U.S. patent application number 14/085722 was filed with the patent office on 2014-03-20 for inhibitors of bruton's tyrosine kinase.
This patent application is currently assigned to Pharmacyclics, Inc.. The applicant listed for this patent is Pharmacyclics, Inc.. Invention is credited to Wei CHEN, David J. LOURY, Wenchen LUO, Tarak D. MODY, Mark Stephen SMYTH, Erik VERNER.
Application Number | 20140080844 14/085722 |
Document ID | / |
Family ID | 42166572 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140080844 |
Kind Code |
A1 |
CHEN; Wei ; et al. |
March 20, 2014 |
INHIBITORS OF BRUTON'S TYROSINE KINASE
Abstract
Described herein are kinase inhibitor compounds, methods for
synthesizing such inhibitors, and methods for using such inhibitors
in the treatment of diseases. Further described herein are methods,
assays and systems for determining an appropriate inhibitor of a
protein, including a kinase.
Inventors: |
CHEN; Wei; (Fremont, CA)
; LOURY; David J.; (San Jose, CA) ; MODY; Tarak
D.; (Sunnyvale, CA) ; VERNER; Erik; (Belmont,
CA) ; SMYTH; Mark Stephen; (Foster City, CA) ;
LUO; Wenchen; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pharmacyclics, Inc. |
Sunnyvale |
CA |
US |
|
|
Assignee: |
Pharmacyclics, Inc.
Sunnyvale
CA
|
Family ID: |
42166572 |
Appl. No.: |
14/085722 |
Filed: |
November 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12903101 |
Oct 12, 2010 |
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14085722 |
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12581044 |
Oct 16, 2009 |
7718662 |
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12903101 |
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12581062 |
Oct 16, 2009 |
7741330 |
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12581044 |
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61250787 |
Oct 12, 2009 |
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Current U.S.
Class: |
514/262.1 ;
544/262 |
Current CPC
Class: |
C07D 519/00 20130101;
A61P 19/08 20180101; A61P 17/00 20180101; A61P 37/00 20180101; A61P
37/06 20180101; A61P 19/10 20180101; A61P 35/02 20180101; A61P
35/00 20180101; A61P 11/06 20180101; A61P 43/00 20180101; A61P
17/02 20180101; A61P 35/04 20180101; C07D 487/04 20130101; A61P
17/06 20180101; A61P 19/02 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/262.1 ;
544/262 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound having the structure of Formula (IV) having the
structure: ##STR00431## wherein: T is a bond,
C.sub.1-C.sub.6alkylene, or C.sub.3-C.sub.6cycloalkylene; Y and Z
are each independently selected from H, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or Y and Z together with the carbon atom to
which they are attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X; wherein when Y and Z
together with the carbon atom to which they are attached form a
nitrogen atom-containing C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X; W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J; X is F, Cl, Br, I, --CN,
--NO.sub.2, --OR.sub.3, --N(R.sub.2).sub.2, --SR.sub.2,
--C.sub.1-C.sub.6alkyl, --C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.5, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2; J is
--C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1; v is 1
or 2; R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H, halogen,
--CN, --NO.sub.2, --SR.sub.2, optionally substituted
C.sub.1-C.sub.6alkyl; N(R.sub.2).sub.2 or NHR.sub.7; R.sub.1 is
selected from F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2,
--OR.sub.3, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, heteroaryl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.8, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment; R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl; R.sub.3 is H, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, or SO.sub.3H; R.sub.6
is selected from H, F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2,
--OR.sub.3, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment; wherein each R.sub.6 cannot all be H; R.sub.7 is an amino
protecting group; R.sub.8 is an optionally substituted
C.sub.1-C.sub.6alkyl, an optionally substituted
C.sub.2-C.sub.6alkenyl, an optionally substituted
C.sub.2-C.sub.6alkynyl, or an optionally substituted
C.sub.3-C.sub.6cycloalkyl; or a pharmaceutically acceptable salt,
solvate, or metabolite thereof.
2. The compound of claim 1 wherein Y and Z together with the carbon
atom to which they are attached form a C.sub.3-C.sub.10cycloalkyl
or C.sub.2-C.sub.10heterocycloalkyl.
3. The compound of claim 2 wherein Y and Z together with the carbon
atom to which they are attached form a
C.sub.2-C.sub.10heterocycloalkyl.
4. The compound of claim 1 wherein W is C(.dbd.O)J.
5. The compound of claim 4 wherein J is --C.sub.1-C.sub.6alkyl or
--C.sub.2-C.sub.6alkene.
6. The compound of claim 5 wherein J is substituted with at least
one R.sub.1.
7. The compound of claim 6 wherein R.sub.1 is selected from F, Cl,
Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, heteroaryl, or phenyl.
8. The compound of claim 3 wherein C.sub.2-C.sub.10heterocycloalkyl
is selected from: ##STR00432##
9. The compound of claim 8 wherein C.sub.2-C.sub.10heterocycloalkyl
is ##STR00433##
10. The compound of claim 5 wherein C.sub.1-C.sub.6alkyl is methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and
tert-butyl.
11. The compound of claim 10 wherein C.sub.1-C.sub.6alkyl is
substituted with one R.sub.1.
12. The compound of claim 10 wherein C.sub.1-C.sub.6alkyl is
substituted with two R.sub.1.
13. The compound of claim 11 wherein R.sub.1 is selected from F,
Cl, Br, I, --CN, NO.sub.2, --OR.sub.3, and at least one amino acid
fragment.
14. The compound of claim 5 wherein J is C.sub.2-C.sub.6alkene.
15. The compound of claim 14 wherein C.sub.2-C.sub.6alkene is
C.sub.2H.sub.3.
16. The compound of claim 15 wherein C.sub.2-C.sub.6alkene is
substituted with at least one R.sub.1 selected from F, Cl, Br, I,
--CN, NO.sub.2, OH, and --OSO.sub.3H.
17. A pharmaceutical formulation comprising a therapeutically
effective amount of a compound of claim 1, and a pharmaceutically
acceptable excipient.
18. The compound of claim 1 wherein the compound forms a covalent
bond with a Cys 481 residue of Btk or a cysteine residue in the
homologous corresponding position of another tyrosine kinase.
19. A method for treating an autoimmune disease or inflammatory
disease or condition comprising administering to a patient in need
the compound of claim 1.
20. A method for treating a cancer comprising administering to a
patient in need the compound of claim 1.
21. A method for treating an inflammatory disease or condition
comprising administering to a patient in need the compound of claim
1.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 12/903,101, filed Oct. 12, 2010; which claims the benefit of
U.S. Provisional Application No. 61/250,787, filed Oct. 12, 2009;
U.S. application Ser. No. 12/581,044 filed Oct. 16, 2009, now U.S.
Pat. No. 7,718,662, issued Jun. 22, 2010; and U.S. application Ser.
No. 12/581,062, filed Oct. 16, 2009, now U.S. Pat. No. 7,741,330,
issued Jun. 22, 2010; which are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] Described herein are kinase inhibitor compounds, methods for
synthesizing such inhibitors, and methods for using such inhibitors
in the treatment of diseases.
BACKGROUND OF THE INVENTION
[0003] A kinase, alternatively known as a phosphotransferase, is a
type of enzyme that transfers phosphate groups from high-energy
donor molecules, such as ATP, to specific target molecules; the
process is termed phosphorylation. Protein kinases, which act on
and modify the activity of specific proteins, are used to transmit
signals and control complex processes in cells. Up to 518 different
kinases have been identified in humans. Their enormous diversity
and role in signaling makes them attractive targets for drug
design.
[0004] Bruton's tyrosine kinase (Btk), a member of the Tec family
of non-receptor tyrosine kinases, is a key signaling enzyme
expressed in all hematopoietic cells types except T lymphocytes and
natural killer cells. Btk plays an essential role in the B-cell
signaling pathway linking cell surface B-cell receptor (BCR)
stimulation to downstream intracellular responses.
[0005] Btk is a key regulator of B-cell development, activation,
signaling, and survival (Kurosaki, Curr Op 1 mm, 2000, 276-281;
Schaeffer and Schwartzberg, Curr Op 1 mm 2000, 282-288). In
addition, Btk plays a role in a number of other hematopoetic cell
signaling pathways, e.g., Toll like receptor (TLR) and cytokine
receptor-mediated TNF-.alpha. production in macrophages, IgE
receptor (FcepsilonRI) signaling in Mast cells, inhibition of
Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and
collagen-stimulated platelet aggregation. See, e.g., C. A.
Jeffries, et al., (2003), Journal of Biological Chemistry
278:26258-26264; N. J. Horwood, et al., (2003), The Journal of
Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal
of Biological Chemistry 280(48):40261-40270; Vassilev et al.
(1999), Journal of Biological Chemistry 274(3):1646-1656, and Quek
et al. (1998), Current Biology 8(20):1137-1140.
SUMMARY OF THE INVENTION
[0006] Described herein are inhibitors of Bruton's tyrosine kinase
(Btk). Also described herein are irreversible inhibitors of Btk.
Further described are irreversible inhibitors of Btk that form a
covalent bond with a cysteine residue on Btk. Further described
herein are irreversible inhibitors of other tyrosine kinases,
wherein the other tyrosine kinases share homology with Btk by
having a cysteine residue (including a Cys 481 residue) that can
form a covalent bond with the irreversible inhibitor (such tyrosine
kinases, are referred herein as "Btk tyrosine kinase cysteine
homologs"). Yet further described herein are methods for
synthesizing such inhibitors, methods for using such inhibitors in
the treatment of diseases (including diseases wherein inhibition of
Btk provides therapeutic benefit to a patient having the disease).
Further described are pharmaceutical formulations that include an
inhibitor of Btk.
[0007] In one aspect, provided herein are compounds of Formula (I)
having the structure:
##STR00001##
wherein:
[0008] L is a bond, CH.sub.2, O, NR.sub.2, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0009] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0010] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0011] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0012] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0013] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0014] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0015] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0016] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0017] v is 1 or 2;
[0018] R.sub.a is H, --SO.sub.3H, or C.sub.1-C.sub.4alkyl;
[0019] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0020] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0021] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; or a pharmaceutically
acceptable salt, solvate, or tautomeric form thereof.
[0022] For any and all of the embodiments, substituents are
optionally selected from among a subset of the listed
alternatives.
[0023] In one embodiment, the tautomeric form of the compound of
Formula (I) has the structure of Formula (IA):
##STR00002##
[0024] Any combination of the groups described above for the
various variables is contemplated herein.
[0025] In another aspect is a compound having the structure of
Formula (II):
##STR00003##
wherein:
[0026] L is a bond, CH.sub.2, O, NR.sub.3, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0027] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0028] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0029] Y is C.sub.1-C.sub.6alkylene-CO.sub.2H or
C.sub.2-C.sub.6alkenylene-C(.dbd.O)H;
[0030] Z is
C.sub.1-C.sub.6alkylene-NR.sub.2C(.dbd.O)C.sub.1-C.sub.6alkyl
optionally substituted with at least one R.sub.1; or Y and Z
together with the carbon atom to which they are attached form a
##STR00004##
group;
[0031] is a single bond or a cis or trans-double bond;
[0032] p is 0-6;
[0033] q is 0-6; wherein p+q is .gtoreq.1;
[0034] n is 0-4;
[0035] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.3C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)NR.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment;
[0036] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0037] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6-dihydroxyalkyl, or C.sub.3-C.sub.6cycloalkyl;
[0038] R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl or SO.sub.3H;
[0039] R.sub.4 and R.sub.5 are each independently selected from H,
F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl, --OSO.sub.3H,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment; or optionally when is a single bond then
R.sub.4 and R.sub.5 together with the carbon atoms to which they
are attached form an epoxide; wherein when is a single bond then
R.sub.4 and R.sub.5 are not both hydrogen;
[0040] W is selected from --C(.dbd.O)--, --C(.dbd.O)R.sub.2--,
--C(.dbd.O)OR.sub.2--, --C(.dbd.NR.sub.2)--,
--C(.dbd.N--OR.sub.3)--, --(C.dbd.S)--, --S(.dbd.O).sub.v--;
[0041] X is
##STR00005##
wherein J is O, NR.sub.6 or C(R.sub.2).sub.2. R.sub.6 is selected
from H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2; or a pharmaceutically
acceptable salt, tautomer, or solvate thereof.
[0042] In one embodiment is a compound selected from:
##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010##
or a pharmaceutically acceptable salt, solvate, or tautomeric form
thereof.
[0043] In a further embodiment is a compound of Formula (IIIA) or
(IIIB) having the structure:
##STR00011##
wherein R.sub.b, T, Y, and Z are as described above and R.sub.4 is
H or OH; and R.sub.5 is a glycone.
[0044] In one embodiment, the glycone is a monosaccharide. In
another embodiment, the glycone is a disaccharide. In a further
embodiment, the glycone is an oligosaccharide. In yet another
embodiment, the glycone is glucose. In a further embodiment, the
glycone is fructose. In another embodiment, the glycone is mannose.
In yet a further embodiment, the glycone is glucuronic acid. In one
embodiment, the glycone is attached to the oxygen atom of the
compound of Formula (IIIA) or (IIIIB) via an .alpha.-glycosidic
bond. In another embodiment, the glycone is attached to the oxygen
atom of the compound of Formula (IIIA) or (IIIB) via a
.beta.-glycosidic bond. In one embodiment, the glycone is a
pyranose. In another embodiment, the glycone is a furanose.
[0045] In another embodiment is a compound of Formula (IIIC) or
(IIID) having the structure:
##STR00012##
wherein:
[0046] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0047] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl,
[0048] wherein C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl are optionally substituted
with at least one R.sub.1; or
[0049] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0050] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0051] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0052] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0053] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0054] v is 1 or 2;
[0055] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0056] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0057] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; R.sub.4 is H or OH; or a
pharmaceutically acceptable salt, solvate, or tautomeric form
thereof.
[0058] In a further embodiment is a compound of Formula (IV) having
the structure:
##STR00013##
wherein:
[0059] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0060] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0061] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0062] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0063] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0064] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.5, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0065] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0066] v is 1 or 2;
[0067] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H, halogen,
--CN, --NO.sub.2, --SR.sub.2, optionally substituted
C.sub.1-C.sub.6alkyl; N(R.sub.2).sub.2 or NHR.sub.7;
[0068] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.8, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0069] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; R.sub.6 is selected from H, F,
Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment; wherein each R.sub.6 cannot all be H; R.sub.7 is an amino
protecting group; R.sub.8 is an optionally substituted
C.sub.1-C.sub.6alkyl, an optionally substituted
C.sub.2-C.sub.6alkenyl, an optionally substituted
C.sub.2-C.sub.6alkynyl, or an optionally substituted
C.sub.3-C.sub.6cycloalkyl; or a pharmaceutically acceptable salt,
solvate, or metabolite thereof.
[0070] In some embodiments are provided pharmaceutically acceptable
salts of compounds of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein. By way of example only, are salts of an amino
group formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid and perchloric
acid or with organic acids such as acetic acid, oxalic acid, maleic
acid, tartaric acid, citric acid, succinic acid or malonic acid.
Further salts include those in which the counterion is an anion,
such as adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, and valerate. Further salts
include those in which the counterion is a cation, such as sodium,
lithium, potassium, calcium, magnesium, ammonium, and quaternary
ammonium (substituted with at least one organic moiety) cations.
Also described herein are salts of a compound of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein having at least one
sulfate group formed with a counterion, such as by way of example
only, sodium, lithium, potassium, calcium, magnesium, ammonium, and
quaternary ammonium cations.
[0071] In another embodiment are pharmaceutically acceptable esters
of compounds of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) (IIIA), (IIIB), (IIIC), or (IIID), or other
pyrazolopyrimidine compounds described herein, including those in
which the ester group is selected from a formate, acetate,
propionate, butyrate, acrylate and ethylsuccinate.
[0072] In another embodiment are pharmaceutically acceptable
carbamates of compounds of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein. In another embodiment are pharmaceutically
acceptable N-acyl derivatives of compounds of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. Examples of N-acyl
groups include N-acetyl and N-ethoxycarbonyl groups.
[0073] In a further aspect are provided pharmaceutical
compositions, which include a therapeutically effective amount of
at least one of any of the compounds described herein, or a
pharmaceutically acceptable salt, pharmaceutically acceptable
tautomer, pharmaceutically acceptable prodrug, or pharmaceutically
acceptable solvate. In certain embodiments, compositions provided
herein further include a pharmaceutically acceptable diluent,
excipient and/or binder.
[0074] Pharmaceutical compositions formulated for administration by
an appropriate route and means containing effective concentrations
of one or more of the compounds provided herein, or
pharmaceutically effective derivatives thereof, that deliver
amounts effective for the treatment, prevention, or amelioration of
one or more symptoms of diseases, disorders or conditions that are
modulated or otherwise affected by tyrosine kinase activity, or in
which tyrosine kinase activity is implicated, are provided. The
effective amounts and concentrations are effective for ameliorating
any of the symptoms of any of the diseases, disorders or conditions
disclosed herein.
[0075] In one aspect, provided herein are methods for treating a
patient by administering a compound provided herein. In some
embodiments, provided herein is a method of inhibiting the activity
of tyrosine kinase(s), such as Btk, or of treating a disease,
disorder, or condition, which benefit from inhibition of tyrosine
kinase(s), such as Btk, in a patient, which includes administering
to the patient a therapeutically effective amount of at least one
of any of the compounds described herein, or pharmaceutically
acceptable salt, pharmaceutically acceptable tautomer,
pharmaceutically acceptable prodrug, or pharmaceutically acceptable
solvate.
[0076] In another aspect, provided herein is the use of a compound
disclosed herein for inhibiting Bruton's tyrosine kinase (Btk)
activity or for the treatment of a disease, disorder, or condition,
which benefit from inhibition of Bruton's tyrosine kinase (Btk)
activity.
[0077] In some embodiments, compounds provided herein are
administered to a human. In some embodiments, compounds provided
herein are orally administered. In other embodiments, the
pharmaceutical formulation that is formulated for a route of
administration is selected from oral administration, parenteral
administration, buccal administration, nasal administration,
topical administration, or rectal administration.
[0078] In other embodiments, compounds provided herein are used for
the formulation of a medicament for the inhibition of tyrosine
kinase activity. In some other embodiments, compounds provided
herein are used for the formulation of a medicament for the
inhibition of Bruton's tyrosine kinase (Btk) activity.
[0079] Articles of manufacture including packaging material, a
compound or composition or pharmaceutically acceptable derivative
thereof provided herein, which is effective for inhibiting the
activity of tyrosine kinase(s), such as Btk, within the packaging
material, and a label that indicates that the compound or
composition, or pharmaceutically acceptable salt, pharmaceutically
acceptable tautomer, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, is used for inhibiting
the activity of tyrosine kinase(s), such as Btk, are provided.
[0080] In a further aspect, provided herein is a method for
treating an autoimmune disease by administering to a subject in
need thereof a composition containing a therapeutically effective
amount of at least one compound having the structure of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. In one embodiment,
the autoimmune disease is arthritis. In another embodiment, the
autoimmune disease is lupus. In some embodiments, the autoimmune
disease is inflammatory bowel disease (including Crohn's disease
and ulcerative colitis), rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, lupus,
diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's
thyroiditis, Graves' disease Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
or vulvodynia.
[0081] In a further aspect, provided herein is a method for
treating a heteroimmune condition or disease by administering to a
subject in need thereof a composition containing a therapeutically
effective amount of at least one compound having the structure of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or
other pyrazolopyrimidine compounds described herein. In some
embodiments, the heteroimmune condition or disease is graft versus
host disease, transplantation, transfusion, anaphylaxis, allergy,
type I hypersensitivity, allergic conjunctivitis, allergic
rhinitis, or atopic dermatitis.
[0082] In a further aspect, provided herein is a method for
treating an inflammatory disease by administering to a subject in
need thereof a composition containing a therapeutically effective
amount of at least one compound having the structure of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. In some embodiments,
the inflammatory disease is asthma, inflammatory bowel disease
(including Crohn's disease and ulcerative colitis), appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or
vulvitis.
[0083] In yet another aspect, provided herein is a method for
treating a cancer by administering to a subject in need thereof a
composition containing a therapeutically effective amount of at
least one compound having the structure of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein. In one embodiment, the cancer is a
B-cell proliferative disorder, e.g., diffuse large B cell lymphoma,
follicular lymphoma, chronic lymphocytic lymphoma, chronic
lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, Burkitt's lymphoma/leukemia, or lymphomatoid
granulomatosis. In some embodiments, where the subject is suffering
from a cancer, an anti-cancer agent is administered to the subject
in addition to one of the above-mentioned compounds. In one
embodiment, the anti-cancer agent is an inhibitor of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,
wortmannin, or LY294002.
[0084] In another aspect, provided herein is a method for treating
a thromboembolic disorder by administering to a subject in need
thereof a composition containing a therapeutically effective amount
of at least one compound having the structure of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. In some embodiments,
the thromboembolic disorder is myocardial infarct, angina pectoris,
reocclusion after angioplasty, restenosis after angioplasty,
reocclusion after aortocoronary bypass, restenosis after
aortocoronary bypass, stroke, transitory ischemia, a peripheral
arterial occlusive disorder, pulmonary embolism, or deep venous
thrombosis.
[0085] In another aspect, provided herein is a method for treating
a mastocytosis by administering to a subject in need thereof a
composition containing a therapeutically effective amount of at
least one compound having the structure of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein.
[0086] In yet another aspect, provided herein is a method for
treating a osteoporosis or bone resorption disorders by
administering to a subject in need thereof a composition containing
a therapeutically effective amount of at least one compound having
the structure of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein.
[0087] In further embodiments, the compound irreversibly inhibits
the Bruton's tyrosine kinase.
[0088] Also described herein are kinase inhibitors that selectively
bind to a protein tyrosine kinase selected from Btk, a Btk homolog,
and a Btk kinase cysteine homolog, in which the kinase inhibitor
reversibly and non-selectively binds to a multiplicity of protein
tyrosine kinases. In one embodiment the plasma half life of the
kinase inhibitor is less than about 4 hours. In another embodiment
the plasma half life of the kinase inhibitor is less than about 3
hours.
[0089] In a further embodiment are kinase inhibitors that
selectively bind to at least one of Btk, Jak3, Blk, Bmx, Tec, and
Itk. In another embodiment are kinase inhibitors that selectively
bind to Btk. In another embodiment are kinase inhibitors that
selectively and irreversibly bind to Jak3. In another embodiment
are kinase inhibitors that selectively bind to Tec. In another
embodiment are kinase inhibitors that selectively bind to Itk. In
another embodiment are kinase inhibitors that selectively bind to
Btk and Tec. In another embodiment are kinase inhibitors that
selectively bind to Blk. In yet a further embodiment are kinase
inhibitors that reversibly and non-selectively bind to a
multiplicity of src-family protein kinase inhibitors.
[0090] Also described herein are inhibitors that are identified
using such methods, assays and systems. In some embodiments, the
inhibitor is a selective inhibitor, including selectivity for a
particular Btk kinase cysteine homolog over other Btk kinase
cysteine homologs.
[0091] Further described herein are pharmaceutical formulations
comprising the kinase inhibitors of any kinase inhibitor compound
previously listed. In one embodiment the pharmaceutical formulation
includes a pharmaceutical acceptable excipient. In some
embodiments, pharmaceutical formulations provided herein are
administered to a human. In some embodiments, the selective kinase
inhibitors provided herein are orally administered. In other
embodiments, the selective kinase inhibitors provided herein are
used for the formulation of a medicament for the inhibition of
tyrosine kinase activity. In some other embodiments, the selective
kinase inhibitors provided herein are used for the formulation of a
medicament for the inhibition of a kinase activity, including a
tyrosine kinase activity, including a Btk activity, including a Btk
homolog activity, including a Btk kinase cysteine homolog
activity.
[0092] In any of the aforementioned aspects are further embodiments
in which administration is enteral, parenteral, or both, and
wherein (a) the effective amount of the compound is systemically
administered to the mammal; (b) the effective amount of the
compound is administered orally to the mammal; (c) the effective
amount of the compound is intravenously administered to the mammal;
(d) the effective amount of the compound administered by
inhalation; (e) the effective amount of the compound is
administered by nasal administration; or (f) the effective amount
of the compound is administered by injection to the mammal; (g) the
effective amount of the compound is administered topically (dermal)
to the mammal; (h) the effective amount of the compound is
administered by ophthalmic administration; or (i) the effective
amount of the compound is administered rectally to the mammal. In
further embodiments the pharmaceutical formulation is formulated
for a route of administration selected from oral administration,
parenteral administration, buccal administration, nasal
administration, topical administration, or rectal
administration.
[0093] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
pharmaceutical formulation, including further embodiments in which
(i) the pharmaceutical formulations is administered once; (ii) the
pharmaceutical formulations is administered to the mammal once a
day; (iii) the pharmaceutical formulations is administered to the
mammal multiple times over the span of one day; (iv) continually;
or (v) continuously.
[0094] In any of the aforementioned aspects are further embodiments
comprising multiple administrations of the effective amount of the
pharmaceutical formulations, including further embodiments in which
(i) the pharmaceutical formulations is administered in a single
dose; (ii) the time between multiple administrations is every 6
hours; (iii) the pharmaceutical formulations is administered to the
mammal every 8 hours. In further or alternative embodiments, the
method comprises a drug holiday, wherein the administration of the
pharmaceutical formulations is temporarily suspended or the dose of
the pharmaceutical formulations being administered is temporarily
reduced; at the end of the drug holiday, dosing of the
pharmaceutical formulations is resumed. The length of the drug
holiday varies from 2 days to 1 year.
[0095] In some aspects described herein the inhibitor is selective
for one kinase selected from Btk, a Btk homolog, and a Btk kinase
cysteine homolog over at least one other kinase selected from Btk,
a Btk homolog, and a Btk kinase cysteine homolog. In other aspects
described herein the inhibitor is selective for at least one kinase
selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog
over at least one other non-kinase molecule having an accessible SH
group.
[0096] In certain embodiments, provided herein is a pharmaceutical
composition containing: i) a physiologically acceptable carrier,
diluent, and/or excipient; and ii) one or more compounds provided
herein.
[0097] Other objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only. The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described.
CERTAIN TERMINOLOGY
[0098] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a," "an" and "the" include plural referents unless the
context clearly dictates otherwise. In this application, the use of
"or" means "and/or" unless stated otherwise. Furthermore, use of
the term "including" as well as other forms, such as "include",
"includes," and "included," is not limiting.
[0099] Definition of standard chemistry terms are found in
reference works, including Carey and Sundberg "ADVANCED ORGANIC
CHEMISTRY 4.sup.TH ED." Vols. A (2000) and B (2001), Plenum Press,
New York. Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the skill of
the art are employed. Unless specific definitions are provided, the
nomenclature employed in connection with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic
organic chemistry, and medicinal and pharmaceutical chemistry
described herein are those known in the art. Standard techniques
are optionally used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and delivery, and
treatment of patients. Standard techniques are optionally used for
recombinant DNA, oligonucleotide synthesis, and tissue culture and
transformation (e.g., electroporation, lipofection). Reactions and
purification techniques are performed using documented
methodologies or as described herein.
[0100] It is to be understood that the methods and compositions
described herein are not limited to the particular methodology,
protocols, cell lines, constructs, and reagents described herein
and as such optionally vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to limit the scope of the
methods and compositions described herein, which will be limited
only by the appended claims.
[0101] Unless stated otherwise, the terms used for complex moieties
(i.e., multiple chains of moieties) are to be read equivalently
either from left to right or right to left. For example, the group
alkylenecycloalkylene refers both to an alkylene group followed by
a cycloalkylene group or as a cycloalkylene group followed by an
alkylene group.
