Avarofloxacin Granted QIDP and Fast Track Designation
CAS NO 878592-87-1 of base
Furiex Pharmaceuticals Inc. announced that the FDA has granted Qualified Infectious Disease Product (QIDP) and Fast Track designation for avarofloxacin (JNJ-Q2). Avarofloxacin is a Phase 3-ready broad-spectrum fluoroquinolone antibiotic for the treatment of acute bacterial skin and skin-structure (ABSSSI) infections, community-acquired pneumonia and has proven to be effective in treating methicillin-resistant Staphylococcus aureus (MRSA) infections.
Avarofloxacin is an investigational novel fluoroquinolone antibiotic that has been shown to be effective in a Phase 2 study of ABSSSI infections. In this study, avarofloxacin demonstrated favorable efficacy for both early clinical response endpoints as well as all clinical cure endpoints for the intent to treat population.
Avarofloxacin has a low tendency for development of drug resistance and exhibits a broad range of antibacterial activities in vitro, including MRSA, fluoroquinolone-resistant Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug resistant strains), gram positive, gram negative, atypical respiratory pathogens (such as legionella and mycoplasma) and anaerobic bacteria, which are often associated with abscesses of the skin and other organs.
The availability of IV and oral formulations for avarofloxacin differentiates it from a number of other products for MRSA infections which are only available for intravenous administration.
For more information call (919) 456-7800or visit http://www.furiex.com/
About Methicillin-Resistant Staphylococcus aureus (MRSA)
MRSA is a strain of the bacteria Staphylococcus aureus (staph) which commonly causes skin and soft tissue infections and is resistant to many antibiotics. Although MRSA had previously been primarily a hospital-acquired pathogen, its incidence has been rising in the community, and it has become the most frequent cause of skin and soft tissue infections presenting to emergency departments in the United States. There are a limited number of antibiotics approved to treat MRSA, and their frequent usage has led to emergence of multi-drug resistant bacteria. Thus, we believe there is significant unmet medical need for new antibiotics such as avarofloxacin that provide flexible (hospital and outpatient) treatment options for MRSA.
WO-2006/101603 describes 7-amino alkylidenyl- heterocyclic quinolones as antimicrobial compounds and the synthesis of 7-[(3E)-3-(2-amino-l-fluoroethylidene)-l- piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid is disclosed as compound (303) in Table 1 on page 20. This compound is conveniently referred to as compound ‘A’ hereafter.
7-[(3E)-3-(2-amino-1 -fluoroethylidene)-1 -piperidinyl]-1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid
The in vitro antibacterial properties of compound ‘A’ are described by Morrow B.J. et al. in Antimicrobial Agents and Chemotherapy, vol. 54, pp. 1995 – 1964 (2010).
WO-2008/005670 discloses one-pot methods for the production of substituted allylic alcohols as well as extractive methods for the separation of certain isomeric alcohol products which are useful for preparing quinolones such as the antimicrobial compound 7-[(3E)-3-(2-amino- 1 -fluoroethylidene)- 1 -piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4- dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid (i.e. compound ‘Α’). An important intermediate in the overall synthesis route of said antimicrobial compound ‘A’ is 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3(2H)- dione and its hydrochloric acid salt thereof : compound (1 )
2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1 H-isoindole-1 ,3(2H)-dione compound (1 ) .HCI
Compound (1) introduces the desired E- stereochemistry into the overall synthesis route for the antimicrobial compound ‘Α’.
WO-2008/005670 discloses a synthesis route for compound (1) on page 38 as depicted below :
– highly enriched (E)
(Step 3a) O
The detailed reaction procedure for compound (1) is disclosed in WO-2008/005670 in Example 1 on pages 37 to 44 affording compound (1) in Method A with a E:Z ratio of 97:3 in an approximate overall yield of 18 % in Method A (step 1 for the first 3 heptane layers has a yield of 34 % with a ratio E:Z of 71 :29, step 2a has a yield of 53.4% with a ratio E:Z of 97:3, and step 3 has quantitave yield), or affording compound (1) in Method B with an approximate overall yield of 15% with a ratio E:Z of 94.4 : 5.6. WO-2008/005670 discloses a synthesis route for the hydrochloric acid addition salt of compound (1) on page 15 in Scheme 2 as depicted below :
1 ) 5/6 N HCl in IPA
2) heat to distill
3) add IPA
compound (1 ) .HCl
The detailed reaction procedure to prepare the HCl salt of compound (1) is disclosed in WO-2008/005670 in Example 4 on pages 49 to 52 affording >95% of desired E-isomer with an overall yield of 18 – 22% starting from N-boc-3-piperidone.
The reaction procedures described in WO-2008/005670 for the preparation of compound (1) or its HCl salt are characterized by lack of selectivity of the Wadsworth- Emmons-Horner reaction which produces the undesired Z-isomer in large quantities. This undesired Z-isomer requires additional time consuming separation steps.
