GB2065113A - Ergoline derivatives, their production and pharmaceutical compositions containing them - Google Patents

Abstract

A compound of formula I <IMAGE> wherein R is (i) alkyl(C2-8), (ii) alkenyl(C3-6) or alkinyl (C3-6) wherein the double bond is other than in the alpha , beta position, (iii) cycloalkylalkyl(C4-10) or (iv) phenylalkylalkyl(C7-10) or a pharmaceutically acceptable acid addition salt thereof is a useful anti- parkinson or vigilance increasing agent.

Description

SPECIFICATION Ergoline derivatives, their production and pharmaceutical compositions containing them This invention relates to ergoline derivatives, their production and pharmaceutical compositions containing them.

The invention provides a compound of formula I

wherein R is (i) alkyl(C2~8), (ii) alkenyl(C36) or alkinyl(C3~6) wherein the double bond is other than in the a, ,B position, (iii) cycloalkylalkyl(C~,O) or (iv) phenylalkyl(,~,,).

In formula I R is preferably alkyl(C2~8), and especially ethyl or n-propyl. When R is alkenyl or alkinyl, this preferably has 3 or 4 carbon atoms. When R is cycloalkylalkyl it has preferably 3 to 6 carbon atoms in the cycloalkyl moiety and 1 or 2 carbon atoms in the alkyl moiety. When R is phenylalkyl, this is preferably benzyl or phenethyl.

According to the invention the compound of formula I may be produced by a process which comprises a) alkylating a compound of formula II

orb) reacting a compound of formula II

wherein R is as defined above, and X is a leaving group, with a compound of formula IV

wherein M is hydrogen or an alkali metal.

Process a) may be effected in conventional manner for the alkylation of secondary amines. For example, the compound of formula II may be reacted with a compound of formula V R-Y V wherein R is as defined above, and Y is an acid radical of a reactive ester, e.g. chlorine, bromine or iodine, or an organic sulphonic acid radical.

The reaction is suitably effected in an inert organic solvent, e.g. dimethylformamide or dimethylsulphoxide. Suitable reaction temperatures may be from about 20 to about 100"C. Preferably a base, e.g. an organic amine such as triethylamine or an alkali metal carbonate such as potassium carbonate.

Process b) may be effected in conventional manner for the production of analogous compounds by condensation processes, e.g. as disclosed in U.S.P 4,147,789.

The radical X is, for example, chlorine or bromine, or --OO-SOO,-R, wherein R is alkyl or substituted phenyl. Preferably the mesylate or the tosylate of the compound of formula III is used.

The resultant compounds of formula I may be isolated and purified in conventional manner.

Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner, and vice versa. Suitable acids for acid addition salt formation include hydrochloric acid, sulphoric acid, maleic acid, fumaric acid and tartaric acid.

A compound of formula II may for example be obtained from a compound of formula Vl

for example, via the 6-cyano derivative as described in Example 1 a) and b).

Compounds of formula III may for example be obtained in conventional manner as follows:- a) reacting lysergol acetate with cyano-bromide, b) reducing the resultant 6-nor-6-cyano derivative with zinc in acid to yield 6-nor-lysergol, c) alkylating the 6-positions, and d) converting the hydroxyl group into a group X, e.g. by reaction with an alkylsulphonic acid chloride.

Insofar as the production of any particular starting material is not particularly described, this compound may be obtained in conventional manner, or in a manner analogous to that described herein.

In the following examples all temperatures are in degrees Centigrade and are uncorrected.

EXAMPLE 1 6-ethyl-9, 1 O-didehydrn-8-(2-p yridylthiom ethyl)ergollne A solution of 5 g (15 mM) of 9,10-didehydro-8,-(2-pyridyltyhiomethyl)ergoline in 40 ml dimethylformamide is treated with 1.45 ml (17.9 mM) ethyl iodide and 3.85 g (28 mM) potassium carbonate at room temperature. The resultant suspension is stirred for 5 hours at room temperature.

The mixture is filtered, evaporated in a high vacuum and partitioned between methylene chloride containing 10% isopropanol and an ice cold potassium bicarbonate solution. The combined organic phases are dried with sodium sulphate, filtered and concentrated in a vacuum. The crude product is crystallized twice from methylene chloride/methanol to give the title compound as a beige crystals.

