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New paper on Trelagliptin succinate
Trelagliptin succinate, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, was approved for the Japanese market on March 26, 2015
Trelagliptin exhibited a better potency against human DPP-4 than alogliptin and sitagliptin, along with its excellent selectivity and slow-binding properties that may partially contribute to its sustained efficacy. In phase III clinical studies, once-weekly oral trelagliptin provided long-term safety and efficacy in both monotherapy and combination with other antidiabetic medicines and was proved to be noninferior to its analogue alogliptin used once daily.
2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile Monosuccinate (1)
Synthesis of Trelagliptin Succinate
An improved process for the synthesis of antidiabetic drug trelagliptin succinate through unprotected (R)-3-aminopiperidine was described. The impurity profile with different conditions of the key substitution was illustrated, and then the best reaction condition was identified. The optimizations also included the bromination of 4-fluoro-2-methylbenzonitrile so that the process became efficient and concise.
- 1.
Zhang, Z.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.; Lee, B.; Aertgeerts, K.; Jennings, A.; Xu, R.; Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb, D. R.; Gwaltney, S. L.J. Med. Chem. 2011, 54, 510– 524, DOI: 10.1021/jm101016w
- 2.
Feng, J.; Gwaltney, S. L.; Dipeptidyl Peptidase Inhibitors. PCT Int. Appl. WO 2005095381, October 13, 2005.
- 3.
Grimshaw, C. E.; Jennings, A.; Kamran, R.; Ueno, H.; Nishigaki, N.; Kosaka, T.; Tani, A.; Sano, H.; Kinugawa, Y.; Koumura, E.; Shi, L.; Takeuchi, K. PLoS One 2016, 11, e0157509, DOI: 10.1371/journal.pone.0157509
4.
- 4.
Inagaki, N.; Onouchi, H.; Maezawa, H.; Kuroda, S.; Kaku, K. Lancet Diabetes Endocrinol.2015, 3, 191– 197, DOI: 10.1016/S2213-8587(14)70251-7
- 5.
Inagaki, N.; Sano, H.; Seki, Y.; Kuroda, S.; Kaku, K. J.Diabetes Investig. 2016, 7, 718– 726, DOI: 10.1111/jdi.12499
6.
Feng, J.; Gwaltney, S. L.; Dipeptidyl Peptidase Inhibitors. PCT Int. Appl. WO 2007035629, March 29, 2007.
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NEW DRUG APPROVALS BLOG HITS 16 LAKH VIEWS IN 213 COUNTRIES
NEW DRUG APPROVALS BLOG HITS 16 LAKH VIEWS IN 213 COUNTRIES
Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor
- Approved based on a first-line Phase III trial that met its primary endpoint of progression-free survival (PFS) at interim analysis due to superior efficacy compared to letrozole alone[1]
- At this interim analysis, Kisqali plus letrozole reduced risk of disease progression or death by 44% over letrozole alone, and demonstrated tumor burden reduction with a 53% overall response rate[1]
- Kisqali plus letrozole showed treatment benefit across all patient subgroups regardless of disease burden or tumor location[1]
- At a subsequent analysis with additional follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]
Basel, March 13, 2017 – The US Food and Drug Administration (FDA) has approved Kisqali®(ribociclib, formerly known as LEE011) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer.
Kisqali is a CDK4/6 inhibitor approved based on a first-line Phase III trial that met its primary endpoint early, demonstrating statistically significant improvement in progression-free survival (PFS) compared to letrozole alone at the first pre-planned interim analysis[1]. Kisqali was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs.
“Kisqali is emblematic of the innovation that Novartis continues to bring forward for people with HR+/HER2- metastatic breast cancer,” said Bruno Strigini, CEO, Novartis Oncology. “We at Novartis are proud of the comprehensive clinical program for Kisqali that has led to today’s approval and the new hope this medicine represents for patients and their families.”
The FDA approval is based on the superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus an aromatase inhibitor, letrozole, reduced the risk of progression or death by 44 percent over letrozole alone (median PFS not reached (95% CI: 19.3 months-not reached) vs. 14.7 months (95% CI: 13.0-16.5 months); HR=0.556 (95% CI: 0.429-0.720); p<0.0001)[1].
More than half of patients taking Kisqali plus letrozole remained alive and progression free at the time of interim analysis, therefore median PFS could not be determined[1]. At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]. Overall survival data is not yet mature and will be available at a later date.
“In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer,” said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator. “These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer.”
Kisqali is taken with or without food as a once-daily oral dose of 600 mg (three 200 mg tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor[1].
Breast cancer is the second most common cancer in American women[3]. The American Cancer Society estimates more than 250,000 women will be diagnosed with invasive breast cancer in 2017[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[4].
Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Kisqali patient support program is available to help guide eligible patients through the various aspects of getting started on treatment, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options. For more information, patients and healthcare professionals can call 1-800-282-7630.
The full prescribing information for Kisqali can be found at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).
About Kisqali® (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.
Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.
About the MONALEESA Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7, that are evaluating Kisqali in multiple endocrine therapy combinations across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy.
About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.
Kisqali® (ribociclib) Important Safety Information
Kisqali® (ribociclib) can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their healthcare provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their healthcare provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their healthcare provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their healthcare provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their healthcare provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) of Kisqali when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the Kisqali + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.
Please see the Full Prescribing Information for Kisqali, available at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).
About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.
Novartis is on Twitter. Sign up to follow @Novartis and @NovartisCancer at http://twitter.com/novartis(link is external) and http://twitter.com/novartiscancer (link is external)
For Novartis multimedia content, please visit www.novartis.com/news/media-library
For questions about the site or required registration, please contact media.relations@novartis.com
References
[1] Kisqali (ribociclib) Prescribing information. East Hanover, New Jersey, USA: Novartis Pharmaceuticals Corporation; March 2016.
[2] Novartis Data on File
[3] American Cancer Society. How Common Is Breast Cancer? Available at https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html(link is external). Accessed January 23, 2017.
[4] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(Suppl 3):20-29.
