JPS582946B2 - 8- Thiomethylergolineruinoseiho - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 8-thiomethylergolines, which are the target substances of the method of the present invention, have a prolactin inhibitory effect.

Compounds with ergoline cores have a surprising variety of pharmacological activities.

For example, lysergic acid and isolysergic acid are 8-carboxy-6-methyl-△9-ergoline (9,10-didehydroergoline), but lysergic acid amides, which have useful and unique pharmacological activities, are natural products. These include labor-promoting alkaloids (ergocornine, ergocriptine, ergonovine, ergocristine, ergosine, ergotamine, etc.), synthetic labor-promoting agents (methelzine), synthetic hallucinogens (lysergic acid diethylamide, LSD), and the like.

6-Methyl-8-carboxydiergolinamides, generally known as dihydroergot alkaloids, are labor promoting agents with milder action and lower toxicity than ergot alkaloids themselves.

Ergotamine, a type of Δ9-ergoline, has been used to treat migraines, but recently ergocornine and 2
- Bromo-alpha-ergocriptine was shown to have prolactin inhibitory effects and inhibitory effects on rat tumors generated by dimethylbenzoanthracene (DMBA) (Proc, Soc. Exp'tl. Bi
ol. Med. , 135, 469 (1970);
op. J. Cancer, 353 (1970); S
．． P. 3,752.888; 3,752.814).

D-6-methyl-8-cyanmethylergoline was prepared by Semonsky et al. (Coll.
．． Czech. Chem. Commun. 33,577
(1968)), and its pregnancy-inhibiting effect in rats was also published by the same group (Nature, 221, 666 (1969); U.S.
．． P. 3,732.231).

This compound was initially identified as pituitary luteinizing hormone (LTH).
It was thought to inhibit the secretion of pituitary and pituitary gonadotropins, but it was also suggested that it inhibits the secretion of prolactin (Seda, et al., Reprod.
rt. , 24, 263 (1971): Mantle, e.
tal, id. , 441).

Semonsky, et al.
ll. Czech, Chem. Comm. ,36,22
0 (1971)) also published a method for producing D-6-methyl-8-ergolinyl acetamide and reported that it has pregnancy-inhibiting effects and lactation-inhibiting effects on rats.

The effects of the above compounds on neoplasms are unknown.

Ergoline and its derivatives having a thiomethyl group as a substituent have never been synthesized.

The method of the present invention provides 8-thiomethylergolines represented by the following formula.

[In the formula, R is hydrogen, cyano, CO-Alk, phenyl or Alk, and Alk is argyl R' having 1 to 3 carbon atoms.
represent hydrogen or halogen, respectively.

R'' and R'' each represent hydrogen or together form a double bond between the carbons to which they are bonded.

However, this excludes the case where R is cyano and R' is hydrogen.

Alk is defined as alkyl having 1 to 3 carbon atoms, and includes methyl, ethyl, probyl, and isopropyl, respectively.

In the above formula, when R'' and R'' are each hydrogen, the compound of the present invention is D-6-methyl-8-thiomethyl (
or mercaptomethyl) ergoline.

Furthermore, when R'' and R'' come together to form a double bond, the compound of the present invention is D-6-methyl-8-thiomethyl (or mercaptomethyl)-9,10-didehydroergoline. .

The compound group represented by the above formula includes the following compounds.

D-2-chloro-6-methyl-8-propionylthiomethylergoline D-2-chloro-6-methyl-8-butyrylthiomethyl-9,10-ditehydroergoline D-2-chloro-6
-Methyl-8-phenylmercabutomethyl-9,10-
ditehydroergoline D-2-bromo-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline D-2-chloro-6-methyl-8-ethylmercaptomethyl-9,10- didehydroergoline D-6-methyl-8-probylmethicaptomethylergoline D-6-methyl-8-isopropylmercaptomethylergoline and the like.

