DK144160B - ANALOGY PROCEDURE FOR THE PREPARATION OF 8-THIOMETHYLERGOLIN - Google Patents

Description

09) DENMARK

(¾

| J | 02) PRESENTATION WRITING OR 11 + 4160 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 2499/75 (51) IntCI * C 07 D A57 / 02 (22) Filing date 4 Jun. 1975 (24) Race day 4 Jun. 1975 (41) Aim. available 7 * dec. 1975 (44) Posted Dec 28 1981 (86) International application # - (86) International filing day (85) Continuation day - (62) Master application no -

(30) Priority Jun 6 1974, 477156, US

(71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.

(72) Inventor Edmund Carl Kornf eld, US: Nicholas James Bach, US.

(74) Associate Engineer Hofman-Bang & Bout ard.

(54) Analogous process for fretting of 8-thiomethylene coils.

The present invention relates to an analogous process for the preparation of novel 8-thiomethylergolines having the general formula II or pharmaceutically acceptable acid addition salts thereof as set forth in the preamble of claim, and the process of the invention is characterized by the characterizing part of the claim. The present compounds are useful as prolactin inhibitors.

±

d "Compounds Based on the Ergoline Ring System of Formula I

t 2 144160 fe 7)

XV ^ L ° eJ'MH

18 N /

| il 11 S | N

^ JLj 'T (i) H-N - 3 has a surprisingly varying amount of pharmaceutical action. Lysergic and isolicergic acid are e.g. 8-carboxy-6-methyl-Å9 ergolines (9,10-didehydroergolines). Lysergic acid amides, many of which have valuable and unique pharmacological properties, include naturally occurring oxytocin alkaloids - ergocornin, ergocryptin, ergonovine, ergocristine, ergosine, ergotamine etc. - and synthetic oxytocins such as methergin as well as the synthetic hallucinogenic lysergic acid LS. Amides of 6-methyl-8-carboxyergoline, generically known as dihydroergoth alkaloids, are oxytocins of lower potency and also of lower toxicity than the ergot alkaloids themselves. Ergotamine, an Aβ-ergoline, has been used in the treatment of migraine, and recently both ergocornin and 2-bromo-α-ergocryptin have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA) -induced tumors in rats, according to Nagasawa and Meites, Proc. Soc. Exp'tl. Biol. With. 135, 469 (1970) and Heuson et al., Europ. J. Cancer, 353, (1970). (see also U.S. Patents Nos. 3 752 888 and 3 752 814).

D-6-methyl-8-cyanomethylergoline was first prepared by Semonsky et al., Coll. Czech. Chem. Commun., 33, 577 (1968), and its use to prevent pregnancy in rats was published by the same group of researchers in Nature, 221, 666 (1969). (See also U.S. Patent No. 3,732,231). The compound is thought to interfere with the secretion of the leuteotropic pituitary hormone and the pituitary gonadotropins. It was also suggested that the compound inhibited the secretion of prolactin. [See Seda et al., Reprod. Fert. 24, 163 (1971) and Mantle and Finn, id. 441)]. Semonsky et al., Coll. Czech. Chem.

Comm., 36, 220 (1971), have disclosed the preparation of D-6-methyl-8-ergolinylacetamide, a compound which is reported to have antifertility and antilacterial effect on rats. The effect of these compounds in neoplastic diseases is unknown.

Danish Patent Specification No. 140,986 discloses 8-substituted D-2-halogen-6-methylergolines or salts thereof, wherein the 8-substituent is either CH 2 CN or CH 2 C (= O) NH 2. These compounds are prolactin inhibitors, but have the disadvantage of being hepatotoxic to humans relative to the compounds of this invention (see Amer.

J. Med. Sci. 278, 65-76 (1979)). This has at least been found to be the case for the compound in which the 8-substituent is CH2-CN and the toxicity may be due to the isano group. The compounds of this invention do not contain any cyano group in the 8-position.