[0102] The suffix "ene" appended to a group indicates that such a
group is a diradical. By way of example only, a methylene is a
diradical of a methyl group, that is, it is a --CH.sub.2-- group;
and an ethylene is a diradical of an ethyl group, i.e.,
--CH.sub.2CH.sub.2--.
[0103] An "alkyl" group refers to an aliphatic hydrocarbon group.
The alkyl moiety includes a "saturated alkyl" group, which means
that it does not contain any alkene or alkyne moieties. The alkyl
moiety also includes an "unsaturated alkyl" moiety, which means
that it contains at least one alkene or alkyne moiety. An "alkene"
moiety refers to a group that has at least one carbon-carbon double
bond, and an "alkyne" moiety refers to a group that has at least
one carbon-carbon triple bond. The alkyl moiety, whether saturated
or unsaturated, includes branched, straight chain, or cyclic
moieties. Depending on the structure, an alkyl group includes a
monoradical or a diradical (i.e., an alkylene group), and if a
"lower alkyl" having 1 to 6 carbon atoms.
[0104] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x.
[0105] The "alkyl" moiety optionally has 1 to 10 carbon atoms
(whenever it appears herein, a numerical range such as "1 to 10"
refers to each integer in the given range; e.g., "1 to 10 carbon
atoms" means that the alkyl group is selected from a moiety having
1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 10 carbon atoms, although the present definition also
covers the occurrence of the term "alkyl" where no numerical range
is designated). The alkyl group of the compounds described herein
may be designated as "C.sub.1-C.sub.4 alkyl" or similar
designations. By way of example only, "C.sub.1-C.sub.4 alkyl"
indicates that there are one to four carbon atoms in the alkyl
chain, i.e., the alkyl chain is selected from among methyl, ethyl,
propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
Thus C.sub.1-C.sub.4 alkyl includes C.sub.1-C.sub.2 alkyl and
C.sub.1-C.sub.3 alkyl. Alkyl groups are optionally substituted or
unsubstituted. Typical alkyl groups include, but are in no way
limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0106] The term "alkenyl" refers to a type of alkyl group in which
the first two atoms of the alkyl group form a double bond that is
not part of an aromatic group. That is, an alkenyl group begins
with the atoms --C(R).dbd.C(R)--R, wherein R refers to the
remaining portions of the alkenyl group, which are either the same
or different. The alkenyl moiety is optionally branched, straight
chain, or cyclic (in which case, it is also known as a
"cycloalkenyl" group). Depending on the structure, an alkenyl group
includes a monoradical or a diradical (i.e., an alkenylene group).
Alkenyl groups are optionally substituted. Non-limiting examples of
an alkenyl group include --CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
--C(CH.sub.3).dbd.CHCH.sub.3. Alkenylene groups include, but are
not limited to, --CH.dbd.CH--, --C(CH.sub.3).dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH.dbd.CHCH.sub.2CH.sub.2-- and
--C(CH.sub.3).dbd.CHCH.sub.2--. Alkenyl groups optionally have 2 to
10 carbons, and if a "lower alkenyl" having 2 to 6 carbon
atoms.
[0107] The term "alkynyl" refers to a type of alkyl group in which
the first two atoms of the alkyl group form a triple bond. That is,
an alkynyl group begins with the atoms --C.ident.C--R, wherein R
refers to the remaining portions of the alkynyl group, which is
either the same or different. The "R" portion of the alkynyl moiety
may be branched, straight chain, or cyclic. Depending on the
structure, an alkynyl group includes a monoradical or a diradical
(i.e., an alkynylene group). Alkynyl groups are optionally
substituted. Non-limiting examples of an alkynyl group include, but
are not limited to, --C.ident.CH, --C.ident.CCH.sub.3,
--C.ident.CCH.sub.2CH.sub.3, and --C.ident.CCH.sub.2--. Alkynyl
groups optionally have 2 to 10 carbons, and if a "lower alkynyl"
having 2 to 6 carbon atoms.
[0108] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0109] "Hydroxyalkyl" refers to an alkyl radical, as defined
herein, substituted with at least one hydroxy group. Non-limiting
examples of a hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl,
1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl,
3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
[0110] "Alkoxyalkyl" refers to an alkyl radical, as defined herein,
substituted with an alkoxy group, as defined herein.
[0111] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x and y are selected from among x=1, y=1 and x=2, y=0.
When x=2, the alkyl groups, taken together with the N atom to which
they are attached, can optionally form a cyclic ring system.
[0112] "Alkylaminoalkyl" refers to an alkyl radical, as defined
herein, substituted with an alkylamine, as defined herein.
[0113] "Hydroxyalkylaminoalkyl" refers to an alkyl radical, as
defined herein, substituted with an alkylamine, and alkylhydroxy,
as defined herein.
[0114] "Alkoxyalkylaminoalkyl" refers to an alkyl radical, as
defined herein, substituted with an alkylamine and substituted with
an alkylalkoxy, as defined herein.
[0115] An "amide" is a chemical moiety with the formula --C(O)NHR
or --NHC(O)R, where R is selected from among alkyl, cycloalkyl,
aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). In some embodiments, an amide
moiety forms a linkage between an amino acid or a peptide molecule
and a compound described herein, thereby forming a prodrug. Any
amine, or carboxyl side chain on the compounds described herein can
be amidified. The procedures and specific groups to make such
amides are found in sources such as Greene and Wuts, Protective
Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons,
New York, N.Y., 1999, which is incorporated herein by reference for
this disclosure.
[0116] The term "amino acid fragment" refers to a portion of an
amino acid, such as by way of example only, the 20 common,
genetically-encoded amino acids (i.e., alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
and valine), or a dipeptide, tripeptide or other polypeptide
comprising a combination of the 20 common amino acids or a
non-natural amino acid. In some embodiments, the amino acid
fragment is attached to the compound of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein via the side chain of the amino acid. In
one embodiment, the amino acid fragment is a cysteine fragment
wherein the remaining portion of the compound of Formula (II) is
bound via a sulfur bond. In another embodiment, the remaining
portion of a compound of Formula (II) is bound via a sulfur bond of
a glutathione fragment. In another embodiment, the amino acid
fragments are derived from beta-amino acids. In further
embodiments, the amino acid fragments are derived from portions of
polypeptides or proteins. In yet further embodiments, the amino
acid fragment is attached to the compound of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein via the N-terminal or
the acyl-terminal of the amino acid.
[0117] The term "ester" refers to a chemical moiety with formula
--COOR, where R is selected from among alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). Any hydroxy, or carboxyl side chain
on the compounds described herein can be esterified. The procedures
and specific groups to make such esters are found in sources such
as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd
Ed., John Wiley & Sons, New York, N.Y., 1999, which is
incorporated herein by reference for this disclosure.
[0118] As used herein, the term "ring" refers to any covalently
closed structure. Rings include, for example, carbocycles (e.g.,
aryls and cycloalkyls), heterocycles (e.g., heteroaryls and
non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls),
and non-aromatics (e.g., cycloalkyls and non-aromatic
heterocycles). Rings can be optionally substituted. Rings can be
monocyclic or polycyclic.
[0119] As used herein, the term "ring system" refers to one, or
more than one ring.
[0120] The term "membered ring" can embrace any cyclic structure.
The term "membered" is meant to denote the number of skeletal atoms
that constitute the ring. Thus, for example, cyclohexyl, pyridine,
pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,
furan, and thiophene are 5-membered rings.
[0121] The term "fused" refers to structures in which two or more
rings share one or more bonds.
[0122] The term "carbocyclic" or "carbocycle" refers to a ring
wherein each of the atoms forming the ring is a carbon atom.
Carbocycle includes aryl and cycloalkyl. The term thus
distinguishes carbocycle from heterocycle ("heterocyclic") in which
the ring backbone contains at least one atom which is different
from carbon (i.e a heteroatom). Heterocycle includes heteroaryl and
heterocycloalkyl. Carbocycles and heterocycles can be optionally
substituted.
[0123] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2.pi. electrons,
where n is an integer. Aromatic rings can be formed from five, six,
seven, eight, nine, or more than nine atoms. Aromatics can be
optionally substituted. The term "aromatic" includes both
carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or
"heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term
includes monocyclic or fused-ring polycyclic (i.e., rings which
share adjacent pairs of carbon atoms) groups.
[0124] As used herein, the term "aryl" refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. Aryl
rings can be formed by five, six, seven, eight, nine, or more than
nine carbon atoms. Aryl groups can be optionally substituted.
Examples of aryl groups include, but are not limited to phenyl,
naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
Depending on the structure, an aryl group can be a monoradical or a
diradical (i.e., an arylene group).
[0125] An "aryloxy" group refers to an (aryl)O-- group, where aryl
is as defined herein.
[0126] The term "carbonyl" as used herein refers to a group
containing a moiety selected from the group consisting of --C(O)--,
--S(O)--, --S(O).sub.2--, and --C(S)--, including, but not limited
to, groups containing a least one ketone group, and/or at least one
aldehyde group, and/or at least one ester group, and/or at least
one carboxylic acid group, and/or at least one thioester group.
Such carbonyl groups include ketones, aldehydes, carboxylic acids,
esters, and thioesters. In some embodiments, such groups are a part
of linear, branched, or cyclic molecules.
[0127] The term "cycloalkyl" refers to a monocyclic or polycyclic
radical that contains only carbon and hydrogen, and is optionally
saturated, partially unsaturated, or fully unsaturated. Cycloalkyl
groups include groups having from 3 to 10 ring atoms. Illustrative
examples of cycloalkyl groups include the following moieties:
##STR00014##
and the like. Depending on the structure, a cycloalkyl group is
either a monoradical or a diradical (e.g., an cycloalkylene group),
and if a "lower cycloalkyl" having 3 to 8 carbon atoms.
[0128] "Cycloalkylalkyl" means an alkyl radical, as defined herein,
substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl
groups include cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, and the like.
[0129] The term "heterocycle" refers to heteroaromatic and
heteroalicyclic groups containing one to four heteroatoms each
selected from O, S and N, wherein each heterocyclic group has from
4 to 10 atoms in its ring system, and with the proviso that the
ring of said group does not contain two adjacent O or S atoms.
Herein, whenever the number of carbon atoms in a heterocycle is
indicated (e.g., C.sub.1-C.sub.6 heterocycle), at least one other
atom (the heteroatom) must be present in the ring. Designations
such as "C.sub.1-C.sub.6 heterocycle" refer only to the number of
carbon atoms in the ring and do not refer to the total number of
atoms in the ring. It is understood that the heterocylic ring can
have additional heteroatoms in the ring. Designations such as "4-6
membered heterocycle" refer to the total number of atoms that are
contained in the ring (i.e., a four, five, or six membered ring, in
which at least one atom is a carbon atom, at least one atom is a
heteroatom and the remaining two to four atoms are either carbon
atoms or heteroatoms). In heterocycles that have two or more
heteroatoms, those two or more heteroatoms can be the same or
different from one another. Heterocycles can be optionally
substituted. Binding to a heterocycle can be at a heteroatom or via
a carbon atom. Non-aromatic heterocyclic groups include groups
having only 4 atoms in their ring system, but aromatic heterocyclic
groups must have at least 5 atoms in their ring system. The
heterocyclic groups include benzo-fused ring systems. An example of
a 4-membered heterocyclic group is azetidinyl (derived from
azetidine). An example of a 5-membered heterocyclic group is
thiazolyl. An example of a 6-membered heterocyclic group is
pyridyl, and an example of a 10-membered heterocyclic group is
quinolinyl. Examples of non-aromatic heterocyclic groups are
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. Examples of aromatic heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The
foregoing groups, as derived from the groups listed above, are
optionally C-attached or N-attached where such is possible. For
instance, a group derived from pyrrole includes pyrrol-1-yl
(N-attached) or pyrrol-3-yl (C-attached). Further, a group derived
from imidazole includes imidazol-1-yl or imidazol-3-yl (both
N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all
C-attached). The heterocyclic groups include benzo-fused ring
systems and ring systems substituted with one or two oxo (.dbd.O)
moieties such as pyrrolidin-2-one. Depending on the structure, a
heterocycle group can be a monoradical or a diradical (i.e., a
heterocyclene group).
[0130] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aromatic group that includes one or more ring
heteroatoms selected from nitrogen, oxygen and sulfur. An
N-containing "heteroaromatic" or "heteroaryl" moiety refers to an
aromatic group in which at least one of the skeletal atoms of the
ring is a nitrogen atom. Illustrative examples of heteroaryl groups
include the following moieties:
##STR00015##
and the like. Depending on the structure, a heteroaryl group can be
a monoradical or a diradical (i.e., a heteroarylene group).
[0131] As used herein, the term "non-aromatic heterocycle",
"heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic
ring wherein one or more atoms forming the ring is a heteroatom. A
"non-aromatic heterocycle" or "heterocycloalkyl" group refers to a
cycloalkyl group that includes at least one heteroatom selected
from nitrogen, oxygen and sulfur. In some embodiments, the radicals
are fused with an aryl or heteroaryl. Heterocycloalkyl rings can be
formed by three, four, five, six, seven, eight, nine, or more than
nine atoms. Heterocycloalkyl rings can be optionally substituted.
In certain embodiments, non-aromatic heterocycles contain one or
more carbonyl or thiocarbonyl groups such as, for example, oxo- and
thio-containing groups. Examples of heterocycloalkyls include, but
are not limited to, lactams, lactones, cyclic imides, cyclic
thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran,
tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin,
1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin,
1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,
succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, morpholine, trioxane,
hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,
pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,
1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,
isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,
thiazolidine, and 1,3-oxathiolane. Illustrative examples of
heterocycloalkyl groups, also referred to as non-aromatic
heterocycles, include:
##STR00016##
and the like. The term heteroalicyclic also includes all ring forms
of the carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides.
Depending on the structure, a heterocycloalkyl group can be a
monoradical or a diradical (i.e., a heterocycloalkylene group).
[0132] The term "halo" or, alternatively, "halogen" or "halide"
means fluoro, chloro, bromo and iodo.
[0133] The term "haloalkyl," refers to alkyl structures in which at
least one hydrogen is replaced with a halogen atom. In certain
embodiments in which two or more hydrogen atoms are replaced with
halogen atoms, the halogen atoms are all the same as one another.
In other embodiments in which two or more hydrogen atoms are
replaced with halogen atoms, the halogen atoms are not all the same
as one another.
[0134] The term "fluoroalkyl," as used herein, refers to alkyl
group in which at least one hydrogen is replaced with a fluorine
atom. Examples of fluoroalkyl groups include, but are not limited
to, --CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3 and the like.
[0135] As used herein, the term "heteroalkyl" refers to optionally
substituted alkyl radicals in which one or more skeletal chain
atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon,
phosphorus or combinations thereof. The heteroatom(s) are placed at
any interior position of the heteroalkyl group or at the position
at which the heteroalkyl group is attached to the remainder of the
molecule. Examples include, but are not limited to,
--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. In addition, in some
embodiments, up to two heteroatoms are consecutive, such as, by way
of example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
[0136] The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically independently selected from
among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not
limited to these atoms. In embodiments in which two or more
heteroatoms are present, the two or more heteroatoms can all be the
same as one another, or some or all of the two or more heteroatoms
can each be different from the others.
[0137] The term "bond" or "single bond" refers to a chemical bond
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure.
[0138] The term "moiety" refers to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0139] A "thioalkoxy" or "alkylthio" group refers to a --S-alkyl
group.
[0140] A "SH" group is also referred to either as a thiol group or
a sulfhydryl group.
[0141] The term "optionally substituted" or "substituted" means
that the referenced group may be substituted with one or more
additional group(s) individually and independently selected from
alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro,
haloalkyl, fluoroalkyl, amino, including mono- and di-substituted
amino groups, and the protected derivatives thereof. By way of
example an optional substituents may be L.sub.sR.sub.s wherein each
L.sub.s is independently selected from a bond, --O--,
--C(.dbd.O)--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--,
--NHC(O)--, --C(O)NH--, S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2,
--OC(O)NH--, --NHC(O)O--, -(substituted or unsubstituted
C.sub.1-C.sub.6 alkyl), or -(substituted or unsubstituted
C.sub.2-C.sub.6 alkenyl); and each R.sub.s is independently
selected from H, (substituted or unsubstituted
C.sub.1-C.sub.4alkyl), (substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl), heteroaryl, or heteroalkyl. The
protecting groups that forms the protective derivatives of the
above substituents include those found in sources such as Greene
and Wuts, above.
[0142] The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or ingredient, as used
herein, means having no persistent detrimental effect on the
general health of the subject being treated or does not abrogate
the biological activity or properties of the compound, and is
relatively nontoxic.
[0143] As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological activity of a protein
that is the same as the biological activity resulting from the
presence of a naturally occurring ligand for the protein, such as,
for example, Btk.
[0144] As used herein, the term "partial agonist" refers to a
compound the presence of which results in a biological activity of
a protein that is of the same type as that resulting from the
presence of a naturally occurring ligand for the protein, but of a
lower magnitude.
[0145] As used herein, the term "antagonist" refers to a compound,
the presence of which results in a decrease in the magnitude of a
biological activity of a protein. In certain embodiments, the
presence of an antagonist results in complete inhibition of a
biological activity of a protein, such as, for example, Btk. In
certain embodiments, an antagonist is an inhibitor.
[0146] As used herein, "amelioration" of the symptoms of a
particular disease, disorder or condition by administration of a
particular compound or pharmaceutical composition refers to any
lessening of severity, delay in onset, slowing of progression, or
shortening of duration, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the compound or composition.
[0147] "Bioavailability" refers to the percentage of the weight of
compounds disclosed herein, such as, compounds of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein, dosed that is
delivered into the general circulation of the animal or human being
studied. The total exposure (AUC.sub.(0-.infin.)) of a drug when
administered intravenously is usually defined as 100% bioavailable
(F %). "Oral bioavailability" refers to the extent to which
compounds disclosed herein, such as, compounds of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein, are absorbed into
the general circulation when the pharmaceutical composition is
taken orally as compared to intravenous injection.
[0148] "Blood plasma concentration" refers to the concentration of
compounds disclosed herein, such as, compounds of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein, in the plasma
component of blood of a subject. It is understood that the plasma
concentration of compounds of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein, may vary significantly between
subjects, due to variability with respect to metabolism and/or
possible interactions with other therapeutic agents. In accordance
with one embodiment disclosed herein, the blood plasma
concentration of the compounds of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein, does vary from subject to subject.
Likewise, values such as maximum plasma concentration (C.sub.max)
or time to reach maximum plasma concentration (T.sub.max), or total
area under the plasma concentration time curve
(AUC.sub.(0-.infin.)) may vary from subject to subject. Due to this
variability, the amount necessary to constitute "a therapeutically
effective amount" of a compound of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein, is expected to vary from subject to
subject.
[0149] The term "Bruton's tyrosine kinase," as used herein, refers
to Bruton's tyrosine kinase from Homo sapiens, as disclosed in,
e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No.
NP.sub.--000052).
[0150] The term "Bruton's tyrosine kinase homolog," as used herein,
refers to orthologs of Bruton's tyrosine kinase, e.g., the
orthologs from mouse (GenBank Accession No. AAB47246), dog (GenBank
Accession No. XP.sub.--549139.), rat (GenBank Accession No.
NP.sub.--001007799), chicken (GenBank Accession No.
NP.sub.--989564), or zebra fish (GenBank Accession No.
XP.sub.--698117), and fusion proteins of any of the foregoing that
exhibit kinase activity towards one or more substrates of Bruton's
tyrosine kinase (e.g. a peptide substrate having the amino acid
sequence "AVLESEEELYSSARQ").
[0151] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0152] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate "effective amount" in any
individual case is optionally determined using techniques, such as
a dose escalation study. The term "therapeutically effective
amount" includes, for example, a prophylactically effective amount.
An "effective amount" of a compound disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effect amount" or "a therapeutically effective amount" can
vary from subject to subject, due to variation in metabolism of the
of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
or other pyrazolopyrimidine compounds described herein, age,
weight, general condition of the subject, the condition being
treated, the severity of the condition being treated, and the
judgment of the prescribing physician.
[0153] The terms "enhance" or "enhancing" means to increase or
prolong either in potency or duration a desired effect. By way of
example, "enhancing" the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the
effect of therapeutic agents on during treatment of a disease,
disorder or condition. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or
condition. When used in a patient, amounts effective for this use
will depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0154] The term "homologous cysteine," as used herein refers to a
cysteine residue found with in a sequence position that is
homologous to that of cysteine 481 of Bruton's tyrosine kinase, as
defined herein. For example, cysteine 482 is the homologous
cysteine of the rat ortholog of Bruton's tyrosine kinase; cysteine
479 is the homologous cysteine of the chicken ortholog; and
cysteine 481 is the homologous cysteine in the zebra fish ortholog.
In another example, the homologous cysteine of TXK, a Tec kinase
family member related to Bruton's tyrosine, is Cys 350. See also
the sequence alignments of tyrosine kinases (TK) published on the
world wide web at kinase.com/human/kinome/phylogeny.html.
[0155] The term "identical," as used herein, refers to two or more
sequences or subsequences which are the same. In addition, the term
"substantially identical," as used herein, refers to two or more
sequences which have a percentage of sequential units which are the
same when compared and aligned for maximum correspondence over a
comparison window, or designated region as measured using
comparison algorithms or by manual alignment and visual inspection.
By way of example only, two or more sequences are "substantially
identical" if the sequential units are about 60% identical, about
65% identical, about 70% identical, about 75% identical, about 80%
identical, about 85% identical, about 90% identical, or about 95%
identical over a specified region. Such percentages to describe the
"percent identity" of two or more sequences. The identity of a
sequence can exist over a region that is at least about 75-100
sequential units in length, over a region that is about 50
sequential units in length, or, where not specified, across the
entire sequence. This definition also refers to the complement of a
test sequence. By way of example only, two or more polypeptide
sequences are identical when the amino acid residues are the same,
while two or more polypeptide sequences are "substantially
identical" if the amino acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 amino acids in length,
over a region that is about 50 amino acids in length, or, where not
specified, across the entire sequence of a polypeptide sequence. In
addition, by way of example only, two or more polynucleotide
sequences are identical when the nucleic acid residues are the
same, while two or more polynucleotide sequences are "substantially
identical" if the nucleic acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 nucleic acids in
length, over a region that is about 50 nucleic acids in length, or,
where not specified, across the entire sequence of a polynucleotide
sequence.
[0156] The terms "inhibits", "inhibiting", or "inhibitor" of a
kinase, as used herein, refer to inhibition of enzymatic
phosphotransferase activity.
[0157] The term "isolated," as used herein, refers to separating
and removing a component of interest from at least some portion of
components not of interest. Isolated substances can be in either a
dry or semi-dry state, or in solution, including but not limited to
an aqueous solution. The isolated component can be in a homogeneous
state or the isolated component can be a part of a pharmaceutical
composition that comprises additional pharmaceutically acceptable
carriers and/or excipients. By way of example only, nucleic acids
or proteins are "isolated" when such nucleic acids or proteins are
free of at least some of the cellular components with which it is
associated in the natural state, or that the nucleic acid or
protein has been concentrated to a level greater than the
concentration of its in vivo or in vitro production. Also, by way
of example, a gene is isolated when separated from open reading
frames which flank the gene and encode a protein other than the
gene of interest.
[0158] The term "irreversible inhibitor," as used herein, refers to
a compound that, upon contact with a target protein (e.g., a
kinase) causes the formation of a new covalent bond with or within
the protein, whereby one or more of the target protein's biological
activities (e.g., phosphotransferase activity) is diminished or
abolished notwithstanding the subsequent presence or absence of the
irreversible inhibitor.
[0159] The term "irreversible Btk inhibitor," as used herein,
refers to an inhibitor of Btk that in some embodiments forms a
covalent bond with an amino acid residue of Btk. In one embodiment,
the irreversible inhibitor of Btk forms a covalent bond with a Cys
residue of Btk; in particular embodiments, the irreversible
inhibitor forms a covalent bond with a Cys 481 residue (or a
homolog thereof) of Btk or a cysteine residue in the homologous
corresponding position of another tyrosine kinase.
[0160] The term "linkage," as used herein to refer to bonds or a
chemical moiety formed from a chemical reaction between the
functional group of a linker and another molecule. In some
embodiments, such bonds include, but are not limited to, covalent
linkages and non-covalent bonds, while such chemical moieties
include, but are not limited to, esters, carbonates, imines,
phosphate esters, hydrazones, acetals, orthoesters, peptide
linkages, and oligonucleotide linkages. Hydrolytically stable
linkages means that the linkages are substantially stable in water
and do not react with water at useful pH values, including but not
limited to, under physiological conditions for an extended period
of time, perhaps even indefinitely. Hydrolytically unstable or
degradable linkages means that the linkages are degradable in water
or in aqueous solutions, including for example, blood. In other
embodiments, enzymatically unstable or degradable linkages means
that the linkage is degraded by one or more enzymes. By way of
example only, PEG and related polymers include degradable linkages
in the polymer backbone or in the linker group between the polymer
backbone and one or more of the terminal functional groups of the
polymer molecule. Such degradable linkages include, but are not
limited to, ester linkages formed by the reaction of PEG carboxylic
acids or activated PEG carboxylic acids with alcohol groups on a
biologically active agent, wherein such ester groups generally
hydrolyze under physiological conditions to release the
biologically active agent. Other hydrolytically degradable linkages
include but are not limited to carbonate linkages; imine linkages
resulted from reaction of an amine and an aldehyde; phosphate ester
linkages formed by reacting an alcohol with a phosphate group;
hydrazone linkages which are reaction product of a hydrazide and an
aldehyde; acetal linkages that are the reaction product of an
aldehyde and an alcohol; orthoester linkages that are the reaction
product of a formate and an alcohol; peptide linkages formed by an
amine group, including but not limited to, at an end of a polymer
such as PEG, and a carboxyl group of a peptide; and oligonucleotide
linkages formed by a phosphoramidite group, including but not
limited to, at the end of a polymer, and a 5' hydroxyl group of an
oligonucleotide.
[0161] The term "Michael acceptor moiety" refers to a functional
group that can participate in a Michael reaction, wherein a new
covalent bond is formed between a portion of the Michael acceptor
moiety and the donor moiety. The Michael acceptor moiety is an
electrophile and the "donor moiety" is a nucleophile. The double
bond groups presented in any of Formula (I) or (IA) are
non-limiting examples of Michael acceptor moieties.
[0162] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0163] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator can
cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in
the absence of the modulator. In certain embodiments, a modulator
is an inhibitor, which decreases the magnitude of one or more
activities of a molecule. In certain embodiments, an inhibitor
completely prevents one or more activities of a molecule. In
certain embodiments, a modulator is an activator, which increases
the magnitude of at least one activity of a molecule. In certain
embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
[0164] The term "nanoparticle," as used herein, refers to a
particle which has a particle size between about 500 nm to about 1
nm.
[0165] As used herein, the term "pERK" refers to phosphorylated
ERK1 and ERK2 at Thr202/Tyr 204 as detected by commercially
available phospho-specific antibodies (e.g. Cell Signaling
Technologies #4377).
[0166] The term "plasma half life," as used herein refers to
half-life in rat, dog or human as determined by measure drug
concentration over time in plasma following a single dose and
fitting data to standard pharmacokinetic models using software such
as WinNonLin to determine the time at which drug has been 50%
eliminated from plasma.
[0167] The term "prophylactically effective amount," as used
herein, refers that amount of a composition applied to a patient
which will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic
applications, such amounts may depend on the patient's state of
health, weight, and the like.
[0168] As used herein, the term "selective binding compound" refers
to a compound that selectively binds to any portion of one or more
target proteins.
