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Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia

September 9, 2014 3:30 am / 3 Comments on Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia

Figure imgf000008_0001

Duvelisib

Infinity and AbbVie partner to develop and commercialise duvelisib for cancer

INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone

1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-((1S)-1-(9H-purin-6-ylamino)ethyl)-
8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one

(S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

UNII-610V23S0JI; IPI-145; INK-1197;

Originator…….. Millennium Pharmaceuticals

Molecular Formula		C₂₂H₁₇ClN₆O
Molecular Weight		416.86
CAS Registry Number		1201438-56-3

Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer.

Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).

AbbVie executive vice-president and chief scientific officer Michael Severino said: “We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers.”

http://www.pharmaceutical-technology.com/news/newsinfinity-abbvie-partner-develop-commercialise-duvelisib-cancer-4363381?WT.mc_id=DN_News

Duvelisib (IPI-145, INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia

INK-1197 is a dual phosphatidylinositol 3-Kinase delta (PI3Kdelta) and gamma (PI3Kgamma) inhibitor in phase III clinical development at Infinity Pharmaceuticals for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The company is also carring phase II trials for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma) are currently under way.
IPI-145 is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma. The PI3K-delta and PI3K-gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and non-overlapping roles in key cellular functions, including cell proliferation, cell differentiation, cell migration and immunity. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of blood cancers and inflammatory diseases.
Licensee Infinity Pharmaceuticals is developing INK-1197. In 2014, Infinity licensed Abbvie for joint commercialization in the U.S. and exclusive commercialization elsewhere. Originator Millennium Pharmaceuticals had also been developing the compound; however, no recent development has been reported for this research. In 2013, orphan drug designations were assigned by the FDA and the EMA for the treatment of chronic lymphocytic leukemia, for the treatment of small lymphocytic lymphoma and for the treatment of follicular lymphoma.

currently enrolling patients DYNAMO™, a Phase 2 study designed to evaluate the activity and safety of IPI-145 in approximately 120 people with refractory indolent non-Hodgkin lymphoma (iNHL) and DUO™, a Phase 3 clinical study of IPI-145 in approximately 300 people with relapsed/refractory chronic lymphocytic leukemia (CLL). These studies are supported by Phase 1 data reported at the 2013 American Society of Hematology (ASH) Annual Meeting which showed that IPI-145 was well tolerated and clinically active in a broad range of malignancies, including iNHL and CLL. These studies are part of DUETTS™, a worldwide investigation of IPI-145 in blood cancers.

Chemical structure for Duvelisib

WO 2011008302

http://www.google.com/patents/WO2011008302A1?cl=en

Reaction Scheme 1

Reaction Scheme 2:

201 202 203

204 205

Reaction Scheme 3:

Reaction Scheme 4A:

Reaction Scheme 4B:

Example 14b: Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904)

Scheme 27b. The synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904) is described.

[00493] The compound of Formula 4904 (compound 292 in Table 4) was synthesized using the synthetic transformations as described in Examples 12 and 14a, but 2-chloro-6-methyl benzoic acid (compound 4903) was used instead of 2, 6 ,dimethyl benzoic acid (compound 4403). By a similar method, compound 328 in Table 4 was synthesized using the synthetic transformations as described starting from the 2-chloro-6-methyl m-fluorobenzoic acid.

…………………………………….

http://www.google.com/patents/WO2012097000A1?cl=en OR http://www.google.com/patents/US8809349?cl=en

Formula (I):

(I),

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the method comprises any one, two, three, four, five, six, seven, or eight, or more of the following steps:

“Formula (I)” includes (S)-3-(l -(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):

(1-1)………………………………………………………………………………… (1-2)

[0055] FIG. 27 shows an FT-IR spectra of Polymorph Form C.

[0056] FIG. 28 shows a ‘H-NMR spectra of Polymorph Form C.

[0057] FIG. 29 shows a ¹³C-NMR spectra of Polymorph Form C.

Example 1

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 1A

1 2

[00563] Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt^»H₂0), triethylamine, Ν,Ο-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at

10 °C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95% yield. The R-enantiomer was not detected by proton NMR using (R)-(- ) -alpha-ace tylmandelic acid as a chiral-shift reagent.

[00564] Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H- pyran (DHP) in ethyl acetate at 75 °C for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.

[00565] Compound 5 (3.30 kg) was treated with thionyl chloride and a catalytic amount of DMF in methylene chloride at 25 °C for five hours. The reaction was monitored by HPLC which indicated a 97.5% (AUC) conversion to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25 °C for 15 hours. The reaction was monitored by HPLC and afforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purity by HPLC analysis. [00566] Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20 °C. The resulting solution was added to Compound 7 (3.30 kg) pre -treated with 2.3 M n-hexyl lithium in tetrahydrofuran at -15 °C. The reaction was monitored by HPLC until a 99% (AUC) conversion to Compound 8 was observed.

Compound 8 was treated in situ with concentrated HC1 in isopropyl alcohol at 70 °C for eight hours. The reaction was monitored by HPLC and afforded Compound 9 as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.

Example ID

[00567] Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55 °C for 1-2 hours. The batch was filtered and treated with ammonium hydroxide in deionized (DI) water to afford enantiomerically enriched Compound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91% (AUC) ee by HPLC analysis.

Example 2

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 2A

[00568] To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. The resulting solution was cooled to about -10 °C and 80 mL of n-hexyl lithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g. , over about 20 min). The resulting solution was stirred at about -10 °C for about 20 min.

[00569] To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF. The resulting mixture was cooled to about -10 °C and 60 mL of isopropyl magnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g. , over about 15-20 min). The resulting mixture was then stirred at about -10 °C for about 20 min. The mixture prepared from Compound 2 was added to the solution prepared from Compound 7 while maintaining the internal temperature between about -10 and about 0 °C. After the addition was complete (about 5 min), the cold bath was removed, and the resulting mixture was stirred at ambient temperature for about 1 h, then cooled. [00570] A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37 equiv.) was prepared. The anisole solution was cooled to an internal temperature of about -3 °C. The above reaction mixture was added to the anisole solution such that the internal temperature of the anisole solution was maintained at below about 5 °C. The ice bath was then removed (after about 15 min, the internal temperature was about 7 °C). To the mixture, 100 mL of 10 wt aqueous NaCl solution was rapidly added (the internal temperature increased from about 7 °C to about 15 °C). After stirring for about 30 min, the two phases were separated. The organic phase was washed with another 100 mL of 10 wt aqueous NaCl. The organic phase was transferred to a flask using 25 mL of anisole to facilitate the transfer. The anisole solution was then concentrated to 109 g. Then, 100 mL of anisole was added.

[00571] To the approximately 200 mL of anisole solution was added 50 mL of TFA (8 equiv.) while maintaining the internal temperature below about 45-50 °C. The resulting solution warmed to about 45-50 °C and stirred for about 15 hrs, then cooled to 20-25 °C. To this solution was added 300 mL of MTBE dropwise and then the resulting mixture was held at 20-25 °C for 1 h. The mixture was filtered, and the wet cake washed with approximately 50 mL of MTBE. The wet cake was conditioned on the filter for about 1 h under nitrogen. The wet cake was periodically mixed and re-smoothed during conditioning. The wet cake was then washed with 200 mL of MTBE. The wet cake was further conditioned for about 2 h (the wet cake was mixed and resmoothed after about 1.5 h). The wet cake was dried in a vacuum oven at about 40 °C for about 18 h to afford Compound 9^»TFA salt in about 97.3% purity (AUC), which had about 99.1 % S- enantiomer (e.g. , chiral purity of about 99.1 %).

[00572] Compound 9^»TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20 °C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueous ammonium hydroxide solution and the internal temperature decreased to about 17 °C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 min. The mixing was stopped and the phases were allowed to separate. The aqueous phase was removed. To the organic phase (combined with 5 mL of EtOAc) was added 10 mL of 10% aqueous NaCl. The biphasic mixture was stirred for about 30 min. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture was concentrated to 14.8 g. With stirring, 10 mL of n-heptane was added dropwise. The suspension was stirred for about 30 min, then an additional 10 mL of n-heptane was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned for 20 min under nitrogen, then dried in a vacuum oven at about 40 °C to afford Compound 9 free base in about 99.3% purity (AUC), which had about 99.2% S-enantiomer (e.g., chiral purity of about 99.2%).

Example 2B [00573] A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol) was prepared and cooled to about 3 °C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6 °C. The resulting solution was stirred at 0 ± 5 °C for about 30 minutes. Concurrently, a mixture of Compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining the temperature below about 5 °C. The resulting mixture was stirred for about 35 minutes at 0 ± 5 °C. The Compound 2 magnesium salt mixture was transferred to the Compound 7 lithium salt mixture over about 1 hour while maintaining a temperature of 0 ± 5 °C. The solution was stirred for about 6 minutes upon completion of the transfer.

[00574] The solution was added to an about -5 °C stirring solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) over about 20 minutes during which time the temperature did not exceed about 6 °C. The resulting solution was stirred for about 40 minutes while being warmed to about 14 °C. Then, a 10% sodium chloride solution (500 mL, 5 vol) was rapidly added to the reaction. The temperature rose to about 21 °C. After agitating the mixture for about 6 minutes, the stirring was ceased and the lower aqueous layer was removed (about 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then, the stirring was ceased and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 vol).

[00575] Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was agitated at about 45 °C for about 15 hours. The mixture was cooled to about 35 °C and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was agitated for about 45 minutes at about 25-30 °C. The solids were collected by vacuum filtration and conditioned under N₂ for about 20 hours to afford Compound 9*TFA salt in about 97.5% purity (AUC), which had a chiral purity of about 99.3%.

[00576] Compound 9^»TFA salt (100 g) was suspended EtOAc (1 L,10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30 minutes, then the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. The mixture was stirred for 30 minutes, then the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added, and the mixture was distilled under vacuum to 500 mL (5 vol) while periodically adding in additional isopropyl acetate (1 L, 10 vol).

[00577] Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes (1.5 L, 15 vol) were added over about 110 minutes while maintaining a temperature between about 20 °C and about 30 °C. The resulting slurry was stirred for about 1 hour, then the solid was collected by vacuum filtration. The cake was washed with heptanes (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid was dried in an about 45 °C vacuum oven for about 20 hours to afford Compound 9 free base in about 99.23% purity (AUC), which has a chiral purity of about 99.4%.

Example 3

Chiral Resolution of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9)

[00578] In some instances, (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) obtained by synthesis contained a minor amount of the corresponding (R)-isomer. Chiral resolution procedures were utilized to improve the enantiomeric purity of certain samples of (S)-3-(l-aminoethyl)-8- chloro-2-phenylisoquinolin- 1 (2H)-one.

[00579] In one experiment, Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55 °C for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized (DI) water to afford Compound 9 in greater than about 99% (AUC) purity, which had a chiral purity of about 91% (AUC).

[00580] In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) were stirred at 55 ± 5 °C. D- Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for about 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. The cake was returned to the reactor and water (16 vol.) was charged. The mixture was stirred at 25 ± 5 °C. NH₄OH was then charged over about 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the cake was washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9 free base with a chiral purity of about 99.0%.

Example 4

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00581] A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) was prepared. Separately, a mixture of Compound 2 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min at about 20 to about 25 °C and then cooled to -25 ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 7 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 2 mixture, maintaining the temperature at > 5 °C. The Compound 2 mixture was transferred to the Compound 7 mixture under anhydrous conditions at 0 ± 5 °C. The resulting mixture was warmed to 20 ± 2 °C and held for about 1 h. Then, the reaction was cooled to -5 ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. IPA (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hours. The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were respectively added to the mixture. Then, NH₄OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 9.

[00582] Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 ± 5 °C. NH₄OH was charged over 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9.

[00583] To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was added Compound 4 (1.8 equiv.), Et₃N (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 ± 5 °C. The mixture was held for 24 h. Then the mixture was cooled to about 20 to about 25 °C over about 2 h. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford Compound 10.

To a mixture of EtOH (2.5 vol.) and Compound 10 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 ± 5 °C. The mixture was held for about 1.5 h. The mixture was cooled to 25 ± 5 °C and then polish filtered to a particulate free vessel. NH₄OH was added, adjusting the pH to about 8 to about 9. Crystal seeds of Form C of a compound of Formula (I) (0.3 wt ) were added to the mixture which was held for 30 minutes. DI water (13 vol.) was added over about 2 h. The mixture was held for 1 h and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned for about 24 h and then DCM (5 vol.) was added. This mixture was agitated for about 12 h at about 20 to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 h. The cake was then vacuum-dried at 50 ± 5 °C. To the cake was added DI water (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at 25 ± 5 °C for about 6 h. An XRPD sample confirmed the compound of Formula (I) was Form C. The mixture was filtered and the cake was washed with DI water (5 vol.) followed by n-heptane (3 vol.). The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford a compound of Formula (I) as polymorph Form C. Example 5

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 5A

[00584] Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine in isopropyl alcohol at 80 °C for 24 hours. The reaction was monitored by HPLC until completion, affording 8-chloro-2-phenyl-3- ((lS)-l-(9-(tetrahydro-2H^yran-2-yl)-9H^urin-6-ylamino)ethyl)isoquinolin-l(2H)-one (compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLC analysis.

[00585] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (compound 10) (3.63 kg) was treated with HC1 in ethanol at 30 °C for 2.3 hours. The reaction was monitored by HPLC until completion, and afforded a compound of Formula (I) as a tan solid in 92% yield with >99% (AUC) purity and 90.9% (AUC) ee by HPLC analysis.

Example 5B

[00586] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (0.72 mmol), 6-chloro- 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA

(279 mg, 2.16 mmol) were dissolved in «-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-l(2H)-one (Compound 10), as a white solid (60% yield). [00587] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC0₃ aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH₂C1₂ (50 mL x 3), dried over anhydrous Na₂S0₄, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1 : 1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(l-(9H-purin-6-ylamino) ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.

Example 5C

[00588] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) and 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82 °C for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35 °C to remove the tetrahydropyranyl group to yield (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.

Example 6

Synthesis of (S)-3-(l-(9H^urin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00589] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (150 g; 90% ee) and 6- chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5 °C, held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25 °C for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48 °C for two and half days to give 227 g (90.1 %) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94 ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.

[00590] The intermediate (Compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol) / water (300 mL; 1.5 vol) mixture at 22 °C followed by addition of cone. HC1 (300 mL; 1.5 vol) and holding for one and half hours at 25-35 °C. Addition of HC1 resulted in complete dissolution of all solids producing a dark brown solution. Ammonium hydroxide (260 mL) was added adjusting the pH to 8-9. Product seeds of polymorph Form C (0.5 g) (Form A seeds can also be used) were then added and the batch which was held for ten minutes followed by addition of water (3 L; 15 vol) over two hours resulting in crystallization of the product. The batch was held for 3.5 hours at 20-25 °C and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52 °C for 23 hours to give 155.5 g (93.5%) of product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).

Example 7

-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00591] A mixtue of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04 mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine (2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 h. The temperature was adjusted to 20 ± 5 °C slowly over a period of about 2 h and the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a Sharkskin paper. The filter cake was rinsed sequentially with IPA (5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane (4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuo at 50 ± 5 °C to afford Compound 10.

[00592] To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88 mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To this mixture was slowly added concentrated HC1 (3.10 kg, 3.5 eq.) while maintaining the temperature below about 35 °C. The mixture was stirred at 30 ± 5 °C for about 1.5 h and HPLC analysis indicated the presence the compound of Formula (I) in 99.8% (AUC) purity with respect to compound 10.

[00593] Then, the compound of Formula (I) mixture was cooled to 25 ± 5 °C. The pH of the mixture was adjusted to about 8 using pre filtered ammonium hydroxide (1.90 kg). After stirring for about 15 min, Form C crystal seeds (13.88 g) were added. After stirring for about 15 min, purified water (58.0 kg, 13 vol.) was charged over a period of about 2 h. After stirring the mixture for 15 h at 25 ± 5 °C, the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper. The filter cake was rinsed with purified water (18.55 kg, 4 vol.) followed by pre -filtered n-heptane (6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h, HPLC analysis of the filter cake indicated the presence the compound of Formula (I) in about 99.2% (AUC) purity.

[00594] To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and the slurry was stirred at 25 ± 5 °C for about 24 h. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cake for about 22 h, the filter cake was dried for about 2 days in vacuo at 50 ± 5 °C to afford the compound of Formula (I) in 99.6% (AUC) purity. The compound of Formula (I) was consistent with a Form A reference by XRPD.

[00595] To this solid was added purified water (44.6 kg, 10 vol.) and pre filtered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, a sample of the solids in the slurry was analyzed by XRPD and was consistent with a Form C reference. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with purified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane (9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h, the filter cake was dried in vacuo for about 5 days at 50 ± 5 °C.

[00596] This process afforded a compound of Formula (I) in about 99.6% (AUC) purity, and a chiral purity of greater than about 99% (AUC). An XRPD of the solid was consistent with a Form C reference standard. ^:H NMR (DMSO-<i₆) and IR of the product conformed with reference standard.

…………………………..

http://www.google.com/patents/US20140120083

In some embodiments, the compound has the following structure:

which is also referred to herein as Compound 292.

In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ‘568 publication”), which is hereby incorporated by reference in its entirety.

In one embodiment, the compound is Form A of Compound 292, as described in the ‘568 publication. In another embodiment, the compound is Form B of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form C of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form F of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ‘568 publication.

In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application.

Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.

Chemical entities described herein can be synthesized according to exemplary methods disclosed in U.S. Patent Publication No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby incorporated by reference in its entirety, and/or according to methods known in the art.

