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Ganaxolone
Ganaxolone
- Molecular FormulaC22H36O2
- Average mass332.520 Da
- CCD-1042
FDA APPROVED 3/18/2022, Ztalmy
To treat seizures in cyclin-dependent kinase-like 5 deficiency disorder
Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD).[1][2]
Ganaxolone was approved for medical use in the United States in March 2022.[1]
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. Ganaxolone is an allosteric modulator of GABAA receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. Ganaxolone has been shown to be well tolerated in adults and children. In early phase II studies, Ganaxolone has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures.
Ganaxolone is in phase III clinical studies for the treatment of partial seizures in adults. Phase II clinical trials is ongoing for treatment of uncontrolled seizures in PCDH19 female pediatric epilepsy and Fragile X syndrome.
Ganaxolone was originally developed by CoCensys (aquired by Purdue Pharma). In 2003, Marinus Pharmaceuticals obtained the compound from Purdue Pharma.
In 2015, it was granted as orphan drug designation for the treatment of PCDH19 female epilepsy.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019209850&_cid=P10-L0YZTI-42413-1
In an embodiment, the disclosure provides a method for using pregnenolone to make 21-OH ganaxolone and other intermediary compounds which are useful for preparing neurosteroid derivatives. The method of making 21-OH ganaxolone is shown below in Route 1.
Route 1
Referring to Route 1, Synthesis of 1-((3S,8R,10S,13S,14S,17S)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethenone :
<a name="
Pregnenolone (3.17 g, 10 mmol) was dissolved in 30 mL of THF and 5 mL of acetic acid. To it, 10% W/C (0.3 g) was added. The resulting mixture was shaken under 60 psi hydrogen at 60°C overnight. It was filtered through a Celite ® pad and concentrated to give 3.2 g of the desired product (100%). 1 H NMR (400 MHz, CDCl3) δ 3.58 (tt, J = 11.0, 4.8 Hz, 1H), 2.50 (t, J = 9.0 Hz, 1H), 2.19 – 2.11 (m, 2H), 2.09 (s, 3H ), 2.06 – 1.93 (m, 2H), 1.85 – 1.75 (m, 1H), 1.74 -1.50 (m, 6H), 1.47 – 1.04 (m, 9H), 1.04 – 0.82 (m, 2H), 0.79 (s , 3H), 0.72 – 0.61 (m, 1H), 0.58 (d, J = 2.4 Hz, 3H).
[0107] Synthesis of (8R,10S,13S,14S,17S)-l7-acetyl-l0,l3-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one:
To a solution of the above product (1-((3S,8R,10S,13S,14S,17S)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone, 3.2 g, 10 mmol) in 40 mL of THF and 10 mL of acetic acid was added NaBr (1.03 g, 0.1 eq.). It was cooled in an ice bath and was followed by the dropwise addition of NaOCl (82 mL, 10-15%, 18 eq.) at such a rate that the internal temperature was maintained <40 °C. After addition, it was stirred at room temperature for 2h. Thin layer chromatography (TLC) indicated it was complete. The mixture was diluted with dichloromethane and layers were separated. The organic layer was washed with Na 2 S 2 O 3 (10% aq.), H 2 O, NaHCO 3 (sat.) and NaCl (sat.). Drying over Na 2SO 4 and concentration afforded 3.8 g of the crude product, which was recrystallized from CH 2 Cl 2 /Hex to give 2.57 g of the desired product (81%). 1 H NMR (400 MHz, CDC13): 2.51 (t, 1H), 2.2-2.4 (m, 3H), 2.1-2.2 (m, 1H), 2.10 (s, 3H), 1.98-2.01 (m, 2H) , 1.6-1.7 (m, 4H), 1.55-1.6 (m, 1H), 1.3-1.4 (m, 7H), 1.1-1.2 (m, 2H), 0.99 (s, 3H), 0.95-0.98 (m, 1H), 0.75-0.78 (m, 1H), 0.62 (s, 3H).
Synthesis of 1-((2’R,8R,10S,13S,14S,17S)-10,11-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2′-oxiran]-17-yl)ethanone.<a name="
Under argon, trimethyl sulfoxonium iodide (2.6 g, 1.7 eq.) and sodium t-butoxide (1.18 g, 1.75 eq.) in DMSO (20 mL) was heated at 65 °C for 2h. After it was cooled to RT, the above di-ketone ((8R, 10S, 13 S, 14S, 17S)-17-acetyl- 10,13 -dimethyl tetradecahy dro-1H-cyclopenta[a]phenanthren-3(2H) -one, 2.2 g, 7 mmol) was added scoop-wise so that the internal temperature was maintained between 25-35 °C. The resulting mixture was stirred at RT for 2h. After TLC indicated it was complete, it was quenched with 30 mL of H 2 O, stirred for 10 min and was kept in fridge overnight. The precipitate was filtered, washed with 20 mL of (4:1 of H 2 O /MeOH), dried to give 94% of the desired product (W = 2.17 g). 1H NMR (400 MHz, CDC13) δ 2.63 (s, 2H), 2.53 (t, J = 8.9 Hz, 1H), 2.20 – 2.13 (m, 1H), 2.11 (s, 3H), 2.10 – 1.95 (m, 2H), 1.87 (dd, J = 13.9, 13.1 Hz, 1H), 1.76 – 1.59 (m, 4H), 1.58 – 1.48 (m, 1H), 1.48 – 1.24 (m, 5H), 1.24 – 1.07 (m, 3H), 1.02 – 0.87 (m, 2H), 0.86 (dd, J = 3.7, 2.2 Hz, 1H), 0.84 (s, 3H), 0.81 – 0.74 (m, 1H), 0.61 (s, 3H).
[0109] Synthesis of 1-((3R,8R,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (ganaxolone) .
To a solution of the above epoxide (1.5 g, 4.56 mmol) in 15 mL of THF and 15 mL of MeOH were added Nal (1.02 g, 1.5 eq.) and HO Ac (0.6 mL, 2.2 eq.). The resulting mixture was heated at 65°C for 2h. After TLC indicated that the epoxy was completely converted to an iodo compound, it was cooled to RT. Sodium acetate (1.02 g, 2.7 eq.) and 150 mg of 10% Pd/C were added and the mixture was transferred to a hydrogenation bottle with the aid of MeOH (10 mL) and was hydrogenated under 50 psi hydrogen over the weekend. It was filtered through<a name="Celite ® and the filtrate was concentrated. The residue was then partitioned between dichloromethane and water. The aqueous solution was extracted twice with CH 2 Cl 2 and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The Biotage flash purification with 10-35% EtOAc in hexane to give 0.5 g of the desired product (33%).
The synthesis was repeated with 1.1 g of the epoxy and 1 g of the product was obtained (90%).
Both lots of product were combined and recrystallized with CH 2 Cl 2 and hexane to give 0.522 g of the product with 96.6% purity by HPLC. 1 H NMR (400 MHz, Chloroform-d) δ 2.51 (t, J = 8.9 Hz, 1H), 2.18 – 2.10 (m, 1H), 2.09 (s, 3H), 2.01 – 1.93 (m, 1H), 1.72 – 1.57 (m, 4H), 1.57 – 1.41 (m, 5H), 1.41 – 1.30 (m, 3H), 1.30 – 1.20 (m, 3H), 1.18 (s, 3H), 1.17 – 1.09 (m, 2H) , 1.00 – 0.85 (m, 1H), 0.78 (ddd, J = 10.6, 7.7, 5.4 Hz, 1H), 0.73 (d, J = 0.6 Hz, 3H), 0.58 (s, 3H). UV: Absorbances at 206.2 nm. TLC: (Silica Gel plates) 20% EtOAc/Hexane; R f = 0.50. HPLC: Sunfire C18 5m 250 x 4.6mm; flow 1.0 mL/min; Waters 996 PDA detection at 210 nm; solvent 80% Acetonitrile in H 2 O (0.1% formic acid) over 30 min; retention time 8.24 min; 96.6%.
SYN
https://patents.google.com/patent/WO2016164763A1/en
SYN
US3953429.
J. Med. Chem. 1997, 40, 61-72.https://pubs.acs.org/doi/10.1021/jm960021x
Two naturally occurring metabolites of progesterone, 3α-hydroxy-5α- and 5β-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3β-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5α- and 5β-series as determined by inhibition of [35S]TBPS binding. In the 5α-series, 3β-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3β-XCH2, where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [35S]TBPS binding. In the 5β-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3β-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5β-sterols tested are full inhibitors of [35S]TBPS binding. Electrophysiological measurements using α1β2γ2L receptors expressed in oocytes show that 3β-methyl- and 3β-(azidomethyl)-3α-hydroxy-5α-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3α-hydroxy-3β-(trifluoromethyl)-5α-pregnan-20-one (24) is a low-efficacy modulator, confirming the results obtained from [35S]TBPS binding. These results indicate that modification of the 3β-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABAA receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites 1 and 2 are inactive when administered orally, suggesting that 3β-substitution slows metabolism of the 3-hydroxyl, resulting in orally bioavailable steroid modulators of the GABAA receptor.
PATENT
WO9303732A1.,
https://patents.google.com/patent/WO1993003732A1/nl
SYN
| GB 1380248 |
Addition of the sulfur ylide generated from trimethylsulfoxonium iodide and NaH to the 20-ethylene ketal of pregnane-3,20-dione (I) furnished the spiro oxirane derivative (II). This was reduced to the tertiary alcohol (III) by means of LiAlH4 in refluxing THF. Then, acid hydrolysis of the ethylene ketal function of (III) provided the title compound. Alternatively, the intermediate ketal (III) was prepared by addition of methylmagnesium bromide to ketone (I), followed by chromatographic separation of the resultant mixture of 3-alpha and 3-beta methyl adducts.
Starting from the unprotected diketone (IV), selective addition of dimethyloxosulfonium methylide to the 3 keto group furnished oxirane (V). This was then reduced to the title alcohol by treatment with tributylstannyl hydride and AIBN.
Regioselective addition of dimethylsulfoxonium methylide to 5-alpha-pregnane-3,20-dione (I) gave the epoxide (II). Opening of the epoxide ring of (II) with sodium methoxide produced the hydroxy ether (III). Bromination of (III) with Br2 in the presence of a catalytic amount of HBr afforded bromo ketone (IV). This was then condensed with imidazole (V) in refluxing acetonitrile to furnish the title compound.
Regioselective addition of dimethylsulfoxonium methylide to 5-alpha-pregnane-3,20-dione (I) gave the epoxide (II). Opening of the epoxide ring of (II) with sodium methoxide produced the hydroxy ether (III). Bromination of (III) with Br2 in the presence of a catalytic amount of HBr afforded bromo ketone (IV). This was then condensed with 6-hydroxyquinoline (V) in the presence of potassium tert-butoxide to furnish the quinolinyl ether (VI). The quinoline ring was then oxidized with m-chloroperbenzoic acid, yielding the title N-oxide.
3. WO9318053A1.
4. WO9427608A1.
WO2011019821A2 / US8362286B2.///////////
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Pharmacology
Mechanism of action
The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.[3][4]
Ganaxolone is thought to modulate both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons.[2] Ganaxolone’s activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling.[2]
Ganaxolone binds to allosteric sites of the GABAA receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron.[2] This causes an inhibitory effect on neurotransmission, reducing the chance of a successful action potential (depolarization) from occurring.[2][3][4]
Chemistry
ResearchGanaxolone is a synthetic pregnane steroid. Other pregnane neurosteroids include alfadolone, alfaxolone, allopregnanolone (brexanolone), hydroxydione, minaxolone, pregnanolone (eltanolone), and renanolone, among others.
Ganaxolone is being investigated for potential medical use in the treatment of epilepsy. It is well tolerated in human trials, with the most commonly reported side effects being somnolence (sleepiness), dizziness, and fatigue.[5] Trials in adults with focal onset seizures and in children with infantile spasms have recently been completed.[6][7] There are ongoing studies in patients with focal onset seizures, PCDH19 pediatric epilepsy, and behaviors in Fragile X syndrome.[6][7]
Ganaxolone has been shown to protect against seizures in animal models,[3][4] and to act a positive allosteric modulator of the GABAA receptor.[2][8]
Clinical trials
The most common adverse events reported across clinical trials have been somnolence (sleepiness), dizziness, and fatigue.[5] In 2015, the MIND Institute at the University of California, Davis, announced that it was conducting, in collaboration with Marinus Pharmaceuticals, a randomized, placebo-controlled, Phase 2 clinical trial evaluating the effect of ganaxolone on behaviors associated with Fragile X syndrome in children and adolescents.[9][10][11]
References
- ^ Jump up to:a b c https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf
- ^ Jump up to:a b c d e f Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW (March 1997). “Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor”. The Journal of Pharmacology and Experimental Therapeutics. 280 (3): 1284–95. PMID 9067315.
- ^ Jump up to:a b c Kaminski RM, Livingood MR, Rogawski MA (July 2004). “Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice”. Epilepsia. 45 (7): 864–7. doi:10.1111/j.0013-9580.2004.04504.x. PMID 15230714. S2CID 21974013.
- ^ Jump up to:a b c Reddy DS, Rogawski MA (May 2010). “Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model”. Epilepsy Research. 89 (2–3): 254–60. doi:10.1016/j.eplepsyres.2010.01.009. PMC 2854307. PMID 20172694.
- ^ Jump up to:a b Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA (September 1997). “Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity”. Epilepsia. 38 (9): 1026–31. doi:10.1111/j.1528-1157.1997.tb01486.x. PMID 9579942. S2CID 27584114.
- ^ Jump up to:a b Nohria V, Giller E (January 2007). “Ganaxolone”. Neurotherapeutics. 4 (1): 102–5. doi:10.1016/j.nurt.2006.11.003. PMC 7479704. PMID 17199022.
- ^ Jump up to:a b Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O (October 2007). “Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy”. Epilepsia. 48 (10): 1870–4. doi:10.1111/j.1528-1167.2007.01182.x. PMID 17634060. S2CID 24656918.
- ^ Reddy DS, Rogawski MA (December 2000). “Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself”. The Journal of Pharmacology and Experimental Therapeutics. 295 (3): 1241–8. PMID 11082461.
- ^ “Fragile X Research and Treatment Center: Clinical Research Studies” (PDF). UC Davis MIND Institute. 10 February 2015. Archived from the original (PDF) on 5 June 2015. Retrieved 27 January 2016.
- ^ “Ganaxolone Treatment in Children With Fragile X Syndrome”. Clinicaltrials.gov. 7 November 2012. Retrieved 27 January 2016.
- ^ “UC Davis Health System. UC Davis researchers win $3 million grant from U.S. Congress to study fragile X” (Press release). UC Davis Health System. 8 February 2011. Archived from the original on 3 February 2016. Retrieved 27 January 2016.
External links
- “Ganaxolone”. Drug Information Portal. U.S. National Library of Medicine.
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| Clinical data | |
|---|---|
| Trade names | Ztalmy |
| Other names | GNX; CCD-1042; 3β-Methyl-5α-pregnan-3α-ol-20-one; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one |
| License data | |
| Routes of administration | By mouth |
| Drug class | Neurosteroid |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.210.937 |
| Chemical and physical data | |
| Formula | C22H36O2 |
| Molar mass | 332.528 g·mol−1 |
| 3D model (JSmol) | |
  (what is this?) (verify) | |
////////////Ganaxolone, ZTALMY, FDA 2022, APPROVALS 2022, CCD 1042
[H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC[C@@]2([H])C[C@](C)(O)CC[C@]12C
https://doi.org/10.1021/acs.jmedchem.3c02374
J. Med. Chem. 2024, 67, 4376−4418
Ganaxolone (Ztalmy). Ganaxolone (10), a first-in class medication, is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator indicated for the treatment of seizures associated with cyclin-dependent kinase like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years
of age and older.
CDKL5 deficiency disorder is a rare neurodevelopmental condition resulting from pathogenic variants in the CDKL5 gene with an incidence rate ranging from 1 in 40,000 to 1 in 60,000 newborns.72 While CDKL5
deficiency is rare, it represents one of the most common forms of genetic epilepsy. 73,74
The synthesis of ganaxolone was previously described in the literature in 1976.75 However, the synthesis illustrated in Scheme 19 was recently published and outlines a manufactory process for ganaxolone.
The approach began with protection of the ketone functional group in pregnanolone 10.1, a naturally occurring steroid. Using acid catalysis, the ketal was formed with refluxing ethylene glycol in toluene, and after neutralizing the acidic solution, ketal 10.2 was obtained in 88% yield. Multiple options for the oxidation of 10.2 to form ketone 10.3 were provided such as Swern, Dess-Martin, and TPAP conditions. The oxidative procedure described in Scheme 19 illustrates the use of calcium hypochlorite and TEMPO to
form ketone 10.3. Next, methylation was accomplished by addition of MeMgBr in the presence of LiCl and FeCl3 to provide tertiary alcohol 10.4. Finally, the acetal protecting group was removed by treatment with iodine in DCM and acetone to provide ganaxolone 10 in 98% yield over the last two steps.
(70) Marinus Pharmaceuticals Inc.: ZTALMY® (ganaxolone)
[package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2022/215904s000lbl.pdf, (accessed June 6, 2023).
(71) Carter, R. B.; Wood, P. L.; Wieland, S.; Hawkinson, J. E.;
Belelli, D.; Lambert, J. J.; White, S. H.; Wolf, H. H.; Mirsadeghi, S.;
Tahir, S. H.; Bolger, M. B.; Lan, N. C.; Gee, K.-W. Characterization of
the anticonvulsant properties of ganaxolone (CCD 1042; 3-alpha
hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affin
ity, steroid modulator of the gamma-aminobutyric acid(A) receptor. J.
Pharmacol. Exp. Ther. 1997, 280, 1284−1295.
(72) Jakimiec, M.; Paprocka, J.; Smigiel, R. CDKL5 deficiency
disorder-A complex epileptic encephalopathy. Brain Sci. 2020, 10,
107.
(73) Cook, M. C.; Lawrence, R.; Phillipps, G. H.; Hunter, A. C.;
Newall, C. E.; Stephenson, L.; Weir, N. G. Anaesthetic steroids of the
androstance and pregnane series. U.S. Patent US 3,953,429, 1976.
(74) Hogenkamp, D. J.; Tahir, S. H.; Hawkinson, J. E.; Upasani, R.
B.; Alauddin, M.; Kimbrough, C. L.; Acosta-Burruel, M.; Whittemore,
E. R.; Woodward, R. M.; Lan, N. C.; et al. Synthesis and in vitro
activity of 3 beta-substituted-3 alpha-hydroxypregnan-20-ones:
allosteric modulators of the GABA-A receptor. J. Med. Chem. 1997,
40, 61−72.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel
FDA APPROVED, 2022/2/28,
| Carvykti |
Treatment of multiple myeloma
- JNJ-68284528
- LCAR-B38M CAR-T cells
Ciltacabtagene autoleucel is a BCMA-directed CAR T-cell therapy used in the treatment of relapsed or refractory multiple myeloma in previously treated patients.
U.S. FDA Approves CARVYKTI™ (ciltacabtagene autoleucel), Janssen’s First Cell Therapy, a BCMA-Directed CAR-T Immunotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma
In the pivotal clinical study, 98 percent of patients with relapsed or refractory multiple myeloma responded to a one-time treatment with ciltacabtagene autoleucel and 78 percent of patients who responded experienced a stringent complete response
HORSHAM, Pa., February 28, 2022 – The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) has approved CARVYKTI™ (ciltacabtagene autoleucel; cilta-cel) for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1 The approval is based on data from the pivotal CARTITUDE-1 study, which included patients who had received a median of six prior treatment regimens (range, 3-18), and had previously received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.1 In December 2017, Janssen entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize ciltacabtagene autoleucel.
CARVYKTI™ is a chimeric antigen receptor T-cell (CAR-T) therapy featuring two B-cell maturation antigen (BCMA)-targeting single domain antibodies.1 In the pivotal CARTITUDE-1 study, one-time treatment with ciltacabtagene autoleucel resulted in deep and durable responses, with 98 percent (95 percent Confidence Interval [CI], 92.7-99.7) of patients with RRMM responding to therapy (98 percent overall response rate [ORR] (n=97).1 Notably, 78 percent (95 percent CI, 68.8-86.1) of the patients achieving this level of response (n=76) experienced a stringent complete response (sCR), a measure in which a physician is unable to observe any signs or symptoms of disease via imaging or other tests after treatment.1 At a median of 18 months follow-up, median duration of response (DOR) was 21.8 months.1
CARVYKTI™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI™ REMS Program.1 The Safety Information for CARVYKTI™ includes a Boxed Warning regarding Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged and/or recurrent cytopenias.1 Warnings and Precautions include prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies, and effects on ability to drive and use machines.1 The most common adverse reactions (≥20 percent) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.1
“We are committed to harnessing our science, deep disease understanding and capabilities to bring forward cell therapies like CARVYKTI as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma,” said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC. “We extend our sincere gratitude to the patients, their families and the teams of researchers and study centers who have participated in the clinical study of CARVYKTI and enabled today’s approval.”
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. 2 Despite the development of additional treatment options in recent years, most people living with multiple myeloma face poor prognoses after experiencing disease progression following treatment with three major therapy classes, which include an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody. 3
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” said Sundar Jagannath, M.D.†, Director of the Center of Excellence for Multiple Myeloma and Professor of Medicine, Hematology and Medical Oncology, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and principal study investigator. “The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time.”
As a personalized medicine, CARVYKTI™ treatment requires extensive training, preparation, and certification to ensure a positive experience for patients. Through a phased approach, Janssen and Legend Biotech will activate a limited network of certified treatment centers as the company works to scale its production capacity and increase the availability of CARVYKTI™ throughout the U.S. in 2022 and beyond, to ensure that we can provide CARVYKTI™ treatment to oncologists and their patients in a reliable and timely manner.
“This approval of Janssen’s first cell therapy is a testament to our continuing commitment in oncology to deliver new therapeutic options and drive toward our vision of the elimination of cancer,” said Mathai Mammen, M.D., Ph.D., Executive Vice President, Pharmaceuticals, Janssen Research & Development, LLC, Johnson & Johnson. “Today’s approval underscores our determination to develop therapies that can help patients living with what remains an intractable blood cancer today and at the same time offer hope for the future.”
The longer-term efficacy and safety profile of ciltacabtagene autoleucel is being assessed in the ongoing CARTITUDE-1 study. Two-year follow-up results recently presented at the American Society of Hematology (ASH) 2021 Annual Meeting showed that 98 percent of patients treated with ciltacabtagene autoleucel for RRMM responded to therapy (98 percent overall response rate [ORR] (n=97), and a majority of patients achieving sustained depth of response with 83 percent of patients achieving an sCR at the 22-month follow-up.4
About CARVYKTI™ (ciltacabtagene autoleucel)
CARVYKTI™ is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express the B-cell maturation antigen (BCMA). BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The CARVYKTI™ CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.1
In December 2017, Janssen Biotech, Inc. entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize ciltacabtagene autoleucel.
In April 2021, Janssen announced the submission of a Marketing Authorisation Application to the European Medicines Agency seeking approval of CARVYKTI™ for the treatment of patients with relapsed and/or refractory multiple myeloma. In addition to a U.S. Breakthrough Therapy Designation granted in December 2019, ciltacabtagene autoleucel received a Breakthrough Therapy Designation in China in August 2020. Janssen also received an Orphan Drug Designation for CARVYKTI™ from the U.S. FDA in February 2019, and from the European Commission in February 2020.
About the CARTITUDE-1 Study
CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, multi-center study evaluating ciltacabtagene autoleucel for the treatment of patients with relapsed or refractory multiple myeloma, who previously received a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody, and who had disease progression on or after the last regimen. All patients in the study had received a median of six prior treatment regimens (range, 3-18). Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.1
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects some white blood cells called plasma cells, which are found in the bone marrow.3 When damaged, these plasma cells rapidly spread and replace normal cells in the bone marrow with tumors. In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.5 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.2
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Ciltacabtagene autoleucel, sold under the brand name Carvykti, is a medication used to treat multiple myeloma.[1][2]
The most common adverse reactions include pyrexia, cytokine release syndrome, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.[2]
Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy.[1][2] Each dose is customized using the recipient’s own T-cells, which are collected and genetically modified, and infused back into the recipient.[1][2]
Ciltacabtagene autoleucel was approved for medical use in the United States in February 2022.[2][3][4]
Medical uses
Ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.[1][2]
History
The safety and efficacy of ciltacabtagene autoleucel were evaluated in CARTITUDE-1 (NCT03548207), an open label, multicenter clinical trial evaluating ciltacabtagene autoleucel in 97 participants with relapsed or refractory multiple myeloma who received at least three prior lines of therapy which included a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen; 82% had received four or more prior lines of antimyeloma therapy.[1][2]
The U.S. Food and Drug Administration (FDA) granted the application for ciltacabtagene autoleucel priority review, breakthrough therapy, and orphan drug designations.[2]
References
- ^ Jump up to:a b c d e f “Carvykti- ciltacabtagene autoleucel injection, suspension”. DailyMed. 9 March 2022. Retrieved 16 March 2022.
