CA1078834A

CA1078834A - Antifertility compounds

Info

Publication number: CA1078834A
Application number: CA263,896A
Authority: CA
Inventors: Tulio Suarez; Charles D. Jones
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1975-10-28
Filing date: 1976-10-21
Publication date: 1980-06-03
Also published as: CH624398A5; SU791220A3; DE2646213C2; CS235057B2; ATA800576A; GB1561687A; PH14538A; HU175227B; GR61816B; ES452735A1; IL50772A; FR2329264A1; AR214622A1; IE43641L; RO70755A; PL111987B1; DK484776A; DE2646213A1; MX4291E; BG27555A3

Abstract

ABSTRACT OF THE INVENTION

The present invention relates to novel deriva-tives of aroyl-phenylnaphthalenes which are useful as anti-fertility and antitumor agents.

Description

)7~

The present invention relates to novel deriva-tives of aroyl-phenylnaphthalenes which are useful as anti-fertility and antitumor agents.
- The prior art has recognized various classes of compounds, each having the general formula I~-'---fr ~ / ~ / \Ar"

; 10 in which Ar is 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-3,4-dihydro-l~ naphthalenes as active antifertility agents. In addition, ! United States Patents Nos. 3,274,213; 3,313,853; 3,396,169;
and 3,567,737 disclose various 1,2-diphenyl-3,4-dihydronaph-thalenes as useful antifertility agents.
Other United States Patents disclose both 1,2-di-phenyl-3,4-dihydronaphthalenes and 2,3-diphenylindenes as active agents. These include United States Patents Nos.

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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, .
(1971), pp. 1185-1190, discloses, among others, various

2,3-diarylbenzothiophenes as exhibiting antifertility activity. Certain of these compounds are claimed in u. s.
Patent 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 No. 3,394,125. -.

A need still exists to provide additional com-pounds 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-4-aroyl-1,2-dihydronaphthalenes and 1-aroyl-2-phenylnaphthal- ;
enes, and, structurally, they differ significantly from those described in the aforementioned prior art. It is an object therefore of this invention to provide novel non-steroidal compounds having antifertility activity.
The present invention provides novel aroyl-phenyl-naphthalene compounds having the formula ~ 0-CH -CH -N

R/ ~ / \X/ \ / ~ I
~ R1 .

X-~402 -3_ -.. ' ~ , . . . '' ~ - .

3~

in which X is -CH2-CH2- or -CH=CH-; R is hydrogen, hydroxyl, or Cl-C5 alkoxy; Rl is hydrogen, hydroxyl, or Cl-C5 alko~y;
and R2 and R3 independently are Cl-C~ alkyl, or R2 and R3 taken together with the nitrogen to which they are bonded constitute a heterocyclic ring selected from the group con-sisting of 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, Rl, R2 and R3 are as defined above, which comprises 1) reacting a substituted tetralone compound of the formula Y
~1, i~,.

~o II
o I ~ I
Ra ~

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

is methoxy, benzyloxy or /N-CH2-CH2-0- wherein R2 and R3 are as defined above; with a phenyl magnesium bromide com-pound of the formula /o==o\ III

.
X-4402 _4_ ~0~834 wherein Rla is hydrogen, Cl-C5 alkoxy or benzylaxy; .
2) optionally reacting the product so obtained wherein X
is -CH2-CH2- with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at a temperature of from 50 to 100C. to provide the ~r- .
responding compound wherein x is -CH=CH-;
3) reacting the prod~ct so obtained wherein Y is methoxy or benzyloxy with a reagent selected from the group consisting of 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 Cl-CH -CH -N\ 2 IV : .
3 ` ~
wherein R2 and R3 are as defined above;

4) reacting the compound so obtained wherein Ra or Rla is `.
benzyloxy with sodium thioethoxide to provide the corres-ponding compound wherein R or Rl is hydroxy; and

5) if desired reacting the compound so obtained wherein Ra or Rla is alkoxy with sodium thioethoxide to provide the corresponding compound wherein R or Rl is hydroxy.
The pharmaceutically acceptable non-toxic acid addition salts of the compounds of formula I include the organic and inor~anic 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. Pref- ~
erably, the acid addition salts are those prepared from ::
. citric acid. Such salts are prepared by conventional methods.
-. "
' . :" .

