U.S. patent application number 12/137892 was filed with the patent office on 2008-12-18 for salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentyl- propanenitrile.
This patent application is currently assigned to INCYTE CORPORATION. Invention is credited to Hui-Yin Li, James D. Rodgers.
Application Number | 20080312259 12/137892 |
Document ID | / |
Family ID | 40029273 |
Filed Date | 2008-12-18 |
United States Patent
Application |
20080312259 |
Kind Code |
A1 |
Rodgers; James D. ; et
al. |
December 18, 2008 |
SALTS OF THE JANUS KINASE INHIBITOR
(R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYL-
PROPANENITRILE
Abstract
The present invention provides salt forms of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile that are useful in the modulation of Janus kinase
activity and are useful in the treatment of diseases related to
activity of Janus kinases including, for example, immune-related
diseases, skin disorders, myeloid proliferative disorders, cancer,
and other diseases.
Inventors: |
Rodgers; James D.;
(Landenberg, PA) ; Li; Hui-Yin; (Hockessin,
DE) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
INCYTE CORPORATION
Wilmington
DE
|
Family ID: |
40029273 |
Appl. No.: |
12/137892 |
Filed: |
June 12, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60943705 |
Jun 13, 2007 |
|
|
|
Current U.S.
Class: |
514/265.1 ;
544/280 |
Current CPC
Class: |
A61K 31/519 20130101;
A61P 31/22 20180101; A61P 35/00 20180101; A61P 37/08 20180101; A61P
31/18 20180101; A61K 9/0053 20130101; A61P 17/06 20180101; A61P
31/12 20180101; A61P 29/00 20180101; A61P 9/00 20180101; A61P 13/12
20180101; A61P 17/00 20180101; A61P 21/04 20180101; A61P 35/04
20180101; A61P 21/00 20180101; A61P 1/04 20180101; A61P 37/02
20180101; A61P 9/10 20180101; A61P 1/00 20180101; A61P 31/20
20180101; C07D 487/04 20130101; A61P 37/06 20180101; A61P 43/00
20180101; A61P 11/00 20180101; C07B 2200/13 20130101; A61P 7/00
20180101; A61P 19/02 20180101; A61P 37/00 20180101; A61P 27/02
20180101; A61P 25/00 20180101; A61K 9/20 20130101; A61P 35/02
20180101; A61P 3/10 20180101; A61P 31/14 20180101; C07B 2200/07
20130101; A61P 17/12 20180101; A61P 17/08 20180101; C07D 487/04
20130101; C07B 2200/13 20130101; C07D 487/04 20130101; C07B 2200/07
20130101 |
Class at
Publication: |
514/265.1 ;
544/280 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/04 20060101 C07D487/04; A61P 37/00 20060101
A61P037/00; A61P 17/00 20060101 A61P017/00; A61P 31/12 20060101
A61P031/12; A61P 35/00 20060101 A61P035/00; A61P 29/00 20060101
A61P029/00; A61P 9/00 20060101 A61P009/00 |
Claims
1. A salt selected from:
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile maleic acid salt;
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile sulfuric acid salt; and
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile phosphoric acid salt.
2. The salt of claim 1 that is
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile maleic acid salt.
3. The salt of claim 1 that is
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile sulfuric acid salt.
4. The salt of claim 1 that is
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile phosphoric acid salt.
5. The salt of claim 1 that is substantially isolated.
6. A method of preparing a salt of claim 1 comprising combining
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile with maleic acid, sulfuric acid, or phorphoric
acid.
7. A composition comprising at least one salt of claim 1 and at
least one pharmaceutically acceptable carrier.
8. The composition of claim 7 which is suitable for oral or topical
administration.
9. The composition of claim 7 which is suitable for topical
administration.
10. A method of modulating an activity of JAK comprising contacting
JAK with a salt of claim 1.
11. The method of claim 10 wherein said modulating is
inhibiting.
12. A method of treating a disease in a patient wherein said
disease is associated with JAK activity, comprising administering
to said patient a therapeutically effective amount of a salt of
claim 1.
13. The method of claim 12 wherein said disease is allograft
rejection or graft versus host disease.
14. The method of claim 12 wherein said disease is an autoimmune
disease.
15. The method of claim 14 wherein said autoimmune disease is a
skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile
arthritis, type I diabetes, lupus, inflammatory bowel disease,
Crohn's disease, myasthenia gravis, immunoglobulin nephropathies,
myocarditis, or autoimmune thyroid disorder.
