Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-29
2002-09-03
Ford, John M. (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
06444680
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to particular salts of an integrin receptor antagonist. More particularly, the invention relates to amine salts of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid, which are potent integrin &agr;
v
&bgr;
3
receptor antagonists. These novel salts are 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-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1, 8]-naphthyridin-2-yl)-nonanoic acid. 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 amine salts of 3-(2-methyl-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 new amine salts of 3-(2-methyl-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, wherein
R
1
and R
2
are both hydrogen,
R
1
is hydrogen and R
2
is C(CH
2
OH)
3
,
R
1
is hydrogen and R
2
is C(CH
3
)
2
CH
2
OH,
R
1
is hydrogen and R
2
is CH
2
CH
2
NH
2
, or
R
1
is CH
2
C
6
H
5
and R
2
is CH
2
CH
2
C
6
H
5
.
The amine salts of the present invention have 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 amine salts of 3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula II:
wherein
R
1
and R
2
are both hydrogen,
R
1
is hydrogen and R
2
is C(CH
2
OH)
3
,
R
1
is hydrogen and R
2
is C(CH
3
)
2
CH
2
OH,
R
1
is hydrogen and R
2
is CH
2
CH
2
NH
2
, or
R
1
is CH
2
C
6
H
5
and R
2
is CH
2
CH
2
C
6
H
5
.
A second embodiment of the present invention provides the amine salts of 3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid of structural formula III:
wherein
R
1
and R
2
are both hydrogen,
R
1
is hydrogen and R
2
is C(CH
2
OH)3,
R
1
is hydrogen and R
2
is C(CH
3
)
2
CH
2
OH,
R
1
is hydrogen and R
2
is CH
2
CH
2
NH
2
, or
R
1
is CH
2
C
6
H
5
and R
2
is CH
2
CH
2
C
6
H
5
.
More specifically, the amine salts of the present invention are comprised of one molar equivalent of 3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid anion and one molar equivalent of ammonium (R
1
=R
2
=H) cation, protonated ethylenediamine cation (R
1
=H, R
2
=CH
2
CH
2
NH
2
), protonated 2-amino-2-methyl-1-propanol cation [R
1
=hydrogen, R
2
=C(CH
3
)
2
CH
2
OH], protonated tris(hydroxymethyl)aminomethane cation [R
1
=hydrogen, R
2
=C(CH
2
OH)
3
], or protonated N-benzyl-2-phenethylamine cation (R
1
=CH
2
C
6
H
5
, R
2
=CH
2
CH
2
C
6
H
5
).
In a further embodiment of the present invention, the amine salts of structural formulae I-III are crystalline.
The crystalline amine salts of structural formula I exhibit greater chemical and physical stability than the parent zwitterionic compound of structural formula (IV) below. These salts are therefore more desirable for the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient.
The amine salts of the present invention, which exhibit potent integrin &agr;
v
&bgr;
3
antagonist activity, are 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.
Another aspect of the present invention provides compounds 2-6a and 2-6b in the form of a zwitterion trihydrate.
REFERENCES:
patent: 6048861 (2000-04-01), Askew et al.
patent: WO99/31061 (1999-06-01), None
Humphrey Guy R.
Waters Marjorie See
Xu Wei
Durette Philippe L.
Ford John M.
Merck & Co. , Inc.
Winokur Melvin
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