CH617196A5 - - Google Patents

Description

The invention now relates to a process for the preparation of compounds with prolactin secretion-inhibiting action of the formula

25th

0 II

CH -S-C-Alk

N-CH.

(iia)

wherein

R1 is hydrogen, chlorine or bromine,

Alk stands for Ci-Cî-alkyl and the dotted line means the possible presence of a double bond,

and the non-toxic pharmaceutically acceptable acid addition salts of the above compounds, and the method is characterized in that an 8β-compound of the formula

35

40

n-ch.

(iii),

wherein R1 and the dotted line have the above meanings and the substituent R2 is a methanesulfonyl or a p-toluenesulfonyl radical, with a nucleophilic reagent of the formula

55

O

II

HS-C-Alk

(IVA)

60

or a salt thereof and, if appropriate, the compounds obtained are converted into the corresponding non-toxic pharma-65 acidically acceptable acid addition salts.

The invention also relates to a further process for the preparation of compounds having a prolactin secretion-inhibiting action of the formula

617196

N-CH

HN

wherein

R represents phenyl or alk,

R1 is hydrogen, chlorine or bromine,

Alk stands for Cj-Gs-alkyl and the dotted line means the possible presence of a double bond,

and the non-toxic, pharmaceutically acceptable acid addition salts of the above compounds, which is characterized in that an 8β-compound of the formula

CHOIR

.n-ch wherein R1 and the dotted line have the above meaning and the substituent R2 is a methanesulfonyl or a p-toluenesulfonyl radical, with a nucleophilic reagent of the formula

HSR (IVB)

or a salt thereof and optionally convert the compounds obtained into the corresponding non-toxic, pharmaceutically acceptable acid addition salts.

Alk in the above formulas relates to Ci-C3-alkyl radicals, namely methyl, ethyl, n-propyl and isopropyl. Individual examples of compounds of the formulas (IIA) and (IIB) which can be prepared according to the invention are as follows:

D-2-chloro-6-methyl-8β-propionylthiomethylergoline,

D-2-chloro-6-methyl-8β-butyrylthiomethyl-9,10-

didehydroergoline,

D-2-chloro-6-methyl-8β-phenylmercaptomethyl-9,10-didehydroergoline,

D-2-bromo-6-methyl-8β-phenylmercaptomethyl-9,10-didehydroergoline,

D-2-chloro-6-methyl-8β-ethyl mercaptomethyl-9,10-didehydroergoline,

D-6-methyl-8β-n-propylmercaptomethylergoline, D-6-methyl-8ß-isopropylmercaptomethylergoline.

The mesyloxy and p-tosyloxy derivatives of the formula III used as starting compounds are either known compounds or can be prepared from the corresponding hydroxy derivatives by known processes.

When carrying out reactions with thiophenol or a C 1 -C 8 -alkylthiol, the sodium salt of the mercaptan group is normally formed when sodium methylate or sodium hydride is used. The nucleophilic rearrangement reactions according to the invention are preferably carried out in an inert solvent, such as dimethylformamide (DMF)

or dimethyl sulfoxide (DMSO). The reactions are normally carried out at room temperature or, if desired, also by heating to a temperature from room temperature to 100 ° C. The reaction products are normally isolated by conventional techniques and purified by chromatography, preferably using “Florisil”.

The compounds of the formulas (IIA) and (IIB) obtained according to the invention are white crystalline solids and form pharmaceutically acceptable salts with non-toxic acids. Non-toxic acids for the formation of these salts are, for example, inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, and also non-toxic organic acids including aliphatic mono- or dicarboxylic acids, phenyl-substituted alkane-carboxylic acids , Hydroxyalkane carboxylic acids and hydroxy alkane dicarboxylic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Pharmaceutically acceptable salts of the above type are, for example, the sulfates, pyro-sulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, Acrylates, formates, isobutyrates, cap rates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1, 4-dioates, hexin-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates , Hydroxybenzoates, methoxy-benzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, ß-hydroxybutyrates, glycollates, methanesulfonate, malatesulfonate, taratesulfonate, malatesulfonate, taratesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, taranesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, taratesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malatesulfonate, malate sulfonate -2-sulfonates.

