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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Sep 012015
 

 

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WO2015124764

ERREGIERRE S.P.A. [IT/IT]; Via Francesco Baracca, 19 I-24060 San Paolo D’argon (IT)

Erregierre SpA

DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE”

Abstract

A novel process is described for the production of Dabigatran etexilate mesylate, a 5 compound having the following structural formula: and two novel intermediates of said process.

(WO2015124764) SYNTHESIS PROCESS OF DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE click herefor patent

Dabigatran etexilate mesylate is an active substance developed by Boehringer

Ingelheim and marketed under the name Pradaxa® in the form of tablets for oral administration; Dabigatran etexilate mesylate acts as direct inhibitor of thrombin (Factor I la) and is used as an anticoagulant, for example, for preventing strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that could form following surgery.

Dabigatran etexilate mesylate is the INN name of the compound 3-({2-[(4-{Amino-[(E)-hexyloxycarbonylimino]-methyl}-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate methanesulphonate, having the following structural formula:

The family of compounds to which Dabigatran etexilate belongs was described for the first time in patent US 6,087,380, which also reports possible synthesis pathways.

The preparation of polymorphs of Dabigatran etexilate or Dabigatran etexilate mesylate is described in patent applications US 2006/0276513 A1 , WO 2012/027543 A1 , WO 2008/059029 A2, WO 2013/124385 A2, WO 2013/124749 A1 , WO 2013/1 1 1 163 A2 and WO 2013/144903 A1 , while patent applications WO 2012/044595 A1 , US 2006/0247278 A1 , US 2009/0042948 A2, US 2010/0087488 A1 and WO 2012/077136 A2 describe salts of these compounds.

One of the objects of the invention is to provide an alternative process for the preparation of Dabigatran etexilate mesylate and two novel intermediates of the process.

These objects are achieved with the present invention, which, in a first aspect thereof, relates to a process for the production of Dabigatran etexilate mesylate, comprising the following steps:

a) reacting 4-methylamino-3-nitrobenzoic acid (I) with thionyl chloride to give 4- methylamino-3-nitrobenzoyl chloride hydrochloride (II):

(I) (ID

b) reacting compound (II) with 3-(2-pyridylamino) ethyl propanoate (III) to give the compound 3-[(4-methylamino-3-nitro-benzoyl)-pyridyn-2-yl-amino]-ethyl propanoate (IV):

(II) (IV)

reducing compound (IV) with hydrogen to 3-[(3-amino-4-methyl benzoyl)-pyridin-2-yl-amino]ethyl propanoate (V):

(IV) (V)

d) reacting N-(4-cyanophenyl)glycine (VI) with 1 ,1 -carbonyldiimidazole (CDI) to give 4-(2-imidazol-1 -yl-2-oxo-ethylamino)-benzonitrile (VII):

(VI) (VII)

e) reacting compound (VII) with compound (V) obtained in step c) to give one of compounds 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino- benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (VIII) and 3-[(3-amino-4-{[(2- (4-cyano-phenylamino)-acetyl]-methylamino}-benzoyl)-pyridin-2-yl- amino]ethyl propanoate (IX), or a mixture of the two compounds (VIII) and (IX):

f) transforming, through treatment with acetic acid, compounds (VIII) or (IX) or the mixture thereof into the compound 3-({2-[(4-cyano-phenylamino)-methyl]- 1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate (X), and then treating compound (X) with hydrochloric or nitric acid to form the corresponding salt (XI):

CHsCOOH

[(VIII) ; (IX)]

wherein A is a chlorine or nitrate anion;

liberating in solution compound (X) from salt (XI), and reacting compound (X) in solution with ethyl alcohol in the presence of hydrochloric acid and 2,2,2-trifluoroethanol to give the compound 3-({2-[(4-ethoxycarbonimidoyl-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate hydrochloride (XII):

reacting compound (XII) with ammonium carbonate to form compound Dabigatran ethyl ester (XIII):

reacting compound (XIII) with maleic acid to produce the maleate salt thereof (XI 11 ‘) and isolating the latter:

j) reacting maleate salt (XI 11 ‘) with hexyl chloroformate to give compound Dabigatran etexilate (XIV :

hexyl chloroformate

k) reacting compound (XIV) with methanesulfonic acid to give the salt Dabigatran etexilate mesylate:

a gatran etex ate mesy ate

EXAMPLE 12

Preparation of Dabigatran etexilate mesylate (step k).

All the Dabigatran etexilate obtained in Example 1 1 (4.7 kg; 7.49 moles) is loaded into a reactor along with 28.2 kg of acetone and the mass is heated at 50-60 °C until a complete solution is obtained; it is then filtered to remove suspended impurities. The filtered solution is brought to 28-32 °C. Separately, a second solution is prepared by dissolving 0.705 kg (7.34 moles) of methanesulfonic acid in 4.7 kg of acetone; the second solution is cooled down to 0-10 °C. The second solution is poured into the Dabigatran etexilate solution during 30 minutes, while maintaining the temperature of the resulting solution at 28-32 °C with cooling. The salt of the title is formed. The mass is maintained at 28-32 °C for 2 hours, then cooled to 18-23 °C to complete precipitation and the system is maintained at this temperature for 2 hours; lastly, centrifugation takes place, washing the precipitate with 5 kg of acetone. The precipitate is dried at 60 °C.

4.88 kg of Dabigatran etexilate mesylate, equal to 6.74 moles of compound, are obtained, with a yield in this step of 90%.

 

EXAMPLE 13

0.5 g of the crystalline compound (XIV) obtained in Example 1 1 are ground thoroughly and loaded into the sample holder of a Rigaku Miniflex diffractometer with copper anode.

The diffractogram shown in Figure 1 is obtained; a comparison with the XRPD data of the known Dabigatran etexilate polymorphs allows to verify that the polymorph of Example 1 1 is novel.

EXAMPLE 14

0.7 g of the crystalline compound (XIV) obtained in Example 1 1 are loaded into

the sample holder of a Perkin-Elmer DSC 6 calorimeter, performing a scan from ambient T to 350 °C at a rate of 10 °C/min in nitrogen atmosphere. The graph of the test is shown in Figure 2, and shows three endothermic phenomena with peaks at 83.0-85.0 °C, 104.0-104.2 °C and 129.9 °C; events linked to the thermal decomposition of the compound are evident at about 200 °C.

Figure 1 is an XRPD spectrum of the novel polymorph of Dabigatran etexilate of the invention;

Figure 2 is the graph of a DSC test on the novel polymorph of Dabigatran etexilate of the invention.

 

 

ERREGIERRE S.p.A

Pietro Carlo Gargani, CEO and president of ERREGIERRE S.p.A., oversees a company with a firm commitment to serving its customers innovative products

ERREGIERRE was founded by two entrepreneurs in 1974 in San Paolo d’Argon, in the northern Italian region of Bergamo. It lodged one of its first major …

San Paolo d'Argon

 

 

 

 

 

 

 

 

 

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Aug 242015
 

 

Figure US20050043334A1-20050224-C00061

 

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

 

ASLAN001 , Varlitinib

C22H19ClN6O2S

Molecular Weight: 466.94

Elemental Analysis: C, 56.59; H, 4.10; Cl, 7.59; N, 18.00; O, 6.85; S, 6.87

CAS: 845272-21-1 (Varlitinib); 1146629-86-8 (Varlitinib tosylate).

ASLAN001; ASLAN-001; ASLAN 001; AR 00334543; ARRY-334543; ARRY334543; ARRY-543; ARRY543; ARRY 543.

(R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

(R)-4-[[3-Chloro-4-[(thiazol-2-yl)methoxy]phenyl]amino]-6-[(4-methyl-4,5-dihydrooxazol-2-yl)amino]quinazoline

4,​6-​Quinazolinediamine, N4-​[3-​chloro-​4-​(2-​thiazolylmethoxy)​phenyl]​-​N6-​[(4R)​-​4,​5-​dihydro-​4-​methyl-​2-​oxazolyl]​-

ASLAN Pharmaceuticals, a Singapore-based drugmaker, announced The Food and Drug Administration (FDA) gave an orphan drug designation on August 13 to its pan-HER inhibitor ASLAN001 (varlitinib), a drug candidate created to treat a destructive form of bile duct cancer called cholangiocarcinoma that has no known cure.  ………http://www.dddmag.com/news/2015/08/aslan-pharmaceuticals-gains-orphan-designation-rare-cancer-drug

Current developer: Array Biopharma Inc,

Varlitinib, also known as ARRY-543 and ASLAN001, is an orally bioavailable inhibitor of the epidermal growth factor receptor family with potential antineoplastic activity.

Varlitinib (ASLAN-001) is an oncolytic drug in phase II clinical trials at ASLAN Pharmaceuticals for the treatment of gastric cancer and for the treatment of metastatic breast cancer in combination with capecitabine. Clinical development is also ongoing for the treatment of solid tumors in combination with cisplatin/FU and cisplatin/capecitabine. The product had been in phase I/II clinical trials at Array BioPharma for the treatment of patients with advanced pancreatic cancer. Phase II clinical trials had also been ongoing for the treatment of solid tumors. No recent development has been reported for this research

Varlitinib selectively and reversibly binds to both EGFR (ErbB-1) and Her-2/neu (ErbB-2) and prevents their phosphorylation and activation, which may result in inhibition of the associated signal transduction pathways, inhibition of cellular proliferation and cell death. EGFR and Her-2 play important roles in cell proliferation and differentiation and are upregulated in various human tumor cell types. Due to the dual inhibition of both EGFR and Her-2, this agent may be therapeutically more effective than agents that inhibit EGFR or Her-2 alone.

The drug is a dual inhibitor of the ErB-2 and EGFR receptor kinases, both of which have been shown to stimulate aberrant growth, prolong survival and promote differentiation of many tumor types. The compound behaves as a reversible ATP-competitive inhibitor with nanomolar potency both in vitro and in cell-based proliferation assays.

In 2011, the compound was licensed to Aslan Pharmaceuticals by Array BioPharma worldwide for the treatment of solid tumors, initially targeting patients with gastric cancer through a development program conducted in Asia.

In 2015, orphan drug designation was assigned to the compound in the U.S. for the treatment of cholangiocarcinoma.

SEE NMR ………….http://www.medkoo.com/Product-Data/Varlitinib/Varlitinib-QC-KB20121128web.pdf

……………..

https://www.google.co.in/patents/US20050043334

Example 52

Figure US20050043334A1-20050224-C00061

 

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (R)-2-aminopropan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 53

Figure US20050043334A1-20050224-C00062

 

(S)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (S)-2-amino-propan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

………………

 

PATENT

http://www.google.co.in/patents/WO2005016346A1?cl=en

Example 52

 

Figure imgf000056_0002

R VN4-r3-Chloro-4-(thiazol-2-v-metho-xy)-phenyll-N6-(4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoUne-4,6-diamine

[00194] Prepared using (R)-2-aminopropan- 1 -ol. MS APCI (+) m/z 467, 469

(M+l, CI pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, IH), 8.47 (s, IH), 8.09 (s, IH), 7.86 (d, IH), 7.81 (d, IH), 7.77 (d, IH), 7.69 (m, 3H), 7.32 (d, IH), 7.02 (s, IH), 5.54 (s, 2H), 4.47 (m, IH), 3.99 (m, IH), 3.90 (m, IH), 1.18 (d, 3H). Example 53

 

Figure imgf000057_0001

(S)-N4-|3-Chloro-4- thiazol-2-ylmethoxy)-phenyll-N6-(4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoline-4,6-diamine [00195] Prepared using (S)-2-amino-propan- 1 -ol. MS APCI (+) m z 467, 469

(M+l, CI pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, IH), 8.47 (s, IH), 8.09 (s, IH), 7.86 (d, IH), 7.81 (d, IH), 7.77 (d, IH), 7.69 (m, 3H), 7.32 (d, IH), 7.02 (s, IH), 5.54 (s, 2H), 4.47 (m, IH), 3.99 (m, IH), 3.90 (m, IH), 1.18 (d, 3H).

 

………

CAUTION a very similar molecule but not same 

C2NOTE……..METHYL NEXT TO OXYGEN ATOM

Design, Synthesis and Bioactivities Evaluation of Novel Quinazoline Analogs Containing Oxazole Units

A novel type of quinazoline derivatives, which were designed by the combination of quinazoline as the backbone and oxazole scaffold as the substituent, have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency. Compound 12b demonstrated the most potent inhibitory activity (IC50=0.95 µmol/L for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR, 2D NMR spectra, IR spectra and MS spectra.

12c: Employing the same method as above, compound 12c was prepared and the amino alcohol was (S)-2-amino-propan-1-ol. Yellow solid, yield 52 %. m.p. 243-244 °C; [α] 20D =﹢22.5 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.54 (s, 1 H), 8.46 (s, 1 H), 8.06 (s, 2 H), 7.85 (d, 2 H, J=3.3 Hz), 7.79 (d, 2 H, J=3.3 Hz), 7.75 (d, 1 H, J=8.9 Hz), 7.64 (d, 1 H, J=8.3 Hz), 7.30 (d, 1 H, J=9.0 Hz), 5.54 (s, 2 H), 4.76 (m, 1 H), 3.72 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.15 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.2 (M+H).

12d: Employing the same method as above, compound 12d was prepared and the amino alcohol was (R)-2-amino-propan-1-ol. Yellow solid, yield 60%. m.p. 242-243 °C; [α] 20D = ﹣22.3 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.52 (s, 1 H), 8.80 (s, 1 H), 8.52 (dd, 1 H, J=2.7 Hz, J=8.9 Hz), 8.45 (s, 1 H), 8.30 (s, 1 H), 8.07 (s, 1 H), 7.85 (d, 1 H, J=3.2 Hz), 7.79 (d, 1 H, J=3.2 Hz), 7.75 (s, 1 H), 7.63 (d, 1 H, J=8.2 Hz), 7.31 (d, 1 H, J=9.0 Hz), 5.53 (s, 2 H), 4.76 (m, 1 H), 3.81 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.2 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.20 (M+H).

The above paper allows you to synthesize the key amino int 11 ………N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

this can be applied to varlitinib till int  11

C1

 

6-Nitro-4-hydroxyquinazoline (3)

2-amino-5-nitrobenzoic acid (5.46 g, 30 mmol) was added to a 250 mL flask equipped with a reflux condenser. Then 50 mL formamide was added. The mixture was heated with vigorous stirring at 160 °C for 3 h. After cooling the solution was poured in ice-water to give 3 in almost pure form (Yellow solid 4.70 g, yield 82.0%). m.p. 317-318 °C; 1 H NMR (DMSO-d6): δ 12.74 (1 H, s, OH, exchangeable), 8.78 (1 H, d, J=2.4 Hz), 8.53 (1 H, dd, J=2.6 Hz, 9.0 Hz), 8.30 (s, 1 H), 7.84 (1 H, d, J=9.0 Hz); 13C NMR (DMSO-d6) δ: 160.1, 152.9, 148.9, 145.0, 129.1, 128.3, 122.7, 121.9. IR (KBr) ν: 3172, 3046, 2879, 1674, 1615, 1577, 1514, 1491, 1469, 1343, 1289, 1242, 1167, 1112, 928, 920, 901, 803, 753, 630, 574, 531 cm-1. Anal. calcd for C8H5N3O3: C 50.27, H 2.64, N 21.98; found C 50.30, H 2.65, N 21.96; MS (ESI) m/z: 189.97 (M-H).

nmr1

nmr113C NMR OF 3 IN DMSOD6

IR

 

nmr1

4-chloro-6-Nitroquinazoline (4)

In a 100 mL flask equipped with a reflux condenser, 6-nitroquinazolin-4-one (2.86 g, 15 mmol) and thionyl chloride (SOCl2) 25 mL were added. The mixture was heated under reflux with vigorous stirring for 2 h. After the solution was clear, the reaction mixture was heated for another 2 h. Then, 150 mL of ice MeOH was dropped into it carefully, the mixture was extracted with CH2Cl2. The organic layer was S3 dried under MgSO4, filtered and the solvent removed to give 4-chloro-6-nitroquinazoline (4). Yellow solid 2.45 g, yield 78%. m.p. 134-135 °C; 1 H NMR (DMSO-d6): δ 8.80 (1 H, d, J=3.0 Hz), 8.54(1 H, dd, J=2.7 Hz, 9.0 Hz), 8.35(s, 1 H), 7.87 (1 H, d, J= 9.0 Hz); 13C NMR (DMSO-d6) δ: 160.0, 152.5, 149.1, 145.1, 128.7, 128.4, 122.7, 122.0. IR (KBr) ν: 3431, 3082, 3038, 2664, 2613, 2567, 1724, 1685, 1676, 1646, 1617, 1578, 1526, 1468, 1359, 1346, 1269 cm-1. Anal. calcd for C8H4N3O2Cl: C 45.84, H 1.92, N 20.05, O 15.27; found C 45.81, H 1.97, N 20.02, O 15.21; MS (ESI) m/z: 207.96 (M-H).

