IE43641B1 - 1-aroyl-2-phenyl-naphthalenes and dihydronaphthalenes, methods for their preparation and their use - Google Patents

Abstract

Aroylphenylnaphthalenes of the formula I in which X is -CH2-CH2- or -CH=CH-, R is hydrogen or C1-C5-alkoxy, R1 is hydrogen or C1-C5-alkoxy, and the substituents R2 and R3 form, together with the nitrogen atom to which they are bonded, a pyrrolidino group, and the pharmaceutically acceptable non-toxic acid addition salts thereof are obtained by reacting a naphthalene derivative with a chloro-2-aminoethane, and converting resulting compounds of the formula I where appropriate into the pharmaceutically acceptable non-toxic acid addition salts. The compounds of the formula (I) which can be prepared according to the invention are, as a rule, valuable medicines. They are normally distinguished particularly by a fertility-inhibiting action and are therefore suitable in particular as orally active fertility-inhibiting agents in birds and mammals. The compounds of the formula (I) which can be prepared according to the invention may therefore be suitable for controlling the animal population and as contraceptives for life forms. These compounds can furthermore also be used, for example, to control animal pests.

Description

The present invention relates to novel derivaLves oE aroyl-phenylnaphthalenes which are useful as antiirtility and antitumor agents.

The prior art has recognized various classes of impounds, each having the general formula Z\ /r' ! Γ“Ι vyv i which Ar1 and Ar11 are each an aryl moiety and Y is any of various groups ich as -CH2-, -CH2-CH2-, -S-, -NH, -OCH2, -0-, -CH2S-, id -SCH2_. Many compounds within these general classes are ascribed as having antifertility activity.

Lednicer et al., J, Med. Chem., 8, (1965), j. 52-57, discloses 2,3-diphenylindenes and derivatives lereof as antifertility agents.

Lednicer et al., J. Med. Chem. , 9^, (1966) , ?. 172-175; Lednicer et al. J. Med. Chem., 10, (1967), 3. 78-84; and Bencze et al., J. Med. Chem., £, (1965), 3. 213-214, each disclose various l,2-diaryl-3,4-dihydroaphthalenes as active antifertility agents. In addition, ited States Patent Specifications. Itos. 3,274,213; 3,313,853; 3,396,169; id 3,567,737 disclose various l,2-diphenyl-3,4-dihydronaphlalenes as useful antifertility agents.

Other United States Patent Specifications disclose both 1,2-diienyl-3,4-dihydronaphthalenes and 2,3-diphenylindenes as ctive agents. These include United States Patent fiipecificatians Nos -24 3 6 11 3,862,232.

In addition, Crenshaw et al., J. Med. Chem., 14, (1971), pp. 1185-1190, discloses, among others, various 5 2,3-diarylbenzcthiophenes as exhibiting anti fertility activity. Certain of these compounds are claimed in 0. S. Patent Specification No. 3,413,305. Crenshaw et al. additionally disclose other compounds which participate in the general classes described hereinabove. 2,3-Diarylbenzofurans corresponding generally to the above benzothiophenes are disclosed and claimed in U. S. Patent Specification No. 3,394,125.

A need still exists to provide additional compounds useful as antifertility agents and, in particular, nonsteroidal antifertility agents. The novel compounds of formula I below fill such a need. They are 3-phenyl-4aroyl-1,2-dihydronaphthalenes and l-aroyl-2-phenylnaphthalenes, and, structurally, they differ significantly from those described in the aforementioned prior art.

This invention provides novel non20 steroidal compounds having antifertility activity.

The present invention provides novel aroyl-phenylnaphthalene compounds having the formula I -34 3 6 41 in which X is -CS^-CS^- or -(-H=CH-; R is hydrogen, hydroxyl, or C^-C2 alkoxy; R^ is hydrogen, hydroxyl, or C^^-Cg alkoxy; and R2 and Rg independently are C^-C^ alkyl, or R2 and Rg taken together with the nitrogen to which they are bonded constitute a heterocyclic ring selected from pyrrolidino, piperidino, hexamethyleneimino, or morpholino; and pharmaceutically acceptable,non-toxic acid addition salts thereof.

The present invention also provides a process for preparing novel aroyl-phenylnaphthalene compounds of formula I wherein X, R, Rg, R2 and Rg are as defined above, which comprises 1) reacting a substituted tetralone compound of the formula Y Λ.

V/ II ζνγ wherein R& is hydrogen, Cg-Cg alkoxy or benzyloxy; and Y R is methoxy, benzyloxy or ,N-CH -CH -0- wherein R„ and R, R 2 2 a are as defined above; with a phenyl magnesium bromide compound of the formula /“\ R —< >—MgBr III ia \ z x·—’“· wherein Rga is hydrogen, Cg-Cg alkoxy or benzyloxy; 2) optionally reacting the product so obtained wherein X is -CHg-CHg- with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone at a temperature of from 50° to 100°C. to provide the corresponding compound wherein X is -CH=CH-; 3) reacting the product obtained in 1) or 2) wherein Y is methoxy or benzyloxy with pyridine hydrochloride or sodium thioethoxide to provide the corresponding compound wherein Y is hydroxy; followed by reaction with a l-chloro-2-aminoethane of the formula CI-CH -CH -n; 2 IV wherein Rg and Rg are as defined above; 4) reacting the compound obtained in 1), 2) or 3) wherein Ra or Rla is benzyloxy with sodium thioethoxide to provide the corresponding oompound wherein R or Rg is hydroxy; and ) if desired reacting the compound obtained in 1), 2) or 3) wherein R, a. or Rg is alkoxy with sodium thioethoxide to provide the corresponding compound wherein R or Rg is hydroxy.

