U.S. patent application number 11/045772 was filed with the patent office on 2005-09-01 for crystalline polymorphs of a cxc-chemokine receptor ligand.
This patent application is currently assigned to Schering Corporation. Invention is credited to Dwyer, Michael, Fu, Xiaoyong, Hu, Mengwei, Kim-Meade, Agnes, Klopfer, Kevin, McAllister, Timothy, Taveras, Arthur, Yin, Jianguo, Yu, Younong, Zhang, Shuyi.
Application Number | 20050192345 11/045772 |
Document ID | / |
Family ID | 34837390 |
Filed Date | 2005-09-01 |
United States Patent
Application |
20050192345 |
Kind Code |
A1 |
Hu, Mengwei ; et
al. |
September 1, 2005 |
Crystalline polymorphs of a CXC-chemokine receptor ligand
Abstract
The present invention relates to four distinct crystalline
polymorphs of a monohydrate of Compound A having the following
chemical structure: 1 These four polymorphic forms, herein referred
to as Forms I, II, III and IV are active as a CXC-chemokine
receptor ligands. The invention is further directed to
formulations, methods of treatment, and processes of synthesis of
these polymorphic forms.
Inventors: |
Hu, Mengwei; (Washington,
NJ) ; Yu, Younong; (East Brunswick, NJ) ;
Dwyer, Michael; (Scotch Plains, NJ) ; Taveras,
Arthur; (Southborough, MA) ; Kim-Meade, Agnes;
(Fanwood, NJ) ; Yin, Jianguo; (Plainsboro, NJ)
; Fu, Xiaoyong; (Edison, NJ) ; McAllister,
Timothy; (Westfield, NJ) ; Zhang, Shuyi;
(Parsipanny, NJ) ; Klopfer, Kevin; (Flemington,
NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
34837390 |
Appl. No.: |
11/045772 |
Filed: |
January 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60540487 |
Jan 30, 2004 |
|
|
|
Current U.S.
Class: |
514/471 ;
549/451 |
Current CPC
Class: |
A61P 31/22 20180101;
A61P 1/18 20180101; A61P 9/10 20180101; A61P 17/00 20180101; A61P
25/28 20180101; A61P 37/08 20180101; A61P 13/12 20180101; A61P
21/00 20180101; A61P 25/04 20180101; A61P 9/00 20180101; A61P 1/04
20180101; A61P 11/00 20180101; A61P 19/06 20180101; A61P 19/10
20180101; A61P 17/10 20180101; A61P 1/02 20180101; A61P 35/00
20180101; A61P 9/14 20180101; A61P 11/06 20180101; A61P 27/02
20180101; A61P 17/02 20180101; A61P 25/00 20180101; A61P 19/02
20180101; A61P 31/04 20180101; A61P 1/16 20180101; A61P 9/12
20180101; A61P 17/06 20180101; A61P 31/12 20180101; A61P 3/02
20180101; A61P 31/18 20180101; A61P 37/06 20180101; A61P 19/00
20180101; A61P 7/02 20180101; C07D 307/52 20130101; A61P 17/04
20180101; A61P 7/06 20180101; A61P 33/06 20180101; A61P 29/00
20180101; A61P 7/00 20180101; A61P 11/14 20180101; A61P 15/00
20180101 |
Class at
Publication: |
514/471 ;
549/451 |
International
Class: |
A61K 031/34 |
Claims
What is claimed is:
1. A crystalline polymorph of a monohydrate of Compound A of the
formula: 13wherein, said polymorph is selected from the group
consisting of: Form I that exhibits a powder x-ray diffraction
pattern substantially the same as the pattern shown in FIG. 1; Form
II that exhibits a powder x-ray diffraction pattern substantially
the same as the pattern shown in FIG. 2; Form III that exhibits a
powder x-ray diffraction pattern substantially the same as the
pattern shown in FIG. 3; and Form IV that exhibits a powder x-ray
diffraction pattern substantially the same as the pattern shown in
FIG. 4.
2. A crystalline polymorph Form I of a monohydrate of Compound A of
the formula: 14that exhibits a powder x-ray diffraction pattern
having characteristic peak locations of 6.612, 8.832, 27.024 and
28.134 degrees 2.theta..
3. The crystalline polymorph of claim 2 that exhibits a powder
x-ray diffraction pattern having characteristic peak locations of
6.612, 8.832, 13.268, 17.696, 19.492, 20.003, 27.024 and 28.134
degrees 2.theta..
4. The crystalline polymorph of claim 2 that exhibits a powder
x-ray diffraction pattern having characteristic peak locations of
6.612, 8.832, 13.268, 17.696, 17.959, 19.492, 20.003, 20.246,
21.123, 26.580, 27.024 and 28.134 degrees 2.theta..
5. The crystalline polymorph Form I of claim 1.
6. A crystalline polymorph Form II of a monohydrate of Compound A
of the formula: 15that exhibits a powder x-ray diffraction pattern
having characteristic peak locations of 9.328, 13.774, 19.78 and
27.305 degrees 2.theta..
7. The crystalline polymorph Form II of claim 6 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 9.328, 13.145, 13.774, 15.79, 17.872, 18.748, 19.78
and 27.305 degrees 2.theta..
8. The crystalline polymorph Form II of claim 6 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 8.742, 9.328, 13.145, 13.774, 15.79, 17.872, 18.748,
19.263, 19.78, 20.166, 26.648 and 27.305 degrees 2.theta..
9. The crystalline polymorph Form II of claim 1.
10. A crystalline polymorph Form III of a monohydrate of Compound A
of the formula: 16that exhibits a powder x-ray diffraction pattern
having characteristic peak locations of 7.748, 18.349, 23.198 and
23.851 degrees 2.theta..
11. The crystalline polymorph Form III of claim 10 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 7.748, 9.632, 14.07, 15.383, 18.349, 23.198, 23.851
and 27.841 degrees 2.theta..
12. The crystalline polymorph Form III of claim 10 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 7.748, 9.118, 9.632, 14.07, 15.383, 18.349, 18.6,
18.938, 19.383, 23.198, 23.851 and 27.841 degrees 2.theta..
13. The crystalline polymorph Form III of claim 1.
14. A crystalline polymorph Form IV of a monohydrate of Compound A
of the formula: 17that exhibits a powder x-ray diffraction pattern
having characteristic peak locations of 11.46, 43.004, 44.097 and
50.107 degrees 2.theta..
15. The crystalline polymorph Form IV of claim 14 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 11.46, 11.848, 15.643, 16.957, 17.524, 43.004, 44.097
and 50.107 degrees 2.theta..
16. The crystalline polymorph Form IV of claim 14 that exhibits a
powder x-ray diffraction pattern having characteristic peak
locations of 8.706, 11.46, 11.848, 15.643, 16.957, 17.524, 19.335,
21.079, 26.917, 43.004, 44.097 and 50.107 degrees 2.theta..
17. The crystalline polymorph Form IV of claim 1.
18. A process for preparing the polymorph Form I of claim 1 from
amorphous Compound A: 18comprising the steps of: a) mixing
amorphous Compound A at room temperature in a first mixture of an
alcohol and water to form a second mixture; b) adding water
dropwise until the second mixture becomes hazy; c) adding the
organic solvent dropwise until the second mixture becomes clear,
and d) allowing the second mixture to stand at room temperature
until Form I crystals precipitate.
19. The process of claim 18, wherein the alcohol is methanol.
20. The process of claim 18 wherein the alcohol is ethanol.
21. A process for preparing the polymorph Form II of claim 1 from
Form I of claim 1 comprising the step of mixing the Form I material
with an organic solvent as a slurry at room temperature until Form
II crystals precipitate.
22. The process of claim 21 wherein the organic solvent is
methylene chloride.
23. The process of claim 21 wherein the organic solvent is
acetone.
24. A process for preparing the polymorph Form III of claim 1 from
Compound A: 19comprising the steps of: a) mixing Compound A at
elevated temperature with a first quantity of an organic solvent to
form a mixture; b) adding water portion-wise until precipitate is
detected; c) adding a second quantity of the organic solvent; d)
heating the mixture to about 70.degree. C.; and e) allowing the
mixture to stand at room temperature until Form III crystals
precipitate.
25. The process of claim 24 wherein the organic solvent is
n-propanol.
26. The process of claim 24 wherein the ratio of the first quantity
to the second quantity is about 2:1.
27. A process for preparing the polymorph Form IV of claim 1 from
Compound A 20comprising the step of mixing Compound A with
acetonitrile as a slurry at room temperature until Form IV crystals
precipitate.
28. A process for preparing the polymorph Form IV of claim 1 from
Compound A 21comprising the steps of: a) mixing Compound A with a
first mixture of n-propanol and water to form a second mixture; b)
agitating said second mixture while heating to about 70.degree. C.
until substantially all solids are dissolved; c) cooling said
second mixture to about 60.degree. C.; and d) agitating said second
mixture until Form IV crystals precipitate.
29. The process of claim 28 wherein the first mixture comprises
n-propanol and water in a ratio of about 1.1:1.
30. A pharmaceutical composition comprising a crystalline polymorph
selected from the group consisting of Form I, Form II, Form III,
and Form IV of claim 1, and at least one pharmaceutically
acceptable excipient or carrier.
31. A purified form of the polymorph of claim 1.
32. A method of treating a chemokine-mediated disease or condition,
in a patient in need of such treatment, comprising administering to
said patient an effective amount of at least one polymorph of claim
1.
33. The method of claim 32 wherein the disease or condition is
selected from the group consisting of: pain, acute inflammation,
chronic inflammation, rheumatoid arthritis, psoriasis, atopic
dermatitis, asthma, COPD, adult respiratory disease, arthritis,
inflammatory bowel disease, Crohn's disease, ulcerative colitis,
septic shock, endotoxic shock, gram negative sepsis, toxic shock
syndrome, stroke, ischemia reperfusion injury, renal reperfusion
injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft
vs. host reaction, allograft rejections, malaria, acute respiratory
distress syndrome, delayed type hypersensitivity reaction,
atherosclerosis, cerebral ischemia, cardiac ischemia,
osteoarthritis, multiple sclerosis, restinosis, angiogenesis,
osteoporosis, gingivitis, respiratory viruses, herpes viruses,
hepatitis viruses, HIV, Kaposi's sarcoma associated virus,
meningitis, cystic fibrosis, pre-term labor, cough, pruritis,
multi-organ dysfunction, trauma, strains, sprains, contusions,
psoriatic arthritis, herpes, encephalitis, CNS vasculitis,
traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post
surgical trauma, interstitial pneumonitis, hypersensitivity,
crystal induced arthritis, acute pancreatitis, chronic
pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis,
chronic sinusitis, angiogenic ocular disease, ocular inflammation,
retinopathy of prematurity, diabetic retinopathy, macular
degeneration with the wet type preferred, corneal
neovascularization, polymyositis, vasculitis, acne, gastric ulcers,
duodenal ulcers, celiac disease, esophagitis, glossitis, airflow
obstruction, airway hyperresponsiveness, bronchiectasis,
bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor
pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation,
hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung
volume reduction, pulmonary fibrosis, pulmonary hypertension, right
ventricular hypertrophy, peritonitis associated with continuous
ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis,
sarcoidosis, small airway disease, ventilation-perfusion
mismatching, wheeze, colds, gout, alcoholic liver disease, lupus,
burn therapy, periodontitis, cancer, transplant reperfusion injury,
and early transplantation rejection.