16. The method of claim 12 wherein said autoimmune disease is
bullous skin disorder.
17. The method of claim 16 wherein said bullous skin disorder is
pemphigus vulgaris (PV) or bullous pemphigoid (BP).
18. The method of claim 12 wherein said disease is a skin
disorder.
19. The method of claim 18 wherein said skin disorder is atopic
dermatitis, psoriasis, skin sensitization, skin irritation, skin
rash, contact dermatitis or allergic contact sensitization.
20. The method of claim 12 wherein said disease is a viral
disease.
21. The method of claim 20 wherein said viral disease is Epstein
Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,
Varicella-Zoster Virus (VZV) or Human Papilloma Virus (HPV).
22. The method of claim 12 wherein said disease is cancer.
23. The method of claim 22 wherein said cancer is a solid tumor
24. The method of claim 22 wherein said cancer is prostate cancer,
renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid
cancer, Kaposi's sarcoma, Castleman's disease or pancreatic
cancer.
25. The method of claim 24 wherein said cancer is prostate
cancer.
26. The method of claim 22 wherein said cancer is
hematological.
27. The method of claim 26 wherein said cancer is lymphoma,
leukemia, or multiple myeloma.
28. The method of claim 22 wherein said cancer is a skin
cancer.
29. The method of claim 28 wherein said skin cancer is cutaneous
T-cell lymphoma or cutaneous B-cell lymphoma.
30. The method of claim 22 wherein said cancer is multiple
myeloma.
31. The method of claim 12 wherein said disease is characterized by
a mutant JAK2.
32. The method of claim 31 wherein at least one mutation of said
mutant JAK2 resides in the pseudo-kinase domain of said JAK2.
33. The method of claim 12 wherein said disease is a
myeloproliferative disorder.
34. The method of claim 33 wherein said myeloproliferative disorder
(MPD) is polycythemia vera (PV), essential thrombocythemia (ET),
myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous
leukemia (CML), chronic myelomonocytic leukemia (CMML),
hypereosinophilic syndrome (HES), or systemic mast cell disease
(SMCD).
35. The method of claim 12 wherein said disease is an inflammatory
disease.
36. The method of claim 35 wherein said disease is an inflammatory
disease of the eye.
37. The method of claim 36 wherein said disease is iritis, uveitis,
scleritis, or conjunctivitis.
38. The method of claim 35 wherein said disease is an inflammatory
disease of the respiratory tract.
39. The method of claim 35 wherein said inflammatory disease
concerns the upper respiratory tract.
40. The method of claim 35 wherein said inflammatory disease
concerns the lower respiratory tract.
41. The method of claim 35 wherein said inflammatory disease is an
inflammatory myopathy.
42. The method of claim 35 wherein said inflammatory disease is
myocarditis.
43. The method of claim 12 wherein said disease is ischemia
reperfusion or related to an ischemic event.
44. The method of claim 12 wherein said disease is anorexia or
cachexia resulting from or associated with cancer.
45. The method of claim 12 wherein said disease is fatigue
resulting from or associated with cancer.
46. A method of treating cancer in a patient, comprising
administering to said patient a therapeutically effective amount of
a salt of claim 1.
47. A method of treating a skin disorder in a patient comprising
topically administering to said patient a therapeutically effective
amount of a salt of claim 1.
48. A method of treating inflammation in a patient comprising
topically administering to said patient a therapeutically effective
amount of a salt of claim 1.
49. A method of treating rheumatoid arthritis in a patient
comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
50. A method of treating prostate cancer in a patient comprising
administering to said patient a therapeutically effective amount of
a salt of claim 1, or pharmaceutically acceptable salt thereof.
51. A method of treating psoriasis in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of a salt of claim 1, or pharmaceutically acceptable
salt thereof.
52. A method of treating multiple myeloma in a patient comprising
administering to said patient a therapeutically effective amount of
a salt of claim 1, or pharmaceutically acceptable salt thereof.
53. A method of treating myeloid metaplasia with myelofibrosis
(MMM) in a patient comprising administering to said patient a
therapeutically effective amount of a salt of claim 1, or
pharmaceutically acceptable salt thereof.
54. A method of treating polycythemia vera (PV) in a patient
comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
55. A method of treating essential thrombocythemia (ET) in a
patient comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
56. A method of treating mycosis fungoides in a patient comprising
administering to said patient a therapeutically effective amount of
a salt of claim 1, or pharmaceutically acceptable salt thereof.
