There are disclosed aminopyrimidinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include aminopyrimidinecarboxamides compounds. More specifically, there is disclosed a genus of CXCR2 inhibitor compounds that are useful for treating a variety of inflammatory and neoplastic disorders.
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0. 7. A compound comprising a compound from formula (1):
##STR00017##
wherein R1 is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein R2 is heteroaryl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro;
wherein R3 is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and R4 is selected from the group consisting of aminoalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or
wherein R3 and R4 are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; or
wherein R3 and R4 are independently selected from the group consisting of —B(R5R6), —BF3−M+, —R7—B(R5R6), —R7—BF3−M+, —C(O)—R7, —O—R7, —S(O)y—R7 (wherein y=0, 1, or 2), —P(O)—(R5R6), and —N(R8R9);
wherein R7 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl;
wherein M+ is a group i or a group II metal;
wherein R5 and R6 are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R5 and R6 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);
wherein R8 and R9 are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R8 and R9 are both oxygen to form a nitro group; or R8 and R9 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein n=1;
or a pharmaceutical composition thereof.
0. 1. A compound comprising a compound from formula (1):
##STR00014##
wherein R1 and R2 are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein R3 is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, R4 is selected from the group consisting of heteroalkyl, aminoalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R3 or R4 are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates;
wherein R3 and R4 are also independently selected from the group consisting of —B(R5R6), —BF3−M+, —R7—B(R5R6), —R7—BF3−M+, R7,—C(O)—R7, —O—R7, —S(O)y—R7 (wherein y=0, 1, or 2), —P(O)—(R5R6) and —N(R8R9);
wherein R7 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
wherein M+ is a group i or a group II metal;
wherein R5 and R6 are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R5 and R6 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);
wherein R8 and R9 are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R8 and R9 are both oxygen to form a nitro group; or R8 and R9 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein n=1;
or pharmaceutical compositions thereof.
##STR00015##
wherein R1 is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein R2 is selected from the group consisting of 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein R3 is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; or selected from the group consisting of —B(R5R6), —BR3−M+, —R7—B(R5R6), —R7—BF3−M+, —C(O)—R7, —O—R7, —S(O)y—R7 (wherein y=0, 1, or 2), —P(O)—(R5R6), and —N(R8R9);
wherein R4 is 4-phenylboronic acid;
wherein R7 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl;
wherein M+ is a group i or a group II metal;
wherein R5 and R6 are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R5 and R6 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical);
wherein R8 and R9 are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R8 and R9 are both oxygen to form a nitro group; or R8 and R9 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein n=1;
or a pharmaceutical composition thereof.
0. 4. A pharmaceutical composition comprising a compound of formula (1):
##STR00016##
wherein R1 and R2 are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
wherein R3 and R4 are independently-selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R3 and R4 are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates;
wherein R3 and R4 are also independently selected from the group consisting of —B(R5R6), —BF3−M+, —R7—B(R5R6), —R7—BF3−M+, R7,—C(O)—R7, —O—R7, —S(O)—R7, —P(O)—(R5R6) and —N(R8R9); wherein y=0, 1, or 2;
wherein R7 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
wherein M+ is a group i or a group II metal;
wherein R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R5 and R6 together form a cyclic ester, or an acid anhydride;
wherein R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R8 and R9 are both oxygen to form a nitro group; or R8 and R9 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein n=1.
0. 5. The pharmaceutical composition of
0. 6. The pharmaceutical composition of
0. 8. The compound of claim 3, wherein R2 is arylalkyl, and wherein the alkyl group in arylalkyl comprises a straight hydrocarbon chain of 1-18 carbon atoms.
0. 9. The compound of claim 3, wherein the compound is in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt.
0. 10. A pharmaceutical composition comprising the compound of claim 3.
0. 11. The composition of claim 10, comprising a therapeutically effective amount of the compound for treating a CXC chemokine-mediated disease.
0. 12. The composition of claim 11, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine.
0. 13. The composition of claim 11, wherein the CXC chemokine-mediated disease is a tumor or cancer.
0. 14. The composition of claim 11, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis.
0. 15. The composition of claim 11, wherein the CXC chemokine-mediated disease is multiple sclerosis.
0. 16. The composition of claim 11, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis.
0. 17. The composition of claim 11, further comprising a therapeutically effective amount of a second medicament.
0. 18. The composition of claim 17, wherein second medicament is an anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or another anti-inflammatory agent.
