JPS5813541B2 - D-6-methyl 2,8-disubstituted ergoline - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound represented by the general formula (wherein R' represents O-SO2-CH3) which is halogenated to form a compound represented by the general formula (wherein R' represents the same meaning as above), X represents a halogen), and then the compound is reacted with an inorganic cyanide in an inert solvent. The present invention relates to novel D-2-substituted-6-methyl 8-substituted ergolines represented by CH2-CN and their salts formed with pharmaceutically acceptable acids.

The "D" prefix in the nomenclature of the compounds of the above structure indicates that the stereochemistry of the ergoline derivative is identical to D-lysengate, the naturally occurring form.

Ergoline salts of the above formula can be prepared from both pharmaceutically acceptable organic and inorganic acids.

Such salts include sulfates such as sulfates, pyrosulfates and hydrogen sulfates, sulfites such as sulfites, sulfites such as bisulfite, phosphates, monohydrogen phosphates, dihydrogen phosphates. Phosphates such as , metaphosphate, and pyrophosphate, halides such as chloride, bromide, iodide and fluoride, acetate, propionate, decanoate, caprylate, acrylate , formate, isobutyrate,
C1-C10 aliphatic carboxylates such as cabrate, heptanoate and propiolate, oxalate,
malonate succinate, suberate, sebatate,
C2-C10 aliphatic dicarboxylate salts such as fumarate, maleate, butyne-1,4,-dibasic acid salt and hexyne-1,6,-dibasic acid salt, benzoate, chlorbenzoic acid salts, benzoates such as methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate; phthalates such as phthalate and terephthalate; toluene sulfonate; benzene; Aromatic sulfonates such as sulfonate, naphthalene sulfonate, p-chlorobenzene sulfonate, and xylene sulfonate, citrate, lactate, β-hydroxybutyrate, and glycolate. C2-C5α-hydroxy fatty acid salts, C4-C6α-hydroxy aliphatic dibasic acid salts such as maleate and tartrate, and C1-C3 alkyl sulfonate salts such as methanesulfonate and propanesulfonate. is included.

Lysergic acid and isolysergic acid are 8-carboxy-6
-Methyl-Δ9-ergoline.

Lysergic acid amides, many of which have valuable and unique pharmacological properties, include the naturally occurring labor promoting alkaloids ergocornine, ergocryptine, ergovine,
These include ergocristine, ergosine, ergotamine, etc., and synthetic stimulants such as mesergine, as well as the synthetic hallucinogen lysergic acid diethylamide or LSD.

6-Methyl-8-carboxyergoline, known generically as dihydroergoalkaloids, is a weak labor promoter and is also less toxic than the ergoalkaloids themselves.

Ergotamine, Δ9-ergoline, has been used to treat migraines, but recently ergocornine and 2-prom-α-ergocriptine have been used to treat prolactin (prolactin).
Nagasana and Mei have shown that ac-tin and dimethylbenzanthrene are inhibitors of tumors caused in rats.
tes) by Proce. Soc. Exp't'l.
Biol. Med. Volume 135, page 469 (19
70) and Hvuson et al.
op. J. Cancer. Page 353 (1970)
It was announced on .

D-6-Methyl-8-dianomethinoleyergoline was first produced by Semonsky and co-workers [
Coll. Czech. Chem. Commun No. 33
Vol. 577 (1968)], and Nat.
uve. Published in Volume 221, Page 666 (1969).

The compound is believed to interfere with the pituitary gland's secretion of luteotropic hormones and pituitary gonadotropins.

It has also been implied that it also interferes with the secretion of prolactin.

[Seda et al., J. ReprodFert. 24, p. 263 (1971) and Mantle and Finn (1971), p. 441)], Semonskiy and co-workers
oll. Czech. Chem. Comm. Volume 36, page 2200 (1971) describes a compound D-6- which is said to have anti-fertility and anti-lactation effects on rats.
The production of methyl-8-ergonylacetamide has been described.

