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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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OI 338


str1

OI 338

OI338GT (NN1953)

NNC0123-0000-0338

Insulin oral (NN 1953); Insulin-338-GIPET-I; LAI 338; NN 1438; NN-1953; NNC-0123-0000-0338; NNC0123-0338; OI-338GT; Oral insulin 338 C10

  • OriginatorNovo Nordisk
  • ClassAntihyperglycaemics; Insulins; Pancreatic hormones
  • Mechanism of ActionOrnithine decarboxylase stimulants; Phosphokinase stimulants; Protein tyrosine kinase stimulants
  • Phase IIType 1 diabetes mellitus; Type 2 diabetes mellitus
  • 28 Jul 2018No recent reports of development identified for phase-I development in Type-1 diabetes mellitus in Germany (SC, Injection)
  • 28 Jul 2018No recent reports of development identified for phase-I development in Type-2-diabetes-mellitus in Denmark (SC, Injection)
  • 11 Sep 2017Efficacy and adverse events data from a phase II trial in Type-2 diabetes mellitus presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD-2017)

OI-338GT is a long-acting oral basal insulin analogue which had been in phase II clinical trials at Novo Nordisk for the treatment of patients with type 2 and type 1 diabetes. In 2016, the company discontinued the development of the product as the emergent product profile and required overall investments were not commercially viable in the increasingly challenging payer environment.

PAPERJ. Med. Chem. 2021, 64, 1, 616–628

Publication Date:December 28, 2020
https://doi.org/10.1021/acs.jmedchem.0c01576https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01576

Abstract Image

Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, 10, in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 (10 and 24, respectively).

Oral insulin 338 (I338) is a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate. We investigated the efficacy and safety of I338 versus subcutaneous insulin glargine (IGlar) in patients with type 2 diabetes. METHODS: This was a phase 2, 8-week, randomised, double-blind, double-dummy, active-controlled, parallel trial completed at two research institutes in Germany. Insulin-naive adult patients with type 2 diabetes, inadequately controlled on metformin monotherapy or combined with other oral antidiabetic drugs (HbA1c 7·0-10·0%; BMI 25·0-40·0 kg/m(2)), were randomly assigned (1:1) to receive once-daily I338 plus subcutaneous placebo (I338 group) or once-daily IGlar plus oral placebo (IGlar group). Randomisation occurred by interactive web response system stratified by baseline treatment with oral antidiabetic drugs. Patients and investigators were masked to treatment assignment. Weekly insulin dose titration aimed to achieve a self-measured fasting plasma glucose (FPG) concentration of 4·4-7·0 mmol/L. The recommended daily starting doses were 2700 nmol I338 or 10 U IGlar, and maximum allowed doses throughout the trial were 16 200 nmol I338 or 60 U IGlar. The primary endpoint was treatment difference in FPG concentration at 8 weeks for all randomly assigned patients receiving at least one dose of trial product (ie, the full analysis set). The trial has been completed and is registered at ClinicalTrials.gov, number NCT02470039. FINDINGS: Between June 1, 2015, and Oct 19, 2015, 82 patients were screened for eligibility and 50 patients were randomly assigned to the I338 group (n=25) or the IGlar group (n=25). Mean FPG concentration at baseline was 9·7 (SD 2·8) in the I338 group and 9·1 (1·7) in the IGlar group. Least square mean FPG concentration at 8 weeks was 7·1 mmol/L (95% CI 6·4-7·8) in the I338 group and 6·8 mmol/L (6·5-7·1) in the IGlar group, with no significant treatment difference (0·3 mmol/L [-0·5 to 1·1]; p=0·46). I338 and IGlar were well tolerated by patients. Adverse events were reported in 15 (60%) patients in the I338 group and 17 (68%) patients in the IGlar group. The most common adverse events were diarrhoea (three [12%] patients in each group) and nasopharyngitis (five [20%] in the I338 group and two [8%] in the IGlar group). Most adverse events were graded mild (47 of 68 events), and no severe adverse events were reported. One patient in the IGlar group had a treatment-emergent serious adverse event (urogenital haemorrhage of moderate intensity, assessed by the investigator as unlikely to be related to treatment; the patient recovered). Incidence of hypoglycaemia was low in both groups (n=7 events in the I338 group; n=11 in the IGlar group), with no severe episodes. INTERPRETATION: I338 can safely improve glycaemic control in insulin-naive patients with type 2 diabetes with no evidence of a difference compared with insulin glargine, a widely used subcutaneously administered basal insulin. Further development of this particular oral insulin project was discontinued because I338 doses were high and, therefore, production of the required quantities of I338 for wide public use was deemed not commercially viable. Improvement of technologies involved in the product’s development is the focus of ongoing research. FUNDING: Novo Nordisk…..Halberg, I. B.; Lyby, K.; Wassermann, K.; Heise, T.; Zijlstra, E.; Plum-Mörschel, L. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol. 2019, 7, 179– 188,  DOI: 10.1016/s2213-8587(18)30372-3

ral insulin 338 is a novel tablet formulation of a long-acting basal insulin. This randomised, open-label, four-period crossover trial investigated the effect of timing of food intake on the single-dose pharmacokinetic properties of oral insulin 338. Methods: After an overnight fast, 44 healthy males received single fixed doses of oral insulin 338 administered 0, 30, 60 or 360 min before consuming a standardised meal (500 kcal, 57 energy percent [E%] carbohydrate, 13 E% fat, 30 E% protein). Blood samples for pharmacokinetic assessment were taken up to 288 h post-dose. Results: Total exposure (area under the concn.-time curve from time zero to infinity [AUCIns338,0-∞]) and max. concn. (Cmax,Ins338) of insulin 338 were both significantly lower for 0 vs. 360 min post-dose fasting (ratio [95% confidence interval (CI)]: 0.36 [0.26-0.49], p < 0.001, and 0.35 [0.25-0.49], p < 0.001, resp.). There were no significant differences in AUCIns338,0-∞ and Cmax,Ins338 for 30 or 60 vs. 360 min post-dose fasting (ratio [95% CI] 30 vs. 360 min: 0.85 [0.61-1.21], p = 0.36, and 0.86 [0.59-1.26], p = 0.42; ratio [95% CI] 60 vs. 360 min: 0.96 [0.72-1.28], p = 0.77, and 0.99 [0.75-1.31], p = 0.95). The mean half-life was ∼ 55 h independent of the post-dose fasting period. Oral insulin 338 was well-tolerated with no safety issues identified during the trial. Conclusions: Oral insulin 338 pharmacokinetics are not affected by food intake from 30 min after dosing, implying that patients with diabetes mellitus do not need to wait more than 30 min after a morning dose of oral insulin 338 before having their breakfast. This is considered important for convenience and treatment compliance. ClinicalTrials.gov identifier: NCT02304627./……Halberg, I. B.; Lyby, K.; Wassermann, K.; Heise, T.; Plum-Mörschel, L.; Zijlstra, E. The effect of food intake on the pharmacokinetics of oral basal insulin: A randomised crossover trial in healthy male subjects. Clin. Pharmacokinet. 2019, 58, 1497– 1504,  DOI: 10.1007/s40262-019-00772-2

///////////////OI 338, OI338GT, NN1953, NNC0123-0000-0338, Insulin oral (NN 1953),  Insulin-338-GIPET-I,  LAI 338,  NN 1438,  NN-1953, NNC-0123-0000-0338, NNC0123-0338, OI-338GT,  Oral insulin 338 C10

Esketamine


Esketamine2DCSD.svg

Esketamine

  • Molecular FormulaC13H16ClNO
  • Average mass237.725 Da

(+)-Ketamine(2S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
(S)-Ketamine33643-46-8[RN]7884Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (2S)-Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (S)-
KetamineCAS Registry Number: 6740-88-1CAS Name: 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanoneMolecular Formula: C13H16ClNOMolecular Weight: 237.73Percent Composition: C 65.68%, H 6.78%, Cl 14.91%, N 5.89%, O 6.73%Literature References: Prepn: C. L. Stevens, BE634208idem,US3254124 (1963, 1966 both to Parke, Davis). Isoln of optical isomers: T. W. Hudyma et al.,DE2062620 (1971 to Bristol-Myers), C.A.75, 118119x (1971). Clinical pharmacology of racemate and enantiomers: P. F. White et al.,Anesthesiology52, 231 (1980). Toxicity: E. J. Goldenthal, Toxicol. Appl. Pharmacol.18, 185 (1971). Enantioselective HPLC determn in plasma: G. Geisslinger et al.,J. Chromatogr.568, 165 (1991). Comprehensive description: W. C. Sass, S. A. Fusari, Anal. Profiles Drug Subs.6, 297-322 (1977). Review of pharmacology and use in veterinary medicine: M. Wright, J. Am. Vet. Med. Assoc.180, 1462-1471 (1982). Review of pharmacology and clinical experience: D. L. Reich, G. Silvay, Can. J. Anaesth.36, 186-197 (1989); in pediatric procedures: S. M. Green, N. E. Johnson, Ann. Emerg. Med.19, 1033-1046 (1990).Properties: Crystals from pentane-ether, mp 92-93°. uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5). pKa 7.5. pH of 10% aq soln 3.5.Melting point: mp 92-93°pKa: pKa 7.5Absorption maximum: uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5) 
Derivative Type: HydrochlorideCAS Registry Number: 1867-66-9Manufacturers’ Codes: CI-581Trademarks: Ketalar (Pfizer); Ketanest (Pfizer); Ketaset (Fort Dodge); Ketavet (Gellini); Vetalar (Bioniche)Molecular Formula: C13H16ClNO.HClMolecular Weight: 274.19Percent Composition: C 56.95%, H 6.25%, Cl 25.86%, N 5.11%, O 5.84%Properties: White crystals, mp 262-263°. Soly in water: 20 g/100 ml. LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal).Melting point: mp 262-263°Toxicity data: LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal) 
NOTE: This is a controlled substance (depressant): 21 CFR, 1308.13.Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Anesthetic (intravenous).Keywords: Anesthetic (Intravenous).Esketamine hydrochloride, S enantiomer of ketamine, is in phase III clinical trials by Johnson & Johnson for the treatment of depression.Drug Name:Esketamine HydrochlorideResearchCode:JNJ-54135419MOA:Dopamine reuptake inhibitor; NMDA receptor antagonistIndication:DepressionStatus:Phase III (Active)Company:Johnson & Johnson (Originator)

Molecular Weight274.19
FormulaC13H16ClNO•HCl
CAS No.33643-46-8 (Esketamine);
33643-47-9 (Esketamine Hydrochloride);

Route 1

Reference:1. US6040479.

https://patents.google.com/patent/US6040479A/en

EXAMPLE 1

50 g (0.21 mol) R,S-ketamine are dissolved in 613 ml of acetone at the boiling point and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid. In order to obtain a clear solution, 40 ml of water are added thereto at the boiling point and subsequently the clear solution is filtered off while still hot. After the addition of seed crystals obtained in a small preliminary experiment, the whole is allowed to cool to ambient temperature while stirring. After standing overnight, the crystals formed are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.).

Yield (tartrate): 64.8 g

m.p.: 161° C.

[α]D : +26.1° (c=2/H2 O)

Thereafter, the crystallisate is recrystallised in a mixture of 1226 ml acetone and 90 ml water. After cooling to ambient temperature and subsequently stirring for 4 hours, the crystals are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C). There are obtained 38.8 g of tartrate (95.29% of theory).

m.p.: 175.3° C.

[α]D : +68.9° (c=2/H2 O)

The base is liberated by taking up 38.8 g of tartrate in 420 ml of aqueous sodium hydroxide solution and stirring with 540 ml of diethyl ether. The ethereal phase is first washed with water and subsequently with a saturated solution of sodium chloride. The organic phase is dried over anhydrous sodium sulphate. After filtering, the solution is evaporated to dryness on a rotary evaporator, a crystalline, colourless product remaining behind.

Yield (crude base): 21.5 g=86.0% of theory

m.p.: 118.9° C. (literature: 120-122° C.)

[α]D : -55.8° (c=2/EtOH) (literature: [α]D : -56.35° ).

In order possibly to achieve a further purification, the base can be recrystallised from cyclohexane. For this purpose, 10.75 g of the crude base are dissolved in 43 ml cyclohexane at the boiling point. While stirring, the clear solution is slowly cooled to about 10° C. and then stirred at this temperature for about 1 hour. The crystallisate which precipitates out is filtered off with suction and dried to constant weight.

Yield (base): 10.3 g=82.4% of theory

m.p.: 120° C. (literature: 120-122° C.)

[α]D : -56.8° (c=2/EtOH) (literature: [α]D : -56.35° )

EXAMPLE 2

125 ml of water are taken and subsequently 31.5 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine added thereto. While stirring, this mixture is warmed to 50-60° C. until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is first washed with water (1-6° C.) and subsequently washed twice with, in each case, 20 ml of acetone. Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 31.79 g of tartrate (78.23%) of theory).

EXAMPLE 3

150 ml of water are taken and subsequently mixed with 39.8 g (0.27 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine. While stirring, this mixture is warmed to 50-60° C. until a clear solution results.

After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is successively washed with 8 ml of water (1-6° C.) and thereafter twice with, in each case, 20 ml acetone.

Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 32.58 g of tartrate (80.02% of theory).

EXAMPLE 4

150 ml of water and 50 ml isopropanol are taken. After the addition of 39.8 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine, the mixture is heated to reflux temperature while stirring until a solution results (possibly add water until all is dissolved).

Subsequently, while stirring, the solution is allowed to cool to ambient temperature and stirred overnight. The crystals are filtered off with suction and subsequently washed with a 1:2 mixture of 20 ml of water/isopropanol and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 24.45 g of tartrate (62.63% of theory).

EXAMPLE 5

50 g (0.21 mol) R,S-ketamine are dissolved at the boiling point in 300 ml acetone and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid and 100 ml of water. The whole is allowed to cool while stirring and possibly seeded.

After standing overnight, the crystals formed are filtered off with suction, then washed twice with, in each case, 20 ml acetone and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 30.30 g of tartrate (74.57% of theory).

EXAMPLE 6

75 ml of water and 50 ml isopropanol are taken and subsequently 39.8 g (0.27 mol) L-(+)-tartaric acid added thereto. While stirring, the mixture is heated to reflux temperature until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is washed with a 1:2 mixture of 20 ml water/isopropanol. After drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.), there are obtained 34.84 g of tartrate (85.74% of theory).

EXAMPLE 7

20 g of the S-(+)-tartrate obtained in Example 4 are dissolved in 100 ml of water at 30-40° C. With about 7 ml of 50% sodium hydroxide solution, an S-(-)-ketamine base is precipitated out up to about pH 13. It is filtered off with suction and washed neutral with water to pH 7-8. Subsequently, it is dried for about 24 hours at 50° C. in a circulating air drying cabinet. There are obtained 11.93 g S-(-)-ketamine (97.79% of theory).

EXAMPLE 8

5 g of the S-(-)-ketamine obtained in Example 7 are dissolved in 50 ml isopropanol at about 50° C. and possibly filtered off with suction over kieselguhr. Subsequently, gaseous hydrogen chloride is passed in at 50-60° C. until a pH value of 0-1 is reached. The reaction mixture is allowed to cool to ambient temperature, filtered off with suction and washed with about 5 ml isopropanol. The moist product is dried overnight at about 50° C. in a circulating air drying cabinet. There are obtained 5.09 g S-(+)-ketamine hydrochloride (88.06% of theory).


Route 2

Reference:1. J. Am. Chem. Soc. 2015137, 3205-3208.

https://pubs.acs.org/doi/10.1021/jacs.5b00229

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

Abstract Image

CLIP

Initial reagent: cyclopentyl Grignard Step 0: Producing cyclopentyl Grignard Reacting cyclopentyl bromide with magnesium in solvent (ether or THF) Best results: distill solvent from Grignard under vacuum and replace with hydrocarbon solvent (e.g. benzene) Step 1: processing to (o-chlorophenyl)-cyclopentyl ketone Adding o-chlorobenzonitrile to cyclopentyl Grignard in solvent, stirring for long period of time (typically three days) Hydrolyzing reaction with mixture containing crushed ice, ammonium chloride and some ammonium hydroxide Extraction with organic solvent gives (o-chlorophenyl)-cyclopentyl ketone

Step 2: processing to alpha-bromo (o-chlorophenyl)-cyclopentyl ketone ketone processed with bromine in carbon tetrachloride at low temperature (typical T = 0°C), addition of bromine dropwise forming orange suspension Suspension washed in dilute aquerous solution of sodium bisufide and evaporated giving 1-bromocyclopentyl-(o-chlorophenyl)-ketone Note: bromoketone is unstable, immeadiate usage. Bromination carried out with NBromosuccinimide result higher yield (roughly 77%) Step 3: processing to 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine Dissolving bromoketone in liquid methylamine freebase (or benzene as possible solvent) After time lapse (1h): excess methylamine evaporated, residue dissolved in pentane and filtered evaporation of solvent yields 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine Note: longer time span (4-5d) for evaporation of methylaminemay increase yield Step 4: processing to 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine) Method: Thermal rearragement (qualitative yield after 30min in 180°C) N-methylimine dissolved in 15ml decalin, refluxed for 2.5h Evaporation of solvent under reduced temperature followed by extraction of residue with dilute hydrochloric acid Treatment with decolorizing charcoal (solution: acidic => basic) Recrystallization from pentane-ether Note – alternative to use of decalin: pressure bomb

racemic compound, in pharmaceutical preparation racemic more active enantiomere esketamine (S-Ketamine) available as Ketanest S, but Arketamine (R-Ketamine) never marketed for clinical use, Optical rotation: varies between salt and free base form free base form: (S)-Ketamine dextrorotation  (S)-(+)-ketamine hydrochloridesalt: levorotation(S)-(-)-ketamine  Reason found in molecular level: different orientation of substituents: freebase: o-chlorophenyl equatorial, methylamino axia

Sources: http://creationwiki.org/Ketamine#Synthesis http://www.lycaeum.org/rhodium/chemistry/pcp/ketamine.html https://pubchem.ncbi.nlm.nih.gov/compound/ketamine https://pubchem.ncbi.nlm.nih.gov/compound/ketamine#section=Drug-Warning http://www.rsc.org/chemistryworld/2014/02/ketamine-special-k-drugs-podcast http://drugabuse.com/library/the-effects-of-ketamine-use/ http://www.drugfreeworld.org/drugfacts/prescription/ketamine.html http://onlinelibrary.wiley.com/doi/10.1002/1615-9314(20021101)25:15/17%3C1155::AID-JSSC1155%3E3.0.CO;2-M/pdf

CLIP

Process Research and Impurity Control Strategy of Esketamine Organic Process Research & Development ( IF 3.023
Pub Date: 2020-03-18 , DOI: 10.1021/acs.oprd.9b00553
Shenghua Gao; Xuezhi Gao; Zhezhou Yang; Fuli Zhang
An improved synthesis of ( S )-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the ( S )-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity . The ICH-grade quality ( S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.


Process Research and ketamine impurity control strategy

has been developed an improved ( S ) – ketamine (esketamine) synthesis, the high cost-effective way, the undesired isomer may be recycled by racemization. Determine the key process parameters and process-related impurities for each step. First, the formation mechanism and control strategy of most impurities are discussed. In addition, ( S )-ketamine tartrate is a dihydrate, which is the first time it has been published. The feasible racemization catalyzed by aluminum chloride proceeds in a quantitative yield with a purity of 99%. ICH grade quality ( S) 5-ketamine hydrochloride can be obtained through chiral resolution and three times the mother liquor recovery rate. The total yield is 51.1% (14.0% without racemization). The robust process of ketamine can be used in Industrial promotion.

CLIP

Ketamine - Wikiwand

CLIP

https://link.springer.com/article/10.1007/s13738-018-1404-1#citeas

Taghizadeh, M.J., Gohari, S.J.A., Javidan, A. et al. A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione. J IRAN CHEM SOC 15, 2175–2181 (2018). https://doi.org/10.1007/s13738-018-1404-1

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Abstract

We present a novel asymmetric synthesis route for synthesis of (S)-ketamine using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group  of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-Ntert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield.

Esketamine, sold under the brand name Spravato[4] among others,[6][7] is a medication used as a general anesthetic and for treatment-resistant depression.[4][1] Esketamine is used as a nasal spray or by injection into a vein.[4][1]

Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.[1][8] It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors.[1] The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly.[1] It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.

Esketamine was introduced for medical use in 1997.[1] In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States.[9]

In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.[10]

Medical uses

Anesthesia

Esketamine is a general anesthetic and is used for similar indications as ketamine.[1] Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shockanaphylactic shockseptic shock, severe bronchospasm, severe hepatic insufficiencycardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.[1]

Depression

See also: List of investigational antidepressants

Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant.[8][11] It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.[12][11] The medication was studied for use in combination with an antidepressant in people with TRD who had been unresponsive to treatment;[12][8][11] six phase III clinical trials for this indication were conducted in 2017.[12][8][11] It is available as a nasal spray.[12][8][11]

In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine,[13] provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after.[14]

In January 2020, esketamine was rejected by the National Health Service of Great Britain. NHS questioned the benefits and claimed that it was too expensive. People who have been already using the medication were allowed to complete treatment if their doctors consider this necessary.[15]

Side effects

Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.[16]

Pharmacology

Esketamine is approximately twice as potent as an anesthetic as racemic ketamine.[17] It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.[18]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine[citation needed] but, in mice, that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.[19] The usefulness of arketamine over eskatamine has been supported by other researchers.[20][21][22]

Esketamine inhibits dopamine transporters eight times more than arketamine.[23] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.[24][25] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.[17][26] This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.[27]

Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.[26] However, another study found no difference between racemic and (S)-ketamine on the patient’s level of vigilance.[24] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% (S)-ketamine.

