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The most common adverse reactions include dizziness, fatigue, bacterial infection, hemorrhage, thrombocytopenia, diarrhea, and nausea.[8]
Momelotinib was approved for medical use in the United States in September 2023,[5][8][9] and in the European Union in January 2024.[6][10]
CYT387 is an ATP-competitive small molecule JAK1 / JAK2 inhibitor with IC50 of 11 and 18 nM for JAK1 and JAK2, respectively. CYT387 is useful for treatment of myeloproliferative disorders and anti-cancer.
CYT-387 is a potent, orally administered JAK1/JAK2/ Tyk2 inhibitor in phase III clinical studiest at Gilead for the treatment of post-polycythemia vera, for the treatment of primary myelofibrosis and for the treatment of post-essential thrombocythemia. Phase II studies are also ongoing, in combination with gemcitabine and nab-paclitaxel, in adults with untreated metastatic pancreatic ductal adenocarcinoma.
The compound possesses an excellent selectivity and safety profile. In 2010 and 2011, orphan drug designation was assigned by the FDA and the EMA, respectively, for the treatment of myelofibrosis. In 2011, orphan drug designation was assigned by the EMA for the treatment of post-essential thrombocythemia myelofibrosis and for the treatment of post-polycythemia vera myelofibrosis.
A mixture of 4-ethoxycarbonylphenyl boronic acid (23.11 g, 119 mmol), 2,4-dichloropyrimidine (16.90 g, 113 mmol), toluene (230 mL) and aqueous sodium carbonate (2 M, 56 mL) was stirred vigorously and nitrogen was bubbled through the suspension for 15 minutes. Tetrakis(triphenylphosphine)palladium[0] (2.61 g, 2.26 mmol) was added. Nitrogen was bubbled through for another 10 min., the mixture was heated to 100° C., then at 75° C. overnight. The mixture was cooled, diluted with ethyl acetate (200 mL), water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml) and the two organic extracts were combined. The organics were washed with brine, filtered through sodium sulfate, concentrated, and the resultant solid was triturated with methanol (100 mL) and filtered. The solids were washed with methanol (2×30 mL) and air dried. This material was dissolved in acetonitrile (150 mL) and dichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days. The solution was filtered, the solids were washed with dichloromethane (2×100 mL), and the filtrate concentrated to give ethyl 4-(2-chloropyrimidin-4-yl)benzoate as an off-white solid (17.73 g, 60%)—additional washing with dichloromethane yielded a further 1.38 g and 0.5 g of product. 1H NMR (300 MHz, d6-DMSO) δ 8.89 (1H, d, J=5.0 Hz); 8.32 (2H, d, J=8.7 Hz); 8.22 (1H, d, J=5.5 Hz); 8.12 (2H, d, J=8.7 Hz); 4.35 (2H, q, J=7.1 Hz); 1.34 (3H, t, J=7.1 Hz); LC-ESI-MS (method B): rt 7.3 min.; m/z 263.0/265.0 [M+H]+.
A mixture of ethyl 4-(2-chloropyrimidin-4-yl)benzoate (26.15 g, 99.7 mmol) and 4-morpholinoaniline (23.10 g, 129.6 mmol) was suspended in 1,4-dioxane (250 mL). p-Toluenesulfonic acid monohydrate (17.07 g, 89.73 mmol) was added. The mixture was heated at reflux for 40 h., cooled to ambient temperature, concentrated then the residue was partitioned between ethyl acetate and 1:1 saturated sodium bicarbonate/water (1 L total). The organic phase was washed with water (2×100 mL) and concentrated. The aqueous phase was extracted with dichloromethane (3×200 mL). The material which precipitated during this workup was collected by filtration and set aside. The liquid organics were combined, concentrated, triturated with methanol (200 mL) and filtered to yield additional yellow solid. The solids were combined, suspended in methanol (500 mL), allowed to stand overnight then sonicated and filtered. The solids were washed with methanol (2×50 mL) to give, after drying, ethyl 4-(2-(4-morphonlinophenylamino)pyrimidin-4-yl)benzoate (35.39 g, 88%). 1H NMR (300 MHz, d6-DMSO) δ 9.49 (1H, s); 8.54 (1H, d, J=5.0 Hz); 8.27 (2H, d, J=8.7 Hz); 8.10 (2H, d, J=8.7 Hz), 7.66 (2H, d, J=9.1 Hz); 7.38 (1H, d, J=5.0 Hz); 6.93 (2H, d, J=8.7 Hz); 4.35 (2H, q, J=6.9 Hz), 3.73 (4H, m); 3.04 (4H, m); 1.34 (3H, t, J=6.9 Hz); LC-ESI-MS (method B): rt 7.5 min.; m/z 404.1 [M+H].
A solution of ethyl 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoate (35.39 g, 87.6 mmol) in 3:1 methanol/tetrahydrofuran (350 mL) was treated with lithium hydroxide (4.41 g, 183.9 mmol) in water (90 mL). The mixture was heated at reflux for 2 h., cooled, concentrated and acidified with hydrochloric acid (2M, 92.5 mL, 185 mmol). The dark precipitate was filtered, washed with water, and dried under vacuum. The solid was ground to a powder with a mortar and pestle, triturated with methanol (500 mL) then filtered again to yield 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid as a muddy solid. This material was washed with ether, air dried overnight, and ground to a fine powder with mortar and pestle. On the basis of mass recovery (34.49 g) the yield was assumed to be quantitative. 1H NMR (300 MHz, d6-DMSO) δ 9.47 (1H, s); 8.53 (1H, d, J=5.2 Hz); 8.24 (2H, d, J=8.5 Hz); 8.08 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=9.1 Hz); 7.37 (1H, d, J=5.2 Hz); 6.93 (2H, d, J=9.1 Hz); 3.73 (4H, m); 3.04 (4H, m). LC-ESI-MS (method C): rt 7.3 min.; m/z 377.1 [M+H]+.
To a suspension of 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid (theoretically 32.59 g, 86.6 mmol) in DMF (400 mL) was added triethylamine (72.4 mL, 519.6 mmol, 6 eq.) The mixture was sonicated to ensure dissolution. Aminoacetonitrile hydrochloride (16.02 g, 173.2 mmol) was added followed by N-hydroxybenzotriazole (anhydrous, 14.04 g, 103.8 mmol) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (19.92 g, 103.8 mmol). The suspension was stirred vigorously overnight. The solvent was evaporated under reduced pressure, the residue was diluted with 5% sodium bicarbonate (400 mL) and water (300 mL), giving a yellow solid, which was broken up and filtered. The solids were washed several times with 100 mL portions of water, triturated with hot methanol/dichloromethane (500 mL, 1:1), concentrated to a volume of approximately 300 mL), cooled and filtered. The solids were washed with cold methanol (3×100 mL), ether (200 mL) and hexane (200 mL) prior to drying to afford
Compound 3 (31.69 g, 88%). M.p. 238-243° C.
Microanalysis: Found C, 66.52; H, 5.41; N, 20.21. C23H26N6O10S2 requires C, 66.65; H, 5.35; N, 20.28%.
Compound 3 (10.0 g) was suspended in methanol (1 L). Concentrated sulfuric acid (10.52 g, 90% w/w) was added dropwise to the stirring solution. A clear brown solution resulted and a solid lump formed. The solution was filtered quickly then allowed to continue stirring for 3 h (a second precipitate appeared within minutes). After this time the pale yellow precipitate was collected by filtration, washed with methanol (10 mL) then dried under vacuum overnight to afford 4-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-1-ium-2-ylamino)phenyl)morpholin-4-ium hydrogensulfate, as a pale yellow solid (10.20 g, 69%). m.p. 205° C. Microanalysis: Found C, 45.18; H, 4.36; N, 13.84; S, 10.24. C23H26N6O10S2 requires C, 45.24; H, 4.29; N, 13.76; S 10.50%. 1H NMR (300 MHz, d6-DMSO) δ 9.85 (br. s, 1H), 9.34 (t, J=5.4 Hz, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 8.03 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.50 (d, J=5.2 Hz, 1H), 7.34 (br. s, 2H), 4.36 (d, J=5.4 Hz, 2H), 3.89 (br. s, 4H), 3.37 (br. s, 4H); 13C NMR (75.5 MHz, d6-DMSO) δ 166.07, 163.36, 159.20, 158.48, 140.19, 139.34, 136.45, 134.89, 128.00, 127.22, 121.13, 119.89, 117.59, 109.05, 64.02, 54.04, 27.82. LC-ESI-MS (method D): rt 10.0 min.; m/z 415.1 [M+H]+.
