Process for the preparation of diaryl naphthyl methanes

Details Process for the preparation of diaryl naphthyl methanes Process for the preparation of diaryl naphthyl methanes

2000-03-31

2003-08-26

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S212010, C514S428000, C514S651000, C546S205000, C548S576000, C556S466000, C564S347000, C564S352000, C568S631000, C568S665000, C568S667000, C568S809000

Reexamination Certificate

active

06610705

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to diaryl naphthyl methanes and a process for preparation of said methane derivatives. The present invention particularly relates to a process or preparation of substituted secondary and tertiary amino alkoxy diaryl naphthyl methane derivatives, preparation of pharmaceutical composition containing such compounds as active ingredients and their use as contraceptives, in the treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy (ERT).
BACKGROUND OF THE INVENTION
Estrogen agonists as well as antagonists act through their interaction with estrogen receptor. This estrogen receptor protein has an active site where the ligand binds. It has been visualized as composed of two units, one having a shape complimentary to the structure of estradiol where estradiol finds a proper fit for producing estrogen agonistic activity. The second site provides binding of structural unit such as a substituted amino alkoxy aryl group thereby causing interference with the initiation of the hormonal activity as observed with estrogen antagonists. Based on this visualization, estrogen receptor model has been proposed easier. This present work utilizes the receptor model towards designing of novel estrogen antagonists.
OBJECTS OF THE INVENTION
The main object of the invention is to provide novel diarylnaphthyl methane compounds having structural Formula 1 and their derivatives, useful in the treatment of estrogen related diseases such as breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy (ERT).
Another object is to provide pharmaceutical compositions containing the novel diarylnaphthyl methane compounds having structural formula 1.
Yet another object is to provide methods for the preparation of novel diarylnapththyl methane compounds and their derivatives.
SUMMARY OF THE INVENTION
In accordance with the above and other objectives, the invention provides novel substituted diaryl naphthyl methane compounds having structural formula 1 and its derivatives, being a novel group of non-steroidal compounds and exhibiting estrogenic, antiestrogenic and contraceptive activities. The invention also provides methods for the preparation of the said novel diaryl naphthyl methane compounds and their derivatives. The invention also provides pharmaceutical compositions containing said novel diary naphthyl methane compounds and their derivatives.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the invention provides novel diaryl naphthyl methane compounds having general formula 1 as shown herein below,
wherein,
R
1
, R
2
, R
3
, R
4
, R
5
represent H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1-6 carbon atoms selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl amino alkoxy, the dotted indicate 1,2,3,4-tetrahydro naphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said compounds exhibiting estrogenic, antiestrogenic and contraceptive activities.
Substituted diaryl naphthyl methane derivatives, a novel group of non-steroidal compounds is showing promising estrogenic, antiestrogenic and contraceptive activities. The hormonal profile of such compounds is suitable for the treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy.
The invention provides a novel substituted aminoalkoxy diaryl naphthyl methane derivatives thereof, represented by general formula 1 as shown hereinbelow:
Wherein R
1
, R
2
, R
3
, R
4
, R
5
are H, OH, lower alkyl, a substituted lower alkoxy group having a straight or branched chain radical containing 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group. Substituent on the alkyl chain of alkoxy radical can be H or OH, a substituted amino lower alkoxy group wherein the lower alkoxy substituent is as defined above, the substituent on the nitrogen atom is H, or a lower alkyl radical as defined above or constitutes a cyclic polymethylene system containing nitrogen atom, i.e. N(CH
2
)
n
wherein n=2-8. The naphthyl residue can be a substituted naphthyl, substituted 1,2,3,4-tetrahydronaphthyl or a substituted 5,6,7,8-tetrahydronaphthyl.
The compounds synthesized were tested for estrogenic, antiestrogenic activies in rats. A number of these compounds showed percent prevention of pregnancy at doses 10 mg per kg or below when administered orally to female albino rats on days 1-7 p.c. or on single day schedule.
The most preferred compounds, represented by formula 1 are given below:
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth-1-yl-methane HCl
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl4-piperidinoethoxyphenyl)-naphth-1-yl-methane
4. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-1,2,3,4-tetrahydro-naphth-1-yl-methane
5. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane HCl
6. (4-Methoxyphenyl)-(4-(2-hydroxy-3-cyclopropylamino)-propoxy)-phenyl-naphth-1-yl-methane
7. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-butylamino-propoxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane
The most preferred compounds belonging to the class of diary naphthyl methanes represented by formula Ia are given below:
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth1-yl-methane HCl
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl-piperidinoethoxyphenyl)-naphth-1-yl-methane
The invention includes within the scope partially reduced substituted naphthalene residue to provide derivatives of substituted diaryl 1,2,3,4-tetrahydro naphthyl methane represented by the general formula Ib wherein R
1
, R
2
, R
3
, R
4
, R
5
, have the meaning as stated above.
Preferred compounds belonging to Ib are:
1. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-1,2,3,4-tetrahydronapth-1-yl-methane.
2. (4-methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane. 3. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-dibutylaminopropoxy)phenyl-1,2,3,4-tetrahydronaphth-1-yl-methane.
In yet another modification included within the scope are the partially reduced naphthalene residue containing derivatives of substituted diaryl 5,6,7,8-tetrahydro naphthyl methane represented by the general formula Ic.
wherein R
1
, R
2
, R
3
, R
4
, R
5
have the meanings as stated above.
Preferred compounds of Ic are:
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane hydrochloride.
2. (4-Methoxyphenyl)-(4-N,N-diethylamino-ethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane.
The preparation of compounds shown in formula 1, wherein R
1
, R
2
, R
3
, R
4
, R
5
are as defined above is described hereinbelow. The process comprises the steps of conducting Friedel-Crafts reaction of substituted &agr;-naphthoic acid with the substituted phenol in the presence of Lewis acid to give a naphthophenone derivative which is reduced by a metal hydride in a protic solvent to the corresponding alcohol which is subjected to a second Friedel-Crafts reaction with a phenol derivative in the presence of a Lewis acid under low temperature to produce compound of formula 1 wherein one of the substituent R
1
, R
2
, R
3
, R
4
, R
5
is a hydroxy group which is reacted with a tertiary amino alkyl chloride to produce corresponding tertiary amino alkoxy compound or alternatively treated with epichlorohydrin under basic condition either neat or in organic solvent such as acetone, DMSO to produce corresponding 2,3-epoxy-propylo

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