CS208164B2 - Method of making the d-2-halogene-6-methyl-8-kyan/carboxamido/methylergolines - Google Patents

Abstract

1423065 D-6-Methyl-2,8-disubstituted ergoline ELI LILLY & CO 10 July 1973 [21 July 1972] 32890/73 Heading C2C Novel D-6-methyl-2,8-disubstituted ergoline compounds of the Formula (I) wherein X is halo, methyl or CN and R is CH 2 CN or CH 2 CONH 2 and their salts formed with pharmaceutically acceptable acids may be obtained (where X is halo) by reacting a compound of formula wherein R<SP>1</SP> is Cl, Br, I, O-SO 2 -CH 3 or O-SO 2 -p-tolyl; with a positive halogenating agent containing positive chlorine, bromine or iodine, to yield a compound of formula and then reacting this with an inorganic cyanide in an inert solvent. Conversion of the cyano group to the amide can be effected by well known procedures. Compounds in which X is CH 3 can be prepared by reacting D-6-methyl- 8-cyanomethyl (or 8-carboxamidomethyl)ergoline with methyl formate and ethanedithiol to form a dithioethylene acetal and desulphurizing the latter to form the 2-methyl derivative. Compounds in which X is CN can be prepared by reaction of a 2-unsubstituted ergoline with chlorosulphonylisocyanate and triethylamine. Pharmaceutical composition for inhibiting the secretion of prolactin in mammals contains as active ingredient a compound of Formula (I) or a salt thereof in forms suitable for oral or parenteral administration.

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the novel 0-2-ω-6-methyl-8-carboxylic acid (methylmethylenes of formula I).

in which

Dizzy group R -CH-CN or -CH ₂ -C-NHZ,

O

X where R represents a group Cha-CN represents a chlorine atom, btromu or iodine, and where R represents a group -CH 2 _NH-C-F,

II o

X represents a bromine atom, and salts thereof with pharmaceutically acceptable acids, characterized in that D-B-methyl-ε-cyanomethylergoline or D-6-methyl-8-carboxamidomethylergoline is subjected to the appropriate halogenation and optionally converted to the desired salt.

The compounds of formula (I) in which X is a halogen atom are prepared by treatment of D-6-methyl-84-cyanomethylergoline or D-6-methyl-8-cyanomethylergoline with an appropriate halogenated reagent with a positively charged halogen. 8-methyl-8-cyclohexamidoimethyleirgoline, prepared as described by Seimonský et al. in Coll. Czech. Chem. Coimmum., 33, 577 (1968).

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

The ergoline salts of the aforementioned general formula (I) may be salts prepared by treatment with both organic and inorganic pharmaceutically acceptable acids. Such salts include sulfates, such as sulfates, pyro ^- sulfates and bisulfates, sulfites such as sulfites and bisulfites, nitrates, phosphates such as phosphates, monohydrogen phosphates, dihydrogein phosphates, motaphosphates and pyrophosphates, halides such as chlorides, bromides , iodides and fluorides, salts with aliphatic carboxylic acids containing 1 to 10 carbon atoms, such as acetylates, propionates, decanoates, caprylates, acrylates, forms, isobutyrates, capronates, heptanoates and propolates, salts with aliphatic dicarboxylic acids with 2 to 10 atoms carbonates such as oxalates, malainates, suicinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioates and hexin-1,6-diolates, as well as benzoates such as benzoates, chlorobenzoates, methylbenzoates, dinitrates .obenzoates, hydroxybenzoes and methoxybenzoates, phthalates, such as phthalates and - terephthalates, arylsulfonates, such as toluenesulfonates, benzene disulfonates, naphthalimullonates, p-chlorobenzenesulfonates and xylenesulfonates, cit. salts, with 2 to 5 carbon atoms of α-hydroxyalkanoic acids, such as lactic, β-hydroxybutyric and glycolic acid salts, with 4 to 6 carbon atoms of α-hydroxy-4-alkoxyalkanedioic acids, such as malic acid salts and tartaric, and C 1 -C 3 alkylsulfonates, such as methanesulfonates and piropanesulfonates.