Compound 3 (0.25 g) was suspended in methanol (25 ml). Methane sulfonic acid (0.255 g) was added dropwise to the stirring solution and a clear brown solution resulted. The solution was allowed to stir for 3 h, after which the volume was reduced to 9 ml. The resultant precipitate was collected and dried under vacuum for 8 h to afford 4-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-1-ium-2-ylamino)phenyl)morpholin-4-ium methanesulfonate as a pale yellow solid (0.22 g). m.p. 208° C. 1H NMR (300 MHz, d6-DMSO) δ 9.83 (br. s, 1H), 9.35 (t, J=5.3 Hz, 1H), 8.59 (d, J=5.1 Hz, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 7.50 (d, J=5.5 Hz, 1H), 7.31 (d, J=9.0 Hz, 2H), 4.36 (d, J=5.5 Hz, 2H), 3.88 (m, 4H), 3.35 (br. s, 4H), 2.36 (s, 6H); LC-ESI-MS (method D): rt 10.2 min.; m/z 415.3 [M+H]+.
Compound 3 (0.50 g) was suspended in methanol (45 ml). A freshly prepared solution of hydrochloric acid in methanol (2.6 ml, HCl conc. 40 mg/ml) was added dropwise to the stirring solution and a clear brown solution resulted. The solution was allowed to stir for 2 h, then the resultant precipitate was collected, washed with methanol (5 ml) and dried under vacuum for 8 h to afford 4-(4-(4-(4-(cyanomethylcarbamoyl)phenyl)pyrimidin-1-ium-2-ylamino)phenyl)morpholin-4-ium chloride a pale yellow solid (0.30 g). m.p. 210° C. 1H NMR (300 MHz, d6-DMSO) 1H NMR (300 MHz, DMSO) δ 9.92 (br. s, 1H), 9.42 (t, J=5.3, 1H), 8.62 (d, J=4.8, 1H), 8.29 (d, J=8.1, 2H), 8.06 (d, J=8.1, 2H), 7.89 (d, J=9.0, 2H), 7.53 (br. s, 3H), 4.36 (d, J=5.4, 2H), 3.82 (br. s, 4H), 3.43 (br. s, 4H)
. [1] A Pardanani et al CYT387, a Selective JAK1 / JAK2 inhibitor: in vitroassessment of kinase selectivity and preclinical s using Cell lines and Primary cells from polycythemia vera Patients Leukemia (2009) 23, 1441-1445 Abstract Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1 / JAK2 kinases ( IC (50) = 11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC (50) = 155 nM). CYT387 inhibits growth of Ba / F3-JAK2V617F and human erythroleukemia (HEL) cells ( IC (50) approximately 1500 nM) or Ba / F3-MPLW515L cells (IC (50) = 200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC = 58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba / F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba / F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC (50) = 400 nM. … [2]. Tyner Jeffrey W. et al CYT387, a novel JAK2 inhibitor, induces Hematologic Responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms Blood June 24, 2010vol. no 115. 255232-5240 Abstract Activating alleles of Janus kinase 2 (JAK2) SUCH as JAK2 (V617F) are Central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting Small molecule inhibitors targeting JAK2 That May be therapeutically Useful. IDENTIFIED We have an aminopyrimidine derivative ( CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5muM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2 (V617F) allele burden, JAK2 (V617F) cells persisted and MPN recurred upon cessation of treatment, suggesting JAK2 inhibitors That May be Unable to Eliminate JAK2 (V617F) cells, Consistent with Preliminary results from Clinical Trials of JAK2 inhibitors in myelofibrosis. … [3]. Sparidans RW, Durmus S, Xu N, Schinkel AH, Schellens JH, Beijnen JH.Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma.J Chromatogr B Analyt Technol Biomed Life Sci 2012 May 1; 895-896:. 174-7 Epub 2012 Mar 23.. abstract A quantitative bioanalytical Liquid Chromatography-Tandem Mass spectrometric (LC-MS / MS) assay for the JAK2 inhibitor CYT387 WAS Developed and validated. Plasma samples Were Treated using pre-Protein precipitation with acetonitrile containing cediranib as Internal Standard. The extract WAS Directly Injected into the chromatographic system after dilution with water. This system consisted of a sub-2 μm particle, trifunctional bonded octadecyl silica column with a gradient using 0.005% (v / v) of formic acid in a mixture of water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 0.25-1000 ng / ml calibration range. Within day precisions were 3.0-13.5%, BETWEEN Day Precisions 5.7% and 14.5%. Accuracies Were BETWEEN 96% and 113% for the Whole Calibration range. The Drug WAS stable under All Relevant Analytical Conditions. Finally, the assay successfully WAS Used to ASSESS Drug Levels in mice. [4] . Monaghan KA, Khong T, Burns CJ, Spencer A.The novel JAK inhibitor CYT387 suppresses Multiple Signalling pathways, and induces apoptosis in Prevents Proliferation phenotypically Diverse myeloma cells.Leukemia 2011 Dec; 25 (12):. 1891-9. Abstract Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6 / JAK / signal transducers and activators of transcription (IL-6 / JAK / STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1 / 2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G (2) / M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, WAS Also apoptosis induced in Primary Patient MM cells (N = 6) with CYT387 as a single agent, and synergy WAS Seen Again when Combined with Conventional therapies. [5]. Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, Druker BJ, Burns CJ, Fantino E, Deininger MW.CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms.Blood 2010 Jun 24; 115 (25):. 5232- 40. Epub 2010 Apr 12. Abstract Activating alleles of Janus kinase 2 (JAK2) SUCH as JAK2 (V617F) are Central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting Small molecule inhibitors targeting JAK2 That May be therapeutically Useful. We have IDENTIFIED an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5muM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2 (V617F) allele burden, JAK2 (V617F) cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2 (V617F) cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.
JAKs are kinases which phosphorylate a group of proteins called Signal Transduction and Activators of Transcription or STATs. When phosphorylated, STATs dimerize, translocate to the nucleus and activate expression of genes which lead to, amongst other things, cellular proliferation.
The central role played by the JAK family of protein tyrosine kinases in the cytokine dependent regulation of both proliferation and end function of several important cell types indicates that agents capable of inhibiting the JAK kinases are useful in the prevention and chemotherapeutic treatment of disease states dependent on these enzymes. Potent and specific inhibitors of each of the currently known four JAK family members will provide a means of inhibiting the action of the cytokines that drive immunological and inflammatory diseases.
Myeloproliferative disorders (MPD) include, among others, polycythemia vera (PV), primary myelofibrosis, thrombocythemia, essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myelogenous leukemia (CML), systemic mastocystosis (SM), chronic neutrophilic leukemia (CNL), myelodisplastic syndrome (MDS) and systemic mast cell disease (SMCD). JAK2 is a member of the JAK family of kinases in which a specific mutation (JAK2V617F) has been found in 99% of polycythemia vera (PV) patients and 50% of essential thrombocytopenia (ET) and idiopathic myelofibrosis (MF). This mutation is thought to activate JAK2, giving weight to the proposition that a JAK2 inhibitor will be useful in treating these types of diseases.
Asthma is a complex disorder characterized by local and systemic allergic inflammation and reversible airway obstruction. Asthma symptoms, especially shortness of breath, are a consequence to airway obstruction, and death is almost invariably due to asphyxiation. Airway Hyper Responsiveness (AHR), and mucus hyper secretion by goblet cells are two of the principle causes of airway obstruction in asthma patients. Intriguingly recent work in animal experimental models of asthma has underscored the importance of IL-13 as a key player in the pathology of asthma. Using a specific IL-13 blocker, it has been demonstrated that IL-13 acts independently of IL-4 and may be capable of inducing the entire allergic asthma phenotype, without the induction of IgE (i.e. in a non-atopic fashion). This and other models have pointed to an important second tier mechanism for elicitating the pathophysiology of asthma, that is not dependent on the production of IgE by resident B-cells or the presence of eonisophils. A direct induction of AHR by IL-13, represents an important process that is likely to be an excellent target for intervention by new therapies. A contemplated effect of a JAK2 inhibitor to the lungs would result in the suppression of the local release of IL-13 mediated IgE production, and therefore reduction in histaminine release by mast cells and eosinophils. This and other consequences of the absence of IL-13 indicate that many of the effects of asthma may be alleviated through administration of a JAK2 inhibitor to the lungs.
Chronic Obstructive Pulmonary Disease (COPD) is a term which refers to a large group of lung diseases which can interfere with normal breathing. Current clinical guidelines define COPD as a disease state characterized by airflow limitation which is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases, particularly cigarette smoke and pollution. Several studies have pointed to an association between increased production of IL-13 and COPD, lending support to the proposition that the potential alleviation of asthma symptoms by use of a JAK2 inhibitor, may also be achieved in COPD. COPD patients have a variety of symptoms including cough, shortness of breath, and excessive production of sputum. COPD includes several clinical respiratory syndromes including chronic bronchitis and emphysema.
Chronic bronchitis is a long standing inflammation of the bronchi which causes increased production of mucus and other changes. The patient’s symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi. The lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood. The predominant symptom in patients with emphysema is shortness of breath.