34. The method of claim 33 wherein said: (a) Allograft rejections
are selected from the group consisting of acute allograft
rejections and chronic allograft rejections; (b) Early
transplantation rejection is an acute allograft rejection; (c)
Autoimmune deafness is Meniere's disease; (d) Myocarditis is viral
myocarditis; (e) Neuropathies are selected from the group
consisting of IgA neuropathy, membranous neuropathy and idiopathic
neuropathy; (f) Autoimmune diseases are anemias; (g) Vasculitis
syndromes are selected from the group consisting of giant cell
arteritis, Behcet's disease and Wegener's granulomatosis; and (h)
pain is selected from the group consisting of: acute pain, acute
inflammatory pain, chronic inflammatory pain, and neuropathic pain,
including acute and chronic neuropathic pain.
35. The method of claim 32 wherein said disease or condition is
angina.
36. The method of claim 32 wherein said disease or condition is
cancer.
37. The method of claim 36 further comprising the administration of
at least one anticancer agent.
38. The method of claim 37 wherein said anticancer agent is
selected from the group consisting of: alkylating agents,
antimetabolites, natural products and their derivatives, hormones,
anti-hormones, anti-angiogenic agents and steroids, and
synthetics.
39. The method of claim 38 wherein said anticancer agent is an
anti-angiogenic agent.
40. A method of treating a disease selected from the group
consisting of: gingivitis, respiratory viruses, herpes viruses,
hepatitis viruses, HIV, kaposi's sarcoma associated virus,
atherosclerosis, ocular inflammation, retinopathy of prematurity,
diabetic retinopathy, macular degeneration, and corneal
neovascularization in a patient in need of such treatment,
comprising administering to said patient an effective amount of at
least one polymorph of claim 1.
41. The method of claim 36 wherein the cancer treated is melanoma,
gastric carcinoma, or non-small cell lung carcinoma.
42. The method of claim 32 wherein said disease or condition is
COPD.
43. The method of claim 32 wherein said disease or condition is
acute inflammation, acute inflammatory pain, chronic inflammatory
pain, or neuropathic pain.
44. The method of claim 32 wherein said disease or condition is
rheumatoid arthritis.
45. The method of claim 32 wherein said disease or condition is
osteoarthritis.
46. The method of claim 32 wherein said disease or condition is
pain.
47. The method of claim 46 wherein said pain is associated with:
allodynia, ankylosing spondylitis, appendicitis, autoimmune
disorders, bacterial infections, Behcet's syndrome, broken bones,
bronchitis, burns, bursitis, cancer including metastatic cancer,
candidiasis, cardiovascular conditions, casualgia, chemical injury,
childbirth, chronic regional neuropathies, Crohn's disease,
colorectal cancer, connective tissue injuries, conjunctivitis,
COPD, decreased intracranial pressure, dental procedures,
dermatitis, diabetes, diabetic neuropathy, dysesthesia,
dysmenorrhea, eczema, emphysema, fever, fibromyalgia, gastric
ulcer, gastritis, giant cell arteritis, gingivitis, gout, gouty
arthritis, headache, headache pain resulting from lumbar puncture,
headaches including migraine headache, herpes simplex virus
infections, HIV, Hodgkin's disease, hyperalgesia, hypersensitivity,
inflammatory bowel disease, increased intracranial pressure,
irritable bowel syndrome, ischemia, juvenile arthritis, kidney
stones, lumbar spondylanhrosis, lower back, upper back and
lumbrosacral conditions, lumbar spondylarthrosis, menstrual cramps,
migraines, minor injuries, multiple sclerosis, myasthenia gravis,
myocarditis, muscle strains, musculoskeletal conditions, myocardial
ischemia, nephritic syndrome, nerve root avulsion, neuritis,
nutritional deficiency, ocular and corneal conditions, ocular
photophobia, ophthalmic diseases, osteoarthritis, otic surgery,
otitis externa, otitis media, periarteritis nodosa, peripheral
neuropathies, phantom limb pain, polymyositis, post-herpetic
neuralgia, post-operative/surgical recovery, post-thoracotomy,
psoriatic arthritis, pulmonary fibrosis, pulmonary edema,
radiculopathy, reactive arthritis, reflex sympathetic dystrophy,
retinitis, retinopathies, rheumatic fever, rheumatoid arthritis,
sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus
headaches, sinusitis, spinal cord injury, spondyloarthropathies,
sprains, stroke, swimmer's ear, tendonitis, tension headaches,
thalamic syndrome, thrombosis, thyroiditis, toxins, traumatic
injury, trigeminal neuralgia, ulcerative colitis, urogenital
conditions, uveitis, vaginitis, vascular diseases, vasculitis,
viral infections and/or wound healing.
48. The method of claim 46, further comprising administering to
said patient a therapeutically effective amount of at least one
medicament selected from the group consisting of: NSAIDs, COXIB
inhibitors, anti-depressants, anti-convulsants, anti-TNF.alpha.
antibodies and TNF.alpha. antagonists.
49. The method of claim 48 wherein: a) said NSAID is selected from
the group consisting of: piroxicam, ketoprofen, naproxen,
indomethacin, and ibuprofen; b) said COXIB inhibitor is selected
from the group consisting of: rofecoxib, celecoxib, etoricoxib,
valdecoxib and melotican; c) said anti-depressant is selected from
the group consisting of: amitriptyline and nortriptyline; d) said
anti-convulsant is selected from the group consisting of:
gabapentin, carbamazepine, pregabalin, and lamotrigine; e) said
anti-TNF.alpha. antibody is selected from the group consisting of:
infliximab and adalimumab; and f) said TNF.alpha. antagonist is
selected from the group consisting of: etanercept, p38 kinase
inhibitors, and TNF receptor fusion proteins.
50. The method of claim 48, wherein said pain is acute pain,
neuropathic pain, acute inflammatory pain or chronic pain.
51. The method of claim 32, further comprising administering to
said patient at least one medicament selected from the group
consisting of: a) disease modifying antirheumatic drugs; b)
nonsteroidal anti-inflammatory drugs; c) COX-2 selective
inhibitors; d) COX-1 inhibitors; e) immunosuppressives; f)
steroids; g) biological response modifiers; and h) other
anti-inflammatory agents or therapeutics useful for the treatment
of chemokine mediated diseases.
52. The method of claim 32 wherein said disease or condition is a
pulmonary disease, further comprising administering to said patient
a therapeutically effective amount of at least one compound
selected from the group consisting of: glucocorticoids,
5-lipoxygenase inhibitors, .beta.-2 adrenoceptor agonists,
muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2
agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene
antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors,
elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors,
phospholipase D inhibitors, histamine H1 antagonists, histamine H3
antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2
antagonists, GABA-b agonists, nociceptin agonists, expectorants,
mucolytic agents, decongestants, antioxidants, anti-IL-8
anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF
antibodies, IL-10, adhesion molecule inhibitors, and growth
hormones.
53. The method of claim 32 wherein said disease or condition is
multiple sclerosis, further comprising administering to said
patient a therapeutically effective amount of at least one compound
selected from the group consisting of glatiramer acetate,
glucocorticoids, methotrexate, azothioprine, mitoxantrone,
chemokine inhibitors, CB2-selective agents, methotrexate,
cyclosporin, leflunimide, sulfasalazine, .beta.-methasone,
.beta.-interferon, glatiramer acetate, and prednisone.
54. The method of claim 51, wherein said disease or condition is
pain.
55. The method of claim 32 wherein said disease or condition is
rheumatoid arthritis.
56. The method of claim 55, further comprising administering to
said patient a therapeutically effective amount of at least one
compound selected from the group consisting of COX-2 inhibitors,
COX inhibitors, immunosuppressives, steroids, PDE IV inhibitors,
anti-TNF-.alpha. compounds, MMP inhibitors, glucocorticoids,
chemokine inhibitors, CB2-selective inhibitors, and other classes
of compounds indicated for the treatment of rheumatoid
arthritis.
57. The method of claim 32 wherein said disease or condition is
stroke or cardiac reperfusion injury, further comprising
administering to said patient a therapeutically effective amount of
at least one compound selected from the group consisting of
thrombolitics, antiplatelet agents, antagonists, anticoagulants,
tenecteplase, TPA, alteplase, abciximab, eftiifbatide, and
heparin.
58. The method of claim 32 wherein said disease or condition is
psoriasis, further comprising administering to said patient a
therapeutically effective amount of at least one compound selected
from the group consisting of immunosuppressives, steroids, and
anti-TNF-.alpha. compounds.
59. The method of claim 32 wherein said disease or condition is
arthritis.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present patent application claims priority from U.S.
Provisional Application No. 60/540,487, filed Jan. 30, 2004.
FIELD OF THE INVENTION
[0002] The present invention relates to crystalline polymorphs of a
substituted cyclobutenedione compound, pharmaceutical compositions
containing the polymorphs, and methods and formulations in treating
CXC chemokine-mediated diseases.
BACKGROUND OF THE INVENTION
[0003] Chemokines are chemotactic cytokines that are released by a
wide variety of cells to attract macrophages, T-cells, eosinophils,
basophils, neutrophils and endothelial cells to sites of
inflammation and tumor growth. There are two main classes of
chemokines, the CXC-chemokines and the CC-chemokines. The class
depends on whether the first two cysteines are separated by a
single amino acid (CXC-chemokines) or are adjacent (CC-chemokines).
The CXC-chemokines include interleukin-8 (IL-8),
neutrophil-activating protein-1 (NAP-1), neutrophil-activating
protein-2 (NAP-2), GRO.alpha., GRO.beta., GRO.gamma., ENA-78,
GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES,
MIP-1.alpha., MIP-2.beta., monocyte chemotactic protein-1 (MCP-1),
MCP-2, MCP-3 and eotaxin. Individual members of the chemokine
families are known to be bound by at least one chemokine receptor,
with CXC-chemokines generally bound by members of the CXCR class of
receptors, and CC-chemokines by members of the CCR class of
receptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2
receptors.
[0004] Since CXC-chemokines promote the accumulation and activation
of neutrophils, these chemokines have been implicated in a wide
range of acute and chronic inflammatory disorders including
psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Lett.
307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992);
Oppenheim et al., Annu. Fev. Immunol. 9, 617 (1991); Seitz et al.,
J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir.
Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993).
[0005] ELRCXC chemokines, including IL-8, GRO.alpha., GRO.beta.,
GRO.gamma., NAP-2, and ENA-78 (Strieter et al. 1995 JBC 270 p.
27348-57), have also been implicated in the induction of tumor
angiogenesis (new blood vessel growth). All of these chemokines are
believed to exert their actions by binding to the 7 transmembrane
G-protein coupled receptor CXCR2 (also known as IL-8RB), while IL-8
also binds CXCR1 (also known as IL-8RA). Thus, their angiogenic
activity is due to their binding to and activation of CXCR2, and
possibly CXCR1 for IL-8, expressed on the surface of vascular
endothelial cells (ECs) in surrounding vessels.