Hence there is a need for a more efficient and less waste-producing procedure for the preparation of compound (1) or its HCl salt. WO-2010/056633 discloses a synthesis scheme XIV on page 87 to prepare tert-butyl 4- (2-ethoxy-2-oxoethylidene)piperidinyl-l-carboxylate and a synthesis scheme XXVI on page 111 to prepare (l-benzyl-piperidin-4-ylidene)bromoacetic acid ethyl ester.
In a first embodiment the present invention relates to an improved process for preparing compounds of formula (III) having an improved ratio of the desired (E)-isomer over the undesired (Z)-isomer.
In a further embodiment the compound (E)-(III) is then converted in to compound (1) or its hydrochloric acid addition salt thereof.
3 eq NaBH4 OH
30 – 4O0C
2a 2b 2a
2b shows the preparation of alcohol 2
1 ) HCI (5 eq )
aqueous layer to enriched E isomer pH 9-10 then extract into n-Butanol, discard aqueous layer
7-[3-(2-Amino-l-fluoroethylidene)piperidin-l-yl]-l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (10) and its HCl salt (12)
7-[3-(2-Amino-1-fluoro-ethyhdene)-piperidin-1-yl]-1-cyclopropyl–fluoro-8-mΘthoxy-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (10)
Step 1: Preparation of 3-(l-fluoro-2-hydroxyethylidene)piperidine-l-carboxylic acid tert-butyl ester (2a)
A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, nitrogen inlet adapter, and stopper, was charged with N-Boc-3-piperidone (663.36 g, 3.34 mol), 2-methoxyethanol (6.0 L) and 2-fluorotriethylphosphonoacetate (843.54 g, 3.49 mol). The mixture was stirred to obtain a homogeneous solution and then CS2CO3 was added in portions over 1.5 h. After the CS2CO3 addition was complete, NaBH4 was added in portions over 6 h; during most of this addition the reaction temperature was maintained between 35 0C to 40 0C. After the addition was complete, the reaction was allowed to stir overnight after which time HPLC analysis indicated that the reaction was complete. This run was combined with two additional runs of equal size and transferred to a stirred 100-L Hastalloy® reactor containing water (90 L). The aqueous mixture was extracted with heptane (4 x 20 L) followed by extraction with MTBE (methyl tert-butyl ether) (20 L). The first three heptane extracts provided 842 g of the allylic alcohol as 71:29 (E: Z) mixture (HPLC and NMR). The product mixture from the first three heptane extractions was carried on to the next step without any additional purification. The fourth heptane extract gave 114 g of product that was a 67:33 mixture of is: Z alcohols (NMR). MTBE extraction and concentration gave 1.1 Kg of product as a 33:67 mixture of E:Z alcohols (HPLC). The total overall yield for both isomers was 2.06 Kg (83%). 1H NMR of 2a (400 MHz, CDCl3): £ 1.45 (s, 9 H), 1.52 (m, 2 H), 2.40 (m, 2 H), 3.45 (m, 2 H), 3.90 (s, 2 H), 4.25 (d, 2 H). 1H NMR of 2b (400 MHz, CDCl3): δ 1.46 (s, 9 H), 1.65 (m, 2 H), 2.27 (m, 2 H), 3.45 (m, 2 H), 4.1 (s, 2 H), 4.25 (d, 2 H).
Step 2, Method A: Preparation of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-ϋ)
A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter, and stopper, was charged with E:Z alcohol mixture 2a and 2b (377.5 g, 1.296 mol corrected), 2-MeTHF (3.31 L), phthalimide (232.8 g, 1.581 mol), and Ph3P (411.3 g, 1.568 mol). The white suspension was stirred under N2 and cooled to -12 0C in an acetone/Dry-Ice bath, DIAD (309 mL, 1.49 mol) was added via the addition funnel over a 36-min period, while the reaction temperature was maintained at -15 0C to -10 0C. After the addition, the reaction was warmed to 20 0C in a water bath and stirred for 2 h. The reaction was cooled to 0 0C in an ice/water bath and quenched with cold 1.0 M HCl (950 mL). The aqueous phase was separated and EtOAc (1.70 L) was added to the organic phase. This phase was washed with cold 1.0 M HCl (0.95 L) (the aqueous phase was pH < 2) and then separated. The organic phase was next washed with cold 4 NNaOH (1.70 L), the alkaline aqueous phase (pH > 13) was separated and the EtOAc layer washed with brine (1.70 L). Concentration of the organic phase at 60 0C under house vacuum (-120 mm Hg) afforded 1,442.0 g of crude 3. This run was repeated on the same scale to provide an additional 1,431.0 g of crude material for a combined yield of 2,873 g (159%). HPLC analysis (area%) indicated crude 3 was a mixture of 3-E (29.4%), 3-Z (10.4 %), Ph3PO (51.0 %), and phthalimide (1.1 %). This was purified by recrystallization as described in step 2a.
