Afatinib

439081-18-2

850140-73-7 dimaleate

Tovok, BIBW2992, Tomtovok

Boehringer Ingelheim Int,

An irreversible EGFR/HER2 inhibitor

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

4 - [(3-chloro-4-fluorophenyl) amino] -6 – {[4 - (N, N-dimethylamino)-1-oxo-2-buten-1-yl] – amino} -7 – ((S )-tetrahydrofuran-3-yloxy)-quinazoline

(E)-4-Dimethylamino-but-2-enoic acid {4-(3-chloro-4-fluoro- phenylanimo)-7-[(S)-(tetrahydro-furan-3-yl) oxy]-quinazolin-6-yl} -amide

 4 – [(3_ chloro-4 - fluorophenyl) amino] -6 – {[4_ (N, N-dimethylamino)-buten-1-oxo-_2_ - yl] amino}-7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline

EMA:Link, US FDA:link

The endorsement for Giotrif (afatinib) covers the drug’s use in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) gene mutation, which is present in about 10 per cent of people with NSCLC.

It caps a good month for Boehringer, which won US approval for the drug under the brand name Gilotrif two weeks ago, adding to the company’s list of therapy areas, which so far include chronic obstructive pulmonary disease (COPD), anticoagulation, HIV, Parkinson’s disease and diabetes.

In the US, the drug is approved alongside a companion diagnostic to help determine if a patient’s lung cancer cells express the EGFR mutations, whereas the EMA recommendation just includes the requirement that Giotrif be initiated and supervised by a physician experienced in the use of anti-cancer therapies.

  http://www.pmlive.com/pharma_news/boehringers_first_cancer_drug_leads_ema_recommendations_493051

GILOTRIF tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:

Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C₃₂H₃₃ClFN₅O₁₁, and a molecular weight of 718.1 g/mol.

GILOTRIF tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of GILOTRIF are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

Afatinib (BIBW2992) is an irreversible EGFR/Neu inhibitor with an IC₅₀ of 14 nM. Afatinib is a potent inhibitor of EGFR phosphorylation. Afatinib showed positive results in assays against a variety of human cancer cell lines, including A431, murine NIH-3T3 cells, and breast cancer cell line BT-474.

Afatinib^[2] (INN; trade name Gilotrif in the US and Giotrif in Europe, previously Tomtovok and Tovok^[3]) is a drug approved inmuch of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim.^[4][5][6] It acts as an angiokinase inhibitor.

Quinazoline derivatives, such as afatinib, are described in WO2002050043. This document also describes certain favourable pharmacological properties of this compound. The dimaleate salt and its crystalline form are described in WO2005037824.

 It is known in the W002/50043, which describes the pharmacological properties has important compounds include in particular their pharmacological properties mediated by the tyrosine kinase inhibitory effect and the signal transmission through the skin growth factor receptor (EGF-R) signal transduction mediated inhibitory effect. Therefore, this type of compounds are useful in the treatment of diseases, in particular for the treatment of tumor diseases, lung and gastrointestinal and respiratory tract and gall bladder and bile duct disease.

 W002/50043 discloses a method for preparing a compound wherein the amino crotonic group (IV), such as 4_ [(3 - chloro-4 - fluorophenyl) amino] -6 – {[4 - (N, N-two methyl-amino)-oxo-2-1_ - buten-1 - yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline in the one-pot reaction from the corresponding aniline component (II), bromo crotonic acid (III), oxalyl chloride and a secondary amine prepared (see Figure 1).

 Figure 1:

 In the method, the yield was 50% at most. In addition, the implementation typically purified by column chromatography. Therefore Preparation of 4 – [(3_ chloro-4 - fluorophenyl) amino] -6 – {[4 - (N, N-dimethylamino)-l-oxo-2 - buten-1 - yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline of the method is not for large-scale industrial production. Moreover, the method is not drawback bromo crotonate purchased by a large number of commercial sources, and the corresponding bromo-methyl crotonate only be obtained in a purity of about 80%.These methods are used in this case is also 4 – [(3 - chloro-4 - fluorophenyl) amino] -6 – {[4 - (N, N-dimethylamino) -1 - oxo - butene-1 - yl] amino} -7 – (⑶ – tetrahydrofuran-3 – yloxy) – quinazoline industrialized production adversely affect the applicability.

 In the above-mentioned drawbacks of known production methods, the present invention is to provide a produce aminocrotonate aryl amides, in particular 4 – [(3 - chloro-4 - fluorophenyl) amino] -6 – {[4 - (N, N-dimethylamino)-buten-1-oxo-_2_ - yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline The method of the method can be easily obtained using high purity starting materials and does not require the use of any material technology. Thus, the new method should be applicable on an industrial scale synthesis grade and therefore suitable for commercial applications.

This task is according to the present invention for preparing 4 – [(3 - chloro-4 - fluorophenyl) amino] -6 – {[4 - (N, N-dimethylamino) -1 - oxo-2 - buten-1 - yl] amino} -7 – (⑶ – tetrahydrofuran-3 – yloxy) – quinazoline, and other amino crotonic method based compound. In addition to high yield industrially embodiment, the synthesis method according to the present invention also has a very good purity and less than 0.1 of the advantages of a low cis content.

 According to Figure 2, in the method according to the present invention, an aryl group corresponding amino compound (V) with two – (Ch-ware yl) _ phosphono acetic acid, preferably with diethyl phosphonoacetate, by After appropriate activation, in a suitable reaction solvent, preferably for the use of the active 1,1 – carbonyldiimidazole, 1,1 – carbonyldiimidazole – triazole or propane phosphonic acid anhydride, is preferred for the use of 1, 1 – carbonyl diimidazole. The solvent used may be, for example, tetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate.

The amide may be connected through any possible approach for activation, i.e., for example, 1,1 _ carbonyldiimidazole, 1,1 – carbonyldiimidazole – triazole, DCC (N, N-dicyclohexyl carbodiimide ), EDC (N ‘_ (dimethylaminopropyl)-N-ethylcarbodiimide), TBTU (0 – (benzotriazol-1 – yl)-N, N, N’, N ‘ – pan tetramethyluronium tetrafluoroborate), thiazolidine-2 – thione, or through the use of thionyl chloride may be converted to the corresponding acyl chloride. If desired, activation may be used an organic base such as triethylamine or pyridine embodiment, and can additionally added DMAP (dimethylaminopyridine). Suitable solvents include DMF, THF, ethyl acetate, toluene, chlorinated hydrocarbons or mixtures thereof.

http://www.google.com/patents/CN1867564B?cl=en

Example 1

[0078] {[4 - (3 - chloro-4 - fluoro - phenylamino) -7 - (⑶ - tetrahydrofuran _3_-yloxy) - quinazoline _6_ yl carbamoyl] methyl}-_ _ Diethyl

[0079]

A 3. 58kg of 1,1 _ carbonyldiimidazole (22.16 mol) was placed in 12.8 l of tetrahydrofuran, and at a temperature of 40 ° C was dissolved in it with 6.5 l of tetrahydrofuran, 4. 52kg (22. 16 mol) of diethyl phosphono acetic acid mixture. Temperature at 40 ° C the mixture was stirred for 30 minutes. The resulting solution was referred to as Solution A.

 A 6. 39kg (17. 05 moles) of N4-(3_ _4_ chloro fluoro – phenyl) _7_ (tetrahydrofuran _3_ yloxy) quinazoline-4, 6 – diamine Add 26 5 of tetrahydrofuran at 40 ° C and the solution A were mixed and stirred at a temperature 30 ° C for 2 hours.To the suspension was added 64 l tert-butyl methyl ether and, after cooling to 20 ° C, the precipitate was removed by centrifugation. Using 16 liters of tetrahydrofuran and 16 l of a mixture of tert-butyl methyl ether, washed, and then washed with 32 liters of water and dried at 50 ° C.

[0082] Yield: 6. 58kg (69. 8%) of white crystals, the content = HPLC 99. IFl%

[0083] Example 2

[0084] (E) -4 – dimethylamino – D -2 – acid – [4 - (chloro-3_ _4_ fluoro - phenylamino) _7_ (⑶ - tetrahydrofuran-3 - yloxy) - quinoline yl-6 - yl] – amide

[0085]

[0086] A 5.6 l of 30% hydrochloric acid (53.17 mol) was added to 4.4 liters of water. Then the temperature is under 30 ° C was added dropwise over 20 minutes 4. 28kg 95% of (dimethylamino) _ acetaldehyde – diethyl acetal (26.59 mol).Temperature at 35 ° C the reaction solution was stirred for 8 hours was cooled to 5 ° C and kept under argon. This solution is called Solution B.

[0087] A 4. 55kg (68. 06 mol) of potassium hydroxide dissolved in 23.5 liters of water and cooled to _5 ° C. This solution is called Solution C.

[0088] A 5. 88kg (10. 63 mol) ((4_ (3_ _4_ chloro fluoro – phenylamino) _7_ (tetrahydrofuran _3_-yloxy) – quinazolin-6 – yl carbamoyl) – methyl)-phosphonic acid diethyl ester and 0.45kg _ lithium chloride (10.63 moles) was placed in 23.5 l of tetrahydrofuran and cooled to -7 ° C. Was added over 10 minutes a cold solution of C. Then _7 ° C temperature of the solution was added over 1 hour B. At _5 ° C temperature for 1 hour under stirring the reaction mixture was heated to 20 ° C and mixed with 15 liters of water. After cooling to; TC temperature, the suspension was suction filtered, the precipitate was washed with water and dried. Yield: 5.21kg The crude product, 100%, water content: 6.7%.

[0089] Using Titanium Dioxide / methyl cyclohexane embodiment the crystallization of the crude product.

[0090] Yield: 78%, purity: HPLC99. 4F1%, water content: 5.4%

[0091] Example 3

[0092] (E) -4 – dimethylamino – D -2 – acid – (4 – (chloro-3_ _4_ fluoro – phenylamino) ~ 7 ~ ((S) – tetrahydrofuran-3 – yl oxy) – quinazolin-6 – yl) – amide dimaleate

[0093] A 6. Okg (12. 35 mol) of (E_) _4_ _2_ dimethylamino acid _ D – (4_ (3_ _4_ chloro fluoro – phenylamino) -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazolin-6 – yl) – amide into 84 liters of ethanol and heated to 70 ° C, and dissolved in 36 l of ethanol and 2.94kg (25.31 moles) of maleic acid was mixed . At the beginning of crystallization, the first mixture was cooled to 20 ° C and stirred for 2 hours and then at 0 ° C temperature for 3 hours. Precipitate was suction filtered, washed with 19 l of ethanol at a temperature of 40 ° C in vacuo.

[0094] Yield: 8. Ilkg (91. 5%)

[0095] Melting point: 178 ° C

[0096] 1H-NMR (CD3OD): δ = 2. 47 + 2. 27 (m + m, 2H), 2. 96 (s, 6H), 4. 03 (m, 2Η), 4. 07 +3 . 92 (m + m, 2Η), 4. 18 +4. 03 (m + m, 2Η), 5. 32 (m, 1Η), 6. 26 (s, 4H), 6. 80 (m, 1H ), 6. 99 (m, 1H), 7 · 27 (s, 1Η), 7 · 30 (t, 1Η), 7 · 66 (m, 1Η), 7 · 96 (dd, 1Η), 8 · 62 (s, 1Η), 9 · 07 (s, 1Η) ppm

13

…………….

Examples:

Example 1

{[4 - (3-chloro-4-fluoro-phenylamino) -7 - ((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl)-phosphonic acid diethyl ester

3.58 kg 1 ,1-carbonyldiimidazole (22.16 mole) were placed in 12.8 liters of tetrahydrofuran at 40 ° C with 4.52 kg (22.16 mol) diethylphosphonoacetic acid, dissolved in 6.5 liters of tetrahydrofuran, . The mixture is stirred for 30 minutes at 40 ° C. The solution thus obtained is referred to as solution A.

6.39 kg (17.05 mol) of N ⁴ - (3-chloro-4-fluoro-phenyl) -7 – (tetrahydrofuran-3-yloxy) quinazolin-4,6-diamine in 26.5 liters of tetrahydrofuran and submitted to 40 ° C and mixed with the solution A and stirred at 30 ° C for 2 hours. To 64 liters of suspension of tert -. Added butyl methyl ether and, after cooling to 20 ° C., the precipitate is removed by centrifugation. It is dried with a mixture of 16 liters and 16 liters of tetrahydrofuran tert-butyl methyl ether and then washed with 32 liters of water at 50 ° C. Yield: 6.58 kg (69.8%) of white crystals Assay: HPLC 99.1 area% Example 2

(E)-4-dimethylamino-but-2-enoic acid [4 – (3-chloro-4-fluoro-phenylamino) -7 – ((S) – tetrahvdrofuran-3-yloxy)-quinazolin-6yl1 amide

5.6 liters to 4.4 liters of water are added 30% hydrochloric acid (53.17 mol). Then 4.28 kg 95% pure (dimethylamino) acetaldehyde diethyl acetal (26.59 mol) at 30 ° C was added dropwise over 20 minutes. The reaction solution is stirred for 8 hours at 35 ° C, cooled to 5 ° C and kept under argon. This solution is referred to as solution B.

4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 liters of water and cooled to -5 ° C. This solution is called solution C..

5.88 kg (10.63 mol) of ((4 – (3-chloro-4-fluoro-phenylamino) -7 – (tetrahydrofuran-3-yloxy) – quinazolin-6-ylcarbamoyl)-methyl)-phosphonic acid diethyl ester, and 0.45 kg lithium chloride (10.63 mole) were placed in 23.5 liters of tetrahydrofuran and cooled to -7 ° C. The cold solution C is added within 10 minutes. The solution B is added at -7 ° C over 1 hour. After stirring for one hour at -5 ° C, the reaction mixture is heated to 20 ° C and mixed with 15 liters of water. After cooling to 3 ° C, the suspension is filtered with suction, the precipitate washed with water and dried. Yield: 5.21 kg raw 100% Water content: 6.7%

The crystallization of the raw product is butyl acetate / methylcyclohexane yield: 78% HPLC purity 99.4 area%, water content 5.4% Example 3

(E)-4-dimethylamino-but-2-enoic acid (4 – (3-chloro-4-fluoro-pheny hvdrofuran-3-yloxy)-quinazolin-6YL) amide dimaleate

6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid (4 – (3-chloro-4-fluoro-phenyl-amino) -7 – ((S)-tetrahydrofuran- 3-yloxy) quinazolin-6YL)-amide are in 84 liters

Submitted ethanol and heated to 70 ° C and a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol added.Following the onset of crystallization is first cooled to 20 ° C. and stirred for 2 hours, then 3 hours at 0 ° C. The precipitate is filtered off, washed with 19 liters of ethanol and dried in vacuum at 40 ° C.