The lysergic and isolysergovone acids are 8-carboxy-6-methyl- ^{9 9} -gerolines. Lysergic acid amides, many of which possess valuable and unique pharmacological properties, include naturally occurring • alkaloids • enhancing contractions of the musculoskeletal muscle, such as ergocornnitine, ergocriptine, ergonovine, ergekiristin, ergosin, ergotamine, and the like, and synthetic analogues of these natural alkaloids, such as methginine, as well as the synthetic hallucinogenic substance diethyaaimide lysergic acid. (LSD). The amides of 6-methyl-S-cahboxyergoline, referred to generically as dihydronainnel alkaloids, have a lower potency to enhance the contraction of the uterine erythrocyte and also lower toxicity than ergot alkaloids alone. Ergotamine, an A9-ergoline, was used to treat migraine and recently The period has been found that both ergocornine and 2-brom.-and-e'rgoik ryptin _I act as inhibitors ·-depression and form tumors in rats induced by dimethylbenz . [See Nagasana and Meites, Proc. Soc. Exptl. Drums. Copper. 135, 469 (1970) and Heuison et al., Europ. . J. Cancer, 353 (1970)].

D-1-D-2-D-2-D-2-D-2-D-2-D-2-D-2-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-ol was first prepared by Semonsky and co-workers [see Coll. Chem. Comlmuin., 33, 577 (1968)] and the use of this compound to prevent pregnancy in rats was reported by the same group of workers in Nature, 221, 666 (1969), and is believed to prevent the secretion of luteotrophic pituitary hormone. and the pituitary gonadotropins It has also been reported that the compound inhibits prolactin secretion [See Gray et al., J. Reprod. Fert., 24, 263 (1971) and Mantle and Finn, ibid., 441] Semonsky et al. have described [see Coll. Czech. 'Chem. Comrnun., 36, 2200 (1971)] preparation

D46-methyl-8-γggotlnylaceta ₁ m ·] du, a compound which is reported to have antifertility and anti-lactation effects. The effect of these compounds on cancer is unknown.

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

Example 1

Preparation of D-2-chloro-6-methyl-8-cyainomethylergoline

400 mg of N - ^ι ohlorlukcini MCDU was reconcentrated in 30 ml of dioxane and -A solution at - a temperature of about 60 ° C, was added dropwise to a stirred suspension of 535 mg of D-6-meehytl8 kkanmčthytergtliclU in 25 ml of dioxane. After the addition was complete, the reaction mixture was heated to 60-65 ° C for about 4.5 hours under a nitrogen atmosphere, then cooled, diluted with water, solid sodium bicarbonate was added thereto, and the resulting mixture was extracted with chloroform. . The chloroform layer was separated, dried, and the chloroform evaporated in vacuo. ChrOmaitogiram of the raw residue on a thin layer contains two spots. The residue is therefore dissolved in chloroform and chromatographed on. column. Each of the chloroform eluted fractions was checked by thin layer chromatography. According to this control chromatography, fractions 7 to 12 contained the largest amount of new component (no starting material). Fractions containing a relatively large amount of this component according to thin layer chromatography were combined and the chloroform evaporated. The residue was recrystallized from ether to give 165 mg.

The procedure described above gave D-2-bromo-6-methyl-8-melting decomposition at 244-247 ° C by bromination of D-6-methyl-8-alkylaminomethyl-N-bromosuccinimide. crystallization from ethanol).

Analysis:

• calculated:

59.31% C, 5.27% H, 12.21 θ / ο N, 23.21 _0/0 Bir Found:

59.33% C, 5.37% H, 11.96% N, 23.39 _0/0 Br.

Reaction of D-6-methyl-5-cyanomethylergoline with N-iodosuccinimide affords D-6-iodo-O-methyl-4-cyanomethyltrgine, m.p. recrystallized from ether with decomposition at 211-213 ^° C.

Analysis:

calculated:

52.19% C 4.64 _0/0 H 10.74 _0/0 N, 32.44% I .natono:

51.90% C 4.51 O / OH, 10.58% N, 32.17 _0/0 I.

Example 2

Preparation of D-2-broim-6-methyl-8-N-carboxamidotmethyylergoline

A solution of 240 mg of D-6-imettiyl-8-carboxamidomethylergoline in 25 ml of dioxane is prepared under a nitrogen atmosphere at 65-70 ° C and a solution of 180 mg of N-bromosuccinimide in 20 ml of dioxane is added dropwise. The resulting mixture was heated under stirring to the above temperature for 0.5 hours and then poured into a saturated aqueous tartaric acid solution. The resulting mixture was extracted with chloroform and the chloroform layer discarded. The aqueous layer was filtered and then basified with dilute ammonium hydroxide solution. The D-2-bromo-6-methyl-8-carbaminoimido-4-carboxylic acid formed in the above reaction is insoluble in the basic aqueous solution and precipitates. The precipitated compound was dissolved in chloroform, the chloroform layer was separated and dried. Evaporation. The solvent was removed in vacuo to give D-2-bromo-6-methyl-8-carboxamide and a dimethylaminol, which crystallized from ether with decomposition at 238-241 ° C.