Step 2a, Method A: Purification of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester
A 22-L 4-neck round bottom flask equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter and stopper was charged with the combined crude 3 (2,873 g) and MeOH (9.0 L). The solution was stirred under nitrogen and heated to 65 0C, while hot (60 0C) D.I. water (7.8 L) was added over a 15-min period. The solution was stirred at 65 0C for 5 min, and then the heating mantle was replaced with a water bath, and the mixture was gradually cooled to 0 0C over a 4-h period, and continued stirring for 1 h at 0 0C. The off-white solid was collected by filtration, and dried by air-suction at 60 0C for 20 h, this provided 1,172.6 g of a mixture of 3-E and 3-Z.
The partially purified product above was recrystallized a second time in the same manner using hot MeOH (7.2 L) and hot water (5.0 L) except that the water was added over a 10-min period to afford 515.6 g (53.4%) of 3-E as a 97:3 mixture of E:Z geometric isomers. This material was used in the next step without additional purification. . 1H NMR of 3-E (400 MHz, CDCl3): δ 1.48 (s, 9 H), 1.52-1.66 (m, 2 H), 2.28-2.38 (m, 2 H), 3.40-3.51 (m, 2 H), 4.18 (s, 2 H), 4.55 (d, J= 21.0 Hz, 2 H), 7.68- 7.77 (m, 2 H), 7.80-7.89 (m, 2 H). MS: 397 (M+Na)+, 771 (2M+Na)+.
3 -E-[2-( 1 ,3 -dioxo- 1 ,3-dihydroisoindol-2-yl)- 1 -fluoroethylidene]-piperidine- 1 – carboxylic acid tert-butyl ester was also prepared with Method B below: Step 2, Method B: Preparation of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-E)
Preparation of the methanesulfonate and chloride derivatives
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 2a (297.0 g, 1.21 mol) and CH2Cl2 (3.9 L). The solution was cooled to 0 0C under N2 and EtsN (320 mL, 2.30 mol) was added via the addition funnel over a 10- min period. This was followed by methanesulfonyl chloride (115 mL, 1.49 mol) added over a 60-min period then the reaction was stirred for an additional 60-min at 0 0C. The mixture was poured into a mixture of deionized water (4.4 L) and saturated NaHCθ3 (0.78 L), the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 2 L). All the CH2Cl2 layers were combined and washed with saturated NaHCθ3 (2 L). The CH2Cl2 was removed under vacuum at 40 0C to afford a mixture of the mesylate and chloride (342.3 g). This mixture was taken on to the next step without any purification.
Conversion of the methanesulfonate/chloride to phthalimide 3
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the mixture of the mesylate and chloride from above (342.2 g, 1.21 mol) and DMF (2.0 L) followed by potassium phthalimide (224.9 g, 1.21 mol). The mixture was stirred at 60 0C for 1-h then at 20 0C for 18 h. The mixture was poured into ice- water, allowed to stand for 30-min and filtered. The liquors from the filtration were allowed to stand at 0 0C over the weekend and filtered again. The combined solids were dissolved in acetone (4 L) and concentrated on the rotary evaporator, this process was repeated a second time to give the phthalimide derivative 3 as a mixture oiEIZ (79/31) isomers (263.2 g, 58.1 %).
Step 2a, Method B: Purification of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the crude phthalimide derivative 3 (263.1 g) and MeOH (2.74 L). The mixture was heated to 66 – 68 0C while water (2.1 L) was added over 20-min, the mixture was stirred at 68 0C for 5-min, then gradually cooled to 20 0C for 18-h. While the crystallization mixture was cooling it was seeded at 60 0C, 56 0C and 530C. This crystallization gave a white solid that was filtered and dried under vacuum at 50 0C to afford 3-E (118.8 g, 45.2%) as a mixture containing 94.4% E and 5.6% Z isomers (NMR analysis).
Step 3: Preparation of 2-[2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3)- dione (4)
A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 3-E (578.0 g, 1.544 mol) and CH2Cl2 (4.5 L). The solution was stirred at 200C under N2 and TFA (476 mL, 6.18 mol) was added via the addition funnel over a 10-min period. The mixture was gently heated to 38 0C and stirred for 3 h. The solvent was removed under vacuum to give the TFA salt of 4 (962.6 g). This material was dissolved in CH2Cl2 (4.0 L) and washed with 2.5 NNa2CO3 (4.6 L)-followed by saturated NaHCO3 (4.6 L). The organic phase was dried (MgSO4), filtered, and condensed in vacuo. The off-white solid was dried at 40 0C under vacuum (20 mm Hg) for 20 h to afford 464.3 g of the free base of 4 as slightly yellowish foamy substance. 1H NMR of 4 TFA salt (400 MHz, CDCl3): δ 1.87-1.98 (m, 2 H), 2.42-2.55 (m, 2 H), 3.38-3.50 (m, 2 H), 4.08-4.18 (br s, 2 H), 4.50 (d, J= 21.0 Hz, 2 H), 7.69-7.78 (m, 2 H), 7.79-7.87 (m, 2 H), 7.98-8.23 (br s, 1 H), 12.48 (s, 1 H). MS: 275 (MH)+, 549 (2M+H)+.
