CH624398A5 - Process for the preparation of aroylphenylnaphthalenes - Google Patents

Abstract

Aroylphenylnaphthalenes of the formula I <IMAGE> in which R is hydrogen or C1-C5-alkoxy and R1 is hydrogen or C1-C5-alkoxy, and the pharmaceutically acceptable non-toxic acid addition salts thereof are obtained by reacting a substituted tetralone with a phenylmagnesium bromide 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 usually distinguished in particular by a fertility-inhibiting action and are therefore particularly suitable as fertility-inhibiting agents with oral activity 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. Furthermore, these compounds can also be used, for example, for controlling animal pests.

Description

The invention relates to a process for the preparation of 30 new derivatives of aroylphenylnaphthalenes, which are generally suitable as fertility inhibitors and antitumor agents, and this process consists in reacting a 1-aroyl-2-tetralone with a phenylmagnesium bromide.

Various classes of compounds are known, the general formula

40

\ / V v "

bliss

R represents hydrogen or Ci — C5 alkoxy, with a phenylmagnesium bromide of the formula III

MgBr

III

bliss

Ri has the meaning given above, and the compounds of the formula I obtained are converted, if appropriate, into the pharmaceutically acceptable non-toxic acid addition salts.

2. The method according to claim 1, characterized in that

that 3- (4-methoxyphenyl) -4 ~ [4- (2-pyrrolidinoethoxy) benzoyl] -1, 2-dihydronaphthalene or the citrate salt thereof is prepared.

3. The method according to claim 1 for the preparation of 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -7-methoxy-l, 2-dihydro-naphthalene citrate, characterized in that 6-meth-oxy -l- [4- (2-pyrrolidinoethoxy) benzoyl] -2-tetralone citrate with phenylmagnesium bromide.

4. The method according to claim 1, characterized in that 3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -

Where Ar is aryl and Ya is any one of different groups, such as —CHz—, —CH2 — CH2—, -S-,

I.

—NH, -OCH2—, —O-, —CH2S- or — SCH2-. A number of compounds from these general classes thus have a fertility-inhibiting 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. 55 Chem. 10 (1967), pages 78 to 84, and J. Med. Chem. 8 (1965), pages 213 to 214, each give different 1,2-diaryl-3,4-dihydronaphthalene, which also have an anti-fertility effect. From US Pat. Nos. 3,274,213,3,313,853.3,396,169 and 3,567,737, various 1,2-diphenyl-3,4-dihydronaphthalenes are known 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 U.S. Patent 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, among other things, various 2,3-diarylbenzothiophenes emerge with an anti-fertility effect. Certain sales

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Binding thereof are described in U.S. Patent 3,413,305. From the above literature 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 given 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. The new aroylphenylnaphthalenes of formula I which can be prepared according to the invention meet this need. These are 3-phenyl-4-aroyl-l, 2-dihydronaphthalenes, and these compounds are structurally very different from the known compound fertilizers 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.

This object is achieved according to the invention by a process for the preparation of new aroylphenylnaphthalenes of the formula I.

N-CH „-CH,

bliss

R is hydrogen or Ci-Cs alkoxy, and Ri is hydrogen or Ci-Cs alkoxy, and the pharmaceutically acceptable non-toxic acid addition salts thereof, which is characterized in that a substituted tetraion of the formula II

30th

Ly

N-CH2-CH2-Q

bliss

R represents hydrogen or Ci-Cs alkoxy, with a phenylmagnesium bromide of the formula III

\ /

• MgBr

Iii wonn

Ri has the meaning given above, and the compounds of the formula I obtained are converted, if appropriate, into the pharmaceutically acceptable non-toxic acid addition salts.

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

The term C1-C5 alkoxy normally means 35 straight-chain and branched alkyl groups, and examples of these are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, isobutyloxy, tert.-butyloxy, sec.-butyloxy, n- Amyloxy, isoamyloxy, tert-amyloxy or sec-amyloxy. Methoxy is particularly preferred.

