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Momelotinib

August 7, 2014 5:19 am / Leave a comment

Figure US08486941-20130716-C00098

Momelotinib

414.47, C₂₃H₂₂N₆O_2,

1056634-68-4

FDA 2023, Ojjaara,

To treat intermediate or high-risk myelofibrosis in adults with anemia Drug Trials Snapshot

N-(Cyanomethyl)-4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]benzamide

N-(Cyanomethyl)-4-[2-[4-(4-morpholinyl)phenylamino]pyrimidin-4-yl]benzamide

Jak2 tyrosine kinase inhibitor; Jak1 tyrosine kinase inhibitor

Inflammatory disease; Myelofibrosis; Myeloproliferative disorder; Pancreatic ductal adenocarcinoma; Polycythemia vera

CYT 387; CYT-387; momelotinib)

GS-0387

CYT387 sulfate salt CAS No: 1056636-06-6

CYT387 Mesylate CAS No: 1056636-07-7

DI HCL SALT 1380317-28-1

Momelotinib, sold under the brand name Ojjaara among others, is an anticancer medication used for the treatment of myelofibrosis.^[5] It is a Janus kinase inhibitor and it is taken by mouth.^[5]

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.

PAT

http://www.google.com.ar/patents/US8486941?cl=ja

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide

Figure US08486941-20130716-C00098

414.18

¹H NMR (300 MHz, d₆-DMSO): δ 9.47 (1 H, s), 9.32 (1 H, t, J = 5.5 Hz), 8.54 (1 H, d, J = 5.0 Hz), 8.27 (2 H, d, J = 8.7 Hz), 8.02 (2 H, d, J = 8.2 Hz), 7.67 (2 H, d, J = 9.1 Hz), 7.41 (1 H, d, J = 5.5 Hz), 6.93 (2 H, d, J = 9.1 Hz), 4.36 (2 H, d, J = 5.5 Hz), 3.75 (4 H, m), 3.05 (4 H, m).

m/z 415.3 [M + H]⁺

N-(cyanomethyl)-4-(2-(4- morpholinophenylamino)pyrimidin- 4-yl)benzamide

Example 1Synthesis of Compound 3

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. C₂₃H₂₆N₆O₁₀S₂requires C, 66.65; H, 5.35; N, 20.28%.

¹³C NMR (75.5 MHz, d₆-DMSO) δ 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68.

Figure US08486941-20130716-C00098

1H NMR GIVEN ABOVE

Example 6Salt Formation from Compound 3

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. C₂₃H₂₆N₆O₁₀S₂requires 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)

LC-ESI-MS (method D): rt 10.3 min.; m/z 415.3 [M+H]⁺.

PAT

WO 2014114274

References on CYT387

. [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.

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References

“Omjjara (GlaxoSmithKline Australia Pty Ltd)”. Therapeutic Goods Administration (TGA). 14 January 2025. Retrieved 20 January 2025.
https://www.tga.gov.au/resources/artg/442230 ^{[bare URL]}
“Notice: Multiple additions to the Prescription Drug List (PDL) [2024-12-20]”. Health Canada. 20 December 2024. Retrieved 21 December 2024.
“Ojjaara product information”. Health Canada. 8 November 2024. Retrieved 27 December 2024.
“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.
“Omjjara Product information”. Union Register of medicinal products. 26 January 2024. Retrieved 18 March 2024.
“FDA Roundup: September 19, 2023”. U.S. Food and Drug Administration (FDA) (Press release). 19 September 2023. Archived from the original on 21 September 2023. Retrieved 20 September 2023. This article incorporates text from this source, which is in the public domain.
“Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 15 September 2023. Archived from the original on 21 January 2023. Retrieved 20 September 2023. This article incorporates text from this source, which is in the public domain.
“GSK’s Omjjara Authorized in EU for Treating Myelofibrosis With Anemia”. MarketWatch. Retrieved 30 January 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. PMID 19295546. S2CID 26947444.
“Omjjara: Pending EC decision”. European Medicines Agency (EMA). 10 November 2023. Archived from the original on 29 November 2023. Retrieved 5 December 2023.

External links

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
Names

Preferred IUPAC name N-(Cyanomethyl)-4-{2-[4-(morpholin-4-yl)anilino]pyrimidin-4-yl}benzamide
Other names CYT-387 CYT-11387 GS-0387 Ojjaara Omjjara
Identifiers
CAS Number	1056634-68-4 as dihydrochloride: 1380317-28-1 1841094-17-4
3D model (JSmol)	Interactive image as dihydrochloride: Interactive image
ChEBI	CHEBI:91407
ChEMBL	ChEMBL1078178
ChemSpider	24676202
DrugBank	DB11763 as dihydrochloride: DBSALT003445
IUPHAR/BPS	7791
KEGG	D10315 as dihydrochloride: D10358 D10889
PubChem CID	25062766
UNII	6O01GMS00P as dihydrochloride: RBH995N496 LDX8893L5D
CompTox Dashboard (EPA)	DTXSID801026049
InChI
SMILES
Properties
Chemical formula	C₂₃H₂₂N₆O₂
Molar mass	414.469 g·mol⁻¹
Pharmacology
ATC code	L01EJ04 (WHO)
Routes of administration	By mouth
Legal status	AU: S4 (Prescription only)^[1]^[2] CA: ℞-only^[3]^[4] US: ℞-only^[5] EU: Rx-only^[6]^[7]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Momelotinib
Clinical data
Other names	Momelotinib hydrochloride hydrate (JAN JP), Momelotinib dihydrochloride (USAN US)
License data	US DailyMed: Momelotinib
Identifiers
PDB ligand	C87 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)

//////////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.

Poziotinib for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

August 7, 2014 4:16 am / Leave a comment

Chemical structure for Poziotinib

Poziotinib

l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazol in-6- yloxy)piperidin-l-yl)prop-2-en-l-one

: 1 – [4 – [[4 – [(3, 4 – dichloro – 2 – phenyl) amino] – 7 – methoxy – 6 – base] quinazoline oxygen radicals] – 1 – piperidine base] – 2 – acrylic – 1 – ketone

UNII-OEI6OOU6IK;

cas 1092364-38-9

HM781-36B

NOV120101

Erbb2 tyrosine kinase receptor inhibitor; EGFR family tyrosine kinase receptor inhibitor

Non-small-cell lung cancer; Stomach tumor

for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

http://www.centerwatch.com/clinical-trials/listings/external-studydetails.aspx?StudyID=NCT01819428

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

KR 1013319

………………………………………………………….

WO2013051883

http://www.google.com/patents/WO2013051883A2?cl=en

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-

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.

Figure imgf000008_0003

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%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

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%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s, 1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

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%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 8.69 (s, 1H), 8.47 (t, 1H), 7.34- 7.29 (m, 2H), 7.20 (s, 1H), 4.63-4.60 (m, 1H), 3.82 (s, 3H), 3.83-3.76 (m, 2H), 3.37-3.29 (m, 2H), 1.99-1.96 (m, 2H), 1.90-1.84 (m, 2H), 1.48 (s, 9H).

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%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.95 (bs, 1H), 9.42 (bs, 1H), 9.18 (bs, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 7.69-7.56 (m, 2H), 7.45 (s, 1H), 5.11- 5.08 (m, 1H), 4.03 (s, 3H), 3.29-3.20 (m, 4H), 2.33-2.30 (m, 2H), 1.96-1.93 (m, 2H).

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%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.31 (bs, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 7.64-7.55 (m, 2H), 7.39 (s, 1H), 6.87-6.78 (m, 1H), 6.12-6.06 (m, 1H), 5.68-5.64 (m, IH), 5.07-5.01 (m, IH), 4.06-3.88 (m, 5H), 3.51 (t, IH), 3.32 (t, IH), 2.10 (t, IH), 1.60 (t, IH).

…………………………………………………………..

WO-2014116070

http://www.sumobrain.com/patents/wipo/Method-preparing-1-4-34/WO2014116070.html

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%).

1H-NMR (DMSO-d ₆, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

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,

1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

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,

1H), 6.10-6.03 (m, 1H), 5.67-5.62 (m, 1H), 4.76-4.71 (m, 1H), 3.70-3.68 (m, 2H), 3.43-3.31 (m, 2H), 2.42 (s, 3H), 1.73 (m, 2H), 1.52 (m, 2H).

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 ₂CO 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)

SEE

http://www.yuaigongwu.com/thread-8891-1-1.html

WO2005030765A1 *	Sep 22, 2004	Apr 7, 2005	Astrazeneca Ab	Quinazoline derivatives as antiproliferative agents
WO2008150118A2 *	Jun 5, 2008	Dec 11, 2008	Hanmi Pharm Ind Co Ltd	Novel amide derivative for inhibiting the growth of cancer cells
WO2010122340A2 *	Apr 22, 2010	Oct 28, 2010	Astrazeneca Ab	Process 738
US20070135463 *	Dec 6, 2006	Jun 14, 2007	Frank Himmelsbach	Bicyclic heterocycles, drugs containing said compounds, the use thereof and method for preparing same

Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

August 6, 2014 8:29 am / 1 Comment on Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds

CLINICALNEWS.ORG

15 JUN 2012

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…

View original post 249 more words

Amgen’s Multiple Myeloma Drug Shows Promise in Phase 3 Trial

August 5, 2014 7:28 am / 2 Comments on Amgen’s Multiple Myeloma Drug Shows Promise in Phase 3 Trial

Carfilzomib

Amgen’s Multiple Myeloma Drug Shows Promise in Phase 3 Trial

https://finance.yahoo.com/video/amgens-multiple-myeloma-drug-shows-195603222.html

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.

Carfilzomib (marketed under the trade name Kyprolis, Onyx Pharmaceuticals, Inc.) is an anti-cancer drug acting as a selectiveproteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin.^[1]

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.

Systematic (IUPAC) name
(S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
Clinical data
Trade names	Kyprolis
Licence data	US FDA:link
Pregnancy cat.	D (US)
Legal status	℞-only (US)
Routes	Intravenous
Identifiers
CAS number	868540-17-4
ATC code	L01XX45
PubChem	CID 11556711
ChemSpider	9731489
KEGG	D08880
ChEMBL	CHEMBL451887
Synonyms	PX-171-007
Chemical data
Formula	C₄₀H₅₇N₅O₇
Mol. mass	719.91 g mol

http://www.info-farmacia.com/medico-farmaceuticos/informes-tecnicos/carfilzomib-new-drug-for-multiple-myeloma

http://pubs.rsc.org/en/content/articlelanding/2013/np/c3np20126k/unauth#!divAbstract

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.

