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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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Cilastatin, циластатин , سيلاستاتين , 西司他丁 ,


ChemSpider 2D Image | Cilastatin | C16H26N2O5S

82009-34-5.png

Cilastatin

Cilastatin.svg

Cilastatin

シラスタチン

циластатин [Russian] [INN]
سيلاستاتين [Arabic] [INN]
西司他丁 [Chinese] [INN]

UNII141A6AMN38

CAS number 82009-34-5

WeightAverage: 358.453
Monoisotopic: 358.156242642

Chemical FormulaC16H26N2O5S

  • (L)-7-(2-Amino-2-carboxy-ethylsulfanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
  • (Z)-(S)-6-carboxy-6-[(S)-2,2-dimethylcyclopropanecarboxamido]hex-5-enyl-L-cysteine
  • (Z)-7-((R)-2-Amino-2-carboxy-ethylsulfanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
  • (2Z)-7-{[(2R)-2-amino-2-carboxyethyl]sulfanyl}-2-{[(1S)-2,2-dimethylcyclopropyl]formamido}hept-2-enoic acid
MK 0791|Primaxin®
Primaxin®
TL8005438
UNII:141A6AMN38
UNII-141A6AMN38
EINECS 279-875-8
 Cilastatin
CAS Registry Number: 82009-34-5
CAS Name: (2Z)-7-[[(2R)-2-Amino-2-carboxyethyl]thio]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]-2-heptenoic acid
Manufacturers’ Codes: MK-791
Molecular Formula: C16H26N2O5S
Molecular Weight: 358.45
Percent Composition: C 53.61%, H 7.31%, N 7.82%, O 22.32%, S 8.95%
Literature References: Prevents renal metabolism of penem and carbapenem antibiotics by specific and reversible dehydropeptidase I inhibition.
Synthesis and combination with thienamycins: D. W. Graham et al., EP 48301; H. Kropp et al., EP48025 (both 1982 to Merck & Co.), C.A. 97, 145271b, 145270a (1982). Combination with penems: F. M. Kahan, H. Kropp, EP72014 (1983 to Merck & Co.), C.A. 99, 70272h (1983). The articles cited below discuss the activity of cilastatin alone and in combination with imipenem, q.v. Dipeptidase inhibition, pharmacokinetics: S. R. Norrby et al., Antimicrob. Agents Chemother. 23,300 (1983). Stimulation of granulocyte function: H. Gnarpe et al., ibid. 25, 179 (1984). HPLC determn in serum: C. M. Myers, J. L. Blumer, ibid. 26, 78 (1984). Enhances intrathecal and ocular penetration of imipenem: A. W. Chow et al., ibid. 23, 634 (1983) and K. R. Finlay et al., Invest. Ophthalmol. Visual Sci. 24, 1147 (1983), respectively. In experimental meningitis: D. E. Washburn et al.,J. Antimicrob. Chemother. 12, 39 (1983). Series of articles on pharmacokinetics, safety and tolerance and efficacy of cilastatin/imipenem: ibid. 12, Suppl. D, 1-155 (1983); Infection 14, Suppl. 2, S111-S180 (1986).
Derivative Type: Sodium salt
CAS Registry Number: 81129-83-1
Additional Names: Cilastatin sodium
Molecular Formula: C16H25N2NaO5S
Molecular Weight: 380.43
Percent Composition: C 50.51%, H 6.62%, N 7.36%, Na 6.04%, O 21.03%, S 8.43%
Properties: Off-white to yellowish-white hygroscopic, amorphous solid. pKa1 2.0; pKa2 4.4; pKa3 9.2. Very sol in water, methanol.
pKa: pKa1 2.0; pKa2 4.4; pKa3 9.2
Therap-Cat: Antibacterial adjunct (dipeptidase inhibitor).
Keywords: Antibacterial Adjuncts; Renal Dipeptidase Inhibitors.

FDA 2019 APPROVED 2019/7/16, Imipenem, cilastatin and relebactam, Recarbrio

Antibacterial
  Disease
Uncomplicated urinary tract infection

Cilastatin inhibits the human enzyme dehydropeptidase.[1]

Yatendra Kumar, “Process for the preparation of amorphous cilastatin sodium.” U.S. Patent US20040152780, issued August 05, 2004.US20040152780

Cilastatin is an inhibitor of renal dehydropeptidase, an enzyme responsible for both the metabolism of thienamycin beta-lactam antibiotics as well as conversion of leukotriene D4 to leukotriene E4. Since the antibiotic, imipenem, is one such antibiotic that is hydrolyzed by dehydropeptidase, cilastatin is used in combination with imipenem to prevent its metabolism. The first combination product containing both drugs was approved by the FDA in November of 1985 under the trade name Primaxin, marketed by Merck & Co.9 A newer triple-drug product was approved in July 2019 under the trade name Recarbrio which also contains relebactam.8

Cilastatin is indicated, in combination with imipenem with or without relebactam, for the treatment of bacterial infections including respiratory, skin, bone, gynecologic, urinary tract, and intra-abdominal as well as septicemia and endocarditis.6,5

Image result for cilastatin

Uses

Dehydropeptidase is an enzyme found in the kidney and is responsible for degrading the antibiotic imipenem. Cilastatin can therefore be combined intravenously with imipenem in order to protect it from degradation, prolonging its antibacterial effect.

Imipenem alone is an effective antibiotic and can be given without cilastatin. Cilastatin itself does not have antibiotic activity, although it has been proved to be active against a zinc-dependent beta-lactamase that usually confers antibiotic resistance to certain bacteria, more precisely, the carbapenem family of antibiotics. This property is due to the physicochemical similarities between membrane dipeptidase (MDP), the compound it is usually set to target, and the bacterial metallo-beta-lactamase carried by the CphA gene.[1] The combination allows the antibiotic to be more effective by changing the pharmacokinetics involved. Thus imipenem/cilastatin, like amoxicillin/clavulanic acid, is a commonly used combination product.

PATENT

https://patents.google.com/patent/EP2402312A1

Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is [R-[R*,S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid, monosodium salt. It is an off-white to yellowish-white, hygroscopic, amorphous compound. PRIMAXIN (Imipenem and Cilastatin) is a formulation of Imipenem (a thienamycin antibiotic) and Cilastatin sodium.

Imipenem with Cilastatin acts as an effective antibiotic for the treatment of infections of various body systems. PRIMAXIN is a potent broad-spectrum antibacterial agent for intramuscular administration. Imipenem can be further described as a semi-synthetic thienamycin that is administered intravenously or intramuscularly in combination with Cilastatin to reduce toxicity. Cilastatin, a renal dipeptidase inhibitor, inhibits the enzymatic breakdown of Imipenem and increases urinary excretion of the active drug.

Originally Cilastatin was disclosed in US patent number 5,147,868 . This patent also discloses various processes for the preparation of Cilastatin, particularly example 19 A of this patent disclose a process for the preparation of Cilastatin. According to this example the condensation of 7-chloro-2-oxoheptanoic acid ethyl ester (I) with (S)-2,2-dimethylcyclopropanecarboxamide (II) by means of p-toluene sulphonic acid in refluxing toluene gives (S)-7-chloro-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (III), which is hydrolyzed in aq. NaOH to yield the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R)-cysteine (V) by means of NaOH in water to afford the target Cilastatin, followed by isomerisation to at 3.0 pH. The process followed in this example is depicted as below:

Figure imgb0002
WO 03/018544 claims a process for the purification of Cilastatin, which comprises contacting a solution of crude Cilastatin with a non-ionic adsorbent resin and recovering pure Cilastatin from a solution thereof. This publication also claims a process for the isomerisation of Cilastatin by heating a solution of Cilastatin containing the corresponding E isomer at a pH of about 0.5 to 1.5. This invention not suitable for plant point of view as it involves column chromatography.
US 2004/0152780 claims a process for the preparation of pure Cilastatin sodium in an amorphous form which comprises recovering Cilastatin sodium from a solution thereof which contains an organic solvent, homogeneous mixture of organic solvents, or homogeneous mixture of organic solvents and water, by solvent precipitation. According to this patent the pure Cilastatin sodium in amorphous form was recovered from the solution of Cilastatin sodium in a solvent (where Cilastatin sodium was soluble) by adding an anti-solvent (where Cilastatin sodium was insoluble).
WO 2006/022511 claims a process for preparing Cilastatin sodium via Cilastatin amine salt, also the said patent claims Cilastatin ammonium salt. However EP 0 048 301 page 2; line 33-37 & US 4,616,038 col 36; 40-44 anticipates the claim of the said publication. Also this patent utilizes the column chromatography for removing sodium chloride.
However taking the consideration the commercial importance of Cilastatin sodium and Imipenem, there remains a need of convenient process. Hence, we focused our research to find an alternative processes and succeeded with a process that eliminates the foregoing problems associated with earlier processes.
Figure imgb0004

Example 1Preparation of 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid (II) (starting material):

  • [0032]
    To the solution of S-2, 2-dimethylcylopropyl carboxamide (100gm) in toluene (500) was added Ethyl-7-chloro-2-oxo-heptanoate (270gm) and p-toluene sulphonic acid (1.5gm). The resulted solution was refluxed for 20hrs azeotropically. The resulted mass was cooled to 5-10°C and added the solution of sodium hydroxide (140gm) in water 500 ml and the resulted two-layered solution was stirred for 8hrs at 25-30°C up to the complete disappearance of ester. The toluene layer was separated and the aqueous layer was washed with toluene. The pH of the aqueous layer was adjusted to 4.0 to 4.5 and extracted with toluene (1 lt). The toluene layer containing 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid was washed with water and used as such for the next step. The ratio of Z and E isomer 90:10% was obtained.

Example 2Isomerisation of 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid (II):

  • [0033]
    To the toluene layer, obtained from example -1, was added hydrochloric acid (11t) and stirred for 4hrs at 25-30°C till the disappearance of E isomer. The toluene layer was separated and washed with water and followed by brine. The toluene layer was distilled out under vacuum up to 50% of the original volume. To the reaction mass hexane/IPE was added at 50°C and cooled to 0-5°C. The precipitated mass was filtered and washed with hexane (200ml) and dried under vacuum to obtained 99% pure Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid (150gm) as white solid.

Example 3Preparation of Cilastatin Acid (I):

  • [0034]
    To the solution of sodium hydroxide (90gm) in water (11t) was added L-Cysteine hydrochloride monohydrate (96gm) and Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred at 25-30°C till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. After completion of reaction, the reaction mass was washed with dichloromethane (500ml). To the aqueous layer was added carbon (10 gm) and stirred and filtered. To the filtrate was added water (11t) and the pH of the solution was adjusted to 3.0 and stirred for 24 hrs. The precipitated mass was filtered, washed with water (200ml) and with acetone (500ml) and dried to obtain 110gm white solid with 97% purity. The solid was dissolved in water (700ml) and added MDC (700ml) and ethyl acetate (100ml) and stirred for 10hrs. The precipitated mass was filtered and washed with water (100ml) and acetone (200ml) and dried to obtain 100gm white Cilastatin acid with 99.5% purity.

