SU791220A3 - Method of preparing aroylphenylnaphthalene derivatives or their pharmaceutically adopted acid-additive salts - Google Patents

Abstract

Aroylphenylnaphthalenes of the formula I <IMAGE> in which X is -CH2-CH2- or -CH=CH-, R is hydrogen or C1-C5-alkoxy, R1 is hydrogen or C1-C5-alkoxy, and the substituents R2 and R3 form, together with the nitrogen atom to which they are bonded, a pyrrolidino group, and the pharmaceutically acceptable non-toxic acid addition salts thereof are obtained by reacting a naphthalene derivative with a chloro-2-aminoethane, and converting resulting compounds of the formula I where appropriate into the pharmaceutically acceptable non-toxic acid addition salts. The compounds of the formula (I) which can be prepared according to the invention are, as a rule, valuable medicines. They are normally distinguished particularly by a fertility-inhibiting action and are therefore suitable in particular as orally active fertility-inhibiting agents in birds and mammals. The compounds of the formula (I) which can be prepared according to the invention may therefore be suitable for controlling the animal population and as contraceptives for life forms. These compounds can furthermore also be used, for example, to control animal pests.

Description

The compounds of the general formula I include additive salts of organic or inorganic acids, for example, acids such as hydrochloric, sulfuric, sulfonic, tartaric, fumaric, hydrobromic, glycolic, citric, maleic, phosphoric, succinic, acetic or nitric acid. Preferred acid salt salts are prepared from citric acid.

The compounds of formula (I) are valuable pharmaceuticals. They have a contraceptive effect, and they are particularly useful as active ingredients when administered orally for contraceptives for birds and mammals. The compounds of formula (1) are useful for controlling the fertility of animals and as contraceptives. Compounds also have value in controlling harmful animals. For example, the compounds can be incorporated into baits and / or baits and placed in food processing facilities accessible to rodents and other small animals, including animals of the Canldae family, such as coyotes, foxes, wolves, jackals and wild dogs, as well as birds such as like starlings, gulls, thrushes or pigeons, to significantly reduce their distribution. Due to the activity of the compounds of the formula (1), they can be used to reduce the harm caused to aircraft by reducing the presence of birds and birds on the runway and in the air. The compounds can also be used to reduce the spread of birds and animals in order to prevent and attenuate diseases, to reduce the destruction of properties in both rural and urban areas.

The compounds of formula (1) may be administered without modification, or they may be compounded and formulated into dosage units for oral and parenteral administration. When compounding or formulating compounds, organic solid and / or liquid substances can be used to treat them with pharmaceutically acceptable carriers. The preparations can be in the form of tablets, granules, capsules, suspensions or solutions.

Compounds of formula 1), when administered in effective amounts, can cause inhibition of pregnancy in animals. The usual daily dose is 0.02-20 mg / kg body weight of the recipient. A preferred daily dose is about 0.020, 4 mg / kg body weight of the recipient.

Example, Preparation of 3-phenyl-4-f4-2-pyrrolidinoethoxy-benzryl-6-methoxy-1, 2-dihydronaphthalene and its citrate.

8.6 g of 0.02 mol of 6-methoxy-1-4-2-pyrrolidinoethoxy-benzoyl-tetralone-2 is added to a solution of phenylmagnesium bromide in tetrahydrofuran (THF). The resulting mixture is stirred for one hour at room temperature, and then it is heated to within three hours. The mixture was poured into a mixture of ice and hydrochloric acid, and the acidic mixture was extracted with ethyl acetate. The ethyl acetate solution is washed, dried and concentrated to give 10.5 g of a reddish oil. The oil is added to 500 ml of acetic acid, and the mixture is heated on the steam bath for 30 minutes. The acid is stripped and water is added to the residue. The aqueous mixture is alkalinized by addition of a base, and the alkaline mixture is extracted with ethyl acetate. The extract is dried and

Q is concentrated to give 8.7 g of product which is dissolved in acetone, one equivalent portion of citric acid is added to the mixture. The acetone is stripped off and methyl ketl5 ketone is added to the residue. The mixture is stripped: it is dried overnight, and the resulting crystals are collected by filtration and chilled with methyl ethyl ketone, and then dried under vacuum. The melting point of the crystals is EZ-SC. The solids are recrystallized from acetone to obtain the title compound as its citrate, the melting point is 98-100 ° C.

5 Found%: C 66.72, H 6.27,

N 2.09, O 24.50.

WITH

Num,%: C, 66.96, H, 6.09,

N 2.17, O 24.78.

0 The above compound as its free base is formed by treating the citrate with a dilute alkali solution.

Found,%: C 79.19, H 6.68,

N 2.91.

WITH.

Calculated: C 79.19, H 6.89, N 3.09.

