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Penfluridol

October 16, 2019 9:35 am / Leave a comment

Penfluridol

Molecular FormulaC₂₈H₂₇ClF₅NO
Average mass523.965 Da

Penfluridol

CAS Registry Number: 26864-56-2

CAS Name: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol

Additional Names: 1-[4,4-bis(p-fluorophenyl)butyl]-4-(4-chloro-a,a,a-trifluoro-m-tolyl)-4-piperidinol; 1-(4,4-bis(4-fluorophenyl)butyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine

Manufacturers’ Codes: R-16341

MCN-JR-16,341 / R 16,341

Trademarks: Semap (Janssen)

Molecular Formula: C28H27ClF5NO

Molecular Weight: 523.97

Percent Composition: C 64.18%, H 5.19%, Cl 6.77%, F 18.13%, N 2.67%, O 3.05%

Literature References: Prepn: H. K. F. Hermans, C. J. E. Niemegeers, DE 2040231; eidem, US 3575990 (both 1971 to Janssen); Sindelár et al., Collect. Czech. Chem. Commun. 38, 3879 (1973). Pharmacology and toxicology: Janssen et al., Eur. J. Pharmacol.11, 139 (1970). Crystal structure: Koch, Acta Crystallogr. 29B, 1538 (1973).

Properties: White, microcrystals, mp 105-107°. Slightly sol in water, dil HCl (<0.5 mg/ml). LD50 orally in mice (day 7): 86.8 mg/kg (Janssen).

Melting point: mp 105-107°

Toxicity data: LD50 orally in mice (day 7): 86.8 mg/kg (Janssen)

Therap-Cat: Antipsychotic.

Keywords: Antipsychotic.

Penfluridol (Semap, Micefal, Longoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic.^[1] It was discovered at Janssen Pharmaceutica in 1968.^[2] Related to other diphenylbutylpiperidine antipsychotics, pimozide and fluspirilene, penfluridol has an extremely long elimination half-life and its effects last for many days after single oral dose. Its antipsychotic potency, in terms of dose needed to produce comparable effects, is similar to both haloperidol and pimozide. It is only slightly sedative, but often causes extrapyramidal side-effects, such as akathisia, dyskinesiae and pseudo-Parkinsonism. Penfluridol is indicated for antipsychotic treatment of chronic schizophrenia and similar psychotic disorders, it is, however, like most typical antipsychotics, being increasingly replaced by the atypical antipsychotics. Due to its extremely long-lasting effects, it is often prescribed to be taken orally as tablets only once a week (q 7 days). The once-weekly dose is usually 10–60 mg. A 2006 systematic review examined the use of penfluridol for people with schizophrenia:

Penfluridol compared to typical antipsychotics (oral) for schizophrenia^[3]
Summary
Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The effectiveness and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for people with long-term schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.^[3]

Penfluridol

- ATC:N05AG03
Use:neuroleptic
Chemical name:1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
Formula:C₂₈H₂₇ClF₅NO

MW:523.97 g/mol
CAS-RN:26864-56-2
EINECS:248-074-5
LD₅₀:87 mg/kg (M, p.o.);
160 mg/kg (R, p.o.)

Synthesis

PAPER

Late stage functionalization of secondary amines via a cobalt-catalyzed electrophilic amination of organozinc reagents
Org Lett 2019, 21(2): 494

https://pubs.acs.org/doi/10.1021/acs.orglett.8b03787

Scheme 6

Scheme 6. A New Synthesis of Penfluridol 5

English: DE patent 2040231

US patent 3575990

doi:10.1135/cccc19733879

SYN

References

- US 3 575 990 (Janssen; 20.4.1971; appl. 3.9.1969).
- DOS 2 040 231 (Janssen; appl. 13.8.1970; USA-prior. 3.9.1969).

alternative synthesis:
- FR-appl. 2 161 007 (Janssen; appl. 23.11.1972; J-prior. 25.11.1971).

PATENT

https://patents.google.com/patent/CN106187863A/en

Although Penfluridol listed for many years, but its chemical preparation technology abroad little studied in the earlier literature, there are several prepared as follows:

[0013] Process (a): 1971 Document Ger.0ffen [P], 2040231, (1971) Hermans.HKF first reported Penfluridol chemical synthesis, which process is as follows:

[0014]

[0015] The process of cyclopropyl methanol (ΙΠ) by 4,4, _-difluorophenyl-one ([pi) as a starting material, the reaction of cyclopropyl magnesium bromide-bis 4- (fluorophenyl), then the reaction with thionyl chloride to give 1,1_-bis (4-fluorophenyl) -4-chloro-butene (IV), obtained by catalytic hydrogenation 1,1_-bis (4-phenyl gas) burning chlorobutanol _4_ (V), and finally with 4-chloro-3-methylphenyl gas-4-piperidinol (X VH) in methyl isobutyl ketone was refluxed for three days the reaction to produce Penfluridol (the I), Document: Sindelar.K.et al, Collect Czech.Chem.Commun [J], 38 (12): 3879-3901, (1973).

[0016] In the above process, starting material and documentation of cyclopropyl magnesium bromide hardly prepared each reaction were not reported preparation yield, and therefore Document Sindelar · K · et al, Collect Czech · Chem · Commun [ J], 38 (12):. 3879-3901, (1973) that this technology is not very good.

[0017] Process (b): 1973, Sindelar.K successful research and the following other technology, which process is as follows:

[0018]

[0019] The process consists of 4,4_-bis (4-fluorophenyl) butoxy alkyl iodide as a starting material, 4,4_ ethylenedioxythiophene condensing piperidone removal of generated hydrogen iodide in N-pentanone – [4,4-bis (4-fluorophenyl) butoxy group] -4,4-dioxo-condensing vinyl piperidone, N-then obtained by acid hydrolysis [4,4-bis (4-fluorophenyl ) azetidinyl] -4-piperidone (W), the compound with 4-chloro-3-trifluoromethyl phenyl magnesium bromide reacted Penfluridol (I).

[0020] This process route may seem simple, but there are more desired to prepare intermediates, the process is more complex, with low yields reported in the literature.

[0021] Process (c): as follows:

[0022]

[0023] In this process, 4-chloro – (4-fluorophenyl) butyryl-one (Shan) starts, 4-fluorophenyl magnesium bromide reacts with 4-chloro – bis (4-fluorophenyl) butanol ( IX), and then boiling the reaction hydroiodic acid to give 4-iodo-in, red phosphorus catalyst – bis (4-fluorophenyl) butoxy left foot and finally burning ^^ – ^ – methyl ^ two gas – chlorophenyl Bu ‘piperidinol prepared products San ^ top five gas profitable ⑴.

[0024] This synthesis has the characteristics of high yield, but the intermediate (IX), (X) quality is not purified, many by-products, difficult to control the quality of products, and hydroiodic acid to be used, the source of raw material is difficult, therefore, not ideal technology.

[0025] Process (d), as follows:

[0026]

[0027] The process begins by Stobber reaction with 4,4 – fluorophenyl ketone reaction product diethyl succinate and compound (XI), and then generates bis (4-fluorophenyl) methine acid or base hydrolysis after succinic acid (M), by catalytic hydrogenation to give 4,4_-bis (4-fluorophenyl) butanoic acid after, the reaction with thionyl chloride without isolating the compound (XIV) with the compound directly (XW), by reduction after obtain the final product – Penfluridol. The disadvantage of this process is that, in the above reaction step, Stobber the reaction yield is low; hydrogenation catalyst manufacturing operation more difficult and unsafe; reaction with thionyl chloride, large air pollution, and other refractory.

[0028] The various preparation techniques Penfluridol other drug earlier British Patent Brit. 1141664 and German patent Ger. Off en. 2040231 has been reported, but no other foreign patent reports. In neither country has patent coverage, and no magazine reported.

The reaction formula is as follows:

[0058]

[0059] Step (5), the preparation of compounds of formula (XW) as shown, may be employed a method reported in the literature, or prepared using a method specifically includes the following steps:

[0060]

0124] (6) Penfluridol drug (I) were prepared:

[0125]

[0126] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a calcium chloride tube, was added 250ml of anhydrous diethyl ether, 2 · 4g (0 · 0631mol) tetrahydro lithium aluminum hydride, stirring was started, was added 20g (0 · 0372mol) amide (6), the addition was completed, 38 ° C for 6 hours.

[0127] completion of the reaction, water was added 4.2ml decomposition for 25 minutes, followed by addition of 5.4ml of 20% by weight concentration of sodium hydroxide solution decomposition for 20 minutes, 14.2ml decomposed with water for 15 minutes;

[0128] The decomposition was filtered, the filtrate (ethyl ether) and dried over anhydrous potassium carbonate. Filtered, the filter cake was washed with a little ether. The filtrate and the washings added to a distillation flask, recovery ether atmospheric distillation, vacuum drained, was added a mixed solvent l〇〇ml [chloroform: petroleum ether (60-90 ° C) = 1: 4, weight ratio, stirred and heated to reflux dissolution, filtered while hot, the filtrate was allowed to stand for crystallization at about 10 ° C, to be naturally deposited crystal after freezing -5 ° C overnight, filtered, the cake was washed with a mixed solvent, drain, ventilation pressure at 70 ° C dried to constant weight to give white crystalline product Penfluridol drug (I), mp 105-107 ° C, yield 81.5%.

[0129] Intermediate 4_ (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (XW) (referred piperidinol) Preparation:

[0130] (1) benzylamine (Beta) Preparation:

[0131]

[0132] equipped with a mechanical stirrer, a condenser, a thermometer 2000ml three reaction bottle, were added ammonium bicarbonate 240g (3.04mol), aqueous ammonia at a concentration of 20 wt %% of 15148 (17.812111〇1,

[0133] 1640ml), benzyl chloride 80g (0.632mol), reaction was stirred for 6 hours.Reaction to complete rested stratification. Aqueous layer was separated, and aqueous ammonia recovery bicarbonate atmospheric heating to 100 ° c, the water was distilled off under reduced pressure, with 50% sodium hydroxide PH12 above, extraction with benzene and dried solid sodium hydroxide. Recovery of benzene atmospheric distillation, vacuum distillation, collecting 33.4 g of the product obtained, yield 50.7%, content 99%,

[0134]

[0135] (3) N_ benzyl – bis ([beta] methoxycarbonyl-ethyl) amine (C) (referred to as diester thereof):

[0136]

[0137] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 250ml, 43g methyl acrylate (0.5111〇1) methanol 328 (401111), was added with stirring 21.48 benzylamine (0.2111〇1), The reaction was stirred for 7 hours. Completion of the reaction, recovery of excess methyl acrylate and methanol, water chestnut vacuum distillation until the internal temperature l〇〇-ll〇 ° C, to give the crude product as a yellow oil (C) 54g, yield 97%, content 94.3%.

