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NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE
WO2016055918) NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF
WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)
KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)
The present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.
Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.
The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-l -(lH-l,2,4-triazol-l-yl)-2-(2,5-difluorophenyl)43utan-2-ol; and has the structural formula I:
Formula I
The ‘353 described the process for the preparation Isavuconazole, involve the use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol (referred herein after “diol base”) in an oil form, which is difficult to isolate and purify. The use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, without purification, reflects the purity of Isavuconazole and Isavuconazonium sulfate. However, the reported process not feasible industrially.
Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for preparation of Isavuconazole or its salt thereof in enhanced yield as well as purity. In a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof.
Examples
Example-1: Preparation of Amorphous Isavuconazole
In a round bottomed flask charged ethanol (250 ml), thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 °C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product.
Yield: 26.5 gm
HPLC purity: 92.7%
Example-2: Preparation of crystalline Isavuconazole Base
Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.
Yield: 18.5 gm
HPLC Purity: 97%
Example-3: Preparation of crystalline Isavuconazole Hydrobromide
Charged isopropanol alcohol (250 ml) followed by thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 C to obtain off-white solid product.
Yield: 26.5 gm
HPLC Purity: 97.3%
Exaniple-4: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Dissolved crude 50 gm 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol base compound in 150 ml of ethyl acetate. Oxalic acid dihydrate 25 gm was added into the reaction mixture and stirred. Heat the reaction mixture for 1 hour at 50-55 °C. The reaction mixture was cooled to 25°C to 35°C. Toluene 300 ml was added into the reaction mixture to precipitate the solid. The precipitate was washed with toluene and dried under vacuum to obtain the solid crystalline form of titled compound.
Yield: 58 g
HPLC Purity: 76%
Exaniple-5: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate salt
Exemplified procedure in example 1 with the replacement ethyl acetate solvent with tetrahydrofuran and antisolvent toluene with petroleum ether were used to get the title compound.
Exaniple-6: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 with the replacement ethyl acetate solvent with isopropyl acetate and antisolvent toluene with diisopropyl ether were used to get the title compound.
Exaniple-7: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and toluene or heptane was used as antisolvent to get the title compound.
Example-8: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and isolation of the product were done by means of partial removal of the solvent under vacuum.
Example-9: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein ethyl acetate is replaced with isopropyl acetate and further, the reaction mass was stirred at lower temperatures to about 10°C to about 15°C for 3-5 hours and subsequently precipitated product was isolated and dried.
Example-10: Synthesis of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base
Stirring the suspension of 260 ml water and 65 gm 2-(2,5-difluoro-phenyl)-l-[l,2,4] triazol-l-yl-butane-2,3-diol oxalate salt were added. The reaction mixture pH was adjusted by addition of 10 % aqueous sodium carbonate solution. The pH was maintained to about pH 7 to about 8, 300 ml dichloro methane was added into the reaction mixture with stirring. The layers were separated and dichloromethane layer was collected. Aqueous layer was extracted with 150 ml dichloromethane. Dichloromethane layer was combined and washed with water. Dichloromethane was distilled out to get titled compound.
Yield: 35 gm
Purity: 87%
Wockhardt Ltd chairman Habil Khorakiwala.
/////////NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE
Isavuconazole – Basilea reports positive results from study
This post is updated in sept 2015……..
Isavuconazole (BAL4815; trade name Cresemba) is a triazole antifungal drug. Its prodrug, isavuconazonium sulfate (BAL8557), was granted approval by the U.S. Food and Drug Administration (FDA) on March 6, 2015[1]
During its Phase III drug trials, Astellas partnered with Basilea Pharmaceutica, the developer of the drug, for rights to co-development and marketing of isavuconazole. [2]
On May 28, 2013, Basilea Pharmaceutica announced it had been granted orphan drug status by the FDA for treatment of aspergillosis.[3] Since then, it has also been granted orphan drug status for the treatment of invasive candidiasis.[4]
Isavuconazonium sulfate (BAL8557)—a prodrug of isavuconazole.
