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It may take guts to cure diabetes: Human GI cells retrained to produce insulin
By switching off a single gene, scientists at Columbia University’s Naomi Berrie Diabetes Center have converted human gastrointestinal cells into insulin-producing cells, demonstrating in principle that a drug could retrain cells inside a person’s GI tract to produce insulin.
The new research was reported today in the online issue of the journal Nature Communications.
“People have been talking about turning one cell into another for a long time, but until now we hadn’t gotten to the point of creating a fully functional insulin-producing cell by the manipulation of a single target,” said the study’s senior author, Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes (in Medicine) at Columbia University Medical Center (CUMC).
The finding raises the possibility that cells lost in type 1 diabetes may be more easily replaced through the reeducation of existing cells than through the transplantation of new cells created from embryonic or adult…
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Artificial enzyme mimics the natural detoxification mechanism in liver cells
Mode of action of molybdenum oxide nanoparticles: (a) treatment of sulfite oxidase deficient liver cells; (b) mitochondria are directly targeted, nanoparticles accumulate in proximity to the membrane; (c) sulfite is oxidized to cellular innocuous sulfate.
Scientists at Johannes Gutenberg University Mainz in Germany have discovered that molybdenum trioxide nanoparticles oxidize sulfite to sulfate in liver cells in analogy to the enzyme sulfite oxidase. The functionalized Molybdenum trioxide nanoparticles can cross the cellular membrane and accumulate at the mitochondria, where they can recover the activity of sulfite oxidase.
Sulfite oxidase is a molybdenum containing enzyme located in the mitochondria of liver and kidney cells, which catalyzes the oxidation of sulfite to sulfate during the protein and lipid metabolism and therefore plays an important role in cellular detoxification processes. A lack of functional sulfite oxidase is a rare but fatal genetic disease causing neurological disorders, mental retardation, physical deformities as well as…
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A Recipe To Make Cannabis Oil For A Chemotherapy Alternative
Awareness with regards to cannabis as a treatment and potential cure for cancer has been rapidly increasing over the past few years. Several studies over the last decade have clearly (without question) demonstrated the anti-tumoral effects of the plant. Cannabinoids (any group of related compounds that include cannabinol and the active constituents of cannabis) activate cannabinoid receptors in the body. The human body itself produces compounds called endocannabinoids and they play a very important role in many processes within the body to help create a healthy environment.
Since radiation and chemotherapy are the only two approved treatments for cancer, it’s important to let people know that other options do exist. There’s nothing wrong with exploring these options and finding out more information about them so people can make the best possible choice for themselves. It’s always important to do your own research.
A number of people have used this treatment…
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TA 1887 a highly potent and selective hSGLT2 inhibitor
6a-4 is TA 1887
TA 1887
CAS 1003005-29-5
Deleted CAS Registry Numbers: 1274890-87-7
C24 H26 F N O5
1H-Indole, 3-[(4-cyclopropylphenyl)methyl]-4-fluoro-1-β-D-glucopyranosyl-
3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside
(2R,3R,4S,5S,6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol,
(TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2
Mitsubishi Tanabe Pharma Corp,
Glucagon-like peptide-1 (GLP-I) is an incretin hormone that is released from L-cells in lower small intestine after food intake. GLP-I has been shown to stimulate glucose-dependent insulin secretion from pancreatic β-cells and increase pancreatic β-cell mass. GLP-I has also been shown to reduce the rate of gastric emptying and promote satiety. However, GLP-I is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) leading to inactivation of its biological activity. Therefore, DPP4 inhibitors are considered to be useful as anti-diabetics or anti-obesity agents.
Sodium-glucose co-transporters (SGLTs) , primarily found in the intestine and the kidney, are a family of proteins involved in glucose absorption. Plasma glucose is filtered in the glomerulus and is reabsorbed by SGLTs in the proximal tubules. Therefore, inhibition of SGLTs cause excretion of blood glucose into urine and leads to reduction of plasma glucose level. In fact, it is confirmed that by continuous subcutaneous administration of an SGLT inhibitor, phlorizin, to diabetic animal models, the blood glucose level thereof can be normalized, and that by keeping the blood glucose level normal for a long time, the insulin secretion and insulin resistance can be improved [cf., Journal of Clinical Investigation, vol. 79, p. 1510 (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991) ] .
In addition, by treating diabetic animal models with an SGLT inhibitor for a long time, insulin secretion response and insulin sensitivity of the animal models are improved without incurring any adverse affects on the kidney or imbalance in blood levels of electrolytes, and as a result, the onset and progress of diabetic nephropathy and diabetic neuropathy are prevented [cf., Journal of Medicinal Chemistry, vol. 42, p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578 (2001)].
In view of the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and to prevent the onset and progress of diabetes mellitus and diabetic complications
DPP4 inhibitors are well known to those skilled in the art, and examples of DPP4 inhibitors can be found in the following publications: (1) TANABE SEIYAKU Co., Ltd.: WO 02/30891 or the corresponding U.S. patent (No. 6,849,622); and WO 02/30890 or the corresponding U.S. patent (No. 7,138,397); .
(2) Ferring BV: WO 95/15309, WO 01/40180, WO 01/81304, WO
01/81337, WO 03/000250, and WO 03/035057; (3) Probiodrug: WO 97/40832, EP1082314, WO 99/61431, WO
03/015775; (4) Novartis AG: WO 98/19998, WO 00/34241, WO 01/96295, US 6,107,317, US 6,110,949, and US 6,172,081;
(5) GlaxoSmithKline: WO 03/002531, WO 03/002530, and WO 03/002553; (6) Bristol Myers Squibb: WO 01/68603, WO 02/83128, and WO 2005/012249;
(7) Merck & Co.: WO 02/76450, and WO 03/004498;
(8) Srryx Inc.: WO 2005/026148, WO 2005/030751, WO 2005/095381, WO 2004/087053, and WO 2004/103993; (9) Mitsubishi Pharma Corp.: WO 02/14271, US 7,060,722, US
7,074,794, WO 2003/24942, Japan Patent Publication No.
