOLD, H. See Stone, C. A., 665
`
`BAER, J. E. See Cragoe, E. J., Jr., 896
`BAILEY, J. H. See Lesher, G. Y., 1063
`BAIOCCHI, R. See O'Brien, D. E., 1085
`BAKER, B. R. Non-classical antimetabolites. VII. The bridge principle of
`specificity with exo-alkylating irreversible inhibitors, 654
`BAKER, B. R. See Hyde, K. A., 1
`BANDURco, V. See Shapiro, S. L., 793
`BARDOS, T. J. See Papanastassiou, Z. B., 1000
`BARSKY, L. I. See Bencze, W. L., 1298
`BAUMANN, M. F. See Pettit, G. R., 800
`BAUMGARTNER, D. See Pinson, R., Jr., 491
`BEAMAN, A. G. See Lewis, L. R., 607
`BEAMAN, A. G., AND RoBINs, R. K. The synthesis of 6-fiuoro-9-methylpurine,
`1067
`BELL, S.C., GocHMAN, C., AND CHILDREss, S. J. Some analogs of chlordiaxepox(cid:173)
`ide,63
`BELLEAU, B., AND MoRAN, J. The mechanism of action of the 2-phenylcyclo(cid:173)
`propylamine type of monoamine oxidase inhibitors, 215
`BELLEAU, B., AND TRIGGLE, D. J. Blockade of adrenergic a-receptors by a car(cid:173)
`bonium ion, 636
`BENCZE, W. L., AND BARSKY, L. I. Selective adrenal cortical and gonadal in-
`hibitors, 1298
`BICKING, J. B. See Schultz, E. M., 660
`BICKOFF, E. M. See Micheli, R. A., 321
`Bwos, C. See Villani, F. J., 373
`BLUMENTHAL, A. See O'Neal, J. B., 617
`BoEHME, W. R., SIEGMUND, E. A., ScHARPF, W. G., AND ScHIPPER, E. Structure(cid:173)
`activit} relations in a series of anticonvulsant bicyclic acylureas, 769
`BoEHME, W. R., SIEGMUND, E. A., ScHARPF, W. G., AND ScHIPPER, E. Struc(cid:173)
`ture-activity relationships in a series of anticonvulsant and hypnotic bicyclic
`carboxamides, 451
`BoLHOFER, W. A. See Schultz, E. M., 660
`1386
`
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`

`
`November, 1962
`
`A UTI-IOR INDEX
`
`1387
`
`BooTH, A. N. See Micheli, R. A., 321
`BooTHE, J. H. See Petisi, J., 538
`BoTTINI, A. T., ANDDEv, V. Structure-activity relationships of ethylenimines.
`II. Methyl-substituted derivatives of tetramin, 925
`BovET, D. See Misiti, D., 1285
`BoWERs, A. See Cross, A. D., 406
`BoWERS, A. See Orr, J. C., 409
`BoWMAN, R. E. See Elslager, E. F., 1159
`BRUNDAGE, R. P. See Lesher, G. Y., 1063
`BROWN, F. C., HARRIS, C. M., AND PERRY, F. 5-Isonitrosorhodanines, 1239
`BucK, A. S. See Cash, W. D., 413
`BucKLEY, J.P. See Neumeyer, J. L., 784
`BuRGER, A. See Kaiser, D., 1243; Zirkle, C. L., 1265
`BuRGER, A. Review of "Chemistry of Drug Metabolism;' (Fishman), 220
`BuRKE, N. See Zalkow, L. H., 1342
`Buu-Hm, N. P., RIPS, R., AND DERAPPE, C. Spasmolytic 1,2,5-trisubstituted
`pyrroles, 1357
`BuzARD, J. A. See Olivard, J., 524
`
`CABAT, G. See Zalkow, L. H., 1342
`CANNON, J. G. See Neumeyer, J. L., 784; Vaidya, M.G., 389
`CANTRALL, W. B. See Wilkinson, R. G., 835
`CARABATEAs, P.M., AND GRUMBACH, L. Strong analgesics. Some !-substituted
`4-pheny 1-4-propionoxypiperidines, 913
`CARROLL, J. J. See Ebetino, F. F., 513
`CAsH, W. D., MAHAFFEY, L. M., BucK, A. S., NETTLETON, D. E., JR., RoMAs, C.,
`AND DU VIGNEAUD, V. Synthesis and biological properties of 9-sarcosine
`oxytocin, 413
`CASPI, E., CHANG, Y. W., AND DoRFMAN, R.I. Degradation of corticosteroids.
