CH624376A5 - Process for the preparation of aroylphenylnaphthalenes - Google Patents

Description

The invention relates to a process for the preparation of new derivatives of aroylphenylnaphthalenes which are suitable, for example, as fertility inhibitors and antitumor agents, and this process consists in reacting a naphthalene derivative with an 1-chloro-2-aminoethane.

Various classes of compounds are known which have the general formula

Ar1

Ar "

where Ar is aryl and Y is any one of different groups such as -CH2—, -CH2-CH2—, -S—,

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-NH, —OCH2—, —O—, -CH2S— or -SCH2—. A number of compounds from these general classes have an anti-fertility effect.

In J. Med. Chem. 8 (1965), pages 52 to 57, 2,3-diphenylindens and derivatives thereof are described which are fertility inhibitors.

From J. Med. Chem. 9 (1966), pages 172 to 175; J. Med. Chem. 10 (1967), pages 78 to 84, and J. Med Chem. 8 (1965), pages 213 to 214, each show various 1,2-diaryl-2,4-dihydronaphthalenes, which also have an anti-fertility effect. Various 1,2-di-phenyl-3,4-dihydronaphthalenes are known from US Pat. Nos. 3274213, 3 313 853, 3 396 169 and 3 567 737 which show an anti-fertility effect.

In other US patents, 1,2-diphenyl-3,4-dihydro-naphthalenes and 2,3-diphenylindens are described as anti-fertility agents. These include US Pat. Nos. 3,293,263, 3,320,271, 3,483,293, 3,519,675, 3,804,851 and 3,862,232. From J. Med. Chem. 14 (1971), pages 1185 to 1190

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various 2,3-diarybenzothiophenes with fertility-inhibiting effects can be seen. Certain compounds thereof are described in U.S. Patent 3,413,305. From the above reference J. Med. Chem. 14 (1971), pages 1185 to 1190, other compounds are also known which fall under the classes of compounds mentioned at the outset. 2,3-Diarylbenzofurans, which generally correspond to the benzothiophenes noted above, are described in U.S. Patent 3,394,125.

However, there is still a need for other compounds with an anti-fertility effect, particularly fertility inhibitors that are not steroids. This

The new aroylphenylnaphthalenes which can be prepared according to the invention meet the requirements of the formula I given below. These are 3-phenyl-4-aroyl-l, 2-di-hydronaphthalenes and l-aroyl-2-phenylnaphthalenes, and 5 these compounds are structurally very different from the known compounds mentioned above. The object of the invention is therefore to provide a method for producing new compounds with an anti-fertility effect which do not belong to the class of steroids.

The object is achieved according to the invention by a process for the preparation of new aroylphenylnaphthalenes of the formula 1

o ^

11 '\

II II

"WY \,

bliss

X represents -CH2-CH2-or-CH = CH-,

R is hydrogen or Q-C5 alkoxy, Ri is hydrogen or C1-Cs alkoxy and the substituents R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidino group,

and the pharmaceutically acceptable non-toxic acid addition salts thereof, which is characterized in that a compound of formula VIII

(VIII)

1

wherein

X, R and Rt have the meaning given above, with an l-chloro-2-aminoethane of the formula IV

/ r2

cl-ch -ch -n

2 2 \

(iv)

wherein the substituents R2 and R3 have the meanings given above, brings to reaction and compounds of the formula I obtained are optionally converted into the pharmaceutically acceptable non-toxic acid addition salts.

Pharmaceutically acceptable, non-toxic acid addition salts of the compounds of formula I above

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the addition salts of organic and inorganic 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. The salts of citric acid are preferred. Such salts are prepared by customary methods.

Cr-C5 alkoxy is normally understood to mean straight-chain and branched alkyl groups, and examples of these are methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, tert.-butyloxy, sec.-butyloxy, n-amyloxy , Isoamyloxy, tert.-amyloxy or sec.-amyloxy. Methoxy is particularly preferred.