57. A method of treating a hematological cancer in a patient
comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
58. A method of treating chronic myelogenous leukemia (CML) in a
patient comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
59. A method of treating acute lymphoblastic leukemia (ALL) in a
patient comprising administering to said patient a therapeutically
effective amount of a salt of claim 1, or pharmaceutically
acceptable salt thereof.
60. A method of treating chronic myelomonocytic leukemia (CMML) in
a patient comprising administering to said patient a
therapeutically effective amount of a salt of claim 1, or
pharmaceutically acceptable salt thereof
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Ser. No.
60/943,705, filed Jun. 13, 2007, the disclosure of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention provides salt forms of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile that are useful in the modulation of Janus kinase
activity and are useful in the treatment of diseases related to
activity of Janus kinases including, for example, immune-related
diseases, skin disorders, myeloid proliferative disorders, cancer,
and other diseases.
BACKGROUND OF THE INVENTION
[0003] Protein kinases (PKs) are a group of enzymes that regulate
diverse, important biological processes including cell growth,
survival and differentiation, organ formation and morphogenesis,
neovascularization, tissue repair and regeneration, among others.
Protein kinases exert their physiological functions through
catalyzing the phosphorylation of proteins (or substrates) and
thereby modulating the cellular activities of the substrates in
various biological contexts. In addition to the functions in normal
tissues/organs, many protein kinases also play more specialized
roles in a host of human diseases including cancer. A subset of
protein kinases (also referred to as oncogenic protein kinases),
when dysregulated, can cause tumor formation and growth, and
further contribute to tumor maintenance and progression
(Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,
oncogenic protein kinases represent one of the largest and most
attractive groups of protein targets for cancer intervention and
drug development.
[0004] The Janus Kinase (JAK) family plays a role in the
cytokine-dependent regulation of proliferation and function of
cells involved in immune response. Currently, there are four known
mammalian JAK family members: JAK1 (also known as Janus kinase-1),
JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus
kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also
known as protein-tyrosine kinase 2). The JAK proteins range in size
from 120 to 140 kDa and comprise seven conserved JAK homology (JH)
domains; one of these is a functional catalytic kinase domain, and
another is a pseudokinase domain potentially serving a regulatory
function and/or serving as a docking site for STATs (Scott,
Godshall et al. 2002, supra).
[0005] Blocking signal transduction at the level of the JAK kinases
holds promise for developing treatments for human cancers.
Inhibition of the JAK kinases is also envisioned to have
therapeutic benefits in patients suffering from skin immune
disorders such as psoriasis, and skin sensitization. Accordingly,
inhibitors of Janus kinases or related kinases are widely sought
and several publications report effective classes of compounds. For
example, certain JAK inhibitors, including
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile depicted below, are reported in U.S. Ser. No.
11/637,545, filed Dec. 12, 2006.
##STR00001##
[0006] Thus, new or improved forms of existing Janus kinase
inhibitors are continually needed for developing new, improved, and
more effective pharmaceutical formulations for the treatment of
cancer and other diseases. The salt forms and methods described
herein are directed toward these needs and other ends.
SUMMARY OF THE INVENTION
[0007] The present invention provides, inter alia, salts selected
from:
[0008]
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclo-
pentylpropanenitrile maleic acid salt;
[0009]
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclo-
pentylpropanenitrile sulfuric acid salt; and
[0010]
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclo-
pentylpropanenitrile phosphoric acid salt.
[0011] The present invention further provides methods of preparing
a salt of the invention comprising combining
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile with maleic acid, sulfuric acid, or phorphoric
acid.
[0012] The present invention further provides compositions
comprising a salt form of the invention and at least one
pharmaceutically acceptable carrier.
[0013] The present invention further provides methods of modulating
an activity of JAK comprising contacting JAK with a salt of the
invention.
[0014] The present invention further provides methods of treating a
disease in a patient, wherein the disease is associated with JAK
activity, comprising administering to the patient a therapeutically
effective amount of a salt of the invention.
[0015] The present invention further provides methods of treating
cancer, skin disorders, or inflammation in a patient, comprising
administering to the patient a therapeutically effective amount of
a salt of the invention.
DETAILED DESCRIPTION
[0016] The present invention provides, inter alia, salts of the JAK
inhibitor
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-c-
yclopentylpropanenitrile selected from the maleic acid salt,
sulfuric acid salt, and phosphoric acid salt. These salts modulate
the activity of one or more JAKs and are useful, for example, in
the treatment of diseases associated with JAK expression or
activity.