[0006] Many different types of tumors have been shown to produce
ELRCXC chemokines and their production has been correlated with a
more aggressive phenotype (Inoue et al. 2000 Clin. Cancer Res. 6 p.
2104-2119) and poor prognosis (Yoneda et al. 1998 J. Nat. Cancer
Inst. 90 p. 447-454). Chemokines are potent chemotactic factors and
the ELRCXC chemokines have been shown to induce EC chemotaxis.
Thus, these chemokines probably induce chemotaxis of endothelial
cells toward their site of production in the tumor. This may be a
critical step in the induction of angiogenesis by the tumor.
Inhibitors of CXCR2 or dual inhibitors of CXCR2 and CXCR1 will
inhibit the angiogenic activity of the ELRCXC chemokines and
therefore block the growth of the tumor. This anti-tumor activity
has been demonstrated for antibodies to IL-8 (Arenberg et al. 1996
J. Clin. Invest. 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J.
Clin. Invest. 102 p. 465-72), and GRO.alpha. (Haghnegahdar et al.
J. Leukoc Biology 2000 67 p. 53-62).
[0007] Many tumor cells have also been shown to express CXCR2 and
thus tumor cells may also stimulate their own growth when they
secrete ELRCXC chemokines. Thus, along with decreasing
angiogenesis, inhibitors of CXCR2 may directly inhibit the growth
of tumor cells.
[0008] Hence, the CXC-chemokine receptors represent promising
targets for the development of novel anti-inflammatory and
anti-tumor agents.
[0009] There remains a need for compounds that are capable of
modulating activity at CXC-chemokine receptors. For example,
conditions associated with an increase in IL-8 production (which is
responsible for chemotaxis of neutrophil and T-cell subsets into
the inflammatory site and growth of tumors) would benefit by
compounds that are inhibitors of IL-8 receptor binding.
SUMMARY OF THE INVENTION
[0010] This invention provides a crystalline polymorph of a
monohydrate of Compound A of the formula: 2
[0011] wherein, said polymorph is selected from the group
consisting of:
[0012] Form I that exhibits a powder x-ray diffraction pattern
substantially the same as the pattern shown in FIG. 1;
[0013] Form II that exhibits a powder x-ray diffraction pattern
substantially the same as the pattern shown in FIG. 2;
[0014] Form III that exhibits a powder x-ray diffraction pattern
substantially the same as the pattern shown in FIG. 3; and
[0015] Form IV that exhibits a powder x-ray diffraction pattern
substantially the same as the pattern shown in FIG. 4.
[0016] This invention further provides a crystalline polymorph Form
I of a monohydrate of Compound A of the formula: 3
[0017] that exhibits a powder x-ray diffraction pattern having
characteristic peak locations of 6.612, 8.832, 27.024 and 28.134
degrees 2.theta..
[0018] In another embodiment, the crystalline polymorph Form I
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 6.612, 8.832, 13.268, 17.696, 19.492, 20.003,
27.024 and 28.134 degrees 2.theta..
[0019] In another embodiment, the crystalline polymorph Form I
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 6.612, 8.832, 13.268, 17.696, 17.959, 19.492,
20.003, 20.246, 21.123, 26.580, 27.024 and 28.134 degrees
2.theta..
[0020] In another embodiment, the invention provides the
crystalline polymorph Form I that exhibits a powder x-ray
diffraction pattern substantially the same as the pattern shown in
FIG. 1.
[0021] The invention further provides a crystalline polymorph Form
II of a monohydrate of Compound A of the formula: 4
[0022] that exhibits a powder x-ray diffraction pattern having
characteristic peak locations of 9.328, 13.774, 19.78 and 27.305
degrees 2.theta..
[0023] In another embodiment, the crystalline polymorph Form II
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 9.328, 13.145, 13.774, 15.79, 17.872, 18.748,
19.78 and 27.305 degrees 2.theta..
[0024] In another embodiment, the crystalline polymorph Form II
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 8.742, 9.328, 13.145, 13.774, 15.79, 17.872,
18.748, 19.263, 19.78, 20.166, 26.648 and 27.305 degrees
2.theta..
[0025] In another embodiment, the invention provides the
crystalline polymorph Form II that exhibits a powder x-ray
diffraction pattern substantially the same as the pattern shown in
FIG. 2.
[0026] The invention further provides a crystalline polymorph Form
III of a monohydrate of Compound A of the formula: 5
[0027] that exhibits a powder x-ray diffraction pattern having
characteristic peak locations of 7.748, 18.349, 23.198 and 23.851
degrees 2.theta..
[0028] In another embodiment, the crystalline polymorph Form III
exhibits a powder ray diffraction pattern having characteristic
peak locations of 7.748, 9.632, 14.07, 15.383, 18.349, 23.198,
23.851 and 27.841 degrees 2.theta..
[0029] In another embodiment, the crystalline polymorph Form III
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 7.748, 9.118, 9.632, 14.07, 15.383, 18.349, 18.6,
18.938, 19.383, 23.198, 23.851 and 27.841 degrees 2.theta..
[0030] In another embodiment, the invention provides the
crystalline polymorph Form III that exhibits a powder x-ray
diffraction pattern substantially the same as the pattern shown in
FIG. 3.
[0031] The invention further provides a crystalline polymorph Form
IV of a monohydrate of Compound A of the formula: 6
[0032] that exhibits a powder x-ray diffraction pattern having
characteristic peak locations of 11.46, 43.004, 44.097 and 50.107
degrees 2.theta..
[0033] In another embodiment, the crystalline polymorph Form IV
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 11.46, 11.848, 15.643, 16.957, 17.524, 43.004,
44.097 and 50.107 degrees 2.theta..
[0034] In another embodiment, the crystalline polymorph Form IV
exhibits a powder x-ray diffraction pattern having characteristic
peak locations of 8.706, 11.46, 11.848, 15.643, 16.957, 17.524,
19.335, 21.079, 26.917, 43.004, 44.097 and 50.107 degrees
2.theta..
[0035] In another embodiment, the invention provides the
crystalline polymorph Form IV that exhibits a powder x-ray
diffraction pattern substantially the same as the pattern shown in
FIG. 4.
[0036] The invention further provides a process for preparing the
polymorph Form I from amorphous Compound A: 7
[0037] comprising the steps of:
[0038] a) mixing amorphous Compound A at room temperature in a
first mixture of an alcohol and water to form a second mixture;
[0039] b) adding water dropwise until the second mixture becomes
hazy;
[0040] c) adding the organic solvent dropwise until the second
mixture becomes clear, and
[0041] d) allowing the second mixture to stand at room temperature
until Form I crystals precipitate.
[0042] The invention further provides a crystalline polymorph Form
I of the monohydrate of Compound A that is the product of the above
process.
[0043] In another embodiment, the alcohol is methanol or
ethanol.
[0044] The invention further provides a process for preparing the
polymorph Form II from Form I comprising the step of mixing the
Form I material with an organic solvent as a slurry at room
temperature until Form II crystals precipitate.
[0045] In another embodiment, the organic solvent is methylene
chloride or acetone.
[0046] The invention further provides a process for preparing the
polymorph Form III from Compound A: 8
[0047] comprising the steps of:
[0048] a. mixing Compound A at elevated temperature with a first
quantity of an organic solvent to form a mixture;
[0049] b. adding water portion-wise until precipitate is
detected;
[0050] c. adding a second quantity of the organic solvent;
[0051] d. heating the mixture to about 70.degree. C.; and
[0052] e. allowing the mixture to stand at room temperature until
Form III crystals precipitate.
[0053] The invention further provides a crystalline polymorph Form
II of the monohydrate of Compound A that is the product of the
above process.
[0054] The invention further provides a crystalline polymorph Form
III of the monohydrate of Compound A that is the product of the
above process.
[0055] In another embodiment, the organic solvent is
n-propanol.
[0056] In another embodiment, the ratio of the first quantity to
the second quantity is about 2:1.
[0057] The invention further provides a process for preparing the
polymorph Form IV from Compound A 9
[0058] comprising the step of mixing the Compound A material with
acetonitrile as a slurry at room temperature until Form IV crystals
precipitate.
[0059] The invention further provides a crystalline polymorph Form
IV of the monohydrate of Compound A that is the product of the
above process.
[0060] The invention further provides a process for preparing the
polymorph Form IV from Compound A 10
[0061] comprising the steps of:
[0062] a. mixing Compound A material with a first mixture of
n-propanol and water to form a second mixture;
[0063] b. agitating said second mixture while heating to about
70.degree. C. until substantially all solids are dissolved;
[0064] c. cooling said second mixture to about 60.degree. C.;
and
[0065] d. agitating said second mixture until Form IV crystals
precipitate.
[0066] The invention further provides a crystalline polymorph Form
IV of the monohydrate of Compound A that is the product of the
above process.
[0067] In another embodiment, the first mixture comprises
n-propanol and water in a ratio of about 1.1:1.
[0068] The invention further provides a pharmaceutical composition
comprising a crystalline polymorph selected from the group
consisting of Form I, Form II, Form III, and Form IV and at least
one excipient or carrier.
[0069] The invention further provides a purified form of the
polymorph Form I.
[0070] The invention further provides a purified form of the
polymorph Form II.
[0071] The invention further provides a purified form of the
polymorph Form III.
[0072] The invention further provides a purified form of the
polymorph Form IV.
[0073] The invention further provides a method of treating a
chemokine-mediated disease, in a patient in need of such treatment,
wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in
said patient, comprising administering to said patient an effective
amount of at least one polymorph of compound A.
[0074] The invention further provides a method of treating a
chemokine-mediated disease, in a patient in need of such treatment,
wherein the chemokine binds to a CXC receptor in said patient,
comprising administering to said patient an effective amount of at
least one polymorph of compound A.
[0075] The invention further provides a method of treating a
chemokine-mediated disease, in a patient in need of such treatment
wherein the chemokine is selected from the group consisting of:
pain, acute inflammation, chronic inflammation, rheumatoid
arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult
respiratory disease, arthritis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, septic shock, endotoxic shock, gram
negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion
injury, renal reperfusion injury, glomerulonephritis, thrombosis,
Alzheimer's disease, graft vs. host reaction, allograft rejections,
malaria, acute respiratory distress syndrome, delayed type
hypersensitivity reaction, atherosclerosis, cerebral ischemia,
cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis,
angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes
viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus,
meningitis, cystic fibrosis, pre-term labor, cough, pruritis,
multi-organ dysfunction, trauma, strains, sprains, contusions,
psoriatic arthritis, herpes, encephalitis, CNS vasculitis,
traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post
surgical trauma, interstitial pneumonitis, hypersensitivity,
crystal induced arthritis, acute pancreatitis, chronic
pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis,
chronic sinusitis, angiogenic ocular disease, ocular inflammation,
retinopathy of prematurity, diabetic retinopathy, macular
degeneration with the wet type preferred, corneal
neovascularization, polymyositis, vasculitis, acne, gastric ulcers,
duodenal ulcers, celiac disease, esophagitis, glossitis, airflow
obstruction, airway hyperresponsiveness, bronchiectasis,
bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor
pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation,
hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung
volume reduction, pulmonary fibrosis, pulmonary hypertension, right
ventricular hypertrophy, peritonitis associated with continuous
ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis,
sarcoidosis, small airway disease, ventilation-perfusion
mismatching, wheeze, colds, gout, alcoholic liver disease, lupus,
burn therapy, periodontitis, cancer, transplant reperfusion injury,
and early transplantation rejection.