A preferred subclass of the compounds of the formula I are the dihydronaphthalenes, namely those compounds of the above formula in which X is -CH2-CH2-.

There are several preferred subclasses of these dihydronaphthalenes. Such a subclass are the 7-alk-oxy-1,2-dihydronaphthalenes, namely those compounds of the formula I in which X denotes the group -CH2-CH2- and R represents C1-C5 alkoxy.

Another subclass are the non-hydroxylated or alkoxylated dihydronaphthalenes, namely those compounds of the formula I in which X is -CH2-CH2—

stands and both substituents R and Rt are hydrogen.

Another subclass includes the 3- (4'-alkoxyphenyl) -1, 2-dihydronaphthalenes, namely those compounds of the formula I in which X is -CH2-CH2- and Rj is Cj-Cs alkoxy.

A further preferred subclass are the 3- (4'-alkoxyphenyl) -7-alkoxy-l, 2-dihydronaphthalenes, namely those compounds of the formula I in which X represents -CH2-CH2 and the substituents R and Rt in each case Q-C5 mean alkoxy.

Another preferred subclass includes those compounds of formula I in which the substituents R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidino ring.

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The compounds of the formula I can be prepared by the following reaction sequence:

A. Preparation of compounds of the formula I in which X is —CH2-CH2—. For this purpose, a tetraion of the formula V

f Y Y

b / w

(V)

bliss

Ra is hydrogen, C! -C5 alkoxy or benzyloxy, with a phenyl benzoate of the formula VI

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is

I / x v /

ro

(VI)

wherein

R,

Y for methoxy, benzyloxy or N-CH2-CH2-0—

R f is and the substituents R2 and R3 have the meanings given above, are reacted.

The reaction is generally carried out in the presence of a moderately strong base, such as sodium amide, at room temperature or below.

A substituted tetraion of the formula II is usually obtained as the reaction product

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i

= 0

7 Y Y

v / V /

(II)

This substituted tetraion of the formula (II) can then be obtained under Grignard reaction conditions using a Grignard reagent of the formula III

R.a- \ / —1 *> Br (III>

wherein

Ria represents hydrogen, Q-Cj alkoxy or benzyloxy.

This generally gives a 3-phenyl-4-aroyl-1,2-dihydronaphthalene of the formula VII

R / V V

(VII)

depending on the identity of the radicals Ra, Rla and Y, it can also be a compound of the formula I.

In those cases in which Y is methoxy and the substituents Ra and Rla are hydrogen, the corresponding hydroxy compound can be obtained by treating the compound of the formula (VII) with pyridine hydrochloride at reflux temperature. However, as stated, this method can generally only be applied to those compounds in which the substituents Ra and Ria are each hydrogen, since in the case of compounds in which the substituents Ra and / or Rla would represent alkoxy or benzyloxy, these groups would be split to form hydroxyl residues.

By treating those compounds of the above type where Y is hydroxy with a compound of formula IV

r_

ci-ch2-ch2-n

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/ \

(iv)

in which the substituents R2 and R3 have the meanings given above, compounds of the formula (I) are obtained.

In those cases where Y in the compounds of the formula (VII) is methoxy or benzyloxy and the substituents Ra and / or Rla are alkoxy or benzyloxy, the substituent Y can usually be split off selectively by reacting such a compound with sodium thioethoxide in N, N-dimethylformamide at a moderately elevated temperature of about 80 to 90 ° C. The course of the selective cleavage can be monitored, for example, by periodic thin-layer chromatographic analysis (TLC) of the reaction mixture. The reaction is usually complete as soon as little or no starting material is available.

The product obtained in the above manner, which contains the hydroxyl group in position Y as the only hydroxyl group in the molecule, is then reacted with an 1-chloro-2-substituted aminoethane in the manner according to the invention.

Depending on the structure desired in the end product, the compound containing the 2-aminoethoxy substituents can then be reacted further with sodium thioethoxide in N, N-dimethylformamide in the manner described above, in order in this way to obtain any z. B. cleave off existing alkoxy or benzyloxy groups and so form those compounds of formula I in which R and / or Rt are each hydroxy.