рибоциклиб , ريبوسيكليب , 瑞波西利
Ribociclib « New Drug Approvals
////////////////Novartis, Kisqali®, ribociclib, LEE011, FDA 2017, HR+/HER2- metastatic breast cancer, рибоциклиб , ريبوسيكليب , 瑞波西利
GDC 0994, Ravoxertinib
GDC 0994
GDC-0994; Ravoxertinib; 1453848-26-4; GDC0994; UNII-R6AXV96CRH; R6AXV96CRH, RG7842; RG-7842; RG 7842
CAS 1453848-26-4
1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one
| Molecular Formula: | C21H18ClFN6O2 |
|---|---|
| Molecular Weight: | 440.863 g/mol |
PHASE 1
Ravoxertinib also known as GDC-0994 and RG7842, is an orally available inhibitor of extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon oral administration, GDC-0994 inhibits both ERK phosphorylation and activation of ERK-mediated signal transduction pathways. This prevents ERK-dependent tumor cell proliferation and survival. The mitogen-activated protein kinase (MAPK)/ERK pathway is upregulated in a variety of tumor cell types and plays a key role in tumor cell proliferation, differentiation and survival.
GDC-0994 is an ERK inhibitor invented by Array under a collaboration agreement with Genentech. Array has received certain clinical milestones and is entitled to additional potential clinical and commercial milestones and royalties on product sales under the agreement. ERK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers. GDC-0994 is currently advancing in a Phase 1 trial in patients with solid tumors.
| Applicants: | ARRAY BIOPHARMA INC. [US/US]; 3200 Walnut Street Boulder, Colorado 80301 (US). GENENTECH, INC. [US/US]; 1 DNA Way South San Francisco, California 94080-4990 (US) |
| Inventors: | BLAKE, James F.; (US). CHICARELLI, Mark Joseph; (US). GARREY, Rustam Ferdinand; (US). GAUDINO, John; (US). GRINA, Jonas; (US). MORENO, David A.; (US). MOHR, Peter J.; (US). REN, Li; (US). SCHWARZ, Jacob; (US). CHEN, Huifen; (US). ROBARGE, Kirk; (US). ZHOU, Aihe; (US) |
- OriginatorArray BioPharma
- DeveloperGenentech
- ClassAntineoplastics; Small molecules
- Mechanism of ActionExtracellular signal-regulated MAP kinase inhibitors; Mitogen activated protein kinase 3 inhibitors; Mitogen-activated protein kinase 1 inhibitors
- Phase ISolid tumours
Most Recent Events
- 29 Nov 2016Pharmacodynamics data from a preclinical trial in Solid tumours presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2016)
- 29 Nov 2016Adverse events, efficacy, pharmacokinetics and pharmacodynamics data from a phase I trial in Solid tumours presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
- 16 Jul 2016No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy, Second-line therapy or greater) in USA
FREE FORM
(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one,
GDC-0994 benzenesulfonate salt
CAS 1817728-45-2, C21 H18 Cl F N6 O2 . C6 H6 O3 S
GDC-0994 as a light yellow solid,
mp 197.7 °C;
1H NMR (600 MHz, DMSO-d6): 9.93, (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 7.27 Hz, 1H), 7.63 (m, 2H), 7.62 (d, J = 1.5 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.44 (dd, J = 10.6, 1.9 Hz, 1H), 7.33 (m, 3H), 7.18 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 7.3, 2.1 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 5.99 (dd, J = 8.1, 5.5 Hz, 1H), 4.17 (dd, J = 11.9, 8.2 Hz, 1H), 4.05 (dd, J = 11.9, 5.5 Hz, 1H), 3.78 (s, 3H).
13C NMR (150 MHz, DMSO-d6): 161.60, 161.14, 160.02, 159.79, 157.02 (d, J = 245 Hz), 148.0, 146.49, 139.53 (d, J = 6.0 Hz), 139.04, 136.96, 136.39, 130.66, 128.42, 127.59, 125.38, 124.99 (d, J = 3.0 Hz), 118.72 (d, J = 18.0 Hz), 117.29, 116.05 (d, J = 22.5 Hz), 109.75, 102.79, 98.77, 60.64, 58.68, 35.29.
19F NMR (282 MHz, DMSO-d6) −115.86 (dd, J = 10.6, 7.8).
HRMS calcd for C21H18ClFN6O2 [M + H] 441.1242, found 441.1245.
PATENT
Example 39
(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one
[00398] Step A: (S)-1-(2-(tert-Butyldimethylsiloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridine-2(1H)-one (47 mg, 0.087 mmol), 2-methyl pyrazole-3 -amine (0.175 mmol, 2.0 equivalents) and anhydrous DMF (3.0 mL) were added to a 25 mL round bottomed flask equipped with a stirring bar. The flask was capped with a rubber septum and flushed with nitrogen. Under a blanket of nitrogen, sodium hydride (8.5 mg, 60% dispersion in mineral oil) was added in one portion. The flask was flushed with
nitrogen, capped and stirred at room temperature. The reaction progress was monitored by LCMS, and after 30 minutes, the starting material was consumed. The reaction mixture was quenched by the addition of water (0.5 mL) and ethyl acetate (15 mL). The contents of the round bottomed flask were transferred to a 125 mL separatory funnel, and the reaction flask was rinsed several times with additional ethyl acetate. Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one was partitioned between ethyl acetate and water (80 mL/30 mL). The ethyl acetate layer was washed once with brine, dried (MgSO4), filtered and concentrated to give crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one. The crude was taken directly into the deprotection step.
[00399] Step B: Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (48 mg) was dissolved in ethyl acetate (4 mL) and treated dropwise slowly (over 2 minutes) with an ethyl acetate solution (1.0 mL, which had been saturated with HCl gas). The reaction stirred at room temperature for 15 minutes, after which time LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated to an oily residue and purified by prep RP HPLC to yield (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20.8 mg, 54.6% yield) as a lyophilized powder. 1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.91 (t, J = 9.0 Hz, 1H),7.58 (t, J = 8.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 10.7,5.1 Hz 2H), 6.86 (dd, J = 7.3, 1.8 Hz, 1H), 6.27(d, J = 1.7 Hz, 1H), 5.97 (dd, J = 7.7, 5.7 Hz, 1H), 5.31(t, J = 5.2 Hz, 1H), 4.15 (m, 1H), 4.10-3.95 (m,1H), 3.69 (s, 3H); LCMS m/z 441 (M+H)+.
PAPER
Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development
The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.
