KR800000942B1 - Process for preparing aroyl-phenylnaphthalene derivatives - Google Patents

Abstract

The title compds-(I; X=-CH2-CH2- or-CH=CH=; R=H or C1-5 alkoxy; R1=H or C1-5 alkoxy; R2 and R3 are C1-4 alkyl) were prepd. by the reaction of a formula II and 1-chloro-2-aminoethane(III). Thus, 18.7 g o-bromoanisole, 1, 2-dibromoethane and 3.6 g magnesium were reacted in ether, following by addition of 1-(p-methoxybenzoly)-2-tetralone and stirred for 2 hr to give I. I showed contraceptive activity when tested on rats.

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 a heterocyclic ring such as pyrrolidino, piperidino, hexamethyleneimino, or morpholino, in which R ₂ and R ₃ are bonded together with a nitrogen atom; To achieve.

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. For example Lednicer et al., J. Med. Chem., 8 (1965), 52-57, describe 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 Benzcze et al., J. Med. Chem., 8, (1965), pp. 213-214 describe 1,2-diaryl-3,4-dihydronaphthalene and U.S. Patent 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 2,3-diarylbenzo thiophenes with modification inhibition among others, some of which are claimed in US Pat. No. 3,413,305. . 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 crystal inhibitors, especially nonsteroidal crystal 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-phenylnaphtharene 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 produce the corresponding compound wherein Y is hydroxy and then with 1-chloro-2-aminoethane 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 with 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 classes of dihydronaphthalene 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′-dihydroxyphenyl) -1,2-dihydronaphthalene and 7-hydroxy-1,2-dihydronaphthalene, ie X is —CH ₂ —CH ₂ — and R or A compound of formula (I) wherein R 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 phenyl benzoate 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 at the specific position will be readily 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 to 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 compounds may be formulated by mixing with bait and the like to produce unnecessary rats and other species, including birds such as coidaes, foxes, wolves, jackals and wild dogs such as canada, starlings, galls, thrush, or pigeons. Place small animals in their feeding places, greatly reducing their growth. Depending on the action of the compounds of formula (I), these compounds may be placed in the vicinity of the field and in places where the harmful animals are well cared for, thereby 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-ethoxyphenyl) -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-hexamethyleneaminoethoxy) 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-ethoxyphenyl) -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-hydroxy naphthalene;

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

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

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-hydroxy naphthalene;

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-methoxy naphthalene;

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

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-engraftment fertilization test, 50 non-engaged mature rats weighing 200-230 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 were prepared in corn oil to contain 0.1 ml of carrier in the daily dose. Test compounds dissolved in the carrier are injected subcutaneously in defined amounts 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. The ratio of 2/5 is the upper limit and more than that is not the 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 breed, the control group has a very high pregnancy rate. 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. Reductions in this number may also be indicative of activity, since in the control group the number of fetuses that can grow per animal is 11 or 12.

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

50 g (0.34 mole) of β-tetralone are added to a suspension in which 15.2 g (0.38 mole) of sodium amide is suspended in 250 ml of tetrahydrofuran (THF). The mixture is stirred for 15-20 minutes and a solution of 78 g of phenyl P-methoxy-benzoate dissolved in THF is added. The temperature is kept below 10 ° C. and then the mixture is stirred overnight at room temperature. The reaction mixture is concentrated, water is added to the residue, the aqueous mixture is extracted with ethyl acetate, the ethyl acetate extract is washed and concentrated. The residue is chromatographed with silica gel using Benzel as the eluent. The purer fractions obtained by chromatography are combined, concentrated and the residue is dissolved in a minimum amount of methanol. The methanol is cooled and the resulting precipitate is filtered to give 35.2 g of 1- (P-methoxybenzoyl) -2-tetratone.