Yield: 8.11 kg (91, 5%)

Mp: 178 ° C.

¹ H NMR (CD ₃ OD): δ = 2.47 + 2.27 (m + m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07 + 3 , 92

(M + m, 2H), 4.18 + 4.03 (m + m, 2H), 5.32 (m, 1 H), 6.26 (s, 4H), 6.80 (m, 1 H ), 6.99 (m, 1 H), 7.27 (s, 1 H), 7.30 (t, 1 H), 7.66 (m, 1 H), 7.96 (dd, 1 H ), 8.62 (s, 1 H), 9.07 (s, 1H) ppm

…………..

U.S. Patent No. : 8,426,586  patent expires : October 10, 2029

WO200250043A1 (compound);

WO2003094921A2 (anticancer purposes);

WO2003066060A2 (anti-inflammatory purposes);

US2005085495A1 (process);

WO2005037824A2 (process);

WO2007085638A1 (process);

US2011207932A1 (process);

WO2011084796A2 (deuterated);

WO2012121764A1 (crystalline);

WO2013052157A1 (crystalline)

Chinese patents : CN1867564 

CN101402631 

Scheme 1

Scheme 2

 

 

Scheme 3

 

 

Scheme 4

 

 

Scheme 5

 

 

 

Scheme 6

 

Scheme 7

 

Scheme 8

 

Scheme 9

 

without methyl

Example 199

(5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-3-(c/^‘s- 4-fluoropiperidin-3-yl)-1 ,3-thiazolidine-2,4-dione

  note………..this is without methyl

(A) 1 ,1 -Dimethylethyl c/^‘s-3-[(5Z)-5-[(1 -[4-chloro-2-(trifluoromethyl)benzyl]-1 H- indazol-5-yl)methylidene]-2,4-dioxo-1 ,3-thiazolidin-3-yl]-4-fluoropiperidine- 1 -carboxylate was prepared from (5Z)-5-({1 -[2-chloro-4-

(trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-2,4-dioxo-1 ,3- thiazolidine (from Example 1 ) and 1 ,1 -dimethylethyl frans-3-hydroxy-4- fluoropiperidine-1 -carboxylate (prepared as described in US 2007/249589) following General Procedure W.

(B) (5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5- yljmethylidene)- 3-(c/s-4-fluoropiperidin-3-yl)-1 ,3-thiazolidine-2,4-dione was prepared from 1 ,1 -dimethylethyl c/s-3-[(5Z)-5-[(1 -[4-chloro-2- (trifluoromethyl)benzyl]-1 /-/-indazol-5-yl)methylidene]-2,4-dioxo-1 ,3- thiazolidin-3-yl]-4-fluoropiperidine-1 -carboxylate following General

Procedure M.

¹ H NMR (400 MHz, CDCI₃): δ 8.21 (s, 1 H), 7.95 (s, 1 H), 7.72 (d, 1 H), 7.65 (s, 1 H), 7.45 – 7.50 (m, 1 H), 7.30 – 7.38 (m, 2H), 6.66 (d, 1 H), 5.80 (s, 2H), 4.83 – 5.04 (m, 2H), 4.08 – 4.20 (m, 2H), 3.99 – 4.08 (m, 1 H), 3.81 – 3.91 (m, 1 H), 2.27 – 2.40 (m, 1 H), 2.02 – 2.13 (m, 1 H).

LC/MS: mass calcd. for C₂₄Hi₉CIF₄N₄O₂S: 538.08, found 539.5 [M+1 ]⁺

Example 201

(5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-3-(c/^‘s- 3-fluoropiperidin-4-yl)-1 ,3-thiazolidine-2,4-dione

 

 note. this is without methyl

(A) 1 ,1 -Dimethylethyl c/^‘s-4-[(5Z)-5-[(1 -[4-chloro-2-(trifluoromethyl)benzyl]-1 H- indazol-5-yl)methylidene]-2,4-dioxo-1 ,3-thiazolidin-3-yl]-3-fluoropiperidine- 1 -carboxylate was prepared from (5Z)-5-({1 -[2-chloro-4- (trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-2,4-dioxo-1 ,3- thiazolidine (from Example 1 ) and 1 ,1 -dimethylethyl frans-4-hydroxy-3- fluoropiperidine-1 -carboxylate (prepared as described in US 2007/249589) following General Procedure J.(B) (5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5- yl}methylidene)-3-(c/s-3-fluoropiperidin-4-yl)-1 ,3-thiazolidine-2,4-dione was prepared from 1 ,1 -dimethylethyl c/^‘s-4-[(5Z)-5-[(1 -[4-chloro-2- (trifluoromethyl)benzyl]-1 /-/-indazol-5-yl)methylidene]-2,4-dioxo-1 ,3- thiazolidin-3-yl]-3-fluoropiperidine-1 -carboxylate following General

Procedure M.

¹ H NMR (400 MHz, CDCI₃): δ 8.22 (s, 1 H), 8.00 (s, 1 H), 7.96 (s, 1 H), 7.72 (d, 1 H), 7.48 – 7.54 (m, 1 H), 7.36 (s, 1 H), 7.34 (s, 1 H), 6.68 (d, 1 H), 5.80 (s, 2H), 4.57 – 4.75 (m, 1 H), 4.40 – 4.56 (m, 1 H), 3.25 – 3.46 (m, 2H), 3.18 (qd, 1 H), 2.83 – 3.03 (m, 1 H), 2.72 (t, 1 H), 1 .88 (br. s., 1 H), 1 .72 (d, 1 H).

LC/MS: mass calcd. for C₂ H₁₉CIF₄N₄O₂S: 538.08, found 539.5 [M+1 ]⁺

Example 273

(5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-3- (frans-3-fluoropiperidin-4-yl)-1 ,3-thiazolidine-2,4-dione

 

note——- this is without methyl but precursor to desired compd

Preparation 1 :

(A) To the solution of 1 ,1 -dimethylethyl frans-4-(2,4-dioxo-1 ,3-thiazolidin-3-yl)- 3-hydroxypiperidine-1 -carboxylate (from Example 270, 0.68 mmol) in DCM (5 ml_) in a plastic bottle was added bis(2-methoxyethyl)aminosulfur trifluoride (3 equiv) and a drop of ethanol. After stirring at rt for 3 h, the reaction was concentrated and the resultant residue was purified by silica gel chromatography (hexane/EtOAc) to provide 1 ,1 -dimethylethyl trans-4- (2,4-dioxo-1 ,3-thiazolidin-3-yl)-3-fluoropiperidine-1 -carboxylate as a pale yellow solid.

(B) (5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5-yl}methylidene)- 3-[frans-3-fluoropiperidin-4-yl]-1 ,3-thiazolidine-2,4-dione was prepared from [4-chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5-carbaldehyde (from

Example 1 ) and 1 ,1 -dimethylethyl frans-4-(2,4-dioxo-1 ,3-thiazolidin-3-yl)-3- fluoropiperidine-1 -carboxylate following General Procedure F.

Preparation 2:

(A) A mixture of 1 ,1 -dimethylethyl 7-oxa-3-azabicyclo[4.1 .0]heptane-3- carboxylate (from Example 270; 47.7 mmol), [(5Z)-5-({1 -[4-chloro-2- (trifluoromethyl)benzyl]-1 /-/-indazol-5-yl}methylidene)-2,4-dioxo-1 ,3- thiazolidine (from Example 1 ; 31 .8 mmol) and magnesium perchlorate (23.9 mmol) in DMF (70 mL) was heated at 1 15 °C for 2-4 h. After cooling to rt, the mixture was slowly poured into water (300 mL) with vigorous stirring, and the resultant precipitate was filtered, thoroughly washed with water and dried to afford a mixture of 1 ,1 -dimethylethyl frans-4-{(5Z)-5-[(1 -

{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1 /-/-indazol-5-yl)methylidene]- 2,4-dioxo-1 ,3-thiazolidin-3-yl}-3-hydroxypiperidine-1 -carboxylate and the corresponding regioisomer, 1 ,1 -dimethylethyl frans-3-{(5Z)-5-[(1 -{[4-chloro- 2-(trifluoromethyl)phenyl]methyl}-1 /-/-indazol-5-yl)methylidene]-2,4-dioxo- 1 ,3-thiazolidin-3-yl}-4-hydroxypiperidine-1 -carboxylate in ratio of ~ 3.3 : 1 .

(B) To an ice-cooled solution of the above mixture of 1 ,1 -dimethylethyl frans- 4-{(5Z)-5-[(1 -{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1 /-/-indazol-5- yl)methylidene]-2,4-dioxo-1 ,3-thiazolidin-3-yl}-3-hydroxypiperidine-1 – carboxylate and the regioisomer, 1 ,1 -dimethylethyl frans-3-{(5Z)-5-[(1 -{[4- chloro-2-(trifluoromethyl)phenyl]methyl}-1 H-indazol-5-yl)methylidene]-2,4- dioxo-1 ,3-thiazolidin-3-yl}-4-hydroxypiperidine-1 -carboxylate in DCM (350 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (47.7 mmol). After stirring for 1 h, the solution was allowed to warm to rt and stir overnight. The reaction was then quenched with sat’d aq. NaHCO3 and after separating phases, the organic phase was dried (Na2SO₄) and concentrated to ~ 40 mL. The solution was loaded onto a silica gel column (Analogix, 200g) and eluted with heptanes/DCM/EtOAc (40:57:3).

Product-containing fractions were combined and concentrated to afford a crude product mixture as a pale yellow foam. Treatment of this foam with ether (~ 20 mL) led to product precipitation; additional ether (200 mL) was added portionwise with stirring and after cooling to ~ 5 °C, the mixture was filtered through a glass fiber filter and washed with cold ether to afford 1 ,1 – dimethylethyl frans-4-{(5Z)-5-[(1 -{[4-chloro-2-(trifluoromethyl)phenyl]- methyl}-1 H-indazol-5-yl)methylidene]-2,4-dioxo-1 ,3-thiazolidin-3-yl}-3- fluoropiperidine-1 -carboxylate as an essentially white powder. (C) (5Z)-5-({1 -[4-Chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5- yl}methylidene)-3-[frans-3-fluoropiperidin-4-yl]-1 ,3-thiazolidine-2,4-dione was prepared from 1 ,1 -dimethylethyl frans-4-{(5Z)-5-[(1 -{[4-chloro-2- (trifluoromethyl)phenyl]methyl}-1 H-indazol-5-yl)methylidene]-2,4-dioxo-1 ,3- thiazolidin-3-yl}-3-fluoropiperidine-1 -carboxylate following General

Procedure M.

¹ H NMR (400 MHz, CDCI₃): δ 8.22 (s, 1 H), 8.02 (s, 1 H), 7.96 (s, 1 H), 7.72 (d, 1 H), 7.47 – 7.56 (m, 1 H), 7.36 (s, 1 H), 7.34 (s, 1 H), 6.68 (d, 1 H), 5.80 (s, 2H), 5.10 – 5.33 (m, 1 H), 4.40 – 4.55 (m, 1 H), 3.52 (d, 1 H), 3.14 (d, 1 H), 2.68 (br. s., 2H), 2.43 (qd, 1 H), 1 .70 – 1 .90 (m, 2H).

LC/MS: mass calcd. for C₂ H2oCIF₄N₄O₂S: 538.09, found 539.3 [M+1 ]⁺

main compd

Example 277

(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3- (frans-3-fluoro-1-methylpiperidin-4-yl)-1 ,3-thiazolidine-2,4-dione

 

 desired compd

(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)- 3-[ trans -3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1 -[4-chloro-2-(trifluoromethyl)benzyl]-1 H-indazol-5- yl}methylidene)-3-[ trans -3-fluoropiperidin-4-yl]-1 ,3-thiazolidine-2,4-dione (Example 273) and formaldehyde following General Procedure R.

1 H NMR (400 MHz, CDCI₃): δ 8.22 (s, 1 H), 8.01 (s, 1 H), 7.96 (s, 1 H), 7.72 (s, 1 H), 7.51 (d, 1 H), 7.36 (s, 1 H), 7.34 (s, 1 H), 6.68 (d, 1 H), 5.80 (s, 2H), 5.25 – 5.48 (m, 1 H), 4.28 – 4.42 (m, 1 H), 3.24 – 3.36 (m, 1 H), 2.85 – 2.96 (m,

1 H), 2.56 (qd, 1 H), 2.37 (s, 3H), 2.07 – 2.17 (m, 2H), 1 .77 (dd, 1 H).

LC/MS: mass calcd. for C25H₂iCIF₄N₄O₂S: 552.1 , found 553.3 [M+1 ]⁺

…………………………………..

a paper

The development of a reproducible process for multihundred gram production of (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione (26), a potent and selective inhibitor of estrogen-related receptor 1 (ERR1), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9) with thiazolidine-2,4-dione (6, TZD) to form a diastereomeric mixture tert-butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (17), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3R,4R)-21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N-methyl 24. Knoevenagel condensation of24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde (5) produced the final product 26 in 10% overall yield (99.7% HPLC area% with ≥99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3R,4R-21 from 3S,4S-22.

Evacetrapib,  LY2484595

Evacetrapib  is an experimental drug being investigated to raise high-density lipoprotein cholesterol (HDL-C) via inhibition of the cholesteryl ester transfer protein (CETP)

Trans-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl-2H-tetrazol-5- yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzazepin-1-yl}methyl) cyclohexanecarboxylic acid

trans-4-[[(5S)-5-[[[3 ,5- bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2, 3,4,5- tetrahydro-7,9-dimethyl- IH- 1 -benzazepin- 1 -yl]methyl]-cyclohexanecarboxylic acid

trans-4-[5(S)-[N-[3,5-Bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylmethyl]cyclohexanecarboxylic acid

1186486-62-3 ^{is cas}

UNII-51XWV9K850

Evacetrapib is a drug under development by Eli Lilly & Company (investigational name LY2484595) that inhibits cholesterylester transfer protein, which transfers and thereby increases high-density lipoprotein and lowers low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease.^[1]

The first CETP inhibitor, torcetrapib, was unsuccessful because it increased levels of the hormone aldosterone and increased blood pressure,^[2] which led to excess cardiac events when it was studied.^[2] Evacetrapib does not have the same effect.^[1] When studied in a small clinical trial in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.^[3]

LY-2484595 is in phase III clinical trials at Lilly for the treatment of high-risk vascular disease and in phase II for the treatment of dyslipidemia.