0. 19. The composition of claim 17, wherein the second medicament is useful for treating cancer and is selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine, microtubule affecting agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, and interferon.
0. 20. The composition of claim 17, wherein the second medicament is useful for treating COPD, asthma, or cystic fibrosis; and is 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-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.
0. 21. The composition of claim 17, wherein the second medicament is useful for treating multiple sclerosis and is selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azathioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunomide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etanercept, and infliximab.
0. 22. The composition of claim 17, wherein the second medicament is useful for treating rheumatoid arthritis or psoriasis and is selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective agents.
0. 23. The composition of claim of 10, wherein composition is suitable for oral administration.
0. 24. The composition of claim 23, wherein the composition is a tablet.
0. 25. The compound of claim 7, wherein the compound is in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt.
0. 26. A pharmaceutical composition comprising the compound of claim 7.
0. 27. The composition of claim 26, comprising a therapeutically effective amount of the compound for treating a CXC chemokine-mediated disease.
0. 28. The composition of claim 27, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine.
0. 29. The composition of claim 27, wherein the CXC chemokine-mediated disease is a tumor or cancer.
0. 30. The composition of claim 27, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis.
0. 31. The composition of claim 27, wherein the CXC chemokine-mediated disease is multiple sclerosis.
0. 32. The composition of claim 27, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis.
0. 33. The composition of claim 27, further comprising a therapeutically effective amount of a second medicament.
0. 34. The composition of claim 33, wherein second medicament is an anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or another anti-inflammatory agent.
0. 35. The composition of claim 33, wherein the second medicament is useful for treating cancer and is selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine, microtubule affecting agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, and interferon.
0. 36. The composition of claim 33, wherein the second medicament is useful for treating COPD, asthma, or cystic fibrosis; and is 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-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.
0. 37. The composition of claim 33, wherein the second medicament is useful for treating multiple sclerosis and is selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azathioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunomide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etanercept, and infliximab.
0. 38. The composition of claim 22, wherein the second medicament is useful for treating rheumatoid arthritis or psoriasis and is selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective agents.
0. 39. The composition of claim 26, wherein composition is suitable for oral administration.
0. 40. The composition of claim 39, wherein the composition is a tablet.
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This application is a at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
The methods of treatment of this disclosure are advantageous in treating diseases where the ELR-CXC chemokine binds to CXCR2. Another embodiment of the disclosure is directed to a method of treating CXCR2 chemokine mediated diseases in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of the disclosure is a method of treating CXCR2 chemokine mediated diseases in a patient in need thereof comprises administering to the patient (a) an effective amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one additional agent, drug, medicament, antibody and/or inhibitor useful for the treatment of CXCR2 chemokine mediated diseases. Examples of the additional medicament, drug or agent include, but are not limited to, disease modifying antirheumatic drugs; nonsteroidal antiinflammatory drugs (NSAIDs); COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; biological response modifiers; and other anti-inflammatory agents or therapeutics useful for the treatment of CXCR2 chemokine mediated diseases.
Another embodiment of the method of treating a CXCR2 chemokine mediated disease is administering (a) a therapeutically effective amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal anti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; biological response modifiers; and other anti-inflammatory agents or therapeutics useful for the treatment of CXCR1 and/or CXCR2 chemokine mediated diseases.
Another embodiment of this disclosure is a method for treating cancer in a patient in need of such treatment, the method comprises administering to said patient a therapeutically effective amount of a the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment of this disclosure is a method for treating cancer comprising administering to the patient a therapeutic amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (a) at least one antineoplastic agent selected from the group consisting of: (1) gemcitabine, (2) paclitaxel, (3) 5-Fluorouracil 5-fluorouracil (5-FU), (4) cyclophosphamide, (5) temozolomide and (6) Vincristine vincristine or (b) at least one agent selected from the group consisting of (1) microtubule affecting agents, (2) antineoplastic agents, (3) anti-angiogenesis agents, (4) VEGF receptor kinase inhibitors, (5) antibodies against the VEGF receptor, (6) interferon, and (7) radiation.
Another embodiment of this disclosure is a method for treating asthma in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment of this disclosure is a method for treating a pulmonary disease (e.g., COPD, asthma, or cystic fibrosis), in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) 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-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.
Another embodiment of this disclosure is a method for treating multiple sclerosis, comprising administering to the patient:(a) a therapeutically effective amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) a therapeutically effective amount of at least one compound selected from the group consisting of: glatiramer acetate, glucocorticoids, methotrexate, azothioprine azathioprine, mitoxantrone, and CB2-selective inhibitors.
