Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-29
2003-08-26
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S352000, C514S423000, C514S573000, C514S530000
Reexamination Certificate
active
06610719
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and pharmaceutical compositions comprising receptor selective prostaglandin (PGE
2
) agonists for the treatment of kidney diseases, such as chronic and acute renal failure or dysfunction, in animals, particularly mammals. More specifically, the present invention relates to such methods and pharmaceutical compositions comprising type 4 (EP
4
) receptor selective prostaglandin (PGE
2
) agonists.
BACKGROUND OF THE INVENTION
The naturally occurring prostaglandins are comprised of several biological entities including PBD, PGE, PGF, PGG, PGH and PGI. It has been well documented that prostaglandins have effects on many of the organs and systems of the body.
In the kidney, the prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects. In clinical studies, PGE, has been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N-acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy, and to improve urea clearance in healthy volunteers. PGE
1
also has been administered intravenously during surgeries to prevent renal failure.
Renal dysfunction and/or renal failure is manifested in the body in a number of different ways. Any one or a combination of the following manifestations could indicate renal dysfunction or failure in a patient: lower than normal creatinine clearance; lower than normal free water clearance; higher than normal blood urea and/or nitrogen and/or potassium and/or creatinine levels; altered activity of kidney enzymes such as gamma glutamyl synthetase, alanine phosphatidase, N-acetyl-beta-D-glucosaminidase, or beta-2-microglobulin; altered urine osmolarity or volume; increase over normal levels or new observation of microalbuminuria or macroalbuminuria; or need for dialysis. Successful prevention of renal dysfunction or renal failure is indicated if the above described events do not occur at all, if they occur with less severity, if they occur in fewer patients at risk for renal dysfunction or renal failure; or if the patient recovers from these problems more quickly than normal.
Acute renal failure caused by the injection of contrast media has been recognized for many years as a complication of procedures utilizing such media. It has been estimated that the incidence of acute renal failure directly induced by contrast media is 10-15%, while the incidence of contrast associated nephropathy defined by clinically significant increases in serum creatinine is as high as 22%. See Porter, Am. J. Cardiol., 64: 22E-26E (1989). U.S. Pat. No. 5,807,895 discloses a method of preventing renal failure or dysfunction caused by medical procedures which utilize contrast media by intravenous administration of a prostaglandin compound selected from PGE
1
, PGE
2
PGI
2
or an analog or pharmaceutically acceptable salt thereof.
Chronic renal failure (CRF) occurs as a result of progressive and later, permanent reduction in the glomerular filtration rate (GFR), which is associated with loss of functional nephron units. When the GFR continues to decline to less than 10% of normal (5-10 ml/min), the subject progresses to end-stage renal failure (ESRD). R. A. Lafayette, R. D. Perrone and A. S. Levey: “Laboratory Evaluation of Renal Function,” in:
Diseases of the Kidney
(Eds: R. W. Schrier and C. W. Gottschalk), Little, Brown and Company, Inc., Vol. 6, 307-354 (1997). At this point, unless the subject receives renal replacement therapy (i.e., chronic hemodialysis, continued peritoneal dialysis or kidney transplantation) renal failure will rapidly progress to cause death. It is believed that the therapies which delay or halt the progression of ESRD will provide a basis for the treatment of chronic renal disease. A variety of growth and differentiation factors, for example, epidermal growth factor (EGF), transforming growth factor-&agr; and -&bgr; (TGF-&agr; and -&bgr;), insulin like growth factor-1 (IGF-1), fibroblast growth factor (FGF), platelet derived growth factor (PDGF) and bone morphogenetic protein (BMP) have been shown to participate in the regulation of the growth and repair of renal tissues. M. R. Hammerman and S. B. Miller, “Therapeutic Use of Growth Factors in Renal Failure,” J. Am. Soc. Nephrolol., 5: 1-11 (1994); and R. C. Harris, “Growth Factors and Cytokines in Acute Renal Failure,” Adv. Renal. Repl. Ther., 4: 43-53 (1997).
Epidermal growth factor (EGF) enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. H. D. Humes, D. A. Cieslinski, T. Coimbra, J. M. Messana and C. Galvao, J. Clin. Invest., 84: 1757-1761 (1989). Insulin-like growth factor I (IGF-1) accelerates recovery from ischemic acute tubular necrosis in the rat. S. B. Miller, D. R. Martin, J. Kissane, and M. R. Hammerman, Proc. Natl. Acad. Sci. USA, 89:11876-11880 (1994). Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats. S. B. Miller, D. R. Martin, J. Kissane, and M. R. Hammerman, Am. J. Physiol., 266:129-134 (1994). Osteogenic protein-1 (bone morphogenetic protein-7 (BMP-7)) reduces severity of injury after ischemic acute renal failure in the rat. S. Vukicevic, V. Basic, D. Rogic, N. Basic, M. S. Shih, A. Shepard, D. Jin et al., J. Clin. Invest., 102: 202-214 (1998).
The term prostaglandin refers to compounds which are analogs of the natural prostaglandins PGD
1
, PGD
2
, PGE
2
, PGE
1
and PGF
2
. These compounds bind to the prostaglandin receptors. Such binding is readily determined by those skilled in the art according to standard assays (e.g., S. An et al., Cloning and Expression of the EP
2
Subtype of Human Receptors for Prostaglandin E
2
, Biochemical and Biophysical Research Communications, 197(1): 263-270 (1993)). These compounds can be synthesized by methods known in the art. See, e.g., Goodman and Gilman,
The Pharmacological Basis of Therapeutics
, Eighth Ed., Pergamon Press, pp. 601-604 (1990).
Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. The carbon atoms of the basic prostaglandin are numbered sequentially from the carboxylic carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Normally the adjacent side chains are in the trans orientation. The presence of an oxo group at C-9 of the cyclopentyl moiety is indicative of a prostaglandin within the E class while PGE
2
contains a trans unsaturated double bond at the C
13
-C
14
and a cis double bond at the C
5
-C
6
position. However, there are severe side effects associated with PGE
2
treatment. W. S. S. Jee and Y. F. Ma, Bone, 21:297-304 (1997).
A variety of prostaglandins are described and referenced below. However, other prostaglandins will be known to those skilled in the art.
U.S. Pat. No. 4,177,346 discloses certain 1,5-disubstituted-2-pyrrolidones which are prostaglandin-like in chemical structure and have vasodilator activity, antihypertensive activity and antisecretory activity.
International Patent Application, Publication No. WO 99/02164, discloses methods and compositions for treating impotence or erectile dysfunction by using prostaglandins that are selective EP
2
or EP
4
prostanoid receptor agaonists.
U.S. Pat. No. 4,112,236 discloses certain interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins which have renal vasodilatory activity and are useful for the treatment of patients with renal impairment. U.S. Pat. No. 4,033,996 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.
Certain 11,12-secoprostaglandins and analogs thereof, which have a variety of therapeutic uses, including their use as renal vasodilators, are disclosed, for example, in the following: Great Brit
Paralkar Vishwas M.
Thompson David D.
Benson Gregg C.
Cook Rebecca
Pfizer Inc.
Richardson Peter C.
Wichtowski John A.
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