CS235057B2 - Method of arylphenylnaphtalen derivatives production - 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 invention relates to a process for the preparation of aroylphenylnaphthalene derivatives which are valuable as anti-fertility and anti-tumor growth agents. Essentially, 1-aroyl-2-tetralones are reacted with phenylmagnesium bromide.

A variety of compounds are known which can be represented by the general formula

«Where

Ar represents an aryl group and

Y may be a variety of functional groups, for example —CH2—, —CH2 —CH2—, —S—, —NH, —OCH2, —Ο—, —CH2-, and —SCH2.

Fertility activity has been described for a number of these substances.

Lednicer et al., J. Med. Chem., 8, (1965), pp. 52-57 disclose 2,3-diphenylindenes and derivatives thereof as anti-fertility drugs.

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, various 1,2-diaryl-3,4-dihydronaphthalenes are described as having similar activity. In addition, U.S. Pat. Nos. 3,274,213, 3,313,853, 3,396,169 and 3,567,737 disclose 1,2-diphenyl-3,4-dihydronaphthalenes as anti-fertility agents. In others. U.S. Patents also disclose both 1,2-diphenyl-3,4-dihydronaphthalenes and 2,3-diphenylindenes as active ingredients in the above sense. For example, U.S. Patent Nos. 3,293,263, 3,320,271,

483 293, 3 519 675, 3 804 851 and 3 862 232.

In Crenshaw et al., J. Med. Chem., 14, (1971), pp. 1185-1190, various 2,3-diarylbenzothiophenes are described as having antifertility activity. Some of these compounds are also described in U.S. Pat. No. 3,412,305. In addition, the authors describe a number of other substances which are structurally related to the basic substances described. 2,3-diarylbenzofurans, which also belong to the class of benzothiophenes, have been described in U.S. Patent No. 3,394,125.

However, other active substances against fertility, in particular of non-steroidal nature, have to be found. The compounds of the present invention, which are represented by Formula I, meet this requirement. It is 3-phenyl-4-aroyl-1,2-di-235057.

Accordingly, the present invention provides a process for the preparation of aroylphenylnaphthalene derivatives of the general formula (I) hydronaphthalene derivatives and 1-aroyl-2-phenylnaphthalene derivatives which differ significantly in their structure from those previously known. It is therefore a major contribution to the pharmacology of non-steroidal anti-fertility drugs.

where

X is -CH 2 -CH 2 - or -CH = CH-

R represents a carbon atom or a methoxy group,

R 1 represents a hydrogen atom or a methoxy group and

R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine residue and citrates of these compounds, characterized in that the substituted tetralone of formula II is reacted

a phenylmagnesium bromide of formula

III (III) where

R1 is as defined above, optionally reacting the product of formula III thus obtained ‘

where

R is as defined above and

Y is methoxy, benzyloxy or wherein Y, R and Rt are as defined above with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at 50-100 ° C to give the corresponding product of formula III “Where

Ra

N-CH ₂ -CH 2 -O-

_R2 and R3 are as defined above, with

wherein R and Rj are as defined above and Y is methoxy or benzyloxy and is reacted with a reagent selected from the group of pyridine hydrochloride or sodium thioethoxide to form compounds of formula IV

where

R, Rt and X are as defined above, followed by reaction with 1-chloro-2-aminoethane of formula V

R ₂

_C1-CH2-CH2-N \

R.3 (V) where

R ₂ and R ₃ are as defined above.

Non-toxic acid addition salts of the compounds of formula I are understood to be organic and inorganic addition salts, for example, salts with hydrochloric, sulfuric, sulfonic, tartaric, fumaric, hydrobromic, glycolic, citric, maleic, phosphoric, succinic, acetic or nitric acids. Preferred addition salts are prepared with citric acid. All salts of this type can be prepared in conventional manner.

A preferred group of compounds of formula I are dihydronaphthalene, i.e. compounds wherein X is -CH ₂ -CH ₂ -.

Among these dihydronaphthalenes, further subgroups are further preferred, for example 7-methoxy-1,2-dihydronaphthalenes, i.e. compounds of formula I wherein X is -CH 2 -CH 2 - and R is methoxy.