The particular particular sequence of synthetic steps for the preparation of a compound with certain substituents at certain positions is normally familiar to the person skilled in the art.

B. Preparation of compounds of formula I in which X is -CH = CH-

These compounds can usually be readily prepared from the above-mentioned compounds in which X is -CH2-CH2-. The selective dehydrogenation of the dihydronaphthalene structure with the formation of the corresponding naphthalene can be achieved by, for example, the first-mentioned compounds at a temperature of about 50 to 100 ° C. with 2,3-dichloro-5,6-dicyano-l, 4-benzo-quinone (DDQ) treated.

The derivatization reactions given above can then usually be used to convert the naphthalene derivative obtained in this way into other naphthalene compounds of the formula (I).

The compounds of the formula (I) which can be prepared according to the invention are generally valuable medicinal products. They are usually primarily characterized by an anti-fertility effect and are therefore particularly suitable as orally active anti-fertility agents in birds and mammals. The compounds of the formula (I) which can be prepared according to the invention can therefore be suitable for controlling the animal population and as contraceptives in living beings. Furthermore, these compounds can also be used, for example, to control harmful animals. For this purpose, these compounds can be formulated, for example, in combination with baits and / or attractants and brought to feed points to which undesirable rodents or other small animals go, for example Canidae, such as coyotes, foxes, wolves, jackals and wild dogs, and birds, such as starlings, Gulls, swamp horde birds or pigeons, in order to greatly reduce the respective population. Because of their activity, the compounds of formula (I) which can be prepared according to the invention can be used to reduce the risk to air traffic by reducing the bird and animal population on taxiways and in the vicinity of airfields. Furthermore, these compounds which can be produced according to the invention can usually be used to reduce the population of undesirable birds and animals, in order to prevent diseases and their spread, and they can be used to reduce damage to buildings in rural and urban areas.

The compounds of formula (I) which can be prepared according to the invention can be administered as such, or they can also be administered orally or parenterally in unit dosage form after appropriate compounding and formulation into pharmaceutical preparations. Organic or inorganic solids and / or liquids, which are pharmaceutically acceptable carriers, can be used for compounding or formulation. Suitable carrier materials for this purpose are generally known to the person skilled in the art. Appropriate preparations can be processed into tablets, powder granules, capsules, suspensions or solutions.

When administered in an effective amount, the compounds of the formula (I) which can be prepared according to the invention normally lead to a pregnancy block in mammals. The usual daily dose can be about 0.02 to 20 mg of active ingredient per kilogram of body weight of the recipient. The preferred daily dose can be about 0.02 to 0.4 mg per kilogram of body weight of the recipient.

Individual examples of compounds of the formula (I) are as follows:

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3- (4-isopropoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) -

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

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

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

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

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

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

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

1,2-dihydronaphthalene; l- [4- (2-Pyrrolidinoethoxy) benzoyl] -2- (4-n-propoxy-

phenyl) naphthalene; l- [4- (2-Pyrrolidinoethoxy) benzoyl] -2- (4-isopropoxy-

phenyl) naphthalene; l- [4- (2-Pyrrolidinoethoxy) benzoyl] -2- (4-t-butyloxy-

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

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

l- [4- (2-Pyrrolidinoethoxy) benzoyl] -2- (4-isopropoxy-

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

1- [4- (2-Pyrrolidinoethoxy) benzoyl] -2-phenyl-6-ethoxy-naphthalene.

