KR800000943B1 - Process for preparing aroyl-phenylnaphthalene derivatives - Google Patents

Abstract

About 80 contraceptive naphthalene derivs. (I; R, R1=H, C1-5 alkoxy; R2 and R3 are C1-4 alkyl independently or heterocyclic ring bonded with N) were prepd. by the reaction of tetralone(II) and R1C6H4MgBr. Thus, p-hydroxy benzoate reacted with 1-chloro-2-pyrrolidino ethane, which reacted with 6-methoxy-2-tetralone and NaOH to geve 6-methoxy-1- 4-(2-pyrrolidino ethoxy)-benzoyl -2-tetralone(m.p. 84≰C)(II). reaction of II with phMgBr, followed by heating with HOAC give 3-phenyl-4- 4-(2-pyrrolidinoethoxy)benzoyl -7-methoxy-1, 2-dihydronaphthalene.

Description

Process for preparing aroyl-phenylnaphthalene derivative

The present invention relates to a method for preparing aroyl-phenylnaphthalene derivatives of structural formula (I) having a fertilization inhibitory action and anticancer activity and pharmaceutically poisonous acid addition salts thereof.

In the above structural formula

X is -CH ₂ -CH ₂ -or -CH = CH-

R is hydrogen, hydroxyl or C ₁ -C ₅ alkoxy

R ₁ is hydrogen, hydroxyl or C ₁ -C ₅ alkoxy

R ₂ and R ₃ are each independently C ₁ -C ₄ alkyl or

R ₂ and R ₃ join together with a nitrogen atom to form a heterocyclic ring such as pyrrolidino, piperidino, hexamethyleneimino, or morpholino.

Several kinds of compounds are already known having the following structural formulas.

In the above structural formula

Ar is an aryl moiety

Y is one of -CH _2- , CH ₂ -CH _2- , -S-, -NH, -OCH ₂ , -O-, -CH ₂ S- and -SCH ₂ -group.

Many compounds in this category are described in the literature as having fertility inhibition. See, eg, Lednicer et al., J. Med. Chem., 8 (1965), pp. 52-57, describes 2,3-diphenylidene and derivatives thereof, and Lednicer et al., J. Med. Chem., 9, (1966) pp. 172-175, Lednicer et al., J. Med. Chem., 10 (1967), pp. 78-84 and Bencze et al., J. Med. Chem., 8, (1965), pp. 213-214 describe 1,2-diaryl 3,4-dihydronaphthalene and U.S. Pat.Nos. 3,274,231, 3,313,853, 3,396,169 and 3,567,737 1,2-diphenyl-3,4-dihydronaphthalene is described.

In addition to the above documents, US patents disclose 1,2-diphenyl-3,6-dihydronaphthalene and 2,3-diphenylidene as active agents, and examples include US Pat. Nos. 3,293,263, 3,320,271, 3,483,293. 3,519,675, 3,804,851, and 3,862,232.

Furthermore, Crenshaw et al., J. Med. Chem. 14, (1971) 1185-1190 describe a variety of other 2,3-diarylbenzo thiophenes with fertility inhibition, among others, several of which are claimed in US Pat. No. 3,413,305. have. Crenshaw also announces other compounds belonging to the class of compounds described above, and 2,3-diarylbenzofuran corresponding to benzothiophene is claimed in US Pat. No. 3,394,125.

However, there is still a need for new compounds of crystallization inhibitors, especially nonsteroidal crystallization inhibitors. The compound of formula (I) is a compound that can sufficiently meet this need. These compounds are 3-phenyl-4-aroyl-1,2-dihydronaphthalene and 1-aroyl-2-phenylnaphthalene and have many differences in structure from those described in the prior art. It is therefore an object of the present invention to prepare new nonsteroidal compounds having fertility inhibition.

