GB1573621A

GB1573621A - Acylated 6-methyl-8a-amino-ergoline i compounds

Info

Publication number: GB1573621A
Application number: GB48/76A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1976-01-02
Filing date: 1976-01-02
Publication date: 1980-08-28
Also published as: ZA767715B; IL51194A; JPS604833B2; HK30484A; FR2337135A2; NL7614522A; DE2657770A1; AU2104177A; IE44206L; AU513821B2; MY8500136A; PH14106A; IE44206B1; JPS5285196A; IL51194A0; FR2337135B2; BE850050R; SG79283G

Description

(54) ACYLATED 6-METHYL-8 a -AMINO-ERGOLINE I COMPOUNDS (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:- The present invention relates to ergolines.

British Patent No. 1,517,971 discloses a class of compounds of formula I. It has now been found that certain compounds of this class not specifically disclosed therein, have particularly interesting properties.

The present invention provides compounds of formula I,

wherein R, and R2 are: Rl R2 -NH-SO2-N(Et)2 H -NH-SO2-3-pyridyl H -NH-SO,-phenyl H -NH-SO2-CF, H -NH-SO2-Me H, or NH-SO2-N(CH,)2 Br A compound of formula I may be produced by acylating 6-methyl-8a-amino-ergoline I.

The compounds of formula I may be produced in analogous manner to that disclosed in the above patent.

Free base forms of the compounds of formula I may be converted into the acid addition salt forms in conventional manner and vice versa.

The starting materials are known or may be produced in known manner.

The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds of formula I exhibit central dopaminergic stimulant activity, as indicated by standard tests, for example according to the principles of U. Ungerstedt, Acta Physiol.

Scand. Suppl., (1971) 367, 69-93, by an induction of contralateral turning in rats lesioned unilaterally in the substantia nigra by 6-hydroxydopamine on i.p. administration of from 1 to 40 mg/kg animal body weight and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test: Rats, 180-222 g, are placed in Perspex [Registered Trade Mark] cylinders of 30 cm diameter on a wire grid floor. After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 minutes at 30 minute intervals for 2 hours and then at 60 minute intervals for a total of up to 7 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Euro J.

Pharmac. 18, S3--94 (1972)].

The scores and criteria are as follows:- 1. Intermittent sniffing 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting In this test the compounds are administered i.p. at from 1 to 40 mg/kg animal body weight.

The compounds are therefore indicated for uze as anti-Parkinson agents.

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

The Example 1 compound shows interesting activity.

Additionally, the compounds exhibit prolactin secretion inhibition activity, for example, in rats by an inhibition of ovum implantion as follows:- The compound under investigation is administered to female rats 5 days after coitus and shown to be sperm positive according to the vaginal smear test. The rats are sacrificed on day 12 and their uteri are examined by means of the Salewski reaction for proof that the nidations process has been interrupted [Arch. exp. Path. Pharm. 247, 367 (1967)].

The compounds are administered s.c. at from 0.01 to 3 mg/kg animal body weight.

For the above-mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and therapy desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to 3 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammal, the total daily dosage is in the range from 0.05 to 10 mg, and dosage forms suitable for oral administration comprise from 0.01 mg to 5 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds are therefore indicated for use as prolactin secretion inhibitors. An indicated daily dose is from 0.05 to 10 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.01 to 5 mg of the compounds, or in sustained release form.

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 or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner, so as to be, for example, a solution or a tablet.

In the following Examples all temperatures are in degrees Centigrade.

EXAMPLE In a manner analogous to that disclosed in Examples 3 to 12 of the above-mentioned British Patent No. 1,517,971, the following compounds of formula I may be produced, wherein Rl R2 M.Pt. [α]D20(c in DMF) D

H 201-202 -57 (0.3) 218-220 4 -27 (0.4)5 262-266 1 -59 (0.5) H 199-201 -55 (0.5) ---NH-SO2-CF3 H 206-208 -45 (0.45) ---NH-SO2-CH3 H 219-220 -69 (0.5) (decomp.)

Br 253-256 4 +70 (0.5) (decomp.) base 2 hydrochloride + 1 mol H2O 3 hydrogen tartrate 4 hydro chloride 5 in pyridine instead of DMF WHAT WE CLAIM IS: 1. A process for the production of a compound of formula I,

wherein R, and R2 are: R1 R2 -NH-S03-N(Et)2 H -NH-SO 2-3-pyridyl H -NH-SO2-phenyl H -NH-SO2-CF3 H -NH-SO2-Me H, or -NH-SO2-N(CH,)2 Br which comprises acylating 6-methyl-Sa-amino- ergoline I.

2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to the Example.

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

4. A compound of formula I, as defined in

Claims

claim 1.

5. A compound of claim 4, wherein R, and R2 are respectively

6. A compound of claim 4, wherein R1 and R2 are respectively

and H.

7. A compound of claim 4, wherein R1 and R2 are respectively

and H.

8. A compound of claim 4, wherein R1 and R2 are respectively -NH-SO1-CF3 and H.

9. A compound of claim 4, wherein R1 and K2 are respectively -NH-SO2-CH3 and H.

10. A compound of claim 4, wherein R and R2 are respectively

11. A compound according to any one of claims 3 to 10 in free base form.

12. A compound according to any one of claims 3 to 10 in acid addition salt form.

13. A pharmaceutical composition comprising a compound according to any one of claims 3 to 10 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.