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S-flurbiprofen (TT-063)

May 19, 2015 4:20 am / Leave a comment

(S)-flurbiprofen.png

Cas 51543-39-6,

MW 244.26,

MF C₁₅ H₁₃ F O₂

[1,1′-Biphenyl]-4-acetic acid, 2-fluoro-α-methyl-, (αS)-

[1,1′-Biphenyl]-4-acetic acid, 2-fluoro-α-methyl-, (S)-
(+)-(S)-Flurbiprofen
(+)-Flurbiprofen
(2S)-2-(2-Fluoro-1,1′-biphenyl-4-yl)propanoic acid
(2S)-2-(2-Fluoro-4-biphenyl)propanoic acid

(S)-Flurbiprofen
Dexflurbiprofen
Esflurbiprofen
S-(+)-Flurbiprofen
d-Flurbiprofen

On October 20, 2014, Taisho filed for manufacturing and marketing approval for TT-063 from the Ministry of Health, Labour and Welfare as a new drug candidate that will follow the Type 2 diabetes treatment Lusefi®, which was launched in May 2014. TT-063 is a patch formulation that has been co-developed by Taisho and TOKUHON Corporation with the aim of obtaining an indication for osteoarthritis. In Phase 3 clinical trials comparing TT-063 with therapeutic drugs already on the market, TT-063 has been found to be more effective than the control drugs in patients with osteoarthritis of the knee joint (January 16, 2014 announcement ).

Furthermore, Taisho is also preparing to file for approval from the Ministry of Health, Labour and Welfare for CT-064, an oral formulation of the osteoporosis treatment agent Bonviva launched in August 2013. Taisho has confirmed the effectiveness of CT-064 for osteoporosis patients through Phase 3 clinical trials (September 22, 2014 announcement).

In the central nervous system field, TS-091 transitioned from Phase 1 to Phase 2 in Japan in May 2014. Clinical trials of TS-091 have commenced to confirm the effectiveness of this drug in patients with central disorders of hypersomnolence. In addition, Phase 1 clinical trials of TS-091 have commenced overseas. TS-111 and TS-121 are undergoing Phase 1 clinical trials overseas with the aim of obtaining an indication for depression.
Faced with intensifying competition in new drug discovery, we will jointly implement R&D activities with research institutions outside the Taisho Group, and with companies in Japan and overseas, as we work to enhance our drug development pipeline (lineup of drugs in development). Our goal is to discover many more new drugs, primarily in our priority fields.

Company	Taisho Pharmaceutical Holdings Co. Ltd.
Description	Topical anti-inflammatory analgesic patch containing S-flurbiprofen


Therapeutic Modality	Small molecule

Latest Stage of Development	Phase III
Standard Indication	Osteoarthritis
Indication Details	Treat osteoarthritis (OA) and scapulohumeral periarthritis
Regulatory Designation

Full-size image (93 K)

Scheme 2.

Reagents and conditions: (a) THF, EDC, Et₃N; (b) TFA; (c) 0.5 equiv 2,5-dimethoxybenzoquinone, EtOH, 50–80 °C for 3–5 h; (d) 1 equiv naphthoquinone, MeOH, rt, overnight.

http://www.sciencedirect.com/science/article/pii/S0960894X13011773

……………………………………………

http://www.google.com/patents/EP2307335A1?cl=en

2-(6-methoxynaphthalen-2-yl) propanoic acid By way of illustration, chemically, flurbiprofen is 2-(2-fluoro-4-biphenylyl) propionic acid and is described in US Patent No. 3,755,427. NSAIDs, such as flurbiprofen, are usually supplied as a racemate. However, recently there has been renewed interest in the separate enantiomers of flurbiprofen, i.e. S-flurbiprofen and R-flurbiprofen.

R-Flurbιprofen

S-Flurtιprofen

Flurbiprofen is a potent inhibitor of cyclooxygenase (both COX-I and COX-2) in humans and it is understood that the inhibitory effect lies predominantly in the S- enantiomer.

Flurbiprofen is generally produced in the form of a racemic compound. It is known that from the racemic compound, flurbiprofen having a high optical purity can be produced by an optical resolution method using, for example, an optically active amine compound, such as α-phenylethylamine, as an optical resolution agent, as is described in US Patent No. 5,599,969. In addition, whether dealing with racemic, S- or R- 2-aryl propionic acid, there is also a need to make the synthetic process as efficient as possible.

Example 2 – Ibuprofen

Example 2.1 Resolution procedure

Racemic ibuprofen (530g) is dissolved in toluene (1335ml) and methanol (900ml).

The mixture is heated to dissolve the solid. S-1-Phenylethylamine (247g) is dissolved in toluene (200ml) and the solution is added with stirring at 60⁰C over about 3 hours while the temperature is maintained at about 65-70⁰C. The mixture is cooled gradually to 0 to 5⁰C to induce crystallisation and stirred at this temperature for 1 hour. The crystals are filtered off, washed with toluene (600ml) and dried in a Vacuum oven at 55⁰C to form crude S-ibuprofen / S-1-phenylethylamine salt (635g).

Crude S-ibuprofen / S-1-phenylethylamine salt (635g) is stirred with toluene (1930ml) and methanol (800ml) and the mixture is heated to 6O⁰C to dissolve the solid. The solution is cooled gradually to 0 to 5°C to induce crystallisation. The crystals are filtered off and dried in a vacuum oven at 55°C to form pure S-ibuprofen / S-I- phenylethylamine salt (510g). This recrystallisation of the S-ibuprofen / S-I- phenylethylamine salt may be repeated if necessary to upgrade the enantiomeric purity if required.

Pure S-ibuprofen / S-1-phenylethylamine salt (485g) is mixed with toluene (1700ml) with stirring. Water (300ml) and concentrated hydrochloric acid (17Og) are added and

÷ibe mixture is stirred at 60⁰C. The lower aqueous layer is separated off and the upper organic layer is retained. The hydrochloric acid wash is repeated, then the toluene solution is washed with water. Water (370ml) and 47% sodium hydroxide

(118g) are added and the solution is heated to 60⁰C and allowed to settle. The lower aqueous layer is separated and the upper toluene layer is washed with water. The aqueous phases are combined and heptane (420ml) is added. Hydrochloric acid

(130g) is added and the mixture is heated to 60⁰C, stirred and settled. The organic layer is separated off and washed with water. The solution is cooled to -10⁰C to induce crystallisation and the crystals are separated off by filtration, washed with heptane and dried under vacuum to yield (S)-ibuprofen (28Og) at an enantiomeric purity of over 99%.

Example 2.2 Racemisation procedure

Toluene/methanol mother liquors from the filtration of crude S-ibuprofen / S-I- phenylethylamine salt in the resolution procedure (2400ml, containing an estimated 130g of ibuprofen) is charged into a 3 L 3 necked round bottomed flask and methanol and toluene are distilled out at atmospheric pressure (volume removed approximately 1400 ml). The batch is then cooled to around 60°C and washed twice with hydrochloric acid (20 ml concentrated hydrochloric acid in 200 ml of water), and then twice with water (200 ml). Toluene is charged (80 ml) followed by methanol (200 ml) and caustic soda solution (45Og of 28% w/w solution, 5 molar equivalents). The mixture is heated to reflux for about 6 hours. Solvent is then removed at atmospheric pressure until the vapour temperature reaches approximately 85°C. The mixture is cooled to around 60°C and concentrated hydrochloric acid is charged at about 60 to 70°C until the pH of the mixture is 1 or less. The layers are allowed to separate and the bottom aqueous layer removed. The organic layer is washed with water (200 ml) and then azeotroped to dryness using a Dean and Stark trap. A solution of racemic ibuprofen in toluene remains.

…………………………………………

PATENT

http://www.google.com/patents/CN104478703A?cl=en

Preparation of R – (+) _ flurbiprofen:

The racemic flurbiprofen as a starting material, to obtain an intermediate product of formula I as shown and then the ester prepared as shown in Formula II with 5-isosorbide monobenzyl ether, ester hydrolysis after obtained R – (+) – flurbiprofen;

wherein, in formula I, X is Cl or Br;

(2) by the R – (+) _ flurbiprofen obtained (RS) – flurbiprofen:

The R _ (+) _ flurbiprofen 200mg, potassium hydroxide 150mg, 0. 5mL water into IOmL reaction flask and heated to 120 ° C and held for 2h, then water was added 15mL, cooled to room temperature, the resulting stirring the mixed solution with 10% hydrochloric acid to pH = 0. 5, extracted with ethyl acetate, combined several layers, washed with water until neutral, the organic solvent is recovered, the resulting residue was added at 60~90 ° C under an appropriate amount of petroleum ether by recrystallization, obtained (RS) – flurbiprofen 100mg, 50% yield.

(3) Preparation of (S) -⑴- flurbiprofen:

In 25mL single-necked flask, followed by adding (RS) – flurbiprofen 123mg, Portugal TOA 29. 8mg, isopropanol lmL, the mixture was stirred at reflux until clear, half the amount of the solvent evaporated under reduced pressure except , set the refrigerator overnight. The precipitate was collected by suction filtration as white crystals, after washing a small amount of isopropanol, which was dissolved in water, washed with 10% aqueous sodium hydroxide (10% NaOH mean mass fraction) adjusted pH = 13, the sheet-like precipitate was filtered off Portuguese octylamine white crystals. The resulting filtrate was added dropwise with stirring 10% hydrochloric acid to pH = 1, extracted with ethyl acetate, the organic layer was washed with water to recover the solvent, the resulting residue was purified by an appropriate amount of petroleum ether and recrystallized at 60~90 ° C. The product was collected by filtration, and dried in vacuo to give a white (S) – (+) _ flurbiprofen needle crystal 45. 3mg, 65% yield, mp 102~103 ° C, [α] = + 44 ° (C = 1, methanol), ee value of 92.6% (ee value measurement method: (S) – (+) – flurbiprofen after chiral amine derivatization reagents, by HPLC analysis).

wherein in step (3) is a byproduct eleven R _ (+) _ flurbiprofen, its follow step (1) of racemic reused.

