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DESLORATADINE, デスロラタジン

April 4, 2019 9:37 am / Leave a comment

Desloratadine

Molecular FormulaC₁₉H₁₉ClN₂
Average mass310.821 Da

100643-71-8 [RN]

5H-Benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-

7817

Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

Desloratadine (trade name Clarinex and Aerius) is a tricyclic H₁-antihistamine that is used to treat allergies. It is an active metaboliteof loratadine.

It was patented in 1984 and came into medical use in 2001.^[1]

Medical uses

Desloratadine is used to treat allergic rhinitis, nasal congestion and chronic idiopathic urticaria (hives).^[2] It is the major metabolite of loratadine and the two drugs are similar in safety and effectiveness.^[2] Desloratadine is available in many dosage forms and under many trade names worldwide.^[3]

An emerging indication for desloratadine is in the treatment of acne, as an inexpensive adjuvant to isotretinoin and possibly as maintenance therapy or monotherapy.^[4]^[5]

Side effects

The most common side-effects are fatigue, dry mouth, and headache.^[2]

Interactions

A number of drugs and other substances that are prone to interactions, such as ketoconazole, erythromycin and grapefruit juice, have shown no influence on desloratadine concentrations in the body. Desloratadine is judged to have a low potential for interactions.^[6]

Pharmacology

Pharmacodynamics

Desloratadine is a selective H₁–antihistamine which functions as an inverse agonist at the histamine H₁ receptor.^[7]

At very high doses, is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug’s action at therapeutic doses.^[8]

Pharmacokinetics

Desloratadine is well absorbed from the gut and reaches highest blood plasma concentrations after about three hours. In the bloodstream, 83 to 87% of the substance are bound to plasma proteins.^[6]

Desloratadine is metabolized to 3-hydroxydesloratadine in a three-step sequence in normal metabolizers. First, n-glucuronidation of desloratadine by UGT2B10; then, 3-hydroxylation of desloratadine N-glucuronide by CYP2C8; and finally, a non-enzymatic deconjugation of 3-hydroxydesloratadine N-glucuronide.^[9] Both desloratadine and 3-hydroxydesloratadine are eliminated via urine and feces with a half-life of 27 hours in normal metabolizers.^[6]^[10]

3-Hydroxydesloratadine, the main metabolite

It exhibits only peripheral activity since it does not readily cross the blood-brain barrier; hence, it does not normally cause drowsiness because it does not readily enter the central nervous system.^[11]

Desloratadine does not have a strong effect on a number of tested enzymes in the cytochrome P450 system. It was found to weakly inhibit CYP2B6, CYP2D6, and CYP3A4/CYP3A5, and not to inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2C19. Desloratadine was found to be a potent and relatively selective inhibitor of UGT2B10, a weak to moderate inhibitor of UGT2B17, UGT1A10, and UGT2B4, and not to inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, UGT1A7, and UGT1A8.^[9]

Pharmacogenomics

2% of Caucasian people and 18% of people from African descent are desloratadine poor metabolizers. In these people, the drug reaches threefold highest plasma concentrations six to seven hours after intake, and has a half-life of about 89 hours. However, the safety profile for these subjects is not worse than for extensive (normal) metabolizers.^[6]^[10]

Clip

https://www.beilstein-journals.org/bjoc/articles/9/265

The value of substituted 3-picoline precursors is illustrated in the synthesis of clarinex (1.22, Desloratadine, Scheme 5), a dual antagonist of platelet activating factor (PAF) and of histamine used in the treatment of allergies. This compound consists of a highly functional tricyclic core with an unsaturated linkage to a pendant piperidine ring. The picoline derivative 1.23 is first treated with two equivalents of n-butyllithium (n-BuLi) followed by alkylation with benzyl chloride to give the chain elongated adduct [27]. The tert-butylamide 1.24 is then dehydrated with phosphorous oxychloride at elevated temperatures to yield the nitrile derivative 1.25. Introduction of the piperidine ring is achieved by utilisation of the appropriately substituted Grignard reagent 1.26. A Friedel–Crafts type acylation promoted by either triflic acid or polyphosphoric acid (PPA) furnishes the tricyclic structure 1.28 which upon N-demethylation affords clarinex (1.22).

CLIP

FTIR

SYN

Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.

SYN

Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).

SYN

Syn

2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

SYN

1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

SYN

The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I), which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V). Finally, this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.

SPECTROSCOPY

[0052] Table 1, desloratadine sample IH-NMR data of the DMS0_d6

[0055] The desloratadine 1H spectra of the samples were assigned:
[0056] (I) 1H spectra show that there are 10 groups of hydrogen from low field to high field integral hydrogen ratio was 1: 1: 1: 1: 1: 1: 2: 4:
2: 4, and desloratadine structure match.
[0057] (2) δ 8.334 处 hydrogen as a set of double doublet, number of protons is I, attributed to two hydrogen;
[0058] (3) δ 7.560 处 hydrogen as a set of double doublet, number of protons is I, attributed to four hydrogen;
[0059] (4) δ 7.282 处 doublet hydrogen as a group, the number of protons is I, 12 attributed to hydrogen.
[0060] (5) δ 7.198 处 hydrogen as a set of double doublet, number of protons is I, 14 attributed to hydrogen;
[0061] (6) δ 7.174 处 hydrogen as a set of double doublet, number of protons is I, attributed to three hydrogen;
[0062] (7) δ 7.064 处 doublet hydrogen as a group, the number of protons is I, 15 attributed to hydrogen;
[0063] (8) δ 3.314 处 hydrogen as a group multiplet, 2 protons attributable to 10 hydrogen;
[0064] (9) δ 2.831,2.554 hydrogen groups at multiplet, protons of 4, 18, 20, the home position is hydrogen;
[0065] (10) δ 2.819 处 hydrogen as a group multiplet, 2 protons attributable to 11 hydrogen;
[0066] (11) δ 2.108 处 hydrogen as a single peak, the number of protons is I, home to 19 active hydrogen;
[0067] (12) δ 2.205, 2.002 处 two hydrogen multiplet, protons of 4, 17, 21 bits attributed to hydrogen; [0068] From the foregoing, 1H-NMR spectrum data and the resulting product in this embodiment is of he will be loratadine same structure as the target product.

http://www.google.com/patents/CN103755682A?cl=en

References

^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 549. ISBN 9783527607495.
^ Jump up to:^a ^b ^c See S (2003). “Desloratadine for allergic rhinitis”. Am Fam Physician. 68 (10): 2015–6. PMID 14655812.
^ Drugs.com Desloratadine entry at drugs.com international Page accessed May 4, 2015
^ Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, Im M (2014). “Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study”. J Eur Acad Dermatol Venereol. 28 (12): 1654–60. doi:10.1111/jdv.12403. PMID 25081735.
^ Layton AM (2016). “Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris”. Dermatol Clin. 34 (2): 147–57. doi:10.1016/j.det.2015.11.008. PMID 27015774.
^ Jump up to:^a ^b ^c ^d “Aerius: EPAR – Product Information” (PDF). European Medicines Agency. 2017-06-07.
^ Canonica GW, Blaiss M (2011). “Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence”. World Allergy Organ J. 4 (2): 47–53. doi:10.1097/WOX.0b013e3182093e19. PMC 3500039. PMID 23268457.

Desloratadine
Clinical data


Trade names	Clarinex (US), Aerius, Dasselta, Deslordis (EU), others
AHFS/Drugs.com	Monograph
MedlinePlus	a602002
License data	EU EMA: by INN US FDA: Desloratadine
Pregnancy category	AU: B1 US: C (Risk not ruled out)
Routes of administration	Oral (tablets, solution)
ATC code	R06AX27 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy only) CA: OTC UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Rapidly absorbed
Protein binding	83 to 87%
Metabolism	UGT2B10, CYP2C8
Metabolites	3-Hydroxydesloratadine
Onset of action	within 1 hour
Elimination half-life	27 hours
Duration of action	up to 24 hours
Excretion	40% as conjugated metabolites into urine Similar amount into the feces
Identifiers
IUPAC name [show]
CAS Number	100643-71-8
PubChem CID	124087
IUPHAR/BPS	7157
DrugBank	DB00967
ChemSpider	110575
UNII	FVF865388R
KEGG	D03693
ChEBI	CHEBI:291342
ChEMBL	ChEMBL1172
ECHA InfoCard	100.166.554
Chemical and physical data
Formula	C₁₉H₁₉ClN₂
Molar mass	310.82 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Clc4cc2c(C(/c1ncccc1CC2)=C3/CCNCC3)cc4
InChI [hide] InChI=1S/C19H19ClN2/c20-16-5-6-17-15(12-16)4-3-14-2-1-9-22-19(14)18(17)13-7-10-21-11-8-13/h1-2,5-6,9,12,21H,3-4,7-8,10-11H2 Key:JAUOIFJMECXRGI-UHFFFAOYSA-N

//////////Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

E 2212

April 1, 2019 2:10 pm / Leave a comment

C₂₅ H₂₃ F₃ N₆ O, 480.48

CAS 1123197-68-1

(+) -2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

(+)-5,6,7,8-Tetrahydro-2-[(1E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-3-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyridine
(+)-2-[(E)-2-[5-Methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]ethenyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

E2212

CAS 1123197-82-9

C₂₅ H₂₃ F₃ N₆ O . ³/₂ C₄ H₆ O₆
[1,2,4]Triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydro-2-[(1E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl]-, (8S)-, (2S,3S)-2,3-dihydroxybutanedioate (2:3)

PATENT

https://patents.google.com/patent/US9453000B2/en

Examples 394 and 395 Synthesis of (+) and (−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

230 mg of the racemic title compound was obtained from 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (343 mg) and (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid (500 mg) by the same method as in Examples 194 and 195. The racemic title compound (220 mg) was separated by CHIRALPAK™ IC manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: methanol) to obtain the title optically active compound with positive optical rotation and a retention time of 16 minutes (92 mg) and the title optically active compound with negative optical rotation and a retention time of 19 minutes (79 mg).

The property value of the title optically active compound with a retention time of 16 minutes is as follows.

ESI-MS; m/z 481 [M⁺+H].

The property values of the title optically active compound with a retention time of 19 minutes are as follows.

ESI-MS; m/z 481 [M⁺+H]. ¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (s, 3H), 2.43-2.52 (m, 1H), 3.95 (s, 3H), 4.27-4.41 (m, 2H), 4.69 (dd, J=6.0, 8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.08 (d, J=16.4 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m, 4H), 7.73 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.34 (s, 1H).

PATENT

WO2009028588

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=D6AD22B6CC7302560AE1ADCED305CDCE.wapp2nC?docId=WO2009028588&tab=FULLTEXT&queryString=%28PA%2Feisai%29%2520&recNum=93&maxRec=725
（＋）および（－）－２－｛（Ｅ）－２－［５－メトキシ－６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］ビニル｝－８－（２－トリフルオロメチルフェニル）－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジンの合成
[化221]

実施例１９４および実施例１９５と同様の方法により、１－アミノ－３－（２－トリフルオロメチルフェニル）ピペリジン－２－オン（３４３ｍｇ）および（Ｅ）－３－［５－メトキシ－６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］アクリル酸（５００ｍｇ）から、ラセミ体の表題化合物を２３０ｍｇ得た。ラセミ体の表題化合物（２２０ｍｇ）をダイセル製ＣＨＩＲＡＬＰＡＫ ^ＴＭ　ＩＣ（２ｃｍ×２５ｃｍ：移動相；メタノール）にて分取し、（＋）の旋光性を有する保持時間１６分の表題光学活性化合物（９２ｍｇ）および（－）の旋光性を有する保持時間１９分の表題光学活性化合物（７９ｍｇ）を得た。
保持時間１６分の表題光学活性体の物性値は以下の通りである。
ＥＳＩ－ＭＳ；ｍ／ｚ　４８１［Ｍ ^＋＋Ｈ］．
保持時間１９分の表題光学活性体の物性値は以下の通りである。
ＥＳＩ－ＭＳ；ｍ／ｚ　４８１［Ｍ ^＋＋Ｈ］． ^１Ｈ－ＮＭＲ（ＣＤＣｌ _３）δ（ｐｐｍ）：１．９０－２．０１（ｍ，１Ｈ），２．１０－２．３５（ｍ，２Ｈ），２．２９（ｓ，３Ｈ），２．４３－２．５２（ｍ，１Ｈ），３．９５（ｓ，３Ｈ），４．２７－４．４１（ｍ，２Ｈ），４．６９（ｄｄ，Ｊ＝６．０，８．４Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝１６．４Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝７．６，７．６Ｈｚ，１Ｈ），７．４４－７．５３（ｍ，４Ｈ），７．７３（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），８．１３（ｄ，Ｊ＝１．６Ｈｚ，１Ｈ），８．３４（ｓ，１Ｈ）．

Example 394 and Example 395
(+) and (−)-2-{(E) -2- [5-methoxy-6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl] Synthesis of vinyl} -8- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine [Formula
221]

Example 194 and By a method similar to Example 195, 1-amino-3- (2-trifluoromethylphenyl) piperidin-2-one (343 mg) and (E) -3- [5-methoxy-6- (4-methyl-) 1 H-Imidazol-1-yl) pyridin-3-yl] acrylic acid (500 mg) gave 230 mg of the racemic title compound. Racemic title compound (220 mg) a Daicel CHIRALPAK ^TM　IC (2 cm × 25 cm: mobile phase; methanol) was collected by min (+) title optically active compound of the retention time of 16 minutes with a optical rotation of (92 mg) The title optically active compound (79 mg) having a polarizability of (−) and a retention time of 19 minutes was obtained.
The physical property values of the title optically active substance with a retention time of 16 minutes are as follows.
ESI-MS; m / z 481 [M ⁺ + H].
The physical property values of the title optically active substance with a retention time of 19 minutes are as follows.
ESI-MS; m / z 481 [M ⁺ + H]. ¹ H-NMR (CDCl ₃₎) Δ (ppm): 1.90 to 2.01 (m, 1 H), 2.10 to 2.35 (m, 2 H), 2.29 (s, 3 H), 2.43 to 2.52 (m) , 1 H), 3.95 (s, 3 H), 4.27-4. 41 (m, 2 H), 4.69 (dd, J = 6.0, 8.4 Hz, 1 H), 7.02 (d , J = 8.0 Hz, 1 H), 7.08 (d, J = 16.4 Hz, 1 H), 7.40 (dd, J = 7.6, 7.6 Hz, 1 H), 7.44-7. 53 (m, 4H), 7.73 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H), 8.34 (s, 1 H).

PATENT

https://patents.google.com/patent/WO2010098490A1/it

As a novel compound that has an effect of reducing the production of Aβ40 and

42 and is expected as a therapeutic or prophylactic agent for Alzheimer’s disease or the like, the present inventors have found a compound represented by the following formula (1) (compound

(D): [Formula 1]

and filed a patent application for the invention (PCT/JP08/065365).

Generally, properties of salts of compounds and those crystals that are useful as pharmaceuticals are highly important for the development of pharmaceuticals, because the properties greatly affect bioavailability of drugs, purity of drug substances, formulation of preparations, and the like. Therefore, it is necessary to research which salts and crystal forms of the compound of the formula (1) are most excellent as pharmaceuticals. Specifically, since their properties depend on the character of the individual compounds, it is generally difficult to estimate salts and crystal forms for drug substances having excellent properties and it is demanded to actually make various studies for each compound.

EXAMPLES [0023] The present invention will be described in detail below with reference to reference examples and examples; however, the present invention is not limited to these reference examples and examples. [0024]

The following abbreviations are used in the following reference examples and examples.

DMF: N,N’-dimethylformamide

THF: Tetrahydrofuran

EDC: lrEmyl-S-β-dimemylammopropytycarbodiimide hydrochloride HOBT: 1-Hydroxybenzotriazole IPEA: Diisopropylethylamine [0025]

In powder X-ray diffractometry of the crystals produced in the following examples, the resulting crystals were placed on a sample stage of a powder X-ray diffractometer and analyzed under the following conditions. [0026] Measurement conditions

Sample holder: Aluminum Target: Copper

Detector: Scintillation counter Tube voltage: 50 kV Tube current: 300 mA

Slit: DS 0.5 mm (Height limiting slit 2 mm), SS Open, RS Open Scanning rate : 5 °/min

Sampling interval: 0.02° Scan range: 5 to 35° Goniometer: Horizontal goniometer [0027] Reference Example 1

Svnmesis ofr8SV2-(fE)-246-memoxy-5-(4-memyl-lH-imidazol-l-vnpyridin-2-yllvmvU-8-(2-trifluoromethylphenyl^‘)-5,6J,8-tetrahvdro-[1.2,41triazolo[l.,5-a]pyridine

[Formula 2]

Synthesis of l-amino-3-(2-trifluoromemylphenyl)piperidin-2-one Thionyl chloride (2.72 mL) was added to a solution of 2-trifluoromethylphenylacetic acid (1.9 g) in methanol (38 mL), followed by stirring at room temperature for three hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with DMF. Sodium hydride (containing 40% mineral oil, 410 mg) was added under ice-cooling, followed by stirring for 10 minutes. The reaction solution was further stirred for 30 minutes and then ice-cooled again. l-Chloro-3-iodopropane (1.02 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was diluted with ethanol (26.6 mL). Hydrazine monohydrate (7.6 mL) was added, and the reaction solution was stirred at room temperature for two hours and then at 60°C for further three hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 1.68 g of the title compound. The property values of the compound are as follows.

ESI-MS; m/z 259 [M⁺H-H]. ¹H-NMR (CDCl₃) δ (ppm): 1.82-2.10 (m, 3H), 2.18-2.26 (m, IH), 3.58-3.76 (m, 2H), 4.07 (dd, J = 10.0, 5.6 Hz, IH), 4.60 (s, 2H), 7.24 (d, J = 7.6 Hz, IH), 7.35 (t, J = 7.6 Hz, IH), 7.51 (t, J = 7.6 Hz, IH)₅ 7.66 (d, J = 7.6 Hz, IH). [0028] Synthesis of (EV3-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2-yl]-N-f2-oxo-3 -(2-trifluoromethylphenyl)piperidin- 1 -yl]acrylamide

EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to a suspension of (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridm-2-yl]acrylic acid trifluoroacetate (1.42 g) and l-amήio-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF (30 mL). After stirring at room temperature for 14 hours, a saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.23 g of the title compound. The property values of the compound are as follows. ESI-MS; m/z 500 [M¹H-HJ. [0029]

Synthesis of r8S>-2-(fEV2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridm’2-vnvinvU-8-(2-trifluoromethvlphenvD-5.6.7.8-tetrahvdro-ri.2.41triazoloπ.5-a1pvridine Phosphorus oxychloride (24.2 mL) was added to (E)-3~[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-l-yl]acrylamide (1.2 g). The reaction solution was stirred at 100⁰C for one hour and then concentrated under reduced pressure. Subsequently, the residue was diluted with acetic acid (24.2 mL) and then ammonium acetate (1.9 g) was added, followed by stirring at 150⁰C for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain a racemate of the title compound (750 mg). The resulting racemate (410 mg) was separated by CHIRALP AK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm x 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 mL/min) to obtain the title compound with a retention time of 33 minutes and negative optical rotation (170 mg) as crystals. The property values of the title compound are as follows.

