Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-18
2004-06-15
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S333000
Reexamination Certificate
active
06750220
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel amine salt of an integrin receptor antagonist. More particularly, the invention relates to the tris(hydroxymethyl)aminomethyl (“TRIS”) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, which is a potent integrin &agr;
v
&bgr;
3
receptor antagonist. The “TRIS” salt of the present invention is therefore useful for the treatment and prevention of diseases and conditions for which an antagonist of the integrin &agr;
v
&bgr;
3
receptor is indicated.
BACKGROUND OF THE INVENTION
Integrin &agr;
v
&bgr;
3
receptor antagonists have been described as being of use for the prevention and/or treatment of osteoporosis, vascular restenosis, macular degeneration, diabetic retinopathy, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth [see, for example, M. E. Duggan, et al., “Ligands to the integrin receptor &agr;
v
&bgr;
3
, Exp. Opin. Ther. Patents,
10: 1367-1383 (2000); M. Gowen, et al., “Emerging therapies for osteoporosis,”
Emerging Drugs,
5: 1-43 (2000); J. S. Kerr, et al., “Small molecule &agr;
v
integrin antagonists: novel anticancer agents,”
Exp. Opin. Invest. Drugs,
9: 1271-1291 (2000); and W. H. Miller, et al., “Identification and in vivo efficacy of small-molecule antagonists of integrin &agr;
v
&bgr;
3
(the vitronectin receptor),”
Drug Discovery Today,
5: 397-408 (2000)].
U.S. Pat. No. 6,048,861, assigned to Merck & Co., describes a class of 9-substituted-3-aryl-nonanoic acid derivatives, which are potent integrin &agr;
v
&bgr;
3
receptor antagonists and therefore useful for inhibiting bone resorption, vascular restenosis, treating and/or preventing osteoporosis, and inhibiting diseases and conditions associated with excessive and undesirable angiogenesis. Specifically disclosed in U.S. Pat. No. 6,048,861 is 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, including the enantiomeric 3(R) and 3(S) forms. Pharmaceutically acceptable salts of this compound are generically encompassed within the scope of U.S. Pat. No. 6,048,861.
However, there is no specific disclosure in the above reference of the newly discovered tris(hydroxymethyl)aminomethyl (“TRIS”) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula I below.
SUMMARY OF THE INVENTION
This invention provides the novel tris(hydroxymethyl)aminomethyl (“TRIS”) salt of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of the following structural formula I:
or a pharmaceutically acceptable solvate, including hydrate, thereof.
The “TRIS” salt of the present invention has a chiral center (indicated with an *) at the C-3 position of the nonanoic acid chain and can thus occur as a racemate, racemic mixture, and single enantiomers, with all isomeric forms being included in the present invention. The separate enantiomers, substantially free of the other, are included within the scope of the invention, as well as mixtures of the two enantiomers.
Therefore, one embodiment of the present invention provides the TRIS salt of 3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula II:
A second embodiment of the present invention provides the “TRIS” salt of 3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula III:
More specifically, the “TRIS” salt of the present invention is comprised of one molar equivalent of 3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid anion and one molar equivalent of protonated tris(hydroxymethyl)aminomethane cation.
In a further embodiment of the present invention, the “TRIS” salts of structural formulae I-III are crystalline.
The crystalline “TRIS” salt of structural formula I exhibits improved chemical and physical properties over the parent zwitterionic compound of structural formula IV below. This salt therefore has advantages for the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient. Moreover, the “TRIS” salt has greater solubility in water than the parent zwitterionic compound rendering it more desirable for the preparation of aqueous formulations containing the active ingredient suitable for parenteral, such as intravenous, administration.
The “TRIS” salt of the present invention, which exhibits potent integrin &agr;
v
&bgr;
3
antagonist activity, is particularly useful for inhibiting bone resorption, treating and/or preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
REFERENCES:
patent: 6048861 (2000-04-01), Askew et al.
patent: 6444680 (2002-09-01), Humphrey et al.
patent: WO 99/31061 (1999-06-01), None
Gu, L., et al., Pharmaceutical Research, (1987) pp. 255-257, vol. 4, No. 3.
Stahl, P. H., Wermuth, C. G.,(2002) pp. 324-325, Wiley-VCH.
Humphrey Guy R.
Xu Wei
Daniel Mark R.
Merck & Co. , Inc.
Raymond Richard L.
Shatynski Patricia A.
Truong Tamthom N.
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