Evacetrapib is one of two CETP inhibitors currently being evaluated (the other being anacetrapib).^[1] Two other CETP inhibitors (torcetrapib and dalcetrapib) were discontinued during trials due to increased deaths and little identifiable cardiovascular benefit (despite substantial increases in HDL). Some hypothesize that CETP inhibitors may still be useful in the treatment of dyslipidemia, though significant caution is warranted.^[2]

……………………………..

http://www.google.com/patents/WO2006002342A1?cl=en

Intermediate Preparation Scheme 1

Preparation Scheme 2

 

Intermediate Preparation Scheme 3

 

Scheme 7

Scheme 8

 

 Scheme 11

 

…………………

http://www.google.com/patents/WO2011002696A1?cl=en

trans-4-[[(5S)-5-[[[3 ,5- bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2, 3,4,5- tetrahydro-7,9-dimethyl- IH- 1 -benzazepin- 1 -yl]methyl]-cyclohexanecarboxylic acid, (identified according to its Chemical Abstracts Index Name (referred to herein as BCCA) having the structure of Formula I illustrated below, and pharmaceutically acceptable salts of this compound.

I

The compound, BCCA, can be a free acid (referred to herein as BCCA free acid), or a pharmaceutically acceptable salt thereof, as a solvate (referred herein as BCCA’solvate) and a hydrate (referred to herein as BCCA ‘hydrate). The solvate molecules include water (as the hydrate), methanol, ethanol, formic acid, acetic acid, and isopropanol.

Scheme 1

(MeO) SO

Scheme 2

Scheme 3 : Alternate method for preparing BCCA

Preparation 11 Preparation 12

Preparation 13 Preparation 14 Preparation 15

Preparation 16

Preparation 17

Example 16

Scheme 4

………….

http://www.google.com/patents/US8299060

 formula III below

with

Preparation 10 (Trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (12)

Charge a flask equipped with an overhead stirrer, temperature probe, nitrogen inlet with (S)—N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine (5 g, 10.03 mmoles) and sodium triacetoxyborohydride (3.19 g, 15.05 mmoles) and acetonitrile (40 mL). Immerse the flask in an ice bath to cool the slurry to below about 5° C., then add (trans)-methyl 4-formylcyclohexanecarboxylate (2.99 g, 17.57 mmoles, prepared essentially according to the procedures in Houpis, I. N. et al, Tetrahedron Let. 1993, 34(16), 2593-2596 and JP49048639) dissolved in THF (10 mL) via a syringe while maintaining the reaction mixture at or below about 5° C. Allow the reaction to warm to RT and stir overnight. Add NH₄Cl (25 mL, 50% saturated aqueous solution) and separate the aqueous layer from the organic layer. The pH of the organic layer should be about 5.5. Warm the organic layer to about 45° C. and add water (16 mL). Add a seed crystal of the titled compound and cool to about 35° C. Collect the resulting solid by filtration and rinse with ACN. Dry to provide 5.80 g of the title compound.

………….

Evacetrapib

http://www.platinummetalsreview.com/article/56/4/229-235/

…………………….paper

   THE ESTER OF EVACETRAPIB

http://pubs.acs.org/doi/abs/10.1021/op500025v

Scheme 1. Synthesis of evacetrapib (5) via a STAB-mediated reductive amination.

^aReagents and conditions: a) Na₂CO₃ (3.0 equiv), toluene, water, 25 °C, 3 h, 98% yield, 99.8:0.2 anti:syn; b) 3 (1.5 equiv), NaBH(OAc)₃ (1.5 equiv), ACN, toluene, −10 °C, 2.5 h, 88% yield, 99.2:0.8 anti:syn; c) NaOH (3.0 equiv), water, IPA, 60 °C, 7 h, 92% yield, 99.5:0.5 anti:syn.

cas no 1416314-55-0

C₂₀ H₁₈ F N₅ O₃

FYL-67  IS HYDROCHLORIDE

(S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide

N-​[[(5S)​-​3-​[3-​fluoro-​4-​[4-​(2-​pyridinyl)​-​1H-​pyrazol-​1-​yl]​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-Acetamide,

 (S)-N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide.

The discovery and application of antibiotics is one of the greatest achievements of mankind in the 20th century, the field of medicine, called a revolution of the history of the human fight against illness. Since then, the field of medicine into a bacterial disease caused by greatly reducing the golden age. Today, however, due to the widespread use of antibiotics or even abuse, the growing problem of bacterial resistance, humans are gradually approaching the “post-antibiotic era, the efficacy of antibiotics is gradually reduced. Clinical have been found on many new drug-resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP) has seriously jeopardize the clinical treatment , the number of varieties of drugs less.

The compounds of the oxazolidinone linezolid was in the United States in 2000, mainly used in clinical acquired pneumonia, soft tissue infections, can also be used for the surgical treatment of infectious diseases, bones, lungs, cerebrospinal fluid permeability pharmacokinetic and tissue concentrations. Domestic and foreign the oxazolidinone drug development is a hot field

WO 2012171479

http://www.google.st/patents/WO2012171479A1?cl=en

The object compound (S N-{[3 - (3 - fluoro-4 - (4 - (2 - pyridyl) pyrazol-yl) phenyl) -2 - oxo-oxazol the embankment -5 - yl] methanone yl}

Weigh 150mg of the compound (26f), was dissolved with 10 ml of anhydrous THF was added under nitrogen protection, an ice water bath 154.1 mg t-BuOLi, ice-water bath after stirring for 5 minutes, 149.9 mg Compound 11, followed by ice-water bath was removed, go reaction at room temperature for 36 hours the reaction was stopped, by adding 10 mL of methylene chloride and 10 ml of water and 22μί acetic acid, stirred for 1 minute, the liquid separation, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, dried and purified by column chromatography to give the product ( 130 white solid 58 mg of yield of 38.2%.

1H-MR (400 MHz, CDC1 _3): δ 8.61 (d, J = 4Hz, IH), 8.52 (d, J = 6.8Hz, 2.4H), 8.22 (s, IH), 7.94 (t, J = 8.8 Hz, IH), 7.77-7.69 (m, 2H), 7.55 (d, J = 8Hz, IH), 7.27-7.26 (m, IH), 7.18-7.15 (m, IH), 6.06 (t, J = 6Hz , IH), 4.86-4.80 (m, IH), 4.11 (t, J = 9.2Hz, IH), 3.86-3.82 (m, IH), 3.78-3.62 (m, 2H), 2.04 (s, 3H ;) .

¹³ C-MR (DMSO-e): ^δ 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91.

ESI-MSm / z 418.08 (M ⁺ Na +).

………………….

Nanoscale (2013), 5(1), 275-283

Changyang Gong,^a   Tao Yang,^a   Xiaoyan Yang,^a   Yuanyuan Liu,^a  Wei Ang,^a   Jianying Tang,^a   Weiyi Pi,^a   Li Xiong,^a   Ying Chang,^a  WeiWei Ye,^a   Zhenling Wang,*^a   Youfu Luo,*^a   Xia Zhao^b and  Yuquan Wei^a  

Show Affiliations

a

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
E-mail: luo_youfu@scu.edu.cn, wangzhenling2007@126.com;
Fax: +86-28-85164060 ;
Tel: +86-28-85164063

^b

Department of Gynecology and Obstetrics, Second West China Hospital, Sichuan University, Chengdu 610041, China

Nanoscale, 2013,5, 275-283

DOI: 10.1039/C2NR32505E

http://pubs.rsc.org/en/content/articlehtml/2013/nr/c2nr32505e

In this work, a novel oxazolidinone compound FYL-67 was synthesized, and the obtained FYL-67 could form nanoassemblies in aqueous solution by a self-assembly method without using any carrier, organic solvent, or surfactant. The prepared FYL-67 nanoassemblies had a particle size of 264.6 ± 4.3 nm. The FYL-67 nanoassemblies can be lyophilized into a powder form without any cryoprotector or excipient, and the re-dissolved FYL-67 nanoassemblies are stable and homogeneous. The in vitro release profile showed a significant difference between rapid release of free FYL-67 and much slower and sustained release of FYL-67 nanoassemblies. In vitro susceptibility tests were conducted in three strains of methicillin-susceptibleStaphylococcus aureus (MSSA) and three strains of methicillin-resistant Staphylococcus aureus(MRSA), using linezolid as a positive control. FYL-67 nanoassemblies exhibited excellent in vitro activity, with a minimum inhibitory concentration (MIC) value of 0.5 μg mL⁻¹ against MRSA. In the in vitro post-antibiotic effect (PAE) evaluation, FYL-67 nanoassemblies showed a more powerful effect than linezolid. Besides, in vitro cytotoxicity tests indicated that FYL-67 nanoassemblies had a very low cytotoxicity on HEK293 cells and L02 cells. Furthermore, in both MSSA and MRSA systemic infection mouse models, FYL-67 nanoassemblies showed a lower ED₅₀ than linezolid. In a murine model of MRSA systemic infection, FYL-67 nanoassemblies displayed an ED₅₀ of less than 4.0 mg kg⁻¹, which is 2.3-fold better than that oflinezolid. Our findings suggested that the FYL-67 nanoassemblies may be a potential drugcandidate in MRSA therapy.

	Fig. 1 Synthetic route of the novel compound FYL-67. (i) 2-(pyridin-2-yl)malonaldehyde, p-TsOH (cat.),ethanol, reflux, 2 h; (ii) Fe, HCl, 95% ethanol, 1 h; (iii) Cbz–Cl, K2CO3, CH2Cl2, 2 h; (iv) (S)-1-acetamido-3-chloropropan-2-yl acetate, LiOt-Bu, THF, r.t.; (v) HCL (g), acetone, ethyl ether

Synthesis of (S)-N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide.

 Benzyl(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl) carbamate (150 mg) was dissolved in absolute tetrahydrofuran under a nitrogen atmosphere in an ice bath. After stirring for 5 minutes, (S)-1-acetamido-3-chloropropan-2-yl acetate (149.9 mg) was added. The reactant was stirred at room temperature for another 36 hours. Then a mixture of dichloromethane (10 mL), distilled water (10 mL) and glacial acetic acid (0.022 mL) was added in order. The dichloromethane phase was collected using a separation funnel. The water phase was extracted with dichloromethane (10 mL) for another 2 times. The organic layer was combined and dried with anhydrous sodium sulfate. After removal of thesolvent, the residue was purified by flash chromatography and the title compound (58 mg) was obtained in a yield of 38.2%.

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d, J = 4 Hz, 1H), 8.52 (d, J = 6.8 Hz, 2.4H), 8.22 (s, 1H), 7.94 (t, J = 8.8 Hz, 1H), 7.77–7.69 (m, 2H), 7.55 (d, J = 8 Hz, 1H), 7.27–7.26 (m, 1H), 7.18–7.15 (m, 1H), 6.06 (t, J = 6 Hz, 1H), 4.86–4.80 (m, 1H), 4.11 (t, J = 9.2 Hz, 1H), 3.86–3.82 (m, 1H), 3.78–3.62 (m, 2H), 2.04 (s, 3H).

¹³C-NMR (DMSO-d₆): δ 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43, 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91.

ESI-MS m/z418.08 (M + Na⁺).

2.2.5. Prepration of FYL-67. 25 mg of (S)-N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was put in a 25 mL round-bottom flask, and 10 mL of acetonewas then added. After stirring for 5 minutes, the mixture turned transparent. Ethyl ether saturated with anhydrous hydrogen chloride was dropped in, and a white precipitate appeared. The collected yellowish powder was dried in a vacuum and 24.1 mg of powder was obtained with a yield of 88.3%.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.33 (s, 1H), 8.80 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.45 (t, J = 7.2 Hz, 1H), 8.38–8.31 (m, 2H), 7.90 (t, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.4 Hz, J = 16.4 Hz, 1H), 7.76 (t,J = 6.0 Hz, 1H); 7.55 (dd, J = 1.6 Hz, J = 8.8 Hz, 1H), 4.83–4.76 (m, 1H), 4.60 (br s, 1H), 4.20 (t, J = 8.8 Hz, 1H), 3.91–3.82 (m, 1H), 3.45 (t, J = 5.2 Hz, 2H), 1.85 (s, 3H);

 ¹³C-NMR (DMSO-d₆) δ: 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43, 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91;

HR-MS(TOF) m/z calcd for C₂₀H₁₈FN₅O₃ [M + Cl⁻]: 430.1082, found: 430.1085; for C₂₀H₁₈FN₅O₃ [M + H⁺]: 396.1472, found: 396.1472.

……………………………

PAPER

A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C–N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid–liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.

\

(S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (1)

• (a) Gong, C. Y.; Yang, T.; Yang, X. Y.; Liu, Y. Y.; Ang, W.; Tang, J. Y.; Pi, W. Y.; Xiong, L.; Chang, Y.; Ye, W. W.; Wang, Z. L.; Luo, Y. F.; Zhao, X.; Wei, Y. Q. Nanoscale. 2013, 5, 275–283

  (b) Luo, Y. F.; Wang, Z. L.; Wei, Y. Q.; Geng, F. WO/2012/171479,2012.

  WO2008143649A2 *	4 Dez 2007	27 Nov 2008	Das Jagattaran	Novel oxazolidinone compounds as antiinfective agents
  CN1172484A *	29 Jan 1996	4 Fev 1998	法玛西雅厄普约翰美国公司	Hetero-aromatic ring substituted phenyloxazolidinone antimicrobials

April 21, 2014 — The U.S. Food and Drug Administration today approved Cyramza (ramucirumab) to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, a form of cancer located in the region where the esophagus joins the stomach.

Stomach cancer forms in the tissues lining the stomach and mostly affects older adults. According to the National Cancer Institute, an estimated 22,220 Americans will be diagnosed with stomach cancer and 10,990 will die from the disease, this year.