M.pt. from 1950 (decomp), [a]20 = ~ 250 (c = 0.49; pyridine).

The starting material may be produced as follows:- a) 6-cyano-9, 1 O-dideh ydro-8P-(2-pyridylthiome th yljergoline 24 g (69 mM) 9,10-didehydro-6-methyl-8,B-(2-pyridylthiomethyl)ergoline are dissolved in 900 ml absolute chloroform under nitrogen and treated at room temperature with a solution of 10.2 g (96 mM) cyanobromide in 100 ml absolute chloroform. After the mixture is stirred for 1 6 hours at room temperature, the mixture is evaporated finally under a high vacuum to a consistant weight, affording crude, t.l.c. pure, heading compound which is further reacted as such.

b) 9,10-didebydro-8,B-F2-pyridylthiomethyl)ergoline 22 g (61 mM) of 6-cyano-9,10-didehydro-8,B-(2-pyridylthiomethyl)ergoline in 250 ml acetic acid and 50 ml water are treated with 22 g zinc powder and stirred for 7 hours at 1 OOdC. The mixture is filtered and evaporated to dryness. The residue is partitioned between methylene chloride containing 15% isopropanol and ice water adjusted to pH 8 to 9 with potassium carbonate. The combined organic phases are dried with sodium sulphate, filtered and evaporated to afford crude, slightly pure by t.l.c..

heading compound which is further reacted as such.

The following compounds of formula I may be obtained in analogous manner:

I I Example R Characterisation (CH2),CH3 Decomp. from 190' la]20 = -23' (e = 0.335 D in Pyridine) 3 -(CH2)CH3 Decomp. from 180 [ai20 -18 (e = 0.395 in Pyridine) 4 (CH2)4CH3 M.pt. = 186-188 C,20 = =o (c=O.435 in Pyridine) 5 -CH2-CH=CH2 M.pt. 177 [a] 2D0 = -11.10 (c=0.465 in Pyridine) 6 -CH2-OH=-CH M.pt.190 [Q20 =-17" (c=0.34 in Pyridine) M.pt 170--173' 'CHZ' [a120 D = -9.8' (e 0.405 (cub2)2 c/ Ca]20 +6.5 (e = 0.45 in Pyridine) EXAMPLE 9 9,1 O-dihydro-6-n-propyl-8P-(2-p yridylthiome thyll-ergolin e 0.4 g of an 40% aqueous potassium hydroxide solution are added to 480 mg (1.4 mM) of 6-nor-6- n-propyl-lysergol mesylate and 0.3 g (2.7 mM) 2-mercapto-pyridine in 5 ml dimethylformamide at 350.

The mixture is stirred. After 22 hours at 400, the mixture is treated with methylene chloride/10% isopropanol, and washed with saturated sodium chloride. The combined organic phases are dried with sodium sulphate, filtered and evaporated. The residue is dissolved in hot methanol. The mixture is treated with active charcoal, filtered and evaporated to give the title compound. M.pt. from 1 900 (decomp) [a]D0 230 (c = 0.335 in Pyridine).

The starting material 6-nor-6-n-propyl-lysergol mesylate is obtained as follows:- a) 1.6 g (14.8 mM) of cyanobromide in 30 ml chloroform are added dropwise to a solution of 2.2 g (7.4 mM) lysergol acetate in 70 ml chloroform at room temperature. The mixture is stirred for 1 5 hours at room temperature, shaken with potassium bicarbonate/water and extracted with chloroform.

The combined organic phases are dried with sodium sulphate, filtered and evaporated to give crude 6nor-6-cyano-lysergol acetate.

b) A suspension of 2.2 g (7.2 mM) of crude 6-nor-6-cyano-lysergol acetate obtained in step a) and 4 g zinc powder in 26 ml acetic acid and 3 ml water is stirred for 24 hours at 1000.