The anti-tumor potency of these compounds is unknown.

The invention will be further illustrated by the following specific examples.

Example 1 (Reference example) Production of D-2-chloro-6-methyl-8-cyanmethylergoline 400 mg of N-chlorsuccinimide was added to 30 mg of dioxane.
The solution was added dropwise at a temperature of about 60 DEG C. to a stirred suspension of 535 mg of D-6-methyl-8-cyanomethylergoline dissolved in 25 ml of dioxane.

After the addition is complete, the reaction mixture is heated to 60-65°C in a nitrogen stream.
The mixture was heated for about 4.5 hours.

The reaction mixture was then cooled and diluted with water.

Solid sodium bicarbonate was added to the mixture, followed by extraction with chloroform.

The chloroform layer was separated, dried and evaporated in vacuo to remove the chloroform.

The crude residue obtained showed the presence of two spots on the thin layer chromatograph.9 The residue was therefore dissolved in chloroform and chromatographed using Florisil.

Thin layer chromatography of each of the chloroform eluted portions showed that portions 7 to 12 contained the most new compound (not the starting material).

The areas where relatively large amounts of this new component were seen by thin layer chromatography were merged and then the chloroform was evaporated.

The resulting residue was recrystallized from ether to give 270-27
165 mg of D-2-chloro-6-methyl-8-cyanmethylergoline, which melts at 3°C, was obtained.

D-6-methyl-8-cyanomethylergoline is brominated using N-promsuccinimide according to the above procedure, recrystallized from ethanol, and then decomposed at about 244-7°C while dissolving.D-2- Bromo-6-methyl-8
-cyanmethylergoline was obtained.

Analysis value C H N Br calculated value 5
9.31 5.27 12.21 23.21 Actual value 59.33 5.37 11.96 23
．． 39 using N-iodosuccinimide according to the procedure described above to react with D-6-methyl-8-cyanomethylergoline at about 211-213°C after recrystallization from ether.
D-2-iodo-6-methyl-8-cyanomethylergoline was obtained which decomposed simultaneously with dissolution.

Analytical value C H N I Calculated value 52.19 4.64 10.74 3
2.44 Experimental value 51.90 4.51 10.5
8 32.17 Example 2 (Reference Example) Production of D-6-methyl-8-prommethylergoline 100 ml of acetonitrile stirred from the beginning in a nitrogen stream
A solution of 5.2 g of triphenylphosphine dissolved in 1 was prepared.

1 ml of bromine was added dropwise to the above triphenylphosphine solution.

After the addition is completed, heating a little will turn into a transparent, colorless solution, indicating the completion of the reaction.

D-6-methyl-8-hydroxymethyl ergoline 5
Add 0.5 mg at a time to the above triphenylphosphonium bromide solution.

The reaction mixture was stirred at room temperature for about 6.5 hours while protected with a calcium chloride drying tube.

Thereafter, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the organic matter was extracted with chloroform.

When the chloroform layer is brought into contact with a saturated aqueous solution of tartaric acid, a water-soluble tartrate of the ergoline base present therein is formed.

Separate the aqueous layer and discard the chloroform layer.

The aqueous layer was then made alkaline with solid sodium bicarbonate.

Since ergoline base is insoluble in alkaline aqueous solution, it was separated and dissolved in chloroform.

The chloroform layer was then separated and dried.

After evaporating chloroform in vacuum, a residue consisting of D-6-methyl-8-prommethylergoline produced in the above reaction was obtained. Analysis result C H N Br Calculated value 60.20 6.00 8.78 25
．． 02 experimental value 60.11 6.06 8.59
25.35 Example 3 Preparation of D-6-methyl-8-cyanomethylergoline A suspension of 10 g of D-6-methyl-8-hydroxymethylergoline in 200 ml of pyridine was prepared.

6. Methanesulfonyl chloride was added to this suspension. A solution containing Oml and 200ml of pyridine was added slowly.