[0076] The invention further provides a method of treating a
chemokine-mediated disease, in a patient in need of such treatment
wherein said:
[0077] Allograft rejections are selected from the group consisting
of acute allograft rejections and chronic allograft rejections,
[0078] Early transplantation rejection is an acute allograft
rejection,
[0079] Autoimmune deafness is Meniere's disease,
[0080] Myocarditis is viral myocarditis,
[0081] Neuropathies are selected from the group consisting of IgA
neuropathy, membranous neuropathy and idiopathic neuropathy,
[0082] Autoimmune diseases are anemias,
[0083] Vasculitis syndromes are selected from the group consisting
of giant cell arteritis, Behcet's disease and Wegener's
granulomatosis, and pain is selected from the group consisting of:
acute pain, acute inflammatory pain, chronic inflammatory pain, and
neuropathic pain, including acute and chronic neuropathic pain.
[0084] The invention further provides a method of treating angina
in a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of at least one
polymorph of Compound A.
[0085] The invention further provides a method of treating cancer
in a patient in need of such treatment comprising administering to
said patient an effective amount of at least one polymorph of
Compound A.
[0086] The invention further provides the above method of treating
cancer in a patient in need of such treatment further comprising
the administration of at least one anticancer agent.
[0087] The invention further provides the above method of treating
cancer in a patient in need of such treatment, wherein said
anticancer agent is selected from the group consisting of:
alkylating agents, antimetabolites, natural products and their
derivatives, hormones, anti-hormones, anti-angiogenic agents and
steroids, and synthetics.
[0088] The invention further provides a method of inhibiting
angiogenesis in a patient in need of such treatment comprising
administering to said patient an effective amount of at least one
polymorph of Compound A in combination with the administration of
an effective amount of at least one anti-angiogenesis compound.
[0089] The invention further provides a method of treating a
disease selected from the group consisting of: gingivitis,
respiratory viruses, herpes viruses, hepatitis viruses, HIV,
kaposi's sarcoma associated virus and atherosclerosis, in a patient
in need of such treatment, comprising administering to said patient
an effective amount of at least one polymorph of Compound A.
[0090] The invention further provides a method of treating a
chemokine mediated disease wherein the disease is an angiogenic
ocular disease.
[0091] The invention further provides a method of treating a
angiogenic ocular disease wherein said angiogenic ocular disease is
selected from the group consisting of: ocular inflammation,
retinopathy of prematurity, diabetic retinopathy, macular
degeneration with the wet type preferred and corneal
neovascularization.
[0092] The invention further provides the above method of treating
cancer in a patient in need of such treatment, wherein the cancer
treated is melanoma, gastric carcinoma, or non-small cell lung
carcinoma.
[0093] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such treatment
wherein said disease is COPD.
[0094] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such treatment
wherein said disease is acute inflammation.
[0095] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such treatment
wherein said disease is rheumatoid arthritis.
[0096] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such treatment
wherein said disease is acute inflammatory pain.
[0097] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such
treatment, wherein said disease is chronic inflammatory pain.
[0098] The invention further provides the above method of treating
a chemokine mediated disease in a patient in need of such
treatment, wherein said disease is neuropathic pain.
[0099] The invention further provides a method of treating pain
comprising the step of administering to a patient in need of
treatment a therapeutically effective amount of at least one
polymorph of Compound A having the structure: 11
[0100] The invention further provides the above method of treating
pain, wherein said pain is associated with: allodynia, ankylosing
spondylitis, appendicitis, autoimmune disorders, bacterial
infections, Behcet's syndrome, broken bones, bronchitis, burns,
bursitis, cancer including metastatic cancer, candidiasis,
cardiovascular conditions, casualgia, chemical injury, childbirth,
chronic regional neuropathies, Crohn's disease, colorectal cancer,
connective tissue injuries, conjunctivitis, COPD, decreased
intracranial pressure, dental procedures, dermatitis, diabetes,
diabetic neuropathy, dysesthesia, dysmenorrhea, eczema, emphysema,
fever, fibromyalgia, gastric ulcer, gastritis, giant cell
arteritis, gingivitis, gout, gouty arthritis, headache, headache
pain resulting from lumbar puncture, headaches including migraine
headache, herpes simplex virus infections, HIV, Hodgkin's disease,
hyperalgesia, hypersensitivity, inflammatory bowel disease,
increased intracranial pressure, irritable bowel syndrome,
ischemia, juvenile arthritis, kidney stones, lumbar
spondylanhrosis, lower back, upper back and lumbrosacral
conditions, lumbar spondylarthrosis, menstrual cramps, migraines,
minor injuries, multiple sclerosis, myasthenia gravis, myocarditis,
muscle strains, musculoskeletal conditions, myocardial ischemia,
nephritic syndrome, nerve root avulsion, neuritis, nutritional
deficiency, ocular and corneal conditions, ocular photophobia,
ophthalmic diseases, osteoarthritis, otic surgery, otitis externa,
otitis media, periarteritis nodosa, peripheral neuropathies,
phantom limb pain, polymyositis, post-herpetic neuralgia,
post-operative/surgical recovery, post-thoracotomy, psoriatic
arthritis, pulmonary fibrosis, pulmonary edema, radiculopathy,
reactive arthritis, reflex sympathetic dystrophy, retinitis,
retinopathies, rheumatic fever, rheumatoid arthritis, sarcoidosis,
sciatica, scleroderma, sickle cell anemia, sinus headaches,
sinusitis, spinal cord injury, spondyloarthropathies, sprains,
stroke, swimmer's ear, tendonitis, tension headaches, thalamic
syndrome, thrombosis, thyroiditis, toxins, traumatic injury,
trigeminal neuralgia, ulcerative colitis, urogenital conditions,
uveitis, vaginitis, vascular diseases, vasculitis, viral infections
and/or wound healing.
[0101] The invention further provides a method of treating pain in
a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of at least one
polymorph of Compound A and administering to said patient a
therapeutically effective amount of at least one medicament
selected from the group consisting of: NSAIDs, COXIB inhibitors,
anti-depressants, anti-convulsants, anti-TNF.alpha. antibodies and
TNF.alpha. antagonists.
[0102] The invention further provides the above method of treating
pain, wherein said polymorph is administered as a pharmaceutical
composition.
[0103] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one NSAID.
[0104] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one COXIB
inhibitor.
[0105] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one
anti-depressant.
[0106] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one
anti-convulsant.
[0107] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one
anti-TNF.alpha. antibody.
[0108] The invention further provides the above method for treating
pain, wherein said medicament comprises at least one TNF.alpha.
antagonist.
[0109] The invention further provides the above method for treating
pain, wherein said NSAID is selected from the group consisting of:
piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.
[0110] The invention further provides the above method for treating
pain, wherein said COXIB inhibitor is selected from the group
consisting of: rofecoxib, celecoxib, etoricoxib, valdecoxib and
melotican.
[0111] The invention further provides the above method for treating
pain, wherein said anti-depressant is selected from the group
consisting of: amitriptyline and nortriptyline.
[0112] The invention further provides the above method for treating
pain, wherein said anti-convulsant is selected from the group
consisting of: gabapentin, carbamazepine, pregabalin, and
lamotrigine.
[0113] The invention further provides the above method for treating
pain, wherein said anti-TNF.alpha. antibody is selected from the
group consisting of: infliximab and adalimumab.
[0114] The invention further provides the above method for treating
pain, wherein said TNF.alpha. antagonist is selected from the group
consisting of: etanercept, p38 kinase inhibitors, and TNF receptor
fusion proteins.
[0115] The invention further provides the above method for treating
pain, wherein said pain is acute pain.
[0116] The invention further provides the above method for treating
pain, wherein said pain is neuropathic pain.
[0117] The invention further provides the above method for treating
pain, wherein said pain is acute inflammatory pain.
[0118] The invention further provides the above method for treating
pain, wherein said pain is chronic.
[0119] The invention further provides a method of treating a
chemokine mediated disease or condition in a patient in need of
such treatment comprising administering to said patient at least
one polymorph of Compound A in combination with at least one other
medicament useful for the treatment of chemokine mediated
diseases.
[0120] The invention further provides a method of treating a
chemokine mediated disease or condition in a patient in need of
such treatment comprising comprising administering to said patient
at least one polymorph of Compound A in combination with at least
one other medicament selected from the group consisting of:
[0121] disease modifying antirheumatic drugs;
[0122] nonsteroidal anitinflammatory drugs;
[0123] COX-2 selective inhibitors;
[0124] COX-1 inhibitors;
[0125] immunosuppressives;
[0126] steroids;
[0127] biological response modifiers; and
[0128] other anti-inflammatory agents or therapeutics useful for
the treatment of chemokine mediated diseases.
[0129] The invention further provides the above method wherein the
chemokine mediated disease or condition is pain.
[0130] The invention further provides a method of treating a
pulmonary disease in a patient in need of such treatment,
comprising administering to said patient a therapeutically
effective amount of at least one polymorph of Compound A, in
combination with at least one compound selected from the group
consisting of: glucocorticoids, 5-lipoxygenase inhibitors, .beta.-2
adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3
antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4
antagonists, cysteinyl leukotriene antagonists, bronchodilators,
PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP
inhibitors, phospholipase A2 inhibitors, phospholipase D
inhibitors, histamine H1 antagonists, histamine H3 antagonists,
dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists,
GABA-b agonists, nociceptin agonists, expectorants, mucolytic
agents, decongestants, antioxidants, anti-IL-8 anti-bodies,
anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies,
IL-10, adhesion molecule inhibitors, and growth hormones. The
invention further provides a method of treating multiple sclerosis
in a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of at least one
polymorph of Compound A in combination with at least one compound
selected from the group consisting of glatiramer acetate,
glucocorticoids, methotrexate, azothioprine, mitoxantrone,
chemokine inhibitors, and CB2-selective agents.
[0131] The invention further provides a method of treating multiple
sclerosis in a patient in need of such treatment comprising
administering to said patient a therapeutically effective amount of
at least one polymorph of Compound A in combination with at least
one compound selected from the group consisting of: methotrexate,
cyclosporin, leflunimide, sulfasalazine, .beta.-methasone,
.beta.-interferon, glatiramer acetate, and prednisone.
[0132] The invention further provides a method of treating
rheumatoid arthritis in a patient in need of such treatment
comprising administering to said patient a therapeutically
effective amount of at least one polymorph of Compouind A.
[0133] The invention further provides a method of treating
rheumatoid arthritis in a patient in need of such treatment
comprising administering to said patient a therapeutically
effective amount of at least one polymorph of Compound A in
combination with at least one compound selected from the group
consisting of COX-2 inhibitors, COX inhibitors, immunosuppressives,
steroids, PDE IV inhibitors, anti-TNF-.alpha. compounds, MMP
inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective
inhibitors, and other classes of compounds indicated for the
treatment of rheumatoid arthritis.