 

nmr14 nmr dmsod6

 

 

13C NMR OF4 IN DMSOD6

nmr1

IR

nmr1

Thiazol-2-yl-methano1 (6)

Sodium borohydride (16.0 g, 140 mmol) was added to a stirred solution of thiazole-2-carbaldehyde (24.2 g, 214 mmol) in MeOH (400 mL) at 0 °C . The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was quenched by the addition of water and the organics were removed by concentration. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were dried under Na2SO4 and concentrated to give thiazol-2-yl-methano1 (23.39 g, 95%). bp:75-76 °C (0.2 mmHg) [lit.[19] bp:70-80 °C (0.2 mmHg)]; m. p. 63-64 °C. 1 H NMR (CDCl3) δ 4.91 (s, 2 H), 5.1(br, l H), 7.28(d, 1 H, J=3.2 Hz), 7.68 (d, 1 H, J=2.9 Hz). IR (KBr) ν: 3135, 3099, 3082, 2814, 1509, 1446, 1351, 1189, 1149, 1073, 1050, 977, 775, 745, 613, 603 cm-1. Anal. calcd for C4H5NOS: C 41.72, H 4.38, N 12.16; found C 41.74, H 4.33, N 12.18; MS (ESI) m/z: 116.11 (M+H).

nmr16 in dmsod6 1H NMR

 

nmr1

2-((2-Chloro-4-nitrophenoxy)methyl)thiazole (8)

2-(2-chloro-4-nitro-phenoxymethy1)-thiazole was prepared by adding thiazol-2-yl-methanol (5.48 g, 47.65 mmol) to a slurry of sodium hydride (2.42 g of a 60% dispersion in oil, 60.5 mmol) in THF (50 ml) at 0 °C After several minutes, 2-chloro-1-fluoro- 4-nitro-benzene (7.58 g, 43.60 mmol) was added and the reaction mixture warmed to room temperature. The reaction mixture was stirred at room temperature for 3 h, and 60 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into 300 mL water. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(2- chloro-4-nitrophenoxymethy1)-thiazole (11.06 g, 86%) which was used in next step without further purification. m.p. 170-171 °C; 1 H NMR (DMSO-d6): δ 8.35 (1 H, d, J=2.8 Hz), 8.25 (1 H, dd, J=2.8 Hz, 9.15 Hz), 7.87 (1 H, d, J=3.3 Hz), 7.83(1 H, d, J=3.3 Hz), 7.54 (1 H, d, J=9.2 Hz), 5.73(s, 1 H); 13C NMR (DMSO-d6) δ: 164.2, 158.5, 143.2, 141.7, 125.9, 124.9, 122.4, 122.2, 114.6, 68.4; IR (KBr) ν: 3112, 3009, 1587, 1509, 1500, 1354, 1319, 1284, 1255, 1154, 1125, 1054, 1006, 894, 780, 746, 728 cm-1. Anal. calcd for C10H7N2O3SCl: C 44.37, H 2.61, N 10.35, O 17.73; found C 44.31, H 2.67, N 10.29; MS (ESI) m/z: 268.89 (M-H).

nmr11H NMR 8 DMSOD6

13C NMR OF 8 IN DMSOD6

nmr1

nmr1

3-Chloro-4-(thiazol-2-ylmethoxy)aniline (9)

In a flask equipped with a reflux condenser, the compound 8 15.00 g (55.6 mmol), reduced zinc powder 14.44 g (222.0 mmo1, 4 eq), saturated ammonia chloride (5 mL) and methanol (100 mL) were mixed. The mixture was stirred at a temperature of 40 °C for 1.5 h. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 13.21 g, yield 99%. m.p. 60-61 °C; 1 H NMR (DMSO-d6): δ 7.80 (1 H, d, J=3.3 Hz), 7.75 (1 H, d, J=3.3 Hz), 6.96 (1 H, d, J=8.8 Hz), 6.64(1 H, d, J=2.7 Hz), 6.46 (1 H, dd, J=2.7 Hz, J=8.7 Hz), 5.30 (s, 2 H), 5.04 (s, 2 H, NH2, exchangeable); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.80, 123.1, 121.5, 117.7, 115.2, 113.6, 69.1. IR (KBr) ν: 3322, 3192, 3112, 1607, 1499, 1457, 1436, 1291, 1274, 1221, 1191, 1144, 1057, 1027, 857, 797, 767, 733, 584 cm-1. Anal. calcd for C10H9N2OSCl: C 49.90, H 3.77, N 11.64, O 6.65; found C 49.95, H 3.76, N 11.66, O 6.60; MS (ESI) m/z: 239.01 (M-H).

nmr11H NMR DMSOD6 OF 9

 

nmr113C NMR OF 9 IN DMSOD6

 

nmr1

N-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-6-nitro- quinazolin-4-amine(10)

In a flask equipped with a reflux condenser, 6-nitro-4-chloro- quinazoline 8.0 g (38.3 mmol) and 3-Chloro-4-(thiazol-2-ylmethoxy)aniline 8.9 g (37.0 mmol) were dissolved into 150 mL of THF, and the solution was refluxed for 3 h.Then a lot of yellow solid was deposited. Then it was filtered affording to yellow solid 12.8 g, yield 81%. m.p. 183-184 °C (decompose); 1 H NMR (DMSO-d6): δ 11.97(s, 1 H, exchangeable), 9.84 (s, 1 H), 9.00 (s, 1 H), 8.76 (1 H, d, J=9.1 Hz), 8.12-8.14 (m, 1 H), 7.94 (1 H, d, J=2.3 Hz), 7.87 (1 H, d, J=3.2 Hz), 7.81 (1 H, d, J=3.2 Hz), 7.44 (1 H, d, J=9.0 Hz), 7.69 (1 H, dd, J=2.5 Hz, J=8.9 Hz), 5.61 (s, 2 H); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.8, 123.1, 121.5, 117.7, 115.2, 113.7, 69.1. IR (KBr) ν: 3442, 3100, 1636, 1618, 1570, 1552, 1523, 1492, 1442, 1400, 1377, 1344, 1301, 1267, 1069, 805 cm-1. Anal. calcd for C18H12N5O3SCl: C 52.24, H 2.92, N 16.92, O 11.60; found C 52.26, H 2.93, N 16.96, O 11.58; MS (ESI) m/z: 412.84 (M-H).

nmr11H NMR DMSOD6 OF 10

 

nmr113C NMR OF 10 IN DMSOD6

 

nmr1

N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

In a flask equipped with a reflux condenser, the compound 10 5.00 g (12.1 mmol), reduced zinc powder 3.2 g (48.5 mmo1, 4 eq), saturated ammonia chloride (3 mL) and methanol (60 mL) were mixed. The mixture was stirred at room temperature for 30 min. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 4.58 g, yield 98%. m.p. 197-198 °C (decompose); 1 H S4 NMR (DMSO-d6): δ 9.33(s, 1 H, exchangeable), 8.31 (s, 1 H), 8.05 (d, 1 H, J=2.6 Hz), 7.85 (d, 1 H, J=3.3 Hz), 7.79 (1 H, d, J=3.3 Hz), 7.73 (1 H, dd, J=2.5 Hz, J=9.0 Hz), 7.51 (1 H, d, J=8.9 Hz), 7.30 (1 H, d, J=2.4 Hz), 7.29 (1 H, d, J=4.7 Hz), 7.23 (1 H, dd, J=2.3 Hz, J=8.9 Hz), 5.57 (s, 2 H, exchangeable), 5.52 (s, 2 H); 13C NMR (DMSO-d6) δ: 165.9, 155.8, 149.7, 148.5, 147.3, 142.6, 142.5, 134.6, 128.7, 123.6, 123.2, 121.4, 121.3, 121.1, 116.5, 114. 7, 100.9, 67.8. IR (KBr) ν: 3443, 3358, 3211, 3100, 1631, 1596, 1577, 1560, 1530, 1494, 1431, 1383, 1217, 910 cm-1. Anal. calcd for C18H14N5OSCl: C 56.32, H 3.68, N 18.24, O 4.17; found C 56.34, H 3.70, N 18.22, O 4.14; MS (ESI) m/z: 382.66 (M-H).

nmr111 1HNMR DMSOD6

 

nmr113C NMR OF 11 IN DMSOD6

nmr1

Construction finally as per patent ……….US20050043334

Treatment of N4-[3-chloro-4-(thiazol-2-ylmethoxy)phenyl]quinazoline-4,6-diamine (11) with 1,1′-thiocarbonyldiimidazole , followed by condensation with 2(R)-amino-1-propanol  in THF/CH2Cl2 affords thiourea derivative , which finally undergoes cyclization in the presence of TsCl and NaOH in THF/H2O to furnish varlitinib .

nmr2

 

  1. ASLAN Pharmaceuticals
  2. Address: 10 Bukit Pasoh Rd, Singapore 089824
    Phone:+65 6222 4235

Map of ASLAN Pharmaceuticals

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carl fith

Mr Carl Firth, CEO, Aslan Pharmaceuticals, Singapore (left) and Mr Dan Devine, CEO, Patrys, Australia (right)

///////ASLAN001, varlitinib, ASLAN Pharmaceuticals,  Orphan Designation, ARRY-534, ARRY-334543 , PHASE 2, ORPHAN DRUG DESIGNATION, array

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Aug 202015
 

 

The title compound was synthesized by opening the epoxide of benzyl 2,3-anhydro-β-L-ribopyranoside with 3,4,5-trimethoxybenzylamine (Scheme 1). The three broad peaks in the 1 H-NMR due to one –NH at δ 2.20 ppm, and two –OH at δ 5.00 ppm and 5.26 ppm, disappeared upon D2O exchange. The chemical shifts of the sugar hydrogens, along with COSY and HMBC were used to assign C7, C1″, C2″, C3″, C4″, C5″ and C7′ atoms. The coupling constant between H-1″ and H-2″ on the sugar ring was found to be 7.98 Hz, indicating that the protons at the 1- and 2-positions were in axial positions and that the molecule exists in solution in 1 C4 conformation (Scheme 1). The coupling constant was similar to related analogs [14,15]. The coupling constant between H-2” and H-3” was found to be 9.12 Hz. The coupling constant between the pro-R and pro-S hydrogens on C7 was found to be 12.24 Hz. The 13C had five pairs of atoms with the same chemical shift. There were three pairs of carbon atoms on the 3,4,5-trimethoxybenzyl ring ( two ortho- and two meta-, and two equivalent methoxy groups) that had similar chemical shifts. On the benzyl group, chemical shifts of two pairs of carbon atoms (two ortho- and two meta-) were observed.

PREPN

molbank-2013-M793.pdf

Benzyl 2,3-anhydro-β-L-ribopyranoside (1) was obtained from L-arabinose in five steps using a previously reported synthetic route [14]. To a mixture of benzyl 2,3-anhydro-β-L-ribopyranoside 1 (0.15 g, 0.68 mmol) and 3,4,5-trimethoxybenzylamine 2 (180 mL, 0.91 mmol) was added ethyl alcohol (3 mL). After refluxing the mixture for 16 h and cooling at room temperature for 12 h, white crystals (needles) formed. Recrystallization from hexane/ethyl acetate mixture (3:2, v/v) produced a pure compound (0.206 g, 72%,

m.p. 158–160 °C);

[α]D 26 +50° (c 1, CHCl3).

C22H29NO7 Calculated: C 62.99; H, 6.97; N, 3.34; O, 26.70 Found: C 62.89; H, 7.01; N, 3.29; O, 26.65

molbank-2013-M793.pdf

1 H-NMR (400 MHz, Me2SO-d6)

δ 2.20 (bs, 1H, –NH),

2.41 (t, J = 9.12, 7.98 Hz, 1H, H-3),

3.21 (m, 2H),

3.45 (bs, 1H),

3.65 (s, 3H, –OCH3),

3.75 (b, 1H),

3.80 (s, 6H, 2-OCH3),

3.97 (m, 2H),

4.31 (d, J = 7.98 Hz, 1H, H-1),

4.61 (d, J = 12.24 Hz, 1H, –OCH2Ar),

4.80 (d, J = 12.24 Hz, 1H, –OCH2Ar),

5.00 (bs, 1H, –OH), 5.26 (bs, 1H, –OH).

 

molbank-2013-M793.pdf

13C-NMR (100 MHz, Me2SO-d6),

δ 53.22 (C-7′),

56.61 (–OCH3),

60.81 (–OCH3),

65.11 (C-3″),

67.37 (C-5″),

70.14 (C-4″),

70.41 (C-7),

73.00 (C-2″),

103.90 (C-1″),

105.80, 128.23, 128.40, 129.00, 136.80, 138.23, 138.93, 153.52.

 

molbank-CHEM

 Nmr predict

Molbank 20132013(1), M793; doi:10.3390/M793

Benzyl 3-deoxy-3-(3,4,5-trimethoxybenzylamino)-β-L-xylopyranoside

Department of Chemistry, Pennsylvania State University-York, 1031 Edgecomb Avenue, York, PA 17403, USA

//////epoxide ring-opening3,4,5-trimethoxybenzylaminebenzyl 2,3-anhydro-β-L-ribopyranoside

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 LUSUTROMBOPAG.png

Lusutrombopag

(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid

(S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid

(2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylacrylic acid

UNII 6LL5JFU42F,  CAS 1110766-97-6,

D10476, MW591.546 , [US2010267783], MF C29H32Cl2N2O5S, S-888711

Shionogi & Co., Ltd.塩野義製薬株式会社 INNOVATOR

Optically active compound (C-3B)  Melting point: 142-145°C………….EP2184279B1

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)………….EP2184279B1

Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C), NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)………EP2184279B1

 

Thrombopoietin receptor agonist, Oral thrombopoietin (TPO) mimetic

  • 24 Mar 2015 Shionogi plans a phase III trial in Thrombocytopenia (in patients with chronic liver disease) in USA (NCT02389621)
  • 31 Dec 2014 Preregistration for Thrombocytopenia in Japan (PO)
  • 08 Nov 2013 Phase II development is ongoing in the US and the Europe

Process for preparing intermediates of an optically active 1,3-thiazole containing thrombopoietin receptor agonist  Also claims crystalline forms of lusutrombopag intermediates and a process for preparing lusutrombopag. Shionogi is developing lusutrombopag, a small-molecule thrombopoietin mimetic, as an oral tablet formulation for treating thrombocytopenia.

In December 2014, an NDA was submitted in Japan. In May 2015, the drug was listed as being in phase III development for thrombocytopenia in the US and Europe.

  

 

The lusutrombopag, a low molecular-human thrombopoietin receptor agonist, its chemical formula, “(E) -3- [2,6-Dichloro-4- [4- [3 – [(S) -1-hexyloxyethyl] – 2-methoxyphenyl] -thiazol- 2-ylcarbamoyl] -phenyl] is a -2-methylacrylic acid “. lusutrombopag is represented by the following chemical structural formula.

 

Figure JPOXMLDOC01-appb-C000001

 

Eltrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000002

 

Avatrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000003

 

 

Totrombopag choline is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000004
C 3B IS THE COMPD OF ROT (-) AND S, E  FORM
Figure imgb0009
      Example 2 Synthesis of (R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3A) (not included in the present invention) and (S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3B)

    • According to the same method as in Example 1, an optically active compound (C-3A) and an opticallly active compound (C-3B) were synthesized from (RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-3) obtained in Reference Example 3.

