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`;_.SHIRE EX._20_09-..
`KVK v. SHIRE
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`' IPR2018—00293
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`p. 1
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`SHIRE EX. 2009
`KVK v. SHIRE
`IPR2018-00293
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`"
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`1.
`
`
`
`MERCK IN DEX
`
`AN ENCYCLOPEDIA OF
`
`_
`
`_
`
`CHEMICALS, DRUGS, AND BIOLOGICALS
`
`ELEVENTH EDITION
`
`
`
`Susan Budavari, Editor
`Maryadele J. O’Neil. Associate Editor
`Ann Smith, Assistant Editor
`Patricia E. Heckelman, Editorial Assistant
`
`
`
`Published by '
`
`MERCK & CO., INC.
`RAHWAY. N.J.. U.S.A.
`
`1989
`
`
`
`p. 2
`
`

`

`Copyright ® 1939 by Merck & Co., Inc.
`Previous Editions
`Copyright © 1940, 1952, 1960, 1963, 1916, 1983
`by Merck & Co., Inc.
`reserved under
`the
`international copyright
`rights
`All
`conventions. Copyright under
`the Universal Copyright
`Convention.
`
`The Merck Index is published on a non-profit basis as a
`service to the scientific community.
`
`Merck 8: 00., Inc.
`Rahway. New Jersey, USA.
`MERCK SHARP 8: DOHME
`West Point, Pa.
`MEHCK SHARP 8: DOHME INTERNATIONAL
`Hahway. NU.
`
`MEHCK SHARP & DOHME RESEARCH LABORATORIES
`Hahway. N.J.iWest Point. Pa.
`-'
`MSD AGVET DIVESION
`Woodbridge. NJ.
`
`HUBBARD FARMS. INC.
`Walpole. N.H.
`MEHCK CHEMICAL MANUFACTURING DIVISION
`Woodbridga N.J.
`MERCK PHARMACEUTICAL MANUFACTURING DIVISION
`Hahway. N.J.
`CALGON CORPORATION
`Water Management Division
`Pittsburgh. Pa.
`'
`Caigon Vesiai Laboratories
`St. Louls. Mo.
`KELCO UNISON
`San Diego, Ca.
`
`lst Edition—1339
`2nd Edition—4396
`3rd Edition—1907
`4th EditiOn—IQSO
`5th Edition—1940
`6th Edition—1952
`7th Edition—1960
`3th Edition—1968
`9th Edition—19%
`10th Edition—1933
`11th Edition—1989
`
`Library of Congress Catalog
`Card Number 89-60001
`ISBN Number 911910~28~X
`
`Printed in the U.S.A
`First Printing—November 1989
`Second Printing—February 1990
`Third Printingfi'icptem ber 1991
`
`\
`
`
`
`p. 3
`
`

`

`
`
`613
`
`Amphecloral
`
`
`
`
`
`pharmacol. 11, 1—98 (1973). Review of use and. abuse: I. P.
`Morgan. Substance Abuse Clinical Problems and Perspec.
`tires. J. H. Lowinson. P. Ruiz. Eds. (Williams &. Wilkins,
`Baltimore. 1981) pp 167-134. Books: C. D. Lenka, The
`Amphetamines: Their Actions and Uses (Thomas. Springfield,
`1953) 161'
`p; O. J. Kalant, The Amphetamines: Toxicity and
`Addiction
`homas. Springfield. 1966) 151 pp.
`
`Onto1““2
`
`Mobile liquid. Amine odor. Acrid, burning taste. Vola.
`tilizes slowly at room temp. di‘ 0.913. 139“" 200-203“; bpu
`82455“. Slightly soluble in water: sol in ale. other; readily 301
`in acids. Aq solns are alkaline to litmus.
`1-1351]
`in rats
`130 s.c. (Warren. Werner).
`{mg} kg):
`Sulfate. Cull-118192048. Alentoi. Benzedrine. Psycitotou,
`Crystals. Slightly bitter taste follchd by a
`. Sim pomina.
`sensation of numbness. mp above 300’ (doc). One part
`dissolves in 8.8 parts water. 515 parts 95% alc. A 30111 of 1
`g1 10 ml water has a pH 5-6. LD in mice. rats fingikg):
`24.2. SS orally (Behrendt. Deiningelrl).
`Phosphate. C9H16N04P. Actemtn, Aktedmn, Monophog,
`Profetamirte Phosphate, Racephcn, Raphetarru'ne Phosphate,
`Crystals. bitter taste. Sinters at about 150'. Dec around
`300". More so] in water than amphetamine sulfate. Slightly
`so] in alcohol. Practically (mo! in benzene, chlorolonn, eth.
`or. The pH of a 10% coin is about 4.6. Prepn: Goggin, I‘LS.
`pat. 2,507,468 (1950 to Clark 8: Clark).
`d—Form tannate. tartphetttmin, Syltatatt. Prepn: Cavallita,
`U.S. pat. 2.9511309 (1960 to Irwin. Neisler and 00.).
`d—Form sulfate, see Dextroamphctamine Sulfate.