PATENT
WO 2015154674
https://www.google.com/patents/WO2015154674A1?cl=pt
(a) contacting 4-bromo-1-chloro-2-fluorobenzene with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 2-chloro-N-methoxy-N-methylacetamide to afford 2-chloro-1- (4-chloro-3-fluorophenyl) ethanone (II) ；
(b) contacting II with sodium formate and formic acid in aqueous ethanol to afford 1- (4-chloro-3-fluorophenyl) -2-hydroxyethanone (III)
(c) contacting III with a ketoreductase to afford (R) -1- (4-chloro-3-fluorophenyl) ethane-1, 2-diol (IV) ；
(d) contacting IV with a silyl chloride (Ra) 3SiCl and at least one base in a non-polar aprotic solvent to afford (V) , and subsequently adding sulfonylchloride RbS (O) 2Cl to afford VI, wherein Ra is independently in each occurrence C1-6 alkyl or phenyl and Rb is selected from C1-4 alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C1-3 alkyl, halogen, nitro, cyano, or C1-3 alkoxy；
(e) contacting 4- (2- (methylsulfonyl) pyrimidin-4-yl) pyridin-2 (1H) -one (VII) with a strong base in an organic solvent and subsequently adding VI to afford XI；
(f) treating XI with an oxidizing agent to afford I；
(g) treating 1-methyl-1H-pyrazol-5-amine with a strong base in an aprotic solvent at reduced temperature and adding the compound of formula I to afford IX； and,
(h) contacting IX with a de-silylating agent to afford VIII.
PAPER
Development of a Practical Synthesis of ERK Inhibitor GDC-0994
, Nicholas Wong†, Hans Iding‡, Vera Jost‡, Haiming Zhang†, Stefan G. Koenig†, C. Gregory Sowell†, and Francis Gosselin†
The process development of a synthetic route to manufacture ERK inhibitor GDC-0994 on multikilogram scale is reported herein. The API was prepared as the corresponding benzenesulfonate salt in 7 steps and 41% overall yield. The synthetic route features a biocatalytic asymmetric ketone reduction, a regioselective pyridone SN2 reaction, and a safe and scalable tungstate-catalyzed sulfide oxidation. The end-game process involves a telescoped SNAr/desilylation/benzenesulfonate salt formation sequence. Finally, the development of the API crystallization allowed purging of process-related impurities, obtaining >99.5A% HPLC and >99% ee of the target molecule.
| Patent ID | Patent Title | Submitted Date | Granted Date |
|---|---|---|---|
| US2016136150 | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK | 2015-11-13 | 2016-05-19 |
| US2016122316 | SERINE/THREONINE KINASE INHIBITORS | 2016-01-12 | 2016-05-05 |
| US2015111869 | USE OF A COMBINATION OF A MEK INHIBITOR AND AN ERK INHIBITOR FOR TREATMENT OF HYPERPROLIFERATIVE DISEASES | 2014-08-29 | 2015-04-23 |
| US2015051209 | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK | 2014-08-05 | 2015-02-19 |
| US2014249127 | SERINE/THREONINE KINASE INHIBITORS | 2014-02-14 | 2014-09-04 |
| US8697715 | Serine/threonine kinase inhibitors | 2013-03-01 | 2014-04-15 |
///////////GDC 0994, Ravoxertinib, 1453848-26-4, GDC0994, UNII-R6AXV96CRH, R6AXV96CRH, RG7842, RG-7842, RG 7842, PHASE 1
CN1C(=CC=N1)NC2=NC=CC(=N2)C3=CC(=O)N(C=C3)C(CO)C4=CC(=C(C=C4)Cl)F
TROXACITABINE троксацитабин , تروكساسيتابين , 曲沙他滨 ,
Troxacitabine
CAS 145918-75-8
- Molecular FormulaC8H11N3O4
- Average mass213.191 Da
Hmd-cytosine; NCGC00183848-01; Beta-L-Dioxolane-cytidine; 4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]pyrimidin-2-one; 2R(-)-cis-Hmd-cytosine, (-)-ODDC
4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]pyrimidin-2-one
Troxacitabine (brand name Troxatyl) is a nucleoside analogue with anticancer activity. Its use is being studied in patients with refractory lymphoproliferative diseases.[1]
Troxacitabine (brand name Troxatyl) is a nucleoside analogue with anticancer activity. Its use is being studied in patients with refractory lymphoproliferative diseases.
| Investigated for use/treatment in leukemia (myeloid). |
PATENT
https://www.google.com/patents/WO1992018517A1?cl=en
WO 9218517
| Inventors | Yung-Chi Cheng, Chung K. Chu, Hea O. Kim, Kirupathevy Shanmuganathan |
| Applicant | Yale University, The University Of Georgia Research Foundation, Inc. |
SYNTHESIS
WO 2016030335
PATENT
WO 2016030335
PATENT
MACHINE TRANSLATED FROM CHINESE, BEAWARE OF FUNNY NAMES
PATENT
PATENT
CN 105503838
PAPER
In vitro optimization of non-small cell lung cancer activity with troxacitabine, L-1,3-dioxolane-cytidine, prodrugs
Journal of medicinal chemistry (2007), 50, (9), 2249-53.
l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N4-Substituted fatty acid amide prodrugs of 10−16 carbon chain length demonstrated significantly improved antitumor activity over l-1,3-dioxolane-cytidine. These in vitro results suggest that the in vivo therapeutic efficacy of l-1,3-dioxolane-cytidine against solid tumors may be improved with prodrug strategies.
PAPER
- Kim, Hea O.; Schinazi, Raymond F.; Shanmuganathan, Kirupathevy; Jeong, Lak S.; Beach, J. Warren; Nampalli, Satyanarayana; Cannon, Deborah L.; Chu, Chung K.
- From Journal of Medicinal Chemistry (1993), 36(5), 519-28.
PAPER
- Jin, Haolun; Tse, Allan Tse; Evans, Colleen A.; Mansour, Tarek S.; Beels, Christopher M.; Ravenscroft, Paul; Humber, David C.; Jones, Martin F.; Payne, Jeremy J.; Ramsay, Michael V. J.
- From Tetrahedron: Asymmetry (1993), 4(2), 211-14
PAPER
- Belleau, Bernard R.; Evans, Colleen A.; Tse, H. L. Allan; Jin, Haolun; Dixit, Dilip M.; Mansour, Tarek S.
- From Tetrahedron Letters (1992), 33(46), 6949-52.
PAPER
http://pubs.acs.org/doi/pdf/10.1021/jm00089a007
J. Med. Chem. 1992,35,1987-1995 Asymmetric Synthesis of 1,3-Dioxolane-Pyrimidine Nucleosides and Their Anti-HIV Activity
References
- Jump up^ Vose, Julie M.; Panwalkar, Amit; Belanger, Robert; Coiffier, Bertrand; Baccarani, Michele; Gregory, Stephanie A.; Facon, Thierry; Fanin, Renato; Caballero, Dolores; Ben-Yehuda, Dina; Giles, Francis (2007). “A phase II multicenter study of troxacitabine in relapsed or refractory lymphoproliferative neoplasms or multiple myeloma”. Leukemia & Lymphoma. 48 (1): 39–45. doi:10.1080/10428190600909578.