[0169] As used herein, the term "selectively binds" refers to the
ability of a selective binding compound to bind to a target
protein, such as, for example, Btk, with greater affinity than it
binds to a non-target protein. In certain embodiments, specific
binding refers to binding to a target with an affinity that is at
least 10, 50, 100, 250, 500, 1000 or more times greater than the
affinity for a non-target.
[0170] As used herein, the term "selective modulator" refers to a
compound that selectively modulates a target activity relative to a
non-target activity. In certain embodiments, specific modulator
refers to modulating a target activity at least 10, 50, 100, 250,
500, 1000 times more than a non-target activity.
[0171] The term "substantially purified," as used herein, refers to
a component of interest that may be substantially or essentially
free of other components which normally accompany or interact with
the component of interest prior to purification. By way of example
only, a component of interest may be "substantially purified" when
the preparation of the component of interest contains less than
about 30%, less than about 25%, less than about 20%, less than
about 15%, less than about 10%, less than about 5%, less than about
4%, less than about 3%, less than about 2%, or less than about 1%
(by dry weight) of contaminating components. Thus, a "substantially
purified" component of interest may have a purity level of about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, about
96%, about 97%, about 98%, about 99% or greater.
[0172] The term "subject" as used herein, refers to an animal which
is the object of treatment, observation or experiment. By way of
example only, a subject may be, but is not limited to, a mammal
including, but not limited to, a human.
[0173] As used herein, the term "target activity" refers to a
biological activity capable of being modulated by a selective
modulator. Certain exemplary target activities include, but are not
limited to, binding affinity, signal transduction, enzymatic
activity, tumor growth, inflammation or inflammation-related
processes, and amelioration of one or more symptoms associated with
a disease or condition.
[0174] As used herein, the term "target protein" refers to a
molecule or a portion of a protein capable of being bound by a
selective binding compound. In certain embodiments, a target
protein is Btk.
[0175] The terms "treat," "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition. The terms "treat," "treating" or "treatment",
include, but are not limited to, prophylactic and/or therapeutic
treatments.
[0176] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as inhibition of Btk,
in an assay that measures such response.
[0177] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
DETAILED DESCRIPTION OF THE INVENTION
Inhibitor Compounds
[0178] In the following description of kinase inhibitor compounds
suitable for use in the methods described herein, definitions of
referred-to standard chemistry terms may be found in reference
works (if not otherwise defined herein), including Carey and
Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B
(2001), Plenum Press, New York. In addition, nucleic acid and amino
acid sequences for Btk (e.g., human Btk) are disclosed in, e.g.,
U.S. Pat. No. 6,326,469. Unless specific definitions are provided,
the nomenclature employed in connection with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic
organic chemistry, and medicinal and pharmaceutical chemistry
described herein are those known in the art. Standard techniques
can be used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and delivery, and
treatment of patients
[0179] In one aspect, provided herein are compounds of Formula (I)
having the structure:
##STR00017##
wherein:
[0180] L is a bond, CH.sub.2, O, NR.sub.2, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0181] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0182] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0183] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0184] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0185] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0186] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0187] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0188] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0189] v is 1 or 2;
[0190] R.sub.a is H, --SO.sub.3H, or C.sub.1-C.sub.4alkyl;
[0191] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0192] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0193] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; or a pharmaceutically
acceptable salt, solvate, or tautomeric form thereof.
[0194] For any and all of the embodiments, substituents are
optionally selected from among from a subset of the listed
alternatives. For example, in some embodiments, L is a bond,
CH.sub.2, O, NR.sub.2, S, CO, C.dbd.NR.sub.2, or C.dbd.N--OR.sub.2.
In other embodiments, L is a bond or O. In yet other embodiments, L
is O.
[0195] In some embodiments, A is an aryl substituted with at least
one R.sub.1. In yet other embodiments, A is a 6-membered aryl. In
some other embodiments, A is phenyl. In other embodiments, phenyl
is substituted with one R.sub.1 selected from F, Cl, Br, I, --CN,
NO.sub.2, --SR.sub.2, --OR.sub.3, --N(R.sub.2).sub.2, methyl, and
ethyl. In further embodiments, phenyl is substituted with --OH, or
--OSO.sub.3H. In yet further embodiments, phenyl is substituted
with two R.sub.1 selected from F, Cl, Br, I, --CN, NO.sub.2,
--SR.sub.2, and --OR.sub.3. In another embodiment, phenyl is
substituted with two --OH, two --OSO.sub.3H or --OH and
--OSO.sub.3H. In some embodiments, T is a bond. In other
embodiments, T is C.sub.1-C.sub.6alkylene. In further embodiments,
C.sub.1-C.sub.6alkylene is CH.sub.2. In other embodiments, R.sub.a
is H, R.sub.b is NH.sub.2, and L is O. In another embodiment, Y is
C.sub.1-C.sub.6alkyl or C.sub.2-C.sub.6alkene. In one embodiment,
C.sub.1-C.sub.6alkyl or C.sub.2-C.sub.6alkene is substituted with
--C(.dbd.O)R.sub.2 or --CO.sub.2R.sub.2. In a further embodiment,
R.sub.2 is H. In one embodiment, Z is C.sub.1-C.sub.6alkyl. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, or --C(.dbd.O)N(R.sub.2).sub.2. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with
--NR.sub.2C(.dbd.O)R.sub.2. In one embodiment, each R.sub.2 is H.
In one embodiment, R.sub.2 is C.sub.1-C.sub.6alkyl. In another
embodiment, C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In one
embodiment, R.sub.2 is C.sub.1-C.sub.6hydroxyalkyl.
[0196] In one embodiment, Y and Z together with the carbon atom to
which they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl. In another embodiment, the
nitrogen atom-containing C.sub.2-C.sub.10heterocycloalkyl is
selected from:
##STR00018##
In yet another embodiment, the nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl is
##STR00019##
In a further embodiment,
##STR00020##
is substituted with at least one X. In yet a further embodiment, X
is selected from F, Cl, Br, I, --CN, --OR.sub.3, and NO.sub.2. In
one embodiment, X is --OH or --OSO.sub.3H. In another embodiment, W
is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J, and
C(.dbd.O)NR.sub.2-J. In yet another embodiment, W is C(.dbd.O)-J.
In a further embodiment, J is C.sub.1-C.sub.6alkyl. In yet a
further embodiment, C.sub.1-C.sub.6alkyl is methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with one R.sub.1.
In another embodiment, C.sub.1-C.sub.6alkyl is substituted with two
R.sub.1. In yet another embodiment, R.sub.1 is selected from F, Cl,
Br, I, --CN, NO.sub.2, --OR.sub.3, and at least one amino acid
fragment. In a further embodiment, W is J. In yet a further
embodiment, J is C.sub.1-C.sub.6alkyl. In one embodiment,
C.sub.1-C.sub.6alkyl is methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, and tert-butyl. In another embodiment,
C.sub.1-C.sub.6alkyl is substituted with one R.sub.1. In yet
another embodiment, C.sub.1-C.sub.6alkyl is substituted with two
R.sub.1. In a further embodiment, R.sub.1 is selected from F, Cl,
Br, I, --CN, NO.sub.2, and OR.sub.3. In yet a further embodiment,
R.sub.1 is at least one amino acid fragment. In one embodiment, the
at least one amino acid fragment is a cysteine or glutathione
fragment. In another embodiment, one R.sub.1 is an amino fragment
and the other R.sub.1 is selected from F, Cl, Br, I, --CN,
NO.sub.2, --OH, and --OSO.sub.3H. In yet another embodiment, the at
least one amino acid fragment is a di-peptide fragment. In a
further embodiment, the at least one amino acid fragment is a
tri-peptide fragment. In yet a further embodiment, the di-peptide
fragment is a fragment of Cys-Gly. In one embodiment, J is
C.sub.2-C.sub.6alkene. In another embodiment, C.sub.2-C.sub.6alkene
is C.sub.2H.sub.3. In one embodiment, C.sub.2-C.sub.6alkene is
substituted with at least one R.sub.1 selected from F, Cl, Br, I,
--CN, NO.sub.2, OH, and --OSO.sub.3H. In one embodiment, J is
C.sub.2-C.sub.6heterocycloalkyl. In another embodiment
C.sub.2-C.sub.6heterocycloalkyl is an epoxide. In a further
embodiment, is a compound of Formula (I) wherein R.sub.1 is
selected from --NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, or --S(.dbd.O).sub.2R.sub.2. In one embodiment,
R.sub.1 is OS(.dbd.O).sub.2R.sub.2. In one embodiment, R.sub.1 is
--S(.dbd.O).sub.2R.sub.2. In another embodiment, R.sub.2 is
C.sub.1-C.sub.6haloalkyl. In a further embodiment,
C.sub.1-C.sub.6haloalkyl is CF.sub.3.
[0197] In one embodiment, the tautomeric form of the compound of
Formula (I) has the structure of Formula (IA):
##STR00021##
[0198] Any combination of the groups described above for the
various variables is contemplated herein.
[0199] In another aspect is a compound having the structure of
Formula (II):
##STR00022##
wherein:
[0200] L is a bond, CH.sub.2, O, NR.sub.3, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0201] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0202] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0203] Y is C.sub.1-C.sub.6alkylene-CO.sub.2H or
C.sub.2-C.sub.6alkenylene-C(.dbd.O)H;
[0204] Z is
C.sub.1-C.sub.6alkylene-NR.sub.2C(.dbd.O)C.sub.1-C.sub.6alkyl
optionally substituted with at least one R.sub.1; or
[0205] Y and Z together with the carbon atom to which they are
attached form a
##STR00023##
group;
[0206] is a single bond or a cis or trans-double bond;
[0207] p is 0-6;
[0208] q is 0-6; wherein p+q is .gtoreq.1;
[0209] n is 0-4;
[0210] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.3C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)NR.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment;
[0211] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0212] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6-dihydroxyalkyl, or C.sub.3-C.sub.6cycloalkyl;
[0213] R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl or SO.sub.3H;
[0214] R.sub.4 and R.sub.5 are each independently selected from H,
F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl, --OSO.sub.3H,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment; or optionally when is a single bond then
R.sub.4 and R.sub.5 together with the carbon atoms to which they
are attached form an epoxide; wherein when is a single bond then
R.sub.4 and R.sub.5 are not both hydrogen;
[0215] W is selected from --C(.dbd.O)--, --C(.dbd.O)R.sub.2--,
--C(.dbd.O)OR.sub.2--, --C(.dbd.NR.sub.2)--,
--C(.dbd.N--OR.sub.3)--, --(C.dbd.S)--, --S(.dbd.O).sub.v--;
[0216] X is
##STR00024##
wherein J is O, NR.sub.6 or C(R.sub.2).sub.2. R.sub.6 is selected
from H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2; or a pharmaceutically
acceptable salt, tautomer, or solvate thereof.
[0217] In one embodiment is a compound of Formula (II) wherein T is
a bond. In one embodiment is a compound of Formula (II) wherein T
is C.sub.1-C.sub.6alkylene. In another C.sub.1-C.sub.6alkylene is
CH.sub.2. In yet another embodiment is a compound of Formula (II)
wherein L is O and R.sub.b is NH.sub.2. In a further embodiment A
is aryl. In yet a further embodiment aryl is phenyl. In one
embodiment phenyl is substituted with one R.sub.1 selected from F,
Cl, Br, I, --CN, NO.sub.2, --OH, SR.sub.2, and --OR.sub.3. In
another embodiment is a compound of Formula (II) wherein phenyl is
substituted with --OH or --OSO.sub.3H. In yet another embodiment is
a compound of Formula (II) wherein phenyl is substituted with two
R.sub.1 selected from F, Cl, Br, I, --CN, NO.sub.2, --SR.sub.29 and
--OR.sub.3. In a further embodiment is a compound of Formula (II)
wherein phenyl is substituted with two --OH or two --OSO.sub.3H or
--OH and --OSO.sub.3H. In yet a further embodiment Y is
C.sub.1-C.sub.6alkylene-CO.sub.2H. In one embodiment
C.sub.1-C.sub.6alkylene is C.sub.2H.sub.5. In another embodiment is
a compound of Formula (II) wherein Y is
C.sub.2-C.sub.6alkenylene-C(.dbd.O)H. In yet another embodiment
C.sub.2-C.sub.6alkenylene is C.sub.2H.sub.3. In a further
embodiment is a compound of Formula (II) wherein Z is
CH.sub.2--NHC(.dbd.O)C.sub.1-C.sub.6alkyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In one
embodiment is a compound of Formula (II) wherein Y and Z together
with the carbon atom to which they are attached form a
##STR00025##
group. In a further embodiment, p is 1 and q is 0-3. In a further
embodiment, q is 3. In yet a further embodiment, is a compound of
Formula (II) wherein Y and Z together with the carbon atom to which
they are attached form a
##STR00026##
group. In one embodiment, Y and Z together with the carbon atom to
which they are attached form a
##STR00027##
group. In another embodiment is a compound of Formula (II) wherein
R.sub.4 and R.sub.5 are each independently selected from H, F, Cl,
Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, and at least one amino acid fragment. In a
further embodiment is a compound of Formula (II) wherein R.sub.4 is
H and R.sub.5 is --OH. In yet another embodiment is a compound of
Formula (II) wherein R.sub.4 is --OH and R.sub.5 is H. In one
embodiment is a compound of Formula (II) wherein R.sub.4 and
R.sub.5 are both --OH. In yet a further embodiment is a compound of
Formula (II) wherein R.sub.4 is H and R.sub.5 is at least one amino
acid fragment. In one embodiment is a compound of Formula (II)
wherein the at least one amino acid fragment is a cysteine or
glutathione fragment. In one embodiment is a compound of Formula
(II) wherein R.sub.1 is selected from F, Cl, Br, I, --CN,
--NO.sub.2, --SR.sub.2, --OR.sub.3, and C.sub.1-C.sub.6alkyl. In
one embodiment is a compound of Formula (II) wherein R.sub.1 is
--OH or --OSO.sub.3H. In a further embodiment is a compound of
Formula (II) wherein X is
##STR00028##
[0218] In one embodiment, p is 1, and q is 2. In another
embodiment, J is C(R.sub.2).sub.2. In a further embodiment, each
R.sub.2 is hydrogen. In yet another embodiment, p is 2, q is 2 and
J is O. In yet a further embodiment, X is morpholine or
pyrrolidine. In yet a further embodiment, X is substituted with at
least one R.sub.1.
[0219] In another embodiment is a compound having the
structure:
##STR00029##
wherein R is an amino protecting group; or a pharmaceutically
acceptable salt, solvate, or metabolite thereof. In another
embodiment, the amino protecting group is selected from Fmoc, Boc,
Cbz, Ac, trifluoroacetamide, Bn, trityl, benzylideneamine, Ts, or
the H attached to the nitrogen atom of the primary amine is absent
and R and the nitrogen atom to which it is attached form a
phthalimide group; or a pharmaceutically acceptable salt, solvate,
or metabolite thereof.
[0220] In one embodiment, R is a Boc group. In another embodiment,
R is an Fmoc group. In a further embodiment, R is a Cbz group.
[0221] In a further embodiment is a compound selected from:
##STR00030##
or a pharmaceutically acceptable salt, solvate, or metabolite
thereof.
[0222] In one embodiment is a compound having the structure:
##STR00031##
wherein R.sub.1 is H or an amino protecting group. In another
embodiment, the amino protecting group is selected from Fmoc, Boc,
Cbz, Ac, trifluoroacetamide, Bn, trityl, benzylideneamine, Ts, or
the H attached to the nitrogen atom of the primary amine is absent
and R.sub.1 and the nitrogen atom to which it is attached form a
phthalimide group; or a pharmaceutically acceptable salt, solvate,
or metabolite thereof.
[0223] In one embodiment, R.sub.1 is H. In one embodiment, R.sub.1
is a Boc group. In another embodiment, R.sub.1 is an Fmoc group. In
a further embodiment, R.sub.1 is a Cbz group.
[0224] In another embodiment is a compound having the
structure:
##STR00032##
wherein R.sub.2 is H, an an amino protecting group,
C.sub.1-C.sub.6alkyl, C(.dbd.O)C.sub.1-C.sub.6alkyl, or
C(.dbd.O)C.sub.2-C.sub.6alkene; wherein C.sub.1-C.sub.6alkyl,
C(.dbd.O)C.sub.1-C.sub.6alkyl, C(.dbd.O)C.sub.2-C.sub.6alkene is
optionally substituted with at least one substituent selected from
F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--OSO.sub.3H, --NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, S(.dbd.O).sub.2R.sub.2 wherein R.sub.2 is H or
C.sub.1-C.sub.6alkyl. In another embodiment, the amino protecting
group is selected from Fmoc, Boc, Cbz, Ac, trifluoroacetamide, Bn,
trityl, benzylideneamine, Ts, or the H attached to the nitrogen
atom of the primary amine is absent and R.sub.2 and the nitrogen
atom to which it is attached form a phthalimide group; or a
pharmaceutically acceptable salt, solvate, or metabolite
thereof.
[0225] In one embodiment, R.sub.2 is H. In another embodiment,
R.sub.2 is a Boc group. In another embodiment, R.sub.2 is an Fmoc
group. In a further embodiment, R.sub.2 is a Cbz group.
[0226] In another embodiment, R.sub.2 is C(.dbd.O)CHCH.sub.2. In
another embodiment, R.sub.2 is C(.dbd.O)CH.sub.2CH.sub.2OH. In a
further embodiment, R.sub.2 is CH.sub.2Cl. In yet a further
embodiment, R.sub.2 is CHCl.sub.2.
[0227] In one embodiment is a compound having the structure:
##STR00033##
wherein L is a bond, CH.sub.2, O, NR.sub.3, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0228] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0229] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.3S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.3C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)NR.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment;
[0230] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0231] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6-dihydroxyalkyl, or C.sub.3-C.sub.6cycloalkyl;
and
[0232] R.sub.5 is a substituted (C(O))alkyl or a substituted
(C(O))alkenyl.
[0233] In one embodiment, R.sub.5 is a substituted
C(O)--C.sub.1-C.sub.6alkyl. In another embodiment, R.sub.5 is a
substituted C(O)-ethyl. In a further embodiment, R.sub.5 is a
substituted C(O)-propyl. In another embodiment, R.sub.5 is a
substituted C(O)--C.sub.2-C.sub.6alkenyl. In a further embodiment,
R.sub.5 is a substituted C(O)-ethylene. In one embodiment,
C(O)alkyl or C(O)alkenyl is substituted with at least one R.sub.1
group. In one embodiment, R.sub.5 is substituted with at least two
R.sub.1 groups. In a further embodiment, at least three R.sub.1
groups. In yet a further embodiment, at least four R.sub.1
groups.
[0234] In a further embodiment is a compound having the
structure:
##STR00034## ##STR00035##
or a pharmaceutically acceptable salt, solvate, or metabolite
thereof wherein the following compounds, having different
substituents (for e.g., R.sub.1 and R.sub.3) are listed in the
table below:
TABLE-US-00001 Cmpd # R.sup.3 R.sup.1 1 ##STR00036## H 2
##STR00037## 3-OH 3 ##STR00038## 4-OH 4 ##STR00039## 2-OH 5
##STR00040## 4-OH 6 ##STR00041## 2-OH 7 ##STR00042## H 8
##STR00043## 3-OH 9 ##STR00044## 3-OH 10 ##STR00045## H 11
##STR00046## 2-OH 12 ##STR00047## H 13 ##STR00048## 3-OH 14
##STR00049## 3-OH 15 ##STR00050## H 16 ##STR00051## 2-OH 17
##STR00052## 3-OH 18 ##STR00053## 3,4- dihydroxy 19 ##STR00054##
4-OH 20 ##STR00055## 2-OH 21 ##STR00056## 3,4- dihydroxy 22
##STR00057## 4-OH 23 ##STR00058## 3,4- dihydroxy 24 ##STR00059##
4-OH 25 ##STR00060## 2-OH 26 ##STR00061## 3,4- dihydroxy 27
##STR00062## 4-OH 28 ##STR00063## 3,4- dihydroxy 29 ##STR00064## H
30 ##STR00065## 3-OH 31 ##STR00066## 3-OH 32 ##STR00067## 4-OH 33
##STR00068## H 34 ##STR00069## 2-OH 35 ##STR00070## H 36
##STR00071## 3-OH 37 ##STR00072## H 38 ##STR00073## 2-OH 39
##STR00074## H 40 ##STR00075## 2-OH 41 ##STR00076## H 42
##STR00077## 3-OH 43 ##STR00078## 2-OH 44 ##STR00079## 4-OH 45
##STR00080## 2-OH 46 ##STR00081## 3,4- dihydroxy 47 ##STR00082## H
48 ##STR00083## 3,4- dihydroxy 49 ##STR00084## 4-OH 50 ##STR00085##
3,4- dihydroxy 51 ##STR00086## 3,4- dihydroxy 52 ##STR00087## 4-OH
53 ##STR00088## 3-OH 54 ##STR00089## 4-OH 55 ##STR00090## 3,4-
dihydroxy 56 ##STR00091## 4-OH 57 ##STR00092## 3,4- dihydroxy 58
##STR00093## 3,4- dihydroxy 59 ##STR00094## 3-OH 60 ##STR00095##
2-OH 61 ##STR00096## 3-OH 62 ##STR00097## H 63 ##STR00098## 2-OH 64
##STR00099## H 65 ##STR00100## 3-OH 66 ##STR00101## H 67
##STR00102## 3-OH 68 ##STR00103## 2-OH 69 ##STR00104## H 70
##STR00105## 3-OH 71 ##STR00106## H 72 ##STR00107## 3-OH 73
##STR00108## 2-OH 74 ##STR00109## H 75 ##STR00110## 2-OH 76
CH.sub.3 H 77 CH.sub.3 3-OH 78 ##STR00111## 4-OH 79 ##STR00112## H
80 ##STR00113## 3,4- dihydroxy 81 ##STR00114## 4-OH 82 ##STR00115##
3,4- dihydroxy 83 ##STR00116## 4-OH 84 ##STR00117## 2-OH 85
##STR00118## 4-OH 86 ##STR00119## 3,4- dihydroxy 87 ##STR00120##
3,4- dihydroxy 88 ##STR00121## 4-OH 89 ##STR00122## 2-OH 90
##STR00123## 4-OH 91 ##STR00124## 3,4- dihydroxy 92 ##STR00125##
3-OH 93 ##STR00126## 4-OH 94 ##STR00127## 3,4- dihydroxy 95
CH.sub.3 4-OH 96 CH.sub.3 3,4- dihydroxy 97 CH.sub.3 2-OH 98
##STR00128## H 99 ##STR00129## 3-OH 100 ##STR00130## H 101
##STR00131## 2-OH 102 ##STR00132## H 103 ##STR00133## 2-OH 104
##STR00134## 3-OH 105 ##STR00135## 2-OH 106 ##STR00136## H 107
##STR00137## 2-OH 108 ##STR00138## H 109 ##STR00139## H 110
##STR00140## 2-OH 111 ##STR00141## 3-OH 112 ##STR00142## 2-OH 113
##STR00143## H 114 ##STR00144## 3-OH 115 ##STR00145## 3,4-
dihydroxy 116 ##STR00146## 4-OH 117 ##STR00147## 4-OH 118
##STR00148## 3,4- dihydroxy 119 ##STR00149## 4-OH 120 ##STR00150##
3,4- dihydroxy 121 ##STR00151## 3,4- dihydroxy 122 ##STR00152##
4-OH 123 ##STR00153## 3,4- dihydroxy 124 ##STR00154## 3-OH 125
##STR00155## 4-OH
126 ##STR00156## 4-OH 127 ##STR00157## 3,4- dihydroxy 128
##STR00158## 3,4- dihydroxy 129 ##STR00159## 4-OH 130 ##STR00160##
3,4- dihydroxy 131 ##STR00161## H 132 ##STR00162## 2-OH 133
CH.sub.2CH.sub.3 H 134 CH.sub.2CH.sub.3 2-OH 135 CH.sub.2CH.sub.3
3-OH 136 ##STR00163## H 137 ##STR00164## 4-OH 138 ##STR00165## 3-OH
139 ##STR00166## H 140 ##STR00167## 4-OH 141 ##STR00168## 3-OH 142
##STR00169## 3-OH 143 ##STR00170## 4-OH 144 ##STR00171## 2-OH 145
##STR00172## 4-OH 146 ##STR00173## H 147 ##STR00174## 2-OH 148
##STR00175## 4-OH 149 ##STR00176## 3-OH 150 CH.sub.2CH.sub.3 4-OH
151 CH.sub.2CH.sub.3 3,4- dihydroxy 152 ##STR00177## 3,4- dihydroxy
153 ##STR00178## 2-OH 154 ##STR00179## 3,4- dihydroxy 155
##STR00180## 3-OH 156 ##STR00181## 3,4- dihydroxy 157 ##STR00182##
2-OH 158 ##STR00183## 2-OH 159 ##STR00184## 3,4- dihydroxy 160
##STR00185## H 161 ##STR00186## 3-OH 162 ##STR00187## 3,4-
dihydroxy 163 ##STR00188## 4-OH 164 ##STR00189## 3,4- dihydroxy 165
##STR00190## 3-OH 166 ##STR00191## 2-OH 167 ##STR00192## 3-OH 168
##STR00193## 2-OH 169 ##STR00194## 4-OH 170 CCH 3-OH 171 CCH 4-OH
172 ##STR00195## 2-OH 173 ##STR00196## 3-OH 174 ##STR00197## 3-OH
175 ##STR00198## 2-OH 176 ##STR00199## 3-OH 177 ##STR00200## 4-OH
178 ##STR00201## 4-OH 180 ##STR00202## 3,4- dihydroxy 181
##STR00203## 3,4- dihydroxy 182 ##STR00204## 3-OH 183 CCH 2-OH 184
CCH 3,4- dihydroxy 185 ##STR00205## 3,4- dihydroxy 186 ##STR00206##
4-OH 187 ##STR00207## 3,4- dihydroxy 188 ##STR00208## 4-OH 189
##STR00209## 2-OH 190 ##STR00210## 3,4- dihydroxy 191 ##STR00211##
2-OH 192 ##STR00212## 3-OH 193 ##STR00213## 4-OH 194 ##STR00214##
3,4- dihydroxy
[0235] Also disclosed herein is a compound of Formula (IIIA) or
(IIIB) having the structure:
##STR00215##
wherein R.sub.b, T, Y, and Z are as previously described and
R.sub.4 is H or OH; and R.sub.5 is a glycone. In one embodiment,
the glycone is a monosaccharide. In another embodiment, the glycone
is a disaccharide. In a further embodiment, the glycone is an
oligosaccharide. In yet another embodiment, the glycone is glucose.
In a further embodiment, the glycone is fructose. In another
embodiment, the glycone is mannose. In yet a further embodiment,
the glycone is glucuronic acid. In one embodiment, the glycone is
attached to the oxygen atom of the compound of Formula (IIIA) or
(IIIIB) via an .alpha.-glycosidic bond. In another embodiment, the
glycone is attached to the oxygen atom of the compound of Formula
(IIIA) or (IIIB) via a .beta.-glycosidic bond. In one embodiment,
the glycone is a pyranose. In another embodiment, the glycone is a
furanose.
[0236] In one aspect, provided herein are compounds of Formula
(IIIC) or (BID) having the structure:
##STR00216##
wherein:
[0237] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0238] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0239] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0240] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0241] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0242] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0243] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0244] v is 1 or 2;
[0245] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0246] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0247] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; R.sub.4 is H or OH; or a
pharmaceutically acceptable salt, solvate, or tautomeric form
thereof.