`l-Form, Iemmphetamt’ue, levamfetamine.
`l—Fonn succinate. Cydril.
`Note: This is a controlled substance (Stimulant) listed in
`1981r .
`E116 U55. Code of Federal Regulations, Title 21 Part 1308.12
`THEM? CAT; CNS stimulant; anorexic.
`THEM? CAT {VET}: CNS stimulant.
`in narcotic poisoning,
`anesthetic collapse. in depression from encephalitis.
`617. Amphetaminil.
`a—[fl-Metityl-2-pheuy£elhyl)ami-
`itojbenzeneacetanitri 1e,- N—(a-methylphenethyl) —2-phenylgly.
`cinonitrlle: a-phenyl-a-{fi-pheny1isopropylamino)acetoni-
`trile; a-phenyl-a-(l-methy1-2-phenyl)ethylaminoacetoni-
`trile; a-phenyl-at-N-(l-phenylisnpropyl)aminoaoetonitrile;
`AN 1; Aponcuron. CnHmNfi mol wt 250.33. C 31.56%. H
`7.25%, N 11.19%.
`Prepd by reaction of oL—fl-phenylisu-
`propylamine with sodium cyanide and benzaldehyde or with
`a.-phenyi-o—bromoacetonitrile: Klosa, Ger. pat. 1,112,987
`{1959), CA. 56, 340911 l[1962); idem. J'. Pruitt. Chem. 20, 2'15
`(1963). Pharmacology: Dominok. Oelssner. Acta Biol. Med
`Ger. 20. 625 (1968); Beyer at at. Deal. Apotlt-Zlg 111. 61?.
`630 C1971). Metabolic Studies: Kornberg et at. Arch. Toxi-
`col. 29, 153 (1972). Chemistry: Beyrich et at. Plenum-1:121: 27,
`28 (1972); Gloeckl. Beyn‘ch.
`ibid. 95.
`-
`
`Cil CHNHC‘H
`2I
`I
`CH3 CU
`
`-
`
`.
`
`Crystals from ethanol-water. mp 85-87“.
`Hydrochloride. CHHI,CIN2. sinters at 100— 104°. mp 13-1-
`136'.
`THERM' CAT: Psychotropic.
`
`618. Amphornycin. Aml'omycin; glumamycin. CHE...-
`Nuom; mol wt 1290.46. C 53.98%. H "1.11%. N 14.11%. 0
`24.80%. Polypeptide antibiotic active against gram positive
`bacteria. Produced. by'Slreptomycer canus from soil collec-
`ted near Syracuse. NFL: B. Heinemann e: at, A tibial. &
`Chemotiler. 3,
`[239 (1953). Production:
`elder-rt.
`.8. put.
`3,126.317-(1964 to Bristol-Myers). Structure and identity
`with glurnamycin: M. Bodanszky et at, J. Am. Chem-Sac
`95, 2352-(1973). Pharmacology and toxicity: D. E. Tisch at
`at. Antibiot. Ami.- 1954-1955,
`lOlI. Machanism of action:
`H. Tannkaet at, Biochem. Biophys. Res. Commun. 86. 901
`
`at-Merhyl-N~(2.2,2-Irichloroethyliw
`613. Amphaclural.
`dens) benzeueethmmmine; a: -methyl -N—(2.2.2 -trichloroethyii -
`done)p he nethylamine; N—[Z —(l ~pbenylpropyll] —2.2.2 -trichlo -
`methylidenimine; amfccloral; Acutran. CHI-IuCIJN; mol wt
`264.60. C 49.93%. H 4.51%. Cl 40.20%. N 5.29%. Prepn:
`Cavallito. US. pat. 2,923,661 (1960 to Irwin. Neisler).
`
`r3
`
`1155 1.530.
`ail-Form, bp.,_5 95'.
`d—Fonn. {o]n_+49.9°i0.3' (c = 5 in dioxane).
`THEM CAT: Anorexic.
`
`'1-(3«unanimo-zoning-1dr..-
`614. Amphenidone.
`one; I-(m-amirtupheilyt)-2(1H}-pyridoue; Dornwa]. Cl Hm'
`14.0; mol wt 136.21. c 70.95%. H 5.41%, N 15.05151. 0
`8.59%. Prepn: Saudi et all, US. pat. 2,947,754 (1960 lo
`Wallace 31; Tiernan).
`.
`
`kHz
`
`I
`
`‘x
`/
`
`LDso orally in mice. rats:
`Crystals. mp 1325-1845“.
`1300. 3200 mgikg. Plekss et at, Fed Proc. 19, 390 {1960).
`THEIR.” CAT: Sedative; hypnotic.
`615.
`'Amphenone B.
`3,3-Bisfd-amirtopitenyIJ-B-bulan-
`one; amphenone; Z—oxo -3.3-IJis[p—aminophenyflbutane. C“-
`HisNIOi mol “1254.32. C 75.56%. H 7.13%. N 11.02%, 0
`6.29%. Prepn: Allen, Corwin. J'. Am. Chem. Soc.