Example 4Preparation of Cilastatin Sodium:

  • [0035]
    The Cilastatin acid (100gm, 99.5%) was dissolved in the mixture of ethanol (2.5lt) and triethylamine (30gm) at 25 to 30°C. To the resulted clear solution was added carbon (10gm) and stirred and filtered. The filtrated was filtered again through sterile micron (0.2 µ) filter. To the resulted clear solution was added solution of sodium ethyl hexanoate (70gm) in ethanol (70ml) and stirred for 3hrs at 25 to 30°C.The precipitated Cilastatin sodium was filtered and washed with ethanol (80ml) and followed by acetone (200ml) and dried under vacuum to obtained 95gm Cilastatin sodium as amorphous white solid with 99.5% purity.

Example 5Preparation of Cilastatin Acid:

  • [0036]
    To the solution of sodium hydroxide (88gm) in methanol (1500ml) was added Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred to dissolve. To the resulted clear solution was added L-Cysteine hydrochloride monohydrate (97gm) and stirred the resulted suspension at 60 to 65°C till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. After completion of reaction, the pH insoluble salts were filtered. The filtrate was distilled out under vacuum. The residue was dissolved in water (500ml) and washed with dichloromethane (500ml). The pH of aqueous layer was adjusted to 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500ml). The butanol layer was washed with water and distilled. The residue was dissolved in water (100ml) and added acetonitrile (1500ml) at 50°C and further refluxed at 80°C for one hr. The precipitated cilastatin acid was filtered and washed with acetonitrile (100ml). The crude wet cake (60gm) was refluxed with acetonitrile water mixture (9:1,1500ml), and cooled to yield 60gm pure cilastatin acid with 99.5% purity.

Example 6Preparation of Cilastatin Acid:

  • [0037]
    To the solution of sodium hydroxide (88gm) in methanol (1500ml) was added Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid and stirred to dissolve. To the resulted clear solution was added L-Cysteine hydrochloride monohydrate (97gm) and stirred the resulted suspension at 60 to 65°C till the disappearance of Z-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid. The pH of the reaction mass was adjusted to 7.0 with conc.HCl and filterd the insoluble salts. The filtrated was distilled out under vacuum. The residue was dissolved in water (500ml) and washed with dichloromethane (500ml). The pH of aqueous layer was adjusted to 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500ml). The butanol layer was washed with water and distilled up to 50% of original volume and stirred at 25°C. The precipitated cilastatin acid was filtered and washed with n-butanol (100ml) followed by acetone to yield 60gm pure cilastatin acid with 99.7% purity.

Example 7Preparation of Cilastatin, Sodium:

  • [0038]
    The Cilastatin acid (100gm, 99.5%) was dissolved in the mixture of n-butanol (2.5lt) and triethylamine (30gm) at 25 to 30°C. To the resulted clear solution was added carbon (10gm) and stirred and filtered. The filtrated was filtered again through sterile micron (0.2 µ) filter. To the resulted clear solution was added solution of sodium ethyl hexanoate (70gm) in n-butanol (70ml) and stirred for 3hrs at 25 to 30°C. The precipitated Cilastatin sodium was filtered and washed with n-butanol (80ml) and followed by acetone (200ml) and dried under vacuum to obtained 80gm Cilastatin sodium as amorphous white solid with 99.78% purity.

Abbreviations;

  • [0039]
  • DBU: diazabicyclo[5,4,0]undec-7-en
  • DBN : 1,5-diazabicyclo[4,3,0]-non-5-ene
  • TMG: 1,1,3,3-tetramethylguanidine
  • DABCO: 1,4-diazabicyclo-[2,2,2]-octane

PATENT

https://patents.google.com/patent/WO2006022511A1/en

Cilasatin sodium salt i.e., [R-[R*, S*-(Z)]] –

7-[(2-amino-2-carboxyethylthio)-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino-2-hepa tenoic acid monosodium salt represented by following chemical formulae (1)1 has been used with imipenem in order to prevent its renal metabolism. Imipenem/cilastatin sodium is used as a potent broad spectrum antibacterial agent. [3] There have been several reports on the method for preparing a cilastatin sodium until now: for example, EP 48301 Bl discloses a method for the preparation of a cilastatin sodium salt using by Grignard reaction started from l-bromo-5-chloropentane (2′) explained by following Reaction Scheme 1; Donald W.

Graham et al discloses a preparation method using ethyl- 1, 3-dithian-2-carboxylate as a starting material (Donald W. Graham et al, J. Med. Chem., 30, pplO74, 1987) etc. [4] [Reaction Scheme 1]

[5]

Figure imgf000002_0001

[6]

Figure imgf000003_0001

[7] [8] As shown in the above Reaction Scheme 1, l-bromo-5-chloropentane (2′) is reacted with diethyl oxalate through Grignard reaction to afford ethyl 7-chloro-2-oxo-hepanoate (3′)at the 1st step; ethyl 7-chloro-2-oxo-heptanoate (3′) is reacted with (S)-2, 2-dimethylcyclopropanecarboxamide to obtain ethyl (Z )-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate (4′) at the 2n step.

[9] However, present inventors has confirmed that considerable amount (about 10 to 13%) of (E)-form isomer thereof (7′)was produced during the 2nd step as a reaction impurity by gas chromatography. The (E)-form isomer is further subjected to hydrolysis resulting in (E)-7-chloro-2-((S)-2,

2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (8′)as shown in following Reaction Scheme 2.

[10] [H] However, present inventors has confirmed that considerable amount (about 10 to 13%) of (E)-form isomer thereof (7′) was produced during the 2nd step as an reaction impurities by gas chromatography as shown in following Reaction Scheme 2. The (E )-form isomer is further subjected to hydrolysis resulting in (E)-7-chloro-2-((S)-2, 2-dimethylcyclopropylcarboxamide)-2-heptanoic acid (8′).

[12] [Reaction Scheme 2] [13]

Figure imgf000004_0001
Figure imgf000004_0002

[14] [15] There have been tried to solve the problems for example, the isomer impurity was removed by the acidification followed by recrystallization step or by adding cysteine to the reaction solution obtained in the 3r step at the above described 4 step, reacting with together to form (E)-7-(L-amino-2-carboxyethylthio)-2-((S )-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid and finally removing the reacted impurity by acidifying and heating step in the known preparation till now. However, the present inventors found that there remained unsolved problem such that the recrystallization yield of the product, i.e., (Z)-7-chloro-2-((S )-2,2-dimethylcyclopropylcarboxamide)-2-heptanoic acid was very poor because of the formed byproduct, i.e., (E

)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid in 3rdstep and further the unknown impurity (10′) and (S)-2,2-dimethylcyclopropanecarboxamide (H’) were produced by acidifying and heating reaction solution at the above described the 4 step as shown in following Reaction Scheme 3 confirmed by HPLC analysis, which give rise to another difficulty in the purification of final products. [16] [17] [Reaction Scheme 3] [18]

Figure imgf000005_0001

NH

(Z) and (E) m ix ture (91)

Figure imgf000005_0002

C ondition

(105 0 15

[19] In addition to above described problems, present inventors have found that the cilastatin isolated through the above described 4th step consisting of eluting the cation exchange resin with ammonia solution, concentrating the eluate and solidifying with ethanol and diethyl ether exists in the form of its ammonium salt not free acid form as disclosed in the patent. Using an acid such as hydrochloric acid in order to obtain free acid accompany with unwanted formation of inorganic ammonium salt such as ammonium chloride, which could not afford high purity of cilastatin sodium salt in the end.

[20] [21] Therefore, there have been tried to solve the above-described problems: for example, PCTAVO 0318544 (Al) discloses the isolation method using by neutral HP 20 resin column instead of cationic resin disclosed in EP 48301 Bl; PCTAVO 02094742 (Al) discloses the method for preparing cilastatin sodium salt (Ia) from cilastatin (6′), the disclosure of which cited documents are incorporated herein by reference.

[22]

[23] However, the above-described methods for preparing cilastatin using column chro¬ matographic process are not suitable for commercial mass production.

[24]

[25] The present inventors have made extensive researches to discover novel method for preparing cilastatin sodium salt with high yield and mass production and finally completed the invention by founding novel preparation for obtaining purposed cilastatin sodium salt; i.e., selectively hydrolyzing (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate, isolating (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt from the reaction mixture, adopting the cilastatin amine salt instead of free acid form disclosed in cited references and the use of sodium hydroxide and cationic exchange resin with pH control in order to obtain cilastatin sodium salt with high purity and high yield.

Example 1: Preparation of ethyl (Z)-7-chloro-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate (4)

[67]

[68] l-bromo-5-chloropentane (29 Ig, 1.57 mol) was reacted with diethyl oxalate

(206.5g) through Grignard reaction to obtain ethyl 7-chloro-2-oxo-heptanoate (3) and the compound (3) was reacted with (S)-2,2-dimethylcyclopropanecarboxamide to obtain ethyl (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptanoate (237g, 0.79 mol). The above-described step was performed by the procedure according to the procedure disclosed in EP 48301 (Bl).

[69]

[70] Example 1: Preparation of ethyl (Z)-7-chloro-((S)-2,

2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12)

[71]

[72] 1-1. ( Z V7-chloro-(YSV2. 2-dimethylcyclopropanecarboxamidoV2-heptanoic acid sodium salt

[73] The ethyl (Z)-7-chloro-2-((S

)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (237g, 0.79 mol) obtained in Comparative Example 1 was dissolved in 877ml of methanol and 1.8 L of sodium hydroxide solution (0.48 M) was added with stirring at room temperature. The reaction was finished when the area ratio of (Z) isomer and (E) isomer becomes 20: 1 by HPLC analysis and the un-reacted organic reagent was extracted with 490 ml of dichloromethane. The pH of the solution was adjusted to 7-8 with 3N HCl and the un- reacted organic reagent was extracted with 490 ml of dichloromethane again. The water layer was concentrated under reduced pressure and 650ml of ethanol was added and stirred until the solid had been dissolved at 50°C, for 30 minute to 1 hour. The un- dissolved solid was removed with filtration and the filtrate was concentrated under reduced pressure. 2.4 L of acetonitrile is added thereto and stirred to obtain 140.8g of ( Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12 ; 55% yield).

[74]

[75]

[76] m.p.: 219°C;

[77] 1H-NMR (D2O, 300MHz) δppm: 0.87 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.61 (m, 2H), 1.68 (dd, IH), 1.78 (m, 2H), 2.12 (m, 2H), 3.62 (t, 2H), 6.47 (t, IH);

[78]

13

[79] 13C ( -NMR (D2O, 300MHz) δppm: 19.47, 19.99, 22.55, 25.74, 26.75, 27.53, 29.44,

32.27, 46.11, 131.41, 136.52, 172.74, 174.62.