0-bromoanisole (18,7 g; 0.1 mol) is added dropwise to THF containing 5 drops of 1,2-dibromoethane and 3.6 g (0.15 mole) magnesium in ether. The reaction proceeds almost immediately and continues to add slowly, releasing enough heat to maintain normal reflux. After the addition was completed, the solution of the substituted β-tetraltone in acetone was stirred dropwise over 2 hours while maintaining the mixture at 40 ° C. The resulting mixture was poured into cooled hydrochloric acid, the acidic mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed, dehydrated and concentrated to an oil phase. This material was chromatographed on silica gel using benzene as eluent to obtain starting material (8.6 g) as green yellow crystals (melting point: 86 to 88 ° C.), 15 g of 3- (4-methoxyphenyl) -4- ( 4-methoxybenzoyl) -1,2-dihydronaphthalene is obtained as an oily substance by eluting the column with a mixture of benzene containing 2% ethyl acetate.

A mixture of 11.1 g of the said dimethoxy product, 7.2 g of sodium hydride (50% in oil), 11 ml of ethyl mercaptan and N, N-dimethylformamide is prepared and then heated at 65-70 ° C. for 2 hours. The mixture is cooled and concentrated, then the concentrate is acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dehydrated and evaporated, and then the residue was dissolved in benzene and chromatographed with silica gel to give 5 g of relatively pure oily 3- (4-methoxyphenyl) -4- (4-hydroxybenzoyl) -1,2. Obtain dihydronaphthalene.

The phenolic product (4.3 g: 0.01 mol) is dissolved in N, N-dimethylformamide. 0.7 g sodium hydride (50% in oil) is added to the solution, and the resulting mixture is warmed to 40 ° C. for 1 hour and then cooled to room temperature. 1.62 g of 1-chloro-2-pyrrolidinoethane was added to the mixed solution, and the mixed solution was warmed to 60 DEG C for 2 hours, and then stirred at room temperature overnight. The mixture is concentrated, water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extract is washed and concentrated to give a residue. The residue is extracted with hexane, the insoluble portion is dissolved in ethyl acetate and the ethyl acetate solution is extracted with 1N hydrochloric acid. The acidic solution is made alkaline and extracted with ethyl acetate, the extract is washed and concentrated, then 1 equivalent of citric acid in acetone is added to the concentrate and the mixture is evaporated and dried. The residue is dissolved in a large amount of methyl ethyl ketone and the ketone solution is concentrated to about 300 ml and then cooled to 0 ° C. Filtration and vacuum drying yields the citrate salt of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene.

Example 2

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

To a solution of 5.0 g (0.018 moles) of 1- (4-methoxybenzoyl) -2-tetralon (prepared according to Example 1) in 50 ml of ether, 0.018 moles of phenylmagnesium bromide in 9 ml of ether Was added dropwise at 0 ° C. After the addition, the mixture is stirred for 20 minutes. The reaction mixture is thin layer chromatographed to check for the presence of starting materials. An additional 13.5 ml of phenylmagnesium bromide solution is added and refluxed for 2 hours, then poured into a cooled and ice-cooled ammonium chloride solution. The organic layer is separated, washed with aqueous sodium chloride solution, the mixture is dehydrated with magnesium sulfate, filtered and evaporated to give 5 g of yellow oily material. To get more product, 5 g of tetralon is added and reacted as above. The products are combined and a total of 10 g of oily material is washed with hexane. Chromatography of the insoluble portion in hexanes was performed on a 1 ″ × 20 ″ neutral alumina column using a 1: 1 gradient mixture of benzene: hexane as eluent (gradually reducing the amount of hexane until benzene is 100%). 4.67 g (38%) of 3-phenyl-4- (4-methoxybenzoyl) -1,2-dihydronaphthalene is obtained. The product is recrystallized from methanol.