There are several preferred subclasses of the dihydronaphthalenes of the formula I. Such a subclass are the 7-alkoxy-l, 2-dihydronaphthalenes, namely those compounds of the formula I in which R is Ci-Cs alkoxy.

Another subclass are the non-alkoxylated dihydronaphthalenes, namely those compounds of the formula I in which both substituents R and Ri are hydrogen.

Another subclass includes the 3- (4'-alkoxy-50 phenyl) -l, 2-dihydronaphthalenes, namely those compounds of the formula I in which Ri is Ci — 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 the substituents R and R 1 each represent C1-C5 alkoxy.

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

60

Preparation of Compounds of Formula I A tetraion of Formula V

65

/ \ / 'V

"'N / A

(V)

624398

bliss

R is hydrogen or Ci — Cs alkoxy, with a phenyl benzoate of the formula VI

0-CH2-CH2-N

(VI)

be implemented.

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

is A reaction product is usually a substituted tetraion of the formula II

(II)

This substituted tetraion of the formula II is then set under Grignard reaction conditions with a Grignard reagent of the formula III

\ /

• MgBr

(Iii)

bliss

Ri represents hydrogen or Ci-Cs alkoxy, um.

This gives a 3-phenyl-4-aroyl-l, 2-dihydro-naphthalene of the formula I.

N-CH2-CH2-

1 (I)

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

The compounds of the formula (I) which can be prepared according to the invention are generally valuable medicinal products. They are usually characterized primarily by an anti-fertility effect and are therefore particularly suitable as orally effective 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.

These compounds can also be used, for example, to control harmful animals. For this purpose, these compounds that can be produced according to the invention 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 also birds, such as Starlings, seagulls, 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 be used to usually reduce the population of unwanted 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 the 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:

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

benzoyl] -1,2-dihy dron aphthaline;

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) benzoyl] -

7-methoxy-l, 2-dihydronaphthalene;

3-phenyl-4- [4- (2-pyrrolidinoethoxy) benzoyl] -

7-ethoxy-l, 2-dihydronaphthalene;

The invention is further illustrated by the following example.

example

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

300 ml DMF are mixed with 107 g p-hydroxybenzoic acid

624 398

phenyl ester and 26 g of sodium hydride (50% dispersion in mineral oil) were added. The mixture is then heated to 60 ° C for two hours. The mixture is then mixed with 67 g of l-chloro-2-pyrrolidinoethane and stirred at 85 ° C. overnight. The main amount of DMF is then evaporated from the mixture. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extract is concentrated and the residue is dissolved in a 1: 1 mixture of ether and ethyl acetate. The organic solution is then extracted with 2N hydrochloric acid and the acid extract is treated dropwise with 2N sodium hydroxide. The resulting mixture is extracted with ethyl acetate, whereupon the ethyl acetate extract is washed and then dried over magnesium sulfate. Evaporation of the ethyl acetate extract gives 110 g of crude phenyl p- (2-pyrrolidinoethoxy) benzoate.

41.7 g of 6-methoxy-2-tetra-ion in THF are added dropwise to a suspension of 20 g (0.5 mol) of sodium amide in tetra-hydrofuran, the temperature of the mixture being kept below 10 ° C. When the addition is complete, the mixture is stirred at below 10 ° C. for 20 minutes and then there is an exothermic reaction, the temperature rising to about 20 ° C. This mixture is then added dropwise to a solution of the p- (2-pyrrolidinoethoxy) benzoic acid phenyl ester prepared in the above manner and the whole is then stirred overnight at room temperature. The mixture is then poured into water and the mixture obtained is extracted with ethyl acetate. The ethyl acetate extract is washed several times with water and dried over magnesium sulfate. Subsequent evaporation of the ethyl acetate gives about 100 g of raw material, which is dissolved in 1.51 acetone. One equivalent of citric acid in 400 ml of ethyl acetate is added to the solution. Filtration of the solid obtained and subsequent vacuum drying gives 85.9 g of product which melts at 84 ° C. and which is not the corresponding citric acid salt but 6-methoxy-l- [4- (2- pyrrolidinoethoxy) benzoyl] -2-tetralone. The product is then chromatographed on silica gel using ethyl acetate as the eluent, and the product obtained is used to produce the citrate salt.

