Not a single version of Windows comes with a native print-to-PDF solution. So what’s the best alternative? We checked 8 of the most popular options to find out. Cancer Protocol, Nutrition, Supplements, Herbs, Enzymes. Note: do not email me unless you would like a personalized protocol (free with a suggested donation of $250. ![]() All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 9 million hits on google, pushing boundaries,2.5 lakh plus connections.How to Stop Linked. In App Notifications in Windows 1. Since Microsoft acquired Linked. In, I’ve been dreading the day notifications to add someone I’ve never met to my professional network pop up in my screen. Turns out that day is here, with Linked. In announcing its Windows 1. Luckily, you can change what apps demand your attention in the Windows 1. Action Center. If you’re one of the brave who decide to install the Linked. In app, you’re probably more plugged in than most to your career. But those updating blog post comments and friend requests are actually detrimental to getting work done. Distractions like notifications take you away from important tasks, and getting back on track after being interrupted takes a lot longer than you think. From your Windows 1. Start, then Settings (the gear in the bottom left of your task bar). From there, hit System > Notifications & Actions to change which notifications you see. You can toggle notification banners and sounds, add or remove notifications from your PC’s lock screen, or shut down all notifications to go distraction- free. Nerds might want to take it a step further by getting rid of the Action Center altogether. It requires a bit of registry editing, something you shouldn’t do unless you’re well- versed in Windows, but if you’ve got the guts to try it out then take a stab at it. New Drug Approvals « All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 9 million hits on google, pushing boundaries,2. VIEWS on this blog in 2. The views expressed are my personal and in no- way suggest the views of the professional body or the company that I represent, USE CTRL AND+ KEY TO ENLARGE BLOG VIEW……………………A 9. I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, nothing will not stop me helping you, except God(S)- 1′- [(5- Methyl- 2- furyl)methyl]spiro[6. ![]() H- furo[3,2- f][1,3]benzodioxole- 7,3′- indoline]- 2′- one. Spiro(furo(2,3- F)- 1,3- benzodioxole- 7(6. H),3′- (3. H)indol)- 2′(1’H)- one, 1′- ((5- (trifluoromethyl)- 2- furanyl)methyl)- , (3’S)- (3’S)- 1′- ((5- (Trifluoromethyl)furan- 2- yl)methyl)- 2. H,6. H- spiro(furo(2,3- F)(1,3)benzodioxole- 7,3′- indol)- 2′(1’H)- one. Spiro[furo[2,3- f]- 1,3- benzodioxole- 7(6. H),3′- [3. H]indol]- 2′(1’H)- one, 1′- [[5- (trifluoromethyl)- 2- furanyl]methyl]- , (7. S)- Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long- lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post- herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short- term, first- line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities. There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2. 00. 6/1. 10. PCT Published Patent Application No. WO 2. 01. 0/0. 45. PCT Published Patent Application No. WO 2. 01. 0/0. 45. PCT Published Patent Application No. WO 2. 01. 1/0. 47. PCT Published Patent Application No. WO 2. 01. 1/0. 02. These compounds are disclosed therein as being useful for the treatment of sodium channel- mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease; cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome. Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2. 00. 6/1. 10. PCT Published Patent Application No. WO 2. 01. 0/0. 45. PCTPublished Patent Application No. WO 2. 01. 0/0. 45. PCT Published Patent Application No. WO 2. 01. 1/0. 47. PCT Published Patent Application No. WO 2. 01. 1/0. 02. Postherpetic neuralgia (PHN) is a rare disorder that is defined as significant pain or abnormal sensation 1. This pain persists after the healing of the associated rash. Generally, this affliction occurs in older individuals and individuals suffering from immunosuppression. There are about one million cases of shingles in the US per year, of which 1. PHN. Topical analgesics such as lidocaine and capsaicin are traditionally used to treat this disorder. Both lidocaine and TV- 4. TV- 4. 