Additionally, there is evidence of STAT activation in malignant tumors, among them lung, breast, colon, ovarian, prostate and liver cancer, as well as Hodgkins lymphoma, multiple myeloma and hepatocellular carcinoma. Chromosomal translocations involving JAK2 fusions to Tel, Bcr and PCM1 have been described in a number of hematopoietic malignancies including chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic eosinophilic leukemia (CEL), myelodisplastic syndrome (MDS), myeloproliferative disease (MPD) and acute lymphocytic leukemia (ALL). This suggests treatment of hyperproliferative disorders such as cancers including multiple myeloma; prostate, breast and lung cancer; Hodgkin’s Lymphoma; CML; AML; CEL; MDS; ALL; B-cell Chronic Lymphocytic Leukemia; metastatic melanoma; glioma; and hepatoma, by JAK inhibitors is indicated.
Potent inhibitors of JAK2, in addition to the above, will also be useful in vascular disease such as hypertension, hypertrophy, cardiac ischemia, heart failure (including systolic heart failure and diastolic heart failure), migraine and related cerebrovascular disorders, stroke, Raynaud’s phenomenon, POEMS syndrome, Prinzmetal’s angina, vasculitides, such as Takayasu’s arteritis and Wegener’s granulomatosis, peripheral arterial disease, heart disease and pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease affecting the pulmonary arterioles resulting in an elevation in pulmonary artery pressure and pulmonary vascular resistance but with normal or only mildly elevated left-sided filling pressures. PAH is caused by a constellation of diseases that affect the pulmonary vasculature. PAH can be caused by or associated with collagen vascular disorders such as systemic sclerosis (scleroderma), uncorrected congenital heart disease, liver disease, portal hypertension, HIV infection, Hepatitis C, certain toxins, splenectomy, hereditary hemorrhagic teleangiectasia, and primary genetic abnormalities. In particular, a mutation in the bone morphogenetic protein type 2 receptor (a TGF-b receptor) has been identified as a cause of familial primary pulmonary hypertension (PPH). It is estimated that 6% of cases of PPH are familial, and that the rest are “sporadic.” The incidence of PPH is estimated to be approximately 1 case per 1 million population. Secondary causes of PAH have a much higher incidence. The pathologic signature of PAH is the plexiform lesion of the lung which consists of obliterative endothelial cell proliferation and vascular smooth muscle cell hypertrophy in small precapillary pulmonary arterioles. PAH is a progressive disease associated with a high mortality. Patients with PAH may develop right ventricular (RV) failure. The extent of RV failure predicts outcome. The JAK/STAT pathway has recently been implicated in the pathophysiology of PAH. JAKs are kinases which phosphorylate a group of proteins called Signal Transduction and Activators of Transcription or STATs. When phosphorylated, STATs dimerize, translocate to the nucleus and activate expression of genes which lead to proliferation of endothelial cells and smooth muscle cells, and cause hypertrophy of cardiac myocytes. There are three different isoforms of JAK: JAK1, JAK2, and JAK3. Another protein with high homology to JAKs is designated Tyk2. An emerging body of data has shown that the phosphorylation of STAT3, a substrate for JAK2, is increased in animal models of PAH. In the rat monocrotaline model, there was increased phosphorylation of the promitogenic transcription factor STAT3. In this same study pulmonary arterial endothelial cells (PAECs) treated with monocrotaline developed hyperactivation of STAT3. A promitogenic agent or protein is an agent or protein that induces or contributes to the induction of cellular proliferation. Therefore, one effect of JAK2 inhibition would be to decrease proliferation of endothelial cells or other cells, such as smooth muscle cells. A contemplated effect of a JAK2 inhibitor would be to decrease the proliferation of endothelial cells or other cells which obstruct the pulmonary arteriolar lumen. By decreasing the obstructive proliferation of cells, a JAK2 inhibitor could be an effective treatment of PAH.
Additionally the use of JAK kinase inhibitors for the treatment of viral diseases and metabolic diseases is indicated.
Although the other members of the JAK family are expressed by essentially all tissues, JAK3 expression appears to be limited to hematopoetic cells. This is consistent with its essential role in signalling through the receptors for IL-2, IL4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. An XSCID syndrome in which patients with either mutated or severely reduced levels of JAK3 protein has been identified, suggesting that immunosuppression should result from blocking signalling through the JAK3 pathway. Gene Knock out studies in mice have suggested that JAK3 not only plays a critical role in B and T lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function. Taken together with the biochemical evidence for the involvement of JAK3 in signalling events downstream of the IL-2 and IL-4 receptor, these human and mouse mutation studies suggest that modulation of immune activity through the inhibition of JAK3 could prove useful in the treatment of T-cell and B-cell proliferative disorders such as transplant rejection and autoimmune diseases. Conversely undesired inhibition of JAK3 could have a devastating effect on the immune status of an individual treated with drug.
Although the inhibition of various types of protein kinases, targeting a range of disease states, is clearly beneficial, it has been to date demonstrated that the identification of a compound which is selective for a protein kinase of interest, and has good “drug like” properties such as high oral bioavailability, is a challenging goal. In addition, it is well established that the predictability of inhibition, or selectivity, in the development of kinase inhibitors is quite low, regardless of the level sequence similarity between the enzymes being targeted.
The challenges in developing therapeutically appropriate JAK2 inhibitors for use in treatment kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases include designing a compound with appropriate specificity which also has good drug-likeliness.
There is therefore a continuing need to design and/or identify compounds which specifically inhibit the JAK family of kinases, and particularly compounds which may preferentially inhibit one of the JAK kinases relative to the other JAK kinases, particularly JAK2. There is a need for such compounds for the treatment of a range of diseases.
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
“Ojjaara- momelotinib tablet”. DailyMed. U.S. National Library of Medicine. 15 September 2023. Archived from the original on 30 November 2023. Retrieved 20 September 2023.
“Omjjara EPAR”. European Medicines Agency. 5 August 2011. Retrieved 18 March 2024.
Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A (August 2009). “CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients”. Leukemia. 23 (8): 1441–1445. doi:10.1038/leu.2009.50. PMID19295546. S2CID26947444.
Clinical trial number NCT04173494 for “A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM)” at ClinicalTrials.gov
Clinical trial number NCT01969838 for “Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis (Simplify 1)” at ClinicalTrials.gov
//////////Momelotinib, APPROVALS 2023, FDA 2023, Ojjaara, high-risk myelofibrosis, anemia, APPROVALS 2024, EU 2024, EMA 2024
REF
European Journal of Medicinal Chemistry 265 (2024) 116124
Scheme 13 illustrates the synthesis of Momelotinib Dihydrochloride [48]. The Pd(PPh3) 4-catalyzed Suzuki coupling reaction between 2,4-dichloropyrimidine (MOME-001) and boronic acid MOME-002 resulted in the formation of MOME-003. Subsequently, MOME-003 underwent a substitution reaction with aniline MOME-004 in the presence of p-toluenesulfonic acid (TsOH), yielding MOME-005. MOME-005 was hydrolyzed by lithium hydroxide, leading to the formation of carboxylic acid MOME-006. MOME-006 underwent amidation with 2-aminoacetonitrile hydrochloride (MOME-007) to produce Momelotinib.
[48] G.D. Smith, R. Fida, M.M. Kowalski, N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl) phenyl]amino]-4-pyrimidinyl]-benzamide [CYT387] or a Related Compound, 2012. WO2012071612A1.
The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation…….http://clinicaltrials.gov/show/NCT01819428
1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)-prop-2-en-l-one hydrochloride of formula (I) below is an important drug having antiproliferative activities such as anti-tumor activity, which can be used for selectively and effectively treating drug resistance caused by tyrosine kinase mutation. Its free base form, i.e., l-(4-(4-(3,4-dichloro-2- fluoropheny lamino)-7-methoxyquinazolin-6-y loxy)piperidin- 1 -y l)-prop-2-en- 1 – one having formula (II) below is identified as CAS Registry Number 1092364-38-
9.
The compound of formula (II) may be prepared by, e.g., the method disclosed in Korean Patent No. 1013319, the reaction mechanism thereof being shown in Reaction Scheme 1 below. The compound of formula (II) prepared according to Reaction Scheme 1 may then be reacted with hydrochloric acid to produce the compound of formula (I).
wherein R is halogen.
formula (I):
In accordance with another aspect of the present invention, there are provided N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride of formula (III), tert-butyl 4-(4-(3,4- dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l- carboxylate of formula (IV) and 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol of formula (V), which can be used as intermediates for preparing the compound of formula (I).
Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenyIamino)-7- methoxyquinazolin-6-yl acetate the compound of formula (VI))
7-methoxy-4-oxo-3,4-dihydroquinazolin-yl acetate (100 g) was added to toluene (850 ml) and NN-diisopropylethylamine (82.5 ml). Phosphorusoxy chloride (100 ml) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 ml) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C. The solid thus obtained was filtered under a reduced pressure and washed with toluene (400 ml). Isopropanol (1,000 ml) was added to the solid, which was then stirred for 2 hours. The resulting solid was filtered and washed with isopropanol (400 ml). The solid was dried at 40°C in an oven to produce the compound of formula (VI) (143 g, yield: 83%).
