DE2646213A1 - AROYLPHENYLNAPHTHALINE AND METHOD FOR MANUFACTURING IT - Google Patents

Description

Eli Lilly and Company , Indianapolis / Indiana, V.St.A. Aroylphenylnaphthalenes and process for their preparation

The invention relates to new derivatives of aroylphenylnaphthalenes, which prove to be fertility inhibitors as well as anti-tumor agents suitable, and on a process :: u their production.

Various classes of compounds are known, including the general formula

VN / V-

where Ar is aryl and Y is any of various groups, such as -CH ₃ -, -CH ₂ -CH ₃ -, -S-, = NH, -OCH ₂ , -0-, -CH ₂ S- or -NS--. A number of compounds from these general classes have fertility-inhibiting effects.

709819 / 10Ö7

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

From J. Med. Chem. 9 (1966), pages 172 to 175; J. Med. Chem. IO (1967), pp. 78-84, and J. Med. Chem. 8 (1965), pp 213 to 214, different 1,2-diaryl-3,4-dihydronaphthalenes go which also have a fertility-inhibiting effect. From U.S. Patents 3,274,213, 3,313,853, 3,396,169 and 3,567,737 are different 1,2 ~ diphenyl-3,4-dihydronaphthalenes known to show the fertility-inhibiting effect.

In other US-PS 1,2-Dipheny1-3,4-dihydronaphthalenes and 2,3-Diphenylindenes have been described as fertility-inhibiting agents. These include U.S. Patents 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, show, inter alia, various 2,3-diaryl benzothiophenes with fertility-inhibiting effects. Certain compounds 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 _r which generally correspond to the benzothiophenes given above, are described in U.S. Patent 3,394,125.

However, there is still a need for further compounds with fertility-inhibiting effects, and in particular for Fertility inhibitors that are not steroids. This need will be the new aroylpheny! naphthalenes of the formula given below I just. These are 3-phenyl-4-aroyl-1,2-dihydronaphthalenes and 1-aroyl-2-pheny! naphthalenes, and these Connections are structurally different from those known above

709819/1097

Connections very different. The object of the invention is therefore to create new compounds with fertility inhibitors Effects that do not belong to the class of steroids.

This object is achieved according to the invention by means of new aroylpheny! Naphthalenes of formula I.

j <> -o-cH -CH -n; ²

Λ / 'νγ \

wherein

X is -CH ₉ -CH ₉ - or -CH = CH-,

R is hydrogen, hydroxy or C.-Cj- alkoxy, R is hydrogen, hydroxy or C.-C, -alkoxy and

the substituents R ₂ and R _{3 are} independently C ₁ -C ₄ alkyl or together with the nitrogen atom to which they are attached, pyrrolidino, piperidino / hexamethyleneimines or morpholino

mean,

as well as the pharmaceutically acceptable non-toxic acid addition salts of this.

The invention is also directed to a process for the preparation of new aroylpheny! Naphthalenes of the above formula I, in which the substituents X, R, R., R ₉ and R _{3 have} the meaning given above, which is characterized in that one

7G98 1 9/1

1) a substituted tetraion of the formula II

< VV

II

represents hydrogen, CC ₅ alkoxy or benzyloxy and

Methoxy, benzyloxy or

represents

where the substituents R2 and R _{3 have} the meanings given above, with a Pheny lir.agne siumbromid. of formula III

III

R. for hydrogen, C.-Cj- alkoxy or benzyloxy, implements, '

70981.9 / 1ÖÄ7

2) the product thus obtained, in which

X is -CH ₂ -CH ₃ -, if desired with 2,3-dichloro-5, ö-dicyano-l ^ -benzoquinone at a temperature of 50 to 100 ° C to the corresponding compound in which

X stands for -CH = CH-, converts,

3) the product obtained in the above manner in which

Y denotes methoxy or benzyloxy, with pyridine hydrochloride and / or sodium thioethoxide to give the corresponding compound, in the

Y is hydroxy, and this compound is then reacted with an 1-chloro-2-aminoethane of the formula IV

Cl-CH -CH ^ -NC IV

R ₃

in which the substituents R ₂ and R _{3 have} the meanings given above, brings about the reaction,

4) the compound obtained in this way / in which the substituents R ^ or R _{1 are} benzyloxy, by conversion

el Id

put with sodium thioethoxide in the corresponding compound in which the substituents R or R. are hydroxy, convicted and

5) the compound obtained in this way, in which the substituents R or R _{1 are} alkoxy, by reacting with

a Χα.

Sodium thioethoxide is converted into the corresponding compound in which the substituents R or R _{1 are} hydroxy,

7,098 1

whereupon the compounds obtained in the above manner, if desired Reacts in a known manner to acid addition salts with pharmaceutically acceptable non-toxic acids.

To pharmaceutically harmless, non-toxic acid addition salts of the compounds of formula I above include the addition salts of organic and inorganic acids such as, for example of 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 made preferred. Such salts are produced by customary methods.

The specification C ₁ -C. Alkyl refers to straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, η-butyl, tert-butyl, isobutyl or sec-butyl.

The term C ₁ -Cj- alkoxy means 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 see-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 I in which X is -CH ₂ -CH ₂ -.

There are several preferred subclasses of these dihydronaphthalenes. One such subclass are the 7-alkoxy-1,2-dihydronaphthalenes, namely those compounds of the formula I in which X is the group —CH ₉ —CH ₉ - and R is C ₁ -C 4 alkoxy.

