PF 04995274, a 5-HT4Partial Agonist

New Drug Approvals

PF-04995274,

(R)-4-((4-(((4-(Tetrahydrofuran-3-yloxy)-1,2-benzisoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol

4-(4-{4-[(R)-(Tetrahydro-furan-3-yl)oxy]-benzo[d]isoxazol-3-yloxymethyl}-piperidin-1-ylmethyl)-tetrahydro-pyran-4-ol

CAS  1331782-27-4
UNII: XI179PG9LV

MF C23-H32-N2-O6

MW 432.5138

a 5-HT4Partial Agonist

PHASE 1 Alzheimer’s type dementia.

Pfizer Inc. INNOVATOR

5-HT4 agonists have attracted attention for therapeutic value in the treatment of Alzheimer’s Disease (AD) and cognitive impairment.Acting to increase levels of acetylcholine and soluble APP alpha, 5-HT4 agonists have the potential to demonstrate both ameliorative and disease modifying effects

(R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2/-/-pyran-4-ol and pharmaceutically acceptable salts thereof. This invention also is directed, in part, to a method for treating a 5-HT4 mediated disorder in a mammal. Such disorders include acute neurological and psychiatric disorders, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer’s disease, Huntington’s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson’s disease, muscular spasms and disorders associated with muscular spasticity including tremors, depression, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance…

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WO 2016012938, New patent, LINACLOTIDE, DR. REDDY’S LABORATORIES LIMITED,

New Drug Approvals

Linaclotide structure.svgWO2016012938,  IMPROVED PROCESS FOR PREPARATION OF AMORPHOUS LINACLOTIDE

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No 3, Banjara Hills, Telangana, INDIA Hyderabad 500034 (IN)

KALITA, Dipak; (IN).
NIVRUTTI, Ramrao Jogdand; (IN).
BALAKUMARAN, Kesavan; (IN).
DESHMUKH, Shivshankar; (IN).
VUTUKURU, Naga Chandra Sekhar; (IN).
KASINA, Vara Prasad; (IN).
NALAMOTHU, Sivannarayana; (IN).
VILVA, Mohan Sundaram; (IN).
KHAN, Rashid Abdul Rehman; (IN).
TIRUMALAREDDY, Ramreddy; (IN).
MUSTOORI, Sairam; (IN)

The present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application also relates to an improved process for the purification of linaclotide.

The present application relates to an improved process for the preparation of amorphous linaclotide. Specifically, the present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application further relates to a purification process for the preparation of…

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Simultaneous measurement of multiple heteronuclear coupling constants

NMR Methodologies

MRC coverSimultaneous determination of the magnitude and the sign of multiple heteronuclear coupling constants in 19F or 31P-containing compounds” by Josep Saurí, Pau Nolis and Teodor Parella. Magn. Reson. Chem. 53, 2015, 427-432.
DOI: 10.1002/mrc.4239

The presence of a highly abundant passive nucleus (Z = 19 F or 31P) allows the simultaneous determination of the magnitude and the sign of up to three different heteronuclear coupling constants from each individual cross-peak observed in a 2D 1H-X selHSQMBC spectrum. Whereas J(HZ) and J(XZ) coupling constants are measured from E.COSY multiplet patterns, J(XH) is independently extracted from the complementary IPAP pattern generated along the detected F2 dimension. The incorporation of an extended TOCSY transfer allows the extraction of a complete set of all these heteronuclear coupling constants and their signs for an entire 1H subspin system. 1H-X/1H-Y time-shared versions are also…

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Fluoxastrobin

Fluoxastrobin

Strukturformel von Fluoxastrobin

Fluoxastrobin

Fluoxastrobin; Disarm; Fluoxastrobin [ISO]; UNII-XQ43WY091Y; HEC 480 SC;

(E)-1-[2-[6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl]oxyphenyl]-1-(5,6-dihydro-1,4,2-dioxazin-3-yl)-N-methoxymethanimine

Molecular Formula: C21H16ClFN4O5
Molecular Weight: 458.826943 g/mol

Fluoxastrobin.png

103-108 deg C

MacBean C, ed; e-Pesticide Manual. 15th ed., ver. 5.1, Alton, UK; British Crop Protection Council. Fluoxastrobin (361377-29-9) (2008-2010)

 http://fluoridealert.org/wp-content/pesticides/fluoxastrobin.2004.article.pdf

 PAPER

 

 http://pubs.rsc.org/en/content/articlehtml/2015/gc/c5gc00402k

PATENT

US-9193698-B2 / 2015-11-24

Process for preparing fluoxastrobin

(E)-(2-((6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime [Fluoxastrobin]