History

Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.[1][28] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.[8][12] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.[8][12] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on September 4, 2018;[29] the application was endorsed by an FDA advisory panel on February 12, 2019, and on March 5, 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.[9]

In the 1980s and ’90s, closely associated ketamine was used as a club drug known as “Special K” for its trip-inducing side effects.[30][31]

Society and culture

Names

Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM.[28] It is also known as S(+)-ketamine(S)-ketamine, or (–)-ketamine, as well as by its developmental code name JNJ-54135419.[28][12]

Esketamine is marketed under the brand name Spravato for use as an antidepressant and the brand names Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.[28]

Availability

Esketamine is marketed as an antidepressant in the United States;[9] and as an anesthetic in the European Union.[28]

Legal status

Esketamine is a Schedule III controlled substance in the United States.[4]

References

  1. Jump up to:a b c d e f g h i j Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie33 (12): 764–70. doi:10.1055/s-2007-994851PMID 9893910.
  2. ^ “Spravato 28 mg nasal spray, solution – Summary of Product Characteristics (SmPC)”(emc). Retrieved 24 November 2020.
  3. ^ “Vesierra 25 mg/ml solution for injection/infusion – Summary of Product Characteristics (SmPC)”(emc). 21 February 2020. Retrieved 24 November2020.
  4. Jump up to:a b c d e “Spravato- esketamine hydrochloride solution”DailyMed. 6 August 2020. Retrieved 26 September 2020.
  5. ^ “Spravato EPAR”European Medicines Agency (EMA). 16 October 2019. Retrieved 24 November 2020.
  6. ^ “Text search results for esketamine: Martindale: The Complete Drug Reference”MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.[dead link]
  7. ^ Brayfield A, ed. (9 January 2017). “Ketamine Hydrochloride”MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August2017.[dead link]
  8. Jump up to:a b c d e f g Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics17 (8): 777–790. doi:10.1080/14737175.2017.1341310PMID 28598698S2CID 205823807.
  9. Jump up to:a b c “FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic”U.S. Food and Drug Administration (FDA) (Press release). Retrieved 2019-03-06.
  10. ^ “FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal”NPR. 4 August 2020. Retrieved 27 September 2020.
  11. Jump up to:a b c d e Lener MS, Kadriu B, Zarate CA (March 2017). “Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression”Drugs77 (4): 381–401. doi:10.1007/s40265-017-0702-8PMC 5342919PMID 28194724.
  12. Jump up to:a b c d e f g “Esketamine – Johnson & Johnson – AdisInsight”. Retrieved 7 November 2017.
  13. ^ Koons C, Edney A (February 12, 2019). “First Big Depression Advance Since Prozac Nears FDA Approval”Bloomberg News. Retrieved February 12, 2019.
  14. ^ Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee (February 12, 2019). “FDA Briefing Document” (PDF). Food and Drug Administration. Retrieved February 12, 2019. Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.
  15. ^ “Anti-depressant spray not recommended on NHS”BBC News. 28 January 2020.
  16. ^ “Esketamine nasal spray” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 21 October 2019.
  17. Jump up to:a b Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 33 (12): 764–70. doi:10.1055/s-2007-994851PMID 9893910.
  18. ^ Ihmsen H, Geisslinger G, Schüttler J (November 2001). “Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine”. Clinical Pharmacology and Therapeutics70 (5): 431–8. doi:10.1067/mcp.2001.119722PMID 11719729.
  19. ^ Zhang JC, Li SX, Hashimoto K (January 2014). “R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine”. Pharmacology, Biochemistry, and Behavior116: 137–41. doi:10.1016/j.pbb.2013.11.033PMID 24316345S2CID 140205448.
  20. ^ Muller J, Pentyala S, Dilger J, Pentyala S (June 2016). “Ketamine enantiomers in the rapid and sustained antidepressant effects”Therapeutic Advances in Psychopharmacology6 (3): 185–92. doi:10.1177/2045125316631267PMC 4910398PMID 27354907.
  21. ^ Hashimoto K (November 2016). “Ketamine’s antidepressant action: beyond NMDA receptor inhibition”. Expert Opinion on Therapeutic Targets20 (11): 1389–1392. doi:10.1080/14728222.2016.1238899PMID 27646666S2CID 1244143.
  22. ^ Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (October 2016). “Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression”Psychopharmacology233 (19–20): 3647–57. doi:10.1007/s00213-016-4399-2PMC 5021744PMID 27488193.
  23. ^ Nishimura M, Sato K (October 1999). “Ketamine stereoselectively inhibits rat dopamine transporter”. Neuroscience Letters274 (2): 131–4. doi:10.1016/s0304-3940(99)00688-6PMID 10553955S2CID 10307361.
  24. Jump up to:a b Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P (October 1992). “[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings]”. Der Anaesthesist (in German). 41 (10): 610–8. PMID 1443509.
  25. ^ Pfenninger E, Baier C, Claus S, Hege G (November 1994). “[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]”. Der Anaesthesist (in German). 43 Suppl 2: S68-75. PMID 7840417.
  26. Jump up to:a b Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). “Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)”. European Neuropsychopharmacology7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9PMID 9088882S2CID 26861697.
  27. ^ Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (September 2015). “R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects”Translational Psychiatry5 (9): e632. doi:10.1038/tp.2015.136PMC 5068814PMID 26327690.
  28. Jump up to:a b c d e “Esketamine”Drugs.com.
  29. ^ “Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression”. Janssen Pharmaceuticals, Inc.
  30. ^ Marsa, Linda (January 2020). “A Paradigm Shift for Depression Treatment”. DiscoverKalmbach Media.
  31. ^ Hoffer, Lee (7 March 2019). “The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression”Vice. Retrieved 11 February 2020.

External links

Clinical data
Trade namesSpravato, Ketanest, Vesierra, others
Other namesEsketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419
AHFS/Drugs.comMonograph
MedlinePlusa619017
License dataUS DailyMedEsketamineUS FDAEsketamine
Addiction
liability
Low–moderate[citation needed]
Routes of
administration
IntranasalIntravenous infusion[1]
Drug classNMDA receptor antagonistsAntidepressantsGeneral anestheticsDissociative hallucinogensAnalgesics
ATC codeN01AX14 (WHON06AX27 (WHO)
Legal status
Legal statusAU: S8 (Controlled drug)UK: POM (Prescription only) [2][3]US: Schedule III [4]EU: Rx-only [5]In general: ℞ (Prescription only)
Identifiers
IUPAC name[show]
CAS Number33643-46-8 as HCl: 33795-24-3 
PubChem CID182137
IUPHAR/BPS9152
DrugBankDB01221 
ChemSpider158414 
UNII50LFG02TXDas HCl: 5F91OR6H84
KEGGD07283 as HCl: D10627 
ChEBICHEBI:6121 
ChEMBLChEMBL742 
CompTox Dashboard (EPA)DTXSID6047810 
ECHA InfoCard100.242.065 
Chemical and physical data
FormulaC13H16ClNO
Molar mass237.73 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CN[C@](C1=C(Cl)C=CC=C1)(CCCC2)C2=O
InChI[hide]InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1 Key:YQEZLKZALYSWHR-ZDUSSCGKSA-N 

/////////////Esketamine, JNJ 54135419, phase 3

Inclisiran


Inclisiran

CAS 1639324-58-5

  • ALN-60212
  • ALN-PCSsc

Inclisiran was first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US). Development has now been assumed by The Medicines Company (Parsippany, New Jersey, US). One phase I and two phase II trials have been completed. Topline results of two phase III trials were also recently presented while other phase III trials are still ongoing as part of the ORION clinical development program. …..https://www.ncbi.nlm.nih.gov/books/NBK555477/

Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol.1,2 Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD.1,2

On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies. It is marketed under the trade name Leqvio 8 and is also currently under review by the FDA.

Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA that inhibits translation of the protein PCSK9.[2][3][4] It is being developed by The Medicines Company which licensed the rights to inclisiran from Alnylam Pharmaceuticals.[5]

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqvio, intended for the treatment for primary hypercholesterolaemia or mixed dyslipidaemia.[6] Inclisiran was approved for use in the European Union in December 2020.[1]

History

In 2019 The Medicines Company announced positive results from pivotal phase III study (all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies). The company anticipates regulatory submissions in the U.S. in the fourth quarter of 2019, and in Europe in the first quarter of 2020.[7] The Medicines Company is being acquired by Novartis.[8]

References

  1. Jump up to:a b “Leqvio EPAR”European Medicines Agency. 13 October 2020. Retrieved 6 January 2021.
  2. ^ Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. (January 2017). “A Highly Durable RNAi Therapeutic Inhibitor of PCSK9”The New England Journal of Medicine376 (1): 41–51. doi:10.1056/NEJMoa1609243PMC 5778873PMID 27959715.
  3. ^ Spreitzer H (11 September 2017). “Neue Wirkstoffe: Inclisiran”. Österreichische Apotheker-Zeitung (in German) (19/2017).
  4. ^ “Proposed INN: List 114” (PDF). WHO Drug InformationWHO29 (4): 531f. 2015.
  5. ^ Taylor NP (26 August 2019). “Medicines Company’s PCSK9 drug hits phase 3 efficacy goals”FierceBiotech.
  6. ^ “Leqvio: Pending EC decision”European Medicines Agency (EMA). 16 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ^ “The Medicines Company Announces Positive Topline Results from First Pivotal Phase 3 Trial of Inclisiran”The Medicines Company. Retrieved 29 August 2019.
  8. ^ “Novartis acquires medicines company”Novartis. Retrieved 15 January 2020.

Further reading

External links

  • “Inclisiran”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03399370 for “Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)” at ClinicalTrials.gov
  • Clinical trial number NCT03400800 for “Inclisiran for Subjects With ACSVD or ACSVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)” at ClinicalTrials.gov
Clinical data
Trade namesLeqvio
Other namesALN-PCSsc, ALN-60212
Routes of
administration
Subcutaneous injection
ATC codeC10AX16 (WHO)
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number1639324-58-5
DrugBankDB14901
UNIIUOW2C71PG5
KEGGD11931
Chemical and physical data
FormulaC520H679F21N175O309P43S6
Molar mass16248.27 g·mol−1

General References

  1. Kosmas CE, Munoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E: Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018 Jul 13;6(3). pii: diseases6030063. doi: 10.3390/diseases6030063. [PubMed:30011788]
  2. German CA, Shapiro MD: Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. 2020 Feb;34(1):1-9. doi: 10.1007/s40259-019-00399-6. [PubMed:31782112]
  3. Doggrell SA: Inclisiran, the billion-dollar drug, to lower LDL cholesterol – is it worth it? Expert Opin Pharmacother. 2020 Nov;21(16):1971-1974. doi: 10.1080/14656566.2020.1799978. Epub 2020 Aug 4. [PubMed:32749892]
  4. Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep;76(3):504-7. doi: 10.1161/01.cir.76.3.504. [PubMed:3621516]
  5. Pratt AJ, MacRae IJ: The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009 Jul 3;284(27):17897-901. doi: 10.1074/jbc.R900012200. Epub 2009 Apr 1. [PubMed:19342379]
  6. Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK: Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28. [PubMed:30487231]
  7. Cupido AJ, Kastelein JJP: Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res. 2020 Sep 1;116(11):e136-e139. doi: 10.1093/cvr/cvaa212. [PubMed:32766688]
  8. Novartis: Novartis receives EU approval for Leqvio (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year [Link]
  9. Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection [Link]

Summary

  • Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of death in Canada. Cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), is a major risk factor for cardiovascular disease (CVD) and is thereby targeted to reduce the likelihood of a cardiovascular event, such as a myocardial infarction (MI) and stroke.
  • Inclisiran, first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US) then by The Medicines Company (Parsippany, New Jersey, US), is a small interfering ribonucleic acid (siRNA) molecule being investigated for the treatment of hypercholesterolemia.
  • ORION-1 was a phase II, double-blind, placebo-controlled, multi-centre, randomized controlled trial of 501 patients. Patients were included in the trial if they had a history of ASCVD or were at high risk of ASCVD. The treatment arms were administered 200 mg, 300 mg, or 500 mg of inclisiran on day 1, or 100 mg, 200 mg, or 300 mg of inclisiran on days 1 and 90. The comparator was either placebo on day 1 or placebo on days 1 and 90. The primary end point was percentage change in LDL-C at day 180 from baseline.
  • The ORION-1 study demonstrated that inclisiran, administered at various doses and intervals, compared with placebo, resulted in a statistically significant reduction in LDL-C levels (P < 0.001 for all comparisons versus placebo). The greatest reduction in LDL-C levels was obtained with the 300 mg dose of inclisiran given at days 1 and 90 with a 52.6% (95% confidence interval [CI]: −57.1 to −48.1) reduction at day 180 compared with baseline, and a mean absolute reduction in LDL-C levels of 1.66 (standard deviation 0.54) mmol/L. Results from the ORION-1 trial provided the necessary data to make a decision regarding the dosing regimen to be used in subsequent phase III trials, in particular the ORION-11 phase III trial.
  • The ORION-11 study was a phase III international, multi-centre, and double-blind trial which randomized 1,617 participants (87% with established ASCVD) to inclisiran 300 mg (n = 810) or placebo (n = 807). An initial inclisiran dose of 300 mg given subcutaneously was administered at day 1, day 90, and then every six months for two doses, that is at days 270 and 450. The mean baseline LDL-C level was 2.8 mmol/L (inclisiran) and 2.7 mmol/L (placebo); 96% of participants were on high-dose statin therapy. There was a 50% time-averaged reduction in LDL-C levels from day 90 to day 540 (P < 0.00001). Pre-specified exploratory cardiovascular composite end point (cardiac death, cardiac arrest, MI, or stroke) occurred in 7.8% of inclisiran treated patients versus 10.3% of patients on placebo; this lower rate was mainly driven by a reduction in MI and stroke. With respect to adverse effects, 4.69% of patients on inclisiran reported an injection site reaction, compared with 0.5% of patients on placebo. All reactions were transient. There was no evidence of liver, kidney, muscle, or platelet toxicity.
  • Inclisiran may be an option in the future as a cholesterol-lowering medication, where it would likely be used in patients who are unable to achieve their LDL-C targets despite maximally tolerated statin therapy or who are intolerant to statin therapy. However, results from the inclisiran cardiovascular outcome trial (ORION-4), are needed to confirm its efficacy in reducing CVD and its long-term safety.
  • Inclisiran is not yet approved by any regulatory authority, but its ORION clinical development program identifies the year 2021 as the goal to reach worldwide markets.

///////////Inclisiran, LEQVIO, ALN 60212, ALN PCSsc , NOVARTIS

IDEBENONE


Idebenone.svg
ChemSpider 2D Image | Idebenone | C19H30O5

IDEBENONE

2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone

  • Molecular FormulaC19H30O5
  • Average mass338.439 Da
  • 58186-27-9
  • Idebenona, Idebenonum, CV 2619

IdesolKS-5193NemocebralSNT-MC17идебенонإيديبينون艾地苯醌

Puldysa (idebenone), for the treatment of Duchenne muscular dystrophyTitle: Idebenone
CAS Registry Number: 58186-27-9
CAS Name: 2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione
Additional Names: 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone; 2,3-dimethoxy-5-methyl-6-(10¢-hydroxydecyl)-1,4-benzoquinone; 6-(10-hydroxydecyl)ubiquinone
Manufacturers’ Codes: CV-2619
Trademarks: Avan (Takeda); Daruma (Takeda); Lucebanol (Hormona); Mnesis (Takeda)
Molecular Formula: C19H30O5Molecular Weight: 338.44
Percent Composition: C 67.43%, H 8.93%, O 23.64%
Literature References: Ubiquinone derivative with protective effects against cerebral ischemia. Prepn: H. Morimoto et al.,DE2519730eidem,US4271083 (1975, 1981 both to Takeda); K. Okamoto et al.,Chem. Pharm. Bull.30, 2797 (1982); C.-A. Yu, L. Yu, Biochemistry21, 4096 (1982). Effect on ischemia-induced amnesia in rats: N. Yamazaki et al.,Jpn. J. Pharmacol.36, 349 (1984). Metabolism in animals: T. Kobayashi et al.,J. Pharmacobio-Dyn.8, 448 (1985). Disposition: H. Torii et al.,ibid. 457. Pharmacokinetics and tolerance in humans: M. F. Barkworth et al.,Arzneim.-Forsch.35, 1704 (1985). Series of articles on pharmacology and clinical studies: Arch. Gerontol. Geriatr.8, 193-366 (1989). Review of chemistry, toxicology and pharmacology: I. Zs-Nagy, Arch. Gerontol. Geriatr.11, 177-186 (1990).Properties: Orange needles from ligroin, mp 46-50° (Morimoto); also reported as crystals from hexane + ethyl acetate, mp 52-53° (Okamoto). Sol in organic solvents. Practically insol in water.Melting point: mp 46-50° (Morimoto); mp 52-53° (Okamoto)Therap-Cat: Nootropic.Keywords: Nootropic.

Idebenone is a member of the class of 1,4-benzoquinones which is substituted by methoxy groups at positions 2 and 3, by a methyl group at positions 5, and by a 10-hydroxydecyl group at positions 6. Initially developed for the treatment of Alzheimer’s disease, benefits were modest; it was subsequently found to be of benefit for the symptomatic treatment of Friedreich’s ataxia. It has a role as an antioxidant. It is a primary alcohol and a member of 1,4-benzoquinones.

Idebenone (pronounced eye-deb-eh-known, trade names CatenaRaxoneSovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer’s disease and other cognitive defects.[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich’s ataxia[2] and Duchenne muscular dystrophy[3] have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber’s hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.[4]

Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10).

Uses

Indications that are or were approved in some territories

Nootropic effects and Alzheimer’s disease

Idebenone improved learning and memory in experiments with mice.[5] In humans, evaluation of Surrogate endpoints like electroretinographyauditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[6] but larger studies with hard endpoints are missing.

Research on idebenone as a potential therapy of Alzheimer’s disease have been inconsistent, but there may be a trend for a slight benefit.[7][8] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.[1]

Friedreich’s ataxia (Sovrima)

Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich’s ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.[9] The latter was only significantly improved in young patients.[10] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.[11]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[12] However, on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.[13] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.[1] As of 2013 the drug was not approved for FA in Europe[14] nor in the US, where there is no approved treatment.[15]

Leber’s hereditary optic neuropathy (Raxone)

Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,[16] and submitted an application to market the drug to European regulators in July 2011.[17] It is approved by EMA for this indication and was designated an orphan drug in 2007.[4]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice[18] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[19]

Other neuromuscular diseases

Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)[20] and primary progressive multiple sclerosis[21] are ongoing as of December 2013.

Life style

Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.[22]

Pharmacology

In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.[1][23] Clinical relevance of these findings has not been established.

Pharmacokinetics

Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.[1]

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0040402014014306

Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis - ScienceDirect
Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis - ScienceDirect

SYN

The palladium-catalyzed olefination of a sp2 or benzylic carbon attached to a (pseudo)halogen is known as the Heck reaction.2,63 It is a powerful tool, mainly used for the synthesis of vinylarenes, and it has also been employed for the construction of conjugated double bonds. The widespread application of this reaction can be illustrated by numerous examples in both academia small-scale64 and industrial syntheses.5 As an example, in 2011, a idebenone (124) total synthesis based on a Heck reaction was described (Scheme 35).65 This compound, initially designed for the treatment of Alzheimer’s and Parkinson’s diseases, presented a plethora of other interesting activities, such as free radical scavenging and action against some muscular illnesses. The key step in the synthesis was the coupling of 2-bromo-3,4,5-trimethoxy-1-methylbenzene (125) with dec-9-en-1-ol affording products 126. Under non-optimized conditions (Pd(OAc)2, PPh3, Et3N, 120 ºC), a mixture composed of 60% linear olefins 126 and 15% of the undesired branched product 127 was obtained after three days of reaction. Therefore, the conditions were optimized, allowing the preparation of 126 in 67% yield with no detection of 127 after only 30 min of reaction employing DMF, Pd(PPh3)4iPr2NEt under microwave heating. To conclude the synthesis, the Heck adducts were submitted to hydroxyl protection/deprotection, hydrogenation, and ring oxidation. After these reactions, idebenone was obtained with 20% overall yield over 6 steps.

Scheme 35 Synthesis of idebenone (124) based on Heck reaction of 2-bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol under microwave irradiation. 

Syn

  1.  Duveau, Damien Y.; Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441 
  2. Okada, Taiiti; EP 289223 A1 1988 
  3. Watanabe, Masazumi; EP 58057 A1 1982 
  4. Okamoto, Kayoko; Chemical & Pharmaceutical Bulletin 1982, V30(8), P2797-819 
  5.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 

Paper

Tsoukala, Anna; Organic Process Research & Development 2011, V15(3), P673-680 

https://pubs.acs.org/doi/10.1021/op200051v

An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.