- ^ Jump up to:a b c d e f g h “FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma”. U.S. Food and Drug Administration (FDA). 7 March 2022. Retrieved 16 March 2022.
This article incorporates text from this source, which is in the public domain. - ^ “Carvykti”. U.S. Food and Drug Administration (FDA). 8 March 2022. Retrieved 16 March 2022.
- ^ “U.S. FDA Approves Carvykti (ciltacabtagene autoleucel), Janssen’s First Cell Therapy, a BCMA-Directed CAR-T Immunotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma”. Janssen Pharmaceutical Companies (Press release). 1 March 2022. Retrieved 16 March 2022.
External links
- “Ciltacabtagene autoleucel”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Carvykti |
| Other names | JNJ-68284528 |
| License data | US DailyMed: Ciltacabtagene_autoleucel |
| Routes of administration | Intravenous |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only [1] |
| Identifiers | |
| DrugBank | DB16738 |
| UNII | 0L1F17908Q |
//////////Ciltacabtagene autoleucel, JNJ 68284528, Carvykti, FDA 2022, APPROVALS 2022, JNJ-68284528, LCAR-B38M CAR-T cells
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TRIAMCINOLONE
TRIAMCINOLONE
- Molecular FormulaC21H27FO6
- Average mass394.434 Da
(11β,16α)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluor-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-on
(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(hydroxyacétyl)-10,13-diméthyl-6,7,8,9,10,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one
(8S,9R,10S,11S,13S,14S,16R,17S)-9-Fluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
124-94-7[RN]
16a-Hydroxy-9a-fluoroprednisolone
1ZK20VI6TY
204-718-7[EINECS]
755
9a-Fluoro-16a-hydroxyprednisolone
TU3850000
トリアムシノロン[Japanese]
去炎松[Chinese]
Triamcinolone
CAS Registry Number: 124-94-7
CAS Name: (11b, 16a)-9-Fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
Additional Names: D1-9a-fluoro-16a-hydroxyhydrocortisone; 9a-fluoro-16a-hydroxyprednisolone; D1-16a-hydroxy-9a-fluorohydrocortisone; 16a-hydroxy-9a-fluoroprednisolone
Manufacturers’ Codes: CL-19823
Trademarks: Aristocort (Lederle); Kenacort (BMS); Ledercort (tabl.) (Lederle); Omcilon (BMS); Tricortale (Bergamon); Volon (BMS)
Molecular Formula: C21H27FO6, Molecular Weight: 394.43
Percent Composition: C 63.95%, H 6.90%, F 4.82%, O 24.34%
Literature References: Prepn: Bernstein et al.,J. Am. Chem. Soc.78, 5693 (1956); 81, 1689 (1959); Thoma et al.,ibid.79, 4818 (1957); Bernstein et al., Allen et al.,US2789118; US3021347 (1957, 1962, both to Am. Cyanamid). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 367-396, 423-442 (1972); D. H. Sieh, ibid.11, 593-614, 651-661 (1982).
Properties: Crystals, mp 269-271°. mp also reported as 260-262.5°. [a]D25 +75° (acetone). uv max: 238 nm (e 15800).
Melting point: mp 269-271°; mp also reported as 260-262.5°
Optical Rotation: [a]D25 +75° (acetone)
Absorption maximum: uv max: 238 nm (e 15800)
………………………………
Derivative Type: 16,21-Diacetate
CAS Registry Number: 67-78-7
CAS Name: (11b,16a)-16,21-Bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene-3,20-dione
Additional Names: 16a,21-diacetoxy-9a-fluoro-11b,17a-dihydroxy-1,4-pregnadiene-3,20-dione
Trademarks: Cenocort (Central Pharm.); CINO-40 (Tutag); Tracilon (Savage)
Molecular Formula: C25H31FO8, Molecular Weight: 478.51
Percent Composition: C 62.75%, H 6.53%, F 3.97%, O 26.75%
Properties: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying). [a]D25 +22° (chloroform). uv max: 239 nm (e 15200).
Melting point: Solvated crystals, mp 186-188° (with effervescence, mp 235° after drying)
Optical Rotation: [a]D25 +22° (chloroform)
Absorption maximum: uv max: 239 nm (e 15200)
Therap-Cat: Glucocorticoid., Therap-Cat-Vet: Glucocorticoid., Keywords: Glucocorticoid.
///////////////////////
Triamcinolone Acetonide
CAS Registry Number: 76-25-5
CAS Name: (11b,16a)-9-Fluoro-11,21-dihydroxy-16,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione
Additional Names: 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone; 9a-fluoro-16a-hydroxyprednisolone acetonide; triamcinolone 16a,17-acetonide; 9a-fluoro-11b,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione; 9a-fluoro-16a,17-isopropylidenedioxyprednisolone
Trademarks: Adcortyl (BMS); Azmacort (Aventis); Delphicort (Lederle); Extracort (Basotherm); Ftorocort (Gedeon Richter); Kenacort-A (BMS); Kenalog (Apothecon); Ledercort Cream (Lederle); Nasacort (Aventis); Respicort (Mundipharma); Rineton (Sanwa); Solodelf (Cyanamid); Tramacin (J & J); Triam (Lichtenstein); Tricinolon (Kaken); Vetalog (Solvay); Volon A (BMS); Volonimat (BMS)
Molecular Formula: C24H31FO6, Molecular Weight: 434.50
Percent Composition: C 66.34%, H 7.19%, F 4.37%, O 22.09%
Literature References: Prepd by stirring a suspension of triamcinolone in acetone in the presence of a trace of perchloric acid: Fried et al.,J. Am. Chem. Soc.80, 2338 (1958); Bernstein et al.,ibid.81, 1689 (1959); Bernstein, Allen, US2990401 (1961 to Am. Cyanamid). Alternate synthesis using 2,3-dibromo-5,6-dicyanoquinone: Hydorn, US3035050 (1962 to Olin Mathieson). Clinical trial in chronic asthma: I. L. Bernstein et al.,Chest81, 20 (1982). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.1, 397-421 (1972); D. H. Sieh, ibid.11, 615-649 (1982).
Properties: Crystals, mp 292-294°. [a]D23 +109° (c = 0.75 in chloroform). uv max (abs alc.): 238 nm (e 14600). Sparingly sol in methanol, acetone, ethyl acetate.
Melting point: mp 292-294°
Optical Rotation: [a]D23 +109° (c = 0.75 in chloroform)
Absorption maximum: uv max (abs alc.): 238 nm (e 14600)
………………..
Derivative Type: 21-Acetate
Properties: Crystals, mp 268-270°. [a]D23 +92° (c = 0.59 in chloroform).
Melting point: mp 268-270°
Optical Rotation: [a]D23 +92° (c = 0.59 in chloroform)
Derivative Type: 21-Disodium phosphate
CAS Registry Number: 1997-15-5
Trademarks: Aristosol (Lederle)
Molecular Formula: C24H30FNa2O9P, Molecular Weight: 558.44
Percent Composition: C 51.62%, H 5.41%, F 3.40%, Na 8.23%, O 25.79%, P 5.55%
………………….
Derivative Type: 21-Hemisuccinate
Trademarks: Solutedarol (Specia)
Molecular Formula: C28H35FO9, Molecular Weight: 534.57
Percent Composition: C 62.91%, H 6.60%, F 3.55%, O 26.94%
Therap-Cat: Glucocorticoid; antiasthmatic (inhalant); antiallergic (nasal).
Therap-Cat-Vet: Glucocorticoid.
Keywords: Antiallergic (Steroidal, Nasal); Antiasthmatic (Steroidal, Inhalant); Glucocorticoid.
//////////////////////////
Title: Triamcinolone Benetonide
CAS Registry Number: 31002-79-6
CAS Name: (11b,16a)-21-[3-(Benzoylamino)-2-methyl-1-oxopropoxy]-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione
Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 21-ester with N-benzoyl-2-methyl-b-alanine; 9a-fluoro-16a-hydroxyprednisolone 16a,17a-acetonide 21-(b-benzoylamino)isobutyrate; triamcinolone acetonide b-benzoylaminoisobutyrate; TBI
Trademarks: Tibicorten (Stiefel)
Molecular Formula: C35H42FNO8, Molecular Weight: 623.71
Percent Composition: C 67.40%, H 6.79%, F 3.05%, N 2.25%, O 20.52%
Literature References: Prepn: C. Cavazza et al.,DE2047218; eidem,US3749712 (1971, 1973 both to Sigma-Tau). Pharmacology: E. T. Ordonez, Arzneim.-Forsch.21, 248 (1971). Percutaneous absorption by rats and rabbits: W. H. Down et al.,Toxicol. Lett.1, 95 (1977). Clinical study: D. J. Tazelaar, J. Int. Med. Res.5, 338 (1977). HPLC analysis: S. Muck et al.,Boll. Chim. Farm.120, 240 (1981). For structure see Triamcinolone Acetonide.
Properties: Crystalline powder, mp 203-207°. [a]D20 +96 ±3° (c = 1 in ethanol). Sol in methanol, acetone, ethanol, dioxane, pyridine, DMF, chloroform. Insol in water.
Melting point: mp 203-207°
Optical Rotation: [a]D20 +96 ±3° (c = 1 in ethanol)
Therap-Cat: Glucocorticoid; anti-inflammatory (topical).
Keywords: Glucocorticoid
////////////////////////
Triamcinolone Hexacetonide
CAS Registry Number: 5611-51-8
CAS Name: (11b,16a)-21-(3,3-dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione
Additional Names: 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, 21-(3,3-dimethylbutyrate); 21-tert-butylacetate-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; 21-(3,3-dimethylbutyryloxy)-9a-fluoro-11b-hydroxy-16a,17a-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione; triamcinolone acetonide tert-butyl acetate; TATBA
Manufacturers’ Codes: CL-34433
Trademarks: Aristospan (Fujisawa); Hexatrione (Lederle); Lederlon (Lederle); Lederspan (Lederle)
Molecular Formula: C30H41FO7, Molecular Weight: 532.64
Percent Composition: C 67.65%, H 7.76%, F 3.57%, O 21.03%
Literature References: The hexacetonide ester of the potent glucocorticoid, triamcinolone, q.v. Prepn of syringeable suspension: Nash, Naeger, US3457348 (1969 to Am. Cyanamid). Anti-inflammatory activity in rabbits: I. M. Hunneyball, Agents Actions11, 490 (1981). Early clinical studies: Bilka, Minn. Med.50, 483 (1967); Layman, Peterson, ibid. 669. Clinical studies of intra-articular therapy in arthritis: R. C. Allen et al.,Arthritis Rheum.29, 997 (1986); M. Talke, Fortschr. Med.104, 742 (1986). Toxicity study: Tonelli, Steroids8, 857 (1966). Comprehensive description: V. Zbinovsky, G. P. Chrekian, Anal. Profiles Drug Subs.6, 579-595 (1977). For structure see Triamcinolone Acetonide.
Properties: Fine, white, needle-like crystals, mp 295-296° (dec), also reported as mp 271-272° (dec). uv max (ethanol): 238 nm (e 15500). [a]D25 +90±2° (c = 1.13% in chloroform). Soly in g/100 ml at 25°: chloroform and dimethylacetamide >5; ethyl acetate 0.77, methanol 0.59, diethyl carbonate 0.50, glycerin 0.42, propylene glycol 0.13; absolute alcohol 0.03; water 0.0004.
Melting point: mp 295-296° (dec); mp 271-272° (dec)
Optical Rotation: [a]D25 +90±2° (c = 1.13% in chloroform)
Absorption maximum: uv max (ethanol): 238 nm (e 15500)
Therap-Cat: Anti-inflammatory.
Keywords: Glucocorticoid.
Product Ingredients
| INGREDIENT | UNII | CAS | INCHI KEY |
|---|---|---|---|
| Triamcinolone acetonide | F446C597KA | 76-25-5 | YNDXUCZADRHECN-JNQJZLCISA-N |
| Triamcinolone diacetate | A73MM2Q32P | 67-78-7 | XGMPVBXKDAHORN-RBWIMXSLSA-N |
| Triamcinolone hexacetonide | I7GT1U99Y9 | 5611-51-8 | TZIZWYVVGLXXFV-FLRHRWPCSA-N |
Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues.
Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others.[6] It is also used to prevent worsening of asthma and COPD.[6] It can be taken in various ways including by mouth, injection into a muscle, and inhalation.[6]
Common side effects with long-term use include osteoporosis, cataracts, thrush, and muscle weakness.[6] Serious side effects may include psychosis, increased risk of infections, adrenal suppression, and bronchospasm.[6] Use in pregnancy is generally safe.[7] It works by decreasing inflammation and immune system activity.[6]
Triamcinolone was patented in 1956 and came into medical use in 1958.[8] It is available as a generic medication.[9] In 2019, it was the 107th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[10][11]
PATENT
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Skin diseases are the medical condition that affects the skin, hair, nails and related muscle and glands.
Skin disorders vary greatly in symptoms and severity. They can be temporary or permanent, and may be painless or painful. Some have situational causes, while others may be genetic. Some skin conditions are minor, and others can be lifethreatening.
There are many different types of skin disorders which include rashes, dermatoses or skin eruptions. Such rashes, dermatoses or skin eruptions include acute, inflammatory reactions of the skin caused by an allergic or irritant reaction, other forms of eczema, lichen simplex chronicus. Chronic nature includes seborrheic dermatitis, psoriasis, and atopic dermatitis or caused by infection, irritation or aggravation of another condition such as occurs with acne, other rashes, dermatoses or skin eruptions, inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, contact dermatitis, impetigo, urticarial and scabies.
Typical symptoms of the skin disorders include but not limited to raised bumps that are red or white, a rash, which might be painful or itchy, scaly or rough skin peeling skin, ulcers, open sores or lesions, dry, cracked skin, discolored patches of skin, fleshy bumps, warts, or other skin growths, changes in mole color or size a loss of skin pigment, excessive flushing or the like.
Atopic dermatitis (AD), also known as eczema or atopic eczema, is a type of inflammation of the skin (dermatitis). Atopic dermatitis (AD) is common worldwide. People of all ages from newborns to adults and older live with this condition. Symptoms range from excessively dry, itchy skin to painful, itchy rashes that cause sleepless nights and interfere with everyday life.
Topical corticosteroids have been the mainstay of treatment for atopic dermatitis over the past years, further the cure for atopic dermatitis involves Lifestyle modification, balanced diet intake, self-care measures, phototherapy, wet wrap therapy, use of medications like tacrolimus, pimecrolimus, crisaborole, dupilumab, ciclosporin, methotrexate, interferon gamma- lb, mycophenolate mofetil, and azathioprine or the like.
Triamcinolone Acetonide is a synthetic corticosteroid. Chemically it is [Pregna-1, 4-diene-3, 20-dione, 9-fluoro-l l, 21 -dihydroxy- 16, 17-[(1 methylethylidene) bis-(oxy)]-, (HP, 16a)-] with the empirical formula C24H31FO6 and molecular weight 434.50. Triamcinolone Acetonide is represented by compound of structural formula I
Triamcinolone Acetonide topical cream and ointment with strengths 0.025%, 0.1% and 0.5% (containing 0.25 mg/gm, 1 mg/gm & 5 mg/gm Triamcinolone Acetonide respectively) were approved in USA prior to Jan 1, 1982 under the trade name “Triamcinolone Acetonide” and were indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
The commercially available products or product known in the prior art produces side effects such as burning, itching, irritation, or dryness of skin at site of application, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria.
Pediatric patients may demonstrate greater susceptibility to topical triamcinolone -induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic -pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome and intracranial hypertension have been reported in children receiving topical triamcinolone. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Chronic corticosteroid therapy may interfere with the growth and development of children.
Making low dose compositions can present technical and economic challenges that are not present for higher dose formulations.
Examples
The following table 1 shows cream formulation containing lOO.OOmcg per gm, 50.00mcg per gm and 25.00mcg per gm of Triamcinolone Acetonide
Table – 1: cream
Drug Strength IQOmcg/gm 50mcg/gm 25mcg/gm
lOO.OOmcg per gm and for lOOgm, it is lO.OOmg*
50.00mcg per gm and for lOOgm, it is 5.00mg*
25.00mcg per gm and for lOOgm, it is 2.50mg**
Manufacturing process:
a) Dispensing following excipients – isopropyl myristate, glyceryl monostearate and white soft paraffin in vessel I;
b) Dispensing the following excipients – polysorbate 40 and purified water in vessel II;
c) Dispensing the following excipients methyl paraben, propylene glycol in vessel III; wherein methyl paraben is dissolved in propylene glycol to form a clear solution;
d) Dispensing the following active & excipients triamcinolone acetonide or salt thereof, propylene glycol in vessel IV; wherein triamcinolone acetonide or salt thereof is dissolved in propylene glycol to form clear solution;
e) Adding content of step (c) into content of step (b) and stirring to form uniform and homogeneous emulsion;
f) Heating content of step (b) and step (a) at about 75 °C and stirring to form a homogenous uniform emulsion;
g) Cooling the above emulsion gradually to temperature of about 25 °C – 30°C h) Adding the content of step (d) to the primary emulsion of (f) with constant stirring; and
i) Making up the volume of the emulsion with purified water to the required quantity.
SYN
DOI: 10.1021/ja01516a043
CLIP
Corticosteroids
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Triamcinolone
Triamcinolone, 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1, 4-dien-3,20-dione (27.1.61), differs from dexamethsone in terms of chemical structure in that the a methyl group at C16 is replaced with a hydroxyl group. It is synthesized from the 21-O-acetate of hydrocortisone 27.1.17. In the first stage, both carbonyl groups of this compound undergo ketalization by ethylene glycol. Next, the hydroxyl group in the resulting diketal 27.1.53 is replaced with chlorine using thionyl chloride, and the product undergoes dehydrochlorination using an alkaline, during which the 21-O-acetyl group also is hydrolyzed. Acetylating the hydroxyl group once again with acetic anhydride gives a triene 27.1.54. Reacting this with osmium tetroxide gives the vicinal diol 27.1.55. The secondary hydroxyl group at C16 of this product undergoes acetylation by acetic anhydride in pyridine, which forms the diacetate 27.1.56. Treating the product with N-bromoacetamide in chloric acid gives a bromohydrin (27.1.57), which upon reaction with potassium acetate is transformed to an epoxide (27.1.58). Opening of the epoxide ring, using hydrofluoric acid, gives the corresponding 9-fluoro-11-hydroxy derivative 27.1.59. Upon microbiological dehydrogenation, the C1–C2 bond is oxidized to a double bond, forming triamcinolone acetate (27.1.60), the acetyl group of which is hydrolyzed, forming the desired triamcinolone (27.1.61) [30–32].
Triamcinolone is similar to dexamethasone in terms of pharmacological action, and it is better tolerated in some cases. Synonyms of this drug are ledercort, cenocort, delsolon, and others.
SYN
Drugs for Treating Respiratory System Diseases
Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016
Triamcinolone–Nasacort
The synthesis of triamcinolone (23.2.1) starts from ketalization of cortisol 21-acetate (23.2.8) using ethylene glycol. Dehydration of the obtained compound (23.2.9) for creation of a double bond in position 16,17 of the steroid skeleton through the series of sequential reactions of chlorination, dehydrochlorination, hydrolysis, and acetylation produces 21-acetoxy-4,9(11),16-pregnatriene-3,20-dione (23.2.10), treatment of which with osmium tetroxide in benzene and pyridine produced diol (23.2.11), the secondary hydroxyl group of which, in position 16, was acetylated with acetic anhydride in pyridine to produce the diacetate (23.2.12). The obtained compound in dioxane and water was treated with N-bromoacetamide and 10% perchloric acid to yield bromohydrine (23.2.13). Dehydrobromination of the bromohydrine (23.2.13) with anhydrous potassium acetate in refluxing ethanol produced the epoxy-derivative (23.2.14). Opening of the epoxide ring in (23.2.14) with anhydrous hydrogen fluoride in chloroform produced (23.2.15). Microbiological dehydrogenation of the obtained product with Corynebacterium simplex produced crude diacetate (23.2.16), saponification of which produced triamcinolone (23.2.1) [108-110] (Scheme 23.7.).
Scheme 23.7. Synthesis of triamcinolone.
Triamcinolone is commonly used in the treatment of respiratory inflammation and improves airway reactivity, decreasing respiratory problems. Strangely, there are only few reviews of the pharmacotherapy of triamcinolone [111-113].
SYN
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 426-39-1 | C25H33FO8 | 16α,21-diacetoxy-11β,17-dihydroxy-3,20-dioxo-9-fluoro-4-pregnene | Pregn-4-ene-3,20-dione, 16,21-bis(acetyloxy)-9-fluoro-11,17-dihydroxy-, (11β,16α)- |
| 96670-24-5 | C25H30O8 | 16α,21-diacetoxy-3,20-dioxo-17-hydroxy-9β,11β-epoxy-1,4-pregnadiene | 9β-Pregna-1,4-diene-3,20-dione, 9,11β-epoxy-16α,17,21-trihydroxy-, 16,21-diacetate |
SYN
https://patents.google.com/patent/WO2016120891A1/en
Glucocorticoids have a number of diverse effects in different body tissues. Glucocorticoids, in topical, oral and inhaled formulations, are useful for their anti-inflammatory and immunosuppressive properties. Several glucocorticoids such as budesonide and ciclesonide are used for treatment of several disorders.
The synthesis and purification of glucocorticoids have been disclosed at different instances. However, most of these synthetic procedures involve toxic solvents or long reaction times and are ineffective for large scale synthesis. For instance, US 3,92,9768 discloses a process for preparation of budesonide by reacting 16, 17-dihydroxy compound with aldehyde in solvents such as dioxane, methylene chloride or their combinations.
DE 4129535 discloses a process for the synthesis of Ciclesonide which involves the intermediate 16A, 17-[(7?,S)-cyclohexylmethylenedioxy]-l 13, 21-dihydroxy-pregna-l 4- dien-3,20-one which is obtained by an acid catalysed reaction of 11 , 16 , 17, 21-tetra hydroxypregna-l,4-dien-3,20-one with cyclohexane aldehyde.
WO 02/38584 discloses the synthesis of Ciclesonide by reacting corresponding 16, 17-ketals with a cyclohexane aldehyde in the presence of 70% perchloric acid, 1-nitropropane as solvent. However, perchloric acid is a dangerous solvent and can cause serious accidents with fatal consequences.
US Patent No. 6169178 relates to a process for the preparation of budesonide and of 16, 17- acetals of pregnane derivatives structurally co-related thereto comprising treating 16, 17-dios or of 16, 17-ketals or cyclic acetals with aldehydes in the presence of aqueous hydrobromic acid or hydroiodic acid used as reaction catalyst or solvents. However, hydroiodic and other hydrohalic solvents are corrosive, light sensitive and expensive. Further, these acids also post environmental problems. Notwithstanding the use of hydrohalo acids requires use of special equipment since they are extremely corrosive and consequently increase the cost of production.
US 5,55,6964 discloses a process for the preparation of budesonide by reacting 16 – Hydroxy Prednisolone in acetonitrile in the presence of /^-toluene sulfonic acid as a catalyst. There are certain other patents that use alkyl sulfonic acid instead of aryl sulfonic acid for the synthesis of budesonide or similar compounds. However, sulfonic acids are hazardous solvents and FDA has expressed significant concern over the presence or traces of sulfonic acid in pharmaceutical products. Hence, there is a need to have a process for the synthesis 16, 17- acetals of pregnane compounds that is industrially scalable and which does not involve the use of harmful solvents.