Another preferred class of compounds of the present invention are non-hydroxylated or alkoxylated dihydronaphthalenes, i.e., those compounds of formula I wherein X is -CH 2 -CH 2 - and both R and R ₁ are hydrogen.

Another group of preferred compounds of the invention includes 3- (4'-methoxyphenyl) -1,2-dihydronaphthalenes, i.e., those compounds of formula I wherein X is -CH ₂ -CH _{2 -} and R 1 is methoxy.

Another preferred class of compounds that can be prepared by the process of the present invention is 3- (4'-methoxyphenyl) -7-alkoxy-1,2-dihydronaphthalenes, i.e. compounds of formula I wherein X is -CH 2 - CH 2 And both R and Rt are methoxy.

Another preferred group of compounds of the invention are the products of formula I wherein _R2 and R3 form together with the nitrogen atom to which they are attached form a pyrrolidine ring.

The compounds of formula (I) may be prepared as follows.

A) Preparation of compounds wherein X is -CH 2 -CH 2 -

A tetralone of formula V (V) wherein

R is hydrogen or methoxy is reacted with a phenylbenzoate of formula VI

O

(VI) where

Y represents methoxy, benzyloxy or a group

R2 \

N — CH2 — CH2 —O—

R3 where

R2 and R3 are as defined above.

The reaction is usually carried out in the presence of a medium-strong base, for example sodium amide, at room temperature or at room temperature. lower temperature.

The product of this reaction is a substituted tetralone of formula II

where

R and Υ are as defined above.

The substituted tetralone of formula II is then reacted with a Grignard reagent of formula III

(III) where

R 1 represents a hydrogen atom or a methoxy group.

The product of this reaction is 3-phenyl-4-aroyl-1,2-dihydronaphthalene (VII)

where

R, R (and Y are as defined above).

Depending on the meaning of these substituents, the compound of formula VII may be a compound of formula I.

In these cases, where Y is methoxy and R and R are. hydrogen atoms can be reacted with a compound of formula VII with pyrrolidine hydrochloride at reflux to give the corresponding hydroxy compound. This procedure is suitable only when R and Rj are hydrogen, since if any of these substituents would be alkoxy, these groups would be cleaved to form a hydroxyl group.

Once a compound in which Y is a hydroxyl group is formed, it can be reacted with a compound of formula V

R2

CI — CH2 — CH2 — N (V) \

R3 where

R2 and R3 are as defined above to form a compound of formula I.

In those cases where Y in compound VII is methoxy or benzyloxy and R and / or R- ₍ represents alkoxy or benzyloxy, the Y-position can be selectively cleaved by reaction with sodium thioethoxide in N, N-dimethylformamide at a temperature range 80-90 [deg.] C. The selective cleavage procedure can be monitored by preparative chromatography of the reaction mixture and the reaction is complete when almost no or no starting material can be detected.

The resulting product which contains the hydroxyl group at the Y position as the only hydroxyl group in the molecule is then reacted as described above with 1-chloro-2-substituted aminoethane.

It will be appreciated that for any desired structure of the resulting materials, one skilled in the art can readily determine the appropriate sequence of reactions.

BJ Preparation of compounds wherein X is —CH = CH—

These compounds can be easily obtained from the above compounds wherein X is -CH ₂ -CH 2. Selective dehydrogenation of the dihydronaphthalene structure to give the corresponding naphthalene can be accomplished by treating the starting material with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at 50-100 ° C.

The resulting naphthalene can be converted to other naphthalene compounds of Formula I in a similar manner to Step A.

The compounds of formula I are valuable pharmaceuticals. They are effective against fertility, particularly when administered orally in birds and mammals. The compounds of formula I can be used to control fertility in humans and other animals, such as pests. For example, they may be mixed with pest-attractive substances and placed in warehouses that are harmed by unwanted rodents and other small animals such as coyotes, foxes, wolves, jackals, wild dogs and birds such as sparrows and pigeons. In this way, the multiplication of the pests can be largely suppressed. In the same way, the number of birds and small animals on the airfields and their proximity can be reduced by the compounds of the formula I. Equally well, the compounds of formula (I) may be used in areas where these animals cause undesirable epidemics, both in the city and in the countryside.