Step (1) of the specific operation is as follows:

(la) 1:. Synthesis of 2,6-sorbitol dehydration -D- -5- benzyl ether: 4: 3

250ml volumetric flask isosorbide 18. 25g (125mmol), lithium hydroxide monohydrate 5. 25g (125mmol) and 60ml of dimethyl sulfoxide (DMSO), heated to 90 ° C, stirred for 30min, constant pressure equalizing dropping funnel was added dropwise benzyl chloride 14. 4ml (125mmol), 90 ° C the reaction 19-20h, reaction mixture was adjusted to pH 1 with 2M hydrochloric acid, extracted with ethyl acetate (50ml * 3), the organic layers combined, washed with water ( 30ml * 2), dried over anhydrous sodium sulfate overnight, filtered and concentrated residue Cheng baby gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give a cream solid, that is 1: 4: 3: 2,6 Dehydration -D- sorbitol -5- benzyl ether 24. 5g, m.p. 59 ~61 ° C.

(Ib) · 2- (2- fluoro-4-biphenylyl) propionyl chloride Synthesis

50ml vial before racemic flurbiprofen was added 2. 44g (IOmmol), anhydrous toluene 20ml, freshly distilled thionyl chloride was added dropwise 0. 8ml (Ilmmol), N, N- dimethylformamide amide (DMF) 2 dropwise, stirred at room temperature 2h, the solvent was distilled off under reduced pressure to give a pale yellow gum, i.e., 2- (2-fluoro-4-biphenylyl) propionyl chloride, it was used directly in the reaction without isolation.

(lc). R-2- (2- fluoro-4-biphenylyl) propionic acid 5- isosorbide monobenzyl ether ester synthesis

The (Ib) resulting acid chloride was dissolved in 20ml of dry toluene was added dropwise at room temperature, dimethyl amine 3. 5ml, solid precipitation, stirred for about Ih, ice salt bath, a bath temperature of minus 10-15Ό, stirred at this temperature IOmin so, and then the constant pressure dropping funnel (Ia) 5 isosorbide monobenzyl ether (2. 83g, 12mmol) in toluene, keeping the reaction temperature, stirring 8h. The ice bath was removed and the reaction mixture under reduced pressure to remove the solvent, the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate overnight, ethyl acetate was removed under reduced pressure, the residue was a white gel, recrystallized from petroleum ether to give a white solid that R-2- (2- fluoro-4-biphenylyl) propionic acid 5- isosorbide monobenzyl ether ester 3. 65g (7. 88mmol), in order to put the racemic flurbiprofen yield based on 78.8%.

(ld) R – Synthesis of flurbiprofen – (+)

Under ice bath (Ic) obtained R-2- (2- fluoro-4-biphenylyl) propionic acid monobenzyl ether isosorbide 5- ester 2. 3Ig (5mmol) was dissolved in 20ml of acetone / water (1/1) was added Iml hydrochloric acid to adjust pH to 3, stirred for 3-4h, the reaction solution was extracted with ethyl acetate (20ml * 2), sash organic layer was washed with ice (10ml * 2), dried over anhydrous sodium sulfate overnight , filtration, and the filtrate was concentrated, the residue was recrystallized from ether to give white crystals, i.e. L-flurbiprofen 1.02g (4 18mmol.), yield 83.5%, optical purity 93% (HPLC method); input-racemic flurbiprofen dollars, the total yield of 78.8% * 83.5% = 65.8%.

Step (1) reaction of the formula:

FLURBIPROFEN RACEMIC

3-Fluoro-4-phenyl-α-methylphenylacetic acid 1

M.p. 110-113°C (lit.3d 111-113.5°C).

1 H NMR (CDCl3, δ ppm) 7.51-7.55 (m, 2H), 7.49-7.37 (m, 4H), 7.21-7.16 (m, 2H), 3.85-3.78 (q, 1H, J = 7.1 Hz, CH), 1.60-1.57 (d, 3H, J = 7.1 Hz, CH3);

13C NMR (CDCl3 δ ppm) 180.4 (COOH), 161.3 & 158.0 (3-Ar-C), 140.9 & 140.8, 135.4, 130.9 & 130.8 (5-Ar-C), 128.9, 128.4, 128.2 & 128.0 (4-Ar-C), 127.7 (4′-Ar-C), 123.7 & 123.7 (6-Ar-C), 115.5 & 115.2 (2-Ar-C), 44.8 (CH), 18.0 (CH3).

(d) Sagami Chemical Research Center. Jpn. Kokai Tokkyo Koho JP 8216840, 1982 (Chem. Abstr. 1982, 97: 5996s).

RACEMIC

Flurbiprofen

CAS : 5104-49-4

: 2-Fluoro-a-methyl[1,1¢-biphenyl]-4-acetic acid

Additional Names: 2-(2-fluoro-4-biphenylyl)propionic acid; 3-fluoro-4-phenylhydratropic acid

Manufacturers’ Codes: BTS-18322; U-27182

Trademarks: Adfeed (Lead Chem.); Ansaid (Pfizer); Antadys (Thamex); Cebutid (Boots); Froben (Boots); Flurofen (Boots); Ocufen (Allergan); Stayban (Boots); Zepolas (Mikasa)

Molecular Formula: C15H13FO2

Molecular Weight: 244.26

Percent Composition: C 73.76%, H 5.36%, F 7.78%, O 13.10%

Literature References: Prepn: FR M5737; Adams et al., US 3755427 (1968, 1973 both to Boots Co., Ltd.). Pharmacology: Chalmers et al., Ann. Rheum. Dis. 31, 319 (1972); ibid. 32, 58 (1973); Glenn et al., Agents Actions 3, 210 (1973); Nishizawa et al.,Thromb. Res. 3, 577 (1973). HPLC determn in urine and plasma: J. M. Hutzler et al., J. Chromatogr. B 749, 119 (2000). Symposium on pharmacokinetics and clinical efficacy in pain management: Am. J. Med. 80, Suppl. 3A, 1-157 (1986).

Properties: Crystals from petr ether, mp 110-111°. Slightly sol in water (pH 7.0); readily sol in most polar solvents.

Melting point: mp 110-111°

Therap-Cat: Anti-inflammatory; analgesic.

racemic

Flurbiprofen NMR spectra analysis, Chemical CAS NO. 5104-49-4 NMR spectral analysis, Flurbiprofen C-NMR spectrum

Flurbiprofen NMR spectra analysis, Chemical CAS NO. 5104-49-4 NMR spectral analysis, Flurbiprofen H-NMR spectrum

s form

(S)-Flurbiprofen NMR spectra analysis, Chemical CAS NO. 51543-39-6 NMR spectral analysis, (S)-Flurbiprofen H-NMR spectrum

(S)-Flurbiprofen NMR spectra analysis, Chemical CAS NO. 51543-39-6 NMR spectral analysis, (S)-Flurbiprofen C-NMR spectrum

Patent	Submitted	Granted
Methods to accelerate the isolation of novel cell strains from pluripotent stem cells and cells obtained thereby [US2008070303]	2006-11-21	2008-03-20
Herpes Virus-Based Compositions and Methods of Use in the Prenatal and Perinatal Periods [US2008226601]	2006-06-05	2008-09-18
METHOD OF REDUCING ABETA42 AND TREATING DISEASES [US2008021085]	2007-06-21	2008-01-24
METHODS TO ACCELERATE THE ISOLATION OF NOVEL CELL STRAINS FROM PLURIPOTENT STEM CELLS AND CELLS OBTAINED THEREBY [US2010184033]	2009-07-16	2010-07-22
Pyridyl Amide T-Type Calcium Channel Antagonists [US2011112064]	2011-05-12
PROCESS FOR THE MANUFACTURE OF RACEMIC 2-ARYL-PROPIONIC ACID [US2011172460]

Patent	Submitted	Granted
Nitroxyderivatives having antinflammatory, analgesic and antithrombotic activity [US6613784]	2003-09-02
Global method for mapping property spaces [US6675136]	2004-01-06
Method of reducing Abeta42 and treating diseases [US2006004086]	2006-01-05
11-Beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia [US7179802]	2004-06-03	2007-02-20
11-BETA-HYDROXYSTEROID DEHYDROGENASE 1 INHIBITORS USEFUL FOR THE TREATMENT OF DIABETES, OBESITY AND DYSLIPIDEMIA [US6730690]	2004-03-11	2004-05-04
Process for producing optically active flurbiprofen [US7214820]	2006-06-22	2007-05-08
Pyridyl Amide T-Type Calcium Channel Antagonists [US7875636]	2009-11-05	2011-01-25
METHOD FOR PRODUCING OPTICALLY ACTIVE ESTER AND METHOD FOR PRODUCING OPTICALLY ACTIVE CARBOXYLIC ACID [US8115008]	2010-09-16	2012-02-14
DRUG SUBSTANCE PREPARATIONS, PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS [US2010087538]	2010-04-08
(R)-2-(3-Benzoylphenyl)propionic acid salts and pharmaceutical preparations containing them [EP0935961]	1999-08-18	2008-04-02

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Taisho Pharmaceutical Co., Ltd. (大正製薬株式会社 Taishō Seiyaku Kabushiki-gaisha^?) (TYO: 4535) is a Japanese pharmaceutical company based in Tokyo.

////////////

Tirupati తిరుపతి
City
Clockwise from top: Tirumala Venkateswara Temple, Tirumala ghat road, City skyline and Chandragiri fort
Tirupati Location in Andhra Pradesh, India
Coordinates: 13.65°N 79.42°ECoordinates: 13.65°N 79.42°E
Country	India
State	Andhra Pradesh
Region	Rayalaseema
District	Chittoor
Government
• Member of Parliament	Varaprasad Rao Velagapalli
Area
• City	24 km² (9 sq mi)
Elevation	161 m (528 ft)
Population (2011)^[1]
• City	287,035
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Languages
• Official	Telugu
Time zone	IST (UTC+5:30)
PIN	517501
Telephone code	+91–877
Vehicle registration	AP 03
Website	Tirupati Mucnicipal Corporation

.
Kapila Theertham in Tirupati

Food Service During Tirumala Tirupati Devastanam’s ‘Srinivasa Kalyanam Utsavam’ at MARG Swarnabhoomi

Harbin Gloria to Commercialize Constipation Drug in China

May 18, 2015 6:52 am / 1 Comment on Harbin Gloria to Commercialize Constipation Drug in China

Harbin Gloria to Commercialize Constipation Drug in China

Harbin Gloria Pharma in-licensed China rights to Amitiza, a novel anti-constipation drug from Sucampo Pharma of the US. Amitiza is a chloride channel activator, approved for US use in 2006, which acts in the small intestine. Gloria will be responsible for obtaining CFDA approval of the drug and then commercializing it in China. Gloria paid $1 million upfront and will be liable for additional milestone payments. More details….