The mixture is cooled, concentrated, adjusted to pH 2 and extracted with methylene chloride/5% isopropanol. 6-nor-lysergol is isolated from the aqueous phase by adjusting to pH 8, washing with saturated brine, extracting with methylene chloride/20% isopropanol, drying and filtering.

c) A solution of 350 mg (1.5 mM) 6-nor-lysergol in 15 ml dimethylformamide is treated with 4.2 g solid potassium carbonate and 0.16 ml (1.64 mM) n-propyl iodide. The mixture is stirred for 10 hours in the dark at room temperature. After filtration and evaporation, there is left 6-nor-6-n-propyl-lysergol.

d) 0.14 ml (1.8 mM) of methane sulphonic acid chloride in 1.5 ml acetonitrile are added to a solution of 400 mg (1.4 mM) of 6-nor-6-n-propyl-lysergol in 3 ml acetonitrile. The mixture is stirred for 45 minutes at room temperature and then evaporated to give a residue which is dissolved in methylene chloride/10% isopropanol and washed with saturated potassium bicarbonate solution. The organic phase is dried with sodium sulphate, filtered and evaporated to give 6-nor-6-n-propyl-lysergol mesylate.

The compounds of Examples 1 and 3 to 8 may be made in analogous manner to Example 9.

The compounds of formula I exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals, i.e. for therapy.

The compounds in particular exhibit dopaminergic åctivity, as indicated in standard tests. For example, in one test rats are used in which a unilateral degeneration of the nigro-neostriatal dopamine pathway was made by injection of 6-hydroxy-dopamine according to the principles of U. Ungerstedt, Acta. physiol. Scand.-suppl., 367, 69-93, (1973). When administered at a dose of from about 0.05 to about 3 mg/kg i.p. animal body weight, the rats turn in the direction of the non-denervated side. The dopaminergic stimulation is confirmed in the apomorphine stereotypy test on administration of 30 mg/kg i.p. of the compound to rats, in accordance with the principles set out in Belgain Patent 831,488.

The compounds are therefore indicated for use as agents for the treatment of Morbus Parkinson.

For this use an indicated daily dose is from about 0.5 to 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.3 to about 100 mg, or in sustained release form.

The compounds of formula I furthermore possess seretonergic activity as indicated in standard tests, for example in the 5.HTP stereotypy test at a dose of 10 to 30 mg/kg i.p. wherein head-shaking, stamping of the front paws and tremor is observed.

The compounds are therefore indicated for use as vigilance increasing agents, for example for the treatment of senile cerebral insufficiency.

For this use an indicated daily dose is from about 0.5 to 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.3 to about 100 mg, or in sustained release form.

The compound of Example 2 exhibits particularly interesting activity.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms 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 composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

Claims (20)

1. A process for the production of a compound of formula I

wherein R is (i) alkyl(C2~8), (ii) alkenyl(C36) or alkinyl(C3~6) wherein the double bond is other than in the a, p position, (iii) cycloalkylalkyl(C4~10) or (iv) phenylalkyl(C~,O) which comprises a) alkylating a compound of formula II

orb) reacting a compound of formula Ill

wherein R is as defined in claim 1, and X is a leaving group with a compound of formula IV

wherein M is hydrogen or an alkali metal.

2. A process for the production of a compound of formula I as defined in claim 1 substantially as hereinbefore defined with reference to any one of the Examples.

3. A compound of formula I whenever produced by a process of claim 1 or 2.

4. A compound of formula I as defined in claim 1.

5. A compound of claim 4 wherein R is alkyl(C2~8).

6. A compound of claim 4 wherein R is ethyl.

7. A compound of claim 4 wherein R is n-propyl.

8. A compound of claim 4 wherein R is n-butyl.

9. A compound of claim 4 wherein R is n-pentyl.

10. A compound of claim 4 wherein R is alkyl.

11. A compound of claim 4 wherein R is 2-propinyl.

12. A compound of claim 4 wherein R is cyclopropylmethyl.

13. A compound of claim 4 wherein R is phenethyl.

14. A compound of any one of claims 3 to 1 3 in acid addition salt form.

15. A compound of any one of claims 3 to 13 in free base form.

16. A compound of any one of claims 3 to 13 for use as pharmaceutical.

1 7. A compound of any one of claims 3 to 1 3 for use in treatment against Morbus Parkinson.

1 8. A compound of any one of claims 3 to 1 3 for use in increasing vigilance.

1 9. A pharmaceutical composition comprising a compound of any one of claims 3 to 13 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

20. A compound of formula II or III as defined in claim 1 or 6-cyano-9,1 0-didehydrn-8-(2- pyridyithiomethyl)ergoline.