THE
`MER.CK.INDEX
`
`AN ENCYCLOPEDIA OF
`CHEMICALS, DRUGS, AND BIOLOGICALS
`
`FOURTEENTH EDITION
`
`Maryadele J. Q'Neil, Editor
`Patricia E. Heckelman, Senior Associate Editor
`Cherie B. Koch, AssociateEditor
`Kristin J. Roman, Assistant Editor
`
`Catherine M.' Kenny, Editorial Assistant
`Maryann R. D' Arecca, Administrative Associate
`
`Published by
`Merck Research Laboratories
`Division of
`
`MERCK & Co., INC.
`Whitehouse.Station, NJ, IJSA
`
`2006
`
`West-Ward Exhibit 1064
`Merck Index 2006
`Page 001
`
`

`

`Evan's Blue
`3905
`3906. Evening Primrose Oil .. · EEO: Seed oil of the evening
`(Springer, New York, 1967} 164 pp; Hulet, Bode, '"Separation
`primrose, Oenotherabiennis L.,Onagraceae,which contains ap(cid:173)
`Chemistry of the Lanthanides and Transplutonium Actinides" in
`prox 72% linoleic acid and approx 9% y-linolenic acid, q.q.v~;as the
`MTP Int.Rev, Sci.: lnorg. Chem., Ser. One vol. 7, K. W. Bagnall,
`two main constituents .... Unique among vegetable oils because of its
`Ed. (University Park Press, Baltimore, 1972) pp 1-45;Moeller, "The
`high content of o/;..1inolenic acid .. · Effect on prostaglandin biosyn,
`Lanthanides" in ComprehensiveInorganic Chemistry vol. 4, J.C.
`thesis inrats: B. Ai· Scholkens et al.t-ProstaglandinsLeukotriene(cid:173)
`Bailar, Jr. et al., Eds. (Pergamon Press, Oxford, 1973) pp 1-101; F.
`Med. 8, 273 (l 982). Clinical studies in atopic eczema: C. R.
`H. Spedding in Kirk-Othmer Encyclopedia of Chemical Technology
`Lovell et al., Lancet l, 278 (1981 ); S) Wright, J. L. Burton, ibid.
`vol..19 (John Wiley &, Sons, Ne\V York, 3rd ed., 1982) pp ~3,}~854;
`2, 1120 (1982); P. L. Biagi et al., Drugs Exp. en». Res. 14, 285
`Chemistry of the Elements, N. N .• Greenwood, A .. Earnshaw, Eds.
`(1988). Ingredient in cosmerics'foraging skin: ·J; P. Marty, DE
`(Pergamon Press, New York, 1984) pp 1423-1449. Brief review of
`properties: p. T. Seaborg, Radiochini.ActaSk, 115-1~2 (1993). •
`3447618 (1985 to Roussel-UCLAF), C.A. 103, 146984r (1985).
`'
`Brief review including discussion of uses; A. J. Barber, Pharm,
`Body-centered cubic crystal lattice; dJ.244; mp 826°. bp 1429°.
`J. 240, 723-725 (1988).
`Heat of fusion: 9.221 kJ/mol. Heat of sublimation (25°): 144.7
`Clear, golden yellow oil. d15 0.9283. ni5 1.4782. •·· Sapon. no:
`kJ/mol. Sol in liq ammonia. Showstwo reduction potentials
`287 .8. Iodine no. 154.8.
`-0.710 and -2.510 v. {referred to a normal calomel electrode):
`Note: Evening primrose oil products include Ef amol, Efamast,
`Noddack, Brukl, Angew. Chem. 50,362 (1Q37); gives two definite
`Epogam.
`series of salts, in one the metal is divalent, and in the other it is
`USE: . Dietary supplement. _
`trivalent.
`THERAP CAT: In ·treatment of atopic eczema and mastaglia,
`Sesquioxide. Europia. Eu203. Pink powder, d 7.42, prepd by
`heating the hydroxide, nitrate,' oxalate or sulfate at 1600°. The
`3907. Everolimus. [159351-69-6] 42-0-(2-Hy~roxyethyl)(cid:173)
`oxide of the divalent metal is prepd by reduction of the sesquioxide
`rapamycin; 40-0-(2-hydroxyethyl)rapa~ycin; RAD-001; SDZ
`RAD; Certican. C53Hg3N014; mol wt ?~:~.·.F·. C~6.43%, H
`at elevated temp.