The invention is further illustrated by the following examples.

example 1

3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene citrate A suspension of 15.2 g (0.38 mol) sodium amide in 250 ml tetrahydrofuran (THF) 50 g (0.34 mol) / i-tetralone are added. The mixture is stirred for 15 to 20 minutes and then 78 g of phenyl p-methoxybenzoate, dissolved in THF, are added. The temperature is kept below 10 ° C and the mixture is then stirred overnight at room temperature. The reaction mixture is then concentrated and water is added to the residue. The aqueous mixture is extracted with ethyl acetate, and the ethyl acetate extract is washed and concentrated. The residue is then chromatographed on silicon dioxide using benzene as the eluent. The purer fractions obtained in the chromatographic separation are combined and concentrated, whereupon the residue obtained is dissolved in a minimal amount of methanol. Subsequent cooling and subsequent filtration of the methanol solution gives 35.2 g of l- (p-methoxybenzoyl) -2-tetralone, which melts at 88 to 91 ° C. Analysis for C18H1603:

calculated: C 77.12 H 5.75 O 17.12 found: C 77.08 H 5.54 O 17.32 mass spectrum: calculated 280; found 280. p-Bromanisole (18.7 g; 0.1 mol) is added dropwise in ether to THF which contains 5 drops of 1,2-dibromoethane and 3.6 g (0.15 mol) of magnesium. A reaction occurs almost immediately and the addition is then continued so slowly that the heat generated is sufficient to maintain a general reflux. When the addition is complete, the whole is then added dropwise with stirring over a period of two hours with the above substituted / 3-tetralone in the form of a solution in acetone, where 5

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keeping the temperature of the mixture at 40 ° C. The mixture obtained is then stirred in the cold and diluted with hydrochloric acid, whereupon the acidic mixture is extracted with ethyl acetate. The ethyl acetate extract is washed, dried and concentrated to an oil. The oil obtained is chromatographed on silica gel using benzene as the eluent. This gives 8.6 g of starting material in the form of greenish-yellow crystals which melt at 86 to 88 ° C., and 15 g of 3- (4-methoxyphenyl) -4- (4-methoxybenzoyl) -l, 2-dihydronaphtha-lin in the form an oil after elution of the column with a mixture of benzene containing 2% ethyl acetate.

Analysis for C25H22O3:

calculated: C 81.06 H 5.99 O 12.96 found: C 81.32 H 6.13 O 13.04 from 11.1 g (0.03 mol) of the above dimethoxy product, 7.2 g sodium hydride (50 % dispersion in oil) and 11 ml of ethyl mercaptan in N, N-dimethylformamide, a mixture is prepared. The mixture is heated to 65 to 70 ° C for two hours. The mixture is then cooled and concentrated. The concentrate is acidified and extracted with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated. The residue is dissolved in benzene, and subsequent chromatography of this solution over silica gel gives 5 g of an oil of relatively pure 3- (4-methoxyphenyl) -4- (4-hydroxybenzoyl) -1,2-dihydronaphthalene.

Analysis for C24H20O3:

calculated: C 80.88 H 5.66 O 13.47 found: C 79.66 H 5.87 O 13.57 The above phenol product (4.3 g, 0.01 mol) is dissolved in N, N-dimethylformamide . 0.7 g of sodium hydride (50% dispersion in mineral oil) is added to the solution, whereupon the mixture obtained is heated to 40 ° C. for one hour and then cooled to room temperature. The mixture is then mixed with 1.62 g of l-chloro-2-pyrrolidinoethane, whereupon it is heated to 60 ° C. for two hours and then stirred at room temperature overnight. The mixture is then concentrated and water is added to the residue obtained. The aqueous mixture is then extracted with ethyl acetate. Subsequent washing and subsequent concentration of the ethyl acetate extract gives a residue. The residue is extracted with hexane, whereupon the insoluble portion is dissolved in ethyl acetate and the ethyl acetate solution is extracted with in hydrochloric acid. The acid extract is made alkaline and then extracted with ethyl acetate. The ethyl acetate extract is washed and concentrated. The concentrate is then mixed with an equivalent of citric acid in acetone, whereupon the mixture is evaporated to dryness. The residue is dissolved in a large volume of methyl ethyl ketone. The ketone solution is concentrated to about 300 ml and then cooled to 0 ° C. Subsequent filtration and subsequent vacuum drying of the product thus obtained gives 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene citrate, which is at 82 to 85 ° C melts. Analysis for C36H39NO10:

