Stickstoffwerke Linz; appl... thiamine COOH COOH chlorine eg I Midoriamin... ?-epichlorohydrin propanecorboxylic acid f-cis-trons- mixture finalisation of Milnocipron hydrochlorid
Trang 1Midodrine M 1331
Reference(s):
DE 2 004 686 (Meiji; prior 3.2.1970)
US 3 761 588 (Meiji; 25.9.1973; J-prior 25.9.1969)
DOS 2 835 547 (Meiji; appl 14.8.1978; J-prior 15.8.1977)
DOS 2 537 375 (Meiji; appl 22.8.1975; J-prior 27.8.1974)
US 4 017 607 (Meiji; 12.4.1977; J-prior 27.8.1974)
US 4 188 480 (Meiji; 12.2.1980; J-prior 15.8.1977)
Omoto, S et al.: J Antibiot (JANTAJ) 24, 536 (1976)
Nakamura, K et al.: Chem Lett (CMLTAG) 1978, 1293
Formulation(s): tabl 400 mg
Trade Name(s):
F: Mosil (Menarini) Miocamen (Menarini; J: Miocamycin (Meiji Seika;
Miokacin (Firma; 1986)
Use: antihypotensive, a-adrenergic, vasoconstrictor
RN: 97476-58-9 MF: CI2Hl8N2O4 MW: 254.29
CN: (+)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
monohydrochloride
RN: 3092-17-9 MF: C,2Hl,N,04 HCl MW: 290.75
LD,,: 56.2 mglkg (M, i.v.); 246 mgkg (M, p.0.);
18.2 mglkg (R, i.v.); 68.8 mglkg (R, p.0.);
150 mglkg (dog, p.0.)
2-omino-2',5'-di- chloroacetyl
methoxyacetophenone chloride
FH3
NaBH,, Pd-C
b
sodium borohydride
Reference ( s ) :
DAS 2 523 735 (Lentia; appl 28.5.1975; A-prior 24.7.1974)
7%
t- OH
(1)
alternative syntheses:
Midodrine
AT 241 435 i ~ s t e r r Stickstoffwerke Linz; appl 11.6.1963; valid from 15.12.1964)
DOS 2 506 110 (Lentia; appl 13.2.1975)
BE 838 512 (Chemie Linz AG; appl 12.8.1976; D-prior 13.2.1975)
Trang 21332 M Midoriamin
Formulation(s): amp 5 mg; drops 10 mgtml; tabl 2.5 mg, 5 mg (as hydrochloride)
Trade Nume(s):
D : Gutron (Nycomed) I: Gutron (Guidotti) USA: ProAmatine (Roberts)
F: Gutron (Nycomed SA) J: Metligine (Taisho)
Midoriamin
(Thiamine cobaltichlorophylline complex)
ATC: A02B
Use: ulcer therapeutic RN: 8721 1-44-7 MF: C4,HS3CoN,O,S MW, 952.98
LD,,: 209 mglkg (M, i.p.); 3066 mg/kg (M, p.0.); 406 rnglkg (M, s.c.);
82 m g k g (R, i.p.); 3590 mglkg (R, p.0.); 201 mglkg (R, s.c.)
