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CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt
Additional Names: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium hydroxide inner salt 72-(Z)-2-(O-methyloxime); 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate
Manufacturers’ Codes: BMY-28142
Molecular Formula: C19H24N6O5S2
Molecular Weight: 480.56
Percent Composition: C 47.49%, H 5.03%, N 17.49%, O 16.65%, S 13.34%
Literature References: Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al.,DE3307550; eidem,US4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al.,J. Antibiot.39, 1092 (1986). In vitro comparative antimicrobial spectrum: N. J. Khan et al.,Antimicrob. Agents Chemother.26, 585 (1984); and b-lactamase stability: H. C. Neu et al.,J. Antimicrob. Chemother.17, 441 (1986). HPLC determn in plasma and urine: R. H. Barbhaiya et al.,Antimicrob. Agents Chemother.31, 55 (1987). Clinical evaluations in infection: N. Clynes et al.,Diagn. Microbiol. Infect. Dis.12, 257 (1989); S. Oster et al.,Antimicrob. Agents Chemother.34, 954 (1990). Review of clinical pharmacokinetics: M. P. Okamoto et al.,Clin. Pharmacokinet.25, 88-102 (1993).
Properties: Colorless powder, mp 150° (dec). uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100).
Melting point: mp 150° (dec)
Absorption maximum: uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100)
Derivative Type: Sulfate
Molecular Formula: C19H24N6O5S2.H2SO4
Molecular Weight: 578.64
Percent Composition: C 39.44%, H 4.53%, N 14.52%, O 24.89%, S 16.62%
Properties: mp 210° (dec). uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900).
Melting point: mp 210° (dec)
Absorption maximum: uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900)
Derivative Type: Hydrochloride monohydrate
CAS Registry Number: 123171-59-5
CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride monohydrochloride monohydrate
FDA APPROVED 2/22/2024, To treat complicated urinary tract infections, Exblifep
BMY 28142
BMY-28142
Cefepime is a fourth-generation cephalosporinantibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negativebacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics.[1] In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.[2]
Cefepime is a broad-spectrum cephalosporin antibiotic and has been used to treat bacteria responsible for causing pneumonia and infections of the skin and urinary tract. Some of these bacteria include Pseudomonas, Escherichia, and Streptococcus species. The following represents MIC susceptibility data for a few medically significant microorganisms:[7]
Escherichia coli: ≤0.007 – 128 μg/ml
Pseudomonas aeruginosa: 0.06 – >256 μg/ml
Streptococcus pneumoniae: ≤0.007 – >8 μg/ml
Chemistry
The combination of the syn-configuration of the methoxyiminomoiety and the aminothiazole moiety confers extra stability to β-lactamase enzymes produced by many bacteria. The N–methylpyrrolidine moiety increases penetration into Gram-negative bacteria. These factors increase the activity of cefepime against otherwise resistant organisms including Pseudomonas aeruginosa and Staphylococcus aureus.
Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al., DE 3307550; eidem, US 4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al., J. Antibiot. 39, 1092 (1986).
Trade names
Following expiration of the Bristol-Myers Squibb patent,[] cefepime became available as a generic and is now] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.
^ Yahav D, Paul M, Fraser A, Sarid N, Leibovici L (May 2007). “Efficacy and safety of cefepime: a systematic review and meta-analysis”. The Lancet. Infectious Diseases. 7 (5): 338–348. doi:10.1016/S1473-3099(07)70109-3. PMID17448937.
^ “Cefepime (maxipime), large spectrum 4th generation cephalosporin, resistant to beta-lactamases]”.
^World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
^ Chapman TM, Perry CM (2003). “Cefepime: a review of its use in the management of hospitalized patients with pneumonia”. American Journal of Respiratory Medicine. 2 (1): 75–107. doi:10.1007/bf03256641. PMID14720024.
Berdazimer sodium, sold under the brand name Zelsuvmi, is a medication used for the treatment for molluscum contagiosum.[1] Berdazimer sodium is a nitric oxide releasing agent.[1] It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3-(trimethoxysilyl)propyl)-1-triazene-2-oxide and tetraethyl silicate.[2]
Berdazimer sodium was approved for medical use in the United States in January 2024.[3][4][5]
Medical uses
Berdazimer sodium is indicated for the topical treatment of molluscum contagiosum.[1]
Pharmacology
Mechanism of action
Berdazimer sodium is a nitric oxide releasing agent.[1] The mechanism of action for the treatment of molluscum contagiosum is unknown.[1]
Pharmacodynamics
The pharmacodynamics of berdazimer sodium are unknown.[1]
Society and culture
Legal status
Berdazimer sodium was approved for medical use in the United States in January 2024.[4]
Berdazimer is a polymeric substance consisting of a polysiloxane backbone (Si-O-Si bonds) with covalently bound N-diazeniumdiolate nitric oxide (NO) donors. It releases NO through exposure to proton donors like water, which will degrade the N-diazeniumdiolate entity.2 Berdazimer was previously investigated as a potential treatment for molluscum contagiosum, a viral cutaneous infection mainly affecting children, sexually active adults, and immunocompromised patients. It is one of the 5 most prevalent skin diseases in the world and the third-most common viral skin infection in children.3 Previously, the first line treatment for molluscum contagiosum was surgical excision, although it poses challenges such as repeated doctor visits, post-surgical scarring and skin discoloration, and fear and anxiety in the pediatric population.3
On Jan 05, 2024, the FDA approved berdazimer under the brand name ZELSUVMI for the treatment of adult and pediatric molluscum contagiosum, and it is the first drug to be approved for this condition. This decision is based on positive results demonstrated in 2 Phase 3 trials, B-SIMPLE 4 and B-SIMPLE 2, where reduced lesion counts were observed with once-a-day uses of berdazimer.5
^World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.
Further reading
Pera Calvi I, R Marques I, Cruz SA, Mesquita YL, Padrao EM, Souza RM, et al. (2023). “Safety and efficacy of topical nitric oxide-releasing berdazimer gel for molluscum contagiosum clearance: A systematic review and meta-analysis of randomized controlled trials”. Pediatric Dermatology. 40 (6): 1060–1063. doi:10.1111/pde.15419. PMID37721050. S2CID262045499.
Han H, Smythe C, Yousefian F, Berman B (February 2023). “Molluscum Contagiosum Virus Evasion of Immune Surveillance: A Review”. Journal of Drugs in Dermatology. 22 (2): 182–189. doi:10.36849/JDD.7230. PMID36745361. S2CID256613906.
Clinical trial number NCT04535531 for “A Phase 3 Molluscum Contagiosum Efficacy and Safety Study (B-SIMPLE4)” at ClinicalTrials.gov
Clinical trial number NCT03927703 for “A Phase 3 Efficacy & Safety of SB206 & Vehicle Gel for the Treatment of MC (B-SIMPLE2)” at ClinicalTrials.gov
Clinical trial number NCT03927716 for “A Phase 3 Randomized Parallel Group Study Comparing the Efficacy & Safety of SB206 & Vehicle Gel in the Treatment of MC (B-SIMPLE1)” at ClinicalTrials.gov
4/23/2024 FDA APROVED, To treat relapsed or refractory pediatric low-grade glioma, Ojemda
AMG 2112819
BIIB 024
BIIB-024
BIIB024
DAY 101
DAY-101
DAY101
MLN 2480
MLN-2480
MLN2480
TAK 580
TAK-580
TAK580
Tovorafenib, sold under the brand name Ojemda, is a medication used for the treatment of glioma.[1] It is a kinase inhibitor.[1]
The most common adverse reactions include rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.[2] The most common grade 3 or 4 laboratory abnormalities include decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.[2]
It was approved for medical use in the United States in April 2024,[1][2][3][4] and is the first approval of a systemic therapy for the treatment of people with pediatric low-grade glioma with BRAF rearrangements, including fusions.[2]
Medical uses
Tovorafenib is indicated for the treatment of people six months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.[1][2]
History
Efficacy was evaluated in 76 participants enrolled in FIREFLY-1 (NCT04775485), a multicenter, open-label, single-arm trial in participants with relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy.[2] Participants were required to have documented evidence of radiographic progression and at least one measurable lesion.[2] Participants with tumors harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded.[2] Participants received tovorafenib based on body surface area (range: 290 to 476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.[2] The US Food and Drug Administration (FDA) granted the application for tovorafenib priority review, breakthrough therapy, and orphan drug designations.[2]
^World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.
Clinical trial number NCT04775485 for “A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)” at ClinicalTrials.gov
fda approved 4/3/2024, To treat certain bloodstream infections, bacterial skin and associated tissue infections, and community-acquired bacterial pneumonia Press Release zevtera
Ceftobiprole, sold under the brand name Zevtera among others, is a fifth-generation[5]cephalosporin antibacterial used for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia. It is marketed by Basilea Pharmaceutica under the brand names Zevtera and Mabelio.[6][7][8][9][10][11] Like other cephalosporins, ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. Ceftobiprole has high affinity for penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus strains and retains its activity against strains that express divergent mecA gene homologues (mecC or mecALGA251). Ceftobiprole also binds to penicillin-binding protein 2b in Streptococcus pneumoniae (penicillin-intermediate), to penicillin-binding protein 2x in Streptococcus pneumoniae (penicillin-resistant), and to penicillin-binding protein 5 in Enterococcus faecalis.[12]
Medical uses
In the US, ceftobiprole is indicated for the treatment of adults with Staphylococcus aureus bloodstream infections (bacteremia) including those with right-sided infective endocarditis;[4] adults with acute bacterial skin and skin structure infections;[4] and people with community-acquired bacterial pneumonia.[4]
Microbiology
Ceftobiprole has shown in vitro antimicrobial activity against a broad range of Gram-positive and Gram-negative pathogens. Among the Gram-positive pathogens, ceftobiprole has demonstrated good in vitro activity against methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, as well as against strains of methicillin-resistant Staphylococcus aureus with reduced susceptibility to linezolid, daptomycin or vancomycin.[13] Ceftobiprole has also displayed potent activity against Streptococcus pneumoniae (including penicillin-sensitive, penicillin-resistant and ceftriaxone-resistant strains) and Enterococcus faecalis, but not against Enterococcus faecium. For Gram-negative pathogens, ceftobiprole has shown good in vitro activity against Haemophilus influenzae (including both ampicillin-susceptible and ampicillin-non-susceptible isolates), Pseudomonas aeruginosa and strains of Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis that do not produce extended-spectrum β-lactamases (ESBL). Like all other cephalosporins, ceftobiprole was inactive against strains that produce extended-spectrum β-lactamases.[14]
The efficacy of ceftobiprole has been demonstrated in two large randomized, double-blind, phase 3 clinical trials in patients with hospital-acquired and community-acquired pneumonia. Ceftobiprole was non-inferior to ceftazidime plus linezolid in the treatment of hospital-acquired pneumonia (excluding ventilator-acquired pneumonia) and non-inferior to ceftriaxone with or without linezolid in the treatment of community-acquired pneumonia.[15][16]
Pharmacology
Ceftobiprole medocaril
Ceftobiprole is the active moiety of the prodrug ceftobiprole medocaril and is available for intravenous treatment only. It is mainly excreted via the kidney.[17]
Society and culture
Legal status
500 mg powder
Ceftobiprole has been approved for the treatment of adults with hospital acquired pneumonia (excluding ventilator-acquired pneumonia) and community-acquired pneumonia in twelve European countries, Canada, and Switzerland.[18]
In February 2010, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a negative opinion, recommending the refusal of the marketing authorization for the medicinal product Zeftera, intended for treatment of complicated skin and soft-tissue infections in adults. The company that applied for authorization is Janssen-Cilag International N.V. The applicant requested a re-examination of the opinion. After considering the grounds for this request, the CHMP re-examined the opinion, and confirmed the refusal of the marketing authorization in June 2010.[19]
Processes for producing ceftobiprole medocaril are known per se. What the processes known from the prior art have in common is that, starting from 7-aminocephalosporanic acid, a large number of intermediates have to be produced, isolated and purified in order to obtain ceftobiprole medocaril of the general formula (1) in sufficient purity.
The compound of the general formula (1) is known per se and is described, for example, in WO 99/65920. It can be used for the treatment and prophylaxis of bacterial infectious diseases, especially infectious diseases caused by methicillin-resistant Staphylococcus Aureus strains.
WO 99/65920 describes, as the last step in the production process of ceftobiprole Medocaril, a reaction in which the Medocaril prodrug unit is introduced into a compound of the general formula (2).
The compound of the general formula (2) is also known per se and has been described, for example, in EP 0 849 269 A1. The compound of the general formula (2) is prepared according to EP 0 849 269 A1 starting from (2R,6R,7R)-te rt. B u toxyc abonylamin o-3-formyl-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester by Wittig reaction with (1 ‘-allyloxycarbonyl-2- oxo-[1,3’]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide. The resulting Δ2 reaction product is reisomerized to the desired Δ3 isomer by sulfoxidation and subsequent reduction and then deprotected from the benzhydryl ester with trifluoroacetic acid. The acylation in position 7 occurs by reaction with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)-trityloxyiminothioacetic acid S-benzothiazol-2-yl ester. The compound of the general formula (2) is then obtained by removing the protective groups.
In EP 1 067 131 A1 the formation of the ylide in toluene or a mixture of toluene and dichloromethane is tert by adding alkali. Butylate in tetrahydrofuran, which allows the base to be added as a solution. The reaction of the ylide with the corresponding aldehyde is described at a reaction temperature of -70 0 C.
EP 0 841 339 A1 relates to cephalosporin derivatives and processes for their production. WO 95/29182 also discloses intermediates for the production of cephalosporins.
WO 01/90111 describes a further production of ceftobiprole Medocaril in several stages starting from desacetyl-7-aminocephalosporanic acid by acylation with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)- trityloxyiminothioacetic acid S-benzothiazol-2-yl ester in N,N-dimethylformamide, followed by in situ esterification with diphenyldiazomethane in dichloromethane to give the corresponding benzohydryl ester, which is precipitated and isolated by adding hexane. In the next step, this product is oxidized to the corresponding aldehyde using TEMPO/NaOCI in dichloromethane/water or with Braunstein in tetrahydrofuran/dichloromethane. The next reaction step involves the Wittig reaction to the 3-vinyl-substituted derivative, in which the reaction takes place in dichloromethane/toluene/tetrahydrofuran at -78°C. The crude product is stirred with ethanol and made from dichloromethane/tert. Butyl methyl ether recrystallized or purified chromatographically. According to the method disclosed in WO 01/901 11, the Wittig reaction is carried out at low temperatures of -80 to -70 0 C in a complex solvent mixture of dichloromethane, toluene and tetrahydrofuran. This leads to significant disadvantages when carrying out the reaction on a production scale, since regeneration of the process solvents is difficult.
5 , 1 4 g of 7-amino-3-formyl-ceph-3-em-4-carboxy I at was dissolved in 2 7 , 8 m bis(trimethylsilyl)acetamide and 50 ml propylene oxide. 16.8 g of (1 R/S,3’R)-(1′-tert-butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02/14332) slowly added in portions. Stirring was continued at 1 ° C until the starting material had reacted and then the crystalline precipitate was added
Nitrogen atmosphere filtered off and washed with 50 ml cyclohexane/bis(tirmethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the desired product was obtained in silylated form.
The material was dissolved in 100ml dichloromethane and at 0 0 C with 50ml 3%
NaHCC> 3 solution added. The phases were separated, the organic phase was washed with 30 ml of water and the combined water phases were adjusted to pH 3.5 with 3% H 3 PO 4 after activated carbon treatment. The crystalline precipitate was filtered, washed with water and dried under vacuum.
10.28 g of 7-amino-3-formyl-ceph-3-em-4-carboxylate were dissolved in 55.6 ml of bis(trimethylsilyl)acetamide and 100 ml of propylene oxide. 33.6 g of (1R/S, 3’R)-(1′-tert. Butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02.) were then added at 0 0 C /14332) slowly added in portions over 22 hours. The mixture was stirred at 1° C. until the starting material had reacted and then the reaction mixture was cooled to -20 ° C. The crystalline precipitate was filtered off under a nitrogen atmosphere and washed in portions with 180 ml of cyclohexane/bis(trimethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the bissilylated
1.0g (6R,7R)-7-Trimethylsilylamino-3[E-(R)-1′-(5-tert.butyloxycarbonyl)-2-oxo-[I.Slbipyrrolidinyl-S-ylidenemethyO-δ-oxo-δ -thia-i-aza-bicyclo^^.Oloct^-ene^- carboxylic acid trimethylsilyl esters were dissolved in 10ml dichloromethane and a solution of 300mg dicyclohexylamine in 1ml EtOH and 10ml ethyl acetate was added. The precipitate was filtered off, washed with ethyl acetate and dried in vacuo.
