Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-09
2002-06-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S428000, C514S429000
Reexamination Certificate
active
06403611
ABSTRACT:
BACKGROUND OF THE INVENTION
Certain estrogen agonists have been reported to be useful in inhibiting pathological conditions related to organ systems which respond to estrogen agonists or antagonists. In particular, 2-phenyl-3-aroylbenzothiophenes and 1-(alkylaminoethoxy phenyl)-1-phenyl-2-phenylbut-1-enes represented by raloxifene and tamoxifen have wide application as estrogen agonists.
Raloxifene has been claimed to be effective in the treatment of acne, U.S. Pat. No. 5,439,923; alopecia, EP 0659414 A2; Alzheimers disease, EP 0659418 A1; atrophy of skin and vagina, U.S. Pat. No. 5,461,064; auto immune disease, EP 0664123; breast cancer, U.S. Pat. No. 4,418,068; breast disease, EP 0659419; cartilage degeneration, U.S. Pat. No. 5,418,252; CNS problems (post menopausal), 94 EP 0309470; pathology of endocrine target organs. U.S. Pat. No. 4,418,068; delayed puberty, U.S. Pat. No. 5,451,589; demyelinating disease, U.S. Pat. No. 5,434,166; dysmyelinating disease, U.S. Pat. No. 5,434,166; dysmenorrhea, U.S. Pat. No. 5,446,053; endometriosis, U.S. Pat. No. 5,461,065; female infertility, EP 659429 A1; fertility disorders; hirsutism, EP 0659414 A2; hypoglycemic, EP 635264 A2; increase libido, U.S. Pat. No. 5,439,931; inhibition of fertility, U.S. Pat. No. 5,462,949; LDL oxidation, EP 0664121 A; hypercholesterolemia, U.S. Pat. No. 5,464,845; lupus erythematosus, EP 0664125; impaired macrophage function, EP 659425 A1; male infertility, EP 0659424 A1; myocardial infaction, ischaemia, thromboembolic disorder, thrombin inhibition, EP 0664126; menopausal disorders, EP 0659415; menstruation disorders, U.S. Pat. No. 5,462,950; obesity, 94 EP 0309481; obsessive compulsive disorder, EP 0659428; osteoporosis, U.S. Pat. No. 5,457,117; ovarian dysgenesis, U.S. Pat. No. 5,451,589; perimenopausal syndrome, U.S. Pat. No. 5,391,557; peripheral vasoconstriction, U.S. Pat. No. 5,470,883; post menopausal CNS, EP 0659415; premenstrual syndrome, U.S. Pat. No. 5,389,670; prostatic carcinoma; prostatic hyperplasia; pulmonary hypertension, U.S. Pat. No. 5,447,941; reperfusion damage, J. AM. Cardiol 25, 189A (1993); resistant neoplasm, EP 0652004 A1; restenosis, U.S. Pat. No. 5.462,937; rheumatoid arthritis, EP 0664125, seborrhea, U.S. Pat. No. 5,439,923; sexual dysfunction; sexual precocity, U.S. Pat. No. 5,451,590; thrombomodulin expression, EP 0659427; Turners syndrome, U.S. Pat. No. 5,441,966; uterine fibrosis U.S. Pat. No. 5,457,116; and vasomotor symptoms (post menopausal), 94 EP 0309473.
Tamoxifen is widely employed in the treatment of breast cancer and has been reported to be effective in the treatment of the following diseases and conditions: high lipid levels, Drug Ther. 22/3, 109 (1992); ovarian cancer, J. Clin. Oncol. 11, No. 10, 1957-68 (1993); renal cell carcinoma, Br. J. Radiol 56, No. 670, 766-7 (1983); suppression of atherogenic factor homocysteine, Env. J. Cancer 29 Suppl. 6, S110 (1993); metastatic melanoma, J. Clin. Oncol. 12, No. 8, 1553-60 (1994); mastalgia, Drugs 32, No. 6, 477-80, (1986); prolactive secreting pituitary tumors, J. Endrocrinol. Invest. 3/4, 343-347 (1980); osteoporosis, Proc. Annu Meet Am Assoc. Cancer Res.; 33: A566-7 (1992); netroperitoneal fibrosis, Lancet 341, No. 8841, 382 (1993).
Small structural changes in the structure of estrogen agonists cause profound differences in biological properties. For example, droloxifene (3-hydroxytamoxifen) formula I below, has a 10-60-fold higher binding affinity to the estrogen receptor compared to tamoxifen. Droloxifene is devoid of in vivo or in vitro carcinogenic or nutagenic effects, whereas tamoxifen causes liver tumors in rats. Hasmamu, et al. Cancer Letter 84, 101-116 (1994).
Droloxifene has been reported to be effective in the treatment of breast cancer U.S. Pat. No. 5,047,431; endometriosis, U.S. Pat. No. 5,455,275; lowering cholesterol, U.S. Pat. No. 5,426,123; osteoporosis, U.S. Pat. No. 5,254,594; prostatic hyperplasia, U.S. Pat. No. 5,441,986; and restenosis, U.S. Pat. No. 5,384,332.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting a pathological condition which is susceptible or partially susceptible to inhibition by an antiestrogen or estrogen agonist, which comprises administering to a mammal in need of inhibition of a pathological condition selected from the group consisting of uterine cancer, adjuvant breast cancer, breast disorder, male breast cancer, migraine, incontinence, vaginal atrophy, bladder infection, senile gynecomastia, diabetes, hypoglycemia, failure of wound healing, melanoma, impotence, inflammatory bowel disease, CNS and GI disorders caused by an excess of tackykinins, decreased libido, immune system disorders, decreased fertility, pulmonary hypertensive disease, acne, seborrhea, autoimmune disease, Turner's syndrome, alopecia, hirsutism, disorders related than excess of neurokinin and obsessive-compulsive disorders including smoking and alcohol abuse, an effective amount of 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′ 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
;
(b)
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′ and G in combination may be
W is
(a) —CH
2
—;
(b) —CH═CH—;
(c) —O—;
(d) —NR
2
—;
(e) —S(O)
n
—;
(f)
(g) —CR
2
(OH)—;
(h) —CONR
2
—;
(i) —NR
2
CO—;
(j)
(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 se
Maclean David B.
Thompson David D.
Crissey Todd M.
Delacroix-Muirheid C.
Henson Gregg C.
Jones Dwayne C.
Pfizer Inc.
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