7O981Ö / 10Ä7

• η.

The non-hydroxylated or alkoxylated dihydronaphthalenes represent another subclass, namely those compounds of the formula I in which X is -CH ₂ -CH ₂ "and both substituents R and R _{1 are} hydrogen.

A further subclass includes the 3- (4'-alkoxyphenyl) -1,2-dihydronaphthalenes, namely those compounds of the formula I in which X is —CH ₂ —CH ₂ - and R _{1 is} C ₁ -C ₅ alkoxy .

Another preferred subclass are the 3- (4'-alkoxyphenyl) -7-alkoxy-1,2-dihydronaphthalenes, namely those compounds of the formula I in which X stands for -CH ₂ -CH ₂ - and the substituents R and R _{1 are} each C ₁ -C ₅ alkoxy.

Further preferred subclasses include the 3- (4'-hydroxyphenyl) -1,2-dihydronaphthalenes and the 7-hydroxy-1,2-dihydronaphthalenes, namely those compounds of the formula I in which X is -CH ₂ -CH ₂ - and the substituents R or R. are hydroxy.

A particularly preferred subclass are the 3- (4'-hydroxyphenyl) -7-hydroxy-1,2-dihydronaphthalenes, namely those compounds of the formula I in which X is -CH ₂ -CH ₂ - and the substituents R and R 2 ₁ each represent hydroxy.

Another preferred subclass includes those compounds of the formula I in which the substituents R ₂ and R _{3 are} each methyl, the substituents R ₃ and R _{3 are} each ethyl or the substituents R ₂ and R ₃ together with the nitrogen atom to which they are bound to form a pyrrolidino ring.

7098 19/1 097

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 —CH ₂ —CH ₂ -.

For this purpose, a tetraion of the formula V

wherein

(V)

Is hydrogen, ^c i ~ ^C 5 alkoxy or benzyloxy, with a phenyl benzoate of the formula VI

where Υ

(VI)

for methoxy, benzyloxy or

; N-CH ₀ -CH ₀ -O- is

and the substituents R ₂ and R _{3 have} the meanings given above.

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

709819/1097

-S-

"f.

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

= 0

(II)

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

(III)

R ₁ for hydrogen, C-Cf. Alkoxy or benzyloxy is around.

XcI X D

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

v /

0 =

/ γ χΛ

σ

(VII)

a

depending on the identity of the radicals R, R ₁ and Y

a la

can also be a compound of formula I.

In those cases in which Y is methoxy and the substituents R _& and R _{la are} hydrogen, treating the compound of the formula (VII) with pyridine hydrochloride at reflux temperature gives the corresponding hydroxy compound. However, as stated, this method can only be applied to those compounds in which the substituents R _a and R _{1a are} each hydrogen, since in compounds in which the substituents R and / or R are alkoxy or benzyl

ei J. el

oxy, these groups form Hydroxy1 residues would split.

By treating those compounds of the above kind in which Y is hydroxy with a compound of the formula IV

-2

Cl-CH ₉ -CH ₉ -N

R ₃ (IV)

in which the substituents R ₀ and R_ have the meanings given above, compounds of the formula (I) are obtained.

In those cases in which Y in the compounds of the formula (VII) is methoxy or benzyloxy and the substituents R and / or R _{1 are} alkoxy or benzyloxy, the

ei JLu

Substituent Y is split off selectively by reacting such a compound with Natriumthioäthoxid in Ν, Ν-dimethylformamide at a moderately elevated temperature of about 80 ° to 9O ⁰ C. The course of the selective cleavage can be monitored by periodic thin-layer chromatographic analysis (TLC) of the reaction mixture. The reaction is complete as soon as little or no starting material is present.

709819/1097

The product obtained in the above manner, that as the only hydroxyl group contains the hydroxyl group in the Y position in the molecule then in the manner described above with an 1-chloro-2-substituted one Aminoethane around.

Depending on the structure desired in the end product, the compound containing the 2-Aminoäthoxyubstituenten in the manner described above can then be reacted further with sodium thioethoxide in N, N-dimethylformamide in order to split off any alkoxy or benzyloxy groups that are still present and thus such compounds To form formula I in which R and / or R _{1 are} each hydroxy.

The particular sequence of stages of synthesis for the preparation of a compound with certain substituents on certain Positions are familiar to the person skilled in the art.

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

These compounds can be readily derived from those mentioned above Compounds in which X is -CH ^ -CH ^ -, prepare. The selective dehydrogenation of the dihydronaphthalene structure with the formation of the corresponding naphthalene can be achieved by treating the first-mentioned compounds at a temperature of about 50 to 100 ° C. with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) treated.

The above-mentioned derivatization reactions can then convert the naphthalene obtained in this way in turn into other naphthalene compounds of the formula (I).

The compounds of formula (I) are valuable medicines. They are characterized above all by a fertility-inhibiting effect and are therefore particularly suitable as orally effective

7098 19/1097

anti-fitness agents in birds and mammals. The connections of formula (I) are therefore suitable for controlling the animal population and as contraceptives in living beings. Further these compounds can also be used to control harmful animals. You can use these compounds for this purpose, for example Formulate it in combination with bait and / or attractants and bring it to feeding places where unwanted rodents are found or other small animals such as Canidae, such as coyotes, foxes, wolves, jackals and wild dogs, as well as birds such as starlings, gulls, swamp horde birds or pigeons in this way to greatly reduce the respective population thereof. The compounds of formula (I) can due to their Activity used to reduce the risk to air traffic by keeping the bird and animal populations on taxiways and reduced in the vicinity of airfields. Furthermore, these compounds can be used to reduce the population undesirable Birds and animals use this to prevent disease and its spread, and they can help Reduction of damage to structures in rural and urban areas.