[0017] The salts of the invention have numerous advantageous
properties over the free base form and other salt forms. In
particular, these salts were highly crystalline which would
facilitate the preparation of pharmaceutical formulations and
improve general handling, manipulation, and storage of the active
ingredient. The salts of the invention also have superior aqueous
solubility, rate of dissolution, chemical stability (with a longer
shelf life), compatibility with excipients, and reproducibility
compared with the free base form.
[0018] In some embodiments, the salts of the invention are
substantially isolated. By "substantially isolated" is meant that
the salt is at least partially or substantially separated from the
environment in which it was formed or detected. Partial separation
can include, for example, a composition enriched in the salt of the
invention. Substantial separation can include compositions
containing at least about 50%, at least about 60%, at least about
70%, at least about 80%, at least about 90%, at least about 95%, at
least about 97%, or at least about 99% by weight of the salt.
[0019] Salts of the invention also include all isotopes of atoms
occurring in the salts. Isotopes include those atoms having the
same atomic number but different mass numbers. For example,
isotopes of hydrogen include tritium and deuterium.
[0020] Salts of the invention can be prepared using known
techniques. Conventionally, a salt form is prepared by combining in
solution the free base compound and an acid containing the anion of
the salt form desired, and then isolating the solid salt product
from the reaction solution (e.g., by crystallization,
precipitation, evaporation, etc.). Other salt-forming techniques
can be employed.
Methods of Use
[0021] Salts of the invention can modulate activity of one or more
Janus kinases (JAKs). The term "modulate" is meant to refer to an
ability to increase or decrease the activity of one or more members
of the JAK family of kinases. Accordingly, compounds of the
invention can be used in methods of modulating a JAK by contacting
the JAK with any one or more of the compounds or compositions
described herein. In some embodiments, salts of the present
invention can act as inhibitors of one or more JAKs. In some
embodiments, compounds of the present invention can act to
stimulate the activity of one or more JAKs. In further embodiments,
the compounds of the invention can be used to modulate activity of
a JAK in an individual in need of modulation of the receptor by
administering a modulating amount of a salt of the invention.
[0022] JAKs to which the present salts bind and/or modulate include
any member of the JAK family. In some embodiments, the JAK is JAK1,
JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAK1 or JAK2.
In some embodiments, the JAK is JAK2. In some embodiments, the JAK
is JAK3.
[0023] The salts of the invention can be selective. By "selective"
is meant that the compound binds to or inhibits a JAK with greater
affinity or potency, respectively, compared to at least one other
JAK. In some embodiments, the compounds of the invention are
selective inhibitors of JAK1 or JAK2 over JAK3 and/or TYK2. In some
embodiments, the salts of the invention are selective inhibitors of
JAK2 (e.g., over JAK1, JAK3 and TYK2). Without wishing to be bound
by theory, because inhibitors of JAK3 can lead to immunosuppressive
effects, a compound which is selective for JAK2 over JAK3 and which
is useful in the treatment of cancer (such as multiple myeloma, for
example) can offer the additional advantage of having fewer
immunosuppressive side effects. Selectivity can be at least about
5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at
least about 100-fold, at least about 200-fold, at least about
500-fold or at least about 1000-fold. Selectivity can be measured
by methods routine in the art. In some embodiments, selectivity can
be tested at the Km of each enzyme. In some embodiments,
selectivity of salts of the invention for JAK2 over JAK3 can be
determined by the cellular ATP concentration.
[0024] Another aspect of the present invention pertains to methods
of treating a JAK-associated disease or disorder in an individual
(e.g., patient) by administering to the individual in need of such
treatment a therapeutically effective amount or dose of a salt of
the present invention or a pharmaceutical composition thereof. A
JAK-associated disease can include any disease, disorder or
condition that is directly or indirectly linked to expression or
activity of the JAK, including overexpression and/or abnormal
activity levels. A JAK-associated disease can also include any
disease, disorder or condition that can be prevented, ameliorated,
or cured by modulating JAK activity.
[0025] Examples of JAK-associated diseases include diseases
involving the immune system including, for example, organ
transplant rejection (e.g. allograft rejection and graft versus
host disease).
[0026] Further examples of JAK-associated diseases include
autoimmune diseases such as multiple sclerosis, rheumatoid
arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid
disorders, and the like. In some embodiments, the autoimmune
disease is an autoimmune bullous skin disorder such as pemphigus
vulgaris (PV) or bullous pemphigoid (BP).