CLINICAL TRIALS…LINK
PATENTS
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6-27-2012
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Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
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11-18-2011
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Antifungal Composition
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9-29-2010
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PROCESS FOR PREPARATION OF WATER-SOLUBLE AZOLE PRODRUGS
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12-3-2008
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N-substituted carbamoyloxyalkyl-azolium derivatives
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3-14-2007
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N-phenyl substituted carbamoyloxyalkyl-azolium derivatives
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11-3-2004
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N-substituted carbamoyloxyalkyl-azolium derivatives
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10-10-2001
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Azoles for treatment of fungal infections
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Several azoles are currently used for systemic mycoses. However, none of them fulfills the needs of clinical requirement in full extent, particularly with regard 0 to broad antifungal spectrum including aspergillus fumigatus, less drug-drug interaction, and appropriate plasma half-life for once a day treatment. Other clinical requirements which are not fulfilled by the azoles currently used, are efficacy against major systemic mycoses including disseminated aspergillosis, safety, and oral or parenteral formulations. Particularly, demand of a 5 parenteral administration of the azoles is increasing for the treatment of serious systemic mycoses. Most of the azoles on the market as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.
Isavuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; formula I, R1 and R3 represent fluorine and R2 represents hydrogen] as well as Ravuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol; formula I, R1 and R2 represent fluorine and R3 represents hydrogen] are useful antifungal drugs as reported in U.S. Pat. No. 5,648,372 from Feb. 1, 1995 or in U.S. Pat. No. 5,792,781 from Sep. 18, 1996 or in U.S. Pat. No. 6,300,353 from Oct. 9, 2001 (WO99/45008).
Since compounds of general formula I contain two adjacent chiral centers, synthesis of enantiomerically pure compound is complex and until now, all patented syntheses are not efficient enough and do not allow cost effective manufacturing on a technical scale:
Thus, U.S. Pat. Nos. 5,648,372 or 5,792,781 describe enantioselective synthesis of compounds of formula I (specifically Ravuconazole) from chiral 3-hydroxy-2-methyl propionic acid in 12 steps with overall yield lower than 5%. In another approach including 13 steps and low overall yield, (R)-lactic acid was used as the starting material (Chem. Pharm. Bull. 46(4), 623 (1998) and ibid. 46(7), 1125 (1998)).
Because both starting materials contain only one chiral center, in a number of inefficient steps, the second, adjacent chiral center has to be created by a diastereoselective reaction (using either Corey or Sharpless epoxidation method) which is not sufficiently selective leading mostly to a mixture of two diastereomers which have to be separated.
The second approach, based on (R)-methyl lactate, was recently very thoroughly optimized by BMS on a multi kilogram scale but it still does not fulfill requirements for cost effective manufacturing process (Organic Process Research & Development 13, 716 (2009)). The overall yield of this optimized 11 steps process is still only 16% (Scheme 1).
The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (U.S. Pat. No. 6,300,353 from Oct. 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to U.S. Pat. No. 6,300,353 claims even already known step as novel (claim 36).
Recent attempts to improve this concept as reported in WO 2007/062542 (Dec. 1, 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in U.S. Pat. No. 6,133,485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid.
This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (U.S. Pat. No. 6,300,353). It is obvious that this process using less expensive (S)-lactic acid makes the entire process with an inversion step even more complex than the original approach.
Elegant and more efficient process has been claimed in US 2004/0176432 from Jun. 26, 2001) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(II)-catalyst and diethyl zinc (Scheme 2).
Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 1611 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.
All known processes for enantiomerically pure compounds of formula I have definitely too many operation steps and specifically very low overall yield. The chiral starting materials used, either 3-hydroxy-2-methyl propionic acid or (S)- or (R)-methyl lactate, contain only one chiral center and consequently, in number of steps, the second adjacent chiral center has to be ineffectively generated which makes the entire process long and expensive. The only known process, which generates both chiral centers simultaneously, requires again expensive chiral starting material (R)-2-butynol.
ISAVUCONAZOLE
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synthetic scheme A, starting from 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propionyl]morpholine [which can be prepared by a same procedure as described in Chem. Pharm. Bull. 41, 1035, 1993.]. This synthesis route has been described for example in European Patent Application No. 99101360.8.
(a)
………………………………………………………………………
Example 1 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee);
m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.);
NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz).
The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).
Example 2 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol
Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).
Example 3 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.