' ~0~7B~3~ `

The term "cl-c4 alkyl" as used herein contemplates both straight and branched chain groups such as methyl, ethyl, n-propyl, isopropyl, _-butyl, t-butyl, isobutyl, and sec-butyl.
The term "Cl-C5 alkoxy" as used herein contem-plates both straight and branched chain alkyl radicals and therefore defines groups such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, _~butyloxy, isobutyloxy, t-butyloxy, sec-butyloxy, n-amyloxy, isoamyloxy, t-amyl-oxy or sec-amyloxy. Of the Cl-C5 alkoxy groups defined herein, methoxy is highly preferred.
A preferred subclass of the compounds o formula I are the dihydronaphth~lenes, that is, in the above formula I, those compounds in which X is -CH2-CH2-.
Of the defined dihydronaphthalenes, several pre-ferred subclasses exist. One such subclass is comprised of 7-alkoxy-1,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CH2-CH2- and R is Cl-C5 alkoxy Another subclass includes the non-hydroxylated or alkoxylated dihydronaphthalenes, that is, those compounds ofof formula I in which X is -CH2-CH2- and both R and Rl are hydrogen.
Another such subclass includes 3-(4'-alkoxyphenyl)-1,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CH2-CH2- and Rl is Cl-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 Rl are Cl-C5 alkoxy-~)7~}~3~

Further preferred subclasses inclu~e 3-(4'-hydroxyphenyl)-1,2-dihydronaphthalenes and 7-hydroxy-1,2-dihydronaphthalenes, that is, those compounds of formula I
in which x is -CH2-CH2- and R or Rl is hydroxy-A most preferred subclass comprises 3-(4'-hy-droxyphenyl)-7-hydroxy-1,2-dihydronaphthalenes, that is, those compounds of formula I in which X is -CH2-CH2- and both R and Rl are hydroxy.
Another preferred subclass includes those com-pounds of formula I in which both R2 and R3 are methyl, bothR2 and R3 are ethyl, or R2 and R3 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 CH2 CH2 ' ~
A tetralone of the formula R / ~ Vl in which Ra is hydrogen, Cl-C5 alkoxy, or benzyloxy, is reacted with a phenyl benzoate of the formula .

~ VI) :.' ~/ , .

X-4402 _7_ -- ~0~33~

in which Y is methoxy, benzyloxy, or ~ CH2-CH2-O-, R2 and R3 being as aforedefined.
- The reaction ge~erally is carried out in the presence of a moderately s-trong base such as sodium amide and at room temperature or below.
The product which is obtained is a substituted tetralone of the formula ~_o R / ~ /5' 'f (II) The substituted tetralone (II) then is reacted under Grignard reaction conditlons with the Grignard reagent of the formula /-=o\
R l a~ MgBr (III) in which Rla is hydrogen, Cl-C5 alkoxy, or benæyloxy.
The compound which is produced, a 3-phenyl-4-aroyl-112-dihydronaphthalene, has the formula `

.:. , ~ .

~L078~33~

f~

and, depending upon the identity of the groups Ra, Rla, and Y, may be a compound of formula I.
In those instances in which Y is methoxy and Ra and Rla are~hydrogen, the compound (VII) can be treated with pyridine hydrochloride at reflux to produce the ~orres-ponding hydroxy compound. As indicated, this method is useful only with respect to those compounds in which Ra and Rla are hydrogen since, if Ra anà/or Rla 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 com-pound of the formula Cl-CH2-CH2- ~ (IV) '; .
in which R2 and R3 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 Rla are alkoxy or ,~ benzyloxy, the group at Y can be selectively cleaved by - treating the compound with sodium thioethoxide in N,N-. X-4402 -9- :

7883~

dimethylformamide at a moderately elevated temperature of about 80C. to about 90~C. The ongoing of the selective cleavage can be monitored by periodic thin-layer chroma-tographic 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 afore-described with a l-chloro-2-substituted aminoe~hane.
Depending upon the intended structure of the final product, the compound containing the 2-aminoèthoxy sub-stituent then can be further treated with sodium thioethoxide in N,N-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 R1 are hydroxyl.
In any of the above, it is evident that the parti-cular 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-5,6-dicyano-1,4-benzoquinone (DDQ) at a temperature of from ' about 50C. to about 100C.