Another embodiment of this disclosure is a method of treating multiple sclerosis comprising concurrent or sequential administration of a therapeutically effective amount of: (a) at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, and (b) at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunimide leflunomide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept etanercept, and infliximab.
Another embodiment of this disclosure is a method for treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one the compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one compound selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives (e.g., methotrexate, aminopterin, cyclosporin, leflunimide leflunomide and sulfasalazine), steroids (e.g., betamethasone, cortisone and dexamethasone), PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective agents, and other classes of compounds indicated for the treatment of rheumatoid arthritis.
Another embodiment of this disclosure is a method for treating stroke and ischemia reperfusion injury in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: thrombolitics thrombolytics (e.g., tenecteplase, TPA, alteplase), antiplatelet agents (e.g., gp11b/111a), antagonists (e.g., abciximab and eftiifbatide eptifibatide), anticoagulants (e.g., heparin), and other compounds indicated for the treatment of rheumatoid arthritis.
Another embodiment of this disclosure is a method for treating stroke and ischemia reperfusion injury in a patient in need of such treatment the method comprising administering to the patient a therapeutically effective amount of: (a) at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof concurrently or sequentially with (b) at least one compound selected from the group consisting of: tenecteplase, TPA, alteplase, abciximab, eftiifbatide eptifibatide, and heparin.
Another embodiment of this disclosure is a method for treating psoriasis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: a) at least one the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressives (e.g., methotrexate, aminopterin, cyclosporin, efalizumab, alefacept, leflunimide leflunomide and sulfasalazine), steroids (e.g., β-methasone) and anti-TNFα compounds (e.g., etonercept etanercept and infliximab).
This disclosure also provides a method for treating 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, bronchopulmonary dysplasia, 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-versus-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, angiogenesis associated with tumor growth, 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, systemic tumors, CNS tumors, tumors dependent on angiogenesis for growth, leukopenia and neutropenia, chemotherapy-induced leukopenia and neutropenia, opportunistic infections associated with neutropenia or leukopenia, subarachnoid hemorrhage, post surgical 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 the compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating diseases such as allograft rejections, early transplantation rejections, autoimmune deafness, myocarditis, neuropathies, autoimmune diseases and vasculitis syndromes 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; and
(g) vasculitis syndromes are selected from the group consisting of giant cell arteries, Behcet's disease and Wegener's granulomatosis.
Another embodiment of this disclosure is a method for 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) a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, and administering a therapeutically effective amount of at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors (e.g., COX-1 and COX-2 inhibitors), anti-depressants, and anti-convulsants.
Another embodiment of this disclosure is a method for treating acute pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (usually one) a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating acute inflammatory pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating chronic inflammatory pain in a patient in need of such treatment comprising administering to said-patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a method for treating neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of this disclosure is a pharmaceutical composition comprising at least one a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof, and at least one other agent, medicament, antibody and/or inhibitor disclosed above, and a pharmaceutically acceptable carrier.
In general the compounds used to treat pain will have CXCR2 antagonistic activity.
NSAIDs are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of NSAIDs include but are not limited to: piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen COXIB inhibitors are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of COXIB inhibitors include, but are not limited to: rofecoxib and celecoxib. Anti-depressants are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of anti-depressants include but are not limited to: amitriptyline and nortriptyline. Anti-convulsants are well known to those skilled in the art and can be used in their known dosages and dosage regimens. Examples of anti-convulsants include but are not limited to: gabapentin, carbamazepine, pregabalin, and lamotragine.
Pharmaceutical Compositions
For preparing pharmaceutical compositions from the compounds described by this disclosure, 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: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md. which is incorporated herein by reference.
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. Liquid form preparations may also include dissolution in lipid-based, self-emulsifying drug delivery systems (SEDDS) such as Labrasol® or Gelucire® for oral administration.
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.
Also included are solid form preparations which 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.
The compounds of this disclosure 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.
The compound can be administered orally.
A suitable 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.
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, or from about 0.01 mg to about 750 mg, or from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according to the particular application.
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.
The amount and frequency of administration of the compounds of this disclosure 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 two to four divided doses.
The amount and frequency of administration of the compounds compound of either formula (1) or formula (2) 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 compound of either formula (1) or formula (2) can be oral administration of from 10 mg to 2000 mg/day, or 10 to 1000 mg/day, or 50 to 600 mg/day, in two to four (or 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.
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.
