KR800000413B1 - Process for preparing 6-methyl-8-(substituted)methylergolines - Google Patents

Abstract

6-Methyl-8-(substituted)methyl ergolines(I, R = CH2 SOCH3), useful as prolactine inhibitors, were prepd. by reaction of compd. II(Q = halogen atom) with dimethylsulfoxide in the presence of a strong base. Thus, a soln. of 2.4 g NaH in dimethylsulfoxide was aded 1.44 g D-6-methyl-8-chloromethyl ergolines in dimethylsulfoxide to give 1.30 g D-6-methyl-8- (2-methylsulfinylether)ergoline, which had 65% inhibition of prolactin in rats.

Description

Manufacturing method of 6-methyl-8- (substituted) methyl ergoline

The present invention relates to the preparation of 6-methyl-8- (substituted) methyl ergoline of formula (II) and its nontoxic pharmaceutically toxic acid addition salts useful as prolactin inhibitors.

R in the above formula is CH ₂ SOCH ₃ .

Pharmacologically active compounds derived from ergot particles, collectively called ergot alkaloids, have been known for centuries and are known to have a wide variety of physiological activities. Most ergo-alkaloids and derivatives thereof are similar in that they have a detracycle ring system, as shown in the following formula (I).

Ergot alkaloids having the above ring system can be generally divided into two classes. One is an amide of D-6-methyl-8-carboxy-Δ ⁹ ergoline (lysag acid) and the other is D-6-methyl- ⁸ -methyl-Δ ⁸ or Δ ⁹ ergoline (clavin) to be. Typically, clavin-based compounds have some degree of prolactin inhibitory effect. Due to this specific activity, these compounds are effective for the treatment of conditions caused by prolactin, which are adversely affected by prolactin secretion.

Numerous clavin-based semisynthetic ergador alkaloid derivatives have recently been produced and are known to have useful properties.

For example, Cardirino et al. Have prepared and evaluated a number of 8-acylaminomethylergolines as described in US Pat. No. 3,238,211. Erich et al. Have extensive and diverse 80-acyloxymethyls with potent uterine contraction. Ergoline was prepared, and Alkamon et al. Produced various ergoline derivatives, including 8-acylaminomethyl ergoline, in US Pat. No. 3,324,133.

OBJECT OF THE INVENTION The present invention relates to a method for preparing ergot alkaloids of the clavin family.

The 6-methyl-8β- (substituted) methyl ergoline of the formula (II) of the present invention and its nontoxic pharmaceutically toxic acid addition salt are prepared as follows. That is, the compound of formula (III) is prepared by reacting with dimethyl sulfoxide in the presence of a strong base.

Q is halogen in the above structural formula.

Since all ergoline of the present invention has a substituent having a strong bond between C ₈ and CH ₂ R of the ergoline ring system, as indicated by structural formula (II), it is designated as β hereinafter. I will omit it. Thus, it can be seen that all compounds of formula (II) have 8β- (substituted) methyl substituents.

Compounds of formula II can be prepared by methods known to experts. Starting materials used to prepare ergoline are known compounds or can be readily prepared by known methods.

6-Methyl-8- (substituted) methylergoline of formula (II) is a dimethyl sulfoxide containing ergoline with 8- (substituted) methyl of the formula (III), wherein the substituent is a leaving group that can be easily substituted. It can be prepared by reacting with a nucleophilic carbanion derived from. An easily substituted leaving group refers to a group that can be easily substituted by reacting with a nucleophilic material. Such easily substituted leaving groups are well known to organic chemists and are, for example, halogens such as iodine, bromine or chlorine.

Typical ergoline starting materials, depending on 8-methyl substituents and having easily substituted leaving groups, include D-6-methyl-8-bromomethyl ergoline, D-6-methyl-8-chloromethyl ergoline, D-6-methyl-8-iodomethylergoline, D-6-methyl-8-methanesulfonyloxymethylergoline and D-6-methyl-8- (P-toluenesulfonyloxy) methylergoline have. Such suitable substituted ergolines are known and readily available. For example, D-6-methyl-8-chloromethyl ergoline can be prepared according to the method of US Pat. No. 3,732,231 to Simonsky et al.

Thus, the substituted ergoline derivatives are treated with carbanion produced by reacting dimethyl sulfoxide with a strong base to replace the leaving group of ergoline with CH ₂ SOCH ₃ . Carbanions of dimethyl sulfoxide are well known reactive derivatives and can be prepared by reacting dimethyl sulfoxide with strong bases such as sodium hydride, n-butyllithium, lithium methoxide or lithium diisopropylamide.

The reaction of substituted ergolines such as 6-methyl-8-bromomethyl ergoline with dimethylsulfoxide is generally carried out in a non-aqueous solvent. Typical solvents commonly used for such substitution reactions include solvents such as diethyl ether, tetrahydrofuran and dioxane.

The substitution reaction is generally carried out at -70 to 100 ° C and the reaction is completed in 1 to 30 hours. The product can be separated as free base or acid addition salt by adjusting the pH. Typical separation methods include, for example, diluting the alkaline reaction mixture with water and extracting the water-insoluble product with an organic solvent which is immiscible with water, such as ethyl diethyl ether or chloroform. Evaporation of the organic solvent affords the compound of formula (II) as a free base and, if necessary, purification is carried out by general methods such as recrystallization chromatography and chloride.