– See more at: http://www.chinabiotoday.com/articles/20150512_1#sthash.YbauZ6qM.dpuf

http://www.chinabiotoday.com/articles/20150512_1

AMITIZA (lubiprostone)

Harbin Gloria Pharmaceuticals Co., Ltd. engages in the research, development, production, and sale of pharmaceutical products primarily in the People’s Republic of China. The company offers orthopedic medicines, antineoplastic products, medical-nutrition products, rheumatology drugs, digestive and respiratory system medicines, cardiovascular medicines, liver disease medications, gynecology medications, and antibiotics. It also provides circulatory system, pediatrics, uropoiesis and reproduction, immune regulation, and other products. Harbin Gloria Pharmaceuticals Co., Ltd. was founded in 2000 and is based in Harbin, the People’s Republic of China.

No. 29, Beijing Road

Limin Economic & Technological Development Zone

Harbin, 150025

China

Founded in 2000

Phone:

86 451 5735 1368

Fax:

86 451 5735 1992

www.gloria.cc

Harbin

Map of harbin china

Lascufloxacin, KRP-AM1977, by Kyorin

May 18, 2015 4:02 am / 1 Comment on Lascufloxacin, KRP-AM1977, by Kyorin

2D chemical structure of 848416-07-9

Lascufloxacin

CAS 848416-07-9

Kyorin Pharmaceutical Co., Ltd., 杏林製薬株式会社

3-Quinolinecarboxylic acid, 7-((3S,4S)-3-((cyclopropylamino)methyl)-4-fluoro-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-8-methoxy-4-oxo-

7-((3S,4S)-3-((Cyclopropylamino)methyl)-4-fluoropyrrolidin-1-yl)-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

{(3S, 4S) -3 – [(cyclopropylamino) methyl] -4-fluoro-1-yl} -6-fluoro-1- (2 – fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

(KRP-AM1977X)

C21-H24-F3-N3-O4

439.4316
SMILES……COc1c2c(cc(c1N3C[C@H](C(C3)CNC4CC4)F)F)c(=O)c(cn2CCF)C(=O)O

…………………………

Lascufloxacin hydrochloride

2D chemical structure of 1433857-09-0

C21-H24-F3-N3-O4.Cl-H

475.8925
CAS 1433857-09-0

3-Quinolinecarboxylic acid, 7-((3S,4S)-3-((cyclopropylamino)methyl)-4-fluoro-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-8-methoxy-4-oxo-, hydrochloride (1:1)

……………….

Lascufloxacin mesylate

3-Quinolinecarboxylic acid, 7-((3S,4S)-3-((cyclopropylamino)methyl)-4-fluoro-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-8-methoxy-4-oxo-, methanesulfonate (1:1)

C21-H24-F3-N3-O4.C-H4-O3-S

535.5372
CAS 1433857-41-0

The other non-fluorinated quinolone under clinical development is KRP-AM1977, by Kyorin, which is in Phase I of clinical trials. The oral formulation of the compound (KRP-AM1977X) is being tested for treatment of respiratory infections and the I.V. formulation is under development for treatment of MRSA infections [1,2].

………………………………..

PATENT

WO 2013069297

http://www.google.co.in/patents/WO2013069297A1?cl=en

The present invention is represented by Formula (1) – {(3S, 4S) -3 – [(cyclopropylamino) methyl] -4-fluoro-1-yl} -6-fluoro-1- (2 – fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (hereinafter, compound (1) crystals of a salt also referred to), and a method for their preparation.

Typically, the pharmaceutical, in addition to the therapeutic effects on diseases, such as safety and quality are required. Therefore, the compound is the active ingredient of drugs, a variety of conditions and that is excellent in storage stability in the (light, temperature, humidity etc. influence the compound) are determined. Also, if the medicament is a dosage form such as oral preparations and injections, it is preferred that higher solubility in active ingredients of the water contained.

Compound (1) is safe, not only exhibit a strong antimicrobial action, conventional hard Gram-positive bacteria antimicrobial agents shown efficacy, particularly MRSA, PRSP, to VRE such resistant strains, to exhibit strong antibacterial activity It is known (for example, Patent Document 1).

WO 2005/026147

Patent Document 1, as the physicochemical characteristics of the compound (1) only has been shown to be a light brown free crystals. Also, Patent Document 1, the solubility in water of Compound (1), stability, no disclosure whatsoever information including characteristics of the crystal.
The present invention aims to provide a technique capable of improving the solubility and storage stability in water of the compound (1).

(Reference Example 4)
Bis (acetato -O) – [6,7-difluoro-1- (2-fluoro-ethyl) -8-methoxy-4-oxo-1,4-dihydro-3-carboxylate ^-O 3, ^{O 4]} boron Under a nitrogen atmosphere, boric acid (catalyst preparation) 86.4 g (1.40mol) was added acetic anhydride 17.9 L (190mol), and was heated and stirred for 30 minutes at 70.0 ~ 77.7 ℃. It was then cooling the mixture to an internal temperature of 24.7 ℃ (hot water set temperature 23.0 ℃). Subsequently, it was added portionwise boric acid to 4 times to the mixture. Specifically, the addition of boric acid (1 time) 842g of (13.6mol) to the mixture and stirred for 30 minutes at 24.7 ~ 27.4 ℃. The addition of boric acid (second) 842g of (13.6mol) to the mixture and stirred for 30 minutes at 24.3 ~ 26.3 ℃. In addition boric acid (third time) 842g the (13.6mol) to the mixture, and the mixture was stirred for 30 minutes at 24.3 ~ 26.8 ℃. In addition boric acid (4 th) 842g the (13.6mol) to the mixture, and the mixture was stirred for 30 minutes at 25.1 ~ 28.3 ℃. The mixture was stirred for 30 minutes at 50.0 ~ 54.9 ℃, was with boric acid triacetate adjusted solution.
In the boric acid triacetate adjusted solution, 6,7-difluoro-1- (2-fluoro-ethyl) -8-methoxy-4-oxo-1,4-dihydro-3-carboxylic acid ethyl ester 4.60kg (14. In a reaction preparation solution are added 0mol), and stirred for 3 hours at 53.7 ~ 56.9 ℃. The reaction preparation was cooled to 30.0 ℃, and allowed to stand overnight at room temperature. The reaction preparation was allowed to dissolve with heating to precipitate up to 55.0 ℃, acetone 13.8L was added and the reaction solution (1).
Separately, under nitrogen atmosphere, it is mixed Tsunemizu 161L and aqueous ammonia (28%) 28.2L (464mol), and cooled the mixture to 1.6 ℃. To the mixture, it was added the reaction solution of the above (1), to obtain a crude crystal acquisition solution crowded washed with acetone 9.20L. After cooling the crude crystal acquisition solution to 15.0 ℃, it was stirred for 1 hour at 6.2 ~ 15.0 ℃. And The precipitated crystals were filtered, washed with Tsunemizu 46.0L, to give 9.07kg of wet crude crystals. Set temperature 65.0 to about 16 hours and dried under reduced pressure at ℃, the crude crystals were obtained 5.89kg.
Under a nitrogen atmosphere, it is mixed acetone and 29.5L crude crystal, the resulting mixture was heated and dissolved (melting temperature 52.6 ℃). When heated, it was dropped until the crystallization of diisopropyl ether 58.9L in a mixture (dropping amount 10.0L; 52.8 → 48.7 ℃; crystallization temperature 49.0 ℃). After crystallization confirmation, stirred for 15 minutes the mixture at 49.0 ~ 50.1 ℃, it was dropped the rest of diisopropyl ether to the mixture (50.1 → 46.4 ℃), 46.7 ~ 51.7 It was stirred for 15 minutes mixture at ℃. After cooling the mixture to 15 ℃, it was stirred for 30 minutes at 8.1 ~ 15.0 ℃. And The precipitated crystals were filtered, washed with acetone and diisopropyl ether 5.89L 11.8L, to obtain 6.19kg of wet crystals. For about 20 hours drying under reduced pressure at warm water set temperature 65.0 ℃, bis (acetato -O) – [6,7-difluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4- dihydro-3-carboxylate ^-O 3, ^{O 4]} was obtained 5.42kg boron (90.4% yield).

Melting point: 183 ~ 185 ℃ (dec).
Elemental analysis _(%): calculated as _{C 17} H 15 _BF 3 NO _{8: C,} 47.58; H, 3.52; N, 3.26.
Measured value: C, 47.91; H, 3.44; N, 3.04.
¹ _H-NMR (CDCl 3, 400 MHz) ^δ: 2.04 (6H, s), 4.22 (3H, d, J = 2.4Hz), 4.88 (2H, dt, J = 47.0 , 4.4Hz), 5.21 (2H, dt, J = 24.9,4.4Hz), 8.17 (1H, t, J = 8.8Hz), 9.11 (1H, s).
ESI MS ^(positive) m / z: 430 (M + ^H) +.
IR ^(KBr) cm -1: 3080,1703.

………………………………………….

WO 2005026147

http://www.google.com/patents/EP1666477A1?cl=en

KEY INTERMEDIATE

3-Pyrrolidinemethanamine,N-cyclopropyl-4-fluoro-,(3R,4S)-(9CI) Structure

604798-54-1

3-Pyrrolidinemethanamine, N-cyclopropyl-4-fluoro-, (3R,4S)-

Chemical Name:3-Pyrrolidinemethanamine, N-cyclopropyl-4-fluoro-, (3R,4S)-CAS: 604798-54-1Molecular Formula: C8H15FN2Molecular Weight: 158.2165032

Chemical Name:	3-Pyrrolidinemethanamine, N-cyclopropyl-4-fluoro-, (3R,4S)-
CAS:	604798-54-1
Molecular Formula:	C8H15FN2
Molecular Weight:	158.2165032

………………………….