The compounds of formula (I) may be administered per se or in conventional dosage forms suitable for both oral and parenteral administration. Organic or inorganic solids and / or liquids can be used as suitable carriers in the manufacture of the aforementioned dosage forms. Suitable carriers can be any of those commonly used in the art for this purpose. In particular, the dosage forms may be tablets, granules made from powder form, capsules, suspensions or solutions.

When administered at a sufficiently high effective dose, the compounds of formula (I) act to inhibit pregnancy in mammals. The usual daily dose of this use is in the range of 0.02 to 20 mg / kg animal body weight. A preferred daily dose is in the range of 0.02 to 0.4 mg per kg body weight of the macroorganism.

The invention will be illustrated by the following examples which describe the practical implementation of the process according to the invention.

Example 1

Preparation of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinethoxy) benzoyl] -1,2-dihydronaphthalene citrate

To a suspension of 15.2 g (0.38 mol) of sodium amide in 250 ml of tetrahydrofuran was added 50 g (0.34 mol) of 3-tetralone, the mixture was stirred for 15-20 minutes, and then 78 g of phenyl p-methoxybenzoate in The temperature is kept below 10 ° C and the mixture is stirred overnight at room temperature, then concentrated, water is added to the residue, the aqueous mixture is extracted with ethyl acetate, the ethyl acetate extract is washed and evaporated to dryness. The pure fractions obtained by chromatography are combined and evaporated to dryness, and the residue is dissolved in a small amount of methanol, cooling the methanol and filtering the resulting precipitate to give 35.2 g of 1- (p-). m.p. 88 DEG-91 DEG C. methoxybenzoyl) -2-tetralone.

Analysis calculated for C ^ HH ^ OsO:

% C, 77.12;% H, 5.75; found:

% H, 5.54;% O, 17.32.

Mass spectrum:

theoretical 280, found 280.

18.7 g (0.1 mol) of p-bromoanisole 'was added dropwise in ether to tetrahydrofuran containing 5 drops of 1,2-dibromoethane and 3.6 g (0.15 mol) of magnesium. The reaction takes place almost immediately and the addition is slowly continued, releasing enough heat to heat the reaction mixture to reflux. After the addition is complete, the substituted / hetralone in acetone solution is added dropwise with stirring over 2 hours to the mixture maintained at 40 ° C. The resulting mixture was poured into cooled dilute hydrochloric acid and the resulting solution was extracted with ethyl acetate. The ethyl acetate extract was washed, dried and concentrated to an oil. This liquid is chromatographed on silica eluting with benzene. 8.6 g of starting material are obtained in the form of green-yellow crystals, m.p. 85 DEG-88 DEG C. and 15 g of 3- (4-methoxyphenyl) -4- (4-ethoxybenzyl) -1,2-dihydronaphthalene are obtained in the form of: oily liquid eluting with benzene with 2% ethyl acetate.

Analysis for C 25 H 22 O 3 calculated:

% C, 81.06;% H, 5.99;% O: 12.96; found:

% C, 81.32;% H, 6.13;% O 13.04.

A mixture of 11.1 g (0.03 mol) of the above product, 7.2 g of sodium hydride as a 50% dispersion in oil and 11 ml of ethyl mercaptan in Ν, Ν-dimethylformamide was heated at 65-70 ° C for 2 hours. The mixture was cooled and concentrated, the concentrated mixture was acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dried and evaporated. The residue was dissolved in benzene and chromatographed on silica to give 5 g of an oily liquid consisting of relatively pure 3- (4-methoxyphenyl) -4- (4-hydroxybenzoyl) -1,2-dihydronaphthalene.

Analysis for C 24 H 20 O 3 calculated:

80.88%; C, 5.66; H, 13.47; found:

% C, 79.66;% H, 5.87;% O. 13.57.

