Patent
4-aminoquinazolin-2-yl-1-pyrrazole-4-carboxylic acid compounds as prolyl hydroxylase inhibitors
| العنوان: | 4-aminoquinazolin-2-yl-1-pyrrazole-4-carboxylic acid compounds as prolyl hydroxylase inhibitors |
|---|---|
| Patent Number: | 8,796,263 |
| تاريخ النشر: | August 05, 2014 |
| Appl. No: | 13/816747 |
| Application Filed: | August 12, 2011 |
| مستخلص: | Aminoquinazolinyl compounds of formula (I) are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., anemia, vascular disorders, metabolic disorders, and wound healing. [chemical expression included] |
| Inventors: | Rabinowitz, Michael H. (San Diego, CA, US); Rosen, Mark D. (San Diego, CA, US); Tarantino, Kyle T. (San Diego, CA, US); Venkatesan, Hariharan (San Diego, CA, US) |
| Assignees: | Janssen Pharmaceutica NV (Beerse, BE) |
| Claim: | 1. A compound of the formula (I): [chemical expression included] wherein: n is 0-3 R 1 is a member independently selected from the group consisting of halo, —O—R c , —C 1-4 alkyl, cyclohexyl, phenyl optionally substituted with —C 1-4 alkyl, benzyl optionally substituted with —C 1-4 alkyl, and —NR a R b ; R a is H and R b is benzyl optionally substituted with —C 1-4 alkyl, or R a and R b are taken together with the nitrogen to which they are attached to form a piperidine ring; R c is cyclohexyl, phenyl optionally substituted with one or more R d members; R d is a member independently selected from the group consisting of —H, halo, and —C 1-4 alkyl; R 2 is a member independently selected from the group consisting of —H, and —C 1-4 alkyl, R 3 is a member independently selected from the group consisting of —H, —C 1-4 alkyl optionally substituted with —OCH 3 or —N(C 1-4 alkyl) 2 , cyano, —SO 2 CH 3 , tetrahydropyran, —(CH 2) m C 3-8 cycloalkyl, —(CH 2) m phenyl optionally substituted with one or more halo, or —C 1-4 alkyl; m is 0-1; R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocycloalkyl ring optionally containing O, N, S optionally substituted with —OH, cyano, halo, —N—C(O)C 1-4 alkyl, and —C 1-4 alkyl; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. |
| Claim: | 2. A compound as defined in claim 1 , where R 1 is a member independently selected from the group consisting of bromo, chloro, fluoro, methyl, isopropyl, cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino. |
| Claim: | 3. A compound of claim 1 where n is 1. |
| Claim: | 4. A compound of claim 1 where n is 2. |
| Claim: | 5. A compound of claim 1 where n is 3. |
| Claim: | 6. A compound as defined in claim 1 , where R a is H and R b is 2,6-dimethylbenzyl. |
| Claim: | 7. A compound as defined in claim 1 , where R c is a member selected from the group consisting of phenyl, cyclohexyl, 4-chlorophenyl, and 2,6-dimethyl-phenyl. |
| Claim: | 8. A compound as defined in claim 1 , where R d is a member selected from the group consisting of —H, chloro, and —CH 3 . |
| Claim: | 9. A compound as defined in claim 1 , where R 2 is —H and R 3 is a member selected from the group consisting of H, cyano, methyl, ethyl, propyl, tertbutyl, cyclopropyl, cyclopropylmethyl, tetrahydropyranyl, cyclohexylmethyl, phenyl, 2-chlorophenyl, 2,6-dimethylbenzyl, and —SO 2 CH 3 . |
| Claim: | 10. A compound as defined in claim 1 , where R 2 is selected from the group consisting of methyl, ethyl, propyl, and butyl. |
| Claim: | 11. A compound as defined in claim 1 , where R 3 is selected from the group consisting of methyl, ethyl, propyl, butyl, tertbutyl, 2-methoxyethyl, 2-methoxy-1-methyl-ethyl and diethylamino-ethyl. |
| Claim: | 12. A compound as defined in claim 1 , where R 2 and R 3 are taken together with the nitrogen to which they are attached to form pyrrolidine, piperidine, 4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine, 4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane, or 4-isopropylpiperidine. |