……………………………………………

KEY Duvelisib, IPI-145, INK-1197, AbbVie, INFINITY, chronic lymphocytic leukemia, phase 3, orphan drug

WO2013088404A1	Dec 14, 2012	Jun 20, 2013	Novartis Ag	Use of inhibitors of the activity or function of PI3K
WO2014004470A1 *	Jun 25, 2013	Jan 3, 2014	Infinity Pharmaceuticals, Inc.	Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014072937A1	Nov 7, 2013	May 15, 2014	Rhizen Pharmaceuticals Sa	Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor

US7449477 *	Nov 22, 2004	Nov 11, 2008	Eli Lilly And Company	7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B)
US20090312319 *	Jul 15, 2009	Dec 17, 2009	Intellikine	Certain chemical entities, compositions and methods
US20100168153 *	Nov 16, 2007	Jul 1, 2010	Novartis Ag	Salts and crystall forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile

WO2013012915A1	Jul 18, 2012	Jan 24, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013012918A1	Jul 18, 2012	Jan 24, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013032591A1	Jul 18, 2012	Mar 7, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013049332A1	Sep 27, 2012	Apr 4, 2013	Infinity Pharmaceuticals, Inc.	Inhibitors of monoacylglycerol lipase and methods of their use
WO2013088404A1	Dec 14, 2012	Jun 20, 2013	Novartis Ag	Use of inhibitors of the activity or function of PI3K
WO2013154878A1	Apr 3, 2013	Oct 17, 2013	Infinity Pharmaceuticals, Inc.	Heterocyclic compounds and uses thereof
WO2014004470A1 *	Jun 25, 2013	Jan 3, 2014	Infinity Pharmaceuticals, Inc.	Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014071105A1	Nov 1, 2013	May 8, 2014	Infinity Pharmaceuticals, Inc.	Treatment of rheumatoid arthritis and asthma using p13 kinase inhibitors
WO2014071109A1	Nov 1, 2013	May 8, 2014	Infinity Pharmaceuticals, Inc.	Treatment of cancers using pi3 kinase isoform modulators
WO2014072937A1	Nov 7, 2013	May 15, 2014	Rhizen Pharmaceuticals Sa	Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor

WO2001081346A2	Apr 24, 2001	Nov 1, 2001	Icos Corp	Inhibitors of human phosphatidyl-inositol 3-kinase delta
US6800620	Jan 6, 2003	Oct 5, 2004	Icos	Contacting leukocytes, osteoclasts with an enzyme inhibitors, a 9h-purin-3h-quinazolin-4-one derivatives, treating bone-resorption disorder, antiproliferative agents treating leukemia cells
US20060276470 *	Aug 18, 2003	Dec 7, 2006	Jackson Shaun P	(+-)-7-Methyl-2-morpholin-4-yl-9-(1-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one, for example; selective inhibitors of phosphoinositide (PI) 3-kinase beta for use in anti-thrombotic therapy
US20080032960 *	Apr 4, 2007	Feb 7, 2008	Regents Of The University Of California	PI3 kinase antagonists

FDA GIVES INSYS PHARMACEUTICAL CANNABIDIOL ORPHAN STATUS

August 26, 2014 10:46 am / 1 Comment on FDA GIVES INSYS PHARMACEUTICAL CANNABIDIOL ORPHAN STATUS

FDA Gives Insys Pharmaceutical Cannabidiol Orphan Status

Insys Therapeutics Inc., a specialty pharmaceutical company that is developing and commercializing innovative drugs and novel drug delivery systems, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its pharmaceutical cannabidiol (CBD) for the treatment of glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in humans.

read at

http://www.dddmag.com/news/2014/08/fda-gives-insys-pharmaceutical-cannabidiol-orphan-status?et_cid=4117613&et_rid=523035093&type=cta

– See more at: http://worlddrugtracker.blogspot.in/#sthash.mFuiI6Hm.dpuf

With Persistence And Phase 3 Win, Amicus Nears First Drug Approval …….Migalastat

August 21, 2014 10:56 am / Leave a comment

Migalastat hydrochloride

CAS Number: 75172-81-5 hydrochloride

CAS BASE….108147-54-2

ABS ROT = (+)

+53.0 °

Conc: 1 g/100mL; Solv: water ; 589.3 nm; Temp: 24 °C

IN Van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-

Molecular Structure:

Formula: C6H14ClNO4

Molecular Weight:199.63

Synonyms: 3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, (2R,3S,4R,5S)- (9CI);

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, [2R-(2a,3a,4a,5b)]-;

Migalastat hydrochloride;Galactostatin hydrochloride;

(2S,3R,4S,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride;

1-Deoxygalactonojirimycin
1-Deoxygalactostatin
Amigal
DDIG
Migalastat
UNII-C4XNY919FW

Melting Point:160 °C-162…….http://www.google.com/patents/DE3906463A1?cl=de

Boiling Point:382.7 °C at 760 mmHg

Flash Point:185.2 °C

Amicus Therapeutics, Inc. innovator

Aug 2014

http://www.xconomy.com/new-york/2014/08/20/with-persistence-and-phase-3-win-amicus-nears-first-drug-approval/?utm_source=rss&utm_medium=rss&utm_campaign=with-persistence-and-phase-3-win-amicus-nears-first-drug-approval

Amicus Therapeutics was on the ropes in late 2012 when its pill for a rare condition called Fabry Disease108147-54-2 failed a late-stage trial. It had already put seven years of work into the drug, and the setback added even more development time and uncertainty to the mix. But the Cranbury, NJ-based company kept plugging away, and now it looks like all the effort could lead to its first approved drug.

Amicus (NASDAQ: FOLD) is reporting today that the Fabry drug, migalastat, succeeded in the second of two late-stage trials. It hit two main goals that essentially measured its ability to slow the decline of Fabry patients’ kidney function comparably to enzyme-replacement therapy (ERT)—the standard of care for the often-fatal disorder.

Amicus believes the results, along with those from an earlier Phase 3 trial comparing migalastat to a placebo, are good enough to ask regulators in the U.S. and Europe for market approval.

“These are the good days to be a CEO,” says Amicus CEO John Crowley (pictured above). “It’s great when a plan comes together and data cooperates.”

Crowley says Amicus will seek approval of migalastat first in Europe and is already in talks with regulators there. In the next few months, Amicus will begin talking with the FDA about a path for approval in the U.S. as well.

End feb 2013

About Amicus Therapeutics

Amicus Therapeutics is a biopharmaceutical company at the forefront of therapies for rare and orphan diseases. The Company is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases. Amicus’ late-stage programs for lysosomal storage disorders include migalastat HCl monotherapy in Phase 3 for Fabry disease; migalastat HCl co-administered with enzyme replacement therapy (ERT) in Phase 2 for Fabry disease; and AT2220 co-administered with ERT in Phase 2 for Pompe disease.

About Migalastat HCl

Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world.

As a monotherapy, migalastat HCl is designed to bind to and stabilize, or “chaperone” a patient’s own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.

For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development.

About Fabry Disease

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called “substrates” of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

1. Bichet, et al., A Phase 2a Study to Investigate the Effect of a Single Dose of Migalastat HCl, a Pharmacological Chaperone, on Agalsidase Activity in Subjects with Fabry Disease, LDN WORLD 2012

2. Benjamin, et al., Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726.

http://clinicaltrials.gov/show/NCT01458119

http://www.docstoc.com/docs/129812511/migalastat-hcl

Migalastat hydrochloride is a pharmacological chaperone in phase III development at Amicus Pharmaceuticals for the oral treatment of Fabry’s disease. Fabry’s disease occurs as the result of an inherited genetic mutation that results in the production of a misfolded alpha galactosidase A (alpha-GAL) enzyme, which is responsible for breaking down globotriaosylceramide (GL-3) in the lysosome. Migalastat acts by selectively binding to the misfolded alpha-GAL, increasing its stability and promoting proper folding, processing and trafficking of the enzyme from the endoplasmic reticulum to the lysosome.

In February 2004, migalastat hydrochloride was granted orphan drug designation by the FDA for the treatment of Fabry’s disease.

The EMEA assigned orphan drug designation for the compound in 2006 for the treatment of the same indication. In 2007, the compound was licensed to Shire Pharmaceuticals by Amicus Therapeutics worldwide, with the exception of the U.S., for the treatment of Fabry’s disease.

In 2009, this license agreement was terminated. In 2010, the compound was licensed by Amicus Therapeutics to GlaxoSmithKline on a worldwide basis to develop, manufacture and commercialize migalastat hydrochloride as a treatment for Fabry’s disease, but the license agreement terminated in 2013.

Chemical Name:	DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE
Synonyms:	DGJ;Amigal;Unii-cly7m0xd20;GALACTOSTATIN HCL;DGJ, HYDROCHLORIDE;Migalastat hydrochloride;Galactostatin hydrochloride;DEOXYGALACTONOJIRIMYCIN HCL;1-DEOXYGALACTONOJIRIMYCIN HCL;1,5-dideoxy-1,5-imino-d-galactitol

DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE Structure

………………………..

Links

http://www.google.co.in/patents/WO1999062517A1?cl=en

Example 1

A series of plant alkaloids (Scheme 1, ref. 9) were used for both in vitro inhibition and intracellular enhancement studies of α-Gal A activity. The results of inhibition experiments are shown in Fig. 1 A.

Among the tested compounds, 1-deoxy-galactonojirimycin (DGJ, 5) known as a powerful competitive inhibitor for α-Gal A, showed the highest inhibitory activity with IC₅₀ at 4.7 nM. α-3,4-Di-epi-homonojirimycin (3) was an effective inhibitor with IC₅₀ at 2.9 μM. Other compounds showed moderate inhibitory activity with IC₅₀ ranging from 0.25 mM (6) to 2.6 mM (2). Surprisingly, these compounds also effectively enhanced α-Gal A activity in COS-1 cells transfected with a mutant α-Gal A gene (R301Q), identified from an atypical variant form of Fabry disease with a residual α- Gal A activity at 4% of normal. By culturing the transfected COS-1 cells with these compounds at concentrations cat 3 – 10-fold of IC₅₀ of the inhibitors, α-Gal A activity was enhanced 1.5 – 4-fold (Fig. 1C). The effectiveness of intracellular enhancement paralleled with in vitro inhibitory activity while the compounds were added to the culture medium at lOμM

concentration (Fig. IB).

………………………

Links

WO 2008045015

or http://www.google.com/patents/EP2027137A1?cl=en, http://www.google.com/patents/US7973157?cl=en

This invention relates to a process for purification of imino or amino sugars, such as D-1-deoxygalactonojirimycin hydrochloride (DGJ’HCl). This process can be used to produce multi-kilogram amounts of these nitrogen-containing sugars.

Sugars are useful in pharmacology since, in multiple biological processes, they have been found to play a major role in the selective inhibition of various enzymatic functions. One important type of sugars is the glycosidase inhibitors, which are useful in treatment of metabolic disorders. Galactosidases catalyze the hydrolysis of glycosidic linkages and are important in the metabolism of complex carbohydrates. Galactosidase inhibitors, such as D-I- deoxygalactonojirimycin (DGJ), can be used in the treatment of many diseases and conditions, including diabetes (e.g., U.S. Pat. 4,634,765), cancer (e.g., U.S. Pat. 5,250,545), herpes (e.g. , U.S. Pat. 4,957,926), HIV and Fabry Disease (Fan et al, Nat. Med. 1999 5:1, 112-5).

Commonly, sugars are purified through chromatographic separation. This can be done quickly and efficiently for laboratory scale synthesis, however, column chromatography and similar separation techniques become less useful as larger amounts of sugar are purified. The size of the column, amount of solvents and stationary phase (e.g. silica gel) required and time needed for separation each increase with the amount of product purified, making purification from multi-kilogram scale synthesis unrealistic using column chromatography.

Another common purification technique for sugars uses an ion- exchange resin. This technique can be tedious, requiring a tedious pre-treatment of the ion exchange resin. The available ion exchange resins are also not necessarily able to separate the sugars from salts (e.g., NaCl). Acidic resins tend to remove both metal ions found in the crude product and amino- or imino-sugars from the solution and are therefore not useful. Finding a resin that can selectively remove the metal cations and leave amino- or imino-sugars in solution is not trivial. In addition, after purification of a sugar using an ion exchange resin, an additional step of concentrating the diluted aqueous solution is required. This step can cause decomposition of the sugar, which produces contaminants, and reduces the yield.

U.S. Pats. 6,740,780, 6,683,185, 6,653,482, 6,653,480, 6,649,766, 6,605,724, 6,590,121, and 6,462,197 describe a process for the preparation of imino- sugars. These compounds are generally prepared from hydroxyl-protected oxime intermediates by formation of a lactam that is reduced to the hexitol. However, this process has disadvantages for the production on a multi-kg scale with regard to safety, upscaling, handling, and synthesis complexity. For example, several of the disclosed syntheses use flash chromatography for purification or ion-exchange resin treatment, a procedure that is not practicable on larger scale. One particularly useful imino sugar is DGJ. There are several DGJ preparations disclosed in publications, most of which are not suitable for an industrial laboratory on a preparative scale (e.g., >100 g). One such synthesis include a synthesis from D-galactose (Santoyo-Gonzalez, et al, Synlett 1999 593-595; Synthesis 1998 1787-1792), in which the use of chromatography is taught for the purification of the DGJ as well as for the purification of DGJ intermediates. The use of ion exchange resins for the purification of DGJ is also disclosed, but there is no indication of which, if any, resin would be a viable for the purification of DGJ on a preparative scale. The largest scale of DGJ prepared published is 13 g (see Fred-Robert Heiker, Alfred Matthias Schueller, Carbohydrate Research, 1986, 119-129). In this publication, DGJ was isolated by stirring with ion-exchange resin Lewatit MP 400 (OH^“) and crystallized with ethanol. However, this process cannot be readily scaled to multi- kilogram quantities.

Similarly, other industrial and pharmaceutically useful sugars are commonly purified using chromatography and ion exchange resins that cannot easily be scaled up to the purification of multi-kilogram quantities.

Therefore, there is a need for a process for purifying nitrogen- containing sugars, preferably hexose amino- or imino-sugars that is simple and cost effective for large-scale synthesis

FIG. 1. HPLC of purified DGJ after crystallization. The DGJ is over 99.5% pure.

FIG. 2A. ¹H NMR of DGJ (post HCl extraction and crystallization), from 0 – 15 ppm in DMSO.

FIG. 2B. ¹H NMR of DGJ (post HCl extraction and crystallization), from 0 – 5 ppm, in DMSO.

FIG. 3 A. ¹H NMR of purified DGJ (after recrystallization), from 0 – 15 ppm, in D₂O. Note OH moiety has exchanged with OD.

FIG. 3B. ¹H NMR of purified DGJ (after recrystallization), from 0 –

4 ppm, in D₂O. Note OH moiety has exchanged with OD.

FIG. 4. ¹³C NMR of purified DGJ, (after recrystallization), 45 – 76 ppm.

One amino-sugar of particular interest for purification by the method of the current invention is DGJ. DGJ, or D-l-deoxygalactonojirimycin, also described as (2R,3S,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine and 1- deoxy-galactostatin, is a noj irimycin (5-amino-5-deoxy-D-galactopyranose) derivative of the form:

Example 1: Preparation and Purification of DGJ

A protected crystalline galactofuranoside obtained from the technique described by Santoyo-Gonzalez. 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-α-D- galactofuranoside (1250 g), was hydrogenated for 1-2 days using methanol (10 L) with palladium on carbon (10%, wet, 44 g) at 50 psi of H₂. Sodium methoxide (25% in methanol, 1.25 L) was added and hydrogenation was continued for 1-2 days at 100 psi ofH₂. Catalyst was removed by filtration and the reaction was acidified with methanolic hydrogen chloride solution (20%, 1.9 L) and concentrated to give crude mixture of DGJ • HCl and sodium chloride as a solid. The purity of the DGJ was about 70% (w/w assay), with the remaining 30% being mostly sodium chloride.

The solid was washed with tetrahydrofuran (2 x 0.5 L) and ether (I x 0.5 L), and then combined with concentrated hydrochloric acid (3 L). DGJ went into solution, leaving NaCl undissolved. The obtained suspension was filtered to remove sodium chloride; the solid sodium chloride was washed with additional portion of hydrochloric acid (2 x 0.3 L). All hydrochloric acid solution were combined and slowly poured into stirred solution of tetrahydrofuran (60 L) and ether (11.3 L). The precipitate formed while the stirring was continued for 2 hours. The solid crude DGJ* HCl, was filtered and washed with tetrahydrofuran (0.5 L) and ether (2 x 0.5 L). An NMR spectrum is shown in FIGS. 2A-2B.

The solid was dried and recrystallized from water (1.2 mL /g) and ethanol (10 ml/1 ml of water). This recrystallization step may be repeated. This procedure gave white crystalline DGJ* HCl, and was usually obtained in about 70- 75% yield (320 – 345 g). The product of the purification, DGJ-HCl is a white crystalline solid, HPLC >98% (w/w assay) as shown in FIG. 1. FIGS. 3A-3D and FIG. 4 show the NMR spectra of purified DGJ, showing the six sugar carbons.

Example 2: Purification of 1-deoxymannojirimycin 1 -deoxymannojirimycin is made by the method described by Mariano

(J. Org. Chem., 1998, 841-859, see pg. 859, herein incorporated by reference). However, instead of purification by ion-exchange resin as described by Mariano, the 1-deoxymannojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the 1-deoxymannojirimycin hydrochloride is precipitated crystallized using solvents known for recrystallization of 1- deoxymannojirimycin (THF for crystallization and then ethanol/water.

Example 3: Purification of (+)-l-deoxynojirimycin

(+)-l-deoxynojirimycin is made by the method Kibayashi et al. (J. Org. Chem., 1987, 3337-3342, see pg. 334I₅ herein incorporated by reference). It is synthesized from a piperidine compound (#14) in HCl/MeOH. The reported yield of 90% indicates that the reaction is essentially clean and does not contain other sugar side products. Therefore, the column chromatography used by Kibayashi is for the isolation of the product from non-sugar related impurities. Therefore, instead of purification by silica gel chromatography, the (+)-l-deoxynojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

Example 4: Purification of Nojirimycin

Nojirimycin is made by the method described by Kibayashi et al. (J.

Org. Chem., 1987, 3337-3342, see pg. 3342). However, after evaporating of the mixture at reduced pressure, instead of purification by silica gel chromatography with ammonia-methanol-chloroform as described by Kibayashi, the nojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the impurities not dissolved in HCl and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

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Links

Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine

Tetrahedron Lett 1995, 36(5): 653

Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine

Original Research Article
Pages 653-654
Carl R. Johnson, Adam Golebiowski, Hari Sundram, Michael W. Miller, Renee L. Dwaihy
Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and indolizidine 4.

Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and the structurally related indolizidine 4.

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Links

Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-galactitol) starting from 1-deoxynojirimycin

Carbohydr Res 1990, 203(2): 314

Synthesis of d-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-d-galactitol) starting from 1-deoxynojirimycin
Pages 314-318
Fred-Robert Heiker, Alfred Matthias Schueller
- First page PDF

………………………………..

Synthesis of (+)-1,5-dideoxy-1,5-imino-D-galactitol, a potent alpha-D-galactosidase inhibitor

Carbohydr Res 1987, 167: 305

Synthesis of (+)-1,5-dideoxy-1,5-imino-d-galactitol, a potent α-d-galactosidase inhibitor
Pages 305-311
Ronald C. Bernotas, Michael A. Pezzone, Bruce Ganem
- First page PDF

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Links

SEE

Monosaccharides containing nitrogen in the ring, XXXVII. Synthesis of 1,5-didexy-1,5-imino-D-galactitol

Chem Ber 1980, 113(8): 2601

…………………………

Links

Org. Lett., 2010, 12 (17), pp 3957–3959

DOI: 10.1021/ol101556k

http://pubs.acs.org/doi/abs/10.1021/ol101556k

+53.0 °

Conc: 1 g/100mL; Solv: water ; 589.3 nm; Temp: 24 °C

van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959

The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction−transimination−sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.

http://pubs.acs.org/doi/suppl/10.1021/ol101556k/suppl_file/ol101556k_si_002.pdf

COMPD 18

D-galacto-1-deoxynojirimicin.HCl (18).

D-N-Boc-6-OBn-galacto-1-deoxynojirimicin (159 mg, 0.450 mmol) was dissolved in a mixture of MeOH

(10 mL) and 6 M HCl (2 mL). The flask was purged with argon, Pd/C-10% (20 mg) was added and a balloon

with hydrogen gas was placed on top of the reaction. The mixture was stirred overnight at room temperature.

Pd/C was removed by filtration and the filtrate evaporated to yield the crude product (90 mg, 100%) as a

white foam that needed no further purification.

[α]24D = + 53.0 (c = 1, H2O);

[lit4a [α]24D = +44.6 (c = 0.9, H2O); lit4b [α]20D = +46.1 (c = 0.9, H2O)].

HRMS calculated for [C6H13NO4 + H]+164.09173; Found 164.09160.

1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 2.7, 1.1 Hz, 1H), 4.11 (ddd, J = 11.4, 9.7, 5.4 Hz, 1H), 3.88 (ddd,

J = 20.9, 12.2, 6.8 Hz, 2H), 3.68 (dd, J = 9.7, 3.0 Hz, 1H), 3.55 (dd, J = 12.5, 5.4 Hz, 1H), 3.46 (ddd, J = 8.6,

4.8, 1.0 Hz, 1H), 2.97 – 2.86 (t, J = 12.0 Hz, 1H). [lit4c supporting information contains 1

H NMR-spectrumof an authentic sample].

13C NMR (101 MHz, D2O) δ 73.01, 66.97, 64.69, 60.16, 59.15, 46.15

4a) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Núñez, F.; Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240

– 2255.

4b) Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601 – 2608. c)

McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565 – 3568.

……………………………………….

(- ) FORM………… BE CAREFUL

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin

Org Lett 2010, 12(6): 1145

http://pubs.acs.org/doi/abs/10.1021/ol100037c

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to α-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.

Figure 1. Structures of nojirimycin (1) and DGJ (2).

SEE SUPP INFO

http://pubs.acs.org/doi/suppl/10.1021/ol100037c/suppl_file/ol100037c_si_001.pdf

(-)-1-deoxygalactojirimycin hydrochloride as transparent colorless needles.

[α]D -51.4 (D2O, c 1.0)

1H-NMR (D2O) δ ppm 4.09 (dd, 1H, J 2.9 Hz, 1.3 Hz), 4.00 (ddd, 1H, J = 11.3 Hz, 9.7 Hz, 5.3 Hz),

3.80 (dd, 1H, J = 12,1 Hz, 8.8 Hz), 3.73 (dd, 1H, J = 12.1 Hz, 8.8 Hz), 3.56 (dd, 1H, J = 9.7 Hz, 2.9

Hz), 3.44 (dd, 1H, J = 12.4 Hz, 5.3 Hz), 3.34 (ddd, 1H, J = 8.7 Hz, 4.8 Hz, 1.0 Hz), 2.8 (app. t, 1H,

J = 12.0 Hz)

13C-NMR (D2O, MeOH iSTD) δ 73.6, 67.5, 65.3, 60.7, 59.7, 46.7

HRMS Measured 164.0923 (M + H – Cl) Calculated 164.0923 (C6H13NO4 + H – Cl)

…………………………………………………..

Links

Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block

Org Lett 2003, 5(14): 2527

http://pubs.acs.org/doi/abs/10.1021/ol034886y

A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 1−3 was carried out via the use of 4in a highly stereocontrolled mode.

mp 135-135.5 °C [lit.3mp 137-139 °C];

[α]D25 +27.8° (c 0.67, H2O)

[lit.3[α]D23 +28° (c 0.5, H2O)];

1H NMR (300 MHz, D2O) δ 2.59–2.65 (m, 1H), 2.81–2.87 (m, 1H),

3.02–3.08 (m, 1H), 3.46–3.48 (m, 2H), 3.59–3.66 (m, 3H); 13C NMR (75 MHz, D2O) δ 44.7, 57.1,

58.4, 70.9, 71.4, 73.3 [lit4 13C NMR (125 MHz, D2O) δ 44.5, 56.8, 58.3, 70.1, 70.7, 72.3];

HRMScalcd for C6H13NO4 (M+) 163.0855, Found 163.0843. Anal. calcd for C6H13NO4: C, 44.16; N,

8.58; H, 8.03. Found: C, 44.31; N, 8.55; H, 7.71.

3. Schaller, C.; Vogel, P.; Jager, V. Carbohydrate Res. 1998, 314, 25-35.

4. Lee, B. W.; Jeong, Ill-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305-1309.

…………………………………………..

Links

Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: Five- versus six-membered ring formation

J Org Chem 2013, 78(19): 9791

http://pubs.acs.org/doi/abs/10.1021/jo401512h

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

……………………………………………

Links

Ruiz, Maria; Journal of Organic Chemistry 2008, 73(6), 2240-2255

http://pubs.acs.org/doi/abs/10.1021/jo702601z

ROT +44.6 ° Conc: 0.9 g/100mL; Solv: water ; 589.3 nm; Temp: 24 °C

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the γ-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, hightrans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-l-altronojirimycin, 1-deoxy-d-gulonojirimycin, 1-deoxy-d-galactonojirimycin, 1-deoxy-l-idonojirimycin and 1-deoxy-d-talonojirimycin.

…………………..

Links

J. Org. Chem., 1991, 56 (2), pp 815–819

DOI: 10.1021/jo00002a057

http://pubs.acs.org/doi/abs/10.1021/jo00002a057

………………

Links

Hinsken, Werner; DE 3906463 A1 1990

http://www.google.com/patents/DE3906463A1?cl=de

Example 1 Preparation of 1,5-dideoxy-1,5-imino-D-glucitol hydrobromide

A suspension of 1,5-dideoxy-1,5-imino-D-glucitol (500 g) in isopropanol (2 l) with 48% hydrochloric acid, bromine (620 g). The suspension is stirred for 2 hours at 40 ° C, cooled to 0 ° C and the product isolated by filtration.

Yield: 700 g (93% of theory),
mp: 184 ° C.

Example 2 Preparation of 1,5-dideoxy-1,5-imino-D-mannitol hydrobromide

The prepared analogously to Example 1 from 1,5-dideoxy 1,5-imino-D-mannitol and 48% hydrobromic acid.

Yield: 89% of theory;

C₆H₁₄NO₄Br (244.1)
Ber .: C 29.5%; H 5.8%; N 5.7%; Br 32.7%;
vascular .: C 29.8%; H 5.8%; N 5.8%; Br 32.3%.

Example 3 Preparation of 1,5-dideoxy-1,5-imino-D-Galactitol- hydrochloride

The preparation was carried out analogously to Example 1 from 1,5-dideoxy-1,5-imino-D-galactitol and corresponding mole ratios of 37% hydrochloric acid.
yield: 91% of theory
, mp: 160-162 ° C.

Amat et al., “Eantioselective Synthesis of 1-deoxy-D-gluonojirimycin From A Phenylglycinol Derived Lactam,” Tetrahedron Letters, pp. 5355-5358, 2004.
2		Chernois, “Semimicro Experimental Organic Chemistry,” J. de Graff (1958), pp. 31-48.
3		Encyclopedia of Chemical Technology, 4th Ed., 1995, John Wiley & Sons, vol. 14: p. 737-741.
4		Heiker et al., “Synthesis of D-galacto-1-deoxynojirimycin (1, 5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin.” Carbohydrate Research, 203: 314-318, 1990.
5		Heiker et al., 1990, “Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin,” Carbohydrate Research, vol. 203: p. 314-318.
6	*	Joseph, Carbohydrate Research 337 (2002) 1083-1087.
7	*	Kinast et al. Angew. Chem. Int. Ed. Engl. 20 (1998), No. 9, pp. 805-806.
8	*	Lamb, Laboratory Manual of General Chemistry, Harvard University Press, 1916, p. 108.
9		Linden et al., “1-Deoxynojirimycin Hydrochloride,” Acta ChrystallographicaC50, pp. 746-749, 1994.
10		Mellor et al., Preparation, biochemical characterization and biological properties of radiolabelled N-alkylated deoxynojirimycins, Biochem. J. Aug. 15, 2002; 366(Pt 1):225-233.
11	*	Mills, Encyclopedia of Reagents for Organic Synthesis, Hydrochloric Acid, 2001 John Wily & Sons.
12		Santoyo-Gonzalez et al., “Use of N-Pivaloyl Imidazole as Protective Reagent for Sugars.” Synthesis 1998 1787-1792.
13		Schuller et al., “Synthesis of 2-acetamido-1, 2-dideoxy-D-galacto-nojirimycin (2-acetamido-1, 2, 5-trideoxy-1, 5-imino-D-galacitol) from 1-deoxynojirimycin.” Carbohydrate Res. 1990; 203: 308-313.
14		Supplementary European Search Report dated Mar. 11, 2010 issued in corresponding European Patent Application No. EP 06 77 2888.
15		Uriel et al., A Short and Efficient Synthesis of 1,5-dideoxy-1,5-imino-D-galactitol (1-deoxy-D-galactostatin) and 1,5-dideoxy-1,5-dideoxy-1,5-imino-L-altritol (1-deoxy-L-altrostatin) From D-galactose, Synlett (1999), vol. 5, pp. 593-595.

1-Deoxygalactonojirimycin:

(a) Liguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron2000, 56, 5819−5833.

(b) Mehta, G.; Mohal, N. Tetrahedron Lett. 2000, 41, 5741−5745.

(d) Johnson, C. R.; Golebiowsky, A.; Sundram, H.; Miller, M. W.; Dwaihy, R. L. TetraherdonLett. 1995, 36, 653−654.

(e) Uriel, C.; Santoyo-Gonzalez, F. Synlett 1999, 593−595.

(f) Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J. M. Tetrahedron Lett. 1999, 40, 2021−2024.

(g) Shilvock, J. P.; Fleet, G. W. J. Synlett 1998, 554−556.

(h) Chida, N.; Tanikawa, T.; Tobe, T.; Ogawa, S. J. Chem. Soc., Chem. Commun. 1994, 1247−1248.

(i) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 815−819.

(j) Kajimoto, T.; Chen, L.; Liu, K. K. C.; Wong, C. H. J. Am. Chem. Soc. 1991, 113, 6678−6680.

(k) Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167, 305−311. 1-Deoxyidonojirimycin:

(l) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387−2391.

(m) Schaller, C.; Vogel, P.; Jager, V. Carbohydr. Res. 1998, 314, 25−35.

(n) Fowler, P. A.; Haines, A. H.; Taylor, R. J. K.; Chrystal, E. J. T.; Gravestock, M. B. Carbohydr. Res. 1993,246 377−381.

(o) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C. H.J. Org. Chem. 1991, 56, 6280−6289. 1-Deoxygulonojirimycin: ref 5l.

(p) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401−404.

(q) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahedron: Asymmetry 2002, 13, 795−799. (r) Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron: Asymmetry 1999, 10, 3649−3657.

Eisai’s lenvatinib 兰伐替尼レンバチニブ to get speedy review in Europe

August 4, 2014 4:28 am / 3 Comments on Eisai’s lenvatinib 兰伐替尼レンバチニブ to get speedy review in Europe

Lenvatinib

For the treatment of patients with progressive radioiodine-refractory, differentiated thyroid cancer (RR-DTC).

CAS 417716-92-8,

CAS 857890-39-2 (lenvatinib mesylate)

E 7080, ER-203492-00, E7080, E 7080,

4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide

Molecular Formula: C₂₁H₁₉ClN₄O₄

Molecular Weight: 426.85296

Eisai Co., Ltd INNOVATOR

	Eisai R&D Management Co., Ltd.

Eisai R&D Management Co., Ltd.

エーザイ・アール・アンド・ディー・マネジメント株式会社

European regulators have agreed to undertake an accelerated assessment of Eisai’s lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer.

The drug, which carries Orphan Status in the EU, is to be filed “imminently” and could become the first in a new class of tyrosine kinase inhibitors, the drugmaker said.

Lenvatinib was granted Orphan Drug Designation for thyroid cancer by the health authorities in Japan in 2012, and in Europe and the U.S in 2013. The first application for marketing authorization of lenvatinib in the world was submitted in Japan on June 2014. Eisai is planning to submit applications for marketing authorization in Europe and the U.S. in the second quarter of fiscal 2014.

Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRalpha, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib a first-in-class treatment, especially given that it simultaneously inhibits the kinase activities of FGFR as well as VEGFR.

Eisai's lenvatinib to get speedy review in Europe

LENVATINIB BASE

COSY PREDICT

Systematic (IUPAC) name
4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide
Clinical data
Legal status	℞ Prescription only
Identifiers
CAS number
ATC code	None
PubChem	CID 9823820
ChemSpider	7999567
UNII	EE083865G2

Chemical data
Formula	C₂₁H₁₉Cl N₄O₄
Mol. mass	426.853 g/mol

Lenvatinib (E7080) is a multi-kinase inhibitor that is being investigated for the treatment of various types of cancer by Eisai Co. It inhibits both VEGFR2 and VEGFR3 kinases.^[1]

The substence was granted orphan drug status for the treatment of various types of thyroid cancer that do not respond toradioiodine; in the US and Japan in 2012 and in Europe in 2013^[2] and is now approved for this use.

Clinical trials

Lenvatinib has had promising results from a phase I clinical trial in 2006^[3] and is being tested in several phase II trials as of October 2011, for example against hepatocellular carcinoma.^[4] After a phase II trial testing the treatment of thyroid cancer has been completed with modestly encouraging results,^[5] the manufacturer launched a phase III trial in March 2011.^[6]

Chemical structure for Lenvatinib

Lenvatinib Mesilate

Molecular formula: C21H19ClN4O4,CH4O3S =523.0.

CAS: 857890-39-2.

UNII code: 3J78384F61.

About the Lenvatinib (E7080) Phase II Study
The open-label, global, single-arm Phase II study of multi-targeted kinase inhibitor lenvatinib (E7080) in advanced radioiodine (RAI)-refractory differentiated thyroid cancer involved 58 patients with advanced RAI refractory DTC (papillary, follicular or Hurthle Cell) whose disease had progressed during the prior 12 months. (Disease progression was measured using Response Evaluation Criteria in Solid Tumors (RECIST).) The starting dose of lenvatinib was 24 mg once daily in repeated 28 day cycles until disease progression or development of unmanageable toxicities.

2. About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat or near the trachea. It affects more women than men and usually occurs between the ages of 25 and 65.
The most common types of thyroid cancer, papillary and follicular (including Hurthle Cell), are classified as differentiated thyroid cancer and account for 95 percent of all cases. While most of these are curable with surgery and radioactive iodine treatment, a small percentage of patients do not respond to therapy.

3. About Lenvatinib (E7080)
Lenvatinib is multi-targeted kinase inhibitor with a unique receptor tyrosine kinase inhibitory profile that was discovered and developed by the Discovery Research team of Eisai’s Oncology Unit using medicinal chemistry technology. As an anti-angiogenic agent, it inhibits tyrosine kinase of the VEGF (Vascular Endothelial Growth Factor) receptor, VEGFR2, and a number of other types of kinase involved in angiogenesis and tumor proliferation in balanced manner. It is a small molecular targeting drug that is currently being studied in a wide array of cancer types.

4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).

However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

[Patent Document 1] WO 02/32872

[Patent Document 2] WO 2004/080462

[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004

………………………..

PATENT

http://www.google.co.in/patents/US8058474

EXAMPLES

Examples will now be described to facilitate understanding of the invention, but the invention is not limited to these examples.

Example 1Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.

¹H-NMR (CDCl₃): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s)

Example 21-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice and the mixture was stirred overnight at room temperature. Water (400 mL), ethyl acetate (300 mL) and 6N HCl (55 mL) were then added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the title compound (77% yield from 4-amino-3-chlorophenol).

¹H-NMR (CDCl₃): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8H)

Example 34-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).

¹H-NMR (d₆-DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz)

Example 44-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).

…………………………

SYNTHESIS

1H NMR PREDICT

13 C NMR PREDICT

…………………..

PATENT

http://www.google.co.in/patents/US7253286

EX 368

Figure US07253286-20070807-C00838

Example 368

4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as white crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70 mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 368-1Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as light brown crystals from 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.745 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.14 (3H, s), 5.89 (1H, br), 6.50 (1H, d, J=5.6 Hz), 7.16 (2H, dd, J=2.4, 8.8 Hz), 7.22–7.30 (4H, m), 7.44 (2H, m), 7.55 (1H, s), 7.81 (1H, br), 8.31 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s).

……………………

CRYSTALLINE FORM

http://www.google.co.in/patents/US7612208

Preparation Example 1

Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)

Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).

