CS200484B2 - Process for preparing 6-methyl-8-nitromethylergoline - Google Patents

Description

The invention relates to a process for the preparation of the novel 6-methyl-8-nitromethylergoline and its non-toxic, pharmaceutically acceptable acid addition salts, which are prolactin inhibitors.

For several centuries, active ingredients derived from ergot grains have been known collectively as ergot alkaloids. Ergot alkaloids have been found to exhibit a wide variety of valuable physiological effects. Almost all ergot alkaloids and their derivatives are similar in that they contain the same general tetracyclic ring system corresponding to formula I

The ergot alkaloids and their derivatives containing the above ring system are usually classified into one of the following two groups:

D-S-methyl-ε-carboxy-η 4 -ergoline amides (lysergic acid) amides; and D-6-methyl-8-methyl-4 or -ergoline derivatives (claves). Compounds of the piano group generally exhibit some degree of activity as prolactin inhibitors. Because of this unique activity, these compounds are useful for the treatment of prolactin-dependent conditions in which prolactin secretion has a deleterious effect.

Recently, a large number of semisynthetic derivatives of ergot alcohols of the piano group have been prepared and have been shown to have useful properties. For example, Camerino et al. have prepared and evaluated a number of 8-acylaminomethylergolines (see U.S. Pat. No. 3,238,211). Erich et al. have prepared a wide variety of 8-acyloxymethylergolines showing potent uterine contraction effects. Furthermore, Arcamone et al. have prepared a number of ergoline derivatives, including 8-acylaminomethylergoline derivatives (see U.S. Pat.

324 133).

It is an object of the present invention to provide novel ergot alkaloid compounds belonging to the clavin family.

Accordingly, the present invention provides a process for the preparation of the novel 6-methyl-8-nitromethylergoline of formula II

and its non-toxic, pharmaceutically acceptable acid addition salts, characterized in that the compound of formula III

wherein Q is an ester residue, such as methanesulfonyl or p-toluenesulfonyloxy, reacted with sodium nitrite, and the resulting product is optionally converted to its non-toxic, pharmaceutically acceptable acid addition salt.

Since all of the ergolines described contain a substituent at the 8beta position, as shown in formula II by a solid line between the carbon atom at the 8-position of the ergoline ring system and the substituted methyl group, the beta symbol will be omitted in the names of all compounds. It goes without saying that all of the disclosed compounds carry an 8-beta-substituted methyl substituent.

The compound of formula II can generally be prepared by procedures known to those skilled in the art. The starting materials used in the preparation of the novel ergolines of the invention are known and can be readily prepared by conventional methods.

The compound of the above formula IX is obtained, for example, by treating a starting ergoline containing an easily cleavable group attached to the methyl substituent at the 8-position with sodium nitrite in an organic solvent such as dimethylformamide or dimethylsulfoxide. Typical ergolines used as starting flights include D-6-methyl-8- (p-toluenesylphonyloxy) methylergoline, D-6-methyl-8-bromomethylergoline, and related compounds. The nitrite substitution reaction is generally carried out at a temperature in the range of about 0 ° C to 100 ° C and is usually completed in 30 to 90 hours. The product, which is an 8-nitromethylergoline derivative, can be isolated either as the free base or as an acid addition salt and, if desired, purified by normal purification operations such as crystallization or chromatography.

The compound of formula XI above is in the form of a white crystalline solid. Said compound readily forms non-toxic, pharmaceutically acceptable salts with any of a variety of acids, including inorganic and organic acids. Mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid and related acids are usually used as inorganic acids. In addition, salts can be prepared by reacting the corresponding ergot alkaloid derivatives with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, n-butyric acid, isobutyric acid, malonic acid, benzoic acid, maleic acid, succinic acid, phenylacetic acid and p -hydroxyphenylacetic acid.

In general, the pharmaceutically acceptable acid addition salts of ergoline of the above formula (II) are prepared by established procedures, such as by reacting the ergoline base with one acid equivalent, or optionally with an excess of acid. The reaction is generally carried out in a solvent such as diethyl ether, ethyl acetate, tetrahydrofuran and the like. Alternatively, an acid addition salt can be prepared by appropriately adjusting the pH of the reaction mixture by adding the appropriate acid and then isolating the corresponding salt.

The compounds of the invention are useful as prolactin inhibitors. The inhibition of prolactin secretion caused by the compounds of the invention is demonstrated by the following experiment:

Male Spraque-Dawley rats weighing about 200 g are placed in an air-conditioned, controlled-lighting chamber (illuminated from 6 to 20 hours) and fed laboratory food and water ad libitum.