.

.

~ ~07~3~

Again, by means of the aforementioned derivatizin~
reactions, the naphthalene which is produced can be con-verted to other naphthalene compounds within the scope of formula I.
The compounds of formula I are valuable pharma-ceutical agents~ They exhibit anti-fertility activity, and they especially are useful as orally active anti-fertility agents in birds and mammals. The compounds o~ 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 com- . .
pounds 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, galls, redwing black- . ~.
birds 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 20 the presence of birds and animals on runways and in the :
vicinity oE 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 pharma-ceutical preparations in unit dosage form for oral or paren-. .

- . . :
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teral administration. In the compounding or formulation, organic or inorganic solids and/or liquids which are pharma-ceutically 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 solu-tions.
The compounds of formula I, when administered in an effective amount, will produce the inhibition of preg-nancy ln mammals. The usual daily dose is from about 0.02milligrams to about 20 milligrams per kilogram body weight of the recipient. The preferred daily dose is from about 0.02 milligrams to about 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-pyrrolidinoethoxy)-benzoyl~-1,2-dihydronaphthalene;
3-(4-methoxyphenyl)-4-14-(2-diethylaminoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-isopropoxyphenyl~-4-[4-(2-pyrrolidinoethoxy)-benzoyll-1,2-dihydronaphthalene;
3-(4-t-butyloxyphenyl)-4-~4-(2-hexamethyleneimino-ethoxy)benzoyll-1,2-dihydronaphthalene;
; 3-(4-pentyloxyphenyl)-4-~4-(2-morpholinoethoxy~-benzoyll-1,2-dihydronaphthalene;
3-(4-methoxyphenyl)-4-[4-(2-piperidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-ethoxyphenyl)-4-[4-(2-dimethylamlnoethoxy)-benzoyl]-1,2-dihydronaphthalene;

, ~

~, 83~

3-(4-n-propoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-~4-sec-butyloxyphenyl)-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-hexamethyleneimino-ethoxy)benzoyl]-1,2-dihydronaphthalene;
3-(4-methoxyphenyl)-4-[4-(2-dimethylaminoethoxy)~
benzoyl]-1,2-dihydronaphthalene;
3-(4-isopropoxyphenyl)-4-14-(2-diethyLaminoethoxy)-benzoyl]-1,2-dihydronaphthalene; .
3-(4-t-butyloxyphenyl)-4-[4-~2-pyrrolidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-pentyloxyphenyl)-4-[4-(2-piperidinoethoxy) benzoyl]-1,2-dihydronaphthalene;
3-(4-isobutyloxyphenyl)-4-[4-(2-morpholinoethoxy)-benzoyll-1,2-dihydronaphthalene;
3-(4-ethoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
: 3-(4-n-propyloxyphenyl)-4-[4-(2 dimethylamino-ethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-hydroxyphenyl)-4-~4-(2-diethylaminoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-~4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-hydroxyphenyl)-4-14-(2-piperidinoethoxy)-benzoyl]-1,2-dihydronaphthalene;

- . - ~ .