[0138] (3) 1 – benzyl-4-piperidone (E) (referred to as the hydrolyzate) is prepared:

[0139]

[0140] In a reaction flask equipped with a 500ml three mechanical stirrer, thermometer, fractional distillation apparatus, was added 27% sodium methoxide 27g, crude diester was 33.4g (0.12mol), toluene 300ml, stirred and heated, the temperature reached 90 when ° C or more, additional 50ml toluene was reacted for 3 hours. Cooled to room temperature, and neutralized with acetic acid to PH6, standing layer. The toluene layer was separated and extracted with 150ml of 22% hydrochloric acid three times. Hydrochloric acid extracts were combined, heated with stirring for 4 hours. Recovered by distillation under reduced pressure and hydrochloric acid (about 120ml distilled dilute hydrochloric acid) was cooled to distillation l〇 ° C below, with 40% sodium hydroxide PH12 above. With 80ml ethyl acetate 3 times extracted with ethyl acetate extracts were combined, sub-net water, dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, recovering ethyl acetate atmospheric distillation, vacuum drained hydrolyzed to give (E) and the crude product 19g, yield 84%.

[0141] (4) 1-ethoxycarbonyl-4-piperidone (F) (referred to as a carbonyl group-piperidone) Preparation:

[0142]

[0143] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, was added ethyl chloroformate 23.9g (0 · 22mo 1), benzene 100ml, stirring slowly added dropwise [The crude hydrolyzate (E ) 37 · 8g (0 · 2mo 1) + 20ml phenyl] solution dropwise, the reaction was heated with stirring for 5 hours.Water chestnut evaporated under reduced pressure and ethyl benzene chlorine, Li mechanical change stream distilled off under reduced pressure, low boiling point evaporated to give the product 268 was collected, yield 76%.

[0144] (5) 1 – ethoxycarbonyl-4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (G) (referred to as a carbonyl group-piperidinol) is:

[0145]

[0146] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a dropping funnel and a calcium chloride drying tube over anhydrous anhydrous absolute, at room temperature was added magnesium metal shoulder 2.5g (0.103mol) 20ml of anhydrous ethyl ether and slowly stirring was started.

[0147] 2-chloro-5-bromo – trifluorotoluene (referred bromide) was dissolved under 27g (0.104mol) at room temperature in 130ml anhydrous diethyl ether and stirred to obtain a uniform liquid mass (W is);

[0148] When the liquid material taken 15ml was added to the above reaction, a solution of iodine 0.13g, 1,2- dibromoethane 0.2g, initiated Grignard reaction was heated until the iodine color disappeared, the reaction slowed down, slow slow dropping liquid material (W). The addition was completed, refluxing was continued for 1 hour. Completion of the reaction, cooled to room temperature, slowly added dropwise at room temperature carbonyl piperidone (F) water solution was cooled at normal [carbonyl-piperidone 13.6g (0.0795mol) + 40ml dry ether], dropwise, the reaction was heated with stirring 1.5 hour. L〇〇ml ammonium chloride solution concentration of 20% by weight was added, refluxed for 15 minutes and allowed to stand 30 minutes at room temperature stratification. Discharged aqueous layer (lower layer), the residual liquid was distilled (upper layer) at an external temperature of 55 ° C atmospheric distillation recovery ether, discharge hot, refrigerated overnight, the precipitated solid. Filtered, washed with a small amount of time, drained, and dried to give the product (G) 24.1g, yield 85.7%, mp 118-126Γ.

[0149] (6) 4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (X VH) (referred piperidinol) Preparation:

[0150]

[0151] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, were added ethanol 40ml, 158 of sodium hydroxide (0.375111〇1), carbonyl piperidinol (6) 2 (^ (0.0569111〇1 ), heated to reflux, and the reaction stirred for 3.5 hours. the reaction was completed, 50ml of water was added, the reaction was refluxed for 10 minutes, the hot reaction solution was placed in 300g of crushed ice, stirred well, and the precipitated solid, -5 ° C frozen standing for 2 hours the above.

[0152] filtered, washed with water to pH 8-9, drained, and dried to give piperidinol (XVH) 15g, yield 94%, mp 137-144 ° C, ash content <5%.

[0153] Example 2

[0154] (a) 3- (4-fluorobenzoyl) propionic acid (2) (the acid) is prepared:

[0155]

[0156] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 500ml, was added 17.1g (0.171mol) of succinic anhydride, l〇5g (1 · 09mol) fluorobenzene, stirred and dissolved. Added in one portion 60g (0 · 306mol) in dry wrong trichloride, stirring, the reaction was stirred at 100 ° C for 2 hours, at a concentration of 10% by weight hydrochloric acid 165ml exploded 30 minutes;

[0157] Other embodiments with Example 1, the product, 111.? 105-107 ° (:, this step a yield of 81.5%, 46.7% overall yield.

References

^ van Praag HM, Schut T, Dols L, van Schilfgaarden R., Controlled trial of penfluridol in acute psychosis, Br Med J. 1971 December 18;4(5789):710-3
^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, Van Nueten JM, Schaper WK., The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug, Eur J Pharmacol. 1970 July 15;11(2):139-54
^ Jump up to:^a ^b Soares, B; Silva de Lima, M (2006). “Penfluridol for schizophrenia”. Cochrane Database of Systematic Reviews. 2: CD002923.pub2. doi:10.1002/14651858.CD002923.pub2.

Penfluridol

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	N05AG03 (WHO)
Identifiers
IUPAC name [show]
CAS Number	26864-56-2
PubChemCID	33630
ChemSpider	31017
UNII	25TLU22Q8H
KEGG	D02630
ChEMBL	ChEMBL47050
CompTox Dashboard(EPA)	DTXSID5049021
ECHA InfoCard	100.043.689
Chemical and physical data
Formula	C₂₈H₂₇ClF₅NO
Molar mass	523.965 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] FC(F)(F)c1c(Cl)ccc(c1)C4(O)CCN(CCCC(c2ccc(F)cc2)c3ccc(F)cc3)CC4
InChI [hide] InChI=1S/C28H27ClF5NO/c29-26-12-7-21(18-25(26)28(32,33)34)27(36)13-16-35(17-14-27)15-1-2-24(19-3-8-22(30)9-4-19)20-5-10-23(31)11-6-20/h3-12,18,24,36H,1-2,13-17H2 Key:MDLAAYDRRZXJIF-UHFFFAOYSA-N

Elacridar

October 13, 2019 10:49 am / Leave a comment

ChemSpider 2D Image | elacridar | C34H33N3O5

Elacridar

C₃₄H₃₃N₃O₅, 563.6 g/mol
依克立达;gw0918
UNII-N488540F94

143664-11-3 [RN]

143851-84-7 (maleate salt(1:1))
143851-98-3 (monoHCl)

4-Acridinecarboxamide, N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-[ACD/Index Name]

7582

AR7621300

N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide

GF120918

Elacridar (GF120918)

GF-120918
GG-918
GW-120918
GW-918
GF-120918A (HCl)

GlaxoSmithKline (previously Glaxo Wellcome ) was developing elacridar, an inhibitor of the multidrug resistance transporter BCRP (breast cancer resistant protein), as an oral bioenhancer for the treatment of solid tumors.

Elacridar is an oral bioenhancer which had been in early clinical trials at GlaxoSmithKline for the treatment of cancer, however, no recent development has been reported. It is a very potent inhibitor of P-glycoprotein, an ABC-transporter protein that has been implicated in conferring multidrug resistance to tumor cells.

SYN

The condensation of 2-(4-nitrophenyl)ethyl bromide with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline,

Which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine . Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid by means of DCC and HOBt in DMF to afford the target carboxamide.

The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acidhas been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid with 2-bromobenzoic acid by means of K2CO3 and copper dust give the diphenylamine , which is cyclized to the target acridine Elacridar by means of POCl3 in refluxing acetonitrile.

PATENT

WO-2019183403

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019183403&tab=PCTDESCRIPTION&_cid=P11-K1LK8Y-65903-1

Deuterated analogs of elacridar as P-gp/BCRP inhibitor by preventing efflux useful for treating cancer.

Elacridar, previously referred to as GF120918, is a compound with the structure of 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1 ,2,3,4-tetrahydro- 6,7-dimethoxy-2-isoquinolinyl)ethyl] phenyl]-4-acridine-carboxamide or, as sometimes written, N-4-[2-(1 ,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide. Elacridar was originally described as a P-gp selective inhibitor but is now recognized as a dual P-gp/BCRP inhibitor. (Matsson P, Pedersen JM, Norinder U, Bergstrom CA, and Artursson P 2009 Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res 26:1816-1831 ).

003 Elacridar has been examined with some success both in vitro and in vivo as a P-gp and BCRP inhibitor. By way of example, in cancer patients, coadministration of elacridar with therapeutic agents such as paclitaxel (P-gp substrate) and topotecan (BCRP substrate) improved their oral absorption – presumably by preventing efflux into the intestinal lumen by P-gp/BCRP pumps located in the Gl tract. Similarly, in rodents, elacridar has been coadministered with some success with pump substrates such as morphine, amprenavir, imatinib, dasatinib, gefitinib, sorafenib, and sunitinib to increase drug levels in the brain (by blocking efflux mediated by P-gp and BCRP at the blood brain barrier). A summary of some of these studies can be found in a study report by Sane et al. (Drug Metabolism And Disposition 40:1612-1619, 2012).

004 Administration of elacridar has several limitations. By way of example, elacridar has unfavorable physicochemical properties; it is practically insoluble in water, making it difficult to formulate as, for example, either an injectable or oral dosage form. Elacridar’s poor solubility and high lipophilicity result in dissolution rate-limited absorption from the gut lumen.

005 A variety of approaches have been pursued in order to increase efficacy of elacridar. For example, United States Patent Application Publication 20140235631 discloses a nanoparticle formulation in order to increase oral bioavailability.

006 Sane et al. (Journal of Pharmaceutical Sciences, Vol. 102, 1343-1354 (2013)) report a micro-emulsion formulation of elacridar to try and overcome its dissolution-rate-limited bioavailability.

007 Sawicki et al. (Drug Development and Industrial Pharmacy, 2017 VOL. 43, NO. 4, 584-594) described an amorphous solid dispersion formulation of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate. However, when tested in healthy human volunteers, extremely high doses (e.g. 1000 mg) were required to achieve a Cmax of 326 ng/ml. (Sawicki et al. Drug Deliv. and Transl.

Res. Published online 18 Nov 2016).

008 Montesinos et al. (Mol Pharm. 2015 Nov 2; 12(11 ):3829-38) attempted several PEGylated liposome formulations of elacridar which resulted in a partial increase in half life, but without an increase in efficacy when co-administered with a therapeutic agent.

009 Because of the great unpredictability in the art and poor correlations in many cases between animal and human data, the value of such formulation attempts await clinical trial.

0010 Studies of the whole body distribution of a microdose of ¹¹C elacridar after intravenous injection showed high level accumulation in the liver (Bauer et al. J Nucl Med. 2016;57:1265-1268). This has led some to suggest that systemic levels of elacridar are also substantially limited by clearance in the liver.