Example- 1: Process for preparation of 16-HPN from 3TR
Stage-I
Stage- 1 Stage-I I
Stage-IV
1 6-HPN acetate 1 6-HPN
Scheme 2: Synthesis of 16HPN from 3TR
Stage-I (oxidation)
Charge 750L of acetone (50 volume), 39L of purified water (2.60 volume) and 15 Kg of 3TR (40.93mol) in a SS Reactor at ambient temperature. Cool to -7°C to -5°C than added 6.0L of formic acid (159.03 mol) and 9.0 kg of potassium permanganate (56.95 mol). Maintain at – 5°Cto -3°C for 30 minutes. In-process check by TLC, 3TR should be less than 1.0%. Added 1.5kg sodium metabisulphite (7.89 mol solution in 12L of purified water at -5°C to -3°C then added 3.0 kg of hyflow super cell at 15°C (+2°C) and filter through 10.0 kg of hyflowbed at 27°C(+3°C) and wash with 150L of acetone Added 1.5 kg of activated charcoal, Stir and filter through hyflow bed and wash with 60L of acetone. Total filtrate was distilled under reduced pressure, while maintaining temperature below 45°C. Added 81L of purified water and cool to 5°C+5°C. Filter through centrifuge and wash with 156L of purified water. Wet material is dry at 60°+5°C till moisture less than 0.50%, Yield=15 kg, HPLC purity=98%.
Stage-II (Bromination)
Charge 75L of tetrahydrofuran, 16L of purified water and 15.0 kg of Stage-I (37.46 mol) in a glass reactor. Cool to -6°C (+2°C) and added 7.50 kg of dibromantin (26.23 mol) and 0.60L of perchloric acid (9.38 mol) and maintain at -6°C (+2°C) for one hour. In-process check by TLC, stage-I should be less than 0.50%. Reaction mass is quench in 390L of purified water at ~5°C. Raised the temperature to 25°C and maintained for 01 hour, filter through centrifuge and wash with 828L of purified water or till neutral pH. Wet material is dry at 40°C+5°C till moisture content should be less than 10%, Yield=21.0kg, HPLC purity=97%.
Stage-Ill (Debromination)
Charge 68.0L of N, N-dimethyl formamide(3.238volume) and 21.0kg of stage-II (42.22 mol) in glass reactor, start argon gas purging and cool to -5°C. Charge 13.0L of N,N- dimethylformamide (0.619volume) , 9.70L of dimethylsulfoxide(0.462volume), 1.62kg of chromium chloride hexahydrate (6.51 mol) and 1.94 kg of zinc dust (0.703 mol). Cool to – 10°Cand added 5.50L of thioglycolic acid (79.21 mol). Maintain for one hour while maintaining temperature around -10°C. In-process check by TLC, stage-II should be less than 1.0%. Added 310 L of purified water and cool to 0°C. Filter through centrifuge and wash with 1600L of purified water. Wet material is dry at 60°C+ (5°C) till moisture content less than 6.0%, Yield=15.0kg, HPLC Purity=90%.
Charge 150L of methylene chloride (10 volume), 150L of methanol (10 volume.) and 15.0kg (30.16 mol) of stage-Ill in a SS Reactor. Heat to clear solution then added 3.0 kg of activated charcoal (20%) and reflux for 04 hours, Filter through hyflow bed and wash with 75L of methylene chloride (5 volume), and 75L of methanol (5 volume) mixture. Total filtrate is distilled till last drop and added 75L (5 volume) of methylene dichloride, reflux for 04 hours than cool to 40°C+(5°C), Filter through centrifuge and wash with 15L (one volume) of methylene chloride. Wet material is dry at 60°C (+5°C) till moisture contents less than 1.0% (Yield =13.0kg, HPLC Purity=96%). Further charge 65.0L (5volume) of ethyl acetate and 13.0 kg (1.0 mol) of purified material. Heat to reflux and maintain for 04 hours under reflux, then cool to 40°C. Filter through centrifuge and wash with 13.0L (one volume) of ethyl acetate. Wet material is dry at 60°C (+5°C) till moisture contents less than 0.50%, Yield=12.0kg, HPLC Purity=98.6%.
Stage-IV (Deacetylation)
Charge 5.83L of methanol (10 volume) and 5.83L of methylene chloride (10 volume) in a glass flask and added 583 gm of 16-HPN acetate(1.397mol) at RT. Start argon gas purging and cool to 0°C to 5°C under argon purging. Prepare 11.66 gm of sodium hydroxide (0.2915mol) solution in 0.583L of methanol (one volume) under argon purging and cool to 0°Cto 5°C. Sodium hydroxide solution is charge in reaction mass at 0°C to 5°C. Maintained the reaction mass at 0°C to 5°C for one hour, In-process check by TLC against 16-HPN acetate it should be nil. Adjust pH to neutral by 21.40ml of acetic acid (0.3742 mol); distill under reduced pressure while maintaining temperature below 40°C, till dry. Cool to ambient temperature and added 1.166L of purified water (02 volume). Cool to 0°C and maintain for one hour. Filter and wash with 300ml of purified water. Dry at 60°C (+5°C) till moisture content less than 1.0%, Yield=490gm (93.50%), HPLC Purity=98.97%, Single impurity= 0.40%. Example 2: Process of synthesis of Budesonide from 16-HPN
16-HPN Budesonide
Charge 800 ml of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to -5°C and maintain for 15 min. then added 100 gm of stage-I (0.27 mol) at -5°C and stir for 15 min., added 30 ml of N-butyraldehyde (0.33 mol) while maintaining temperature -5°C to 0°C in around 30 minutes and maintain at 0°C to 5°C for 150 min. under stirring. In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 1200 ml of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 100 kg of sodium bicarbonate (1.19 mol) and 1 ml of purified water (10 volume) in reaction mass at 5°C to 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =110 gm (96.49%), HPLC purity=96.45%, single impurity=1.29%, Epimer-A=47.76%, Epimer-B=49.69%.
(Purification)
Charge 2.5 L of methanol (25 volume) in a Glass flask and added 100 gm of above mentioned crude product. Dissolved at 25°C+5°C till clear solution, added 10 gm of activated charcoal and stir for 30 min. than filter through hyflow bed and wash with 200 ml of methanol (2 volume). Combined filtrates charged in a Glass flask and cool to 10°C to 15°C and added 5.40 L of purified water (54 volume) at 5°Cto 10°C, stir for 15min., filter and wash with purified water. Wet material is dry at 50°C (+5°C) under vacuum till moisture content less than 0.50%, Output=90.0gm, HPLC purity=99.66%, single impurity=0.1%, Epimer-A=44.47%, Epimer-B=55.01%.
Example 2.1: Scale-up process of manufacturing of Budesonide from 16-HPN
Charge 40 L of aqueous hydrochloric acid (8 volume) in a glass flask, start nitrogen gas purging and Cool to – 10°C and maintain for 15 min. then added 5.0 kg of stage-I (13.315 mol) at – 10°C and stir for 45 min. added 1.5 L of N-butyraldehyde (16.68 mol) while maintaining temperature -7°C to – 11°C in around 30 minutes and maintain at -2°C to -6°C for 60 min. under stirring In-process check by TLC against stage-I, it should be nil. Reaction mass is quench in 60 L of purified water (12 volume) at 5°C to 10°C and stir for 15 min. Added solution of 5.0 kg of sodium bicarbonate (59.525 mol) and 50L of purified water (10 volume) in reaction mass at 5°Cto 10°C. Stir at 5°C to 10°C for 15 min. Filter and wash with purified water till neutral pH. Wet material is dry at 50°C (+5°C) till moisture contents less than 1.0 %, Yield =5.293 kg (94.46%), HPLC purity=95.45%, single impurity=1.45%, Epimer-A=53.51 %, Epimer-B=43.78% Effect of temperature and its variation on epimer ratio (A and B) with respect to batch size (From lab to commercial batch)
Example 3: Process for synthesis ofCiclesonide from 16HPN
Preparation of cyclohexane carboxaldehydemetabisulphite complex
200gm of Cyclohexane carboxaldehyde (1.786 mol) was dissolved in 3.0L of denatured sprit (15 volume) and a solution of 190gm of sodium metabisulphite (1.827 mol) in 300ml of purified water (1.5 volume) was added. The resulting precipitate was filtered and washed with 1.0L of denatured sprit(5.0 volume) and dried under vacuum at 50°C, till moisture content less than 6.00%, Yield=400gm (97 %)
Stage I: Preparation of stage-I from 16-HPN
Cyclohexane carboxaldehyde
sodium metabisulphite complex
170gm of 16-HPN (0.4528 mol) was suspended in 3.40L of dichloromethane (20 volume) and treated with 340ml of 70% perchloric acid. (5.65 mol) and 110.5gm of cyclohexane carboxaldehyde metabisulphite complex (0.512 mol) was added in lots while maintaining the temperature between 0°Cto 5°C. The reaction mass was stirred at 0°C to 5°C for 03 hours. In- process check by TLC 16-HPN should be nil and then neutralized with 10% aqueous sodium bicarbonate solution. The organic layer was separated and concentrated under vacuum to obtain a residue which was stripped with methanol (1.0 volume). The solvent was concentrated and the residue was dissolved by refluxing in methanol (5.0 volume). The clear solution was cooled to 0°C to 5.0°C and the resulting solid was filtered and dried at 50°C till moisture content less than 0.50%, Yield=170.0gm (80.0%), HPLC purity=91.68%.
Stage -II Preparation of Ciclesonide from Stage -I
Stage-I Ciclesonide
158gm of stage-I (0.34mol) was suspended in 1.58L of methylene chloride (10.0 volume) at 25°C to 30°C. The reaction mass was chilled to 0°C to 5°C and 81.0ml of triethylamine(0.581 mol) was added, followed by the addition of 79.0ml of isobutyryl chloride [0.75 mol; diluted with 79.0 ml of methylene chloride (0.50 volume)] slowly at 0° to 5°C and maintained at same temperature for 60min. In-process check by TLC, Stage-I should be nil. The reaction mass was diluted with 2.53L of purified water (16.0 volume) , the organic layer was separated and washed with purified water till neutral pH, than organic layer was separated and concentrated under vacuum to obtained a residue. The residue was dissolved by refluxing in 948ml of methanol (6.0 volume); the clear solution was cooled to 0°C to 5°C under stirring and filtered. The product was dried under vacuum at ~50°C till moisture contents comes less than 0.50%, Yield=158.0 gm (87.0%), HPLC purity=95.74%.
(Purification)
120gm of Ciclesonide crude was dissolved by refluxing in 600ml of methanol. The clear solution was chilled to 20°C under stirring and filtered. The product was dried under vacuum at 90°C till moisture content less than 0.50%. Yield=105 gm (87.50%), HPLC purity=99.7 %.
Example 4: Process for synthesis of Desonide from 16HPN acetate
Stage-I : Preparation of Desonide acetate from 16 HPN acetate
Desonide acetate
16HPN acetate 190.0 ml of acetone (7.0 volume) was charged in a glass flask under nitrogen blanketing than added 27 gm of 16HPN acetate (0.0645mol) at ambient temperature. Temperature raised to 28°C (+2°C) and stir for 20 minutes. 1.35 ml of perchloric acid 70% (0.02 lmol) was added at 28°C (+2°C) and stir for 30 minutes. Temperature further raised to 35°C and stir for 60 minutes. In-process check by TLC against 16HPN acetate, it should be nil. Reaction mass cooled to 10°C, filtered and washed with purified water till neutral pH (~7) and finally washed with acetone. Wet material dried at 50°C+5°C till moisture content less than 0.50% to get stage-I. Yield =23gm (77.76%), HPLC Purity=98.28%
Stage-II: Preparation of Desonide from Desonide acetate
Desonide
Desonide acetate
200 ml of methanol (10 volume) and 200ml of methylene dichloride (10 volume) was charged in a glass flask and start argon gas purging. 20 gm of stage- 1st (0.0436mol) was added at ambient temperature. Cool to 0°C+5°C. 0.40gm of sodium hydroxide (O.Olmol) solution in 20ml of methanol (l.Ovolume) was added at 0°C+5°C. Stir at 0°C+5°C for 120 minutes. In-process check by TLC against stage- 1st it should be nil. Adjust pH to neutral (~7) by 2.0ml of acetic acid at 0°C+5°C. Distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume get reduced to 3 to 4 volume of the input. Cool to 0°C and further added 60ml of purified water and stir for 30 minutes. Filtered, washed with purified water till neutral pH (~7). Wet material dried at 50°C+5°C till moisture content less than 0.50% to get crude Desonide. Yield =14.70gm (80.92%), HPLC Purity=88.15%.
(Purification)
140 ml of methanol (10 volume) and 140 ml of methylene chloride (10 volume) was charged in a glass flask and added 14.0 gm of crude material (0.034mol) than stir till clear solution. Added 1.5 gm of activated charcoal and stir for 30 minutes than filtered through hyflow supercel bed and washed with 30ml of methanol and 30ml of methylene chloride mixture. Combined filtrate and distilled the solvent from reaction mass under vacuum while maintaining temperature below 40°C till the volume reduced to 3 to 4 volume of the input. Cool to 0°C. Filtered the reaction mass and washed with 10ml of precooled methanol. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get Desonide. Yield=8.60gm, HPLC Purity= 99.43%
lOOgm of 3TR (0.27 mol.)was suspended in 1300ml (13 volume) acetone. Cooled it to -5°C to -10°C than added 4.0 ml (0.062 mol.) perchloric acid solution and 50gm of dibromantin. Maintained the reaction at same temperature for 02 hours. In-process check by TLC against 3TR it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol.) in 5 lots and reaction was maintained at 35°C+2°C. In-process check by TLC against step-I reaction mass, it should be nil. Cooled to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol.). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50%. Yield =87gm, (83.36%), HPLC Purity=97.883%.
Stage – II:
80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permagnate (0.30 mol.) at -5°C (+2°C). Reaction was maintained at – 5°C+2°Cfor one hour. In-process check by TLC against stage-I it should be nil. Added 8gm of sodium metabisulphite (0.042 mol.) In 80 ml purified water (01 volume) solution at -5°C (+2°C). Temperature raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4volume of stage-I than cool to 0°C to 5°C and added 480ml of purified water stir and filter and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0%. Yield =78.30gm, (89.88%), HPLC Purity=99.178%. Stage -III:
Stage-ll Stage-
300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction was maintained at -45°C to -50°C for 02 hours. In-process check by TLC against before acetone reaction mass. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at ~20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C (+2°C), stir and filter and washed with purified water till neutral pH. Wet material was dried at 45°C to 50°C, Yield =78.50gm, (91.48%), HPLC Purity=91.593%.
(Purification)
76 gm of stage-Ill Crude (0.16 mol.) was dissolved in 760ml of methylene chloride (lOvolume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stir till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than stir for 30minutes, filter through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and stir for 02 hours. Filtered and washed with minimum precooled methanol, Wet material was dried 45°C to 50°C till moisture contents less than 0.50%, Yield=62gm, HPLC Purity=98.633%.
Stage – IV (Process for synthesis of Triamcinolone acetonide from Stage – III):
Stage- Ill Triamcinolone acetonide
60gm of stage-Ill (0.13 mol) was dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 1.2gm of sodium hydroxide (0.03mol.) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C (+2°C) for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C (+2°C). Reaction mass was distilled at below 40°C under vacuum till 3 to 4 volume of input. Cool to 30°C and added 120ml of purified water, stir for one hour than filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield =52gm, (95.04%), HPLC Purity=99.21%
(Purification)
50gm of crude material (0.12 mol.) was dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stir for one hour at same temperature, Filter through hyflow bed and washed with 120ml of acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°Cand maintained for one hour at same temperature. Filter and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%, Yield=43gm, HPLC Purity=99.40%.
Example 6: Process for synthesis of Flunisolide from 16HPN acetate Stage -I (Preparation of Desonide acetate from 16HPN acetate):
1 6 H PN acetate eson e acetate
140ml of acetone (7 volume) was charged in glass flask and start argon blanketing than added 20 gm of 16-HPN acetate (0.048mol) at ambient temperature. Cooled to 28°C (+2°C). 1.0ml of perchloric acid 70% (0.016mol) was added at 28°C (+2°) C and stirred for 30 minutes. Temperature raised up to 35°Cand stirred for 60 minutes. In-process check by TLC against 16-HPN acetate, it should be nil. Reaction mass was cooled to 10°C (+2°C). Reaction mass was filtered and washed with purified water till neutral pH (~7) to get wet material. Wet material was dried at 50°C+5°C till moisture content less than 0.50% to get stage-lst. Yield=17.40gm, (79.40%), HPLC Purity=98.241%.
Stage -II (Preparation of Desonide from Desonide acetate):
170ml of methanol (lOvolume) and 170ml of methylene chloride (lOvolume) was charged in a glass flask and start inert atmosphere. 17gm of stage-lst (0.037mol) was added at ambient temperature. Cooled to -5°C. 0.4gm of sodium hydroxide (O.Olmol) solution in 17ml of methanol was added at 0°C (+5°C). Reaction mass was stirred for 02 hours at 0°C (+5°C). In- process check by TLC against stage- 1st it should be nil. Neutral pH (~7) was adjusted by acetic acid. Reaction mass was distilled under vacuum at below 40°C till ~ 100ml. Concentrated mass was cooled to 0°C (+5°C) and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get stage-2nd. Yield=14.0gm, (90.67%), HPLC Purity=99.426%, Single impurity=0.136%.
Stage -III (Preparation of Flunisolide acetate from Desonide):
Desonide Flunisolide acetate
50ml of isopropenyl acetate (5 volume) was charged in a glass flask and added lOgm of stage-2nd (0.024mol) at ambient temperature than heated to 65°C and added 1.5ml of methane sulphonic acid (0.023mol) and temperature raised up to 80°C and stir for one hour. In-process check by TLC against stage-2, it should be nil. Reaction mass cooled to 25°C and adjust pH neutral (~7) by triethylamine. Reaction mass was distilled under vacuum till last drop and degases with acetonitrile. 90ml of acetonitrile (09 volume) was added and cooled to -5°C and than further added 10ml of purified water. lOgm of selectfluor(0.028mol) was added in two lots at 0°C(+5°C) in 02 volume of acetonitrile. Reaction mass was stirred at 10°C to 15°C for 12 hours. In-process check by TLC against before selectfluor reaction mass it should be nil. Adjust pH neutral (~7) by liq. ammonia solution at 0°C+5°C. Reaction mass was quenched in 500ml of purified water (lOOvolume) at ambient temperature. Reaction mass was filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C+5°C till moisture content less than 0.50% to get stage-3rd. Yield=8.60gm, (75.17%), HPLC Purity= 94.12%.
Stage -IV (Preparation of Flunisolide from Flunisolide acetate):
Flunisolide acetate Flunisolide
80ml of methanol (lOvolume) and 80ml of methylene chloride (lOvolume) was charged in a glass flask under inert atmosphere at ambient temperature than added 8.0gm of stage-3r (0.017mol) at ambient temperature. Cooled to -5°C and added 0.16gm of sodium hydroxide (0.004mol) solution in 8ml of methanol at -5°C(+5°C) and stir for 02 hours at -5°C(+5°C). In-process check by TLC against stage-3 ‘ it should be nil. Adjust pH neutral(~7) by acetic acid and reaction mass was distilled under vacuum at below 40°C(+5°C) till ~40ml of volume. Cool to 0°C to 5°C and stir for one hour. Reaction mass was filtered and washed with precooled methanol to get wet material. Wet material was dried at 45°C (+5°C) till moisture content less than 0.50% to get Flunisolide crude. Yield=6.0gm, (82.30%), HPLC Purity=86.50%.
(Purification)
6.0gm of crude Flunisolide(0.014mol) was dissolved in 65ml of ethyl acetate (10.83volume) and 35ml of n-hexane (5.83volume) mixture and clear solution was passed through 60gm of silica gel column. Column was washed with 975ml of ethyl acetate (162.5volume) and 525ml of ft-hexane (87.5volume) mixture. Eluted fraction was distilled under vacuum till 3 to 4 volume of input than cooled it to 0°C and filter to get wet material. Wet material was dried at 50°C (+5°C) till moisture content less than 0.50% to get Flunisolide. Yield=4.28gm, HPLC Purity=95.60%.
Example 7: Process for synthesis of Triamcinolone from 3TR
S
lOOgm of 3TR (0.27mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to- 10°C than added 4.0 ml (0.062mol) perchloric acid solution and 50gm of dibromantin. Reaction maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C+5°Cand adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH (~7). Wet material was dried at 45°C (+2°C) till moisture content less than 0.50% to get stage-I. Yield=85.30gm, (81.74%), HPLC Purity=96.54%. Stage -II:
80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C (+2°C) than added 32ml of formic acid (0.85 mol.) and 48gm of potassium per magnate (0.30 mol) at -5°C (+2°C). Reaction was maintained at same temperature for one hour. In-process check by TLC against stage-I, it should be nil. Added sodiummetabisulphite solution (8 gm in 80 ml of water) at -5°C+2°C. Temperature was raised up to 27°C and filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than further cooled to 0°C to 5°C and added 480ml of purified water, stirred, filter and washed with purified water to get wet stage- II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-II. Yield=82gm, (94.13%), HPLC Purity=97.75%.
Stage -III:
Stage-II Triamcinolone acetate
160ml of hydrofluoric acid (70%) (6.72mol) was cooled at -25°C to -30°C than added 40gm of stage-II (0.096mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II, it should be nil. Added 280ml of purified water at 0°C and 650ml of liq. ammonia at 20°C than reaction mass was quenched in 200ml of liq. ammonia and 500ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH(~7). Wet material was dried at 45°C to 50°C to get stage-Ill Yield=40gm, (95.42%), HPLC Purity=88.71%
(Purification)
40gm of stage-Ill crude (0.0916 mol) was refluxed in 160ml of acetone. Cool to 0°C. Filtered and washed with minimum precooled acetone. Wet material was dried at 50°C+5°C till moisture content comes less than 0.50% to get stage-Ill. Yield=24.9gm HPLC Purity=95.17%.
24gm of stage-Ill (0.055mol) was dissolved in 240ml of methanol (lOvolume) and 240ml of methylene chloride (lOvolume) mixture under argon bubbling. Cool to -5°C+2°C and added 0.48gm of sodium hydroxide (0.012mol) solution in 24ml of methanol (Olvolume) at – 5°C+2°C. Reaction was maintaining at -5°C (+2°C) for 03hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral by adding 0.70ml of acetic acid at -5°C (+2°C). Reaction mass distilled at below 40°C under vacuum till 04-05 volume of input. Cooled to 0°C+5°Cand stir for one hour than filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50%. Yield=18.50gm, (85.29%), HPLC Purity=98.60%.
Example 8: Process for synthesis of Triamcinolone Hexacetonide from 3TR
S
lOOgm of 3TR (0.27288 mol) was suspended in 1300ml (13 volume) acetone. Cool to -5°C to -10°C than added 4.0 ml (0.0625 mol) perchloric acid solution and 50gm of dibromantin. Reaction was maintained at same temperature for 02 hours. In-process check by TLC against 3TR, it should be nil. Added lOOgm of potassium carbonate solution (0.723 mol) in 5 lots and reaction was maintained at 35°C (+2°C). In-process check by TLC against step-I reaction mass, it should be nil. Cool to 0°C (+5°C) and adjust pH neutral (~7) by 36ml of acetic acid (0.63 mol). Added 3.0L of purified water (30 volume). Filter and washed with purified water till neutral pH. Wet material was dried at45°C(+2°C) till moisture content less than 0.50% to get stage-lst. Yield =87gm, (83.36%), HPLC Purity=97.883%. Stage-II :
80gm of stage-I (0.21 mol) was dissolved in 4.0L of acetone (50 volume) and 208ml of purified water (2.6 volume). Cool to -5°C than added 32ml of formic acid (0.85 mol.) and 48gm of potassium permanganate (0.30 mol) at -5°C+2°C. Reaction maintained at -5°C (+2°C) for one hour. In-process check by TLC against stage-I, it should be nil. Added sodium metabisulphite solution (8 gm in 80 ml water) at -5°C (+2°C). Temperature raised up to 27°Cand filtered through hyflow bed and washed with acetone. Acetone was distilled under vacuum till 3 to 4 volume of stage-I than cooled to 0°C to 5°C and added 480ml of purified water, stirred, filtered and washed with purified water to get wet stage-II. Wet material was dried at 50°C (+5°C) till moisture content less than 3.0% to get stage-2nd. Yield=78.30gm, (89.88%), HPLC Purity=99.18%.