The above-mentioned 8-thiomethylergolines, which are the target substances of the present invention, have the general formula: [wherein R', R'' and R''' have the same meanings as above.

An active derivative of the hydroxyl group of 8-hydroxydimethylergoline represented by R-S- [wherein R has the same meaning as above.

] by reacting with a compound capable of donating a nucleophilic group, and optionally hydrolyzing the product.

Here, the compound capable of donating one R--S group is usually a salt thereof, such as metal hydrosulfide, thiocyanate alkylthiol salt, and the like.

On the other hand, sulfonic acid esters are particularly useful as active derivatives for the hydroxyl group of 8-hydroxymethylergolines, including mesyl (methanesulfonyl), tosyl (p
-toluenesulfonyl).

These sulfonic acid esters are known per se or can be derived from the corresponding hydroxyl derivatives by conventional methods.

When carrying out the process of the invention with thiophenols or alkylthiols, they are usually converted into their sodium salts with sodium hydride or sodium methylate.

Also used are alkali metal naocyanates and alkali metal hydrosulfides.

Nucleophilic substitution reactions are carried out in inert solvents such as dimenalformamide (DMF), dimethyl sulfoxide (DMSO), etc.

This reaction is usually carried out at room temperature, but if necessary, the reaction may be carried out with heating in the range of room temperature to 100°C.

Isolation of the reaction product is carried out by standard techniques, often purified by chromatography on Florisil.

In the above formula, the integrated body of R=H is, for example, R=CO-Alk.
It can also be produced by hydrolyzing the product in the presence of a base.

The object substance of the present invention is a crystalline white solid and can be converted into a pharmaceutically acceptable salt of a non-toxic acid.

These salts are also included within the scope of the target substances of the present invention.

Non-toxic acids used to form salts include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrooxalic acid, hydroiodic acid, nitrous acid,
Included are inorganic acids such as phosphorous acid and organic acids such as aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, hydroxyalkanedioic acids, aromatic acids, aliphatic or aromatic sulfonic acids.

Salts obtained from these acids include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, phosphate-hydrogen salts, dihydrogen phosphates, metaphosphates,
Pyrophosphate, hydrochloride, hydrooxalate, hydroiodide, hydrofluoride, acetate, propionate, decanoate, caprylate acrylate, quartate, isobutyrate , cabrate, heptanoate, propiolate,
oxalate, malonate, succinate, suberate,
Sebatate, fumarate, maleate, butin-1
, 4-dioisocate, hexyne 1,6-dioisocate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, fuculate, terefucle acid salt, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, quizylene sulfonate, phenyl acetate enylpropionate, phenyl butyrate, citrate,
Examples include lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and the like.

The compounds of the present invention are useful as prolactin inhibitors.

The effect of the compound of the present invention on prolactin secretion and light is demonstrated by the following experiment.

Experiment Spraque-Dawley
Adult male rats (weighing approximately 200 g) were used.

All rats were exposed to controlled light exposure (light exposure time: 6 AM).
p.m. to 8 p.m.) in an air-conditioned house, with lab chow and water provided ad libitum.

In each experiment, rats were killed by decapitation;
50 μl of serum was subjected to prolactin assay.

Each male rat received 20 mg of reserpine suspended in water intraperitoneally 18 hours before administration of the ergoline derivative.

Reserpine was administered to uniformly increase prolactin concentration levels.

Test compounds were dissolved in 10% ethanol at a concentration of 10 μg/ml and injected intraperitoneally at a constant dose of 50 μg/kg.

For each test compound, 10 rats were used per group;
A control group of 0 animals received an equal volume of 10% ethanol.

One hour after administration, all rats were killed by decapitation, and serum was separated and assayed for prolactin.

The results were statistically processed and the significance level "p" was calculated by Student's "t" test.

The inhibition rate of the compound of the present invention on prolactin secretion was determined by dividing the difference between the prolactin level of the treated rats and the prolactin level of the control rats by the prolacnan level of the control rats.