Rats from all experiments were sacrificed by decapitation, 150 µl serum samples were taken and tested for prolactin content. Prior to administration of the ergoline derivative, each male rat received an intraperitoneal injection of 2.0 mg of reserpine in an aqueous suspension (18 hours prior to administration of the ergoline derivative). The administration of reserpine is intended to maintain a uniformly elevated prolactin level. The ergoline derivative to be tested is dissolved in 10% ethanol to a solution of 10 µg / ml and injected intraperitoneally at a dose of 50 µg / kg. The test compound is administered to a group of 10 rats, with a control group of 10 male rats given an equivalent amount of 10% ethanol. 1 hour after this administration, all rats were sacrificed by decapitation, their serum collected and tested for prolactin content as above.

The difference between the prolactin level in the treated rats and the prolactin level in the control rats divided by the prolactin level in the control rats indicates the percentage inhibition of prolactin secretion for the compound of formula II.

In this test, the D-6-methyl-8-nitromethylergoline of the invention, when administered at a dose of 10 µg / rat, inhibits prolactin by 48%.

As prolactin inhibitors, the compounds of the invention are useful in the treatment of inadequate lactation, such as unwanted lactation after delivery and galactorrhoea. In addition, these compounds can be used to treat prolactin secretion-dependent adenocarcinomas and to treat prolactin-secreting pituitary tumors, as well as to treat the following disorders: Ftsrbes-Albright syndrome, Chiari-Frommel syndrome, gynecomastia per se and gynecomastia occurring as a result of estrogen-mediated steroid administration in prostate hypertrophy, fibrocystic mammary gland disease (benign nodes), prophylaxis of mammary gland and unwanted mammary gland enlargement due to administration of psychotropic drugs such as thorazine, or prostate hypertrophy,

The novel compounds of the invention may be administered to patients to inhibit prolactin secretion. The compound may be converted to the appropriate dosage form and administered orally or parenterally to the patient at doses ranging from about 0.01 to about 10 mg / kg body weight once to four times daily. The novel compounds of the invention are particularly suitable for oral administration and are preferably formulated for oral administration, such as tablets, suspensions or capsules. Parenterally, the compounds of the invention may be administered by subcutaneous, intravenous and intramuscular injections. The compounds of the invention are formulated into the appropriate dosage forms by standard procedures using conventional diluents, excipients and carriers such as starches, lactose, talc, magnesium stearate or other excipients commonly used in pharmacy.

Representative embodiments of the method of the invention are described in the following non-limiting examples.

He did

A solution of 1.07 g of D-6-methyl-8- (p-toluenesulfonyloxymethyl) ergoline in 25 ml of dimethyl sulfoxide containing 1.5 g of sodium nitrite was stirred under nitrogen at 25 ° C for 46 hours. The reaction mixture is poured into 100 ml of water, the water-insoluble product is extracted with ethyl acetate, the organic extracts are combined, washed with a saturated aqueous sodium chloride solution, dried and the solvent is evaporated off under reduced pressure to give a foamy residue. The foam-like product was applied to a chromatography column with 50 g of diatomaceous earth (florisil) and the column was eluted with chloroform. The eluate fractions containing the desired product by thin layer chromatography were combined and the solvent was evaporated under reduced pressure. 75 mg of D-6-methyl-8-nitromethylergoline melting with decomposition at 263 DEG-265 DEG C. is obtained.

For C ₆ H ₁₉ N ₃ O ₂ . H, 6.71; N, 14.73. Found: C, 67.09; H, 6.81; N, 14.93.

Example 2

To a solution of 2 g of D-6-methyl-8-nitromethyl-yergoline prepared as described in Example 1 in 50 ml of diethyl ether was added excess hydrogen chloride gas with stirring. Filtration of the reaction mixture afforded D-6-methyl-8-nitromethylergoline hydrochloride as a white crystalline solid.

Claims (2)

SUBJECT OF THE INVENTION Process for the preparation of 6-methyl-8-nitromethylergoline of formula II (II) and its non-toxic, pharmaceutically acceptable acid addition salts, characterized in that the compound of the formula III is _H CH ₂ Q M-CH 3 (III) wherein Q is an ester residue, such as methanesulfonyloxy or p-toluenesulfonyloxy, is reacted with sodium nitrite, and the resulting product is optionally converted to its nontoxic, pharmaceutically acceptable acid addition salt. 2. A process according to claim 1 for the preparation of D-6-methyl-8-nitromethylergoline, characterized in that D-6-methyl-8- (p-toluenesulfonyloxymethyl) ergoline is reacted with sodium nitrite. Sevrropnfi *. ** · p- «« manual 7. Moet