Pharmaceutical Substances Syntheses, Patents, Applications - Part 218 docx

Vincamine
V
2171
combination with
glucose I-phosphate:
BE
874 154
(E.
Corvi Mora; appl. 14.2.1979).
quaternary ammonium salts:
DE
1
244 794 (Richter Gedeon; appl. 16.12.1963; H-prior. 19.12.1962).
Formulation(s):
amp. 15 mg/l ml, 20 mg; cps. 20 mg, 60 mg
Trade Name(s):
F:
Cervoxan (SmithKline
1:
Eburnal (Chiesi)
Beecham) Scleramin (Ibirn)
Tensiplex (Francia Farm.)
Vincamine
ATC: C04AX07
Use: vasodilator, antihypertensive,
cerebrotonic
RN:
1617-90-9 MF: C2,H2,N203 MW: 354.45 EINECS: 216-576-3
LD,,,:
47.74 mgtkg (M, i.v.); 460 mg/kg
(M,

p.0.);
1200 mgkg (R, p.0.)
CN:
(3a,14~,16a)-14,15-dihydro-l4-hydroxyebumamenine-
14-carboxylic acid methyl ester
@
by extraction of pulverized and NH3-solution treated plant material of Vinca minor
L.
(myrtle) with
toluene and column chramatographic separation of numerous (c.
30
biogenetic related) by-alkaloids
(indole
alkaloids)
@
partial synthesis (Omnium process)
(-)-tabersanine
(from Voacanga grains)
0
CI
0
3-chloroper-
0/CH3 benzoic acid
(-)-vincadifformine
9-oxide
(I)
(-)-3-hydroxy-3-methoxy-
carbonyl-l,2-didehydro-
aspidospermidine
9-oxide (11)

(CgH5)3P.
CHJCOOH
I1
+
triphenyl-
phasphine HOW,
apovincamine
(-)-I
4-epivincamine (111) (+)-Gncamine
2172
V
Vincamine
(in the product
mixture)
@
total synthesis
@
Richter Gedeon synthesis:
NoOC2H5 H3C7 NoOH
+
B~-CI

HOOC
0
0
k~,
diethyl ethyl-
1
-brorno-3- diethyl 2-ethyl-2- 2-ethyl-2-(3-
rnolonate

chloropropane (3-chloropropyl)- hydroxypropy1)-
rnolonate rnalonic ocid (IV)
perchlorote
1.
CH,OH. HCI
H2/Pd-C or NoBH4
2.
NoZCO,
VII
HCIO,
0
di~~clohexylcorbodiimide,
H,P04.
DMSO
VlIl
.%+%
H,C'
O
hi3
I
0
'CH~
H3C
(+)-epivincornine
(M)
(2)-vincomine
(X)
Vincamine
V
2173

racernate resolution with
(+)-tartaric acid or
(+)-0.0'-dibenz~~ltartoric
ocid or
Aq2CO3/celite or Pt/Rh (+)-carnphorsulfonic acid
M
-X
(in the mixture
of racernotes)
@
Roussel-Uclof synthesis:
1. H3C/0v'~~2
butyr- pyrrolidine
aldehyde
1 -pyrrolidino- ocrylate
1-butene
dimethyl 4-ethyl-4-
formylpimelote
(XI)
(2)-trans-1 -ethyl-1-(2- (f)-cis-1 -ethyl-1-(2-
methoxycarb0nylethyl)- methoxycarbonylethyl)-
4-0x0-
I
.2.3.4.6.7.12.12b-
4-0x0-1.2,3.4.6.7.12.12b-
octahydraindolo[2.3-01- octohydroindolo[2.3-a]-
quinolizine quinolirine
(XU)
1.
NoOH

2.
(-)-ephedrine (racernate resolution)
3. CH,OH, H2S04
XI1
b
___,
phosphorus
pentosulfide H3C
Raney-Ni No terl-amylote, toluene
XlII
-
.
(-)-la-ethyl-1-(2-
rnethoxycarbonylethyl)-
1.2.3,4,6,7,12.12ba-
octohydroindolo-
[2,3-o]quinolizine
tert-butyl nitrite
CHpO. HCI, H20
xm.
.
(3a.16a)-14,15-di-
hydro-14-oxo-D-
homoeburnomenine
(XIV)
%
o
\CH~
(3a.16a)-14.154-
hydro-14.15-dioxo-