Abstract Image

PAPER

Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441 

https://www.sciencedirect.com/science/article/abs/pii/S0968089610006322

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 68) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 68 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Idebenone (5)18 To a stirred solution containing 200 mg (0.467 mmol) of 2,3- dimethoxy-6-methyl-5-benzyloxydecyl-p-benzoquinone (38) in 5 mL of anhydrous methanol at 23 C was added 15 mg of 10 % Pd/C in one portion. The reaction mixture was stirred at 23 C under an atmosphere of hydrogen for 24 h. Air was then bubbled through the reaction mixture at 23 C for 24 h. The suspension was filtered through Celite and the filtrate was concentrated under diminished pressure to afford idebenone (5) as an orange solid: yield 130 mg (82%); mp: 46–47 C; 1 H NMR (400 MHz, CDCl3) d 1.34 (m, 14H), 1.60 (quint, 2H, J = 7.6 Hz), 2.04 (s, 3H), 2.44 (t, 2H, J = 8.0 Hz), 3.63 (t, 2H, J = 6.8 Hz), and 3.99 (s, 6H); 13C NMR (100 MHz, CDCl3) d 11.9, 25.7, 26.4, 28.7, 29.3, 29.3, 29.4, 29.5, 29.8, 32.7

References

  1. Jump up to:a b c d e “CHMP Assessment Report for Sovrima” (PDF). European Medicines Agency. 20 November 2008: 6, 9–11, 67f.
  2. ^ Clinical trial number NCT00229632 for “Idebenone to Treat Friedreich’s Ataxia” at ClinicalTrials.gov
  3. Jump up to:a b Clinical trial number NCT00654784 for “Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI)” at ClinicalTrials.gov
  4. Jump up to:a b “Raxone”http://www.ema.europa.eu. Retrieved 12 July 2019.
  5. ^ Liu, XJ; Wu, WT (1999). “Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance”. Zhongguo Yao Li Xue Bao20 (11): 987–90. PMID 11270979.
  6. ^ Schaffler, K; Hadler, D; Stark, M (1998). “Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug”. Arzneimittel-Forschung48 (7): 720–6. PMID 9706371.
  7. ^ Gutzmann, H; Kühl, KP; Hadler, D; Rapp, MA (2002). “Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study”. Pharmacopsychiatry35 (1): 12–8. doi:10.1055/s-2002-19833PMID 11819153.
  8. ^ Parnetti, L; Senin, U; Mecocci, P (1997). “Cognitive enhancement therapy for Alzheimer’s disease. The way forward”. Drugs53 (5): 752–68. doi:10.2165/00003495-199753050-00003PMID 9129864S2CID 46987059.
  9. ^ Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (October 2007). “Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial”Lancet Neurol6 (10): 878–86. doi:10.1016/S1474-4422(07)70220-XPMID 17826341S2CID 24749816.
  10. ^ Tonon C, Lodi R (September 2008). “Idebenone in Friedreich’s ataxia”. Expert Opin Pharmacother9 (13): 2327–37. doi:10.1517/14656566.9.13.2327PMID 18710357S2CID 73285881.
  11. ^ Buyse G, Mertens L, Di Salvo G, et al. (May 2003). “Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring”. Neurology60 (10): 1679–81. doi:10.1212/01.wnl.0000068549.52812.0fPMID 12771265S2CID 36556782.
  12. ^ “Heath Canada Fact Sheet – Catena”. Archived from the original on 19 June 2014.
  13. ^ Voluntary Withdrawal of Catena from the Canadian Market
  14. ^ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
  15. ^ NINDS Fact Sheet
  16. ^ Klopstock, T; et al. (2011). “A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy”Brain134 (9): 2677–86. doi:10.1093/brain/awr170PMC 3170530PMID 21788663.
  17. ^ Staff (26 July 2011). “Santhera publishes pivotal trial results of idebenone and goes for EU approval”European Biotechnology News. Archived from the original on 2013-02-17.
  18. ^ Buyse, GM; Van Der Mieren, G; Erb, M; D’hooge, J; Herijgers, P; Verbeken, E; Jara, A; Van Den Bergh, A; et al. (2009). “Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance”European Heart Journal30 (1): 116–24. doi:10.1093/eurheartj/ehn406PMC 2639086PMID 18784063.
  19. ^ Clinical trial number NCT01027884 for “Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)” at ClinicalTrials.gov
  20. ^ Clinical trial number NCT00887562 for “Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)” at ClinicalTrials.gov
  21. ^ Clinical trial number NCT00950248 for “Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)” at ClinicalTrials.gov
  22. ^ McDaniel D, Neudecker B, Dinardo J, Lewis J, Maibach H (September 2005). “Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone”. J Cosmet Dermatol4 (3): 167–73. doi:10.1111/j.1473-2165.2005.00305.xPMID 17129261S2CID 2394666.
  23. ^ Suno M, Nagaoka A (May 1988). “[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate]”Nippon Yakurigaku Zasshi (in Japanese). 91 (5): 295–9. doi:10.1254/fpj.91.295PMID 3410376.
Clinical data
Trade namesCatena, Raxone, Sovrima
AHFS/Drugs.comInternational Drug Names
License dataEU EMAby INN
ATC codeN06BX13 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability<1% (high first pass effect)
Protein binding>99%
Elimination half-life18 hours
ExcretionUrine (80%) and feces
Identifiers
IUPAC name[show]
CAS Number58186-27-9 
PubChem CID3686
ChemSpider3558 
UNIIHB6PN45W4J
KEGGD01750 
ChEMBLChEMBL252556 
CompTox Dashboard (EPA)DTXSID0040678 
Chemical and physical data
FormulaC19H30O5
Molar mass338.444 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=C1/C(=C(\C(=O)C(\OC)=C1\OC)C)CCCCCCCCCCO
InChI[hide]InChI=1S/C19H30O5/c1-14-15(12-10-8-6-4-5-7-9-11-13-20)17(22)19(24-3)18(23-2)16(14)21/h20H,4-13H2,1-3H3 Key:JGPMMRGNQUBGND-UHFFFAOYSA-N 

////////////IDEBENONE, Puldysa, Duchenne muscular dystrophy, Idesol, KS 5193, Nemocebral, SNT MC17, идебенон, إيديبينون , 艾地苯醌 , CV 2619

CC1=C(C(=O)C(=C(C1=O)OC)OC)CCCCCCCCCCO

PF 3635659


PF-3635659 (hydrochloride).png
2D chemical structure of 931409-24-4
PF-3635659|931409-24-4|Active Biopharma Corp

PF-3635659

CAS 931409-24-4 FREE FORM

Molecular Formula, C28-H32-N2-O3, Molecular Weight, 444.5718

1-Azetidinepentanamide, 3-(3-hydroxyphenoxy)-delta,delta-dimethyl-alpha,alpha-diphenyl-

5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;hydrochloride

Molecular FormulaC28H33ClN2O3
SynonymsPF-3635659 (hydrochloride)1079781-31-95-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic acid amide hydrochloride
Molecular Weight481 g/mol

READwww.soci.org › David_Price_Presentation_0945_1030 

PDFDiscovery of PF3635659. An Inhaled Once. An Inhaled Once-daily M3. A t. i t. A t. i t f A th & COPD f A th & COPD. Antagonist. Antagonist for Asthma & COPD.file:///C:/Users/Inspiron/Downloads/David_Price_Presentation_0945_1030.pdf

Pf03635659 has been used in trials studying the treatment of Chronic Obstructive Pulmonary Disease.

Inhaled long-acting muscarinic antagonists in chronic obstructive pulmonary disease | Future Medicinal Chemistry

Synthetic Route

Previous 1/4 Next

5-[3-(3-hydroxy… 931409-66-4~65%PF-3635659931409-24-4
Literature: PFIZER LIMITED Patent: WO2008/135819 A1, 2008 ; Location in patent: Page/Page column 14; 15 ; WO 2008/135819 A1
N/A 1374308-52-7~%PF-3635659931409-24-4
Literature: Dillon, Barry R.; Roberts, Dannielle F.; Entwistle, David A.; Glossop, Paul A.; Knight, Craig J.; Laity, Daniel A.; James, Kim; Praquin, Celine F.; Strang, Ross S.; Watson, Christine A. L. Organic Process Research and Development, 2012 , vol. 16, # 2 p. 195 – 203
N/A 521267-13-0~%PF-3635659931409-24-4
Literature: Glossop, Paul A.; Watson, Christine A. L.; Price, David A.; Bunnage, Mark E.; Middleton, Donald S.; Wood, Anthony; James, Kim; Roberts, Dannielle; Strang, Ross S.; Yeadon, Michael; Perros-Huguet, Christelle; Clarke, Nicholas P.; Trevethick, Michael A.; MacHin, Ian; Stuart, Emilio F.; Evans, Steven M.; Harrison, Anthony C.; Fairman, David A.; Agoram, Balaji; Burrows, Jane L.; Feeder, Neil; Fulton, Craig K.; Dillon, Barry R.; Entwistle, David A.; Spence, Fiona J. Journal of Medicinal Chemistry, 2011 , vol. 54, # 19 p. 6888 – 6904

PAPER

Organic Process Research & Development (2012), 16(2), 195-203.

https://pubs.acs.org/doi/10.1021/op200233r

Abstract Image

An efficient and scalable process for the synthesis of muscarinic antagonist, PF-3635659 1, is described, illustrating redesign of an analogue-targeted synthesis which contained a scale-limiting rhodium-activated C–H amination step. The final route includes a reproducible modified Bouveault reaction which has not previously been reported on a substrate of this complexity, or on such a scale with over 5 kg of the requisite gem-dimethylamine prepared via this methodology.

5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide (1).

First Discovery Route.

To a solution of 5-methyl-2,2-diphenyl-5-{3-[3-(prop-2-en-1-yloxy)phenoxy]azetidin1-yl}hexane nitrile 9 (2.8 g, 6.01 mmol) in 3-methyl-pentan-3-ol (30 mL) was added potassium hydroxide (6.7 g, 120 mmol) and the resulting solution was stirred at 120 ºC for 22 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo to yield 5-methyl-2,2-diphenyl-5-(3-{3- (propenyl)oxy-phenoxy}-azetidin-1-yl)-hexanamide 10 as a yellow oil (3 g, 6.01 mmol, 100%) which was taken on crude to the next step. To a solution of 5-methyl-2,2-diphenyl-5-(3-{3-(propenyl)oxy-phenoxy}-azetidin-1-yl)- hexanoic acid amide 10 (3.0 g, 6.01 mmol) in methanol (100 mL) was added a 2M aqueous hydrochloric acid solution (30 mL, 15 mmol) and the resulting solution was stirred at 60 ºC for 40 minutes. The volatile solvents were removed in vacuo and the remaining aqueous residue was basified with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried with magnesium sulphate and concentrated in vacuo.

The crude residue was purified by flash chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a colourless foam (1.5 g, 3.37 mmol, 54.5%).

Second Discovery Route.

To a solution of 5-[3-(3-methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide 19 (9.0 g, 19.6 mmol) in dichloromethane (1.25 L) at 0 ºC was dropwise added a solution of boron tribromide (1M in dichloromethane, 58.9 mL, 58.9 mmol) and the mixture stirred for 2 hours at 0 ºC to 20 oC. The mixture was cooled to 0 ºC and quenched with 1M aqueous sodium hydroxide solution (200 mL). The reaction mixture was allowed to warm to 20 oC and stirred as such for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried with sodium sulphate and concentrated in vacuo. The crude residue was purified by column chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a white foam (3.4 g, 7.64 mmol, 39%)

1H NMR (MeOD): δ=0.93 (s, 6H), 1.09-1.14 (m, 2H), 2.38-2.42 (m, 2H), 3.11-3.15 (m, 2H), 3.43-3.47 (m, 2H), 4.57-4.62 (m, 1H), 6.19-6.23 (m, 2H), 6.36 (d, 1H), 7.02 (t, 1H), 7.23-7.38 (m, 10H); MS: m/z 445 [M+H]+.

PAPER

Journal of Medicinal Chemistry (2011), 54(19), 6888-6904.

https://pubs.acs.org/doi/10.1021/jm200884j

Abstract Image

A novel tertiary amine series of potent muscarinic M3 receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M3 receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug–drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Patent

WO 2007034325

WO 2008135819

US 8263583

Patent

WO-2020261160

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020261160

Methods and intermediates for preparing the hydrochloride salt of PF-3635659 ,

Cholinergic muscarinic receptors are members of the G-protein coupled receptor super-family and are further divided into 5 subtypes, M to Ms. Muscarinic receptor sub-types are widely and differentially expressed in the body. Genes have been cloned for all 5 sub-types and of these, Mi, M>, and Ms receptors have been extensively pharmacologically characterized in animal and human tissue. Mi receptors are expressed in the brain (cortex and hippocampus), glands and in the ganglia of sympathetic and parasympathetic nerves. M2 receptors are expressed in the heart, hindbrain, smooth muscle and in the synapses of the autonomi c nervous system. Ms receptors are expressed m the brain, glands and smooth muscle. In the airways, stimulation of Ms receptors evokes contraction of airway smooth muscle leading to bronchoeonstnction, while in the salivary-gland Ms receptor stimulation increases fluid and mucus secretion leading to increased salivation. M2 receptors expressed on smooth muscle are understood to be pro-contractile while pre-synaptic M2 receptors modulate acetylcholine release from parasympathetic nerves. Stimulation of M2 receptors expressed in the heart produces bradycardia.

[0003] Short and long-acting muscarinic antagonists are used in the management of asthma and chronic obstructive pulmonary disease (COPD); these include the short acting agents Atrovent® (ipratropium bromide) and Oxivent® (oxitropium bromide) and the long acting agent Spiriva® (tiotropium bromide). These compounds produce bronchodilation following inhaled administration. In addition to improvements in spirometric values, anti-muscarinic use in COPD is associated with improvements m health status and quality of life scores. As a consequence of the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipation, mydriasis, urinary retention (all predominantly mediated via blockade of M3 receptors) and tachycardia (mediated by blockade of M2 receptors).

[0004] A newer M3 receptor antagonist that is in the carboxamide family is 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride. This carboxamide compound exhibits the following structure (formula II):

[0005] To date, it has not been appreciated that 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be synthesized from the benzoate salt of 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanenitrile Therefore, there is a need for methods and intermediates used to efficiently prepare 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanamide hydrochloride of good quality from the benzoate salt of 5~[3~ (3~hydroxyphenoxy)azetidin-l-yl]-5-rn ethyl-2, 2-diphenylhexanenitrile.

Reaction Scheme 1 -Preparation of Crude Carboxamide Hydrochloride

formula I formula II

[0061] The coupled benzoate compound of formula 1 can be reacted with KOH, 2-methyl-2-butano!, water, then HC1 aqueous, HC1, and TBME to obtain the crude carboxamide hydrochloride of formula II. The benzoate salt of the nitrile provides for easier purification of the nitrile.

[0062] The reagents useful in the preparation of 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-metiiyl-2,2-diphenyl-hexanamide hydrochloride include a base and an alcohol In some embodiments, a useful base includes potassium hydroxide, while a useful alcohol includes tertiary amyl alcohol also known as 2-methyl-2-butanol. The reaction of the benzoate compound of formula II in tertiary amyl alcohol and potassium hydroxide can be carried in a temperature range from about 85 ± 5°C to about 103 ± 2°C. In a later stage, the temperature of 103 ± 2°C can be maintained in that range for from about 30 hours to about 65 hours. A cooling period to about room temperature is followed by adjusting the pH to a range from about 6.5 to about 8.0. Hydrochloric acid is added to the product of this initial reaction to form a crude carboxamide hydrochloride compound of formula II. The initially isolated crude carboxamide hydrochloride compound of formula II can be washed with an alcohol and then washed with, or slurried in an ether. In some embodiments, the alcohol can be tertiary amyl alcohol and the ether can be methyl tertiary butyl ether.

[0063] In various embodiments, the crude 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be further purified by treating this carboxamide hydrochloride compound with a slurry of activated charcoal, for example, commercially available ENQPC, PF133 or PF511 SPL (A) carbon, in isopropyl alcohol and water at 85 ± 5°C and filtering as illustrated m the Reaction Scheme 2 below:

Reaction Scheme 2 – Purification of Carboxamide Hydrochloride

Reaction Scheme 3 – Preparation of the Coupled Compound Benzoate

O

[0065] In some embodiments, the benzyl coupled compound of formula III is prepared by reacting an azetidine mesyl HC1 1 -(5-cyano-2-methyl-5,5-diphenylpentan-2-yl)azetidin-3-yl methanes ulfonate hydrochloride with a reagent comprising benzyl resorcinol as illustrated in the Reaction Scheme 4 below:

Reaction Scheme 4 – Preparation of the Benzyl Coupled Compound

In Reaction Scheme 4, the azetidine mesyl hydrochloride of formula IV

is reacted with benzyl resorcinol of formula V

The reagent can comprise benzyl resorcinol and, in some aspects, acetonitrile, a carbonate salt of either cesium or potassium, sodium hydroxide, water, ethyl acetate, hexanes or a mixture thereof. The order of addition of reagents in this step overcomes the need for specific equipment (e.g., a bespoke/unusual agitator) and allows the step to be run in a general purpose reactor.

[0066] Benzyl resorcinol is commercially available and can be obtained commercially, for example, from Sigma Aldrich Corp. In various embodiments, benzyl resorcinol of formula V can be prepared by reacting resorcinol with benzyl chloride to form benzyl resorcinol according to the Reaction Scheme 5 below:

Reaction Scheme 5 — Preparation of Benzyl Resorcinol

Resorcinol DMF/Hexane

Toluene Benzyl Resorcinol

or

3-{benzyioxy) phenol

V

[0067] In certain aspects, the benzyl resorcinol is prepared by reacting resorcinol with benzyl chloride m a reagent which can include potassium carbonate, dimethylformamide, water, sodium hydroxide, toluene, hydrochloric acid, hexanes or a combination thereof. In some instances, benzyl resorcinol seeding material may also be added. For the conversion of the resorcinol to the benzyl resorcinol (V), the developed chemistry’- allows effective removal of remaining resorcinol starting material and dibenzyl impurity to give the benzyl resorcinol product in good yield and quality.

Reaction Scheme 6 – Preparation of Azetidine Mesyl Hydrochloride

Azetidine alcohol Azetidine mesyl

VI hydrochloride

Reaction Scheme 7 – Preparation of Azetidine Alcohol

Scheme 8 – Preparation of Diphenyl Amine

Reaction Scheme 9 Preparation of Diphenyl Chloro Amide

Reaction Scheme 10 – Preparation of Diphenyl Alkene

3-methyl-3-buien-t-ol Mesyi Alkene Diphenyl Alkene

PATENT

WO2007034325

https://patents.google.com/patent/WO2007034325A1/en

The compound was originally claimed without an action as example 108 in WO2007034325 , for the treatment of chronic obstructive pulmonary disease, and this is the first filing from Pfizer relating to the compound since the program was presumed discontinued in 2011.

Example 108 5-r3-(3-Hvdroxyphenoxy)azetidin-1-vπ-5-methyl-2,2-diphenylhexanamide

Figure imgf000130_0001

Boron tribromide (1M in dichloromethane, 1.75mL, 1.75mmol) was added to an ice-cooled solution of the product of example 100 (200mg, 0.44mmol) in dichloromethane (5mL) and the mixture was stirred at O0C for 1 hour. Further boron tribromide (1M in dichloromethane, 0.5mL, O.δmmol) was added and the mixture was stirred at O0C for 30 minutes. The reaction was then quenched with 1M sodium hydroxide solution (5mL), diluted with dichloromethane (2OmL) and stirred at room temperature for 40 minutes. The aqueous layer was separated, extracted with ethyl acetate (2x25mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, afforded the title compound as a colourless foam in 91% yield, 176mg.

1HNMR(400MHz, CDCI3) δ: 1.10(s, 6H), 1.22-1.34(m, 2H), 2.42-2.55(m, 2H), 3.28-3.40(m, 2H), 3.65-3.88(m, 2H), 4.70-4.80(m, 1H), 5.55-5.70(brs, 2H), 6.23-6.36(m, 2H), 6.45-6.53(m, 1H), 7.03-7.12(m, 1H), 7.19-7.39(m, 10H); LRMS ESI m/z 445 [M+H]+ E

PATENT

WO2018167804

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018167804

It does however, follow on from WO2018167804 , assigned solely to Mylan , claiming amorphous and crystalline forms designated as Forms I-XI, for treating allergy, and this seems to confirm the potential of the candidate is being revisited, and possibly licensed.

(5-[3-(3-Hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride has a structure depicted below as Compound-A.

Compound-A

Compound-A is a muscarinic antagonist useful for treating allergy or respiratory chronic obstructive pulmonary disease.

Compound-A and pharmaceutically acceptable salts are claimed in U.S. Pat. No. 7,772,223 B2 and one of its non-solvated crystalline forms is claimed in U.S. Pat. No. 8,263,583 B2.

Examples:

Example 1: Processes for the preparation of amorphous form of Compound-A.

Compound-A (5 g) was dissolved in methanol (150 ml) at 60-65°C. The solution was filtered at 60-65°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Compound-A was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a 5 ml/min feed rate of the solution and inlet temperature at 75°C with 100% aspiration to yield an amorphous form of Compound-A.

///////////// PF-3635659,  PF 3635659

CC(C)(CCC(C1=CC=CC=C1)(C2=CC=CC=C2)C(=O)N)N3CC(C3)OC4=CC=CC(=C4)O.Cl

Ansuvimab-zykl


Ebola Virus Treatment Ebanga Gets FDA Approval - MPR

Ansuvimab-zykl

FDA APPROVED, 12/21/2020, EBANGA

To treat ebola

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-treatment-ebola-virus

The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.

Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.

During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.

In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.

Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.

Ebanga was granted an Orphan Drug designation, which provides incentives to assist and encourage drug development for rare diseases. Additionally, the agency granted Ebanga a Breakthrough Therapy designation.

FDA granted the approval to Ridgeback Biotherapeutics, LP.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.[1][2]

The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.[1]

Ansuvimab was approved for medical use in the United States in December 2020.[1][2]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo.[3] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune.[4][5]

Mechanism of action

Neutralization

Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody,[3] meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus’s cell receptor protein, Niemann-Pick C1 (NPC1).[6][7][8] This “competition” by ansuvimab prevents Ebola virus from binding to NPC1 and “neutralizes” the virus’s ability to infect the targeted cell.[6]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicityantibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity.[3] Other functional killing tests have not been performed.

