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Selexipag Meets Primary Endpoint in Pivitol Phase III Griphon Outcome Study in Patients with Pulmonary Arterial Hypertension
June 16, 2014
Actelion Ltd today announced the top-line results of the pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial hypertension (PAH) with selexipag, the first selective oral prostacyclin IP receptor agonist. Initial analysis shows that the event-driven outcome study has met its primary efficacy endpoint with high statistical significance.
June 16, 2014
Actelion Ltd today announced the top-line results of the pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial hypertension (PAH) with selexipag, the first selective oral prostacyclin IP receptor agonist. Initial analysis shows that the event-driven outcome study has met its primary efficacy endpoint with high statistical significance.
Selexipag
N-[2-[4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy]acetyl]methanesulfonamide
2-[4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy]-N-(methylsulfonyl)acetamide
phase 3 pulmonary hypertention
Selexipag (ACT-293987, NS-304) is a drug currently in development by Actelion as a treatment of pulmonary arterial hypertension. Selexipag and its active metabolite, ACT-333679, are agonists at the PGI2 prostaglandin receptor, which leads to vasodilation in the pulmonary circulation
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of
5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors.
In April 2008, Actelion and Nippon Shinyaku signed a licensing agreement, under which Actelion will be responsible for the global development and commercialization of selexipag outside Japan, and the two companies will co-develop and co-commercialize the drug in Japan.
http://www1.actelion.com/sites/en/scientists/development-pipeline/phase-3/selexipag.page
ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE
Actelion and Nippon Shinyaku entered into an exclusive worldwide alliance in April 2008 to collaborate on selexipag, a first-in-class orally-available, selective IP receptor agonist for patients suffering from pulmonary arterial hypertension (PAH). This compound was originally discovered and synthesized by Nippon Shinyaku. Phase II evaluation has been completed, and a Phase III program in PAH patients has been initiated. Actelion is responsible for global development and commercialization of selexipag outside Japan, while the two companies will co-develop and co-commercialize in Japan. Nippon Shinyaku will receive milestone payments based on development stage and sales milestones as well as royalties on any sales of selexipag.
| Selexipag | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 475086-01-2  |
| PubChem | 9913767 |
| ChemSpider | 8089417 |
| UNII | 5EXC0E384L |
| KEGG | D09994 |
| Jmol-3D images | Image 1 |
| Properties | |
| Molecular formula | C26H32N4O4S |
| Molar mass | 496.6 g·mol−1 |
NS-304 (ACT-293987), an orally available long acting non-prostanoid prostaglandin I2 (PGI-2) receptor agonist, is in phase III clinical trials at Actelion for the oral treatment of pulmonary hypertension. Nippon Shinyaku is conducting phase III clinical trials with NS-304 for this indication in Europe. In Japan, phase II clinical trials are ongoing for the treatment of pulmonary hypertension and chronic thromboembolic pulmonary hypertension.
Originally discovered and synthesized by Nippon Shinyaku, NS-304 stimulates PGI-2 receptors in blood vessels and exerts vasodilating effects.
In 2008, the compound was licensed to Actelion by Nippon Shinyaku on a worldwide basis with the exception of Japan for the oral treatment of pulmonary arterial hypertension (PAH). According to the final licensing agreement, Actelion will be responsible for global development and commercialization of NS-304 outside Japan, while the two companies will codevelop and co-commercialize the product candidate in Japan. In 2005, orphan drug designation was assigned in the E.U. by Nippon Shinyaku for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
…………………….
US2012/101276
http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en
The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).
BACKGROUND OF THE INVENTION
Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).
Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).
In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).
Production of Compound A
Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.
Step 1:
6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.
Step 2:
5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.
Step 3:
Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.
The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.
…………………………………
WO 2002088084
and
http://www.google.fm/patents/WO2009157398A1?cl=en
………………………
Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 21 p. 6692 – 6704
compd 31
……………………
Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 24 p. 7720 – 7725
2a isthe drug
N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.
http://www.sciencedirect.com/science/article/pii/S0968089607007614
References
- Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
- Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
- Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
- Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
- Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
ABOUT SELEXIPAG
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [2,4,5]
Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [6]
SELEXIPAG
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [2,4,5]
Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [6]
SELEXIPAG
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [2,4,5]
Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [6]
SELEXIPAG
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective prostacyclin IP receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [2,4,5]
Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [6]
Pharma vies to unleash immune system power on cancer
http://www.rsc.org/chemistryworld/2014/06/pharma-vies-unleash-immune-system-power-cancer
Provectus Phase III Melanoma Trial Results Earlier Than Planned?