Cyramza is an angiogenesis inhibitor that blocks the blood supply to tumors. It is intended for patients whose cancer cannot be surgically removed (unresectable) or has spread (metastatic) after being treated with a fluoropyrimidine- or platinum-containing therapy.

“Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cyramza is new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.”

Cyramza’s safety and effectiveness were evaluated in a clinical trial of 355 participants with unresectable or metastatic stomach or gastroesophageal junction cancer. Two-thirds of trial participants received Cyramza while the remaining participants received a placebo. The trial was designed to measure the length of time participants lived before death (overall survival).

Results showed participants treated with Cyramza experienced a median overall survival of 5.2 months compared to 3.8 months in participants receiving placebo. Additionally, participants who took Cyramza experienced a delay in tumor growth (progression-free survival) compared to participants who were given placebo. Results from a second clinical trial that evaluated the efficacy of Cyramza plus paclitaxel (another cancer drug) versus paclitaxel alone also showed an improvement in overall survival.

Common side effects experienced by Cyramza-treated participants during clinical testing include diarrhea and high blood pressure.

The FDA reviewed Cyramza under its priority review program, which provides an expedited review for drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cyramza was also granted orphan product designation because it is intended to treat a rare disease or condition.

Cyramza is marketed by Indianapolis-based Eli Lilly.

Source: FDA

http://www.drugs.com/newdrugs/fda-approves-cyramza-stomach-cancer-4033.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+April+21%2C+2014

old article

Eli Lilly’s third-quarter earnings fell 9 percent compared with last year, when the maker of Cymbalta and Cialis booked a sizeable revenue-sharing payment from a former drug developer partner.

The Indianapolis company beat Wall Street expectations for the quarter and narrowed its earnings forecast for the year.

Lilly also said Wednesday that the U.S. Food and Drug Administration will give its stomach cancer treatment ramucirumab a priority review, which means the drugmaker will learn about its fate inside of eight months rather than a year, which is the norm.

read at

http://www.dddmag.com/news/2013/10/eli-lillys-profit-slides-gets-priority-review

cut paste old article

Eli Lilly and Co. announced that results from the Phase 3 REGARD trial of ramucirumab (IMC-1121B) as a single agent in patients with advanced gastric cancer who have had disease progression after initial chemotherapy were published today in The Lancet. REGARD is the first Phase 3 study with either a single-agent biologic or an anti-angiogenic therapy to show improved overall survival and progression-free survival in advanced gastric cancer patients.

READ ALL AT

http://www.dddmag.com/news/2013/10/ramucirumab-trial-shows-improved-os-gastric-cancer?et_cid=3516952&et_rid=523035093&type=cta

Ramucirumab (IMC-1121B)^[1] is a fully human monoclonal antibody (IgG1) being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF inangiogenesis.

Ramucirumab is being tested in several phase III clinical trials for the treatment of metastatic gastric adenocarcinoma,^[2] non-small cell lung cancer,^[3] among other types of cancer. On September 26, 2013 Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.^[4][5]

This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

1.  Statement On A Nonproprietary Name Adopted By The USAN Council – Ramucirumab, American Medical Association.
2.  ClinicalTrials.gov NCT01170663 A Study of Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW)
3.  ClinicalTrials.gov NCT01168973 A Study in Second Line Non Small Cell Lung Cancer
4. ClinicalTrials.gov NCT00703326 Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer
5.  Fierce Biotech. “In another stinging setback, Eli Lilly’s ramucirumab fails PhIII breast cancer study”. Retrieved 27 September 2013.

1236408-39-1

C₁₉ H₁₉ N₅ O₂

 US 20100197591

1-(4-(4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclobutanecarbonitrile

 1-​[4-​(4-​amino-​7,​8-​dihydro-​2-​methoxy-​5-​oxopyrido[4,​3-​d]​pyrimidin-​6(5H)​-​yl)​phenyl]​-Cyclobutanecarbonitr​ile,

nmr……http://pubs.acs.org/doi/suppl/10.1021/op400215h/suppl_file/op400215h_si_001.pdf

Enzyme acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the rate-limiting step in triglyceride synthesis. It has recently emerged as an attractive target for therapeutic intervention in the treatment of Type II diabetes and obesity.

It is estimated that somewhere between 34 and 61 million people in the US are obese and, in much of the developing world, incidence is increasing by about 1% per year. Obesity increases the likelihood of death from all causes by 20%, and more specifically, death from coronary artery disease and stroke are increased by 25% and 10%, respectively. Key priorities of anti-obesity treatments are to reduce food intake and/or hyperlipidemia. Since the latter has been suggested to provoke insulin resistance, molecules developed to prevent the accumulation of triglyceride would not only reduce obesity but they would also have the additional effect of reducing insulin resistance, a primary factor contributing to the development of diabetes. The therapeutic activity of leptin agonists has come under scrutiny through their potential to reduce food intake and, also, to reverse insulin resistance; however, their potential may be compromised by leptin-resistance, a characteristic of obesity. Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT-1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis and an enzyme that is tightly implicated in both the development of obesity and insulin resistance. DGAT-1 deficient mice are resistant to diet-induced obesity through a mechanism involving increased energy expenditure. US researchers have now shown that these mice have decreased levels of tissue triglycerides, as well as increased sensitivity to insulin and to leptin. Importantly, DGAT-1 deficiency protects against insulin resistance and obesity in agouti yellow mice, a model of severe leptin resistance. Thus, DGAT-1 may represent a useful target for the treatment of insulin and leptin resistance and hence human obesity and diabetes. Chen, H. C., et al., J Clin Invest, 109(8), 1049-55 (2002).

Although studies show that DGAT-1 inhibition is useful for treating obesity and diabetes, there remains a need for DGAT-1 inhibitors that have efficacy for the treatment of metabolic disorders (e.g., obesity, Type 2 diabetes, and insulin resistance syndrome (also referred to as “metabolic syndrome”)).

………………………………..

 US 20100197591

Scheme II outlines the general procedures one could use to provide compounds of the general Formula (II).

Scheme IV outlines a general procedure for the preparation of compounds of the general Formula VI.

 

 

 

 

1-[4-(4-amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclobutanecarbonitrilePotassium nitrate (7.88 g, 77.0 mmol) was suspended in sulfuric acid (45 mL) at 0° C. and stirred for 30 minutes until a clear and colorless solution was obtained (NOTE—a blast shield is highly recommended). An addition funnel was charged with 1-phenylcyclobutanecarbonitrile (11.40 g, 72.5 mmol), and this neat starting material was added drop wise at such a rate that the internal reaction temperature did not exceed 10° C. Upon completion of the addition (which required 90 min), the mixture was poured onto 300 g of ice and stirred vigorously for 30 minutes. The resulting suspension was filtered, and the solid was washed with water and dried under vacuum to afford give 1-(4-nitrophenyl)cyclobutanecarbonitrile (13.53 g, 92%) as a light tan powder.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.11-2.21 (m, 1H) 2.47-2.58 (m, 1H) 2.66 (s, 2H) 2.88-2.96 (m, 2H) 7.63 (d, J=8.54 Hz, 2H) 8.29 (d, J=8.54 Hz, 2H).

A steel hydrogenation vessel was loaded with 1-(4-nitrophenyl)cyclobutanecarbonitrile (103.6 g, 0.51 mol), 10% palladium on activated carbon (10.3 g; contains ˜50% of water), and 2-methyltetrahydrofuran (1.3 L). The mixture was stirred under 30 psi of hydrogen gas at 45° C. for 4 h. The mixture was filtered through a pad of celite and filtrate concentrated. Heptane (1 L) was added to the obtained oil and the heterogeneous mixture was stirred while slowly cooled to room temperature, causing the product aniline to solidify. The solid was filtered off and dried in vacuum to give 1-(4-aminophenyl)cyclobutanecarbonitrile (86.6 g, 98%).

1H NMR (CHLOROFORM-d) δ ppm 7.12-7.25 (m, 2H), 6.61-6.76 (m, 2H), 3.68 (br. s., 2H), 2.68-2.88 (m, 2H), 2.48-2.64 (m, 2H), 2.30-2.45 (m, 1H), 1.94-2.14 (m, 1H)

A mixture of 1-(4-aminophenyl)cyclobutanecarbonitrile (42.2 g, 245 mmol), triethylamine (27.1 mL, 394 mmol), and ethyl acrylate (28.0 mL, 258 mmol) were combined in ethanol (27 mL) and heated to reflux for 24 hours. The mixture was concentrated to dryness and toluene (600 mL) added and concentrated to dryness to give ethyl N-[4-(1-cyanocyclobutyl)phenyl]beta-alaninate as brown oil, which was used without further purification.

1H NMR (CHLOROFORM-d) δ ppm 7.22 (d, 2H), 6.63 (d, 2H), 4.12-4.21 (m, 3H), 3.47 (q, J=6.3 Hz, 2H), 2.74-2.83 (m, 2H), 2.53-2.66 (m, 4H), 2.33-2.45 (m, 1H), 2.00-2.11 (m, 1H), 1.28 (t, 3H)

Ethyl N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate was combined with cyanoacetic acid (22.9 g, 270 mmol) and 4-dimethylaminopyridine (2.30 g, 18.8 mmol) in N,N-dimethylformamide (400 mL) and cooled to 0° C. Diisopropylcarbodiimide (41.7 mL, 270 mmol) was then added drop wise over 30 minutes. Once addition was complete, the reaction was slowly warmed up to room temperature and stirred for 16 hours. Reaction was then poured into saturated aqueous sodium bicarbonate (600 mL) and stirred for 30 mintues. Ethyl acetate (1 L) was added and the mixture was filtered to remove the insoluble diisopropylurea. The phases of the filtrate were separated, and the organic phase was washed with brine and dried over sodium sulfate and concentrated to give ethyl N-(cyanoacetyl)-N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate as yellow oil that was used with out further purification in the following step.

ethyl N-(cyanoacetyl)-N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate and 1,8-diazabicyclo[5.4.0]undec-7-ene (350 mmol) were combined in methanol (400 mL) and heated to 70° C. for 30 minutes. The mixture was concentrated to dryness then partitioned between water (400 mL) and 2:1 ethyl acetate:heptane (400 mL). The aqueous phase was separated and acidified to pH 2 by the addition of 1M hydrochloric acid (400 mL). The precipitate was filtered off and washed with water (300 mL) and 2:1 ethyl acetate:heptane (300 mL) give 1-(4-(1-cyanocyclobutyl)phenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (31.7 g, 44% over 3 steps) as an off-white solid.

1H NMR (DMSO-d6) δ ppm 7.39-7.45 (m, 2H), 7.31 (d, 2H), 3.78 (t, J=6.7 Hz, 2H), 2.79 (t, 2H), 2.66-2.75 (m, 2H), 2.53-2.64 (m, 2H), 2.16-2.31 (m, 1H), 1.91-2.04 (m, 1H)

m/z (M+1)=294.4

1-(4-(1-Cyanocyclobutyl)phenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (50.0 g, 170 mmol) and N,N-dimethylformamide (0.66 mL, 8.5 mmol) in dichloromethane (350 mL) was cooled to 0° C. Oxalyl chloride (18.0 mL, 203 mmol) was added over 15 minutes. The mixture was warmed to room temperature over 2 hours. Methanol (300 mL) was then added as a steady stream, and the mixture was heated at 45° C. for 16 hours. The mixture was cooled to room temperature and concentrated to get rid of most of the dichloromethane. Methanol (200 mL) was added and the thick slurry was stirred for 2 hours. The solid was filtered and dried under vacuum to give 1-(4-(1-cyanocyclobutyl)phenyl)-4-methoxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (48.3 g, 92%) as an off-white powder.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.91-2.03 (m, 1H) 2.18-2.31 (m, 1H) 2.54-2.63 (m, 2H) 2.67-2.75 (m, 2H) 3.03 (t, J=6.73 Hz, 2H) 3.85 (t, J=6.73 Hz, 2H) 4.01 (s, 3H) 7.33 (d, J=8.78 Hz, 2H) 7.44 (d, J=8.78 Hz, 2H)

m/z (M+1)=308.4

1-(4-(1-Cyanocyclobutyl)phenyl)-4-methoxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (12.04 g, 37.9 mmol) and cyanamide (1.64 g, 41.0 mmol) were suspended in methanol (200 mL) at room temperature. A solution of 25% sodium methoxide in methanol (45.0 mmol) was then added drop wise over 10 minutes to obtain a clear homogeneous solution of the intermediate cyanamide adduct. In one portion, sulfuric acid (5.06 mL, 94.9 mmol) was added, and the mixture was heated to 50° C. for 16 hours. The mixture was then cooled to room temperature and basified to pH 10-11 by the addition of 1N sodium hydroxide, and the thick suspension was stirred for 20 minutes. The solid was filtered, washed with cold methanol and water, and dried under vacuum to obtain the crude product as a mixture contaminated with the vinylogous amide (4-amino-1-[4-(1-cyanocyclobutyl)phenyl]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile). This solid mixture was heated to reflux in methanol (150 mL) for 3 hours then cooled to room temperature and filtered. The solid collected was then dissolved in a minimal amount of acetic acid (30 mL) at 60° C. to obtain a clear yellow solution. Water was then added drop wise at 60° C. until the cloudiness persisted, and the mixture was allowed to return to room temperature. Another 50 mL of water was added and the fine suspension was filtered, washed with water, and dried under vacuum to afford the title compound (4A) (6.80 g, 51%) as a light yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.97-2.06 (m, 1H) 2.23-2.34 (m, 1H) 2.59-2.67 (m, 2H) 2.71-2.79 (m, 2H) 2.96 (t, J=6.71 Hz, 2H) 3.86 (s, 3H) 3.91 (t, J=6.71 Hz, 2H) 7.39-7.44 (d, J=8.54, 2H) 7.47-7.51 (d, J=8.54, 2H) 7.81 (br. s., 1H) 8.35 (br. s., 1H).

m/z (M+1)=350.4

………………………..

paper

http://pubs.acs.org/doi/abs/10.1021/op400215h

664338-39-0 

Arterolane

Arterolane, also known as OZ277 or RBx 11160,is a substance being tested for antimalarial activity^[1] by Ranbaxy Laboratories.^[2] It was discovered by US and European scientists who were coordinated by the Medicines for Malaria Venture (MMV).^[3] Its molecular structure is uncommon for pharmacological compounds in that it has both an ozonide group and an adamantane substituent.^[4]

Phase III clinical trials of arterolane, in combination with piperaquine, began in India in 2009.^[5] When clinical trial results were disappointing, the MMV withdrew support^[2] and Ranbaxy continued developing the drug combination on its own.