If the compound of either formula (1) or formula (2), and the chemotherapeutic agent and/or radiation is not administered simultaneously or essentially simultaneously, then the initial order of administration of the compound of either formula (1) or formula (2), and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compound of either formula (1) or formula (2) 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 compound of either formula (1) or formula (2). 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.
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 compound of either formula (1) or formula (2) followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
The particular choice of a compound from either formula (1) or formula (2), 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.
Also, in general, the compound of either formula (1) or formula (2) 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 compound of either formula (1) or formula (2) 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.
Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a component (therapeutic agent; i.e., the compound from either formula (1) or formula (2), chemotherapeutic agent or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.
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 radiological 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.
The disclosure provided herein is exemplified by the following preparations and examples that should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.
6-Bromonicotinic acid (8.1 g, 40 mmol) was dissolved in anhydrous DMF (50 mL) under an N2 atmosphere. 4-Fluoroaniline (3.9 mL, 41 mmol) and EEDQ (9.9 g, 40 mmol) were added and stirred at room temperature for 18 hours. The product was precipitated by dilution into deionized water (1.2 L), and the precipitate was filtered and washed with additional water. The product was dried under vacuum to yield 8.1 g (69%) of 2 as a white solid. ESI-MS m/z 294.9/296.9 [M+H]+. Analysis: Calcd for C12H8BrFN2O: C, 48.84; H, 2.73; N, 9.49. Found: C, 48.75; H, 2.57; N, 9.40. 1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.25-8.23 (m, 1H), 7.86-7.85 (m, 1H), 7.79 (d, J=3.8 Hz, 2H), 7.24-7.23 (m, 2H).
Compound 2 (1.486 g, 5.04 mmol), 2-bromo-N-methylbenzylamine (0.74 mL, 5.00 mmol) and triethylamine (1.40 mL, 10.0 mmol) were dissolved in anhydrous dimethylformamide (10 mL) and placed in a pressure bottle, under an N2 atmosphere. The reaction was heated to 130° C. for 2 days. The reaction was cooled to room temperature and diluted into deionized water (250 mL). The suspension was basified to pH>9 with 1 N NaOH, and extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered through a pad of silica gel (ethyl acetate), and dried under vacuum. The crude product was dissolved in ethyl acetate and minimal methanol and adhered to silica gel (25 g). The silica adhered compound was purified by flash silica gel chromatography (250 g silica, 3:1 hexanes:ethyl acetate) to yield 1.74 g (84%) of 4 as a white solid. ESI-MS m/z 414.1/416.1 [M+H]+. Analysis: Calcd for C20H17BrFN3O: C, 57.98; H, 4.14; N, 10.14. Found: C, 58.08; H, 4.20; N, 10.02. 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.09 (dd, J=9.0 Hz, 2.3 Hz, 1H), 7.77-7.74 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.18 (t, J=9.0 Hz, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 4.89 (s, 2H), 3.20 (s, 3H).
2-Bromobenzylamine hydrochloride (1.520 g, 6.83 mmol) was dissolved in water and brought to pH 12 with 1 N NaOH (15 mL). The suspension was extracted twice with ethyl acetate, and the combined ethyl acetate extracts were dried over Na2SO4, filtered, and dried under vacuum. Compound 2 (1.915 g, 6.49 mmol) was placed in a pressure bottle, and 2-bromobenzylamine (1.244 g, 6.69 mmol) was added with stirring, dissolved in N-methylpyrrolidine (13 mL), under N2 atmosphere. Triethylamine (1.92 mL, 13.8 mmol) was added under N2, and the bottle was heated to 130° C. for 3 days. The reaction was cooled to room temperature and added dropwise to a stirring solution of deionized water (300 mL), forming a fine precipitate. The suspension was refrigerated overnight and filtered. The crude solid was dried in a vacuum desiccator. The crude product was dissolved in tetrahydrofuran, combined with material from a previous synthesis (0.5 mmol scale), and adhered to silica gel (25 g). The combined compounds were purified by flash silica gel chromatography (250 g silica, 3:2 hexanes:ethyl acetate, then 2:1 ethyl acetate:hexanes) to yield 1.86 g (66%) of 5 as a white solid. ESI-MS m/z 400.0/402.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.79-7.74 (m, 3H), 7.65 (d, J=8.0 Hz, 1H), 7.36 (d, J=4.2 Hz, 2H), 7.24-7.20 (m, 1H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=8.6 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H).