2002-265439, Japan Patent Publication No. 2005-170792, and
WO 2006/088129;
(10) Taisho Pharma Co., Ltd.: WO 2004/020407; (12) Yamanouchi Pharmaceutical Co., Ltd.: WO 2004/009544,-
(13) Kyowa Hakko Kogyo : WO 02/051836;
(14) Kyorin Seiyaku: WO 2005/075421, WO 2005/077900, and WO 2005/082847;
(15) Alantos Pharmaceuticals: WO 2006/116157; (16) Glenmark Pharmaceuticals: WO 2006/090244, and WO 2005/075426;
(17) Sanwa Kagaku Kenkyusho : WO 2004/067509; and
(18) LG lifescience: WO 2005/037828, and WO 2006/104356.
In a preferable embodiment of the present invention, DPP4 inhibitors are the aliphatic nitrogen-containing 5- membered ring compounds disclosed in US 6,849,622, which are represented by Formula (29) :
…………………………………………..
WO 2012162115
http://www.google.com/patents/EP2712359A2?cl=en
The present invention is further directed to a process for the preparation of a compound of formula (l-S)
(l-S)
(also known as 3-(4-cyclopropylbenzyl)-4-fluoro-1 -p-D-glucopyranosyl- 1 /-/-indole); or a pharmaceutically acceptable salt or prodrug thereof;
comprising
reacting a compound of formula (V-S), wherein PG1 is an oxygen protecting group with an acylating reagent; wherein the acylating reagent is present in an amount in the range of from about 1 .5 to about 3.0 molar equivalents; in the presence of a carbonyl source; in a first organic solvent; at a temperature in the range of from about room temperature to about 40°C; to yield the corresponding compound of formula (Vl-S);
reacting the compound of formula (Vl-S) with a compound of formula (Vll-S), wherein A1 is MgBr or MgCI; in an anhydrous organic solvent; to yield the corresponding compound of formula (Vlll-S);
reacting the compound of formula (Vlll-S) with a reducing agent; in the presence of a Lewis acid; in a second organic solvent; to yield the
corresponding compound of formula (IX-S);
Scheme 2.
Example 1 : f2R.3R.4S.5R.6R)-2-facetoxymethyl)-6-f4-fluoro-3-formyl-1 H- indol-1 -yl)tetrahvdro-2H-pyran-3,4,5-triyl triacetate
A 5-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, addition funnel, condenser, heating mantle, and a nitrogen inlet adapter was (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-fluoro-1 H- indol-1 -yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (225.0 g, 0.459 mol), DCE (1 .5 L) and DMF (50.2 ml_, 0.643 mol). The resulting mixture was warmed to 25°C, then phosphoryl chloride (107.8 ml_, 1 .15 mol) was added slowly via an addition funnel over 75 min. The resulting mixture was stirred for 30 min after the addition was completed, then slowly warmed to 40°C over 30 min, and then agitated at 40°C for an additional 12 h. The resulting solution was slowly poured into a rapidly stirred warm (40°C) 3M aqueous NaOAc (3.0 L) solution over 45 min. After the addition was completed, CH2CI2 (4.0 L) was added and the phases were separated. The aqueous phase was back extracted with CH2CI2 (1 .0 L) and the organic phases were combined, washed with 0.05 M HCI (2.0 L) and deionized water (2.0 L), then dried over MgS04. After filtration, the solvents were concentrated to dryness in vacuo to yield a solid, which was flushed with ethanol (1 .0 L) and re-evaporated. The resulting solid was transferred into a vacuum oven and dried at 40°C for 20 h to yield the title compound as a slightly yellow-brown solid.
1 H NMR (DMSO-d6, 300 MHz) δ 10.1 (s, 1 H), 8.53 (s, 1 H), 7.66 (d, J = 7.3 Hz, 1 H), 7.38 (m, 1 H), 7.10(dd, J = 6.7, 6.9 Hz, 1 H), 6.38 (d, J = 7.5 Hz, 1 H), 5.68 (dd, J = 6.5, 6.6 Hz, 1 H), 5.56 (t, J = 7.1 Hz, 1 H), 5.32 (t, J = 7.2 Hz, 1 H) 4.41 – 4.28 (m, 1 H), 4.24 – 4.06 (m, 2 H), 2.05 (s, 3H), 2.0 (s, 3H), 1 .98 (s, 3H), 1 .64 (s, 3H) 1JC NMR (DMSO-c(6, 75.47 MHz) £183.8, 169.9, 169.5, 169.3, 168.4, 155.8, 139.2, 135.7, 124.8, 1 17.7, 1 13.1 , 108.3, 107,9, 81 .9, 73.5, 72.1 , 70.3, 67.6, 61 .9, 20.4, 20.3, 20.1 , 19.6
LC-MS mlz MH+ = 494 (MH+), 516 [M+Na]+, 1009 [2M+Na]+
[a]D 25 = -0.099 (c = 0.316, CHCI3).
Example 2: f2R.3R.4S.5R.6R)-2-facetoxymethyl)-6-f3-ff4-cvclopropyl- phenyl)(hvdroxy)methyl)-4-fluoro-1 H-indol-1 -yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate
A 12-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter was charged with the compound prepared as in Example 1 (230 g, 0.457 mol) and anhydrous THF (4.2 L), and the resulting solution was cooled to 0°C with stirring under N2. A solution of freshly prepared (4-cyclopropylphenyl)magnesium bromide in THF (530 mL) was added dropwise via a double-tipped needle under gentle positive nitrogen pressure over 20 min, while the internal temperature was maintained between 0-8°C by adjusting the rate of addition. The resulting mixture was stirred at 0°C for 30 min. The reaction was quenched with saturated aqueous NH4CI solution (5.4 L) and then extracted with EtOAc (4 L, 3 L). The combined organic phase was washed with brine (2.7 L) and dried over MgS04. After filtration, the filtrate was concentrated at 66°C under house vacuum (-120 mmHg) followed by hi-vacuum (-20 mmHg) to yield a residue which contained a large amount of EtOAc, which residue was chased with ΟΗ2ΟΙ2 (800 mL) to yield the title compound as a yellowish solid, which was used in next step without further purification.