Ranbaxy launched India’s first new drug, Synriam^TM, treating Plasmodium falciparummalaria in adults. The drug provides quick relief from most malaria-related symptoms, including fever, and has a high cure rate of over 95 %.

Just one tablet per day is required, for three days, instead of two to four tablets, twice daily, for three or more days with other medicines. The drug is independent of dietary restrictions for fatty foods or milk.

Ranbaxy developed Synriam as a fixed-dose combination of arterolane maleate and piperaquine phosphate, where arterolane is the new chemical entity (NCE) that was developed as an alternative to artemisinin. It is the first recently developed antimalarial not based on artemisinin, one of the most effective treatments for malaria, which has shown problems with resistance in recent years. Arterolane was discovered by a collaborative drug discovery project funded by the Medicines for Malaria Venture. Since Synriam^TM has a synthetic source, unlike artemisinin-based drugs, production can be scaled up whenever required and a consistent supply can be maintained at a low cost.

The new drug, has been approved by the Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria. Ranbaxy is also working to make it available in African, Asian and South American markets where Malaria is rampant. Synriam^TM trials are ongoing for Plasmodium vivax malaria and a paediatric formulation.

Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit). They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010. So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world. This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”. So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug? In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India's Department of Science & Technology] was Rs.5 crore. The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million.

• Ranbaxy Laboratories Limited (Ranbaxy), India

  now taken over by sun

Synriam^TM

Description Synriam^TM is a fixed dose combination of two antimalarial active ingredients arterolane maleate and piperaquine phosphate.

Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:

Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and pregnant women.

According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.

The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.

Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940′s, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug- resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.

Malarial treatment further progressed with the discovery of Artemisinin

(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000, 66, p. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 1 1, p. 1753-1760).

Although the clinically useful artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence,

neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205). Further all these artemisinin derivatives are conventionally obtained from plant source and are therefore expensive. As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a switch to cheaper and effective medicine is highly desirable.

Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dependent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.

Following that, many synthetic antimalarial 1 ,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S.

Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486, 199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1 ,2,4- trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.

Active compounds representing various Spiro and dispiro 1 ,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.

Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of resistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.

Artemsinin based combinations are available in the market for a long time.

Artemether-lumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin derivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.

Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all the available artemisinin based combinations have complicated dosage regimens making it difficult and inconvenient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem® for an adult having body weight of more than 35 kg includes 6 doses over three days. The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg – 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.

It is evident that the available artemisinin-based combinations have a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could result in reduced efficacy due to non-compliance and may even lead to development of resistance for the drug. Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.

Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.

……………………..

http://www.google.st/patents/US6906205

……………………

http://www.google.st/patents/WO2013008218A1?cl=en

structural Formula II.

Formula II

Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos.

6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.

The term “Active compound I” herein means cis-adamantane-2-spiro-3′-8′-[[[(2'- amino-2'-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be present in an amount of from about 5% to about 25%, w/w based on the total dosage form.

………………

http://www.google.st/patents/WO2007138435A2?cl=en

A synthetic procedure for preparing compounds of Formula I, salts of the free base c«-adamantane-2-spiro-3′-8′-[[[(2'-amino-2'-methyl propyl) amino] carbonyl] methyl]- 1 ‘, 2′, 4′-trioxaspiro [4.5] decane has been disclosed in U.S. 6,906,205.

The process for the preparation of compounds of Formula I wherein a compound of Formula II (wherein R is lower alkyl) is reacted with a compound of Formula III (wherein R is lower alkyl) to obtain compound of Formula IV;

Formula Formula IV

followed by hydrolysis of the compounds of Formula IV to give a compound of Formula V;

Formula V followed by the reaction of the compound of Formula V with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl chloro formate, n-butyl chloro formate, isobutyl chloroformate or pivaloyl chloride leads to the formation of mixed anhydride, which is reacted in situ reaction with 1 ,2-diamino-2-methyl propane to give a compound of Formula VI; and

Formula Vl reacting the compound of Formula VI with an acid of Formula HX (wherein X can be the same as defined earlier) to give compounds of Formula I.

Example 1 : Preparation of O-methyl-2-adamantanone oxime

To a solution of 2-adamantanone (50 g, 0.3328 mol, 1 equiv.) in methanol (0.25 lit), sodium hydroxide solution (15 g, 0.3761mol, 1.13 equiv, in 50 mL water) was added followed by methoxylamine hydrochloride (37.5 g x 81.59% Purity= 30.596 g, 0.366 mol, 1.1 equiv) at room temperature under stirring. The reaction mixture was stirred at room temperature for 1 to 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated at 40- 45°C under vacuum to get a thick residue. Water (250 mL) was added at room temperature and the reaction mixture was stirred for half an hour. The white solid was filtered, washed with water (50 mL), and dried at 40 to 45°C under reduced pressure. O-methyl 2- adamantanone oxime (57 g, 95 % yield) was obtained as a white solid.

(M⁺+l) 180, ¹HNMR (400 MHz, CDCl₃ ): δ 1.98 – 1.79 (m, 12H), 2.53 (s, IH), 3.46 ( s, IH), 3.81 (s, 3H).

Example 2: Preparation of 4-(methoxycarbonvmethvPcvclohexanone A high pressure autoclave was charged with a mixture of methyl (4- hydroxyphenyl)acetate (50 g, 0.30 mol), palladium ( 5g) (10 %) on carbon (50 % wet) and O- xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 140⁰C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4 %).

(M⁺+!) 171, ‘ HNMR (400 MHz, CDCl ₃): δ 1.48 – 1.51 ( m, 2H), 2.1 1-2.07 (m, 2H), 2.4- 2.23 (m, 7H), 3.7 (s, 3H).

Example 3: Preparation of methyl (Is, 4s)-dispiro [cyclohexane-l, 3'-f 1,2,4] trioxolane-5′, 2″-tricvclor3.3.1.1³-⁷1decan1-4-ylacetate

A solution of O-methyl-2-adamantanone oxime (example 1) (11.06 g, 61.7 mmol, 1.5 equiv.) and 4-(methoxycarbonymethyl)cyclohexanone (example 2) (7.0 g, 41.1 mmol, 1 equiv.) in cyclohexane ( 200ml) and dichloromethane (40 mL) was treated with ozone (ozone was produced with an OREC ozone generator [0.6 L/min. O_2, 60 V] passed through an empty gas washing bottle that was cooled to -78⁰C). The solvent was removed after the reaction was complete. After removal of solvents, the crude product was purified by crystallization from 80% aqueous ethanol (200 mL) to afford the title compound as a colorless solid. Yield: 10.83 g, 78%, mp: 96-98⁰C; ¹HNMR (500 Hz₃CDCl₃): δ 1.20-1.33 (m, 2H), 1.61-2.09 (m, 5 21H), 2.22 (d, J = 6.8Hz, 2H), 3.67(s,3H).

Example 4: Preparation of (Is, 4s)-dispiro [cyclohexane-1, 3'-[l,2,4] trioxolane-5′, 2″- tricvclo [3.3.1.1³'⁷] decanl-4-ylacetic acid

Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (\s, 4s)-dispiro [cyclohexane-1, 3'-[l,2,4] trioxolane-5′, 2″-tricyclo

10 [3.3.1.I³'⁷] decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 50⁰C for about 4 h, cooled to O⁰C, and treated with IM hydrochloric acid (129ml, 4 equiv). The precipitate was collected by filtration, washed with 50 % aqueous ethanol (150 mL) and dried in vacuum at 40 ⁰C to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-148⁰C ( 95% ethanol), ¹HNMR (500 Hz,

15 CDCl₃): δ 1.19-1.41 (m,2H), 1.60-2.05 (m,21H), 2.27 (d, J=6.8 Hz,2H).

Example 5: Preparation of c?s-adamantane-2-spiro-3′-8′-[[[(2'-amino-2'-methyl propyl) amino] carbonyl] methyl]-! ‘, T , 4′-trioxaspiro [4.5] decane

Method A:

(Is, 4s)-dispiro[cyclohexane- 1 ,3 '-[ 1 ,2,4]trioxolane-5 ‘,2 ‘ ‘-tricyclo[3.3.1.1³'⁷]decan]-4-

.0 ylacetic acid (example 4) (5 g ,15.5mmol, 1 equiv) was mixed with triethylamine (2.5 g , 24.8 mmol, 1.6 equiv) in 100ml of dichloromethane. The reaction mixture was cooled to – 1O⁰C to 0⁰C. Ethyl chloro formate (1.68 g, 17 mmol, 1.0 equiv) in 15 mL dichloromethane was charged to the above reaction mixture at – 10⁰C to 0⁰C. The reaction mixture was stirred at the same temperature for 10 to 30 minutes. The resulting mixed anhydride reaction mixture

15 was added dropwise to a previously prepared solution of l,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv), in 100 mL dichloromethane at -10⁰C to O⁰C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the same temperature till the reaction was complete. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete

>0 within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (50 mL) was charged, organic layer was separated and washed with 10% sodium bicarbonate solution (50 mL) and water (50 mL) at room temperature. The organic layer was dried over sodium sulphate and the solvent was removed at 25 to 4O⁰C under reduced pressure. Hexane (50ml) was added to obtain residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. The solid was dried under reduced pressure at room 5 temperature.

Yield: 5.2 g (85.4 %), (M⁺+l) 393, ¹HNMR (400 MHz, DMSO-J₆ ): δ 0.929 ( s, 6H), 1.105 – 1.079 (m, 2H), 1.887-1.641 (m, 21H), 2.030-2.017 (d, 2H), 2.928 (d, 2H).

Method B:

(Is, 4s)-dispiro [cyclohexane-1, 3'-[l,2,4] trioxolane-5′, 2″-tricyclo [3.3.1.I³'⁷]

10 decan]-4-ylacetic acid (example 4) (10 g, 31mmol, 1 equiv) was treated with isobutyl chloroformate (4.5 g, 33mmol, 1.1 equiv) in presence of organic base like triethyl amine (5 g, 49.6mmol, 1.6 equiv) at 0⁰C to 7°C in 250ml of dichloromethane. The solution was stirred at O⁰C to 7°C for aboutlO to 30 minutes. To the above reaction mixture, previously prepared solution of l,2-diamino-2-methylpropane (3.27 g, 37 mmol, 1.2 equiv), in 50 mL of

15 dichloromethane was added at O⁰C to 7°C in one lot. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. Reaction was complete within 2 h. The reaction nitrogen atmosphere was maintained throughout the reaction. Water (250 mL) was charged, organic

20 layer was separated and washed with 10% sodium bicarbonate solution (200 mL) and water (100 mL) at room temperature and the solvent was removed at 25 to 4O⁰C under reduced pressure. Hexane (100ml) was added to the residue, under stirring, at room temperature. The mixture was filtered and washed with chilled hexane (10 mL). The resultant solid was dried under reduced pressure at room temperature. Yield: 10.63 g (87%), (M⁺+l) 393, ¹HNMR

>5 (400 MHz, DMSO-J₆ ) :δ 0.928 ( s, 6H), 1.102 – 1.074 (m, 2H), 1.859-1.616 (m, 21H), 2.031- 2.013 (d, 2H), 2.94-2.925 (d, 2H). Method C:

(\s, 4s)-dispiro[cyclohexane-l,3'-[l,2,4]trioxolane-5′,2″-tricyclo[3.3.1.1^3>7]decan]-4- ylacetic acid (example 4) (5 g, 15.5mmol, 1 equiv) was treated with pivaloyl chloride (1.87 g, 15.5 mmol, 1 equiv) and triethylamine (2.5gm, 24.8mmol, 1.6 equiv) at -15°C to -10⁰C in dichloromethane (125 mL). The solution was stirred at -15⁰C to -10⁰C for aboutlO to 30 minutes. It resulted in the formation of mixed anydride. To the above reaction mixture, previously prepared solution of 1 ,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv) in 25 mL dichloromethane was added at -15°C to -10⁰C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (125 mL) was charged, organic layer was separated and washed with 50 mL of 10% sodium bicarbonate solution and 125 mL of water, respectively at room temperature. Finally solvent was removed at 25 to 4O⁰C under reduced pressure. 50 mL of 5% Ethyl acetate – hexane solvent mixture was added to the residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. Solid was dried under reduced pressure at room temperature. Yield: 5.03 g (83 %), (M⁺+l) 393, ¹JINMR (400 MHz, OMSO-d₆ ):δ 0.93 ( s, 6H), 1.113 – 1.069 (m, 2H), 1.861-1.644 (m, 21H), 2.033-2.015 (d, 2H), 2.948-2.933 (d, 2H).

Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2′ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4′-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 10⁰C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-45⁰C.

Yield: 67 g, 77.4%, mp: 149⁰C (decomp), (M⁺+l) 393.5, ¹HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).

References

ACT-280778

(1R,2R,4R)-2-(2-((3-(4,7-Dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl Isobutyrate

Propanoic acid, 2-​methyl-​, (1R,​2R,​4R)​-​2-​[2-​[[3-​(4,​7-​dimethoxy-​1H-​benzimidazol-​2-​yl)​propyl]​methylamino]​ethyl]​-​5-​phenylbicyclo[2.2.2]​oct-​5-​en-​2-​yl ester

isobutyric acid (1R,2R,4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester

Actelion Pharmaceuticals Ltd innovator

C₃₃ H₄₃ N₃ O₄

 1075744-31-8

bis-MALEATE SALT  1537197-53-7

Chiral bicyclic benzimidazole 1 (ACT-280778) is a L/T calcium channel blocker potentially indicated for the treatment of hypertension and angina pectoris 

 Many cardiovascular disorders have been associated with a ‘calcium overload’ resulting from an abnormal elevated calcium influx through the plasma membrane of cardiac and vascular smooth muscle cells. There are 3 major pathways through which extracellular calcium can enter these cells: 1 ) receptor-activated calcium channels, 2) ligand-gated calcium channels and 3) voltage-operated calcium channels (VOCs). 0 VOCs have been classified into 6 main categories: L (Long-lasting), T (Transient), N (Neuronal), P (Purkinje cells), Q (after P) and R (Remaining or Resistant).