[80] [81] [82]

[83] 1-2. ( Z V7-chloro-(YSV2. 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

(12-D

[84] 140.8g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12) obtained from Example 1-1 was dissolved in 422 ml of distilled water. The pH of the solution was adjusted to 2.0-3.0 with 3N HCl, extracted with 592 ml of isopropylether two times and 59.2g of anhydrous magnesium sulfate was added to isopropylether layer, stirred and subjected to filtration. The filtrate was concentrated to afford 127.7g of (Z)-7-chloro-2-((S )-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (12-1, 98% yield).

[85]

[86] 1H-NMR (CDCl3, 300MHz) δppm: 0.83 (dd, IH), 1.19 (s, 7H), 1.44 (dd, IH), 1.19

(s, 3H), 1.64 (m, 2H), 1.81 (m, 2H), 2.21 (m, 2H), 3.54 (t, 2H), 6.78 (t, IH), 7.04 (br, IH);

[87]

13

[88] 13C ( -NMR (CDCl3, 300MHz) δppm: 18.69, 20.82, 22.86, 25.36, 27.03, 28.53,

29.27, 32.17, 44.60, 124.88, 139.49, 168.96, 170.15.

[89]

[90]

[91] 1-3. ( Z V7-chloro-((SV2. 2-dimethylcyclopropanecarboxamidoV2-heptenoic acid ammonium salt (12-2)

[92] 127.7g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (12-1) obtained from Example 1-2 was dissolved in 422 ml of EtOH. 100 ml of 25% ammonia water solution was added thereto, stirred and concentrated to obtain 135.6g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ammonium salt (12-2, 100% yield).

[93]

[94] Example 2: Preparation of cilastatin ammonium salt (13-1)

[95] 4Og of (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12, 0.14 mol) obtained in Example 1-1 was dissolved in 120 ml of 0.48 M sodium hydroxide solution and 240 ml of ethanol and the mixture of 1.4g of NaBr (0.013 mol) and 25.3g of L-cysteineDHClDH) was added thereto, stirred at 55°C, for 8 hours.

[96] The pH of the reaction solution was adjusted to 5.5-5.0 with 3N HCl, concentrated and 800ml of methanol was added, stirred at 55°C for 1 hour and un-dissolved salt was filtered out. The filtrate was concentrated to the extent that the volume of total solution was reduced to about 1/2. The concentrate was adsorbed with cationic exchange resin (PK208 model, Samyang Co.), washed with distilled water to the extent that the con¬ ductivity of the solution became less than lθμs(microsiemens), eluted with 2N ammonia water and the eluate was concentrated under the reduced pressure to give brown solid compound. The compound was dissolved in 40 ml of distilled water. 0.8 L of 2-propanol was added thereto and the solution was subjected to salting out method with reflux for 2 hours. The resulting solid was cooled and filtered to obtain 45.66g of cilastatin ammonium salt (13-1. 90% yield).

[97]

[98] m. p.: 161°C;

[99] Element Analysis: C16H29N3O5S (MW: 375.183): CaI. Q51.18; 7.78; N:11.19; Est.

C:51.01; H: 7.97; N: 11.04;

[100] MS m/z : 375 (M+, 49), 312(36), 97 (84.2), 69 (100);

[101] 1H-NMR (D2O, 300MHz) δppm: 0.87 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.62 (m, 5H), 2.1 l(q, 2H), 2.62 (t, 2H), 3.06 (m, 4H), 3.91 (dd, IH), 6.47 (t, IH);

13

[102] ” (C-NMR (D2O, 300MHz) δppm: 19.49, 19.97, 22.53, 26.74, 27.44, 27.86, 29.09,

29.43, 31.94, 32.85, 54.44, 131.23, 136.83, 172.70, 173.71, 174.64.

[103]

[104] Example 3: Preparation of cilastatin ethylamine salt (13-2)

[105] 4Og of (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12-1, 0.15 mol) obtained in Example 1-2 was dissolved in 165 ml of 0.66 M sodium hydroxide solution and 330 ml of ethanol and the mixture of 1.5g of NaBr (0.015 mol) and 27.6g of L-cysteineDHClDH) was added thereto, stirred at 55°C, for 8 hours.

[106] The pH of the reaction solution was adjusted to 5.5-5.0 with 3N HCl, concentrated and 800ml of methanol was added, stirred at 55°C for 1 hour and un-dissolved salt was filtered out.. The filtrate was concentrated to the extent that the volume of total solution was reduced to about 1/2. The concentrate was adsorbed with cationic exchange resin (PK208 model, Samyang Co.), washed with distilled water to the extent that the conductivity of the solution became less than 10μs(microsiemens), eluted with 2N ethylamine water and the eluate was concentrated under the reduced pressure to give brown solid compound. The compound was dissolved in 40 ml of distilled water. 0.8 L of 2-propanol was added thereto and the solution was subjected to salting out method with reflux for 2 hours. The resulting solid was cooled and purified with filtration to obtain 49.38g of cilastatin ethylamine salt (13-2. 90% yield).

[107]

[108] 1H-NMR (D2O, 300MHz) δppm: 0.86 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.27 (t, 3H), 1.60 (m, 5H), 2.1 l(q, 2H), 2.62 (t, 2H), 3.06 (m, 4H), 3.91 (dd, IH), 6.47 (t, IH); [109] 13C-NMR (D2O, 300MHz) δppm: 14.7, 21.57, 22.04, 24.63. 28.82, 29.52, 29.94,

31.16, 31.49, 34.00, 34.91, 37.78, 56.50, 133.27, 138.96, 174.75, 175.81, 176.74.

[HO]

[111] Example 4 : Purification of cilastatin ammonium salt

[112] 4-1. Purification using by water and ethanol

[113] 45.66g of cilastatin ammonium salt (13-1,0.12 mol) obtained in Example 2 was dissolved in 45.66 ml of distilled water and 1.3L of anhydrous ethanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 38.81g of cilastatin ammonium salt (Yield: 85%, Purity: 99.8%).

[114]

[115] 4-2. Purification using by ammonia water and propanol Q)

[116] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 50 ml of 25% ammonia water and 1.5L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 41.2g of cilastatin ammonium salt (Yield: 82.4%, Purity: 99.3%).

[117]

[118] 4-3. Purification using by ammonia water and propanol (1)

[119] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in

100 ml of 25% ammonia water and 2.0L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was purified with filtration to obtain 35.4g of cilastatin ammonium salt (Yield: 70.8%, Purity: 99.3%)

[120]

[121] 4-4. Purification using by ammonia water and ethanol

[122] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 50 ml of 25% ammonia water and 1.5 L of anhydrous ethanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 35.6g of cilastatin ammonium salt (Yield: 71.2%, Purity: 99.8%).

[123]

[124] 4-5. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (1)

[125] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 50ml of 4N ammonia water, and 2.0 L of 1 -propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 89.3g of cilastatin ammonium salt (Yield: 89.3%, Purity: 99.6%).

[126]

[127] 4-6. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (1) [128] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 50ml of 2N ammonia water, and 2.0 L of 1-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 95.0g of cilastatin ammonium salt (Yield: 95.0%, Purity: 99.5%).

[129]

[130] 4-7. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (3)

[131] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 100 ml of distilled water and 50ml of 25% ammonia water, and 2.0 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 89.7g of cilastatin ammonium salt (Yield: 89.7%, Purity: 99.8%).

[132]

[133] 4-8. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (4)

[134] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 100ml of 25% ammonia water, and 3.0 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 80.Og of cilastatin ammonium salt (Yield: 80.0%, Purity: 99.7%).

[135]

[136] 4-9. Purification using by water and propanol

[137] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 100 ml of distilled water and 1.5 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 87.2g of cilastatin ammonium salt (Yield: 87.2%, Purity: 99.6%).

[138]

[139] Example 5: Preparation of cilastatin sodium salt

[140] 4.28g of sodium hydroxide (0.107 mol) was dissolved in 38.3 ml of distilled water and 191.5 ml of ethanol. 38.81g of cilastatin ammonium salt (0.1 mol) obtained in Example 4-1 was added thereto and stirred for 30 minutes. The solution was con¬ centrated under reduced pressure at 60°C and 153 ml of distilled water was added to the concentrate. The solution was stirred to dissolve the concentrate and the pH of the solution was adjusted to 7.0 using by cationic exchange resin and filtered. The filtrate was lyophilized to obtain high purity (99.4%) of cilastatin sodium salt.

[141]

[142] Experimental Example 1: Purity Determination [143] The purity of cilastatin ammonium salt obtained in Example 4 was determined by

HPLC on condition as shown in Table 1 and the determined result was shown in Table 2.

[144] Table 1

Figure imgf000017_0001

[145] Table 2

Figure imgf000017_0002

[146]

Industrial Applicability

[147] The novel method of the present invention could prevent the formation of (E )-isomer from the preparation of novel intermediate for preparing cilastatin sodium, i.e., (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt and isolate the intermediate in situ providing simpler process with high yield and purity. Furthermore, it can provide with highly purified cilastatin sodium salt by isolating novel cilastatin amine salt and using sodium hydroxide and cationic exchange resin. Accordingly, the method can be very useful in preparing cilastatin sodium salt with high yield and high purity.

Claims
Hide Dependent
Claims
[1] A method for preparing (Z)-7-chloro-2-((S)-2,
2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by general chemical formula (12) comprising the steps consisting of: selectively hy- drolyzing (Z)-7-chloro-2-((S
)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate represented by chemical formula (4) in reaction solvent under basic condition and removing un-reacted reactant remained in reaction solvent layer with washing organic solvent with controlling the pH of reaction solution with acid at the 1st step; concentrating remaining water layer, adding alcohol thereto with heating, stirring to the extent to dissolve the solid, filtering out un-dissolved salt, and concentrating the filtrate under reduced pressure at the 2n step; adding organic solvent thereto to solidify the concentrate, filtering the solution to isolate (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by chemical formula (12) at the final step:
Figure imgf000018_0001
Wherein M+ is alkali metal salt.
[2] The method according to claim 1, said R group of general formula (12) is selected from lithium salt, sodium salt and potassium salt. [3] The method according to claim 1, said reaction solvent at the 1st step is selected from the mixture of water and methanol, water and ethanol or water and propanol.
[4] The method according to claim 1, said pH of the reaction solution at the 1ststep ranges from 6 to 8. [5] The method according to claim 1, said organic solvent for isolating final product from the salt thereof is acetonitrile, acetone or the mixture solvent mixed with water and alcohol.
[6] A method for preparing cilastatin sodium salt represented by chemical formula (1) comprising the steps consisting of: reacting (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid or the salt thereof represented by chemical formula (12) with cysteine in basic solution at the 1ststep; controlling the pH of the reaction solution obtained in step 1, concentrating, adsorbing the concentrate with cationic exchange resin, washing with water, eluting with amine solution to concentrate the eluant at the 2nd step; dissolving the concentrate in recrystallization solvent and subjecting to recrystallization process by adding alcohol in a dropwise manner to afford pure cilastatin amine salt (13) at the 3r step; reacting cilastatin amine salt (13) with sodium hydroxide and controlling the pH with cationic exchange resin at the 4thstep.
Figure imgf000019_0001
Wherein M+ is alkali metal salt.
Figure imgf000019_0002
Figure imgf000020_0001
Wherein R is a hydrogen atom or lower alkyl group.
[7] The method according to claim 6, said R group of general chemical formula (13) is a hydrogen atom or C1-C4 alkyl group. [8] The method according to claim 6, said recrystallization solvent at the 3 step is water, ammonia water, or the mixture thereof in the amount ranging from 1 :3 to
2:1 (w/v) of the weight of cilastatin amine salt.
[9] The method according to claim 6, said alcohol added for recrystallization at the 3 step is ethanol, 1-propanol, 2-propanol, n-butanol, or the mixture thereof. [10] The method according to claim 6, said recrystallization process at the 3rdstep is performed at the temperature ranging from 5 to 97°C.
[H] The method according to claim 6, said cationic exchange resin at the 4thstep is styrene strong acidic resin. [12] An intermediate represented by chemical formula (13)
Figure imgf000020_0002
Wherein R is a hydrogen atom or lower alkyl group.