`Hydroxide. Eu(OHh. Prepd by adding ammonia or an alkali
`8.73%, N 1.46%, 0 2B8~. ~,facroHde imm~nosuppre~sant; de(cid:173)
`hydroxide to a soln of an europic salt.
`rivative o{ rapamycin, q. V •. Jnh~bit.s cytokine-mediated lymphocyte
`Europic chloride. EuC13. Greenish-yellow needles; mp 623° in
`proliferation. Prepn: s. Cou~n~, R Sedrani,WO 94.~?0l?; eidem;
`nitrogen (in a closed tube), d35 4.471, prepd by passing sulfur
`US 5665772 (1994, .1997 both to Sandoz); Pharm~c<?l?gy: W.
`chloride over the heated oxide at 200-500° .. LD50 of trichloride in
`Schuler et al., TransplantationSa'; 3q (1997} .. Whole plpod determn
`mice: 550 mg/kg i.p.; 5 g/kg orally (Haley).
`by LC/MS: N. Brignol et al., Rapid Commun. Mass Specirom. 15,
`Europous chloride. EuCI2• Prepd by reduction of EuC13 with
`898 (2001); by HPLC: S. Baldelli et al., J. Chromatogr. B 816, 99
`hydrogenat 600°. White amorphous powder, sol in water.
`(2005). Clinical pharmacokinetics in combination with cyclo(cid:173)
`Europic sulfate. Eu2(S04)3. Octahydrate, a pinkish cryst
`sporine: J. M. Kovarik et al., Clin, Pharmacol. Ther. 69, 48
`solid, prepd by dissolving the oxide in sulfuric acid. Soly in water:
`(2001). Clinical study in preventionof cardiac-allograft vasculop(cid:173)
`2.56 parts per 100 parts at 20°, 1.93 parts per 100 parts at 40°. On
`athy: H. J. Eisen et al., N. Engl. J. Med. 349, 847 (2003). Review:
`heating at.375° yields the anhydr sulfate. ·
`·
`·
`·
`F. J. Dumont et al., Curr. Opin. lnvest. Drugs 2, 1220-1234 (2001);
`Europic nitrate. Eu(N03 h Hexahydrate, mp 85° in its water
`B. Nashan, Ther. Drug Monit. 24, 53-58 (2002).
`of crystallization (sealed tube). LD50 in rats (mg/kg): 210 i.p.;
`>5000 orally (Haley).
`Europous sulfate. EuS04. Colorless crystals. Insol in water
`and in dil acids. Prepd by electrolytic reduction of europic salts.
`USE: The salts in cathode ray tube coatings for color television
`receivers. Eu has a very high cross-section for the capture of
`thermal neutrons which is of value in the construction of electric
`atomic power stations. Organic derivs as shift reagents in NMR
`spectroscopy: C. C. Hinckley, J. Al;n. Chem. Soc. 91, 5160 (1969);
`R. E. Sievers, Nuclear Magnetic Resonance Shift Reagents (Aca(cid:173)
`demic Press, New York, 1973).
`3905. Evan's Blue. [314-13-6] 6,6'-[(3,3'-Dimethyl[l,l'-bi(cid:173)
`phenyl]-4,4' -diyl)bis(azo)]bis[4-amino-5-hydroxy-1,3-naphthalene(cid:173)
`disulfoni~ acid] tetrasodium salt; C.I. Direct Blue 53; 4,4' ::-bis[7-(1-
`amino-8-hydroxy-2,4-disulfo )naphthylazo ]-3,3 '-bitoly\ tetrasodium
`salt; C.I. 23860; T-1824; Azovan Blue. C34H24N6Na4014S4; mol
`wt 960.81. C 42.50%, H 2.52%, N 8.75%, Na 9.57%, 0 23.31 %, S
`13.35%. Prepd by coupling 1 mol of diazotizedo-tolidine with 2
`mols of Chicago acid (l-amino-8-naphthol-2,4-disulfonic acid):
`DE 35341; DE 38802 Frdl. 1,469, 488 (1877-1887); DE 3949;
`DE 57327; DE 75469 Frdl. 3,685,687,690 (1890-1894); Hartwell,
`Fieser, Org. Synth. coll. vol. II, 145 (1943). Diagnostic use: M. H.
