Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-23
2004-11-23
Jones, Dwayne (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S331000, C514S427000, C514S428000
Reexamination Certificate
active
06821989
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma that comprise administering to a patient having cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma a therapeutically effective amount of an estrogen agonist/antagonist. The present invention also provides kits for treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma that comprises a pharmaceutical composition comprising an estrogen agonist/antagonist and instructions for administering the pharmaceutical composition to treat cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.
BACKGROUND OF THE INVENTION
Cancer is still one of the most dreaded diseases, and much effort and money has been spent trying to discover ways to treat cancer. The present invention provides methods of treating certain cancers, namely cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.
There are two main types of cancer of the liver. The first type is the result of metastasis of cancer from another area in the body. In this type of liver cancer, a cancer cell from another part of the body migrates to the liver and begins growth and tumor formation there. Commonly, the cancer cells that metastasize to the liver come from cancer in the lungs, breast, colon, pancreas or stomach.
The second general type of liver cancer has been called primary liver cancer. This type is composed of subtypes of cancers such as hepatocelluar carcinoma, which is the most common type of liver cancer, fibrolamellar carcinoma, cholangiocarcinoma, hepatoblastoma and angiosarcoma.
Ovarvian cancer is the second most commonly diagnosed and most deadly gynecologic malignancy. Ovarian cancer affects predominantly perimenopausal and postmenopausal women.
Desmoid tumors, also called aggressive fibromatosis, are dense connective tissue tumors.
Glioma is a type of brain tumor, which accounts for 45% of intracranial tumors.
Pancreatic cancer has several varieties including ductal adenocarcinoma, cystadenocarcinoma, intraductal papillary-mucinous tumors, insulinoma, Zollinger-Ellison Syndrome (also known as gastrinoma), vipoma and glucagonoma.
Renal cell carcinoma accounts for about two percent of cancers.
The cancers listed above can all be treated by administering to a patient suffering therefrom a therapeutically effective amount of an estrogen agonist/antagonist.
The use of tamoxifen to treat ovarian cancer, heptaocellular carcinoma, desmoid tumors, malignant gliomas, carcinoma of the pancreas and melanoma is discussed in Gelman, Edward P.,
Tamoxifen for the Treatment of Malignancies Other Than Breast and Endometrial Carcinoma, Seminars in Oncology
, Vol. 24, No. 1, Suppl I (February), 1997, pp SI-65-SI 70.
SUMMARY OF THE INVENTION
The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma, the methods comprising the step of administering to a patient having cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma a therapeutically effective amount of an estrogen agonist/antagonist.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula (I):
wherein:
A is selected from CH
2
and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R
4
;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R
4
;
(c) C
3
-C
8
cycloalkyl, optionally substituted with 1-2 substituents independently selected from R
4
;
(d) C
3
-C
8
cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R
4
;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from R
4
;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
— optionally substituted with 1-3 substituents independently selected from R
4
; or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from R
4
;
Z
1
is
(a) —(CH
2
)
p
W(CH
2
)
q
—;
(b) —O(CH
2
)
p
CR
5
R
6
—;
(c) —O(CH
2
)
p
W(CH
2
)
q
—;
(d) —OCHR
2
CHR
3
—; or
(e) —SCHR
2
CHR
3
—;
G is
(a) —NR
7
R
8
;
wherein n is 0, 1 or 2; m is 1, 2 or 3; Z
2
is —NH—, —O—, —S—, or —CH
2
—; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R
4
; or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R
4
; or
Z
1
and G in combination may be
W is
(a) —CH
2
—;
(b) —CH═CH—;
(c) —O—;
(d) —NR
2
—;
(e) —S(O)
n
—;
(g) —CR
2
(OH)—;
(h) —CONR
2
—;
(i) —NR
2
CO—;
(k) —C≡C—;
R is hydrogen or C
1
-C
6
alkyl;
R
2
and R
3
are independently
(a) hydrogen; or
(b) C
1
-C
4
alkyl;
R
4
is
(a) hydrogen;
(b) halogen;
(c) C
1
-C
6
alkyl;
(d) C
1
-C
4
alkoxy;
(e) C
1
-C
4
acyloxy;
(f) C
1
-C
4
alkylthio;
(g) C
1
-C
4
alkylsulfinyl;
(h) C
1
-C
4
alkylsulfonyl;
(i) hydroxy (C
1
-C
4
)alkyl;
(j) aryl (C
1
-C
4
)alkyl;
(k) —CO
2
H;
(l) —CN;
(m) —CONHOR;
(n) —SO
2
NHR;
(o)—NH
2
;
(p) C
1
-C
4
alkylamino;
(q) C
1
-C
4
dialkylamino;
(r) —NHSO
2
R;
(s) —NO
2
;
(t) -aryl; or
(u) —OH;
R
5
and R
6
are independently C
1
-C
8
alkyl or together form a C
3
-C
10
carbocyclic ring;
R
7
and R
8
are independently
(a) phenyl;
(b) a C
3
-C
10
carbocyclic ring, saturated or unsaturated;
(c) a C
3
-C
10
heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C
1
-C
6
alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R
5
or R
6
;
R
7
and R
8
in either linear or ring form may optionally be substituted with up to three substituents independently selected from C
1
-C
6
alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R
7
and R
8
may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula (IA)
wherein G is
R
4
is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, raloxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthal
Benson Gregg C.
Jones Dwayne
Pfizer Inc.
Richardson Peter C.
Wichtowski John A.
LandOfFree
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