LU85212A1 - NOVEL DERIVATIVES OF LYSERGIC ACID, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

The subject of the present invention is new derivatives of lysergic acid, their preparation and their use in therapy as active principles of medicaments.

US Patent No. 4,348,391 describes a broad class 5 of f + {(8a) -ergoline-8-yl] -sulfonamides used as anti-parkinsonian agents, anti-depressants and inhibitors of prolactin secretion. All the compounds specifically described contain an allyl group or a methyl group in position 1. La. The Applicant has now found that certain compounds which are not specifically described or suggested in this patent have a particularly advantageous pharmacological profile, in particular a prolonged activity, especially as anti-parkinsonian agents, and a good tolerance, especially when administered by orally.

The present invention relates in particular to

compounds of formula I

NH- $ 0? -NC ^ 2 3 20 i ^ CH2 “CH3 cxS ^ h" CH3

25 R-N-M

in which R represents an ethyl or isopropyl group in the form of a free base or in the form of acid addition salts. The present invention also relates to a method of

preparation of the compounds of formula I and their acid addition salts, said process comprising the alkylation of a compound of formula II

2 NH-S0? - <CH ^ H3! xch2-ch3 5 OÎj ^ ’3 (n) HM-a 10 and the recovery of the resulting compound in the form of a free base or in the form of an acid addition salt.

The process can be carried out according to the usual methods of alkylation of indo-nitrogen in compounds

15 analogs. For example a compound of formula III

. R-X (III) wherein X represents the acid residue of a reactive ester, for example a halogen such as iodine, or the residue of an organic sulfonic acid, can be used as an alkylating agent.

- The reaction can be carried out in a solvent, for example liquid ammonia, at a temperature between about 25 -40 ° C and the boiling temperature, if necessary in the presence of a base, for example sodium butylate or iron trichloride.

The resulting compound of formula I can be isolated and purified according to the usual methods.

3

The free bases of the compounds of formula I can be transformed according to the usual methods into acid addition salts and vice versa. The compounds of formula II are known.

The following examples illustrate the present invention without limiting its scope. All temperatures are given in degrees Celsius.

Example 1: N> N-dieth.yl-Nl - [(8g) -l-ethy1-6-met'h, yl-erqoline-8-yl3-sulfamide

While stirring, 1.61 g (70 mM) of sodium is added in portions to a mixture cooled with dry ice and consisting of 35 mg (0.22 mM) of iron trichloride, 7.52 ml ( 80 mM) tert-butyl alcohol and 40 ml of ammonia. 7.53 g (20 mM) of N, N-diethyl-N '- [(8ot) -6 ~ methyl-ergoline- 8-yl] -sulfamide are then added, the reaction mixture is heated to reflux and added. drop by drop 1.938 ml (24 mM) of ethyl iodide over 4 hours and the mixture is heated to reflux for a further 3 hours with stirring.

The ammonia is allowed to evaporate overnight, with stirring. The reaction mixture is allowed to warm to room temperature and is partitioned between 80 ml of a 2N aqueous solution of ammonium sulfate and methylene chloride. The organic extracts are washed, dried over sodium sulphate, concentrated and chromatographed on a column (170 g of silica gel) with a 98/2 mixture of toluene and methanol as eluent. The title compound is eluted and crystallized from a toluene / hexane mixture (50:50). M = 101-102 °; [a] 2 ^ = -64.6 °

D

(c = 1.018¾ in chloroform).

Example 2: N, N-dieth, y1-N'-C (8-ft) -l-isopropyl-6-meth.yl-ergoline-8- 30 yl Isulfamide

The title compound is obtained in a similar manner to that described in Example 1. M = 108-110 °; [a] 20 = -63.5 °

D

(c = 1.038¾ in chloroform).

4

The compounds of formula I in free form or in the form of an acid addition salt have interesting pharmacological properties and can therefore be used therapeutically as medicaments.

In particular, the compounds of the invention exert an action on the central dopaminergic receptors as appears from the conventional tests. This activity was demonstrated in the test carried out according to the method described by U. Ungerstedt et al 1. in Acta Physiol. Scand. Suppl. 387, 69-93 (1971) in rats in which unilateral degeneration of the nigro-striated pathways was caused after unilaterally injecting 6-hydroxy-dopamine into the substantia nigra. Rotational behavior contralateral to the lesion is observed for a long time, for example for several hours, after administration of the compounds orally at doses of between about 3 and about 30 mg / kg.

The compounds of the invention can therefore be used in therapy as anti-parkinsonian agents.

The compounds of the invention also exert an inhibitory activity on the secretion of prolactin as is apparent from conventional tests.