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To a solution of (E)-(2-((6-chloro-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14)(100 g, 0.564 mol) in toluene was added 2-chlorophenol (54 g, 0.846 mol), K2CO3 (50 g, 0.733 mol), and DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 50-60° C. for 3-4 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, aqueous NaOH (10%) (200 mL) was charged followed by water (300 mL). The mixture was stirred and the toluene layer was separated. The toluene layer was washed with a solution of brine (600 mL). The final toluene layer was recovered completely to get the crude product. To the above crude product, methanol was charged and heated to 60° C. until the clear solution is formed. The solution was stirred at room temperature to get the pure product precipitated. The pure fluoxastrobin product was filtered and washed with methanol. The product was further dried to obtain the pure fluoxastrobin product meeting the desired specifications. Yield—75-88%.

IR (cm−1, KBr) 3072.99w, 2981.58w, 2936.76s, 2819.79w, 2502.01w, 1601.14s, 1572.37s, 1447.88s, 1305.43m, 1268.11m, 1217.15m, 1191.21m, 1092.60m, 1049.05m, 1001.26w, 910.25w, 762.81w.

1H NMR (CDCl3, 400 MHz) δ 3.846 (s, 3H), 4.170-4.160 (t, J=4 Hz, 2H), 4.464-4.484 (t, J=4 Hz, 2H), 7.261-7.295 (m, 2H), 7.322-7.409 (2, 4H), 8.069 (s, 1H).

 13C NMR (CDCl3, 400 MHz) δ 63.103, 64.153, 64.550, 122.659, 123.259, 123.823, 125.712, 127.150, 127.397, 128.094, 130.511, 130.679, 130.776, 131.473, 134.138, 146.004, 148.166, 148.943, 150.354, 150.478, 151.819, 157.395, 157.466, 157.783, 157.854.

MS (EI) m/z 459.1 (M+1); MS2 (EI) m/z 427.1, 383.0, 366.9, 342.1, 306.2, 246.0, 231.1, 188.0.

HPLC (Area %): 99.40%. M.P. 108-112° C.

(Z)-(2-((6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime[(Z)-fluoxastrobin]

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Isomerisation of (Z)-Fluoxastrobin to (E)-Fluoxastrobin using methane sulphonic acid. To a stirred solution of (Z)-Fluoxastrobin (0.3 g; 0.65 mmole) in acetonitrile (3 ml) was dropwise added methane sulphonic acid (0.04 ml, 0.65 mmole) at an ambient temperature. The reaction mixture was stirred for 2-3 hr at the same temperature. The progress of reaction was monitored by thin layer chromatography (TLC). Dichloromethane (5 ml) and DM water (5 ml) was added to reaction mass at an ambient temperature. After vigorous stirring, the layers were separated. The aqueous layer was back extracted with dichloromethane (5 ml) and the combined dichloromethane layer was washed with 10% aqueous sodium bicarbonate solution (20 ml) followed by washing with 10% brine solution (20 ml). Dichloromethane was distilled off at reduced pressure at 35-45° C. to obtain (E)-Fluoxastrobin as crude product (0.25 g, 83% of theoretical yield). Crude fluoxastrobin on purification in ethanol affords pure (E)-Fluoxastrobin. Isolated product HPLC purity (% area): (Z)-fluoxastrobin: 1.02% and (E)-fluoxastrobin: 95.92%.

Isomerisation of (Z)-Fluoxastrobin to (E)-Fluoxastrobin using phosphoric acid. To a stirred solution of (Z)-Fluoxastrobin (0.25 g; 0.54 mmole) in acetonitrile (4 ml) was dropwise added phosphoric acid (0.03 g, 0.54 mmole) at an ambient temperature. The reaction mixture was stirred for 2-3 hr at the same temperature. Progress of reaction was monitored by thin layer chromatography/HPLC. Dichloromethane (5 ml) and DM water (5 ml) was added to reaction mass at an ambient temperature. After vigorous stirring, layers were separated. The aqueous layer was back extracted with dichloromethane (5 ml). The combined dichloromethane layers were washed with 10% aq. Sodium bicarbonate solution (20 ml) followed by washing with 10% brine solution (20 ml). Dichloromethane was distilled off at reduced pressure at 40-45° C. to obtained (E)-Fluoxastrobin (0.22 g, 88% of Theoretical yield). Reaction monitoring by HPLC (% area): (Z)-Fluoxastrobin: 6.79% and (E)-Fluoxastrobin: 88.84%. Isolated product HPLC purity (% area): (Z)-Fluoxastrobin: 6.94% and (E)-Fluoxastrobin: 84.43%.