Rose Bengal disodium
4 ,5,6,7-Tetrachloro-2′,4′,5′,7′-tetraiodo-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-3′,6′-diolate disodium salt
| cas | 632-69-9 |
C20 H2 Cl4 I4 O5 . 2 Na, mw 1017.36, PH 10
| innovator | Provectus |
The FDA has granted PV-10 Orphan Drug Status for the treatment of highly lethal metastatic melanoma and metastatic liver cancer. It has a successful and expanding Compassionate Use Program in operation and successfully completed trials on metastatic cancer of the breast, liver and melanoma, with positive results in all three. Positive effects in this context is that, if you inject PV-10 into a solid tumor, it kills cancer cells, usually within a week and doesn’t harm normal tissue. Many injected tumors actually disappear while others shrink and stop growing. The dual action of the drug is that the destruction of the cancer by direct injection of PV-10 serves to sensitize the patient’s immune system to seek out and kill similar cancer throughout the body. There is convincing evidence that untreated cancer distant from the treated cancer is attacked by the patient’s immune system after treatment.
PROVECTUS COMPANY OVERVIEW
Provectus (PVCT) is a clinical stage bio-pharmaceutical drug development company. There are 3 key scientific managers running the business along with the CFO, who is also the Chief Operating Officer. They preside over a stable of expert and specialized consultants. The company has two lead drug candidates: PH-10 for significant, often severe, and common skin disorders and PV-10, a dual action, local ablation and immunological anti-cancer drug. PH-10 is currently the subject of post-Phase II trial research into mode of action. PV-10 has successfully completed Phase II trials for malignant melanoma, is currently the subject of independent research on mode of actioRose Bengal disodium is in early clinical trials at Provectus for the topical treatment of psoriasis and atopic dermatitis. An intralesional injectable formulation is also in early clinical development as breast cancer, liver cancer and melanoma therapy. Development for the treatment of actinic keratosis had been ongoing; however, no recent development for this indication has been reported. The company is seeking approval in the U.S. to begin clinical evaluation of this formulation for the treatment of liver and prostate cancer. A compassionate use program is under way for Rose Bengal disodium for the treatment of non-visceral cancers.
The drug’s mechanism of action is believed to be characterized by the creation of free radicals upon activation, which eliminate diseased cells. The compound concentrates in tumors at cytotoxic levels while quickly dissipating from healthy tissue. Simultaneously, the drug triggers an immune response that can eliminate metastatic tumor tissue.
In 2007, orphan drug designation was assigned to Rose Bengal disodium by the FDA for the treatment of metastatic melanoma. This designation was also assigned to the compound in the U.S. in 2011 for the treatment of hepatocellular carcinoma.n and efficacy in conjunction with radiation, and it will have a Phase III pivotal trial starting shortly.
SUMMARY
1. If PV-10 and the Chemotherapies act as the prior data indicate, an NDA for melanoma may be submitted by Provectus in the first half of 2015.
2. If this occurs, the FDA denial of the Breakthrough Therapy designation will not have slowed PV-10’s progress to commercialization.
3. Given the relative safety and efficacy of the different drugs, if the trial is not stopped very early for humanitarian reasons, the planned Interim Analysis is likely to result in the cancellation of the trial, prior to the end of 2015.
4. Given PV-10’s superior safety and lack of significant side effects, if it is only as good as Chemotherapy, it will deserve FDA approval.
The Phase III pivotal trial will demonstrate the safety and efficacy of PV-10 to the market and to prospective acquirers a lot earlier than many have presumed.
Rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) is a stain. Its sodium salt is commonly used in eye drops to stain damaged conjunctival and corneal cells and thereby identify damage to the eye. The stain is also used in the preparation of Foraminifera for microscopic analysis, allowing the distinction between forms that were alive or dead at the time of collection.
A form of Rose Bengal is also being studied as a treatment for certain cancers and skin conditions. The cancer formulation of the drug, known as PV-10, is currently undergoing clinical trials for melanoma and breast cancer. The company also has formulated a drug based on Rose Bengal for the treatment of eczema and psoriasis; this drug, PH-10, is currently in clinical trials as well.
| Rose bengal | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 11121-48-5 |
| ATC code | S01 |
| Jmol-3D images | Image 1 |
| Properties | |
| Molecular formula | C20H4Cl4I4O5 |
| Molar mass | 973.67 g mol−1 |
Chemical applications
Light microscopy image of the undescribed species of Spinoloricus from Loricifera stained with Rose Bengal.
Rose Bengal is also used in synthetic chemistry to generate singlet oxygen from triplet oxygen. The singlet oxygen can then undergo a variety of useful reactions, particularly [2 + 2] cycloadditions with alkenes and similar systems.