3.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 150 ml of dichloromethane at 0°. 600 μl of DMF/water 5/1 and 1.8 ml of bis(trimethylsilyl) acetamide and 2.29 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetic acid chloride were then added Hydrochoride (J. Antibiotics 37:557 – 571, 1984) was added in portions.
After 3 hours at 0°, the mixture was poured into 30 ml MeOH/120 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 66g and 25ml of trifluoroacetic acid was added. After 10 minutes, 1.5 ml triethylsilane and 10 ml water were added and the mixture was cooled to -15 ° C. The organic phase was separated off and again with 6 ml
Washed trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 150 ml with water and filtered through an adsorber resin column with XAD-1600. After washing out the column with water, elution was carried out with water/acetonitrile 85/15. The product-containing fractions were concentrated in vacuo and allowed to stand at 0° for post-crystallization. The crystalline
Product was filtered off, washed with water and dried under vacuum.
Auswaage: 2,66g
4.2 Variant B:
7.4g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid was dissolved at 0° in 781 ml of dichloromethane with the addition of 6.7 ml of triethylamine. 8.65 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid chloride hydrochloride were then added in portions. After the starting material had reacted, the mixture was poured into 500 ml of water and the methylene chloride phase was separated off. The organic phase was dried over Na 2 SC> 4 and concentrated in vacuo.
The residue was dissolved in 148 ml of dichloromethane and 4.5 ml of triethylsilane and 74 ml of trifluoroacetic acid were added at room temperature. After 30 minutes, 222 ml of dichloromethane and 222 ml of water were added and the mixture was cooled to -20 0 C. The organic phase was separated off and washed again with a mixture of 37 ml of trifluoroacetic acid and 148 ml of water. The combined aqueous phases were diluted with water to 364 ml, filtered through an adsorber resin and eluted with acetonitrile/water 15/85.
The filtrate was concentrated to 35g on a Rotavapor, filtered and washed with water.
After drying in a vacuum, 4.5 g of the sample was obtained.
6.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 300 ml of dichloromethane at 0°. 1200 μl of DMF/water 5/1 and 8.1 ml of bis(tirmethylsilyl)acetamide were then added as well as 5.3g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid chloride Hydrochoride (J. Antibiotics 37:557 – 571, 1984) added in portions. The mixture was then poured into 60 ml MeOH/240 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 48g and 1.5 ml of triethylsilane was added. After adding 50ml
Trifluoroacetic acid was stirred at room temperature for 60 min, 20 ml of water was added and the mixture was cooled to -15°C. The organic phase was separated off and washed again with 20 ml trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 500 ml with water and treated with 2.0 g of activated carbon. After filtration, the solution was concentrated in vacuo.
The residue was diluted to 50 ml with water and adjusted to pH 6.9 with saturated NaHCO 3 solution. The mixture was stirred at 0 0 C for 2 hours, filtered and the precipitate washed with water.
0, 5 3 g ( 6 R , 7 R )-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8- oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1 – aza-bicyclo[4.2.0]oct-2-ene- 2 carboxylic acid were dissolved in 5 ml of dimethyl sulfoxide and 0.27 g of carbonic acid (5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-nitrophenyl ester were added and stirred at room temperature. A solution of sodium ethyl hexanoate in 30 ml of acetone was added for precipitation. The precipitate was filtered and washed with acetone.
^ Zhanel GG, Lam A, Schweizer F, Thomson K, Walkty A, Rubinstein E, et al. (2008). “Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin”. American Journal of Clinical Dermatology. 9 (4): 245–254. doi:10.2165/00128071-200809040-00004. PMID18572975. S2CID24357533.
^ Farrell DJ, Flamm RK, Sader HS, Jones RN (April 2014). “Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin, linezolid or vancomycin, and strains with defined SCCmec types”. International Journal of Antimicrobial Agents. 43 (4): 323–327. doi:10.1016/j.ijantimicag.2013.11.005. PMID24411474.
^ Nicholson SC, Welte T, File TM, Strauss RS, Michiels B, Kaul P, et al. (March 2012). “A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation”. International Journal of Antimicrobial Agents. 39 (3): 240–246. doi:10.1016/j.ijantimicag.2011.11.005. PMID22230331.
^“Zeftera (previously Zevtera) EPAR”. European Medicines Agency (EMA). 18 February 2010. Retrieved 6 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
External links
Clinical trial number NCT03138733 for “Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia” at ClinicalTrials.gov
Clinical trial number NCT03137173 for “Ceftobiprole in the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infections” at ClinicalTrials.gov
Clinical trial number NCT00326287 for “Ceftobiprole in the Treatment of Patients With Community-Acquired Pneumonia” at ClinicalTrials.gov
Clinical trial number NCT03439124 for “Ceftobiprole in the Treatment of Pediatric Patients With Pneumonia” at ClinicalTrials.gov
////////Ceftobiprole, BAL-9141, BAL-9141-000, BAL-9141000, BAL9141-000, RO 63-9141, RO-63-9141, RO-639141, fda 2024, zevtera, approvals 2024, Ceftobiprole medocaril sodium salt
Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.[2] It is a complement inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated hemolysis and deposition of complement C3 proteins on red blood cells.[2]
Danicopan was approved for medical use in Japan in January 2024, and in the United States in March 2024.[3][4]
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematologic disease characterized by hemolysis, thrombophilia, and bone marrow dysfunction.1,7 Both hemolysis and thrombophilia are mediated primarily by the complement system.1 Standard therapy for PNH involves the use of complement C5 inhibitors (e.g. eculizumab, ravulizumab) which are effective in mitigating complement-mediated intravascular hemolysis and thromboembolism.1 Unfortunately, complement C5 inhibition does not address C3-mediated extravascular hemolysis, which occurs earlier in the complement cascade within the alternative pathway.1,5
Danicopan is a small molecule complement factor D inhibitor that selectively blocks the alternative pathway, thereby working to address extravascular hemolysis when used in conjunction with C5 inhibitors.3 It was first approved in January 2024 in Japan for patients with PNH,2,6 shortly after which the EMA adopted a positive opinion and recommended granting it marketing authorization.2 It was subsequently approved by the FDA in March 2024.4
Step 1: Synthesis of tert-Butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl) fluoropyrrolidine-1-carboxylate (3): N-Boc-trans-4-Fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor under an atmosphere of nitrogen. The reaction mixture was cooled to 0±5° C. and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0±5° C. Methanesulfonyl chloride (29.97 kg) was slowly added to the reaction mixture followed by the addition of 2-amino-6-bromopyridine (2). The reaction temperature was warmed to room temperature and stirred for 12 h. The reaction was monitored by HPLC. After completion of the reaction water (2,000 kg) was added, the reaction was stirred and the DCM layer separated. The aqueous layer was once more extracted with DCM (1000 L). The combined DCM layer was washed in succession with dilute HCl, aqueous NaHCO3 and brine. The DCM extract was evaporated to dryness and tert-butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (3) was isolated using DCM heptane mixture and dried. Yield, 71.76 Kg (84.86%))
[0404] Step 2: Synthesis of (2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (4): To a solution 4M HCl/Dioxane (168 kg) was added intermediate 3 (40 kg) at 25±5° C. under an atmosphere of nitrogen and the reaction was stirred for 1 h. The reaction was monitored by HPLC and after completion, the reaction was diluted with DCM (800 L) and washed with aqueous NaHCO3. The DCM layer was separated and concentrated. The product, 2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide, (4), was isolated using DCM/heptane and dried. Yield, 25.81 kg, 87%.
[0405] Step 3: Synthesis of tert-Butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (6): 1-(5-Bromo-1H-indazol-yl)ethan-1-one (5, 30 kg) was added to a reactor containing DMF (210 L) under an atmosphere of nitrogen followed by potassium carbonate (4.05 kg). Tert-butyl bromoacetate (3.42 kg) was added to the reaction mixture with stirring and maintaining the temperature at 30±10° C. After addition was complete, the reaction mixture was heated at 50±5° C. for 1 h. After the reaction was complete the reaction mixture was cooled to 25±5° C. and diluted with water (630 L). The precipitated solid was filtered, washed with water (90 L) and dried. Yield, 43.13 kg, 97.13%.
[0406] Step 4: Synthesis of tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (9): Bispinnacolato diboron (14.67 kg) was added to a solution of 4-bromo methylpyrimidine (7, 10 kg) in dioxane (206 kg) under an atmosphere of nitrogen followed by the addition of potassium acetate (17 kg). The reaction mixture was degassed using nitrogen. Pd(dppf)Cl2 (0.94 kg) was added and the reaction mixture heated to 90±5° C. until the pyrimidine was consumed. The reaction mixture was cooled to 25±5° C. and intermediate 6 (16.33 kg) was added followed by potassium carbonate (20.7 kg) and water (16.33 kg) and the reaction was degassed using nitrogen. The reaction was again heated to 90±5° C. until completion. The reaction mixture was cooled to 25±5° C. and diluted with ethyl acetate (269 kg) and water (150 kg) maintaining the temp at 10±5° C. Activated charcoal (1 kg) was added to the mixture with stirring and then filtered through a bed of celite. The ethyl acetate layer was separated, washed with 5% aqueous sodium chloride followed by 5% L-Cysteine solution to remove palladium related impurities. The ethyl acetate layer was evaporated to dryness. The product (9) was isolated from MTBE/heptane. Yield, 11.8 kg, 56%.
[0407] Step 5: Synthesis of 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (10): To a stirred solution of intermediate 9 (50 kg) in DCM (465 kg) at 15±5° C. was added TFA (374.5 kg) while maintaining the said temperature. The reaction was warmed to 35±5° C. and stirring continued until completion of the reaction. DCM and TFA were distilled off under reduced pressure. The residue was dissolved in DCM (kg) and stirred with aqueous sodium bicarbonate. The biphasic mixture was acidified with concentrated HCl and the pH was adjusted to 2-3. The precipitated solid was filtered, washed with water and dried. Yield, 42.4 kg, quantitative.
[0408] Step 6: Synthesis of Compound 1: To a solution of intermediate 9 (42 kg) in DMF (277 kg) was added intermediate 4 (38.7 kg) and the reaction was cooled to 10±5° C. Coupling agent TBTU (56.7 kg) was added to the reaction mixture followed by the addition of DIPEA (86.5 kg) while maintaining the reaction temperature at 10±5° C. The reaction was warmed to 25±+5° C. and stirred until complete. The reaction mixture was diluted with ethyl acetate (1344 kg) and washed with water twice. (The reaction may be washed with aq. K2CO3 if fluorine related impurities are present.) Anhydrous sodium sulfate was added to silica gel and added to the ethyl acetate layer and filtered. The ethyl acetate layer was passed over a column of silica gel (40 kg) and the pure fractions were collected. The fractions were treated with activated charcoal and then filtered over celite. The palladium content was checked, and if above 10 ppm, the ethyl acetate layer was treated with palladium scavenging resin (SilabondThiol®). The ethyl acetate was evaporated to dryness under vacuum and the residue was crystallized from IPA (crystalline seed may be added) and heptane to afford Compound 1 Form II. Yield, 60 kg, 78%.
Society and culture
Legal status
In February 2024, the Committee for Medicinal Products for Human Use of the EMA adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Voydeya, intended as add-on therapy to ravulizumab or eculizumab for the treatment of residual hemolytic anemia in adults with paroxysmal nocturnal hemoglobinuria (PNH).[2][5] The applicant for this medicinal product is Alexion Europe.[2]
^ Jump up to:abcd“Voydeya EPAR”. European Medicines Agency. 22 February 2024. Archived from the original on 23 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1). hdl:10665/330896.
Further reading
Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, et al. (December 2023). “Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial”. The Lancet. Haematology. 10 (12): e955–e965. doi:10.1016/S2352-3026(23)00315-0. PMID38030318.
fda approved 4/26/2024, To treat WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis), Xolremdi
Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively.
AMD-070 is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Approximately 76% of HIV-patients with measurable viral load are infected with a strain of virus that is resistant to one or more classes of antiretroviral agents, thus reducing treatment options. Unlike many existing HIV drugs that target the virus after it has infected a healthy cell, AMD-070 blocks the virus from entering a healthy cell, thus preventing the replication process. AMD-070 targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. AMD-070 is specific for the CXCR4 receptor and does not interact with any other chemokine receptors in vitro. AMD-070 strongly inhibits viral infection by all CXCR4 using virus (including virus using CXCR4 alone and/or virus using CXCR4 and CCR5) in vitro. AMD-070 is orally bioavailable in animals, it has suitable PK and toxicity profile for oral dosing. AMD-070 shows additive or synergistic effects in vitro in combination with other known anti-HIV agents. AMD-070 is active against CXCR4 using HIV strains that are resistant to existing antiretroviral therapies in vitro, reveals potent anti-HIV activity against CXCR4-using laboratory strains and clinical isolates. MD-070 had been in phase II clinical trials by Genzyme for the treatment of HIV infection. However, this research has been discontinued. AMD-070 has been studied in Phase I/II clinical trials for the treatment of Renal cell carcinoma and Phase I clinical trials for the treatment of malignant melanoma and solid tumours.
A novel and practical synthesis of mavorixafor (1) is reported. The novelty of this synthetic route is the use of 8-chloro-5,6,7,8-tetrahydroquinoline (9) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline (4) and N,N-diprotected aminobutyraldehyde (6a or 6b). The preparation of (S)-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline (13) by resolution with N-acetyl-l-leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.
Charge diethyl-4-aminobutyl acetal (E) (1.00 wt, 1.00 eq) to vessel A. Charge acetonitrile (10.0 vol, 7.8 wt) and adjust temperature to 20°C. Heat the mixture to 40°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.
[0098] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure 35 to 45°C. This step is repeated once as described below.
[0099] Acetonitrile filler (5.0 vol, 3.9wt) at 35 to 45°C. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C. Cool to 20°C.
[00100] Charge di-tert-butyl dicarbonate (1.1 eq, 1.5 wt) to a drum, followed by acetonitrile (0.4 vol, 0.3 wt) and agitate until fully dissolved. Concentrate the reaction mixture to 6.0 vol under reduced pressure at 35 to 45°C.
[00101] Charge this di-tert-butyl dicarbonate solution in acetonitrile to vessel A maintaining 20°C. Charge acetonitrile (1.5 vol, 1.1 wt) to the solution as a line rinse and stir at 20°C for 30 to 60 min..
[00102] Charge 4-dimethylaminopyridine (0.076 wt, 0.10 eq) to the vessel A at 20°C. Heat the solution to 40°C. Concentrate the reaction mixture to 5.0 vol under reduced pressure. Charge acetonitrile (5.0 vol, 3.9 wt) to the solution. Concentrate the reaction mixture to 5.0 vol under reduced pressure.
[00103] Take the resulting solution of Dl into next reaction without isolation.
Step IB: Preparation of Cl
[00104] Charge acetonitrile (2.0 vol, 1.6 wt) at 35 to 45°C to vessel A containing solution of D-1 from Step 1A.
[00105] Charge di-tert-butyl dicarbonate (1.4 eq, 1.9 wt) to a drum, followed by acetonitrile (10.0 vol, 7.8 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A, 2 to 6 h while distilling under vacuum at 35 to 45°C maintaining the volume of the reaction at 7.0 vol. Load acetonitrile (3.0 vol, 2.4 wt) over 20 to 40 min. as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.
[00106] Charge di-tert-butyl dicarbonate, (0.14 eq, 0.19 wt) to a drum, followed by acetonitrile (1.0 vol, 0.74 wt) and agitate until fully dissolved. Charge this di-tert-butyl dicarbonate solution to vessel A over 20 to 40 min.. Charge acetonitrile (0.3 vol, 0.24 wt) over 10 to 20 min as a line rinse while distilling under vacuum at 35 to 45°C, maintaining the volume of the reaction at 7.0 vol.