The table below shows the prolacnan inhibition rate (
%).

In the table, the first column is the compound name, the second column is the dose in the prolactin inhibition test, the third column is the prolactin inhibition rate (%), and the fourth column is the significance level.

The compounds of the present invention may be useful as prolactin inhibitors and at the same time may be useful for suppressing the growth of mammary adenocarcinoma in female mammals.

The compound of the present invention can be administered by being suspended in a vegetable oil such as corn oil, or can be administered as an aqueous solution of a pharmaceutically acceptable acid addition salt.

In addition, conventional dosage forms and administration methods may be used as necessary.

Examples of the present invention are shown below.

Example 1 Production of D-6-methyl-8-phenylmerkabutomethylergoline D-6-methyl-8-hydroxydimethylergoline 10
g was suspended in 200 ml of pyridine, and a solution consisting of 60 ml of methanesulfonyl chloride and 200 ml of pyridine was gradually added thereto.

After stirring this mixture at room temperature in a nitrogen stream for about 0.5 hours,
Pour into 2.5 liters of saturated aqueous sodium bicarbonate solution.

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

The resulting D-6-methyl-8-mesyloxymethylergoline gradually crystallized from the above solution.

The solution was cooled to about 0° C. for further precipitation.

The solution was then filtered and the resulting cake was recrystallized from ethanol.

Further, the filtrate was extracted with ethyl acetate, the ethyl acetate layer was separated, and the ethyl acetate was distilled off under reduced pressure to obtain a considerable amount of D-6-methyl=8-mesyloxymethylergoline.

When this D-6-methyl-8-mesyloxymethylergoline is recrystallized from ethanol, the mp is 192-194℃.
(decomposition) gave substance.

Elemental analysis calculation value C. 61.05;H. 6.63;N. 8.38;
S. 9.59 Experimental value C. 60.85;H. 6.46;N. 8.45;
S. 9.30 2.5 ml of thiophenol was dissolved in 2.5 ml of DMSO and 1.1 g of sodium methylate was added.

Next, D- was added to this solution of sodium thiophenol.
6-Methyl-8-mesyloxymethylergoline 700
A solution prepared by dissolving 50 mg of DMSO in 50 ml of DMSO was added dropwise.

After completion of the dropwise addition, the reaction solution was stirred at room temperature in a nitrogen stream for about 2 hours.
Then, it was poured into a saturated aqueous tartaric acid solution.

This acidic solution was extracted with chloroform and the extract was separated and discarded.

The acidic aqueous layer was made basic with excess 14N ammonium hydroxide, and the basic aqueous solution was extracted with chloroform.

The chloroform extract was separated and dried.

The residue after chloroform distillation was dissolved in ethyl acetate, and this ethyl acetate solution was thoroughly washed with water and then with saturated brine.

The ethyl acetate layer was dried, and the ethyl acetate was distilled off under reduced pressure.
When the remaining D-6-methyl-8-phenylmercaptomethylergoline is recrystallized from ethanol, mp194
~195°C (decomposition).

This compound was dissolved in chloroform and Florisil (2.
5g) was used for chromatography.

Developed with a chloroform-methanol (19:1) mixture,
Fractions containing D-6-methyl-8-phenylmercaptomethylergoline were collected while assayed by TLC.

After distilling off the solvent from the combined fractions, the residue was recrystallized from an ether-hexane mixture to obtain D-6-methyl-8-phenylmerkabutomethylergoline with a mp of 195-196°C (decomposed).

Elemental analysis calculation value C. 75.82;H. 6.95;N. 8.04
;S. 9.20 Experimental value C. 75.85;H. 6.69;N. 7.97
;S. 9.19 In the same manner, D-6-methyl-8-mesyloxymethyl-9,10-didehydroergoline and thiophenol were reacted to produce D-6-methyl-8-phenylmercabutomethyl-9, 10-didehydroergoline was obtained.

