GB1561687A

GB1561687A - Aroyl-2 - phinyl - naphthalenes and dihydronaphthalenes methods for their preparation and their use

Info

Publication number: GB1561687A
Application number: GB43884/76A
Authority: GB
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1975-10-28
Filing date: 1976-10-22
Publication date: 1980-02-27
Also published as: NL7611974A; SU818476A3; PT65752A; ZA766439B; PH14538A; NL187164C; NL187164B; DE2646213C2; JPS5253845A; FR2329264B1; GR61816B; AU1900476A; PT65752B; FR2329264A1; HU175227B; CS235057B2; CH624376A5; PL104551B1; BG27555A3; PL111987B1

Abstract

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

Description

(54) 1-AROYL-2-PHENYL-NAPHISALENES AND DIHYDRONAPHTHALENES, METHODS FOR THEIR PREPARATION AND THEIR USE (71) ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to novel derivatives of aroyl-phenylnaphthalenes which are useful as antifertility and antitumor agents.

The prior art has recognized various classes of compounds, each having the general formula

in which Ar' and Ar" are each an aryl moiety and Y is any of various groups, such as -CH2-, -CH2-CH2, -S-, -NH-, -OCH2-, -O-, -CH2S-, and -SCH2-. Many compounds within these general classes are described as having antifertility activity.

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

Lednicer et al., J. Med. Chem., 9, (1966), pp. 172-175; Lednicer et al., J. Med. Chem., 10, (1967), pp. 78-84; and Bencze et al., J. Med. Chem., 8, (1965), pp. 213-214, each disclose various 1,2 - diaryl - 3,4dihydronaphthalenes as active antifertility agents. In addition, United States Patent Specifications Nos. 3,274,213; 3,313,853; 3,396,169; and 3,567,737 disclose various 1,2diphenyl - 3,4 - dihydronaphthalenes as useful antifertility agents.

Other United States Patent Specifications disclose both 1,2 - diphenyl - 3,4 - dihydronaphthalenes and 2,3-diphenylindenes as active agents. These include United States Patent Specifications Nos. 3,293,263; 3,320,271; 3,483;293; 3,519,675; 3,804,851; and 3,862,232.

In addition, Crenshaw et al., J. Med. Chem., 14, (l971), pp. 1185-1190, discloses, among others, various 2,3 diarylbenzothiophenes as exhibiting antifertility activity. Certain of these compounds are claimed in U.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 an antifertility agents and, in particular, nonsteroidal antifertility agents.

The novel compounds of formula I below fill such a need. They are 3 - phenyl - 4 - aroyl1,2 - dihydronaphthalenes and 1 - aroyl - 2phenylnaphthalenes, and, structurally, they differ significantly from those described in the aforementioned prior art. This invention provides novel non-steroidal compounds having antifertility activity.

The present invention provides novel aroylphenyl-naphthalene compounds having the formula

in which X is -CH2-CH2- or -CH= CH-; R is hydrogen, hydroxyl, or C1-C2 alkoxy; R1 is hydrogen, hydroxyl, or C1-C5 alkoxy; and R2 and R3 independently are C1 -C4 alkyl, or R2 and R3 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, Ri, R2 and R, are as defined above, which comprises 1) reacting a substituted tetralone compound of the formula

wherein R@ is hydrogen, C1-C5 alkoxy or benzyloxy; and Y is methoxy, benzyloxy or

wherein R2 and Rg are as defined above; with a phenyl magnesium bromide compound of the formula

wherein Rl" is hydrogen, C1----C5 alkoxy or benzyloxy; 2) optionally reacting the product so obtained wherein X is ----CH2-CH2- with 2,3dichloro - 5,6 - dicyano - 1,4 - 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 1 - chloro - 2 - aminoethane of the formula

wherein R2 and R3 are as defined above; 4) reacting the compound obtained in 1), 2) or 3) wherein R2 or Ri, is benzyloxy with sodium thioethoxide to provide the correspond ing compound wherein R or Ra is hydroxy; and 5) if desired reacting the compound ob tained in 1), 2) or 3) wherein Ra or Ri, is alkoxy with sodium thioethoxide to provide the corresponding compound wherein R or Ra is hydroxy.