Stage – III:
300ml of hydrofluoric acid (12.60mol) was cooled at -25°C to -30°C than added 75gm of stage-II (0.180mol). Reaction was maintained at -25°C to -30°C for 04 hours. In-process check by TLC against stage-II. It should be nil. Reaction mass was cooled to -50°C than added 45ml of acetone (0.60volume) at -45°C to -50°C. Reaction maintained at -45°Cto – 50°C for 02 hours. In-process check by TLC against reaction input, it should be nil. Added 565ml of purified water at 0°C and 340ml of liq. ammonia at 20°C than reaction mass was quenched in 410ml of liq. ammonia and 735ml of purified water solution at 15°C(+2°C), stirred, filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°Cto get stage-3rd. Yield=78.50gm, (91.48%), HPLC Purity=91.59%.
(Purification)
76 gm of stage-Ill Crude (0.16 mol) was dissolved in 760ml of methylene chloride (01 volume) and 760ml of methanol (lOvolume) mixture at ambient temperature. Stirred till clear solution and added 7.6gm of activated charcoal (0. lOvolume) than further stir for 30 minutes and filtered through hyflow bed and washed with methanol (one volume) and methylene chloride (one volume) mixture. Total filtrate was distilled under vacuum till 3 to 4 volume of input. Cooled to 0°C to 5°Cand stir for 02 hours. Filtered and washed with minimum precooled methanol. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-3rd. Yield=62gm, HPLC Purity=98.633%
Stage -IV : (Preparation of Triamcinolone acetonide from Stage – III)
Stage- Ill Triamcinolone acetonide
60gm of stage-Ill (0.1259 mol) dissolved in 600ml of methanol (lOvolume) and 600ml of methylene chloride (lOvolume) mixture under inert atmosphere. Cool to -5°C and added 1.2gm of sodium hydroxide (0.03mol) solution in 60ml of methanol (Olvolume) at -5°C (+2°C). Reaction maintained at -5°C+2°C for 03 hours. In-process check by TLC against stage-Ill, it should be nil. Adjust pH neutral (~7) by adding 1.8ml of acetic acid at -5°C+2°C. Reaction mass was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to
30°C and added 120ml of purified water, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get stage-4111 (Triamcinolone acetonide). Yield=52gm, (95.04%), HPLC Purity=99.21%.
(Purification)
50gm of crude material (0.12 mol) dissolved in 1100ml of acetone (22volume) and 100ml of purified water (02volume) at 50°C than added 2.5gm of activated charcoal and stirred for one hour at same temperature. Filter through hyflow bed and washed with 120ml acetone (2.40volume). Filtrate was distilled below 40°C under vacuum till 3 to 4 volume of input. Cool to 0°C to 5°C and maintained for one hour at same temperature. Filtered and washed with water. Wet material was dried at 45°C to 50°C till moisture content less than 0.50% to get purified stage-4th. Yield =43gm, HPLC Purity=99.40%
-V: (Preparation of Triamcinolone Hexacetonide from Triamcinolone acetonide):
50ml of pyridine (lOvolume) charged in a glass flask and added lOgm of Triamcinolone acetonide (0.023mol) at ambient temperature. Heated to 80°C to 90°C than added 10ml of 3, 3-dimethyl butyryl chloride (O.l lmol) at 80°C to 90°C. Stirred at 80°C to 90°C for 02 hours. In-process check by TLC against Triamcinolone acetonide, it should be nil. Reaction mass cooled to ambient temperature and reaction mass was quenched in 1000ml of purified water (lOOvolume) at ambient temperature, stir for one hour than filtered and washed with purified water till neutral pH (~7). Wet material was dried at 50°C (+5°C) till moisture content less than 1.0% to get stage-5th (Triamcinolone Hexacetonide). Yield=12gm, (97.90%), HPLC Purity=98.63%.
(Purification)
120ml of methanol and 120ml of methylene chloride charged in a glass flask and added 12gm of crude material, stir till clear solution than added 1.2gm of activated charcoal and stir for 30 minutes. Filtered through hyflow bed and washed with 12ml of methanol and 12ml of methylene chloride mixture. Total filtrate was distilled under vacuum at below 40°C till 5 to 6 volume of crude. Cooled to 0°C+5°C and stir for one hour. Filtered and washed with 12ml of precooled methanol. Wet material was dried at 40°C+5°C till moisture content less than 0.50% to get TrimcinolneHexacetonide. Yield=8.8gm, HPLC Purity=99.625%//////////////////////////////////////////
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Medical uses
Aristocort brand triamcinolone cream
Triamcinolone is used to treat a number of different medical conditions, such as eczema, alopecia areata, lichen sclerosus, psoriasis, arthritis, allergies, ulcerative colitis, lupus, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, keloids, urushiol-induced contact dermatitis, aphthous ulcers (usually as triamcinolone acetonide), central retinal vein occlusion, visualization during vitrectomy and the prevention of asthma attacks.[12][13][14]
The derivative triamcinolone acetonide is the active ingredient in various topical skin preparations (cream, lotion, ointment, aerosol spray) designed to treat skin conditions such as rash, inflammation, redness, or intense itching due to eczema[15] and dermatitis.[16]
Contraindications
Contraindications for systemic triamcinolone are similar to those of other corticoids. They include systemic mycoses (fungal infections) and parasitic diseases, as well as eight weeks before and two weeks after application of live vaccines. For long-term treatment, the drug is also contraindicated in people with peptic ulcers, severe osteoporosis, severe myopathy, certain viral infections, glaucoma, and metastasizing tumours.[17]
There are no contraindications for use in emergency medicine.[4]
Side effects
Further information: Glucocorticoid § Side effects
Side effects of triamcinolone are similar to other corticoids. In short-term treatment up to ten days, it has very few adverse effects; however, sometimes gastrointestinal bleeding is seen, as well as acute infections (mainly viral) and impaired glucose tolerance.[4]
Side effects of triamcinolone long-term treatment may include coughing (up to bronchospasms), sinusitis, metabolic syndrome–like symptoms such as high blood sugar and cholesterol, weight gain due to water retention, and electrolyte imbalance, as well as cataract, thrush, osteoporosis, reduced muscle mass, and psychosis.[5][6][17] Triamcinolone injections can cause bruising and joint swelling.[5] Symptoms of an allergic reaction include rash, itch, swelling, severe dizziness, trouble breathing,[18] and anaphylaxis.[17]
Overdose
No acute overdosing of triamcinolone has been described.[17]
Interactions
Drug interactions are mainly pharmacodynamic, that is, they result from other drugs either adding to triamcinolone’s corticoid side effects or working against its desired effects. They include:[4][17]
- Atropin and other anticholinergics can substantially increase pressure in the eyes.
- Antidiabetic drugs can become less effective because triamcinolone causes diabetes-like symptoms.
- Aspirin and other NSAIDs, as well as anticoagulants such as warfarin, add to the risk of gastrointestinal bleeding.
- Diuretics that excrete potassium (such as loop diuretics and thiazides) can increase the risk of hypokalemia and thus lead to abnormal heart rhythm.
- Cardiac glycosides may have more adverse effects due to reduced potassium levels in the blood.
- The risk for blood count changes is increased when combining triamcinolone with ACE inhibitors.
Triamcinolone and other drugs can also influence each other’s concentrations in the body, amounting to pharmacokinetic interactions such as:[4][17]
- Rifampicin, phenytoin, carbamazepine and other inducers of the liver enzyme CYP3A4[19] speed up metabolization of triamcinolone and can therefore reduce its effectiveness.
- Conversely, CYP3A4 inhibitors such as ketoconazole and itraconazole can increase its concentrations in the body and the risk for adverse effects.
- Blood concentrations of ciclosporin can be increased.
Pharmacology
Mechanism of action
Further information: Glucocorticoid § Mechanism of action
Triamcinolone is a glucocorticoid that is about five times as potent as cortisol, but has very little mineralocorticoid effects.[4]
Pharmacokinetics
When taken by mouth, the drug’s bioavailability is over 90%. It reaches highest concentrations in the blood plasma after one to two hours and is bound to plasma proteins to about 80%. The biological half-life from the plasma is 200 to 300 minutes; due to stable complexes of triamcinolone and its receptor in the intracellular fluid, the total half-life is significantly longer at about 36 hours.[4][5]
A small fraction of the substance is metabolized to 6-hydroxy- and 20-dihydro-triamcinolone; most of it probably undergoes glucuronidation, and a smaller part sulfation. Three quarters are excreted via the urine, and the rest via the faeces.[4][17]
Due to corticoids’ mechanism of action, the effects are delayed as compared to plasma concentrations. Depending on the route of administration and the treated condition, the onset of action can be from two hours up to one or two days after application; and the drug can act much longer than its elimination half-life would suggest.[4][5]
Chemistry
Triamcinolone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-hydroxyhydrocortisone or 9α-fluoro-16α-hydroxyprednisolone as well as 9α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione.[20][21]
The substance is a light-sensitive, white to off-white, crystalline powder, or has the form of colourless, matted crystals. It has no odour or is nearly odourless. Information on the melting point varies, partly due to the substance’s polymorphism: 260 to 263 °C (500 to 505 °F), 264 to 268 °C (507 to 514 °F), or 269 to 271 °C (516 to 520 °F) can be found in the literature.[4]
Solubility is 1:500 in water and 1:240 in ethanol; it is slightly soluble in methanol, very slightly soluble in chloroform and diethylether, and practically insoluble in dichloromethane. The specific rotation is {\displaystyle [\alpha ]_{D}^{20}}![{\displaystyle [\alpha ]_{D}^{20}}](https://wikimedia.org/api/rest_v1/media/math/render/svg/b67b300e0d318e964fcdab92c872ed89d1d4f43f)
Society and culture
In 2010, TEVA and Perrigo launched the first generic inhalable triamcinolone.[22]
According to Chang et al. (2014), “Triamcinolone acetonide (TA) is classified as an S9 glucocorticoid in the 2014 Prohibited List published by the World Anti-Doping Agency, which caused it to be prohibited in international athletic competition when administered orally, intravenously, intramuscularly or rectally”.[23]
See also
- Glucocorticoid (a chart comparing various glucocorticoids)
References
- ^ “Kenalog Intra-articular / Intramuscular Injection – Summary of Product Characteristics (SmPC)”. (emc). 10 June 2020. Retrieved 20 August 2020.
- ^ “Nasacort Allergy 55 micrograms/dose Nasal Spray suspension – Summary of Product Characteristics (SmPC)”. (emc). 30 August 2018. Retrieved 20 August 2020.
- ^ “Adcortyl Intra-Articular/Intradermal Injection 10mg/ml – Summary of Product Characteristics (SmPC)”. (emc). 11 December 2017. Retrieved 20 August 2020.
- ^ Jump up to:a b c d e f g h i j k l m n Dinnendahl V, Fricke U, eds. (2004). Arzneistoff-Profile (in German). Vol. 10 (19 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. Triamcinolon. ISBN 978-3-7741-9846-3.
- ^ Jump up to:a b c d e f Triamcinolone (systemic) Professional Drug Facts. Accessed 2020-08-19.
- ^ Jump up to:a b c d e f g “Triamcinolone Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
- ^ “Triamcinolone Use During Pregnancy”. Drugs.com. Retrieved 3 March 2019.
- ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 486. ISBN 978-3-527-60749-5.
- ^ Vallerand, April Hazard (2018). Davis’s Drug Guide for Nurses. F.A. Davis. p. 365. ISBN 978-0-8036-7000-6.
- ^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
- ^ “Triamcinolone – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
- ^ Triamcinolone – Drugs.com
- ^ Triamcinolone Inhalation – Drugs.com
- ^ Alcon Receives FDA Approval of Triesence Injectable Triamcinolone Suspension for Use in Eye Surgery – Drugs.com
- ^ Chong M, Fonacier L (December 2016). “Treatment of Eczema: Corticosteroids and Beyond”. Clinical Reviews in Allergy & Immunology. 51 (3): 249–262. doi:10.1007/s12016-015-8486-7. PMID 25869743. S2CID 44337035.
- ^ Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al. (July 2014). “Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies”. Journal of the American Academy of Dermatology. 71 (1): 116–32. doi:10.1016/j.jaad.2014.03.023. PMC 4326095. PMID 24813302.
Topical corticosteroids (TCS) are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy.
- ^ Jump up to:a b c d e f g Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Volon 4 mg-Tabletten.
- ^ “Drugs and Treatments – Nasacort AQ Nasl – Patient Handout”. WebMD. Retrieved 2008-03-24.
- ^ Moore CD, Roberts JK, Orton CR, et al. (2012). “Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes”. Drug Metab. Dispos. 41 (2): 379–389. doi:10.1124/dmd.112.046318. PMC 3558858. PMID 23143891.
- ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1228–. ISBN 978-1-4757-2085-3.
- ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1054–. ISBN 978-3-88763-075-1.
- ^ Perrigo Announces Launch Of Generic Version Of Nasacort AQ – CBS Detroit
- ^ Chang CW, Huang TY, Tseng YC, Chang-Chien GP, Lin SF, Hsu MC (November 2014). “Positive doping results caused by the single-dose local injection of triamcinolone acetonide”. Forensic Science International. 244: 1–6. doi:10.1016/j.forsciint.2014.07.024. PMID 25126738.
External links
- “Triamcinolone”. Drug Information Portal. U.S. National Library of Medicine.
- “Triamcinolone Topical”. MedlinePlus.
- “Triamcinolone Nasal Spray”. MedlinePlus.
- “Triamcinolone Acetonide Cream”. HealthClubFinder.
///////////////TRIAMCINOLONE, TU3850000, トリアムシノロン , 去炎松 , Glucocorticoid
[H][C@@]12C[C@@H](O)[C@](O)(C(=O)CO)[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C
NEW DRUG APPROVALS
ONE TIME
$10.00
CDSCO INDIA APPROVED 20.01.2022
Triamcinolone Hexacetonide injectable suspension
20mg/ml
For intraarticular, intra-synovial or
periarticular use in adults and adolescents for
the symptomatic treatment of subacute and
chronic inflammatory joint diseases including
rheumatoid arthritis and Juvenile Idiopathic
Arthritis (JIA), Osteoarthritis and posttramautic arthritis, Synovitis, tendinitis,
bursitis and epicondylitis.
Triamcinolone hexacetonide (brand name Aristospan; also known as triamcinolone acetonide 21-tebutate) is a synthetic glucocorticoid corticosteroid.[1][2][3]
References
- ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1228–. ISBN 978-1-4757-2085-3.
- ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. p. 1657. ISBN 978-3-88763-075-1.
- ^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 280–. ISBN 978-94-011-4439-1.
UPDATE
| Clinical data | |
|---|---|
| Trade names | Aristospan |
| Other names | Triamcinolone acetonide 21-tebutate; Triamcinolone acetonide 21-(tert-butylacetate); 9α-Fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, 21-(3,3-dimethylbutyrate); 9α-Fluoro-11β-hydroxy-16α,17α-((1-methylethylidene)bis(oxy))pregna-1,4-diene-3,20-dione 21-(3,3-dimethylbutyrate) |
| Drug class | Corticosteroid; Glucocorticoid |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 5611-51-8 |
| PubChem CID | 21826 |
| ChemSpider | 20516 |
| UNII | I7GT1U99Y9 |
| ChEBI | CHEBI:9670 |
| ChEMBL | ChEMBL1200878 |
| CompTox Dashboard (EPA) | DTXSID0048634 |
| ECHA InfoCard | 100.024.575 |
| Chemical and physical data | |
| Formula | C30H41FO7 |
| Molar mass | 532.649 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
ENSITRELVIR
Ensitrelvir
S-217622, S 217622, Xocova, SHIONOGI,
6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione
CAS 2647530-73-0
| C22H17ClF3N9O2531.9 | |
| Synonyms | BDBM513874bioRxiv20220126.477782, S-217622 |
|---|
Ensitrelvir fumarate
CAS No. : 2757470-18-9
C22 H17 Cl F3 N9 O2 . C4 H4 O4
1,3,5-Triazine-2,4(1H,3H)-dione, 6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]dihydro-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-, (6E)-, (2E)-2-butenedioate (1:1)
| Formula: | C26H21ClF3N9O6 |
|---|---|
| M. Wt. : | 647.95 |
A Phase 1 study of S-217622 in healthy adult participants (jRCT2031210202)
Japan Registry of Clinical Trials Web Site 2021, July 16
PMDA APPROVED 2022/11/22, Xocova
Ensitrelvir[1] (code name S-217622, brand name Xocova)[2] is an antiviral drug developed by Shionogi in partnership with Hokkaido University, which acts as an orally active 3C-like protease inhibitor for the treatment of COVID-19 infection.[3][4] It is taken by mouth, and has been successfully tested against the recently emerged Omicron variant.[5]
About S-217622
S-217622, a therapeutic drug for COVID-19, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. S-217622 suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. Shionogi has already been submitting the non-clinical, manufacturing/CMC data, and clinical trial data obtained so far to the PMDA. Currently the Phase 3 part of a Phase 2/3 clinical trial in patients with mild/moderate symptoms and the Phase 2b/3 part in patients with asymptomatic/only mild symptoms are in progress.
SYN
J.Med.Chem.2024,67,4376−4418
Ensitrelvir fumaric acid (3), also referred to as S-217622, is an oral noncovalent SARS-CoV-2 main protease (Mpro) inhibitordeveloped by Shionogi & Co. that was approved by the japan Pharmaceuticals and Medical Devices Agency (PMDA)for the treatment of disease caused by SARS-CoV-2 (COVID
19) infection. Dosed once daily for 5 days, ensitrelvirsuppresses the replication of SARS-CoV-2 in infected patients as a result of its inhibition of the viral mpro.25,26
Ensitrelvir retains potent inhibitory activity against many of the most common M mutants and exhibits antiviral activity against a wide variety of circulating SARS-CoV-2 variants. 27is the second Mpro
Ensitrelvir inhibitor approved for the treatment of 28 disease caused by COVID-19. Unlike the first approved treatment, Paxlovid, ensitrelvir does not require coadministration with a CYP3A4 inhibitor to attenuate metabolism in vivo.
Furthermore, crystal structures of ensitrelvir in complex with the main proteases of three other human-infecting coronaviruses (MERS-CoV, SARS-CoV, and HCoV-NL63)
A convergent, kilogram-scale synthesis of ensitrelvir suitable for manufacturing has been described in the literature by researchers at Shionogi. 30 The synthetic approach involved the union of two key building blocks indazole 3.7 and 1,3,5triazinone 3.14, each necessitating development of a scale worthy route. The preparation of triazinone 3.14 necessitated construction of a triazolyl methylene chloride subunit which
began with the reduction of triazole ester 3.1 with aluminum hydride 3.2 (a less pyrophoric alternative to LAH yet still required aqueous Rochelle salt quench to chelate excess aluminum) 31to provide alcohol 3.3, which was then convertedto the corresponding chloride and isolated as the triazole HCl
salt 3.4 (Scheme 6). Assembly of indazole intermediate 3.7began with regioselective nitration of benzaldehyde 3.5followed by treatment with hydrazine hydrate in aqueous EtOHtoprovide indazole3.6(Scheme7).Fascinatingly, the Shionogi team isolated a variety of byproducts during the
conversionof3.5to3.6whichsupportedtheirhypothesisforareaction mechanism that likely equilibrated through a dibenzylidenehydrazine intermediateenroute tothedesired
indazole3.6.Ascreenofelectrophilicmethyl sourcesrevealed thatMeerwein’s salt facilitatedthebest conversionof 3.6to the correspondingN2-monomethylated indazole; subsequenthydrogenative nitro reduction furnished the key indazole intermediate 3.7.Construction of the ensitrelvir core started with reaction of carboximidamide 3.8 with t-butyl isocyanate followed by N,N′carbonyldiimidazole (CDI) to secure 1,3,5-triazinone 3.10(Scheme 8). Subsequent N-alkylation with bromide 3.11provided benzyl triazinone 3.12. Substitution of the pyrazolewith m-cresol was accomplished under acidic conditions. The
authors report that m-cresol was identified as a leaving group that facilitated introduction of indazole 3.7 with a minimal number of byproducts in a later step of the synthesis. The TFA-mediated reaction concomitantly removed the N-tertbutyl group providing compound 3.13 in 91% yield. Nalkylation with chloride 3.4 in the presence of a base resulted in intermediate 3.14 which was then treated with building
block 3.7 in the presence of anhydrous acetic acid. Isolation of ensitrelvir fumaric acid was achieved by exposure to fumaric acid in aqueous acetone.
(25) Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura, T.;
Sonoyama, T.; Ichihashi, G.; Sanaki, T.; Tsuge, Y.; Uehara, T.;
Mukae, H. A phase 2/3 study of S-217622 in participants with SARS
CoV-2 infection (Phase 3 part). Medicine 2023, 102, No. e33024.
(26) Mukae, H.; Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura,
T.; Sonoyama, T.; Fukuhara, T.; Ichihashi, G.; Sanaki, T.; Baba, K.;
Takeda, Y.; Tsuge, Y.; Uehara, T. A randomized phase 2/3 study of
ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in
Japanese patients with mild-to-moderate COVID-19 or asymptomatic
SARS-CoV-2 infection: results of the phase 2a part. Antimicrob. Agents
Chemother. 2022, 66, No. 00697.
(27) Kawashima, S.; Matsui, Y.; Adachi, T.; Morikawa, Y.; Inoue, K.;
Takebayashi, S.; Nobori, H.; Rokushima, M.; Tachibana, Y.; Kato, T.
Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants
circulating globally. Biochem. Biophys. Res. Commun. 2023, 645, 132−
136.
(28) Unoh, Y.; Uehara, S.; Nakahara, K.; Nobori, H.; Yamatsu, Y.;
Yamamoto, S.; Maruyama, Y.; Taoda, Y.; Kasamatsu, K.; Suto, T.;
et al. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL
protease inhibitor clinical candidate for treating COVID-19. J. Med.
Chem. 2022, 65, 6499−6512
(29) Lin, C.; Jiang, H.; Li, W.; Zeng, P.; Zhou, X.; Zhang, J.; Li, J.
Structural basis for the inhibition of coronaviral main proteases by
ensitrelvir. Structure 2023, 31, 1016.
(30) Kawajiri, T.; Kijima, A.; Iimuro, A.; Ohashi, E.; Yamakawa, K.;
Agura, K.; Masuda, K.; Kouki, K.; Kasamatsu, K.; Yanagisawa, S.; et al.
Development of a manufacturing process toward the convergent
synthesis of the COVID-19 antiviral Ensitrelvir. ACS Cent. Sci. 2023,
9, 836−843.
(31) Gugelchuk, M.; Silva, III, L. F.; Vasconcelos, R. S.; Quintiliano,
S. A. P. Sodium bis(2-methoxyethoxy)aluminum hydride. In
Encyclopedia of Reagents for Organic Synthesis; Charette, A., Bode, J.,
Rovis, T., Shenvi, R., Eds.; John Wiley & Sons, Ltd., 2007.
Syn
Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19
View ORCID ProfileYuto Unoh, View ORCID ProfileShota Uehara, View ORCID ProfileKenji Nakahara, View ORCID ProfileHaruaki Nobori, Yukiko Yamatsu, View ORCID ProfileShiho Yamamoto, View ORCID ProfileYuki Maruyama, View ORCID ProfileYoshiyuki Taoda, View ORCID ProfileKoji Kasamatsu, View ORCID ProfileTakahiro Suto, Kensuke Kouki, View ORCID ProfileAtsufumi Nakahashi, Sho Kawashima, View ORCID ProfileTakao Sanaki, Shinsuke Toba, Kentaro Uemura, Tohru Mizutare, View ORCID ProfileShigeru Ando, View ORCID ProfileMichihito Sasaki, View ORCID ProfileYasuko Orba, View ORCID ProfileHirofumi Sawa, View ORCID ProfileAkihiko Sato, View ORCID ProfileTakafumi Sato, View ORCID ProfileTeruhisa Kato, View ORCID ProfileYuki Tachibana
doi: https://doi.org/10.1101/2022.01.26.477782
https://www.biorxiv.org/content/10.1101/2022.01.26.477782v1.full
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.