| Claim: | 13. A compound as defined in claim 1 , where n is 2, R 1 is a member independently selected from the group consisting of halo, cyclohexyl, and 2,6-dimethyl-phenoxy, and R 2 and R 3 are C 1-4 alkyl, or R 2 and R 3 are taken together with the nitrogen to which they are attached to form morpholine. |
| Claim: | 14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of compound having PHD inhibitor activity of formula (I): [chemical expression included] wherein: n is 0-3 R 1 is a member independently selected from the group consisting of halo, —O—R c , —C 1-4 alkyl, cyclohexyl, phenyl optionally substituted with —C 1-4 alkyl, benzyl optionally substituted with —C 1-4 alkyl, and —NR a R b ; R a is H and R b is benzyl optionally substituted with —C 1-4 alkyl, or R a and R b are taken together with the nitrogen to which they are attached to form a piperidine ring; R c is cyclohexyl, phenyl optionally substituted with one or more R d members; R d is a member independently selected from the group consisting of —H, halo, and —C 1-4 alkyl; R 2 is a member independently selected from the group consisting of —H, and —C 1-4 alkyl, R 3 is a member independently selected from the group consisting of —H, —C 1-4 alkyl optionally substituted with —OCH 3 or —N(C 1-4 alkyl) 2 , cyano, —SO 2 CH 3 , tetrahydropyran, —(CH 2) m C 3-8 cycloalkyl, —(CH 2) m phenyl optionally substituted with one or more halo, or —C 1-4 alkyl; m is 0-1; R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocycloalkyl ring optionally containing O, N, S optionally substituted with —OH, cyano, halo, —N—C(O)C 1-4 alkyl, and —C 1-4 alkyl; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. |
| Claim: | 15. A pharmaceutical composition comprising an effective amount of at least on chemical entity of claim 1 . |
| Claim: | 16. A method for the treatment of anemia, hypoxia, ischemia, peripheral vascular disease, myocardial infarction, stroke, diabetes, obesity, inflammatory bowel disease, ulcerative colitis, Crohn's disease, wounds, infection, burns and bone fracture comprising the step of administering to a patient in need thereof a therapeutically effective amount of compound having PHD inhibitor activity of formula (I): [chemical expression included] wherein: n is 0-3 R 1 is a member independently selected from the group consisting of halo, —O—R c , —C 1-4 alkyl, cyclohexyl, phenyl optionally substituted with —C 1-4 alkyl, benzyl optionally substituted with —C 1-4 alkyl, and —NR a R b ; R a is H and R b is benzyl optionally substituted with —C 1-4 alkyl, or R a and R b are taken together with the nitrogen to which they are attached to form a piperidine ring; R c is cyclohexyl, phenyl optionally substituted with one or more R d members; R d is a member independently selected from the group consisting of —H, halo, and —C 1-4 alkyl; R 2 is a member independently selected from the group consisting of —H, and —C 1-4 alkyl, R 3 is a member independently selected from the group consisting of —H, —C 1-4 alkyl optionally substituted with —OCH 3 or —N(C 1-4 alkyl) 2 , cyano, —SO 2 CH 3 , tetrahydropyran, —(CH 2) m C 3-8 cycloalkyl, —(CH 2) m phenyl optionally substituted with one or more halo, or —C 1-4 alkyl; m is 0-1; R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocycloalkyl ring optionally containing O, N, S optionally substituted with —OH, cyano, halo, —N—C(O)C 1-4 alkyl, and —C 1-4 alkyl; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. |