The pharmaceutically acceptable, non-toxic acid addition salts of the compounds of formula I include the organic and inorganic acid addi tion 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 pre pared by conventional methods.

The term "C1----C4 alkyl" as used herein means methyl, ethyl, n-propyl, isopropyl, n butyl, t-butyl, isobutyl, and sec-butyl.

The term "C1-C5 alkoxy" as used herein defines groups such as methoxy, ethoxy, n propoxy, isopropoxy, n-butyloxy, isobutyloxy, t-butyloxy, sec-butyloxy, n-amyloy, isoamyl oxy, t-amyloxy or sec-amyloxy. Of the C1-C 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 -CH2-CH2 Of the defined dihydronaphthalenes, several preferred subclases exist One such subclass is -comprised of 7 - alkoxy - 1,2 - dihydro naphthalenes, that is, those compounds of formula I in which X is ---CH2--CH,- and R is C1---C, alkoxy.

Another subclass includes the non-hydroxyl ated or alkoxylated dihydronaphthalenes, that is, those compounds of formula 1 in which X is -CH2-CH2 and both R an R1 are hydrogen.

Another such subclass includes 3 - (4' alkoxyphenyl) - 1,2 - dihydronaphthalenes, that is, those compounds of formula 1 in which X is -CH2-CH2- and R1 is C1-C5 alkoxy.

A further preferred subclass includes 3 (4' - alkoxyphenyl) - 7 - alkoxy - 1,2 dihydronaphthalenes, that is, those compounds of formula I in which X is -CH2-CH2 and both R and R1 are C1-C5 alkoxy.

Further preferred subclasses include (3 (4' - hydroxyphenyl) - 1,2 - dihydronaphtha- lenes and 7 - hydroxy - 1,2 - dihydronaphtha lenes, that is, those compounds of formula 1 in which X is -CH2-CH2- and both R and R1 is hydroxy.

A most preferred subclass comprises 3 - (4' hydroxyphenyl) - 7 - hydroxy - 1,2 - dihydro naphthalenes, that is, those compounds of formula I in which X is -CH2-CH2- and both R and R1 are hydroxy.

Another preferred subclass includes those compounds of formula I in which both R2 and Rg are methyl, both R2 and Ra are ethyl, or Ra and Ra 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.

A. Preparation of Compounds in which X is CH,H A tetralone of the formula

in which Ra is hydrogen, C;--C, alkoxy, or benzyloxy, is reacted with a phenyl benzoate of the formula

in which Y is methoxy, benzyloxy, or

Ra and Ra 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

The substituted tetralone (II) then is reacted under Grignard reaction conditions with the Grignard reagent of the formula

in which R, is hydrogen, Ci alkoxy, or benzyloxy.

The compound which is produced, a 3- phenyl - 4 - aroyl - 1,2 - dihydronaphthalene, has the formula

and, depending upon the identity of the groups R@, R1@, and Y, may be a compound of formula I.

In those instances in which Y is methoxy and Ra and Ra, 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 Ra and R, are hydrogen since, if R, and/or R, were alkoxy or 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

in which Ra and Ra are as aforedescribed, to produce a compound of formula I.

In those instances in which Y in compound (VII) is methoxy or benzyloxy, and Ra and/or R1a are alkoxy or benzyloxy, the group at Y can be selectively cleaved by treating the compound with sodium thioethoxide in N,Ndimethylformamide at a moderately elevated temperature of 80 C. to 900C. 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 1 - chloro2 - substituted aminoethane.

Depending upon the intended structure of the final product, the compound containing the 2-aminoethoxy substituent then can be further treated with sodium thioethoxide in N,Ndimethylformamide 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 Ra 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 CH2-CH2-. Selective dehydrogenation of the dihydronaphthalene structure to produce specifically the corresponding naphthalene can be accomplished by treatment of the former with 2,3 - dichloro - 5j6 - dicyano - 1,4benzoquinone (DDQ) at a temperature of from 50"C. to 1000C.