Chemistry
The synthetic scheme for compound 1 is described in Scheme 1. Starting from the pyrazole derivative 4, cyclization with Ethyl isocyanatoacetate and CDI was conducted, giving 5 in 90% yield. Then, an alkylation with 5-bromomethyl-1,2,3-trifluorobenzene followed by introduction of a 4-difluoromethoxy-2-methylaniline unit, to give 7 (40% in 2 steps). The ester group in 7 was hydrolyzed and then amidated with methylamine, yielding 1 (58% in 2 steps). Compound 2 was synthesized similarly as shown in Scheme 2.
S-217622 (3) was synthesized as described in Scheme 3. Starting from known compound 9,21 an alkylation with 1-(bromomethyl)-2,4,5-trifluorobenzene gave 10 in 93% yield. Then, the 3-tert-Bu group was removed and the triazole unit was introduced, and the substitution of the SEt moiety with the indazole unit finally gave S-217622 (3).
21 Kai, H.; Kameyama, T.; Horiguchi, T.; Asahi, K.; Endoh, T.; Fujii, Y.; Shintani, T.; Nakamura, K.; Matsumoto, S.; Hasegawa, T.; Oohara, M.; Tada, Y.; Maki, T.; Iida, A. Preparation of triazine derivatives and pharmaceutical compound that contains same and exhibits analgesic activity. WO 2012020749 A1, Feb 16, 2012
Scheme 1.
Reagents and Conditions: (a) ethyl isocyanato-acetate, DBU, CDI, DMA, –10 °C to rt, 90%; (b) 5-bromomethyl-1,2,3-trifluorobenzene, N,N-diisopropylethylamine, DMA, 60 °C; (c) 4-difluoromethoxy-2-methylaniline, tert-butanol, 100 °C, 40% in 2 steps; (d) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 58% in 2 steps.
Scheme 2.
Reagents and Conditions: (a) 6-chloro-2-methyl-2H-indazol-5-amine, tert-amyl alcohol, 100 °C, 44% in 2 steps from 5; (b) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 29% in 2 steps.
Scheme 3.
Reagents and Conditions: (a) 1-(bromomethyl)-2,4,5-trifluorobenzene, K2CO3, MeCN, 80 °C, 93%; (b) TFA, rt, 97%; (c) 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, K2CO3, DMF, 60 °C, 45%; (d) 6-chloro-2-methyl-2H-indazol-5-amine, LHMDS, THF, 0 °C to rt., 25%.
(6E)-6-[(6-Chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (3, S-217622)
To a solution of 12 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF; 1.46 mL, 1.46 mmol) dropwisely at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h and then at rt for 40 min. The reaction was quenched with aqueous NH4Cl solution, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH gradient, 0-20% MeOH). The solid was recrystallized from acetone/H2O to afford 3 (S-217622) (95.3 mg, 25%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6, DCl in D2O) δ 3.90 (3H, s), 4.15 (3H, s), 5.04 (2H, s), 5.26 (2H, s), 7.44 (1H, m), 7.52-7.65 (2H, m), 7.73 (1H, s), 8.40 (1H, s), 9.31 (1H, s). 13C NMR (100 MHz, DMSO-d6, DCl in D2O) δ 37.34, 38.04, 40.06, 40.29, 106.16 (dd, J = 28.2, 21.6 Hz), 116.46-116.70, 116.70, 120.54-120.76, 120.76, 125.93, 129.10, 132.35, 143.84, 145.98, 146.38 (ddd, J = 241.4, 12.5, 3.7 Hz), 146.60, 148.52 (td, J = 247.7, 13.6 Hz), 150.43, 150.50, 155.22 (ddd, J = 244.3, 10.3, 2.2 Hz), 155.58. HRMS-ESI (m/z): [M + H]+ calcd for [C22H18 F3ClN9O2]+ 532.1219; found 532.1221.
Preparation of Compound 3 (S-217622) fumaric acid co-crystal
A mixture of 3 (S-217622) (1.17 g, 2.2 mmol) and fumaric acid (278 mg, 2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45 min. The suspension was filtrated to afford 3 (S-217622) fumaric acid co-crystal (1.37 g, 95 %) as a white solid. 1H NMR (400 MHz, pyridine-d5) δ 3.64 (s, 3H), 3.99 (s, 3H), 5.56 (s, 2H), 5.61 (s, 2H), 7.16-7.25 (m, 2H), 7.44 (s, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 7.89-7.97 (m, 1H), 8.32 (s, 1H).
Notes
SHIONOGI has applied for a patent covering 1, 2, and 3 (S-217622). Y.U., S.U., K.N., H.N., Y.Y., S.Y., Y.M., Y.T., K.K., T.S., K.K., A.N., S.K., T.S., S.T., K.U., T.M., S.A., A.S., T.S., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. S.U., K.N., H.N., Y.M., Y.T., K.K., T.S., K.K., S.K., TS, S.T., K.U., T.S., and T.K. are shareholders in SHIONOGI & Co., Ltd. M.S., Y.O., and H.S. are financially supported by the joint research fund from SHIONOGI & Co., Ltd.
- Supporting information[supplements/477782_file02.pdf]
see spectrum at end of page
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Oral antiviral medications, in addition to vaccines, are expected to play an important role in treating coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory disease coronavirus-2 (SARS-CoV-2).
These drugs must have significant antiviral activity, as well as target specificity, oral bioavailability, and metabolic stability. Although several antiviral compounds have been reported as possible SARS-CoV-2 inhibitors in vitro, only a few of these drugs have been shown to be effective in vivo.
Ensitrelvir, a novel SARS-CoV-2 antiviral
Ensitrelvir (code name S-217622, brand name Xocova), is a new inhibitor of the SARS-CoV-2 major protease (Mpro), also known as 3C-like protease, has been shown to reduce the viral load and help alleviate the severity of SARS-CoV-2 in infected hamsters. In cells, low nanomolar to sub-micromolar doses of S-217622 suppress viral growth. In hamsters, oral treatment of S-217622 showed excellent pharmacokinetic qualities and hastened recovery from acute SARS-CoV-2 infection.
S-217622 also demonstrated antiviral effectiveness against SARS-CoV-2 variants of concern (VOCs), such as the highly pathogenic Delta variant and the newly discovered Omicron variant. Overall, these findings show that S-217622, which is an antiviral drug that is currently being tested in Phase II/III clinical trials, has impressive antiviral efficiency and effectiveness against SARS-CoV-2 and could be a viable oral treatment option for COVID-19.
History
It has reached Phase III clinical trials.[3] The Japanese government is reportedly considering allowing Shionogi permission to apply for approval for medical use before the final steps of trials are completed, potentially speeding up the release for sale. This conditional early approval system has previously been used in Japan to accelerate the progression to market of other antiviral drugs targeting COVID-19, including remdesivir and molnupiravir.[6] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced. [7]
It became the first Japanese domestic pill to treat COVID-19, third to be regulatorally approved in Japan; in February 2022.[8]
NEW DRUG APPROVALS
ONE TIME
$10.00
References
- ^ World Health Organization (2021). “International Nonproprietary Names for Pharmaceutical Substances. Proposed INN: List 126” (PDF). WHO Drug Information. 35 (4): 1135.
- ^ Xocova: Powerful New Japanese Pill for Coronavirus Treatment. BioPharma Media, February 2022
- ^ Jump up to:a b Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (January 2022). “Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”. bioRxiv. doi:10.1101/2022.01.26.477782. S2CID 246367525.
- ^ “Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622”. thepharmaletter.com. 31 January 2022.
- ^ Shionogi’s new COVID pill appears to ease omicron symptoms. Nikkei Asia, 21 December 2021
- ^ Japan to consider early approval for Shionogi COVID-19 pill. Japan Times, 8 February 2022
- ^ https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-seeks-approval-oral-covid-19-drug-2022-02-25/[bare URL]
- ^ “Japan’s Shionogi seeks approval for COVID-19 pill”. Reuters. Reuters. 25 February 2022.
| Clinical data | |
|---|---|
| Other names | S-217622 |
| Identifiers | |
| showIUPAC name | |
| PubChem CID | 162533924 |
| Chemical and physical data | |
| Formula | C22H17ClF3N9O2 |
| Molar mass | 531.88 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
Journal reference:
- Sasaki, M., Tabata, K., Kishimoto, M., et al. (2022). Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases the viral load and accelerates recovery from clinical aspects of COVID-19. bioRxiv. doi:10.1101/2022.02.14.480338. https://www.biorxiv.org/content/10.1101/2022.02.14.480338v1.full.
///////////Ensitrelvir, S-217622, S 217622, Xocova, SHIONOGI, CORONA VIRUS, covid 19
RADOTINIB
RADOTINIB
- Molecular FormulaC27H21F3N8O
- Average mass530.504 Da
4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(2-pyrazinyl)-2-pyrimidinyl]amino}benzamide
4-methyl-N-[3-(4-methylimidazole-l-yl)-5-trifluoromethyl-phenyl] –
3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)benzamide
9242
926037-48-1[RN]
| 926037-48-1 (Radotinib); 926037-85-6 (Radotinib 2HCl); |
Benzamide, 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(2-pyrazinyl)-2-pyrimidinyl]amino]-
I284LJY110, IY5511
UNII-I284LJY110
радотиниб
رادوتينيب
雷度替尼
MOA：Bcr-Abl tyrosine kinase inhibitor
Indication：Chronic myeloid leukemia (CML )
Company：IL-Yang (Originator)
IY-5511; IY-5511A3001
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2012-01-05 | Marketing approval | Supect | Chronic myeloid leukemia (CML ) | Capsule | 100 mg/200 mg | IL-Yang |
Radotinib dihydrochloride was approved by Korea Food and Drug Administration (KFDA) on January 5, 2012. It was developed and marketed as Supect® by IL-Yang in KR.
Radotinib dihydrochloride is a second-generation tyrosine kinase inhibitor of Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR). It is indicated for the second-line treatment of patients with Philadelphia chromosome-positive (Ph+) CML that is refractory to Imatinib mesilate.
Supect® is available as capsule for oral use, containing 100 mg or 200 mg of free Radotinib. The recommended dose is 400 mg twice daily.
Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML)[1] with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.
Radotinib is being developed by Ilyang Pharmaceutical Co., Ltd of South Korea[2] and is co-marketed by Daewoong Pharmaceutical Co. Ltd, in South Korea.[3] Radotinib completed a multi-national Phase II clinical trial study in 2012[4] and in August 2011, Ilyang initiated a Phase III, multinational, multi-center, open-label, randomized study for first-line indication.[5] Its mechanism of action involves inhibition of the Bcr-Abl tyrosine kinase and of platelet-derived growth factor receptor (PDGFR).[6]
In January 2012, radotinib hydrochloride (marketed as Supect ®) obtained its approval from the KFDA (Korea Food and Drug Administration) for the treatment of patients with Philadelphia chromosomepositive chronic myeloid leukemia (CML) who have become resistant to existing drugs such as Gleevec, Tasigna and Sprycel. Originally developed by IL-YANG pharmaceuticals of South Korea as an orally second-generation tyrosine kinase inhibitor, the drug inhibits both Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR).
Chemical Synthesis
Because of the structural similarity of radotinib to that of nilotinib (Tasigna ®), the process-scale synthetic route (which is depicted in the scheme) is capable of furnishing both drugs.Claisen condensation of commerical 2-acetylpyrazine (142) with N,N-dimethylformamide dimethylacetal gave rise to the enamino ketone 143 in 81% yield. Under basic conditions, vinylogous amide 143 was coupled with commercial guanidine nitrate 144187 to produce aminopyridine 145. Subsequent condensation with commercial aniline (146) by means of potassium t-butoxide in THF constructed radotinib 147 in 85% yield as the free base, and this material could be converted to the radotinib dihydrochloride (XXII) upon exposure to concentrated hydrochloric acid in chilled acetone. 
PATENT1.
WO2007018325A1 / US7501424B2.
https://patents.google.com/patent/WO2007018325A1/en
PATENT
WO2010018895A1 / CN101648946A.
https://patents.google.com/patent/WO2010018895A1/en
The compound represented by Formula 1 was disclosed in Korea Patent Registration
No. 10-0674813. A preferred compound according to Formula 1 includes 4-methyl-N- [3-(4-methylimidazole- 1 -yl)-5-trifluoromethyl-phenyl] -3-(4-pyrazine-2-yl -pyrimidine-2-yl amino)benzamide. It has been known that the compound represented by Formula 1 can inhibit at least one kind of tyrosine kinase, for example, c-Abl, Bcr- AbI, and receptor tyrosine kinases (PDGF-R, Flt3, VEGF-R, EGF-R and c-Kit). Accordingly, the compound represented by Formula 1 may be used for treatment of various kinds of cancers in a warm blooded animal, such as lung cancer, stomach cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, hematological malignancy, brain tumor, bladder cancer, rectal cancer, uterine cervical cancer, lymphoma, etc.
[7] According to a conventional method, the compound represented by Formula 1 is synthesized through hydrolysis of ethyl ester into carboxylic acid and then a reaction with aniline, and herein, diethyl cyano phosphonate is used as a coupling agent (see Reaction Scheme 1).
[8] [Reaction Scheme 1]
NsOIf
( 2 ) { s :
Diethyl cyano phosphate
( 1 )
[10] The above method requires a process of hydrolyzing ethyl ester (2) into carboxylic acid (3). In order to obtain the compound represented by Formula 3 as shown in Reaction Scheme 1, a preparation process and a purifying process require a long time. Also, in the condensation reaction, there have been problems such as high production cost due to a low yield (30 to 40%) of the compound represented by Formula 1. Especially, it is very difficult to treat carboxylic acid (3) after purification and reaction, due to its very low solubility in general organic solvent. Also, diethyl cyano phosphonate used for the condensation reaction is an expensive reagent, and an environmentally harmful and very toxic material, which has LD50 values of 25mg/Kg and 4mg/Kg in mice and rabbits (that is, rodents), respectively. Therefore, there is a requirement for an alternative method of conveniently, consistently, efficiently and rapidly preparing a high-purity compound (represented by Formula 1) with low production cost in high yield, which is not harmful for humans and the environment.
Example 2
[69] Synthesis of 4-methyl-N-[3-(4-methylimidazole-l-yl)-5-trifluoromethyl-phenyl] –
3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)benzamide
[70]
[71] Method A
[72] A pale yellow solid final compound (18.7g, yield 85%) was obtained by reacting
3-(4-methyl-imidazole-l-yl)-5-trifluoromethyl-phenylamine (1Og, 41.46mmol) with 4-methyl -3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)-benzoic acid ethyl ester in a similar manner as described in Method A of Example 1, except that 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl amino) -benzoic acid ethyl ester (15.3g, 45.60mmol) was used, instead of 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl amino)benzoic acid ethyl ester.
[73] 1H-NMR(DMSOd , δ= 2.21(s,3H), 2.38(s,3H), 7.35(s,lH), 7.39(s,lH), 7.54(s,lH),
7.63(d,lH), 7.75(d,lH), 8.14(d,2H), 8.38(d,2H), 8.54(d,2H), 8.68(s,lH), 9.06(s,lH), 9.45(s, IH), 10.56(s,lH)
[74]
[75] Method B
[76] A pale yellow solid final compound (18.3g, yield 83%) was obtained by reacting
3-(4-methyl-imidazole-l-yl)-5-trifluoromethyl-phenylamine (1Og, 41.46mmol) with 4-methyl -3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)-benzoic acid methyl ester in a similar manner as described in Method A of Example 1, except that 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl amino) -benzoic acid methyl ester (14.7g, 45.60mmol) was used, instead of 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl amino)benzoic acid ethyl ester.
[77]
[78] Method C
[79] A pale yellow solid final compound (17.2g, yield 78%) was obtained by reacting
3-(4-methyl-imidazole-l-yl)-5-trifluoromethyl-phenylamine (1Og, 41.46mmol) with 4- methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)benzoic acid methyl ester (14.7g, 45.60mmol) in a similar manner as described in Method A of Example 1, except that sodium tert-butoxide was used, instead of potassium tert-butoxide.
[80]
[81] Method D
[82] A pale yellow solid final compound (16. Ig, yield 73%) was obtained by reacting
3-(4-methyl-imidazole-l-yl)-5-trifluoromethyl-phenylamine (1Og, 41.46mmol) with 4- methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl amino)benzoic acid phenyl ester in a similar manner as described in Method A of Example 1, except that 4-methyl-3-(4-pyrazine-2-yl-pyrimidine-2-yl amino) -benzoic acid phenyl ester (17.5g, 45.60mmol) was used, instead of 4-methyl-3-(4-thiazole-2-yl-pyrimidine-2-yl amino)benzoic acid ethyl ester.
SYN
https://www.sciencedirect.com/science/article/abs/pii/S0968089614001230
Radotinib hydrochloride (Supect) In January 2012, radotinib hydrochloride (marketed as Supect) obtained its approval from the KFDA (Korea Food and Drug Administration) for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who have become resistant to existing drugs such as Gleevec, Tasigna and Sprycel.181 Originally developed by IL-YANG pharmaceuticals of South Korea as an oral second-generation tyrosine kinase inhibitor, the drug inhibits both Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR).182 Because of the structural similarity of radotinib to that of nilotinib (Tasigna), the processscale synthetic route (which is depicted in Scheme 27) is capable of furnishing both drugs.183–185 Claisen condensation of commerical 2-acetylpyrazine (142) with N,N-dimethylformamide dimethylacetal gave rise to the enamino ketone 143 in 81% yield.186 Under basic conditions, vinylogous amide 143 was coupled with commercial guanidine nitrate 144187 to produce aminopyridine 145. 184 Subsequent condensation with commercial aniline (146) by means of potassium t-butoxide in THF constructed radotinib 147 in 85% yield as the free base, and this material could be converted to the radotinib dihydrochloride (XXII) upon exposure to concentrated hydrochloric acid in chilled acetone.185
181. Droppert, P. In Biotech Strategy Blog: http://biotechstrategyblog.com/2012/01/ radotinib-approved-in-south-korea-for-cml.html/, 2012.
182. Radotinib hydrochloride http://www.cancer.gov/drugdictionary?cdrid= 723999.
183. Davies, S.; Bolos, J.; Serradell, N.; Bayes, M. Drugs Future 2007, 32, 17.
184. Kim, D.-Y.; Cho, D.-J.; Lee, G.-Y.; Kim, H.-Y.; Woo, S.-H.; Kim, Y.-S.; Lee, S.-A.; Han, B.-C. WO Patent 2007/018325 A1, 2007.
185. Kim, D. Y.; Cho, D. J.; Lee, G. Y.; Kim, H. Y.; Woo, S. H. WO Patent 2010/018895 A1, 2010.
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References
- ^ Joanne Bronson; Amelia Black; T. G. Murali Dhar; Bruce A. Ellsworth; J. Robert Merritt (2013). “To Market, To Market – 2012”. Radotinib (Anticancer). Annual Reports in Medicinal Chemistry. Vol. 48. pp. 523–524. doi:10.1016/b978-0-12-417150-3.00028-4. ISBN 9780124171503.
- ^ “Il-Yang Pharmaceutical”.
- ^ http://www.dailypharm.com/Users/News/EnglishNews.html?NewsID=3108&nStart=1023&mode=&searchValue=[dead link]
- ^ Kim SH, Menon H, Jootar S, Saikia T, Kwak JY, Sohn SK, Park JS, Jeong SH, Kim HJ, Kim YK, Oh SJ, Kim H, Zang DY, Chung JS, Shin HJ, Do YR, Kim JA, Kim DY, Choi CW, Park S, Park HL, Lee GY, Cho DJ, Shin JS, Kim DW (2014). “Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors”. Haematologica. 99 (7): 1191–6. doi:10.3324/haematol.2013.096776. PMC 4077080. PMID 24705186.
- ^ https://clinicaltrials.gov/ct2/show/NCT01511289?term=radotinib&rank=1
- ^ “Radotinib hydrochloride”. NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
| Clinical data | |
|---|---|
| Trade names | Supect |
| ATC code | None |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 926037-48-1 |
| PubChem CID | 16063245 |
| ChemSpider | 17222861 |
| UNII | I284LJY110 |
| CompTox Dashboard (EPA) | DTXSID90239069 |
| Chemical and physical data | |
| Formula | C27H21F3N8O |
| Molar mass | 530.515 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
Patent
Publication numberPriority datePublication dateAssigneeTitle
WO2003066613A1 *2002-02-072003-08-14Novartis AgN-phenyl-2-pyrimidine-amine derivatives
WO2004005281A1 *2002-07-052004-01-15Novartis AgInhibitors of tyrosine kinases
KR100674813B1 *2005-08-052007-01-29일양약품주식회사N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
Publication numberPriority datePublication dateAssigneeTitle
US9132126B22011-04-192015-09-15Il-Yang Pharm. Co., Ltd.Phenyl-isoxazole derivatives and preparation process thereof
KR20180032784A *2016-09-232018-04-02재단법인 대구경북첨단의료산업진흥재단Novel imidazolyl pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient
Family To Family Citations
KR101956586B1 *2012-03-272019-03-11일양약품주식회사Pharmaceutical composition and preparation method thereof
////////////////////RADOTINIB, UNII-I284LJY110, радотиниб , رادوتينيب , 雷度替尼 , IY5511, IY 5511, korea 2012, Chronic myeloid leukemia
Cyclobenzaprine
Cyclobenzaprine
- Molecular FormulaC20H21N
- Average mass275.387 Da
- MK-130
- TNX-102
1-(3-Dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene
1-Propanamine, 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-[ACD/Index Name]
206-145-8[EINECS]
3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine
303-53-7[RN]
5-(3-Dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene
циклобензаприн[Russian][INN]
سيكلوبنزابرين[Arabic][INN]
环苯扎林[Chinese][INN]
Cyclobenzaprine, CAS Registry Number: 303-53-7
CAS Name: 3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine
Additional Names:N,N-dimethyl-5H-dibenzo[a,d]cyclohepten-D5,g-propylamine; 5-(3-dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene; 1-(3-dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene; proheptatriene
Manufacturers’ Codes: MK-130; Ro-4-1577; RP-9715
Molecular Formula: C20H21N, Molecular Weight: 275.39
Percent Composition: C 87.23%, H 7.69%, N 5.09%
Literature References: Prepn: GB858187 (1961 to Hoffmann-La Roche); Villani et al.,J. Med. Pharm. Chem.5, 373 (1962); Winthrop et al.,J. Org. Chem.27, 230 (1962). Pharmacology: C. D. Barnes, W. L. Adams, Neuropharmacology17, 445 (1978); N. N. Share, ibid. 721; and toxicology: J. Metysova et al.,Arch. Int. Pharmacodyn. Ther.144, 481 (1963). Metabolism: G. Belvedere et al.,Biomed. Mass Spectrom.1, 329 (1974); H. B. Hucker et al.,Drug Metab. Dispos.6, 184 (1978). Bioavailability: eidem,J. Clin. Pharmacol.17, 719 (1977). Clinical studies: J. V. Basmajian, Arch. Phys. Med. Rehabil.5, 58 (1978); B. R. Brown, J. Womble, J. Am. Med. Assoc.240, 1151 (1978). Comprehensive description: M. L. Cotton, G. R. B. Down, Anal. Profiles Drug Subs.17, 41-72 (1988).
Properties: bp1 175-180°. uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)
Boiling point: bp1 175-180°
Absorption maximum: uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)
Derivative Type: Hydrochloride
CAS Registry Number: 6202-23-9
Trademarks: Flexeril (Merck & Co.); Flexiban (Merck & Co.)
Molecular Formula: C20H21N.HCl, Molecular Weight: 311.85
Percent Composition: C 77.03%, H 7.11%, N 4.49%, Cl 11.37%
Literature References: Use as muscle relaxant: N. N. Share, FR2100873 (1972 to Frosst), C.A.78, 47801n (1973).
Properties: Crystals from isopropanol, mp 216-218°. Soly in water: >20 g/100 ml. Freely sol in water, methanol, ethanol; sparingly sol in isopropanol; slightly sol in chloroform, methylene chloride. Practically insol in hydrocarbons. uv max: 226, 295 nm (e 52300, 12000). LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova).
Melting point: mp 216-218°
Absorption maximum: uv max: 226, 295 nm (e 52300, 12000)
Toxicity data: LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova)
Therap-Cat: Muscle relaxant (skeletal).