Step 4: Preparation of l-Cyclopropyl-ό^-difluoro-S-methoxy^-oxo-l^- dihydroquinoline-3-carboxylic acid difluoroborate ester (6)
A 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure equalizing addition funnel, and a nitrogen inlet adapter was charged with quinoline-3-carboxylic acid 5 (450.0 g, 1.524 mol), THF (5.40 L) and K2CO3 (247.2 g, 1.753 mol). This suspension was first stirred at 20 0C under N2 for 5 min, and BF3 »Et20 (259 mL, 2.04 mol) was added dropwise via the addition funnel to the stirred mixture over a 5-min period. After the addition, the mixture was heated to reflux (66 0C) for 6 h. The reaction was cooled to 10 0C, diluted with Et2O (9.0 L) and stirred for 10 min. The solid was filtered and washed with Et2O (200 mL x 2) and then dried at 50 0C under house vacuum (-160 mm Hg) for 20 h to afford 771.O g of crude difluoroborate ester 6. After this, the crude material was suspended in MeCN (8.0 L) and stirred at 20 0C for 20 min; the solid was collected by filtration. The filter cake was re-suspended and stirred in MeCN four more times (2.0 L x 4), and all filtrates were combined and concentrated at 60 0C under hi-vac (~10 mmHg). The resulting off- white solid was dried at 50 0C under house vacuum (-160 mmHg) for 20 h to afford 508.66 g (97.2% isolated yield, HPLC = 99.2% by area) of pure difluoroborate ester 6. 1H NMR of 6 (400 MHz, CD3CN): «51.17-1.28 (m, 2 H), 1.29-1.40 (m, 2 H), 4.19 (s, 3 H), 4.40-4.52 (m, 1 H), 8.16 (dd, J= 6.9, 7.0 Hz, 1 H), 9.17 (s, 1 H). MS: 344 (MH)+, 667 (2M-F)+.
Step 5: Preparation of intermediate 8
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with difluoroborate ester 6 (320.0 g, 0.933 mol), DMF (1.10 L) and piperidine 4 (289.0 g, 1.053 mole). This suspension was stirred at 20 0C under N2 for 5 min, EtsN (299 mL, 2.15 mol) was added to the stirred mixture via the addition funnel over an additional 5-min period. After this addition, the mixture was heated to 60 0C and stirred for 3 h, to give crude intermediate 7. HPLC analysis (area%) indicated crude 7 is a mixture of 7 (40.5%), 8 (1.7 %), 6 (24.1%), and the rest of unknowns (33.7%). MS: 598 (MH)+. The coupled crude product 7 was carried on to the next step without isolation.
Removal of the Fluoroborate Ester The above stirred reaction mixture containing 7 was treated in the same flask with EtOH (6.80 L) and Et3N (299 mL, 2.147 mol) under N2 at 60 0C. The amber solution was heated to reflux at 72 0C for 2 h and cooled to 20 0C. The reaction mixture was poured into a rapidly stirred 22-L 4-neck round bottom flask containing a 1 : 1 (v/v) ice-water mixture (8.0 L) over a 10-min period; stirring was continued for -10 min. Cold 1 NHCl (4.0 L) was added to the solution over 20 min to adjust the pH from 9-10 to 3; stirring was continued for an additional 20 min at 0 0C. The yellow solid was isolated by filtration and dried in a filter funnel by air-suction using house vacuum (-160 mm Hg) at 20 0C for 20 h to afford 1,889.0 g of crude 8 as a damp solid (HPLC = 33.6%, area%).
Purification of Intermediate 8
To a 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with crude 8 (1889.0 g), MeCN (3.6 L) and EtOH (3.2 L). The suspension was heated to reflux (76 0C), while D.I. H2O (500 mL) was added over 10 min. The solution was stirred at 76 0C for 5 min, and then gradually cooled to 10 0C over 1 h; stirred for an additional hour. The yellow solid was collected by filtration, dried in a vacuum oven under house vacuum (-160 mm Hg) at 60 0C for 20 h to afford 229. Ig (45%) of 8, which was used in next step without further purification. 1H ΝMR of 8 (400 MHz, DMSO-d6): £ 1.02-1.10 (m, 2 H), 1.11-1.19 (m, 2 H), 1.67-1.79 (m, 2 H), 2.34-2.45 (m, 2 H), 3.38-3.49 (m, 2 H), 3.78 (s, 3 H), 4.10 (s, 2 H), 4.15-4.26 (m, 1 H), 4.54 (d, J= 21.0 Hz, 1 H), 7.72 (d, J= 9.1 Hz, 1 H), 7.81 (s, 4 H), 8.71 (s, I H), 14.98 (s, 1 H). MS: 550 (MH)+.