In the preparation method of the present invention, after reacting the Tetraron compound of formula (II) with a phenyl magnesium bromide derivative of formula (III), X is -CH ₂ -CH _2-. Optionally reacting with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at a temperature of ˚C to prepare the corresponding compound wherein X is -CH = CH- and thus obtained is methoxy or The benzyloxyin product is reacted with a reagent selected from the group of pyridine hydrochloride or sodium thioethoxide to prepare the corresponding compound wherein Y is hydroxy and then with 1-chloro-2-aminotecan of formula (IV) And then reacting the product wherein R _a or R _1a is benzyloxy with sodium thioethoxide to produce the corresponding compound wherein R or R ₁ is hydroxy and, if necessary, this product wherein R _a or R _1a is alkoxy. Sodium tea Reaction with an ethoxide to give the corresponding compound wherein R or R ₁ is hydroxy.

In the above structural formula

R _a and R _1a are hydrogen, C ₁ -C ₅ alkoxy or benzyloxy

의 그룹이고Y is methoxy, benzyloxy or a structural formula

Is a group of

R ₂ and R ₃ are as described above.

Pharmaceutically nontoxic acid addition salts of the compounds of formula (I) include inorganic or organic acids such as hydrochloric acid, sulfuric acid, sulfonic acid, tartaric acid, fumaric acid, hydrobromic acid, glycolic acid, citric acid, maleic acid, phosphoric acid, succinic acid, acetic acid or nitric acid. There is acid addition salt prepared. Preferred acid addition salts are acid addition salts of citric acid. Such salts are prepared according to conventional methods.

“C ₁ -C ₄ alkyl” in this specification is a straight or branched group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and secondary-butyl, and “C _1- C ₅ alkoxy ”has a linear or branched alkyl group and is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, tert-butyloxy, secondary-butyloxy , n-amyloxy, isoamyloxy, tert-amyloxy or secondary-amyloxy and the like. As C ₁ -C ₅ alkoxy, methoxy is most preferred.

Preferred subclass of the compound of formula (I) is dihydro naphthalene, wherein X is -CH ₂ -CH _2- . There are several preferred types of dihydro naphthalene and these compounds are 7-alkoxy-1,2-dihydronaphthalene, i.e., a compound of formula (I) wherein X is -CH ₂ -CH ₂ -and R is C ₁ -C ₅ alkoxy. .

Other compounds include dihydronaphthalenes which are not hydroxylated or alkoxylated, i.e., structure (I) wherein X is -CH ₂ -CH ₂ -and both R and R ₁ are hydrogen.

As another compound, 3- (4′-alkoxyphenyl) -1,2-dihydronaphthalene, i.e., a compound of formula (I) wherein X is -CH ₂ -CH ₂ -and R ₁ is C ₁ -C ₅ -alkoxy have.

Preferred compounds are 3- (4′-alkoxyphenyl) -7-alkoxy-1,2-dihydronaphthalene, i.e., X is -CH ₂ -CH ₂ -and R and R ₁ are both C ₁ -C ₅ alkoxy (I) A compound.

More preferred compounds are 3- (4′-hydroxyphenyl) -1,2-dihydronaphthalene and 7-hydroxy-1,2-dihydronaphthalene, ie X is —CH ₂ —CH ₂ — and R or R _A compound of formula (I) wherein ₁ is hydroxy.

Most preferred compounds are 3- (4′-hydroxyphenyl) -7-hydroxy-1,2-dihydronaphthalene, i.e., wherein X is -CH ₂ -CH ₂ -and R and R ₁ are hydroxy ) Is a compound.

Other preferred compounds are compounds of formula (I) wherein both R ₂ and R ₃ are methyl, both R ₂ and R ₃ are ethyl or R ₂ and R ₃ are bonded together with a nitrogen atom to form a pyrrolidino ring.

The compound of formula (I) is prepared according to the following method.

A. Preparation of Compounds wherein X is -CH ₂ -CH _2-

Tetralon of the following formula (V) is reacted with phenylbenzoate of the following formula (VI).

In the above structural formula

R _a is hydrogen, C ₁ -C ₅ alkoxy or benzyloxy

의 그룹이고Y is methoxy, benzyloxy or a structural formula

Is a group of

R ₂ and R ₃ are as described above.