¹H-NMR (CDCl₃) δ (ppm): 1.90-2.01 (m, IH), 2.10-2.35 (m, 2H), 2.29 (d, J = 1.2 Hz, 3H), 2.42-2.51 (m, IH), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J = 8.4, 6.0 Hz, IH), 6.92 (d, J = 8.0 Hz, IH), 6.95 (t, J = 1.2 Hz, IH), 7.01 (d, J = 7.6 Hz, IH), 7.39 (t, J = 7.6 Hz₅ IH), 7.44 (d, J = 16.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.49 (t, J = 7.6 Hz, IH), 7.63 (d, J = 16.0 Hz₅ IH), 7.72 (d, J = 7.6 Hz, IH), 7.76 (d, J = 1.2 Hz, IH). [0030]

(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-lH-imidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine synthesized according to the above reference example was used for the following synthesis of salts. [0031] Example 1

Synthesis of r8SV2-{rEV2-[6-methoxy-5-(4-methyl-lH-imidazol-l-vπpyridin-2-vnvinvU-8-f2-trifluoromethylphenyl)-5.6.7.8-tetrahvdro-fl,2,4]triazolo[l.,5-a]pyridine 1.5 D-tartrate

(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (33.70 mg) was dissolved in 285 μL of a D-tartaric acid-ethanol solution (110.92 mg/3 mL) with stirring at room temperature. The oil was precipitated when 1 mL of heptane was added. Accordingly, the oily substance was dissolved by adding 1 mL of ethanol. Further, 0.5 mL of heptane was added, and the mixture was transferred to a low temperature laboratory at about 5⁰C (under shading) and continuously stirred for 24 hours. Thus, partial gelation occurred. Thereafter, the mixture was brought back to room temperature and continuously stirred, resulting in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 21.25 mg of the title compound as white solid crystals. ¹H-NMR (600 MHz, DMSOd₆) δ (ppm): 1.96 (m, IH), 2.14 (s, 3H), 2.16 (m, 2H), 2.29 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 3H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (s, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH)₅ 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J = 8 Hz, IH), 7.61 (brdd, J = 8 Hz₅ IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (s, IH). [0032] Example 2

Synthesis of (^‘8SV2-l(Ε)-2-f6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridm-2-yllvinyl>-8-f2-trifluoromethylphenylV5,6J,8-tetrahvdro-[l ,2,4]triazolo[l ,5-a]pyridine di-D-tartrate

(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6₅7,8-tetrahydro-[l ,2,4]triazolo[l ,5-a]ρyridine (810.18 mg) was dissolved in 8 mL of a D-tartaric acid-ethanol solution (751.13 mg/10 mL) with stirring at room temperature. The oil was precipitated when 2 mL of heptane was added. Accordingly, the oily substance was dissolved by ultrasonic treatment to prepare a clear solution. Several mg of crystals of the 1.5 D-tartrate prepared according to Example 1 were added, followed by stirring at room temperature. Stirring for about one hour resulted in gelation and subsequent precipitation of a solid. Further, stirring was continued while gradually adding 14 mL of heptane. A part of the suspension (2 mL) was separated and the solid was collected by filtration through a glass filter. The solid was dried under reduced pressure at room temperature to obtain 71.14 mg of the title compound as white solid crystals. ¹H-NMR (400 MHz, DMSOd₆) δ (ppm): 1.97 (m, IH), 2.15 (s, 3H), 2.16 (m, 2H), 2.30 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 4H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (brs, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH), 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J – 8 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (brs, IH). [0033] Example 3

Synthesis of r8SV2-(rE)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridin-2-yl1vinvU-8-α-trifluoromethylphenyl)-5,6J,8-tetrahydro-[1.2,4]triazolo[l,5-a]pyridine disulfate

Concentrated sulfuric acid (11.5 μL) was added to a solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-txifluoromethylphenyl)-5,6,7,8-tetrahydro-[l₅2,4]triazolo[l₅5-a]pyridine (98.09 mg) in ethanol (1 mL), and 1 mL of ethyl acetate was added with stirring at room temperature. Since the oily portion was confirmed on the bottom of the recovery flask, the oily substance was dissolved by ultrasonic treatment. Stirring at room temperature under shading for about 30 minutes resulted in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 127.94 mg of the title compound as white solid crystals. ¹H-NMR (400 MHz, DMSOd₆) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz, 3H), 4.01 (s, 3H), 4.29 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH)₅ 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (m, IH), 7.78 (m, IH), 8.00 (d, J = 8 Hz, IH), 9.36 (d, J = 2 Hz, IH). [0034] Example 4 Synthesis of (8SV2-((E)-2-[^“6-methoxy-5-(4-methyl-lH-imidazol-l-yl^N)ρyridin-2-yllvinvU-8-(^‘2-trifluoromethylphenyl)-5,6,7,8-tetrahvdiO-[1.2,41triazolo[l,5-a]pyridine dihydrobromide

Concentrated hydrobromic acid (24.8 μL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,84etrahydro-[l,2₅4]triazolo[l₅5-a]pyridine (51.42 mg) m ethanol (1 mL), and 1 mL of heptane was added with stirring at room temperature. After several minutes, 1 mL of heptane was further added to the solution and stirring was continued. The solution was stirred at room temperature for one hour and then further stirred at about 5⁰C for 20 minutes. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 49.24 mg of the title compound as white solid crystals. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.99 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz₅ 3H), 4.01 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz₅ IH), 7.25 (brd, J = 8 Hz₅ IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 7 Hz, IH)₅7.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz₅ IH), 7.77 (m, IH)₅ 7.78 (m, IH), 8.00 (d, J = 7 Hz, IH), 9.37 (d, J = 2 Hz, IH). [0035] Example 5

Synthesis of r8SV2-((Ε)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-yl)ρyridin-2-vnvinyl}-8-r2-trifluoromethylphenyl)-5,6J,8-tetrahvdro-[1.2,41triazolo[1.5-alpyridine hydrochloride

Concentrated hydrochloric acid (3.6 μL) was added to a solution of (8S)-2-{(E)- 2-[6-methoxy-5-(4-metiiyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylplienyl)-5,6,7,8-te1xahydro-[l,2,4]triazolo[l,5-a]pyridme (19.80 mg) in 2-propanol (1 mL), and a total of 4 mL of heptane was added in 1 mL portions with stirring at room temperature. The solution was stirred at room temperature under shading for five days. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 7.45 mg of the title compound as white solid crystals. ¹H-NMR (400 MHz, DMSOd₆) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H)₅ 2.30 (m, IH), 2.30 (s, 3H), 4.00 (s, 3H), 4.30 (m, 2H)₅ 4.52 (dd, J = 9, 6 Hz₅ IH), 7.25 (brd, J – 8 Hz₅ IH), 7.36 (d, J = 16 Hz₅ IH), 7.37 (d₅ J = 8 Hz, IH), 7.50 (brt, J = 8 Hz₅ IH)₅ 7.53 (d, J = 16 Hz₅ IH)₅ 7.61 (brt, J = 8 Hz₅ IH)₅ 7.66 (brs, IH), 7.77 (brd, J = 8 Hz, IH)₅ 7.96 (d, J = 8 Hz₅ IH), 9.06 (brs, IH). [0036] Example 6

Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(^‘4-methyl-lH-imidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5.6,7,8-tetrahvdro-[l,2,4]triazolo[L5-a1pyridine hydrochloride Concentrated hydrochloric acid (14.3 μL) and heptane (7 mL) were added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6₅7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (79.77 mg) in 2-propanol (3 mL). A small amount of the crystals obtained in Example 5 were added as seed crystals with stirring at room temperature. The mixture was transferred to a low temperature laboratory at about 5⁰C and stirred for one hour. Thereafter, 1 mL of heptane was further added, followed by stirring for several minutes. When the precipitated solid was collected by filtration through a glass filter, the solid was precipitated in the filtrate. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 38.02 mg of the title compound as white solid crystals. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 1.97 (m, IH), 2.17 (m₅ 2H), 2.29 (m, IH), 2.32 (brd, J = 1 Hz, 3H), 4.00 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH), 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz₅ IH), 7.38 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH)₅ 7.54 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.72 (brs, IH), 7.77 (brd, J = 8 Hz, IH), 7.98 (d, J = 8 Hz₅ IH)₅ 9.24 (brs, IH). [0037] Example 7

SvnJhesis off8SV2-f(E>2-r6-memoxy-5-(4-mefovπ trifluoromethylt>henylV5,6,7,8-tetrahvdro-[l,2,4]triazolo[l,5-a]pyridine mesylate

Mesylic acid (0.8 μL) was added to a mixed solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphen^ tetrahydro-[l₅2,4]triazolo[l,5-a]pyridine (50 mg) in t-butyl methyl ether (0.8 mL)-ethaαol (0.1 mL). The mixture was solidified as a result of stirring at room temperature for two hours. The solid was collected by filtration through a glass filter. The solid was washed with t-butyl methyl ether-ethanol (8:1) and then dried under reduced pressure at room temperature to obtain 51.9 mg of the title compound as pale yellow solid crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.90-2.05 (m, IH)₃ 2.10-2.22 (m, 2H), 2.28-2.40 (m, IH), 2.31 (s, 3H), 2.35 (s, 3H)₅ 4.02 (s, 3H)₅ 4.25-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.27 (d₅ J = 8.0 Hz₅ IH)₅ 7.38 (d, J = 16.0 Hz₅ IH)₅ 7.41 (d, J = 8.0 Hz, IH)₅ 7.51 (t₅ J = 8.0 Hz₅ IH)₅ 7.55 (d, J = 16.0 Hz₅ IH), 7.63 (t, J = 8.0 Hz₅ IH)₅ 7.78 (d, J = 8.0 Hz₅ IH)₅ 7.79 (s, IH), 8.01 (d, J = 8.0 Hz₅ IH), 9.37 (s, IH). [0038] Example 8 Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-vnvinvn-8-r2-trifluoromethylphenyl)-5.6,7,8-tetrahydro-[l.,2,4^‘|triazolo[l,5-a]pyridine diphosphate

A solution of phosphoric acid (52.8 mg) in acetonitrile (0.2 mL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-mτidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5₅6₅7₅8-tetrahydro-[l₅2₅4]triazolo[l,5-a]pyridine (100 mg) in acetonitrile (0.8 mL) at room temperature. The precipitated oil was solidified as a result of stirring with spatula. The solid was collected by filtration through a glass filter. The solid was washed with ice-cold acetonitrile, air-dried at room temperature for 10 minutes and then dried under reduced pressure at room temperature to obtain 120 mg of the title compound as white solid crystals. ¹H-NMR (DMSO-d₆) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H)₅ 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH)₅ 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz₅ IH), 7.47 (d, J = 16.0 Hz₅ IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH). [0039] Example 9 Svnmesis of(8SV2-{(E)-2-[6-memoxy-5-(4-methyl-lH-irnidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahvdro-[l .2.41triazolo[l .5-a]pyridine diphosphate

A solution of phosphoric acid (13.2 mg) in ethanol (0.05 mL) was added to a mixed solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2_!,4]triazolo[l,5-a]pyridme (50 mg) in heptane (0.6 mL)-ethanol (0.15 mL) at room temperature. The reaction solution was stirred at room temperature, and the precipitated solid was collected by filtration through a glass filter. The solid was washed with heptane-ethanol (3:1) and then dried under reduced pressure at room temperature to obtain 37.6 mg of the title compound as white solid crystals. ¹H-NMR (DMSOd₆) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H), 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz, IH), 7.47 (d, J = 16.0 Hz, IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH).

CLIP

Development of an Efficient Manufacturing Process for E2212 toward Rapid Clinical Introduction

Minetaka Isomura *^‡

, Taiju Nakamura^‡, Atsushi Kamada^†, Takeo Sasaki^§, Toshiyuki Uemura^§, Yorihisa Hoshino^†, Masaaki Matsuda^†, Yongbo Hu^∥, Daiju Hasegawa^§, Kazato Inanaga^‡, Nobuaki Sato^§, Kazuhiro Yoshizawa^‡, George A. Moniz^∥, Gordon D. Wilkie^∥, Francis G. Fang^∥, Yoshihiro Nishikawa^‡, and Katsuya Tagami *^‡

^† API Research Japan, Pharmaceutical Science & Technology, CFU, Medicine Development Center, Eisai Co. Ltd., 5-1-3-Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan

^‡ API Research Japan, Pharmaceutical Science & Technology, CFU, Medicine Development Center, Eisai Co. Ltd., 22-Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan

^§ Neurology Tsukuba Research Department, Discovery, Medicine Creation, NBG, Eisai Co. Ltd., 5-1-3-Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan

^∥ Integrated Chemistry, Eisai AiM Institute, 4 Corporate Drive, Andover, Massachusetts 01810, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00444

*E-mail: m-isomura@hhc.eisai.co.jp., *E-mail: k-tagami@hhc.eisai.co.jp.

This article is part of the Japanese Society for Process Chemistry special issue.

Process studies of E2212 (1) toward rapid clinical introduction are described. Through comprehensive route-finding studies and optimization of key condensation and cyclization steps, a racemate-based manufacturing route was established and successfully scaled-up to the hundred kilogram scale. For the rapid delivery of a drug substance containing the Z isomer for preclinical safety studies, the successful scale-up of the photoisomerization of an olefin in a flow system is also presented.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00444

E2212 (1) (18.0 kg, 92.5% yield) as a white solid. Mother liquor 3 were recycled according to the procedure described below. FTIR (cm^–1, KBr) 3461, 3173, 2956, 1734, 1584, 1536, 1476, 1309, 1130, 835, 765, 752; ¹H NMR (600 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.77 (br d, J = 8.4 Hz, 1H), 7.61 (br dd, J = 7.8, 7.8 Hz, 1H), 7.49 (br dd, J = 7.8, 7.8 Hz, 1H), 7.46 (d, J= 15.6 Hz, 1H), 7.32 (d, J = 15.6 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.25 (br d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 4.51 (dd, J = 9.0, 6.0 Hz, 1H), 4.29 (s, 3H), 4.28 (m, 2H), 3.98 (s, 3H), 2.29 (m, 1H), 2.14 (s, 3H), 2.16 (m, 2H), 1.96 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ 173.3, 159.3, 155.4, 155.0, 150.1, 141.1, 137.1, 136.9, 133.6, 132.9, 131.0, 130.5, 127.6, 127.1 (q, J_C–F = 30 Hz), 125.8 (q, J_C–F = 5.6 Hz), 124.7 (q, J_C–F = 270 Hz), 122.2, 120.7, 117.2, 116.5, 72.3, 53.7, 47.0, 37.6, 30.7, 21.3, 13.6; HRMS (ESI+) calcd for C₂₅H₂₃F₃N₆O ([M + H]⁺) 481.1958, found 481.1953.

E/Z mixture of E2212 (196.0 g (containing residual n-PrOH), E:Z = 61.8:37.4 by UV (271 nm), 1.3:1.0 by ¹H NMR) as an orange oil. HPLC conditions to monitor the isomerization conversion and E/Z ratio: XBridge-Shield-RP18 (5 μm, 4.6 mm × 250 mm), 1.0 mL/min, oven temperature = 40 °C, mobile phase A = 900:100:1 v/v/w H₂O/MeCN/AcONH₄, mobile phase B = 100:900:1 v/v/w H₂O/MeCN/AcONH₄, gradient (time (min)/B conc (%)) = 0/5 → 5/45 → 35/45 → 50/100 → 55/100 → 55.01/5 → 65/5 → 65.01/stop, RRT of Z form = 0.73.

From this mixture, a small portion was purified by silica gel column chromatography to give the Zisomer in free form. FTIR (cm^–1, KBr) 3416, 2952, 1586, 1500, 1487, 1313, 1161, 1114, 1036, 966, 858, 769; ¹H NMR (600 MHz, CDCl₃) δ 7.90 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.6, 7.4 Hz, 1H), 7.37 (dd, J = 7.7, 7.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.93 (dd, J = 1.2, 1.0 Hz, 1H), 6.73 (d, J = 13.3 Hz, 1H), 6.64 (d, J = 13.3 Hz, 1H), 4.63 (dd, J = 9.3, 5.9 Hz, 1H), 4.34 (br ddd, J = 13.0, 5.6, 4.1 Hz, 1H), 4.28 (ddd, J = 13.0, 9.9, 4.9 Hz, 1H), 3.92 (s, 3H), 2.45 (dddd, J = 13.2, 6.5, 6.5, 2.6 Hz, 1H), 2.29 (d, J= 1.0 Hz, 3H), 2.28 (m, 1H), 2.15 (m, 1H), 1.94 (dddd, J = 12.9, 11.4, 8.3, 2.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 159.4, 155.2, 154.4, 150.8, 140.2, 138.3, 136.6, 133.2, 131.9 131.6, 129.9, 128.5 (q, J_C–F = 29.8 Hz), 127.2, 126.2 (q, J_C–F = 5.6 Hz), 124.4 (q, J_C–F = 274.0 Hz), 121.8, 120.1, 118.4, 116.0, 53.6, 47.3, 37.9, 31.0, 21.7, 13.6; HRMS (ESI+) calcd for C₂₅H₂₄F₃N₆O ([M + H]⁺) 481.1958, found 481.1960.

///////////E2212, E 2212

Certolizumab pegol, セルトリズマブペゴル (遺伝子組換え)

April 1, 2019 2:05 pm / 1 Comment on Certolizumab pegol, セルトリズマブペゴル (遺伝子組換え)

Image result for certolizumab pegol

>Amino acid sequence of the light chain
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

>Amino acid sequence of the heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY
ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA

Certolizumab pegol

CAS: 428863-50-7

セルトリズマブペゴル (遺伝子組換え)

CDP 870 / CDP-870 / CDP870 / PHA-738144

Formula	C2115H3252N556O673S16
Cas	428863-50-7
Mol weight	47748.8128

Reducing signs and symptoms of Crohn’s disease and treatment of moderately to severely active rheumatoid arthritis (RA).

Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). Polyethylene glycol helps to delay the metabolism and elimination of the drugs. Chemically, the light chain is made up of 214 amino acid residues while the heavy chain is composed of 229 amino acid residues. The molecular mass of the Fab’ antibody fragment itself is 47.8 kDa. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008

Certolizumab pegol (CDP870, tradename Cimzia) is a biologic medication for the treatment of Crohn’s disease,^[1]^[2] rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha(TNF-α) and is manufactured by UCB.^[3]^[4]^[5]

Image result for certolizumab pegol

Medical uses

Crohn’s Disease: On April 22, 2008, the U.S. FDA approved Cimzia for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.^[4]^[6]^[7]

Rheumatoid arthritis: On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.^[8]

Psoriatic arthritis: On September 27, 2013, the U.S. FDA approved Cimzia for the treatment of adult patients with active psoriatic arthritis.^[9]

Method of action

Certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fabfragment of a humanized TNF inhibitor monoclonal antibody.^[10]

Clinical trials

Crohn’s disease: Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease.^[1]^[10]^[11]^[12]

Axial spondyloarthritis: In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive results in patient self-reported questionnaires, with rapid improvement of function and pain reduction, in patients with axial spondyloarthritis.^[13]

Rheumatoid arthritis: Certolizumab appears beneficial in those with rheumatoid arthritis.^[14]

Side effects

Significant side effects occur in 2% of people who take the medication.^[14]

References

^ Jump up to:^a ^b Sandborn WJ, Feagan BG, Stoinov S, et al. (July 2007). “Certolizumab pegol for the treatment of Crohn’s disease”. N. Engl. J. Med. 357 (3): 228–38. doi:10.1056/NEJMoa067594. PMC 3187683. PMID 17634458.
^ Goel, Niti; Sue Stephens (2010). “Certolizumab pegol”. mAbs. 2 (2): 137–147. doi:10.4161/mabs.2.2.11271. PMC 2840232. PMID 20190560.
^ Kaushik VV, Moots RJ (April 2005). “CDP-870 (certolizumab) in rheumatoid arthritis”. Expert Opinion on Biological Therapy. 5 (4): 601–6. doi:10.1517/14712598.5.4.601. PMID 15934837.
^ Jump up to:^a ^b index.cfm?fuseaction=Search.Label_ApprovalHistory “Cimzia Label and Approval History” Check |url= value (help). Drugs@FDA. U.S. Food and Drug Administration(FDA). Retrieved 2009-11-15.
^ “Cimzia Prescribing Information” (PDF). US Food and Drug Administration (FDA). April 2016. Retrieved 2016-08-21.
^ UCB press release – Cimzia Approved in the US for the Treatment of Moderate to Severe Crohn’s Disease. Retrieved April 22, 2008.
^ Waknine, Yael (May 1, 2008). “FDA Approvals: Patanase, Actonel, Cimzia”. Medscape. Retrieved 2008-05-01.
^ “Cimzia European Public Assessment Report”. European Medicines Agency. Retrieved November 15, 2009.
^ “Cimzia (certolizumab pegol) approved by the U.S. FDA for treatment of adult patients with active psoriatic arthritis”. Archived from the original on October 1, 2013. Retrieved October 1, 2013.
^ Jump up to:^a ^b Schreiber S. et al., Certolizumab pegol, a humanised anti-TNF pegylated FAb’ fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn’s disease: a phase 3 study (precise), Gut, 2005, 54, suppl7, A82
^ Sandborn et al., Certolizumab pegol administered subcutaneously is effective and well tolerated in patients with active Crohn’s disease: results from a 26-week, placebo-controlled Phase 3 study (PRECiSE 1), Gastroenterology, 2006, 130, A107
^ “New Analysis Shows Cimzia (Certolizumab Pegol) Maintained Remission and Response in Recent Onset Crohn’s Disease” (Press release). UCB. October 23, 2006. Retrieved 2009-11-15.
^ Sieper J, Tubergen A, Coteur G, Woltering F, Landewe R (May 2013). “PMS50 – Rapid Improvements In Patient-Reported Outcomes With Certolizumab Pegol In Patients With Axial Spondyloarthritis, Including Ankylosing Spondylitis And Non-Radiographic Axial Spondyloarthritis: 24-Week Results Of A Phase 3 Double Blind Randomized Placebo-Controlled Study”. Value in Health. 16 (3): A227. doi:10.1016/j.jval.2013.03.1150.
^ Jump up to:^a ^b Ruiz Garcia, V; Jobanputra, P; Burls, A; Vela Casasempere, P; Bort-Marti, S; Bernal, JA (Sep 8, 2017). “Certolizumab pegol (CDP870) for rheumatoid arthritis in adults”(PDF). The Cochrane Database of Systematic Reviews. 9: CD007649. doi:10.1002/14651858.CD007649.pub4. PMID 28884785.

External links

certolizumab+pegol at the US National Library of Medicine Medical Subject Headings (MeSH)
Cimzia Website

FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis

March 28, 2019

Release

The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.

“Today’s approval of Cimzia fulfills an unmet need for patients suffering from non-radiographic axial spondyloarthritis as there has been no FDA-approved treatments until now,” said Nikolay Nikolov, M.D., associate director for rheumatology of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms. There is no visible damage seen on x-rays, so it is referred to as non-radiographic.

The efficacy of Cimzia for the treatment of nr-axSpA was studied in a randomized clinical trial in 317 adult patients with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein (CRP) levels and/or sacroiliitis (inflammation of the sacroiliac joints) on MRI. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score, a composite scoring system that assesses disease activity including patient-reported outcomes and CRP levels. Responses were greater for patients treated with Cimzia compared to patients treated with placebo. The overall safety profile observed in the Cimzia treatment group was consistent with the known safety profile of Cimzia.

The prescribing information for Cimzia includes a Boxed Warning to advise health care professionals and patients about the increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis (infection in the blood steam), invasive fungal infections (such as histoplasmosis, an infection that affects the lungs), and other infections. Cimzia should be discontinued if a patient develops a serious infection or sepsis. Health care providers are advised to perform testing for latent TB and, if positive, to start treatment for TB prior to starting Cimzia. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative. The Boxed Warning also advises that lymphoma (cancer in blood cells) and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which Cimzia is a member. Cimzia is not indicated for use in pediatric patients. Cimzia must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Cimzia was originally approved in 2008 and is also indicated for adult patients with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The FDA granted the approval of Cimzia to UCB.

Certolizumab pegol
Monoclonal antibody
Syringe with 200mg Certolizumab pegol
Type	Fab’ fragment
Source	Humanized (from mouse)
Target	TNF alpha
Clinical data
Trade names	Cimzia
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a608041
License data	EU EMA: by INN
Pregnancy category	US: B (No risk in non-human studies)
Routes of administration	Subcutaneous
ATC code	L04AB05 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Elimination half-life	about 11 days
Excretion	Renal (PEG only)
Identifiers
CAS Number	428863-50-7
ChemSpider	none
UNII	UMD07X179E
KEGG	D03441
ChEMBL	ChEMBL1201831
Chemical and physical data
Formula	C₂₁₁₅H₃₂₅₂N₅₅₆O₆₇₃S₁₆
Molar mass	47,750 g/mol g·mol⁻¹

///////////////FDA 2019, Cimzia, certolizumab pegol, inflammatory arthritis, UCB

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634671.htm?utm_campaign=032819_PR_FDA%20approves%20treatment%20for%20patients%20with%20a%20type%20of%20inflammatory%20arthritis&utm_medium=email&utm_source=Eloqua

Cevimeline, セビメリン

March 29, 2019 1:20 pm / Leave a comment

Cevimeline

セビメリン

Molecular FormulaC₁₀H₁₇NOS
Average mass199.313 Da

cis-2′-Methylspiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxathiolane]

Evoxac [Trade name]

Spiro[1-azabicyclo[2.2.2]octane-3,5′-[1,3]oxathiolane], 2′-methyl-, (2’R,3R)-

Cevimeline

CAS Registry Number: 107233-08-9

CAS Name: (2¢R,3R)-rel-2¢-Methylspiro[1-azabicyclo[2.2.2]octane-3,5¢-[1,3]oxathiolane]

Additional Names: (±)-cis-2-methylspiro[1,3-oxathiolane-5,3¢-quinuclidine]

Molecular Formula: C10H17NOS

Molecular Weight: 199.31

Percent Composition: C 60.26%, H 8.60%, N 7.03%, O 8.03%, S 16.09%

Literature References: Muscarinic M1 and M3 receptor agonist. Prepn: A. Fisher et al., JP Kokai 61 280497; eidem, US 4855290; (1986, 1989 both to State of Israel). Improved process: K. Hayashi et al., US 5571918 (1996 to Ishihara Sangyo Kaisha). Sialogogic effect in animals: H. Masunaga et al., Eur. J. Pharmacol. 339, 1 (1997). General pharmacology: H. Arisawa et al., Arzneim.-Forsch. 52, 14, 81 (2002). Clinical experience in Sjögren’s syndrome dry eye: M. Ono et al., Am. J. Ophthalmol. 138, 6 (2004); in dry mouth: K. Suzuki et al., Pharmacology 74, 100 (2005). Review of clinical pharmacokinetics and efficacy in Sjögren’s syndrome: H. Yasuda, H. Niki, Clin. Drug Invest. 22, 67-73 (2002).

Derivative Type: Hydrochloride hemihydrate

CAS Registry Number: 153504-70-2; 107220-28-0 (anhydrous)

Manufacturers’ Codes: AF-102B; SNI-2011

Trademarks: Evoxac (Daiichi)

Molecular Formula: C10H17NOS.HCl.½H2O

Molecular Weight: 244.78

Percent Composition: C 49.07%, H 7.82%, N 5.72%, O 9.80%, S 13.10%, Cl 14.48%

Properties: White to off white crystalline powder, mp 201-203°. Freely sol in alcohol, chloroform; very sol in water. Virtually insol in ether.

Melting point: mp 201-203°

Therap-Cat: Sialagogue.

Keywords: Sialagogue.

Cevimeline hydrochloride

- Synonyms:AF-102B, SNI-2011, SNK-508, Evoxac
- ATC:N07
Use:cognition disorder, treatment of Sjogren’s syndrome, muscarinic M₃-receptor agonist
Chemical name:(2′R,3R)-rel-2′-methylspiro[1-azabicyclo[2.2.2]octane-3,5′-[1,3]oxathiolane] hydrochloride hydrate (2:2:1)
Formula:C₁₀H₁₇NOS • HCl • 1/2H₂O

MW:489.57 g/mol
CAS-RN:153504-70-2
InChI Key:SURWTGAXEIEOGY-GHXDPTCOSA-N
InChI:InChI=1S/C10H17NOS.ClH/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11;/h8-9H,2-7H2,1H3;1H/t8-,10-;/m1./s1

Derivatives

base

Formula:C₁₀H₁₇NOS
MW:199.32 g/mol
CAS-RN:107233-08-9

anhydrous hydrochloride

Formula:C₁₀H₁₇NOS • HCl
MW:235.78 g/mol
CAS-RN:107220-28-0

Cevimeline is cis-2′-methylspiro {1-azabicyclo [2.2.2] octane-3, 5′ -[1,3] oxathiolane} hydro-chloride, hydrate (2:1). Its empirical formula is C₁₀H₁₇NOS•HCl•½ H₂O, and its structural formula is:

Cevimeline has a molecular weight of 244.79. It is a white to off white crystalline powder with a melting point range of 201 to 203°C. It is freely soluble in alcohol and chloroform, very soluble in water, and virtually insoluble in ether. The pH of a 1% solution ranges from 4.6 to 5.6. Inactive ingredients include lactose monohydrate, hydroxypropyl cellulose, and magnesium stearate.

Image result for Cevimeline STRUCTURE

Cevimeline hydrochloride [USAN]
RN: 153504-70-2

(+-)-cis-2-Methylspiro(1,3-oxathiolane-5,3′-quinuclidine) hydrochloride, hemihydrate

Cevimeline (trade name Evoxac) is a parasympathomimetic and muscarinic agonist,^[1] with particular effect on M₁ and M₃ receptors. It is used in the treatment of dry mouth and especially associated with Sjögren’s syndrome.

Mechanism of action

By activating the M₃ receptors of the parasympathetic nervous system, cevimeline stimulates secretion by the salivary glands, thereby alleviating dry mouth.

Side effects

Known side effects include nausea, vomiting, diarrhea, excessive sweating, rash, headache, runny nose, cough, drowsiness, hot flashes, blurred vision, and difficulty sleeping.^[2]

Contraindications include asthma and angle closure glaucoma.

Clip

https://www.sciencedirect.com/science/article/abs/pii/S0731708515302260

Image result for cevimeline

CLIP

https://www.sciencedirect.com/science/article/pii/S0040403913005042

Image result for cevimeline

CLIP

Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.
Synthesis of Cevimeline Hydrochloride (EN:134916): Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III) (1,2). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate (1) or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid (2) affords a mixture of two diastereomeric spiro-racemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid (1,2). The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3 (2,3). Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane (4).(Scheme 13491601a) Description M.p. 203 C (4). Sources Discovered by Israel Institute for Biological Research, Ness-Ziona (IL) and licensed to Snow Brand Milk Products Co. Ltd. (JP). In the U.S., comarketed by Snow Brand Milk Products and Daiichi Pharmaceutical Co., Ltd. In Japan, codeveloped with Nippon Kayaku Co. Ltd. Ishihara Sangyo Co., Ltd. (JP) is the bulk supplier. References 1. Fisher, A., Heldman, E., Grunfeld, Y., Karton, I., Levy, A. (Israel Institute for Biological Research); Derivs. of quinuclidine; EP 0205247, JP 1986280497, US 4855290. 2. Hayashi, K., Tokumoto, S., Yoshizawa, H., Isogai, T. (Ishihara Sangyo Kaisha, Ltd.); Method for producing 2-methylspiro(1,3-oxathiolan-5,3′)quinuclidine; EP 0683168, US 5571918. 3. Haga, T., Koyanagi, T., Hara, K., Maeda, M., Shigehara, I. (Ishihara Sangyo Kaisha, Ltd.); Method for isomerization of trans-form 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine or acid addition salts thereof; EP 0298491, US 4861886. 4. Saito, K., Ono, T., Honda, N. (Snow Brand Milk Products Co., Ltd.); Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily; JP 1992108792.

PATENT

https://patents.google.com/patent/US8080663B2/en

The present invention refers to a novel, industrially advantageous process for the preparation of an intermediate useful for the preparation of Cevimeline hydrochloride (1, cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine, Scheme 1). This pharmaceutical is useful for the treatment of diseases of the central nervous system due to disturbances of central cholinergic function and autoimmune system (Sjörgen’s syndrome) and is marketed as Evoxac®.

U.S. Pat. No. 4,855,290 describes a process for preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process comprises the preparation of the epoxide of 3-methylenequiniclidine, which is subsequently reacted with hydrogen sulfide to produce 3-hydroxy-3-mercaptomethylquiniclidine and condensed with acetaldehyde in the presence of a Lewis acid (boron trifluoride etherate) to provide 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. This process is depicted in Scheme I.

This process suffers from major disadvantages when transiting to industrial scale. These include the use of the highly hazardous and difficult to handle hydrogen sulfide gas. Also, boron trifluoride etherate is employed during the condensation step with acetaldehyde. The boron trifluoride etherate reagent is an air and moisture sensitive Lewis acid which has to be used under anhydrous conditions, thus creating a serious disadvantage in industrial settings. Another drawback of this process is the use of sodium hydride. U.S. Pat. Nos. 5,571,918 and 4,861,886 relate to the isomerization of the trans- to cis-form of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine but do not describe methods for its preparation. Thus, an industrially acceptable and cost-effective method for the preparation of Cevimeline hydrochloride which overcomes the deficiencies of the prior art is required.

Further and other objects of the invention will be realized by those skilled in the art from the following Summary of the Invention and Detailed Description of Preferred Embodiments of the Invention thereof.

According to one aspect of the invention, a novel process is provided for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process is industrially practical, efficient, safe and economical, as well as being environmentally friendly. The general method is shown in the Scheme II.

wherein R is selected from C1 to C6 alkyl and aryl groups, most preferably a methyl, ethyl or propyl group; R¹is hydrogen or a C2 to C7 alkyl or aryl carbonyl group; R²is a C1 to C6 alkyl group, preferably methyl, ethyl, propyl, or butyl group.

Figure US08080663-20111220-C00003

EXAMPLE I Preparation of the Epoxide of 3-methylenequiniclidine (3)

A mixture of the hydrochloric salt of 3-quiniclidinone (2, 120 g, 795.7 mmol) and trimethylsulfoxonium iodide (219 g, 993.3 mmol) in dimethylsulfoxide (91.0 g, 0.63 mol) was cooled to 0-5° C. in an ice/water bath under nitrogen atmosphere. A solution of potassium tert-butoxide (201 g, 1789.1 mmol) in dimethylsulfoxide (500 mL) was added dropwise over 45 minutes. The mixture was warmed gradually to room temperature and stirred for an additional 16 hours at room temperature. After cooling to 0-5° C. (ice/water bath) the mixture was poured into an ice/water mixture (500 g) and then sodium chloride (300 g) was added. The mixture was stirred for 30 minutes and extracted with toluene (3×400 mL). The toluene phase was dried over sodium sulfate, filtered and evaporated to furnish the epoxide of 3-methylenequiniclidine (60 g, 431.7 mmol, 54% yield) as a yellow oil. The product could be used in the next step neat or as toluene solution after the extraction without further purification.

¹H NMR (400 MHz, CDCl₃): δ=3.10 (d, 1H, J=14.6 Hz); 2.98-2.77 (m, 5H); 2.74 (d, 1H, J=4.8 Hz); 2.70 (d, 1H, J=4.8 Hz); 1.96-1.89 (m, 1H); 1.79-1.62 (m, 2H); 1.60-1.54 (m, 1H); 1.38-1.36 (m,1H).

LRMS (ES+): 140.0 (100, M+H⁺).

EXAMPLE II Preparation of the Thiolacetic Acid Salt of 3-hydroxy-3-acetoxymercaptomethylquiniclidine (4)

A solution of the epoxide of 3-methylenequiniclidine (3, 54 g, 388.5 mmol) in toluene (200 mL) was cooled to 0-5° C. (ice/water bath). Thiolacetic acid was added dropwise over 10-15 minutes. The mixture was stirred at 0-5° C. for 30 minutes and then allowed to come to room temperature. After stirring at room temperature for 2 hours the formed precipitate was filtered and washed with toluene (2×100 mL) to give the 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R¹is H and R is methyl, 77 g, 264.6 mmol, 68%) as a light yellow solid. The product was used in the next step without any further purification.

¹H NMR (400 MHz CD₃OD): δ=3.47 (d, 1H, J=14.1 Hz); 3.37-3.18 (m, 7H); 2.40 (s, 3H); 2.38 (s, 3H); 2.36-2.27 (m, 1H), 2.14-2.05 (m, 2H); 2.03-1.93 (m, 1H); 1.81-1.78 (m, 1H).

LRMS (ES+): 216.1 (100, M−[SCOCH₃]⁻+H⁺).

EXAMPLE III Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine using p-toluenesulfonic acid (1)

To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R¹is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was heated to reflux for 3.5 hours. The mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to reflux and stirred for an additional 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (50 mL). The mixture was cooled to 0-5° C. and a 25% aqueous solution of sodium hydroxide (80 mL) was added. The mixture was stirred for 10-15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (3×50 mL). The organic phases were combined and extracted with 5% aqueous solution of sulfuric acid (3×50 mL). The acidic aqueous phases were combined and the pH was adjusted to 12 with a 25% aqueous solution of sodium hydroxide. The aqueous phase was extracted with heptane (3×50 mL) and the organic phases were combined, dried over sodium sulfate and the solvent was evaporated to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by ¹H NMR).

LRMS (ES+): 200.1 (100, M+H⁺).

EXAMPLE IV Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using racemic camphorsulfonic acid

In a similar experiment as Example III, racemic camphorsulfonic acid (7.2 g, 30.9 mmol) was added to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R¹is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL). The mixture was refluxed for 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional an 8 hours and processed according to Example III to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.32 g, 6.63 mmol, 64% yield) in a 3.5:1 cis/trans ratio mixture of diastereomers (determined by ¹H NMR).