CN: [OC-6-24-(2S-tra1~s)]-[N-[(4-amino-2-methyl-5-pynmidinyl)methyl]-N-(4-hydroxy-2-mercapto-l-
methyl-l-butenyl)formamide]aqua[18-carboxy-20-(carboxymethyl)-8-ethenyl-l3-ethyl-2,3-dihydro- 3,7,1 2,17-tetramethyl-21H,23H-porphine-2-propan0at0(5-)-fl',fl2,~3,~]dihy&0genc0ba1tate(2-)
@%
H3C 3 silica gel or H2N gel permeation chrornatogrophy
-N_ ''I / C H ~ 7 Co(11) acetate
~3~'"' COOH 2 thiamine
COOH
COOH
chlorine eg
I Midoriamin
Trang 3Mifevristone M 1333
Reference(s):
JP 1 052 779 (Green Cross; appl 15.7.1988)
JP 63 264 483 (Green Cross; appl 11.3.1988)
JP 63 264 420 (Green Cross; appl 11.3.1988)
JP 57 062 281 (Green Cross; Nisshin Flour Mill; appl 1.10.1980)
JP 58 041 885 (Green Cross, Nisshin Flour Mill; appl 1.4.1982)
medical use for treatment of gastritis:
JP 2 149 522 (Green Cross; appl 30.1 1.1988)
Fonizulation(s): tabl 5 mg
Trade Name(s):
J: Midoriamin (Green Cross;
Nisshin Flour; 1988)
(RU-486) Use: abortifacient, orally active
progesterone and glucocorticoid receptor antagonist, contraceptive RN: 84371-65-3 MF: C,,H35N0, MW: 429.60
CN: (1 1 P, 17P)- 11-[4-(dimethylamino)phenyl]-l7-hydroxy-17-(l-propynyl)estra-4,9-dien-3-one
estro-4.9-diene- ethylene
I -propynylmognesium
bromide
FH3
4-dimethylaminophenyl-
dien-17-one (I)
7'43
1 Mifepristane
Trang 41334 M Miglitol
Referencefs):
EP 57 1 15 (Roussel-Uclaf; appl 8.1.1982; F-prior 9.1.1981)
US 4 386 085 (Roussel-Uclaf; 3 1.5.1983; appl 10.6.1982; F-prior 9.1.1981)
US 4 447 424 (Roussel-Uclaf; 8.5.1984; appl 10.6.1982; F-prior 9.1.1981)
US 4 5 19 946 (Roussel-Uclaf; 28.5.1985; appl 25.5.1984; prior 9.1.1982, 10.6.1982,30.3.1984; F-prior 9.1.1981)
US 4 634 695 (Roussel-Uclaf; 6.1.1987; appl 22.1.1985; prior 9.1.1982, 25.5.1984, 10.6.1982, 30.3.1984; F-prior 9.1.1981)
synthesis of 3,3-(ethy1enedioxy)estra-5(10),9(11)-dien- 17-one:
BE 651 813 (Merck & Co.; appl 1964)
alternative synthesis:
FR 1 336 083 (Roussel-Uclaf; appl 1962)
NL 6 406 712 (Roussel-Uclaf; appl 1964; F-prior 1963)
BE 651 812 (Merck & Co.; appl 1964)
Trade Namefs):
F: Mifkgyne (Exelgyn) GB: Mifegyne (Exelgyn)
Miglitol
(Bay-m- 1099)
ATC: AlOBF02 Use: antidiabetic, a-glucosidase inhibitor RN: 72432-03-2 MF: C,HI,NOs MW: 207.23 EINECS: 276-661-6
CN: [2R-(2a,3P,4a,5P)]-1-(2-Hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol
NH,, 2 enzymatic oxidation
3 deprotection with H+
CHO
H2 Raney-Ni
I -*
ethylene
0 H oxide (11)
0 H
6-deoxy-6- amino-L-sorbose (I)
pi
Trang 5Milnacipran hydrochloride M 1335
1 Gluconobocter oxydons MgSO,, H,O
-1 2 HZ, cat Miglitol
preparution of moranoline via N-formyl-6-amino-6-deoxy-L-sorbose:
DE 3 61 1 841 (Bayer; appl 9.4.1986; D-prior 9.4.1986)
a DE 2 758 025 (Bayer AG; 12.7.1979; appl 24.12.1977; D-prior 27.8.1977)
E P 4 9 858 (Bayer AG; appl 7.10.1981; D-prior 15.10.1981)
JP 54 106 477 (Nippon Shinyaku; appl 3.2.1978)
b DE 3 024 901 (Bayer AG; appl 1.7.1980)
c EP 477 160 (Monsanto Co.; 25.3.1992; appl 19.9.1991; USA-prior 20.9.1990)
Formulution(s): tabl 25 mg, 50 mg, 100 mg
Trude Numtfs):
D: Diastabol (Sanofi- USA: Glyset (Pharmacia &
Synthelabo; 1998) Upjohn; 1999)
Milnacipran hydrochloride
(Midalcipran hydrochloride)
ATC: N06AX17 Use: antidepressant, 5-HT and norepinephrine reuptake-inhibitor RN: 101 152-94-7 MF: C,sH22N20 HC1 MW: 282.82
CN: (+)-cis-2-(Aminomethyl)-N,N-diethyl- 1-phenylcyclopropanecarboxamide monohydrochloride
(+)-cis-base
RN: 92623-85-3 MF: C,,H2,N2O MW: 246.35
Trang 61336 M Milnacipran hydrochloride
synthesis of intermediate I: 2-0x0-1 -phenyl-3- oxabicyclo[3.1 O]hexone
1 1 50°C, 45 min
1 NoNH2, benzene 2 distillotion
3 H+
2 (?)-epichlorohydrin
propanecorboxylic acid ((f)-cis-trons- mixture)
finalisation of Milnocipron hydrochloride
1 SOBr2 C2H50H 2 r C H 3
tN
3 NoOH, H 2 0 %ooh 3 H C C2H50H
h
(+)-2-0x0- 1 -
phenyl-3-0x0- bicyclo[3.1.0]- hexane (I)
Milnocipran hydrochloride
1 SOCI, CH2C12
AIC13,
HO 1 thionyl chloride
2 phthalimide (+)-cis-2-hydraxy- potassium (111) methyl-N.N-diethyl-
1 -phenylcyclopropone-
corboxomide
1 N2H,, C2HSOH
2 HCI, C2HSOH
A Milnocipron hydrochloride
(N)
1 N2H4, C2H50H
Trang 7Milnacipran hydrochloride M 1337
(*)-cis- 1 -phenyl- 2-(brornornethy1)- cyclopropane- carboxylic acid
hexa-
rnethylene-
tetrarnine
1 N2H,, C2H50H
DMF 2 HCI, C2H50H Milnacipran
hydrochlaride
synthesis of intertnediate I:
Mouzi, G ; Cousse, H.; Bonnaud, B: Synthesis (SYNTBF) 1978 (4), 304
a EP 068 999 (Pierre Fabre S A.; appl 21.6.1982; F-prior 23.6.1981)
b EP 377 381 (Pierre Fabre S A,; appl 27.12.1987; F-prior 28.12.1988)
c EP 200 638 (Pierre Fabre S A.; appl 22.4.1986; F-prior 25.4.1985)
d FR 2 58 1 060 (Pierre Fabre Medicament; appl 3 1.10.1986; F-prior 25.4.1985)
synthesis of I -aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives:
Bonnaud, B et a].: J Med Chem (JMCMAR) 30,318 (1987)
alternative syntheses:
Shuto, S eta].: J Org Chem (JOCEAH) 61,915 (1996)
Shuto, S et a].: J Med Chem (JMCMAR) 38, 2964 (1995)
prolonged-release pharmaceuticals containing milnacipran:
WO 9 808 495 (Pierre Fabre S A,; appl 26.8.1997; F-prior 28.8.1996)
cotnpositions containing milnacipran and idazoxan:
WO 9 735 574 (Pierre Fabre S A.; appl 25.3.1997; F-prior 25.3.1996)
Formulation(s): cps 50 mg (as hydrochloride)
Trade Name(s):
F: Ixel (Pierre Fabre; 1997)
Trang 81338 M Milrinone
Use: cardiotonic, phosphodiesterase 111- inhibitor
RN: 7841 5-72-2 MF: C,,HYN3O MW: 21 1.22 EINECS: 278-903-6
LDS,,: 79mgkg(M,i.v.); 137mgkg(M,p.o.);
73 m g k g (R, i.v.); 91 m g k g (R, p.0.)
CN: 1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile
lactate
RN: 100286-97-3 MF: C1,HYN3O xC3H,03 MW: unspecified
4-picoline ethyl ocetote 1 -(4-pyridyl)-2-
proponone
4-dimethylomino-3-(4- 2-cyanoacetarnide
pyridy1)-3-buten-Zone (I)
dirnethylforrnarnide dimethyl acetal
Milrinone
DOS 3 044 568 (Sterling Drug; appl 26.1 1.1980; USA-prior 26.1 1.1979, 20.10.1980, 28.3.1980, 6.1 1.1980)
US 4 312 875 (Sterling Drug; 26.1.1982; prior 26.1 1.1979, 20.10.1980, 28.3.1980,6.11.1980)
US 4 313 95 1 (Sterling Drug; 2.2.1982; prior 26.1 1.1979, 20.10.1980,28.3.1980, 6.1 1.1980)
Singh, B.: Heterocycles (HTCYAM) 23, 1479 '(1985)
alternative synthesis:
ES 544 504 (Inke; appl 25.6.1985)
DD 274 620 (Arzneimittelwerk Dresden; appl 2.8.1988)
DD 256 13 1 (Akademie der Wissenschaften; appl 4.7.1986)
sustained release pharmaceutical composition:
EP 164 959 (Sterling Drug; appl 30.5.1985; GB-prior 4.6.1984, 30.5.1985)
Formulation(s): amp 10 mg1lO ml (as free base); USA: bag 100 ml, 200 ml (200 pglml); vial 10 ml, 20 ml (1
mglml) (as lactate)
Trade Name(s):
D: Corotrop (Sanofi Winthrop) F: Corotrope (Sanofi J: Milrila (Yamanouchi)
Winthrop; as lactate) USA: Primcor (Sanofi)
Trang 9Miltefosine M 1339
Miltefosine
(D 18506; Hexadecylphosphocholine)
ATC: LOlXXO9 Use: antitumor (topical treatment) RN:
LD,,:
CN:
(3
58066-85-6 MF: C,,H4,N04P MW: 407.58
246 mglkg (R, p.0);
680 mglkg (Mm, p.0);
603 m g k g (Mf, p.0)
2-[[(Hexadecyloxy)hydroxyphosphinyl]oxy]-N,N,N-trimethylethanaminium inner salt
1 POC13 THF, NEt3
2
3 H20, HCOOH H3C-(CH2),5-0\ 9
1 phosphoric trichloride HO/ \O-NH2 hexadeconol (1) 2 ethonolamine (11)
2-chloro-
1,3,2-dioxo-
phospholone
2-oxide
dimethyl sulfote
-
3 HpO H3C-(CH2)15-0\ /P
2 2-bromoethonol HO/ \O/\/Br
Miltetosine
1 POCI3 CHCI3, pyridine
3 H 2 0
2 choline tosylate
Trang 101340 M Minaprine
Reference (s):
a Kaatze, U et al.: Chem Phys Lipids (CPLIA4) 27 (3), 263-280 (1980)
EP 225 608 (Max-Planck-Ges.; appl 4.1 2.1986; D-prior 4.12.1985)
preparation of quuternized ethunamine phosphate estersfor oral or topical treulment of leishmaniasis:
EP 534 445 (Max-Planck-Ges.; appl 24.9.1992; D-prior 27.9.1991)
b Eibl, H.; Engel, J.: Prog Exp Tumor Res (EXPTAR) 34, 1 (1992)
Kamctani, F et al.: Nippon Kagaku Kaishi (NKAKB8) 9, 1452-1458 (1984)
c Nuhn, P et al.: Pharmazie (PHARAT) 37 (lo), 706-708 (1982)
d EP 521 297 (ASTA Medica; appl 26.6.1992; D-prior 4.7.1991)
synergistic antitumor pharmuceuticals containing them and allylglycerins:
AT 393 505 (Max-Planck-Gesellschaft; appl 27.4.1987)
Formulation(s): sol 60 mg/ml(lO ml bottles)
Trade Name(s):
D: Miltex (ASTA Mcdica
AWD)
Use: antidepressant RN: 25905-77-5 MF: Cl,H,2N40 MW: 298.39 EINECS: 247-329-8
CN: N-(4-methyl-6-phenyl-3-pyridazinyl)-4-morpholineethanamine
dihydrochloride
RN: 25953-17-7 MF: Cl,H22N,0 2HCI MW: 37 1.3 1
LD,,,: 63 mgkg (M, i.p.)
Cu, butanol,A
+
Reference (s):
DOS 2 229 215 (CEPBEPE; appl 15.6.1972; GB-prior 18.6.1971)
GB 1 345 880 (CEPBEPE; valid from 16.6.1972; prior 18.6.1971)
ZA 730 671 (CEPBEPE; appl 3.1.1 973)
medical use:
US 4 169 158 (Laborit Henri; 25.9.1979, GB-prior 18.6.1971)
Formulation(s): drops 5 %; tabl 50 mg, 100 mg (as dihydrochloride)
Trade Name(s):
F: Cantor (Clin-Comar-Byla; Cantor (Clin-Midy); wfm J:
Alcas (Taisho)