The compounds obtained according to the invention are suitable as prolactin inhibitors. The inhibition of prolactin secretion by the compounds mentioned is demonstrated by the following experiment: Adult male Spraque-Dawley rats weighing approximately 200 g are used for the experiment. All rats are housed in an air-conditioned room under controlled lighting (the light is on from 6:00 a.m. to 8:00 p.m.) and they are fed laboratory food and water ad libitum.

After each experiment, the rats are sacrificed by cutting off the head and aliquots of 150 ml serum are examined for their prolactin content. 18 hours before administration of the ergoline derivative, 2.0 mg reserpine in aqueous suspension are injected intraperitoneally into each rat. The purpose of this reserpine treatment is to keep the prolactin levels uniformly high. The ergoline derivatives are dissolved in 10% ethanol in a concentration of 10 [i / ml, and the solutions obtained are injected intraperitoneally in a standard dose of 50 u / kg. Each compound is administered to a group of 10 rats, and a control group of 10 healthy rats is given an appropriate amount of 10 percent ethanol. One hour after treatment, all rats are sacrificed by cutting their heads, after which they do this

4th

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

5

Serum collects and examined for its prolactin content in the manner described above. The results obtained are statistically evaluated according to the so-called student “t” test (a mathematical comparison between target values), the significance level “p” being calculated.

The difference between the prolactin level of the treated rats and the prolactin level of the control rats divided by the prolactin level of the control rats gives the percentage inhibition of prolactin secretion, the 10th

617196

is due to the compounds produced according to the invention. The following table shows the percent prolactin inhibition values for a number of compounds from general formulas (IIA) and (IIB) above. Column 1 of this table shows the name of the compound used, column 2 of the table shows the dose of the compound used in the prolactin inhibition test, column 3 shows the percentage prolactin inhibition, and column 4 shows the level of significance, namely the «p» value.

table

Compound name Dose% prolactin inhibition "p" value

D-6-methyl-8β-phenylmercaptomethyl-9,10-didehydroergoline 10IG 50 <0.05

D-6-methyl-8β-methylmercaptomethyl-9,10-didehydroergoline 10 jxg 62 <0.01

D-6-methyl-8β-acetylthiomethylergoline 10 (ig 40 <0.01

D-6-methyl-8β-methylmercaptomethylergoline 10 [xg 49 <0.001

D-2-chloro-6-methyl-8β-methylmercaptomethylergoline 10 µg 46 <0.001

D-6-methyl-8β-acetylthiomethyl-9,10-didehydroergoline 10 (ig 44 <0.01

Since the compounds which can be prepared according to the invention are prolactin inhibitors, they may also be suitable for suppressing the growth of breast adenocarcinomas in female mammals. For example, B. with such a compound suppress the growth of adenocarcinomas, which are induced by administration of dimethylbenzanthracene, in female rats at a dose level of 1.2 mg / kg. The compound is administered to the female rat in a form suspended in corn oil, but it can also be administered in the form of a pharmaceutically acceptable acid addition salt in aqueous solution.

The invention is illustrated by the following examples.

example 1

A suspension is prepared from 10 g of D-6-methyl-8β-hydroxymethylergoline in 200 ml of pyridine. This suspension is slowly mixed with a solution of 6 ml of methane sulfonyl chloride and 200 ml of pyridine. The reaction mixture is stirred at room temperature under nitrogen over a period of 0.5 hours and then poured into 2.5 liters of saturated aqueous sodium bicarbonate. The alkaline aqueous layer is diluted with 6 liters of water and the diluted layer is left to stand at room temperature.

The D-6-methyl-8β-mesyloxymethylergoline formed in the above reaction slowly crystallizes out. To further precipitate the compound, the solution is cooled to etsa 0 ° C. The solution is then filtered, whereupon the filter cake is recrystallized from ethanol. Further D-6-methyl-8β-mesyloxymethylergoline is obtained by extracting the filtrate with ethyl acetate, separating the ethyl acetate layer and evaporating the ethyl acetate in vacuo. By recrystallizing the above-prepared D-6-methyl-55 8β-mesyloxymethylergoline from ethanol, a material melting at about 192-194 ° C with decomposition is obtained.