`'72. 117
`(1950); U.S. pat. 2,539,388 (1951).
`Structure: Bcncze.
`Allen. J'. Org. Chem. 22. 352 (1957). Shows anliestrogenic
`activity in the chick oviduct test: Hertz et all, Recent ngr.
`Horm. Res 11, 119-141' (1955). Decreases adrenal action.
`Review: Subsidic Median 11]. 99-102 (1958).
`'
`
`NH?
`
`"in“
`13
`1}C=0
`
`| “
`
`“3
`
`11211
`
`-
`
`Crystals. mp 1315—138“.
`Dihydrochloride. CmHmCIINIO, crystals from ethanol.
`doc 272-375”. Soluble in water.
`Nate: Formerly a pinacolone structure was assignbd to
`amphenone B:
`.l,Z-BisfiJ-aminopheuylJ-Z-JHetlIyl-l-pro-
`pan-zine.
`'
`USE: 1n biological research.
`616. Amphetamine.
`(i)-at-Methyibeuzeneetharmmine;
`til-o:-merhyighenethyiamins,- 1-pheny1-2-aminopropane:
`(phenylisopropyl)amine; B-aminopropylbenzcne; racemic
`desoxy mar-ephedrine; Actedron; Allodene; Adipan; Sym-
`patedrine; Psychedrine; Isomyn; lsoamyne; Mecodrin:
`Norephedmne‘. Novydrine: Elastononi Ortédrine‘. Phene-
`drine; Profamins; Propisamine; Sympamine; Simpatedrin.
`(2.11.91: mol wt 1:15.20. c 79.95%. H 9.159%. N 10.36%.
`Prepn; U.S. pats. 1,879,003 (1932); 1,921,424 (1933);
`2.015.408 (1935); Hartung, Munch. J. Am. Chem. Soc. 53.
`1375 (1931). Demonstration of stereospecific binding Sites
`for (+)-3H-amphetamine in hypothalamic membranes and
`correlations with anorexic potency of phenylethylamines: S.
`M. Paul at at. Science 218. 487 (1932). Toxicity data: M.
`R. Warren, H. W. Werner. J. Pharmacol. Exp. Titer. 85, 119
`(1945); W. A. Behrendt. R. Deininger. Anrtet'mittel-Forsch.
`13. 711 (1963). Series of articles on the bioehemical and
`behavioral effects of amphetamines in man and animals:
`Handb. Exp. Pharmalcoi. 45. 3-304 (1977); Handbt Psycho-
`
`Page 92
`
`Consult the cross index before using this section.
`
`p. 4
`
`

`

`Ephedrine
`J-one disodium salt; 2342517"48imbmm0flu0rescein: bro-
`moeosine; tetrabromofluorescein sol; bromofluoreseeic acid;
`D .5: C Red No. 22; Cl. Acid Red 37; EOsine; (3.1. 45330.
`CnHfiBrdNazos; mol wt 691.91. C 34.12%, H 0.37%. Br
`43.20%, Na 6.65%. 0 11.56%. Prepd by bromination of
`fiucrcscein: Colour Index 701. 4 (3rd ed., 1911) p 4426.
`Br
`Br
`
`3561
`
`Crystals from acetonitrile, mp [IS—120'.
`THERAF CAT: Antihypertensive; anti —anginal.
`
`I-(4-Ethylphenyi)»2-methyl-3-(l.
`3553. Eperisone.
`pipert’dinyU-i-propanone; 4‘-ethyl-2-methyl-3-piperidino-
`propiophenone. CuflzsNO; mol Wt 259.40. C 78.12%. H
`9.71%, N 5.40%, O 6.17%. Spasmolytic agent related struc-
`turally to tolperisone, qty. Prepn: E. Morita et at, Ger. pat.
`2,458,633 corresp to US. pat. 3,995,047 (I975, [975 both to
`E5330. PharmacologiCal study: K. Tanaka et 51.. Nippon
`Yakurigaku Zasshi 77, 5:1 ([981). CA. 95, 3547“ (1980.
`Absorption, distribution. excretion in rats and guinea pigs:
`'1‘. Fujita et at. Oyo Yakuri 2], 835 {1981}. C.A. 96, 23193w
`(1982}. Toxicity study: H. Miyagawa at 0.1.. MM. 939. CA.
`96, 197228 (1982).
`
`
`
`N30 0 O I 0
`
`/
`
`Br
`
`Br
`
`I
`
`CWNa
`
`Red crystats with bluish tinge, or brownish-red powder.
`Freely sol in water, less in alcohol; insol in ether. The concd
`3.1:] min is deep bI‘OWHish-red. the dilute (1:500) soln is yel-
`lowish-red with greenish fluorescence:
`the alcoholic soln
`exhibits a strong green fluorescence.
`USE: Lipstick and nailmpolish coloring; dyeing wool. silk
`and paper; in red inks. Approved by FDA for use in drugs
`and cosmetics except for use in eye area: Fed. Regist. 47,
`53843 (1982).
`(E,E)-.S-(Z-M'ethyt-S—plieuyl—Z-pro-
`3556. Epalrestat.