By way of example, this activity has been demonstrated J in the spleen according to the method described by E. Fllickiger et al., In Experienta 14, 1330-1332 (1978) by the inhibition of gestation after administration of the compounds subcutaneously at doses of, for example, between 0.03 and about 3 mg / kg, and in rats according to the method described by Flückiger et al., in Postgraduate Medical School Journal 52_, Suppl. 1,57 (1976) by reducing prolactin levels in the blood after administration of the compounds orally at doses ranging, for example, from 0.001 to about 0.5 mg / kg. The effects surprisingly extend over a long period, for example several hours.

The compounds of the invention can therefore be used in therapy as inhibitors of prolactin secretion, the compound of Example 2 being the preferred compound for this indication.

The compounds of the invention are also distinguished by an anti-depressive action demonstrated in conventional tests, for example by the inhibition of acinesia caused by reserpine in mice after administration of the compounds by the subcutaneous route. cutaneous at doses between about 0.5 and about 10 mg / kg and by the inhibition of ptosis and catalepsy caused by tetrabenazine in rats after administration of the compounds orally at doses between about 10 and 30 mg / kg, according to the method described by JM Vigourét et al., in 15 Pharmacology 16 (Suppl. 1) 156-193 (1978).

Thanks to this property, the compounds of the invention can also be used in therapy as anti-depressants.

For these indications, the compounds of the invention will be administered at a dose of between 0.5 and 100 mg, advantageously in divided doses 1 to 4 times a day in the form of unit doses each containing from approximately 0.1 to approximately 50 mg of active substance, or in a delayed release form.

\ The compounds are surprisingly distinguished by their good tolerance. For example, no significant emetic effect has been found in dogs after daily administration of the compounds orally at a dose of 0.3 mg / kg. In addition, administered to cats intravenously at a dose of about 37pg / kg, the compounds have no significant influence on blood circulation and on heart rate. These results demonstrate a high selectivity of the effect, which is advantageous for the use of the compounds as anti-parkinsonian agents.

6

The preferred compound is that of Example 1.

The preferred therapeutic use is use as an anti-parkinsonian.

For their therapeutic application, the compounds of the invention can be administered in the form of a free base or in the form of a pharmaceutically acceptable salt. These salts have an activity of the same order as that of the free bases.

The invention therefore comprises a compound according to the invention, in the form of a free base or in the form of a pharmaceutically acceptable salt, for use as a medicament, for example for use as an anti-parkinsonian agent, as an inhibitor of prolactin secretion and as an anti-depressant.

The invention also includes a medicament containing, as active principle, a compound of the invention in the form of a free base or in the form of a pharmaceutically acceptable salt.

As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing a compound of the invention in the form of a free base or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically diluent or vehicle acceptable. Such pharmaceutical compositions, which also form part of the present invention, can be prepared according to the usual methods and can be presented, for example, in the form of tablets or solutions.

Claims (9)

7 1. A derivative of T lysergic acid of formula I NH-SO - NQ 6 J 5 · L ^ CH2-CH3 RN-8 in which R represents an ethyl or isopropyl group, in the form of free base or in the form of. an acid addition salt. 2. N »Ν-diethyl-N'-C (8a) -l-ethyl-6-methyl-ergoline- 8-yl3-sulfamide, in the form of the free base or in the form of an addition salt 'acid. 3. N, N-diethyl-N '- [(8a) -l-isopropyl-6-methyl-ergoline-8-yl] -sulfamide, in the form of the free base or in the form of an addition salt acid. 4. A process for the preparation of a compound of formula I defined in claim 1, and of its acid addition salts, 1 characterized in that it comprises the alkylation of a compound of formula II NH -SO? -N ^ 2 3 î X (* H2'CH3 IU) 30. I J * H 3 HN- "35 * ι 8 *" and the recovery of the resulting compound in the form of the free base or in the form of an acid addition salt. 5. A lysergic acid derivative according to any one of claims 1 to 3, in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt, for use as a medicament. "6. A lysergic acid derivative according to claim 5, for use as an anti-parkinsonian agent or as an inhibitor of prolactin secretion or as an anti-depressant agent. 7. A medicament, characterized in that it contains, as active principle, a derivative of lysergic acid according to any one of claims 1 to 3, in the form of the free base or in the form of an addition salt pharmaceutically acceptable acid. 8. A pharmaceutical composition, characterized in that it contains a derivative of lysergic acid as specified in any one of claims 1 to 3, in the form of the free base or in the form of an acid addition salt pharmaceutically acceptable, in combination with a pharmaceutically acceptable diluent or carrier. 9. Products and processes in substance as described above with reference to the examples cited.