Analysis for C30H35NO11:

C H N

Calculated: 61.53 6.02 2.39 Found: 61.39 5.78 2.25

The above product (8.6 g, 0.02 mol) is added to a solution of phenyl magnesium bromide in THF. The resulting mixture is stirred for one hour at room temperature and then heated to 50 ° C for three hours. The mixture is then poured into a mixture of ice and hydrochloric acid and the acidic mixture is extracted with ethyl acetate. The ethyl acetate extract is washed

dried and concentrated to give 10.5 g of a reddish brown oil. The oil is added to 500 ml of acetic acid and the resulting mixture is heated on a steam bath for about 30 minutes. The acid is then stripped off and water is added to the residue. The aqueous mixture is then made alkaline by adding a base and the alkaline mixture is then extracted with ethyl acetate. Subsequent drying and evaporation of the extract gives 8.7 g of product. This is dissolved in acetone and one equivalent of citric acid is added to the solution. The acetone is stripped off and the residue

5

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

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6

mixed with methyl ethyl ketane. The mixture is then kept at a temperature of 0 ° C. overnight, whereupon the crystals formed are filtered off, washed with cold methyl ethyl ketone and dried under vacuum. The solid obtained in this way melts at 95 to 100 ° C. and its subsequent recrystallization from acetone gives the citrate salt specified in the title, which melts at 98 to 100 ° C.

Analysis for CjôH.wNOio:

C.

H

N

O

Calculated:

66.96

6.09

2.17

24.78

Found:

66.72

6.27

2.09

24.50

The free base is prepared by treating this citrate salt with dilute alkali.

Analysis for C30H31NO5:

C.

H

N

Calculated:

79.44

6.89

3.09

Found:

79.19

6.68

2.91

The compounds of the formula I can be investigated as follows with regard to their precoital as well as their postcoital 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 male 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 10 rats are killed 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 is considered effective if this ratio is 15 0: 5 or 1: 5. A ratio of 2: 5 means marginal effectiveness and any higher value is considered inactive.

For the postcoital studies, adult female rats weighing at least 200 g 20 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 active substance is administered daily 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 30 per number of total animals) is determined. After all experimental animals have been shown to be fertilized, the values for control animals are quite high. A pregnancy ratio of 50% is therefore considered a sign of effectiveness.

35 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, 40 any reduction in this figure is evidence of effectiveness.

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

table

Fertility-inhibiting effect

Connection post-pregnancy

R R, dose pregnancy ratio number of mg / day ratio ratio number of live resorptions

P / 5 P = pregnant woman /

Number of the group

H

-OCH :,

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

-

-

-

—OCHs

H

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

0.05

-

0/3

0

0

0.01

-

1/6

2nd

0

0.005

-

2/4

12

7

-OCH;

-Oh?

0.05

-

0/3

0

0

0.01

-

1/3

2nd

0

0.005

-

2/3

13

3rd

Claims (2)

624398 2nd PATENT CLAIMS 1. Process for the preparation of aroylphenylnaphthalenes of the formula I N-CH2-CH2 bliss R is hydrogen or Ci-C 5 alkoxy, and Ri is hydrogen or Ci-Cs alkoxy, and the pharmaceutically acceptable non-toxic Acid addition salts thereof, characterized in that a substituted tetraion of the formula II 20 produces 1,2-dihydronaphthalene or the citrate salt thereof. 5. 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. 25th