Example 1 a d 3

Preparation of starting material

A suspension of 10 g of D-6-methyl-8-hydroxymethylergoline in 20 ml of pyridine is prepared and a solution of 6.0 ml of methanesulfonyl chloride in 200 ml of pyridine is slowly added to this suspension. The resulting mixture was stirred at room temperature under a 0.5 hour nitrogen atmosphere and then poured into 2.5 L of saturated aqueous sodium bicarbonate solution. The basic aqueous layer was diluted with water to a volume of 6 liters and allowed to stand at room temperature to crystallize the D-6-methyl-S-mesyloxy-trimethylergoline 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-methyl-8-dimethyloxymethylergoline was obtained by extracting the filtrate with ethyl acetate, separating the ethyl acetate layer and evaporating the ethyl acetate in vacuo. Recrystallization of the above-prepared D-6-methyl-S-mesylammonium hy- goline from ethanol yields the product melting at 192-194 ° C with decomposition.

Analysis: «calculated:

61.05% C, 6.63% Η, 8.38 o / ₀ N, 9.59% S, found:

% H, 6.46;% N, 8.45;

12.5 g of D-6-methyl-8-mesyloxy, methyleirgoliin prepared as described above was heated with 12 g of sodium cyanide in the presence of 3'5'-ml dimethylsulfoxide at 100-105 ° under nitrogen for 45 minutes. C. The reaction mixture was poured into 2 L of saturated aqueous sodium chloride solution, and the resulting mixture was filtered. The solid thus obtained is stirred in warm water and filtered again to obtain

8.4 g of D-6-methyl-8-cyanomethyl-ergoline.

Salts of the compounds of formula I according to the invention with pharmaceutically acceptable acids can be prepared by dissolving some of the ergoline base in ether and adding an equivalent amount of pharmaceutically acceptable acid, also dissolved in ether. The salts thus prepared are usually insoluble in ether and can be isolated by filtration and purified by recrystallization. Alternatively, the ergoline base is dissolved in ethanol and an ethainolioic solution of an equivalent amount of pharmaceutically acceptable acid is added to the solution. In this reaction system, the salts are soluble and isolated by evaporation of the solvent in vacuo. The residue, if not crystalline, can easily be crystallized from ethanol or other suitable solvents.

Preparation of salts

Prepare a solution of 560 mg of D-2- ^{i i} rom b-6-methyl-8-kyanmethylergolinu in about 40 ml of THF and to this solution ergoline base added with stirring about 10 ml of solution prepared by dissolving 1 g · maleic acid in 50 ml of tetrahydrofuran . About 200 ml of ether is added and the precipitate formed is filtered off. The D-2-bromo-6-methyl-8-cyanomethyltergoline hydrogen maleate thus prepared melts at 207 DEG-209 DEG C. with decomposition.

D-Chloro-ε-methyl-ε-cyainomethylergoline hydrogen maleate was also prepared by the above procedure, melting at 204-206 ° C with decomposition.

In the same manner as above, 320 mg of D-2-chloro-6-methyl-8-cyanomethylergoline are dissolved in 15 ml of tetrahydrofuran and a solution of methanesulfonic acid in tetrahydrofuran is added dropwise until a further drop is added. does not give rise to any further precipitate. Siměis The tetrahydrofuran was diluted with ether and the resulting mixture was filtered to give the salt of D-2-chloro-6-methyl-8-kyanimethyleirgoliinu methanesulfonic acid, M.P. · crystallisation from a mixture of ethanol and ether with decomposition at 295 DEG C. ^Cl

Analysis:

calculated:

% C, 54.61;% H, 5.60;% N, 10.61;

8,10% S, found:

54.43% C 5.79 ° / o H, 10.86 o / ₀ N, 9.22% Cl, 8.18% S.

In analogy to the above, 220 mg of D-2-chloro-6-methyl-8-cyanomethyl-pholine is dissolved in 15 ml of tetrahydrofuran and the residue is treated with a saturated solution of d-tartaric acid in tetnahydrofuran. Excluded. a gelatinous precipitate which slowly crystallizes. The mixture was diluted with ether and filtered to give the D-2-chloro-6-methyl-8-cyanomethylergoline salt with tartaric acid, melting after recrystallization from ethanol-ether at 247-249 ° C.