- Lee CK, Rowinsky EK, Li J, Giles F, Moore MJ, Hidalgo M, Capparelli E, Jolivet J, Baker SD: Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2158-65. [PubMed:16609029 ]
- Quintas-Cardama A, Cortes J: Evaluation of the L-stereoisomeric nucleoside analog troxacitabine for the treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2007 Apr;16(4):547-57. [PubMed:17371201 ]
- Swords R, Giles F: Troxacitabine in acute leukemia. Hematology. 2007 Jun;12(3):219-27. [PubMed:17558697 ]
- Orsolic N, Giles FJ, Gourdeau H, Golemovic M, Beran M, Cortes J, Freireich EJ, Kantarjian H, Verstovsek S: Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation. Br J Haematol. 2004 Mar;124(6):727-38. [PubMed:15009060 ]
- Boivin AJ, Gourdeau H, Momparler RL: Action of troxacitabine on cells transduced with human cytidine deaminase cDNA. Cancer Invest. 2004;22(1):25-9. [PubMed:15069761 ]
- Kim TE, Park SY, Hsu CH, Dutschman GE, Cheng YC: Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines. Mol Pharmacol. 2004 Aug;66(2):285-92. [PubMed:15266019 ]
| Patent ID | Patent Title | Submitted Date | Granted Date |
|---|---|---|---|
| US2013011392 | METHOD FOR ASSESSING THE ABILITY OF A PATIENT TO RESPOND TO OR BE SAFELY TREATED BY A NUCLEOSIDE ANALOG BASED-CHEMOTHERAPY | 2010-11-19 | 2013-01-10 |
| US7927613 | Pharmaceutical co-crystal compositions | 2003-09-11 | 2011-04-19 |
| US7790905 | Pharmaceutical propylene glycol solvate compositions | 2003-12-29 | 2010-09-07 |
 |
|
| Identifiers | |
|---|---|
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C8H11N3O4 |
| Molar mass | 213.19 g/mol |
| 3D model (Jmol) | |
//////////////TROXACITABINE, троксацитабин , تروكساسيتابين , 曲沙他滨 , Hmd-cytosineM, NCGC00183848-01, Beta-L-Dioxolane-cytidine, 2R(-)-cis-Hmd-cytosine, (-)-ODDC
Astellas Pharma Inc. new Glucokinase Activator, ASP ? for Type 2 Diabetes
ASP ?
(2R)-2-(4-cyclopropanesulfonyl-3-cyclopropylphenyl)-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(R)-3-oxocyclopentyl]propanamide
- Molecular Weight, 483.58
- [α]D20 −128.7 (c 1.00, MeOH);
- 1H NMR (DMSO-d6, 400 MHz) δ 11.07 (s, 1H), 9.20 (d, J = 1.4 Hz, 1H), 8.41 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 5.52 (t, J = 5.7 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.04 (t, J = 7.6 Hz, 1H), 3.03–2.97 (m, 1H), 2.79 (tt, J = 8.4, 5.1 Hz, 1H), 2.25–1.81 (m, 8H), 1.53–1.47 (m, 1H), 1.17–1.12 (m, 2H), 1.08–1.02 (m, 4H), 0.89–0.84 (m, 2H);
- 13C NMR (DMSO-d6, 101 MHz) δ 218.5, 171.8, 152.1, 147.3, 145.7, 143.2, 140.3, 138.2, 134.8, 129.0, 125.3, 125.1, 62.5, 49.9, 44.4, 38.4, 38.2, 34.8, 32.1, 29.1, 12.4, 10.8, 10.7, 5.8;
- FTIR (ATR, cm–1) 3544, 3257, 1727, 1692, 1546, 1507, 1363, 1285, 1149, 719;
- HRMS (ESI) m/z [M + Na]+ calcd for C25H29N3O5S 506.1726, found 506.1747.
- Anal. Calcd for C25H29N3O5S: C, 62.09; H, 6.04; N, 8.69. Found: C, 61.79; H, 6.19; N, 8.62.
| Inventors | Masahiko Hayakawa, Yoshiyuki Kido, Takahiro Nigawara, Mitsuaki Okumura, Akira Kanai, Keisuke Maki, Nobuaki Amino |
| Applicant | Astellas Pharma Inc. |
Synthesis
contd…………………………..
PATENT
- PAPER
A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C–N Coupling Reaction
, Yasuhiro Morinaga†, Makoto Kasai†, Takao Hashimoto†, Yuji Takahama†, Atsushi Ohigashi†, Satoshi Yonishi‡, and Motohiro Akazome§
Here we describe the research and development of a process for the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C–N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of (R)-1. Moreover, an epimerization process to obtain (R)-7 from the undesired (S)-7 was developed.
Hayakawa, M.; Kido, Y.; Nigawara, T.; Okumura, M.; Kanai, A.; Maki, K.; Amino, N. PCT Int. Appl. WO/2009/091014 A1 20090723,2009.
https://www.astellas.com/en/ir/library/pdf/3q2017_rd_en.pdf
///////////1174229-89-0, ASTELLAS, Glucokinase Activator, TYPE 2 DIABETES, PRECLINICAL, ASP ?, WO 2009091014, Masahiko Hayakawa, Yoshiyuki Kido, Takahiro Nigawara, Mitsuaki Okumura, Akira Kanai, Keisuke Maki, Nobuaki Amino, WO2009091014,
O=C(Nc1cnc(cn1)CO)[C@H](C[C@@H]2CC(=O)CC2)c3ccc(c(c3)C4CC4)S(=O)(=O)C5CC5
FDA approves first treatment Noctiva (Desmopressin acetate) nasal spray for frequent urination at night due to overproduction of urine
Desmopressin acetate
March 3, 2017
The U.S. Food and Drug Administration today approved Noctiva (desmopressin acetate) nasal spray for adults who awaken at least two times per night to urinate due to a condition known as nocturnal polyuria (overproduction of urine during the night). Noctiva is the first FDA-approved treatment for this condition.
“Today’s approval provides adults who overproduce urine at night with the first FDA-approved therapeutic option to help reduce the number of times a night they wake up to urinate,” said Hylton V. Joffe, M.D., M.M.Sc., director of the Division of Bone, Reproductive, and Urologic Products in the FDA’s Center for Drug Evaluation and Research. “It is important to know that Noctiva is not approved for all causes of night-time urination, so patients should discuss their symptoms with their health care provider who can determine the underlying cause of the night-time urination and whether Noctiva is right for them.”
