GCC 4401C , GC 2107 , Nokxaban for treating thrombosis

GCC-4401C ( GC-2107), Nokxaban
In phase 1 for treating thrombosis
5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide methanesulfonate
5-chloro-N-[[3-[4-(5,6-dihydro-2H-1,2,4-triazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide
CB02-0133; GC-2107; GC4401; GCC-2107; GCC-4401; GCC-4401C; I Fxa – LegoChem Biosciences; LCB02-0133; Nokxaban

WO2010002115; LegoChem Bioscience INNOVATOR

Green Cross Corporation, Legochem Bioscience Ltd.

DEVELOPER

CAS NO FREE FORM

CAS 1159610-29-3, 159610-29-3, C₁₈ H₁₈ Cl N₅ O₃ S
2-​Thiophenecarboxamide​, 5-​chloro-​N-​[[(5S)​-​3-​[4-​(5,​6-​dihydro-​1,​2,​4-​triazin-​1(2H)​-​yl)​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-
Molecular Formula: C₁₈H₁₈ClN₅O₃S Molecular Weight: 419.88522 g/mol

METHANE SULFONATE

CAS 1261138-12-8, C₁₈ H₁₈ Cl N₅ O₃ S . C H₄ O₃ S,
2-​Thiophenecarboxamide​, 5-​chloro-​N-​[[(5S)​-​3-​[4-​(5,​6-​dihydro-​1,​2,​4-​triazin-​1(2H)​-​yl)​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-​, methanesulfonate (1:1)

HYDROCHLORIDE
CAS 1261138-08-2., C₁₈ H₁₈ Cl N₅ O₃ S . Cl H, 2-​Thiophenecarboxamide​, 5-​chloro-​N-​[[(5S)​-​3-​[4-​(5,​6-​dihydro-​1,​2,​4-​triazin-​1(2H)​-​yl)​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-​, hydrochloride (1:1)

SUMMARY

• 09 Jan 2015GC 2107 is available for licensing as of 09 Jan 2015. http://www.greencross.com
• 01 May 2014Green Cross Corporation completes a phase I trial in Healthy volunteers in USA (NCT01954238)
• 26 Sep 2013Green Cross initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT01954238)

Used as factor Xa antagonist for treating coronary artery disease, inflammatory disease, myocardial infarction and thrombosis.
Green Cross Corp in collaboration with LegoChem Bioscience, is developing GCC-4401C ( phase I), for treating thrombosis including venous thromboembolism

KDDF-201210-04

Development and Market Objectives

Green Cross Corporation is developing an orally available direct Factor Xa inhibitor, GCC-4401C, which has shown an excellent safety profile during Phase I clinical study. After completion of Phase II and III studies for the prevention of venous thromboembolism (VTE) on hip or knee replacement surgery patients, we will explore additional indications for the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation.

Unmet Medical Need & Target Patients

GCC-4401C may prove its greatest impact in providing a much-needed and attractive alternative to warfarin in various indications. Prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing hip or knee arthroplasty, is considered to be a primary unmet medical need. It is the most common cause for rehospitalisation in this patient group. Each year in the United States, between 350,000 and 600,000 people experience a blood clot in the legs or in the lungs. The US and European hip and knee implant markets are the two largest, accounting for nearly 80 percent of total procedures conducted worldwide. The 2005 revenues for hip and knee implants in the US and Europe were $6.5 billion.  Demand driven by an aging population and an increasing number of younger patients are contributing to the continuous growth of hip and knee replacement procedures.

Thromboembolism involving arterial or venous circulation is a common cause of morbidity and mortality. As an anticoagulation therapy, heparin and Vitamin K antagonists (VKAs) such as warfarin have been used in clinical settings for more than 50 years, but both are associated with several limitations requiring frequent coagulation monitoring due to unpredictable effects of anticoagulant .  Therefore, there is an urgent need for novel, oral agents with a predictable anticoagulant action. The greatest unmet medical need in anticoagulation therapy is to find a replacement for VKAs for long-term therapy, particularly stroke prevention in patients with atrial fibrillation (a heart rhythm disorder).  Recently, Factor Xa has emerged as an attractive target for novel anticoagulants and a number of Factor Xa inhibitors are currently under development as oral anticoagulants for long-term use.
A major unmet medical need is for direct FXa inhibitors that are simpler to administer than VKAs, with fewer strokes and less intracranial bleeding compared with warfarin and less bleeding yet similar or better efficacy with a lower-dose regimen. In addition, the availability of simple, fixed-dose, unmonitored therapies should increase the use of direct FXa inhibitor therapy in patients with atrial fibrillation at risk for stroke.

Status

Phase I Clinical Study

To investigate the safety and tolerability of single doses of GCC-4401C in healthy male subjects, a Phase Ia study (GCC-4401C-101) was recently conducted at Quintiles in the United States under the conditions of randomized, double-blind, placebo-controlled, and single ascending dose. Forty eight healthy male subjects were enrolled in 6 cohorts and administered at 6 dose-escalation levels up to 80 mg/subject. GCC-4401C was well-tolerated without any significant adverse events, and was detected in blood plasma dose-proportionally across the dose range of 2.5 mg to 80 mg per patient. The pharmacodynamic variables were also statistically correlated with GCC-4401C plasma concentrations.
We plan to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of GCC-4401C in healthy male subjects based on the safety margins of the SAD study. An appropriate dose and dosing regimen of oral GCC-4401C from subsequent clinical trials on VTE patients are expected to be identified. The Phase 1b study will be completed with Global CRO in the US in 3Q, 2014.

Intellectual Property

Material patent for GCC-4401C, covering a wide range of chemical structures, was awarded in early 2008 within S. Korea, followed by its production method patent in early 2011. Moreover, patent applications for both material and production method, are in progress in 21 and 5 overseas countries including the US, respectively.
–          KR811865 : Pyrimidinone derivatives or pyridazinone derivatives for inhibition of factor VIIa activity
–          KR109594 : FXa inhibitors with cyclic amidines as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
–          KR898361 : FXa inhibitors with cyclic amidoxime or cyclic amidrazone as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
–          KR1037051 : Method for preparing of (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
–          KR1037052 : Method for preparing 5-chloro-N-(((5S)-2-oxo-3-(4-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophen-2-carboxamide derivatives, and their intermediates
–          PCT/KR2010/004420 : Method for preparing (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
–          PCT/KR2010/004421 : Method for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide derivative and intermediate used therein

Competitive Advantages

GCC-4401C has been specifically designed for chronic, once-a-day treatment. It has a half-life that supports true, once-daily dosing and a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability. Since GCC-4401C has an excellent aqueous solubility, there has been potential for the development of both po and iv formulations. Data from comparative efficacy studies in animals have also demonstrated the superiority of GCC-4401C against other direct FXa inhibitors with less bleeding effects. From the recent Phase Ia clinical study, GCC-4401C did not show any significant sign of adverse events. PK parameters and PD markers were predictable dose-proportionally across the all dose ranges. GCC-4401C is expected to show excellent safety profiles, less bleeding and less liver toxicity through human clinical studies.

Contact & Company Overview

• Company Name :

  Green Cross Corporation
• Homepage :

  http://eng.greencross.com/
• Contact Person :

  Hyoung Geun Beak, Deputy General Manager, Business
• E-mail :

  hgbeak@greencross.com
• Contact :

  +82-31-260-9337

PATENT

WO 2016010178
GREEN CROSS CORPORATION [KR/KR]; 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-770 (KR).
LEGOCHEM BIOSCIENCES, INC. [KR/KR]; 8-26, Munpyeongseo-ro, Daedeok-gu, Daejeon 306-220 (KR)
The present invention relates to a novel crystalline form of 5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide methanesulfonate and a pharmaceutical composition containing the same. The novel crystalline form of a compound according to the present invention exhibits excellent stability even in high-temperature and humidity environments, and thus can be favorably used to prevent or treat diseases, such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty, and thromboembolism.
According to the present invention 5-chloro -N – ({(5 S) -2- oxo-3- [4- (5,6-dihydro the -4H- [1, 2, 4] triazine-1-yl) phenyl] -1, 3-oxazolidin-5-yl} methyl) thiophene-2-mid copy methane sulfonic acid salt (hereinafter referred to as a new crystal form has excellent solubility referred to) in “GCO4401C”, Ko Un and wet environments It is excellent in stability.
Novel crystalline forms of GCC-4401C of the present invention, the organic solvent under reduced pressure crystallization method, a cooling crystallization method or solvent-can be easily obtained by the anti-solvent crystallization process.
Ateumyeo GCC-4401C is used as a reaction raw material can be prepared according to the procedure described in PCT Publication No. W02011 / 005029 No., dissolving the starting compound in an organic solvent the semi-adding a solvent after filtration to determine the resulting mixture was cooled and then dried to give the novel crystalline form can be a compound according to the invention.

