NL8006461A - ERGOLINE DERIVATIVES, METHODS FOR PREPARING THESE DERIVATIVES AND THE MEDICINAL PRODUCTS CONTAINING THEM AND THEIR USE IN THERAPEUTIC TREATMENTS. - Google Patents

Description

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Ergoline derivatives, methods of preparation of these derivatives and of drugs containing them and their use in therapeutic treatments.

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The invention relates to ergoline derivatives, methods of preparing these derivatives and of drugs containing these ergoline derivatives, and to the use of these ergoline derivatives in therapeutic treatments.

The invention particularly relates to compounds of the formula I, wherein R is an alkyl group with 2 to 8 I carbon atoms, an alkenyl or alkinyl group, each with 3 to 6! carbon atoms, the multiple bond of which is not adjacent to the nitrogen atom, represents a cycloalkylalkyl group with U to 10 carbon atoms or a phenylalkyl group with 7 to 10 carbon atoms, and the acid addition salts thereof.

Substituent R preferably represents a previously defined alkyl group, in particular an ethyl or n-propyl-15 group. When R represents a previously defined alkenyl or alkinyl group, it preferably contains 3 or b carbon atoms.

R-symbolized cycloalkylalkyl groups defined above preferably contain 3 to 6 carbon atoms in the cycloalkyl portion and 1 or 2 'carbon atoms in the alkylene chain.

R represents a previously defined phenylalkyl group, this is preferably benzyl or phenethyl.

The compounds of the formula I and the salts thereof according to the invention can be prepared by a) alkylating the compound of the formula 2, or b) a compound of the formula 3, in which R has the meaning indicated above 800 6 46 1 - 2 - and X represents an interchangeable residue, to react with a compound of formula 1 *, wherein M represents a hydrogen atom or an alkali metal metal, and, if desired, convert the resulting compounds into their acid addition salts.

Method a) can be prepared according to a per se for the alkyl Secondary amines conventional method can be performed.

For example, the compound of formula 2 can be reacted in a known manner with a compound of formula 5, in which R has the meaning indicated above and Y has the acid residue of a. i -; 10 is a reactive ester, preferably halogen or an organic sulfonic acid residue. The reaction is preferably carried out in an organic solvent, inert under the reaction conditions, such as dimethylformamide or dimethyl sulfoxide, at a temperature between about 10 and 100 ° C, in the presence of a base, for example an organic amine, such as triethylamine or an alkali metal carbonate, such as potassium carbonate.

The reaction of a compound of the formula III with a compound of the formula U according to method b) can be carried out analogously to the methods customary for preparing corresponding compounds, as described, for example, in German Offenlegungsschrift 2509-171.

Rest X is, for example, halogen, such as a chlorine or bromine atom or an O-SO8-R 1 radical, wherein R 1 is a lower alkyl group or an optionally substituted phenyl group. The corresponding mesylate or tosylate is preferably used as the compound of formula 3.

The compounds of formula I obtained can be separated from the reaction mixture in a known manner and purified.

The free bases can be converted into acid addition salts and vice versa. Examples of the acids suitable for salt formation are, for example, hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.

The starting compound of the formula II can be prepared in a manner known per se from the compound of the formula 6, for example via the 6-cyano-ergoline derivative, such as 8 0 0 6 4 6 1 ......... 3 .........- gpjjj.gygH in example f cinder a) and bj.

The compounds of formula III can be prepared from lysergol acetate by methods known per se, as described, for example, in example IX under a) and d).

Insofar as the preparation of the starting materials has not been described, they are known or can be prepared according to a method known per se or analogous to methods known per se.

The compounds of formula 1 and the acid addition salts thereof have not been described in the literature to date. They show interesting pharmacological properties in animal experiments and can therefore be used as a medicine.

In particular, these compounds exhibit a dopamine! receptors-stimulating effect. The dopaminergic properties in rats, where a 6-hydroxydopamine injection j into the substantia nigra caused unilateral damage to the nigro-neostriatal dopamine pathway, can be determined in doses of bags at about 0.05 and 3 mg / kg / method according to U. Ungerstedt, Acta physiol, scand. Suppl. 367, 69-93 (1973).?.

After administration of the active substance (s), a clear activation could be observed that the rats turned towards the undenervated side.

The dopaminergic properties of the new compounds were tested according to the apomorphine stereotype test on rats (see Belgian patent 831 ^ 88) after administration of 30 mg / kg i.p. confirmed.

The new compounds, because of their dopaminergic properties, can be used to treat the disease; from Parkinson's. In addition, the new compounds have serotoninergic properties, which in the 5-HTP stereotype test on rats after administration of 30 mg / kg i.p. was determined. This test differs from the o.e. Apomorphine stereotype test only because the behavioral symptoms assessed here are the following: head shaking, front leg kicking and whole body trembling.