History

Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease.[9] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo roughly ten years later.[3]

In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood.[5][4][11] Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.[12]

Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.[13][14]

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo.[3][10] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] A survivor from the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered.[3] Memory B cells isolated from the survivor’s blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells.[3] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells.[3]

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.[3]

Ansuvimab monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived.[3] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.[5][4]

Development

Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.[4][5]

Human safety testing

In early 2018,[9] a Phase 1 clinical trial of ansuvimab’s safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood.[5][4][11] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days.[5][4]

Ridgeback Biotherapeutics

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of HealthNational Institute of Allergy and Infectious Diseases.[15] Ansuvimab was given orphan drug status in May 2019 and March 2020.[16][17][18]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites.[19][20][11] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.[11]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols.[11] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.[21][22][13][12]

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus.[23]

FDA approves ansuvimab-zykl for Ebola virus infection

DECEMBER 21, 2020 BY JANICE REICHERThttps://www.antibodysociety.org/antibody-therapeutic/fda-approves-ansuvimab-zykl-for-ebola-virus-infection/embed/#?secret=zWW0Sr0BdW

On December 21, 2020, the US Food and Drug Administration approved Ebanga (ansuvimab-zykl) for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga had been granted US Orphan Drug designation and Breakthrough Therapy designations. Ansuvimab is a human IgG1 monoclonal antibody that binds and neutralizes the virus.

The safety and efficacy of Ebanga were evaluated in the multi-center, open-label, randomized controlled PALM trial. In this study, 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

Ebanga is the 12th antibody therapeutic to be granted a first approval in the US or EU during 2020.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

References

  1. Jump up to:a b c d “FDA Approves Treatment for Ebola Virus”U.S. Food and Drug Administration. 21 December 2020. Retrieved 23 December 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “Ridgeback Biotherapeutics LP Announces the Approval of Ebanga for Ebola” (Press release). Ridgeback Biotherapeutics LP. 22 December 2020. Retrieved 23 December 2020– via Business Wire.
  3. Jump up to:a b c d e f g h i j k l Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. (March 2016). “Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody”Science351 (6279): 1339–42. Bibcode:2016Sci…351.1339Cdoi:10.1126/science.aad5224PMID 26917593.
  4. Jump up to:a b c d e f Clinical trial number NCT03478891 for “Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults” at ClinicalTrials.gov
  5. Jump up to:a b c d e f Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, et al. (March 2019). “Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody ansuvimab targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study”Lancet393 (10174): 889–898. doi:10.1016/S0140-6736(19)30036-4PMC 6436835PMID 30686586.
  6. Jump up to:a b Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, et al. (March 2016). “Structural and molecular basis for Ebola virus neutralization by protective human antibodies”Science351 (6279): 1343–6. Bibcode:2016Sci…351.1343Mdoi:10.1126/science.aad6117PMC 5241105PMID 26917592.
  7. ^ Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (August 2011). “Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection”Nature477 (7364): 344–8. Bibcode:2011Natur.477..344Cdoi:10.1038/nature10380PMC 3230319PMID 21866101.
  8. ^ Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 2011). “Ebola virus entry requires the cholesterol transporter Niemann-Pick C1”Nature477 (7364): 340–3. Bibcode:2011Natur.477..340Cdoi:10.1038/nature10348PMC 3175325PMID 21866103.
  9. Jump up to:a b “NIH begins testing Ebola treatment in early-stage trial”National Institutes of Health (NIH). 2018-05-23. Retrieved 2018-10-15.
  10. Jump up to:a b c Hayden EC (2016-02-26). “Ebola survivor’s blood holds promise of new treatment”Naturedoi:10.1038/nature.2016.19440ISSN 1476-4687.
  11. Jump up to:a b c d e “NIH VideoCast – CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development”videocast.nih.gov. Retrieved 2019-08-09.
  12. Jump up to:a b Kingsley-Hall A. “Congo’s experimental mAb114 Ebola treatment appears successful: authorities | Central Africa”http://www.theafricareport.com. Retrieved 2018-10-15.
  13. Jump up to:a b McNeil DG (12 August 2019). “A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo”The New York Times. Retrieved 13 August 2019.
  14. ^ Molteni M (12 August 2019). “Ebola is Now Curable. Here’s How The New Treatments Work”Wired. Retrieved 13 August 2019.
  15. ^ “Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases” (Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  16. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 8 May 2019. Retrieved 24 December 2020.
  17. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 30 March 2020. Retrieved 24 December 2020.
  18. ^ “Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114”(Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  19. ^ Check Hayden, Erika (May 2018). “Experimental drugs poised for use in Ebola outbreak”Nature557 (7706): 475–476. Bibcode:2018Natur.557..475Cdoi:10.1038/d41586-018-05205-xISSN 0028-0836PMID 29789732.
  20. ^ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  21. ^ Mole B (2019-08-13). “Two Ebola drugs boost survival rates, according to early trial data”Ars Technica. Retrieved 2019-08-17.
  22. ^ “Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates”National Institutes of Health (NIH). 2019-08-12. Retrieved 2019-08-17.
  23. ^ “FDA Approves First Treatment for Ebola Virus”U.S. Food and Drug Administration(FDA) (Press release). 14 October 2020. Retrieved 14 October 2020.  This article incorporates text from this source, which is in the public domain.

External links

  • “Ansuvimab”Drug Information Portal. U.S. National Library of Medicine.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetZaire ebolavirus
Clinical data
Trade namesEbanga
Other namesAnsuvimab-zykl, mAb114
License dataUS DailyMedAnsuvimab
Routes of
administration
Intravenous
Drug classMonoclonal antibody
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number2375952-29-5
DrugBankDB16385
UNIITG8IQ19NG2
KEGGD11875
Chemical and physical data
FormulaC6368H9924N1724O1994S44
Molar mass143950.15 g·mol−1

//////////Ansuvimab-zykl , EBANGA, FDA 2020, 2020 APPROVALS, MONOCLONAL ANTIBODY, Orphan Drug designation, , Breakthrough Therapy designation , Ridgeback Biotherapeutics, 

CITRULLINE


L-Citrullin2.svg

CITRULLINE

CAS 372-75-8

  • L-Citrulline
  • 瓜氨酸

Used for nutritional supplementation, also for treating dietary shortage or imbalance.

L-Citrulline

  • Molecular FormulaC6H13N3O3
  • Average mass175.186 Da

SYN

Hua Bai, Peijie Yang, Zhengjie Chen, Chongyan Xu, Zhaorul Li, Zigang Zhao, Luyan Jiang, Zongyi Yang, Jiang Li, “PROCESSES FOR THE PRODUCTION OF L-CITRULLINE.” U.S. Patent US20090142813, issued June 04, 2009.

US20090142813(S)-2-Amino-5-ureidopentanoic acid1725416[Beilstein]206-759-6[EINECS]372-75-8[RN]a-Amino-d-ureidovaleric Acid

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Citrulline malatePAB4036KHO70796-17-7DROVUXYZTXCEBX-WCCKRBBISA-N

CitrullineCAS Registry Number: 372-75-8
CAS Name:N5-(Aminocarbonyl)-L-ornithine
Additional Names: d-ureidonorvaline; a-amino-d-ureidovaleric acid; Nd-carbamylornithine
Molecular Formula: C6H13N3O3Molecular Weight: 175.19
Percent Composition: C 41.13%, H 7.48%, N 23.99%, O 27.40%Line Formula: H2NCONH(CH2)3CH(NH2)COOH
Literature References: An amino acid, first isolated from the juice of watermelon, Citrullus vulgaris Schrad., Cucurbitaceae: Wada, Biochem. Z.224, 420 (1930); isoln from casein: Wada, ibid.257, 1 (1933). Synthesis from ornithine through copper complexes: Kurtz, J. Biol. Chem.122, 477 (1938); by alkaline hydrolysis of arginine: Fox, ibid.123, 687 (1938); from cyclopentanone oxime: Fox et al.,J. Org. Chem.6, 410 (1941). Crystallization: Matsuda et al.,JP71 174 (1971 to Ajinomoto), C.A.74, 126056u (1971). Crystal and molecular structure: Naganathan, Venkatesan, Acta Crystallogr.27B, 1079 (1971); Ashida et al.,ibid.28B, 1367 (1972). Use in asthenia and hepatic insufficiency: FR2198739 (1974 to Hublot & Vallet), C.A.82, 144952c (1975). Clinical trial in treatment of lysinuric protein intolerance: J. Rajantie et al.,J. Pediatr.97, 927 (1980); T. O. Carpenter et al.,N. Engl. J. Med.312, 290 (1985).Properties: Prisms from methanol + water, mp 222°. [a]D20 +3.7° (c = 2). pK1 2.43; pK2 9.41. Sol in water. Insol in methanol, ethanol.Melting point: mp 222°pKa: pK1 2.43; pK2 9.41Optical Rotation: [a]D20 +3.7° (c = 2) Derivative Type: HydrochlorideCAS Registry Number: 34312-10-2Molecular Formula: C6H13N3O3.HClMolecular Weight: 211.65Percent Composition: C 34.05%, H 6.67%, N 19.85%, O 22.68%, Cl 16.75%Properties: Crystals, dec 185°. [a]D22 +17.9° (c = 2).Optical Rotation: [a]D22 +17.9° (c = 2) Derivative Type: Malate (salt)CAS Registry Number: 54940-97-5Trademarks: Stimol (Biocodex)Molecular Formula: C6H13N3O3.C4H6O5Molecular Weight: 309.27Percent Composition: C 38.84%, H 6.19%, N 13.59%, O 41.39% Therap-Cat: Treatment of asthenia.

Asklepion is developing an iv formulation of citrulline, Citrupress, for the potential treatment of pulmonary hypertension and for the potential prevention of clinical sequelae of acute lung injury complicating congenital heart repair surgery in pediatric patients, and also investigating the drug for the potential treatment of acute sickle cell crisis. In August 2016, a phase III study was initiated for preventing clinical sequelae of acute lung injury?in pediatric patients undergoing cardiopulmonary bypass (CPB) for heart defects; in July 2019, results were expected in October 2019.

Citrulline is an amino acid. It is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.

The organic compound citrulline is an α-amino acid.[2] Its name is derived from citrullus, the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1914 by Japanese researchers Yotaro Koga and Ryo Odake[3][note 1] and further codified by Mitsunori Wada of Tokyo Imperial University in 1930.[4] It has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase.[5]

Biosynthesis

Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a byproduct of the reaction catalyzed by NOS family (NOS; EC 1.14.13.39).[6] It is made from arginine by the enzyme trichohyalin at the inner root sheath and medulla of hair follicles.[7] Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide.

Citrulline is also made by enterocytes of the small intestine.[2][8]

Function

Several proteins contain citrulline as a result of a posttranslational modification. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination with the help of calcium ion. Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation.

Circulating citrulline concentration is a biomarker of intestinal functionality.[9][10

PAPER

Biochemistry, 53(41), 6511-6519; 2014

PAPER

Journal of the Chemical Society of Pakistan, 34(2), 451-454; 2012

PAPER

Journal of Agricultural and Food Chemistry, 66(33), 8841-8850; 2018

https://pubs.acs.org/doi/10.1021/acs.jafc.8b02858

l-Citrulline is a nonessential amino acid with a variety of physiological functions and can be enzymatically produced by arginine deiminase (ADI, EC 3.5.3.6). The enzymatic-production approach is of immense interest because of its mild conditions, high yield, low cost, and environmental benignity. However, the major hindrances of l-citrulline industrialization are the poor thermostability and enzyme activity of ADI. Hence, in this work, directed evolution and site-directed mutagenesis aided with in silico screening, including the use of b-factor values and HoTMuSiC, were applied to a previously identified ADI from Enterococcus faecalis SK23.001 (EfADI), and a triple-site variant R15K–F269Y–G292P was obtained. The triple-site variant displays a 2.5-fold higher specific enzyme activity (333 U mg–1), a lower Km value of 6.4 mM, and a 6.1-fold longer half-life (t1/2,45°C = 86.7 min) than wild-type EfADI. This work provides a protein-engineering strategy to improve enzyme activity and thermostability, which might be transferrable to other ADIs and enzymes.

Abstract Image

PAPER

ACS Sustainable Chemistry & Engineering, 7(9), 8522-8529; 2019

https://pubs.acs.org/doi/10.1021/acssuschemeng.9b00301

Biocatalytic transformation of carbamate formed readily from CO2 and NH3 provides attractive green routes for mitigation of these important environmental pollutants. Accordingly, a coupled-enzyme system was developed for the one-pot production of citrulline through carbamoylation of ornithine in aqueous solutions of CO2 and NH3. Hyperthermophilic ornithine carbamoyltransferases are produced recombinantly in E. coli with carbamate kinases known to have a propensity for carbamoyl phosphate synthesis. Importantly, in vitro biocatalysis is carried out by E. coli cell lysate prepared through coexpression of the required recombinant enzymes in a single bacterial culture, greatly reducing limitations normally associated with protein production and purification. Acetate kinase that is endogenous in the lysate also recycles the required ATP cofactor, which would otherwise have been required in costly stoichiometric amounts. Recombinant lysates catalyze the production of carbamoyl phosphate with substoichiometric ATP (>300 turnovers) as well as its in situ reaction with ornithine to give citrulline in high yield (>95%) and g L–1 h–1 titers. The system is active over a wide range of NH3 concentrations (2.5 mM – 2 M), and >90% conversions of NH3 may be reached within 1.5 h. Aqueous NH3 used to sequester CO2 gas (10% v/v) may be directly used as the biocatalyst feedstock. In preliminary studies, citrulline is found to be an effective organic nitrogen fertilizer of the wheat grass Brachypodium distachyon. Therefore, lysates described here constitute a cost-effective biocatalytic platform for one-pot production of a promising organic nitrogen fertilizer, under mild reaction conditions, from environmental pollutants as feedstock.

Abstract Image

PATENT

WO 2015050276

https://patents.google.com/patent/WO2015050276A1/en

PATENT

WO2018125999 claiming method for maintaining the coupling of endothelial nitric oxide synthase.

PATENT

WO-2020247853

front page image

Process for preparing citrulline from a transition metal complex of ornithine using cyanate useful to reduce the incidence or severity of cardiopulmonary bypass-induced pulmonary injury due to free radical formation in a patient during cardiopulmonary bypass.

Ornithine is an alpha amino acid with a terminal amino group opposite the alpha carbon.

Citrulline is an alpha amino acid with a terminal carbamido group in the same position as the terminal amino group of ornithine. Dr. A. Kurtz described synthesis of racemic citrulline from racemic ornithine in 1938 (J. Biol. Chem., 122:477-484), and that disclosure was followed up by synthesis of optically active /-citrulline from /-ornithine in 1949 (J. Biol. Chem., 180: 1253-1267). Optical activity was preserved by complexing the starting material (/-ornithine) in a transition metal complex via the alpha amino and carboxyl groups, then reacting the terminal amino group with urea to from a carbamido derivative (see Figure 1). Kurth 1949 describes numerous other syntheses, all depending on the transition metal complex to preserve the alpha amino acid character of the starting compound while derivatizing other parts of the molecule. An example of this synthesis is described in Example 1 below.

Details of various steps in the improved processes developed by the present inventors for producing pharmaceutical grade citrulline are discussed below.

Synthesis of Citrulline from Ornithine

[00014] The present inventors preserved the stereochemical structure around the alpha carbon of the alpha amino acid during reaction of amino groups elsewhere on the compound by complexing the alpha end of the molecule with a transition metal atom, as reported by

Kurth 1938 and 1949. The initial production of the /-ornithine-copper complex is carried out as described by Kurtz. Kurtz describes a variety of transition metals as the complexing metal in the 1949 paper, but the preferred metal is copper (II), based on the ease of forming stable complexes and the ease with which copper (II) may subsequently be removed from the product. The copper is typically supplied as cupric sulfate, although complex formation from copper (II) acetate, cupric carbonate, or cupric oxide have also been reported.

[00015] The present inventors have discovered an alternative method of derivatizing the terminal amino group of the complexed alpha amino acid using cyanate rather than the urea reaction reported by Kurth. An example of this improved synthesis is shown in Figure 2A and described in Example 3 below. Use of cyanate as the derivatizing agent has been found to produce fewer distinct product compounds, which simplifies purification of the desired citrulline product. Kurth carried out urea derivatization by refluxing the copper complex in the presence of excess urea. Cyanate derivatization may be carried out at lower temperatures (e.g. 55°C-65°C) which may contribute to higher yield of citrulline, based on the initial amount of ornithine. Cyanate is preferably provided in excess, and the reaction is driven by precipitation of the citrulline: copper complex. The precipitated complex is washed with water to remove unreacted copper (e.g., wash until no blue coloration persists in the filtrate). The precipitated copper complex of citrulline may be recovered and dried.

Enriching Citrulline as a Copper Complex

[00016] The inventors have discovered that the relative citrulline content of the reaction

product(s) can be enhanced by reprecipitation of the citrulline: copper complex. Precipitated copper complex of citrulline (produced, for example, by reaction of a ornithine: copper complex with urea or cyanate in water) may be dried. The

citrulline: copper complex may be redissolved by suspending the precipitate in water and acidifying the suspension until the complex dissolves. Acidification may be

accomplished by adding concentrated acid, preferably hydrogen chloride, to the suspension while stirring. Once the copper: citrulline complex solution is clear, base (typically sodium hydroxide) is added to bring the pH up to 7-10. Both the acidification and subsequent neutralization steps are actively cooled (temperature not more than 45°C) to protect the citrulline product from hydrolysis or reaction to produce side products. The precipitate is washed with water (e.g., until the filtrate is free of chloride by checking the filtrate for turbidity with silver nitrate), and then the precipitate is dried. Reprecipitation under these conditions is selective for citrulline: copper complex over ornithine: copper complex, because the ornithine complex is more soluble in water. If the dried complex contains higher than the desired level of ornithine contamination (e.g., greater than 10 mole% ornithine – as measured by NMR, for example), the complex may be redissolved and reprecipitated as necessary to further lower the relative amount of ornithine.

Recovering Citrulline from Its Copper Complex

[00017] Once the ornithine content in the copper: citrulline complex precipitate is sufficiently low

(preferably less than 10 mole% ornithine), the precipitate is resuspended in water and citrulline is freed from the complex by removing the copper as an inorganic precipitate, typically copper sulfide (See Figure 2B). Sulfide may be introduced in a variety of salt forms, but the inventors have found it preferable to use hydrogen sulfide gas as the sulfide source. In a preferred mode, the aqueous suspension is placed in a stirred, pressure vessel. The air is then pumped out of the reactor’s head space to form an under pressure. The reactor is then repressurized with hydrogen sulfide gas over the aqueous suspension (preferably at low temperature, e.g., 0°C-5°C, to maximize the solubility of hydrogen sulfide). Hydrogen sulfide is continuously added to the reactor to maintain parity with ambient pressure during consumption of this gas. Copper salts will precipitate, leaving citrulline in solution. As hydrogen sulfide is consumed, the pressure in the vessel decreases; the reaction is complete when the pressure stabilizes. Reaction of hydrogen sulfide with residual copper salts (for example chloride or sulfate) will lower the pH; typically the pH will be below 4, preferably pH~3. Copper salts typically include copper (II) sulfide, but may also include copper (I) sulfide and copper oxide. The solution temperature is elevated for filtration, typically to about 30°C, to promote solubility of the citrulline and drive off excess hydrogen sulfide gas, while precipitated copper salts are removed by filtration.

Purifying Citrulline

[00018] For pharmaceutical use, the active compound must be substantially free of contaminants, and further purification steps are necessary to produce a pharmaceutical grade product. For the purposes of this invention, substantially free of contaminants is considered to include: ornithine not more than (NMT) 0.8%, individual specified impurities NMT 0.15%, individual unspecified (unknown) impurities NMT 0.1%; total related substances NMT 1.3%, and Cu not more than lOppm. For citrulline manufactured from ornithine using copper complex to protect the alpha amino acid functions, the inventors have found that desired purification after citrulline is released from the copper complex can be achieved by activated carbon adsorption of contaminants and solvent/anti- solvent crystallization of the active pharmaceutical component.

[00019] The citrulline-containing aqueous solution remaining after removal of precipitated copper salts is neutralized to stabilize the citrulline against hydrolysis, to enhance adsorption of residual copper to activated carbon, and to facilitate solvent/anti-solvent precipitation of citrulline; pH is preferably adjusted to 5.9 ± 0.2, the isoelectric point of citrulline. The neutralized citrulline solution may be passed through a nano-filter to remove any bacteria and/or bacterial cell wall fragments that contaminate the solution. The nano-filtered solution may be held in a semi-sterile reservoir for staging purposes between the subsequent purification steps. The neutralized citrulline solution is treated with activated carbon, either by mixing with carbon dust or passing the solution through an activated carbon adsorber bed. The aqueous citrulline-containing effluent from the activated carbon is mixed with an anti-solvent to induce anti-solvent crystallization. Suitable anti solvents are miscible with water, including aliphatic alcohols, such as 2-propanol, ethanol or methanol, as well as acetone. A preferred antisolvent for citrulline is acetone, when mixed with approximately two volumes of water (e.g., 1 volume of water to 1.8 volumes of acetone). Acetone is preferably pre-cooled so that the resultant suspension is 0°C- 10°C. The cooled suspension may be collected in a reservoir or processed by filtration immediately to recover the citrulline precipitate.

Microbial control:

[00020] Because citrulline synthesis and purification occur in aqueous solution, there is increased risk of microbial contamination and endotoxin accumulation in the product. Washing the citrulline: copper precipitate, and addition of H2S to acid solution minimize any accumulation of microbes. From the exposure of the complex to FES until treatment with acetone the aqueous solutions of citrulline are preferably kept in sealed vessels to limit microbial contamination and growth. Enclosing the purification steps to minimize contact with the environment and use of sterile filters to capture potential microbial contamination allows the manufacturing to be performed in an ISO 8 cleanroom. Alternatively, the final purification steps can be carried out in a sterile GMP environment of the sort used for aseptic filling of sterile dosage products (e.g., ISO Class 5/6).

[00021] If examination of the solution prior to the anti-solvent precipitation shows the amounts of microbes or endotoxin levels exceed those aceptable for injectable therapeutic compositions (e.g., 50 EU/g API, more preferably 20 EU/g), the product may be subjected to nano-filtration to remove microbes and endotoxin, before being recovered by anti-solvent precipitation and drying. The citrulline and water molecules pass through the nano-filtration membrane, but the larger bacteria and bacterial cell wall fragments are retained by the filter.