PATENT
http://www.google.com/patents/WO2011005029A2?cl=en
5-Chloro-N-( {(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[ 1 ,2,4]triazin- 1-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)thiophene-2-carboxamide of formula (A) has been known as an inhibitor of blood coagulation factor Xa and used for treating and preventing thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, recurrent stricture after angioplasty, and thromboembolism such as intermittent claudication.

Korea Patent No. 2008-64178, whose application has been filed by the present invetors, discloses a use of the compound as an inhibitor of blood coagulation factor Xa and a preparation method thereof. The preparation method comprises the step of preparing a cyclic amidrazone starting from 4-nitroaniline, as shown in reaction scheme 1 :
Reaction Scheme 1

Specifically, the cyclic amidrazone (A) is prepared by the steps of: preparing the compound (B) using 4-nitroaniline; treating the compound (B) with a t-butoxycarbonyl amine protecting group to prepare the compound (C); introducing a nitroso group into the compound (C) using NaNO₂, followed by reduction using zinc to prepare the compound (D); and treating the compound (D) successively with hydrochloric acid and an ortho-formate.
However, the above preparation method is complicated and gives a low yield of the compound (A) (e.g., a total yield of 9 %), and it also requires the use of a column chromatography purification step, which limits mass production of the cyclic amidrazone. In particular, the step for preparing the compound (D) from the compound (C) is required to use a harmful heavy metal-containg materal such as zinc amalgam which gives an unsatisfactorily low yield, and the isolation step of the compound (D) does not proceed easily.

Reaction Scheme 2


Reaction Scheme 3


Example 1: Preparation of Ethyl formimidate hydrochloride

To a solution of benzoyl chloride (1212 g, 8.62 mol, 1 eq) in anhydrous ether (5.8 L) was added dropwise a solution of formamide (388 g, 8.62 mol, 1 eq) in EtOH (396 g, 8.60 mol, 0.998 eq) at 0 ^°C for lhr. The mixture thus obtained was stirred at 0 ^°C for 30min. The solid was filtered off, washed with ether (3 L) and EA (3 L). The solid was dried under high vacuum.
Yield : 625 g (66%)
Example 1: 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-lH-[l,2,4]triazin-4-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide hydrochloride
Step 1: Preparation of 2- [N-(4-nitro-phenyl)-hydrazino]-ethanol

l-Fluoro-4-nitrobenzene (7.1 g, 50 mmol) was dissolved in CH₃CN (70 ml), 2-hydroxyethylhyrazine (purity: 90 %, Aldrich, 5.0 g, 66 mmol) and K₂CO₃ (7.6 g, 55 mmol) were added thereto. The suspension thus obtained was stirred for 4 hrs with reflux. The resulting orange-colored suspension was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) and ethylacetate (EA, 90 ml) and water (18 ml) were added thereto. The resulting mixture was stirred strongly at r.t. for 10 min. The organic layer was extracted and washed with the saturated brine (10 ml). The resulting solution was cooled to 10 °C and 48 % HBr solution (3.7 ml) was added thereto dropwise with stirring. The pale yellow colored solid thus obtained was filtered off and dried under high vacuum (1 torr, 40 “C) to obtain the title compound as an intermediate.
Yield: 7.1 g (51 %).
TLC : Rf= 0.62 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (600 MHz, DMSO-J₆) δ 8.17 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 3.82 (t, J= 5.4 Hz, 2H), 3.69 (t, J= 5.4 Hz, 2H)
LCMS: 198 (M+H⁺) (C₈H₁₁N₃O₃)
Step 2: Preparation of l-bromo-2-[N-(4-nitro-phenyl)-hydrazino] -ethane

The compound obtained in Step 1 (38.9 g, 0.140 mol) was suspended in anhydrous 1 ,2-dimethoxyethane (585 ml). The resultant suspension was cooled to 0 ^°C and PBr₃ (15.9 ml, 0.168 mol) was added thereto dropwise for 30 min. The mixture thus obtained was stirred at 60 ^°C for 4 hrs. The pale yellow colored solution thus obtained was concentrated under reduced pressure (reflux condenser, 10 torr, 45 ^°C). The resultant residue (oil) was suspended with water (150 ml) and stirred. Aq. sat’d NaHCO₃ solution (150 m) was added to the resultant suspension to be pH 4. The resulting mixture was stirred for 30 min to precipitate the pale yellow colored precipitates. The precipitates were filtered off and washed with water (100 ml). The resulting solid was mixed with water (100 ml), aq. sat’d NaHCO₃ solution (70 ml) and CH₂Cl₂ (500 ml). The resulting mixture was stirred for 10 min and stood to separate organic and aqueous layers. The organic layer was dried over 20 g of MgSO₄ and filtered off. The resulting filterate was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) to obtain the title compound as a pale yellow solid.
Yield : 31.3 g (86 %)
TLC : Rf= 0.91 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J = 10.2 Hz, 2H), 6.92 (d, J= 10.2 Hz, 2H), 4.00 (t, J= 7.2 Hz, 2H), 3.65 (t, J= 7.2 Hz, 2H)
LCMS: 261 (M+H⁺) (C₈H₁₀BrN₃O₂)
Step 3: Preparation of 4-(5,6-dihydro-4H-[l,2,4]triazin-l-yl)-l-nitrobenzene

The compound obtained in Step 2 (13.0 g, 50.0 mmol) was completely dissolved in anhydrous 1,2-dimethoxyethane (200 ml) which is prepared by mixing 1,2-dimethoxyethane (purity: 99 %, Junsei Co. Ltd) with an desired amount of molecular sieve 4A and standing for 5 hrs or more with stirring at times. Ethyl formimidate HCl salt (5.8 g, 52.5 mmol) was added thereto. The suspension thus obtained was stirred at 25 ^°C for 10 min. Anhydrous sodium acetate (NaOAc, 8.6 g, 105 mmol) was added thereto and stirred for 15 hrs with reflux. The orange colored suspension thus obtained was concentrated under reduced pressure (10 torr, 50 “C). The orange colored residue thus obtained was mixed with IN HCl (140 ml), EA (50 ml) and hexane (100 ml), and stirred at r.t for 10 min. A small amount of insoluble suspended solids was remained in aqueous layer and filtered off. The resulting aqueous layer was washed with a mixture of EA (30 ml) and hexane (60 ml). 12 g of sodium carbonate was added to the resulting solution to be pH 8.5. The orange colored solid thus obtained was filtered off under reduced pressure, washed with water (15 ml) and dried under vacuum to obtain the title compound .
Yield : 7.7 g (75 %).
TLC : R/= 0.45 (EA/MeOH/AcOH = 20/1/0.5)
HPLC : R, = 8.65 (Gradient A), purity 91.1%
¹H NMR (400 MHz, DMSO-^₆) δ 8.03 (d, J= 9.6 Hz, 2H), 7.16 (d, J = 9.6 Hz, 2H), 7.12 (br s, IH), 7.01 (d, J= 4.0 Hz, 2H), 3.77 (t, J= 5.2 Hz, 2H), 3.43-3.40 (m, 2H)
LCMS: 207 (M+H⁺) (C₉H₁₀N₄O₂)
Step 4: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)-1-nitrobenzene

To the orange colored suspension prepared by suspending the compound obtained in Step 3 (12.4 g, 60 mmol) in tetrahydrofurane (THF, 200 ml), 4-dimethylaminopyridine (DMAP, 0.367 g, 3 mmol) and di-tert-butyl dicarbonate
(BoC₂O, 19.6 g, 90 mmol) were added and stirred with reflux for 1.5 hrs. The yellow colored suspension thus obtained was concentrated under reduced pressure
(reflux condenser, 10 torr, 40 ^°C) to remove the solvent. The resulting yellow colored residue was completely dissolved in CH₂Cl₂ (700 ml) and washed with IN HCl (700 ml). The organic layer was extracted, dried over 25 g of MgSO₄, and concentrated under reduced pressure (condenser, 10 torr, 40 ^°C). The resultant yellow colored residue was dissolved in cyclohexane (250 ml) and stirred strongly at r.t. for 30 min. The resulting mixture was concentrated under reduced pressure to obtain yellow colored solids. The solids were dried (1 torr, 50 ^°C ) to obtain a disried compound.
Yield: 15.6 g (85 %)
TLC : R/= 0.93 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (600 MHz, DMSO-J₆) δ 8.14 (d, J= 9.6 Hz, 2H), 7.62 (br s, IH), 7.30 (d, J = 9.6 Hz, 2H), 3.89 (br s, 2H), 3.79 (br s, 2H), 1.50 (s, 9H)
LCMS: 307 (M+H⁺) (C₁₄H₁₈N₄O₄)
Step 5: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)aniline