Step 6: Preparation of 7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10)
8 10 A
22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with 8 (253.6 g, 0.462 mol) and MeOH (5.10 L). This suspension was stirred at 20 0C under N2 and H2NNH2 (86.9 mL, 2.796 mol) was added over a 5-min period. The yellow suspension was heated to 65 0C and refluxed for 1 h. The reaction was cooled to 60 0C and MeCN (3.84 L) was added. The mixture was heated to reflux for 5 min, and then cooled to 20 0C in a water bath. The light-yellow solid was collected by filtration and the filter cake was washed with MeCN (150 mL x 2). The combined filtrate was concentrated at 60 0C affording 322.0 g of crude product 10. This product was recrystallized from a mixture of MeOH (1.0 L) and water (1.195 L) to give 176.6 g (91.2%) of pure product 10 as a light yellow solid.
1H NMR of 10 (400 MHz, DMSO- d6): £ 1.0-1.09 (m, 2 H), 1.10-1.19 (m, 2 H), 1.66-1.78 (m, 2 H), 2.30-2.41 (m, 2 H), 3.17 (s, 2 H), 3.35 (s, 1 H), 3.36-3. 47 (m, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 4.13-4.22 (m, 1 H), 5.35-6.18 (br, 2 H), 7.74 (d, J= 8.9 Hz, 1 H), 8.69 (s, 1 H).
MS: 420 (MH)+.
6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid hydrogen chloride salt (12)
7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10) was prepared as described in Step 6 of Example 1.
A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with compound 10 (176.0 g, 0.4196 mol) and EtOH (2.40 L). The suspension was stirred under N2 and cooled to 10 0C with an ice/water bath. A solution of HCl in EtOH (1.25 M, 350 mL) was added via the addition funnel over a 20-min period. After the addition, the reaction was stirred at 10 0C for 5 min. The water bath was replaced with a heating mantle and the solution was heated to 76 0C and stirred for 5 min. The heating mantle was replaced with the water bath, the solution was cooled to 0 0C over 1 h and stirred at this temperature for an additional 1 h. The solid was collected by filtration, washed with ice-cold EtOH (100 mL x 2) and dried at 60 0C under vacuum (~4 mmHg) for 60 h. There was obtained 88.9 g (82%) of HCl salt 12 as an off-white to very light-yellow solid.
1H NMR of HCl salt 12 (400 MHz, CD3CO2D): £ 1.10-1.19 (m, 2 H), 1.29-1.38 (m, 2 H), 1.81-1.93 (m, 2 H), 2.51-2.60 (m, 2 H), 3.48- 3.60 (m, 2 H), 3.86 (s, 3 H), 4.08 (s, 2 H), 4.18 (s, 1 H), 4.19-4.30 (m, 2 H), 7.92 (d, J= 8.6 Hz, 1 H), 8.98 (s, 1 H) 11.65 (s, 1 H).
MS: 420 (MH)+
(VI) compound (1 ) .HCI
Compound (1) .HCI salt from Compound (Via) :
9.8 ml (90.6 mmol) of 1-chloroethyl chloro formate are added slowly to a solution of 30 g (82.3 mmol) of compound (E)-(Va) in 165 ml of toluene kept at 0°C. The reaction mixture is stirred 1 hour at room temperature than 1 hour at 80°C and filtered. 24 ml of ethanol and 15.35 ml (90.6 mmol) of 6M HCI solution in isopropanol are added to the filtrate and the resulting mixture is refluxed for 4 hours then cooled to 0°C. The precipitate is filtered, washed with 16 ml of acetone and 16 ml of toluene and dried under vacuum to give 21.94 g of compound (1) . HCI salt. Yield: 86%>.
NMR and MS data are identical to those of the literature.
WO2006101603A1 Feb 2, 2006 Sep 28, 2006 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones WO2008005670A2 Jun 14, 2007 Jan 10, 2008 Janssen Pharmaceutica Nv One-pot condensation reduction methods for preparing substituted allylic alcohols WO2010056633A2 Nov 10, 2009 May 20, 2010 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones
Phase3 Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy
Chemical structure of ganetespib and its co-crystal structure with Hsp90 N-terminal.
A, chemical structure of ganetespib.
B, crystallographic complex of ganetespib in the Hsp90 N-terminal.
C, hydrogen bond interactions between ganetespib with amino acid residues in the Hsp90 N-terminal ATP-binding pocket.
Synta Pharmaceuticals has opened a ClinicalTrials.gov listing for their much discussed GALAXY-2 phase 3 trial of their HSP90 inhibitor ganetespib in second-line non-small cell lung cancer (NSCLC), in combination with docetaxel. For the moment at least, the phase 2b GALAXY-1 trial is still listed as enrolling patients, but that would be expected to complete soon.