Keywords: Muscle Relaxant (Skeletal).
Cyclobenzaprine, a centrally-acting muscle relaxant, was first synthesized in 196111 and has been available for human use since 1977.10 It was initially studied for use as antidepressant given its structural similarity to tricyclic antidepressants – it differs from Amitriptyline by only a single double bond.11,10 Since its approval, it has remained relatively popular as an adjunctive, short-term treatment for acute skeletal muscle spasms secondary to musculoskeletal injury.
Cyclobenzaprine (sold under the brand name Flexeril, among others) is a medication used for muscle spasms from musculoskeletal conditions of sudden onset.[6] It is not useful in cerebral palsy.[6] It is taken by mouth.[6] Use is not recommended for more than a few weeks.[6]
Common side effects include headache, feeling tired, dizziness, and dry mouth.[6] Serious side effects may include an irregular heartbeat.[6] There is no evidence of harm in pregnancy, but it has not been well studied in this population.[6] It should not be used with an MAO inhibitor.[6] How it works is unclear.[6]
Cyclobenzaprine was approved for medical use in the United States in 1977.[6] It is available as a generic medication.[6] In 2019, it was the 45th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[7][8] It was not available in the United Kingdom as of 2012.[9]
Synthesis Reference
Villani, F.J.; US. Patent 3,409,640; November 5,1968; assigned to Schering Corporation.
Paper
By: Gowda, Narendra B.; Rao, Gopal Krishna; Ramakrishna, Ramesha A.
Tetrahedron Letters (2010), 51, (43), 5690-5693.
https://www.sciencedirect.com/science/article/abs/pii/S0040403910014668
A simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride–Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.
Graphical abstract
Cyclobenzaprine N-oxide, CAS RN: 6682-26-4
Dissolve (1 mmol) of cyclobenzaprine N-oxide in 2.5 mL of water at 60 °C. 2. Add Raney nickel (0.10 g, W6 grade) to the solution. 3. Stir the reaction mixture for 10 minutes. 4. Add (2 mmol) of sodium borohydride slowly in portions over 15-20 minutes to the reaction mixture. 5. Stir the reaction mixture at the same temperature for 2.5 hours (the completion of the reaction as monitored by TLC). 6. Once the reaction is completed, add chloroform (50 mL) to the reaction mixture. 7. Filter the resulted mixture to remove Raney nickel. 8. Dry the chloroform layer over anhydrous magnesium sulfate. 9. Filter the reaction mixture. 10. Evaporate the solvent under vacuum. 11. Purify the obtained residue through short path flash chromatography with silica gel and chloroform.
1H NMR (400 MHz, CDCl3) δ: 1.12 (s, 6H, N-CH3), 1.23- 1.34 (m, 4H, CH2), 4.58 (t, J= 4.0 Hz, 1H, CH), 5.82(d, J= 4.0 Hz, 2H, CH), 6.21- 6.33 (m, 8H, ArH).
13C NMR (100 MHz, CDCl3) δ: 27.89, 45.93, 60.12, 127.40, 127.55, 128.30, 128.59, 128.92, 129.33, 129.45, 129.67, 131.74, 131.96, 132.40, 134.63, 135.39, 137.97, 142.95, 143.30.
SYN
PATENT
https://patents.google.com/patent/WO2012098563A2/en
Cyclobenzaprine hydrochloride, chemically known as 5-(3-dimethylaminopropylidene)- dibenzo (a,e) cycloheptatriene hydrochloride (Formula I),
Formula I is a commonly prescribed tricyclic amine having muscle relaxant pharmaceutical activity. After sustaining an injury, muscle spasms may occur to stabilize the affected body part and prevent further damage. Cyclobenzaprine hydrochloride is used to treat such muscle spasm associated with acute, painful musculoskeletal conditions.
Few multistep processes for the preparation of this tricyclic amine are already available in the literature which involves isolation and purification of intermediate compounds. The conventional route of synthesis as reported in US3454643, ES8201950 includes preparation of Grignard reagent (GR) of 3-dimethylaminopropyl chloride in a first step, reacting with 5-dibenzosuberenone (Formulall) in a second step. The reaction mass was extracted with benzene, solid obtained was recrystallized from alcohol to produce 5- hydroxy intermediate (Formula III) and further dehydrated in third step using acetyl chloride or acetic anhydride in presence of chloroform as a solvent medium followed by purging HC1 gas to produce hydrochloride salt (Formula I). CH,
CI-(CH2)3 NS
CH,
Dimeth laminopropyl chloide
Di methy lam i nopropy I 5-dibenzosubrenone – y roxy compoun magnesium chloide
(Formula II) (Formula III)
Cyclobenzaprine base Cyclobenzaprine hydrochloride
(Formula IV) (Formula I)
The multistep synthesis is cumbersome and use of hazardous solvents and reagents like chloroform, benzene and acetyl chloride etc are not recommended for the preparation of pharmaceutical substances.
J. Org. Chem. Vol. 27, 230-240 (1961) also portrayed similar procedure for the synthesis of cyclobenzaprine hydrochloride, wherein 5-hydroxy compound of formula III was isolated and recrystallized before dehydration reaction.
Synthetic Comm. 11 (3), 241-246 (1981) described a process which involves isolation and purification of the intermediate at magnesium -complex stage. Hydrolysis of the isolated complex afforded desired tricyclic amine. GB858186 and GB858187 jointly described a process which comprises preparation of 5- hydroxy compound (Formula III) and subsequent conversion of the same to cyclobenzaprine hydrochloride. However the overall yield reported is significantly low.
In a different approach, a high temperature dehydrogenation of amitriptyline base resulting in formation of cyclobenzaprine hydrochloride is reported in Indian patent application 387/CHE/2005.
. EXAMPLE:
In a reaction vessel, THF (1 10ml), magnesium turnings 20gm (0.823mole) were charged and the mixture was warmed to 45-55°C for 20 min. A solution of l OOgm (0.823mole) of 3-dimethylaminopropyl chloride prepared in 1 10ml THF was added dropwise to the reaction mixture by controlling the reflux generated due to reaction initiation and maintained for 2hrs. The formed Grignard reagent was then cooled to 0-5°C and a solution of lOOgm (0.485mole) 5-dibenzosuberenone prepared in 220ml THF was charged to the reaction mass at temperature below 10°C. The reaction mass was stirred for 45 min at temperature 10-15°C. The absence of 5-dibenzosuberenone was checked by TLC and 770ml of 20% aq. HC1 was charged to the reaction mass at a temperature below 10°C. The reaction mass was then heated to 70-80°C for 3 hrs. The acidic mass was neutralized by using aqueous Na2C03 solution and extracted with 900ml methylene dichloride. The solvent was removed completely under reduced pressure and oil thus formed was dissolved in 450ml IPA and acidified with 240 ml of 20% IPA .HC1 solution and stirred for 2 hrs at 0-5°C for complete precipitation. The precipitate is filtered, recrystallized from IPA (800 ml) and dried to obtain 1 18 gm (78%) white crystalline cyclobenzaprine hydrochloride with purity 99.93% by HPLC.
PATENT
PATENT
CN 111393305
CLIP
Muscle Relaxants
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Cyclobenzaprine
Cyclobenzaprine, N,N-dimethyl-3-(dibenzo[a,d]cyclohepten-5-ylidene) propylamine (15.3.9), is synthesized by reacting 5H-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropylmagnesium chloride and subsequent dehydration of the resulting carbinol (15.3.8) in acidic conditions into cyclobenzaprine (15.3.9) [30–32].
Cyclobenzaprine is structurally similar to tricyclic antidepressants. It acts at the brain stem level. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. A synonym of this drug is flexeril.
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Medical use
Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.[10] After sustaining an injury, muscle spasms to stabilize the affected body part occur, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions.[11] It decreases pain in the first two weeks,[12][13] peaking in the first few days, but has no proven benefit after two weeks.[12][14] Since no benefit is proven beyond that, therapy should not be continued long-term.[11] It is the best-studied muscle relaxer.[12] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[11][15]
A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points.[16] A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.[17] It may also be used along with other treatments for tetanus.[18]
Side effects
Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).[14] Drowsiness and dry mouth appear to intensify with increasing dose.[19] The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors.[medical citation needed]
Agitation is a common side effect observed, especially in the elderly. Some experts[who?] believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment.[20][21] In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.[22]
Dysphagia, a life-threatening side-effect, may rarely occur.[23] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[24]
Overdose
The most common effects of overdose are drowsiness and tachycardia.[11] Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome.[11] Life-threatening overdose is rare,[11] however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats.[11] The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.[11]
Interactions
Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.[25]
These substances may interact with cyclobenzaprine:
- Central nervous system depressants (e.g. alcohol, opioids, benzodiazepines, nonbenzodiazepines, phenothiazines, carbamates, barbiturates, major tranquilizers)
- Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.[11]
Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.[26]
Pharmacology
Cyclobenzaprine is a centrally acting muscle relaxant.[27] Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves.[28]
Pharmacodynamics
| Site | CBP | NCBP | Action | Ref |
|---|---|---|---|---|
| 5-HT1A | 5.3 | 3.2 | Agonist | [29] |
| 5-HT2A | 5.2 | 13 | Antagonist | [29] |
| 5-HT2B | 100 | ??? | Antagonist | [29] |
| 5-HT2C | 5.2 | 43 | Antagonist | [29] |
| α1A | 5.6 | 34 | ND | [29] |
| α2A | 4.3 | 6.4 | Antagonist | [29] |
| α2B | 21 | 150 | ND | [29] |
| α2C | 21 | 48 | ND | [29] |
| H1 | 1.3 | 5.6 | ND | [29] |
| M1 | 7.9 | 30 | ND | [29] |
| Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. |
Pharmacokinetics
Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute.[27][30][31]
Comparison to other medications
Cyclobenzaprine has been found to be not inferior to tizanidine, orphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment). No differences in pain or spasm scores were noted among these agents, nor when compared to benzodiazepines.[32] However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice.[medical citation needed] Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.[medical citation needed]
In a study on the treatment of musculoskeletal pain treatment with cyclobenzaprine alone or in combination with ibuprofen, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day seven of the treatment for all groups.[33]
Formulations
Cyclobenzaprine 10mg tablets
By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[34] Cyclobenzaprine is also used by compounding pharmacies in topical creams.[citation needed]
References
- ^ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
- ^ “Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only”. nih.gov. Retrieved 1 October 2016.
- ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
- ^ U.S. Food and Drug Administration. “NDA 17-821/S-045 Flexeril (Cyclobenzaprine HCl) Tablets” (PDF).
- ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
- ^ Jump up to:a b c d e f g h i j k “Cyclobenzaprine Monograph for Professionals”. Drugs.com. AHFS. Retrieved 22 December 2018.
- ^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
- ^ “Cyclobenzaprine – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
- ^ “Fibromyalgia, psychiatric comorbidity, and the somatosensory cortex”. British Journal of Medical Practitioners. 5 (2): a522. 2012.
- ^ Yang YW, Macdonald JB, Nelson SA, Sekulic A (December 2017). “Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review”. Journal of the American Academy of Dermatology. 77 (6): 1170–1172. doi:10.1016/j.jaad.2016.12.017. PMID 29132849. S2CID 8265576.
- ^ Jump up to:a b c d e f g h i “Cyclobenzaprine- cyclobenzaprine hydrochloride tablet, film coated”. DailyMed. 30 December 2019. Retrieved 26 September 2020.
- ^ Jump up to:a b c Chou R, Peterson K, Helfand M (August 2004). “Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review”. Journal of Pain and Symptom Management. 28 (2): 140–75. doi:10.1016/j.jpainsymman.2004.05.002. PMID 15276195.
- ^ van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM (2003). Van Tulder MW (ed.). “Muscle relaxants for non-specific low back pain”. The Cochrane Database of Systematic Reviews. 2 (2): CD004252. doi:10.1002/14651858.CD004252. PMC 6464310. PMID 12804507.
- ^ Jump up to:a b Browning R, Jackson JL, O’Malley PG (July 2001). “Cyclobenzaprine and back pain: a meta-analysis”. Archives of Internal Medicine. 161 (13): 1613–20. doi:10.1001/archinte.161.13.1613. PMID 11434793.
- ^ Ashby P, Burke D, Rao S, Jones RF (October 1972). “Assessment of cyclobenzaprine in the treatment of spasticity”. Journal of Neurology, Neurosurgery, and Psychiatry. 35 (5): 599–605. doi:10.1136/jnnp.35.5.599. PMC 494138. PMID 4563483.
- ^ Tofferi JK, Jackson JL, O’Malley PG (February 2004). “Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis”. Arthritis and Rheumatism. 51 (1): 9–13. doi:10.1002/art.20076. PMID 14872449.
- ^ Leite FM, Atallah AN, El Dib R, Grossmann E, Januzzi E, Andriolo RB, da Silva EM (July 2009). “Cyclobenzaprine for the treatment of myofascial pain in adults”. The Cochrane Database of Systematic Reviews (3): CD006830. doi:10.1002/14651858.CD006830.pub3. PMC 6481902. PMID 19588406.
- ^ Smith BT (2014). Pharmacology for Nurses. Jones & Bartlett Publishers. p. 122. ISBN 9781449689407.
- ^ “Flexeril: Side effects”. RxList.com. Archived from the original on 12 September 2008. Retrieved 22 February 2010.
- ^ “Long-term Use of Cyclobenzaprine for Pain: A Review of the Clinical Effectiveness”. CADTH Rapid Response Reports. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health. 23 February 2015. PMID 25763449.
- ^ Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. [1]
- ^ “High risk medications” (PDF). National Committee for Quality Assurance. Archived from the original (PDF) on 1 February 2010. Retrieved 22 February 2010.
- ^ “MEDICATIONS AND DYSPHAGIA/ SWALLOWING RISKS” (PDF).
- ^ Chabria SB (July 2006). “Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity”. Journal of Occupational Medicine and Toxicology. 1 (1): 16. doi:10.1186/1745-6673-1-16. PMC 1540431. PMID 16846511.
- ^ Keegan MT, Brown DR, Rabinstein AA (December 2006). “Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs”. Anesthesia and Analgesia. 103 (6): 1466–8. doi:10.1213/01.ane.0000247699.81580.eb. PMID 17122225.
- ^ Medical Practice of William H. Gorman, M.D. (18 February 2014). “Medications to Avoid, Continue, or Stop – Before & After Surgery”.
- ^ Jump up to:a b “Cyclobenzaprine”. http://www.drugbank.ca.
- ^ Kobayashi H, Hasegawa Y, Ono H (September 1996). “Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems”. European Journal of Pharmacology. 311 (1): 29–35. doi:10.1016/0014-2999(96)00402-5. PMID 8884233.
- ^ Jump up to:a b c d e f g h i j k “Cyclobenzaprine (CBP) and Its Major Metabolite Norcyclobenzaprine (nCBP) Are Potent Antagonists of Human Serotonin Receptor 2a (5HT2a), Histamine Receptor H-1 and á-Adrenergic Receptors: Mechanistic and Safety Implications for Treating Fibromyalgia Syndrome by Improving Sleep Quality”. ACR Meeting Abstracts. Retrieved 27 January 2022.
- ^ “Cyclobenzaprine”. pubchem.ncbi.nlm.nih.gov.
- ^ Winchell GA, King JD, Chavez-Eng CM, Constanzer ML, Korn SH (January 2002). “Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency”. Journal of Clinical Pharmacology. 42 (1): 61–9. doi:10.1177/0091270002042001007. PMID 11808825. S2CID 7749001.
- ^ “Medscape: Medscape Access”. medscape.com. Retrieved 1 October 2016.
- ^ Childers MK, Petri M, Laudadio C, Harrison D, Silber S, Bowen D (2004). “Comparison of cyclobenzaprine alone versus cyclobenzaprine plus ibuprofen in patients with acute musculoskeletal spasm and pain”. Annals of Emergency Medicine. 44 (4): S87–S88. doi:10.1016/j.annemergmed.2004.07.286.
- ^ “Patient Web site for Amrix (Cyclobenzaprine Hydrochloride Extended‐Release Capsules)”. amrix.com. Retrieved 1 October 2016.
External links
- “Cyclobenzaprine”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Flexeril, Amrix, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682514 |
| License data | US DailyMed: Cyclobenzaprine |
| Routes of administration | By mouth |
| ATC code | M03BX08 (WHO) |
| Legal status | |
| Legal status | US: ℞-onlyIn general: ℞ (Prescription only) |
| Pharmacokinetic data | |
| Bioavailability | 33–55%[1][2] |
| Protein binding | 93% |
| Metabolism | major: CYP3A4, CYP1A2; minor: CYP2D6, N-demethylation[5] |
| Metabolites | Norcyclobenzaprine |
| Elimination half-life | 32 hours (extended-release, range 8-37 hours),[3] 18 hours (immediate release, range 8–37 hours)[4] |
| Excretion | Kidney |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 303-53-7 |
| PubChem CID | 2895 |
| IUPHAR/BPS | 7152 |
| DrugBank | DB00924 |
| ChemSpider | 2792 |
| UNII | 69O5WQQ5TI |
| KEGG | D07758 |
| ChEBI | CHEBI:3996 |
| ChEMBL | ChEMBL669 |
| CompTox Dashboard (EPA) | DTXSID0046933 |
| ECHA InfoCard | 100.005.588 |
| Chemical and physical data | |
| Formula | C20H21N |
| Molar mass | 275.395 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
///////////////cyclobenzaprine, циклобензаприн , سيكلوبنزابرين , 环苯扎林 , MK-130, TNX-102, Muscle Relaxant
CN(C)CCC=C1C2=CC=CC=C2C=CC2=CC=CC=C12
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Pyritinol
Pyritinol
- Molecular FormulaC16H20N2O4S2
- Average mass368.471 Da
1098-97-1[RN]
1308
214-150-1[EINECS]
233-178-5[EINECS]
3,3′-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]
4-Pyridinemethanol, 3,3′-[dithiobis(methylene)]bis[5-hydroxy-6-methyl-
пиритинол[Russian][INN]
بيريتينول[Arabic][INN]
吡硫醇[Chinese][INN]
Pyritinol, CAS Registry Number: 1098-97-1
CAS Name: 3,3¢-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]
Additional Names: bis(4-hydroxymethyl-5-hydroxy-6-methyl-3-pyridylmethyl) disulfide; bis[(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methyl] disulfide; dipyridoxolyldisulfide; pyridoxine-5-disulfide; pyrithioxin
Molecular Formula: C16H20N2O4S2, Molecular Weight: 368.47
Percent Composition: C 52.15%, H 5.47%, N 7.60%, O 17.37%, S 17.40%
Literature References: Prepn: Zima, Schorre, US3010966 (1961 to E. Merck); Iwanami et al.,Bitamin36, 122 (1967); J. Vitaminol.14, 321, 326 (1968). HPLC determn in urine: K. Kitao et al.,Chem. Pharm. Bull.25, 1335 (1977). Pharmacokinetics and metabolism: Darge et al.,Arzneim.-Forsch.19, 5, 9, (1969); Nowak, Schorre, ibid. 11. Clinical trial in dementia: S. Hoyer et al.,ibid.27, 671 (1977); A. J. Cooper, R. V. Magnus, Pharmacotherapeutica2, 317 (1980); in cerebrovascular disorders: Y. Tazaki et al.,J. Int. Med. Res.8, 118 (1980).
Properties: Crystals, mp 218-220°.
Melting point: mp 218-220°
Derivative Type: Dihydrochloride monohydrate
Trademarks: Biocefalin (Benvegna); Bonifen (Merck KGaA); Enbol (Chugai); Encephabol (Merck KGaA); Enerbol (Polfa); Epocan (Merck KGaA); Life (SIT)
Molecular Formula: C16H20N2O4S2.2HCl.H2O, Molecular Weight: 459.41
Percent Composition: C 41.83%, H 5.27%, N 6.10%, O 17.41%, S 13.96%, Cl 15.43%
Properties: mp 184°. Note: Has no vitamin B6 activity.
Melting point: mp 184°
Therap-Cat: Nootropic.
Keywords: Nootropic.
Derivatives
Dihydrochloride monohydrate
- Formula:C16H20N2O4S2 • 2HCl • H2O
- MW:459.42 g/mol
- CAS-RN:10049-83-9
- EINECS:233-178-5
- LD50:221 mg/kg (M, i.v.); 5786 mg/kg (M, p.o.);
300 mg/kg (R, i.v.); 6 g/kg (R, p.o.)
Pyritinol has been used in trials studying the treatment of Dementia, Depression, Schizophrenia, Anxiety Disorders, and Psychosomatic Disorders.
Pyritinol also called pyridoxine disulfide or pyrithioxine (European drug names Encephabol, Encefabol, Cerbon 6) is a semi-synthetic water-soluble analog of vitamin B6 (Pyridoxine HCl). It was produced in 1961 by Merck Laboratories by bonding 2 vitamin B6 compounds (pyridoxine) together with a disulfide bridge. Since the 1970s, it has been a prescription and OTC drug in several countries for cognitive disorders, rheumatoid arthritis,[1] and learning disorders in children. Since the early 1990s it has been sold as a nootropic dietary supplement in the United States.
SYN
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 39984-49-1 | C8H10Br3NO | 3,4-bis(bromomethyl)-5-hydroxy-6-methylpyridine hydrobromide | 3-Pyridinol, 4,5-bis(bromomethyl)-2-methyl- |
| 92147-37-0 | C11H15NO3S2 | ethylxanthic acid [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester | Xanthic acid, ethyl-, [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester |
| 140-89-6 | C3H5KOS2 | potassium ethylxanthogenate | Carbonodithioic acid, O-ethyl ester, potassium salt |
PATENT
PATENT
https://patents.google.com/patent/CN103992268A/en
Pyritinol, it is the derivative of vitamin B6, for nootropic agents, can promote glucose and amino acid metabolism in brain, improve whole body assimilation, increase Flow of carotid artery, improve cerebral blood flow (CBF), be applicable to the dizzy distending pain, insomnia, hypomnesis of cerebral trauma sequela, encephalitis and meningitis sequela etc., the improvement of absent minded, emotional change; Also for cerebral arteriosclerosis, senile dementia mental symptom etc.
The pyritinol of applying clinically at present, it is pyritinol hydrochloride, be specially the monohydrate of hydrochloride, its chemical name is 3,3-(dithio methylene radical) two (5-hydroxyl-6-methyl-pyridine methane) dihydrochloride monohydrate, has recorded in < < Chinese Pharmacopoeia version > > in 2010.The preparation of this product listing has sheet, capsule and sterile powder injection, and its injection easily causes venous stimulation when clinical application, has greatly limited clinical application.The powder injection of pyritinol hydrochloride easy caking after standing storage, not soluble or dissolve and thoroughly cause liquid unclarity, particulate matter to exceed standard and easily cause the untoward reactions such as Microembolization during use.
CN101003509A discloses hydrobromate and the mesylate of pyritinol, record its stability having had, solvability and bland advantage, but in fact, Hydrogen bromide pyritinol, methylsulfonic acid pyritinol store easy moisture absorption under normal condition, in purification refine, be difficult to separate out with conventional crystallization method, need loaded down with trivial details aftertreatment technology, Hydrogen bromide and methylsulfonic acid have strong corrodibility in addition, comparatively difficult to its suitability for industrialized production.
CN101066266A discloses organic acid salt of pyritinol and preparation method thereof, wherein preferred pyritinol nicotinate.Yet, in nicotinic acid pyritinol water solvability a little less than, and nicotinic acid pyritinol preparation technology used dry-out benzene, toxicity is larger, and aftertreatment technology is complicated, is not suitable for suitability for industrialized production.
Yet, existing pyritinol or its salt, or pyritinol salt exists defect in the use, or the production technique that obtains this pyritinol salt is unsuitable for suitability for industrialized production.For this reason, need to provide a kind of safe, pyritinol salt and production method thereof of stablizing, meeting industrialization production requirements.