| Claim: | 17. A method for treating a hypoxic disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of compound having PHD inhibitor activity of formula (I): [chemical expression included] wherein: n is 0-3 R 1 is a member independently selected from the group consisting of halo, —O—R c , —C 1-4 alkyl, cyclohexyl, phenyl optionally substituted with —C 1-4 alkyl, benzyl optionally substituted with —C 1-4 alkyl, and —NR a R b ; R a is H and R b is benzyl optionally substituted with —C 1-4 alkyl, or R a and R b are taken together with the nitrogen to which they are attached to form a piperidine ring; R c is cyclohexyl, phenyl optionally substituted with one or more R d members; R d is a member independently selected from the group consisting of —H, halo, and —C 1-4 alkyl; R 2 is a member independently selected from the group consisting of —H, and —C 1-4 alkyl, R 3 is a member independently selected from the group consisting of —H, —C 1-4 alkyl optionally substituted with —OCH 3 or —N(C 1-4 alkyl) 2 , cyano, —SO 2 CH 3 , tetrahydropyran, —(CH 2) m C 3-8 cycloalkyl, —(CH 2) m phenyl optionally substituted with one or more halo, or —C 1-4 alkyl; m is 0-1; R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocycloalkyl ring optionally containing O, N, S optionally substituted with —OH, cyano, halo, —N—C(O)C 1-4 alkyl, and —C 1-4 alkyl; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. |
| Claim: | 18. The method of claim 17 , wherein said hypoxic disorder is selected from the group consisting of anemia, ischemia, stroke, myocardial infarction, and coronary artery disease. |
| Claim: | 19. A method for treating diabetes comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof. |
| Claim: | 20. A method for wound treatment comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof. |
| Claim: | 21. A method for treating a metabolic disorder comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof. |
| Claim: | 22. The method of claim 21 wherein said metabolic disorder is obesity or diabetes. |
| Current U.S. Class: | 51421/706 |
| Patent References Cited: | 2006/0276477 December 2006 Klaus et al. 2007/0299086 December 2007 Kawamoto et al. 2009/0239876 September 2009 Clements et al. 2010/0204226 August 2010 Bembenek et al. 39023409 October 1964 WO 2004 052284 June 2004 WO 2004 052285 June 2004 WO 2007 070359 June 2007 WO 2007 103905 September 2007 WO 2007 150011 December 2007 WO 2009 117269 September 2009 WO 2010093727 August 2010 |
| Other References: | International Search Report for Corresponding International Application PCT/US2011/047626 Mailed on Sep. 28, 2011 3 Pgs. cited by applicant International Search Report for Corresponding International Application PCT/US2010/023794 Mailed on May 7, 2010, 3 Pgs. cited by applicant Abbott et al., “Stromal Cell-Derived Factor-1[Alpha] Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction But Is Not Sufficient to Induce Homing in the Absence of Injury” Circulation, 2004 vol. 110(21), pp. 3300-3305. cited by applicant Al-Sheikh et al., “Disturbance in the HIF-1 Alpha Pathway Associated With Erythrocytosis: Further Evidences Brought by Frameshift and Nonsense Mutations in the Prolyl Hydroxylase Domain Protein 2 (PHD2) Gene” Blood Cells Mol Dis., 2008 vol. 40, pp. 160-165. cited by applicant Aragones et al., “Deficiency or Inhibition of Oxygen Sensor PHD1 Induces Hypdxia Tolerance by Reprogramming Basal Metabolism” Nature Genetics 2008, vol. 40(2), pp. 170-180. cited by applicant Arcasoy, “The Non-Haematopoietic Biological Effects of Erythropoietin”, British Journal of Haematology, 2008 vol. 141 (1), pp. 14-31. cited by applicant Armellini et al. “The Effects of High Altitude Trekking on Body Composition and Resting Metabolic Rate”, Hormone & Metabolic Research, 1997 vol. 29(9), pp. 458-461. cited by applicant Bagshawe et al. “Antibody-Directed Enzyme Prodrug