FR2470131A1 - NOVEL DERIVATIVES OF ERGOLINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS NEW ERGOLINE DERIVATIVES RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R MEANS AN ALKYL, ALCENYL, ALCYNYL, CYCLOALKYL-ALKYL OR PHENYLALKYL GROUP, AND THEIR PREPARATION. THESE COMPOUNDS CAN BE USED THERAPEUTICALLY AS ACTIVE INGREDIENTS OF MEDICINAL PRODUCTS.

Description

The subject of the present invention is new

  ergoline derivatives, their preparation and their application

  in therapeutics as active ingredients of drugs. The invention relates more particularly to the novel ergoline derivatives corresponding to formula I

0CH 2-S

1Is * A2 ES

X N-R (I

Of

  in which R represents an alkyl group containing from 2 to 8 carbon atoms, an alkenyl or alkynyl group each containing from 3 to 6 carbon atoms and whose unsaturated bond is located at a position different from the position a, p, a group cycloalkylalkyl containing from 4 to 10 carbon atoms, or a phenylalkyl group containing from 7 to 10 carbon atoms, and the salts that these compounds form with acids

minerals or organic.

  In the compounds of formula 1, R preferably means an alkyl group containing from 2 to 8 carbon atoms.

  carbon, especially an ethyl or n-propyl group.

  When R is an alkenyl or alkynyl group, this

  group preferably contains 3 or 4 carbon atoms.

  When R is a cycloalkylalkyl group, it is

  preferably a group whose cycloalkyl

  has 3 to 6 carbon atoms and the alkyl residue contains 1 or 2 carbon atoms. When R is a phenylalkyl group, it is preferably a group

benzyl or phenethyl.

  According to the process of the invention, in order to prepare the compounds of formula I a) the compound of formula II CH 2 -S As (II) N 2 HNH 2 is reacted. The reaction is carried out according to the methods

  known, used for the alkylation of secondary amines.

  For example, a compound of formula II can be reacted with a compound of formula V

R-Y (V)

  in which R has the meaning already given, and Y represents the acidic residue of a reactive ester, for example chlorine, bromine or iodine, or the remainder of an acid

organic sulfonic acid.

  Advantageously, an organic solvent is used.

  than inert, for example dimethylformamide or dimethylformamide

  thylsulfoxide at a reaction temperature of from about 20 to 100. A base is preferably used, for example an organic amine such as triethylamine, or an alkali metal carbonate such as sodium carbonate.

potassium.

  b) A compound of formula III is reacted (formula III see next page)

CH 2-X

X1 (III)

  -R UN in which R has the meaning already given, and X represents a group capable of being eliminated, with a compound of formula IV

M-S O (IV)

  in which M signifies a hydrogen atom or

alkali metal.

  The reaction can be carried out according to

  known condensation methods used for prepa-

  analogous compounds, for example as described

  in U.S. Patent No. 4,147,789.

  The radical X may mean, for example, a chlorine or bromine atom or a residue -O-SO2-R1 where R1 signifies an alkyl group or a substituted phenyl group. The mesylate or tosylate of the

formula III.

  The compounds of formula I thus obtained can

  then be isolated and purified by the usual methods

  tual. If appropriate, the free bases of formula I can be converted into their acid addition salts by following known methods from the salts,

  the bases can be released by known methods.

  Suitable acids for the formation of salts include hydrochloric acid, sulfuric acid,

  maleic acid, fumaric acid and tartaric acid.

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  The compound of formula II can be prepared for example from the compound of formula VI (VI)

H CCH2-H (I

Jf Hfrc {-

  MwN ----_ for example via a 6-cyano derivative, as

described in Examples 1a) and 1b).

  To prepare the compounds of formula III, one can proceed as follows: a) reacting lysergol acetate with cyanogen bromide, b) reducing the resulting 6-nor-6-cyano derivative with

  zinc in the presence of acid, which gives the 6-nor-

  lysergol, c) the position 6 is alkylated, and d) the hydroxyl group is converted into a group X, by

  by reaction with an alkylsulfonyl chloride.

  When the preparation of the starting materials is not described, these compounds can be obtained according to known methods, or in a similar manner to those

indicated in the description.

  The following examples illustrate this

  invention without in any way limiting its scope. The weather

  All temperatures are in degrees Celsius.