Compound 4 (1.74 g, 4.2 mmol) was dissolved in anhydrous dimethylformamide and degassed under vacuum. A pressure bottle was charged with PdCl2(dppf) (255 mg, 0.312 mmol), bis(pinacolato) diboron (3.21 g, 12.6 mmol) and potassium acetate (1.22 g, 12.4 mmol), along with a stir bar. The DMF solution was added to the pressure bottle with an oven-dried pipette, rinsing with dry DMF (5 mL). The tube was sealed under nitrogen gas and heated at 80° C. for 41 hours, then cooled to room temperature. The reaction was filtered through Celite, rinsing with DMF, dried in vacu, and partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, and filtered through a pad of silica gel (ethyl acetate). The filtrate was dried under vacuum to yield 4.3 g of a crude red mixture containing 6, which was used without further purification. ESI-MS (of major product) m/z 462.2 [M+H]+.
Compound 5 (201 mg, 0.50 mmol) was dissolved in anhydrous dimethylformamide and degassed under vacuum. A pressure bottle was charged with PdCl2(dppf) (13 mg, 0.016 mmol), bis(pinacolato) diboron (384 mg, 1.5 mmol) and potassium acetate (150 mg, 1.5 mmol) and the solution was added under N2 atmosphere. The tube was heated with stirring at 80° C. for 26 hours, then cooled to room temperature. The reaction was partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, and filtered through a pad of silica gel (ethyl acetate). The filtrate was dried under vacuum, dissolved in 3:2 hexanes:ethyl acetate, and purified by flash silica gel chromatography (30 g, 3:2 hexanes:ethyl acetate) to yield 123 mg (67%) of 7 as a white foam. ESI-MS m/z 366.1 [(M-pinacol)+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.63 (d, J=1.9 Hz, 1H), 7.93 (dd, J=8.9 Hz, 2.2 Hz, 1H), 7.76-7.74 (m, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (t, J=5.7 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.17 (t, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 1H), 4.78 (d, J=5.8 Hz, 2H), 1.31 (s, 12H). IC50 in whole cell assay (Pharmacology Example 1)=1.5±0.3 μM.
Crude compound 6 (4.2 mmol) was suspended with stirring in methanol (36 mL), and 4.5 M KHF2 (4.0 mL, 21 mmol) was added dropwise by pipette. Additional methanol was added to rinse the walls of the flask, and the reaction was stirred at room temperature. After 2.5 hr, additional 4.5 M KHF2 (8.0 mL, 42 mmol) was added to drive the reaction to completion. After stirring for another 2 hr, the reaction was diluted with methanol and dried under vacuum to yield a dark tarry substance, which was diluted with water. Sonication yielded a brown precipitate, which was isolated by vacuum filtration and dried in a vacuum desiccator to a gray solid (1.8 g). The solid was dissolved in acetonitrile (40 mL), and stirred with trimethylsilylchloride (4.8 mL, 38 mmol) and water (0.68 mL, 38 mmol) at room temperature. After stirring for about 2 hr, the reaction was quenched with saturated sodium bicarbonate (19 mL). After several minutes of stirring, the reaction was diluted with water (400 mL), and a tan solid (773 mg) was isolated by vacuum filtration and drying in a vacuum desiccator. The solid was dissolved in a mixture of ethyl acetate and methanol, adhered to silica gel (8 g), and purified by flash silica gel chromatography (80 g, step gradient of 3:2 ethyl acetate:hexanes to ethyl acetate) to yield a red foam, which was dissolved in ethyl acetate, from which 294 mg (18% from 4) of 8 precipitated as a fine white solid. ESI-MS m/z 380.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.37 (s, 2H), 8.05 (dd, J=9.1 Hz, 2.1 Hz, 1H), 7.77-7.74 (m, 2H), 7.56 (d, J=7.3 Hz, 1H), 7.30-7.26 (m, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.18 (t, J=8.8 Hz, 2H), 7.03 (d, J=7.9 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 5.00 (s, 2H), 3.19 (s, 3H). IC50 in whole cell assay (Pharmacology Example 1)=3.7±0.6 μM.