[0027] Further examples of JAK-associated diseases include allergic
conditions such as asthma, food allergies, atopic dermatitis and
rhinitis. Further examples of JAK-associated diseases include viral
diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis
C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma
Virus (HPV).
[0028] Further examples of JAK-associated diseases or conditions
include skin disorders such as psoriasis (for example, psoriasis
vulgaris), atopic dermatitis, skin rash, skin irritation, skin
sensitization (e.g., contact dermatitis or allergic contact
dermatitis). For example, certain substances including some
pharmaceuticals when topically applied can cause skin
sensitization. In some embodiments, co-administration or sequential
administration of at least one JAK inhibitor of the invention
together with the agent causing unwanted sensitization can be
helpful in treating such unwanted sensitization or dermatitis. In
some embodiments, the skin disorder is treated by topical
administration of at least one JAK inhibitor of the invention.
[0029] In further embodiments, the JAK-associated disease is cancer
including those characterized by solid tumors (e.g., prostate
cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric
cancer, breast cancer, lung cancer, cancers of the head and neck,
thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's
disease, melanoma etc.), hematological cancers (e.g., lymphoma,
leukemia such as acute lymphoblastic leukemia, acute myelogenous
leukemia (AML), or multiple myeloma), and skin cancer such as
cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
Example cutaneous T-cell lymphomas include Sezary syndrome and
mycosis fungoides.
[0030] JAK-associated diseases can further include those
characterized by expression of a mutant JAK2 such as those having
at least one mutation in the pseudo-kinase domain (e.g.
JAK2V617F).
[0031] JAK-associated diseases can further include
myeloproliferative disorders (MPDs) such as polycythemia vera (PV),
essential thrombocythemia (ET), myeloid metaplasia with
myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic
myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES),
systemic mast cell disease (SMCD), and the like.
[0032] Further JAK-associated diseases include inflammation and
inflammatory diseases. Example inflammatory diseases include
inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis,
conjunctivitis, or related disease), inflammatory diseases of the
respiratory tract (e.g., the upper respiratory tract including the
nose and sinuses such as rhinitis or sinusitis or the lower
respiratory tract including bronchitis, chronic obstructive
pulmonary disease, and the like), inflammatory myopathy such as
myocarditis, and other inflammatory diseases. Other inflammatory
diseases treatable by the compounds of the invention include
systemic inflammatory response syndrome (SIRS) and septic
shock.
[0033] The JAK inhibitors described herein can further be used to
treat ischemia reperfusion injuries or a disease or condition
related to an inflammatory ischemic event such as stroke or cardiac
arrest. The JAK inhibitors described herein can further be used to
treat anorexia, cachexia, or fatigue such as that resulting from or
associated with cancer. The JAK inhibitors described herein can
further be used to treat restenosis, sclerodermitis, or fibrosis.
The JAK inhibitors described herein can further be used to treat
conditions associated with hypoxia or astrogliosis such as, for
example, diabetic retinopathy, cancer, or neurodegeneration. See,
e.g., Dudley, A. C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and
Sriram, K. et al. J. Biol. Chem. 2004, 279(19):19936-47. Epub Mar.
2, 2004.
[0034] The JAK inhibitors described herein can further be used to
treat gout and increased prostate size due to, e.g., benign
prostatic hypertrophy or benign prostatic hyperplasia.
[0035] As used herein, the term "contacting" refers to the bringing
together of indicated moieties in an in vitro system or an in vivo
system. For example, "contacting" a JAK with a salt of the
invention includes the administration of a salt of the present
invention to an individual or patient, such as a human, having a
JAK, as well as, for example, introducing a salt of the invention
into a sample containing a cellular or purified preparation
containing the JAK.
[0036] As used herein, the term "individual" or "patient," used
interchangeably, refers to any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans.
[0037] As used herein, the phrase "therapeutically effective
amount" refers to the amount of active salt or pharmaceutical agent
that elicits the biological or medicinal response that is being
sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician.
[0038] As used herein, the term "treating" or "treatment" refers to
one or more of (1) preventing the disease; for example, preventing
a disease, condition or disorder in an individual who may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease; (2) inhibiting the disease; for example, inhibiting a
disease, condition or disorder in an individual who is experiencing
or displaying the pathology or symptomatology of the disease,
condition or disorder; and (3) ameliorating the disease; for
example, ameliorating a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (i.e.,
reversing the pathology and/or symptomatology) such as decreasing
the severity of disease.