0011 A potentially attractive strategy for improving metabolic stability of some drugs is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the rate of formation of inactive metabolites by replacing one or more hydrogen atoms with deuterium atoms.

Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the absorption, distribution, metabolism, excretion and/or toxicity (‘ADMET’) properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

0012 Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975, 64:367-91 ; Foster, A B, Adv Drug Res 1985, 14:1 -40 (“Foster”); Kushner, D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, Curr Opin Drug Discov Devel, 2006, 9:101 -09 (“Fisher”)). The results have been variable and unpredictable. For some compounds, deuteration indeed caused decreased metabolic clearance in vivo. For others, no change in metabolism was observed. Still others demonstrated increased metabolic clearance. The great unpredictability and variability in deuterium effects has led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting metabolism (see Foster at p. 35 and Fisher at p. 101 ).

0013 The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991 , 34, 2871 -76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

0014 Considering elacridar’s challenging physicochemical and ADMET properties in humans, in spite of recent formulation advancements, there remains a need in the art for elacridar analogs that can achieve higher, less variable levels in the systemic circulation, at the blood-brain barrier, and elsewhere to optimize efflux inhibition.

Example 1 : Synthesis of Instant Analogs and Compositions

00179 This example demonstrates a synthetic method for making elacridar analogs, deuterium substitutions based upon the deuteration of the starting compounds. The synthesis and the analog numbers refer to Figure 4.

00180 Step 1

00181 A 12L three-neck flask was charged with compound 1 (270.5 g, 1.618 mol), compound 2 (357.8 g, 1.78 mol, 1.1 eq.), K2C03 (447 g, 3.236 mol, 2.0 eq), Cu (20.6 g, 0.324 mol, 0.2 eq.) and ethanol (2.7 L) and the resulting mixture was heated to reflux under nitrogen for 1 hour. The reaction mixture was cooled to room

temperature after the reaction progress was checked with LC-MS. Water (2.7 L) was added and the mixture was filtered through a pad of Celite. The Celite was washed with water (1.35L) and the combined filtrate was adjusted to pH~2 by addition of concentrated HCI (~410 mL) over 15 min. The resulting suspension was stirred at 10°C for 1.5 hours and the solid was filtered, washed with water (2.7 L) and dried at 45°C using a vacuum oven for 2 days to give compound 3 (465 g, ~100%) as a yellow solid.

00182 Step 2

00183 A suspension of compound 3 (498 g, 1.734 mol) in acetonitrile (4.0 L) was heated to reflux under stirring. To the suspension was added POCb (355.5 mL,

3.814 mol, 2.2 eq.) drop-wise over 2h. The mixture was heated at reflux for 2.5h and then cooled to 30 °C. To the mixture was slowly added water (3.0 L) and the resultant thick slurry was heated to reflux for 1 5h. The slurry was cooled to 10 °C and filtered. The solid was washed with water (2 X 1.0 L), acetonitrile (2 X 1.0 L) and dried using a vacuum oven overnight at 45 °C to afford compound 4 (426 g, 91.3%) as a yellow solid.

00184 Step 3:

00185 A 12L three-neck flask was charged with compound 5 (475g, 2.065 mol), compound 6 (474.8g, 2.065 mol), K₂C03 (314g, 2.273 mol), Kl (68.6g, 0.413 moL) and DMF (2.5L) and the resulting mixture was heated to 70 °C and stirred for 2.5 hours. After LC-MS showed that the reaction was complete, the mixture was cooled to 50 °C and methanol (620 ml_) was added. Then the mixture was cooled to 30 °C and water (4.75 L) was added. The resulting suspension was cooled to 10 °C and for 1 hour. The solid was filtered, washed with water (2 X 2.5 L) and air dried for 2 days to afford the compound 7 (630 g, 89.1 %) as a yellow solid.

00186 Step 4

00187 To a solution of compound 7 (630 g, 1.84 mol) in THF/ethanol (8 L at 1 :1 ) was added Pd/C (10%, 50% wet, 30 g). The mixture was stirred under an

atmosphere of hydrogen (1 atm, balloon) at 15-20 °C for 4h. The reaction mixture was filtered through a pad of Celite and the pad was washed with TFIF (1.0 L). The filtrate was concentrated to 3 volumes under vacuum and hexanes (4.0 L) was added. The resulting slurry was cooled to 0 °C and stirred for 1 h. The solid was filtered and washed with hexanes (2 X 500 ml_) and air dried overnight to afford the compound 8 (522 g, 90.8%) as an off -white solid.

00188 Step 5

00189 A 5L three-neck flask was charged with compound 4 (250 g, 0.929 mol, 1 eq.), compound 8 (290 g, 0.929mol, 1 eq.) and DMF (2.5 L) and the resulting mixture was stirred at room temperature until it became a clear solution. To the solution was added TBTU (328 g, 1.021 mol, 1.1 eq.), followed by triethylamine (272 ml_, 1.95 mol, 2.1 eq.) and the resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was poured slowly into water (7.5 L) with stirring and the resulting suspension was stirred for 1 hour at room temperature. The solid was filtered and washed with water (2 X 7 L). The solid thus obtained was dried using a vacuum oven at 50 °C for two days and 509.0 g (97.3%) of compound 9 was obtained as yellow solid.

00190 Step 6

00191 300.0 g (0.532 mol) of compound 9 was suspended in acetic acid (1.2 L) and heated to 70 °C. The resultant solution was hot filtered and heated to 70°C again. Preheated ethanol (70 °C, 3.6 L) was then added. To this solution was added concentrated HCI (66.0 ml_, 0.792 mol, 1.5 eq.) dropwise over 30 min. The resulting solution was stirred at 70°C until crystallization commenced (~about 20 min). The suspension was cooled to room temperature over 3h, filtered, washed with ethanol (2 X 1.8 L) and dried using a vacuum oven at 60°C over the weekend to afford compound 10 (253.0 g, 79.2%) as a brown solid.

Example 2 Manufacture of a Deuterated Elacridar analog EE60.

00192 EE60 is synthesized by the procedure shown in Figure 4 and as continued in Figure 5.

00193 The structure of EE60 is confirmed as follows: Samples of 5 pi are measured using an LC system comprising an UltiMate 3000 LC Systems (Dionex, Sunnyvale, CA) and an 2996 UV diode array detector (Waters). Samples are injected on to a 100 x 2mm (ID) 3.5 pm ZORBAX Extend-C18 column (Agilent, Santa Clara, CA). Elution is done at a flow rate of 0.4 mL/min using a 5 minute gradient from 20% to 95% B (mobile phase A was 0.1 % FICOOFI in water (v/v) and mobile phase B was methanol). 95% B is maintained for 1 min followed by re-equilibration at 20% B. Chromeleon (v6.8) is used for data acquisition and peak processing.

Example 3: Manufacture of a Deuterated Elacridar analog EE59

00194 EE59 was synthesized by the procedure shown in Figure 6.

00195 The resulting yellowish brown precipitate was removed by filtration and the filter cake was dried overnight (72 mg). Analysis of the filter cake by LCMS indicated the presence of a single peak at multiple wavelengths (215 nm, 220 nm, 254 nm,

280 nm); each peak confirmed the presence of the desired product (LC retention time, 5.3 min; m/z = 575 [(M+FI)+]).

00196 ¹H NMR of EE598 revealed ¹H NMR (400 MHz, DMSO-d₆) d 12.3 ( s , 1H), 10.6 (s, 1H), 8.51-8.46 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.45-7.38 (m, 2H), 7.32-7.25 (m, 3H), 6.66 (d, J = 6.8 Hz, 2H), 3.62 (s, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.66 (m, 4H).

Example 4: Demonstration of superior properties of instant analogs and compositions: in vivo ADMET.

00197 Pharmacologic studies are performed according to Ward KW et al (2001 Xenobiotica 317783-797) and Ward and Azzarano (JPET 310:703-709, 2004).

Briefly, instant analogs are administered solutions in 10% aqueous polyethylene glycol-300 (PEG-300) or 6% Cavitron with 1 % dimethyl sulfoxide, or as well triturated suspensions in 0.5% aqueous HPMC containing 1 % Tween 80. Blood samples are collected at various times up to 48 h after drug administration; plasma samples are prepared and at “70°C until analysis.

00198 Mice. Instant analogs are administered to four groups of animals by oral gavage (10 ml/kg dose volume). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and the fourth group receive instant analogs as a solution in Cavitron at 3 mg/kg. Blood sampling in mice is performed via a tail vein at 0.5, 1 , 2, 4, 8, 24, and 32 h postdose.

00199 Rats. A total of seven groups of animals receive instant analogs by oral gavage (10 ml/kg). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and a fourth and fifth group each receive instant analogs as a solution in Cavitron or PEG-300, respectively, at 3 mg/kg. A sixth and seventh group of rats with indwelling hepatic portal vein catheters receive instant analogs by oral gavage (10 ml/kg) as a suspension at 3 or 30 mg/kg, respectively. Blood sampling in rats are performed via a lateral tail vein; samples are also obtained from the hepatic portal vein catheter. Blood samples are obtained before dosing and at 5, 15, 30, and 45 min, and 1 ,1.5, 2, 3, 4, 6, 8, 10, 24, and 32 h postdose.

00200 Dogs. Dogs receive instant analogs by lavage (4 ml/kg) on three separate occasions with dosages at 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a cephalic vein and from the hepatic portal vein catheter before dosing and at 5, 15, 30, and 45 min and 1 , 1.5, 2, 3, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00201 Monkeys. Monkeys receive instant analogs by oral gavage (8 ml/kg dose volume) on three separate occasions at dosages of 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a femoral vein via an indwelling catheter and from the hepatic portal vascular access port

before dosing and at 5, 15, and 30 min and 1 , 1.5, 2, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00202 Humans. Healthy volunteers receive instant analogs orally at doses ranging from 25 mg to 1000 mg. Blood samples are obtained and analyzed for analog concentrations at 0, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 2 hr, 4 hr, 6hr, 8 hr, 12 hr, 24 hr, and 48 h after administration .

Analytical Methods

00203 Instant analogs are isolated from samples by precipitation with acetonitrile and quantified by LC/MS/MS coupled with an atmospheric pressure chemical ionization interface (475°C). Internal standards [in acetonitrile/10 mM ammonium formate, pH 3.0; 95:5 (v/v)] are added to 50 pi samples and vortexed and centrifuged for 30 min at 4000 rpm. The supernatants are injected onto the LC/MS/MS system using an HTS PAL autosampler (CTC Analytics, Zwingen, Switzerland) coupled to an Aria TX2 high-throughput liquid chromatographic system using turbulent flow technology (Cohesive Technologies, Franklin, MA) in focus mode. The mobile phase consists of a mixture of 0.1 % formic acid in water and 0.1 % formic acid in

acetonitrile. The turbulent flow column is a 0.5 X 50-mm Cyclone P column

(Cohesive Technologies) in series to a 2 X 20 mm, 4 pm Polar RP (Phenomenex, Torrance, CA) analytical column. Positive-ion multiple reaction monitoring is used for the detection of instant analogs and internal standard and the selected precursor and product ions are mlz 564 and 252, respectively. Using a (1/x) weighted linear regression analysis of the calibration curve, linear responses in analyte/internal standard peak area ratios are observed for instant analog concentrations ranging from 2 to 10,000 ng/ml.