Example 2: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol (the com ound of formula (V))
4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate (100 g) was admixed with methanol (1,000 ml). The mixture was cooled to 10 to 15°C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 ml) and water (200 ml). The resulting solid was dried at 40°C in an oven to produce the compound of formula (V) (74 g, yield: 83%).
Example 3: Preparation of /er/-but l-4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (the compound of formu
4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (60 g) was admixed with N-dimethylformamide (360 ml) under stirring, followed by addition of tert-butyl 4-(tosyloxy)piperidin-l-carboxylate (120 g) and potassium carbonate (72 g) to the mixture. The reaction temperature was raised to 70°C, and the mixture was stirred for 14 hours. The temperature of the resulting solution was cooled to 25°C, and water (480 ml) was slowly added thereto. The solid thus obtained was filtered and dried. The solid was dissolved in a mixed solvent (600 ml) of dichloromethane and methanol. Active carbon (6 g) was then added thereto, followed by stirring for 30 minutes. The resulting mixture was filtered through a Celite pad, distilled under a reduced pressure, added with acetone (300 ml), and stirred for 2 hours. The resulting solid was filtered and washed with acetone (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (IV) (75 g, yield: 83%).
Example 4: Preparation of N-(3,4-dichIoro-2-fluorophenyi)-7- methoxy-6-(piperidin-4-yloxy)quinazoIin-4-amine dihydrochloride (the compound of formula (III))
Acetone (740 ml) was added to ter/-butyl 4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (75 g), which was then stirred. The mixture was added with hydrochloric acid (145 ml) for 10 minutes and stirred for 5 hours. Upon completion of the reaction, the resulting mixture was filtered, and the solid thus obtained was washed with acetone (73 ml). The solid was dried at 30°C in an oven to produce the compound of formula (III) (71 g, yield: 99%).
Example 5: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en- 1-one (the compound of formula II))
N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0°C with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0°C for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)prop-2-en-l-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield = 57%).
Ή-NMR (CDC13, 300 MHz, ppm) 68.68(s, 1H), 8.39(t, 3H), 7.3 l(m, 3H), 6.61(m, 1H), 6.29(m, 1H), 5.72(m, 1H), 4.75(m, 1H), 4.02(s, 3H), 3.89(m, 2H), 3.60(m, 2H), 1.86(m, 4H). Example 6: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yIoxy)piperidin-l-yl)prop-2-en- 1-one hydrochloride (the com ound of formula (I))
1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidine-l-yl)prop-2-en-l-one (150 g) was added to methanol (700 ml). Hydrochloric acid (38.2 ml) diluted with methanol (300 ml) was added thereto, followed by stirring for 24 hours. The solid thus obtained was filtered and washed with acetone (100 ml). The resulting solid was dried at 40°C in an oven for 24 hours to produce the compound of formula (I) (131 g, yield: 81%).
Process for preparing poziotinib – comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative.
A process for preparing poziotinib comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative in the presence of an inert polar protic solvent (eg N,N-dimethylformamide), and a base (eg sodium bicarbonate) is claimed. Also claimed are processes for preparing intermediates of poziotinib. Poziotinib is known to be an inhibitor of EGFR family, and Erbb2 tyrosine kinase receptors, useful for the treatment of stomach tumor and non-small-cell lung cancer. Novel method for preparing poziotinib. Follows on from WO2013051883 claiming method for preparing poziotinib and its intermediates. Hanmi, in collaboration with National Oncoventure, is developing poziotinib for the oral treatment of non small cell lung cancer and gastric cancer. As of August 2014, the drug is in phase 2 trials for both indications.
Compound of formula (II) is (I) and compound of formula (I) (poziotinib) is (II) (claim 1, page 13).The synthesis of (II) via intermediate (I) is described (example 1, pages 8-11).
Preparation Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)- 7-methoxyquinazolin-6-ol, the compound of formula (II)
Step (i): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yl acetate, the compound of formula (V)
7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (100 g) was added to toluene (850 mL) and NN-diisopropylethylamine (82.5 mL). Phosphorus oxychloride (100 mL) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 mL) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C, and the solid thus obtained was filtered under a reduced pressure and washed with toluene (400 mL). Isopropanol (1,000 mL) was added to the solid, and the resulting mixture was stirred for 2 hours. The solid thus obtained was filtered and washed with isopropanol (400 mL), and then was dried at 40°C in an oven to obtain the target compound (143 g, yield: 83%).
Step (ii): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol, the compound of formula (II)
4-(3,4-dichloro-2-fluorophenyIamino)-7-methoxyquinazolin-6-y l acetate (100 g) prepared in step (i) was admixed with methanol (1,000 mL). The mixture was cooled to 10 to 1 °C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 mL) and water (200 mL). The resulting solid was dried at 40°C in an oven to obtain the target compound (74 g, yield: 83%). 1H-NMR (DMSO-d 6 , 300 MHz, ppm) 5 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s,
Example 1: Preparation of l-(4-(4-(3,4-dichIoro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I) Step (1-1 : Preparation of l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate. the compound of formula (HI)
Piperidin-4-yl 4-methylbenzenesulfonate hydrochloride (200 g, 685 mmol), tetrahydrofuran (THF, 1.6 L) and NaHCO 3 (172 g, 2047 mmol) were added to water (2 L), and the mixture was cooled to 0°C. A solution prepared by adding acryloyl chloride (56 mL, 519 mmol) to THF (0.4 L) was added thereto over 30 minutes, followed by stirring for 1 hour. Upon completion of the reaction, MeOH (0.4 L) was added thereto for quenching. The solution was extracted with ethyl ester (2 L), and washed with water (2 L). The organic layer was separated, distilled under a reduced pressure, and the residue thus obtained was recrystallized from dichloromethane-hexane to obtain the target compound (174 g, yield: 82%). 1H-NMR (300 MHz, DMSO-d 6 ) δ 7.82 (d, 2H), 7.48 (d, 2H), 6.80-6.71 (m,
Step (1-2): Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)
4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-o l (12 g, 34 mmol) prepared in Preparation Example 1, l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), K 2 CO 3 (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 mL) were admixed. The reaction temperature was raised to 70°C, and the mixture was stirred for 24 hours. Upon completion of the reaction, the mixture was cooled down to room temperature, extracted with ethyl ester (300 mL), and then washed with water (300 mL). The organic layer was separated, and distilled under a reduced pressure. The residue thus obtained was solidified by adding ethyl ester, filtered, and dried to obtain the target compound (12.8 g, yield: 77%). 1H-NMR (300 MHz, DMSO-d 6 ) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H),
7.64-7.56 (m, 2H), 7.24 (s, 1H), 6.89-6.80 (m, 1H), 6.15-6.08 (m, 1H), 5.70-5.66 (m, 1H), 4.78 (m, 1H), 3.94 (s, 3H), 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, 1H). Example 2: Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)
ROCHESTER, Minn. — High doses of the herb American ginseng (Panax quinquefolius) over two months reduced cancer-related fatigue in patients more effectively than a placebo, a Mayo Clinic-led study found. Sixty percent of patients studied had breast cancer. The findings are being presented at the American Society of Clinical Oncology’s annual meeting.
Researchers studied 340 patients who had completed cancer treatment or were being treated for cancer at one of 40 community medical centers. Each day, participants received a placebo or 2,000 milligrams of ginseng administered in capsules containing pure, ground American ginseng root.
“Off-the-shelf ginseng is sometimes processed using ethanol, which can give it estrogen-like properties that may be harmful to breast cancer patients,” says researcher Debra Barton, Ph.D., of the Mayo Clinic Cancer Center.
At four weeks, the pure ginseng provided only a slight improvement in fatigue symptoms. However, at eight weeks, ginseng offered cancer…
Anna Popova, Head of the Federal Service for Supervision of Consumer Protection and Welfare (Rospotrebnadzor)
MOSCOW, August 5 (RIA Novosti) – A Russian vaccine against Ebola hemorrhagic fever is now undergoing preclinical tests, Russian consumer rights watchdog, Rospotrebnadzor, head Anna Popova told journalists.
As of today, it is in a stage of preclinical drug trials. The works are intensified now,” Popova said. She added that there are currently no licensed drugs …
Identifying target product profile (TPP). TPP has been defined as a “prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized”. This includes dosage form and route of administration, dosage form strength(s), therapeutic moiety release or delivery and pharmacokinetic characteristics (e.g., dissolution and aerodynamic performance) appropriate to the drug product dosage form being developed and drug product-quality criteria (e.g., sterility and purity) appropriate for the intended marketed product. The concept of TPP in this form and its application is novel in the QbD paradigm.
