TRADUCTION NON-DISPONIBLE

VINCAMINE DERIVATIVES

Abrégé anglais

Case 100-4886
VINCAMINE DERIVATIVES
Abstract of the Disclosure:
10-Bromovincamine, useful as a vigilance
increasing agents may be made from vincadifformine.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined
as follows:
1. A process for the production of optically
active or racemic 10-bromovincamine in pure form, which
comprises treating under acidic conditions an optically
active or racemic compound of formula I,
<IMG> I
wherein either n is 0 and X is oxygen
or n is 1, X is hydrogen and Y is an anion,
in the presence of a reducing agent when n is 0, thereby
to effect rearrangement of said compound of formula I,
and isolating pure, optically active or racemic
10-bromovincamine; and where desired, forming a
pharmaceutically acceptable acid addition salt of said
10-bromovincamine.
2. Optically active or racemic 10-bromovincamine,
in pure form, or a pharmaceutically acceptable, acid
addition salt thereof, whenever produced by a process
according to claim 1 or by an obvious chemical equivalent
thereof.
11

Description

3~
V NCAMINE DERIVATIVES
The present invention provides optically active
or racemic 10-bromovincamine, especially in pure form, viz
substan~ially free from ll-~romovincamine~
The present invention provides a process for
the production of optlcally active or racemic 10-bromo-
vincamine which comprises treating under acidic conditions an
opticallv active or racemic compoung of formula I,
, X IY ]
+)n ¦
OH COOCH3
wherein either n is 0 and X is oxygen
or n is 1, X is hydrogen and Y is an anion,
in the presence of a reducing agent when n is 0, thereby
to effect rearrangement of said compound of formula I, and
isolating pure, optically active or racemic 10-bromovincamine,
and where desix~d, forming a pharmaceutically acceptable acid
addition salt of said 10-bromovincamine.
The process may be effected in conventional,
manner for rearranging analogous compounds of formula I
into vincamines. For example the reaction may be effected

3~i 100-4~86
under acidic conditions. When n iS 0 the reducing agent
iS conveniently triphenylphosphine. Suitable reaction
temperatUres may be from 0 to 150C. When n iS 1 the
choice Of the anion Y iS no~ cri~ical~ bUt thiS iS con-
veniently triflUoroaCetate/ trichloroacetate, or acetate.10-epibromovincamine may be isolated as a side product~
and Inay be converted into 10-bromovincamine in ConVen-
tional manner~ e.g. in boiling xylene ~ ~~~ ~~~~~~~~ ~~
in the presence of silver aCetate or mercUr~ (I) aCetate.
A compound of formula I may be prepared by
oxidising an optically active or racemic compound of
formula II~
T(+)n ~y_~n,
Br~
COOCH3
wherein n,~ X and Y are as de~ine~ ab
e.g. Using a peracid such aSmeta-chloroperben~oic acid~
para-nitroperbenzoic acid, performic acid or peracetic
acid. Suitable reaCtiOrl temperatures may be from O to
50C
~ 2 ~

100-~1886
A compound of formula II may be produced by
treating optically active or racemic 15-bromovincadiffor-
mine of formula III,
N
~r ~ ~
~ COOCH3
with either a peracid to produce a compound of formula II,
wherein n is 0, or an acid of ~ormula HY to produce a
compound of formula II, wherein n is 1~
The reactlon may be effected when n lS 0 under
the same conditions as for the conversion of a compound
of formula II into a compound of formula I. When n is 1
the reaction may be effected at a temperature of from 0
to 20C~
It is not necessary that the c~nds of formula II
be isolated as the pure compounds. For example, a com-
` pound of formul~ III may be treated with at least two
moles of a peracid to result in the direct formation ofa compound of formula I, wherein n is 0. Alternatively~
a compound of formula III may be treated fi.rst with an
acid other than a peracid and then with a peracid to
result in the direct formation of a compound of formula
20 I, whèrein n is 1.
,
-- 3 --

~ 35 100-4886
A compound of formula III may be produced by
rearranging an optically active or racemic compound of
formula IV,
~ r ~ IV
Br
COOCH3
with hydrogen chloride or hydrogen bromide gas. A suitable
solvent is chloroform. Suitable reaction temperatures
are from 10 to 30C.
A compound of formula IV may b~ produced by
brominating optically activQ or racemic vincadifformine
e.g. with one molar Pquivalent of bromine at-30 to -10C.
A compound of formu~a III may preferably be
directly produced by reacting vincadifformine with one
molar equiva~ent of bromine in the presence of hydrogen
chloride or hydrogen bromide at from 10 to 30C.
It will be appreciated that when opt1cally
active startin~ materials are used the corresponding
optically active products are produced. The starting
materials are either known or may be produced in known
mannQr .
-- 4

~ 100-48~6
The free base form of 10-bromovincamine may be
converted into acid addition salt forms in conventional
manner and vice versa. A suitable acid is fumaric acid.
In the following Exampl~ all ~emperatures axe
uncorrected and are in degrees Centigrade.
.
- 5
.~,