Example 1

  6-ethyl-9,10-didehydro-8P- (2-pyridylthiométhyl) ergoline

  At room temperature, a solution is

  5 g (15 mM) of 9,10-didehydro-8D- (2-pyridylthio)

  methyl) ergoline in 40 ml of dimethylformamide with

24701 3

  1.45 ml (17.9 mM) ethyl iodide and 3.85 g (28 mM) potassium carbonate. After stirring the suspension for 5 hours at room temperature, the mixture is filtered, the filtrate is evaporated under high vacuum and partitioned between methylene chloride containing 10% isopropanol and an ice-cold solution of potassium bicarbonate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product is then recrystallized twice from a mixture of methylene chloride and methanol to give the title compound as beige crystals melting from

    (with decomposition); [] D (c = 0.49, pyridine).

  To prepare the starting material, the following can be carried out as follows: a) 6: Cyalo-2-O-didehydro-8H-8 (2-ylylthiomethyl) -carbonine 24 g (69 mM) 9.10 are dissolved under a nitrogen atmosphere. dihydro-6-methyl-3- (2-pyridylthiomethyl) ergoline in 900 ml of anhydrous chloroform and this solution is treated at room temperature with a solution of 10.2 g (96 mM) of cyanogen bromide in 100 ml of

  anhydrous chloroform. After stirring the reaction mixture

  for 16 hours at room temperature, evaporated under reduced pressure to constant weight;

  6-cyano-9,10-didehydro-8- (2-pyridyl) is thus obtained.

  thiomethyl) crude ergoline which is pure in chromatography.

  --phie in minu-oh-this-co-so-called

-the next reaction - .. - -

  b) 92.1-Dideh-85- (2-yryidylthiomethyl) Eraoline

  22 g (61 mM) of 6-cyano-9,10-didehydro-

  89- (2-pyridylthiomethyl) ergoline in 250 ml of acetic acid and 50 ml of water with 22 g of zinc powder and stirred for 7 hours at 100. After filtration and evaporation to dryness, the residue is partitioned between methylene chloride containing 15% isopropanol and ice-cold water adjusted to pH 8-9 by addition of potassium carbonate 2470131. The organic phases are combined, the overall solution is dried over sodium sulphate, filtered and

  evaporates to give 9,10-didehydro-8f- (2-pyridylthio)

  methyl) ergoline crude, almost pure according to chromatography.

  phie in thin layers. This product is used as is

for the next reaction.

  By proceeding as described above, the compounds of formula I specified in

table below.

  Example R Physicochemical Characteristics 2 - (CH2) 2 CH3 Decomposition from l90 '[a] = _23 (c = 0.335 in D pyridine) 3 - (CH2) 3CH Decomposition from 180

-C2) 3CH3 20

  [ac] D = -18 (c = 0.395 in pyridine) 4 - (CH2) 4CH3 melts at 186-188 [(] D = -15 (c = 0.435 in [ID pyridine) -CH2-CH = CH it melts at 1770 [] 20 = 11.1 (c = 0.465 D in pyridine) 6 -CH2-CHCH it melts at 190

2 20

  [a] D = -17 (c = 0.34 in pyridine) it melts at 170-173

-CH 2 <. _ 20

  [2D] = - 9.8 (c = 0.405 in D - pyridine) __________________________ _________________________________________ ______________________________l____________ __________________

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Example 9

  9,10-Didehydro-6-n-propyl-8- (2-pyridylthiomethyl) ergoline To 40 g of a 40% aqueous solution of potassium hydroxide at 480 mg (1.4 mM) is added to mesylate

  6-nor-6-n-propyl-lysergol and 0.3 g (2.7 mM) of 2-

  mercapto-pyridine in 5 ml of dimethylformamide. After stirring the mixture for 22 hours at 40, it is

  treated with a mixture of methylene chloride and iso-

  10% propanol, and washed with a saturated solution of

  sodium. The organic phases are combined, the solution is dried

  The resulting mixture is filtered through sodium sulfate and evaporated. The evaporation residue is then dissolved in hot methanol, treated with activated charcoal, filtered and evaporated to give

  composed of the title melting from 190 (with decompo-

  sition); [?] OD -23 (c = 0.335 in pyridine).

  To prepare the starting material, the procedure is as follows: a) 1.6 g (14.8 mM) of cyanogen bromide in 30 ml of chloroform are added dropwise at room temperature to a solution of 2.2 g (7.4 mM) of lysergol acetate in 70 ml of chloroform. After stirring this mixture for 15 hours at room temperature, it is shaken with aqueous potassium bicarbonate solution and extracted with chloroform. The organic phases are combined, the resulting solution is dried over sodium sulfate, filtered and evaporated.

  which gives crude 6-nor-6-cyano-lysergol acetate.

  b) A suspension of 2.2 g (7.2 mM) of crude 6-nor-6-cyano-lysergol acetate is stirred for 24 hours at 100 ° C. Example R Physico-chemical characteristics 8 (C) 2 175-177 2 2 - [a] 2 = + 6.5 (c = 0.45 dan D pyridine) 2470131 l obtained above and 4 g of zinc powder in

  26 ml of acetic acid and 3 ml of water.

