Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-06
2004-06-15
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S466000, C548S467000, C548S486000, C514S418000
Reexamination Certificate
active
06750241
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel compounds which inhibit or modulate the activity of protein kinases and to pharmaceutical compositions comprising such compounds. This invention also relates to methods of treating diseases or medical conditions mediated by protein kinases using such compounds.
2. State of the Art
Protein kinases are enzymes which catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. See, for example, Hardie, G. and Hanks, S. (1995)
The Protein Kinase Facts Book, I and II,
Academic Press, San Diego, Calif.; Stover, D. R. et al.,
Current Opin. in Drug Discovery,
(1999) 2(4), 274-285; Adams, J. L.,
Current Opin. in Drug Discovery,
(1999) 2(2), 96-109; and Lawrence D. S. et al.,
Pharmacol. Ther.
(1998) 77(2), 81-114. By doing so, protein kinases mediate virtually all aspects of cell life including cell growth, cell differentiation and cell proliferation. In this regard, abnormal activity of protein kinases has been associated with a host of diseases or medical disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). See, for example, Levitzki, A. et al., Science, (1995) 267, 1782-1788.
Accordingly, a need exists for compounds and compositions which inhibit or modulate the activity of protein kinases.
SUMMARY OF THE INVENTION
This invention provides novel compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions comprising such compounds. Accordingly, the compounds and compositions of this invention are useful for treating diseases or medical disorders mediated by protein kinases.
The compounds of this invention are multimeric, i.e., they comprise two or more ligand(moieties covalently linked together by one or more linking groups. While not wishing to be limited by theory, it is believed that each ligand moiety of these compounds binds to a ligand binding domain of a protein kinase or a related binding site, thereby inhibiting or modulating the activity of the protein kinase. By binding to multiple binding sites, compounds of this invention exhibit improved properties including, by way of example, increased efficacy, selectivity or duration of action, relative to the monomeric ligands.
Accordingly, in one of its composition aspects, this invention provides a compound of formula I:
(L)
p
(X)
q
I
and pharmaceutically acceptable salts thereof; wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20;
each L is a ligand independently selected from the group consisting of:
(i) a moiety of formula III:
wherein
each R
a
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
each R
b
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
R
c
is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
provided one and only one of R
a
and R
b
comprises a covalent bond linking the moiety to the linker;
(ii) a moiety of formula IV:
wherein
R
d
is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
R
e
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
each R
f
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
provided one and only one of R
e
or R
f
comprises a covalent bond linking the moiety to the linker;
(iii) a moiety of formula V:
wherein
each R
g
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R
h
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R
i
is a covalent bond linking the moiety to the linker;
Q
1
is NR
i′
, O, S, alkylene or a covalent bond, where R
i
, is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or acyl;
(iv) a moiety of formula VI:
wherein
each R
j
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
R
k
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, hydroxy, halogen and —CHO;
each Q
2
is independently NR
j′
, O and S, where R
j′
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
provided one and only one of R
j
comprises a covalent bond linking the moiety to the linker;
(v) a moiety of formula VII:
wherein
each R
l
and R
m
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R
n
is a covalent bond linking the moiety to the linker;
Q
3
is NR
n′
, O, S or alkylene;
Q
4
is NR
n′
, O, S, alkylene or a covalent bond, where each R
n′
in Q
3
and Q
4
is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
(vi) a moiety of formula VIII:
wherein
each R
o
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
R
p
is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with —OZ′ where Z′ is a covalent bond linking the moiety to the linker;
Z is 2H or O;
m is an integer from 1 to 3;
(vii) a moiety of formula IX:
wherein
each R
q
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocyclic and a covalent bond linking the moiety to the linker;
each R
q′
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R
s
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
R
r
is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker;
provided one and only one of R
q
or R
r
comprises a covalent bond linking the moiety to the linker;
(viii) a moiety of formula X:
wherein each R
t
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, su
Griffin John H.
Ji Yu-Hua
Moran Edmund J.
Wray Jonathan W.
Berch Mark L.
Cohen Joyce G.
Habte Kahsay
Hagenah Jeffrey A.
Saxon Roberta P.
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