Graphical abstract: From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes

References

Carfilzomib, NCI Drug Dictionary
“FDA Approves Kyprolis for Some Patients with Multiple Myeloma”. FDA. 2012-07-20. Retrieved 2013-07-23.
Meng, L; Mohan, R.; Kwok, B.H.; Elofsson, M.; Sin, N.; Crews, C.M. (1999).“Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity”. Proc Natl Acad Sci USA 96 (18): 10403–8.doi:10.1073/pnas.96.18.10403. PMC 17900. PMID 10468620.
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 Cell 7 (2): 411–20. doi:10.1016/S1097-2765(01)00188-5. PMID 11239469.
^ Jump up to:^a ^b “Carfilzomib: From Discovery To Drug”. Chemical & Engineering News. 2012-08-27. Retrieved 2013-07-30.
“Onyx multiple myeloma drug wins FDA fast-track status”. San Francisco Business Times. 2011-01-31. Retrieved 2011-09-01.
“Beacon Breaking News – Carfilzomib to Get Standard, Not Priority, FDA Review”. The Myeloma Beacon. Retrieved 2012-02-27.
“Fast Track, Accelerated Approval and Priority Review; Accelerating Availability of New Drugs for Patients with Serious Diseases”. FDA. Retrieved 2012-02-27.
“PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis”. ASCO 2011; Abstract 8027. 2011. Retrieved 2011-09-01.
“FDA Approves Kyprolis (Carfilzomib) For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2012-07-20.
“Carfilzomib Prescribing Information”. NCI Drug Dictionary. Retrieved 2013-07-23.
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 Haematol 158 (6): 739–748. doi:10.1111/j.1365-2141.2012.09232.x. PMID 22845873.
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.”. Blood 119 (24): 5661–70. doi:10.1182/blood-2012-03-414359.PMID 22555973.
Badros, AZ (2013). “Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety.”. Leukemia 27 (8): 1707–14. doi:10.1038/leu.2013.29.PMID 23364621.
“European Hematology Association (EHA) 18th Congress. June 13-16, 2013.”. The Myeloma Beacon. 2013. Retrieved 2013-07-13.
“Nikoletta Lendval, MD PhD et al. Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma.”. Presented at: 54th ASH Annual Meeting and Exposition: December 2012. Retrieved 2013-07-23.
“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.
“Siegel DS, Martin T, Wang, M, et al. Results of PX-171- 003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.”. OncLive.com. 2011-03-09. Retrieved 2011-09-01.
“Final Results of a Frontline Phase 1/2 Study of Carfilzomib Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)”. ASH 20111; Abstract 631. Retrieved 2012-02-27.
“Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Versus Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma”. ClinicalTrials.gov. 2011-08-04. Retrieved 2011-09-01.

External links

“Carfilzomib Prescribing Information”. NCI Drug Dictionary.

Mangafodipir

August 4, 2014 11:50 am / 1 Comment on Mangafodipir

Mangafodipir

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-)

Add Names: manganese(II)-N,N¢-dipyridoxylethylenediamine-N,N¢-diacetate-5,5-bis(phosphonate); manganese dipyridoxal diphosphate; MnDPDP

Manufacturers’ Codes: S-095

C22H24MnN4O14P2

685.33

Percent Composition: C 38.56%, H 3.53%, Mn 8.02%, N 8.18%, O 32.68%, P 9.04%

Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	Not to be used

Routes	Intravenous infusion
Pharmacokinetic data
Bioavailability	NA
Protein binding	27% (manganese) Negligible (DPDP)
Half-life	20 minutes (manganese) 50 minutes (DPDP)
Excretion	Renal and fecal (manganese) Renal (DPDP)
Identifiers

ATC code	V08CA05
PubChem	CID 3086672
ChemSpider	2343239
UNII	N02W67RKJS

Chemical data
Formula	C₂₂H₂₈Mn N₄O₁₄P₂
Mol. mass	689.362 g/mol

Diagnostic Aid (MRI Contrast Agent)

Manganese dipyridoxal diphosphate trisodium salt, Mangafodipir trisodium, Win-59010-2, S-095, MnDPDP, Teslascan

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.

References

Literature References:

Paramagnetic manganese (II) chelate designed as a tissue specific imaging agent taken up by normal liver parenchyma. Prepn: S. M. Rocklage, S. C. Quay, EP 290047; eidem, US 4933456 (1988, 1990 both to Salutar); idem et al.,Inorg. Chem. 28, 477 (1989).

Pharmacology, toxicity and image enhancement studies: G. Elizondo et al., Radiology 178, 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)

……………………………………

Mangafodipir Trisodium

C22H27MnN4Na3O14P2 757.33
Trisodium trihydrogen (OC-6-13)-[[N,N¢-1,2-ethanediylbis[N-[[3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinyl]methyl]glycinato]](8-)] manganate(6-).
Trisodium trihydrogen (OC-6-13)-[[N,N¢-ethylenebis[N-[[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridyl]methyl]glycine] 5,5¢-bis(phosphato)](8-)]manganate(6-) [140678-14-4].

Derivative Type: Trisodium salt

CAS Registry Number: 140678-14-4

Additional Names: Magnafodipir trisodium

Manufacturers’ Codes: Win-59010

Trademarks: Teslascan (Nycomed)

Molecular Formula: C22H27MnN4Na3O14P2

Molecular Weight: 757.32

Percent Composition: C 34.89%, H 3.59%, Mn 7.25%, N 7.40%, Na 9.11%, O 29.58%, P 8.18%

Properties: Pale yellow, triclinic hygroscopic crystals. d 1.537. uv max (water): 220, 257, 319 nm (e 37600, 10300, 13400). Soly (g/ml): 0.4596 water, 0.0230 methanol, 0.0008 ethanol, 0.0006 acetone, 0.0011 chloroform. Log P (1-octanol:water) -5.62; (1-butanol: water) -3.68. Prepd as 0.01 mmol/ml aqueous infusion: bright yellow, clear soln, pH 7.5. Viscosity (mPa.s): 1.0 at 20°, 0.7 at 37°. Osmolality (37°): 290 mosmol/kg. d20 1.01 g/ml.

Log P: Log P (1-octanol:water) -5.62; (1-butanol: water) -3.68

Absorption maximum: uv max (water): 220, 257, 319 nm (e 37600, 10300, 13400)

Density: d 1.537; d20 1.01 g/ml

Therap-Cat: Diagnostic aid (MRI contrast agent).

Keywords: Diagnostic Aid (MRI Contrast Agent).http://www.drugfuture.com/Pharmacopoeia/USP32/pub/data/v32270/usp32nf27s0_m47135.html

NS 398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.

August 3, 2014 8:47 am / 1 Comment on NS 398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.

NS 398

N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide

Taisho (Originator)

Taisho Pharmaceutical Co. Ltd

N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.

123653-11-2, 123653-43-0 (Ca salt), 123653-44-1 (Na salt)

Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Cyclooxygenase-2 Inhibitors

NS-398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.^[2]

Selective cyclooxygenase-2 inhibitor (IC₅₀ values are 3.8 and > 100 μM for COX-2 and COX-1 respectively). Orally active. Anti-inflammatory, anti-pyretic, analgesic and non-ulcerogenic in vivo. Induces apoptosis and cell cycle arrest

Cyclooxygenase (COX-2) has been recently suggested to play a role in hepatocarcinogenesis. However, the exact pathway by which COX-2 affects the growth of hepatocellular carcinoma (HCC) is not clear. This study investigated the effects of a specific COX-2 inhibitor, NS-398, on the cell proliferation and apoptosis of COX-2-expressing and non-expressing HCC cell lines.

In addition, the modulatory effect of NS-398 on apoptosis-regulating gene expression was examined. Semi-quantitative/quantitative reverse transcription-polymerase chain reaction and Western blot showed that Hep3B and HKCI-4 cells expressed COX-2 mRNA and protein, but HepG2 cells did not. NS-398 suppressed cell proliferation and induced apoptosis in the two COX-2-expressing cell lines in a dose-dependent manner, but not in HepG2 cells.

Fas ligand mRNA and protein expression were increased by the treatment with NS-398 (10 micro M) in COX-2-expressing cell lines. The expressions of Fas and Bcl-2 family genes (Bax, Bcl-2, Bcl-xL, Bcl-xS) were not affected by NS-398 treatment in all three cell lines. In conclusion, specific COX-2 inhibitor suppresses cell proliferation and induces apoptosis in HCC cell lines that express COX-2. Our finding suggests that COX-2 inhibition may offer a new approach for HCC chemoprevention.

Identifiers
IUPAC name N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide
CAS number	123653-11-2
PubChem	4553

Jmol-3D images	Image 1
SMILES [show]
Properties
Molecular formula	C₁₃H₁₈N₂O₅S
Molar mass	314.36 g mol⁻¹
Appearance	Off-white solid
Solubility in water	Insoluble
Solubility in DMSO	5 mg/mL
Hazards
S-phrases	S22 S24/25

The condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.

EP 0317332

http://www.google.com/patents/EP0317332A2?cl=en

[0045]

(1) To 40 ml of a dioxane suspension containing 0.92 g of 60% sodium hydride was added 2.5 ml of cyclohexanol at room temperature over a 15-minute period, and the mixture was stirred at the same temperature for 1 hour and then at 50°C for 3.5 hours. The temperature of the reaction solution was returned to room temperature, 10 ml of a dioxane containing 3.2 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred at room temperature overnight. The dioxane was evaporated, the residue was extracted with chloroform, and the chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil, which was then distilled under reduced pressure to give 3.8 g of 2-cyclohexyloxynitrobenzene.
b.p. 130 – 134°C/0.5 – 0.7 mmHg
[0046]

(2) Fifty ml of a methanol solution containing 3.7 g of 2-cyclohexyloxynitrobenzene and 0.2 g of 5% palladium on carbon was stirred at room temperature under a hydrogen atmosphere for catalytic reduction. The catalyst was removed by filtration, and the filtrate was evaporated off to give 2.9 g of 2-cyclohexyloxyaniline as pale brown crystals.
m.p. 55 – 56°C
[0047]

(3) To 20 ml of a pyridine solution containing 2.7 g of 2-cyclohexyloxyaniline was added dropwise 1.8 g of methanesulfonyl chloride under ice cooling with stirring. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and made acidic with dilute hydrochloric acid. The crystals which formed were collected by filtration, washed with water and dried to give 3.8 g of the crude crystals, which were then recrystallized from ethanol-n hexane to give 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide.
m.p. 113 – 115°C
[0048]

(4) To 20 ml of an acetic acid solution containing 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide was added dropwise 1.5 g of 61% nitric acid on heating at 110°C over a 30-minute period, and then the mixture was stirred for 1 hour. The reaction solution was poured into ice water and neutralized with a dilute aqueous sodium hydroxide solution. The crystals which formed were collected by filtration, washed with water and dried to give 4.5 g of the crude crystals, which were then recrystallized from ethanol-n-hexane to give 3.3 g of N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
m.p. 136 – 137°C

EP0093591A1 *	Apr 29, 1983	Nov 9, 1983	Eli Lilly And Company	Selective sulfonation process
FR2244473A1 *				Title not available
US3725451 *	Apr 13, 1970	Apr 3, 1973	Riker Laboratories Inc	Substituted benzoylhaloalkanesulfonanilides
US3840597 *	Jul 3, 1972	Oct 8, 1974	Riker Laboratories Inc	Substituted 2-phenoxy alkane-sulfonanilides
US3856859 *	Jun 8, 1973	Dec 24, 1974	Riker Laboratories Inc	Selective nitration process

Citing Patent	Filing date	Publication date	Applicant	Title
EP1535614A2 *	Aug 22, 1997	Jun 1, 2005	University OofFlorida	Materials and methods for detection and treatment of immune system dysfunctions

……………………………………………………..