Filter press

[00022] The reaction mixtures may be pumped through a filter press to collect / remove the

suspended solids. See the general picture in Figure 3, and the attached photograph in Figure 4. The press is composed of a series of plates 1 which are then hydraulically pressed together. The hydraulic pressure ensures that the system is sealed. The suspension is then pumped through a central tube 2 where it spreads-out across several chambers 3 between the plates. The walls of the plates have a filter sheet, which allows the filtrate to flow past and exit via an internal cavity 4.

[00023] The general advantage of a filter press is that it allows a high surface area for filtration.

This effect greatly accelerates the portion-wise collection and washing of the complex and API. This system may be used to collect the copper salts after exposure to hydrogen sulfide. In the latter case, the suspension is pumped from the reactor into the press, and the filtrate may then be passed through an in-line 5 pm filter to catch any residual particulate copper, then an in-line sterile 0.2 pm filter at the entry port of a semi-sterile container for holding.

The press may be used to collect:

• Crude citrulline copper complex

• The complex after the pH-driven re-precipitation

• Precipitated copper salts (where citrulline leaves as solution in the filtrate)

• Precipitated citrulline from anti-solvent precipitation prior to drying

Semi-sterile containers

[00024] A useful semi-sterile container is basically a closed vessel equipped with a stirrer and ports for the addition and removal of liquid, and a pH meter. The container should be sterilized (e.g., treated with isopropyl alcohol solution and rinsed with water) directly prior to use and not opened during use. A sterile, air filter attached to the lid allows air to flow into the container as the liquid is being pumped out. The pH adjustment may be performed in this container, before treatment with activated carbon. The container is not particularly suitable for the long-term storage of the solutions.

Activated carbon adsorber bed

[00025] The solution may be pumped from the semi sterile container through the activated carbon bed (a column packed with granulated activated carbon) pre-flushed with argon. The liquid is then returned to the semi-sterile container via an in-line 5 pm filter and the 0.2 pm sterile filter at the entry port. If the solution is pumped in a cyclic manner with the stirrer activated for not less than 6 hours, the sterile filter acts as a“microbial scrubber” continually collecting any microbes in the solution. The activated carbon primarily removes any organic impurities and will also remove any residual dissolved copper ions. The 5 pm filter catches any carbon particles which detach from the bed.

Sterile bags

[00026] After processing in the activated carbon adsorber bed, the solution may be passed into a single use sterile bag via another sterile filter. The solution may be stored longer in the bag than in the semi-sterile container. At this point, a test for the presence of microbes and/or bacterial endotoxins can be carried out. If endotoxins are observed, then the cut off (nano-filtration) membrane may be employed. If not, the citrulline is ready to be

recovered from the solution by anti-solvent precipitation. Collection of the solution in a sterile bag allows the citrulline solution to be processed batch-wise, where conveniently sized portions of citrulline are precipitated and recovered in the filter press.

Solvent/Anti-solvent Mixing

[00027] The aqueous citrulline solution is mixed with pre-cooled anti-solvent to precipitate the citrulline from solution. After mixing with anti-solvent, the threat posed by bacterial growth is not higher than that for other APIs. The addition of the organic solvent makes the resulting solution bacteriostatic at a minimum. This precipitation improves the purity of citrulline, reducing, in particular, the ornithine levels, and allows for the rapid extraction of citrulline from solution.

Final drying

[00028] The precipitate is dried to remove residual acetone and water. Drying may be carried-out in a conical dryer, firstly to drive off the acetone anti-solvent, then moisture and finally the water of crystallization. The conical dryer can also be used to homogenize the product. The final, dry product of anti-solvent precipitation may be stored, and ultimately dissolved in sterile aqueous diluent for therapeutic administration.

[00029] On dissolution in sterile aqueous media, citrulline prepared as described herein may be used to treat pulmonary hypertension (WO/2000/073322), bronchopulmonary dysplasia (WO/2009/099998), sickle cell crisis (WO/2018/157137), cardiac surgery patients (WO/2005/082042), cardiopulmonary bypass patients (WO/2018/125999), and vasospasm as a complication of subarachnoid hemorrhage (WO/2009/099999), by parenteral administration as described in these documents, incorporated herein by reference.

EXAMPLES

Example 1. Synthesis of citrulline from ornithine using urea.

[00030] L-Citrulline is synthesized from L-omithine and urea. A flow chart of the reaction is shown in Figure 1 A.

[00031] L-Citrulline is prepared synthetically starting from L-ornithine hydrochloride. Into a 120- L reactor containing approximately 50 liters of water, 10 kilograms of L-omithine hydrochloride is added and dissolved. The solution is neutralized with potassium hydroxide and then converted to its copper complex by the addition of 15kg copper sulfate (molar equivalent amount). The copper complex protects the 2-amino carboxylic acid functionality in the molecule while chemistry is performed on the terminal amino group. The L-ornithine copper complex is then exposed to an excess of urea at reflux, which promotes its conversion to the copper complex of L-citrulline. The resulting copper complex of L-citrulline then is precipitated and collected by filtration.

[00032] The isolated copper complex of L-citrulline is dried and testing is performed. The

appearance is verified, and an in-use performance test is done to determine suitability to proceed.

Example 2. Purification of citrulline from copper-citrulline complex.

[00033] L-Citrulline synthesized from L-ornithine and urea is purified by resin-based purification and recrystallization. A flow chart of the reaction is shown in Figure IB.

[00034] In a 120-L reactor, ~13 kilograms of the L-citrulline copper complex prepared in

Example 1 is added to a stirring solution of sodium sulfide (Na2S) in water

(approximately 8 kilograms Na2S in 50 liters of water), causing the precipitation of copper sulfide and the freeing of L-citrulline. The solution is filtered to remove the copper salts. The pH of the resulting aqueous solution containing the sodium salt of L- citrulline and residual sodium sulfide is lowered to 4 by the addition of an acidic ion exchange resin (such as Amberlite™). A constant stream of argon gas is passed through the solution to remove the residual sulfide as hydrogen disulfide. The pH of the solution is then raised to 5.9 ± 0.2 using sodium hydroxide to form isoelectric L-citrulline.

Activated carbon is then added to the reaction mixture to remove residual impurities, in particular residual copper ions. The solids (Amberlite™ and activated carbon) are then removed by filtration, and the filtrate is concentrated to approximately 50 liters (either by evaporation or reverse osmosis). L-citrulline is then precipitated from the aqueous solution by the addition of an equal part of acetone, and the mixture is cooled to near 0°C. The precipitate is collected by filtration and dried in a vacuum oven.

[00035] The non-sterile bulk powder is then reconstituted and processed for endotoxin reduction and sterile filtration steps followed by crystallization, drying and micronization in an aseptic environment. The sterile bulk powder is then used as the“raw material” for aseptic filling into glass vials to produce the finished drug product which may be reconstituted with a sterile diluent prior to use.

Example 3. Synthesis of citrulline from ornithine using cyanate

[00036] L-Citrulline was prepared synthetically starting from L-omithine hydrochloride. Into a reactor containing sodium hydroxide (11 kg) in water (170 kg), L-ornithine hydrochloride (44 kg) was added and dissolved. The temperature was maintained at no more than 40°C by active cooling. The ornithine was then converted to its copper complex by the addition of 0.5 molar equivalents of copper sulfate (33 kg) and stirring at ambient temperature for more than 15 minutes. The copper complex protects the 2-amino carboxylic acid functionality of the molecule while chemistry is performed on the terminal amino group. A molar excess of potassium cyanate (32 kg) is then added to the L-ornithine copper complex, and the solution is held at 55°C-65°C for 4.0-4.5 hours, which promotes its conversion to the copper complex of L-citrulline. The resulting copper complex of L-citrulline precipitates during the reaction, and it is collected by filtration.

Example 4. Purification of therapeutic grade citrulline.

[00037] The dry copper: citrulline complex produced in Example 3 is added to a reactor

containing water, which is stirred to resuspend the complex. Concentrated hydrogen chloride solution is added to convert the complex into a solution of copper (II) chloride and citrulline hydrochloride, while the temperature of the reactor is maintained at no more than 45°C by active cooling. Once the contents of the reactor are in solution, sodium hydroxide is added to raise the pH to 7-10, while the temperature is maintained at no more than 40°C. The copper complex of citrulline then precipitates. The precipitate is collected and washed with water until no blue coloration persists in the filtrate.

[00038] The washed precipitate is tested to determine the relative ornithine content. If ornithine is greater than 10 mole%, the precipitate is redissolved and resuspended as described above, until the ornithine content is lowered to not more than 10 mole%.

[00039] Once the precipitate achieves the desired ornithine content, it is resuspended in water in a stirred reactor, and hydrogen sulfide gas is introduced into the suspension to precipitate copper sulfide and dissolve citrulline. The solution is warmed to 30°C ± 2°C to ensure citrulline is fully solubilized, and precipitated copper salts are removed by filtration. The citrulline-containing filtrate is passed thorough micro- and sterile-filtrations and collected in a semi-sterile reactor.

[00040] Activated carbon is used to remove residual impurities, in particular an organic

component and residual copper ions. The pH of the resulting aqueous solution containing L-citrulline and residual copper is adjusted to 5.9 ± 0.2 with sodium hydroxide to form isoelectric citrulline solution. The isoelectric citrulline solution is treated with active carbon granules, preferably by passing the solution through an active carbon adsorber bed, and passed through micro and sterile filters after the active carbon treatment.

[00041] L-citrulline is then precipitated from the aqueous solution by the addition of acetone anti solvent, and the mixture is cooled to near 0°C. Addition of 1.5 to 2 volume equivalents of acetone produce dihydrate crystals of citrulline. The precipitate is collected by filtration. The crystals are dried in a vacuum in a conical dryer at temperature of no more than 45°C to remove acetone and water, resulting in an anhydrous crystalline solid. This solid citrulline corresponds to the orthorhombic d form anhydrous crystals reported by Allouchi, et al., 2014 ( Cryst . Growth Des., 14: 1279-1286).

[00042] Either the dihydrate crystals or the anhydrous crystals may be used therapeutically. The solid or an aqueous solution/suspension may be administered enterally, or the solid may be redissolved for parenteral administration. To produce a final therapeutic product, the non-sterile bulk powder was reconstituted and underwent endotoxin reduction and sterile filtration steps followed by crystallization, drying and micronization in an aseptic environment. The sterile bulk powder was then used as the“raw material” for aseptic filling into glass vials to produce the finished drug product which was reconstituted with a sterile diluent prior to use.

References

  1. ^ “Citrulline – Compound Summary”PubChem Compound. USA: National Center for Biotechnology Information. 16 September 2004. Identification. Retrieved 1 May 2012.
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  4. ^ Fearon, William Robert (1939). “The Carbamido Diacetyl Reaction: A Test For Citrulline”Biochemical Journal33 (6): 902–907. doi:10.1042/bj0330902PMC 1264464PMID 16746990.
  5. ^ “Nos2 – Nitric Oxide Synthase”Uniprot.org. Uniprot Consortium. Retrieved 10 February 2015.
  6. ^ Cox M, Lehninger AL, Nelson DR (2000). Lehninger principles of biochemistry (3rd ed.). New York: Worth Publishers. p. 449ISBN 978-1-57259-153-0. Retrieved 13 March 2020.
  7. ^ Rogers, G. E.; Rothnagel, J. A. (1983). “A sensitive assay for the enzyme activity in hair follicles and epidermis that catalyses the peptidyl-arginine-citrulline post-translational modification”. Current Problems in Dermatology11: 171–184. doi:10.1159/000408673ISBN 978-3-8055-3752-0PMID 6653155.
  8. ^ DeLegge, Mark H. (2019-01-01), Corrigan, Mandy L.; Roberts, Kristen; Steiger, Ezra (eds.), “Chapter 7 – Enteral Access and Enteral Nutrition in Patients With Short Bowel Syndrome”Adult Short Bowel Syndrome, Academic Press, pp. 81–96, doi:10.1016/b978-0-12-814330-8.00007-xISBN 978-0-12-814330-8, retrieved 2020-11-10
  9. ^ Fragkos, Konstantinos C.; Forbes, Alastair (2017-10-12). “Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis”United European Gastroenterology Journal6 (2): 181–191. doi:10.1177/2050640617737632PMC 5833233PMID 29511548.
  10. ^ Crenn, P.; et al. (2000). “Post-absorptive plasma citrulline concentration is a marker of intestinal failure in short bowel syndrome patients”. Gastroenterology119 (6): 1496–505. doi:10.1053/gast.2000.20227PMID 11
Names
IUPAC name2-Amino-5-(carbamoylamino)pentanoic acid[1]
Identifiers
CAS Number627-77-0 [SciFinder]13594-51-9 R [SciFinder]372-75-8 S 
3D model (JSmol)Interactive image
3DMetB01217
Beilstein Reference1725417, 1725415 R, 1725416 S
ChEBICHEBI:18211 
ChEMBLChEMBL444814 
ChemSpider810 553200 R 9367 S 
DrugBankDB00155 
ECHA InfoCard100.006.145 
EC Number211-012-2
Gmelin Reference774677 S
IUPHAR/BPS722
KEGGD07706 
MeSHCitrulline
PubChem CID833637599 R9750 S
UNII29VT07BGDA 
CompTox Dashboard (EPA)DTXSID80883373 
InChI[show]
SMILES[show]
Properties
Chemical formulaC6H13N3O3
Molar mass175.188 g·mol−1
AppearanceWhite crystals
OdorOdourless
log P−1.373
Acidity (pKa)2.508
Basicity (pKb)11.489
Thermochemistry
Heat capacity (C)232.80 J K−1 mol−1
Std molar
entropy
 (So298)
254.4 J K−1 mol−1
Related compounds
Related alkanoic acidsN-Acetylaspartic acidAceglutamideN-Acetylglutamic acidPivagabine
Related compoundsBromisovalCarbromal
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒ verify (what is  ?)
Infobox references

///////CITRULLINE, L-Citrulline, 瓜氨酸  ,

Melatonin


Melatonin.svg
ChemSpider 2D Image | Melatonin | C13H16N2O2

Melatonin

メラトニン
FormulaC13H16N2O2
CAS73-31-473-31-4
Mol weight232.2783

APPROVED, Melatobel, JAPAN 2020/3/25

200-659-6[EINECS]

200-797-7[EINECS]

205542[Beilstein]

73-31-4[RN]

Acetamide, N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-Acetamide

MelatoninCAS Registry Number: 73-31-4CAS Name:N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide

Additional Names:N-acetyl-5-methoxytryptamine

Trademarks: Regulin (Young)

Molecular Formula: C13H16N2O2Molecular Weight: 232.28Percent Composition: C 67.22%, H 6.94%, N 12.06%, O 13.78%

Literature References: A hormone of the pineal gland, also produced by extra-pineal tissues, that lightens skin color in amphibians by reversing the darkening effect of MSH, q.v. Melatonin has been postulated as the mediator of photic-induced antigonadotrophic activity in photoperiodic mammals and has also been shown to be involved in thermoregulation in some ectotherms and in affecting locomotor activity rhythms in sparrows. Isoln from the pineal glands of beef cattle: Lerner et al.,J. Am. Chem. Soc.80, 2587 (1958); Wurtman et al.,Science141, 277 (1963). Structure: Lerner et al.,J. Am. Chem. Soc.81, 6084 (1959). Crystal and molecular structure: A. Wakahara, Chem. Lett.1972, 1139. Synthesis from 5-methoxyindole as starting material by two different routes: Szmuszkovicz et al.,J. Org. Chem.25, 857 (1960). Biochemical role of melatonin: Chem. Eng. News45, 40 (May 1, 1967). Pharmacological studies: Barchas et al.,Nature214, 919 (1967). Identification of antigonadal action sites in mouse brain: J. D. Glass, G. R. Lynch, Science214, 821 (1981). Binding studies in human hypothalamus: S. M. Reppert et al.,Science242, 78 (1988). Efficacy in control of estrus in red deer: G. W. Asher, Anim. Reprod. Sci.22, 145 (1990). Reviews: M. K. Vaughn, Int. J. Rev. Physiol.24, 41-95 (1981); D. C.Klein et al.,Life Sci.28, 1975-1986 (1981). Book: Advan. Biosci.vol. 29, N. Birau, W. Schlott, Eds. (Pergamon Press, New York, 1981) 420 pp. Review of etiological role in clinical disease: A. Miles, D. Philbrick, Crit. Rev. Clin. Lab. Sci.25, 231-253 (1987); in psychiatric disorders: eidem,Biol. Psychiatry23, 405-425 (1988).Properties: Pale yellow leaflets from benzene, mp 116-118°. uv max: 223, 278 nm (e 27550, 6300).Melting point: mp 116-118°Absorption maximum: uv max: 223, 278 nm (e 27550, 6300)Therap-Cat-Vet: Control of estrus.

Melatonin is a hormone primarily released by the pineal gland that regulates the sleep–wake cycle.[3][4] As a dietary supplement, it is often used for the short-term treatment of insomnia, such as from jet lag or shift work, and is typically taken by mouth.[5][6][7] Evidence of its benefit for this use, however, is not strong.[8] A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.[6] The melatonin receptor agonist medication ramelteon may work as well as melatonin supplements,[6] at greater cost but with different adverse effects, for some sleep conditions.[9]

Side effects from melatonin supplements are minimal at low doses for short durations.[3][10] They may include somnolence (sleepiness), headaches, nauseadiarrhea, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, hypertension, abdominal pain, heartburnmouth ulcers, dry mouth, hyperbilirubinaemiadermatitisnight sweatspruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria (sugar in the urine), proteinuria (protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover.[11][12][10][13][14] Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.[7][14]

In animals (including humans), melatonin is involved in synchronizing the circadian rhythm, including sleep–wake timing, blood pressure regulation, and seasonal reproduction.[15] Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant.[16][17][18] In plants, it functions to defend against oxidative stress.[19] It is also present in various foods.[10]

Melatonin was discovered in 1958.[3] It is sold over the counter in Canada and the United States;[10][13] in the United Kingdom, it is a prescription-only medication.[7] It is not approved by the US Food and Drug Administration (FDA) for any medical use.[10] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.[20][11] In the European Union, it is indicated for the treatment of insomnia in children and adolescents.[12] It was approved for medical use in the European Union in 2007.[11]

SYN

https://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html

Synthesis of Melatonin

SYNTHESIS

Chemical Synthesis of Melatonin
  The methods for the chemical synthesis of melatonin are generally not so complicated and do not involve more than three steps of conversion. Three synthesis reactions of melatonin from primary literatures are shown below;

Reaction 1

 In 1958 melatonin was first isolated and characterised by A.B.Lerner. It was know as one of a substituted 5-hydroxyindole derivative in the pineal gland that could lighten pigment cells. It had not been know to exist in biological tissue although it had been isolated as a urinary excretion product in rats after administration of 5-hydroxytryptamine.
 Melatonin or N-acetyl-5-methoxytryptamine (40 mg) was prepared by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. Then the product was acetylated with 4 ml of both glacial acetic acid and acetic anhydride at 100 oC for 1 minute. Purification was achieved by countercerrent distribution and silicic acid chromatography.

Reaction 2

 5-Methoxytryptamine  hydrochloride (1g, 4.75 mmole) was dissolved in pyridine (10 ml) and acetic anhydride (10 ml) and kept overnight at 20 oC. The solution was poured onto iced, neutralised with dilute hydrochloric acid and extracted with chloroform (2×25 ml). The combined extracts were washed with water, dried in MgSO4 and evaporated to afford a liquid of N,N diacetyltryptamine derivative. The liquid was then poured into water (50 ml) and extracted with chlroform (2×25 ml). The combined organic layers were washed with water (25 ml), dried in MgSO4 and evaporated to dryness. The residual solid crystallised from benzene to afford melatonin 819 mg, 80% yield.

Reaction 3

The more reactive indoles (1a-1d) were alkylated at the 3 position by reaction with nitroethene generated in situ by thermolysis of nitroethyl acetate. The nitroethyl acetate used for this purpose was prepared by acetylation of nitroethanol with acetic anhydride using NaOAc as a catalyst. These conditions constitute a substantial improvement of the overal yield of the reation. Reduction of the nitroethylated indoles (2a-d) by hydrogenation over PtO2, followed by acetylation fo the resluting tryptamines with acetic anhydride-pyridine completed the synthesis of melatonin and its derivatives (4a-d).