Nocturia (wakening at night to urinate) is a symptom that can be caused by a wide variety of conditions, such as congestive heart failure, poorly controlled diabetes mellitus, medications, or diseases of the bladder or prostate. Before considering Noctiva, health care providers should evaluate each patient for possible causes for the nocturia, and optimize the treatment of underlying conditions that may be contributing to the night-time urination. Because Noctiva is approved only for adults with nocturia caused by nocturnal polyuria, health care providers should confirm overproduction of urine at night with a 24-hour urine collection, if one has not been obtained previously. Health care providers should also be mindful of underlying conditions that can cause nocturia, but that make treatment with Noctiva unsafe, such as excessive drinking of fluids or symptomatic congestive heart failure.
Noctiva is taken daily, approximately 30 minutes before going to bed. It works by increasing the absorption of water through the kidneys, which leads to less urine production.
Noctiva’s efficacy was established in two 12-week, randomized, placebo-controlled trials in 1,045 patients 50 years of age and older with nocturia due to nocturnal polyuria. Although these trials showed a small reduction in the average number of night-time urinations with Noctiva compared to placebo, more patients treated with Noctiva were able to at least halve their number of night-time urinations, and patients treated with Noctiva had more nights with one or fewer night-time urinations.
Noctiva is being approved with a boxed warning and a Medication Guide because it can cause low sodium levels in the blood (hyponatremia). Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest or death. Health care providers should make sure the patient’s sodium level is normal before starting Noctiva, and should check sodium levels within one week and approximately one month after starting treatment and periodically thereafter. The lower Noctiva dose is recommended as the starting dose for those who may be at risk for hyponatremia, such as the elderly. Noctiva should not be used in patients at increased risk of severe hyponatremia, such as those with excessive fluid intake, those who have illnesses that can cause fluid or electrolyte imbalances, certain patients with kidney damage, and in those using certain medicines, known as loop diuretics or glucocorticoids.
Noctiva should also not be used in patients with symptomatic congestive heart failure or uncontrolled hypertension because fluid retention can worsen these underlying conditions. Use of Noctiva should be discontinued temporarily in patients with certain nasal conditions such as colds or allergies until those conditions have resolved.
Noctiva is also not recommended for the treatment of nocturia in pregnant women. Nocturia is usually related to normal changes in pregnancy that do not require treatment with Noctiva. Noctiva should not be used in children.
The most common side effects of Noctiva in clinical trials included nasal discomfort, cold symptoms (nasopharyngitis), nasal congestion, sneezing, high or increased blood pressure, back pain, nose bleeds, bronchitis and dizziness.
Although there are other FDA-approved medications that also contain desmopressin, none of those medications are approved to treat nocturia.
Noctiva is marketed by Milford, Pennsylvania-based Renaissance Lakewood, LLC for Serenity Pharmaceuticals, LLC.
C48H68N14O14S2 C48H68N14O14S2·xH2O
(anhydrous) 
1129.27[62288-83-9].
1-(3-Mercaptopropionic acid)-8-D-arginine-vasopressin monoacetate (salt).
[62357-86-2].
oxopentan-2-yl]-1-[4-(2-amino-2-oxoethyl)-7-(3-amino-3-oxopropyl)-10-benzyl-13-[(4-hydroxyphenyl)methyl]-3,6,9,12,15-pentaoxo-18,19-dithia-2,5,8,11,14-pentazacycloicosane-1-carbonyl]pyrrolidine-2-carboxamide;
Synonyms: 3-MERCAPTOPROPIONYL-TYR-PHE-GLN-ASN-CYS-PRO-D-ARG-GLY-NH2 ACETATE SALT;DDAVP ACETATE;[DEAMINO-CYS1,D-ARG8]-VASOPRESSIN ACETATE SALT;DESMOPRESSIN MONOACETATE;DESMORESSIN ACETATE;Mpr-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2(S-S:1-5);DESMOPRESSIN ACETATE;DESMOPRESSIN ACETATE SALT;
The Molecular Weight of Desmopressin Acetate(62288-83-9): 1129.27
Analytica Chimica Acta (2006), 572, (2), 197-204
Abstract
A monolithic column was prepared using l-phenylalanine as template and a covalent approach through the formation of Schiff base with o-phthalaldehyde (OPA). OPA, allylmercaptan, l-phenylalanine, and triethylamine were stirred at first, then methacrylic acid, 2-vinylpyridine, ethyleneglycol dimethacrylate, α,α-azobisisobutyronitrile, and 1-propanol were added to the reaction mixture. The resulting material was introduced into a capillary column. Following thermal polymerization, the template was then extracted with a mixture of HCl and methanol. The column was employed for the capillary electrochromatographic separation of oligopeptides. A capillary column of 75 (50) cm × 75 μm ID with a mobile phase of phosphate buffer (pH 7.0, 40 mM)/methanol (5%, v/v), an applied voltage of +15 kV, and detection at 214 nm, could baseline separate angiotensin I, angiotensin II, [Sar1, Thr8] angiotensin, oxytocin, vasopressin, tocinoic acid, β-casomorphin bovine, β-casomorphin human, and FMRF amide within 20 min. The separation behavior of the templated polymer was also compared with that of the non-templated polymer. As a result, it can be concluded that the electrochromatographic separation of this set of peptides was mediated by a combination of electrophoretic migration and chromatographic retention involving hydrophobic, hydrogen bonding, electrostatic as well as the Schiff base formation with OPA in the cavity of the templated polymer.
PATENT
CN 101372504
WO 2010119450
IN 2009CH00794
CN 103102395
CN 103467574
CN 105131079
CN 104761619
Desmopressin acetate is a structural analogue of natural arginine vasopressin, which is the result of two changes in the chemical structure of natural hormones. The structure is as follows:
M $ a-Tyr-Phe-Gln-Asn-C such as -Pro-D-Arg-GIy-N
Desmopressin acetate has a good hemostatic effect and does not produce side effects of pressurization. Mainly used to treat central diabetes insipidus, hemophilia and therapeutic control of bleeding and preoperative bleeding prevention. Good results and small side effects.
In the existing synthetic method of desmopressin acetate, liquid phase synthesis to produce more waste, the reaction time is long, each coupling an amino acid need to be purified, post-processing cumbersome, low yield, is not conducive to Industrial production.