The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E₂ (PGE₂) synthesis. This study examines the expression and regulation of the prostaglandin synthesizing enzymes cyclooxygenase-1 (COX-1) and -2 in the CCD. By indirect immunofluorescence using isoform-specific antibodies, COX-1 and -2 immunoreactivity was localized to all cell types of the murine M-1 CCD cell line. By immunohistochemistry, both COX-1 and COX-2 were localized to intercalated cells of the CCD on paraffin-embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE₂ synthesis. These results demonstrate that COX-2 is the major contributor to the pool of PGE₂synthesized by the CCD. By Western blot analysis, COX-2 expression was significantly upregulated by incubation with either indomethacin or NS-398. These drugs did not affect COX-1 protein expression. Evaluation of COX-2 mRNA expression by Northern blot analysis after NS-398 treatment demonstrated that the COX-2 protein upregulation occurred independently of any change in COX-2 mRNA expression. These studies have for the first time localized COX-2 to the CCD and provided evidence that the intercalated cells of the CCD express both COX-1 and COX-2. The results also demonstrate that constitutively expressed COX-2 is the major COX isoform contributing to PGE₂synthesis by the M-1 CCD cell line. Inhibition of COX-2 activity in the M-1 cell line results in an upregulation of COX-2 protein expression.

http://jasn.asnjournals.org/content/10/11/2261.abstract
…………………………………………….

NS398 inhibits the growth of OSCC cells by mechanisms that are dependent and independent of suppression of PGE₂ synthesis. Molecular targeting of COX-2, PGE₂ synthase, or PGE₂ receptors may be useful as a chemopreventive or therapeutic strategy for oral cancer.

http://clincancerres.aacrjournals.org/content/9/5/1885.full

…………………………………

References

NS-398 at Sigma-Aldrich
Wei Shen, Yong Li, Ying Tang, James Cummins and Johnny Huard (2005). “NS-398, a Cyclooxygenase-2-Specific Inhibitor, Delays Skeletal Muscle Healing by Decreasing Regeneration and Promoting Fibrosis”. American Journal of Pathology 167 (4): 1105–1117.doi:10.1016/S0002-9440(10)61199-6. PMC 1603662. PMID 16192645.
MORE References

Futaki et al (1993) NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen.Pharmacol. 24 105. PMID: 8482483.

Futaki et al (1994) NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 47 55. PMID: 8140262.

Elder et al (2002) The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. Int.J.Cancer 99 323. PMID: 11992399.

Gemoprost

August 2, 2014 12:47 pm / Leave a comment

Gemeprost, SC-37681, Ono-802, Cergem, Preglandin, Cervagem,

(E) -7 – [(1R, 2R, 3R-3-Hydroxy-2 – [(E) – (3R) -3-hydroxy-4,4-dimethyl-1-octenyl] -5-oxocyclopentyl] -2 -heptenoic acid methyl ester;

16,16-Dimethyl-DELTA2-trans-PGE1 methyl ester;

9-Oxo-11alpha, 15alpha-dihydroxy-16,16-dimethyl-2-trans, 13-trans-prostadiene-1-oic acid

Gemeprost (16, 16-dimethyl-trans-delta2 PGE₁ methyl ester) is an analogue of prostaglandin E₁.

Gemoprost, Preglandin (TN), SC-37681, AC1NQZPG, SureCN43075, Gemeprost (JAN/USAN/INN),

Molecular Formula: C₂₃H₃₈O₅

Molecular Weight: 394.54482

Clinical use

It is used as a treatment for obstetric bleeding.

It is used with mifepristone to terminate pregnancy up to 24 weeks gestation. ^[1]

Side effects

Vaginal bleeding, cramps, nausea, vomiting, loose stools or diarrhea, headache, muscle weakness; dizziness; flushing; chills; backache; dyspnoea; chest pain; palpitations and mild pyrexia. Rare: Uterine rupture, severe hypotension, coronary spasms with subsequent myocardial infarctions

Gemeprost
Systematic (IUPAC) name

methyl (2E,11α,13E,15R)-11,15-dihydroxy-16,16-dimethyl-9-oxoprosta-2,13-dien-1-oate
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Routes	Pessary
Identifiers
CAS number	64318-79-2
ATC code	G02AD03
PubChem	CID 5282237
ChemSpider	4445416
UNII	45KZB1FOLS
KEGG	D02073
Synonyms	methyl (E)-7-[(1R,2S,3R)-3-hydroxy-2-[(E,3R)-3-hydroxy-4,4-dimethyl-oct-1-enyl]-5-oxo-cyclopentyl]hept-2-enoate
Chemical data
Formula	C₂₃H₃₈O₅
Mol. mass	394.545 g/mol

Chemical structure for gemeprost

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http://www.chemdrug.com/databases/8_0_oqxuqtwlqgeukaaa.html

The reaction of 3-bromopropionic acid (I) with triphenylphosphine (II) in refluxing acetonitrile gives (2-carboxyethyl) -triphenylphosphonium bromide (III), which by a Wittig reaction with 2-oxa-3-hydroxy-6-syn- ( 3alpha-tetrahydropyranyloxy-4,4-dimethyl-1-trans-octen-1-yl) -7-anti-tetrahydropyranyloxybicyclo- [3.3.0] cis-octane (IV) (prepared according to reference 2) by means of sodium dimethylsulfinate in DMSO yields 9alpha-hydroxy-11alpha, 15alpha-bis (tetrahydropyranyloxy) -16,16-dimethyl-alpha-dinorprosta-5-cis-13-trans-dienoic acid (V). The reduction of (V) with H2 over Pd / C in methanol affords the 13-trans-prostenoic acid (VI), which is methylated with CH2N2 in ether yielding the methyl ester (VII). The reduction of (VII) with diisobutyl aluminum hydride in toluene affords the corresponding aldehyde (VIII) , which by a Wittig reaction with triethyl phosphonoacetate (IX) by means of NaH in THF is converted into 9alpha-hydroxy-11alpha, 15alpha-bis (tetrahydropyranyloxy) -16,16-dimethylprosta-2-trans-dienoic acid ethyl ester (X .) The hydrolysis of the ester (X) with KOH in ethanol-water gives the corresponding acid (XI), which is oxidized with CrO3, MnSO4 and H2SO4 in ether – water yielding the protected ketoacid (XII) The hydrolysis of (XII. ) with acetic acid-water at 80 C gives 9-oxo-11alpha, 15alpha-dihydroxy-16,16-dimethyl-prosta-2-trans-13-trans-dienoic acid (16,16-dimethyl-DELTA2-trans-PGE1 ) (XIII), which is finally methylated with CH2N2 in ether

References

Bartley J, Brown A, Elton R, Baird DT (October 2001). “Double-blind randomized trial of mifepristone in combination with vaginal gemeprost or misoprostol for induction of abortion up to 63 days gestation”. Human reproduction (Oxford, England) 16 (10): 2098–102.doi:10.1093/humrep/16.10.2098. PMID 11574498. Retrieved 2008-10-29.

: Gemeprost

CAS 64318-79-2

CAS Name: (2E,11a,13E,15R)-11,15-Dihydroxy-16,16-dimethyl-9-oxoprosta-2,13-dien-1-oic acid methyl ester

Additional Names: 16,16-dimethyl-trans-D2-PGE1 methyl ester

Manufacturers’ Codes: ONO-802

Trademarks: Cergem (Searle); Cervagem(e) (M & B); Preglandin (Ono)

Molecular Formula: C23H38O5

Molecular Weight: 394.54

Percent Composition: C 70.02%, H 9.71%, O 20.28%

Literature References:

Analog of prostaglandin E1, q.v. Prepn: M. Hayashi et al., DE 2700021; eidem, US 4052512 (both 1977 to Ono);

H. Suga et al., Prostaglandins 15, 907 (1978).

Effects on uterine contractility and steroid hormone plasma levels: K. Oshimaet al., J. Reprod. Fertil. 55, 353 (1979).

Effects on reproductive function: K. Matsumoto et al., Nippon Yakurigaku Zasshi 79, 15 (1982), C.A. 96, 98392 (1982).

Use in termination of first trimester pregnancy: O. Reiertsen et al., Prostaglandins Leukotrienes Med. 8, 31 (1982).

Therap-Cat: Abortifacient; oxytocic.

Keywords: Abortifacient/Interceptive; Oxytocic; Prostaglandin/Prostaglandin Analog

Latanoprost

August 2, 2014 8:51 am / Leave a comment

Latanoprost

isopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.

130209-82-4

XA41, PhXA34 [as 15 (R, S) -isomer], PhXA41, Xalatan

(Zanoni, G. et al., Tetrahedron 2010, 66, 7472)

Latanoprost (pronounced la-TA-noe-prost) ophthalmic solution is a medication administered into the eyes to control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is a prostaglandin analogue (more specifically an analogue ofprostaglandin F_2α^[1]) that lowers the pressure by increasing the outflow of aqueous fluid from the eyes through the uvealsclearal tract.^[2] Latanoprost is an isopropyl ester prodrug, meaning it is inactive until it is hydrolyzed by esterases in the cornea to the biologically active acid.^[3]

It is also known by the brand name of Xalatan manufactured by Pfizer. Annual sales are approximately $1.6 billion. The patent for latanoprost expired in March 2011, and at least one generic version (manufactured by Mylan Inc.) is now widely available in the U.S. The Veterans Health Administration, part of the U.S. Department of Veterans Affairs, uses generic Latanoprost manufactured by Alcon Laboratories of Fort Worth, Texas distributed by Novartis generic brand Sandoz Pharmaceuticals.