00204 Alternatively, useful analytical methods to demonstrate the surprising and superior properties of the instant elacridar analogs are the methods as described by Stokvis et al, J Mass Spectr 2004: 39: 1122-1130.

PATENT

WO2014018932

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014018932&recNum=9&docAn=US2013052402&queryString=diabetes&maxRec=85830

claiming nano-particle composition comprising breast cancer resistance protein inhibitor (eg elacridar). Family member of the elacridar

PAPER

J Med Chem 1995, 38(13): 2418

PATENT

Product PATENT WO9212132

PATENT

US5604237

NMR includes d 2.60-2.95 (m,8H,CH₂); 3.58 (s,2H,N–CH₂ –Ph); 3.72 (s,6H,OMe); 4.05 (s,3H,OMe acridone); 6.78 (2s,2H,Ar.isoquinoline), 7.20-7.88 (m,8H,Ar.), 8.48 (t,2H,H₁ and H₈ acridone), 10.60 (s, 1H,CONH), 12.32 (s, 1H,NH acridone)

///////////Elacridar, GF-120918, GG-918 , GW-120918, GW-918, GF-120918A (HCl), solid tumors, GSK, GLAXO

[11C]-elacridar

Valacyclovir HCl

October 3, 2019 1:54 pm / Leave a comment

Valacyclovir

ChemSpider 2D Image | Valaciclovir | C13H20N6O4

VALACYCLOVIR

124832-26-4 [RN]

2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl L-valinate

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate [ACD/IUPAC Name]

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl-L-valinat [German] [ACD/IUPAC Name]

2-{[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]oxy}ethyl L-valinate

7106

L-Valinate de 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)méthoxy]éthyle [French] [ACD/IUPAC Name]

L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester

L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine

L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester [ACD/Index Name]

L-valine, 2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl ester

MZ1IW7Q79D

Valacyclovir

CAS Registry Number: 124832-26-4

CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester

Additional Names: L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine; valaciclovir; ValACV

Molecular Formula: C13H20N6O4

Molecular Weight: 324.34

Percent Composition: C 48.14%, H 6.22%, N 25.91%, O 19.73%

Literature References: L-Valine ester prodrug of acyclovir, q.v. Prepn: T. A. Krenitsky et al., EP 308065; L. M. Beauchamp, US4957924 (1989, 1990 both to Wellcome). Evaluation as prodrug: L. M. Beauchamp et al., Antiviral Chem. Chemother. 3, 157 (1992). Clinical pharmacokinetics: S. Weller et al., Clin. Pharmacol. Ther. 54, 595 (1993). Review of pharmacology and clinical efficacy in herpes virus infections: C. M. Perry, D. Faulds, Drugs 52, 754-772 (1996). Clinical trial to prevent cytomegalovirus disease in renal transplantation: D. Lowance et al., N. Engl. J. Med. 340, 1462 (1999); to prevent transmission of genital herpes: L. Corey et al., ibid. 350, 11 (2004).

Derivative Type: Hydrochloride

CAS Registry Number: 124832-27-5

Manufacturers’ Codes: 256U; BW-256U87; BW-256

Trademarks: Valtrex (GSK)

Properties: Crystalline solid, occurs as hydrate. uv max (water): 252.8 nm (e 8530). Soly in water: 174 mg/ml.

Absorption maximum: uv max (water): 252.8 nm (e 8530)

Therap-Cat: Antiviral.

Keywords: Antiviral; Purines/Pyrimidinones

Valaciclovir is the hydrochloride salt of L-valyl ester of the antiviral drug aciclovir (Zovirax[R]). It was first launched in 1995 by GlaxoSmithKline (GSK) for the oral treatment of recurrent genital herpes, varicella zoster virus (VZV) and herpes simplex virus (HSV) infection in immunocompetent adults.

Valaciclovir was originally developed by GSK and was subsequently licensed to Sigma-Tau and Sanofi (formerly known as sanofi-aventis). In March 2003, GSK and Shionogi signed a letter of intent to copromote both aciclovir and valaciclovir in Japan, where it has been marketed by GSK since 2000.

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster(shingles).^[1] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.^[1] It is taken by mouth.^[1]

Common side effects include headache and vomiting.^[1] Severe side effects may include kidney problems.^[1] Use in pregnancy appears to be safe.^[1] It is a prodrug, which works after being converted to aciclovir in a person’s body.^[1]

Valaciclovir was patented in 1987 and came into medical use in 1995.^[2]^[3] It is available as a generic medication.^[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.^[4] In the United States the wholesale cost of this amount is about US$2.80.^[5]In 2016 it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.^[6]

Medical uses

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:^[7]

Oral and genital herpes simplex (treatment and prevention)
Reduction of HSV transmission from people with recurrent infection to uninfected individuals
Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.^[8]
Prevention of cytomegalovirus following organ transplantation
Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)^[9]
Chickenpox in children ages 2-18)^[10]

It has shown promise as a treatment for infectious mononucleosis^[11]^[12]^[13] and is preventively administered in suspected cases of herpes B virus exposure.^[14]

Valaciclovir is not recommended in Bell’s palsy due to lack of benefit.^[15]

Adverse effects

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.^[7]

Pharmacology

Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.^[10] It is converted by esterases to the active drug, aciclovir, and the amino acid, valine, via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.^[10]

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase.^[10] Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.^[16]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:^[17]

Herpes simplex virus type I (HSV-1)
Herpes simplex virus type II (HSV-2)
Varicella zoster virus (VZV)
Epstein–Barr virus (EBV)
Cytomegalovirus (CMV)

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.^[11]^[12]^[13] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.^[17]

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.^[18]

It also is used for herpes B virus postexposure prophylaxis.^[14]

History

Valaciclovir was patented in 1987 and came into medical use in 1995.^[2]^[3] It is available as a generic medication.^[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.^[4] In the United States the wholesale cost of this amount is about US$2.80.^[5] In 2019, it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.^[6]

Formulations

It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.^[19]

Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.^[20]

SYN

Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708

SYN 2

In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.

SYN3

The esterification of acyclovir (I) with N-(tert-butoxycarbonyl)-L-valine (II) by means of EDC, TEA and DMAP in DMF gives the corresponding ester (III) which is finally deprotected by means of HCl in water to afford the target valacyclovir.

Valaciclovir

- Synonyms:Valacyclovir, BW-256U, 256 U 87
- ATC:J05AB11
Use:antiviral, prodrug of aciclovir
Chemical name:l-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
Formula:C₁₃H₂₀N₆O₄

MW:324.34 g/mol
CAS-RN:124832-26-4
InChI Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N
InChI:InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1

Derivatives

monohydrochloride

Formula:C₁₃H₂₀N₆O₄ • HCl
MW:360.80 g/mol
CAS-RN:124832-27-5

Substance Classes

Ethylene glycol ether esters
Guanines (2-Amino-1,9-dihydro-6H-purin-6-ones)
Valines, esters

Synthesis Path

References

- US 4 957 924 (Burroughs Wellcome; 18.9.1990; GB-prior. 15.8.1987).
- EP 308 065 (Wellcome Found. Ltd; appl. 12.8.1988; GB-prior. 15.8.1987, 5.11.1987).

combination with lamotrigine:
- WO 9 505 179 (Wellcome Found. Ltd; appl. 17.8.1994; GB-prior. 18.8.1993).

water-dispersible tablets:
- WO 9 213 527 (Wellcome Found. Ltd; appl. 29.1.1992; GB-prior. 30.1.1991, 22.11.1991, 25.11.1991).

medical use for preventing post herpetic neuralgia:
- GB 2 282 759 (SmithKline Beecham; appl. 14.10.1994; GB-prior. 16.10.1993).

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Valacyclovir Hydrochloride Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 17 March 2019.
^ Jump up to:^a ^b Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
^ Jump up to:^a ^b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
^ Jump up to:^a ^b ^c ^d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
^ Jump up to:^a ^b “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019. Cite error: The named reference “NADAC2019” was defined multiple times with different content (see the help page).
^ Jump up to:^a ^b “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018. Cite error: The named reference “:1” was defined multiple times with different content (see the help page).
^ Jump up to:^a ^b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3^{[page needed]}
^ Lille, H. Martina; Wassilew, Sawko W. (2006). “Antiviral therapies of shingles in dermatology”. In Gross, Gerd; Doerr, H.W. (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
^ Elad S, Zadik Y, Hewson I, et al. (August 2010). “A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea”. Support Care Cancer. 18 (8): 993–1006. doi:10.1007/s00520-010-0900-3. PMID 20544224.
^ Jump up to:^a ^b ^c ^d “VALTREX (valacyclovir hydrochloride) Caplets -GSKSource”. gsksource.com. Retrieved 2019-08-02.
^ Jump up to:^a ^b Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
^ Jump up to:^a ^b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). “The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study” (PDF). International Pediatrics. 18 (3): 164–169.^{[dead link]}
^ Jump up to:^a ^b Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). “A virologic pilot study of valacyclovir in infectious mononucleosis”. Journal of Clinical Virology. 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082.
^ Jump up to:^a ^b “B Virus—First Aid and Treatment—Herpes B—CDC”. Retrieved June 6, 2015.
^ Baugh, Reginald F.; Basura, Gregory J.; Ishii, Lisa E.; Schwartz, Seth R.; Drumheller, Caitlin Murray; Burkholder, Rebecca; Deckard, Nathan A.; Dawson, Cindy; Driscoll, Colin (November 2013). “Clinical Practice Guideline: Bell’s Palsy”. Otolaryngology–Head and Neck Surgery. 149 (3_suppl): S1–S27. doi:10.1177/0194599813505967. ISSN 0194-5998. In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.
^ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm^{[permanent dead link]}
^ Jump up to:^a ^b O’Brien JJ, Campoli-Richards DM (March 1989). “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy”. Drugs. 37 (3): 233–309. doi:10.2165/00003495-198937030-00002. PMID 2653790.
^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116.^{[page needed]}
^ Ahmed, Rumman (November 27, 2009). “Ranbaxy Launches Generic Valtrex in U.S.”The Wall Street Journal. Retrieved January 16, 2010.
^ “Valtrex Prescribing Information” (PDF). GlaxoSmithKline. September 2008. Retrieved May 7, 2009.