6-Bromonicotinamide (590 mg, 2.0 mmol), 2-(N-methylaminomethyl)phenyl boronic pinacol ester (495 mg, 2.0 mmol), potassium tert-butoxide (450 mg, 4.0 mmol), and 18-crown-6 ether (28 mg, 0.1 mmol) were suspended in anhydrous toluene under N2 atmosphere and brought to reflux for 22 hours. The reaction mixture was diluted with ethyl acetate extracted twice with aqueous saturated bicarbonate. The combined saturated bicarbonate extracts were extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to yield 0.9 g of the crude boronate pinacol ester intermediate. The intermediate boronate ester was then treated with peroxide in tetrahydrofuran with methanol and adhered to silica gel. The desired compound 9 with residual boronate pinacol ester was isolated by flash silica gel chromatography (90 g, 2:1 hexanes:ethyl acetate). The compound mixture was dissolved in peroxide in tetrahydrofuran, adhered to silica gel, and purified by flash silica gel chromatography (55 g, step gradient in dichloromethane: 0, 2, 5, and 10% ethyl acetate) to yield 71 mg (10%) of 9 as an off-white solid. ESI-MS m/z 352.1 [M+H]+. Analysis: Calcd for C20H15FN3O2 ½H2O: C, 66.66; H, 5.31; N, 11.66. Found: C, 66.83; H, 5.16; N, 11.43. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.92 (s, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.2 Hz, 2.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.18 (t, J=8.8 Hz, 2H), 7.09 (t, J=7.8 Hz, 1H), 6.98 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75-6.72 (m, 2H), 4.76 (s, 2H), 3.17 (s, 3H). IC50 in whole cell assay (Pharmacology Example 1)=0.59±0.09 μM.
Compound 7 (522 mg, 1.17 mmol) was suspended with stirring in methanol (10 mL), and 4.5 M KHF2 (1.1 mL, 5.89 mmol) was added dropwise by pipette. After stirring for an hour, the reaction was diluted with methanol and dried under vacuum to yield an oily solid, which was diluted with water. Sonication yielded a precipitate, which was isolated by vacuum filtration and dried in a vacuum desiccator. The solid was dissolved in acetonitrile (10 mL), and stirred with trimethylsilylchloride (0.44 mL, 3.5 mmol) and water (63 μL, 3.5 mmol) at room temperature. After stirring for an hour, the reaction was quenched with saturated sodium bicarbonate (2 mL). After several minutes of stirring, the reaction was diluted with water to a volume of 80 mL, and the precipitate that formed was isolated by vacuum filtration to yield 10 as white solid (323 mg, 76%). ESI-MS m/z 366.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.26 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.63-7.60 (m, 2H), 7.54 (d, J=1.9 Hz, 1H), 7.45-7.36 (m, 3H), 7.29 (t, J=7.1 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 1H), 4.83-4.75 (m, 2H). IC50 in whole cell assay (Pharmacology Example 1)=1.7±0.2 μM.
2-Chloropyrimidine-5-carboxylic acid (1.99 g, 12.5 mmol) was dissolved in anhydrous DMF (10 mL) under an N2 atmosphere. 4-Fluoroaniline (1.2 mL, 12.5 mmol) and EEDQ (3.11 g, 12.6 mmol) were added and stirred at room temperature for 40 hours. The product was partitioned between deionized water and ethyl acetate. The aqueous layer was washed with ethyl acetate, and the combined ethyl acetate layers were dried over sodium sulfate, filtered, and dried in vacu. The crude product was dissolved in ethyl acetate and minimal methanol and adhered to silica gel (28 g) The silica adhered compound was purified by flash silica gel chromotography (340 g, 3:1 hexanes/ethyl acetate) to yield 1.2 g (37%) of 12 as a white solid. ESI-MS m/z 252.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.23 (s, 2H), 7.78-7.75 (m, 2H), 7.25 (t, J=8.8 Hz, 2H).
Compound 2 (1.486 g, 5.04 mmol), 4-bromo-N-methylbenzylamine (1.00 mL, 5.00 mmol) and triethylamine (1.40 mL, 10.0 mmol) were dissolved in anhydrous dimethylformamide (10 mL) and placed in a pressure bottle, under an N2 atmosphere. The reaction was heated to 130° C. for 3 days. The reaction was cooled to room temperature and diluted into deionized water (250 mL), yielding a fluffy white precipitate with a few brown clumps. After cooling briefly and sonicating and crushing the clumps, the precipitate was collected by vacuum filtration, washing with deionized water, and dried under vacuum. The crude product was dissolved in ethyl acetate and adhered to silica gel (20 g). The silica adhered compound was purified by flash silica gel chromatography (200 g silica, 3:2 hexanes:ethyl acetate) to yield 1.67 g (81%) of 14 as a white solid. ESI-MS m/z 414.1/416.1 [M+H]+. Analysis: Calcd for C20H17BrFN3O: C, 57.98; H, 4.14; N, 10.14. Found: C, 57.82; H, 4.20; N, 10.01. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.77-7.75 (m, 2H), 7.53 (d, J=7.0 Hz, 2H), 7.20-7.16 (m, 4H), 6.76 (d, J=9.7 Hz, 1H), 4.86 (s, 2H), 3.11 (s, 3H).
