GB1601700A - 10-bromovincamine - Google Patents
10-bromovincamine Download PDFInfo
- Publication number
- GB1601700A GB1601700A GB5271477A GB5271477A GB1601700A GB 1601700 A GB1601700 A GB 1601700A GB 5271477 A GB5271477 A GB 5271477A GB 5271477 A GB5271477 A GB 5271477A GB 1601700 A GB1601700 A GB 1601700A
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- GB
- United Kingdom
- Prior art keywords
- racemic
- compound
- optically active
- bromovincamine
- addition salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) 10-BROMOVINCAMINES
(71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body
Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
Patent Specification No. 1,492,579 discloses and claims a class of substituted vincamine derivatives which are indicated for use as vigilance increasing agents.
The present invention provides optically active or racemic 10-bromovincamine, especially in pure form, viz substantially free from 11-bromovincamine. 10 bromovincamine is neither specifically disclosed nor specifically suggested by Patent Specification No.
1,492,579 but it has been found, e.g. from the tests described hereinafter to be especially interesting as a potent well tolerated pharmaceutical agent e.g. for the treatment of cerebral insufficiency.
The present invention provides a process for the production of optically active or racemic 10-bromovincamine which comprises rearranging, under acidic conditions, an optically active or racemic compound of formula I,
wherein either n is 0 and X is oxygen
or n is 1, Xis hydrogen and Y is an anion, in the presence of a reducing agent when n is0, and isolating pure, optically active or racemic 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 under acidic conditions. When n is 0 the reducing agent is conveniently triphenylphosphine.
Suitable reaction temperatures may be from 0 to 1500C. When n is 1 the choice of the anion
Y is not critical, but this is conveniently trifluoroacetate, trichloroacetate, or acetate.
10-bromoepivincamine, which also forms part of the invention (in racemic or optically active form) may be isolated as a side product, and may be converted into 10bromovincamine in conventional manner, e.g. in boiling xylene in the presence of silver acetate or mercury (I) acetate.
A compound of formula I may be prepared by oxidising an optically active or racemic compound of formula II,
wherein n, X and Y are as defined above, e.g. using a peracid such as metachloroperbenzoic acid, para-nitroperbenzoic acid, performic acid or peracetic acid. Suitable reaction temperatures may be from 0 to 500C.
A compound of formula II may be produced by treating optically active or racemic 15-bromovincadifformine of formula III,
with either a peracid to produce a compound of formula II, wherein n is O, or an acid of formula HY to produce a compound of formula II, wherein n is 1.
The reaction may be effected with n is 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 200C.
It is not necessary that the compounds of formula II be isolated as the pure compounds.
For example, a compound of formula III may be treated with at least two moles of a peracid to result in the direct formation of a compound of formula I, wherein n is 0. Alternatively, a compound of formula III may be treated first with an acid other than a peracid and then with a peracid to result in the direct formation of a compound of formula I, wherein n is 1.
A compound of formula III may be produced by rearranging an optically active or racemic compound of formula IV,
with hydrogen chloride or hydrogen bromide gas. A suitable solvent is chloroform. Suitable reaction temperatures are from 10 to 30"C.
A compound of formula IV may be produced by brominating optically active or racemic vincadifformine e.g with one molar equivalent of bromine at -30 to -100C.
A compound of formula III may preferably be directly produced by reacting vincadifformine with one molar equivalent of bromine in the presence of hydrogen chloride or hydrogen bromide at from 100 to 300C.
It will be appreciated that when optically active starting materials are used the corresponding optically active products are produced. The starting materials are either known or may be produced in known manner.
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 Example all temperatures are uncorrected and are in degrees
Centigrade.
EXAMPLE 1 (-)-15-bromovincadifformine (compound of formula III) a) Direct process
A solution of 20 g (-)-vincadifformine base in 200 ml chloroform is saturated with HC1 gas at 200. A solution of 9.92 g bromine in 40 ml chloroform is added dropwise over 25 minutes. After 30 minutes stirring the reaction mixture is poured onto 500 ml ice and 10 g sodium carbonate. The organic phase is separated off, washed and dried. The dried organic phase may be worked up to give (-)-15-bromovincadifformine [hydrogen fumarate M.Pt.
200 -201 [a]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 -20 C. The reaction mixture is poured onto ice and sodium bicarbonate. The organic phase is separated off, washed, dried, evaporated at 50"C and chromatographed to yield an elution with chloroform and 5 % acetone 3-bromo- 1 ,2-didehydroaspidospermidine-3-carboxylic acid methyl ester M.Pt.
from 95"C (decomp).
The methyl ester is immediately treated at 20"C with hydrogen bromide gas in chloroform to yield after working up (- )-15-bromovincadifformine.
EXAMPLE 2 15-bromo-1,2-didehydro-3-hydroxy-aspidosperdine-3-carboxylic acid 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-chloroperbenzoic 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 -205 (decomp.).
EXAMPLE 3 (+)-[(3S, 14S, 16S)]-l0-bromovincamine A solution of 20 g of the 9-oxide obtained from Example 2, 400 ml acetic acid, 40 ml water and 17.4 g 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 thereby formed is taken up in chloroform and chromatographed on silica-gel eluting (+!-10-bromovincamine base with chloroform containing 3% methanol. M.Pt. 202 -205 ; [a]D(3 = + 35.2 (c = 1 in CHCl3). A more polar fraction yields [(3S, 14R, 16S)]-10-bromoepivincamine. M.Pt. 195-196 [a]20 = 8.60 (c=1 in CHCl3) which may be converted into (+)-10-bromovincamine in conventional manner.