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 antifertility 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 populaticn 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 parenteral administration. In the compounding or formulation, organic or inorganic solids and/or liquids which are pharmaceutically 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 effective amount, will produce the inhibition of pregnancy in mammals. The usual daily dose is from 0.02 milligrams to 20 milligrams per kilogram 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 - (2pyrrolidinoethoxy) - benzoylj - 1,2 - dihydronaphthalene; 3 - (4 - methoxyphenyl) - 4 - [4 - (2diethylaminoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - isopropoxyphenyl) - 4 - [4 - (2- pyrrolidinoethoxy) - benzoyl] - 2,2 - dihydronaphthalene; 3 - (4 - t - butyloxyphenyl) - 4 - [4 - (2 hexamethyleneiminoethoxy ) benzoyl] - 1,2dihydronaphthalene; 3 - (4 - pentyloxyphenyl) - 4 - [4 - (2morpholinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - methoxyphenyl) - 4 - [4 - (2piperidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - ethoxyphenyl) - 4 - [4 - (2dimethylaminoethoxy) - benzoylj - 1,2 - dihydronaphthalene; 3 - (4 - n - propoxyphenyl) - 4 - [4 - (2pyrrolidinoethoxy) - benzoylj - 1,2 - dihydronaphthalene; 3 - (4-sec-butyloxyphenyl) -4- [4- (2piperidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - ethoxyphenyl) - 4 - [4 - (2- morpholinoethoxy) - benzoyl]- 1,2 - dihydronaphthalene; 3 - (4 - hydroxyphenyl) - 4 - [4 - (2hexamethyleneiminoethoxy)benzoyl] - 1,2dihydronaphthalene; 3 - (4 - methoxyphenyl) - 4 - [4 - [2- dimethylaminoethoxy) - benzoylj - 1,2 - dihydronaphthalene; 3 - (4 - isopropoxyphenyl) - 4 - [4 - (2 diethylaminoethoxy) - benzoyl] - 1,2 - di hydronaphthalene; 3 - (4 - t - butyloxyphenyl) - [4 - 4 - (2 pyrrolidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - pentyloxyphenyl) - 4 - [4 - (2piperidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - isobutyloxyphenyl) - 4 - [4 - (2morpholinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - ethoxyphenyl) - 4 - [4 - (2pyrrolidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - n - propoxyphenyl) - 4 - [4 - (2dimethylaminoethoxy) - benzoylj - 1,2- dihydronaphthalene; 3 - (4 - hydroxyphenyl) - 4 - [4 - (2diethylaminoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - methoxyphenyl) - 4 - [4 - (2piperidino) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - hydroxyphenyl) - 4 - [4 - (2- diethylaminoethoxy) - benzoyl] - 7 - methoxynaphthalene; 3 - (4 - hydroxyphenyl) - 4 - [4 - (2morpholinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene; 3 - (4 - hydroxyphenyl) - 4 - [4 - (2dimethylaminoethoxy) - benzoyl] - 7hydroxy - 1,2 - dihydronaphthalene; 3 - (4 - methoxyphenyl) - 4 - [4 - (2diethylaminoethoxy) - benzoyl] - methoxy1,2 - dihydronaphthalene; 3 - (4 - isopropoxyphenyl) - 4 - [4 - (2- pyrrolidinoethoxy) - benzoyl] - 7 - ethoxy1,2 - dihydronaphthalene; 3 - (4 - t - butyloxyphenyl) - 4 - [4 - (2dimethylamino - ethoxy)benzoyl] - 7 - prop oxy - 1,2 - dihydronaphthalene; 3 - (4 - pentyloxyphenyl ) - 4 - [4 - (2piperidinoethoxy) - benzoylj - 7 - pentyloxy1,2 - dihydronaphthalene; 3 - (4 - hydroxyphenyl) - [4 - (2pyrrolidinoethoxy) - benzoyl] - 7 - pentyloxy1,2 - dihydronaphthalene; 3 - (4 - ethoxyphenyl) - 4 - [4 - (2morpholinoethoxy) - benzoylj - 7 - ethoxy1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - dimethylamino ethoxy)benzoyl] - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - pyrrolidinoethoxy)benzoyl] - 7 - methoxy - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - dimethylaminoethoxy)benzoyl] - 7 - hydroxy - 1,2 - dihydronaphthalenes; 3 - phenyl - 4 - [4 - (2 - hexamethyleneiminoethoxy)benzoyl] - 7 - methoxy - 1,2dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - pyrrolidinoethoxy) - benzoyl] - 7 - hydroxy - 1,2dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - hexamethyleneethoxy)benzoyl] - 7 - ethoxy - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - morpholinoethyl)benzoyl] - 7 - methoxy - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - hexamethyleneiminoethoxy)benzoyl] - 7 - isopropoxy - 1,2dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - dimethylamino ethoxy)benzoyl] - 7 - pentyloxy - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - pyrrolidinoethoxy)benzoyl] - 7 - ethoxy - 1,2 - dihydronaphthalene; 3 - phenyl 4 r4 (2 - morpholinoethoxy)benzoyl] - 7 - isopropxy - 1,2 - dihydronaphthalene; 3 - phenyl - 4 - [ - (2 - hexamethyleneiminoethoxy)benzoyl] - 17 - butyloxy - 1,2dihydronaphthalene; 3 - phenyl - 4 - [4 - (2 - diethylamino ethoxy)henzoylj - 7 - hydroxy - 1,2 - dihydronaphthalene; 1 - [4 - (2 - pyrrolidinoethoxy)benzoyl] 2 - (4 - hydroxyphenyl)naphthalene; 1 - [4 - (2 - piperidinoethoxy)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; 1 - [4 - (2 - pyrrolidinoethoxy)benzoyl] 2 - (4 - isopropoxyphenyl)naphthalene; 1 - [4 - (2 - hexamethyleneiminoethoxy) benzoyl] - 2 - (4 - t - butyloxyphenyl)naph thalene; 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)benzoylj - 2 - (4 - ethoxy - phenyl)naphthalene; 1 - [4 - (2 - hexamethyleneiminoethoxy)benzoyl] - 2 - (4 - hydroxyphenyl)naphthalene; 1 - [4 - (2 - dimethylaminoethoxy)- benzoyl] - 2 - (4 - methcxyphenyl)naphtha lene; I - [4 - (2 - diethyiaminoethoxy)benzoylj - 2 - (4 - iso - propoxyphenyl)naphthalene; 1 - [4 - (2 - pyrrolidinoethoxy)benzoylj- 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)benzoylj - 2 - (4 - ethoxyphenyl)naphthalene; 1 - [4 - (2 - dimethylaminoethoxy)benz oyl] - 2 - (4 - n - propoxyphenyl)naphtha lene; 1 - [4 - (2 - diethylaminoethoxy)benzoyl]- 2 - (4 - hydroxyphenyl)naphthalene; 1 - [4 - (2 - pyrrolidinoethoxy)benzoyl]- 2 - (4 - methoxyphenyl)naphthalene; 1 - [4 - (2 - piperidinoethoxy)henzoylj - 2 - (4 - hydroxyphenyl)naphthalene; 1 - (4 - (2 - morpholinoethoxy)benzoyll 2 - (4 - hydroxyphenyl)naphthalene; 1 - [4 - (2 - dimethylaminoethoxy) benzoyl] - 2 - (4 - hydroxyphenyl) - 6 hydroxynaphthalene; 1 - [4 - (2 - diethylaminoethoxy)benzoylj - 2 - (4 - methoxyphenyl) - 6 - methoxynaph thalene; 1 - [4 - (2 - pyrrolidinoethoxy)benzoylj - 2 - (4 - isopropoxyphenyl) - 6 - ethoxynaph thalene; 1 - [4 - (2 - dimethylaminoethoxy) benzoylj - 2 - (4 - t - butyloxyphenyl) - 6 propoxynaphthalene; 1 - [4 - (2 - piperidinoethoxy)benzoyl] - 2 - (4 - pentyloxyphenyl) - 6 - pentyloxynapthhalene; 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 - hydroynaphtha- lene; 1 - [4 - (2 - hexamethyleneiminoethoxy)benzoyl] - 2 - phenyl - 6 - methoxynaphthalene; 1 - [4 - (2 - pyrrolidinoethoxy)benzoyl]2 - phenyl - 6 - hydroxynaphthalene; 1 - [4 - (2 - piperidinoethoxy)benzoylj - 2 - phenyl - 6 - ethoxynaphthalene; 1 - [4 - (2 - morpholinoethoxy)benzoyl]2 - phenyl - 6 - methoxynaphthalene; 1 - [4 - (2 - hexamethyleneiminoethoxy)- benzoyl] - 2 - phenyl - 6 - isopropoxynaphthalene; 1 - [4 - (2 - dimethylaminoethoxy)- benzoyl] - 2 - phenyl - 6 - pentyloxynaphthalene; 1 - [4 - (2 - pyrrolidinoethoy)benzoyl]- 2 - phenyl - 6 - ethoxynaphthalene; 1 - p4 - (2 - morpholinoethoxy)benzoyl]- 2 - phenyl - 6 - isopropoxynaphthalene; 1 - [4 - (2 - hexamethyleneiminoethoxy)- benzoyl] - 2 - phenyl - 6 - butyloxynaphthalene; 1 - [4 - (2 - diethylaminoethoxy)benzoyl]2 - phenyl - 6 - hydroxynaphthalene.