`Nielsen, N. C. Nielsen, Scand. J. Clin. Lab. Invest. 14,605 (1962);
`0. Linderkamp et al., Eur. J. Pediatr. 125, 135 (1 ~77).
`
`.·½·· .. •, .. H
`'
`.
`;
`N
`
`0 ..
`.H
`....
`
`0
`
`CHs
`
`Na+ -03S~.. NH,
`
`H,C ·.· ·.
`
`·.
`
`-.
`
`CH, ~·.o H,N, ~.SQ,- Na'
`
`N=N ·n rl ·N=N f -
`
`Na+ -03S ~ - S03- Na+
`
`Blue crystals with bronze to green luster. Sol in water, alcohol,
`acids, alkalies. Indicator changing color near pH 10. Destroyed by
`strong oxidizing and reducing agents and precipitated from soln by
`strong concns of neutral salts. Rather stable in aq soln, and may be
`autoclaved at 15 lbs pressure for 30 min. Dye made up in physio(cid:173)
`logical saline should not be autoclaved.
`THERAP CAT: Diagnostic aid (blood volume determination);
`
`THERAP CAT: Immunosuppressant.
`3908. Evodiamine., [518-17-2] 8,13,13b,14-Tetrahydro-14-
`methylindolo[2' ,3' :3,4]pyrid,o[2,l-b]quinazolin-5(7H}-one. C19-
`H17N30; mol wt 303.36; C 75~23%, H 5.65.%, N 13.85%, 0
`5.27%. From Evodia rutaecarpa Hook. &Thoms and bark of
`Zanthoxylum rhetsa DC., Rutaceae: Y. Asahina, K. Kashiwaki, J.
`Pharm. Soc. Jpn. 1915, 1293, C.A. 10, 607 (1916);<.Gopinath et al.,
`Tetrahedron 8, 293 (1960). Structure: Y. Asahina J. Pharm. Soc.
`Jpn. 1924, l; Ohta, J, Pharm. Soc. Jpn. 65, 15 (1945), C.A. 45, 5697
`(1951). Synthesis: Asahina, Ohta, Ber. 61B, 319 (1928); T. Ka(cid:173)
`metani et al., J. Am. Chem. Soc. 98, 6186 (1976); eidem, Hetero(cid:173)
`cycles 4, 23 (1976). Biosynthesis.. M. Yamazaki et al., Tetra(cid:173)
`hedron Lett. 1966, 3221; 1967, 3317. Mass spec.: J. Tamas et
`al., Acta Chim. Acad. Sci. Hung. 89, 85 (1976).
`
`Page 666
`
`Consult the Name Index before using this section.
`
`West-Ward Exhibit 1064
`Merck Index 2006
`Page 002
`
`

`

`8114. _ .... _Utapafttyc.in:· \[5~ 123-88~9]', SirJ1iitiJsPRWPA:;.~~;
`AY-22989; NSC-226080; Rapamune. C51H79N013; mol wt914.I'7.
`C 67.01%, H 8.71%, N153%, 0 t.2:75,'f !riene macrolide anti(cid:173)
`biotic isolated from.Streptomycf?~ liygrosconicus .. -Name derived
`from the native wor~t~or Easter.lsl~n,~, Rapa Nui. Isoln: S. N.
`Sehgal et al., BE234768~,;eidem,/US 3929992 (1974, 1975 both to
`Ayerst McKenna Harrison); pu~!~fation and characterization: C.
`Vezina et al., J. Antibiot. 28;721 (1975); S. N. Sehgal et al., ibid.