[0134] The invention further provides a method of treating stroke
and cardiac reperfusion injury in a patient in need of such
treatment comprising administering to said patient a
therapeutically effective amount of at least one polymorph of
Compound A in combination with at least one compound selected from
the group consisting of thrombolitics, antiplatelet agents,
antagonists, anticoagulants, and other compounds indicated for the
treatment of rheumatoid arthritis.
[0135] The invention further provides a method of treating stroke
and cardiac reperfusion injury in a patient in need of such
treatment comprising administering to said patient a
therapeutically effective amount of at least one polymorph of
Compound A in combination with at least one compound selected from
the group consisting of tenecteplase, TPA, alteplase, abciximab,
eftiifbatide, and heparin.
[0136] The invention further provides a method of treating
psoriasis in a patient in need of such treatment, comprising
administering to said patient a therapeutically effective amount of
at least one polymorph of Compound A in combination with at least
one compound selected from the group consisting of
immunosuppressives, steroids, and anti-TNF-.alpha. compounds.
[0137] The invention further provides a method of treating COPD in
a patient in need of such treatment, comprising administering to
said patient a therapeutically effective amount of at least one
polymorph of Compound A.
[0138] The invention further provides a method of treating
arthritis in a patient in need of such treatment, comprising
administering to said patient a therapeutically effective amount of
at least one polymorph of Compound A.
[0139] The invention further provides a method of treating
osteoarthritis in a patient in need of such treatment, comprising
administering to said patient a therapeutically effective amount of
at least one polymorph of Compound A.
BRIEF DESCRIPTION OF THE DRAWINGS
[0140] FIG. 1 is a graph of a powder x-ray diffraction (PXRD)
pattern of Form I of a monohydrate of Compound A, generated using
an X-ray diffractometer. The graph plots the intensity of the peaks
as defined by counts per second versus the diffraction angle
2.theta. in degrees.
[0141] FIG. 2 is a graph of a PXRD pattern of Form II of a
monohydrate of Compound A. The graph was generated using an X-ray
diffractometer. The graph plots the intensity of the peaks as
defined by counts per second versus the diffraction angle 2.theta.
in degrees.
[0142] FIG. 3 is a graph of a PXRD pattern of Form III of a
monohydrate of Compound A, generated using an X-ray diffractometer.
The graph plots the intensity of the peaks as defined by counts per
second versus the diffraction angle 2.theta. in degrees.
[0143] FIG. 4 is a graph of a PXRD pattern of Form IV of a
monohydrate of Compound A. The graph was generated using an X-ray
diffractometer. The graph plots the intensity of the peaks as
defined by counts per second versus the diffraction angle 2.theta.
in degrees.
DETAILED DESCRIPTION
[0144] Compound A is disclosed in WO 02/083624 as Examples 360.31
and 405, which reflect the following chemical structure: 12
[0145] Anhydrous Compound A is particularly active as a
CXC-chemokine receptor ligand. A monohydrate form of Compound A was
found to have substantially similar activity. Four distinct
crystalline polymorphs of a monohydrate of Compound A were found to
exist. These four forms are herein referred to as Forms I, II, III
and IV. Each of the four polymorphs is neutral, i.e., in neither
ionic nor salt form. The four crystalline forms can be referred to
as polymorphs. Since the intended use of this compound is as a
therapeutically active pharmaceutical agent, the most stable
pharmaceutically acceptable forms of the monohydrate of Compound A
will be of great interest.
[0146] Polymorphism can be characterized as the ability of a
compound to crystallize into different crystal forms, while
maintaining the same chemical formula. A crystalline polymorph of a
given drug substance is chemically identical to any other
crystalline polymorph of that drug substance in containing the same
atoms bonded to one another in the same way, but differs in its
crystal forms, which can affect one or more physical properties,
such as stability, solubility, melting point, bulk density, flow
properties, bioavailability, etc.
[0147] As used throughout the specification, the following terms,
unless otherwise indicated, shall be understood to have the
following meanings:
[0148] "Patient" includes both human and other animals.
[0149] "Mammal" includes humans and other mammalian animals.
[0150] "Polymorph" means a crystalline form of a substance that is
distinct from another crystalline form but that shares the same
chemical formula.
[0151] "Inventive polymorph" means any of the four crystalline
polymorphs Forms I-IV of the monohydrate of Compound A, and is not
limited to a single polymorph but can include more than one
form.
[0152] "Alcohol" means an organic compound containing a hydroxyl
group (--OH).
[0153] "Nitrile" means an organic compound containing a --C.ident.N
group.
[0154] "Excipient" means an essentially inert substance used as a
diluent or to give form or consistency to a formulation.
[0155] "Effective" or "therapeutically effective" is meant to
describe a polymorph of a compound or a composition of the present
invention effective as a chemokine receptor ligand and thus
producing the desired therapeutic, ameliorative, inhibitory or
preventative effect. "Effective amount" or "therapeutically
effective amount" is meant to describe an amount of polymorph or a
composition of the present invention effective as a chemokine
receptor ligand and thus producing the desired therapeutic,
ameliorative, inhibitory or preventative effect.
[0156] Sample Preparation
[0157] Forms I-IV of Compound A were analyzed as a dry powder for
powder x-ray diffraction ("PXRD") analyses. Forms I, II and III
were analyzed without first being micronized. Form IV was analyzed
after micronization.
[0158] A micronizer was used to grind and classify the Form IV
material. The micronizer grinds and classifies the Compound A
material in a single shallow chamber. Filtered nitrogen is
introduced through peripheral jets. These jets are spaced at
regular intervals around the periphery of the grinding chamber.
During operation, a high-speed vortex is generated, and the
Compound A material is injected into the vortex near the peripheral
wall. Strong velocity gradients near the jets cause the suspended
particles to collide and reduce one another by impact. Heavier
oversized particles are held in the grinding area by centrifugal
force. The rate of feed and the grinding gas pressure are the main
factors that control the output particle size. The grinding gas
exits through an outlet at the top center of the chamber and draws
the micronized product with it into the collection bag. The
Compound A material is collected in double-polyethylene-bag-lined
drums. The batch was micronized at a feed rate of 100 g/min and a
mill pressure of 40 psig on a 4 inch micronizer.
[0159] The samples were analyzed with minimal preparation to
prevent any form changes. The samples were lightly rubbed to insure
that particles were not agglomerated. No solvents, drying or other
preparation steps were used for these analyses. The PXRD data can
uniquely identify the polymorphic forms.
[0160] Powder X-Ray Diffraction
[0161] The Bruker D8 diffractometer (manufactured in 2002) was used
in the powder x-ray powder diffraction studies. It has a parallel
optic configuration with a GBEL beam focusing mirror and a Position
Sensitive Detector ("PSD") equipped with a fixed radial soller slit
was used with an Anton Paar TTK450 temperature stage. The radiation
source is copper (K.alpha.). The divergence slits are fixed at 0.6
mm. The sample holder was a top-loading brass block. PSD fast scan
was used to scan from 3.0.degree. to 69.9.degree.. Specimens were
loaded onto the sample holder and leveled with a glass microscope
slide. The sample chamber temperature was set at 30.degree. C.,
under ambient humidity and not purged with nitrogen and not under
vacuum. Instrument calibration was verified using mica standards.
During scanning, the step size was 0.013 degrees over step
durations of 2 seconds. Data analysis was accomplished using EVA
analysis software, version 7.0.0.1, supplied by Bruker.RTM. written
by SOCABIM.RTM.. The data were not smoothed by the software while
the peak search was performed with a threshold of 3.
[0162] Using the methods and equipment described above, Forms I-IV
of Compound A were subjected to PXRD analysis. PXRD patterns were
generated and are displayed in FIGS. 1-4. The intensity of the
peaks (y-axis is in counts per second) is plotted vesus the
2.theta. angle (x-axis is in degrees 2.theta.). In addition, the
data were plotted with detector counts normalized for the
collection time per step versus the 20 angle. Peak locations (on
the 2.theta. X-axis) consistent with these profiles are displayed
in Table 1. The locations of these PXRD peaks are characteristic of
crystalline polymorphs of Forms I-IV of Compound A.
1TABLE 1 PXRD Peak Positions for Forms I-IV of Compound A Form I
Form II Form III Form IV Peak Location Intensity Peak Location
Intensity Peak Location Intensity Peak Location Intensity (deg.
2.theta.) (Cps) (deg. 2.theta.) (Cps) (deg. 2.theta.) (Cps) (deg.
2.theta.) (Cps) 3.280 11328 3.205 2020 3.287 1384 3.35 1359 3.832
1484 6.54 10968 5.52 5845 3.971 1154 6.612 17385 8.742 14922 6.258
1564 6.8 2404 8.832 18353 9.328 11006 7.748 7923 8.706 7071 9.345
1230 10.97 584 9.118 14807 9.067 1491 9.983 883 11.471 392 9.632
6748 9.616 512 11.642 2643 12.101 1960 10.452 483 11.46 2128 12.018
2208 12.543 769 11.081 383 11.848 2298 12.551 2328 12.822 1350
13.145 2996 13.158 783 13.268 6017 13.145 6355 14.07 5081 13.545
2022 14.195 665 13.774 3441 14.384 2785 14.014 313 15.232 1331
14.768 817 15.083 4755 15.15 678 15.921 1820 15.79 4271 15.383 7925
15.643 2288 16.370 3250 16.104 1506 16.376 1706 16.957 2166 17.161
2379 17.13 1800 16.931 3003 17.524 3268 17.696 8306 17.872 15217
17.684 1884 18.114 1778 17.959 4931 18.748 12033 18.349 6974 18.623
1000 18.254 2255 19.263 4102 18.6 9640 19.335 2266 18.852 3577
19.78 4396 18.938 7057 20.407 1715 19.492 4935 20.166 8994 19.383
7682 21.079 3288 20.003 5410 20.507 2201 20.645 2861 21.569 741
20.246 7443 21.675 787 21.415 1858 22.387 1299 21.123 4989 22.023
1467 21.667 1475 23.348 810 21.581 1856 22.42 1394 22.187 4174
23.687 2040 22.473 1070 23.078 2332 22.796 2881 24.335 1030 23.063
2946 23.705 965 23.198 6709 24.946 1266 23.687 1548 24.229 1215
23.851 5987 25.425 926 24.904 1862 24.761 1491 24.883 2118 25.854
1240 25.438 1979 25.209 2937 25.336 1780 26.357 1546 26.580 8497
25.741 1402 25.682 2210 26.917 3247 27.024 5901 26.648 9917 26.221
1613 27.29 1040 27.409 2024 27.305 4457 27.139 2199 28.307 2084
28.134 5093 27.941 2750 27.841 8966 29.028 625 28.931 2049 28.312
1354 29.031 1159 29.75 389 29.731 3445 29.182 1217 30.017 1604
30.429 512 30.637 1362 29.579 1151 30.931 1046 30.858 415 31.449
1482 31.253 2112 31.253 1276 32.883 902 31.829 997 32.286 1047
31.926 1704 33.242 763 33.156 2063 32.92 994 32.525 1155 34.091 663
33.855 1204 33.296 1435 33.926 1485 36.114 607 34.798 1020 34.475
1408 34.828 881 36.816 497 35.583 1199 35.123 1227 35.433 1003
37.961 493 36.958 1084 35.741 1310 36.242 1123 38.588 486 37.810
933 36.09 1071 37.026 908 39.748 483 38.817 840 36.901 728 37.452
760 41.38 2000 40.589 1039 38.098 794 38.844 1107 42.436 857 41.372
1372 39.353 748 39.479 876 43.004 4192 42.475 1130 40.098 859
40.007 939 44.097 4109 43.001 2527 40.312 896 41.379 1690 44.854
1216 44.092 2754 41.364 1557 42.377 1017 46.225 1611 44.898 1214
42.445 988 43.005 3041 50.107 2355 46.221 1470 42.997 3142 44.086
3147 51.431 1359 47.635 822 44.101 3187 44.847 1085 52.345 835
50.105 1587 44.842 1197 46.228 1349 51.426 1142 45.487 1029 47.127
789 52.349 819 46.218 1396 50.101 1718 56.023 547 48.074 577 51.439
1116 50.099 1841 52.343 861 51.439 1148 54.953 469 52.346 772 58.52
459 54.928 526
[0163] Starting with PXRD peak locations as displayed in Table 1,
the most characteristic peak locations of each polymorph can be
selected and grouped by relative intensity to conveniently
distinguish the crystalline structure from others.