The reaction mixture was stirred at room temperature in a nitrogen stream for about half an hour and then poured into 2.5 liters of saturated aqueous sodium bicarbonate solution.

The alkaline aqueous layer was diluted to 6 liters with water, and the diluted aqueous layer was left at room temperature.

D-6-methyl-8-mesyloxymethylergoline produced in the above reaction became crystals.

The solution was cooled to 0° C. so that more of the desired material precipitated.

The solution was filtered and the filter cake was recrystallized from ethanol.

The filtrate was extracted with ethyl acetate, the ethyl acetate layer was separated, and the ethyl acetate was evaporated in vacuo to further extract D-6-methyl-
8-Mesyloxymethylergoline was obtained.

While recrystallizing and decomposing D-6-methyl-8-mesyloxymethylergoline obtained as above, about 192
A material was obtained that melts at ~4°C.

Analysis result C H N S Calculated value 61.05 6.63 8.38 9.
59 Experimental value 60.85 6.46 8.45
9.30 D-6-methyl-8 prepared as above
12.5 g of mesyloxymethylergoline were heated with 12.9 g of sodium cyanide in the presence of 350 ml of DMSO at a temperature of 100-105 DEG C. in a stream of nitrogen for 45 minutes.

The reaction mixture was poured into 2 l of saturated sodium chloride solution and the resulting mixture was filtered.

The solid thus obtained was made into a slurry in warm water and refiltered to produce about 8.4 g of D-6-methyl-8.
-cyanmethylergoline was obtained.

Example 4 Alternate production of D-2-bromo-6-methyl-8-cyanomethylergoline 955 mg of D-6-methyl-8-prommethylergoline produced by the method of Example 2 (Reference Example) was dissolved in 50 ml of dioxane. The solution was heated to 60-65°C in a nitrogen stream.

N-promsuccinimide 600 in 70 ml dioxane
mg solution was added dropwise.

The reaction mixture was heated to 60-65° C. for an additional half hour after all of the N-promsuccinimide had been added.

The reaction mixture was then cooled and an aqueous solution of tartaric acid was added to form the water-soluble tartrate salt of the ergoline base present.

The resulting mixture was extracted using chloroform and the chloroform layer was discarded.

After filtering the water layer, solid sodium bicarbonate was added to make it alkaline, in which ergoline base does not dissolve.

The aqueous layer was extracted using chloroform, the chloroform layer was separated, dried and evaporated in vacuo to remove the chloroform.

The chromatogram on Florisil was chromatographed using chloroform as the eluent, and an extract was obtained that showed spots on the thin layer chromatograph that were mainly composed of substances other than the starting material.

These extracts were combined and the solvent was removed in vacuo, and the resulting residue was recrystallized from ether to obtain D produced by the above reaction.
-2-bromo-6-methyl-8-promomethylergoline was produced.

The compound melted at 215° C. with decomposition.

Analysis result C H N Br Calculated value 48.27 4.56 7.04 40
．． 14 Experimental value 48.01 4.66 7.16
40.38 90 mg of D-2-bromo-6-methyl-8-prommethylergoline prepared as above were dissolved in 10 ml of dimethyl sulfoxide (DMSO).

100 mg of sodium dianide was added and the resulting mixture was heated at 105° C. in a nitrogen stream for about 45 minutes.

The reaction mixture was cooled, diluted with water and filtered.

After dissolving the filter cake in an ethanol-chloroform mixed solvent, the solvent was removed by evaporation in vacuo.

The residue was recrystallized from ether to obtain D-2-bromo-6-methyl-8-cyanomethylergoline produced in the above reaction.

The compound melted at about 240-243°C with decomposition.

According to the above method, D-6-methyl-8-mesyloxymethylergoline (Example 3) can be halogenated at its 21 position by the method of Example 1 (Reference example) to form D-2-chloro-6- Methyl-8-mesyloxymethylergoline, D-2-bromo-6-methyl-8-mesyloxymethylergoline or D-'2-iodo-6-methyl-
8-mesyloxymethylergoline is produced, each of which can then be converted to the 8-cyanmethyl derivative by reaction with sodium cyanide as described above.