KEY INTERMEDIATE

CAS 848498-67-9

Boron, bis(acetato-κO)[6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinolinecarboxylato-κO]-, (T-4)-

Coordination Compound

ビス（アセチルオキシ）［６，７－ジフルオロ－１－（２－フルオロエチル）
－８－メトキシ－４－オキソ－１，４－ジヒドロキノリン－３－カルボニルオ
キシ］ボラン

化学物質名	ビス（アセチルオキシ）［６，７－ジフルオロ－１－（２－フルオロエチル）－８－メトキシ－４－オキソ－１，４－ジヒドロキノリン－３－カルボニルオキシ］ボラン
構造別分類コード番号	F60622212422
化学式、構造式（マウス左クリックで拡大します。）
安衛法官報通し番号	21534
安衛法官報公示整理番号	8-(1)-3764
安衛法官報公示時期	平成24年9月27日
化審法官報公示整理番号	－
CAS番号	848498-67-9
出典	厚生労働省

……………………………….

KEY INTERMEDIATE

3-Quinolinecarboxylic acid, 6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-8-methoxy-4-oxo-, ethyl ester

114214-60-7

C15H14F3NO4

６，７－ジフルオロ－１－（２－フルオロエチル）－８－メトキシ－４－オキ
ソ－１，４－ジヒドロキノリン－３－カルボン酸エチル

化学物質名	６，７－ジフルオロ－１－（２－フルオロエチル）－８－メトキシ－４－オキソ－１，４－ジヒドロキノリン－３－カルボン酸エチル
構造別分類コード番号	F60622322422
化学式、構造式（マウス左クリックで拡大します。）
安衛法官報通し番号	21467
安衛法官報公示整理番号	8-(1)-3758
安衛法官報公示時期	平成24年9月27日
化審法官報公示整理番号	－
CAS番号	114214-60-7
出典	厚生労働省

Citing Patent	Filing date	Publication date	Applicant	Title
WO2003076428A1 *	8 Mar 2002	18 Sep 2003	Toshifumi Akiba	Quinolonecarboxylic acid derivative
WO2005026147A1	8 Sep 2004	24 Mar 2005	Yoshikazu Asahina	7-(4-substituted 3- cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative
WO2007082471A1 *	18 Jan 2007	26 Jul 2007	Guangzhou Baiyunshan Pharmaceu	Anti-infective compound, preparation method thereof and use thereof
CN1158846A *	9 May 1995	10 Sep 1997	昆山市康壮达兽药厂	Synthesis technology of norfluxacini hydrochloride
WO2014174846A1 *	24 Apr 2014	30 Oct 2014	Kyorin Pharmaceutical Co., Ltd.	Solid pharmaceutical composition
WO2014174847A1 *	24 Apr 2014	30 Oct 2014	Kyorin Pharmaceutical Co., Ltd.	Solid pharmaceutical composition
WO2014174848A1 *	24 Apr 2014	30 Oct 2014	Kyorin Pharmaceutical Co., Ltd.	Tablet

Kyorin. Kyorin—Main R&D Activities-1 (4 February 2013 Release). Available online: http://www.kyorin-pharm.co.jp/en/business/pdf/main_rd_activities_20130204_en.pdf (accessed on 4 February 2013).
Kyorin. Drug discovery, development, and lcm with medical professionals and patients in mind. Available online: http://www.kyorin-gr.co.jp/en/business/gensen/r_and_d.shtml (accessed on 11 April 2013).

……….

Ochyanomizu Sola City 16F,
Kanda Surugadai 4-6, Chiyoda-ku,
Tokyo 101-8311 Japan
TEL: 03-3525-4711

Access
One-minute walk from the Hijiribashi exit of Ochanomizu station on JR Chuo and Sobu lines
One-minute walk from the B2 exit of Shin-Ochanomizu station on Tokyo Metro Chiyoda line
Four-minutes walk from the No.1 exit of Ochanomizu station on Tokyo Metro Marunouchi line
Six-minutes walk from the B3 exit of Ogawamachi station on Toei Subway Shinjuku line

Trade Name	KYORIN Pharmaceutical Co.,Ltd.
Business	Manufacture and sales of prescription medicines
Head Office	Ochyanomizu Sola City 16F, Kanda Surugadai 4-6, Chiyoda-ku, Tokyo 101-8311 Japan (Access Map)
Telephone	03-3525-4711
Foundation	1923
Establishment	1940

Shimotsuga-gun, Tochigi

Tochigi Wanpaku Park – Mibu-machi – Reviews of Tochigi Wanpaku Park –

MARKET

Ochanomizu station

Lupin buys Brazilian pharmaceutical firm Medquímica

May 18, 2015 3:15 am / 1 Comment on Lupin buys Brazilian pharmaceutical firm Medquímica

Lupin buys Brazilian pharmaceutical firm Medquímica
India-based drugmaker Lupin has acquired 100% equity interest in Brazilian pharmaceutical firm Medquímica Indústria Farmacêutica.

read at

http://www.pharmaceutical-technology.com/news/newslupin-buys-brazilian-pharmaceutical-firm-medqumica-4578219?WT.mc_id=DN_News

Group president and CEO, Lupin Pharmaceuticals, and director on the board of Lupin Limited, Vinita Gupta

Medquímica

A Medquímica Indústria Farmacêutica é uma empresa genuinamente brasileira que atua na produção de medicamentos para o uso humano. Com sua linha de produção instalada em Juiz de Fora, a Medquimica está presente em todo o Brasil através de seus representantes.

Working in syntony with the market. There are 30 years that it is the north that takes the Medquímica Pharmaceutical Industry Ltda. to dedicate to the production of pharmaceutical products of proven effectiveness and certain return for all its net of customers. For such, the Medquímica invests in physical and human resources, forming a qualified and highly experienced technical team, who detaches in the marketplace for producing medicines of uncontestable quality and trustworthiness.

With the quality certified through the Good Practical of Manufacture, the Medquímica detaches for having a laboratory of reference inside its installations. Moreover, respecting the resolution 134 from Anvisa, gradually, all its medicines are being evaluated for the tests of pharmaceutical equivalence, proving, in this way, the quality of Medquímica’s product. Such actions had resulted in a supported growth of credibility and sales.

For giving support to all this development, the Medquímica will start the construction of the first projected national plant in the most rigorous and recent requirements of the ANVISA. Thirty years of history, qualified technician team, tests of equivalence and bioequivalência and a model plant makes from Medquímica the certain alternative for the success of its businesses

Fábrica:
(32) 3224-4087 (Telefax)

Administração:
(32) 2101-4000 (Telefax)

The Medquímica Pharmaceutical Industry is a genuinely Brazilian company that acts in the medicine production for the human use. With its line of production installed in Juiz de Fora, the Medquimica is present in all over Brazil through its representatives.

Industry
Rua Otacílio Esteves da Silva, 40
Bairro Granjas Betânia
CEP: 36047-400
Juiz de Fora – MG

Administration
Rua Fernando Lamarca, 255
Bairro Distrito Industrial
CEP: 36092-030
Juiz de Fora – MG

Juiz de Fora

Map of juiz de fora

Paço Municipal de Juiz de Fora

No todo parece bem interessante. Dá pra tirar muitas fotos boas. Já teve outro thread bem legal sobre a cidade.

CARMEN DRAHL….Tribute to a Great Writer

May 15, 2015 5:17 am / 3 Comments on CARMEN DRAHL….Tribute to a Great Writer

CARMEN DRAHL

Award-winning science communicator and social media power user based in Washington, DC.

Carmen Drahl is a multimedia science journalist and chemistry communicator based in Washington, DC.

A social media evangelist, Carmen started her first chemistry blog in 2006. Today, she regularly leverages Twitter, Facebook, and Google Plus Hangouts in her reporting.

Carmen has written about how life may have originated on Earth, explained how new medications get their names, and covered the ongoing issues plaguing the forensic science community. Her video on the food science behind 3D printed cocktail garnishes won the 2014 Folio Eddie Award for Best Association Video.

Until December 2014, Carmen worked at Chemical & Engineering News magazine. Her work has also been featured at Scientific American’s blog network, SiriusXM’s Doctor Radio, and elsewhere.

Carmen holds a Ph.D. in chemistry from Princeton University.

Specialties:
interviewing, science writing, social media, Twitter, Storify, YouTube,
public speaking, hosting, video production, iPhone videography,
non-linear video editing, blogging (WordPress and Blogger), HTML website
coding

We have been reading her for the past several years and a inspiration for many

Links

FACEBOOK

https://www.facebook.com/carmenwrites

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

Education

Princeton University

Ph.D., Chemistry

2002 – 2007

Ph.D. with Erik J. SorensenShe was on a team that completed the first total synthesis of
abyssomicin C, a molecule found in small quantities in nature that
showed hints of promise as a potential antibiotic. I constructed
molecular probes from abyssomicin for proteomics studies of its
biological activity.

M.A. with George L. McLendon

worked
toward developing a drug conjugate as a potential treatment for cancer. I
synthesized a photosensitizer dye-peptide conjugate for targeting the
cell death pathway called apoptosis.

At a reception before the Alumni Day luncheon, President Tilghman (third
from left) congratulated the winners of the University’s highest awards
for students: (from left) Pyne Prize winners Lester Mackey and Alisha
Holland; and Jacobus Fellowship recipients Sarah Pourciau, Egemen
Kolemen and Carmen Drahl. Unable to attend the event was Jacobus Fellowship winner William Slauter. (photo: Denise Applewhite

Jennifer Maclachlan, Carmen Drahl, Antony Williams

Drew University

B.A., Chemistry

1998 – 2002

Graduated
summa cum laude with specialized honors in chemistry. Honors thesis
entitled “Structural, kinetic, and mechanistic studies: the protein
tyrosine phosphatases CD45 and PTP1B”

Activities and Societies: Phi Beta Kappa

Carmen Drahl, Class of 2002,

Experience

Science Journalist

Freelance

January 2014 – Present Washington D.C. Metro Area

Multimedia
science journalist – I deliver clean products on time. Experience in
reporting on chemistry, food science, history of science, drug
development, science education.