Rose Bengal can be used to form many derivatives that have important medical functions. One such derivative was created so to be sonosensative but photoinsensative, so that with a high intensity focused ultrasound, it could be used in the treatment of cancer. The derivative was formed by amidation of Rose Bengal, which turned off the fluorescent and photosensitive properties of Rose Bengal, leading to a usable compound, named in the study as RB2.[1]
Salts of Rose Bengal can also be formed, with the molecular formula C20 H4 Cl4 I4 O5 . 2 Na, molecular weight of 1017.64 g/mol and CAS # 632-69-9. Known as Rose Bengal Sodium Salt, this compound has its own unique uses and properties, but also functions as a dye.[2]
Biological applications
PV-10 was found to cause an observable response in 60 percent of tumors treated, according to researchers in a phase II melanoma study. Locoregional disease control was observed in 75 percent of patients. Also confirmed was a “bystander effect”, previously observed in the phase I trial, whereby untreated lesions responded to treatment as well, potentially due to immune system response. These data were based on the interim results of the first 40 patients treated in an 80 patient study.[3] Rose Bengal has been shown to not just prevent the growth and spread of ovarian cancer, but also to cause apoptotic cell death of the cancer cells. This has been proven in vitro, in order to prove that Rose Bengal is still a possible option in the treatment of cancer, and further research should be done.[4]
Rose Bengal is also used in animal models of ischemic stroke (photothrombotic stroke models) in biomedical research. A bolus of the compound is injected into the venous system. Then the region of interest (e.g., the cerebral cortex) is exposed and illuminated by LASER light of 561 nm. A thrombus is formed in the illuminated blood vessels, causing a stroke in the dependent brain tissue.[5][6]
Rose bengal has been used for 50 years to diagnose liver and eye cancer. It has also been used as an insecticide.[7][8]
Rose Bengal is able to stain cells whenever the surface epithelium is not being properly protected by the preocular tear film, because Rose Bengal has been proven to not be able to stain cells because of the protective functioning of these preocular tear films.[9] This is why Rose Bengal is often useful as a stain in diagnosing certain medical issues, such as conjunctival and lid disorders.[10]
Rose Bengal has been used for ocular surface staining to study the efficacy of punctal plugs in the treatment of keratoconjunctivitis sicca. [11]
Rose Bengal is being researched as an agent in creating nano sutures.[12] Wounds are painted on both sides with it and then illuminated with an intense light. This links the tiny collagen fibers together sealing the wound.[13][14][15] Healing is faster and the seal reduces chances of infection.[16][17]
Rose Bengal is used in several microbiological media, including Cooke’s Rose Bengal agar, to suppress bacterial growth.
Rose Bengal has been used as a protoplasm stain to discriminate between living and dead micro-organisms, particularly Foraminifera, since the 1950s when Bill Walton developed the technique.[18]
Electronic applications
Rose Bengal demonstrates at least six distinct electronic properties[19] which are otherwise hidden in the molecule. Rose Bengal is a double planar molecule and relative rotation of the planes generate unique electronics. Therefore, Rose Bengal is a suitable candidate for molecular electronics.
History
Rose Bengal was originally prepared in 1884 by Gnehm, as an analogue of fluorescein.[20] The name is due to its similarity to alta, a dye that women in Bengal have used for centuries to colour their feet red during weddings and festivals.
References
- Kim, Y; Valentina Rubio, Jianjun Qi, Rongmin Xia, Zheng-Zheng Shi, Leif Peterson, Ching-Hsuan Tung, and Brian E. O’Neill (2012). “Cancer treatment using an optically inert Rose Bengal derivative combined with pulsed focused ultrasound”. AIP Conference Proceedings 1481: 175.
- “Rose Bengal Sodium Salt”. Sigma-Aldrich. Sigma Aldrich Co. Retrieved 12 November 2013.
- Metastatic Melanoma PV-10 Trial Results Encouraging Says Drug Company, Medical News Today, 09 Jun 2009
- Koevary, S (2012). “Selective toxicity of rose bengal to ovarian cancer cells in vitro”. International Journal of Physiology, Pathophysiology and Pharmacology 4: 99–107.
- Salber D, et al. (2006). “Differential uptake of [18F]FET and [3H]l-methionine in focal cortical ischemia”. Nuclear Medicine and Biology 33 (8): 1029–1035. doi:10.1016/j.nucmedbio.2006.09.004. PMID 17127177.
- Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD (1985). “Induction of reproducible brain infarction by photochemically initiated thrombosis”. Ann Neurol 17 (5): 497–504. doi:10.1002/ana.410170513. PMID 4004172.
- Capinera, John L.; Squitier, Jason M. (2000). “Insecticidal Activity of Photoactive Dyes to American and Migratory Grasshoppers (Orthoptera: Acrididae)”. Journal of Economic Entomology 93 (3): 662–666. doi:10.1603/0022-0493-93.3.662. PMID 10902313.