Analysis:

60

C.

H

N

S

calculated:

61.05

6.63

8.38

9.59

found:

60.85

6.46

8.45

9.30

65

A solution is prepared from 2.5 ml of thiophenol in 25 ml of DMSO. The solution is mixed with 1.1 g of sodium

methylate. A solution of 700 mg of D-6-methyl-8β-mesyloxymethylergoline in 50 ml of DMSO is then added dropwise to the sodium thiophenolate solution thus obtained. When the addition is complete, the reaction mixture is stirred at room temperature under a nitrogen atmosphere for about 2 hours and then poured into a saturated aqueous tartaric acid solution. The acidic layer is extracted with chloroform. The chloroform extract is separated off and discarded. The acidic layer is then made basic with excess 14N ammonium hydroxide, and the alkaline layer obtained is extracted with chloroform. The chloroform extract is separated off and dried. The residue obtained after evaporating the chloroform is dissolved in ethyl acetate. The ethyl acetate solution is washed thoroughly with water, after which it is washed with saturated aqueous sodium chloride solution. The ethyl acetate layer is dried. Evaporation of the ethyl acetate in vacuo gives a residue of D-6-methyl-8β-phenylmercaptomethylergoline, which melts after recrystallization from ethanol at 194-195 ° C with decomposition. The compound thus obtained is then dissolved in chloroform and chromatographed over "Florisil" (25 g). The chromatogram is developed with a 19: 1 mixed solvent of chloroform and methanol. The fractions which, according to the thin-layer chromatographic analysis, contain D-6-methyl-8β-phenyl-mercaptomethylergoline are pooled. Evaporation of the solvent from the combined fractions and recrystallization of the resulting residue from a solvent mixture of ether and hexane gives D-6-methyl-8β-phenylmercaptomethylergoline, which melts at 195-196 ° C. with decomposition.

Analysis:

C.

H

N

S

calculated:

75.82

6.95

8.04

9.20

found:

75.85

6.69

7.97

9.19

According to the procedure described above, D-6-methyl-8β-mesyloxymethyl-9,10-didehydroergoline is reacted with thiophenol, whereby D-6-methyl-8ß-phenylmercaptomethyl-9,10-didehydroergoline is obtained. This compound melts after recrystallization from methanol at about 200-203 ° C with decomposition.

30th

617196

6

Analysis:

C.

H

N

S

calculated:

76.26

6.40

8.08

9.25

found:

76.02

6.42

7.99

9.02

To prepare the corresponding 9,10-didehydromaleate salt, the above compound is dissolved in tetrahydrofuran and the solution is mixed with an equivalent amount of maleic acid in tetrahydrofuran. The maleate salt obtained melts after recrystallization from methanol at 188-189 ° C.

Analysis:

C.

H

N

S

calculated:

67.51

5.67

6.06

6.93

found:

67.29

5.89

5.79

6.71

Example 2

10 milliliters of dimethylformamide (DMF) are cooled to about 0 ° C., whereupon 1 ml of methanethiol and then 1.0 g of sodium hydride in the form of a 50 percent suspension in mineral oil are added in portions. The solution obtained is stirred for about 1 hour, after which it is allowed to come to room temperature. A solution of 1 g of D-6-methyl-8β-mesyloxymethylergoline in 50 ml of DMF is then added dropwise to the sodium salt of methanethiol by the process described in Example 1. The product obtained is isolated and purified by the process described in Example 1, giving D-6-methyl-8β-methylmercaptomethylergoline,

that melts at about 153-155 ° C. By recrystallizing this compound (omitting the chromatographic purification step of Example 1) from a solvent mixture of ether and hexane, D-6-methyl-8β-methylmercaptomethylergoline with an mp of 153-154 ° C.

Analysis:

C.