[0248] In some embodiments, T is a bond. In other embodiments, T is
C.sub.1-C.sub.6alkylene. In further embodiments,
C.sub.1-C.sub.6alkylene is CH.sub.2. In another embodiment, Y is
C.sub.1-C.sub.6alkyl or C.sub.2-C.sub.6alkene. In one embodiment,
C.sub.1-C.sub.6alkyl or C.sub.2-C.sub.6alkene is substituted with
--C(.dbd.O)R.sub.2 or --CO.sub.2R.sub.2. In a further embodiment,
R.sub.2 is H. In one embodiment, Z is C.sub.1-C.sub.6alkyl. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, or --C(.dbd.O)N(R.sub.2).sub.2. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with
--NR.sub.2C(.dbd.O)R.sub.2. In one embodiment, each R.sub.2 is H.
In one embodiment, R.sub.2 is C.sub.1-C.sub.6alkyl. In another
embodiment, C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In one
embodiment, R.sub.2 is C.sub.1-C.sub.6hydroxyalkyl.
[0249] In one embodiment, Y and Z together with the carbon atom to
which they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl. In another embodiment, the
nitrogen atom-containing C.sub.2-C.sub.10heterocycloalkyl is
selected from:
##STR00217##
[0250] In yet another embodiment, is a compound of Formula (IIIC)
or (IIID) wherein the nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl is
##STR00218##
[0251] In a further embodiment,
##STR00219##
is substituted with at least one X. In yet a further embodiment, X
is selected from F, Cl, Br, I, --CN, --OR.sub.3, and NO.sub.2. In
one embodiment, X is --OH or --OSO.sub.3H. In another embodiment, W
is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J, and
C(.dbd.O)NR.sub.2-J. In yet another embodiment, W is C(.dbd.O)-J.
In a further embodiment, J is C.sub.1-C.sub.6alkyl. In yet a
further embodiment, C.sub.1-C.sub.6alkyl is methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In one
embodiment, C.sub.1-C.sub.6alkyl is substituted with one R.sub.1.
In another embodiment, C.sub.1-C.sub.6alkyl is substituted with two
R.sub.1. In yet another embodiment, R.sub.1 is selected from F, Cl,
Br, I, --CN, NO.sub.2, --OR.sub.3, and at least one amino acid
fragment.
[0252] In a further embodiment, W is J. In yet a further
embodiment, J is C.sub.1-C.sub.6alkyl. In one embodiment,
C.sub.1-C.sub.6alkyl is methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, and tert-butyl. In another embodiment,
C.sub.1-C.sub.6alkyl is substituted with one R.sub.1. In yet
another embodiment, C.sub.1-C.sub.6alkyl is substituted with two
R.sub.1. In a further embodiment, R.sub.1 is selected from F, Cl,
Br, I, --CN, NO.sub.2, and OR.sub.3. In yet a further embodiment,
R.sub.1 is at least one amino acid fragment. In one embodiment, the
at least one amino acid fragment is a cysteine or glutathione
fragment. In another embodiment, one R.sub.1 is an amino fragment
and the other R.sub.1 is selected from F, Cl, Br, I, --CN,
NO.sub.2, --OH, and --OSO.sub.3H. In yet another embodiment, the at
least one amino acid fragment is a di-peptide fragment. In a
further embodiment, the at least one amino acid fragment is a
tri-peptide fragment. In yet a further embodiment, the di-peptide
fragment is a fragment of Cys-Gly. In one embodiment, J is
C.sub.2-C.sub.6alkene. In another embodiment, C.sub.2-C.sub.6alkene
is C.sub.2H.sub.3. In one embodiment, C.sub.2-C.sub.6alkene is
substituted with at least one R.sub.1 selected from F, Cl, Br, I,
--CN, NO.sub.2, OH, and --OSO.sub.3H. In one embodiment, J is
C.sub.2-C.sub.6heterocycloalkyl. In another embodiment
C.sub.2-C.sub.6heterocycloalkyl is an epoxide. In a further
embodiment, is a compound of Formula (I) wherein R.sub.1 is
selected from --NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, or --S(.dbd.O).sub.2R.sub.2. In one
embodiment,
[0253] R.sub.1 is --S(.dbd.O).sub.2R.sub.2. In another embodiment,
R.sub.2 is C.sub.1-C.sub.6haloalkyl. In a further embodiment,
C.sub.1-C.sub.6haloalkyl is CF.sub.3.
[0254] In a further embodiment is a compound having the
structure:
##STR00220## ##STR00221##
or a pharmaceutically acceptable salt, solvate, or metabolite
thereof wherein the following compounds, having different
substituents (for e.g., R.sub.1 and R.sub.3) are listed in the
table below:
TABLE-US-00002 Cmpd # R.sub.3 R.sub.1 196 ##STR00222## H 197
##STR00223## 3-OH 198 ##STR00224## 4-OH 199 ##STR00225## 2-OH 200
##STR00226## H 201 ##STR00227## 4-OH 202 ##STR00228## 2-OH 203
##STR00229## 3-OH 204 ##STR00230## 3,4- dihydroxy 205 ##STR00231##
4-OH 206 ##STR00232## 3-OH 207 ##STR00233## 3-OH 208 ##STR00234## H
209 ##STR00235## 2-OH 210 ##STR00236## H 211 ##STR00237## 3-OH 212
##STR00238## 3-OH 213 ##STR00239## H 214 ##STR00240## 2-OH 215
##STR00241## H 216 ##STR00242## 3-OH 217 ##STR00243## 3-OH 218
##STR00244## 4-OH 219 ##STR00245## 2-OH 220 ##STR00246## 3,4-
dihydroxy 221 ##STR00247## 4-OH 222 ##STR00248## 3,4- dihydroxy 223
##STR00249## 4-OH 224 ##STR00250## 2-OH 225 ##STR00251## 3,4-
dihydroxy 226 ##STR00252## 4-OH 227 ##STR00253## 3,4- dihydroxy 228
##STR00254## 4-OH 229 ##STR00255## 2-OH 230 ##STR00256## 3,4-
dihydroxy 231 ##STR00257## H 232 ##STR00258## H 233 ##STR00259##
2-OH 234 ##STR00260## H 235 ##STR00261## 3-OH 236 ##STR00262## H
237 ##STR00263## 2-OH 238 ##STR00264## H 239 ##STR00265## 2-OH 240
##STR00266## H 241 ##STR00267## 3-OH 242 ##STR00268## 2-OH 243
##STR00269## 3-OH 244 ##STR00270## 2-OH 245 ##STR00271## 3-OH 246
##STR00272## H 247 ##STR00273## 2-OH 248 ##STR00274## 3,4-
dihydroxy 249 ##STR00275## 4-OH 250 ##STR00276## 3,4- dihydroxy 251
##STR00277## 3,4- dihydroxy 252 ##STR00278## 4-OH 253 ##STR00279##
3-OH 254 ##STR00280## 4-OH 255 ##STR00281## 3,4- dihydroxy 256
##STR00282## 4-OH 257 ##STR00283## 3,4- dihydroxy 258 ##STR00284##
3,4- dihydroxy 259 ##STR00285## 4-OH 260 ##STR00286## H 261
##STR00287## 3,4- dihydroxy 262 ##STR00288## 4-OH 263 ##STR00289##
3,4- dihydroxy 264 ##STR00290## H 265 ##STR00291## 3-OH 266
##STR00292## H 267 ##STR00293## 3-OH 268 ##STR00294## 2-OH 269
##STR00295## H 270 ##STR00296## 3-OH 271 ##STR00297## H 272
##STR00298## 3-OH 273 ##STR00299## 2-OH 274 ##STR00300## H 275
##STR00301## 2-OH 276 CH.sub.3 H 277 CH.sub.3 3-OH 278 CH.sub.3
2-OH 279 ##STR00302## H 280 ##STR00303## 3-OH 281 ##STR00304## H
282 ##STR00305## 2-OH 283 ##STR00306## 4-OH 284 ##STR00307## 2-OH
285 ##STR00308## 4-OH 286 ##STR00309## 3,4- dihydroxy 287
##STR00310## 3,4- dihydroxy 288 ##STR00311## 4-OH 289 ##STR00312##
2-OH 290 ##STR00313## 4-OH 291 ##STR00314## 3,4- dihydroxy 292
##STR00315## 3-OH 293 ##STR00316## 4-OH 294 ##STR00317## 3,4-
dihydroxy 295 CH.sub.3 4-OH 296 CH.sub.3 3,4- dihydroxy 297
##STR00318## 3-OH 298 ##STR00319## 3,4- dihydroxy 299 ##STR00320##
4-OH 300 ##STR00321## 4-OH 301 ##STR00322## 3,4- dihydroxy 302
##STR00323## H 303 ##STR00324## 2-OH 304 ##STR00325## 3-OH 305
##STR00326## 2-OH 306 ##STR00327## H 307 ##STR00328## 2-OH 308
##STR00329## H 309 ##STR00330## H 310 ##STR00331## 2-OH 311
##STR00332## 3-OH 312 ##STR00333## 2-OH 313 ##STR00334## H 314
##STR00335## H 315 ##STR00336## 2-OH 316 CH.sub.2CH.sub.3 H 317
CH.sub.2CH.sub.3 2-OH 318 CH.sub.2CH.sub.3 3-OH 319 ##STR00337##
4-OH 320 ##STR00338## 3,4- dihydroxy
321 ##STR00339## 3,4- dihydroxy 322 ##STR00340## 4-OH 323
##STR00341## 3,4- dihydroxy 324 ##STR00342## 3-OH 325 ##STR00343##
4-OH 326 ##STR00344## 4-OH 327 ##STR00345## 3,4- dihydroxy 328
##STR00346## 3,4- dihydroxy 329 ##STR00347## 4-OH 330 ##STR00348##
3,4- dihydroxy 331 ##STR00349## 4-OH 332 ##STR00350## 3-OH 333
CH.sub.2CH.sub.3 4-OH 334 CH.sub.2CH.sub.3 3,4- dihydroxy 335
##STR00351## 3,4- dihydroxy 336 ##STR00352## H 337 ##STR00353##
4-OH 338 ##STR00354## 3-OH 339 ##STR00355## H 340 ##STR00356## 4-OH
341 ##STR00357## 3-OH 342 ##STR00358## 3-OH 343 ##STR00359## 4-OH
344 ##STR00360## 2-OH 345 ##STR00361## 4-OH 346 ##STR00362## H 347
##STR00363## 2-OH 348 ##STR00364## 3-OH 349 ##STR00365## 2-OH 350
##STR00366## 2-OH 351 ##STR00367## 3,4- dihydroxy 352 ##STR00368##
3-OH 353 ##STR00369## 3,4- dihydroxy 354 ##STR00370## 2-OH 355
##STR00371## 2-OH 356 ##STR00372## 3,4- dihydroxy 357 ##STR00373##
H 358 ##STR00374## 3-OH 359 ##STR00375## 3,4- dihydroxy 360
##STR00376## 4-OH 361 ##STR00377## 3,4- dihydroxy 362 ##STR00378##
4-OH 363 ##STR00379## 3,4- dihydroxy 364 ##STR00380## 3-OH 365
##STR00381## 2-OH 366 ##STR00382## 4-OH 367 CCH 3-OH 368 CCH 4-OH
369 ##STR00383## 2-OH 370 ##STR00384## 3-OH 371 ##STR00385## 3-OH
372 ##STR00386## 2-OH 373 ##STR00387## 3-OH 374 ##STR00388## 4-OH
375 ##STR00389## 3-OH 376 ##STR00390## 4-OH 377 ##STR00391## 3,4-
dihydroxy 378 ##STR00392## 3-OH 380 CCH 2-OH 381 CCH 3,4- dihydroxy
382 ##STR00393## 3,4- dihydroxy 383 ##STR00394## 4-OH 384
##STR00395## 3,4- dihydroxy 385 ##STR00396## 4-OH 386 ##STR00397##
2-OH 387 ##STR00398## 3,4- dihydroxy 388 ##STR00399## 2-OH 389
##STR00400## 3,4- dihydroxy
[0255] In another embodiment is a compound selected from:
##STR00401## ##STR00402## ##STR00403##
or a pharmaceutically acceptable salt, solvate, or metabolite
thereof.
[0256] In another embodiment is a compound having the
structure:
##STR00404## ##STR00405##
or a pharmaceutically acceptable salt, solvate, or metabolite
thereof.
[0257] Also described herein is a compound having the
structure:
##STR00406##
pharmaceutically acceptable salt, solvate, or metabolite
thereof.
[0258] In one aspect, provided herein is a compound selected from
among:
1-(3-(4-amino-3-(4-(3,4-dihydroxyphenoxy)phenyl)-6-hydroxy-1H-pyrazolo[3,-
4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one,
1-(3-(4-amino-6-hydroxy-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-1-yl)piperidin-1-yl)-3-hydroxypropan-1-one,
4-(4-(4-amino-1-(1-(1-hydroxypropyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyr-
imidin-3-yl) phenoxy)benzene-1,2-diol,
1-(3-(4-amino-3-(4-(3,4-dihydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-1-yl) piperidin-1-yl)-3-hydroxypropan-1-one,
4-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y-
l)-5-propionamidopentanoic acid,
1-(3-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl) piperidin-1-yl)-3-hydroxypropan-1-one,
1-(3-(4-amino-6-hydroxy-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-1-yl) piperidin-1-yl)propan-1-one,
1-(3-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl) piperidin-1-yl)-2,3-dihydroxypropan-1-one,
1-(3-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl) piperidin-1-yl)-3-hydroxypropan-1-one,
1-(3-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl) piperidin-1-yl)propane-1,3-diol,
1-(3-(4-amino-6-hydroxy-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,
N-(2-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl)-5-oxopentyl)propionamide,
2-(2-amino-3-(3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-1-yl)piperidin-1-yl)-3-hydroxypropylthio)propanamido)acetic
acid,
2-amino-3-(3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl)piperidin-1-yl)-3-oxopropylthio)propanoic acid,
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-hyd-
roxypiperidin-1-yl)propan-1-one,
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-hyd-
roxypiperidin-1-yl)-2,3-dihydroxypropan-1-one,
N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-oxo-
pent-3-enyl)-3-hydroxypropanamide,
3-(3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pip-
eridin-1-yl)-3-oxopropylthio)-2-(carboxyamino)propanoic acid,
4-amino-3-(4-phenoxyphenyl)-1-(1-propionylpiperidin-3-yl)-1H-pyrazolo[3,4-
-d]pyrimidin-6(7H)-one,
4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3--
yl)phenoxy)phenyl hydrogen sulfate, and
1-(3-(4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
1-yl)piperidin-1-yl)prop-2-en-1-one; or a pharmaceutically
acceptable salt, solvate or tautomeric form thereof.
[0259] In one embodiment is a compound selected from:
##STR00407## ##STR00408## ##STR00409## ##STR00410##
##STR00411##
or a pharmaceutically acceptable salt, solvate, or tautomeric form
thereof.
[0260] In a further embodiment is a compound of Formula (IV) having
the structure:
##STR00412##
wherein:
[0261] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0262] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0263] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0264] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0265] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0266] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.5, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0267] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0268] v is 1 or 2;
[0269] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H, halogen,
--CN, --NO.sub.2, --SR.sub.2, optionally substituted
C.sub.1-C.sub.6alkyl; N(R.sub.2).sub.2 or NHR.sub.7;
[0270] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.8, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0271] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; R.sub.6 is selected from H, F,
Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --OS(.dbd.O).sub.2R.sub.2,
--OS(.dbd.O).sub.2OR.sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment; wherein each R.sub.6 cannot all be H; R.sub.7 is an amino
protecting group; R.sub.8 is an optionally substituted
C.sub.1-C.sub.6alkyl, an optionally substituted
C.sub.2-C.sub.6alkenyl, an optionally substituted
C.sub.2-C.sub.6alkynyl, or an optionally substituted
C.sub.3-C.sub.6cycloalkyl; or a pharmaceutically acceptable salt,
solvate, or metabolite thereof.
[0272] In one embodiment is the compound of Formula (IV) wherein Y
and Z together with the carbon atom to which they are attached form
a
##STR00413##
group;
[0273] is a single bond, a cis or trans-double bond, or a triple
bond wherein R.sub.4 is absent;
[0274] p is 0-6;
[0275] q is 0-6; wherein p+q is .gtoreq.1;
[0276] n is 0-4;
[0277] R.sub.4 and R.sub.5 are each independently selected from H,
F, Cl, Br, I, --CN, --NO.sub.2, --SR.sub.2, --OR.sub.3, optionally
substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6hydroxyalkyl, --OC.sub.1-C.sub.6haloalkyl,
C.sub.1-C.sub.6heteroalkyl, optionally substituted
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--OSO.sub.3H, --NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --CO.sub.2R.sub.2, --C(.dbd.O)R.sub.2,
--OC(.dbd.O)R.sub.2, --C(.dbd.O)N(R.sub.2).sub.2,
--OS(.dbd.O).sub.2R.sub.2, --OS(.dbd.O).sub.2OR.sub.2,
--S(.dbd.O)R.sub.2, --S(.dbd.O).sub.2R.sub.2, and at least one
amino acid fragment; or optionally when is a single bond then
R.sub.4 and R.sub.5 together with the carbon atoms to which they
are attached form an epoxide; wherein when is a single bond then
R.sub.4 and R.sub.5 are not both hydrogen; or a pharmaceutically
acceptable salt, solvate or metabolite thereof.
[0278] In one embodiment is a compound of Formula (IV) wherein Y
and Z together with the carbon atom to which they are attached form
a
##STR00414##
group.
[0279] In another embodiment is a compound of Formula (IV) wherein
Y and Z together with the carbon atom to which they are attached
form a
##STR00415##
group.
[0280] In a further embodiment is a compound of Formula (IV)
wherein W is C(.dbd.O)-J. In another embodiment, W is
S(.dbd.O).sub.v-J.
[0281] In a further embodiment is a compound of Formula (IV)
wherein J is an optionally substituted C.sub.2-C.sub.6alkene. In
another embodiment, J is an optionally substituted
C.sub.1-C.sub.6alkyl. In a further embodiment,
C.sub.2-C.sub.6alkene is ethylene. In a further embodiment,
ethylene is substituted with C.sub.1-C.sub.6alkylN(R.sub.2).sub.2;
wherein R.sub.2 is selected from H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl.
[0282] In yet another embodiment is a compound of Formula (IV)
wherein R.sub.6 is OH. In one embodiment, OH is substituted at the
2-position. In another embodiment, OH is substituted at the
3-position. In a further embodiment, OH is substituted at the
4-position. In yet a further embodiment, OH is substituted at the 3
and 4-positions.
[0283] In yet another embodiment is a compound of Formula (IV)
wherein R.sub.b is NHR.sub.7 wherein R.sub.7 is an amino protecting
group. In one embodiment is a compound of Formula (IV) wherein the
amino protecting group is selected from Fmoc, Boc, Cbz, Ac,
trifluoroacetamide, Bn, trityl, benzylideneamine, Ts, or the H
attached to the nitrogen atom of the primary amine is absent and R
and the nitrogen atom to which it is attached form a phthalimide
group; or a pharmaceutically acceptable salt, solvate, or
metabolite thereof.
[0284] In a further embodiment is a compound of Formula (IV)
wherein R.sub.b is N(R.sub.2).sub.2. In one embodiment R.sub.2 is
selected from optionally substituted C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl. In another embodiment, R.sub.2 is
C.sub.1-C.sub.6haloalkyl.
[0285] Also described herein are irreversible inhibitors of Btk.
Further described are irreversible inhibitors of Btk that form a
covalent bond with a cysteine residue on Btk. Further described
herein are irreversible inhibitors of other tyrosine kinases,
wherein the other tyrosine kinases share homology with Btk by
having a cysteine residue (including a Cys 481 residue) that can
form a covalent bond with the irreversible inhibitor (such tyrosine
kinases, are referred herein as "Btk tyrosine kinase cysteine
homologs"). Also described herein are methods for synthesizing such
irreversible inhibitors, methods for using such irreversible
inhibitors in the treatment of diseases (including diseases wherein
irreversible inhibition of Btk provides therapeutic benefit to a
patient having the disease). Further described are pharmaceutical
formulations that include an irreversible inhibitor of Btk.
[0286] Also described herein are irreversible inhibitors of
tyrosine kinases that have an accessible cysteine residue near an
active site of the tyrosine kinase (referred herein as "Accessible
Cysteine Kinases" or ACKs). Also described herein are irreversible
inhibitors of any of the aforementioned tyrosine kinases, in which
the irreversible inhibitor includes a Michael acceptor moiety.
Further described are such irreversible inhibitors in which the
Michael acceptor moiety preferentially forms a covalent bond with
the appropriate cysteine residue on the desired tyrosine kinase
relative to forming a covalent bond with other biological molecules
that contain an accessible SH moiety. Also described herein are
methods for synthesizing such irreversible inhibitors, methods for
using such irreversible inhibitors in the treatment of diseases
(including diseases wherein irreversible inhibition of Btk provides
therapeutic benefit to a patient having the disease). Further
described are pharmaceutical formulations that include an
irreversible inhibitor of Btk.
[0287] In one aspect is a compound of Formula (I) wherein Y and Z
together with the carbon atom to which they are attached form a
##STR00416##
wherein is a cis or trans-double bond. In one embodiment, is a
compound of Formula (I) having the structure
##STR00417##
In another embodiment, the compound of Formula (I) forms a covalent
bond with a cysteine residue of a Bruton's tyrosine kinase.
[0288] In another aspect are methods for modulating, including
irreversibly inhibiting the activity of Btk or other tyrosine
kinases, wherein the other tyrosine kinases share homology with Btk
by having a cysteine residue (including a Cys 481 residue) that can
form a covalent bond with at least one irreversible inhibitor
described herein, in a mammal comprising administering to the
mammal at least once an effective amount of at least one compound
having the structure of any of Formula (I). In another aspect are
methods for modulating, including including irreversibly
inhibiting, the activity of Btk in a mammal comprising
administering to the mammal at least once an effective amount of at
least one compound having the structure of any of Formula (I). In
another aspect are methods for treating Btk-dependent or Btk
mediated conditions or diseases, comprising administering to the
mammal at least once an effective amount of at least one compound
having the structure of any of Formula (I).
[0289] In a further or alternative embodiment, the compound of
Formula (I) having a Michael acceptor are irreversible inhibitors
of Bruton's tyrosine kinase (Btk), while in still further or
alternative embodiments, such irreversible inhibitors are selective
for Btk. In even further or alternative embodiments, such
inhibitors have an IC.sub.50 below 10 microM in enzyme assay. In
one embodiment, a Btk irreversible inhibitor has an IC.sub.50 of
less than 1 microM, and in another embodiment, less than 0.25
microM.
[0290] In further or alternative embodiment, the compound of
Formula (I) is a selective irreversible inhibitor for Btk over Itk.
In further or alternative embodiment, the compound of Formula (I)
is a selective irreversible inhibitor for Btk over Lck. In further
or alternative embodiment, the compound of Formula (I) is a
selective irreversible inhibitor for Btk over ABL. In further or
alternative embodiment, the compound of Formula (I) is a selective
irreversible inhibitor for Btk over CMET. In further or alternative
embodiment, the compound of Formula (I) is a selective irreversible
inhibitor for Btk over EGFR. In further or alternative embodiment,
the compound of Formula (I) is a selective irreversible inhibitor
for Btk over Lyn.
[0291] In one embodiment, the irreversible Btk inhibitor compound
selectively and irreversibly inhibits an activated form of its
target tyrosine kinase (e.g., a phosphorylated form of the tyrosine
kinase). For example, activated Btk is transphosphorylated at
tyrosine 551. Thus, in these embodiments the irreversible Btk
inhibitor inhibits the target kinase in cells only once the target
kinase is activated by the signaling events.
[0292] Generally, an irreversible inhibitor compound used in the
methods described herein is identified or characterized in an in
vitro assay, e.g., an acellular biochemical assay or a cellular
functional assay. Such assays are useful to determine an in vitro
IC.sub.50 for an irreversible inhibitor compound.
[0293] For example, in some embodiments, an acellular kinase assay
is used to determine kinase activity after incubation of the kinase
in the absence or presence of a range of concentrations of a
candidate inhibitor compound. If the candidate compound is in fact
an inhibitor, kinase activity will not be recovered by repeat
washing with inhibitor-free medium. See, e.g., J. B. Smaill, et al.
(1999), J. Med. Chem. 42(10):1803-1815. Further, covalent complex
formation between a Kinase and a candidate inhibitor is a useful
indicator of inhibition of the Kinase that can be readily
determined by a number of methods (e.g., mass spectrometry). For
example, in some embodiments, some Kinase-inhibitor compounds form
a covalent bond with the aforenoted cysteine residue (e.g., via a
Michael reaction).
[0294] High throughput assays for many acellular biochemical assays
(e.g., kinase assays) and cellular functional assays (e.g., calcium
flux) are documented methodologies. In addition, high throughput
screening systems are commercially available (see, e.g., Zymark
Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;
Beckman Instruments, Inc. Fullerton, Calif.; Precision Systems,
Inc., Natick, Mass., etc.). These systems typically automate entire
procedures including all sample and reagent pipetting, liquid
dispensing, timed incubations, and final readings of the microplate
in detector(s) appropriate for the assay. Automated systems thereby
allow the identification and characterization of a large number of
compounds.
[0295] In some embodiments, the inhibitors described herein are
used for the manufacture of a medicament for treating any of the
foregoing conditions (e.g., autoimmune diseases, inflammatory
diseases, allergy disorders, B-cell proliferative disorders, or
thromboembolic disorders).
[0296] In some embodiments, the inhibitor compound used for the
methods described herein inhibits a Kinase activity with an in
vitro IC.sub.50 of less than about 10 .mu.M. (e.g., less than about
1 .mu.M, less than about 0.5 .mu.M, less than about 0.4 .mu.M, less
than about 0.3 .mu.M, less than about 0.1, less than about 0.08
.mu.M, less than about 0.06 .mu.M, less than about 0.05 .mu.M, less
than about 0.04 .mu.M, less than about 0.03 .mu.M, less than about
0.02 .mu.M, less than about 0.01, less than about 0.008 .mu.M, less
than about 0.006 .mu.M, less than about 0.005 .mu.M, less than
about 0.004 .mu.M, less than about 0.003 .mu.M, less than about
0.002 .mu.M, less than about 0.001, less than about 0.00099 .mu.M,
less than about 0.00098 .mu.M, less than about 0.00097 .mu.M, less
than about 0.00096 .mu.M, less than about 0.00095 .mu.M, less than
about 0.00094 .mu.M, less than about 0.00093 .mu.M, less than about
0.00092, or less than about 0.00090 .mu.M).
[0297] In one embodiment, the inhibitor compound selectively
inhibits an activated form of its target tyrosine kinase (e.g., a
phosphorylated form of the tyrosine kinase). For example, activated
Btk is transphosphorylated at tyrosine 551. Thus, in these
embodiments the Btk inhibitor inhibits the target kinase in cells
only once the target kinase is activated by the signaling
events.
[0298] In further embodiments, the compounds of Formula (I)
irreversibly inhibit Btk and are used to treat patients suffering
from Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase
mediated conditions or diseases, including, but not limited to,
cancer, autoimmune and other inflammatory diseases.
Preparation of Compounds
[0299] Compounds of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein are optionally synthesized using standard
synthetic techniques or using such methods known in combination
with methods described herein. In additions, solvents, temperatures
and other reaction conditions are presented herein for illustration
only, and not to limit the scope of the methods and compositions
described herein. As a further guide the following synthetic
methods may also be utilized.
[0300] The reactions are optionally employed in a linear sequence
to provide the compounds described herein or used to synthesize
fragments which are subsequently joined by the methods described
herein and/or documented elsewhere.