- CAS Number:
- Molecular Structure:
- Formula: C20H20N4O3
Hsp90, a chaperone essential for the folding of JAK2, is the target of Synta Pharmaceuticals’ ganetespib.
WEDNESDAY Feb. 27, 2013 — A genetically modified protein could provide the first effective treatment for the skin condition vitiligo, a new study in mice suggests.
People with vitiligo have white patches on the face, hands and other parts of the body. Vitiligo is an autoimmune disorder in which the immune system becomes overactive and kills the pigment cells that give skin its color.
Researchers at the Loyola University Chicago Stritch School of Medicine developed a genetically modified protein that reversed vitiligo in mice and had similar effects on human skin tissue samples. Findings from animal studies do not always hold up in human trials, however.
A protein called HSP70i plays a major role in the autoimmune response that causes vitiligo. The researchers genetically modified an amino acid in the protein in order to create a mutant version of HSP70i. This version replaces normal HSP70i and reverses the autoimmune response that causes vitiligo, the study authors explained in a Loyola news release.
When the mutant HSP70i was given to mice with vitiligo, their salt-and-pepper fur turned black, giving them a normal appearance. The mutant protein had a similar effect on human skin samples, according to the study, published in the current issue of the journal Science Translational Medicine.
Researcher I. Caroline Le Poole, a professor in Loyola’s Oncology Institute, and colleagues are seeking approval and funding to conduct a clinical trial of the modified protein in humans.
About 1 million Americans have vitiligo, which affects about one in 200 people worldwide. There are no long-term effective treatments for the condition. Current options include steroid creams, light therapy and skin grafts, but none of them can prevent vitiligo from progressing.
The U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases has more about vitiligo.
Naloxegol (INN; NKTR-118), or PEGylated naloxol, is a peripherally-selective opioid antagonist under development by AstraZeneca (licensed from Nektar) for the treatment of opioid-induced constipation.
- Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi, Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 14 May 2012.
- “Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119”. Retrieved 2012-05-14.
AstraZeneca has presented positive data from a late-stage trial of naloxegol in patients with non-cancer related pain and opioid-induced constipation.
In the fourth trial in a Phase III development programme designed to evaluate long-term safety and adverse event profile , 534 patients received naloxegol once-daily for up to 52 weeks, while 270 were on usual care (laxatives) for OIC. The most commonly-reported AEs occurring more frequently on naloxegol than on usual care included abdominal pain, diarrhoea, nausea and headache but the trial reported no imbalances in serious adverse events.
Briggs Morrison, head of the global medicines development at AstraZeneca, said “these high-level results are similar to the safety results seen in the Phase III studies previously reported and provide further confidence in the data we’ve seen to date for naloxegol”. The programme is now complete and filings in the USA and Europe are planned for the third quarter.
Globally, some 40–50% (28-35 million) of patients taking opioids for long-term pain develop constipation and about 40–50% (11-18 million) of those OIC sufferers achieve the desired outcomes with current options, ie laxatives.
The actual timing of the submissions depend in part on a meeting with the US Food and Drug Administration as naloxegol is currently considered a Schedule II controlled substance across the Atlantic based on its “structural relatedness” to noroxymorphone. AstraZeneca says it has conducted the studies necessary to evaluate the abuse potential and dependence-producing properties of naloxegol and a petition to de-control the drug was submitted in March 2012.
Naloxegol, a peripherally-acting mu-opioid receptor antagonist and formerly known as NKTR-118, was licensed from Nektar Therapeutics in September 2009.
CAS Number: 128607-22-7
Molecular Formula: C24H23ClO2
Molecular Weight: 378.89 g.mol-1
February 26, 2013 — The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
Dyspareunia is a condition associated with declining levels of estrogen hormones during menopause. Less estrogen can make vaginal tissues thinner, drier and more fragile, resulting in pain during sexual intercourse.
Osphena, a pill taken with food once daily, acts like estrogen on vaginal tissues to make them thicker and less fragile, resulting in a reduction in the amount of pain women experience with sexual intercourse.
“Dyspareunia is among the problems most frequently reported by postmenopausal women,” said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Osphena provides an additional treatment option for women seeking relief.”
Osphena’s safety and effectiveness were established in three clinical studies of 1,889 postmenopausal women with symptoms of vulvar and vaginal atrophy. Women were randomly assigned to receive Osphena or a placebo. After 12 weeks of treatment, results from the first two trials showed a statistically significant improvement of dyspareunia in Osphena-treated women compared with women receiving placebo. Results from the third study support Osphena’s long-term safety in treating dyspareunia.
Common side effects reported during clinical trials included hot flush/flashes, vaginal discharge, muscle spasms, genital discharge and excessive sweating.