[00107] Concentrate the reaction mixture to 5.0 vol distilling under vacuum at 35 to 45°C.
[00108] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C. This step is repeated once as described below.
[00109] Charge n-heptane, (7.5 vol, 5.1 wt) to the reaction mixture, and concentrate the reaction mixture to 5.0 vol under reduced pressure at 40°C.
[00110] Charge decolorizing, activated charcoal (0.2 wt) to the solution and stir for 1 to 2 h at 40°C. Filter the reaction mixture at 40°C. Charge n-heptane, (2.0 vol, 1.4 wt) to the reactor vessel and stir for 5 to 15 min. at 20°C before charging to the filter as a line rinse. Combine the filtrate and wash, and as required adjust to 20°C.
[00111] Take the resulting solution of Cl into next reaction without isolation.
Step 1C: Preparation of Bl
[00112] Charge 15% v/v acetic acid (2.0 vol) caution gas evolution, to vessel A containing solution of Cl from Step IB, maintaining the temperature at 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A. This step is repeated once as described below.
[00113] Charge 15% v/v acetic acid (2.0 vol) maintaining 20°C and stir for 10 min. at 20°C. Allow the phases to separate for 15 min. at 20°C. Discharge the aqueous phase to waste, retaining the organic phase in vessel A.
[00114] Adjust the reaction to 30°C. Charge 4% w/w sodium chloride solution (2.1 vol) to the vessel maintaining the temperature at 30°C. Charge glacial acetic acid (4.1 vol, 4.3 wt) to the vessel maintaining 30°C. Stir the reaction mixture for 2 h maintaining the temperature at 30°C.
[00115] Charge purified water, (6.0 vol) at 30°C. Stir the contents for 5 to 10 min. at 30°C, and separate the phases, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.
[00116] Charge purified water (4.0 vol) at 30°C and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, retaining the upper organic phase in vessel A. Charge the lower aqueous phase to vessel B.
[00117] Adjust the temperature to 30°C of vessel B containing combined aqueous phases. Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B. This step is repeated two additional times as described below.
[00118] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min.. Charge the upper organic phase to vessel A and recharge the lower aqueous phase to vessel B.
[00119] Charge n-heptane, (2.0 vol, 1.4 wt) to vessel B and stir for 5 to 10 min. maintaining the temperature at 30°C. Separate the phases at 30°C, over 15 min., discharge the lower aqueous phase to waste and charge the upper organic layer to vessel A.
[00120] Concentrate the combined organic phases in vessel A to 3.0 vol at 10 to 20°C under reduced pressure. Offload the solution to new HDPE drum(s) and line rinse with n-heptane (0.5
vol, 0.4 wt) at 20°C. Homogenize the drum and store as “Bl solution in n-heptane,” and take into next reaction without isolation.
Step ID: Preparation of F-2d
[00121] Calculate a new 1.00 wt based on the above assay.
[00122] Charge “Bl solution in n-heptane” from Step 1C (1.00 wt, 1.00 eq, corrected for w/w assay, ca. 3.0 vol), into an appropriate vessel. THF load (3.0 vol, 2.7 wt). Heat the reaction mixture to 40°C.
[00123] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C. This step was repeated four additional times to add the reagent in five portions total, as detailed below.
[00124] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00125] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00126] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 30 to 35 min. at 40°C.
[00127] Charge purified water, (0.02 vol, 0.02 wt) followed by sodium metabisulphite, (0.125 eq, 0.08 wt) as a solid via the charge hole at 40°C. Stir the resulting mixture for 36 hours at 40°C.
[00128] Cool the reaction mixture to 20°C over 3 to 4 h at a target constant rate. Filter the reaction mixture at 20°C on a 1-2 pm cloth.
[00129] Wash the solid with a pre-mixed mixture of THF (0.5 vol, 0.5 wt) and n-heptane (0.5 vol, 0.3 wt) maintaining the temperature at 20°C. This step was repeated an additional three times, as detailed below.
[00130] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.
[00131] Wash the solid with n-heptane, (2.0 vol, 1.4 wt) as a line rinse and apply to the filtercake at 20°C.
[00132] Wash the solid with acetonitrile, (2.0 vol, 1.6 wt) as a line rinse and apply to the filtercake at 20°C.
[00133] Dry the solid at 38°C under a flow of nitrogen for 12 h.
[00137] Charge J, (1.00 wt, 1.00 eq) to vessel A. Charge purified water, (1.0 vol, 1.0 wt) to vessel A and as necessary adjust the temperature to 20°C. Charge concentrated hydrochloric acid, (4.0 eq, 3.0 vol, 3.6 wt) to vessel A maintaining the temperature at 20°C. Line rinse with purified water, (0.5 vol, 0.5 wt) maintaining the contents of vessel A at 15 to 25°C.
[00138] Charge chloroacetic acid, (1.3 wt, 1.5 eq) and purified water, (1.0 vol, 1.0 wt) to vessel B and as necessary, adjust the temperature to 20°C. Stir until fully dissolved, expected 10 to 20 min.
[00139] Charge the chloroacetic acid solution to vessel A maintaining the temperature of vessel A at 20°C. Line rinse vessel A with purified water, (0.5 vol, 0.5 wt) at 15 to 25°C and charge to vessel B at 20°C. Heat the reaction mixture to 80°C. Stir the reaction mixture at 80°C for 20 h.
[00140] Cool the reaction mixture to 10°C over 1.5 h. Load 47% w/w potassium phosphate solution (6.0 vol) over 60 min. targeting a constant rate maintaining 10°C. Adjust the pH of the reaction mixture by charging 47% w/w potassium phosphate solution to pH 7.0 maintaining the reaction temperature at 10°C. Expected charge is 2.0 to 3.5 vol 47% w/w potassium phosphate solution.
[00141] Stir the slurry for >30 min. maintaining 10°C and rechecking the pH, pass criterion pH 7.0. Filter the reaction mixture through 20 pm cloth at 10°C. Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. This step is repeated additional three times as described below.
[00142] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00143] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00144] Slurry wash the filter-cake in the reactor vessel with purified water, (10.0 vol, 10.0 wt) for 45 min. to 90 min. at 10°C. Filter the mixture through 20 pm cloth at 10°C.
[00145] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C. The filter-cake was washed with purified water additional five times as described below.
[00146] Wash the filter-cake with purified water, (1.0 vol, 1.0 wt) at 10°C.
[00147] Wash the filter-cake with acetonitrile, (2×1.3 vol, 2×1.0 wt) at 10°C.
[00148] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 20°C until the water content is <15.0% w/w by Karl-Fisher analysis.
[00149] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 30°C until the water content is <5.0% w/w by Karl-Fisher analysis.
[00150] Dry the filter-cake on the filter under vacuum and strong nitrogen flow through the filter cake at 50°C until the water content is <1.0% w/w by Karl-Fisher analysis.
[00151] Yield of compound Gl: about 75%.
Step 2B: Preparation of F-3a
Charge di-/c/7-butyl dicarbonate, (1.85 wt, 1.4 eq) to vessel A followed by N,N-dimethylformamide, (2.6 wt, 2.7 vol) and stir at 20°C for 20 min. until dissolution achieved. Add A,A-diisopropylethylamine, (0.08 wt, 0.11 vol, 0.1 eq) to contents of vessel A at 20°C. Heat the contents of vessel A to 40°C.
[00153] Charge Gl, (1.00 wt) to vessel B followed by YW-di methyl form am ide, (5.2 wt, 5.5 vol) and adjust to 14°C.
[00154] Charge the Gl/DMF solution from vessel B to vessel A over 5 h at 40°C, at an approximately constant rate. Line rinse with Y,Y-di methyl form am ide, (0.4 wt, 0.4 vol), maintaining vessel A at 40°C. Stir the resulting reaction mixture at 40°C for 16 h.
[00155] Charge decolorizing charcoal activated, (0.20 wt). Adjust the mixture to 40°C and stir at 40°C for 60 to 90 min..
[00156] Clarify (filter) the reaction mixture into vessel B at 40°C. Charge N,N-dimethylformamide, (0.9 wt, 1.0 vol) via vessel A and filter at 40°C. Charge purified water, (3.5 vol) to the combined filtrates, over 60 min., maintaining the temperature at 40°C. As required, cool the mixture to 35°C over 30 to 60 min..
[00157] Filler F-3a, (0.02 wt) as seed material at 35°C. Stir at 34°C for 1.5 h then check for crystallization. Cool slurry to 30°C over 40 min.
[00158] Filler F-3a, (0.02 wt) as seed material at 30°C. Stir at 30°C for 1.5 h then check for crystallization.
[00159] Cool slurry at 20°C over 3.5 h at a targeted constant rate. Stir at 20°C for 3 hours. Charge purified water, (1.0 vol), maintaining the temperature at 20°C over 60 min..
Stir at 20°C for 3 hours.
[00160] Cool slurry to 2°C over 2.5 h. Stir at 2°C for 2.5 hours. Filter through 20 pm cloth and pull dry until no further filtrate passes. Wash the solid with pre-mixed Y,Y-di methyl form am ide / purified water, (2.0 vol, 1:2 v:v) at 2°C. Wash the solid with purified water, (2 x 3.0 vol) at 2°C. Dry under vacuum at 28°C until KF <0.2% w/w, and Y,Y-di methyl form am ide <0.4% w/w.
[00161] Yield of compound F-3a: 62-70%.
Example 3: Synthesis of Mavorixafor:
Scheme VI:
nce
Step 3A: Preparation of imine Q-1
[00162] To vessel A charge purified water, (8.7 vol, 8.7 wt) followed by potassium phosphate, (5.52 eq, 5.3 wt) portion-wise and cool to 15°C. Charge tetrahydrofuran, (4.3 vol, 3.8 wt) and n-heptane, (2.2 vol, 1.5 wt) to vessel A and cool the biphasic mixture to 0°C. Charge Fl, (1.00 eq, 1.00 wt) to the vessel in 2 portions maintaining 0°C.
[00163] Charge F-2d, (1.10 eq, 1.95 wt) to the vessel in 4 portions maintaining 0°C, ensuring portions are spaced by 10 min.. Stir the resulting biphasic mixture for 1.5 h at 0°C. Allow the layers to separate for 45 min. at 0°C before separating the layers. Retain the upper organic phase within vessel A.
[00164] Take the resulting solution of Ql into next reaction without isolation.
Step 3B: Preparation of amine P-1
[00165] To vessel B, charge tetrahydrofuran, (6.0 vol, 5.3 wt) and adjust to 15°C. Charge zinc chloride, (1.5 eq, 0.92 wt) to vessel B in 4 portions, maintaining 10 to 30°C. Adjust the reaction mixture in vessel B to 15°C. Stir the mixture at 15°C for 1 hour. Charge sodium borohydride,(1.0 eq, 0.17 wt) to vessel B in 2 portions maintaining 15°C. Cool the reaction mixture in vessel B to 15°C. Stir the mixture for 1 hour maintaining 15°C. Cool the reaction mixture in vessel B to -5°C.
[00166] Cool the retained organic solution of Ql in vessel A, from Step 3A, to -5°C.
[00167] Charge the organic solution in vessel A into vessel B over 1 to 2 h maintaining -5°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel A as a line rinse and adjust to -5°C. Transfer the contents of vessel A to vessel B maintaining -5°C.
[00168] Stir the resulting reaction mixture in vessel B for 1.5 h maintaining -5°C.
[00169] Charge purified water, (4.5 vol, 4.5 wt) and glacial acetic acid, (1.0 eq, 0.27 wt, 0.26 vol) to the cleaned vessel A and cool to 0°C. Charge the contents of vessel B to vessel A over 1 to 2 h maintaining 0°C. Charge tetrahydrofuran, (1.0 vol, 0.9 wt) to vessel B as a vessel rinse, cool to 0°C and transfer to vessel A maintaining 0°C.
[00170] Warm the resulting mixture in vessel A to 30°C. Stir the resulting mixture in vessel A at 30°C for 1 h. Allow the layers to settle for 15 min. at 30°C before separating the layers. Retain the upper organic phase.
[00171] Cool the retained organic phase to 15°C. Charge to the vessel 25% w/w ammonia solution (3.0 vol) at 10 to 30°C. Cool the reaction mixture to 20°C. Charge to the vessel 25% w/w ammonium chloride solution (3.0 vol) at 20°C and stir for 1 h. Separate the layers for 15 min. at 20°C, retain the upper organic phase. Wash the retained organic phase with 10% w/w sodium chloride solution (3.0 vol) at 20°C for 10 min.. Allow the layers to settle for 10 min. at 20°C before separating and retaining the upper organic phase within the vessel.
[00172] Charge tert-butyl methyl ether, (0.5 vol, 0.4 wt) to the organic phase. Cool the mixture to 5°C. Adjust the pH of the reaction mixture to pH 5 with hydrochloric acid aqueous solution (expected ca. 9.0 vol) over 1 h at a targeted constant rate at 5°C. Stir the mixture at 5°C for 45 min.. Measure the pH of the aqueous phase to confirm the value is pH 5.
[00173] Charge sodium chloride, (2.1 wt) to the reaction mixture at 5°C and stir the mixture until everything is dissolved. Adjust the temperature of the reaction mixture to 20°C. Separate the layers at 20°C and retain the organic phase within the vessel. Tetrahydrofuran charge, (1.5 vol, 1.3 wt) maintaining 20°C.
[00174] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel. This step is repeated additional one more time as described below.
[00175] Charge to the vessel 24% w/w sodium chloride solution (7.5 vol) at 20°C and stir for 10 min.. Separate the layers at 20°C and retain the organic phase in the vessel.
[00176] Heat the retained organic phase to 35°C and concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.
[00177] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 6.0 vol under reduced pressure maintaining 35°C.
[00178] Tetrahydrofuran charge, (15.0 vol, 13.2 wt) maintaining 35°C. Concentrate the mixture to 11.0 vol under reduced pressure maintaining 35°C.
[00179] Cool the mixture to -5°C. Load tert-butyl methyl ether, (10.0 vol, 7.4 wt) over 1 h maintaining -5°C. Stir the mixture at -5°C for 1.5 hours. Filter the solid on 1 to 2 pm filter cloth at -5°C. Wash the solid with pre-mixed tetrahydrofuran, (1.9 vol, 1.7 wt) and tert-butyl methyl ether, (3.1 vol, 1.9 wt) at -5°C as a displacement wash.
[00180] Wash the solid with tert-butyl methyl ether, (5.0 vol, 3.7 wt) at -5°C.
[00181] Dry the solid on the filter under a flow of nitrogen at 23°C.
[00182] Yield of compound P-1: 76-87%.
Step 3C: Preparation of compound 0-1
[00183] Charge purified water, (2.0 vol, 2.0 wt) followed by potassium phosphate, (3.3 eq, 1.54 wt), carefully portion-wise, maintaining <15°C, to vessel A. Charge toluene, (4.5 vol, 3.9 wt) to the vessel maintaining <15°C. As necessary, adjust the temperature to 10°C.
[00184] Charge P-1, (1.00 eq, 1.00 wt) to the vessel in two portions maintaining 10°C. Stir the reaction mixture at 10°C for 15 min..
[00185] Load F-3a, (1.1 eq, 0.64 wt) in 4 equal portions ensuring portions are spaced by 10 min. at 10°C.
[00186] Tetrabutylammonium iodide (TBAI) filler (0.20 eq, 0.16 wt). Heat the reaction mixture to 40°C. Stir the reaction mixture at 40°C for 30 h.
[00187] Charge pre-mixed 2-mercaptoacetic acid, (0.40 eq, 0.08 wt, 0.06 vol), and toluene, (0.5 vol, 0.4 wt) over 20 min. to Vessel A at 40°C. Line rinse with toluene, (0.5 vol, 0.4 wt) at 40°C. Adjust the temperature of the reaction mixture to 50°C. Stir the mixture at 50°C for 2.5 hours.
[00188] Adjust the temperature of Vessel A to 20°C. Charge purified water, (3.0 vol, 3.0 wt) maintaining 20°C. Stir the reaction mixture at 20°C for 15 min. and transfer to a new, clean HDPE container. Line/vessel rinse with toluene, (0.5 vol, 0.4 wt) at 20°C. Clarify (filter) the reaction mixture via a 1 pm filter at 20°C into clean Vessel A. Wash the vessel and the filter with toluene, (0.5 vol, 0.4 wt) at 20°C. Allow the layers to separate for 15 min. at 20°C, retaining the upper organic layer (organic layer 1).