To the yellow colored suspension prepared by suspending the compound obtained in Step 4 (19.9 g; 65 mmol) in methanol (200 ml), 10 % palladium on carbon (4.0 g) was added. The resulting mixture was subjected to vacuum outgassing and stirred at r.t., for 2 hrs in the flask connected with hydrogen bollum. The resulting mixture was filtered through celite 545 under redued pressure to remove the palladium on carbon. The fϊlterate was concentrated under reduced pressure (reflux condenser, 10 torr, 40 °C). The resulting pale brown colored residue was dissolved in isopropylalcohol (140 ml) and refluxed to dissolve completely. The resulting solution was stood at 0 ^°C for 2 hrs to cool, stirred for 30 min and filtered off under redued pressure. The resulting ivory crystalline solid was dried in vacuo to obtain the title compound (15.8 g, 88 %).
TLC : R_f= 0.38 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, DMSO-(I₆) δ 7.34 (br s, IH), 6.91 (d, J = 12.0 Hz, 2H), 6.51 (d, J = 12.0 Hz, 2H), 6.64 (br s, 2H), 3.74 (br s, 2H), 3.41 (br s, 2H), 1.48 (s, 9H)
LCMS: 277 (M+H⁺) (C₁₄H₂₀N₄O₂)
Step 6: Preparation of N-(3-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yI)anilino-(2R)-2-hydroxypropyI)-5-chloro-2-thiophene carboxamide

The compound obtained in Step 5 (19.3 g, 70 mmol) and 5-chloro-N-(((S)-oxiran-2-yl)methyl)thiophene-2-carboxamide (19.1 g, 88 mmol) were suspended in isobutyl alcohol (350 ml) and stirred for 18 hrs with reflux. The dark blue colored solution thus obtained was concentrated under reduced pressure (reflux condenser, 10 torr, 50 °C). To the yellow solid residue thus obrained, ethylacetate (200 ml) was added and the resulting mixture was stirred at r.t. for 30 min and further stirred strongly at 0 ^°C for 30 min. The suspended solid thus obtained was filtered off under reduced pressure and dried in vaccum (1 torr, 50 °C ) to obtain the title compound as ivory crude.
Yield : 25.9 g (75 %)
TLC : R_/= 0.34 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR of a crude sample (600 MHz, DMSO-</₆) δ 8.62 (t, J = 5.4 Hz, IH), 7.69 (d, J = 3.6 Hz, IH), 7.36 (br s, IH), 7.18 (d, J = 4.2 Hz, IH), 6.95 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 9.0 Hz, 2H), 5.10 (t, J = 6.6 Hz, IH), 5.05 (d, J = 5.4 Hz, IH), 3.81-3.75 (m, 3H), 3.44 (br s, 2H), 3.37-3.34 (m, IH), 3.25-3.21 (m, IH), 3.08-3.04 (m, IH), 2.94-2.89 (m, IH), 1.48 (s, 9H)
LCMS: 494 (M+H⁺) (C₂₂H₂₈ClN₅O₄S)
Step 7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yI}-methyl)-2-thiophene carboxamide

The compound obtained in Step 6 (25.2 g, 51 mmol) was completely dissolved in THF (325 ml), and Ll’-carbonyldiimidazole (10.8 g, 66 mmol) and DMAP (0.31 mg, 2.6 mmol) were added thereto. The resulting mixture was stirred with reflux for 18 hrs. The resulting pale yellow colored suspension was cooled to r.t, concentrated under reduced pressure and dried in vacuo (1 torr, 50 ^°C) to obtain the title compound as an ivory solid.
Yield : 23.3 g (88 %)
TLC : R/= 0.75 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, DMSO-J₆) δ 8.97 (t, J = 5.4 Hz, IH), 7.69 (d, J= 4.2 Hz, IH), 7.43 (br s, IH), 7.41 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 4.2 Hz, IH), 7.19 (d, J= 9.0 Hz, 2H), 4.82-4.77 (m, IH), 4.12 (t, J= 9.0 Hz, IH), 3.80-3.78 (m, 3H), 3.62 (br s, 2H), 3.59 (t, J= 6.0 Hz, 2H), 1.49 (s, 9H)
LCMS: 520 (M+H⁺) (C₂₃H₂₆ClN₅O₅S)
Step 8: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene
carboxamide hydrochloride

The compound obtained in Step 7 (16.1 g, 31 mmol) was completely
dissolved in THF (193 ml), 3N HCl (193 ml) was added thereto. The resulting solution was stirred with reflux for 1 hr. The white suspension thus obtained was cooled tq r.t, concentrated under reduced pressure and dried in vacuo (1 torr, 40 ^°C ) to obtain the title compound as a white solid.
Yield : 13.4 g (95 %)
TLC : R/= 0.82 (MC/MeOH/AcOH = 10/1/0.5)
HPLC : R, = 12.39 (Gradient A), purity 99.5%
¹H NMR (600 MHz, OMSO-d₆) δ 12.12 (br s, IH), 10.20 (br s, IH), 9.08
(t, J = 6.0 Hz, IH), 8.60 (d, J = 5.2 Hz, IH), 7.74 (d, J= 4.2 Hz, IH), 7.53 (d, J = 9.0 Hz, 2H), 7.20 (d, J= 4.2 Hz, IH), 7.13 (d, J= 9.0 Hz, 2H), 4.85-4.81 (m, IH),
4.15 (t, J = 8.8 Hz, IH), 3.85 (dd, J = 6.0, 9.2 Hz, IH), 3.66 (t, J = 4.8 Hz, 2H),
3.63-3.56 (m, 2H), 3.19 (br s, 2H)
LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃S)
Example 2: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yI)phenyl]-l,3-oxazolidin-5-yl}-methyI)-2-thiophene
carboxamide

The HCl salt obtained in Example 1 (6.9 g, 15 mmol) was completely dissolved in 33 % methanol aqueous solution (1.1 L) and heated to 50 ^°C while stirring. To the resulting colorlessness solution, 0.6M aq. Na₂CO₃ solution (25 ml) was added and the white suspension thus obtained was stood at 0 ^°C for 0.5 hr to cool. The white solid thus obtained was concentrated under reduced pressure, wished with H₂O (150 ml) and dried in vacuo (1 torr, 40 “C) to obtain the title compound (yield: 5.5 g, 87 %). The title compound was dissolved in methanol (330 ml) and stirred with reflux. The pale yellow colored solution thus obtained was stood at 0 ^°C for 2 hrs to cool. The resulting white solid was concentrated under reduced pressure, washed with methanol (10 ml), and dried in vacuo (1 torr, 40 ^“C) to obtain a crystal of the title compound (yield: 5.0 g, 80 %).
HPLC : R, = 12.37 (Gradient A), purity 99.7 %
¹H NMR (400 MHz, DMSO-^₆) δ 8.97 (t, J = 6.0 Hz, IH), 7.69 (d, J = 4.0 Hz, IH), 7.32 (d, J = 9.2 Hz, 2H), 7.20 (d, J = 4.0 Hz, IH), 7.12 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 4.0 Hz, IH), 6.52 (br s, IH), 4.80-4.75 (m, IH), 4.10 (t, J = 8.8 Hz, IH), 3.77 (dd, J= 6.0, 9.2 Hz, IH), 3.58 (t, J= 5.6 Hz, 2H), 3.33 (s, 4H)
LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃S)
Example 3: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yI}-methyI)-2-thiophene carboxamide methane sulfonate