`penylidene)-4-oxo~2-thioxo-3-thiatolia‘ineacetic acid; 5-
`[(E.E)-,G —methylcinnamylidenel-4—oxo-2-thioxo-3-thiazoli-
`dineacetic acid; 3-Carboxymethyl-5-(2-methyicinnamylid-
`enc)rhodanine; Ono-2235; Kinedak: Sorbistat. CHI-1,3190:—
`3:: mOl wt 3-19.39. C 56.41%, H 4.10%, N43???» 0 15.03%.
`3 20.08%. Aida-5e reductase inhibitor. Prepn: T. Tndao at
`at, Eur. pat. App]. 47,109; eid'em. US. pat. 4,464,382 {1982.
`1934 both to Ono Pharmaceutical).
`Inhibitory effect on
`aldose reductase In ultra: H. Terashima et at. J. Pharmacol.
`Exp. Ther. 229, 226 (1983). Effect on motor nerve conduc—
`tion and sorbitol levels in diabetic rats: R. Kikkawa et at,
`Diabetologt'u 24, 290 {1983}.
`lifted in rats on peripheral
`nerve dysfunction:
`eidem. Metabolism 33, 212 (1984); on
`retinal microangiopathy: K. Kojima e! at, Japan. J. Oph-
`thalmol. 29, 99 ([985).
`
`H
`1
`l
`s
`c
`c\
`\c/‘\‘ Y
`3:1
`N
`_
`'3 o
`\
`
`s
`
`election
`
`Crystals from ethanol ~water, mp 210 417'.
`N-Methyl—mglueamine salt. CHHMNIOEST crystals from
`methanol, mp 163-165“.
`THERAP CAT: Treatment of diabetic neuropathy.
`3557. Epanolol. N42{[3-(2-Cyanophenoxy1-2-ltydroxy-
`propyljamitrogerhyU-d-hydroxybeuzeneacetamEde;
`l-(2-
`cyanophenoxy -3-B-(4-hydroxyphenylaeetamido)ethylami-
`no-Z-propanol; ICI 141292; Visacor. C35H3N304; mol wt
`369.42. C 65.03%. H 6.28%. N 11.37%. 0 17.32%. Cardio-
`seleetive pI-adrenergie blocker with intrinsic sympathomi—
`metic activity.
`Prepn:
`L. H. Smith. Ger. pat. 2,362,563;
`Hem. U.S. pat. 4,167,581 (1974. 1979 both to ICI). Phar—
`macology in dogs: H. J. Smith et at. J. Pharm. Exp. Ther.
`226, 211 (1983); in humans: T. H. Pringle et (11.. Brit. J.
`Clin. Pharmacol. 21, 249 (1986).
`Pharmacokinetics and
`bioavailability in dogs:
`I. McAinsh at at. Eur. J Drug
`Metabol. Pharmacoltinet. 9, 129 (1984). Preliminary clinical
`trial in hypertension:
`13. Dahloi er 61., Brit. J. Clin. Pharmm
`Col. 18, 831 {1934}. Comparison with atenoiol. q. it, of bron-
`choeonstriCtor effect in asthmatics: S. Groth et 51., Eur. J.
`Clin. Pharmaem‘. 30, 653 (1986).
`
`CN
`
`HBOCHICONHCHICIQNI‘ICH;CHCHIO
`
`OH
`|
`
`Clinch2
`
`COCHCHQ.
`
`rs C
`
`
`
`Hydrochloride. CnHKCINO. E-646, EMPP, Michal,
`Mystical. Needles from isopmpanol. mp 170-172”. LI)“ in
`male S.D. rats. Wistar rats. mice {mglkg}: 1300. 1850. 1024
`orally (Miyagawa).
`THERAP CAT: Muscle relaxant (skeletal).
`Stems and
`3559. Ephedra Equisetina.
`‘ Ma Huang.
`leaves of Ephedra equisett'na Bunge. E. sinica Stapf. and other
`species of Epliedro. Goetaeeoe.
`Indigenous to China and
`India. It contains 0.75 to over-1% ephedrine; it is the source
`of natural ephedrine. Contains also Variable quantities of
`pseudoephedrine.
`3560. Ephedra Nevadensis. Cay note: canutillo; whore-
`house tea; tapopotei teamsters' tea. Leaves and branches of
`Ephedru nevadensrs 8. Watts. (E. antisyphilitica C. A. Mey.),
`Gneraceae. Habit. U.S. (Calm. Nevada). Contains little or
`no ephedrine.
`o:-[I~(Methy1amino)erhyl}benzgne.
`3561. Ephedrine.
`methanol; at -[l -{methy]amino}ethlebenzyl alcohol; 2-meth-
`ylamino -1—phenyl-l-propanol;
`l-phen yl-l -hydroxy-2-
`methylaminopmpanc;
`l-pheny1~2-methylamincpropanol:
`a-hydrcxy13-methylaminopropylbenzene.
`le-II NO; mol
`wt 165.23. C 72.69%, H 9.15%. N 8.48%. O 9.658 a.
