Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-06
2004-11-16
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...
C514S332000, C530S300000, C530S333000
Reexamination Certificate
active
06818659
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a novel arginine mimic, (2S)-2-amino-4-(2-amino-(3,4,5,6-tetrahydropyrimidin-4-yl))butanoyl, methods of using the same, peptides that bind to biological receptors containing the same, and pharmaceuticals comprising the same.
The pharmaceuticals are comprised of a targeting moiety that binds to a biological receptor, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The therapeutically effective radioisotope emits a particle or electron sufficient to be cytotoxic. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
BACKGROUND OF THE INVENTION
JP 07/030037 describes antithrombotics of the following formula.
Compounds of this sort are not considered to be part of the present invention.
U.S. Pat. No. 5,332,745 illustrates tetrahydropyrimidine fungicides of the following formula.
These types of compounds are not considered to be part of the present invention.
U.S. Pat. No. 5,854,234 depicts cyclic amidino nitric oxide synthase inhibitors of the following formula.
Such compounds are not considered to be part of the present convention.
Duggan et al, J. Med. Chem. 2000, 43, 3736-3745, describe non-peptide, a
v
b
3
antagonists, an example of which is the following.
Such compounds are not considered to be part of the present invention.
SUMMARY OF THE INVENTION
It is one object of the present invention to provide a novel amino acid.
It is another object of the present invention to provide a novel method of making a novel amino acid.
It is another object of the present invention to provide a novel method of using a novel amino acid.
It is another object of the present invention to provide novel acyclic and cyclic peptides comprising a novel amino acid, wherein the peptides bind to a novel biological receptor.
It is another object of the present invention to provide novel pharmaceuticals comprising a targeting moiety that binds to a biological receptor, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety, wherein the targeting moiety is an acyclic or cyclic peptide comprising a novel amino acid.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the amino acid of formula I:
is an effective arginine mimic.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in an embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or salt form thereof, wherein:
R
1
is H or a hydroxy protecting group;
alternatively, OR
1
is an activated ester;
R
2
is H, CH
3
, or an amine protecting group;
R
2a
is H or an amine protecting group;
R
3
is H or an amine protecting group;
R
4
is H or an amine protecting group; and,
R
4a
is H or an amine protecting group;
provided that one of R
1
, R
2
, R
2a
, R
3
, R
4
, and R
4
is other than H.
In another embodiment, the present invention provides a novel compound of formula Ia or Ib:
or a stereoisomer or salt form thereof.
In another preferred embodiment, the present invention provides a compound of formula I, wherein:
R
1
is selected from H, OMe, OEt, OBzl, Oallyl, and Ot-Bu;
alternatively, OR
1
is selected from OSu, OBt, OPfp, and Onp;
R
2
is Fmoc or Boc
R
2a
is H;
R
3
is H;
R
4
is selected from Tos, Mtr, Pbf, Mts, Pmc, Boc, Mbs, NO
2
, and Cbz;
R
4a
is H;
alternatively, when R
4
Boc, R
4
is Boc; and,
alternatively, when R
4
Cbz, R
4a
is Cbz;
In a more preferred embodiment, the compound of I is selected from:
Fmoc-cyArg(Tos)-OH, Fmoc-cyArg(Mtr)-OH, Fmoc-cyArg(Pbf)-OH, Fmoc-cyArg(Mts)-OH, Fmoc-cyArg(Pmc)-OH, Fmoc-cyArg(Boc)2-OH, Boc-cyArg(Mbs)-OH, Boc-cyArg(Boc)2-OH, Boc-cyArg(Mtr)-OH, Boc-cyArg(NO
2
)-OH, Boc-cyArg(Pbf)-OH, Boc-cyArg(Pmc)-OH, Boc-cyArg(Tos)-OH, and Boc-cyArg(Cbz)2-OH;
wherein cyArg corresponds to the unmodified amino acid.
In another embodiment, the present invention provides a novel process for making a compound of formula I:
the process comprising: reducing a pyrimidine of formula II to form a compound of formula I.