calculated: C 66.96 H 6.09 N 2.17 O 24.78 found: C 66.70 H 6.27 N 2.27 O 24.54

Example 2

3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene citrate A solution of 5.0 g (0.018 mol) l- (4-methoxybenzoyl) -2-tetralone (prepared according to Example 1) in 50 ml of ether is added dropwise at a temperature of 0 ° C with a solution of 0.018 mol of phenylmagnesium bromide in 9 ml of ether. When the addition is complete, the mixture is stirred for 20 minutes. A thin-layer chromatographic examination of the reaction mixture shows that starting material is still present. A further 13.5 ml of the phenyl magnesium bromide solution are then added. The mixture is then heated to reflux temperature for two hours,

then cooled and poured into an ice-cooled aqueous ammonium chloride solution. The organic layer is separated and washed with aqueous sodium chloride solution. The mixture is then dried over magnesium sulfate, filtered and evaporated to give about 5 g of a yellow oil. To produce further product, a second amount of 5.0 g of tetraion is reacted in the above manner. The products are combined and the total amount of about 10 g of oil is washed with hexane. The portion insoluble in hexane is chromatographed on a column filled with neutral aluminum oxide and about 2.5 x 50 cm in size, using a 1: 1 mixture of benzene and hexane as gradient, the hexane content of which is continuously reduced until only 100 % Benzene are present. In this way, 4.67 g (38%) of 3-phenyl-4- (4-methoxybenzoyl) -1, 2-dihydronaphthalene are obtained. The material obtained after recrystallization from methanol melts at 106 to 107 ° C analysis for C24H20O2:

calculated: C 84.68 H 5.92 O 9.40

found: C 84.96 H 6.13 O 9.65

Mass spectrum: calculated 340; found 340.

2.0 g (0.006 mol) of the above dihydronaphthalene, dissolved in 10 ml of N, N-dimethylformamide, are mixed with 7.5 mmol of sodium thioethoxide in 15 ml of DMF. The addition is carried out under a nitrogen atmosphere at a temperature of 80 ° C. The mixture is then kept at 80 ° C. for 15 hours. The mixture is then cooled and poured into an aqueous ammonium chloride solution containing ice. The resulting mixture is then extracted with ethyl acetate, whereupon the ethyl acetate extract is washed four times with aqueous sodium chloride solution. The ethyl acetate extract is dried over magnesium sulfate and evaporated to give an oil. This oil is rapidly chromatographed over a 5 x 5 cm silica gel acid using benzene to elute the contaminant. Subsequent elution of the product with ethyl acetate and subsequent evaporation of the ethyl acetate gives 1.69 g (88%) of 3-phenyl-4- (4-hydroxybenzoyl) -1, 2-dihydronaphthalene in the form of a clear, pale yellow oil.

Mass spectrum: calculated 326, found 326.

A mixture of 1.61 g (4.95 mmol) of the above product in 10 ml of dry DMF is added dropwise to 20 ml of DMF containing 119 mg (4.95 mmol) of sodium hydride and 800 ml of freshly distilled 1-chloro-2 contains pyrrolidinoethane. The addition is carried out under a nitrogen atmosphere at a temperature of about 10 ° C. The mixture obtained after foam formation has ceased is heated to 80 ° C. for two hours. Then the mixture is poured into water and the whole is extracted with ether. The ether extract is washed five times with aqueous sodium chloride solution and then dried over magnesium sulfate. The ether layer is then filtered and then evaporated to a gray oil. The oil obtained in this way is then chromatographed on a 5 × 5 cm silica gel column using an ethyl acetate-methanol gradient. This gives 1.18 g (56%) of 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -1,2-dihydronaphthalene.

Mass spectrum: calculated 423, found 423.