Formation of Covalent Linkages by Reaction of an Electrophile with
a Nucleophile
[0301] The compounds described herein can be modified using various
electrophiles or nucleophiles to form new functional groups or
substituents. Table 1 entitled "Examples of Covalent Linkages and
Precursors Thereof" lists selected examples of covalent linkages
and precursor functional groups which yield and can be used as
guidance toward the variety of electrophiles and nucleophiles
combinations available. Precursor functional groups are shown as
electrophilic groups and nucleophilic groups.
TABLE-US-00003 TABLE 1 Examples of Covalent Linkages and Precursors
Thereof Covalent Linkage Product Electrophile Nucleophile
Carboxamides Activated esters amines/anilines Carboxamides acyl
azides amines/anilines Carboxamides acyl halides amines/anilines
Esters acyl halides alcohols/phenols Esters acyl nitriles
alcohols/phenols Carboxamides acyl nitriles amines/anilines Imines
Aldehydes amines/anilines Hydrazones aldehydes or ketones
Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkyl amines
alkyl halides amines/anilines Esters alkyl halides carboxylic acids
Thioethers alkyl halides Thiols Ethers alkyl halides
alcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkyl
sulfonates carboxylic acids Ethers alkyl sulfonates
alcohols/phenols Esters Anhydrides alcohols/phenols Carboxamides
Anhydrides amines/anilines Thiophenols aryl halides Thiols Aryl
amines aryl halides Amines Thioethers Azindines Thiols Boronate
esters Boronates Glycols Carboxamides carboxylic acids
amines/anilines Esters carboxylic acids Alcohols hydrazines
Hydrazides carboxylic acids N-acylureas or Anhydrides carbodiimides
carboxylic acids Esters diazoalkanes carboxylic acids Thioethers
Epoxides Thiols Thioethers haloacetamides Thiols Ammotriazines
halotriazines amines/anilines Triazinyl ethers halotriazines
alcohols/phenols Amidines imido esters amines/anilines Ureas
Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenols
Thioureas isothiocyanates amines/anilines Thioethers Maleimides
Thiols Phosphite esters phosphoramidites Alcohols Silyl ethers
silyl halides Alcohols Alkyl amines sulfonate esters
amines/anilines Thioethers sulfonate esters Thiols Esters sulfonate
esters carboxylic acids Ethers sulfonate esters Alcohols
Sulfonamides sulfonyl halides amines/anilines Sulfonate esters
sulfonyl halides phenols/alcohols Alkyl thiol
.alpha.,.beta.-unsaturated ester thiols Alkyl ethers
.alpha.,.beta.-unsaturated ester alcohols Alkyl amines
.alpha.,.beta.-unsaturated ester amines Alkyl thiol Vinyl sulfone
thiols Alkyl ethers Vinyl sulfone alcohols Alkyl amines Vinyl
sulfone amines Vinyl sulfide Propargyl amide thiol
Use of Protecting Groups
[0302] In the reactions described, it may be necessary to protect
reactive functional groups, for example hydroxy, amino, imino, thio
or carboxy groups, where these are desired in the final product, to
avoid their unwanted participation in the reactions. Protecting
groups are used to block some or all reactive moieties and prevent
such groups from participating in chemical reactions until the
protective group is removed. In one embodiment, each protective
group be removable by a different means. Protective groups that are
cleaved under totally disparate reaction conditions fulfill the
requirement of differential removal. Protective groups can be
removed by acid, base, and hydrogenolysis. Groups such as trityl,
dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile
and may be used to protect carboxy and hydroxy reactive moieties in
the presence of amino groups protected with Cbz groups, which are
removable by hydrogenolysis, and Fmoc groups, which are base
labile. Carboxylic acid and hydroxy reactive moieties may be
blocked with base labile groups such as, but not limited to,
methyl, ethyl, and acetyl in the presence of amines blocked with
acid labile groups such as t-butyl carbamate or with carbamates
that are both acid and base stable but hydrolytically
removable.
[0303] Carboxylic acid and hydroxy reactive moieties may also be
blocked with hydrolytically removable protective groups such as the
benzyl group, while amine groups capable of hydrogen bonding with
acids may be blocked with base labile groups such as Fmoc.
Carboxylic acid reactive moieties may be protected by conversion to
simple ester compounds as exemplified herein, or they may be
blocked with oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while co-existing amino groups may be blocked
with fluoride labile silyl carbamates.
[0304] Allyl blocking groups are useful in then presence of acid-
and base-protecting groups since the former are stable and can be
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid can be deprotected with a
Pd.sup.0-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. Yet
another form of protecting group is a resin to which a compound or
intermediate may be attached. As long as the residue is attached to
the resin, that functional group is blocked and cannot react. Once
released from the resin, the functional group is available to
react.
[0305] Typically blocking/protecting groups may be selected
from:
##STR00418##
[0306] Other protecting groups, plus a detailed description of
techniques applicable to the creation of protecting groups and
their removal are described in Greene and Wuts, Protective Groups
in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York,
N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New
York, N.Y., 1994, which are incorporated herein by reference for
such disclosure.
Synthesis of Compounds
[0307] In certain embodiments, provided herein are methods of
making and methods of using tyrosine kinase inhibitor compounds
described herein. In certain embodiments, compounds described
herein can be synthesized using the following synthetic schemes.
Compounds may be synthesized using methodologies analogous to those
described below by the use of appropriate alternative starting
materials.
[0308] Described herein are compounds that inhibit the activity of
tyrosine kinase(s), such as Btk, and processes for their
preparation. Also described herein are pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, pharmaceutically
active metabolites and pharmaceutically acceptable prodrugs of such
compounds. Pharmaceutical compositions that include at least one
such compound or a pharmaceutically acceptable salt,
pharmaceutically acceptable solvate, pharmaceutically active
metabolite or pharmaceutically acceptable prodrug of such compound,
are provided.
[0309] The starting material used for the synthesis of the
compounds described herein is either synthesized or obtained from
commercial sources, such as, but not limited to, Aldrich Chemical
Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma Chemical
Co. (St. Louis, Mo.). The compounds described herein, and other
related compounds having different substituents are optionally
synthesized using techniques and materials, such as described, for
example, in March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley
1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed.,
Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE
GROUPS IN ORGANIC SYNTHESIS 3.sup.rd Ed., (Wiley 1999); Fieser and
Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley
and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5
and Supplementals (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
Other methods for the synthesis of compounds described herein may
be found in International Patent Publication No. WO 01/01982901,
Arnold et al. Bioorganic & Medicinal Chemistry Letters 10
(2000) 2167-2170; Burchat et al. Bioorganic & Medicinal
Chemistry Letters 12 (2002) 1687-1690. As a guide the following
synthetic methods may be utilized.
[0310] The products of the reactions are optionally isolated and
purified, if desired, using conventional techniques, including, but
not limited to, filtration, distillation, crystallization,
chromatography and the like. Such materials are optionally
characterized using conventional means, including physical
constants and spectral data.
[0311] Compounds described herein are optionally prepared using the
synthetic methods described herein as a single isomer or a mixture
of isomers.
[0312] A non-limiting example of a synthetic approach towards the
preparation of compounds of any of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein is shown in Scheme I.
##STR00419##
[0313] Halogenation of commercially avalaible
1H-pyrazolo[3,4-d]pyrimidin-4-amine provides an entry into the
synthesis of compounds of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein. In one embodiment,
1H-pyrazolo[3,4-d]pyrimidin-4-amine is treated with
N-iodosuccinamide to give
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. Metal catalyzed cross
coupling reactions are then carried out on
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. In one embodiment,
palladium mediated cross-coupling of a suitably substituted phenyl
boronic acid under basic conditions constructs intermediate 2.
Intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (as
non-limiting example) via Mitsunobu reaction to give the Boc
(tert-butyloxycarbonyl) protected intermediate 3. After
deprotection with acid, coupling with, but not limited to, an acid
chloride, such as, but not limited to, acryloyl chloride, completes
the synthesis to give compound 4.
[0314] A non-limiting example of a synthetic approach towards the
preparation of compounds of Formula (II) is shown in Scheme II.
Scheme II.
Synthesis of
3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-
-1-yl)-2,3-dihydroxypropan-1-one
##STR00420##
[0316] Compounds of the general structure of compound 4 having an
alkene, undergo dihydroxylation in the presence of OsO.sub.4.
Following workup, the resulting compounds of general structure 5
are afforded.
[0317] A non-limiting example of a synthetic approach towards the
preparation of compounds of Formula (II) is shown in Scheme
III.
##STR00421## ##STR00422##
[0318] A non-limiting example of a synthetic approach towards the
preparation of compounds of Formula (II) is shown in Scheme IV.
##STR00423##
[0319] The compounds prepared by the methods disclosed herein are
purified by conventional means, such as, for example, filtration,
recrystallization, chromatography, distillation, and combinations
thereof.
[0320] Any combination of the groups described above for the
various variables is contemplated herein. It is understood that
substituents and substitution patterns on the compounds provided
herein can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
synthesized by techniques known in the art, as well as those set
forth herein.
Further Forms of Compounds
[0321] Compounds disclosed herein have a structure of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. It is understood
that when reference is made to compounds described herein, it is
meant to include compounds of any of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein, as well as to all of the specific
compounds that fall within the scope of these generic formulae,
unless otherwise indicated.
[0322] The compounds described herein may possess one or more
stereocenters and each center may exist in the R or S
configuration. The compounds presented herein include all
diastereomeric, enantiomeric, and epimeric forms as well as the
appropriate mixtures thereof. Stereoisomers may be obtained, if
desired, by methods such as, for example, the separation of
stereoisomers by chiral chromatographic columns
[0323] Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods known, for example, by chromatography and/or
fractional crystallization. In one embodiment, enantiomers can be
separated by chiral chromatographic columns In other embodiments,
enantiomers can be separated by converting the enantiomeric mixture
into a diastereomeric mixture by reaction with an appropriate
optically active compound (e.g., alcohol), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. All such
isomers, including diastereomers, enantiomers, and mixtures thereof
are considered as part of the compositions described herein.
[0324] The methods and formulations described herein include the
use of N-oxides, crystalline forms (also known as polymorphs), or
pharmaceutically acceptable salts of compounds described herein, as
well as active metabolites of these compounds having the same type
of activity. In some situations, compounds exist as tautomers. All
tautomers are included within the scope of the compounds presented
herein. In addition, the compounds described herein can exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also
considered to be disclosed herein.
[0325] Compounds of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein in unoxidized form can be prepared from N-oxides
of compounds of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein by treating with a reducing agent, such as, but
not limited to, sulfur, sulfur dioxide, triphenyl phosphine,
lithium borohydride, sodium borohydride, phosphorus trichloride,
tribromide, or the like in a suitable inert organic solvent, such
as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or
the like at 0 to 80.degree. C.
[0326] Compounds described herein include isotopically-labeled
compounds, which are identical to those recited in the various
formulas and structures presented herein, but for the fact that one
or more atoms are replaced by an atom having an atomic mass or mass
number different from the atomic mass or mass number usually found
in nature. Examples of isotopes that can be incorporated into the
present compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F,
.sup.36Cl, respectively. Certain isotopically-labeled compounds
described herein, for example those into which radioactive isotopes
such as .sup.3H and .sup.14C are incorporated, are useful in drug
and/or substrate tissue distribution assays. Further, substitution
with isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements.
[0327] Compounds described herein (for example, compounds of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or
other pyrazolopyrimidine compounds described herein) are optionally
in the form of, and/or used as, pharmaceutically acceptable salts.
The type of pharmaceutical acceptable salts, include, but are not
limited to: (1) acid addition salts, formed) by reacting the free
base form of the compound with a pharmaceutically acceptable:
inorganic acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid,
and the like; or with an organic acid such as acetic acid,
propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic
acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic
acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic
acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; (2) salts formed when an acidic proton present
in the parent compound either is replaced by a metal ion, e.g., an
alkali metal ion (e.g. lithium, sodium, potassium), an alkaline
earth ion (e.g. magnesium, or calcium), or an aluminum ion; or
coordinates with an organic base. Acceptable organic bases include
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate, sodium hydroxide, and the like.
[0328] The corresponding counterions of the pharmaceutically
acceptable salts are optionally analyzed and identified using
various methods including, but not limited to, ion exchange
chromatography, ion chromatography, capillary electrophoresis,
inductively coupled plasma, atomic absorption spectroscopy, mass
spectrometry, or any combination thereof.
[0329] The salts are recovered by using at least one of the
following techniques: filtration, precipitation with a non-solvent
followed by filtration, evaporation of the solvent, or, in the case
of aqueous solutions, lyophilization.
[0330] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms or crystal forms thereof, particularly solvates or
polymorphs. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are optionally formed
during the process of crystallization with pharmaceutically
acceptable solvents such as water, ethanol, and the like. Hydrates
are formed when the solvent is water, or alcoholates are formed
when the solvent is alcohol. Solvates of compounds described herein
can be conveniently prepared or formed during the processes
described herein. In addition, the compounds provided herein can
exist in unsolvated as well as solvated forms. In general, the
solvated forms are considered equivalent to the unsolvated forms
for the purposes of the compounds and methods provided herein.
[0331] It should be understood that a reference to a salt includes
the solvent addition forms or crystal forms thereof, particularly
solvates or polymorphs. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are often formed
during the process of crystallization with pharmaceutically
acceptable solvents such as water, ethanol, and the like. Hydrates
are formed when the solvent is water, or alcoholates are formed
when the solvent is alcohol. Polymorphs include the different
crystal packing arrangements of the same elemental composition of a
compound. Polymorphs usually have different X-ray diffraction
patterns, infrared spectra, melting points, density, hardness,
crystal shape, optical and electrical properties, stability, and
solubility. Various factors such as the recrystallization solvent,
rate of crystallization, and storage temperature may cause a single
crystal form to dominate.
[0332] Compounds described herein are optionally in various forms,
including but not limited to, amorphous forms, milled forms and
nano-particulate forms. In addition, compounds described herein
include crystalline forms, also known as polymorphs. Polymorphs
include the different crystal packing arrangements of the same
elemental composition of a compound. Polymorphs usually have
different X-ray diffraction patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical
properties, stability, and solubility. Various factors such as the
recrystallization solvent, rate of crystallization, and storage
temperature may cause a single crystal form to dominate.
[0333] The screening and characterization of the pharmaceutically
acceptable salts, polymorphs and/or solvates may be accomplished
using a variety of techniques including, but not limited to,
thermal analysis, x-ray diffraction, spectroscopy, vapor sorption,
and microscopy. Thermal analysis methods address thermo chemical
degradation or thermo physical processes including, but not limited
to, polymorphic transitions, and such methods are used to analyze
the relationships between polymorphic forms, determine weight loss,
to find the glass transition temperature, or for excipient
compatibility studies. Such methods include, but are not limited
to, Differential scanning calorimetry (DSC), Modulated Differential
Scanning calorimetry (MDCS), Thermogravimetric analysis (TGA), and
Thermogravi-metric and Infrared analysis (TG/IR). X-ray diffraction
methods include, but are not limited to, single crystal and powder
diffractometers and synchrotron sources. The various spectroscopic
techniques used include, but are not limited to, Raman, FTIR, UVIS,
and NMR (liquid and solid state). The various microscopy techniques
include, but are not limited to, polarized light microscopy,
Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray
Analysis (EDX), Environmental Scanning Electron Microscopy with EDX
(in gas or water vapor atmosphere), IR microscopy, and Raman
microscopy.
Therapeutic Uses of Inhibitor Compounds
[0334] Described herein are methods, compositions, uses and
medicaments for the treatment of disorders comprising administering
to a patient in need an inhibitor of an ACK. In some embodiments,
the ACK is Btk or a Btk homolog. In further embodiments, the ACK is
Blk or a Blk homolog. In yet further embodiments, the ACK is
tyrosine kinases that share homology with Btk by having a cysteine
residue (including a Cys 481 residue) that can form a covalent bond
with the inhibitor.
[0335] The methods described herein (which includes uses of a
pharmaceutical composition to treat a disease or disorder, or uses
of a compound to form a medicament for treating a disease or
disorder) include administering to a subject in need a composition
containing a therapeutically effective amount of one or more Btk
inhibitor compounds described herein. Without being bound by
theory, the diverse roles played by Btk signaling in various
hematopoietic cell functions, e.g., B-cell receptor activation,
show that small molecule Btk inhibitors are useful for reducing the
risk of or treating a variety of diseases affected by or affecting
many cell types of the hematopoietic lineage including, e.g.,
autoimmune diseases, heteroimmune conditions or diseases,
inflammatory diseases, cancer (e.g., B-cell proliferative
disorders), and thromboembolic disorders.
[0336] In some embodiments, are methods for treating an autoimmune
disease or condition comprising administering to a patient in need
a pharmaceutical formulation of any inhibitor of Btk (or a Btk
homolog) of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein. Such an autoimmune disease or condition includes, but is
not limited to, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, lupus,
diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's
thyroiditis, Graves' disease Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
and vulvodynia. In some embodiments, the autoimmune disease is
selected from rheumatoid arthritis or lupus.
[0337] In some embodiments, are methods for treating a heteroimmune
disease or condition comprising administering to a patient in need
a pharmaceutical formulation of any inhibitor of Btk (or a Btk
homolog) of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein. Such a heteroimmune condition or disease includes, but is
not limited to graft versus host disease, transplantation,
transfusion, anaphylaxis, allergies (e.g., allergies to plant
pollens, latex, drugs, foods, insect poisons, animal hair, animal
dander, dust mites, or cockroach calyx), type I hypersensitivity,
allergic conjunctivitis, allergic rhinitis, and atopic
dermatitis.
[0338] In some embodiments, are methods for treating a cancer
comprising administering to a patient in need a pharmaceutical
formulation of any inhibitor of Btk (or a Btk homolog) of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. Such a cancer, e.g.,
B-cell proliferative disorders, includes but is not limited to
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, burkitt
lymphoma/leukemia, and lymphomatoid granulomatosis.
[0339] In some embodiments, are methods for treating mastocytosis
comprising administering to a patient in need a pharmaceutical
formulation of any inhibitor of Btk (or a Btk homolog) of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein. Mastocytosis
includes but is not limited to diseases characterized by
hyperactive mast cells.
[0340] In some embodiments, are methods for treating osteoporosis
or bone resorption disorders comprising administering to a patient
in need a pharmaceutical formulation of any inhibitor of Btk (or a
Btk homolog) of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein. Bone resorption disorders include but are not limted to
Paget's disease of bone, osteoporosis, and the bone changes
secondary to cancer, such as occur in myeloma and metastases from
breast cancer.
[0341] In some embodiments, are methods for treating inflammatory
diseases comprising administering to a patient in need a
pharmaceutical formulation of any inhibitor of Btk (or a Btk
homolog) of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein. Inflammatory diseases include but are not limited to
asthma, inflammatory bowel disease, appendicitis, blepharitis,
bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,
cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,
dermatitis, dermatomyositis, encephalitis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
hepatitis, hidradenitis suppurativa, laryngitis, mastitis,
meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,
orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis,
pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, tendonitis,
tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.
[0342] Further, the Btk inhibitor compounds described herein can be
used to inhibit a small subset of other tyrosine kinases that share
homology with Btk by having a cysteine residue (including a Cys 481
residue) that can form a covalent bond with the inhibitor. Thus, a
subset of tyrosine kinases other than Btk are also expected to be
useful as therapeutic targets in a number of health conditions,
including: [0343] autoimmune diseases, which include, but are not
limited to, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, lupus,
diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's
thyroiditis, Graves' disease Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
and vulvodynia. [0344] heteroimmune conditions or diseases, which
include, but are not limited to graft versus host disease,
transplantation, transfusion, anaphylaxis, allergies (e.g.,
allergies to plant pollens, latex, drugs, foods, insect poisons,
animal hair, animal dander, dust mites, or cockroach calyx), type I
hypersensitivity, allergic conjunctivitis, allergic rhinitis, and
atopic dermatitis. [0345] inflammatory diseases, which include, but
are not limited to asthma, inflammatory bowel disease,
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,
cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,
cystitis, dacryoadenitis, dermatitis, dermatomyositis,
encephalitis, endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and
vulvitis. [0346] a cancer, e.g., B-cell proliferative disorders,
which include, but are not limited to diffuse large B cell
lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,
chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid
granulomatosis. [0347] thromboembolic disorders, which include, but
are not limited to myocardial infarct, angina pectoris (including
unstable angina), reocclusions or restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischemia, peripheral
arterial occlusive disorders, pulmonary embolisms, and deep venous
thromboses. [0348] mastocytosis, which include but are not limited
to diseases characterized by hyperactive mast cells. [0349] bone
resorption disorders, which include but are not limted to Paget's
disease of bone, osteoporosis, and the bone changes secondary to
cancer, such as occur in myeloma and metastases from breast
cancer.
[0350] Symptoms, diagnostic tests, and prognostic tests for each of
the above-mentioned conditions includ, e.g., Harrison's Principles
of Internal Medicine.COPYRGT.," 16th ed., 2004, The McGraw-Hill
Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the
"Revised European American Lymphoma" (REAL) classification system
(see, e.g., the website maintained by the National Cancer
Institute).
[0351] A number of animal models are useful for establishing a
range of therapeutically effective doses of inhibitors, including
Btk inhibitor compounds for treating any of the foregoing diseases.
Also, for example, dosing of inhibitor compounds for treating an
autoimmune disease can be assessed in a mouse model of rheumatoid
arthitis. In this model, arthritis is induced in Balb/c mice by
administering anti-collagen antibodies and lipopolysaccharide. See
Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837. In another
example, dosing of inhibitors for the treatment of B-cell
proliferative disorders can be examined in, e.g., a human-to-mouse
xenograft model in which human B-cell lymphoma cells (e.g. Ramos
cells) are implanted into immunodefficient mice (e.g., "nude" mice)
as described in, e.g., Pagel et al. (2005), Clin Cancer Res
11(13):4857-4866 Animal models for treatment of thromboembolic
disorders are also known.
[0352] In one embodiment, the therapeutic efficacy of the compound
for one of the foregoing diseases is optimized during a course of
treatment. For example, a subject being treated optionally
undergoes a diagnostic evaluation to correlate the relief of
disease symptoms or pathologies to inhibition of in vivo Btk
activity achieved by administering a given dose of an Btk
inhibitor. Cellular assays are used to determine in vivo activity
of Btk in the presence or absence of an Btk inhibitor. For example,
since activated Btk is phosphorylated at tyrosine 223 (Y223) and
tyrosine 551 (Y551), phospho-specific immunocytochemical staining
of P-Y223 or P-Y551-positive cells are used to detect or quantify
activation of Bkt in a population of cells (e.g., by FACS analysis
of stained vs unstained cells). See, e.g., Nisitani et al. (1999),
Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the
Btk inhibitor inhibitor compound that is administered to a subject
is optionally increased or decreased as needed so as to maintain a
level of Btk inhibition optimal for treating the subject's disease
state.
Combination Treatments
[0353] The Btk inhibitor compositions described herein can also be
used in combination with other well known therapeutic reagents that
are selected for their therapeutic value for the condition to be
treated. In general, the compositions described herein and, in
embodiments where combinational therapy is employed, other agents
do not have to be administered in the same pharmaceutical
composition, and are optionally, because of different physical and
chemical characteristics, have to be administered by different
routes. The initial administration is made, for example, according
to established protocols, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration are modified.
[0354] In certain instances, it is appropriate to administer at
least one Btk inhibitor compound described herein in combination
with another therapeutic agent. By way of example only, if one of
the side effects experienced by a patient upon receiving one of the
Btk inhibitor compounds described herein is nausea, then it is
appropriate to administer an anti-nausea agent in combination with
the initial therapeutic agent. Or, by way of example only, the
therapeutic effectiveness of one of the compounds described herein
is enhanced by administration of an adjuvant (i.e., by itself the
adjuvant has minimal therapeutic benefit, but in combination with
another therapeutic agent, the overall therapeutic benefit to the
patient is enhanced). Or, by way of example only, the benefit
experienced by a patient is increased by administering one of the
compounds described herein with another therapeutic agent (which
also includes a therapeutic regimen) that also has therapeutic
benefit. In any case, regardless of the disease, disorder or
condition being treated, the overall benefit experienced by the
patient is in some embodiments simply additive of the two
therapeutic agents or in other embodiments, the patient experiences
a synergistic benefit.
[0355] The particular choice of compounds used will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment protocol.
The compounds are optionally administered concurrently (e.g.,
simultaneously, essentially simultaneously or within the same
treatment protocol) or sequentially, depending upon the nature of
the disease, disorder, or condition, the condition of the patient,
and the actual choice of compounds used. The determination of the
order of administration, and the number of repetitions of
administration of each therapeutic agent during a treatment
protocol, is based on an evaluation of the disease being treated
and the condition of the patient.
[0356] Therapeutically-effective dosages can vary when the drugs
are used in treatment combinations. Methods for experimentally
determining therapeutically-effective dosages of drugs and other
agents for use in combination treatment regimens are described in
the literature. For example, the use of metronomic dosing, i.e.,
providing more frequent, lower doses in order to minimize toxic
side effects, has been described extensively in the literature
Combination treatment further includes periodic treatments that
start and stop at various times to assist with the clinical
management of the patient.
[0357] For combination therapies described herein, dosages of the
co-administered compounds will of course vary depending on the type
of co-drug employed, on the specific drug employed, on the disease
or condition being treated and so forth. In addition, when
co-administered with one or more biologically active agents, the
compound provided herein may be administered either simultaneously
with the biologically active agent(s), or sequentially. If
administered sequentially, the attending physician will decide on
the appropriate sequence of administering protein in combination
with the biologically active agent(s).
[0358] In any case, the multiple therapeutic agents (one of which
is a compound of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein described herein) are optionally administered in any order
or even simultaneously. If simultaneously, the multiple therapeutic
agents are optionally provided in a single, unified form, or in
multiple forms (by way of example only, either as a single pill or
as two separate pills). One of the therapeutic agents may be given
in multiple doses, or both may be given as multiple doses. If not
simultaneous, the timing between the multiple doses may vary from
more than zero weeks to less than four weeks. In addition, the
combination methods, compositions and formulations are not to be
limited to the use of only two agents; the use of multiple
therapeutic combinations are also envisioned.
[0359] It is understood that the dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, can be
modified in accordance with a variety of factors. These factors
include the disorder from which the subject suffers, as well as the
age, weight, sex, diet, and medical condition of the subject. Thus,
the dosage regimen actually employed can vary widely and therefore
can deviate from the dosage regimens set forth herein.
[0360] The pharmaceutical agents which make up the combination
therapy disclosed herein may be a combined dosage form or in
separate dosage forms intended for substantially simultaneous
administration. The pharmaceutical agents that make up the
combination therapy may also be administered sequentially, with
either therapeutic compound being administered by a regimen calling
for two-step administration. The two-step administration regimen
may call for sequential administration of the active agents or
spaced-apart administration of the separate active agents. The time
period between the multiple administration steps may range from, a
few minutes to several hours, depending upon the properties of each
pharmaceutical agent, such as potency, solubility, bioavailability,
plasma half-life and kinetic profile of the pharmaceutical agent.
Circadian variation of the target molecule concentration may also
determine the optimal dose interval.
[0361] In addition, the compounds described herein also are
optionally used in combination with procedures that provide
additional or synergistic benefit to the patient. By way of example
only, patients are expected to find therapeutic and/or prophylactic
benefit in the methods described herein, wherein pharmaceutical
composition of a compound disclosed herein and/or combinations with
other therapeutics are combined with genetic testing to determine
whether that individual is a carrier of a mutant gene that is known
to be correlated with certain diseases or conditions.