[00189] Wash the aqueous layer with toluene, (2.5 vol, 2.2 wt) at 20°C for 15 min.. Allow the layers to separate for 15 min. at 20°C. Retain the upper organic layer (organic layer 2).
[00190] Combine the organic layer 1 and organic layer 2 and adjust the temperature to 20°C. Wash the combined organic layers with 10% w/w sodium chloride solution (5.0 vol) at 20°C for 15 min.. Allow the layers to settle for 15 min. at 20°C. Retain the upper organic layer.
[00191] Take the resulting solution of Ol into next reaction without isolation.
Step 3D: Preparation of compound Kl
[00192] Charge n-butanol, (2.4 wt, 3.0 vol) to vessel B and adjust to 5°C. Charge concentrated sulfuric acid, (1.1 wt, 5.0 eq, 0.6 vol) slowly to Vessel B maintaining <15°C. Line rinse with toluene, (0.4 wt, 0.5 vol) maintaining <15°C. Adjust the temperature of Vessel B to 25°C.
[00193] Heat the n-butanol/ sulfuric acid solution in Vessel B to 55°C. Charge the organic layer from Vessel A (from Step 3C) to the butanol/ sulfuric acid solution in Vessel B over 60 to 90 min. maintaining 55°C. Charge toluene, (1.3 wt, 1.5 vol) to Vessel A as a line rinse and transfer to Vessel B maintaining 55°C. Stir the contents of Vessel B at 55°C for 1.5 h.
[00194] Stir the mixture in Vessel B for 4.5 h at 55°C. Cool the contents of Vessel B to 20°C over 10 h. Filter the slurry over 1-2 pm filter cloth under nitrogen at 20°C. Wash the filter cake with pre-mixed toluene, (3.5 wt, 4.0 vol) and n-butanol, (1.0 vol, 0.8 wt) at 20°C. Wash the filter cake with toluene, (4.3 wt, 5.0 vol) at 20°C. Dry the solid at 30°C under vacuum.
[00195] Correct the output weight for assay. Expected 50-55% w/w.
[00196] Yield of compound K1: 89-92%.
Step 3E: Preparation of Mavorixafor Drug Substance
[00197] Charge Kl, (1.00 eq, 1.00 wt, corrected for HPLC assay) in vessel A followed by nitrogen-purged purified water, (2.0 wt, 2.0 vol) and if necessary, adjust the temperature to 20°C. Charge nitrogen-purged toluene, (12.0 wt, 14.0 vol) to the solution maintaining 20°C. Charge nitrogen-purged n-butanol, (0.8 wt, 1.0 vol) to the solution maintaining 20°C. Heat the biphasic mixture to 30°C. Charge nitrogen-purged 3.0 M aqueous sodium hydroxide solution (6.2 eq, 5.9 vol) maintaining 30°C. Check the pH (expected 12 to 13). Adjust the pH of the aqueous layer to pH 10.0 with nitrogen-purged 0.3 M sulfuric acid solution (expected up to 2.5 vol) maintaining 30°C. Stir the mixture at 30°C for 45 min..
[00198] Measure the pH to confirm the value is pH 10.0.
[00199] Allow the layers to settle at 30°C for 30 min. and separate the layers retaining the organic phase in the vessel, and discharge the aqueous layer into a separate container (container C).
[00200] Charge pre-mixed toluene, (4.1 wt, 4.7 vol) and n-butanol, (0.24 wt, 0.3 vol) to a separate vessel; heat the contents to 30°C and charge the aqueous layer from container C. As required adjust the temperature to 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste and combine the organic phase to the organic phase in vessel A.
[00201] Charge nitrogen-purged purified water, (2.0 wt, 2.0 vol) to the organic layer maintaining the temperature at 30°C and stir for 5 to 10 min. at 30°C. Allow the phases to separate for 10 to 15 min. at 30°C. Discharge the aqueous phase to waste retaining the organic phase in the vessel. Heat the retained organic solution to 40°C. Concentrate the resulting organic phase to 7.0 vol by vacuum distillation at 40°C.
[00202] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C. This step is repeated additional one time as described below.
[00203] Charge nitrogen -purged toluene, (13.0 wt, 15.0 vol) to the mixture and concentrate the solution 7.0 vol by vacuum distillation at 40°C.
[00204] Charge nitrogen-purged toluene, (7.0 wt, 8.0 vol) to the mixture at 40°C, heat to 55°C and clarify the hot reaction mixture under nitrogen via a 1 pm filter.
[00205] Charge clarified nitrogen-purged toluene, (1.7 wt, 2.0 vol) to the mixture as a line and vessel rinse at 40°C. Concentrate the solution to 7.0 vol by vacuum distillation at 40°C. At the end of the distillation the product is expected to have precipitated. Heat the mixture to 63°C.
[00206] Adjust the temperature to 60.5°C. This batch will be referred to as the main batch.
[00207] Load seed material, (0.02 wt) to a new clean container. Charge clarified nitrogen-purged toluene, (0.09 wt, 0.10 vol) to this seed material and gently shake.
[00208] Seed the main batch with the slurry maintaining the temperature at 60.5 ± 2°C. Stir the reaction at the 60.5± 2°C for 1 hour.
[00209] Cool to 40°C for 2.5 h. Stir the reaction at 40°C for 1 hour.
[00210] Cool to 30°C over 2 h.. Stir the reaction at 30°C for 1 h.
[00211] Cool to 25°C 50 min. Stir the reaction at 25°C over 2 hours.
[00212] Cool to 2°C over 4 h. Stir the mixture for 12 hours at 2°C.
[00213] Filter the mixture at 2°C over 1 to 2 pm cloth. Wash the filter cake with clarified nitrogen-purged toluene, (2.0 vol, 1.7 wt) at 2°C. Dry the filter cake under vacuum and a flow of nitrogen for 1.5 h.
[00214] Dry the solid at 40°C under vacuum and a flow of nitrogen until drying specification is achieved.
[00215] Yield of the final compound mavorixafor: 72%.
[00216] When toluene is used as the recrystallization solvent, optionally with a dissolution aid such butanol or methanol, for maxorixa for recrystallization, advantages were found compared to using dichloromethane and isopropyl acetate. We have found that these solvents do not react with the API, and accordingly we believe that this change has caused the significant reduction of impurities A (imine), B (N-formyl) and C (acetamide) that we have observed.
[00217] In some embodiments, the mavorixafor composition included 7000, 6000, 5000, 4500, 4450, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1400, 1400, 1400 gold 50 ppm of toluene or less. In some embodiments, the mavorixafor composition comprises a detectable amount of toluene. In some embodiments, the mavorixafor composition comprises from a detectable amount of toluene to 1350 ppm of toluene.
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Mavorixafor (AMD-070) is a potent, selective and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively.
125I-SDF-CXCR413 nM (IC50)HIV-1 (NL4.3 strain)1 nM (IC50, in MT-4 cells)HIV-1 (NL4.3 strain)9 nM (IC50, in PBMCs)HIV-1 (NL4.3 strain)3 nM (IC90, in MT-4 cells)HIV-1 (NL4.3 strain)26 nM (IC90, in PBMCs)
In Vitro
Mavorixafor (AMD-070) is a potent and orally available CXCR4 antagonist, with an IC50 value of 13 nM against CXCR4 125I-SDF binding, and also inhibits the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 1 and 9 nM, respectively. Mavorixafor (AMD-070) shows no effect on other chemokine receptors (CCR1, CCR2b, CCR4, CCR5, CXCR1, and CXCR2)[1]. Mavorixafor (AMD-070) (6.6 µM) significantly suppresses the anchorage-dependent growth, the migration and matrigel invasion of the B88-SDF-1 cells[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Mavorixafor (AMD-070) (2 mg/kg, p.o.) significantly reduces the number of metastatic lung nodules in mice, and lowers the expression of human Alu DNA in mice, without body weight loss[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Arimoclomol maleate is in a phase III clinical trials by Orphazyme for the treatment of Niemann-Pick disease type C (NP-C). It is also in phase II clinical studies for the treatment of amyotrophic lateral sclerosis (ALS).
Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[1] The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[2][3]
Fig. 1 Structures of (±)-bimoclomol (1) and (R)-(+)-arimoclomol (2).
The present disclosure provides an optimized four-step process for preparing an ultra-pure composition comprising arimoclomol citrate, i.e. N-{[(2R)-2-hydroxy-3-piperidin-l-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate. The optimized process comprises a plurality of optimized sub-steps, each contributing to an overall improved process, providing the ultra-pure composition comprising arimoclomol citrate. The ultra-pure composition comprising arimoclomol citrate meets the medicines agencies’ high regulatory requirements. An overview of the four-steps process is outlined below:
Step 1: Overview of process for preparing ORZY-01
Step 2: Overview of process for preparing ORZY-03
Step 4: Overview of process for preparing BRX-345 (ORZY-05)
The previously reported two-step synthesis of ORZY-01 as shown below includes a 2 hour reflux in step 1A, followed by purification of intermediate compound (V) to increase the batch quality.
(R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide1 – (R)-(+)-Arimoclomol – 2 A solution of (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carbamimidoyl)pyridine-1-oxide 12 (205 mg, 0.70 mmol) in conc. hydrochloric acid (1.1 mL, 13.9 mmol) and water (3 mL) was cooled to -5 °C for 15 minutes. Sodium nitrite (63 mg, 0.91 mmol) in water (0.5 mL) was then added dropwise to the reaction mixture and the reaction was stirred at -5 °C for 2.5 hours. The reaction mixture was made alkaline with NaOH (7 M, 3 mL). An additional 10 mL of water was added followed by DCM (30 mL) containing EtOAc (5 mL) and the organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on Biotage Isolera using Biotage SNAP 10 g Si cartridge eluting with gradient elution 0-30% MeOH:DCM both containing 0.1% Et3N to afford the title compound (160 mg, 73% yield) as a colourless semi-solid. Analytical data was consistent with literature values. See ESI section SFC traces for specific enantiomeric ratios of 2 synthesised under the various methodologies quoted in the text. Optical rotation was not determined as it was determined in the ultimate product of this 2·citrate and comparative run times on SFC. 1H NMR (600 MHz, CDCl3) δ: 8.63 (t, J = 1.4 Hz, 1H), 8.16 (ddd, J = 6.4, 1.6, 0.9 Hz, 1H), 7.66 – 7.62 (m, 1H), 7.25 (dd, J = 8.0, 6.6 Hz, 1H), 4.26 (qd, J = 11.3, 5.2 Hz, 2H), 4.07 (dd, J = 9.2, 4.7 Hz, 1H), 2.62 (s, 2H), 2.47 – 2.31 (m, 4H), 1.65 – 1.51 (m, 4H), 1.42 (s, 2H); 13C NMR (151 MHz, CDCl3) δ: 140.3, 137.7, 133.1, 132.5, 125.7, 123.9, 78.7, 64.9, 60.9, 54.8, 25.8, 24.0.
(R)-(+)- Arimoclomol citrate – 2·citrate (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide (159 mg, 0.51 mmol) was dissolved in acetone (3 mL) and citric acid (97 mg, 0.51 mmol) was added. The reaction mixture was left to stir at room temperature for 18 hours. After this time the mixture was sonicated and the precipitate was filtered, rinsed with cold acetone (1 mL) and dried under vacuum to afford the title compound (165 mg, 64% yield) as a white amorphous solid. Analytical data was consistent with literature values. m.p. 161-162 °C, Acetone (lit. 163-165 °C, EtOH); [α]D 20 +8.0 (c=1, H2O); IR νmax (neat): 3423, 3228, 2949, 2868, 1722, 1589, 1483, 1433, 1307, 1128, 972, 829 cm-1; 1H NMR (600 MHz, d6-DMSO) δ: 8.54 (t, J = 1.5 Hz, 1H), 8.39 – 8.35 (m, 1H), 7.72 – 7.68 (m, 1H), 7.55 (dd, J = 8.0, 6.5 Hz, 1H), 4.28 (ddd, J = 17.6, 13.3, 7.4 Hz, 3H), 3.35 (br. s, 2H), 3.13 – 2.74 (m, 6H), 2.59 (d, J = 15.2 Hz, 2H), 2.56 – 2.51 (m, 2H), 1.77 – 1.61 (m, 4H), 1.48 (s, 2H); 13C NMR (151 MHz, d6-DMSO) δ: 176.6, 171.3, 140.5, 136.4, 132.7, 131.5, 126.8, 123.3, 77.8, 71.4, 63.8, 58.7, 53.1, 44.0, 30.7, 23.0, 21.9; HRMS (m/z TOF MS ES+) for C14H20ClN3O3 [M+H]+ calc. 314.1271, observed 314.1263; SFC er purity R:S >99:1
Procedure for the conversion of (R)-(+)-Bimoclomol 1 into (R)-(+)-Arimoclomol 2 To a solution of (R)-(+)-bimoclomol (61 mg, 0.21 mmol) in acetone (2 mL) was added benzenesulfonic acid (33 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. Separately to a suspension of hydrogen peroxide-urea adduct (39 mg, 0.41 mmol) in acetonitrile (6 mL) at -5°C (ice-salt bath) was added trifluoroacetic anhydride (58 μL, 0.41 mmol) dropwise. A suspension of (R)-(+)-bimoclomol, 1, benzenesulfonic acid salt, as made above, in acetonitrile (3 mL) was then added dropwise to this solution. The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. Aqueous Na2S2O5 solution (0.5 M, 1 mL) was added and the reaction mixture stirred for 1 hour. The reaction mixture was made alkaline with NaOH (7 M) and extracted with DCM (2 x 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on a Biotage Isolera using Biotage SNAP 10g Si cartridge eluting with gradient elution 0-35% MeOH in DCM to afford the title compound (35 mg, 55% yield) as a colourless semi-solid. Analytical data of the products was consistent with literature and/or previous samples synthesised above.
Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.
Arimoclomol has been shown to extend life in an animal model of ALS[11] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[12]
Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy’s Disease).[13]
Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[14][15] and diabetic complications such as retinopathy, neuropathy and nephropathy. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003.
^ Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (April 2004). “Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice”. Nat. Med. 10 (4): 402–5. doi:10.1038/nm1021. PMID15034571. S2CID2311751.
^ Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G (December 2003). “The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury”. Exp. Neurol. 184 (2): 636–47. doi:10.1016/S0014-4886(03)00343-1. PMID14769355. S2CID5316222.
^ Rakonczay Z, Iványi B, Varga I, et al. (June 2002). “Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats”. Free Radic. Biol. Med. 32 (12): 1283–92. doi:10.1016/S0891-5849(02)00833-X. PMID12057766.
^ Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L (July 2002). “Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats”. Exp. Neurol. 176 (1): 87–97. doi:10.1006/exnr.2002.7945. PMID12093085. S2CID16071543.
