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Lascufloxacin, KRP-AM1977, by Kyorin

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Figure JPOXMLDOC01-appb-C000001

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 mesylate2D chemical structure of 1433857-41-0

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-, 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.

Figure JPOXMLDOC01-appb-C000001

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-​Pyrrolidinemethanami​ne, N-​cyclopropyl-​4-​fluoro-​, (3R,​4S)​-

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
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
  1. 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).
  2. 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).

……….

 

KYORIN Pharmaceutical Co., Ltd. - Your health is Kyorin's mission.

Mitsutomo Miyashita, Representative Director, President and Chief Executive Officer

Mitsutomo Miyashita

  • KYORIN Co,.Ltd.

Access Map

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

.

Company Profile

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
Map of shimotsuga district
Tochigi Wanpaku Park – Mibu-machi – Reviews of Tochigi Wanpaku Park –
.
.
MARKET
Ochanomizu station

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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