~ : ~

7~83~

3-(4-hydroxyphenyl)-4-14-(2-morpholinoethoxy)-benzoyl]-1,2-dihydronaphthalene;
3-(4-hydroxyphenyl)-4-[4-(2-dimethylaminoethoxy)-benzoyl]-7-hydroxy-1,2-dihydronaphthalene;
3-(4-methoxyphenyl)-4-~4-(2-diethylaminoethoxyj-benzoyl]-7-methoxy-1,2-dihydronaphthalene;
3-(4-isopropoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)-benzoyl]-7-ethoxy-1,2-dihydronaphthalene;
3-(4-t-butyloxyphenyl)-4-[4-(2-dimethylamino-ethoxy)benzoyl}-7-propoxy-1,2-dihydronaphthalene;
3-(4-pentyloxyphenyl)-4-14-(2-piperidinoethoxy)-benzoyl]-7-pentyloxy-1,2-dihydronaphthalene;
3-(4-hydroxyphenyl) 4-~4-(2-pyrrolidinoethoxy)-benzoyl]-7-hydroxy-1,2-dihydronaphthalene;
3-(4-ethoxyphenyl)-4-[4-(2-morpholinoethoxy)-benzoyl]-7-ethoxy-1,2-dihydronaphthalene;
3-phenyl-4-[4-(2-dimethylaminoethoxy)benzoyll-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-dihydronaphthalene;
3-phenyl-4-[4-(2-hexamethyleneiminoethoxy)benz-oyll-7-methoxy-1,2-dihydronaphthalene;

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

' :~

. ~

~7~1~3~

3-phenyl-4-14-(2-morpholinoethoxy)benzoyl]-7-methoxy-1,2-dihydronaphthalene;
3-phenyl-4-[4-(2-hexamethyleneiminoethoxy)benz-oyl]-7-isopropoxy-1,2-dihydronaphthalene;
3-phenyl-4-~4-(2-dimethylaminoethoxy)benzoyl]-7-pentyloxy-1,2-dihydronaphthalene;
3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-ethoxy-1,2-dihydronaphthalene;
3-phenyl-4-[4-(2-morpholinoethoxy)benzoyl]-7-isopropoxy-1,2-dihydronaphthalene;
3-phenyl-4-l4-(2-hexamethyleneiminoethoxy)benz-oyl]-7-butyloxy-1,2-dihydronaphthalene:
3-phenyl-4-[4-(2-diethylaminoethoxy)benzoyl]-7-hydroxy-1,2-dihydronaphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-hydroxy-phenyl)naphthalene;
l-[4-(2-pyrrolidinoethoxy)benzoyl]-2-~4-n-propoxy-phenyl)naphthalene;
l-[4-(2-piperidinoethoxy)benzoyl]-2-~4-sec-butyloxyphenyl)naphthalene;
1-[4-(2-diethylaminoethoxy)benzoyl]-2-(4-methoxy-phenyl)naphthalene;
1-~4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-isopro-poxyphenyl)naphthalene;
1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2-(4-t-butyloxyphenyl)naphthalene;
1-[4-(2-morpholinoethoxy)benzoyl]-2-(4-pentyloxy-phenyl)naphthalene;

: . .
X-4402 -15- :

-- 10~7~83~L

1-14-(2-piperidinoethoxy)benzoyl]-2-(4-methoxy-phenyl~naphthalene;
1-[4-(2-aimethylaminoethoxy)benzoyl]-2-(4-ethoxyphenyl)naphthalene;
1-[4-(2-morpholinoethoxy)benzoyl]-2-(4-ethoxy-phenyl)naphthalene;
1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2-(4-hydroxyphenyl)naphthalene;
1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-methoxy-phenyl)naphthalene;
1-14-(2-diethylaminoethoxy)benzoyll-2-(4-iso-propoxyphenyl)naphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-t-butyl-oxyphenyl)naphthalene;
1-[4-(2-piperidinoethoxy)benzoyl]-2-(4-pentyloxy-phenyl)naphthalene;
1-14-(2-morpholinoethoxy)benzoyl]-2-(4-isobutyl-oxyphenyl)naphthalene;
1-~4-(2-pyrrolidinoethoxy)benzoyl]-2-(4-ethoxy-phenyl)naphthalene;
1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-n-propoxyphenyl)naphthalene;
1-~4-(2-diethylaminoethoxy)benzoyl]-2-~4-hydroxy- 1 .
phenyl)naphthalene;
1-14-(2-pyrrolidinoethoxy)benzoyl]-2-(4-methoxy-phenyl)naphthalene;
1-14-(2-piperidinoethoxy)benzoyl]-2-(4-hydroxy- .
phenyl)naphthalene;