- Martin, Phyllis; Mischke, Sue; Schroder, Robert (1998). “Compatibility of Photoactive Dyes with Insect Biocontrol Agents”. Biocontrol Science and Technology 8 (4): 501–508. doi:10.1080/09583159830018.
- Feenstra, R; Tseng, S (July 1992). “What is actually stained by rose bengal?”. Arch Ophthalmol 110: 984–993. doi:10.1001/archopht.1992.01080190090035.
- Yokoi, Norihiko (2012). “Vital staining for disorders of conjunctiva and lids”. Atarashii Ganka 29: 1599–1605.
- Ervin AM, Wojciechowski R, Schein O (2010). “Punctal occlusion for dry eye syndrome”. Cochrane Database Syst Rev 9: CD006775. doi:10.1002/14651858.CD006775.pub2. PMID 20824852.
- Chan, B; Chan, O; So, K (2008). “Effects of photochemical crosslinking on the microstructure of collagen and a feasibility study on controlled protein release”. Acta Biomaterialia 4 (6): 1627–1636. doi:10.1016/j.actbio.2008.06.007. PMID 18640085.
- O’Neill A.C., Winograd J.M, Zeballos J.M., Johnson T.S., Randolph M.A., Bujold K.E., Kochevar I.E., Redmond R.W. (2007). “Microvascular anastomosis using a photochemical tissue bonding technique”. Lasers in Surgery and Medicine 39 (9): 716–722. doi:10.1002/lsm.20548. PMID 17960755.
- Mulroy L., Kim J., Wu I., Scharper P., Melki S.A., Azar D.A., Redmond R.W., Kochevar I.E. (2000). “Photochemical keratodesmos for repair of lamellar corneal incisions”. Invest Ophthalmol Vis Sci 41 (11): 3335–3340. PMID 11006222.
- Proano C.E., Mulroy L., Erika Jones E., Azar D.A., Redmond R.W., Kochevar I.E. (2004). Invest Ophthalmol Vis Sci: 2177–2181.
- Laser Show in the Surgical Suite, Technology Review, March/April 2009
- Laser Show in the Surgical Suite, Technology Review, 02.11.2009
- Walton, W. (1952), Techniques for recognition of living foraminifera, Contrib. Cushman Found. Foraminiferal Res., 3, 56 – 60
- A new approach to extract multiple distinct conformers and co-existing distinct electronic properties of a single molecule by point-contact method Anirban Bandyopadhyay, Satyajit Sahu, Daisuke Fujita and Yutaka Wakayama, Phys. Chem. Chem. Phys., 2010 view highlights in Royal Society of Chemistry,
- Alexander, Walter (2010). “American Society of Clinical Oncology, 2010 Annual Meeting and Rose Bengal: From a Wool Dye to a Cancer Therapy”. Pharmacy and Therapeutics 35 (8): 469–474. PMC 2935646. Retrieved 5 November 2013.
- US 2010021566
- WO 2011050164
- US 2011250296
External links
- Rose Bengal at the US National Library of Medicine Medical Subject Headings (MeSH)
- Absorption and extinction data
A new twist on neuro disease: Discovery could aid people with dystonia, Parkinson’s and more
Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.
That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.
The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new re-search from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.
In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also…
View original post 688 more words
Lung-MAP Launches: First Precision Medicine Trial From National Clinical Trials Network
Today, NCI and many collaborators launched a unique clinical trial for people with a form of lung cancer. The study, LungMAP, will match participants to one of several different investigational treatments based on the genomic profiles of their tumors: http://1.usa.gov/1qkzdgB
A unique public-private collaboration among the National Cancer Institute (NCI), part of the National Institutes of Health, SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health (FNIH), five pharmaceutical companies (Amgen, Genentech, Pfizer, AstraZeneca, and AstraZeneca’s global biologics R&D arm, MedImmune), and Foundation Medicine today announced the initiation of the Lung Cancer Master Protocol (Lung-MAP) trial.
Parasitic worms of pigs could provide new treatments of human diseases
New treatments for inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, diabetes and autism could be on the horizon, after a global University of Melbourne – lead study successfully mapped the genes of a parasitic worm in pigs.
Lead researcher, Dr Aaron Jex, Faculty of Veterinary Science, said, “We know that humans infected with the harmless, ‘pig whipworm’ can have significantly reduced symptoms linked to autoimmune diseases. And now we have the genetic sequence of the worm, it opens the door to future human drug designs and treatment.”
Although the ‘pig whipworm’ causes disease and losses in livestock, it does not cause disease in humans.
