pharrnac~utical cornposifion: RE 881 209 Merrell-Toraude; appl.. Formuldon~s: vial 200 mg/rnl 20 g as hydrochloride hydrate Trade Narnes: USA: Ornidyl Ilex Oncology; as Ornidyl Marion
Trang 1Edrophonium chloride E 731
Nutraflow (A1con)-comb Soaclens (Alcon)-comb
Polyclean (A1con)-comb GB: Limclalr (Sinclair)
Use: cholinergic, antidote to curare principles
RN: 116-38-1 MF: CloH,,CINO MW: 201.70 EINECS: 204-1 38-4
LD,: 8500 p g k g (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
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)
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
Trang 2732 E Efavirenz
4-chloroaniline pivaloyl
chloride
N-(4-chloropheny1)- 2.2-dimethylproponamide (I) MTBE: methyl tert-butyl ether
1 BuLi TMEOA, MTBE
2 H, 0yCF3 , H 0 a 0 x c ~ 3 No0.4~ MTBE
0
3 HCI, HOAc NH2 HCI 2 To%-OH H,C-CN
2 ethyl trifluoroocetote
0 1 p-methoxybenzyl alcohol
cyclopropyl- acetylene (N)
C O C I ~ p 0 k H 3
K2C03
heptane, THF
F,C \u
C
@ p r e p o r d o n of cyclopropylacetylene
(as)-5-chloro-a- (cyclopropylethynyl)- 2-[[(4-methoxypheny1)- methyllamino]-a- (trifluoromethyl) benzenemethanol (V)
Ce(N03)3NH4N03 CH3CN, H20 *
ceric ammonium
Efavirenz
HC* BuLi, cyclohexane
Trang 32 resolution by crystall~zat~on
Efavrenz
c 1 (S)-(-)-camphanay1
('a
@ 1 BuLl
OLi
b
Efavirenz
1
a Thornpason, A S et al.: Tetrahedron Lett (TELEAY) 36 (49), 8937-40 (1995)
Thornpason, A S 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)
W 0 9 637 457 (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
Trang 47 3 4 E Ef ornithine
Trade Name(s):
D: SUSTIVA (Du Pont; 1999) USA: Sustiva (Du Pont; 1998)
Eflornithine
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 H 2 0 MW: 236.65
0
CI
L i N ~ C C 3 &
propylamide
~~,~~-dibenz~lidene- chlorodifluoro-
arnithine methyl ester m e t h a n e
Eflornithine
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:
E P 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
Trang 5Efonidipine hydrochloride ethanol E 735
Efonidipine hydrochloride ethanol ATC: C O ~ C A
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)-
Trang 6736 E Efonidipine hydrochloride ethanol
V I I + IV
2-(benzylphenylamino)- ethyl 2-(3-nitrobenzy- lidene)acetoacetote (VI)
Efonidipine hydrochloride ethanol
1 toluene,A
2 chromotogrophy
3 H,C"OH , ~ q HCI
4.4'-[(3-nitro-
phenyl)methylene]-
bismorpholine
1 toluene, A
2 chromatography
3 H~C-OH, oq HCI
11 + VI -b Efonidipine hydrachloride ethanol
Trang 73 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,
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
Trang 8738 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)
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)
Trang 9Emorfazone 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
0 3 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)
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 O C
diethyl oxolate
Trang 10740 E Enalapril
H ~ C T ~ ~ 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
2 4 h, room temperature 7
*
(V)
Enalapril
E l
l.THF, 1 5 ° C
2 concentrotion and stripping off HCI in vacuum
L-alonine anhydride (V1)
I C2H,0H H, Roney-Ni
H KOH K,CO,, H, 3 A molecular sieve
L- proline
Reference(s):
Patchett, A.A et al.: Nature (London) (NATUAS) 288, 280 (1980)