`a: +
`5~Adrenergic agonist. Occurs in Ma Huang (Ephedm ml.
`gun's, E. sit-tics Stapf.. E. equiselfna Bunge, Gnetaceae) and in
`several other Ephedra spp. Extraction procedure: Rymill.
`McDonald. Quart.
`J. Pharm. Pharmacol. 10, 463 (1937).
`Isomeric forms include d- and l-ephedrine as well as d— and
`t-pseudoephedrine with l-ephedr'ine and d~pseudoephedrine
`as the naturally occurring isomers. Syntheses: Spiith, 65h-
`ring. Monatsh. 41, 319 (1920); Manske. Johnson.
`J. Am.
`Chem. Soc. 51, 580, 1906 (1929). Stereochernjstry: Freu-
`denberg et at.
`ibid. 54, 234 {1932): Freudenberg. Nikolai,
`Ann. 510, 223 (1934): Witkop, Foltz, J. Am. Chem. Soc. 79,
`197 {1957); Pfanz, Kirchner. Amt. 614, 14911958}. Sepn of
`isomers:
`Paris et at. Ann. Pharm. Franc. 25, 177 {1967).
`Mechanism of action of l-ephedrine: Drudi-Baraeeo e: at,
`Compt. Read. Soc. Biol. 158, 259 (I964). Toxicity: M. D.
`Fairchtld. G. A. Alles. «I Pharmacol. Exp. Ther’. 158, 135
`(1967). Review of new methods and developments in stereo-
`chemistry: Fodor. Recent Develop. Chem. Nat. Carbon
`Compounds 1, 15-160 (1965). Comprehensive description:
`8. A, Benezra, I. W. McRae in Analytical Profiles of Drug
`Substances. vol. 3, K. Florey. Ed.
`(Academic Press, New
`York, 1979) pp 489-507.
`-
`
`C“:
`.
`l
`HOCHCHNHCH
`
`racemr'c ephedrine. mcepltedrine. Crystals, mp
`dinorm.
`79‘. Sol in water, alcohol, ether. chlorofonn,oils.
`til-Form hydrochloride, CWHIECINO. Epiletonirt, Race-
`
`
`
`Consult the cross index before using this section.
`
`Page 565
`
`p. 5
`
`

`

`3562
`
`Epiandrnsierone
`
`
`
`phedriue Hydrochloride. Crystals. mp 187-133". One gram
`dissolves in 4 ml water. in about 40 ml of 95% alc at 20°.
`Practically insol in other. pH. about 6.
`til-Form sulfate. Giulia-£111,063. Rucepiiedriue Sulfate.
`Crystals. mp 247‘. Sol in water and alcohol. pH about 6.
`l-Form.
`l.-t.'r_ytlrro-Z-(methylar11.i11aJ-I-phenyipropart-l-ot'.
`Waxy solid. crystals or granules. Soapy feel. Gradually doc
`on exposure to light. May contain up to to mole 11.0
`(5.2%). Anhydr material is hygroscopic. mp 34“. Absorp-
`tion of water raises the mp to 40“. bp 255‘. pH of :1q solu-
`tion (I in 200) 10.8. One gram dissolves in about 20 ml Wa—
`ter. 0.2 ml alcohol; 801 in chloroform. ether. oils. Keep well
`closed in a cool place.
`Symposium on sympathomimetic
`agents:
`Ind. Eng. Chem. 37. 115-143 (1945).
`I-Forrn hydrochloride. Biapliedrin. Ephedrol, Ephedrosst.
`Sanedrlrre. Orthorhombic needles. affected by light. mp
`216-220“.
`[aim5 —33' to —-3§.S‘ (c = 5).
`131-1 of aq 30111 (1 in
`200) 5.9. One gram diSSolves in 3 ml water. l4 rnl alcohol.
`Practically insol in ether. chloroform.
`i-Form sulfate, orthorhombic needles. affected by light,
`mp 245° (dec).
`[(11135 "29.5 to —32.0° (c = 5). One gram
`dissolves in 1.2 ml water. 95 ml alcohol. Freely sol in hot
`alcohol. pH about 6.
`di- Pseudoephedrine. DL-rirrea- 2-(methylominoJ-l-
`phenyipropart--I-ol. Crystals. mp 113'.
`duPserr doephadrirte, d-lit-9p hedrlne, d-tsoep hedrirre.
`Rhombic tablets from ether. mp 119‘.
`[.143I +51? (c = 0.6
`in ale). pH of ac] soln (1 in 200) 10.8. Sparingly sol in water
`(differs from l—ephedrinc). Freely sol in alc or ether.
`d-Pseudoephedrine hydrochloride. Galpsettd, Navafed,
`Rhinoloir, Slrrufed, Sudafed. Symptom 2. Needles. mp 181-
`132“.
`[01]” +62” (c = 0. 8).
`1.1V max (ethanol):
`208. 251.
`2511‘, 264 nm (e 8300. 161, 2.01. 161). pKa 9.22. pH of do
`soln (1 in 200) 5. 9. Sol in water. alc. chloroform. LDsn'1 p.