Optically active compound (C-3A)Melting point: 139-141°C   UNDESIRED

    • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82 – 0.87 (m, 3H) Optical rotaion +4.5 degrees (DMSO, c = 1.001, 25°C)

Optically active compound (C-3B)Melting point: 142-145°C  DESIRED

  • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)
      Example 4: Synthesis of (C-3B)

    • Figure imgb0021

First step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol (17)

    • Using the same method as that of the first step of Example 3, the compound (17) was obtained from the compound (16) at a yield 77%.
      Optical rotation: -23.5 ± 0.6 degrees (CHCl3, c = 1.050, 21°C)
      NMR (CDCl3) θ ppm: 1.49 (3H, d, J = 6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s), 5.19 (1H, q, J = 6.4 Hz), 7.01 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 7.7 Hz, J = 1.1 Hz), 7.46 (1H, dd, J = 8.0 Hz, J = 1.4 Hz)

Second step: Synthesis of (S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

    • Using the same method as that of the second step of Example 3, the compound (18) was obtained from the compound (17) at a yield of 96%.
      Optical rotation: -29.8 ± 0.6 degrees (CHCl3, c = 1.055, 21°C)
      NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.42 (3H, d, J = 6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 7.02 (1H, t, J = 7.9 Hz), 7.39 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 1.7 Hz)

Third step and fourth step: Synthesis of (S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

    • Using the same method as that of the fourth step of Example 3, the compound (19) was obtained from the compound (18), subsequently according to the same method as that of the fourth step, the compound (20) was obtained.

Compound (19)

    • NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d, J = 6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80 (1H, q, J = 6.4 Hz), 7.24 (1H, t, J = 7.8Hz), 7.52 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.65 (1H, dd, J = 7.7 Hz, J = 1.8 Hz)

Compound (20)

  • Optical rotation: -4.2 ± 0.4 degrees (DMSO, c = 1.025, 21°C)
    NMR (CDCl3) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)

 

      Fifth step: Synthesis of ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (21)

    • Using the same method as that of the fifth step of Example 3, the compound (21) was obtained from the compound (20) at a yield of 94%.
      Optical rotation: +4.7 ± 0.4 degrees (CHCl3, c = 1.07, 21°C)
      NMR (CDCl3 ) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2 – 1.35 (6H, m), 1.38 (3H, t, J = 7.1
      Hz), 1.44 (3H, d, J = 6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J = 1.4 Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.42 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 7.6 Hz, J = 1.7 Hz), 7.89 (2H, s), 10.30 (1H, brs)

Sixth step: Synthesis of (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-3B)

  • Using the same method as that of the sixth step of Example 3, the compound (C-3B) was obtained from the compound (21) at a yield of 80%.
    Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C)
    NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
  • Results of powder X-ray deffraction are shown in Fig. 5.
  • Diffraction angle of main peak: 2θ = 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees

WO2005014561/EP1655291A1

 https://www.google.co.in/patents/EP1655291A1?cl=en

 

 

WO2014003155, claiming a composition comprising lusutrombopag, useful for treating thrombocytopenia.

https://www.google.co.in/patents/US20150148385?cl=en

.

WO  2015093586

Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound 

 

(Step 1) Synthesis of compound (VII ‘)  under a nitrogen atmosphere, it was dissolved compound 1 (2.00kg) in 1,2-dimethoxyethane (28.0kg). 25% LDA tetrahydrofuran – heptane – ethyl benzene solution (13.20kg) was added dropwise over 1 hour at -55 ℃, and stirred for 30 minutes. It was added dropwise over 40 minutes to 1,2-dimethoxyethane (3.0kg) solution of N- formyl morpholine (3.74kg) at -55 ℃, and stirred for 1 hour. 1,2-dimethoxyethane (3.0kg) solution of 2-phosphono-propanoic acid triethyl (3.74kg) was added dropwise over 45 minutes at 0 ℃, and stirred for 2 hours. 35% aqueous solution of sulfuric acid (15.8kg) was added dropwise over 40 minutes to the reaction solution. Water (16.0kg) was added and extracted. The resulting organic layer was washed with water (8.0kg), and the solvent was evaporated under reduced pressure. Acetonitrile (16.0kg) was added, and the mixture was stirred for 1 hour at 25 ℃, and the mixture was stirred and cooled to 0 ℃ 5 hours and 30 minutes. The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (16.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Over 1 hour and then cooled to 30 ℃, and the mixture was stirred for 45 minutes. Over 40 minutes and then cooled to 5 ℃, and the mixture was stirred for 3 hours.The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (13.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Furthermore, up to 30 ℃ over 1 hour and then cooled and stirred for 70 minutes. Over 30 minutes and then cooled to 5 ℃, and the mixture was stirred for 4 hours. I precipitated crystals were collected by filtration. Washed with 5 ℃ acetonitrile (3.2kg), and dried to give the compound (VII ‘) (1.63kg, 51.2% yield). NMR (CDCl 3 ) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (Q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)  Results of powder X-ray diffraction and I shown in Figure 1 and Table 3. [Table 3]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0. 2 °, the peak was observed at 24.8 ± 0.2 °, and 39.0 ± 0.2 ° degrees.

 

(Synthesis of Compound (XI ‘))

(Step 2) Synthesis of Compound 4  under a nitrogen atmosphere over Compound 3 (3.00kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (11.40kg) 1 hour at 25 ℃ in The dropped, and stirred for 2 hours. 1mol / L isopropylmagnesium chloride in tetrahydrofuran solution (0.56kg) was added at 25 ℃, and stirred for 2 hours. To the reaction mixture N- methoxymethyl -N- methylacetamide the (1.45kg) was added dropwise over at 25 ℃ 40 minutes, and stirred for 80 minutes. 7% hydrochloric acid (9.7kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0kg). The resulting organic layer twice with water (each 7.5kg) washed, the solvent was evaporated under reduced pressure to give Compound 4 (2.63kg). NMR (CDCl 3 ) delta ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H) ppm:

(Step 3) Synthesis of Compound 5  Under a nitrogen atmosphere, chloro [(1S Compound 4 (2.63kg), 2S) -N- ( p- toluenesulfonyl) -1,2-diphenyl-ethane diamine] (p- cymene) ruthenium (II) (28.6g), it was added to tetrahydrofuran (1.3kg) and triethylamine (880.0g). Formic acid (570.0g) was added dropwise over 6 hours at 40 ℃, and stirred for 1 hour. In addition 3.5% hydrochloric acid (14.4kg) to the reaction mixture, and the mixture was extracted with toluene (13.0kg).The organic layer was washed with 3.5% hydrochloric acid (14.4kg) and water (7.5kg), the solvent was concentrated under reduced pressure to obtain a toluene solution of Compound 5 (4.44kg).

(Step 4) Synthesis of Compound 6  under a nitrogen atmosphere, it was a potassium hydroxide (6.03kg) was dissolved in water (6.0kg). To the solution, it added tetrabutylammonium bromide (182.0g) and toluene solution of Compound 5 (4.44kg). 1-bromo-hexane (2.79kg) was added dropwise over 1 hour at 60 ℃, and the mixture was stirred for 4 hours. And extracted by adding water (4.4kg) to the reaction solution. The resulting organic layer was filtered through powdered cellulose and extracted with toluene (3.0kg) and water (7.6kg) to the filtrate. The solvent it was evaporated under reduced pressure from the organic layer. Toluene operation of evaporated under reduced pressure and the solvent by the addition of a (7.8kg) was repeated five times to obtain a toluene solution of Compound 6 (10.0kg).

(Step 5) Synthesis of Compound 7  under a nitrogen atmosphere, magnesium powder (301.0g), in tetrahydrofuran (1.3kg), the compound in toluene (6.4kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (432.0g) 6 In addition of the toluene solution (0.50kg) at 30 ℃, and the mixture was stirred for 2 hours. Toluene solution of Compound 6 (9.50kg) was added dropwise over 3 hours at 50 ℃, and stirred for 2 hours. 1-bromo-hexane (746.0g) was added at 50 ℃, and the mixture was stirred for 1 hour. It was added dropwise over 1 hour at 5 ℃ toluene (5.3kg) solution of 2-chloro -N- methoxy -N- methyl-acetamide (1.78kg), and stirred for 1 hour. 3.7% hydrochloric acid (16.7kg) was added to the reaction mixture, and the mixture was extracted. The obtained organic layer was washed with water (15.0kg), and concentrated under reduced pressure to give a toluene solution of Compound 7 (8.25kg).

 

(Step 6) Synthesis of Compound (II ‘)  under a nitrogen atmosphere, thiourea (1.03kg), in ethanol (1.2kg) and 65 ℃ toluene solution of compound 7 (8.25kg) in toluene (6.3kg) over 3 hours was added dropwise and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6kg), and washed twice with water (30.0kg). Ethanol in the organic layer (9.5kg), and extracted by addition of heptane (10.0kg) and 3.5% hydrochloric acid (5.9kg). The resulting aqueous layer with 4% hydrochloric acid (1.5kg) and ethanol (3.5kg) merged the aqueous layer was extracted from the organic layer, the ethanol was washed with heptane (10.0kg) (3.1kg) It was added. 8% aqueous sodium hydroxide (6.0kg) was added dropwise over at 5 ℃ 30 minutes, and stirred for 20 minutes. 8% aqueous sodium hydroxide (5.8kg) was added dropwise over a period at 5 ℃ 15 minutes.The precipitated crystals were collected by filtration, washed with 45% aqueous ethanol (10.9kg) and water (15.0kg) (crude crystals of Compound (II ‘)). The resulting crude crystals were dissolved in 50 ℃ in ethanol (8.1kg), over a period of 1 hour and then cooled to 10 ℃, and the mixture was stirred for 30 minutes. Water (10.0kg) over 2 hours was added dropwise and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol (7.5kg) and water (10.0kg) (crystals of the compound after recrystallization from ethanol / water system (II ‘)). The resulting crystals were dissolved at 55 ℃ in toluene (1.6kg) and heptane (1.3kg), over 1 hour and cooled to 20 ℃, and stirred for 30 minutes. Heptane (6.3kg) over a period of 30 minutes was added dropwise and stirred for 15 minutes. The obtained crystals precipitated were collected by filtration, washed with a mixed solvent of toluene (0.3kg) and heptane (2.3kg), and dried to give compound (II ‘) (1.67kg, 44.5% yield) a (crystalline compound after recrystallization from toluene / heptane system (II ‘)).

NMR (CDCl 3 ) delta ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, M), 1.35 (3H, D, J = 6.5 Hz), 1.48 (2H, M), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)  it is shown in Figure 2 and Table 4 the results of powder X-ray diffraction. [Table 4]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0. 2 °, 23.0 ± 0.2 °, a peak was observed at 24.3 ± 0.2 ° degrees.  Above, each of the compounds (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) crystallographic purity of the results of the , Fig. 3, I 4 and 5 as well as Table 5. [Table 5](HPLC was measured by the above method A.)  As shown in the results of the above table, as compared to recrystallization from ethanol / water, recrystallized with toluene / heptane system, compounds having a high optical purity it is possible to manufacture a crystal of (II ‘).  Next, the above-mentioned compound (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) results of crystals of HPLC of the respectively, Fig. 6, I 7 and 8 and Table 6. [Table 6] (units, .N.D shows the peak area of the (%). is, .HPLC to indicate not detected was measured by the above method B.)  As shown in the results of Table, with ethanol / water system Compared to recrystallization, recrystallization from toluene / heptane system is found to be efficiently remove organic impurities A and organic impurities B.

(Step 7) Compound ‘Synthesis of DMSO adduct of (VIII)  Under a nitrogen atmosphere, the compound (II ‘) (1.50kg) and compound (VII’) (1.43kg) in ethyl acetate (17.6kg) and triethylamine (1.09kg) were sequentially added, was dissolved.Diphenyl phosphorochloridate the (1.46kg) was added dropwise over 1 hour at 50 ℃, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 25 ℃, after the addition of 2.6% hydrochloric acid (8.1kg), and extracted. The resulting organic layer to 6.3% aqueous solution of sodium hydroxide (3.2kg) and 14% aqueous sodium carbonate (5.2kg) was added and stirred for 20 minutes. Adjusted to pH7.5 with 8.3% hydrochloric acid and extracted. The organic layer it was washed with 4.8% sodium chloride aqueous solution (11.0kg). DMSO and (16.5kg) was added, and the mixture was concentrated under reduced pressure.DMSO and (5.8kg) was added, over a period at 40 ℃ 30 minutes was added dropwise water (0.9kg), and stirred for 1 hour. Over a period of 30 minutes, cooled to 25 ℃, and the mixture was stirred for 30 minutes. Over at 25 ℃ 30 minutes was added dropwise water (1.4kg), and the precipitated crystals were collected by filtration. After washing with 90% DMSO solution (10.0kg) and water (27.0kg), to obtain crystals of DMSO adduct and dried to Compound (VIII ‘) (2.98kg, 95.2% yield).

1H-NMR (CDCl 3 ) delta: 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.34 (M, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.44 (D, J = 6.5 Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H).  The results of the powder X-ray diffraction and I are shown in Figure 9 and Table 7. [Table 7]

In the powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° peak was observed to ± 0.2 ° and 24.1 ° ± 0.2 °.  TG / DTA analysis result it is shown in Figure 10.  Then, each result of HPLC of concentrated dry solid and the above DMSO adduct crystals described in the following Reference Examples 1, 11 and 12, 13 and 14, and I are shown in Table 8. [Table 8] (unit, .HPLC showing peak areas of (%) was measured by the above methods C.)  As shown in the results of the above Table, when compared with the extract, DMSO adduct of the compound (VIII ‘) The in the crystal, less residual organic impurities D, and it found to be about 56% removal.

(Step 8)  under nitrogen atmosphere, DMSO adduct of the compound (VIII ‘) and (2.50kg) it was dissolved in ethanol (15.8kg). 24% sodium hydroxide aqueous solution (1.97kg) was added dropwise over a period at 45 ℃ 30 minutes to the solution and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, water was added (20.0kg) and ethanol (7.8kg). 18% hydrochloric acid (2.61kg) was added dropwise over at 25 ℃ 30 minutes, followed by addition of seed crystals prepared according to the method described in Patent Document 23. After stirring for 3 hours and allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, to give after washing with 50% aqueous ethanol solution (14.2kg), and dried to a compound (XI ‘) (1.99kg, 93.9% yield).

NMR (CDCl 3 ) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, M), 1.48 (3H, D, J = 6.4 Hz), 1.52 – 1.64 (2H, M), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)  I is shown in Figure 15 the results of powder X-ray diffraction.

 

Patent Document 1: JP-A-10-72492 JP
Patent Document 2: WO 96/40750 pamphlet
Patent Document 3: JP-A-11-1477 JP
Patent Document 4: Japanese Unexamined Patent Publication No. 11-152276
Patent Document 5: International Publication No. 00/35446 pamphlet
Patent Document 6: JP-A-10-287634 JP
Patent Document 7: WO 01/07423 pamphlet
Patent Document 8: International Publication WO 01/53267 pamphlet
Patent Document 9: International Publication No. 02 / 059 099 pamphlet
Patent Document 10: International Publication No. 02/059100 pamphlet
Patent Document 11: International Publication No. 02/059100 pamphlet
Patent Document 12: International Publication No. 02/062775 pamphlet
Patent Document 13: International Publication No. 2003/062233 pamphlet
Patent Document 14: International Publication No. 2004/029049 pamphlet
Patent Document 15: International Publication No. 2005/007651 pamphlet
Patent Document 16: International Publication No. 2005/014561 pamphlet
Patent Document 17: JP 2005-47905 Japanese
patent Document 18: Japanese Patent Publication No. 2006-219480
Patent Document 19: Japanese Patent Publication No. 2006-219481
Patent Document 20: International Publication No. 2007/004038 pamphlet
Patent Document 21: International Publication No. 2007/036709 pamphlet
Patent Document 22: International Publication No. 2007/054783 pamphlet
Patent Document 23: International Publication No. 2009/017098 pamphlet

Non-Patent Document 1: Proceedings of the National Akademyi of Science of the United State of America (…. Proc Natl Acad Sci USA) 1992, Vol. 89, p 5640-5644.
Non-Patent Document 2: Journal of Organic (.. J. Org Chem) Chemistry 1984, Vol. 49, p 3856-3857.
Non-Patent Document 3: (.. J. Org Chem). Journal of Organic Chemistry, 1992, Vol. 57, p 6667-6669
Non-Patent Document 4:. Shinretto (Synlett) 2004 year Vol. 6, p 1092-1094

 

 

 

 

 

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CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl

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Gamendazole.svg

Gamendazole

(E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid

trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)

(E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid

  • C18H11Cl2F3N2O2
  • mw415.193
  • RC-MC-110

Heat Shock Protein 90 (HSP90) Inhibitors

University of Kansas  Innovator

Gamendazole is a novel drug candidate for male contraception. It is an indazole carboxylic acid derived from lonidamine (LND). Gamendazole produced 100% antispermatogenic effects at 25 mg/kg i.p. in rats, whereas 200 mg/kg was fatal for 60% of rats tested. Since gamendazole produced 100% efficacy, it was tested orally. At a dose of 6 mg/kg, 100% of rats were infertile 4 weeks after a single administration. Complete infertility was maintained for 2 weeks, followed by complete recovery in 4 of 7 rats. The other 3 never recovered fertility. Upon dosing 6 mg/kg orally for 7 days, it produced similar infertility results, but only 2 of 7 rats recovered fertility. There were no abnormalities in rates of conception or abnormal conception in rats who recovered fertility.