Compound 12 (254 mg, 1.01 mmol), 4-bromo-N-methylbenzylamine (200 μL, 1.00 mmol) and triethylamine (280 μL, 2.01 mmol) were dissolved in anhydrous dimethylformamide (2 mL) and placed in a pressure bottle, under an N2 atmosphere. The reaction was stirred at room temperature for 3 hours, then diluted dropwise into deionized water (60 mL), yielding a fluffy white precipitate. After cooling briefly, the precipitate was collected by vacuum filtration, washing with deionized water, and dried under vacuum to yield 410 mg (99%) of 15 as a white solid. ESI-MS m/z 415.1/417.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.90 (s, 1H), 7.75-7.73 (m, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.23-7.17 (m, 4H), 4.92 (s, 2H), 3.18 (s, 3H).
Compound 14 (1.65 g, 4.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL) and degassed under vacuum. A pressure bottle was charged with PdCl2 (dppf) (244 mg, 0.299 mmol), bis(pinacolato) diboron (3.05 g, 12.0 mmol) and potassium acetate (1.17 g, 11.9 mmol), along with a stir bar. The DMF solution was added to the pressure bottle with an oven-dried pipette, rinsing with dry DMF (2×5 mL). The tube was sealed under nitrogen gas and heated at 80° C. for 8.5 hours, then cooled to room temperature. The reaction was filtered through Celite, rinsing with DMF, dried in vacu, and partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, and filtered through a pad of silica gel (ethyl acetate). The filtrate was dried under vacuum, dissolved in ethyl acetate, and adhered to silica gel (20 g). The silica adhered compound was purified by flash silica gel chromatography (200 g, 2:1 hexanes:ethyl acetate) to yield 1.67 g (91%) of 16 as a white flaky solid. ESI-MS m/z 462.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.06 (dd, J=9.2 Hz, 2.5 Hz, 1H), 7.77-7.74 (m, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.24 (d, J=7.2 Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.75 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 3.11 (s, 3H), 1.28 (s, 12H).
Compound 15 (395 mg, 0.951 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and degassed under vacuum. A pressure bottle was charged with PdCl2(dppf) (60 mg, 0.074 mmol), bis(pinacolato) diboron (726 mg, 2.86 mmol) and potassium acetate (280 mg, 2.85 mmol), along with a stir bar. The DMF solution was added to the pressure bottle with an oven-dried pipette, rinsing with dry DMF (2×2 mL). The tube was sealed under nitrogen gas and heated at 80° C. for 6.5 hours, then cooled to room temperature. The reaction was filtered through Celite, rinsing with DMF, dried in vacu, and partitioned between water and ethyl acetate, and the aqueous layer was washed with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, and filtered through a pad of silica gel (ethyl acetate). The filtrate was dried under vacuum, dissolved in ethyl acetate, and adhered to silica gel (7.5 g). The silica adhered compound was purified by flash silica gel chromatography (78 g, 5:2 hexanes:ethyl acetate) to yield 379 mg (86%) of 17 as a white solid. ESI-MS m/z 463.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.90 (s, 2H), 7.75-7.72 (m, 2H), 7.66 (d, J=7.6 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 7.19 (t, J=8.9 Hz, 2H), 4.98 (s, 2H), 3.17 (s, 3H), 1.28 (s, 12H).
Compound 16 (1.64 g, 3.55 mmol) was suspended with stirring in methanol (50 mL), and 4.5 M KHF2 (4.0 mL, 18.0 mmol) was in portions by pipette. After stirring for 1.5 hours, the reaction was diluted with methanol and dried under vacuum to yield a white solid, which was diluted with water. Sonication yielded a precipitate, which was isolated by vacuum filtration and dried in a vacuum desiccator. The solid (1.43 g, 3.25 mmol) was dissolved in acetonitrile (36 mL), and stirred with trimethylsilylchloride (1.24 mL, 9.77 mmol) and water (176 μL, 9.78 mmol) at room temperature. After stirring for 1.5 hours, the reaction was quenched with saturated sodium bicarbonate (6 mL). After several minutes of stirring, the reaction was diluted with water to dissolve the compound and dried in vacu. The residual solid was suspended in water with sonication, and the precipitate that formed was isolated by vacuum filtration and dried in a vacuum desiccator to yield 18 as white solid (1.33 g, 99%). ESI-MS m/z 380.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.72 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.76-7.75 (m, 4H), 7.20-7.16 (m, 4H), 6.84 (d, J=8.5 Hz, 1H), 4.90 (s, 2H), 3.15 (s, 3H). IC50 in whole cell assay (Pharmacology Example 1)=0.247±0.035 μM.