The reaction is usually carried out at room temperature or below in the presence of a base having a moderate strength, such as sodium amide.

The obtained compound is tetraralone of the following formula (II).

Subsequently, the substituted tetralon (II) is reacted with Grignard reagent of the following formula (III) under Grignard reaction conditions.

In the above structural formula

R _1a is hydrogen, C ₁ -C ₅ alkoxy or benzyloxy.

The resulting compound 3-phenyl-4-aroyl-1,2-dihydronaphthalene has the following structural formula (VII) and can be a compound of formula (I) according to the definitions of R _a , R _1a , and Y groups.

When Y is methoxy and R _a and R _1a are hydrogen, the corresponding hydroxy compound can be prepared by treating the compound of the formula with pyridine hydrochloride under reflux conditions. As already pointed out, this method is only effective for compounds in which R _a and R _1a are hydrogen, since if R _a and / or R _1a are alkoxy or benzyloxy they can also be broken down into hydroxy groups. .

Once the compound, wherein Y is hydroxyl, is produced, the compound of formula (I) is prepared by treating with the compound of formula (IV).

In the above structural formula

R ₂ and R ₃ are as described above.

In the compounds of formula Y, methoxy or benzyloxy and R _a and / or R _1a are alkoxy or benzyloxyyl only the group of Y is N, N-dimethylformamide under a temperature heated to about 80 ° to 90 ° C. May be selectively decomposed by treatment with sodium thioethoxide. The progress of the selective degradation can be checked by periodic analysis of the reaction mixture by pest chromatography. The reaction is said to be complete when little starting material remains.

The product containing hydroxyl at Y, ie the only hydroxyl in the molecule, is then treated with 1-chloro-2-substituted aminoethane as mentioned above.

The compound containing the 2-aminoethoxy substituent is then treated with sodium thioethoxide in N, N-dimethyl formamide as described above to decompose the remaining alkoxy or benzyloxy groups, depending on the structure of the desired final product. This produces a compound of formula (I) wherein R and / or R ₁ are hydroxyl.

The specific reaction sequence of the synthetic step of preparing a compound having a specific group and a substituent of the specific position will be easily understood by those skilled in the art.

B. Preparation of Compounds in which X is -CH = CH-

These compounds are readily prepared from the above compounds wherein X is -CH ₂ -CH _2- . The reaction in which the dehydronaphthalene structure is selectively dehydrogenated and converted to the corresponding particular naphthalene is reacted by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (50 ° to 100 ° C) by the above treatment method. DDQ). Again, by reaction with the aforementioned derivatives, the resulting naphthalene can be converted into other naphthalene compounds falling within the scope of the compound of formula (I).

The compound of formula (I) has an effective pharmaceutical action. These compounds have fertilization inhibitory action and have an effective action as a fertilizer inhibitor by oral administration, especially in birds and mammals. Therefore, the compound of formula (I) plays an effective role in controlling the number of animals and contraception of living organisms. This compound is also useful for controlling pests in animals. For example, the compound may be formulated by mixing with bait and the like to produce unnecessary rats and other species, including birds such as coots, foxes, wolves, jackals and wild dogs such as canida, starlings, galls, thrush, or pigeons. Place small animals in their feeding places, greatly reducing their growth. Depending on the action of the compounds of the structural formula (I), these compounds can be placed near the fields and in places where the harmful animals live, reducing the number of birds and animals, thereby reducing disasters. The compound can also be used to prevent the spread and prevention of disease by reducing the number of unwanted birds and animals, as well as to reduce the destruction of property throughout both cities and provinces.

The compound of formula (I) may be formulated in unit dosage form for administration by itself or in combination orally or parenterally. When mixed or formulated it is possible to use organic or inorganic solids and / or liquids which are pharmaceutically nontoxic carriers. Suitable carriers are those that will be well understood to those skilled in the art and the composition may be in tablets, powders, granules, capsules, suspensions or solutions.

When the compound of formula (I) is administered in an effective amount, it exhibits a pregnancy suppression effect in mammals. Typical daily doses are 0.02-20 mg / kg of recipient body weight and preferred daily doses are 0.02-0.4 mg.