1 H NMR (DMSO-cfe, 300 MHz) δ 7.53 (dd, J = 7.9, 1 .1 Hz, 1 H), 7.41 (dd, J = 8.0, 1 .0 Hz, 1 H), 7.10-6.92 (m, 3 H), 6.78 (m, 1 H), 6.15 (m, 1 H), 5.92 (dd, J = 5.0, 4.1 Hz, 1 H), 5.65 (dd, J = 5.1 , 4.2 Hz, 1 H), 5.50 (m, 1 H), 5.24 (dd, J = 7.9, 8.3 Hz, 1 H), 4.38 – 4.22 (m, 1 H), 4.20-4.0 (m, 2 H), 2.05 (s, 3 H), 2.01 (s, 3 H), 1 .98 (s, 3 H), 1 .84 (m, 1 H), 0.92 (m, 2 H), 0.61 (m, 2 H)
13C NMR (DMSO-c/6, 75.47 MHz): £ 170.1 , 170.0, 169.9, 169.3, 156.1 , 140.9 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.6, 1 16.3, 1 14.6, 107.4, 105.2, 81 .5, 76.8, 73.0, 72.6, 70.1 , 68.2, 62.0, 20.6, 20.4, 20.2, 19.8, 14.8, 8.96 (2 C)
LC-MS mlz MH+ = 612 (MH+), 634 [M+Na]+.
Example 3: (2R.3R.4S.5R.6R)-2-(acetoxymethyl)-6-(3-(4- cvclopropylbenzyl)-4-fluoro-1H-indol-1 -yl)tetrahvdro-2H-pyran-3,4.5-triyl triacetate
OAc
A 3-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter, was charged with the product prepared as in Example 2 above (82%, 334.6 g, 0.449 mol), DCE (1 .14 L), CH3CN (2.28 L), and Et3SiH (108.6 mL, 0.671 mol) and the resulting mixture was stirred and cooled to 0°C under N2. Boron trifluoride etherate (68.8 mL; 0.539 mol) was added dropwise over 10 min and the resulting mixture was stirred at 0°C for 30 minutes. After completion, saturated aqueous NaHCC>3 solution (4.2 L) was added to the mixture, which was extracted with EtOAc (5 L, 4 L) and the combined organic phase was dried over MgS04. After filtration, the filtrate was concentrated under house vacuum at 60°C to yield the title compound as a slightly yellowish solid.
The slightly yellowish solid (315.0 g) was triturated with EtOH (2.1 L, 200 proof) in a 4-L heavy duty Erlenmeyer flask at 76°C (with sonication x 3), and then gradually cooled to 20°C and stirred under N2 for 1 h. The solid was then collected by filtration and washed with cold (0°C) EtOH (200 ml_), dried by air- suction for 30 min, and then placed in a vacuum oven under house vacuum with gentle of N2 stream at 60°C for 18 h, to yield the title compound as an off- white crystalline solid.
1 H NMR (DMSO-de, 300 MHz) δ 7.47 (d, J = 8.3 Hz, 1 H), 7.22 (s, 1 H),
7.20-7.10 (m, 1 H), 7.06 (d, J = 8.1 , 2 H), 6.95 (d, J = 8.1 Hz, 1 H), 6.78 (dd, J = 7.1 , 7.0 Hz, 1 H), 6.16 (d, J = 7.1 Hz, 1 H), 5.61 -5.44 (m, 2 H), 5.21 (t, J = 7.3, 7.1 Hz, 1 H), 4.34 – 4.21 (m, 1 H), 4.18-4.04 (m, 2 H), 4.0 (s, 2 H), 2.04 (s, 3 H), 1 .97 (s, 3 H), 1 .95 (s, 3 H), 1 .84 (m, 1 H), 1 .63 (s, 3 H), 0.89 (m, 2 H), 0.61 (m, 2 H)
13C NMR (DMSO-d6, 75.47 MHz): £ 169.9, 169.5, 169.3, 168.3, 156.2, 140.9, 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.7, 1 16.1 , 1 14.1 , 107.2, 105.0, 81 .7, 73.0, 72.5, 69.8, 68.0, 62.0, 31 .2, 20.4, 20.3, 20.2, 19.7, 14.6, 8.93 (2 C)
LC-MS mlz MH+ = 596 (MH+), 618 [M+Na]+, 1213 [2M+Na]+
[a]D 25 = -0.008 (c = 0.306, CHCI3).
Example 4: (2R.3R.4S.5S.6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol, ethanolate
OH
A 12-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter, was charged with the compound prepared as in Example 3 above (250 g, 0.413 mol), MeOH (1 .2 L) and THF (2.4 L), and the resulting mixture was stirred at 20°C under N2.
Sodium methoxide (2.5 ml_, 0.012 mol) solution was added dropwise and the resulting mixture was stirred at 20°C for 3 h. The solvent was concentrated at 60°C under house vacuum to yield a residue, which was dissolved in EtOAc (8.0 L), washed with brine (800 mL x 2) (Note 2), and dried over MgS04. The insoluble materials were removed by filtration, and the filtrate was concentrated at 60-66°C under hi-vacuum (20 mmHg) to yield the title compound as a slightly yellowish foamy solid.
The above obtained slightly yellowish foamy solid (195.1 g) was dissolved in EtOH (900 mL) at 76°C, and deionized H20 (1800 mL) was added slowly in a small stream that resulted in a slightly yellowish clear solution, which was then gradually cooled to 40°C with stirring while seeded (wherein the seeds were prepared, for example, as described in Example 5, below). The resulting slightly white-yellowish suspension was stirred at 20°C for 20 h, the solids were collected by filtration, washed with cold (0°C) EtOH/H20 (1 :4), and dried by air-suction for 6 h with gentle stream of N2 to yield the title compound as an off-white crystalline solid, as its corresponding EtOH/H20 solvate.
The structure of the EtOH/H20 solvate was confirmed by its 1H-NMR and LC-MS analyses. 1H-NMR indicated strong H20 and EtOH solvent residues, and the EtOH residue could not be removed by drying process. In addition, p-XRD of this crystalline solid showed a different pattern than that measured for a hemi-hydrate standard.
Example 5: (2R,3R,4S,5S,6R)-2-(3-(4-cvclopropylbenzyl)-4-fluoro-1 H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol, ethanolate
A 500-mL 3-neck round bottom flask equipped with a mechanical stirrer was charged with the compound prepared as in Example 3 above (4.67 g, 0.00784 mol), MeOH (47 mL) and THF (93 mL), and the resulting mixture was stirred at room temperature under argon atmosphere. Sodium methoxide (catalytic amount) solution was added dropwise and the resulting mixture was stirred at room temperature for 1 h. The solvent was concentrated at 30°C under reduced pressure. The residue was purified by silica gel column chromatography (chloroform : methanol = 99 : 1 – 90 : 10) to yield a colorless foamy solid (3.17 g).