N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-2-propenamideThe epidermal growth factor receptor (EGFR, Herl, ErbB l) is a principal member of the ErbB family of four structurally-related cell surface receptors with the other members being Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its primary cellular functions though its intrinsic catalytic tyrosine protein kinase activity. The receptor is activated by binding with growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-a), which transform the catalytically inactive EGFR monomer into catalytically active homo- and hetero- dimers. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to the autophosphorylation of specific EGFR tyrosine residues and elicits the downstream activation of signaling proteins. Subsequently, the signaling proteins initiate multiple signal transduction cascades (MAPK, Akt and JNK), which ultimately mediate the essential biological processes of cell growth, proliferation, motility and survival.EGFR is found at abnormally high levels on the surface of many types of cancer cells and increased levels of EGFR have been associated with advanced disease, cancer spread and poor clinical prognosis. Mutations in EGFR can lead to receptor overexpression, perpetual activation or sustained hyperactivity and result in uncontrolled cell growth, i.e. cancer. Consequently, EGFR mutations have been identified in several types of malignant tumors, including metastatic lung, head and neck, colorectal and pancreatic cancers. In lung cancer, mutations mainly occur in exons 18 to 21, which encode the adenosine triphosphate (ATP)-binding pocket of the kinase domain. The most clinically relevant drug- sensitive EGFR mutations are deletions in exon 19 that eliminate a common amino acid motif (LREA) and point mutations in exon 21, which lead to a substitution of arginine for leucine at position 858 (L858R). Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations have perpetual tyrosine kinase activity and as a result they are oncogenic. Biochemical studies have demonstrated that these mutated EGFRs bind preferentially to tyrosine kinase inhibitor drugs such as erlotinib and gefitinib over adenosine triphosphate (ATP).Erlotinib and gefitinib are oral EGFR tyrosine kinase inhibitors that are first line monotherapies for non-small cell lung cancer (NSCLC) patients having activating mutations in EGFR. Around 70% of these patients respond initially, but unfortunately they develop resistance with a median time to progression of 10-16 months. In at least 50% of these initially responsive patients, disease progression is associated with the development of a secondary mutation, T790M in exon 20 of EGFR (referred to as the gatekeeper mutation). The additional T790M mutation increases the affinity of the EGFR kinase domain for ATP, thereby reducing the inhibitory activity of ATP- competitive inhibitors like gefitinib and erlotinib.Recently, irreversible EGFR tyrosine kinase inhibitors have been developed that effectively inhibit the kinase domain of the T790M double mutant and therefore overcome the resistance observed with reversible inhibitors in the clinic. These inhibitors possess reactive electrophilic functional groups that react with the nucleophilic thiol of an active-site cysteine. Highly selective irreversible inhibitors can be achieved by exploiting the inherent non-covalent selectivity of a given scaffold along with the location of a particular cysteine residue within the ATP binding site. The acrylamide moieties of these inhibitors both undergo a Michael reaction with Cys797 in the ATP binding site of EGFRT790M to form a covalent bond. This covalent mechanism is thought to overcome the increase in ATP affinity of the T790M EGRF double mutant and give rise to effective inhibition. However, these inhibitors may cause various undesired toxicities. Therefore, development of new inhibitors for treatment of various EGFR-related cancers is still in high demand. PatentCN201580067776) N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound of formula I) can be prepared by the following synthetic route:
N-(4-(2-(Dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH- indol-3-yl)pyrimidin-2-amine (Scheme 1, Intermediate B). To a slurry of NaH (30 mmol, 60% oil dispersion prewashed with hexanes) and 50 mL of 1,4-dioxane was added 2-dimethylaminoethanol (27 mmol, 2.7 mL) dropwise with stirring under N2. After stirring for 1 h, a slurry of A (5.4 mmol) in 50 mL of 1,4-dioxane was added portion-wise over 15 min under a stream of N2. The resulting mixture was stirred overnight, then poured into water and the solid was collected, rinsed with water, and dried under vacuum to yield 2.6 g of product as a yellow solid. A purified sample was obtained from chromatography (silica gel; CH2C12-CH30H gradient). 1H NMR (300 MHz, DMSO) δ 2.26 (s, 6H), 2.70 (t, 2H, J = 6 Hz), 3.87 (s, 3H), 4.01 (s, 3H), 4.32 (t, 2H, J = 6 Hz), 7.00-7.53 (m, 5H), 8.18-8.78 (m, 5H); C24H26N604 m/z MH+ 463.4-(2-(Dimethylamino)ethoxy)-6-methoxy-Nl-(4-(l-methyl-lH-indol-3- yl)pyrimidin-2-yl)benzene-l,3-diamine (Scheme 1, Intermediate C). A suspension of 2.6 g of Intermediate B, 1.6 g of Fe°, 30 mL of ethanol, 15 mL of water, and 20 mL of cone. HC1 was heated to 78 °C for 3 h. The solution was cooled to room temperature, adjusted to pH 10 with 10% NaOH (aq) and diluted with CH2C12. The mixture was filtered through Dicalite, and the filtrate layers were separated. The aqueous phase was extracted with CH2C12 twice, and the combined organic extracts were dried over Na2S04 and concentrated. Column chromatography (silica gel, CH2Cl2-MeOH gradient) afforded 1.2 g of Intermediate C as a solid. C24H28N602 m/z MH+ 433.N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide (1). To a solution of Intermediate C (2.8 mmol) in 50 mL of THF and 10 mL of water was added 3-chloropropionychloride (2.8 mmol) dropwise with stirring. After 5 h of stirring, NaOH (28 mmol) was added and the mixture was heated at 65°C for 18 h. After cooling to room temperature, THF was partially removed under reduced pressure, and the mixture was extracted with CH2C12, dried over Na2S04, and concentrated. Chromatography of the crude product (silica gel, CH2Cl2-MeOH) afforded 0.583 g of Example 1 as a beige solid. 1H NMR (300 MHz, DMSO) δ 2.28 (s, 6H), 2.50-2.60 (m, 2H), 3.86 (s, 3H), 3.90 (s, 3H), 4.19 (t, 2H, = 5.5 Hz), 5.73-5.77 (m, IH), 6.21-6.27 (m, IH), 6.44-6.50 (m, IH), 6.95 (s, IH), 7.11-7.53 (overlapping m, 3H), 7.90 (s, IH), 8.27-8.30 (overlapping m, 3H), 8.55 (s, IH), 8.84 (s, IH), 9.84 (s, IH) ppm; C27H30N6O3 m/z MH+ 487
PATENT WO2021115425
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021115425&tab=FULLTEXT&_cid=P20-KQN9F3-73566-1Epidermal growth factor receptors (EGFR, Her1, ErbB1) are the main members of the ErbB family of four structurally related cell surface receptors, and the other members are Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its main cellular functions through its inherent catalytic tyrosine protein kinase activity. The receptor is activated by binding to growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). The catalytically inactive EGFR monomer is transformed into a catalytically active homopolymer and Heterodimer. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to autophosphorylation of specific EGFR tyrosine residues and elicits downstream activation of signaling proteins. Subsequently, the signal protein initiates multiple signal transduction cascades (MAPK, Akt, and JNK), which ultimately regulate the basic biological processes of cell growth, proliferation, motility, and survival.
EGFR has been found to have abnormally high levels on the surface of many types of cancer cells, and elevated EGFR levels have been associated with advanced disease, cancer spread, and poor clinical prognosis. Mutations in EGFR can lead to overexpression of the receptor, permanent activation or continuous hyperactivity, leading to uncontrolled cell growth, which is cancer. Therefore, EGFR mutations have been identified in several types of malignant tumors, including metastatic lung cancer, head and neck cancer, colorectal cancer, and pancreatic cancer. In brain cancer, mutations mainly occur in exons 18-21, which encode the adenosine triphosphate (ATP)-binding pocket of the kinase domain. The most clinically relevant drug-sensitive EGFR mutations are deletions in exon 19 and point mutations in exon 21. The former eliminates a common amino acid motif (LREA), and the latter results in position 858 (L858R). The arginine is replaced by leucine. Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations have permanent tyrosine kinase activity, so they are carcinogenic. In at least 50% of patients who initially responded to current therapies, the progression of the disease is related to the development of a secondary mutation, T790M (also known as the goalkeeper mutation) in exon 20 of EGFR. BPI-7711 is a third-generation EGFR-TKI compound developed by Beida Pharmaceuticals and disclosed in International Patent No. WO2017/218892. It is the N-(2-(2-(dimethylamino) )Ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonic acid salt:
Need to develop improved properties containing N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indole-3 -Yl)pyrimidin-2-yl)amino)phenyl)acrylamide pharmaceutically acceptable salt, in particular the pharmaceutical composition of BPI-7711 and its use, and the preparation of said pharmaceutical composition suitable for large-scale production method.
PATENT
WO2021061695 , for another filing, assigned to Beta Pharma, claiming a combination of an EGFR inhibitor (eg BPI-7711) and a CDK4/6 inhibitor, useful for treating cancer.
Novel crystalline polymorphic form A of rezivertinib – presumed to be BPI-7711 – useful for treating diseases mediated by EGFR mutations eg lung cancer, preferably non-small cell lung cancer (NSCLC).Epidermal growth factor receptor (EGFR) is a type of transmembrane receptor tyrosine kinase in the human body. The activation (ie phosphorylation) of this kinase is of great significance to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. EGFR kinase is involved in the disease process of most cancers, and these receptors are overexpressed in many major human tumors. Overexpression, mutations, or high expression of ligands associated with these family members can lead to some tumor diseases, such as non-small cell lung cancer, colorectal cancer, breast cancer, head and neck cancer, cervical cancer, bladder cancer, and thyroid. Cancer, stomach cancer, kidney cancer, etc. In recent years, epidermal growth factor receptor tyrosine kinase has become one of the most attractive targets in current anti-tumor drug research. In 2003, the US FDA approved the first epidermal growth receptor tyrosine kinase inhibitor (EGFR-TKI) drug (gefitinib) for the treatment of advanced non-small cell lung cancer (NSCLC). Development of a generation of EGFR inhibitors. Numerous clinical trials have confirmed that for patients with EGFR-positive non-small cell lung cancer, the therapeutic effect of molecular targeted drugs is significantly better than traditional chemotherapy. Although the first-generation EGFR-inhibiting targeted drugs responded well to the initial treatment of many non-small cell lung cancer (NSCLC) patients, most patients will eventually develop disease progression due to drug resistance (such as EGFR secondary T790M mutation). The emergence of drug resistance is caused by various mechanisms based on the mutations in the original EGFR pathway activity. In the drug resistance research on the first generation of EGFR inhibitors, the research frontier is the irreversible third generation EFGR inhibitor. But so far, the third-generation EGFR inhibitors worldwide, in addition to AstraZeneca O’Higgins imatinib developed, there is no other effective against T790M resistance mutations in patients with drug approved for clinical use; Several drug candidates for the T790M mutation are in clinical development. The chemical structure of this third-generation EGFR inhibitor is completely different from that of the first-generation. The main difference from the first-generation EGFR inhibitors is that they both use a highly selective core structure to replace the low-selective aminoquinoline core structure of the first and second-generation EGFR-TKIs. Compared with wild-type EGFR, these third-generation compounds are highly specific and selective for the T790M mutation after EGFR positive resistance. Chinese Patent Application No. CN201580067776.8 discloses a compound of the following formula I, which also belongs to the third-generation EGFR-TKI class of small molecule targeted drugs. The compound has a high inhibitory effect on non-small cell lung cancer (NSCLC) cells with single-activity mutation and T790M double-mutant EGFR, and its effective inhibitory concentration is significantly lower than the concentration required to inhibit the activity of wild-type EGFR tyrosine kinase. It has good properties, low side effects and good safety.
Chinese Patent Application No. CN201780050034.3 also discloses various salts and corresponding crystal forms of the compound of the above formula I. Example 2 discloses two crystal forms of the methanesulfonate of the compound of formula I, 2A and 2B, respectively.In the following examples, the “room temperature” can be 15-25°C.[0041](1) N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine -2-yl)amino)phenyl)acrylamide (compound of formula I)[0042]
[0043]Known (for example, see CN201580067776.8) N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound of formula I) can be prepared by the following synthetic route:[0044]
[0045]Step 1-Preparation of Intermediate J:[0046]
[0047]Preparation: In a 10L reaction flask, add 6L of anhydrous tetrahydrofuran solvent, protected by nitrogen, and cool to 0°C. While stirring, slowly add 101 g of sodium hydride (101 g, 2.52 mol), and the internal temperature does not exceed 10° C., and add 234 g of dimethylaminoethanol (234 g, 2.62 mol). After the addition, the temperature is adjusted to room temperature to prepare a sodium alkoxide solution.[0048]In a 30L reaction flask, add N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine ( Starting material B) (430g, 1.10mol), then add 9L of tetrahydrofuran, start stirring, dissolve it, control the temperature at 10±10°C, slowly add the prepared sodium alkoxide solution dropwise. Control the temperature at 10±10℃ and keep it for 5.0h. When the raw material content is ≤0.5%, the reaction ends. Control the temperature at 10±10°C, slowly add 3% hydrochloric acid solution dropwise, adjust the pH of the solution to 6-7, stir for 1.5h and then stand for stratification, separate the organic phase, and concentrate to 15-20L. After cooling to 20±5°C, 4.3 kg of water was slowly added dropwise, filtered, and dried to obtain 497 g of yellow powder intermediate J with a yield of 98.0% and an HPLC purity of 99.3%. MS m/z: 463.2 [M+1].[0049]Nuclear magnetic data: 1 HNMR (d 6 -DMSO): δ ppm: 8.78 (s, 1H); 8.42-8.28 (m, 3H); 8.16 (s, 1H); 7.53 (d, 1H, J = 8.28); 7.29- 7.20 (m, 2H); 7.13-7.07 (m, 1H); 7.01 (s, 1H); 4.33 (t, 2H, J = 5.65); 4.02 (s, 3H); 3.88 (s, 3H); 2.71 ( t, 2H, J = 5.77); 2.27 (s, 6H).[0050]Step 2-Preparation of Intermediate K:[0051]
[0052]Preparation: Add 5L of tetrahydrofuran and Intermediate J (350g, 108mmol) to a 10L hydrogenation reactor, add 17.5g of wet palladium charcoal, replace the hydrogenation reactor with hydrogen, adjust the pressure value to 0.2MPa, control the temperature at 25°C, and keep the temperature for reaction. At 9h, HPLC monitors the progress of the reaction, and stops the reaction when the substrate is ≤0.5%. Filter, concentrate the filtrate under reduced pressure until the solvent volume is about 2L, adjust the internal temperature to room temperature, slowly add 4L n-heptane dropwise within 4-7 hours, filter and dry the solid under reduced pressure to obtain 285g of white powder intermediate K The yield was 86%, and the HPLC purity was 99.60%. MS m/z: 433.3 [M+1].
Add 250 mL of anhydrous tetrahydrofuran solvent and Intermediate K (14 g, 32 mmol) to the reaction flask and stir, cool to 0-5° C., add 10% hydrochloric acid (12 ml), and stir for 20 minutes. At 0-5°C, slowly drop 3-chloropropionyl chloride (5.6 g, 45 mmol) into the reaction flask. Stir for 3 hours, after sampling test (K/(U+K)≤0.5%) is qualified, add 36% potassium hydroxide aqueous solution (75ml, 480mmol), heat to 23-25°C, and stir for 12 hours. Raise the temperature to 50-60°C and stir for 4 hours. After the sampling test (U/(U+L)≤0.1%) is qualified, stand still for liquid separation. Separate the organic phase, wash with 10% brine three times, dry, filter, and concentrate the organic phase to 150 ml. The temperature was raised to 40° C., 150 ml of n-heptane was slowly added dropwise, and the temperature was lowered to room temperature to precipitate crystals. Filtered and dried to obtain 10.71 g of light brown solid (compound of formula I), yield 68%, HPLC purity: 99.8% (all single impurities do not exceed 0.15%). MS m/z: 487.3 [M+1].[0057]Nuclear magnetic data (Figure 1): 1 HNMR (d 6 -DMSO): δppm: 9.84 (s, 1H), 8.90 ~ 8.82 (m, 1H), 8.32-8.25 (m, 2H), 7.89 (s, 1H) ,7.51(d,1H,J＝8.25), 7.27～7.10(m,1H), 6.94(s,1H), 6.49(dd,1H,J＝16.88,10.13), 6.25(dd,1H,J＝16.95 ,1.81),5.80～5.75(m,1H),4.19(t,2H,J＝5.57),3.88(d,6H,J＝14.63,6H),3.34(s,3H),2.58(d,2H, J=5.5), 2.28 (s, 6H).