Identifying CQAs. Once TPP has been identified, the next step is to identify the relevant CQAs. A CQA has been defined as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”10. Identification of CQAs is done through risk assessment as per the ICH guidance Q9 . Prior product knowledge, such as the accumulated laboratory, nonclinical and clinical experience with a specific product-quality attribute, is key in making these risk assessments. Such knowledge may also include relevant data from similar molecules and data from literature references. Taken together, this information provides a rationale for relating the CQA to product safety and efficacy. The outcome of the risk assessment would be a list of CQAs ranked in order of importance. Use of robust risk assessment methods for identification of CQAs is novel to the QbD paradigm.
Defining product design space. After CQAs for a product have been identified, the next step is to define the product design space (that is, specifications for in-process, drug substance and drug product attributes). These specifications are established based on several sources of information that link the attributes to the safety and efficacy of the product, including, but not limited to, the following:
Clinical design space
Nonclinical studies with the product, such as binding assays, in vivo assays and in vitro cell-based assays
Clinical and nonclinical studies with similar platform products
Published literature on other similar products
Process capability with respect to the variability observed in the manufactured lots
The difference between the actual experience in the clinic and the specifications set for the product would depend on our level of understanding of the impact that the CQA under consideration can have on the safety and efficacy of the product. For example, taking host cell proteins as a CQA, it is common to propose a specification that is considerably broader than the clinical experience. This is possible because of a greater ability to use data from other platform molecules to justify the broader specifications. On the other hand, in the case of an impurity that is unique to the product, the specifications would rely solely on clinical and nonclinical studies.
In QbD, an improved understanding of the linkages between the CQA and safety and efficacy of the product is required. QbD has brought a realization of the importance of the analytical, nonclinical and animal studies in establishing these linkages and has led to the creation of novel approaches.
Defining process design space. The overall approach toward process characterization involves three key steps. First, risk analysis is performed to identify parameters for process characterization. Second, studies are designed using design of experiments (DOE), such that the data are amenable for use in understanding and defining the design space. And third, the studies are executed and the results analyzed to determine the importance of the parameters as well as their role in establishing design space.
Failure mode and effects analysis (FMEA) is commonly used to assess the potential degree of risk for every operating parameter in a systematic manner and to prioritize the activities, such as experiments, necessary to understand the impact of these parameters on overall process performance. A team consisting of representatives from process development, manufacturing and other relevant disciplines performs an assessment to determine severity, occurrence and detection. The severity score measures the seriousness of a particular failure and is based on an estimate of the severity of the potential failure effect at a local or process level and the potential failure effect at end product use or patient level. Occurrence and detection scores are based on an excursion (manufacturing deviation) outside the operating range that results in the identified failure. Although the occurrence score measures how frequently the failure might occur, the detection score indicates the probability of timely detection and correction of the excursion or the probability of detection before end product use. All three scores are multiplied to provide a risk priority number (RPN) and the RPN scores are then ranked to identify the parameters with a high enough risk to merit process characterization. FMEA outcome for a process chromatography step in a biotech process. RPN scores are calculated and operating parameters with an RPN score >50 are characterized using a qualified scaled-down model. For the case study presented here, these include gradient slope, temperature, flow rate, product loading, end of pool collection, buffer A pH, start of pool collection, volume of wash 1, buffer B pH, buffer C pH and bed height. Process characterization focused on parameters such as temperature, that have a high impact on the process (severity = 6), occur frequently in the manufacturing plant (occurrence = 6) and are difficult to quickly correct if detected (detection = 7). In contrast, parameters such as equilibration volume, with a low impact on the process (severity = 3), low occurrence (occurrence = 2) and a limited ability to detect and correct (detection = 5), were not examined in process characterization.
Shanghai Natural Bio-engineering Co., Ltd, export branch of Hunan Keyuan Bio-products co., Ltd, established in 2003, is a professional large-scale high-tech manufacturer of raw materials for nutraceuticals, nutritional supplements, and pharmaceuticals. Plant extracts, Active Pharmaceutical Ingredient (API) & intermediates are our focused areas.Key products include resveratrol, curcumin,artemisinin,artemether,artesunate,dihydroartemisinin,Lumefantrine,etc
Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%
August 05, 2014
Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%
Japanese knotweed extract, Polygonum cuspidatum, red wine extract, trans-3,5,4′-trihydroxystilbene, trans-Resveratrol, cis-resveratrol
CAS number
501-36-0
Latin Name
Polygonum cuspidatum
Botanical source
1.Japanese knotweed plant Polygonum cuspidatum
2. red wine
3. red grape extracts
Molecular Formula
C14H12O3
Molecular weight
228.24
Appearance
white powder with slight yellow
Solubility in water
0.03 g/L
Dosage
500mg
Key benefits
Anti-aging, Anti-Cancer, cardiovascular support, regulate estrogen level, weight loss
Applied industry
Sports nutrition, nutraceuticals, cosmetics
What is resveratrol?
When talk about resveratrol, we have to mention red wine since resveratrol is first popularly known in red wine. In fact, resveratrol was actually first isolated in 1940 from white hellebore roots by the Japanese scientist Michio Takaoka. Red wine, in moderation, has long been thought of as heart healthy. However, the most popular source of resveratrol is from Japanese knotweed extract (Latin name:Polygonum cuspidatum)
Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.
Resveratrol exists as two geometric isomers: “cis-” (“Z”) and “trans-” (“E”). The ”trans-” form can undergo isomerisation to the “cis-” form when exposed to ultraviolet irradiation. Trans-resveratrol in the powder form was found to be stable under “accelerated stability” conditions of 75% humidity and 40 degrees C in the presence of air. Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.
Sources of resveratrol
The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Red and purple grape juices may have some of the same heart-healthy benefits of red wine.
Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.
Benefits of taking reveratrol supplements
Numerous studies have been conducted regarding various purported resveratrol benefits. Studies have primarily been conducted on laboratory animals, and while human search is very promising, is still in its earliest stages. Current research into resveratrol benefits points to resveratrol having amazing anti-aging properties, hence dubbed “The Fountain of Youth.” Many other key benefits such as cardiovascular effects, anti-cancer, estrogen regulating effects are mentioned here.
1.Resveratrol and its anti-aging benefits
The study by Harvard Medical School researchers shows that resveratrol stimulates production of SIRT1, a serum that blocks diseases by speeding up the cell’s energy production centers known as mitochondria.
Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. Resveratrol is only one of many natural and synthetic sirtuin-activating compounds (STACs) now known. Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.
2.Resveratrol and cardiovascular benefits
Resveratrol is famous for its Cardioprotective effects.According to Wikipedia, moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox”.
Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) inhibition of vascular cell adhesion molecule expression;(2) inhibition of vascular smooth muscle cell proliferation;(3) stimulation of endolethelial nitric oxide synthase (eNOS) activity;(4) inhibition of platelet aggregation;and (5) inhibition of LDL peroxidation.
The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das, however, who has been found guilty of scientific fraud and many of his publications related to resveratrol have been retracted. A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via theSAFE pathway.”
Resveratrol, a polyphenol in red wine, induces nitric oxide (NO) synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that Resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase.
3.Reveratrol and anti-cancer benefits
Experts already claim it can help you beat cancer – from brain tumours to breast, colon, prostate cancers and many more. Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation, inhibited enzymes that promote tumor growth, and exerted antitumor effects in neuroblastomas. Noting that in animal studies, resveratrol was effective against tumors of the skin, breast, gastrointestinal tract, lung, and prostate gland. Memorial Sloan-Kettering, the American pillar of cancer treatment, conducted research on theinflammatory effects on cells leading to cancer. It is widely known that an enzyme, COX-2, lies behind the stimulation of localised hormones (eicosanoids) causing inflammation, the precursor to cancer. In the research Resveratrol completely turned off the COX-2 driver. MD Anderson´s studies have shown this same anti-inflammatory benefit too. Plus, after conversion in the liver to a sulphated form the compound can attack several of the steps in the cancer process even killing cancer cells.
4. The Benefits of Resveratrol Weight Loss
Resveratrol is actually a very popular nutrient that has been shown on Dr. Oz, Oprah, Barbara Walters, and a number of other national television shows. It is quickly becoming one of the country’s best natural supplements.
How does Resveratrol help you lose weight? Resveratrol on its own will not be effective at helping you to lose weight, but you have to use it in conjunction with exercise and a proper diet if you really want to obtain the maximum benefits from the supplement.
However, the vitamin, when in concentrated form, has been proven to help speed up the metabolism. This speeding up of the metabolism causes the body to metabolize and process to food consumed faster, which causes the calories in the food to be used more effectively. When the body metabolizes food faster, there is less risk of excess calories being stored in the body in the form of fat.
However, in order to ensure that Resveratrol actually works, you need to take sufficient amounts of the vitamin. The supplement is effective because it is a concentrated form of the helpful vitamin, and taking the supplement is the best way to ensure that Resveratrol works effectively in helping you shed those excess pounds.
