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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

Zevotrelvir, EDP 235

September 8, 2024 3:11 am / Leave a comment

Zevotrelvir, EDP 235

cas 2773516-53-1

N-[(2S)-1-[(2′S,3R)-2′-cyano-2-oxospiro[1H-indole-3,4′-pyrrolidine]-1′-yl]-4-methyl-1-oxopentan-2-yl]-4,6,7-trifluoro-N-methyl-1H-indole-2-carboxamide

C₂₈H₂₆F₃N₅O_3, 537.5

4U32ECV8B7

1H-Indole-2-carboxamide, N-[(1S)-1-[[(3R,5’S)-5′-cyano-1,2-dihydro-2-oxospiro[3H-indole-3,3′-pyrrolidin]-1′-yl]carbonyl]-3-methylbutyl]-4,6,7-trifluoro-N-methyl-

Zevotrelvir (Compound 52) is a coronavirus inhibitor with IC₅₀ ranges of <0.1 μM and <0.1mM for 229E hCoV and SARS-CoV-23C-like (3CL) proteases, respectively. Zevotrelvir has the potential to study viral infections.

Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs has a 5′-cap structure and 3′-poly-A tail and contains at least 6 open reading frames (ORFs). The first ORF (ORF 1a/b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed by a 3C-Like protease (3CLpro), also known as the main protease (Mpro), into 16 non-structural proteins. These non-structural proteins engage in the production of subgenomic RNAs that encode four structural proteins, namely envelope, membrane, spike, and nucleocapsid proteins, among other accessory proteins. As a result, it is understood that 3C-Like protease has a critical role in the coronavirus life cycle.

3CLpro is a cysteine protease involved in most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and features a Cys-His dyad located in between domains I and II.3CLpro is conserved among coronaviruses and several common features are shared among the substrates of 3CLpro in different coronaviruses. As there is no human homolog of 3CLpro, it is an ideal antiviral target. Although compounds have been reported to inhibit 3CLpro activity, they have not been approved as coronavirus therapies. (Refer to

WO 2004101742 A2, US 2005/0143320 Al, US 2006/0014821 Al, US 2009/0137818

Al, WO 2013049382 A2, WO 2013166319 A1, WO2018042343, WO2018023054, WO 2022013684, WO 2021252644, WO2022020711, WO 2022020242, US 11,174,231 B1, US 11,124,497 B1, WO 2005113580, and WO2006061714).

There is a need in the art for novel therapeutic agents that treat, ameliorate or prevent SARS-CoV-2 infection. The present invention provides the process of novel compounds which act in inhibiting or preventing SARS-CoV-2 viral replication and thus are used in the treatment of COVID-19 (see PCT/US21/60247).

Synthesis of substituted spirooxindole and its intermediate has been previously published (Refer to PCT/US21/60247, WO2019086142, WO 2020221811, WO2020221826, J. Med. Chem.2012, 55, 9069). However, the scale-up using previous process is very challenging due to the safety concern associated with certain intermediates, instability of certain intermediates as well as lack of purification process other than column chromatograph. Thus, there is a strong need for developing a safe and efficient processes for the large-scale preparation of these novel substituted spirooxindole derivatives.

SYNTHESIS

US11352363, Example 52

https://patents.google.com/patent/US11352363B1/en

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US362064348&_cid=P10-M0SZPD-12620-1

SYN

[1]. Guoqiang Wang, et al. Novel spiropyrrolidine derived antiviral drugs. Patent CN114524821A.

1.20230295175PROCESSES FOR THE PREPARATION OF SUBSTITUTED SPIROOXINDOLE DERIVATIVES

2.WO/2023/177854PROCESSES FOR THE PREPARATION OF SUBSTITUTED SPIROOXINDOLE DERIVATIVES

3.WO/2022/109363NOVEL SPIROPYRROLIDINE DERIVED ANTIVIRAL AGENTS

Enanta Pharmaceuticals, Inc.

WO2023177854

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023177854&_cid=P10-M0SZ7T-99709-1

Example 15. Preparation of Preparation of (3R,5’S)-1′-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide (Compound (n))

DMF (760 kg, 8V) was added into the reaction at 0 °C (-5~5 °C) followed by compound (j) (63 kg, 1.05 eq) and N-Methylmorpholine (56 kg, 2 eq), HATU

(106 kg, 1.0 eq) and Compound (m-1) (100 kg, 1.0 eq). The reactor was rinsed with DMF (190 kg, 2V) under and warmed up to 25 °C (20~30 °C) and stirred for 5 h (3~6 h) at 25 °C (20~30 °C). After that, additional HATU (0.1 eq) was added and the reaction mixture was stirred for 16-24 h.25% Ammonium hydroxide (38 kg) was added to the reaction mixture at 25 °C (20~30 °C) and stirred for 2 h (1~3 h) at 25 °C (20~30 °C). The reaction mixture was then added to water (5000 kg, 50V) at 20-30°C over 2 h and the resulting slurry was stirred for 2 h (1~5 h) at 25 °C (20~30 °C). The mixture was filtered and the cake was rinsed with water (500 kg, 5 V). The cake was dissolved in ethyl acetate (1350 kg, 15 V) and washed with 10% sodium chloride solution (500 kg) for three times. The organic layer was separated to 1.5-2.5V at not more than 45℃ under vacuum. The solution was cooled to 25 °C (20~30 °C) and Dichloromethane (660 kg, 5V) was added. The mixture was stirred for 2 h (2~5 h) at 25 °C (20~30 °C) and a slurry was formed. n-Heptane (137 kg, 2V) was added dropwise over 0.5 h (0.5~2 h) at 25 °C (20~30 °C) and stirred for additional 2 h (1~3 h) at 25 °C (20~30 °C). The reaction mixture was filtered and the wet cake was rinsed with DCM/heptane (5/2). The wet cake was dried at 50 °C (45~55 °C) for 20 h (15~25 h) to provide Compound (n) as the white solid in 80-85% yield.

Example 16. Preparation of (3R,5’S)-1′-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide (Compound (n))

DMF solution of Compound (m-2) (1 kg, 1.0 eq.) was added to a reactor at around 0-10^oC. Compound (l) (600 g, 1.0 eq.), NMM (3.00 eq., 850 g) and HATU (1.00 eq., 1.06 kg) was added to the reactor while maintaining the temperature at 0-10^oC; The reaction was warmed to 20±5^oC, and stirred for at least 6 hours at 20±5^oC. HATU (0.20 eq., 210 g) was added to the reactor at 20±5^oC and stirred for at least 6 hours at 20±5^oC.25% Ammonium hydroxide (390 g, 1.0 eq) was added to the reaction mixture at 20 °C and stirred for 2 h (1~3 h) at 20 °C. EtOAc (14.0 V) and water (14 V) was added at around 25^oC over 20 minutes, and the

solution was stirred for at least 30 min. Aqueous phase was extracted with EtOAc for three times and the organic phase was combined, and washed with 10% aq. NaCl for three times at 20±5^oC. The organic phase was concentrated to 6 V then EtOH (7.0 V) was charged. The EtOAc-EtOH solvent swap was repeated for three times and concentrated to 5 V before water (7.0 v) was added at 20±5^oC. The mixture was cooled to 0-10^oC and stirred for 1 h before being filtered. The filter cake was dissolved in ethyl acetate (15 V) and washed with 10% sodium chloride solution for three times. The organic layer was concentrated to 2-3V at not more than 45℃ under vacuum. The solution was cooled to 25 °C (20~30 °C) and Dichloromethane (5V) was added. The mixture was stirred for 2 h (2~5 h) at 25 °C (20~30 °C) and a slurry was formed. n-Heptane (2V) was added dropwise over 0.5 h (0.5~2 h) at 25 °C (20~30 °C) and stirred for additional 2 h (1~3 h) at 25 °C (20~30 °C). The reaction mixture was filtered and wet cake was rinsed with DCM/heptane (5/2). The wet cake was dried at 50 °C (45~55 °C) for 20 h (15~25 h) to provide Compound (n) as the white solid in about 70-75% yield over two steps.

