THE
`MERCK INDEX
`
`AN ENCYCLOPEDIA OF
`
`CHEMICALS, DRUGS, AND BIOLOGICALS
`
`TWELFfH EDITION
`
`Susan Budavari, Editor
`Maryadele J. O'Neil, Senior Associate Editor
`Ann Smith, Associate Editor
`Patricia E. Heckelman, Assistant Editor
`Joanne F. Kinneary, Assistant Editor
`
`COVINGTON & BURLING
`FOOD & DRUG LAW
`LIBRARY
`
`Published by
`Merck Research Laboratories
`Division of
`
`MERCK & CO., INc.
`
`Whitehouse Station, NJ
`
`1996
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2008 page 1
`
`

`
`MERCK & CO., INC.
`Whitehouse Station, N.J.
`U.S.A.
`
`1st Edition-1889
`2nd Edition-1896
`3rd Edition-1907
`4th Edition-1930
`5th Edition-1940
`6th Edition-1952
`7th Edition-1960
`8th ,Edition-1968
`9th Edition-1976
`lOth Edition-1983
`11th Edition-1989
`
`Library of Congress Catalog
`Card Number 89-60001
`ISBN Number 0911910-12-3
`
`Copyright © 1996 by MERCK & CO., INC.
`All rights reserved. Copyright under the Universal Copyright Convention
`and the International Copyright Convention.
`Copyright reserved under the Pan-American Copyright Convention.
`
`Printed in the U.S.A.
`
`Actavis v. Research Corp. Techs.
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`RCT EX. 2008 page 2
`
`

`
`462
`
`p-Aminohippuric Acid
`See also adrenochrome, adrenolutin, carbazochrome salic-
`ies: Kiichel, Pharmacol. Clin. 2, 138 (1970). Use in treat-
`ylate.
`ment of Cushing's syndrome: R. I. Misbin et al., J. Clin.
`THERAP CAT: Hemostatic.
`Pharmacol. 16, 645 (1976); of metastatic breast cancer: R.
`F. Asbury et al.. Cancer 47, 1954 (1981). Comparative
`clinical trial with tamoxifen:
`I. E. Smith et al., Brit. Med. J.
`283, 1432 (1981). Hematologic toxicity study: A. A.
`Messeih et al., Cancer Treat. Rep. 69, 1003 (1985). Clinical
`trial in advanced prostatic carcinoma: R. Murray, P. Pitt,
`Eur. J. Cancer Clin. Oncol. 21, 453 (1985). Comprehensive
`guide to therapeutic use: Pharmanual (Basel) vol. 2, R. J.
`Santen, I. C. Henderson, Eds. (Karger, Basel, 1981) 160 pp.
`Reviews of mechanisms of action, endocrinological effects
`and, clinical experience in breast cancer: R. C. Stuart-
`Harris, I. E. Smith, Cancer Treat. Rev. 11, pp 189-204
`(1984); A. L. Harris, Exp. Cell. Biol. 53, pp 1-8 (1985).
`Comprehensive description: H. Y. Aboul-Enein in Analyti-
`cal Profiles of Drug Substances vol. 15, K. Florey, Ed. (Aca-
`demic Press, New York, 1986) pp 35-69.
`
`2,4-Dichloro-6-
`2-Amino-4,6-dichlorophenol.
`457.
`aminophenol; 4,6-dichloro-o-aminophenol. C61-I5ClzNO;
`mol wt 178.02. C 40.48%, H 2.83%, CI 39.83%, N 7.87%, O
`8.99%. Prepd by reduction of the corresponding nitrophe—
`nol: F. Fischer, Z. Chem. [N.F.] 4, 386 (1868); Ann.. suppl
`vol. 7, 189 (1870); Katz, Cohen, J. Org. Chem. 19, 758
`1958 .
`(1954). Purification:
`J. Meyer, Helv. Chim. Acta 41, 1890
`OH
`
`O
`
`HN
`
`Cl
`
`NH2
`
`Crystals from methanol or ethyl acetate, mp 149-150°.
`Freely sol in most organic solvents; poorly so] in ethyl ace-
`tate, 0.1N HCl and absolute ethanol; readily sol in acetone
`and 100% acetic acid. Practically insol in water.
`Hydrochloride, CuH1.,ClNzO1, mp 223-225‘. Freely sol
`in water.
`In Cushing’s syndrome and other adrenal
`Tl-IERAP CAT:
`honnone disorders. Palliative treatment of breast and pros-
`tatic cancer. Formerly as anticonvulsant.
`461. Aminoguanidine. Hydrazinecarbaximidamide;
`guanylhydrazine; pimagedine. CI-I6N,; mol wt 74.09. C
`16.21%, H 8.16%, N 75.62%. Nucleophilic hydrazine; inhi-
`bits the formation of advanced glycosylation end products
`(AGES) that have been implicated in the etiology of diabetic
`complications. Prepn:
`J. Thiele, Ann. 270, 1 (1892); G. B.
`L. Smith, E. Anzelmi, J. Am. Chem. Soc. 57, 2730 (1935).
`Review of chemistry of aminoguanidine and related com-
`pounds: E. Lieber, G. B. L. Smith, Chem Rev. 25, 213-271
`(1939); of preparative methods: F. Kurzer, L. E. A. God-
`trey, Chem. & Ind. (London) 1962, 1584-1595. Prevention
`of glucose-derived aortic collagen cross-linking in diabetic
`rats: M. Brownlee et al., Science 232, 1629 (1986). Mecha-
`nism of action study: D. Edelstein, M. Brownlee, Diabetes
`41, 26 (1992). Review of therapeutic potential: B. H. R.
`1993 .
`-
`2Voll’f§:nbuttel, M. S. P. Huijberts, Neth. J. Med. 42, 205-208
`
`HN
`
`H2N
`
`\n/ \NH2
`NH
`
`Crystals. Sol in water. ale. Practically insol in ether. Aq
`soln is strongly alkaline and reddens on standing in air;
`ammonia is evolved on heating.
`Hydrochloride, CH,N,.HCl, GER-11. Large prisms from
`dil alc, mp 163'’. Very sol in water; sol in alc. Practically
`insol in ether.