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 - pyrrol idinoethoxy)benzoyl] - 1,2 - dihydro naphthalene.

To a suspension of 15.2 grams (0.38 mole) of sodium amide in 250 ml. of tetrahydrofuran (TBF) were added 50 grams (0.34 mole) of (3-tetralone. The mixture was stirred for 15-20 minutes, and 78 grams of phenyl p-methoxybenzoate dissolved in THF were added. The temperature was maintained below 100 C., and the mixture then was stirred at 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 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) - 2tetralone were collected by filtration, melting point 88-910C.

Analysis, Called. for C,,H,,O,: C, 77.08; H, 5.54; 0, 17.32.

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

Mass spectrum: Theory, 280; Found, 280. p-Bromoaiiisole (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 p-tetralone dissolved in acetone was added dropwise with stirring over a two-hour period, the mixture being maintained at 400 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 greenish-yellow crystals, melting point 86 -880C., and 15 grams of 3 - (4 - methoxyphenyl) - 4 - (4 - methoxybenzoyl) - 1,2dihydronaphthalene were obtained as an oil upon elution of the column with a mixture of benzene containing 2 percent ethyl acetate.

Analysis, Calcd. for C2.H2203: C, 81.06; H, 5.99; 0, 12.96.

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

A mixture of 11.1 grams (0.03 mole) of the above dimethoxy product, 7.2 grams of sodium hydride (50 percent in oil), and 11 ml. of ethyl mercaptan in N,N-dimethylformamide was prepared. The mixture was heated to 65--700G. for two hours. The mixture then was cooled and concentrated. The concentrate was acidified and extracted with ethyl acetate.

The ethyl acetate extract was washed, dried, and evaporated. The residue was dissolved in benzene and chromatographed over silica to obtain five grams of an oil comprising relatively pure 3 - (4 - methoxyphenyl) - 4 - (4hydroxybenzoyl) - 1,2 - dihydronaphthalene.

Analysis, Calcd. for C24H20O2: 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 N,N-dimethylformamide. To this solution was added 0.7 gram of sodium hydride (50 percent in oil), and the resulting mixture was warmed to 400 C. for one hour and then was cooled to room temperature. To the mixture then were added 1.62 grams of 1 - 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 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 conconcentrated 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 OOC. The product, the citrate salt of 3 - (4 - methoxyphenyl) - 4 - [4 - (2 - pyrrolidinoethoxy)benzoyll - 1,2 - dihydronaphthalene, was collected by filtration and vacuum dried, melting point 82-350C.

Analysis: Calcd. for C3^H39NOso C, 66.96; H, ó.09; N, 2.17; O. 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 - 1,2 - dihydronaphthalene.

To 300 ml. of DMF were added 107 grams of phenyl p-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 1chloro - 2 - pyrrolidinoethane, and the mixture

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

Analysis, Calcd. for C30H3lNOa: 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 ml. of ether was added dropwise at OOC. 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 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 Al2O, column using, as gradient, a 1:1 mixture of benzene and hexane which progressively diminshed in hexane until 100 percent benzene was present. There were obtained 4.67 grams (38 percent) of 3 - phenyl - 4 - t4 - methoxy benzoylj - 1,2 - dihydronaphthalene. The material was recrystallized from methanol, melting point 10 & 1070C.