[0362] In some embodiments, the compounds described herein and
combination therapies are administered before, during or after the
occurrence of a disease or condition, and the timing of
administering the composition containing a compound can vary. Thus,
for example, the compounds can be used as a prophylactic and can be
administered continuously to subjects with a propensity to develop
conditions or diseases in order to prevent the occurrence of the
disease or condition. The compounds and compositions can be
administered to a subject during or as soon as possible after the
onset of the symptoms. The administration of the compounds can be
initiated within the first 48 hours of the onset of the symptoms,
within the first 6 hours of the onset of the symptoms, or within 3
hours of the onset of the symptoms. The initial administration can
be via any route practical, such as, for example, an intravenous
injection, a bolus injection, infusion over 5 minutes to about 5
hours, a pill, a capsule, transdermal patch, buccal delivery, and
the like, or combination thereof. A compound should be administered
as soon as is practicable after the onset of a disease or condition
is detected or suspected, and for a length of time necessary for
the treatment of the disease, such as, for example, from about 1
month to about 3 months. The length of treatment can vary for each
subject, and the length can be determined using the known criteria.
For example, the compound or a formulation containing the compound
can be administered for at least 2 weeks, between about 1 month to
about 5 years, or from about 1 month to about 3 years.
Exemplary Therapeutic Agents for Use in Combination with an
Inhibitor Compound
[0363] In some embodiments, where the subject is suffering from or
at risk of suffering from an autoimmune disease, an inflammatory
disease, or an allergy disease, a Btk inhibitor compound is used in
with one or more of the following therapeutic agents in any
combination: immunosuppressants (e.g., tacrolimus, cyclosporin,
rapamicin, methotrexate, cyclophosphamide, azathioprine,
mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g.,
prednisone, cortisone acetate, prednisolone, methylprednisolone,
dexamethasone, betamethasone, triamcinolone, beclometasone,
fludrocortisone acetate, deoxycorticosterone acetate, aldosterone),
non-steroidal anti-inflammatory drugs (e.g., salicylates,
arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids,
oxicams, coxibs, or sulphonanilides), Cox-2-specific inhibitors
(e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold
thioglucose, gold thiomalate, aurofin, sulfasalazine,
hydroxychloroquinine, minocycline, TNF-.alpha. binding proteins
(e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra,
interferon-.beta., interferon-.gamma., interleukin-2, allergy
vaccines, antihistamines, antileukotrienes, beta-agonists,
theophylline, anticholinergics or other selective kinase inhibitors
(e.g p38 inhibitors, Syk inhibitors, PKC inhibitors).
[0364] In yet other embodiments, where the subject is suffering
from or at risk of suffering from a B-cell proliferative disorder
(e.g., plasma cell myeloma), the subjected is treated with a Btk
inhibitor compound in any combination with one or more other
anti-cancer agents. In some embodiments, one or more of the
anti-cancer agents are proapoptotic agents. Examples of anti-cancer
agents include, but are not limited to, any of the following:
gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic
acid (ATRA), bryostatin, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all
trans retinoic acid, doxorubicin, vincristine, etoposide,
gemcitabine, imatinib (Gleevec.RTM.), geldanamycin,
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or
PD184352, Taxol.TM., also referred to as "paclitaxel", which is a
well-known anti-cancer drug which acts by enhancing and stabilizing
microtubule formation, and analogs of Taxol.TM., such as
Taxotere.TM.. Compounds that have the basic taxane skeleton as a
common structure feature, have also been shown to have the ability
to arrest cells in the G2-M phases due to stabilized microtubules
and may be useful for treating cancer in combination with the
compounds described herein.
[0365] Further examples of anti-cancer agents for use in
combination with an Btk inhibitor compound include inhibitors of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,
wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and
antibodies (e.g., rituxan).
[0366] In further embodiments, other anti-cancer agents are
employed in combination with an Btk inhibitor compound include
Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; iimofosine; interleukin Il (including
recombinant interleukin II, or rlL2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazoie; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0367] In yet other embodiments, other anti-cancer agents are
employed in combination with an Btk inhibitor compound include:
20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0368] Yet other anticancer agents that can be employed in
combination with a Btk inhibitor compound include alkylating
agents, antimetabolites, natural products, or hormones, e.g.,
nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, etc.), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin).
[0369] Examples of natural products useful in combination with a
Btk inhibitor compound include but are not limited to vinca
alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins
(e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin,
bleomycin), enzymes (e.g., L-asparaginase), or biological response
modifiers (e.g., interferon alpha).
[0370] Examples of alkylating agents that are employed in
combination a Btk inhibitor compound in some embodiments, include,
but are not limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and
methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl
sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomusitne, semustine, streptozocin, etc.), or triazenes
(decarbazine, ete.). Examples of antimetabolites include, but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),
purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
[0371] Examples of hormones and antagonists useful in combination
with a Btk inhibitor compound include, but are not limited to,
adrenocorticosteroids (e.g., prednisone), progestins (e.g.,
hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,
leuprolide). Other agents that can be used in the methods and
compositions described herein for the treatment or prevention of
cancer include platinum coordination complexes (e.g., cisplatin,
carboblatin), anthracenedione (e.g., mitoxantrone), substituted
urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g.,
procarbazine), adrenocortical suppressant (e.g., mitotane,
aminoglutethimide).
[0372] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which are
used in some embodiments, in combination with a Btk inhibitor
compound include without limitation marketed drugs and drugs in
development.
[0373] Where the subject is suffering from or at risk of suffering
from a thromboembolic disorder (e.g., stroke), the subject, in some
embodiments is treated with a Btk inhibitor compound in any
combination with one or more other anti-thromboembolic agents.
Examples of anti-thromboembolic agents include, but are not limited
any of the following: thrombolytic agents (e.g., alteplase
anistreplase, streptokinase, urokinase, or tissue plasminogen
activator), heparin, tinzaparin, warfarin, dabigatran (e.g.,
dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux,
draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),
factor VIIa inhibitors, ticlopidine, clopidogrel, CS-747
(prasugrel, LY640315), ximelagatran, or BIBR 1048.
Pharmaceutical Composition/Formulation
[0374] Pharmaceutical compositions are formulated in a conventional
manner using one or more physiologically acceptable carriers
including excipients and auxiliaries which facilitate processing of
the active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. A summary of pharmaceutical compositions
described herein is found, for example, in Remington: The Science
and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0375] A pharmaceutical composition, as used herein, refers to a
mixture of a compound described herein, such as, for example,
compounds of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein, with other chemical components, such as carriers,
stabilizers, diluents, dispersing agents, suspending agents,
thickening agents, and/or excipients. The pharmaceutical
composition facilitates administration of the compound to an
organism. In practicing the methods of treatment or use provided
herein, therapeutically effective amounts of compounds described
herein are administered in a pharmaceutical composition to a mammal
having a disease, disorder, or condition to be treated. Preferably,
the mammal is a human. The compounds, in some embodiments, are used
singly or in combination with one or more therapeutic agents as
components of mixtures.
[0376] The pharmaceutical formulations described herein in some
embodiments, is administered to a subject by multiple
administration routes, including but not limited to, oral,
parenteral (e.g., intravenous, subcutaneous, intramuscular),
intranasal, buccal, topical, rectal, or transdermal administration
routes. The pharmaceutical formulations described herein include,
but are not limited to, aqueous liquid dispersions,
self-emulsifying dispersions, solid solutions, liposomal
dispersions, aerosols, solid dosage forms, powders, immediate
release formulations, controlled release formulations, fast melt
formulations, tablets, capsules, pills, delayed release
formulations, extended release formulations, pulsatile release
formulations, multiparticulate formulations, and mixed immediate
and controlled release formulations.
[0377] Pharmaceutical compositions including a compound described
herein are optionally manufactured in a conventional manner, such
as, by way of example only, by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes.
[0378] The pharmaceutical compositions in further embodiments,
include at least one compound described herein, such as, for
example, a compound of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein, as an active ingredient in free-acid or free-base
form, or in a pharmaceutically acceptable salt form. In addition,
the methods and pharmaceutical compositions described herein
include the use of N-oxides, crystalline forms (also known as
polymorphs), as well as active metabolites of these compounds
having the same type of activity. In some situations, compounds
exist as tautomers. All tautomers are included within the scope of
the compounds presented herein. By way of example only, in one
embodiment, the tautomeric form of the compound of Formula (I) has
the structure of Formula (IA):
##STR00424##
wherein:
[0379] L is a bond, CH.sub.2, O, NR.sub.2, S, CO, C.dbd.NR.sub.2,
or C.dbd.N--OR.sub.2;
[0380] T is a bond, C.sub.1-C.sub.6alkylene, or
C.sub.3-C.sub.6cycloalkylene;
[0381] A is aryl or heteroaryl wherein aryl or heteroaryl is
optionally substituted with at least one R.sub.1;
[0382] Y and Z are each independently selected from H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.2-C.sub.6heteroalkenyl, C.sub.4-C.sub.10heterocycloalkenyl
and C.sub.2-C.sub.10heterocycloalkyl, wherein C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6heteroalkyl, C.sub.2-C.sub.6heteroalkenyl,
C.sub.4-C.sub.10heterocycloalkenyl and
C.sub.2-C.sub.10heterocycloalkyl are optionally substituted with at
least one R.sub.1; or
[0383] Y and Z together with the carbon atom to which they are
attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X;
[0384] wherein when Y and Z together with the carbon atom to which
they are attached form a nitrogen atom-containing
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl, the nitrogen atom of the
C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl is optionally substituted with W
and the carbon atoms of the C.sub.2-C.sub.10heterocycloalkyl or
C.sub.4-C.sub.10heterocycloalkenyl are optionally substituted with
at least one X;
[0385] W is selected from J, C(.dbd.O)-J, C(.dbd.O)O-J,
C(.dbd.O)NR.sub.2-J, C(.dbd.NR.sub.2)-J,
--C(.dbd.NR.sub.2)NR.sub.2-J, C(.dbd.N--OR.sub.3)-J, C(.dbd.S)-J,
S(.dbd.O).sub.v-J, S(.dbd.O).sub.vO-J;
[0386] X is F, Cl, Br, I, --CN, --NO.sub.2, --OR.sub.3,
--N(R.sub.2).sub.2, --SR.sub.2, --C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)R.sub.2, --NR.sub.2C(.dbd.O)N(R.sub.2).sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --C(.dbd.NR.sub.2)N(R.sub.2).sub.2,
--C(.dbd.N--OR.sub.2)N(R.sub.2).sub.2, --C(.dbd.S)R.sub.2,
--S(.dbd.O).sub.vR.sub.2, --OS(.dbd.O).sub.vR.sub.2,
--NR.sub.2C(.dbd.O)OR.sub.2, --NR.sub.2S(.dbd.O).sub.vR.sub.2;
[0387] J is --C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkene, C.sub.2-C.sub.6heterocycloalkyl, aryl, or
heteroaryl optionally substituted with at least one R.sub.1;
[0388] v is 1 or 2;
[0389] R.sub.b is NH.sub.2, OH, OSO.sub.3H or NHSO.sub.3H;
[0390] R.sub.1 is selected from F, Cl, Br, I, --CN, --NO.sub.2,
--SR.sub.2, --OR.sub.3, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl,
--OC.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
--NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2N(R.sub.2).sub.2, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)NR.sub.2S(.dbd.O).sub.2R.sub.2,
--S(.dbd.O).sub.2NR.sub.2C(.dbd.O)R.sub.2, --N(R.sub.2).sub.2,
wherein optionally the two R.sub.2 groups of N(R.sub.2).sub.2 and
the nitrogen atom to which they are attached form a C.sub.2-C.sub.6
heterocycloalkyl ring, --NR.sub.2C(.dbd.O)R.sub.2,
--NR.sub.2C(.dbd.O)N(R.sub.2).sub.2, --CO.sub.2R.sub.2,
--C(.dbd.O)R.sub.2, --OC(.dbd.O)R.sub.2,
--C(.dbd.O)N(R.sub.2).sub.2, --S(.dbd.O)R.sub.2,
--S(.dbd.O).sub.2R.sub.2, --SO.sub.3H, and at least one amino acid
fragment;
[0391] R.sub.2 is H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6hydroxyalkyl, or
C.sub.3-C.sub.6cycloalkyl;
[0392] R.sub.3 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, or SO.sub.3H; or a pharmaceutically
acceptable salt, solvate, or tautomeric form thereof.
[0393] In one embodiment, is a compound of Formula (IA) wherein
R.sub.b is NH.sub.2. In another embodiment, is a compound of
Formula (IA) wherein L is O and A is an aryl group. In a further
embodiment, is a compound of Formula (IA) wherein T is a bond or
CH.sub.2. In another embodiment, Y and Z together with the carbon
atom to which they are attached form a C.sub.3-C.sub.10cycloalkyl,
C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, wherein
C.sub.3-C.sub.10cycloalkyl, C.sub.2-C.sub.10heterocycloalkyl,
C.sub.4-C.sub.10heterocycloalkenyl, aryl, or heteroaryl, are
optionally substituted with at least one X.
[0394] Additionally, the compounds described herein can exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also
considered to be disclosed herein.
[0395] A "carrier" or "carrier materials" includes excipients in
pharmaceutics and is selected on the basis of compatibility with
compounds disclosed herein, such as, compounds of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) and the release
profile properties of the desired dosage form. Exemplary carrier
materials include, e.g., binders, suspending agents, disintegration
agents, filling agents, surfactants, solubilizers, stabilizers,
lubricants, wetting agents, diluents, and the like. See, e.g.,
Remington: The Science and Practice of Pharmacy, Nineteenth Ed
(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkins 1999).
[0396] A "measurable serum concentration" or "measurable plasma
concentration" describes the blood serum or blood plasma
concentration, typically measured in mg, .mu.g, or ng of
therapeutic agent per ml, dl, or 1 of blood serum, absorbed into
the bloodstream after administration. As used herein, measurable
plasma concentrations are typically measured in ng/ml or
.mu.g/ml.
[0397] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
a site of action. "Pharmacokinetics" refers to the factors which
determine the attainment and maintenance of the appropriate
concentration of drug at a site of action.
[0398] "Steady state," as used herein, is when the amount of drug
administered is equal to the amount of drug eliminated within one
dosing interval resulting in a plateau or constant plasma drug
exposure.
[0399] Dosage Forms
[0400] Moreover, the pharmaceutical compositions described herein,
which include a compound of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), or (IIID) are, in some embodiments, formulated into
any suitable dosage form, including but not limited to, aqueous
oral dispersions, liquids, gels, syrups, elixirs, slurries,
suspensions and the like, for oral ingestion by a patient to be
treated, solid oral dosage forms, aerosols, controlled release
formulations, fast melt formulations, effervescent formulations,
lyophilized formulations, tablets, powders, pills, dragees,
capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, multiparticulate
formulations, and mixed immediate release and controlled release
formulations.
[0401] The pharmaceutical solid dosage forms described herein
optionally include a compound described herein and one or more
pharmaceutically acceptable additives such as a compatible carrier,
binder, filling agent, suspending agent, flavoring agent,
sweetening agent, disintegrating agent, dispersing agent,
surfactant, lubricant, colorant, diluent, solubilizer, moistening
agent, plasticizer, stabilizer, penetration enhancer, wetting
agent, anti-foaming agent, antioxidant, preservative, or one or
more combination thereof. In still other aspects, using standard
coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000), a film coating is
provided around the formulation of the compound of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), or (IIID) In one embodiment,
some or all of the particles of the compound of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) are coated. In
another embodiment, some or all of the particles of the compound of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
are microencapsulated. In still another embodiment, the particles
of the compound of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) are not microencapsulated and are uncoated.
[0402] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipient with one or more of the
compounds described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients include, for example, fillers such as
sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth,
methylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or
others such as: polyvinylpyrrolidone (PVP or povidone) or calcium
phosphate. If desired, disintegrating agents may be added, such as
the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar,
or alginic acid or a salt thereof such as sodium alginate.
[0403] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol
gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0404] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0405] In some embodiments, the solid dosage forms disclosed herein
may be in the form of a tablet, (including a suspension tablet, a
fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet),
a pill, a powder (including a sterile packaged powder, a
dispensable powder, or an effervescent powder) a capsule (including
both soft or hard capsules, e.g., capsules made from animal-derived
gelatin or plant-derived HPMC, or "sprinkle capsules"), solid
dispersion, solid solution, bioerodible dosage form, controlled
release formulations, pulsatile release dosage forms,
multiparticulate dosage forms, pellets, granules, or an aerosol. In
other embodiments, the pharmaceutical formulation is in the form of
a powder. In still other embodiments, the pharmaceutical
formulation is in the form of a tablet, including but not limited
to, a fast-melt tablet. Additionally, pharmaceutical formulations
described herein may be administered as a single capsule or in
multiple capsule dosage form. In some embodiments, the
pharmaceutical formulation is administered in two, or three, or
four, capsules or tablets.
[0406] In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared by mixing
particles of a compound of any of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) with one or more pharmaceutical
excipients to form a bulk blend composition. When referring to
these bulk blend compositions as homogeneous, it is meant that the
particles of the compound of any of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), (IIID), or (IV) are dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective unit dosage forms, such as
tablets, pills, and capsules. The individual unit dosages may also
include film coatings, which disintegrate upon oral ingestion or
upon contact with diluent. These formulations can be manufactured
by conventional pharmacological techniques.
[0407] Conventional pharmacological techniques include, e.g., one
or a combination of methods: (1) dry mixing, (2) direct
compression, (3) milling, (4) dry or non-aqueous granulation, (5)
wet granulation, or (6) fusion. See, e.g., Lachman et al., The
Theory and Practice of Industrial Pharmacy (1986). Other methods
include, e.g., spray drying, pan coating, melt granulation,
granulation, fluidized bed spray drying or coating (e.g., wurster
coating), tangential coating, top spraying, tableting, extruding
and the like.
[0408] The pharmaceutical solid dosage forms described herein can
include a compound described herein and one or more
pharmaceutically acceptable additives such as a compatible carrier,
binder, filling agent, suspending agent, flavoring agent,
sweetening agent, disintegrating agent, dispersing agent,
surfactant, lubricant, colorant, diluent, solubilizer, moistening
agent, plasticizer, stabilizer, penetration enhancer, wetting
agent, anti-foaming agent, antioxidant, preservative, or one or
more combination thereof. In still other aspects, using standard
coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000), a film coating is
provided around the formulation of the compound of any of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), or (IIID) In one
embodiment, some or all of the particles of the compound of any of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
are coated. In another embodiment, some or all of the particles of
the compound of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) are microencapsulated. In still another
embodiment, the particles of the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) are not
microencapsulated and are uncoated.
[0409] Suitable carriers for use in the solid dosage forms
described herein include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate,
dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
monoglyceride, diglyceride, pregelatinized starch,
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate
stearate, sucrose, microcrystalline cellulose, lactose, mannitol
and the like.
[0410] Suitable filling agents for use in the solid dosage forms
described herein include, but are not limited to, lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, cellulose powder, dextrose,
dextrates, dextran, starches, pregelatmized starch,
hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS),
sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0411] In order to release the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) from a solid
dosage form matrix as efficiently as possible, disintegrants are
often used in the formulation, especially when the dosage forms are
compressed with binder. Disintegrants help rupturing the dosage
form matrix by swelling or capillary action when moisture is
absorbed into the dosage form. Suitable disintegrants for use in
the solid dosage forms described herein include, but are not
limited to, natural starch such as corn starch or potato starch, a
pregelatinized starch such as National 1551 or Amijel.RTM., or
sodium starch glycolate such as Promogel.RTM. or Explotab.RTM., a
cellulose such as a wood product, methylcrystalline cellulose,
e.g., Avicel.RTM., Avicel.RTM. PH101, Avicel.RTM. PH102,
Avicel.RTM. PH105, Elcema.RTM. P100, Emcocel.RTM., Vivacel.RTM.,
Ming Tia.RTM., and Solka-Floc.RTM., methylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked
sodium carboxymethylcellulose (Ac-Di-Sol.RTM.), cross-linked
carboxymethylcellulose, or cross-linked croscarmellose, a
cross-linked starch such as sodium starch glycolate, a cross-linked
polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone,
alginate such as alginic acid or a salt of alginic acid such as
sodium alginate, a clay such as Veegum.RTM. HV (magnesium aluminum
silicate), a gum such as agar, guar, locust bean, Karaya, pectin,
or tragacanth, sodium starch glycolate, bentonite, a natural
sponge, a surfactant, a resin such as a cation-exchange resin,
citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in
combination starch, and the like.
[0412] Binders impart cohesiveness to solid oral dosage form
formulations: for powder filled capsule formulation, they aid in
plug formation that can be filled into soft or hard shell capsules
and for tablet formulation, they ensure the tablet remaining intact
after compression and help assure blend uniformity prior to a
compression or fill step. Materials suitable for use as binders in
the solid dosage forms described herein include, but are not
limited to, carboxymethylcellulose, methylcellulose (e.g.,
Methocel.RTM.), hydroxypropylmethylcellulose (e.g. Hypromellose USP
Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate
(Aqoate HS-LF and HS), hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.),
microcrystalline dextrose, amylose, magnesium aluminum silicate,
polysaccharide acids, bentonites, gelatin,
polyvinylpyrrolidone/vinyl acetate copolymer, crosspovidone,
povidone, starch, pregelatinized starch, tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.),
lactose, a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone
(e.g., Povidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10,
and Povidone.RTM. K-12), larch arabogalactan, Veegum.RTM.,
polyethylene glycol, waxes, sodium alginate, and the like.
[0413] In general, binder levels of 20-70% are used in
powder-filled gelatin capsule formulations. Binder usage level in
tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of other excipients such
as fillers which itself can act as moderate binder. Formulators
skilled in art can determine the binder level for the formulations,
but binder usage level of up to 70% in tablet formulations is
common.
[0414] Suitable lubricants or glidants for use in the solid dosage
forms described herein include, but are not limited to, stearic
acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumarate, alkali-metal and alkaline earth metal salts, such as
aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates,
magnesium stearate, zinc stearate, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
Carbowax.TM., PEG 4000, PEG 5000, PEG 6000, propylene glycol,
sodium oleate, glyceryl behenate, glyceryl palmitostearate,
glyceryl benzoate, magnesium or sodium lauryl sulfate, and the
like.
[0415] Suitable diluents for use in the solid dosage forms
described herein include, but are not limited to, sugars (including
lactose, sucrose, and dextrose), polysaccharides (including
dextrates and maltodextrin), polyols (including mannitol, xylitol,
and sorbitol), cyclodextrins and the like.
[0416] The term "non water-soluble diluent" represents compounds
typically used in the formulation of pharmaceuticals, such as
calcium phosphate, calcium sulfate, starches, modified starches and
microcrystalline cellulose, and microcellulose (e.g., having a
density of about 0.45 g/cm.sup.3, e.g. Avicel, powdered cellulose),
and talc.
[0417] Suitable wetting agents for use in the solid dosage forms
described herein include, for example, oleic acid, glyceryl
monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds
(e.g., Polyquat 10.RTM.), sodium oleate, sodium lauryl sulfate,
magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and
the like.
[0418] Suitable surfactants for use in the solid dosage forms
described herein include, for example, sodium lauryl sulfate,
sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like.
[0419] Suitable suspending agents for use in the solid dosage forms
described here include, but are not limited to,
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to
about 6000, or about 3350 to about 4000, or about 7000 to about
5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, polysorbate-80,
hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[0420] Suitable antioxidants for use in the solid dosage forms
described herein include, for example, e.g., butylated
hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[0421] It should be appreciated that there is considerable overlap
between additives used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of additives that can be
included in solid dosage forms described herein. The amounts of
such additives can be readily determined by one skilled in the art,
according to the particular properties desired.
[0422] In other embodiments, one or more layers of the
pharmaceutical formulation are plasticized. Illustratively, a
plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0.01% to about 50% by
weight (w/w) of the coating composition. Plasticizers include, but
are not limited to, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides, triacetin, polypropylene
glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate,
stearic acid, stearol, stearate, and castor oil.
[0423] Compressed tablets are solid dosage forms prepared by
compacting the bulk blend of the formulations described above. In
various embodiments, compressed tablets which are designed to
dissolve in the mouth will include one or more flavoring agents. In
other embodiments, the compressed tablets will include a film
surrounding the final compressed tablet. In some embodiments, the
film coating can provide a delayed release of the compound of any
of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
from the formulation. In other embodiments, the film coating aids
in patient compliance (e.g., Opadry.RTM. coatings or sugar
coating). Film coatings including Opadry.RTM. typically range from
about 1% to about 3% of the tablet weight. In other embodiments,
the compressed tablets include one or more excipients.
[0424] A capsule may be prepared, for example, by placing the bulk
blend of the formulation of the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) described
above, inside of a capsule. In some embodiments, the formulations
(non-aqueous suspensions and solutions) are placed in a soft
gelatin capsule. In other embodiments, the formulations are placed
in standard gelatin capsules or non-gelatin capsules such as
capsules comprising HPMC. In other embodiments, the formulation is
placed in a sprinkle capsule, wherein the capsule may be swallowed
whole or the capsule may be opened and the contents sprinkled on
food prior to eating. In some embodiments, the therapeutic dose is
split into multiple (e.g., two, three, or four) capsules. In some
embodiments, the entire dose of the formulation is delivered in a
capsule form.
[0425] In various embodiments, the particles of the compound of any
of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
and one or more excipients are dry blended and compressed into a
mass, such as a tablet, having a hardness sufficient to provide a
pharmaceutical composition that substantially disintegrates within
less than about 30 minutes, less than about 35 minutes, less than
about 40 minutes, less than about 45 minutes, less than about 50
minutes, less than about 55 minutes, or less than about 60 minutes,
after oral administration, thereby releasing the formulation into
the gastrointestinal fluid.
[0426] In another aspect, dosage forms may include
microencapsulated formulations. In some embodiments, one or more
other compatible materials are present in the microencapsulation
material. Exemplary materials include, but are not limited to, pH
modifiers, erosion facilitators, anti-foaming agents, antioxidants,
flavoring agents, and carrier materials such as binders, suspending
agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers, lubricants, wetting agents, and
diluents.
[0427] Materials useful for the microencapsulation described herein
include materials compatible with compounds of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) which
sufficiently isolate the compound of any of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) from other
non-compatible excipients. Materials compatible with compounds of
any of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or
(IV) are those that delay the release of the compounds of any of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) in
vivo.
[0428] Exemplary microencapsulation materials useful for delaying
the release of the formulations including compounds described
herein, include, but are not limited to, hydroxypropyl cellulose
ethers (HPC) such as Klucel.RTM. or Nisso HPC, low-substituted
hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl
cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat.RTM.,
Metolose SR, Methocel.RTM.-E, Opadry YS, PrimaFlo, Benecel MP824,
and Benecel MP843, methylcellulose polymers such as
Methocel.RTM.-A, hydroxypropylmethylcellulose acetate stearate
Aqoat (HF-LS, HF-LG, HF-MS) and Metolose.RTM., Ethylcelluloses (EC)
and mixtures thereof such as E461, Ethocel.RTM., Aqualon.RTM.-EC,
Surelease.RTM., Polyvinyl alcohol (PVA) such as Opadry AMB,
hydroxyethylcelluloses such as Natrosol.RTM.,
carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as Aqualon.RTM.-CMC, polyvinyl alcohol and polyethylene glycol
co-polymers such as Kollicoat IR.RTM., monoglycerides (Myverol),
triglycerides (KLX), polyethylene glycols, modified food starch,
acrylic polymers and mixtures of acrylic polymers with cellulose
ethers such as Eudragit.RTM. EPO, Eudragit.RTM. L30D-55,
Eudragit.RTM. FS 30D Eudragit.RTM. L100-55, Eudragit.RTM. L100,
Eudragit.RTM. S100, Eudragit.RTM. RD100, Eudragit.RTM. E100,
Eudragit.RTM. L12.5, Eudragit.RTM. S12.5, Eudragit.RTM. NE30D, and
Eudragit.RTM. NE 40D, cellulose acetate phthalate, sepiflms such as
mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of
these materials.