H

N

S

calculated:

71.28

7.74

9.78

11.19

found:

71.08

7.59

9.83

10.99

D-6-methyl-8β-methylmercaptomethyl-9,10-didehydroergoline is prepared by the process described above by reacting the corresponding 8ß-mesyloxymethyl derivative with methyl mercaptan. The resulting compound melts after recrystallization from a solvent mixture of ether and hexane at 181-183 ° C with decomposition.

Analysis:

C.

H

N

S

71.79

7.09

9.85

11.27

72.01

6.84

9.62

11.27

To prepare the corresponding 9,10-didehydro-maleate salt, the above compound is dissolved in ether and this solution is mixed with an equivalent amount of maleic anhydride, likewise dissolved in ether. The maleate salt obtained in this way melts at 159-160 ° C. with decomposition.

Analysis:

C.

H

N

S

calculated:

62.98

6.07

6.99

8.01

found:

62.99

6.13

6.78

7.86

Example 3

Following the procedure described in Example 1, thioacetic acid (in the form of the sodium salt) is reacted with D-6-methyl-6β-mesyloxymethylergoline in DMF solution, whereby D-6-methyl-8ß-acetylmercaptomethyl-ergoline is obtained. The compound obtained is isolated and purified as described in Example 1. Chromatography of the crude product on "Florisil" using chloroform containing 2% ethanol as the eluent gives purified D-6-methyl-8β-acetyl-mercaptomethylergoline, which melts at 153-155 ° C with decomposition.

Analysis:

C.

H

N

S

calculated:

68.75

7.05

8.91

10.20

found:

68.70

7.22

8.62

10.47

D-6-methyl-8β-acetylmercaptomethyl-9,10-didehydroergoline is prepared from the corresponding 8β-mesyloxymethyl compound by the method described above. The purified compound prepared in this way melts after recrystallization from a solvent mixture of ether and hexane at 165-167 ° C. with decomposition.

Analysis:

calculated: 69.20 6.45 8.97 10.26 found: 69.48 6.71 9.00 10.56

To prepare the corresponding 9,10-didehydro-maleate salt, the above base is dissolved in ether and the solution is mixed with an equivalent amount of maleic acid in ether. The maleate salt obtained melts at 178-179 ° C with decomposition.

Analysis:

C.

H

N

S

calculated:

61.67

5.65

6.54

7.48

found:

61.95

5.50

6.84

7.63

D-2-chloro-6-methyl-8β-acetylmercaptomethylergoline is also produced by the process described above. The fractions obtained in the chromatography, which contain D-2-chloro-6-methyl-8β-acetylmercaptomethylergoline on the basis of thin-layer chromatography analysis, are combined and the corresponding residue is recrystallized using a solvent mixture of ether and hexane, giving a purified Receives material that melts at 140-141 ° C.

Analysis:

C.

H

N

S

Cl calculated:

61.97

6.07

8.03

9.19

10.16

found:

61.75

5.78

7.75

9.41

10.32

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

617196

Example 4

Methyl mercaptan is used for the reaction with D-2-chloro-6-methyl-8β-mesyloxymethylergoline.

This gives D-2-chloro-6-methyl-8β-methylmercapto-methylergoline. Chromatography of the residue obtained by combining chromatographic fractions shows that it is the desired material. This is recrystallized from a mixture of ether and hexane, whereby purified D-2-chloro-6-

methyl-8β-methylmercaptomethylergoline, which melts at 194-195 ° C.

Analysis:

c

H

N

S

Cl

63.63

6.60

8.73

9.99

11.05

63.42

6.55

8.47

10.12

11.35

B

Claims (6)