First Crystallization
A portion of the colorless foamy solid prepared as described above (0.056 g) was crystallized from EtOH/H20 (1 :9, 5mL), at room temperature, to yield the title compound, as its corresponding EtOH solvate, as colorless crystals (0.047 g).
Second Crystallization
A second portion of the colorless foamy solid prepared as described above (1 .21 g) was dissolved in EtOH (6 mL) at room temperature. H20 (6 mL) was added, followed by addition of seeds (the colorless crystals, prepared as described in the first crystallization step above). The resulting suspension was stirred at room temperature for 18 h, the solids were collected by filtration, washed with EtOH/H20 (1 :4), and dried under reduced pressure to yield the title compound t, as its corresponding EtOH solvate, as an colorless crystalline solid (0.856 g).
The structure for the isolated compound was confirmed by 1H NMR, with peaks corresponding to the compound of formula (l-S) plus ethanol. Example 6: f2R.3R.4S.5S.6R)-2-f3-f4-cvclopropylbenzyl)-4-fluoro-1H-indol- 1 -yl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol hemihydrate
OH
A 5-L 4-neck round bottom flask equipped with a mechanical stirrer, a thermocouple, a septum and nitrogen inlet adapter was charged with the ethanolate (solvate) compound prepared as in Example 4 above (198.5 g, 0.399 mol) and deionized H20 (3.2 L). After the off-white suspension was warmed to 76°C in a hot water bath, along with sonication (x 4), it was gradually cooled to 20°C. The white suspension was stirred for 20 h at 20°C and then at 10°C for 1 h. The solid was collected by filtration, washed with deionized H20 (100 mL x 2), dried by air-suction for 2 h, and then placed in an oven under house vacuum with gentle stream of N2 at 50°C for 20 h, then at 60°C for 3 h to yield the title compound as an off-white crystalline solid.1 H NMR showed no EtOH residue and the p-XRD confirmed that the isolated material was a crystalline solid. TGA and DSC indicated that the isolated material contained about 2.3% of water (H20). M.P. = 108-1 1 1 °C.
1 H NMR (DMSO-c(6, 300 MHz) δ 7.36 (d, J = 8.2 Hz, 1 H), 7.22 (s, 1 H), 7.14 (d, J = 8.1 , 2 H), 7.10-7.0 (m, 1 H), 6.96 (d, J = 8.1 Hz, 2 H), 6.73 (dd, J = 7.5, 7.7 Hz, 1 H), 5.38 (d, J = 7.7 Hz, 1 H), 5.21 (d, J = 6.9 Hz, 1 H), 5.18 (d, J = 6.8 Hz, 1 H), 5.10 (d, J = 6.9 Hz, 1 H), 4.54 (t, J = 6.9, 1 .8 Hz, 1 H), 4.04 (s, 2 H), 3.75-3.60 (m, 2 H), 3.52-3.30 (m, 3 H), 3.20-3.17 (m, 1 H), 1 .84 (m, 1 H), 0.89 (m, 2 H), 0.61 (m, 2 H)
13C NMR (DMSO-de, 75.47 MHz): £ 156.2, 140.8, 139.4, 138.2, 128.2 (2 C), 125.2 (2 C), 124.4, 121 .8, 1 15.9, 1 12.8, 107.4, 104.2, 84.8, 79.3, 77.4, 71 .7, 69.8, 60.8, 31 .3, 14.6, 8.92 (2 C) LC-MS mlz MH+ = 428 (MH+), 450 [M+Na]+, 877 [2M+Na]+
[a]D 25 = -0.026 (c = 0.302, CH3OH)
Elemental Analysis: C2 H26NF05 + 0.54 H20 (MW = 437.20):
Theory: %C, 65.93; %H, 6.24; %N, 3.20; %F, 4.35, %H20, %2.23. Found: %C, 65.66; %H, 6.16; %N, 3.05; %F, 4.18, %H20, %2.26.
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SEE
JP 2009196984
……………………………………………..
WO 2008013322
http://www.google.com/patents/WO2008013322A1?cl=en
Scheme 1 :
( III ) (ID
Scheme 2 :
( In the above scheme , R4 is bromine , or iodine , and the other symbols are the same as defined above.
The starting compounds of formula (V) can be prepared in accordance with the following scheme:
(V) (In the above scheme, the symbols are the same as defined above. )
The compounds of formula (XII ) can be prepared in accordance with the following scheme :
(In the above scheme, R5 is alkyl, and the other symbols are the same as defined above.)
Example 1 :
3- (4-Cyclopropylphenylmethyl) -4-fluoro-1- (β-D-gluco- pyranosyl) indole
OH
(1) A mixture of 4-fluoroindoline (185 mg) and D-glucose (267 mg) in H2O (0.74 ml) – ethyl alcohol (9 ml) was refluxed under argon atmosphere for 24 hours. The solvent was evaporated under reduced pressure to give crude 4-fluoro-1- (β-D-glucopyranosyl) indoline, whichwas used in the subsequent step without furtherpurification.
(2) The above compound was suspended in chloroform (8 ml) , and thereto were added successively pyridine (0.873 ml), acetic anhydride (1.02 ml) and 4- (dimethylamino) pyridine (a catalytic amount) . After being stirred at room temperature for 21 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate , and the solution was washed witha 10 % aqueous copper (II) sulfate solutiontwice anda saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 60 : 40) to give 4-fluoro-1- (2, 3, 4, 6- tetra-O-acetyl-β-D-glucopyranosyl) indoline (365 mg) as colorless amorphous. APCI-Mass m/Z 468 (M+H) . 1H-NMR (DMSO-d6) δ 1.93 (s, 3H) , 1.96 (S1 3H) , 1.97 (s, 3H) , 2.00 (s, 3H) , 2.83 (ddd, J = 15.5, 10.5 and 10.3 Hz, IH) , 2.99 – 3.05 (m, IH) , 3.49 – 3.57 (m, 2H), 3.95 – 3.99 (m, IH), 4.07 – 4.11 (m, 2H), 4.95 (t, J = 9.5 Hz, IH) , 5.15 (t, J = 9.4 Hz, IH) , 5.42 (t, J= 9.6Hz, IH) , 5.49 (d, J= 9.3 Hz, IH) , 6.48 (t, J = 8.6 Hz, IH) , 6.60 (d, J = 8.0 Hz, IH) , 7.05 – 7.10 (m, IH) .