In a preferred embodiment, reduction is performed by contacting the compound of formula II with trifluoroacetic acid and a trialkylsilane. One of ordinary skill in the art would recognize that a number of trialkylsilanes could be used for this reduction, including trimethylsilane, triethylsilane, and triisopropylsilane. Alternatively, the reduction is performed via catalytic hydrogenation.
In a more preferred embodiment, the trialkylsilane is triisopropylsilane.
A method of preparing an arginine-containing peptide, comprising: synthesizing the peptide using a compound of formula I in place of arginine or protected arginine:
or a stereoisomer or salt form thereof, wherein:
R
1
is H or a hydroxy protecting group;
alternatively, OR
1
is an activated ester;
R
2
is H or an amine protecting group;
R
2a
is H or an amine protecting group;
R
3
is H or an amine protecting group;
R
4
is H or an amine protecting group; and,
R
4a
is H or an amine protecting group;
provided that one of R
1
, R
2
, R
2a
, R
3
, R
4
, and R
4
is other than H.
In another embodiment, the present invention provides a novel compound, comprising: an acyclic or cyclic peptide that targets a biological receptor, wherein the peptide comprises an arginine mimic of formula IIIa or IIIb:
In another preferred embodiment, the biological receptor is selected from the group: Tuftsin, Thrombin catalytic site, Thrombin exosite, Factor XIIIa, Factor Xa, Factor IXa, Factor VIIa, Neurotensin, Bombesin, the Bradykinin receptors, and an intergrin selected a
v
b
3
, a
IIb
b
3
, a
v
b
5
, a
5
b
1
, a
2
b
1
, a
1
b
1
, and Mac-1
In a more preferred embodiment, the biological receptor is selected from the group: Tuftsin, Thrombin catalytic site, Thrombin exosite, Factor XIIIa, Factor Xa, Factor IXa, Factor VIIa, and an intergrin selected from a
v
b
3
, a
IIb
b
3
, a
v
b
5
, a
5
b
1
, a
2
b
1
, a
1
b
1
, and Mac-1
In another more preferred embodiment, the peptide comprises an RGD, TKPR, or TKPPR segment wherein arginine has been replaced by the arginine mimic of formula III.
In an even more preferred embodiment, the compound further comprises: a chelator and 0-1 linking groups between the peptide and the chelator.
In a still more preferred embodiment, the linking group is present.
In another embodiment, the present invention provides a novel compound, comprising: a cyclic peptide that targets a biological receptor, a chelator, and a linking group between the chelator and peptide, wherein the receptor is the integrin &agr;
v
&bgr;
3
and the compound is of the formula:
(Q)
d
—L
n
—C
h
or (Q)
d
—L
n
—(C
h
)
d
,
wherein, Q is a peptide independently selected from the group:
K is a group of formula IIIa or IIIb:
K′ is a group of formula IIIc or IIIc:
L is independently selected at each occurrence from the group: glycine, L-alanine, and D-alanine;
M is L-aspartic acid;
M′ is D-aspartic acid;
R
1
is an amino acid substituted with 0-1 bonds to L
n
, independently selected at each occurrence from the group: glycine, L-valine, D-valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, phenylalanine, thienylalanine, phenylglycine, cyclohexylalanine, homophenylalanine, 1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penicillamine, and methionine;
R
2
is an amino acid, substituted with 0-1 bonds to L
n
, independently selected at each occurrence from the group: glycine, valine, alanine, leucine, isoleucine, norleucine, 2-aminobutyric acid, 2-aminohexanoic acid, tyrosine, L-phenylalanine, D-phenylalanine, thienylalanine, phenylglycine, biphenylglycine, cyclohexylalanine, homophenylalanine, L-1-naphthylalanine, D-1-naphthylalanine, lysine, serine, ornithine, 1,2-diaminobutyric acid, 1,2-diaminopropionic acid, cysteine, penic
Bristol-Myers Squibb Pharma, Inc.
Davis, Esq. Stephen B.
Raymond Richard L.
Truong Tamthom N.
Woodcock & Washburn LLP
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