The pharmaceutically acceptable,non-toxic acid addition salts of the compounds of formula I include the organic and inorganic acid addition salts, for example, those prepared from acids such as hydrochloric, sulfuric, sulfonic, tartaric, fumaric, hydrobromic, glycolic, citric, maleic, phosphoric, succinic, acetic or nitric. Preferably, the acid addition salts are those prepared from citric acid. Such salts are prepared by conventional methods. -5;6 ·1ί The term Cj-C^ alkyl as used herein means methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl.

The term C^-Cg alkoxy as used herein defines groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, t-butyloxy, sec-butyloxy, n-amyloxy, isoamyloxy, t-amyloxy or sec-amyloxy. Of the C^-Cg alkoxy groups defined herein, methoxy is highly preferred.

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

Of the defined dihydronaphthalenes, several preferred subclasses exist. One such subclass is comprised of 7-alkoxy-l,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CHg-CHg- and R is C^-Cg alkoxy.

Another subclass includes the non-hydroxylated or alkoxylated dihydronaphthalenes, that is, those compounds of formula I in which X is -CHg-CHg- and both R and R| are hydrogen.

Another such subclass includes 3-(4'-alkoxyphenyl)1,2-dihydronaphthalenes, that is, those compounds of formula X in which X is -CHg-CHg- and is C^-Cg alkoxy.

A further preferred subclass includes 3-(4'alkoxyphenyl)-7-alkoxy-l,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CHg-CHg- and both R and are C^-Cg alkoxy. -6Further preferred subclasses include 3-(4'hydroxyphenyl)-l,2-dihydronaphthalenes and 7-hydroxy-l,2dihydronaphthalenes, that is, those compounds of formula I in which X is -CHg-CHg- and R and Rg is hydroxy.

A most preferred subclass comprises 3-(4'-hydroxyphenyl) -7-hydroxy-l,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CHg-CHg- and both R and Rg are hydroxy.

Another preferred subclass includes those com10 pounds of formula I in which both R2 and Rg are methyl, both Rg and Rg are ethyl, or Rg and Rg taken together with the nitrogen to which they are bonded constitute a pyrrolidino ring.

The compounds of formula I are prepared by the following sequence. which X is (V) benzyloxy, is reacted with a phenyl benzoate of the formula A. Preparation of Compounds in -CHg-CHgA tetralone of the formula A/v .m in which R is hydrogen, C,-Cr alkoxy, or (VI) -73341 R in which Y is methoxy, benzyloxy, or ^N-CH -CH -0- , R R2 and R3 being as aforedefined.

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

The product which is obtained is a substituted tetralone of the formula Y Λ X/ (IX) The substituted tetralone (II) then is reacted under Grignard reaction conditions with the Grignard reagent of the formula •~0 / \ Rla~\ >-M9Br (111) —r in which R^a is hydrogen, C^-Cg alkoxy, or benzyloxy.

The compound which is produced, a 3-phenyl-4aroyl-l,2-dihydronaphthalene, has the fofmula -843641 Z\/ Id fYYv (VII) and, depending upon the identity of the groups R , R. , and Y, may be a compound of formula I.

In those instances in which Y is methoxy and R& and Rga are hydrogen, the compound (VII) can be treated with pyridine hydrochloride at reflux to produce the corresponding hydroxy compound. As indicated, this method is useful only with respect to those compounds in which R, and a Rga are hydrogen since, if Rg and/or Rga were alkoxy or 10 benzyloxy, these groups also would be cleaved to hydroxyl groups.

Once the aforedescribed compound in which Y is hydroxyl has been generated, it can be treated with a compound of the formula C1-CH2-CH2-Y 2 (IV) R3 in which R2 and Rg are as aforedescribed, to produce a compound of formula I.

In those instances in which Y in compound (VII) is methoxy or benzyloxy, and R and/or R. are alkoxy or a ia benzyloxy, the group at Y can be Selectively cleaved by treating the compound with sodium thioethoxide in N,N-94 3 6 4 ί dimethylformamide at a moderately elevated temperature of 80°C. to 90°C. The progress of the selective cleavage can be monitored by periodic thin-layer chromatographic analysis (TLC) of the reaction mixture. The reaction is complete when little or no starting material remains.

The resulting product, containing a hydroxyl at Y, the sole hydroxyl in the molecule, then is treated as aforedescribed with a l-chloro-2-substituted aminoethane.

Depending upon the intended structure of the final product, the compound containing the 2-amlnoethoxy substituent then can be further treated with sodium thioethoxide in Ν,Ν-dimethylformamide as aforedescribed to effect cleavage of any remaining alkoxy or benzyloxy groups, thereby to achieve formation of those compounds of formula I in which R and/or R^ are hydroxyl.

In any of the above, it is evident that the particular sequence of synthetic steps designed to produce a compound having substituents of particular definition and location is such as one of ordinary skill in the art will well recognize.

B. Preparation of Compounds in which X is -CH=CH-.

These compounds are readily prepared from the aforementioned compounds in which X is -CHj-CHg”. Selective dehydrogenation of the dihydronaphthalene structure to produce specifically the corresponding naphthalene can be accomplished by treatment of the former with 2,3-dichloro5,6-dicyano-l,4-benzoquinone (DDQ) at a temperature of from 50°C. to 100°C. -10 8 .{ 4 Again, by means of the aforementioned derivatizing reactions, the naphthalene which is produced can be converted to other naphthalene compounds within the scope of formula I.

The compounds of formula I are valuable pharmaceutical agents. They exhibit anti-fertility activity, and they especially are useful as orally active anti-fertility agents in birds and mammals. The compounds of formula I thus are useful in controlling the animal population and as contraceptives in living beings. The compounds also are valuable for animal pest control. For example, the compounds can be formulated in combination with baits and/or attractants and placed in feeding stations accessible to undesirable rodents and other small animals including Canidae such as coyotes, foxes, wolves, jackals, and wild dogs, and birds, such as starlings, quills, redwing blackbirds or pigeons, to greatly reduce the population thereof. By reason of the activity of the compounds of formula I, they can be used to reduce hazards to aviation by lessening the presence of birds and animals on runways and in the vicinity of air fields. The compounds also can be used to reduce the population of undesirable birds and animals so as to aid in the prevention and the spread of disease, and to reduce the destruction of property in both rural and urban areas.