Example 4 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Example 5 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol
A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
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WO 1999045008
The following synthetic scheme 1 illustrates the manufacture of one of the compounds of formula I′:
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Bioorganic and medicinal chemistry letters, 2003 , vol. 13, 2 p. 191 – 196
http://www.sciencedirect.com/science/article/pii/S0960894X02008922
A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.
A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.
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Scheme 1.
Chemistry
Scheme 1.We synthesized a series of new triazolium derivatives of Figure 1, Figure 3 and Scheme 1. CompoundsScheme 1 and Scheme 2, 6, 9, 10 and 11 were first prepared as outlined in Scheme 2 in order to analyze their stability and ability to release Figure 1, Figure 3 and Scheme 1. Next, aromatic analogues 18, 19, 20,21 and Figure 1, Figure 3 and Scheme 3 were synthesized for optimization of 11 to increase its water solubility and conversion rate. Compounds in the second series had sarcosine esters6 to make them water soluble, and they were also designed to generate acetaldehyde7 instead of formaldehyde for a better safety profile. The synthetic procedures for the second series of the derivatives are outlined in Scheme 3.
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Scheme 2.
(a) ClCOOCH2Cl, diisopropylethylamine, CH2Cl2, rt (quant); (b) Figure 1, Figure 3 and Scheme 1, CH3CN, 80 °C (60%); (c) (1) ClCOOCH2Cl, Et3N, CH2Cl2, rt; (2) Ac2O, pyridine, rt (30%, two steps); (d) (1) NaI, CH3CN, 50 °C ; (2) Figure 1, Figure 3 and Scheme 1, CH3CN, 50 °C (88%, two steps); Synthesis of Scheme 1 and Scheme 2: (1) N-3-hydroxypropyl-N-methylamine, ClCOOCH2Cl, Et3N, CH2Cl2, rt; (2) AcCl, Et3N, CH2Cl2, rt (20%, two steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH3CN, 50 °C (82%); Synthesis of 10: (1) l-prolinol, ClCOOCH2Cl, Et3N, CH2Cl2, rt; (2) Ac2O, pyridine, rt (<10%, 2 steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH3CN, 50 °C (92%); Synthesis of 11: (1) 2-hydroxymethyl-N-methylaniline, ClCOOCH2Cl, diisopropylethylamine, CH2Cl2, rt; (2) Ac2O, diisopropylethylamine, rt (20%, two steps); (3)Figure 1, Figure 3 and Scheme 1, cat. NaI, CH3CN, reflux (63%).
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Figure options
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Scheme 3.
(a) (1) oxalyl chloride, DMF, 0 °C; (2) KOtBu, THF, −5 °C (97%, two steps); (b) CH3NH2, MeOH, rt (90%); (c) LiAlH4, THF, 0 °C (80%); (d) (1) ClCOOCH(CH3)Cl, diisopropylethylamine, CH2Cl2, 0 °C; (2) Boc-Sarcosine, WSCI, DMAP, CH2Cl2, 0 °C (84%, two steps); (e) (1) Figure 1, Figure 3 and Scheme 1, NaI, CH3CN, 50 °C; (2) DOWEX-1 Cl− form, aqueous MeOH, rt (65%, two steps); (f) (1) HCl, EtOAc, rt; (2) lyophilization (69%, two steps); Synthesis of 18: (1) (i) (4,5-difluoro-2-methylaminophenyl)methanol, ClCOOCH(CH3)Cl, diisopropylethylamine, CH2Cl2, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH2Cl2, 0 °C (quant, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH3CN, 80 °C; (50%,); (3) HCl, EtOAc, rt (90%); Synthesis of 19: (1) (i) 2-fluoro-6-methylaminophenyl)methanol, ClCOOCH(CH3)Cl, diisopropylethylamine, CH2Cl2, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH2Cl2, 0 °C (74%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH3CN, reflux; (3) HCl, EtOAc, rt (29%, two steps); Synthesis of 20: (1) (i) (5-fluoro-2-methylaminophenyl)methanol, ClCOOCH(CH3)Cl, diisopropylethylamine, CH2Cl2, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH2Cl2, 0 °C (91%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH3CN, 70 °C (72%); (3) HCl, EtOAc, rt (88%); Synthesis of 21: (1) (i) (4-chloro-2-methylaminophenyl)methanol, ClCOOCH(CH3)Cl, diisopropylethylamine, CH2Cl2, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH2Cl2, 0 °C (71%, two steps); (2) Figure 1, Figure 3 and Scheme 1, CH3CN, 65 °C; (3) HCl, EtOAc, rt (65%, two steps).