The compounds of the formula (I) can be administered as such, or they can also be administered after appropriate compounding and formulating them into pharmaceutical preparations in unit dosage form orally or parenterally. To the Compounding or formulation can include organic or inorganic solids and / or liquids are pharmaceutically acceptable carriers. Support materials suitable for this purpose are known to the person skilled in the art. Appropriate preparations can be processed into tablets, powder granules, capsules, suspensions or solutions v / earth.

When administered in an effective amount, the compounds of the formula (I) lead to an obstruction of pregnancy in mammals

709819/1097

animals. The usual daily dose is about 0.02 to 20 mg Active ingredient per kilogram of body weight of the recipient. The preferred daily dose is about 0.02 to 0.4 mg per kilogram Body weight of the recipient.

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

3- (4-HydroxyphenylH ~ Z ⁴ ~ (2-pyrrolidinoethoxy) benzoy 1 _ / - 1,2-

dihy dronaph thalin; -

3- (4-methoxyphenyl) -4- / 4- (2-diethylaminoethoxy) benzoy 1 _ / - 1,2-

dihydronaphthalene? .

3- (4-Isopropoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoy 1_ / -1,2-dihydronaphthalene; 3- (4-t-butyloxyphenyl) -4- / 4- (2-hexamethyleneiminoethoxy) -benzoy1_ / - 1,2-dihydronaphthalene; 3- (4-pentyloxyphenyl) -4- / 4- (2-morpholinoethoxy) benzoy1_ / -1,2-dihydronaphthalene;

3- (4-methoxyphenyl) -4- / 4- (2-piperidinoethoxy) benzoy 1 _ / - 1,2-

dihydronaphthalene; 3- (4-ethoxyphenyl) -4- / 4- (2-dimethylaminoethoxy) benzoy1_ / -1,2-dihydronaphthalene; 3- (4-n-propoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoy1_ / -1,2-dihydronaphthalene;

3- (4-sec-Butyloxyphenyl) -4- / 4- (2-piperidinoethoxy) benzoyl- /

-1,2-dihydronaphthalene; 3- (4-ethoxyphenyl) -4- / 4- (2-morpholinoethoxy) benzoy1_ / -1,2-dihydronaphthalene; 3- (4-hydroxyphenyl) -4- / 4- (2-hexamethyleneiminoethoxy) benzoyl / - 1,2-dihydronaphthalene; 3- (4-methoxyphenyl) -4- / 4- (2-dime thy laminaethoxy) benzoy 1_ / -1,2-dihydronaphthalene;

3- (4-Isopropoxyphenyl) -4- / 4- (2-diethylaminoethoxy) benzoy 1_ /

-1,2-dihydronaphthalene;

709819 / 1Ö97

3- (4-t-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 ζ 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-t-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;

709819/1097

3-Pheny 1-4- / 4- (2-dimethylaminoethoxy) benzoy 1 _ / -1, 2-dihydronaphthalene; 3-Pheny 1-4- / 4- (2-pyrrolidinoethoxy) benzoy 1-7-methoxy-1,2-dihydronaphthalene;

3-Pheny 1-4- / 4- (2-dimethylaminoethoxy) benzoyl _ / - 7-hydroxy-

-1,2-dihydronaphthalene; 3-Pheny1-4- / 4- (2-hexamethyleneiminoethoxy) benzoy1_ / - 7-methoxy-1,2-dihydronaphthalene; 3-Pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 7-hydroxy ~ -1,2-dihydronaphthalene; 3-phenyl-4- / 4- (2-piperidinoethoxy) benzoyl _ / - 7-ethoxy- -1,2-dihydronaphthalene; 3-pheny 1-4- / 4- (2-morpholinoethoxy) benzoyl _ / - 7-methoxy- -1,2-dihydronaphthalene; 3-Pheny1-4- / 4- (2-hexamethyleneiminoethoxy) benzoyl_ / - 7-isopropoxy-1,2-dihydronaph thalin;

3-pheny 1-4- / 4- (2-dimethylaminoethoxy) benzoyl _ / - 7-pentyloxy-

1,2-dihydronaphthalene?

3-Pheny 1-4- / 4- (2-pyrrolidinoethoxy) benzoyl _ / - 7-ethoxy-1 , 2-dihydronaphthalene?