L-type calcium channels are responsible for the inward movement of calcium that initiates contraction in cardiac and smooth muscle cells suggesting a putative application for blockers of these channels in the cardiovascular field. In this view, L-type calcium channel blockers5 have been used in clinic since the early 60s and are now recommended as a first line of treatment for systolic-diastolic hypertension and angina pectoris.

T-type calcium channels are found in various tissues such as coronary and peripheral vasculature, sinoatrial node and Purkinje fibres, brain, adrenal glands and in the kidney. This broad distribution suggests a T-type channel blocker to have a putative cardiovascular0 protection, to have en effect on sleep disorders, mood disorders, depression, migraine, hyperaldosteroneemia, preterm labor, urinary incontinence, brain aging or neurodegenerative disorders such as Alzheimers disease.

Mibefradil (Posicor®), the first L-type and T-type calcium channels blocker demonstrated a superior effect over calcium channel blockers, which target the L channel predominantly. Mibefradil was used for the treatment of hypertension and angina without showing negative side-effects often seen by L channel blockers like inotropy, reflex tachycardia, vasoconstrictive hormone release or peripheral edema. Additionally, mibefradil showed a potentially cardioprotective effect (Villame, Cardiovascular Drugs and Therapy 15, 41-28, 2001 ; Ramires, J MoI Cell Cardiol 1998, 30, 475-83), a renal protective effect (Honda, Hypertension 19, 2031-37, 2001 ), and showed a positive effect in the treatment of heart failure (Clozel, Proceedings Association American Physicians 1999, 1 11 , 429-37).

Despite the enormous demand for a compound of this profile, mibefradil was withdrawn from the market in 1998 (one year after its launch), due to unacceptable CYP 3A4 drug interactions. Moreover, ECG abnormalities (i.e. QT prolongations) and interaction with the MDR-1 mediated digoxin efflux were also reported (du Souich, Clin Pharmacol Ther 67, 249- 57, 2000; Wandel, Drug Metab Dispos 2000, 28, 895-8).

It has now been found that crystalline salt forms of COMPOUND (isobutyric acid (1 R^*,2R^*,4R^*)-2-(2-{[3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)- 5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester) may under certain conditions be found. Said crystalline salt forms of COMPOUND are novel and may have advantageous properties, especially compared to the free base (WO2008/132679) or the di-hydrochloride salt of COMPOUND. Such advantages may include better flow properties, better solubility, less hygroscopicity, better reproducibiliy in manufacturing (for example better filtration parameters, better reproducibility of formation, better sedimentation),

………………………

http://www.google.com/patents/WO2009130679A1?cl=en

Scheme 1

……………

http://www.google.com/patents/CN102186828A?cl=en

http://www.google.com/patents/EP2344461A1?cl=en

The preparation of COMPOUND is known from WO2008/132679: Preparation of intermediates

General procedures for the preparation of key intermediates K: Key intermediates K1A and K2A which are bicyclo[2.2.2]oct-5-en-2-yl or bicyclo[3.2.2]non-8- en-6-yl derivatives are obtained as a mixture between the major racemate having the relative configuration (R^*, R^*, R^*) (i.e. the bridge -(CH₂)₂- of the cyclohexene moiety is cis to the group -OR² being hydroxy) and the minor racemate having the relative configuration (R^*, S^*, R^*) (i.e. the bridge -(CH₂)₂- of the cyclohexene moiety is trans to the group -OR² being hydroxy). The major and the minor racemates can be separated as described for key intermediate K1A in procedure A1.5. The major racemate is isolated and used in the preparation of the examples below.

K1 A: rac-(1 R*,2R*,4R*)-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert. -butyl ester K1 A.1 (Procedure A1.1 ): rac-(1 R^*.4R^*VBicvclor2.2.21octane-2.5-dione

25 ml. of 2-(trimethylsilyloxy)-1 ,3-cyclohexadiene and 13 ml. of α-acetoxyacrylonitrile were mixed and heated at 150⁰C in a closed vessel for 22 h. The obtained dark orange viscous oil was dissolved in 200 ml. of MeOH. After dropwise addition of a solution of 2.2 g of sodium methoxide in 150 ml. of MeOH the reaction mixture was stirred for 3 h at rt, poured into ice/water and extracted with DCM. The organic phases were concentrated in vacuo and the crude residue was purified by CC with EtOAc-Hept (1 :2) to yield 7.9 g of rac-(1 R^*,4R^*)- bicyclo[2.2.2]octane-2,5-dione. LC-MS: t_R = 0.44 min.

K1A.2 (Procedure A1.2): rac-(1 R^*.4R^*VSpirorbicvclor2.2.2loctane-2.2′-ri .3ldioxolanl-5-one To 4.0 g of rac-(1 R^*,4R^*)-bicyclo[2.2.2]octane-2,5-dione (intermediate K1A.1 ), dissolved in 120 ml. of toluene, 1.7 ml. of ethylene glycol and 0.27 g of TsOH were added and the solution was heated under vigorous stirring to reflux for 3.5 h. The reaction mixture was cooled to rt, quenched with saturated aq. NaHCO₃, extracted with Et₂O, and the organic phase was evaporated. The crude product was purified by CC with Hex-EtOAc (7:3) to yield 2.41 g of rac-(1 R^*,4R^*)-spiro[bicyclo[2.2.2]octane-2,2′-[1 ,3]dioxolan]-5-one as yellow oil. LC-MS: t_R = 0.64 min; [M+H+CH₃CN]⁺: 224.35. K1A.3 (Procedure A1.3): Mixture of rac-(7R^*.8R^*.10R^*V and rac-(7R^*.8S^*.10R^*V7.10-(1.2- Ethylen)-8-phenyl-1 ,4-dioxa-spiror4.5ldecan-8-ol

To a solution of 2.41 g of rac-(1 R^*,4R^*)-spiro[bicyclo[2.2.2]octane-2,2′-[1 ,3]dioxolan]-5-one

(intermediate K1A.2) in 80 ml. Et₂O, 14.5 ml. phenylmagnesium bromide solution (1 M in Et₂O) was added dropwise over 10 min. The reaction mixture was stirred for 4 h at rt. Then, the mixture was quenched carefully with ice, 8 ml. 2N HCI were added and the phases were separated. The organic phase was evaporated and the crude product was purified by CC with Hept-EtOAC (7:3) to give 0.37 g of 7,10-(1 ,2-ethylen)-8-phenyl-1 ,4-dioxa- spiro[4.5]decan-8-ol as colorless oil. (Separation of the diastereomers by CC is possible but was not performed here.)

LC-MS: t_R = 0.84 min; [M-H₂O+H]⁺: 243.34.

K1A.4 (Procedure A1.4): rac-(1 R^*,4R^*)-5-Phenyl-bicvclor2.2.2loct-5-en-2-one

To a solution of 0.54 g of 7,10-(1 ,2-ethylen)-8-phenyl-1 ,4-dioxa-spiro[4.5]decan-8-ol (intermediate K1A.3) in 20 ml. acetone was added 200 mg of TsOH and then the mixture was stirred for 2 d at rt. The reaction mixture was quenched with sat. aq. NaHCO₃, extracted with EtOAC and the organic phase was evaporated. The crude product was purified by CC with Hept-EtOAC (7:3) to give 0.34 g of rac-(1 R^*,4R^*)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-one as colorless oil. LC-MS: t_R = 0.93 min; [M+H+CH₃CN]⁺: 240.1 1. K1A.5 (Procedure A1.5): rac-(1 R^*.2R^*.4R^*H2-Hvdroxy-5-phenyl-bicvclor2.2.2loct-5-en-2-vn- acetic acid tert.-butyl ester and rac-(1 R^*,2S^*,4R^*H2-hvdroxy-5-phenyl-bicvclor2.2.2loct-5-en- 2-yl)-acetic acid tert.-butyl ester

To a solution of 0.51 mL of DIPA in 0.5 mL THF 2.2 mL of n-butyllithium (1.6M in Hex) were added dropwise at -20⁰C. After 10 min, 0.5 mL of toluene were added and the solution was stirred for 30 min. The mixture was cooled to -50⁰C, 0.73 mL of tert.-butyl acetate were added and stirring was continued for 1 h at -50⁰C. Then 0.32 g of rac-(1 R^*,4R^*)-5-phenyl- bicyclo[2.2.2]oct-5-en-2-one (intermediate K1A.4) dissolved in 1 mL of THF was added and the solution was stirred at -50 to -20⁰C over 2.5 h. The reaction mixture was poured on ice/aq. HCI, the organic phase was separated, washed and evaporated. The crude reaction product was purified by CC with Hept-EtOAc (9:1 ) to yield 0.30 g of the major racemate, rac- (1 R^*,2R^*,4R^*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester, as white solid and 0.07 g of the minor racemate, rac-(1 R^*,2S^*,4R^*)-2-hydroxy-5-phenyl- bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester, as colorless oil. LC-MS (major racemate): t_R = 1.06 min; [M-(CH₃)₃-H₂O+H]⁺: 241.1 1. LC-MS (minor racemate): t_R = 1.05 min; [M+H]⁺: 315.18. K1A.6: (1 S.2S.4SV(2-Hvdroxy-5-Dhenyl-bicvclor2.2.2loct-5-en-2-vn-acetic acid tert.-butyl ester and (1 R,2R,4R)-(2-Hvdroxy-5-phenyl-bicvclor2.2.2loct-5-en-2-yl)-acetic acid tert.-butyl ester rac-(1 R^*,2R^*,4R^*)-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester was separated into the respective enantiomers using prep, chiral HPLC (column: Daicel ChiralPak AD-H, 20×250 mm, 5 μm; Hex/ EtOH 95:5, flow 16 mL/min) Chiral analytic HPLC (Daicel ChiralPak AD-H, 4.6×250 mm, 5 μm; Hex/ EtOH 95:5, flow 0.8 mL/min):

(1 R,2R,4R)-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester: Enantiomer A: t_R = 6.70 min.

(1S,2S,4S)-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester: Enantiomer B: t_R = 7.93 min.

BB. [3-(4,7-Dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amine

BB.1 3,6-Dimethoxy-benzene-1 ,2-diamine 3, 6-Dimethoxy-benzene-1 ,2-diamine was synthesized by dissolving 6.0 g of 1 ,4-dimethoxy- 2,3-dinitro-benzene (Eur.J.Org.Chem. 2006, 2786-2794) in 220 mL EtOH, evacuating 3 times with N₂ and adding 600 mg of 10wt% Pd/C. The reaction was stirred under a H₂ atmosphere (balloon). Another 300 mg of 10wt% Pd/C were added after 2 days and the mixture was stirred for another 24 h. Filtration over a pad of celite and washing with EtOH and EtOAc yielded after concentration in vacuo 4.3 g of 3, 6-dimethoxy-benzene-1 ,2-diamine as black solid. LC-MS: t_R = 0.48 min; [M+H]⁺: 169.09.

BB.2 r3-(2-Amino-3,6-dimethoxy-phenylcarbamoyl)-propyll-methyl-carbamic acid benzyl ester To a solution of 3.1 g of 4-(benzyloxycarbonyl-methyl-amino)-butyric acid in 80 mL DCM were added 6.5 mL of DIPEA, 1.8 g of HOBt, 2.6 g of EDC and 154 mg of DMAP. After stirring for 10 min, 2.1 g of 3, 6-dimethoxy-benzene-1 ,2-diamine, dissolved in 20 mL DCM, were added and the mixture was stirred at rt overnight. The reaction was quenched with sat. aq. NaHCO₃, the phases were separated and the organic phase was washed with brine, dried over MgSO₄ and concentrated in vacuo to yield the crude title compound as black oil. LC-MS: t_R = 0.88 min; [M+H]⁺: 402.06.

BB.3 [3-(4,7-Dimethoxy-1 H-benzoimidazol-2-yl)-propyl1-methyl-carbamic acid benzyl ester

To a mixture of the above crude 3-(2-amino-3,6-dimethoxy-phenylcarbamoyl)-propyl]-methyl- carbamic acid benzyl ester in 16 mL toluene were added 4 mL of DMF and 1.9 g of TsOH and the reaction was heated to 150⁰C for 2 h in the microwave. Sat. aq. NaHCO₃ was added and the phases were separated. The organic phase was washed with brine, dried over MgSO₄, concentrated in vacuo, filtered over a short pad of silica gel with EtOAc and concentrated again. Purification by CC with EtOAc yielded 2.7 g of 3-(4,7-dimethoxy-1 H- benzoimidazol-2-yl)-propyl]-methyl-carbamic acid benzyl ester as brown resin. LC-MS: t_R = 0.85 min; [M+H]⁺: 384.62.

BB.4 r3-(4,7-Dimethoxy-1 H-benzoimidazol-2-yl)-propyll-methyl-amine

A solution of 2.6 g of 3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid benzyl ester in 60 ml. EtOH was evacuated 3 times with N₂ before 260 mg of 10 wt% Pd/C were added. The reaction mixture was then stirred under a H₂atmosphere (balloon) for 5 h at rt. Filtration over a pad of celite and washing with EtOH yielded after concentration in vacuo 1.7 g of 3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amine as brown foam. LC-MS: t_R = 0.57 min; [M+H]⁺: 250.13.

Preparation of COMPOUND Reference Example 1A: rac-lsobutyric acid (1 R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H- benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester

1.1 (Procedure P1.1 V rac-(1 R^*.2R^*.4R^*H2-Hvdroxy-5-phenyl-bicvclor2.2.2loct-5-en-2-vn- acetic acid To a solution of 4.0 g of rac-(1 R^*,2R^*,4R^*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)- acetic acid tert.-butyl ester in 25 mL EtOH were added 2.1 g of LiOH-H₂O, 8 mL H₂O and 22 mL MeOH. The reaction mixture was stirred at rt for 3 d and then concentrated. The residue was partitioned between water and Et₂O. The aq. layer was separated and acidified with 1 N HCI resulting in the formation of a white solid. The solid was filtrated, washed with 5 mL aq. HCI and dried in vacuo to obtain 3.2 g of rac-(1 R^*,2R^*,4R^*)-(2-hydroxy-5-phenyl- bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid as white solid. LC-MS: t_R = 0.86 min; [M-H₂O+H]⁺: 241.28.