`In prevention and treatment of chronic
`THERAP CAT:
`diabetic complications.
`462. p-Aminohippuric Acid. N-(4-Aminobenzoyl)gly-
`cine; N-(p-aminobenzoy1)aminoacetic acid; PAH. C,H“,N2-
`03; mol wt 194.19. C 55.67%, H 5.19%. N 14.43%. 0
`24.72%. Prepd by reduction of p-nitrohippuric acid: Shimi-
`zu, Okano, J. Pharm. Soc. Japan 73, 523 (1953).
`
`Long needles from carbon disulfide, warts from benzene.
`mp 95-96". Sublimes (0.06 torr) 70-80° (bath temp). Freely
`sol in benzene, somewhat less in carbon disulfide, much less
`in petr ether. The stability of the free base (snow—White
`when pure) seems to be impaired by impurities.
`Hydrochloride, C61-I5Cl1NO.HCl, crystals, dec 280-285".
`Very stable when pure. The commercial product may be
`dark brown. Sol in water, alcohol. Precipitated from aq
`soln by the addition of concd HCI.
`USE:
`Important azo-dye intermediate.
`458.
`1-[(2-Aminoetliyl)amino]-2-propanol. N-(2-Hy-
`droxypropyl)ethylenediamine; Monolene.
`C_.,HuN2O; mol
`wt 118.18. C 50.82%, H 11.94%, N 23.70%, 0 13.54%.
`CH3CH(0l-DCHZNHCI-IICHINHZ. Prepn Kitchen, Pol-
`lard, J. Org. Chem. 8, 342 (1943).
`Viscous liquid; mild ammoniacal odor.
`112°.
`.155 0.9837. nf,51.4738.
`Dihydrochloride, C,H,5C12N,0, mp 184.7-185.0“.
`USE: Rapid curing agent in the manuf of epoxy resins.
`
`bP3.o 94°; bP1o.n
`
`459. 2-Amino-2-ethyl-1,3-propanediol. C5H,,NO,;
`mol wt 119.16. C 50.40%. H 11.00%. N 11.75%, 0 26.85%.
`An amino glycol prepd by reduction of cataytic hydrogena-
`tion of the corresp nitro compound: Vanderbilt, Hass, U.S.
`pat. 2,174,242 (1940); Johnson, Degering, J. Org. Chem. 8, 7
`(1943). Manuf: McMillan, U.S. pat. 2,485,982 (1949 to
`Comm. Solvents).
`
`Hz
`
`H0
`
`1‘
`\jC\/CH9
`H0
`
`(The commercial prod-
`Crystalline mass, mp 37.5-38.5".
`uct may be a viscous liquid.) dilfl 1.099.
`n{,‘’ 1.490. bp“, 152-
`153‘. Miscible with water. So! in alcohols. pH of 0.1 molar
`aq soln 10.8.
`USE:
`In the synthesis of surface-active agents, vulcaniza-
`tion accelerators, pharmaceuticals. As emulsifying agent for
`cosmetic creams and lotions, mineral oil and paraffin wax
`emulsions, leather dressings,
`textile specialties, polishes,
`cleaning compounds, so-called soluble oils. For absorbing
`CO1 and H15 from industrial gases.
`3-(4-Aminophenyl)-3-ethyI-
`2,6-piperidinedione; 2-(p-aminophenyl)-2-ethylglutarimide; 3-
`ethyl-3-(p-aminophenyl)-2,6-dioxopiperidine; Cytadren;
`Elipten; Orimeten. CHI-INNZO2; mol wt 232.28. C 67.22%,
`H 6.94%, N 12.06%, 0 13.78%. Adrenocortical suppressant
`that also inhibits conversion of androgens to estrogens by
`the aromatase enzyme system. Prepn: Hoffmann, Urech,
`U.S. pat. 2,848,455 (1958 to Ciba). Metabolism: Douglas,
`Nicholls, J. Pharm. Pharmacol. Suppl. 17, 115S (1965).
`Mass spectrum: Ruecker, Bohn, Arch. Pharm. (Weinheim)
`302, 204 (1969). Resolution and abs config of antipodes:
`Finch et aL, Experientia 31, 1002 (1975). Review of its role
`as an inhibitor of adrenocortical steroidogenesis: Touitou et
`al., Biomedicine 18, 185-191, 272-278 (1973). Clinical stud-
`
`Consult the Name Index before using this section.
`
`Page 77
`
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`IPR2014-01126
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`

`
`Carbamazepine
`Ameban; Amibiarson; Arsambide; Carb-O-Sep; Histocarb;
`Fenarsone; Leucarsone; Aminarsone; Amebarsone. C.,H,-
`AsNzO,; mol wt 260.08. C 32.33%, H 3.49%, As 28.81%, N
`10.77%, 0 24.61%. Prepd from the sodium salt of arsanilic
`acid by treatment with potassium cyanate or cyanogen bro-
`mide: Ger. pat. 213,155; Stickings, J. Chem. Soc. 1928,
`3131; from arsanilic acid by treatment with phosgene: Na-
`katsu. Kawase, Ann. Rept. Takamine Lab. 8, 44-47 (1956);
`Japan. pat. 4418('58) (to Sankyo).
`
`0 I
`
`. Vu cc...
`C190”?
`
`Minute yellow crystals, mp 239.5-240°. uv max (water):
`236, 251, 303, 366, 373 nm (6 11000, 10900, 36400, 16100,
`16200). Practically insol in water.
`THERAP CAT (VEF): Antimicrobial.
`
`5H-Dibenz[b,f]azepirre-5-car-
`-
`boxamide; S-carbamoyl-5H-dibenz[b,/]azepine; G-32883;
`Biston; Calepsin; Carbelan; Epitol; Finlepsin; Sirtal; Staze-
`pine; Tegretal; Tegretol; Telesmin; Timonil. CISHHNZO;
`mol wt 236.27. C 76.25%, H 5.12%, N 11.86%, 0 6.77%.
`Prepn:
`Schindler, U.S. pat. 2,948,718 (1960 to Geigy).
`Metabolism: P. L. Morselli, A. Frigerio, Drug Metab. Rev.