3-pheny 1-4- / 4- (2-morpholinoethoxy) benzoyl _ / - 7-isopropoxy-

1,2-dihydronaphthalene; 3-Pheny 1-4- / 4- (2-hexamethyleneiminoethoxy) benzoy 1-7-butyloxy-1,2-dihydronaphthalene; 3-Pheny 1-4- / 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-sec.-butyloxyphenyl) -

naphthalene;

1- / 4- (2-diethylaminoethoxy) benzoyl _ / - 2- (4-methoxyphenyl) -

naphthalene; -

709819/1097

1- / 4- (2-pyrrolidinoethoxy) benzoyl __ / - 2- (4-isopropoxyphenyl) -

naphthalene;

1- / 4- (2-hexamethyleneiminoethoxy) benzoyl __ / - 2- (4-t-butyloxy-

phenyl) 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-t-butyloxyphenyl) -

naphthalene; 1- / 4- (2-piperidinoethoxy) 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-n-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;

709819/109

1- / 4- (2-morpholinoethoxy) benzoyl_ / - 2- (4-hydroxyphenyl) naphthalene;

1- / 4- (2-dimethylaxninoethoxy) benzoyl_ / - 2- (4-hydroxyphenyl) 6-hydroxynaphthalene;

1- / 4- (2-diethylaminoethoxy) benzoyl_ / - 2- (4-methoxyphenyl) 6-methoxynaphthalene;

1- / 4- (2-pyrrolidinioethoxy) benzoyl_ / - 2- (4-isopropoxyphenyl) 6-ethoxynaphthalene;

1- / 4- (2-dimethylaminoethoxy) benzoyl_ / - 2- (4-tert-butyloxyphenyl) -6-propoxynaphthalene;

1- / 4- (2-piperidinoethoxy) benzoyl_ / - 2- (4-pentyloxyphenyl) -6-pentyloxynaphthalene; 1- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 2- (4-hydroxyphenyl) 6-hydroxynaphthalene; 1- / 4- (2-morpholinoethoxy) benzoyl_ / - 2- (4-ethoxyphenyl) -6-ethoxynaphthalene; 1- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 2-phenyl-6-methoxynaphthalene; 1- / 4- (2-dimethylaminoethoxy) benzoyl_ / - 2-phenyl-6-hydroxynaphthalene; 1- / 4- (2-hexamethyleneiminoethoxy) benzoyl_ / ~ 2-phenyl-6-methoxynaphthalene; 1- / 4- (2-pyrrolidinoethoxy) benzoy 1- / - 2-phenyl-6-hydroxynaphthalene; 1- / 4- (2-piperidinoethoxy) benzoyl_ / - 2-phenyl-6-ethoxynaphthalene; 1- / 4- (2-morpholinoethoxy) benzoyl_ / - 2-phenyl-6-methoxynaphthalene; 1- / 4- (2-hexamethyleneiminoethoxy) benzoyl_ / - 2-pheny1-6-isopropoxynaphthalene;

1- / 4- (2-dimethylaminoethoxy) benzoy 1- / - 2-phenyl-6-pentyloxynaphthalene;

1- / 4- (2-pyrrolidinoethoxy) benzoyl / - 2-phenyl-6-ethoxynaphthalene;

709819/1097

1- / 4- (2-morpholinoethoxy) benzoyl_ / - 2-phenyl-6-isopropoxynaphthalene; 1- / 4- (2-hexamethyleneiminoethoxy) benzoyl_ / - 2-phenyl-6-butyloxynaphthalene; 1- / 4- (2-diethylaminoethoxy) benzoyl_ / - 2-pheny 1-6-hydroxynaphthalene.

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) of sodium amide in 250 ml Tetrahydrofuran (THF) is mixed with 50 g (0.34 mol) of β-tetralone. 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 with Ethyl acetate extracted and the ethyl acetate extract washed and focused. The residue is then chromatographed on silica using benzene as the eluant. Those obtained in the chromatographic separation The purer fractions are combined and concentrated, whereupon the residue thus obtained can be used in a minimal amount Methanol dissolves. Subsequent cooling and subsequent filtration of the methanol solution gives 35.2 g of 1- (p-methoxybenzoyl) -2-tetralone, that melts at 88 to 91 ° C.

70 9 8 19/1097

Analysis for C ₁ S ¹¹ Io ⁰ S ¹

calculated: C 77.12? H 5.75? O 17.12? Found: C, 77.08; H 5.54; 0 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 general reflux. After completion of the addition is added to the whole then added dropwise with stirring over a period of two hours with the above substierten .beta.-tetralone as a solution in acetone, keeping the temperature of the mixture to 40 ⁰ C. The resulting mixture 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 over silica gel using benzene as the eluent. This gives 8.6 q 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) -1,2-dihydronaphthalene in the form of a Oil after elution of the column with a mixture of benzene containing 2% ethyl acetate.

Analysis for ^C 25 ^H 22 ° 3 ^:

calculated: C 81.06? H 5.99? 0 12.96; found: C 81.32? H 6.13? 0 13.04.

From 11.1 g (0.03 mole) of the above dimethoxy product, 7.2 g

709819/1097

A mixture is prepared from sodium hydride (50% dispersion in oil) and 11 ml of ethyl mercaptan in Ν, Ν-dimethylformarnide. 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 chomotography 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 ^c ₂ 4 ^H 2O ° 3 ^:

Calculated: C 80.88; H 5.66; 0 13.47; Found: C, 79.66; H 5.87; 0 13.57.

The above phenol product (4.3 g, 0.01 mole) is dissolved in N, N-dimethylformamide solved. 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 warmed to 60 ° C. for two hours and then stirred at room temperature overnight. The mixture is then concentrated and added the residue obtained with water. The aqueous mixture is then extracted with ethyl acetate. By subsequent Washing and subsequent concentration of the ethyl acetate extract gives a residue. The residue is extracted with hexane, whereupon the insoluble fraction is dissolved in ethyl acetate and the ethyl acetate solution is extracted with 1 η hydrochloric acid. The acid extract is made alkaline and then extracted with ethyl acetate. The ethyl acetate extract is washed and focused. The concentrate is then added

709819/1097

with one 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. at 0 ° C
chilled. Subsequent filtration and subsequent vacuum drying of the product obtained in this way leads to 3- (4-methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) -benoyl _ / - 1,2-dihydronaphthalene citrate, which at 82 to
85 ° C melts.