A pharmaceutically acceptable acid salt of a compound of the invention (formula (I) above) can be prepared by dissolving an amount of the particular ergoline base in ether and adding a pharmaceutically acceptable acid salt similarly dissolved in ether. It can be prepared by adding an equivalent amount of acid.

The salts thus produced are usually insoluble in ether and can be isolated by filtration and purified by recrystallization.

Alternatively, the ergoline base can be dissolved in ethanol and an equivalent of the pharmaceutically acceptable acid, also dissolved in ethanol, can be added.

In this example, the salt dissolves in ethanol, so the solvent is removed by evaporation in vacuo to recover the salt.

When the resulting residue is not crystalline, it can be easily recrystallized from ethanol or a suitable solvent.

Preparation of the salt D-2- in about 40 ml of tetrahydrofuran (THF)
Bromo-6-methyl-8-cyanmethylergoline 56
A solution containing 0 mg was prepared.

Approximately 10 ml of a solution prepared by dissolving 1 g of maleic acid in 50 ml of THF was added to the solution of ergoline base with stirring.

Approximately 200 ml of ether was added and the resulting precipitate was filtered off.

D-2-bromo-6-methyl- thus produced
8-cyanomethylergoline acid malate is approximately 207
It melted with decomposition at ~209°C.

D-2-chloro-6-methyl-8- according to the method described above
Cyanmethylgoline acid malate was produced.

It melts with decomposition at about 204-206°C.

320 mg of D-2-chloro-6-methyl-8-cyanmethylergoline in 15 ml of THF according to the method described above.
was dissolved.

To this solution was added dropwise a solution of methanesulfonic acid in THF until no further precipitate formed when added dropwise.

The THF solution was diluted with ether, the resulting mixture was filtered, recrystallized from an ethanol-ether mixed solvent, and D-2-chloro-6-methyl-8-cyano melted while decomposing at about 295°C. Methanesulfonate of methylergoline was obtained.

Analysis result C H N C1 S Calculated value 54.61 5.60 10.61 8
．． 95 8.10 Experimental value 54.43 5.79
10.86 9.22 8.18 D-2-Chloro-6-methyl-
220 mg of 8-cyanomethylergoline was dissolved.

An excess of a saturated solution of d-tartaric acid in THF was added.

The obtained seratin-like precipitate gradually turned into crystals.

The mixture was diluted with ether and filtered to obtain D-2-chloro-6-methyl-8-cyanomethylergoline tartrate, which was recrystallized from an ethanol-ether mixed solvent at about 247-249°C. Melted.

Analysis result C H N C1 Calculated value 60.88 5.65 11.21 9
．． 46 Experimental value 60.66 5.41 11.41
9.49 The compounds of the invention are useful as gonadotropin inhibitors.

As such it inhibits lactation and is specifically a prolactin inhibitor.

The compounds are effective in treating postpartum milk secretion and inappropriate milk secretion such as galactorrhea.

Moreover, the compound is effective against prolactin-derived adenocarcinomas and prolactin-secreting pituitary tumors in the following diseases:
bright) syndrome, Chia-Frommel (Chia bright) syndrome,
ri-Frommel) syndrome, female pattern breasts occurring as a result of estrous steroid administration for the female pattern breast itself and excessive prostatic obesity, fibrocystic disease of the breast (benighnodules) b breast cancer preventive treatment and psychotherapy. Tropical drugs (psych)
(etropic drugs) such as thorazine (th
It can be used in the same way as for breast growth resulting from the administration of orazine).

2,8-disubstituted-6-methylergoline corresponding to formula (I) or a preparation thereof when carrying out our novel preparation process using the compounds of the invention to inhibit prolactin. The biologically acceptable salt is suspended in corn oil and injected parenterally and fed to female suckling animals in amounts ranging from 0.01 to 10 mg.