Preparation Example 2Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)

(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.

¹H-NMR Spectrum (CDCl₃) δ(ppm): 5.12 (1H, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s).
(2) Preparation of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).

¹H-NMR Spectrum (CDCl₃) δ(ppm): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8 Hz)
(3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).

Preparation Example 3Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)

7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).

¹H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.

Example 5

A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)

(Preparation Method 1)

In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).

(Preparation Method 2)

In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).

Example 6A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)

A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg)…………MORE IN PATENT

……………………………..

PATENT

https://www.google.com/patents/WO2014098176A1?cl=en

According to the present invention 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide amorphous is excellent in solubility in water.

Example 1 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide manufacture of amorphous amide
4- (3-chloro-4- (cyclopropylamino-carbonyl) amino phenoxy) -7-methoxy-6-quinolinecarboxamide B-type crystals (Patent Document 2) were weighed to 300mg, is placed in a beaker of 200mL volume, it was added tert- butyl alcohol (tBA) 40mL. This was heated to boiling on a hot plate, an appropriate amount of tBA to Compound A is dissolved, water was added 10mL. Then, the weakened heated to the extent that the solution does not boil, to obtain a sample solution. It should be noted, finally the solvent amount I was 60mL. 200mL capacity eggplant type flask (egg-plant shaped flask), and rotated in a state of being immersed in ethanol which had been cooled with dry ice. It was added dropwise a sample solution into the interior of the flask and frozen. After freezing the sample solution total volume, to cover the opening of the flask in wiping cloth, and freeze-dried. We got an amorphous A of 290mg.

Patent Document 2: US Patent Application Publication No. 2007/0117842 Patent specification

Amorphous A ¹³ C-solid state NMR spectrum in Figure 2, the chemical shifts and I are shown in Table 3.

[Table 3] *: peak of t- butyl alcohol

………………………..

Paper

ACS Medicinal Chemistry Letters (2015), 6(1), 89-94

http://pubs.acs.org/doi/full/10.1021/ml500394m

……………..

Paper

Journal of Pharmaceutical and Biomedical Analysis (2015), 114, 82-87

http://www.sciencedirect.com/science/article/pii/S0731708515002940

KEEP WATCHING WILL BE UPDATED………….most of my posts are updated regularly

References

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“Phae III trial shows lenvatinib meets primary endpoint of progression free surival benefit in treatment of radioiodine-refactory differentiated thyroid cancer”. Eisai. 3 February 2014.
Glen, H; D. Boss; T. R. Evans; M. Roelvink; J. M. Saro; P. Bezodis; W. Copalu; A. Das; G. Crosswell; J. H. Schellens (2007). “A phase I dose finding study of E7080 in patients (pts) with advanced malignancies”. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 25 (18S): 14073.
ClinicalTrials.gov NCT00946153 Study of E7080 in Patients With Advanced Hepatocellular Carcinoma (HCC)
Gild, M. L.; Bullock, M.; Robinson, B. G.; Clifton-Bligh, R. (2011). “Multikinase inhibitors: A new option for the treatment of thyroid cancer”. Nature Reviews Endocrinology 7 (10): 617–624.doi:10.1038/nrendo.2011.141. PMID 21862995. edit
ClinicalTrials.gov NCT01321554 A Trial of E7080 in 131I-Refractory Differentiated Thyroid Cancer

UPDATES

EXTRAS……………

Martin Schlumberger et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib(E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). 2014 ASCO Annual Meeting. Abstract Number:LBA6008. Presented June 2, 2014. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA6008). Clinical trial information: NCT01321554.

Bando, Masashi. Quinoline derivative-containing pharmaceutical composition. PCT Int. Appl. (2011), WO 2011021597 A1

Tomohiro Matsushima, four Nakamura, Kazuhiro Murakami, Atsushi Hoteido, Yusuke Ayat, Naoko Suzuki, Itaru Arimoto, Pinche Hirose, Masaharu Gotoda.Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor. US patent number US7612208 Also published as: CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1 , US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date: Aug 7, 2007 Original Assignee: Eisai Co., Ltd

Funahashi, Yasuhiro et al.Preparation of urea derivatives containing nitrogenous aromatic ring compounds as inhibitors of angiogenesis. US patent number US7253286, Also published as:CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1, US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date:Aug 7, 2007. Original Assignee:Eisai Co., Ltd

Sakaguchi, Takahisa; Tsuruoka, Akihiko. Preparation of amorphous salts of 4-[3-chloro-4-[(cyclopropylaminocarbonyl)amino]phenoxy]-7-methoxy-6-quinolinecarboxamide as antitumor agents. PCT Int. Appl. (2006), WO2006137474 A1 20061228.

Naito, Toshihiko and Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. PCT Int. Appl., WO2005044788, 19 May 2005

Itaru Arimoto et al. Crystal of salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy]-7-methoxy-6-quinolinecarboxamide or solvate thereof and processes for producing these. PCT Int. Appl. (2005), WO2005063713 A1 20050714.

US2009264464	10-23-2009	ANTITUMOR AGENT FOR UNDIFFERENTIATED GASTRIC CANCER
US2009247576	10-2-2009	ANTI-TUMOR AGENT FOR MULTIPLE MYELOMA
US2009209580	8-21-2009	ANTITUMOR AGENT FOR THYROID CANCER
US2009203693	8-14-2009	THERAPEUTIC AGENT FOR LIVER FIBROSIS
US2009053236	2-27-2009	USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR
US2008214604	9-5-2008	Medicinal Composition
US7253286	8-8-2007	Nitrogen-containing aromatic derivatives
US2007117842	5-25-2007	Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
US2006160832	7-21-2006	Nitrogen-containing aromatic derivatives
US2006135486	6-23-2006	Use of sulfonamide-including compounds in combination with angiogenesis inhibitors

US8058474	11-16-2011	UREA DERIVATIVE AND PROCESS FOR PREPARING THE SAME
US7994159	8-10-2011	c-Kit kinase inhibitor
US7973160	7-6-2011	Nitrogen-Containing Aromatic Derivatives
US2010324087	12-24-2010	COMBINED USE OF ANGIOGENESIS INHIBITOR AND TAXANE
US2010239688	9-24-2010	COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND ANTI-TUMOR PLATINUM COMPLEX
US2010105031	4-30-2010	METHOD FOR PREDICTION OF THE EFFICACY OF VASCULARIZATION INHIBITOR
US2010092490	4-16-2010	METHOD FOR ASSAY ON THE EFFECT OF VASCULARIZATION INHIBITOR
US7683172	3-24-2010	Urea derivative and process for preparing the same
US2010048503	2-26-2010	COMPOSITION FOR TREATMENT OF PANCREATIC CANCER
US2010048620	2-26-2010	COMPOSITION FOR TREATMENT OF UNDIFFERENTIATED GASTRIC CANCER

US7253286 *	18 Apr 2003	7 Aug 2007	Eisai Co., Ltd	Nitrogen-containing aromatic derivatives
US20040053908	18 Apr 2003	18 Mar 2004	Yasuhiro Funahashi	Nitrogen-containing aromatic derivatives
US20040242506	9 Aug 2002	2 Dec 2004	Barges Causeret Nathalie Claude Marianne	Formed from paroxetine hydrochloride and ammonium glycyrrhyzinate by precipitation, spray, vacuum or freeze drying, or evaporation to glass; solid or oil; masks the bitter taste of paroxetine and has a distinctive licorice flavor; antidepressants; Parkinson’s disease
US20040253205	10 Mar 2004	16 Dec 2004	Yuji Yamamoto	c-Kit kinase inhibitor
US20070004773 *	22 Jun 2006	4 Jan 2007	Eisai R&D Management Co., Ltd.	Amorphous salt of 4-(3-chiloro-4-(cycloproplylaminocarbonyl)aminophenoxy)-7-method-6-quinolinecarboxamide and process for preparing the same
US20070078159	22 Dec 2004	5 Apr 2007	Tomohiro Matsushima	Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor
US20070117842 *	22 Apr 2004	24 May 2007	Itaru Arimoto	Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
EP0297580A1	30 Jun 1988	4 Jan 1989	E.R. SQUIBB & SONS, INC.	Amorphous form of aztreonam
JP2001131071A	Title not available
JP2005501074A	Title not available
JPS6422874U	Title not available
WO2002032872A1	19 Oct 2001	25 Apr 2002	Itaru Arimoto	Nitrogenous aromatic ring compounds
WO2003013529A1	9 Aug 2002	20 Feb 2003	Barges Causeret Nathalie Claud	Paroxetine glycyrrhizinate
WO2004039782A1	29 Oct 2003	13 May 2004	Hirai Naoko	QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES INHIBITING AUTOPHOSPHORYLATION OF Flt3 AND MEDICINAL COMPOSITIONS CONTAINING THE SAME
WO2004080462A1	10 Mar 2004	23 Sep 2004	Eisai Co Ltd	c-Kit KINASE INHIBITOR
WO2004101526A1	22 Apr 2004	25 Nov 2004	Itaru Arimoto	Polymorphous crystal of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-qunolinecarboxamide and method for preparation thereof
WO2005044788A1	8 Nov 2004	19 May 2005	Eisai Co Ltd	Urea derivative and process for producing the same
WO2005063713A1	22 Dec 2004	14 Jul 2005	Itaru Arimoto	Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
WO2006030826A1	14 Sep 2005	23 Mar 2006	Eisai Co Ltd	Medicinal composition

UPDATE………….

1H NMR PREDICT OF LENVATINIB BASE

LC MS SEE…………http://www.abmole.com/download/Lenvatinib-batch-01-lcms-abmole.pdf

FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

July 24, 2014 4:53 am / 1 Comment on FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

Dantrolene sodium

1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione

VIEW THIS POST AT BELOW LINK UNTIL FORMATTING IS FIXED

http://www.allfordrugs.com/2014/07/24/fda-approves-ryanodex-for

-the-treatment-of-malignant-hyperthermia/

FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

WOODCLIFF LAKE, N.J.(BUSINESS WIRE) July 23, 2014 —

Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”)

(Nasdaq:EGRX) today announced that the U. S. Food and Drug Administration (FDA)

has approved Ryanodex (dantrolene sodium) for injectable

suspension indicated for

the treatment of malignant hyperthermia (MH), along

with the appropriate supportive measures.

MH is an inherited and potentially fatal disorder triggered

by certain anesthesia agents

in genetically susceptible individuals. FDA had designated

Ryanodex as an Orphan Drug in

August 2013. Eagle has been informed by the FDA that it will learn over the next four to

six weeks if it has been granted the seven year Orphan Drug market exclusivity.

read at

http://www.drugs.com/newdrugs/fda-approves-ryanodex-malignant-

hyperthermia-4058.html?utm_source=ddc&utm_medium=email&utm_

campaign=Today%27s+

news+summary+-+July+23%2C+2014

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF)

July 1, 2014 3:28 am / Leave a comment

ATALUREN

PTC 124

3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

MF C₁₅H₉FN₂O₃
Molecular Weight		284.24
CAS Registry Number		775304-57-9

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF) – MarketWatch

SOUTH PLAINFIELD, N.J., June 30, 2014 /PRNewswire/ — PTC Therapeutics, Inc. /quotes/zigman/16944148/delayed/quotes/nls/ptct PTCT -0.01% today announced the initiation of a global confirmatory Phase 3 clinical trial of Translarna™ (ataluren), an investigational new drug, in patients with nonsense mutation cystic fibrosis (nmCF). Nonsense mutations within cystic fibrosis are categorized as Class I mutations, a severe form of CF that results in little or no production of the CFTR protein. The Phase 3 confirmatory trial is referred to as ACT CF (ataluren confirmatory trial in cystic fibrosis) and the primary endpoint is lung function as measured by relative change in percent predicted forced expiratory volume in one second, or FEV1.read at

http://www.marketwatch.com/story/ptc-therapeutics-initiates-confirmatory-phase-3-clinical-trial-of-translarna-ataluren-in-patients-with-nonsense-mutation-cystic-fibrosis-nmcf-2014-06-30?reflink=MW_news_stmp

Ataluren, formerly known as PTC124, is a small-molecular agent designed by PTC Therapeutics and sold under the trade nameTranslarna. It makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.^[1]

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,^[2]^[3] such as some people with cystic fibrosis and Duchenne muscular dystrophy. In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.^[4] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. However, other phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.^[5] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.^[6]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.^[7]

Ataluren appears to be most effective for the stop codon ‘UGA’.^[2]

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).^[8]

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

References

Derek (2013-09-18). “The Arguing Over PTC124 and Duchenne Muscular Dystrophy. In the Pipeline:”. Pipeline.corante.com. Retrieved 2013-11-28.
Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91.doi:10.1038/nature05756. PMID 17450125.
Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 2007). “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers”. Journal of clinical pharmacology 47 (4): 430–444. doi:10.1177/0091270006297140. PMID 17389552.
“PTC THERAPEUTICS AND GENZYME CORPORATION ANNOUNCE PRELIMINARY RESULTS FROM THE PHASE 2B CLINICAL TRIAL OF ATALUREN FOR NONSENSE MUTATION DUCHENNE/BECKER MUSCULAR DYSTROPHY (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271. edit Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272.doi:10.1164/rccm.201001-0137OC. PMID 20622033. edit
“PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved 2013-11-28.
Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115. edit
http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23

External links

Ataluren’s official page on PTC Therapeutics’s website

other sources

rINN: Ataluren

Other Names

PTC124^®, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

Pharmacological Information

Pharmacology Images

Ataluren Molecule

Web information on Ataluren

NHS Evidence on Ataluren

DrugBank on Ataluren

Relevant Clinical Literature

Pubmed on Ataluren

RCT with Ataluren

Systematic reviews of Ataluren

Ataluren in N Eng J Med, Lancet, JAMA, BMJ

Ataluren in Cochrane Collaboration

TRIP Database on Ataluren

Google Scholar on Ataluren

Bandolier on Ataluren

UK Guidance

Nice Guidance on Ataluren

BNF-registration required
BNF for children-registration required

UK directory of medicines

UK Medicine Guide (eg pictures of capsules)

Centre for Reviews and Dissemination databases -DARE & NHS EED (evaluates reliability of research)

SNOMED search

Prodigy Guidance on Ataluren

Regulatory Literature

UK SPCs of medicines with marketing authorisation

EMEA search

FDA search

Other Literature

PubChem on Ataluren

CTD (Comparative Toxicogenomics Database) link

ChemIndustry.com link

Protein Structural Information

Biological Information (GenomeNet)

Protein Knowledgebase (UniProtKB)

Orphan drug under investigation for treatment of genetic conditions where nonsense mutations result in premature termination of polypeptides. This drug, which is convenient to deliver orally, appears to allow ribosomal transcription ofRNA to continue past premature termination codon mutations with correct reading of the full normal transcript which then terminates at the proper stop codon. Problematically it has been postulated that assay artifact may have complicated evaluation of its efficacy which appears to be less than gentamicin.^[1] Faults of this class in the transcription process are involved in several inherited diseases.

Some forms of cystic fibrosis and Duchenne muscular dystrophy are being targeted in the development stage of the drug.^[2] Phase I and II trials are promising for cystic fibrosis.^[3]^[4] In a mouse model of Duchenne muscular dystrophy, restoration of muscle function occurred.^[5]

A potential issue is that there may be parts of the human genome whose optimal gene function through evolution has resulted from relatively recent in evolutionary terms insertion of a premature termination codon and so functional suboptimal transcripts of other proteins or functional RNAs might result.

References

old cut paste

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation — also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

PTC124 has been developed by PTC Therapeutics.

US Orphan Drug Market Outlook 2018 ……….download available

June 26, 2014 3:17 am / Leave a comment

US Orphan Drug Market Outlook 2018
Academia.edu

󰁕󰁓 󰁏󰁲󰁰󰁨󰁡󰁮 󰁄󰁲󰁵󰁧 󰁍󰁡󰁲󰁫󰁥󰁴 󰁏󰁵󰁴󰁬󰁯󰁯󰁫 󰀲󰀰󰀱󰀸 󰂩󰁋󰁵󰁩󰁣󰁋 󰁒󰁥󰁳󰁥󰁡󰁲󰁣󰁨
US Orphan Drug Pipeline Insight by Phase & Indication 5.1 Research 5.2 Preclinical 5.3 Phase I 5.4 Phase I/II 5.5 Phase II 5.6 Phase II/III 5.7 Phase III …

http://www.academia.edu/7453102/US_Orphan_Drug_Market_Outlook_2018 …………… download at this site

Market Overview

In the largest market for orphan drugs, USA, there was a shortage of adequate therapies for treating many rare diseases. These therapies were not developed as companies did not expect these drugs to be highly profitable. Hence there was a lack of interest and thus investment on the part of pharma companies in the USA. Therefore, the FDA introduced incentives for developing such drugs. This step taken by the FDA was successful in creating a thriving market for orphan drugs. It was in the USA first that a special law exclusively for governing orphan drugs was framed in the form of the Orphan Drug Act of 1983. This led to an increase in the popularity of orphan drugs. The FDA also has been continuously increasing its efforts to support this market by providing significant financial and non-financial incentives to the pharmaceutical companies to attract them. This has been one of the major drivers of growth for the US orphan drugs market.

Figure 3-1: US Orphan Drug Market (US$ Billion), 2012-2018

2012201320142015201620172018

Source: KuicK Research

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The future of orphan drugs - drugdiscovery.com

Karyopharm Announces Initiation of Phase 2 Study of Selinexor (KPT-330) an orphan drug

June 10, 2014 4:28 am / Leave a comment

Selinexor (KPT-330)

1393477-72-9

Karyopharm Therapeutics, Inc.