`4, 97 (1975). Review of pharmacokinetics in man: L. Ber-
`tilsson, Clin. Pharmacokinet. 3, 128-143 (1978); S. Pyn-
`néinen, Ther. Drug Monit. 1, 409-431 (1979). Toxicity: E.
`G. Stenger, F. C. Roulet, Med. Exp. 11, 191 (I964). Com-
`prehensive description: H. Y. Aboul-Enein, A. A. Al-Badr
`in Analytical Profiles of Drug Substances vol. 9, K. Florey.
`Ed. (Academic Press. New York, 1980) pp 87-106.
`
`00
`
`0
`
`NH,
`
`Crystals from abs ethanol + benzene, mp 190-193‘. Sol in
`alcohol, acetone, propylene glycol. Practically insol
`in
`water. LDN orally in mice, rats: 3750, 4025 mg/ kg (Steng-
`er, Roulet).
`THERAP CAT: Analgesic; anticonvulsant.
`1827. Carbamyl Chloride. Carbamic chloride; chloro-
`formamide. CI-12ClNO; mol wt 79.49. C 15.11%, H 2.54%,
`Cl 44.60%, N 17.62%. 0 20.13%. H,NCoC1. Prepd by
`passing HC1 gas over heated cyanuric acid: Gattermann,
`Rossolymo, Ber. 23, 1190 (1890); Gattermann, Ber. 32,
`1117 (1899). From ammonia and phosgene at 400°: Rupe,
`1888 .
`g..abl'u;rd, Ber. 33, 236 (1900), cf Gattermann, Ann. 244, 30
`Liquid. Acrid, offensive odor. Has been obtained cryst,
`mp about 50’, bp 61-62“ (decompn). Reacts violently on
`contact with water, forming ammonium chloride and car-
`bon dioxide. During storage it gives off HC1 and slowly
`changes to cyanuric acid.
`1828. Carbanilic Acid. Phertylcarbamic acid; N-carb-
`oxyaniline. C7H.,NO1; mol wt 137.14. CEHSNHCOOH.
`Known only by its derivatives (esters, etc.).
`1829. Carbauilide. N,N’-Diphenylurea; diphenylcarb-
`amide; 1,3-diphenylurea; sym-diphenylurea. CHHHNZO;
`mol wt 212.25. C 73.57%, H 5.70%, N 13.20%, 0 7.54%.
`C6H,NHCONHC6H5. Obtained during the preparation of
`phenylurea from aniline hydrochloride and urea: Davis,
`Blanchard, Org. Syn. coll. vol. I, 453 (2nd ed., 1941). Crys-
`tal structure: W. Dannecker et al., Cryst. Struct. Commun.
`8, 429 (1979).
`Orthorhombic prisms from ale. d 1.239. mp 238°. bp
`260° (decompn). Sublimes in current of hydrogen at 220'.
`S01 in ether, glacial acetic acid. Sparingly sol in water (0.15
`g/l), acetone, alcohol, chloroform. Moderately sol in pyri-
`dine (69.0 g»/1).
`[4-[(Aminocarbonyl)amino]phenyl]-
`1830. Carbarsoue.
`arsonic acid; N-carbamoylarsanilic acid; p-ureidobenzeneaiu
`sonic acid; N-carbamylarsanilic acid; p-carbamidobenzene-
`arsonic acid; 4-ureido-1-phenylarsonic acid; 4-carbamyl-
`aminophenylarsonic acid; p-arsonophenylurea; Amabevan;
`
`HN
`’
`
`N
`H
`
`White powder. mp 174°. Slightly sol in water, alcohol;
`sol in solns of alkali hydroxides and carbonates. The satd
`aq soln is acid to litmus. Nearly insol in ether or chloro-
`fonn. LD50 orally in rats: 510 mg/ kg.
`THERAP CAT: Antiamebic.
`T1-{ERAP CAT (VET): Antihistomonad in turkeys.
`1831. Carbaryl.
`1-Naphthalenol methylcarbamate;
`methyl carbamic acid I-naphthyl ester; 1-naphthyl N-methyl-
`carbamate; ENT-23969; OMS-29; UC-7744; Arylam; Caryl-
`derm; Clinicide; Derbac; Dicarbam; Ravyon; Seffein; Sevin.
`CHHHNOZ; mol wt 201.22. C 71.63%, H 5.51%, N 6.96 a,
`O 15.90%. Prepn and description: Haynes et al., Contrib.
`Boyce Thompson Inst. 18, 507 (1957); Lambrech, U.S. pat.
`2,903,478 (1959 to Union Carbide). Metabolism: W. E.
`Whitehurst et al., J. Agr. Food Chem. 11, 167 (1963); J. B.
`Houston et al., Xenobiotica 5, 637 (1975). Degradation: D.
`G. Crosby et al., J. Agr. Food Chem. 13, 204 (1965); D. L.
`Heywood, Environ. Qual. Safi 4, 128 (1975). Toxicology:
`I.
`Nisbet, D. Miner, Environment 13, 10 (1971). Toxicity: M.
`Vandekar et al., Bull. World Health Org. 44, 241 (1971).
`Clinical
`trial
`in pediculosis:
`J. W. Maunder, Clin. Exp.
`Dermatol. 6, 605 (1981). Review: Carbamate Insecticides:
`Chemistry, Biochemistry and Toxicology, R. J. Kuhr, H. W.
`Dorough, Eds. (CRC Press, Cleveland, 1976) 301 pp.
`0
`
`,lL ca.
`N’H
`
`0
`
`CO
`
`Crystals, mp 142°. dfi 1.232. Moderately sol in DMF,
`acetone, isophorone, cyclohexanone. Soly in water at 30'’:
`120 mg/l. Vapor pressure at 25°: <4 X 10'’ mm Hg.
`Stable to heat, light, acids; hydrolyzed in alkalies; noncorro-
`sive. LDM orally in rats: 250 mg/ kg (Vandekar).
`Caution: Nausea, vomiting, diarrhea, bronchoconstric-
`tion, blurring vision, excessive salivation, muscle twitching,
`cyanosis, convulsions, coma, respiratory failure. Clinical
`Toxicology of Commercial Products, R. E. Gosselin et al.,
`Eds. (Williams & Wilkins, Baltimore, 4th ed., 1976) Section
`III, pp 79-82.