Analysis for ^C 36 ^H 39 ^NO ] _o ^:

Calculated: C, 66.96; H 6.09; N 2.17; 0 24.78;
found: C, 66.70; H 6.27; N 2.27; 0 24.54.

Example2

3-Pheny 1-4- / 4- (2-pyrrolidinoethoxy) benzoyl __ / - 7-methoxy -1,2-dihydronaphthalene citrate

300 ml of DMF are mixed with 107 g of p-hydroxybenzoic acid phenyl ester and 26 g of sodium hydride (50% dispersion in mineral oil) are added. The mixture is then heated to 60 ° C. for two hours. 67 g are then added to the mixture l-chloro-2-pyrrolidinoethane and stir overnight at 85 ° C. The main amount of DMF is then evaporated from the mixture. The residue is mixed with water, and that 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 2 η hydrochloric acid and add 2 η sodium hydroxide dropwise to the acid extract. The resulting mixture is extracted with ethyl acetate, whereupon the ethyl acetate extract is washed and then

709819/1097

dries over magnesium sulfate. By evaporation of the ethyl acetate extract 110 g of crude phenyl p- (2-pyrrolidinoethoxy) benzoate are obtained.

A suspension of 20 g (0.5 mol) of sodium amide in tetrahydrofuran is added dropwise with 41.7 g of 6-methoxy ~ 2-tetralone added in THF / the temperature of the mixture being kept below 10 ° C. When the addition is complete, the mixture is stirred 20 minutes at below 10 C, and then it comes to an exothermic reaction, the temperature rising to about 20 ° C. This mixture is then added dropwise with a solution of the p- (2-pyrrolidinoethoxy) benzoic acid pheny ester prepared in the above manner and stir the whole then overnight at room temperature. The mixture is then poured into water, whereupon the resulting mixture 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 1.5 l of acetone. the One equivalent of citric acid in 400 ml of ethyl acetate is added to the solution. By filtering off the resulting Solid and subsequent vacuum drying gives 85.9 g of product which melts at 84 ° C. and which are not the corresponding citric acid salt is 6-methoxy-1- / 4- (2-pyrrolidinoethoxy) benzoyl _ / -2-tetralone. The product is then chromatographed over silica gel using ethyl acetate as the eluent, and from the the product obtained in the process is used to produce the citrate salt.

Analysis for ^C 3 _O ^H 35 ^NO n ^:

calculated: C, 61.53; H 6.02; N 2.39; Found: C, 61.39; H 5.78; N 2.25.

1 09819/1 097

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 for three hours heated to 50 ° C. The mixture is then poured into a mixture of ice and hydrochloric acid and extracted the acidic mixture with ethyl acetate. The ethyl acetate extract is washed, dried and concentrated, whereby one 10.5 g of a red-brown oil is obtained. The oil is added to 500 ml of acetic acid and the resulting mixture is heated take about 30 minutes on a steam bath. The acid is then stripped off and water is added to the residue. On that the aqueous mixture is 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 mixed the solution with one equivalent of citric acid. The acetone is stripped off and methyl ethyl ketane is added to the residue. The mixture is then kept overnight at a temperature of 0 ° C, whereupon the resulting crystals 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 is precipitated by its subsequent recrystallization Acetone gives the citrate salt indicated in the title, which melts at 98 to 100.degree.

Analysis for C35H ₃₉ NO ₁₀ :

Calculated: C, 66.96; H 6.09; N 2.17; 0 24.78; Found: C, 66.72; H 6.27; N 2.09; 0 24.50.

Treating this citrate salt with dilute alkali produces the free base.

709819/1097

Analysis for ^c ₃ o ^H 3i ^NO 5 ^:

Calculated: C 79.44; H 6.89; N 3.09;

Found: C, 79.19; H 6.68; N 2.91.

Example 3

3-Pheny 1-4- / 4- (2-pyrrolidinoethoxy) benzoyl _ / - 1,2-dihydro naphthalene nitrate

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 is added dropwise at a temperature of 0 C with a Solution of 0.018 mol of phenyl magnesium bromide in 9 ml of ether. When the addition is complete, the mixture is stirred for 20 minutes. One thin-layer chromatographic investigation 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 transferred to an ice-cold one Poured aqueous ammonium chloride solution. The organic layer is separated and washed with aqueous sodium chloride solution. The mixture is then dried over magnesium sulphate, filtered and evaporated to give about 5 g of a yellow Receives oil. To prepare further product, a second amount of 5.0 g of tetraion is reacted in the above manner. The products are combined and the total of about 10 g of oil is washed with hexane. The iir. Hexane insoluble fraction is chromatographed one over a column filled with neutral aluminum oxide and about 2.5 × 50 cm in size, using a 1: 1 mixture as a gradient used from benzene and hexane, the hexane content of which is constantly reduced until only 100% benzene is present. To this 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.