Biological Synthesis and Metabolism of Melatonin

                    The biosynthesis of melatonin (Fig.1) is initiated by the uptake of the essential amino acid tryptophan into pineal parenchymal cells. Tryptophan is  the least abundant of essential amino acids in normal diets. It is converted to another amino acid, 5-hydroxytryptophan, through the action of the enzyme tryptopahn hydroxylase and then to 5-hydroxytryptamine (serotonin) by the enzyme aromatic amino acid decarboxylase. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm remaining at a maximum level during the daylight hours and falling by more than 80% soon after the onset of darkness as the serotonin is converted to melatonin, 5-hydroxytryptophol and other methoxyindoles. Serotonin’s conversion to melatonin involves two enzymes that are characteristic of the pineal : SNAT (serotonin-N-acetyltransferase) which converts the serotonin to N-acetylserotonin, and HIOMT (hydroxyindole-O-methyltrasferase) which trasfers a methyl group from S-adenosylmethionine to the 5-hydroxyl of the N-acetylserotonin. The activities of both enzymes rise soon after the onset of darkness because of the enhanced release of norepinephrine from sympathetic neurons terminating on the pineal parenchymal cells.
                        Another portion of the serotonin liberated from pineal cells after the onset of darkness is deaminated by the enzyme monoamine oxidase (MAO) and then either oxidized to form 5-hydroxyindole acetic acid or reduced to form 5-hydroxytryptophol (Fig.1). Both  of these compounds are also substrates for HIOMT and can thus be converted in the pineal to 5-methoxyindole acetic acid 5-methoxytryptophol (Fig.1). The level of this latter indole, like that of melatonin, rises markedly in the pineal with the onset of darkness. Since 5-methoxytryptophol synthesis does not require the acetylation of serotonin, the nocturnal increase in pineal SNAT activity cannot be the trigger that causes pineal methoxyindole levels to rise. More likely, a single unexplained process- the intraparenchymal release of stored pineal serotonin, which then becomes accessible to both SNAT and MAO. This process ultimately controls the rates at which all three major pineal methoxyindoles are synthesized and generates the nocturnal increases in pineal melatonin and 5-methoxytryptophol. The proportion of available serotonin acetylated at any particular time of day or night depends on the relative activities of pineal SNAT and MAO at that time. The rates of methylation of all three 5-hydroxyindoles formed from pinela serotonin depends on HIOMT activity.Fig.1 Biosynthesis of pineal methoxyindoles from serotonin

Serotonin may be either acetylated to form N-acetylserotonin through the action of the enzyme serotonin-N-acetyltransferase (SNAT), or oxidatively deaminated by monoamine oxidase (MAO) to yield an unstable aldehyde. This compound is then either oxidized to 5-hydroxyindole acetic acid by the enzyme aldehyde dehydrogenase (ADH), or reduced to from 5-hydroxytryptophol by aldehyde reductase (AR). Each of these 5-hydroxyindole derivatives of serotonin is a substrate for hydroxyindole-O-methyltrasferase (HIMOT). The enzymatic trasfer of a methyl group from S-adenosylmethionine to these hydroxyindoles yields melatonin (5-hydroxy-N-acetyltryptamine), 5-methoxyindole acetic acid and 5-methoxytryptophol respectively.  Pineal serotonin is synthesized from the essential amino acid tryptophan by 5-hydroxylation folloed by decarboxylation. The first step in ths enzymic sequence is catalysed by tryptophan hydroxylase. The second step is catalysed by aromatic L-amino acid decarboxylase.

Medical uses

In the European Union it is indicated for the treatment of insomnia in children and adolescents aged 2–18 with autism spectrum disorder (ASD) and / or Smith–Magenis syndrome, where sleep hygiene measures have been insufficient[12] and for monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep in people who are aged 55 or over.[11]

Sleep disorders

Positions on the benefits of melatonin for insomnia are mixed.[8] An Agency for Healthcare Research and Quality (AHRQ) review from 2015 stated that evidence of benefit in the general population was unclear.[8] A review from 2017, found a modest effect on time until onset of sleep.[3] Another review from 2017 put this decrease at six minutes to sleep onset but found no difference in total sleep time.[6] Melatonin may also be useful in delayed sleep phase syndrome.[3] Melatonin appears to work as well as ramelteon but costs less.[6]

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson’s disease and dementia with Lewy bodies.[21][22][23] In Europe it is used for short-term treatment of insomnia in people who are 55 years old or older.[24] It is deemed to be a first line agent in this group.[6]

Melatonin reduces the time until onset of sleep and increases sleep duration in children with neurodevelopmental disorders.[25]

Dementia

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer’s disease.[26] A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer’s it has little to no effect.[27] Melatonin may, however, help with sundowning.[28]

Jet lag and shift work

Melatonin is known to reduce jet lag, especially in eastward travel. If the time it is taken is not correct, however, it can instead delay adaption.[29]

Melatonin appears to have limited use against the sleep problems of people who work shift work.[30] Tentative evidence suggests that it increases the length of time people are able to sleep.[30]

Adverse effects

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses.[clarification needed] Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo.[31][32] Prolonged-release melatonin is safe with long-term use of up to 12 months.[33] Although not recommended for long term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over the counter sleep aids if a sleeping medication must be used for an extended period of time. Low-doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect, but instead appear to cause drowsiness for a longer period of time.[34]

Melatonin can cause nausea, next-day grogginess, and irritability.[35] In the elderly, it can cause reduced blood flow and hypothermia.[36][needs update] In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[37][38][needs update]

Melatonin can lower follicle-stimulating hormone levels.[39] Melatonin’s effects on human reproduction remain unclear.[40]

In those taking warfarin, some evidence suggests there may exist a potentiating drug interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.[41]

Functions

When eyes receive light from the sun, the pineal gland’s production of melatonin is inhibited and the hormones produced keep the human awake. When the eyes do not receive light, melatonin is produced in the pineal gland and the human becomes tired.

Circadian rhythm

In animals, melatonin plays an important role in the regulation of sleep–wake cycles.[42] Human infants’ melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.[43] Human melatonin production decreases as a person ages.[44] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.[45]

Antioxidant

Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.[46] In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH, O2, and NO.[47][48] In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.[48] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.[49] Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutaseglutathione peroxidaseglutathione reductase, and catalase.[50][51]

Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin.[52][53][54] Due to its capacity for free radical scavenging, indirect effects on the expression of antioxidant enzymes, and its significant concentrations within mitochondria, a number of authors have indicated that melatonin has an important physiological function as a mitochondrial antioxidant.[50][52][53][54][55]

The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals.[51][55] Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).[51][55]

Immune system

While it is known that melatonin interacts with the immune system,[56][57] the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,[58] and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[59] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

Biosynthesis

Overview of melatonin biosynthesis

In animals, biosynthesis of melatonin occurs through hydroxylationdecarboxylationacetylation and a methylation starting with L-tryptophan.[60] L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase to produce 5-hydroxytryptophan. This intermediate (5-HTP) is decarboxylated by pyridoxal phosphate and 5-hydroxytryptophan decarboxylase to produce serotonin.

Serotonin is itself an important neurotransmitter, but is also converted into N-acetylserotonin by serotonin N-acetyltransferase with acetyl-CoA.[61] Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.[61]

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the synthesising reactions are similar, but with slight variations in the last two enzymes.[62][63]

It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.[64]

Mechanism

Mechanism of melatonin biosynthesis

In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the THB to O2 could produce a superoxide which could recombine with the THB radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O2 could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan.[65]

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.[66] PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO2. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.[67]

It has been proposed that histidine residue His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetylserotonin.[68]

N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.[67][69]

Regulation

In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine.[70] Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis.[71] Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.

Blue light, principally around 460–480 nm, suppresses melatonin biosynthesis,[72] proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light.[citation needed] The incandescent light bulb widely used in the 20th century produced relatively little blue light.[73] Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.[74] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.[75]

Pharmacology

Pharmacodynamics

In humans, melatonin is a full agonist of melatonin receptor 1 (picomolar binding affinity) and melatonin receptor 2 (nanomolar binding affinity), both of which belong to the class of G-protein coupled receptors (GPCRs).[51][76] Melatonin receptors 1 and 2 are both Gi/o-coupled GPCRs, although melatonin receptor 1 is also Gq-coupled.[51] Melatonin also acts as a high-capacity free radical scavenger within mitochondria which also promotes the expression of antioxidant enzymes such as superoxide dismutaseglutathione peroxidaseglutathione reductase, and catalase via signal transduction through melatonin receptors.[50][51][52][53][54][55]

Pharmacokinetics

 

When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg[77]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.[78] Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated.[61] Melatonin has a half life of 35–50 minutes.[79] In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.[5] The bioavalibility of melatonin is between 10 and 50%.[61]

Melatonin is metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. 5% of melatonin is excreted in the urine as the unchanged drug.[61]

Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).[51][55]

The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.[51][55]

For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.[80]

History

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.[81][82] As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.[83][84]

In 1958, dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.[85] In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.[86]

The discovery that melatonin is an antioxidant was made in 1993.[87] The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.[88] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[89] The New England Journal of Medicine editorialized in 2000: “With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear.”[90]

It was approved for medical use in the European Union in 2007.[11]

Other animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[91] located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes[92][93] rather than the melatonin signal (as was once postulated). Known as “the hormone of darkness”, the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.

Many animals use the variation in duration of melatonin production each day as a seasonal clock.[94] In animals including humans,[95] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals.[95] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[96] and hamsters.[97] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering its levels.

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors.[98] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.[98]

Plants

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions.[19][99] Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.[63][100] Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.[19] In some common foods and beverages, including coffee[19] and walnuts,[101] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.[63][102][103]

Occurrence

Dietary supplement

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.[5] FDA regulations applying to medications are not applicable to melatonin,[15] though the FDA has found false claims that it cures cancer.[104] As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin.[29] In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[105]

Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,[106] bananas and grapes, rice and cereals, herbs, plums,[107] olive oil, wine[108] and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[109] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.[110]

Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[111] The FDA considered whether these food products could continue to be sold with the label “dietary supplements”. On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive.[112] A different company selling a melatonin-containing beverage received a warning letter in 2015.[113]

Commercial availability

Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication. It is available in doses from less than half a milligram to 5 mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.[medical citation needed]

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.[15][114]

Melatonin is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US$400 million during 2017.[115]

Research

A bottle of melatonin tablets. Melatonin is available in timed-release and in liquid forms.

Various uses and effects of melatonin have been studied. A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.[116]

Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.[117][118]

Cancer

A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.[119] A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.[120]

Protection from radiation

Both animal[121] and human[122][123][124] studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure.[125] Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known, major side effects.[126]

Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.[127]

Secondary dysmenorrhoea

A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.[128]

Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.[129]

Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.[130]

Psychiatry

Melatonin might improve sleep in people with autism.[131] Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin.[132][133] Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings.[132][134][135] However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed.

While the packaging of melatonin often warns against use in people under 18 years of age, studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD, including children. However, larger and longer studies are needed to establish long-term safety and optimal dosing.[136]

Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.[137]

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.[138] Some evidence supports an antidepressant effect.[139]

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External links

"Melatonin"Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Pronunciation/ˌmɛləˈtoʊnɪn/ (listen)
Trade namesCircadin, Slenyto, others[1]
Other namesN-acetyl-5-methoxy tryptamine[2]
AHFS/Drugs.comConsumer Drug Information
License dataEU EMAby INNUS DailyMedMelatonin
Routes of
administration
By mouthsublingualtransdermal
ATC codeN05CH01 (WHO)
Physiological data
Source tissuespineal gland
Target tissueswide spread, including brainretina, and circulatory system
Receptorsmelatonin receptor
PrecursorN-acetylserotonin
MetabolismLiver via CYP1A2 mediated 6-hydroxylation
Legal status
Legal statusAU: OTC / Rx-onlyCAOTCUK: POM (Prescription only)EU: Rx-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability30–50%
MetabolismLiver via CYP1A2 mediated 6-hydroxylation
Metabolites6-hydroxymelatonin, N-acetyl-5lhydroxytryptamine, 5-methoxytryptamine
Elimination half-life30–50 minutes[3]
ExcretionKidney
Identifiers
IUPAC name[show]
CAS Number73-31-4 
PubChem CID896
IUPHAR/BPS224
DrugBankDB01065 
ChemSpider872 
UNIIJL5DK93RCL
KEGGD08170 
ChEBICHEBI:16796 
ChEMBLChEMBL45 
CompTox Dashboard (EPA)DTXSID1022421 
ECHA InfoCard100.000.725 
Chemical and physical data
FormulaC13H16N2O2
Molar mass232.283 g·mol−1
3D model (JSmol)Interactive image
Melting point117 °C (243 °F)
SMILES[hide]COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
InChI[hide]InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16) Key:DRLFMBDRBRZALE-UHFFFAOYSA-N 

//////////Melatonin, Melatobel, メラトニン , JAPAN 2020, 2020 APPROVALS

RALOXIFENE


Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481(free base), LY-156758, Optruma, Loxifen, EvistaTitle: RaloxifeneCAS Registry Number: 84449-90-1CAS Name: [6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneAdditional Names: keoxifeneManufacturers’ Codes: LY-139481Molecular Formula: C28H27NO4SMolecular Weight: 473.58Percent Composition: C 71.01%, H 5.75%, N 2.96%, O 13.51%, S 6.77%Literature References: Nonsteroidal, selective estrogen receptor modulator (SERM). Prepn: C. D. Jones, EP62503idem,US4418068 (1982, 1983 both to Lilly); idemet al.,J. Med. Chem.27, 1057 (1984). Review of pharmacology and toxicology: J. Buelke-Sam et al.,Reprod. Toxicol.12, 217-221 (1998); of clinical pharmacology and pharmacokinetics: D. Hochner-Celnikier, Eur. J. Obstet. Gynecol. Reprod. Biol.85, 23-29 (1999); of clinical efficacy in osteoporosis: D. Agnusdei, ibid. 43-46. Clinical effect on risk of breast cancer: S. R. Cummings et al.,J. Am. Med. Assoc.281, 2189 (1999); on reduction of fracture risk: B. Ettinger et al.,ibid.282, 637 (1999).Properties: Crystals from acetone, mp 143-147°. uv max (ethanol): 290 nm (e 34000).Melting point: mp 143-147°Absorption maximum: uv max (ethanol): 290 nm (e 34000) 
Derivative Type: HydrochlorideCAS Registry Number: 82640-04-8Manufacturers’ Codes: LY-156758Trademarks: Evista (Lilly)Molecular Formula: C28H27NO4S.HClMolecular Weight: 510.04Percent Composition: C 65.94%, H 5.53%, N 2.75%, O 12.55%, S 6.29%, Cl 6.95%Properties: Crystals from methanol/water, mp 258°. uv max (ethanol): 286 nm (e 32800).Melting point: mp 258°Absorption maximum: uv max (ethanol): 286 nm (e 32800) 
Therap-Cat: Antiosteoporotic.Keywords: Antiosteoporotic; Selective Estrogen Receptor Modulator (SERM).

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids.[4] For osteoporosis it is less preferred than bisphosphonates.[4] It is also used to reduce the risk of breast cancer in those at high risk.[4] It is taken by mouth.[4]

Common side effects include hot flashesleg crampsswelling, and joint pain.[4] Severe side effects may include blood clots and stroke.[4] Use during pregnancy may harm the baby.[4] The medication may worsen menstrual symptoms.[5] Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonistantagonist of the estrogen receptor (ER).[4] It has estrogenic effects in bone and antiestrogenic effects in the breasts and uterus.[4]

Raloxifene was approved for medical use in the United States in 1997.[4] It is available as a generic medication.[4][6] A month supply in the United Kingdom costs the NHS about 3.50 £ as of 2019.[6] In the United States the wholesale cost of this amount is about $16.[7] In 2017, it was the 330th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[8

Medical uses

Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women.[9] It is used at a dosage of 60 mg/day for both the prevention and treatment of osteoporosis.[10] In the case of either osteoporosis prevention or treatment, supplemental calcium and vitamin D should be added to the diet if daily intake is inadequate.[11]

Raloxifene is used to reduce the risk of breast cancer in postmenopausal women. It is used at a dosage of 60 mg/day for this indication.[10] In the Multiple Outcomes of Raloxifene (MORE) clinical trial, raloxifene decreased the risk of all types of breast cancer by 62%, of invasive breast cancer by 72%, and of invasive estrogen receptor-positive breast cancer by 84%.[12] Conversely, it does not reduce the risk of estrogen receptor-negative breast cancer.[12] There were no obvious differences in effectiveness of raloxifene in the MORE trial for prevention of breast cancer at a dosage of 60 mg/m2/day relative to 120 mg/m2/day.[12] In the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was 78% as effective as 20 mg/day tamoxifen in preventing non-invasive breast cancer.[13] Women with undetectable levels of estradiol (<2.7 pg/mL) have a naturally low risk of breast cancer and, in contrast to women with detectable levels of estradiol, do not experience significant benefit from raloxifene in terms of reduction of breast cancer risk.[12]

Contraindications

Raloxifene is contraindicated in lactating women or women who are or who may become pregnant.[14] It also may be of concern to women with active or past history of venous thromboembolic events, including deep vein thrombosispulmonary embolism, and retinal vein thrombosis.[15]

Side effects

Common side effects of raloxifene include hot flashes (25–28% vs. 18–21% for placebo),[12] vaginal dryness, and leg cramps (generally mild; 5.5% vs. 1.9% for placebo).[14][1][16] Raloxifene does not cause breast tendernessendometrial hyperplasiamenstrual bleeding, or endometrial cancer.[17] It does not appear to affect cognition or memory.[15][12] Raloxifene is a teratogen; i.e., it can cause developmental abnormalities such as birth defects.

Raloxifene may infrequently cause serious blood clots to form in the legslungs, or eyes.[1] Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, and vision changes. Black box warnings were added to the label of raloxifene in 2007 warning of increased risk of death due to stroke for postmenopausal women with documented coronary heart disease or at increased risk for major coronary events, as well as increased risk for deep vein thrombosis and pulmonary embolism.[14] The risk of venous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RR = 3.1).[18][12] Raloxifene has a lower risk of thromboembolism than tamoxifen.[13] In the MORE trial, raloxifene caused a 40% decrease in risk of cardiovascular events in women who were at increased risk for coronary artery disease, although there was no decrease in cardiovascular events for the group as a whole.[12]

A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer, significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[19]

A recent human case report in July 2016 suggests that raloxifene may in fact, at some point, also stimulate breast cancer growth leading to a reduction of advanced breast cancer disease upon the withdrawal of the drug.[20]

Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RR = 0.8).[1][18][13]

Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.[16][21]

Overdose

Raloxifene has been studied in clinical trials across a dosage range of 30 to 600 mg/day, and was well-tolerated at all dosages.[16]

Pharmacology

Pharmacodynamics

Mechanism of action

Raloxifene is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist and antagonist of the estrogen receptor (ER) in different tissues.[4] It has estrogenic activity in some tissues, such as bone and the liver, and antiestrogenic activity in other tissues, such as the breasts and uterus.[4] Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol.[16] Relative to estradiol, raloxifene has been reported to possess about 8 to 34% of the affinity for the ERα and 0.5 to 76% of the affinity for the ERβ.[22][23] Raloxifene acts as a partial agonist of the ERα and as a pure antagonist of the ERβ.[24][25] In contrast to the classical ERs, raloxifene is an agonist of the G protein-coupled estrogen receptor (GPER) (EC50 = 10–100 nM), a membrane estrogen receptor.[26][27]

Clinical effects

Raloxifene has antiestrogenic effects in the mammary glands in preclinical studies.[16] In accordance, raloxifene reduces breast density in postmenopausal women, a known risk factor for breast cancer.[28] It does not stimulate the uterus in postmenopausal women, and results in no increase in risk of endometrial thickening, vaginal bleedingendometrial hyperplasia, or endometrial cancer.[29][16][21] At the same time, raloxifene has minimal antiestrogenic effect in the uterus in premenopausal women.[29] This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals.[29]

In premenopausal women, raloxifene increases levels of follicle-stimulating hormone (FSH) and estradiol.[12] Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropinsluteinizing hormone (LH) and FSH, while not affecting levels of estradiol.[12][29] Raloxifene also decreases prolactin levels in postmenopausal women.[29] In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels.[30][31][32][33] Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene.[30]

Raloxifene has estrogenic effects on liver protein synthesis.[12] It increases SHBG levels in both pre- and postmenopausal women as well as in men.[12][30] The medication decreases levels of total and low-density lipoprotein (LDL) cholesterolC-reactive proteinapolipoprotein B, and homocysteine.[12][29] Conversely, it has little effect on levels of triglycerides and high-density lipoprotein (HDL).[12] Raloxifene has been shown to inhibit the oxidation of LDL cholesterol in vitro.[16] The medication has been found to decrease insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men.[31] It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women.[12] Due to activation of estrogen receptors in the liver, raloxifene has procoagulatory effects, such as decreasing levels of fibrinogen and influencing levels of other coagulation factors.[12][29][16] For these reasons, raloxifene increases the risk of thrombosis.[12][29]

Raloxifene increases bone mineral density in postmenopausal women but decreases it in premenopausal women.[12] In the MORE trial, the risk of vertebral fractures was decreased by 30%, and bone mineral density was increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg).[18] It has been found to possess estrogenic effects in adipose tissue in postmenopausal women, promoting a shift from an android fat distribution to a gynoid fat distribution.[34][35] The medication has been found to increase levels of leptin, an adipokine.[12]


AbsorptionPharmacokinetics

The absorption of raloxifene is approximately 60%.[1][2] However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%.[1][2] Raloxifene is rapidly absorbed from the intestines upon oral administration.[1] Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose.[1][2]

Distribution

Raloxifene is widely distributed throughout the body.[1] There is extensive distribution of raloxifene into the liverserumlungs, and kidneys.[1] The volume of distribution of raloxifene with a single 30 to 150 mg oral dose is approximately 2348 L.[1][36] Both raloxifene and its metabolites show high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin.[1][2]

Metabolism

Raloxifene is metabolized in the liver and undergoes enterohepatic recycling.[2] It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system.[1][2] Less than 1% of radiolabeled material in plasma comprises unconjugated raloxifene.[2] The metabolites of raloxifene include several glucuronides.[1] The elimination half-life of raloxifene after a single dose is 27.7 hours (1.2 days), whereas its half-life at steady state at a dosage of 60 mg/day is 15.8 to 86.6 hours (0.7–3.6 days), with an average of 32.5 hours (1.4 days).[1][2] The extended half-life of raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding.[1] Raloxifene and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of raloxifene with oral administration.[2] The medication is deconjugated into its active form in a variety of tissues, including liver, lungs, spleenboneuterus, and kidneys.[1]

Elimination

Raloxifene is mainly excreted in bile and is eliminated in feces.[1][2] Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.[2]

Chemistry

See also: List of selective estrogen receptor modulators and Benzothiophene

Raloxifene hydrochloride has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene hydrochloride is an off-white to pale-yellow solid that is slightly soluble in water.[14]

Raloxifene is a benzothiophene derivative and is structurally distinct from the triphenylethylene SERMs like tamoxifenclomifene, and toremifene.[37] It is the only benzothiophene SERM to have been marketed.[37] A benzothiophene SERM that was not marketed is arzoxifene (LY-353381).[38] Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.[38]

History

Raloxifene was approved in the United States for the prevention of postmenopausal osteoporosis in 1997, the treatment of postmenopausal osteoporosis in 1999, and to prevent or reduce the risk of breast cancer in certain postmenopausal women in 2007.[39][40][41][42] It received orphan designation in 2005.[39]

Society and culture

A bottle of raloxifene.