- ~7~391 1-[4-(2-morpholinoethoxy)benzoyl]-2-t4-hydroxy-phenyl)naphthalene;
1-14-(2-dimethylaminoethoxy)benzoyll-2-(4-hydroxy-phenyl)-6-hydroxynaphthalene;
1-[4-(2-diethylaminoethoxy)benzoyl]-2-(4-methoxy-phenyl)-6-methoxynaphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2- (4-i50pro-poxyphenyl)-6-ethoxynaphthalene;
1-[4-(2-dimethylaminoethoxy)benzoyl]-2-(4-t-butyloxyphenyl)-6-propoxynaphthalene;
1-[4-(2-piperidinoethoxy)benzoyl]-2-~4-pentyloxy-phenyl)-6-pentyloxynaphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-~4-hydroxy-phenyl)-6-hydroxynaphthalene;
1-[4-(2-morpholinoethoxy)benzoyl]-2-(4-ethoxy-phenyl)-6-ethoxynaphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-phenyl-6-methoxynaphthalene;
1-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl-6-hydroxynaphthalene;
1-[4-(2-hexamethyleneiminoethoxy)benzoyl]-2-phenyl-6-methoxynaphthalene;
1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-phenyl-6-hydroxynaphthalene;
1-~4-(2-piperidinoethoxy)benzoyl]-2-phenyl-6-ethoxynaphthalene;
1-[4-(2-morpholinoethoxy)benzoyl]-2-phenyl-6-methoxynaphthalene;

.' , . . .
, ~ ' , , "'' . '' ' " " ' ' X-4402- . -i7_ .

- ' . . .

- -''. :.; ' -. ,. ' '' ' ' ' '' ' . -',' '' :. - . . . - . . : - :

.. . . . . .

8~9~

l-14-(2-hexamethyleneiminoethoxy~benzoyll-2-phenyl-6-isopropoxynaphthalene;
l-14-(2-dimethylaminoethoxy)benzoyll-2-phenyl-

6-pentyloxynaphthalene;
l-[4-(2-pyrrolidinoethoxy)benzoyl]-2-phenyl-6-ethoxynaphthalene;
l-[4-(2-morpholinoethoxy)benzoyl]-2-phenyl-~-isopropoxynaphthalene;
l-[4-~2-hexamethyleneiminoethoxy)benzoyl}-2-phenyl-6-butyloxy~aphthalene;
l-[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 l -- Preparation of the Citrate Salt of 3-(4-methoxyphenyl)-4-~4-(2-pyrrolidinoethoxy)benzoyl]-l,2-dihydronaphthalene.
To suspension of 15.2 grams (0.38 moIe) of sodium amide in 250 ml. of tetrahydrofuran (THF) were added 50 grams (0.34 mole) of ~-tetralone. The mixture was stirred for 15-20 minutes, and 78 grams of phenyl p-methoxy-benzoate dissolved in TH~ were added. The temp~rature was maintained below lO~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 .

' . , - . '::' ' : , '' ' ~ -,,, .: .~ . :

- 1C37883~

residue was chromatographed on silica using benzene a8 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 88-91C.
Analysis, Calcd. for C18H16O3:
C, 77.12; H, 5.75; O, 17.12.
Found:
10C, 77.08; H, 5.54; O, 17.32.
Mass spectrum: Theory, 280; Found, 280.
p-Bromoanisole (18.7 grams; 0.1 mole) was added dropwise in ether to THF containing 5 drops of 1,2-dibromo-ethane 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 ~-tetralone dissolved in acetone was added dropwise with stirring over a two-hour period, the mixture being maintained at 40C. 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, drled, 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 86-88~C., and 15 gram~ of 3-(4-methoxyphenyl)-4-(4-methoxybenzoyl)-1,2-dihydronaph-thalene were obtained as an oil upon elution of the column with a mixture of benzene containing 2 percent ethyl acetate.
' X-4402 -19- ~

~ . .

