DE2657771A1 - NEW ORGANIC COMPOUNDS, THEIR USE AND PRODUCTION - Google Patents

Description

New organic compounds, their uses and
Manufacturing

DOS 2,509,471 includes a class of ergolines. It has been found that certain in the said
DOS compounds of this class not specifically listed have particularly interesting properties.

The invention relates in particular to the compounds of the formula I.

CH ₂ -SR

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Config.

3-pyridyl -CH = C = 8ß 2-pyridyl -CH ₂ -CH- 8α 2-pyridyl -CH = C = 8α

as bases or in the form of acid addition salts.

The present invention also includes a method for the preparation of compounds of the formula I and their acid addition salts by adding a compound of formula II

N-CH.

II

with a compound of the formula III,

MSR

III

where X is an exchangeable radical, M is hydrogen or an alkali metal and χ y, R and the Configuration of the side chain in position 8 are chosen so that they match the three listed above under the formula I. Compounds correspond, converts and the compounds of formula I thus obtained as bases or wins in the form of acid addition salts.

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-S-

The compounds of the formula I can be prepared analogously to process a as described in the DOS above.

The compounds of the formula I, i.e. the compounds of the formula I in free form or in the form of addition salts with physiologically compatible acids, have has interesting pharmacodynamic properties in animal experiments. They can be used as a remedy will.

Thus, these compounds have centrally dopaminergic stimulating properties and antagonize im Animal experiment catalepsy caused by reserpine. Both pharmacodynamic properties determine the Use of the compounds of the formula I in the treatment of Parkinson's disease and of depressive disorders Conditions close.

The central dopaminergic stimulating properties of the compounds of the formula I are enhanced by phosphodiesterase inhibitors, especially by compounds that inhibit the phosphodiesterase effect in the brain.

Suitable phosphodiesterase inhibitors are, in particular, methylxanthines such as caffeine or theophylline, but also derivatives of the 4-amino-1H-pyrazolo [3,4 ~ b] -pyridine-5-carboxylic acid esters like l-ethyl-4- (isopropylidenehydrazino) -lH-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl ester, Ethyl l-ethyl-4-hydrazino-lH-pyrazolo [3,4-b] pyridine-5-carboxylate and l-ethyl-4-butylamino-lH-pyrazolo [3,4-b]

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ethyl pyridine-5-carboxylate, 4- (3,4-dimethoxybenzyl) -2-imidazolidinone and analogs thereof such as 4- (3-butoxy-4-methoxybenzyl) -2-imidazolidinone, Minor tranquillizers, for example the 1,4-benzodiazepine series such as 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide, tricyclic antidepressants such as 4- [3- (5H-dibenz [b-, f] azepin-5-yl) propyl] -l-piperazine-ethanol and papaverine. The invention therefore also relates to pharmaceutical preparations which are a compound of the Formula I and a phosphodiesterase inhibitor, also the use in the form of those mentioned Preparations or by combined but separate application for the treatment of disease Parkinson's.

The daily dose when using a compound of the formula I as the sole active ingredient is in the range from about 1 to about 100 mg of the substance; contain suitable dosage forms for e.g. oral applications generally about 0.20 to 100 mg of active substance; If necessary, the administration can work in several, for example in 2, 3, 4 or 5 portions daily or as a sustained-release form.

When using preparations that contain a compound of the formula I and a phosphodiesterase inhibitor included, or when using the individual components in a combination therapy, depends on the Dosage also depends on the type of substance used, the administration and the individual Needs. When treated with

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bonds of the formula I in combination with a phosphodiesterase inhibitor is the daily dose in the range of about 0.5 to about 50 mg of a compound of formula I in combination with about 25 to about 500 mg of a phosphodiesterase inhibitor. Here, too, the daily dose can be divided into several for example 2, 3, 4 or 5 portions are administered. The single doses then contain, for example, about 0.1 to about 50 mg of a compound of the formula I in combination with about 5 to 500 mg of a phosphodiesterase inhibitor. The quantitative ratio of the compound of the formula I: phosphodiesterase inhibitor is in generally between 1:10 and 1:50.

The compounds of formula I in which χ y is -CH_-CHC stands, show particularly interesting zer dopaminergic stimulating properties.

The compounds of the formula I can be administered in the form of pharmaceutical preparations. For example, the pharmaceutical preparations can be in the form of tablets, powders, granules, capsules, syrups and elixirs for oral
Administration, as well as in the form of solutions, emulsions, dispersions and emulsions for parenteral administration.

These pharmaceutical preparations can be produced in a manner known per se using the usual auxiliaries.

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The invention therefore also relates to medicaments which contain a compound of the formula I, and their manufacture.

A special embodiment of this are remedies, which contain a compound of the formula I and a phosphodiesterase inhibitor. To the The latter preparations are made using a compound of formula I and a phosphodiesterase inhibitor mixed. This mixture can then be converted into a for suitable dosage form for therapeutic purposes.

In the following example, which explains the invention in more detail, in no way its scope should restrict, all temperatures are given in degrees Celsius.

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Example;

Using the one described in the DOS above Method (e.g. in Example 1) and corresponding starting compounds lead to the following compounds of formula I:

6-methyl-8ß- (3-pyridylthiomethyl) ergols

[a] ^ ° = + 38 ° (c = 0.5 in DMF), m.p. 192-196 °

e-Methyl-SCX (2-pyridyltbiomethyl) ergoline (I) ^[tx] D ~ ^"58 ° <= ^c ° ^{'6 in DMF)'} P · ^{Sm 195-197} °

6-methyl-8a- (2-pyridylthiomethyl) ergols

[a] ^ ⁰ = + 185 ° (c = 0.3 in DMF), m.p. 220-224 °

1 in the form of the free base

2 in the form of the dihydrochloride

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Claims (3)

Claims; 100-4469 1. The compounds of formula I. CH ₂ -SR X y Config. 3-pyridyl -CH = C = 8ß 2-pyridyl -CH ₂ -CH- 8a 2-pyridyl -CH = C = 8a as bases or in the form of acid addition salts, 2. Process for the preparation of compounds of the formula I and their acid addition salts, thereby marked that one connects the Fornel II CH ₂ -X L M- CH. 709828/0961 II 100-4469 -4 ' with a compound of the formula IIΓ, MSR III where X is an exchangeable radical, M is hydrogen or an alkali metal and x ~ γ, R and the configuration of the side chain in position 8 are selected so that they correspond to the three compounds listed above under the formula I. Compounds of the formula I as bases
or wins in the form of acid addition salts. 3. Medicament, characterized in that it is a compound of the formula I or its acid addition salts contains. 3700 / BA / ER 709828/0981