Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-16
2003-03-11
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000, C514S354000, C514S356000, C514S381000, C514S364000, C514S365000, C514S464000, C514S419000, C514S415000, C514S456000, C514S439000, C514S530000, C514S570000, C546S147000, C546S268400, C546S269100, C546S269400, C548S494000, C548S204000, C548S252000, C548S253000, C548S131000, C548S132000, C549S447000, C549S079000, C549S399000, C562S503000, C562S504000, C560S121000, C560S118000
Reexamination Certificate
active
06531485
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 including the treatment of conditions which present with low bone mass in 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. 3,932,389, incorporated herein by reference, discloses certain tetrazolyl prostaglandin derivatives as vasodilators, bronchodilators, antiulcer and antisecretory agents.
U.S. Pat. No. 4,097,601, incorporated herein by reference, discloses selected compounds from U.S. Pat. No. 3,932,389 as having utility in the treatment of bone disorders.
British patent number GB 1 521 688 discloses certain cyclopentanones for the production of hypotension, bronchodilation, inhibition of gastric acid secretion, healing of gastric ulcers, luteolysis and the stimulation of uterine contraction.
U.S. Pat. No. 3,980,700, incorporated herein by reference, discloses certain cyclopentanones as antibacterial agents.
U.S. Pat. No. 4,197,407, incorporated herein by reference, discloses certain cyclopentanones as smooth muscle stimulants, arterial blood pressure lowering agents and antagonists of epinephrine-induced mobilization of free fatty acid.
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. While there are several promising therapies (bis-phosphonates, etc.) in development to prevent bone loss with age and thus reduce the probability of incurring debilitating fractures, these therapies are not indicated for restoration of bone mass once the fracture has occurred.
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.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula I
prodrugs thereof and pharmaceutically acceptable salts of said compounds and prodrugs wherein
A is hydrogen or hydroxy;
B is propylene, propenylene or propynylene;
Q is propylene, —CH
2
OCH
2
—, thiazolyl, pyridyl, phenyl or thienyl;
Z is carboxyl, (C
1
-C
6
)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl or 5-oxo-1,2,4-oxadiazolyl;
K is ethylene or ethenylene;
L is a bond or —CO—;
M is —Ar, —Ar
1
—V—Ar
2
, —Ar
1
—S—Ar
2
or —Ar
1
—O—Ar
2
wherein
Ar and Ar
1
are either (1) each independently a fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, any of said partially saturated or fully saturated rings optionally having one or more oxo groups substituted on carbon, or
(2) each independently a fully saturated five to eight membered ring;
Ar
2
is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, any of said partially saturated or fully saturated rings optionally having one or more oxo groups substituted on carbon;
said Ar and Ar
1
moieties, when a fully unsaturated five to eight membered ring, a bicyclic ring or a tricyclic ring, and said Ar
2
moieties are each independently optionally substituted on carbon, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic,
Cameron Kimberly O.
DaSilva-Jardine Paul A.
Benson Gregg C.
Crissey Todd M.
Huang Evelyn Mei
Pfizer Inc.
Richardson Peter C.
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