References

  1. Jump up to:a b Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ (1995). “The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA”Antimicrob. Agents Chemother39 (7): 1629–31. doi:10.1128/aac.39.7.1629PMC 162797PMID 7492120.
  • Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120]
  • Buckley MM, Brogden RN, Barradell LB, Goa KL: Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1992 Sep;44(3):408-44. [PubMed:1382937]
  • Balfour JA, Bryson HM, Brogden RN: Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs. 1996 Jan;51(1):99-136. doi: 10.2165/00003495-199651010-00008. [PubMed:8741235]
  • Koller M, Brom J, Raulf M, Konig W: Cilastatin (MK 0791) is a potent and specific inhibitor of the renal leukotriene D4-dipeptidase. Biochem Biophys Res Commun. 1985 Sep 16;131(2):974-9. doi: 10.1016/0006-291x(85)91335-x. [PubMed:3863619]
  • FDA: Recarbrio Label [Link]
  • FDA: Primaxin Label [Link]
  • ChemSpider: Cilastatin [Link]
  • FDA Label: Apadaz [Link]
  • Drugs@FDA: Primaxin [Link]

Synthesis

By Panchapakesan, Ganapathy et alFrom Indian, 269299, 16 Oct 2015

IN 269299

SYN

Patent

Publication numberPriority datePublication dateAssigneeTitle
EP0048301A11980-09-241982-03-31Merck & Co., Inc.2-(Cyclopropane-carboxamido)-2-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same and a thienamycin-type compound
EP0072014A1 *1981-08-101983-02-16Merck & Co., Inc.Combination of 2-substituted penems with dipeptidase inhibitors
US4616038A1978-07-241986-10-07Merck & Co., Inc.Combination of thienamycin-type antibiotics with dipeptidase inhibitors
WO2003018544A12001-08-242003-03-06Ranbaxy Laboratories LimitedProcess for the preparation of cilastatin
US20040152780A12001-05-182004-08-05Yatendra KumarProcess for the preparation of amorphous cilastatin sodium
WO2006022511A12004-08-252006-03-02Dong Kook Pharm. Co., Ltd.Novel process for the preparation of cilastatin sodium salt
Publication numberPriority datePublication dateAssigneeTitle
Family To Family Citations
KR100957725B12009-07-092010-05-12디에이치씨 (주)Method for preparing intermediate of cilastatin
WO2011061609A22009-11-192011-05-26Ranbaxy Laboratories LimitedProcesses for the preparation of cilastatin
US20120253066A1 *2010-01-012012-10-04Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of cilastatin sodium
CN102675175B *2011-03-082014-02-19深圳市海滨制药有限公司Method for separating and purifying cilastatin
CN102875433A *2012-10-292013-01-16江西金顿香料有限公司Preparation method of cilastatin acid

Cilastatin

    • ATC:J01DH51
  • Use:dehydropeptidase inhibitor (for combination with imipenem)
  • Chemical name:[R-[R*,S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid
  • Formula:C16H26N2O5S
  • MW:358.46 g/mol
  • CAS-RN:82009-34-5
  • InChI Key:DHSUYTOATWAVLW-WFVMDLQDSA-N
  • InChI:InChI=1S/C16H26N2O5S/c1-16(2)8-10(16)13(19)18-12(15(22)23)6-4-3-5-7-24-9-11(17)14(20)21/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23)/b12-6-/t10-,11+/m1/s1
  • EINECS:279-875-8
  • LD50:8 g/kg (M, route unreported);
    8 g/kg (R, route unreported)

Derivatives

monosodium salt

  • Formula:C16H25N2NaO5S
  • MW:380.44 g/mol
  • CAS-RN:81129-83-1
  • EINECS:279-694-4
  • LD50:6786 mg/kg (M, i.v.); >10 g/kg (M, p.o.);
    5027 mg/kg (R, i.v.); >10 g/kg (R, p.o.)
Cilastatin
Cilastatin.svg
Cilastatin ball-and-stick.png
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a686013
Routes of
administration
IV
ATC code
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.072.592 Edit this at Wikidata
Chemical and physical data
Formula C16H26N2O5S
Molar mass 358.454 g/mol g·mol−1
3D model (JSmol)

/////////////cilastatin, シラスタチン  , FDA 2019, циластатин سيلاستاتين , 西司他丁 , MK-791, Recarbrio

CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O

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FDA approves first treatment Dupixent (Dupilumab) for chronic rhinosinusitis with nasal polyps


The U.S. Food and Drug Administration today approved Dupixent (dupilumab) to treat adults with nasal polyps (growths on the inner lining of the sinuses) accompanied by chronic rhinosinusitis (prolonged inflammation of the sinuses and nasal cavity). This is the first treatment approved for inadequately controlled chronic rhinosinusis with nasal polyps.

“Nasal polyps can lead to loss of smell and often patients require surgery to remove the polyps,” said Sally Seymour, M.D., Director of the Division of Pulmonary, Allergy and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “Dupixent provides an important treatment option for patients whose nasal polyps are not …

June 26, 2019

The U.S. Food and Drug Administration today approved Dupixent (dupilumab) to treat adults with nasal polyps (growths on the inner lining of the sinuses) accompanied by chronic rhinosinusitis (prolonged inflammation of the sinuses and nasal cavity). This is the first treatment approved for inadequately controlled chronic rhinosinusis with nasal polyps.

“Nasal polyps can lead to loss of smell and often patients require surgery to remove the polyps,” said Sally Seymour, M.D., Director of the Division of Pulmonary, Allergy and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “Dupixent provides an important treatment option for patients whose nasal polyps are not adequately controlled with intranasal steroids. It also reduces the need for nasal polyp surgery and oral steroids.”

Dupixent is given by injection. The efficacy and safety of Dupixent were established in two studies with 724 patients, 18 years and older with chronic rhinosinusitis with nasal polyps who were symptomatic despite taking intranasal corticosteroids. Patients who received Dupixent had statistically significant reductions in their nasal polyp size and nasal congestion compared to the placebo group. Patients taking Dupixent also reported an increased ability to smell and required less nasal polyp surgery and oral steroids.

Dupixent may cause serious allergic reactions and eye problems, such as inflammation of the eye (conjunctivitis) and inflammation of the cornea (keratitis). If patients experience new or worsening eye symptoms, such as redness, itching, pain or visual changes, they should consult their health care professional. The most common side effects reported include injection site reactions as well as eye and eyelid inflammation, which included redness, swelling and itching. Patients receiving Dupixent should avoid receiving live vaccines.

Dupixent was originally approved in 2017 for patients 12 and older with eczema that is not controlled adequately by topical therapies or when those therapies are not advisable. In 2018, Dupixent was approved as an add-on maintenance treatment for patients 12 years and older with moderate-to-severe eosinophilic asthma or with oral corticosteroid-dependent asthma.

The FDA granted this application Priority Review. The approval of Dupixent was granted to Regeneron Pharmaceuticals.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-chronic-rhinosinusitis-nasal-polyps?utm_campaign=062619_PR_FDA%20approves%20first%20treatment%20for%20chronic%20rhinosinusitis%20with%20nasal%20polyps&utm_medium=email&utm_source=Eloqua

///////////Dupixent, dupilumab, fda 2019, nasal polyps, chronic rhinosinusitis, Priority Review, Regeneron Pharmaceuticals,

FDA approves new add-on drug Nourianz (istradefylline) to treat off episodes in adults with Parkinson’s disease


Istradefylline.png

READ AT https://newdrugapprovals.org/2016/04/25/istradefylline/

FDA approves new add-on drug  Nourianz (istradefylline)  to treat off episodes in adults with Parkinson’s disease

The U.S. Food and Drug Administration today approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

“Parkinson’s disease is a debilitating condition that profoundly impacts patients’ lives,” said Eric Bastings, M.D., acting director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

According to the National Institutes of Health, PD is the second-most common neurodegenerative disorder in the U.S. after Alzheimer’s disease. An estimated 50,000 Americans are diagnosed with PD each year, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, although it can occur earlier. It happens when cells in the brain, which produce a chemical called dopamine, become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movements – such as eating, writing, and shaving. Early symptoms of the disease are subtle and typically worsen gradually; however, the disease progresses more quickly in some people than in others.

The effectiveness of Nourianz in treating “off” episodes in patients with PD who are already being treated with levodopa/carbidopa was shown in four 12-week placebo-controlled clinical studies that included a total of 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily “off” time compared to patients receiving a placebo.

The most common adverse reactions observed in patients taking Nourianz were involuntary muscle movement (dyskinesia), dizziness, constipation, nausea, hallucination and sleeplessness (insomnia).  Patients should be monitored for development of dyskinesia or exacerbation of existing dyskinesia. If hallucinations, psychotic behavior, or impulsive/compulsive behavior occurs, a dosage reduction or stoppage of Nourianz should be considered. Use of Nourianz during pregnancy is not recommended. Women of childbearing potential should be advised to use contraception during treatment.

The FDA granted approval of Nourianz to Kyowa Kirin, Inc.

////// Nourianz, istradefylline, Kyowa Kirin, FDA 2019, Parkinson’s disease

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FDA approves treatment Inrebic (fedratinib) for patients with rare bone marrow disorder


FDA approves treatment Inrebic (fedratinib) for patients with rare bone marrow disorder

Today, the U.S. Food and Drug Administration approved Inrebic (fedratinib) capsules to treat adult patients with certain types of myelofibrosis.

“Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder. Our approval today provides another option for patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to encouraging the development of treatments for patients with rare diseases and providing alternative options, as not all patients respond in the same way.”

Myelofibrosis is a chronic disorder where scar tissue forms in the bone marrow and the production of the blood cells moves from the bone marrow to the spleen and liver, causing organ enlargement. It can cause extreme fatigue, shortness of breath, pain below the ribs, fever, night sweats, itching and bone pain. When myelofibrosis occurs on its own, it is called primary myelofibrosis. Secondary myelofibrosis occurs when there is excessive red blood cell production (polycythemia vera) or excessive platelet production (essential thrombocythemia) that evolves into myelofibrosis.

Jakafi (ruxolitinib) was approved by the FDA in 2011. The approval of Inrebic for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis was based on the results of a clinical trial where 289 patients with myelofibrosis were randomized to receive two different doses (400 mg or 500 mg daily by mouth) of fedratinib or placebo. The clinical trial showed that 35 of 96 patients treated with the fedratinib 400 mg daily dose (the dose recommended in the approved label) experienced a significant therapeutic effect (measured by greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 (week 24) as measured by an MRI or CT scan with a follow-up scan four weeks later). As a result of treatment with Inrebic, 36 patients experienced greater than or equal to a 50% reduction in myelofibrosis-related symptoms, such as night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under ribs on left side, and bone or muscle pain.

The prescribing information for Inrebic includes a Boxed Warning to advise health care professionals and patients about the risk of serious and fatal encephalopathy (brain damage or malfunction), including Wernicke’s, which is a neurologic emergency related to a deficiency in thiamine. Health care professionals are advised to assess thiamine levels in all patients prior to starting Inrebic, during treatment and as clinically indicated. If encephalopathy is suspected, Inrebic should be immediately discontinued.

Common side effects for patients taking Inrebic are diarrhea, nausea, vomiting, fatigue and muscle spasms. Health care professionals are cautioned that patients may experience severe anemia (low iron levels) and thrombocytopenia (low level of platelets in the blood). Patients should be monitored for gastrointestinal toxicity and for hepatic toxicity (liver damage). The dose should be reduced or stopped if a patient develops severe diarrhea, nausea or vomiting. Treatment with anti-diarrhea medications may be recommended. Patients may develop high levels of amylase and lipase in their blood and should be managed by dose reduction or stopping the mediation. Inrebic must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The FDA granted this application Priority Review designation. Inrebic also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly-owned subsidiary of Celgene Corporation.

LINK

http://s2027422842.t.en25.com/e/es?s=2027422842&e=245172&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=2a5deafa24e642ce8b78e60dd7bc7120&elqaid=9163&elqat=1

///////Inrebic , fedratinib, FDA 2019, Priority Review , Orphan Drug, Biomedicines, Celgene , bone marrow disorder

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor


FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor 

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority ReviewBreakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority ReviewBreakthrough Therapy,  Orphan Drug designation, fda 2019, Genentech, cancer

FDA approves new antibiotic Xenleta (lefamulin) to treat community-acquired bacterial pneumonia


FDA approves new antibiotic  Xenleta (lefamulin) to treat community-acquired bacterial pneumonia

The U.S. Food and Drug Administration today approved Xenleta (lefamulin) to treat adults with community-acquired bacterial pneumonia.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease,” said Ed Cox, M.D., M.P.H., director of FDA’s Office of Antimicrobial Products. “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”

Community-acquired pneumonia occurs when someone develops pneumonia in the community (not in a hospital). Pneumonia is a type of lung infection that can range in severity from mild to severe illness and can affect people of all ages. According to data from the Centers from Disease Control and Prevention, each year in the United States, about one million people are hospitalized with community-acquired pneumonia and 50,000 people die from the disease.

The safety and efficacy of Xenleta, taken either orally or intravenously, was evaluated in two clinical trials with a total of 1,289 patients with CABP. In these trials, treatment with Xenleta was compared to another antibiotic, moxifloxacin with or without linezolid. The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid.

The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting. Xenleta has the potential to cause a change on an ECG reading (prolonged QT interval). Patients with prolonged QT interval, patients with certain irregular heart rhythms (arrhythmias), patients receiving treatment for certain irregular heart rhythms (antiarrhythmic agents), and patients receiving other drugs that prolong the QT interval should avoid Xenleta. In addition, Xenleta should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class, or any of the components of Xenleta. Based on findings of fetal harm in animal studies, pregnant women and women who could become pregnant should be advised of the potential risks of Xenleta to a fetus. Women who could become pregnant should be advised to use effective contraception during treatment with Xenleta and for two days after the final dose.

Xenleta received FDA’s Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, Xenleta was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Xenleta to Nabriva Therapeutics.

A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections. Among the FDA’s other efforts to address antimicrobial resistance, is the focus on facilitating the development of safe and effective new treatments to give patients more options to fight serious infections.

LINK

http://s2027422842.t.en25.com/e/er?utm_campaign=081919_PR_FDA%20approves%20new%20antibiotic%20to%20treat%20community-acquired%20bacterial%20pneumonia&utm_medium=email&utm_source=Eloqua&s=2027422842&lid=9299&elqTrackId=AC98B5F2F3FDA7EADC5780AB18C8861A&elq=a5d6c9e321e34425b20035738f0e4edf&elqaid=9185&elqat=1

//////////Xenleta,  Nabriva Therapeutics, Qualified Infectious Disease Product, QIDP, fda 2019, Generating Antibiotic Incentives Now, GAIN, lefamulin, community-acquired bacterial pneumonia, antibacterial, Priority Review

Selinexor


Skeletal formula of selinexor

Selinexor.png

Selinexor

セリネクソル

KPT-330

UNII-31TZ62FO8F

(Z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-N‘-pyrazin-2-ylprop-2-enehydrazide

Formula
C17H11F6N7O
CAS
1393477-72-9
Mol weight
443.306

FDA, APPROVED 2019/7/3, Xpovio

CAS : 1393477-72-9 (free base)   1421923-86-5 (E-isomer)   1621865-82-4 (E-isomer)   Unknown (HCl)

Treatment of cancer, Antineoplastic, Nuclear export inhibitor

Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis.[1] It is the first drug with this mechanism of action.[2][3]

Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.[3][4]

Selinexor is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), with potential antineoplastic activity. Selinexor modifies the essential CRM1-cargo binding residue cysteine-528, thereby irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1/2, pRB, FOXO, and other growth regulatory proteins. As a result, this agent, via the approach of selective inhibition of nuclear export (SINE), restores endogenous tumor suppressing processes to selectively eliminate tumor cells while sparing normal cells. CRM1, the major export factor for proteins from the nucleus to the cytoplasm, is overexpressed in a variety of cancer cell types.

Selinexor has been used in trials studying the treatment of AML, Glioma, Sarcoma, Leukemia, and Advanced, among others.

 Selinexor, also known as KPT-330, is an orally bioavailable, potent and selective XPO1/CRM1 Inhibitor. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Selinexor potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Selinexor has strong activity against primary AML cells while sparing normal stem and progenitor cells.

SYN

Medical uses

Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myelomawhich has failed to respond to at least four or five other therapies (so-called “quad-refractory” or “penta-refractory” myeloma),[5] for whom no other treatment options are available.[3][4] It is the first drug to be approved for this indication.[6]

Adverse effects

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia(28%), neutropenia (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%).[4][7] The most common non-hematological side effects were gastrointestinal reactions (nausea, anorexia, vomiting, and diarrhea), hyponatremia (low blood sodium levels, occurring in up to 40% of patients), and fatigue.[7][8] More than half of all patients who received the drug developed infections, including fatal cases of sepsis.[7] However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.

Mechanism of action

Schematic illustration of the Ran cycle of nuclear transport. Selinexor inhibits this process at the nuclear export receptor (upper right).

Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressorsoncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer.[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.[1][2][7] In vitro, this effect appeared to spare normal (non-malignant) cells.[1][8]

Because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which explains the high incidence of adverse reactions to selinexor.[2] Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets.[2]

Chemistry

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is not irreversible.[1]

History

Selinexor was developed by Karyopharm Therapeutics of Newton, Massachusetts, a pharmaceutical company devoted entirely to the development of drugs that target nuclear transport. It was approved by the FDA on July 3, 2019, on the basis of a single uncontrolled clinical trial. The decision was controversial, and overruled the previous recommendation of an FDA Advisory Panel which had voted 8–5 against approving the drug, due to concerns about efficacy and toxicity.[3]

Research

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancerbreast cancernon-small-cell lung cancerlymphomas, and acute and chronic leukemias.[9] In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphomablast crisis, and a wide range of advanced or refractory solid tumors, including colon cancerhead and neck cancermelanomaovarian cancer, and prostate cancer.[9] Compassionate use in patients with acute myeloid leukemia has also been reported.[9]

The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.[7] In all of the enrolled patients, selinexor was used as fifth-line or sixth-line therapy after conventional chemotherapytargeted therapy with bortezomibcarfilzomiblenalidomidepomalidomide, and a monoclonal antibody (daratumumab or isatuximab)[5]; nearly all had also undergone hematopoietic stem cell transplantation to no effect.[7] The overall response rate was 25%, and no patients had a complete response.[7] However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis).[5] The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.[2]

As of 2019, phase I/II and III trials are ongoing,[3][9] including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.[2]

PATENT

WO 2013019561

WO 2013019548

US 9079865

PATENT

WO 2016025904 A

https://patents.google.com/patent/WO2016025904A1/tr

International Publication No. WO 2013/019548 describes a series of compounds that are indicated to have inhibitory activity against chromosomal region maintenance 1 (CRM1, also referred to as exportin 1 or XPO1) and to be useful in the treatment of disorders associated with CRM1 activity, such as cancer. (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide (also referred to as selinexor) is one of the compounds disclosed in International Publication No. WO 2013/019548. Selinexor has the chemical structure shown in Structural Formula I:

Example 1. Preparation of Selinexor Lot No.1305365 (Form A).

[00274] Selinexor for Lot No. 1305365 was made in accordance with the following reaction scheme:

[00275] A solution of propane phosphonic acid anhydride (T3P®, 50% in ethyl acetate, 35Kg) in THF (24.6Kg) was cooled to about -40 °C. To this solution was added a solution of KG1 (13.8Kg) and diisopropylethylamine (12.4Kg) in tetrahydrofuran (THF, 24.6Kg). The resulting mixture was stirred at about -40°C for approximately 2.5 hours.

[00276] In a separate vessel, KJ8 (4.80Kg) was mixed with THF (122.7Kg), and the resulting mixture cooled to about -20°C. The cold activated ester solution was then added to the KJ8 mixture with stirring, and the reaction was maintained at about -20°C. The mixture was warmed to about 5°C, water (138.1Kg) was added and the temperature adjusted to about 20°C. After agitating for about an hour, the lower phase was allowed to separate from the mixture and discarded. The upper layer was diluted with ethyl acetate (EtOAc). The organic phase was then washed three times with potassium phosphate dibasic solution (~150Kg), then with water (138.6Kg).