The compounds of formula I can be administered as such, or they can be compounded and formulated into pharmaceutical preparations in unit dosage form for oral or paren-11· 2 6',Ρteral administration. In the compounding or formulation, organic or inorganic solids and/or liquids which are pharma eeutically acceptable carriers can be employed. Suitable such carriers will be well recognized by those of ordinary skill in the art. The compositions may take the form of tablets, powder granules, capsules, suspensions or solutions .

The compounds of formula I, when administered in an effective amount, will produce the inhibition of pregnancy in mammals. The usual daily dose is from 0.02 milligrams to 20 milligrams per kilog'ram body weight of the recipient. The preferred daily dose is from 0.02 milligrams to 0.4 milligrams per kilogram body weight of the recipient.

Examples of compounds of formula I include the following: 3-(4-hydroxyphenyl)-4-]4-(2-pyrrolxdinoethoxy)benzoyl]-1,2-dihydronaphthalene ; 3-(4-methoxyphenyl)-4-[4-(2-diethylaminOethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-isopropoxyphenyl)-4-[4-(2-pyrrolidinoethoxy) benzoyl]-1,2-dihydronaphthalene; 3-(4-t-butyloxyphenyl)-4-[4-(2-hexamethyleneimino ethoxy)benzoyl]-1,2-dihydronaphthalene; 3- (4-pentyloxyphenyl)-4-[4-(2-morpholinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-methoxyphenyl)-4-[4-(2-piperidinoethoxy)benzoyl1-1,2-dihydronaphthalene; 3-(4-ethoxyphenyl)-4-[4-(2-dimethylaminoethoxy)benzoyl]-1,2-dihydronaphthalene; -123-(4-n-propoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-sec-butyIoxyphenyl)-4-[4-(2-piperidinoethoxy)benzoyl)-1,2-dihydronaphthalene; 3-(4-ethoxyphenyl)-4-[4-(2-morpholinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-hydroxyphenyl)-4-[4-(2-hexamethyleneiminoethoxy) benzoyl]-1,2-dihydronaphthalene; 3-(4-methoxyphenyl)-4-[4-(2-dimethylaminoethoxy)10 benzoyl]-1,2-dihydronaphthalene; 3- (4-isopropoxyphenyl)-4-[4-(2-diethylaminoethoxy)benzoylJ-1,2-dihydronaphthalene; 3-(4-t-butyIoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3- (4-pentyIoxyphenyl)-4-(4-(2-piperidinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-isobutyIoxyphenyl)-4-[4-(2-morpholinoethoxy)benzoyl]-1,2-dihydronaphthalene; 3-(4-ethoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)20 benzoyl]-l,2-dihydronaphthalene; 3-(4-n-propoxyphenyl)-4- [4-(2-dimethylaminoethoxy) -benzoylJ-1,2-dihydronaphthalene; 3-(4-hydroxyphenyl)-4-[4-(2-diethylaminoethoxy,benzoyl]-1,2-dihydronaphthalene; 3-(4-methoxyphenyl)-4-(4-(2-plperidino)benzoyl]-1,2-dihydronaphthalene; 3-(4-hydroxyphenyl,-4- [4- (2-diethylaminoethoxy)benzoyl]-7-methoxy-naphthalene; -134 3 5 41 3-(4-hydroxyphenyl)-4-[4-(2-morpholinoethoxy)benzoyl] -1,2~dihydronaphthalene; 3-(4-hydroxyphenyl)-4-[4-(2-dimethylaminoethoxy)benzoyl]-7-hydroxy-l,2-dihydronaphthalene; 3-(4-methoxyphenyl)-4-[4-(2-diethylaminoethoxy)benzoyl]-7-methoxy-l,2-dihydronaphthalene; 3-(4-isopropoxyphenyl)-4-[4-(2-pyrrolidinoethoxy) benzoyl]-7-ethoxy-l,2-dihydronaphthalene; 3-(4-t-butyloxyphenyl)-4-[4-(2-dimethylaminoethoxy) benzoyl ]-7-propoxy-l, 2-dihydronaphthalene; 3-(4-pentyloxyphenyl)-4-[4-(2-piperidinoethoxy)benzoyl]-7-pentyloxy-1,2-dihydronaphthalene; 3-(4-hydro'xyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-pentyloxy-1,2-dihydronaphthalene; 3-(4-ethoxyphenyl)-4-[4-(2-morpholinoethoxy)benzoyl]-7-ethoxy-l,2-dihydronaphthalene; 3-phenyl-4-[4-(2-dimethylaminoethoxy)benzoyl]1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7methoxy-1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-dimethylaminoethoxy)benzoyl]-7hydroxy-1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-hexamethyleneiminoethoxy)benzoyl] -7-methoxy-l, 2-dihydronaphthalene; 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7hydroxy-1,2-dihydronaphthalene; 3-phenyl-4-[4- (2-hexamethyleneethoxy)benzoyl} -7ethoxy-1,2-dihydronaphthalene; -1443641 3-phenyl-4-[4-(2-morpholinoethyl)benzoylJ-7methoxy-1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-hexamethyleneiminoethoxy)benzoyl ]-7-isopropoxy-l,2-dihydronaphthalene; 3-phenyl-4-[4-(2-dimethylaminoethoxy)benzoyl]7-pentyloxy-l,2-dihydronaphthalene; 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7ethoxy-1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-morpholinoethoxy)benzoyl]-710 isopropoxy-1,2-dihydronaphthalene; 3-phenyl-4-[4-(2-hexamethyleneiminoethoxy)benzoyl] -7-butyloxy-l, 2-dihydronaphthalene; 3-phenyl-4-[4-(2-diethylaminoethoxy)benzoyl]-7hydroxy-1,2-dihydronaphthalene; 1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-hydroxyphenyl ) naphthalene; 1-(4-(2-plperidinoethoxy)benzoy1J-2-(4-n-propoxypheny1) naphthalene; 1-[4-(2-piperidinoethoxy)benzoyl]-2-(4-sec2 0 butyIoxyphenyl) naphthalene; 1-[4-(2-diethylaminoethoxy)benzoyl]-2-(4-methoxyphenyl)naphthalene; 1-(4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-isopropoxyphenyl) naphthalene; 1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2(4-t-butyIoxyphenyl) naphthalene; 1-(4-(2-morpholinoethoxy)benzoyl]-2-(4-pentyIoxyphenyl) naphthalene; -15. 43641 1-[4-(2-piperidinoethoxy)benzoyl]-2-(4-methoxyphenyl)naphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4ethoxyphenyl)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-methoxy phenyl) 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-ethoxypheny1) naphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-npropoxyphenyl)naphthalene; 1-[4-(2-diethylaminoethoxy)benzoyl]-2-(4-hydroxyphenyl)naphthalene; 1-(4-(2-pyrrolidinoethoxy) benzoyl]-2-(4-fflethoxypheny1) naphthalene; 1-[4-(2-piperidinoethoxy)benzoyl)-2-(4-hydroxyphenyl ) naphthalene; -1643641 1-(4-(2-morpholinoethoxy)benzoyl]-2-(4-hydroxyphenyl)naphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-hydroxyphenyl)-6-hydroxynaphthalene; 1-[4-(2-diethylaminoethoxy)benzoyl]-2-(4-methoxyphenyl) -6-methoxynaphthalene; 1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-isopropoxyphenyl)-6-ethoxynaphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-t10 butyIoxyphenyl)-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-6methoxynaphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-pheny1-620 hydroxynaphthalene; 1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2phenyl-6-methoxynaphthalene; 1- [4-(2-pyrrolidinoethoxy) benzoyl]-2-phenyl-6hydroxynaphthalene; 1-[4-(2-piperidinoethoxy)benzoyl]-2-phenyl-6e thoxynaphthalene; 1-(4-(2-morpholinoethoxy)benzoyl]-2-phenyl-6methoxynaphthalene; -174 2 6 41 1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2phenyl-6-isopropoxynaphthalene; 1-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl6-pentyloxynaphthalene; 1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-phenyl6-ethoxynaphthalene ,Ι- [4-(2-morpholinoethoxy)behzoyl]-2-phenyl-6i sopropoxynaphthalene; 1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-20 phenyl-6-butyloxynaphthalene; 1-[4-(2-diethylaminoethoxy)benzoyl]-2-phenyl-6hydroxynaphthalene.

