Calanolides for inhibiting BTK

Details Calanolides for inhibiting BTK Calanolides for inhibiting BTK

1999-07-15

2001-10-23

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06306897

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to inhibitors of the Tec family tyrosine kinases, and particularly, inhibitors of Bruton's tyrosine kinase (BTK).
BACKGROUND OF THE INVENTION
Bruton's tyrosine kinase (BTK) is a key regulatory enzyme in B-cells, mast cells, and platelets. The ability of B-cells to appropriately respond to antigen has been shown to be dependent on the enzymatic activity of BTK. Similarly, IgE-receptor mediated leukotriene synthesis and release in mast cells is dependent on BTK. BTK is also critical for collagen-induced aggregation of platelets. BTK promotes the survival and drug resistance of leukemia and lymphoma cells. Finally, BTK is required for radiation-induced apoptosis (Ucken et al. 1996,
Science,
273:1096-1100). Thus, BTK inhibitors have potential for treatment and prevention of various pathologic health conditions due to their activity, for example:
Inhibition of B-cells by BTK Inhibitors: Because of the vital role of BTK in B-cells, BTK inhibitors can be used to inhibit B-cell function and/or to induce B-cell death or apoptosis. Thus, BTK inhibitors are useful in the treatment and inhibition of B-cell mediated autoimmune diseases such as Lupus, B-cell mediated organ transplant rejection (especially xenotransplantation), B-cell mediated drug reactions (anaphalactic shock and the like), B-cell mediated immune-complex disorders, and B-cell mediated resistance to drugs and other treatment agents (neutralizing antibodies to immunotoxins or L-asparaginase in cancer patients, Factor VIII antibodies in hemophiliacs, and the like).
Inhibition of mast cells by BTK inhibitors: Because of the vital role of BTK in mast cells, BTK inhibitors can be used to inhibit mast cell function and/or to induce mast cell death. Thus, BTK inhibitors are useful to treat mast-cell mediated disorders, including allergic and inflammatory disorders (asthma, arthritis, inflammatory bowel disease, and the like).
Inhibition of platelet aggregation by BTK inhibitors: Because of the role of BTK in platelets, BTK inhibitors can be used to inhibit platelet function. Thus, BTK inhibitors are useful to treat or prevent thromboembolic conditions, abnormal platelet aggregation in the context of sepsis, atherosclerosis, vascular injury, and the like.
Inhibition of BTK in leukemia and lymphoma cells: BTK inhibitors can be used to promote apoptosis and reduce drug resistance in leukemia and lymphoma cells.
Inhibition of BTK in B-cell during radiation therapy: BTK inhibitors can be used to prevent undesired immunosuppression during radiation therapy by preventing radiation-induced death of B-cells.
Accordingly, novel inhibitors of BTK and methods for inhibiting BTK are needed for therapeutic use.
SUMMARY OF THE INVENTION
The invention provides calanolide and calanolide analogs or derivatives (hereinafter, collectively referred to as “calanolides”) as inhibitors of Tec family tyrosine kinases, and particularly of BTK. The inhibitors of the invention are useful in the treatment of pathologic conditions involving cells expressing Tec family tyrosine kinases, such as T cells (Tec, Itk) and B cells (BTK). Suitable compounds of the invention include compounds of the formula (I). Methods of the invention include the use of such compounds to inhibit Tec family tyrosine kinases, and particularly to inhibit BTK.
where:
R
7
is —C(═O)R
8
, —CH(—OH)—R
8
, or —CH
2
—R
8
wherein R
8
is (C
1
-C
4
)alkyl, or R
7
and X
1
together form a fused heterocyclic ring;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
14
, and R
15
are the same or different, and are each independently H, OH, SH, CN, halogen, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, aryl, heteroaryl, or NR
a
R
b
; wherein R
a
and R
b
are each independently hydrogen, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, aryl, or heteroaryl; or R
a
and R
b
together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino;
— — — is an optional bond;
X
1
is a hydrogen bonding group capable of forming a hydrogen bond. Suitable examples of hydrogen bonding groups for use as X
1
include OH, SH, NH
2
, CONH
2
, COOH. Alternatively, X
1
can be a (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more hydrogen bonding group, such as OH, SH, NH
2
, CONH
2
, COOH. Alternatively, X
1
together with R
7
, forms a fused heterocycle ring; and
X
2
is a hydrogen bonding group capable of forming a hydrogen bond. Suitable examples of hydrogen bonding groups for use as X
2
include ═O, ═S, ═NH, ═N—OH, ═N—OR
9
, where R
9
is (C
1
-C
4
) alkyl or (C
3
-C
7
) cycloalkyl. Or X
2
can be a (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more hydrogen bonding group, such as ═O, ═S, ═NH, ═N—OH, ═N—OR
9
, where R
9
is (C
1
-C
4
) alkyl or (C
3
-C
7
) cycloalkyl;
or a pharmaceutically acceptable salt thereof.
Those of skill in the art will recognize that when the optional double bond is present, two groups attached adjacent the double bond, such as R
14
and R
15
, will not be present.
Some suitable compounds of formula I include compounds of formula II:
where:
R is (C
1
-C
4
)alkyl;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, and R
16
have the same meanings as given above in formula I;
X
1
is OH, SH, NH
2
, CONH
2
, COOH; or X
1
is (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more of OH, SH, NH
2
, CONH
2
, COOH; and
X
2
is ═O, ═S, ═NH, ═N—OH, ═N—OR
9
, where R
9
is (C
1
-C
4
) alkyl, or (C
3
-C
7
) cycloalkyl; or X
2
is (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more of ═O, ═S, ═NH, ═N—OH, ═N—R
9
, where R
9
is (C
1
-C
4
) alkyl or (C
3
-C
7
) cycloalkyl;
or a pharmaceutically acceptable salt thereof.
Other suitable compounds of formula I include compounds of formula III:
where:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and X
2
have the same meanings as given above in formula (I);
R
10
, R
11
, R
12
, R
13
, R
16
and R
17
are the same or different, and are each independently H, OH, SH, halogen, (C
1
-C
4
) alkoxy, (C
1
-C
4
) alkylthio, (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl, heteroaryl or NR
a
R
b
; wherein R
a
and R
b
are each independently hydrogen, (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, aryl or heteroaryl; or R
a
and R
b
together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino; and
X
3
is ═O, ═S, ═NH, ═N—OH, ═N—OR
9
, OH, SH, NH
2
, CONH
2
or COOH, where R
9
is (C
1
-C
4
) alkyl or (C
3
-C
7
) cycloalkyl; and
— — — is an optional bond,
or a pharmaceutically acceptable salt thereof.
Those of skill in the art will recognize that when the optional double bond is present, two groups attached adjacent the double bond, such as R
13
and R
16
, will not be present.
Examples of specific compounds of the invention include HI-D12, HI-D63, and HI-D86, having the following formulae:
The inhibitory compounds of the invention are designed to fit a composite binding pocket model of the BTK catalytic domain. The approximate total volume in catalytic binding sites of BTK is 585 Å
3
. The compounds of the invention have a molecular volume of less than the volume of the binding pocket (e.g., less than about 585 Å
3
) and preferably a volume that approaches ⅔ the volume of the pocket, e.g., approximately 400 Å
3
. Most preferably, the inhibitors of the invention are designed to fill the shape and available space of the binding pocket and to interact favorably with amino acid residues of the pocket for enhanced binding.
The invention provides compositions and methods for inhibiting BTK in a cell by administering to the cell an effective amount of an agent that inhibits or prevents the action of Tec family tyrosin

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