Embodiment 1: pyritinol maleate synthetic
Get 5.0g pyritinol powder, drop in reaction flask, add 100ml purified water, then under agitation add toxilic acid 3.8g, finish, be heated to 60-65 ℃ and stir 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.97g, yield 72.9%.Purity: 99.5%; M.p.:134～137 ℃; Ultimate analysis (C16H20N2O4S22C4H4O4): C:47.9%, H:4.8%, N:4.6%, S:10.6%, O:32.1% (theory: C:48.0%, H:4.7%, N:4.7%, S:10.7%, O:32.0%); 1H-NMR (600MHz, DMSO) δ: 2.39 (6H, s), 3.93 (4H, s), 4.76 (4H, s), 6.18 (4H, s), 7.87 (2H, s).By the 1H-NMR (Fig. 2) of toxilic acid pyritinol and the 1H-NMR (Fig. 1) of pyritinol contrast, in a part toxilic acid pyritinol, contain 2 molecule toxilic acids.
Embodiment 2: pyritinol maleate synthetic
Get 5.0g pyritinol powder, drop in reaction flask, add 100ml ethanol, then under agitation add toxilic acid 3.0g, finish, be heated to return stirring 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.50g, yield 67.5%.After measured, the toxilic acid pyritinol that structure makes with embodiment 1.
PATENT
https://patents.google.com/patent/CN105153021A/en
Embodiment 1
Toxilic acid 3.8g is dissolved in 100ml ethanol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1 hour, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid toxilic acid pyritinol crystal form A 4.9g.X-ray powder diffraction analysis, as Fig. 1, its 2 θ value is as following table.
Embodiment 2
Toxilic acid 3.8g is dissolved in 100ml acetone, be warming up to 45 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1.5 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.2g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
Embodiment 3
Toxilic acid 3.8g is dissolved in and adds 100ml Virahol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 2 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.1g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
PATENT
https://patents.google.com/patent/CN101066266A/en
Specific embodiment:
Embodiment 1: nicotinic acid pyritinol salt synthetic
Get nicotinic acid 24.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 6: 0.6) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 62.1g nicotinic acid pyritinol salt, yield 89.7%.Determination of acid-basetitration nicotinic acid and pyritinol content are measured moisture with the karl Fischer method.The result is: nicotinic acid 37.2%, and pyritinol 62.0%, water 5.8%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C52.8% H5.3% O25.2%N6.6% S10.1%; Measured value C52.4% H5.2% O25.1%N6.5% S10.0%.
Embodiment 2: fumaric acid pyritinol salt synthetic
Get fumaric acid 11.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 4: 0.8) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 49.9g fumaric acid pyritinol salt, yield 88.9%.Determination of acid-basetitration fumaric acid and pyritinol content are measured moisture with the karl Fischer method.The result is: fumaric acid 20.8%, and pyritinol 72.7%, water 6.5%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C49.6% H5.0%O26.4% N5.8% S13.2%; Measured value C49.4% H5.2% O26.5% N5.9%S13.1%.
PATENT
https://patents.google.com/patent/CN102516297A/en
Embodiment 1: the preparation of compd A
With Pyrithioxine hydrochloride 10g, be dissolved in the 20ml pyridine, slowly drip POCl3 solution 10ml under the room temperature; Drip and finish, stirring at room reaction 12 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; Toluene gradation extraction 30ml * 3, water layer evaporated under reduced pressure, Virahol dissolution residual substance; Filter, evaporate to dryness gets compd A 4.2g.
Embodiment 2: the preparation of compd B
With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml POCl3, stirring reaction 16 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; ETHYLE ACETATE gradation extraction 30ml * 3, the water layer evaporated under reduced pressure adds 80ml Virahol dissolution residual substance; Add 40ml water, freezing crystallization gets compd B 5.6g.
Embodiment 3: the preparation of Compound C
With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml chloroiodomethane, stirring reaction 16 hours, 60 ℃ of evaporated under reduced pressure add 20ml acetonitrile dissolution residual substance; As midbody, other gets triethylamine 9ml and is dissolved in the 10ml acetonitrile, drips 3.6ml phosphoric acid, after dropping finishes; Stir down and slowly splash into midbody, continued 60 ℃ of stirring reactions 12 hours, steaming desolventizes; Residue adds water 20ml dissolving, and water layer filters clarification, and freeze-drying promptly gets compd B 6.7g.
Embodiment 4: the preparation of Compound D
Serine 3 grams, ethylene bromohyrin 2.5g, N with the BOC protection; N-Dimethylamino pyridine 3g and NSC 57182 3g are dissolved in the THF; Stirring at room 10 hours, vacuum concentration is with the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 30%); Merging filtrate, evaporate to dryness gets intermediate A; Pyrithioxine hydrochloride 2g and intermediate A 2.5g are dissolved with THF 30ml, add triphenyl phosphorus 2g, slowly drip diethyl azodiformate solution 2ml, room temperature reaction 5 hours; Reaction is finished, and evaporated under reduced pressure adds ETHYLE ACETATE 50ml dissolving, filters insolubles; With the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 10%), merging filtrate, evaporate to dryness dissolves with methylene dichloride 20ml then; Feed hydrogen chloride gas to saturated, stirring reaction 5 hours filters; Get the hydrochloride of Compound D, transferring pH behind the use dissolved in distilled water is about 8, and the water layer lyophilize gets Compound C 0.27g.
Embodiment 5: the preparation of compd E
Get compd A 10g, be dissolved in the 30ml Virahol, add 25gBoc-Ser-OBZL in batches, 50 ℃ of stirring reactions; HPLC monitoring react to compd B less than 5%, add 0.1M hydrochloric acid soln 20ml, 60 ℃ of heating hydrolysis 5 hours are regulated pH to 7; Evaporated under reduced pressure adds anhydrous alcohol solution, removes by filter insolubles, evaporated under reduced pressure; Add the 5ml water dissolution, filtering, lyophilize get compd E 6.9g
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Availability
It is approved for “symptomatic treatment of chronically impaired brain function in dementia syndromes” and for “supportive treatment of sequelae of craniocerebral trauma” in various European countries, including Austria, Germany, France, Italy, Portugal, and Greece. In France it is also approved for rheumatoid arthritis as a disease modifying drug, on the basis of the results of clinical trials. In many countries it is available over the counter and is widely advertised on the internet as being for “memory disturbances.”
Effects
review refs needed
Adverse effects
Adverse effects include nausea, headache,[2] and rarely allergic reaction (mild skin reactions).[3] A 2004 survey of six case reports suggested a link between pyritinol and severe cholestatic hepatitis when on several drugs for certain diseases.[4]
Other rare side effects: acute pancreatitis[5] and photoallergic eruption.[6]
References
- ^ Lemmel EM (May 1993). “Comparison of pyritinol and auranofin in the treatment of rheumatoid arthritis. The European Multicentre Study Group”. British Journal of Rheumatology. 32 (5): 375–82. doi:10.1093/rheumatology/32.5.375. PMID 8495257.
- ^ Nachbar F, Korting HC, Vogl T (1993). “Erythema multiforme-like eruption in association with severe headache following pyritinol”. Dermatology. 187 (1): 42–6. doi:10.1159/000247196. PMID 8324277.
- ^ de Groot, Anton C.; Nater, Johan Pieter; Weyland, J. Willem. Unwanted Effects of Cosmetics and Drugs Used in Dermatology.[full citation needed][page needed]
- ^ Maria V, Albuquerque A, Loureiro A, Sousa A, Victorino R (March 2004). “Severe cholestatic hepatitis induced by pyritinol”. BMJ. 328 (7439): 572–4. doi:10.1136/bmj.328.7439.572. PMC 381054. PMID 15001508.
- ^ Straumann A, Bauer M, Pichler WJ, Pirovino M (August 1998). “Acute pancreatitis due to pyritinol: an immune-mediated phenomenon”. Gastroenterology. 115 (2): 452–4. doi:10.1016/S0016-5085(98)70212-4. PMID 9679051.
- ^ Tanaka M, Niizeki H, Shimizu S, Miyakawa S (October 1996). “Photoallergic drug eruption due to pyridoxine hydrochloride”. The Journal of Dermatology. 23 (10): 708–9. doi:10.1111/j.1346-8138.1996.tb02685.x. PMID 8973037. S2CID 28810619.
External links
- Media related to Pyritinol at Wikimedia Commons
| Clinical data | |
|---|---|
| ATC code | N06BX02 (WHO) |
| Pharmacokinetic data | |
| Elimination half-life | 2.5 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1098-97-1 |
| PubChem CID | 14190 |
| ChemSpider | 13561 |
| UNII | AK5Q5FZH2R |
| KEGG | D02160 |
| ChEMBL | ChEMBL488093 |
| CompTox Dashboard (EPA) | DTXSID3048362 |
| ECHA InfoCard | 100.012.864 |
| Chemical and physical data | |
| Formula | C16H20N2O4S2 |
| Molar mass | 368.473 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
//////////////Pyritinol, пиритинол , بيريتينول , 吡硫醇 , Nootropic,
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Liranaftate
Liranaftate
リラナフタート
88678-31-3
(6-Methoxy-2-pyridinyl)methylcarbamothioic Acid O-(5,6,7,8-Tetrahydro-2-naphthalenyl) Ester
O-(5,6,7,8-Tetrahydronaphthalen-2-yl) (6-methoxypyridin-2-yl)methylcarbamothioate
Zefnart;Piritetrate;M-732
лиранафтат
ليرانافتات
利拉萘酯
| Formula | C18H20N2O2S |
|---|---|
| CAS | 88678-31-3 |
| Mol weight | 328.4286 |
| Efficacy | Antifungal, Ergosterol biosynthesis inhibitor |
|---|---|
| Comment | Thiocarbamate |
Liranaftate (trade name Zefnart) is a topical antifungal drug.[1] It is used as a 2% cream used to treat tinea pedis (athlete’s foot), tinea corporis (ringworm), and tinea cruris (jock itch).[2] It was approved for use in Japan in August 2000.[3][4]
Liranaftate works by inhibiting the fungal enzyme squalene epoxidase that is necessary for the fungus to synthesize sterols which are essential for cell membrane integrity.[5]
SYN
IN 2010MU02699
PAPER
Journal of Chemical and Pharmaceutical Research (2013), 5(11), 219-222,
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007010744
Conventionally, 0-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthio-force rubamate has generally been produced by a method using thiophosgen. For example, in Patent Document 1, 0- (5, 6, 7, 8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N- represented by the following reaction formula 0 or ii) A method for producing methylthiolbamate (4) is disclosed.
(Example 1)
1) Sodium 5, 6, 7, 8-Tetrahydro-2-naphthoside synthesis
[hua 6]
,She
To methanol (10 ml), 0.54 g (10.0 mmol) of sodium methoxide was added, and the mixture was stirred at room temperature. There, 1.50 g (10.0 mmol) of 5,6,7,8-tetrahydro-2-naphthol was added and he stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure to obtain 3.75 g ( q uant.) Of white powder. I left it overnight in a desiccator.
2) 2- [Ν- (1-imidazolithiocarbol) -Ν’-methyl] amino-6-methoxypyridin compound
[hua 7]
To ethyl acetate (30 ml), 2.07 g (15.0 mmol) of 6-methoxy-2-methylaminoviridin and 2.67 g (15.0 mmol) of 1,1, -thiocarboldiimidazole were added, and the mixture was heated under reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure to obtain 3.70 g of brown oil. (Yield 99.3%). If necessary, further purification was performed by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain pale yellow crystals.
Melting point: 58.0~60.0°C
NMR(CDC1 3 ) δ ppm:3.86(3H,s), 3.87(3H,s), 6.38 (lH’dd, J=7.5Hz, 0.7Hz), 6.61 (1H
,dd, J=8.3Hz, 0.7Hz), 6.82 (lH,t, J=1.0Hz) , 7.03 (lH,t, J=1.0Hz) , 7.46 (lH’dd, J= 8.3Hz, 7.5Hz), 7.72 (lH,t, J=1.0Hz)
IR(KBr)cm_1: 1604, 1590, 1571, 1465, 1359, 1303, 1120, 1013, 986, 822, 798 MS m/z: 248(M+)
3) Synthesis of 0- (5, 6, 7, 8-tetrahydro-2-naphthyl) -N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate
Dissolve 2- [N- (1-imidazolithiocarbol) -N-methyl] amino-6-methoxypyridin 250 mg (1.0 mmol) in N, N-dimethylformamide (4 ml), and then dissolve. At room temperature, Natrium 5, 6, 7, 8-tetrahydro-2-naphthoside 360 mg (2.0 mmol) was added. -After stirring at room temperature, the reaction solution was extracted with ethyl acetate (10 mlx2), and the insoluble material was filtered off on the way. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (eco-gel C-200, hexane: ethyl acetate = 10: 1) gave the title compound 266.6 mg (yield 81.3%).
Melting point: 99~100°C
NMR(CDCl 3) δ ppm:1.77(4H,bs), 2.75(4H,bs), 3.75(3H,s), 3.93(3H,s), 6.65(lH,d, J
=8.0Hz), 6.78-7.08(4H,m), 7.64(lH,t,J=8.0Hz)
IR(KBr) cm_1 : 1603, 1460, 1413, 1369, 1325, 1262, 1175, 1035, 808, 785
MS m/z: 328(M+)
(Example 2)
0- (5, 6, 7, 8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthio force Rubamate synthesis
[Chemical 9]
1.34 g (33.6 mmol) of 60% sodium hydride was added to N, N-dimethylformamide (20 ml), followed by the addition of 5, 6, 7, 8-tetrahydro-2-naphthol 4.65 g (30.5 mmol). After gas generation is complete, add 2- [N- (1-imidazolthiocarbonyl) -N-methyl] amino-6-methoxypyridin 7.45 g (30.0 mmol) and zinc chloride 2.05 g (15.0 mmol). rice field. After heating and stirring at 60 ° C for 3 hours and allowing to cool, the reaction solution was extracted with ethyl acetate (150 mlx2), and the insoluble material was filtered off on the way. The organic layer is washed with saturated brine, dried over magnesium sulfate, and filtered through magnesium sulfate.
Separately, the solvent was distilled off under reduced pressure. The obtained crystals were purified by one of the following methods.
[0028] A) Purification was performed by silica gel column chromatography (eco-gel C 200, hexane: ethyl silicate = 10: 1) to obtain 9.80 g of the indicated compound (yield 99.5%).
B) Suspended in hexane (10 ml), stirred for 30 minutes, and then the crystals were collected by filtration to obtain 9.65 g of crystals. Further, the mixture was suspended in methanol (10 ml), stirred for 30 minutes, and then the crystals were collected by filtration to obtain 8.62 g (yield 87.5%) of the indicated compound.
The physics and physics data of the obtained compound were consistent with the compounds obtained in the examples.
(Example 3)
1) Synthesis of 2- [N- [1-2 (1H) -pyridonylthiocarbol] -N-methyl] amino-6-methoxypyridine
[Chemical 10]
OMe
Add 6-methoxy-2-methylaminoviridin 690 mg (5.0 mmol) and 1, 1, -thiocarbol-di-2 (1H) -pyridone 1.16 g (5.0 mmol) to ethyl acetate (15 ml). Heated and refluxed for 1 hour. After allowing to cool, the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane: ethyl acetate = 10: 1)! ヽ, 297.4 mg of brown oil was obtained. (Yield 21.6%).
NMR(CDC1 3 ) δ ppm:3.77(3H,s), 3.93(3H,s), 6.66 (lH’dd, J=8.0Hz, 0.7Hz), 7.07 ( lH,d, J=8.0Hz), 7.14 (lH,d, J=7.5Hz) , 7.25 (lH’dd, J=8.0Hz, 4.0Hz) , 7.62 (lH’dd , J=8.0Hz, 7.5Hz), 7.78 (lH’dd, J=2.0Hz, 0.7Hz) , 8.43 (lH’dd, J=4.0Hz, 0.7Hz)
MS m/z: 275(M+)
[0031] 2) Synthesis of 0- (5, 6, 7, 8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate
[Chemical 11]
OMe
N, N-dimethylformamide (2 ml), 2- [N- [1-2 (1H) -pyridonylthiocarbol] –N-methyl] amino-6-methoxypyridin 297 mg (1.08 mmol) and sodium 5 , 6, 7, 8-Tetrahydro-2-naphthoside 390 mg (2.16 mmol) was added and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (50 mlx2), the organic layer was washed with saturated brine, dried over magnesium sulfate, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained crystals were purified by silica gel column chromatography (eco-gel C-200, hexane: ethyl acetate = 10: 1) to obtain the title compound 288.2 mg (81.4%).
SYN
CN 104725302
| Liranafate is a new-generation antifungal drug, a squalene cyclooxygenase inhibitor and a cell wall synthesis inhibitor, with the chemical name of 6-methoxy-2-N-methyl-pyridylamino-thio Formic acid-(5,6,7,8-tetrahydro)-β-naphthyl ester. A new type of antifungal drug jointly developed by Tosoh Corporation of Japan and Zenyaku Kogyo Corporation was first listed in Japan by Torii Corporation in August 2000. The antifungal drug exerts antifungal activity by inhibiting the squalene epoxidation reaction of fungal cells and inhibiting the synthesis of ergosterol, a component of cell membranes. effect is particularly evident. Today, with the increasing concern of the world about environmental pollution, the development of new green and effective drug synthesis methods is an important task faced by the research of drug synthesis. In recent years, room temperature ionic liquids have been widely used in various organic synthesis reactions as a new type of environmentally friendly reaction media. Compared with traditional organic solvents, ionic liquids have many advantages, such as extremely low vapor pressure, non-flammability, good thermal stability and recyclability. |
| At present, the main synthetic route of liranaftate is as follows: |
| |
| Among the four synthetic routes, the pyridine derivative intermediates of routes C and D need to be prepared through multi-step reactions, the routes are long, the steps are cumbersome, the actual operation is cumbersome, the cost is high, and they are not suitable for industrialized large-scale production. Although route A has simple steps, the yield of pyridine derivatives is low. Each intermediate structure in route B is relatively simple and easy to prepare, but this route uses 6-methoxy-2-methylaminopyridine and 5,6,7,8-tetrahydro-2-naphthoxysulfuryl chloride as raw materials to synthesize the In the process of lanaphthalate, isopropanol-water is used as the reaction medium, and the experiment shows that with the progress of the reaction, the reaction solution becomes viscous, and the reaction is difficult to complete. |
| Example 1 |
| (1) Ionic liquid [bmim]BF 4 Synthesis |
| |
| Add N-methylimidazole (14.8g, 0.18mol) and trichloroethane (80mL) to a dry 250mL three-neck flask, stir to make the mixture uniform, add 20.4mL of freshly distilled n-bromine to the dropping funnel Butane (26.03g, 0.19mol) was added dropwise for about 30min, and the reaction was refluxed for 4-5h (the reflux temperature was about 78±1℃). With the progress of the reaction, the reaction solution changed from colorless and transparent to white turbidity, light yellow turbidity, and the color gradually became darker until brownish red. After the reaction is completed, the liquids are separated into layers, the upper layer is lighter in color, which is the trichloroethane layer, and the lower layer is darker in color (brown red), which is the ionic liquid [bmim]Br layer. The prepared ionic liquid [bmim]Br and trichloroethane were separated, and the ionic liquid [bmim]Br was washed twice with trichloroethane, and then the trichloroethane in the ionic liquid [bmim]Br was washed with a water pump. The alkane was pumped away until the ionic liquid [bmim]Br liquid was no longer turbid, and then dried in a vacuum drying oven at 90 °C for 10-12 h to obtain relatively pure ionic liquid [bmim]Br. |
| |
| Then prepare 0.03mol NaBF 4 of aqueous solution. Add 6.58g (about 0.03mol) ionic liquid [bmim]Br and 5-10mL water to a 100mL round-bottomed single diameter flask, stir, ice-water bath, and dropwise add NaBF 4 The solution (completed dropwise addition in about 5min), continue to stir for 10-20min, the solution is yellow and transparent, pour it into a separatory funnel, extract twice with dichloromethane, combine the dichloromethane layers, and wash the dichloromethane layer 2 with 50 mL of water times, and then the dichloromethane layer was washed with anhydrous MgSO 4 Dry, filter, evaporate the dichloromethane under normal pressure in a water bath (50-52°C), and dry the remaining dark yellow viscous liquid in a vacuum drying oven at 90°C for 10-12h to obtain the ionic liquid [bmim]BF 4 。 |
| |
| (2) Synthesis of 6-methoxy-2-chloropyridine 2 |
| 2,6-dichloropyridine (10g, 0.068mol) and sodium methoxide (24.5g, 0.136mol) were put into the reaction flask, heated under reflux for 4-5h, and the reaction was completed by TLC (ethyl acetate: petroleum ether=1 : 15), concentrated to remove methanol, added 100 mL of water, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried, filtered, and the filtrate was concentrated to obtain 9 g of a crude colorless oily product with a yield of 92.5%. used for the next reaction. |
| (3) Synthesis of 6-methoxy-2-methylaminopyridine 3 |
| Take 6-methoxy-2-chloropyridine 2 (9g, 0.127mol), cuprous chloride (1.72g, 0.0017mol) and methylamine aqueous solution (29mL, mass concentration is 25%-30%) and add it to the autoclave , sealed and heated to 120 °C for 7 h, the reaction was stopped, ethyl acetate was added for extraction, the organic phases were combined, washed with saturated brine, dried, and the filtrate was concentrated to obtain 6.18 g of brown oil, the yield was 71.2%, and the HPLC purity was 98% . |
| (4) Synthesis of 5,6,7,8-tetrahydro-2-naphthyloxysulfuryl chloride 4 |
| Mix 50 mL of ethyl acetate, thiophosgene (4.25 mL, 0.056 mol) and 5,6,7,8-tetrahydro-2-naphthol (6.3 g, 0.0425 mol), and cool it in an ice-salt bath to below 0 °C. Add 10 mL of potassium carbonate (3 g, 0.022 mol) solution, continue to stir the reaction after the dropwise addition, and check by TLC (developing solvent: petroleum ether) that the reaction is complete, add 100 mL of water, extract with ethyl acetate, wash the organic phase with saturated brine, Dry, filter, and concentrate the filtrate to obtain 8.7 g of yellow oil with a yield of 90.4%, which can be directly used in the next reaction without purification. |
| (5) Synthesis of Liranaftate 1 |
| The prepared ionic liquid [bmim]BF 4 (100mL), 6-methoxy-2-methylaminopyridine 3 (5.7g, 0.0413mol) and potassium carbonate (5.7g, 0.0413mol) were mixed, cooled with ice water, and slowly added dropwise 5,6,7,8 -Tetrahydro-2-naphthyloxysulfuryl chloride 4 (8.7g, 0.0385mol) was added dropwise for 4h, slowly added 150mL of water under full stirring, continued to stir for 20min, filtered, washed with deionized water to obtain 12.2g of crude product, collected The yield was 96.81%, and acetone was recrystallized to obtain 11 g of white crystalline powder, the yield was 90%, and the HPLC purity was 99.7%. mp: 98.8-99.5°C, IR (2973cm -1 , 2930cm -1 , 2852cm -1 , 1416cm -1 , 1264cm -1 , 1037cm -1 ), 1 HNMR: 1.8 (m, 4H); 6.68(d, 1H) ;6.86(dd,1H);3.78(s,3H);3.98(s,3H);6.68(d,1H);6.86(dd,1H);7.05(d,1H);7.10(d.1H); 7.65 (dd, 1H), MS (m/z: 328, 181, 165, 108). |
| Example 2 |
| Under the same conditions, the ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF 4 ), N-ethylpyridine tetrafluoroborate ([EPy]BF 4 ), 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF 6 ), 1-hydroxyethyl-2,3-dimethylimidazolium chloride (LOH), 1-cyanopropyl-3-methylimidazolium chloride (LCN), 1-carboxyethyl-3-methylimidazole Chloride salt (LOOH), [Hnmp]HSO 4 The effects of and [bmim]OH on the synthesis of liranaftate are shown in Table 1. The results show that different ionic liquids have little effect on the yield of the synthesis and the yields are relatively high. |
| Table 1 Effects of different ionic liquids on the reaction yield |
| ionic liquidYield/%[bmim] BF 496.81[EPy]BF 496.83[bmim]PF 696.82LOH96.75LCN96.67LOOH96.05[Hnmp]HSO 496.06[bmim]OH95.98 |
| Example 3 |
| Whether the reaction medium used can be recovered and reused is an important content of “green chemistry”. This example specifically examines the reuse of ionic liquid for synthesizing liranaftate. After 5 times of use of ionic liquid, the product yield It just started to decrease, which shows that the ionic liquid can be recovered and reused effectively, and the reuse performance is good. It is a recyclable green solvent. |
SYN
| Comparative Example 1: |
| Put 10 g of 2,6-dichloropyridine, 100 ml of methanol, and 15 g of sodium methoxide into a reaction flask, heat under reflux for about 4 to 5 hours, concentrate to remove methanol, add 150 ml of water, extract with ethyl acetate, and concentrate under reduced pressure to remove ethyl acetate. 6-Methoxy2-chloropyridine was obtained as a colorless oil. |
| 9 g of 6-methoxy 2-chloropyridine, 1.72 g of cuprous chloride, and 29 ml of 30% methylamine aqueous solution were put into the reaction flask, heated and added with a mass fraction of 11.6 g of cuprous chloride, and the temperature was kept at 120 ° C for the reaction 8h, extracted three times with 150 ml of ethyl acetate, washed with saturated brine, concentrated under reduced pressure to remove the ethyl acetate to obtain 6.18 g of 6-methoxy-2-methylaminopyridine as a brown oily product. The two-step yield was 71.2%. |
| 50ml of carbon tetrachloride, 4.25g of thiophosgene, 6.3g of 5,6,7,8-tetrahydro-2-naphthol were added to the reaction flask, the ice-salt bath was lowered to below 0°C, and 10ml of 3g potassium carbonate aqueous solution was added dropwise. , Continue the reaction at 0°C after the dropwise addition, and detect by TLC (developing solvent: petroleum ether) after the reaction is completed, separate the organic phase, wash three times with saturated brine, and concentrate under reduced pressure to obtain red oily products 5, 6, 7 , 8.7g of 8-tetrahydro-2-naphthyloxysulfuryl chloride was directly used in the next reaction. |
| 100ml of acetone, 5.7g of 6-methoxy-2-methylaminopyridine and 5.7g of potassium carbonate were added to the reaction flask, cooled with ice water, and 5,6,7,8-tetrahydro-2-naphthyloxysulfuryl chloride was added dropwise 8.7g, continue to stir and react for 4h after dropping, add 150ml of water, continue to stir for 30min, and filter to obtain the crude product. The crude product was recrystallized with acetone to obtain 11 g of off-white crystalline powder. The weight yield was 174.6% based on 5,6,7,8-tetrahydro-2-naphthol. The maximum single impurity content determined by HPLC was 1.5%, which did not meet the requirements of the Pharmacopoeia. |
SYN
CN 106632018
| Example 1 |
| A preparation method of liranaftate of the present invention comprises the following steps: |
| (1) preparation of Liranaftate crude product: |
| Feeding: 250g of absolute ethanol was added to the reaction flask, 12.5g of 2-methoxy-6-methylaminopyridine, 8.8g of anhydrous sodium carbonate and 31.3g of purified water were added to the reaction flask in turn, stirred for 30 minutes, slowly 18.8 g of 2-(5,6,7,8-tetrahydronaphthyloxy) thioformate chloride was added, and the addition was completed in 2 hours; |
| Reaction: control the temperature at 20°C for 2 hours, add 125.0g of purified water, and stir for 30 minutes; |
| Suction filtration: the reaction solution was suction filtered, and the filter cake was washed three times with purified water, and the consumption of purified water was 25.0 g each time; |
| Drying: put the wet product into a drying box, control the temperature to 45 ℃ and dry for 4 hours, to obtain 24 g of the crude product of lira naphthate; |
| The synthesis yield is 81%; |
| (2) preparation of Liranaftate fine product: |
| Impurity removal: put 23g of Liranaftate crude product and 115g of absolute ethanol into the reaction flask, add 1.38g of medicinal charcoal, decolorize at 55°C under temperature control, remove impurities for 30 minutes, filter, transfer the filtrate to the reaction flask, control the temperature Crystallize at 55°C, centrifuge, dry, pulverize, and pack to obtain 22g of Lira naphthate fine product. |
| The purification yield was 92%. |
| Example 2 |
| A preparation method of liranaftate of the present invention comprises the following steps: |
| (1) preparation of Liranaftate crude product: |
| Feeding: 500g of absolute ethanol was added to the reaction flask, 25g of 2-methoxy-6-methylaminopyridine, 17.6g of anhydrous sodium carbonate and 62.6g of purified water were added to the reaction flask in turn, stirred for 30 minutes, and slowly added 2-(5,6,7,8-tetrahydronaphthyloxy) chlorothioformate 37.6g, added in 2.5 hours; |
| Reaction: control the temperature at 25°C for 2.5 hours, add 250 g of purified water, and stir for 30 minutes; |
| Suction filtration: the reaction solution was suction filtered, and the filter cake was washed three times with purified water, 50 g each time; |
| Drying: put the wet product into a drying box, control the temperature to 55 ℃ and dry for 4 hours to obtain 49 g of the crude product of lira naphthate; |
| The synthesis yield is 82%; |
| (2) preparation of Liranaftate fine product: |
| Impurity removal: put 49g of Liranaftate crude product and 245g of absolute ethanol into the reaction flask, add 2.9g of medicinal charcoal, decolorize at 55～65 ℃ of temperature, remove impurities for 30 minutes, filter, and transfer the filtrate to the reaction flask, The temperature was controlled at 65°C for crystallization, centrifugation, drying, pulverization, and packaging to obtain 45g of fine lanaftate. |
| The purification yield was 92%. |
| Example 3 |
| A preparation method of liranaftate of the present invention comprises the following steps: |
| (1) preparation of Liranaftate crude product: |
| Feeding: 250g of absolute ethanol was added to the reaction flask, 12.5g of 2-methoxy-6-methylaminopyridine, 8.8g of anhydrous sodium carbonate and 31.3g of purified water were added to the reaction flask in turn, stirred for 30 minutes, slowly 18.8 g of 2-(5,6,7,8-tetrahydronaphthyloxy) thioformate chloride was added, and the addition was completed in 2 hours; |
| Reaction: control the temperature at 20°C for 2 hours, add 125.0g of purified water, and stir for 30 minutes; |
| Suction filtration: the reaction solution was suction filtered, and the filter cake was washed three times with purified water, 25.0 g each time; |
| Drying: put the wet product into a drying oven, control the temperature to 45～55 ℃ and dry for 4 hours, to obtain the crude product, 23.3 g of the crude liranaftate; |
| The synthesis yield is 82%; |
| (2) preparation of Liranaftate fine product: |
| Removal of impurities: 140g of absolute ethanol was added to the reaction flask, 23.3g of crude liranaftate was added, the temperature was controlled at 50°C and stirred for 30 minutes, 1.5g of medicinal charcoal was added, the temperature was controlled at 60°C for decolorization for 30 minutes, filtered, and the temperature was controlled Crystallize at 60°C, centrifuge, dry, pulverize, and package to obtain 23g of Lira naphthate fines. |
| The purification yield was 92%. |
SYN
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References
- ^ Koga H, Nanjoh Y, Makimura K, Tsuboi R (2009). “In vitro antifungal activities of luliconazole, a new topical imidazole”. Medical Mycology. 47 (6): 640–7. doi:10.1080/13693780802541518. PMID 19115136.