Analysis, Calcd. for C24H2002: 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 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 benzene to elute impurities. The product then was eluted with ethyl acetate to give, upon evaporation of the ethyl acetate, 1.69 grams (818%) 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 1 - 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 800 C. for two hours. The mixture was then 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 89 930.C.

Analysis, Calcd. for C,,H2?NO, . 1/2 H20: 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 - phenyl naphthalene.

To 30 ml. of dioxane were added 1.90 grams (5.58 mmoles) of 3 - phenyl - 4 - (4methoxybenzoyl) - 1,2 - dihydronaphthalene (prepared as in Example 3) and 2.00 grams (8.81 mmoles) of 2,3 - dichloro - 5,6dicyano - 1,4 - 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) - 2phenylnaphthalene 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 obtains the 1.40 grams (80%) of 1 - (4- hydroxybenzoyl) - 2 - phenylnaphthalene, melting point 204-205 0C.

Analysis, Calcd. for C,,H1O2: C, 85.16; H, 4.97; 0, 9.86.

Found: C, 84.99; H, 5.12; 0, 9.58.

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 containing 120 mg. (5.0 mmoles) of sodium hydride and 800 mg. of 1 - 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.Q grams (about 100%) of 1 - [4 - (2 - pyrrol- idinoethoxy) - benzoylj - 2 - phenylnaphtha lene 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 com poured was obtained as an amorphous solid which crystallized on standing overnight in ether, melting point 105-1080C.

Analysis, Calcd. for C,H,,NOg . H20: 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 - pyrrol- idinoethoxy)benzoyl] - 7 - methoxy - 1,2 dihydronaphthalene.

To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1 - (p - 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 p-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 - 1,2 - dihydronaphthalene was obtained as an oil.

Analysis, Calcd. for C2H28 4: C, 80.65; H, 5.92; 0, 13.43.

Found: C, 80.96; H, 5.91; 0, 13.61.

To 150 ml. of N,N - dimethylformamide (DMF) were added 5.4 grams (0.011 mole) of the above dihydronaphthalene. To the mixture were added 30 ml. of DME containing 0.5 mole of sodium thioethoxide. The resulting mixture was heated under nitrogen at 900C.

Progress of the reaction was followed by TLC.

Upon completion, the mixture was poured 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 - hydrox.ybenzoyl) - 7 - methoxy - 1,2dihydronaphthalene, were combined and con centrated to dryness to obtain 3.3 grams of a yellow oil. The product was used as such in the next step.

A mixture of 3.2 grams of the above product in 150 ml. of DME 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 teffi- perature, 1.2 grams of 1 - chloro - 2 - pyrrolidinoethane was added, and the mixture was heated to 600--700C. for about one hour. The resulting mixture then was stirred at room temperature overnight after which 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 - (4 - methoxy phenyl) - 4 - [4 - (2 - pyrrolidinoethoxy) benzoylj - 7 - methoxy - 1,2 - 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. The mixture was maintained at OOC. 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 CH41NO11: 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 tested for antifertility activity both pre- and post coitally.

In the precoital antifertility test, fifty young adult virgin female rats weighing 200230 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 admin istration 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. Admin istration 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 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 were 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 amount 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 animals 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.

TABLE Antifertility Activity

Postcoital Compound Precoital R R1

Pregnancy Ratio Dose Ratio No. Pregnant/ No. No.

X mg./day P/5 P= No. in Group Viable Resorptions H -OCH3 pyrrolidinoa -CH2-CH2- 0.5 - 0/2 0 0 0.05 0 0/5 0 0 0.01 1 1/5 0 1 0.005 - 2/5 14 0 0.001 5 - - -OCH3 H pyrrolidinoa -CH2-CH2- 0.05 0 0/3 0 0 0.01 2 4/6 44 0 0.005 - 5/5 44 3 0.001 - 3/3 35 0 H H pyrrolidinoa -CH2-CH2- 0.05 - 0/3 0 0 0.01 - 1/6 2 0 0.005 - 2/4 12 7 H H pyrrolidino -CH=CH- 0.1 - 7 0 0.01 - 2/3 21 0 0.05 - 3/3 32 0 -OCH3 -OCH3 pyrrolidinoa -CH2-CH2- 0.05 - 0/3 0 0 0.01 - 1/3 2 0 0.005 - 2/3 13 3 aCitrate Salt