!78834 Analysis, Calcd. for C25H22O3:
Cj 81.06; H, 5.99; O, 12.96.
Found:
C, 81.32; H, 6.13; O, 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-dimethyl-formamide was prepared. The mixture was heated to 65-70C.
for two hours. The mixture then was cooled and concen-trated. 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-(4-hydroxy-benzoyl)-1,2-dihydronaphthalene.
Analysis, Calcd. for C24H20O3:
C, 80.88; ~, 5.66; O, 13.47.
Found:
C, ?9.66; H, 5.87; o, 13.5~.
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 he resulting mixture was warmed to 40C. for one hour and then was cooled to room temperature. ~o the mixture then were added 1.62 grams of 1-chloro-2-pyrrolidinoethanP, 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 ~ .

' 078~;~34 aqueous mi~ture 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 concen-trated to dryness. The residue was dissolved in a large volume of methyl ethyl ketoneO The ketone solution was concentrated to about 300 ml. and was cooled to 0C. The product, the citrate salt of 3-(4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene, was collected by filtration and a vacuum dried, melting point 82-85C~
Analysis, Calcd. for C36H39NOlo:
C, 66.96; H, 6.09; N, 2.17; O, 24.78.
Found:
C, 66.70; H, 6.27; N, 2.27; O, 24.54.
Example 2 -- 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 60C. for two hours. To the mixture then were added 67 grams of 1-chloro-2-pyrroli- ;
dinoethane, and the mixture was stirred overnight at 85C.
,, .
~.

~ X-4402 -21-., .
!
. . ' ~ ' ~ ' ' :

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 p-(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 10C. Upon completion o~ the addi-tion, the mixture was stirred for 20 minutes at below 10C.
after which time an exothermic reaction occurred, the temperature rising to about 20C~ The above-prepared phenyl ~-(2-pyrrolidinoethoxy)benzoate dissolved in THF then was added dropwise, and the mixture was stirred at room tem-perature 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 ~ ~07~383~

84C~, which proved to be 6-methoxy~ 4-(2-pyrrolidino-ethoxy)benzoyl]-2-tetralone and not the corresponding ~tric 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 o~ phenylmagnesium bromide in THF. The re-sulting mixture was stirred for one hour at room temperature and then was warmed to 50C. 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 concen-trated to obtain 10.5 grams of a-red-brown oil. The oil was added to 500 ml. of acetic acid, and the misture 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 0C. overnight, and the crystals which formed were collected by filtration and washed with cold methyl ethyl ketone and vacuum dried, X-440~ -23-.. .

)78~3~L

mel~ing point 95-100C. The solid wa~ recrystallized from acetone to obtain the title compound in the form of its citrate salt, melting point 98-100C.
Analysis, Calcd. for C36H39NO1o:
C, 66.96; H, 6.09; N, 2.17; o, 24.78.
Found:
C, 66.72; H, 6.27; N, 2.09; O, 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 C3~H31NO5: ;
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-dihydro-naphthalene.
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 0C. a solution of 0.018 mole of phenylmaghesium 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 ' ' " :'" "' ` . : : .

7883~ `

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 A12O3 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 107C.
Analysis, Calcd. for C24H20O2:
C, 84.68; H, 5.92; O, 9.40.
Found:
C, 84.96; H, 6.13; O, 9.65.
Mass spectrum: Theory, 340; Found, 340.
To 2.0 grams ~0.006 mole) of the above dihydro-naphthalene dissolved in 10 ml. of N,N-dimethyl formamide were added 7.5 mmoles of sodium thioethoxide in lS ml. of DMF. The addition was carried out under a nitrogen atmos-phere and at 80C. The mixture was maintained at 80C. for fifteen hours. The mixture then was cooled and poured into an iced aqueous ammonium chloride solution. The resulting mix~ure was extracted with ethyl acetate, and the ethyl acetate extract was washed four times with aqueous sodiu~
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 a07~83~

benzene to elute impurities. ~he product then was eluted with ethyl acetate to give, upon evaporation of the ethyl acetate, 1.69 grams (88%) of 3-phenyl-4-~4-hydroxybenz-oyl)-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. ~he ad-dition was made under a nitrogen atmo~phere with the temper-ature being maintained at about 10C. Upon completion of the resulting effervescence, the mixture was heated at 80C.
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)benzoyl3-1,2-dihydro-naphthalene.
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 89-93C.