(2) N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine -2-yl)amino)phenyl)acrylamide methanesulfonate (Form A) preparation Example 1
The compound of formula I (3 g, 6.1 mmol) was dissolved in 24 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 65° C., and the mixture was stirred and dissolved. Add an equivalent amount of methanesulfonic acid (0.59 g, 6.1 mmol) to the system. The temperature was lowered to 50°C, and 12ml of isopropyl acetate IPAc was slowly added. Stir at 50°C for 1 hour, then lower the temperature to 15°C. 21ml IPAc was added in 4 hours. The solution was stirred and crystallized at 15°C, filtered under reduced pressure, the filter cake was washed with isopropyl acetate, and washed with acetone to reduce the residual DMSO solvent. Blow drying at 50°C (or vacuum drying at 50°C) to obtain 3.16 g of a pale yellow solid (crystal form A). HPLC purity is 100%, yield is 88%, DMSO: <100ppm; IPAc: <100ppm. MS m/z: 487.2 [M+1-MsOH]. Melting point: 242-244°C. Nuclear magnetic data (figure 2): 1 HNMR(d 6 -DMSO): δppm: 9.57(brs,1H), 9.40(s,1H), 8.71(s,1H), 8.48(s,1H), 8.32(d ,1H,J=7.9),8.29(d,1H,J=5.3),7.96(s,1H),7.51(d,1H,J=8.2),7.23(ddd,1H,J=7.9,7.1,0.8 ), 7.19 (d, 1H, J = 5.4), 7.15 (ddd, 1H, J = 7.8, 7.3, 0.5), 6.94 (s, 1H), 6.67 (dd, 1H, J = 16.9, 10.2), 6.27 ( dd, 1H, J = 16.9, 1.8), 5.57 (dd, 1H, J = 16.9, 1.7), 4.44 (t, 2H, J = 4.6), 3.89 (s, 3H), 3.88 (s, 3H), 3.58 (t, 2H, J=4.6), 2.93 (s, 6H), 2.39 (s, 3H). After testing, the powder X-ray diffraction pattern of crystal form A obtained in this example has diffraction angle 2θ values of 11.06±0.2°, 12.57±0.2°, 13.74±0.2°, 14.65±0.2°, 15.48±0.2°, 16.58±0.2°, 17.83±0.2°, 19.20±0.2°, 19.79±0.2°, 20.88±0.2°, 22.05±0.2°, 23.06±0.2°, 24.23±0.2°, 25.10±0.2°, 25.71±0.2°, 26.15±0.2°, 27.37±0.2°, 27.42±0.2° has a characteristic peak; its XRPD spectrum is shown in Figure 3 and the attached table, DSC diagram is shown in Figure 4, TGA diagram is shown in Figure 5, and infrared spectrum IR diagram is shown in Figure 6. Show. Example 2
[0066]The compound of formula I (28.25 g, 58.1 mmol) was dissolved in 224 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 15-35° C., and the mixture was stirred to clear. 0.97 equivalents of methanesulfonic acid (5.4 g, 0.97 mmol) were added to the system in batches. Slowly add 448 ml of methyl isobutyl ketone (MIBK). Stir for 1 hour, then lower the temperature to 10-15°C. The solution was reacted with salt formation at 10-15°C, sampled, and HPLC detected the residue of the compound of formula I in the mother liquor (≤0.4%). After the reaction was completed, vacuum filtration was performed to obtain 32 g of the crude methanesulfonate of the compound of formula I.Add 3g of the crude methanesulfonate of the compound of formula I into 24ml of dimethyl sulfoxide DMSO solvent, stir to clear at 65°C, cool down, slowly add 48ml of methyl isobutyl ketone (MIBK) dropwise, stir and crystallize 6-8 After hours, vacuum filtration, drying at 60° C. (or 60° C. vacuum drying) to obtain the target crystal form A. Melting point: 242-244°C. The XRPD pattern of the crystal form is consistent with Figure 3 (Figure 7), and all characteristic peaks are within the error range.
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Rezivertinib, also known as BPI-7711, is a third-generation epidermal growth factor receptor (EGFR) TKI, developed by Beta Pharm. Rezivertinib selectively targets both EGFR-sensitizing mutations and the T790 M resistance mutation, thereby addressing resistance mechanisms associated with first- and second-generation EGFR-tyrosine kinase inhibitors. In 2024, the NMPA approved Rezivertinib mesylate capsules (trade name: Ruibida) for the treatment of adult patients with locally advanced or metastatic NSCLC who have progressed during or after EGFR-TKI therapy and have confirmed EGFR T790 M mutation-positive status. Rezivertinib exerts its antitumor activity by forming covalent bonds with mutant EGFR, particularly the T790 M mutation, which effectively blocks the downstream signaling pathways responsible for promoting tumor cell proliferation and survival [21]. The mechanism of Rezivertinib effectively inhibits tumor growth in patients harboring T790M-mediated resistance to first- and second-generation EGFR-TKIs. In a Phase IIb clinical trial (NCT03812809), Rezivertinib demonstrated significant clinical efficacy among patients with EGFR T790 M mutation-positive NSCLC who had experienced disease progression following prior EGFR-TKI therapy. The trial reported an ORR of 64.6 % and a median PFS of 12.2 months, highlighting its potent antitumor activity in this specific patient cohort. In terms of safety, Rezivertinib exhibited a favorable tolerability profile [22]. The most frequently observed treatment-related adverse events were rash, diarrhea, and elevated liver enzymes, predominantly of mild to moderate severity (grade 1 or 2). No dose-limiting toxicities were noted, and its safety profile aligned with those of other third-generation EGFR-TKIs. The synthesis of Rezivertinib, illustrated in Scheme 5, initiates with nucleophilic substitution reaction between Rezi-001 and Rezi-002,affording Rezi-003 [23]. Fe-mediated reduction of Rezi-003 yields Rezi-004, followed by amidation with Rezi-005 to deliver Rezivertinib [20] J.J. Cui, E.W. Rogers, Preparation of Fluorodimethyltetrahydroethenopyrazolobenzoxatriazacyclotridecinone Derivatives for Use as Antitumor Agents, 2017. US20180194777A1.
[21] Y. Shi, Y. Zhao, S. Yang, J. Zhou, L. Zhang, G. Chen, J. Fang, B. Zhu, X. Li, Y. Shu, J. Shi, R. Zheng, D. Wang, H. Yu, J. Huang, Z. Zhuang, G. Wu, L. Zhang, Z. Guo, M. Greco, X. Li, Y. Zhang, Safety, efficacy, and pharmacokinetics of rezivertinib (BPI-7711) in patients with advanced NSCLC with EGFR T790M mutation: a phase 1 dose-escalation and dose-expansion study, J. Thorac. Oncol. 17 (2022) 708–717.
1H-1,2,3-Triazolium, 3-(((2S,3S,5R)-2-carboxy-3-methyl-4,4-dioxido-7-oxo-4-thia-1-azabicyclo(3.2.0)hept-3-yl)methyl)-1-methyl-, inner salt
Enmetazobactam
The Board of directors of Orchid Pharma Ltd has announced that the company had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the company is happy to announce that the molecule has cleared the Phase 3 clinical trials.
Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.
As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.
Orchid had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the molecule has cleared the Phase 3 clinical trials.
Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.
As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.
INVENTOR
Senthilkumar U P
ORCHID
Summary of Profile of Dr. U. P. Senthilkumar, R&D Centre, Orchid Pharma Ltd. Dr. U. P. Senthilkumar Ph.D., the principal inventor of novel beta-lactamase inhibitor, OCID5090, is currently serving as the senior vice-president at Orchid’s Research and Development Centre, Chennai. With illustrious credentials — top ranks in B.Sc. and M.Sc. degrees, first rank in the Graduate Aptitude Test in Engineering (GATE), UGC-CSIR Junior Research Fellowship (JRF) and the prestigious Dr. K.S. Krishnan Fellowship from the Department of Atomic Energy (DAE) and publication of M.Sc. project work in the Indian Journal of Chemistry in 1987 — Mr. Senthilkumar chose to pursue his doctoral research in synthetic organic chemistry with his mentor Prof. Ramasubbu Jeyaraman at Bharathidasan University, Tiruchirapalli. His research focus on the conformational preferences of sterically challenged novel N-Nitroso heterocycles and their conformation dependent anti-cancer properties, led to the publication of 9 articles in reputed peer-reviewed international journals – a commendable accomplishment in the 90s. After a brief post-doctoral stint on fluorescent dicyclopentapyridines, Dr. U. P. Senthilkumar joined Torrent Research Centre at Ahmedabad and started his new endeavor of drug discovery on ACE inhibitors. At the process research and development laboratory, he was actively involved in asymmetric and stereo-selective synthesis of Active Pharmaceutical Ingredients (APIs), and exploited the full potential of chiral prep-HPLC to realize the target molecules. After joining Orchid Pharma Ltd., Chennai, Dr. Senthilkumar led the efforts in the development of differentiated and patentable manufacturing processes for APIs related to both non-antibiotics and beta-lactam antibiotics. He played a significant role in successfully implementing the manufacturing processes overcoming several challenging problems. In addition, his scientific insights and breath of understanding on the patent landscape were invaluable and impactful in creating significant value to the organization and growth of the company in realizing the mission to become a leader in the pharmaceutical generic business. One finds more than 100 articles/patents/publications to his credit, which include inventions on new drugs, drug-intermediates, products, processes, new synthetic routes, rearrangements and novel polymorphs. As a Leadership Persona of the IP management team, he had exhibited a thoroughness of the science/invention and meticulously executed the task of prosecution of few hundred patents in many countries from both New Drug Discovery and Process Chemistry space. All the successful effort earned Orchid Pharma Ltd the National Intellectual Property Award from the Department of Industrial Policy and Promotion, Ministry of Commerce and Industry,Government of India. Through his executive and decision-making skills combined with scientific rationale and clarity, Dr. Senthilkumar played significant role in the selection of products and creation of generic product portfolio for Orchid, with unique IP strategies, analysis of patents, patent mapping, designing & developing invalidation/non-infringing positions, and early launch opportunity, including first-to-file (FTF) positioning. His appearance in the US courts, for deposition in couple of patent litigations, and successful accomplishment of the same are testimony to his depth, thoroughness of science and the ability to defend the invention with grit and professionalism. Additionally, his effectual role in the first-to-launch of one of the large volume sterile penicillins with regulatory exclusivity, achieved successfully by overcoming the citizen petition process in the regulatory pathway, is another shining example of his leadership and scientific strength. To support in-house projects as well as multinational pharma majors, Dr. Senthilkumar has taken up CRAMS (Contract Research and Manufacturing Services) and CMC (Chemistry, Manufacturing and Control) for new chemical entities. Besides, he passionately focused on novel beta-lactamase inhibitors and their antibiotic combinations that were envisaged by him to exhibit potent activity against multi-drug resistant bacteria. His dedicated effort brought a novel extended spectrum beta-lactamase inhibitor, OCID5090, which was out-licensed to Allecra Inc. OCID5090/cefepime combination has completed successfully the Phase III clinical trials for treating complicated urinary-track-infections (cUTI), including acute pyelonephritis (AP), and rightfully, OCID5090 has gotten the US FDA fast track designation as a Qualified Infectious Disease product (QIDP) that provides a five-year additional market exclusivity and priority review. His never-ending passion for research is infectious and roped him with academic institutions to explore novel technologies including electron-beam irradiated heterogeneous catalysis. His commendable knowledge on intellectual property is being utilized by the IP Cells of various institutions as well as the Tamil Nadu State Technology Development and Promotion Centre. A sincere student he is, Dr. Senthilkumar is also a founder-member of Prof. Ramasubbu Jeyaraman Science Foundation (RJSF). Since 2011, he has been playing a significant role in rganizing several academic events (seminars, work-shops, invited lectures, state-level proficiency tests, and research-orientation programs) for post-graduate chemistry students to create passion for research. His concern and help for poor and rural students show his human face.
[0051]To a suspension of (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (25 g) in acetone (100 mL) at 25-30° C. was added slowly N,O-bis(silylacetamide) (18.6 g) with stirring. The reaction mixture was stirred at this temperature (25-30° C.) for 15-20 min. To the clear solution obtained, methyl iodide (100 mL) was added over a period of 15 min. and stirred at 25-30 min. for 24 h. The precipitated solid was separated by filtration and washed with acetone (25 mL). Wet weight of the solid obtained was 30 g.
[0052]The above wet solid was stirred with purified water (300 mL) at 10-15° C. for 2.5 h. To the resulted reaction mixture was added sodium thiosulfate (0.1 g) and stirred at 10-15° C. for 10-15 min. To the reaction mixture, dichloromethane (300 mL) was added, stirred and the organic layer separated. The aqueous layer was washed with a solution of Amberlite LA-2 resin (5% solution in dichloromethane twice, followed by dichloromethane twice. To the aqueous solution, activated carbon (1 g) was added, stirred for 15 min, filtered and washed with purified water (25 mL). The solution was filtered and lyophilized to get the title compound in pure form (10 g). 1H NMR (400 MHz, DMSO) δ ppm: 1.39 (s, 3H), 3.14 (dd, J=16.0, 1.3 Hz, 1H), 3.55 (dd, J=16.0, 4.2 Hz, 1H), 3.97 (s, 1H), 4.34 (s, 3H), 5.05 (dd, J=4.2, 1.3 Hz, 1H), 5.29 (d, J=14.7 Hz, 1H), 5.42 (d, J=14.7 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H). Mass m/z: M+1 peak at 315. Alternatively the solution could be subjected to spray-drying to yield the title compound.
Synthesis of (2535.5R)-3-methyl-3-((3-methyl-lH-1.2 -triazol-3-ium-l-yl)methvn-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4),
Compound (4) was prepared according to Scheme 2.
Scheme 2
i) Ν,Ο-bis-trimethylsilylacetamide, CH2CI2; ii) CH3OTf; iii) Na 2-ethylhexanoate
In a round bottom flask under nitrogen flow 100 g of Tazobactam acid (1) and 500 mL of Dichloromethane are loaded. The temperature is adjusted to +30/35°C then 37 g of Ν,Ο-Bis(trimethylsilyl) acetamide are loaded in 15-20 minutes maintaining the temperature to +35/42°C. The mixture is heated to reflux (+40/42°C) for 60 minutes. If the solution is not clear, N,0-Bis(trimethylsilyl) acetamide is loaded in small portions (0,5-1.0 g each) waiting 15 minutes every time till a clear solution containing intermediate (2) is obtained. 0.55 moles of N,0-Bis(trimethylsilyl) acetamide is used, with further 0.1-0.2 equivalents being added if the reaction is not complete.
Then the temperature is cooled down to 0/+5°C and 70 g of Methyl trifluoromethanesulfonate are loaded in 60-90 minutes maintaining the temperature at 0/+5°C. After 30 minutes the reaction is monitored by HPLC to control the disappearance of intermediate (2) and formation of intermediate (3). The reaction is monitored every 30 minutes until completion.
In a round bottom flask, under nitrogen, are loaded 500 mL of Ethanol and 55 g of Sodium 2-Ethylhexanoate and the temperature is adjusted to +20/25°C, then the reaction solution containing intermediate (3) is added in 60-90 minutes maintaining the temperature of +20/25 °C under vigorous stirring. The suspension is stirred for 30 minutes then is filtered and washed with 300 mL of Ethanol followed by 500 mL of Dichloromethane under nitrogen. The crude product (4) is dried under nitrogen flow till constant weight (150 g) is obtained. The crude product compound (4) was isolated as a solid product (HPLC assay = 70%, yield = 80%).
Purification of (2tS’,3^5^)-3-methyl-3-((3-methyl-lH-l,2,3-triazol-3-ium-l-yl)methyl)-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4)
In a round bottom flask 800 mL of Dimethylformamide are loaded, the temperature is adjusted to +20/25°C then crude Compound 4 (150g) obtained above is loaded using 100 mL of Dimethylformamide to facilitate the transfer. The mixture is stirred for 5 minutes and a solution is obtained, then and after a few minutes crystallization takes place. The suspension is stirred for about 3 hours, then is cooled to 0/+5°C and stirred for another 3 hours.
The solid is filtered and washed with 300 mL of Dimethylformamide pre-cooled to 0/+5°C. Compound 4 is then suspended in 700 mL of Ethyl acetate and the temperature is adjusted to +40/45°C. The suspension is stirred for 30 minutes then the solid is filtered and washed with 150 mL of Ethyl acetate pre-heated to +40/45°C. The suspension with
Ethyl acetate is repeated twice. Finally Compound 4 is dried under vacuum at +40°C till constant weight is achieved (66 g, HPLC assay = 99%, yield = 76%).