[00277] The resulting organic solution was concentrated under reduced pressure to 95L, EtOAc (186.6Kg) was added and the distillation repeated to a volume of 90L. Additional EtOAc (186.8Kg) was added and the distillation repeated a third time to a volume of 90L. The batch was filtered to clarify, further distilled to 70L, then heated to about 75°C, and slowly cooled to 0 to 5°C. The resulting slurry was filtered and the filter cake washed with a mixture of EtOAc (6.3Kg) and toluene (17.9Kg) before being dried in a vacuum oven to provide selinexor designated Lot No. 1305365 (Form A).

Example 2. Preparation of Selinexor Lot No.1341-AK-109-2 (Form A).

[00278] The acetonitrile solvate of selinexor was prepared in accordance with Example 6.

[00279] The acetonitrile solvate of selinexor (2.7g) was suspended in a mixture of isopropanol (IPA, 8mL) and water (8mL), and the resulting mixture heated to 65 to 70 °C to effect dissolution. The solution was cooled to 45 °C, and water (28mL) was added over 15 minutes, maintaining the temperature between 40 and 45 °C. The slurry was cooled to 20 to 25 °C over an hour, then further cooled to 0 to 5 °C and held at that temperature for 30 minutes before being filtered. The filter cake was washed with 20% v/v IPA in water and the product dried under suction overnight, then in vacuo (40°C).

Example 3. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-005 (Form A).

[00280] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00281] The acetonitrile solvate of selinexor (1.07Kg) was suspended in a mixture of IPA (2.52Kg) and water (3.2Kg) and the mixture heated to 70 to 75 °C to dissolve. The temperature was then adjusted to 40 to 45 °C and held at that temperature for 30 minutes. Water (10.7Kg) was added while maintaining the temperature at 40 to 45 °C, then the batch was cooled to 20 to 25 °C and agitated at that temperature for 4 hours before being further cooled to 0 to 5 °C. After a further hour of agitation, the slurry was filtered and the filter cake washed with a cold mixture of IPA (0.84Kg) and water (4.28Kg) before being dried.

Example 4. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-009 (Form A).

[00282] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00283] The acetonitrile solvate of selinexor (1.5Kg) was suspended in IPA (3.6Kg) and water (4.5Kg) and warmed to 37 to 42 °C with gentle agitation. The suspension was agitated at that temperature for 4 hours, and was then cooled to 15 to 20 °C over 1 hour. Water (15.1Kg) was added, maintaining the temperature, then the agitation was continued for 1 hour and the batch was filtered. The filter cake was washed with a mixture of IPA (1.2Kg) and water (6Kg), then dried under a flow of nitrogen.

Example 5. Preparation of Selinexor Lot Nos.1339-BS-142-1, 1339-BS-142-2 and PC-14-008 (Form A).

[00284] A reactor, under nitrogen, was charged with KG1 (1Kg, 1.0 Eq), KJ8 (0.439 Kg, 1.4 Eq) and MeTHF (7L, 7 parts with respect to KG1). Diisopropylethylamine (0.902Kg, 2.45 Eq with respect to KG1) was added to the reaction mixture at -20 °C to -25 °C with a MeTHF rinse. To the reaction mixture, 50% T3P® in ethyl acetate (2.174Kg, 1.2 Eq with respect to KG1) was then charged, maintaining the temperature at -20 °C to -25 °C with a MeTHF rinse. After the completion of the addition, the reaction mixture was stirred briefly

and then warmed to 20 °C to 25 °C. Upon completion, the reaction mixture was washed first with water (5L, 5 parts with respect to KG1) and then with dilute brine (5L, 5 parts with respect to KG1). The organic layer was concentrated by vacuum distillation to a volume of 5 L (5 parts with respect to KG1), diluted with acetonitrile (15L, 15 parts with respect to KG1) at approximately 40 °C and concentrated again (5L, 5 parts with respect to KG1). After solvent exchange to acetonitrile, the reaction mixture was then heated to approximately 60 °C to obtain a clear solution. The reaction mixture was then cooled slowly to 0-5 °C, held briefly and filtered. The filter cake was washed with cold acetonitrile (2L, 5 parts with respect to KG1) and the filter cake was then dried under a stream of nitrogen to provide the acetonitrile solvate of selinexor (Form D) as a slightly off-white solid.

[00285] Form D of selinexor (0.9Kg) was suspended in IPA (2.1Kg, 2.7L, 3 parts with respect to Form D) and water (2.7Kg, 2.7L, 3 parts with respect to Form D) and warmed to approximately 40 °C. The resulting suspension was agitated for about 4 hours, selinexor, cooled to approximately 20 °C, and diluted with additional water (9Kg, 10 parts with respect to Form D). The mixture was stirred for a further 4-6 hours, then filtered, and the cake washed with a mixture of 20% IPA and water (4.5L, 5 parts with respect to Form D). The filter cake was then dried under vacuum to provide selinexor designated Lot No. PC-14-008 as a white crystalline powder with a >99.5% a/a UPLC purity (a/a=area to area of all peaks; UPLC-ultra performance HPLC).

Example 6. Preparation of Selinexor Lot No.1405463 (Form A).

[00286] Selinexor Lot No. 1405463 was prepared in accordance with the following reaction scheme:

 .

[00287] A reactor was charged with KG1 (15.8Kg), KJ8 (6.9Kg) and MeTHF (90Kg). Diisopropylethylamine (14.2Kg) was added to the reaction mixture over approximately 35 minutes at about -20 °C. Following the addition of the diisopropylethylamine, T3P® (50%

solution in EtAOc, 34.4Kg) was added maintaining the temperature at -20 °C. The mixture stirred to complete the reaction first at -20 °C, then at ambient temperature.

[00288] Upon completion of the reaction, water (79Kg) was added over about 1 hour. The layers were separated and the organic layer was washed with a mixture of water (55Kg) and brine (18Kg), The mixture was filtered, and the methyl-THF/ethyl acetate in the mixture distillatively replaced with acetonitrile (volume of approximately 220L). The mixture was warmed to dissolve the solids, then slowly cooled to 0 to 5 °C before being filtered. The filter cake was washed with acetonitrile to provide the acetonitrile solvate of

selinexorSelinexorSelinexor (Form D).

[00289] The acetonitrile solvate of selinexorSelinexorSelinexor was dried, then mixed with isopropanol (23Kg) and water (55Kg). The slurry was warmed to about 38 °C and held at that temperature for approximately 4 hours before being cooled to 15 to 20 °C. Water (182Kg) was added. After a further 5 hours of agitation, the mixture was filtered and the filter cake washed with a mixture of isopropanol (14Kg) and water (73Kg), before being dried under vacuum (45 °C). The dried product was packaged to provide

selinexorSelinexorSelinexor Lot No. 1405463 (Form A).

Example 7. Polymorphism Studies of Selinexor.

[00290] A comprehensive polymorphism assessment of selinexor was performed in a range of different solvents, solvent mixtures and under a number of experimental conditions based on the solubility of selinexor. Three anhydrous polymorphs of

selinexorSelinexorSelinexor were observed by XRPD investigation, designated Form A, Form B and Form C. Form A is a highly crystalline, high-melting form, having a melting point of 177 °C, and was observed to be stable from a physico-chemical point of view when exposed for 4 weeks to 25 °C/97% relative humidity (RH) and to 40 °C/75% RH. A solvated form of selinexor was also observed in acetonitrile, designated Form D. A competitive slurry experiment confirmed Form A as the stable anhydrous form under the conditions investigated, except in acetonitrile, in which solvate formation was observed. It was further found that in acetonitrile, below 50 °C, only Form D is observed, at 50 °C both Form A and Form D are observed, and at 55 °C, Form A is observed .

PATENT

CN 106831731

https://patents.google.com/patent/CN106831731A/en

Selinexor is an orally bioavailable selective nuclear export inhibitors, 2012 for the first time in clinical, so far carried out a total of 21 trials, indications include chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma into, gynecological cancer, diffuse large B-cell lymphoma, squamous cell carcinoma, colorectal cancer and the like. May 2014, FDA granted orphan drug designation Selinexor treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, in June 2014, EMA is also granted orphan drug designation Selinexor treatment of both diseases. January 2015, received FDA orphan drug to treat multiple myeloma identified.

[0003] Currently, the synthesis process has been disclosed, the following reaction equation:

Figure CN106831731AD00041

[0006] wherein the compound is 5 Selinexor drug.

[0007] In this method, however, easy to produce Intermediate 1-2 double bond is easily reversed when synthetically produced from trans impurities, in addition to more difficult to impact yield; Intermediate 3 Intermediate 4 Synthesis APIs 5 when required ultra-low temperature, and the product was purified by column required, only a yield of 20%.

SUMMARY

[0008] The object of the present invention to provide a novel compound Selinexor drug synthesis of 5, in order to solve technical problems.

[0009] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0010] A, Compound 7

[0011] Compound 6, dichloromethane and ethyl acetate mixture, stirred and dissolved, compound 4, T3P (n-propyl phosphoric anhydride) and DIPEA (N, N- diisopropylethylamine) at a low temperature; the reaction was stirred for 25-35min at a low temperature, dichloromethane and water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0012] B, Synthesis of Compound 8

[0013] the compound obtained in Step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; After completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF (dimethyl fumarate) to give compound in DMF 8;

Synthesis [0014] C, of Compound 5

[0015] Compound 1, DBAC0 (triethylenediamine), the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; the reaction after completion, water and ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.

[0016] Preferably, said step A, the low temperature is 0-2 ° C.

[0017] Preferably, said step B in DMF, the crude compound 8 concentration of less than 1%.

[0018] The novel synthetic methods of the present invention Selinexor drug, the chemical equation is as follows:

Figure CN106831731AD00051

[0020] The present invention has the following advantages: novel synthetic method Selinexor drug of the present invention to overcome the conventional synthesis process, is easy to produce trans impurities, more difficult in addition, the influence the yield and the need for ultra-low temperature, and the product requires problems purified by column, the yield is very low, reducing the synthetic steps, increased yield, there is provided a new process for the synthesis of the drug Selinexor.

[0021] In addition to the above-described objects, features and advantages of the present invention as well as other objects, features and advantages. Below the invention will be described in further detail present.

Example 1

[0024] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0025] A, Compound 7

[0026] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 0 ° C; the system at 0 ° C the reaction was stirred for 30min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0027] B, Synthesis of Compound 8

[0028] 50ml three-necked flask, added the compound obtained in Step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115. (:, The reaction 3H; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated washed with sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0029] C, of Compound 5

[0030] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after completion of the reaction, 20ml water was added to the system and 50ml ethyl acetate, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.158g of compound 5, yield 50.9%.