Solid phase synthesis method, Chinese Patent CN 101372505, CN103992389 using Sieber Amide Resin or Rink Amide AM Resin one by one coupling to obtain linear peptide resin, and then solid-phase oxidation resin, cleavage and purification of desmopressin acetate. Chinese Patent CN103102395, CN102863513 Using Sieber Amide Resin or Rink AM Resin, linear peptide resin was obtained by coupling one by one, and liquid desulfurization was obtained after lysis to obtain desmopressin.
| Patent ID | Patent Title | Submitted Date | Granted Date |
|---|---|---|---|
| US8765152 | Pharmaceutical or neutraceutical formulation | 2010-02-25 | 2014-07-01 |
| Cited Patent | Filing date | Publication date | Applicant | Title | |
|---|---|---|---|---|---|
| US005726287 | Title not available | ||||
| US005990273 | Title not available | ||||
| US20060276626 | May 2, 2006 | Dec 7, 2006 | Avi Tovi | Methods for the production of peptide derivatives | |
| WO2004092202A1 | Apr 5, 2004 | Oct 28, 2004 | Novetide, Ltd. | Process for production of cyclic peptides |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| CN102863513A * | Sep 12, 2012 | Jan 9, 2013 | 无锡市凯利药业有限公司 | Preparation method of desmopressin acetate |
Ramizol
1,3,5-Tris[(1E)-2′-(4′′-benzoic acid)vinyl]benzene] (Ramizol™)
TSB-007
| Allan James Mckinley, Thomas V Riley, Nigel Lengkeek, Scott Stewart, Ramiz Boulos | |
| Applicant | The University Of Western Australia |
1,3,5-Tris[(1E)-2′-(4′′-benzoic acid)vinyl]benzene] (Ramizol™) is a potent and non-toxic synthetic antimicrobial agent, and we now establish that it is also a potent inhibitor of reactive oxygen species (ROS) generation, with similar antioxidant activity to α-tocopherol (Vitamin E), which is a standard antioxidantdrug.
Ramizol, useful for treating bacterial infections such as Gram positive bacterial infection. Boulos & Cooper Pharmaceuticals could be seen to have ramizol in preclinical development for treating Clostridium difficile associated diseases. preparation of ramizol that was first described by the inventor Dr Ramiz Boulos, one of the company’s founding directors and CEO, in WO2011075766 as TSB-007 (claim 3, page 71) – said family of patenting having been originally assigned to the University of Western Australia and from whom Dr Boulos is reported to have acquired the rights to said intellectual property in late 2012 (ramizol having seemingly been previously being developed by the University with the name NAL-135B for treating Gram positive bacterial infections).
Professor Ramiz Boulos with a vial of Ramizol
A scientific paper released today in the Journal of Antibiotics presents the pre-clinical development of Ramizol®, a first generation drug belonging to a new class of styrylbenzene antibiotics with a novel mechanism of action.
The research was undertaken by Australian company Boulos & Cooper Pharmaceuticals in partnership with the University of South Australia, Flinders University, Eurofins Panlabs and Micromyx LLC. The study found that over 99.9% of the drug, administered orally, stays in the gastrointestinal tract where it can reach the bacteria in the colon at high enough concentrations to yield a therapeutic effect.
Chief Executive Officer of Boulos & Cooper Pharmaceuticals, Dr Ramiz Boulos, said “this new class of antibiotics has antioxidant properties and can be manufactured for a low cost; benefits that will be felt by the end-user”.
The new antibiotic has low frequency of resistance and shows promise as a monotherapy for the treatment of Clostridium difficile associated disease. Dr Boulos stated “we are very excited about these results given the unforgiving nature of Clostridium difficile infections”. He added “In a world where there are few treatment options, we are desperate for new antibiotics to fight intractable infections”.
The company expects to start Phase I clinical trials in 2017.
1,3,5-Tris[(1E)-20 -(400-benzoic acid)vinyl]benzene……………….recrystallised from THF/H2O and dried to give the triacid as a pale brown powder.
1 H NMR (500.1 MHz, d6-DMSO): d 7.49 (m, 6H, vinyl CH), 7.76 (d, J 8.5, 6H, ArH), 7.88 (s, 3H, core ArH), 7.98 (d, J 8.5, 6H, ArH);
13C NMR (125.8 MHz, d6-DMSO): d [ppm] 125.0, 126.5, 128.4, 129.7, 129.9, 130.50, 137.6, 141.3, 167.1;
IR (KBr): n [cm1 ] 3067, 3026, 1684 (nC¼O), 1604, 1566, 1420, 1384, 1312, 1286, 1179;
HR-EIþ-MS: C33H24O6 requires 516.1573 amu, found 516.1564;
EIþ-MS: MI ¼ C33H24O6; m/z: 516.1 (100%) ¼ MIþ, 472.1 (11.3%) ¼ [MI CO2] þ.
The Synthesis of Fluorescent DNA Intercalator Precursors through Efficient Multiple Heck Reactions
Nigel A. Lengkeek A , Ramiz A. Boulos A , Allan J. McKinley A , Thomas V. Riley C , Boris Martinac B and Scott G. Stewart A D
A M313, Chemistry, School of Biomedical, Biomolecular and Chemical Science, University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.
B Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia.
C M502, Microbiology and Immunology, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Hwy, Nedlands, WA 6009, Australia.
D Corresponding author. Email: sgs@cyllene.uwa.edu.au
Australian Journal of Chemistry 64(3) 316-323 http://dx.doi.org/10.1071/CH10374
PATENT
PATENT
WO-2017027933
Compounds with antimicrobial properties have attracted great interest in recent times as a result of an increase in the prevalence of infections caused by Gram-positive bacteria, resulting in serious or fatal diseases. Furthermore, the regular use of broad spectrum antibiotic formulas has led to the increased occurrence of bacterial strains resistant to some antimicrobial formulations.
Novel antimicrobial compounds have the potential to be highly effective against these types of treatment-resistant bacteria. The pathogens, having not previously been exposed to the antimicrobial formulation, may have little to no resistance to the treatment.
International patent application WO 2012/075766 describes a series of novel aryl compounds and their use as antimicrobials to treat bacterial infections or diseases. The chemical synthesis of a therapeutic drug has a direct effect on its cost, dosing regimens and popularity. Drugs with complicated or expensive chemical synthesis will find it challenging to reach the market, notwithstanding their efficacy. Further, syntheses amenable to application at commercial scales are highly advantageous. The development of an efficient and large-scale synthesis of a therapeutic drug is critical for its drug developmental pathway, and highly commercially advantageous.