To a solution of 2.0 g (0.006 mol) of dihydronaphthalene in 10 ml of N, N-dimethylformamide was added a solution of 7.5 mmol of sodium thioethoxide in 15 ml of DMF. The addition reaction is carried out at 80 ° C. under nitrogen gas. The mixture is kept at 80 ° C. for 15 hours and then poured into a cooled, ice-cooled aqueous ammonium solution. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed four times with aqueous sodium chloride solution, and then the ethyl acetate solution was dehydrated with magnesium sulfate and evaporated to obtain an oily substance. This was quickly obtained by using benzene as an eluent. Chromatography on silica column elutes impurities. The product is eluted with ethyl acetate and ethyl acetate is evaporated to yield 1.69 g (88%) of 3-phenyl-4- (4-hydroxybenzoyl) -1,2-dihydronaphthalene as a clear pale yellow oily substance.

A solution of 1.61 g (4.95 mmol) of the product in 10 ml of anhydrous DMF was added dropwise to 20 ml of DMF containing 119 mg (4.95 mmol) of sodium hydride and freshly distilled 1-chloro-2-pyrrolidinoethanol. The dropwise addition is carried out under nitrogen gas while maintaining the temperature below 10 ° C. When boiling is complete, the mixture is heated at 80 ° C. for 2 hours, poured into water, and the total solution is extracted with ether. The ether extract is washed five times with aqueous sodium chloride solution, dehydrated with magnesium sulfate, and the ether layer is filtered and evaporated to yield a white oily material. The oily substance was chromatographed on a silica column (2 ″ × 2 ″) using ethyl acetate, a gradient solution of methanol, to 1.18 g (56%) of 3-phenyl-4- [4- (2-pyrrolidino Oxy) benzoyl] -1,2-dihydronaphthalene is recovered.

The product is converted to the corresponding citrate salt by treatment with a solution of 0.59 g citric acid dissolved in 50 ml of hot acetone. The resulting mixture is evaporated to dryness to afford a residue, which is stirred with ether for 15 hours to give the citrate salt. The salt is dried in vacuo to give 1.62 g (53%) of the title compound.

Example 3

Preparation of citrate salt of 1- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenylnaphthalene

In 30 ml dioxane, 1.90 g (5.58 mmol) 3-phenyl-4- (4-methoxybenzoyl) -1,2-dihydronaphthalene (prepared by Example 3) and 2.00 g (8.81 mmol) 2,3-dihydro-5,6-dicyano-1,4-benzoquinone was added, followed by heating under reflux for 12 hours under nitrogen atmosphere. After cooling the mixture and evaporating to dryness, water and ether were added to the residue, the ether layer was separated, and then washed 5 times with 20 ml of 5N sodium hydroxide and then again with an aqueous sodium chloride solution. The mixture is dehydrated and evaporated on magnesium sulfate to give 1.9 g of substantially pure 1- (4-methoxybenzoyl-2-phenylnaphthalene as green oily material.

Substantially the same demethylation reaction as described in Example 3, 1.83 g (5.41 mmol) of this product was treated with sodium thioethoxide to 1.40 g (80%) of 1- (2-hydroxybenzoyl)- Obtain 2-phenylnaphthalene.

1.25 g (3.86 mg) of the compound was added to 10 ml of DMF, and the mixture was mixed with 20 ml of DMF containing 120 mg (5.0 mmol) of sodium hydride and 800 mg of 1-chloro-2-pyrrolidinoethane. It is added at ℃. When boiling is complete, the mixture is heated at 80 ° C. for 3 hours during which time sodium chloride precipitates. The mixture is cooled and evaporated to dryness. The resulting residue was dissolved in a mixture of ethyl acetate and water, the ethyl acetate layer was separated and washed five times with 25 ml of sodium chloride aqueous solution. The ethyl acetate solution is then dehydrated and evaporated to yield 1.62 g (100% of solution) of 1- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenylnaphthalene as a yellow oily substance.

The free base is converted to the corresponding citrate salt using 0.811 g citric acid hydrate according to the method of Example 3. The title compound is obtained as an amorphous solid and left to crystallize in ether overnight.