Compounds of formula II are generally present as white crystals. They react with organic or inorganic acids to easily form nontoxic pharmaceutically toxic acid addition salts. In general, inorganic acids used include hydrochloric acid, sulfuric acid, phosphoric acid, bromic acid, iodide, and nitric acid.

Organic acids also include methylsulfonic acid, P-toluenesulfonic acid, n-butyric acid, sobutyric acid, malonic acid, benzoic acid, maleic acid, succinic acid, phenylacetic acid, P-hydroxyphenyl acetic acid.

In general, pharmaceutically toxic acid addition salts of ergoline of formula II are prepared by reacting ergoline base with an equivalent amount of acid or a slight excess of acid if necessary. The reaction is carried out in a solvent such as diethyl ether, ethyl acetate or tetrahydrofuran.

Alternatively, acid addition salts may be prepared by adjusting the pH by adding a suitable acid to the reaction mixture and separating the corresponding salts.

Compounds of formula II are useful as prolactin inhibitors. It can be seen from the following experiment that the compound of formula II inhibits the secretion of prolactin: A male of 200 g body weight of Sprague-Daw1ey rats is controlled by lighting in an air-conditioned room (6 AM at light). From 8:00 pm) to feed the lab chow and water (with lithium). Rats were beheaded in each experiment and 150 μl of a small amount of serum was analyzed for prolactin. Elevinpine 2.0 is suspended in water and injected intraperitoneally 18 hours prior to administration of the egotolin derivatives. The reason for administering leisure pin is to keep the amount of prolactin constant.

The testosterone ergoline derivative is dissolved in 10% ethanol to a concentration of 10 μg / m1 and 50 μg / kg intraperitoneally injected. Each compound is administered to a group of 10 rats and only 10% ethanol is administered to one of the 10 groups as a control. One hour after treatment, all rats were beheaded and serum was collected to measure prolactin.

Dividing the difference between the prolactin content of the control rats and the control group by the prolactin content of the control group results in the percent prolactin inhibition by the compound of formula (II). The following table shows the percent prolactin inhibition tested at 10 μg / rat of the compound of formula II.

[table]

Other compounds of formula (II) also showed prolactin inhibitory effects at 10 g / rat but more pronounced at higher doses (100 μg-1 mg).

As prolactin inhibitors, the compounds are useful for the treatment of inappropriate milk secretions such as postpartum milk secretions and sequelae.

It can also be used to treat papillary adenocarcinoma or pituitary gland secreting prolactin by prolactin and the following diseases: Severe forbes-Albright injuries, Tiari-prommel injuries, gynecopathy itself and prostatic hyperplasia and breast mastopathy ( Benign cytokines), prophylactic treatment of breast cancer, gynecomastia resulting from the administration of estrogen-type staroids for the treatment of breast hypertrophy due to the administration of aroma drugs such as rorazine.

Errol of formula (II) and their pharmaceutically harmless salts can be administered to inhibit prolactim secretion. The compound may be appropriately prepared, and about 0.011 to 10 mg / kg may be administered orally or parenterally 1 to 4 times a day. The compound of formula (II) is particularly suitable for oral administration. The tablet or suspension is used as a capsule. In parenteral administration, the compound may be administered by subcutaneous, intravenous or intramuscular injection. The compound of formula (II) is prepared in a conventional manner using conventional diluents and excipients, carriers such as starch or lactose, talc, magnesium szenrate, or excipients used in other pharmaceuticals.

The following examples illustrate the invention in detail and do not limit the scope of the invention.

Example 1

Dissolve 2.4 g of sodium hydride in 60 ml of dimethyl sulfoxide and stir at 80 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture is cooled to about 25 ° C. and a suspension of 1.44 g of D-6-methyl-8-chloro methyl ergoline in 100 ml of dimethyl sulfoxide is added dropwise over 60 minutes. The reaction mixture is stirred for 3.5 h at ambient temperature under a nitrogen atmosphere, cooled to 5 ° C. in an ice cube and then 100 ml of water is added. The aqueous reaction mixture is extracted with dichloromethane, the combined organic extracts are washed with water, dried and the solvent is evaporated under reduced pressure to obtain a foam.

The foam was recrystallized from ethanol to obtain 1.3 g of D-6-methyl-8- (2-methylsulfinylethyl) ergoline having a melting point of 203 to 205 캜.

Analysis of C ₁₈ H ₂₄ N ₂ OS

Theoretic: C, 68.32 H, 7.64 N, 8.85 S, 10.13

Found: C, 68.07 H, 7.71 N, 9.00 S, 10.49

Example 2

410 mg of D-6-methyl-8- (2-methylsulfinylethyl) ergoline prepared in Example was dissolved in 75 ml of tatrahydrofuran, and 0.010 ml of methanesulfonic acid in 10 ml of tatrahydrofuran was added while stirring.

The reaction mixture was filtered and recrystallized from a mixture of methanol and tatrahydrofuran to determine 340 mg of D-6-methyl-8- (2-methyl sulfinyl ethyl) ergoline methanesulfonate having a melting point of 224 to 225 ° C (decomposition). Obtained as a sexual solid.

Analysis of C ₁₉ H ₂₈ N ₂ O ₄ S ₂

Theory: 55.31; 6.84; 6.79; 15.54

Calculated: 55.08; 7.10; 6.62; 15.25

Claims (1)

A process for preparing the compound of formula (II) and acid addition salts thereof by reacting the compound of formula (III) with dimethyl sulfoxide in the presence of a strong base.

In the above structural formula R is CH ₂ SOCH ₃

Is halogen.