709819/1097

Analysis for ^C 24 ^H 2O ° 2 ^:

Calculated: C 84.68; H 5.92; O 9.40; found: C, 84.96; H 6.13; 0 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 added to 15 ml of DMF. The addition takes place under a nitrogen atmosphere at a temperature of 80 ° C. The mixture is then held at 80 ° C. for 15 hours. The mixture is then cooled and poured into ice-containing aqueous ammonium chloride solution poured. The mixture obtained is then extracted with ethyl acetate, whereupon the ethyl acetate extract is extracted four times Washed with aqueous sodium chloride solution. The ethyl acetate extract is dried over magnesium sulfate and evaporated, whereby one obtains an oil. This oil is quickly obtained through a 5 χ 5 cm silica gel acid using benzene Chromatographed to elute the contaminant. By subsequently eluting the product with Ethyl acetate and subsequent evaporation of the ethyl acetate give 1.69 g (88%) of 3-phenyl-4- (4-hydroxybenzoyl) -l, 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 takes place under a nitrogen atmosphere at a temperature of about 10 ° C. That after the end of the. The mixture obtained from foam formation is ^{heated to 80 °} C. for two hours. The mixture is then poured into

709819/1097

Water and extracted the whole 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 turned into a gray oil evaporated. The oil obtained in this way is then chromatographed over a 5 × 5 cm silica gel column using an ethyl acetate - methanol gradient. This gives 1.18 g (56%) of 3-pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl-1,2-dihydronaphthalene.

Mass spectrum: calculated 423, found 423.

The product thus obtained is then transferred by treating with 0.59 g of citric acid in 50 ml of hot Acetone into the corresponding citrate salt. For this purpose, the mixture obtained is evaporated to dryness and the residue is stirred 15 minutes with ether, which gives the citrate salt. Subsequent vacuum drying of this salt leads to to 1.62 g (53%) of the title compound, which melts at 89 to 93.degree.

Analysis for C ₃₃ H ₃₇ NO ₉ 1/2 H ₃ O:

calculated: C, 67.34; H 6.13; N 2.25; Found: C, 67.06; H 6.41; N 2.66.

Example 4 1- / 4- (2-pyrrolidinoethoxy) benzoyl / -2-pheny! Naphthalene citrate

30 ml of dioxane are mixed with 1.90 g (5.58 μmol) of 3-phenyl-4- (4-methoxybenzoyl) -l, 2-dihydronaphthalene (prepared according to Example 3) and 2.00 g (8.81 mmol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The resulting mixture is refluxed for 12 hours in a nitrogen atmosphere. The mixture is then cooled and allowed to dry

709819/1097

steamed. Ether and water are added to the residue. The ether layer is separated and five times with each 20 ml of 5N sodium hydroxide solution and then washed with aqueous sodium chloride solution. Through the following Dry over magnesium sulfate and then evaporate the mixture gives 1.9 g of essentially pure 1- (4-methoxybenzoyl) -2-phenylnaphthalene in the form of a green oil.

Using virtually the same demethylation process as in Example 3, treating 1.83 g (5.41 mmol) of the above product with sodium thioethoxide is obtained 1.40 g (80%) 1- (4-hydroxybenzoyl) -2-pheny! Naphthalene, which melts at 204 to 205 ° C.

Analysis for ^C 23 ^H i6 ° 2 ^:

calculated: C, 85.16; H 4.9 7; 0 9.86;

Found: C 84.99; H 5.12.0 9.58.

1.25 g (3.86 mmol) of the above product are added to 10 ml of DMF. The mixture obtained is then added at a temperature from about 10 ° C to 20 ml of DMF containing 120 mg (5.0 mmol) of sodium hydride and 800 mg of l-chloro-2-pyrrolidinoethane. After foaming has ceased, the mixture is heated to 80 ° C. for three hours, during which time sodium chloride falls the end. The mixture is then cooled and evaporated to dryness. The residue obtained is in a mixture of Dissolved ethyl acetate and water. The ethyl acetate layer will separated and washed five times with 25 ml of aqueous sodium chloride solution each time. By drying the ethyl acetate solution and subsequent evaporation gives 1.62 g (about 100%) of 1- / 4- (2-pyrrolidinoethoxy) benzoyl _ / - 2-phenylnaphthalene in Form of a yellow oil.

70981 9/1097

Using 0.811 g of citric acid hydrate, the above free base is then converted according to that described in Example 3 Procedure to the corresponding citrate salt. This gives the title compound in the form of an amorphous one Solid which, when left to stand overnight, crystallizes in ether and has a melting point of 105 to 108 ° C

Analysis for C ₃₃ H ₃₅ NO ₉ · H ₂ O:

calculated: C, 65.55; H 5.9O> N 2.22; found: C, 66.90; H 5.85; N 2.25.

Example 5

3- (4-methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoy 1 _ / - 7- methoxy-1,2-dihydronaphthalene citrate

A solution of about 50 g (0.24 mol) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) is admixed at room temperature with 30.2 g (0.08 mol) of 1- (p-benzyloxybenzoyl) -6-methoxy-2-tetralone in the form of a solution in THF. After complete addition, the whole reaction mixture is heated to 45 ⁰ C. The thin-layer chromatographic analysis of a sample of the mixture shows that there is no longer any starting material present. The mixture is then poured into aqueous ammonium chloride solution and the resulting mixture 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 treated with a catalytic amount of p-toluenesulfonic acid. The mixture is then stirred at room temperature until a thin-layer chromatography 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 aluminum oxide using 6 liters of benzene. Elution of the product is carried out using

709819/1097

a mixture of 2% ethyl acetate in benzene. In this way, the product obtained is 3- (4-methoxyphenyl) -4- (4-benzyloxybenzoyl) -7-methoxy-1,2-dihydronaphthalene in the form of an oil.