Analysis:

calculated:

60.88% C 5.65% H 11.21 _0/0 N, 9.46% Cl found:

60.66% C, 5.41% H, 11.41% N, 9.49 _0/0 Cl.

The compounds of the invention are useful as gonadotropin inhibitors. As such, they inhibit lactation and are specific inhibitors of prolactin. The disclosed compounds are useful in the treatment of inappropriate lactation, such as postpartum lactation and galactoirrhea. In addition, the compounds of the present invention may be used to treat prolactin-dependent adenocarcinomas and pituitary-producing pituitary tumors, as well as to treat the following diseases: Forbes-Albright syndrome, ChianFr ommel syndrome, gynecomastia, both self-produced and gynecomastia occurring as a consequence of the administration of estrogenic sterolds in prostate hypertrophy, fibrocystic breast diseases (benign nodules), for the prophylactic treatment of breast cancer, and for the treatment of excessive breast growth due to the administration of psychotropic drugs such as thoraizine.

When using the compounds of the present invention to inhibit prolactin, the 2,8-disubstituted 6-methylgololine of the above formula (I) or a salt thereof with a pharmaceutically acceptable acid is suspended in corn. % of the oil and / or the animal is injected or orally administered to the female mammal in an amount ranging from 0.01 to 10 mg / kg of mammal body weight per day. In a preferred manner; administration is oral. When parenteral administration is used, this is preferably by subcutaneous injection, although other methods of parenteral administration, such as intraperitoneal, intramuscular or intravenous administration, are equally effective. As is well known in the art, a carrier vehicle other than corn oil should be used for these other routes of parenteral administration. The intravenóznlmu 'administration - intramuscular administration or -k normally used soluble Fami ^^^ i ^ i ^ i ^ d ^ ťcky acceptable salt of the D-6-m'ethyl-8- kyanrmetbylergolinu ^i. For oral administration, the compound of formula (I) or a salt thereof may also be mixed with standard pharmaceutical carriers and excipients and filled in or filled into a gelatin capsule.

Inhibition of prolactin secretion by the compounds of the invention was demonstrated by the following experiment:

Groups of rats with postpartum lactation are dosed with test compound from day 4 to day 8 after litter (day of litter is counted as day 0). The control group receives only -0.2 ml corn oil per day, the other groups receive D-2-bromo-6-methyl-8-cyanophenylglycol, or the corresponding chlorine, in various doses. At the start of the experiment, the number of pups thrown is reduced to six, and the total weight of each litter is recorded. Both the young and the nursing female are weighed on the fourth, sixth and eighth day. On day 8, the nursing females are removed from the offspring and the desserts are immediately drunk. The blood is collected and the prolactin content is determined in the serum obtained by radioimmunoassay.

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

TABLE 1 Treatment (4th to 8th day after litter) Pcčel к ys Average change in weight of reduced litter (fourth to oismic day) Average change in body weight of a nursing female Mean prolactin serum levels of nursing females (day eight) control corn oil 30 + 43.8 ± 1.9 g + 11.3 ± 3.2 g 60.6 ± 4.8 ng / ml (0.2 ml / deu) 2-bromo-6-methyl-ethyl-4'-8'-acitonitiril 11 + 24.9 ± 4.2 g ‘) + 18.5 ± 5.1 g ^NZ ) 11.9 ± 1.9 ng / ml ” (0.6 mg / day) 2-Broim-6-methylergoline-8 H -acetonitrile 10 + 14.8 ± 2.0 g ‘) + 3.9 ± 4.0 g ^NZ ] 12.4 ± 1.3 ng / ml ”‘ (1.0 mg / day) 2-chloro-6-methylergoline-8/3-acetonitrile 11 + 5.5 ± 2.6 g *) + 0.9 ± 4.7 g ^NZ ) 11.8 ± 1.0 ng / ml ”

(0.6 mg / day)

Legend:

* significant change from control (poku 0.001) ^NZ ) most significant change ^(a ) value calculated from determinations in 5 animals

As can be seen from the above table, both compounds falling within the scope of Formula I greatly reduce the level of prolactin and hence prolactin secretion in nursing rat females.