[0164] Such a selection of unique peaks is displayed in Table 2.
Thus, for example, the crystalline structure of Form I of Compound
A may be identified by the Peak Location Group No. 1, consisting of
4 characteristic PXRD peak locations. Alternatively, the
crystalline structure of Form I of Compound A may be identified by
the Peak Location Group No. 2, consisting of the 4 characteristic
PXRD peak locations of Group No. 1 and an additional 4 peak
locations. Alternatively, the Form I crystalline structure of
Compound A may be identified by the Peak Location Group No. 3,
consisting of the 8 characteristic PXRD peak locations of Group No.
2 and an additional 4 peak locations. This scheme is applied to all
four polymorphic forms to identify and distinguish each form from
the others.
2TABLE 2 Characteristic PXRD Peak Locations for Forms I-IV of
Compound A Peak Location Peak Locations (degrees 2.theta.) Group No
Form I Form II Form III Form IV 1 6.612 9.328 7.748 11.46 8.832
13.774 18.349 43.004 27.024 19.78 23.198 44.097 28.134 27.305
23.851 50.107 2 6.612 9.328 7.748 11.46 8.832 13.145 9.632 11.848
13.268 13.774 14.07 15.643 17.696 15.79 15.383 16.957 19.492 17.872
18.349 17.524 20.003 18.748 23.198 43.004 27.024 19.78 23.851
44.097 28.134 27.305 27.841 50.107 3 6.612 8.742 7.748 8.706 8.832
9.328 9.118 11.46 13.268 13.145 9.632 11.848 17.696 13.774 14.07
15.643 17.959 15.79 15.383 16.957 19.492 17.872 18.349 17.524
20.003 18.748 18.6 19.335 20.246 19.263 18.938 21.079 21.123 19.78
19.383 26.917 26.58 20.166 23.198 43.004 27.024 26.648 23.851
44.097 28.134 27.305 27.841 50.107
[0165] Those skilled in the art will recognize that the
measurements of the PXRD peak locations for a given crystalline
form of the same compound will vary within a margin of error. Such
variation can be introduced by differences in sample preparation,
instrumentation, or analytical technique, among other factors.
Measurements of individual peak locations can vary to a small
degree, but an entire peak profile can vary by a greater degree,
due to variations in density of packed samples, for example.
[0166] Synthesis of Polymorphic Forms
[0167] Form I:
[0168] Compound A Form I is a neutral form with 1:1 molar ratio of
hydrate water. It was prepared by crystallizing amorphous neutral
Compound A from a mixture of an alcohol and water, in some
embodiments, the alcohol is methanol or ethanol. The amorphous
Compound A was dissolved in a minimum amount of methanol or ethanol
at room temperature. Water was added dropwise until the solution
became hazy, whereupon the alcohol was added to make the solution
clear. The solution was allowed to stand at room temperature
overnight until solid formed. The precipitate was collected by
filtration. The PXRD profile of Form I as crystallized from an
ethanol/water mixture is displayed in FIG. 1.
[0169] Compound A Form I was also prepared by crystallizing
amorphous neutral Compound A from commercial grade (non-anhydrous)
methanol. The amorphous Compound A was dissolved in a minimum
amount of methanol at room temperature and the solution was allowed
to stand at room temperature and concentrate via evaporation until
solid materials formed. The precipitate was collected by
filtration.
[0170] Form II:
[0171] Compound A Form II is a neutral form with 1:1 molar ratio of
hydrate water. It was prepared by mixing Compound A Form I in an
organic solvent as a slurry at room temperature. In some
embodiments, the organic solvent is methylene chloride or acetone.
Conversion to Form II occurs spontaneously. The PXRD profile of
Form II as crystallized from a slurry of Form I and methylene
chloride is displayed in FIG. 2.
[0172] Form III:
[0173] Compound A Form III is a neutral form with a 1:1 molar ratio
of hydrate water. It was prepared by crystallizing Compound A
amorphous neutral form from a mixture of an organic solvent and
water at elevated temperature. Preferably, the organic solvent is
n-propanol. The procedure is described below:
[0174] About 6 g of amorphous, unmicronized Compound A solid was
dissolved in 45 mL n-propanol by warming in a heating mantle under
a nitrogen atmosphere. About 80 mL of water was added portion-wise
until precipitation was detected. Another 20 mL of n-propanol was
added to the slurry and the mixture was heated to 70.degree. C. The
heating mantle was removed and a precipitate formed. The slurry was
stirred overnight and filtered and washed with 4:1
H.sub.2O/n-propanol. The solid was dried in vacuo at 40.degree. C.
The PXRD profile of Form III as crystallized from amorphous,
unmicronized Compound A and a mixture of n-propanol/water is
displayed in FIG. 3.
[0175] Form IV:
[0176] Compound A Form IV is a neutral form with a 1:1 molar ratio
of hydrate water. It was prepared by mixing Compound A Form I in
either acetonitrile or n-propanol as a slurry at room temperature.
Conversion to Form IV occurs spontaneously. In large scale, it was
prepared by the procedure described below:
[0177] To a 5 Liter, three-necked round bottom flask equipped with
a mechanical stirrer, thermocouple, and reflux condenser, was
charged 200 g of Compound A neutral form monohydrate, 2.2 L of
n-propanol and 2.0 L of water. The suspension was agitated and
heated up to 70.degree. C. to dissolve all solids. The solution was
then cooled to 60.degree. C. and Form IV seeds were charged (about
0.5 g). The mixture was stirred at a temperature between 58 and
60.degree. C. for 4 hours while allowing the product to
precipitate. The mixture was then cooled to 50.degree. C. over one
hour and agitated at this temperature over night. The batch was
further cooled to a temperature between 5 and 10.degree. C. over
three hours. The product was collected by filtration and dried in a
vacuum oven at 50.degree. C. for 10 hours. The recovery was 180.4 g
(90.2%). The PXRD analysis is displayed in FIG. 4 and shows pure
Form IV crystals.
[0178] In the above procedures for the preparation of Forms III and
IV, the form of Compound A used as the starting material can
alternately be amorphous, Forms I-IV, or any combination
thereof.
[0179] Polymorph Purity
[0180] Preferably, the crystalline polymorphs Forms I-IV of the
monohydrate of Compound A are substantially free of chemical
impurities (e.g., by-products generated during the preparation of
the polymorphs) and of other polymorphic crystalline forms.
"Substantially free" of chemical impurities for the purposes of
this invention means less than or equal to about 5% w/w of chemical
impurities, preferably, less than or equal to about 3% w/w of
chemical impurities, more preferably, less than or equal to about
2% w/w of chemical impurities, and even more preferably, less than
or equal to about 1% w/w of chemical impurities. The term
"purified" or "in purified form" for a polymorph refers to the
physical state of said polymorph after being obtained from a
purification process or processes described herein or well known to
the skilled artisan, in sufficient purity to be characterizable by
standard analytical techniques described herein or well known to
the skilled artisan. Purified forms of the crystalline polymorph
Forms I-IV of the monohydrate of Compound A are substantially free
of chemical impurities.
[0181] Pharmaceutical Compositions
[0182] For preparing pharmaceutical compositions from the
polymorphs described by this invention, inert, pharmaceutically
acceptable carriers can be either solid or liquid. Solid form
preparations include powders, tablets, dispersible granules,
capsules, cachets and suppositories. The powders and tablets may be
comprised of from about 5 to about 95 percent active ingredient.
Suitable solid carriers are known in the art, e.g., magnesium
carbonate, magnesium stearate, talc, sugar or lactose. Tablets,
powders, cachets and capsules can be used as solid dosage forms
suitable for oral administration. Examples of pharmaceutically
acceptable carriers and methods of manufacture for various
compositions may be found in A. Gennaro (ed.), Remington's
Pharmaceutical Sciences, 18.sup.th Edition, (1990), Mack Publishing
Co., Easton, Pa.
[0183] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0184] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0185] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0186] The inventive polymorphs may also be deliverable
transdermally. The transdermal composition can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0187] In some embodiments, the inventive polymorph is administered
orally.
[0188] In some embodiments, the pharmaceutical preparation is in a
unit dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0189] Dosages
[0190] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.01 mg to about
1000 mg, preferably from about 0.01 mg to about 750 mg, more
preferably from about 0.01 mg to about 500 mg, and most preferably
from about 0.01 mg to about 250 mg, according to the particular
application.
[0191] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total dosage may be divided and administered in
portions during the day as required.
[0192] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 0.04 mg/day to about 4000
mg/day, in one to four divided doses.
[0193] Co-Formulations
[0194] In some embodiments of the treatment of cancer, at least one
of the polymorphs disclosed herein is administered in combination
with one of the following antineoplastic agents: gemcitabine,
paclitaxel (Taxol.RTM.), 5-Fluorourcil (5-FU), cyclophosphamide
(Cytoxan.RTM.), temozolomide, or Vincristine.
[0195] Classes of compounds that can be used as the
chemotherapeutic agent (antineoplastic agent) include: alkylating
agents, antimetabolites, natural products and their derivatives,
hormones and steroids (including synthetic analogs), and
synthetics. Examples of compounds within these classes are given
below.
[0196] Alkylating agents (including nitrogen mustards, ethylenimine
derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil
mustard, Chlormethine, Cyclophosphamide (Cytoxan.RTM.), Ifosfamide,
Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,
Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,
Streptozocin, Dacarbazine, and Temozolomide.
[0197] Antimetabolites (including folic acid antagonists,
pyrimidine analogs, purine analogs and adenosine deaminase
inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
Pentostatine, and Gemcitabine.