`in mice:
`1.0 mmolelkg (Faimhild. Allen).
`d-Pseudoephedrine sulfate. Afrirtoi.
`Thaw CAT:
`l-Form as hronchodilator.
`fine as dccon gestant.
`THEM CAT (VET): Sympathomimetic. has been used to
`counteract hypotcnsion associated with anesthfiial as a
`mydriatic; in allergic reactions and as a CNS stimulant.
`3562. Epinndrnstel‘one.
`3.6-Hydroxy-5o1mrtdrostarI-I'F-
`one; 319- hydroxy-l'f--androsrnnone; isoandrosterone; 313-1111-
`drostanol- 1'?--one;
`313 hydroxyetioallocholan- l'i-one.
`H3001: mol wt 290.42.12.15 57%. H 19.41%. 0 11.92$...
`Present in normal human urine as a minor constituent. it is a
`less active androgen than androsteronc. Synthesis: Card.-
`well at at. J. Chem. Soc. 1953, 361: Johnson at 111.. J. Am.
`Chem. SOC. 75, 2275 (1953); Johnson er of.
`ibid. 78, 6331
`(1956). Review: R. l. Dorfroan. R A. Shipley. Androgens
`(may. New York. 19515).
`
`51- P560 doephcd -
`
`
`
`dl‘Form. crystals. mp 161-162“. Gives off a musk-like
`odor when hot.
`03-Form. crystals from ethyl acetate + petr other. mp
`1'14. 5‘.
`[411]” +88“ (111 methanol). Precipitated by digitonin.
`Practically msol in water. Soluble1n organic solvents.
`Acetate. 0.11.103. stout prisms. mp 103 104’.
`[121]}?
`+63. 5’ (chloroform)
`Benzoate. Czél-Lnoy. crystals. mp 210-212”.
`3563. Epichlfll‘oi'lydrln. Chlorolnethyioxiranc- dl-a-epi-
`chloroh ydrln:
`1 -chlo ro 4.3 -e poxypro pane;
`'y -chloropropyl -
`one oxide. groom.- mol wt 92.53. c 33.94%. H 5.45%. (:1
`38.32%. D 17.29%. Prepn: H. T. Clarke. W. W. Hartman.
`Org. Syrr. cull. voL I, 233 (211d ed.. 1941); G. Braun,
`I'bt'd.
`coll. vol. II, 256 (1943). Manuf: Faith. Kcyes 3r. Clark‘s
`Industrial Chemicals. F. A. Lowonheim, M. K. Moran. Eds.
`(Wileynlotcrsciencc. New York, 44.1: BEL. 1975) pp 335-338.
`
`Toxicity data: H. F. Smyth. C. P. Carpenter. J. Ind. Hyg.
`Toxicol. 30. 63 (1943)
`
`/”\
`cug—- 121112112131
`
`Liquid. d§° 1.1312: of 1.1750: 115“ 1.1436;
`.135 1.1101. mp
`-_-25.6'. bpm 117.9“: lap“, 98 0°: 13pm 79 3“;
`1
`’bfilm 62.;0‘ bp
`421)“; bpm 1515-; hp... —16.5'
`..1,161".44195:n
`43969: Ell
`1.43585. Flash pt. open cup:
`105°F (WC). Insolin “late?
`Misc with alcohol. ether. chloroform, trichloroethylene. Citr-
`bon tetrachloride; immiscible with petr hydrocarbons. LDsn
`orally in rats: 0.09 glkg (Smyth. Carpenter)
`Caution.“ Strong skin irritant. scnsitizcr Chronic expo.
`sure can cause kidney Injury: Pattys Industrial Hygiene and
`Toxicology Vol. 2A, (3. D. Clayton. F. E. Clayton. Eds. (Wi.
`icy-Intemcience. New York. 3rd ed.. 1981) pp 2242-2241
`This substance may reasonably be anticipated to be a carci-
`nogen: Fourth Arm 11111 Report on Cm‘ci'rtogens (NT? 35—002,
`1985) p 99.
`USE: Solvent for natural and. synthetic resins. gums, cellu-
`lose esters and ethers. paints. Varnishm. nail. enamels and
`lacquers. cement for Celluloid.
`
`3564. Epicholcstanol. So-Cholestou-Jn-al; Bmhydroxy.
`cholestane; e-cholcstanol.
`0,111.50; mol wt 388.65. c
`83.43%. H 12.45%. 0 4.12%. The 3u-hydroxy cplmer of
`cholestanol.
`Prepn from cholestanone: Ruzicka. H9111.
`Chim. Acta 17, 1407 (1934); cf. Marker, er al. J. Am. Chem,
`Soc. 57, 2359 (1935); Barnett er al.. J. Chem. 80.9. 1.940, 1390.
`
`
`
`[a]1°+34' (c—— 1.?
`Needles from alcohol. mp 1115486“.
`in chloroform). Less sol than Cholestanol.
`ll‘lot precipitated
`by digitonin.
`Acetate. (111-1502. mp 95.5-96“. Crystals from methanol.