[0031] Example 2

[0032] – new type Se Iinexor drug synthesis, comprising the steps of:

Synthesis [0033] A, Compound 7

[0034] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 1 ° C; system at 1 ° C the reaction was stirred for 35min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0035] B, Synthesis of Compound 8

Three-neck flask [0036] 50ml of addition of the compound obtained in Step 7,40ml glacial acetic acid and 1.38g of sodium iodide was heated to 120. (:, The reaction for 2.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 60ml water and 120ml dichloromethane was added, after stirring for 15min, allowed to stand for separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, 12mLDMF was dissolved in DMF to give a solution of compound 8;

Synthesis [0037] C, of Compound 5

[0038] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring continued for 3 hours; after completion of the reaction, 25ml of water and 50ml of ethyl acetate was added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.152g of compound 5, yield 49.0% billion

[0039] Example 3

[0040] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0041] A, Compound 7

Three [0042] 50ml of flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 2 ° C; system from 0 ° C the reaction was stirred for 25min, 40ml of dichloromethane and 35ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0043] B, Synthesis of Compound 8

Three-neck flask [0044] 50ml of addition of the compound obtained in Step 7,35ml glacial acetic acid and 1.38g of sodium iodide was heated to 110. (:, The reaction for 3.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and dichloromethane IOOml After Smin of stirring, standing separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0045] C, of Compound 5

[0046] 50ml three-neck flask was added 0.2g compound 1,0.24gDBA⑶, 20mlDMF, and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 4 hours; after completion of the reaction, 20ml of water and 40ml ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.155g of compound 5, yield 49.9% billion

PATENT

WO 2017118940

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017118940&tab=PCTDESCRIPTION

The drug compound having the adopted name “Selinexor” has chemical name:(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-1 -yl)-N’-(pyrazin-2yl) acrylohydrazide as below.

Figure imgf000003_0001

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XP01 (also called CRM1 ), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1 ,200 patients have been treated with Selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of Selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of Selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of Selinexor in combination with low dose dexamethasone. Randomized 1 :1 , Selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.

US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-

bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-l-yl)acrylic acid in 1 :1 CH2CI2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2CI2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%. However, it is not disclosed about the nature of the compound obtained therein.

WO 2016025904 A1 discloses various crystalline forms of Selinexor namely Form A, Form B, Form C, Form D, compositions and MoU thereof for the treatment of disorder associated with CRM1 activity and their preparative processes.

Prior art process for the preparation of Selinexor suffers from disadvantages interms of process such as the use of lengthy procedures to practice and resulting in low yields, which may not be viable at industrial scale. Synthetic product obtained therein has very low purity and contains significant amounts of unreacted starting materials and trans-isomer of Selinexor, which are further purified by time consuming and expensive chromatographic separations leading to loss of yield. Hence, there remains a need for improved process for the preparation of Selinexor which is industrially viable and reproducible. Particularly, it is desirable to have a process avoiding purification steps still meeting desired pharmaceutical quality.

EXAMPLES

Example-1 : Preparation of isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1 H- -triazol-1 -yl)acrylate

Figure imgf000061_0001

3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazole (250 g) was dissolved in tetrahydrofuran (2 I) under nitrogen atmosphere at 27°C and cooled to -5°C. 1 ,4- diazabicyclo[2.2.2]octane (DABCO, 1 99.5 g) was added to the reaction mixture at -5°C and stirred at the same temperature for 40 minutes. Isopropyl (Z)-3- iodoacrylate (234.8 g in 500 mL of tetrahydrofuran) was added drop wise to the reaction mixture in 1 hour 1 0 minutes at -5°C and stirred at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to ice cold water (2 I) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 1 I). The combined organic layer was washed with brine solution (1 I) and dried over sodium sulphate. The dried solution was evaporated completely under vacuum at 40°C to obtain crude product with HPLC purity of 93.53% The crude product was triturated with hexane (700 mL) and stirred for 20 minutes at -30°C and filtered the solid. Trituration of crude product with hexane was repeated for three times and dried under vacuum to obtain the title compound with HPLC purity of 97.46% and trans-isomer content of 0.66%. Yield: 297 g Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- triazol-1 -yl)acr lic acid.

Figure imgf000062_0001

To a mixture of tetrahydrofuran (300 mL) and water (300 mL), Isopropyl (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylate (30 g) was added and cooled to 0°C. Lithium hydroxide monohydrate (16.03 g) under cooling condition at 0°C was added to the reaction mixture and stirred the reaction mixture at same temperature for 7 hours. After completion of the reaction, 2 N HCI (180 mL) was added to adjust the pH of the reaction mixture to 2 and extracted it with ethyl acetate (300 mL). Organic layer was dried over sodium sulphate and evaporated under vacuum at 40°C. The crude compound was stirred with hexane (150 mL) and filtered the solid. Dried the compound under vacuum at 40°C for 0.5 hour to obtain the title compound with HPLC purity of 97.25% with trans-isomer content of 3 %. Yield: 24 g

Example-3: Purification of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- tria

Figure imgf000062_0002

A mixture of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (24 g) and acetone (240 mL) was stirred for complete dissolution at 30°C. Dicyclohexyl amine (1 5 mL) was added drop wise for 20 minutes under stirring at the same temperature. Acetone (50 mL) was added to the reaction mixture and stirred for 2 hours at 27°C. Filtered the solid and washed with hot acetone (150 mL) and dried in vacuum drier at 30°C for 1 hour to obtain the Dicyclohexyl amine salt of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid. To the above salt, dichloromethane (150 mL) and water (1 00 mL) was added and stirred for complete dissolution at 30and adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to 2. Filtered the reaction mixture and washed the product with water (1 00 mL) and then with hexane (150 mL). The solid was dried under vacuum at 40°C for 0.5 hour to obtain title compound with HPLC purity 99.98% with no detectable content of trans-isomer. Yield: 17 g

Example-4: Preparation of Selinexor

Figure imgf000063_0001

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86%. Yield : 7 g

PATENT
WO 2018129227

References

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  6. ^ Barrett, Jennifer (2019-07-03). “New Treatment for Refractory Multiple Myeloma Granted FDA Approval”Pharmacy Times. Retrieved 2019-07-07.
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  8. Jump up to:a b Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N (2018). “Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia”. Blood131 (8): 855–863. doi:10.1182/blood-2017-08-797886PMID 29203585.
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Selinexor
Skeletal formula of selinexor
Clinical data
Trade names Xpovio
Pregnancy
category
  • Known to cause fetal harm
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding 95%
Metabolism Hepatic oxidation, glucuronidation, and conjugation, by CYP3A4UGTand GST
Elimination half-life 6–8 h
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C17H11F6N7O
Molar mass 443.313 g·mol−1
3D model (JSmol)

Karyopharm’s Selinexor Receives Fast Track Designation from FDA for the Treatment of Patients with Penta-Refractory Multiple Myeloma

NEWTON, Mass., April 10, 2018 (GLOBE NEWSWIRE) — Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company’s lead, oral Selective Inhibitor of Nuclear Export (SINE) compound selinexor for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.  The FDA’s statement, consistent with the design of Karyopharm’s Phase 2b STORM study, noted that the three prior lines of therapy include regimens comprised of an alkylating agent, a glucocorticoid, Velcade® (bortezomib), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), Pomalyst® (pomalidomide) and Darzalex® (daratumumab).  In addition, the patient’s disease must be refractory to at least one proteasome inhibitor (Velcade or Kyprolis), one immunomodulatory agent (Revlimid or Pomalyst), glucocorticoids and to Darzalex, as well as to the most recent therapy.  The Company expects to report top-line data from the STORM study at the end of April 2018.

ChemSpider 2D Image | selinexor | C17H11F6N7O

The FDA’s Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs.  A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug’s development, review and potential approval.  In addition, the Fast Track program allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

“The designation of Fast Track for selinexor represents important recognition by the FDA of the potential of this anti-cancer agent to address the significant unmet need in the treatment of patients with penta-refractory myeloma that has continued to progress despite available therapies,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.  “We are fully committed to working closely with the FDA as we continue development of this potential new, orally-administered treatment for patients who currently have no other treatment options of proven benefit.”

About the Phase 2b STORM Study

In the multi-center, single-arm Phase 2b STORM (Selinexor Treatment oRefractory Myeloma) study, approximately 122 patients with heavily pretreated, penta-refractory myeloma receive 80mg oral selinexor twice weekly in combination with 20mg low-dose dexamethasone, also dosed orally twice weekly.  Patients with penta-refractory disease are those who have previously received an alkylating agent, a glucocorticoid, two immunomodulatory drugs (IMiDs) (Revlimid® (lenalidomide) and Pomalyst® (pomalidomide)), two proteasome inhibitors (PIs) (Velcade® (bortezomib) and Kyprolis® (carfilzomib)), and the anti-CD38 monoclonal antibody Darzalex® (daratumumab), and their disease is refractory to at least one PI, at least one IMiD, Darzalex, glucocorticoids and their most recent anti-myeloma therapy.  Overall response rate is the primary endpoint of the study, with duration of response and clinical benefit rate being secondary endpoints.  All responses will be adjudicated by an Independent Review Committee (IRC).

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,300 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and as a potential backbone therapy in combination with approved therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a clinical-stage pharmaceutical company focused on the discovery, development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Karyopharm’s SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm, which was founded by Dr. Sharon Shacham, currently has several investigational programs in clinical or preclinical development.

/////////Selinexor, FDA 2019, セリネクソル  ,KPT-330, KPT 330 , KPT330,  AML, Glioma, Sarcoma, Leukemia, Fast Track, CANCER

FDA approves first treatment Soliris (eculizumab) for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system


The U.S. Food and Drug Administration today approved Soliris (eculizumab) injection for intravenous use for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. NMOSD is an autoimmune disease of the central nervous system that mainly affects the optic nerves and spinal cord.

“Soliris provides the first FDA-approved treatment for neuromyelitis optica spectrum disorder, a debilitating disease that profoundly impacts patients’ lives,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval changes the landscape of therapy for patients with NMOSD. Having an approved therapy for this condition is the culmination of extensive work we have engaged in with drug companies to …

June 27, 2019

The U.S. Food and Drug Administration today approved Soliris (eculizumab) injection for intravenous use for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. NMOSD is an autoimmune disease of the central nervous system that mainly affects the optic nerves and spinal cord.

“Soliris provides the first FDA-approved treatment for neuromyelitis optica spectrum disorder, a debilitating disease that profoundly impacts patients’ lives,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval changes the landscape of therapy for patients with NMOSD. Having an approved therapy for this condition is the culmination of extensive work we have engaged in with drug companies to expedite the development and approval of safe and effective treatments for patients with NMOSD, and we remain committed to these efforts for other rare diseases.”