The following examples are illustrative of the preparation and activities of the compounds of formula I.

They are not intended to be limiting upon the scope thereof Example 1 — Preparation of the Citrate Salt of 3-(4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]1,2-dihydronaphthalene.

To a suspension of 15.2 grams (0.38 mole) of sodium amide in 250 ml. of tetrahydrofuran (THF) were added 50 grams (0.34 mole) of β-tetralone. The mixture was stirred for 15-20 minutes, and 78 grams of phenyl £-methoxy benzoate dissolved in THF were added. The temperature was maintained below 10°C., and the mixture then was stirred at i room temperature overnight. The reaction mixture was concentrated, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and concentrated. The -1842641 residue was chromatographed on silica using benzene as eluant. The purer fractions obtained by the chromatographic separation were combined and concentrated, and the residue was dissolved in a minimum of methanol. The methanol was cooled, and 35.2 grams of 1-(p-methoxybenzoyl)-2-tetralone were collected by filtration, melting point 88-91°C.

Analysis, Calcd. for cx3Hxg°3: C, 77.12; ii, 5.75; 0, 17.12.

Found: C, 77.08; II, 5.54; 0, 17.32.

Mass spectrum: Theory, 280; Found, 280. g-Bromoanisole (18.7 grams; 0.1 mole) was added dropwise in ether to THF containing 5 drops of 1,2-dibromoethane and 3.6 grams (0.15 mole) of magnesium. Reaction occurred almost immediately, and the addition was continued at a slow rate with evolution of heat sufficient to maintain a general reflux. Upon completion of the addition, the above substituted [1-tetralone dissolved in acetone was added dropwise with stirring over a two-hour period, the mixture being maintained at 40°C. The resulting mixture then was poured into cold, dilute hydrochloric acid, and the acidic mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and concentrated to an oil. The oil was chromatographed over silica using benzene as eluant. Starting material (8.6 grams) was obtained as greenishyellow crystals, melting point 86-88°C., and 15 grams of 3-(4-methoxyphenyl)-4-(4-methoxybenzoyl)-1,2-dihydronaphthalene were obtained as an oil upon elution of the column with a mixture of benzene containing 2 percent ethyl acetate. -19Analysis, Calcd. for C25H22°3: C, 81.06; H, 5.99; O, 12.96.

Found: C, 81.32; H, 6.13; 0, 13.04.

A mixture of 11.1 grams (0.03 mole) of the above imethoxy product, 7.2 grams of sodium hydride (50 percent a oil), and 11 ml. of ethyl mercaptan in N,N-dimethy1□rmamide was prepared. The mixture was heated to 65-70°C. or two hours. The mixture then was cooled and cOncenrated. The concentrate was acidified and extracted with thyl acetate. The ethyl acetate extract was washed, dried nd evaporated. The residue was dissolved in benzene and hromatographed over silica to obtain five grams of an oil omprising relatively pure 3-(4-methoxyphenyl)-4-(4-hydroxy lenzoyl)-1,2-dihydronaphthalene.