`VII. The synthesis of 7-membered ring-A enol-lactones, 714
`CAVALLA, J. F., AND SELWAY, R. A. Analgetics based on the pyrrolidine ring.
`II., 441
`CETENKO, W.A. SeeAnderson,F.E.,221
`CHANG, Y. W. See Caspi, E., 714
`CHARNEY, W. See Shapiro, E., 975 ·
`CHAVEZ-LARA, B. See Sourkes, T. L., 204
`CHEN, K. K. See Henderson, F. G., 988
`CHENEY, L. C. See Perron, Y. G., 1016
`CHENG, C. C. See Greco, C. V., 861; Koppel, H. C., 639; O'Brien, D. E., 1085;
`Sutcliffe, E. Y., 588; Zee-Cheng, K. Y., 1008
`CHIAINI, J. See Pinson, R., Jr., 491
`CHIAVARELLI, S., FENNOY, L. V., SETTIMJ, G., AND DE BARAN, L. The effect of
`methoxyphenyl substitutions on the strychnine-like activity of aryldiaza(cid:173)
`adamantanones and aryldiazaadamantanols, 1293
`CHILDRESS, S. J. See Bell, S.C., 63
`CLARKE, R. L., AND HARRIS, L. S. a-Benzyltetrahydrofurfurylamines-a new
`series of psychomotor stimulants.
`I, 77
`CLARKE, R. L., TuLLAR, B. F., AND HARRIS, L. S. a-Benzyltetrahydrofur(cid:173)
`II. Resolution of
`furylamines. A new series of psychomotor stimulants.
`isomers, 362
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2131 - 10/21
`
`

`
`1388
`
`Aurnon INDFJX
`
`Vol. 5
`
`CLEVENGER, R. L. See Wiley, R.H., 1367
`CoNIGLIO, C. T. See Shapiro, E., 975
`CooK, D. L. See Counsell, R. E., 720
`CooK, W. B. See Subbaratnam, A. V., 1376
`CouNSELL, R. E. See Klimstra, P. C., 1216
`CouNSELL, R. E., AND KLIMSTRA, P. D. Anabolic agents: derivatives of 2-halo-
`5a-androst-1-ene, 477
`CouNSELL, R. E., KLIMSTRA, P. D., RANNEY, R. E., AND CooK, D. L. Hypo(cid:173)
`I. 20a- (2- Dialkylaminoethyl)aminopregn-5-en-
`cholesterolemic agents.
`3{:1-ol derivatives, 720
`CouNSELL, R. E., KLIMSTRA, P. D., AND RANNEY, R. E. Hypocholesterolemic
`III. N-Methyl-N -( diamino )alkyl-17 ,8-aminoandrost-5-en-3{:1-ol de(cid:173)
`agents.
`rivatives, 1224
`CRAIG, P. N. See Zirkle, C. L., 341
`.CRAGOE, E. J., JR. See Rooney, C. S., 155
`CRAGOE, E. J., JR., WoLTERSDORF, 0. W., JR., BAER, J. E., AND SPRAGUE, J. M.
`Synthesis and diuretic activity of 3,3-spiro-substituted hydrothiazides, 896
`CRAGOE, E. J., JR. See Schultz, E. M., 660
`CRAST, L. B. See Perron, Y. G., 1016
`CRoss, A. D., EDWARDS, J. A., AND BoWERs, A.
`Steroids. CLXXX.
`2-Methyl-1.12-androstenes and 2-methylene-androstanes. A new class of
`potent anabolic agents, 406
`CuLLEN, E. See Popp, F. D., 398
`
`DAPERO, M. R. See Mull, R. P., 651,944
`DAVIS, C. S. See Kaiser, D., 1243
`DAVIS, M.A. See Winthrop, S. 0., 1199, 1207
`DAvis, R. B. See Popp, F. D., 398
`DAVANzo, J.P. See Schumann, E. L., 46-1
`DEBARAN, L. See Chiavarelli, S., 1295
`DELIA, T. J. See Kaiser, D., 1243
`DEMARCHI, F. See Misiti, D., 1285
`DENET, R. W. See Zaugg, H. E., 430
`DERAPPE, C. See Buu-Hoi, N. P., 1357
`DERENzo, E. C. See Gadekar, S.M., 531
`DESTEVENS, G., SKLAR, M., LuKAszEWSKI, H., AND WITKIN, L. Dicarbamates
`and thiolcarbamates, 919
`DEv, V. See Bottini, A. T., 925
`DIEDRICH, D. F. Some new synthetic flavonoid glycosides related in structure to
`phlorizin, 1055
`DILLARD, R. D. See Ryan, C. W., 780
`DoRFMAN, R.I. See Caspi, E., 714
`DosKoTcH, R. W. See Kupchan, S.M., 657
`DuBNICK, B. See Anderson, F. E., 221
`DU VIGNEAUD, V. See Cash, W. D., 413
`
`EAsTERDAY, D. See Ellin, R.I., 404
`EASTON, N. R. See Ainsworth, C., 383; Ryan, C. W., 780
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2131 - 11/21
`
`

`
`N ovomber, UJG2
`
`Awrnon IN1mx
`
`I.