(3) The above compound (348 mg) was dissolved in 1,4-dioxane (14 ml), and thereto was added 2, 3-dichloro-5, 6-dicyano-l, 4- benzoquinone (306 mg) . After being stirred at room temperature for 33 hours , thereto was added a saturated aqueous sodium hydrogen carbonate solution (20 ml) , and the organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate twice, and the combinedorganic layerwas washedwithbrine, dried over magnesium sulfate and treated with activated carbon. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 60 : 40) and recrystallization from ethyl alcohol to give 4-fluoro-1- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) indole (313 mg) as colorless crystals, mp 132-135°C. APCI-Mass m/Z 483 (M+NH4) . 1H-NMR (DMSO-d6) δ 1.64 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.04 (S, 3H), 4.10 (ABX, J = 12.4, 2.7 Hz, IH), 4.14 (ABX, J = 12.4, 5.2 Hz, IH) , 4.31 (ddd, J = 10.0, 5.2 and 2.7 Hz, IH) , 5.25 (t, J = 9.7 Hz, IH) , 5.53 (t, J = 9.5 Hz, IH) , 5.61 (t, J = 9.3 Hz, IH) , 6.22 (d, J = 9.0 Hz, IH) , 6.58 (d, J = 3.4 Hz, IH) , 6.88 (dd, J = 10.8, 7.9 Hz, IH) , 7.19 (td, J = 8.1, 5.3 Hz, IH) , 7.51 (d, J“ = 8.5 Hz, IH) , 7.53 (d, J = 3.4 Hz, IH) . (4) The above compound (3.50 g) and N, N-dimethylformamide (3.49 ml) were dissolved in 1, 2-dichloroethane (70 ml) , and thereto was added dropwise phosphorus (III) oxychloride (2.10 ml) . The mixture was stirred at 7O0C for 1 hour, and thereto was added water (100 ml) at 00C. The resultant mixture was extracted with ethyl acetate (200 ml) twice, and the combined organic layer was washed with brine (40 ml) and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 – 50 : 50) and recrystallization from ethyl alcohol (20 ml) to give
4-fluoro-1- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) – indole-3 -carboxaldehyde (2.93 g) as colorless crystals, tnp 190 – 192°C. APCI-Mass m/Z 511 (M+NH4) . 1H-NMR (DMSO-de) δ 1.64 (s,
3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 4.12 (A part of
ABX, J = 12.4, 2.5 Hz, IH) , 4.17 (B part of ABX, «7 = 12.4, 5.5
Hz, IH) , 4.33 (ddd, J= 10.0, 5.5 and 2.5 Hz, IH) , 5.32 (t, J= 9.8 Hz, IH) , 5.56 (t, J = 9.6 Hz, IH) , 5.66 (t, J = 9.3 Hz, IH) ,
6.36 (d, J = 9.0 Hz, IH) , 7.11 (dd, J = 10.6, 8.0 Hz, IH) , 7.38
(td, J = 8.1, 5.1 Hz, IH) , 7.65 (d, J = 8.3 Hz, IH) , 8.53 (s, IH) ,
10.0 (d, J = 2.9 Hz, IH) .
(5) To a mixture of magnesium turnings (664 mg) and 1, 2-dibromoethane (one drop) in tetrahydrofuran (40 ml) was added dropwise a solution of l-bromo-4-cyclopropylbenzene (see WO 96/07657) (5.2Ig) in tetrahydrofuran (12 ml) over 25 minutes under being stirred vigorously, and the mixture was vigorously stirred for 30 minutes at room temperature. The resultant mixture was then dropwise added to a solution of the above 4-fluoro-1- (2 , 3 , 4, 6- tetra-O-acetyl-β-D-glucopyranosyl) indole-3 -carboxaldehyde (4.35 g) in tetrahydrofuran (130 ml) over 15 minutes at -780C under argon atmosphere . The mixture was stirred at same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution (200 ml) . The resultant mixture was extracted with ethyl acetate (150 ml) twice, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4-cyclopropylphenyl 4-fluoro-l- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) indol-3-yl methanol, which was used in the subsequent step without further purification.
(6) To a stirred solution of the above compound and triethylsilane (2.11 ml) in dichloromethane (44 ml) – acetonitrile (87 ml) was added boron trifluoride -diethyl ether complex (1.34 ml) at O0C under argon atmosphere . The mixture was stirred at same temperature for 20 minutes, and thereto was added a saturated aqueous sodium
m/Z 479/481 (M+NH4) . 1H-NMR (DMSO-d6) δ 0.59 – 0.62 (m, 2H) , 0.88
– 0.91 (m, 2H) , 1.83 – 1.87 (m, IH) , 3.21 – 3.50 (m, 4H) , 3.57
– 3.63 (m, IH) , 3.65 – 3.71 (m, IH) , 4.18 (s, 2H) , 4.54 (t, J = 5.5 Hz, IH) , 5.10 (d, J = 5.3 Hz, IH) , 5.16 (d, J = 5.0 Hz, IH) , 5.23 (d, J“ = 5.8 Hz, IH) , 5.38 (d, J“ = 9.0 Hz, IH) , 6.97 (d, J“ = 8.2 Hz, 2H) , 7.01 (dd, J“ = 9.4, 2.0 Hz, IH) , 7.08 (d, J“ = 8.0 Hz, 2H) , 7.22 (s, IH) , 7.47 (dd, J = 10.1, 2.1 Hz, IH) .
……………………………………………………………..
US 20110065200
http://www.google.com/patents/US20110065200
Glucose analogs have long been used for the study of glucose transport and for the characterization of glucose transporters (for review, see Gatley (2003) J Nucl Med. 44(7):1082-6). Alpha-methylglucoside (AMG) is often the analog of choice for cell-based assays designed to study the activity of SGLT1 and/or SGLT2.
……………………………………..
WO 2009091082
http://www.google.com/patents/WO2009091082A1?cl=en
R1 = FLUORO, R2= H
……………….
Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes
(ACS Medicinal Chemistry Letters) Thursday November 21st 2013
Author(s): Sumihiro Nomura, Yasuo Yamamoto, Yosuke Matsumura, Kiyomi Ohba, Shigeki Sakamaki, Hirotaka Kimata, Keiko Nakayama, Chiaki Kuriyama, Yasuaki Matsushita, Kiichiro Ueta, Minoru Tsuda-Tsukimoto,
DOI:10.1021/ml400339b
GO TO: [Article]
http://pubs.acs.org/doi/full/10.1021/ml400339b
………………
Organic Process Research & Development (2012), 16(11), 1727-1732.
A practical synthesis of two N-glycoside indoles 1 and 2, identified as highly potent sodium-dependent glucose transporter (SGLT) inhibitors is described. Highlights of the synthetic process include a selective and quantitative Vilsmeier acylation and a high-yielding Grignard coupling reaction. The chemistry developed has been applied to prepare two separate SGLT inhibitors 1 and 2 for clinical evaluation without recourse to chromatography.
http://pubs.acs.org/doi/abs/10.1021/op3001355
…………………
Journal of Medicinal Chemistry (2010), 53(24), 8770-8774
http://pubs.acs.org/doi/abs/10.1021/jm101080v
………………….
TETRAACETYL COMPD
Organic Process Research & Development (2012), 16(11), 1727-1732.
http://pubs.acs.org/doi/full/10.1021/op3001355
1003005-35-3
- C32 H34 F N O9
- 1H-Indole, 3-[(4-cyclopropylphenyl)methyl]-4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
-
Preparation of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-(4-cyclopropylbenzyl)-4-fluoro-1H-indol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (6)To a stirred solution of 5 (82%, 334.6 g, 0.449 mol) in DCE (1.14 L) and MeCN (2.28 L) at 0 °C was added Et3SiH (108.6 mL, 0.671 mol) followed by the addition of boron trifluoride etherate (68.8 mL, 0.539 mol) ———DELETE………………….. There was obtained 228.6 g (85% isolated yield, 98.4 LCAP) of pure 6 as an off-white crystalline solid. Mp 168–169 °C. 1H NMR (DMSO-d6, 300 MHz) δ 7.47 (d, J = 7.2 Hz, 1H), 7.22 (s, 1H), 7.20–7.10 (m, 1H), 7.06 (d, J = 8.1, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.78 (dd, J = 7.3, 7.0 Hz, 1H), 6.16 (d, J = 7.1 Hz, 1H), 5.61–5.48 (m, 2H), 5.21 (t, J = 7.3, 7.1 Hz, 1H), 4.34 – 4.25 (m, 1H), 4.18–4.04 (m, 2H), 4.0 (s, 2H), 2.04 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.84 (m, 1H), 1.61 (s, 3H), 0.89 (m, 2H), 0.61 (m, 2H). 13C NMR (DMSO-d6, 75.47 MHz): δ 169.9, 169.5, 169.3, 168.3, 156.2, 140.9, 139.0, 137.9, 128.0 (2 C), 125.2 (2 C), 124.2, 122.7, 116.1, 114.1, 107.2, 105.0, 81.7, 73.0, 72.5, 69.8, 68.0, 62.0, 31.2, 20.4, 20.3, 20.2, 19.7, 14.6, 8.93 (2 C). HRMS: m/z = 596.2261 [M – 1]+. [α]25D = −0.008 (c = 0.306, CHCl3).
WO2005012326A1 * Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter WO2006035796A1 * Sep 28, 2005 Apr 6, 2006 Norihiko Kikuchi 1-(β-D-GLYCOPYRANOSYL)-3-SUBSTITUTED NITROGENOUS HETEROCYCLIC COMPOUND, MEDICINAL COMPOSITION CONTAINING THE SAME, AND MEDICINAL USE THEREOF WO2010092124A1 * Feb 11, 2010 Aug 19, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof WO2010092125A1 * Feb 11, 2010 Aug 19, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof WO2011143296A1 * May 11, 2011 Nov 17, 2011 Janssen Pharmaceutica Nv Pharmaceutical formulations comprising 1 – (beta-d-glucopyranosyl) – 2 -thienylmethylbenzene derivatives as inhibitors of sglt US8163704 Oct 18, 2010 Apr 24, 2012 Novartis Ag Glycoside derivatives and uses thereof US8466114 Mar 21, 2012 Jun 18, 2013 Novartis Ag Glycoside derivatives and uses thereof WO2009091082A1 * Jan 16, 2009 Jul 23, 2009 Mitsubishi Tanabe Pharma Corp Combination therapy comprising sglt inhibitors and dpp4 inhibitors WO2009117421A2 * Mar 17, 2009 Sep 24, 2009 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease WO2011048148A2 Oct 20, 2010 Apr 28, 2011 Novartis Ag Glycoside derivative and uses thereof WO2012089633A1 * Dec 22, 2011 Jul 5, 2012 Sanofi Novel pyrimidine derivatives, preparation thereof, and pharmaceutical use thereof as akt(pkb) phosphorylation inhibitors WO2012162113A1 * May 18, 2012 Nov 29, 2012 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibittors of sglt-2 WO2012162115A2 * May 18, 2012 Nov 29, 2012 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt-2 WO2013090550A1 * Dec 13, 2012 Jun 20, 2013 National Health Research Institutes Novel glycoside compounds US7666845 Dec 3, 2007 Feb 23, 2010 Janssen Pharmaceutica N.V. Compounds having inhibitory activity against sodium-dependent glucose transporter US8394772 Oct 20, 2010 Mar 12, 2013 Novartis Ag Glycoside derivative and uses thereof US8697658 Dec 13, 2012 Apr 15, 2014 National Health Research Institutes Glycoside compounds
FDA grants breakthrough therapy designation to Boehringer’s Idarucizumab, BI 655075
- 1-225-Immunoglobulin G1, anti-(dabigatran) (human-Mus musculus γ1-chain) (225→219′)-disulfide with immunoglobulin G1, anti-(dabigatran) (human-Mus musculus κ-chain)Protein SequenceSequence Length: 444, 225, 219
BI 655075, Idarucizumab
- Idarucizumab [INN]
- UNII-97RWB5S1U6
CAS 1362509-93-0
Treatment of dabigatran associated haemorrhage
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Boehringer Ingelheim Pharmaceuticals’ idarucizumab, an investigational fully humanised antibody fragment being studied as a specific antidote for Pradaxa.