`'1~~· hlpj~W9~ ()~¥A~W1:l.•r l,"'f~~on~e: ~. R. M~t&l1'5·~·~fa~.t~~~.t1·
`Physiol, Ph~r~a9~l~·;~st;4~,.~.~9,7t); .. ~f ~aft..rej~~4~¥ ~.itR~: .¢t ft
`sm~~,J~t .~ .• c.
`Eng et al., Transplant. Proc. 23, 8f?t~i,~~V:r.:t «
`Nicolaou et al., J. Am. Chem. Soc. 115, 4419 (1
`;D. Romo et al.,
`ibid. 7906. Se:riies oif articles>ontnerapeutiemonitotiig and phar(cid:173)
`macok:ineti<;s:.-i<Jlin.1:f/ier:22,S:upph~, Bl~B132 t2.000); onpbarA
`macologf ari.d,clinieal exp:erienee,in t~splantation: ·•• 'Frarisrplant!
`Proc. 35;•·.SuppL.1, S1PS2i3 ~2Q03J:···01inicalnrialin':prevention . .or
`coronary)re~t~nosis; ···1D.>~rMolmes; Ir: et al:, <Jirculation·• tOI; ,634
`(20.04.).····,
`
`8113:?c Rapaeuromum Bromide~ [l56l37:~SJ.9;.4J 1-[~2/t~a,-
`5a,16{3, 17'/3)~3,(AcetyloxyFl 'fl:.(hoxopropox,J-2-(l".'piperidinjd) ..
`androstan_4o~yl]~l 1-(2..:prdpenyl)piperidinium bro';Ulide; • l~JilJ.lylL2~
`(3a, 17 t3:.dihyclroxy-./Jf3~piperitlirld..:5 <X-'an.drostansl<S;~yl)piperidin;
`ium bromine 3-acetate • lf7..,propi<:>n~t¢; Org .. 9487 ;,Riaplon. [!37Hif'4
`N204.Br; mol wt 67'7;80: C 6Si:S6%1H 9.07%, N ttl3%;{) 9~¥14-%;
`Br 1L79%~ A.minosteroid;conu,etitive neuromuscular blocker.·
`Prepne ·T.Sleigh et al:JCS!Jt: 2094457;eiaem,lUS 5418226 (both
`to Akzo)» Clinical pharmacodynamics: ···P. ·M:.e:,~ Wi,-ight etal~;
`Anesthesiology 90, 16(1999).••.Clinkaltrial inpediat:rio patients:
`R~ F.,Kaplanet al.,>Anesth. Analg .. ,~9;11'12 (1999l/1R.eview of
`pharmacology and useiiti e11dotra6heatintul:>at:i.om ... s~ iV / Omust; R;.
`H. Foster, Drugs 58, 887-918 :(l999J.
`
`West-Ward Exhibit 1064
`Merck Index 2006
`Page 003
`
`

`

`9141
`USE: In organic chemistry as.aradical trap, a catalyst and in
`polymerization mediation.
`9141. TEMPOL. [2226-~6-2] 4-Hydroxy-2,2,6,6-tetra(cid:173)
`methyl-1-piperidinyloxy; 4-hydroxy-TEMPO; 4-hydroxy-2,2,6,6-
`tetramethyl piperidine N-oxide; 4-hydroxy-2,2,6,6-tetramethylpip(cid:173)
`eridinooxy. C9H18N02; molwt 172.24. C 62.76%, H 1'0.53%, N
`8.13%, 0 1~.58%. Stable nitroxyl radical; water-soluble analogue
`of TEMPO, 'q. v. Functions as a membrane-permeable radical scav(cid:173)
`enger. Prepn: E.G. Rozantsev, Bull. Acad. Sci: USSR Div. Chem.
`Sci. 12, 2085'(1964). Energy transfer studies: N. N. Quan, A. V.
`Guzzo, J. Phys. Chem. 85, 140 (1981). IR conformation study: W.
`A. Bueno, L. Degreve, J. Mol. Struct. 7~, 291 (1981). Solid state
`NMR spectra: C. J. Groombridge, M. J. Perkins, J. Chem. Soc.
