IE49611B1 - A 2-methyl ergot peptide alkaloid - Google Patents

Description

The present invention relates to the ergot peptide alkaloid 2-methyl-a-ergocryptine of formula I The free base form of the compound of formula I may be converted 5 into acid addition salt forms in conventional manner, and vice versa. Suitable salts for acid addition formation include, for example, hydrochloric acid, maleic acid, sulphuric acid, fumaric acid and tartaric acid.

The following examples illustrate the preparation of the compound of formula Ϊ. All temperatures are in degrees Centigrade and are uncorrected.

EXAMPLE 1: 2-methyl-a-ergocryptine 2.82 g (10 mMol) anhydrous 2-methyl lysergic acid are dissolved in 25 ml absolute dimethylformamide on the addition of 2.28 g (20 mMol) trifiuoroacetic acid, and with stirring brought to -1O°C. At this temperature, a mixture of 2.52 g (12 mMol) trifiuoroacetic acid anhydride in 12 ml absolute acetonitrile is added dropwise and the resultant clear solution is stirred for 10 minutes. 12 ml pyridine and 1.81 g (5 mMol) (2R,5S,10aS,10bS)-2-amino-5lo isobutyl-10b-hydroxy-2-isopropyl-octahydro-3,6-dioxo-8Hoxazolo[3,2-a]pyrrolo(2,l-c]pyrazine hydrochloride are added and the reaction mixture is stirred for 1 hour at between -10° and 0°.

To work up, 200 ml methylene chloride is added and the mixture is well shaken with 100 ml 2N sodium carbonate solution. The organic phase is separated and the aqueous phase is washed three times with 100 ml methylene chloride. The combined organic phase are dried over sodium sulphate and concentrated in a vacuum. The residue is chromatographed .20 on silicagel eluted with 2% methanol in methylene chloride to give pure 2-methyl-a-ergocryptinine. M.pt. 225-227° (de20 comp) from methylene chxoride/ether; [a] θ =+ 412° (c = 0.4 in chloroform).

Elution with 3% methanol in methylene chloride yielded 2-methyl-a-ergocryptine. The hydrogen fumarate is obtained by reaction with 1 equivalent of fumaric acid.M. pt. 181-184° (decomp) [a]2° = + 25.0 (c=0.2 in ethanol).

EXAMPLE 2: 2-methyl-g-ergocryptine a) thian^^yl) 2"Ze£9°°£YEtin£ A solution of 11.5 g (20 mMol) of a-ergocryptlne in absolute chloroform - is added dropwise quickly s to a vigorously stirred solution of about 1.2 equivalents of 2-chloro-l,3-dithiane in absolute chloroform ——-cooled to -15°. The reaction mixture is allowed to warm to 5 to 10° resulting in a· black dirty precipitate. The mixture is stirred at 10° and worked up. Working up comprises IO making the mixture alkaline with 2N sodium carbonate solution and extracting with methylene chloride/methanol (9:1). The organic phases are washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated. 16.7 g of a foam con- 15 taining the heading compound is obtained which can be used further as such or else chromatographed on silicagel using 2» CHjOH in CHjClj as eluant to yield the heading compound. The hydrogen maleate of the heading compound has M.pt 163165* (from ethyl acetate/ether); (aJD^ =· + 111’ (c 20 0.55 in dimethylformamide). 105 ml of an aqueous suspension of Raney Nickel W6 is repeatedly washed with 100 ml amounts of acetone/ dimethylformamide (8:2). Samples of the supernatant liquid are taken as the acetone/dimethylformamide is added. When the sample on treatment with methylene chloride yields no unclarity, then the washing with acetone/dimethylformamide is stopped. 7.5 g of 2-(l,3-dithian-2-yl)-a-ergoeryptine in 150 ml acetone containing 20% dimethylformamide are treated with 105 ml or this treated Raney Nickel W6 in 100 ml of the same solvent. After 15 minutes, the catalyst is filtered off and it is washed several times with about 300 ml of the solvent mixture. The solvent is distilled IS from the combined organic phases to give a brown foam which is taken up in ethanol and reacted with fumaric acid (1 equivalent) to give the hydrogen fumarate of the heading compound. M.pt. 181-184° (decomp); [α]^θ = + 25.1 (c = 0.2 ethanol). 2.0 The compound of formula Γ and its pharmacologically acceptable acid addition salts, hereinafter referred to as compounds of the invention, exhibit pharmacological activity in animals.

The compounds of the invention exhibit a dopaminergic stimulating effect as indicated in standard animal > tests. For example, the compounds when administered at from about 0.03 to about.3 mg/kg inhibit the rotations induced by i.p. injection of 6-hydroxydopamine into the substantia nigra unilaterally into the nigra-neostriat&la dopamine pathway [method according to U. Ungerstaedt Acta physiol, scand. Suppl. 367, 64-93 (1973)1. The compounds also inhibit stereotypy in the apomorphine stereotypy test in i.p. administration ot about 30 mg/kg of the compound.

The compounds are therefore indicated for use as anti-parkinson agents for e.g. for the treatment of Morbus IS Parkinson.

As indicated daily dosage is in the range from about 0.5 to about 100 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 mg to about 50 mg of the compounds, or in 2.0 sustained release form.

The compounds of the invention furthermore exhibit prolactin secretion inhibitory activity, as indicated by standard tests, e.,g. by inhibition of implanatation in the rat on s.c. administration of from about 0.01 to about 1 mg/ 2.S kg of the compounds and an inhibit'-n of lactation on p.o. administration of from about 1 to about 10 mg/kg of the compounds.

The compounds are therefore indicated for use as prolactin secretion inhibitors .

An indicated daily dosage is in the range from about 0.5 to about 100 mg, conveniently given in divided S doses 2 to 4 times a day in unit dosage form containing from about 0.1 mg to about 50 mg of the compounds, or in sustained release form.

The compounds of the invention additionally exhibit anti-depressant activity, as indicated by an inhibition of IO ptosis and catalepsy induced by reserpine in rats on i.p. administration of 1 to 50 mg/kg of the compounds.

The compounds are therefore indicated for use as anti-depressant agents.

An indicated daily dosage is in the range from about 1·5 0.5 to about 100 mg, conveniently given in divided doses to 4 times a day in unit dosage form containing from about 0.1 mg to about 50 mg of the compounds, or in sustained release form.

The compounds of the invention furthermore exhibit 2.0 vigilance increasing activity as indicated by an increase in the wake phase and a decrease in the paroxodical and classical sleep phases in the sleep/wake cycle test in the rat in p.o. administration of from about 5 to about 20 mg/kg of the compounds.

The compounds are therefore indicated for use as vigilance increasing agents.

The compounds of the invention additionally exhibit 48611 a vasoconstricting effect in standard animal tests, e.g. in the Mellander-cat test [Angiologica 3, 77-99 (1966)] by an arterial vasotonic effect, on i.a. administration of from about 5 to about 45 yug/kg animal body weight.

The compounds are therefore indicated for use in the treatment of migraine and orthostatic disorders.

For the above two indications, an indicated daily dosage is in the range from about 0.5 to about 100 mg , conveniently given in to divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 mg to about 50 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of the invention may be administered in IS 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 the compound of formu3.0 la I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

Claims (4)

1. The compound of formula I

2. An acid addition salt form of the compound of claim 1.

3. A pharmaceutical composition comprising the compound of

4. 5 claim 1 in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.