To the compound obtained in Example 2 (3.3 g, 7.9 mmol), a mixture solution of MeOH/CH₂Cl₂ (1/4 v/v, 70 ml) was added and stirred with reflux. The pale yellow colored solution thus obtained was cooled to 0 ^°C and methylsulfonic acid (0.56 ml, 8.6 mmol) was added thereto. The resulting mixture was concentrated under reduced pressure (reflux condenser, 10 torr, 40 ^°C) to obtain pale yellow foamy solid. To the resultant solid, absolute ethanol (20 ml) was added and the resulting mixture was stirred with reflux to dissolve solid clearly. The resulting solution was cooled to 0 ^°C to 2 hrs. The resulting white solid was concentrated under reduced pressure, washed with absolute EtOH (5 ml), and dried in vacuo (1 torr, 40 “C) to obtain a crystalline methane sulfonate.
Yield : 3.8 g (93 %)
HPLC : R, – 12.35 (Gradient A), purity 99.8%
¹H NMR (400 MHz, DMSO-CZ₆) δ 11.97 (br s, IH), 10.07 (br s, IH), 8.99
(t, J= 6.0 Hz, IH), 8.59 (U₁ J= 6.0 Hz, IH), 7.70 (d, J= 4.0 Hz, IH), 7.53 (d, J =
9.2 Hz, 2H), 7.20 (d, J= 4.0 Hz, IH), 7.13 (d, J= 9.2 Hz, 2H), 4.86-4.80 (m, IH),
4.16 (t, J = 9.2 Hz, IH), 3.82 (dd, J = 6.0, 9.2 Hz, IH), 3.67 (m, 2H), 3.60 (t, J = 5.6 Hz, 2H), 3.20 (br s, 2H), 2.31 (s, 3H)
LCMS: 420 (M⁺H⁺)(C₁₈H₁₈ClN₅O₃S)
Example 4: (S)-5-chloro-N-((3-(4-(5,6-dihydro-l,2,4-triazin-l(4H)-yl)phenyI)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide methane sulfonate
Step 1: Preparation of (2-[N-(4-nitro-phenyl)-hydrazinyl]-ethanol) hydrobromide

l-Flouro-4-nitrobenzene (428 g, 3.03 mol, Aldrich Fl 1204) was dissolved in CH₃CN (4.3 L), and 2 -hydroxy ethylhyrazine (300 g, 3.94 mol, 1.3 eq, imported from China, >98 %) and K₂CO₃ (461 g, 3.34 mol, 1.1 eq, Aldrich
347825) were added thereto. The mixture thus obtained was stirred at 80 ^°C for
19 hrs. The mixture was cooled to r.t. and evaporated to remove solvent. The residue was dissolved with EA (1.5 L) and H₂O (1 L). The organic layer was extracted and washed with H₂O (500 mL) and brine (200 mL). The extracted
EA layer was cooled to 0 °C and 48 % HBr solution (360 mL, Aldrich 244260) was added thereto dropwise at 0 °C with stirring. The resultant mixture was stirred at 0 ^°C for 1 hr. The solid thus obtained was filtered off and washed with
EA (5 L). The obtained solid was dried under high vacuum to obtain the title compound.
Yield : 531 g (63 %)
TLC : Rf= 0.62 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, OMSO-d₆) δ 7.94 (d, J = 9.6 Hz, 2H), 7.12 (br s, 2H), 6.63
5.8 Hz, 2H) LCMS: 198 (M+H⁺) (C₈H₁₁N₃O₃)
Step 2: Preparation of l-bromo-2-[N-(4-nitro-phenyl)-hydrazino]-ethane

The compound obtained in Step 1 (531 g, 1.90 mol) was suspended in
anhydrous 1,2-dimethoxyethane (4.5 L). The resultant suspension was cooled to 0 ^°C and PBr₃ (220 niL, 2.29 mol, 1.2 eq, Aldrich 256536) was added thereto dropwise at 0 ^°C . The mixture thus obtained was warmed up to r.t. and stirred at 6O ⁰C for l5 hrs.
The mixture was cooled to r.t., and filtered off to remove remained insoluble solid. The filter cake thus obtained was washed with 1,2- dimethoxyethane (700 mL) and the filtrate was concentrated in vacuo. The resultant residue was suspended with H₂O (2.5 L), stirred and cooled to 0 ^°C . Aq. 2N NaOH solution (1.7 L) was added thereto at 0^°C to neutralize the suspension mixture (pH 6-7). The solid was filtered off and washed with H₂O (5 L). The filtered solid was air-dried for 5 hrs.
The air-dried solid was dissolved with CH₂Cl₂ (3 L), and aq. sat’d
NaHCO₃ solution (1.5 L) and H₂O (700 mL) were added thereto. The resultant
– mixture was stirred for 15 min and stood to separate organic and aqueous layers. Insoluble solid which was not dissolved in organic layer and H₂O was remained in the mixture. The mixture was filtered off to remove insoluble solid and the filter cake was washed with CH₂Cl₂ (700 mL). The organic layer was extracted, dried over MgSO₄, filtered off, and concentrated in vacuo. The resultant solid was dried under high vacuum to obtain the title compound.
Yield : 383 g (77% : When product was dissolved in CDCl₃ to check the
¹H NMR spectroscopy, insoluble solid was stilled remained in CDCl₃)
TLC : Rf= 0.91 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 9.6 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.65 (t, J = 6.6 Hz, 2H)
LCMS: 261 (M+H⁺) (C₈H₁₀BrN₃O₂)
Step 3: Preparation of 4-(5,6-dihydro-4H-[l,2,4]triazin-l-yl)-l-nitrobenzene
Ethyl formimidate HCI, NaOAc
1 ,2-dimethoxyethane

The compound obtained in Step 2 (384 g, 1.48 mol) was dissolved in anhydrous 1,2-dimethoxyethane (4 L) and ethyl formimidate HCl salt (322 g, 2.94 mol, 2 eq) was added thereto at r.t. The resultant mixture was stirred at r.t. for 30 min. NaOAc (364 g, 4.44 mol, 3.0 eq, Aldrich 110191) was added to the mixture and the mixture was stirred at 75 ^°C for 15 hrs.
The mixture was cooled to r.t. and evaporated to remove solvent. The resultant residue was suspended in EA (2 L) and 1,2-dimethoxyethane (I L). Aq.
3N HCl solution (2.5 L) was added to the suspension. Insoluble solid was remained in resultant mixture. The solid was filtered off two times to remove insoluble solid. Ether (3 L) was added to the filtrate to separate organic and aqueous layers effectively. Aqueous layer was separated and washed with mixed organic solution (EA (1 L) + Hexane (500 mL)). The combined organic layer should be kept to recover the product.
(The treatment of aqueous layer)
The aqueous layer was cooled to 0 ^°C and aq. 6N NaOH solution (2.2 L) was added thereto slowly to basify the H₂O layer (pH ~ 9). The resultant suspension was stirred at r.t. for 12 hrs. The solid was filtered off and washed with H₂O (3 L) and dried under high vacuum.
(The treatment of combined organic layer)
The combined organic layer was concentrated in vacuo. The resultant residue was acidified with aq. 3N HCl solution (500 mL). Filtration was carried out to remove insoluble solid. The filtrate (H₂O layer) thus obtained was washed with ether (700 mL X 2). The aqueous layer was stirred and cooled to 0 ^°C . Aq. 5N NaOH solution (1 L) was added to the cooled aqueous layer to basify (pH ~9). The mixture thus obtained was stirred at r.t. for 12 hrs. The solid thus obtained was filtered off and washed with H₂O (1.5 L). The solid was dried under high vacuum to obtain the title compound.
Yield : 187 g (62 %)
TLC : Rf= 0.45 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, DMSO-</₆) δ 7.99 (d, J = 9.6 Hz, 2H), 7.16 (d, J =
9.6 Hz, 2H), 7.09 (br s, IH), 6.97 (d, J = 3.6 Hz, 2H), 3.73 (t, J = 5.0 Hz, 2H), 3.45-3.46 (m, 2H)
LCMS: 207 (M+H⁺) (C₉H₁₀N₄O₂)
Step 4: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)- 1-nitrobenzene

The compound obtained in Step 3 (187g, 0.907 mol) was suspended in anhydrous THF (2.2 L), and BoC₂O (30Og, 1.36 mol, 1.5 eq, Aldrich 205249) and DMAP (6g, 0.045 mol, 0.05 eq, Aldrich 107700) were added thereto. The mixture thus obtained was stirred at 65 ^°C for 5 hrs.
The mixture was cooled to 0 ^°C . MeOH (1.5 L) was added to the mixture at 0 ^°C and stirred at 0 °C for 1 hr. The solid thus obtained was filtered off, washed with MeOH (750 niL) and dried under high vacuum.
Filtrate thus obtained was concentrated in vacuo. MeOH (1 L) was added to the resultant residue with stirring. The mixture thus obtained was stirred at r.t for 12 hrs. Solid thus obtained was filtered off, washed with MeOH (500 mL), and dried under high vacuum to obtain the title compound.
Yield : 182 g (65 %)
TLC : R_f= 0.93 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, DMSO-J₆) δ 8.17 (d, J= 9.6 Hz, 2H), 7.57 (br s, IH), 7.19 (d, J= 9.6 Hz, 2H), 3.93-3.86 (m, 2H), 3.83-3.745 (m, 2H), 1.56 (s, 9H)
LCMS: 307 (M+H⁺) (C₁₄H₁₈N₄O₄)
Step 5: Preparation of 4-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)aniline