In contrast, the ‘human whipworm’ infects around 1 billion people, mainly children in developing nations, and causes dysentery, malnourishment and impairment of physical and mental development.
Coauthor, Prof Robin Gasser, Faculty of Veterinary Science, said, “The genes tells us about the proteins that this worm uses…
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Polymorphs and co-crystals of haloprogin: an antifungal agent
Haloprogin
Haloprogin is a topical antifungal agent. Its structure does not contain any of the functional groups typically exploited in hydrogen bond based co-crystal design. On the other hand, its 1-iodoalkyne moiety is nicely tailored to a crystal engineering strategy based on halogen bonding. Here we describe the formation of three polymorphs of haloprogin and of three co-crystals that this active pharmaceutical ingredient forms with both neutral and ionic co-crystal formers. The halogen bond plays a major role in all of the six structures and the interaction is thus confirmed to be a valuable tool which may complement the hydrogen bond when polymorphs and co-crystals of active pharmaceutical ingredients are pursued.
Graphical abstract: Polymorphs and co-crystals of haloprogin: an antifungal agent
http://pubs.rsc.org/en/Content/ArticleLanding/2014/CE/C4CE00367E?utm_medium=email&utm_campaign=pub-CE-vol-16-issue-26&utm_source=toc-alert#!divAbstract
Polymorphs and co-crystals of haloprogin: an antifungal agent
Michele Baldrighi,a Davide Bartesaghi,a Gabriella Cavallo,a Michele R. Chierotti,b Roberto Gobetto,b Pierangelo Metrangolo,*a Tullio Pilati,a Giuseppe Resnati*a and Giancarlo Terraneo*a
*Corresponding authors
aNFMLab-Laboratory of Nanostructured Fluorinated Materials (NFMLab), Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Via L. Mancinelli 7, 20131 Milan, Italy
E-mail: pierangelo.metrangolo@polimi.it, giuseppe.resnati@polimi.it, giancarlo.terraneo@polimi.it
bDepartment of Chemistry, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
CrystEngComm, 2014,16, 5897-5904
DOI: 10.1039/C4CE00367E
EXTRA INFO
| Systematic (IUPAC) name | |
|---|---|
| 1,2,4-trichloro-5-[(3-iodoprop-2-yn-1-yl)oxy]benzene | |
| Clinical data | |
| Legal status | Not available in U.S. |
| Routes | Topical |
| Identifiers | |
| CAS number | 777-11-7 |
| ATC code | D01AE11 |
| PubChem | CID 3561 |
| DrugBank | DB00793 |
| ChemSpider | 3440 |
| UNII | AIU7053OWL |
| KEGG | D00339 |
| ChEMBL | CHEMBL1289 |
| Chemical data | |
| Formula | C9H4Cl3IO |
| Mol. mass | 361.39 g/mol |
| Physical data | |
| Melt. point | 113.5 °C (236 °F) |
| Solubility in water | insoluble mg/mL (20 °C) |
Haloprogin is an antifungal drug used to treat athlete’s foot and other fungal infections. It is marketed in creams under the trade names Halotex, Mycanden, Mycilan, and Polik.
Action
Haloprogin was previously used in 1% topical creams as an antifungal agent. It was marketed over the counter primarily to treat tinea infections of the skin. The mechanism of action is unknown.[1]
Haloprogin had a high incidence of side effects including: irritation, burning, vesiculation (blisters), scaling, and itching. It has since been discontinued due to the emergence of more modern antifungals with fewer side effects.[2]
Haloprogin is used as a topical ointment or cream in the treatment of Tinea infections. Tinea infections are superficial fungal infections caused by three species of fungi collectively known as dermatophytes (Trichophyton, Microsporum and Epidermophyton). Commonly these infections are named for the body part affected, including tinea corporis (general skin), tinea cruris (groin), and tinea pedis (feet). Haloprogin is a halogenated phenolic ether administered topically for dermotaphytic infections. The mechanism of action is unknown, but it is thought to be via inhibition of oxygen uptake and disruption of yeast membrane structure and function. Haloprogin is no longer available in the United States and has been discontinued.
U.S. Patent 3,322,813.
References
- “Haloprogin”. Drugs@FDA. Food and Drug Administration. Retrieved 2007-02-17.
- “Haloprogin”. DrugBank. University of Alberta. Nov 6, 2006. Retrieved 2007-02-17.
Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects
Graphical abstract: Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects
Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects
Dyanne L. Cruickshank, Yassir Younis, Nicholas M. Njuguna, Dennis S. B. Ongarora, Kelly Chibale and Mino R. Caira
CrystEngComm, 2014, 16, 5781 DOI:10.1039/C3CE41798K
3-(6-Methoxypyridin-3-yl)-5-(4-methylsulfonyl phenyl)-pyridin-2-amine (MMP) is a member of a novel class of orally active antimalarial drugs. This aminopyridine molecule has shown potent in vitro antiplasmodial activity and in vivo antimalarial activity in Plasmodium berghei-infected mice. The aqueous solubility of this molecule is, however, limited.
Thus investigations aimed at improving the physicochemical properties, including solubility, of MMP were accordingly conducted. Five salts of MMP were formed with co-former molecules saccharin, salicylic acid, fumaric acid, oxalic acid and suberic acid, but a cocrystal was obtained when the co-former adipic acid was employed.
All these new multi-component systems have been fully characterised using X-ray diffraction and thermal methods. Semi-quantitative, turbidimetric solubility tests in a phosphate-buffered saline solution at a pH of 7.4 were performed on the salts and the cocrystal of MMP. The saccharinate salt, fumarate salt and the cocrystal of MMP proved to have greater solubility than MMP itself. This work illustrates the importance of screening and modifying candidate drug compounds in their preliminary stages of development.
Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects
Dyanne L. Cruickshank,a Yassir Younis,a Nicholas M. Njuguna,a Dennis S. B. Ongarora,a Kelly Chibalea and Mino R. Caira*a
*corresponding authors
aDepartment of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
E-mail: mino.caira@uct.ac.za;
Fax: +27 21 650 5195 ;
Tel: +27 21 650 3071
CrystEngComm, 2014,16, 5781-5792
DOI: 10.1039/C3CE41798K
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US
GADOBUTROL
gadolinium(III) 2,2′,2”-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
Gadobutrol, SH-L-562, Gadovist,138071-82-6
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.
The agency has approved the new indication for Gadavist injection for intravenous use with magnetic resonance imaging of the breast to assess the presence and extent of malignant breast disease.
Approval is based on priority review of two Phase III studies with identical design (GEMMA-1 and GEMMA-2).
Bayer HealthCare’s Gadavist (gadobutrol)
Bayer’s Gadavist injection cleared for breast cancer evaluation
UPDATE……. Gadoteridol 279.3 mg/ml for injection , CDSCO INDIA 29.07.2021
For intravenous use in magnetic
reasonance imaging (MRI) in adults and
pediatric patients over 2 years of age for
whole body MRI including the head, neck,
liver, breast, musculoskeletal system and
soft tissue pathologies
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.
GADOBUTROL
| Clinical data | |
|---|---|
| AHFS/Drugs.com | International Drug Names |
| Licence data | US FDA:link |
| Pregnancy cat. | C (US) |
| Legal status | POM (UK) ℞-only (US) |
| Routes | IV |
| Identifiers | |
| CAS number | 138071-82-6 |
| ATC code | V08CA09 |
| PubChem | CID 72057 |
| DrugBank | DB06703 |
| UNII | 1BJ477IO2L |
| KEGG | D07420 |
| Chemical data | |
| Formula | C18H31GdN4O9 |
| Mol. mass | 604.710 g/mol |
………………………..
Gadobutrol (INN) (Gd-DO3A-butrol) is a gadolinium-based MRI contrast agent (GBCA).
It received marketing approval in Canada[1] and in the United States.[2][3][4]
As of 2007, it was the only GBCA approved at 1.0 molar concentrations.[5]
Gadobutrol is marketed by Bayer Schering Pharma as Gadovist, and by Bayer HealthCare Pharmaceuticals as Gadavist.[6]
WORLDCUP FOOTBALL WEEK 2014 BRAZIL
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http://www.google.com/patents/EP0988294B1?cl=en
-
This type of complexes with metal ions, in particular with paramagnetic metal ions; is used for the preparation of non-ionic contrast agents for the diagnostic technique known as magnetic resonance (MRI, Magnetic Resonance Imaging), among which are ProHance(R) (Gadoteridol, gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), and Gadobutrol (gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid).
-
[0003]Two different synthetic approaches are described in literature for the preparation of this kind of complexes, said approaches differing in the strategy taken to discriminate one of the four nitrogen atoms: the first one (Dischino et al., Inorg. Chem., 1991, 30, 1265 or EP 448191, EP 292689, EP 255471) is based on the selective protection of one of the nitrogen atoms by formation of the compound of formula (III), 5H,9bH-2a,4a,7-tetraazacycloocta[cd]pentalene, and on the subsequent hydrolysis to compound of formula (IV), 1-formyl-1,4,7,10-tetraazacyclododecane, followed by the carboxymethylation of the still free nitrogen atoms and by the deprotection and alkylation of the fourth nitrogen atom, according to scheme 1.