`USE: Contact insecticide.
`THERAP CAT: Ectoparasiticide.
`THERAP CAT (VET): Ectoparasiticide.
`2—Hydroxybenzoic
`1832. Carbazoclirome Salicylate.
`acid monosodium salt compd with 2-(1,2,3,6-tetrahydro-3-
`hydroxy-1 -methyl-6-oxo-5H-indol-5-ylidene)hydrazinecarbox-
`amide (1:1); 3-hydroxy-1-methyl-1,5,6-indolinedione semicar-
`bazone compd with sodium salicylate; adrenochrome semi-
`carbazone compd with sodium salicylate; adrenochrome
`monosemicarbazone sodium salicylate complex; Adenogen;
`Adrenosem; Adrestat-F; Statimo. C,7H,7N4NaO‘; mol ‘wt
`396.34. C 51.52%, H 4.32%. N 14.14%, Na 5.80%, 0
`24.22%. CmHnN4O,.C7I-I5NaO3. Prepd by refluxing adre-
`nochrome semicarbazone and Na salicylate in 30% meth-
`anol:
`Iwao et al., Japan. pat. 57 546 (1957 to Tanabe), CA.
`52, 4693 (1958).
`
`Page 290
`
`Consult the Name Index before using this section.
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2008 page 4
`
`

`
`2447
`
`Clomipramine
`
`Yellow material. Dec 145-170°. Sensitive to light and air.
`pH of 2% aq soln 6.3-6.5. Sol in citrate-phosphate buffer,
`pH 6-8.
`THERAP CAT: Antibacterial.
`
`- — 5-(2—Chloraphenyl)-1,3-dihydro-7-
`ni¢ro-2H-1,4-benzodiazepin-2-one; 7-nitro-5-(2-chlorophem
`yl)-3H-1.4-benzodiazepin-2(1H)-one; Ro-5-4023; Clonopin;
`Ikton'vil; Klonopin; Landsen; Rivotril. C“HwClN3O,; mol
`wt 315.72. C 57.07%, H 3.19%. C] 11.23%. N 13.31%. 0
`15.20%. Antiepileptic agent with anxiolytic and antimanic
`properties. Prepn: L. H.‘ Stembach et al.. J. Med. Chem. 6,
`261 (1963); 0. Keller et al., U.S. pat. 3,121,076 (1964 to
`Hoffmann-La Roche). Prepd but not claimed:
`J. Kariss,
`H. L. Newmark, U.S. pat. 3,116,203 (1963 to Hoffmann-La
`Roche). Alternate process: A. Focella, A. I. Rachlin, U.S.
`pat. 3,335,181 (1967 to Hoffmann-La Roche). Pharmacol-
`ogy: Guerrero-Figueroa et al., Curr. Ther. Res. Clin. Ex .
`11, 40 (1969); Lechat et al., Therapie 25, 893 (1970§;
`D_’Armagnac et aI.,
`ibid. 26, 439 (1971). Toxicology: Blum
`et aI., Arzneimittel-Forsch. 23, 377 (1973). Determn of
`clonazepam and its main metabolites: S. Ebel. H. Schiitz.
`ibid. 27, 325 (1977). Clinical efficacy in acute mania: G.
`Chouinard, Psychasomatics 26(l2), Suppl., 7 (1985); in panic
`disorders and agitation: R. Fontaine, ibid. 13. Comprehen-
`sive description: W. C. Winslow. Anal. Profiles Drug Subs.
`6, 61-81 (1977).
`
`0
`
`White crystals from ethanol-methylene chloride, mp
`236.5-238.5”. uv max (7.5% methanol in isopropanol): 248,
`310 nm (E 14500. 11600). Soly in mg/ml at 25°: acetone 31;
`chloroform 15; methanol 8.6; ether 0.7; benzene 0.5; water
`<0.1. pK, 1.5, pK2 10.5. LD” orally in mice: >4000
`mg/kg (Blum).
`Note: This is a controlled substance (depressant) listed in
`1995 .
`the U).S. Code of Federal Regulations, Title 21 Part 1308.14
`THERAP CAT: Anticonvulsant.
`
`2450. Clonidine. N-(2,6-Diehlarophenyl)-4,5-dihydro-
`1H-imidazol-2-amine; 2-(2,6-dichloroanilino)-2-imidaznline;
`2,6-dichloro-N-2-imidazolidinylidenebenzenamine; 2-(2,6-
`dichloroanilino)-1,3-diazacyclopentene-(2); 2-[(2,6-dichloro-
`pheny1)imino]-2-imidazoline. C,H,Cl,N,; mol wt 230.10. C
`46.98%, H 3.94%, CI 30.82%, N 18.26%.
`a1-Adrenergic
`agonist. Prepn: Zeile et al.. U.S. pat. 3,202,660 (1965 to
`Boehringer, Ing.). Use in shaving soap formulations:
`eidem, U.S. pat. 3,190,802 (1965 to Boehringer, Ing.).
`Pharmacology: Bolme. Fuxe. Eur. J. Pharmacol. 13, 168
`(1971). Revised structure: L. M. Jackman. T. Jen. J. Am.
`Chem. Soc. 97, 2811 (1975). GC detemin in plasma: P. O.
`Edlund, J. Chmmatog. 187, 161 (1980). Preliminary studies
`on potential antidepressant activity: D. C. Jimerson et aI..
`Biol. Psychiatry 15, 45 (1980); J. B. Malick, Prog. Clin. Biol.
`Res. 71, 165 (1981): Exptl use in drug rehabilitation: M. S.
`Gold, A. C. Pottash. Ann. N.Y. Acad. Sci. 362, 191-202
`(1981). Activity as oz-adrenoceptor agonist: A. G. Roach et
`al., J. Pharmacol. Exp.,Ther. 227, 421 (1983). Symposium
`
`phenylvinyl)phen0xy]triethylamine; 2-[p-(fi-chloro-a-phenyl-
`styryl)phenoxy]triethylarnine; 1-[p—(fi-diethylaminoethoxy)-
`phenyl]-1,2-diphenylchloroethylene; clomifene; chlorami-
`phene; MRL-41. CZEHRCINO; mol wt 405.97. C 76.92%,
`H 6.95%, Cl 8.73%, N 3.45%, 0 3.94%. Synthetic estrogen
`agonist-antagonist. Prepn: Allen et al., U.S. pat. 2,914,563
`(1959 to Merrell).