1H NMR PREDICT
13C NMR PREDICT
REFERENCES
N. A. Lengkeek, R. A. Boulos, A. J. McKinley, T. V. Riley, B. Martinac and S. G. Stewart, Aust. J. Chem., 2011, 64, 316–323
http://pubs.rsc.org/en/content/articlehtml/2013/ra/c3ra40658j#cit11
/////////////Ramizol, PHASE 1, TSB-007
OC(=O)c4ccc(/C=C/c3cc(/C=C/c1ccc(cc1)C(=O)O)cc(/C=C/c2ccc(cc2)C(=O)O)c3)cc4
Oxymetazoline, оксиметазолин , أوكسيميتازولين , 羟甲唑啉
Oxymetazoline
1491-59-4 CAS NUMBER
- Molecular FormulaC16H24N2O
- Average mass260.375 Da
Oxymetazoline is a selective α1 adrenergic receptor agonist and α2 adrenergic receptorpartial agonist. It is a topical decongestant, used in the form of oxymetazoline hydrochloride. It was developed from xylometazoline at E. Merck Darmstadt by Fruhstorfer in 1961.[1]Oxymetazoline is generally available as a nasal spray.
Oxymetazoline HCl; CAS 2315-02-8
Oxymetazoline hydrochloride is a vasoconstrictor. Chemically it is 3-[(4,5-dihydro-1H-imidazol-2-yl)methyl]6-(1,1,-dimethylethyl)-2,4-dimethylphenolmono-hydrochloride. Its molecular weight is 296.8 for the hydrochloride salt and 260.4 for the free base. It is freely soluble in water and ethanol and has a partition coefficient of 0.1 in octanol/water. Its structural formula is:
 |
Medical uses
Oxymetazoline is available over-the-counter as a topical decongestant in the form of oxymetazoline hydrochloride in nasal sprays such as Afrin, Operil, Dristan, Dimetapp, oxyspray, Facimin, Nasivin, Nostrilla, Sudafed OM, Vicks Sinex, Zicam, SinuFrin, and Mucinex Full Force.[2]
Due to its vasoconstricting properties, oxymetazoline is also used to treat nose bleeds[3][4]and eye redness due to minor irritation (marketed as Visine L.R. in the form of eye drops).[5]
Company:
Allergan
Approval Status:
Approved January 2017
Specific Treatments:
facial erythema associated with rosacea
Therapeutic Areas
Dermatology
Find Related Trials for The Following Conditions
Rosacea
General Information
Rhofade (oxymetazoline hydrochloride) is an alpha1A adrenoceptor agonist. Oxymetazoline acts as a vasoconstrictor.
Rhofade is spccifically indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.
Rhofade is supplied as a cream for topical administration. Apply a pea-sized amount of Rhofade cream, once daily in a thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. Wash hands immediately after applying Rhofade cream.
Side effects and special considerations
Rebound congestion
It is recommended that oxymetazoline not be used for more than three days, as rebound congestion, or rhinitis medicamentosa, may occur.[6] Patients who continue to use oxymetazoline beyond this point may become dependent on the medication to relieve their chronic congestion.
Effects of benzalkonium chloride
Some studies have found that benzalkonium chloride, a common additive to oxymetazoline nasal sprays, may damage nasal epithelia and exacerbate rhinitis medicamentosa. However, the majority of studies find benzalkonium chloride to be a safe preservative.[7]
Use in pregnancy
The Food and Drug Administration places oxymetazoline in category C, indicating risk to the fetus cannot be ruled out. While it has been shown that a single dose does not significantly alter either maternal or fetal circulation,[8] this subject has not been studied extensively enough to draw reliable conclusions.
Overdose
If accidentally ingested, standard methods to remove unabsorbed drugs should be considered.[clarification needed] There is no specific antidote for oxymetazoline, although its pharmacological effects may be reversed by α adrenergic antagonists such as phentolamine. In the event of a possibly life-threatening overdose (such as a hypertensive crisis), benzodiazepines should be considered to decrease the likelihood of seizures and convulsions, as well as reduce anxiety and to lower blood pressure. In children, oxymetazoline may produce profound central nervous system depression due to stimulation of central α2receptors and imidazoline receptors, much like clonidine.
Pharmacology
Mechanism of action
Oxymetazoline is a sympathomimetic that selectively agonizes α1 and, partially, α2 adrenergic receptors.[9] Since vascular beds widely express α1 receptors, the action of oxymetazoline results in vasoconstriction. In addition, the local application of the drug also results in vasoconstriction due to its action on endothelial postsynaptic α2 receptors; systemic application of α2 agonists, in contrast, causes vasodilation because of centrally-mediated inhibition of sympathetic tone via presynaptic α2 receptors.[10] Vasoconstriction of vessels results in relief of nasal congestion in two ways: first, it increases the diameter of the airway lumen; second, it reduces fluid exudation from postcapillary venules.[11] It can reduce nasal airway resistance (NAR) up to 35.7% and nasal mucosal blood flow up to 50%.[12]
Pharmacokinetics
Imidazolines are sympathomimetic agents, with primary effects on α adrenergic receptors and little if any effect on β adrenergic receptors. Oxymetazoline is readily absorbed orally. Effects on α receptors from systemically absorbed oxymetazoline hydrochloride may persist for up to 7 hours after a single dose. The elimination half-life in humans is 5–8 hours. It is excreted unchanged both by the kidneys (30%) and in feces (10%).
History
The oxymetazoline brand Afrin was first sold as a prescription medication in 1966. After finding substantial early success as a prescription medication, it became available as an over-the-counter drug in 1975. Schering-Plough did not engage in heavy advertising until 1986.[13]From the late 1980s to mid 1990s, Afrin featured in many notable television advertisements. Some of these commercials showed men, women, and children using other brands of nasal sprays, and then standing upside down or hanging upside down from playground equipment to prevent their nasal spray from dripping out. This was juxtaposed with Afrin users having no problems.
Society and culture
Brand names
Brand names include Afrin, Dristan, Nasivin, Nezeril, Nostrilla, Logicin, Vicks Sinex, Visine L.R., Sudafed OM, Zicam, SinuFrin and Mucinex Sinus-Max.
References
- Jump up^ German Patent 1,117,588
- Jump up^ “Oxymetazoline: Drug Information Provided by Lexi-Comp: Merck Manual Professional”. Merck.com. Retrieved 2013-04-15.