Claims

WHAT WE CLAIM IS:

1. An aroyl-phenylnaphthalene compound of the formula

in which X is -CH2-CH2- or -CH= CH-; R is hydrogen, hydroxyl, or C1-C5 alkoxy; R1 is hydrogen, hydroxyl, or alkoxy; and R2 and R3 independently are C1 -C4 alkyl, or R2 and R3 taken together with the nitrogen to which they are bonded constitute a heterocyclic ring selected from pyrrolidino, piperidino, hexamethyleneimino, or morpholino; or a pharmaceutically acceptable, non-toxic acid addition salt thereof.

2. Compound of claim 1, in which both R2 and R3 are methyl or both R2 and R3 are methyl, or R2 and R3 taken together with the nitrogen to which they are bonded constitute a pyrrolidino ring.

3. Compound of claim 2, in which R2 and R, 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 of its pharmaceutically acceptable, non-toxic acid addition salt.

5. Compound of claim 4, in the form of its citrate salt.

6. Compound of any of claims 1 to 5, in which R1 is --C, alkoxy and R is hydrogen.

7. Compound of any of claims 1 to 5, in which R is C1-C, alkoxy and R1 is hydrogen.

8. Compound of any of claims 1 to 5, in which both R and R1 are C1----C, alkoxy.

9. Compound of any of claims 1 to 5, in in which both R and R1 are hydrogen.

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

11. Compound of any of claims 1 to 9, in which X is -CH2-CH2-.

12. 3 - (4 - Methoxyphenyl) - 4 - [4 (- 2pyrrolidinoethoxy) - benzoyl] - 1,2 - dihydronaphthalene.

13. 3- (4-Methoxyphenyl)-4- [4-(2 pyrrolidinoethoxy) - benzoylj - 1,2 - dihydronaphthalene citrate salt.

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

15. 3 - Phenyl - 4 - [4 - (2 - pyrrolidinoethoxy)benzoyl] - 7 - methoxy - 1,2 - dihydronaphthalene citrate salt.

16. 3 - Phenyl - 4 - [4 - (2 - pyrrolidino- ethoxy)benzoyl] - 1,2 - dinitronaphthalene.

17. 3 - Phenyl - 4 - [4 - (2 - pyrrolidino- ethoxy)benzoyl] - 1,2 - dihydronaphthalene citrate salt.

18. 1 [4 - (2 - Pyrrolidinoethoxy)benzoyl]2 - phenylnaphthalene.

19. 1 - [4 - (2 - Pyrrolidinoethoxy)benzoyl] - 2 - phenylnaphthalene citrate salt.

20. 3 - -(4 - Methoxyphenyl) - 4 - [4 - -(2pyrrolidinoethoxy) - benzoyl] - 7 - methoxy1,2 - dihydronaphthalene.

21. 3 - (4 - Methoxyphenyl) - 4 - [4 - (2pyrrolidinomethoxy) - benzoyl] - 7- methoxy1,2 - dihydronaphthalene citrate salt

22. A process for preparing an aroylphenylnaphthalene compound of formula I as defined in claim 1, which comprises 1) Reacting a substituted tetralene compound of the formula

wherein Ra is hydrogen, C1-C5 alkoxy or benzyloxy; and Y is methoxy, benzyloxy or

wherein R2 and R3 are as defined in claim 1; with a phenyl magnesium bromide compound of the formula

wherein R1a is hydrogen, C1-C5 alkoxy or benzyloxy; 2) optionally reacting the product so obtained wherein X is -CH2-CH2- with 2,3dichloro - 5,6 - dicyano - 1,4 - 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 1 - chloro - 2 - aminoethane of the formula

wherein R2 and Rs are as defined above; 4) reacting the compound obtained in 1), 2) or 3), wherein R, or R1, 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 Ra or Ru 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 aroyl-phenylnaphthalene 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 pharmaceuticJly-acceptable salt thereof, associated with a pharmaceutically acceptable carrier therefor.

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 salt thereof.