`Stereochemistry of the geometric iso-
`mers: Ernst et al., J. Pharm. Sci. 65, 148 (1976).
`Induction
`of ovulation: R. B. Greenblatt, Fertil. Steril. 12, 402 (1961).
`Clinical trial in anovulatory women:
`J. Garcia et al.,
`ibid.
`28, 707 (1977). Use in male infertility: P. J. Sorbie, R.
`Perez-Marrero, J. Urol. 131, 425 (1984). HPLC determn of
`isomers in human plasma: C. L. Baustian, T. J. Mikkelson,
`J. Pharm. Biomed. Anal. 4, 237 (1986).
`
`Enclamiphene
`
`Citrate. Cz6H,,ClNO.C6H,,O.,. Clomid, Clomphid, Clomi-
`vid, Clastilbegyt, Dyneric, Ikaclomine, Pergotime, Serophene.
`Crystals, mp 116.5-118°. Slightly sol in water, chloroform;
`freely sol in methanol; sparingly sol
`in alcohol.
`Insol in
`ether.
`cis-Form, zuclomiphene.
`trans-Form, enclomiphene.
`THERAP CAT: Gonad-stimulating principle.
`2447. Clomipramine.
`3-Chloro-10,I1-dihydro-MN-db
`methyl-5H-dibenz[b,f]azepine-5-propanamine; 3-chloro-5-[3-
`(dimethylamino)propyl]-1 0,1 1 -dihydro-51-I-di benz[b,f]aze-
`pine; 3-chloro- 10, 11-dihydro-5-(3-dimethylaminopropy1)-
`SH-dibenz[b,f]az2epine; 5-(-y-dimethy1aminopropyl)-3-chloro-
`iminodibenzyl; chlorimipramine; G-34,586. C,,H1,ClN1;
`mol wt 314.86. C 72.48%. H 7.36%. Cl 11.26%. N 8.90%.
`Prepn: P. N. Craig et al.. J. Org. Chem. 26, 135 (1961); W.
`Schindler. H. Dietrich. Swiss. pat. 371,799; eidem, U.S. pat.
`3,467,650 (1963, 1969 both to Geigy). Crystal and molecu-
`lar structure of the hydrochloride: M. L. Post, A. S. Horn.
`Acta Crystallogr. 33B, 2590 (1977). Clinical trial in obses-
`sive-compulsive disorder: J. DeVeaugh-Geiss et al., Psycho-
`pharmacol. BuIL 25, 36 (1989).
`
`0N
`
`/CH3
`
`Ic
`
`u,
`
`bpu 160-170°.
`Hydrochloride. C,,Hz3ClN,.HC1, Anafranil. Crystals
`from acetone-ether/methanol-ether, mp 189-190“ (Craig);
`also reported as crystals from acetone, mp 191.5’-192°.
`(Schindler, Dietrich).
`THERAP CAT: Antidepressant.
`2448. Clomocycline.
`7-Chloro-4-(dimethylamino)-1,4,-
`4a, 5,511, 6, 11, 12a-actahydro-3, 6, 1 0, 12, 12a-pentahydrox_y-N-
`(hydraxymethyl) -6-methyl-1, 11 -dioxa-2-naphthacenecarbox-
`amide; chlorrnethylenecycline; N7-(hydroxymethyl)chlortet-
`racycline; N-methylol-7-chlortetracycline; Megaclor.
`C13-
`H,_5ClNzO,; mol wt 508.91. C 54.28%, H 4.95%, CI 6.97%,
`N 5.50%, O 28.29%. Semi-synthetic broad spectrum anti-
`biotic related to tetracycline, q. v. Prepn: Banci, Tubaro,
`Boll. Chim. Farm. 102, 471 (1963); Belg. pat. 628,142 (1963
`to AB Leo). CA. 60,, 158051 (1964).
`
`Page
`
`Consult the Name Index before using this section.
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2008 page 5
`
`

`
`Clorazepic Acid
`
`Crystals from acetonel hexane.
`THERAP CAT: Glucocorticoid.
`
`[Ia(Z),2B(IE,3R'*),3o¢,5o:]-(:t)-7-
`2461. Cloprostenol.
`[2-[4-(3-Chlorophenoxy)—3-hydroxy-I-butenyl]—3,5-dihydroxy—
`cyclopentyl]-5-heptenoic acid. CH1-I2,ClO; mol wt 424.92.
`C 62.19%. H 6.88%. Cl 8.34%. 0 22.5973. Aryloxymethyl
`analog of prostaglandin F . q.v. Prepn:
`J. Bowler, Ger.
`pat. 2,223,365 (1972 to ICI , CA. 78,
`l10692v (1973); D.
`Binder er al.. Prpstaglandins 6, 87 (1974).
`.Synthesis and
`biological activity: eidem,
`ibid. 15, 773 (1978). Short syn-
`thesis: N. R._A. Beeley er al., Tetrahedron 37, Suppl. 9, 411
`(1981). Disposition in the rat and marmoset: G. R. Boume
`et aI., Xenabiotica 9, 623 (1979). Effect on fertility in cows:
`N. Baishya et aI., Brit. Vet. J. 136, 227 (1980); on super-
`ovulation. fertilization. egg transport in ewes: D. Whyman,
`R. W. Moore, J. Reprod. Fertil. 60, 267 (1980).
`
`Sodium salt, C,,HuClNa0,, ICI-80996, Estrumate, Plan-
`ate.
`THERAP CAT (vim: 1n treatment of infertility in sows. gilts.
`In synchronization of estrus.
`2462. Clopyralid.
`3,6-Dichloro—2-pyridinecarboxylic
`acid; 3,6-dichlompicolinic acid; 3,6-DCP; Dowco 290; Lon-
`trel; Shield; Reclaim.