Pathology reports were conducted on gamendazole treated rats. At 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p., there were no remarkable findings, with no evidence of inflammationnecrosistumors, or hemorrhage. There was also a lack of observable behavioral effects at 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p. Gamendazole treatment had no effect on testosterone levels, and was reported to affect Sertoli cell function, leading to decreased levels of inhibin B. Low levels of inhibin B were correlated to the infertility of the rat

Female oral contraceptive drugs are widely available in the market by several trade names, including Altravera, Brevicon, Levora, and i-pill, whereas potentially safer, more convenient, and more effective oral male contraceptives are not yet commercially available. However, there are some experimental drugs.AF-2785 1, gamendazole 2, lonidamine 3, and adjudin 4 are most promising among the experimental

Experimental drugs.

 

Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic male contraceptive agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1.

Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

 

Synthesis

 

Figure imgf000051_0003

 

Figure imgf000052_0001

Figure imgf000052_0002

Figure imgf000053_0001

Figure imgf000053_0002

Figure imgf000054_0001

 

Figure imgf000054_0002

 

Figure imgf000055_0001

Figure imgf000055_0001

…………………….

2-Halo benzoic acid is converted into aroyl chloride and then to aroyl cyanide in an overall yield of 82%. Aroyl cyanides 5 are converted to 2-halophenyl glyoxylate ester 7 via ketoamide 6 in 85% yields as shown in Scheme below. Direct conversion of aroyl cyanide 5 to ester 7 is also reported[ U.S. Patent 4,596,885, 1986 .] but with lesser yields.

Synthesis of 2-halophenylglyoxalate.

The 2-halophenylglyoxylate 7 esters are reacted with monosubstituted hydrazines 8 to give hydrazones 9. The monosubstituted hydrazones 9 are cyclized to give indazole esters 10. This cyclization is best conducted  in the presence of DPPF · PdCl2 in 94.54% yield as shown in Scheme below.

Synthesis of 1-substituted indazole-3-carboxylate.

The indazole-3-carboxylic esters 10 were reduced with sodium borohydride to alcohol 11 and were oxidized to aldehyde 12with MnO2. The aldehyde is converted to acrylic acids with malonic acid (Knoevenagel condensation) to give 88–95.6% yield of the final compounds, as shown in Schemebelow.

Synthesis of AF-2785 and gamendazole.

Preparation of (E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid (R = CF3) (Gamendazole) (2)

ChemSpider 2D Image | Gamendazole | C18H11Cl2F3N2O2

 desired product 2 as a colorless solid (wt 5.32 g, yield 95.6%, HPLC purity 99.30%
DSC: 203.4 °C).
IR (KBr) (cm−1): 3447, 1697, 1641, 1311, 1122, 872; 
1H NMR (400 MHz, DMSO): δ 5.90 (2H, s), 6.72 (1H, d,J = 16.22 Hz), 6.94 (1H, d, J = 8.34 Hz), 7.36–7.39 (1H, dd, J 1 = 8.24 Hz, J 2 = 1.42 Hz), 7.55 (1H, d, J = 8.56 Hz), 7.69 (1H, d,J = 1.46 Hz), 7.78 (1H, d, J = 16.22 Hz), 8.37 (1H, d, J = 8.63 Hz), 8.40 (1H, s), 12.61 (1H, s); 
19F NMR (400 MHz, CDCl3):δ − 59.97(CF3); 
13C NMR (100 MHz, DMSO): δ 50.05, 109.16, 118.73, 121.61, 122.76, 123.39, 123.98, 127.76, 128.11, 129.42, 131.26, 133.56, 133.65, 133.76, 134.10, 140.64, 140.70, 167.57.
MW for C18H11Cl2F3N2O2 calcd. 415.19; observed: 415.3 and 417.2. HRMS: calcd.: 415.0228, observed: 415.0225.
DOI:
10.1080/00397911.2012.696306

Arava Veerareddya*, Gogireddy Surendrareddya & P. K. Dubeyb

pages 2236-2241

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 43Issue 16, 2013

………………

trans 3-[l- (l^-dichlorobenzy^-ό-trifluoromethyl-lH-indazol-S-ylj-acrylic acid (RC-MC-110) is provided.

 

Figure imgf000011_0002

EXAMPLE 2: Synthesis of a-ll-fl^-dichlorobenzyn-ό-trifluoromethyl-lH-indazol-S-yll-acrylic acid (RC-MC-110)

Step 1 : 2-(2-nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester.

 

Figure imgf000051_0003

Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67 0C. 1H NMR (CDCl3) 8.30 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5.37 (s, 1 H), 3.80 (s, 6 H). MS (FAB) m/z: 322.1 (M+ + 1).

Step 2: (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester.

 

Figure imgf000052_0001

2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120 0C (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105 0C. 1H

NMR (CDCl3) 8.3 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 4.12 (s, 2 H), 3.60 (s, 3 H). MS (FAB) m/z: 275.2 (M+ + 1).

Step 3: (2-Acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester.

 

Figure imgf000052_0002

Hydrogenation and acetylation of (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester (25 g, 0.095 mol) in the presence of 5% Pd-C (2.5 g, 50% wet) and acetic anhydride (38 g, 0.37 mol) in toluene (200 mL) was carried out under vigorous stirring at room temperature and atmospheric pressure for about 4-5 h (reaction monitored by TLC). The catalyst was removed by filtration and washed with toluene two times. The combined organics were evaporated in vacuo to yield the product (24.8 g, 95%), which was used without further purification in the next step. A small sample was crystallized from hexane to yield the product as a yellow solid, mp 92-94 0C. H NMR (CDCl3) 8.86 (s, 1 H), 8.21 (s, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1 H), 3.74 (s, 3 H), 3.68 (s, 2 H), 2.23 (s, 3 H). Step 4: ό-Trifluoromethyl-lH-indazole^-carboxylic acid methyl ester.

Figure imgf000053_0001

To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95 0C. The mixture was then stirred for 0.5 h at 95 0C, poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242 0C. H NMR (DMSO-d-6) 8.25 (d, J = 8.5 Hz, 1 H), 8.04 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 3.95 (s, 3 H). MS (FAB) m/z: 245.1 (M+ + 1).

Step 5: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester.

 

Figure imgf000053_0002

ό-Trifluoromethyl-lH-indazole-S-carboxylic acid methyl ester (2.75 g, 0.0112 mol) was dissolved in acetonitrile (50 mL), and potassium carbonate (1O g, 0.07 mol), 2,4-dichlorobenzyl chloride (2.42 g, 0.01239 mol) and tetrabutylammonium iodide (catalytic) were added. The reaction mixture was heated to reflux and refluxed for 2 h under good stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, potassium carbonate was filtered while hot and then washed with acetone. The combined solvents were distilled off under reduced pressure to afford the crude mixture of Nl and N2 benzylated products. The isomers were separated by column chromatography (silica gel, eluent started with hexane then changed to 8:2 hexane, ethyl acetate). l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester. Yield: 3.62 g (80%), white crystals mp 118-120 0C. ‘ H NMR (CDCl3) 8.39 (d, J = 8.4 Hz, 1 H) 7.74 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.12 (dd, J = 8.4 and 2.1 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 5.82 (s, 2 H), 4.07 (s, 3 H). MS (FAB) m/z: 403 (M+ + 1).Z-^^-DichlorobenzylJ-δ-trifluoromethyl-ZH-indazole-S-carboxylic acid methyl ester. Yield: 680 mg (15%), white crystals mp 132-134 0C. ‘ H NMR (DMSO-d-6) 8.27 (s, 1 H), 8.20 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 8.3 and 1.8 Hz, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 6.17 (s, 2 H), 3.96 (s, 3 H).

Step 6: [l-(2.4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl1-methanol.

 

Figure imgf000054_0001

l -(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester (3.0 g, 0.0075 mol) dissolved in CH2Cl2(50 mL) was cooled to -78 0C. DIBAL-H (8.18 mL, 0.00818 mol) was added slowly dropwise via a syringe under an argon blanket over a period of 15 minutes. After the complete addition of DIBAL-H, the reaction mixture was stirred at -78°C for another 2 h (reaction monitored by TLC). The reaction was quenched carefully with methanol at -78 0C. The reaction mixture was then carefully poured into water and the layers were separated. The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent yielded the crude alcohol (2.6 g, 93%), which was used without purification in the next step. The alcohol was a white solid, mp 137-139 0C. 1H NMR (CDCl3) 7.97 (d, J = 8.4 Hz, 1 H), 7.66 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.12 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.65 (s, 2 H), 5.09 (s, 2 H). MS (FAB) m/z: 375 (M+ + 1).Step 7: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehvde.

 

Figure imgf000054_0002

[l-(2,4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl]-methanol (3.75 g, 0.01 mol) was dissolved in CH2Cl2 (100 mL) and manganese(IV)oxide (8.7 g, 0.1 mol) was added and stirred for 2-3 h at room temperature (reaction monitored by TLC). The solids were removed by filtration and the removal of the CH2Cl2 in vacuo yielded the crude aldehyde. The aldehyde was used without further purification in the next step. The aldehyde (3.54 g, 95%) was a white solid, mp 97-98 0C. 1H NMR (CDCl3) 10.25 (s, 1 H), 8.45 (d, J = 8.5 Hz, 1 H), 7.79 (s, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J = 8.3 Hz and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.79 (s, 2 H). MS (FAB) m/z: 373 (M+ + 1).

Step 8: 3-ri-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazol-3-yll-acrylic acid ethyl ester.

 

Figure imgf000055_0001

l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehyde (2.0 g, 0.00536 mol) was dissolved in CH2Cl2 (50 niL) and Wittig reagent (carbethoxymethylene) triphenylphosphorane (1.06 g, 0.0536 mol) was added to the solution. The homogeneous reaction mixture was heated to reflux in an oil bath for 12 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and worked up by quenching into water and separating the organic layer. Removal of the CH2Cl2 yielded the crude product, which was purified by column chromatography to yield the pure product (2.25 g, 95%) as a white solid, mp 186-188 0C. 1H NMR (CDCl3) 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 16.2 Hz, 1 H), 7.74 (s, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.16 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 16.2 Hz, 1 H), 5.72 (s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). MS (FAB) m/z: 443 (M+ + 1).It will be appreciated that the acrylic acid ethyl ester can be hydrogenated using 5% Pd-C in the presence of methanol, DCM at RT and 1 atm-pressure to give the propionic acid ester derivative. For example, treatment under such conditions yields 3-[l-(2,4-dichlorobenzyl)-6- trifluoromethyl-lH-indazol-3-yl]-propionic acid ethyl ester (JWS-2-70).

Step 9: l-(2,4-Dichlorobenzyl)-3-r6-trifluoromethyl-lΗ-indazol-3-yll-acrvlic acid.

 

Figure imgf000055_0002

l-(2,4-Dichlorobenzyl)-3-[6-trifluoromethyl-lH-indazol-3-yl]-acrylic acid ethyl ester (2.0 g, 0.0045 mol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (25 mL). A lithium hydroxide solution (0.33 g, 0.013 mol lithium hydroxide in 7.5 mL water) was added slowly at room temperature under good stirring. The reaction mixture was then warmed to 40 0C and held at that temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate in order to remove neutral impurities. The layers were separated and the aqueous layer was cooled to 0 0C and then acidified with 20% sulfuric acid to pH 2. White solids precipitated and were filtered and dried to constant weight. The crude product was recrystallized from ethyl acetate and hexane (1 :1) to afford the pure product (1.68 g, 90%) as a white solid,

mp 186-188 0C.
1H NMR (DMSO-d-6) 8.39 (s, 1 H), 8.36 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 16.2 Hz, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.35 (dd, J = 8.3 and 1.6 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 6.76 (d, J = 16.2 Hz, 1 H), 5.89 (s, 2 H).
Anal, calcd. for C18HnCl2F3N2O2: C, 52.02; H, 2.65; N, 6.74. Found: C, 50.63; H, 2.63; N, 6.63.
HRMS (FAB +) m/z calcd. for C18HnCl2F3N2O2 415.01, found 415.0233.
MS (FAB) m/z: 415 (M+ + 1).
1H NMR
1h nmr 13c nmr
13C NMR

REFERENCES

  • 1. Corsi , G. ; Palazzo , G. ; Germani , C. ; Barcellona , P. S. ; Silvestrini , B. 1-Halobenzyl-1H-indazole-3-carboxylic acids: A new class of antispermatogenic agents . J. Med. Chem. 1976 , 19 , 778 
  • 2. Palazzo , G. ; Corsi , G. ; Baiocchi , L. ; Silvestrini , B. Synthesis and pharmalogical properties of 1-substituted-3-dimethylaminoalkoxy-1H-indazoles . J. Med. Chem. 1966 , 9 , 38 – 41 . 
  • 3. Silvestrini , B. Basic and applied research in the study of indazole carboxylic acids . Chemotherapy 1981 , 27 ( Suppl.2 ), 9 – 20 . 
  • 4. Silvestrini , B. ; Palazzo , G. ; De Gregorio , M. D. 3-Lonidamine and related compounds . Progr. Med. Chem. 1985 , 21 , 111 – 135 .
  • 5. Cheng , C. Y. ; Silvestrini , B. ; Grima , J. ; Mo , M. Y. ; Zhu , L. J. ; Johnsson , E. ; Saso , L. ; Leone , M. G. ; Palmery , M. ; Mruk , D. Two new male contraceptives exert their effects by depleting germ cells prematurely from the testes . Biol. Reprod. 2001 , 65 , 449 – 461 . 
  • 6. Xia , W. ; Mruk , D. D. ; Lee , W. M. ; Ceng , C. Y. Unraveling the molecular targets pertinent to junction restructuring events during spermatogenesis using the Adjudin-induced germ cell depletion model . J. Endocrinol. 2007 , 192 , 563 – 583 .
  • 7. Cheng , C. Y. ; Mruk , D. D. ; Silvestrini , B. ; Bonanomi , M. ; Wong , C. H. ; Siu , M. K. Y. ; Lee , N. P. Y. ; Mo , M. Y. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: A review of recent data . Contraception2005 , 72 , 251 – 261 . 
  • 8. Tash , J. S. ; Attardi , B. ; Hild , S. A. ; Chakrasali , R. ; Jakkarg , S. R. ; Georg , G. I. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose . Biol. Reprod. 2008 , 78 , 1127 – 1138 .
  • 9. Sarkar , O. ; Mathur , P. P. Adjudin-mediated germ cell depletion alters the anti-oxidant status of adult rat testes . Mol. Reprod. Dev. 2009 , 76 , 31 – 37 . 
  • 10. Mok , K.-W. ; Mruk , D. D. ; Lie , P. P. Y. ; Lui , W.-Y. ; Cheng , C. Y. Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. Reproduction. 2011, 141, 571–580. 
  • 11. Wang , H. ; Chen , X. X. ; Wang , L.-R. ; Mao , Y.-D. ; Zhou , Z. M. ; Sha , J.-H. AF-2364 is a prospective spermicide candidate .Asian J. Androl. 2010 , 12 , 322 – 335 . 
    1.  “Gamendazole”NextBio. www.nextbio.com. Retrieved 31 July 2011.
    2.  Tash, Joseph (July 2008). “A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose”. Biology of Reproduction 78 (6): 1127–1138. doi:10.1095/biolreprod.106.057810PMID 18218612.