  After cooling, the mixture is concentrated, adjusted to pH 2 and extracted with a mixture of methylene chloride and 5% isopropanol. To isolate

  6-nor-lysergol of the aqueous phase, the solution is adjusted

  at pH 8, washed with saturated sodium chloride solution, extracted with a mixture of methylene chloride and 20% isopropanol, dried and

we filter.

  c) A solution of 350 mg (1.5 mM) of 6-Nor-

  lysergol in 15 ml of dimethylformamide with 4.2 g of solid potassium carbonate and 0.16 ml (1.64 mM) of n-propyl iodide. The mixture is stirred for 10 hours in the dark at room temperature. After

  filtration and evaporation, 6-nor-6-n-

propyl-lysergol.

  (d) 0.14 ml (1.8 mni) of methanesulphloride

  fonyl in 1.5 ml of acetonitrile to a solution of 400 mg (1.4 mM) of 6nor-6-n-propyl-lysergol in 3 ml of acetonitrile. After stirring this mixture at room temperature for 45 minutes, it is evaporated, the evaporation residue is dissolved in a mixture of methylene chloride and 10% isopropanol and washed.

  with a saturated solution of potassium bicarbonate.

  The organic phase is dried over sodium sulfate, filtered and evaporated to give the mesylate.

6-nor-6-n-propyl-lysergol.

  ___ .. Hooking-as described in Example 9, one can

  ._ ,, ._, ........................................... ........................

  ..... DTD: prepare the examples of Examples 1 and 3 to 8.

  In tests carried out on laboratory animals, the compounds of the invention are

  by interesting pharmacodynamic properties.

  In particular, they exercise stimulation of central dopaminergic receptors, as shown by

following tests.

  The action of compounds of formula I on the central dopaminergic receptors was studied in the rat according to the method described by U. Ungerstedt in Acta physiol. Scand., Suppl. 367, 69-93 (1971). One injects unilaterally 6-hydroxydopamine into the substance

  which, after a week, leads to degeneration

  of unilateral nigrostriated pathways. This unilateral lesion causes hypersensitivity of the receptors

  dopaminergic streak which, after administration, is

  tion of a stimulating substance by rotational behavior contralateral to the lesion. Administered intraperitoneally at doses of between about 0.05 and 3 mg / kg, the compounds of the invention induce, in

  this test, a clear stimulation of dopamine receptors

central banks.

  The action of the compounds of formula I on the dopaminergic receptors has also been demonstrated.

  by studying the stereotypical symptoms of

  of the type of apomorphine generated in the rat. We

  proceeds as described in Belgian Patent No. 831,488.

  Administered intraperitoneally at a dose of approximately mg / kg, the compounds of the invention induce a clear stimulation of the central dopaminergic receptors.

  translating, in this essay, by the induction of a stereo-

  type of the type of apomorphine.

  Thanks to this property, the compounds of the invention

  and their salts can be used therapeutically for the treatment of Parkinson's disease. They will be prescribed in daily doses of between 0.5 and 200 mg, administered at one time or

  several unit doses. The daily doses

  required for oral administration contain

  about 0.3 to 100 mg of active ingredient.

  The compounds of the invention and their salts are also indicated by a seratoninergic action as

  this has been demonstrated by standard tests. ad-

2470131]

  administered intraperitoneally at a dose of between 10 and 30 mg / kg, the compounds of formula I induce

  stereotyped behavior of the type of 5 HTP (5-hydroxy-

  tryptamine) which results in jerky movements of the head and forelegs and tremors. Thanks to these properties, the compounds of formula I and their pharmaceutically acceptable salts can be used therapeutically to increase the

  vigilance, for example for the treatment of insufficiency.

  senile cerebral They will be prescribed at daily doses

  between 0.5 and 200 mg which are

  will administer in one or more single doses

  tary. Daily doses appropriate for administration

  Oral administration contains approximately 0.3 to

100 mg of active ingredient.

  In these tests, 6-n-propyl-9,10-didehydro-

  83- (2-pyridylthiomethyl) ergoline is indicated by a

  particularly interesting activity.

  The compounds of formula I can be administered

  both in the form of free bases and in the form of pharmaceutically acceptable salts; the activity of these salts is of the same order as that of the corresponding free bases. The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, either alone or in the form of

  pharmaceutical compositions suitable for administration

  by the oral, rectal or parenteral route. To prepare

  appropriate pharmaceutical compositions, the active substance is worked with mineral excipients

  or organic, inert from the pharmacological point of view.

  As excipients, it may be used for example: for tablets and dragees: lactose, starch, talc, stearic acid etc .; for syrups: solutions of sucrose, invert sugar, glucose etc. .