Example 2. 3- (4-Methoxy) phen 0-nyl-4-4-2-pyrrolidinoethoxy) benzoyl |} -1, 2-dihydronaphthalene.

p-Bromoanisole (380 g, 0.2 mol) is added dropwise to magnesium (10 g, 0.4 mol), maintaining the reaction temperature of the SO-B C, in order to obtain p-methoxyphenyl magnesium bromide. The reaction mixture is cooled to room temperature. Then (2-pyrrolidine-ethoxy) benzoyl} -2-tetra-0 (28.5 g, 0.0785 mol) in tetrahydrofuran is added to the obtained Grignard mixture with tetrahydrofuran for 3 hours with stirring. The tetrahydrofuran is distilled off and water is added to the residue. The aqueous mixture is alkalinized and extracted with 5 ethyl acetate. 1N hydrochloric acid was added to the extract and the solution was extracted with ether. Add a large volume of water to dissolve it. The air is dropped. The acidic layer is made alkaline and extracted with ethyl acetate, from which 28.5 g of oil1 is obtained after drying; (80% yield). The oil is dissolved in carbon tetrachloride and left overnight at room temperature. The yellow solid is separated. Filtering is repeated three times. The remaining substance (24 g) of chromium is entrained on alumina with eluent ethyl acetate. The method of thin-layer chromatography isolated 12 g of a substance with two close spots a1. 12 g of the substance is chromatographed again with a gradient from benzene to a mixture of benzene ethyl acetate (Ijl) and both spots are separated. The larger substance corresponds to the desired free base of 3- (4-methoxy) phenyl-4- f4- (2-pyrrolidine-ethoxy) benzoyl} -1,2-dihydronaphthalene. Found,%: C 79.68, H b, 89 N 2.90, O 10.74. Calculated,%: C 79.62, H 6.68, N 3.09, O 10.61. Compound form mi (1) is tested for contraceptive action both before and postcoital. In experiments on the rare contraceptive effect of 50 young individuals of female Virgins of rats breed weighing 200-230 g are divided into 10 groups of 5 each. One of the groups serves as a control, and the other 9 groups serve as experimental groups, each group receiving the test compound at a certain dose. The test compound for each group of 5 rats is obtained in the form of a solution in corn oil of such a concentration that 0.1 MP of the binder is administered per day. The indicated amount of the test compound was administered to each rat of a certain group subcutaneously daily (pc) in connection with a vm vm vm. The KoH roller group received only a referral. The introduction of the binder or combination of the test substance and the binder is continued on a daily basis for 15 days. On the 5th day of treatment, two adult male rats weighing at least 250 g were introduced into each group, cohabitation was continued until the 15th day, after which the male rats were removed from the group. X1 each group of female rats is then incubated for an additional 7 days, after which the rats are opened and examined for the presence of a living or resorbed fetus. The number of animals in which pregnancy is observed in relation to the number of animals in the group is the degree of pregnancy. A compound is considered active if this degree is between 0/5 and 2/5. A grade of 2/5 is considered as a decrease in activity, and an indicator higher than this degree is considered as a lack of activity. In post-vitro experiments, virgin female breeds weighing at least 200 g are used as experimental Sivotnye. Females are placed together with males in separate cells, and vaginal tampons or the presence of sperm in the vagina are evaluated daily. When breeding is evident, the males are removed and the test compound is administered daily for 11 days. On the 12th day, the females are opened and the presence of a living or resorbed fetus is assessed. The degree of pregnancy is given (the ratio of the number of pregnant animals to the number of animals in the group). Since all experimental animals give confirmed breeding, the rates for control animals are quite high. Therefore, a pregnancy rate of 50% indicates activity. In addition, the number of live embryos and the total number of resorption sites are indicated as an indicator of fertility and degree of implantation. Since, in the control, the usual number of live embryos per animal is about 11 or 12, a decrease in this indicator also indicates activity. The table shows the contraceptive activity of the compounds of formula (1). "., Where R is hydrogen, and R is methoxy or R-i is methoxy, and Rj is hydrogen, or pharmaceutically acceptable acid addition salts thereof, different from: in that the substituted tetralone of general formula II is R2. has 1L11e specified values, Sources of information taken into account during the examination 1. US patent number 3396169, cl. 260-294.1, publ. 1968. 2.Patent IT 3567737, cl. 260-326.5, publ. 1971. 3. General Workshop on Organic Chemistry. M., Mir, 1965, p. 488.

Claims (1)

Claim 1. A method of obtaining derivatives of aroylphenylnaphthalenes of the general formula (J) is hydrogen, a R _a R4 is a label 40 where is a methoxy group or a sigroup, a R ₂ is hydrogen, or> pharmaceutically acceptable acid ^addition salts, characterized in that the substituted tetralone is ^H 2 ^CH 2 ~ l (ID where R ^ has the above meanings, is reacted in tetrahydrofuran medium at a temperature of 0100 X with ^{phenyl magnesium} bromide of the general formula III / r _z - (HD where R £ has the above meanings.