Chakrasali, R.; Jakkaraj, S.R.; Tash, J.S.; Hild, S.A.; Attardi, B.; Georg, G.I.
Design, synthesis and in vivo evaluation of Gamendazole(R), a novel orally active male contraceptive agent
228th Am Chem Soc (ACS) Natl Meet (August 22-26, Philadelphia) 2004, Abst MEDI 305

CHENG C.Y. ET AL: “Two New Male Contraceptives Exert Their Effects by Depleting Germ Cells Prematurely from the Testis” BIOLOGY OF REPRODUCTION, SOCIETY FOR THE STUDY OF REPRODUCTION, CHAMPAIGN, IL, US, vol. 65, no. 2, 1 August 2001 (2001-08-01), pages 449-461, XP002547492 ISSN: 0006-3363
2 * GATTA F. ET AL: “Pyrazolo[3,4-d]pyrimidines. Related to Lonidamine” JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 26, no. 3, 1 March 1989 (1989-03-01), pages 613-618, XP002547493 ISSN: 0022-152X
US3895026 * Feb 9, 1973 Jul 15, 1975 Acraf Substituted 1-benzyl-1h-indazole-3-carboxylic acids and derivatives thereof
WO2003097063A1 * May 5, 2003 Nov 27, 2003 Bayer Ag Derivatives of 2-(1-benzyl-1h-pyrazolo (3, 4-b)pyridine-3yl) -5-(4-pyridinyl)-4-pyrimidine amine and the use thereof as guanylate cyclase stimulators
WO2006015263A2 * Jul 29, 2005 Feb 9, 2006 Duan Jian-Xin Lonidamine analogs
Gamendazole
Gamendazole.svg
Gamendazole ball-and-stick model.png
Names
IUPAC name

(E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid[1]
Other names

trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)
Identifiers
877773-32-5 Yes
ChemSpider 9387234 
Jmol-3D images Image
PubChem 11212172
Properties
C18H11Cl2F3N2O2
Molar mass 415.19 g·mol−1

 

 

 

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Aug 192015
 

Flibanserin

BIMT-17
BIMT-17-BS
1,3-Dihydro-1-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-2H-benzimidazol-2-one
167933-07-5

FDA approves first treatment for sexual desire disorder
Addyi approved to treat premenopausal women

SEE FULL SYNTHESIS …CLICK HERE

The U.S. Food and Drug Administration today approved  to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

 

August 18, 2015

Release

The U.S. Food and Drug Administration today approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

“Today’s approval provides women distressed by their low sexual desire with an approved treatment option,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation or the sexual partner.

“Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies,” continued Dr. Woodcock. “Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.”

Addyi can cause severely low blood pressure (hypotension) and loss of consciousness (syncope). These risks are increased and more severe when patients drink alcohol or take Addyi with certain medicines (known as moderate or strong CYP3A4 inhibitors) that interfere with the breakdown of Addyi in the body. Because of the alcohol interaction, the use of alcohol is contraindicated while taking Addyi. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

Addyi is also being approved with a Boxed Warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment with Addyi, in those who also use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment. Addyi is contraindicated in these patients. In addition, the FDA is requiring the company that owns Addyi to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol.

Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is taken once daily. It is dosed at bedtime to help decrease the risk of adverse events occurring due to possible hypotension, syncope and central nervous system depression (such as sleepiness and sedation). Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness of the 100 mg bedtime dose of Addyi was evaluated in three 24-week randomized, double-blind, placebo-controlled trials in about 2,400 premenopausal women with acquired, generalized HSDD. The average age of the trial participants was 36 years, with an average duration of HSDD of approximately five years. In these trials, women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks (scored on a range of 1.2 to 6.0) and reported distress related to low sexual desire (on a range of 0 to 4). On average, treatment with Addyi increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo increased the sexual desire score by 0.3 to 0.4 over placebo, and decreased the distress score related to sexual desire by 0.3 to 0.4 over placebo. Additional analyses explored whether the improvements with Addyi were meaningful to patients, taking into account the effects of treatment seen among those patients who reported feeling much improved or very much improved overall. Across the three trials, about 10 percent more Addyi-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire or distress. Addyi has not been shown to enhance sexual performance.

The 100 mg bedtime dose of Addyi has been administered to about 3,000 generally healthy premenopausal women with acquired, generalized HSDD in clinical trials, of whom about 1,700 received treatment for at least six months and 850 received treatment for at least one year.

The most common adverse reactions associated with the use of Addyi are dizziness, somnolence (sleepiness), nausea, fatigue, insomnia and dry mouth.

The FDA has recognized for some time the challenges involved in developing treatments for female sexual dysfunction. The FDA held a public Patient-Focused Drug Development meeting and scientific workshop on female sexual dysfunction on October 27 and October 28, 2014, to solicit perspectives directly from patients about their condition and its impact on daily life, and to discuss the scientific challenges related to developing drugs to treat these disorders. The FDA continues to encourage drug development in this area.

Consumers and health care professionals are encouraged to report adverse reactions from the use of Addyi to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling 1-800-FDA-1088.

Addyi is marketed by Sprout Pharmaceuticals, based in Raleigh, North Carolina.

 

NMR PREDICT

H EXPLODED

 

1H NMR PREDICT1H NMR DB GRAPH 1H NMR DB VAL CHEMDDODLE

 

 

13C NMR PREDICT

fliban chemspider image

13C NMR DB GRAPH 13C NMR DB VAL fliban chemspider image

 

COSY PREDICT

COSY NMR prediction (27)

////////

Addyi, flibanserin, fda 2015, sexual desire disorder

 

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Aug 182015
 

Filgotinib.png

Filgotinib

  • C21H23N5O3S
  • MW425.504
  • Elemental Analysis: C, 59.28; H, 5.45; N, 16.46; O, 11.28; S, 7.54
1206161-97-8
Cyclopropanecarboxamide, N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-
G146034
GLPG0634
N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
Galapagos Nv  INNOVATOR

IL-6 antagonist; Jak1 tyrosine kinase inhibitor; Tyk2 tyrosine kinase inhibitor; Jak3 tyrosine kinase inhibitor; Jak2 tyrosine kinase inhibitor

Autoimmune disease; Cancer; Colitis; Crohns disease; Inflammatory disease; Neoplasm; Rheumatoid arthritis; Transplant rejection

Filgotinib (GLPG0634), by the Belgian biotech company Galápagos NV, is a drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn’s disease.

Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn’s disease.

3D

Mechanism of action

Filgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively. Less selective JAK inhibitors (e.g. tofacitinib) are already being marketed. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects.[1] It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. This is the rationale for the development of newer and more selective inhibitors like filgotinib.

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against RA. Nonetheless it is thought that JAK2 inhibition might lead to anemia and thrombopenia by interference witherythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor. Therefore one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2.[2] It is however still to be seen to what extent JAK2 inhibition should be avoided.

Novel crystalline forms of filgotinib salts, particularly hydrochloride salt, useful for treating JAK-mediated diseases eg inflammatory diseases, autoimmune diseases, proliferative diseases, allergy and transplant rejection.  Galapagos and licensee AbbVie are developing filgotinib, a selective JAK-1 inhibitor, for treating rheumatoid arthritis (RA) and Crohn’s disease (CD). In August 2015, the drug was reported to be in phase 2 clinical development for treating RA and CD. The drug is also being investigated for the treatment of colitis and was discovered as part of the company’s arthritis alliance with GSK; however in August 2010 Galapagos reacquired the full rights. See WO2013189771, claiming use of filgotinib analog for treating inflammatory diseases. Also see WO2010010190 (co-assigned with GSK and Abbott) and WO2010149769 (assigned to Galapagos) claiming filgotinib, generically and specifically, respectively.

Clinical trials and approval

The efficacy of filgotinib is currently studied in a phase2b program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn’s disease patients.

Phase 1 study

It was shown in phase 1 studies that the pharmacokinetics of filgotinib metabolism is independent of hepatic CYP450 enzymatic degradation. The drug metabolism is however mediated by carboxylesterases. There is no interference reported with the metabolism of methotrexate nor with any of the investigated transport proteins.[3]

Phase 2 study: Proof of concept (2011)

In november 2011 Galápagos released the results of their phase 2 study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 patients were treated who showed a suboptimal clinical response to methotrexate treatment. Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports ofanemia nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that “GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments”.[4]

DARWIN 1 trial

The DARWIN 1 trial is a 24 week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants have moderate to severe RA and showed an insufficient response to standard methotrexate treatment. The trial compares three dosages of filgotinib as a once or twice per day regimen. During the trial all participants remain on their methotrexate treatment. According to the company, the results of this trial are expected in July 2015.[5]

DARWIN 2 trial

The DARWIN 2 trial is a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. This trial, in contrast to the previous DARWIN 1 trial, methotrexate is discontinued. Therefore, this trial investigates filgotinib as a monotherapy.[6] The recruitment of DARWIN trial 2b ended in november 2014.[7] Preliminary results are expected in the second quarter of 2015 and a full completion of the study is expected in the third quarter of 2015.

DARWIN 3 trial

Patients who complete DARWIN 1 and 2 will be eligible for DARWIN 3.

Time line

  • june 2011: results of first phase 2 trial
  • november 2014: initiation of DARWIN 1 and 2 trials
  • april 2015: expected date of DARWIN 1 trial results
  • june 2015: expected date of DARWIN 2 trial results

ChemSpider 2D Image | Filgotinib | C21H23N5O3S

CHEMIETEK

…………

PATENT

http://www.google.com/patents/WO2010149769A1?cl=en

Step 3:

Figure imgf000029_0001

[00131] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-

2-yl]-amide (leq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO^ Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

………..

PATENT

US2010/331319 A1, ; Page/Page column 13-14

http://www.google.com/patents/US20100331319

Synthetic Preparation of the Compound of the Invention and Comparative Examples

The compound of the invention and the comparative examples can be produced according to the following scheme.

Figure US20100331319A1-20101230-C00003

wherein Ar represents phenyl-L1-heterocycloalkyl, where L1 is a bond, —CH2— or —CO— and the heterocycloalkyl group is optionally substituted.

General 1.1.1 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

Figure US20100331319A1-20101230-C00004

To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5° C. is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20° C.) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. 1H (400 MHz, CDCl3) δ 12.03 (1H, br s, NH), 8.81 (1H, d, J=7.8 Hz, H-3), 8.15 (1H, br s, NH), 7.60 (1H, t, J=8.0 Hz, H-4), 7.32 (1H, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).

1.1.2 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3)

Figure US20100331319A1-20101230-C00005

To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).

1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4)

Figure US20100331319A1-20101230-C00006

To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5° C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2×50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A Preparation of Compounds of the Invention Via Suzuki Coupling (5):

An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K2CO(2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSOand evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Method B

Figure US20100331319A1-20101230-C00007

B1. 4 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoyl chloride

Figure US20100331319A1-20101230-C00008

2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under Natmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide Formation (General Method)

Figure US20100331319A1-20101230-C00009

An appropriate amine (1.1 eq) and Et3N (5 eq) are dissolved in DCM under Natmosphere and cooled at 0° C. The acid chloride (B1, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Synthesis of the Compound of the Invention and Comparative Examples Compound 1 (the Compound of the Invention) Step 1:

Figure US20100331319A1-20101230-C00014

2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under Nand thiomorpholine 1,1-dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

STEP 2: Suzuki coupling

Figure US20100331319A1-20101230-C00015

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO(2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSOand evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H2O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50° C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative Route to Compound 1 (the Compound of the Invention): Step 1:

Figure US20100331319A1-20101230-C00016

4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO(2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSOand evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

Figure US20100331319A1-20101230-C00017

To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSO4, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

Figure US20100331319A1-20101230-C00018

Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under Nand thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

…………………….

PATENT

WO 2015117981

Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Also claims a method for preparing filgotinib hydrochloride trihydrate. The present filing forms a pair with this week’s filing, WO2015117980, claiming a tablet composition comprising filgotinib hydrochloride.

The compound cyclopropanecarboxylic acid {5-[4-(l,l-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl -amide (Compound 1), which has the chemical structure:

is disclosed in our earlier application WO 2010/149769 (Menet C. J., 2010) as being an inhibitor of JAK and as being useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons. Hereafter this compound is named Compound 1. The data presented in WO 2010/149769 demonstrate that despite similar in vitro activities, Compound 1 has unexpectedly high in vivo potency compared with structurally similar compounds.

Example 1. Preparation of Compound 1

1.1. Route 1

1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

[00205] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated without further purification.

1.1.2. Cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide

1.1.2.1. Step i): l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea

[00206] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5°C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction

mixture is then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3 x 600 niL) and air-dried to afford the desired product. The thiourea may be used as such for the next step without any purification. lH (400 MHz, CDC13) δ 12.03 (1H, br s), 8.81 (1H, d), 8.15 (1H, br s), 7.60 (1H, t), 7.32 (1H, dd), 4.31 (2H, q), 1.35 (3H, t).

1.1.2.2. Step ii): 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine

[00207] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) is added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H20 (250 mL) and filtration. The combined solids are washed successively with H20 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 : 1, M+H+, 100%).

1.1.2.3. Step Hi): Cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide

[00208] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5°C is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et20 (50 mL). The solids are collected by filtration, washed with H20 (2x50mL), acetone (50 mL) and Et20 (50 mL), then dried in vacuo to give the desired compound.

1.1.3. Compound 1

[00209] 4-[4-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-benzyl] hiomoφholine , l -dioxide (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo.

[00210] The final compound is obtained after purification by flash chromatography.

[00211] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50°C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.

1.2. Route 2

1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2, 4]triazolo[l, 5- a] pyridin-2-yl] -amide

[00212] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water

(4:1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The resulting mixture is used without further purification.

1.2.2. Step 2: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5- a Jpyridin-2-ylJ -amide

[00213] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl] -amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO i, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.

1.2.3. Step 3:

[00214] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N2 and thiomorpho line 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.

…………………

PATENT

http://www.google.co.in/patents/WO2013189771A1?cl=en

Example 1. Synthesis of the compounds

1.1. Route 1

1.1.1. Synthesis of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (Intermediate 3)

Figure imgf000030_0001

led to 5 °C was added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gave a solid which was collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea was used as such in the next step without any purification.

[00157] lH (400 MHz, CDC13) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).

1.1.1.2. 5-Bromo-f 1,2, 4]triazolo[ 1 ,5-a] pyridin-2-ylamine (3)

[00158] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) was added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber was required to quench H2S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H20 (250 mL) and filtration. The combined solids were washed successively with H20 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound was used as such in the next step without any purification.

[00159] lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 : 1, M+H+, 100%).

1.1.2. Synthesis of 4-[ 4-(4, 4, 5, 5-Tetramethyl-f 1, 3,2] ‘ dioxaborolan-2-yl) -benzyl] ‘- thiomor holine- 1, 1 -dioxide (Intermediate 4)

Figure imgf000031_0001

[00160] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

1.1.3. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- a ridin-2-ylamine (Formula I)

Figure imgf000031_0002

[00161] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) was added to a solution of 5-bromo-[l,2,4]triazolo[l,5-a]pyrid in-2-ylamine (4: 1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90°C for 16h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSC>4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00162] lH (400 MHz, CDC13) δ 7.94-7.92 (d, 2H), 7.52-7.48 (m, 3H), 7.37-7.34 (m, 1H), 7.02-7.00 (m, 1H), 6.00 (d, 2H), 3.76 (d, 2H), 3.15-3.13 (m, 4H), 2.93-2.91 (m, 4H).