Example 4

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

In a solution of about 50 g (0.24 mole) of P-methoxyphenyl magnesium bromide in THF, 30.2 g (0.08 mole) of 1- (P-benzyloxybenzoyl) -6-methoxy-2-tetralone in THF The dissolved solution is added at room temperature. After the addition reaction is completed, the mixture is warmed to 45 ° C. Samples of the mixture are analyzed by TLC to check for the presence of starting materials. The mixture is then poured into aqueous ammonium chloride solution and extracted with ethyl acetate, followed by washing, dehydration and evaporation of the ethyl acetate extract. The resulting residue is dissolved in benzene, and a catalytic amount of P-toluene sulfonic acid is added, followed by TLC, followed by stirring at room temperature until no carbinol intermediate is detected. The mixture is washed with water, dehydrated and evaporated and the residue is chromatographed on 1 kg of alumina with 6 L of benzene. The product is eluted with ethyl acetate in 2% in benzene to give the product 3- (4-methoxyphenyl) -4- (4-benzyloxybenzoyl) -7-methoxy-1,2-dihydronaphthalene in oil.

5.4 g (0.011 mole) of the dihydronaphthalene is added to 150 ml of DMF, followed by 30 ml of DMF containing 0.5 mole of sodium thioethoxide. After the mixture is heated to 90 ° C. in nitrogen gas, the progress of the reaction is examined by TLC. Upon completion of the reaction, the mixture is poured into an aqueous solution of ammonium chloride, the aqueous mixture is extracted with ethyl acetate, and then the ethyl acetate extract is separated, washed, dehydrated and concentrated to obtain an oily substance which is chromatographed on silica using benzene. Fractions containing the desired product, namely 3- (4-methoxyphenyl) -4- (4-hydroxybenzoyl) -7-methoxy-1,2-dihydronaphthalene, were collected and concentrated to give 3.3 g of a yellow oil phase. Get the substance. The product is used for the reaction of the next step.

A solution of 3.2 g of this product in 150 ml of DMF containing 0.25 g of sodium hydride is heated at 40 ° C. on an oil bath for 2 hours. The mixture begins to appear reddish. After heating, the mixture is cooled to room temperature and then 1.2 g of 1-chloro-2-pyrrolidinoethane is added and the mixture is heated to 60 to 70 ° C. for about 1 hour. The resulting solution is then stirred at room temperature overnight, washed several times with a large amount of water and sodium bicarbonate solution, and the ethyl acetate mixture is dehydrated with magnesium sulfate, concentrated and dried to yield 3.2 g of a pale yellow oily substance. This oily material was purified by chromatography on silica using ethyl acetate to give 3.0 g of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-meth Obtain oxy-1,2-dihydronaphthalene.

The free base product (2,9 g) was dissolved in 150 ml of acetone and 1 equivalent of citric acid dissolved in hot acetone was added and then maintained at 0 ° C. for 3 days. The product is not crystallized and the mixture is evaporated and the residue obtained is dissolved in a minimum amount of acetone, then ethyl ether (500 ml) is added and the resulting mixture is stirred overnight. When the product crystallizes, it is collected by filtration and dried in vacuo to give 3.2 g of the title compound.

Claims (1)

The aroyl-phenylnaphthalene derivative of the following formula (VII) is reacted with 1-chloro-2-aminoethane of the following formula (VI) A process for preparing nontoxic acid addition salts thereof.

Wherein X is —CH ₂ —CH ₂ — or —CH═CH— and R is hydrogen or C ₁ -C ₅ alkoxy and R ₁ is hydrogen or C ₁ -C ₅ alkoxy and R ₂ and R ₃ are Each independently is C ₁ -C ₄ alkyl or R ₂ and R ₃ combine with a nitrogen atom to form a heterocyclic ring such as pyrrolidino, piperidino, hexamethyleneimino or morpholino.