Analysis for ^C 32 ^H 28 ° 4 ^:

calculated: C 80.65? H 5.92; 0 13.43; found: C, 80.96; H 5.91; 0 13.61.

150 ml of N, N-dimethylformamide (DMF) are 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 mol of sodium thioethoxide. The mixture obtained is then heated to 90 ° C. under a nitrogen atmosphere. The progress of the implementation becomes thin followed chromatographically. After completion of the implementation 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 over silica gel chromatographed using benzene. Those fractions which contain the desired 3- (4-methoxyphenyl) -4- (4-hydroxybenzoy1) -7-methoxy-1,2-dihydronaphthalene contained, are combined and concentrated to dryness, whereby one 3.3 g of a yellow oil are obtained. This product is used directly for the next process step.

A mixture of 3.2 g of the above product in 150 ml of DMF containing 0.25 g of sodium hydride is warmed in an oil bath for two Hours at a temperature of 40 ° C. The mixture takes on a reddish appearance. Then the mixture cooled to room temperature with 1.2 g of 1-chloro-2-pyrrolidinoethane added and heated to 60 to 70 ° C for about an hour. The resulting mixture is then left at room temperature overnight stirred, after which it is poured into a large amount of water

70 98 19/1097

and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extract is washed several times with water and sodium bicarbonate solution washed. By drying the ethyl acetate mixture over magnesium sulfate and then evaporating 3.2 g of a pale yellow oil are obtained to dryness. The oil is chromatographed on silica gel using Purified of ethyl acetate, resulting in 3.0 g of 3- (4-methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoyl _ / - 7-methoxy-1,2-dihydronaphthalene got. The free base obtained from the product (2.9 g) is dissolved in 150 ml of acetone and the mixture is added whole with one equivalent of citric acid in the form of a solution in hot acetone. The mixture will last about three days on one Maintained temperature of 0 C. There is no crystallization of the product. The mixture is then evaporated and dissolve the residue in a minimal amount of acetone. The solution is treated with ethyl ether (500 ml) and the obtained Mixture stirred overnight. The then crystallized product is filtered off and dried under vacuum, whereby 3.2 g of the title compound are obtained.

Analysis for ^C ₃ 7 ^H 4 ₁ ^NO ₁₁ ^:

Calculated: C, 65.77; H 6.12; N 2.07; Found: C, 65.54; H 6.10; N 2.28.

The compounds of formula I are precoital in terms of their as well as their postcoital fertility-inhibiting effect.

The investigation of the precoital fertility-inhibiting effect is carried out using 50 young adult virginal ones 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

709819/1097

Animal groups are used as experimental groups, whereby one each of these test groups a certain dose of active ingredient administered. The active ingredients to be administered to each group of five rats are prepared in corn oil in such a way that that the amount to be administered daily is present in 0.1 ml of 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 vehicle. Carrier or combination the active ingredient and carrier are administered daily for a total of 15 days. On the fifth day of treatment, you admit each group of animals two adult male rats weighing at least 250 g and then leaves these animals up to on the 15th day together with the female animals, whereupon the males are separated from the individual animal groups removed. Each group of female rats is then kept for a further seven days, after which the rats are killed and be examined for living or resorbing fetuses.

The pregnancy ratio results from the number of pregnant animals to the total number of animals. A connection is considered effective when this ratio is 0: 5 or 1: 5. A ratio of 2: 5 means a marginal one Effectiveness, and any higher value is considered inactive.

Adult female rats weighing at least 200 g are used as test animals for the post-coital studies used. The females are placed in individual cages with a male and placed daily on vaginal plugs or examining semen in the vagina. Once there is evidence of fertilization, it is removed the male and begin daily administration

703 8 19/1097

of active ingredient over a period of 11 days in total. On the 12th day, the female animal is killed and checked for its presence living and / or resorbing fetuses examined. Here, too, it is the pregnancy ratio (Number of fertilized animals per number of total animals) determined. After all experimental animals have been proven are fertilized, the values for control animals are quite high. A pregnancy ratio of 50% will be therefore viewed as a sign of effectiveness.

As evidence of fertilization and of the implantation ratio in addition, the values for the total number of living fetuses and the total number of resorption sites are also shown determined. Since the normal number of live fetuses per animal at the control is about eleven or twelve, each one also provides A reduction in this numerical value is proof of effectiveness.

The fertility-inhibiting effect of compounds of the formula I. is shown in the table below.

709819/1097

Tabel Anti-fertility effect

-OH,

link

-N

Α / γγ \ \ ./ ^u

■ O-CH -CH-

-OCH ₃ pyrrolidino *

-CH ₂ -CH ₂ -

H pyrrolidino ⁵¹ -CH ₂ -CH ₂ -

Postcoital pregnancy

Pregnant relationship number Number 1 understandable Number of pregnant women / the the dose ratio Number of group living Resorptions mg / day P / 5 P = 0.5 . 0/2 0 0 0.05 O 0/5 0 0 0.01 1 1/5 0 1 0.005 - 2/5 14th 0 0.001 5 - - "ro CO 0.05 O 0/3 0 Οι ¹ -. 0.01 2 4/6 44 ocn 0.005 - 5/5 44 3K) 0.001 - 3/3 35 0— * CO

Table (continued)

CO _H
CO

R.