Latanoprost was invented by Johan W. Stjernschantz and Bahram Resul, employees of the Pharmacia Corporation of Upsalla, Sweden.^[4]

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.^[5]

Latanoprost
Systematic (IUPAC) name


isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2- [(3R)3-hydroxy-5-phenylpentyl]-cyclopentyl] hept-5-enoate
Clinical data
Trade names	Xalatan
AHFS/Drugs.com	monograph
MedlinePlus	a697003
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Topical (eye drops)
Pharmacokinetic data
Half-life	17 minutes
Identifiers
CAS number	130209-82-4
ATC code	S01EE01
PubChem	CID 5311221
IUPHAR ligand	1961
DrugBank	DB00654
ChemSpider	4470740
UNII	6Z5B6HVF6O
KEGG	D00356
ChEBI	CHEBI:6384
ChEMBL	CHEMBL1051
Chemical data
Formula	C₂₆H₄₀O₅
Mol. mass	432.593 g/mol

Medical uses

Ocular hypertension

In well-controlled clinical trials including patients with open-angle glaucoma or ocular hypertension (IOP ≥21 mm Hg), monotherapy with latanoprost reduced IOP levels by 22 to 39% over 1 to 12 months’ treatment. Latanoprost was significantly more effective than timolol 0.5% twice daily in 3 of 4 large (n = 163 to 267) randomised, double-blind trials. Latanoprost demonstrated a stable long-term IOP-lowering effect in 1- or 2-year continuations of these trials, with no sign of diminishing effect during prolonged treatment.^[6]

Meta analysis suggests that latanoprost is more effective than timolol in lowering IOP. However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified.^[7]

Closed-angle glaucoma

Patients who had elevated IOP despite iridotomy and/or iridectomy (including patients of Asian descent), latanoprost was significantly more effective than timolol in two double-blind, monotherapy trials (8.2 and 8.8 mm Hg vs 5.2 and 5.7 mm Hg for latanoprost vs timolol at 12 and 2 weeks, respectively).^[8]

Method of administration

One drop in the affected eye(s) once daily in the evening; do not exceed the once daily dosage because it has been shown that more frequent administration may decrease the intraocular-pressure (IOP) lowering effect^[2]

Adverse effects[

Listed from most to least common:

>5% to 15%: Blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris causing (heterochromia), punctate epithelial keratopathy
4%: Cold or upper respiratory tract infections, flu-like syndrome
1-4%: Dry eyes, excessive tearing, eye pain, lid crusting, lid edema, lid erythema (hyperemia), lid pain, photophobia (light intolerance)
1 % – 2%: Chest pain, allergic skin reactions, arthralgia, back pain, myalgia, thickening of the eyelashes.(used,also bimatoprost,in cosmetic industry as eyelash growth enhancers)
<1% (Limited to important or life-threatening): Asthma, herpes keratitis, iritis, keratitis, retinal artery embolus, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage from diabetic retinopathy
A single case report links latanoprost use to the progression of keratoconus.^[9]

Concerns related to adverse effects:

Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions, has caused bacterial keratitis.
Ocular effects: May permanently change/increase brown pigmentation of the iris, the eyelid skin, and eyelashes. In addition, may increase the length and/or number of eyelashes (may vary between eyes); changes occur slowly and may not be noticeable for months or years. Long-term consequences and potential injury to eye are not known.
Ocular disease: Use with caution in patients with intraocular inflammation, aphakic patients, pseudophakic patients with a torn posterior lens capsule, or patients with risk factors for macular edema. Safety and efficacy have not been determined for use in patients with angle-closure-, inflammatory-, or neovascular glaucoma.

Special populations

Contact lens wearers: Contains benzalkonium chloride which may be absorbed by contact lenses; remove contacts prior to administration and wait 15 minutes before reinserting

Contraindications

Hypersensitivity to latanoprost, benzalkonium chloride, or any component of the formulation

Drug Interactions

Bimatoprost: The concomitant use of Latanoprost and Bimatoprost may result in increased intraocular pressure. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapy

Pregnancy

Prescription of Latanoprost is limited in human studies due to high incidence of abortion shown in animal experiments. Because of this, Latanoprost is classified as Risk factor C (Adverse events were observed in animal reproduction studies at maternally toxic doses)according to United States Food and Drug Administration’s use-in-pregnancy ratings.^[10]Lactation Excretion in breast milk unknown/use caution. Breast-Feeding Considerations It is not known if latanoprost is excreted in breast milk. The manufacturer recommends that caution be exercised when administering latanoprost to nursing women.^[2]

Storage

Latanoprost is a substance exhibiting thermal and solar instability. Concentration of latanoprost will decrease by 10% when stored at 50 and 70 degrees Celsius every 8.25 and 1.32 days respectively. Reaction with ultraviolet radiation will cause rapid degradation of Latanoprost. It is therefor important to store Latanoprost ideally in temperature below room temperature and free from sunlight in order to attain acceptable drug quality. ^[11]

Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C₂₆H₄₀O₅and its chemical structure is:

Xalatan®<br /><br /><br /><br />
(latanoprost) Structural Formula Illustration
XALATAN Sterile Ophthalmic Solution (latanoprost ophthalmic solution) is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of XALATAN contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. One drop contains approximately 1.5 μg of latanoprostLatanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically insoluble in water.

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http://www.google.com/patents/EP2495235A1?cl=en

When Latanoprost is the desired product the double bond on the side chain of compound 9a is hydrogenated to form compound 11, then by Wittig reaction with 4-carboxybutyltriphenylphosphonium bromide compound 11 is converted into Latanoprost acid 12. By conversion of the carboxylic acid into isopropyl ester, the final product Latanoprost is obtained:

EXAMPLE 16

(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid (Latanoprost acid)

4-Carboxybutyltriphenylphosphonium bromide 15 (32.7 g, 0.074 mol) was suspended in tetrahydrofuran (75.0 mL) at 0°C under nitrogen atmosphere. A 1M solution of potassium tert-butoxide in tetrahydrofuran (296.0 mL, 0.296 mol) was added dropwise and the mixture turned into orange. After stirring for 45 minutes at 0°C the system was cooled to ―15°C. A solution of (3aR,4R,5R,6aS)-4-((R)-3-hydroxy-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol (5.0 g, 0.016 mol) in tetrahydrofuran (23.0 mL) was added dropwise at a temperature lower than -10°C. After stirring overnight at -15°C no more starting was visible on TLC and water (100 mL) was added. The mixture was extracted with diisopropyl ether (70 mL) and after separation the aqueous phase was treated with 0.6 N HCl to pH 6.0. Three extractions with ethyl acetate (3x 125 mL) were then performed, each time adjusting the pH of the aqueous phase to 6.0. The combined organic layers were concentrated under vacuum at 35°C. An oil (13.87 g) was obtained which was used in the subsequent step without further purification.
¹H-NMR {400 MHz, CDCl₃, δ (ppm)}: 7.71 (m, 1H, Ph), 7.49 (m, 1H, Ph), 7.30-7.17 (m, 3H, Ph), 5.52-5.35 (m, 2H, -CH=CH-), 4.34 (bs, 4H, OH), 4.17 (m, 1H, -CH-OH(C-9)), 3.96 (m, 1H, -CH-OH (C-11)), 2.78 (m, 1H, -CH-OH (C-15)), 2.78 (m, 1H, -CH₂Ph), 2.66 (m, 1H, -CH₂Ph), 2.36-1.27 (m, 18H).
¹³C-NMR {400 MHz, CDCl₃, δ (ppm)}: 176.5 (C), 142.2 (C), 130.8 (CH), 130.7 (CH), 129.4 (CH), 128.8 (CH), 128.7 (CH), 128.4 (CH), 125.7 (CH), 78.3 (CH), 74.2 (CH), 71.4 (CH), 52.2 (CH), 51.6 (CH), 42.4 (CH₂), 38.8 (CH₂), 35.2 (CH₂), 33.4 (CH₂), 32.0 (CH₂), 29.1 (CH₂), 26.6 (CH₂), 26.4 (CH₂), 24.7 (CH₂).
HPLC-MS (ESI): [M+Na]⁺ = 413, [M+H]⁺ = 391.

EXAMPLE 17(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Latanoprost)

Latanoprost acid (6.78 g, corresponding to 0.008 mol) was dissolved in N,N-dimethylformamide (108 mL) and cesium carbonate (8.48 g, 0.026 mol) was added at room temperature. 2-Iodopropane (3.46 mL, 0.035 mol) was added and the suspension was stirred at 40°C for 3 hours, checking the conversion on TLC. The mixture was then allowed to reach 25°C and a mixture of ice (184 g), water (40 mL), sodium thiosulfate (1M, 18 mL), was added stirring at -5/0°C for 15 minutes. The mixture was extracted with tert-butylmethylether (285 mL) and the phases were separated. The aqueous phase was extracted twice with tert-butylmethyl ether (2x 200 mL) and the combined organic layers were washed with brine (176 mL, 130 mL). The organic phase was concentrated under reduced pressure at 25°C and the crude product was obtained as a yellow oil (6.60 g). Purification by column chromatography on silica gel was performed eluting with dichloromethane:methanol increasing the percentage of methanol from 0 to 5%. A second purification on silica gel afforded Latanoprost (2.36 g, 0.005 mol, 68% over two steps).
¹H-NMR {400 MHz, CDCl₃, δ (ppm)}: 7.32-7.19 (m, 5H, Ph), 5.45-5.51 (m, 2H, H-5 e H-6 vinyl), 5.0 (hept, J=6.3 Hz, 1H, CH₃CHCH₃), 4,18 (bs, 1H, CHOH), 3.95 (bs, 1H, CHOH), 3.67 (bs, 1H, CHOH), 2.76 (m, 2H, CH ₂Ph), 1.23 (d, J=6.3Hz, 6H, C(CH₃)₂), 2.55-1.3, 21H).
HPLC-MS (ESI): [M+Na]⁺ = 455, [M+H]⁺ = 432.

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http://www.google.com/patents/EP2454227A1?cl=en

Example 3

Synthesis of Latanoprost

ether MTBE

8c-iso

Latanoprost

Scheme 5. Synthesis of Latanoprost

Synthesis of Latanoprost from 12c:

As shown in Scheme 5 in Example 3, a 250 ml.3-necked round-bottom flask equipped with a magnetic bar, a temperature probe, rubber septa, and a nitrogen gas inlet was charged at room temperature with 7.3 g (19.6 mmol) of deprotected lactone 12c in 70 mL of 2-propanol and 1.6 g (39.2 mmol) of sodium hydride, 60%, in mineral oil. The reaction mixture was heated at 35 ⁰C for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 60 mL of water and the pH was adjusted to 6 with 1 N HCI. The layers were separated and the aqueous layer was back extracted with 40 mL of 2-propanol four times. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered, and concentrated.

The material was dissolved in 60 mL of THF, 5.0 mL (33.3 mmol) of DBU and 3.3 mL (33.3 mmol) of iodopropane. The reaction mixture was stirred at room temperature for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 60 mL of ethyl acetate and 60 mL of water. The layers were separated and the aqueous layer was back extracted with 40 mL of ethyl acetate for two times. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered, and concentrated.