Analysis, Calcd. for C24H20°3! C, 80.88; H, 5.66; 0, 13.47.

Found: C, 79.66; H, 5.87; 0, 13.57.

The above phenolic product (4.3 grams; 0.01 mole) was dissolved in Ν,Ν-dimethylformamide. To this solution was added 0.7 gram of sodium hydride (50 percent in oil), and the resulting mixture was warmed to 40°C. for one hour and then was cooled to room temperature. To the mixture then were added 1.62 grams of l-chloro-2-pyrrolidinoethane, and the mixture was warmed to 60°C. for two hours and then was stirred at room temperature overnight. The mixture was concentrated, and water was added to the residue. The 3 6 41 aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed and concentrated to a residue.

The residue was extracted with hexane, the insoluble portion was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with 1 N hydrochloric acid. The acid extract was rendered alkaline, and then was extracted with ethyl acetate. The ethyl acetate extract was washed and concentrated. One equivalent of citric acid in acetone then was added to the concentrate, and the mixture was concentrated to dryness. The residue was dissolved in a large volume of methyl ethyl ketone. The ketone solution was concentrated to about 300 ml. and was cooled to O’C. The product, the citrate salt of 3-(4-methoxyphenyl)-4-[4-(2pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene, was collected by filtration and vacuum dried, melting point 82-85’C.

Analysis, Calcd. for CggH^gNO^Q: 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.

Example 2 — Preparation of the Citrate Salt of 3-Phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2dihydronaphthalene.

To 300 ml. of DMF were added 107 grams of phenyl £-hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil). The mixture was heated at 60’C. for two hours. To the mixture then were added 67 grams of l-chloro-2-pyrrolidinoethane, and the mixture was stirred overnight at 85’C. -21436^1 The bulk of the DMF then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate. The organic solution then was extracted with 2N hydrochloric acid, and the acid extract was added dropwise to 2N sodium hydroxide. The resulting mixture was extracted With ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium, sulfate. The ethyl acetate was concentrated to obtain 110 grams of crude phenyl £-(2-pyrrolidinoethoxy)benzoate.

To a suspension of 20 grams (0.5 mole) Of sodium amide in tetrahydrofuran were added dropwise 41.7 grams of 6-methoxy-2-tetralone in THF, the temperature of the mixture being maintained below 10°C. Upon completion of the addition, the mixture was stirred for 20 minutes at below 10eC. after which time an exothermic reaction occurred, the temperature rising to about 20°C. The above-prepared phenyl £-(2-pyrrolidinoethoxy)benzoate dissolved in THF then was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed several times with water and dried over magnesium sulfate. The ethyl acetate then was concentrated to obtain about 100 grams of crude material which was dissolved in 1.5 liters of acetone, and one equivalent of citric acid in 400 ml. of ethyl acetate was added. The resulting solid was isolated by filtration and vacuum dried to obtain 85.9 grams of product, melting point -2284°C., which proved to be 6-methoxy-l-{4-(2-pyrrolidinoethoxy)benzoyl]-2-tetralone and not the corresponding citric acid salt. The product then was chromatographed over silica using ethyl acetate as eluant, and the citrate salt was prepared from the recovered product.

Analysis, Calcd. for C30H35NOll! C, 61.53; H, 6.02; N, 2.39; Found: C, 61.39; H, 5.78; N, 2.25.

The above product (8.6 grams; 0.02 mole) was added to a solution of phenylmagnesium bromide in THF. The resulting mixture was stirred for one hour at room temperature and then was warmed to 50°C. for three hours. The resulting mixture was poured into a mixture of ice and hydrochloric acid, and the acid mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and concentrated to obtain 10.5 grams of a red-brown oil. The oil was added to 500 ml. of acetic acid, and the mixture was heated on a steam bath for about 30 minutes. The acid was stripped off, and water was added to the residue. The aqueous mixture was rendered alkaline by addition of base, and the alkaline mixture was extracted with ethyl acetate. The extract was dried and concentrated to obtain 8.7 grams of product which were dissolved in acetone, and one equivalent of citric acid was added to the mixture. The acetone was stripped off, and methyl ethyl ketone was added to the residue. The mixture was maintained at 0°C. overnight, and the crystals which formed were collected by filtration and washed with cold methyl ethyl ketone and vacuum dried, 43841 melting point 95-100°C. The solid was recrystallized from acetone to obtain the title compound in the form of its citrate salt, melting point 98-100°C.

Analysis, Calcd. for C3gH39NOio: 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.

The title compound in the form of its free base was generated by treatment of the citrate salt with dilute alkali.

Analysis, Calcd. for C3oH3iN03: C, 79.44; H, 6.89; N, 3.09; Found: C, 79.19; H, 6.68; N, 2.91.

Example 3 — Preparation of the Citrate Salt of 3-Phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene.

To a solution of 5.0 grams (0.018 mole) of 1(4-methoxybenzoyl)-2-tetralone (prepared as in Example 1) in 50 mi. of ether was added dropwise at 0°C. a solution of 0.018 mole of phenylmagnesium bromide in 9 ml. of ether.