Combination Therapies
[0039] One or more additional pharmaceutical agents such as, for
example, chemotherapeutics, anti-inflammatory agents, steroids,
immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase
inhibitors such as, for example, those described in WO 2006/056399,
or other agents can be used in combination with the salts of the
present invention for treatment of JAK-associated diseases,
disorders or conditions. The one or more additional pharmaceutical
agents can be administered to a patient simultaneously or
sequentially.
[0040] Example chemotherapeutics include proteosome inhibitors
(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents
such as melphalan, doxorubicin, cyclophosphamide, vincristine,
etoposide, carmustine, and the like.
[0041] Example steroids include coriticosteroids such as
dexamethasone or prednisone.
[0042] Example Bcr-Abl inhibitors include the compounds, and
pharmaceutically acceptable salts thereof, of the genera and
species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281,
EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491.
[0043] Example suitable Flt-3 inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
03/037347, WO 03/099771, and WO 04/046120.
[0044] Example suitable RAF inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 00/09495 and
WO 05/028444.
[0045] Example suitable FAK inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO
04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO
01/014402.
[0046] In some embodiments, the salt forms of the invention can be
used in combination with other kinase inhibitors such as imatinib,
particularly for the treatment of patients resistant to imatinib or
other kinases.
[0047] In some embodiments, one or more salt forms of the invention
can be used in combination with a chemotherapeutic in the treatment
of cancer, such as multiple myeloma, and may improve the treatment
response as compared to the response to the chemotherapeutic agent
alone, without exacerbation of its toxic effects. Examples of
additional pharmaceutical agents used in the treatment of multiple
myeloma, for example, can include, without limitation, melphalan,
melphalan plus prednisone [MP], doxorubicin, dexamethasone, and
Velcade (bortezomib). Further additional agents used in the
treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK
kinase inhibitors. Additive or synergistic effects are desirable
outcomes of combining a JAK inhibitor of the present invention with
an additional agent. Furthermore, resistance of multiple myeloma
cells to agents such as dexamethasone may be reversible upon
treatment with a JAK inhibitor of the present invention. The agents
can be combined with the present compounds in a single or
continuous dosage form, or the agents can be administered
simultaneously or sequentially as separate dosage forms.
[0048] In some embodiments, a corticosteroid such as dexamethasone
is administered to a patient in combination with at least one JAK
inhibitor where the dexamethasone is administered intermittently as
opposed to continuously.
[0049] In some further embodiments, combinations of one or more JAK
inhibitors of the invention with other therapeutic agents can be
administered to a patient prior to, during, and/or after a bone
marrow transplant or stem cell transplant.
Pharmaceutical Formulations and Dosage Forms
[0050] When employed as pharmaceuticals, the salts of the invention
can be administered in the form of pharmaceutical compositions.
These compositions can be prepared in a manner well known in the
pharmaceutical art, and can be administered by a variety of routes,
depending upon whether local or systemic treatment is desired and
upon the area to be treated. Administration may be topical
(including transdermal, epidermal, ophthalmic and to mucous
membranes including intranasal, vaginal and rectal delivery),
pulmonary (e.g., by inhalation or insufflation of powders or
aerosols, including by nebulizer; intratracheal or intranasal),
oral or parenteral. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal, intramuscular or
injection or infusion; or intracranial, e.g., intrathecal or
intraventricular, administration. Parenteral administration can be
in the form of a single bolus dose, or may be, for example, by a
continuous perfusion pump. Pharmaceutical compositions and
formulations for topical administration may include transdermal
patches, ointments, lotions, creams, gels, drops, suppositories,
sprays, liquids and powders. Conventional pharmaceutical carriers,
aqueous, powder or oily bases, thickeners and the like may be
necessary or desirable. Coated condoms, gloves and the like may
also be useful.
[0051] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds of the invention above in combination with one or more
pharmaceutically acceptable carriers (excipients). In making the
compositions of the invention, the active ingredient is typically
mixed with an excipient, diluted by an excipient or enclosed within
such a carrier in the form of, for example, a capsule, sachet,
paper, or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which acts as a
vehicle, carrier or medium for the active ingredient. Thus, the
compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments containing, for example, up to 10% by weight of the
active compound, soft and hard gelatin capsules, suppositories,
sterile injectable solutions, and sterile packaged powders.
[0052] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
[0053] The compounds of the invention may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nanoparticulate) preparations of the compounds of
the invention can be prepared by processes known in the art, for
example see International Patent Application No. WO
2002/000196.