`
`I.
`EnERSON, L. E., AND PERssoN, K. Studies on monoamine oxidase inhibitors.
`Autoxidation of /1-phenylisopropylhydrazine as a model reaction for irrevm·(cid:173)
`sible monoamine oxidase inhibition, 738
`EBETINO, F. F., CARROLL, J. J., AND GEVER, G. Reduction cif nitrofurans.
`Aminofurans, 513
`EDWARDs, J. A. See Cross, A. D., 406
`EGBERT, M. E. See Mull, R. P., 651, 944
`EISLER, M. See Shapiro, E., 975
`ELLIN, R. I., EASTERDAY, D., AND KoNDRITZER, A. A. An improved procedure
`for preparing 1-methyl-pyridinium-2-aldoxime chloride, 404
`ELLis, C. A. See Villani, F. J., 373
`ELsLAGER, E. F., AND TENDICK, F. H. Synthetic amebicides. VI. Benzo lb ](cid:173)
`l1,8]phenanthrolines,
`benzo [b] [1,10]phenanthrolines,
`dibenzo[b,h] [1,() ](cid:173)
`naphthyridines, and benzo [h] quina [4,3-b ]quinolines, 546
`ELSLAGER,, E. F., AND TENDICK, F. H. Synthetic amebicides. VII. 6,6'(cid:173)
`Diallyl-a,a'-bis( dialkylaminoalkylamino )-4,4'-bi-o-cresols, 646
`ELsLAGER, E. F., AND TENDICK, F. H. 9-Amino-2,3-dimethoxy-6-nitroacridine
`10-oxides, 1149
`ELsLAGER, E. F., AND TENDICK, F. H. 4-(3-Chloro-9-acridinylamino)-a-amino-o(cid:173)
`cresol10 oxides, 1153
`ELsLAGER, E. F., BowMAN, R. E., TENDicK, R. H., TivEY, D. J., AND WoRTH, D. F.
`3-Chloro-9-( 4-diethylamino-1-methylbutyl-amino)acridine 10-oxide and other
`9-aminoacridine N-oxides, 1159
`ELSLAGER, E. F. See Short, F. W., 642
`EL TAYEB, 0. See Sih, C. J., 629
`
`FALCO, E. A. See Roth, B., 1103
`FELDKAMP, R. F. See Wu, Y.-H., 752, 762
`FENNOY, L. V. See Chiavarelli, S., 1293
`FisHER, D. See Minor, W. F., 96
`FisHMAN, W. H. Chemistry of Drug Metabolism (book review), 220
`FLANAGAN, T. L. See Ross, J. J., Jr., 1035
`FoYE, W. 0., AND MICKLES, J. Antiradiation compounds.
`b'amates, 846
`FREDERICK, J. L. See Gadekar, S.M., 531
`FREEDMAN, L. See Shapiro, S. L., 69, 793
`FROELICH, E. J. See Lesher, G. Y., 1063
`Fu, S.-C. J. para-[N-Bis-(2-chloroethyl) ]-aminobenzoylglutamic acid, 33
`
`II. Dithiocar-
`
`GADEKAR, S. M., FREDERICK, J. L., AND DERENZO, E. C. Synthesis and biologi(cid:173)
`cal activity of pyridoxine analogs, 531
`GAINES, W. A. See Stone, C. A., 665
`GARDNER, T. S., WENIS, E., AND LEE, J. Monoamine oxidase inhibitors.