.3~; ï00-4886
EX~MPLE 1 (-) bromovi~cadifformine (compound of for-
a) Direct ~rocess mula III)
A solution of 20 g (-~-vincadifformine b~se
in 200 ml chloroform is saturated with HCl gas at 20o
A solution of 9.92 y bromine in 40 ml chloroform is
added dropwise over 25 minutes. After 30 minutes stirring
the xeaction mixture is poured onto 500 ml ice and 10 g
sodium carbonate. The organic phase is separat,ed off,
washed and dried. The dried,organic phase may be worked
up to give (-)~15-bromovincadifformine [hydrogen umarate
M Pt 200-201 [~]20= -445 (c - 1 in acetone)].
b) Via isolation of a compound of formula IV
______________________ ____ ____________._
A solution of 2.36 g bromine in 20 ml chloroform
is added to a solution of 5 g (-)-vincadifformine in 20 ml
chloroform maintained at -20C. The reaction mixture is
poured onto ice and sodium bicarbonate. The organic phase
is separated of, washed, dried, evaporated at 50C and
chromatographed to yield an elution with chloroform and 5
acetone 3-bromo-1,2-didehydroaspidospermidine-3-Garboxylic
acid methyl ester~M.Pt.from 95C (decomp.~.
The m~thyl ester is immediately treated at 20C
with hydrogen bromide gas in chloroform to yield after
working up (-)-15-bromovincadifformine.
..
-- 6 --

3S 1OO-~886
EXAMPLE 2~ 15-bromo-1,2-didehydro-3-hydroxy-aspidosper-
iaine-3=carboxylic_cld methyl ester 9-oxide
(compound of formula I, wherein n is 0)
The dried organic phase obtained from Example la
is treated portionwise at 20 with 20.4 g 82.5% m-chloro-
perbenzoic acid and allowed to stand for 30 minutes. The
mixture is washed with 5% (w/v) sodium carbonate solution,
dried over sodium sulphate and concentrated in a vacuum
at 50. The residue is treated with 200 ml acetone to
give crystals of the title compound, M.Pt. (from acetone/
chloroform) 202-205G (decomp.).
EXAMPLE 3~ [(3S, 14S, 16S)]-10-bro~novincamine
A solution o 20 g of the 9-oxide obtained
from Example 2, 400 ml acetic acid, 40 ml water and 17.4
~ triphenylphosphine is stirred for 4 hours at 50. The
reaction mixture is concentrated in a vacuum and the
residue treated with sodium hydroxide solution. The
base therebv formed is taken up in chloroform and
chromatographed on silica-gel eluting (~)-10-bromovinc~
amine base with chloroform containing 3% methanol.
~0 M.Pt. 202-205; [c~]D = +35.2 (c = 1 in CHC13). A more
... .
polar fraction yields [(3S, 14R, 16S)]-10-bromoepivinc~
amine. M.Pt. 195-196 [a]D - -8.6 (c- 1 in CHC13) which may
be converted into (+)-lO~bromovincamine in conventional manner.

0-4886
3S
EXAMPLE 4: (+~-~(3S~ 14S, 16S)] lO-bromovincamine
._ _ _ _
A solution of 4.17 g (-)-15-bromovinca~ifformine
in lOO ml toluene is treated at 5 with l.15 g trifluoro-
acetic acid~ The mixture containing a compound of formula
II wherein n is l and Y is ~rifluoroacetate is maintained
at 5 and 2,00 g para-nitroperbenzoic acid is added
portionwise. The mixture is allowed to warm to room
temperature, maintained for lS hours, and then evaporated
to dryness. The residue containing a compound of formula I
wherein n is l and Y is trifluoroacetate is taken up in
45 ml glacial acetic acid and 5 ml water. The mixture is
stirred for two hours at room temperature, then ad~usted
to pH 9 by the addition of sodium hydroxide, and extracted
three times with dichloromethane. Washing with water,
drying over sodium sulphate, evaporation and resultant
chromatography as in Example 3, yields the title compound
and ~(3S, l4R, 16S)]-lO-bromoepivincamineO
- Optically active and racemic lO-bromovir.camine
exhibits pharmacological activity which is more beneficial
than expected for the compound. Xn particular, it
exhibits vigilance~increasing and psychostimulant activity,
as indicated by a notable increase in excitability of
significant duration observed in mice on p.o. and sOc.
administration of from lO to lOO mg/kg animal body weight
of the compound, and furthermore by a notable increase in
-- 8

~--~ 100-4886
3~
wakefulness as observed in the electroencepha]ogram on
i.p. or p~o ad~inistration of 10 mg/kg body weight of
the compound.
The compound is therefore indicated for use in
the treatment of cerebral insufficiency.
1(3S, 14S, 16S~}10-bromovincamine is the
preferred compound.
The compounds of formula I wherein Y is a
pharmacologically tolerable anion are also indicated for
use in the treatment of cerebral insufficiency by virtue
of their activity in the above tests.
For this use an indicated daily dose is from
abou~ 10 to about 50 mg, conveniently administered in
divided doses 2 to 4 times a day in unit dosage form
containing from about 2 to about 25 mg, or in sustained
release form.
The lO~bromovincamine ma~ be administered in
crystalline form, e.g. in pharmaceutically acceptable
acid addition salt form. Such acid addition salt forms

~ 3~ 100-~886
exhibit the same order of activity as the free base forms
and are readily prepared in conventional manner. The
present invention also provides a pharmaceutical compos-
ition comprising 10-bromovincamine, in free base form or
in pharmaceu~ically acceptable acid addition salt form,
or a compound of formula I, a~ defined above, in pharma-
ceutically acceptable form, in association with a
pharmaceutical carrier or diluent.
Such compositions may be in the form of, for
example~ a solution or a tablet.
-- 10 --
.