Edrophonium chloride E 731 Nutraflow (A1con)-comb. Soaclens (Alcon)-comb. Polyclean (A1con)-comb. GB: Limclalr (Sinclair) Edrophonium chloride ATC: N07A Use: cholinergic, antidote to curare principles RN: 116-38-1 MF: CloH,,CINO MW: 201.70 EINECS: 204-1 38-4 LD,: 8500 pgkg (M, i.v.1 CN: N-ethyl-3-hydroxy-N,N-dimethylbenzenaminium chloride hydroxide RN: 473-37-0 MF: C,,H1,NO2 MW: 183.25 LD,,: 9 mgkg (M, i.v.); 600 mglkg (M, p.0.) bromide RN: 302-83-0 MF: C,,,H,,BrNO MW: 246.15 LD50: 9 mglkg (M, i.v.); 600 mglkg (M, p.0.); 15 mgkg (dog, i.v.) 3-dimethylomino- ethyl edrophonium phenol bromide bromide Referencefs): US 2 647 924 (Hoffmann-La Roche; 1953; prior. 1950). Formulation(s): amp. 10 mglml; vial 10 mgllO ml Trade Namefs). GB: Tensilon (Roche); wfm USA: Enlon (Ohmeda) J: Antirex (Kyorin) Revers01 (Organon) Edrophonium chloride Tensilon (ICN) Efavirenz (DMP-266; L-743726) ATC: J05AG03 Use: antiviral for AIDS, reverse transcriptase inhibitor RN: 154598-52-4 MF: C14H,CIF,N0, MW: 3 15.68 CN: (4S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,l-benzoxazin-2-one (R)-enantiomer RN: 154801-74-8 MF: C14H9C1F3N0, MW: 315.68 racemate RN: 177530-93-7 MF: C,4H9C1F3N02 MW. 315.68 732 E Efavirenz 4-chloroaniline pivaloyl chloride N-(4-chloropheny1)- 2.2-dimethylproponamide (I) MTBE: methyl tert-butyl ether 1. BuLi. TMEOA, MTBE 2. H,C,0yCF3 , H0a0xc~3 . No0.4~. MTBE 0 3. HCI, HOAc NH2 . HCI 2. To%-OH. H,C-CN I - c,qCF3 111 2. ethyl trifluoroocetote 0 1. p-methoxybenzyl alcohol cyclopropyl- acetylene (N) COCI~ p0kH3 K2C03 heptane, THF " , CI GT" phosgene 3 c F,C \u C @ prepordon of cyclopropylacetylene (as)-5-chloro-a- (cyclopropylethynyl)- 2-[[(4-methoxypheny1)- methyllamino]-a- (trifluoromethyl) benzenemethanol (V) Ce(N03)3NH4N03 CH3CN, H20 ____* ceric ammonium nitrote pqi Efavirenz HC* BuLi, cyclohexane 'C~CI 4 C"3 2 resolution by crystall~zat~on Cl 3 HCI Efavrenz c 1 (S)-(-)-camphanay1 ('a @ 1 BuLl OLi n +IV + b Efavirenz 1 a Thornpason, AS. et al.: Tetrahedron Lett. (TELEAY) 36 (49), 8937-40 (1995). Thornpason, AS. et al.: J. Am. Chem. Soc. (JACSAT) 120,2028-2038 (1998). Pierce, M.E. et al.: J. Org. Chem. (JOCEAH) 63 (23), 8536-8543 (1998). W09 637 457 (Merck + Co.; appl. 21.5.1996; USA-prior. 25.5.1995). aa WO 9 622 955 (Merck + Co.; appl. 19.1.1996; USA-prior. 23.1.1995). WO 9 827 034 (Du Pont Merck; appl. 15.12.1997; USA-prior. 16.12.1996). b EP 582455 (Merck + Co.; appl. 3.8.1993; USA-prior. 7.8.1992, 27.4.1993). WO 9 520 389 (Merck + Co.; appl. 24.1 .l995; USA-prior. 28.1.1994). WO 9 834 928 (Merck + Co.; appl. 9.2.1998; USA-prior. 