Osphena is marketed by Florham Park, N.J.-based Shionogi, Inc.
- Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy – May 9, 2012
phase 2 NCT01671956; C2a/BRT/UC-01
A Randomized, Double-Blind, Placebo-Controlled Study Designed to Evaluate the Safety, Clinical Efficacy, and Pharmacokinetic Profile of Bertilimumab in Subjects With Active Moderate to Severe Ulcerative Colitis
25 February 2013
Immune Pharmaceuticals has started Phase II study of its bertilimumab (iCo-008 or CAT-213) drug, designed for the treatment of moderate-to-severe ulcerative colitis.
Bertilimumab is a human immunoglobulin monoclonal antibody which targets eotaxin-1, a member of the chemokine family of proteins regulating eosinophilic inflammation.
The double-blind, parallel group, randomized, placebo-controlled 90 patients-based study is designed to demonstrate the safety, clinical efficacy, and pharmacokinetic profile of bertilimumab in subjects with active moderate-to-severe ulcerative colitis.
60 patients in the study will be treated with bertilimumab 7mg/kg, while 30 patients with placebo every two weeks at days 0, 14, and 28, according to the company.
In addition, the patients will be evaluated for clinical response after six weeks to determine the decrease if any in the full Mayo Clinic Ulcerative Colitis Score.
Secondary and exploratory end points of the study include clinical remission defined as symptom free, fecal calprotectin, a recognized marker of gastro-intestinal inflammation, histopathology improvement and degree of mucosal injury.
The company, which is expecting to follow-up the patients for up to day 90, said the patient enrollment and clinical results are likely to be completed in 2014.
The company has also announced that bertilimumab will be the lead clinical stage development drug for the combined company following completion of the proposed merger with EpiCept in the second quarter of 2013.
It was discovered by Cambridge Antibody Technology using their phage displaytechnology. Named CAT-213 during early discovery and development by CAT, it was to be used to treat severe allergic disorders.
In January 2007, CAT licensed the drug for treatment of allergy disorders to iCo Therapeutics Inc. iCo Therapeutics Inc. is a Vancouver-based reprofiling company focused on redosing or reformulating drugs with clinical history for new or expanded indications – a so-called ‘search and development company’.
In March 2008, iCo announced iCo-008 had been in 126 patients in Phase I and II clinical trials. The drug substance had been manufactured by Lonza, in its cGMP facilities inSlough, UK. Subsequently iCo moved the drug substance to a fill-finish site for the final stage of manufacturing. iCo reported that the iCo-008 drug product was within specifications and contained a high antibody yield.
In June 2011, IMMUNE Pharmaceuticals (Herzliya, Israel) in-licensed Bertilimumab from iCo for non-ophthalmic indications. IMMUNE is initiating Phase II clinical trials of Bertilimumab in inflammatory bowel disease (ulcerative colitis & Crohn’s disease) in 2012 and 2013.
- Bertilimumab Cambridge Antibody Technology Group. 5. November 2004. pp. 1213–8. PMID 15573873.
DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,
Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.
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SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo identifying the product and strength in white ink. It contains buprenorphine HCl, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of 4:1 (ratio of free bases). It is intended for sublingual administration and is available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone, and 12 mg buprenorphine with 3 mg naloxone . Each sublingual film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink.
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:
Buprenorphine HCl has the molecular formula C29H41NO4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.
Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure:
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H 20 and the molecular weight is 399.87. It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.
Feb. 25, 2013 — The United States Food and Drug Administration (FDA) has approved generic versions of Reckitt Benckiser Healthcare’s Suboxone sublingual tablets. Buprenorphine HCl and Naloxone HCl Dihydrate SL Tablets, 2 mg/0.5 mg and 8 mg/2 mg will be produced by two U.S. based generic manufacturers – Actavis, Inc. and Amneal Pharmaceuticals, LLC.
Suboxone is indicated for maintenance treatment of opioid dependence.
For the 12 months ending December 31, 2012, Suboxone® tablets had total U.S. sales of approximately $625 million, according to IMS Health data. The generic equivalents are expected to save millions in healthcare costs.
Chemical Name: (2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Uses: Pain, Opiate/Opioid Abuse Treatment
Half-Life (H½): 37 Hours
Bioavailability: ~50-60% (Sublingual Tablet)
Protein Binding: 96%
Potency: 30-50x (Oral Morphine)
State Food and Drug Administration, China Grants Approval to Sihuan Pharmaceutical for Clinical Trial of Innovative Drug — Pinoxacin Hydrochloride
HONG KONG, Feb. 22, 2013, Sihuan Pharmaceutical Holdings Group Ltd. a leading pharmaceutical company with the largest cardio-cerebral vascular (“CCV”) drug franchise in China’s prescription market, today announced that Pinoxacin Hydrochloride, a Category 1.1 new drug developed by the Company’s innovative drug research and development team, received Approval for Clinical Studies from the State Food and Drug Administration. Phase I of clinical studies are set to begin in the first half of this year. It is the fourth Category 1 innovative drug for which the Company has received Approval for Clinical Studies.