The material was purified by using reverse phase biotage, 70 : 30 ACN :

H₂O to obtain 4.1 g (49% yield) of Latanoprost, confirmed by ¹H NMR.

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Wittig condensation of lactol (XIII) with (carboxybutyl) triphenylphosphonium bromide (XV) in the presence of potassium tert-butoxide produced the Z-olefin (XVI). Conversion of carboxylic acid (XVI) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of DBU.

http://www.chemdrug.com/databases/8_0_xmmatmlqjiethrwn.html

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http://www.nature.com/nature/journal/v489/n7415/full/nature11411.html?WT.ec_id=NATURE-20120913

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http://brsmblog.com/?p=1525

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http://www.google.com/patents/WO2013186550A1?cl=en

(la) (Ic)

Example 6 – Experimental procedures for the synthesis of latanoprost

A synthesis of latanoprost is shown and described below.

latanoprost (77)

2-Phenethyloxirane, 61

m-CPBA,

A modified procedure of Woodward was used (Bernier, D. et al., The Journal of Organic Chemistry 2008, 73, 4229). A stirred solution of 4-phenyl-l-butene 62 (500 mg, 568 μΙ, 3.78 mmol) in CH₂CI₂ (20 ml) was cooled to 0 °C. m-CPBA (816 mg, 4.73 mmol) was added as a solid and the reaction mixture was stirred at 0 °C for 1.5 h, then r.t. for 24 h. The reaction mixture was poured into saturated K₂C0₃ solution (50 ml) and extracted with CH₂CI₂ (2 x 50 ml). The combined organic phases were washed with saturated K₂C0₃ solution (50 ml) before being dried (MgS0₄), filtered and concentrated to give a clear colourless liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the epoxide 61 (10.2 g, 91%) as a clear colourless liquid. The ¹³C, and IR data were consistent with the literature (Mitchell, J. M. et al., Journal of the American Chemical Society 2001, 123, 862; Elings, J. A. et al., European Journal of Organic Chemistry 1999, 1999, 837).

R_f = 0.42 (petrol :EtOAc, 9:1) v_max (neatycnrr¹ 3027, 2989, 2922, 2859, 1602, 1495, 1454, 1410, 835, 750, 699

*H NMR (400 MHz; CDCI₃) δ_Η = 1.83-1.99 (2 H, m, CH₂), 2.53 (1 H, dd, J = 5.0, 2.7 Hz, CHH), 2.75-2.93 (2 H, m, CH₂), 2.80 (1 H, dd, J = 5.0, 4.0 Hz, CHH), 3.01 (1 H, dddd, J = 6.5, 5.0, 4.0, 2.7 Hz, CH), 7.22-7.38 (5 H, m, Ar H’s)

1³C NMR (100 MHz; CDCI₃) 5_C = 32.2 (CH₂), 34.2 (CH₂), 47.2 (CH₂), 51.7 (CH), 126.0 (2 x ArCH), 128.3 (2 x ArCH), 128.4 (ArCH), 141.2 (ArC)

m/z (EI) 148.1 (M⁺, 10%), 130.1 (23%), 129.0 (18%), 118.1 (29%), 117.1 (83%), 115.0 (28%), 105.0 (22%), 104.0 (61%), 92.0 (22%), 91.0 (100%), 83.9 (37%), 77.0 (17%), 65.0 (31%)

(2S)-2-Phenethyloxirane, 63

A modified procedure of Jacobsen was used (Schaus, S. E. et al., Journal of the American Chemical Society 2002, 224, 1307). Racemic epoxide 61 (10.0 g, 67.5 mmol) was dissolved in THF (10 ml) and stirred at r.t.. (S^-i+J-^A/’-BisiS^-di-tert-butylsalicylidene)-!^- cyclohexanediaminocobalt(II) (204 mg, 0.34 mmol) was added and the resultant dark brown solution cooled to 0 °C. Acetic acid (77 μΙ, 1.35 mmol) and water (669 μΙ, 37.1 mmol) were added. The reaction was stirred at 0 °C for 1 h and then at r.t. for 23 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (~200 g silica), eluting with petrol/EtOAc (9:1), to give the epoxide 3 as a dark red liquid. This was re- purified by column chromatography eluting with petrol/EtOAc (9.5:0.5 to 9:1), to give the epoxide 3 (4.62 g, 46%) as an orange liquid. The analytical data matched that of the racemic material described above. The enantioselectivity of the resolution was determined after subsequent conversion to the allylic alcohol 66. The optical rotation matched closely with that reported in the literature (Martynow, J. G. et al., European Journal of Organic Chemistry 2007, 2007, 689).

[a]_D ²¹ -21.0 (c. 1.0, CHC ) (lit., [a]_D ²⁰ -22.5 (c. 1.0, CHCI₃)) 5-Phenyl-l-penten-3-ol, 64

A modified procedure of Molander was used (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297). A stirred solution of hydrocinnamaldehyde 65 (2.50 g, 2.45 ml, 18.6 mmol) in THF (25 ml) was cooled to -78 °C. Vinyl magnesium bromide solution (1 M in THF) (22.4 ml, 22.4 mmol) was added dropwise over ~ 5 min. The reaction mixture was stirred at -78 °C for 1.5 h, then 0 °C for 3 h. The reaction mixture was poured into saturated NH₄CI solution (50 ml) and extracted with Et₂0 (3 x 50 ml). The combined organic phases were washed with saturated NaCI solution (50 ml) before being dried (MgS0₄), filtered and concentrated to give a pale yellow liquid. This material was purified by column

chromatography, eluting with petrol/EtOAc (9: 1), to give the vinyl alcohol 64 (1.89 g, 63%) as a clear colourless liquid. The *H, ¹³C, and IR data were consistent with the literature (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297; Kim, J. W. et al., Chemistry – A European Journal 2008, 24, 4104). R_f = 0.40 (petrol :EtOAc, 4: 1)

max (CHC Vcnrr¹ 3335, 3026, 2923, 2859, 1496, 1454, 990, 922, 747, 698

*H NMR (400 MHz; CDCI₃) δ_Η = 1.55 (1 H, br.s, OH), 1.84-1.99 (2 H, m, CH₂), 2.70-2.89 (2 H, m, CH₂), 4.19 (1 H, app q, J = 6.0 Hz, CHO ), 5.20 (1 H, app dt, J = 10.5, 1.4 Hz, HC=C), 5.30 (1 H, app dt, J = 17.1, 1.4 Hz, HHC=C), 5.96 (1 H, ddd, J = 17.1, 10.5, 6.0 Hz, H₂C=CH), 7.20-7.40 (5 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 31.6 (CH₂), 38.5 (CH₂), 72.4 (HCOH), 114.9 (H₂C=C), 125.8 (ArCH), 128.4 (2 x ArCH), 128.4 (2 x ArCH), 141.0 (H₂C=Q, 141.8 (ArC)

m/z (EI) 162.1 (M⁺, 30%), 144.1 (52%), 129.1 (72%), 105.1 (68%), 92.1 (71%), 91.0 (100%), 57.0 (61%) 6D. (3S)-5-Phenyl-l-penten-3-ol, 66

A modified procedure of Falck was used (Alcaraz, L. et al., Tetrahedron Letters 1994, 35, 5449). A suspension of trimethylsulfonium iodide (18.2 g, 89.1 mmol) in anhydrous THF (220 ml) was stirred and cooled to -20 °C. 1.6 M n-BuLi (55.7 ml, 89.1 mmol) was added slowly and the reaction stirred at -20 °C for 1 h. A solution of epoxide 63 (4.40 g, 29.7 mmol) in anhydrous THF (50.0 ml) was added slowly. The reaction was stirred at -20 °C for 1 h and then allowed to warm to r.t. slowly. The reaction mixture was poured into water (200 ml) and extracted with Et₂0 (1 x 200 ml, 1 x 100 ml). The combined organic phases were washed with saturated NaCI solution (100 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by column chromatography (130 g silica), eluting with petrol/EtOAc (9:1), to give partially purified material. This was re-purified by column chromatography (50 g silica), eluting with petrol/EtOAc (9:1), to give allylic alcohol 66 (3.19 g, 66%) as a pale yellow liquid. The analytical data matched that described for the racemic material above.

[α]ο²¹ -11.0 (c. 1.0, CHCI₃) (lit – Kanbayashi, N. et al., Angewandte Chemie International Edition 2011, 50, 5197, [a]_D ²⁵ -3.6 (for 85% ee (c. 0.4, CHCI₃)))

Chiral-HPLC data: er = >99:1 (Chiralcel AD-H column, 210 nm, hexane/2-propanol: 98/2, flow rate: 0.5 mlVmin, room temperature; ¾: minor 41.0 min, major 43.7 min) 6E. tert-Butyl(dimethyl)[(lS)-l-phenethyl-2-propenyl]oxysilane, 67

67 A stirred solution of allylic alcohol 66 (3.00 g, 18.5 mmol) in CH₂CI₂ (53 ml) was cooled to 0 °C. Imidazole (2.27 g, 33.3 mmol) was added in one portion followed by t- butylchlorodimethylsilane (3.34 g, 22.2 mmol). The cooling bath was removed and the reaction mixture stirred at r.t. for 16 h before being poured into 10% aq. HCI (100 ml). The mixture was extracted with 40/60 petroleum ether (2 x 100 ml). The combined organics were washed with saturated NaCI solution (100 ml), dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by column chromatography, eluting with 40/60 petroleum ether, to give the protected alcohol 67 (4.68 g, 92%) as a colourless liquid. The *H NMR data and optical rotation matched that reported in the literature (Uenishi, J. i. et al., Organic Letters 2011, 13, 2350).

R_f = 0.25 (40/60 petroleum ether)

v_max (film)/cm-¹3064, 3027, 2952, 2929, 2886, 2856, 1497, 1472, 1462, 1455, 1361, 1251, 1122, 1083, 1030, 990, 921, 834, 774, 697

*H NMR (400 MHz; CDCI₃) δ_Η = 0.05 (3 H, s, SiCH₃), 0.08 (3 H, s, SiCH₃), 0.93 (9 H, s, C(CH₃)₃), 1.82 (2 H, m, CH₂), 2.66 (2 H, m, CH₂), 4.17 (1 H, m, OCH), 5.08 (1 H, ddd, J = 10.4, 1.5, 1.3 Hz, HA =CH), 5.19 (1 H, app dt, J = 17.2, 1.5 Hz, HHC=CH), 5.86 (1 H, ddd, J = 17.2, 10.4, 6.0 Hz, H₂C=CH), 7.18 (3 H, m, ArH’s), 7.28 (2 H, m, ArH’s)

1³C NMR (100 MHz; CDCI₃) 5_C = -4.8 (SiCH₃), -4.3 (SiCH₃), 18.3 (C(CH₃)₃), 25.9 (C(CH₃)₃), 31.5 (CH₂), 39.8 (CH₂), 73.3 (CHOSi), 114.0 (H₂C=C), 125.7 (ArCH), 128.3 (2 x ArCH), 128.4 (2 x ArCH), 141.4 (H₂C=Q, 142.5 (ArC).