WO2011109799A1

WO2013019548A1

synthesis at http://www.allfordrugs.com/2014/06/10/karyopharm-announces-initiation-of-phase-2-study-of-selinexor-kpt-330/

C17-H11-F6-N7-O

443.3099

Synonyms

(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide
2-Propenoic acid, 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-, 2-(2-pyrazinyl)hydrazide, (2Z)-
3-[3-[3,5-Bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl]-N’-(pyrazin-2-yl)acrylohydrazide

KPT-330
Selinexor

Karyopharm Announces Initiation of Phase 2 Study of Selinexor (KPT-330) in Patients with …

MarketWatch

“These patients were treated in our Phase 1 clinical trial of Selinexor in … Additional Phase 1 and Phase 2 studies are ongoing or currently planned and … the discovery and development of novel first-in-class drugs directed against …

synthesis

http://www.allfordrugs.com/2014/06/10/karyopharm-announces-initiation-of-phase-2-study-of-selinexor-kpt-330/

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TASIMELTION…FDA Approves Hetlioz: First Treatment for Non-24 Hour Sleep-Wake Disorder in Blind Individuals

February 1, 2014 8:51 am / Leave a comment

TASIMELTION, an orphan drug for non24

N-([(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl)propanamide

(1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]pro- pananamide VEC162

(-)-(trans)-N-[[2-(2,3-Dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl]propanamide

N-(((1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl)methyl)propanamide

Bristol-Myers Squibb Company

PRODUCT PATENT

U.S. Pat. No. 5,856,529

CAS number	609799-22-6

Formula	C₁₅H₁₉N O₂
Mol. mass	245.3 g/mol

VEC-162, BMS-214778, 609799-22-6, Hetlioz, UNII-SHS4PU80D9,

January 31, 2014 — The U.S. Food and Drug Administration today approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24- hour sleep-wake disorder (“non-24”) in totally blind individuals. Non-24 is a chronic circadian rhythm (body clock) disorder in the blind that causes problems with the timing of sleep. This is the first FDA approval of a treatment for the disorder.

Non-24 occurs in persons who are completely blind. Light does not enter their eyes and they cannot synchronize their body clock to the 24-hour light-dark cycle.

http://www.drugs.com/newdrugs/fda-approves-hetlioz-first-non-24-hour-sleep-wake-disorder-blind-individuals-4005.html

Tasimelteon

TASIMELTION , BMS-214,778) is a drug which is under development for the treatment of insomnia and other sleep disorders.^[1] It is a selective agonistfor the melatonin receptors MT₁ and MT₂ in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon.^[2] It has been through Phase III trials successfully and was shown to improve both onset and maintenance of sleep, with few side effects.^[3]

A year-long (2011-2012) study at Harvard is testing the use of tasimelteon in blind subjects with non-24-hour sleep–wake disorder.^[4] In May 2013Vanda Pharmaceuticals submitted a New Drug Application to the Food and Drug Administration for Tasimelteon for the treatment of non-24-hour sleep–wake disorder in totally blind people.^[5]

SEQUENCE

Discovered by Bristol-Myers Squibb (BMS) and co-developed with Vanda Pharmaceuticals, tasimelteon is a hypnotic family benzofuran. In Phase III development, it has an orphan drug status.

JAN2014.. APPROVED FDA

In mid-November 2013 the FDA announced their recommendation for the approval of Tasimelteon for the treatment of non-24-disorder.Tasimelteon effectively resets the circadian rhythm, helping to restore normal sleep patterns.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM374388.pdf

January 2010: FDA granted orphan drug tasimelteon to disturbed sleep / wake in blind without light perception.

February 2008: Vanda has completed enrollment in its Phase III trial in chronic primary insomnia.

June 2007: Results of a Phase III trial for transient insomnia tasimelteon presented by Vanda at the 21st annual meeting of the Associated Professional Sleep Societies. These results demonstrated improvements in objective and subjective measures of sleep and its maintenance.

2004 Vanda gets a license tasimelteon (or BMS-214778 and VEC-162) from Bristol-Myers Squibb.

About Tasimelteon: Tasimelteon is a circadian regulator in development for the treatment of Non-24. Tasimelteon is a dual melatonin receptor agonist (DMRA) with selective agonist activityat the MT1 and MT2 receptors.Tasimelteon’s ability to reset the master body clock in the suprachiasmatic nucleus (SCN) results in the entrainment of the body’s melatonin and cortisol rhythms with the 24-hour day-night cycle. The patent claiming tasimelteon as a new chemical entity extends through December 2022, assuming a 5-year extension to be granted under the Hatch-Waxman Act. Tasimelteon has been granted orphan drug designation for the treatment of Non-24 from both the U.S. and the European Union.

Previously, BMS-214778, identified as an agonist of melatonin receptors, has been the subject of pre-clinical studies for the treatment of sleep disorders resulting from a disturbance of circadian rhythms.The first Pharmacokinetic studies were performed in rats and monkeys.

The master body clock controls the timing of many aspects of physiology, behavior and metabolism that show daily rhythms, including the sleep-wake cycles, body temperature, alertness and performance, metabolic rhythms and certain hormones which exhibit circadian variation. Outputs from the suprachiasmatic nucleus (SCN) control many endocrine rhythms including those of melatonin secretion by the pineal gland as well as the control of cortisol secretion via effects on the hypothalamus, the pituitary and the adrenal glands.

This master body clock, located in the SCN, spontaneously generates rhythms of approximately 24.5 hours. These non-24-hour rhythms are synchronized each day to the 24-hour day-night cycle by light, the primary environmental time cue which is detected by specialized cells in the retina and transmitted to the SCN via the retino-hypothalamic tract. Inability to detect this light signal, as occurs in most totally blind individuals, leads to the inability of the master body clock to be reset daily and maintain entrainment to a 24-hour day.

Non-24-Hour Disorder

Non-24, also referred to as Non-24-Hour Sleep-Wake Disorder (N24HSWD) or Non-24-Hour Disorder, is an orphan indication affecting approximately 65,000 to 95,000 people in the U.S. and 140,000 in Europe. Non-24 occurs when individuals, primarily blind with no light perception, are unable to synchronize their endogenous circadian pacemaker to the 24-hour light/dark cycle. Without light as a synchronizer, and because the period of the internal clock is typically a little longer than 24 hours, individuals with Non-24 experience their circadian drive to initiate sleep drifting later and later each day. Individuals with Non-24 have abnormal night sleep patterns, accompanied by difficulty staying awake during the day. Non-24 leads to significant impairment, with chronic effects impacting the social and occupational functioning of these individuals.

In addition to problems sleeping at the desired time, individuals with Non-24 experience excessive daytime sleepiness that often results in daytime napping. Tasimelteon TASIMELTION

The severity of nighttime sleep complaints and/or daytime sleepiness complaints varies depending on where in the cycle the individual’s body clock is with respect to their social, work, or sleep schedule. The “free running” of the clock results in approximately a 1-4 month repeating cycle, the circadian cycle, where the circadian drive to initiate sleep continually shifts a little each day (about 15 minutes on average) until the cycle repeats itself. Initially, when the circadian cycle becomes desynchronous with the 24 h day-night cycle, individuals with Non-24 have difficulty initiating sleep. As time progresses, the internal circadian rhythms of these individuals becomes 180 degrees out of synchrony with the 24 h day-night cycle, which gradually makes sleeping at night virtually impossible, and leads to extreme sleepiness during daytime hours.

Eventually, the individual’s sleep-wake cycle becomes aligned with the night, and “free-running” individuals are able to sleep well during a conventional or socially acceptable time. However, the alignment between the internal circadian rhythm and the 24-hour day-night cycle is only temporary. In addition to cyclical nighttime sleep and daytime sleepiness problems, this condition can cause deleterious daily shifts in body temperature and hormone secretion, may cause metabolic disruption and is sometimes associated with depressive symptoms and mood disorders.

It is estimated that 50-75% of totally blind people in the United States (approximately 65,000 to 95,000) have Non-24. This condition can also affect sighted people. However, cases are rarely reported in this population, and the true rate of Non-24 in the general population is not known.

The ultimate treatment goal for individuals with Non-24 is to entrain or synchronize their circadian rhythms into an appropriate phase relationship with the 24-hour day so that they will have increased sleepiness during the night and increased wakefulness during the daytime.

INTRODUCTION

Tasimelteon has the chemical name: trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide, has the structure of Formula I:

and is disclosed in U.S. Pat. No. 5,856,529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78° C. (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MT1R. It’s affinity (K_i) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

………………………..

SYNTHESIS

(1R-trans)-N-[[2 – (2,3-dihydro-4 benzofuranyl) cyclopropyl] methyl] propanamide PATENT: BRISTOL-MYERS SQUIBB PRIORITY DATE: 1996 HYPNOTIC

Synthesis Tasimelteon

PREPARATION OF XV

XXIV D-camphorsulfonic acid IS REACTED WITH THIONYL CHLORIDE TO GIVE

…………XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

TREATED WITH

XXVI ammonium hydroxide

TO GIVE

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

TREATED WITH AMBERLYST15

….XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

TREATED WITH LAH, ie double bond is reduced to get

…..XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Intermediate

I 3-hydroxybenzoic acid methyl ester

II 3-bromo-1-propene

III 3 – (2-propenyloxy) benzoic acid methyl ester

IV 3-hydroxy-2-(2-propenyl) benzoic acid methyl ester

V 2,3-dihydro-4-hydroxy-2-benzofurancarboxylic acid methyl ester

VI benzofuran-4-carboxylic acid methyl ester

VII benzofuran-4-carboxylic acid

VIII 2,3-dihydro-4-benzofurancarboxylic acid

IX 2,3-dihydro-4-benzofuranmethanol

X 2,3-dihydro-4-benzofurancarboxaldehyde

XI Propanedioic acid

XII (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoic acid

XIII thionyl chloride

XIV (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoyl chloride

XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

XVI (3aS,6R,7aR)-1-[(E)-3-(2,3-dihydro-4-benzofuranyl)-1-oxo-2-propenyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVII (3aS,6R,7aR)-1-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]carbonyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVIII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanol

XIX [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarboxaldehyde

XX hydroxylamine hydrochloride

XXI [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarbaldehyde oxime

XXII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanamine

XXIII propanoyl chloride

XXIV D-camphorsulfonic acid

XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

XXVI ammonium hydroxide

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Bibliography

– Patents: Benzofuran and dihydrobenzofuran melatonergic agents: US5856529 (1999)

Priority: US19960032689P, 10 Dec. 1996 (Bristol-Myers Squibb Company, U.S.)

– Preparation III (quinazolines): US2004044015 (2004) Priority: EP20000402845, 13 Oct. 2000

– Preparation of VII (aminoalkylindols): Structure-Activity Relationships of Novel Cannabinoid Mimetics Eissenstat et al, J.. Med. Chem. 1995, 38, 3094-3105

– Preparation XXVIII: Towson et al. Organic Syntheses, Coll. Vol. 8, p.104 (1993) Vol. 69, p.158 (1990)

– Preparation XV: Weismiller et al. Organic Syntheses, Coll. Vol. 8, p.110 (1993) Vol. 69, p.154 (1990).

– G. Birznieks et al. Melatonin agonist VEC-162 Improves sleep onset and maintenance in a model of transient insomnia. Sleep 2007, 30, 0773 Abstract.

-. Rajaratnam SM et al, The melatonin agonist VEC-162 Phase time immediately advances the human circadian system, Sleep 2006, 29, 0159 Abstract.

-. AK Singh et al, Evolution of a manufacturing route for a highly potent drug candidate, 229th ACS Natl Meet, March 13-17, 2005, San Diego, Abstract MEDI 576.

– Vachharajani NN et al, Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist, J Pharm Sci. 2003 Apr; 92 (4) :760-72.

. – JW Scott et al, Catalytic Asymmetric Synthesis of a melotonin antagonist; synthesis and process optimization. 223rd ACS Natl Meet, April 7-11, Orlando, 2002, Abstract ORGN 186.

…………………….

SYNTHESIS CONSTRUCTION AS IN PATENT

WO1998025606A1

GENERAL SCHEMES

Reaction Scheme 1

The syntheses of the 4-aryl-propenoic acid derivatives, 2 and 3, are shown in Reaction Scheme 1. The starting aldehydes, 1 , can be prepared by methods well known to those skilled in the art. Condensation of malonic acid with the aldehydes, 1, in solvents such as pyridine with catalysts such as piperidine or pyrrolidine, gives the 4-aryl- propenoic acid, 2. Subsequent conversion of the acid to the acid chloride using reagents such as thionyl chloride, phosphoryl chloride, or the like, followed by reaction with N,0-dimethyl hydroxylamine gives the amide intermediate 3 in good yields. Alternatively, aldehyde 1 can be converted directly to amide 3 using reagents such as diethyl (N-methoxy- N-methyl-carbamoylmethyl)phosphonate with a strong base such as sodium hydride.

Reaction Scheme 2

The conversion of the amide intermediate 3 to the racemic, trans- cyclopropane carboxaldehyde intermediate, 4, is shown in Reaction Scheme 2. Intermediate 3 was allowed to react with cyclopropanating reagents such as trimethylsulfoxonium iodide and sodium hydride in solvents such as DMF, THF, or the like. Subsequent reduction using reagents such as LAH in solvents such as THF, ethyl ether, or the like, gives the racemic, trans-cyclopropane carboxaldehyde intermediates, 4.

Reaction Scheme 3

Racemic cyclopropane intermediate 5 (R = halogen) can be prepared from intermediate 2 as shown in Reaction Scheme 3. Intermediate 2 was converted to the corresponding allylic alcohol by treatment with reducing agents such as sodium borohydride plus iodine in solvents such as THF. Subsequent acylation using reagents such as acetic anhydride in pyridine or acetyl chloride gave the allylic acetate which was allowed to react with cyclopropanating reagents such as sodium chloro-difluoroacetate in diglyme to provide the racemic, trans- cyclopropane acetate intermediates, 5. Reaction Scheme 4

The conversion of the acid 2 to the chiral cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, is shown in Reaction Scheme 4. Intermediate 2 is condensed with (-)-2,10-camphorsultam under standard conditions, and then cyclopropanated in the presence of catalysts such as palladium acetate using diazomethane generated from reagents such as 1-methyl-3-nitro-1-nitrosoguanidine. Subsequent reduction using reagents such as LAH in solvents such as THF, followed by oxidation of the alcohol intermediates using reagents such as DMSO/oxalyl chloride, or PCC, gives the cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, in good yields. The enantiomer, (+)-(trans)-4, can also be obtained employing a similar procedure using (+)-2,10- camphorsultam in place of (-)-2,10-camphorsultam.

When it is desired to prepare compounds of Formula I wherein m = 2, the alcohol intermediate may be activated in the conventional manner such as with mesyl chloride and treated with sodium cyanide followed by reduction of the nitrile group with a reducing agent such as LAH to produce the amine intermediate 6.

Reaction Scheme 5

Reaction Scheme 5 shows the conversion of intermediates 4 and 5 to the amine intermediate, 7, and the subsequent conversion of 6. or 7 to compounds of Formula I. The carboxaldehyde intermediate, 4, is condensed with hydroxylamine and then reduced with reagents such as LAH to give the amine intermediate, 7. The acetate intermediate 5 is hydrolyzed with potassium hydroxide to the alcohol, converted to the mesylate with methane sulfonyl chloride and triethyl amine in CH₂CI₂and then converted to the azide by treatment with sodium azide in solvents such as DMF. Subsequent reduction of the azide group with a reducing agent such as LAH produced the amine intermediate 7. Further reaction of 6 or 7 with acylating reagents gives compounds of Formula I. Suitable acylating agents include carboxylic acid halides, anhydrides, acyl imidazoles, alkyl isocyanates, alkyl isothiocyanates, and carboxylic acids in the presence of condensing agents, such as carbonyl imidazole, carbodiimides, and the like. Reaction Scheme 6

Reaction Scheme 6 shows the alkylation of secondary amides of Formula I (R² = H) to give tertiary amides of Formula I (R² = alkyl). The secondary amide is reacted with a base such as sodium hydride, potassium tert-butoxide, or the like, and then reacted with an alkylating reagent such as alkyl halides, alkyl sulfonate esters, or the like to produce tertiary amides of Formula I.

Reaction Scheme 7

Reaction Scheme 7 shows the halogenation of compounds of Formula I. The carboxamides, i (Q¹ = Q² = H), are reacted with excess amounts of halogenating agents such as iodine, N-bromosuccinimide, or the like to give the dihalo-compounds of Formula I (Q¹ = Q² = halogen). Alternatively, a stoichiometric amount of these halogenating agents can be used to give the monohalo-compounds of Formula I (Q¹ = H, Q² = halogen; or Q¹ = halogen, Q² = H). In both cases, additives such as lead IV tetraacetate can be used to facilitate the reaction. Biological Activity of the Compounds

The compounds of the invention are melatonergic agents. They have been found to bind human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin- stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostatic hyperplasia and related conditions

EXPERIMENTAL PROCEDURES

SEE ORIGINAL PATENT FOR CORECTIONS

Preparation 1

Benzofuran-4-carboxaldehyde

Step 1 : N-Methoxy-N-methyl-benzofuran-4-carboxamide

A mixture of benzofuran-4-carboxylic acid [Eissenstat, et al.. J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (2.8 g, 17.4 mmol) and thionyl chloride (25 mL) was heated to reflux for 2 h and then concentrated in vacuo. The solid residue was dissolved in ethyl acetate (50 mL) and a solution of N,O-dimethylhydroxylamine hydrochloride (2.8 g) in saturated NaHC0₃(60 mL) was added with stirring. After stirring for 1.5 h, the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated NaHCO₃ and concentrated in vacuo to give an oil (3.2 g, 95.4%).

Step 2: Benzofuran-4-carboxaldehyde

A solution of N-methoxy-N-methyl-benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45°C and then LAH (0.7 g, 18.7 mmol) was added. The mixture was stirred for 15 min, allowed to warm to -5°C, and then recooled to -45°C. Saturated KHS0₄ (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%). Preparation 2

2,3-Dihydrobenzofuran-4-carboxaldehyde

Step 1 : 2,3-Dihydrobenzofuran-4-carboxylic acid

Benzofuran-4-carboxylic acid (10.0 g, 61 .7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3- dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5°C).

Step 2: (2,3-Dihydrobenzofuran-4-yl)methanol

A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1 N HCI (150 mL). The mixture was then made acidic with 12 N HCI until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was Kϋgelrohr distilled to a clear oil that crystallized upon cooling (8.53 g, 87.6%).

Step 3: 2.3-Dihydrobenzofuran-4-carboxaldehyde

DMSO (8.10 mL, 1 14 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH₂CI₂ (40 mL of a 2M solution). A solution of (2,3- dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH₂CI₂ (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH₂CI₂ (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.

Preparation 16

(±)-(trans)-2-(2,3-Dihyd robenzofuran-4-yl)cyclopropane- carboxaldehyde

Step 1 : (±Htrans)-N-Methoxy-N-methyl-2-(2.3-dihydrobenzofuran-4- yhcyclopropanecarboxamide

Trimethylsulfoxonium iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1 .8 g, 45 mmol) in DMF (120 mL). After the foaming had subsided (10 min), a solution of (trans)- N-methoxy-N-methyl-3-(2,3-dihydrobenzofuran-4-yl)propenamide (3.5 g, 15 mmol) in DMF (60 mL) was added dropwise, with the temperature maintained between 35-40°C. The mixture was stirred for 3 h at room temperature. Saturated NH₄CI (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H₂O and brine, dried over K₂CO₃, and concentrated in vacuo to give a white wax (3.7 g, 100%).

Step 2: (±)-(trans)- 2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde

A solution of (±)-(trans)-N-methoxy-N-methyl-2-(2,3-dihydrobenzofuran- 4-yl)cyclopropanecarboxamide (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45°C, maintaining the temperature below -40°C throughout. The cooling bath was removed, the reaction was allowed to warm to 5°C, and then the reaction was immediately recooled to -45°C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H₂0 (50 mL) was cautiously added dropwise, the temperature maintained below – 30°C throughout. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through Celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1 N HCI, 1 N NaOH, and brine. The filtrates were dried over MgSO4, and concentrated in vacuo to give a clear oil (2.6 g, 99%).

Preparation 18

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde

Step 1 : (-Htrans)-N-[3-(2.3-Dihvdrobenzofuran-4-yl)-propenoyll-2.10- camphorsultam

To a solution of (-)-2,10-camphorsultam (8.15 g, 37.9 mmol) in 50 mL toluene at 0°C was added sodium hydride (1.67 g, 41.7 mmol). After stirring for 0.33 h at 0°C and 0.5 h at 20°C and recooling to 0°C, a solution of 3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl chloride
(37.9 mmol), prepared in situ from the corresponding acid and thionyl chloride (75 mL), in toluene (50 mL), was added dropwise. After stirring for 18 h at 20°C, the mixture was diluted with ethyl acetate and washed with water, 1 N HCI, and 1 N NaOH. The organic solution was dried and concentrated in vacuo to give 15.8 g of crude product. Recrystallization form ethanol-methanol (600 mL, 1 :1) gave the product (13.5 g, 92%, mp 199.5-200°C).

Step 2: (-)-N-[[(trans)-2-(2,3-Dihydrobenzofuran-4-yl)-cyclopropylj- carbonylj-2, 10-camphorsultam

1 -Methyl-3-nitro-1 -nitrosoguanidine (23.88g 163 mmol) was added in portions to a mixture of 10 N sodium hydroxide (60 mL) and ether (200 mL) at 0°C. The mixture was shaken vigorously for 0.25 h and the ether layer carefully decanted into a solution of (-)-N-[3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl]-2,10-camphorsultam (9.67 g, 25 mmol) and palladium acetate (35 mg) in methylene chloride (200 mL). After stirring for 18 h, acetic acid (5 mL) was added to the reaction and the mixture stirred for 0.5 h. The mixture was washed with 1 N HCI, 1 N NaOH and brine. The solution was dried, concentrated in vacuo and the residue crystallized twice from ethanol to give the product (6.67 g, 66.5%, mp 157-159°C).

Step 3: (-)-(trans)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropane- methanol

A solution of (-)-N-[(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclo-propanecarbonylj-2,10-camphorsultam (4.3 g, 10.7 mmol) in THF (50 mL) was added dropwise to a mixture of LAH (0.81 g, 21.4 mmol) in THF (50 mL) at -45°C. The mixture was stirred for 2 hr while it warmed to 10°C. The mixture was recooled to -40°C and hydrolyzed by the addition of saturated KHS0 (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was washed twice with acetone. The combined filtrate and acetone washes were concentrated in vacuo. The gummy residue was dissolved in ether, washed with 1 N NaOH and 1 N HCI, and then dried in vacuo to give the product (2.0 g, 98.4%).

Step 4: (-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH₂CI₂(7.4 mL of 2 M solution, 14.8 mmole) at -78°C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH₂CI₂(15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH₂CI₂ and washed with water, 1 N HCI, and then 1 N NaOH. The organic layer was dried and concentrated iι> vacuo to give the aldehyde product (1.98 g, 100%).

Preparation 24

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-methanamine A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1
ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo. and the residue mixed with water. The mixture was extracted with CH₂CI₂. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H₂S0₄ (1.47 g, 15 mmol) at 0°Cj. The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1 N HCI. The acid washes were made basic and extracted with CH₂CI . The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197-198°C).
Anal. Calc’d for C₁₂H₁₅NO • C₄H₄0₄: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.87; H, 6.31 ; N, 4.52.

FINAL PRODUCT TASIMELTEON

Example 2

(-)-(trans)-N-[[2-(2,3-Dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl]propanamide

This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)- cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61 %, mp: 71-72°C). IR (NaCI Film): 3298, 1645, 1548, 1459, 1235 cm^“1.

Mo⁵ : -17.3°

Anal. Calc’d for C₁₅H₁₉N0₂: C, 73.44; H, 7.87; N, 5.71 . Found: C, 73.28; H, 7.68; N, 5.58.

Discovery and development of melatonin receptor agonists

References

‘Time-bending drug’ for jet lag. BBC News. 2 December 2008
Vachharajani, Nimish N., Yeleswaram, Krishnaswamy, Boulton, David W. (April 2003). “Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist”. Journal of Pharmaceutical Sciences 92 (4): 760–72. doi:10.1002/jps.10348. PMID 12661062.
Shantha MW Rajaratnam, Mihael H Polymeropoulos, Dennis M Fisher, Thomas Roth, Christin Scott, Gunther Birznieks, Elizabeth B Klerman (2009-02-07). “Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials”. The Lancet 373 (9662): 482–491. doi:10.1016/S0140-6736(08)61812-7. PMID 19054552. Retrieved 2010-02-23.
Audio interview with Joseph Hull of Harvard, spring 2011
Vanda Pharmaceuticals seeks FDA approval
Recent progress in the development of agonists and antagonists for melatonin receptors.Zlotos DP.

Curr Med Chem. 2012;19(21):3532-49. Review.

7 Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist.

Vachharajani NN, Yeleswaram K, Boulton DW.J Pharm Sci. 2003 Apr;92(4):760-72.

TASIMELTION

PATENTS

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WO2007137244A1 *	May 22, 2007	Nov 29, 2007	Gunther Birznieks	Melatonin agonist treatment
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extra info

Org. Synth. 1990, 69, 154

(−)-D-2,10-CAMPHORSULTAM

[3H-3a,6-Methano-2,1-benzisothiazole, 4,5,6,7-tetrahydro-8,8-dimethyl-2,2-dioxide, (3aS)-]

Submitted by Michael C. Weismiller, James C. Towson, and Franklin A. Davis¹.

Checked by David I. Magee and Robert K. Boeckman, Jr..

1. Procedure

(−)-2,10-Camphorsultam. A dry, 2-L, three-necked, round-bottomed flask is equipped with a 1.5-in egg-shaped Teflon stirring bar, a 250-mL addition funnel, and a 300-mL Soxhlet extraction apparatus equipped with a mineral oil bubbler connected to an inert-gas source. The flask is charged with 600 mL of dry tetrahydrofuran (THF) (Note 1) and6.2 g (0.16 mol) of lithium aluminum hydride (Note 2). Into the 50-mL Soxhlet extraction thimble is placed 35.0 g (0.16 mol) of (−)-(camphorsulfonyl)imine (Note 3) and the reaction mixture is stirred and heated at reflux. After all of the(camphorsulfonyl)imine has been siphoned into the reaction flask (3–4 hr), the mixture is allowed to cool to room temperature. The unreacted lithium aluminum hydride is cautiously hydrolyzed by dropwise addition of 200 mL of 1 Nhydrochloric acid via the addition funnel (Note 4). After the hydrolysis is complete the contents of the flask are transferred to a 1-L separatory funnel, the lower, silver-colored aqueous layer is separated, and the upper layer placed in a 1-L Erlenmeyer flask. The aqueous phase is returned to the separatory funnel and washed with methylene chloride (3 × 100 mL). After the reaction flask is rinsed with methylene chloride (50 mL), the organic washings are combined with the THF phase and dried over anhydrous magnesium sulfate for 10–15 min. Filtration through a 300-mL sintered-glass funnel of coarse porosity into a 1-L round-bottomed flask followed by removal of the solvent on arotary evaporator gives 33.5 g (95%) of the crude (−)-2,10-camphorsultam. The crude sultam is placed in a 250-mL Erlenmeyer flask and crystallized from approximately 60 mL of absolute ethanol. The product is collected on a 150-mL sintered-glass funnel of coarse porosity and dried in a vacuum desiccator to give 31.1 g (88%) of the pure sultam. A second crop of crystals can be gained by evaporating approximately half the filtrate; the residue is crystallized as above to give 1.4 g (4%). The combined yield of white crystalline solid, mp 183–184°C, [α]_D −30.7° (CHCl₃, c 2.3) is92% (Note 5) and (Note 6).

2. Notes

1. Tetrahydrofuran (Aldrich Chemical Company, Inc.) was distilled from sodium benzophenone.

2. Lithium aluminum hydride was purchased from Aldrich Chemical Company, Inc.

3. (−)-(Camphorsulfonyl)imine, [(7S)-(−)-10,10-dimethyl-5-thia-4-azatricyclo[5.2.1.0^3,7]dec-3-ene 5,5-dioxide] was prepared by the procedure of Towson, Weismiller, Lal, Sheppard, and Davis, Org. Synth., Coll. Vol. VIII, 1993, 104.

4. The addition must be very slow at first (1 drop/5 sec) until the vigorous reaction has subsided.

5. The NMR spectrum of (−)-2,10-camphorsultam is as follows: ¹H NMR (CDCl₃) δ: 0.94 (s, 3 H, CH₃), 1.14 (s, 3 H, CH₃), 1.33 (m, 1 H), 1.47 (m,, 1 H), 1.80–2.05 (5 H), 3.09 (d, 1 H, J = 14), 3.14 (d, 1 H, J = 14), 3.43 (m, 1 H), 4.05 (br s, 1 H, NH); ¹³C NMR (CDCl₃) δ: 20.17 (q, CH₃), 26.51 (t), 31.55 (t), 35.72 (t), 44.44 (d), 47.15 (s), 50.08 (t), 54.46 (s), 62.48 (d).

6. Checkers obtained material having the same mp (183–184°C) and [α]_D − 31.8° (CHCl₃, c 2.3).

3. Discussion

(−)-2,10-Camphorsultam was first prepared by the catalytic hydrogenation of (−)-(camphorsulfonyl)imine overRaney nickel.² Lithium aluminum hydride reduction was used by Oppolzer and co-workers in their synthesis of the sultam.³^,⁴ However, because of the low solubility of the sultam in tetrahydrofuran, a large amount of solvent was required.⁴ In the procedure described here the amount of solvent is significantly reduced by using a Soxhlet extractor to convey the imine slowly into the reducing medium.⁵

Oppolzer’s chiral auxiliary,⁶ (−)-2,10-camphorsultam, is useful in the asymmetric Diels–Alder reaction,³^,⁴ and for the preparation of enantiomerically pure β-substituted carboxylic acids⁷ and diols,⁸ in the stereoselective synthesis of Δ²-isoxazolines,⁹ and in the preparation of N-fluoro-(−)-2,10-camphorsultam, an enantioselective fluorinating reagent.¹⁰

References and Notes

Department of Chemistry, Drexel University, Philadelphia, PA 19104.
Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc. 1938, 60, 2794.
Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397.
Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron 1986, 42, 4035.
Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G.; Carroll,, P. J. J. Am. Chem. Soc. 1988, 110, 8477.
Oppolzer, W. Tetrahedron 1987, 43, 1969.
Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta 1986, 69, 1542; Oppolzer, W.; Schneider, P. Helv. Chim. Acta 1986, 69, 1817; Oppolzer, W.; Mills, R. J.; Réglier, M. Tetrahedron Lett. 1986, 27, 183; Oppolzer, W.; Poli. G.Tetrahedron Lett. 1986, 27, 4717; Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1988, 29, 3559.
Oppolzer, W.; Barras, J-P. Helv. Chim. Acta 1987, 70, 1666.
Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555.
Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087.

Org. Synth. 1990, 69, 158

(+)-(2R,8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE

[4H-4A,7-Methanooxazirino[3,2-i][2,1]benzisothiazole, tetrahydro-9,9-dimethyl-, 3,3-dioxide, [4aS-(4aα,7α,8aR^*)]]

Submitted by James C. Towson, Michael C. Weismiller, G. Sankar Lal, Aurelia C. Sheppard, Anil Kumar, and Franklin A. Davis¹.

Checked by David I. Magee and Robert K. Boeckman, Jr..

1. Procedure

A. (+)-(1S)-10-Camphorsulfonamide. Into a 2-L, two-necked, round-bottomed flask, equipped with a 250-mL dropping funnel, a magnetic stirring bar, and a reflux condenser fitted with an outlet connected to a disposable pipettedipped in 2 mL of chloroform in a test tube for monitoring gas evolution, were placed 116 g (0.5 mol) ofcamphorsulfonic acid (Note 1) and 750 mL of reagent-grade chloroform. The suspension of camphorsulfonic acid was heated to reflux and 71.4 g (43.77 mL, 0.6 mol, 1.2 equiv) of freshly distilled thionyl chloride was added dropwise over a 1-hr period. Heating was continued until gas evolution (sulfur dioxide and hydrogen chloride) had ceased (approximately 9–10 hr). The resultant solution of camphorsulfonyl chloride in chloroform was converted tocamphorsulfonamide without further purification.

In a 5-L, two-necked, round-bottomed flask fitted with a 250-mL dropping funnel and a mechanical stirrer was placed a solution of 1.6 L of reagent-grade ammonium hydroxide solution and the flask was cooled to 0°C in an ice bath. The solution of the crude camphorsulfonyl chloride, prepared in the preceding section, was added dropwise to the ammonium hydroxide solution at 0–10°C over a period of 1 hr. The reaction mixture was warmed to room temperature, stirred for 4 hr, the organic layer separated, and the aqueous layer was extracted with methylene chloride (3 × 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrousmagnesium sulfate. Removal of the solvent on the rotary evaporator gave 104.0 g (90%) of the crudecamphorsulfonamide (Note 2) and (Note 3).

B. (−)-(Camphorsulfonyl)imine. A 1-L, round-bottomed flask is equipped with a 2-in. egg-shaped magnetic stirring bar, a Dean–Stark water separator, and a double-walled condenser containing a mineral oil bubbler connected to an inert gas source. Into the flask are placed 5 g of Amberlyst 15 ion-exchange resin (Note 4) and 41.5 g of the crude(+)-(1S)-camphorsulfonamide in 500 mL of toluene. The reaction mixture is heated at reflux for 4 hr. After the reaction flask is cooled, but while it is still warm (40–50°C), 200 mL of methylene chloride is slowly added to dissolve any(camphorsulfonyl)imine that crystallizes. The solution is filtered through a 150-mL sintered glass funnel of coarse porosity an the reaction flask and filter funnel are washed with an additional 75 mL of methylene chloride.

Isolation of the (−)-(camphorsulfonyl)imine is accomplished by removal of the toluene on the rotary evaporator. The resulting solid is recrystallized from absolute ethanol (750 mL) to give white crystals, 34.5–36.4 g (90–95%), mp225–228°C; [α]_D −32.7° (CHCl₃, c 1.9) (Note 5).

C. (+)-(2R, 8aS)-10-Camphorylsulfonyloxaziridine. A 5-L, three-necked, round-bottomed Morton flask is equipped with an efficient mechanical stirrer, a 125-mm Teflon stirring blade, a Safe Lab stirring bearing (Note 6), and a 500-mL addition funnel. Into the flask are placed the toluene solution of (−)-(camphorsulfonyl)imine (39.9 g, 0.187 mol)prepared in Step B and a room-temperature solution of 543 g (3.93 mol, 7 equiv based on oxone) of anhydrouspotassium carbonate dissolved in 750 mL of water. The reaction mixture is stirred vigorously and a solution of 345 g (0.56 mol, 6 equiv of KHSO₅) of oxone dissolved in 1250 mL of water is added dropwise in three portions over 45 min(Note 7) and (Note 8). Completion of the oxidation is determined by TLC (Note 9) and the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity to remove solids. The filtrate is transferred to a 3-L separatory funnel, the toluene phase is separated and the aqueous phase is washed with methylene chloride (3 × 100 mL). The filtered solids and any solids remaining in the Morton flask are washed with an additional 200 mL of methylene chloride. The organic extracts are combined and washed with 100 mL of saturated sodium sulfite, dried over anhydrousmagnesium sulfate for 15–20 min, filtered, and concentrated on the rotary evaporator. The resulting white solid is crystallized from approximately 500 mL of hot 2-propanol to afford, after drying under vacuum in a desiccator, 35.9 g(84%) of white needles, mp 165–167°C, [α]_D +44.6° (CHCl₃, c 2.2) (Note 10) and (Note 11).

(−)-(2S,8aR)-10-(camphorylsulfonyl)oxaziridine is prepared in a similar manner starting from (−)-10-camphorsulfonic acid; mp 166–167°C, [α]_D +43.6° (CHCl₃, c 2.2).

2. Notes

1. (1S)-(+)-10-Camphorsulfonic acid was purchased from Aldrich Chemical Company, Inc.

2. The crude sulfonamide is contaminated with 5–10% of the (camphorsulfonyl)imine, the yield of which increases on standing.

3. The ¹H NMR spectrum of (+)-(1S)-10-camphorsulfonamide is as follows: (CDCl₃) δ: 0.93 (s, 3 H, CH₃), 1.07 (s, 3 H, CH₃), 1.40–2.50 (m, 7 H), 3.14 and 3.53 (AB quartet, 2 H, CH₂-SO₂, J = 15.1), 5.54 (br s, 2 H, NH₂).