Examples of compounds of formula (I) are as follows:

3- (4-hydroxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- [4- (2-diethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-isopropoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-tert-butyloxyphenyl) -4- [4- (2-hexamethyleneiminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-pentyloxyphenyl) -4- [4- (2-morpholinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- [4- (2-piperidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-ethoxyfeyl) -4- [4- (2-dimethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-n-propoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-tert-butyloxyphenyl) -4- [4- (2-piperidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-ethoxyphenyl) -4- [4- (2-morpholinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-hexamethyleneiminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- [4- (2-dimethylaminoepoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-isopropoxyphenyl) -4- [4- (2-diethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-tert-butyloxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-pentyloxyphenyl) -4- [4- (2-piperidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-isobutyloxyphenyl) -4- [4- (2-morpholinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-ethoxypezoyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-n-propyloxyphenyl) -4- [4- (2-dimethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-diethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-piperidinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-morpholinoethoxy) benzoyl] -1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-dimethylaminoethoxy) benzoyl] -7-hydroxy-1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- [4- (2-diethylaminoethoxy) benzoyl] -7-methoxy-1,2-dihydronaphthalene;

3- (4-isopropoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-ethoxy-1,2-dihydronaphthalene;

3- (4-tert-butyloxyphenyl) -4- [4- (2-dimethylaminoethoxy) benzoyl] -7-propoxy-1,2-dihydronaphthalene;

3- (4-pentyloxyphenyl) -4- [4- (2-piperidinoethoxy) benzoyl] -7-pentyloxy-1,2-dihydronaphthalene;

3- (4-hydroxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-hydroxy-1,2-dihydronaphthalene;

3- (4-ethoxyphenyl) -4- [4- (2-morpholinoethoxy) benzoyl] -7-ethoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-dimethylaminoethoxy) benzoyl] -1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-dimethylaminoethoxy) benzoyl] -7-hydroxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-hexamethyleneaminoethoxy) benzoyl] -7-methoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-hydroxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-piperidinoethoxy) benzoyl] -7) benzoyl] -7-ethoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-morpholinoethoxy) benzoyl] -7-methoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-hexamethyleneiminoethoxy) benzoyl] -7-isopropoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-dimethylaminoethoxy) benzoyl] -7-pentyloxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-ethoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-morpholinoethoxy) benzoyl] -7-isopropoxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-hexamethyleneiminoethoxy) benzoyl] -7-butyloxy-1,2-dihydronaphthalene;

3-phenyl-4- [4- (2-diethylaminoethoxy) benzoyl] -7-hydroxy-1,2-dihydronaphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-hydroxyphenyl) naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-n-propoxyphenyl) naphthalene;

1- [4- (2-piperidinoethoxy) benzoyl] -2- (4-tert-butyloxyphenyl) naphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2- (4-methoxyphenyl) naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-isopropoxyphenyl) naphthalene;

1- [4- (2-hexamethyleneiminoethoxy) benzoyl] -2- (4-tert-butyloxyphenyl) naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2- (4-pentyloxyphenyl) naphthalene;

1- [4- (2-piperidinoethoxy) benzoyl] -2- (4-methoxyphenyl) naphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2- (4-ethoxyphenyl) naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2- (4-ethoxyphenyl) naphthalene;

1- [4- (2-hexamethyleneiminoethoxy) benzoyl] -2- (4-hydroxyphenyl) naphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2- (4-methoxyphenyl) naphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2- (4-isopropoxyphenyl) naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-tert-butyloxyphenyl) naphthalene;

1- [4- (2-pipeinoethoxy) benzoyl] -2- (4-pentyloxyphenyl) naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2- (4-isobutyloxyphenyl) naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-ethoxyphenyl) naphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2- (4-propoxyphenyl) naphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2- (4-hydroxyphenyl) naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-methoxyphenyl) naphthalene;