Boehringer Ingelheim Pharmaceuticals Medicine & Regulatory Affairs senior vice-president Sabine Luik said: “We are committed to innovative research and to advancing care in patients taking Pradaxa.
http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2013-004813-41-EE
- IDARUCIZUMAB (BI 655075)
- What is it? It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
- What anticoagulant drugs might it reverse? Dabigatran.
- Clinical trial status: (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is in the planning stages and will likely start in 2014. (b) A phase 1 study to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers has been completed (NCT01688830), another two are ongoing (NCT01955720; NCT02028780).
June 26, 2014
Pradaxa Antidote, Idarucizumab Designated Breakthrough Therapy
Boehringer Ingelheim announced that the FDA has granted Breakthrough Therapy designation to idarucizumab, an investigational fully humanized antibody fragment (Fab), being evaluated as a specific antidote for Pradaxa (dabigatran etexilate mesylate).
Data from a Phase 1 trial demonstrated that idarucizumab was able to achieve immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy humans. The on-set of action of the antidote was detected immediately following a 5-minute infusion while thrombin time was reversed with idarucizumab. Reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2g dose and in 8 out of 8 subjects who received the 4g dose. The 1g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran.
RELATED: Anticoagulant Dosing Conversions
A global Phase 3 study, RE-VERSE AD, is underway in patients taking Pradaxa who have uncontrolled bleeding or require emergency surgery or procedures. Currently there are no specific antidotes for newer oral anticoagulants.
Pradaxa is approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (AF). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulant for 5–10 days. To reduce risk of recurrent DVT/PE in patients who have been previously treated.
For more information call (800) 542-6257 or visit Boehringer-Ingelheim.com.
FDA approves Alcobra’s protocol for Phase IIb study of metadoxine drug candidate
Metadoxine
Israel-based Alcobra has received approval from the US Food and Drug Administration (FDA) for its protocol for planned Phase IIb clinical study of Metadoxine Extended Release (MDX) drug candidate for the treatment of Fragile X Syndrome.
The multi-center, randomized, placebo-controlled, Phase IIb study, will be conducted primarily in the US and patient enrollment is expected to begin in the near future.
The study is supported by data collected from multiple earlier pre-clinical studies which demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction.
Metadoxine, or Pyridoxol L-2-pyrrolidone-5-carboxylate, whose structure formula is reported hereinbelow
is known for its effectiveness in acute and chronic alcoholism and for the prevention of alcohol related pathology
 |
|
| Systematic (IUPAC) name | |
|---|---|
| L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1) | |
| Clinical data | |
| Legal status | PHASE 2 |
| Routes | Oral, IV |
| Identifiers | |
| CAS number | 0074536-44-0 |
| ATC code | N07BB |
| Chemical data | |
| Formula | C13H18N2O6 |
| Mol. mass | 298 g/mol |
………..
Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol abuse.[1] Metadoxine improved the clinical signs of acute alcohol intoxication and accelerated alcohol clearance from the blood [2]It is presently in human clinical trials as an attention-deficit/hyperactivity disorder predominantly inattentive treatment.[3]
Pyridoxine is one form of vitamin B6 and a precursor to the metabolically active pyridoxal phosphate. Pyridoxal phosphate is a coenzyme to many enzymes: see vitamin B6 metabolic functions.
Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway.[4] Glutathione is an important antioxidant and combats redox imbalance. It also supports de novo ATP synthesis.[5]
Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.
Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual. For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:
(1) (2)
WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents. WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2El, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.
Several studies have shown that in order to effectively treat alcohol intoxication, there is a need for a relatively high daily dose (ca. 900 mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007, 120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26 (3), 340-346). These studies disclose side effects associated with the use of metadoxine, including nausea and vomiting.
Thus, there exists a need in the art for effective and safe drugs for treating alcohol intoxication and other associated diseases.
History
Metadoxine is predominantly used in developing nations for acute alcohol intoxication. Alternate names include: Abrixone (Eurodrug, Mexico), Alcotel (Il Yang, South Korea), Ganxin (Qidu Pharmaceutical, China), Metadoxil (Baldacci, Georgia; Baldacci, Italy; Baldacci, Lithuania; CSC, Russian Federation; Eurodrug, Colombia; Eurodrug, Hungary; Eurodrug, Thailand; Micro HC, India), Viboliv (Dr. Reddy’s, India), and Xin Li De (Zhenyuan Pharm, China).[6]
Fatty liver refers to a pathogenic condition where fat comprises more than 5% of the total weight of the liver. Liver diseases including the fatty liver, hepatitis, fibrosis and cirrhosis are known to be the most serious disease next to cancer causing death in people with ages 40 to 50, in the advanced countries. In advanced countries, nearly about 30% of the population is with fatty liver, and about 20% of people with fatty liver progresses to cirrhosis. About half of the cirrhosis patients die of liver diseases within 10 years after the diagnosis. Fatty liver and steatohepatitis are frequently found in people who intake excessive alcohols and who have obesity, diabetes, hyperlipemia, etc. Among them, alcoholic steatohepatitis (ASH), which is caused by excessive alcohol intake, is at high risk of progressing to hepatitis, cirrhosis and hepatoma, along with non-alcoholic steatohepatitis (NASH).
When taken in, alcohol is carried to the liver and oxidized to acetaldehyde by such enzymes as alcohol dehydrogenase, catalase, etc. The acetaldehyde is metabolized and converted into acetate and is used as energy source. Repeated alcohol intake induces the increase of NADH and NADP+ during the metabolism and acetaldehyde which as the metabolite product of alcohol depletes GSH, thereby changing intracellular oxidation-reduction homeostasis and inducing oxidative stress. Oxidative stress may cause mitochondrial dysfunction, lipid peroxidation and protein modification, thereby leading to death of hepatocytes, inflammation, activation of astrocytes, and the like. In addition, the increase of NADH promotes lipid synthesis, thereby inducing fatty liver.
At present, there are few therapeutically effective drugs for treating fatty liver. Exercise and controlled diet are recommended, but these are not so effective in treating fatty liver. The development of an effective treatment drug is in desperate need. As it is known that fatty liver is related with insulin resistance which is found in diabetes and obesity, the therapeutic effect of some anti-diabetic drugs, e.g., metformin, on fatty liver has been reported. But, the drug has the problem that it may induce adverse reactions such as hepatotoxicity or lactic acidosis. Betaine, glucuronate, methionine, choline and lipotrophic agents are often used as alternative supplementary drug therapy, but they are not fully proven on medical or pharmaceutical basis. Accordingly, development of a fatty liver treatment having superior effect and safety with no adverse reactions is in need.