1.2 (Procedure P1.2): rac-(1 R^*,2R^*,4R^*)-N-r3-(4,7-Dimethoxy-1 H-benzoimidazol-2-yl)- propyl1-2-(2-hvdroxy-5-phenyl-bicvclo[2.2.21oct-5-en-2-yl)-N-methyl-acetamide To a solution of 280 mg of rac-(1 R^*,2R^*,4R^*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2- yl)-acetic acid in 7 mL THF were added 0.58 mL of DIPEA, 175 mg of HOBt and 250 mg of EDC at rt. After stirring for 10 min, 270 mg of 3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)- propyl]-methyl-amine were added and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO₃, the phases were separated and the organic phase was washed with water and brine, dried over MgSO₄ and concentrated in vacuo. Purification by CC using EtOAc-MeOH (5:1 to 2:1 ) yielded 475 mg of rac- (1 R^*,2R^*,4R^*)-N-[3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-2-(2-hydroxy-5-phenyl- bicyclo[2.2.2]oct-5-en-2-yl)-N-methyl-acetamide as white foam. LC-MS: t_R = 0.91 min; [M+H]⁺: 490.06.

1.3 (Procedure P1.3): rac-(1 R^*.2R^*.4R^*V2-(2-fr3-(4.7-Dimethoxy-1 H-benzoimidazol-2-ylV propyll-methyl-amino}-ethyl)-5-phenyl-bicvclor2.2.21oct-5-en-2-ol

To a solution of 310 mg of rac-(1 R^*,2R^*,4R^*)-N-[3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)- propyl]-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-N-methyl-acetamide in 8 mL toluene were added dropwise 0.77 ml. of a Red-AI solution (65% in toluene) at 0⁰C. After stirring for 10 min at 0⁰C, the cooling bath was removed and stirring was continued for 3 h at rt. The reaction mixture was then carefully poured onto a mixture of 1 M NaOH/ice and stirred for 10 min. The aq. phase was extracted with toluene, the combined organic phases were washed with brine, dried over MgSO₄ and concentrated in vacuo. Purification by CC using EtOAc-MeOH (2:1 ) yielded 230 mg of rac-(1 R^*,2R^*,4R^*)-2-(2-{[3-(4,7-dimethoxy-1 H- benzoimidazol^-y^-propyll-methyl-aminoj-ethy^-δ-phenyl-bicyclop^^loct-δ-en^-ol as white foam. LC-MS: t_R = 0.79 min; [M+H]⁺: 476.13. 1.4: rac-lsobutyric acid (1 R^*.2R^*.4R^*‘)-2-(2-fr3-(4.7-dimethoxy-1 H-benzoimidazol-2-vn- propyll-methyl-amino}-ethyl)-5-phenyl-bicvclor2.2.21oct-5-en-2-yl ester

To a solution of 199 mg of rac-(1 R^*,2R^*,4R^*)-2-(2-{[3-(4,7-dimethoxy-1 H-benzoimidazol-2- yO-propyO-methyl-aminoJ-ethy^-δ-phenyl-bicycloP^^loct-δ-en^-ol in 4 mL DCM were added 0.2 mL of NEt₃ and 0.1 mL of isobutyrylchloride at 0°C. The reaction mixture was stirred overnight allowing the temperature to reach slowly rt. The reaction was quenched with sat. aq. NaHCO₃, the phases were separated and the water phase was re-extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was redissolved in 3 mL EtOAc, silica gel and 1.5 mL MeOH were added and the mixture was stirred vigorously for 7 d. The mixture was filtered, thouroughly washed with EtOAc-MeOH (2:1 ) and evaporated. Purification by CC using EtOAc-MeOH (5:1 to 3:1 + 0.1 % NEt₃) yielded 186 mg of rac-isobutyric acid (1 R^*,2R^*,4R^*)-2- (2-{[3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl- bicyclo[2.2.2]oct-5-en-2-yl ester as beige foam. LC-MS: t_R = 0.90 min; [M+H]⁺: 546.23. Reference Example 2A: lsobutyric acid (1S,2S,4S)-2-(2-{[3-(4,7-dimethoxy-1H- benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester

2.1 : (1S.2S.4SV(2-Hvdroxy-5-Dhenyl-bicvclor2.2.2loct-5-en-2-vn-acetic acid Prepared according to procedure P1.1 in Reference Example 1A using enantiomer B of rac- (1 R^*,2R^*,4R^*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester (see K1A.6). LC-MS: t_R = 0.91 min; [M-H₂CHH]⁺: 241.10.

2.2: (1S.2S.4SV2-(2-fr3-(4.7-Dimethoxy-1 H-benzoimidazol-2-ylVDroDyll-methyl-amino>- ethyl)-5-phenyl-bicvclor2.2.21oct-5-en-2-ol

Prepared according to procedures P1.2 to P1.3 in Reference Example 1A using the above (2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid. LC-MS: t_R = 0.78 min; [M+H]⁺: 476.09.

2.3: Isobutyric acid (1S,2S,4S)-2-(2-{[3-(4J-dimethoxy-1 H-benzoimidazol-2-yl)-propyl1- methyl-amino}-ethyl)-5-phenyl-bicvclor2.2.21oct-5-en-2-yl ester

Prepared according to procedure P1.4 in Reference Example 1A using the above 2-(2-{[3-

(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl- bicyclo[2.2.2]oct-5-en-2-ol.

LC-MS: t_R = 0.89 min; [M+H]⁺: 546.19. Reference Example 3A: lsobutyric acid (1 R,2R,4R)-2-(2-{[3-(4,7-dimethoxy-1H- benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester

3.1 : (1 R.2R.4RH2-Hvdroxy-5-phenyl-bicvclor2.2.21oct-5-en-2-vn-acetic acid

Prepared according to procedure P1.1 in Reference Example 1 using enantiomer A of rac- (1 R^*,2R^*,4R^*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester (see K1A.6). LC-MS: t_R = 0.91 min; [M-H₂CHH]⁺: 241.16.

3.2: (1 R,2R,4R)-2-(2-{[3-(4,7-Dimethoxy-1 H-benzoimidazol-2-yl)-propyl1-methyl-amino}- ethvD-δ-phenyl-bicvclo^^^loct-δ-en^-ol Prepared according to procedures P1.2 to P1.3 in Reference Example 1 using the above (2- hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid. LC-MS: t_R = 0.79 min; [M+H]⁺: 476.09. 3.3: Isobutyric acid (1 R.2R.4RV2-(2-{r3-(4.7-dimethoxy-1 H-benzoimidazol-2-ylVpropyll- methyl-amino}-ethyl)-5-phenyl-bicvclor2.2.21oct-5-en-2-yl ester

Prepared according to procedure P1.4 in Reference Example 1A using the above 2-(2-{[3- (4,7-dimethoxy-1 H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl- bicyclo[2.2.2]oct-5-en-2-ol.

LC-MS: t_R = 0.89 min; [M+H]⁺: 546.11. Optical rotation: alpha D (c = 10 mg/mL EtOH) = -21.5°.

1 H NMR (MeOD, 400 MHz) δ 7.39-7.37 (m, 2H), 7.30 (t, J = 6.4 Hz, 2H), 7.24-7.20 (m, 1 H), 6.60 (s, 2 H), 6.43 (br d, J = 7.6 Hz, 1 H), 3.91 (s, 6H), 3.27-3.23 (m, 1 H), 3.18-3.15 (m, 1 H), 2.87 (t, J = 7.6 Hz, 2H), 2.54 (sept, J = 7.0 Hz, 1 H), 2.47-2.37 (m, 4H), 2.21 (s, 3H), 2.19- 2.12 (m, 1 H), 2.01-1.92 (m, 5H), 1.75-1.65 (m, 2H), 1.48-1.38 (m, 1 H), 1.27-1.19 (m, 1 H), 1.16 (d, J = 7.0 Hz, 6H).

Example S5: Preparation and characterization of the di-maleic acid salt of COMPOUND

Maleic acid (256 g, 2.2 mol, 2.1 eq), dissolved in MeOH (630 ml_, 1.1 volumes) was added to a refluxing solution of COMPOUND (682 g, 84% w/w (NMR assay), 1.05 mol) in EtOAc (6.3 L, 11 volumes). The resulting mixture was stirred under reflux for 15 minutes and was then cooled to 65-68°C within 30 minutes and seeded with 0.04% w/w of seeding crystals of di- maleic acid salt of COMPOUND (Seeding crystals were obtained after careful crystallisation using the same protocol.). The mixture was then cooled from 65-68°C to 40⁰C within 3 h. The obtained suspension was then cooled down to 20⁰C over 1 h, filtered under 0.2 bar of nitrogen and rinsed with EtOAc (1500 ml. 2.6 volumes). The obtained white solid was then dried under 1 atmosphere of nitrogen for 24 hours to yield 715 g (88%) of the di-maleic acid salt of COMPOUND.

Table S5: Characterisation data for the di-maleic acid salt of COMPOUND

………….

paper

A scalable access to 1 (ACT-280778), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (3) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to the success of this fit-for-purpose approach are a robust and atom-efficient access to benzimidazole 4, the substrate-controlled diastereoselective enolate addition toward carboxylic acid 2 that was isolated by simple crystallization with high dr (>99:1), the convenient selective N-deacylation of intermediate 10, and the identification of a suitable solid form of 1 as the bis-maleate salt (1·2 C₄H₄O₄). As an illustration of the robustness of this process, 14 kg of drug substance, suitable for human use, was produced with an overall yield of 38% over the longest linear sequence (7 steps).

RG-7388

Hoffmann-La Roche, Inc. , INNOVATOR

4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid

 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid

4-[[(3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-D-prolyl]amino]-3-methoxybenzoic acid

CAS Number:1229705-06-9

Mol. Formula:C₃₁H₂₉Cl₂F₂N₃O₄

MW:616.5

RG-7388 is an MDM2 (hdm2) inhibitor in early clinical trials at Roche for the oral treatment of solid tumors and hematologic cancer.

INTRO

 RG7388 is a MDM2 inhibitor with superior potency and selectivity

RG7388 is an oral, selective, small molecule MDM2 antagonist that inhibits binding of MDM2 to p53.

RG7388 is the second generation inhibitor of P53-MDM2 interaction. It is orally active, potently and selectively antagonizing the P53-MDM2 interaction with Ki at low nM. It is designed to selectively target MDM2, a key negative regulator of the p53 tumor suppressor protein. Blocking this essential interaction may lead to apoptosis via activation of p53 in tumor cells with functional p53 signaling. It is currently in clinical evaluation.

Description: 
Value IC50: 30 nM (IC50 Average of three wt-p53 SJSA1 Cancer cell lines, RKO, HCT116) 
. RG7388 is an Oral, Selective, small molecule antagonist that inhibits binding of MDM2 to p53 MDM2 Blocking the MDM2-p53 Interaction stabilizes p53 and activates p53-mediated cell death and inhibition of cell Growth. 
RG7388 Showed all the Characteristics expected of an MDM2 inhibitor in terms of speci? c binding to the target, mechanistic outcomes Resulting from Activation of the p53 pathway, and in vivo ?. Although e cacy Mechanism of Action of the cellular is identical to that of RG7388 RG7112, it is much More potent and Selective. 

Tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein that plays a central role in protection from tumor development.A potent transcription factor, p53 is activated following cellular stress and regulates multiple downstream genes implicated in cell cycle control, apoptosis, DNA repair, and senescence.While p53 is inactivated in about 50% of human cancers by mutation or deletion, it remains wild-type in the remaining cases but its function is impaired by other mechanisms. One such mechanism is the overproduction of MDM2, the primary negative regulator of p53, which effectively disables p53 function.An E3 ligase, MDM2 binds p53 and regulates p53 protein levels through an autoregulatory feedback loop. Stabilization and activation of wild-type p53 by inhibition of MDM2 binding has been explored as a novel approach for cancer therapy.

Ding Q, Zhang Z, Liu JJ, et al Discovery of RG7388, a Potent and Selective Inhibitor p53-MDM2 in Clinical Development J Med Chem 2013 Jun 28 DOI:. 10.1021/jm400487c

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

Restoration of p53 activity by inhibition of the p53–MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein–protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53–MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

http://pubs.acs.org/doi/suppl/10.1021/jm400487c/suppl_file/jm400487c_si_001.pdf         …………..for exptal section

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

US20100152190

http://www.google.com/patents/US20100152190

(Scheme 4).

In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol), was combined with CH₂Cl₂ (5 ml). DIPEA (277 mg, 374 μl, 2.14 mmol) and dipenylphospenic chloride (380 mg, 306 μl, 1.6 mmol) were added and the reaction was stirred at RT for 20 minutes. Methyl 4-amino-3-methoxybenzoate (100 mg, 552 μumol) was added and the reaction mixture was stirred at RT overnight.

The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 25% EtOAc/Hexanes) to give the desired product as a white solid (275 mg, 81% yield).

Example 448 Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid

In a 25 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (150 mg, 238 μmol, Eq: 1.00) was combined with CH₂Cl₂ (2 ml) to give a colorless solution. Aluminum bromide (Aldrich, 254 mg, 952 μmol, Eq: 4) and dimethyl sulfide (1.69 g, 2 mL, 27.2 mmol, Eq: 114) were added. The reaction mixture was stirred for overnight.

The reaction mixture was diluted with CH₃CN (6 ml), EtOAc (10 ml) and water (10 ml), stirred and layers separated. The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with saturated NaCl (1×15 mL), dried over MgSO₄ and concentrated in vacuum.

The crude material was dissolved in DMSO (4 ml) and was purified by preparative HPLC (70-100% ACETONITRILE/water). The fractions were combined, concentrated and freeze dried to give a white powder as desired product (75 mg, 51% yield). (ES+) m/z Calcd: [(M+H)+]: 616, found: 616.

Alternatively, the title compound could be prepared by the following method.

In a 500 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (3.74 g, 5.93 mmol, Eq: 1.00) was combined with THF (140 ml) and MeOH (160 ml) at 50° C. to give a colorless solution. 1 N NaOH (23.7 ml, 23.7 mmol, Eq: 4) was added. The reaction mixture was stirred at 40° C. for 18 hrs.

The reaction mixture was concentrated to remove about ½ of the solvent, filtered to removed the insoluble, acidified with 1N HCl to PH=4-5 and the resulting solid was collected by filtration and was washed with water, small amount of MeOH and diethyl ether. It was then dried in vacuum oven (60° C.) overnight. Obtained was a white solid as the desired product (2.96 g, 80.5% yield). H¹NMR and LC/MASS data were the same as that in the above procedure.