[0429] In still other embodiments, plasticizers such as
polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450,
PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,
and triacetin are incorporated into the microencapsulation
material. In other embodiments, the microencapsulating material
useful for delaying the release of the pharmaceutical compositions
is from the USP or the National Formulary (NF). In yet other
embodiments, the microencapsulation material is Klucel. In still
other embodiments, the microencapsulation material is methocel.
[0430] Microencapsulated compounds of any of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) may be formulated by
methods known by one of ordinary skill in the art. Such known
methods include, e.g., spray drying processes, spinning
disk-solvent processes, hot melt processes, spray chilling methods,
fluidized bed, electrostatic deposition, centrifugal extrusion,
rotational suspension separation, polymerization at liquid-gas or
solid-gas interface, pressure extrusion, or spraying solvent
extraction bath. In addition to these, several chemical techniques,
e.g., complex coacervation, solvent evaporation, polymer-polymer
incompatibility, interfacial polymerization in liquid media, in
situ polymerization, in-liquid drying, and desolvation in liquid
media could also be used. Furthermore, other methods such as roller
compaction, extrusion/spheronization, coacervation, or nanoparticle
coating may also be used.
[0431] In one embodiment, the particles of compounds of any of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
are microencapsulated prior to being formulated into one of the
above forms. In still another embodiment, some or most of the
particles are coated prior to being further formulated by using
standard coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000).
[0432] In other embodiments, the solid dosage formulations of the
compounds of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) are plasticized (coated) with one or more
layers. Illustratively, a plasticizer is generally a high boiling
point solid or liquid. Suitable plasticizers can be added from
about 0.01% to about 50% by weight (w/w) of the coating
composition. Plasticizers include, but are not limited to, diethyl
phthalate, citrate esters, polyethylene glycol, glycerol,
acetylated glycerides, triacetin, polypropylene glycol,
polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic
acid, stearol, stearate, and castor oil.
[0433] In other embodiments, a powder including the formulations
with a compound of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) described herein, may be formulated to
include one or more pharmaceutical excipients and flavors. Such a
powder may be prepared, for example, by mixing the formulation and
optional pharmaceutical excipients to form a bulk blend
composition. Additional embodiments also include a suspending agent
and/or a wetting agent. This bulk blend is uniformly subdivided
into unit dosage packaging or multi-dosage packaging units.
[0434] In still other embodiments, effervescent powders are also
prepared in accordance with the present disclosure. Effervescent
salts have been used to disperse medicines in water for oral
administration. Effervescent salts are granules or coarse powders
containing a medicinal agent in a dry mixture, usually composed of
sodium bicarbonate, citric acid and/or tartaric acid. When salts of
the compositions described herein are added to water, the acids and
the base react to liberate carbon dioxide gas, thereby causing
"effervescence." Examples of effervescent salts include, e.g., the
following ingredients: sodium bicarbonate or a mixture of sodium
bicarbonate and sodium carbonate, citric acid and/or tartaric acid.
Any acid-base combination that results in the liberation of carbon
dioxide can be used in place of the combination of sodium
bicarbonate and citric and tartaric acids, as long as the
ingredients were suitable for pharmaceutical use and result in a pH
of about 6.0 or higher.
[0435] In other embodiments, the formulations described herein,
which include a compound of Formula (A), are solid dispersions.
Methods of producing such solid dispersions are known in the art
and include, but are not limited to, for example, U.S. Pat. Nos.
4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S.
Pub. Appl 2004/0013734, each of which is specifically incorporated
by reference. In still other embodiments, the formulations
described herein are solid solutions. Solid solutions incorporate a
substance together with the active agent and other excipients such
that heating the mixture results in dissolution of the drug and the
resulting composition is then cooled to provide a solid blend which
can be further formulated or directly added to a capsule or
compressed into a tablet. Methods of producing such solid solutions
are known in the art and include, but are not limited to, for
example, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each
of which is specifically incorporated by reference.
[0436] The pharmaceutical solid oral dosage forms including
formulations described herein, which include a compound of any of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
can be further formulated to provide a controlled release of the
compound of Formula (A). Controlled release refers to the release
of the compound of any of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) from a dosage form in which it is
incorporated according to a desired profile over an extended period
of time. Controlled release profiles include, for example,
sustained release, prolonged release, pulsatile release, and
delayed release profiles. In contrast to immediate release
compositions, controlled release compositions allow delivery of an
agent to a subject over an extended period of time according to a
predetermined profile. Such release rates can provide
therapeutically effective levels of agent for an extended period of
time and thereby provide a longer period of pharmacologic response
while minimizing side effects as compared to conventional rapid
release dosage forms. Such longer periods of response provide for
many inherent benefits that are not achieved with the corresponding
short acting, immediate release preparations.
[0437] In some embodiments, the solid dosage forms described herein
can be formulated as enteric coated delayed release oral dosage
forms, i.e., as an oral dosage form of a pharmaceutical composition
as described herein which utilizes an enteric coating to affect
release in the small intestine of the gastrointestinal tract. The
enteric coated dosage form may be a compressed or molded or
extruded tablet/mold (coated or uncoated) containing granules,
powder, pellets, beads or particles of the active ingredient and/or
other composition components, which are themselves coated or
uncoated. The enteric coated oral dosage form may also be a capsule
(coated or uncoated) containing pellets, beads or granules of the
solid carrier or the composition, which are themselves coated or
uncoated.
[0438] The term "delayed release" as used herein refers to the
delivery so that the release can be accomplished at some generally
predictable location in the intestinal tract more distal to that
which would have been accomplished if there had been no delayed
release alterations. In some embodiments the method for delay of
release is coating. Any coatings should be applied to a sufficient
thickness such that the entire coating does not dissolve in the
gastrointestinal fluids at pH below about 5, but does dissolve at
pH about 5 and above. It is expected that any anionic polymer
exhibiting a pH-dependent solubility profile can be used as an
enteric coating in the methods and compositions described herein to
achieve delivery to the lower gastrointestinal tract. In some
embodiments the polymers described herein are anionic carboxylic
polymers. In other embodiments, the polymers and compatible
mixtures thereof, and some of their properties, include, but are
not limited to:
[0439] Shellac, also called purified lac, a refined product
obtained from the resinous secretion of an insect. This coating
dissolves in media of pH>7;
[0440] Acrylic polymers. The performance of acrylic polymers
(primarily their solubility in biological fluids) can vary based on
the degree and type of substitution. Examples of suitable acrylic
polymers include methacrylic acid copolymers and ammonium
methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm Pharma) are available as solubilized in organic solvent,
aqueous dispersion, or dry powders. The Eudragit series RL, NE, and
RS are insoluble in the gastrointestinal tract but are permeable
and are used primarily for colonic targeting. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are
insoluble in stomach and dissolve in the intestine;
[0441] Cellulose Derivatives. Examples of suitable cellulose
derivatives are: ethyl cellulose; reaction mixtures of partial
acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type of substitution.
Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric
(FMC) is an aqueous based system and is a spray dried CAP
psuedolatex with particles <1 Mm. Other components in Aquateric
can include pluronics, Tweens, and acetylated monoglycerides. Other
suitable cellulose derivatives include: cellulose acetate
trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);
hydroxypropylmethyl cellulose phthalate (HPMCP);
hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin
Etsu)). The performance can vary based on the degree and type of
substitution. For example, HPMCP such as, HP-50, HP-55, HP-555,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions;
[0442] Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in
pH>5, and it is much less permeable to water vapor and gastric
fluids.
[0443] In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0444] Colorants, detackifiers, surfactants, antifoaming agents,
lubricants (e.g., carnuba wax or PEG) may be added to the coatings
besides plasticizers to solubilize or disperse the coating
material, and to improve coating performance and the coated
product.
[0445] In other embodiments, the formulations described herein,
which include a compound of Formula (A), are delivered using a
pulsatile dosage form. A pulsatile dosage form is capable of
providing one or more immediate release pulses at predetermined
time points after a controlled lag time or at specific sites.
Pulsatile dosage forms including the formulations described herein,
which include a compound of any of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) may be administered using a variety
of pulsatile formulations known in the art. For example, such
formulations include, but are not limited to, those described in
U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each
of which is specifically incorporated by reference. Other pulsatile
release dosage forms suitable for use with the present formulations
include, but are not limited to, for example, U.S. Pat. Nos.
4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and
5,837,284, all of which are specifically incorporated by reference.
In one embodiment, the controlled release dosage form is pulsatile
release solid oral dosage form including at least two groups of
particles, (i.e. multiparticulate) each containing the formulation
described herein. The first group of particles provides a
substantially immediate dose of the compound of any of Formula (I),
(IA), (II), (IRA), (IIIB), (IIIC), (IIID), or (IV) upon ingestion
by a mammal. The first group of particles can be either uncoated or
include a coating and/or sealant. The second group of particles
includes coated particles, which includes from about 2% to about
75%, from about 2.5% to about 70%, or from about 40% to about 70%,
by weight of the total dose of the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) in said
formulation, in admixture with one or more binders. The coating
includes a pharmaceutically acceptable ingredient in an amount
sufficient to provide a delay of from about 2 hours to about 7
hours following ingestion before release of the second dose.
Suitable coatings include one or more differentially degradable
coatings such as, by way of example only, pH sensitive coatings
(enteric coatings) such as acrylic resins (e.g., Eudragit.RTM. EPO,
Eudragit.RTM. L30D-55, Eudragit.RTM. FS 30D Eudragit.RTM. L100-55,
Eudragit.RTM. L100, Eudragit.RTM. 5100, Eudragit.RTM. RD100,
Eudragit.RTM. E100, Eudragit.RTM. L12.5, Eudragit.RTM. 512.5, and
Eudragit.RTM. NE30D, Eudragit.RTM. NE 40D.RTM.) either alone or
blended with cellulose derivatives, e.g., ethylcellulose, or
non-enteric coatings having variable thickness to provide
differential release of the formulation that includes a compound of
any of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), or
(IIID)
[0446] Many other types of controlled release systems known to
those of ordinary skill in the art and are suitable for use with
the formulations described herein. Examples of such delivery
systems include, e.g., polymer-based systems, such as polylactic
and polyglycolic acid, polyanhydrides and polycaprolactone; porous
matrices, nonpolymer-based systems that are lipids, including
sterols, such as cholesterol, cholesterol esters and fatty acids,
or neutral fats, such as mono-, di- and triglycerides; hydrogel
release systems; silastic systems; peptide-based systems; wax
coatings, bioerodible dosage forms, compressed tablets using
conventional binders and the like. See, e.g., Liberman et al.,
Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990);
Singh et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd
Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848,
4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105,
5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is
specifically incorporated by reference.
[0447] In some embodiments, pharmaceutical formulations are
provided that include particles of the compounds of any of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) described
herein and at least one dispersing agent or suspending agent for
oral administration to a subject. The formulations may be a powder
and/or granules for suspension, and upon admixture with water, a
substantially uniform suspension is obtained.
[0448] Liquid formulation dosage forms for oral administration can
be aqueous suspensions selected from the group including, but not
limited to, pharmaceutically acceptable aqueous oral dispersions,
emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh
et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed.,
pp. 754-757 (2002). In addition to the particles of compound of
Formula (A), the liquid dosage forms may include additives, such
as: (a) disintegrating agents; (b) dispersing agents; (c) wetting
agents; (d) at least one preservative, (e) viscosity enhancing
agents, (f) at least one sweetening agent, and (g) at least one
flavoring agent. In some embodiments, the aqueous dispersions can
further include a crystalline inhibitor.
[0449] The aqueous suspensions and dispersions described herein can
remain in a homogenous state, as defined in The USP Pharmacists'
Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The
homogeneity should be determined by a sampling method consistent
with regard to determining homogeneity of the entire composition.
In one embodiment, an aqueous suspension can be re-suspended into a
homogenous suspension by physical agitation lasting less than 1
minute. In another embodiment, an aqueous suspension can be
re-suspended into a homogenous suspension by physical agitation
lasting less than 45 seconds. In yet another embodiment, an aqueous
suspension can be re-suspended into a homogenous suspension by
physical agitation lasting less than 30 seconds. In still another
embodiment, no agitation is necessary to maintain a homogeneous
aqueous dispersion.
[0450] Examples of disintegrating agents for use in the aqueous
suspensions and dispersions include, but are not limited to, a
starch, e.g., a natural starch such as corn starch or potato
starch, a pregelatinized starch such as National 1551 or
Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM.; a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH 101,
Avicel.RTM. PH102, Avicel.RTM. PH1105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose; a cross-linked starch such as sodium starch
glycolate; a cross-linked polymer such as crosspovidone; a
cross-linked polyvinylpyrrolidone; alginate such as alginic acid or
a salt of alginic acid such as sodium alginate; a clay such as
Veegum.RTM. HV (magnesium aluminum silicate); a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth; sodium starch
glycolate; bentonite; a natural sponge; a surfactant; a resin such
as a cation-exchange resin; citrus pulp; sodium lauryl sulfate;
sodium lauryl sulfate in combination starch; and the like.
[0451] In some embodiments, the dispersing agents suitable for the
aqueous suspensions and dispersions described herein are known in
the art and include, for example, hydrophilic polymers,
electrolytes, Tween.RTM. 60 or 80, PEG, polyvinylpyrrolidone (PVP;
commercially known as Plasdone.RTM.), and the carbohydrate-based
dispersing agents such as, for example, hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L),
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,
hydroxypropylmethyl-cellulose acetate stearate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer
(Plasdone.RTM., e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)). In other embodiments, the dispersing agent is selected from
a group not comprising one of the following agents: hydrophilic
polymers; electrolytes; Tween.RTM. 60 or 80; PEG;
polyvinylpyrrolidone (PVP); hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L);
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and
Pharmacoat.RTM. USP 2910 (Shin-Etsu)); carboxymethylcellulose
sodium; methylcellulose; hydroxyethylcellulose;
hydroxypropylmethyl-cellulose phthalate;
hydroxypropylmethyl-cellulose acetate stearate; non-crystalline
cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl
alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with
ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics
F68.RTM., F88.RTM., and F108.RTM., which are block copolymers of
ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM.).
[0452] Wetting agents suitable for the aqueous suspensions and
dispersions described herein are known in the art and include, but
are not limited to, cetyl alcohol, glycerol monostearate,
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
available Tweens.RTM. such as e.g., Tween 20.RTM. and Tween 80.RTM.
(ICI Specialty Chemicals)), and polyethylene glycols (e.g.,
Carbowaxs 3350.RTM. and 1450.RTM., and Carbopol 934.RTM. (Union
Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,
sorbitan monolaurate, triethanolamine oleate, polyoxyethylene
sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium
oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin
E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and
the like.
[0453] Suitable preservatives for the aqueous suspensions or
dispersions described herein include, for example, potassium
sorbate, parabens (e.g., methylparaben and propylparaben), benzoic
acid and its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl alcohol or benzyl alcohol,
phenolic compounds such as phenol, or quaternary compounds such as
benzalkonium chloride. Preservatives, as used herein, are
incorporated into the dosage form at a concentration sufficient to
inhibit microbial growth.
[0454] Suitable viscosity enhancing agents for the aqueous
suspensions or dispersions described herein include, but are not
limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
Plasdon.RTM. S-630, carbomer, polyvinyl alcohol, alginates, acacia,
chitosans and combinations thereof. The concentration of the
viscosity enhancing agent will depend upon the agent selected and
the viscosity desired.
[0455] Examples of sweetening agents suitable for the aqueous
suspensions or dispersions described herein include, for example,
acacia syrup, acesulfame K, alitame, anise, apple, aspartame,
banana, Bavarian cream, berry, black currant, butterscotch, calcium
citrate, camphor, caramel, cherry, cherry cream, chocolate,
cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton
candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate (MagnaSweet.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin,
tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof. In one embodiment, the aqueous liquid dispersion
can comprise a sweetening agent or flavoring agent in a
concentration ranging from about 0.001% to about 1.0% the volume of
the aqueous dispersion. In another embodiment, the aqueous liquid
dispersion can comprise a sweetening agent or flavoring agent in a
concentration ranging from about 0.005% to about 0.5% the volume of
the aqueous dispersion. In yet another embodiment, the aqueous
liquid dispersion can comprise a sweetening agent or flavoring
agent in a concentration ranging from about 0.01% to about 1.0% the
volume of the aqueous dispersion.
[0456] In addition to the additives listed above, the liquid
formulations can also include inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents, and
emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide,
sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol
esters, taurocholic acid, phosphotidylcholine, oils, such as
cottonseed oil, groundnut oil, corn germ oil, olive oil, castor
oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols, fatty acid esters of sorbitan, or mixtures of
these substances, and the like.
[0457] In some embodiments, the pharmaceutical formulations
described herein can be self-emulsifying drug delivery systems
(SEDDS). Emulsions are dispersions of one immiscible phase in
another, usually in the form of droplets. Generally, emulsions are
created by vigorous mechanical dispersion. SEDDS, as opposed to
emulsions or microemulsions, spontaneously form emulsions when
added to an excess of water without any external mechanical
dispersion or agitation. An advantage of SEDDS is that only gentle
mixing is required to distribute the droplets throughout the
solution. Additionally, water or the aqueous phase can be added
just prior to administration, which ensures stability of an
unstable or hydrophobic active ingredient. Thus, the SEDDS provides
an effective delivery system for oral and parenteral delivery of
hydrophobic active ingredients. SEDDS may provide improvements in
the bioavailability of hydrophobic active ingredients. Methods of
producing self-emulsifying dosage forms are known in the art and
include, but are not limited to, for example, U.S. Pat. Nos.
5,858,401, 6,667,048, and 6,960,563, each of which is specifically
incorporated by reference.
[0458] It is to be appreciated that there is overlap between the
above-listed additives used in the aqueous dispersions or
suspensions described herein, since a given additive is often
classified differently by different practitioners in the field, or
is commonly used for any of several different functions. Thus, the
above-listed additives should be taken as merely exemplary, and not
limiting, of the types of additives that can be included in
formulations described herein. The amounts of such additives can be
readily determined by one skilled in the art, according to the
particular properties desired.
[0459] Intranasal Formulations
[0460] Intranasal formulations are known in the art and are
described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and
6,391,452, each of which is specifically incorporated by reference.
Formulations that include a compound of any of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) which are prepared
according to these and other techniques well-known in the art are
prepared as solutions in saline, employing benzyl alcohol or other
suitable preservatives, fluorocarbons, and/or other solubilizing or
dispersing agents known in the art. See, for example, Ansel, H. C.
et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,
Sixth Ed. (1995). Preferably these compositions and formulations
are prepared with suitable nontoxic pharmaceutically acceptable
ingredients. These ingredients are known to those skilled in the
preparation of nasal dosage forms and some of these can be found in
REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21 st edition,
2005, a standard reference in the field. The choice of suitable
carriers is highly dependent upon the exact nature of the nasal
dosage form desired, e.g., solutions, suspensions, ointments, or
gels. Nasal dosage forms generally contain large amounts of water
in addition to the active ingredient. Minor amounts of other
ingredients such as pH adjusters, emulsifiers or dispersing agents,
preservatives, surfactants, gelling agents, or buffering and other
stabilizing and solubilizing agents may also be present. The nasal
dosage form should be isotonic with nasal secretions.
[0461] For administration by inhalation, the compounds of any of
Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV)
described herein may be in a form as an aerosol, a mist or a
powder. Pharmaceutical compositions described herein are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebuliser, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount.
Capsules and cartridges of, such as, by way of example only,
gelatin for use in an inhaler or insufflator may be formulated
containing a powder mix of the compound described herein and a
suitable powder base such as lactose or starch.
[0462] Buccal Formulations
[0463] Buccal formulations that include compounds of any of Formula
(I), (IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) may be
administered using a variety of formulations known in the art. For
example, such formulations include, but are not limited to, U.S.
Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of
which is specifically incorporated by reference. In addition, the
buccal dosage forms described herein can further include a
bioerodible (hydrolysable) polymeric carrier that also serves to
adhere the dosage form to the buccal mucosa. The buccal dosage form
is fabricated so as to erode gradually over a predetermined time
period, wherein the delivery of the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) is provided
essentially throughout. Buccal drug delivery, as will be
appreciated by those skilled in the art, avoids the disadvantages
encountered with oral drug administration, e.g., slow absorption,
degradation of the active agent by fluids present in the
gastrointestinal tract and/or first-pass inactivation in the liver.
With regard to the bioerodible (hydrolysable) polymeric carrier, it
will be appreciated that virtually any such carrier can be used, so
long as the desired drug release profile is not compromised, and
the carrier is compatible with the compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) and any other
components that may be present in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic
(water-soluble and water-swellable) polymers that adhere to the wet
surface of the buccal mucosa. Examples of polymeric carriers useful
herein include acrylic acid polymers and co, e.g., those known as
"carbomers" (Carbopol.RTM., which may be obtained from B.F.
Goodrich, is one such polymer). Other components may also be
incorporated into the buccal dosage forms described herein include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like. For
buccal or sublingual administration, the compositions may take the
form of tablets, lozenges, or gels formulated in a conventional
manner.
[0464] Transdermal Formulations
[0465] Transdermal formulations described herein may be
administered using a variety of devices which have been described
in the art. For example, such devices include, but are not limited
to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683,
3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073,
3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211,
4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280,
5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is
specifically incorporated by reference in its entirety.
[0466] The transdermal dosage forms described herein may
incorporate certain pharmaceutically acceptable excipients which
are conventional in the art. In one embodiments, the transdermal
formulations described herein include at least three components:
(1) a formulation of a compound of any of Formula (I), (IA), (II),
(IIIA), (IIIB), (IIIC), or (IIID); (2) a penetration enhancer; and
(3) an aqueous adjuvant. In addition, transdermal formulations can
include additional components such as, but not limited to, gelling
agents, creams and ointment bases, and the like. In some
embodiments, the transdermal formulation can further include a
woven or non-woven backing material to enhance absorption and
prevent the removal of the transdermal formulation from the skin.
In other embodiments, the transdermal formulations described herein
can maintain a saturated or supersaturated state to promote
diffusion into the skin.
[0467] Formulations suitable for transdermal administration of
compounds described herein may employ transdermal delivery devices
and transdermal delivery patches and can be lipophilic emulsions or
buffered, aqueous solutions, dissolved and/or dispersed in a
polymer or an adhesive. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents. Still further, transdermal delivery of the compounds
described herein can be accomplished by means of iontophoretic
patches and the like. Additionally, transdermal patches can provide
controlled delivery of the compounds of any of Formula (I), (IA),
(II), (IIIA), (IIIB), (IIIC), or (IIID) The rate of absorption can
be slowed by using rate-controlling membranes or by trapping the
compound within a polymer matrix or gel. Conversely, absorption
enhancers can be used to increase absorption. An absorption
enhancer or carrier can include absorbable pharmaceutically
acceptable solvents to assist passage through the skin. For
example, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to
deliver the compound to the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to
secure the device to the skin.
[0468] Injectable Formulations
[0469] Formulations that include a compound of any of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) suitable for
intramuscular, subcutaneous, or intravenous injection may include
physiologically acceptable sterile aqueous or non-aqueous
solutions, dispersions, suspensions or emulsions, and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and non-aqueous carriers,
diluents, solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, cremophor and the
like), suitable mixtures thereof, vegetable oils (such as olive
oil) and injectable organic esters such as ethyl oleate. Proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants.
Formulations suitable for subcutaneous injection may also contain
additives such as preserving, wetting, emulsifying, and dispensing
agents. Prevention of the growth of microorganisms can be ensured
by various antibacterial and antifungal agents, such as parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, such as sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, such as aluminum monostearate and gelatin.
[0470] For intravenous injections, compounds described herein may
be formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hank's solution, Ringer's solution, or
physiological saline buffer. For transmucosal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art.
For other parenteral injections, appropriate formulations may
include aqueous or nonaqueous solutions, preferably with
physiologically compatible buffers or excipients. Such excipients
are generally known in the art.
[0471] Parenteral injections may involve bolus injection or
continuous infusion. Formulations for injection may be presented in
unit dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The pharmaceutical composition
described herein may be in a form suitable for parenteral injection
as a sterile suspensions, solutions or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. Pharmaceutical formulations
for parenteral administration include aqueous solutions of the
active compounds in water-soluble form. Additionally, suspensions
of the active compounds may be prepared as appropriate oily
injection suspensions. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or dextran. Optionally, the suspension may
also contain suitable stabilizers or agents which increase the
solubility of the compounds to allow for the preparation of highly
concentrated solutions. Alternatively, the active ingredient may be
in powder form for constitution with a suitable vehicle, e.g.,
sterile pyrogen-free water, before use.
[0472] Other Formulations
[0473] In certain embodiments, delivery systems for pharmaceutical
compounds may be employed, such as, for example, liposomes and
emulsions. In certain embodiments, compositions provided herein can
also include an mucoadhesive polymer, selected from among, for
example, carboxymethylcellulose, carbomer (acrylic acid polymer),
poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium alginate and dextran.
[0474] In some embodiments, the compounds described herein may be
administered topically and can be formulated into a variety of
topically administrable compositions, such as solutions,
suspensions, lotions, gels, pastes, medicated sticks, balms, creams
or ointments. Such pharmaceutical compounds can contain
solubilizers, stabilizers, tonicity enhancing agents, buffers and
preservatives.
[0475] The compounds described herein may also be formulated in
rectal compositions such as enemas, rectal gels, rectal foams,
rectal aerosols, suppositories, jelly suppositories, or retention
enemas, containing conventional suppository bases such as cocoa
butter or other glycerides, as well as synthetic polymers such as
polyvinylpyrrolidone, PEG, and the like. In suppository forms of
the compositions, a low-melting wax such as, but not limited to, a
mixture of fatty acid glycerides, optionally in combination with
cocoa butter is first melted.
Examples of Methods of Dosing and Treatment Regimens
[0476] The compounds described herein, in some embodiments, is used
in the preparation of medicaments for the inhibition of Btk or a
homolog thereof, or for the treatment of diseases or conditions
that benefit, at least in part, from inhibition of Btk or a homolog
thereof. In addition, a method for treating any of the diseases or
conditions described herein in a subject in need of such treatment,
involves administration of pharmaceutical compositions containing
at least one compound of any of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) described herein, or a
pharmaceutically acceptable salt, pharmaceutically acceptable
N-oxide, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof,
in therapeutically effective amounts to said subject.
[0477] The compositions containing the compound(s) described
herein, in other embodiments, are administered for prophylactic
and/or therapeutic treatments. In therapeutic applications, the
compositions are administered to a patient already suffering from a
disease or condition, in an amount sufficient to cure or at least
partially arrest the symptoms of the disease or condition. Amounts
effective for this use will depend on the severity and course of
the disease or condition, previous therapy, the patient's health
status, weight, and response to the drugs, and the judgment of the
treating physician.
[0478] In prophylactic applications, compositions containing the
compounds described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. Such an amount is defined to be a
"prophylactically effective amount or dose." In this use, the
precise amounts also depend on the patient's state of health,
weight, and the like. When used in a patient, effective amounts for
this use will depend on the severity and course of the disease,
disorder or condition, previous therapy, the patient's health
status and response to the drugs, and the judgment of the treating
physician.
[0479] In some embodiments, the kinase inhibitor is administered to
the patient on a regular basis, e.g., three times a day, two times
a day, once a day, every other day or every 3 days. In other
embodiments, the kinase inhibitor is administered to the patient on
an intermittent basis, e.g., twice a day followed by once a day
followed by three times a day; or the first two days of every week;
or the first, second and third day of a week. In some embodiments,
intermittent dosing is as effective as regular dosing. In further
or alternative embodiments, the kinase inhibitor is administered
only when the patient exhibits a particular symptom, e.g., the
onset of pain, or the onset of a fever, or the onset of an
inflammation, or the onset of a skin disorder.