Upon completion of the addition, the mixture was stirred for twenty minutes. Thin-layer chromatography of the reaction mixture indicated the presence of starting material. An additional 13.5 ml. of the phenylmagnesium bromide solution were added. The mixture was refluxed for 2 hours and then was cooled and poured over iced aqueous ammonium chloride solution. The organic layer was separated and washed with aqueous sodium chloride solution. The mixture then was -2443641 dried over magnesium sulfate, filtered, and evaporated to give about 5 grams of a yellow oil. In order to obtain more product, a second 5.0 grams of the tetralone was reacted as above. The products were combined, and the total, about 10 grams of oil, was washed with hexane. The portion which was insoluble in the hexane was chromatographed over a 1 x 20 neutral AljO^ column using, as gradient, a 1:1 mixture of benzene and hexane which progressively diminished in hexane until 100 percent benzene was present. There were obtained 4.67 grams (38 percent) of 3-phenyl-4-(4-methoxybenzoyl)1,2-dihydronaphthalene. The material was recrystallized from methanol, melting point 106-107°C.

Analysis, Calcd. for C2i&2Q°2: C, 84.68? H, 5.92; 0, 9.40.

Found: C, 84.96; H, 6.13; 0, 9.65.

Mass spectrum: Theory, 340; Found, 340.

To 2.0 grams (0.006 mole) of the above dihydronaphthalene dissolved in 10 ml. of N,N-dimethylformamide 20 were added 7.5 mmoles of sodium thioethoxide in 15 ml. of DMF. The addition was carried out under a nitrogen atmosphere and at 80°c. The mixture was maintained at 80°C. for fifteen hours. The mixture then was cooled and poured into an iced aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed four times with aqueous sodium chloride solution. The ethyl acetate then was dried over magnesium sulfate and evaporated to give an oil which was chromatographed rapidly over a 2 x 2 silica column using 25641 benzene to elute impurities. The product then was eluted with ethyl acetate to give, upon evaporation of the ethyl acetate, 1.69 grams (88%) of 3-phenyl-4-(4-hydroxybenzoyl)-1,2-dihydronaphthalene as a clear pale yellow oil.

Mass spectrum: Theory 326; Found 326.

A mixture of 1.61 grams (4.95 mmoles) of the above product in 10 ml. of dry DMF was added dropwise to 20 ml. of DMF containing 119 mg. (4.95 mmoles) of sodium hydride and freshly distilled l-chloro-2-pyrrolidinoethane. The addition was made under a nitrogen atmosphere with the temperature being maintained at about 10°C. Upon completion of the resulting effervescence, the mixture was heated at 80eC. for two hours. The mixture then was poured into water, and the total was extracted with ether. The ether extract was washed 5 times with aqueous sodium chloride and dried over magnesium sulfate. The ether layer then was filtered and evaporated to give a grey oil. The oil was chromatographed over a 2 x 2 silica column using an ethyl acetate * methanol gradient. There.were recovered 1.18 grams (56%) of 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene.

Mass spectrum: Theory, 423; Found, 423.

The product was converted to the corresponding citrate salt by treatment with 0.59 grams of citric acid in 50 ml. of hot acetone. The resulting mixture was evaporated to dryness, and the residue was stirred for 15 hours with ether to obtain the citrate salt. The salt was vacuum dried to give 1.62 grams (53%) of the title compound, melting point 89-93°C. -2643641 Analysis, Calcd. for C^gH^NO^ · 1/2 HgO: C, 67.34; H, 6.13; N, 2.25.

Found: C, 67.06; H, 6.41; N, 2.66.

Example 4 — Preparation of the Citrate Salt of 1-(4-(2-Pyrrolidinoethoxy) benzoyl]-2-phenylnaphthalene.

To 30 ml. of dioxane were added 1.90 grams (5.58 mmoles) of 3-phenyl-4-(4-methoxybenzoyl)-1,2-dihydronaphthalene (prepared as in Example 3) and 2.00 grams (8.81 mmoles) of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone. The resulting mixture was heated at reflux for twelve hours in a nitrogen atmosphere. The mixture then was cooled and evaporated to dryness. Water and ether were added to the residue. The ether layer was separated and washed 5 times with 20 ml. portions of 5N sodium hydroxide and then with aqueous sodium chloride. The mixture then was dried over magnesium sulfate and evaporated to give 1.9 grams of substantially pure 1-(4-methoxybenzoyl)-2-phenylnaphthalene as a green oil.

Employing substantially the same demethylation procedure as described in Example 3, 1.83 grams (5.41 mmoles) of the above product were treated with sodium thioethoxide to obtain the 1.40 grams (80%) of 1-(4-hydroxybenzoyl)-2-phenylnaphthalene, melting point 204-205°C.

Analysis, Calcd. for C23Hig°2! C, 85.16; H, 4.97; 0, 9.86; Found: C, 84.99; H, 5.12; 0, 9.58. 3 6 41 To 10 ml. of DMF were added 1.25 grams (3.86 mmoles) of the above product. The resulting mixture was added at about 10°C. to a mixture of 20 ml. of DMF oontaining 120 mg. (5.0 mmoles) of sodium hydride and 800 mg. of l-chloro-2-pyrrolidinoethane. Upon completion of the resulting effervescence, the mixture was heated at 80°C. for 3 hours during which time sodium chloride precipitated. The mixture was cooled and evaporated to dryness. The resulting residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated and washed 5 times with 25 ml. each of aqueous sodium chloride Solution. The ethyl acetate solution then was dried and evaporated to give 1.62 grams (about 100%) of 1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-phenylnaphthalene as a yellow oil.

The above free base was converted to the corresponding citrate salt in accordance With the method of Example 3 employing 0.’811 grams of citric acid hydrate. The title compound was obtained as an amorphous solid which crystallized on standing overnight in ether, melting point 105-108°C.

Analysis, Calcd. for C33H35NOg · HgO; C, 65.55; H, 5.90; N, 2.22; Found: C, 66.90; H, 5.85; N, 2.25, Example 5 — Preparation of the Citrate Salt of 3-(4-Methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7methoxy-1,2-dihydronaphthalene.