1- [4- (2-piperidinoethoxy) benzoyl] -2- (4-hydroxyphenyl) naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2- (4-hydroxyphenyl) naphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2- (4-hydroxyphenyl) -6-hydroxynaphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2- (4-methoxyphenyl) -6-methoxy naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-isopropoxyphenyl) -6-ethoxynaphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2- (4-tert-butyloxyphenyl) -6-propoxynaphthalene;

1- [4- (2-piperidinoethoxy) benzoyl] -2- (4-pentyloxyphenyl) -6-pentyloxy naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2- (4-hydroxyphenyl) -6-hydroxynaphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2- (4-ethoxyphenyl) -6-ethoxy naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenyl-6-methoxy naphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2-phenyl-6-hydroxy naphthalene;

1- [4- (2-hexamethyleneiminoethoxy) benzoyl] -2-phenyl-6-methoxy naphthalene;

1- [4- (2-pyrrolinoethoxy) benzoyl] -2-phenyl-6-hydroxy naphthalene;

1- [4- (2-piperidinoethoxy) benzoyl] -2-phenyl-6-ethoxy naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2-phenyl-6-methoxynaphthalene;

1- [4- (2-hexamethyleneiminoethoxy) benzoyl] -2-phenyl-6-isopropoxynaphthalene;

1- [4- (2-dimethylaminoethoxy) benzoyl] -2-phenyl-6-pentyloxy naphthalene;

1- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenyl-6-ethoxy naphthalene;

1- [4- (2-morpholinoethoxy) benzoyl] -2-phenyl-6-isopropoxy naphthalene;

1- [4- (2-hexamethyleneiminoethoxy) benzoyl] -2-phenyl-6-butyloxy naphthalene;

1- [4- (2-diethylaminoethoxy) benzoyl] -2-phenyl-6-hydroxy naphthalene;

Fertilization inhibitory tests are carried out before and after mating for the compound of formula (I).

In the pre-engaged fertility test, 50 non-engaged mature rats, weighing between 200 and 230 g, were divided into 10 groups of 5 rats each. One group is used as a control group and the other 9 groups are experimental groups. A specific dose of the test compound is administered to the experimental group. Test compounds for each group of five are prepared in corn oil to contain 0.1 ml of carrier in the daily dose. The test compound dissolved in the carrier is injected subcutaneously in a defined amount to each rat. Only the carrier is administered to the control group. Administration of the carrier alone or a mixture of carrier and test compound continues on a daily basis for 15 days. On day 5, at least 250 g of mature male rats are placed in each group, continued living together for 15 days, and then removed from the group on the last day. Each group of rats is then examined for the existence of a fetus that can be grown after killing the rats and letting them sit for seven more days.

The ratio of the number of animals showing signs of pregnancy to the number of animals in the group is the pregnancy rate. If this ratio is 0/5 or 1/5, it is considered to have effective activity, and the ratio of 2/5 is the upper limit and it is assumed that there is no activity.

In the post-engraftment test, at least 200 g of non-engaged mature rats are used as test subjects. The rats are placed in a single mouse cage with males and tested for vaginal vaginal or seminal injections daily. If there are signs of reproduction, the males are removed and daily administration of the test compound is continued for 11 days. On day 12, the rats are killed and examined for the presence of a grown and / or reabsorbed fetus.

Pregnancy rates are expressed as the ratio of the number of pregnant animals to the number of animals in the group. Because all test animals are sure to reproduce, the control rates of control animals are very high. Therefore, a pregnancy rate of 50% is considered to be active.

In addition, the total number of viable fetuses and the total number of reabsorbed parts indicates the rate of fertility and implantation. Since the normal number of fetuses that can grow per animal in the control group is 11 or 12, a decrease in this number may also be an indicator of activity.

The following table shows the results of the fertilization inhibitory action of the compound of formula (I).

[table]

The following examples illustrate the preparation and activity of the compounds of formula (I) and do not limit the scope of the invention.

Example 1

Preparation of citrate salt of 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-1,2-dihydronaphthalene

To 300 ml of DMF is added 107 g of phenyl P-hydroxybenzoate and 26 g of sodium hydride (50% in oil). The mixture is heated at 60 ° C. for 2 hours, then 67 g of 1-chloro-2-pyrrolidinoethane is added and stirred at 85 ° C. overnight.