Therapy: A Review” Drug Dev Res, 1995, vol. 34, pp. 220-230. cited by applicant Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977 vol. 66, pp. 1-19. cited by applicant Bernaudin et al., “Normobaric Hypoxia Induces Tolerance to Focal Permanent Cerebral Ischemia in Association With an Increased Expression of Hypoxia-Inducible Factor-1 and Its Target Genes, Erythropoietin and VEGF, In the Adult Mouse Brain” J Cereb Blood Flow Metab., 2002 vol. 22(4), pp. 393-403. cited by applicant Bernhardt et al., “Organ Protection by Hypoxia and Hypoxia-Inducible Factors” Methods Enzymol., 2007 vol. 435, pp. 221-245. cited by applicant Berra et al., “HIF Prolyl-Hydroxylase 2 Is the Key Oxygen Sensor Setting Low Steady-State Levels of HIF-1Alpha in Normoxia”, EMBO (European Molecular Biology Organization) Journal, 2003 vol. 22(16), pp. 4082-4090. cited by applicant Bertolini et al. “A New Rational Hypothesis for the Pharmacophore of the Active Metabolite of Leflunomide, A Potent Immunosuppressive Drug” J. Med. Chem., 1997, vol. 40, pp. 2011-2016. cited by applicant Bodor et al.,“Novel Approaches to the Design of Safer Drugs: Soft Drugs and Site-Specific Chemical Delivery Systems” Adv Drug Res. 1984, vol. 13 pp. 255-329. cited by applicant Braliou et al., “2-Oxoglutarate-Dependent Oxygenases Control Hepcidin Gene Expression ”, Journal of Hepatology, 2008 vol. 48 (5) pp. 801-810. cited by applicant Breen, “VEGF in Biological Control” J Cell Biochem., 2007 vol. 102(6), pp. 1358-1367. cited by applicant Notari R.E. “Pharmacokinetic Aspects of Prodrug Design and Evaluation” Chapter 3 pp. 135-156 Design of Prodrugs Ed. H. Bundgaard Elsevier Press 1985. cited by applicant Cai et al., “Complete Loss of Ischaemic Preconditioning-Induced Cardioprotection in Mice With Partial Deficiency of HIF-1 Alpha ” Cardiovasc Res., 2008 vol. 77(3), pp. 463-470. cited by applicant Carmeliet,“Manipulating Angiogenesis in Medicine ” J Intern Med., 2004 vol. 255(5), pp. 538-561. cited by applicant Carrière et al. “Mitochondrial Reactive Oxygen Species Control the Transcription Factor Chop-10/GADD153 and Adipocyte Differentiation: A Mechanism for Hypdxia-Dependent Effect” J Biol Chem., 2004 vol. 279(39), pp. 40462-40469. cited by applicant Chang et al “Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypdxia-Inducible Factor 1A Stabilization During Ischemia” Circulation 2007 vol. 116 pp. 2818-2829. cited by applicant Ceradini et al., “Homing to Hypoxia: HIF-1 As a Mediator of Progenitor Cell Recruitment to Injured Tissue” Trends Cardiovasc Med., 2005 vol. 15(2), pp. 57-63. cited by applicant Ceradini et al., “Progenitor Cell Trafficking Is Regulated by Hypoxic Gradients Through HIF-1 Induction of SDF-1”, Nat Med., 2004 vol. 10(8), pp. 858-864. cited by applicant Chin et al. “Hypoxia-Inducible Factor 1Alpha Stabilization by Carbon Monoxide Results in Cytoprotective Preconditioning”, Proc Natl Acad Sci. U.S.A., 2007 vol. 104(12), pp. 5109-5114. cited by applicant Darling et al., “‘Postconditioning’ The Human Heart: Multiple Balloon Inflations During Primary Angioplasty May Confer Cardioprotection.” Basic Res Cardiol., 2007, vol. 102(3), pp. 274-278. cited by applicant Das et al., “Molecular Mechanism of Preconditioning”, IUBMB Life, 2008,vol. 60(4), pp. 199-203. cited by applicant Ebert et al. “Hypoxia and Mitochondrial Inhibitors Regulate Expression of Glucose Transporter-1 Via Distinct CIS-Acting Sequences”, J Biol Chem., 1995 vol. 270(49), pp. 29083-29089. cited by applicant Elson et al., “Induction of Hypervascularity Without Leakage or Inflammation in Transgenic Mice Overexpressing Hypoxia-Inducible Factor-1Alpha”, Genes Dev., 2001 vol. 15(19), pp. 2520-2532. cited by applicant Epstein et