Another way Resveratrol helps you to lose weight is through reducing the amounts of estrogen that your body produces. Estrogen increases body fat and decreases muscle mass, so reducing the amounts of estrogen produced by your body will help you lose weight and build muscle. Taking Resveratrol can be a good way to ensure that your body doesn’t produce the amounts of estrogen that will keep it from building muscle.
Side Effects of taking resveratrol supplements
Because there have been very few studies conducted on resveratrol in humans, doctors still can’t confirm what adverse effects these supplements might have on people over the long term. So far, studies have not discovered any severe side effects, even when resveratrol is taken in large doses. However, resveratrol supplements might interact with blood thinners such as warfarin (Coumadin), and nonsteroidal anti-inflammatory medications such as aspirin and ibuprofen, increasing the risk for bleeding.
Like other supplements, resveratrol isn’t regulated by the FDA, so it’s difficult for consumers to know exactly what they’re getting when they buy a bottle, or whether the product is actually effective.
Dosage of resveratrol supplements
There also isn’t any specific dosage recommendation, and dosages can vary from supplement to supplement. The dosages in most resveratrol supplements are typically far lower than the amounts that have been shown beneficial in research studies. Most supplements contain 250 to 500 milligrams of resveratrol. To get the equivalent dose used in some animal studies, people would have to consume 2 grams of resveratrol (2,000 milligrams) or more a day.
Fallopia japonica, commonly known as Japanese knotweed, is a large, herbaceousperennial plant of the family Polygonaceae, native toEastern Asia in Japan, China and Korea. In North America and Europe the species is very successful and has been classified as aninvasive species in several countries. Japanese knotweed has hollow stems with distinct raised nodes that give it the appearance ofbamboo, though it is not closely related. While stems may reach a maximum height of 3–4 m each growing season, it is typical to see much smaller plants in places where they sprout through cracks in the pavement or are repeatedly cut down. The leaves are broad oval with a truncated base, 7–14 cm long and 5–12 cm broad,[1] with an entire margin. The flowers are small, cream or white, produced in erectracemes 6–15 cm long in late summer and early autumn.
Closely related species include giant knotweed (Fallopia sachalinensis, syn. Polygonum sachalinense) and Russian vine (Fallopia baldschuanica, syn. Polygonum aubertii, Polygonum baldschuanicum).
Other English names for Japanese knotweed include fleeceflower, Himalayan fleece vine, monkeyweed, monkey fungus, Hancock’s curse, elephant ears, pea shooters, donkey rhubarb (although it is not a rhubarb), sally rhubarb, Japanese bamboo, American bamboo, and Mexican bamboo (though it is not a bamboo). In Chinese medicine, it is known as Huzhang (Chinese: 虎杖; pinyin: Hǔzhàng), which translates to “tiger stick.” There are also regional names, and it is sometimes confused with sorrel. In Japanese, the name is itadori (虎杖, イタドリ?).[2]
Old stems remain in place as new growth appears
A hedgerow made up of roses and Japanese knotweed in Caersws, Wales in 2010
The invasive root system and strong growth can damage concrete foundations, buildings, flood defences, roads, paving, retaining walls and architectural sites. It can also reduce the capacity of channels in flood defences to carry water.[4]
It is a frequent colonizer of temperateriparianecosystems, roadsides and waste places. It forms thick, dense colonies that completely crowd out any other herbaceous species and is now considered one of the worst invasive exotics in parts of the eastern United States. The success of the species has been partially attributed to its tolerance of a very wide range of soil types, pH and salinity. Its rhizomes can survive temperatures of −35 °C (−31 °F) and can extend 7 metres (23 ft) horizontally and 3 metres (9.8 ft) deep, making removal by excavation extremely difficult.
The plant is also resilient to cutting, vigorously resprouting from the roots. The most effective method of control is by herbicideapplication close to the flowering stage in late summer or autumn. In some cases it is possible to eradicate Japanese knotweed in one growing season using only herbicides. Trials in the Queen Charlotte Islands (Haida Gwaii) of British Columbia using sea water sprayed on the foliage have demonstrated promising results, which may prove to be a viable option for eradication where concerns over herbicide application are too great.[citation needed]
It is classed as an unwanted organism in New Zealand and is established in some parts of the country.[7]
United Kingdom
In the UK, Japanese Knotweed is established in the wild in many parts of the country and creates problems due to the impact on biodiversity, flooding management and damage to property. It is an offence under section 14(2) of the Wildlife and Countryside Act 1981 to “plant or otherwise cause to grow in the wild” any plant listed in Schedule nine, Part II to the Act, which includes Japanese knotweed. It is also classed as “controlled waste” in Britain under part 2 of the Environmental Protection Act 1990. This requires disposal at licensed landfill sites. The species is expensive to remove; Defra‘s Review of Non-native Species Policy states that a national eradication programme would be prohibitively expensive at £1.56 billion.[8]
The decision was taken on 9 March 2010 in the UK to release into the wild a Japanese psyllid insect, Aphalara itadori.[9] Its diet is highly specific to Japanese knotweed and shows good potential for its control.[10][11]
In Scotland, the Wildlife and Natural Environment (Scotland) Act 2011 came into force in July 2012 that superseded the Wildlife and Countryside Act 1981. This act states that is an offence to spread intentionally or unintentionally Japanese knotweed (or other non-native invasive species).
A variegated variety of Japanese Knotweed, used as a landscape plant
Japanese knotweed flowers are valued by some beekeepers as an important source of nectar for honeybees, at a time of year when little else is flowering. Japanese knotweed yields a monofloral honey, usually called bamboo honey by northeastern U.S.beekeepers, like a mild-flavored version of buckwheat honey (a related plant also in the Polygonaceae).
The young stems are edible as a spring vegetable, with a flavor similar to extremely sour rhubarb. In some locations, semi-cultivating Japanese knotweed for food has been used as a means of controlling knotweed populations that invade sensitive wetland areas and drive out the native vegetation.[14]It is eaten in Japan as sansai or wild foraged vegetable.
Both Japanese knotweed and giant knotweed are important concentrated sources of resveratrol and its glucoside piceid,[16] replacing grape byproducts. Many large supplement sources of resveratrol now use Japanese knotweed and use its scientific name in the supplement labels. The plant is useful because of its year-round growth and robustness in different climates.[17]
This antique locomotive at Beekbergen,Netherlands is overgrown by knotweed. A few years before, it was free of knotweed
Control
Japanese knotweed has a large underground network of roots (rhizomes). To eradicate the plant the roots need to be killed. All above-ground portions of the plant need to be controlled repeatedly for several years in order to weaken and kill the entire patch. Picking the right herbicide is essential, as it must travel through the plant and into the root system below. Glyphosate is the best active ingredient in herbicide for use on Japanese knotweed as it is ’systemic’; it penetrates through the whole plant and travels to the roots.
Digging up the rhizomes is a common solution where the land is to be developed, as this is quicker than the use of herbicides, but safe disposal of the plant material without spreading it is difficult; knotweed is classed as controlled waste in the UK, and disposal is regulated by law.Digging up the roots is also very labor-intensive and not always efficient. The roots can go to up to 10 feet (3 meters) deep, and leaving only a few inches of root behind will result in the plant quickly growing back.
Covering the affected patch of ground with a non-translucent material can be an effective follow-up strategy. However, the trimmed stems of the plant can be razor sharp and are able to pierce through most materials. Covering with non-flexible materials such as concrete slabs has to be done meticulously and without leaving even the smallest splits. The slightest opening can be enough for the plant to grow back.
More ecologically-friendly means are being tested as an alternative to chemical treatments. Soil steam sterilization[18] involves injecting steam into contaminated soil in order to kill subterranean plant parts. Research has also been carried out on Mycosphaerella leafspot fungus, which devastates knotweed in its native Japan. This research has been relatively slow due to the complex life cycle of the fungus.[19]
Research has been carried out by not-for-profit inter-governmental organisation CABI in the UK. Following earlier studies imported Japanese knotweed psyllid insects (Aphalara itadori), whose only food source is Japanese knotweed, were released at a number of sites in Britain in a study running from 1 April 2010 to 31 March 2014. In 2012, results suggested that establishment and population growth were likely, after the insects overwintered successfully.[20][21]
Detail of the stalk
Controversy
In the United Kingdom, Japanese Knotweed has received a lot of attention in the press as a result of very restrictive lending policies by banks and other mortgage companies. Several lenders have refused mortgage applications on the basis of the plant being discovered in the garden or neighbouring garden.[22] The Royal Institution of Chartered Surveyors published a report in 2012 in response to lenders refusing to lend “despite [knotweed] being treatable and rarely causing severe damage to the property.” [23]
There is a real lack of information and understanding of what Japanese Knotweed is and the actual damage it can cause. Without actual advice and guidance, surveyors have been unsure of how to assess the risk of Japanese Knotweed, which can result in inconsistent reporting of the plant in mortgage valuations. RICS hopes that this advice will provide the industry with the tools it needs to measure the risk effectively, and provide banks with the information they require to identify who and how much to lend to at a time when it is essential to keep the housing market moving.