2470131 1

  1l for injectable preparations: water, alcohols, glycerol, vegetable oils etc .; for suppositories: natural or hardened oils,

waxes etc ...

  The pharmaceutical compositions may further contain suitable preservatives, stabilizers, wetting agents, dissolving aids, sweeteners, colorants, flavors, and the like.

2470131 1

Claims (10)

  1.- novel ergoline derivatives, characterized in that they correspond to the formula I Cil2 -s (I) HN in which R represents an alkyl group containing from 2 to 8 carbon atoms, an alkenyl or alkynyl group containing each having 3 to 6 carbon atoms and having the unsaturated bond located at a position other than position a, 3, a cycloalkylalkyl group containing from 4 to 10 carbon atoms, or a phenylalkyl group containing from 7 to 10 carbon atoms , and the salts that these compounds form with acids minerals or organic.   2.- New derivatives of ergoline, characterized   in that they are selected from 6-ethyl-9,10-didehydro-   8p- (2-pyridylthiomethyl) ergoline, 6-n-butyl-9,10-dide-   hydro-8D- (2-pyridylthiomethyl) ergoline, 6-n-pentyl-9,10-   didehydro-8β- (2-pyridylthiomethyl) ergoline, 6-allyl   9,10-didehydro-8- (2-pyridylthiomethyl) ergoline, the 6-   propyne-2-yl-9,10-didehydro-8D- (2-pyridylthiomethyl)   ergoline, 6-cyclopropylmethyl-9,10-didehydro-8p- (2-   pyridylthiomethyl) ergoline and 6-phenethyl-9,10-didehydro-   8p- (2-pyridylthiomethyl) ergoline and the salts that these   compounds form with mineral or organic acids.   3.- 6-n-propyl-9,10-didehydro-8β- (2-pyridyl) 24701 31   thiomethyl) ergoline, and the salts that this compound forms with inorganic or organic acids.   4. A process for the preparation of ergoline derivatives of formula I Cl -S.   Wherein R represents an alkyl group containing from 2 to 8 carbon atoms, an alkenyl or alkynyl group each containing from 3 to 6 carbon atoms and having an unsaturated bond located at a position different from the a cycloalkylalkyl group containing from 4 to 10 carbon atoms, or a phenylalkyl group containing from 7 to 10 carbon atoms, and salts thereof, characterized in that the compound of formula II is alkylated C3402-S l. 30. geA (II) 2470! 31]   and, if appropriate, converting the compounds of formula I thus obtained into their salts by reaction with inorganic or organic acids.   5. A process for the preparation of ergoline derivatives of formula I CH 2 N-R   Where R represents an alkyl group containing from 2 to 8 carbon atoms, an alkenyl or alkynyl group each containing from 3 to 6 carbon atoms and having an unsaturated bond located at a position different from the position a, p, a cycloalkylalkyl group containing from 4 to 10 carbon atoms, or a phenylalkyl group containing from 7 to 10 carbon atoms, and salts thereof, characterized in that a compound of formula III CH2-X is reacted HI I (III) -R HN I   in which R has the meaning already given, and X represents a group which can be eliminated, 2470131]   with a compound of formula IV (IV) M.sub.SO in which M represents a hydrogen or alkali metal atom, and, if appropriate, the compounds of formula I thus obtained are converted into their salts by reaction with acids minerals or organic.   6.- The therapeutic application of derivatives   ergoline specified in any one of the claims   1 to 3, as active ingredients of drugs.   7. A medicament, characterized in that it contains, as active principle, an ergoline derivative corresponding to the formula I CH -S M t \ (I) HN ----_   in which R represents an alkyl group containing from 2 to 8 carbon atoms, an alkenyl or alkynyl group each containing from 3 to 6 carbon atoms and whose unsaturated bond is located at a position different from the position a, p, a group cycloalkylalkyl containing from 4 to 10 carbon atoms, or a phenylalkyl group containing from 7 to 10 carbon atoms, in the free state or in the form of an acceptable salt of the pharmaceutical point of view.   8.- A medicament, characterized in that it   contains, as active principle, an ergoline derivative as specified in claim 2, in the free state or   in the form of a pharmaceutically acceptable salt. ceutical.   9.- A medicament, characterized in that it   holds, as an active ingredient, 6-n-propyl-9,10-   didehydro-81- (2-pyridylthiomethyl) ergoline, in the free state or in the form of a salt acceptable from the pharmaceutical view.   10. A pharmaceutical composition, characterized in that it contains at least one active ingredient   specified in any of claims 7 to 9,   in combination with acceptable excipients and vehicles   from the pharmaceutical point of view.