FI65430C - FOERFARANDE FOER FRAMSTAELLNING AV NYA 8ALFA-ERGOLIN I-DERIVATVILKA HAR DOPAMINERGISKA OCH PROLAKTINSEKRETIONSHAEMMANDE EENSKAPER - Google Patents

Description

1 65430

Method for the preparation of novel dopaminergic and prolactin-inhibiting, 8 ct-ergoline I derivatives.

The invention relates to a process for the preparation of novel 8? -Ergoline I derivatives of the formula I or their acid addition salts having dopaminergic and prolactin-inhibiting properties, 10 H 2. NR 5 SO-N 2 7 R 8 f H | The formula is hydrogen or alkyl of 1 to 4 carbon atoms and R 1 and R 10 are independently hydrogen or alkyls of 1 to 4 carbon atoms. The alkyl group preferably contains 2 and especially 1 carbon atom, is preferably hydrogen.

If and / or Rg are alkyl, these preferably contain 1 to 3 and in particular 2 or 1 carbon atoms.

R7 3a Rg are preferably the same.

FR-A-1 360 618 discloses ergolines closely resembling the compounds of the present application which have serotonin antagonist activity.

In contrast, the compounds of the present application have dopaminergic and prolactin secretion inhibiting properties. U.S. Patent 3,922,347 discloses 8-acylaminoergolins having prolactin secretion inhibitory activity. N, N-dialkyl-N '- (6-methylergolin-8-yl) sulfamides described in FI patent application 752 011, which differ from the analogous compounds of the present invention in that position 1 is hydrogen instead of methyl. Comparing 2,65430 N, N'-dimethyl-N '- (6-methyl-ergolin-8-yl) sulfamide (FI application 752 011, Example 4) and N, N-dimethyl-N' - (1, 6-dimethyl-ergolin-8-yl) sulfamide (a compound of the present invention, Example 1), it can be stated that both compounds have excellent dipaminergic and prolactin-inhibiting properties, and the latter has been found to be particularly advantageous in the field of pharmacy due to its good physiological tolerability.

FI patent publication 53 127 discloses N- (D-6-methyl-108-isoergin-1-yl) -N ', N'-diethylurea, which has a similar mode of action to the compounds of the present application. However, it has been found by means of therapeutic comparative experiments that the 1,6-dimethyl-8- (Ν, Ν-dimethylsulfamoylamino) ergoline I according to Example 1 of the present application has a stronger dopaminergic effect than the above-mentioned compound known from FI patent publication 53,127. In the Unger-stedt experiment, the number of contralateral rotations in unilaterally degenerate nigrostriatal pathways in rats has been obtained for 741 compounds known from the FI patent publication and 1336 for the compound according to Example 1 of the present application.

According to the invention, compounds of formula I are prepared by reacting a compound of formula II, 25 -NHR4

I H

/ '/ 4-NCH3 II

UJ

30 Jn__T

CH3 \ in which R. has the same meaning as above, give the reaction

4 R

goida acid ../ 7, where R., and R. have the same meaning

Xr8 as above, with a reactive functional derivative 35 3 65430, and the compounds of formula I thus prepared are recovered in the form of bases or acid addition salts.

The method can be carried out analogously to known methods. p / K7 5 The method is an N-acylation method. For example, an acid-corresponding chloride or bromide can be used to attach the group -SO 2 -N <R 2 to the compounds of formula II.

Most preferably, the method is carried out in solution.

Suitable solvents are, for example, methylene chloride or dioxane.

In general, a reaction temperature of between -10 ° C and about room temperature is preferably used.

The process is conveniently carried out in the presence of a tertiary base, e.g. triethylamine, or preferably in the presence of pyridine or 2,6-lutidine.

The compounds of formula I may be in free base form or as their acid addition salts. Acid addition salts can be prepared from the free bases in a known manner and vice versa. The preferred salt is the hydrochloride.

The starting compounds are known or can be prepared by known methods, e.g. as described in the examples.