EXAMPLE V Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using phenyl sulfonic acid

In a similar experiment as Example III, to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R¹is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added phenyl sulfonic acid (4.9 g, 30.9 mmol) and the mixture was refluxed 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional 8 hours and worked up in a manner similar to Example III to furnish 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.6 g, 8.2 mmol, 80% yield) as a 2.5:1 cis/trans ratio mixture of diastereomers (determined by ¹H NMR).

EXAMPLE VI Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using p-toluenesulfonic acid in butanol

To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R¹is H and R is methyl, 3 g, 10.3 mmol) in butanol (100 mL) was added of p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was refluxed for 3 hours with a Dean-Stark apparatus attached to the flask. The reaction mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to 80° C. for an additional 8 h and worked up according to Example III to afford 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by ¹H NMR).

References

^ Ono M, Takamura E, Shinozaki K, et al. (July 2004). “Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: a randomized, double-blind clinical study”. Am. J. Ophthalmol. 138 (1): 6–17. doi:10.1016/j.ajo.2004.02.010. PMID 15234277.
^ [1] MedicineNet: Cevimeline. Accessed 10/12/2007
- - US 4 855 290 (Israel Institute for Biological Research; 8.8.1989; IL-prior. 10.5.1985).
  - US 4 876 260 (Israel Institute for Biological Research; 24.10.1989; USA-prior. 28.10.1987).
  - EP 683 168 (Ishihara Sangyo Kaisha; appl. 19.5.1995; J-prior. 19.5.1994).
- Method for isomerization of trans-isomer:
  - US 4 861 886 (Ishihara Sangyo Kaisha; 29.8.1989; J-prior. 10.7.1987).
- Method of separation:
  - IL 81 652 (Israel Institute for Biological Research; 12.5.1991; appl. 23.2.1987).
  - JP 01 290 680 (Ishihara Sangyo Kaisha; 22.11.1989; J-prior. 18.5.1988).
- Synthesis of enantiomerically pure (S)-3-hydroxy-3-mercaptomethylquinuclidine (S)-II:
  - Bos, M.; Canesso, R.: Heterocycles (HTCYAM) 38 (8), 1889 (1994).
- Synthesis of 3-quinuclidone:
  - Sternbach, L.H.; Kaiser, S.: J. Am. Chem. Soc. (JACSAT) 74, 2215 (1952).

External links

Evoxac (cevimeline HCl hydrate capsules) Full Prescribing Information

Cevimeline
Clinical data


Trade names	Evoxac
AHFS/Drugs.com	Monograph
MedlinePlus	a608025
Pregnancy category	C
Routes of administration	By mouth (capsules)
ATC code	N07AX03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	<20%
Identifiers
IUPAC name [show]
CAS Number	107233-08-9
PubChem CID	83898
DrugBank	DB00185
ChemSpider	75707
UNII	K9V0CDQ56E
KEGG	D07667
ChEBI	CHEBI:3568
ChEMBL	ChEMBL1201267
Chemical and physical data
Formula	C₁₀H₁₇NOS
Molar mass	199.31308 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O1[C@H](SC[C@@]12CN3CCC2CC3)C
InChI [hide] InChI=1S/C10H17NOS/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11/h8-9H,2-7H2,1H3/t8-,10-/m1/s1 Key:WUTYZMFRCNBCHQ-PSASIEDQSA-N

/////////// Cevimeline, AF-102B, SNI-2011, SNK-508, Evoxac, セビメリン

Batimastat, バチマスタット

March 28, 2019 1:11 pm / Leave a comment

Batimastat

バチマスタット

Formula	C23H31N3O4S2
cas	130370-60-4
Mol weight	477.6399

Butanediamide, N4-hydroxy-N1-(2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl)-2-(2-methylpropyl)-3-((2-thienylthio)methyl)-, (2R-(1(S*),2R*,3S*))-

DESCARBOXY-NOR-N(ω)-HYDROXY-L-ARGININE

DSX

EJ6675000

UNII:BK349F52C9

(2R,3S)-N⁴-Hydroxy-2-isobutyl-N¹-[(2S)-1-(methylamino)-1-oxo-3-phenylpropan-2-yl]-3-[(2-thienylsulfanyl)methyl]succinamide

(2R,3S)-N⁴-hydroxy-N¹-[(2S)-1-(methylamino)-1-oxo-3-phenylpropan-2-yl]-2-(2-methylpropyl)-3-[(thiophen-2-ylsulfanyl)methyl]butanediamide

(2R,3S)-N4-Hydroxy-N1-[(1S)-2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-2-(2-methylpropyl)-3-[(2-thienylthio)methyl]butanediamide

(2S,3R)-5-Methyl-3-(((aS)-a-(methylcarbamoyl)phenethyl)carbamoyl)-2-((2-thienylthio)methyl)hexanohydroxamic Acid

[2R-[1(S*),2R*,3S*]]-N4-Hydroxy-N1-[2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-2-(2-methylpropyl)-3-[(2-thienylthio)methyl]butane Diamide

130370-60-4 [RN]

7154

Batimastat [BAN] [INN] [USAN] [Wiki]

BK349F52C9

CAS Registry Number: 130370-60-4

CAS Name: (2R,3S)-N4-Hydroxy-N1-[(1S)-2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-2-(2-methylpropyl)-3-[(2-thienylthio)methyl]butanediamide

Additional Names: (2S,3R)-5-methyl-3-[[(aS)-a-(methylcarbamoyl)phenethyl]carbamoyl]-2-[(2-thienylthio)methyl]hexanohydroxamic acid; [4-(N-hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)succinyl]-L-phenylalanine-N-methylamide

Manufacturers’ Codes: BB-94

Molecular Formula: C23H31N3O4S2

Molecular Weight: 477.64

Percent Composition: C 57.84%, H 6.54%, N 8.80%, O 13.40%, S 13.43%

Literature References: Synthetic matrix metalloproteinase inhibitor. Prepn: C. Campion et al., WO 9005719; eidem, US 5240958(1990, 1993 both to British Biotech.). Effect on transplanted human ovarian carcinoma: B. Davies et al., Cancer Res. 53, 2087 (1993). Inhibition of metastasis of transplanted human colorectal carcinoma: X. Wang et al., ibid. 54, 4726 (1994).

Properties: Fine white powder. mp 236-238°.

Melting point: mp 236-238°

Therap-Cat: Antineoplastic adjunct (antimetastatic agent).

Keywords: Antineoplastic Adjunct; Antimetastatic Agent; Matrix Metalloproteinase Inhibitor.

Batimastat (INN/USAN, codenamed BB-94) is an anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. It acts as a matrix metalloproteinase inhibitor (MMPI) by mimicking natural MMPI peptides.

Batimastat was the first MMPI that went into clinical trials. First results of a Phase I trial appeared in 1994. The drug reached Phase III but was never marketed; mainly because it couldn’t be administered orally (as opposed to the newer and chemically similar MMPI marimastat), and injection into the peritoneum caused peritonitis.^[1]

SYN

U.S. Patent 5,453,438

U.S. Patent 5,240,958

U.S. Patent 5,530,161

Image result for batimastat

SYN

US 5240958; US 5310763; WO 9005719

The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.

SPEC

HPLC

References

^ Rothenberg, M. L.; Nelson, A. R.; Hande, K. R. (1999). “New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors”. Stem Cells. 17 (4): 237–240. doi:10.1002/stem.170237. PMID 10437989.

Batimastat
Clinical data

Pregnancy category	N/A
Routes of administration	Injection into pleural space or abdomen
ATC code	none
Legal status
Legal status	Never marketed
Identifiers
IUPAC name [show]
CAS Number	130370-60-4
PubChem CID	5362422
IUPHAR/BPS	5145
DrugBank	DB03880
ChemSpider	4515033
UNII	BK349F52C9
KEGG	D03061
ChEMBL	ChEMBL279786
ECHA InfoCard	100.222.897
Chemical and physical data
Formula	C₂₃H₃₁N₃O₄S₂
Molar mass	477.64 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C(NC)[C@@H](NC(=O)[C@@H]([C@@H](C(=O)NO)CSc1sccc1)CC(C)C)Cc2ccccc2
InChI [hide] InChI=1S/C23H31N3O4S2/c1-15(2)12-17(18(22(28)26-30)14-32-20-10-7-11-31-20)21(27)25-19(23(29)24-3)13-16-8-5-4-6-9-16/h4-11,15,17-19,30H,12-14H2,1-3H3,(H,24,29)(H,25,27)(H,26,28)/t17-,18+,19+/m1/s1 Key:XFILPEOLDIKJHX-QYZOEREBSA-N

//////////Batimastat, BB-94, バチマスタット ,

[H][C@@](CC1=CC=CC=C1)(NC(=O)[C@]([H])(CC(C)C)[C@]([H])(CSC1=CC=CS1)C(=O)NO)C(=O)NC

Abikoviromycin

March 27, 2019 8:51 am / Leave a comment

Abikoviromycin

Molecular FormulaC₁₀H₁₁NO
Average mass161.200 Da

CAS Registry Number: 31774-33-1

CAS Name: 7-Ethylidene-1a,2,3,7-tetrahydrocyclopent[b]oxireno[c]pyridine

(1aR,7E,7aS)-7-Ethylidene-1a,2,3,7-tetrahydrocyclopenta[b]oxireno[c]pyridine [ACD/IUPAC Name]

abikoviromycin

Cyclopent(b)oxireno(c)pyridine, 7-ethylidene-1a,2,3,7-tetrahydro-, (1aR,7E,7aS)-

Cyclopent[b]oxireno[c]pyridine, 7-ethylidene-1a,2,3,7-tetrahydro-, (1aR,7E,7aS)-

Additional Names: 4,4a-epoxy-5-ethylidene-2,3,4,4a-tetrahydro-5H-1-pyridine; abicoviromycin; latumcidin

Molecular Formula: C10H11NO

Molecular Weight: 161.20

Percent Composition: C 74.51%, H 6.88%, N 8.69%, O 9.93%

Literature References: Antiviral antibiotic produced by Streptomyces abikoensis and Streptomyces rubescens. Chromatographic isoln from broth cultures: Umezawa et al., Jpn. Med. J. 4, 331 (1951); C.A. 46, 7167 (1952); Umezawa, JP 54 6200 (1954 to Nippon). Identity with latumcidin: Sakagami et al., J. Antibiot. 11A, 231 (1958). Structure: Gurevich et al., Tetrahedron Lett. 1968,2209. Stereochemistry: Kono et al., J. Antibiot. 23, 572 (1970); Gurevich et al., Khim. Prir. Soedin. 7, 104 (1971), C.A. 75, 5752e (1971). Crystal and molecular structure of the selenate: Y. Kono et al., Acta Crystallogr. B27, 2341 (1971). In vitro antiviral activity: V. M. Roikhel, N. A. Zeitlenok, Antibiotiki 14, 969 (1969), C.A. 72, 19394q (1969).

Properties: Highly unstable and polymerizes promptly on isolation even at -50°; however, it can be handled in dilute solutions and in the form of its salts. uv max (neutral ethanol or 0.1N KOH): 218, 244, 289 nm (log e 3.83, 3.99, 3.94); (0.1N HCl) 236, 341 nm (log e 3.99, 4.05).

Absorption maximum: uv max (neutral ethanol or 0.1N KOH): 218, 244, 289 nm (log e 3.83, 3.99, 3.94); (0.1N HCl) 236, 341 nm (log e 3.99, 4.05)

Isolation of abikoviromycin and dihydroabikoviromycin as inhibitors of polyketide synthase involved in melanin biosynthesis by Colletotrichum lagenarium
Journal of Antibiotics (2003), 56, (9), 801-804.

https://www.jstage.jst.go.jp/article/antibiotics1968/56/9/56_9_801/_pdf/-char/en

purified by normal-phase HPLC (column: Senshu-Pak Aquasil SS-752N, 10×250mm, Senshu Kagaku; mobile phase: isocratic elution of nhexane: 2-propanol: H2O: triethylamine, 70:30:1:0.02; flow rate: 5ml/minutes; retention time: 9.0 minutes) to obtain 1 (6.3mg). 1:

FAB-MS (NBA matrix) m/z 162 (M+H)+; [α]20D+67.5° (c 0.025, 0.1N NaOH) [lit. [α]21D +148.9° (c 1, 0.1N NaOH)]9);

1H NMR (500MHz, CDCl3) δ 7.43 (1H, d, J=6.5Hz, 7-H), 6.53 (1H, d, J=6.5Hz, 6- H), 5.50 (1H, q, J=7.0Hz, 8-H), 3.92 (1H, s, 4-H), 3.81 (1H, dd, J=5.5, 15Hz, 2-Ha), 3.69 (1H, dt, J=5.5, 15Hz, 2-Hb), 2.19 (1H, m, 3-Ha), 1.90 (3H, d, J=7.0Hz, 9-H), 1.62 (1H, m, 3-Hb);

13C NMR (125MHz, CDCl3) δ 172.1 (C-7a), 142.3 (C-7), 136.5 (C-5), 132.8 (C-6), 119.5 (C-8), 59.5 (C-4), 54.5 (C-4a), 44.5 (C-2), 21.8 (C-3),14.0 (C-9).

////////////Abikoviromycin

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Cenobamate

March 8, 2019 10:24 am / Leave a comment

Cenobamate
CAS: 913088-80-9
Chemical Formula: C10H10ClN5O2
Molecular Weight: 267.67

Related CAS #: 913088-80-9 913087-59-9

Synonym: YKP-3089; YKP3089; YKP3089; Cenobamate

IUPAC/Chemical Name: (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, carbamate (ester), (αR)- (9CI)
(1R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
Carbamic acid (R)-(+)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl ester
2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, 2-carbamate, (αR)-

Cenobamate, also known as YKP-3089, is a novel new antiepileptic drug candidate. Cenobamate showed broad-spectrum anticonvulsant activity. Cenobamate entered into clinical trials and was discontinued in 2015.

PATENT

WO 2006112685

SK HOLDINGS CO., LTD. [KR/KR]; 99 Seorin-dong Jongro-ku Seoul 110-110, KR

CHOI, Yong-Moon; US

KIM, Choon-Gil; KR

KANG, Young-Sun; KR

YI, Han-Ju; KR

LEE, Hyun-Seok; KR

KU, Bon-Chul; KR

LEE, Eun-Ho; KR

IM, Dae-Joong; KR

SHIN, Yu-Jin; KR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006112685

Patent

US 20100323410

PATENT

WO 2011046380

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=9CF54FB903EC3DFB7B3237259E6419EB.wapp2?docId=WO2011046380&recNum=36&office=&queryString=&prevFilter=%26fq%3DOF%3AIL%26fq%3DICF_M%3A%22C07D%22&sortOption=Relevance&maxRec=1345

As disclosed in U. S. Patent Application Publication No. 2006/0258718 A1, carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters (hereinafter referred to as “the carbamate compounds”) with anticonvulsant activity are useful in the treatment of disorders of the central nervous system, especially including anxiety, depression, convulsion, epilepsy, migraines, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorders, neuropathic pain, strokes, cognitive impairment, neurodegeneration, strokes and muscle spasms.

Depending on the position of N in the tetrazole moiety thereof, the carbamate compounds are divided into two positional isomers: tetrazole-1-yl (hereinafter referred to as “1N tetrazole”) and treatzole-2-yl (hereinafter referred to as “2N tetrazole”). The introduction of tetrazole for the preparation of the carbamate compounds results in a 1:1 mixture of the two positional isomers which are required to be individually isolated for pharmaceutical use.

Having chirality, the carbamate compounds must be in high optical purity as well as chemical purity as they are used as medications.

In this regard, U. S. Patent Application Publication No. 2006/0258718 A1 uses the pure enantiomer (R)-aryl-oxirane as a starting material which is converted into an alcohol intermediate through a ring-opening reaction by tetrazole in the presence of a suitable base in a solvent, followed by introducing a carbamoyl group into the alcohol intermediate. For isolation and purification of the 1N and 2N positional isomers thus produced, column chromatography is set after the formation of an alcohol intermediate or carbamate.

For use in the preparation, (R)-2-aryl-oxirane may be synthesized from an optically active material, such as substituted (R)-mandelic acid derivative, via various routes or obtained by asymmetric reduction-ring formation reaction of α-halo arylketone or by separation of racemic 2-aryl-oxirane mixture into its individual enantiomers. As such, (R)-2-aryl-oxirane is an expensive compound.

In addition, the ring-opening reaction of (R)-2-aryl-oxirane with tetrazole is performed at relatively high temperatures because of the low nucleophilicity of the tetrazole. However, the ring opening reaction includes highly likely risk of a runaway reaction because tetrazoles start to spontaneously degrade at 110 ~ 120℃.

In terms of a selection of reaction, as there are two reaction sites in each (R)-2-aryl-oxirane and tetrazole, the ring-opening reaction therebetween affords the substitution of 1N- or 2N-tetrazole at the benzyl or terminal position, resulting in a mixture of a total of 4 positional isomers. Therefore, individual positional isomers are low in production yield and difficult to isolate and purify.

Preparation Example 1: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one

To a suspension of 2-bromo-2′-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 mL) was added a 35 w/w% 1H-tetrazole dimethylformamide solution (215.1 g, 1.080 mol) at room temperature. These reactants were stirred for 2 h at 45℃ and distilled under reduced pressure to remove about 1500 mL of the solvent. The concentrate was diluted in ethyl acetate (2000 mL) and washed with 10% brine (3 x 2000 mL). The organic layer thus separated was distilled under reduced pressure to afford 216.4 g of an oily solid residue. To a solution of the solid residue in ethyl acetate (432 mL) was slowly added heptane (600 mL). The precipitate thus formed was filtered at room temperature and washed to yield 90.1 g (0.405 mol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as 1N ketone ).

¹H-NMR(CDCl ₃) 8.87(s, 1H), d7.77(d, 1H), d7.39-7.62(m, 3H), d5.98(s, 2H)

Preparation Example 2: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one

After the filtration of Preparation Example 1, the filtrate was concentrated and dissolved in isopropanol (100 mL), and to which heptane (400 mL) was then added to complete the crystallization. Filtering and washing at 5℃ afforded 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (hereinafter referred to as “2N ketone”) as a solid. 94.7 g (0.425 mol).

¹H-NMR(CDCl ₃) d8.62(s, 1H), d7.72(d, 1H), d7.35-7.55(m, 3H), d6.17(s, 2H)

PREPARATION EXAMPLE 3: Preparation of Alcohol Compound of (R)-Configuration by enantioselective enzymatic reduction via various oxidoreductases

The following four solutions were prepared as follows:

Enzyme Solution 1

Competent Escherichia coli StarBL21(De3) cells (Invitrogen) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25 ℃ and 220 rpm, the cells were harvested and frozen at -20 ℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 2

RB791 cells ( E.coli genetic stock, Yale, USA) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25℃ and 220 rpm, the cells were harvested and frozen at -20℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 3

Enzyme solutions 3 was prepared in the same manner as described in Enzyme solution 1 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 3 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1 was used.