617196 2nd PATENT CLAIMS 1. Process for the preparation of compounds with prolactin secretion-inhibiting action of the formula 0 II CH -S-C-Alk N-CH. (IIA) wherein R1 is hydrogen, chlorine or bromine, Alk stands for Ci-C3-alkyl and the dotted line means the possible presence of a double bond, and the non-toxic, pharmaceutically acceptable acid addition salts of the above compounds, characterized in that an 8β-compound of the formula ch2or ' N-CH. wherein R1 and the dotted line have the above meanings and the substituent R2 represents a methanesulfonyl or a p-toluenesulfonyl radical, with a nucleophilic reagent of the formula O II HS-C-Alk 50 55 (IVA) or a salt thereof and optionally convert the compounds obtained into the corresponding non-toxic, pharmaceutically acceptable acid addition salts. 2. The method according to claim 1 for the preparation of D-6-methyl-8β-acetylmercaptomethylergoline, characterized in that D-6-methyl-8ß-mesyloxymethylergoline is reacted with sodium thioacetate. 3. Process for the preparation of compounds with prolactin secretion-inhibiting action of the formula 65 H CH -S-R N-CH. 10th (IIB) IS 20th wherein R represents phenyl or alk, R1 is hydrogen, chlorine or bromine, Alk stands for Ci-C3-alkyl and the dotted line means the possible presence of a double bond, and the non-toxic, pharmaceutically acceptable acid addition salts of the above compounds, characterized in that an 8β-compound of the formula ch2OR ' 35 (III), 40 n-ch. (III), wherein R1 and the dotted line have the above meaning and the substituent R2 is a methanesulfonyl or a 45 p-toluenesulfonyl radical, with a nucleophilic reagent of the formula HSR (IVB) or a salt thereof and optionally convert the compounds obtained into the corresponding non-toxic, pharmaceutically acceptable acid addition salts. 4. The method according to claim 3 for the preparation of D-6-methyl-8β-phenylmercaptomethyl-9,10-didehydro-ergoline, characterized in that D-6-methyl-8ß-mesyloxymethyl-9,10-didehydroergoline is reacted with thiophenol . 5. The method according to claim 3 for the preparation of D-6-methyl-8ß-methylmercaptomethyl-9,10-didehydro-ergoline, characterized in that D-6-methyl-8ß-mesyloxymethyl-9,10-didehydroergoline is reacted with methyl mercaptan . 6. The method according to claim 3 for the preparation of D-6-methyl-8ß-methylmercaptomethylergoline, characterized in that D-6-methyl-8ß-mesyloxymethyl-ergoline is reacted with methanethiol. 3rd 617196 Compounds based on the ergoline ring system of the formula 10th (I) show a surprising variety of pharmaceutical effects. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-A9-ergoline (9,10-didehydroergoline). The amides of lysergic acid, a number of which have interesting and unique pharmacological properties, include, for example, the naturally occurring labor-stimulating or oxytocin alkaloids, such as ergocorin, ergocryptin, ergonovin, ergocristin, ergosine, ergotamine and the like, and the synthetic oxytocins, such as methergin , and also the synthetic hallucinogens, such as Lysergsäurediäthylamid or LSD. The amides of 6-methyl-8-carboxyergoline, which are generically known as dihydroergo-talcaloids, are oxytocide agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Ergotamine, namely an A9-ergoline, is used to treat migraines. Recently, it was also shown that ergocornin and 2-bromo-alpha-ergocryptin are inhibitors for prolactin and for tumors induced by dimethylbenzanthracene (DMBA) in rats, which is evident from Proc. Soc. Exp'tl. Biol. Med. 135,469 (1970) and Europ. J. Cancer 353 (1970). Reference is also made to US Pat. Nos. 3,752,881 and 3,752,814. D-6-methyl-8-cyanomethyiergolin was first obtained from Coli, Czech. Chem. Commun. 33, 577 (1968), and the use of this compound as a contraceptive in rats is described in Nature 221, 666 (1969). Reference is also made to US Pat. No. 3,732,231. It is stated that this compound interferes with the separation of pituitary luteotropic hormone and pituitary gonadotropins. This compound is also said to inhibit prolactin deposition. For this purpose, Reprod. Fert. 24, 263 and 441 (1971). In Coli, Czech, Chem. Comm. 36.220 (1971) describes the preparation of D-6-methyl-8-ergolinylacetamide, and this compound is said to have an anti-fertility and anti-lactation effect in rats. The effect of these compounds in neoplastic diseases is unknown. Ergolines with a thiomethyl substituent or a derivative thereof have not previously been produced.