Compound 4 Sterile filtration and recrystallization Procedure
In a round bottom flask 350 mL of Methanol are loaded, the temperature is adjusted to +30/35°C then 100 g of Compound 4 are loaded and finally the flask is washed with 60 mL of Methanol. After 5-10 minutes a solution is obtained. The solution is diluted with 330 mL of acetone adjusting the temperature to +20/+25°C. The obtained solution is treated with 2,2 g of charcoal for 20 minutes then filtered using a 0.22microM filter and the filter is washed with a mixture of 13 mL of Methanol and 110 mL of Acetone. The temperature of the solution is adjusted to +30/35°C and under vigorous stirring 830 mL of Acetone are loaded in about 15-20 minutes. After stirring for 60 minutes at temperature of +30/35°C 1170 mL of Acetone are loaded in 45-60 minutes. Then the temperature is adjusted to +20/25 °C in about 30-60 minutes and maintained for 30 minutes. The obtained crystalline solid is filtered and washed with 430 mL of Acetone. Finally the product is dried under vacuum at +40°C till constant weight is achieved (83 g of Compound 4) are obtained with an HPLC assay = 98-99%, yield =t 80%).
Mr. Ram Gopal Agarwal
Chairman and Non-Executive Director
Mr. Ram Gopal Agarwal is Founder Chairman of Dhanuka Group.
He is a decisive and action oriented visionary who took over a sick pesticide Company named Northern Mineral Pvt. Ltd. in 1980 and transformed it today into a Rs 1000 Crore organization called Dhanuka Agritech Ltd.
His deep commitment and inspiring leadership in initial turbulent days is an example worth inculcating and his passion to contribute to Indian Agriculture is commendable.
His ability to prioritize and deal effectively with a number of tasks simultaneously reinforced with the skills to make effective decisions, has metamorphosed the business venture into one of the fastest growing Agrochemical Company in India which has thrice been rated as ‘Best under a Billion Company’ by Forbes Magazine.
In order to achieve his aspiration of “Transforming India through Agriculture” he has dedicated himself to bring changes in Agrochemicals Industry and the farming community. His contribution for adopting newer farming techniques at the grass root level, judicious use of agro chemicals in farming and imparting knowledge through his nationwide network of distributors and Dhanuka Doctors in field has resulted in the overall prosperity of farmers.
Mr. Ram Gopal Agarwal has been the past Chairman of CCFI, (Crop Care Federation of India) the apex Chamber of all Indian Agrochemical majors. He is also Chairman of Advisory Committee of AGRO Chemicals Federation of India.
Mr. Ram Gopal Agarwal, Group Chairman, has been bestowed with many Awards for his tremendous contribution in Agro Industry like “Life Time Achievement Award” by Agri Business Summit and Agri Awards 2019, “Distinguished Contribution to Indian Agrochemicals Industry” during India Chem 2016 International Conference organised by FICCI etc.
Mr. Manish Dhanuka
Managing Director
Mr. Manish Dhanuka is the Director of Orchid Pharma Limited; he has the vision to rejuvenate Orchid Pharma Ltd. and take it on a fruitful path. His wide-ranging experience of handling operations, commercial, marketing and finance in the manufacturing industry provides for his analytical and decision-making skills facilitating the restoration of the company to its glorious past and to achieve even greater heights.
He excels in creating economical Pharmaceutical technologies and accelerated evaluation process for improving healthcare. Experience of 25 years in research, evaluation, and teaching in the pharmaceutical industry equips him with the expertise in innovative pharmaceutical technologies…
He holds a B.Tech in Chemical Engineering from IIT, New Delhi, and M.S in Chemical Engineering from the University of Akron, USA.
Before establishing Dhanuka Laboratories Ltd. in 1993, he began his career at Ranbaxy Labs Ltd. in New Delhi and worked there for 5 years. His vision and strategy to grow the Pharmaceutical industry in the Indian sub-continent, have helped the Dhanuka Group of companies enhance its Bulk Drugs manufacturing arm exponentially. He spearheaded the acquisition of Synmedic Laboratories in the year 2013 which is involved in pharmaceutical formulations. This entrepreneurial vigor enabled him to take over the operations of Orchid Pharma Ltd. in March 2020.
Outside of work, he likes to travel for wildlife adventures.
Mr. Mridul Dhanuka
Whole-Time Director
He is associated with Dhanuka Group Ltd. since 2005. He was responsible in successfully realigning the entire supply chain vertical from procurement to sales. At Orchid, he hopes to replicate the Group’s success and put another feather in Dhanuka cap.
CLIP
Orchid Chemicals & Pharmaceuticals, or Orchid Pharma since its recent name change in 2015, was established in 1992 in Chennai to manufacture antibiotics, and entered drug discovery in 2001 with projects in the areas of anti-infectives and treatments for pain.32, 197 In 2002, the company engaged in a joint venture to develop US-based firm Bexel Biotechnology’s BLX-1002, an oral, non-PPAR AMPK activator for the treatment of diabetes,198 later repositioned for NASH (2012), but no further progress has been reported recently.197 In 2008, Orchid invested in Diakron Pharmaceuticals, a US-based company that had an exclusive license to MSD′s investigational oral anticoagulant drug, a direct thrombin inhibitor later known as DPOC-4088 (or DP-4088),199 which reached Phase 1 clinical studies in Europe in 2012 (Supporting Information Table 6b, entries 5–6).200 The company’s own internal discovery efforts had a broad therapeutic focus, covering infectious diseases, inflammation, pain, oncology, metabolic disorders, and CNS diseases. OCID-2987,197, 201 a PDE4 inhibitor for the treatment of inflammatory disorders such as COPD, completed successfully Phase 1 studies in Europe in 2012, and OCID-4681 29,202, 203 a histone deacetylase (HDAC) inhibitor for cancer had received approval in 2011 for Phase 1 studies for solid tumors in India, but we assume both have been abandoned, as cancer and inflammation are not mentioned in the company’s latest annual reports.197 Two additional compounds were abandoned at the preclinical stage: OCID-5005, a STAT-3/IL-6 inhibitor for oncology, and a unnamed Th1/Th2 cytokine synthesis inhibitor for inflammation (Supporting Information Table 2a, entries 134–138).197 Financial issues led Orchid, as of 2009, to sell parts of its business to Hospira (now part of Pfizer). As a consequence, no progress has been reported on its discovery programs since 2010, and no further NCE patent application has been published since 2012. However, in 2013 Orchid licensed its broad-spectrum β-lactamase inhibitor OCID-5090, a zwitterionic N-methylated tazobactam derivative, to the German Allecra Therapeutics for a 20 % stake in the company, for use in combination with antibiotics to treat multidrug-resistant gram negative bacteria.204–207 Allecra’s lead compound AAI202, a combination of cefepime and AAI101/OCID-5090 30, is currently in Phase 1 studies in France.208, 209
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Dr. B. Gopalan
Scientific Advisor
Dr. Gopalan is a synthetic organic chemist with extensive experience in the field of drug discovery and development. After completing his PhD from University of Madras, he went to Harvard University where he worked with the Nobel Laureate, Prof. E.J. Corey, as a post-doctoral fellow. Subsequent to this he joined Syntex Research Inc. in California to work on the synthesis of unnatural amino acids. After a year, he moved to Bristol-Meyers Squibb, Princeton, New Jersey, to contribute to their program on novel antibiotics and ACE inhibitors. Dr. Gopalan then moved back to India in 1982 to join the Drug Discovery Research Division of Boots Pharmaceuticals (India) Ltd. in Mumbai. Over his decade long stint there he contributed extensively to their drug discovery program, and one of the product candidates that he developed went up to Phase-2 clinical trials in both USA and UK. He then moved to Sun Pharma Advanced Research Center as Vice-President and, after a year, took up the position as General Manager at Glaxo (India) Ltd. in 1993. Here, he worked in a broad range of areas that included process development, synthesis of impurities of APIs, and generation of small molecule libraries to support drug discovery efforts to Glaxo, France. In 1999 he took over as Senior Vice President of the Drug Discovery Chemistry Division of Glenmark Pharmaceuticals Ltd. where he was involved in the design and development of inhibitors for PDE IV and DPP IV, as well as agonists for CB2. After a 6-year stint at Glenmark, Dr. Gopalan joined Matrix Laboratories Ltd. as CSO and Executive Vice-President, where he successfully helped to develop novel and selective inhibitors for PDE4 and DPP4. Five years later he became CSO and Executive Director of Orchid Pharmaceuticals Ltd in Chennai. He served in this capacity for close to a decade, contributing extensively to drug design and development in the broad segments of oncology, anti-infectives, and anti-inflammatory & metabolic disorders. Since 2017, Dr. Gopalan has been associated with CSIR-Indian Institute of Chemical Technology as a Scientific Advisor.
Dr. Gopalan’s illustrious career is endowed with numerous successes. He has been inventor, or co-inventor, of several drugs or candidate drugs. These include the novel potassium channel blockers BTS-67582 (BTI-2927) for tpe-2 diabetes, the PDE IV inhibitors Oglemilast (COPD) and Revamilast (RA); DPP IV inhibitor Melogliptin; a selective Cannaboid-2 agonist Tedalinib (Neuropathic pain); a Beta lactamase inhibitor Enmetazobactum (OCID-5090); OCID-18034 (an inhibitor of KPC enzyme); and OCID-18174 (an inhibitor of P. arugenosa). Most of these compounds were out-licensed to major international pharmaceutical companies such as Forest Laboratories Inc. USA, Teijin of Japan, Merck KGaA of Germany, Allecra of Switzerland, and Merck & Co. USA. Dr.Gopalan has 34 publications in National and International Journals, has contributed a Chapter,Co-authored with Professor K.K.Balasubramanian (IITM) on Applications of Click Chemistry in Drug Discovery and Development in a Book on Click reaction in Organic Synthesis, published by Wiley-VCH VERLAG GmbH &Co,KGaA, Weinheim,Germany,Chapter 2, p 25-70,2016, edited by Prof. S. Chandrasekharan (IISc,Bangalore) & 51 Patents.
Commensurate with his achievements, Dr. Gopalan has also received many awards. The more prominent of these include Inventor’s award by Glenmark (2004), Ranbaxy Science Foundation Award in Pharmaceutical Sciences (2005), and the Lifetime Achievement Award in the Field of Chemistry from Vels University (2011).
Madrigal Pharmaceuticals , following the merger between Synta and Madrigal Pharmaceuticals (pre-merger) (following the acquisition of VIA Pharmaceuticals ‘ assets (originally under license from Roche )), is developing resmetirom (MGL-3196, VIA-3196), the lead from oral capsule formulation thyroid hormone receptor (THR) beta agonists, cholesterol and triglyceride modulators, for the use in the treatment of metabolic disorders including hypercholesterolemia and other dyslipidemias, and non-alcoholic steatohepatitis.
MGL-3196 is a first-in-class, orally administered, small-molecule, liver-directed, THR β-selective agonist. Preclinical, toxicology and Phase 1 clinical data suggest MGL-3196 has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemias. THR-β selectivity also enhances the safety profile of MGL-3196, compared to non-selective agents. MGL-3196 has shown no suppression of the central thyroid axis, no THR-α effects on heart rate or bone, and no elevation of liver enzymes. These characteristics make MGL-3196 among the most promising molecules in development in this therapeutic area. MGL-3196 is in a Phase 2 clinical trial for the treatment of non-alcoholic steatohepatitis (NASH).
PATENT
WO-2020010068
Novel crystalline salt of resmetirom as thyroid hormone receptor agonists useful for treating obesity, hyperlipidemia, hypercholesterolemia and diabetes. Appears to be the first filing from the assignee and the inventors on this compound,
Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological reviews, Vol. 81(3): pp. 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior.
[0005] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs or THRs) (M. A. Lazar, Endocrine Reviews, Vol. 14: pp. 348-399 (1993)). TRs belong to the superfamily known as nuclear receptors. TRs form heterodimers with the retinoid receptor that act as ligand-inducible transcription factors. TRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain, and regulate gene expression through interactions with DNA response elements and with various nuclear co-activators and co repressors. The thyroid hormone receptors are derived from two separate genes, a and b. These distinct gene products produce multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms are aΐ, a2, bΐ, and b2. Thyroid hormone receptors aΐ, bΐ, and b2 bind thyroid hormone. It has been shown that the thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. Recent studies suggest that TIIb 1 plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver. T11b2 plays an important role in the regulation of TSH (thyroid stimulating hormone) (Abel et. al, J. Clin. Invest., Vol 104: pp. 291-300 (1999)). TIIb 1 plays an important role in regulating heart rate (B. Gloss et. al. Endocrinology, Vol. 142: pp. 544-550 (2001); C. Johansson et. al, Am. J. Physiol., Vol. 275: pp. R640-R646 (1998)).
[0006] Efforts have been made to synthesize thyroid hormone analogs which exhibit increased thyroid hormone receptor beta selectivity and/or tissue selective action. Such thyroid hormone mimetics may yield desirable reductions in body weight, lipids, cholesterol, and lipoproteins, with reduced impact on cardiovascular function or normal function of the hypothalamus/pituitary/thyroid axis (see, e.g., Joharapurkar et al, J. Med. Chem, 2012, 55 (12), pp 5649-5675). The development of thyroid hormone analogs which avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones would open new avenues of treatment for patients with metabolic disease such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as liver steatosis and NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, a resistance to thyroid hormone (RTH) syndrome, and related disorders and diseases.
Example 3: Preparation of (Z)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6- oxo- l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)carbamate (Int. 8)
A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet was charged with Int. 7 (75.0 g, 0.239 mol, 1 wt), acetic acid (600 mL, 8 vol), water (150 mL, 2 vol), and concentrated HC1 (71.3 mL, 0.95 vol). The resulting thin slurry was cooled to 6 °C and a solution of NaN02 (16.8 g, 0.243 mol, 1.02 equiv) in water (37.5 mL, 0.5 vol) was added over a period of 10 min while maintaining a batch temperature below 10 °C. After an additional 10 min of agitation between 5-10 °C, HPLC analysis showed complete conversion of Int. 7 to the diazonium intermediate. A solution of NaOAc (54.5 g, 0.664 mol, 2.78 equiv) in water (225 mL, 3 vol) was added over a period of 6 min while maintaining a batch temperature below 10 °C. N-cyanoacetylurethane (37.9 g, 0.243 mol, 1.02 equiv) was immediately added, the cooling was removed, and the batch naturally warmed to 8 °C over 35 min. HPLC analysis showed complete consumption of the diazonium intermediate and the reaction was deemed complete. The batch warmed naturally to 21 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (375 mL, 5 vol) twice. The collected orange solid was dried in a 35 °C vacuum oven for 64 h to provide crude Int. 8 (104.8 g, 91%).
A I L, three-neck, round-bottom flask equipped with overhead stirring, a
thermocouple, and N2 inlet/outlet was charged with crude Int. 8 (104.4 g, 1 wt) and acetic acid (522 mL, 5 vol). The resulting slurry was heated to 50 °C and held at that temperature for 1.5 h. The batch cooled naturally to 25 °C over 2 h and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (522 mL, 5 vol) and the cake conditioned under vacuum for 1.75 h. The light orange solid was dried to constant weight in a 40 °C vacuum oven to provide 89.9 g (78% from Int. 7) of the desired product. 1H NMR (DMSO) was consistent with the assigned structure.
Example 4: Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)
A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a
thermocouple, N2 inlet/outlet, and reflux condenser was charged with Int. 8 (89.3 g, 0.185 mol, 1 wt), DMAC (446 mL, 5 vol), and KOAc (20.0 g, 0.204 mol, 1.1 equiv). The mixture was heated to 120 °C and held at that temperature for 2 h. HPLC analysis showed complete conversion to Compound A. The batch temperature was adjusted to 18 °C over 1 h, and acetic acid (22.3 mL, 0.25 vol) was added. The batch temperature was adjusted to 8 °C, and water (714 mL, 8 vol) was added over 1 h; an orange slurry formed. The batch was filtered through Sharkskin filter paper and the cake was allowed to condition overnight under N2 without vacuum for convenience. A premixed solution of 1 : 1 acetone/water (445 mL, 5 vol) was charged to the flask and added to the cake as a rinse with vacuum applied. After 2 h of conditioning the cake under vacuum, it was transferred to a clean 1 L, three-neck, round- bottom flask equipped with overhead stirring, a thermocouple, and N2inlet/outlet. Ethanol (357 mL, 4 vol) and acetone (357 mL, 4 vol) were charged and the resulting slurry was heated to 60 °C; dissolution occurred. Water (890 mL, 10 vol) was added over a period of 90 min while maintaining a batch temperature between 55-60 °C. The resulting slurry was allowed to cool to 25 °C and filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with a solution of 1:1 EtOH/water (446 mL, 5 vol). The cake was conditioned overnight under N2 without vacuum for convenience. The cracks in the cake were smoothed and vacuum applied. The cake was washed with water (179 mL, 2 vol) and dried in a 45 °C vacuum oven to a constant weight of 70.5 g (87%, crude Compound A). HPLC analysis showed a purity of 94.8%.