The product obtained in this way is then converted into the corresponding citrate salt by treatment with 0.59 g of citric acid in 50 ml of hot acetone. For this purpose, the mixture obtained is evaporated to dryness and the back 5 is stirred

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stood for 15 minutes with ether, which gives the citrate salt. Subsequent vacuum drying of this salt gives 1.62 g (53%) of the title compound, which melts at 89 to 93 ° C.

Analysis for C33H37N09- V2H2O:

calculated: C 67.34 H 6.13 N 2.25 found: C 67.06 H 6.41 N 2.66

Example 3

i- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenylnaphthalene citrate 30 ml of dioxane are mixed with 1.90 g (5.58 mmol) of 3-phenyl-4- (4-methoxybenzoyl) -l, 2-dihydronaphthalene (prepared according to Example 3) and 2.00 g (8.81 mmol) of 2,3-dichloro-5,6-di-cyano-l, 4-benzoquinone were added. The resulting mixture is heated to reflux temperature in a nitrogen atmosphere for 12 hours. The mixture is then cooled and evaporated to dryness. The residue is mixed with ether and water. The ether layer is separated off and washed five times with 20 ml of 5N sodium hydroxide solution and then with aqueous sodium chloride solution. Subsequent drying over magnesium sulfate and subsequent evaporation of the mixture gives 1.9 g of essentially pure l- (4-methoxybenzoyl) -2-phenylnaphthalene in the form of a green oil.

Using practically the same demethylation procedure as in Example 3, by treating 1.83 g (5.41 mmol) of the above product with sodium thioethoxide, 1.40 g (80%) of 1- (4-hydroxybenzoyl) - 2-phe-nylnaphthalene, which melts at 204 to 205 ° C.

Analysis for C23H1602:

calculated: C 85.16 H 4.97 O 9.86 found: C 84.99 H 5.12 O 9.58 10 ml DMF are mixed with 1.25 g (3.86 mmol) of the above product. The mixture obtained is then added at a temperature of about 10 ° C to 20 ml of DMF containing 120 mg (5.0 mmol) of sodium hydride and 800 mg of 1-chloro-2-pyrrolidino-ethane. After foaming ceases, the mixture is heated at 80 ° C for three hours, during which time sodium chloride precipitates. The mixture is then cooled and evaporated to dryness. The residue obtained is dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer is separated off and washed five times with in each case 25 ml of aqueous sodium chloride solution. Drying the ethyl acetate solution and subsequent evaporation gives 1.62 g (about 100%) of 1- [4- (2-pyrrolodinoethoxy) benzoyl] -2-phenylnaphthalene in the form of a yellow oil.

Using 0.811 g of citric acid hydrate, the above free base is then converted to the corresponding citrate salt according to the procedure described in Example 3. The title compound is obtained in the form of an amorphous solid which crystallizes in ether when left to stand overnight and has a melting point of 105 to 108 ° C. Analysis for C33H35N09 • H2Ö:

calculated: C 65.55 H 5.90 N 2.22 found: C 66.90 H 5.85 N 2.25

Example 4

3- (4-MethoxyphenyI) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-l, 2-dihydronaphthalene citrate A solution of about 50 g (0.24 mol) of p-methoxyphenyl-magnesium bromide in tetrahydrofuran (THF), 30.2 g (0.08 mol) of l- (p-benzyloxy-benzoyl) -6-methoxy-2-tetraline are added at room temperature in the form of a solution in THF. When the addition is complete, the entire reaction mixture is heated to 45 ° C. The thin-layer chromatographic analysis of a sample of the mixture shows that no starting material is left. The mixture is then poured into aqueous ammonium chloride solution and the mixture obtained is extracted with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated. The residue obtained is dissolved in benzene, and the solution is mixed with a catalytic amount of p-toluenesulfonic acid. The mixture is then stirred at room temperature until a thin-layer chromatographic examination of the mixture no longer shows any carbinol intermediate. The mixture is then washed with water, dried and concentrated. The residue is chromatographed over 1 kg of alumina using 61 benzene. The product is eluted using a mixture of 2% ethyl acetate in benzene. In this way the product 3- (4-methoxyphenyl) -4- (4-benzyloxy-benzoyl) -7-methoxy-l, 2-dihydronaphthalene is obtained in the form of an oil. Analysis for C32H2804:

calculated: C 80.65 H 5.92 O 13.43 found: C 80.96 H 5.91 O 13.61 150 ml of N, N-dimethylformamide (DMF) were mixed with 5.4 g (0.011 mol) of the above Dihydronaphthalene added. The mixture is then mixed with 30 ml of DMF containing 0.5 sodium thioethoxide. The mixture obtained is then heated to 90 ° C. under a nitrogen atmosphere. The progress of the reaction is monitored by thin layer chromatography. When the reaction is complete, the mixture is poured into an aqueous ammonium chloride solution. The aqueous mixture is then extracted with ethyl acetate. The ethyl acetate extract is separated, washed, dried and concentrated to an oil. The oil is chromatographed on silica gel using benzene. Those fractions containing the desired 3- (4-methoxyphenyl) -4- (4-hydroxybenzoyl) -7-methoxy-l, 2-dihydronaphthalene are pooled and concentrated to dryness to give 3.3 g of a yellow oil . This product is used directly for the next stage of the process.

A mixture of 3.2 g of the above product in 150 ml of DMF containing 0.25 g of sodium hydride is heated in an oil bath for two hours at a temperature of 40 ° C. The mixture takes on a reddish appearance. The mixture is then cooled to room temperature, mixed with 1.2 g of l-chloro-2-pyrrolidinoethane and heated to 60 to 70 ° C. for about an hour. The mixture obtained is then stirred at room temperature overnight, whereupon it is poured into a large amount of water and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extract is washed several times with water and sodium bicarbonate solution. By drying the ethyl acetate mixture over magnesium sulfate and then evaporating to dryness, 3.2 g of a pale yellow oil are obtained. The oil is purified chromatographically on silica gel using ethyl acetate to give 3.0 g of 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-l, 2-dihydronaph -thaline arrives. The free base (2.9 g) obtained from the product is dissolved in 150 ml of acetone and the whole is treated with one equivalent of citric acid in the form of a solution in hot acetone. The mixture is kept at a temperature of 0 ° C for about three days. There is no crystallization of the product. The mixture is then evaporated and the residue is dissolved in a minimal amount of acetone. Ethyl ether (500 ml) is added to the solution and the resulting mixture is stirred overnight. The product which then crystallized out is filtered off and dried under vacuum, giving 3.2 g of the title compound. Analysis for Q ^ H ^ NOu:

calculated: C 65.77 H 6.12 N 2.07 found: C 65.54 H 6.10 N 2.28

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The compounds of formula I can be investigated as follows with regard to their pre-coital as well as their post-coital fertility-inhibiting effect:

The study of the precoital fertility-inhibiting effect is carried out using 50 young adult virgin female rats weighing 200 to 230 g, which are each divided into 10 groups of five animals each. One of these groups serves as a control group, while the other nine animal groups are used as test groups, each of these test groups being administered a specific dose of active compound. The active ingredients to be administered to each group of five rats are prepared in corn oil in such a way that the amount to be administered daily is present in 0.1 ml carrier. The administration of the respective amount of active ingredient in the carrier to each rat within the respective group takes place daily by subcutaneous route. The control group only receives the carrier. Carrier or combination of active ingredient and carrier are administered daily for a total of 15 days. On the fifth day of treatment, two adult rats weighing at least 250 g are added to each group of animals and these animals are then left together with the female animals until the 15th day, after which the male animals are removed from the individual animal groups. Each group of female rats is then kept for a further seven days, after which the rats are sacrificed and examined for live or resorbing fetuses.

The pregnancy ratio results from the number of pregnant animals to the total number of animals. A connection

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15

25th

is considered effective if this ratio is 0: 5 or 1: 5. A ratio of 2: 5 means marginal effectiveness and any higher value is considered inactive.