`c,H,c1,No; mol wt 192.00. c
`37.53%. H 1.57%. CI 36.93%. N 7.3
`a. O 16.67%. Systemic
`post-emergence herbicide for use in food crops and mes-
`quite. Prepn: H. Johnston, Belg. pat. 644,105; idem, U.S.
`pat. 3,317,549 (1964, 1967 both to Dow’). 'Altemate pro-
`cess: S. D. McGregor, U.S. pat. 4,087,431 (1978 to Dow).
`Physicochemical properties, toxicity and herbicidal activity;
`J. G. Brown, S. D. Uprichard. Proc. Brit. Crop Prat. Confi '-
`Weeds 1976, 119. GLC detennn: A. J. Pik. G. W. Hodg-
`son. J. Assoc. Offic. Anal. Chem. 59, 264 (1976). Persistence
`in soil: A. J. Pik et al., J. Agr. Food Chem. 25, 1054 (1977).
`Field trial in mesquite control: R. W. Bovey, R. E. Meyer,
`Weed Sci. 33, 349 (1985).
`
`Cl
`
`‘
`
`N
`
`COOH
`
`ii/ Cl
`
`White, odorless crystalline solid, mp 151-152“. Vapor
`pressure at 25°: 1.2)<10'-" mm Hg. Soly'at 25°: ~1000
`ppm in water,‘ >25% w/w in methanol, acetone, xylene.
`LDSO in male, female rats‘ (mg/kg):
`'> 5000, 4300 orally;
`LC (96 hr) to rainbow trout: 103.5 mg/1 (Brown. Uprich-
`ard .
`USE: Herbicide.
`[(5-Chloro—8-quinolinyI)-
`2463. Cloquintocet-Mexyl.
`oxyjacetic acid 1-methylhexyl ester; CGA-185072. CuHn-
`C1NO,; mol wt 335.83. C 64.38%. H 6.60%. Cl 10.56%. N
`4.17%. O 14.29%.
`Safening agent
`to~protect crops from
`herbicidal injury. Prepn: A. Hubele, Eur. pat. Appl. 94,-
`349; idem. U.S. pat. 4,902,340 (1983. .1990 both to Ciba-
`Geigy). Description:
`J. Amrein et al., Proc. Brighton Crop
`Prat. Confi
`- Weeds 1989, 71-76. Effects on herbicide
`metabolism in cereals: K. Kreuz et aI.. Z. Naturforsch. 46c,
`901 (1991).
`
`-
`
`Odorless crystals, mp 69°. Vapor pressure (20"): 2.5 X
`10-‘ Pa. Soly in water (20°): 0.8 ppm. Sol in most organic
`solvents. LD5, in rats (mg/kg):
`>2000 orally; >2000
`dermally. LC50 (4 hr) in rats: >935 mg/m3 by inhalation
`(Amrein).
`=
`‘
`Mixture with clodinafop-propargyl, Célip.
`USE: Herbicide safener.
`2464. Cloranolol.
`1'—(2,5-Dichlaraphenaxy)-3-[(1,1-di-
`methylethybamin0]-2-propanol; 1-(tert-butylamino)-3-(2.5-
`dichlorophenoxy)-2-propanol.V C,3H,,Cl2NOz, mol ”wt
`292.20. C 53.44%, H 6.55%, Cl 24.27%. N 4.79%, O
`10.95%.
`fl-Adrenergic blocker. Prepn: G. Richter, Ger.
`pat. 2,213,044 (1972 to Res.* Inst. Pharm. Chem. Hungary),
`CA. 78, l5780p (1973). Effect on plasma renin and blood
`pressure:
`I. Tenyi. Curr. Ther. Res. 21, 823 (1977). Phar-
`macology: M. I. K. Fekete et al., Arch. Int. Pharmacodyn.
`248, 190 (1980). Electrophysiological characteristics:
`F.
`Solti. E. Czako, Int. J. Clin. Pharmacol. Ther. Toxicol. 18,
`229 (1980). Clinical-phannacological evaluation: E. Tiiriik
`et aI., ibid. 200. GC-MS determn in plasma: E. Tomori. E.
`Elekes, J. Chromatog. 204, 355 (1981). Multicenter clinical
`trial: E. Tiiriik et al.. Int. J. Clin. Pharmacol. Ther. Toxicol.
`23, 650 (1985).
`
`Crystals, mp 82-83”.
`Hydrochloridef C,3H,,Cl1NOz.HCl, GYKI-41099, To-
`banum. Crystals, mp 210-212“.
`‘
`THERAP CAT: Antiarrhythmic.
`7-Chloro-2,3—dihydra-2-oxo-5-
`.
`phenyl-1H-1,4—benzodiazepine-3-carboxylic acid.
`.C,,Hu-
`ClN,O;,; n1ol_wt 314.73. C 61.06%. H 3.52%. C] 11.26%.
`N 8.90%. O 15.25%. Prepn: Neth. pat. Appl. 6,507,637; J.
`Schmitt, U.S. pat. 3,516,988; reissued as U.S. pat. Re. 28,-‘
`315 (1965. 1970, 1975 all to Clin-Byla). Synthesis and ac-
`tivity of the dipotassium salt: J. Schmitt et al., Chim. Ther.
`4, 239 (1969). Solution chemistry: R. Raveux, M. Briot,
`ibid. 303. Metabolism:
`P. Gros, R. Raveux,
`ibid. 312.
`Toxicity data: M. Brunaud et aL, Arzneimittel-Forsch. 20,
`123 (1970). Series of articles on pharmacology and clinical
`use:
`ibid, 123-137.’, HPLC deterrnn in plasma: P. Colin, G.
`Sirois. J. Chromatog. 273, 367 (1983). Clinical trial in anxi-
`ety: w. w. K. zung, J. Clin Psychiatry 48, 13 (1987); in
`comparison with buspirone, q.v.: K. Rickels et al., Arch.
`Gen. Psychiatry 45, 444 (1988). Comprehensive description:
`J. A. Raihle, V. E. Papendick, Anal. Profiles Drug Subs. 4,
`91-112 (1975).
`
`’Dipotassium salt. C,,HmClKN1O3.KOH. 7-ChIoro-2,3-di-
`hydro-2-axo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic
`
`Consult the Name Index before using this section.