A 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet, and reflux condenser was charged with crude Compound A (70.0 g) and MIBK (350 mL, 5 vol). The orange slurry was heated to 50 °C and held at that temperature for 2 h. The batch cooled naturally to 23 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with MIBK (35 mL, 0.5 vol) twice. The collected solids were dried in a 45 °C vacuum oven to a constant weight of 58.5 g (84%). This solid was charged to a 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet, and reflux condenser. Ethanol (290 mL, 5 vol) was added and the slurry was heated to reflux. After 3.5 h at reflux, XRPD showed the solid was consistent with Form I, and heating was removed. Upon reaching 25 °C, the batch was filtered through filter paper, and the reactor and cake were washed sequentially with EtOH (174 mL, 3 vol). The tan solid Compound A was dried in a 40 °C vacuum oven to a constant weight of 50.4 g (87%, 64% from Int. 8). HPLC analysis showed a purity of 99.1%. 1H NMR (DMSO) was consistent with the assigned structure.
Example 5: Scaled up preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)
A larger scale batch of Compound A was synthesized according to the scheme below. The conditions in the scheme below are similar to those described in Examples 1-4 above.
6A
Compound A
Synthesis of 4: A 50 L jacketed glass vessel (purged with N2) was charged with 3,6- dichloropyridazine (2.00 kg), 4-amino-2,6-dichlorophenol (2.44 kg) and N,N- dimethylacetamide (10.0 L). The batch was vacuum (26 inHg) / nitrogen (1 PSIG) purged 3 times. Cesium carbonate (5.03 kg) was added and the batch temperature was adjusted from 22.3 °C to 65.0 °C over 3.5 hours. The batch was held at 65.0 °C for 20 hours. At this point,
NMR analysis indicated 3.34% 3.6-dichloropyridazine relative to 2. The batch temperature was adjusted to 21.5 °C and ethyl acetate (4.00 L) was added to the batch. The batch was agitated for 10 minutes and then filtered through a 18″ Nutsche filter equipped with polypropylene filter cloth. The filtration took 15 minutes. Ethyl acetate (5.34 L) was charged to the vessel and transferred to the filter as a rinse. The batch was then manually re- suspended in the filter before re-applying vacuum. This process was repeated 2 more times and the filter cake was conditioned for 10 minutes. The filtrate was charged to a 100-L vessel that contained (16.0 L) of a previously prepared 15% sodium chloride in H20. The batch was agitated for 5 minutes and then allowed to separate for 35 minutes. The interface was not visible, so the calculated 23 L of the lower aqueous phase was removed. 16.0 L of 15% Sodium chloride in H20 was added to the batch. The batch was agitated for 6 minutes and then allowed to separate for 7 minutes. The interface was visible at -19 L and the lower aqueous phase was removed. 17.0 L of 15% Sodium chloride in H20 was added to the batch. The batch was agitated for 7 minutes and then allowed to separate for 11 minutes. The lower aqueous phase was removed. The vessel was set up for vacuum distillation and the batch was concentrated from 17.0 L to 8.0 L over 2 hours 20 minutes with the batch temperature kept around 21 °C. Benzoic anhydride (3.19 kg) and acetic acid (18.0 L) were charged to the vessel. The vessel was set up for vacuum distillation and the batch was concentrated from 28.0 L to 12.0 L over 2 days (overnight hold at 20 °C) with the batch temperature kept between 20 and 55 °C. At this point, JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.015. Acetic acid (4.0 L) was charged to the batch and the batch was distilled to 12 L. JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.0036. Acetic acid (20.0 L) was charged to the batch and the batch temperature was adjusted to 70.0 °C. The batch was sampled for HPLC analysis and 2 was 0.16%. Sodium acetate (2,20 kg) was added to the batch and the batch temperature was adjusted from 72.4 °C to 110.0 °C. After 18.5 hours, HPLC analysis indicated no Int. B detected. The batch temperature was adjusted from 111.3 to 74.7 °C and DI water (30.0 L) was added to the batch over 2 hours. The batch temperature was adjusted to 20 .5 °C and then filtered using a 24″ Haselloy Nutsche filter equipped with polypropylene filter cloth. A previously prepared solution of 1:1 acetic acid in DI H20 (10.0 L) was charged to the vessel and agitated for 5 minutes. The wash was transferred to the filter and the batch was then manually re- suspended in the filter before re-applying vacuum. DI H20 (10.0 L) was charged to the vessel and then transferred to the filter. The batch was manually re-suspended in the filter before re-applying vacuum. DI H20 (10.0 L) was charged directly to the filter and the batch was then manually re-suspended in the filter before re-applying vacuum. The filter cake was allowed to condition for 18 hours to give 14.4 kg of 4. HPLC analysis indicated a purity of 93.7%. This wet cake was carried forward into the purification. A 100 L jacketed glass vessel (purged with N2) was charged with crude 4 (wet cake 14.42 kg), acetic acid (48.8 L) and the agitator was started. DI H20 (1.74 L) was charged. The batch (a slurry) temperature was adjusted from 18.1 to 100.1 °C over 4.25 hours. The batch was held at 100.1 to 106.1 °C for 1 hour and then adjusted to 73.1 °C. DI H20 (28.0 L) was added to the batch over 1 hour keeping the batch temperature between 73.1 and 70.3 °C. The batch temperature was adjusted further from 70.3 °C to 25.0 °C overnight. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with polypropylene filter cloth. The filtration took 13 minutes. A solution of DI H20 (9.00 L) and acetic acid (11.0 L) was prepared and added to the 100 L vessel. The mixture was agitated for 5 minutes and then transferred to the filter cake. DI H20 (20.0 L) was charged to the vessel, agitated for 6 minutes and then transferred to the filter cake. DI H20 (20.0 L) was charged to the vessel, agitated for 9 minutes and then transferred to the filter cake. The batch was allowed to condition for 3 days and then transferred to drying trays for vacuum oven drying. After 3 days at 50 °C and 28’7Hg, the batch gave a 74% yield (3.7 kg) of4 as an off-white solid. The JH NMR spectrum was consistent with the assigned structure, HPLC analysis indicated a purity of 98.87% and KF analysis indicated 0.14% H20. Synthesis of Int. 7: A 100-L jacketed glass vessel (purged with N2) was charged with tetrahydrofuran (44.4 L). The agitator was started (125 RPM) and 4 (3.67 kg) was charged followed by lithium chloride (1.26 kg). The batch temperature was observed to be 26.7 ° C and was an amber solution. Isopropenylmagnesium bromide 1.64 molar solution in 2-methyl THF (21.29 kg) was added over 2 ½ hours keeping the batch between 24.3 and 33.6 °C. The batch was agitated at 24.5 °C for 17 hours at which point HPLC analysis indicated 9% 4. A 2nd 100-L jacketed glass vessel (purged with N2) was charged with 3N hydrogen chloride (18.3 L). The batch was transferred to the vessel containing the 3N HC1 over 25 minutes keeping the batch temperature between 20 and 46 °C. A bi-phasic solution was observed. The quenched batch was transferred back to the 1st 100-L vessel to quench the small amount of residue left behind. THF (2.00 L) was used as a rinse. The batch temperature was observed to be 40.9 ° C and was agitated at 318 RPM for 45 minutes. The batch temperature was adjusted to 21.8 ° C and the layers were allowed to separate. The separation took 10 minutes. The lower aqueous phase was removed (-26.0 L). A solution of sodium chloride (1.56 kg) in DI water (14.0 L) was prepared and added to the batch. This was agitated at 318 RPM for 10 minutes and agitator was stopped. The separation took 3 minutes. The lower aqueous phase was removed (-16.0 L). The batch was vacuum distilled from 58.0 L to 18.4 L using ~24’7Hg and a jacket temperature of 50 to 55 °C. A solution of potassium hydroxide (2.30 kg) in DI water (20.7 L) was prepared in a 72-L round bottom flask. The vessel was set up for atmospheric distillation using 2 distillation heads and the batch was transferred to the 72-L vessel. THF (0.75 L) was used as a rinse. The batch volume was -41.0 L, the temperature was adjusted to 64.1 °C and distillation started with the aid of a N2 sweep. Heating was continued to drive the batch temperature to 85.4 °C while distilling at which point the 72-L vessel was set up for reflux (batch volume was about 28.0 L at the end of the distillation). The batch was held at 85 °C for 13 hours at which point HPLC analysis indicated 0.3% compound 6A. Heating was stopped and the batch was transferred to a 100-L jacketed glass vessel. Solids were observed. The batch temperature was adjusted from 70.6 °C to 56.7 °C. A previously prepared solution of sodium hydrogen carbonate (2.82 kg) in DI water (35.0 L) was added over 80 minutes keeping the batch temperature between 56.7 and 46.7 °C. The batch pH at the end of the addition was 9.8. The batch was held at
46.7 to 49.0 °C for 40 minutes and then cooled to 25.0 °C. The batch was filtered using a 18″ stainless steel Nutsche filter. DI water (18.4 L) was charged to the vessel and transferred to the filter. The filter cake was manually re-suspended in the filter and then the liquors were removed. This process was repeated once more and the filter cake was 3″ thick. The filter cake was conditioned on the filter for 3 days, was transferred to drying trays and dried in a vacuum oven at 45 °C to provide 2.93 kg Int. 7 (95% yield) with an HPLC purity of 87.6%.
Synthesis of Int. 8: A 100 L jacketed glass vessel (purged with N2 and plumbed to a caustic scrubber) was charged with acidic acid (13.0 L). Int. 7 (2.85 kg) was charged to the vessel and the agitator was started. N-Cyanoacetylurethane (1.56 kg) and DI water (5.70 L) were charged to the vessel. The batch temperature was adjusted from 17.0 °C to 5.5 °C and a thin slurry was observed. At this point 37% hydrogen chloride (2.70 L) was added over 10 minutes keeping the batch temperature between 4.8 °C and 8.8 °C. A previously prepared solution of sodium nitrite (638 g) in DI water (1.42 L) was added over 26 minutes keeping the batch temperature between 5.8 °C and 8.7 °C. A brown gas was observed in the vessel head space during the addition. HPLC analysis indicated no Int. 7 detected. At this point a previously prepared solution of sodium acetate (2.07 kg) in DI water (8.50 L) was added over 47 minutes keeping the batch temperature between 5.5 °C and 9.5 °C. After the addition, a thin layer of orange residue was observed on the vessel wall just above the level of the batch. The batch temperature was adjusted from 9.4 °C to 24.5 °C and held at 25 °C (+ 5 °C) for 12 hours. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with tight-weave polypropylene filter cloth. The filtration took 30 minutes. The vessel was rinsed with 14.3 L of a 1 : 1 acidic acid / DI water. The orange residue on the reactor washed away with the rinse. The rinse was transferred to the filter where the batch was manually re-suspended. Vacuum was re-applied to remove the wash. A 2nd 1 : 1 acidic acid / DI water wash was performed as above and the batch was conditioned on the filter for 26 hours. HPLC analysis of the wet filter cake indicated purity was 90.4%. The batch was dried to a constant weight of 3.97 kg (91% yield) in a vacuum oven at 45 °C and 287Hg. Preparation of Compound A DMAC Solvate
A 100 L, jacketed, glass vessel purged with N2 was charged with Int. 8 (3.90 kg) and potassium acetate (875 g). N,N-dimethylacetamide (DMAC, 18.3 L) was charged to the vessel and the agitator was started. The batch temperature was adjusted to 115 °C over 2 h. After 2 h at 115 °C, the batch was sampled and HPLC analysis indicated 0.27% Int. 8 remained. The batch temperature was adjusted to 25.0 °C overnight. Acetic acid (975 mL) was added to the batch and the batch was agitated further for 3 h. The batch was transferred to a carboy and the vessel was rinsed clean with 800 mL of DMAC. The batch was transferred back to the 100 L vessel using vacuum through a 10 μιη in-line filter and a DMAC rinse (1.15 L) was used. The filtration was fast at the beginning but slow at the end, plugging up the filter. The batch temperature was adjusted to 11.1 °C and DI water (35.1 L) was added over 2 h 20 min, keeping the batch temperature between 5-15 °C. The batch was held for 1 h and filtered, using an 18″ Nutsche filter equipped with tight-weave
polypropylene cloth. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel, cooled to 10 °C, and transferred to the filter cake. The cake was allowed to condition under N2 and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg to give 89% yield (3.77 kg) of Compound A DMAC solvate as an orange/tan solid. The 1H NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated 0.49% H20. XRPD indicated the expected form, i.e., Compound A DMAC solvate. Thermogravimetric analysis (TGA) indicated 16% weight loss. HPLC analysis indicated a purity of 93.67%.
Preparation of Crude Compound A
A 100 L, jacketed, glass vessel purged with N2 was charged with Compound A
DMAC solvate (3.75 kg) and ethanol (15.0 L). The agitator was started and acetone (15.0 L) was added. The batch temperature was adjusted from 10.6 °C to 60.0 °C over 1 h. At this point, the batch was in solution. DI water was added to the batch over 1.5 h, keeping the batch temperature at 60 + 5 °C. The batch was held at 60 + 5 °C for 1 h and cooled to 23.5 °C. An 18″ Nutsche filter equipped with tight-weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel and transferred to the filter cake. The cake was allowed to condition under N2 and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg for five days to give a 94% yield (2.90 kg) of Compound A as a powdery tan solid. The NMR spectrum is consistent with the assigned structure and Karl Fischer analysis indicated 6.6% H20. XRPD indicated the expected form of dihydrate. TGA indicated 6.7% weight loss. HPLC analysis indicated a purity of 96.4% (AUC).
Purification of Crude Compound A
A 50 L, jacketed, glass vessel purged with N2 was charged with Compound A crude
(2.90 kg) and methyl isobutyl ketone (14.5 L). The agitator was started and the batch temperature was adjusted from 20.2 °C to 50.4 °C over 1.5 h. The batch was held at 50 °C (+ 5 °C) for 1 h and cooled to 20-25 °C. The batch was held at 20-25 °C for 2.5 h. An 18″ Nutsche filter equipped with tight- weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 20 min. Methyl isobutyl ketone (MIBK, 1.45 L) was charged to the vessel and transferred to the filter cake. The cake was manually resuspended and the liquors were pulled through with vacuum. Methyl isobutyl ketone (2.90 L) was charged to the filter cake and the cake was manually resuspended. The liquors were pulled through with vacuum and the cake was conditioned with vacuum and nitrogen for 15 h. The filter cake dried into a tan, hard 18″ x 1 ½” disc. This was manually broken up and run through coffee grinders to give a 76% yield (2.72 kg) of MGL-3196 MIBK solvate as a tan, powdery solid. No oven drying was necessary. The NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated <0.1 % H20. XRPD indicated the expected form MIBK solvate. TGA indicated 17.3% weight loss. HPLC analysis indicated a purity of 98.5%.
Example 6: Conversion of Compound A to Form I
Purified Compound A (4802 g) as a 1:1 MIBK solvate which was obtained from Int. 8 as described in Example 5 above was added into a jacketed, 100 L reactor along with 24 liters of ethanol. The resulting slurry was heated to 80 + 5 °C (reflux) over 1 h 25 min; the mixture was stirred at that temperature for 4 h 25 min. Analysis of the filtered solids at 2 h 55 min indicated that the form conversion was complete, with the XRPD spectra conforming to Form I. The mixture was cooled to 20 + 5 °C over 45 min and stirred at that temperature for 15 min. The slurry was filtered and the filter cake was washed twice with prefiltered ethanol (2 x 4.8 L). The wet cake (4.28 kg) was dried under vacuum at 40 + 5 °C for 118 h to afford 3390 g of Compound A form I.
PAPER
Journal of Medicinal Chemistry (2014), 57(10), 3912-3923
The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
//////////////RESMETIROM , MGL-3196, VIA-3196, UNII-RE0V0T1ES0, Phase III
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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References
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