`1141mm.
`(53.115202. mp 102-193:
`[0.]... +212” in chlo-
`rolorm.
`
`:mol
`3565. EpicholestcroL Cholera-S-en-Ja -oi.
`wt 386.64. C 83.87%. H 11.99%. 0 44.14%. The03’; ydroxy
`cpirner of cholesterol. Prepd from B-oxocholcsteryl chloride
`or from cholest —5-on -3-onB or by passing 01 into a 50111 of
`cholesteryl Mg chloride: Ruzicka, Goldberg. Holy. Chim.
`Acid 19, 140? (1936); Market. at al. J. Am. Chem. Soc. 511,
`481 (1936); Marker. 1.1.5. pat. 2.117.355 (1938); Barnett at
`11.1.. J. Chem. Soc. 1941]. 1390.
`
`c‘
`
`.
`
`1131:
`(91;.
`
`CH3
`
`1:11
`
`:1
`
`C113
`
`no"
`
`1 in
`
`101113" —35’ (c =
`
`Crystals from alcohol. mp 141.5“.
`alcohol). No1: prccipitcd by digitonin.
`Acetate, CHI-I430? crystals from methanol. mp 35‘.
`3566. Epicillifl.
`6-[(Amir1u-I,4-cycloiiexodiert-I-ylacet-
`yl)mrrirlo]-3,3-dirt:etityi-7-oxo-4-thio~l-azabicyclo[3.2.0]—
`hopinrreal-carboxylic acid; 6-[D-o1namino »2 -( 1. 4-1: yclohetul-
`dien-1-yl)acctamido]penlcillanic acid; D-u-atnino«(l.4-cy—
`clohexadlcn-l—yl)mcthylpenicillin: SQ 11302; Dcxaciiina;
`Dexaciiiin; Omnisan; Spectacillin. C“H”N05; mol wt
`351.43. c 54.69%. H 6.02%. N 11.96%. 0 is21%., s 9.12%.
`Semi-synthetic antibiotic related to penicillin. . Prepn:
`
`Page 566
`
`Consult the cross index before 115'ng this section.
`
`
`
`p. 6
`
`

`

`61123
`
`.
`
`5 -Methyl -5 -(3 -phenanthryl)hyd antoin
`
`yt-z,4-lmidazolidinedione; Norantoin; Nuvaronc. CmH _
`N 0,; mol wt 190.20. C 63.15%, H 5.30%, N 14.73%,‘23
`[
`.3291}. Prepn: Pinner, Ber. 21, 2325 (1388); Kjaer. Acm
`Chem. Sound. 4, 892 {1950); Klosa. Arch. Pharm. 2115, 274
`(1952).
`
`Fine needles from aq ethanol, mp 162-163“.
`THERAP CAT: Anticonvulsant.
`
`2-{[(3~Methylphe...
`6027. 3'-Methylphthalanilic Acid.
`yleinojcm-bouyljbenzoic acid; N~m-tolylphthalarnic acid;
`Duraset; Duraeet 20W; Tomasct.
`C 5111315103; mol Wt
`255.26. c 70.53%. H 5.13%, N 5.49%, d 18.30%. Prepam-
`lion: Smith. Hoffmann. US. pat. 2,556,665 (l95l to U,3_
`Rubber).
`
`C00“
`
`com. : .cn3
`
`Crystals, mp 149451”. Slightly 501 in water; sol in polar
`solvents with rapid decompn to the imicle. LDm orally in
`rats: $230 mgtltg.
`to prevent premature drop of ap.
`use: As a fruit set. :29.
`ples, pears. cherries. peaches. and of certain vegetable crops,
`such as tomatoes and peppers. Antishock treatment
`for
`plants. Caution: On ingestion is hydrolyzed to produce
`m-toluidine. This may cause kidney injury, anemia. met.
`hemoglobinemia.
`
`11,1 7,21-Trihydroxy-5.
`6028. Methylprcdnisolonc.
`lvdehydro-éa ~ methyl.
`methyl»)?,4-pregnadiene-3, 20-611mm;
`hydrocortisone; Al-6rx-mnthylhydrocortisone;
`fiat-methyl.
`l1fl.l?q.21-triol-1.4-pregnadieue-S.20-dione; Artisonc.
`Wyeth; Medrate: Medrol; Medrone; Metastab; Metrisone;
`Promacortine; Suprametil; Urbason.
`szl-IGGOS; mol wt
`SIM-.46. C 70.56%, H 8.08%; O 2l.35%. Prepn: Spcro et 81.,
`J. Am. Chem. Soc. 73, 6213 (1956); Fried,
`find. 31, 1235
`(1959); Sebek. Spero, US. pat. 2,897,218 ([959 to Upjohn);
`Gould. US. pat. 3,053,832 ([962 to Schering).
`
`01120“
`
`
`
`uv max
`
`[a]? +83° (dioxhne).
`Crystals. mp 223-237”.
`(95% ethanol): 243 nm («M 14,875).
`21 -A,cetat::, Dem-Medrate, Depo~rWedrol, Dem-Medrorte,
`Mepred. Crystals, mp 205 408'. ME," +10l° (dioxane).