al., “C. Elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases That Regulate HIF by Prolyl Hydroxylation”, Cell, 2001 vol. 107(1), pp. 43-54. cited by applicant Feldser et al., “Reciprocal Positive Regulation of Hypoxia-Inducible Factor 1Alpha and Insulin-Like Growth Factor 2”, Cancer Res. 1999 vol. 59 (16), pp. 3915-3918. cited by applicant Firth et al. “Oxygen-Regulated Control Elements in the Phosphoglycerate Kinase 1 and Lactate Dehydrogenase A Genes: Similarities With the Erythropoietin 3′ Enhancer”, Proc Natl Acad Sci. USA, 1994 vol. 91(14), pp. 6496-6500. cited by applicant Fleisher et al. “Improved Oral Delivery: Solubility Limitations Overcome by the Use of Prodrugs” Advanced Drug Delivery Review, 1996, vol. 19, pp. 115-130. cited by applicant Floyd et al., “Effects of Prolyl Hydroxylase Inhibitors on Adipogenesis and Hypoxia Inducible Factor 1 Alpha Levels Under Normoxic Conditions”, J Cell Biochem., 2007 vol. 101(6), pp. 1545-1557. cited by applicant Fukuda et al., “HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells”, Cell, 2007 vol. 129(1), pp. 111-122. cited by applicant Grosfeld et al. “Hypoxia-Inducible Factor 1 Transactivates the Human Leptin Gene Promoter”, J Biol Chem., 2002 vol. 277(45), pp. 42953-42957. cited by applicant Gustafsson et al., “Exercise-Induced Angiogenesis-Related Growth and Transcription Factors in Skeletal Muscle, and Their Modification in Muscle Pathology.” Frontiers in Bioscience, 2001, vol. 6, pp. 75-89. cited by applicant Hu et al., “Transplantation of Hyodxia-Preconditioned Mesenchymal Stem Cells Improves Infarcted Heart Function Via Enhanced Survival of Implanted Cells and Angiogenesis”, Journal of Thoracic & Cardiovascular Surgery, 2008 vol. 135(4), pp. 799-808. cited by applicant Ivan et al. “Biochemical Purification and Pharmacological Inhibition of a Mammalian Prolyl Hydroxylase Acting on Hypoxia-Inducible Factor” Proc Natl Acad Sci. USA, 2002, vol. 99(21), pp. 13459-13464. cited by applicant Ivan et al., “HIF[Alpha] Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing”, Science, 2001 vol. 292(5516), pp. 464-468. cited by applicant Jaakkola et al., “Targeting of HIF-[Alpha] to the Von Hippel-Lindau Ubiquitylation Compex by O2-Regulated Prolyl Hydroxylation” Science, 2001, vol. 292(5516), pp. 468-472. cited by applicant Kaelin, “Proline Hydroxylation and Gene Expression ” Annu Rev Biochem., 2005, vol. 74, pp. 115-128. cited by applicant Ke et al., “Hypdxia-Inducible Factor-1 (HIF-1)”, Mol Pharmacol. 2006, vol. 70(5), pp. 1469-1480. cited by applicant Kelly et al., “Cell Type-Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1”, Circ Res., 2003 vol. 93(11), pp. 1074-1081. cited by applicant Kim et al., “HIF-1-Mediated Expression of Pyruvate Dehydrogenase Kinase: A Metabolic Switch Required for Cellular Adaptation to Hypoxia, Cell Metab” 2006 vol. 3(3), pp. 177-185. cited by applicant Kojima I et al.,“Protective Role of Hypdxia-Inducible Factor-2 Alpha Against Ischemic Damage and Oxidative Stress in the Kidney ” J Am Soc Nephrol., 2007, vol. 18 (4), pp. 1218-1226. cited by applicant Lee et al. “Hypoxia Inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia”, J Biol Chem., 1997, vol. 272(9), pp. 5375-5381. cited by applicant Lin et al. “Differentiation Arrest by Hypoxia”, J Biol Chem., 2006, vol. 281(31), pp. 30678-30683. cited by applicant Liu et al., “Hypdxia Regulates Vascular Endothelial Growth Factor Gene Expression in Endothelial Cells: Identification of a 5 Prime Enhancer”, Circ Res., 1995, vol. 77(3), pp. 638-643. cited by applicant Lok et al. “Identification of a Hypoxia Response Element in the Transferrin Receptor Gene”, J Biol Chem., 1999, vol. 274(34), pp. 24147-24152. cited by applicant Luttun et