Senior Editor, Chemical & Engineering News

American Chemical Society

August 2007 – December 2014 (7 years 5 months)Washington D.C. Metro Area

Reporting:Cover the science of chemistry for C&EN, the American Chemical
Society’s weekly magazine, circulation 160,000. Track new research
findings daily, particularly in forensic science, drug discovery,
organic chemistry, and food science.

Video:

Doubled circulation to C&EN’s YouTube channel in 2013. Scripted, narrated, edited footage.

Managed a core team of 4 and collaborated with other reporters to
produce 30 videos, some reproduced in The Atlantic, Scientific American,
Eater National, The Daily Mail.

Incepted, scripted, and co-hosted
“Speaking of Chemistry”, a monthly web show that summarizes top
chemistry news for the busy scientist.

Social Media:

Developed magazine-wide best practices for YouTube videos and Twitter. Ran staff workshops about Storify, Slashdot, and Reddit.

Hosting/Public Speaking:

Topics include communicating chemistry simply, transitioning from a
Ph.D. to careers in science communication. Moderated discussions on
chemophobia, social media usage in the chemical sciences. On-camera
co-host for web newscasts produced by ACS.

Innovation:

With
C&EN art and web teams, developed first-for-the-magazine features,
including a 90th anniversary commemorative timeline poster, a pullout
guide to top conference speakers, interactive quizzes and database
searches.

Carmen Drahl, senior editor of Chemical and Engineering News,
used her Ph.D. in chemistry as a springboard into the career she
envisioned for herself. Here she shares some advice that helped her make
the decision.

Carmen Drahl made the transition to a writing
career while earning a Ph.D. in chemistry at Princeton University. Born
and raised in New Jersey, she now lives in Washington, D.C., and reports
for Chemical and Engineering News (C&EN). At C&EN
she has written about how new medications get their names, explained
the science behind a controversial hair-straightening product, and
covered the scientific firestorm sparked by an alleged arsenic life
form. Her work has been featured on SiriusXM’s Doctor Radio, Radio New Zealand’s This Way Up, and elsewhere. Her coverage has also been recognized by MIT’s Knight Science Journalism Tracker.

(Open)1 honor or award

Scientific Cocktails: Award-winning video

Speaking of Chemistry: All About Tinsel

Carmen Drahl

Twitter Maven

World Central Kitchen

March 2013 – August 2014 (1 year 6 months)Washington D.C. Metro Area

she was the “voice of Twitter” for World Central Kitchen, the humanitarian

organization founded by renowned Chef José Andrés. Doubled followers to
Twitter account in 2013, developed Twitter strategy for projects and
events. Edited Annual Report, press releases and other communication
materials. Volunteered in person at outreach events.

Contributing Editor, AWIS Magazine

Association of Women in Science

December 2005 – August 2007 (1 year 9 months)

sHE
reported and wrote profiles of prominent women scientists in a range of
fields (molecular biology, physics, geoscience) for the Research
Advances column in AWIS Magazine.

Writer, various publications

Princeton University

April 2005 – May 2007 (2 years 2 months)

She
reported and wrote news for the Princeton University News Office’s
Research Notes, and wrote news and features for the Princeton University
Chemistry Department’s Industrial Affiliates Program Newsletter and
Chemistry Alumni Newsletter.

Honors & Awards

Eddie Digital Award- Best Video (B-to-B)

FOLIO Magazine

December 2014

Porter Ogden Jacobus Fellowship

Princeton University

February 2007

NSF Graduate Research Fellowship

National Science Foundation

2002

Volunteer Experience & Causes

Board Member

Princeton Alumni Weekly Magazine

October 2013

Advisory Committee

American Institute of Physics News and Media Services

October 2013

Member, Graduate Alumni Leadership Council

Princeton University

2009 – 2012 (3 years)

INTERVIEW

http://scienceblogs.com/clock/2010/04/12/scienceonline2010-interview-33/

Continuing with the tradition from last two years, I will occasionally post interviews with some of the participants of the ScienceOnline2010 conference that was held in the Research Triangle Park, NC back in January. See all the interviews in this series here. You can check out previous years’ interviews as well: 2008 and 2009.Today, I asked Carmen Drahl, Associate Editor for Science/Technology/Education at Chemical & Engineering News (find her as @carmendrahl on Twitter) to answer a few questions.Welcome
to A Blog Around The Clock. Would you, please, tell my readers a little
bit more about yourself? Where are you coming from (both geographically
and philosophically)? What is your (scientific) background?

i-b183f89fe33d3d9f0b308a6cb30d9b5b-Carmen Drahl pic1.JPG

It’s a pleasure and a privilege to be interviewed, Bora.Good
conversations make me happy. School was fun for me (well, maybe not
grad school) and that’s evolved into a desire to always be learning
something new. I enjoy doing nothing as much as I enjoy doing things. On
Mondays, if I’m not too busy, I take hip-hop dance classes.her hometown is Hackettstown, New Jersey. M&M’s are made there. I got a
bachelor’s in chemistry from Drew University and a Ph.D. in chemistry at
Princeton. Scientifically my expertise hovers somewhere around the
interface between organic chemistry and biochemistry. A short while
after defending my dissertation, I moved to Washington DC to write for Chemical & Engineering News, and that’s where I’ve been for almost three years now.When and how did you first discover science blogs?Scandal
led me to science blogs. Seriously. In March 2006 I was still an
organic chemistry grad student. Everyone in my lab was buzzing about a
set of retractions in the Journal of the American Chemical Society
(disclosure: today I work for the American Chemical Society, which
publishes JACS). A rising young organic chemistry star retracted the
papers because work by one of his graduate students couldn’t be
reproduced. It was a big deal and became an even bigger deal as the
inevitable rumors (salacious and otherwise) surfaced. The blogosphere
had the details first. So that’s where Google pointed me and the other
members of my lab when we searched for more information. I learned about
the awesome (but sadly now defunct) blogs Tenderbutton and The Endless
Frontier, by Dylan Stiles and Paul Bracher, both chemistry grad students
like me. I also discovered the solid mix of chemistry and pharma at
Derek Lowe’s In the Pipeline, which is still the first blog I visit every day.Tell us a little more about your career trajectory so far: interesting projects past and present?

By
the time I discovered science blogs I knew my career goals were
changing. I’d already been lucky enough to audit a science writing
course at Princeton taught by Mike Lemonick from TIME, and thought that
maybe science writing was a good choice for me. After reading chemistry
blogs for a while I realized “Hey, I can do this!” and started my own
blog, She Blinded Me with Science, in July 2006. It was the typical grad student blog, a mix of posts about papers I liked and life in the lab.

At C&E News I’ve contributed to its C&ENtral Science
blog, which premiered in spring 2008. I’ve experimented with a few
different kinds of posts- observations and on-the-street interviews when
I run into something chemistry-related in DC, in-depth posts from
meetings, and video demos of iPod apps. One of my favorite things to do
is toy with new audio/video/etc technology for the blog.

What is taking up the most of your time and passion these days? What are your goals?

In March I just started a new era in my web existence- I’m becoming a pharma blogger. I’m the science voice at The Haystack,
C&E News’s new pharma blog and one of seven new blogs the magazine
launched last month. My co-blogger is the talented Lisa Jarvis, who’s
written about the business side of pharma for ten years and who brings a
solid science background to the table as well. I kicked us off by
liveblogging/livetweeting a popular session at the American Chemical
Society’s meeting in San Francisco where drug companies reveal for the
first time the chemical structures of potential new drugs being tested
in clinical trials. The whole thing synced to FriendFeed as well. Folks
followed the talks from all three venues, which was great. I hope I can
continue doing that sort of thing in the future.

For
this August, I’m co-organizing a mini-symposium at the American
Chemical Society meeting in Boston about the chem/pharma blogosphere and
its impact on research and communication. I’m in the process of
inviting speakers right now. It’s my first time doing anything like this
and part of me is petrified that no one will show up. Tips on
organizing a conference session and how not to stress when doing so are
welcome!

More broadly, I’d love to get more chemistry bloggers to
connect with the community that attends ScienceOnline. I don’t ever want
to become that old (or not-so-old) person who is clueless about
them-thar newfangled whosiwhatsits that the kids are using nowadays.

What aspect of science communication and/or particular use of the Web in science interests you the most?

A
few things come to mind, actually. I’d like to think that the web has
made grad school a helluva lot less isolating for science grad students.
You have the virtual journal clubs like Totally Synthetic, posts like SciCurious’s letter to a grad student, etc.

As
a journalist the web’s capacity to equalize fascinates me. I’m
extremely lucky to have a staff gig as a science writer without having
gone to journalism school or landed a media fellowhip and it’s weird to
think that my old blog might’ve helped my visibility. I didn’t know Ed
Yong’s story until Scio10 but I think he’s a highly talented example of
how the web can open doors.

The web’s equalizing power goes to
readers of science content as well as writers, of course. In the ideal
situation a reader can give a writer instant feedback and you can get a
real conversation going, something that was much harder with the
snail-paced system of letters to the editor and reader surveys. Not that
the conversation is always civil. Most of C&EN’s readers have a
decent amount of scientific training, but the debate that rages whenever
we run an editorial about climate change is as intense as any I’ve
seen.

In cases like that I don’t know that the web gives people a
good representation of what the consensus is. For folks who don’t have
scientific training, how do you ensure that people don’t just go to the
content that already confirms their pre-existing beliefs about autism or
global warming? John Timmer touched on this more eloquently in his interview with you,
and I agree with him that I don’t think we have an answer yet. Though
on a slightly different note, I will mention that I’ve been enjoying the
New York Times’s recent attempts to recapture the spontaneity of
flipping through the newspaper in online browsing, like the Times Skimmer for Google Chrome.

What are some of your favourite science blogs? Have you discovered any cool science blogs by the participants at the Conference?