12.2.1997). Radesca, L.A. et al.: Synth. Commun. (SYNCAV) 27 (24). 4373-4384 (1997). WO 9 845 278 (Du Pont; appl. 2.4.1998; USA-prior. 7.4.1997). c Tan, L. et al.: Angew. Chem. (ANCEAD) 111 (5), 724 (1999). process for the crystallization using an anti-solvent: WO 9 833 782 (Merck + Co.; appl. 2.2.1998; USA-prior. 5.2.1997). antiviral combinations: WO 9 844 9 13 (Triangle Pharrn.; appl. 7.4.1998; USA-prior. 7.4.1997). WO 9 852 570 (Glaxo; appl. 14.5.1998; GB-prior. 17.5.1997). Formulariori(s): cps. 50 mg, 100 rng, 200 mg 734 E Ef ornithine Trade Name(s): D: SUSTIVA (Du Pont; 1999) USA: Sustiva (Du Pont; 1998) Eflornithine (DFMO; RMI-7 1782) ATC: P01CX03 Use: antineoplastic, antiprotozoal, inhibitor of ornithine decarboxylase, antipneumocystis RN: 67037-37-0 MF: C,H,2F2N202 MW: 182.17 LD,,: >3000 mglkg (M, i.p.); >5000 mglkg (M, p.0.); 1364 pglkg (R, intracerebral) CN: 2-(difluoromethy1)-DL-ornithine monohydrochloride RN: 68278-23-9 MF: C,H,,F2N,0,. HCI MW: 218.63 EINECS: 269-532-0 monohydrochloride monohydrate RN: 96020-9 1-6 MF: C6H12F2N20,. HCI . H20 MW: 236.65 0 CI LiN~CC3& + 'yF . lithium diiso- propylamide ~~,~~-dibenz~lidene- chlorodifluoro- arnithine methyl ester methane Eflornithine I/ Referencels): US 4 413 141 (MerrelL'loraude; 1.11.1983; appl. 17.9.1982; prior. 11.7.1977, 2.7.1979). US 4 330 559 (Merrell-Toraude; 18.5.1982; appl. 3.2.1981; prior. 11.7.1977, 10.4.1979). Bey, P. et al.: J. Org. Chem. (JOCEAH) 44. 2732 (1979). Metcalf, B.W. el al.: J. Am. Chem. Soc. (JACSAT) 100,2551 (1978). sy~tlzesis oJ (-)-iso~ner: EP 357 029 (Merrell Dow; appl. 30.8.1989: USA-prior. 31.8.1988). pharrnac~utical cornposifion: RE 881 209 (Merrell-Toraude; appl. 16.5.1980; USA-prior. 10.4.1979) conlbination with interferon: US 4 499 072 (Merrell Dow; 12.2.1985; appl. 24.1.1983; prior. 29.1 1.1982). Formuldon~s): vial 200 mg/rnl (20 g as hydrochloride hydrate) Trade Narne(s): USA: Ornidyl (Ilex Oncology; as Ornidyl (Marion Merrell hydrochloride hydrate): Dow; 1990); wfrn wfrn m Efonidipine hydrochloride ethanol E 735 Efonidipine hydrochloride ethanol ATC: CO~CA (NZ- 105) Use: antihypertensive, calcium channel blocker RN: 11 101 1-76-8 MF: C,,H,,N,07P . C,H,O HC1 MW: 7 14.20 LD,,: > 5 glkg (R, p.0.) CN: (+)-5-(5,s-dimethyl- 1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- pyridinecarboxylic acid 2-[phenyl(phenylmethyl)amino]ethyl ester P-oxide monohydrochloride compd. with ethanol (I: I) efonidipine RN: 11 101 1-63-3 MF: C3,H3,N307P MW: 631.67 hydrochloride RN: 11 101 1-53-1 MF: C34H3uN307P. HCI MW: 668.13 @)-base RN: 128194-13-8 MF: C34H,uN,07P MW: 63 1.67 @)-base RN: 128194-12-7 MF: C3,H,,N,07P MW: 631.67 1-rnethoxy-4,4-dimethyl- 1-phospho-2.6-dioxa- cyclohexone 2.2-dimethyltrimethylene acetonylphosphonote (I) 2.2-dimethyltrimethy- lene Z-amino-l-pro- penyiphosphonate (U) 2-(benzylphenylamino)- ethyl acetoacetate (111) 2-(benzylphenylamino)- ethyl 3-aminocrotonate (IV) 736 E Efonidipine hydrochloride ethanol VII + IV 2-(benzylphenylamino)- ethyl 2-(3-nitrobenzy- lidene)acetoacetote (VI) Efonidipine hydrochloride ethanol 1. toluene,A 2. chromotogrophy 3. H,C"OH , ~q. HCI I + V + N + Efonidipine hydrochloride ethanol + + 1 Efonidipine hydrochloride ethanol 4.4'-[(3-nitro- phenyl)methylene]- bismorpholine 1. toluene, A 2. chromatography 3. H~C-OH, oq. HCI 11 + VI -b Efonidipine hydrachloride ethanol 2. toluene.P 3. chrornotography -b Efonidipine hydrochloride ethanol Reference(s1: &to, K.; Sakoda, R.; Tanaka, S.: loth Int. Symp. Med. Chem. (Aug. 15-19, Budapest) 1988,301. preparation of efonidipine hydrochloridc ethanol: WO 8 704 439 (Nissan Chemical Industries; appl. 5.8.1987; J-prior. 22.1.1986,23.1.1986; USA-prior. 14.4.1986; J-prior. 25.1 1.1986). preparation of optically active (dihydropyridy1)phosphonate esters: PO2 01 1 592 (Nissan Chemical Industries; appl. 16.1.1990; J-prior. 29.6.1988). lrrc of topical ophthalmic composition. WO 9 323 082 (Alcon Laboratories; appl. 25.1 1.1993; USA-prior. 13.5.1992). pharmaceutical compositions: EP 344 603 (Zeria Pharmaceutical & Co.; Nissan Chemical Industries; appl. 6.12.1986; J-prior. 30.5.1988, 2.3.1989). combination with immunosuppressive, cardiovascular and cerebral activity: DE4430 128 (Hoechst; appl. 29.2.1996; D-prior. 25.8.1994). I Wrmuhion(s): tabl. I0 mg, 20 mg lkade Name(s): " Landel (Nissan Chem Shionogi-Zeria) 2 i, ! Elliptinium acetate ATC: L0IC;LOlXX Use: antineoplastic : RN: 58337-35-2 MF: C,,HI7N2O. C2H,0, MW: 336.39 EINECS: 261-216-0 : CN: 9-hydroxy-2,5,11 -tnmethyl-6H-pyrido[4,3-b]carbazolium acetate (salt) : 58447-24-8 MF: C,,H,,IN,O MW: 404.25 EINECS: 261-259-5 pyridine hydrochloride CH, 9-rnethoxyellipticine (extracted from Ochrosia maculata) methyl elliptmium iodide (U) iodide B 738 E Emedastine 1. Amberlite CG-50 2. oq. NaOH 3. H,C-COOH Elliptiniurn ocetote Reference(s): DOS 2 618 223 (Anvar; appl. 26.4.1976; F-prior. 25.4.1975). Formnlation(s): vial (lyo.) 50 mg Trade Name(s): F: Celiptium (Pasteur Vaccins) Emedastine ATC: R06AE Use: antihistaminic RN: 87233-61-2 MF: C,,H2,N40 MW: 302.42 CN: 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-l-yl)-lH-benzimidazole . fumarate (1:2) RN: 87233-62-3 MF: C,,H,,N,O . 