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Because of their serotoninergic properties, the new compounds of the invention can be used to increase alertness.

For the aforementioned uses, a daily dose of between about 0.5 to 100 mg of the active compound (s) is required. Suitable dosage forms for oral applications, for example, generally contain about 0.3-100 mg of active compound (s), optionally in addition to solid or liquid carriers or diluents.

The invention also relates to a method for the preparation of medicaments by bringing one or a number of the compounds according to the invention into a dosage form suitable for such use. If desired, the auxiliary substances and / or carriers customary in pharmacy can be used for their preparation or manufacture.

Furthermore, the invention also relates to the use of the new drugs or compound (s) according to j | the invention as pharmaceuticals, for example in therapeutic treatment, in particular of cerebral insufficiency. j 20 The temperatures in degrees Celsius given in the following examples have not been corrected.

Example IX is directed to the preferred compound.

Example I; 6-Ethyl-9.10-di dehydro-8 β- (2-pyridylthiomethyl) ergoline (method a)

A solution of 5g (15mM) of 9-10-didehydro-8 // (2-pyridyl-thiomethyl) ergoline in kO ml of dimethylformamide was added at room temperature 1.1 * 5 ml (17 * 9 mM) ethyl iodide 30 and 3.85g (28mM) potassium carbonate. The resulting suspension was then stirred at room temperature for 5 hours. It was then filtered, evaporated under high vacuum and shaken with methylene chloride containing 10% isopropanol against an ice-cooled potassium bicarbonate solution. The combined organic phases were dried over sodium sulfate, filtered and evaporated on a rotary evaporator 800 6 46 1 ...... 5. The crude product obtained was recrystallized twice from a mixture of methylene chloride and methanol to give the pure title compound as beige crystallizate. Melting point: decomposition from 195 ° C, 5 C <J ^ * - 25 ° (c = 0.49 in pyridine).

The starting material can be prepared as follows: i j i i a) 6-Cyano-9,1Q-didehydro-8y2- (2-pyridyl-thiomethyl) ergoline. ! 10 24g (69mM) of 9,10-didehydro-6-methyl-8/3 - {2-pyridyl-thiomethyl) ergoline were dissolved in 900 ml of absolute chloroform in a nitrogen atmosphere and a solution of 10.2g was added at room temperature (96 mM) cyanogen bromide in 100 ml of absolute chloroform. After stirring at room temperature for 16 hours, it was evaporated in a rotary evaporator and dried under high vacuum to constant weight. Thus, crude 6-cyano-9-10-didehydro-8? Was obtained by thin layer chromatography. - (2-Pyridyl-thiomethyl) ergoline, which is reduced without further purification.

B) 9,10-Didehydro-8- (2-pyridyl-thiomethyl) ergoline.

22g of I (R = CN) (61m.M) were dissolved in 250ml of acetic acid and 50ml of water, 22g of zinc powder was added and stirred at 100 ° C for 7 hours. It was then filtered and evaporated to dryness using a rotary evaporator. The resulting residue was extracted with methylene chloride containing 15% isopropanol against ice water, which had been adjusted to a pH between 8 and 9 with potassium carbonate. The combined organic phases were dried over sodium sulfate, filtered and evaporated on a rotary evaporator. There was thus obtained a crude 9,10-didehydro-8- (2-pyridyl-thiomethyl) ergoline, which was minimally contaminated by thin layer chromatography, which was alkylated without further purification.

Analogous to example I, the following compounds of formula 1 were prepared using the corresponding compounds of formula 5. ______ __ 8 00 6 46 1 t - 6 -.....

Example R Characterization II - (CHgJgCHg Decomposition from 190 ° / "- * '7 ^ ° = - 23 ° (c = 0.335 in pyridine) 5 III - (CHgJgCHg Decomposition from 180 ° | - - 18 ° (c * 0.395 in pyridine) IV - (CHg ^ CHg Melting point = 186 - 188 °; 10 fdjf - - 15 ° (c = 0.1 * 35 in pyridine) V -CH2-CH = CH2 Melting point = 177 ° J ZV7p ° = - 11 , 1 ° (c = 0.1 * 65 in pyridine) 15 | VI -CH2-C = CH Decomposition from 190 ° Γο <7? ° * - 17 ° (c = 0.3l * in pyridine)

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j VII -CH2 Melting point = 170 - 173 ° 20 Γ <0 ^ ° - - 9.8 ° (c = 0.1 * 05 in pyridine) i VIII - (CH2) 2 - / "~ \ Melting point = 175-177 °

£ ”ο (7β0 = + 6 * 5 ° (c * 0.1 * 5 in pyridine) 25 I

Example IX; 9.10-Didehydro-6-n-propyl-8 / ff- (2-pyridyl-thiomethyl) ergoline (method b)

