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Vanzacaftor

  • CAS 2374124-49-7
  • COM1POP492
  • VX-121
  • 617.8 g/mol, C32H39N7O4S

FDA APPROVED vanzacaftor, tezacaftor, and deutivacaftor, 12/20/2024, Alyftrek , To treat cystic fibrosis

(14S)-8-[3-(2-dispiro[2.0.24.13]heptan-7-ylethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2-dioxo-2λ6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5(10),6,8,19(23),20-hexaen-4-one

13H-17,20-Methano-8,12-nitrilo-12H-pyrido[3,2-d][1,2,6,13]thiatriazacyclooctadecin-5(6H)-one, 2-[3-(2-dispiro[2.0.2.1]hept-7-ylethoxy)-1H-pyrazol-1-yl]-14,15,16,17,18,19-hexahydro-19,19-dimethyl-, 7,7-dioxide, (17S)-

(14S)-8-[3-(2-Dispiro[2.0.24.13]heptan-7-ylethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2-dioxo-2?6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5(10),6,8,19(23),20-hexaen-4-one

(14S)-8-[3-(2-dispiro[2.0.24.13]heptan-7-ylethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2-dioxo-2|E6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5(10),6,8,19(23),20-hexaen-4-one

Vanzacaftor (VX-121) is an orally active noval corrector of Cystic fibrosis transmembrane conductance regulator (CFTR). Vanzacaftor improves processing and trafficking of CFTR protein as well as increases chloride transport in triple combined with Tezacaftor (HY-15448) and Deutivacaftor. Vanzacaftor-Tezacaftor-Deutivacaftor is safe and well tolerated, improving lung function, respiratory symptoms, and CFTR function with cystic fibrosis, which is promising for research in the field of cystic fibrosis diseases.

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.
      In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.
      Sequence analysis of the CFTR gene has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease.
      The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
      CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
      Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na +-K +-ATPase pump and Cl − channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl − channels, resulting in a vectorial transport. Arrangement of Na +/2Cl −/K + co-transporter, Na +-K +-ATPase pump and the basolateral membrane K + channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

PATENTS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US356967369&_cid=P12-M9W6P5-06241-1

Example 104: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl(20-deuterio)-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 300)

Step 1: (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaen-20-yl 4-methylbenzene-1-sulfonate

 To a stirred solution of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20-hydroxy-12,12-dimethyl-2λ 6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1 (23),5,7,9,19,21-hexaene-2,2,4-trione (150 mg, 0.2367 mmol) in anhydrous dichloromethane (3.000 mL) was added 4-methylbenzenesulfonyl chloride (58 mg, 0.3042 mmol), triethylamine (80 μL, 0.5740 mmol) and catalytic amount of N,N-dimethylpyridin-4-amine (10 mg, 0.08185 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resultant brown residue was purified by silica gel column chromatography using a shallow gradient 100% hexanes to 100% ethyl acetate to afford (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ 6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaen-20-yl 4-methylbenzene-1-sulfonate (120 mg, 51%) as a white solid. ESI-MS m/z calc. 787.28217, found 788.42 (M+1) +; Retention time: 1.39 min (LC Method J).

Step 2: (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl(20-deuterio)-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 300)

 A solution of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ 6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaen-20-yl 4-methylbenzene-1-sulfonate (120 mg, 0.1523 mmol) in dry N,N-dimethylformamide (1 mL) was purged with nitrogen for 5 min using a balloon. Then, dichloronickel; triphenyl-phosphane (30 mg, 0.04586 mmol) and tricyclohexylphosphane (34 mg, 0.1212 mmol) were added. The resultant green solution was stirred for 5 min under nitrogen atmosphere and tetradeuterioboranuide (sodium salt) (87 mg, 2.079 mmol) was added in one portion. The resultant dark reddish brown mixture was stirred at room temperature for 1 h. Additional dichloronickel; triphenylphosphane (30 mg, 0.04586 mmol), tricyclohexylphosphane (34 mg, 0.1212 mmol) and tetradeuterioboranuide (sodium salt) (87 mg, 2.079 mmol) were added and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was dissolved in dimethyl sulfoxide and filtered through a Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient run from 50%-99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to afford (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl(20-deuterio)-2λ 6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 300) (35 mg, 37%) as a white solid. 1H NMR (400 MHz, dimethyl sulfoxide-d 6) δ 12.52 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.25-4.17 (m, 2H), 3.92 (d, J=12.5 Hz, 1H), 3.17 (s, 1H), 2.94 (d, J=13.2 Hz, 1H), 2.72 (s, 1H), 2.20-2.06 (m, 1H), 1.81 (q, J=6.6 Hz, 4H), 1.60 (s, 3H), 1.56 (d, J=13.5 Hz, 2H), 1.51 (s, 3H), 1.46 (d, J=6.5 Hz, 1H), 1.36-1.26 (m, 1H), 1.23 (s, 1H), 0.87-0.76 (m, 4H), 0.70-0.59 (m, 2H), 0.50 (dd, J=8.0, 4.3 Hz, 2H). ESI-MS m/z calc. 618.2847, found 619.25 (M+1) +; Retention time: 1.28 min (LC Method J).

//////Vanzacaftor, Alyftrek , cystic fibrosis, COM1POP492, VX-121, FDA 2024, APPROVALS 2024

#Vanzacaftor, #Alyftrek , #cystic fibrosis, #COM1POP492, #VX-121, #FDA 2024, #APPROVALS 2024

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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