al., “Placental Growth Factor (PIGF) and Its Receptor FLT-1 (VEGFR-1): Novel Therapeutic Targets for Angiogenic Disorders” Series Information: Annals of the New York Academy of Sciences, 2002, vol. 979, pp. 80-93. cited by applicant Mace et al., “Sustained Expression of HIF-1 Alpha in the Diabetic Environment Promotes Angiogenesis and Cutaneous Wound Repair ”, Wound Repair Regen., 2007, vol. 15(5), pp. 636-645. cited by applicant Mallick et al., “Ischemia-Reperfusion Injury of the Intestine and Protective Strategies Against Injury”, Digestive Diseases & Sciences, 2004, vol. 49(9), pp. 1359-1377. cited by applicant Metzen E. et al., “Intracellular Localisation of Human HIF-1Alpha Hydroxylases: Implications for Oxygen Sensing” J Cell Sci., 2003,vol. 116, pp. 1319-1326. cited by applicant Mukhopadhyay et al. “Role of Hypoxia-Inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency”, J Biol Chem., 2000, vol. 275(28), pp. 21048-21054. cited by applicant Murry et al. “Preconditioning With Ischemia: A Delay of Lethal Cell Injury in Ischemic Myocardium”, Circulation, 1986 vol. 74(5), pp. 1124-1136. cited by applicant Nagai et al “Becaplermin: Recombinant Platelet Derived Growth Factor, A New Treatment for Healing Diabetic Foot Ulcers” Exp Opin Biol Ther 2002 vol. 2(2) pp. 211-218. cited by applicant Natarajan et al., “Hypdxia Inducible Factor-1 Upregulates Adiponectin in Diabetic Mouse Hearts and Attenuates Post-Ischemic Injury” 2008, J Cardiovasc Pharmacol., vol. 51(2), pp. 178-187. cited by applicant Natarajan et al., “Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury”, Circulation Res.,2006, vol. 98(1), pp. 133-140. cited by applicant Pajusola et al., “Stabilized HIF-1Alpha Is Superior to VEGF for Angiogenesis in Skeletal Muscle Via Adeno-Associated Virus Gene Transfer” FASEB Journal, 2005, vol. 19(10), pp. 1365-1367. cited by applicant Papandreou et al., “HIF-1 Mediates Adaptation to Hypoxia by Actively Downregulating Mitochondrial Oxygen Consumption” Cell Metab., 2006, vol. 3(3), pp. 187-197. cited by applicant Pasupathy et al., “Ischaemic Preconditioning Protects Against Ischaemia/Reperfusion Injury: Emerging Concepts” European Journal of Vascular and Endovascular Surgery, 2005, vol. 29, pp. 106-115. cited by applicant Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Organce Book Database”, J. Med. Chem., 2007, vol. 50 pp. 6665-6672. cited by applicant Percy et al. “A Family With Erythrocytosis Establishes a Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis” PNAS, 2006, vol. 103(3), pp. 654-659. cited by applicant Peyssonnaux et al., “Critical Role of Hif-1 Alpha in Keratinocyte Defense Against Bacterial Infection” J Invest Dermatol., 2008 vol. 128(8), pp. 1964-1968. cited by applicant Peyssonnaux et al., “HIF-1 Alpha Expression Regulates the Bactericidal Capacity of Phagocytes” J Invest Dermatol, 2005, vol. 115(7), pp. 1806-1815. cited by applicant Peyssonnaux et al., “Regulation of Iron Homeostasis by the Hypoxia-Inducible Transcription Factors (HIFS).” J Clin Invest., 2007, vol. 117(7), pp. 1926-1932. cited by applicant Robinson et al., “Mucosal Protection by Hypdxia-Inducible Factor Prolyl Hydroxylase Inhibition” Gastroenterology, 2008, vol. 134(1), pp. 145-155. cited by applicant Rolfs et al. “Oxygen-Regulated Transferrin Expression Is Mediated by Hypoxia-Inducible Factor-1” J Biol Chem., 1997, vol. 272(32), pp. 20055-20062. cited by applicant Scheuermann et al., “Hypdxia-Inducible Factors PER/ARNT/SIM Domains: Structure and Function” Methods Enzymol., 2007, vol. 435, pp. 3-24. cited by applicant Schmid et al., “HIF-1 and P53: Communication of Transcription Factors Undr Hypoxia” Journal of Cellular & Molecular Medicine, 2004, vol. 8(4), pp. 