`
`Page 407
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2008 page 6
`
`

`
`2466
`
`Clorexolone
`
`acid monopotassium salt compd with potassium hydroxide,
`clorazepote dipotassium, Abbott 35616, CB-4306, Belseren,
`Mendon, Tranxilene, Tranxilium, Transene, Tranxene.
`White powder, freely sol in water. Very poorly sol in
`ethanol. Practically in sol in ether, chloroform. Aq solns
`are alkaline to phenolphthalein. uv max (anhydrous prod(cid:173)
`uct in water): 231, 311 nm (E 33500, 2450). LD50 in mice
`(mg/kg): 700 orally; 290 i.p. LD50 orally in rats: > 1000
`mg/kg (Brunaud).
`Monopotassium salt, C 16H 10ClKN10 4, CB-4311, Azene.
`Note: This is a controlled substance (depressant) listed in
`the U.S. Code of Federal Regulations, Title 21 Part 1308.14
`(1995).
`THERAP CAT: Anxiolytic.
`2466. Clorexolone. 6-Chloro-2-cyclohexyl-2,3-dihydro-
`3-oxo-1H-isoindole-5-sulfonamide; 6-chloro-2-cyclohexyl-3-
`oxo-5-isoindolinesuljonamide; 5-chloro-2-cylohexyl-1-oxo-6-
`sulfamoylisoindoline; 5-chloro-2-cyclohexyl-6-sulfamoyliso(cid:173)
`indolin -l-one; 5-chloro-2-cyclohexylphthalimidine-6-sulfon(cid:173)
`amide; M & B 8430; RP-12833; Flonatril; Nefrolan. C 14-
`H17ClN103S; mol wt 328.82 .. C 51.14%, H 5.21%, Cl
`10.78%, N 8.52%, 0 14.60%, S 9.75%. Prepn: Belg. pat.
`620,654 corresp to G. E. Lee, W. R. Wragg, U.S. pat.
`3,183,243 (1963, 1965 both to May & Baker).
`
`0
`
`Cl
`
`Dark red needles from alcohol, pale yellow needles from
`dil acetic acid, mp 145-146•. Practically insol in water. Sol
`in organic solvents except petr ether. LD50 orally in mice:
`1220 mg/kg (Fontaine).
`THERAP CAT: Anticoagulant.
`2469. Clorophene. 4-Chloro-2-(phenylmethyl)phenol; 4- ·
`chloro-a-phenyl-o-cresol; 2-benzyl-4-chlorophenol; 5-chloro-
`2-hydroxydiphenylmethane; o-benzyl-p-chlorophenol; Septi(cid:173)
`phene; Santophen 1. C 13H 11Cl0; mol wt 218.68. C 71.40%,
`H 5.07%, Cl 16.21%, 0 7.32%. Prepn: Klarmann et al., J.
`Am. Chern. Soc. 54, 3315 (1932); Klarmann, Gate, U.S. pat.
`1,967,825 (to Lehn & Fink); from Na or K phenoxide and
`benzyl chloride followed by chlorination of the resulting o(cid:173)
`benzylphenol: Kaiser, Ger. pat. 703,955 (1941 to Deutsche
`Hydrierwerke).
`
`Prisms, mp 266-268•. Soly in water at 25•: 16 mg/1.
`THERAP CAT: Diuretic.
`2467. Cloricromen. [[8-Chloro-3-[2-( diethylamino )eth(cid:173)
`yl}-4-methyl-2-oxo-2H-1-benzopyran-7-yl]oxy]acetic acid ethyl
`ester; ethyl [[8-chloro-3-[2-(diethylamino)ethyl]-4-methyl-2-
`oxo-2H-l-benzopyran-7 -yl]oxy ]acetate; 8-monochloro-3-{tl(cid:173)
`diethylaminoethyl}-4-methyl-7 -ethoxycarbonylmethoxy(cid:173)
`coumarin; 8-chlorocarbochromen; AD6• Cl!lH16ClN05; mol
`wt 395.88. C 60.68%, H 6.62%, Cl 8.96'Jo, N 3.54%, 0
`20.21%. Derivative of coumarin, q. v. Prepn: F. della Valle,
`Belg. pat. 871,315; idem, U.S. pat. 4,452,811 (1979, 1984
`both to Fidia). In vivo studies of activity as coronary vaso(cid:173)
`dilator: F. Aporti et a/., Pharmacal. Res. Commun. 10, 469
`(1978); as inhibitor of platelet aggregation: M. Prosdocimi
`et a/., Thromb. Res. 39, 399 (1985). Pharmacology in
`human platelets: R. A. Travagli et a/., ibid. 54, 327 (1989).
`Mechanism of action: S. Porcellati eta/., Agents Actions 29,
`364 (1990).
`
`Crystals, mp 48.5". bp3.5 160-162•. dU.s 1.186-1.190.
`In household, hospital and veterinary disinfectant
`USE:
`preparations.
`2470. Clorprenaline. 2-Chloro-a-[{( 1-methylethyl)ami(cid:173)
`no]methyl]benzenemethanol; o-chloro-a-(isopropylamino(cid:173)
`methyl)benzyl alcohol; 1-(o-chlorophenyl}-2-isopropylamino(cid:173)
`ethanol; N-(/3-o-chlorophenyl-/3-hydroxyethyl)isopropyl(cid:173)
`amine; isoprophenamine; isoprofenamine. C 11H 16ClNO;
`mol wt 213.71. C 61.82%. H 7.55%, Cl 16.59%, N 6.55%, 0
`/3-Adrenergic agonist. Prepn: Mills, U.S. pat.
`7.49%.
`2,816,059 (1957 to Lilly); Nash, U.S. pat. 2,887,509 (1959
`to Lilly).
`
`Crystals from ethyl acetate, mp 147-148·.
`Hydrochloride, C 10H 16ClN05.HCl, Cromocap, Proendotel.
`mp 219-220".
`THERAP CAT: Antithrombotic; vasodilator (coronary).