4.3 g (0.01 mol) of the above product are dissolved in Ν, Ν-dimethylformamide. To the resulting solution was added 0.7 g of sodium hydride as a 50% dispersion in mineral oil, and the resulting mixture was heated to 40 ° C for one hour and then cooled to room temperature. Then 1.62 grams of 1-chloro-4-pyrrolidinethane was added to the mixture, and the mixture was heated at 60 ° C for 2 hours and then stirred at room temperature overnight. evaporate and water is added to the residue. The aqueous mixture was extracted with ethyl acetate, the ethyl acetate extract was washed and concentrated to a residue which was extracted with hexane. The insoluble matter was dissolved in ethyl acetate and the ethyl acetate solution was extracted with 1 N hydrochloric acid.

The extract was basified and then extracted with ethyl acetate. The ethyl acetate was washed and concentrated and 1 equivalent of citric acid in acetone solution was added to the concentrate, then the mixture was evaporated to dryness. The residue was dissolved in a large volume of methyl ethyl ketone and the resulting solution was concentrated to a volume of 300 mL and then cooled to 0 ° C. Then, the resulting product 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinethoxy) benzoyl] -1,2-dihydronaphthalene citrate, m.p. 82-85 ° C, was collected by filtration and dried in vacuo.

Analysis for C39H39NO10 calculated:

66.96% C, 6.09% H, N 2.17%, O 24.78%;

found:

H, 6.27; N, 2.27; O, 24.54.

Example 2

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

To 300 ml of dimethylformamide was added 107 g of phenyl p-hydroxybenzoate and 26 g of sodium hydride as a 50% dispersion in oil. The mixture was heated at 60 ° C for 2 hours and then 67 g of 1-chloro-2-pyrrolidinone was added and the mixture was stirred at 85 ° C overnight. Most of the dimethylformamide was then evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate.

The ethyl acetate extract was evaporated and the residue was dissolved in a 1: 1 mixture of ether and ethyl acetate. The organic solution was then extracted with 2N hydrochloric acid and the extract was added dropwise to 2N sodium hydroxide. The resulting mixture was extracted with ethyl acetate, the ethyl acetate extract was washed and dried with magnesium sulfate, and then concentrated to give 110 g of crude phenyl p- (2-pyrrolidinethoxy) benzoate.

To a suspension of 20 g (0.5 mol) of sodium amide in tetrahydrofuran was added dropwise

41.7 g of 6-methoxy-2-tetralone in tetrahydrofuran while maintaining the temperature of the mixture below 10 ° C. After the addition was complete, the mixture was stirred at less than 10 ° C for 20 minutes and then allowed to rise to 20 ° C due to the exothermic reaction. The above solution of phenyl-β-β-pyrrolidinethoxybenzotate in tetrahydrofuran was added dropwise to the mixture and the mixture was stirred overnight at room temperature. The mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The ethyl acetate extract was washed several times with water and then dried over magnesium sulfate and evaporated to give 100 g of crude material. This material was dissolved in 1.5 L of acetone, 1 equivalent of citric acid in solution in 400 mL of ethyl acetate was added, and the precipitated solid was collected by filtration and dried in vacuo to give 85.9 grams of product, m.p. 84 ° C. .

This product is 6-methoxy-1- [4- (2-pyrrolidinethoxy) benzoyl] -2-tetralone and not the corresponding citrate. The product is then chromatographed on silica eluting with ethyl acetate and citrate is prepared from the isolated product.

Analysis calculated for C ^ ^H ^NO-n:

% C, 61.53;% H, 6.02;% N, 2.39; found:

% C, 61.39;% H, 5.78;

8.6 g (0.02 mol) of the above product was added to a solution of phenylmagnesium bromide in tetrahydrofuran. The resulting mixture was stirred at room temperature for 1 hour and then heated at 50 ° C for 3 hours. The solution was poured into ice / water / hydrochloric acid and the acidic mixture was extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated to give 10.5 g of a reddish-brown oil which was poured into 500 ml of acetic acid and heated on a steam bath for 30 minutes. The acid was removed, water was added to the residue, the aqueous mixture was basified by addition of a base, and the basified mixture was basified with ethyl acetate. The extract was dried and concentrated to give 8.7 g of product which was dissolved in acetone and 1 equivalent of citric acid was added. The acetone was evaporated and methyl ethyl ketone was added to the residue and the mixture was maintained at 0 ° C overnight. The formed crystals were collected by filtration, washed with cold methyl ethyl ketone and dried in vacuo to give the title product, m.p. 95-100 ° C. This solid was recrystallized from acetone to give a citrate of m.p. 98-100 ° C.