The compounds of the formula I in free form or as physiologically acceptable acid addition salts (compounds according to the invention) have interesting pharmacological properties and can therefore be used as medicaments.

Thus, due to their dopamine-like properties, the compounds of the invention can be used in the treatment of Parkinson's disease and depression.

In addition, the compounds of the invention have an antiproliferative effect. Compounds that inhibit prolactin secretion can be used, for example, in the prevention and treatment of physiological breastfeeding and milk leakage.

The compounds of the formula I according to the invention, in which R 1 is H and Ry and R 8 are methyl, have a very clear inhibitory effect on prolactin secretion.

4,65430

The invention also relates to medicaments which contain a compound of the formula I in free form or in the form of physiologically acceptable acid addition salts. These drugs, e.g. as solutions or tablets, can be prepared by known methods using conventional excipients and carriers.

The following examples illustrate the invention. Temperatures are in degrees Celsius and uncorrected.

Example 1 1,6-Dimethyl-8 - <* - (Ν, Ν-dimethylsulfamoylamino) -

ergoline I

2.55 g (10 mmol) of 1,6-dimethyl-8-α-aminoergoline I were dissolved in 20 ml of 2,6-lutidine, and the solution was added dropwise over 10 minutes to a stirred mixture of 3.58 g. (25 mmol) N, N-dimethylsulfamic acid chloride, 40 ml methylene chloride and 10 ml 2,6-lutidine. After stirring for 1 hour at room temperature, 1.5 ml of Ν, Ν-dimethylsulfamic acid chloride were added and stirred for a further two hours at room temperature. Li-20 was adjusted at 0 ° C with 2N ammonia until a basic reaction was obtained and extracted with a mixture of 10% methanol in methylene chloride. The mixture was dried over sodium sulfate, the organic phase was decolorized with activated carbon and evaporated on a rotary evaporator. The greenish foam thus obtained was chromatographed on 150 g of silica gel and the title compound was eluted as a yellowish resin with 2% methanol in methylene chloride. The hydrochloride of the title compound was crystallized from ethanol, m.p. 226 ° -228 ° C, ^ C ^ D ° = "23 ° (c = 0.3 in pyridine).

The starting material 1,6-dimethyl-8'-aminoergoline I was obtained by hydrogenation of 1-methyl-N'-glyceric acid methyl ester after addition of platinum oxide to give 1-methyl-9,10-dihydroisolysergic acid 1-methyl ester (m.p. 150-151 ° C) to react with a mixture of hydrazine hydrate and hydrazine-35 dihydrochloride and converting the 1-methyl-9,1O-dihydroisolysergic acid I-hydrazide thus obtained into the desired compound (m.p. 208 ° -211 ° C) according to Curtius.

5,65430

Example 2

1,6-Dimethyl-8α- (N, Ν-diethylsulfamoylamino) -ergoline I

According to Example 1, 1,6-dimethyl-80-5 aminoergoline I was reacted with N, N-diethylsulfamic acid chloride. Methanesulfonate m.p. 199-201 ° C, = -25 ° (c = 0.3 in dimethyl sulfoxide).

Claims (2)

65430 Claim A process for the preparation of new 8 cl · -ergoline I derivatives of the formula I or their acid addition salts having dopaminergic and prolactin-inhibiting properties, H 2 NR 4 SO 2 -N <* 7 10 H '„ΓηΙ VV Ci ¢ 1 H 15 3 in which R4 is a hydrogen atom or alkyl having 1 to 4 carbon atoms and Ry and Rg are independently hydrogen atoms or alkyls having 1 to 4 carbon atoms, characterized in that the compound of formula II 20 H NHR. V HS TT ^> - X> H3 II 2. 1H in which R4 is as defined above, is reacted with a reactive, functional derivative of the acid H0S0_N · ^ 7, in which Ry and R8 are as defined above, and the compounds of formula I thus prepared are recovered from the bases. or in the form of acid addition salts.