Pinoxacin Hydrochloride is DPP-4 inhibitor class of oral hypoglycemic agents, a drug with a brand new structure for treating type II diabetes. It is clinically used to enhance the function of endogenous insulin for improving glycemic control, and long-term use can improve islet beta-cells function. Pre-clinical research has shown that DPP-4 inhibitors have potent in vitro and in vivo activities, a good selection profile, great stability and controllable quality, as well as better tolerance, with long-term administration showing a protective effect on pancreatic beta-cells. In addition, the DPP-4 inhibitor will not cause serious side effects such as weight gain and hypoglycaemia seen in traditional diabetes drugs. Pinoxacin Hydrochloride has good pharmacokinetic characteristics, high oral bioavailability, quick absorption, rapid onset and a longer duration. A once daily dosage is expected to keep the patients’ symptoms under control. The advantages of Pinoxacin Hydrochloride have proven the drug’s growth potential present in the market.
February 25, 2013 — The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease.
GIST is a tumor in which cancerous cells form in the tissues of the gastrointestinal tract, part of the body’s digestive system. According to the National Cancer Institute, an estimated 3,300 to 6,000 new cases of GIST occur yearly in the United States, most often in older adults.
Stivarga, a multi-kinase inhibitor, blocks several enzymes that promote cancer growth. With this new approval, Stivarga is intended to be used in patients whose GIST cancer cannot be removed by surgery or has spread to other parts of the body (metastatic) and is no longer responding to Gleevec (imatinib) and Sutent (sunitinib), two other FDA-approved drugs to treat GIST.
“Stivarga is the third drug approved by the FDA to treat gastrointestinal stromal tumors,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective.”
Stivarga was approved in September 2012 to treat colorectal cancer. It is marketed by Bayer HealthCare Pharmaceuticals, based in Wayne, N.J. Gleevec is marketed by East Hanover, N.J.-based Novartis, and Sutent is marketed by New York City-based Pfizer.
Regorafenib (BAY 73-4506, commercial name Stivarga) is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targetedVEGFR2-TIE2 tyrosine kinase inhibition. It is currently being studied as a potential treatment option in multiple tumor types.
Metastatic colorectal cancer
Regorafenib demonstrated to increase the overall survival of patients with metastaticcolorectal cancer and has been approved by the US FDA on September 27, 2012.Stivarga is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with Stivarga during clinical studies. The most common side effects reported in patients treated with Stivarga include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).
- “Bayer Announces New Data on Oncology Portfolio To Be Presented at the ECCO-ESMO Congress 2009”. Retrieved 2009-09-19.
- “Phase III Trial of Regorafenib in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival”. Retrieved 2011-10-26.
- “FDA approves new treatment for advanced colorectal cancer”. 27 Sep 2012.
- “FDA Prescribing Information”. 27 Sept 2012.
UC Riverside’s Michael Pirrung announces development of TIR-199 for renal (kidney) cancer at conference in Dubai
The compound TIR-199 that holds much promise in the laboratory in fighting renal (kidney) cancer. feb19,2013
RIVERSIDE, Calif. — Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (kidney) cancer.
Named TIR-199, the compound targets the “proteasome,” a cellular complex in kidney cancer cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple myeloma cells, a cancer coming from bone marrow.
Michael Pirrung, a distinguished professor of chemistry at UC Riverside, announced the development of TIR-199 in a lecture he gave on Feb. 19 at the 5th International Conference on Drug Discovery and Therapy, held in Dubai, UAE.
Operating like the garbage dump of a cell, the proteasome breaks down proteins. Drugs that block the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a variety of cancer cell lines, albeit with mixed results. For example, bortezomib, though effective against multiple myeloma, has many side effects because cells other than bone marrow cells are affected.
“The novel feature of our new proteasome inhibitor, TIR-199, is that it is nearly as potent as bortezomib, but is selective in inhibiting the growth of only renal cancer cell lines,” Pirrung said. “It’s what makes TIR-199 attractive.”
The TIR-199 research project at UC Riverside began about four years ago after a multidisciplinary, international team reported on a class of compounds that act on the proteasome. These compounds are the “syringolin” natural products — such as a compound produced naturally by the wheat-infecting bacterium Pseudomonas syringae. TIR-199 is a synthetic relative of syringolin.
Michael Pirrung is a distinguished professor of chemistry at UC Riverside. Photo credit: I. Pittalwala, UC Riverside.
Structure of Syringolin A.
The ring structure of syringolin A is formed by the two nonproteinogenic amino acids 5-methyl-4-amino-2-hexenoic acid and 3,4-dehydrolysine. The α-amino group of the latter is joined by a peptide bond to a valine residue, which is linked to another valine residue via a urea moiety.