`2468. Clorindione. 2-( 4-Chlorophenyl)-1 H-indene-1,3-
`(2H)-dione; 2-(p-chlorophenyl)-1,3-indandione; 2-(4-chloro(cid:173)
`phenyl)indan-1.3-dione; chlophenadione; G-25766; MG-
`2552; lndaliton. C15H 9Cl01; mol wt 256.69. C 70.19%, H
`3.53%,,Cl 13.81%, 0 12.47%. Prepn: Cavallini et al., Far(cid:173)
`maca Ed. Sci. 10, 710 (1955); Brit. pat. 748,251 (1956 to
`Geigy). Pharmacokinetics: Danek, Pogonowska-Wala, Pol.
`J. Pharmacal. Pharm. 25, 307 (1973), C.A. 79, lll540b
`(1973). Toxicity study: Fontaine et al., Med. Pharmacal.
`Exp. 17, 497 (1967).
`
`Hydrochloride monohydrate, C 11H 16ClNO.HCl.H10,
`Broncon, Clopinerin, Conselt, Fusca, Kalutein, Pentadoll,
`Restanolon. mp 163-164•.
`THERAP CAT: Bronchodilator.
`2471. Clorsulon. 4-Amino-6-(trichloroethenyl)-1,3-
`benzenedisuljonamide; 4-amino-6-(trichlorovinyl)-m-benz(cid:173)
`enedisulfonamide; MK-401; Curatrem. C8H 8Cl3N30 4S1;
`mol wt 380.66. C 25.24%, H 2.12%, Cl 27.94%, N 11.04%,
`0 16.81%, S 16.85%. Benzenedisulfonamide deriv with fas(cid:173)
`ciolicidal activity. Prepn: H. H. Mrozik, Ger. pat. 2,556,-
`122 (1976 to Merck & Co.), C.A. 85, 94100n (1976); H.
`Mrozik et al .• J. Med. Chern. 20, 1225 (1977). GLC de·
`termn in biological fluids: W. J. A. Vanden Heuvel et al .• J.
`Agr. Food Chern. 25, 389 (1977). Efficacy against liver
`fluke, Fasciola hepatica: D. A. Ostlind et al., Brit. Vet. J.
`133, 211 (1977); M. D. Schulman et al., J. Parasitol. 65, 555
`(1979). In vitro inhibition of glycolysis: M. D. Schulman,
`D. Valentino, Exp. Parasitol. 49, 206 (1980). Mechanism of
`action: M. D. Schulman et al., Mol. Biochem. Parasitol. 5,
`133 (1982). Pharmacokinetics: eidem, J. Parasitol. 68, 603
`(1982).
`
`Page 408
`
`Consult the Name Index before using this section.
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2008 page 7
`
`

`
`3042
`
`Diazepam
`
`7-Chloro-1,3-dihydro-1-methyl-5-
`phenyl—2H—1,4-benzodiazepin-2-one; 7-ch1oro-l-methy1-5-
`phenyl-3H-l,4-benzodiazepin-2(1H)-one; methyl diazepin-
`one; diacepin; LA-III; R0-5-2807; Wy-3467; NSC-77518;
`Apaurin; Atensine; Atilen; Bialzepam; Calmpose; Ceregu-
`lart; Dialar; Diazemuls; Dipam; Eridan; Eurosan; Evacalm;
`Faustan; Gewacalm; Horizon; Lamra; Lembrol; Levium;
`Mandrozep; Neurolytril; Noan; Novazam; Paceum; Paci-
`tran; Paxate; Paxel (obsolete); Pro-Pam; Q-Pam; Relanium;
`Sedapam; Seduxen; Servizepam; Setonilg Solis; Stesolid;
`Tranquase; Tranquo-Puren; Tranquo-Tablineu; Unisedil;
`Valaxona; Valiquid; Valium; Valrelease; Viva]; Vivol. C,‘-
`I-IHCINZVO; mol wt 284.74. C 67.49%, H 4.60%, C] 12.45%,
`N 9.84%. O 5.62%.
`Prepn:
`Stembach, Reeder, J. Org.
`Chem. 26, 4936 (1961); Reeder, Stembach, U.S. pat. 3,371,-
`085 (l968 to Hoffmann—La Roche); prepd but not claimed:
`eidem. U.S. pats. 3,109,843 and 3,136,815 (1963, 1964 to
`Hoffrnann-La Roche); M.‘Gates, J. Org. Chem. 45, 1675
`(1980); M. Ishikura et al.,
`ibid. 47, 2456 (1982). Purifica-
`tion: Chase, U.S. pat. 3,102,116 (1963 to Hoffmann-La
`Roche). Pharmacology: Hudson, Wolpert, Arch. Int. Phar-
`macodyn. Ther. 186, 388 (1970). Metabolism: Randall et
`al., Curr. Ther. Res. Clin. Exp. 7, 590 (1965); Van der
`Kleijn, Ann. N. Y. Acad. Sci. 179, 115 (1971). Toxicity: E. I.
`Goldenthal, Toxicol. Appl. Pharmacol. 18, 185 (1971). Bind-
`ing study in rat brain: R. F. Squires, C. Braestrup, Nature
`266, 732 (1977). Comprehensive description: A. Mac-
`Donald et aI., Anal. Profiles Drug Subs. 1, 79-99 (1972).
`Clinical pharmacokinetics: M. Mandelli et al.. Clin. Phar-
`macokinet. 3, 72 (1978).
`'
`
`H3C\
`
`o
`
`Plates from acetone + petr ether, mp 125-126‘. pK_ 3.4.
`So] in chloroform, DMF, benzene. acetone. alc; slightly sol
`in water. LD“, orally in rats: 710 mg/kg (Goldenthal).
`Note: This is a controlled substance (depressant) listed in
`the U.S. Code of Federal Regulations, Title 21 Part 1308.14
`(1995).
`THERAP CAT: Anxiolytic; muscle relaxant (skeletal).
`3043. Diazinon. Phasphorothioic acid 0,0-diethyl 0-
`[6-methyl-2—(I-methylethyl)—4-pyrimidinyl] ester; 'thiophos-
`phoric acid 2-isopropyl-4-methyl-6-pyrimidyl diethyl ester;
`0,0-diethyl 0-2-isopropyl-4-methyl-6-pyrimidyl
`thiophos-
`phate;