[0054] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0055] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1000 mg (1 g), more
usually about 100 to about 500 mg, of the active ingredient. The
term "unit dosage forms" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[0056] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0057] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, about 0.1 to about 1000 mg of the active ingredient of the
present invention.
[0058] The tablets or pills of the present invention can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0059] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0060] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions can be nebulized
by use of inert gases. Nebulized solutions may be breathed directly
from the nebulizing device or the nebulizing device can be attached
to a face masks tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions can be
administered orally or nasally from devices which deliver the
formulation in an appropriate manner.
[0061] The amount of salt or composition administered to a patient
will vary depending upon what is being administered, the purpose of
the administration, such as prophylaxis or therapy, the state of
the patient, the manner of administration, and the like. In
therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. Effective doses will depend on the disease
condition being treated as well as by the judgment of the attending
clinician depending upon factors such as the severity of the
disease, the age, weight and general condition of the patient, and
the like.
[0062] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0063] The therapeutic dosage of the salts of the present invention
can vary according to, for example, the particular use for which
the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment
of the prescribing physician. The proportion or concentration of a
salt of the invention in a pharmaceutical composition can vary
depending upon a number of factors including dosage, chemical
characteristics (e.g., hydrophobicity), and the route of
administration. For example, the salts of the invention can be
provided in an aqueous physiological buffer solution containing
about 0.1 to about 10% w/v of the compound for parenteral
administration. Some typical dose ranges are from about 1 .mu.g/kg
to about 1 g/kg of body weight per day. In some embodiments, the
dose range is from about 0.01 mg/kg to about 100 mg/kg of body
weight per day. The dosage is likely to depend on such variables as
the type and extent of progression of the disease or disorder, the
overall health status of the particular patient, the relative
biological efficacy of the compound selected, formulation of the
excipient, and its route of administration. Effective doses can be
extrapolated from dose-response curves derived from in vitro or
animal model test systems.
[0064] The compositions of the invention can further include one or
more additional pharmaceutical agents such as a chemotherapeutic,
steroid, anti-inflammatory compound, or immunosuppressant, examples
of which are listed hereinabove.
Labeled Compounds and Assay Methods
[0065] Another aspect of the present invention relates to labeled
salts of the invention (radio-labeled, fluorescent-labeled, etc.)
that would be useful not only in imaging techniques but also in
assays, both in vitro and in vivo, for localizing and quantitating
JAK in tissue samples, including human, and for identifying JAK
ligands by inhibition binding of a labeled compound. Accordingly,
the present invention includes JAK assays that contain such labeled
compounds.
[0066] The present invention further includes isotopically-labeled
salts of the invention. An "isotopically" or "radio-labeled"
compound is a salt of the invention where one or more atoms are
replaced or substituted by an atom having an atomic mass or mass
number different from the atomic mass or mass number typically
found in nature (i.e., naturally occurring). Suitable radionuclides
that may be incorporated in compounds of the present invention
include but are not limited to .sup.2H (also written as D for
deuterium), .sup.3H (also written as T for tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and
.sup.131I. The radionuclide that is incorporated in the instant
radio-labeled compounds will depend on the specific application of
that radio-labeled compound. For example, for in vitro
metalloprotease labeling and competition assays, compounds that
incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I,
.sup.35S or will generally be most useful. For radio-imaging
applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I,
.sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[0067] It is understood that a "radio-labeled " or "labeled
compound" is a salt that has incorporated at least one
radionuclide. In some embodiments the radionuclide is selected from
the group consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and
.sup.82Br.
[0068] The present invention can further include synthetic methods
for incorporating radio-isotopes into compounds of the invention.
Synthetic methods for incorporating radio-isotopes into organic
compounds are well known in the art, and a person of ordinary skill
in the art will readily recognize the methods applicable for the
compounds of invention.
[0069] A labeled salt of the invention can be used in a screening
assay to identify/evaluate compounds. For example, a newly
synthesized or identified compound (i.e., test compound) which is
labeled can be evaluated for its ability to bind a JAK by
monitoring its concentration variation when contacting with the
JAK, through tracking of the labeling. For example, a test compound
(labeled) can be evaluated for its ability to reduce binding of
another compound which is known to bind to a JAK (i.e., standard
compound). Accordingly, the ability of a test compound to compete
with the standard compound for binding to the JAK directly
correlates to its binding affinity. Conversely, in some other
screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the
labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound,
and the relative binding affinity of the test compound is thus
ascertained.
