DK143899B - ANALOGY PROCEDURE FOR PREPARATION OF PIPERAZINYLPYRAZINE DERIVATIVES - Google Patents

Description

(19) DENMARK (W,

W da) PUBLICATION <n) 11 + 3899 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 1 644/76 (51) lnt.CI.3 C 07 D 241/20 (22) Filing date 7 Apr. 1976 (24) Race day 7 · Apr. 1976 (41) Aim. available Oct 22 1976 (44) Posted Oct 26 1981 (86) International application no.

(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Priority 21 Apr 1975 * 570052, US

(71) Applicant MERCK & CC. INC., Rahway, US.

(72) Invented by Walfred Spencer Saari, US: William Carl Lumma Jr., US.

(74) Hofraan-Bang & Bout ard engineering firm.

(54) Analogous process for preparing piperazinylpyrazine = derivatives.

The present invention relates to an analogous process for the preparation of novel piperazinylpyrazine derivatives which are suitable anorexically active compounds.

Overweight or corpulence is a fairly common condition that can have quite serious consequences considering the association between various different diseases and the degree of overweight. Por 7) example, obese people suffer statistically more frequently from cardiovascular kidney disease than normal weight people. Overweight: ± also results in higher mortality rates for people suffering from diabetes, nephritis, pneumonia, cirrhosis, appendicitis έ 3 2 143899 and postoperative complications. Since obesity is most often due to the consequence of excessive caloric intake, these cases can be easily treated by limiting food intake. However, patients frequently have difficulty in starting and maintaining diets, so it may be necessary to use anorexic agents to comply with such dietary restrictions.

French Patent No. 2,236,499 discloses 2- (1,1-piperazinyl) quinoxaline derivatives having, among other things, an appetite-controlling effect, but they do not have as good an effect as the compounds of the process according to the invention, since the other effects of the known compounds are not always are desired.

The compounds of the present invention which are non-toxic, effective and highly anorexic have the general formula: two-o, wherein R is hydrogen, halogen, trifluoromethyl, alkoxy of 1-4 carbon atoms, alkylthio of 1-7 carbon atoms, phenylthio or dialkylamino having 2-6 carbon atoms, 2 1 2 R are hydrogen, halogen or phenyl, however, R and R are not both hydrogen and 5 R is hydrogen or alkanoyl having 1-3 carbon atoms, or pharmaceutically acceptable salts thereof.

The present active compound of formula I is prepared by the process according to the invention, which is characterized by the characterizing part of the claim.

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The course of the reaction is as follows: * ΥΊι _l «o 5 E1-WnA.x +

II III

\ / X is halogen in k ^ -R5

The reaction can be carried out at temperatures from room temperature to 90 ° C, preferably under an inert atmosphere such as nitrogen, helium or argon until a substantial amount of the desired adduct of formula I is formed, preferably within 0.5 to 6 hours. optimally between 1 and 4 hours.

The compounds of this invention can be administered as anorexic agents to humans or mammals, such as rats and mice, in amounts of 0.01 to 20 mg per day. kg of body weight, preferably between 0.1 and 10 mg per kg. kg body weight in a single dose or in 2 - 4 smaller doses.

The compounds may be administered orally at the doses described, but other methods of administration such as intraperitoneal, subcutaneous, intramuscular or intravenous may also be used.

Examples of suitable pharmaceutically acceptable salts of the subject compounds are pharmaceutically acceptable acid addition salts. Suitable acids for preparing these acid addition salts include inorganic acids such as hydrohalic acid (e.g., hydrochloric and hydrobromic acid), sulfuric, nitric and phosphoric, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic, succinic, chlortheophylline, p-aminobenzoic acid, p-acet-amidobenzoic acid or methanesulfonic acid.

The compounds exhibit increased efficacy and less toxicity than known anorexic agents. For example, 6-chloro-2- (1'-piperazinyl) piperazine is 10 times as effective as fenfluramine in oral administration to cats,

The active compounds of the invention also act pharmacologically, affecting the serotonin concentration in such a way that they can also be used as anti-depressant, anti-hypertensive, analgesic and sleep-inducing agents. For these purposes, the compounds may be administered in the same manner as described above.

The process according to the invention is further explained by some examples.

EXAMPLE 1 6-Chloro-2 (1- in vacuo and the residue is partitioned between 1N aqueous sodium hydroxide and benzene. The combined benzene extracts are washed with 1N aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated in vacuo to a yellow oil which is dissolved in 200 ml of absolute ethanol containing 10 ml of cold saturated anhydrous ethanolic hydrochloric acid. The precipitated hydrochloride is recrystallized from 95% ethanol to give pale yellow needles, mp: 350 ° C, dec. Yield: 50%.

EXAMPLE 2 6-Chloro-2- (4β-acetyl-1'-gigerazinyl) Eyrazine 6-Chloro-2- (1'-piperazinyl) pyrazine hydrochloride (0.064 mol) from Example 1 is dissolved in 250 ml of ice water containing 20 g of sodium acetate, trihydrate, and the solution with vigorous stirring are treated with 15 ml of acetic acid. After 3 hours, the mixture is extracted with benzene. The benzene is dried and filtered and the solvent is replaced by n-butyl chloride. Recrystallization gives the above compound, mp: 106 - 107.5 ° C.

EXAMPLE 5 5-Chloro-2 - (2) - (1) erazinyl (8) azin-h;

The above compound, mp: 301-302 ° C, is prepared as set forth in Example 1 using 2,5-dichloropyrazine instead of 2,6-dichloropyrazine.