In addition to the blogs I’ve already mentioned I enjoy Carbon-Based Curiosities, Wired Science, Chemistry Blog, and Terra Sigillata, to name a few of the 50 or so blogs on my feed reader.

I discovered scads of new blogs at Scio10 but I’ll focus on the one that’s become required reading for me these days: Obesity Panacea.
I’d covered obesity drug development for C&EN but I’d never met
Travis Saunders and Peter Janiszewski or heard of their blog until the
conference.

What was the best aspect of ScienceOnline2010 for
you? Is there anything that happened at this Conference – a session,
something someone said or did or wrote – that will change the way you
think about science communication, or something that you will take with
you to your job, blog-reading and blog-writing?

Dave Mungeris
my hero – his blogging 102 session was packed with practical tips that I
brought back to C&EN for incorporating into our blogs, such as the
use of the Disqus plugin for catching conversations on social networks,
getting smart about using stats and surveys, etc. Some of that’s already
happened, and some of the ideas are still in the works.

I came
for the nuts-and-bolts blogging tips but I stayed for the conversations,
especially the ones at the bar after the official program was done for
the night. And the icing on the cake was seeing folks I’d worked with
but never met, like Cameron Neylon and you, Bora, and catching up with
people I hadn’t seen in months, like Jean-Claude Bradley, Aaron Rowe,
Jennifer Ouellette and Nancy Shute.

It was so nice to meet you in person and thank you for the interview. I hope to see you again next January.

Company: GlaxoSmithKline

Meant to treat: tumors with loss-of-function in the tumor suppressor
protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated
tumor suppressor after p53- cancers where this is often the case include
prostate and endometrial

Mode of action: inhibitor of
phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence
suggest that proliferation in certain PTEN-deficient tumor cell lines is
driven primarily by PI3K-beta.

Medicinal chemistry tidbits: The GSK
team seemed boxed in because in 3 out of 4 animals used in preclinical
testing, promising drug candidates had high clearance. It turned out
that a carbonyl group that they thought was critical for interacting
with the back pocket of the PI3K-beta enzyme wasn’t so critical after
all. When they realized they could replace the carbonyl with a variety
of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown)
is the tris salt of GSK2636771.

Status in the pipeline: Phase I clinical trials……….http://cenblog.org/the-haystack/2012/03/liveblogging-first-time-disclosures-from-acssandiego/

CARMEN

Posted By Carmen Drahl on Mar 24, 2012

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

Company: GlaxoSmithKline

Status in the pipeline: Phase I clinical trials……….http://cenblog.org/the-haystack/2012/03/liveblogging-first-time-disclosures-from-acssandiego/

CARMEN

Posted By Carmen Drahl on Mar 24, 2012

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

Washington, D.C.

Colleges and Universities

.

Motesanib (AMG-706)

May 15, 2015 4:47 am / 4 Comments on Motesanib (AMG-706)

Motesanib (AMG-706)

Amgen Inc.

Motesanib (AMG 706) is an experimental drug candidate originally developed by Amgen^[1] but is now being investigated by theTakeda Pharmaceutical Company. It is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors.^[2] It is used as thephosphate salt motesanib diphosphate.

Motesanib, also known as AMG-706, is an orally administered multikinase inhibitor that selectively targets VEGF receptors, platelet-derived growth factor receptors, and Kit receptors.

Clinical trials

Motesanib was originally investigated for effectiveness against advanced nonsquamous non-small-cell lung cancer (NSCLC), withPhase II trials indicating an effectiveness comparable to bevacizumab when they were both used in combination withpaclitaxel/carboplatin.^[3] However a later and more detailed Phase III trial failed to show any benefit for the treatment of NSCLC.^[2]^[4]A second Phase III trial was started in 2012,^[5] which focused on patients from Asian backgrounds (performed on the bases ofsubgroup analysis)^[6] however this also failed to meet its primary endpoint.^[7]

The drug has undergone a Phase II evaluation as first-line therapy for breast cancer^[2] however this study found no evidence to support further investigation.^[8] Phase II testing against persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas was also unsuccessful.^[9]

There have also been 2 separate Phase II clinical trials for thyroid cancer which have both shown promising results.^[10]^[11]^[12]

Developed at Amgen, the compound is also being evaluated as both monotherapy and in combination with other agents in the treatment of breast, colorectal, lung, thyroid and ovarian cancers. Clinical trials for the treatment of bladder cancer have been terminated.

The National Cancer Institute had been evaluating the potential of the drug in patients with low-grade neuroendocrine tumors; however, no recent development has been reported for this research. The FDA awarded fast track status to motesanib in 2004. In 2008, the compound was licensed to Takeda in Japan.

AMG-706 is synthesized as follows: 1-Acetyl-3,3-dimethyl-6-nitroindoline (I) is reduced by catalytic hydrogenation over Pd/C, giving the aminoindoline (II), which is then coupled with 2-chloronicotinoyl chloride (III) in the presence of DIEA to yield the corresponding nicotinamide (IV). Subsequent condensation of (IV) with neat 4-(aminomethyl)pyridine (V) at 120 °C affords the 2-aminonicotinamide derivative (VI). The N-acetyl group of (VI) is finally removed by acidic hydrolysis to furnish the title compound (1,2).

,………………………………………

US 2003125339

http://www.google.com/patents/US20030125339

………………………………………………….

US 2003225106

https://www.google.com/patents/US20030225106

EXAMPLE 133

[2295]

N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

Step A—Preparation of 1-acetyl-6-amino-3,3-dimethylindoline

1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H₂for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH₂Cl₂to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc’d. for C₁₂H₁₆N₂O—204.27.

Step B—Preparation of N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from 1-acetyl-6-amino-3,3-dimethylindoline (Step A) by the method described in Example 82.

Step C—Preparation of N-(3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (Step B) by the deacylation method described in Example 993. MS: 374 (M+1). Calc’d. for C₂₂H₂₃N₅O—373.45.

…………………….

http://www.google.com/patents/WO2012063085A3?cl=en

Example 133

N- (3, 3-Dimethy1indolin-6-yl) {2- [ (4-pyridylmethyl) amino] (3- pyridyl) }carboxamide Step A – Preparation of l-acetyl-6-amino-3 , 3- dimethylindoline l-Acetyl-3 , 3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL) , the mixture was bubbled with H₂ for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H₂ overnight. The mixture was filtered through Celite^® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc :CH₂C1₂ to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc’d. for C₁₂H₁₆N₂O-204.27.

Step B – Preparation of N-(l-acetyl- 3 , 3-dimethylindolin-6- yl) (2-[ (4-pyridylmethyl) amino] (3-pyridyl) } carboxamide The titled compound was prepared from l-acetyl-6- amino-3 , 3-dimethylindoline (Step A) by the method described in Example 82.

Step C – Preparation of N- (3 , 3-dimethylindolin-6-yl) {2- [ (4- pyridylmethyl) amino] (3-pyridyl) }carboxamide

The titled compound was prepared from N-(l-acetyl- 3 , 3-dimethylindolin-6-yl) {2- [ (4-pyridylmethyl) amino] (3- pyridyl) } carboxamide (Step B) by the deacylation method described in Example 993. MS: 374 (M+1). Calc’d. for C₂₂H₂₃N₅0-373.45.

References

Stafford, edited by Rongshi Li, Jeffrey A. (2009). “Chapter 5. Discovery of Motesanib”. Kinase inhibitor drugs. Hoboken, N.J.: Wiley. pp. 113–130. ISBN 978-0-470-27829-1.
“Amgen and Takeda’s NSCLC Drug Fails in Phase III Study”. 30 Mar 2011.
Blumenschein Jr, G. R.; Kabbinavar, F.; Menon, H.; Mok, T. S. K.; Stephenson, J.; Beck, J. T.; Lakshmaiah, K.; Reckamp, K.; Hei, Y.- J.; Kracht, K.; Sun, Y.- N.; Sikorski, R.; Schwartzberg, L. (14 February 2011). “A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer”. Annals of Oncology 22 (9): 2057–2067. doi:10.1093/annonc/mdq731.
Jump up^ Scagliotti, G. V.; Vynnychenko, I.; Park, K.; Ichinose, Y.; Kubota, K.; Blackhall, F.; Pirker, R.; Galiulin, R.; Ciuleanu, T.-E.; Sydorenko, O.; Dediu, M.; Papai-Szekely, Z.; Banaclocha, N. M.; McCoy, S.; Yao, B.; Hei, Y.-j.; Galimi, F.; Spigel, D. R. (2 July 2012). “International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer: MONET1”. Journal of Clinical Oncology 30 (23): 2829–2836. doi:10.1200/JCO.2011.41.4987. PMID 22753922.
“Takeda Initiates Phase 3 Trial of Motesanib in Japan and Additional Asian Countries”. Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
Kubota, K.; Ichinose, Y.; Scagliotti, G.; Spigel, D.; Kim, J. H.; Shinkai, T.; Takeda, K.; Kim, S.- W.; Hsia, T.- C.; Li, R. K.; Tiangco, B. J.; Yau, S.; Lim, W.- T.; Yao, B.; Hei, Y.- J.; Park, K. (13 January 2014). “Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis”.Annals of Oncology 25 (2): 529–536. doi:10.1093/annonc/mdt552.
Jump up^ “Takeda Announces Phase 3 MONET-A Study Evaluating Motesanib (AMG 706) in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Does Not Meet Primary Endpoint”. Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
Martin, Miguel; Roche, Henri; Pinter, Tamas; Crown, John; Kennedy, M John; Provencher, Louise; Priou, Frank; Eiermann, Wolfgang; Adrover, Encarna; Lang, Istvan; Ramos, Manuel; Latreille, Jean; Jagiełło-Gruszfeld, Agnieszka; Pienkowski, Tadeusz; Alba, Emilio; Snyder, Raymond; Almel, Sachin; Rolski, Janusz; Munoz, Montserrat; Moroose, Rebecca; Hurvitz, Sara; Baños, Ana; Adewoye, Henry; Hei, Yong-Jiang; Lindsay, Mary-Ann; Rupin, Matthieu; Cabaribere, David; Lemmerick, Yasmin; Mackey, John R (April 2011). “Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study”. The Lancet Oncology 12 (4): 369–376. doi:10.1016/S1470-2045(11)70037-7. PMID 21429799.
Schilder, R.J.; Sill, M.W.; Lankes, H.A.; Gold, M.A.; Mannel, R.S.; Modesitt, S.C.; Hanjani, P.; Bonebrake, A.J.; Sood, A.K.; Godwin, A.K.; Hu, W.; Alpaugh, R.K. (April 2013). “A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: A Gynecologic Oncology Group study”. Gynecologic Oncology 129 (1): 86–91. doi:10.1016/j.ygyno.2013.01.006. PMID 23321064.
Motesanib Diphosphate Provides Anticancer Activity Among Patients with Progressive Thyroid Cancer, CancerConnect.com
Jump up^ Schlumberger, M. J.; Elisei, R.; Bastholt, L.; Wirth, L. J.; Martins, R. G.; Locati, L. D.; Jarzab, B.; Pacini, F.; Daumerie, C.; Droz, J.-P.; Eschenberg, M. J.; Sun, Y.-N.; Juan, T.; Stepan, D. E.; Sherman, S. I. (29 June 2009). “Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer”.Journal of Clinical Oncology 27 (23): 3794–3801. doi:10.1200/JCO.2008.18.7815. PMID 19564535.
Sherman, Steven I.; Wirth, Lori J.; Droz, Jean-Pierre; Hofmann, Michael; Bastholt, Lars; Martins, Renato G.; Licitra, Lisa; Eschenberg, Michael J.; Sun, Yu-Nien; Juan, Todd; Stepan, Daniel E.; Schlumberger, Martin J. (3 July 2008). “Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer”. New England Journal of Medicine 359 (1): 31–42.doi:10.1056/NEJMoa075853. PMID 18596272.