EXAMPLE 4 (+)-[(3S, 14S, 165)140-bromovincamine A solution of 4.17 g (-)-15-bromovincadifformine in 100 ml toluene is treated at 50 with 1.15 g trifluoroacetic acid. The mixture containing a compound of formula II wherein n is 1 and Y is trifluoroacetate is maintained at 50 and 2.00 g para-nitroperbenzoic acid is added portionwise. The mixture is allowed to warm to room temperature, maintained for 15 hours, and then evaporated to dryness. The residue containing a compound of formula I wherein n is 1 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 adjusted 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, 14R, 16S)]-10 bromoepivincamine..
Optically active and racemic 10-bromovincamine exhibits pharmacological activity which is more beneficial than expected for the compound. In particular, it exhibits vigilanceincreasing and psychostimultant activity, as indicated by a notable increase in excitability of significant duration observed in mice on p.o. and s.c. administration of from 10 to 100 mg/kg animal body weight of the compound, and furthermore by a notable increase in wakefulness as observed in the electroencephalogram on i.p. or p.o. administration of 10 mg/kg body weight of the compound.
The compound is therefore indicated for use in the treatment of cerebral insufficiency.
[(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 10 to 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 2 to 25 mg, or in sustained release form.
The 10-bromovincamine may be administered in crystalline form, e.g. in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising 10-bromovincarnine, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
WHAT WE CLAIM IS:
1. A process for the production of optically active or racemic 10-bromovincamine in pure form, which comprises rearranging under acidic conditions an optically active or racemic compound of formula I,
wherein either n is 0 and X is oxygen
or n is 1, Xis hydrogen and Y is an anion, in the presence of a reducing agent when n is O, and isolating pure, optically active or racemic 10-bromovincamine.
2. A process according to Claim 1, wherein the compound of formula I is obtained by treating optically active or racemic 15-bromovincadifformine with a peracid to produce a compound I wherein n is 0 or first an acid other than a peracid and then a peracid to produce a compound I where n is 1.
3. A process for the production of optically active or racemic 10-bromovineamine, in pure form, substantially as hereinbefore described with reference to Example 3 or 4.
4. Optically active or racemic 10-bromovincamine, in pure form, whenever produced by a process according to Claim 1, 2 or 3.
5. Pure optically active or racemic 10-bromovineamine.
6. Optically active or racemic 10-bromovincamine substantially free from 11bromovincamine.
7. A compound according to Claim 4, 5 or 6, in crystalline form.
8. A compound according to any one of Claims 4 to 7 in racemic form.
9. A compound according to any one of Claims 4 to 7 in (3S, 14S, 16S) form.
10. A compound according to any one of Claims 4 to 9, in free base form.
11. A compound according to any one of Claims 4 to 9 in acid addition salt form.
12. A pharmaceutical composition comprising 10-bromovincamine in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
13. A composition as claimed in Claim 12 wherein the 10-bromovincamine is (3S, 14S, 16S) form.
14. 10-Bromoepivincamine.
15. A compound of Claim 14, in optically active form.
16. A compound of Claim 14 in racemic form.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (16)
1. A process for the production of optically active or racemic 10-bromovincamine in pure form, which comprises rearranging under acidic conditions an optically active or racemic compound of formula I,
wherein either n is 0 and X is oxygen
or n is 1, Xis hydrogen and Y is an anion, in the presence of a reducing agent when n is O, and isolating pure, optically active or racemic 10-bromovincamine.
2. A process according to Claim 1, wherein the compound of formula I is obtained by treating optically active or racemic 15-bromovincadifformine with a peracid to produce a compound I wherein n is 0 or first an acid other than a peracid and then a peracid to produce a compound I where n is 1.
3. A process for the production of optically active or racemic 10-bromovineamine, in pure form, substantially as hereinbefore described with reference to Example 3 or 4.
4. Optically active or racemic 10-bromovincamine, in pure form, whenever produced by a process according to Claim 1, 2 or 3.
5. Pure optically active or racemic 10-bromovineamine.
6. Optically active or racemic 10-bromovincamine substantially free from 11bromovincamine.
7. A compound according to Claim 4, 5 or 6, in crystalline form.
8. A compound according to any one of Claims 4 to 7 in racemic form.
9. A compound according to any one of Claims 4 to 7 in (3S, 14S, 16S) form.
10. A compound according to any one of Claims 4 to 9, in free base form.
11. A compound according to any one of Claims 4 to 9 in acid addition salt form.
12. A pharmaceutical composition comprising 10-bromovincamine in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
13. A composition as claimed in Claim 12 wherein the 10-bromovincamine is (3S, 14S, 16S) form.
14. 10-Bromoepivincamine.
15. A compound of Claim 14, in optically active form.
16. A compound of Claim 14 in racemic form.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5271477A GB1601700A (en) | 1978-05-30 | 1978-05-30 | 10-bromovincamine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5271477A GB1601700A (en) | 1978-05-30 | 1978-05-30 | 10-bromovincamine |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1601700A true GB1601700A (en) | 1981-11-04 |
Family
ID=10465001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB5271477A Expired GB1601700A (en) | 1978-05-30 | 1978-05-30 | 10-bromovincamine |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB1601700A (en) |
-
1978
- 1978-05-30 GB GB5271477A patent/GB1601700A/en not_active Expired
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |