CS208165B2 - Method of making the d-6-methyl-8-mesyloxymethyl-argoline - Google Patents

Description

(54) A process for the preparation of D-6-methyl-8-mesyloxymethylergoline

The present invention provides a process for the preparation of the novel D-e-methyl-8-mesyloxymethyl ether of formula II,

characterized in that D-6-methyl-8-hydroxymethyleirgoline is reacted with methanesulfoinyl halemide to form a compound of formula II.

Most of the above formula II is used as an intermediate in the preparation of the novel D-6-methyl-2,8-disulfated ergolines in which the substituents at positions 2 and 8 may be different, corresponding to formula I,

in which,

X is halogen, methyl or cyano; and

R represents a group of the formula —CIIz — CN or —CH 2 —C — NH 2:

And their salts with pharmaceutically acceptable acids.

The compounds of the formula I in which X represents a halogen atom are prepared

2D81B5 with N-hromsukcinimidu, N chlorsukcinimiidu Neibu respective 'another halogenating agent IS positively charged halogen, D-6-methyl-8-cyano ^E! Thyílergolin Neibu De-miethyl S-karboxamidoimethylergogolin, prepared as described by Semonská and spol. in Coll. Chem. Gomlrnum., 33, 577 (1968).

Alternatively, those compounds in which R is cyanomethyl may be prepared by reacting a halogenated reagent with a positively charged halogen with D-6-methyl-8-halomethylergol and then replacing the halogen atom in the halomethyl group with sodium cyanide or the like with cyano. Conversion of the cyanogluipine to the amide group can be accomplished by well known methods. Similar halogenation of D-6-methyl-8-inesyloxyuiethyl (or 8-tosyloxymethyl) eirgoline in polise 2 readily yields an intermediate which, by reaction with sodium cyanide or a similar inorganic cyanide in an inert solvent affords compounds within the scope of formula I above.

Compounds of formula (I) in which X is methyl are prepared by reacting D-6-methyl-8-cyamomethyl (or ε-calboxamidomethyljeirgoline) with meithium (II) formate and ethanedithiol to form D-2-formyl-acetal dithioethalene 6 Desulphation of this dithioacetal yields the desired 2-methyl derivative [see P. Sclhutz and DA Staidleir, Hely. Chem. Acta, 55, 75 (1972)]. The ε-methyl-β-thiomethylergolimus is confirmed in polise 2 in the presence of ethaindithiol to give the dithioacetal of the corresponding 2-fartnyl derivative, by deisulfurization of the dithioacetal to give the 2-methyl derivative which reacts with sodium cyanide on the brotamethyl group.

Finally, those compounds of formula I in which X is cyano are prepared by reacting a 2-unsubstituted eirgoline with clorsulfouyl isocyanate and triethylaimine (see H. Vorbriiggen, Teltrahedron Letters, 1631 (1968)).

The prefix "D" in the names of the compounds of the above structure means that the stereochemistry of the ergoline derivative is identical to that of D-lysergic acid, a form occurring in nature.

The ergolines of the above-mentioned general formula (I) may be salts prepared by the action of both organic and inorganic fairly pharmaceutically acceptable acids. Such salts include sulphates such as sulphates, pyrosulphates and bisulphates, sulphites, suflites and bisulphites, nitrates, phosphates such as phosphates, monohydrogen phosphates, dihydrogemphosphates, metaphosphates and pyrophosphates, halides such as chlorides, bromides, iodides. and fluorides, salts with aliphatic carboxylic acids containing 1 to 10 carbon atoms, such as acetates, propionates, decanoates, caprylates, afcrylates, formates, isobutyrates, capronates, heptanoates and propiolates, salts with aliphatic dicarboxylic acids having 2 to 10 carbon atoms, as oxalates, mialonates, succinates, suberates, sebacates, fumarates, roelates, butim-1,4-dioates and hexin-1,6-dioates, as well as benzoates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybemzoates and methoxybenzoates, phthalates and terephthalates, arylsulphonates, such as tolueinsulphonates, benzenesulphonates, naphthalenesulphonates, p-chloirbenisemulphonates and xylene sulphonates, citrates, salts with 2 to 5 carbon atoms of the α-hydroxyalkanoic acid, such as salts with lactic acid, β-hydroxycolic acid and (C 4 -C 6) hydroxyalkanedioic acids, such as malic and tartaric acid salts, and (C 1 -C 3) alkyl sulfonates; and such as imethanesulfonates and propanesulfonates.