Kits
[0070] The present invention also includes pharmaceutical kits
useful, for example, in the treatment or prevention of
JAK-associated diseases or disorders, such as cancer, inflammation,
or skin disorders, which include one or more containers containing
a pharmaceutical composition comprising a therapeutically effective
amount of a salt of the invention. Such kits can further include,
if desired, one or more of various conventional pharmaceutical kit
components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc.,
as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities
of the components to be administered, guidelines for
administration, and/or guidelines for mixing the components, can
also be included in the kit.
[0071] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified
to yield essentially the same results.
EXAMPLES
Example 1
Preparation of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile maleic acid salt
[0072] To a test tube was added
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile (153.7 mg, 0.5 mmol) and maleic acid (61.7 mg)
followed by isopropyl alcohol (IPA) (4 mL). The resulting mixture
was heated to clear, cooled to room temperature, and then stirred
for another 2.5 hours. The precipitate was collected by filtration
and the cake was washed with 0.8 mL of cold IPA. The cake was dried
under vacuum to constant weight to provide the final salt product
(173 mg).
[0073] The maleic acid salt was shown to be a 1:1 salt by H.sup.1
NMR and crystallinity was confirmed by X-ray powder diffraction
(XRPD). Differential scanning calorimetry (DSC) gave a sharp
melting peak at about 175.96.degree. C. (onset at 175.67.degree.
C.). The product showed only slight weight loss up to 150.degree.
C. by thermogravimetric analysis (TGA).
Example 2
Preparation of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile phosphoric acid salt
[0074] To a test tube was added
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile (153.5 mg) and phosphoric acid (56.6 mg) followed by
isopropyl alcohol (IPA) (5.75 mL). The resulting mixture was heated
to clear, cooled to room temperature, and then stirred for another
2 hours. The precipitate was collected by filtration and the cake
was washed with 0.6 mL of cold IPA. The cake was dried under vacuum
to constant weight to provide the final salt product (171.7
mg).
[0075] The phosphoric acid salt was shown to be a 1:1 salt by
.sup.1H NMR and crystallinity was confirmed by X-ray powder
diffraction (XRPD). Differential scanning calorimetry (DSC) gave a
sharp melting peak at about 198.66.degree. C. The product showed
little weight loss up to 200.degree. C. by TGA.
Example 3
Preparation of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile sulfuric acid salt
[0076] To a test tube was added
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile (153.0 mg) and sulfuric acid (56.1 mg) followed by
acetonitrile (7.0 mL). The resulting mixture was heated to clear,
cooled to room temperature, and then stirred for another 2 hours.
The precipitate was collected by filtration and the cake was washed
with 0.8 mL of cold acetonitrile. The cake was dried under vacuum
to constant weight to provide the final salt product (180 mg).
[0077] The sulfuric acid salt was shown to be a 1:1 salt by .sup.1H
NMR and crystallinity was confirmed by X-ray powder diffraction
(XRPD). Differential scanning calorimetry (DSC) gave a sharp
melting peak at about 186.78.degree. C. The product showed little
weight loss up to 175.degree. C. by TGA.
Example A
[0078] In vitro JAK Kinase Assay
[0079] Inhibitory activity of test compounds on JAK targets can be
tested according to the following in vitro assay described in Park
et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic
domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and
Jak3 (a.a. 781-1124) with an N-terminal His tag are expressed using
baculovirus in insect cells and purified. The catalytic activity of
JAK1, JAK2 or JAK3 is assayed by measuring the phosphorylation of a
biotinylated peptide. The phosphorylated peptide was detected by
homogenous time resolved fluorescence (HTRF). IC.sub.50s of
compounds are measured for each kinase in the reactions that
contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8)
buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. The
ATP concentration in the reactions is 90 .mu.M for Jak1, 30 .mu.M
for Jak2 and 3 .mu.M for Jak3. Reactions are carried out at room
temperature for 1 hr and then stopped with 20 .mu.L 45 mM EDTA, 300
nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston,
Mass.). Binding to the Europium labeled antibody takes place for 40
minutes and HTRF signal is measured on a Fusion plate reader
(Perkin Elmer, Boston, Mass.). Both the phosphoric acid salt of the
invention, and the corresponding free base compound, were found to
have IC.sub.50 values of less than 50 nM for each of JAK1, JAK2,
and JAK3.
[0080] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference cited
in the present application is incorporated herein by reference in
its entirety.
* * * * *