-
[0004]The step from 1,4,7,10-tetraazacyclododecane disulfate (a commercially available product) to compound (III) is effected according to the conventional method disclosed in US 4,085,106, followed by formation of the compound of formula (IV) in water-alcohol medium.
-
[0005]This intermediate is subsequently tricarboxymethylated with tert-butyl bromoacetate (TBBA) in dimethylformamide at 2.5°C and then treated with a toluene-sodium hydroxide diphasic mixture to give the compound of formula (V), 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic, tris(1,1-dimethylethyl) ester, which is subsequently hydrolysed to compound of formula (II) in acidic solution.
-
[0006]In the process described in WO 93/24469 for the synthesis of Gadobutrol, at first one of the nitrogen atoms is alkylated in conditions such as to minimize the formation of polyalkylated derivatives, then the monoalkylderivative is purified and carboxymethylated, according to scheme 2.
-
[0007]The alkylation of 1,4,7,1,0-tetraazacyclododecane with the epoxide of formula (VI), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, is carried out in anhydrous n-BuOH under reflux and the reaction mixture is extracted with water, evaporated to dryness and the residue is subsequently diluted with water and extracted with methylene chloride.
-
[0008]The aqueous phase containing the mono-alkylated product (65% yield in Example 7 which reports the procedure for the preparation of 5 kg of Gadobutrol) is directly carboxymethylated at 70°C with chloroacetic acid, keeping pH 9.5 by addition of NaOH. The reaction mixture is adjusted to pH 1, concentrated to dryness and dissolved in methanol to remove the undissolved salts. The filtrate is then concentrated under vacuum, dissolved in water, and loaded onto a cation exchanger in the H+ form to fix the product. The subsequent elution with ammonia displaces the desired product, which is concentrated to small volume and subsequently complexed with gadolinium oxide according to conventional methods, and the resulting complex is purified by means of ion exchange resins. The overall yield is 42%.
-
[0009]Although the first of these two processes could theoretically provide a higher yield, in that all the single steps (protection, carboxymethylation and deprotection) are highly selective, the complexity of the operations required to remove salts and solvents and to purify the reaction intermediates makes such theoretical advantage ineffective: the overall yield is in fact, in the case of Gadoteridol, slightly higher than 37%.
-
[0010]The preparation of Gadobutrol according to the alternative process (WO 93/24469) provides a markedly better yield (72%) only on laboratory scale (example 2): example 7 (represented in the above Scheme 2) actually evidences that, when scaling-up, the yield of this process also remarkably decreases (42%).
-
[0011]In addition to the drawback of an about 40% yield, both processes of the prior art are characterized by troublesome operations, which often involve the handling of solids, the use of remarkable amounts of a number of different solvents, some of them having undesirable toxicological or anyway hazardous characteristics.
-
[0012]Moreover, the synthesis described by Dischino makes use of reagents which are extremely toxic, such as tert-butyl bromoacetate, or harmful and dangerous from the reactivity point of view, such as dimethylformamide dimethylacetal.
-
[0013]An alternative to the use of dimethyl formamide dimethylacetal is suggested by J. Am. Chem. Soc. 102(20), 6365-6369 (1980), which discloses the preparation of orthoamides by means of triethyl orthoformate.
-
[0014]EP 0596 586 discloses a process for the preparation of substituted tetraazacyclododecanes, among them compounds of formula (XII), comprising:
- formation of the tricyclo[5.5.1.0] ring;
- alkylation with an epoxide;
- hydrolysis of the 10-formyl substituent;
- reaction with an acetoxy derivative bearing a leaving group at the alpha-position.
-
[0015]Nevertheless, this method requires quite a laborious procedure in order to isolate the product of step b).
-
[0016]It is the object of the present invention a process for the preparation of the complexes of general formula (XII)
wherein
- R1 and R2
- are independently a hydrogen atom, a (C1-C20) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy group, which can be unsubstituted or substituted with a (C1-C5) alkyl or hydroxy, (C1-C5) alkoxy, carbamoyl or carboxylic groups,
- Me3+
- is the trivalent ion of a paramagnetic metal;
comprising the steps represented in the following Scheme 3:
-
The process of the present invention keeps the high selectivity typical of the protection/deprotection strategy described by Dischino in the above mentioned paper, while removing all its drawbacks, thus providing for the first time a reproducible industrial process for the preparation of the concerned compounds in high yields and without use of hazardous substances.
-
[0019]The preparation of the gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic) acid (Gadoteridol), according to scheme 4, is particularly preferred:
in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) is propylene oxide.
-
[0020]The preparation of the gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic) acid (Gadobutrol), according to the scheme 5, is also preferred.
in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) corresponds to the one of formula (VI), defined above.