Compound 17 (365 mg, 0.789 mmol) was suspended with stirring in methanol (7 mL), and 4.5 M KHF2 (0.88 mL, 3.96 mmol) was in portions by pipette. After stirring for 1.5 hours, the reaction was diluted with methanol and dried under vacuum to yield a white solid, which was diluted with water. Sonication yielded a precipitate, which was isolated by vacuum filtration and dried in a vacuum desiccator. The solid (322 mg, 0.728 mmol) was dissolved in acetonitrile (6 mL), and stirred with trimethylsilylchloride (276 μL, 2.18 mmol) and water (40 μL, 2.22 mmol) at room temperature. After stirring for 1.5 hours, the reaction was quenched with saturated sodium bicarbonate (1.3 mL). After several minutes of stirring, the reaction was concentrated in vacu and suspended in water (40 mL) with sonication, yielding a fluffy white solid, which was isolated by vacuum filtration and dried in a vacuum desiccator to yield 19 as white solid (280 mg, 93%). ESI-MS m/z 381.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.91 (s, 2H), 7.76-7.73 (m, 4H), 7.21-7.17 (m, 4H), 4.96 (s, 2H), 3.18 (s, 3H). IC50 in whole cell assay (Pharmacology Example 1)=0.244±0.015 μM.
An in vitro assay showed inhibition of CXCR2-mediated intracellular calcium release by treatment with compound 9 (IC50=586±91 nM). Briefly, human neutrophils were suspended in HBSS− (without Ca2+ and Mg2+) containing 10 mM HEPES and FLIPR Calcium 3 dye (3.1×107 cells in total volume 1.7 mL). Cells were aliquoted (200 μL of the cell suspension per tube, 8 tubes total) and 2 μL of compound 9 (with appropriate dilutions) were added to each of 6 tubes. The tested concentrations of compound 9 were 156 nM, 312 nM, 625 nM, 1250 nM, 2500 nM and 5000 nM. As controls, 2 μL of DMSO (1% final concentration) were added to 2 other tubes. Cells were incubated for 30 min at 37° C. After dye loading, tubes were centrifuged at 6,000 rpm for 1 min, supernatant was removed and the cell pellet was re-suspended in 200 μL of HBSS+ (with Ca2+ and Mg2+) containing 10 mM HEPES. The test compound or DMSO (control) was added again at the same concentrations that were used during cell loading. The cell suspension was aliquoted into a 96-well Reading Plate (Corning) in a volume of 90 μL (105 cells/well). The Compound Plate contained agonist (GROα in HBSS−) or HBSS− (control). After 15 sec of reading the basal level of fluorescence by FlexStation II, 10 μL of GROα or HBSS− were automatically transferred from the Compound Plate into the Reading Plate (final concentration of GROα was 25 nM). Changes in fluorescence were monitored (λex=485 nm, λem=525 nm) every 5 s for 240 to 500 s at room temperature.
The maximum change in fluorescence, expressed in arbitrary units over baseline (Max-Min), was used to determine the GROα response. The effect of each compound on the GROα response was normalized and expressed as a percent of the DMSO control, which was designated as “100% response.” Curve fitting and calculation of the compound inhibitory concentration that reduces the level of the GROα response by 50% (IC50), or the compound agonist concentration that increases the level of the calcium release by 50% of the maximum agonist-induced change (EC50) were determined by nonlinear regression analysis of the dose-response curves generated using Prism 4 (GraphPad Software, Inc., San Diego, Calif.).
TABLE 1
Inhibition of CXCR2
Com
Com
pound
Mole-
pound
Num-
cular
Name
ber
Weight
Structure
IC50 (μM)
SX-626
9
351.37
##STR00008##
0.586 ± 0.91
SX-627
7
447.31
##STR00009##
1.5 ± 0.3
SX-628
8
379.19
##STR00010##
1.0 ± 0.2
SX-629
10
365.17
##STR00011##
1.7 ± 0.2
SX-632
18
379.19
##STR00012##
0.247 ± 0.35
SX-633
19
380.18
##STR00013##
0.244 ± 0.15
Zebala, John A., Maeda, Dean Y., Schuler, Aaron D.
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