In the above Formula II, alky groups having 1-3 carbon atoms include the following groups: methyl, ethyl, n-propyl and iso-Q ΤΛ propyl. When the A 'bond of formula II is saturated, the compounds are referred to as D-6-methyl-8-thiomethyl (or mercaptomethyl) ergolines. When the 4'10 bond is unsaturated, the resulting compounds are generically referred to as D-6-methyl-8thiomethyl- or mercep-pheo-methyl-9,10-didehydroergolines. Illustrative compounds obtained by the process of the present invention are: D-2-chloro-6-methyl-8-propionylthiomethylergoline D-2-ehloro-6-methyl-8-butyrylthiomethyl-9,1O-didehydroergoline D-2 chloro-6-methyl-8-phenylmeroaptomethyl-9,1O-didehydroergoline D-2-bromo-6-methyl-8-phenylmercaptomethyl-9,1O-didehydroergoline D-2-chloro-6-methyl-8-ethylmercaptomethyl-9, 1O-didehydroergoline D-6-methyl-8-n-propylmercaptomethylergoline D-6-methyl-8-isopropylmercaptomethylergoline,

The compounds of the invention are prepared via nucleophilic substitution by reacting one of the following esters of a D-6-methyl-8-hydroxymethylergoline or -9,10-didehydroergoline, optionally substituted by carbon atom 2 with chlorine or bromine, with salts of thiophenol, a thioalkanecarboxylic acid (alk-COSH) or an alkyl-thiol (alk-SH). The esters used as starting materials in the above synthesis are mesyl (methanesulfonyl) and p-toluenesulfonyl (p-tosyl) esters formed with the hydroxy group in 8-hydroxy-methyl-6-methylergoline, 8-hydroxymethyl-6-roethyl 9, 10-didehydro-ergoline or of a 2-halogen derivative of both of these compounds of formula III. These mesyloxy and p-tosyloxy derivatives are either known compounds or can be prepared from corresponding hydroxy derivatives by known methods. In carrying out reactions with thiophenol or with an alkylthiol, the sodium salt of the mercap-tan group is usually formed, using sodium methylate or sodium hydroxide. The nucleophilic substitution reaction is carried out in an inert solvent such as dimethylformamide or dimethylsulfoxide. Usually the reaction is carried out at room temperature or, if desired, heated to a temperature of up to 100 ° C. The products of the reaction are usually isolated by standard technique and purified by chromatography, preferably over florisil.

The compounds of the invention are white crystalline solids and form pharmaceutically acceptable salts with non-toxic acids. Non-toxic acids useful in the formation of these salts include such inorganic acids as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrogen bromide acid, hydrogen iodide acid, nitric acid and phosphoric acid, as well as non-toxic organic acids comprising aliphatic mono- and dicarboxylic acids. phenyl-substituted alkanecarboxylic acids, hydroxy-alkane and alkanedicarboxylic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, meta-phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, deeanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, * maleate, butyn-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate , methoxybenzoate, phthalate, terephthalate, benzenesulfonates, toluene sulfoate, chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, maleate, propane sulfate, methane sulfate and naphthalene-2-sulfonate.

The compounds of the invention are useful as prolactin inhibitors. Inhibition of prolactin secretion by the compounds is seen in the following experiment. Adult male rats of 5 mieo

The Spraque-Dawley tribe that weighed ea. 200 g, was used. All rats were placed in an air-conditioned room with light from 6 am to 8 pm and were fed feed and water ad libitum.

In each experiment, each male rat was given an intraperitoneal injection of 2.0 mg of reserpine in an aqueous suspension 18 hours prior to the administration of the ergoline derivative. The purpose of the resperpine administration was to keep the prolactin level uniformly high. The derivatives were dissolved in 10 pet. ethanol at a concentration of 10 µm / m! and was injected intraperitoneally at a standard dose of 50 µg / kg.

Each compound was administered to a group of ten rats and a control group of ten healthy rats received a similar amount of 10 pet. ethanol. One hour after treatment, all rats were killed by decapitation and 150 μΐ serum were collected and examined for prolactin. The results were statistically assessed using Student's "t" test (a mathematical comparison of mean values) to calculate the significance level expressed by "p".

The difference between the prolactin concentration in the treated rats and the prolactin concentration in the control rats divided by the prolactin concentration in the control rats indicates the percentage inhibition of prolactin secretion attributable to the administration of the compounds of the invention. The following table lists the prolactin inhibition for a variety of compounds of formula II prepared according to the invention. In the table, column 1 gives the name of the compound, column 2 dose of the compound administered, column 3 percent prolactin inhibition, and column 4 the significance level.

Since the compounds of the present invention are prolactin inhibitors, they are also potentially useful in suppressing the growth of breast adenocarcinoma in female mammals.