423-431. cited by applicant Schultz et al., “Hypoxia and Hypoxia-Inducible Factor-1 Alpha Promote Growth Factor-Induced Proliferation of Human Vascular Smooth Muscle Cells” Am J Physiol Heart Circ Physiol., 2006, 290(6), pp. H2528-H2534. cited by applicant Semenza et al. “A Nuclear Factor Induced by Hypoxia Via De Novo Protein Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation”, , Mol Cell Biol., 1992, vol. 12(12), pp. 5447-5454. cited by applicant Semenza et al., “Vasculogenesis, Angiogenesis, and Arteriogenesis: Mechanisms of Blood Vessel Formation and Remodeling”, J Cell Biochem.,2007 vol. 102(4), pp. 840-847. cited by applicant Semenza, “Hypoxia-Inducible Factor 1: Oxygen Homeostasis and Disease Pathophysiology” Trends in Molecular Medicine, 2001, vol. 7(8), pp. 345-350. cited by applicant Semenza, “Oxygen-Dependent Regulation of Mitochondrial Respiration by Hypoxia-Inducible Factor 1”, Biochem J., 2007 vol. 405 (1), pp. 1-9. cited by applicant Semenza, “Regulation of Tissue Perfusion in Mammals by Hypoxia-Inducible Factor 1.” Exp Physiol., 2007, vol. 92(6), pp. 988-991. cited by applicant Semenza, “Hypoxia-Inducible Factor 1 (HIF-1) Pathway” Science's STKE (Signal Transduction Knowledge Environment) 2007, vol. 407(CM8), pp. 1-3. cited by applicant Shan et al. “Prodrug Strategies Based on Intramolecular Cyclization Reaction”, Journal of Pharmaceutical Sicences 1997, vol. 86(7), pp. 765-767. cited by applicant Shaw, “Glucose Metabolism and Cancer” Curr Opin Cell Biol., 2006, vol. 18(6), pp. 598-608. cited by applicant Siddiq et al. “Hypoxia-Inducible Factor Prolyl 4-Hydroxylase Inhibition: A Target for Neuroprotection in the Central Nervous System”, J Biol Chem., 2005, vol. 280(50), pp. 41732-41743. cited by applicant Simon et al., “The Role of Oxygen Availability in Embryonic Development and Stem Cell Function” Nature Reviews Molecular Cell Biology, 2008, vol. 9(4), pp. 285-296. cited by applicant Steed, “Clinical Evaluation of Recombinant Human Platelet-Derived Growth Factor for the Treatment of Lower Extemity Ulcers” Plast Reconstr Surg., 2006 vol. 117(7 Suppl), pp. 143S-149S. cited by applicant Tacchini et al. “Transferrin Receptor Induction by Hypoxia. HIF-1-Mediated Transcriptional Activation and Cell-Specific Post-Transcriptional Regulation”, J Biol Chem., 1999, vol. 274(34), pp. 24142-24146. cited by applicant Thurston et al., “Angiopoietin-1 Protects the Adult Vasculature Against Plasma Leakage” Nature Medicine, 2000, vol. 6(4), pp. 460-463. cited by applicant Thurston et al., “Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1”, Science,1999, vol. 286, pp. 2511-2514. cited by applicant Vincent et al., “Angiogenesis Is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1[Alpha]/VP16 Hybrid Transcription Factor”, Circulation, 2000, vol. 102 (18), pp. 2255-2261. cited by applicant Wang et al. “Characterization of Hypoxia-Inducible Factor 1 and Regulation of DNA Binding Activity by Hypoxia” J Biol Chem., 1993, vol. 268(29), pp. 21513-21518. cited by applicant Wang et al. “General Involvement of Hypoxia-Inducible Factor 1 in Transcriptional Response to Hypoxia ” Proceedings of the National Academy of Sciences of the United States of America, 1993, vol. 90, pp. 4304-4308. cited by applicant Wang et al. “Purification and Characterization of Hypoxia-Inducible Factor 1”, J Biol Chem.,1995, vol. 270(3), pp. 1230-1237. cited by applicant Warshakoon et al., “A Novel Series of Imidazol[1,2-A]Pyridine Derivatives As HIF-1A Prolyl Hydroxylase Inhibitors” Bioorg Med Chem Lett., 2006, vol. 16(21) pp. 5598-5601. cited by applicant Warshakoon et al., “Design and Synthesis of Substituted Pyridine Derivatives As HIF-1A Prolyl Hydroxylase Inhibitors”, Bioorg Med Chem