Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-02
2001-12-04
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S323000, C514S414000, C514S415000
Reexamination Certificate
active
06326367
ABSTRACT:
The present invention relates to new 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds.
BACKGROUND OF THE INVENTION
The use of hormone replacement therapy for bone loss prevention in post-menopausal women is well precedented. The normal protocol calls for estrogen supplementation using such formulations containing estrone, estriol, ethynyl estradiol or conjugated estrogens isolated from natural sources (i.e. Premarin® conjugated estrogens from Wyeth-Ayerst). In some patients, therapy may be contraindicated due to the proliferative effects of unopposed estrogens (estrogens not given in combination with progestins) have on uterine tissue. This proliferation is associated with increased risk for endometriosis and/or endometrial cancer. The effects of unopposed estrogens on breast tissue is less clear, but is of some concern. The need for estrogens which can maintain the bone sparing effect while minimizing the proliferative effects in the uterus and breast is evident. Certain nonsteroidal antiestrogens have been shown to maintain bone mass in the ovariectomized rat model as well as in human clinical trials. Tamoxifen (sold as Novadex® brand tamoxifen citrate by Zeneca Pharmaceuticals, Wilmington, Del.), for example, is a useful palliative for the treatment of breast cancer and has been demonstrated to exert an estrogen agonist-like effect on the bone, in humans. However, it is also a partial agonist in the uterus and this is cause for some concern. Raloxifene, a benzothiophene antiestrogen, has been shown to stimulate uterine growth in the ovariectomized rat to a lesser extent than Tamoxifen while maintaining the ability to spare bone. A suitable review of tissue selective estrogens is seen in the article “Tissue-Selective Actions Of Estrogen Analogs”, Bone Vol. 17, No. 4, October 1995, 181S-190S.
The use of indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract No. 53886u. Also, see, J.Med.Chem. 1990, 33, 2635-2640; J.Med.Chem. 1987, 30, 131-136. Also see Ger. Offen., DE 3821148 A1 891228 and WO 96/03375. These prior art compounds share some structural similarities with the present compounds, but are functionally different. For compounds containing a basic amine, there is no phenyl group to ridgidify the side chain. The reported data for these compounds indicates that they may have a weaker binding to estrogen receptor than the compounds of the present invention and the reported compounds containing the basic side chain show some uterotrophic effect in the rat uterus. One compound from the listed family of compounds in WO 96/03375 possesses a benzyl group, but does not have a basic side chain. The majority of these compounds fall into a class of compounds best characterized as being “pure antiestrogens”. Many of the compounds described presently, due to their particular side chain, act as pure antiestrogens in the uterus, however, show strong estrogenic action in the bone and cardiovascular systems. No such action is demonstrated for the related prior art compounds described herein.
WO A 95 17383 (Kar Bio AB) describes indole antiestrogens with long straight chains. Another related patent WO A 93 10741 describes 5-Hydroxyindole with a generic descriptor incorporating other side chains. WO 93/23374 (Otsuka Pharmaceuticals, Japan) describes compounds which differ from the present invention; where R
3
in the present formulas I and II, below, is defined as thioalkyl and the reference discloses no such compounds having chains from the indole nitrogen having the same structure as the ones provided by the present invention. Where the side chain claimed is similar to that described herein, the compounds are amides: Acylated indoles are not claimed in the present invention.
DESCRIPTION OF THE INVENTION
2-Phenylindoles of the general structure type shown in formulas (I) and (II) are estrogen agonists/antagonists useful for the treatment of diseases associated with estrogen deficiency. The compounds of the present invention show strong binding to the estrogen receptor. In vitro assays, including an Ishikawa alkaline phoshatase assay and an ERE transfection assay, show these compounds are antiestrogens with little to no intrinsic estrogenicity and they have proven capable of completely antagonizing the effects of 17&bgr;-estradiol while showing little or no uterine stimulation in a rat uterine assay when dosed alone. Additionally, some of these compounds are capable of inhibiting bone loss in an ovariectomized rat while showing little or no uterine stimulation. These compounds also decrease the weight gain normally seen in the ovariectomized animals as well as reduce total cholesterol levels.
The present invention includes compounds of the formulas I or II, below:
wherein:
R
1
is selected fry H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
(straight chain or branched or cyclic) alkyl ethers thereof, or halogens; or C
1
-C
4
halogenated ethers including trifluoromethyl ether and trichloromethyl ether.
R
2
, R
3
, R
4
, R
5
, and R
6
are independently selected from H, OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C
1
-C
4
halogenated ethers including triflouromethyl ether and trichloromethyl ether, cyano, C
1
-C
6
alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R
1
is H, R
2
is not OH.
X is selected from H, C
1
-C
6
alkyl cyano, nitro, trifluoromethyl, halogen;
n is 2 or 3;
Y is selected from:
a) the moiety:
wherein R
7
and R
8
are independently selected from the group of H, C
1
-C
6
alkyl, or phenyl optionally substituted by CN, C
1
-C
6
alkyl (straight chain or branched), C
1
-C
6
alkoxy (straight chain or branched), halogen, —OH, —CF
3
, or —OCF
3
;
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
-C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
-C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
1
—, —NHCOR
1
—, —NO
2
, and phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl;
d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
-C
4
alkyl)-, —N═, and —S(O)
m
—, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, —CO
2
H—, —CN—, —CONHR
1
—, —NH
2
—, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, —NHSO
2
R
Collini Michael D.
Miller Chris P.
Santilli Arthur A.
Tran Bach D.
American Home Products Corporation
Eck Steven R.
Kifle Bruck
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