The compound obtained in Step 4 (134 g, 438 mmol) was suspended in
MeOH (1.3 L) at r.t., and NH₄Cl (12 g, 0.5 eq, Aldrich A4514) and Zn (15 g, 0.5 eq, Aldrich 209988) were added 6 times at intervals of 15 min at r.t. (total amounts Of NH₄Cl = 73 g (1356 mmol, 3.1 eq) and total amounts of Zn = 88 g
(1356 mmol, 3.1 eq))
Temperature of the resultant mixture was risen gradually to 65 ^°C and the mixture was stirred at 65 ^°C for 12 hrs. The mixture was cooled to 40 ^°C and NH₄Cl (12 g, 0.5 eq, Aldrich A4514) and Zn (15 g, 0.5 eq, Aldrich 209988) were added thereto. Temperature of the resultant mixture was risen gradually to 65 ^°C and the mixture was stirred at 65 “C for 1 hr.
The mixture was cooled to r.t. and filtered off through celite pad. The filter cake was washed with MeOH (700 mL) and THF (700 mL) and the filtrate was concentrated. The crude product thus obtained was dried under high vacuum and used without further purification.
Yield : 124 g (quantitative)
TLC : Rf= 0.38 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, OMSO-d₆) δ 7.31 (br s, IH), 6.86 (d, J = 12.0 Hz, 2H), 6.48 (d, J = 12.0 Hz, 2H), 4.60 (s, 2H), 3.71 (br s, 2H), 3.38 (br s, 2H), 1.44 (s, 9H)
LCMS: 277 (M+H⁺) (C₁₄H₂₀N₄O₂)
Step 6: Preparation of N-(3-(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)anilino-(2R)-2-hydroxypropyl)-5-chloro-2-thiophene carboxamide

The compound obtained in Step 5 (120 g, 435 mmol) and 5-chloro-N-(((S)-oxiran-2-yl)methyl)thiophene-2-carboxamide (123 g, 566 mmol, 1.3 eq, purchased from RStech (Daejeon, Korea) was suspended in absolute EtOH (1450 mL). The mixture thus obtained was stirred at 85 ^°C for 16 hrs. The mixture was cooled to r.t. and evaporated in vacuo to remove solvent. The resultant residue was dried under high vacuum for 18 hrs. The dried solid was suspended in EA (2 L). The suspension thus obtained was stirred at r.t. for 1 hr. The solid thus obtained was filtered off and washed with EA (500 mL) and ether (500 mL). The filtered solid was dried under high vacuum to obtain the title compound.
Aniline (starting material), epoxide, over-reacted by product were contained in crude product.
Yield : 158 g (74 %)
TLC : Rf= 0.34 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR of a crude sample (400 MHz, DMSO-^₆) δ 8.57 (t, J = 5.4 Hz,
IH), 7.65 (d, J = 3.6 Hz, IH), 7.32 (br s, IH), 7.14 (d, J = 4.2 Hz, IH), 6.90 (d, J
= 9.0 Hz, 2H), 6.51 (d, J = 9.0 Hz, 2H), 5.04 (t, J = 6.6 Hz, IH), 5.00 (d, J = 5.4 Hz, IH), 3.87-3.65 (m, 3H), 3.40 (br s, 2H), 3.37-3.34 (m, IH), 3.25-3.21 (m, IH),
3.17-2.96 (m, IH), 2.94-2.84 (m, IH), 1.44 (s, 9H)
LCMS: 494 (M+H⁺) (C₂₂H₂₈ClN₅O₄S)
Step 7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4-t-butoxycarbonyl-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide

The compound obtained in Step 6 (158 g, 320 mmol) was suspended in
THF (1000 niL), and 1,1-carbonyldiimidazole (68 g, 416 mmol, 1.3 eq, Aldrich 115533) and DMAP (2 g, 16 mmol, 0.05 eq, Aldrich 107700) were added thereto. The mixture thus obtained was stirred at 75 ^°C for 3 hrs, cooled to r.t, and evaporated in vacuo to remove solvent. The resultant residue was suspended in EtOH (1300 mL). The suspension thus obtained was stirred at 0 ^°C for 1 hr. The solid thus produced was filtered off and washed with cold EtOH (800 mL) and cold MeOH (300 mL). The filtered solid was dried under high vacuum to obtain the title compound.
Yield : 101 g (61 %)
TLC : R/= 0.75 (EA/MeOH/AcOH = 20/1/0.5)
¹H NMR (400 MHz, DMSO-^₆) δ 8.93 (t, J= 5.4 Hz, IH), 7.66 (d, J= 4.2 Hz, IH), 7.43-7.33 (m, 3H),7.29-7.12 (m, 3H), 4.82-4.73 (m, IH), 4.09 (t, J = 9.0 Hz, IH), 3.82-3.70 (m, 3H), 3.65-3.52 (m, 4H), 1.45 (s, 9H)
LCMS: 520 (M+H⁺) (C₂₃H₂₆ClN₅O₅S)
Step 8: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene
carboxamide hydrochloride

The compound obtained in Step 7 (101 g, 194 mmol) was suspended in aq.
3N HCl solution (1.1 L) and THF (1.1 L), and stirred at 80 “C for 3 hrs. The mixture thus obtained was cooled to r.t. The solid thus produced was filtered off, washed with THF (700 mL) and dried under high vacuum to obtain the title compound.
Yield : 75 g (85 %)
TLC : Rf= 0.82 (MC/MeOH/AcOH = 10/1/0.5)
¹H NMR (400 MHz, DMSO-J₆) δ 12.12 (br s, IH), 10.32 (br s, IH), 9.13
(t, J = 6.0 Hz, IH), 8.57 (d, J= 5.2 Hz, IH), 7.75 (d, J = 4.2 Hz, IH), 7.49 (d, J =
9.0 Hz, 2H), 7.15 (d, J= 4.2 Hz, IH), 7.09 (d, J= 9.0 Hz, 2H), 4.85-4.74 (m, IH), 4.11 (t, J = 8.8 Hz, IH), 3.85 (dd, J = 6.0, 9.2 Hz, IH), 3.62 (t, J = 4.8 Hz, 2H),
3.59-3.49 (m, 2H), 3.15 (br s,2H)
LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)
Example 5: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l_^yl)phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene
carboxamide

The compound obtained in Example 4 (20 g, 43.8 mmol) was suspended in MeOH/H₂O (1/2 wt/wt, 3.2 L) and stirred at 100 ^°C until the compound obtained in Example 4 was dissolved clearly. 0.6M aq. Na₂CO₃ solution (75 mL) was added thereto. The mixture thus obtained was stood at 0 ^°C for 2 hrs. The solid thus produced was filtered off, washed with H₂O (400 mL) and dried
under high vacuum to obtain the title compound.
Yield : 17 g (93 %)
¹H NMR (400 MHz, DMSO-J₆) δ 8.93 (t, J = 6.0 Hz, IH), 7.66 (d, J = 4.0 Hz, IH), 7.29 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 4.0 Hz, IH), 7.08 (d, J = 9.2 Hz, 2H), 6.76 (d, J = 4.0 Hz, IH), 6.48 (br s, IH), 4.78-4.69 (m, IH), 4.07 (t, J = 8.8 Hz, IH), 3.74 (dd, J = 6.0, 9.2 Hz, IH), 3.54 (t, J = 5.6 Hz, 2H), 3.38 (s, 4H)
LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)
Example 6: Preparation of 5-chIoro-N-({(5S)-2-oxo-3-[(5,6-dihydro-4H-[l,2,4]triazin-l-yl)phenyI]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene
carboxamide methane sulfonate