`11"
`max (95% ethanol): 243 nm (QM 14,825). Practically insol in
`water.
`21 «PhDSphale disodium salt, CanNazosP. Medror' Stabi-
`sol.
`.
`21-Succinate sodium salt, C HuNaOs. Urbamn-Solubila
`Setu-Medrot‘. Prepn: Sebek.
`pero.
`lac. ctr. Sol in water:
`forms buffered soln suitable for i.v. injection.
`THERAP CAT: Glucouortieoid.
`THERAP CAT (VET): Glucocorticol'd.
`
`6029. p-(Z-Methylpmpenyl)phenol Acetate. p-Anetoxy-
`phenylisobutene; p-isobutenylphauol acetate; A042: Isotyl.
`0.1111402.- mol wt 190.23. c 75.76%. H 7.42%. 0 16.32%.
`Prcpn:
`v. Braun, Ann. 472, 7] (1929).
`
`14, 24 orally; 6?. 6'?
`LDsu in male. female rats (mglkg):
`Clem-tally (Gaines).
`USE:
`Insecticide. Caution: Cholinesterase inhibitor.
`
`s-Merhyt-
`6023. 5-Methyl-5-(3 -phenanthryl)hydantoin.
`5-(J-phenaatltmay0-2,4-imidazolidinediane; 5-(3’-phen-
`anthryl)-5-methylhydantoin. CHI-LAN Oz; moi wt 290.31.
`c 74.41%. H 4.36%. N 9.55%. 0 11.02%. Prepn: Nitz e: at,
`Amneimlttel-Farsch. 5, 33'! (1955); Brit. pat. 774.394 (195?
`to Camellia Farhw.)
`
`
`
`Crystals from ethanol. mp 236-231”.
`Sodium salt. Bagmsln-Natrium.
`THERAP CAT: Anticonvulsaat.
`
`S-Methyt-
`6024. N—Methylphenazonium Methosulfate.
`plwuazinium methyl sulfate; phenazine methosulfate. C“-
`Hume‘s; moi wt.306.34. C 54.89%. H 4.61%. N 9.5%. O
`20.89%, S 10.47%. Preprr: Kehrmnnn. Ber. 46, 341 (1913);
`Hillemann, ibid. 71, 34 (1938); Dickens, McIlWain, Biochem.
`J. 32, 1615 (1933). Mutagenicit
`study: S. Venitt, C. Crof-
`ton -Sleigh, Mutat Res. 68, 101‘I 1979).
`
`_
`
`Nf
`
`3
`
`11
`u
`
`1c
`
`Flat yellow to brown parallelepipcds from alc, mp 155~
`15?” (Hillemann); mp 167° (Dickens). Oxidation-reduction
`potential at 30‘ and pH 7: Eh. = +0080 v.
`USE: AS an electron carrier “'1 place of the Havine enzyme
`of Warburg in the hexosemonophosphzte system: Dickens.
`lac. cit.
`1n the prepn of succinic dehydrogenase: Green at
`01., J'. Biol. Chem. 217, 551 (1955).
`61325. Methylpllenidale.
`a-Phenyl-2-pt'peridineacetic
`acid methyl ester; methyl phenidylacetate; a-phenyl-a-(2-
`piperidyl)acetic acid methyl ester; methyl mphenyl-a-(Z-
`piperidyl)aoetate; methylphenidén; 431131) Ciba; Ritalin;
`Contedrin; Phenidylate. CqugNoz; mol wt 233.30. C
`72.07%. H 8.21%, N 6.00%, O 13.71251). Prepn: Panizzon,
`Helv. Chim. Acta 27, 1748 (1944). Separation of isomers:
`Rometseh. Us. pat. 2,957,880 (1960 to Ciba). Toxicity
`data: E. N. Green blatt. A. C. Osterberg, J'. Pharmacol. Exp.
`Ther. 131, 115 (196l). Comprehensive description: G. R.
`Padrnanabhan in Analytical Profiles of Drug Substances- vol.
`10, K. Florey. Ed. (Academic Press, New York. 1981) pp
`473-497.
`
`ll
`
`fBHS
`
`("j/cucmcn3
`
`Crystals from 50% alc, mp 'M-TS'. Sol in alcohol, ethyl
`acetate. ether. Practically insol in water. pet: ether.
`Hydrochloride, C 4H ClNOz. crystals, mp 224-226’. pKa
`B. 9. Sol in water. ale. ghlorofonn. A? 5% ac] soln is neutral
`to litmus.
`LDSfl orally in mice:
`[90 mglkg (Greenbiatt,
`Osterberg).
`Note: This is a controlled substance (stimulant) listed in
`198‘? .
`Elm UjS. Code of Federal Regulations, Title 21 Part 1308.12
`111mm? CA1“, CNS stimulant.
`
`6026. 3-Methyl-5-phenylllydantoln.
`
`J-Methyl-S-phen-
`
`Page 961}
`
`Carmel: the cross index before using this section.
`
`p. 7
`
`