Analysis for C ₃₆ H 9 NO _{3 1} 0 Calculated:

H, 6.09; N, 2.17; O, 24.78; found *

% C, 66.72;% H, 6.27;% N, 2.09;

The resulting free-form material is obtained by treating the citrate with a dilute base.

Analysis for 0> ₍₎ Η _{} 1} Ν0 ₅ calculated:

% C, 79.44;% H, 6.89;% N, 3.09; found:

H, 6.68; N, 2.91.

Example 3

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

To a solution of 5.0 g (0.018 mol) of 1- (4-methoxybenzoyl) -2-tetralone prepared according to Example 1 in 50 ml of ether was added dropwise at 0 ° C a solution of 0.018 mol of phenylmagnesium bromide in 9 ml of ether. After the addition was complete, the mixture was stirred for 20 minutes. Preparative chromatography still showed starting materials. 13.5 ml of phenylmagnesium bromide solution are added and the mixture is refluxed for 2 hours, cooled and poured into a mixture of ice and aqueous ammonium chloride solution. The organic layer was separated and washed with brine. The mixture was dried over magnesium sulfate, filtered and evaporated to 5 g of a yellow oil.

A further proportion of the resulting product can be obtained by reacting 5.0 g of tetralone in the same manner as above. The two portions of the product were combined and a total of 10 g of the oil was washed with hexane, the insoluble material was chromatographed on a 2.5 x 50 cm neutral alumina column, eluting initially with 1: 1 benzene / hexane, followed by 1: 1. The hexane was gradually reduced until the column was eluted with 100% benzene to give 4.67 g (38%) of 3-phenyl-4- (4-methoxybenzoyl) -1,2-dihydronaphthalene (38%). After recrystallization from methanol, the product has a melting point of 106-107 ° C.

Analysis for C 24 H 20 O 2 calculated:

% C, 84.68;% H, 5.92;

% C, 84.96;% H, 6.13 ^; O.

Mass spectrum;

theoretical 340, found 340.

To 2.0 g (0.006 mol) of the above dihydronaphthalene in solution in 10 ml of N, N-dimethylformamide was added 7.5 mmol of sodium thioethoxide in 15 ml of dimethylformamide. The addition was carried out at 80 degrees Celsius under a nitrogen atmosphere, then the mixture was maintained at 80 DEG C. for a further 15 hours, then cooled and poured into a mixture of ice and aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed four times with aqueous sodium chloride solution, then dried over magnesium sulfate and evaporated to an oil which was chromatographed quickly on a 5x5 cm silica column using benzene to remove impurities. The product was then eluted with ethyl acetate to give 3-phenyl-4- (4-hydroxybenzoyl) -1,2-dihydronaphthalene as a clear yellow oil after evaporation of ethyl acetate in 88 why.

Mass spectrum:

theoretical 326, found 326.

A mixture of 1.61 g (4.95 mmol) of the above product in 10 ml of anhydrous dimethylformamide was added dropwise to 20 ml of dimethylformamide containing 119 mg (4.95 mmol) of sodium hydride and freshly distilled 1-chloro-2-pyrrolidinethane. The addition was carried out under a nitrogen atmosphere while maintaining the temperature at 10 ° C. Once gas evolution ceased, the mixture was heated to 80 ° C for 2 hours. The mixture was poured into water and extracted with ether. The ethereal extract was washed 5 times with aqueous sodium chloride solution and dried over magnesium sulfate. The ether layer was collected by filtration and evaporated to a gray oil which was chromatographed on a 5x5 cm silica column using ethyl acetate / methanol incrementally increasing the methanol to 100% to yield a yield. 56% 1.18 g of 3-phenyl-4- [4- (2-pyrrolidinethoxy) benzoyl-1,2-dihydronaphthalene.