External links

Motesanib molecular details

Motesanib Diphosphate (AMG-706)

857876-30-3 diphosphate
453562-69-1 (free base)

N-(2,3-Dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide diphosphate

3-Pyridinecarboxamide, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-, phosphate (1:2)

N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide diphosphate

569.4
Formula	C22H23N5O.2H3PO4

Motesanib
Names

IUPAC name N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide
Other names AMG 706
Identifiers
CAS Registry Number	453562-69-1
ChEMBL	ChEMBL572881
ChemSpider	9842625
InChI [show]
Jmol-3D images	Image
PubChem	11667893
SMILES [show]
Properties
Molecular formula	C₂₂H₂₃N₅O
Molar mass	373.45 g·mol⁻¹

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TAKEDA, JAPAN

TOKYO HO

Takeda Pharmaceutical CEO Yasuchika Hasegawa

Takeda Pharmaceutical Co. President Christophe Weber is interviewed recently in Tokyo.

Christophe Weber (L), the new president of Takeda Pharmaceutical Co., and CEO Yasuchika Hasegawa pose

Dr. Paul Chapman of Takeda Pharmaceuticals colors in the eye…

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OSAKA

Dotonbori, Osaka, Japan

OSAKA

AZD 3264 an IKK2 Inhibitor from Astra Zeneca

May 15, 2015 3:32 am / 2 Comments on AZD 3264 an IKK2 Inhibitor from Astra Zeneca

AZD 3264

MW 441.50

CAS 1609281-86-8

MF C₂₁ H₂₃ N₅ O₄ S

3-Thiophenecarboxamide, 2-[(aminocarbonyl)amino]-5-[4-(3,5-dimethyl-4-isoxazolyl)-2-[(3S)-3-pyrrolidinyloxy]phenyl]-

2-(Carbamoylamino)-5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3S)-pyrrolidin-3-yloxy]phenyl]thiophene-3-carboxamide

Inhibition of IkB-kinase IKK2 has been identified as one of the novel pathways to treat inflammatory conditions such as asthma, chronic pulmonary obstructive disorder (COPD) and rheumatoid arthritis

Astrazeneca Ab,

……………………..

PATENT

WO 2003010158

https://www.google.com/patents/WO2003010158A1?cl=en

The synthesis began with the aromatic nucleophilic substitution reaction of 2-fluorobromobenzene (2) with (S)-N-Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which was borylated via halogen metal exchange using n-hexLi in THF followed by treatment with triisopropyl borate and acidic work-up to give the boronic acid intermediate 5. Suzuki coupling of the boronic acid 5 with bromothiophene 6(2)afforded the intermediate 7. Intermediate 7 was subjected to regioselective bromination using bromine in acetic acid. This reaction was nonregioselective and yielded 17% of the required isomer 8. The bromo compound 8 was coupled with isoxazole boronate ester 9 by another Suzuki reaction to get the title compound. The overall yield of the synthesis was <6%.

………………………..

PAPER

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500105n

http://pubs.acs.org/doi/full/10.1021/op500105n

Abstract Image

An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.

AZD3264 (1)

A stirred solution of tert-butyl (3S)-3-[2-(4-carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in tetrahydrofuran (25 L) w……………………………………………………title compound in 91% yield.

Purification

To a stirred suspension of crude AZD3264 (1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64 L) was added formic acid (0.24 kg, 5.18 mol), and the mixture was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol). The product was isolated by filtration.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.92–2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 3H), 5.11–5.12 (m, 1H), 6.90 (br, 2H), 7.00–7.03 (m, 2H), 7.30 (br, 1H), 7.70–7.72 (m, 2H), 7.83 (s, 1H), 10.93 (s, 1H).

¹³C NMR (DMSO-d₆, 100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76, 114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84, 150.12, 152.54, 154.50, 158.13, 165.14, 167.06.

DEPT NMR (DMSO-d₆, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01, 79.35, 114.17, 120.70, 121.20, 126.92.

HRMS calcd for C₂₁H₂₄N₅O₄S (M + H)⁺: 442.1543, found 442.1554.

[α]²⁵_D −13.80 (c 0.5, DMSO)

Journal of Medicinal Chemistry (2013), 56(18), 7232-7242 reports similar analogues

Elemental impurities – A database to facilitate the risk assessment of active ingredients and excipients

May 14, 2015 3:26 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

One of the main demands of the Guideline ICH Q3D is to carry out risk assessments on metallic impurities. A database with analytical data provides a valuable support. Learn more about the data sharing using the new elemental impurities database.

http://www.gmp-compliance.org/enews_04843_Elemental-impurities—A-database-to-facilitate-the-risk-assessment-of-active-ingredients-and-excipients_9263,9300,S-QSB_n.html

Released in December 2014, the ICH Q3D Guideline on Elemental Impurities contains extensive specifications for the control of a total of 24 elements (21 metals, 3 metalloids) that can be present as impurities in pharmaceutical products. Main sources can be

Active ingredients
Excipients (including water)
Processing auxiliaries and catalysts
Production equipment
Container and closure systems

The Guideline ICH Q3D calls for a risk assessment with regard to the presence of metallic impurities in various dosage forms, taking into account the respective limit values. The main factors of influence are to be included (see fishbone diagram on p. 6 of the Guideline). The risks identified in a comprehensive analysis…

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ECA and PQG publish Chapter 6 of the interpretation of the ECA and PQG publish Chapter 6 of the interpretation of the EU GDP Guideline

May 14, 2015 3:22 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Read more about the GDP Guidance Chapter 6.

http://www.gmp-compliance.org/enews_04844_ECA-and-PQG-publish-Chapter-6-of-the-interpretation-of-the-EU-GDP-Guideline_9271,S-GDP_n.html

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. The interpretation of five chapters have been published already. The following 5 Guidance chapters on the EU GDP Guideline are available:

Chapter 1: Quality Management
Chapter 9: Transportation (also contains a template for a Technical Agreement)
Chapter 7: Outsourced Activities
Chapter 2: Personnel
Chapter 5: Operations

Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Chapter 6 of the EU GDP…

View original post 124 more words

Allisartan isoproxil

May 13, 2015 7:27 am / 1 Comment on Allisartan isoproxil

Allisartan isoproxil

CAS: 947331-05-7

553.01, C27 H29 Cl N6 O5

An angiotensin II receptor antagonist used to treat mild to moderate essential hypertension.

Approved china, cfda July 1 2012

Shanghai Allist Pharmaceutical, Inc.

Allist Shanghai Pharmaceutical Co., Ltd.

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester,

2-Butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid isopropoxycarbonyloxymethyl ester

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester

Allisartan is an orally-available angiotensin AT1 antagonist in phase II clinical trials at Shanghai Allist Pharmaceutical for the treatment of mild to moderate essential hypertension.

Shanghai Allist Pharmaceutical PHASE 2 for Hypertension

The prior art discloses Arleigh medoxomil illiquid, low bulk density, electrostatic phenomena evident. Chinese patent discloses a CN200710094131.0 Alicante medoxomil polymorph and method of preparation. Allie medoxomil based crystal prepared by the method has high stability characteristics, but relatively small bulk density of the crystal clear after the electrostatic phenomenon and poor liquidity dried, crushed and used for easy dispensing generate dust, operating the site clean and labor protection inconvenience, on the other hand also for accurate weighing and packaging products inconvenience.

CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

Allisartan isoproxil

Angiotensin II AT-1 receptor antagonist

Essential hypertension

Amorphous form of allisartan isoproxil is claimed in WO 2015062498. Useful for treating hypertension. Shenzhen Salubris Pharmaceuticals, in collaboration with Allist, has developed and launched allisartan isoproxil. In October 2012, Shenzhen Salubris signed a strategic cooperation framework agreement with Allist Pharmaceutical for the production and marketing of allisartan isoproxil. Family members of the product case of allisartanWO2007095789, expire in the EU and in the US in 2026. For a prior filing see WO2009049495 (assigned to Allist Pharmaceuticals), claiming the crystalline form of allisartan and its method of preparation.

The compound of formula (I) is an Ang II receptor antagonist. Its chemical name is 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carb-oxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester. Chinese Patent CN101024643A describes the structure, and its use as antihypertensive drugs.

As regards to the solid physical properties of the compound of formula (I), the patent document of CN101024643A discloses that it is a white solid, and its melting point is 134.5-136° C. However, CN101024643A dose not disclose the crystalline structure of the compound of formula (I).

