Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-22
2002-04-23
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S269000, C514S336000, C514S342000, C514S369000, C514S407000, C514S444000, C514S473000, C514S448000, C544S333000, C546S269700, C546S280400, C546S283400, C548S183000, C548S375100, C549S059000, C549S062000, C549S071000, C549S475000
Reexamination Certificate
active
06376502
ABSTRACT:
BACKGROUND OF INVENTION
This invention relates to prostaglandin agonists, pharmaceutical compositions containing such agonists and the use of such agonists to prevent bone loss or restore or augment bone mass and to enhance bone healing including the treatment of conditions which present with low bone mass and/or bone defects in vertebrates, and particularly mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis. The first is the use of anti-resorptive compounds to reduce the resorption of bone tissue.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen reduces fractures. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL's). However, estrogen failed to restore bone back to young adult levels in the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable effect on serum LDL but do not cause undesirable effects.
A second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton.
U.S. Pat. No. 4,112,236, incorporated herein by reference, discloses certain interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins for the treatment of patients with renal impairment.
Certain prostagladin agonists are disclosed in GB 1478281, GB1479156 and U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 as being useful as, for example, renal vasodilators. U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 are each incorporated herein by reference.
U.S. Pat. No. 4,033,996, which is incorporated herein by reference, discloses certain 8-aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins which are useful as renal vasodilators, for the prevention of thrombus formation, to induce growth hormone release, and as regulators of the immune response.
French Pat. No. 897,566 discloses certain amino acid derivatives for the treatment of neurological, mental or cardiovascular disease.
J. Org. Chem. 26; 1961; 1437 discloses N-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid.
Certain 11,12-secoprostaglandins are disclosed in U.S. Pat. Nos. 3,991,087 and 4,066,692, each of which is incorporated herein by reference.
In addition to osteoporosis, approximately, 20-25 million women and an increasing number of men have detectable vertebral fractures as a consequence of reduced bone mass, with an additional 250,000 hip fractures reported yearly in America alone. The latter case is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population.
Estrogens have been shown (Bolander et al., 38th Annual Meeting Orthopedic Research Society, 1992) to improve the quality of the healing of appendicular fractures. Therefore, estrogen replacement therapy might appear to be a method for the treatment of fracture repair. However, patient compliance with estrogen therapy is relatively poor due to its side effects, including the resumption of menses, mastodynia, an increased risk of uterine cancer, an increased perceived risk of breast cancer, and the concomitant use of progestins. In addition, men are likely to object to the use of estrogen treatment. Clearly the need exists for a therapy which would be beneficial to patients who have suffered debilitating bone fractures and which would increase patient compliance.
Although there are a variety of osteoporosis therapies there is a continuing need and a continuing search in this field of art for alternative osteoporosis therapies. In addition, there is a need for bone fracture healing therapies. Also, there is a need for therapy which can promote bone re-growth into skeletal areas where defects exist such as defects caused or produced by, for example, tumors in bone. Further, there is a need for therapy which can promote bone re-growth into skeletal areas where bone grafts are indicated.
SUMMARY OF THE INVENTION
This invention is directed to a compound of Formula I
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
B is N or C(Q
1
), where Q
1
is H or (C
1
-C
3
)alkyl;
L is n-propylenyl-X— or CH
2
-metaphenylene-CH
2
, wherein X is furanyl, thienyl, thiazolyl or tetrahydrofuranyl, said CH
2
-metaphenylene-CH
2
or X being optionally mono-, di- or tri-substituted on aromatic carbon independently with one to three chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
R is carboxyl, (C
1
-C
6
)alkoxycarbonyl, tetrazolyl, 5-oxo-1,2,4-thiadiazolyl; 5-oxo-1,2,4-oxadiazolyl, (C
1
-C
4
)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
R
1
is H, methyl, ethyl or propyl;
R
2
is H or (C
2
-C
5
) alkanoyl;
R
3
is independently H, fluoro or methyl;
R
4
is H, (C
1
-C
7
) alkyl, or R
4
and R
1
are taken together to form a 5-9 membered carbocydic ring, said alkyl being optionally monounsaturated and optionally mono-, di- or tri-substituted independently with one to three fluoro, chloro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
R
5
is (C
1
-C
6
)alkylsulfonyl, (C
3
-C
7
)cycloalkylsulfonyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)alkylcarbonyl, (C
3
-C
7
)cycloalkylcarbonyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkylcarbonyl, G-sulfonyl or G-carbonyl, said (C
1
-C
6
)alkylsulfonyl, (C
3
-C
7
)cycloalkylsulfonyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)alkylcarbonyl, (C
3
-C
7
)cycloalkylcarbonyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkylcarbonyl optionally mono-, di- or tri-substituted on carbon independently with hydroxy, fluoro, chloro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
Z is methylene, ethylene, propylene or ethenylene;
G is Ar, Ar
1
—V—Ar
2
, Ar—(C
1
-C
6
)alkylene, Ar—CONH—(C
1
-C
6
)alkylene, R
12
R
13
-amino, oxy(C
1
-C
6
)alkylene, amino substituted with Ar, or amino substituted with Ar(C
1
-C
4
)alkylene and R
11
, wherein R
11
is H or (C
1
-C
8
)alkyl, R
12
and R
13
may be taken separately and are independently selected from H and (C
1
-C
8
)alkyl, or R
12
and R
13
are taken together with the
Cameron Kimberly O.
Lefker Bruce A.
Rosati Robert L.
Benson Gregg C.
Davis Zinna Northington
Munchhof Martha G.
Pfizer Inc.
Richardson Peter C.
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