Oral administration is preferred. If parenteral administration is utilized, the subcutaneous route is preferred although other parenteral routes of injection such as intraperitoneal, intramuscular, or intravenous routes are equally effective.

For these other routes of parenteral administration, vehicles other than corn oil must be used, as is well known to those skilled in the art.

Pharmaceutically acceptable acid salts of D-6-methyl-8-cyanomethylergoline are customarily used, particularly for intravenous or intramuscular administration.

For oral administration, the compound of formula (I) or a salt thereof may also be mixed with standard pharmaceutical excipients and placed in a nested gelatin capsule or formed into a tablet.

The inhibition of prolactin secretion by the compounds of the present invention is demonstrated by the following experiments, which were administered to several groups of lactating postpartum female rats from 4 to 8 days after parturition (the day of parturition is defined as 0).
.

The control group received only 0.2 ml of corn oil daily, and the other groups received different drug levels of D-2-bromo-6-methyl-8-cyanomethylergoline or its corresponding chlor compound.

At the beginning of the experiment, rat litter groups were reduced to six pups each and the total weight of each litter group was recorded.

Both litter groups and suckling female rats were weighed on days 4, 6, and 8.

On day 8, suckling females were removed from the litter with young and immediately killed.

Radio-immunoassay (radio-immunoassay) was performed to determine the prolactin content of serum obtained by collecting blood.
ssay).

The results of this experiment are recorded in the following table.

The first column is the treatment method and the second column is the number of rats in the treatment group. Third
Column 4 shows the average weight change of litters with reduced numbers of young, column 4 shows the average weight change of suckling female rats, and column 5 shows the average level of prolactin in serum on day 8.

As can be seen in Table 1, two compounds within the range of formula (I) above significantly reduced prolactin levels and therefore prolactin secretion in suckling female rats.

Experiments designed to demonstrate the inhibitory effect of the compounds of the present invention on the growth of adenocarcinoma in female mammals were conducted using rats as an example of female mammals susceptible to adenocarcinoma, as described below. did.

Rats were given 20 mg of 7,12-dimethylbenzanthracene (DMBA) orally once to induce mammary tumor development.

The mammary glands were palpated for tumors at weekly intervals.

Rats with at least one measurable tumor approximately 0.5 cm in diameter were selected for experiments.

Tumor-bearing test animals were divided into 5 groups and given different doses of D-
Treatment was with 2-halo-6-methyl-8-cyanmethylergoline suspended in corn oil.

The control group was treated with corn oil only.

The results are shown in Table 2. In Table 2, the first column is the name of the compound tested, the second column is the amount used, the third column is the route of administration, the fourth column is the initial diameter of the tumor, and the fifth column is 12 days after treatment. and the sixth column represents the percentage change.

As shown in the above experiments, the compounds of the present invention cause significant regression of mammary tumors when administered subcutaneously or orally.

The compounds of the present invention are much less toxic than those of the prior art that do not have substituents at the 2-position; for example, acute toxicity studies using mice have shown that D-2-halo-6-methyl-8 -cyanmethyl (or -8-carboxamide)
Ergoline showed an LD50 of approximately 1000 mg/kg, while D-6-methyl-8-cyanomethylergoline had an LD50 of approximately 100 mg/kg for mice.
It was g.

However, as a prolactin inhibitor, the 2-
Compounds with substituents in the 2-position have similar potency to the prior art D-6-methyl-8-cyanomethyl (or 8-carboxamidomethyl)ergoline without a substituent in the 2-position.

Claims (1)

[Scope of Claims] 1. A compound represented by the general formula (wherein R' represents O-SO2-CH3) is halogenated to form a compound represented by the general formula (wherein R' represents the same meaning as above and X is It is characterized in that it produces a compound represented by (representing a halogen) and then reacts said compound with an inorganic cyanide in an inert solvent. Formed from a novel D-2-substituted-6-methyl-8-substituted ergoline represented by the general formula (wherein X represents halogen and R represents -CH2-CN) and a pharmaceutically acceptable acid. How these salts are made.