[a]_D” 12.0 (c. 1.0, CHCI₃) (lit., [a]_D ²⁰ 14.5 (c. 1.0, CHCI₃)) 6F. (3S)-3-[l-(tert-Butyl)-l,l-dimethylsilyl]oxy-5-phenylpentan-l-ol, 68

A modified procedure of Denmark was used (Denmark, S. E. et al., Organic Letters 2005, 7, 5617). Compound 67 (2.00 g, 7.23 mmol) was added to a flame dried schlenk flask under N₂. 9-BBN (0.5 M in THF) (15.9 ml, 7.96 mmol) was added via syringe and the resulting solution stirred at r.t. for 1 h. A further 1.1 eq. (15.9 ml, 7.96 mmol) of 9-BBN was added and the reaction stirred at r.t. for 2 h. Water (16.0 ml) and NaB0₃.4H₂0 (5.56 g, 36.2 mmol) were added and the reaction stirred at r.t. for 2 h. The reaction mixture was poured into saturated NH₄CI solution (60 ml) and extracted with Et₂0 (3 x 100 ml). The combined organic phases were washed with sat. NaCI solution (100 ml), dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified 3 times by column chromatography (twice eluting with petrol/EtOAc (6:1) and once with petrol/ EtOAc/Eti⁾ (9:0.5:0.5)) to give the alcohol 68 (672 mg, 32%) as a clear colourless oil.

R_f = 0.18 (petrol :EtOAc, 9:1)

v_max (film)/cm-¹3351 (broad), 3063, 2950, 2928, 2885, 2856, 1496, 1471, 1462, 1454, 1360, 1253, 1092, 1057, 1028, 1005, 834, 773, 746, 698

*H NMR (400 MHz; CDCI₃) δ_Η = 0.09 (3 H, s, SiCH₃), 0.10 (3 H, s, SiCH₃), 0.92 (9 H, s, C(CH₃)₃), 1.75 (1 H, m, CHH), 1.83-1.94 (3 H, m, CH₂, CHH), 2.32 (1 H, app t, J = 5.2 Hz, OH), 2.64 (2 H, m, CH₂), 3.75 (1 H, app dq, J = 10.8, 5.5 Hz, OCHH), 3.87 (1 H, app ddt, J = 10.8, 8.1, 4.8 Hz, OCHtf), 3.99 (1 H, app qd, J = 6.1, 4.4 Hz, HCOTBDMS), 7.16-7.23 (3 H, m, ArCH’s), 7.27-7.33 (2 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = -4.7 (SiCH₃), -4.4 (SiCH₃), 18.0 (C(CH₃)₃), 25.8 (C(CH₃)₃), 31.7 (CH₂), 37.8 (CH₂), 38.7 (CH₂), 60.1 (CH₂), 71.2 (SiOCH), 125.8 (ArCH), 128.2 (2 x ArCH), 128.4 (2 x ArCH), 142.1 (ArC)

HRMS (ESI) calcd for Ci₇H₃₀O₂SiNa [MNa⁺] 317.1907, found 317.1906

[a]_D ²³ 23.0 (c. 1.0, CHCI₃) 6G. tert-Butyl[(lS)-3-iodo-l-phenethylpropyl]oxydimethylsilane, 69

68 A modified procedure of Rychnovsky was used (Dalgard, J. E. et al., Organic Letters 2004, 6, 2713). Alcohol 68 (600 mg, 2.04 mmol) was added to a flame dried schlenk flask under N₂. CH₂CI₂ (10 ml) was added via syringe and the resulting solution stirred at r.t..

Triphenylphosphine (695 mg, 2.65 mmol) and imidazole (222 mg, 3.26 mmol) were added as solids in one portion. Iodine (672 mg, 2.65 mmol) was added to the resulting solution. A slight exotherm was noted and the solution changed from a light yellow colour to a brown colour with the formation of a precipitate. The reaction was stirred at r.t. for 1 h. The reaction mixture was dry loaded onto silica (2 g) and purified by column chromatography (14 g silica), eluting with petrol to petrol/EtOAc (9: 1). This gave the iodide 69 (725 mg, 88%) as a clear, colourless oil.

R_f = 0.20 (40/60 petroleum ether)

ifiln /cnr^OeS, 3026, 2951, 2928, 2886, 2856, 1495, 1471, 1461, 1360, 1253, 1187, 1165, 1140, 1092, 1063, 1005, 975, 931, 833, 773, 697

*H NMR (400 MHz; CDCI₃) δ_Η = 0.09 (3 H, s, SiCH₃), 0.10 (3 H, s, SiCH₃), 0.92 (9 H, s, (C(CH₃)₃), 1.79 (2 H, m, CH₂), 2.05 (2 H, m, CH₂), 2.64 (2 H, m, CH₂), 3.24 (2 H, m, CH₂), 3.82 (1 H, quin., J = 5.7 Hz, OCH), 7.16-7.23 (3 H, m, ArCH’s), 7.27-7.33 (2 H, m, ArCH’s) ¹³C NMR (100 MHz; CDCI₃) 5_C = -4.3 (SiCH₃), -4.3 (SiCH₃), 3.0 (CH₂), 18.1 (C(CH₃)₃), 25.9 (C(CH₃)₃), 31.3 (CH₂), 38.7 (CH₂), 40.8 (CH₂), 71.7 (OCH), 125.8 (ArCH), 128.3 (2 x ArCH), 128.4 (2 x ArCH), 142.1 (ArC)

HRMS (ESI) calcd for Ci₇H₃₀OSiI [MH⁺] 405.1108, found 405.1105

[a]_D ²³ 26.0 (c. 1.0, CHCI₃)

6H. [(lR)-3-((3aR,4R,6aS)-2-Methoxy-5-(£)-l-[(l,l,l- trimethylsilyl)oxy]methylideneperhydrocyclopenta[d]furan-4-yl)-l- phenethylpropyl]oxy(tert-butyl)dimethylsilane, 70

70 Iodide 69 (1.32 g, 3.27 mmol, 1.1 eq.) was added via syringe to a flame dried schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous Et₂0 (13.3 ml) was added via syringe and the resulting solution cooled to -78 °C. 1.63 M t-BuLi (4.01 ml, 6.54 mmol, 2.2 eq.) was added dropwise and the reaction mixture stirred at -78 °C for 2 h and -40 °C for 2 h before being cooled back to -78 °C. Meanwhile, thiophene (275 mg, 262 μΙ, 3.27 mmol, 1.1 eq.) was added via syringe to a flame dried schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous THF (13.3 ml) was added via syringe and the resulting solution cooled to -30 °C. 1.63 M n-BuLi (2.01 ml, 3.27 mmol, 1.1 eq.) was added dropwise and the solution stirred at -30 °C for 30 min. CuCN (293 mg, 3.27 mmol, 1.1 eq.) was added as a solid, in one portion. The cooling bath was removed and the suspension allowed to warm to r.t. The resulting tan/brown solution of cuprate was added dropwise via syringe to the schlenk flask containing the alkyl lithium and anhydrous THF (13.3 ml) added. The mixture was stirred at -20 °C for 1 h to allow formation of mixed cuprate 71. This was cooled to -78 °C and a solution of enal 24 (500 mg, 2.97 mmol, 1.0 eq.) in anhydrous THF (13.3 ml) was added dropwise. The mixture was stirred at -78 °C for 1 h and then allowed to warm slowly to -20 °C. TMSCI (1.61 g, 1.89 ml, 14.9 mmol, 5.0 eq.) was added via syringe followed by NEt₃ (1.80 g, 2.49 ml, 17.8 mmol, 6 eq.). The reaction was quenched by the addition of saturated NH₄CI solution (50 ml) and extracted with Et₂0 (3 x 50 ml). The combined organic phases were washed with saturated NH₄CI solution (50 ml) and saturated NaCI solution (50 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material as a yellow oil. This was used directly in the next step.

61. (3aR 4R,5R,6aS)-4-((3R)-3-[l-(tert-Butyl)-l,l-dimethylsilyl]oxy-5- phenylpentyl)-2-methoxyperhydrocyclopenta[d]furan-5-ol, 73

70 73 The crude material from the conjugate addition / trapping experiment, containing 70, was dissolved in CH₂Cl2/MeOH (3: 1) (30 ml) and cooled to -78 °C. A stream of ozone was passed through the stirred solution. The reaction was monitored periodically by TLC in order to judge completion of the ozonolysis (judged by consumption of silyl enol ether). The reaction mixture was flushed with a stream of N₂, for 15 min, to remove excess 0₃. NaBH₄ (202 mg, 5.35 mmol) was added in one portion. The reaction mixture was stirred at -78 °C for 2 h before the cooling bath was removed and the reaction allowed to warm to r.t.. The reaction was stirred at r.t. for 1 h. NaBH₄ (67.4 mg, 1.78 mmol) was added and the reaction stirred at r.t. for a further 15 min. The reaction mixture was poured into saturated NaCI solution (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the crude product as a pale yellow oil. This was purified by column chromatography on silica, eluting with petrol/EtOAc (4: 1), giving the alcohol 73 (as an approximately 2:1 mixture of diastereoisomers) as a clear, colourless oil (800 mg, 62% (2 steps from enal 24)).