`Chem. Commun. 1991, 1164. LC/MS/MS determn: I. D. Podmore,
`J. Chem. Res. Synop. 2002, 574. Use as a phase transfer catalyst:
`X.-Y. Wang et al., Synth. Commun. 29, 157 (1999). Review of
`effects in animal models for shock; ischemia-reperfusion injury, and
`inflammation: C. Thiemermann, Crit. Care Med. 31, S76-S84 _(2003).
`0
`
`HaC y .CH3
`Ha:Y.N 1'{.
`·. C.Ha
`
`OH
`Crystals from ether+ hexane, mp 71.5°. uv max (hexane): 240,
`450-500 (e --1800, --5). uv max (ethanol): 242, 435-A55(e
`--3800, --10). ,Sol in water.
`USE: Spin label. for EPR studies; phase transfer dehydration
`catalyst; antioxidant; inhibitor of olefin free radical polymerization.
`9142. · Temsirolimus, [1626:35-04-3] Rapamycin 42-[3-Hy(cid:173)
`droxy-2-(hydroxymethyl)-2-methylpropanoate]; rapamycin 42-es(cid:173)
`ter with 2,2..:bis-(hydroxymethyl)propionic acid; CCl-779. C56H87-
`N016; mol wt 1030.29. C 65.28%, H 8.51 %, N 1.36%, 0 24.85%~.
`Ester analog of rapamycin, q. v.; selectively inhibits mammalian
`target of rapamycin (mTOR). Prepn: · J. S. Skotnicki et al., US
`5362718 (1994 to Am. Home Prod.). Lipase-catalyzed synthesis
`from rapamycin: J. Gu et al., Org. Lett. 7, 3945 (2005). Clinical
`pharmacology: E. Raymond et al., J. Clin. Oncol. 22, 2336 (2004).
`Clinical study in advanced refractory renal cell carcinoma: M. B.
`Atkins et al., ibid. 909. Clinical evaluation in glioblastoma multi(cid:173)
`forme: E. Galanis et al., J. Clin. Oncol. 23, 5294 (2005); in breast
`cancer: S. Chan et al., ibid. 5314; in mantle cell lymphoma: T. E.
`Witzig et al., ibid. 5347.
`
`/OH
`
`'l" \:::OH
`
`H
`
`(I. .. H. H
`"(Yo .. _
`
`0
`
`00~ ·.!3
`
`0
`OCH3
`
`0
`
`nineplasminegen activater (human tissue .. type); TNK.-tPA; Meta,
`lyse ... Genetically engineered variant of human· tissue IJllasm.lliogen
`activator(t-PA), q.v.; expressed mCbinese hamster.ovary cells.' mol
`wt. --65. lcll·a,'Construoted by eligenucleotide ... directedmutagene(cid:173)
`sis at3 specific sites. Prepn:,W.F.1Bennett·etal.;WO ,9324635
`(1993 to Genentech); B. A; Keyt et al., Proc. Natt Acad: Seil USA
`91,· 3670• (1994) .. .Pbarmacelegyt C.R. Benedict etul., €J.irculation
`92, 3032 (J99d). Clinic.alphartnacokinetics: N. B~ Modi et al.,
`Thromb. Haemostasis 79, 134 .. (1998). Clinical trial in acute myo(cid:173)
`cardial infarction: ASSENT-2 lnvestigators,Lancet 354, 716 (1999).
`THERAP CA.T: Thrombolytic.
`9144. Tenidap. [120210-48~2~ ~Z):-?-Chlpro-2,3-dihydro-3-
`(hydroxy-2-thienylmethylene)-2-oxo, lH-indole-1-carboxamide; 5-
`chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)- lH-indole-1-car(cid:173)
`boxamide; 5-chloro-'S-(2-theno~d) .. 2..:oxindole-l:carbm~.amide; CP-
`66248. C14H9C1N203S; mol wt 320.75. C 5,2.42%, H 2.83%,
`Cl 11.05%, N 8.73%/0 14.9(;>%, S 10.00%. Inhibitor of 5-lipoxy(cid:173)
`genase and interleukin-I (IL~l) activity. Prepn: S. B. Katlin, EP
`156603; idem,JJS 4556672. (both 1985 t9 Pfizer), Effe,ct .. ?P 5-
`Iipoxygenase aytivity in vitro: *'·\ Jf9gq et al., Arc~r~e.1;,,n/!l~f .. Res.