[0198] Natural products and their derivatives (including vinca
alkaloids, antitumor antibiotics, enzymes, lymphokines and
epipodophyllotoxins): Vinblastine, Vincristine, Vindesine,
Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin,
Idarubicin, paclitaxel (paclitaxel is commercially available as
Taxol.RTM. and is described in more detail below in the subsection
entitled "Microtubule Affecting Agents"), Mithramycin,
Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons
(especially IFN-a), Etoposide, and Teniposide.
[0199] Hormones and steroids (including synthetic analogs):
17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,
Prednisone, Fluoxymesterone, Dromostanolone propionate,
Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone,
Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,
Zoladex.
[0200] Synthetics (including inorganic complexes such as platinum
coordination complexes): Cisplatin, Carboplatin, Hydroxyurea,
Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and
Hexamethylmelamine.
[0201] Methods for the safe and effective administration of most of
these chemotherapeutic agents are known to those skilled in the
art. In addition, their administration is described in the standard
literature. For example, the administration of many of the
chemotherapeutic agents is described in the "Physicians' Desk
Reference" (PDR), e.g., 2002 edition (Medical Economics Company,
Montvale, N.J. 07645-1742, USA); the disclosure of which is
incorporated herein by reference thereto.
[0202] In another embodiment, the present invention provides a
method of treating cancer, comprising administering, concurrently
or sequentially, an effective amount of at least one of the
polymorphs disclosed herein and a microtubule affecting agent e.g.,
paclitaxel.
[0203] Another embodiment of the invention is directed to a method
treating cancer, comprising administering to a patient in need
thereof, concurrently or sequentially, a therapeutically effective
amount of (a) at least one of the polymorphs disclosed herein, and
(b) an antineoplastic agent, microtubule affecting agent or
anti-angiogenesis agent.
[0204] As used herein, a microtubule affecting agent is a compound
that interferes with cellular mitosis, i.e., having an anti-mitotic
effect, by affecting microtubule formation and/or action. Such
agents can be, for instance, microtubule stabilizing agents or
agents that disrupt microtubule formation.
[0205] Microtubule affecting agents useful in the invention are
well known to those of skill in the art and include, but are not
limited to allocolchicine (NSC 406042), Halichondrin B (NSC
609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC
33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858),
rhizoxin (NSC 332598), paclitaxel (Taxol.RTM., NSC 125973),
Taxol.RTM. derivatives (e.g., derivatives (e.g., NSC 608832),
thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),
vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),
epothilone A, epothilone, and discodermolide (see Service, (1996)
Science, 274:2009) estramustine, nocodazole, MAP4, and the like.
Examples of such agents are also described in the scientific and
patent literature, see, e.g., Bulinski (1997) J. Cell Sci.
110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA
94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou
(1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell.
8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.
[0206] In some embodiments, the agents are compounds with
paclitaxel-like activity. These include, but are not limited to
paclitaxel and paclitaxel derivatives (paclitaxel-like compounds)
and analogues. Paclitaxel and its derivatives are available
commercially. In addition, methods of making paclitaxel and
paclitaxel derivatives and analogues are well known to those of
skill in the art (see, e.g., U.S. Pat. Nos. 5,569,729; 5,565,478;
5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809;
5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057;
5,422,364; 5,411,984; 5,405,972; and 5,296,506).
[0207] More specifically, the term "paclitaxel" as used herein
refers to the drug commercially available as Taxol.RTM. (NSC
number: 125973). Taxol.RTM. inhibits eukaryotic cell replication by
enhancing polymerization of tubulin moieties into stabilized
microtubule bundles that are unable to reorganize into the proper
structures for mitosis. Of the many available chemotherapeutic
drugs, paclitaxel has generated interest because of its efficacy in
clinical trials against drug-refractory tumors, including ovarian
and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23,
Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990)
J. Natl. Canc. Inst. 82: 1247-1259).
[0208] Additional microtubule affecting agents can be assessed
using one of many such assays known in the art, e.g., a
semiautomated assay which measures the tubulin-polymerizing
activity of paclitaxel analogs in combination with a cellular assay
to measure the potential of these compounds to block cells in
mitosis (see Lopes (1997) Cancer Chemother. Pharmacol.
41:37-47).
[0209] Generally, activity of a test compound is determined by
contacting a cell with that compound and determining whether or not
the cell cycle is disrupted, in particular, through the inhibition
of a mitotic event. Such inhibition may be mediated by disruption
of the mitotic apparatus, e.g., disruption of normal spindle
formation. Cells in which mitosis is interrupted may be
characterized by altered morphology (e.g., microtubule compaction,
increased chromosome number, etc.).
[0210] Compounds with possible tubulin polymerization activity can
be screened in vitro. In a preferred embodiment, the compounds are
screened against cultured WR21 cells (derived from line 69-2
wap-ras mice) for inhibition of proliferation and/or for altered
cellular morphology, in particular for microtubule compaction. In
vivo screening of positive-testing compounds can then be performed
using nude mice bearing the WR21 tumor cells. Detailed protocols
for this screening method are described by Porter (1995) Lab. Anim.
Sci., 45(2):145-150.
[0211] Other methods of screening compounds for desired activity
are well known to those of skill in the art. Typically such assays
involve assays for inhibition of microtubule assembly and/or
disassembly. Assays for microtubule assembly are described, for
example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S.
Pat. No. 5,569,720 also provides in vitro and in vivo assays for
compounds with paclitaxel-like activity.
[0212] Methods for the safe and effective administration of the
above-mentioned microtubule affecting agents are known to those
skilled in the art. In addition, their administration is described
in the standard literature. For example, the administration of many
of the chemotherapeutic agents is described in the "Physicians'
Desk Reference" (PDR), e.g., 1996 edition (Medical Economics
Company, Montvale, N.J. 07645-1742, USA); the disclosure of which
is incorporated herein by reference thereto.
[0213] The amount and frequency of administration of the inventive
polymorphs and the chemotherapeutic agents and/or radiation therapy
will be regulated according to the judgment of the attending
clinician (physician) considering such factors as age, condition
and size of the patient as well as severity of the disease being
treated. A dosage regimen of the inventive polymorphs can be oral
administration of from 10 mg to 2000 mg/day, preferably 10 to 1000
mg/day, more preferably 50 to 600 mg/day, in two to four
(preferably two) divided doses, to block tumor growth. Intermittent
therapy (e.g., one week out of three weeks or three out of four
weeks) may also be used.
[0214] The chemotherapeutic agent and/or radiation therapy can be
administered according to therapeutic protocols well known in the
art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent or radiation) on the patient, and in view of
the observed responses of the disease to the administered
therapeutic agents.
[0215] In the methods of this invention, the inventive polymorph is
administered concurrently or sequentially with a chemotherapeutic
agent and/or radiation. Thus, it is not necessary that, for
example, the chemotherapeutic agent and the inventive polymorph, or
the radiation and the inventive polymorph, should be administered
simultaneously or essentially simultaneously. The advantage of a
simultaneous or essentially simultaneous administration is well
within the determination of the skilled clinician.
[0216] Also, in general, the inventive polymorph and the
chemotherapeutic agent do not have to be administered in the same
pharmaceutical composition, and may, because of different physical
and chemical characteristics, have to be administered by different
routes. For example, the inventive polymorph may be administered
orally to generate and maintain good blood levels thereof, while
the chemotherapeutic agent may be administered intravenously. The
determination of the mode of administration and the advisability of
administration, where possible, in the same pharmaceutical
composition, is well within the knowledge of the skilled clinician.
The initial administration can be made according to established
protocols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0217] The particular choice of an inventive polymorph, and
chemotherapeutic agent and/or radiation will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment
protocol.
[0218] The inventive polymorph, and chemotherapeutic agent and/or
radiation may be administered concurrently (e.g., simultaneously,
essentially simultaneously or within the same treatment protocol)
or sequentially, depending upon the nature of the proliferative
disease, the condition of the patient, and the actual choice of
chemotherapeutic agent and/or radiation to be administered in
conjunction (i.e., within a single treatment protocol) with the
inventive polymorph.
[0219] If the inventive polymorph, and the chemotherapeutic agent
and/or radiation are not administered simultaneously or essentially
simultaneously, then the initial order of administration of the
inventive polymorph, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the inventive polymorph may
be administered first, followed by the administration of the
chemotherapeutic agent and/or radiation; or the chemotherapeutic
agent and/or radiation may be administered first, followed by the
administration of the inventive polymorph. This alternate
administration may be repeated during a single treatment protocol.
The determination of the order of administration, and the number of
repetitions of administration of each therapeutic agent during a
treatment protocol, is well within the knowledge of the skilled
physician after evaluation of the disease being treated and the
condition of the patient.
[0220] For example, the chemotherapeutic agent and/or radiation may
be administered first, especially if it is a cytotoxic agent, and
then the treatment continued with the administration of the
inventive polymorph followed, where determined advantageous, by the
administration of the chemotherapeutic agent and/or radiation, and
so on until the treatment protocol is complete.
[0221] The inventive polymorphs may also be useful in the treatment
of pain associated with a chemokine mediated disease. Such pain can
be described by or associated with the following: acute
inflammatory pain, chronic inflammatory pain, acute neuropoathic
pain, chronic neuropathic pain, acute inflammation, rheumatoid
arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult
respiratory disease, arthritis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, septic shock, endotoxic shock, gram
negative sepsis, toxic shock syndrome, stroke, cardiac and renal
reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's
disease, graft vs. host reaction, allograft rejections, malaria,
acute respiratory distress syndrome, delayed type hypersensitivity
reaction, atherosclerosis, cerebral and cardiac ischemia,
osteoarthritis, multiple sclerosis, restinosis, angiogenesis,
osteoporosis, gingivitis, respiratory viruses, herpes viruses,
hepatitis viruses, HIV, Kaposi's sarcoma associated virus,
meningitis, cystic fibrosis, pre-term labor, cough, pruritis,
multi-organ dysfunction, trauma, strains, sprains, contusions,
psoriatic arthritis, herpes, encephalitis, CNS vasculitis,
traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post
surgical trauma, interstitial pneumonitis, hypersensitivity,
crystal induced arthritis, acute and chronic pancreatitis, acute
alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis,
angiogenic ocular disease, ocular inflammation, retinopathy of
prematurity, diabetic retinopathy, macular degeneration with the
wet type preferred and corneal neovascularization, polymyositis,
vasculitis, acne, gastric and duodenal ulcers, celiac disease,
esophagitis, glossitis, airflow obstruction, airway
hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis
obliterans, chronic bronchitis, cor pulmonae, cough, dyspnea,
emphysema, hypercapnea, hyperinflation, hypoxemia,
hyperoxia-induced inflammations, hypoxia, surgical lung volume
reduction, pulmonary fibrosis, pulmonary hypertension, right
ventricular hypertrophy, peritonitis associated with continuous
ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis,
sarcoidosis, small airway disease, ventilation-perfusion
mismatching, wheeze, colds, gout, alcoholic liver disease, lupus,
burn therapy, periodontitis, transplant reperfusion injury and
early transplantation rejection, and chronic inflammation.