Enzyme Solution 4

Enzyme solutions 4 was prepared in the same manner as described for enzyme solution 2 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 4 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2 was used.

Different oxidoreductases contained in each enzyme solutions 1 to 4 were examined as follows for the conversion of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (1N ketone) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (2N ketone) to the corresponding 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (hereinafter, referred to as 1N alcohol ) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter, referred to as “2N alcohol”), respectively.

Reaction batch A

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 1

2 mg 1N ketone or 2N ketone

Reaction batch B

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 2

2 mg 1N ketone or 2N ketone

Reaction batch C

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

0,05 mg NADP

50 ㎕ enzyme solution 3

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

Reaction batch D

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8

0,05 mg NADP

50 ㎕ enzyme solution 4

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

After 24h of incubating each reaction batch A, B, C and D, 1 mL of acetonitrile was added to each reaction batch which was centrifuged and transferred into a HPLC analysis vessel for enantiomeric excess and conversion. Conversion and ee-value of products are listed in Table 1 below calculated using the following equations:

Conversion Rate (%) = [(Area of Product)/(Area of Reactant + Area of Product)]x100

ee-value(%) = [(Area of R-Configuration – Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100

Table 1 [Table 1]

PREPARATION EXAMPLE 4: Enzymatic reduction via oxidoreductase SEQ NO: 2

For the conversion of 1N/2N ketone to R-1N/R-2N alcohol, 30㎕ of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 300㎕ of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 100mg of a mixture of 1N ketone and 2N ketone (1N:2N=14%:86%), 0.04mg NADP and 300㎕ 2-butanol. The reaction mixture was incubated at room temperature under constant thorough mixing. After 48 hours, more than 98% of the ketones were reduced to an alcohol mixture of the following composition(R-2N alcohol 80%; S-2N alcohol 0%; R-1N alcohol 20%, S-1N alcohol 0%; 1N ketone 0%; 2N ketone 0%).

After general work up and recrystallization with ethyl acetate/hexane, optically pure alcohols were obtained as below:

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (1N alcohol

¹H-NMR(CDCl ₃) d8.74(s, 1H), d7.21-7.63(m, 4H), d5.57(m, 1H), d4.90(d, 1H), d4.50(d, 1H), d3.18(d, 1H);

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (2N alcohol)

¹H-NMR(CDCl ₃) d8.55(s, 1H), d7.28-7.66(m, 4H), d5.73(d, 1H), d4.98(d, 1H), d4.83(d, 1H), d3.38(br, 1H).

Preparation of Carbamate

Preparation Example 5: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl ester

50ml of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 250ml of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 50g (225mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one(2N ketone), 4mg NAD, 300 ml of 2-propanol and 150mL of butyl acetate. The reaction mixture was stirred at room temperature. After 48 hours more than 98% of 2N ketone was reduced to corresponding (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol) with >99%ee values. To this resulting mixture, 500mL of ethyl acetate was added. After being separated, the organic layer thus formed was washed with 10% brine (3 x 500mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 50.4g (224 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol, optical purity 99.9%) as an oily residue. To this resulting crude product, 450mL of tetrahydrofuran was added. After cooling to -15℃, 38g (267mmol) of chlorosulfonyl isocyanate was slowly added and stirred at -10℃ for 2 h. The slow addition of water induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 300 mL of the solvent was removed. The concentrate was diluted with 600mL of ethyl acetate and washed with 10% brine (3 x 500 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (90 mL) to which heptane (180 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 51.8 g (194 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (optical purity 99.9%).

¹H-NMR(Acetone-d ₆) d8.74(s, 1H), d7.38-7.54(m, 4H), d6.59(m, 1H), d6.16(Br, 2H), d4.90(d, 1H), d5.09(m, 2H)

As described hitherto, carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

AMINO ACID SEQUENCES

SEQ ID NO 1: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 2: Candida magnoliae DSMZ 22052 protein sequence carbonyl reductase

SEQ ID NO 3: Candida vaccinii CBS7318 protein sequence carbonyl reductase

SEQ ID NO 4: Candida magnoliae CBS6396 protein sequence carbonyl reductase

NUCLEIC ACID SEQUENCES

SEQ ID NO 5: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 6: Candida magnoliae DSMZ 22052 nucleic acid sequence carbonyl reductase

SEQ ID NO 7: Candida vaccinii CBS7318 nucleic acid sequence carbonyl reductase

SEQ ID NO 8: Candida magnoliae CBS6396 nucleic acid sequence carbonyl reductase

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Our team enjoyed celebrating the news of FDA acceptance of our new drug application (NDA) for investigational antiepileptic drug, cenobamate. A special thank you to everyone on our team who worked tirelessly to make this milestone possible!

https://www.linkedin.com/company/sk-life-science-inc./

https://www.sklifescienceinc.com/

https://www.sklifescienceinc.com/pdf/SKLSI%20NDA%20Acceptance%20Press%20Release%20-FINAL-Updated%202-3-19.pdf

SK life science announces FDA acceptance of NDA submission for cenobamate, an investigational antiepileptic drug PDUFA date set for November 21, 2019 Fair Lawn, New Jersey, February 4, 2019 – SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company.

SK life science plans to commercialize cenobamate independently. The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings. “The FDA’s acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy,” said Marc Kamin, M.D., chief medical officer at SK life science. “We look forward to working with the FDA during their review of our data on cenobamate.” Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years

1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families. 2 Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.

2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy).

3 About Epilepsy Epilepsy is a common neurological disorder characterized by seizures.

4 There are approximately 3.4 million people in the U.S. living with epilepsy, and approximately 65 million worldwide.

5 The majority of people with epilepsy (60%) have partial-onset seizures, which are located in just one part of the brain.

6 People with epilepsy are also at risk for accidents and other health complications including falling, drowning, car accidents, depression and anxiety and SUDEP. 3

About Cenobamate Cenobamate (YKP3089) was discovered by SK Biopharmaceuticaals and SK life science and is being investigated for the potential treatment of partial-onset seizures in adult patients. Cenobamate’s mechanism of action is not fully understood, but it is believed to work through two separate mechanisms: enhancing inhibitory currents through positive modulation of GABA-A receptors and decreasing excitatory currents by inhibiting the persistent sodium current. Global trials for adults with partial-onset seizures are ongoing to evaluate cenobamate safety.

Additional clinical trials are investigating cenobamate safety and efficacy in other seizure types. The U.S. Food and Drug Administration (FDA) accepted the filing of the New Drug Application for cenobamate for the potential treatment of partial-onset seizures in adults in February 2019. Cenobamate is not approved by the FDA or any other regulatory authorities. Safety and efficacy have not been established. About SK life science SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals, Co., Ltd., is focused on developing and commercializing treatments for disorders of the central nervous system (CNS).

Both are a part of the global conglomerate SK Group, the second largest company in Korea. SK life science is located in Fair Lawn, New Jersey. We have a pipeline of eight compounds in development for the treatment of CNS disorders including epilepsy, sleep disorder and attention deficit hyperactivity disorder, among others. The first product the company is planning to commercialize independently is cenobamate (YKP3089), an investigational compound for the potential treatment of partial-onset seizures in adult patients, currently in a Phase 3 global clinical trial.

For more information, visit SK life science’s website at http://www.SKLifeScienceInc.com.

For more information, visit SK Biopharmaceuticals’ website at http://www.skbp.com/eng. —-

1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. https://www.ncbi.nlm.nih.gov/pubmed/29279892 Published online December 26, 2017.

2. Center for Disease Control and Prevention. Active Epilepsy and Seizure Control in Adults — United States, 2013 and 2015. https://www.cdc.gov/mmwr/volumes/67/wr/mm6715a1.htm?s_cid=mm6715a1 Accessed December 27, 2018.

3. Epilepsy Foundation. Staying Safe. https://www.epilepsy.com/learn/seizure-first-aid-and-safety/staying-safe Accessed November 20, 2018.

4. Epilepsy Foundation. What Is Epilepsy? https://www.epilepsy.com/learn/about-epilepsy-basics/what-epilepsy Accessed November 20, 2018.

5. Epilepsy Foundation. Facts about Seizures and Epilepsy. https://www.epilepsy.com/learn/about-epilepsybasics/facts-about-seizures-and-epilepsy Accessed November 20, 2018.

6. National Institute of Neurological Disorders and Stroke. The Epilepsies and Seizures: Hope through Research. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Epilepsies-andSeizures-Hope-Through#3109_9 Accessed November 20, 2018.

REFERENCES

1: Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013
Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294. Epub 2012 Nov 26. Review.
PubMed PMID: 23176519.

2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress
report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT
IX). Epilepsy Res. 2009 Jan;83(1):1-43. doi: 10.1016/j.eplepsyres.2008.09.005.
Epub 2008 Nov 12. PubMed PMID: 19008076.

/////////////YKP-3089, YKP3089, YKP3089, Cenobamate

NC(O[C@H](C1=CC=CC=C1Cl)CN2N=CN=N2)=O

Viloxazine, ヴィロキサジン;

February 27, 2019 1:18 pm / Leave a comment

ChemSpider 2D Image | Viloxazine | C13H19NO3

Viloxazine

Molecular FormulaC₁₃H₁₉NO₃
Average mass237.295 Da

update FDA APPROVED 2021/4/2, Qelbree, Viloxazine hydrochloride

Formula	C13H19NO3. HCl
CAS	35604-67-2
Mol weight	273.7558

2-[(2-Ethoxyphenoxy)methyl]morpholine

256-281-7 [EINECS]

3489

46817-91-8 free [RN], Hcl 35604-67-2

5I5Y2789ZF

Emovit [Wiki]

Morpholine, 2-((2-ethoxyphenoxy)methyl)-

Morpholine, 2-[(2-ethoxyphenoxy)methyl]-

UNII:5I5Y2789ZF

Viloxazine hydrochloride

OQW30I1332

35604-67-2

Polymorph

FORM A , B US226136693, US2011032013

NEW DRUG APPROVALS

ONE TIME

$10.00

Viloxazine (trade names Vivalan, Emovit, Vivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.

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https://www.sciencedirect.com/science/article/pii/S0040402015302659

Patent

US 20180265482

https://patentscope.wipo.int/search/en/detail.jsf?docId=US226136693&tab=PCTDESCRIPTION&maxRec=1000

Viloxazine ((R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine]) is a bicyclic morpholine derivative, assigned CAS No. 46817-91-8 (CAS No. 35604-67-2 for the HCl salt). It is characterized by the formula C ₁₃H ₁₉NO ₃, with a molecular mass of 237.295 g/mol. Viloxazine has two stereoisomers, (S)-(−)- and (R)-(+)-isomer, which have the following chemical structures:

Viloxazine is known to have several desirable pharmacologic uses, including treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism, among others. In vivo, viloxazine acts as a selective norepinephrine reuptake inhibitor (“NRI”).

Between the two stereoisomers, the (S)-(−)-isomer is known to be five times as pharmacologically active as the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074) in which it is disclosed that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine were prepared and absolute configurations assigned. The synthesis of optical isomers of viloxazine analogs of known configuration was accomplished by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.

Some unsatisfactory methods of synthesizing viloxazine are known in the art. For example, as disclosed in U.S. Pat. No. 3,714,161, viloxazine is prepared by reacting ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine followed with chloroacetyl chloride. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield viloxazine free base.

Yet another unsatisfactory synthesis of viloxazine is disclosed in U.S. Pat. No. 3,712,890, which describes a process to prepare viloxazine HCl, wherein the epoxide intermediate, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, is reacted with 2-aminoethyl hydrogen sulfate in ethanol in the presence of sodium hydroxide to form viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over a drying agent and the solvent is removed. Viloxazine HCl salt is finally obtained by dissolving the previous residue in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration.

The foregoing methods of synthesizing viloxazine suffer from a number of deficiencies, such as low reaction yield and unacceptably large amount of impurities in the resulting product. Effective elimination or removal of impurities, especially those impurities possessing genotoxicity or other toxicities, is critical to render safe pharmaceutical products. For example, certain reagents traditionally utilized in viloxazine HCl preparation, such as epichlorohydrin and 2-aminoethyl hydrogen sulfate, present a special problem due to their toxicity. There is a need for effective methods to remove or limit harmful impurities down to a level that is appropriate and safe according to contemporary sound medical standards and judgment. Accordingly, a continuing and unmet need exists for new and improved methods of manufacturing viloxazine and its various salts to yield adequate quantities of pharmacologically desirable API with predictable and reliable control of impurities.

Polymorph control is also an important aspect of producing APIs and their associated salts that are used in pharmaceutical products. However, no polymorphs of viloxazine HCl have previously been disclosed. A need therefore exists for new polymorphic forms of viloxazine that have improved pharmacological properties.

PATENT

WO 2011130194

US2011032013

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011130194&recNum=110&docAn=US2011032013&queryString=(%20pheno*%20or%20isopropoxy*%20or%20oxiran*%20or%20bisoprolol*%20)%20and%20(%20C07C213*%20or%20C07C217*%20or%20C07C209*%20or%20C07C41*%20or%20C07D263*%20)&maxRec=2245

For the sake of convenience and without putting any limitations thereof, the methods of manufacture of viloxazine have been separated into several steps, each step being disclosed herein in a multiplicity of non-limiting embodiments. These steps comprise Step 1, during which 2-ethoxyphenol and epichlorhydrin are reacted to produce l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1); Step 2, during which l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1) is converted into viloxazine base which is further converted into viloxazine salt, and Step 3, during which viloxazine salt is purified/recrystallized, and various polymorphic forms of viloxazine salt are prepared.

The above-mentioned steps will be considered below in more details.

[0031] The process of the Step 1 may be advantageously carried out in the presence of a phase-transfer catalyst to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane. Alternatively, the process may make use of a Finkelstein catalyst described in more details below. Additionally, the reaction may take place without the use of the catalyst.

FIG. 1, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with Step I of an exemplary synthesis of viloxazine:

STEP I:

Epoxide 1

In one embodiment of the Step 1, the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (epoxide 1) can be effected by the use of a phase transfer catalyst in the presence of a solid or liquid base with a solution of a corresponding phenol and epichlorohydrin in one or more solvents (Fig. 1). The phase transfer catalyst can be selected from ammonium salts, such as benzyltriethylammonium salts, benzyltrimethylammonium salts, and tetrabutylammonium salts, phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The solid or liquid base can be a carbonate such as alkali carbonate, NaOH, KOH, LiOH, LiOH/LiCl, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, or other appropriate base. The solvents used in the solution of a corresponding phenol and epichlorohydrin include but are not limited to ethers such as methyl t-butyl ether, ketones, non-substituted or substituted aromatic solvents (xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, DMF, dioxanes, non-substituted and substituted pyridines, acetonitrile, pyrrolidones, nitromethane , or other appropriate solvent. Additional catalyst, such as, for example, Finkelstein catalyst, can also be used in the process of this embodiment. This reaction preferably takes place at an elevated temperature. In one variation of the embodiment, the temperature is above 50°C. In another variation, epichlorohydrin, potassium carbonate, and a phase transfer catalyst are mixed with a solution of 2-ethoxyphenol in a solvent at an elevated temperature, such as 50 – 60°C. After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Variations of this embodiment of the invention are further disclosed in Examples 1-8.

[0033] In one variation of the above embodiment of the Step 1 , Epoxide 1 is prepared by reacting 2-ethoxyphenol and epichlorohydrin in a solvent in the presence of two different catalysts, and a base in a solid state. The first catalyst is a phase transfer catalyst as described above; the second catalyst is a Finkelstein reaction catalyst. Without putting any limitation

hereon, metal iodide and metal bromide salts, such as potassium iodide, may be used as an example of a Finkelstein catalyst. The phase transfer catalyst and a solvent may be selected from any phase transfer catalysts and solvents known in the art. Potassium carbonate may be used as a non-limiting example of a solid base. Using the solid base in a powdered form may be highly beneficial due to the greatly enhanced interface and limiting the side reactions. This variation of the embodiment is further illustrated by Example 9. In another variation of the embodiment, liquid base such as triethylamine can be used to replace the solid base.

[0034] In a different embodiment of Step 1 , 2-ethoxyphenol and epichlorohydrin are reacted in a solvent-free system that comprises a solid or liquid base, a phase transfer catalyst as listed above and a Finkelstein catalyst.

[0035] FIG. 2, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with the Step I of another exemplary synthesis of viloxazine ( biphasic):

STEP I (alternative embodiment):

In this embodiment of Step 1, illustrated in Fig. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after

removal of excess epichlorohydrin, using a base and a solvent. The reaction produces l-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di-or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60°C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60 – 90°C for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.

[0036] In yet another embodiment of Step 1 , Epoxide 1 can also be prepared by using a catalyst for a so-called Finkelstein reaction in the presence of a Finkelstein catalyst but without the need to use a phase transfer catalyst. Finkelstein catalysts useful herein include metal iodide salts and metal bromide salts, among others. In one variation of this embodiment, 2-ethoxyphenol and epichlorohydrin are dissolved in a polar aprotic solvent such as DMF, and a catalytic amount of an iodide such as potassium iodide and a base, as solid or liquid, are used. Preferably, the base is used as a solid, such as potassium carbonate powder. This embodiment is further illustrated by the Example 11.

[0037] In the alternative embodiment of Step 1 , Epoxide 1 can also be prepared by a different method that comprises reacting epichlorohydrin and the corresponding phenol in the presence of a base at a temperature lower than the ambient temperature, especially when a base solution is used, and without the use of a phase transfer catalyst. This embodiment is illustrated by the Example 10.

[0038] A very high, almost quantitative, yield of 1 -(2-ethoxyphenoxy)-2,3-epoxypropane can be obtained through realizing the above-described embodiments of Step 1 , with less impurities generated in Epoxide 1.

[0039] Epoxide 1 , produced in Step 1 as described above, is used to prepare viloxazine base (viloxazine), which is further converted into viloxazine salt through the processes of Step 2.

[0040] FIG. 3, depicted below, schematically illustrates the preparation of viloxazine

(“Step Ila”) and the preparation of viloxazine hydrochloride (“Step lib”), as well as their purification (“Step III”) in accordance with another example embodiment hereof:

STEP Ila:

Hydrogen Sulfate

STEP lib:

Step III:

Conversion

Viloxazine free base ► Viloxazine salt

Wash/ raction

Recrystallization

Purified viloxazine salt

In the embodiment of Step 2, illustrated in Fig. 3, the preparation of viloxazine base is achieved by reacting the Epoxide 1 intermediate prepared in Step 1 and aminoethyl hydrogen sulfate in presence of a large excess of a base as illustrated by the Examples 5-7 and 14. The base may be present as a solid or in a solution. Preferably, the molar ratio of the base to Epoxide 1 is more than 10. More preferably the ratio is more than 12. Even more preferably, the ratio is between 15 and 40. It was unexpectedly discovered that the use of a higher ratio of a base results in a faster reaction, less impurities, and lower reaction temperature.