External links

DailyMed from the NIH

Valaciclovir
Clinical data

Trade names	Valtrex, Zelitrex, others
AHFS/Drugs.com	Monograph
MedlinePlus	a695010
License data	US FDA: Valacyclovir
Pregnancy category	AU: B3 US: B (No risk in non-human studies)
Routes of administration	By mouth
ATC code	J05AB11 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	55%
Protein binding	13–18%
Metabolism	Liver (to aciclovir)
Elimination half-life	<30 minutes (valaciclovir); 2.5–3.6 hours (aciclovir)
Excretion	Kidney 40–50% (aciclovir), faecal 47% (aciclovir)
Identifiers
IUPAC name [show]
CAS Number	124832-26-4
PubChem CID	60773
IUPHAR/BPS	4824
DrugBank	DB00577
ChemSpider	54770
UNII	MZ1IW7Q79D
KEGG	D00398
ChEBI	CHEBI:35854
ChEMBL	ChEMBL1349
NIAID ChemDB	070982
CompTox Dashboard (EPA)	DTXSID1023732
ECHA InfoCard	100.114.479
Chemical and physical data
Formula	C₁₃H₂₀N₆O₄
Molar mass	324.336 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C
InChI [hide] InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1 Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N

//////////////Valacyclovir HCl,hydrochloride salt of L-valyl ester, aciclovir, GlaxoSmithKline ,

Flecainide acetate

October 3, 2019 1:53 pm / Leave a comment

Flecainide

54143-56-5
54143-55-4 (free base)

(±)-Flecainide

200-659-6 [EINECS]

258-997-5 [EINECS]

54143-55-4 [RN]

Apocard

Benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-

Flecainide

Molecular FormulaC₁₇H₂₀F₆N₂O₃
Average mass414.343 Da

CAS Registry Number: 54143-55-4

CAS Name: N-(2-Piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide

Molecular Formula: C17H20F6N2O3

Molecular Weight: 414.34

Percent Composition: C 49.28%, H 4.87%, F 27.51%, N 6.76%, O 11.58%

Literature References: Prepn: E. H. Banitt, W. R. Brown, US 3900481 (1975 to Riker); of the acetate: eidem, US 4005209 (1977 to Riker); E. H. Banitt et al., J. Med. Chem. 20, 821 (1977). Preliminary pharmacological study: J. R. Schmid et al., Fed. Proc. 34,775 (1975). In vitro electrophysiological study: A. B. Hodess et al., J. Cardiovasc. Pharmacol. 1, 427 (1979). Antiarrhythmic effects: P. Somani, Clin. Pharmacol. Ther. 27, 464 (1980). Use in acute exptl myocardial infarction: H. Gülker et al., Z. Cardiol. 70, 124 (1981). Clinical study in ventricular arrhythmias: J. L. Anderson et al., N. Engl. J. Med. 305, 473 (1981). Determn of acetate in human plasma by spectrophotofluorometry: S. F. Chang et al., Arzneim.-Forsch. 33, 251 (1983). Review of pharmacology and clinical efficacy: D. M. Roden, R. L. Woosley, N. Engl. J. Med. 315, 36-41 (1986). Symposium on clinical experience: Am. J. Cardiol. 62, Suppl., 1D-67D (1988). Comprehensive description: S. Alessi-Severini et al., Anal. Profiles Drug Subs. Excip. 21, 169-195 (1992).

Properties: uv max (ethanol): 205, 230, 300 nm (E1%1cm 521, 219, 59).

Absorption maximum: uv max (ethanol): 205, 230, 300 nm (E1%1cm 521, 219, 59)

White crystalline powder, m.p. 148-51 °C; hydrochloride, m.p. 228-9 °C

E-0735
R-818

Derivative Type: Monoacetate

CAS Registry Number: 54143-56-5

Manufacturers’ Codes: R-818

Trademarks: Almarytm (Synthelabo); Apocard (Esteve); Ecrinal (Pharma Investi); Flécaine (3M Pharma); Tambocor (3M Pharma)

Molecular Formula: C17H20F6N2O3.C2H4O2

Molecular Weight: 474.39

Percent Composition: C 48.10%, H 5.10%, F 24.03%, N 5.91%, O 16.86%

Properties: White granular solid from isopropyl alcohol/isopropyl ether, mp 145-147°. Soly at 37° (mg/ml): water 48.4, alcohol 300.

Melting point: mp 145-147°

Therap-Cat: Antiarrhythmic (class IC).

Keywords: Antiarrhythmic.

Flecainide acetate is an antiarrhythmic that was first launched by 3M Pharmaceuticals in 1985 for the oral treatment of ventricular arrhythmias and supraventricular tachyarrhythmias

In 2007, the product was approved in Japan for the treatment of atrial fibrillation.

The compound was originally developed at 3M Pharmaceuticals. In January 1984, 3M signed a development and marketing agreement with Eisai for the Japanese market.

3M’s pharmaceutical operations as well as regional marketing and intellectual property rights were acquired by Graceway in the U.S., Canada and Latin America, by Meda in Europe, and by Ironbridge Capital and Archer Capital in the Asia Pacific region, including Australia and South Africa. In 2011, Graceway’s active compounds were acquired by Medicis. In 2012, Medicis was acquired by Valeant (now Bausch Health).

Flecainide is a medication used to prevent and treat abnormally fast heart rates.^[1] This includes ventricular and supraventricular tachycardias.^[1] Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments.^[1] Its use does not decrease a person’s risk of death.^[1] It is taken by mouth or injection into a vein.^[1]^[2]

Common side effects include dizziness, problems seeing, shortness of breath, chest pain, and tiredness.^[1] Serious side effects may include cardiac arrest, arrhythmias, and heart failure.^[1] It may be used in pregnancy, but has not been well studied in this population.^[2]^[3] Use is not recommended in those with structural heart disease or ischemic heart disease.^[1] Flecainide is a class Ic antiarrhythmic agent.^[1] It works by decreasing the entry of sodium in heart cells, causing prolongation of the cardiac action potential.^[1]

Flecainide was approved for medical use in the United States in 1985.^[1] It is available as a generic medication.^[2] A month supply in the United Kingdom costs the NHS about £7.68 as of 2019.^[2] In the United States the wholesale cost of this amount is about 18.60 USD.^[4]In 2016 it was the 273rd most prescribed medication in the United States with more than a million prescriptions.^[5]

Medical uses

Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal re-entrant tachycardia (AVNRT) and Wolff-Parkinson-White syndrome (WPW).

It also has limited use in the treatment of certain forms of ventricular tachycardia (VT). In particular, flecainide has been useful in the treatment of ventricular tachycardias that are not in the setting of an acute ischemic event. It has use in the treatment of right ventricular outflow tract (RVOT) tachycardia^[6] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).^[7]Studies (notably the Cardiac Arrhythmia Suppression Trial) have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.^[8]^[9]

In individuals suspected of having the Brugada syndrome, the administration of flecainide may help reveal the ECG findings that are characteristic of the disease process. This may help make the diagnosis of the disease in equivocal cases.^[10]

Flecainide has been introduced into the treatment of arrhythmias in children.

In the long-term, flecainide seems to be safe in people with a healthy heart with no signs of left ventricular hypertrophy, ischemic heart disease, or heart failure.^[11]

Side effects

Results of a medical study known as the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients with structural heart disease (such as a history of MI (heart attack), or left ventricular dysfunction) and also patients with ventricular arrhythmias, should not take this drug. The results were so significant that the trial was stopped early and preliminary results were published.^[12]

The dose may need to be adjusted in certain clinical scenarios. As with all other antiarrhythmic agents, there is a risk of proarrhythmiaassociated with the use of flecainide. This risk is probably increased when flecainide is co-administered with other class Ic antiarrhythmics, such as encainide. The risk of proarrhythmia may also be increased by hypokalemia.^[13] The risk of proarrhythmia is not necessarily associated with the length of time an individual is taking flecainide, and cases of late proarrhythmia have been reported.^[14] Because of the role of both the liver and the kidneys in the elimination of flecainide, the dosing of flecainide may need to be adjusted in individuals who develop either liver failure or renal failure.

Because of the negative inotropic effects of flecainide, it should be used with caution in individuals with depressed ejection fraction, and may worsen congestive heart failure in these individuals. It should be avoided in people with ischaemic heart disease and the elderly.^[15]

As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers.^[16]

Heart

Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsades de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug,^[17] it is unfeasible to check the plasma concentration in an individual on a regular basis.

Signs of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility.

Treatment

Treatment of flecainide cardiac toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent,^[17] and administration of a sodium load^[17](often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily remove the need for a beating heart and to increase blood flow to the liver.^[18]^[19]

Lungs

Flecainide has a very high affinity for lung tissue ^[20] and is associated with drug-induced interstitial lung disease.^[21]^[22]^[23]^[24]^[25]

Interactions

Flecainide has high bioavailability after an oral dose,^[26] meaning that most of the drug that is ingested will enter the systemic blood stream. Peak serum concentrations can be seen 1 to 6 hours after ingestion of an oral dose. While the plasma half-life is about 20 hours, it is quite variable, and can range from 12 to 27 hours.^[27] During oral loading with flecainide, a steady state equilibrium is typically achieved in 3 to 5 days.

The majority of flecainide is eliminated by the kidneys, with the remainder metabolized by the cytochrome P450 2D6 isoenzyme in the liver.^[28] Therefore, alterations in renal function or urine pH will greatly affect the elimination of flecainide, as more is eliminated by the kidney than by the hepatic route.

Because of the dual elimination routes of flecainide and its tendency to decrease myocardial contractility,^[15] flecainide interacts with numerous pharmaceuticals and can potentiate the effects of other myocardial depressants and AV node blocking agents. In addition, flecainide can decrease the metabolism or elimination of many (but not all) agents that use the cytochrome P450 enzyme system.

A full list of drug interactions with flecainide can be obtained from the manufacturer. Some important drug interactions with flecainide include:^{[citation needed]}

Alcohol – may further depress normal heart function
Amiodarone – inhibits cytochrome P450 2D6 and may increase flecainide levels
Cimetidine – increases flecainide levels by 30% and half-life by 10%
Digoxin – may increase digoxin levels
Paroxetine – increased effect of both drugs
Propafenone – increased effect of both drugs and increased risk of toxicity
Quinidine – inhibits cytochrome P450 2D6 and may increase flecainide levels

Overdose

Flecainide intoxication is rare but serious due to the cardiogenic shock that it provokes. Its diagnosis can be difficult in the lack of contributing anamnestic elements. Clinical and paraclinical signs are not specific. Treatment is primarily symptomatic, which gives good results thanks to the hypertonic solution of sodium salts. Organ donation is possible in the case of braindead patients who suffered a flecainide intoxication.^[29]

Mechanism of action

Flecainide works by blocking the Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential.^[30] This thereby slows conduction of the electrical impulse within the heart, i.e. it “reduces excitability”. The greatest effect is on the His-Purkinje system and ventricular myocardium. The effect of flecainide on the ventricular myocardium causes decreased contractility of the muscle, which leads to a decrease in the ejection fraction.