)78~3~

Analysis, Calcd. for C33H37NOg 1/2 H2O:
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-dihydronaph-thalene (prepared as in Example 3) and 2.00 grams (80 81 mmoles) of 2,3-dichloro-5~6-dicyano 1,4-benzoquinone. The resulting mixture was heated at reflux for twelve hours in a nitrogen atmosphere. The mixture then was cooled and eva-porated 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 sub-stantially 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-hydroxy-benzoyl)-2-phenylnaphthalene, melting point 204-205C.
Analysis, Calcd. for C23Hl~O2:
C, 85.16; H, 4.97; O, 9.85;
Found:
C, 84.99; H, 5.12; O, 9.58.

.

.
. .: , ~1~7~3~
.

To 10 ml. of DMF were added 1.25 grams (3.86 mmoles) of the above product. The resulting mixture was added at about 10C. to a mixture of 20 ml. of DMF con-taining 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 80C. 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 cor-responding citrate salt in accordance with the method of Example 3 employing 0O811 grams of citric acid hydrate. The title compound was obtained as an amorphous solid which crystallized on standing overnight in ether, melting point 105-108C.
Analysis, Calcd. for C33H35NOg H2O:
C, 65.55; H, 5.90; N, 2.22;
Found:
C, 66.90; H, 5.85; N, 2.25.
Example S -- Preparation of the Citrate Salt of 3-(4-Methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2-dihydronaphthalene.
To a solution of about 50 grams (0.24 mole) of ~-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of ~ benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured in*o 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 _-toluene-sulfonic 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. Th~ product, 3-(4-methoxyphenyl)-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.
Analysis Calcd. for C32H28O4:
C, 80.65; H, 5.92; O, 13.43;
Found:
C, 80.96; H, 5.91; O, 13.61.
To 150 ml. of N,N-dimethylformamide (DMF) were added 5.4 grams (0.011 mole) of the above dihydronaphthal-ene. To the mixture were added 30 ml. of DMF containing 0.5 mole of sodium thioethoxide. The re3ulting mixture was heated under nitrogen at 90C. Progress of the reaction was followed by TLC. Upon completion, the mixture was poured -- ~ ~7~83~L

i~to an aqueous ammonium chloride solution. The aqueous mixture then was extracted with ethyl acetate. The ethyl acetate extract was separated, washed, dried, and concen-trated to an oil. The oil was chromatographed over silica using benzene. Those fractions containing the desired product, 3-(4-methoxyphenyl)-4-(4-hydroxybenzoyl)-7-methoxy-1,2-dihydronaphthalene, were combined and concentrated to dryness to obtain 3.3 grams of a yellow oil. The product was used as is in the next succeeding 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 40C. 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 60-70C. 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 gram~ of a pale yellow oil. The oil was purified by chromatography over silica using ethyl acetate to obtain 3.0 grams of 3-(4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2-dihydronaphthalene. The above free base product (2.9 grams~ was dissolved in 150 ml. of acetone, and one equiv-alent of citric acid dissolved in hot acetone was added.

:' .

- ~Loq~33~l The mixture was maintained at 0C. for about three days.
The product failed to crystallize. The mixture was evap-orated, 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 C37H41NOll:
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 anti-fertility 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 subcu-taneously (sc) daily. The control group receives only the vehicle. Administration of the vehicle or the combination of test compound and vehicle is continued on 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 83~

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 waighing at least 200 grams are used as test subjects.
The females are placed with a male Ln single cages and are examined daily for vayinal plugs or for sperm in the vagina.
When evidence of breeding is present, the male is removed and daily adminlstration 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 o viable and/or resorbing fetuses.
The pregnancy ratio (number of animals pregnant per nu~ber 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 . : .

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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.