`280, 430(19$8). Effect 011 IL-1 ~ctivity in patients .. ;oY.it\1,rh,e~pw~oid
`arthritis; ,B. McDonald·etgl.,.Arthritis Rheum, 31, S1.1;pp.1.,S52
`(1988). Clinical evaluation: P. Katz et al., ibid. S52.
`O~: .
`. I NH2
`
`N
`
`Fluffy, yellow crystals from acetic acid, mp 23()0 (dee) ..
`Sodium salt. [11.9784-94-Ql. CP-6µ24872 ... C14H8ClN2NaQ3S;
`molwt 342.73. Crystals from metµ~ol-:-isopropanol, mp 237-i38,0
`r
`THERAP CAT:, .Anti-inflammatory,
`9145. Tenip~8:i(le~ .. [29767-20,;.2] (5R,s~;8~,9S)~5,8,~,i,92
`Tetrahydro-~-(~-hy~rox:r-3,5-dim~thoxyph~nyl~-9.:[£4;6-0-[(1{),;.2-
`thienylmethylene ]""/3""D""glucopyranosyl]oxy]fllro[~ :,4' :6, 7]~~ph(cid:173)
`tho[2,3-d]-1;3~dioxol-6(5aH)-on~; 4' .:9emetp.ylepipo.1opµylJotoxin
`9-( 4,6.;.0~2-thenylidene-{3..:o-glucopyranoside ); ~, -dernethylepi(cid:173)
`podophyllotoxin-/3:.0-theri.ylidine ghicoside; ETf>; NS(:>122819;
`VM~26; Vehem-Sandoz; Vumon .. G32H3201'3S; ~olwt 6~6.65.
`C 58.5'3%, H ~.91 %, () 31.67%, S 4,.88%. · Semi-synt~~~i? ~~riva(cid:173)
`tive of podophyllotoxin, q.v: Prepn: A. Von \V:3:f{pUtJ~{fA
`6607585; C. Keeler-Juslen et al., US 3524844 (1968, 1970'ooth to
`Sandoz). Mechanism of action: H. Stahlen, Eur. ] .. Cancer 6,303
`(1970). Pharmacology: M. Hacker, Q. Roberts, Cqncer Res. 37,
`3287 (1977); S. M. Sieber et al., Teratology l~, 31 (1978); T. J.
`Vietti et al., Cancer Treat.Rep, 62', 1313 (1978). Metabolism: L.
`Allen, Drug Metab. Rev. 8, 119 (1978); Cancer Res. 38, 2549
`(1978). Clinical studies; N. M:Gadel-Mawla et al., Cancer Treat.
`Rep. 62, 993 (1978); R. E. Beliet et al., ibid. 445. Studies on
`delayed toxicity in 'mice after i.p. injections: M. Hacker, D. Rob(cid:173)
`erts, Cancer Res. 35, 1756 (1975); H .. Stahlin, Eur.J; Ca~c,~r ~i,,.~~5
`(1976). Review of pharmacology, pharmacokinetics an~l a~say
`methods: P. I. Clark, M. L. Slevin, cu« .. P~t;z{~qcakinet. l~,~t3-
`252 (1987). Comprehensive description:" J. J. Kettenes-van den
`Bosch et'al., Andi. Profiles Drug Subs.19, 575;..6QO(l990).
`s
`··
`_·: ·· ,
`_
`·
`.··
`.. ·.·-·.
`;
`
`if~o
`
`·
`
`·oli
`
`White solid. Sol in water. Lipophilic.
`THERAP CAT: Antineoplastic.
`9143. Tenecteplase. [191588-94-0] 103-L-Asparagine-117-
`L-glutamine-296-L-alanine-297-L-alanine-298-L-alanine,;.299+uala-
`
`Page 1572
`
`Consult the.Name Index before using this section.
`
`West-Ward Exhibit 1064
`Merck Index 2006
`Page 004
`
`