Example 17. Preparation of (3R,5’S)-1′-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide (Compound (n))

DMF (10.0 v) was added to a reactor at 25 °C followed by Compound (l) (4.4 kg, 1.0 eq.), NMM (3.0 eq.) Compound (m-3) (1.0 eq.) and HATU (1.0 eq) at 20-25^oC. The reaction mixture was stirred for at least 12 hours at 20-25 ^°C. Once reaction was complete, aqueous ammonium hydroxide (1.0 eq.) was to the reaction system at 20-25 °C, then stirred for at least 2 hours at 20-25^oC. The reaction mixture was then added to water (220 kg, 50V) at 20-30°C over 2 h and the resulting slurry was stirred for 2 h (1~5 h) at 25 °C (20~30 °C). The mixture was filtered and the cake was rinsed with water (22 kg, 5 V). The cake was dissolved in ethyl acetate (135 g, 15 V) and washed with 10% sodium chloride solution (22 kg) for three times. The organic layer was separated to 1.5-2.5V at not more than 45 ℃ under vacuum. The solution was cooled to 25 °C (20~30 °C) and Dichloromethane (5V) was added. The mixture was stirred for 2 h (2~5 h) at 25 °C (20~30 °C) and a slurry was formed. n-Heptane (2V) was added dropwise over 0.5 h (0.5~2 h) at 25 °C (20~30 °C) and stirred for additional 2 h (1~3 h) at 25 °C (20~30 °C). The reaction mixture was filtered and wet cake was rinsed with DCM/heptane (5/2). The wet cake was dried at 50 °C (45~55 °C) for 20 h (15~25 h) to provide Compound (n) as the white solid in 80-85% yield.

¹H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.68 (s, 1H), 7.56 (s, 1H), 7.15 – 7.00 (m, 3H), 6.91 (t, J = 4.4 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 5.34 (t, J = 7.3 Hz, 1H), 4.63 (dd, J = 9.8, 8.0 Hz, 1H), 3.83 (q, J = 10.3 Hz, 2H), 3.45 (qd, J = 7.0, 5.1 Hz, 1H), 3.16 (s, 3H), 2.35 – 2.13 (m, 2H), 1.69 (t, J = 7.1 Hz, 2H), 1.56 (dq, J = 13.1, 6.5 Hz, 1H), 0.93 (dd, J = 12.2, 6.3 Hz, 6H). Example 18. Preparation of N-((S)-1-((3R,5’S)-5′-cyano-2-oxospiro[indoline-3,3′-pyrrolidin]-1′-yl)-4-methyl-1-oxopentan-2-yl)-4,6,7-trifluoro-N-methyl-1H-indole-2-carboxamide toluene solvate (Compound (I))

(I))

Ethyl acetate (630 kg, 10 V) was added into reactor (R1) followed by Compound (n) (70 kg). Make sure the water content was less than 0.20% (w/w). The reaction was cooled to 0 °C (-5 – 5°C) and then triethylamine (89.6 kg) was added followed by trifluoroacetic anhydride (92.4 kg) at 0 °C (-5 – 5°C). The reaction was stirred for 1 h (0.5~2 h) at 0 °C (-5 – 5°C). Once the reaction was complete, the reaction mixture was added slowly to 0.2 N aqueous HCl solution (700 kg) over 1 h at 0 °C (-5~5 °C). The resulting solution was stirred for 30 min at 0 °C (-5~5 °C) and the organic layer was separated.1% aqueous ammonium hydroxide (700 kg) was added to the organic layer and stirred at 20 °C for 30 min (15~25 °C). The organic layer was separated and washed with 10% brine for four times. Then the organic layer was separated and distilled to 2-3 V. Toluene-EtOAc swap was performed until precipitate was observed at 3-4 V. Then Toluene (5-6 V) was added and the slurry was stirred at 50 ^oC for 2 h. Then the solution was cooled down to 20 ^oC over 1-2 h and stirred for 10 hr (6~14 hr) at 20 °C (15~25 °C). The reaction mixture was filtered and the wet cake was rinsed with toluene (120 kg, 2V). The wet cake was then dried at 50˚C (45~55 °C) for 48 hr to provide desired compound (o) as a white solid in 80-85% yield.

¹H NMR (400 MHz, Acetone-d6) δ 11.17 (s, 1H), 9.65 (s, 1H), 7.02 (dd, J = 13.7, 7.3 Hz, 2H), 6.94 (dd, J = 6.0, 3.5 Hz, 1H), 6.92 – 6.85 (m, 2H), 6.81 (t, J = 7.5 Hz, 1H), 5.56 (dd, J = 9.4, 5.6 Hz, 1H), 5.21 (t, J = 8.3 Hz, 1H), 4.25 (d, J = 10.7 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H), 3.43 (s, 3H), 2.79 – 2.61 (m, 2H), 1.93 (ddd, J = 14.4, 9.5, 5.1 Hz, 1H), 1.79 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H), 1.64 (dpd, J = 8.7, 6.6, 5.1 Hz, 1H), 0.98 (dd, J = 18.5, 6.6 Hz, 6H).

US20230103494

CN114524821

SCHEME

MAIN

////////Zevotrelvir, EDP 235

O=C1[C@@]2(CN([C@@H](C2)C#N)C([C@H](CC(C)C)N(C)C(C3=CC4=C(F)C=C(F)C(F)=C4N3)=O)=O)C5=CC=CC=C5N1

Afimetoran

September 7, 2024 5:59 am / Leave a comment

Afimetoran BMS-986256, WHO 11516

cas 2171019-55-7

2-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]acetamide

C₂₆H₃₂N₆O,444.583, phase 1

Afimetoran is an immunomodulator and an antagonist of toll-like receptors 7 and 8.^1,2 It is also is under investigation in clinical trial NCT04269356 (Study to Assess the Way the Body Absorbs, Distributes, Breaks Down and Eliminates Radioactive BMS-986256 in Healthy Male Participants).

US10071079, Example 15

Ref

WO2018005586

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018005586&_cid=P20-M0RQ0D-09010-1

The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to TLR modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting the activity of TLRs in a mammal.

Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J.E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Toll-like receptors (TLRs) are a family of evolutionarily conserved, transmembrane innate immune receptors that participate in the first-line defense. As pattern recognition receptors, the TLRs protect against foreign molecules, activated by pathogen associated molecular patterns (PAMPs), or from damaged tissue, activated by danger associated molecular patterns (DAMPs). A total of 13 TLR family members have been identified, 10 in human, that span either the cell surface or the endosomal compartment. TLR7-9 are among the set that are endosomally located and respond to single-stranded RNA (TLR7and TLR8) or unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).

Activation of TLR7/8/9 can initiate a variety of inflammatory responses (cytokine production, B cell activation and IgG production, Type I interferon response). In the case of autoimmune disorders, the aberrant sustained activation of TLR7/8/9 leads to worsening of disease states. Whereas overexpression of TLR7 in mice has been shown to exacerbate autoimmune disease, knockout of TLR7 in mice was found to be protective against disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9 showed further enhanced protection.

As numerous conditions may benefit by treatment involving modulation of cytokines, IFN production and B cell activity, it is immediately apparent that new compounds capable of modulating TLR7 and/or TLR8 and/or TLR9 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds found to be effective inhibitors of signaling through TLR7/8/9. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

EXAMPLE 15

2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl) piperidin-1-yl)acetamide

To a reaction flask were added

6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrid ine, 2 HCl (47.66 g, 104 mmol), DCE (220 mL), DBU (62.4 mL, 414 mmol), and 2-bromoacetamide (17.14 g, 124 mmol). The reaction flask was capped. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with water, and stirred for 30 minutes then filtered. The solid was recrystallized using ethanol to afford 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a] pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (42.3 g, 93 mmol,

90% yield) as a white solid. LCMS MH⁺: 445. HPLC Ret. Time 1.20 min. Method QC-ACN-TFA-XB. ¹HNMR (400 MHz, DMSO-d₆) δ 10.97-10.86 (m, 1H), 8.78-8.69 (m, 1H), 8.54-8.40 (m, 1H), 7.64-7.49 (m, 1H), 7.30-7.21 (m, 2H), 7.17-7.09 (m, 1H), 7.06-6.93 (m, 1H), 2.99-2.82 (m, 5H), 2.62-2.54 (m, 4H), 2.24-2.12 (m, 5H), 1.92-1.72 (m, 4H), 1.37-1.29 (m, 6H).

ACS Medicinal Chemistry Letters (2022), 13(5), 812-818 83%

References

Bristol-Myers Squibb: Investor Series [Link]
Bristol-Myers Squibb: Investor Series [Link]
MedKoo Biosciences: Afimetoran [Link]

//////////////Afimetoran, BMS-986256, BMS 986256, WHO 11516, phase 1

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.

Cefepime

May 17, 2024 6:23 am / Leave a comment

Cefepime

88040-23-7

INGREDIENT	UNII	CAS	INCHI KEY
Cefepime hydrochloride	I8X1O0607P	123171-59-5	LRAJHPGSGBRUJN-OMIVUECESA-N

Cefepime

CAS Registry Number: 88040-23-7

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt

Additional Names: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium hydroxide inner salt 72-(Z)-2-(O-methyloxime); 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate

Manufacturers’ Codes: BMY-28142

Molecular Formula: C19H24N6O5S2

Molecular Weight: 480.56

Percent Composition: C 47.49%, H 5.03%, N 17.49%, O 16.65%, S 13.34%

Literature References: Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al.,DE3307550; eidem,US4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al.,J. Antibiot.39, 1092 (1986). In vitro comparative antimicrobial spectrum: N. J. Khan et al.,Antimicrob. Agents Chemother.26, 585 (1984); and b-lactamase stability: H. C. Neu et al.,J. Antimicrob. Chemother.17, 441 (1986). HPLC determn in plasma and urine: R. H. Barbhaiya et al.,Antimicrob. Agents Chemother.31, 55 (1987). Clinical evaluations in infection: N. Clynes et al.,Diagn. Microbiol. Infect. Dis.12, 257 (1989); S. Oster et al.,Antimicrob. Agents Chemother.34, 954 (1990). Review of clinical pharmacokinetics: M. P. Okamoto et al.,Clin. Pharmacokinet.25, 88-102 (1993).

Properties: Colorless powder, mp 150° (dec). uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100).

Melting point: mp 150° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100)

Derivative Type: Sulfate

Molecular Formula: C19H24N6O5S2.H2SO4

Molecular Weight: 578.64

Percent Composition: C 39.44%, H 4.53%, N 14.52%, O 24.89%, S 16.62%

Properties: mp 210° (dec). uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900).

Melting point: mp 210° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900)

Derivative Type: Hydrochloride monohydrate

CAS Registry Number: 123171-59-5

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride monohydrochloride monohydrate

Additional Names: cefepime hydrochloride

Trademarks: Axepim (BMS); Cepimex (Mead Johnson); Maxipime (BMS)

Molecular Formula: C19H25ClN6O5S2.HCl.H2O

Molecular Weight: 571.50

Percent Composition: C 39.93%, H 4.94%, Cl 12.41%, N 14.71%, O 16.80%, S 11.22%

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

FDA APPROVED 2/22/2024, To treat complicated urinary tract infections, Exblifep

BMY 28142
BMY-28142

Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics.^[1] In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.^[2]

Cefepime was patented in 1982 by Bristol-Myers Squibb and approved for medical use in 1994.^[3] It is available as a generic drug and sold under a variety of trade names worldwide.^{[citation needed]}^[4]

It was removed from the World Health Organization’s List of Essential Medicines in 2019.^[5]

Medical use

Cefepime is usually reserved to treat moderate to severe nosocomial pneumonia, infections caused by multiple drug-resistant microorganisms (e.g. Pseudomonas aeruginosa) and empirical treatment of febrile neutropenia.^[6]

Cefepime has good activity against important pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and multiple drug-resistant Streptococcus pneumoniae. A particular strength is its activity against Enterobacteriaceae. Whereas other cephalosporins are degraded by many plasmid– and chromosome-mediated beta-lactamases, cefepime is stable and is a front-line agent when infection with Enterobacteriaceae is known or suspected.^{[medical citation needed]}

Spectrum of bacterial susceptibility

Cefepime is a broad-spectrum cephalosporin antibiotic and has been used to treat bacteria responsible for causing pneumonia and infections of the skin and urinary tract. Some of these bacteria include Pseudomonas, Escherichia, and Streptococcus species. The following represents MIC susceptibility data for a few medically significant microorganisms:^[7]

Escherichia coli: ≤0.007 – 128 μg/ml
Pseudomonas aeruginosa: 0.06 – >256 μg/ml
Streptococcus pneumoniae: ≤0.007 – >8 μg/ml

Chemistry

The combination of the syn-configuration of the methoxy imino moiety and the aminothiazole moiety confers extra stability to β-lactamase enzymes produced by many bacteria. The N–methyl pyrrolidine moiety increases penetration into Gram-negative bacteria. These factors increase the activity of cefepime against otherwise resistant organisms including Pseudomonas aeruginosa and Staphylococcus aureus.

Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al., DE 3307550; eidem, US 4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al., J. Antibiot. 39, 1092 (1986).

Trade names

Following expiration of the Bristol-Myers Squibb patent,^[] cefepime became available as a generic and is now^] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.

Clinical data


Pronunciation	/ˈsɛfɪpiːm/ or /ˈkɛfɪpiːm/
Trade names	Maxipime, Voco
AHFS/Drugs.com	Monograph
MedlinePlus	a698021
Pregnancy category	AU: B1
Routes of administration	Intravenous, intramuscular
ATC code	J01DE01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability	100% (IM)
Metabolism	Hepatic 15%
Elimination half-life	2 hours
Excretion	Renal 70–99%
Identifiers
showIUPAC name
CAS Number	88040-23-7
PubChem CID	5479537
DrugBank	DB01413
ChemSpider	4586395
UNII	807PW4VQE3
KEGG	D02376
ChEBI	CHEBI:478164
ChEMBL	ChEMBL186
CompTox Dashboard (EPA)	DTXSID70873208
ECHA InfoCard	100.171.025
Chemical and physical data
Formula	C₁₉H₂₄N₆O₅S₂
Molar mass	480.56 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	150 °C (302 °F) (dec.)
showSMILES
showInChI
(verify)

References

^ Yahav D, Paul M, Fraser A, Sarid N, Leibovici L (May 2007). “Efficacy and safety of cefepime: a systematic review and meta-analysis”. The Lancet. Infectious Diseases. 7 (5): 338–348. doi:10.1016/S1473-3099(07)70109-3. PMID 17448937.
^ “FDA Alert: Cefepime (marketed as Maxipime)”. Information for Healthcare Professionals. Food and Drug Administration. Archived from the original on 2 November 2017. Retrieved 2 August 2009.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 496. ISBN 9783527607495. Archived from the original on 19 June 2021. Retrieved 19 September 2020.
^ “Cefepime (maxipime), large spectrum 4th generation cephalosporin, resistant to beta-lactamases]”.
^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
^ Chapman TM, Perry CM (2003). “Cefepime: a review of its use in the management of hospitalized patients with pneumonia”. American Journal of Respiratory Medicine. 2 (1): 75–107. doi:10.1007/bf03256641. PMID 14720024.
^ “Cefepime Susceptibility and Concentration Range (μg/ml) Minimum Inhibitory Concentration (MIC) Data” (PDF). The Antimicrobial Index. toku-e.com. Archived from the original (PDF) on 1 November 2018.

External links

“Cefepime”. Drug Information Portal. U.S. National Library of Medicine.

//////////cefepime, Exblifep, FDA 2024, APPROVALS 2024, BMY 28142, BMY-28142

Berdazimer

May 14, 2024 8:33 am / Leave a comment

Berdazimer

1846565-00-1

CAS NA SALT, 1846565-00-1

FDA APPROVE 1 /5/2024, To treat molluscum contagiosum
Drug Trials Snapshot

NVN-1000 free acid
NVN1000 free acid
Silsesquioxanes, 3-(2-hydroxy-1-methyl-2-nitrosohydrazinyl)propyl 3-(methylamino)propyl, polymers with silicic acid (h4sio4) tetra-et ester, hydroxy-terminated

Berdazimer sodium, sold under the brand name Zelsuvmi, is a medication used for the treatment for molluscum contagiosum.^[1] Berdazimer sodium is a nitric oxide releasing agent.^[1] It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3-(trimethoxysilyl)propyl)-1-triazene-2-oxide and tetraethyl silicate.^[2]

Berdazimer sodium was approved for medical use in the United States in January 2024.^[3]^[4]^[5]

Medical uses

Berdazimer sodium is indicated for the topical treatment of molluscum contagiosum.^[1]

Pharmacology

Mechanism of action

Berdazimer sodium is a nitric oxide releasing agent.^[1] The mechanism of action for the treatment of molluscum contagiosum is unknown.^[1]

Pharmacodynamics

The pharmacodynamics of berdazimer sodium are unknown.^[1]

Society and culture

Legal status

Berdazimer sodium was approved for medical use in the United States in January 2024.^[4]

Names

Berdazimer sodium is the international nonproprietary name.^[6]

Berdazimer

Berdazimer is a polymeric substance consisting of a polysiloxane backbone (Si-O-Si bonds) with covalently bound N-diazeniumdiolate nitric oxide (NO) donors. It releases NO through exposure to proton donors like water, which will degrade the N-diazeniumdiolate entity.² Berdazimer was previously investigated as a potential treatment for molluscum contagiosum, a viral cutaneous infection mainly affecting children, sexually active adults, and immunocompromised patients. It is one of the 5 most prevalent skin diseases in the world and the third-most common viral skin infection in children.³ Previously, the first line treatment for molluscum contagiosum was surgical excision, although it poses challenges such as repeated doctor visits, post-surgical scarring and skin discoloration, and fear and anxiety in the pediatric population.³

On Jan 05, 2024, the FDA approved berdazimer under the brand name ZELSUVMI for the treatment of adult and pediatric molluscum contagiosum, and it is the first drug to be approved for this condition. This decision is based on positive results demonstrated in 2 Phase 3 trials, B-SIMPLE 4 and B-SIMPLE 2, where reduced lesion counts were observed with once-a-day uses of berdazimer.⁵

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Zelsuvmi (berdazimer) topical gel” (PDF). Archived (PDF) from the original on 19 January 2024. Retrieved 9 January 2024.
^ “GSRS”. gsrs.ncats.nih.gov. Archived from the original on 8 January 2024. Retrieved 8 January 2024.
^ “Drug Approval Package: Zelsuvmi”. U.S. Food and Drug Administration (FDA). 2 February 2024. Archived from the original on 11 March 2024. Retrieved 11 March 2024.
^ Jump up to:^a ^b “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.
^ “U.S. Food and Drug Administration Approves Zelsuvmi as a First-in-Class Medication for the Treatment of Molluscum Contagiosum”. Ligand Pharmaceuticals. 5 January 2024. Archived from the original on 8 January 2024. Retrieved 8 January 2024 – via Business Wire.
^ 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

“Berdazimer Sodium (Code C174810)”. NCI Thesaurus.
Clinical trial number NCT04535531 for “A Phase 3 Molluscum Contagiosum Efficacy and Safety Study (B-SIMPLE4)” at ClinicalTrials.gov
Clinical trial number NCT03927703 for “A Phase 3 Efficacy & Safety of SB206 & Vehicle Gel for the Treatment of MC (B-SIMPLE2)” at ClinicalTrials.gov
Clinical trial number NCT03927716 for “A Phase 3 Randomized Parallel Group Study Comparing the Efficacy & Safety of SB206 & Vehicle Gel in the Treatment of MC (B-SIMPLE1)” at ClinicalTrials.gov

Clinical data

Trade names	Zelsuvmi
Other names	SB206
License data	US DailyMed: Berdazimer sodium
Routes of administration	Topical
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1846565-00-1
DrugBank	DBSALT003491 DB18712
UNII	ORT9SID4QY B23P7SM943
KEGG	D12758
ChEMBL	ChEMBL4298064
Chemical and physical data
Formula	Indeterminate^[1]
Molar mass	Indeterminate^[1]

/////Berdazimer, Zelsuvmi, FDA 2024, APPROVALS 2024, NVN-1000 free acid, NVN1000 free acid

Tovorafenib

May 10, 2024 2:50 am / Leave a comment

(r)-2-(1-(6-Amino-5-chloropyrimidine-4-carboxamido)ethyl)-n-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide.png

Tovorafenib

506.29

C₁₇H₁₂Cl₂F₃N₇O₂S

1096708-71-2

6-amino-5-chloro-N-[(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}-1,3-thiazol-2-yl)ethyl]pyrimidine-4-carboxamide

4/23/2024 FDA APROVED, To treat relapsed or refractory pediatric low-grade glioma, Ojemda

AMG 2112819
BIIB 024
BIIB-024
BIIB024
DAY 101
DAY-101
DAY101
MLN 2480
MLN-2480
MLN2480
TAK 580
TAK-580
TAK580

Tovorafenib, sold under the brand name Ojemda, is a medication used for the treatment of glioma.^[1] It is a kinase inhibitor.^[1]

The most common adverse reactions include rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.^[2] The most common grade 3 or 4 laboratory abnormalities include decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.^[2]

It was approved for medical use in the United States in April 2024,^[1]^[2]^[3]^[4] and is the first approval of a systemic therapy for the treatment of people with pediatric low-grade glioma with BRAF rearrangements, including fusions.^[2]

Medical uses

Tovorafenib is indicated for the treatment of people six months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.^[1]^[2]

History

Efficacy was evaluated in 76 participants enrolled in FIREFLY-1 (NCT04775485), a multicenter, open-label, single-arm trial in participants with relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy.^[2] Participants were required to have documented evidence of radiographic progression and at least one measurable lesion.^[2] Participants with tumors harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded.^[2] Participants received tovorafenib based on body surface area (range: 290 to 476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.^[2] The US Food and Drug Administration (FDA) granted the application for tovorafenib priority review, breakthrough therapy, and orphan drug designations.^[2]

Society and culture

Names

Tovorafenib is the international nonproprietary name.^[5]

SYN

PATENT

WO 2009/006389

Huang et al., Angew. Chem. int. Ed. (2016), 55, 5309-5317

Jiang Xiao-bin et al., Org. Lett. (2003), 5, 1503

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43216699&_cid=P22-LW02JF-43766-1

10Da

(R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4- (trifluoromethyl)pyridin-2-yl)thiazole-5- carboxamide

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009006389&_cid=P22-LW025M-38416-1

Patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US131345763&_cid=P22-LW02NH-45076-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US201396258&_cid=P22-LW02NH-45076-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP292571929&_cid=P22-LW02NH-45076-1

References

^ Jump up to:^a ^b ^c ^d ^e “Archived copy” (PDF). Archived (PDF) from the original on 24 April 2024. Retrieved 24 April 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma”. U.S. Food and Drug Administration (FDA). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 25 April 2024. This article incorporates text from this source, which is in the public domain.
^ “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.
^ “Day One’s Ojemda (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor”. Day One Biopharmaceuticals (Press release). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 24 April 2024.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

External links

“Tovorafenib”. NCI Drug Dictionary.
“Tovorafenib (Code C106254)”. NCI Thesaurus.
Clinical trial number NCT04775485 for “A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)” at ClinicalTrials.gov

Clinical data

Trade names	Ojemda
Other names	BIIB-024, MLN2480, AMG 2112819, DAY101, TAK-580
License data	US DailyMed: Tovorafenib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1096708-71-2
PubChem CID	25161177
DrugBank	DB15266
ChemSpider	28637796
UNII	ZN90E4027M
KEGG	D12291
ChEBI	CHEBI:167672
ChEMBL	ChEMBL3348923
PDB ligand	QOP (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₇H₁₂Cl₂F₃N₇O₂S
Molar mass	506.29 g·mol⁻¹
showInChI

////////Tovorafenib, Ojemda, FDA 2024. APPROVALS 2024, AMG 2112819, BIIB 024, BIIB-024, BIIB024, DAY 101, DAY-101, DAY101, MLN 2480, MLN-2480, MLN2480, TAK 580, TAK-580, TAK580

Ceftobiprole

April 15, 2024 2:37 am / Leave a comment

C₂₀H₂₂N₈O₆S₂

534.57

209467-52-7

(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(N-hydroxyimino)acetamido]-8-oxo-3-{[(3E,3’R)-2-oxo-[1,3′-bipyrrolidin]-3-ylidene]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

BAL-9141
BAL-9141-000
BAL-9141000
BAL9141-000
RO 63-9141
RO-63-9141
RO-639141

ceftobiprole medocaril sodium

Molecular Weight	712.64
Formula	C₂₆H₂₅N₈NaO₁₁S₂
CAS No.	252188-71-9
Appearance	Solid
Color	Off-white to light yellow
SMILES	O=C(C(N(C1=O)[C@@](SC2)([H])[C@@H]1NC(/C(C3=NSC(N)=N3)=N\O)=O)=C2/C=C(CCN4[C@@](CC5)([H])CN5C(OCC(OC6=O)=C(O6)C)=O)/C4=O)O[Na]

fda approved 4/3/2024, To treat certain bloodstream infections, bacterial skin and associated tissue infections, and community-acquired bacterial pneumonia
Press Release zevtera

Ceftobiprole, sold under the brand name Zevtera among others, is a fifth-generation^[5] cephalosporin antibacterial used for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia. It is marketed by Basilea Pharmaceutica under the brand names Zevtera and Mabelio.^[6]^[7]^[8]^[9]^[10]^[11] Like other cephalosporins, ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. Ceftobiprole has high affinity for penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus strains and retains its activity against strains that express divergent mecA gene homologues (mecC or mecALGA251). Ceftobiprole also binds to penicillin-binding protein 2b in Streptococcus pneumoniae (penicillin-intermediate), to penicillin-binding protein 2x in Streptococcus pneumoniae (penicillin-resistant), and to penicillin-binding protein 5 in Enterococcus faecalis.^[12]

Medical uses

In the US, ceftobiprole is indicated for the treatment of adults with Staphylococcus aureus bloodstream infections (bacteremia) including those with right-sided infective endocarditis;^[4] adults with acute bacterial skin and skin structure infections;^[4] and people with community-acquired bacterial pneumonia.^[4]

Microbiology

Ceftobiprole has shown in vitro antimicrobial activity against a broad range of Gram-positive and Gram-negative pathogens. Among the Gram-positive pathogens, ceftobiprole has demonstrated good in vitro activity against methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, as well as against strains of methicillin-resistant Staphylococcus aureus with reduced susceptibility to linezolid, daptomycin or vancomycin.^[13] Ceftobiprole has also displayed potent activity against Streptococcus pneumoniae (including penicillin-sensitive, penicillin-resistant and ceftriaxone-resistant strains) and Enterococcus faecalis, but not against Enterococcus faecium. For Gram-negative pathogens, ceftobiprole has shown good in vitro activity against Haemophilus influenzae (including both ampicillin-susceptible and ampicillin-non-susceptible isolates), Pseudomonas aeruginosa and strains of Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis that do not produce extended-spectrum β-lactamases (ESBL). Like all other cephalosporins, ceftobiprole was inactive against strains that produce extended-spectrum β-lactamases.^[14]

The efficacy of ceftobiprole has been demonstrated in two large randomized, double-blind, phase 3 clinical trials in patients with hospital-acquired and community-acquired pneumonia. Ceftobiprole was non-inferior to ceftazidime plus linezolid in the treatment of hospital-acquired pneumonia (excluding ventilator-acquired pneumonia) and non-inferior to ceftriaxone with or without linezolid in the treatment of community-acquired pneumonia.^[15]^[16]

Pharmacology

Ceftobiprole is the active moiety of the prodrug ceftobiprole medocaril and is available for intravenous treatment only. It is mainly excreted via the kidney.^[17]

Society and culture

Legal status

Ceftobiprole has been approved for the treatment of adults with hospital acquired pneumonia (excluding ventilator-acquired pneumonia) and community-acquired pneumonia in twelve European countries, Canada, and Switzerland.^[18]

In February 2010, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a negative opinion, recommending the refusal of the marketing authorization for the medicinal product Zeftera, intended for treatment of complicated skin and soft-tissue infections in adults. The company that applied for authorization is Janssen-Cilag International N.V. The applicant requested a re-examination of the opinion. After considering the grounds for this request, the CHMP re-examined the opinion, and confirmed the refusal of the marketing authorization in June 2010.^[19]

syn

https://www.sciencedirect.com/topics/neuroscience/ceftobiprole

syn

WO2010136423

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010136423&_cid=P20-LV0C7F-38615-1

Processes for producing ceftobiprole medocaril are known per se. What the processes known from the prior art have in common is that, starting from 7-aminocephalosporanic acid, a large number of intermediates have to be produced, isolated and purified in order to obtain ceftobiprole medocaril of the general formula (1) in sufficient purity.

The compound of the general formula (1) is known per se and is described, for example, in WO 99/65920. It can be used for the treatment and prophylaxis of bacterial infectious diseases, especially infectious diseases caused by methicillin-resistant Staphylococcus Aureus strains.

WO 99/65920 describes, as the last step in the production process of ceftobiprole Medocaril, a reaction in which the Medocaril prodrug unit is introduced into a compound of the general formula (2).

The compound of the general formula (2) is also known per se and has been described, for example, in EP 0 849 269 A1. The compound of the general formula (2) is prepared according to EP 0 849 269 A1 starting from (2R,6R,7R)-te rt. B u toxyc abonylamin o-3-formyl-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester by Wittig reaction with (1 ‘-allyloxycarbonyl-2- oxo-[1,3’]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide. The resulting Δ2 reaction product is reisomerized to the desired Δ3 isomer by sulfoxidation and subsequent reduction and then deprotected from the benzhydryl ester with trifluoroacetic acid. The acylation in position 7 occurs by reaction with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)-trityloxyiminothioacetic acid S-benzothiazol-2-yl ester. The compound of the general formula (2) is then obtained by removing the protective groups.

In EP 1 067 131 A1 the formation of the ylide in toluene or a mixture of toluene and dichloromethane is tert by adding alkali. Butylate in tetrahydrofuran, which allows the base to be added as a solution. The reaction of the ylide with the corresponding aldehyde is described at a reaction temperature of -70 ⁰ C.

EP 0 841 339 A1 relates to cephalosporin derivatives and processes for their production. WO 95/29182 also discloses intermediates for the production of cephalosporins.

WO 01/90111 describes a further production of ceftobiprole Medocaril in several stages starting from desacetyl-7-aminocephalosporanic acid by acylation with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)- trityloxyiminothioacetic acid S-benzothiazol-2-yl ester in N,N-dimethylformamide, followed by in situ esterification with diphenyldiazomethane in dichloromethane to give the corresponding benzohydryl ester, which is precipitated and isolated by adding hexane. In the next step, this product is oxidized to the corresponding aldehyde using TEMPO/NaOCI in dichloromethane/water or with Braunstein in tetrahydrofuran/dichloromethane. The next reaction step involves the Wittig reaction to the 3-vinyl-substituted derivative, in which the reaction takes place in dichloromethane/toluene/tetrahydrofuran at -78°C. The crude product is stirred with ethanol and made from dichloromethane/tert. Butyl methyl ether recrystallized or purified chromatographically. According to the method disclosed in WO 01/901 11, the Wittig reaction is carried out at low temperatures of -80 to -70 ⁰ C in a complex solvent mixture of dichloromethane, toluene and tetrahydrofuran. This leads to significant disadvantages when carrying out the reaction on a production scale, since regeneration of the process solvents is difficult.

EXAMPLES

1. Example: (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[I.S’lbipyrrolidinyl-S-ylidenemethyll-β- oxo-S-thia-i -aza-bicyclo^^.Oloct^-ene-2-carboxylic acid

5 , 1 4 g of 7-amino-3-formyl-ceph-3-em-4-carboxy I at was dissolved in 2 7 , 8 m bis(trimethylsilyl)acetamide and 50 ml propylene oxide. ^16.8 g of (1 R/S,3’R)-(1′-tert-butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02/14332) slowly added in portions. Stirring was continued at 1 ° C until the starting material had reacted and then the crystalline precipitate was added

Nitrogen atmosphere filtered off and washed with 50 ml cyclohexane/bis(tirmethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the desired product was obtained in silylated form.

The material was dissolved in 100ml dichloromethane and at 0 ⁰ C with 50ml 3%

NaHCC> ₃ solution added. The phases were separated, the organic phase was washed with 30 ml of water and the combined water phases were adjusted to pH 3.5 with 3% H ₃ PO ₄ after activated carbon treatment. The crystalline precipitate was filtered, washed with water and dried under vacuum.

Auswaage: 6,09g

¹H-nmr(DMSO-d₆) δ 1.39(s,9H), 2.00(m, 2H), 2.8-3.2(m, 2H), 3.2-3.5(m,6H), 3.84(ABq, 2H, J= 18.2Hz), 4.57(m,1H), 4.82(d,1H, J=5.1Hz), 5.01 (d,1H, J=5.1Hz), 7.21 (m,1H)

¹³ C-nmr(DMSO-d ₆ ) d 24.63, 26.11 , 28.09, 28.89, 41.54, 44.94, 45.31 , 47.98, 48.34, 51.27, 52.00, 58.98, 63.76, 79.95, 121.95 , 126.19, 126.28, 129.90, 134.21, 154.97 , 164.36, 169.05, 169.13

MS- ESI negative mode: 927.2(2M-H, 100%, 463.1(M-H, 25%)

H2O content: _2.2 %

IR (golden gate, cm^“1): 2978, 1793, 1682, 1551, 1397, 1363, 1330

2. Beispiel: (6R,7R)-7-Trimethylsilylamino-3[E-(R)-1′-(5-tert.butyloxycarbonyl)-2- oxo-[1 , 3′]bipyrrolidinyl -3 -ylidenemethyll-δ-oxo-δ-thia-i-aza-bicyclo^^.0]oct- 2-ene-2-carbonsäure trimethylsilylester

10.28 g of 7-amino-3-formyl-ceph-3-em-4-carboxylate were dissolved in 55.6 ml of bis(trimethylsilyl)acetamide and 100 ml of propylene oxide. 33.6 g of (1R/S, 3’R)-(1′-tert. Butyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide (EP1067131, WO02.) were then added at 0 ⁰ C /14332) slowly added in portions over 22 hours. The mixture was stirred at 1° C. until the starting material had reacted and then the reaction mixture was cooled to -20 ^° C. The crystalline precipitate was filtered off under a nitrogen atmosphere and washed in portions with 180 ml of cyclohexane/bis(trimethylsilyl)acetamide 99.5/0.5. After drying under vacuum, the bissilylated

Product received.

Weight: 16.2g

¹H-nmr(CDCI₃) δ 0.04,0.10,0.12(3s, 9H), 0,34(s, 9H), 1,43 (s, 9H), 1.74 (br s, 1H),

1.9-2.2 (m, 2H), 2.8-3.0 (m,2H), 3.2-3.7 (m,8H), 4.7-4.95 (m, 3H), 7.43 (m, 1H)

3. Beispiel: Dicyclohexylammonium (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert. butyloxycarbonyl)-2-oxo-[1 ,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1 – aza-bicyclo[4.2.0]oct-2-ene-2-carboxylat

1.0g (6R,7R)-7-Trimethylsilylamino-3[E-(R)-1′-(5-tert.butyloxycarbonyl)-2-oxo-[I.Slbipyrrolidinyl-S-ylidenemethyO-δ-oxo-δ -thia-i-aza-bicyclo^^.Oloct^-ene^- carboxylic acid trimethylsilyl esters were dissolved in 10ml dichloromethane and a solution of 300mg dicyclohexylamine in 1ml EtOH and 10ml ethyl acetate was added. The precipitate was filtered off, washed with ethyl acetate and dried in vacuo.

Auswaage: 0,9g ¹H-nmr(D₂O/DMSO-d₆) δ 0.9-1 .3(m, 10H), 1 .30(s,9H), 1 .4-2.18m,12H), 2.7- 3.5(01,1 OH), 3.64(ABq, J= 17.2Hz, 2H), 4.5 (m,1 H) ^* , 4.58 (d,1 H, J=5.1 Hz); 4.88 (d,1 H, J=5.1 Hz), 7.07 (s,1 H)

^* partly overlaid by D20 signal

MS- ESI negative mode: 927.2(2M-H, 100%), 463.1 (M-H, 25%)

IR (golden gate, cm ^“1): 2932, 2856, 1754, 1692, 1671 , 1630, 1569, 1394, 1329

4. Specifically: (6R, 7R )-7-[(Z)-2-(5-Amino-[1 ,2,4]thiadiazol-3-yl)-2-hydroxyimino- acetylamino]-8-oxo- 3-[(E)-(R)-2-oxo-[1 , 3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-jen-2 carbons Trifluoroacetate

4.1 Variant A:

3.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 150 ml of dichloromethane at 0°. 600 μl of DMF/water 5/1 and 1.8 ml of bis(trimethylsilyl) acetamide and 2.29 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetic acid chloride were then added Hydrochoride (J. Antibiotics 37:557 – 571, 1984) was added in portions.

After 3 hours at 0°, the mixture was poured into 30 ml MeOH/120 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 66g and 25ml of trifluoroacetic acid was added. After 10 minutes, 1.5 ml triethylsilane and 10 ml water were added and the mixture was cooled to -15 ° C. The organic phase was separated off and again with 6 ml

Washed trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 150 ml with water and filtered through an adsorber resin column with XAD-1600. After washing out the column with water, elution was carried out with water/acetonitrile 85/15. The product-containing fractions were concentrated in vacuo and allowed to stand at 0° for post-crystallization. The crystalline

Product was filtered off, washed with water and dried under vacuum.

Auswaage: 2,66g

4.2 Variant B:

7.4g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid was dissolved at 0° in 781 ml of dichloromethane with the addition of 6.7 ml of triethylamine. 8.65 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid chloride hydrochloride were then added in portions. After the starting material had reacted, the mixture was poured into 500 ml of water and the methylene chloride phase was separated off. The organic phase was dried over Na ₂ SC> ₄ and concentrated in vacuo.

The residue was dissolved in 148 ml of dichloromethane and 4.5 ml of triethylsilane and 74 ml of trifluoroacetic acid were added at room temperature. After 30 minutes, 222 ml of dichloromethane and 222 ml of water were added and the mixture was cooled to -20 ⁰ C. The organic phase was separated off and washed again with a mixture of 37 ml of trifluoroacetic acid and 148 ml of water. The combined aqueous phases were diluted with water to 364 ml, filtered through an adsorber resin and eluted with acetonitrile/water 15/85.

The filtrate was concentrated to 35g on a Rotavapor, filtered and washed with water.

After drying in a vacuum, 4.5 g of the sample was obtained.

¹H-nmr(DMSO-d₆) δ 1.9-2.2(m,2H), 2.8-3.5(m, 8H), 3.85(Abq, 2H; J=18.3Hz), 4.63(m,1 H), 5.16(d, 2H, J=4.9Hz), 5.85(dd, 1 H, J1 = 4.9Hz, J2=8.4Hz), 7.23(s, 1 H),

8.06(s, 2H), 9.08 (br. s, 2H), 9.49(d, 2H, J=8.4Hz), 1 1.95 (s, 1 H)

5. Being typical: (6R.7R )-7-[(Z)-2-(5-Amino-[1 ,2,4]thiadiazol-3-yl)-2-hydroxyimino- acetylamino]- 8-oxo- . 3-[(E)-(R)-2-oxo-[1 ,3′]bipyrrolidinyl-3-ylidenemethyl]-5- thia-1 -aza-bicyclo[4.2.0]oct-2-jan-2 carbons

6.0g (6R,7R)-7-Amino-3[E-(R)-1′-(5-tert-butyloxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in silylated form was dissolved in 300 ml of dichloromethane at 0°. 1200 μl of DMF/water 5/1 and 8.1 ml of bis(tirmethylsilyl)acetamide were then added as well as 5.3g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid chloride Hydrochoride (J. Antibiotics 37:557 – 571, 1984) added in portions. The mixture was then poured into 60 ml MeOH/240 ml water and the methylene chloride phase was separated off. The organic phase was concentrated to 48g and 1.5 ml of triethylsilane was added. After adding 50ml

Trifluoroacetic acid was stirred at room temperature for 60 min, 20 ml of water was added and the mixture was cooled to -15°C. The organic phase was separated off and washed again with 20 ml trifluoroacetic acid/water 1/1. The combined aqueous phases were diluted to 500 ml with water and treated with 2.0 g of activated carbon. After filtration, the solution was concentrated in vacuo.

The residue was diluted to 50 ml with water and adjusted to pH 6.9 with saturated NaHCO ₃ solution. The mixture was stirred at 0 ⁰ C for 2 hours, filtered and the precipitate washed with water.

Auswaage: 4,5g

¹H-nmr(DMSO-d₆/CF₃COOD) δ 1.9-2.3(m,2H), 2.8-3.5(m,8H), 3.85(ABq, 2H, 18.7Hz), 4.61 (m,1 H), 5.16(d, 1 H,J=4.8Hz), 5.86(dd, 1 H,J1 =4.8Hz, J2=8.4Hz),

7.24(s,1 H), 8.05(br s, 2H), 8.93(s, 2H), 9.50(d,1 H,J=8.4Hz), 11.96(s, 1 H)

MS- ESI negative mode: 533.2(M-H, 10%)

6. Beispiel: Ceftobiprol Medocaril Na-SaIz

0, 5 3 g ( 6 R , 7 R )-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8- oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1 – aza-bicyclo[4.2.0]oct-2-ene- 2 carboxylic acid were dissolved in 5 ml of dimethyl sulfoxide and 0.27 g of carbonic acid (5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-nitrophenyl ester were added and stirred at room temperature. A solution of sodium ethyl hexanoate in 30 ml of acetone was added for precipitation. The precipitate was filtered and washed with acetone.

Auswaage: 0,6g

¹H-nmr(DMSO-d₆) δ 1.9-2.05(m, 2H), 2.10(s,3H), 2.7-3.1 (m,2H), 3.1-3.6(m,6H), 3.64(q, 2H; J=17.1 Hz), 4.56(m,1 H), 4.87(s,2H), 4.98(d,1 H,J=4.9Hz), 5.65(dd,1 H,J1 =4.9Hz, J2=8.4Hz), 7.34(s,1 H), 8.02(s,2H), 9.36(d,1 H,J=8.4Hz)

MS- ESI negative mode: 689.0(M-H, 100%)

Clinical data

Trade names	Zevtera, Mabelio
Other names	RO0639141-000,^[1] BAL9141,^[2] ceftobiprole medocaril
AHFS/Drugs.com	International Drug Names
License data	US DailyMed: Ceftobiprole
Routes of administration	Intravenous
Drug class	Cephalosporin antibacterial
ATC code	J01DI01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)^[3]UK: POM (Prescription only)US: ℞-only^[4]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number	209467-52-7252188-71-9
PubChem CID	6918430
DrugBank	DB04918
ChemSpider	23350302
UNII	5T97333YZK
KEGG	D08885
ChEMBL	ChEMBL520642
CompTox Dashboard (EPA)	DTXSID40870229
ECHA InfoCard	100.129.666
Chemical and physical data
Formula	C₂₀H₂₂N₈O₆S₂
Molar mass	534.57 g·mol⁻¹
3D model (JSmol)	Interactive image
hideSMILESC1CNC[C@@H]1N2CC/C(=C\C3=C(N4[C@@H]([C@@H](C4=O)NC(=O)/C(=N\O)/c5nc(sn5)N)SC3)C(=O)O)/C2=O
hideInChIInChI=1S/C20H22N8O6S2/c21-20-24-14(26-36-20)11(25-34)15(29)23-12-17(31)28-13(19(32)33)9(7-35-18(12)28)5-8-2-4-27(16(8)30)10-1-3-22-6-10/h5,10,12,18,22,34H,1-4,6-7H2,(H,23,29)(H,32,33)(H2,21,24,26)/b8-5+,25-11-/t10-,12-,18-/m1/s1Key:VOAZJEPQLGBXGO-SDAWRPRTSA-N
(what is this?) (verify)

References

^ Hebeisen P, Heinze-Krauss I, Angehrn P, Hohl P, Page MG, Then RL (March 2001). “In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci”. Antimicrobial Agents and Chemotherapy. 45 (3): 825–836. doi:10.1128/AAC.45.3.825-836.2001. PMC 90381. PMID 11181368.
^ Jones RN, Deshpande LM, Mutnick AH, Biedenbach DJ (December 2002). “In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci”. The Journal of Antimicrobial Chemotherapy. 50 (6): 915–932. doi:10.1093/jac/dkf249. PMID 12461013.
^ “Prescription medicines: registration of new chemical entities in Australia, 2015”. Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
^ Jump up to:^a ^b ^c ^d https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218275s000lbl.pdf
^ Scheeren TW (1 January 2015). “Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia”. Future Microbiology. 10 (12): 1913–1928. doi:10.2217/fmb.15.115. PMID 26573022.
^ “Basilea announces distribution agreement with Cardiome to commercialize antibiotic Zevtera/Mabelio (ceftobiprole) in Europe and Israel”. Basilea (Press release). 12 September 2017. Retrieved 7 April 2024.
^ “Basilea to launch Zevtera/Mabelio (ceftobiprole medocaril) in Europe through a commercial services provider” (Press release). Basilea Pharmaceutica. Archived from the original on 31 March 2019. Retrieved 20 September 2016.
^ “Basilea announces launch of antibiotic Zevtera (ceftobiprole medocaril) in Germany”. Basilea (Press release). 5 December 2014. Retrieved 7 April 2024.
^ “Swissmedic approves Basilea’s antibiotic Zevtera (ceftobiprole medocaril) for the treatment of pneumonia”. Basilea (Press release). 22 December 2014. Retrieved 7 April 2024.
^ “Basilea signs exclusive distribution agreement for Zevtera (ceftobiprole medocaril) in the Middle East and North Africa with Hikma Pharmaceuticals LLC”. Basilea (Press release). 15 October 2015. Retrieved 7 April 2024.
^ “Basilea announces that Health Canada approved Zevtera for the treatment of bacterial lung infections”. Basilea (Press release). 12 October 2015. Retrieved 7 April 2024.
^ Syed YY (September 2014). “Ceftobiprole medocaril: a review of its use in patients with hospital- or community-acquired pneumonia”. Drugs. 74 (13): 1523–1542. doi:10.1007/s40265-014-0273-x. PMID 25117196. S2CID 2925496.
^ Zhanel GG, Lam A, Schweizer F, Thomson K, Walkty A, Rubinstein E, et al. (2008). “Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin”. American Journal of Clinical Dermatology. 9 (4): 245–254. doi:10.2165/00128071-200809040-00004. PMID 18572975. S2CID 24357533.
^ Farrell DJ, Flamm RK, Sader HS, Jones RN (July 2014). “Ceftobiprole activity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010”. Antimicrobial Agents and Chemotherapy. 58 (7): 3882–3888. doi:10.1128/AAC.02465-14. PMC 4068590. PMID 24777091.
^ Farrell DJ, Flamm RK, Sader HS, Jones RN (April 2014). “Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin, linezolid or vancomycin, and strains with defined SCCmec types”. International Journal of Antimicrobial Agents. 43 (4): 323–327. doi:10.1016/j.ijantimicag.2013.11.005. PMID 24411474.
^ Nicholson SC, Welte T, File TM, Strauss RS, Michiels B, Kaul P, et al. (March 2012). “A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation”. International Journal of Antimicrobial Agents. 39 (3): 240–246. doi:10.1016/j.ijantimicag.2011.11.005. PMID 22230331.
^ Awad SS, Rodriguez AH, Chuang YC, Marjanek Z, Pareigis AJ, Reis G, et al. (July 2014). “A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia”. Clinical Infectious Diseases. 59 (1): 51–61. doi:10.1093/cid/ciu219. PMC 4305133. PMID 24723282.
^ “Zevtera 500 mg powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC)”. (emc). 5 April 2023. Retrieved 1 June 2023.
^ “Zeftera (previously Zevtera) EPAR”. European Medicines Agency (EMA). 18 February 2010. Retrieved 6 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

Clinical trial number NCT03138733 for “Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia” at ClinicalTrials.gov
Clinical trial number NCT03137173 for “Ceftobiprole in the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infections” at ClinicalTrials.gov
Clinical trial number NCT00326287 for “Ceftobiprole in the Treatment of Patients With Community-Acquired Pneumonia” at ClinicalTrials.gov
Clinical trial number NCT03439124 for “Ceftobiprole in the Treatment of Pediatric Patients With Pneumonia” at ClinicalTrials.gov

////////Ceftobiprole, BAL-9141, BAL-9141-000, BAL-9141000, BAL9141-000, RO 63-9141, RO-63-9141, RO-639141, fda 2024, zevtera, approvals 2024, Ceftobiprole medocaril sodium salt

[H][C@@]1(NC(=O)C(=N/O)\C2=NSC(N)=N2)C(=O)N2C(C(O)=O)=C(CS[C@]12[H])\C=C1/CCN(C1=O)[C@]1([H])CCNC1

DANICOPAN

April 11, 2024 10:24 am / Leave a comment

Danicopan

USFDA 3/29/2024, To treat extravascular hemolysis with paroxysmal nocturnal hemoglobinuria, Voydeya

C₂₆H₂₃BrFN₇O₃

580.418

1903768-17-1

(2S,4R)-1-[2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl]-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide

ACH 0144471
ACH-4471
ACH0144471
ALXN 2040
ALXN-2040
ALXN2040

Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.^[2] It is a complement inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated hemolysis and deposition of complement C3 proteins on red blood cells.^[2]

Danicopan was approved for medical use in Japan in January 2024, and in the United States in March 2024.^[3]^[4]

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematologic disease characterized by hemolysis, thrombophilia, and bone marrow dysfunction.^1,7 Both hemolysis and thrombophilia are mediated primarily by the complement system.¹ Standard therapy for PNH involves the use of complement C5 inhibitors (e.g. eculizumab, ravulizumab) which are effective in mitigating complement-mediated intravascular hemolysis and thromboembolism.¹ Unfortunately, complement C5 inhibition does not address C3-mediated extravascular hemolysis, which occurs earlier in the complement cascade within the alternative pathway.^1,5

Danicopan is a small molecule complement factor D inhibitor that selectively blocks the alternative pathway, thereby working to address extravascular hemolysis when used in conjunction with C5 inhibitors.³ It was first approved in January 2024 in Japan for patients with PNH,^2,6 shortly after which the EMA adopted a positive opinion and recommended granting it marketing authorization.² It was subsequently approved by the FDA in March 2024.⁴

SYN

WO2015130795

SYN

https://patents.google.com/patent/US9796741

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023158772&_cid=P10-LUV2QK-25994-2

PAT

https://patents.google.com/patent/US20230094124A1/en

Step 1: Synthesis of tert-Butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl) fluoropyrrolidine-1-carboxylate (3): N-Boc-trans-4-Fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor under an atmosphere of nitrogen. The reaction mixture was cooled to 0±5° C. and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0±5° C. Methanesulfonyl chloride (29.97 kg) was slowly added to the reaction mixture followed by the addition of 2-amino-6-bromopyridine (2). The reaction temperature was warmed to room temperature and stirred for 12 h. The reaction was monitored by HPLC. After completion of the reaction water (2,000 kg) was added, the reaction was stirred and the DCM layer separated. The aqueous layer was once more extracted with DCM (1000 L). The combined DCM layer was washed in succession with dilute HCl, aqueous NaHCO₃and brine. The DCM extract was evaporated to dryness and tert-butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (3) was isolated using DCM heptane mixture and dried. Yield, 71.76 Kg (84.86%))
[0404]
Step 2: Synthesis of (2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (4): To a solution 4M HCl/Dioxane (168 kg) was added intermediate 3 (40 kg) at 25±5° C. under an atmosphere of nitrogen and the reaction was stirred for 1 h. The reaction was monitored by HPLC and after completion, the reaction was diluted with DCM (800 L) and washed with aqueous NaHCO₃. The DCM layer was separated and concentrated. The product, 2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide, (4), was isolated using DCM/heptane and dried. Yield, 25.81 kg, 87%.
[0405]
Step 3: Synthesis of tert-Butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (6): 1-(5-Bromo-1H-indazol-yl)ethan-1-one (5, 30 kg) was added to a reactor containing DMF (210 L) under an atmosphere of nitrogen followed by potassium carbonate (4.05 kg). Tert-butyl bromoacetate (3.42 kg) was added to the reaction mixture with stirring and maintaining the temperature at 30±10° C. After addition was complete, the reaction mixture was heated at 50±5° C. for 1 h. After the reaction was complete the reaction mixture was cooled to 25±5° C. and diluted with water (630 L). The precipitated solid was filtered, washed with water (90 L) and dried. Yield, 43.13 kg, 97.13%.
[0406]
Step 4: Synthesis of tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (9): Bispinnacolato diboron (14.67 kg) was added to a solution of 4-bromo methylpyrimidine (7, 10 kg) in dioxane (206 kg) under an atmosphere of nitrogen followed by the addition of potassium acetate (17 kg). The reaction mixture was degassed using nitrogen. Pd(dppf)Cl₂(0.94 kg) was added and the reaction mixture heated to 90±5° C. until the pyrimidine was consumed. The reaction mixture was cooled to 25±5° C. and intermediate 6 (16.33 kg) was added followed by potassium carbonate (20.7 kg) and water (16.33 kg) and the reaction was degassed using nitrogen. The reaction was again heated to 90±5° C. until completion. The reaction mixture was cooled to 25±5° C. and diluted with ethyl acetate (269 kg) and water (150 kg) maintaining the temp at 10±5° C. Activated charcoal (1 kg) was added to the mixture with stirring and then filtered through a bed of celite. The ethyl acetate layer was separated, washed with 5% aqueous sodium chloride followed by 5% L-Cysteine solution to remove palladium related impurities. The ethyl acetate layer was evaporated to dryness. The product (9) was isolated from MTBE/heptane. Yield, 11.8 kg, 56%.
[0407]
Step 5: Synthesis of 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (10): To a stirred solution of intermediate 9 (50 kg) in DCM (465 kg) at 15±5° C. was added TFA (374.5 kg) while maintaining the said temperature. The reaction was warmed to 35±5° C. and stirring continued until completion of the reaction. DCM and TFA were distilled off under reduced pressure. The residue was dissolved in DCM (kg) and stirred with aqueous sodium bicarbonate. The biphasic mixture was acidified with concentrated HCl and the pH was adjusted to 2-3. The precipitated solid was filtered, washed with water and dried. Yield, 42.4 kg, quantitative.
[0408]
Step 6: Synthesis of Compound 1: To a solution of intermediate 9 (42 kg) in DMF (277 kg) was added intermediate 4 (38.7 kg) and the reaction was cooled to 10±5° C. Coupling agent TBTU (56.7 kg) was added to the reaction mixture followed by the addition of DIPEA (86.5 kg) while maintaining the reaction temperature at 10±5° C. The reaction was warmed to 25±+5° C. and stirred until complete. The reaction mixture was diluted with ethyl acetate (1344 kg) and washed with water twice. (The reaction may be washed with aq. K₂CO₃if fluorine related impurities are present.) Anhydrous sodium sulfate was added to silica gel and added to the ethyl acetate layer and filtered. The ethyl acetate layer was passed over a column of silica gel (40 kg) and the pure fractions were collected. The fractions were treated with activated charcoal and then filtered over celite. The palladium content was checked, and if above 10 ppm, the ethyl acetate layer was treated with palladium scavenging resin (SilabondThiol®). The ethyl acetate was evaporated to dryness under vacuum and the residue was crystallized from IPA (crystalline seed may be added) and heptane to afford Compound 1 Form II. Yield, 60 kg, 78%.

Society and culture

Legal status

In February 2024, the Committee for Medicinal Products for Human Use of the EMA adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Voydeya, intended as add-on therapy to ravulizumab or eculizumab for the treatment of residual hemolytic anemia in adults with paroxysmal nocturnal hemoglobinuria (PNH).^[2]^[5] The applicant for this medicinal product is Alexion Europe.^[2]

Names

Danicopan is the international nonproprietary name.^[6]

Clinical data

Trade names	Voydeya
Other names	ACH-4471
Routes of administration	By mouth
Drug class	Complement factor D inhibitor
ATC code	L04AJ09 (WHO)
Legal status
Legal status	US: ℞-only^[1]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number	1903768-17-1
DrugBank	DB15401
ChemSpider	75531295
UNII	JM8C1SFX0U
KEGG	D11641
ChEMBL	ChEMBL4250860
ECHA InfoCard	100.398.865
Chemical and physical data
Formula	C₆H₃BrFN₇O₃
Molar mass	320.038 g·mol⁻¹
3D model (JSmol)	Interactive image
hideSMILESCC(=O)C1=NN(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NC2=CC=CC(Br)=N2)C2=C1C=C(C=C2)C1=CN=C(C)N=C1
hideInChIInChI=1S/C26H23BrFN7O3/c1-14(36)25-19-8-16(17-10-29-15(2)30-11-17)6-7-20(19)35(33-25)13-24(37)34-12-18(28)9-21(34)26(38)32-23-5-3-4-22(27)31-23/h3-8,10-11,18,21H,9,12-13H2,1-2H3,(H,31,32,38)/t18-,21+/m1/s1Key:PIBARDGJJAGJAJ-NQIIRXRSSA-N

References

^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration. 1 April 2024. Retrieved 2 April 2024.
^ Jump up to:^a ^b ^c ^d “Voydeya EPAR”. European Medicines Agency. 22 February 2024. Archived from the original on 23 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Voydeya (danicopan) granted first-ever regulatory approval in Japan for adults with PNH to be used in combination with C5 inhibitor therapy”. AstraZeneca (Press release). 19 January 2024. Archived from the original on 24 February 2024. Retrieved 24 February 2024.
^ Research Cf (4 April 2024). “Novel Drug Approvals for 2024”. FDA.
^ “First oral treatment against residual hemolytic anemia in patients with paroxysmal nocturnal hemoglobinuria”. European Medicines Agency (EMA) (Press release). 23 February 2024. Retrieved 24 February 2024.
^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information. 33 (1). hdl:10665/330896.

External links

“Danicopan (Code C148181)”. NCI Thesaurus.

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EXAMPLE

Preparation A: Benzylsulfamide Potassium Salt

A.i. Benzylsulfamide

A.ii. Benzylsulfamide Potassium Salt

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

B.i. 4-bromophenylacetic acid methyl ester

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

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

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

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

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

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

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

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Following expiration of the Bristol-Myers Squibb patent,[] cefepime became available as a generic and is now] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.

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PATENT

PATENT

Following expiration of the Bristol-Myers Squibb patent,^[] cefepime became available as a generic and is now^] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.