R_f = 0.23 (petrol :EtOAc, 4:1)

v_max (neatycnrr¹ 3434 (broad), 3026, 2928, 2856, 1496, 1471, 1454, 1360, 1343, 1254, 1098, 1053, 1004, 937, 833, 773, 698

¹H NMR (400 MHz; CDCI₃) 5H = (mixture of 2 diastereoisomers, signals of minor diastereoisomer indicated by *) 0.05 (3 H, s, CH₃), 0.06* (3 H, s, CH₃), 0.07 (3 H, s, CH₃), 0.07* (3 H, s, CH₃), 0.91 (9 H, s, C(CH₃)₃), 0.92* (9 H, s, C(CH₃)₃), 1.12-1.80 (7 H, m), 1.12- 1.80* (7 H, m), 1.90-2.38 (5 H, m), 1.90-2.38* (5 H, m), 2.53-2.75 (2 H, m, CH₂), 2.53-2.75* (2 H, m, CH₂), 3.32 (3 H, s, OCH₃), 3.39* (3 H, s, OCH₃), 3.72 (1 H, m, CHOTBDMS), 3.72* (1 H, m, CHOTBDMS), 3.79* (1 H, m, CHOH), 3.89 (1 H, m, CHOH), 4.55 (1 H, app td, J = 6.3, 2.5 Hz, CH), 4.64* (1 H, app td, J = 6.8, 2.7 Hz, CH), 5.06* (1 H, d, J = 5.5 Hz, OCHO), 5.11 (1 H, d, J = 4.9 Hz, OCHO), 7.19 (3 H, m, ArCH’s), 7.19* (3 H, m, ArCH’s), 7.29 (2 H, m, ArCH’s), 7.29* (2 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = (observed signals, mixture of 2 diastereoisomers) -4.42 (SiCH₃), -4.41 (SiCH₃), -4.33 (SiCH₃), 18.1 (2 x C(CH₃)₃), 25.9 (2 x C(CH₃)₃), 29.3 (CH₂), 30.3 (CH₂), 31.7 (CH₂), 35.1 (CH₂), 38.8 (CH₂), 39.9 (CH₂), 40.0 (CH₂), 41.1 (CH₂), 42.7 (CH₂),

46.5, 47.2, 54.4, 55.1, 55.3, 55.7, 71.8, 71.8, 79.3, 79.7, 82.5, 85.8, 106.5 (OCHOCH₃), 108.0 (OCHOCH₃), 125.7 (ArCH), 125.7 (ArCH), 128.3 (4 x ArCH), 128.3 (4 x ArCH), 142.6 (ArC), 142.6 (ArC). One SiCH₃ and three CH₂‘s could not be assigned due to overlapping signals. 6J. (3aR,4R,5R,6aS)-4-[(3R)-3-Hydroxy-5- phenylpentyl]perhydrocyclopenta[b]furan-2,5-diol, 74

Alcohol 73 (400 mg, 0.920 mmol) was stirred with 1.5% aqueous HQ / THF (3:2) (18 ml) at r.t. for 16 h. The mixture was neutralised with 1 M NaOH and extracted with CH₂CI₂ (5 x 30 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the triol 74 and silanol by-product as a clear, colourless oil (~400 mg). This material was taken forward for the subsequent transformation without purification.

(4-Carboxybutyl)(triphenyl)phosphonium bromide 29 (2.45 g, 5.52 mmol) was added to a flame dried schlenk flask, under N₂, and anhydrous THF (20.0 ml) added. The resulting suspension was cooled to 0 °C. KOt-Bu (1.24 g, 11.0 mmol) was added in one portion and the resulting orange mixture stirred at 0 °C for 40 min. A solution of crude triol 74 (282 mg, 0.920 mmol) in anhydrous THF (5.0 ml) was added dropwise via syringe. After complete addition the cooling bath was removed and the mixture was stirred at r.t. for 1.5 h. The reaction was quenched with H₂0 (30 ml) and washed with Et₂0 (2 x 30 ml) to remove triphenylphosphine oxide. The aqueous phase was made acidic with 1 M HQ (~10 ml) and extracted with CH₂CI₂ (5 x 25 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the crude material as solids. These were placed on a sinter funnel and washed with petrol/EtOAc (1: 1) (4 x 20 ml) and then EtOAc (2 x 40 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with CH₂Cl2/MeOH (9.5:0.5 to 9:1) to give acid 75 (163 mg, 45% over 2 steps from alcohol 73) as a clear, colourless oil. The *Η data and optical rotation were consistent with the literature (Martynow, J. G. et al., European Journal of Organic Chemistry 2007, 2007, 689).

R_f = 0.27 (CH₂CI₂:MeOH, 9:1)

v_max (neatycnrr¹ 3338 (broad), 2930, 2857, 1704, 1452, 1407, 1254, 1028, 747, 699, 636 *H NMR (400 MHz; CDCI₃) δ_Η = 1.39 (2 H, m, CH₂), 1.47-1.97 (10 H, m, 4 x CH₂, 2 x CH), 2.07-2.48 (6 H, m, 3 x CH₂), 2.67 (1 H, m, CH ), 2.80 (1 H, m, CH/-/), 3.60-4.85 (6 H, broad signal, 2 x OCH, 3 x OH, COOH), 3.72 (1 H, m, OCH), 5.40 (1 H, m, =CH), 5.49 (1 H, m, =CH), 7.15-7.24 (3 H, m, ArCH’s), 7.25-7.32 (2 H, m, ArCH’s)

[a]_D ²⁴ 29.0 (c. 1.0, MeOH) (lit, [a]_D ²⁰ 29.7 (c. 1.0, MeOH)) 6L. Isopropyl (Z)-7-(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyl]cyclopentyl-5-heptenoate, latanoprost, 77

A modified procedure of Zanoni and Vidari was used (Zanoni, G. et al., Tetrahedron 2010, 66, 7472). Carboxylic acid 75 (100 mg, 0.256 mmol) was dissolved in DMF (2.0 ml) and stirred at r.t.. Cs₂C0₃ (125 mg, 0.384 mmol) was added in one portion followed by 2- iodopropane (51 μΙ, 0.512 mmol). The reaction was stirred at r.t. for 18 h. The reaction mixture was poured into 3% citric acid solution (10 ml) and extracted with TBME (4 x 10 ml). The combined organic phases were washed with 10% NaHC0₃ solution (10 ml) and saturated NaCI (2 x 10 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude product as a clear, colourless oil (95 mg). This was purified by column chromatography (3 g silica), eluting with petrol/EtOAc (2: 1 to 1:2), to give latanoprost 77 (71 mg, 64 %) as a clear colourless oil. The IR, ¹³C, and optical rotation data were consistent with the literature (Zanoni, G. et al., Tetrahedron 2010, 66, 7472). R_f = 0.44 (EtOAc)

v_max (neatVcm^“1 3360 (broad), 2980, 2931, 2857, 1712, 1495, 1454, 1374, 1311, 1247, 1180, 1106, 1030, 966, 910, 820, 731, 699

*H NMR (400 MHz; CDCI₃) δ_Η = 1.23 (6 H, d, J = 6.4 Hz, 2 x CH₃), 1.30-1.90, (14 H, m, 5 x CH₂, 2 x CH, 2 x OH), 2.07-2.39 (6 H, m, 3 x CH₂), 2.45 (1 H, d, J = 5.5 Hz, OH), 2.63- 2.86 (2 H, m, CH₂), 3.68 (1 H, br.s, CHO ), 3.95 (1 H, br.s, CHOH), 4.18 (1 H, br.s, CHO ), 5.01 (1 H, sept., J = 6.4 Hz, OCH(CH₃)₂), 5.35-5.52 (2 H, m, 2 x =CH), 7.16-7.24 (3 H, m, ArH’s), 7.25-7.32 (2 H, m, ArH’s)

¹³C NMR (125 MHz; CDCI₃) 5_C = 21.9 (2 x CH₃), 24.9 (CH₂), 26.6 (CH₂), 26.8 (CH₂), 29.6 (CH₂), 32.1 (CH₂), 34.0 (CH₂), 35.7 (CH₂), 39.0 (CH₂), 42.5 (CH₂), 51.8 (CH), 52.7 (CH), 67.6 (OCH), 71.2 (OCH), 74.5 (OCH), 78.6 (OCH), 125.7 (CH), 128.3 (2 x ArCH), 128.3 (2 x ArCH), 129.3 (CH), 129.5 (CH), 141.1 (ArC), 173.5 (C=0)

[a]_D ²³ 33.0 (c. 1.0, MeCN) (lit, [a]_D ²⁰ 32.7 (c. 1.0, MeCN))

References

Ishikawa H, Yoshitomi T, Mashimo K, Nakanishi M, Shimizu K (February 2002). “Pharmacological effects of latanoprost, prostaglandin E2, and F2alpha on isolated rabbit ciliary artery”. Graefes Arch. Clin. Exp. Ophthalmol. 240 (2): 120–5. doi:10.1007/s00417-001-0412-4. PMID 11931077.
Patel SS, Spencer CM (1996). “Latanoprost. A review of its pharmacological properties, clinical efficacy and tolerability in the management of primary open-angle glaucoma and ocular hypertension”. Drugs Aging 9 (5): 363–378. doi:10.2165/00002512-199609050-00007. PMID 8922563.
Huttunen et al. (2011) Prodrugs—from Serendipity to Rational Design. Pharmacol Rev 63:750–771
“Patent US5296504 – Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension – Google Patents”.
“WHO Model List of EssentialMedicines”. World Health Organization. October 2013. Retrieved 22 April 2014.
Perry CM, McGavin JK, Culy CR, Ibbotson T (2003). “Latanoprost. An Update of its Use in Glaucoma and Ocular Hypertension”. Drugs Aging 20 (8): 1170–2229.PMID 12795627.
Zhang WY, Wan Po AL, Dua HS, Azuara-Blanco A (2001). “Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension”. British Journal of Ophthalmology 85: 983–990. doi:10.1136/bjo.85.8.983. PMID 11466259.
Aung T; Wong HT; Yip CC; et al. (2000). “Comparison of the intraocular pressure-lowering effect of latanoprost and timolol in patients with chronic angle closure glaucoma: a preliminary study.”. Ophthalmology 107 (6): 1178–83. doi:10.1016/s0161-6420(00)00073-7. PMID 10857840.
Amano S, Nakai Y, Ko A, Inoue K, Wakakura M (2008). “A case of keratoconus progression associated with the use of topical latanoprost”. Japanese Journal of Ophthalmology 52 (4): 334–6. doi:10.1007/s10384-008-0554-6. PMID 18773275.
De Santis, M., Lucchese, A., Carducci, B., Cavaliere, A., De Santis, L., & Merola, A. et al. (2004). Latanoprost exposure in pregnancy. American Journal Of Ophthalmology, 138(2), 305.pmid=15289149.1
Morgan, P., Proniuk, S., Blanchard, J., & Noecker, R. (2001). Effect of temperature and light on the stability of latanoprost and its clinical relevance. Journal Of Glaucoma, 10(5), 401–405.

External links

LATANOPROST solution [Greenstone LLC] (Nov 2011), Daily Med, U.S. National Library of Medicine, National Institutes of Health

Travoprost

August 2, 2014 8:27 am / Leave a comment

Travoprost

cas 157283-68-6

[1R-[lα(Z),2β(lE,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1 -butenyl]cyclopentyl]-5-heptenoic acid, 1 -methylethylester

(+)-16-m-trifluoromethylphenoxy tetranor Prostaglandin F_2α isopropyl ester; (+)-Fluprostenol ispopropyl ester

(+)-(5Z,9α,1α,13E,15R)-trihydroxy-16-(3-(trifluoromethyl)phenoxy)-17,18,19,20-tetranor-prosta-5,13-dien-1-oic acid, isopropyl ester

(+) – Fluprostenol isopropyl ester,

CAS Name: (5Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid 1-methylethyl ester

Additional Names: (+)-16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranorprostaglandin F2a isopropyl ester; (+)-9a,11a,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid isopropyl ester

Manufacturers’ Codes: AL-6221

Trademarks: Travatan (Alcon)

Percent Composition: C 62.39%, H 7.05%, F 11.39%, O 19.18%

Travatan, Travatan Z, AL-6221, Travatanz, Travatan Alcon, Travatan (TN), Travatan, Travoprost, Travoprost [USAN]

Molecular Formula: C₂₆H₃₅F₃O₆

Molecular Weight: 500.54771

Alcon (Originator)

Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists

Properties: Colorless oil. [a]D20 +14.6° (c = 1.0 in methylene chloride). Very sol in acetonitrile, methanol, octanol, chloroform. Practically insol in water.