50. 70 (formerly XEN- 4. Teva from Xenon Pharmaceuticals and is reported to be an antagonist of the Nav. It is currently in Phase II clinical trials for PHN. Interestingly, the loss of function of the Nav. Primary erythromelalgia is another rare disease where alterations in Nav. SCN9. A have been reported to result in chronic burning pain that can last for hours or even days. Thus, compounds which regulate this protein have potential therapeutic value as analgesics for chronic pain. PATENTUS 2. 01. 00. WO 2. 01. 11. 06. US 2. 01. 10. 08. US 2. 01. 10. 08. US 2. 01. 30. 14. US 2. 01. 30. 21. WO 2. 01. 31. 54. US 2. 01. 50. 21. WO 2. 01. 61. 27. WO 2. 01. 61. 09. CN 1. 06. 51. 88. US 2. 01. 70. 23. SYNTHESISWO 2. 01. CONTD……. Synthesis. CN 1. 06. 51. 88. PATENTUS 2. 01. 00. Preparation of the (S)- Enantiomer of the Invention. The (S)- enantiomer of the invention and the corresponding (R)- enantiomer are prepared by the resolution of the compound of formula (I), as set forth above in the Summary of the Invention, using either chiral high pressure liquid chromatography methods or by simulated moving bed chromatography methods, as described below in the following Reaction Scheme wherein “chiral HPLC” refers to chiral high pressure liquid chromatography and “SMB” refers to simulated moving bed chromatography: The compound of formula (I) can be prepared by the methods disclosed in PCT Published Patent Application No. WO 2. 00. 6/1. 10. One of ordinary skill in the art would recognize variations in the above Reaction Scheme which are appropriate for the resolution of the individual enantiomers. Alternatively, the (S)- enantiomer of formula (I- S) and the (R)- enantiomer of formula (I- R), can be synthesized from starting materials which are known or readily prepared using process analogous to those which are known. Preferably, the (S)- enantiomer of the invention obtained by the resolution methods disclosed herein is substantially free of the (R)- enantiomer or contains only traces of the (R)- enantiomer. The following Synthetic Examples serve to illustrate the resolution methods disclosed by the above Reaction Schemes and are not intended to limit the scope of the invention. Synthetic Example 1. Synthesis of 1- {[5- (trifluoromethyl)furan- 2- yl]methyl}spiro[furo[2,3- f][1,3]benzodioxole- 7,3′- indol]- 2′(1′H)- one (Compound of formula (I))To a suspension of spiro[furo[2,3- f][1,3]benzodioxole- 7,3′- indol]- 2′(1′H)- one (1. PCT Published Patent Application No. WO 2. 00. 6/1. 10. L) was added 2- bromomethyl- 5- trifluoromethylfuran (1. C. for 1. 6 hours. Upon cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (1/9- 1/1) to afford 1′- {[5- (trifluoromethyl)furan- 2- yl]methyl}spiro[furo[2,3- f][1,3]benzodioxole- 7,3′- indol]- 2′(1 ′H)- one, i. I), (1. 1. 7 g, 7. C.; 1. H NMR (3. 00 MHz, CDCl. H), 6. 7. 2 (d, J=3. Hz, 1. H), 6. 6. 6 (s, 1. H), 6. 0. 7 (s, 1. H), 5. 9. 0- 5. 8. H), 5. 0. 5, 4. 8. ABq, JAB=1. 6. 1 Hz, 2. H), 4. 9. 1 (d, J=9. Hz, 1. H), 4. 6. 6 (d, J=9. Hz, 1. H); 1. 3C NMR (7. MHz, CDCl. 3) δ 1. MS (ES+) m/z 4. 30. M+1), 4. 52. 2 (M+2. Cal’d for C2. 2H1. F3. NO5: C, 6. 1. H, 3. 2. 9%; N, 3. Found: C, 6. 1. 5. H, 3. 2. 9%; N, 3. Synthetic Example 2. Resolution of Compound of Formula (I) by Chiral HPLCThe compound of formula (I) was resolved into the (S)- enantiomer of the invention and the corresponding (R)- enantiomer by chiral HPLC under the following conditions: Column: Chiralcel® OJ- RH; 2. I. D.×2. 50 mm, 5 mic; Lot: OJRH CJ- EH0. Daicel Chemical Industries, Ltd)Eluent: Acetonitrile/Water (6. Flow rate: 1. 0 m. L/min. Run time: 6. Loading: 1. 00 mg of compound of formula (I) in 1 m. L of acetonitrile. Temperature: Ambient. Under the above chiral HPLC conditions, the (R)- enantiomer of the compound of formula (I), i. R)- 1′- {[5- (trifluoromethyl)furan- 2- yl]methyl}spiro[furo[2,3- f][1,3]- benzodioxole- 7,3′- indol]- 2′(1′H)- one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)> 9. OJ- RH, 5. 5% acetonitrile in water); mp 1. C.; 1. H NMR (3. 00 MHz, DMSO- d. H), 6. 7. 1 (d, J=3.
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