[0041] Further advantages may be offered by a specific variation of this embodiment, wherein the base is added to the reaction mixture in several separate steps. For example, a third of the base is added to the reaction mixture, and the mixture is stirred for a period of time. Then the rest of the base is added followed by additional stirring. Alternatively, half of the base is added initially followed by the second half after some period of time, or the base is added in three different parts separated by periods of time. The bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, and combinations thereof. . In one embodiment of the invention, the base is KOH. In another embodiment, the base is NaOH. In a further embodiment, the base is K2C03 powder. In yet further embodiment, the base is triethylamine. This embodiment is illustrated further by

Examples 13,15 and 16.

[0042] In another exemplary embodiment of Step 2, viloxazine is produced by cyclization of novel intermediate compound “Diol 1 ,” which is made from Epoxide 1 and N-benzyl-aminoethanol. This method allows one to drastically reduce the use of potentially toxic materials in the manufacturing process, completely eliminating some of them such as aminoethyl hydrogen sulfate. The first stage of the reaction results in the formation of an intermediate of Formula 3 (Diol 1), which is a new, previously unidentified compound.

[0043] Formula 3

Diol 1

FIG. 4, depicted below, schematically illustrates the preparation of viloxazine and its salts via “Diol 1” in accordance with another exemplary embodiment hereof (Bn = benzyl, Et = ethyl):

Viloxazine HCI

As illustrated in Fig. 4, Diol 1 is turned into N-benzyl viloxazine by cyclization. Removal of the benzyl protective group yields viloxazine base. Similarly, FIG. 5, depicted below, schematically illustrates the cyclization of Diol 1, as well as some side-reactions thereof.

Uses

Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.^[4]^[5]

Side effects

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,^[6]) and increased libido.^[7]

Drug interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.^[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,^[9] sometimes resulting in accidental overdose of theophylline.^[10]

Mechanism of action

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.^[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.^[11]

It was also found to up-regulate GABA_B receptors in the frontal cortex of rats.^[12]

Chemical properties

It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.^[13]

History

Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.^[14]^:610^[15]^:9 The drug was first marketed in 1976.^[16] It was never approved by the FDA,^[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.^[17] It was withdrawn from markets worldwide in 2002 for business reasons.^[14]^[18]

As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.^[19]^[20]

Research

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.^[21]^[22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.^[23]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM^[24] without really improving daytime somnolence.^[25]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.^[18]

Viloxazine has also been studied for the treatment of alcoholism, with some success.^[26]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.^[27]

It is also under investigation as a treatment for attention deficit hyperactivity disorder.^[28]

REFERNCES

^ Bouchard JM, Strub N, Nil R (October 1997). “Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial”. Journal of Affective Disorders. 46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5. PMID 9387086.
^ Case DE, Reeves PR (February 1975). “The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans”. Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
^ “SID 180462– PubChem Substance Summary”. Retrieved 5 November 2005.
^ Pinder, RM; Brogden, RN; Speight, ™; Avery, GS (June 1977). “Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness”. Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751.
^ Jump up to:^a ^b Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
^ Edwards JG, Glen-Bott M (September 1984). “Does viloxazine have epileptogenic properties?”. Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). “Antidepressants and sexual stimulation: the correlation” [Antidepressants and sexual stimulation: the correlation]. L’Encéphale (in French). 24 (3): 180–4. PMID 9696909.
^ Pisani F, Fazio A, Artesi C, et al. (February 1992). “Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction”. Journal of Neurology, Neurosurgery, and Psychiatry. 55 (2): 126–7. doi:10.1136/jnnp.55.2.126. PMC 488975. PMID 1538217.
^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). “A study of the interaction of viloxazine with theophylline”. Therapeutic Drug Monitoring. 11 (5): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.
^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). “Theophylline intoxication following viloxazine induced decrease in clearance”. European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375.
^ Jump up to:^a ^b Lippman W, Pugsley TA (August 1976). “Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities”. Canadian Journal of Physiology and Pharmacology. 54 (4): 494–509. doi:10.1139/y76-069. PMID 974878.
^ Lloyd KG, Thuret F, Pilc A (October 1985). “Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock”. The Journal of Pharmacology and Experimental Therapeutics. 235 (1): 191–9. PMID 2995646.
^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). “Behavioral and radioreceptor analysis of viloxazine stereoisomers” [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten’ Eksperimental’noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
^ Jump up to:^a ^b Williams DA. Antidepressants. Chapter 18 in Foye’s Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
^ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
^ Olivier B, Soudijn W, van Wijngaarden I. Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. Prog Drug Res. 2000;54:59-119. PMID 10857386
^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
^ Jump up to:^a ^b Vignatelli L, D’Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. Review. PMID 18254030
^ Bloomberg Supernus profile Page accessed August 1, 2015
^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
^ Attenburrow AA, Stanley TV, Holland RP (January 1984). “Nocturnal enuresis: a study”. The Practitioner. 228 (1387): 99–102. PMID 6364124.
^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). “Viloxazine versus imipramine in the treatment of enuresis”. The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.
^ Libert MH (1990). “The use of viloxazine in the treatment of primary enuresis” [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). “Viloxazine hydrochloride in narcolepsy: a preliminary report”. Sleep. 9 (1 Pt 2): 275–9. PMID 3704453.
^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). “Narcolepsy”. Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.
^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). “Alcoholism and depression: a placebo controlled study with viloxazine”. International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.
^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). “Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia” [Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353.
^ Mattingly, GW; Anderson, RH (December 2016). “Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems”. CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946.

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Clinical data


Routes of administration	By mouth, intravenous infusion^[1]
ATC code	N06AX09 (WHO)
Legal status
Legal status	In general: uncontrolled
Pharmacokinetic data
Elimination half-life	2–5 hours
Excretion	Renal^[2]
Identifiers
IUPAC name [show]
CAS Number	46817-91-8 35604-67-2 (HCl salt)
PubChem CID	5666
ChemSpider	5464
UNII	5I5Y2789ZF
KEGG	D08673
ChEMBL	ChEMBL306700
ECHA InfoCard	100.051.148
Chemical and physical data
Formula	C₁₃H₁₉NO₃
Molar mass	237.295 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES [hide]O(c1ccccc1OCC)CC2OCCNC2
InChI [hide]InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N

/////////////////Viloxazine, ヴィロキサジン , Emovit, Vivalan, Emovit, Vivarint, Vicilan

TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 , チアベンダゾール;

February 1, 2019 10:23 am / Leave a comment

ChemSpider 2D Image | Tiabendazole | C10H7N3S

TIABENDAZOLE

CAS: 148-79-8

Molecular FormulaC₁₀H₇N₃S
Average mass201.248 Da
тиабендазол [Russian] [INN]

تياباندازول [Arabic] [INN]

噻苯达唑 [Chinese] [INN]
チアベンダゾール;

1436

148-79-8 [RN]

1H-Benzimidazole, 2-(4-thiazolyl)-

2-(1,3-Thiazol-4-yl)-1H-benzimidazole

2-(4-Thiazoly)benzimidazole

205-725-8 [EINECS]

28558-32-9 [RN]

90507-06-5 [RN]

Arbotect [Trade name]

Benzimidazole, 2-(4-thiazolyl)-

Mintezol [Trade name]

N1Q45E87DT

MK 360 / MK-360 / NSC-525040 / NSC-90507

Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ (and the trade names Mintezol, Tresaderm, and Arbotect) is a preservative^[1]

2-Substituted benzimidazole first introduced in 1962. It is active against a variety of nematodes and is the drug of choice for strongyloidiasis. It has CNS side effects and hepatototoxic potential. (From Smith and Reynard, Textbook of Pharmacology, 1992, p919)

Thiabendazole

CAS Registry Number: 148-79-8

CAS Name: 2-(4-Thiazolyl)-1H-benzimidazole

Additional Names: 4-(2-benzimidazolyl)thiazole

Manufacturers’ Codes: MK-360

Trademarks: Equizole (Merial); Mertect (Syngenta); Mintezol (Merck & Co.); Tecto (Syngenta)

Molecular Formula: C10H7N3S

Molecular Weight: 201.25

Percent Composition: C 59.68%, H 3.51%, N 20.88%, S 15.93%

Literature References: Prepd by the reaction of 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid: H. D. Brown et al., J. Am. Chem. Soc. 83, 1764 (1961); L. H. Sarett, H. D. Brown, US 3017415 (1962 to Merck & Co.). Synthesis of labeled thiabendazole: D. J. Tocco et al., J. Med. Chem. 7, 399 (1964). Alternate route of synthesis: V. J. Grenda et al., J. Org. Chem. 30, 259 (1965). Anthelmintic props: H. D. Brown et al., loc. cit.; K. C. Kates et al., J. Parasitol. 57, 356 (1971). Fungicidal props: H. J. Robinson et al., J. Invest. Dermatol. 42, 479 (1966). Systemic props in plants: D. C. Erwin et al., Phytopathology 58,860 (1968). Toxicity: H. J. Robinson et al., Toxicol. Appl. Pharmacol. 7, 53 (1965). Residue analysis: IUPAC Appl. Chem. Div., Pure Appl. Chem. 52, 2567 (1980). Comprehensive description: V. K. Kapoor, Anal. Profiles Drug Subs. 16, 611-639 (1986).

Properties: Colorless crystals, mp 304-305°. uv max (methanol): 298 nm (e 23330). Fluorescence max in acid soln: 370 nm (310 nm excitation). Max soly in water at pH 2.2: 3.84%. Soluble in DMF, DMSO. Slightly soluble in alcohols, esters, chlorinated hydrocarbons. LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson).

Melting point: mp 304-305°

Absorption maximum: uv max (methanol): 298 nm (e 23330)

Toxicity data: LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson)

Derivative Type: Hypophosphite

CAS Registry Number: 28558-32-9

Trademarks: Arbotect (Syngenta)

Properties: Amber liquid. d25 1.103.

Density: d25 1.103

Use: Fungicide for spoilage control of citrus fruit; for treatment and prevention of Dutch elm disease in trees; for control of fungal diseases of seed potatoes.

Therap-Cat: Anthelmintic (Nematodes).

Therap-Cat-Vet: Anthelmintic, fungicide.

Keywords: Anthelmintic (Nematodes).

Thiabendazole, 2-(4′-thiazolyl)-benzimidazole (TBZ) (I) is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Owing to the commercial importance of thiabendazole, the various synthetic routes are disclosed in the literature for preparing this pharmacologically and fungicidally active compound.

The various literature discloses the synthesis of thiabendazole by using aniline, 4-cyanothiazole and hydrogen chloride in polychlorobenzene such as dichloro- or a trichlorobenzene solvent under high pressure reaction conditions to obtain N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride). This amidine hydrochloride is then treated with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate to obtain thiabendazole.

NMR

The US patent no. US 3,274,208 discloses the process for preparation of amidine hydrochloride by reacting 4-cynothiazole and aniline in presence of aluminum chloride at 180 °C. The amidine hydrochloride is purified by acid base treatment.

The US patent no. US 3,299,081 (henceforth patent ‘081) discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) and thiabendazole by heating together 4-cyanothiazole and aniline hydrochloride and purging of excess dry hydrogen chloride gas under pressure (15 psig) reaction condition in a 1,2-dichlorobenzene solvent at 135 to 140 °C using closed reactor. The amidine hydrochloride is isolated by filtration and it is then cyclized to N-chloro-N’-phenyl-(thiazole-4-amidine) intermediate by reaction with sodium hypochlorite in water-methanol solvent, further the intermediate is then converted to thiabendazole by treatment with potassium hydroxide in ethanol. The preferred embodiment of the said patent discloses the use of excess hydrogen chloride in a polychlorobenzene medium to achieve higher yields of amidine hydrochloride. The reaction with gas under pressure is exothermic, so the reaction is unsafe.

As per the background of the patent ‘081, the prior art processes were disclosed that the N-aryl amidines could be prepared by reacting together a nitrile and an aromatic amine in the presence of a metal catalyst such as aluminum chloride or zinc chloride. The process involved the use of a metallic halide as an additional substance in the reaction mixture with the result that metal complexes are obtained which have to be decomposed and the metal removed before pure amidine compounds can be recovered. It was also known to prepare N-aryl amidines by reacting the nitrile and the aromatic amine hydrochloride in a solvent such as ether in the absence of metallic halide. The process referred to affords only poor yields of the desired amidine. Hence, neither of these methods are entirely satisfactory.

13C NMR

The US patent no. US 3,299,082 discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) by reacting aniline and 4-cyanothiazole in in the presence of a Friedel Crafts type catalyst such as aluminum chloride at temperature 180 °C. The amidine hydrochloride is reacted with hydroxylamine hydrochloride, in presence of base such as sodium bicarbonate and water as solvent to obtain N-phenyl-(thiazole-4-hydroxyamidine) which is then treated with alkyl or aryl sulfonyl halide such methane sulfonyl chloride in the presence of a base such as pyridine to obtain thiabendazole.

The US patent no. US 3,325,506 discloses the process for preparation of thiabendazole by reacting amidine hydrochloride with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate in water or mixtures of water and organic solvents to obtain thiabendazole.

The significance of by-products from reactions in process development work arises from the need to control or eliminate their formation which might affect product cost, process safety, product purity and environmental health. Very few reactions go to 100% completion in the desired sense. Even when conversion is 100% selectivity is not 100%. Most reactions are accompanied by by-products which arise as a direct consequence of a primary synthetic step including work-up and isolation and as a result of various types of side reactions. By-products from the latter type also include tars, polymeric materials, and coloring matters. The level of some by-products from side reactions depends frequently on the batch size.

MASS

In the pharmaceutical industry, an impurity is considered as any other inorganic or organic material, or residual solvents other than the drug substances, or ingredients, arise out of synthesis or unwanted chemicals that remains with APIs. Organic impurities are those substances which are formed in the drug substance during the process of synthesis of drug product or even formed during the storage of drug product. This type of impurity includes-intermediate, starting material, degradation product, reagents, ligands, catalyst and by product. Inorganic impurities present mainly include heavy metals, residual solvents, inorganic salts, filter aids, charcoal, reagent, ligands and catalyst.

Impurity profiling includes identification, structure elucidation and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations. Impurity profiling has gained importance in modern pharmaceutical analysis since an unidentified, potentially toxic impurities are hazardous to health and the presence of unwanted impurities may influence bioavailability, safety and efficacy of APIs. Now days, not only purity profile but also impurity profile has become mandatory according to various regulatory authorities. The International Conference on Harmonization (ICH) has published guidelines on impurities in new drug substances, products, and residual solvents.

The prior art processes for preparing thiabendazole suffer from inherent drawbacks and inconveniences, such as low yields, additional reaction steps, high-pressure and unsafe reaction conditions. Moreover, the prior art processes for preparation of thiabendazole are end up with surplus level of potential impurities such as 4-chloro thiabendazole (V) or 5-chloro thiabendazole (VI). Also, the prior processes are silent about these impurities. Since, the strict regulations of the regulatory authorities pertaining to the presence of impurities in the active ingredient, it is highly essential to align the research inline with the guidelines of the regulatory authorities in accordance to appropriate regulations and limits to register and commercialize the product in respective countries.

(V) (VI)

Hence, with objective of developing the short process, more direct and less expensive methods, significant improvement in the art for preparation of thiabendazole with controlled level of 4-chloro thiabendazole or 5-chloro thiabendazole impurities, residual solvents (methanol, benzene) and heavy metals (selenium, cobalt, molybdenum), the inventors of the instant invention are motivated to pursue the research to synthesize thiabendazole in under atmospheric conditions with high yield and high chemical purity for agricultural and pharmaceutical use.

CLIP

http://www.inchem.org/documents/jecfa/jecmono/v31je04.htm

Uses

Preservative

It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.

Use in treatment of aspergillosis has been reported.^[2]

Used in anti-fungal Purple wallboards (optiSHIELD AT, mixture of azoxystrobin and thiabendazole).

Parasiticide

As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis),^[3] hookworms, and other helminth species which attack wild animals, livestock and humans.^[4]

Angiogenesis inhibitor

Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells.^[5]

Pharmacodynamics

TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.^[6]

Other

Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.

In dogs and cats, thiabendazole is used to treat ear infections.

Thiabendazole is also used as a food additive,^[7]^[8] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,^[9] Australia and New Zealand.^[10]

Safety

The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below LD₅₀ level).^{[citation needed]} Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.^{[citation needed]} Carcinogenic effects have been shown at higher doses.^[11]

Synthesis

Thiabendazole synthesis:^[12] L. H. Sarett, H. D. Brown, U.S. Patent 3,299,081 (1967 to Merck & Co.).

Intermediate arylamidine 2 is prepared by the dry HCl catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (1). Amidine (2) is then converted to its N-chloro analog 3by means of NaOCl. On base treatment, this apparently undergoes a nitrene insertion reaction (4) to produce thiabendazole (5). Note the direction of the arrow is from the benzene to the nitrene since the nitrene is an electrophilic species.

Alternative route of synthesis: 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid.^[13]

Synthesis of labeled thiabendazole:^[14]

Analogues

Cambendazole preparation and activity studies:^[15]^[16]

Cambendazole (best of 300 agents in an extensive study),^[17] is made by nitration of tiabendazole, followed by catalytic hydrogenation to 2, and acylation with Isopropyl chloroformate.

Additionally, tiabendazole was noted to exhibit moderate anti-inflammatory and analgesic activities, which led to the development of KB-1043.

PATENT

WO-2019016834

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019016834&tab=PCTDESCRIPTION&maxRec=1000

The present invention relates to an improved process for preparing thiabendazole of formula (I) with high yield, high purity, in economical and commercially viable manner for agricultural and pharmaceutical use.

Process for preparing thiabendazole with higher yield, purity, in an economical and commercially viable manner. Thiabendazole is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Represents the first filing from the Hikal Ltd and the inventors on thiabendazole.

The structural details of the 4-chloro thiabendazole (V) and 5-chloro thiabendazole (VI) impurities are as follow.

1. 4-Chloro thiabendazole:

(a) FT-IR study: The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA-2000 FT-IR Spectrometer. The IR data is tabulated below.

Frequency (cm^“1) Assignment (s)

1576.37 C=C stretching

1309.16 C-N stretching

3073.38 N-H stretching

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO at 2.5 ppm. The 1H spectra displayed in respectively. The NMR assignment of 4-chloro thiabendazole is shown below.

Proton assignments of 4-Chloro thiabendazole:

s-singlet, d-doublet, t -triplet, q- quartet, dd-doublet of doublet, br-broad, m-multiplet.

2. 5-Chloro thiabendazole:

(a) FT-IR study:

The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA- 2000 Spectrometer. The IR data is tabulated below.

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO-d₆ as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO-d₆ at 2.50

ppm. The 1H spectra displayed in respectively. The NMR assignment of 5-chloro thiabendazole is shown below.

Proton assignments 5-Chloro thiabendazole:

s-singlet, d-doublet, q-quartet m-multiplet, br-broad.