Mass spectrum:

theoretical 423, found 423.

The product is converted to the corresponding citrate by treatment with 0.59 g of citric acid in 50 ml of hot acetone. The resulting mixture was evaporated to dryness and the residue was stirred with ether for 15 hours to give the citrate which was dried in vacuo. Yield 1.62 g (53%), m.p. 89-93 ° C.

Analysis for C 33 H 37 NO 9. 1/2 H ₂ O calculated:

67.34% C, 6.13% I-I, 2.25% N; found:

% H, 6.41;% N, 2.66.

Example 4

Production of 1- [4- (2-pyrrolidinethoxy) benzoyl] -2-phenylnaphthalene citrate

To 30 ml of dioxane was added 1.90 g (5.58 mmol) of 3-phenyl-4- (4-methoxybenzoyl) -1,2235057

dihydronaphthalene, prepared according to Example 3, and 2.00 g (8.81 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The resulting mixture was refluxed under nitrogen for 12 hours. The mixture was cooled and evaporated to dryness. Water and ether were added to the residue, the ether layer was separated and washed with 5 x 20 mL of 5 N sodium hydroxide followed by brine, then dried over magnesium sulfate and evaporated to give 1.9 g of substantially pure 1- ( 4-methoxybenzoyl) -2-phenylnaphthalene as a green oil.

Using essentially the same demethylation method as in Example 3, 1.83 g (5.41 mmol) of the thus obtained sodium thioethoxide product are treated, yielding 1.40 g of 1- [4-hydroxybenzoyl) in 80% yield. M.p. 204-205 ° C.

Analysis for C23H16O2 calculated:

% C, 85.16;% H, 4.97; found:

84.99% C, 5.12% II, 9.58% O.

To 10 ml of dimethylformamide was added 1.25 grams (3.86 mmol) of the above product. The resulting mixture was added at a temperature of 10 ° C to a mixture of 20 ml of dimethylformamide, 120 mg (5.0 mmol) of sodium hydride and 800 mg of 1-chloro-2-pyrrolididineethane. Once gas evolution ceased, the mixture was heated to 80 ° C for 3 hours. During this time, sodium chloride precipitated, the mixture was then 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 with 5 x 25 mL aqueous sodium chloride solution. The ethyl acetate solution was dried and evaporated to give 1.62 g of 1- [4- (2-pyrrolidinethoxy) benzoyl] phenylnaphthalene as a yellow oil (100% yield).

The free material thus obtained was converted to the corresponding citrate by the method of Example 3, using 0.811 g of citric acid hydrate. Upon standing overnight, the title compound was obtained as an amorphous solid, m.p.

Analysis for C ^ HH ^NOg. H2O calculated:

65.55% C, 5.90% H, 2.22 '% ^N; found:

% C, 66.90;% H, 5.85;% N, 2.25.

Example 5

Preparation of 3- (4-methoxyphenyl) -4- (4- (2-pyrrolidinethoxy) benzoyl) -7-methoxy-1,2-dihydronaphthalene citrate

To a solution of 50 g (0.24 mol) of p-methoxyphenylmagnesium bromide in tetrahydrofuran at room temperature 30.2 g (0.08 mol) of 1- (p-benzyloxybenzoyl) -6-methoxy-2-tetralone in tetrahydrofuran solution. After the addition was complete, the mixture was heated to 45 ° C.

Analysis of the sample by preparative chromatography showed the absence of starting material. The mixture was poured into aqueous ammonium chloride solution and the resulting solution was extracted with ethyl acetate, the ethyl acetate extract was washed, dried and evaporated. The resulting residue was dissolved in benzene and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred at room temperature until preparative chromatography of the reaction mixture showed the absence of any carbinol-like intermediate. The mixture was then washed with water, dried and evaporated to dryness. The residue is chromatographed on 1 kg of alumina using 6 liters of benzene. The product was eluted with a mixture of benzene and 2% ethyl acetate. The resulting product 3- (4-methoxyphenyl) -4- (4-benzyloxybenzoyl) -7-methoxy-1,2-dihydronaphthalene was obtained as an oil.