The compound obtained in Example 5 (16.7 g, 39.8 mmol) was suspended in MeOH/CH₂Cl₂ (1/4 v/v, 350 mL) and stirred at 50 ^°C until the compound obtained in Example 5 was dissolved clearly. The mixture thus obtained was cooled to 0 ^°C and methylsulfonic acid (2.9 mL, 43.8 mmol, 1.3 eq, Aldrich 471356) was added thereto at 0 ^°C . The resulting mixture was evaporated in vacuo to remove solvent. The resultant solid was suspended in absolute EtOH (100 mL) and the suspension was stirred at 90 ^°C to dissolve solid clearly. The resulting mixture was cooled to 0 ^°C and stirred at 0 ^°C for 2 hrs. The solid thus produced was filtered off, washed with absolute EtOH (100 mL), and dried under high vacuum to obtain the title compound.
Yield : 18.4 g (89.7 %)
¹H NMR (400 MHz, DMSO-J₆) δ 11.93 (br s, IH), 10.03 (br s, IH), 8.94 (t, J = 6.0 Hz, IH), 8.55 (d, J = 6.0 Hz, IH), 7.66 (d, J = 4.0 Hz, IH), 7.49 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 4.0 Hz, IH), 7.08 (d, J = 9.2 Hz, 2H), 4.93-4.87 (m, IH), 4.10 (t, J = 9.2 Hz, IH), 3.77 (dd, J = 6.0, 9.2 Hz, IH), 3.63 (m, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.16 (br s, 2H), 2.28 (s, 3H)
LCMS: 420 (M+H⁺) (C₁₈H₁₈ClN₅O₃)


PATENT
WO2010002115
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010002115

[Reaction Scheme 1] [96] A., O
^NCO^NH2 + &J\ – NC NC- boc IPA, reflux O*B£.H. .κ> boc DMAP boc 2

Example 10: Preparation of compound 109

Compound 15a (450 mg, 0.88 mmol) obtained in Manufacturing Example 3 was dissolved in dichloromethane (10 mL), to which HCl (4 M 1,4-dioxane solution) (10 mL) was added, followed by stirring at room temperature for 1 hour. The reactant was concentrated under reduced pressure and dried to give light yellow solid compound (425 mg, 0.88 mmol, 100%). This compound (392 mg, 0.81 mmol) was dissolved in acetic acid (4 mL), to which trimethylorthoformate (2 mL) was added, followed by reflux with stirring. 10 hours later, after solvent was evaporated all, column chromatography (dichlorome thane/me thanol(v/v) 20/1 → 12/1) was performed to give the title compound 109 as a light yellow solid (215 mg, 5.12 mmol, 63 %).
¹H NMR (400 MHz, CDCl₃) δ 7.35 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 4.4 Hz, IH), 7.14 (d, J = 9.2 Hz, 2H), 7.01 (t, J = 6.4 Hz, IH), 6.88 (s, IH), 6.85 (d, J = 4.4 Hz, IH), 4.87-4.79 (m, IH), 4.06 (t, J = 9 Hz, IH), 3.86 (ddd, J = 14.4 ,6, 3 Hz, IH), 3.81 (dd, J = 9, 6.4 Hz, IH), 3.69 (dt, J = 14.4, 6 Hz, IH), 3.62-3.58 (m, 2H), 3.55-3.51 (m, 2H); LCMS: 420 (M+H⁺) to Ci₈H₁₈ClN₅O₃S


REFERENCES
https://clinicaltrials.gov/ct2/show/NCT01954238
SEE EARLIER MOLECULE   LCB01-0371…..http://newdrugapprovals.org/2014/03/31/lcb01-0371-new-oxazolidinone-has-improved-activity-against-gram-positive-pathogens/



////////////////phase 1, Green Cross Corp,  LegoChem Bioscience, GCC 4401C, thrombosis, venous thromboembolism, GC 2107, CB02-0133, GC-2107, GC4401, GCC-2107, GCC-4401, GCC-4401C, I Fxa – LegoChem Biosciences, LCB02-0133, Nokxaban
O=C(NC[C@H]3CN(c1ccc(cc1)N2CCNC=N2)C(=O)O3)c4ccc(Cl)s4.CS(=O)(=O)O   METHANE SULFONATE
O=C(NC[C@H]3CN(c1ccc(cc1)N2CCNC=N2)C(=O)O3)c4ccc(Cl)s4      FREE FORM
C1CN(NC=N1)C2=CC=C(C=C2)N3CC(OC3=O)CNC(=O)C4=CC=C(S4)Cl

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Ibudilast

IBUDILAST, MN 166

AV-411
KC-404
MN-166

2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one

1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one

KYORIN Kyorin Seiyaku Kk……….INNOVATOR

Properties: Crystals from hexane, mp 53.5-54°. Slightly sol in water, freely sol in organic solvents. LD50 i.v. in mice: 260 mg/kg (Irikura, 1973).

Melting point: mp 53.5-54°

Toxicity data: LD50 i.v. in mice: 260 mg/kg (Irikura, 1973)

Therap-Cat: Antiallergic; antiasthmatic; vasodilator (cerebral).

Ibudilast is an anti-inflammatory and neuroprotective oral agent which shows an excellent safety profile at 60 mg/day and provides significantly prolonged time-to-first relapse and attenuated brain volume shrinkage in patients with relapsing-remitting (RR) and/or secondary progressive (SP) multiple sclerosis (MS). Ibudilast is currently in development in the U.S. (codes: AV-411 or MN-166), but is approved for use as an antiinflammatory in Japan.

CAS: 50847-11-5, Ibudilastum, Ketas, KC-404, MN-166, Ke Tas

Molecular Formula:C14H18N2O

Molecular Weight:230.30552 g/mol

 

Ibudilast is a leukotriene antagonist and phosphodiesterase inhibitor which has been commercialized in Japan and other parts of Asia for over 15 years as capsules for the treatment of bronchial asthma and cerebrovascular disturbances. In 2000, the product was launched for the topical treatment of allergic conjunctivitis. At present, the drug is undergoing phase II trials at MediciNova for the oral treatment of multiple sclerosis (MS), for the treatment of medication overuse headache (MOH), for the treatment of diabetic neuropathic pain, for the treatment of methamphetamine addiction and for the treatment of opioid withdrawal.

Early clinical trials are ongoing for the treatment of amyotrophic lateral sclerosis as an adjunt to riluzole.MediciNova and the University of Colorado had been evaluating the product in preclinical studies for the treatment of post-traumatic brain injury; however, no recent development has been reported for this research.Ibudilast exhibits antiplatelet properties mainly by inhibiting phosphodiesterase V (PDE V), which in turn potentiates antiplatelet function of endothelium-derived nitric oxide (NO). The compound has also been shown to suppress hippocampal apoptosis induced by amyloid beta hypoxia.

 

Ibudilast (development codes: AV-411 or MN-166) is an antiinflammatory drug used mainly in Japan, which acts as aphosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent,[1] but also showing significant inhibition of other PDE subtypes.[2][3]

Ibudilast has bronchodilator, vasodilator [4] and neuroprotective effects,[5][6] and is mainly used in the treatment of asthma andstroke.[7] It inhibits plateletaggregation,[8] and may also be useful in the treatment of multiple sclerosis.[9]

Ibudilast crosses the blood–brain barrier and suppresses glial cell activation. This activity has been shown to make ibudilast useful in the treatment ofneuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development oftolerance.[10]

It may have some use reducing methamphetamine[11] and alcohol[12] addiction.

It may have some use reducing methamphetamine addiction.[11]

Avigen has identified the potential of ibudilast (AV-411) for the treatment of neuropathic pain and other neurological indications, including opiate withdrawal. As an inhibitor of glial cells, ibudilast can deactivate these cells which produce various chemicals, including proinflammatory cytokines, in response to nerve damage or viral infection to amplify and maintain pain. Preclinical evaluation to date indicates that it reverses the painful sensory abnormality allodynia in chemotherapy- and trauma-induced neuropathic pain models.

Originator Kyorin and Banyu Pharmaceutical (now MSD KK following the merger of Banyu and Schering-Plough KK in 2010) have been developing ibudilast under a collaborative agreement. MediciNova obtained exclusive, worldwide rights outside of Japan, China, Taiwan and South Korea from Kyorin in October 2004 to develop and commercialize the compound for MS. In 2012, a codevelopment agreement was signed between MediciNova and the University of Colorado for the treatment of post-traumatic brain injury.