When this product is recrystallized from methanol, it has a mp Ca. 20
0-203°C (decomposition).

Elemental analysis calculation value C. 76.26;H. 6.40;N. 8.08
;S. 9.25 Experimental value C. 76.02;H. 6.42;N. 7.99
;S. 9.02 Dissolve this product in tetrahydrofuran, add a solution of leic acid in tetrahydrofuran to produce maleic acid, and recrystallize from methanol to obtain mp198-1.
It showed 99°C.

Elemental analysis calculation value C. 67.51;H. 5.67;N. 6.06
;S. 6.93 Experimental value C. 67.29;H. 5.89;N. 5.79
;S. 6.71 Example 2 Preparation of D-6-methyl-8-methylmerkabutomethylergoline 10 ml of dimethylformamide (DMF) was cooled to about 0°C, 1 ml of methanethiol was added, and then 50% sodium hydride (mineral oil) was added. 1.0 g of suspension) was added little by little.

This mixed solution was stirred for about 1 hour and then heated to room temperature.

Then, following the procedure of Example 2, D-6-methyl-8-
A solution of 1 g of mesyloxymethylergoline dissolved in 50 ml of DMF was added dropwise to the above methanethiol/sodium solution.

The product was isolated and purified by the method of Example 2 and mp
Ca. D-6-methyl-8-methylmercaptomethylergoline at 153-155°C was obtained.

By recrystallizing this from an ether-hexane mixture (chromatography in Example 1 is omitted), mp 15
D-6-methyl-8-methylmercaptomethylergoline at 3-154°C was obtained.

Elemental analysis calculation value C. 71.28;H. 7.74;N. 9.78
;S. 11.19 Experimental value C. 71.08;H. 7.59;N. 9.83
;S. 10.99 Similarly, D-6-methyl-8-methylmer? butomethyl-9,10-didehydroergoline with the corresponding 8-
It was produced by the reaction of mesyloxymethyl compound and methyl mercabutane.

When this product is recrystallized from an ether-hexane mixture, the mp
It showed 181-183°C (decomposition).

Elemental analysis calculation value C. 71.79;H. 7.09;N. 9.85
;S. 11.27 Experimental value C. 72.01;H. 6.84;N. 9.62
;S. 11.27 An equivalent amount of an ether solution of maleic acid was added to an ether solution of this product to obtain a maleate salt.

This maleate salt exhibited a mp of 159-160°C (decomposition).

Example 3 Preparation of D-6-methyl-8-acetylmerkabutomethylergoline Thioacetic acid (as the sodium salt) and D-6-methyl-8-mesyloxymethylergoline were prepared by the method described in Example 2 in DMF. D-6 was reacted with phosphorus according to the same example.
-Methyl-8-acetylmerkabutomethylergoline was isolated and purified.

The crude product was chromatographed on Florisil using chloroform containing 2% ethanol to give purified D-6~methyl-
8-acetylmerkabutomethylergoline was obtained.

mpl5: 3-155°C (decomposition). Elemental analysis calculation value C. 68.75;H. 7.05;N. 8.91
;S. 10.20 Experimental value C. 68.70;H. 7.22;N. 8.62
;S, 10.47 Similarly, D-6-methyl-8-acetylmercabutomethyl-9,10-didehydroergoline was converted to the corresponding 8
- prepared from mesyloxymethyl compound.

A purified product obtained by recrystallizing this from an ether-hexane mixture showed an mp of 165 to 167°C (decomposition).

Elemental analysis calculation value C. 69.20;H. 6.45;N. 8.97
;S. 10.26 Experimental value C. 69.48;H. 6.71;N. 9.00
;S. 10.56 When an ether solution containing an equivalent amount of maleic acid was added to an ether solution of this product, a maleate salt having a mp of 178-179°C (decomposed) was obtained.