read more at
Boyd, B.; Castaner, J. BAL-4815/BAL-8557
Drugs Fut 2006, 31(3): 187
Antimicrobial Agents and Chemotherapy, 2008 , vol. 52, 4 p. 1396 – 1400
Ohwada, J.; Tsukazaki, M.; Hayase, T.; Oikawa, N.; Isshiki, Y.; Umeda, I.; Yamazaki, T.; Ichihara, S.; Shimma, N.Development of novel water antifungal, RO0098557
21st Med Chem Symp (November 28-30, Kyoto) 2001, Abst 1P-06
Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.
RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-820
Tasaka et al., Chem. Pharm. Bull. 41(6) pp. 1035-1042 (1993).
Clinical trials
There have been three phase III clinical trials of isavuconazole, ACTIVE, VITAL and SECURE. As of June 2015, SECURE and VITAL have been presented in abstract form and results from ACTIVE have not been released.[9]
The SECURE trial compared voriconazole and isavuconazole in invasive fungal infections due to aspergillus. Isuvaconazole was found to be non-inferior to voriconazole, anothertriazole antifungal, with all cause mortality at 18.6%, compared to 20.2% in the voriconazole group. It additionally demonstrated a similar side effect profile.[10]
Data from the VITAL study showed that isavuconazole could be used in treatment of invasive mucormycosis, but did not evaluate its clinical efficacy for this indication.[11]
The ACTIVE trial is a comparison of isuvaconazole and caspofungin for invasive candida infections and results are anticipated in the second half of 2015.[12][13]
References
- [1]
- Saboo, Alok. “Basilea Announces Global Partnership With Astellas for Its Antifungal Isavuconazole.” FierceBiotech. N.p., 24 Feb. 2010. Web.
- “Basilea reports isavuconazole orphan drug designation by U.S. FDA.” Market Wired. 28 May 2013.
- “FDA Grants Orphan Drug Designation to Astellas for Isavuconazole for the Treatment of Invasive Candidiasis.” News Releases. Astellas. 3 Nov 2014.
- Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
- Jump up^ “Aspergillosis.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
- Jump up^ “Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis.” PR Newswire. N.p., 6 Mar. 2015.
- Jump up^ “Isavuconazonium.” Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
- Jump up^ Pettit, Natasha N.; Carver, Peggy L. (2015-07-01). “Isavuconazole A New Option for the Management of Invasive Fungal Infections”. Annals of Pharmacotherapy 49 (7): 825–842.doi:10.1177/1060028015581679. ISSN 1060-0280. PMID 25940222.
- Mujais, A. “2014: M-1756. A Phase 3 Randomized, Double-Blind, Non-Inferiority Trial Evaluating Isavuconazole (ISA) vs. Voriconazole (VRC) for the Primary Treatment of Invasive Fungal Disease (IFD) Caused by Aspergillus spp. or other Filamentous Fungi (SECURE): Outcomes by Malignancy Status”. http://www.icaaconline.com. Retrieved 2015-06-19.
- “Abstract: An Open-Label Phase 3 Study of Isavuconazole (VITAL): Focus on Mucormycosis (IDWeek 2014)”. idsa.confex.com. Retrieved 2015-06-19.
- Ltd., Basilea. “Basilea Pharmaceutica – Portfolio – Isavuconazole”. http://www.basilea.com. Retrieved 2015-06-19.
- “Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2015-06-19.
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 |
|
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile
|
|
| Clinical data | |
| Trade names | Cresemba (prodrug form) |
| AHFS/Drugs.com | entry |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
Oral, intravenous |
| Identifiers | |
| ATC code | None |
| PubChem | CID: 6918485 |
| ChemSpider | 5293682  |
| UNII | 60UTO373KE |
| ChEBI | CHEBI:85979  |
| ChEMBL | CHEMBL409153 |
| NIAID ChemDB | 416566 |
| Chemical data | |
| Formula | C22H17F2N5OS |
| Molecular mass | 437.47 g/mol |
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