6 144160

TABLE

$> prolactin "p"

Compound Dose inhibition value D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline 10 pg 50 <0.05 D_6-me t hy 1-8-me thylmer c apt o -methyl-9,10- dide hydroergoline 10 µg 62 <0.01 D-6-methyl-8-acetylthiomethylergoline 10 µg 40 <0.01 D-6-methyl-8-methylmercaptomethylergoline 10 µg 49 <0.001 D-2-chloro-6- methyl 8-methylmercaptomethylergoline 10 pg 46 <0.001 D-6-methyl-8-acetylthiornethyl1,9,10-didehydroergoline 10 pg 44 <0.01 The following examples further illustrate the process of the invention: EXAMPLE 1

A suspension of 10 g of D-6-methyl-8-hydroxymethylergoline in 200 ml of pyridine "was prepared. To this suspension was slowly added a solution containing 6.0 ml of methanesulfonyl chloride and 200 ml of pyridine. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for one hour. half an hour and poured into 2.5 liters of saturated aqueous sodium bicarbonate, the aqueous basic phase was diluted to 6 liters with water and the diluted phase was allowed to stand at room temperature D-6-methyl-8-mesyloxymethylergoline formed by the above reaction slowly crystallized out. The solution was cooled to about 0 ° C to precipitate more of the compound, the solution was filtered and the filter cake was recrystallized from ethanol An additional amount of D-6-methyl-8-mesyloxymethylergoline was obtained by extracting the filtrate with ethyl acetate, 144160 and remove the ethyl acetate from it by evaporation in vacuo. Recrystallization from ethanol of D-6-methyl-8-mesyloxymethylergoline to prepare t as above gave a substance which melted at 192 -194 ° C during decomposition.

Analysis: Calculated: 061.05 - H6.63 - N 8.38 - S 9.59

Pound: C 60.85 - N 6.46 - N 8.45 - S 9.30.

A solution of 2.5 ml of thiophenol in 25 ml of dimethyl sulfoxide was prepared. 1.1 g of sodium methylate was added. Then, a solution of 700 mg of the above product was added in 50 ml of dimethyl sulfoxide, the addition being carried out dropwise. Upon completion of the addition, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and poured into a saturated aqueous tartaric acid solution. Bone acidic phase was extracted with chloroform. The chloroform extract was separated and poured off. The acidic phase was made basic with excess 14N ammonium hydroxide and the resulting basic phase extracted with chloroform. The chloroform extract was separated and dried. Evaporation of the chloroform gave a residue which was dissolved in ethyl acetate. The ethyl acetate solution was thoroughly washed with water and then washed with a saturated sodium chloride solution. The ethyl acetate phase was dried. Removal of ethyl acetate by evaporation in vacuo gave a residue consisting of D-6-methyl-8-phenylmereaptomethylergoline, which was recrystallized from ethanol and melted at 194 - 195 ° C under decomposition. The compound was dissolved in chloroform and chromatographed over florisil (25 g). The chromatogram was developed with a chloroform-methanol-solvent mixture (19: 1). Operations containing D-6-methyl-8-phenylmercaptomethylergoline as determined by thin layer chromatography were pooled. Evaporation of the solvent from the combined fractions and recrystallization of the resulting residue from an ether-hexane-solvent mixture gave D-6-methyl-8-phenylmer-captomethylergoline, m.p. 195 - 196 ° C during decomposition.

Analysis: Calculated: C 75.82 - H 6.95 - N 8.04 - S 9.20

Pound: C 75.85 - H 6.69 - N 7.97 - S 9.19.

144160 8

Following the above method, D-6-methyl-8-mesyloxymethyl-9,1O-didehydroergoline was reacted with thiophenol to give D-6-methyl-8-phenylmereaptomethyl-9,1O-didehydroergoline, which melted at about 200-203 ° C under decomposition after recrystallization from methanol.

Analysis: Calculated: C 76.26 - H 6.40 - N 8.08 - S 9 »25

Bound: 0 76.02 - H 6.42 - N 7.99 - S 9.02.

The corresponding 9,1O-didehydromaleate salt was prepared by dissolving the compound in tetrahydrofuran and adding an equivalent amount of maleic acid, also dissolved in tetrahydrofuran. The maleate salt melted at 188 - 189 ° C after recrystallization from methanol.

Analysis: Calculated: 0 67.51 - H 5.67 - N 6.06 - S 6.93

Found: C 67.29 - H 5.89 - N 5.79 - S 6.71.

EXAMPLE 2

Ten milliliters of dimethylformamide was cooled to 0 ° C. 1 ml of methanethiol was added followed by 1 g of sodium hydride as a 50 per cent. suspension in mineral oil in small portions. The resulting mixture was stirred for 1 hour and then warmed to room temperature. Following the method of Example 1, a solution of 1 g of D-6-methyl-8-mesyl-oxymethylergoline in 50 ml of dimethylformamide was added dropwise to the sodium salt of the methanethiol. The resulting product was isolated and purified by the method of Example 1 to give D-6-methyl-8-methylmercaptomethylergoline melting at 153 - 155 ° C. Recrystallization of the compound (omitting the chromatographic purification of Example 1) from an ether-hexane-solvent mixture gave D-6-methyl-8-methylmercaptomethylergoline, m.p. 153 - 154 ° C.