The effect of flecainide on the sodium channels of the heart increases as the heart rate increases; This is known as use-dependence and is why that flecainide is useful to break a tachyarrhythmia.^[31]

Flecainide also inhibits ryanodine receptor 2 (RyR2),^[32] a major regulator of sarcoplasmic release of stored calcium ions. It can reduce calcium sparks and thus arrhythmogenic calcium waves in the heart.^[33] While Flecainide therapy has been shown to suppress ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia(CPVT) and mouse models of this disease, the relative contribution from the inhibition of sodium channels and of RyR2 in this effect on CPVT is unclear.^[34]

Brand names

Flecainide is sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February 10, 2004. In addition to being marketed as Tambocor, it is also available in generic version and under the trade names Almarytm, Apocard, Ecrinal, and Flécaine.

Following is one of the synthesis routes: 2-Aminomethylpyridine (II) is condensed with 2,2,2-trifluoroethyl-2,5-bis(2,2,2-trifluoroethoxy)benzoate (I) in refluxing glyme to produce 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (III), and the yielding product is then hydrogenated with H₂ over Pd/C in acetic acid.

Systematic Method of Flecainide acetate

PATENT

https://patents.google.com/patent/US7196197B2/en

Flecainide acetate, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (I), is a drug for the treatment of arrhythmia. It and its neutral base are described in U.S. Pat. No. 3,900,481.

A key intermediate for the synthesis of Flecainide and its pharmaceutically acceptable salts is 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II). One prior method for the preparation of this intermediate, disclosed in British patent No. GB 2045760, is a multistep process which comprises the preparation of 1,4-bis(2,2,2-trifluoroethoxy)benzene from hydroquinone using the very expensive reagent trifluoroethyltriflate (CF₃CH₂OSO₂CF₃). 1,4-bis(2,2,2-trifluoroethoxy)benzene is then converted to 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II) through a multistep process. An alternative method described in the same patent begins from 1,4-dibromobenzene, which is then condensed with more than 8 equivalents of 2,2,2-trifluoroethanol, to furnish the 1,4-bis(2,2,2-trifluoroethoxy)benzene intermediate. 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (II) is also be prepared starting from 1-bromo-4-fluorobenzene (PCT WO 02/066413) or from 2-bromo-5-chlorobenzoic acid (PCT WO 99/02498). All these approaches have limited commercial utility due to the cost of the reagents and the necessity for specialized equipment.

The method disclosed in British patent No. GB 2045760 for the preparation of the Flecainide base starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid which is converted to its acid chloride and reacts either with 2-(aminomethyl)piperidine to form Flecainide in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide base in two steps. The disadvantage of the one step process is that the acid chloride reacts non-selectively with both nitrogen atoms of the 2-(aminomethyl)piperidine, resulting in a mixture of the two acylated isomers.

Other preparations of Flecainide base are disclosed in WO 99/02498 and US2003/0032835. The process disclosed in WO 99/02498 starts from the cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, which selectively reacts with the primary amino group of 2-(aminomethyl)piperidine to furnish Flecainide. US 2003/032835 discloses a procedure which involves converting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid to its activated 2,2,2-trifluoroethyl ester which then selectively reacts with the primary amino group of 2-(aminomethyl)piperidine to furnish Flecainide. Although activated esters of this type can be used for the formation of Flecainide, the reagents required to prepare them are expensive on the industrial scale. Moreover, the resulting cyanomethanol and 2,2,2-trifluoroethanol by-products are highly toxic. Esters from less expensive, non-toxic and readily available alcohols are still desired for commercial purposes. Based on the above deficiencies, a new process overcoming these deficiencies was required.

Figure US07196197-20070327-C00002

Figure US07196197-20070327-C00003

Figure US07196197-20070327-C00004

Figure US07196197-20070327-C00005

Figure US07196197-20070327-C00006

EXAMPLE 1

Preparation of 2-(2,2,2-trifluoroethoxy)benzoic acid

To a solution of 2,2,2-trifluoroethanol (40.0 g) and DMF (100 ml) was added sodium tert-butoxide (23.0 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 2-chlorobenzoic acid (25.0 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 120° C. for 5 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (3×50 ml) and the volume was concentrated to 90 ml. Hexane (150 ml) was added to the residues, and the mixture was concentrated to volume of 120 ml and a further portion of hexane (30 ml) was added. The mixture was heated at 50° C. for 30 minutes and then stirred at room temperature for 1 hour. The solids were filtered to yield the crude product. This material was dissolved in ethyl acetate (50 ml), charcoal (1.7 g) was added and the mixture was stirred at room temperature a further 2 hours. The solution was filtered through Celite™ and crystallized from ethyl acetate/hexane to yield the pure product (30.9 g, yield 88.0%) as a white solid, m.p. 85–86° C.

EXAMPLE 2

Preparation of 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid

To a solution of 2-(2,2,2-trifluoroethoxy)benzoic acid (22 g) in methylene chloride (100 ml), was added AlCl₃(13.3 g) at 0° C.followed by bromine (16.0 g, 0.1 mol). The reaction mixture was stirred at 0° C. for 1 hour and then at reflux for 2 hours. The solids were filtered and water (50 ml) and ethyl acetate (50 ml) were added to the filtrate. The aqueous layer was separated and extracted with ethyl acetate (2×60 ml) and the combined organic layers were washed with water (2×60 ml). The organic layer was concentrated under vacuum to dryness and hexane (100 ml) was added and the resulting suspension was stirred at 20 to 25° C. for 1 hour. The mixture was filtered and the cake was rinsed with heptanes (2×20 ml). The damp solids were dried in vacuum at 45° C. for 5–6 hours to give a white solid (28.3 g, yield 94.6%), m.p. 126–128° C.

EXAMPLE 3

Preparation of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid.

To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×80 ml), and the combined organic layers were washed with water (3×60 ml). The solution was concentrated to one-third of the original volume and hexane (200 ml) was added. The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2×40 ml). The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3%).

EXAMPLE 4

Preparation of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate

A solution of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (20 g) and thionyl chloride (15.0 g) in methanol (100 ml) was stirred at 80° C. for 2 hours. The solvents were evaporated under vacuum to give an oil residue. Toluene (100 ml) was added to the residue and the solution was washed with saturated NaHCO₃(30 ml) solution followed by water (3×30 ml). The organic layer was concentrated under reduced pressure to give the product as a white solid (20.5 g, yield 98.0%).

EXAMPLE 5

Preparation of Flecainide

A mixture of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (1.5 g), 2-(aminomethyl)piperidine (0.62 g) in toluene (3 ml) was stirred at reflux for 10 hours. After cooling to room temperature, water (10 ml) was added and two layers solution were separated. The aqueous layer was extracted with toluene (2×10 ml) and the combined organic layers were washed with water (3×10 ml). The organic layer was concentrated under reduced pressure to give Flecainide free base as a white solid (1.63 g, 85%).

EXAMPLE 6

Preparation of Flecainide acetate

To a solution of Flecainide free base (1.5 g) in isopropanol (7.5 ml) was added glacial acetic acid (0.3 g) and the solution was stirred under reflux for 2 hours. The solution was cooled to room temperature and hexane (15 ml) was added and solids began to precipitate. The resulting suspension was stirred at 20–25° C. for 2 hours and the solids were filtered and then rinsed with hexane (2×10 ml). The damp cake was dried in vacuum for 4 hours to give Flecainide acetate as a white solid (1.54 g, Yield 89%).

Patent

Publication numberPriority datePublication dateAssigneeTitle

US3900481A1974-04-011975-08-19Riker Laboratories IncDerivatives of pyrrolidine and piperidine

US4005209A *1974-04-011977-01-25Riker Laboratories, Inc.Antiarrhythmic method utilizing fluoroalkoxy-N-piperidyl and pyridyl benzamides

GB2045760A1979-03-191980-11-05Riker Laboratories IncProcess for the preparation of 2,5- bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl) benzamide (flecainide)

WO1999002498A11997-07-111999-01-21Finetech Ltd.Process and a novel intermediate for the preparation of flecainide

WO2002004419A22000-07-122002-01-17Geneva Pharmaceuticals, Inc.α,α-DIBROMO-α-CHLORO-ACETOPHENONES AS SYNTHONS

WO2002066413A12001-02-202002-08-29Narchem CorporationFlecainide synthesis

US20030032835A12001-08-102003-02-13Enrico ViganoProcess for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (FLECAINIDE)

US6593486B21997-04-212003-07-15Par Pharmaceutical, Inc.Process for making cyanomethyl ester precursors of flecainide

Flecainide

- ATC:C01BC04
Use:antiarrhythmic
Chemical name:N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Formula:C₁₇H₂₀F₆N₂O₃

MW:414.35 g/mol
CAS-RN:54143-55-4
InChI Key:DJBNUMBKLMJRSA-UHFFFAOYSA-N
InChI:InChI=1S/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26)

Derivatives

acetate

Formula:C₁₇H₂₀F₆N₂O₃ • C₂H₄O₂
MW:474.40 g/mol
CAS-RN:54143-56-5

Synthesis Path

References

- Banitt, E.H. et al.: J. Med. Chem. (JMCMAR) 18, 1130 (1975); 20, 821 (1977).
- DE 2 513 916 (Riker; prior. 27.3.1975).
- US 3 900 481 (Riker; 19.8.1975; prior. 1.4.1974).
- US 4 005 209 (Riker; 25.1.1977; USA-prior. 1.4.1974, 27.5.1975).

