CA1104135A - Vincamine derivatives - Google Patents

Abstract

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

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 ¦

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~

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 ~ 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.
, ~ 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 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 .

~ 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.

.

.~, .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.
..

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.

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 ~--~ 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.

.

Claims (2)

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, 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.