`Structural variations in 1-alkyl and 1-aralkyl-1( or 2)-acylhydrazines, 503
`GARRETT, E. R. The solvolysis of 21-hydrocortisone esters and hemiesters, 112
`GAUDRY, R. See Winthrop, S. 0., 1199, 1207
`GERNS, F. R. See Zirkle, C. L., 341
`GEYER, G. See Ebetino, F. F., 513; Michels, J. G., 1042
`GINSBURG, S. Methanesulfonates of tertiary and quaternary amino alcohols, 1364
`GocHMAN, C. See Bell, S.C., 63
`
`III.
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2131 - 12/21
`
`

`
`1390
`
`AuTHOR INDEX
`
`Vol. 5
`
`GoLDKAMP, A. H. Mono- and difluorination of steroids at C-16 through enamine
`intermediates, 1176
`GoLDSTEIN, T. P., PLAPINGER, R. E., NAcHLAS, M. M., AND SELIGMAN, A. M.
`Synthesis of chromogenic substrates for the assay of aminopeptidase activity,
`852
`GooDMAN, L. See Hyde, K. A., 1
`GoRDON, M., LAFFERTY, J. J., TEDESCHI, D. H., AND SuTTON, B. M. New
`benzomorphan analgetics, 633
`GouLD, W. A. See Wu, Y.-H., 752
`GouREVITcH, A. See Perron, Y. G., 1016
`GREco, C. V., NYBERG, W. H., AND CHENG, C. C. Rynthesis of sydnones and
`sydnone imines, 861
`GREENBERG, J. See Hyde, K. A., 1
`GREIG, M. E. See Schumann, E. L., 464
`GRUENFELD, N. See Kupchan, S.M., 690
`GRUETT, M.D. See Lesher, G. Y., 1063
`GRULA, E. A. See Zalkow, L. H., 1342
`GRUMBACH, L. See Carabateas, P.M., 913
`GuBITz, F. W., AND McKEoN, W. B., JR. Mercury derivatives of allylhydantoins,
`168
`GYLYS, J. See Anderson, F. E., 221
`
`HALPERN, 0. See Orr, J. C., 409
`HART, J. A. See Anderson, F. E., 221
`HARRIS, C. M. See Brown, F. C., 1239
`HARRis, L. S. See Clarke, R. L., 77, 362
`HEDGCOTH, C. See Segal, H., 871
`HEINZELMAN, R. V. See Schumann, E. L., L!64
`HENDERSON, F. G. See Ryan, C. W., 780
`HENDERSON, F. G., AND CHEN, K. K. Cardiac activity of newer digitalis g]yco-
`sides and aglycones, 988
`HENNESSEY, M.G. See Shapiro, E., 975
`HERR, F. See Winthrop, S. 0., 1199,1207
`HEwsoN, K. See Montgomery, J. A., 15
`RIGA, S. See Shankman, S., 42
`HITCHINGs, G. H. See Roth, B., 1103
`HLAVKA, J. J. See Petisi, J., 538
`HoEKSTRA, J. B. See Minor, W. F., 96
`HoKFELT, B., AND JoNssoN, A. Hypoglycemic activity in relation to chemical
`I. 1-Sulfonyl-3-
`structure of potential oral antidiabetic substances.
`alkylureas, 231; hypoglycemic activity in relation to chemical structure of
`potential oral antidiabetic substances.
`II. Analogs of 1-sulfonyl-3-alkyl(cid:173)
`ureas, 240; hypoglycemic activity in relation to chemical structure of po(cid:173)
`III. 2-Benzenesulfonamido-5-alkyl-
`tential oral antidiabetic substances.
`1,3,4-thiadiazoles and -oxadiazoles, 247
`HoFFMAN, A. S. See Rissman, H. M., 950
`HoFFMAN,. A. S., RISSMAN, H. M., AND WEiss, M. J. Synthesis of certain 16a(cid:173)
`substituted derivatives of 9a-fluoro-ll-dehydrocorticosterone, 962
`HoLTON, P. G., AND NEcOECHEA, E. Steroids. CLXXV. Further steroidal
`anabolic agents, 1352
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2131 - 13/21
`
`

`
`November, 1962
`
`AUTHOR INDEX
`
`1391
`
`HuFFMAN, M. N. See Rhone, J. R., 107
`HuGGINS, C. G., AND WALASZEK, E. J. Large scale preparation and purification of
`the vasopressor polypeptide, substance A, 183
`HYDE, K. A., AcTON, E., SKINNER, vV. A., GooDMAN, L., GREENBERG, J., AND
`BAKER, B. R. Potential anticancer agents. LXII. The relationship of
`chemical structure to antileukemic activity with analogs of 1-methyl-3-
`nitro-1-nitrosoguanidine (NSC-9369).