- ^ “Torii Pharmaceutical to Launch Antifungal Agent for External Use, “ZEFNART SOLUTION 2%”, in Japan” (Press release). Torii Pharmaceutical Co. Retrieved June 27, 2021.
- ^ “Liranaftate”. ncats.io. Retrieved June 27, 2021.
- ^ “Liranaftate”. Adis Insight. Retrieved June 27, 2021.
- ^ “Liranaftate”. targetmol.com. Retrieved June 27, 2021.
///////////////////Liranaftate , リラナフタート , Zefnart, Piritetrate, M-732, лиранафтат , ليرانافتات , 利拉萘酯 , ANTIFUNGAL, JAPAN 2000
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Fabomotizole
Fabomotizole
Afobazole
- Molecular FormulaC15H21N3O2S
- Average mass307.411 Da
0F8K1X115C
173352-21-1[RN], 173352-21-1 (free base) 173352-39-1 (HCl) 189638-30-0 (2HCl)
1H-Benzimidazole, 6-ethoxy-2-[[2-(4-morpholinyl)ethyl]thio]-
Obenoxazine, Afobazol, Afobazole, Aphobazole, Fabomotizole dihydrochloride, CM-346, CM346, CM 346,
фабомотизол[Russian][INN]
فابوموتيزول[Arabic][INN]
法莫替唑[Chinese][INN]
Fabomotizole dihydrochloride
CAS#: 189638-30-0 (2HCl)
Chemical Formula: C15H23Cl2N3O2S
Molecular Weight: 380.33
Fabomotizole (also known as Afobazole) is a selective non-benzodiazepine anxiolytic which was developed in Russia and launched in 2006. The drug is used for the treatment of wide range of diseases: generalized anxious disorders, neurasthenia, adaptation disorders, sleep disorders, for alleviation of withdrawal syndrome. According to the drug label (in Russian), its action is related to the interaction with sigma-1 receptors.
Fabomotizole (INN;[1] brand name Afobazole) is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions.[citation needed] Its mechanism of action remains poorly defined however, with GABAergic, NGF– and BDNF-release-promoting, MT1 receptor agonism, MT3 receptor antagonism, and sigma agonism suggested as potential mechanisms. Fabomotizole was shown to inhibit MAO-A reversibly and there might be also some involvement with serotonin receptors.[2][3][4][5][6] Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety.[7]
Experiments of mice have shown antimutagenic and antiteratogenic properties.[8]
Fabomotizole has found little clinical use outside Russia and has not been evaluated by the FDA.
PATENT
WO 9534304
https://patents.google.com/patent/WO1995034304A1/en
PAPER
European Journal of Medicinal Chemistry (2021), 211, 113110
https://www.sciencedirect.com/science/article/abs/pii/S0223523420310825?
A ligand-based virtual screening study to search for giardicidal compounds on a 6551 ChEMBL drugs database was carried out using molecular similarity. Three fingerprints implemented in MayaChemTools with different design and validated by ROC curves, were used. Twelve compounds were retrieved from this screening, from which, four representative compounds were selected to carry out biological assays. Whereas two compounds were commercially available, the additional two compounds were synthesized during the development of this work. The biological assays revealed that the compounds possess in vitro activity against five strains of Giardia intestinalis, each with different susceptibility/resistance rates to metronidazole, albendazole and nitazoxanide. Particularly, tenatoprazole showed the best effect against the WB and IMSS strains. Furthermore, fabomotizole, tenatoprazole and ipriflavone showed a higher activity against resistant strains than the reference drugs: metronidazole, albendazole and nitazoxanide.
Graphical abstract
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| Clinical data | |
|---|---|
| Trade names | Afobazole |
| Other names | Fabomotizole |
| Routes of administration | Oral |
| ATC code | N05BX04 (WHO) |
| Legal status | |
| Legal status | US: Unscheduled Not FDA approved |
| Pharmacokinetic data | |
| Bioavailability | 43.64%, pronounced first-pass effect |
| Metabolism | extensive hepatic |
| Onset of action | 0.85±0.13 hours |
| Elimination half-life | 0.82±0,54 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 173352-39-1 |
| PubChem CID | 9862937 |
| ChemSpider | 8038633 |
| UNII | HDO6HX6NZU |
| CompTox Dashboard (EPA) | DTXSID00169606 |
| Chemical and physical data | |
| Formula | C15H21N3O2S |
| Molar mass | 307.41 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
References
- ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF). WHO Drug Information. 26 (1): 63. 2012. Retrieved 21 March 2015.
- ^ Neznamov, GG; Siuniakov, SA; Chumakov, DV; Bochkarev, VK; Seredenin, SB (2001). “Clinical study of the selective anxiolytic agent afobazol”. Eksperimental’naia i Klinicheskaia Farmakologiia. 64 (2): 15–9. PMID 11548440.
- ^ Silkina, IV; Gan’shina, TC; Seredin, SB; Mirzoian, RS (2005). “Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon”. Eksperimental’naia i Klinicheskaia Farmakologiia. 68 (1): 20–4. PMID 15786959.
- ^ Seredin, SB; Melkumian, DS; Val’dman, EA; Iarkova, MA; Seredina, TC; Voronin, MV; Lapitskaia, AS (2006). “Effects of afobazole on the BDNF content in brain structures of inbred mice with different phenotypes of emotional stress reaction”. Eksperimental’naia i Klinicheskaia Farmakologiia. 69 (3): 3–6. PMID 16878488.
- ^ Antipova, TA; Sapozhnikova, DS; Bakhtina, LIu; Seredenin, SB (2009). “Selective anxiolytic afobazole increases the content of BDNF and NGF in cultured hippocampal HT-22 line neurons”. Eksperimental’naia i Klinicheskaia Farmakologiia. 72 (1): 12–4. PMID 19334503.
- ^ Seredenin, SB; Antipova, TA; Voronin, MV; Kurchashova, SY; Kuimov, AN (2009). “Interaction of afobazole with sigma1-receptors”. Bulletin of Experimental Biology and Medicine. 148 (1): 42–4. doi:10.1007/s10517-009-0624-x. PMID 19902093. S2CID 37411324.
- ^ Medvedev, VE; Trosnova, AP; Dobrovol’skiĭ, AV (2007). “Psychopharmacotherapy of anxiety disorders in patients with cardio-vascular diseases: the use of aphobazole”. Zh Nevrol Psikhiatr Im S S Korsakova. 107 (7): 25–9. PMID 18379478.
- ^ Durnev AD, Zhanataev AK, Shreder OV, Seredenin SB (Jan–Feb 2009). “Antimutagenic and antiteratogenic properties of afobazole”. Eksp Klin Farmakol. 72 (1): 46–51. PMID 19334511.
//////////////Fabomotizole, Afobazole, фабомотизол , فابوموتيزول , 法莫替唑 , Obenoxazine, Afobazol, Afobazole, Aphobazole, Fabomotizole dihydrochloride, CM-346, CM346, CM 346,
CCOc1ccc2c(c1)[nH]c(n2)SCCN3CCOCC3.Cl.Cl
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Sutimlimab-jome
(Heavy chain)
EVQLVESGGG LVKPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVAT ISSGGSHTYY
LDSVKGRFTI SRDNSKNTLY LQMNSLRAED TALYYCARLF TGYAMDYWGQ GTLVTVSSAS
TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFEGGPSVFL
FPPKPKDTLM ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV
VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP PSQEEMTKNQ
VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSRLTV DKSRWQEGNV
FSCSVMHEAL HNHYTQKSLS LSLGK
(Light chain)
QIVLTQSPAT LSLSPGERAT MSCTASSSVS SSYLHWYQQK PGKAPKLWIY STSNLASGVP
SRFSGSGSGT DYTLTISSLQ PEDFATYYCH QYYRLPPITF GQGTKLEIKR TVAAPSVFIF
PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST
LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC
(Disulfide bridge: H22-H96, H132-L216, H145-H201, H224-H’224, H227-H’227, H259-H319, H365-H423, H’22-H’96, H’132-L’216, H’145-H’201, H’259-H’319, H’365-H’423, L23-L89, L136-L196, L’23-L’89, L’136-L’196)
Sutimlimab-jome
スチムリマブ (遺伝子組換え)
| Formula | C6436H9912N1700O2016S46 |
|---|---|
| CAS | 2049079-64-1 |
| Mol weight | 144832.7369 |
- BIVV009
- Sutimlimab
- Sutimlimab [INN]
- Sutimlimab [WHO-DD]
- TNT009
- UNII-GNWE7KJ995
- WHO 10757
| Efficacy | Anti-anemic, Anti-complement C1s antibody |
|---|---|
| Comment | Monoclonal antibody |
FDA APPROVED 2/4/2022, To decrease the need for red blood cell transfusion due to hemolysis in cold agglutinin disease, Enjaymo
A Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway.
Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD).[1][2][3] It is given by intravenous infusion.[1]
The most common side effects include respiratory tract infection, viral infection, diarrhea, dyspepsia (indigestion), cough, arthralgia (joint stiffness), arthritis, and swelling in the lower legs and hands.[2]
Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.[4]
This drug is being developed by Bioverativ, a Sanofi company.[5] Sutimlimab was approved for medical use in the United States in February 2022.[2][6]
Sutimlimab-jome, a classical complement inhibitor, is a humanized monoclonal antibody expressed by recombinant in Chinese hamster ovary (CHO) cells and produced in vitro using standard mammalian cell culture methods. Sutimlimab-jome is composed of two heterodimers. Each heterodimer is composed of a heavy and a light polypeptide chain. Each heavy chain (H-chain) is composed of 445 amino acids and each light chain (L-chain) contains 216 amino acids. Sutimlimab-jome has a molecular weight of approximately 147 kDa.
ENJAYMO (sutimlimab-jome) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free solution for intravenous use. Each single-dose vial contains 1,100 mg sutimlimab-jome at a concentration of 50 mg/mL with a pH of 6.1. Each mL contains 50 mg of sutimlimab-jome and also contains polysorbate 80 (0.2 mg), sodium chloride (8.18 mg), sodium phosphate dibasic heptahydrate (0.48 mg), sodium phosphate monobasic monohydrate (1.13 mg), and Water for Injection, USP. https://www.rxlist.com/enjaymo-drug.htm#clinpharm
Medical uses
Sutimlimab is indicated to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease (CAD).[1][2]
History
The effectiveness of sutimlimab was assessed in a study of 24 adults with cold agglutinin disease who had a blood transfusion within the past six months.[2] All participants received sutimlimab for up to six months and could choose to continue therapy in a second part of the trial.[2] Based on body weight, participants received either a 6.5g or 7.5g infusion of sutimlimab into their vein on day 0, day 7, and every 14 days through week 25.[2]
In total, 54% of participants responded to sutimlimab.[2] The response was defined in the study as an increase in hemoglobin (an indirect measurement of the amount of red blood cells that are not destroyed) of 2 g/dL or greater (or to 12 g/dL or greater), and no red blood cell transfusions after the first five weeks of treatment; and no other therapies for cold agglutinin disease as defined in the study.[2]
The application for sutimlimab received orphan drug,[2][7] breakthrough therapy,[2] and priority review designations.[2]
Society and culture
Names
Sutimlimab is the International nonproprietary name (INN).[8]
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https://www.sanofi.com/en/media-room/press-releases/2022/2022-02-04-23-00-00-2379517
FDA approves Enjaymo™ (sutimlimab-jome), first treatment for use in patients with cold agglutinin disease
- Enjaymo is the only approved treatment to decrease the need for red blood cell transfusion due to hemolysis, the destruction of red blood cells, in adults with cold agglutinin disease (CAD)
- Enjaymo addresses a serious and chronic unmet medical need for adults living with CAD, a rare blood disorder
Paris, February 4, 2022. The U.S. Food and Drug Administration (FDA) has approved Enjaymo™ (sutimlimab-jome) to decrease the need for red blood cell transfusion due to hemolysis in adults with cold agglutinin disease (CAD). Enjaymo is the first and only approved treatment for people with CAD and works by inhibiting the destruction of red blood cells (hemolysis).
Bill Sibold
Executive Vice President, Head of Specialty Care
“Until now, people living with cold agglutinin disease haven’t had an approved treatment option to manage the constant destruction of red blood cells. Without healthy, viable red blood cells, a chain reaction of debilitating signs and symptoms can be triggered, starting with severe anemia. Enjaymo is the only approved treatment to inhibit red blood cell destruction in CAD and help stop the chain reaction from the start.”
CAD, a rare autoimmune hemolytic anemia, is caused by antibodies called cold agglutinins binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). As red blood cells have the vital job of carrying oxygen throughout the body, patients with CAD may experience severe anemia, which can result in fatigue, weakness, shortness of breath, light-headedness, chest pain, irregular heartbeat, and other potential complications. CAD is a chronic and rare blood disorder that impacts the lives of an estimated 5,000 people in the U.S.
Enjaymo, targeting C1s in the classical complement pathway
Enjaymo is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways.
Enjaymo Phase 3 pivotal CARDINAL study results supporting approval
The approval of Enjaymo in the U.S. is based on positive results from the 26-week open label, single arm pivotal Phase 3 study in patients with CAD (n=24) who have a recent history of blood transfusion, also known as the CARDINAL study.
Catherine Broome, MD
Associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, and a principal investigator in the CARDINAL study
“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients. In the pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin and bilirubin levels during the 26-week study.”
In the study, Enjaymo met its primary efficacy endpoint, which was a composite endpoint defined as the proportion of patients who achieved normalization of hemoglobin (Hgb) level ≥12 g/dL or demonstrated an increase from baseline in Hgb level ≥2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26 or medications prohibited per the protocol from weeks 5 through 26. Secondary endpoints were also met, including improvements in hemoglobin and normalization of bilirubin.
- The majority of patients (54%; n=13) met the composite primary endpoint criteria with 63% (n=15) of patients achieving a hemoglobin ≥ 12 g/dL or an increase of at least 2 g/dL; 71% (n=17) of patients remaining transfusion-free after week five; and 92% (n=22) of patients did not use other CAD-related treatments.
- For the secondary measures on disease process, patients enrolled experienced a mean increase in hemoglobin level of 2.29 g/dL (SE: 0.308) at week 3 and 3.18 g/dL (SE: 0.476) at the 26-week treatment assessment timepoint from the mean baseline level of 8.6 g/dL. The mean reduction in bilirubin levels (n=14) was by -2.23 mg/dL (95% CI: -2.49 to -1.98) from a mean baseline level of 3.23 mg/dL (2.7-fold ULN).
In the CARDINAL study, the most common adverse reactions occurring in 10 percent or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 13 percent (3/24) of patients who received Enjaymo. These serious adverse reactions were streptococcal sepsis and staphylococcal wound infection (n=1), arthralgia (n=1), and respiratory tract infection (n=1). None of the adverse reactions led to discontinuation of Enjaymo in the study. Dosage interruptions due to an adverse reaction occurred in 17 percent (4/24) of patients who received Enjaymo.
Following the completion of the 26-week treatment period of CARDINAL (Part A), eligible patients continued to receive Enjaymo in an extension study.
The recommended dose of Enjaymo is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people >75 kg). Enjaymo is administered intravenously weekly for the first two weeks with administration every two weeks thereafter.
Enjaymo is expected to be available in the U.S. in the coming weeks. The U.S. list price, or wholesale acquisition cost, of Enjaymo is $1,800 per vial. Actual costs to patients are generally anticipated to be lower as the list price does not reflect insurance coverage, co-pay support, or financial assistance from patient support programs. As part of our commitment to ensure treatment access and affordability for innovative therapies, Enjaymo Patient Solutions provides disease education, financial and co-pay assistance programs and other support services to eligible patients. For more information, please call 1-833-223-2428.
Enjaymo received FDA Breakthrough Therapy and Orphan Drug designation, and priority review, which is reserved for medicines that, if approved, would represent significant improvements in safety or efficacy in treating serious conditions. Outside of the U.S., sutimlimab has been submitted to regulatory authorities in Europe and Japan and reviews are ongoing.
About Sanofi
We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions.
Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY
References
- ^ Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761164s000lbl.pdf
- ^ Jump up to:a b c d e f g h i j k l “FDA approves treatment for adults with rare type of anemia”. U.S. Food and Drug Administration. 4 February 2022. Retrieved 6 February 2022. This article incorporates text from this source, which is in the public domain.
- ^ Tvedt TH, Steien E, Øvrebø B, Haaverstad R, Hobbs W, Wardęcki M, et al. (February 2022). “Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery”. American Journal of Hematology. 97 (2): E51–E54. doi:10.1002/ajh.26409. PMID 34778998. S2CID 244116614.
- ^ Nikitin PA, Rose EL, Byun TS, Parry GC, Panicker S (February 2019). “C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro”. Journal of Immunology. 202 (4): 1200–1209. doi:10.4049/jimmunol.1800998. PMC 6360260. PMID 30635392.
- ^ “Sutimlimab FDA Approval Status”. FDA. 19 May 2020.
- ^ “FDA approves Enjaymo (sutimlimab-jome), first treatment for use in patients with cold agglutinin disease”. Sanofi (Press release). 4 February 2022. Retrieved 6 February 2022.
- ^ “Sutimlimab Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 27 July 2016. Retrieved 6 February 2022.
- ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information. 32 (3). hdl:10665/330907.
External links
- “Sutimlimab”. Drug Information Portal. U.S. National Library of Medicine.
- Clinical trial number NCT03347396 for “A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion (Cardinal Study)” at ClinicalTrials.gov
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