Optical Rotation: [a]D20 +14.6° (c = 1.0 in methylene chloride)

Therap-Cat: Antiglaucoma.

Ophthalmic solution used for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication.

Travoprost free acid is a selective FP prostanoid receptor agonist and is believed to reduce intraocular pressure by increasing the drainage of aqueous humor, which is done primarily through increased uveoscleral outflow and to a lesser extent, trabecular outflow facility.

Travoprost, an isopropyl ester prodrug, is a synthetic prostaglandin F2 alpha analogue that is rapidly hydrolyzed by esterases in the cornea to its biologically active free acid. The travoporst free acid is potent and highly selective for the FP prostanoid receptor.

Chemical structure for travoprost

Travoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a synthetic prostaglandin analog (or more specifically, an analog of prostaglandin F_2α)^[1]^[2] that works by increasing the outflow of aqueous fluid from the eyes.^[3] It is also known by the brand names of Travatan and Travatan Z, manufactured by Alcon, and Travo-Z, manufactured by Micro Labs.

Travoprost is a synthetic prostaglandin F analogue. Its chemical name is [1R-[lα(Z),2β(lE,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1 -butenyl]cyclopentyl]-5-heptenoic acid, 1 -methylethylester. It has a molecular formula of C₂₆H₃₅F₃O₆ and a molecular weight of 500.55. The chemical structure of travoprost is:

TRAVATAN®<br /><br /><br /><br />
(travoprost) Structural Formula Illustration

Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water.

TRAVATAN® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 6.0 and an osmolality of approximately 290 mOsmol/kg.

TRAVATAN® contains Active: travoprost 0.04 mg/mL; Preservative: benzalkonium chloride 0.15 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, tromethamine, boric acid, mannitol, edetate disodium, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.

Country	Patent Number	Approved	Expires (estimated)
Canada	2181172	2003-04-29	2015-12-19
Canada	2129287	2002-05-14	2014-08-02
United States	5631287	1994-12-22	2014-12-22
United States	6503497	1995-05-06	2012-05-06

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Side effects

Possible side effects of this medication are:

May cause blurred vision
May cause eyelid redness
May permanently darken eyelashes
May cause eye discomfort
May eventually cause permanent darkening of the iris to brown (heterochromia)
May cause a temporary burning sensation during use
May cause thickening of the eyelashes
May cause inflammation of the prostate gland, restricting urine flow (BPH)

Travoprost
Systematic (IUPAC) name

propan-2-yl 7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-but-1-enyl]-cyclopentyl]hept-5-enoate
Clinical data
Trade names	Travatan
AHFS/Drugs.com	monograph
MedlinePlus	a602027
Pregnancy cat.	C US
Legal status	Rx only (US)
Routes	Topical (eye drops)
Identifiers
CAS number	157283-68-6
ATC code	S01EE04
PubChem	CID 5282226
DrugBank	DB00287
ChemSpider	4445407
UNII	WJ68R08KX9

Chemical data
Formula	C₂₆H₃₅F₃O₆
Mol. mass	500.548 g/mol

The condensation of 2- [3- (trifluoromethyl) phenoxy] acetyl chloride (I) with methylphosphonic acid dimethyl ester (II) by means of BuLi in THF gives 2-oxo-3- [3- (trifluoromethyl) phenoxy] propylphosphonic acid dimethyl ester (III), which is condensed with the known bicyclic aldehyde (IV) by means of BuLi in dimethoxyethane, yielding the unsaturated ketone (V). The reduction of (V) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (VI), which is treated with K2CO3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (VII). The protection of (VII) with dihydropyran and TsOH in dichloromethane provides the bis (tetrahydropyranyl) ether (VIII), which by reduction of the lactone ring with diisobutylaluminum hydride in THF gives the lactol (IX). The condensation of (IX) with the phosphonium bromide (X) by means of NaH in DMSO yields the prostenoic acid (XI), which is esterified with isopropyl iodide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) in acetone to afford the corresponding isopropyl ester (XII). Finally, this compound is deprotected with acetic acid in hot THF / water.

http://www.chemdrug.com/databases/8_0_qkvreurfepijmjcf.html

…………………………………………..

Org Process Res Dev2002,6, (2): 138

http://pubs.acs.org/doi/abs/10.1021/op010097p

A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer−Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

(5Z,13E)–(9S,11R,15R)-9,11,15-Trihydroxy-16-(m-trifluoromethylphenoxy-17,18,19,20-tetranor-5,13-prostadienoic Acid, Isopropyl Ester (2).

The silyl-protected compound (20a+b) (202 g, 277 mmol) ………..DELETED……………………………………… All relevant fractions were combined and concentrated to give the title compound 2 (97 g, 70%) as a colourless oil, +14.6 (c 1.0, CH₂Cl₂); IR ν_max (film) 3374 and 1727 cm^–¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (1H, t, J = 8), 7.22 (1H, d, J = 8), 7.15 (1H, s), 7.08 (1H, d, J = 8), 5.70 (2H, m), 5.40 (2H, m), 4.98 (1H, heptet, J = 6.5), 4.52 (1H, m), 4.18 (1H, m), 3.97 (3H, m), 3.25 (2H, br s), 2.60 (1H, br s), 2.38 (1H, m), 2.30−1.96 (7H, m), 1.76 (1H, dd, J = 16, 4), 1.65 (2H, quintet, J = 7), 1.55 (1H, m), and 1.20 (6H, d, J = 6); ¹³C NMR (100 MHz, CDCl₃) δ 173.57, 158.67, 135.45, 131.87 (q, J = 32), 130.02, 129.85, 129.75, 128.93, 123.89 (q, J = 270), 118.06, 117.82, 111.48, 77.77, 72.70, 71.99, 70.86, 67.72, 55.82, 50.24, 42.84, 34.00, 26.60, 25.48, 24.83, and 21.81; m/z (CI) 501 (MH⁺, 21), 321 (34), 303 (44), and 249 (100).

…………………………………………

http://www.google.com/patents/EP2495235A1?cl=en

In the case of Travoprost, compound 9 with A=3-(trifluoromethyl)phenoxy (in the following scheme, compound 9b) is converted into 10b, which in turn is converted into Travoprost by esterification of the carboxylic acid by reaction with 2-iodopropane, according to scheme 10:

……………………………

http://www.google.com/patents/EP2454227A1?cl=en

Example 2

Synthesis of Travoprost MTBE MTBE

9b-iso

Travoprost Scheme 4. Synthesis of Travoprost

References

Alcon Laboratories, Inc. (September 2011). “TRAVATAN – travoprost solution”. DailyMed. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.
Alcon Laboratories, Inc. (September 2011). “TRAVATAN Z (travoprost) solution”. DailyMed. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.
AHFS Consumer Medication Information (2011-01-01). “Travoprost Ophthalmic”. MedlinePlus. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.

More References:

Selective FP prostaglandin receptor agonist. Isopropyl ester of (+)-fluprostenol, q.v. General prepn (not claimed): J. W. Stjernschantz, EP 364417 (1989 to Pharmacia).

Large scale synthesis: L. T. Boulton et al., Org. Process Res. Dev. 6, 138 (2002).

Pharmacology: M. R. Hellberg et al., J. Ocul. Pharmacol. Ther. 17, 421 (2001).

LC/MS/MS determn in plasma: B. A. McCue et al., J. Pharm. Biomed. Anal. 28, 199 (2002). Ocular hypotensive effects in dogs: A. B. Carvalho et al., Vet. Ophthalmol. 9, 121 (2006).

Clinical trial in glaucoma or ocular hypertension: R. L. Fellman et al., Ophthalmology 109, 998 (2002); in combination with timolol: J. S. Schuman et al., Am. J. Ophthalmol. 140, 242-250 (2005).

Ota T, Aihara M, Narumiya S, Araie M: The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4159-63. PubMed: 16249494

Thieme H, Schimmat C, Munzer G, Boxberger M, Fromm M, Pfeiffer N, Rosenthal R: Endothelin antagonism: effects of FP receptor agonists prostaglandin F2alpha and fluprostenol on trabecular meshwork contractility. Invest Ophthalmol Vis Sci. 2006 Mar;47(3):938-45. PubMed: 16505027

Lim KS, Nau CB, O’Byrne MM, Hodge DO, Toris CB, McLaren JW, Johnson DH: Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study. Ophthalmology. 2008 May;115(5):790-795.e4. PubMed: 18452763

Neacsu AM: [Receptors involved in the mechanism of action of topical prostaglandines] Oftalmologia. 2009;53(2):3-7. PubMed: 19697832

Costagliola C, dell’Omo R, Romano MR, Rinaldi M, Zeppa L, Parmeggiani F: Pharmacotherapy of intraocular pressure – part II. Carbonic anhydrase inhibitors, prostaglandin analogues and prostamides. Expert Opin Pharmacother. 2009 Dec;10(17):2859-70. PubMed: 19929706

Ferrari G, Scagliotti GV: Serum and urinary vascular endothelial growth factor levels in non-small cell lung cancer patients. Eur J Cancer. 1996 Dec;32A(13):2368-9. PubMed: 9038626

Toris CB, Gabelt BT, Kaufman PL: Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction. Surv Ophthalmol. 2008 Nov;53 Suppl1:S107-20. PubMed: 19038618

Arranz-Marquez E, Teus MA: Prostanoids for the management of glaucoma. Expert Opin Drug Saf. 2008 Nov;7(6):801-8. PubMed: 18983226

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. PubMed: 11752352

Common drugs adversely impair older adults ability to feed and dress oneself

August 1, 2014 1:17 am / Leave a comment

CLINICALNEWS.ORG

Public Release: 31-Jul-2014

Common drugs adversely impair older adults’ physical as well as cognitive functioning

INDIANAPOLIS — A class of medications previously linked to cognitive impairment in older adults also appears to negatively affect their physical functioning according to investigators from the Regenstrief Institute, the Indiana University Center for Aging Research, the University of East Anglia and several other United Kingdom institutions.

In a systemic review of more than a decade of studies on the effects of drugs with anticholinergic properties, they report that these drugs have a significant adverse effect on both cognitive and physical functioning, including the ability to feed and dress oneself. Anticholinergic medications affect the brain by blocking acetylcholine, a nervous system neurotransmitter. They are sold over the counter as sleep aids and bladder leakage preventives and prescribed for many diseases including hypertension and congestive heart failure.

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