For the post-coital studies, adult female rats weighing at least 200 g are used as test animals. The female animals are placed in single cages with a male animal and checked daily for vaginal plugs or semen in the vagina. As soon as there is evidence of fertilization, the male animal is removed and the daily administration of active ingredient is started for a total of 11 days. On the 12th day, the female animal is sacrificed and examined for the presence of living and / or resorbing fetuses. Here, too, the pregnancy ratio (number of fertilized animals per number of total animals) is determined. After all experimental animals have been proven to be fertilized, the values for control animals are quite high. A pregnancy ratio of 50% is therefore considered a sign of effectiveness.

As evidence of fertilization and the implantation ratio, the values for the total number of live fetuses and the total number of absorption sites are also determined. Since the normal number of live fetuses per animal in the control is about eleven or twelve, any reduction in this figure is also proof of effectiveness.

The fertility-inhibiting effect of compounds of the formula I can be seen from the following table.

table

Fertility-inhibiting effect

/ \

/

À / VY) -

\ y 1

■ <

connection

Knockout

dose

Pregnant

Postcoital vulnerability

-N

mg / day

relationship

number

number of

\

R,

relationship

Number of the

Resorp

P / 5 P =

Pregnant /

Life ions

3rd

Number of den

R

Ri

R3

x

group

H

-och3

Pyrrolidinoa

-ch2-ch2-

0.5

_

0/2

0

0

0.05

0

0/5

0

0

0.01

1

1/5

0

1

0.005

-

2/5

14

0

0.001

5

-

-

-

-och3

H

Pyrrolidinoa

-ch2-ch2-

0.05

0

0/3

0

0

0.01

2nd

4/6

44

0

0.005

-

5/5

44

3rd

0.001

-

3/3

35

0

h h

Pyrrolidino®

-ch2-ch2-

0.05

-

0/3

0

0

0.01

-

1/6

2nd

0

0.005

-

2/4

12th

7

h h

Pyrrolidino

-ch = ch—

0.1

-

1/2

7

0

0.01

-

2/3

21st

0

0.05

-

3/3

32

0

-och3

-och3

Pyrrolidinoa

—Ch2-ch2—

0.05 0.01

-

0/3 1/3

0

2nd

0 0

a citrate salt

0.005

-

2/3

13

3rd

S

Claims (6)

624 376 2. The method according to claim 1, characterized in that 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -1, 2-dihydronaphthalene or the citrate salt thereof is prepared. 2nd PATENT CLAIMS 1. Process for the preparation of aroylphenylnaphthalenes of the formula I / \ y \ / , c • - • 0. • (V-O-CH -CH a Ä 2 . < fW bliss X represents -CH2-CH2- or -CH = CH-, 2o R represents hydrogen or Q-C5 alkoxy, Rx is hydrogen or Q-C5 alkoxy and the substituents R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidino group and the pharmaceutically acceptable non-toxic acid addition salts thereof, characterized in that a compound of the formula VIII 30th cl-ch -ch -n / r2 r \ (iv) wherein (VIII) bliss X, R and Ri have the meaning given above, with an l-chloro-2-aminoethane of the formula IV the substituents R2 and R3 have the meanings given above, reacting and converting compounds of the formula I obtained, if appropriate, into the pharmaceutically acceptable non-toxic acid addition salts. 3. The method according to claim 1, characterized in that 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-l, 2-dihydronaphthalene citrate is prepared. 4. The method according to claim 1, characterized in that 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -l, 2-dihydronaphthalene or the citrate salt thereof is prepared. 5. The method according to claim 1, characterized in that l- [4- (2-pyrrolidinoethoxy) benzoyl] -2-phenyl-naphthalene or the citrate salt thereof is prepared. 6. The method according to claim 1, characterized in that 3- (4-methoxyphenyl) -4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-l, 2-dihydronaphthalene or the citrate salt thereof is prepared.