Analysis: Calculated: 071.28 - H7.74 - N 9.78 - S 11.19

Bound: 071.08 - H 7.59 - N 9.83 - S 10.99.

Following the above method, D-6-methyl-8-methyl-mercaptomethyl-9,1O-didehydroergoline was prepared from the corresponding 8-mesyloxy-methyl compound by reacting with methylmercaptan. The boron compound melted at 181 - 183 ° C with decomposition after recrystallization from an ether-hexane solvent mixture.

9 144160

Analysis: Calculated: 071.79 - H7.09 - N 9.85 - S 11.27

Pound: C 72.01 - H 6.84 - N 9.62 - S 11.27 ·

The corresponding 9,10-didehydromaleate salt was prepared by dissolving the compound in ether and adding an equivalent amount of maleic acid, also dissolved in ether. The maleate salt melted at 159 - 160 ° C during decomposition.

Analysis: Calculated: C 62.98 - H 6.07 - N 6.99 - S 8.01

Pound: C 62.99 - H 6.15 - N 6.78 - S 7.86.

EXAMPLE 5

Following the method of Example 1, thioacetic acid (as sodium salt) was reacted with D-6-methyl-8-mesyloxymethylergoline in dimethylformamide solution to give D-6-methyl-8-acetylmercaptomethylergoline, which was isolated and purified by the method of Example 1 Chromatography of the crude product over florisil using chloroform containing 2 pet. ethanol as eluent gave it purification. D-6-methyl-8-acetylmercaptomethylergoline, m.p .: 155 - 155 ° C during decomposition.

Analysis: Calculated: C 68.75 - H 7.05 - N 8.91 - S 10.20

Pound: C 68.70 - H 7.22 - N 8.62 - S 10.47.

Following the above method, D-6-methyl-8-acetylmer-captomethyl-9,10-didehydroergoline was prepared from the corresponding 8-mesyloxy-methyl compound. The purified compound melted at 165 - 167 ° C during decomposition after recrystallization from ether-hexane.

Analysis: Calculated: 0 69.20 - H 6.45 - N 8.97 - S 10.26

Pound: C 69.48 - H 6.71 - N 9.00 - S 10.56.

The corresponding 9,1O-didehydromaleate salt was prepared by dissolving the base in ether and adding an equivalent amount of maleic acid in ether. The maleate salt melted at 178 - 179 ° C during decomposition.

Analysis: Calculated: C 61.67 - H 5.65 - N 6.54 - S 7.48

Pound: C 61.95 - H 5.50 - N 6.84 - S 7.65.

U4160 of D-2-chloro-6-methyl-8-acetylmercaptomethylergoline was also prepared by the above method. Recrystallization of the residue remaining after combining the fractions from chromatography was found to contain D-2-chloro-6-methyl-8-acetylmereaptomethylergoline by thin layer chromatography, using a solvent mixture of ether and hexane to recrystallize. purified material with a melting point of 140 - 141 ° C.

Analysis: Calculated: C 61.97 - H 6.07 - N 8.03 - S 9.19 -

Cl 10.16

Pound: C 61.75 - H 5.78 - N 7.75 - S 9.41 -

Cl, 10.32.

The above method "was repeated, however, using methylmercaptan instead of thioacetic acid for reaction with D-2-chloro-6T methyl-8-mesyloxymethylergoline to give D-2-chloro-6-methyl-8-methylmercaptomethylergoline. of florisil of the residue obtained by mixing the chromatographic fractions showed that this residue contained the desired material, using an ether-hexane mixture for recrystallization, and a purified D-2-chloro-6-methyl-8 was obtained. -methylmercaptomethylergoline with a melting point of 194 - 195 ° C.

Analysis: Calculated: C 63.63 - H 6.60 - N 8.73 - S 9.99 - Cl 11.05 Found: C 63.42 - H 6.55 - N 8.47 - S 10.12 - Cl 11.35.

Claims (1)

An analogous process for the preparation of 8-thiomethylergolines of the general formula II: (II) o II wherein R is C-alk, phenyl or alk; R is hydrogen, ehloro or hromo; alk is alkyl of 1-3 carbon atoms, and the dotted line represents any double bond present, or non-toxic, pharmaceutically acceptable acid addition salts thereof, characterized by reacting a compound of the general formula III -, "" R1 (III)