Lysergic and isolysergic acid are ^{8-carboxy-6-m ethyl-9} A -eirgoliny. Lysergic acid amides, many of which possess valuable and unique pharmacological properties, include naturally occurring, erythrocyclic alkaloids that increase uterine muscle contractions, such as ergofcoirnin, eirgocryptin, ergonovine, ergo-christin, eirgosin, alkalolamines, and the like, and the like. as methergin, although the synthetic hallucinogenic substance - lysergic acid diethylamide (LSD). 6-Methyl-8-carboxyergoline amides, termed generically dihydronamel alkaloids, have lower potency to enhance uterine muscle contraction and also lower toxicity than saimoto ergot alkaloids. Brgotamiin, which is ^{9 9} -ergoline, has been used in the treatment of migraine and last; Over time, both ergobornine and 2-hrouii-α-eirgocryptine have been found to act as inhibitors of prolaictin and tumor formation induced by kiryis dimethylbenzanthririacein [see Nagasana and Meites, Proc. Soc. Expltl. Biol. Copper. 135, 469 (1970) and Heuson et al., Euro.

J. Canceir, 353 (1970)].

D-6-methyl-8-cyano: ethylergoline was first prepared by Semonsky and co-workers [see Coll. Czech. Chem. Commun., 33, 577 (1968)] and the use of the compound to prevent pregnancy in rats was reported by the same group of piriacos in Nature, 221, 666 (1989). This compound is believed to prevent secretion of the luteotropic pituitary hormone and pituitary gohadotropins. It has also been reported that the purified compound inhibits prolaictin secretion [see Gray et al., J. Reprod. Feirt., 24, 263 (1971) and Mantle and Finn, ibid., 441]. Semonsky et al. [Coll. Czech. Obeim. Coimmun., 36, 2209 (1971)) for the preparation of D-6-methyl-8-ergolinyl acetamide, a compound which is reported to exhibit aintifertility and anti-lactation effects in rats. The effect of these compounds on cancer is unknown.

208163

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The invention is illustrated by the following non-limiting example.

Example

Preparation of D-6-methyl-8-mesyloxyimethylergoline

A suspension of 10 g of D-6-methyl-8-hydroxymethylergolimus in 200 ml of pyridine is prepared and a solution of 6.0 ml of methanesulfonyl chloride in 200 ml of pyridine is slowly added. The resulting mixture was stirred at room temperature under nitrogen for 0.5 h and then poured into 2.5 L of saturated aqueous sodium bicarbonate. The basic aqueous layer was diluted with water to 6 liters of water and allowed to stand at room temperature], whereupon the D-6-methyl-5-mesyloxymethylmethyl-olefin formed in the above reaction. To precipitate more of the desired product, the solution is cooled to about 0 ° C, the solid product is filtered off and the filter cake is recrystallized from ethanol. An additional portion of D-6-m-ethyl-8-m-ethyloxym-e-thyryl-golinine was obtained by extracting the filtrate with ethyl acetate, separating the ethyl acetate layer and evaporating off the filtrate. ethyl acetate in vacuo. Recrystallization of the above-prepared D-6-methyl-8-methyl-oxymethylethyleirgoline from ethanol gives the product melting with decomposition, at 19-2 to 194 ° C.

Analysis:

calculated:

H, 6.63; N, 8.38; S, 9.59. Found:

60.85 a / _o C, 6.46% H, 8.45% N, 9.30% P.

The D-2-substituted ergoline derivatives prepared from the intermediate of Formula II of the invention are useful as goadoitropin inhibitors. As such, these substances inhibit lactation and are specific inhibitors of β-rolactin. The disclosed compounds are useful in the treatment of inappropriate lactation, such as postpartum lactation and galactorrhea. In addition, the compounds of the invention may be used for the treatment of proline-dependent adenocarciomas and prolactin-producing pituitary tumors, as well as for the treatment of the following diseases: Forbes-Albrlght syndrome, Chiar-1-Frommel syndrome, gynec-Omastia, both intrinsic and gyneicomastia. occurs as a result of the administration of elstrogenic steirides in prostate hyperthyroidism, fibrocystic breast diseases (benign nodules), the pre-opylactic treatment of breast cancer, and the treatment of excessive breast growth due to the administration of psychotropic drugs such as thorazine .

When using the above-described substances for inhibiting prolactin, the 2,8-disubstituted 6-meithyleirgone of the above formula (I) or a pharmaceutically acceptable acid salt thereof is suspended in corn oil and injected parenterally neibo orally to female mammals in an amount ranging from 0.01 to 10 mg / kg body weight of the mammal tar. Oral administration is the preferred route of administration. When palremteral administration is used, this is preferably done by subcutaneous injection, although other parenteral administration is equally effective as intraperitoneal, intiramuscular or imtiravemic. As is well known in the art, a carrier substance other than corn oil needs to be used for these other routes of parenteral administration. A soluble, pharmaceutically acceptable salt of D-6-methyl-8-cyanlmethylergoline is usually used for intravenous administration or for intramuiskulairmim. For oral administration, the compound of formula (I) or a salt thereof may also be mixed with standard pharmaceutical carriers and excipients and blended with or may be filled into a gelatin capsule.

The following experiment demonstrates the inhibition of prolactin secretion by D-2-substituted 1-eirgoline derivatives prepared from the intermediate of formula (II) of the invention:

Groups of rats with postnatal lactation are dosed with test compound from the fourth to eighth day after the litter (litter id counts as day zero). The control group receives only 0.2 ml of corn oil per day, other groups receive D- 2-bromo-6-imethyl-8-cyano-ethylergoline or the corresponding chloro derivative at various doses At the beginning of the experiment, the number of pups thrown is always reduced to six and the total bm-o-darkness of each litter is recorded. Both the pups and the nursing females are weighed on the fourth, sixth, and eighth day, and on the eighth day the nursing females are removed from the pups and decapitated immediately. -lactin.

The results of this test are summarized in Table 1. The first column of this table lists the test compound and its pharmaceuticals, the second column the number of rats in the treatment group, the third column the average change in body weight of the nursing female and the fifth column the average prolactin level. in the serum on the eighth day of the experiment.

As shown in the above table, both compounds within the scope of Formula I greatly reduce the level of prolactin and hence prolactin secretion in nursing rats.

The efficacy of the D-2-isubstituted ergoline derivatives prepared from the intermediate of formula II of the invention in suppressing adenocarcinoma growth in female mammals is illustrated by the following experiment in which only rats were used for ilulstrative purposes as female adenocarcinoma-prone mammals. The experiment is performed as follows:

A single oral administration of 7,12-dimethylbenzantracene at a dose of 20 mg induces a mammary tumor in the rats. At weekly intervals, the mammary glands of the treated animals are then palpated for tumor incidence. Rats are selected for the experiment if they have at least one measurable tumor about 0.5 cm in diameter. The tumor-bearing animals are divided into groups of five specimens and given daily at various doses of D-2-halo-6-methyl-8-cyanomethylergoline suspended in corn oil. One group of control rats receives only corn oil.

The results of this experiment are summarized in Table 2. The first column of this table lists the test compound names, the second column of their dose, the third column the route of administration, the fourth column the average tumor, the fifth column the tumor diameter after 12 days treatment and The sixth column is grained in percent.

TABLE 2

Testing with 1 lesson a dose mg / kg route of administration ⁺ diameter ’Original tumor in mm tumor diameter after 12 days of wound treatment % change D-2-bromo-6-methyl- 5 SC 6.7 2.8 —58 -8-cyanomethyl- 7 sc 7.7 5.6 —27 -ergoline 5 AFTER 7.1 3.1 —56 ! · / 10 AFTER 7.7 4,5 —42 control (0.2 ml corn oil) - AFTER 7.0 8.9 +27 D-2-chloro-6-methyl- 5 sc 7.5 5.3 —29 -8-cyanomethyl- 7 sc 6.3 4.8 —24 -ergoline 5 AFTER' 7.1 4,5 —37 10 AFTER 7,2 ' 4,5 - 38 Legend: ⁺⁾ SC = subcutaneous administration, PO = oral administration As follows from the above attempt, For example from the acute toxicity test on us acts D-2-substituted ergolinové derivatives- It follows that wherein D-2-halo-8-methyl-8 those prepared from the intermediate of formula (II) -kyammethyl (or 8-carboxamidomethyl) according to the invention significant regression tumors eirgolins have LD50 value around 1000 mg

mammary glands, both after suibcutaneous and oral administration.

The D-2-substituted ergoline derivatives of formula (I) prepared from the intermediate of formula (II) according to the invention have considerably lower toxicity compared to those known in the art in which position 2 is unsubstituted.

/ kg. In contrast, the LD 50 of D-6-methyl-8-γ, methylmethylergine, for mice is about 100 mg / kg. However, as prolactin inhibitors, the 2-halo-substituted compounds of formula I are as effective as the non-substituted D-6-methyl-8-cyimethyl (or 8-carboxamidomethyl jergolines known in the art).

characterized in that D-6-meithyl-8-hydroxymethylergoline is reacted with a non-sulfonyl halide to form a compound of formula II.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of D-6-iinethyl-8-meisyloxy, methylergoline of formula II,