To a solution of about 50 grams (0.24 mole) of jo-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) -28'< 3 G 4 1 were added at room temperature 30.2 grams (0.08 mole) of 1-(jj-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45°C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of g-toluenesulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 1. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl)4-(4-benzyloxybenzoyl)-7-methoxy-l,2-dihydronaphthalene was obtained as an oil.

Analysis Calcd. for C32H28°4: C, 80.65; H, 5.92; 0, 13.43; Found: C, 80.96; H, 5.91; 0, 13.61.

To 150 ml. of Ν,Ν-dimethylformamide (DMF) were added 5.4 grams (0.011 mole) of the above dihydronaphthalene. To the mixture were added 30 ml. of DMF containing 0.5 mole of sodium thioethoxide. The resulting mixture was heated under nitrogen at 90°C. Progress of the reaction was followed by TLC. Upon completion, the mixture was poured -294 5 6-11 into an aqueous ammonium chloride solution. The aqueous mixture then was extracted with ethyl acetate. The ethyl acetate extract was separated, washed, dried, and concentrated to an oil. The oil was chromatographed over silica using benzene. Those fractions containing the desired product, 3-(4-methoxyphenyl)-4-(4-hydroxybenzoyl)-7-methoxy1.2- dihydronaphthalene, were combined and concentrated to dryness to obtain 3.3 grams of a yellow oil. The product was used as such in the next suceeding step.

A mixture of 3.2 grams of the above product in 150 ml. of DMF containing 0.25 grams of sodium hydride was heated in an oil bath at 40’c. for two hours. The mixture became reddish in appearance. Upon completion of the heating, the mixture was cooled to room temperature, 1.2 grams of l-chloro-2-pyrrolidinoethane were added, and the mixture was heated to 60°-70°C. for about one hour. The resulting mixture then was stirred at room temperature overnight after whioh it was poured into a large amount of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed several times with water and sodium bicarbonate solution. The ethyl acetate mixture then was dried over magnesium sulfate and was concentrated to dryness to obtain 3.2 grams of a pale yellow oil. The oil was purified by chromatography over silica using ethyl acetate to obtain 3.0 grams of 3-(4methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy1.2- dihydronaphthalene. The above free base product (2.9 grams) was dissolved in 150 ml. of acetone, and one equivalent of citric acid dissolved in hot acetone was added. -304 C 6 4 ι The mixture was maintained at O°C. for about three days.

The product failed to crystallize. The mixture was evaporated, and the residue was dissolved in a minimum of acetone. Ethyl ether (500 ml.) was added, and the resulting mixture was stirred Overnight. The product crystallized and was collected by filtration and vacuum dried to obtain 3.2 grams of the title compound.

Analysis Calcd. for C, 65.77; H, 6.12; N, 2.07; Pound: C, 65.54; H, 6.10; N, 2.28.

The compounds of formula I are tested for antifertility activity both pre- and postcoitally.

In the precoital antifertility test, fifty young adult virgin female rats weighing 200-230 g. each are separated into ten groups of five each. One of the groups serves as the control group and the other nine groups as experimental groups, each such experimental group receiving test compound at a particular dose level. The test compound for each group of five rats is prepared in corn oil such that the daily administration is in 0.1 ml. of vehicle. The designated quantity of the test compound in the vehicle is administered to each rat within the defined group subcutaneously (sc) daily. The control group receives only the vehicle. Administration of the vehicle or the combination of test compound and vehicle is continued at a daily basis for 15 days. On the 5th day of treatment, two adult male rats weighing at least 250 g. each are added to each group, and cohabitation is continued until the 15th day at which -3143641 time the male rats are withdrawn from the group. Each group of female rats then is maintained for an additional seven days after which the rats are sacrificed and examined for the presence of viable or resorbing fetuses.

The number of animals that exhibit evidence of pregnancy over the number of animals in the group is the pregnancy ratio. A compound is considered active when the ratio is 0/5 or 1/5. A ratio of 2/5 constitutes marginal activity, and anything higher is inactive.

In the postcoital test, adult cyclic virgin female rats weighing at least 200 grams are used as test subjects. The females are placed with a male in single cages and are examined daily for vaginal plugs or for sperm in the vagina. When evidence of breeding is present, the male is removed and daily administration of the test compound is begun and is continued for 11 days. On the 12th day, the female is sacrificed and is examined for the presence of viable and/or resorbing fetuses.

The pregnancy ratio (number of animals pregnant per number of animals in the group) is given. Since all test animals represent confirmed breedings, the figures for control animals are quite high. Therefore, a 50 percent pregnancy rate is deemed to indicate activity.

In addition, the total number of viable fetuses and the total number of resorption sites are given as an indication of fecundity and of rate of implantation. Since, in the control, the customary number of viable fetuses per -324 3 6 41 animal is about 11 or 12, any reduction of this figure is also an indicator of activity.

The Table following illustrates the antifertility activity of compounds of formula I. -3343641 w G •rt • a p p s o ui Q) P4 Φ • H 043 3 nJ •rt > X 44 Oj G 3 ti 0 Sts Φ k G rt +J <β . . „ rt ft ’rt 0 is & OOrt o I Antifertility Activity irt ti 0 II +> G 0 ft •rt ti *rt 0 G 44 in o tntix I oh I in O CJ I I L> >4 ti fl)O w\ · Q Cn • e in rrt in r-ι ο o in ο ο ο o • · > · · ο © © σ a in Η in rrt o © o © © © z \ \_y ι Cl a o I CJ a υ I cj a σ cj m rt rt V ti o G •rt •rt k k >4 ft ti o G •rt •0 •rt rH k k >4 ft ro a u o O I 344 2 6 41 ο ο γ- οοο ο ο ω φ • rH Ο Λ S flj •Η > \ jj Ch β β φ 0 0 β p •iH cnu -Ρ Φ «5 β a a •rH 0 0 z z ro ο Ο rH CM rH >1 Φ υ n JJ β 0 Ch •rl Id *«H 0 fi JJ in ϋ tn fl\ Φ φ a a M M Ch a >1 Φ φ Ό ω\ ο · Q tn e Ο CM CM rH in in rH o ooo CM W u I CM a o ι Γ”· Η CM Ν ΓΟ cm ro co ΗΝω H in Η ο o ro cO ro O rH Ν in in η o ooo ooo ooo I a o I! a o I CM a u CM a o CM Γ0 Οί Λ y id § •H »H rH k Jh fr Ch β •H TJ Ή rH p M >1 Ch β •H •H H JH tH >1 Ch CO 4J a r—1 υ id o w1 Φ jj id ro M a JJ υ •rH o u 1 id -35'