4. Amberlyst 15 ion-exchange resin is a strongly acidic, macroreticular resin purchased from Aldrich Chemical Company, Inc.

5. The spectral properties of (−)-(camphorsulfonyl)imine are as follows: ¹H NMR (CDCl₃) δ: 1.03 (s, 3 H, CH₃), 1.18 (s, 3 H, CH₃), 1.45–2.18 (m, 6 H), 2.65 (m, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH₂-SO₂, J = 14.0); ¹³C NMR (CDCl₃) δ: 19.01 (q, CH₃), 19.45 (q, CH₃), 26.64 (t), 28.44 (t), 35.92 (t), 44.64 (d), 48.00 (s), 49.46 (t), 64.52 (s), 195.52 (s); IR (CHCl₃) cm⁻¹: 3030, 2967, 1366. Checkers obtained material having identical melting point and [α]_D−32.3° (CHCl₃, c 1.8).

6. The SafeLab Teflon bearing can be purchased from Aldrich Chemical Company, Inc. A glass stirring bearing lubricated with silicone grease is unsatisfactory because the dissolved salts solidify in the shaft, causing freezing.

7. Efficient stirring is important and indicated by a milky white appearance of the solution.

8. Occasionally batches of oxone purchased from Aldrich Chemical Company, Inc., have exhibited reduced reactivity in this oxidation. Oxone exposed to moisture prior to use also gives reduced reactivity in this oxidation. If this occurs, oxone is added until oxidation is complete as determined by TLC (Note 9). Potassium carbonate is added as needed to maintain the pH at approximately 9.0. Oxone stored in the refrigerator under an inert atmosphere has shown no loss in reactivity for up to 6 months.

9. Oxidation is generally complete after addition of the oxone solution. The oxidation is monitored by TLC as follows. Remove approximately 0.5 mL of the toluene solution from the nonstirring solution, spot a 250-μm TLC silica gel plate, elute with methylene chloride, and develop with 10% molybdophosphoric acid in ethanol and heating(camphorsulfonyl)imine R_f = 0.28 and (camphorylsulfonyl)oxaziridine R_f = 0.62. If (camphorsulfonyl)imine is detected, stirring is continued at room temperature until the reaction is complete (see (Note 8)). If the reaction mixture takes on a brownish color after addition of oxone and has not gone to completion after 30 min, the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity, and the solids are washed with 50 mL of methylene chloride. The aqueous/organic extracts are returned to the 5-L Morton flask and stirred vigorously and 52 g (0.08 mol, 1 equiv KHSO₅) of oxone is added over 5 min and stirring continued until oxidation is complete (approximately 10–15 min).

10. The submitters employed a toluene solution of crude imine prepared in Part B and obtained somewhat higher yields (90–95%). However, the checkers obtained yields in this range on one half the scale using isolatedsulfonylimine.

11. The spectral properties of (+)-(camphorsulfonyl)oxaziridine are as follows: ¹H NMR (CDCl₃) δ: 1.03 (s, 3 H, CH₃), 1.18 (s, 3 H, CH₃), 1.45–2.18 (m, 6 H), 2.65 (d, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH₂-SO₂, J = 14.0); ¹³C NMR (CDCl₃) δ: 19.45 (q, CH₃), 20.42 (q, CH₃), 26.55 (t), 28.39 (t), 33.64 (t), 45.78 (d), 48.16 (s), 48.32 (t), 54.07 (s), 98.76 (s). The checkers obtained material (mp 165–167°C) having [α]_D +44.7° (CHCl₃, c 2.2).

3. Discussion

Camphorsulfonamide, required for the preparation of the (camphorsulfonyl)imine, was previously prepared in two steps. The first step involved conversion of camphorsulfonic acid to the sulfonyl chloride with PCl₅ or SOCl₂. The isolated sulfonyl chloride was converted in a second step to the sulfonamide by reaction with ammonium hydroxide. This modified procedure is more efficient because it transforms camphorsulfonic acid directly to camphorsulfonamide, avoiding isolation of the camphorsulfonyl chloride.

(Camphorsulfonyl)imine has been reported as a by-product of reactions involving the camphorsulfonamide.²^,³^,⁴^,⁵Reychler in 1898 isolated two isomeric camphorsulfonamides,² one of which was shown to be the(camphorsulfonyl)imine by Armstrong and Lowry in 1902.³ Vandewalle, Van der Eycken, Oppolzer, and Vullioud described the preparation of (camphorsulfonyl)imine in 74% overall yield from 0.42 mol of the camphorsulfonyl chloride.⁶ The advantage of the procedure described here is that, by using ammonium hydroxide, the camphorsulfonyl chloride is converted to the sulfonamide in >95% yield.⁷ The sulfonamide is of sufficient purity that it can be used directly in the cyclization step, which, under acidic conditions, is quantitative in less than 4 hr. These modifications result in production of the (camphorsulfonyl)imine in 86% overall yield from the sulfonyl chloride.

In addition to the synthesis of enantiomerically pure (camphorylsulfonyl)oxaziridine⁷ and its derivatives,⁸ the(camphorsulfonyl)imine has been used in the preparation of (−)-2,10-camphorsultam (Oppolzers’ auxiliary),⁶^,⁹ (+)-(3-oxocamphorysulfonyl) oxaziridine,¹⁰ and the N-fluoro-2,10-camphorsultam, an enantioselective fluorinating reagent.¹¹

The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.¹² ¹³ ¹⁴ Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30–91% ee),¹⁵selenides to selenoxides (8–9% ee).¹⁶ disulfides to thiosulfinates (2–13% ee),⁵ and in the asymmetric epoxidation of alkenes (19–65% ee).¹⁷^,¹⁸ Oxidation of optically active sulfonimines (R^*SO₂N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.³

(+)-(Camphorylsulfonyl)oxaziridine described here is prepared in four steps from inexpensive (1S)-(+)- or (1R)-(+)-10-camphorsulfonic acid in 77% overall yield.⁷ Separation of the oxaziridine diastereoisomers is not required because oxidation is sterically blocked from the exo face of the C-N double bond in the (camphorsulfonyl)imine. In general, (camphorsulfonyl)oxaziridine exhibits reduced reactivity compared to other N-sulfonyloxaziridines. For example, while sulfides are asymmetrically oxidized to sulfoxides (3–77% ee), this oxaziridine does not react with amines or alkenes.⁷ However, this oxaziridine is the reagent of choice for the hydroxylation of lithium and Grignard reagents to give alcohols and phenols because yields are good to excellent and side reactions are minimized.¹⁹ This reagent has also been used for the stereoselective oxidation of vinyllithiums to enolates.²⁰

The most important synthetic application of the (camphorylsulfonyl)oxaziridines is the asymmetric oxidation of enolates to optically active α-hydroxy carbonyl compounds.¹⁴^,²¹^,²²^,²³^,²⁴ Chiral, nonracemic α-hydroxy carbonylcompounds have been used extensively in asymmetric synthesis, for example, as chiral synthons, chiral auxiliaries, and chiral ligands. This structural array is also featured in many biologically active natural products. This oxidizing reagent gives uniformly high chemical yields regardless of the counterion, and stereoselectivities are good to excellent (50–95% ee).⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴ Since the configuration of the oxaziridine three-membered ring controls the stereochemistry, both α-hydroxy carbonyl optical isomers are readily available. Representative examples of the asymmetric oxidation of prochiral enolates by (+)-(2R,8aS)-camphorylsulfonyl)oxaziridine are given in Tables I and II.

This preparation is referenced from:

Org. Syn. Coll. Vol. 8, 110
Org. Syn. Coll. Vol. 9, 212
References and Notes
1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
2. Reychler, M. A. Bull. Soc. Chim. III 1889, 19, 120.
3. Armstrong, H. E.; Lowry, T. M. J. Chem. Soc., Trans. 1902, 81, 1441.
4. Dauphin, G.; Kergomard, A.; Scarset, A. Bull. Soc. Chim. Fr. 1976, 862.
5. Davis, F. A.; Jenkins, Jr., R. H.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. J. Am. Chem. Soc. 1982, 104, 5412.
6. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron, 1986, 42, 4035.
7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc. 1988, 110, 8477.
8. Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.; Przeslawski, R. M. Tetrahedron Lett., 1989, 30, 1613.
9. Oppolzer, W. Tetrahedron 1987, 43, 1969.
10. Glahsl, G.; Herrmann, R. J. Chem. Soc., Perkin Trans. I 1988, 1753.
11. Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087.
12. For recent reviews on the chemistry of N-sulfonyloxaziridines, see: (a) Davis, F. A.; Jenkins, Jr., R. H. in “Asymmetric Synthesis,” Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984, Vol. 4, Chapter 4;
13. Davis, F. A.; Haque, S. M. in “Advances in Oxygenated Processes,” Baumstark, A. L., Ed.; JAI Press: London, Vol. 2;
14. Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
15. Davis, F. A.; McCauley, Jr., J. P.; Chattopadhyay, S.; Harakal, M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem. Soc. 1987, 109, 3370.
16. Davis, F. A.; Stringer, O. D.; McCauley, Jr., J. M. Tetrahedron 1985, 41, 4747.
17. Davis, F. A.; Chattopadhyay, S. Tetrahedron Lett. 1986, 27, 5079.
18. Davis, F. A.; Harakal, M. E.; Awad, S. B. J. Am. Chem. Soc. 1983, 105, 3123.
19. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick S. Tetrahedron Lett. 1987, 28, 5115.
20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269.
21. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986, 51, 2402.
22. Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083; Davis, F. A.; Haque, M. S.; Przeslawski, R. M. J. Org. Chem. 1989, 54, 2021.
23. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem. 1987, 52, 5288.
24. Davis, F. A.; Sheppard, A. C., Lal, G. S. Tetrahedron Lett. 1989, 30, 779.
25. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc. 1990, 112, 6679.

dedicated to lionel my son

my daughter Aishal

THEY KEEP ME GOING

PANOBINOSTAT

January 23, 2014 8:40 am / 2 Comments on PANOBINOSTAT

Panobinostat

HDAC inhibitors, orphan drug

cas 404950-80-7

2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide)

Molecular Formula: C₂₁H₂₃N₃O₂ Molecular Weight: 349.42622

Faridak
LBH 589
LBH589
Panobinostat
UNII-9647FM7Y3Z

A hydroxamic acid analog histone deacetylase inhibitor from Novartis.

NOVARTIS, innovator

Histone deacetylase inhibitors

Is currently being examined in cutaneous T-cell lymphoma, CML and breast cancer.

clinical trials click here phase 3

DRUG SUBSTANCE–LACTATE AS IN http://www.google.com/patents/US7989639 SEE EG 31

Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid^[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor).^[2]

panobinostat

Panobinostat is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. HDAC is an enzyme that deacetylates chromatin histone proteins. Check for

As of August 2012, it is being tested against Hodgkin’s Lymphoma, cutaneous T cell lymphoma (CTCL)^[3] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.^[4]^[5]

Panobinostat is a histone deacetylase (HDAC) inhibitor which was filed for approval in the U.S. in 2010 for the oral treatment of relapsed/refractory classical Hodgkin’s lymphoma in adult patients. The company is conducting phase II/III clinical trials for the oral treatment of multiple myeloma, chronic myeloid leukemia and myelodysplasia. Phase II trials are also in progress for the treatment of primary myelofibrosis, post-polycythemia Vera, post-essential thrombocytopenia, Waldenstrom’s macroglobulinemia, recurrent glioblastoma (GBM) and for the treatment of pancreatic cancer progressing on gemcitabine therapy. Additional trials are under way for the treatment of hematological neoplasms, prostate cancer, colorectal cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), malignant mesothelioma, acute lymphoblastic leukemia, acute myeloid leukemia, head and neck cancer and gastrointestinal neuroendocrine tumors. Early clinical studies are also ongoing for the treatment of HER2 positive metastatic breast cancer. Additionally, phase II clinical trials are ongoing at Novartis as well as Neurological Surgery for the treatment of recurrent malignant gliomas as are phase I/II initiated for the treatment of acute graft versus host disease. The National Cancer Institute had been conducting early clinical trials for the treatment of metastatic hepatocellular carcinoma; however, these trials were terminated due to observed dose-limiting toxicity. In 2009, Novartis terminated its program to develop panobinostat for the treatment of cutaneous T-cell lymphoma. A program for the treatment of small cell lung cancer was terminated in 2012. Phase I clinical trials are ongoing for the treatment of metastatic and/or malignant melanoma and for the treatment of sickle cell anemia. The University of Virginia is conducting phase I clinical trials for the treatment of newly diagnosed and recurrent chordoma in combination with imatinib. Novartis is evaluating panobinostat for its potential to re-activate HIV transcription in latently infected CD4+ T-cells among HIV-infected patients on stable antiretroviral therapy.

Mechanistic evaluations revealed that panobinostat-mediated tumor suppression involved blocking cell-cycle progression and gene transcription induced by the interleukin IL-2 promoter, accompanied by an upregulation of p21, p53 and p57, and subsequent cell death resulted from the stimulation of caspase-dependent and -independent apoptotic pathways and an increase in the mitochondrial outer membrane permeability. In 2007, the compound received orphan drug designation in the U.S. for the treatment of cutaneous T-cell lymphoma and in 2009 and 2010, orphan drug designation was received in the U.S. and the E.U., respectively, for the treatment of Hodgkin’s lymphoma. This designation was also assigned in 2012 in the U.S. and the E.U. for the treatment of multiple myeloma.

Cardiovascular disease is the leading cause of morbidity and mortality in the western world and during the last decades it has also become a rapidly increasing problem in developing countries. An estimated 80 million American adults (one in three) have one or more expressions of cardiovascular disease (CVD) such as hypertension, coronary heart disease, heart failure, or stroke. Mortality data show that CVD was the underlying cause of death in 35% of all deaths in 2005 in the United States, with the majority related to myocardial infarction, stroke, or complications thereof. The vast majority of patients suffering acute cardiovascular events have prior exposure to at least one major risk factor such as cigarette smoking, abnormal blood lipid levels, hypertension, diabetes, abdominal obesity, and low-grade inflammation.

Pathophysiologically, the major events of myocardial infarction and ischemic stroke are caused by a sudden arrest of nutritive blood supply due to a blood clot formation within the lumen of the arterial blood vessel. In most cases, formation of the thrombus is precipitated by rupture of a vulnerable atherosclerotic plaque, which exposes chemical agents that activate platelets and the plasma coagulation system. The activated platelets form a platelet plug that is armed by coagulation-generated fibrin to form a biood clot that expands within the vessel lumen until it obstructs or blocks blood flow, which results in hypoxic tissue damage (so-called infarction). Thus, thrombotic cardiovascular events occur as a result of two distinct processes, i.e. a slowly progressing long-term vascular atherosclerosis of the vessel wall, on the one hand, and a sudden acute clot formation that rapidly causes flow arrest, on the other. This invention solely relates to the latter process.

Recently, inflammation has been recognized as an important risk factor for thrombotic events. Vascular inflammation is a characteristic feature of the atherosclerotic vessel wall, and inflammatory activity is a strong determinant of the susceptibility of the atherosclerotic plaque to rupture and initiate intravascular clotting. Also, autoimmune conditions with systemic inflammation, such as rheumatoid arthritis, systemic lupus erythematosus and different forms of vasculitides, markedly increase the risk of myocardial infarction and stroke.

Traditional approaches to prevent and treat cardiovascular events are either targeted 1) to slow down the progression of the underlying atherosclerotic process, 2) to prevent clot formation in case of a plaque rupture, or 3) to direct removal of an acute thrombotic flow obstruction. In brief, antiatherosclerotic treatment aims at modulating the impact of general risk factors and includes dietary recommendations, weight loss, physical exercise, smoking cessation, cholesterol- and blood pressure treatment etc. Prevention of clot formation mainly relies on the use of antiplatelet drugs that inhibit platelet activation and/or aggregation, but also in some cases includes thromboembolic prevention with oral anticoagulants such as warfarin. Post-hoc treatment of acute atherothrombotic events requires either direct pharmacological lysis of the clot by thrombolytic agents such as recombinant tissue-type plasminogen activator or percutaneous mechanical dilation of the obstructed vessel.

Despite the fact that multiple-target antiatherosclerotic therapy and clot prevention by antiplatelet agents have lowered the incidence of myocardial infarction and ischemic stroke, such events still remain a major population health problem. This shows that in patients with cardiovascular risk factors these prophylactic measures are insufficient to completely prevent the occurrence of atherothrombotic events.

Likewise, thrombotic conditions on the venous side of the circulation, as well as embolic complications thereof such as pulmonary embolism, still cause substantial morbidity and mortality. Venous thrombosis has a different clinical presentation and the relative importance of platelet activation versus plasma coagulation are somewhat different with an preponderance for the latter in venous thrombosis, However, despite these differences, the major underlying mechanisms that cause thrombotic vessel occlusions are similar to those operating on the arterial circulation. Although unrelated to atherosclerosis as such, the risk of venous thrombosis is related to general cardiovascular risk factors such as inflammation and metabolic aberrations.

Panobinostat can be synthesized as follows: Reduction of 2-methylindole-3-glyoxylamide (I) with LiAlH4 affords 2-methyltryptamine (II). 4-Formylcinnamic acid (III) is esterified with methanolic HCl, and the resulting aldehyde ester (IV) is reductively aminated with 2-methyltryptamine (II) in the presence of NaBH3CN (1) or NaBH4 (2) to give (V). The title hydroxamic acid is then obtained by treatment of ester (V) with aqueous hydroxylamine under basic conditions.

Panobinostat is currently being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique panobinostat is used to drive the HI virus’s DNA out of the patient’s DNA, in the expectation that the patient’s immune system in combination with HAART will destroy it.^[6]^[7]

panobinostat

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.^[8]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering fromspinal muscular atrophy.^[9]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.^[10]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.^[11]

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.^[1]

The compound N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide) has the formula

as described in WO 02/22577. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as a histone deacetylase inhibitor useful in therapy for diseases which respond to inhibition of histone deacetylase activity. WO 02/22577 does not disclose any specific salts or salt hydrates or solvates of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide.