Elemental analysis calculation value C. 61.67;H. 5.65;N. 6.54
;S. 7.48 Experimental value C. 61.95;H. 5.50;N. 6.84
;S. 7.63 D-2-chloro-6-methyl-8-acetylmerkabutomethylergoline was also produced in the same manner.

A chromatographic fraction containing D-2-chloro-6-methyl-8-acetylmerkabutomethylergoline was collected by TLC, the solvent was removed, and the purified product obtained by recrystallizing from an ether-hexane mixture had a mp of 140 to 141. ℃ was shown.

Elemental analysis calculation value C. 61.97;H. 6.07;N. 8.03;
S. 9.19;C7.10.16 Experimental valueC. 61.75;H. 5.78;N. 7.75;
S. 9.41; Cl. 10.32 A similar operation was performed using methyl mercabutane instead of thioacetic acid to obtain D-2-chloro-6-methyl-8.
-Mesyloxymethylergoline to D-2-chloro-
6-Methyl-8-methylmercaptomethylergoline was obtained.

Fractions containing the target substance were collected by Florisilk stomatography, and the concentrated residue was recrystallized from an ether-hexane mixture to give purified D-2-chloro-6-methyl-8-methylmercaptomethylergoline at mp 194-195°C. I got it.

Elemental analysis calculation value C. 63.63;H. 6.60;N. 8.73
;S. 9.99; Cl. 11.05 Experimental value C. 63.42;H. 6.55;N. 8.47;
S. 10.12; Cl. 11.35 Example 4 Production of D-6-methyl-8-mercaptomethylergoline D-6-methyl-8-acetylmercaptomethylergoline (from Example 3) 1.0g, ethanol 100ml
and 100 ml of 4N hydrochloric acid in a nitrogen stream for 5.5
Refluxed for an hour.

The reaction solution was cooled and made basic by adding an excess of 14N ammonium hydroxide.

The basic aqueous layer was extracted with chloroform, and the chloroform solution was concentrated to obtain a residue containing the product D-6-methyl-8-mercaptomethylergoline.

This residue was chromatographed using 75 g of Florisil and eluted with chloroform containing 5% ethanol.

D-6-methyl-8-mercabutomethylergoline is
It was detected by TLC as a substance that was more polar than the starting material and therefore migrated more slowly.

Fractions containing D-6-methyl-8-mercaptomethylergoline were collected and recrystallized from ethanol, resulting in mp 255
A purified product was obtained at ~257°C (decomposed).

Elemental analysis calculation value C. 70.55;H. 7.40;N. 10.28
;S. 11.77 Experimental valueC. 70.31;H. 7.65;N. 10.04
;S. 12.00

Claims (1)

[Claims] 1. General formula [In the formula, and l each represent hydrogen, or together form a double bond between the carbons to which they are bonded. ] The active derivatives of 8-hydroxymethylergolines related to the hydroxyl group are represented by the general formula R-S-H [wherein R represents hydrogen, cyan, CO-Alk, phenyl or Alk, and Alk has 1 carbon number. Represents 3 to 3 alkyl. A compound of the general formula [wherein R, R', R'' and R'' have the same meanings as defined above] is reacted with a salt related to the SH group of a compound represented by the formula: However, when R' is hydrogen, R is not hydrogen or cyano. ] A method for producing 8-thiomethylergolines, characterized by obtaining a compound represented by the following. 2 General formula [In the formula, R' represents hydrogen or halogen, and R'' and R'' each represent hydrogen or together form a double bond between the carbons to which they are bonded. . 8-Hydroxydimethylergolines having the general formula Alk-CO-S-H [where Alk represents alkyl having 1 to 3 carbon atoms]. ] to form a compound represented by the general formula [wherein R', R'', R''' and Alk have the same meanings as above. ], which is hydrolyzed to form a compound represented by the general formula [wherein R', R'' and R''' have the same meanings as above. ] A method for producing 8-thiomethylergolines, characterized by obtaining a compound represented by the following.