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Claims

The embodiments of the invention for which an ex-clusive property or privilege is claimed are as follows:

1. A process for preparing aroyl-phenylnaphthal-ene compounds 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 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 the group con-sisting of pyrrolidino, piperidino, hexamethyleneimino, or morpholino; and pharmaceutically acceptable non-toxic acid addition salts thereof; which comprises 1) reacting a substituted tetralone compound of the formula II

wherein Ra is hydrogen, C1-C5 alkoxy or benzyloxy; and Y
is methoxy, benzyloxy or wherein R2 and R3 are as defined above; with a phenyl magnesium bromide com-pound of the formula III

wherein R1a is hydrogen, C1-C5 alkoxy or benzyloxy;
2) optionally reacting the product so obtained wherein X
is -CH2-CH2- with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at a temperature of from 50° to 100°C. to provide the cor-responding compound wherein X is -CH=CH-;
3) reacting the product so obtained wherein Y is methoxy or benzyloxy with a reagent selected from the group consisting of 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 IV

wherein R2 and R3 are as defined above;
4) reacting the compound so obtained wherein Ra or R1a is benzyloxy with sodium thioethoxide to provide the corres-ponding compound wherein R or R1 is hydroxy; and 5) if desired reacting the compound so obtained wherein Ra or R1a is alkoxy with sodium thioethoxide to provide the corresponding compound wherein R or R1 is hydroxy.

2. Aroyl-phenylnaphthalene compounds of formula I wherein X, R, R1, R2 and R3 are as defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for preparing 3-(4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene or the citrate salt thereof which comprises reacting 1-(4-methoxybenzoyl)-2-tetralone with 4-methoxyphenyl magnesium bromide; followed by reaction with sodium thioethoxide;
followed by reaction with 1-chloro-2-pyrrolidinoethane;
optionally followed by reaction with citric acid.

4. 3-(4-Methoxyphenyl)-4-[4-(2-pyrrolidino-ethoxy)benzoyl]-1,2-dihydronaphthalene or the citrate salt thereof when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process for preparing 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2-dihydronaphthalene or the citrate salt thereof which comprises reacting 6-methoxy-1-[4-(2-pyrrolidinoethoxy)benzoyl]-2-tetralone citrate salt with phenyl magnesium bromide; optionally followed by treatment with dilute alkali.

6. 3-Phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2-dihydronaphthalene or the citrate salt thereof when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. A process for preparing 3-phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene or the citrate salt thereof which comprises reacting 1-(4-methoxy-benzoyl)-2-tetralone with phenyl magnesium bromide; followed by reaction with sodium thioethoxide; followed by reaction with 1-chloro-2-pyrrolidinoethane; optionally followed by reaction with citric acid.

8. 3-Phenyl-4-[4-(2-pyrrolidinoethoxy)benzoyl]-1,2-dihydronaphthalene or the citrate salt thereof when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process for preparing 1-[4-(2-pyrrolidino-ethoxy)benzoyl]-2-phenylnaphthalene or the citrate salt thereof which comprises reacting 1-(4-methoxybenzoyl)-2-tetralone with phenyl magnesium bromide; followed by reac-tion with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; fol-lowed by reaction with sodium thioethoxide; followed by reaction with 1-chloro-2-pyrrolidinoethane; optionally fol-lowed by reaction with citric acid.

10. 1-[4-(2-Pyrrolidinoethoxy)benzoyl]-2-phenyl-naphthalene or the citrate salt thereof when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

11. A process for preparing 3-(4-methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)benzoyl]-7-methoxy-1,2-dihydro-naphthalene or the citrate salt thereof which comprises reacting 1-(4-benzyloxybenzoyl)-6-methoxy-2-tetralone with 4-methoxyphenyl magnesium bromide; followed by reaction with sodium thioethoxide; followed by reaction with 1-chloro-2-pyrrolidinoethane; optionally followed by reaction with citric acid.

12. 3-(4-Methoxyphenyl)-4-[4-(2-pyrrolidinoethoxy)-benzoyl]-7 methoxy-1,2-dihydronaphthalene or the citrate salt thereof when prepared by the process of claim 11 or by an obvious chemical equivalent thereof.