Lett., 2006, vol. 16(21) pp. 5616-5620. cited by applicant Wang et al “The Hypoxia Inducible Factor a Pathway Couples Angiogenesis to Osteogenesis During Skeletal Development” Clin Invest 2007 vol. 17(6) pp. 1616-1626. cited by applicant Warshakoon et al., “Design and Synthesis of a Series of Novel Pyrazolopyridines as HIF 1-A Prolyl Hydroxylase Inhibitors” Bioorg Med Chem Lett., 2006, vol. 16(21) pp. 5687-5690. cited by applicant Yun et al., “Inhibition of PPAR Gamma 2 Gene Expression by the HIF-1-regulated Gene DEC1/STRA13: A Mechanism for Regulation of Adipogenesis by Hypoxia.” Develomental Cell, 2002, vol. 2, pp. 331-341. cited by applicant Zhang H et al. “Mitochondrial Autophagy Is an HIF-1-Dependent Adaptive Metabolic Response to Hypoxia” J Biol Chem. 2008, vol. 283 pp. 10892-10903. cited by applicant Bundgaard H. “Design and Application of Prodrugs” Chapter 5 pp. 113-191 A Textbook of Drug Desing and Development 1991 Krogsgaard-Larsen et Eds Hardwood Academic Publishers. cited by applicant Pfander et al “HIF-1A Controls Extracellular Matrix Synthesis by Epiphyseal Chondrocytes” J Cell Sci 2003 116(9) pp. 1819-1826. cited by applicant Hirota et al “Targeting Hypdxia-Inducible Factor-1 (HIF-1) Signaling in Therapeutics: Implications for the Treatment of Inflammatory Bowel Disease” Recent Patents on Inflammation and Allergy Drug Discovery 2009 vol. 3 pp. 1-16. cited by applicant Bowker Michael J. “A Procedure for Salt Selection and Optimization” Chapter 7 pp. 161-189 Handbook of Pharmaceutical Salts, Properties, Selection and Use Stahl and Wermuth Eds 2002 Wiley-VCH and VHCA Zurich. cited by applicant Zeghida et al “Concise Synthesis of 2-Amino-4(3H)-Quinazolinones From Simple (Hetero)Aromatic Amines” Journal of Organic Chemistry 2008 vol. 73(6) pp. 2473-2475. cited by applicant Shyu et al “Intramyocardial Injection of Naked DNA Encoding HIF-1A/VP16 Hybrid to Enhance Angiogenesis in an Acute Myocardial Infarction Model in the Rat” Cardiovasc Res 2002 vol. 54 pp. 576-583. cited by applicant Yoshida et al “Hypoxia Inducible Factor 1-A Regulates of Platelet Derived Growth Factor-B in Human Glioblastoma Cells” J of Neuro-Oncology 2006 vol. 76 pp. 13-21. cited by applicant Robinson et al “ Discovery of the Hemifumarate and (α.-L- Alanyloxy)Methyl Ether as Prodrugs of an Antirheumatic Oxindole: Prodrugs for the Enolic OH Group” J Med Chem 1996 vol. 39(1) pp. 10-18. cited by applicant Feng et al “Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV” Journal of Medicinal Chemistry 2007 vol. 50 pp. 2297-2300. cited by applicant Zhichkin et al “The Use of Formamidine Protection for the Derivatization of Aminobenzoic Acids” J Org Chem 2008 vol. 73 pp. 8954-5959. cited by applicant Goto et al “The Process Development of a Novel Aldose Reductase Inhibiot, FK366, Part 1. Improvement of Discovery Process and New Syntheses of 1-Substituted Quinazolinediones” Organic Process Research and Development 2003 vol. 7 pp. 700-706. cited by applicant Zinkernagel et al “Pharmacologic Augmentation of Hypoxia-Inducible Factor 1-A With Mimosine Boosts the Bacterial Capacity of Phagocytes” The Journal of Infectious Diseases 2008 vol. 197 pp. 214-217. cited by applicant Ram et al “Synthesis and Antihyperglycemic Activity of Suitably Functionalized 3H-Quinazolin-4-Ones” Bioorganic & Medicinal Chemistry 2003 vol. 11 pp. 2439-2444. cited by applicant Smith et al “Infection With a Helminth Parasite Prevents Experimental Colitis Via a Macrophage-Mediated Mechanism” J Immunol 2007 vol. 178 pp. 4557-4566. cited by applicant |
| Assistant Examiner: | Masha, Oluwafemi |
| Primary Examiner: | Murray, Jeffrey H |
| رقم الانضمام: | edspgr.08796263 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |