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Ensartinib

April 16, 2025 2:53 am / Leave a comment

Ensartinib

X396, X 396

1370651-20-9
C26H27Cl2FN6O3,
561.4 g/mol
SMA5ZS5B22

6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide

FDA 12/18/2024, Ensacove, To treat non-small cell lung cancer

Ensartinib, sold under the brand name Ensacove, is an anti-cancer medication used for the treatment of non-small cell lung cancer.^[1] Ensartinib is an Anaplastic lymphoma kinase (ALK) inhibitor used as the salt ensartinib hydrochloride.^[1] It is taken by mouth.^[1]

The most common adverse reactions include rash, musculoskeletal pain, constipation, cough, pruritis, nausea, edema, pyrexia, and fatigue.^[2]

Ensartinib was approved for medical use in the United States in December 2024.^[1]^[2]^[3]^[4]

PATENT

US9126947, 18

https://patentscope.wipo.int/search/en/detail.jsf?docId=US90227390&_cid=P11-M9JBTT-36001-1

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (B)

Step 1: To a solution of A5 (219 g, 1.05 mol) in 1,2-dichloroethane (3500 mL) was added Boc-D-Pro (141 g, 0.65 mol) followed by EDCI (163 g, 0.85 mol) and DMAP (21.57 g, 0.18 mol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (3500 mL) was added and separated, the water phase was extracted with DCM(1500 mL×3), dried over MgSO ₄, concentrated and purified by column chromatography to (PE:EA=30:1) to give B1 (55.96 g, yield: 51.1%)

Step 2: To a solution of B1 (59.96 g, 268 mmol) in THF (1200 mL) was added 60% NaH (10.71 g, 268 mmol) at 0° C., the resulting mixture was stirred at that temperature for 30 min, was then added A3 (55.82 g, 268 mmol) quickly. The resulting mixture was heated under reflux overnight and evaporated. The residue was purified by column chromatography (PE:EA=4:1) to provide the advanced intermediate B2 (33.95 g, 37.7%). 1H-NMR (300 MHz, CDCl ₃): δ=1.87 (d, 3H), 5.08 (s, 2H), 6.03-6.09 (m, 1H), 6.42 (s, 1H), 7.14 (t, 1H), 7.35 (dd, 1H). LC-MS [M+H] ⁺: 336.0.

Step 3: To a solution of B2 (33.95 g, 101 mmol) in DMF (400 mL) was added BOC ₂O (39.59 g, 182 mmol) and DMAP (2.46 g, 20.2 mmol). The mixture was stirred at r.t. overnight and evaporated. The residue was purified by column chromatography (PE:EA=10:1) and the residue was treated with PE:EA=10:1 to afford B3 (46.9 g, 86.7%).

Step 4: Sodium acetate (14.34 g, 175 mmol) was added to a solution of B3 (46.9 g, 87.4 mmol) in ethanol/DMF [(5:1) (480 mL)]. The mixture was degassed, then added Pd(dppf)Cl ₂.CH ₂Cl ₂(7.14 g, 8.74 mmol). The resulting mixture was heated at CO atmosphere at 90° C. overnight, then evaporated. The residue was purified by column chromatography (PE:EA=4:1) to afford B4 (47.1 g, 94.0%). 1H-NMR (300 MHz, CDCl ₃): δ=1.38 (s, 18H), 1.46 (t, 3H), 1.88 (d, 3H), 4.45-4.53 (m, 2H), 6.18 (q, 1H), 7.13 (t, 1H), 7.34 (dd, 1H), 7.57 (s, 1H). LC-MS [M+H] ⁺: 574.0.

Step 5: To the solution of B4 (47.1 g, 82.1 mmol) in THF (400 mL) was added 1N LiOH aq. (98.5 mL). The resulting mixture was stirred at r.t. over weekend, then acidified by 2N HCl to pH=5, extracted with ethyl acetate (400 mL×3). The combined organic phase was dried over Na ₂SO ₄, filtrated and concentrated to give B (45.94 g, ˜100%).

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1S)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (C)

Step 1: To a solution of A5 (41.8 g, 200 mmol) in 1,2-dichloroethane (800 mL) was added Boc-L-Pro (26.9 g, 125 mmol) followed by EDCI (31.1 g, 163 mmol) and DMAP (4.12 g, 33.8 mmol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (350 mL) was added and separated, the water phase was extracted with DCM(150 mL×3), dried over MgSO ₄, concentrated and purified by column chromatography to (PE:EA=30:1) to give C1 (13.72 g, yield: 65.6%).

Step 2: The procedure from C1 to C was similar to that of B1 to B (9.46 g, yield: 26.4% from C1).

Synthesis of {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide

Step 1: The mixture of B (10.92 g, 20.0 mmol)), HATU (9.12 g, 24.0 mmol) and DIEA (3.87 g, 30.0 mmol) in DMF (100 mL) was stirred at room temperature for 0.5 h, then was added 1a (5.26 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 0.5 h and evaporated. The residue was purified by column chromatography (EA:MeOH=5:1) to provide 1b (12.43 g, 83.2%).

Step 2: 1b (12.43 g, 16.7 mmol) was dissolved in a mixture of DCM (90 mL) and TFA (30 mL), stirred at r.t. for 2 hours and evaporated. The residue was adjusted by sat. Na ₂CO ₃to pH=8 and extracted with DCM (150 mL×5). The combined organic phase was dried over MgSO ₄and concentrated. The residue was triturated with methanol and filtered, then the solid was dissolved in DCM and a solution of HCl in Et ₂O was added, the mixture was stirred at r.t. overnight, then concentrated and dried over oil pump to afford 1 (8.31 g, 80.5%). 1H-NMR (300 MHz, DMSO-d ₆): δ=1.84 (d, 3H), 2.76 (d, 3H), 3.02-3.10 (m, 2H), 3.37-3.53 (m, 5H), 3.40-4.26 (m, 1H), 6.27 (q, 1H), 7.11 (s, 1H), 7.42-7.51 (m, 3H), 7.58-7.62 (m, 1H), 7.86-7.88 (m, 2H). LC-MS [M+H] ⁺:547.2.

Medical uses

Ensartinib is indicated for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer who have not previously received an ALK-inhibitor.^[1]^[2]

History

Efficacy was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter trial in 290 participants with locally advanced or metastatic ALK-positive non-small cell lung cancer who had not previously received an ALK-targeted therapy.^[2] Participants were randomized 1:1 to receive ensartinib or crizotinib.^[2]

Society and culture

Legal status

Ensartinib was approved for medical use in the United States in December 2024.^[2]^[3]^[5]

Name

Ensartinib is the international nonproprietary name.^[6]

Ensartinib is sold under the brand name Ensacove.^[1]^[2]^[3]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Ensacove (ensartinib) capsules, for oral use” (PDF). Xcovery Holdings, Inc. U.S. Food and Drug Administration. December 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 18 December 2024. Retrieved 20 December 2024. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ “FDA Approval of Ensartinib for ALK-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)” (Press release). Xcovery Holdings. 19 December 2024. Retrieved 20 December 2024 – via Business Wire.
^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77”. WHO Drug Information. 31 (1). hdl:10665/330984.

External links

“Ensartinib (Code C102754)”. NCI Thesaurus.
Clinical trial number NCT02767804 for “eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients” at ClinicalTrials.gov

Horn L, Infante JR, Reckamp KL, Blumenschein GR, Leal TA, Waqar SN, Gitlitz BJ, Sanborn RE, Whisenant JG, Du L, Neal JW, Gockerman JP, Dukart G, Harrow K, Liang C, Gibbons JJ, Holzhausen A, Lovly CM, Wakelee HA: Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study. Clin Cancer Res. 2018 Jun 15;24(12):2771-2779. doi: 10.1158/1078-0432.CCR-17-2398. Epub 2018 Mar 21. [Article]
FDA Approved Drug Products: ENSACOVETM (ensartinib) capsules, for oral use (Dec 2024) [Link]
NCI Formulary: Ensartinib (X-396) [Link]

Clinical data

Trade names	Ensacove
Other names	X-396
License data	US DailyMed: Ensartinib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1370651-20-9
PubChem CID	56960363
DrugBank	DB14860
ChemSpider	58828042
UNII	SMA5ZS5B22
KEGG	D11346
ChEMBL	ChEMBL4113131
ECHA InfoCard	100.306.918
Chemical and physical data
Formula	C₂₆H₂₇Cl₂FN₆O₃
Molar mass	561.44 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

\/////////Ensartinib, FDA 2024, APPROVALS 2024, Ensacove, X396, X 396, GLXC-15836, BCP26265, EX-A2941, NSC793150, s8230

Olezarsen

April 14, 2025 2:47 am / Leave a comment

Olezarsen

Olezarsen is an ASO directed inhibitor of Apolipoprotein C-III (apoC-III) mRNA, conjugated to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes.

TRYNGOLZA contains olezarsen sodium as the active ingredient. Olezarsen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of olezarsen sodium is C 296H 419N 71O 154P 20S 19Na 20and the molecular weight is 9124.48 daltons. The chemical name of olezarsen sodium is DNA, d(P-thio) ([2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)] rG-[2′- O-(2-methoxyethyl)] m5rC-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)]m5rU), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20).

Olezarsen

FDA APPROVED 12/19/2024, Tryngolza, To treat familial chylomicronemia syndrome
Drug Trials Snapshot

Synonyms

AKCEA-APOCIII-LRX
ALL-P-AMBO-5′-O-(((6-(5-((TRIS(3-(6-(2-ACETAMIDO-2-DEOXY-.BETA.-D-GALACTOPYRANOSYLOXY)HEXYLAMINO)-3-OXOPROPOXYMETHYL))METHYL)AMINO-5-OXOPENTANAMIDO)HEXYL))PHOSPHO)-2′-O-(2-METHOXYETHYL)-P-THIOADENYLYL-(3′-O->5′-O)-2′-O-(2-METHOXYETHYL)-P-THIOGUANYLYL-(3
DNA, D(P-THIO)((2′-O-(2-METHOXYETHYL))RA-(2′-O-(2-METHOXYETHYL))RG-(2′-O-(2-METHOXYETHYL))M5RC-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-M5C-T-T-G-T-M5C-M5C-A-G-M5C-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETH
IONIS-APOCIII-LRX
ISIS-APOCIII-LRX

External IDs

ISIS-678354

Olezarsen, sold under the brand name Tryngolza, is a medication used in the treatment of familial chylomicronemia syndrome.^[1]^[2] It is given by injection under the skin.^[1]

Olezarsen was approved for medical use in the United States in December 2024.^[1]^[3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9127276	No	2015-09-08	2034-05-01
US9181549	No	2015-11-10	2034-05-01
US9593333	No	2014-02-14	2034-02-14
US9157082	No	2012-04-27	2032-04-27
US9163239	No	2014-05-01	2034-05-01

Medical uses

Olezarsen is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome.^[1]

Pharmacology

Olezarsen is an apolipoprotein C-III-directed antisense oligonucleotide.^[1] By binding to apolipoprotein C-III mRNA, it causes its degradation, which in turn increases clearance of plasma triglycerides and very low-density lipoprotein (VLDL).^[5]

Adverse effects

In a 66-patient trial, olezarsen was demonstrated to cause following side effects:^[5]^[6]

injection site reactions
hypersensitivity reactions (due to immunogenic potential of the medication)
arthralgia
thrombocytopenia
hyperglycemia
elevation of liver enzymes

History

The US Food and Drug Administration (FDA) granted the application of olezarsen orphan drug designation in February 2024.^[7] In August 2024, European Medicines Agency also granted olezarsen this designation.^[8]

Society and culture

Legal status

Olezarsen was approved for medical use in the United States in December 2024.^[3]^[9]

Names

Olezarsen is the international nonproprietary name.^[10]

Olezarsen is sold under the brand name Tryngolza.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Tryngolza- olezarsen sodium injection, solution”. DailyMed. 19 December 2024. Retrieved 25 January 2025.

^ Spagnuolo, Catherine M; Hegele, Robert A (2023). “Recent advances in treating hypertriglyceridemia in patients at high risk of cardiovascular disease with apolipoprotein C-III inhibitors”. Expert Opinion on Pharmacotherapy. 24 (9): 1013–1020. doi:10.1080/14656566.2023.2206015. PMID 37114828.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Jump up to:^a ^b Stroes, Erik S.G.; Alexander, Veronica J.; Karwatowska-Prokopczuk, Ewa; Hegele, Robert A.; Arca, Marcello; Ballantyne, Christie M.; et al. (16 May 2024). “Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome”. New England Journal of Medicine. 390 (19): 1781–1792. doi:10.1056/NEJMoa2400201. ISSN 0028-4793.
^ Ionis Pharmaceuticals, Inc. (11 December 2024). A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA-APOCIII-LRx Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS) (Report). clinicaltrials.gov.
^ “Olezarsen Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 20 December 2024.
^ “EU/3/24/2973 – orphan designation for treatment of familial chylomicronaemia syndrome | European Medicines Agency (EMA)”. http://www.ema.europa.eu. 21 August 2024. Retrieved 22 February 2025.
^ “Tryngolza (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet” (Press release). Ionis Pharmaceuticals. 19 December 2024. Retrieved 20 December 2024 – via PR Newswire.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.

External links

“Olezarsen (Code C180652)”. NCI Thesaurus.

Clinical trial number NCT04568434 for “A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial Chylomicronemia Syndrome (FCS) (BALANCE)” at ClinicalTrials.gov

Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O’Dea LSL, Tsimikas S, Gaudet D: Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820. [Article]
Karwatowska-Prokopczuk E, Tardif JC, Gaudet D, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Amour ES, Alexander VJ, Xia S, Otvos JD, Witztum JL, Tsimikas S: Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia. J Clin Lipidol. 2022 Sep-Oct;16(5):617-625. doi: 10.1016/j.jacl.2022.06.005. Epub 2022 Jun 23. [Article]
Hooper AJ, Bell DA, Burnett JR: Olezarsen, a liver-directed APOC3 ASO therapy for hypertriglyceridemia. Expert Opin Pharmacother. 2024 Oct;25(14):1861-1866. doi: 10.1080/14656566.2024.2408369. Epub 2024 Sep 26. [Article]
Bergmark BA, Marston NA, Prohaska TA, Alexander VJ, Zimerman A, Moura FA, Murphy SA, Goodrich EL, Zhang S, Gaudet D, Karwatowska-Prokopczuk E, Tsimikas S, Giugliano RP, Sabatine MS: Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med. 2024 May 16;390(19):1770-1780. doi: 10.1056/NEJMoa2402309. Epub 2024 Apr 7. [Article]
FDA News: FDA approves drug to reduce triglycerides in adult patients with familial chylomicronemia syndrome [Link]
FDA Approved Drug Products: TRYNGOLZA (olezarsen) injection, for subcutaneous use [Link]

Clinical data

Trade names	Tryngolza
Other names	IONIS-APOCIII-LRX
License data	US DailyMed: Olezarsen
Routes of administration	Subcutaneous
Drug class	Antisense oligonucleotide
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	2097587-83-0 2298451-31-5
DrugBank	DB18728
UNII	S3RS2SA30L NSY2BY6PSB
KEGG	D13023

////Olezarsen, FDA 2024, APPROVALS 2025, Tryngolza, ISIS-678354, ISIS 678354, familial chylomicronemia syndrome

BENZGALANTAMINE

April 2, 2025 10:03 am / Leave a comment

BENZGALANTAMINE

CAS 224169-27-1

Benzgalantamine gluconate, 1542321-58-3

6H-Benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, benzoate (ester), (4aS,6R,8aS)- (9CI)
Alpha 1062
GLN 1062
Memogain

6h-benzofuro(3a,3,2-ef)(2)benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, benzoate (ester), (4as,6r,8as)-

Formula	C₂₄H₂₅NO₄
Molar mass	391.467 g·mol⁻¹

External IDs GLN-1062 gluconate

UNIILN7PMJ4P57

CAS Number1542321-58-3

WeightAverage: 587.622
Monoisotopic: 587.236661015

Chemical FormulaC₃₀H₃₇NO₁₁

Benzgalantamine, sold under the brand name Zunveyl, is a medication used for the treatment of mild to moderate dementia of the Alzheimer’s type.^[1] It is a cholinesterase inhibitor.^[1] Benzgalantamine is a prodrug of galantamine.^[1]

The most common side effects include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.^[1]

Benzgalantamine was approved for medical use in the United States in July 2024.^[1]^[2]^[3]

compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and to their agonists, of neuronal cholinergic receptors, and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g., Galantamine, Narwedine and Lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as “pro-drugs”, in the sense that after reaching their target regions in the body, they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this disclosure may be used as medicaments for the treatment of human brain diseases associated with a cholinergic deficit, including the neurodegenerative diseases Alzheimer’s and Parkinson’s disease and the neurological/psychiatric diseases vascular dementia, schizophrenia and epilepsy. Galantamine derivatives disclosed herein have higher efficacy and lower levels of adverse side effects in comparison to galantamine, in treatment of human brain diseases.

Benzgalantamine is a prodrug of galantamine. Gastrointestinal adverse effects are the most frequently reported side effects in patients undergoing treatment with cholinesterase inhibitors, including galantamine, and are often a reason for treatment discontinuation.² As a prodrug, benzagalantamine remains inert as it passes through the stomach, thereby avoiding many of the gastrointestinal effects associated with peripheral cholinesterase inhibition.⁴

Benzgalantamine was approved by the FDA in July 2024 for the treatment of mild-to-moderate dementia in Alzheimer’s patients.^3,4

SCHEME

US20090253654

https://patentscope.wipo.int/search/en/detail.jsf?docId=US42863485&_cid=P12-M8ZQT3-74791-1

O-Benzoyl-galantamine(=(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, benzoate (ester)); yield: 78%

O-3,4-Dichlorobenzoyl-galantamine(=(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 3,4-dichlorobenzoate (ester)); off-white solid; mp. 69-70° C.

¹H NMR (200 MHz, CDCl ₃) δ (ppm) 8.02 (d, J=1.88 Hz, 1H), 7.81 (dd, J=1.88 Hz, J=8.38 Hz, 1H), 7.38 (d, J=8.32 Hz, 1H), 6.62 (d, J=8.18 Hz, 1H), 6.52 (d, J=8.18 Hz, 1H), 6.32 (d, J=10.34 Hz, 1H), 5.89-5.97 (m, 1H), 5.51 (t, J=4.43 Hz, 1H), 4.58 (s, 1H), 4.07 (d, J=15.16 Hz, 1H), 3.18 (s, 3H), 3.61 (d, J=15.16 Hz, 1H), 3.21-3.45 (m, 1H), 2.96-3.05 (m, 1H), 2.66-2.76 (m, 1H), 2.34 (s, 3H), 2.0-2.19 (m, 2H), 1.51-1.59 (m, 1H).

WO2009127218

US20220220121

https://patentscope.wipo.int/search/en/detail.jsf?docId=US368470159&_cid=P12-M8ZR8V-88578-1

Experiment 1

The Alpha-1062 gluconate (CA19-0673) was re-slurried in MEK/H2O at 20° C. 5.6 g of Alpha-1062 gluconate was used in 19.3 g MEK+1.9 g H2O. The slurry was stirred for 30 min before washing of the filter cake with 4.1 g MEK, re-filtration and drying.

The reaction mixture was yellow to orange. The suspension was initially relatively thin, then became thicker upon longer stirring. After 30 min a very thick paste-like suspension was obtained that was difficult to stir and transfer to filter. The suspension was deemed too thick and therefore unsuitable for production. The isolated material was slightly yellowish (white to pale yellow).

Synthesis of Alpha-1062 Gluconate
The gluconate salt of Alpha-1062 was created according to the following previously established general scheme:

AND

US20090253654

Medical uses

Benzgalantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type in adults.^[1]^[2]

Side effects

The most common side effects include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.^[1]

Society and culture

Legal status

Benzgalantamine was approved for medical use in the United States in July 2024.^[1]^[2]

Names

Benzgalantamine is the international nonproprietary name.^[4]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Zunveyl- benzgalantamine tablet, delayed release”. DailyMed. 8 August 2024. Retrieved 15 August 2024.
^ Jump up to:^a ^b ^c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/218549Orig1s000ltr.pdf
^ “Alpha Cognition’s Oral Therapy Zunveyl Receives FDA Approval to Treat Alzheimer’s Disease” (Press release). Alpha Cognition. 29 July 2024. Archived from the original on 4 August 2024. Retrieved 4 August 2024 – via Business Wire.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

Baakman AC, ‘t Hart E, Kay DG, Stevens J, Klaassen ES, Maelicke A, Groeneveld GJ: First in human study with a prodrug of galantamine: Improved benefit-risk ratio? Alzheimers Dement (N Y). 2016 Jan 20;2(1):13-22. doi: 10.1016/j.trci.2015.12.003. eCollection 2016 Jan. [Article]
Bakker C, van der Aart J, Hart EP, Klaassen ES, Bergmann KR, van Esdonk MJ, Kay DG, Groeneveld GJ: Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine. Alzheimers Dement (N Y). 2020 Oct 13;6(1):e12093. doi: 10.1002/trc2.12093. eCollection 2020. [Article]
FDA Approved Drug Products: Zunveyl (benzgalantamine) delayed-release tablets for oral use [Link]
Fierce Pharma: Alpha Cognition’s delayed-release Alzheimer’s drug Zunveyl passes muster with FDA [Link]
Alpha Cognition: Corporate Presentation Oct 2024 [Link]

External links

“Benzgalantamine (Code C188656)”. NCI Thesaurus.

Clinical data

Trade names	Zunveyl
Other names	ALPHA-1062
AHFS/Drugs.com	Zunveyl
License data	US DailyMed: Benzgalantamine
Routes of administration	By mouth
Drug class	Cholinesterase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	224169-27-1 1542321-58-3
DrugBank	DB19353
UNII	XOI2Q0ZF7G LN7PMJ4P57
KEGG	D12930 D12931
ChEMBL	ChEMBL5095056
Chemical and physical data
Formula	C₂₄H₂₅NO₄
Molar mass	391.467 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES

//////////BENZGALANTAMINE, Alpha 1062, GLN 1062, Memogain, FDA 2024, APPROVALS 2024, Zunveyl

Deuruxolitinib

September 11, 2024 6:20 am / Leave a comment

Deuruxolitinib

C₁₇H₁₈N₆, 314.422

Fda approved Leqselvi, 7/25/2024, To treat severe alopecia areata

C-21543, CTP 543, CTP-543, CTP543

(3r)-3-(2,2,3,3,4,4,5,5-d8)cyclopentyl-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)propanenitrile

1h-pyrazole-1-propanenitrile, .beta.-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-, (.beta.r)-D8-ruxolitinib

Ingredient	UNII	CAS	InChI Key
Deuruxolitinib phosphate	8VJ43S4LCM	2147706-60-1	JFMWPOCYMYGEDM-NTVOUFPTSA-N

unii
0CA0VSF91Y

Deuruxolitinib, sold under the brand name Leqselvi, is a medication used for the treatment of alopecia areata.^[1] It is a Janus kinase inhibitor selective for JAK1 and JAK2.^[2] Although the relative effectiveness of deuruxolitinib and another Janus kinase inhibitor—baricitinib—for alopecia areata may vary depending on the population studied, both drugs are more effective than alternative treatments.^[3]

Deuruxolitinib was approved for medical use in the United States in July 2024.^[1]^[4]

Medical uses

Deuruxolitinib is indicated for the treatment of adults with severe alopecia areata.^[1]

Side effects

The FDA prescribing label for deuruxolitinib contains a boxed warning for serious infections; malignancies; cardiovascular death, myocardial infarction, and stroke; and thrombosis.^[5]

Society and culture

Names

Deuruxolitinib is the international nonproprietary name^[6] and the United States Adopted Name.^[7]

SYN

20240108633METHOD FOR PREVENTING OR TREATING DISEASE OR CONDITION ASSOCIATED WITH ANTITUMOR AGENT

20240058345TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2023553253重水素化ＪＡＫ阻害剤による脱毛障害の治療のためのレジメン

20230390292REGIMENS FOR THE TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

20230322787PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

1020230093504중수소화된 JAK 억제제를 이용한 탈모 장애의 치료를 위한 요법

WO/2023/018954TREATMENT OF JAK-INHIBITION-RESPONSIVE DISORDERS WITH PRODRUGS OF JAK INHIBITORS

2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR

20220226327Combination therapy comprising JAK pathway inhibitor and rock inhibitor

20220213105PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

20220202834JAK inhibitor with a vitamin D analog for treatment of skin diseases

20210387991Deuterated JAK inhibitor and uses thereof SUN

WO/2020/163653PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS CONCERT

20200222408TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2019516684Treatment of Hair Loss Disorders with Deuterated JAK Inhibitors

PATENT

US20210387991

USE OF COMPD NOT SYNTHESIS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US344953814&_cid=P12-M0XGHQ-19840-2

Example 1

Synthesis of Compound 10

The synthesis of Compound 10, or a pharmaceutically acceptable salt thereof (such as the phosphate salt) may be readily achieved, e.g., reaction of CTP-543 under conditions suitable to provide hydrolysis of the nitrile functionality of CTP-543. CTP-543 can be prepared, e.g., according to the methods described in U.S. Pat. No. 9,249,149 and US Patent Pub. No. 2019/0160068 (the teachings of which are incorporated herein by reference), to produce CTP-543 and/or its phosphate salt. CTP-543 phosphate salt may be transformed into Compound 10 or its phosphate salt according to Scheme 1 below.

To a round bottom flask, equipped with a magnetic stir bar, was charged sulfuric acid (2 mL) followed by careful addition of CTP-543 Phosphate (4.05 g, 9.8 mmol). To the mixture was added another portion of sulfuric acid (2 mL) and water (0.8 mL). The reaction was stirred at room temperature for 4 hours, then quenched by addition of a potassium carbonate solution (80 g, 30% w/w). The product was extracted using isopropyl alcohol. The organic phase was concentrated under vacuum to dryness. The product was dissolved in isopropyl alcohol (100 mL) and phosphoric acid (1 mL, 85% w/w) was added to crystallize the product as the phosphate salt. The precipitate was filtered and dried in a vacuum oven (5 torr, room temp, slight nitrogen purge) to yield the desired compound as an off-white solid (1.82 g, 4.2 mmol, 43% yield). The product was analyzed by HPLC, HRMS, and NMR.

¹H-NMR (400 MHz, DMSO-d ₆): δ 12.05 (s, 1H), 8.64 (s, 1H), 8.56 (d, J=0.9 Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J=3.6, 2.3 Hz, 1H), 7.33 (s, 1H), 6.96 (dd, J=3.6, 1.6 Hz, 1H), 6.76 (s, 1H), 4.57 (td, J=9.7, 4.0 Hz, 1H), 2.88 (dd, J=15.3, 10.0 Hz, 1H), 2.64 (dd, J=15.3, 4.0 Hz, 1H), 2.32 (d, J=9.3 Hz, 1H).

HPLC method summary: column=Waters XBridge C18, 4.6×150 mm, 3.5 μm column; gradient elution: mobile phase A=10 mM ammonium formate, pH 3.9; mobile phase B=acetonitrile; detection=ultraviolet absorbance at 254 nm. Result: Compound (I)=98.7 area %; retention time=11.1 min.

HRMS: Agilent 6530 Q-TOF LC/MS system with electrospray ionization in positive mode. The measured time-of-flight mass-to-charge ratio (m/z) is 333.22839 (theoretical value=333.22735).

Clinical data

Trade names	Leqselvi
Other names	CTP-543
License data	US DailyMed: Deuruxolitinib
Routes of administration	By mouth
Drug class	Janus kinase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1513883-39-0as phosphate: 2147706-60-1
PubChem CID	72704611as phosphate: 154572727
DrugBank	DB18847
ChemSpider	115010950
UNII	0CA0VSF91Yas phosphate: 8VJ43S4LCM
KEGG	D11866as phosphate: D11867
ChEMBL	ChEMBL4594381
Chemical and physical data
Formula	C₁₇H₁₈N₆
Molar mass	306.373 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES

References

King B, Mesinkovska N, Mirmirani P, Bruce S, Kempers S, Guttman-Yassky E, Roberts JL, McMichael A, Colavincenzo M, Hamilton C, Braman V, Cassella JV: Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J Am Acad Dermatol. 2022 Aug;87(2):306-313. doi: 10.1016/j.jaad.2022.03.045. Epub 2022 Mar 29. [Article]Yan T, Wang T, Tang M, Liu N: Comparative efficacy and safety of JAK inhibitors in the treatment of moderate-to-severe alopecia areata: a systematic review and network meta-analysis. Front Pharmacol. 2024 Apr 10;15:1372810. doi: 10.3389/fphar.2024.1372810. eCollection 2024. [Article]Barati Sedeh F, Michaelsdottir TE, Henning MAS, Jemec GBE, Ibler KS: Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis. Acta Derm Venereol. 2023 Jan 25;103:adv00855. doi: 10.2340/actadv.v103.4536. [Article]Sardana K, Bathula S, Khurana A: Which is the Ideal JAK Inhibitor for Alopecia Areata – Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib – Revisiting the Immunomechanisms of the JAK Pathway. Indian Dermatol Online J. 2023 Jun 28;14(4):465-474. doi: 10.4103/idoj.idoj_452_22. eCollection 2023 Jul-Aug. [Article]FDA Approved Drug Products: LEQSELVI (deuruxolitinib) tablets, for oral use [Link]AJMC: FDA Approves Deuruxolitinib for Alopecia Areata [Link]

^ Jump up to:^a ^b ^c ^d “Archived copy” (PDF). Archived (PDF) from the original on 29 July 2024. Retrieved 26 July 2024.

^ King, Brett; Mesinkovska, Natasha; Mirmirani, Paradi; Bruce, Suzanne; Kempers, Steve; Guttman-Yassky, Emma; et al. (August 2022). “Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata”. Journal of the American Academy of Dermatology. 87 (2): 306–313. doi:10.1016/j.jaad.2022.03.045. ISSN 1097-6787. PMID 35364216. S2CID 247866262.
^ SEDEH, Farnam Barati; MICHAELSDÓTTIR, Thorunn Elísabet; HENNING, Mattias Arvid Simon; JEMEC, Gregor Borut Ernst; IBLER, Kristina Sophie (25 January 2023). “Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis”. Acta Dermato-Venereologica. 103: 4536. doi:10.2340/actadv.v103.4536. ISSN 0001-5555. PMC 10391778. PMID 36695751.
^ “U.S. FDA Approves Leqselvi (deuruxolitinib), an Oral JAK Inhibitor for the Treatment of Severe Alopecia Areata” (Press release). Sun Pharmaceutical. 25 July 2024. Archived from the original on 26 July 2024. Retrieved 26 July 2024 – via PR Newswire.
^ http://www.leqselvi.com/&a=Prescribing Information
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
^ “Deuruxolitinib”. American Medical Association. Retrieved 27 July 2024.

External links

“Deuruxolitinib (Code C175770)”. NCI Thesaurus.
“Deuruxolitinib Phosphate (Code C175771)”. NCI Thesaurus.
Clinical trial number NCT04518995 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA1) (THRIVE-AA1)” at ClinicalTrials.gov
Clinical trial number NCT04797650 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA2) (THRIVE-AA2)” at ClinicalTrials.gov

////Deuruxolitinib, alopecia areata, Leqselvi , approvals 2024, fda 2024, C-21543, CTP 543, CTP-543, CTP543, UNII-0CA0VSF91Y, WHO 11622

Vorasidenib

September 10, 2024 7:58 am / Leave a comment

Vorasidenib
6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine

CAS 1644545-52-7, C₁₄H₁₃ClF₆N₆, 414.74

FDA APPROVED, 8/6/2024, Voranigo, To treat Grade 2 astrocytoma or oligodendroglioma

UNII 789Q85GA8P

AG 881
AG-881
AG881

Ingredient	UNII	CAS	InChI Key
Vorasidenib citrate	X478M962XG	2316810-02-1	YOUTVRFNJAAFNS-DLVAHKFUSA-N
Vorasidenib citrate anhydrous	W4XG3EQK7B	2316810-00-9	OCEHQNOYRLHJCI-WPRTUUMNSA-N

Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.^[1]^[2] Vorasidenib acts to inhibit the enzymes isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2).^[1]^[2]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2]

Vorasidenib was approved for medical use in the United States in August 2024.^[2]^[3] It is the first approval by the US Food and Drug Administration (FDA) of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.^[2]

Medical uses

Vorasidenib is indicated for the treatment of people aged twelve years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.^[2]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.^[2]

History

Efficacy was evaluated in 331 participants with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial.^[2] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.^[2] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.^[2] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.^[2] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.^[2]

Society and culture

Legal status

Vorasidenib was approved for medical use in the United States in August 2024.^[2]

The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.^[2]

SYN

WO/2024/161041NOVEL COMPOUNDS THAT CAN BE USED AS THERAPEUTIC AGENTS

20240254118PRMT5 INHIBITORS AND USES THEREOF

118359585共晶体、其药物组合物以及涉及其的治疗方法

WO/2024/148437USE OF PCLX-001 OR PCLX-002 AS A RADIOSENSITIZER

20240238424HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE

1020240097895CD73 화합물

WO/2024/137852PRMT5 INHIBITORS AND USES THEREOF

2024057088THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

20240116928CD73 COMPOUNDS

117586228Preparation method of triazine medicine

20240041892THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

117529323Therapeutically active compounds and methods of use thereof

WO/2024/006929CD73 COMPOUNDS

PATENT

US10028961, Compound 101

https://patents.google.com/patent/US10028961B2/en

Step 3: Preparation of 6-(6-chloropyridin-2-yl)-N²,N⁴-bis((R)-1,1,1-trifluoro propan-2-yl)-1,3,5-triazine-2,4-diamine

A mixture of 2,4-dichloro-6-(6-chloro-pyridin-2-yl)-1,3,5-triazine (0.27 g, 1.04 mol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (0.39 g, 2.6 mol), and potassium carbonate (0.43 g, 3.1 mol) in dry 1,4-dioxane (2.5 mL) was stirred under the atmosphere of N₂at 50° C. for 36 hr then at 100° C. for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired product.

¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 5.61 (m, 1.5H), 5.25 (m, 0.5H), 5.09 (m, 0.5H), 4.88 (m, 1.5H), 1.54-1.26 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²—((R)-1,1,1-trifluoropropan-2-yl)-N⁴—((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.41-8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J=6.2 Hz, 1H), 5.68-5.20 (m, 2H), 5.18-4.81 (m, 2H), 1.48-1.39 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

Clinical data

Trade names	Voranigo
License data	US DailyMed: Vorasidenib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1644545-52-7
PubChem CID	117817422
IUPHAR/BPS	10663
DrugBank	DB17097
ChemSpider	64835242
UNII	789Q85GA8P
KEGG	D11834
ChEMBL	ChEMBL4279047
Chemical and physical data
Formula	C₁₄H₁₃ClF₆N₆
Molar mass	414.74 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c “Voranigo- vorasidenib citrate tablet, film coated”. DailyMed. 9 August 2024. Retrieved 15 August 2024.

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o “FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation”. U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024. This article incorporates text from this source, which is in the public domain.
^ “Servier’s Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma” (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.

External links

Clinical trial number NCT04164901 for “Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)” at ClinicalTrials.gov

Clinical trial number NCT02481154 for “Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation” at ClinicalTrials.gov
Clinical trial number NCT03343197 for “Study of AG-120 and AG-881 in Subjects With Low Grade Glioma” at ClinicalTrials.gov

////////Vorasidenib, Voranigo, FDA 2024, APPROVALS 2024, AG 881, AG-881, AG881

Palopegteriparatide

September 9, 2024 6:04 am / Leave a comment

Palopegteriparatide

Yorvipath , FDA 2024, 8/9/2024, To treat hypoparathyroidism

Palopegteriparatide

Palopegteriparatide is a human parathyroid hormone analogue corresponding to amino acid residues 1 – 34 of human parathyroid hormone, to which a methoxy polyethylene glycol (molecular weight: ca. 43,000) is bound via a cleavable linker (pegylation site: S1). Palopegteriparatide is a pegylated synthetic peptide (molecular weight: ca. 48,000) consisting of 34 amino acid residues.

[2222514-07-8]

Palopegteriparatide, sold under the brand name Yorvipath, is a hormone replacement therapy used for the treatment of hypoparathyroidism.^[1]^[2] It is a transiently pegylated parathyroid hormone.^[4] It is a parathyroid hormone analog.^[1]

Palopegteriparatide was approved for medical use in the European Union in November 2023,^[2] and in the United States in August 2024.^[1]^[5]

Medical uses

Palopegteriparatide is indicated for the treatment of adults with hypoparathyroidism.^[1]^[2]

Adverse effects

The US Food and Drug Administration (FDA) prescription label for palopegteriparatide includes warnings for a potential risk of risk of unintended changes in serum calcium levels related to number of daily injections and total delivered dose, serious hypocalcemia and hypercalcemia (blood calcium levels that are too high), osteosarcoma (a rare bone cancer) based on findings in rats, orthostatic hypotension (dizziness when standing), and a risk of a drug interaction with digoxin (a medicine for certain heart conditions).^[5]

History

The effectiveness of palopegteriparatide was evaluated in a 26-week, randomized, double-blind, placebo-controlled trial that enrolled 82 adults with hypoparathyroidism.^[5] Prior to randomization, all participants underwent an approximate four-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration ≥1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL.^[5] During the double-blind period, participants were randomized to either palopegteriparatide (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D).^[5] Study drug and conventional therapy were subsequently adjusted according to the albumin-corrected serum calcium levels.^[5] At the end of the trial, 69% of the participants in the palopegteriparatide group compared to 5% of the participants in the placebo group were able to maintain their calcium level in the normal range, without needing active vitamin D and high doses of calcium (calcium dose ≤ 600 mg/day).^[5]

The FDA granted the application for palopegteriparatide orphan drug and priority review designations.^[5]

Society and culture

Legal status

In September 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yorvipath, intended for the treatment of chronic hypoparathyroidism in adults.^[4]^[6] The applicant for this medicinal product is Ascendis Pharma Bone Diseases A/S.^[4] Palopegteriparatide was approved for medical use in the European Union in November 2023.^[2]

Palopegteriparatide was granted an orphan drug designation by the US Food and Drug Administration (FDA) in 2018,^[7] and by the EMA in 2020.^[8]

Brand names

Palopegteriparatide is the international nonproprietary name.^[9]^[10]

Palopegteriparatide is sold under the brand name Yorvipath.^[2]

References

^ Jump up to:^a ^b ^c ^d ^e “Yorvipath injection, solution”. DailyMed. 14 August 2024. Retrieved 5 September 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f “Yorvipath EPAR”. European Medicines Agency. 19 October 2020. Archived from the original on 10 December 2023. Retrieved 11 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Yorvipath Product information”. Union Register of medicinal products. 20 November 2023. Archived from the original on 26 November 2023. Retrieved 11 December 2023.
^ Jump up to:^a ^b ^c “Yorvipath: Pending EC decision”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA approves new drug for hypoparathyroidism, a rare disorder”. U.S. Food and Drug Administration (FDA) (Press release). 9 August 2024. Archived from the original on 13 August 2024. Retrieved 13 August 2024. This article incorporates text from this source, which is in the public domain.
^ “Ascendis Pharma Receives Positive CHMP Opinion for TransCon PTH (palopegteriparatide) for Adults with Chronic Hypoparathyroidism”. Ascendis Pharma (Press release). 14 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
^ “TransCon Parathyroid Hormone (mPEG conjugated parathyroid hormone 1-34) Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Archived from the original on 24 September 2023. Retrieved 24 September 2023.
^ “EU/3/20/2350”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
^ World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89”. WHO Drug Information. 37 (1). hdl:10665/366661.

External links

Palopegteriparatide Global Substance Registration System
Palopegteriparatide NCI Thesaurus
Clinical trial number NCT04701203 for “A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism (PaTHway)” at ClinicalTrials.gov

Clinical data

Trade names	Yorvipath
Other names	ACP-014, TransCon PTH
License data	US DailyMed: Palopegteriparatide
Routes of administration	Subcutaneous
Drug class	Hormonal agent
ATC code	H05AA05 (WHO)
Legal status
Legal status	US: ℞-only^[1]EU: Rx-only^[2]^[3]
Identifiers
CAS Number	2222514-07-8
UNII	G2N64C3385
KEGG	D12395

//////Palopegteriparatide, APPRoVALS 2024, FDA 2024, Yorvipath, hypoparathyroidism, UNII-G2N64C3385, ACP-014, TransCon PTH, WHO 11060

Aneratrigine

September 9, 2024 2:58 am / Leave a comment

Aneratrigine

2097163-74-9

5-chloro-2-fluoro-4-[4-fluoro-2-[methyl-[2-(methylamino)ethyl]amino]anilino]-N-(1,3-thiazol-4-yl)benzenesulfonamide

5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

Benzenesulfonamide, 5-chloro-2-fluoro-4-[[4-fluoro-2-[methyl[2-(methylamino)ethyl]amino]phenyl]amino]-N-4-thiazolyl-

C₁₉H₂₀ClF₂N₅O₂S₂ 488.0 g/mol

UNII 6A5ZY5LT78

WHO

SYN

Assignee: Daewoong Pharmaceutical Co., Ltd.

World Intellectual Property Organization, WO2017082688

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017082688&_cid=P11-M0UEPF-95506-1

Preparation of 5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

Step 1) Preparation of tert-butyl (1-(2-amino-5-fluorophenyl)pyridin-3-yl)(methyl)carbamate

2,4-Difluoro-1-nitrobenzene (2.0 g, 12.6 ng/mol) and tert-butyl methyl (pyridin-3-yl)carbamate (2.5 g, 1.0 eq.) were dissolved in DMF (20 mL), and K2C03 ₍_2.6 g , 1.5 _eq .) was added. The internal temperature was maintained at 60–70 ^° C and the mixture was stirred for 2 hours. The completion of the reaction was confirmed by TLC when the reaction solution turned deep yellow. After cooling to room temperature, ethyl acetate (EA)/H20 _{was added, stirred, and the layers were separated.}_MgS04 was added to the separated organic layer, stirred, dried, and filtered. After concentrating the filtrate under reduced pressure, the residue was dissolved in EtOH (10 mL) and distilled water (10 mL), and then Na ₂ S ₂ 0 ₄ (13.0 g, 6 eq.) was added. After stirring for 2 hours while maintaining the internal temperature at 60 to 70 ^° C, the completion of the reaction was confirmed by TLC when the yellow color of the reaction solution lightened and became almost colorless. After cooling to room temperature, distilled water (50 mL) was added and extracted twice with EA (100 mL). MgS0 ₄ was added to the organic layer, stirred, dried, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography (n-Hexane/EA = 3/1) to obtain the title compound (2.0 g, 51. ).

1H NMR (MeOD): 6.73(m, 1H), 6.57(t, 1H), 3.23(m, 1H), 3.10(m, 2H), 2.94(m, 1H), 2.91(s, 3H), 2.25( m, 1H)， 1.99(m, 1H)

Step 2) Preparation of tert-butyl thiazol-4-ylcarbamate

Thiazole-4-carboxylic acid (5.0 g, 38.8 vol) was dissolved in t-Bu0H (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL, 1.5 eq.) were added. The internal temperature was maintained at 90–100 ^° C, and the mixture was stirred for 3 days. The completion of the reaction was confirmed by TLC. The product was concentrated under reduced pressure, distilled water (50 mL) was added, and the solution was washed with EA (100 mL).

It was extracted twice. MgSQ ₄ was added to the organic layer, stirred, dried, and filtered.

After concentrating the filtrate under reduced pressure, the residue was added to a small amount of EA, slurried, and the resulting solid was filtered to obtain the white title compound (4.0 g, 51.5%).

1H NMR (MeOD): 8.73(s, 1H), 7.24(s, 1H), 1.52(s, 9H)

Step 3) Preparation of tert-butyl ((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

Step 2) The tert-Butyl thiazol-4-ylcarbamate (4.0 g, 20.0 ng ol) prepared in the reaction vessel was placed in a reaction vessel and the interior was replaced with nitrogen gas. After dissolving in THF (32 mL), it was cooled to _78 ^° C using dry ice— acetone. After cooling, LiHMDS (22.4 mL, 1.5 eq.) was slowly added and the reaction mass was stirred for 30 minutes. 4-Bromo-5-chloro-2-fluorobenzenesulfonyl chloride (6.0 g, 1.0 eq.) was dissolved in THF (10 mL) and slowly added to the reaction mixture. The reaction mass was stirred overnight and the completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL). MgS0 ₄ was added to the organic layer, stirred, dried, and filtered. After concentrating the filtrate under reduced pressure, the residue was crystallized from THF/n-hexane to obtain the title compound (4.4 g, 59.0%).

1H NMR (MeOD): 9.00(s, 1H), 8.22(d, 1H), 7.90(d, 1H), 7.78(s, 1H), 1.35(s, 9H)

Step 4) Preparation of tert-butyl (l-(2-((4-(N-(tert-butyloxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)-5-fluorophenyl)pyrlidin-3-yl)(methyl)carbamate

Tert-butyl (1-(2-amino-5-fluorophenyl)pyrlidin-3-yl)(methyl)carbamate (0.5 g, 1.1 ng ol) prepared in Step 1) and tert-butyl ((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.9 g, 1.2 eq.) prepared in Step 3) were dissolved in 1,4-dioxane (10 mL). Pd(OAc) ₂ (0.03 g, 0.1 eq), rac-BINAP (0.19 g, 0.2 eq.), Cs ₂ C0 ₃ (1.5 g, 3.0 eq.) were added to the reaction solution. After reacting at 120 ^° C for 30 minutes using a microwave initiator, the completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL).

MgS0 ₄ was added to the organic layer, stirred, filtered and dried. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (EA/n-Hexane = 1/1). This was repeated twice to obtain the title compound (2.0 g, 88.2%).

1H NMR (MeOD): 8.95(s, 1H), 7.94(d, 1H), 7.65(s, 1H), 7.14(t, 1H), 6.70(d, 1H), 6.64(t, 1H), 6.07( d, 1H)ᅳ 3.40(m, 1H), 3.28(m, 2H), 3.16(m, 1H), 2.64(s, 3H), 2.06(m, 1H), 1.89(m, 1H), 1.41(s , 9H), 1.36(s, 9H)

Step 5) Preparation of 5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

Step 4) was prepared by adding 1.25 M HCl in MeOH (15 mL) to tert-butyl (1-(2-((4-(Ν-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)—2-chloro-5-fluorophenyl)amino)-5-fluorophenyl)pyrlidin-3-yl) (methyl)carbamate (2.0 g, 2.9 µl). The mixture was heated to 40–50 ^° C and stirred overnight, and the completion of the reaction was confirmed by TLC. The product was concentrated, and methylene chloride (15 mL) was added to the residue, which was stirred for 1 hour, and the resulting solid was filtered to obtain the title compound (0.9 g, 58.8%).

1H 證 (MeOD): 8.73(s, 1H), 7.75(d, 1H), 7.12(t, 1H), 7.00(s, 1H), 6.69(d, 1H), 6.67(t, 1H), 6.05( d, 1H), 3.73(m, 1H) , 3.54(m, 1H), 3.45(m, 1H), 3.38(m, 1H), 3.26(m, 1H), 2.63(s, 3H) , 2.31(m , 1H), 1.96(m, 1H)

PATENTS

0002705578SODIUM CHANNEL BLOCKER

20180346459Substituted benzenesulfonamides as sodium channel blockers

2018533606ナトリウムチャネル遮断剤

3375782SODIUM CHANNEL BLOCKER

108349963SODIUM CHANNEL BLOCKER

1020170056461SODIUM CHANNEL BLOCKER

////////////Aneratrigine, DAEWOONG

Seladelpar

September 8, 2024 8:39 am / Leave a comment

Seladelpar

cas 851528-79-5

C₂₁H₂₃F₃O₅S, 444.47

fda approved 8/14/2024, To treat primary biliary cholangitis (PBC), Livdelzi

Ingredient	UNII	CAS	InChI Key
Seladelpar lysine	N1429130KR	928821-40-3	WTKSWPYGZDCUNQ-JZXFCXSPSA-N

(+)-MBX-8025
MBX 8025
MBX-8025
MBX8025
RWJ-800025

((4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)THIO)-2-METHYLPHENYL)OXY)ACETIC ACID
(4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)SULFANYL)-2-METHYLPHENOXY)ACETIC ACID PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR (PPAR) AGONIST,ANTIHYPERLIPIDAEMIC
(R)-2-(4-((2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)-THIO)-2-METHYLPHENOXY)ACETIC ACID
ACETIC ACID, (4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)THIO)-2-METHYLPHENOXY)-
ACETIC ACID, (4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)THIO)-2-METHYLPHENOXY)- ((4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)THIO)-2-METHYLPHENYL)OXY)ACETIC ACID
ACETIC ACID, 2-(4-(((2R)-2-ETHOXY-3-(4-(TRIFLUOROMETHYL)PHENOXY)PROPYL)THIO)-2-METHYLPHENOXY)-
Seladelpar

Seladelpar, sold under the brand name Livdelzi, is a medication used for the treatment of primary biliary cholangitis.^[1] It is used as the lysine dihydrate salt.^[1] It is a PPARδ receptor agonist.^[1]^[2]^[3] The compound was licensed from Janssen Pharmaceutica NV.^[4]

Seladelpar was approved for medical use in the United States in August 2024.^[1]^[5]

Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-delta (δ) agonist. Seladelpar is a single enantiomer of the R-configuration.⁵ On August 14, 2024, seladelpar was granted accelerated approval by the FDA for the treatment of primary biliary cholangitis,⁶ which is a condition associated with aberrant bile acid metabolism. Seladelpar works to block bile acid synthesis.¹

Medical uses

Seladelpar is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults who have an inadequate response to ursodeoxycholic acid, or as monotherapy in people unable to tolerate ursodeoxycholic acid.^[1]

Clinically, Seladelpar reduces pruritus and IL-31 in patients with primary biliary cholangitis.^[6]

compound 3r [PMID: 17524639]
Bioorg Med Chem Lett. 2007 Jul 15;17(14):3855-9. doi: 10.1016/j.bmcl.2007.05.007. Epub 2007 May 10.
10.1016/j.bmcl.2007.05.007

Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, 8 Clarke Drive, Cranbury, NJ 08512, USA

Scheme 1. Reagents and condition: (a) Cs2CO3, dioxane, 100 C 80%; (b) TBAF (cat), THF, 85%; (c) NaH, RI, THF or DMF for esters of 2–5, 8–9, 10–80%; iPr2NEt, RBr or MOMCl, THF for esters of 6–7, 58–79%; ADDP, Ph3P, phenol, CH2Cl2 for esters of 10–11, 68–73%; (d) LiOH, H2O, THF, 90–95%.

Scheme 2. Reagents: (a) Ba(MnO4)2, CH2Cl2, 89%; (b) DIAD, Ph3P, DMF, THF, 17%; (c) n-Bu3P, 24, Py, 55%; (d) i—NaHMDS, EtOTf, THF for the ethyl ester of 12, 47%; DIAD, Ph3P, para-trifluoromethylphenol for the ethyl ester of 13, 79%; ii—LiOH, H2O, THF, 84–88%.

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Livdelzi- seladelpar lysine capsule”. DailyMed. 14 August 2024. Retrieved 5 September 2024.
^ Billin AN (October 2008). “PPAR-beta/delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home”. Expert Opinion on Investigational Drugs. 17 (10): 1465–1471. doi:10.1517/13543784.17.10.1465. PMID 18808307. S2CID 86564263.
^ Bays HE, Schwartz S, Littlejohn T, Kerzner B, Krauss RM, Karpf DB, et al. (September 2011). “MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin”. The Journal of Clinical Endocrinology and Metabolism. 96 (9): 2889–2897. doi:10.1210/jc.2011-1061. PMID 21752880.
^ “Targeting Mixed Dyslipidemia and Metabolic Syndrome”. Metabolex, Inc. 2005. Archived from the original on 17 October 2006.
^ “Gilead’s Livdelzi (Seladelpar) Granted Accelerated Approval for Primary Biliary Cholangitis by U.S. FDA” (Press release). Gilead. 14 August 2024. Retrieved 15 August 2024 – via Business Wire.
^ Kremer AE, Mayo MJ, Hirschfield GM, Levy C, Bowlus CL, Jones DE, et al. (July 2024). “Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis”. Hepatology. 80 (1): 27–37. doi:10.1097/HEP.0000000000000728. PMC 11191048.

Clinical data

Trade names	Livdelzi
Other names	MBX-8025; RWJ-800025
License data	US DailyMed: Seladelpar
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	851528-79-5
PubChem CID	11236126
DrugBank	DB12390
ChemSpider	9411171
UNII	7C00L34NB9
KEGG	D11256
ChEMBL	ChEMBL230158
CompTox Dashboard (EPA)	DTXSID001045332
Chemical and physical data
Formula	C₂₁H₂₃F₃O₅S
Molar mass	444.47 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

///////////////Livdelzi, Seladelpar, (+)-MBX-8025, MBX 8025, MBX-8025, MBX8025, RWJ-800025, FDA 2024, APPROVALS 2024

lazertinib

September 7, 2024 2:57 am / Leave a comment

lazertinib

CAS 1903008-80-9

554.655, C₃₀H₃₄N₈O₃

FDA APPROVED, 8/19/2024, Lazcluze, To treat non-small cell lung cancer
Drug Trials Snapshot

2-PROPENAMIDE, N-(5-((4-(4-((DIMETHYLAMINO)METHYL)-3-PHENYL-1H-PYRAZOL-1-YL)-2-PYRIMIDINYL)AMINO)-4-METHOXY-2-(4-MORPHOLINYL)PHENYL)-

N-(5-((4-(4-((DIMETHYLAMINO)METHYL)-3-PHENYL-1H-PYRAZOL-1-YL)PYRIMIDIN-2-YL)AMINO)-4-METHOXY-2-MORPHOLINOPHENYL)ACRYLAMIDE
C-18112003-G
GNS 1480
GNS-1480
GNS1480
JNJ-73841937-AAA
YH 25448
YH-25448
YH25448

FDA APPROVED

8/19/2024

To treat non-small cell lung cancer, Lazcluze

Ingredient	UNII	CAS	InChI Key
Lazertinib mesylate monohydrate	WUT449BEG5	2411549-88-5	ZJPNGZUERUYZEG-UHFFFAOYSA-N

Lazertinib is an oral, third-generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).^2,3 Lazertinib was first approved in South Korea on January 18, 2021, for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) with EGFR mutations.¹ It was approved by the FDA on August 19, 2024.⁵ Lazertinib is used alone or in combination with other chemotherapeutic agents.⁴

Lazertinib, sold under the brand name Lazcluze and Leclaza, is an anti-cancer medication used for the treatment of non-small cell lung cancer.^[1]^[2]^[3] It is a kinase inhibitor of epidermal growth factor receptor.^[1]

The most common adverse reactions include rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity.^[2]

Lazertinib was approved for medical use in South Korea in January 2021,^[4]^[5] and in the United States in August 2024.^[2]^[6]

Medical uses

Lazertinib is indicated in combination with amivantamab for the first-line treatment of adults with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 L858R substitution mutations.^[2

History

Efficacy was evaluated in MARIPOSA (NCT04487080), a randomized, active-controlled, multicenter trial of 1074 participants with exon 19 deletion or exon 21 L858R substitution mutation-positive locally advanced or metastatic non-small cell lung cancer and no prior systemic therapy for advanced disease.^[2] Participants were randomized (2:2:1) to receive lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy (an unapproved regimen for non-small cell lung cancer) until disease progression or unacceptable toxicity.^[2]

Society and culture

Legal status

Lazertinib was approved for medical use in the United States in August 2024.^[2]Names

Lazertinib is the international nonproprietary name.^[7]

/////////////////////

References

^ Jump up to:^a ^b ^c “Lazcluze- lazertinib tablet, film coated”. DailyMed. 20 August 2024. Retrieved 5 September 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer”. U.S. Food and Drug Administration (FDA). 19 August 2024. Retrieved 21 August 2024. This article incorporates text from this source, which is in the public domain.
^ Dhillon S (June 2021). “Lazertinib: First Approval”. Drugs. 81 (9): 1107–1113. doi:10.1007/s40265-021-01533-x. PMC 8217052. PMID 34028784.
^ “Yuhan wins approval as MFDS clear T790M EGFR TKI drug ‘Lazertinib'”. 바이오스펙테이터. Retrieved 23 August 2024.
^ Dhillon S (2021). “Lazertinib: First Approval”. Drugs. 81 (9): 1107–1113. doi:10.1007/s40265-021-01533-x. ISSN 0012-6667. PMC 8217052. PMID 34028784.
^ “Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer”. Johnson & Johnson (Press release). 20 August 2024. Retrieved 21 August 2024.
^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.

External links

Clinical trial number NCT04487080 for “A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA)” at ClinicalTrials.gov

Clinical data

Trade names	Lazcluze, Leclaza
License data	US DailyMed: Lazertinib
Routes of administration	By mouth
Drug class	EGFR inhibitor
ATC code	L01EB09 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1903008-80-9
PubChem CID	121269225
IUPHAR/BPS	10136
DrugBank	DB16216
ChemSpider	64835231
UNII	4A2Y23XK11
KEGG	D11980 D12245
ChEMBL	ChEMBL4558324
Chemical and physical data
Formula	C₃₀H₃₄N₈O₃
Molar mass	554.655 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

/////////lazertinib, C-18112003-G, GNS 1480, GNS-1480, GNS1480, JNJ-73841937-AAA, YH 25448, YH-25448, YH25448, Lazcluze, FDA 2024, APPROVALS 2024

COC1=C(NC2=NC=CC(=N2)N2C=C(CN(C)C)C(=N2)C2=CC=CC=C2)C=C(NC(=O)C=C)C(=C1)N1CCOCC1

ACT-132577, Aprocitentan

May 19, 2024 9:08 am / Leave a comment

ACT-132577, Aprocitentan,

N-Despropyl-macitentan

1103522-45-7

546.19, C₁₆H₁₄Br₂N₆O₄S

WHO 10552

3/19/2024 FDA APPROVED, To treat hypertension, Tryvio

N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]aminosulfonamide

Aprocitentan, sold under the brand name Tryvio, is a medication used to treat hypertension (high blood pressure).^[1] It is developed by Idorsia.^[2] It is taken by mouth.^[1]

Aprocitentan is a dual endothelin-1 antagonist that targets both endothelin A and endothelin B receptors.^[3]^[4]

Aprocitentan was approved for medical use in the United States in March 2024.^[1]^[2]^[5] It is the first endothelin receptor antagonist to be approved by the US Food and Drug Administration (FDA) to treat systemic hypertension.^[2]

Medical uses

Aprocitentan is indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other medications.^[1]

Adverse effects

Aprocitentan may cause hepatotoxicity (liver damage), edema (fluid retention), anemia (reduced hemoglobin), and decreased sperm count.^[1]

Contraindications

Data from animal reproductive toxicity studies with other endothelin-receptor agonists indicate that use is contraindicated in pregnant women.^[1]

Mechanism of action

Aprocitentan is an endothelin receptor agonist that inhibits the protein endothelin-1 from binding to endothelin A and endothelin B receptors.^[1]^[4] Endothelin-1 mediates various adverse effects via its receptors, such as inflammation, cell proliferation, fibrosis, and vasoconstriction.^[1]

Society and culture

Economics

Aprocitentan is developed by Idorsia, which sold it to Janssen and purchased the rights back in 2023, for US$343 million.^[6]

Legal status

Aprocitentan was approved for medical use in the United States in March 2024.^[1]

In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jeraygo, intended for the treatment of resistant hypertension in adults.^[7] The applicant for this medicinal product is Idorsia Pharmaceuticals Deutschland GmbH.^[7]

SYN

US Patent

Trade Name

Application Number

Applicant

8324232

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11174247

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11787782

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11680058

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

10919881

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

PATENT

WO 02/053557

PATENT

Martin Bolli, Christoph Boss, Alexander Treiber. ” 4-pyrimidinesulfamide derivative “, US Patent US8324232B2.

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73589939&_cid=P12-LWDB8Y-85368-1

EXAMPLE

The following example was prepared according to the procedures described below. All compounds were characterized by ¹H-NMR (300 MHz) and occasionally by ¹³C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet; m=multiplet), by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6×50 mm, Develosil RP Aqueous, 5 μm, 120 A, gradient: 5-95% acetonitrile in water, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 ml/min), t _Ris given in min; by TLC (TLC-plates from Merck, Silica gel 60 F ₂₅₄) and occasionally by melting point.

Preparation A: Benzylsulfamide Potassium Salt

A.i. Benzylsulfamide

Chlorosulfonylisocyanate (14.14 g) was dissolved in DCM (50 mL) and cooled to 0° C. A solution of t-BuOH (9.6 mL) in DCM (50 mL) was added within 30 min. Stirring was continued for additional 30 min at rt. The solution thus obtained was then added at 0° C. within 1 h to a solution of benzylamine (10.7 g) and TEA (15.32 mL) in DCM (200 mL). Stirring is continued for 10 h at rt. The mixture was concentrated in vacuo, taken up in EA (500 mL) and washed with water (2×40 mL) and brine (30 mL), dried over MgSO ₄, filtered. The filtrate was concentrated in vacuo and the crude material was crystallized from EA and dried under HV to give N-benzyl-N′-tert-butoxycarbonyl sulfamide (13.68 g).

¹H NMR (CDCl ₃): δ 1.46 (s, 9H); 4.25 (s, 2H); 5.42 (s br., 1H); 7.30-7.40 (m, 5H).

LC-MS: t _R=0.90 min, [M+H] ⁺=287.09.

This material was dissolved in dioxane (20 ml) and 4 M HCl in dioxane (120 mL) was added within 1 h at rt. The mixture was stirred for 8 h before the solvent was evaporated and the residue dried under HV to give benzylsulfamide as an off-white powder (9.47 g).

¹H NMR (D ₆-DMSO): δ 4.05 (d, J=6.4 Hz, 2H); 6.60 (s, 2H); 7.04 (s, J=6.4 Hz, 1H); 7.20-7.36 (m, 5H).

LC-MS: t _R=0.60 min, [M+H+CH ₃CN] ⁺=228.17.

A.ii. Benzylsulfamide Potassium Salt

To a solution of benzylsulfamide (17.98 g) in McOH (300 mL) was carefully added potassium tert-butylate (10.8 g). The mixture was stirred at rt for 15 min before the solvent was evaporated. The remaining residue was dried under HV to give benzylsulfamide potassium salt as an off-white powder (21.73 g).

Preparation B: 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

B.i. 4-bromophenylacetic acid methyl ester

To a solution of 4-bromophenylacetic acid (50 g) in methanol (250 ml) was added dropwise thionyl chloride (34.2 mL) while the temperature of the reaction mixture was kept at 0-5° C. Upon complete addition cooling was stopped and the mixture was allowed to warm to rt. Stirring was continued for 75 min before the solvent was removed in vacuo. The yellow oil was dissolved in benzene and again concentrated. The residue was dissolved in EA, washed with water, brine, 2 N aq. Na ₂CO ₃, and again brine. The org. extract was dried over MgSO ₄, filtered, concentrated and dried under HV at 85° C. for 30 min to give the expected product as a yellow oil (52.4 g).

¹H-NMR (D ₆-DMSO): δ 3.60 (s, 3H); 3.67 (s, 2H); 7.22 (d, 8.5, 2H); 7.50 (d, J=8.5 Hz, 2H).

B.ii. 2-(4-bromophenyl)-malonic acid dimethyl ester

At 40° C., a solution of intermediate B.i (52 g) in THF (100 mL) was carefully added over a period of 40 min to a suspension of NaH (15.6 g) in dry THF (450 mL). Stirring was continued for 70 min without heating and the temperature dropped to 27° C. The evolution of gas stopped before dimethylcarbonate (76.42 mL) was added dropwise while the temperature of the mixture was maintained at 29-31° C. Stirring was continued for 22 h at rt. The mixture was cooled to −10° C. and then carefully neutralized to pH 6-7 with aq. HCl before bulk of the THF was removed in vacuo. The residue was dissolved in EA (700 mL), washed 3 times with 1 N aq. HCl-solution and once with brine, dried over MgSO ₄. Most of the EA was evaporated before Hex was added. The product crystallised overnight at 4° C. The crystals were collected, washed with Hex and dried to give the expected product as pale yellow crystals (45.9 g).

¹H-NMR (D ₆-DMSO): δ 3.66 (s, 6H); 5.07 (s, 1H); 7.30-7.34 (m, 2H); 7.55-7.59 (m, 2H),

B.iii. 5-(4-bromophenyl)-pyrimidine-4,6-diol

A solution of intermediate B.ii (11.73 g) in MeOH (100 mL) was added at 0° C. to a solution of sodium (2.83 g) in MeOH (100 mL). The mixture was stirred for 18 h at rt before formamidine hydrochloride (4.10 g) was added. The suspension was stirred at rt for 4 h. The solvent was removed and the residue was suspended in 10% aq. citric acid (100 mL) and stirred for 10 min. The white precipitate was collected, washed with 10% aq. citric acid, water, evaporated three times from cyclohexane and dried under HV at 40° C. to give 5-(4-bromophenyl)-pyrimidine-4,6-diol as a pale beige powder (9.90 g).

¹H-NMR (D ₆-DMSO): δ 7.43-7.48 (m, 2H), 7.50-7.55 (m, 2H), 8.13 (s, 1H), 12.1 (s br., 2H).

LC-MS: t _R=0.62 min, [M+H] ⁺=266.89/268.89 (Br-isotopes).

B.iv. 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

To a suspension of 5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g) in POCl ₃(130 mL) was carefully added N,N-dimethylaniline (13.5 mL). The mixture is heated to 130° C. for 2 h. The dark brown solution is concentrated in vacuo and the residue was poured into ice/water. The suspension is diluted with 2 N HCl and water and stirred for 20 min. The precipitate that formed is collected and washed with water. The solid material is dissolved in EA, washed with 1 N aq. HCl and brine. The org. phase is dried over MgSO ₄and evaporated. The material is further purified by column chromatography on silica gel eluting with Hex:EA 95:5 to 1:1 followed by crystallisation from Hex/EA at −20° C. to give 4,6-dichloro-5-(4-bromophenyl)-pyrimidine as pale yellow crystals (8.3 g).

¹H-NMR (D ₆-DMSO): δ 7.39-7.44 (m, 2H), 7.72-7.76 (m, 2H), 8.94 (s, 1H).

LC-MS: t _R=1.02 min.

Example 1

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

1.i. Benzyl-sulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide

A solution of 5-(4-bromophenyl)-4,6-dichloro-pyrimidine (4.00 g, 13.2 mmol) and benzylsulfamide potassium salt (7.38 g, 32.9 mmol) in DMSO (30 mL) was stirred at it for 24 h before being diluted with a 10% aq. citric acid solution (200 mL). The suspension that formed was filtered. The collected solid was washed well with water and dried under HV at 40° C. for 48 h to give the expected product as a white powder (6.15 g).

¹H NMR (CDCl ₃): δ 4.23 (d, J=5.9 Hz, 2H); 5.94 (t br., J=6 Hz, 1H); 7.05 (d, J=8.2 Hz, 2H); 7.20-7.35 (m, 5H); 7.68 (d, J=8.2 Hz, 2H); 8.61 (s, 1H).

LC-MS: t _R=1.02 min, [M+H] ⁺=452.95.

1.ii. Benzyl-sulfamic acid [5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-amide

t-BuOK (18.5 g, 164.5 mmol) was added portionwise to a suspension of intermediate 1.i (7.46 g, 16.4 mmol) in ethylene glycol (50 mL). The mixture became warm and thick and was diluted with DME (75 mL). The mixture was stirred at 95° C. for 24 h before it was cooled to rt, diluted with water (50 mL) and a 10% aq. citric acid solution (250 mL). The milky suspension was extracted with EA (2×300 mL). The combined org. extracts were dried over MgSO ₄, filtered and the filtrate was concentrated. The remaining crystalline solid was suspended in MeOH, collected, washed well with MeOH and dried under HV to give the expected product as a white crystalline powder (6.49 g).

¹H NMR (CDCl ₃): δ 2.50 (t br., J=6 Hz, 1H); 3.80-3.88 (m, 2H); 4.20 (d, J=5.9 Hz, 2H); 4.46-4.50 (m, 2H); 5.99 (t br., J=6.4 Hz, 1H); 6.85 (s br., 1H); 7.12 (d, J=8.2 Hz, 2H); 7.23-7.34 (m, 5H); 7.64 (d, J=8.2 Hz, 2H); 8.44 (s, 1H).

LC-MS: t _R=0.93 min, [M+H] ⁺=479.08.

1.iii Benzyl-sulfamic acid [5-(4-bromophenyl)-6-{2-(5-bromo-pyrimidin-2-yloxy)-ethoxy}-pyrimidin-4-yl]-amide

To a solution of intermediate 1.ii (6.49 g, 13.5 mmol) in THF (120 mL) was added carefully NaH (1.77 g, 40.6 mmol, 55% dispersion in mineral oil). The mixture was stirred for 10 min before 2-chloro-5-bromo-pyrimidine (3.93 g, 20.3 mmol) was added. The mixture was diluted with DMF (15 mL) and then stirred at rt for 20 min. The mixture was heated to 60° C. and stirred for 3 h before being again cooled to rt. The reaction was quenched with water and 10% aq. citric acid solution (250 mL) and the mixture was extracted with EA (2×300 mL). The org. extracts were washed with water, combined, dried over MgSO ₄, filtered and the solvent of the filtrate was evaporated. The crude product was crystallised from MeOH/ether. The crystalline material was collected, washed with additional MeOH/ether and dried under HV to give the expected product as a white powder (6.47 g).

¹H NMR (CDCl ₃): δ 4.20 (d, J=6.4 Hz, 2H); 4.59-4.64 (m, 2H); 4.69-4.74 (m, 2H); 5.98 (t br., J=6.4 Hz, 1H); 6.83 (s br., 1H); 7.06-7.10 (m, 2H); 7.24-7.34 (m, 5H); 7.54-7.58 (m, 2H); 8.44 (s, 1H); 8.50 (s, 2H).

LC-MS: t _R=1.06 min, [M+H] ⁺=634.98.

1.iv. {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

A solution of borontribromide (25.5 mL, 1 M in DCM) was slowly added to a solution of intermediate 1.iii (6.50 g, 10.2 mmol) in chloroform (250 mL). The mixture became turbid and an oily residue separated. The mixture was stirred at rt. Another portion of BBr ₃solution (5 mL) was added after 6, 24, and 33 h. After the last addition of BBr ₃, the beige suspension was stirred vigorously for additional 2 h before being carefully quenched with MeOH. The mixture became slightly warm and clear. The solution was washed with cold water (0° C., 2×150 mL). The washings were extracted back with DCM. The combined org. extracts were again washed with water, dried over MgSO ₄, filtered and concentrated. The crude product was purified by CC on silica gel eluting with heptane:EA 1:1 followed by crystallisation from DCM. The purified crystalline product was dried under HIV at 45° C. for 48 h to give the expected product as a white, crystalline powder (1.62 g).

¹H NMR (CDCl ₃): δ 4.60-4.65 (m, 2H), 4.71-4.74 (m, 2H), 5.50 (s br, 2H), 7.10 (s br, 1H), 7.13-7.17 (m, 2H), 7.55-7.59 (m, 2H), 8.49 (s, 2H), 8.50 (s, 1H).

LC-MS: t _R=0.93 min, [M+H] ⁺=544.70.

Clinical data

Trade names	Tryvio
Other names	ACT-132577
AHFS/Drugs.com	Tryvio
Routes of administration	By mouth
Drug class	Antihypertensive
ATC code	C02KN01 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1103522-45-7
PubChem CID	25099191
IUPHAR/BPS	10070
DrugBank	DB15059
ChemSpider	25027753
UNII	MZI81HV01P
KEGG	D11441
ChEBI	CHEBI:76609
ChEMBL	ChEMBL2165326
Chemical and physical data
Formula	C₁₆H₁₄Br₂N₆O₄S
Molar mass	546.19 g·mol⁻¹
3D model (JSmol)	Interactive image
hideSMILESC1=CC(=CC=C1C2=C(N=CN=C2OCCOC3=NC=C(C=N3)Br)NS(=O)(=O)N)Br

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “Tryvio- aprocitentan tablet, film coated”. DailyMed. 29 March 2024. Archived from the original on 25 April 2024. Retrieved 25 April 2024.
^ Jump up to:^a ^b ^c “US FDA approves Idorsia’s once-daily Tryvio (aprocitentan) – the first and only endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled in combination with other antihypertensives” (Press release). Idorsia. 20 March 2024. Archived from the original on 28 April 2024. Retrieved 28 April 2024 – via PR Newswire.
^ Ojha, Utkarsh; Ruddaraju, Sanjay; Sabapathy, Navukkarasu; Ravindran, Varun; Worapongsatitaya, Pitchaya; Haq, Jeesanul; et al. (2022). “Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension”. American Journal of Cardiovascular Drugs. 22 (3): 271–285. doi:10.1007/s40256-021-00510-9. PMC 8651502. PMID 34878631.
^ Jump up to:^a ^b Xu, Jingjing; Jiang, Xiaohua; Xu, Suowen (November 2023). “Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential”. Drug Discovery Today. 28 (11): 103788. doi:10.1016/j.drudis.2023.103788. PMID 37742911.
^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
^ Deswal, Phalguni (6 September 2023). “Idorsia reacquires aprocitentan rights from Janssen for $343m”. Pharmaceutical Technology. Archived from the original on 8 November 2023. Retrieved 8 November 2023.
^ Jump up to:^a ^b “Jeraygo EPAR”. European Medicines Agency. 25 April 2024. Archived from the original on 30 April 2024. Retrieved 27 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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