—Philip Santo, RICS Residential Professional Group[23]
In response to this guidance, several lenders have relaxed their criteria in relation to discovery of the plant. As recently as 2012, the policy at the Woolwich (part of Barclays plc) was “if Japanese Knotweed is found on or near the property then a case will be declined due to the invasive nature of the plant.”[24][25] Their criteria have since been relaxed to a category-based system depending on whether the plant is discovered on a neighbouring property (categories 1 and 2) or the property itself (categories 3 and 4) incorporating proximity to the property curtilage and the main buildings. Even in a worst-case scenario (category 4), where the plant is “within 7 metres of the main building, habitable spaces, conservatory and/or garage and any permanent outbuilding, either within the curtilage of the property or on neighbouring land; and/or is causing serious damage to permanent outbuildings, associated structures, drains, paths, boundary walls and fences” Woolwich lending criteria now specify that this property may be acceptable if “remedial treatment by a Property Care Association (PCA) registered firm has been satisfactorily completed. Treatment must be covered by a minimum 10-year insurance-backed guarantee, which is property specific and transferable to subsequent owners and any mortgagee in possession.” [26] Santander have relaxed their attitude in a similar fashion (citation needed).
Property Care Association chief executive Steve Hodgson, whose trade body has set up a task force to deal with the issue, said: “japanese knotweed is not “house cancer” and could be dealt with in the same way qualified contractors dealt with faulty wiring or damp.”[27]
Japan
The plant is known as itadori (イタドリ, 虎杖?). The kanji expression is from the Chinese meaning “tiger staff”, but as to the Japanese appellation, one straightforward interpretation is that it comes from “remove pain” (alluding to its painkilling use),[28][29] though there are other etymological explanations offered.
It grows widely throughout Japan and is foraged as a wild edible vegetable (sansai), though not in sufficient quantities to be included in statistics.[30] They are called by such regional names as: tonkiba (Yamagata),[30]itazuiko (Nagano, Mie),[30]itazura (Gifu, Toyama, Nara, Wakayama, Kagawa),[30]gonpachi (Shizuoka, Nara, Mie, Wakayama),[30]sashi (Akita, Yamagata),[30]jajappo (Shimane, Tottori, Okayama),[30]sukanpo (many areas).
Young leaves and shoots, which look like asparagus, are used. They are extremely sour; the fibrous outer skin must be peeled, soaked in water for half a day raw or after parboiling, before being cooked.
Places in Shikoku such as central parts of Kagawa Prefecture[31] pickle the peeled young shoots by weighting them down in salt mixed with 10% nigari (magnesium chloride).Kochi also rub these cleaned shoots with coarse salt-nigari blend. It is said (though no authority is cited) that the magnesium of the nigari binds with the oxalic acid thus mitigating its hazard.[32]
Jump up^Morelle, Rebecca (2010-03-09). “BBC News”. BBC News. Retrieved 2014-06-30.
Jump up^Richard H. Shaw, Sarah Bryner and Rob Tanner. “The life history and host range of the Japanese knotweed psyllid, Aphalara itadori Shinji: Potentially the first classical biological weed control agent for the European Union”. UK Biological Control. Volume 49, Issue 2, May 2009, Pages 105-113.
Jump up^Wang, H.; Liu, L.; Guo, Y. -X.; Dong, Y. -S.; Zhang, D. -J.; Xiu, Z. -L. (2007). “Biotransformation of piceid in Polygonum cuspidatum to resveratrol by Aspergillus oryzae”. Applied Microbiology and Biotechnology75 (4): 763–768. doi:10.1007/s00253-007-0874-3. PMID17333175.edit
The drug maker is seeing great signs in the development of treatment for multiple myeloma, a bone marrow cancer. The results from its Phase 3 of Kyprolis’ clinical trial shows that patients can live almost nine months longer without worsening symptoms. According to Amgen, about 70,000 people in the U.S. are living with the disease and 24,000 new cases are diagnosed every year. With the good clinical trial result, Amgen plans to begin regulatory submissions around the world next year. Dr. Pablo Cagnoni, president of Amgen’s subsidiary Onyx Pharmaceuticals said, “The results demonstrate that Kyprolis can significantly extend the time patients live without their disease progressing. The ability of novel therapies to produce deep and durable responses may, one day, transform this uniformly fatal disease to one that is chronic and manageable.” Male patients over the age of 65 have the highest risk of developing it.
The U.S. Food and Drug Administration (FDA) approved it on 20 July 2012 for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.[2]
The abbreviation CFZ is common for referring to carfilzomib, but abbreviating drug names is not best practice in medicine.
Discovery, early development and regulatory approval
Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.[3] The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101,[4] which was licensed to Proteolix, Inc. Craig Crews, Raymond Deshaies from Caltech, Phil Whitcome, the former CEO of Neurogen and Larry Lasky, a venture capitalist, founded Proteolix, and along with other researchers and scientists, advanced YU101. The scientists at Proteolix invented a new, distinct compound that had potential use as a drug in humans, known as carfilzomib. Proteolix advanced carfilzomib to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval.[5]Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009.[5]
In January 2011, the FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.[6] In December 2011, the FDA granted Onyx standard review designation,[7][8] for its new drug application submission based on the 003-A1 study, an open-label, single-arm Phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide.[9] It costs approximately $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma.[10]
Mechanism
Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.[1]
Clinical trials
Completed
A single-arm, Phase II trial (003-A1) of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib demonstrated a clinical benefit rate of 36 percent in the 266 patients evaluated and had an overall response rate of 22.9 percent and median duration of response of 7.8 months. The FDA approval of carfilzomib was based on results of the 003-A1 trial.[11]
In a Phase II trial (004), carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. This study also included a bortezomib-treated cohort. Results were reported separately.[12] This study also found prolonged carfilzomib treatment was tolerable, with approximately 22 percent of patients continuing treatment beyond one year. The 004 trial was a smaller study originally designed to investigate the impact of carfilzomib treatment in relationship to bortezomib treatment in less heavily pretreated (1-3 prior regimens) patients.[13]
A Phase II trial (005), which assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, in patients with multiple myeloma and varyi ng degrees of renal impairment, where nearly 50 percent of patients were refractory to both bortezomib and lenalidomide, demonstrated that pharmacokinetics and safety were not influenced by the degree of baseline renal impairment. Carfilzomib was tolerable and demonstrated efficacy.[14]
In another Phase II trial (006) of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 69 percent.[15]
A Phase II trial (007) for multiple myeloma and solid tumors showed promising results.[16][17]
In Phase II trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia.[18]
In a frontline Phase I/II study, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone was highly active and well tolerated, permitting the use of full doses for an extended time in newly-diagnosed multiple myeloma patients, with limited need for dose modification. Responses were rapid and improved over time, reaching 100 percent very good partial response.[19]
Ongoing
A phase III confirmatory clinical trial, known as the ASPIRE trial, comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.[20] It is no longer recruiting and should report in 2014.
The initial enthusiasm following the discovery of a pharmacologically active natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin’s pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of carfilzomib (Kyprolis™), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.
Myung, J; Kim, K.B.; Lindsten, K.; Dantuma, N.P.; Crews, C.M. (2001). “Lack of proteasome active site allostery as revealed by subunit-specific inhibitors”. Mol Cell7 (2): 411–20. doi:10.1016/S1097-2765(01)00188-5. PMID11239469.
Vij, R (2012). “An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib”. Br J Haematol158 (6): 739–748. doi:10.1111/j.1365-2141.2012.09232.x. PMID22845873.
Vij, R (2012). “An open-label, single-arm, phase ii (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma.”. Blood119 (24): 5661–70. doi:10.1182/blood-2012-03-414359.PMID22555973.
Badros, AZ (2013). “Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety.”. Leukemia27 (8): 1707–14. doi:10.1038/leu.2013.29.PMID23364621.
“Phase II results of Study PX-171-007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors” – ASCO 2009; Abstract 3515.
CAS : 118248-94-5 (free acid); 155319-91-8 (hexahydrogen)
CAS Name: (OC-6-13)-[[N,N¢–1,2-Ethanediylbis[N-[[3-(hydroxy-kO)-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinyl]methyl]glycinato-kN,kO]](8-)]manganate(6-)
Mangafodipir (sold under the brand name Teslascan as mangafodipir trisodium) is a contrast agent delivered intravenously to enhance contrast in magnetic resonance imaging (MRI) of the liver. It has two parts, paramagnetic manganese (II) ions and thechelating agent fodipir (dipyridoxyl diphosphate, DPDP). Normal liver tissue absorbs the manganese more than abnormal or cancerous tissue. The manganese shortens the longitudinal relaxation time (T1), making the normal tissue appear brighter in MRIs. This enhanced contrast allows lesions to be more easily identified.