Analysis for C32H28O4 calculated:

C 80.65; H 5.92; O 13.43; found:

% C, 80.96;% H, 5.91;% O. 13.61.

To 150 ml of Ν, sv-dimethylformamide was added 5.4 g (0.011 mol) of the above dihydronaphthalene. 30 ml of dimethylformamide containing 0.5 mol of sodium thioethoxide are added to the mixture. The resulting mixture was heated to 90 degrees Celsius under nitrogen. The progress of the reaction was monitored by preparative chromatography. After completion of the reaction, the reaction mixture was poured into aqueous ammonium chloride solution. The aqueous mixture was extracted with ethyl acetate, the ethyl acetate extract was separated, washed, dried and concentrated to an oil which was chromatographed on silica using benzene as eluent.

Fractions containing 3- [4-methoxyphenyl) -4- (4-hydroxybenzoyl) -7-methoxy-1,2-hydronaphthalene as the final product were combined and evaporated to dryness to give 3.3 g of a yellow oil. which was used in the next step without further purification.

A mixture of 3.2 g of the above product in 150 ml of dimethylformamide containing 0.25 g of sodium hydride was heated in an oil bath at 40 ° C for 2 hours. After this time the mixture turns red. After heating was complete, the mixture was cooled to room temperature, 1.2 g of 1-chloro-2-pyrrolidinethane was added and the mixture was heated at 60-70 ° C for 1 hour. The resulting mixture was stirred overnight at room temperature, then poured into a large amount of water and the aqueous mixture was shaken with ethyl acetate ex235057. The ethyl acetate extract was washed several times with water and sodium bicarbonate solution. The ethyl acetate mixture was then dehydrated with magnesium sulfate and then evaporated to dryness to give 3.2 g of a pale yellow oil.

The liquid was purified by chromatography on silica eluting with ethyl acetate to give 3.0 grams of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidimethoxy) benzoyl] -7-methoxy-1; 2-dihydronaphthalene. The above free compound (2.9 g) was dissolved in 150 ml of acetone and 1 equivalent of citric acid in solution in hot acetone was added. The mixture is kept at 0 ° C for 3 days, yet the product does not crystallize. The reaction mixture was evaporated and the residue was dissolved in a small amount of acetone, 500 mL of ethyl ether was added and the resulting mixture was stirred overnight. The crystallized product was collected by filtration and dried in vacuo to give 3.2 g of the title compound.

Analysis for C37H41NO11 calculated:

H, 6.12; N, 2.07; found:

H, 6.10; N, 2.28.

The compounds of formula I have been tested in rats for their anti-fertility activity before and after mating of females.

In the anti-fertility test prior to mating, 50 young adult female rats weighing 200-230 g, previously kept separate from males, were divided into 10 groups of 5 females. One group was control, the other 9 were experimental. Each of the treatment groups was dosed with the test substance. For this purpose, the active substance was mixed with corn oil so that the daily dose was contained in 0.1 ml of this oil. This amount was administered subcutaneously to each rat. The control group received only corn oil. Administration of corn oil and a mixture of maize о1е ₃ е with the test substance was performed daily for 15 days. On day 5, 2 adult male rats weighing at least 250 g were added to each group of females and kept in groups until day 15, when they were separated from the treatment groups again. Each group of females was sacrificed after a further 7 days and the rats were examined for the presence of viable or resorptive germs.

The pregnancy index is the number of animals with fetuses in proportion to the number of animals in the group. The substance is effective if this index is 0/5 or 1/5. A ratio of 2/5 represents a cut-off value, at a higher value the compound is completely ineffective.

In the test for the efficacy of the compound of the invention after admission of the females, rat females weighing at least 200 g, which have so far been kept separate from males, were used. These rats were housed with a male and examined daily to detect the presence of semen in the rat vagina. Then the males were removed and the active ingredient was administered daily for 11 days. On day 12, the rats were sacrificed and examined for the presence of viable or resident germs.