-
[0021]On the other hand, step a) of the process of the present invention involves the use of triethyl orthoformate in the presence of an acid catalyst, instead of dialkylformamide-dialkylacetal.
-
[0022]Triethyl orthoformate can be added in amounts ranging from 105% to 200% on the stoichiometric value.
-
[0023]The reaction temperature can range from 110 to 150°C and the reaction time from 5 to 24 h.
-
[0024]The catalyst is a carboxylic acid having at least 3 carbon atoms, C3-C18, preferably selected from the group consisting of propionic, butyric and pivalic acids.
-
[0025]Triethyl orthoformate is a less toxic and less expensive product than N,N-dimethylformamide-dimethylacetal and does not involve the formation of harmful, not-condensable gaseous by-products. Moreover, triethyl orthoformate is less reactive than N,N-dimethylformamide-dimethylacetal, which makes it possible to carry out the loading procedures of the reactives as well as the reaction itself in utterly safe conditions even on a large scale, allows to better monitor the progress of the reaction on the basis of such operative parameters as time and temperature, without checking the progress by gas chromatography, and makes dosing the reactive less critical, in that it can be added from the very beginning without causing the formation of undesired by-products: all that rendering the process suitable for the production of compound (III) on the industrial scale in easily reproducible conditions.
-
[0026]The subsequent step b) involves the carboxymethylation of compound (III) in aqueous solution, using a haloacetic acid, to give compound (IX), i.e. the 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid salt with an alkali or alkaline-earth metal, the salts of compound (IX) with sodium, potassium or calcium being most preferred.
Example 2
-
[0065]
-
[0066]The procedure of Example 1 is followed until step C included, to obtain a solution of DO3A trisodium salt.
-
[0067]pH is adjusted to 12.3 with conc. HCl and 57.7 kg (0.4 kmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane are added. After reaction for 4 h at 40°C and for 8 h at 80°C, the solution is cooled to 50°C, 120 kg of an aqueous solution containing 0.135 kmol of gadolinium trichloride are added. After 1 h the mixture is cooled at 17°C and acidified to pH 1.7 with conc. HCl, keeping this pH for 2 h. The solution is subsequently warmed to 50°C, pH is adjusted to 7 with sodium hydroxide, keeping these conditions for 1 h.
-
[0068]After that, the resulting crude Gadobutrol is purified repeating exactly the same process as in steps E and F of Example 1.
Recovery of the product (Gadobutrol)
-
[0069]The product-rich fraction is then thermally concentrated to a viscous residue and the residue is added with 350 kg of ethanol at 79°C.
-
[0070]The resulting suspension is refluxed for 1 h, then cooled, centrifuged and dried under reduced pressure to obtain 66.0 kg of Gadobutrol (0.109 kmol), HPLC assay 99.5% (A%).
Overall yield: 79.1% -
[0071]The IR and MS spectra are consistent with the indicated structure.
References
- Cheng, KT (2007). “Gadobutrol”. Molecular Imaging and Contrast Agent Database (MICAD) (Bethesda, MD: National Center for Biotechnology Information (NCBI)). PMID 20641787. NBK23589.
- http://bayerimaging.com/products/gadavist/index.php
- “FDA approves imaging agent for central nervous system scans” (Press release). U.S. Food and Drug Administration (FDA). March 15, 2011. Retrieved March 31, 2011.
- “U.S. FDA Approves Bayer’s Gadavist (Gadobutrol) Injection for MRI of the Central Nervous System” (Press release). Bayer HealthCare Pharmaceuticals. March 14, 2011. Retrieved March 31, 2011.
- “Gadobutrol 1.0-molar in Cardiac Magnetic Resonance Imaging (MRI) – Further Enhancing the Capabilities of Contrast-enhanced MRI in Ischaemic and Non-ischaemic Heart Disease?”
- “Gadavist full prescribing information”. Retrieved 2011-03-14.
Scientists take totally tubular journey through brain cells
NIH scientists watched the inside of brain cell tubes, called microtubules, get tagged by a protein called TAT. Tagging is a critical process in the health and development of nerve cells. Credit: Roll-Mecak lab, NINDS, Bethesda, MD
In a new study, scientists at the National Institutes of Health took a molecular-level journey into microtubules, the hollow cylinders inside brain cells that act as skeletons and internal highways. They watched how a protein called tubulin acetyltransferase (TAT) labels the inside of microtubules. The results, published in Cell, answer long-standing questions about how TAT tagging works and offer clues as to why it is important for brain health.
Microtubules are constantly tagged by proteins in the cell to designate them for specialized functions, in the same way that roads are labeled for fast or slow traffic or for maintenance. TAT coats specific locations inside the microtubules with a chemical called an…
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 