-N

Post coital pregnancy

Pregnancy failure

Dose ratio mg / day P / 5 P =

Ratio number number

Number of pregnant women

Number of group living resorptions

Pyrrolidino ⁵¹ -CH-CH- 0.05

* 0.01 0.005

Pyrrolidino -CH = CH-

-OH. -OH. Pyrrolidino -CH ₀ -CH,

0.1

0.01

0.05

0.05 0.01 0.005

0/3 0 0 I. 1/6 2 0 2/4 12th 7th f 1/2 7th 0 < * I 2/3 21 0 * 3/3 32 0 0/3 0 0 1/3 2 0 2/3 13th 3

a citrate salt

Claims (3)

Patent claims the substituents R ₂ and R _{3 are} independently C -, - C, alkyl or, together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino, hexamethyleneimxno or morpholino, as well as the pharmaceutically acceptable non-toxic acid addition salts of this. 2. A compound according to claim 1, characterized in that the substituents R ₂ and R ₃ each represent methyl, the substituents R ₂ and R ₃ each represent ethyl or the substituents R ₂ and R ₃ together with the nitrogen atom to which they are bonded are to form a pyrrolidino ring. 709819 / 1Ö97 3. A compound according to claim 2, characterized in that the substituents R ₀ and R- «together with the nitrogen atom to which they are bonded, one
Form pyrrolidino ring. 4. Compound according to claim 1 to 3, characterized in that it is a pharmaceutical is a harmless, non-toxic acid addition salt. 5. A compound according to claim 4, characterized in that it is the citrate salt. 6. A compound according to claim 1 to 5, characterized in that the substituent R, for
C ₁ -C ₅ alkoxy and the substituent R is hydrogen. 7. A compound according to claim 1 to 5, characterized that the substituent R for CC _{5 is} alkoxy and the substituent R is hydrogen, 8. A compound according to claim 1 to 5, characterized in that the substituents R and R _{1 are} each C ₁ TC ₁ - alkoxy. 9. A compound according to claim 1 to 5, characterized in that the substituents R and R _{1 are} each hydrogen. 10. A compound according to claim 1 to 9, characterized that X stands for -CH = CH-. 11. A compound according to claim 1 to 9, characterized in that X is -CH ₂ -CH ₂ -. 7098 19 / 1Ö97 12. Compounds according to claim 1, characterized that these are the following: 3- (4-methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 1,2-dihydronaphthalene 3- (4-methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 1,2-dihydonaphthalene citrate 3-Pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 7-methoxy-1,2-dihydonaphthalene 3-Pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 7-methoxy-1,2-dihydronaphthalene nitrate 3-Pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 1,2-dihydonaph thalin 3-Pheny1-4- / 4- (2-pyrrolidinoethoxy) benzoyl _ / - 1,2-dihydonaph Thai eitrate 1- / 4- (2-pyrrolidinoethoxy) benzoyl_ / -2-phenylnaphthalene 1- / 4- (2-pyrrolidinoethoxy) benzoyl_ / -2-phenylnaphthalenesi tr at 3- (4-Methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 7-methoxy-1,2-dihydronaph thalin 3- (4-Methoxyphenyl) -4- / 4- (2-pyrrolidinoethoxy) benzoyl_ / - 7-methoxy-1,2-dihydronaphthalene citrate 13. A process for the preparation of aroylphenylnaphthalenes of the formula I mentioned in claim 1, wherein the substituents X, R, R, R "and R _{3 have} the meanings given in claim 1, characterized in that one 1) a substituted tetraion of formula II II 7O9819 / rÖ§7 R for hydrogen, C ₁ -Cj. Alkoxy or benzyloxy is a J. D and ^R 2 Y represents methoxy, benzyloxy or ^ N-CH ₉ -CH ₉ -O-, R ₃ where the Sübstitutenten R ₉ and R-> have the meanings given above, with a phenylmagnesium bromide of the formula III R - · \ / · -MgBr III ^ Β j R ₁ for hydrogen, C , -C ₁ . Is alkoxy or benzyloxy, la J. D implements, 2) the product thus obtained, in which X stands for -CH ₂ -CH ₂ -, if desired with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at a temperature of 50 to 100 ⁰ C- to the corresponding compound in which X stands for -CH = CH-, converts, 3) the product obtained in the above manner in which Y is methoxy or benzyloxy, with pyridine hydrochloria and / or sodium thioethoxide to the corresponding compound, in the 709819/1097 Hydroxy means, and this compound then reacts with a l-chloro-2-aminoethane of the formula IV Cl-CH ₂ -CH ₂ -NC ^ IV ^R 3 wherein the substituents R «and R- have the meanings given above have, react, 4) the compound obtained in this way, in which the substituents R ^ or R _{1 are} benzyloxy, by conversion el Xa set with sodium thioethoxide in the corresponding compound in which the substituents R or R _{1 are} hydroxy, converted and 5) the compound obtained in this way, in which the substituents R_ or R ₁ _ are alkoxy, by reacting with 3. Xa Sodium thioethoxide into the corresponding compound in which. the substituents R or R. are hydroxy, transferred. 709819 / 1ÖI7