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: 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.

1 . A crystalline polymorph of a monohydrate of Compound A of the formula:  
       
         
           
           
               
               
           
         
         wherein, 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:  
       
         
           
           
               
               
           
         
         that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 6.612, 8.832, 27.024 and 28.134 degrees 2θ.  
       
     
     
         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 2θ.  
     
     
         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 2θ.  
     
     
         5 . The crystalline polymorph Form I of  claim 1 .  
     
     
         6 . A crystalline polymorph Form II of a monohydrate of Compound A of the formula:  
       
         
           
           
               
               
           
         
         that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 9.328, 13.774, 19.78 and 27.305 degrees 2θ.  
       
     
     
         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 2θ.  
     
     
         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 2θ.  
     
     
         9 . The crystalline polymorph Form II of  claim 1 .  
     
     
         10 . A crystalline polymorph Form III of a monohydrate of Compound A of the formula:  
       
         
           
           
               
               
           
         
         that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 7.748, 18.349, 23.198 and 23.851 degrees 2θ.  
       
     
     
         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 2θ.  
     
     
         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 2θ.  
     
     
         13 . The crystalline polymorph Form III of  claim 1 .  
     
     
         14 . A crystalline polymorph Form IV of a monohydrate of Compound A of the formula:  
       
         
           
           
               
               
           
         
         that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 11.46, 43.004, 44.097 and 50.107 degrees 2θ.  
       
     
     
         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 2θ.  
     
     
         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 2θ.  
     
     
         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:  
       
         
           
           
               
               
           
         
         comprising 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:  
       
         
           
           
               
               
           
         
         comprising 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° 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  
       
         
           
           
               
               
           
         
         comprising 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  
       
         
           
           
               
               
           
         
         comprising 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° C. until substantially all solids are dissolved;  
         c) cooling said second mixture to about 60° 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-TNFα antibodies and TNFα 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-TNFα antibody is selected from the group consisting of: infliximab and adalimumab; and    f) said TNFα 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, β-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, β-methasone, β-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-α 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-α compounds.  
     
     
         59 . The method of  claim 32  wherein said disease or condition is arthritis.