The condensation of pyridoxal 5-phosphate (I) with ethylenediamine (II) in methanol by means of NaOH gives the corresponding diimine (III), which is reduced with hydrogen over Pt/C in methanol/water yielding the expected diamine (IV). The reaction of (IV) with bromoacetic acid (V) by means of NaOH in methanol/water affords the N,N’-diacetic acid derivative (VI), which is finally treated with MnCl2 in water containing NaOH.
Paramagnetic manganese (II) chelate designed as a tissue specific imaging agent taken up by normal liver parenchyma. Prepn: S. M. Rocklage, S. C. Quay, EP290047; eidem,US4933456 (1988, 1990 both to Salutar); idemet al.,Inorg. Chem.28, 477 (1989).
Pharmacology, toxicity and image enhancement studies: G. Elizondo et al.,Radiology178, 73 (1991).
HPLC determn in plasma: K. G. Toft et al.,J. Pharm. Biomed. Anal.15, 973 (1997).
Series of articles on clinical studies, toxicology and physicochemical properties: Acta Radiol.38, 626-789 (1997).
Review of use as contrast agent for liver lesion detection: N. M. Rofsky, J. P. Earls, MRI Clin. North Am.4, 73-85 (1996).
Properties: LD50 i.v. in mice: 5.4 mmol/kg (Elizondo).
Toxicity data: LD50 i.v. in mice: 5.4 mmol/kg (Elizondo)
European regulators have agreed to undertake an accelerated assessment of Eisai’s lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer.
The drug, which carries Orphan Status in the EU, is to be filed “imminently” and could become the first in a new class of tyrosine kinase inhibitors, the drugmaker said.
Lenvatinib was granted Orphan Drug Designation for thyroid cancer by the health authorities in Japan in 2012, and in Europe and the U.S in 2013. The first application for marketing authorization of lenvatinib in the world was submitted in Japan on June 2014. Eisai is planning to submit applications for marketing authorization in Europe and the U.S. in the second quarter of fiscal 2014.
Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRalpha, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib a first-in-class treatment, especially given that it simultaneously inhibits the kinase activities of FGFR as well as VEGFR.
Lenvatinib (E7080) is a multi-kinase inhibitor that is being investigated for the treatment of various types of cancer by Eisai Co. It inhibits both VEGFR2 and VEGFR3 kinases.[1]
The substence was granted orphan drug status for the treatment of various types of thyroid cancer that do not respond toradioiodine; in the US and Japan in 2012 and in Europe in 2013[2] and is now approved for this use.
Clinical trials
Lenvatinib has had promising results from a phase I clinical trial in 2006[3] and is being tested in several phase II trials as of October 2011, for example against hepatocellular carcinoma.[4] After a phase II trial testing the treatment of thyroid cancer has been completed with modestly encouraging results,[5] the manufacturer launched a phase III trial in March 2011.[6]
Lenvatinib Mesilate
Molecular formula: C21H19ClN4O4,CH4O3S =523.0.
CAS: 857890-39-2.
UNII code: 3J78384F61.
About the Lenvatinib (E7080) Phase II Study
The open-label, global, single-arm Phase II study of multi-targeted kinase inhibitor lenvatinib (E7080) in advanced radioiodine (RAI)-refractory differentiated thyroid cancer involved 58 patients with advanced RAI refractory DTC (papillary, follicular or Hurthle Cell) whose disease had progressed during the prior 12 months. (Disease progression was measured using Response Evaluation Criteria in Solid Tumors (RECIST).) The starting dose of lenvatinib was 24 mg once daily in repeated 28 day cycles until disease progression or development of unmanageable toxicities.
2. About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat or near the trachea. It affects more women than men and usually occurs between the ages of 25 and 65.
The most common types of thyroid cancer, papillary and follicular (including Hurthle Cell), are classified as differentiated thyroid cancer and account for 95 percent of all cases. While most of these are curable with surgery and radioactive iodine treatment, a small percentage of patients do not respond to therapy.
3. About Lenvatinib (E7080)
Lenvatinib is multi-targeted kinase inhibitor with a unique receptor tyrosine kinase inhibitory profile that was discovered and developed by the Discovery Research team of Eisai’s Oncology Unit using medicinal chemistry technology. As an anti-angiogenic agent, it inhibits tyrosine kinase of the VEGF (Vascular Endothelial Growth Factor) receptor, VEGFR2, and a number of other types of kinase involved in angiogenesis and tumor proliferation in balanced manner. It is a small molecular targeting drug that is currently being studied in a wide array of cancer types.
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).
However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
[Patent Document 1] WO 02/32872
[Patent Document 2] WO 2004/080462
[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004
Examples will now be described to facilitate understanding of the invention, but the invention is not limited to these examples.
Example 1Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate
After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.
Example 21-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea
After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice and the mixture was stirred overnight at room temperature. Water (400 mL), ethyl acetate (300 mL) and 6N HCl (55 mL) were then added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the title compound (77% yield from 4-amino-3-chlorophenol).
Example 34-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).
Example 44-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).
The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as white crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70 mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example 11.
The starting material was synthesized in the following manner.
Production Example 368-1Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate
The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as light brown crystals from 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.745 mmol), by the same procedure as in Production Example 17.
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).
Preparation Example 2Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)
(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate
To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.
To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).
To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).
Preparation Example 3Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)
7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).
1H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.
Example 5
A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)
(Preparation Method 1)
In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).
(Preparation Method 2)
In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).
Example 6A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)
A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg)…………MORE IN PATENT
According to the present invention 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide amorphous is excellent in solubility in water.
Example 1 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide manufacture of amorphous amide
4- (3-chloro-4- (cyclopropylamino-carbonyl) amino phenoxy) -7-methoxy-6-quinolinecarboxamide B-type crystals (Patent Document 2) were weighed to 300mg, is placed in a beaker of 200mL volume, it was added tert- butyl alcohol (tBA) 40mL. This was heated to boiling on a hot plate, an appropriate amount of tBA to Compound A is dissolved, water was added 10mL. Then, the weakened heated to the extent that the solution does not boil, to obtain a sample solution. It should be noted, finally the solvent amount I was 60mL. 200mL capacity eggplant type flask (egg-plant shaped flask), and rotated in a state of being immersed in ethanol which had been cooled with dry ice. It was added dropwise a sample solution into the interior of the flask and frozen. After freezing the sample solution total volume, to cover the opening of the flask in wiping cloth, and freeze-dried. We got an amorphous A of 290mg.
Gild, M. L.; Bullock, M.; Robinson, B. G.; Clifton-Bligh, R. (2011). “Multikinase inhibitors: A new option for the treatment of thyroid cancer”. Nature Reviews Endocrinology7 (10): 617–624.doi:10.1038/nrendo.2011.141. PMID21862995.edit
Tomohiro Matsushima, four Nakamura, Kazuhiro Murakami, Atsushi Hoteido, Yusuke Ayat, Naoko Suzuki, Itaru Arimoto, Pinche Hirose, Masaharu Gotoda.Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor. US patent number US7612208 Also published as: CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1 , US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date: Aug 7, 2007 Original Assignee: Eisai Co., Ltd
Funahashi, Yasuhiro et al.Preparation of urea derivatives containing nitrogenous aromatic ring compounds as inhibitors of angiogenesis. US patent number US7253286, Also published as:CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1, US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date:Aug 7, 2007. Original Assignee:Eisai Co., Ltd
Sakaguchi, Takahisa; Tsuruoka, Akihiko. Preparation of amorphous salts of 4-[3-chloro-4-[(cyclopropylaminocarbonyl)amino]phenoxy]-7-methoxy-6-quinolinecarboxamide as antitumor agents. PCT Int. Appl. (2006), WO2006137474 A1 20061228.
Naito, Toshihiko and Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. PCT Int. Appl., WO2005044788, 19 May 2005
Itaru Arimoto et al. Crystal of salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy]-7-methoxy-6-quinolinecarboxamide or solvate thereof and processes for producing these. PCT Int. Appl. (2005), WO2005063713 A1 20050714.
Formed from paroxetine hydrochloride and ammonium glycyrrhyzinate by precipitation, spray, vacuum or freeze drying, or evaporation to glass; solid or oil; masks the bitter taste of paroxetine and has a distinctive licorice flavor; antidepressants; Parkinson’s disease
Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor
Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
Cenacitinib CAS 2641636-52-2 MF C19H19F2N7O3 MW431.4 Urea, N-[(1R,2S)-2-fluorocyclopropyl]-N′-[5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]- N-{5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl}-N′-[(1R,2S)-2-fluorocyclopropyl]urea Janus kinase inhibitor, anti-inflammatory, VTX958, VTX 958, SB88R8KGL3 VTX958 for the Treatment of Moderately to Severely…
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