D-hornoeburnornenine
(XV)
2174
V
Vincamine
Referencefs):
a
Schlittler, E. et al.: Helv. Chim. Acta (HCACAV) 36, 2017 (1953).
HU 147 282 (Richter Gedeon; appl. 30.7.1960).
Trojanek,
J.
et al.: Collect. Czech. Chem. Commun. (CCCCAK) 26, 867 (1961); 27,2801 (1962).
b
DAS 2 201 795 (Omnium Chimique; appl. 14.1.1972; B-prior. 15.1.1971,3.3.1971).
DOS 2 652 165 (Omnium Chimique; appl. 16.1 1.1976; F-prior. 20.1 1.1975).
similar processes from (-)-vincadifformine:
GB 1 514 337 (Buskine S.A.; appl. 22.7.1975; CH-prior. 9.8.1974).
US 4 145 552 (Parcor;
20.3.1979; F-prior. 13.7.1976).
DOS 2 731 480 (Parcor; appl. 12.7.1977; F-prior. 13.7.1976).
DOS 2 745 415 (Boehringer Mannh.; appl. 8.10.1977).
synthesis of vincadifformine:
DOS 2 758 896 (M.
E.
Kuehne; appl. 30.12.1977).
cl DAS 2 222 186 (Richter Gedeon; appl. 5.5.1972; H-prior. 7.5.1971).
US 3 755 333 (Richter Gedeon; 28.8.1973; H-prior. 7.5.1971).
Sziintay, Cs. et al.: Tetrahedron Lett. (TELEAY) 1973, (3), 191.
precursors:
DOS 2 345 068 (Richter Gedeon; appl. 6.9.1973; H-prior. 6.9.1972).

rearrangement epi-vincamine
+
vincamine:
DAS 2 203 655 (Richter Gedeon; appl. 26.1.1972; H-prior. 29.1.1971).
DOS 2 807 912 (Boehringer Mannh.; appl. 24.2.1978).
c2 DAS 2 115 718 (Roussel-Uclaf; appl. 31.3.1971; F-prior. 31.3.1970, 10.9.1970).
further synfheses:
Kuehne, E.: J. Am. Chem. Soc. (JACSAT) 86,2946 (1964).
US 3 454 583 (US-Secret. of Health; 8.7.1969; prior. 19.7.1965).
Gibson, K.H.; Saxton, J.E.: Chem. Commun. (CCOMA8) 1969, 1490.
Pfaffli,
P.
et al.: Helv. Chim. Acta (HCACAV)
58,
1131 (1975).
DOS 2 314 876 (Sandoz; appl. 26.3.1973; CH-prior. 29.3.1972, 20.4.1972, 17.5.1972, 2.2.1973).
DOS 2 330 990 (Anvar; appl. 18.6.1973; F-prior. 19.6.1972).
GB 1 450 198 (Synthelabo; appl. 14.12.1973; F-prior. 15.12.1972).
LJS 3 925 392 (Synthclabo; 9.12.1975; F-prior. 15.12.1972).
US 4 001 251 (Synthelabo; 4.1.1977; F-prior. 15.12.1972).
DOS 2 752 776
(ELMU;
appl. 25.1 1.1977; E-prior. 27.4.1977).
lyophilisate of vincamine with glycine:
FR-M
7 222 (L.
0.
Olivier; appl. 6.2.1968).
vincamine pamoate:
NL-appl. 7 304 654

(Merrell-Toraude; appl. 4.4.1973; F-prior.
1
1.4.1972).
con~bination with ergot alkaloids:
GB 1 494 625 (Unilever; appl. 4.2.1 974; valid from 4.2.1975)
ronibitintion with rutin, hesperidin, eriodxtin or esculoside:
DOS
2 337 202 (Centrc dlEtudes pour 1'Industrie Pharmaceutique; appl. 21.7.1973; F-prior. 24.7.1972).
5-bronionicofinafe
of
vincamine:
DOS 2 714 486 (Ferrer Internat.; appl. 3 1.3.1977; F-prior. 31.3.1976).
vincamine 5-pyridoxalphosphate:
DAS 2 721 171 (Soc. &Etudes de Produits Chimiques; appl. 11 S.1977; GB-prior. 11.5.1976).
diverse
salts:
US 4 122 179 (E. Corvi Mora; 24.10.1979; CH-prior. 3.6.1976).
Fomulation(s): amp. 15
mg;
cps. 30 mg; s. r. cps. 30 mg, 60
mg;
tabl. 10 mg
Vincristine
V
2175
Trade Name(s):
D: Cetal (Parke Davis) Vincafor (Pharmafarm) Vincari (Alfa Intes; as
Vincamin-retard- Vincarutine (Pharbiol) hydrochloride)
ratiopharm (ratiopharm)
I:

Anasclerol (Stallergenes; as Vincatreis (Ecobi)
F:
Pe~incamine (SynthClabo) hydrochloride) Vinsal (Salus Research)
RhCobal (Niverpharm) Vasonett (Alfa Intes) Vraap (Inverni della Beffa)
Vinca (Substipharm) Vincadar (Hoechst Marion generics
Vinca Retard Roussel)
(Substipharm)
Vincristine
(Leurocristine)
ATC: LOICA02
Use: antineoplastic
RN: 57-22-7 MF: C,6HS6N4010
MW:
824.97 EINECS: 200-3 18-1
LD,,,: 3990
kg/kg
(M, i.v.);
1 mglkg
(R,
i.v.)
CN:
22-oxovincaleukoblastine
sulfate
(1:l)
RN: 2068-78-2
MF:
C4,H5,N401,,
.
H,SO, MW: 923.05 EINECS: 218-190-0
LD,,,: 1700

pg/kg
(M,
i.v.);
1010
pgkg
(R, i.v.)
Vincristine
By extraction from leaves of Vinca rosea.
Reference(s):
BE 867 670 (Richter Gedeon; appl.
31
S.1978; H-prior. 31.5.1977).
FR
2 2103'12 (Richter Gedeon; appl. 19.12.1972).
DOS 2 259 388 (Richter Gedeon; appl. 5.12.1972).
DOS 2 124 023 (Richter Gedeon; appl.
14.5.1971
;
H-prior. 27.5.1970).
DAS
1
445 689 (Eli Lilly; appl. 23.10.1962).
GB
1
382 460 (Richter Gedeon; valid from prior. 4.12.1972).
purification:
DOS 2 442 245 (Eli Lilly; appl. 4.9.1974; USA-prior. 24.10.1973).
total synthesis:
DOS
2

614 863 (A. Rahman; appl. 6.4.1976).
DOS 2 622 894 (United States Dep. of Commerce; appl. 21.5.1976; USA-prior. 30.5.1975).
7
2176
V
Vindesine
semisynthetic preparation:
DOS 2 259 447 (Richter Gedeon; appl. 5.12.1972).
CA 989 829 (Richter Gedeon; appl. 4.12.1972).
BE 823 560 (Richter Gedeon; appl. 19.12.1 974; H-prior. 20.12.1973).
US 3 899 493 (Richter Gedeon; 12.8.1975; prior. 22.12.1972).
FR 2 210 392 (Richter Gedeon; appl.
19.1 2.1972).
ZA 7 208 535 (Richter Gedeon; appl. 1.12.1972).
complex formation with
tubulin for treatment of leucemia:
BE 854 053
(Inst. Intern. de Pathologic Cell. et Mol.; appl. 18.4.1977; F-prior. 28.4.1976).
use for treatment of psoriasis:
US 3 749 784 (Eli Lilly; 31.7.1973; prior. 26.10.1970, 3.5.1972).
Formulation(s):
vial 1 mglml, 1 mgIlO ml, 2 mglml, 5 mglml (as sulfate)
Trade Name(s):
D: cellcristine (cell pharm) Vincristin liquid Lilly GB: Oncovin (Lilly)
FARMISTIN (Pharmacia
&
(Lilly) I: Vincristina (Lilly)
Upjohn)
Vincristinsulfat-GRY (Gry) Vincristina Tera (Tera)
Vincristin (biosyn)

F:
Oncovin (Lilly)
.
J:
Oncovin (Shionogi)
Vincristin Bristol (Bristol- Vincristine Pierre Fabre USA: Oncovin (Lilly)
Myers Squibb) (Pierre Fabre Oncologie)
Vindesine
A'K: LOICAO~
Use: antineoplastic
RN: 53643-48-4 MF:
C,3HssNs07 MW: 753.94 EINECS: 258-682-2
LD,,,: 13.8 mglkg (M, i.v.)
CN:
3-(aminocarbonyl)-@-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine
NH,,
CH,OH,
100
OC
-
0
vinblastine Vindesine
(9.
v.1
Reference(s):
US 4 203 898 (Lilly, 20.5.1980; prior. 29.8.1977).
US 4 479 957 (Lilly; 30.10.1984; prior. 2.4.1973).
DOS 2 415 980 (Eli Lilly; appl. 2.4.1974; USA-prior. 2.4.1973).
Formulation(s): amp. 5 mg15 ml, 1 mg, 4 mg, 5 mg
Trade Name(s):

D: Eldisine (Lilly; 1980) GB: Eldisine (Lilly; 1980)
J:
Fildesin (Shionogi; 1985)
F: Eldisine (Lilly) I: Eldisine (Lilly)
r
Vinorelbine
V
2177
Vinorelbine
(5'-Noranhydrovinblastine;
PM259)
ATC: LOlCA04
Use:
antineoplastic (non small cell lung
cancer)
RN: 71486-22-1 MF: C,,H,,N,O, MW: 778.95
LD,,,:
26 mgkg (M, i.p.)
CN:
3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine
hydrogen tartrate
(1:l)
RN: 105661 -07-2 MF: C45H54N408
.
C4H6O6 MW: 929.03
tartrate
RN: 1253 17-39-7 MF: C45H54N108
.
2C4Hh06 MW: 1079.12
anhydrovinblastine

(1)
V
_*
trifluoroocetic
K
onhydride
0
CH3
2178
V
Vinuocetine
THF,
H20
111
b
Reference(s):
EP 10 458 (ANVAR Agence Nat. Valorisation; F-prior. 24.8.1978,6.2.1979).
Andriamialisoa, R.Z. et al.: Tetrahedron (TETRAB) 36, 20 (1980).
Mangeney, P. et
a].: Tetrahedron (TETRAB) 35,2175 (1979); J. Org. Chem. (JOCEAH) 44,3765 (1979).
Gueritte, F. et al.: Eur. J. Med. Chem. (EJMCAS) 18,419 (1983).
Potier, P.: Semin. Oncol. (SOLGAV) 16, (2. Suppl. 4), 2 (1989); J. Nat. Prod. (JNPRDF) 43,72 (1980).
pharmaceutical formulation for parenteral administration:
EP 31 7 401 (PierreFabre; appl. 10.1 1.1988; F-prior. 13.1 1.1987).
synthesis of
anhydrovinblastine:
EP 354 778 (Mitsui Petrochem.; appl. 9.8.1989; J-prior. 11.8.1988).
DOS 3 826 412 (Univ. of British Columbia; appl. 6.8.1988; CND-prior. 6.8.1987).
FR
2 544 319 (Pierre Fabre; appl. 14.4.1983).

HU 20 601 (Richter Gedeon; appl. 17.3.1977).
WO 8 802 002 (Mitsui Petrochem.; appl. 16.9.1987; USA-prior. 18.9.1986).
JP 63 119 690 (Mitsui Petrochem.; appl. 4.8.1987; USA-prior. 4.8.1986).
Kutney, J.P. et al.: Helv. Chim.
Acta (HCACAV) 58, 1690, 171 1 (1975); 59, 2858 (1976).
Raucher, S. et al.: J. Am. Chem. Soc. (JACSAT) 109,442 (1987).
Kutney, J.P. et a].: Heterocycles (HTCYAM) 27,621, 1845 (1988).
Goodbody, A.E. et al.: Planta Med. (PLMEAA) 54, 136, 210 (1988).
Vokovic, J. et al.: Tetrahedron (TETRAB) 44, 325 (1988).
Atta-Ur-Rahman, P.S.: J. Nat. Prod. (JNPRDF) 51, 1275 (1988).
Bray, B.L.: Dissertation Univ. Washington (Seattle), Diss. Abstr. Int. B
1988,48 (12), Pt. 1, 3567.
Formulation(s):
amp. 10 mglml, 50 mg15 ml (as base); vial 10 mglml, 50 mg15 ml (as tartrate)
Trade Name(s):
F: Navelbine (Pierre Fabre; GB: Navelbine (Pierre Fabre; as USA: Navelbine (Glaxo
1988) tartrate) Wellcome; as tartrate)
1: Navelbine (Pierre Fabre)
Vinpocetine
ATC: N06BX18
Use: vasodilator, cerebrostimulant
RN: 42971-09-5 MF: C22H26N202 MW: 350.46 EINECS: 256-028-0
LD,,,: 45 mgkg (M, i.v.); 534 mgkg (M, p.0.);
32 mgkg (R, i.v.); 503 mgkg (R, p.0.)
CN:
(3a,
l6a)-eburnamenine-14-carboxylic
acid ethyl ester
Vinvlbital
V 2179