DMF is evaporated from the mixture, water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extract was concentrated, the residue was dissolved in a mixture of ether and ethyl acetate (1: 1), the organic solution was extracted with 2N hydrochloric acid, and the acid extract was added dropwise to 2N sodium hydroxide. The resulting mixture is extracted with ethyl acetate and the ethyl acetate extract is washed and then dehydrated with magnesium sulfate. Concentrate the ethyl acetate solution to afford 110 g of impure phenyl P- (2-pyrrolidino ethoxy) benzoate.

To a solution in which 20 g (0.5 mol) of sodium amide is suspended in THF, a solution in which 41.7 g of 6-methoxy-2-tetralone is dissolved in THF is added dropwise while maintaining the temperature at 10 ° C or lower. After the dropwise addition, the mixed solution is stirred at 10 ° C. or lower for 20 minutes to generate an exothermic reaction and the temperature rises to 20 ° C. Next, a solution of phenyl P- (2-pyrrolidinoethoxy) benzoate dissolved in THF prepared above is added dropwise, and the mixed solution is stirred at room temperature overnight. The mixture is poured into water, and the resulting material is extracted with ethyl acetate. The ethyl acetate extract is washed several times with water and dehydrated with magnesium sulfate. Ethyl acetate was concentrated to give 100 g of crude product, which was dissolved in 1.0 L of acetone. Then, a solution of 1 equivalent of citric acid was added to 400 ml of ethyl acetate. The resulting solid was isolated by filtration and dried in vacuo to afford 85.9 g of the product as 6-methoxy-1- [4- (2-pyrrolidinoethoxy) -benzoyl] -2-tetralone (melting point 84 ° C.). ), Which is not the corresponding citrate. The product is then chromatographed on silica gel using ethyl acetate as eluent to prepare the citrate salt from the dilution product.

The product (8.6 g; 0.02 mol) was added to a solution of phenylmagnesium bromide in THF, stirred at room temperature for 1 hour and then warmed to 50 ° C. for 3 hours. The resulting mixture is poured into a mixture of ice and hydrochloric acid, and the acid mixture is washed, dehydrated and concentrated with ethyl acetate extract to obtain 10.5 g of a reddish brown oily substance. This oil is added to 500 ml of acetic acid and warmed in a steam bath for about 30 minutes, then the acid is removed and water is added to the residue. The aqueous mixture was made alkaline by adding a base, the alkaline mixture was extracted with ethyl acetate, the extract was dehydrated and concentrated to yield 8.7 g of product, which was dissolved in acetone and 1 equivalent of citric acid was added. After removing acetone, methyl ethyl ketone was added to the residue and left at 0 ° C. overnight. The resulting crystals were collected by filtration, washed with cooled methyl ethyl ketone and dried under vacuum (melting point: 95 to 100 ° C.). The solid material is recrystallized from acetone to obtain the title compound in the form of a citrate salt (melting point: 98 to 100 ° C).

The title compound citrate salt in free base can be obtained by treatment with dilute alkali.

Claims (1)

Aroyl-phenylnaphthalene derivatives of the following formula (I) and pharmaceutically toxic acid addition salts thereof are prepared by reacting the tetratalone compounds of the following formula (II) with phenylmagnesium bromide derivatives of the following formula (III): How to.

Wherein X is —CH ₂ —CH ₂ —, R is hydrogen or C ₁ -C ₅ alkoxy, R ₁ is hydrogen or C ₁ -C ₅ alkoxy and R ₂ and R ₃ are each independently C ₁ -C ₄ Alkyl or R ₂ and R ₃ join together with a nitrogen atom to form a heterocyclic ring such as pyrrolidino, piperidino, hexamethyleneimino or morpholino, and R _a is hydrogen or C ₁ -C ₅ alkoxy And Y is structural formula

And R _1a is hydrogen or C ₁ -C ₅ alkoxy.