Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-13
2003-07-22
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S194000
Reexamination Certificate
active
06596746
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to cyclic compounds and salts thereof, to methods of using such compounds in treating protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders, and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases (PTKs) are enzymes which, in conduction with ATP as a substrate, phosphorylate tyrosine residues in peptides and proteins. These enzymes are key elements in the regulation of cell signaling including cell proliferation and cell differentiation. PTKs comprise, inter alia, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet derived growth factor (PDGF), and kinases that play a role in angiogenesis (Tie-2 and KDR); and, in addition, non-receptor tyrosine kinases, including members of the Syk, JAK and Src (e.g. Src, Fyn, Lyn, Lck and Blk) families (see Bolen, J. B., Rowley, R. B., Spana, C., and Tsygankov, A. Y., “The src family of tyrosine protein kinases in hemopoietic signal transduction”,
FASEB J
., 6, 3403-3409 (1992); Ullrich, A. and Schlessinger, J., “Signal transduction by receptors with tyrosine kinase activity”,
Cell
, 61, 203-212 (1990); and Ihle, J. N., “The Janus protein tyrosine kinases in hematopoetic cytokine signaling”,
Sem. Immunol
., 7, 247-254 (1995)).
Enhanced activity of PTKs has been implicated in a variety of malignant and nonmalignant proliferative diseases. In addition, PTKs play a central role in the regulation of cells of the immune system. PTK inhibitors can thus impact a wide variety of oncologic and immunologic disorders. Such disorders may be ameliorated by selective inhibition of a certain receptor or non-receptor PTK, such as Lck, or due to the homology among PTK classes, by inhibition of more than one PTK by an inhibitor.
A PTK of particular interest is Lck which is found in T cells where it is involved in phosphorylating key protein substrates. It is required for productive antigen receptor signaling and cell activation. In the absence of Lck activity, the T cell receptor (TCR) zeta chain is not phosphorylated, the kinase ZAP-70 is not activated, and Ca
2+
mobilization essential for T cell activation does not occur (see Weiss, A. and Littman, D. R., “Signal transduction by lymphocyte antigen receptors”,
Cell
, 76, 263-274 (1994); Iwashima, M., Irving, B. A., van Oers, N. S. C., Chan, A. C., and Weiss, A., “Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases”,
Science
, 263, 1136-1139 (1994); and Chan, A. C., Dalton, M., Johnson, R., Kong, G., Wang, T., Thoma, R., and Kurosaki, T., “Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function”,
EMBO J
., 14, 2499-2508 (1995)). Inhibitors of Lck are thus useful in the treatment of T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
SUMMARY OF THE INVENTION
The present invention provides cyclic compounds of the following formula I and salts thereof, for use as protein tyrosine kinase inhibitors:
where
Q is:
(1) a 5-membered heteroaryl ring;
(2) a 6-membered heteroaryl ring; or (3) an aryl ring;
optionally substituted with one or more groups R
1
;
Z is:
(1) a single bond;
(2) —R
15
C═CH—; or (3) —(CH
2
)
m
—, where m is 1 to 2;
X
1
and X
2
are each hydrogen, or together form ═O or ═S;
R
1
is:
(1) hydrogen or R
6
,
where R
6
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z
1
, Z
2
and one or more (preferably, one or two) groups Z
3
;
(2) —OH or —OR
6
;
(3) —SH or —SR
6
;
(4) —C(O)
2
H, —C(O)
q
R
6
, or —O—C(O)
q
R
6
, where q is 1 or 2;
(5) —SO
3
H or —S(O)
q
R
6
;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z
4
—NR
7
R
8
;
(10) —Z
4
—N(R
9
)—Z
5
—NR
10
R
11
;
(11) —Z
4
—N(R
12
)—Z
5
—R
6
;
(12) —P(O)(OR
6
)
2
;
R
2
and R
3
are each independently:
(1) hydrogen or R
6
;
(2) —Z
4
—R
6
; or
(3) —Z
13
—NR
7
R
8
;
R
4
and R
5
:
(1) are each independently hydrogen or R
6
;
(2) —Z
4
—N(R
9
)—Z
5
—NR
10
R
11
;
(3) —N(R
9
)Z
4
R
6
; or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z
1
, Z
2
and Z
3
, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z
1
, Z
2
and Z
3
;
R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
:
(1) are each independently hydrogen or R
6
;
(2) R
7
and R
8
may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z
1
, Z
2
and Z
3
; or
(3) any two of R
9
, R
10
, and R
11
may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z
1
, Z
2
and Z
3
;
R
13
is:
(1) cyano;
(2) nitro;
(3) —NH
2
;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO
2
alkyl;
(10) —NHSO
2
aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl; or (14) —Oaryl;
R
14
is:
(1) —NO
2
;
(2) —COOalkyl; or
(3) —COOaryl;
R
15
is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl; or
(5) cycloalkyl;
Z
1
, Z
2
and Z
3
are each independently:
(1) hydrogen or Z
6
, where Z
6
is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z
1
, Z
2
and Z
3
;
(2) —OH or —OZ
6
;
(3) —SH or —SZ
6
;
(4) —C(O)
q
H, —C(O)
q
Z
6
, or —O—C(O)
q
Z
6
;
(5) —SO
3
H, —S(O)
q
Z
6
; or S(O)
q
N(Z
9
)Z
6
;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z
4
—NZ
7
Z
8
;
(10) —Z
4
—N(Z
9
)—Z
5
—NZ
7
Z
8
;
(11) —Z
4
—N(Z
10
)—Z
5
—Z
6
;
(12) —Z
4
—N(Z
10
)—Z
5
—H;
(13) oxo;
(14) —O—C(O)—Z
6
;
(15) any two of Z
1
, Z
2
, and Z
3
may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(16) any two of Z
1
, Z
2
, and Z
3
may together be —O—(CH
2
)
r
—O—, where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
Z
4
and Z
5
are each independently:
(1) a single bond;
(2) —Z
11
—S(O)
q
—Z
12
—;
(3) —Z
11
—C(O)—Z
12
—;
(4) —Z
11
—C(S)—Z
12
—;
(5) —Z
11
—O—Z
12
—;
(6) —Z
11
—S—Z
12
—;
(7) —Z
11
—O—C(O)—Z
12
—; or
(8) —Z
11
—C(O)—O—Z
12
—;
Z
7
, Z
8
, Z
9
and Z
10
:
(1) are each independently hydrogen or Z
6
;
(2) Z
7
and Z
8
, or Z
6
and Z
10
, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z
1
, Z
2
and Z
3
; or
(3) Z
7
or Z
8
, together with Z
9
, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z
1
, Z
2
and Z
3
;
Z
11
and Z
12
are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene; or
(4) alkynylene; and
Z
13
is:
(1) a single bond;
(2) —Z
11
—S(O)
q
—Z
12
—;
(3) —Z
11
—C(O)—Z
12
—;
(4) —Z
11
—C(S)—Z
12
—;
(5) —Z
11
—O—Z
12
—;
(6) —Z
11
—S—Z
12
—;
(7) —Z
11
—O—C(O)—Z
12
—;
(8) —Z
11
—C(O)—O—Z
12
—;
Barrish Joel C.
Chen Ping
Das Jagabandhu
Doweyko Arthur M. P.
Norris Derek J.
Bristol--Myers Squibb Company
Gerstl Robert
Hermenau Ronald S.
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