1.
KOH,
CHJOH
2.
CH3COOH
3.
H&-OH
,
H,SO,
_________+
Vinpocetine
1
1.
KOH
2.
w-6
,
KOH,
C2H50H
0
tH,,
Reference(s):
US
4
035 370 (Richter Gedeon; 12.7.1977; prior. 11.10.1972).
DAS
2 253 750 (Richter Ccdeon; appl. 2.1 1.1972; H-prior. 3.11.1971).
Lorincz,
C.
et al.: Arzneim Forsch. (ARZNAD) 26, 1907 (1976).

citrate phosphate:
EP
154 756 (Covex; appl. 21.3.1984;
E-prior.
29.2.1984).
Formulation(s):
tabl. 5
mg
Trade Nume(s):
D.
Cavinton (Thiemann)
J:
Calan (Takeda; 1984)
Vinylbital
(Butylvinal)
ATC: N05CA08
Use: hypnotic
RN:
2430-49-1
MF:
C,,H,,N,O,
MW:
224.26 EINECS: 219-395-8
CN:
5-ethenyl-5-(k-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione
1-methyl-2-pyrrolidane/zinc
stearate,
H3cd,"
+
HC'CH

25
atrn
+
CH,O
5-(1
-methylbutyl)- acetylene
barbituric acid
Reference(s):
FR
11 825 256 (BASF; appl. 9.9.1957).
FR-M
896 (BASF; appl. 4.1.196 1
).
Fomulution(s):
tabl. 150
mg
2180
V
Viomycin
Trade Name(s):
D: Speda (Byk Gulden); wfm Optanox (Valpan); wfm Suppoptanox (Valpan);
F:
Optanox (Delagrange); Suppoptanox (Delagrange); wfm
wfm wfm
Viomycin
ATC:
JO~A
Use: antibiotic
RN: 32988-50-4 MF: C2sH43N,3010 MW: 685.70 EINECS: 251-323-0
CN: stereoisomer of

3,6-diamino-N-[6-[[(aminocarbonyl)amino]methylene]-3-(2-amino-1,4,5,6-tetrahydro-6-
hydroxy-4-pyrimidinyl)-9,12-bis(hydroxymethyl)-2,5,8,11,1
Cpentaoxo-1,4,7,10,13-
pentaazacyclohexadec- 15-yllhexanamide
sulfate
RN: 37883-00-4 MF: C,,H43Nl,0,,
.
xH2S04 MW: unspecified
LD,,,:
1
12 mglkg (M, i.v.);
340 mg/kg (R, i.v.)
I
\OH
Viomycin
From fermentation solutions of
Srreptomycesfloridae
or
Streptomyces puniceus.
Reference(s):
US 2 633 445 (Ciba; 1953; prior. 1947).
US 2 828 245 (Commerc Solvents; 1958; prior. 1954).
Forniulation(s):
amp. 1 g
Trade Name(s):
D: Viocin (Pfizer); wfm J: Viomicin (Parke Davis- Viomycin Pfizer (Taito
F:
Panto-Viocine (Pfizer); Sankyo) Pfizer)
wfm USA: Viocin (Pfizer); wfm
Visnadine

ATC: C04AX24
Use: coronary vasodilator
RN: 477-32-7
MF:
C2,H,,0, MW: 388.42 EINECS: 207-515-1
LD&: 2240 mglkg (M, p.0.);
12 13 mglkg (R, p.0.)
CN:
[9R-[9a(R*),1Oa]]-2-methylbutanoic
acid
10-(acetyloxy)-9,10-dihydro-8,8-dimethy1-2-oxo-2H,8H-
benzo[l,2-b:3,4-b']dipyran-9-yl
ester