Sixteenth revised Japanese Pharmacopoeia chemicals, etc. IBUDILAST　 Ibudilast C14H18N2O: 230.31 [ 50847-11-5 ] that this product was dried when to quantify, including ibudilast (C14H18N2O) 98.5 ~ 101.0%.

http://www.google.co.in/patents/US3850941PATENT

EXAMPLE 1 Synthesis of 2-isopropyl-3-is0butyrylpyrazolo[1,5-a] pyridine (KC404) A mixture of 1-amino-Z-methylpyridinium iodide g.), isobutyric anhydride (500 g.) and K CO (81 g.) was refluxed for 8 hr. After cooling, the precipitated crystals were filtered off and water was added to the filtrate, The solution was made basic to pH 11 with K CO’ and extracted with ethyl acetate (1000 ml.). The extract’was washed with water (400 ml.), dried over Na SO and concentrated under reduced pressure. The residue was distilled to give 58 g. of colorless crystalline product, hp, 110- 175 (7.5 mm. Hg). Recrystallization from hexane gave colorless prisms, melting point 53.554.

Analysis- Calcd.: C, 73.01; H, 7.88; N, 12.17 Found: C, 72.86; H, 7.94; N, 12.09

CLIP

http://www.customsynthesis.com/ibud.html

PATENT

http://www.google.com/patents/US8119657

FIG. 6 is a synthetic reaction scheme illustrating one approach for preparing (S)-AV1013; the approach employs chiral chromatography of an N-protected form of the racemate as described in detail in Example 1.

FIG. 7 demonstrates additional reaction schemes for synthesizing (S)-AV1013.

Example 1Synthesis of (S)-2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride

(S)-2-Amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride (also referred to herein as S-AV1013.HCl) was prepared on a preparative scale using two different routes to obtain the intermediate isopropylpyrazolo[1,5-a]pyridine (IPPP). In the first approach (method 1), ibudilast was employed as the starting material to obtain IPPP; an alternate synthetic approach (method 2) employed ibudilast acid as the starting material.

Step 1Method 1Preparation of Isopropylpyrazolo[1,5-a]pyridine (IPPP) from ibudilast

A 5 L 3-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, heating mantle and a Y-adapter with a nitrogen inlet. The flask was charged with water (350 mL, USP), concentrated sulfuric acid (350 mL) and ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) (140 g, 0.608 mol). The flask was purged with nitrogen, and the mixture was stirred while it was heated to 135° C. An aliquot was removed for HPLC analysis, which showed that all starting material was consumed after 5 hours at 135° C., so the mixture was allowed to cool to room temperature overnight. The mixture was cooled in an ice bath, and water (1400 mL, USP) was added over 10 min, with the temperature maintained below 25° C. With continuous cooling in an ice bath, the mixture was neutralized by adding sodium hydroxide (50% w/w aq., 1150 mL) dropwise, with the temperature maintained below 25° C. Ethyl acetate (250 mL) was added, and the layers were separated. The aqueous layer was washed with ethyl acetate (2×300 mL). The combined ethyl acetate extracts were washed sequentially with 250 mL portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate for 30 minutes. Activated carbon (20 g) and silica (60 g) were added and stirred before filtering over a pad of Celite. The filtrate was concentrated under reduced pressure to obtain 96.5 g of IPPP (2-isopropyl-pyrazolo[1,5-a]pyridine, 99% crude yield, 99.6 area % pure by HPLC) as an amber oil.

1H-NMR (CDCl3) δ 1.4 (d, 6H), 3.2 (m, 1H), 6.3 (s, 1H), 6.6 (t, 1H), 7.0 (m, 1H), 7.4 (d, 1H), 8.4 (d, 1H). HPLC: RT=9.1 min (99.6 area %).

CLIP

Ibudilast (3-isobutyryl-2-isopropylpyrazolo[l,5-α]pyridine) is a small molecule drug that has been used for many years in Japan and Korea for the treatment of bronchial asthma as well as for treatment of cerebrovascular disorders such as post-stroke dizziness. It is sold in these countries under the tradename, Ketas®. Marketed indications for ibudilast in Japan include its use as a vasodilator, for treating allergy, eye tissue regeneration, ocular disease, and treatment of allergic ophthalmic disease (Thompson Current Drug Reports). Its use in the treatment of both chronic brain infarction (ClinicalTrials.gov) and multiple sclerosis (News.Medical.Net; Pharmaceutical News, 2 Aug 2005) is currently being explored in separate, ongoing clinical trials.

The mechanisms of action of ibudilast have been widely explored. Its role as a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) has been described

(Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Additionally, ibudilast has been reported to act as an LTD4 antagonist, an anti-inflammatory, a PAF antagonist, and a vasodilatator agent (Thompson Current Drug Reports). Ibudilast is also thought to exert a neuroprotective role in the central nervous system of mammals, presumably via suppression of the activation of glial cells (Mizuno et al. (2004) Neuropharmacology 46: 404-411). New uses for ibudilast continue to be explored.http://www.google.com/patents/WO2007146087A2?cl=en

PATENT

http://www.google.com/patents/WO2007142924A1?cl=en

IBUDILAST

Ibudilast is a small molecule drug (molecular weight of 230.3) having the structure shown below.

Ibudilast is also found under ChemBank ID 3227, CAS # 50847-1 1-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its molecular formula corresponds to [Ci4HIgN2O]. Ibudilast is also known by various chemical names which include 2- methyl-l-(2-(l-methylethyI)pyrazolo(l,5-a)pyridin-3-yl)l-propanone; 3-isobutyryl-2- isopropylpyrazolo(l,5-a)pyridine]; and l-(2-isopropyl-pyrazolo[l,5-a]pyridin-3-yl)-2- methyl-propan-1-one. Other synonyms for ibudilast include Ibudilastum (Latin), BRN 0656579, KC-404, and the brand name Ketas®. Ibudilast, as referred to herein, is meant to include any and all pharmaceutically acceptable salt forms thereof, prodrug forms (e.g., the corresponding ketal), and the like, as appropriate for use in its intended formulation for administration.

Ibudilast is a non-selective nucleotide phosphodiesterase (PDE) inhibitor (most active against PDE-3 and PDE-4), and has also been reported to have LTD4 and PAF antagonistic activities. Its profile appears effectively anti-inflammatory and unique in comparison to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of the phosphoester bond on the 3 ‘-carbon to yield the corresponding 5′- nucleotide monophosphate. Thus, they regulate the cellular concentrations of cyclic nucleotides. Since extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, the PDEs also regulate cellular responses to these extracellular signals. There are at least eight classes of PDEs: Ca2+/calmodul in-dependent PDEs (PDEl); cGMP-stimulated PDEs (PDE2); cGMP- inhibited PDEs (PDE3); cAMP-specific PDEs (PDE4); cGMP-binding PDEs (PDE5); photoreceptor PDEs (PDE6); high affinity, cAMP-specific PDEs (PDE7); and high affinity cGMP-specific PDEs (PDE9).

SYNTHESIS

DE 2315801; FR 2182914; JP 7714799, WO 0196278

By condensation of 1-amino-2-methylpyridinium iodide (I) with isobutyric anhydride (II) by means of K2CO3 at reflux temperature.

Patent

 US 20140037547

PATENT

CN 102617579

2-methyl -l- [2- (l- methylethyl) – pyrazolo [l, 5_a] pyrimidine _3_ yl] _1_ acetone (ibudilast, generic drug name: IBUDILAST ) is an anti-allergic asthma drugs, anti-leukotrienes can twist and platelet-activating factor, promote the secretion of mucus in the respiratory tract, respiratory cilia function, enhance the role of prostacyclin, increase cerebral blood flow, improve brain metabolism. For the treatment of bronchial asthma, sequelae of cerebral embolism, cerebral arteriosclerosis.

 ibudilast preparation methods are mainly the following two:

 Method a: (The Jourrtal of Organic Chemistry, 1968, 33, 3766 ~3770) Synthesis Road

Lines are as follows:

 The route to 2-picoline as starting material to give amino-2-methyl-pyridine iodide I-, after pyrimidine, the role of isobutyryl chloride to give the title compound. The final product obtained by this route need be purified by column chromatography, thereby increasing the difficulty of the operation, in addition to column chromatography, eluent used larger benzene toxicity, is not suitable for industrial production.

 Method II: (Journal of the American Chemical Society, 2005,127, 751-760) co

A route is as follows:

The route to 2-picoline as starting material to obtain the sulfamic acid, potassium iodide I- amino-2-picoline under the action of potassium carbonate, then with isobutyric anhydride to give the title compound effect. This route of the first-stage reaction process locked, the yield is low, is not suitable for industrial production.

 so there ibudilast conventional method for preparing the operational difficulties or low yield, making it impossible to achieve industrial production problems.