The efficacy of the compounds of the invention in controlling the growth of adenocarcinomas in female mammals is illustrated by the following experiment in which only rats were used as examples of female mammals susceptible to adenocarcinoma. The experiment is performed as follows:

A single oral administration of 7,12-dimethyibenzainthracene at a dose of 20 mg induces a mammary tumor in rats. The mammary glands of the treated animals are then palpated at weekly intervals to detect the incidence of tumors. Rats are selected for testing if they have at least one measurable tumor about 0.5 cm in diameter. Tumor-bearing experimental animals are divided into groups of five specimens and given daily at various doses of D-2-halo-6-methyl-8-cyanomethyl-ethylglutin 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 sixth column change in percent.

TABLE 2

Test compound Dose mg / kg Method of administration *] Origin diameter- Tumor diameter % Change tumor in mm рз 12 days of treatment in mm D-2-bromo-6-methyl-8-cyanomethyl- 5 SC 6.7 2.8 - 58 thylergoline 7 SC 7.7 5.6 - 27 5 PO · 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-8-cyanomethyl- 5 SC 7.5 5.3 - 29 thiylergoline 7 SC 6.3 4.8 - 24 5 AFTER 7.1 4,5 - 37 10 AFTER 7.2 .4,5 - 38

Legend: *] SC = subcutaneous, PO = oral

As can be seen from the above experiment, the compounds of the invention cause a significant regression of the mammary gland tumors, both after suibcutaneous and oral administration.

The compounds of the invention have a considerably lower toxicity compared to those known in the art in which position 2 is unsubstituted. For example, the acute toxicity test in mice shows that D-2-halo-6-methyl-8-cyanomethyl (or 8-icarboxamide-methyl) ergoliins have an LD 50 value of about * 1000 mg / kg. In contrast, the LD50 of D-6-methyl-8-cyanomethylergoline for mice is about 100 mg / ikg. However, as prodrug inhibitors, the 2-halo-substituted compounds of the invention are as effective as unsubstituted D-6-methyl-8-cyanimethyl (or 8-carboxamiidomethyl) ergolines known in the art.

Furthermore, the following experiment demonstrates the efficacy of the compounds of the invention as inhibitors of proline secretion:

Adult female rats (Spraque-Dawley strain) weighing about 200 g are used in the experiment. All rats are stored in an air-conditioned chamber with controlled lighting (illumination from 6.00 to 2> 0.010 hours) and fed with laboratory food and water and ad libitum.

In each experiment, the rats were sacrificed by de-capitation and the proportion of serum having a volume of 150 μΐ was analyzed for prolactin content. Eighteen hours prior to administration of the ergoline derivative, each rat female was injected intraperitoneally with 2.0 mg of reserpine in aqueous suspension. The administration of reserpine is intended to maintain a uniformly elevated prolactin level. The test derivative was dissolved in 10 ° / ₀ ethanol at a concentration of 10 .mu.g / ml, and are administered by injection intrapeiritoneální the standard dose of 50 .mu.g / / mL. Each compound is administered to a group of 10 rats, with a control group of 10 intact rats receiving only an equivalent amount of 10% ethanol.

One hour after treatment, all rats were sacrificed by decapitation, their serum collected and analyzed for prolactin content as described above. The results obtained are statistically evaluated using the Student &apos; s &apos; &apos; &apos; &apos;

The difference between the level of prolactin in treated rats and the level of prolactin in control rats divided by the level of prolactin in control rats represents the inhibition of prolactin secretion in percent, corresponding to the test compound of the invention.

The results obtained are summarized in Table 3 below. The first column of this table shows the name of the test compound, the second column the concentration of test compound used, the third column the prolactin inhibition percentage and the fourth column the statistical significance-olst.

TABLE 3

Compound Concentration Prolactin Inhibition Statistical% Relevance Ethanol (Control) - 0 0.0

D-2-chloro-6-methyl-8-carboxamidomethylergoline 10 µg / ml 60 0.0001

Claims (1)

SUBJECT OF THE INVENTION Process for preparing D-2-halo-6-methyl-8-cyano (carboxamido) (methylergolines formula I, R 1 i 1 , N-CH ₃ HN— by (1) in which R ¹ is -CH2 CN or -CH2-C-II on N№ X when R is —CH21 —CN is chlorine, bromine or iodine, and when R is —CH2 —C — NH2, II is X is bromine, and salts thereof with pharmaceutically acceptable acids characterized by the fact that D-6-Imethyl-8-cyanomethylergoline or D-6-methyl-8-carboxamidomethylergoline is subjected to the appropriate halogenation and the product obtained is optionally converted to the desired salt.