[0222] This invention also provides a method of treating a CXCR1
and/or a CXCR2 mediated disease or condition selected from the
group consisting of: pain (e.g., acute pain, acute inflammatory
pain, chronic inflammatory pain, and neuropathic pain), acute
inflammation, chronic inflammation, rheumatoid arthritis,
psoriasis, atopic dermatitis, asthma, COPD, adult respiratory
disease, arthritis, inflammatory bowel disease, Crohn's disease,
ulcerative colitis, septic shock, endotoxic shock, gram negative
sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury,
renal reperfusion injury, glomerulonephritis, thrombosis,
Alzheimer's disease, graft vs. host reaction (i.e., graft vs. host
disease), allograft rejections (e.g., acute allograft rejection,
and chronic allograft rejection), malaria, acute respiratory
distress syndrome, delayed type hypersensitivity reaction,
atherosclerosis, cerebral ischemia, cardiac ischemia,
osteoarthritis, multiple sclerosis, restinosis, angiogenesis,
osteoporosis, gingivitis, respiratory viruses, herpes viruses,
hepatitis viruses, HIV, Kaposi's sarcoma associated virus (i.e.,
Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor,
cough, pruritis, multi-organ dysfunction, trauma, strains, sprains,
contusions, psoriatic arthritis, herpes, encephalitis, CNS
vasculitis, traumatic brain injury, CNS tumors, subarachnoid
hemorrhage, post surgical trauma, interstitial pneumonitis,
hypersensitivity, crystal induced arthritis, acute pancreatitis,
chronic pancreatitis, acute alcoholic hepatitis, necrotizing
enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular
inflammation, retinopathy of prematurity, diabetic retinopathy,
macular degeneration with the wet type preferred, corneal
neovascularization, polymyositis, vasculitis, acne, gastric ulcers,
duodenal ulcers, celiac disease, esophagitis, glossitis, airflow
obstruction, airway hyperresponsiveness (i.e., airway
hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis
obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema,
hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced
inflammations, hypoxia, surgical lung volume reduction, pulmonary
fibrosis, pulmonary hypertension, right ventricular hypertrophy,
peritonitis associated with continuous ambulatory peritoneal
dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small
airway disease, ventilation-perfusion mismatching, wheeze, colds,
gout, alcoholic liver disease, lupus, burn therapy (i.e., the
treatment of burns), periodontitis, cancer, transplant reperfusion
injury, early transplantation rejection (e.g., acute allograft
rejection) in a patient in need of such treatment comprising
administering to said patient an effective amount of at least one
of the inventive polymorphs.
[0223] This invention also provides a method of treating a CCR7
mediated disease or condition selected from the group consisting
of: pain (e.g., acute pain, acute inflammatory pain, chronic
inflammatory pain, and neuropathic pain), acute inflammation,
chronic inflammation, acute allograft rejection, acute respiratory
distress syndrome, adult respiratory disease, airway
hyperreactivity, allergic contact dermatitis, allergic rhinitis,
alopecia areata, alzheimer's disease, angiogenic ocular disease,
antiphospholipid syndromes, aplastic anemia, asthma,
atherosclerosis, atopic dermatitis, autoimmune deafness (including,
for example, Meniere's disease), autoimmune hemolytic syndromes,
autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian
failure, autoimmune orchitis, autoimmune thrombocytopenia,
bronchiolitis, bronchiolitis obliterans syndrome, bullous
pemphigoid, burn therapy (i.e., the treatment of burns), cancer,
cerebral ischemia, cardiac ischemia, chronic allograft rejection,
chronic allograft vasculopathy, chronic bronchitis, chronic
inflammatory demyelinating polyneuropathy, chronic sinusitis,
cirrhosis, CNS vasculitis, COPD, Cor pneumoniae, Crohn's disease,
cryoglobulinemia, crystal-induced arthritis, delayed-type
hypersensitivity reactions, dermatomyositis, diabetes, diabetic
retinopathy, drug-induced autoimmunity, dyspnea, emphysema,
epidermolysis bullosa acquisita, endometriosis, fibrotic diseases,
gastritis, glomerulonephritis, Goodpasture's syndrome, graft vs
host disease, Graves' disease, Gullain-Barre disease, Hashimoto's
thyroiditis, hepatitis-associated autoimmunity, HIV-related
autoimmune syndromes and hematologic disorders, hyperoxia-induced
inflammation, hypercapnea, hyperinflation, hypophytis, hypoxia,
idiopathic thrombocytic pupura, inflammatory bowel diseases,
interstitial cystitis, interstitial pneumonitis, juvenile
arthritis, Langerhans' cell histiocytitis, lichen planus,
metal-induced autoimmunity, multiple sclerosis, myasthenia gravis,
myelodysplastic syndromes, myocarditis including viral myocarditis,
myositis, neuropathies (including, for example, IgA neuropathy,
membranous neuropathy and idiopathic neuropathy), nephritic
syndrome, ocular inflammation, optic neuritis, osteoarthritis,
pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus,
polymyalgia, polymyositis, post-infectious autoimmunity, pulmonary
fibrosis, primary biliary cirrhosis, psoriasis, pruritis,
rheumatoid arthritis, reactive arthritis, ankylosing spondylitis,
psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome,
ischemia injury, restenosis, sarcoidosis, scleritis, scleroderma,
secondary hematologic manifestation of autoimmune diseases (such
as, for example, anemias), silicone implant associated autoimmune
disease, Sjogren's syndrome, systemic lupus erythematosus,
thrombocytopenia, thrombosis, transverse myelitis,
tubulointerstitial nephritis, ulcerative colitis, uveitis,
vasculitis and vasculitis syndromes (such as, for example, giant
cell arteritis, Behcet's disease and Wegener's granulomatosis), and
vitiligo in a patient in need of such treatment comprising
administering to said patient an effective amount of at least one
inventive polymorph.
[0224] This invention also provides a method of treating a
chemokine mediated disease or condition in a patient in need of
such treatment comprising administering to said patient at least
one (usually 1) inventive polymorph, in combination with at least
one (usually 1) other medicament (e.g., a drug, agent or
therapeutic) selected from the group consisting of:
[0225] a) disease modifying antirheumatic drugs;
[0226] b) nonsteroidal anitinflammatory drugs;
[0227] c) COX-2 selective inhibitors;
[0228] d) COX-1 inhibitors;
[0229] e) immunosuppressives;
[0230] f) steroids;
[0231] g) biological response modifiers; and
[0232] h) other anti-inflammatory agents or therapeutics useful for
the treatment of chemokine mediated diseases.
[0233] The above-listed medicaments can be used in conjunction with
at least one inventive polymorph in the treatment of pain.
[0234] This invention also provides a method of treating a
pulmonary disease (e.g., COPD, asthma or cystic fibrosis) in a
patient in need of such treatment comprising administering to said
patient a therapeutically effective amount of at least one
inventive polymorph in combination with at least one (usually 1)
compound selected from the group consisting of: glucocorticoids,
5-lipoxygenase inhibitors, .beta.-2 adrenoceptor agonists,
muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2
agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene
antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors,
elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors,
phospholipase D inhibitors, histamine H1 antagonists, histamine H3
antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2
antagonists, GABA-b agonists, nociceptin agonists, expectorants,
mucolytic agents, decongestants, antioxidants, anti-IL-8
anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF
antibodies, IL-10, adhesion molecule inhibitors, and growth
hormones.
[0235] This invention also provides a method of treating multiple
sclerosis in a patient in need of such treatment comprising
administering to said patient, a therapeutically effective amount
of at least one (usually 1) inventive polymorph, in combination
with at least one compound selected from the group consisting of
glatiramer acetate, glucocorticoids, methotrexate, azothioprine,
mitoxantrone, chemokine inhibitors, and CB2-selective agents.
[0236] This invention also provides a method of treating multiple
sclerosis in a patient in need of such treatment comprising
administering to said patient a therapeutically effective amount of
at least one (usually 1) inventive polymorph, in combination with
at least one compound selected from the group consisting of:
methotrexate, cyclosporin, leflunimide, sulfasalazine,
.beta.-methasone, .beta.-interferon, glatiramer acetate, and
prednisone.
[0237] This invention also provides a method of treating rheumatoid
arthritis in a patient in need of such treatment comprising
administering to said patient a therapeutically effective amount of
at least one (usually one) inventive polymorph.
[0238] Alternatively, such treatment may further comprise
administering to said patient a therapeutically effective amount of
at least one compound selected from the group consisting of COX-2
inhibitors, COX inhibitors, immunosuppressives (e.g., methotrexate,
cyclosporin, leflunimide and sulfasalazine), steroids (e.g.,
betamethasone, cortisone and dexamethasone), PDE IV inhibitors,
anti-TNF-.alpha. compounds, MMP inhibitors, glucocorticoids,
chemokine inhibitors, CB2-selective inhibitors, and other classes
of compounds indicated for the treatment of rheumatoid
arthritis.
[0239] This invention also provides a method of treating stroke and
ischemia reperfusion injury in a patient in need of such treatment
comprising administering to said patient a therapeutically
effective amount of at least one inventive polymorph in combination
with at least one compound selected from the group consisting of
thrombolitics (e.g., tenecteplase, TPA, alteplase), antiplatelet
agents (e.g., gpIIb/IIIa), antagonists (e.g., abciximab and
eftiifbatide), anticoagulants (e.g., heparin), and other compounds
indicated for the treatment of rheumatoid arthritis.
[0240] This invention also provides a method of treating psoriasis
in a patient in need of such treatment comprising administering to
said patient a thereapeutically effective amount of at least one
(usually 1) inventive polmorph, in combination with at least one
compound selected from the group consisting of immunosuppressives
(e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine),
steroids (e.g., .beta.-methasone) and anti-TNF-.alpha. compounds
(e.g., etonercept and infliximab).
[0241] This invention also provides a method of treating COPD in a
patient in need of such treatment comprising administering to said
patient a therapeutically effective amount of at least one (usually
one) inventive polymorph.
[0242] This invention also provides a method of treating arthritis
in a patient in need of such treatment comprising administering to
said patient a therapeutically effective amount of at least one
(usually one) inventive polymorph.
[0243] This invention also provides a method of treating
osteoarthritis in a patient in need of such treatment comprising
administering to said patient a therapeutically effective amount of
at least one (usually one) inventive polymorph.
[0244] In accordance with experience and knowledge, the practicing
physician can modify each protocol for the administration of a
component (therapeutic agent--i.e., the inventive polymorph,
chemotherapeutic agent or radiation) of the treatment according to
the individual patient's needs, as the treatment proceeds.
[0245] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the patient as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radio-logical
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
[0246] Other than as shown in the operating examples or as
otherwise indicated, all numbers used in the specification and
claims expressing quantities of ingredients, reaction conditions,
and so forth, are understood as being modified in all instances by
the term "about." The above description is not intended to detail
all modifications and variations of the invention. It will be
appreciated by those skilled in the art that changes can be made to
the embodiments described above without departing from the
inventive concept. It is understood, therefore, that the invention
is not limited to the particular embodiments described above, but
is intended to cover modifications that are within the spirit and
scope of the invention, as defined by the language of the following
claims.
* * * * *