[00163] m/z 358.2 (M+H+, 100%). 1.2. Route 2

1.2.1. Cyclopropanecarboxylic acid {5-[4-(l, l-dioxo-thiomorpholin-4-ylmethyl)-phenylJ- [l,2,4]triazolo[l,5-a]pyridin-2-yl}-amide (Formula II)

[00164] The compound according to Formula II may be synthesized according to the procedure described in WO 2010/149769.

1.2.2. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- aJpyridin-2-ylamine (Formula I)

[00165] The compound according to Formula I can also be produced by hydrolysis of the compound accor ing to Formula II:

Figure imgf000032_0001

[00166] Hydrochloric acid 30% aq (12.06 kg; 3.9 rel. volumes) was added to a slurry of the compound according to Formula II (3.45 kg; 1.0 equiv.) in demineralized water (10.0 kg; 3.0 rel. volumes). Subsequently, a line rinse was performed with demineralized water (3.4 kg; 1.0 rel. volumes). The reaction mixture was heated to 80±5°C for 14.5 h. After completion of the reaction (conversion > 99%>), the reaction mixture was cooled to 20±5°C. The reaction mixture was diluted with demineralized water (6.8 kg; 2.0 rel. volumes) and sodium hydroxide 33%> aq (9.52 kg; 3.7 rel volumes) was dosed at such a rate that the temperature of the reactor contents remained below 35°C. An additional amount of sodium hydroxide 33%> aq (2.55 kg; 1.0 rel. volumes) was needed to get the pH > 10. The product was filtered off, washed twice with demineralized water (1.5 rel. volumes) and dried under vacuum for 1 h, thus yielding the crude compound according to Formula I.

[00167] The crude compound according to Formula I (5.70 kg) was re-slurried in demineralized water (23.0 kg; 8.5 rel. volumes). Hydrochloric acid 30%> aq (1.65 kg; 0.7 rel. volumes) and demineralized water (4.3 kg; 1.6 rel. volumes) were added and the reaction mixture was stirred at 20±5°C for 45 min. As the compound according to Formula I was not dissolved completely, the reaction mixture was stirred at 45±5°C for 1 h. The reaction mixture was filtered and the residue was washed with demineralized water (2.0 kg 0.75 rel. volumes). Sodium hydroxide 33%> aq (1.12 kg; 0.6 rel volumes) was added to the filtrate. An additional amount of sodium hydroxide 33%> aq (1.01 kg) was needed to get the pH > 10. The resulting reaction mixture was stirred at 20±5°C for about 3 h. The product was filtered off, washed twice with demineralized water (4.1 kg; 1.5 rel. volumes), and twice with methyl tert-butyl ether (MTBE; 3.0 kg; 1.5 rel. volumes) and dried under vacuum for 15.5 h on the filter. The product was further dried in a vacuum oven at 40±5°C for 202 h, thus affording the desired compound according to Formula I.

 

1H NMR PREDICT

1H NMR MOLBASE GRAPH 1H NMR MOLBASE VAL

 

13C NMR PREDICT

 

13C NMR MOLBASE GRAPH 13C NMR MOLBASE VAL

H EXPLODED

H EXPLODED

1H NMR FROM NET ABMOLE DMSOD6

NMR ABMOLE NMR MEDKOO

 

 

 

SPECTRAL PREDICT

 

FIL CHEMDDOODLE

 

 

1H NMR PREDICT

 

1H NMR DB GRAPH

H EXPLODED

1H NMR DB VAL

 

13C NMR PREDICT

13C NMRDB GRAPH 13C NMRDB VAL

COSY

COSY NMR prediction (26)

References

  1.  Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van’t Klooster, Gerben (2015-02-14). “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”. Clin Pharmacokinet. Epub ahead of print.doi:10.1007/s40262-015-0240-z.
  2.  Van Rompaey, L; Galien, R; Van der Aar, E; Clement-Lacroix, P; Van der Aar, E; Nelles, L; Smets, B; Lepescheux, L; Cristophe, T; Conrath, K; Vandeghinste, N; Vayssiere, B; De Vos, S; Fletcher, S; Brys, R; Van’t Klooster, G; Feyen, J; Menet, C (2013-10-01). “Preclinical characterization of GLPG0634, a selective inhibitor of JAK1 for the treatment of inflammatory diseases”. J Immunol. 191(7). doi:10.4049/jimmunol.1201348.
  3.  http://acrabstracts.org/abstracts/phase-1-and-phase-2-data-confirm-that-glpg0634-a-selective-jak1-inhibitor-has-a-low-potential-for-drug-drug-interactions/
  4.  “Galapagos’ GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study” (PDF) (Press release). Retrieved 2015-02-26.
  5.  “Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment” (PDF) (Press release). Retrieved 2015-02-26.
  6.  “Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA”EuroInvestor. Retrieved 2015-02-26.
  7.  NASDAQ OMX Corporate Solutions. “Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA”Yahoo Finance. Retrieved 2015-02-26.
US8551980 Nov 17, 2010 Oct 8, 2013 Bayer Intellectual Property Gmbh Substituted triazolopyridines
US8796457 Jun 25, 2010 Aug 5, 2014 Galapagos Nv Compound useful for the treatment of degenerative and inflammatory diseases
Filgotinib
Filgotinib.png
Systematic (IUPAC) name
N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
Clinical data
Routes of
administration
Oral
Pharmacokinetic data
Biological half-life 6 hours[1]
Identifiers
CAS Registry Number 1206161-97-8 Yes
ATC code L01XE18
IUPHAR/BPS 7913
ChemSpider 28189566 Yes
UNII 3XVL385Q0M Yes
ChEMBL CHEMBL3301607 
Chemical data
Formula C21H23N5O3S
Molecular mass 425.50402 g/mol
Patent Submitted Granted
Compound useful for the treatment of degenerative and inflammatory diseases [US8088764] 2010-12-30 2012-01-03
NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES [US2011190260] 2011-08-04

 

/////////Galapagos,  GLPG0634, Filgotinib, PHASE 2

SMILES code: O=C(C1CC1)NC2=NN3C(C4=CC=C(CN5CCS(CC5)(=O)=O)C=C4)=CC=CC3=N2

 

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Aug 182015
 

ChemSpider 2D Image | Orilotimod | C16H19N3O5

Orilotimod

(2R)-2-amino-5-{[(1R)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino}-5-oxopentanoic acid
186087-26-3 
Apo805,UNII-Q66Z43C5XM; Thymodepressin; Orilotimod [USAN]; AC1OIBUF; 
  • C16H19N3O5
  • MW 333.339

Apotex Technologies Inc.  INNOVATOR

2D chemical structure of 960155-19-5

Orilotimod potassium,

D-Tryptophan, D-gamma-glutamyl-, potassium salt (1:1), CAS 960155-19-5

The drug, orilotimod, was originally developed and launched by Immunotech Developments; however, ApoPharma (a subsidiary of Apotex) is developing orilotimod, presumably a topical formulation, for the treatment of psoriasis. In August 2015, the ApoPharma’s drug was reported to be in phase 2 clinical development.

Thymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and  is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

 

Orilotimod.png

PAPENT

BEAWARE EXAMPLE WITH AN ESTER GP

http://www.google.im/patents/WO2012129671A1?cl=en

Preparation of H-D-Glu( -Trp-OH)-0-Et hydrochloride salt (Apo836.HCI)

 

Figure imgf000037_0001

A. Preparation of Boc-D-Glu(D-Trp-0-Bzl)-0-Et

Proceeding in a similar manner as described under Example 3A, Boc-D- Glu(D-Trp-0-Bzl)-0-Et was prepared in 87% yield.1H NMR ( DMSO-D6l 400 MHz) δ ppm: 10.87, (s, 1 H), 8.35 (d, J = 7.2 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.29-7.33 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 7.09-7.22 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7,7 Hz, 1 H), 4.98 – 5.06 (m, 2H), 4.55 (apparent q, J = 7.3 Hz, 1 H), 4.04 – 4.11 (m, 2H), 3.90 – 3.95 (m, 1 H), 3.04 – 3.19 (m, 2H), 2.18 – 2.23 (m, 2H), 1.84 – 1.89 (m, 1 H), 1.70 – 1.77 (m, 1 H), 1.38 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 552 [ +1]+.

B. Preparation of Boc-D-Glu(D-Trp-OH)-0-Et

Proceeding in a similar manner as described under Example 3B, Boc-D-

Glu(D-Trp-OH)-0-Et was prepared in quantitative yield. 1H NMR ( DMSO-D6, 400 MHz) δ ppm: 12.62 (br. 1H), 10.82, (s, 1 H), 8.10 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1 H), 7.12 (s, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H)„ 4.45 (apparent q, J = 7.7 Hz, 1 H), 4.03 – 4.11 (m, 2H), 3.87 – 3.92 (m, 1 H), 3.13 – 3.18 (m, 1H), 2.96 – 3.03 (m,

1 H), 2.13 – 2.20 (m, 2H), 1.82 – 1.88 (m, 1H), 1.69-1.75 (m, 1 H), 1.38 (s, 9H>, 1.17 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 462 [M+1]+.

C. Preparation of H-D-Glu(D-Trp-OH)-0-Et.HCI (Apo836 HCI)

To an ice-cooled solution of Boc-D-Glu(D-Trp-OH)-0-Et (4.55 g, 9.8 mmol) obtained in Section B above in dichloromethane (100 mL) was bubbled HCI gas for 15 min. The reaction mixture was concentrated under vacuum by rotary evaporation to give H-D-Glu(D-Trp-OH)-0-Et hydrochloride (Apo836.HCI, 4.0 g) as a foamy solid. 1 H NMR ( DMSO-D6, 400 MHz) δ ppm: 12.68 (br. s, 1 H), 10.90, (s, 1H), 8.66 (br, s, 3H), 8.33 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1 H), 6.98 (t, J = 7.2 Hz, 1 H), 4.47 (apparent q, J = 4.8 Hz, 1 H), 4.13 – 4.19 (m, 2H), 3.90 (br, 1 H), 3.16 – 3.20 (m, 1H), 2.98 – 3.04 (m, 1 H), 2.29 – 2.33 (m, 2H), 1.94 – 1.98

(m, 2H), 1.20 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 362 [M+1]+ (free base).

……………………..

US 20150225341

file:///H:/ORILOTIMODUS20150225341A1.pdf

Novel crystalline and amorphous salts of thymodepressin (orilotimod), particularly potassium salt, useful for treating psoriasis and atopic dermatitis. Also claims salt exchange method for preparing thymodepressin salts.

 

hymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and which is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

Through investigations in our laboratory, we have determined that the freeze-dried disodium salt of D-isoglutamyl-D-tryptophan is extremely hygroscopic turning into a gel in a matter of minutes in air and cannot easily be handled.

A powdery or amorphous form of a compound, intended for pharmaceutical use may give rise to manufacturing problems due to bulk density issues, hygroscopicity and variable water content that cannot be corrected by vacuum drying. D-isoglutamyl-D-tryptophan is a dipeptide and the drying of an amorphous form at elevated temperature, for example, 80-100° C. under vacuum is not recommended. Thus, there are serious difficulties experienced during the purification of the disodium salt of D-isoglutamyl-D-tryptophan and obtaining the pure disodium salt on a manufacturing scale. Further, there is no published procedure for its preparation.

The monosodium salt of D-isoglutamyl-D-tryptophan is identified by the CAS Registry System and is listed in the CAS REGISTRYSM File with a CAS Registry Number@ of 863988-88-9. However, there are no references citing the substance and thus no publication of its identity, its physical and/or chemical properties, its characterization or a procedure for its preparation. Freeze-dried powders of mono sodium and disodium salts of peptide drugs may not have controllable powder bulk density ranges for formulation. They may require significant investment in freeze-dried dispersion technology.

EXAMPLES

Example 1

Preparation of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from D-isoglutamyl-D-tryptophan and potassium hydroxide

In a 100-mL round bottom flask equipped with a magnetic stir bar was placed 5 mL of potassium hydroxide solution (0.5 N). The solution was cooled to 0° C. in an ice-water bath, and solid H-D-iGlu-D-Trp-OH (1.00 g, 3 mmol) was added. The mixture was stirred while the pH of the solution was adjusted to ca. 6.0 by adding a few drops of potassium hydroxide solution (0.5 N). The solution was filtered to remove any solid particulates. The filtrate was evaporated to dryness at a bath temperature of about 30° C. to afford a solid. After drying under vacuum at room temperature for overnight, the salt was obtained in quantitative yield, with a HPLC purity (peak area percent) of 98.3%. HPLC method; Column: XTerra MS C18; 5 μm, 4.6×250 mm; Mobile phase: A=the aqueous phase: 4 mM Tris, 2 mM EDTA, pH 7.4; B=the organic phase: CH3CN; gradient: B %: 0 min. 5%, 15 min. 55%, 30 min. 55%, 32 min. 5%, 35 min. 5%; Flow rate: 1 mL/min; injection volume: 5 μL; λ: 222, 254, 282, 450 nm; retention time of the product: 6.41 min. The XRPD pattern of this crystalline material is shown in FIG. 1A; the water content by Karl-Fischer test is 0.7%; UV (water, c=23.8 ρM, λmax nm): 221 (ε 33270), 280 (ε 5417); MS (m/z): 372.0 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%). The FT-IR (KBr) spectrum is shown in FIG. 1B.

Example 2

A. Preparation of mono potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (1.66 g, 4.05 mmol) and potassium hydroxide (253 mg, 4.50 mmol) in water (20 mL) was stirred at room temperature for 15 min. The pH of the solution was about 9. The reaction mixture was evaporated under reduced pressure to a volume of about 1 mL. After cooling to room temperature, isopropanol was added until a solid precipitated out. The resulting suspension was stirred at room temperature for 15 min, then filtered. The solid was washed with isopropanol (2×20 mL) and ethyl acetate (20 mL), then dried under vacuum in an oven at 42° C. overnight. An off white solid was obtained (1.49 g, 99% yield). The water content by Karl-Fischer test is 2.5%. Analytical data (XRPD pattern, FT-IR and MS spectra) are similar to those described in Example 1.

B. Preparation of amorphous form of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (517 mg, 1.40 mmol) and potassium hydroxide (82 mg, 1.46 mmol) in water (10 mL) was stirred at room temperature for 30 minutes. The resulting mixture was freeze-dried overnight. An off white solid was obtained in quantitative yield. The XRPD pattern spectrum confirmed that this material is amorphous.

1H NMR (D2O) δ: 7.69 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.22 (s, 1H), 7.16 (t, J=7.4 Hz, 1H), 4.59 (dd, J=8.7, 4.8 Hz, 1H), 3.51 (dd, J=6.8, 5.8 Hz, 1H), 3.38 (dd, J=14.8, 4.8 Hz, 1H), 3.11 (dd, J=14.8, 8.8 Hz, 1H), 2.20-2.49 (m, 2H) and 1.85-1.94 (m, 2H); 

13C NMR (D2O) δ: 181.4, 177.0, 176.6, 138.8, 129.9, 126.9, 124.5, 121.9, 121.4, 114.5, 113.2, 58.6, 57.0, 34.6 (CH2), 30.2 (CH2) and 29.3 (CH2);

the water content by Karl-Fischer test is 5.4%;

the FT-IR (KBr) spectrum is shown in FIG. 1C;

MS (m/z): 371.7 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%);

HPLC purity (peak area percent): 99.8%, Retention time: 5.04 min; HPLC conditions: Column Waters Symmetry C18, 3.9×150 mm, 5 μm; Mobile phase: 0.035% HClO4, pH 2/CH3CN, 85/15, isocratic, Flow rate: 1 mL/min; λ: 220, 254, 280 nm.