DETAILED DESCRIPTION IX: with a specific embodiment of the present embodiment is one of one to eight different points: in the second step of the recrystallization specific operation is as follows: First, the collected fractions was cooled to 10 ° c~25 ° C, to give a pale yellow solid, and then n-hexane was added to the pale yellow solid, and the temperature was raised to 50 ° C~68 ° C, at a temperature of 50 ° C~68 ° C incubation 5min~IOmin, then cooled to 10 ° C~ 25 ° C, and at a temperature of 10 ° C~25 ° C incubated O. 5h~Ih, and finally filtered to obtain ibudilast; the volume of the pale yellow solid quality and hexane ratio of Ig: (ImL~2mL), to obtain ibudilast.

PAPER

Bioorganic & medicinal chemistry letters (2011), 21(11), 3307-12.

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure–activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.

UPDATE AS ON JAN 2016

…………..MediciNova’s ibudilast gets FDA rare paediatric disease status to treat Krabbe disease 
MediciNova has received rare paediatric disease status from the US Food and Drug Administration (FDA) for its MN-166 (ibudilast) to treat Type 1 Early Infantile Krabbe disease.

References

1.  Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K. Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sciences. 2006 May 1;78(23):2663-8.
2.  Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Research. 1999 Aug 7;837(1-2):203-12.
3.  Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family.European Journal of Pharmacology. 2006 May 24;538(1-3):39-42.
4.  Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. Cardiovascular Drug Reviews. 2001 Fall;19(3):215-25.
5.  Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia.Neuropharmacology. 2004 Mar;46(3):404-11.
6.  Yoshioka M, Suda N, Mori K, Ueno K, Itoh Y, Togashi H, Matsumoto M. Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia.Pharmacological Research. 2002 Apr;45(4):305-11.
7.  Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Research. 2003 Nov 28;992(1):53-9.
8.  Rile G, Yatomi Y, Qi R, Satoh K, Ozaki Y. Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells.Thrombosis Research. 2001 May 1;102(3):239-46.
9.  Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Multiple Sclerosis. 2004 Oct;10(5):494-8.
10. Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935-50.
11.  http://www.huffingtonpost.com/2013/04/03/meth-addiction-cure-ucla-ibudilast_n_2863126.html?utm_hp_ref=mostpopular#slide=more268305
12.  http://onlinelibrary.wiley.com/doi/10.1111/adb.12106/abstrac

SEE……Synthesis technology of ibudilast
Shandong Huagong (2014), 43, (8), 29-30. Publisher: (Shandong Huagong Bianjibu, ) CODEN:SHHUA4 ISSN:1008-021X.

Literature References:

Leukotriene D4 antagonist. Prepn: T. Irikura et al., DE 2315801; eidem, US3850941 (1973, 1974 both to Kyorin).

Pharmacology and antiallergic activity: K. Nishino et al., Jpn. J. Pharmacol. 33,267 (1983); H. Nagai et al., ibid. 1215.

In vitro cerebral vasodilating activity: M. Ohashi et al., Arch. Int. Pharmacodyn.280, 216 (1986);

in vivo activity: W. M. Armstead et al., J. Pharmacol. Exp. Ther. 244, 138 (1988).

Bronchodilating activity in animals: S. Mue et al., Arch. Int. Pharmacodyn.283,153 (1986).

Antiplatelet activity in animals: M. Ohashi et al., ibid. 321; M. Ohashi et al., Gen. Pharmacol. 17, 385 (1986).

PATENT	SUBMITTED	GRANTED
Method for treating neuropathic pain and associated syndromes [US7534806]	2006-07-20	2009-05-19
Synergistic combination [US2006205806]	2006-09-14
Pharmaceutical composition of a pde4 or pde 3/4 inhibitor and histamine receptor antagonist [US2005112069]	2005-05-26
Methods and reagents for the treatment of immunoinflammatory disorders [US2005119160]	2005-06-02
Methods of inducing ovulation using a non-polypeptide camp level modulator [US7507707]	2005-07-07	2009-03-24
Methods and reagents for the treatment of immunoinflammatory disorders [US2005192261]	2005-09-01
Synergistic combination [US7056936]	2004-02-19	2006-06-06
Methods for the treatment of respiratory diseases and conditions with a selective iNOS inhibitor and a PDE inhibitor and compositions therefor [US2004087653]	2004-05-06
Remedies for multiple sclerosis [US6395747]		2002-05-28
Combination [US2005014762]	2005-01-20

PATENT	FILING DATE	PUBLICATION DATE	APPLICANT	TITLE
US4097483	Aug 31, 1976	Jun 27, 1978	Kyorin Pharmaceutical Co., Ltd.	Pyrazolo 1,5-a!pyridines
US7585875 *	Jun 6, 2007	Sep 8, 2009	Avigen, Inc.	Phosphodiesterase inhibitors; neuropathic pain, inflammation, opioid dependence or withdrawal; 2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one for example
US20070015924	Jun 15, 2006	Jan 18, 2007	Cardiome Pharma Corp.	stereoselective preparation of aminocyclohexyl ether compounds such as trans-(1R,2R)-aminocyclohexyl ether compounds and/or trans-(1S,2S)-aminocyclohexyl ether compounds; useful in treating arrhythmias
US20080070912	Jun 6, 2007	Mar 20, 2008	Avigen, Inc.	Phosphodiesterase inhibitors; neuropathic pain, inflammation, opioid dependence or withdrawal; 2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one for example
US20090062330	Jul 8, 2008	Mar 5, 2009	Medicinova, Inc.	Treatment of progressive neurodegenerative disease with ibudilast
US20090318437 *	Jun 10, 2009	Dec 24, 2009	Gaeta Federico C A	SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE
WO2007142924A1	May 29, 2007	Dec 13, 2007	Avigen Inc	Ibudilast for inhibiting macrophage migration inhibitory factor (mif) activity
WO2007146087A2*	Jun 6, 2007	Dec 21, 2007	Avigen Inc	SUBSTITUTED PYRAZOLO [1,5-α] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE

WO2010151551A1*	Jun 22, 2010	Dec 29, 2010	Medicinova, Inc.	ENANTIOMERIC COMPOSITIONS OF 2-AMINO-1-(2-ISOPROPYLPYRAZOLO[1,5-a]PYRIDIN-3-YL)PROPAN-1-ONE AND RELATED METHODS
US8119657	Jun 22, 2010	Feb 21, 2012	Medicinova, Inc.	Enantiomeric compositions of 2-amino-1-(2-isopropylpyrazolo[1,5-α]pyridin-3-yl)propan-1-one and related methods

PATENT	FILING DATE	PUBLICATION DATE	APPLICANT	TITLE
WO2003104178A1*	Jun 6, 2003	Dec 18, 2003	Cortical Pty Ltd	Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
WO2003104203A1*	Jun 6, 2003	Dec 18, 2003	Cortical Pty Ltd	Therapeutic molecules and methods-1
WO2004058713A1*	Dec 18, 2003	Jul 15, 2004	Jason Chyba	Differential tumor cytotoxocity compounds and compositions
WO2005058304A1*	Dec 17, 2004	Jun 30, 2005	Cortical Pty Ltd	Implantable device containing inhibitor of macrophage migration inhibitory factor
WO2006045505A1*	Oct 19, 2005	May 4, 2006	Novartis Ag	Mif-inhibitors
WO2006108671A1*	Apr 13, 2006	Oct 19, 2006	Novartis Ag	3,4-dihydro-benzo[e][1,3]oxazin-2-ones

IBUDILAST

SYSTEMATIC (IUPAC) NAME
2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
CLINICAL DATA
AHFS/DRUGS.COM	International Drug Names
IDENTIFIERS
CAS NUMBER	50847-11-5
ATC CODE	R03DC04
PUBCHEM	CID: 3671
IUPHAR/BPS	7399
DRUGBANK	DB05266
CHEMSPIDER	3543
UNII	M0TTH61XC5
KEGG	D01385
CHEMBL	CHEMBL19449
CHEMICAL DATA
FORMULA	C14H18N2O
MOLECULAR MASS	230.31 g/mol

Keywords: Antiallergic; Antiasthmatic (Nonbronchodilator); Leukotriene Antagonist; Vasodilator (Cerebral).

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CC(C)C1=NN2C=CC=CC2=C1C(=O)C(C)C

SEE.........http://newdrugapprovals.org/2014/10/27/ibudilast/