2C,H40, MW: 534.57 LD,,,: 93 mglkg (M, i.v.); 2206 mdkg (M, p.0.); 609 mdkg (M, s.c.); 72 mglkg (R, i.v.); 1854 mglkg (R, p.0.); 643 mdkg (R, s.c.); 193 mglkg (dog, p.0.) 2-chloro- 2-chlora- benzirnidozole ethoxyethorne 2-chloro-1 -(2-ethoxy- e!hyl)benzirnidozole (I) N-methylhomo- Ernedostine piperozine Reference(s): EP 79 545 (Kanebo; appl. 5.1 1.1982; J-prior. 6.1 1.1981). percutaneous administration; EP 440 81 1 (Kanebo; appl. 23.8.1990; J-prior. 28.8.1989). Formulation(s): cps. 1 mg, 2 mg (as difumarate) Emorfazone E 739 I: Daren (Kanebo; 1992) Lemicut (Kowa) ATC: NO2 Use: anti-inflammatory, analgesic RN: 38957-41-4 MF: C,,H,,N30, MW: 239.28 EINECS: 254-220-9 LD,,: 700 mglkg (M, i.p.1 CN: 4-ethoxy-2-methyl-5-(4-morpholinyl)-3-(2N)-pyridazinone 1. NoOCH, 1. K,Cr,O,. H2S0, CI CI dichromote CI 4.5-dichloro-2- melhyl-3-(2H)- pyridarone (I) [>xi 03 0-CH3 rnorpholine Reference(s): DOS 2 225 218 (Morishita; appl. 24.5.1972). GB 1351 569 (Morishita; appl. 15.5.1972). synfhesis of4,5-dichloro-2-methyI-3(2H)-pyridazone: Homer, R.F. et al.: J. Chem. Soc. (JCSOA9) 1948, 2191. Formulalion(s); tabl. 100 mg, 200 mg Trade Name(s): J: Pentoil (Morishita; 1984) Enalapril ATC: C09AA02 Use: antihypertensive (ACE inhibitor) RN: 75847-73-3 MF: Cx,H2,N205 MW: 376.45 CN: (S)-l-[N-[l-(ethoxycarbonyl)-3-phenylpropyl]-~-alanyl]-~-pro~ine maleate (1:l) RN: 76095-16-4 MF: C,oH2,N205 . C,H,O, MW: 492.53 EINECS: 278-375-7 Mg. THF THF. -10 OC diethyl oxolate (2-brornoethy1)- ethyl 2-0x0- benzene 4-phenyl- butyrote (I) 740 E Enalapril H~CT~~ y3 H 0 DCC. CHZCIZ H,C 0 N COOH + H L-proline benzyl ester L-olonyl-L-proline benzyl ester (111) No[BH3(CN)] or H2/Pd-C, molecular sieve 0.4 nm N + l + sodium cyonoborohydride ethyl 3-benzoyl- acrylote Hz, Roney-Ni v + H C 24 h, room temperature 7 ______* (V) Enalapril El l.THF, 15°C 2. concentrotion and stripping off HCI in vacuum L-alonine anhydride (V1) I . C2H,0H. H,. Roney-Ni. H KOH. K,CO,, H,O 3 A molecular sieve YI + ~~COOH - N . L- proline Reference(s): Patchett, A.A. et al.: Nature (London) (NATUAS) 288, 280 (1980). . antihistaminic RN: 8723 3-6 1-2 MF: C,,H2,N40 MW: 302.42 CN: 1-( 2-ethoxyethyl )-2 -( hexahydro-4-methyl-1H-1,4-diazepin-l-yl)-lH-benzimidazole . fumarate (1:2) RN: 8723 3-6 2-3 MF: C,,H,,N,O 631.67 1-rnethoxy-4,4-dimethyl- 1-phospho-2.6-dioxa- cyclohexone 2.2-dimethyltrimethylene acetonylphosphonote (I) 2.2-dimethyltrimethy- lene Z-amino-l-pro- penyiphosphonate (U) 2-( benzylphenylamino )-. 7584 7-7 3-3 MF: Cx,H2,N205 MW: 376.45 CN: (S)-l-[N-[l-(ethoxycarbonyl )-3 -phenylpropyl ]-~ -alanyl ]-~ -pro~ine maleate (1:l) RN: 7609 5-1 6-4 MF: C,oH2,N205 . C,H,O, MW: 492.53 EINECS: 27 8-3 7 5-7