IR (cm−1, KBr) 3066.28w, 2981.58w, 2939.36s, 2825.71w, 2500.61w, 1602.36s, 1572.76s, 1441.05s, 1297.05m, 1218.17m, 1116.52s, 1046.15m 1000.86w, 904.73s, 764.71w. 1H NMR (CDCl3, 400 MHz) δ 3.983 (s, 3H), 4.163-4.218 (t, 2H), 4.432-4.440 (t, J=3.2 Hz, 2H), 7.217-7.352 (m, 4H), 7.371-7.390 (m, 2H), 7.483-7.516 (m, 2H), 7.702-7.722 (d, J=8 Hz, 1H), 8.016 (s, 1H). MS (EI) m/z 459.1 (M+1); MS2 (EI) m/z 427.0, 382.9, 366.7, 340.0, 305.8, 246.1, 188.0. HPLC (Area %): 99.11%. M.P. 150-152° C.

 

Title: Fluoxastrobin

CAS Registry Number: 361377-29-9

CAS Name: (1E)-[2-[[6-(2-Chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime

Manufacturers’ Codes: HEC-5725

Trademarks: Fandango (Bayer CropSci.)

Molecular Formula: C21H16ClFN4O5

Molecular Weight: 458.83

Percent Composition: C 54.97%, H 3.51%, Cl 7.73%, F 4.14%, N 12.21%, O 17.43%

Literature References: Leaf-systemic broad-spectrum fungicide for use in cereal and food crops; member of methoxyimiodihydro-dioxazines. Prepn (stereochem. unspecified): U. Heinemann et al., DE 19602095; eidem, US 6103717 (1997, 2000 both to Bayer). Comprehensive description: S. Dutzmann et al., BCPC Conf. – Pests Dis. 2002, 365. Field trial in winter wheat seeds: I. Haeuser-Hahn et al., BCPC Int. Cong. – Crop Sci. Tech. 2003, 801. Series of articles on chemistry, biology, determn, and environmental fate: Pflanzenschutz-Nachr. Bayer (Engl. Ed.) 57, 299-449 (2004). Ecotoxicology: P. Breuer, ibid. 319.

Properties: White crystals with slight characteristic odor, mp 103-108°. bp 497° (est.). d420 1.422. Log P (octanol/water): 2.86 (20°). Vapor pressure at 20° (extrapolated): 6 ´ 10-10 Pa. Soly at 20° (g/l): n-heptane 0.04; 2-propanol 6.7; xylene 38.1; dichloromethane >250; in water (mg/l): 2.56 (unbuffered); 2.43 (pH 4); 2.29 (pH 7); 2.27 (pH 9). LD50 in rats, bobwhite quail (mg/kg): >2500, >2000 orally; LC50 (96 hr) rainbow trout, bluegill sunfish, carp (mg/l): 0.44, 0.97, 0.57 (Breuer).

Melting point: mp 103-108°

Boiling point: bp 497° (est.)

Log P: Log P (octanol/water): 2.86 (20°)

Density: d420 1.422

Toxicity data: LD50 in rats, bobwhite quail (mg/kg): >2500, >2000 orally; LC50 (96 hr) rainbow trout, bluegill sunfish, carp (mg/l): 0.44, 0.97, 0.57 (Breuer)

Use: Agricultural fungicide.

Zucapsaicin for osteoarthritis

New Drug Approvals

Chemical structure of zucapsaicin

Zucapsaicin (珠卡赛辛)

cis-Capsaicin; (Z)-Capsaicin

Zucapsaicin; Civamide; Cis-Capsaicin; 25775-90-0; (Z)-Capsaicin; (Z)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide;

(Z)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide

CAS No. 25775-90-0

MF C18H27NO3
Molecular Weight: 305.41188 g/mol

WINSTON INNOVATOR

SANOFI

(Zuacta®/Civanex®

A medication used to treat osteoarthritis of the knee and other neuropathic pain.TRPV1 CHANNEL AGONIST

Zucapsaicin.png

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. It reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use (patch and cream).[1]

Zucapsaicin has been tested for treatment of a variety of conditions associated with ongoing nerve pain. This includes herpes simplex infections; cluster headaches and migraine; and knee osteoarthritis.[2]

Civanex (zucapsaicin)…

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2-(BENZYLOXYL)-6-ETHYL-2H-PYRAN-4-ONE

2-(BENZYLOXYL)-6-ETHYL-2H-PYRAN-4-ONE

 
 

 

see………http://orgspectroscopyint.blogspot.in/2015/12/6-ethyl-4-hydroxy-2-pyrone.html

 

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