Example 52a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile

 

In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (9 g, 97%).

Example 52b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester

 

In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).

Example 52c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid

 

In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 52b (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).

HRMS (ES⁺) m/z Calcd for C₂₃H₂₂Cl₂F₂N₂O₂+H [(M+H)⁺]: 467.1099, found: 467.1098.

Example 137 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide

 

In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with a dioxane solution (0.5 M) of ammonia (2 mL, 1 mmol), HATU (0.38 g, 1 mmol) and iPr₂NEt (0.6 g, 4.6 mmol) in CH₂Cl₂ at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide as a white solid (0.3 g, 75%).

HRMS (ES⁺) m/z Calcd for C₂₃H₂₃Cl₂F₂N₃O+H [(M+H)⁺]: 466.1259, found: 466.1259.

REFERENCES

1 Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development. By Ding, Qingjie; Zhang, Zhuming; Liu, Jin-Jun; Jiang, Nan; Zhang, Jing; Ross, Tina M.; Chu, Xin-Jie; Bartkovitz, David; Podlaski, Frank; Janson, Cheryl; et al  From Journal of Medicinal Chemistry (2013), 56(14), 5979-5983.

2. Pyrrolo[1,2-c]imidazolone derivatives as inhibitors of MDM2-p53 interactions and their preparation and use for the treatment of cancer. By Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Zhuming From U.S. Pat. Appl. Publ. (2012), US 20120065210 A1 20120315.

3. Pyrrolidine-2-carboxamide derivatives and their preparation and use as anticancer agents. By Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Zhuming. From U.S. Pat. Appl. Publ. (2012), US 20120010235 A1 20120112.

4. Preparation of substituted pyrrolidine-2-carboxamides as anticancer agents. By Bartkovitz, David Joseph; Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Jing; Zhang, Zhuming
From PCT Int. Appl. (2011), WO 2011098398 A1 20110818.

5. Preparation of substituted pyrrolidine-2-carboxamides as anticancer agents. By Bartkovitz, David Joseph; Chu, Xin-Jie; Ding, Qingjie; Jiang, Nan; Liu, Jin-Jun; Ross, Tina Morgan; Zhang, Jing; Zhang, Zhuming
From U.S. Pat. Appl. Publ. (2010), US 20100152190 A1 20100617.

6  B. Higgins, et al, Antitumor Activity of the MDM2 Antagonist RG7388, Mol Cancer Ther 2013;12(11 Suppl):B55

Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development
J Med Chem 2013, 46(14): 5979

find here

http://medcheminternational.blogspot.in/p/flozin-series.html

1 TOFOGLIFLOZIN
2 SERGLIFLOZIN
3 DAPAGLIFLOZIN
4 IPRAGLIFLOZIN
5 EMPAGLIFLOZIN
6 LUSEOGLIFLOZIN
7 REMOGLIFLOZIN
8 ERTUGLIFLOZIN
9 SOTAGLIFLOZON

DR ANTHONY

BLOGS………

ALL ABOUT DRUGS,

WORLD DRUG TRACKER,

MEDICINAL CHEM INTERNATIONAL,

DRUG SYN INTERNATIONAL

SCALEUP OF DRUGS,

MEDICINAL CHEM INTERNATIONAL,

DRUG SYN INTERNATIONAL,

SCALEUP OF DRUGS, 

EUREKAMOMENTS

GTK 137831

1218942-37-0

Genkyotex Sa INNOVATOR

1H-​Pyrazolo[4,​3-​c]​pyridine-​3,​6(2H,​5H)​-​dione, 2-​(2-​chlorophenyl)​-​4-​[3-​(dimethylamino)​phenyl]​-​5-​methyl-

C₂₁ H₁₉ Cl N₄ O₂

• 2-(2-Chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione

• 394.8601 mw
• in phase 2
• UNII-45II35329V

drug recently advancing to phase II trials is GKT-137831, a NOX1 and NOX4 inhibitor from GenKyoTex being developed for diabetic nephropathy, the leading cause of chronic kidney disease in the US and Europe.

GKT137831 is a selective NOX1/4 inhibitor in Phase II clinical development for the treatment of diabetic nephropathy, one of the complications of diabetes. It is a potent, NOX specific, small molecule with good oral availability.

Data from the Phase 1 programme to assess safety and exposure to single and multiple oral doses of GKT137831 was presented at the ASN Kidney week in San Diego in 2012. More than 100 subjects have been exposed to GKT137831 and the drug was well tolerated with no serious adverse events. In summer 2013, the FDA approved the IND to allow commencement of the Ph2 PoC trial of GKT137831 in diabetic nephropathy. Subsequently, approvals have been received from the competent authorities in Australia, Canada, Germany, Czech Republic and Poland. Enrollment to this study is ongoing and data is expected in H1 2015.

GKT137831 has been found to be effective in a range of preclinical disease models. This work has been conducted by leading academic collaborators in disease models of diabetic nephropathy, atherosclerosis, idiopathic pulmonary fibrosis, liver fibrosis and angiogenesis. GKT137831 has therefore, the potential to treat a wide range of important and poorly managed diseases

PATENT

WO 2010035221

http://www.google.com/patents/WO2010035221A1?cl=en

Scheme 1

R18 = Me Pr, iPr, Bu

_{G /}NH Toluen

Il

G₁ as described above G₁ = H (Ib) (Ia) VIII

Scheme 2

R¹⁸ = Me, Et, Pr, iPr, Bu

Toluene

G^

G₁ as described above G₁ = H (Ib) (Ia) VIII

Scheme 3

IV R¹⁹ = Me, Et, XII

R¹⁸ = Me, Et, Pr, iPr, Bu

G₁ = H, G₃ = CH₂NR²⁰R²¹ (Ia) XIV XIII

G₁, G₃ as described above (Ib)

Genkyotex’s GKT137831 Found to Reverse Fibrosis and Improve Survival in a Model of Persistent Lung Fibrosis

Genkyotex, the leading developer of selective NOX enzyme inhibitors, announced today the publication of data showing that GKT137831, a first in class NOX1 and 4 inhibitor, was able to reverse lung fibrosis associated with aging in a new model of idiopathic pulmonary fibrosis. Collaborators led by Professor Victor Thannickal at the University of Alabama at Birmingham published the results in the April 9, 2014 issue of Science Translational Medecine. Genkyotex is investigating GKT137831 in a Phase II trial in patients with diabetic nephropathy, another progressive fibrotic disease.

23 MARCH 2014

Keystone Symposia Conference 2014

March 26th, 2014. Today, Dr. Philippe Wiesel, CMO at Genkoytex presented preclinical data showing the beneficial effect of NOX1/4 inhibitor for the treatment of NASH (Non-Alcoholic Steatohepatitis)

Genkyotex held a breakfast meeting on the 28th on the role of NADPH oxidases in fibrosis

The presentations can be downloaded here

11 NOVEMBER 2013

Genkyotex NOX Inhibitor GKT137831 Successfully Shown to Halt Diabetic Kidney Disease

Genkyotex, the leading developer of selective NOX enzyme inhibitors, announced today that data from a group of academic collaborators demonstrated that NOX4 is an important driver of kidney injury in diabetes and that its novel, first in class NOX 1 and 4 inhibitor, GKT137831, has the potential to prevent or delay the development of diabetic nephropathy. Data were presented at the American Society of Nephrology’s Kidney Week 2013 in Atlanta and have been accepted for publication in the Journal of the American Society of Nephrology (JASN).

08 NOVEMBER 2013

Genkyotex attended the American Society of Nephrology Annual Meeting during Kidney week in Atlanta GA.

November 7^th to 10^th, 2013. Genkyotex attended the American Society of Nephrology Annual Meeting during Kidney week in Atlanta, GA. Ursula Ney, CEO, Philippe Wiesel, CMO, and the clinical team attended. Presentations from the Ancillary meeting held on 8^th November can be found here.

05 NOVEMBER 2013

Genkyotex Initiates Multinational Phase II Study with First in Class NOX Inhibitor GKT137831 in Diabetic Nephropathy Patients

Genkyotex, the leading developer of selective NOX enzyme inhibitors, announced today the initiation of a multinational Phase II clinical study of GKT137831 in patients with diabetic nephropathy. GKT137831 is a first in class inhibitor targeting NOX1 and NOX4 enzymes, both of which play a key role in the development of diabetic complications and chronic kidney disease in particular. In phase I studies in more than 100 subjects, GKT137831 was found to be safe and well tolerated when administered orally once and twice daily.

21 OCTOBER 2013

Genkyotex Collaborators Elucidate Role of NOX4 in Osteoporosis

Genkyotex, the leading developer of NOX enzyme inhibitors, announced today that a group of collaborators have discovered a link between the enzyme NOX4 and development of osteoporosis. These results, published online in the Journal of Clinical Investigationdoi:10.1172/JCI67603), indicate that inhibitors of NOX4, such as GKT137831 developed by Genkyotex could lead to a novel way of treating patients with osteoporosis. GKT137831, the first in class NOX1 and 4 inhibitor, has shown favorable safety and pharmacokinetic profiles in Phase I studies, and following a recently FDA approved IND will enter a Phase II trial in patients with diabetic nephropathy.

08 SEPTEMBER 2013

Genkyotex Receives FDA IND Approval for Phase II Clinical Study with First in Class NOX Inhibitor GKT137831

Genkyotex, the leading developer of NOX enzyme inhibitors, announced today that the U.S. Food and Drug Administration has approved the company’s Investigational New Drug (IND) application to begin a Phase II clinical study of GKT137831 in patients with diabetic nephropathy. GKT137831 is a first in class inhibitor targeting NOX1 and NOX4 enzymes. Enrollment of patients into the multinational Phase II study is expected to begin during Q4, 2013.

07 MAY 2013

Genkyotex Collaborators Discover Role of NOX in Development of Atherosclerosis in Diabetic Mice

Genkyotex, the leading developer of NOX inhibitors to treat oxygen-radical mediated diseases, announced today that its collaborators at the Baker IDI Heart & Diabetes Research Institute, Melbourne (Australia) and Maastricht University (The Netherlands) have elucidated the role of NOX1 in causing atherosclerosis in diabetic mice. The researchers found that NOX1 produces toxic amounts of oxygen radicals in the wall of blood vessels, which along with other inflammatory chemicals led to atherosclerotic plaque development. The researchers also demonstrated that Genkyotex’s selective NOX1 and 4 inhibitor, GKT137831, was able to dramatically reduce development of atherosclerosis. The research and accompanying editorial from Dr. David G. Harrison from Vanderbilt University was published in May 7^th issue ofCirculation.

17 DECEMBER 2012

Genkyotex Issued U.S. Patent Covering Parent NOX Inhibitor Chemical Series

Genkyotex, the leading developer of NOX inhibitors to treat oxygen-radical mediated diseases, today announced that the United States Patent and Trademark Office (USPTO) has issued a Notice of Allowance for U.S. Patent Application No. 12/532,336, titled “pyrazolo pyridine derivatives as NADPH oxidase inhibitors”.

02 NOVEMBER 2012

Genkyotex’s NOX Inhibitor GKT137831 Phase I Data Presented at Kidney Week 2012

Genkyotex, the leading developer of NOX inhibitors to treat oxygen-radical mediated diseases, announced today that Phase I studies have demonstrated excellent safety and tolerability following single and multiple oral doses of GKT137831, the first in class NOX 1 and 4 inhibitor. In addition, GKT137831 demonstrated a favourable pharmacokinetic profile in these subjects.

15 OCTOBER 2012

Genkyotex’s First in Class NOX Inhibitor GKT137831 to be Presented at Kidney Week

Genkyotex will present data from single and multiple dose Phase I studies with the NOX 1 and 4 inhibitor, GKT137831, at Kidney Week 2012 (San Diego, October 30 – November 4). The Phase I data will be presented on Friday, November 2, 2012, 10.00 AM -12.00 PM (PosterBoard# FR-PO831; Abstract# 2279).

08 AUGUST 2012

Genkyotex’s Lead NOX Inhibitor GKT137831 Demonstrates Activity in Models of Liver Fibrosis

Genkyotex, with collaborator Professor David Brenner, M.D., Dean, School of Medicine, University of California San Diego, has published data online in Hepatology regarding its lead (NOX) inhibitor, GKT137831, in models of liver fibrosis, a scarring process associated with chronic liver disease that can lead to loss of liver function. The data demonstrates the specificity of GKT137831 and its ability to attenuate development of fibrosis in the liver and production of reactive oxygen species (ROS) in two models of disease, as well as inhibiting messenger RNA expression of fibrotic and NOX genes.

09 JULY 2012

Genkyotex closes CHF25 million (USD26 million) extension to its Series C financing.

Investors in the Series C round, including Eclosion, Edmond de Rothschild Investment Partners, Vesalius Biocapital Partners, MP Healthcare Venture, all participated in the financing extension. The proceeds will be used to advance clinical development of Genkyotex’s lead compound, the NOX1/4 inhibitor GKT137831, through Phase II development for the treatment of diabetic nephropathy.

22 JUNE 2012

Genkyotex Announces Successful Phase Ia Data with First in Class NOX Inhibitor GKT137831

Diabetic Nephropathy First Target Indication for NOX1/4 Inhibitor

31 OCTOBER 2011

GenKyoTex Starts Phase I Trial with First in Class NOX inhibitor GKT137831

GenKyoTex, the leading developer of NOX inhibitors to treat oxygen-radical mediated diseases, announced today that a Phase I study has been initiated with GKT137831, a first in class dual inhibitor of NOX1 and NOX4 enzymes.

GenKyoTex raises CHF 18 million in a Series C Venture Financing to develop NOX enzyme inhibitors.

Appoints New Management Team & Board

02 DECEMBER 2010

GKT137831 granted Orphan Drug status for Idiopathic Pulmonary Fibrosis by the EC (EMEA)

Genkyotex announced today that its lead clinical candidate GKT137831 has been granted the orphan drug status by the European Commission for the treatment of idiopathic pulmonoary fibrosis.

27 SEPTEMBER 2010

FDA granting Genkyotex Orphan Drug Designation of GKT137831 for IPF

Genkyotex announced today having received a letter from FDA dated of 21st September 2010, granting Genkyotex Orphan Drug Designation of GKT137831 for the treatment of Idiopathic Pulmonary Fibrosis (IPF).