[0480] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
compounds may be administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disease or condition.
[0481] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended
for a certain length of time (i.e., a "drug holiday"). The length
of the drug holiday can vary between 2 days and 1 year, including
by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50
days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The
dose reduction during a drug holiday may be from about 10%-about
100%, including, by way of example only, about 10%, about 15%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, about 95%, or about 100%.
[0482] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[0483] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, disease or condition and its severity, the identity
(e.g., weight) of the subject or host in need of treatment, and is
determined according to the particular circumstances surrounding
the case, including, e.g., the specific agent being administered,
the route of administration, the condition being treated, and the
subject or host being treated. In general, however, doses employed
for adult human treatment will typically be in the range of about
0.02-about 5000 mg per day, or from about 1-about 1500 mg per day.
The desired dose may conveniently be presented in a single dose or
as divided doses administered simultaneously (or over a short
period of time) or at appropriate intervals, for example as two,
three, four or more sub-doses per day.
[0484] The pharmaceutical composition described herein may be in
unit dosage forms suitable for single administration of precise
dosages. In unit dosage form, the formulation is divided into unit
doses containing appropriate quantities of one or more compound.
The unit dosage may be in the form of a package containing discrete
quantities of the formulation. Non-limiting examples are packaged
tablets or capsules, and powders in vials or ampoules. Aqueous
suspension compositions can be packaged in single-dose
non-reclosable containers. Alternatively, multiple-dose reclosable
containers can be used, in which case it is typical to include a
preservative in the composition. By way of example only,
formulations for parenteral injection may be presented in unit
dosage form, which include, but are not limited to ampoules, or in
multi-dose containers, with an added preservative.
[0485] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not
uncommon. Such dosages may be altered depending on a number of
variables, not limited to the activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0486] Toxicity and therapeutic efficacy of such therapeutic
regimens can be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 (the dose lethal to 50% of
the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the
toxic and therapeutic effects is the therapeutic index and it can
be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds exhibiting high therapeutic indices are preferred. The
data obtained from cell culture assays and animal studies can be
used in formulating a range of dosage for use in human. The dosage
of such compounds lies preferably within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity.
The dosage may vary within this range depending upon the dosage
form employed and the route of administration utilized.
Dosing Strategies to Increase Selectivity
[0487] Described herein are kinase inhibitors that are selective
for one or more ACKs, including a Btk, a Btk homolog, and a Btk
kinase cysteine homolog. In some embodiments, the inhibitors
described herein also bind reversibly to other kinases (some of
which, in some embodiments, are also ACKs). As a means of enhancing
the selectivity profile, such inhibitors are formulated
(formulation includes chemical modifications of the inhibitor, use
of excipients in a pharmaceutical composition, and combinations
thereof) such that the pharmacokinetic profile favors enhanced
selectivity of the inhibitors for an ACK over a non-ACK. By way of
example only, an ACK is formulated to have a short plasma
half-life. In other embodiments, an ACK is formulated to have an
extended plasma half-life.
[0488] In one embodiment are kinase inhibitors that selectively and
irreversibly binds to a protein tyrosine kinase selected from Btk,
a Btk homolog, and a Btk kinase cysteine homolog, in which the
kinase inhibitor reversibly and non-selectively binds to a
multiplicity of protein tyrosine kinases, and further in which the
plasma half life of the kinase inhibitor is less than about 4
hours. In such an embodiment, the kinase inhibitor selectively and
irreversibly binds to at least one of Btk, Jak3, Blk, Bmx, Tec, and
Itk. In a further embodiment, the kinase inhibitor selectively and
irreversibly binds to Btk. In a further embodiment, the kinase
inhibitor selectively and irreversibly binds to Jak3. In a further
embodiment, the kinase inhibitor selectively and irreversibly binds
to Tec. In a further embodiment, the kinase inhibitor selectively
and irreversibly binds to Btk and Tec. In a further embodiment, the
kinase inhibitor selectively and irreversibly binds to Blk. In a
further embodiment, the kinase inhibitor reversibly and
non-selectively binds to a multiplicity of src-family protein
kinase inhibitors. In a further embodiment, the plasma half life of
the kinase inhibitor is less than about 3 hours. In a further
embodiment, the plasma half life of the kinase inhibitor is less
than about 2 hours.
[0489] In one embodiment are kinase inhibitors that selectively and
irreversibly binds to a protein tyrosine kinase selected from Btk,
a Btk homolog, and a Btk kinase cysteine homolog, in which the
kinase inhibitor reversibly and non-selectively binds to a
multiplicity of protein tyrosine kinases, and further in which the
plasma half life of the kinase inhibitor is greater than about 12
hours. In such an embodiment, the kinase inhibitor selectively and
irreversibly binds to at least one of Btk, Jak3, Blk, Bmx, Tec, and
Itk. In a further embodiment, the kinase inhibitor selectively and
irreversibly binds to Btk. In a further embodiment, the kinase
inhibitor selectively and irreversibly binds to Jak3. In a further
embodiment, the kinase inhibitor selectively and irreversibly binds
to Tec. In a further embodiment, the kinase inhibitor selectively
and irreversibly binds to Btk and Tec. In a further embodiment, the
kinase inhibitor selectively and irreversibly binds to Blk. In a
further embodiment, the kinase inhibitor reversibly and
non-selectively binds to a multiplicity of src-family protein
kinase inhibitors In a further embodiment, the kinase inhibitor the
plasma half life of the kinase inhibitor is greater than about 16
hours.
[0490] In another aspect of such dosing methods are pharmaceutical
formulations comprising any of the aforementioned ACK inhibitors
and a pharmaceutically acceptable excipient. In some embodiments,
such pharmaceutical formulations are formulated for a route of
administration selected from oral administration, parenteral
administration, buccal administration, nasal administration,
topical administration, or rectal administration. In certain
embodiments, the pharmaceutical formulations are formulated for
oral administration.
[0491] In another aspect of such dosing methods are methods for
treating rheumatoid arthritis comprising administering to a subject
any of the aforementioned ACK inhibitors that selectively and
irreversibly binds to Btk and Tec.
[0492] In a further aspect of such dosing strategies are methods
for treating a B-cell proliferative disorder or a mast cell
proliferative disorder comprising administering to a patient in
need a pharmaceutical composition of any of the aforementioned ACK
inhibitors.
[0493] In a further aspect of such dosing strategies are methods
for treating a rheumatoid arthritis or condition comprising
administering to a patient in need a pharmaceutical composition of
any of the aforementioned ACK inhibitors. In a further aspect of
such dosing strategies are methods for treating a disease
characterized by hyperactive B cells comprising administering to a
patient in need a pharmaceutical composition of any of the
aforementioned ACK inhibitors. In a further aspect of such dosing
strategies are methods for treating a disease characterized by
hyperactive mast cells comprising administering to a patient in
need a pharmaceutical composition of any of the aforementioned ACK
inhibitors. In a further aspect of such dosing strategies are
methods for treating a disease characterized by both hyperactive B
cells and hyperactive mast cells comprising administering to a
patient in need a pharmaceutical composition of any of the
aforementioned ACK inhibitors. In any of the aforementioned
treatment methods using such dosing strategies, the pharmaceutical
composition is administered once a day or less frequently than once
a day.
Kits/Articles of Manufacture
[0494] For use in the therapeutic applications described herein,
kits and articles of manufacture are also described herein. Such
kits can include a carrier, package, or container that is
compartmentalized to receive one or more containers such as vials,
tubes, and the like, each of the container(s) including one of the
separate elements to be used in a method described herein. Suitable
containers include, for example, bottles, vials, syringes, and test
tubes. The containers can be formed from a variety of materials
such as glass or plastic.
[0495] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products include, e.g., U.S. Pat. Nos. 5,323,907,
5,052,558 and 5,033,252. Examples of pharmaceutical packaging
materials include, but are not limited to, blister packs, bottles,
tubes, inhalers, pumps, bags, vials, containers, syringes, bottles,
and any packaging material suitable for a selected formulation and
intended mode of administration and treatment. A wide array of
formulations of the compounds and compositions provided herein are
contemplated as are a variety of treatments for any disease,
disorder, or condition that benefit by inhibition of Btk, or in
which Btk is a mediator or contributor to the symptoms or
cause.
[0496] For example, the container(s) can include one or more
compounds described herein, optionally in a composition or in
combination with another agent as disclosed herein. The
container(s) optionally have a sterile access port (for example the
container can be an intravenous solution bag or a vial having a
stopper pierceable by a hypodermic injection needle). Such kits
optionally comprising a compound with an identifying description or
label or instructions relating to its use in the methods described
herein.
[0497] A kit will typically include one or more additional
containers, each with one or more of various materials (such as
reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user standpoint for use of a
compound described herein. Non-limiting examples of such materials
include, but not limited to, buffers, diluents, filters, needles,
syringes; carrier, package, container, vial and/or tube labels
listing contents and/or instructions for use, and package inserts
with instructions for use. A set of instructions will also
typically be included.
[0498] A label can be on or associated with the container. A label
can be on a container when letters, numbers or other characters
forming the label are attached, molded or etched into the container
itself; a label can be associated with a container when it is
present within a receptacle or carrier that also holds the
container, e.g., as a package insert. A label can be used to
indicate that the contents are to be used for a specific
therapeutic application. The label can also indicate directions for
use of the contents, such as in the methods described herein.
[0499] In certain embodiments, the pharmaceutical compositions can
be presented in a pack or dispenser device which can contain one or
more unit dosage forms containing a compound provided herein. The
pack can for example contain metal or plastic foil, such as a
blister pack. The pack or dispenser device can be accompanied by
instructions for administration. The pack or dispenser can also be
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. Such notice, for example, can be the
labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Compositions
containing a compound provided herein formulated in a compatible
pharmaceutical carrier can also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
EXAMPLES
[0500] The following specific and non-limiting examples are to be
construed as merely illustrative, and do not limit the present
disclosure in any way whatsoever.
Synthesis of Compounds
Example 1
Preparation of
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (2a)
[0501] 4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
(Intermediate 2) is prepared as disclosed in International Patent
Publication No. WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g)
is added to thionyl chloride (100 mL) and heated under gentle
reflux for 1 hour. Thionyl chloride is removed by distillation, the
residual oil dissolved in toluene and volatile material removed at
80.degree. C./20 mbar. The resulting acid chloride is dissolved in
toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8
g) is added and the solution and stirred at -10.degree. C. while
adding diisopropylethylethylamine (57.9 g) in toluene (150 mL),
while maintaining the temperature below 0.degree. C. After 1 hour
at 0.degree. C., the mixture is stirred at 20.degree. C. overnight.
Amine hydrochloride is removed by filtration and the filtrate
evaporated in vacuo. The residue is taken up in ethyl acetate and
washed with 1.25 M sulphuric acid, then with brine and dried over
sodium sulfate. Evaporation of the solvents gives a semisolid
residue which is treated with a little ethyl acetate to give 4.1 g
of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a white solid
(m.p. 160-162.degree. C.). The filtrate on evaporation gives 56.58
(96%) of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a
grey-brown solid, which is sufficiently pure for further use.
[0502] 1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in
acetonitrile (780 mL) and methanol (85 mL) is stirred under
nitrogen at 0.degree. C. while adding diisopropylethylamine (52.5
mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The
reaction is stirred for 2 days at 20.degree. C., and then 2 g of
silica is added (for chromatography). The brown-red solution is
evaporated in vacuo, the residue dissolved in ethyl acetate and
washed well with water then brine, dried and evaporated. The
residue is extracted with diethyl ether (3.times.250 mL), decanting
from insoluble oil. Evaporation of the ether extracts gives 22.5 g
of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange
solid. The insoluble oil is purified by flash chromatography to
give 15.0 g of a red-orange oil.
[0503] 1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and
1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are
treated with a solution of hydrazine hydrate (18 mL) in ethanol (25
mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is
added followed by water (10 mL). The precipitated solid is
collected and washed with ethanol:water (4:1) and then dried in air
to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale
orange solid.
[0504] 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is
suspended in formamide (300 mL) and heated under nitrogen at
180.degree. C. for 4 hours. The reaction mixture is cooled to
30.degree. C. and water (300 mL) is added. The solid is collected,
washed well with water, then with methanol and dried in air to give
of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.
Example 1a
Synthesis of
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one (4)
##STR00425##
[0505] Synthesis of Compound 4a
[0506] a) polymer-bound triphenylphosphine (TPP), diisopropyl
diazodicarboxylate (DIAD), tetrahydrofuran (THF); b) HCl/dioxane;
then acryloyl chloride, triethylamine (TEA).
[0507] Compounds described herein were synthesized by following the
steps outlined in Scheme III. A detailed illustrative example of
the reaction conditions shown in Scheme III is described for the
synthesis of
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one (Compound 4a).
[0508] 101 mg of
4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and 330 mg
of polymer-bound triphenylphosphine (TPP) (polymerlab) were mixed
together with 5 mL of tetrahydrofuran (THF). tert-Butyl
3-hydroxypiperidine-1-carboxylate (200 mg; 2.0 equivalents) was
added to the mixture followed by the addition of diisopropyl
diazodicarboxylate (0.099 mL). The reaction mixture was stirred at
room temperature overnight. The reaction mixture was filtered to
remove the resins and the reaction mixture was concentrated and
purified by flash chromatography (pentane/ethyl acetate=1/1) to
give intermediate 3a (55 mg).
[0509] Intermediate 3a (48.3 mg) was treated with 1 mL of 4N HCl in
dioxane for 1 hour and then concentrated to dryness. The residue
was dissolved in dichloromethane and triethylamine (0.042 mL) was
added followed by acryl chloride (0.010 mL). The reaction was
stopped after 2 hours. The reaction mixture was washed with 5% by
weight aqueous citric acid and then with brine. The organic layer
was dried with MgSO.sub.4, and concentrated. Flash chromatography
(with CH.sub.2Cl.sub.2/MeOH=25/1) gave 22 mg of compound 4a as a
white solid. MS (M+1): 441.2; .sup.1H-NMR (400 MHz): 8.26, s, 1H,
7.65, m, 2H, 7.42, m, 2H, 7.1-7.2, m, 5H, 6.7-6.9, m, 1H, 6.1, m,
1H, 5.5-5.7, m, 1H, 4.7, m, 1H, 4.54, m, 0.5H, 4.2, m, 1H, 4.1, m,
0.5H, 3.7, m, 0.5H, 3.2, m, 1H, 3.0, m, 0.5H, 2.3, m, 1H, 2.1, m,
1H, 1.9, m, 1H, 1.6, m, 1H.
Example 1b
Synthesis of
3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-
-1-yl)-2,3-dihydroxypropan-1-one (5a)
##STR00426##
[0511] A mixture of
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one (4a, 220 mg), OsO.sub.4 (2.5 wt % in
t-BuOH, 6.9 mL) and pyridine (0.04 mL) was stirred at room
temperature for 18 hrs. The mixture was worked up with sat. aqueous
NaHSO.sub.3 solution (6 mL) and stirred for another hour. The
aqueous mixture was extracted with EtOAc (30 mL, 15 mL and 5 mL).
The combined organic extractants were dried (Na.sub.2SO.sub.4),
filtered and evaporated in vacuo. The crude was dissolved in small
amount of dichloromethane, and purified by flash chromatography
(silica, 5% MeOH in CH.sub.2Cl.sub.2 to 10% MeOH in
CH.sub.2Cl.sub.2) to afford the title compound as a white solid
(105 mg).
Example 2
Synthesis of
(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)-2-hydroxyethanone (7)
##STR00427##
[0513] To a mixture of (R)-3-(4-phenoxy
phenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6)
(38.62 g), glycolic acid (9.13 g) and triethylamine (27.90 mL) in
THF (500 mL) stirring in an ice bath, was added HATU (45.63 g) in
one portion. The reaction was allowed to warm up to room
temperature and stirred overnight (16 hrs). Solvent was removed by
rotoevaporation. The residue was diluted with dichloromethane (500
mL), washed with aqueous NaOH solution (10%, 300 mL). The solid was
filtered off and the bi-layer system was separated. The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4), filtered and
evaporated in vacuo. The residue was triturated with acetonitrile
(300 mL) with some heating and cooled to room temperature. The
mixture was filtered after sitting at room temperature overnight
(16 hrs) and filtered. The solid collected was washed with small
amount of acetonitrile and dried under high vacuo to provide the
title compound a white powder with slight pink color (34.8 g).
Example 3
Synthesis of
(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)ethanone (8)
##STR00428##
[0515] To a solution of
(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4--
amine (6) (0.05 g) in THF (1 mL) was added acetic anhydride (12.8
.mu.L) and DIPEA (23.1 .mu.L). The reaction was stirred at room
temperature for 2 hours. A sample of the reaction mixture was
prepared for LC/MS analysis. 10 .mu.L of the reaction mixture was
diluted with H.sub.2O:ACN=6:4 to result in a 0.1 mg/mL preparation.
LC/MS confirmed that the resulting product (having a m/z of 429) is
the title compound.
Example 4
Synthesis of
(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)-3-chloropropan-1-one (9)
##STR00429##
[0517] To a solution of
(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4--
amine (6) (0.40 g, 1.04 mmol) and TEA (0.29 mL, 2.08 mmol) in THF
(15 mL) cooled to 0.degree. C. was added 3-chloropropanoyl chloride
(0.132 g, 2.08 mmol). After stiffing 1 hr at 0.degree. C., the
reaction mixture was diluted with ethyl acetate (100 mL) and washed
with water (50 mL). The organic layer was dried (MgSO.sub.4),
filtered and concentrated to collect 0.49 g of a white solid. The
white solid was subjected to flash chromatography (5% MeOH/EtOAc)
to provide 0.31 g (62%) of
(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)-3-chloropropan-1-one (9) as a white solid. .sup.1H
NMR (300 MHz, DMSO) .delta. 8.25 (s, 1H), 7.64 (d, 2H, J=8.5 Hz),
7.40 (m, 2H), 7.20-7.00 (m, 7H), 4.60 (m, 1H), 4.12-3.10 (m, 6H),
2.94-1.60 (m, 6H).
Example 5
Synthesis of
1((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pip-
eridin-1-yl)-3-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrim-
idin-1-yl)piperidin-1-yl)propan-1-one (10)
##STR00430##
[0519] The desired title compound (10) is synthesized in basic
conditions. For example, compound 4a (52 mg) and compound 6 (46 mg)
were dissolved in anhydrous THF (0.6 mL). DIPEA (20 .mu.L) is added
to the reaction mixture and heated to 30-35 deg C. The reaction was
stirred continuously for 48 hours. Prep TLC (acetone:MeOH 1:1) of
the reaction mixture resulted in the desired title compound 10.
Therapeutic Uses of Inhibitor Compounds
Example 6
Btk In Vitro Inhibitory Activity
[0520] The Btk IC.sub.50 of compounds disclosed herein is
determined in both an acellular kinase assay and in a cellular
functional assay of BCR-induced calcium flux as described
below.
[0521] Btk kinase activity is determined using a time-resolved
fluorescence resonance energy transfer (TR-FRET) methodology.
Measurements are performed in a reaction volume of 50 .mu.L using
96-well assay plates. Kinase enzyme, inhibitor, ATP (at the K.sub.m
for the kinase), and 1 .mu.M peptide substrate
(Biotin-AVLESEEELYSSARQ-NH.sub.2) are incubated in a reaction
buffer composed of 20 mM Tris, 50 mM NaCl, MgCl.sub.2 (5-25 mM
depending on the kinase), MnCl.sub.2 (0-10 mM), 1 mM DTT, 0.1 mM
EDTA, 0.01% bovine serum albumin, 0.005% Tween-20, and 10% DMSO at
pH 7.4 for one hour. The reaction is quenched by the addition of
1.2 equivalents of EDTA (relative to divalent cation) in 25 .mu.L
of 1.times. Lance buffer (Perkin-Elmer). Streptavidin-APC
(Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (Perkin-Elmer) in
1.times. Lance buffer are added in a 25 .mu.L it volume to give
final concentrations of 100 nM and 2.5 nM, respectively, and the
mixture is allowed to incubate for one hour. The TR-FRET signal is
measured on a multimode plate reader with an excitation wavelength
(.lamda..sub.Ex) of 330 m and detection wavelengths
(.lamda..sub.Em) of 615 and 665 nm Activity iss determined by the
ratio of the fluorescence at 665 nm to that at 615 nm. For each
compound, enzyme activity iss measured at various concentrations of
compound. Negative control reactions are performed in the absence
of inhibitor in replicates of six, and two no-enzyme controls are
used to determine baseline fluorescence levels Inhibition
constants, K.sub.i(app), are obtained using the program
BatchK.sub.i (Kuzmic et al. (2000), Anal. Biochem. 286:45-50).
IC.sub.50s are obtained according to the equation:
IC.sub.50={Ki(app)/(1+[ATP]/K.sub.m.sup.ATP)}+[E].sub.total/2;
For all kinases, [ATP]=K.sub.m.sup.ATP, [Btk].sub.total=0.5 nM and
[Lck].sub.total=6 nM.
[0522] Calcium flux fluoresence-based assays are performed in a
FlexStation II384 fluorometric imaging plate reader (Molecular
Devices) according to manufacturer instructions. In brief, actively
growing Ramos cells (ATCC) in RPM1 medium supplemented with 10% FBS
(Invitrogen) are washed and re-plated in low serum medium at
approximately 5.times.10.sup.5 cells per 100 .mu.l per well in a
96-well plate. Compounds to be assayed are dissolved in DMSO and
then diluted in low serum medium to final concentrations ranging
from 0 to 10 .mu.M (at a dilution factor of 0.3). The diluted
compounds are then added to each well (final DMSO concentration was
0.01%) and incubated at 37 degree in 5% CO.sub.2 incubator for one
hour. Afterwards, 100 .mu.l of a calcium-sensitive dye (from the
Calcium 3 assay kit, Molecular Devices) is added to each well and
incubated for an additional hour. The compound-treated cells are
stimulated with a goat anti-human IgM antibody (80 ug/ml; Jackson
ImmunoResearch) and read in the FlexStation 11384 using a
.lamda..sub.Ex=485 nm and .lamda..sub.Em=538 .mu.m for 200 seconds.
The relative fluorescence unit (RFU) and the IC.sub.50 were
recorded and analyzed using a built-in SoftMax program (Molecular
devices).
Example 7
Inhibition of Btk
[0523] The properties of the compounds disclosed herein are further
characterized by assaying a number of cellular biochemical and
functional endpoints. In particular, we sought to assess the
selectivity of these compounds for inhibition of Btk versus the
closely related protein kinases Lck, Lyn, and Syk. In
anti-IgM-stimulated Ramos cells (a human B cell line), are assayed
Btk-dependent phosphorylation of PLC-.gamma.1; Lyn and
Syk-dependent phosphorylation of tyrosine 551 on Btk; and
BCR-activated calcium flux. The effect of compounds disclosed
herein on Jurkat cells are measured wherein a human T cell line in
which Lck and Itk, but not Btk are required for T cell receptor
mediated Ca.sup.2+ flux.
Example 8
Use of a Compound Described Herein to Treat Rheumatoid
Arthritis
[0524] The in vivo efficacy of the compounds described herein are
evaluated in a mouse model of rheumatoid arthitis. Arthritis is
induced in Balb/c mice by administration of anti-collagen
antibodies and lipopolysaccharide (LPS). See Nandakumar et al.
(2003), Am. J. Pathol. 163:1827-1837. Female Balb/c mice are
treated with 100 mg/kg of Chemicon mAb cocktail to Type II collagen
intravenously on Day 0 and 1.25 mg/kg of LPS intraperitoneally on
Day 1. A test compound is administered orally in a
methylcellulose-based aqueous suspension formulation at 1, 3, 10
and 30 mg/kg once daily starting on Day 2 through Day 12. Blood
samples are collected at 0.5 and 2 hours post dose of the test
compound administration on Day 12. The serum concentrations of the
test compound are quantified by LC/MS/MS. Twenty four hours post
dose, levels of the test compound below the level of
quantitation.
Example 9
Inhibition of Mast Cell Degranulation
[0525] Human CD34+ cells differentiated to mast cells by 9 weeks in
culture in the presence of 1 ng/ml IL-3, 50 ng/ml IL-6, 100 ng/ml
SCF. Cells are incubated with IgE+IL-4 for 4 days and then
degranulation is induced by cross-linking with anti-IgE.
Degranulation quantitated using hexosaminidase assay. The IC.sub.50
in MC degranulation of the compounds are determined Compounds with
desired IC.sub.50 values are used for the treatment of inflammatory
diseases, such as asthma.
Example 10
Pharmaceutical Compositions
[0526] The compositions described below are presented with a
compound described herein for illustrative purposes; any of the
compounds described herein are optionally used in such
pharmaceutical compositions.
Example 10a
Parenteral Composition
[0527] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a water-soluble salt of
a compound of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein is dissolved in DMSO and then mixed with 10 mL of 0.9%
sterile saline. The mixture is incorporated into a dosage unit form
suitable for administration by injection.
Example 10b
Oral Composition
[0528] To prepare a pharmaceutical composition for oral delivery,
100 mg of a compound of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein is mixed with 750 mg of starch. The mixture is
incorporated into an oral dosage unit for, such as a hard gelatin
capsule, which is suitable for oral administration.
Example 10c
Sublingual (Hard Lozenge) Composition
[0529] To prepare a pharmaceutical composition for buccal delivery,
such as a hard lozenge, mix 100 mg of a compound of Formula (I),
(IA), (II), (IIIA), (IIIB), (IIIC), (IIID), or (IV) or other
pyrazolopyrimidine compounds described herein, with 420 mg of
powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL
distilled water, and 0.42 mL mint extract. The mixture is gently
blended and poured into a mold to form a lozenge suitable for
buccal administration.
Example 10d
Inhalation Composition
[0530] To prepare a pharmaceutical composition for inhalation
delivery, 20 mg of a compound of Formula (I), (IA), (II), (IIIA),
(IIIB), (IIIC), (IIID), or (IV) or other pyrazolopyrimidine
compounds described herein is mixed with 50 mg of anhydrous citric
acid and 100 mL of 0.9% sodium chloride solution. The mixture is
incorporated into an inhalation delivery unit, such as a nebulizer,
which is suitable for inhalation administration.
Example 10e
Rectal Gel Composition
[0531] To prepare a pharmaceutical composition for rectal delivery,
100 mg of a compound of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein is mixed with 2.5 g of methylcellulose (1500 mPa),
100 mg of methylparaben, 5 g of glycerin and 100 mL of purified
water. The resulting gel mixture is then incorporated into rectal
delivery units, such as syringes, which are suitable for rectal
administration.
Example 10f
Topical Gel Composition
[0532] To prepare a pharmaceutical topical gel composition, 100 mg
of a compound of Formula (I), (IA), (II), (IIIA), (IIIB), (IIIC),
(IIID), or (IV) or other pyrazolopyrimidine compounds described
herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of
propylene glycol, 10 mL of isopropyl myristate and 100 mL of
purified alcohol USP. The resulting gel mixture is then
incorporated into containers, such as tubes, which are suitable for
topical administration.
Example 10 g
Ophthalmic Solution Composition
[0533] To prepare a pharmaceutical ophthalmic solution composition,
100 mg of a compound of Formula (I), (IA), (II), (IIIA), (IIIB),
(IIIC), (IIID), or (IV) or other pyrazolopyrimidine compounds
described herein is mixed with 0.9 g of NaCl in 100 mL of purified
water and filtered using a 0.2 micron filter. The resulting
isotonic solution is then incorporated into ophthalmic delivery
units, such as eye drop containers, which are suitable for
ophthalmic administration.
* * * * *