Claims (11)

1. CLAIMS:1. An aroyl-phenylnaphthalene compound of the formula ;X „R / 2 r w. VYV\ ·. R in which X is -CHg-CHg- or -CH=CH-; R is hydrogen, hydroxyl, or Cg-Cg alkoxy; Rg is hydrogen, hydroxyl, or Cg-Cg alkoxy; and Rg and Rg independently are Cg-C^ alkyl, or Rg and Rg taken together with the nitrogen to which they are bonded constitute a heterocyclic ring selected from pyrrolidino, piperidino, hexamethyleneimino, or norpholino; or a pharmaceutically acceptable non-toxic acid addition salts thereof.

2. Compound of claim 1, in which both Rg and Rg are methyl or both Rg and Rg are ethyl, or Rg and Rg taken together with the nitrogen to which they are bonded constitute a pyrrolidino ring.

3. Compound of claim 2, in which Rg and Rg taken together with the nitrogen to which they are bonded constitute a pyrrolidino ring.

4. Compound of any of claims 1 to 3, in the form >f its pharmaceutically acceptable, non-toxic acid addition salt.

5. Compound of claim 4, in the form of its :itrate salt. -364S641

6. Compound of any of claims 1 to 5, in which R^ is alkoxy and R is hydrogen.

7. Compound of any of claims 1 to 5, in which R is C^-Cg alkoxy and Rj is hydrogen. 5

8. Compound of any of claims 1 to 5, in which both R and Rj are Cj-C,- alkoxy.

9. Compound of any of claims 1 to 5, in which both R and are hydrogen.

10. Compound of any of claims 1 to 9» in which 10 X is -CH=CH~.

11. Compound of any of claims 1 to 9, in which X is -CH 2 -CH 2 -.

12. 3- (4-Methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoylj-1,2-dihydronaphthalene 15 13. 3-(4-Methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)~ benzoyl]-l,2-dihydronaphthalene citrate salt

14. 3-Phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7methoxy-1,2-dihydronaphthalsne

15. 3-Pheny1-4-[4-(2-pyrrolidinoethoxy)benzoyl]-720 met:hoxy-l, 2-dihydronaphthalene citrate salt

16. 3-Pheny1-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2dihydronaphthalene

17. 3-Phenyl-4-[4-(2-pyrrolidinoethoxy) benzoyl]-1,2dihydronaphthalene citrate salt 25 18. 1-[4-(2-Pyrrolidinoethoxy)benzoyl)-2-phenylnaphthalene

19. 1- [4- (2-Pyrrolidinoethoxy)benzoyl]-2-phenylnaphthalene citrate salt -3720. 3-(4-Methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-l,2-dihydronaphthalene

21. 3- (4-Metljoxyphenyl) -4- [4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-l,2-dihydronaphthalene citrate salt.

22. A process for preparing an aroyl-phenylnaphthalene compound of formula I as defined in Claim 1, which comprises 1) Reacting a substituted tetralone compound of the formula Y II ! Z YY R \/\/ a · · wherein R g is hydrogen, Cg-Cg alkoxy or benzyloxy; and Y is R nethoxy, benzyloxy or wherein R 2 and Rg R a are as defined.in claim 1» with a phenyl magnesium bromide compound of the formula >~MgBr III wherein Rg is hydrogen, Cg-Cg alkoxy or benzyloxy; J) optionally reacting the product so obtained wherein X ls -CHj-CHj- with 2,3-dichloro-5,6-dioyano-l,4-benzoquinone it a temperature of from 50° to 100°C. to provide the corresponding compound wherein X is -CH=CH-; -3843641 3) reacting the product obtained in 1) or 2) wherein Y is methoxy or benzyloxy with pyridine hydrochloride or sodium thioethoxide to provide the corresponding compound wherein V is hydroxy; followed by reaction with a l-chloro-2-aminoethane of the formula F CI-CH -CH -Μ. IV z 2 R ί wherein and are as defined above; Z 5 4) reacting the compound obtained in 1), 2) or 3), xdierein R & or R la is benzyloxy with sodium thioethoxide to provide the corresponding compound wherein R or R^ is hydroxy; and 5) if desired reacting the compound obtained in 1), 2) or 3) wherein R a or is alkoxy with sodium thioethoxide to provide the corresponding compound wherein R or R^ is hydroxy.

23. A process according to claim 22 for preparing an arcylphenylnaphthalene compound of formula I substantially as hereinbefore described with particular reference to any one of the Examples.

24. An aroyl-phenylnaphthalene compound of formula I as defined in claim 1, substantially as hereinbefore described with particular reference to any one of the Examples.

25. A compound of formula I whenever prepared by a process according to claim 22 or 23.

26. A pharmaceutical formulation which comprises a compound of formula I as claimed in claim 1, or a pharmaceutically-acceptable salt thereof, associated with a pharmaceutically acceptable carrier thereof.

27. A method of preventing, or reducing the incidence of, conception in an animal which comprises orally dosing said animal with a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable acceptable salt thereof.