Examples

Example 1: Preparation of amidine hydrochloride (IV)

To the 4-neck, 1 lit RBF, fixed with thermo pocket, condenser and hydrogen chloride (HC1) gas inlet, 100 g (0.908 moles, 1.0 eq) of 4-cyanothiazole, 386 (3.86 V) ml of 1,2-dichlorobenzene and 86.02 (0.924 moles, 1.02 eq) g of aniline were charged. The reaction mass was heated to 55 to 60 °C and hydrogen chloride (HC1) gas was purged till exotherm ceased. Then the temperature of the reaction mass was raised to 135 to 140 °C and again dry HC1 gas was purged till 4-cyanothiazole was reduced to less than 0.2 % (w/w) analyzed by HPLC. The reaction mass was cooled to 45 to 50° C and 500 mL of water was charged and the reaction mass was stirred for half an hour. The pH of the reaction mass was adjusted between 3 to 5 using caustic lye. The reaction mass was filtered through hyflo bed, and bed was washed with 50 (0.5 V) mL of water. The organic layer was separated, and the aqueous layer was charged back to the RBF. 20 g of activated charcoal was added in aqueous layer under stirring at 45 to 50 °C. The reaction mass was heated to 55 to 60 °C and maintained under stirring for 1.0 hour. The reaction mass was filtered through the hyflo bed under

vacuum, and bed was washed with 50 mL of hot water and suck dried till no more filtrate collected. 300-400 mL of water was distilled from the aqueous layer at 55 °C under 50 m bar of vacuum. Then the reaction mass was cooled to 0 to 5 °C and maintained under stirring for 1 hour. The obtain amidine hydrochloride was filtered by using Buckner funnel and suck dried till no more filtrate collected from it. The wet cake was dried under vacuum at 55 to 60 °C to get 189 g (86.83% yield, HPLC purity 99.85%) of amidine hydrochloride.

Example 2: Preparation of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 185 g (0.772 moles, 1.0 eq.) of amidine hydrochloride and 1536 mL (7.33V) of water were charged. The reaction mass was cooled to 0 to 5 °C. 1233 mL of methanol was added to the mass and the pH of the reaction mass was adjusted between 9 to 10 by using 5N sodium carbonate solution. The reaction mass was warmed to 10 to 15 °C and 415.35 g (12.57 % w/w, 0.91 eq.) sodium hypochlorite was slowly added by maintaining temperature between 10 to 15 °C. The reaction mass was stirred at same temperature for half an hour. Then the reaction mass was heated to 60 to 65 °C and 46.15 g (12.57 % w/w, 0.1 eq) sodium hypochlorite was added. The reaction mass was stirred at 60 to 65 °C for 1.0 hour and the reaction mass was cooled to 30 to 40 °C. The reaction mass was filtered, the bed was washed with 925 mL of water (5.0 V) and suck dried for 10 minutes to get 238 g (152 g on dry basis, 97.82 % yield, HPLC purity 99.77%) of thiabendazole.

Example 3: Purification of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 224 g of wet crude thiabendazole (145 g on dry basis) was charged at 25 to 30 °C. 2392 mL (16.5 V) of water was charged and the reaction mass was heated to 75 to 80 °C. The pH of the reaction mass was adjusted between 1 to 2 by adding concentrated hydrochloride. Then 21.75 g (15 %, w/w) activated charcoal was added and the reaction mass was stirred for 1.0 hour at 75 to 80 °C. The reaction mass was filtered through hyflo bed and the bed was washed with 1445 mL (1.0 V) of hot water. The aqueous layer was charged back to clean RBF and cooled to 0 to 5 °C and stirred for 10 hours. The solid was filtered and suck dried under vacuum to get 224 g wet cake of thiabendazole hydrochloride (135 g on dry basis).

1261 niL (10 V w.r.t dry thiabendazole hydrochloride) was charged and then 224 g wet cake of thiabendazole hydrochloride was added. The reaction mass was heated to 70 to 80 °C and maintained under stirring for half an hour to get clear solution. The pH of the reaction mass was adjusted to 7 to 8 by using liquor ammonia. The reaction mass was cooled to 25 to 30 °C and stirred for 1.0 hour. The reaction mass was filtered, and the wet cake was slurry washed twice with 1350 mL (10V x 2 times). Then the bed was washed with 675 mL (5.0 V) water. The solid was dried under vacuum at 60 to 70 °C to afford 119 g (79.33% yield, HPLC purity 99.96%) of pure thiabendazole.

CLIP

Fig. 5 Raman spectrum of solid thiabendazole, and SERS spectra of ethanol – water solutions on a re-used 3 m m thick Au woodpile array. Spurious bands from impurities are marked with asterisks.

CLIP

Fig. 6 (A) Proton NMR spectrum of thiabendazole in DMSO-d 6 solution. (B) Plots of normalized selective relaxation rate enhancements of H1/ H2, H14, and H12. [TBZ] ¼ 2 Â 10 À3 mol L À1 , [DNA] ¼ 1, 2, 5, 10, 20 Â 10 À5 mol L À1 , pH ¼ 7.4, T ¼ 298 K. (C) Equilibrium constant of the TBZ-DNA system. [DNA] ¼ 2 Â 10 À5 mol L À1 , [TBZ] ¼ 2, 2.5, 3, 3.5, 4 Â 10 À3 mol L À1 , pH ¼ 7.4, T ¼ 298 K.

CLIP

Thiabendazole has been prepared by heating thiazole-4-carboxamide and benzene-1,2-diamine in polyphosphoric acid (Scheme 13) (1961JA(83)1764). An alternative synthesis involves 4-carboxythiazole (CA 162 590253 (2015), CA 62 90958 (1964)) or 4-cyanothiazole (CA 130 110264 (1996), CA 121 57510 (1994)) as starting materials. A different approach to the synthesis of thiabendazole has been described starting from N-arylamidines; in the presence of sodium hypochlorite and a base, N-arylamidine hydrochlorides are transformed to benzimidazoles via formation of N-chloroamidine intermediate followed by ring closure in a stepwise or concerted mechanism (1965JOC(30)259).

References

^ “E233 : E Number : Preservative”. http://www.ivyroses.com. Retrieved 2018-08-28.
^ Upadhyay MP, West EP, Sharma AP (January 1980). “Keratitis due to Aspergillus flavus successfully treated with thiabendazole”. Br J Ophthalmol. 64 (1): 30–2. doi:10.1136/bjo.64.1.30. PMC 1039343. PMID 6766732.
^ Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sánchez-Sánchez P, Matogo-Oyana J, Rodríguez-Calabuig D (December 2004). “Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis”. Expert Opin Pharmacother. 5 (12): 2615–9. doi:10.1517/14656566.5.12.2615. PMID 15571478. Archived from the original on 2016-03-06.
^ Portugal R, Schaffel R, Almeida L, Spector N, Nucci M (June 2002). “Thiabendazole for the prophylaxis of strongyloidiasis in immunosuppressed patients with hematological diseases: a randomized double-blind placebo-controlled study”. Haematologica. 87 (6): 663–4. PMID 12031927.
^ Cha, HJ; Byrom M; Mead PE; Ellington AD; Wallingford JB; et al. (August 2012). “Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent”. PLoS Biology. 10 (8): e1001379. doi:10.1371/journal.pbio.1001379. PMC 3423972. PMID 22927795. Retrieved 2012-08-21.
^ Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 970
^ Rosenblum, C (March 1977). “Non-Drug-Related Residues in Tracer Studies”. Journal of Toxicology and Environmental Health. 2 (4): 803–14. doi:10.1080/15287397709529480. PMID 853540.
^ Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989., p. 3251
^ UK Food Standards Agency: “Current EU approved additives and their E Numbers”. Retrieved 2011-10-27.
^ Australia New Zealand Food Standards Code“Standard 1.2.4 – Labelling of ingredients”. Retrieved 2011-10-27.
^ “Reregistration Eligibility Decision THIABENDAZOLE” (PDF). Environmental Protection Agency. Retrieved 8 January 2013.
^ Setzinger, Meyer; Painfield, North; Gaines, Water A.; Grenda, Victor J. (1965). “Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole1”. The Journal of Organic Chemistry. 30: 259–261. doi:10.1021/jo01012a061.
^ Brown, H. D.; Matzuk, A. R.; Ilves, I. R.; Peterson, L. H.; Harris, S. A.; Sarett, L. H.; Egerton, J. R.; Yakstis, J. J.; Campbell, W. C.; Cuckler, A. C. (1961). “Antiparasitic Drugs. Iv. 2-(4′-Thiazolyl)-Benzimidazole, A New Anthelmintic”. Journal of the American Chemical Society. 83 (7): 1764–1765. doi:10.1021/ja01468a052.
^ Tocco, D. J.; Buhs, R. P.; Brown, H. D.; Matzuk, A. R.; Mertel, H. E.; Harman, R. E.; Trenner, N. R. (1964). “The Metabolic Fate of Thiabendazole in Sheep1”. Journal of Medicinal Chemistry. 7 (4): 399–405. doi:10.1021/jm00334a002.
^ Hoff, Fisher, ZA 6800351 (1969 to Merck & Co.), C.A. 72, 90461q (1970).
^ Hoff, D. R.; Fisher, M. H.; Bochis, R. J.; Lusi, A.; Waksmunski, F.; Egerton, J. R.; Yakstis, J. J.; Cuckler, A. C.; Campbell, W. C. (1970). “A new broad-spectrum anthelmintic: 2-(4-Thiazolyl)-5-isopropoxycarbonylamino-benzimidazole”. Experientia. 26 (5): 550–551. doi:10.1007/BF01898506.
^ Chronicles of Drug Discovery, Book 1, pp 239-256.

Tiabendazole
Clinical data


Trade names	Mintezol, others
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B3
Routes of administration	By mouth, topical
ATC code	D01AC06 (WHO) P02CA02 (WHO) QP52AC10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	С_max 1–2 hours (oral administration)
Metabolism	GI tract
Elimination half-life	8 hours
Excretion	Urine (90%)
Identifiers
IUPAC name [show]
CAS Number	148-79-8
PubChem CID	5430
IUPHAR/BPS	7304
DrugBank	DB00730
ChemSpider	5237
UNII	N1Q45E87DT
KEGG	D00372
ChEMBL	ChEMBL625
NIAID ChemDB	007903
ECHA InfoCard	100.005.206
Chemical and physical data
Formula	C₁₀H₇N₃S
Molar mass	201.249 g/mol
3D model (JSmol)	Interactive image
Density	1.103 g/cm³
Melting point	293 to 305 °C (559 to 581 °F)
SMILES [hide] [nH]1c2ccccc2nc1c3cscn3
InChI [hide] InChI=1S/C10H7N3S/c1-2-4-8-7(3-1)12-10(13-8)9-5-14-6-11-9/h1-6H,(H,12,13) Key:WJCNZQLZVWNLKY-UHFFFAOYSA-N

Synthesis Reference

Lynn E. Applegate, Carl A. Renner, “Preparation of high purity thiabendazole.” U.S. Patent US5310923, issued October, 1977.

US5310923

/////////////////MK 360, MK-360, NSC-525040, NSC-90507, チアベンダゾール, TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 ,

Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物 ,

January 23, 2019 12:29 pm / 1 Comment on Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物 ,

Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物

2019/1/8, PMDA, JAPAN, Selincro,

In January 2019, Otsuka received regulatory approval in Japan

Antialcohol dependence, Narcotic antagonist, Opioid receptor partial agonist/antagonist

Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-, hydrochloride, hydrate (1:1:2), (5α)-

Formula	C21H25NO3. HCl. 2H2O
CAS	1228646-70-5 5096-26-9 free form 58895-64-0 (Nalmefene HCl)
Mol weight	411.9196

JF-1; NIH-10365; ORF-11676; SRD-174, Lu-AA36143

APPROVED 1995 USA

Trade Name：Revex^®MOA：Opioid receptor antagonist Indication：Respiratory depression

Company：Baxter (Originator)

17- (cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol

(5α)-17-(Cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol;

(-)-Nalmefene;

6-Deoxo-6-methylenenaltrexone; 6-Desoxy-6-methylenenaltrexone;

JF 1; Nalmetrene; ORF 11676;

CHINA 2013

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2013-11-13	Marketing approval		Respiratory depression	Injection	1 ml:0.1 mg	灵宝市豫西药业	3.1类
2013-09-22	Marketing approval	抒纳	Respiratory depression	Injection	1 ml:0.1 mg(以纳美芬计)	辽宁海思科制药	3.1类
2013-08-02	Marketing approval	乐萌	Respiratory depression	Injection	1 ml:0.1 mg	成都天台山制药	3.1类
2012-12-31	Marketing approval		Respiratory depression	Injection	1 ml:0.1 mg (以C21H25NO3计)	北京四环制药
2012-05-15	Marketing approval		Respiratory depression	Injection	1 ml:0.1 mg	西安利君制药

EMA LINK

In February 2013, EC approval in all EU member states was granted for the reduction of alcohol consumption in adults with alcohol dependence

Nalmefene hydrochloride dihydrate is a white or almost white crystalline powder. The chemical name is 17-(Cyclopropylmethyl)-4,5-α-epoxy-6-methylene-morphinan-3,14-diol hydrochloride dihydrate, has the following molecular formula C21H25NO3 ⋅ HCl ⋅ 2 H2O

Nalmefene hydrochloride dihydrate is very soluble in water and is not hygroscopic. Nalmefene hydrochloride dihydrate is a chiral compound, containing 4 asymmetric carbon atoms. Only one crystal form of Nalmefene hydrochloride dihydrate has been identified. Nalmefene hydrochloride dihydrate does not melt, but becomes amorphous after dehydration.

The structure of nalmefene hydrochloride dihydrate was demonstrated by elemental analysis, IR, UV/Vis, 1 H-NMR and 13C-NMR spectroscopy as well as MS spectrometry. Its crystal structure was analysed by X-ray diffraction and specific optical rotation was determined. It has been shown that no polymorphic forms were observed.

PATENTS AND GENERICS

The original product patent was based on US 03814768 which expired in 1991. However, a number of patents cover formulations and use. Lundbeck and Biotie have a family based on WO 2010063292 which claims novel crystal forms and hydrate salts, in particular Nalmefene hydrochloride dihydrate, and their use in alcohol dependence. There are European and US patents granted on this EP 02300479 will expire December 2029 and US-08530495 will expire August 2030.

Nalmefene hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Apr 17, 1995. It was developed and marketed asRevex^® by Baxterin in the US.
Nalmefene is an opioid receptor antagonist. It acts as a silent antagonist of the μ-opioid receptor and as a partial agonist of the κ-opioid receptor, it also possesses affinity for the δ-opioid receptor. Revex^® is indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids. It is also indicated in the management of known or suspected opioid overdose.

Revex^® is available as a sterile solution for intravenous, intramuscular and subcutaneous administration in two concentrations, containing 100 μg or 1.0 mg of nalmefene free base per mL. The recommended dose is initiating at 0.25 μg/kg followed by 0.25 μg/kg incremental doses at 2-5 minute intervals for reversal of postoperative opioid depression, stopping as soon as the desired degree of opioid reversal is obtained.

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid antagonist used primarily in the management of alcohol dependence. It has also been investigated for the treatment of other addictions such as pathological gambling.^[1]

Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity.^[2]

As with other drugs of this type, nalmefene may precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively, to counteract the effects of strong opioids used in surgery.

Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.^[3]

This is not the usual application for this drug, for two reasons:

The half-life of nalmefene is longer than that of naloxone. One might have thought this would make it useful for treating overdose involving long-acting opioids: it would require less frequent dosing, and hence reduce the likelihood of renarcotization as the antagonist wears off. But, in fact, the use of nalmefene is not recommended in such situations. Unfortunately, opioid-dependent patients may go home and use excessive doses of opioids in order to overcome nalmefene’s opioid blockade and to relieve the discomfort of opioid withdrawal. Such large doses of opioids may be fatal. This is why naloxone (a shorter-acting drug) is normally a better choice for overdose reversal.^[4]
In addition, injectable nalmefene is no longer available on the market.

When nalmefene is used to treat an opioid overdose, doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit than doses of only 1.5 mg.

Alcohol dependence

Nalmefene is used in Europe to reduce alcohol dependence^[5] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.^[6]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.^[7] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.^[7]^[8] The medication may also be taken “as needed”, when a person feels the urge to consume alcohol.^[8]

Side effects

The following adverse effects have been reported with nalmefene:

Very Common (≥1⁄10)[edit]

Insomnia
Dizziness
Headache
Nausea

Common (≥1⁄100 to <1/10)[edit]

Decreased appetite
Sleep disorder
Confusional state
Restlessness
Libido decreased (including loss of libido)
Somnolence
Tremor
Disturbance in attention
Paraesthesia
Hypoaesthesia
Tachycardia
Palpitations
Vomiting
Dry mouth
Diarrhoea
Hyperhidrosis
Muscle spasms
Fatigue
Asthenia
Malaise
Feeling abnormal
Weight decreased

The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.^[9]

Pharmacology

Pharmacodynamics

Nalmefene acts as a silent antagonist of the μ-opioid receptor (MOR) (K_i = 0.24 nM) and as a weak partial agonist (K_i = 0.083 nM; E_max = 20–30%) of the κ-opioid receptor (KOR), with similar affinity for these two receptors but a several-fold preference for the KOR.^[10]

^[11]^[12] In vivo evidence indicative of KOR activation, such as elevation of serum prolactin levels due to dopamine suppression and increased hypothalamic-pituitary-adrenal axisactivation via enhanced adrenocorticotropic hormone and cortisol secretion, has been observed in humans and animals.^[10]^[13] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.^[14] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.^[15] In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower affinity for the δ-opioid receptor (DOR) (K_i = 16 nM), where it behaves as an antagonist.^[10]^[12]^[16]

Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂). It binds to the MOR with similar affinity relative to naltrexone, but binds “somewhat more avidly” to the KOR and DOR in comparison.^[10]^[13]

Pharmacokinetics

Nalmefene is extensively metabolized in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.^{[citation needed]}

Chemistry

Nalmefene is a derivative of naltrexone and was first reported in 1975.^[17]

Society and culture

United States

In the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name Revex. The product was discontinued by its manufacturer around 2008.^[18]^[19] Perhaps, due to its price, it never sold well. (See § Opioid overdose, above.)

Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, has never been sold in the United States.^[2]

Europe

Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.^[20] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.^[21] The drug was approved for use in the EU in March 2013.^[22] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.^[23] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.^[24] In November 2014 nalmefene was appraised and approved as a treatment supplied by Britain’s National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence.^[25]

Research

Nalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.^[26]

SYN

Nalmefene (CAS NO.: 55096-26-9), with its systematic name of Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-, (5alpha)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
By a Wittig reaction at naltrexone (I) with triphenylmethylphosphonium bromide (II) in DMSO in the presence of NaH as base.

Image result for nalmefene synthesis

PAPER

J. Med. Chem. 1975, 18, 259-262

https://pubs.acs.org/doi/pdf/10.1021/jm00237a008

PATENT

WO 2010136039

PATENT

US 3814768

Mol. Formula: C21H25NO3

Appearance: Off-White to Pale Yellow Solid

Melting Point: 182-185˚C

Mol. Weight: 339.43

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor antagonist developed in the early 1970s,^[1] and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.^[2] The doses tested for treating pathological gambling were between 25–100 mg per day.^[3] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.

Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose,^[4] although this is not the usual application for this drug as naloxone is less expensive.

Doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene’s longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.

Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.^[5] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.^[6] It has not been available on the US market since at least August 2008.^{[citation needed]}

Side effects

Common: drowsiness, hypertension, tachycardia, dizziness, nausea, vomiting
Occasional: fever, hypotension, vasodilatation, chills, headache
Rare: agitation, arrhythmia, bradycardia, confusion, hallucinations, myoclonus, itching^[7]

Properties

Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
pK_a 7.6
Distribution half-life: 41 minutes

Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists deriving from the opioid system. The clinical usefulness of nalmefene as antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the frequently observed depressions in the central nervous system and the respiratory system.

Nalmefene has primarily been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect in doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al, Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In testing the drug in these developmental programs, nalmefene has been used, for example, in the form of parental solution (Revex™).

Nalmefene is an opiate derivative quite similar in structure to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half- life, greater oral bioavailability and no observed dose-dependent liver toxicity. Nalmefene differs structurally from naltrexone in that the ketone group at the 6- position of naltrexone is replaced by a methylene (CH₂) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (K and δ receptors) and is known as a “universal antagonist” as a result of its ability to block all three receptor types.

Nalmefene can be produced from naltrexone by the Wittig reaction. The Wittig reaction is a well known method within the art for the synthetic preparation of olefins (Georg Wittig, Ulrich Schόllkopf (1954). “Uber Triphenyl-phosphin- methylene ah olefinbildende Reagenzien I”. Chemische Berichte 87: 1318), and has been widely used in organic synthesis.

The procedure in the Wittig reaction can be divided into two steps. In the first step, a phosphorus ylide is prepared by treating a suitable phosphonium salt with a base. In the second step the ylide is reacted with a substrate containing a carbonyl group to give the desired alkene.

The preparation of nalmefene by the Wittig reaction has previously been disclosed by Hahn and Fishman (J. Med. Chem. 1975, 18, 259-262). In their method, naltrexone is reacted with the ylide methylene triphenylphosphorane, which is prepared by treating methyl triphenylphosphonium bromide with sodium hydride (NaH) in DMSO. An excess of about 60 equivalents of the ylide is employed in the preparation of nalmefene by this procedure.

For industrial application purposes, the method disclosed by Hahn and Fishman has the disadvantage of using a large excess of ylide, such that very large amounts phosphorus by-products have to be removed before nalmefene can be obtained in pure form. Furthermore, the NaH used to prepare the ylide is difficult to handle on an industrial scale as it is highly flammable. The use of NaH in DMSO is also well known by the skilled person to give rise to unwanted runaway reactions. The Wittig reaction procedure described by Hahn and Fishman gives nalmefene in the form of the free base. The free base is finally isolated by chromatography, which may be not ideal for industrial applications.

US 4,535,157 also describes the preparation of nalmefene by use of the Wittig reaction. In the method disclosed therein the preparation of the ylide methylene triphenylphosphorane is carried out by using tetrahydrofuran (THF) as solvent and potassium tert-butoxidc (KO-t-Bu) as base. About 3 equivalents of the ylide are employed in the described procedure.

Although the procedure disclosed in US 4,535,157 avoids the use of NaH and a large amount of ylide, the method still has some drawbacks which limit its applicability on an industrial scale. In particular, the use of THF as solvent in a Wittig reaction is disadvantageous because of the water miscibility of THF. During the aqueous work-up much of the end product (nalmefene) may be lost in the aqueous phases unless multiple re-extractions are performed with a solvent which is not miscible with water.

Furthermore, in the method described in US 4,535,157, multiple purification steps are carried out in order to remove phosphine oxide by-products of the Wittig reaction. These purification steps require huge amounts of solvents, which is both uneconomical and labor extensive requiring when running the reaction on an industrial scale. As in the case of the Wittig reaction procedure described by Hahn and Fishman (see above) the Wittig reaction procedure disclosed in US 4,535,157 also yields nalmefene as the free base, such that an additional step is required to prepare the final pharmaceutical salt form, i.e. the hydrochloride, from the isolated nalmefene base.

US 4,751,307 also describes the preparation of nalmefene by use of the Wittig reaction. Disclosed is a method wherein the synthesis is performed using anisole (methoxybenzene) as solvent and KO-t-Bu as base. About 4 equivalents of the ylide methylene triphenylphosphorane were employed in this reaction. The product was isolated by extraction in water at acidic pHs and then precipitating at basic pHs giving nalmefene as base.

Even though the isolation procedure for nalmefene as free base is simplified, it still has some disadvantages. The inventors of the present invention repeated the method disclosed in US 4,751,307 and found that the removal of phosphine oxide by-products was not efficient. These impurities co-precipitate with the nalmefene during basifϊcation, yielding a product still contaminated with phosphorus byproducts and having, as a consequence, a low chemical purity, as illustrated in example 2 herein.

There is therefore a need within the field to improve the method of producing nalmefene by the Wittig reaction. In particular, there is a need for a method that is readily applicable on a large industrial scale and which avoids the use of water- miscible solvents, such as THF, in the Wittig reaction, and permits easy isolation of nalmefene in a pure form suitable for its transformation to the final pharmaceutical salt form.

………………………………..

http://www.google.com/patents/EP2435439A1?cl=en

present invention the Wittig reaction may be performed by mixing a methyltriphenylphosphonium salt with 2- methyltetrahydrofuran (MTHF) and a suitable base to afford the ylide methylene triphenylphosphorane :

Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde

The preformed ylide is subsequently reacted ‘in situ’ with naltrexone to give nalmefene and triphenylphosphine oxide (TPPO):

Naltrexone Yhde Nalmefene TPPO

Example 1 Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2- methyltetrahydrofuran (MTHF, 56 litres). Keeping the temperature in the range 20-25⁰C, KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 litres) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 litres) and then further diluted with water (30.4 litres). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 litres). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 litres) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 litres) was added over one hour at 20- 25⁰C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 litres) and then with acetone (16 litres). The solid was then re-suspended in dichloromethane (32 litres) at 20-25⁰C for a few hours and then filtered and washed with dichloromethane (16 litres), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.

HPLC Chromatographic conditions

Column: Zorbax Eclipse XDB C-18, 5 μm, 150 x 4.6 mm or equivalent Mobile Phase A: Acetonitrile / Buffer pH = 2.3 10 / 90

Mobile Phase B: Acetonitrile / Buffer pH = 2.3 45 / 55

Buffer: Dissolve 1.1 g of Sodium Octansulfonate in 1 L of water. Adjust the pH to 2.3 with diluted

H₃PO₄. Column Temperature: 35°C

Detector: UV at 230 nm

Flow: 1.2 ml/min

Injection volume: 10 μl

Time of Analysis: 55 minutes

Example 2

The procedure described in US 4,751,307 was repeated, starting from 1Og of naltrexone and yielding 8.5g of nalmefene. The isolated product showed the presence of phosphine oxides by-products above 15% molar as judged by 1HNMR.

Example 3.

Methyltriphenylphosphonium bromide (MTPPB, 112.9g) was suspended in 2- methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20- 25°C, KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10. Ig) was added over one hour at 20- 25°C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1g of Nalmefene HCl. Example 4

Example 3 was repeated but the Wittig reaction mixture after olefmation completeness was treated with acetone and then with an aqueous solution of ammonium chloride. After phase separation, washings, distillation and dilution with dichloromethane, the product was precipitated as hydrochloride salt using HCl 37%. The solid was filtered and dried affording 37.6 g of Nalmefene HCl.

Example 5 Preparation of Nalmefene HCl dihydrate from Nalmefene HCl Nalmefene HCl (7.67 Kg, purity 99.37%, assay 93.9%) and water (8.6 litres) were charged into a suitable reactor. The suspension was heated up to 80⁰C until the substrate completely dissolved. Vacuum was then applied to remove organic solvents. The resulting solution was filtered through a 0.65 μm cartridge and then diluted with water (2.1 litres) that has been used to rinse the reactor and pipelines. The solution was cooled down to 50⁰C and 7 g of Nalmefene HCl dihydrate seeding material was added. The mixture was cooled to 0-5⁰C over one hour with vigorous stirring and then maintained under stirring for one additional hour. The solid was filtered of and washed with acetone. The wet product was dried at 25°C under vacuum to provide 5.4 Kg of Nalmefene HCl dihydrate (purity 99.89%, KF 8.3% , yield 69%).

………………….

http://www.google.com/patents/EP2316456A1?cl=en

……………………

http://www.google.com/patents/US8598352

Figure US08598352-20131203-C00003

Lundbeck’s novel alcohol dependency drug has been endorsed by the National Institute for Health and Care Excellence (NICE) for use in Britain’s state health service.

read at

http://www.clinicalleader.com/doc/nice-endorses-lundbeck-s-alcohol-dependency-drug-for-use-in-uk-0001

A structural analog of Naltrexone (N285780) with opiate antagonist activity used in pharmaceutical treatment of alcoholism. Other pharmacological applications of this compound aim to reduce food cravings, drug abuse and pulmonary disease in affected individuals. Used as an opioid-induced tranquilizer on large animals in the veterinary industry. Narcotic antagonist.

NALMEFENE

References

^ NCT00132119 ClinicalTrials.gov
^ Jump up to:^a ^b See: “Drug Record: Nalmefene”. LiverTox. National Library of Medicine. 24 March 2016.
^ Label information. U.S. Food and Drug Administration“Archived copy” (PDF). Archived from the original on October 13, 2006. Retrieved 2014-11-07.
^ Based on: Stephens, Everett. “Opioid Toxicity Medication » Medication Summary”. Medscape. WebMD LLC.
^ “Selincro 18mg film-coated tablets”. UK Electronic Medicines Compendium. September 2016.
^ “Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence”. NICE. 26 November 2014.
^ Jump up to:^a ^b Palpacuer, C; Laviolle, B; Boussageon, R; Reymann, JM; Bellissant, E; Naudet, F (December 2015). “Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials”. PLOS Medicine. 12 (12): e1001924. doi:10.1371/journal.pmed.1001924. PMC 4687857. PMID 26694529.
^ Jump up to:^a ^b Paille, François; Martini, Hervé (2014). “Nalmefene: a new approach to the treatment of alcohol dependence”. Substance Abuse and Rehabilitation. 5 (5): 87–94. doi:10.2147/sar.s45666. PMC 4133028. PMID 25187751.
^ “Selincro”. European Medicines Agency. Retrieved 3 November 2015.
^ Jump up to:^a ^b ^c ^d Bart, G; Schluger, JH; Borg, L; Ho, A; Bidlack, JM; Kreek, MJ (December 2005). “Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?” (PDF). Neuropsychopharmacology. 30 (12): 2254–62. doi:10.1038/sj.npp.1300811. PMID 15988468.
^ Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (2005). “Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?”. Neuropsychopharmacology. 30 (12): 2254–62. doi:10.1038/sj.npp.1300811. PMID 15988468.
^ Jump up to:^a ^b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–. ISBN 978-0-12-420177-4.
^ Jump up to:^a ^b Niciu, Mark J.; Arias, Albert J. (2013). “Targeted opioid receptor antagonists in the treatment of alcohol use disorders”. CNS Drugs. 27 (10): 777–787. doi:10.1007/s40263-013-0096-4. ISSN 1172-7047. PMC 4600601. PMID 23881605.
^ “Nalmefene (new drug) Alcohol dependence: no advance”. Prescrire International. 23(150): 150–152. 2014. PMID 25121147. (subscription required)
^ Stephen M. Stahl (15 May 2014). Prescriber’s guide: Stahl’s essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9.
^ Grosshans M, Mutschler J, Kiefer F (2015). “Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience”. International Clinical Psychopharmacology. 30 (4): 237–8. doi:10.1097/YIC.0000000000000069. PMID 25647453.
^ Fulton, Brian S. (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 341. ISBN 9781118889572.
^ See: “Baxter discontinues Revex injection”. Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Retrieved 10 October 2016.
^ “Drug Shortages”. FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008.
^ “Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)”.
^ “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. The Pharma Letter. 22 December 2011.
^ “Selincro”. European Medicines Agency. 13 March 2013.
^ “Alcohol cravings drug nalmefene granted approval in Scotland”. BBC News. 7 October 2013.
^ “Nalmefene granted approval in England”. The Independent. 3 October 2014.
^ “Alcohol dependence treatment accepted for NHS use”. MIMS. 26 November 2014.
^ Bidlack, Jean M (2014). “Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence”. Adv. Pharmacol. 69: 387–418. doi:10.1016/B978-0-12-420118-7.00010-X. PMID 24484983.

Nalmefene
Clinical data

Trade names	Selincro
AHFS/Drugs.com	Monograph
MedlinePlus	a605043
License data	EU EMA: by INN
Routes of administration	By mouth, intravenous
ATC code	N07BB05 (WHO)
Legal status
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
Protein binding	45%
Metabolism	hepatic
Elimination half-life	10.8 ± 5.2 hours
Excretion	renal
Identifiers
IUPAC name [show]
CAS Number	55096-26-9 58895-64-0 (HCl)
PubChem CID	5284594
IUPHAR/BPS	1628
ChemSpider	4447642
UNII	TOV02TDP9I
ChEMBL	ChEMBL982
ECHA InfoCard	100.164.948
Chemical and physical data
Formula	C₂₁H₂₅NO₃
Molar mass	339.43 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C
InChI [hide] InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1 Key:WJBLNOPPDWQMCH-MBPVOVBZSA-N

Nalmefene

17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol

march 1 2013

Lundbeck will be celebrating news that European regulators have issued a green light for Selincro, making it the first therapy approved for the reduction of alcohol consumption in dependent adults.

Selincro (nalmefene) is a unique dual-acting opioid system modulator that acts on the brain’s motivational system, which is dysregulated in patients with alcohol dependence.

The once daily pill has been developed to be taken on days when an alcoholic feels at greater risk of having a drink, in a strategy that aims to reduce – rather than stop – alcohol consumption, which some experts believe is a more realistic goal.

Clinical trials of the drug have shown that it can reduce alcohol consumption by approximately 60% after six months treatment, equating to an average reduction of nearly one bottle of wine per day.

In March last year, data was published from two Phase III trials, ESENSE 1 and ESENSE 2, showing that the mean number of heavy drinking days decreased from 19 to 7 days/month and 20 to 7 days/month, while TAC fell from 85 to 43g/day and from 93 to 30g/day at month six. However, the placebo effect was also strong in the studies.

According to Anders Gersel Pedersen, Executive Vice President and Head of Research & Development at Lundbeck, Selincro “represents the first major innovation in the treatment of alcohol dependence in many years,” and he added that its approval “is exciting news for the many patients with alcohol dependence who otherwise may not seek treatment”.

Alcohol dependence is considered a major public health concern, and yet it is both underdiagnosed and undertreated, highlighting the urgent need for better management of the condition.

In Europe, more than 90% of the 14 million patients with alcohol dependence are not receiving treatment, but research suggests that treating just 40% of these would save 11,700 lives each year.

The Danish firm said it expects to launch Selincro in its first markets in mid-2013, and that it will provide the drug as part of “a new treatment concept that includes continuous psychosocial support focused on the reduction of alcohol consumption and treatment adherence”.

Nalmefene (Revex), originally known as nalmetrene, is an opioid receptor antagonistdeveloped in the early 1970s, and used primarily in the management of alcoholdependence, and also has been investigated for the treatment of other addictions such aspathological gambling and addiction to shopping.

US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719.
Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
“Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”. “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
Nalmefene Hydrochloride Drug Information, Professional

NALMEFENE
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol

Sihuan’s Drug Nalmefene Hydrochloride Receives Approval for Pharmaceutical Registration from State Food and Drug Administration

Sihuan Pharmaceutical Holdings Group Ltd a leading pharmaceutical company with the largest cardio-cerebral vascular drug franchise in China’s prescription market, announced that the new Category 3.1 drug, the Nalmefene Hydrochloride Injection received a new drug certificate (H20120078) and approval for production (2012S00818) from the State Food and Drug Administration. Nalmefene Hydrochloride is yet another generic drug for which the Company has received approval for production following the Roxatidine Acetate Hydrochloridefor Injection. It will be manufactured by Beijing Sihuan Pharmaceutical Co., Ltd., a wholly-owned manufacturing subsidiary of the Company.

Nalmefene hydrochloride is a next generation opioid (opium) receptor inhibitor following Naloxone and Naltrexone. The injection formulation of Naloxone hydrochloride was invented by Ohmeda Pharmaceuticals and was approved by the US Food and Drug Administration (FDA) in 1995. The clinical uses of Nalmefene hydrochloride include anti-shock, neuroprotection, treatment for acute morphine poisoning, drug relapse prevention, recovery from the after-effects of anesthesia such as respiratory and nerve center depression and the treatment of unconsciousness persons.

The drug is also effective for treating heart failure and spinal cord injuries, for cerebral protection, etc. Multi-centre, randomized, blind, and positive-controlled clinical research of Nalmefene hydrochloride of Sihuan Pharmaceutical were performed by the Peking University First Hospital, the First Affiliated Hospital of China Medical University, Xijing Hospital (The First Affiliated Hospital of the Fourth Military Medical College) and Qingdao Municipal Hospital.

Compared to Naloxone, Nalmefene demonstrates longer curative effects and fewer adverse reactions. With its high bioavailability, biological activities and biofilm penetration ability, it helps to regulate respiration, circulation, digestion, and the endocrine and nervous systems. It is becoming a substitute for Naloxone, and has been included in Part B of the National Medicine Catalogue. At present, the size of the Nalmefene hydrochloride market in China is approximately RMB1 billion. As a substitution for Naloxone hydrochloride, Nalmefene hydrochloride has enormous market potential.

Diseases of the central nervous system (CNS) are common in China, which has an immense patient base. Due to the rapid pace of modern life, accelerated urbanisation and mental stress, the demand for CNS medicines has seen rapid growth in recent years given the rising number of patients. According to IMS, the size of the CNS drug market now exceeds RMB 23 billion. With the CNS drug market expected to reach RMB 100 billion in 2020, the Group sees great potential and strong growth prospects in the market.Dr. Che Fengsheng, Chairman and CEO of Sihuan Pharmaceutical, said, “Nalmefene Hydrochloride has shown better characteristics for treatment and higher clinical value than Naloxone. Its market demonstrates great potential to expand. Leveraging Sihuan Pharmaceutical’s strong marketing capabilities and extensive sales and distribution network, we believe that our market share for Nalmefene Hydrochloride will see rapid growth, which will strengthen our position in drugs for the treatment of major diseases of the central nervous system. Together with other new products, this will in turn enhance the continuous development and growth of Sihuan Pharmaceutical in China’s prescription drug market and create value for the shareholders and the Company.”

REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below:

REVEX (nalmefene hydrochloride) Structural Formula Illustration

Molecular Formula: C₂₁H₂₅NO₃•HCl

Molecular Weight: 375.9, CAS # 58895-64-0

Chemical Name: 17-(Cyclopropylmethyl)-4,5a-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt.

Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pK_a of 7.6.

REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid.

Concentrations and dosages of REVEX are expressed as the free base equivalent of nalmefene

////////////////////JF-1, NIH-10365, ORF-11676, SRD-174, JAPAN 2019, FDA 1995, Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物 , Nalmefene, ema 2013, china, 2013, Lu-AA36143

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