In patients with NMOSD, the body’s immune system mistakenly attacks healthy cells and proteins in the body, most often in the optic nerves and spinal cord. Individuals with NMOSD typically have attacks of optic neuritis, which causes eye pain and vision loss. Individuals also can have attacks resulting in transverse myelitis, which often causes numbness, weakness, or paralysis of the arms and legs, along with loss of bladder and bowel control. Most attacks occur in clusters, days to months to years apart, followed by partial recovery during periods of remission. Approximately 50% of patients with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks. According to the National Institutes of Health, women are more often affected by NMOSD than men and African Americans are at greater risk of the disease than Caucasians. Estimates vary, but NMOSD is thought to impact approximately 4,000 to 8,000 patients in the United States.

NMOSD can be associated with antibodies that bind to a protein called aquaporin-4 (AQP4). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system.

The effectiveness of Soliris for the treatment of NMOSD was demonstrated in a clinical study of 143 patients with NMOSD who had antibodies against AQP4 (anti-AQP4 positive) who were randomized to receive either Soliris treatment or placebo. Compared to treatment with placebo, the study showed that treatment with Soliris reduced the number of NMOSD relapses by 94 percent over the 48-week course of the trial. Soliris also reduced the need for hospitalizations and the need for treatment of acute attacks with corticosteroids and plasma exchange.

Soliris has a boxed warning to alert health care professionals and patients that life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris, and that such infections may become rapidly life-threatening or fatal if not recognized and treated early. Patients should be monitored for early signs of meningococcal infections and evaluated immediately if infection is suspected. Use should be discontinued in patients who are being treated for serious meningococcal infections. Health care professionals should use caution when administering Soliris to patients with any other infection. In the NMOSD clinical trial, no cases of meningococcal infection were observed.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Prescribers must enroll in the REMS program. Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials and ensure patients are vaccinated with meningococcal vaccine(s). The drug must be dispensed with the FDA-approved patient Medication Guide that provides important information about the drug’s uses and risks.

The most frequently reported adverse reactions reported by patients in the NMOSD clinical trial were: upper respiratory infection, common cold (nasopharyngitis), diarrhea, back pain, dizziness, influenza, joint pain (arthralgia), sore throat (pharyngitis) and contusion.

The FDA granted the approval of Soliris to Alexion Pharmaceuticals.

Soliris was first approved by the FDA in 2007. The drug is approved to reduce destruction of red blood cells in adults with a rare blood disease called paroxysmal nocturnal hemoglobinuria, for the treatment of adults and children with a rare disease that causes abnormal blood clots to form in small blood vessels in the kidneys (atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy), and for the treatment of adults with Myasthenia Gravis who are anti-acetylcholine receptor antibody positive.

The FDA granted this application Priority Review. The use for NMOSD received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-neuromyelitis-optica-spectrum-disorder-rare-autoimmune-disease-central?utm_campaign=062719_PR_FDA%20approves%20first%20treatment%20for%20NMOSD&utm_medium=email&utm_source=Eloqua

///////////////fda 2019, Soliris, eculizumab, neuromyelitis optica spectrum disorder, Orphan DrugPriority Review

FDA approves new treatment Vyleesi (Bremelanotide) for hypoactive sexual desire disorder in premenopausal women


Bremelanotide chemical structure.png

Bremelanotide

SYNTHESIS……. https://newdrugapprovals.org/2015/02/18/palatins-bremelanotide-under-clinical-trials-female-libido-enhancer/

The U.S. Food and Drug Administration today approved Vyleesi (bremelanotide) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment. Today’s approval provides women with another treatment option for this condition,” said Hylton V. Joffe, M.D., M.M.Sc., director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive and Urologic Products. “As part of the FDA’s commitment to protect and advance the health of women, we’ll continue to support the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship or the effects of a medication or other drug substance. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire. Generalized HSDD refers to …

June 21, 2019

The U.S. Food and Drug Administration today approved Vyleesi (bremelanotide) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment. Today’s approval provides women with another treatment option for this condition,” said Hylton V. Joffe, M.D., M.M.Sc., director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive and Urologic Products. “As part of the FDA’s commitment to protect and advance the health of women, we’ll continue to support the development of safe and effective treatments for female sexual dysfunction.”

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

Vyleesi activates melanocortin receptors, but the mechanism by which it improves sexual desire and related distress is unknown. Patients inject Vyleesi under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity and may decide the optimal time to use Vyleesi based on how they experience the duration of benefit and any side effects, such as nausea. Patients should not use more than one dose within 24 hours or more than eight doses per month. Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness and safety of Vyleesi were studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. Most patients used Vyleesi two or three times per month and no more than once a week. In these trials, about 25% of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire) compared to about 17% of those who took placebo. Additionally, about 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of zero to four, with higher scores indicating greater distress from low sexual desire) compared to about 31% of those who took placebo. There was no difference between treatment groups in the change from the start of the study to end of the study in the number of satisfying sexual events. Vyleesi does not enhance sexual performance.

The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect.

In the clinical trials, Vyleesi increased blood pressure after dosing, which usually resolved within 12 hours. Because of this effect, Vyleesi should not be used in patients with high blood pressure that is uncontrolled or in those with known cardiovascular disease. Vyleesi is also not recommended in patients at high risk for cardiovascular disease.

When naltrexone is taken by mouth, Vyleesi may significantly decrease the levels of naltrexone in the blood. Patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it could lead to naltrexone treatment failure.

In 2012, the FDA identified female sexual dysfunction as one of 20 disease areas of high priority and focused attention. The FDA held a two-day meeting in October 2014 to advance the agency’s understanding of female sexual dysfunction. During the first day of the meeting, the FDA solicited perspectives directly from patients about their condition and its impact on daily life. In 2016, the FDA published a draft guidance titled “Low Sexual Interest Desire and/or Arousal in Women: Developing Drugs for Treatment,” to assist companies developing drugs for the treatment of these conditions. The FDA is committed to continuing to work with companies to develop safe and effective treatments for female sexual dysfunction.

The FDA granted approval of Vyleesi to AMAG Pharmaceuticals.

REF

https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women?utm_campaign=062119_PR_FDA%20approves%20new%20treatment%20for%20HSDD%20in%20premenopausal%20women&utm_medium=email&utm_source=Eloqua

//////////////Vyleesi, bremelanotide, FDA 2019, HSDD, female sexual dysfunction, AMAG Pharmaceuticals, , LIBIDO ENHANCER,

FDA approves new treatment Victoza (liraglutide) for pediatric patients with type 2 diabetes


The U.S. Food and Drug Administration today approved Victoza (liraglutide) injection for treatment of pediatric patients 10 years or older with type 2 diabetes. Victoza is the first non-insulin drug approved to treat type 2 diabetes in pediatric patients since metformin was approved for pediatric use in 2000. Victoza has been approved to treat adult patients with type 2 diabetes since 2010.

“The FDA encourages drugs to be made available to the widest number of patients possible when there is evidence of safety and efficacy,” said Lisa Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Victoza has now been shown to improve blood sugar control in pediatric patients with type 2 diabetes. The expanded indication provides an additional treatment option at a time when

June 17, 2019

The U.S. Food and Drug Administration today approved Victoza (liraglutide) injection for treatment of pediatric patients 10 years or older with type 2 diabetes. Victoza is the first non-insulin drug approved to treat type 2 diabetes in pediatric patients since metformin was approved for pediatric use in 2000. Victoza has been approved to treat adult patients with type 2 diabetes since 2010.

“The FDA encourages drugs to be made available to the widest number of patients possible when there is evidence of safety and efficacy,” said Lisa Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Victoza has now been shown to improve blood sugar control in pediatric patients with type 2 diabetes. The expanded indication provides an additional treatment option at a time when an increasing number of children are being diagnosed with this disease.”

Type 2 diabetes is the most common form of diabetes, occurring when the pancreas cannot make enough insulin to keep blood sugar at normal levels. Although type 2 diabetes primarily occurs in patients over the age of 45, the prevalence rate among younger patients has been rising dramatically over the past couple of decades. The Diabetes Report Card published by the U.S. Centers for Disease Control and Prevention estimates that more than 5,000 new cases of type 2 diabetes are diagnosed each year among U.S. youth younger than age 20.

Victoza improves blood sugar levels by creating the same effects in the body as the glucagon-like peptide (GLP-1) receptor protein in the pancreas. GLP-1 is often found in insufficient levels in type 2 diabetes patients. Like GLP-1, Victoza slows digestion, prevents the liver from making too much glucose (a simple sugar), and helps the pancreas produce more insulin when needed. As noted on the label, Victoza is not a substitute for insulin and is not indicated for patients with type 1 diabetes or those with diabetic ketoacidosis, a condition associated with diabetes where the body breaks down fat too quickly because there is inadequate insulin or none at all. Victoza is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease; however, its effect on major adverse cardiovascular events in pediatrics was not studied and it is not indicated for this use in children.

The efficacy and safety of Victoza for reducing blood sugar in patients with type 2 diabetes was studied in several placebo-controlled trials in adults and one placebo-controlled trial with 134 pediatric patients 10 years and older for more than 26 weeks. Approximately 64% of patients in the pediatric study had a reduction in their hemoglobin A1c (HbA1c) below 7% while on Victoza, compared to only 37% who achieved these results with the placebo. HbA1c is a blood test that is routinely performed to evaluate how well a patient’s diabetes is controlled, and a lower number indicates better control of the disease. These results occurred regardless of whether the patient also took insulin at the same time. Adult patients who took Victoza with insulin or other drugs that increase the amount of insulin the body makes (e.g., sulfonylurea) may have an increased risk of hypoglycemia (low blood sugar). Meanwhile, pediatric patients 10 years and older taking Victoza had a higher risk of hypoglycemia regardless of whether they took other therapies for diabetes.

The prescribing information for Victoza includes a Boxed Warning to advise health care professionals and patients about the increased risk of thyroid C-cell tumors. For this reason, patients who have had, or have family members who have ever had medullary thyroid carcinoma (MTC) should not use Victoza, nor should patients who have an endocrine system condition called multiple endocrine neoplasia syndrome type 2 (MEN 2). In addition, people who have a prior serious hypersensitivity reaction to Victoza or any of the product components should not use Victoza. Victoza also carries warnings about pancreatitis, Victoza pen sharing, hypoglycemia when used in conjunction with certain other drugs known to cause hypoglycemia including insulin and sulfonylurea, renal impairment or kidney failure, hypersensitivity and acute gallbladder disease. The most common side effects are nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation.

The FDA granted this application Priority Review. The approval of Victoza was granted to Novo Nordisk.

https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pediatric-patients-type-2-diabetes?utm_campaign=061719_PR_FDA%20approves%20new%20treatment%20for%20pediatric%20patients%20with%20type%202%20diabetes&utm_medium=email&utm_source=Eloqua

//////Victoza, liraglutide, FDA 2019, Priority Review, Novo Nordisk, DIABETES

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