Names

Raloxifene is the generic name of the drug and its INN and BAN, while raloxifène is its DCF and raloxifene hydrochloride is its USANBANM, and JAN.[43][44][45][46] It has also been known by the name keoxifene.[43][44][46]

Raloxifene is sold mainly under the brand name Evista and to a lesser extent the brand name Optruma.[46][44] It is also sold under a variety of other brand names in various countries.[46]

Availability

Raloxifene is available widely throughout the world, including in the United StatesCanada, the United KingdomIreland, elsewhere throughout EuropeAustraliaNew ZealandSouth AfricaLatin AmericaSouthernEastern, and Southeastern Asia, and elsewhere in the world such as in Israel and Egypt.[46][44]

Raloxifene is provided in the form of 60 mg oral tablets.[10]

Controversy

An editorial in Lancet Oncology criticized the way that research about the medication for breast cancer prevention was released.[47]

Research

Clinical studies of raloxifene for metastatic breast cancer in women have been conducted but found little effectiveness at 60 mg/day in those previously treated with tamoxifen, though modest effectiveness has been observed at higher doses.[12][48] In contrast to tamoxifen, raloxifene is not approved for the treatment of breast cancer.[49]

Raloxifene has been studied in men for a variety of uses, such as for treatment of schizophreniaprostate cancer, and osteoporosis.[50][51][52][53][54][33][32][55][56][57][58] It has been studied in combination with castration and bicalutamide, a nonsteroidal antiandrogen, for the treatment of prostate cancer.[58][55]

Raloxifene has been studied as an adjunct in the treatment of schizophrenia in postmenopausal women.[59] A 2017 meta-analysis concluded that it was safe and effective for this indication, although further studies with larger sample sizes are needed for confirmation.[59] It may be effective in women with less severe symptoms.[59]

A tissue-selective estrogen-receptor complex (TSEC) of estradiol and raloxifene has been studied in postmenopausal women.[60]

Raloxifene (60 mg/day) was reported to be effective in the treatment of pubertal gynecomastia in adolescent boys in a small retrospective chart review.[61][62][63] Other SERMs are also known to be effective in the treatment of gynecomastia.[64]

Raloxifene has been reported to augment the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs).[65]

June 18th 2020, Exscalate4CoV, the private-public consortium supported by the EU’s Horizon 2020 programme for research and innovation, led by Dompé farmaceutici and currently representing 18 partners (including Fraunhofer InstituteCINECAChelonia Applied ScienceSwiss Institute of Bioinformatics and others) has requested access to clinical trials for the use of Raloxifene in Covid 19 patients. Raloxifene, already proven effective against Mers and Sars in precliinical tests, has been indicated as effective against Sars-Cov2 by the “in-silico” research conducted by the consortium which has shown efficacy in countering the replication of the virus in cells. The IP for its use against Sars-Cov2 has already been protected on May 6 2020 in the name Dompé farmaceutici, Fraunhofer Institute and KU Leuven, to facilitate the largest possible access. Raloxifene would be used in mildly symptomatic Covid19 patients to halt the spread of infection. This result emerged from the first virtual (in silico) screening conducted on the Consortium’s supercomputers of more than 400.000 molecules (safe-in-man drugs and natural products) made available by Dompé farmaceutici and the partner Fraunhofer (IME) to the Consortium. The molecules were prioritized if in clinical stage or already on the market. 7.000 molecules with certain promising characteristics were tested.

SYN

Raloxifene syn.png

Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. (1984). “Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity”. Journal of Medicinal Chemistry 27 (8): 1057–66.doi:10.1021/jm00374a021PMID 6431104.

syn 1

EP 0062053; GB 2097788

Keoxifene has been synthesized using the following process: A portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-pipendinoethoxy)benzoyl]benzo[b]thiophene hydrochloride (I) was combined with denatured alcohol and 5N sodium hydroxide, and stirred under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under vacuum, and the residue dissolved in water and washed with diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture was then acidified with 1N hydrochloric acid, and then made basic with excess sodium bicarbonate The precipitate was collected by filtration and washed with cold water to obtain crude product, which was purified on a column of silica gel. The column was eluted first with 700 ml of 5% methanol in chloroform, followed by 1l of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain a yellow oil. The oil was dissolved in acetone seeded and chilled in a freezer to obtain the purified product.

syn2

J Label Compd Radiopharm 1995,36(1),43

The synthesis of radiolabeled raloxifene has been reported: The esterification of 3,5-dibromo-4-hydroxybenzoic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is condensed with 1-(2-chloroethyl)piperidine (III) by means of K2CO3 in DMF yielding 3,5-dibromo-4-[2-(1-piperidyl)ethoxy]benzoic acid methyl ester (IV). The hydrolysis of (IV) with NaOH in methanol affords the corresponding free acid (V), which by treatment of SOCl2 in toluene is converted to the acyl chloride (VI). The Friedel-Crafts condensation of (VI) with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (VII) by means of AlCl3 in dichloromethane gives [3,5-dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl]-[6-methoxy-2-(4-methoxy phenyl)benzo[b]thien-3-yl]methanone (VIII), which is demethylated with AlCl3 and ethylmercaptane to dibromoraloxifene (IX). Finally, this compound is submitted to hydrogenolysis with tritium over Pd/C in methanol.

syn 3

Bioorg Med Chem Lett 1997,7(8),993

The two major metabolites of raloxifene, the glucuronide conjugates (VI) and (VIII) are synthesized as follows: The partial silylation of raloxifene (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) by means of dimethylaminopyridine (DMAP) in THF/DMF gives a mixture of the monosilylated compounds (II) and (III), which are separated by chromatography. Compounds (II) and (III) are independently condensed with methyl 1,2,3,4-tetra-O-acetyl-D-glucuronate (IV) by means of BF3.OEt2 in dichloromethane yielding protected glucuronides (V) and (VII), respectively. Finally, both compounds are deprotected by a treatment first with LiOH in dioxane to hydrolyzed the ester groups, and then with tetrabutylammonium fluoride in THF to eliminate the silyl groups, thus obtaining the desired metabolites (VI) and (VIII), respectively.

syn 4

Tetrahedron Lett 1999,40(28),5155

Two related new syntheses of raloxifene have been described: 1) The acylation of N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine (I) with 4-fluorobenzoyl chloride (II) by heating at 100 C in chlorobenzene gives the 3-acyl derivative (III), which is condensed with 4-methoxyphenylmagnesium bromide (IV) in THF yielding 3-(4-fluorobenzoyl)-6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene (V). The condensation of (V) with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH in DMF affords the ether (VII), which is finally demethylated with AlCl3 and ethanethiol. 2) The intermediate (III) can also be condensed first with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH as before giving the piperidinoethyl ether (VIII), which is then condensed with the Grignard reagent (IV) affording the previously reported ether (VII).

syn

Org Chem Ind J, Volume: 14( 3)

https://www.tsijournals.com/articles/industrially-viable-demethylation-reaction-in-synthesis-of-raloxifene-hydrochloride-13848.html

A GREEN PROCESS FOR DEMETHYLATION REACTION IN SYNTHESIS OF RALOXIFENE HYDROCHLORIDEAuthors : Ramadas Chavakula *, Chakradhar Saladi J S, Narayana Rao Mutyalaa , Vijaya Raju Maddalaa and Raghu Babu Kb

A green process for  demethylation reaction in synthesis of raloxifene hydrochloride by using aluminium chloride and odorless  decanethiol as demethylation agent instead of aluminium chloride and ethanethiol (foul smell) under normal conditions is described.

Raloxifene hydrochloride [1], is an estrogen agonist/antagonist, commonly referred to as a Selective Estrogen Receptor Modulator (SERM) [1,2] that belongs to the benzothiophene class of compounds. Raloxifene decreases the resorption of bone and reduces the biochemical markers of bone turnover to the premenopausal range [35]. Raloxifene hydrochloride may also lower the chance of developing a certain type of breast cancer (invasive breast cancer) in post-menopausal women [6,7]. It can be synthesized [3] directly from aroylation of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene [2] by the acid chloride(4) of 4-[2-(1-piperidinyl)ethoxy]benzoic acid hydrochloride [3] in the presence of AlCl3 followed by addition of ethanethiol (FIG. 1).

Experimental Section

4-[2-(1-Piperidinyl)ethoxy]benzoic acid hydrochloride [3] and 6-methoxy-2-(4-methoxyphenyl) benzo[b] thiophene [2] were prepared by procedures reported previously [3]. Decanethiol was from commercial source. All melting points are uncorrected and were determined in capillary tubes on an Electothermal melting point apparatus. 1NMR spectra were recorded on a Brucker ADVANCE 400 MHz spectrometer, using DMSO-d6 as solvent and TMS as internal standard. Electrospray ionization mass spectroscopy was performed using an ion trap mass spectrometer (Model 6310 Agilent). All reactions were monitored and checked by Thin Layer Chromatography (TLC) using methanol and spots examined by a UV lamp.

Preparation of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-[2-(1-piperidyl)ethoxy]phenyl] methanone hydrochloride (Raloxifene hydrochloride) [1]

To a solution of 4-[2-(1-piperidinyl)ethoxy]benzoic acid hydrochloride (3) (14.3 g, 0.05 mol) in methylene dichloride (400 mL) and pyridine (0.5 mL) at 25ºC to 35ºC, thionyl chloride (23.8 g, 0.20 mol) was added dropwise under argon for 15-30 minute. The reaction mixture was stirred for 2 hr. at 40ºC to 45ºC. Excess thionyl chloride and solvent were removed in vacuum at 40◦C to afford 15.0 g of the crude acid chloride hydrochloride salt [4]. The crude solid acid chloride hydrochloride [4] was dissolved in methylene dichloride (150 mL), cooled to 0ºC to 10ºC, 6-methoxy-2-(4-methoxyphenyl)benzo[b] thiophene [2] (10.8 g, 0.04 mol) was added. Then, anhydrous aluminium chloride (37.0 g, 0.28 mol) was added portion wise over a period of 30 min and then the mixture was allowed to warm to 30ºC and stirred for 2 hr at 25-35ºC. Then decanethiol (28.0 g, 0.16 mol) was added and stirred for 2 hr. at 25-35ºC. The reaction mixture was quenched with mixture of methanol (100 mL), ice (200 g) and Conc. HCl (15 mL) and stirred for 1 hr. at 25-35ºC. The precipitated solid was collected, washed with water (100 mL X 2) and dried at 65ºC for 4 h to afford 20.0 g of crude compound 1, which was crystallized from methanol/water (23/1, vol/vol) to yield 13.6 g of compound 1 (53.3 %yield) as a white solid, MP 258-260°C, liter 3, 258°C ; 1NMR: δ 1.34, 1.72 [2H, m, (CH2CH2)2CH2], 1.76 [4H, m, N(CH2CH2)2], 2.96 (2H, m, N-CH2), 3.43 [4H, m, N(CH2CH2)2], 4.44 (2H, m, O-CH2), 6.67 (2H, d, Ar), 6.85 (1H, d, Ar), 6.95 (2H, d, Ar), 7.18 (2H, d, Ar), 7.25 (1H, d, Ar), 7.35 (1H, s, Ar), 7.70 (2H, d, Ar), 9.77 (1H, s, OH), 9.82 (1H, s, OH), 10.16 (1H, brs, NH), MS (ESI): m/z 474.6 (M +H). “This procedure has been scaled up using 250g of compound 1.”

Results and Discussion

Commonly used thiols like ethanethiol and benzyl mercaptan in demethylation reactions have a foul smell making them difficult and unpleasant to use in the laboratory without fume hoods. The problem becomes even worse in industry on a large scale. Odorless substitutes are therefore always required. Few papers [8,9] discuss the use of long chain thiols to minimize odor, so we used this work as a basis for choosing a long chain thiol for our demethylation reaction. We now report a new, highly active demethylation reagent, an aluminum chloride and decanethiol, characterized by rapid action under mild conditions, easy workup of the reaction product, and high yield (FIG. 2.).

organic-chemistry-synthesis

Figure 2: Synthesis of Raloxifene hydrochloride.

Conclusion

In conclusion, we have found that decanethiol is odorless thiol compared to ethanethiol. We believe that removing the foul-smelling thiols and use of these odorless thiols will greatly improve the greenchemistry.

References

  1. Grese TA, Dodge JA. Selective Estrogen Receptor Modulators (SERMs). Curr Pharm Des. 1998;4:71-92.
  2. Bryant HU, Dere WH. Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med. 1998;217:45-52.
  3. Jones CD, Jevnikar MG, Pike AJ, et al. Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo [b] thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl) benzo [b] thien-3-yl]-[4-[2-(1-piperidinyl) ethoxy] phenyl] methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J Med Chem. 1984;27:1057-66.
  4. Sato M, Grese TA, Dodge JA, et al. Emerging therapies for the prevention or treatment of postmenopausal osteoporosis. J Med Chem. 1999;42:1-24.
  5. Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996;11:835-42.

paper

https://www.sciencedirect.com/science/article/abs/pii/S0223523412001122

Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator - ScienceDirect
Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator - ScienceDirect
Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator - ScienceDirect
Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator - ScienceDirect
Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator - ScienceDirect

syn

https://www.tandfonline.com/doi/abs/10.1080/00397911.2014.943348?journalCode=lsyc20

Piperidine Nucleophilic Substitution Without Solvent: An Efficient Synthesis of RaloxifeneYewei Yang,Tao Zhang,Wenhai Huang &Zhenrong Shen Pages 3271-3276 |

Mild and high-yielding synthesis is described for raloxifene via piperdine nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and 2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such as low cost, and is suitable for industrial production.

Graphical abstract

Keywords: Friedel–Crafts acylationgreen chemistrynucleophilesraloxifeneSERM

The improved synthesis of raloxifene 1 was accomplished as shown in Scheme 2. Methyl p-hydroxybenzoate 2, 1-bromo-2-chloroethane, and K2CO3 were refluxed in acetone, yielding compound 3 in 94% yield. Without prior purification, 3 was hydrolyzed to the corresponding p-substituted benzoyl acids 4 in 100% yield. The application of general reaction conditions of methanol as solvent and hydrochloric as acid would afford the substitution impurity 4-(2-methoxyethoxy)-benzoic acid. To control this impurity during reaction, various solvents such as alcohol, ethyl acetate, acetone, and tetrahydrofuran (THF) were screened, and THF gave the best result from the view of impurity formation and yield. Compound 4 is a solid and was easily isolated from THF by adding water. Then 4 was transferred to acid chlorides 5 and substantially reacted with benzothiophene 6 using AlCl3 in dichloromethane at 50 C to afford aroylated benzothiophene 7 in two steps, with yield of 95% (79% from method A[8] and 65.5% from method B[3]). With the requisite 7 in hand, we next examined piperidine nucleophilic substitution to produce the desired beno[b]thien-3-yl ketones 8. In general using reaction conditions A (acetone, NaI, K2CO3, reflux, 70%) and B (acetonitrile, NaI, K2CO3, reflux, 85%), impurity formation was observed from the beginning of the reaction. We screened various conditions and were delighted to found that using excess piperidine at reflux temperature gave negligible impurity formation. Piperidine was not only reagent but also solvent. The isolated product 8 was stable and was converted into the desired raloxifene 1 as reported. In conclusion, we have developed a viable alternative route for the synthesis of raloxifene. The new synthesis would have been better able to support the increase in bulk demand for this drug for the chemoprevention of breast cancer and novel formulations. Our synthetic route has several advantages: the use of difunctionalized coumpunds 5 as key intermediate makes Friedel–Crafts acylation and nucleophilic substitution highly efficient. The using of piperine as reagent and solvent avoids the large waste streams derived from neutralization reaction of sodium hydride. The cost of the new route is less than the current route of manufacture. 


 Preparation of [4-(2-Chloro-ethoxy)-phenyl]-[6-methoxy-2- (4-methoxy-phenyl)-benzo[b]thiophen-3-yl]-methanone (7) Under an N2 atmosphere, 5 was added to a mixture of 6 (20.25 g, 75 mmol) and AlCl3 (13.30 g, 100 mmol) in DCM (2 mL), and the mixture was stirred for 12 h. The reaction was monitored by TLC (n-hexane/EtOAc, 4:1). After the reaction was judged complete, the reaction mixture was allowed to cool. The crude mixture was poured into H2O and extracted with EtOAc. The organic layer was separated and concentrated. The residue was crystallized from EtOAc to give the product 7 (32.26 g, 95%): yellow solid crystals; mp 119–120 C; IR (KBr) nmax: 2960, 2835, 1647, 1599, 1472, 1251, 1169, 1032, 830 cm1 ; 1 H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 8.8 Hz, 2H), 7.53 (d, J ¼ 8.8 Hz, 1H), 7.32 (d, J ¼ 8.4 Hz, 2H), 7.31 (s, 1H), 6.95 (dd, J ¼ 8.4, 2.4 Hz, 1H), 6.75 (dd, J ¼ 9.2, 7.2 Hz, 4H), 4.20 (t, J ¼ 4.0 Hz,2H), 3.87 (s, 3H), 3.78 (t, J ¼ 6.0 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 193.1, 162.1, 159.7, 157.6, 142.7, 139.9, 133.8, 132.3, 130.9, 130.2, 130.1, 125.9, 123.9, 114.8, 114.1, 113.9, 104.4, 67.8, 55.6, 55.2, 41.5; MS (EI) m/z (%):452 (Mþ, 100.0), 437 (13.0), 297 (25.0), 183 (39.0), 121 (44.0). HRMS m/z (EI) calcd. for C25H22ClO4S: (MþH) þ: 453.0927; found: 453.0933. 
Preparation of [6-Methoxy-2-(4-methoxy-phenyl)-benzo[b] thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (8) Under an N2 atmosphere, a mixture of 7 (8.50 g, 19 mmol) and piperdine (30 ml) was stirred under reflux for 12 h. The reaction was monitored by TLC (n-hexane/EtOAc, 4:1). After the reaction was judged complete, the reaction mixture was allowed to cool. The mixture was concentrated for recovery of piperidine. EtOAc was added and the residue was washed with saturated NaHCO3 aqueous solution. The organic layer was separated and concentrated to give the product 8 (8.80 g, 94%): yellow viscous oil; IR (KBr) nmax: cm1 2933, 1645, 1597, 1535, 1501, 1470, 1249, 1164, 1030, 827; 1 H NMR (400 MHz, CDCl3) d7.76 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz, 1H), 7.33 (d, J ¼ 8.8 Hz, 2H), 7.30 (d, J ¼ 2.4 Hz, 1H), 6.94 (dd, J ¼ 8.8, 2.0 Hz, 1H), 6.75 (dd, J ¼ 7.2, 5.2 Hz, 4H), 4.08 (t, J ¼ 6.0 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.71 (t, J ¼ 6.0 Hz, 2H), 2.46 (s, 4H), 1.60–1.54 (m, 4H), 1.43–1.41 (m, 2H).13C NMR (100 MHz, CDCl3) d 193.2, 163.0, 159.7, 157.6, 142.4, 140.1, 133.9, 132.3, 130.6, 130.4, 130.2, 126.0, 124.0, 114.8, 114.2, 114.1, 104.5, 66.3, 57.7, 55.6, 55.2, 55.1, 25.9, 24.1. MS (EI) m/z (%): 501 (Mþ, 100.0), 452 (12.0), 402 (21.0), 297 (24.0), 98 (100.0). HRMS m/z (EI) calcd. for C30H32NO4S: (MþH) þ: 502.2052; found: 502.2055.REFERENCES 1. Clemett, D.; Spencer, C. M. Drugs 2000, 60 (2), 379–411. 2. Land, S. R. JAMA 2007, 298 (9), 973–973. 3. Dadiboyena, S. Eur. J. Med. Chem. 2012, 51, 17–34. 4. Schmid, C. R.; Sluka, J. P.; Duke, K. M. Tetrahedron Lett. 1999, 40 (4), 675–678. 5. Bradley, D. A.; Godfrey, A. G.; Schmid, C. R. Tetrahedron Lett. 1999, 40 (28), 5155–5159. 6. Shinde, P. S.; Shinde, S. S.; Renge, A. S.; Patil, G. H.; Rode, A. B.; Pawar, R. R. Lett. Org. Chem. 2009, 6 (1), 8–10.7. Sach, N. W.; Richter, D. T.; Cripps, S.; Tran-Dube, M.; Zhu, H. C.; Huang, B. W.; Cui, J.; Sutton, S. C. Org. Lett. 2012, 14 (15), 3886–889. 8. Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J. A. J. Med. Chem. 1984, 27 (8), 1057–1066. 9. Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; Jones, C. D.; Lugar, C. W.; Martin, M. J.; Matsumoto, K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1997, 40 (2), 146–167. 
synChapter 2 – 1-Substituted PiperidinesAuthor links open overlay panelRubenVardanyan
https://doi.org/10.1016/B978-0-12-805157-3.00002-8Piperidine-Based Drug DiscoveryHeterocyclic Drug Discovery2017, Pages 83-1011-Substituted Piperidines

Ruben Vardanyan, in Piperidine-Based Drug Discovery, 2017

Raloxifene (7685)

Raloxifene (Evista) (1.3.4) is a second-generation selective estrogen receptor modulator that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. Raloxifene is an antiresorptive agent, a new representative of a class of drugs that prevent the loss of bone mass, i.e., used to treat osteoporosis and similar diseases in postmenopausal women and those postmenopausal women at increased risk of invasive breast cancer [41–53].

It was shown that raloxifene can have some affect on cognition, mental health, sleep, and sexual function in menopausal women [54]. Raloxifene was used also as an adjuvant treatment in postmenopausal women with schizophrenia [55].

The first reported synthesis of the raloxifene scaffold consists in Friedel-Crafts aroylation in 1,2-dichloroethane and using AlCl3 as a catalyst by coupling of 4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (2.3.15) with benzothiophene derivative (2.3.16) followed by alkaline hydrolysis of mesyl groups, which give the desired raloxifene (2.3.4) [56–58] (Scheme 2.9).

The key intermediate – 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (2.3.16) – was prepared by the cyclization-rearrangement of 1-(4-methoxyphenyl)-2-((3-methoxyphenyl)thio)ethan-1-one (2.3.20) induced by polyphosphoric acid (PPA). This rearrangement (Kost rearrangement [59]) is general for 3-(R-substituted)indoles, -benzofurans, and -benzothiophenes, which are converted to the corresponding 2-isomers by heating with PPA.

The synthesis started from thiophenol (2.3.18) and bromoketone (2.3.19), which were coupled in presence of KOH in ethanol/water solution. Obtained (2.3.20) was heated with PPA to give a mixture that is easily separable by crystallization isomeric 2-phenylbenzo[b]thiophenes (2.3.21) and (2.3.22), where preferable, isomer (2.3.22) predominates. Cleavage of the methoxy groups in (2.3.22) was done conveniently with pyridine hydrochloride to give (2.3.23), which was easily converted to mesylate (2.3.16) with methanesulfonyl chloride in pyridine and 4-dimethylaminopyridine as a catalyst (Scheme 2.10).

The second reagent—4-(2-(piperidin-1-yl)ethoxy)benzoyl chloride (2.3.15)—was prepared starting with 4-hydroxybenzoate (2.3.24), which with 1-(2-chloroethyl)piperidine (2.3.25) in anhydrous DMF, and K2CO3 or sodium hydride, gave methyl 4-(2-(piperidin-1-yl)ethoxy)benzoate (2.3.26) hydrolyzed in MeOH/water NaOH solution. The acid (2.3.26) was converted to its chloride (2.3.15) with SOCl2 in 1,2-dichloroethane and a catalytic amount of DMF (Scheme 2.11).

Another novel convenient synthesis of raloxifene (2.3.4) have been proposed [60]. According to this method anisaldehyde (2.3.28) was transformed to corresponding cyanohydrin (2.3.29) using a mixture of sodium cyanide ethanol containing triethylamine through which HCl gas was passed over 30 minutes at 5–10°C.

Gaseous HCl was added to the solution of prepared cyanohydrin (2.3.29) in ethanol at room temperature over 30 minutes in order to give p-methoxybenzaldehyde cyanohydrin iminoether hydrochloride (2.3.30). Then, hydrogen sulfide was bubbled into a solution of the methyl imidate (2.3.30) and triethylamine in methanol at 0°C to give α-(4-methoxy phenyl)-α-hydroxy-N,N dimethylthioacetamide (2.3.31).

To the obtained α-hydroxythioamide (2.3.31) dissolved-in-methylene chloride methanesulfonic acid was slowly added, which transformed the starting material to 2-N,N-dimethylamino-6-methoxy benzo[β]thiophene (2.3.32).

The obtained 2-dimethylaminobenzothiophene (2.3.32) and known 4-(2-piperidinoethoxy)-benzoyl chloride (2.3.15) were partially dissolved in chlorobenzene and the mixture was warmed in a 100–105°C to give 2-(4-methoxyphenyl)-6-methoxy-3-[4-(piperidinoethoxy)benzoyl]-benzo[β]thiophene (2.3.33). 4-Methoxyphenylmagnesium bromide (2.3.34) in THF was added to chilled to 0°C prepared compound (2.3.33) in THF, which gave 2-(4-methoxyphenyl)-6-methoxy-3-[4-(piperidinoethoxy)benzoyl] benzo[β] thiophene (2.3.35). To the prepared benzothiophene (2.3.35) suspended in chlorobenzene was added AlCl3, followed by the addition of n-propanethiol, and the mixture was heated at 35°C. After the workup with aqueous HCl, the desired raloxifene (2.3.4) was separated [60] (Scheme 2.12).

There exist plenty of modifications for these two approaches, as reviewed in [61,62].

Clinical data
Trade namesEvista, Optruma, others
Other namesKeoxifene; Pharoxifene; LY-139481; LY-156758; CCRIS-7129
AHFS/Drugs.comMonograph
MedlinePlusa698007
License dataEUEMAby INNUSDailyMedRaloxifeneUSFDAEvista
Pregnancy
category
AU: X (High risk)US: X (Contraindicated)
Routes of
administration
By mouth
Drug classSelective estrogen receptor modulator
ATC codeG03XC01 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability2%[1][2]
Protein binding>95%[1][2]
MetabolismLiverintestines (glucuro-
nidation
);[1][2][3]CYP450 system not involved[1][2]
Elimination half-lifeSingle-dose: 28 hours[1][2]
Multi-dose: 33 hours[1]
ExcretionFeces[2]
Identifiers
IUPAC name[show]
CAS Number84449-90-1 
82640-04-8 (hydrochloride)
PubChemCID5035
IUPHAR/BPS2820
DrugBankDB00481 
ChemSpider4859 
UNIIYX9162EO3I
ChEBICHEBI:8772 
ChEMBLChEMBL81 
PDB ligandRAL (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID3023550 
ECHA InfoCard100.212.655
Chemical and physical data
FormulaC28H27NO4S
Molar mass473.584 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=C(c1c3ccc(O)cc3sc1c2ccc(O)cc2)c5ccc(OCCN4CCCCC4)cc5
InChI[hide]InChI=1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2 Key:GZUITABIAKMVPG-UHFFFAOYSA-N 

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  48. ^ Provinciali N, Suen C, Dunn BK, DeCensi A (October 2016). “Raloxifene hydrochloride for breast cancer risk reduction in postmenopausal women”. Expert Rev Clin Pharmacol9 (10): 1263–1272. doi:10.1080/17512433.2016.1231575PMID 27583816S2CID 26047863.
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  63. ^ Lawrence SE, Faught KA, Vethamuthu J, Lawson ML (July 2004). “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia”. J. Pediatr145 (1): 71–6. doi:10.1016/j.jpeds.2004.03.057PMID 15238910.
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Further reading

External links

///////Keoxifene hydrochloride, Raloxifene hydrochloride, LY-139481, LY 156758, Optruma, Loxifen, Evista

REPROXALAP


2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol.png

REPROXALAP

レプロキサラップ;

ADX-102

2-(3-amino-6-chloroquinolin-2-yl)propan-2-ol

C12H13ClN2O, 236.7 g/mol

CAS 916056-79-6

UNII-F0GIZ22IJH

2-(3-amino-6-chloroquinolin-2-yl)propan-2-ol

Phase 3 Clinical

Aldeyra Therapeutics is developing reproxalap, which binds and traps free aldehydes, formulated using Captisol technology licensed from Ligand Pharmaceuticals as an eye drop formulation, for treating acute noninfectious anterior uveitis, allergic conjunctivitis and dry eye syndrome.

PATENT

product case, WO2006127945 ,

EU states until 2026

expire US in 2029 with US154 extension.

PATENTS

WO2018170476

United States patent application serial number US 13/709,802, filed December 10, 2012 and published as US 2013/0190500 on July 25, 2013 (“the ‘500 publication,” the entirety of which is hereby incorporated herein by reference), describes certain aldehyde scavenging compounds. Such compounds include com ound A:

[0036] Compound A, (6-chloro-3-amino-2-(2-hydroxypropyl)-l-azanaphthalene), is designated as compound A in the ‘500 publication and the synthesis of compound A is described in detail at Example 5 of the ‘500 publication, and is reproduced herein for ease of reference.

Example A – General Preparation of Compound A

Compound A

[00436] The title compound was prepared according to the steps and intermediates (e.g., Scheme 1) described below and in the ‘500 publication, the entirety of which is incorporated herein by reference.

Step 1: Synthesis of Intermediate A- 1

[00437] To a 2 L round bottom flask was charged ethanol (220 mL), and pyridine (31 g, 392 mmol) and the resulting solution stirred at a moderate rate of agitation under nitrogen. To this solution was added ethyl bromopyruvate (76.6 g, 354 mmol) in a slow, steady stream. The reaction mixture was allowed to stir at 65±5° C. for 2 hours.

Step 2: Synthesis of Intermediate A-2

[00438] Upon completion of the 2-hour stir time in example 1, the reaction mixture was slowly cooled to 18-22° C. The flask was vacuum-purged three times at which time 2-amino-5-chloro-benzaldehyde (ACB) (50.0 g, 321 mmol) was added directly to the reaction flask as a solid using a long plastic funnel. Pyridine (64.0 g, 809 mmol) was added followed by an EtOH rinse (10 mL) and the reaction mixture was heated at 80±3° C. under nitrogen for about 16 hours (overnight) at which time HPLC analysis indicated that the reaction was effectively complete.

Step 3: Synthesis of Intermediate A-3

[00439] The reaction mixture from example 2 was cooled to about 70° C. and morpholine (76.0 g, 873 mmol)) was added to the 2 L reaction flask using an addition funnel. The reaction mixture was heated at 80±2° C. for about 2.5 hours at which time the reaction was considered complete by HPLC analysis (area % of A-3 stops increasing). The reaction mixture was cooled to 10-15° C. for the quench, work up, and isolation.

Step 4: Isolation of Intermediate A-3

[00440] To the 2 L reaction flask was charged water (600 g) using the addition funnel over 30-60 minutes, keeping the temperature below 15° C. by adjusting the rate of addition and using a cooling bath. The reaction mixture was stirred for an additional 45 minutes at 10-15° C. then the crude A-3 isolated by filtration using a Buchner funnel. The cake was washed with water (100 mLx4) each time allowing the water to percolate through the cake before applying a vacuum. The cake was air dried to provide crude A-3 as a nearly dry brown solid. The cake was returned to the 2 L reaction flask and heptane (350 mL) and EtOH (170 mL) were added and the mixture heated to 70±3° C. for 30-60 minutes. The slurry was cooled to 0-5° C. and isolated by filtration under vacuum. The A-3 was dried in a vacuum drying oven under vacuum and 35±3° C. overnight (16-18 hours) to provide A-3 as a dark green solid.

Step 5: Synthesis of Compound A

[00441] To a 2 L round bottom flask was charged methylmagnesium chloride (200 mL of 3.0 M solution in THF, 600 mmol). The solution was cooled to 0-5° C. using an ice bath.

[00442] A 500 mL flask (magnetic stirring) was charged with 22.8 grams A-3 from example 4 and THF (365 mL), stirred to dissolve then transferred to an addition funnel on the 2 L Reaction Flask. The A-3 solution was added drop-wise to the reaction flask over 5.75 hours, keeping the temperature of the reaction flask between 0-5° C throughout the addition. At the end of the addition the contents of the flask were stirred for an additional 15 minutes at 0-5° C. then the cooling bath was removed and the reaction was allowed to stir overnight at ambient temperature.

[00443] The flask was cooled in an ice bath and the reaction mixture was carefully quenched by adding EtOH (39.5 g, 857 mmol) drop-wise to the reaction mixture, keeping the temperature of the reaction mixture below 15° C. during the course of the addition. An aqueous solution of H4C1 (84.7 g H4C1 in 415 mL water) was then carefully added and the mixture stirred under moderate agitation for about 30 minutes then transferred to a separately funnel to allow the layers to separate. Solids were present in the aqueous phase so HO Ac (12.5 g) was added and the contents swirled gently to obtain a nearly homogeneous lower aqueous phase. The lower aqueous layer was transferred back to the 2 L reaction flask and stirred under moderate agitation with 2-methylTHF (50 mL) for about 15 minutes. The original upper organic layer was reduced in volume to approximately 40 mL using a rotary evaporator at≤40° C. and vacuum as needed. The phases in the separatory funnel were separated and the upper 2-MeTHF phase combined with the product residue, transferred to a 500 mL flask and vacuum distilled to an approximate volume of 25 mL. To this residue was added 2-MeTHF (50 mL) and distilled to an approximate volume of 50 mL. The crude compound A solution was diluted with 2-MeTHF (125 mL), cooled to 5-10° C. and 2M H2S04 (aq) (250 mL) was slowly added and the mixture stirred for 30 minutes as the temperature was allowed to return to ambient. Heptane (40 mL) was charged and the reaction mixture stirred for an additional 15 minutes then transferred to a separatory funnel and the layers were allowed to separate. The lower aqueous product layer was extracted with additional heptane (35 mL) then the lower aqueous phase was transferred to a 1 L reaction flask equipped with a mechanical stirrer and the mixture was cooled to 5-10° C. The combined organic layers were discarded. A solution of 25% NaOH(aq) was prepared (NaOH, 47 g, water, 200 mL) and slowly added to the 1 L reaction flask to bring the pH to a range of 6.5-8.5.

[00444] EtOAc (250 mL) was added and the mixture was stirred overnight. The mixture was transferred to a separatory funnel and the lower phase discarded. The upper organic layer was washed with brine (25 mL) then the upper organic product layer was reduced in volume on a rotary evaporator to obtain the crude compound A as a dark oil that solidified within a few minutes. The crude compound A was dissolved in EtOAc (20 mL) and filtered through a plug of silica gel (23 g) eluting with 3/1 heptane/EtOAc until all compound A was eluted (approximately 420 mL required) to remove most of the dark color of compound A. The solvent was removed in vacuo to provide 14.7 g of compound A as a tan solid. Compound A was taken up in EtOAc (25 mL) and eluted through a column of silica gel (72 g) using a mobile phase gradient of 7/1 heptane/EtOAc to 3/lheptane/EtOAc (1400 mL total). The solvent fractions containing compound A were stripped, compound A diluted with EtOAc (120 mL) and stirred in a flask with Darco G-60 decolorizing carbon (4.0 g) for about 1 hour. The mixture was filtered through celite using a fitted funnel, rinsing the cake with EtOAc (3 x 15 mL). The combined filtrates were stripped on a rotary evaporator and compound A dissolved in heptane (160 mL)/EtOAc(16 mL) at 76° C. The

homogeneous solution was slowly cooled to 0-5° C, held for 2 hours then compound A was isolated by filtration. After drying in a vacuum oven for 5 hours at 35° C. under best vacuum, compound A was obtained as a white solid. HPLC purity: 100% (AUC).

Example 1 – Preparation of Free Base Forms A and B of Compound A

Compound A

[00445] Compound A is prepared according to the method described in detail in Examples 1-5 of the ‘500 publication, the entirety of which is hereby incorporated herein by reference.

PATENT

example 5 [WO2018039197A1]

https://patents.google.com/patent/WO2018039197A1/en

Exam le 5: Synthesis of NS2

Figure imgf000055_0001

NS2

[00190] 2-(3-amino-6-chloroquinolin-2-yl)propan-2-ol. To a 2 L round bottom flask was charged methylmagnesium chloride (200 mL of 3.0 M solution in THF, 600 mmol). The solution was cooled to 0-5 °C using an ice bath.

[00191] A 500 mL flask (magnetic stirring) was charged with 22.8 grams A-3a from Example 4 and THF (365 mL), stirred to dissolve, and then transferred to an addition funnel on the 2 L reaction flask. The A-3a solution was added drop-wise to the reaction flask over 5.75 hours, keeping the temperature of the reaction flask between 0-5 °C throughout the addition. At the end of the addition the contents of the flask were stirred for an additional 15 minutes at 0-5 °C, then the cooling bath was removed and the reaction was allowed to stir overnight at ambient temperature.

[00192] The flask was cooled in an ice bath and the reaction mixture was carefully quenched by adding EtOH (39.5 g, 857 mmol) drop-wise to the reaction mixture, keeping the temperature of the reaction mixture below 15 °C during the course of the addition. An aqueous solution of H4CI (84.7 g H4CI in 415 mL water) was then carefully added and the mixture stirred under moderate agitation for about 30 minutes then transferred to a separatory funnel to allow the layers to separate. Solids were present in the aqueous phase so HOAc (12.5 g) was added and the contents swirled gently to obtain a nearly homogeneous lower aqueous phase. The lower aqueous layer was transferred back to the 2 L reaction flask and stirred under moderate agitation with 2-methyl-tetrahydrofuran (2-MeTHF) (50 mL) for about 15 minutes. The original upper organic layer was reduced in volume to approximately 40 mL using a rotary evaporator at < 40 °C under vacuum as needed. The phases in the separatory funnel were separated and the upper 2-MeTHF phase combined with the product residue was transferred to a 500 mL flask and vacuum distilled to an approximate volume of 25 mL. To this residue was added 2-MeTHF (50 mL) and the mixture again distilled to an approximate volume of 50 mL. The crude compound NS2 solution was diluted with 2-MeTHF (125 mL), cooled to 5-10 °C, and 2 M H2S04 (aq) (250 mL) was slowly added and the mixture stirred for 30 minutes as the temperature was allowed to return to ambient. Heptane (40 mL) was charged and the reaction mixture stirred for an additional 15 minutes then transferred to a separatory funnel, and the layers were allowed to separate. The lower aqueous product layer was extracted with additional heptane (35 mL), then the lower aqueous phase was transferred to a 1 L reaction flask equipped with a mechanical stirrer, and the mixture was cooled to 5-10 °C. The combined organic layers were discarded. A solution of 25% NaOH (aq) was prepared (NaOH, 47 g, water, 200 mL) and slowly added to the 1 L reaction flask to bring the pH to a range of 6.5 – 8.5.

[00193] EtOAc (250 mL) was added and the mixture was stirred overnight. The mixture was transferred to a separatory funnel and the lower phase discarded. The upper organic layer was washed with brine (25 mL), then the upper organic product layer was reduced in volume on a rotary evaporator to obtain a obtain the crude compound NS2 as a dark oil that solidified within a few minutes. The crude compound NS2 was dissolved in EtOAc (20 mL) and filtered through a plug of silica gel (23 g) eluting with 3/1 heptane/EtOAc until all compound NS2 was eluted (approximately 420 mL required) to remove most of the dark color of compound NS2. The solvent was removed in vacuo to provide 14.7 g of compound NS2 as a tan solid. Compound NS2 was taken up in EtOAc (25 mL) and eluted through a column of silica gel (72g) using a mobile phase gradient of 7/1 heptane/EtOAc to 3/1 heptane/EtOAc (1400 mL total). The solvent fractions containing compound NS2 were evaporated. Compound NS2 was diluted with EtOAc (120 mL) and stirred in a flask with Darco G-60 decolorizing carbon (4.0 g) for about 1 hour. The mixture was filtered through celite using a firtted funnel, rinsing the cake with EtOAc (3 x 15 mL). The combined filtrates were evaporated on a rotary evaporator and compound NS2 dissolved in heptane (160 mL)/EtOAc (16 mL) at 76 °C. The homogeneous solution was slowly cooled to 0-5 °C, held for 2 hours, then compound NS2 was isolated by filtration. After drying in a vacuum oven for 5 hours at 35 °C under best vacuum, compound NS2 was obtained as a white solid. HPLC purity: 100% (AUC); HPLC (using standard conditions): A-2: 7.2 minutes; A-3 : 11.6 minutes.

Preparation of ACB

Figure imgf000057_0001

[00194] After a N2 atmosphere had been established and a slight stream of N2 was flowing through the vessel, platinum, sulfided, 5 wt. % on carbon, reduced, dry (9.04 g, 3.0 wt. % vs the nitro substrate) was added to a 5 L heavy walled pressure vessel equipped with a large magnetic stir-bar and a thermocouple. MeOH (1.50 L), 5-chloro-2-nitrobenzaldehyde (302.1 g, 1.63 mol), further MeOH (1.50 L) and Na2C03 (2.42 g, 22.8 mmol, 0.014 equiv) were added. The flask was sealed and stirring was initiated at 450 rpm. The solution was evacuated and repressurized with N2 (35 psi), 2x. The flask was evacuated and repressurized with H2 to 35 psi. The temperature of the solution reached 30 °C w/in 20 min. The solution was then cooled with a water bath. Ice was added to the water bath to maintain a temperature below 35 °C. Every 2h, the reaction was monitored by evacuating and repressurizing with N2 (5 psi), 2x prior to opening. The progress of the reaction could be followed by TLC: 5-Chloro-2-nitrobenzaldehyde (Rf = 0.60, CH2CI2, UV) and the intermediates (Rf = 0.51, CH2CI2, UV and Rf = 0.14, CH2CI2, UV) were consumed to give ACB (Rf = 0.43, CH2CI2, UV). At 5 h, the reaction had gone to 98% completion (GC), and was considered complete. To a 3 L medium fritted funnel was added celite (ca. 80 g). This was settled with MeOH (ca. 200 mL) and pulled dry with vacuum. The reduced solution was transferred via cannula into the funnel while gentle vacuum was used to pull the solution through the celite plug. This was chased with MeOH (4 x 150 mL). The solution was transferred to a 5 L three-necked round-bottom flask. At 30 °C on a rotavap, solvent (ca. 2 L) was removed under reduced pressure. An N2 blanket was applied. The solution was transferred to a 5L four-necked round-bottomed flask equipped with mechanical stirring and an addition funnel. Water (2.5 L) was added dropwise into the vigorously stirring solution over 4 h. The slurry was filtered with a minimal amount of vacuum. The collected solid was washed with water (2 x 1.5 L), 2-propanol (160 mL) then hexanes (2 x 450 mL). The collected solid (a canary yellow, granular solid) was transferred to a 150 x 75 recrystallizing dish. The solid was then dried under reduced pressure (26-28 in Hg) at 40°C overnight in a vacuum-oven. ACB (> 99% by HPLC) was stored under a N2 atmosphere at 5°C.

PATENT

WO-2020223717

Process for preparing reproxalap as acetaldehyde dehydrogenase inhibitor useful for treating ocular diseases and cancer.

PATENT

WO-2020223685

Novel crystalline forms of reproxalap (compound 1; designated as Forms A and B) as acetaldehyde dehydrogenase inhibitor useful for treating ocular diseases and cancer.

PATENT

WO 2020123730

//////////REPROXALAP, レプロキサラップ  , ADX-102, Phase 3 Clinical

CC(C)(C1=C(C=C2C=C(C=CC2=N1)Cl)N)O

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