Example 4 2-Pyrazinic acid (25 g, 0.20 mol) is converted to 2-trifluoromethylpyrazine by heating sulfur tetrafluoride (54 g) to an initial pressure of 11.2 bar and 150 ° C in a stainless steel autoclave for 6 hours.

After cooling the reaction mixture and adding sufficient sodium hydroxide to adjust the pH to 6, the crude product is extracted into methylene chloride. Distillation gives 2-trifluoromethylpyrazine, boiling point 118 ° C. The freshly distilled 2-trifluoromethylpyrazine (15> 9 g) is converted to the 4-N oxide with 30 ml of glacial acetic acid and 20 ml of 30% aqueous hydrogen peroxide for 48 hours at 70 ° C. After cooling the reaction mixture on ice, the product is extracted into benzene. The benzene extracts are washed with aqueous sodium carbonate, dried over sodium sulfate and evaporated in vacuo to give crystalline 4-N-oxide, mp: 57-59 ° C. The N-oxide (3.28 g) is almost completely rearranged to 2-chloro-6-trifluoromethyl-pyrazine, mp: 115 ° C (635 mmHg) by heating with 5 ml of benzenesulfonyl chloride for 4 hours at 100 ° C and distillation of the reaction mixture.

The above compound, m.p. 292 - 294 ° C is prepared as described in Example 1 from the 2-chloro-6-trifluoromethylpyrazine as described above.

EXAMPLE 5 2,6-Dichloropyrazine (0.067 mol) is treated with a solution of sodium methoxide (0.067 mol) in 100 ml of dry methanol for 1 hour at 25 ° C. The solvent is evaporated in vacuo and the residue is extracted with boiling hexane. From the extract, 2-chloro-6-methoxypyrazine is crystallized. Another recrystallization of isopropanol at -70 ° C gives 2-chloro-6-methoxypyrazine in the form of an oil at room temperature.

The above compound, mp 189-191 ° C, is prepared in the same manner as in Example 1, using 2-chloro-6-methoxypyrazine prepared as described above instead of 2,6-dichloropyrazine.

EXAMPLE 6

The procedure of Example 1 is repeated by reacting 2,6-dibromopyrazine with piperazine in acetonitrile to give 6-bromo-2- (1'-piperazinyl) pyrazine hydrochloride, m.p. 320 ° C, dec.

EXAMPLE 7 6-Dimethylamino-2- (11-piperazinyl) pyrazine dihydrochloride 20 millimoles (3.14 g) 6- (N, N-dimethylamino) -2-chloropyrazine and piperazine (3 g) are melted under nitrogen at 135 ° C for 6 hours. The mixture is treated with water and after filtration to remove insolubles is made basic with ION sodium hydroxide and extracted with chloroform. The combined chloroform extracts are washed with 2N sodium hydroxide, dried (anhydrous sodium sulfate), filtered and evaporated to an oil under reduced pressure. The product is isolated in the form of the dihydrochloride salt, mp: 249 - 250 ° C, of isopropanol.

EXAMPLE 8

A mixture of 0.13 mole of sodium methyl mercaptide (prepared from 3.12 g of sodium hydride and excess of methyl mercaptan), 20 g (0.13 mole) of 2,6-dichloropyrazine and 200 ml of benzene is heated at reflux for 24 hours, cooled and washed times with 50 ml of water. The benzene layer is separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Distillation of the residue gives 2-chloro-6-methylthiopyrazine.

To a solution of 10 g of piperazine in 150 ml of 2-butanol is added 8.03 g (0.050 mole) of 2-chloro-6-methylthiopyrazine. After heating under reflux over nitrogen for 6 hours, the solvent is reduced under reduced pressure and the residue is partitioned between dilute sodium hydroxide solution and benzene. The benzene extract is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is dissolved in ethanol and acidified with anhydrous ethanolic hydrogen chloride solution. The precipitated salt is recrystallized from a methanol-ethyl acetate mixture to give 6-methylthio-2- (1T-piperazinyl) pyrazine hydrochloride, m.p. 269-270 ° C.

Pharmacological report

One day immediately prior to the test day (control day), feed consumption was measured for a group of 7 - 10 rats who only had access to feed for 2 hours per day. day. On the next day (trial day), the rats are injected with different doses of the test compound 30 minutes prior to the beginning of the 2 hour feeding period. The feed consumption on the test day is then measured and compared (paired r sample) with the consumption on the control day. The results by means of typical compounds of the invention are set forth in the following table.

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Compound Dose mg / Gram eaten on Gram eaten according to. eg kg i.p. control day trial day 1 1.5 14.2 ± 2.5a 7.5 ± 2.0a 2 12.0 19.5 - 2.2 14.1 ± 2.2 3 6.0 15.9 in 2.9 5 , 5 ± 2.2 4 3.0 14.0 i 2.3 8.3 i 2.1 5 6.0 12.3 ± 4.6 3.1 ± 0.9 3.

standard deviation

Procedure:

The compounds listed below were evaluated for their effect on feed intake in rats. The test procedure was as follows: 1. On the control day (ie, the day immediately before the test day), feed intake was measured on rats that only had access to feed for 2 hours per day. day.

2. On the test day, groups of 7 rats per dose injected i.p. with 1.5, 3.0, 6.0 or 12.0 mg / kg of the test compound 30 minutes before the beginning of the 2 hour feeding period.

3. The feed consumption on the test day was compared (paired t-test) with the intake on the control day.

143899 9

Compound ED ^ Q i.p. mg / kg / Λ> 12 '°

-N NH

ar * \ _ /

Cl UQLa> 12, o \ - - /

-N

(DO1 ^ -N NK 3> 4 K \ _ / c -N NH ^ 12 0 \ / '' QLrA- 1> 6