Metadoxine (pyridoxol 1-2-pyrrolidone-5-carboxylate) is a complex compound of pyridoxine and pyrrolidone carboxylate represented by the formula (1) below:
Metadoxine is a drug used to treat alcoholic liver disease. It is used to treat liver fibrosis and fatty liver through increasing alcohol metabolism and turnover, reducing toxicity of free radicals and restoring the level of ATP and glutathione (Arosio, et al., Pharmacol. Toxicol. 73: 301-304, 1993; Calabrese, et al., Int. J. Tissue React. 17: 101-108, 1995; Calabrese, et al., Drugs Exp. Clin. Res. 24: 85-91, 1998; Caballeria, et al., J. Hepatol. 28: 54-60, 1998; and Muriel, et al., Liver Int. 23: 262-268, 2003).
However, metadoxine is unable to inhibit the expression and activation of alcohol-induced cytochrome P4502E1 (CYP2E1), which is a key enzyme involved in alcohol-induced toxicity, and thus unable to control the augmentation of inflammation mediated by CYP2E1. Therefore, the treatment of alcohol-induced fatty liver using metadoxine is very limited. Further, the expression of CYP2E1 is related with insulin resistance, thus metadoxine cannot not overcome insulin resistance.
Garlic oil is a liquid including about 1% of allicin along with reduced allicin and other sulfur-containing substances. Upon binding to vitamin B1, allicin is turned into allithiamin, which is chemically stable, acts swiftly, and is easily absorbed by the digestive organs. The substance inhibits carcinogenesis induced by chemicals in white rats (Brady, et al., Cancer Res. 48: 5937-5940, 1988; and Reddy, et al., Cancer Res. 53: 3493-3498, 1993), induces phase II enzyme (Hayes, et al., Carcinogenesis 8: 1155-1157, 1987; and Sparnins, et al., Carcinogenesis 9: 131-134, 1988), and inactivates CYP2E1 (Brady, et al., Chem. Res. Toxicol. 4:642-647, 1991). In addition, garlic oil is reported to have antithrombotic, anti-atherosclerotic, antimutagenic, anticancer and antibacterial activities (Agarwal, Med. Res. Rev. 16: 111-124, 1996; and Augusti, Indian J. Exp. Biol. 34: 634-660, 1996).
Pharmacology
Treatment for acute alcohol abuse
In an animal model, metadoxine treatment increased the clearance of alcohol and acetaldehyde, reduced the damaging effect of free radicals, and enabled cells to restore cellular ATP and glutathione levels. [7][8] It increases the urinary elimination of ketones, which are formed when the oxidation rate of acetaldehyde into acetate is exceeded on massive alcohol intoxication.[8][4]
As a medical treatment, it is typically given intravenously.
Treatment for AD/HD-PI
Metadoxine is a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family.[3] Electrophysiological studies also showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.[3] It is given orally in an extended release pill, which differs from the instant release alcohol treatment.
Treatment for liver disease
Metadoxine may block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein b during hormone-induced adipogenesis.[7]
Treatment for Fragile X Syndrome
Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory.[3] The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.[3]
…………………..
PATENT
http://www.google.com/patents/WO2010013242A1?cl=en
Scheme 1
[0054] In another aspect, the invention provides methods of synthetically preparing, e.g., carboxylated lactam ring of formula (II) (e.g. wherein n=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactam ring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) in Scheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4 for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.
Scheme 2
pyridoxine
Compound IVb, n=2,3,4
[0055] In another aspect, the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:
(a) suspending an optionally substituted amino dioic acid in water and heating for a sufficient period of time to allow completing lactamization reaction;
(b) optionally decolorizing the reaction mixture to eliminate impurities;
(c) isolating the lactam carboxylate;
(d) optionally purifying the obtained lactam carboxylate by crystallization;
(e) admixing the obtained lactam carboxylate and a pyridoxine base or a derivative thereof in a solvent mixture optionally under heating; and
(f) isolating the product.
In certain embodiments, a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water. [0059] According to yet another embodiment, there is provided methods of preparing N-substituted L-pyroglutamic acid and the carboxylate thereof, such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below. Scheme 3
1-methyl-L-pyroglutamic acid
[0060] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below. The starting reagent is 2-methyl-3-hydroxy-4- methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)). The preparation of the corresponding salt is described in Example 1. Scheme 4
HCI NH 3 / MeOH 2 L-pyroglutamic acid
Compound V Compound Vl
Salt lid
[0061] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below. The starting reagent in scheme 5 is 2-methyl-3-hydroxy- 4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V). The preparation of the corresponding salt is described in Example 2. Scheme 5
Compound V
HCI
Compound VIII IX Compound L-pyroglutamic acid
, SaIt IIe
| WO2010150261A1 * | June 24, 2010 | Dec 29, 2010 | Alcobra Ltd. | A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition |
| WO2011061743A1 * | Nov 18, 2010 | May 26, 2011 | Alcobra Ltd. | Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders |
| US8476304 | Jul 3, 2012 | Jul 2, 2013 | Alcobra Ltd. | Method for decreasing symptoms of alcohol consumption |
| US8710067 | Jul 3, 2012 | Apr 29, 2014 | Alcobra Ltd. | Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition |
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| WO2009004629A2 * | Jul 3, 2008 | Jan 8, 2009 | Alcobra Ltd | A method for decreasing symptoms of alcohol consumption |
| FR2172906A1 * | Title not available | |||
| US4313952 * | Dec 8, 1980 | Feb 2, 1982 | Maximum Baldacci | Method of treating acute alcoholic intoxication with pyridoxine P.C.A. |
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Recently a team of researchers from Shanghai University conducted a study exploring a traditional Chinese Herbal Formula called Zuo Jin Wan on stomach cancer cells. The formula itself is quite basic compared to many in the materia medica with only two ingredients -Huang Lian and Whu Zhu Yu (ina 6:1 ratio). In TCM it is primarily used for what we would call liver fire leading to rebellious qi – which in some cases could be rephrase so to speak as poor diet and emotional stress leading to reflux.
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Laser Used to Deliver Dopamine in Hope for Parkinson’s Treatment
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The effect of catch-up growth by various diets and resveratrol intervention on bone status
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 