`II, 1
`
`INDIK, Z. K. See Zirkle, C. L., 341
`IRICK, G. See Wiley, R. H., 49
`IsAACS, E. S. See Shapiro, S. L., 69,793
`
`JAMES, D. M., AND REEs, A. H. A chemical and pharmacological study of some
`compounds derived from 4,5-xylidine, 1234
`JEN, T., AND WoLFF, M. E. C(19)-Substituted steroid hormone analogs.
`17 {J-Hydroxy -3-oxoandrost-4-ene-1 9-nitrile, 87 6
`JoNssoN, A. See Hokfelt, B., 231,240,247
`JoRGENSEN, E. C., AND SLADE, P. Thyroxine analogs. VI. Synthesis and
`antigoitrogenic activity of 3,5-diiodo-4-( 4'-aminophenoxy )-L-phenylalanines,
`including the 4'-amino analog of 3,5,3'-triiodo-L-thyronine, 729
`JoRGENSEN, E. C., AND \iVILEY, R. A. Thyroxine analogs. VIII. 3-Methyl(cid:173)
`and 3,5-dimethyl-DL-thyroxines and iodinated derivatives, 1307
`
`I.
`
`KAISER, C. See Zirkle, C. L., 1265
`KAISER, D., LESTER, B. M., ZIRKLE, C. L., BuRGER, A., DAvis, C. S., DELIA, T. J.
`AND ZIRNGIBL, L. 2-Substituted cyclopropylamines.
`I. Derivatives and
`analogs of 2-phenylcyclopropylamine, 1243
`KAMINSKY, D. See Anderson, F. E., 221
`KATSUI, N. See Kupchan, S.M., 690
`KIMURA, E. T. See Zaugg, H. E., 430
`KING, K. F. SeeN ace, H. R., 1316
`KIRscH, W. See Popp, F. D., 398
`KisSMAN, H. M. See Allen, W. S., 133
`KissMAN, H. M. See Hoffman, A. S., 962
`KissMAN, H. M., HoFFMAN, A. S., PoLETTo, J. F., AND WEiss, M. J. Synthesis
`of certain C-2 and C-6 substituted derivatives of 9~-fluoro-16a-hydroxy­
`hydrocortisone 16,17-acetonide, 950
`KJELLBERG, R. M. See Soloway, A. H., 1371
`KLIMSTRA, P. C., AND CouNSELL, R. E., Hypocholesterolemic agents.
`Halo-5a-androstane derivatives, 1216
`KLIMSTRA, P. D. See Counsell, R. E., 477, 720, 1224
`KLUTCHKO, S. R. See Anderson, F. E., 221
`KoNDRITZER, A. A. See Ellin, R.I., 404
`KoNOPKA, E. A. See Kuehne, M. E., 257, 281
`KoPPEL, H. C., SPRINGER, R. H., RoBINs, R. K., AND CHENG, C. C. Pyrimidines.
`VIII. Pyrimidine derivatives of thioguanine, 639
`KuEHNE, M. E., AND KoNOPKA, E. A. Dihydro-1,3-oxazines as antitumor agents,
`257
`KuEHNE, M. E., KoNOPKA, E. A., AND LAMBERT, B. F. Steroidal dihydro-1,3-
`oxazines as antitumor agents, 281
`
`II. 2{J-
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2131 - 14/21
`
`

`
`1:102
`
`AUTHOR INDEX
`
`Vol.!)
`
`KuGITA, H., SAITO, S., AND MAY, E. L. Structures related to morphine. XXII.
`A benz om orphan congener of meperidine, 357
`KuPCHAN, S. M., AND DosKOTCH, R. VI. Tumor inhibitors.
`acid, the active principle of aristolochia indica, 657
`KuPCHAN, S.M., GRUENFELD, N., AND KATSUI, N. Veratrum alkaloids. XLIX.
`The structures and configurations of sabine n,nd sabndine, 690
`KuPCHAN, S.M. See Sih, C. J., 629
`KussNER, C. L. See Temple, C., Jr., 866
`
`I. Aristolochic
`
`LAFFERTY, J. J. See Gordon, M., 633
`LANDIS, E. B. See Poos, G. I., 883
`LANDs, A.M. See Arch