Patent Submitted Granted
GAMMA-GLUTAMYL AND BETA-ASPARTYL CONTAINING IMMUNOMODULATOR COMPOUNDS AND METHODS THEREWITH [EP1042286] 2000-10-11 2010-08-25
CRYSTALLINE D-ISOGLUTAMYL-D-TRYPTOPHAN AND THE MONO AMMONIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8119606] 2010-01-21 2012-02-21
Pharmaceutically Acceptable Salts of Thymodepressin and Processes for their Manufacture [US8138221] 2010-03-04 2012-03-20
CRYSTALLINE FORMS OF THE MONO-SODIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8207217] 2010-02-04 2012-06-26

 

 

 

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09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

 

 

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  

////////Orilotimod, PHASE 2, thymodepressin, APO 805K1

C1=CC=C2C(=C1)C(=CN2)CC(C(=O)O)NC(=O)CCC(C(=O)O)N

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Aug 172015
 

Ivacaftor.svg

 

IVACAFTOR

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide

N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Molecular formula: C24H28N2O3
CAS#: 873054-44-5
MW: 392.49
Melting Point: 292-295°C

NMR——-http://file.selleckchem.com/downloads/nmr/s114401-ivacaftor-vx770-hnmr-selleck.pdf

COSY NMR PREDICT

 

 

 

COSY

Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis.[1][2] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with theCystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.[3] Called “the most important new drug of 2012”,[4] and “a wonder drug”[5] it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost.

Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively

Ivacaftor is a white to off-white crystalline solid. It is freely soluble in methylethyl ketone/water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone and ethanol and practically insoluble in water and buffers with pH 1.0 – 7.0.  The active substance shows polymorphism. Mixture of two major crystalline neat polymorphic forms (B and C) is obtained when manufactured by the commercial manufacturing process described. Form C is the most thermodynamically stable neat form. The polymorphic form is not of concern during the synthesis of the active substance, as the active substance is fully dissolved during manufacture of the finished product…………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002494/WC500130766.pdf

Quality by Design (QbD) approach has been used in product and process development of ivacaftor. For the active substance synthesis, a combination of multivariate analyses and range-finding studies was used to define a design space for each step. All parameters with a potential impact on critical quality attributes (CQAs) of the active substance were identified and thoroughly investigated. The Applicant has proposed a combination of proven acceptable ranges (PARs) and design spaces (DSs) for the manufacturing process of the active substance. Design spaces have been developed at small laboratory scales (0.5-20 g) and the scale-up to production levels (100 kg) is wide (x 5000, x 10.000…).

 

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator (CFTR), which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. One such defect is the G551D mutation, in which the amino acid glycine (G) in position 551 is replaced with aspartic acid (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.[6][7][8]

 

HPLC

HPLC

Economics

The cost of ivacaftor is $311,000 per year, roughly similar to the price of other drugs for extremely rare diseases.[18] In the first 9 months of its second year on the market (2014), ivacaftor sales were $339M, representing 54% of Vertex’s product sales revenue. During the same period, drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.[19]

An editorial in JAMA called the price of ivacaftor “exorbitant”, citing the support by the Cystic Fibrosis Foundation in its development and the contribution made by fundamental scientific research performed by the National Institutes of Health and relied upon by Vertex in its cystic fibrosis drug discovery programs.[20] The company responded in an email that “while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by the company, before the drug won approval.”[21]

The Cystic Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the drug was successfully developed and commercialized. In 2014, the Foundation sold these royalty rights for $3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.[22][23]

Vertex said it would make the drug available free to patients in the United States with no insurance and a household income of under $150,000.[24] In 2012, 24 US doctors and researchers involved in the development of the drug wrote to Vertex to protest the price of the drug, which had been set at about $300,000 per year. In the UK, the company provided the drug free for a limited time for certain patients, then left the hospitals to decide whether to continue to pay for it for those patients. UK agencies estimated the cost per quality adjusted life year (QALY) at between £335,000 and £1,274,000 —well above the National Institute for Health and Care Excellence thresholds.[25]

The drug was not covered under the Ontario Drug Benefit plan until June 2014 when the Province of Ontario and the manufacturer negotiated for what “Ontario Health MinisterDeb Matthews had called a “fair price” for taxpayers”. The negotiations took 16 months and it was estimated that around 20 Ontarians required the drug at the time.[26]

The province of Alberta began covering the drug in July 2014, and in September the province of Saskatchewan became the third province to include it in its provincial drug plan.[27]

Government delays in agreeing to provide ivacaftor in national health plans led to patient group protests in Wales,[28][29] England,[30] and Australia.[31]

.


PURE

NMR GRAPH FROM NET

NMR

 

NMR ABMOLE

 

 

NMR CHEMDOODLE

1H NMR PREDICT

molbase 1h graph molbase 1h val

 

13C NMR PREDICT

molbase 13c graph molbase 13cval

1H NMR PREDICT VIA NMRDB

H EXPLODED

1H NMR DB VAL

 

1H NMR DB GRAPH

 

13C NMR VIA NMRDB

13C NMR DB VAL 13C NMR DBGRAPH IVACAFTOR IMAGE

 

 

 

…………

JMC

http://pubs.acs.org/doi/pdf/10.1021/jm5012808

N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

(0.2 g, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.82 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.84−7.78 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.56−7.45 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H).

HRMS-ESI (m/z): [M + H]+ calcd for C24H28N2O3, 393.2178; found, 393.2164.

………

VERTEX PHARMACEUTICALS INCORPORATED Patent: US2008/90864 A1, 2008 ; Location in patent: Page/Page column 8; 9 ;

Heterocycles, , vol. 89, # 4 p. 1035 – 1040

US2011/230519 A1, ;

 

 

 

References

  1.  Jones AM, Helm JM (October 2009). “Emerging treatments in cystic fibrosis”. Drugs 69(14): 1903–10. doi:10.2165/11318500-000000000-00000PMID 19747007.
  2.  McPhail GL, Clancy JP (April 2013). “Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis”. Drugs Today 49 (4): 253–60.doi:10.1358/dot.2013.49.4.1940984PMID 23616952.
  3.  “Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation”Press Release. Cystic Fibrosis Foundation. 2011-02-23.
  4.  “The Most Important New Drug Of 2012 – Forbes”.
  5. “The $300,000 Drug – NYTimes.com”.
  6.  Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012). “Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner”. J. Biol. Chem. 287 (44): 36639–49.doi:10.1074/jbc.M112.393637PMID 22942289.
  7. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (November 2009).“Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770”.Proc. Natl. Acad. Sci. U.S.A. 106 (44): 18825–30. doi:10.1073/pnas.0904709106.PMC 2773991PMID 19846789.
  8.  Sloane PA, Rowe SM (November 2010). “Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis”. Curr Opin Pulm Med 16(6): 591–7. doi:10.1097/MCP.0b013e32833f1d00PMID 20829696.
  9.  “pi.vrtx.com” (PDF).
  10.  “FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More | CF Foundation”.
  11.  Bobadilla JL, Macek M, Fine JP, Farrell PM (June 2002). “Cystic fibrosis: a worldwide analysis of CFTR mutations–correlation with incidence data and application to screening”.Hum. Mutat. 19 (6): 575–606. doi:10.1002/humu.10041PMID 12007216.
  12. “pi.vrtx.com” (PDF).
  13.  “pi.vrtx.com” (PDF).
  14.  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php
  15.  Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (November 2010). “Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation”N. Engl. J. Med. 363(21): 1991–2003. doi:10.1056/NEJMoa0909825PMC 3148255PMID 21083385.
  16.  “Kalydeco: Annex I: Summary of product characteristics” (PDF). European Medicines Agency.
  17.  “pi.vrtx.com” (PDF).
  18.  “F.D.A. Approves New Cystic Fibrosis Drug”New York Times. January 31, 2012. Retrieved 2015-02-10.
  19.  “Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014”. Retrieved2015-02-10.
  20.  Brian P. O’Sullivan; David M. Orenstein; Carlos E. Milla (October 2, 2013). “Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?”JAMA. 310 (13): 1343–1344. doi:10.1001/jama.2013.278129.
  21.  “Cystic Fibrosis: Charity and Industry Partner for Profit”. MedPage Today. May 19, 2013. Retrieved 2015-02-10.
  22.  “CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma | Xconomy”.
  23.  “CF Foundation Royalty Sale Will Be Transformational for People with CF”.
  24.  “FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis” (Press release). Cambridge, Massachusetts: Vertex Pharmaceuticals. 2012-01-31. Retrieved 2014-02-01.
  25.  Deborah Cohen; James Raftery (12 February 2014). “Orphan Drugs: Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding”BMJ348: g1445. doi:10.1136/bmj.g1445.
  26. Ferguson, Rob (June 20, 2014). “OHIP to cover cystic fibrosis drug Kalydeco”The Toronto Star. Retrieved June 20, 2014.
  27.  “Saskatchewan to cover $300K cystic fibrosis drug Kalydeco”CBC News. 2014-08-28. Retrieved 2014-08-28.
  28.  “Plea for Kalydeco drug to be introduced | Wales – ITV News”.
  29.  “BBC News – Cystic fibrosis: New drug Kalydeco refused for Welsh NHS”.
  30.  “Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug – Birmingham Mail”.
  31.  “Kalydeco breakthrough: Plea for life-saving medicine proves a winner | Manning River Times”.

External links

 

US4556658 * Apr 24, 1984 Dec 3, 1985 Bayer Aktiengesellschaft 7-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids and antibacterial agents containing these compounds
US4822801 * Oct 20, 1986 Apr 18, 1989 Warner-Lambert Company 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
US20060074075 * Jun 24, 2005 Apr 6, 2006 Sara Hadida-Ruah Modulators of ATP-binding cassette transporters
US20100267768 * Mar 19, 2010 Oct 21, 2010 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US20110064811 * Dec 28, 2006 Mar 17, 2011 Patricia Hurter Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

 

 

 

Systematic (IUPAC) name
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Clinical data
Trade names Kalydeco
Licence data US FDA:link
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Protein binding 99%
Metabolism CYP3A
Biological half-life 12 hrs (single dose)
Excretion 88% faeces
Identifiers
CAS Registry Number 873054-44-5 
ATC code R07AX02
PubChem CID: 16220172
IUPHAR/BPS 4342
ChemSpider 17347474 Yes
UNII 1Y740ILL1Z Yes
ChEBI CHEBI:66901 
Synonyms VX-770
Chemical data
Formula C24H28N2O3
Molecular mass 392.490 g/mol

 

 

 

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ChemSpider 2D Image | Mirabegron | C21H24N4O2SMIRABEGRON

  • Betanis
  • Myrbetriq
  • UNII-MVR3JL3B2V
  • YM 178
  • YM178

Мирабегрон ميرابيغرون 米拉贝隆

2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
MF: C21H24N4O2S =396.5

Mirabegron (YM-178, Astellas Pharma), is an orally active, first-in-class selective β₃-adrenoceptor agonist for the symptomatic treatment of overactive bladder (OAB), and has been approved for urinary frequency and urinary incontinence associated with OAB

Mirabegron (YM-178) is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder. Mirabegron (0.3 and 1 mg/kg) inhibits mechanosensitive single-unit afferent activities (SAAs) of Aδ fibers in response to bladder filling. Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Mirabegron (YM-178) acts partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Mirabegron at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. Mirabegron decreases primary bladder afferent activity and bladder microcontractions in rats. Mirabegron (YM-178) also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction.

Mirabegron is a white crystalline powder, not hygroscopic and freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH. The chemical name is 2-(2- Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide., Mirabegron exhibits stereoisomerism due to the presence of one chiral centre. The R enantiomer has been used in the manufacture of the finished product. The enantiomeric purity is controlled routinely by chiral HPLC-UV. Polymorphism has been observed for the active substance. The polymorphic form α is routinely and consistently produced by the synthetic process and it is used in the manufacture of the finished product…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002388/WC500137308.pdf

 

Mirabegron (formerly YM-178, trade name MyrbetriqBetmiga in Spain) is a drug for the treatment of overactive bladder.[2] It was developed by Astellas Pharma and was approved in the United States in July 2012.[3]

Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.[4]\

NMR PREDICT

NMR CHEMDOODLE

 

PAPER

http://jocpr.com/vol7-iss4-2015/JCPR-2015-7-4-1473-1478.pdf

Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478

In the first approach, the introduction of the chiral hydroxyl group was planned at the later stage (Scheme 1). Accordingly, 2-(4-nitrophenyl)ethyl amine 4 was protected as the Boc-derivative 5, followed by the reduction of the nitro group using stannous chloride to furnish corresponding aniline 6. Alternate reducing conditions such as hydrogenation in the presence of 10% Pd-C were also provided the desired 6 in good yield. Amide coupling of the aniline 6 with 2-(2-aminothiazol-4-yl) acetic acid 7 in the presence of EDC, HOBt/DIPEA furnished the desired amide 8. Interestingly, lower reactivity of 2-aminothiazole precluded any self-coupling of 7.

MIRA SYN 1

Removal of Boc-group in 8, set the stage for the critical step of introducing the chiral hydroxyl by means of stereocontrolled ring opening of the chiral (R)-styrene epoxide 10. Epoxide opening reaction of 10 was initially attempted with amine 9 in the presence of Et3N in MeOH as the solvent. Alternatively, epoxy opening was also performed under simple isopropanol reflux condition to get the desired 1. The desired product 1 was isolated in 27% yield after purification by column chromatography. This is due to the formation of N-alkylated derivatives of 1 by undesired reaction of 10 with amino functionalities of 1. However, the inefficiency of the epoxide opening reaction precluded a high purity of final product, Mirabegron 1. Since it is not practical to embark on repeated purifications at the last stage (which leads to poor yields), this route was not pursued for further optimization.

13C NMR PREDICT

C-NMR MOLBASE

 

1H NMR PREDICT

H-NMR MOLBASE

………………

1H NMR PREDICT

H EXPLODED H-NMR NMRDB GRAPH H-NMR NMRDB VAL

 

 

13C NMR PREDICT

C-NMR NMRDB GRAPH C-NMR NMRDB VAL

 

Cosy predict

COSY NMR prediction (24)

……….

WO 2015096604

Patent WO2003037881 Mira Veron synthesis report were as follows: D- mandelic acid and amine compounds of nitrobenzene as a starting material, the amide condensation system as shown in Formula 9, followed by reduction by borane obtained as a compound of formula 10, and then by catalytic hydrogenation to obtain a compound represented by formula 11, and the final compound of formula 7 of condensation system Mira Veron, specific synthetic route is as follows

Example 13 (R) -2- (2- aminothiazol-4-yl) -N- (4- {2 – [(2- hydroxy-2-phenylethyl) amino] ethyl} phenyl) ethyl amide (Mira Veron) the preparation and purification
HPLC test specific conditions are as follows:
Column Waters X-Bridge C18 column (4.6mm × 150mm, 3.5μm); mobile phase 0.1% aqueous trifluoroacetic acid (A) -0.1% trifluoroacetic acid in acetonitrile (B), gradient elution: 0 → 10min, A ︰B = 90︰10; 10 → 25min, A︰B = 90︰10 → 30︰70; 25 → 32min, A︰B = 30︰70 → 90︰10; flow rate of 1ml / min; detection wavelength 210nm; column temperature 30 ℃).
Mira preparation method of the background art reference Veron patent number WO2003037881 Mira Veron patent application preparation, as follows:
The compounds of Formula 11 as shown in (5.0g, 17.08mmol), compound (2.7g, 17.07mmol) as shown in Formula 7, water (75mL), concentrated hydrochloric acid (1.66g, 17.07mmol), EDC (3.60g , 18.78mmol) were sequentially added to the reaction flask, stirred at room temperature 1h. 1.5M sodium hydroxide solution was then added dropwise (25mL) added to the reaction mixture, the precipitated white solid. Filtration and vacuum dried to give Mira Veron crude (6.45g, 95.26%).

Take Mira Veron crude 3.0g, was added thereto, and 30mL of purified water 1.5mL, stirring to dissolve at 80 ℃, slow cooling until the solution clear solution, and incubated at 55 ℃ stirring 1h, white solid precipitate, and slowly cooled to room temperature, filtered and dried under vacuum to give a white Mira Veron product 2.41g, HPLC purity of 99.96%.

mp 138.7 ~ 139.4 ℃. ESI-MS (m / z): 397 [M + H] + , 419 [M + Na] + .

1 H NMR (400 MHz, DMSO-d 6 ) [delta]: 1.60 (1H, s), 2.61-2.68 (4H, m), 2.70-2.79 (2H, m), 3.46 (2H, s), 4.59-4.62 (1H , t), 5.14 (1H, br), 6.30 (1H, s), 6.84 (2H, s), 7.11-7.13 (2H, d), 7.20-7.24 (1H, m), 7.28-7.34 (4H, m ), 7.48-7.50 (2H, d), 9.93 (1H, s).