CHINA

NEW PATENT

WO-2015062498

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015062498

2-butyl-4-chloro -1- [2 ‘- (1H- tetrazol-5-yl) -1,1’-biphenyl- – methyl] – imidazole-5-carboxylic acid, 1 – [(isopropoxy) – oxy] -, methyl ester, is a novel angiotensin Ⅱ receptor antagonist. China Patent CN200680000397.8 disclosed structural formula Alicante medoxomil compound. Allie medoxomil toxicity, blood pressure better than the same type of products (such as losartan), which by generating active metabolite (EXP3174) in vivo metabolism, and thus play its antihypertensive effect.

CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

……………………..

PATENT

http://www.google.com/patents/CN103965171A?cl=en

Hypertension is a major disease threat to human health, looking for efficiency, low toxicity anti-hypertensive drugs can help relieve social pressures and family responsibilities, with good social and economic benefits.

Angiotensin II (Ang II) is the renin – angiotensin – aldosterone system (RAAS) main vasoconstrictor hormone, which plays an important role in the pathobiology of many chronic diseases, particularly its the role of blood pressure regulation is particularly prominent, and therefore Ang II receptor is believed to be a good target for the development of anti-hypertensive drugs.

EP0253310 discloses a series of imidazole derivatives, DuPont declared and obtained by the study of losartan potassium-listed in 1994, was the first non-peptide Ang II receptor antagonist anti-hypertensive drugs. Thereafter, he listed a series of losartan antihypertensive drugs: candesartan cilexetil, valsartan, irbesartan, telmisartan and olmesartan medoxomil, etc. (EP0253310, W02005049587, GB2419592, EP1719766, US5196444) .

The losartan potassium in the body, the active metabolite EXP3174 has a stronger antihypertensive effect than losartan potassium, but EXP3174 polar molecular structure, is difficult to form passive absorption by diffusion through the cell membrane. US5298915 discloses five carboxyl ester group transformation EXP3174 is a series of derivatives, focusing on the compound HN-65021, and discloses hypotensive test results HN-65021 administered by the oral route, its hypotensive activity with chlorine Similar losartan potassium (BritishJouurnal ofClinical Pharmacology, 40,1995,591).

CN200680000397.8 _5_ discloses a class of imidazole carboxylic acid derivatives, namely Alicante medoxomil compound 8 has a good blood pressure lowering effect, the structure of formula I, the preparation method disclosed in this patent document follows the route A, losartan potassium by oxidation, the protecting group into an ester, deprotected to give a compound of formula I, the route step oxidation process of hydroxyl to carboxyl groups, will be reduced to very fine granular potassium permanganate, manganese dioxide, filtration This manganese mud time-consuming, inefficient, polluting; the second step conversion was about 70%, and post-processing cumbersome; byproducts and produced the first two steps more. This makes the high cost of the entire route, not suitable for the production of amplification.

CN200710094021.4 discloses another method for preparing the compounds of formula I, the following route B, the starting material by nucleophilic substitution, oxidation, an ester, a tetrazole ring to obtain a compound of formula I, the first step of the method nucleophilic substitution easy to generate an imidazole ring -3 para isomer impurities difficult to remove; the last step into the ring to use sodium azide, operating dangerous.

CN201210020174.5 disclosed a series of anti-hypertensive compound and preparation method, the following line C, the temperature control in the first step of its preparation O ~ 5 ° C, a mixed solution of acetone and water, with a 5% aqueous solution of sodium hypochlorite oxidation, yield 70%, the second step use of potassium permanganate, manganese dioxide will produce the same, and a yield of only 40%, the first two steps total yield of 28%, is very low, and the post-treatment methods are by column separation, the first two steps are used are organic and inorganic mixed solvent is not conducive to recovery, not suitable for scale-up.

Example 8 2-Butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil crude)

To a 20L reactor 9800ml of methanol, stirring was started, the rotational speed is added at 200r / min 1225.3g solid compound of formula II, and heated to reflux. The reaction 8-10h evacuation HPLC detection, the formula II compound residue <1.0% seen as a response endpoint. After reaching the end of the reaction the heating was stopped, continued stirring speed of 180r / min. About 3_4h fell 20_25 ° C, colorless transparent crystalline solid precipitated. The reaction mixture was cooled to continue to 15-20 ° C, to maintain 15-20 ° C with stirring 3h, the reaction mixture was filtered to give a pale yellow clear filtrate. The filtrate was concentrated under reduced pressure to move 20L flask, vacuum degree of 0.075MPa, 40_45 ° C methanol distilled off under until no distillate. 800ml of absolute ethanol was added, a vacuum degree of 0.075MPa, 40-45 ° C under distillation until no distillate.

900ml of absolute ethanol was added, heated to reflux. N-heptane was added slowly 1100ml, reflux 15min, to -10 ° c / h speed cooled to 15 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration lh, was Allie medoxomil crude (800.lg, yield 93.8%).Purification was used directly in the next step without drying.

Example 9 2-butyl-4-chloro-_1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole-5-carboxylic acid, 1 – [(isopropylamino oxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

850ml of absolute ethanol was added to the 3L reaction vessel was charged with crude Alicante medoxomil (800.lg, 1.45mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1300ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration, the purified Alicante medoxomil (780.9g, 97.6% yield).

Example 10 2-butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

950ml of absolute ethanol was added to the 5L reaction vessel was charged with crude Alicante medoxomil (549.9g, 1.72mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1200ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = cake was washed with a mixture of 1/3, and dried under reduced pressure after filtration to obtain a purified Alicante medoxomil (540.0g, 98.2% yield).

……………….

PATENT

http://www.google.com/patents/US20090036505

Example 122-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester (compound 8)

To a 100 ml of one-necked flask, 0.523 g of material, 0.124 g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. Then 0.562 g of 1-chloromethyl isopropyl carbonate was added and the mixture was reacted at 45-50° C. for 16 hours. After the reaction was completed, the mixture solution was filtered, and 30 ml of water was added into the filtrate. The resulting mixture was extracted with 30 ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.724 g of oil, which was directly used in the next reaction without purification.

10 ml of dioxane and 5 ml of 4 mol/L HCl were added, and the resulting mixture was reacted at room temperature for 16 hours. The reaction was stopped and the solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.436 g of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester.

In addition, the following reaction condition can be used to deprotect the protecting group. To 1.7 g of oily product, 5 ml absolute methanol was added and the mixture was heated slowly to reflux and stirred for 8 hours. When the insoluble solid disappeared totally, the mixture was discontinued to heating and cooled to 5° C. The white solid precipitated, and was separated by filtration, and the filter cake was washed with a small quantity of methanol. The combined filtrate was concentrated to dryness to give 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester with the yield of 70%.

¹H-NMR (CDCl₃) δ H (ppm): 0.89 (t, 3H, J=14.6), 1.24 (d, 6H, J=6.3), 0.37 (m, 2H, J=22.1), 1.69 (m, 2H, J=30.5), 2.64 (t, 2H, J=15.5), 4.81 (m, 1H, J=12.4), 5.54 (s, 2H), 5.86 (s, 2H), 6.95-7.64 (8H), 8.08 (d, 1H, J=7.42)

ESI(+) m/z: 552.7

Mp: 134.5-136° C.

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Shanghai Allist Pharmaceutical, Inc.

WO2005011646A2 *	20 Jul 2004	10 Feb 2005	Nicoletta Almirante	Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-ii receptor blockers for the treatment of cardiovascular diseases

US7943648 *	Jun 5, 2009	May 17, 2011	Shanghai Allist Pharmaceutical Inc.	Salts of imidazole-5-carboxylic acid derivatives, a method for preparing same and pharmaceutical compositions comprising same
US8138214	Jul 2, 2009	Mar 20, 2012	Shanghai Allist Pharmaceutical, Inc.	Pharmaceutical composition
USRE44873	Jul 31, 2006	Apr 29, 2014	Salubris Asset Management Co., Ltd.	Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof

Citing Patent	Filing date	Publication date	Applicant	Title
US8455526 *	6 Jun 2008	4 Jun 2013	Shanghai Allist Pharmaceuticals, Inc.	Therapeutic use of imidazole-5-carboxylic acid derivatives
US20100168193 *	6 Jun 2008	1 Jul 2010	Shanghai Allist Pharmaceuticals, Inc.	Therapeutic use of imidazole-5-carboxylic acid derivatives
USRE44873	31 Jul 2006	29 Apr 2014	Salubris Asset Management Co., Ltd.	Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof

CN101024643A	20 Feb 2006	29 Aug 2007	上海艾力斯医药科技有限公司	Imidazo-5-carboxylic-acid derivatives, its preparing method and use
US5298519 *	24 Sep 1992	29 Mar 1994	Chemish Pharmazeutische Forschungsgesellschaft M.B.H.	Acylals of imidazole-5-carboxylic acid derivatives, and their use as angiotensin (II) inhibitors

……………….

update……………..

WO 2015192722

Example 1

Weigh 25g 2- butyl-4-chloro-1- [2 ‘- (1-trityl–1H- tetrazol-5-yl) -1,1’-biphenyl – methyl] – imidazole 5-carboxylic acid, 1 – [(isopropoxy) – carbonyloxy] -, methyl ester, was added to a 500ml three-necked flask, methanol was added 200ml, refluxed for 9h, methanol was distilled off under reduced pressure to give crude Alicante medoxomil .

To the residue (i.e., medoxomil crude Alicante) were added 33ml of isopropanol and 66ml of n-heptane, heated to 76 ℃ stirred for 2h. After cooling to 60 ℃ stirring for 1h, and then the system was slowly cooled to 0 ℃, stirring was continued for 3h. Filtered, the filter cake was washed with n-heptane. At 40 ℃ 8 hours and dried in vacuo to give 15.3g Alicante medoxomil (purity 99.3%) as a XRD spectrum as shown in Figure, the main peak of the diffraction peaks as shown in the following table, the DSC spectrum shown in figure II . Compared with the published crystal, the crystal obtained by the absence of significant electrostatic phenomena.

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