1 * 80 mg, (1.1 * m.M) 6-nor-6-n-propyl-lysergol mesylate and 0.3 g (2.70 m.M) 2-mercaptopyridine were dissolved in 5 ml dimethyl-30 formamide. 0.1 * g of a KQ% solution of potassium hydroxide in water was dripped at 35 ° C. After stirring at 100 ° C for 22 hours, methylene chloride containing 10% isopropanol was added and shaken against a saturated sodium chloride solution. The combined organic phases were harvested over sodium 800 6 46 1 7 sulfate, filtered and evaporated. The residue was dissolved in hot methanol, boiled for a short time with activated charcoal, filtered and concentrated using a rotary evaporator, whereby the pure compound mentioned in the title crystallizes out. Melting point: decomposition from 190 ° C, CoL, = - 23 ° (c = 0.335 in pyridine).

The starting material can be prepared as follows: a) 6-Nor-6-cyano-lysergola acetate. 10 It was added dropwise to a solution of 2.2 g (7.0 µM) | lysergol acetate in 70 ml of chloroform at room temperature add 1.6 g (1 ^ 8 m.M) of cyanogen bromide in 30 ml of chloroform. After 15 hours! stirring at room temperature, it was poured onto a potassium bicarbonate solution and extracted with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Thus, the crude title compound is obtained as a brown foam.

b) 6-Nor-lysergol.

A suspension of 2.2 g (7.2 mM) of the compound obtained under a) and ¾g of zinc powder in 26 ml of acetic acid and 7 ml of water was heated for 2 hours at 100 ° C with stirring. After evaporation, the pH was adjusted to 2 using a mixture of hydrochloric acid and water and extracted with methylene chloride containing 5 # isopropanol. 0.5 g of unreacted starting material were isolated from the organic phase. The aqueous phase was adjusted to pH 8 with 2N sodium hydroxide, saturated with sodium chloride and extracted with methylene chloride containing 20% isopropanol. After drying over sodium sulfate and filtration, the crude title compound was obtained.

c) 6-Nor-6-n-propyl-lysergol.

A solution of 350 mg (1.5 mM) of the compound obtained according to b) in 15 ml of dimethylformamide - U, 2 g of solid potassium carbonate and 0.16 ml (1.6 µmM) of n-propyl iodide 800646 1 • 8 was added. .........

♦ and stir the mixture thus obtained in dark for 10 hours at room temperature. After filtration, it was evaporated and dried under high vacuum.

5 d) 6-Nor-6-n-propyl lysergol mesylate.

To a solution of U00 mg (1.1 * mM) of the compound obtained according to c) in 3 ml of acetonitrile and 1.7 ml of pyridine at 0 ° C was dripped 0.1U ml (1.80 mM) of methanesulfonic acid chloride in 1. Add 5 ml of acetonitrile. The mixture was then stirred at room temperature for 5 minutes and concentrated using a rotary evaporator. The resulting residue was dissolved with methylene chloride containing 10% isopropanol and shaken against a saturated solution of potassium bicarbonate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to yield the crude title compound. j

The compounds of Examples I and III - VIII were also prepared analogously to Example IX.

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Claims (8)

4 - 9 - 4 1. Compounds of formula 1, in which R is an alkyl group S with 2 to 8 carbon atoms, an alkenyl or alkinyl group with 3 to 6 carbon atoms, the multiple bond of which does not adjoin the nitrogen atom, a cycloalkylalkyl group with 4 t / 10 carbon atoms or a phenylalkyl group with 7 to 10! represents carbon atoms and their acid addition salts. Compounds of formula 1 according to claim 1, wherein R represents an alkyl group with 2 to 8 carbon atoms. 3. 9,10-Didehydro-6-n-propyl-82-pyridyl-thiomethyl) ergoline, and its acid addition salts. k. Process for preparing an ergoline derivative, characterized in that a compound of formula 1 according to claim 1, or an acid addition salt thereof, is prepared by a) alkylating the compound of formula 2, or b) a compound of formula 3, wherein R has a meaning as defined in claim 1 and X represents an interchangeable residue, to react with a compound of formula 1+, wherein M is a hydrogen atom or an alkali metal, and optionally the compound obtained in an acid addition salt thereof to put. 5. A method of preparing a medicament, characterized in that a compound according to claims 1-3, in the form of the free base and / or a physiologically tolerated salt thereof, optionally together with a pharmacologically indifferent substance, is a dosage form suitable for such application. A Compound according to claims 1-3 for use as a pharmaceutical. A compound according to claims 1-3, for use against Parkinson's disease. j A compound according to claims 1-3 for use; as a means of increasing vigilance. The compound of formula 2 according to claim 4. A compound of formula 3 according to claim k. 11. Method as described in the description and / or exemplary ...... ............; // 800 6 46 1