- Jump up^ Katz, Robert I.; Hovagim, Alec R.; Finkelstein, Harvey S.; Grinberg, Yair; Boccio, Remigio V.; Poppers, Paul J. (1990). “A comparison of cocaine, lidocaine with epinephrine, and oxymetazoline for prevention of epistaxis on nasotracheal intubation”. Journal of Clinical Anesthesia. 2 (1): 16–20. doi:10.1016/0952-8180(90)90043-3. PMID 2310576.
- Jump up^ Krempl, G. A.; Noorily, A. D. (1995). “Use of oxymetazoline in the management of epistaxis”. The Annals of otology, rhinology, and laryngology. 104 (9 Pt 1): 704–6.PMID 7661519.
- Jump up^ “VISINE® Original Red Eye Drops | VISINE® products”. Visine.com. Retrieved2013-04-15.
- Jump up^ Ramey, J. T.; Bailen, E; Lockey, R. F. (2006). “Rhinitis medicamentosa”. Journal of investigational allergology & clinical immunology. 16 (3): 148–55. PMID 16784007.
- Jump up^ Marple, B; Roland, P; Benninger, M (2004). “Safety review of benzalkonium chloride used as a preservative in intranasal solutions: An overview of conflicting data and opinions”. Otolaryngology – Head and Neck Surgery. 130 (1): 131–41.doi:10.1016/j.otohns.2003.07.005. PMID 14726922.
- Jump up^ Rayburn, W. F.; Anderson, J. C.; Smith, C. V.; Appel, L. L.; Davis, S. A. (1990).“Uterine and fetal Doppler flow changes from a single dose of a long-acting intranasal decongestant”. Obstetrics and gynecology. 76 (2): 180–2. PMID 2196495.
- Jump up^ Westfall Thomas C, Westfall David P, “Chapter 6. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems” (Chapter). Brunton LL, Lazo JS, Parker KL: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11e: http://www.accessmedicine.com/content.aspx?aID=954433.
- Jump up^ Biaggioni Italo, Robertson David, “Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs” (Chapter). Katzung BG: Basic & Clinical Pharmacology, 11e: http://www.accessmedicine.com/content.aspx?aID=4520412.
- Jump up^ Widdicombe, John (1997). “Microvascular anatomy of the nose”. Allergy. 52 (40 Suppl): 7–11. doi:10.1111/j.1398-9995.1997.tb04877.x. PMID 9353554.
- Jump up^ Bende, M.; Löth, S. (2007). “Vascular effects of topical oxymetazoline on human nasal mucosa”. The Journal of Laryngology & Otology. 100 (3): 285–8.doi:10.1017/S0022215100099151. PMID 3950497.
- Jump up^ Dougherty, Phillip H. (20 October 1986). “Advertising; Afrin Goes After Users Of Nasal Decongestants”. The New York Times. The New York Times Company. Retrieved 2015-03-30.
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| Clinical data | |
|---|---|
| Trade names | Afrin, Ocuclear, Drixine |
| AHFS/Drugs.com | Monograph |
| Pregnancy category |
|
| Dependence liability |
Moderate |
| Routes of administration |
Intranasal |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Metabolism | Kidney (30%), fecal (10%) |
| Biological half-life | 5–6 hours |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.014.618 |
| Chemical and physical data | |
| Formula | C16H24N2O |
| Molar mass | 260.375 g·mol−1 |
| 3D model (Jmol) | |
| Melting point | 301.5 °C (574.7 °F) |
/////////Oxymetazoline, оксиметазолин , أوكسيميتازولين , 羟甲唑啉 , Rhofade, oxymetazoline hydrochloride, alpha1A adrenoceptor agonist, vasoconstrictor
CC1=CC(=C(C(=C1CC2=NCCN2)C)O)C(C)(C)C.Cl
FDA approves Odactra for house dust mite allergies
March 1, 2017
Release
The U.S. Food and Drug Administration today approved Odactra, the first allergen extract to be administered under the tongue (sublingually) to treat house dust mite (HDM)-induced nasal inflammation (allergic rhinitis), with or without eye inflammation (conjunctivitis), in people 18 through 65 years of age.
“House dust mite allergic disease can negatively impact a person’s quality of life,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “The approval of Odactra provides patients an alternative treatment to allergy shots to help address their symptoms.”
House dust mite allergies are a reaction to tiny bugs that are commonly found in house dust. Dust mites, close relatives of ticks and spiders, are too small to be seen without a microscope. They are found in bedding, upholstered furniture and carpeting. Individuals with house dust mite allergies may experience a cough, runny nose, nasal itching, nasal congestion, sneezing, and itchy and watery eyes.
Odactra exposes patients to house dust mite allergens, gradually training the immune system in order to reduce the frequency and severity of nasal and eye allergy symptoms. It is a once-daily tablet, taken year round, that rapidly dissolves after it is placed under the tongue. The first dose is taken under the supervision of a health care professional with experience in the diagnosis and treatment of allergic diseases. The patient is to be observed for at least 30 minutes for potential adverse reactions. Provided the first dose is well tolerated, patients can then take Odactra at home. It can take about eight to 14 weeks of daily dosing after initiation of Odactra for the patient to begin to experience a noticeable benefit.
The safety and efficacy of Odactra was evaluated in studies conducted in the United States, Canada and Europe, involving approximately 2,500 people. Some participants received Odactra, while others received a placebo pill. Participants reported their symptoms and the need to use symptom-relieving allergy medications. During treatment, participants taking Odactra experienced a 16 to 18 percent reduction in symptoms and the need for additional medications compared to those who received a placebo.
The most commonly reported adverse reactions were nausea, itching in the ears and mouth, and swelling of the lips and tongue. The prescribing information includes a boxed warning that severe allergic reactions, some of which can be life-threatening, can occur. As with other FDA-approved allergen extracts administered sublingually, patients receiving Odactra should be prescribed auto-injectable epinephrine. Odactra also has a Medication Guide for distribution to the patient.
Odactra is manufactured for Merck, Sharp & Dohme Corp., (a subsidiary of Merck and Co., Inc., Whitehouse Station, N.J.) by Catalent Pharma Solutions Limited, United Kingdom.
(sublingually) to treat house dust mite (HDM)-induced nasal inflammation (allergic rhinitis), with or without eye inflammation (conjunctivitis), in people 18 through 65 years of age
/////////////Odactra, Merck, Sharp & Dohme Corp, Catalent Pharma Solutions Limited, United Kingdom, FDA 2017, approves, house dust mite allergies
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 