Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-19
2004-08-17
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S345000, C514S681000, C514S682000, C514S317000, C514S331000, C514S428000, C514S213010
Reexamination Certificate
active
06777424
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and kits for treating osteoarthritis using an estrogen agonist/antagonist.
BACKGROUND OF THE INVENTION
Osteoarthritis is the most common joint disorder and is characterized by loss of joint cartilage and hypertrophy of bone at the joint. This disorder usually begins asymtomatically in the 2nd to 3rd decade of life and is very common by age seventy. Almost all persons by age forty have some pathological change in weight-bearing joints. Men and women are equally affected, but onset is earlier in men.
Joint cartilage, also called hyaline cartilage, is made up of 95% water and extracellular matrix and 5% chondrocytes. The extracellular matrix comprises proteoglycans and Type II collagen.
Osteoarthritis is a progressive disease. Typical symptomatic treatment includes the management of pain that accompanies osteoarthritis and changes in lifestyle such as diet and exercise. Examples of compounds that have been used to treat the pain associated with osteoarthritis include acetominophen and nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, ketoprofen, nabumetone, etodolac, salsalate, sulindac, diclofenac, tolmetin, flurbiprofen, piroxicam, fenoprofen, indomethacin, meclofenamate, oxaprozin, diflunisal, and ketorolac; and selective cyclooxygenase-2 (COX-2) inhibitors such as Celebrex® and Vioxx®. Because NSAIDs can have unwanted side effects such as ulcers, NSAIDs are sometimes administered with other compounds that ameliorate the side effects of the NSAIDs. Typical compounds that are used in combination with NSAIDs include proton pump inhibitors such as omeprazole; antacids such as sucralfate; and H2 blockers such as ranitidine, cimetidine, famotidine, and nizatidine. In addition, products derived from natural substances have been used to treat osteoarthritis. Examples of natural substances include hyaluronic acid, glucosamine, chondroitin sulfate, and capsaicin. Intraarticular corticosteriods have also been used to treat osteoarthritis. Presently, there are no widely accepted treatments that reduce the progression of cartilage damage in osteoarthritis.
It has been found that chondrocytes, which are a main component of cartilage and produce proteoglycans and Type II collagen, contain estrogen receptors. The present invention provides methods for preventing or reducing the rate of cartilage degradation using an estrogen receptor agonist/antagonist.
SUMMARY OF THE INVENTION
The present invention provides methods of treating osteoarthritis, the methods comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist 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
;
(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
1
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;
(i) —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 a 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 a 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 in the form of a D-tartrate salt.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof. In addition, raloxifene can be used to prevent or reduce the rate of cartilage degradation.
Also provided are methods of treating osteoarthritis, the methods comprising administering to a patient having or at risk of having osteoarthritis, a therapeutically effective amount of an estrogen agonist/antagonist of formula V or VI:
wherein:
R
1B
is selected from H, OH, —O—C(O)—C
1
-C
12
alkyl (straight chain or branched), —O—C
1
-C
12
alkyl (straight chain or branched or
Benson Gregg C.
Criares Theodore J.
Pfizer Inc.
Richardson Peter C.
Wichtowski John A.
LandOfFree
Methods for treating osteoarthritis using an estrogen... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for treating osteoarthritis using an estrogen..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for treating osteoarthritis using an estrogen... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3355090