IE46688B1

IE46688B1 - N-(2,3 -dihydro-9-ergolen-8 -yl methyl)ureas

Info

Publication number: IE46688B1
Application number: IE580/78A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1977-03-25
Filing date: 1978-03-23
Publication date: 1983-08-24
Also published as: DE2810774A1; AT366685B; DK147072B; CA1105009A; ZA781714B; DK147072C; IL54342A; GB1596210A; ES468133A1; AU3448378A; IL54342A0; BE865267A; IE780580L; NL7803031A; CH628049A5; AU520738B2; FI66375B; JPS53119898A; IT7848557A0; DK119778A

Abstract

A description is given of the preparation of ergolene derivatives with an action lowering blood pressure and the formula I in which R1 and R2 are each hydrogen or an alkyl group with 1 to 4 carbon atoms, or else together form an alkylidene chain with a maximum of 5 carbon atoms, and their salts with acids. Corresponding compounds unsaturated in position 2,3 are reduced selectively in position 2,3 and the resulting compounds of the formula I are converted where appropriate into their acid addition salts.

Description

This‘invention relates to ergot derivatives.

* I The present invention provides compounds of formula I, ' I wherein Rj and R2 are independently hydrogen 5 or alkyl of 1 to 4 carbon ’atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, Rg is alkyl of 1 to 4 carbon iatoms, and R^ is hydrogen, alkyl of 1 td atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the α-carbon atom does not carry any halogen atom, or alkoxymethyl of carbon to 5 carbon atoms. -4-6688 -3-Halogen means bromine and especially fluorine and chlorine. Alkyl is preferably methyl or ethyl except where otherwise stated. Alkoxy is preferably methoxy. Alkylidene is preferably tetra- or penta5 methylene. When alkyl is substituted by halogen, the halogen atom is preferably on the terminal carbon atom. Preferably alkyl, when substituted by halogen, has 2 carbon atoms, and R2 are preferably alkyl, Rg is preferably methyl or isopropyl. R^ is preferably hydrogen. In a group of compounds Rg is methyl and R^ is hydrogen The present invention also provides a process for the production of a compound of formula I as defined above, which comprises selectively reducing the 2,3 position of a compound of formula II, wherein R. to R, are as defined above. 1 4 The process may be effected in conventional manner for the reduction of the 2,3 double bond in an ergot alkaloid. A complex hydride such as sodium borohydride, e.g. in the presence of trifluoroacetic acid, may be used. Suitable solvents include trifluoroacetic acid, ether, tetrahydrofuran or dioxane or mixtures thereof. The reduction may also be effected using zinc in hydrochloric acid.

Suitable reaction temperatures may be from 0 to 40 ° C.

The starting materials are either known or may be made in conventional manner.

Free base forms of the compounds of formula I may be converted into acid addition salt forms, e.g. the hydrochloride or hydrogen fumarate, in conventional manner and vice versa.

In the following examples all temperatures are in degrees Centigrade and are uncorrected. ; All ratios refer to parts by volume. ·' ό υ ο 8 EXAMPLE 1: 1,l-dimethyl-3-[6-methy1-2, 3S-dihydro-9ergolen-8_0-y Ime thyl]urea 1.95 g of sodium borohydride are added portionwise to 10.5 g 1,1-dimethy1-3-[6-methy1-95 ergolen-8p-ylmethyl]urea in 115 ml trifluoroacetic acid. The mixture is stirred for 20 minutes and poured Onto ice/water. Solid potassium carbonate is added to the mixture, which is vigorously stirred, until a pH of 8 is reached. The mixture is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulphate, filtered and evaporated to give a beige foam, which is chromatographed on 120 g silicagel using methylene chloride/methanol (9 : 1) + 0.5 % concentrated NH^ as eluant.

The resultant base is converted into the hydrochloride or hydrogen fumarate.

HCl salt - M.P. from 185 ° (decomp.); [a]Q = + 50 ° (c = 0.675 in ethanol/water 1:1).

Hydrogen fumarate salt - M.P. from 120 ° (decomp.); [a)^ =+20.9° (c = 0.44 in ethanol/water 1:1).

In analogous manner to that described in Example 1 the following compounds may be produced: 4 ο ϋ 3 8 ro Ο CN Q Ί? L—1 - 67.5 ° (c = 0.68) KO CO © · CN O CO || in 1 0 1 ft 3 - 145 ol) om 165 °2> • fi* μ a H ΜΗ fi· ro ffl CN ffl 0 , CT ft ' Di u 0 (0 co ffl co ffl ft 0 0 CN ro ffl co ffl ft U 0 rfi co ffl co ffl P5 u u Ex.No. CN co 4J C •fi Ο ft β Ο •fi -Ρ •fi (0 Ο ί υ ο Ό Β 0 0 MH Φ 0) m (0 ro rt rt lfi X} Λ 0 ffl Φ GJ 0 GJ GJ μ μ β ft ft H rfi CN CO »6688 - 7 The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat, in the awake spontaneous hypertonic rat, and in the awake renal hypertonic Goldblatt dog, upon administration of 0.05 to 3 mg/kg animal body weight of the compounds.

The compounds are therefore indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from. 0.5 to 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.1 to. 100 mg, or in sustained release form.

A particularly interesting compound is the Example 1 compound. 6 6 8 8 The compounds of formula X may be ' I administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free base forms.

The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule.

Claims

CLAIMS:

1. A process for the production of a compound of formula X, Wherein R^ and Rg are independently hydrogen or alkyl of 1 to 4 carbon atoms, ’ ' or are together an alkylidene chain of 2 to 5 carbon atoms, Rg is alkyl of 1 to 4 carbon atoms, and R^ is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the α-carbon atom does not carry any halogen atom, or alkoxymethyl of

2. To 5 carbon atoms, - 10 which comprises selectively reducing the 2,3 position of a compound of formula II, wherein Rg to R^ are as defined above. I 5 2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples

3. A compound of formula I, whenever produced by a process according to claim 1 or 2. I 10 .

4. A compound of formula I, as defined in claim 1. - 11 '

5. A compound of claim 4, wherein is methyl and r‘ 4 is hydrogen.

6. *A compound of claim 4, which is 1,1-dimethy1-3-[6-methy1-2,3p-dihydro-9-ergolen-8pylmethyl]urea.

7. A compound of claim 4, wherein Rg, R 2 and R g are all methyl.

8. A compound of claim 7, wherein R^ is CH 3 .

9. A compound of claim 7, wherein R^ is cf 3 -ch 2 -.

10. A compound according to any one of claims 3 to 9 in free base form.

11. A compound according to any one of claims 3 to 9 in acid addition salt form.

12. A pharmaceutical composition comprising a compound according to any one of claims 3 to 11 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.