……………….

WO 2015040605

http://www.google.co.in/patents/WO2015040605A1?cl=en

Mirabegron is a beta-3 adrenergic agonist disclosed in U.S. Patent No. 6,346,532. It is chemically designated as 2-(2-aminothiazol-4-yl)-N-[4-[2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, having the structure depicted by Formula I.

 

Formula I

Polymorphs of mirabegron are disclosed in U.S. Patent No. 7,342,117; PCT Publication No. WO 2012/156998; and IP.com Disclosure No. IPCOM000228561D.

U.S. Patent No. 7,342,117 discloses a-Form and β-Form of mirabegron; PCT Publication No. WO 2012/156998 discloses an amorphous form of mirabegron; and IPCOM000228561D discloses crystalline forms of mirabegron and mirabegron monohydrochloride .

Summary of the Invention

The present invention provides a crystalline form of mirabegron, a process for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of overactive bladder.

The crystalline form of mirabegron of the present invention is highly pure and free-flowing. It is stable towards polymorphic conversion and shows little or no variation in dissolution profile.

A first aspect of the present invention provides a crystalline form of mirabegron characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of 5.74, 4.41, 4.28, 4.16, and 3.80 A.

A second aspect of the present invention provides a process for the preparation of a crystalline form of mirabegron of Formula I characterized by an XRPD pattern having peaks at d-spacings of 5.74, 4.41, 4.28, 4.16, and 3.80 A

 

Formula I

comprising desolvation of the mirabegron dimethyl sulphoxide solvate of Formula II.

 

Formula II

A third aspect of the present invention provides a pharmaceutical composition comprising a crystalline form of mirabegron characterized by an XRPD pattern having peaks at d-spacings of 5.74, 4.41, 4.28, 4.16, and 3.80 A and one or more

pharmaceutically acceptable carriers, diluents, or excipients.

A fourth aspect of the present invention provides use of a crystalline form of mirabegron, characterized by an X-ray powder diffraction having peaks at d-spacings of about 5.74, 4.41, 4.28, 4.16, and 3.80 A, for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and urinary frequency.

Other objects, features, advantages, and aspects of the present invention will become apparent to those skilled in the art from the description provided herein.

………………..

WO 2015044965

http://www.google.com/patents/WO2015044965A1?cl=en

(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl] acetanilide (henceforth “Mirabegron”) also known as MYRBETRIQ™, has a CAS number of 223673-61-8, a molecular formula of C2iH24N402S and the following.structure:

FORMULA (I)

Mirabegron, an orally active beta-3 adrenergic receptor agonist is used for the treatment of urinary frequency, urinary incontinence, or urgency associated with overactive bladder.

U.S. Patent No. 6,346,532 (henceforth US’532) discloses Mirabegron of formula (I) or salt and its derivatives and process for the preparation of the same.

Example 41 of US’532 describes preparation of Mirabegron dihydrochloride of formula (la), wherein 4-nitrophenylethylamine hydrochloride of formula (III) is reacted with R-styrene oxide of formula (II) to provide (R)-2-[2′-(4-nitrophenyl)ethyl]amino]-l -phenylethanol of formula (XIV) (Reference example 1). Subsequently amino group of compound of formula (XIV) is protected by the amino protecting groups like tert-butoxycarbonyl to obtain compound of formula (V) (Reference example 2). Nitro group of compound (V) is reduced to amino group to obtain compound of formula (VI) using Palladium-carbon (Reference example 3). The compound of formula (VI) is coupled with compound of formula of (VII) to form amide of formula (VIII). Amino protecting group i.e. tert-butoxycarbonyl, is removed by using hydrogen chloride in ethyl acetate to form dihydrochloride salt of Mirabegron of formula (la) as represented in Scheme I.

 

 

Thus, example 41 of US’532 does not discuss or exemplify the process for preparation of Mirabegron free base. Some of the limitations of the above synthetic routes are;

i. The protection and deprotection steps makes the synthesis lengthy and contributes to poor atom economy;

ii. The yields of styrene oxide ring opening are low (20-30 %);

iii. R-styrene oxide employed in the process is expensive and thereby adds to the economics of the process; and

iv. Use of column chromatography for the purification of final compound is not feasible at industrial scale.

US .7,342, 1 17 (henceforth US’ 1 17) discloses two crystalline forms namely, a- and beta (β)-crystalline forms of Mirabegron and the process for its preparation. The process for making Mirabegron as per US’ 1 17 involves reaction of (/?)-mandelic acid of formula (XII) with 4-nitrophenylethylamine hydrochloride of Formula (Ilia) in presence of triethylamine, EDC and HOBt to yield compound of formula (XIII), which is further reacted with borane-tetrahydrofuran solution, 1 , 3-dimethyl-2-imidazolidinone in tetrahydrofuran, to obtain compound of formula (XlVa). Compound of formula (XlVa) was reduced in presence of palladium-carbon under hydrogen atmosphere in methanol to obtain compound of formula (XVa). The compound of formula (XVa) was then reacted with 2-aminothiazole-4-yl-acetic acid (VII) in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC.HCI) in acidic medium to obtain Mirabegron of formula (I) as a clear solution (Scheme II). The acidic reaction mass was basified with sodium hydroxide solution to obtain the crystals of Mirabegron of Formula (I), which were filtered and dried. The process according to above always provides β-crystalline form.

The methods of making the a-crystalline form always uses β-crystalline form as a starting material wherein the process comprises dissolving the β-crystals in water and ethanol mixture at 80°C, seeding the solution with a-crystals, filtering and drying to obtain the a-crystalline form of Mirabegron of Formula (I).

Subsequently, patent application WO2012156998 discloses some more processes for making the α-crystalline form by dissolving the Mirabegron solid in a solvent or solvent mixture at elevated temperature, cooling the solution or adding an anti solvent to obtain the Mirabegron of Formula (I)·

Some of the limitations of US’ l 17 are as follows:

i. Process is not user-friendly, as there is difficulty in handling and storing of highly flammable and moisture sensitive reagents such as borane-tetrahydrofuran complex; ii. The disclosed process involves use of l-ethyl-3-(3-dimethylaminoprpyl) carbodiimide HC1 (EDC.HCl) and hydroxybenzotriazole (HOBt) in step- 1 which are expensive;

iii. Process is not cost-efficient as it employs addition of expensive borane-tetrahydrofuran complex and l ,3-dimethyl-2-imidazolidinone reagents in step-2, and catalyst like palladium for nitro reduction in step-3; and

iv. Preparation of a-crystalline form always involve reprocessing of β-crystalline form in separate step, use of seed material, reproducibility, use of limited solvents, which does not result in an industrially feasible process for making the α-crystalline form.

Hence, there is a need for a solution that overcomes the above stated limitations by developing process for preparation of Mirabegron and its α-crystalline form which is simple, reproducible, economic and industrially feasible.

said process comprising;

a) reacting 4-nitrophenylethylamine of formula (III) or its acid addition salt of formula (Ilia) with compound of formula (XII) in presence of a solvent and reagent, optionally in presence of base, and/or catalyst to obtain (ii)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2- phenylacetamide of formula (XIII);

(XII) (Ml) (Ilia)

b) reducing (i?)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) in presence of reducing agent and a solvent to obtain (i?)-2-[2′-(4- nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV), optionally converting it into its acid addition salt of formula (XlVa);

 

c) reducing (i?)-2-[2′-(4-nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV) or its acid addition salt of formula (XlVa) in solvent to obtain (i?)-2-[[2-(4-aminophenyl)ethyl]- amino]-l -phenylethanol of formula (XV) or its acid addition salt of formula (XV a) respectively;

 

d) reacting compound (i?)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol of formula (XV) or its acid addition salt of formula (XVa) obtained in the step (c) with compound of formula (VII) in the presence of solvent, acid and a condensing agent, optionally in the presence of a catalyst to obtain Mirabegron of formula (I);

and

e) Isolating a-crystalline form of Mirabegron of formula (I) obtained in step (d) and optionally purifying by solvent crystallization.

EXAMPLE 9

Preparation of a-form of crystalline (R)-2-(2-aminothiazol-4-yl)-4′-[2-f(2-hvdroxy-2-phenylethylaminol-ethyn-acetanilide (Mirabegron)

Mirabegron (10 g) and 2-propanol (100 mL) were charged in round bottom flask at 28°C (±2). The solution was heated to reflux temperature to obtain clear solution. To this solution, n-Heptane (200 mL) was added at same temperature to obtain crystals. The obtained crystals were cooled to 28°C (±2). The crystals were filtered, washed with n-Heptane (40 mL) and dried under vacuum at 48°C (±2) for 3 hours to obtain 9.2 g of a form of Mirabegron having PXRD pattern shown in Fig.1 and Infrared spectrum (IR) show in Fig 2.

Yield: 8.5 g (85 %); Purity by HPLC: 99.65 %

Impurities

According to the present invention, Mirabegron prepared according to any of the said processes having impurities comprising a compound of formula (A), compound of formula (B), compound

of formula (C), compound of formula (D), compound of formula (E), compound of formula (F), compound of formula (G), compound of formula (H), compound of formula (I), compound of formula (J), compound of formula (K), compound of formula (L), compound of formula (M), compound of formula (N), compound of formula (O), compound of formula (P), compound of formula (Q), compound of formula (R), compound of formula (S), compound of formula (T), compound of formula (U), compound of formula (V), compound of formula (W), compound of formula (X), and compound of formula (Y).

 


Compound H

 


Compound I Compound J

Compound W 

………………….

http://www.google.com/patents/CN104230840A?cl=en

Mira Veron (Mirabegron) in Chinese chemical name: (R) -2- (2- amino-1,3-thiazol-4-yl) -4’_ [2- [(2-hydroxy-2 – phenylethyl) amino] ethyl] phenylacetamide; English chemical name: (R) -2- (2-aminothiazol-4-yl) -4, – [2_ [(2-hydroxy-2-phenylethyl) amino ] ethyl] acetanilide; Molecular formula: C21H24N402 S; molecular weight: 396; CAS registry number: 223673-61-8, Mira Veron chemical structural formula shown below.

 

Figure CN104230840AD00041

[0003] Mira Veron belong aryl ethanolamines β 3 receptor agonists, acting on bladder detrusor smooth muscle β 3 adrenergic receptors, bladder relaxation, promote and increase the storage of urine bladder filling, can effectively reduce the frequency of urination, improve overactive bladder, frequent urination caused by urinary urgency and incontinence, therefore, Mira Veron research synthesis also appears important.

[0004] US6346532B1 (publication date of February 12, 2002) discloses a method for synthesizing Mira Veron, the route is as follows:

 

Figure CN104230840AD00042

This synthesis of nitrobenzene hydrochloride as the raw material, through condensation, protection, reduction, and then condensation deprotected Mira Veron. The process is the first step in a yield of less than 50%, and the resulting product content and chiral purity is low, we need to column chromatography, which severely restricted the massive scale-up.

[0005] Document (… Chem Pharm Bull 58 (4) 533-545 (2000)) reported an improved method for the synthesis of Mira Veron, the route is as follows:

 

Figure CN104230840AD00051

The method uses N- benzyl 2- (4-nitrophenyl) ethylamine as a raw material and R- styrene oxide condensates, then reduction, condensation, debenzylation to give Mira Veron. The first step of the method condensation products can be purified by crystallization, but the reduction of the nitro group with a metal reduction, pollution, can not be large-scale amplification, and the final step off too benzyl byproducts, the yield is low, and this step impurities and more difficult purification, seriously affecting the purity of Mira Veron.

[0006] In addition, US 7982049 B2 (publication date of July 19, 2011) discloses another method of synthesis, synthetic route Mira Veron as follows:

 

Figure CN104230840AD00052

In this method, R- mandelic acid and nitrobenzene hydrochloride or hemisulfate as raw material by EDC condensation, borane, palladium on carbon catalytic hydrogenation, then condensation Mira Veron, however, that Methods exist the following problems: (1) reduction reaction of the second step of borane – tetrahydrofuran solvent amount is too large, a high boiling cosolvent 1,3-dimethyl imidazolidinone difficult to recycle, but also difficult to remove, and the cost of the solvent After the huge cost of treatment, is not conducive to industrial production; (2) reduction of the nitro palladium-carbon catalytic hydrogenation reaction of this step is difficult to obtain high-purity products, and through further study of the present inventors have found that this step will produce more impurities, if the reaction high temperature or pressure, the nitro reduction process will dehydroxylation, CN bond cleavage decomposition impurity production, two of which are difficult to remove impurities in this step and will bring to the next step, and then in Mira Veron finished in generating new impurities.

Example 3, a rice shell drop Eurya synthesis comprises the following steps: Step (1) to the 50L glass reaction vessel was charged with R- mandelic 1.01kg, 4- nitrobenzene hydrochloride 1.4 kg, HOBt 0. 2kg, DMF 6L; control the internal temperature <25 ° C slowly triethylamine 0. 7kg; the addition was complete, the batch was added EDC, plus complete, continue stirring for 1-2 hours; TLC monitoring completion of the reaction ; adding ethyl acetate and 28L 14L water, stirred for 30 minutes, standing layer, the organic phase was lmol / L hydrochloric acid solution 15L wash again, 20% (w / w) aqueous potassium carbonate solution was washed twice (each 15L); The organic phase was dried, suction filtered, and concentrated to give crude product; to give the crude product as a white solid (Intermediate Compound I) was recrystallized from toluene 1. 92kg, 91% yield, content of 99. 6%, ee value of 99%;

Figure CN104230840AD00063

Step (2) to cryogenic 50L glass reactor was added 3kg intermediate compound I, tetrahydrofuran 30L, nitrogen system, control the internal temperature 5 ° C, sodium borohydride was added portionwise, and then boron trifluoride ether solution was added dropwise, with sodium borohydride and equivalent of boron trifluoride compound I equivalent of three times the dropwise addition, the reaction was heated to 80 ° C 10 hours; TLC tracking reaction was completed; controlling the internal temperature <5 ° C, methanol was added dropwise 1L, concentrated hydrochloric acid 2L, Bi dropwise, with stirring; for half an hour, concentrated to recover the organic solvent; to the residue was added 30% (w / w) 20L of an aqueous solution of potassium carbonate, 20L ethyl acetate, stirred for half an hour, standing layer; concentrated; the residue 30L of isopropanol was added and heated to 40 ° C stirred solution clear, 1L concentrated hydrochloric acid was dropped, and stirred to room temperature 20-25 ° C, filtration, 60 ° C and drying to obtain a white solid 2. 93kg (intermediate compound II), yield 91%, purity more than 99%, ee greater than 99%;

Figure CN104230840AD00062

Step (3) To a 20L hydrogenation reaction vessel was charged with intermediate compound 1. 6kg 11,10% palladium on carbon 100g, methanol, 15L; Maintain a hydrogen pressure billion 5MPa, control the internal temperature 25 ° C, 20 hours; TLC tracking reaction to the raw material disappeared; filtration and concentrated; the residue from methanol / ethyl acetate mixture (by volume methanol / ethyl acetate ratio of 1: 10) crystallization, 60 ° C to give 1. 17 kg dry intermediate compound III, yield 81%; purity greater than 99%, ee greater than 99% ^ H-NMR (DMS0-d6) δ (ppm) = 2 . 75-2.90 (2Η, m), 2.96-3.15 (4H, m), 4.96-5.11 (3H, m), 6.21 (1H, d), 6.53 (2H, d), 6.89 (2H, d), 7.29 -7.43 (5H, m), 8.96 (1 H, br), 9.29 (1H, br.);

Figure CN104230840AD00061

step (4) in the reaction vessel was charged with 1. lkg intermediate compound III, 2- aminothiazol-4-acetic acid 0. 65kg, water 16kg; control the internal temperature <25 ° C, the addition of concentrated hydrochloric acid was 0. 4kg, stir in batches to join EDC 0. 784kg, the reaction was stirred at room temperature 20-25 ° C, TLC monitoring of the reaction is complete (about need 1-2 hours); 5L at room temperature was added aqueous sodium hydroxide solution (6% by weight concentration), and stirred for 30 minutes; suction filtered, the filter cake slurried with 10L of water 30 minutes before filtration, drained to obtain a wet produ