The pregnancy index is expressed by the number of pregnant animals per number of animals in the group. Since all rats were allowed, the values for the control group are high. For this reason, with a 50% decrease, considerable efficacy of the test substance is already considered.

In addition, the total number of viable fetuses and the total number of fetuses that are absorbed as fertility and implantation data are reported. For the control groups, the number of viable fetuses is usually 11 or 12, any decrease in number indicating the efficacy of the test substance.

The following table shows the activity of the compounds of the formula I against fertility.

Table

Efficacy against fertility

Ol Ol от 1 Ol X E Я o I CJ I ω AND O II ω 1 1 Я 1 Ol 1 Ol II Я Г Ί 1 Ol Д O 1 CJ 1 O 1 1 O 1

CQ cd я 4d 'cd O я 'cd CD > cd > cd > cd ri o ri o ^q g G О Д Он .s К S a , s к ri Ό ri Ό 3 S ri Ό ri Д Д X o 2 ^ω Д СЛ Q СЛ o ω r. о

Claims (5)

A process for the preparation of aroylphenylnaphthalene derivatives of the general formula I wherein X is -CH ₂ -CH ₉ - or -CH = CH- R represents a carbon atom or a methoxy group, R 1 represents a hydrogen atom or a methoxy group; R 2 and R 5 together with the nitrogen atom to which they are attached form a pyrrolidine residue and the citrates of these compounds, characterized in that the reacted tetralene of formula II is reacted wherein: R is as defined above and Y is methoxy, benzyloxy or r &_lt; ₂ &_gt; N-CH ₂ -CH ₂ -O- Rb where R ₂ and R ₃ are as defined above, with a phenyl magnesium bromide of formula III wherein R _{@ 1} is as defined above, optionally reacting the product thus obtained, wherein Y, R _@ 1 and R _{@ 1} are as defined above with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at a temperature of from 50 to 50 DEG C. 100 ° C to give the corresponding product of formula III "wherein R and R 1 are as defined above and Y is methoxy or benzyloxy and is reacted with a reagent selected from pyridine hydrochloride or sodium thioethoxide to form compounds of formula IV ( IV) where R, R а X are as hereinbefore defined, followed by reaction with l-chloro-2-aminoethane of the formula V R ₂ / Cl-CH ₂ -CH ₂ -Ν (V) \ R ₃ where R ₂ and R ₃ are as defined above, and optionally followed by reaction with citric acid. 2. A process according to claim 1 for the preparation of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinethoxy) -benzoyl] -1,2-dihydronaphthalene or citrate thereof, characterized in that it is reacted in reaction 1. - (4-methoxybenzoyl) -2-tetralone with 4-methoxyphenylmagnesium bromide followed by reaction with sodium thioethoxide and then with 1-chloro-2-pyrrolidinethane and optionally with citric acid. 3. A process according to claim 1 for the preparation of 3-phenyl-4- [4- (2-pyrrolidinethoxy) benzoyl] -1,2-dihydronaphthalene or a citrate thereof, characterized in that it is reacted with 1- (4-methoxybenzoyl) -. 2-tetralone with phenylmagnesium bromide followed by reaction with sodium thioethoxide and then with 1-chloro-2-pyrrolidinethane and optionally with citric acid. 4. A process according to claim 1 for the preparation of 1- [4- (2-pyrrolidinethoxy) benzoyl] -2-phenylnaphthalene or citrate thereof, characterized in that 1- (4-methoxybenzoyl) -2-tetralone is reacted and phenylmagnesium bromide followed by reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and then with sodium thioethoxide, then 1-chloro-2-pyrrolidinethane and optionally with citric acid. 5. A process according to claim 1 for the preparation of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinethoxy} benzoyl] -7-methoxy-1,2-dihydronaphthalene or citrate thereof, characterized in that by reacting 1- (4-benzyloxybenzoyl) -6-methoxy-2-tetralone with 4-methoxyphenylmagnesium bromide, then with sodium thioethoxide and then with 1-chloro-2-pyrrolidinethane and optionally with citric acid.