The compounds described above are often used in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonate salts. Acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate. Examples of metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of ammonium salts are ammonium salt and tetramethylammonium salt. Examples of organic amine addition salts are salts with morpholine and piperidine. Examples of amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.

……………………………..

GENERAL METHOD OF SYNTHESIS

ADD YOUR METHYL AT RIGHT PLACE

WO2002022577A2

As is evident to those skilled in the art, the many of the deacetylase inhibitor compounds of the present invention contain asymmetric carbon atoms. It should be understood, therefore, that the individual stereoisomers are contemplated as being included within the scope of this invention.

The hydroxamate compounds of the present invention can be produced by known organic synthesis methods. For example, the hydroxamate compounds can be produced by reacting methyl 4-formyl cinnamate with tryptamine and then converting the reactant to the hydroxamate compounds. As an example, methyl 4-formyl cinnamate 2, is prepared by acid catalyzed esterification of 4-formylcinnamic acid 3 (Bull. Chem. Soc. Jpn. 1995; 68:2355-2362). An alternate preparation of methyl 4-formyl cinnamate 2 is by a Pd- catalyzed coupling of methyl acrylate 4 with 4-bromobenzaldehyde 5.

CHO

Additional starting materials can be prepared from 4-carboxybenzaldehyde 6, and an exemplary method is illustrated for the preparation of aldehyde 9, shown below. The carboxylic acid in 4-carboxybenzaldehyde 6 can be protected as a silyl ester (e.g., the t- butyldimethylsilyl ester) by treatment with a silyl chloride (e.g., f-butyldimethylsilyl chloride) and a base (e.g. triethylamine) in an appropriate solvent (e.g., dichloromethane). The resulting silyl ester 7 can undergo an olefination reaction (e.g., a Horner-Emmons olefination) with a phosphonate ester (e.g., triethyl 2-phosphonopropionate) in the presence of a base (e.g., sodium hydride) in an appropriate solvent (e.g., tetrahydrofuran (THF)). Treatment of the resulting diester with acid (e.g., aqueous hydrochloric acid) results in the hydrolysis of the silyl ester providing acid 8. Selective reduction of the carboxylic acid of 8 using, for example, borane-dimethylsuflide complex in a solvent (e.g., THF) provides an intermediate alcohol. This intermediate alcohol could be oxidized to aldehyde 9 by a number of known methods, including, but not limited to, Swern oxidation, Dess-Martin periodinane oxidation, Moffatt oxidation and the like.

The aldehyde starting materials 2 or 9 can be reductively aminated to provide secondary or tertiary amines. This is illustrated by the reaction of methyl 4-formyl cinnamate 2 with tryptamine 10 using sodium triacetoxyborohydride (NaBH(OAc)₃) as the reducing agent in dichloroethane (DCE) as solvent to provide amine 11. Other reducing agents can be used, e.g., sodium borohydride (NaBH ) and sodium cyanoborohydride (NaBH₃CN), in other solvents or solvent mixtures in the presence or absence of acid catalysts (e.g., acetic acid and trifluoroacetic acid). Amine 11 can be converted directly to hydroxamic acid 12 by treatment with 50% aqueous hydroxylamine in a suitable solvent (e.g., THF in the presence of a base, e.g., NaOH). Other methods of hydroxamate formation are known and include reaction of an ester with hydroxylamine hydrochloride and a base (e.g., sodium hydroxide or sodium methoxide) in a suitable solvent or solvent mixture (e.g., methanol, ethanol or methanol/THF).

NOTE ….METHYL SUBSTITUENT ON 10 WILL GIVE YOU PANOBINOSTAT

……………………………….

Journal of Medicinal Chemistry, 2011 , vol. 54, 13 pg. 4694 – 4720

(E)-N-Hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide
lactate

(34, panobinostat, LBH589)

http://pubs.acs.org/doi/full/10.1021/jm2003552

http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf

for str see above link

α-methyl-β-(β-bromoethyl)indole (29) was made according to method reported by Grandberg et al.(2. Grandberg, I. I.; Kost, A. N.; Terent’ev, A. P. Reactions of hydrazine derivatives. XVII. New synthesis of α-methyltryptophol. Zhurnal Obshchei Khimii 1957, 27, 3342–3345. )

The bromide 29 was converted to amine 30 by using similar method used by Sletzinger et al.(3. Sletzinger, M.; Ruyle, W. V.; Waiter, A. G. (Merck & Co., Inc.). Preparation of tryptamine
derivatives. U.S. Patent US 2,995,566, Aug 8, 1961.)

To a 500 mL flask, crude 2-methyltryptamine 30 (HPLC purity 75%, 1.74 g, 7.29 mmol) and 3-(4-
formyl-phenyl)-acrylic acid methyl ester 31 (HPLC purity 84%, 1.65 g, 7.28 mmol) were added,
followed by DCM (100 mL) and MeOH (30 mL). The clear solution was stirred at room temp for 30
min, then NaBH3CN (0.439 g, 6.99 mmol) was added in small portions. The reaction mixture was
stirred at room temp overnight. After removal of the solvents, the residue was diluted with DCM and
added saturated NaHCO3 aqueous solution, extracted with DCM twice. The DCM layer was dried
and concentrated, and the resulting residue was purified by flash chromatography (silica, 0–10%
MeOH in DCM) to afford 33 as orange solid (1.52 g, 60%). LC–MS m/z 349.2 ([M + H]+). 33 was
converted to hydroxamic acid 34 according to procedure D (Experimental Section), and the freebase
34 was treated with 1 equiv of lactic acid in MeOH–water (7:3) to form lactic acid salt which was
further recrystallized in MeOH–EtOAc to afford the lactic acid salt of 34as pale yellow solid. LC–MS m/z 350.2 ([M + H − lactate]+).

= DELTA

1H NMR (DMSO-d6)  10.72 (s, 1H, NH), 7.54 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 16 Hz, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.97 (td, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 7.01 (t, J = 7.4, 0.9 Hz, 1H), 6.91 (td, J = 7.4, 0.9 Hz, 1H), 6.47 (d, J = 15.2 Hz, 1H), 3.94(q, J = 6.8 Hz, 1H, lactate CH), 3.92 (s, 2H), 2.88 and 2.81 (m, each, 4H, AB system, CH2CH2),2.31 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H).;

13C NMR (DMSO-d6)  176.7 (lactate C=O), 162.7, 139.0,
137.9, 135.2, 134.0, 132.1, 129.1, 128.1, 127.4, 119.9, 119.0, 118.1, 117.2, 110.4, 107.0, 66.0, 51.3,
48.5, 22.9, 20.7, 11.2.

…………………………………………..

PANOBINOSTAT DRUG SUBSTANCE SYNTHESIS AND DATA

http://www.google.com/patents/US7989639

Figure US07989639-20110802-C00002

A flow diagram for the synthesis of LBH589 lactate is provided in FIG. A. A nomenclature reference index of the intermediates is provided below in the Nomenclature Reference Index:


Nomenclature reference index
Compound	Chemical name

1	4-Bromo-benzaldehyde
2	Methyl acrylate
3	(2E)-3-(formylphenyl)-2-propenoic acid, methyl ester
4	3-[4-[[[2-(2-Methyl-1H-indol-3-
	yl)ethyl]amino]methyl]phenyl]-2-
	propenoic acid, methyl ester, monohydrochloride
5	(2E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-
	yl)ethyl]amino]methyl]phenyl]-2-propenamide
6	2-hydroxypropanoic acid, compd. with 2(E)-N-
	hydroxy-3-[4-[[[2-(2-methyl-1H-
	indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide
Z3a	2-Methyl-1H-indole-3-ethanamine
Z3b	5-Chloro-2-pentanone
Z3c	Phenylhydrazine

The manufacture of LBH589 lactate (6) drug substance is via a convergent synthesis; the point of convergence is the condensation of indole-amine Z3a with aldehyde 3.

The synthesis of indole-amine Z3a involves reaction of 5-chloro-2 pentanone (Z3b) with phenylhydrazine (Z3c) in ethanol at reflux (variation of Fischer indole synthesis).

Product isolation is by an extractive work-up followed by crystallization. Preparation of aldehyde 3 is by palladium catalyzed vinylation (Heck-type reaction; Pd(OAc)2/P(o-Tol)3/Bu3N in refluxing CH3CN) of 4-bromo-benzyladehyde (1) with methyl acrylate (2) with product isolation via precipitation from dilute HCl solution. Intermediates Z3a and 3 are then condensed to an imine intermediate, which is reduced using sodium borohydride in methanol below 0° C. (reductive amination). The product indole-ester 4, isolated by precipitation from dilute HCl, is recrystallized from methanol/water, if necessary. The indole ester 4 is converted to crude LBH589 free base 5 via reaction with hydroxylamine and sodium hydroxide in water/methanol below 0° C. The crude LBH589 free base 5 is then purified by recrystallization from hot ethanol/water, if necessary. LBH589 free base 5 is treated with 85% aqueous racemic lactic acid and water at ambient temperature. After seeding, the mixture is heated to approximately 65° C., stirred at this temperature and slowly cooled to 45-50° C. The resulting slurry is filtered and washed with water and dried to afford LBH589 lactate (6).

If necessary the LBH589 lactate 6 may be recrystallised once again from water in the presence of 30 mol % racemic lactic acid. Finally the LBH589 lactate is delumped to give the drug substance. If a rework of the LBH589 lactate drug substance 6 is required, the LBH589 lactate salt is treated with sodium hydroxide in ethanol/water to liberate the LBH589 free base 5 followed by lactate salt formation and delumping as described above.

All starting materials, reagents and solvents used in the synthesis of LBH589 lactate are tested according to internal specifications or are purchased from established suppliers against a certificate of analysis.

EXAMPLE 7 Formation of Monohydrate Lactate Salt

About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base was suspended in 1 ml of a solvent as listed in Table 7. A stoichiometric amount of lactic acid was subsequently added to the suspension. The mixture was stirred at ambient temperature and when a clear solution formed, stirring continued at 4° C. Solids were collected by filtration and analyzed by XRPD, TGA and ¹H-NMR.

TABLE 7

				LOD, %
		Physical	Crystallinity	(T_desolvation)
Solvent	T, ° C.	Appear.	and Form	T_decomposit.	¹H-NMR

IPA	4	FFP	excellent	4.3 (79.3)	—
			H_A	156.3
Acetone	4	FFP	excellent	4.5 (77.8)	4.18 (H_bz)
			H_A	149.5

The salt forming reaction in isopropyl alcohol and acetone at 4° C. produced a stoichiometric (1:1) lactate salt, a monohydrate. The salt is crystalline, begins to dehydrate above 77° C., and decomposes above 150° C.

EXAMPLE 18 Formation of Anhydrous Lactate Salt

DL-lactic acid (4.0 g, 85% solution in water, corresponding to 3.4 g pure DL-lactic acid) is diluted with water (27.2 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution is allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (10.0 g) is placed in a 4-necked reaction flask with mechanical stirrer. Demineralized water (110.5 g) is added, and the suspension is heated to 65° C. (inner temperature) within 30 minutes. The DL-lactic acid solution is added to this suspension during 30 min at 65° C. During the addition of the lactate salt solution, the suspension converted into a solution. The addition funnel is rinsed with demineralized water (9.1 g), and the solution is stirred at 65° C. for an additional 30 minutes. The solution is cooled down to 45° C. (inner temperature) and seed crystals (10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate monohydrate) are added at this temperature. The suspension is cooled down to 33° C. and is stirred for additional 20 hours at this temperature. The suspension is re-heated to 65° C., stirred for 1 hour at this temperature and is cooled to 33° C. within 1 hour. After additional stirring for 3 hours at 33° C., the product is isolated by filtration, and the filter cake is washed with demineralized water (2×20 g). The wet filter-cake is dried in vacuo at 50° C. to obtain the anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt as a crystalline product. The product is identical to the monohydrate salt (form H_A) in HPLC and in 1H-NMR, with the exception of the integrals of water signals in the 1H-NMR spectra.

In additional salt formation experiments carried out according to the procedure described above, the product solution was filtered at 65° C. before cooling to 45° C., seeding and crystallization. In all cases, form A (anhydrate form) was obtained as product.

EXAMPLE 19 Formation of Anhydrous Lactate Salt

DL-lactic acid (2.0 g, 85% solution in water, corresponding to 1.7 g pure DL-lactic acid) is diluted with water (13.6 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution was allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (5.0 g) is placed in a 4-necked reaction flask with mechanical stirrer. Demineralized water (54.85 g) is added, and the suspension is heated to 48° C. (inner temperature) within 30 minutes. The DL-lactic acid solution is added to this suspension during 30 minutes at 48° C. A solution is formed. Seed crystals are added (as a suspension of 5 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form A, in 0.25 g of water) and stirring is continued for 2 additional hours at 48° C. The temperature is raised to 65° C. (inner temperature) within 30 minutes, and the suspension is stirred for additional 2.5 hours at this temperature. Then the temperature is cooled down to 48° C. within 2 hours, and stirring is continued at this temperature for additional 22 hours. The product is isolated by filtration and the filter cake is washed with demineralized water (2×10 g). The wet filter-cake is dried in vacuo at 50° C. to obtain anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A) as a crystalline product.

EXAMPLE 20 Conversion of Monohydrate Lactate Salt to Anhydrous Lactate Salt

DL-lactic acid (0.59 g, 85% solution in water, corresponding to 0.5 g pure DL-lactic acid) is diluted with water (4.1 g), and the solution is heated to 90° C. (inner temperature) for 15 hours. The solution is allowed to cool down to room temperature and is used as lactic acid solution for the following salt formation step.

10 g of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt monohydrate is placed in a 4-necked reaction flask. Water (110.9 g) is added, followed by the addition of the lactic acid solution. The addition funnel of the lactic acid is rinsed with water (15.65 g). The suspension is heated to 82° C. (inner temperature) to obtain a solution. The solution is stirred for 15 minutes at 82° C. and is hot filtered into another reaction flask to obtain a clear solution. The temperature is cooled down to 50° C., and seed crystals are added (as a suspension of 10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form, in 0.5 g of water). The temperature is cooled down to 33° C. and stirring is continued for additional 19 hours at this temperature. The formed suspension is heated again to 65° C. (inner temperature) within 45 minutes, stirred at 65° C. for 1 hour and cooled down to 33° C. within 1 hour. After stirring at 33° C. for additional 3 hours, the product is isolated by filtration and the wet filter cake is washed with water (50 g). The product is dried in vacuo at 50° C. to obtain crystalline anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A).

EXAMPLE 21 Formation of Anhydrous Lactate Salt

DL-lactic acid (8.0 g, 85% solution in water, corresponding to 6.8 g pure DL-lactic acid) was diluted with water (54.4 g), and the solution was heated to 90° C. (inner temperature) for 15 hours. The solution was allowed to cool down to room temperature and was used as lactic acid solution for the following salt formation step.

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (20 g) is placed in a 1 L glass reactor, and ethanol/water (209.4 g of a 1:1 w/w mixture) is added. The light yellow suspension is heated to 60° C. (inner temperature) within 30 minutes, and the lactic acid solution is added during 30 minutes at this temperature. The addition funnel is rinsed with water (10 g). The solution is cooled to 38° C. within 2 hours, and seed crystals (20 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt, anhydrate form) are added at 38° C. After stirring at 38° C. for additional 2 hours, the mixture is cooled down to 25° C. within 6 hours. Cooling is continued from 25° C. to 10° C. within 5 hours, from 10° C. to 5° C. within 4 hours and from 5° C. to 2° C. within 1 hour. The suspension is stirred for additional 2 hours at 2° C., and the product is isolated by filtration. The wet filter cake is washed with water (2×30 g), and the product is dried in vacuo at 45° C. to obtain crystalline anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt (form A).

EXAMPLE 28 Formation of Lactate Monohydrate Salt

3.67 g (10 mmol) of the free base monohydrate (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2E-2-propenamide) and 75 ml of acetone were charged in a 250 ml 3-neck flask equipped with a magnetic stirrer and an addition funnel. To the stirred suspension were added dropwise 10 ml of 1 M lactic acid in water (10 mmol) dissolved in 20 ml acetone, affording a clear solution. Stirring continued at ambient and a white solid precipitated out after approximately 1 hour. The mixture was cooled in an ice bath and stirred for an additional hour. The white solid was recovered by filtration and washed once with cold acetone (15 ml). It was subsequently dried under vacuum to yield 3.94 g of the lactate monohydrate salt of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (86.2%).

References

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US7989639	8-3-2011	PROCESS FOR MAKING SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
US2010286409	11-12-2010	SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
US2010179208	7-16-2010	Use of HDAC Inhibitors for the Treatment of Bone Destruction
US2010160257	6-25-2010	USE OF HDAC INHIBITORS FOR THE TREATMENT OF MYELOMA
US2010137398	6-4-2010	USE OF HDAC INHIBITORS FOR THE TREATMENT OF GASTROINTESTINAL CANCERS
US2009306405	12-11-2009	PROCESS FOR MAKING N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE AND STARTING MATERIALS THEREFOR
US2009281159	11-13-2009	USE OF HDAC INHIBITORS FOR THE TREATMENT OF LYMPHOMAS
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US2009197936	8-7-2009	SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
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…………………………………..

extras

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).
Mocetinostat, has the following chemical structure and name:

,………………………………

Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).
Vorinostat has the following chemical structure and name:

………………………

Belinostat (PXD-101 , PX-105684)

(2E)-3-[3-(anilinosulfonyl)phenyl]-N-hydroxyacrylamide

……………………………………………….

Dacinostat (LAQ-824, NVP-LAQ824,)

((E)-N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1 H-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide

…………………………………………

Entinostat (MS-275, SNDX-275, MS-27-275)

4-(2-aminophenylcarbamoyl)benzylcarbamate

………………….

(a) The HDAC inhibitor Vorinostat™ or a salt, hydrate, or solvate thereof.

Vorinostat………………..

(b) The HDAC inhibitor Givinostat or a salt, hydrate, or solvate thereof.

Givinostat or a salt, hydrate, or solvate thereof.

……………………………………………

SEE COMPILATION ON SIMILAR COMPOUNDS AT …………..http://drugsynthesisint.blogspot.in/p/nostat-series.html

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