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “Flecainide Acetate Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 7 April 2019.
^ Jump up to:^a ^b ^c ^d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 103. ISBN 9780857113382.
^ “Flecainide (Tambocor) Use During Pregnancy”. Drugs.com. Retrieved 7 April 2019.
^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018.
^ Gill J, Mehta D, Ward D, Camm A (1992). “Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality”. Br Heart J. 68 (4): 392–97. doi:10.1136/hrt.68.10.392. PMC 1025139. PMID 1449923.
^ Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, Motomiya T, Sugiura M, Hiraoka M (1990). “[Effects of oral flecainide treatment of refractory tachyarrhythmias]”. Kokyu to Junkan. 38 (5): 471–76. PMID 2115193.
^ Echt D, Liebson P, Mitchell L, Peters R, Obias-Manno D, Barker A, Arensberg D, Baker A, Friedman L, Greene H (1991). “Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial”. N Engl J Med. 324 (12): 781–88. doi:10.1056/NEJM199103213241201. PMID 1900101.
^ Greenberg H, Dwyer E, Hochman J, Steinberg J, Echt D, Peters R (1995). “Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I”. Br Heart J. 74 (6): 631–35. doi:10.1136/hrt.74.6.631. PMC 484119. PMID 8541168.
^ Gasparini M, Priori S, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S (2003). “Flecainide test in Brugada syndrome: a reproducible but risky tool”. Pacing Clin Electrophysiol. 26 (1 Pt 2): 338–41. doi:10.1046/j.1460-9592.2003.00045.x. PMID 12687841.
^ Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J (2011). “Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation”. Eurospace. 13 (2): 161–73. doi:10.1093/europace/euq382. PMC 3024037. PMID 21138930.
^ Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989). “Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction”. N Engl J Med. 321 (6): 406–12. doi:10.1056/NEJM198908103210629. PMID 2473403.
^ Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, Ikeda U, Shimada K (2001). “Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia”. Pacing Clin Electrophysiol. 24 (1): 119–21. doi:10.1046/j.1460-9592.2001.00119.x. PMID 11227957.
^ Morganroth J (1992). “Early and late proarrhythmia from antiarrhythmic drug therapy”. Cardiovasc Drugs Ther. 6 (1): 11–14. doi:10.1007/BF00050910. PMID 1533532.
^ Jump up to:^a ^b Santinelli V, Arnese M, Oppo I, Matarazzi C, Maione S, Palma M, Giunta A (1993). “Effects of flecainide and propafenone on systolic performance in subjects with normal cardiac function”. Chest. 103 (4): 1068–73. doi:10.1378/chest.103.4.1068. PMID 8131440.
^ Fornieles-Pérez H, Montoya-García M, Levine P, Sanz O (2002). “Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate”. Pacing Clin Electrophysiol. 25 (5): 871–72. doi:10.1046/j.1460-9592.2002.00871.x. PMID 12049386.
^ Jump up to:^a ^b ^c Winkelmann B, Leinberger H (1987). “Life-threatening flecainide toxicity. A pharmacodynamic approach”. Annals of Internal Medicine. 106 (6): 807–14. doi:10.7326/0003-4819-106-6-807. PMID 3107447.
^ Corkeron M, van Heerden P, Newman S, Dusci L (1999). “Extracorporeal circulatory support in near-fatal flecainide overdose”. Anaesth Intensive Care. 27 (4): 405–08. doi:10.1177/0310057×9902700413. PMID 10470398.
^ Yasui R, Culclasure T, Kaufman D, Freed C (1997). “Flecainide overdose: is cardiopulmonary support the treatment?”. Annals of Emergency Medicine. 29 (5): 680–82. doi:10.1016/S0196-0644(97)70257-9. PMID 9140253.
^ Latini R, Cavalli A, Maggioni AP, Volpi A (December 1987). “Flecainide distribution in human tissues”. British Journal of Clinical Pharmacology. 24 (6): 820–22. doi:10.1111/j.1365-2125.1987.tb03252.x. PMC 1386410. PMID 3125854.
^ Ozkan M, Dweik RA, Ahmad M (September 2001). “Drug-induced lung disease”. Cleve Clin J Med. 68 (9): 782–85, 789–95. doi:10.3949/ccjm.68.9.782. PMID 11563482.
^ Camus P, Fanton A, Bonniaud P, Camus C, et al. (2004). “Interstitial lung disease induced by drugs and radiation”. Respiration. 71 (4): 301–26. doi:10.1159/000079633. PMID 15316202.
^ Pesenti S, Lauque D, Daste G, Boulay V, et al. (2002). “Diffuse Infiltrative Lung Disease Associated with Flecainide”. Respiration. 69 (2): 182–85. doi:10.1159/000056325. PMID 11961436.
^ Haas M, Pérault MC, Bonnefoy P, Rodeau F, Caron F (2001). “[Interstitial pneumopathy due to flecainide]”. Presse Med. 30 (21): 1062. PMID 11471279.
^ Robain A, Perchet H, Fuhrman C (February 2000). “Flecainide-associated pneumonitis with acute respiratory failure in a patient with the LEOPARD syndrome”. Acta Cardiol. 55 (1): 45–57. doi:10.2143/ac.55.1.2005718. PMID 10707759.
^ Smith G (1985). “Flecainide: a new class Ic antidysrhythmic”. Drug Intell Clin Pharm. 19(10): 703–07. doi:10.1177/106002808501901001. PMID 3902429.
^ Padrini R, Piovan D, Busa M, al-Bunni M, Maiolino P, Ferrari M (1993). “Pharmacodynamic variability of flecainide assessed by QRS changes”. Clin Pharmacol Ther. 53 (1): 59–64. doi:10.1038/clpt.1993.9. PMID 8422742.
^ Haefeli W, Bargetzi M, Follath F, Meyer U (1990). “Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo”. J Cardiovasc Pharmacol. 15 (5): 776–79. doi:10.1097/00005344-199005000-00013. PMID 1692938.
^ Abdelilah, Ghannam; et al. (2014). “Non-Accidental Flecainide Overdose, A Case Report”. International Journal of Medicine and Surgery. 1 (2): 53. doi:10.15342/ijms.v1i2.18.
^ Ramos E, O’leary M (2004). “State-dependent trapping of flecainide in the cardiac sodium channel”. J Physiol. 560 (Pt 1): 37–49. doi:10.1113/jphysiol.2004.065003. PMC 1665201. PMID 15272045.
^ Wang Z, Fermini B, Nattel S (1993). “Mechanism of flecainide’s rate-dependent actions on action potential duration in canine atrial tissue”. J Pharmacol Exp Ther. 267 (2): 575–81. PMID 8246130.
^ Mehra D, Imtiaz MS, van Helden DF, Knollmann BC, Laver DR (2014). “Multiple modes of ryanodine receptor 2 inhibition by flecainide”. Molecular Pharmacology. 86 (6): 696–706. doi:10.1124/mol.114.094623. PMC 4244595. PMID 25274603.
^ Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC (2010). “Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass”. Journal of Molecular and Cellular Cardiology. 48 (2): 293–301. doi:10.1016/j.yjmcc.2009.10.005. PMC 2813417. PMID 19835880.
^ Smith GL, MacQuaide N (2015). “The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT”. Circulation Research. 116 (8): 1284–86. doi:10.1161/CIRCRESAHA.115.306298. PMID 25858058.

External links

RxList: Tambocor (Flecainide)

Flecainide
Clinical data


Pronunciation	/flɛˈkeɪnaɪd/flek-AY-nyde
Trade names	Tambocor, others
AHFS/Drugs.com	Monograph
MedlinePlus	a608040
Pregnancy category	C
ATC code	C01BC04 (WHO)
Pharmacokinetic data
Bioavailability	95%
Protein binding	40%
Metabolism	CYP2D6 (limited)
Elimination half-life	20 hours (range 12–27 hours)
Excretion	Kidney
Identifiers
IUPAC name [show]
CAS Number	54143-55-4
PubChemCID	3356
IUPHAR/BPS	2560
DrugBank	DB01195
ChemSpider	3239
UNII	K94FTS1806
KEGG	D07962
ChEBI	CHEBI:75984
ChEMBL	ChEMBL652
CompTox Dashboard(EPA)	DTXSID8023054
ECHA InfoCard	100.211.334
Chemical and physical data
Formula	C₁₇H₂₀F₆N₂O₃
Molar mass	414.343 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES [hide] FC(F)(F)COc2cc(C(=O)NCC1NCCCC1)c(OCC(F)(F)F)cc2
InChI [hide] InChI=1S/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26) Key:DJBNUMBKLMJRSA-UHFFFAOYSA-N

/////////Flecainide acetate, E-0735, R-818

Desvenlafaxine Succinate

October 3, 2019 1:51 pm / Leave a comment

Desvenlafaxine

Desvenlafaxine Succinate Monohydrate

386750-22-7
93413-62-8 (free base, anhydrous)
448904-47-0 (anhydrous)
448904-48-1 (hemisuccinate)

DVS-233
PF-05212375
WY-45233 (free base)

Name	:	Desvenlafaxine Succinate
Synonym	:	1-(2-(Dimethylamino)-1-(4- hydroxyphenyl)ethyl)cyclohexanol butanedioate; O-Desmethylvenlafaxine Succinate
Mol Formula	:	C20H31NO6 / C16H25NO2.C4H6O4
CAS	:	448904-47-0

Name	:	Desvenlafaxine Succinate Monohydrate
Synonym	:	1-((1RS)-2-(Dimethylamino)-1-(4- hydroxyphenyl)ethyl)cyclohexanol hydrogen butanedioate monohydrate ; O-Desmethylvenlafaxine Succinate monohydrate; Desvenlafaxine Succinate
Mol Formula	:	C20H33NO7 / C16H25NO2.C4H6O4.H2O
CAS	:	386750-22-7

Inventor/Developer – Wyeth Pharma Inc.
Status/Comment – FDA approved

Desvenlafaxine Succinate Hydrate

Research Code：DVS-233

Trade Name：Pristiq^®

MOA：Serotonin and norepinephrine reuptake inhibitor (SNRI)

Indication：Major depressive disorder (MDD)

Status：Approved

Company：Pfizer (Originator)

Sales：$715 Million (Y2015);
$737 Million (Y2014);;
$698 Million (Y2013);;
$630 Million (Y2012);;
$577 Million (Y2011);ATC Code：N06AX23

Desvenlafaxine succinate hydrate was approved by the U.S. Food and Drug Administration (FDA) on February 29, 2008.It was developed by Pfizer, then marketed as Pristiq^® by Pfizer in the US.

The exact mechanism of the antidepressant action of Desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that Desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is indicated for the treatment of major depressive disorder (MDD).

Pristiq^® is available as extended release tablet for oral use, containing 50 mg or 100 mg of free Desvenlafaxine. The recommended dose is 50 mg once daily with or without food.

PRISTIQ®
(desvenlafaxine) Extended-release Tablets

WARNING

SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS].

PRISTIQ is not approved for use in pediatric patients [ see Use in Specific Populations].

DESCRIPTION

PRISTIQ is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C₁₆H₂₅NO₂ (free base) and C₁₆H₂₅NO₂ •C₄H₆O₄•H₂O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

PRISTIQ® (desvenlafaxine) Structural Formula Illustration

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.

PRISTIQ is formulated as an extended-release tablet for once-a-day oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.

Osmotica Pharmaceutical, Par Pharmaceutical and Pernix Therapeutics are marketing the product in the U.S. under the brand name Khedezla (TM) for the treatment of major depressive disorder.

In 2019, Pfizer and Mochida signed an agreement for joint development and commercialization of the product in Japan.

Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat major depressive disorder.^[1] It is recommended that the need for further treatment be occasionally reassessed.^[1] It appears less effective than its parent compound venlafaxine.^[2] It is taken by mouth.^[1]

Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems.^[1]Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure.^[1]A withdrawal syndrome may occur if the dose is rapidly decreased.^[1] It is unclear if use during pregnancy or breastfeeding is safe.^[3] It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.^[1]

Desvenlafaxine was approved for medical use in the United States in 2008.^[1] Use in Europe was declined in 2009.^[2] In the United States the wholesale cost is about 25.20 USD per month.^[4] In 2016, it was the 272nd most prescribed medication in the United States, with more than a million prescriptions.^[5]

Medical uses

Desvenlafaxine is primarily used as a treatment for major depressive disorder.^[6] Use has only been studied up to 8 weeks.^[1] It, however, appears less effective than venlafaxine.^[2]

Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.^[7]

Desvenlafaxine improves the HAM-D17 score^[8] and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organization Well-Being Index (WHO-5).^[9]

Adverse effects[edit]

Frequency of adverse effects:^[6]^[10]^[11]

Very common adverse effects include:

Nausea
Headache
Dizziness
Dry mouth
Hyperhidrosis
Diarrhea
Insomnia
Constipation
Fatigue

Common adverse effects include:

Tremor
Blurred vision
Mydriasis
Decreased appetite
Sexual dysfunction
Insomnia
Anxiety
Elevated cholesterol and triglycerides
Proteinuria
Vertigo
Feeling jittery
Asthenia
Nervousness
Hot flush
Irritability
Abnormal dreams
Urinary hesitation
Yawning
Rash

Uncommon adverse effects include:

Hypersensitivity
Syncope
Depersonalization
Hypomania
Withdrawal syndrome
Urinary retention
Epistaxis (nose bleed)
Alopecia (hair loss)
Orthostatic hypotension
Peripheral coldness

Rare adverse effects include:

Hyponatraemia (low blood sodium)
Seizures
Extrapyramidal side effects
Hallucinations
Angioedema
Photosensitivity reaction
Stevens-Johnson syndrome

Common however unknown intensity of adverse effects include:

Abnormal bleeding (gastrointestinal bleeds)
Narrow-angle glaucoma
Mania
Interstitial lung disease
Eosinophilic pneumonia
Hypertension
Suicidal behavior and thoughts
Serotonin syndrome

Pharmacology

Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolizers take venlafaxine, approximately 70% of the dose is metabolized into desvenlafaxine, so the effects of the two drugs are expected to be very similar.^[12] It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.^[13]

Transporter	K_i[nM]^[13]^[14]
SERT	40.2
NET	558.4

Approval status

United States

Pristiq 50 mg tablets (US)

Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
Clarity by Wyeth around the company’s product education plan for physicians and patients;
Approval of desvenlafaxine’s proprietary name, Pristiq.^[15]

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.^[16]

In March 2017, the generic form of the drug was made available in the US.

Canada

On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression.^[17]^[18]

European Union

In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined.^[2] In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.^[19]^[20]

Australia

Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.

PATENT

https://patents.google.com/patent/CN104326923A/en

Sign succinic acid desvenlafaxine (Desvenlafaxinesuccinate, tradename Pristiq), chemical name RS-4- [2- dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenol succinic acid salt monohydrate; English name RS-4- (2 – (dimethylamino) -I- (1-hydroxycyclohexyl) ethyl) phenolsuccinatehydrate; formula C16H25NO2 · C4H6O · 4H20; relative molecular mass:. 399 48; CAS Registry number: 386750-22-7; of formula of formula I:

[0003]

[0004] The drug is produced by the US company Wyethphainsinc, February 29, 2008 listed by the US FDA approved, a serotonin – norepinephrine reuptake inhibitor is venlafaxine main active metabolite primarily for the treatment of major depressive disorder (MDD).

[0005] desvenlafaxine succinate is generally made with 0- desvenlafaxine succinate, aqueous salt synthesized, synthesized 0- desvenlafaxine earlier reports found in US Patent US4535186 discloses a method to 4-oxo-acetonitrile was synthesized from benzyl phenyl 0- desvenlafaxine, wherein the methylation step due to the use of formaldehyde as a methylating agent such that the reaction yield is very low, only 39 %, thereby affecting the overall yield of the overall reaction.

[0006] Currently many reported synthesis method of desvenlafaxine succinate is mostly based on the prior art (US4535186) Synthesis of venlafaxine, venlafaxine as a raw material to another, for which demethylation step reaction process improvement to synthesize 0- desmethylvenlafaxine, succinic acid and finally with water to a salt of desvenlafaxine succinate synthesis. The patent CN 1319934C, W0 0059851, CN101823969A venlafaxine are disclosed in as raw materials, the thiolate anion, lithium diphenylphosphide, HBr / HOAc as demethylating agent norepinephrine synthesis 0- venlafaxine oct, yields were> 73%. The reaction equation is as follows:

[0007]

[0008] In this class synthesis process, the raw material venlafaxine is synthesized by known techniques, the thiol compound used in the step of methylation away easily air pollution toxic, flammable irritant diphenyl compound and using a phosphine compound for corrosive HBr, increasing the difficulty of the operation and the post-treatment process such that the reaction unsuitable for industrial production.

[0009] Patent US7026508, US6689912 and US2005 / 0197392 each discloses a hydroxyphenyl acetonitrile as raw material, hydroxymethylated, α- ketone containing active hydrogen compound condensation, reducing the cyano group, an amino group and removal of methyl synthesis of methyl 〇- reaction desvenlafaxine, which synthetic route is shown below:

[0011] In such processes, the raw materials used are expensive cyano reagent, wherein the reagent lithium tri-secondary butyl borohydride risk patents US7026508 and method disclosed in patent US 6689912 to use, the patent US2005 / 0197392 use flammable irritating to diphenylphosphine compound, in addition, such methods involve harsh reaction conditions the reduction step cyano.Therefore, this method does not meet the economy, and is not suitable for industrial production.

[0012] Chinese Patent CN101781221Α discloses a synthetic method for the synthesis of 0- hydroxyphenylacetic acid desvenlafaxine, the acid-halo – aminolysis cyclohexanone condensation, amide reduction Synthesis 〇- desvenlafaxine, which scheme is as follows:

[0014] World Patent WO2008 / 093142 discloses a method similar to the above kind of oxygen acid as a raw material by benzyl, and finally debenzylation by synthesis 0- desvenlafaxine.

[0015] In such methods, the former are in a condensation reaction step with reduction of the amide using an unstable compound n-butyllithium, lithium tetrahydroaluminate; then using a compound unstable to hexamethyldisilazide amide, borane, this two-step reaction be carried out under an inert gas, dangerous reagents used twice, is not suitable for industrial operation.

Figure CN104326923AD00062

Example 1

Synthesis [0041] The compound of formula III

The [0042] room temperature, was added the compound of formula II (81.69g, 0. 60mol), 1200mL acetone 3L reaction flask, stirred and dissolved. To this was added 1〇) 3 (265.368,1.92111〇1) was slowly added dropwise (112.888,0.65111〇1) of benzyl bromide was heated at reflux for LH, starting material after the reaction was cooled to room temperature, filtered off with suction, the filter cake was washed with a suitable amount of acetone , the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying ΠI134 7g, yield 99% ZHNMR (300MHz, DMS0):… δ7 50-7 22 (m, 7H), δ6.93 (d, 2H) , S5.03 (s, 2H), S2.53 (s, 3H); 13C-NMR:… S197.02, δ163 · 42, δ136 · 51, δ129 · 83, δ129 02, δ128 91, δ127 64 , δ127. 10, δ114. 29, δ70. 13, δ26. 6.

[0043] Example 2

[0044] following the experimental procedure of Example 1, benzyl bromide (112. 88g, 0. 65mol) is replaced with benzyl chloride (82. 28g, 0. 65mol), heated at reflux overnight, cooled to room temperature after completion of the reaction evacuated filter cake washed with a suitable amount of acetone, the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying III103. 17g, yield 76%.

[0045] Example 3

Synthesis [0046] The compound of Formula IV

[0047] The compound of formula III is added to the 3L reaction flask (67. 9g, 0 · 30mol), Cufc2 (147. 4g, 0 · 65mol), 0 · 9L methylene chloride, I. 35LEA, heated to reflux, after completion of the reaction cooling suction filtered, the filter cake was washed with 200mL dichloromethane. The filtrates were combined, and the filtrate was washed with hydrochloric acid and then washed twice with water, dried, rotary evaporation, 50 ° C overnight blast drying. A compound of formula IV to give the crude 89.438, yield 98%.

[0048] 89. 43g was added the compound of formula IV (crude) was added to IL-neck round bottom flask, recrystallized from isopropanol, filtered off with suction, the filter cake was dried by blowing 45 ° C. Refined products 84. 9g, 95% yield. .. 1Hnmr (SoomhzJMSO-CI6): δ7 53-7 20 (m, 7H), 5 6. 95 (d, 2H), δ5 09 (s, 2H), δ4 69 (s, 2H); 13C-.. NMR:. δ190 83, 5 164.12, 5 136.71, δ129 96, δ128 91, δ128 31, δ127 00, δ126 73, δ114 37, δ70 82, δ32 45………

[0049] Example 4

Synthesis [0050] The compound of formula V

[0051] Add the compound of formula IV (36. 6g, 0. 12mol) A 250mL round bottom flask, 120mL of ethanol was stirred. Aqueous solution was slowly added dropwise thereto 39mL of dimethylamine (33%), dropwise, with stirring until completion of the reaction starting material. Rotary evaporation and water, to which ethanol was added, under ice-water bath, thereto was slowly added dropwise 12mL hydrobromic acid. After stirring 30min 25 ° C incubation rotary evaporation and water was added thereto and dissolved with 70mL of methylene chloride over anhydrous sodium sulfate, after rotary evaporation, and thereto was added 60mLEA refluxed 30min, 30min stirring ice-water bath. Filtered off with suction, 45 ° C blast drying to give the purified product compound of formula V41.lg, yield 98%.1H NMR (300MHz, DMS0-d6): δ7 · 55-7 · 24 (πι, 7Η), S6.97 (d, 2H), S5.13 (s, 2H), S3.79 (s, 2H), 5 2. 23 (s, 6H); 13C-NMR:….. δ195 45, 5 163.12, 5 136.53, 5 129.85, 5 128.96, 5 127.61, δ127 27, δ127 06, δ114 65, δ75 31, δ70 . 72, δ46. 55.

[0052] Example 5

Synthesis [0053] The compound of formula VI

[0054] Compound of formula V was added to 500mL round bottom flask (41g, 0. 12mol), 205mL of ethanol under ice-water bath, to which was added a likelihood of 0! 1 (9.368,0.23111〇1), after stirring for 11 ^ 301, to which was added portionwise like 8! 14 (8.888,0.23111〇1). The reaction was stirred for 4h at End material to room temperature. Rotary evaporation, and thereto was added 60mL of water, 120mL of methylene chloride, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry.The crude 31. 0g, 98% yield.

[0055] The crude product 31g was dissolved in 180mL of ethanol, under ice-water bath, was slowly added dropwise thereto 16mL of concentrated hydrochloric acid to pH = 1-2, stirred at room temperature for 30 min. Rotary evaporation, 45 ° C blast drying. A compound of formula VI to give crude product 31. 2g, 89% yield.

[0056] To a 250mL round-bottom flask was added 31. 2g crude compound of formula VI, 78 mL ethyl acetate, heated to reflux to dissolve, cooled to room temperature naturally, filtered off with suction, the filter cake was washed with the amount of EA. Refined products 29. 3g, 94% yield. 1HNMR (300MHz, DMS0-d6):….. Δ7 45-7 24 (m, 7H), δ6 95 (d, 2H), δ5 07 (s, 2H), δ4 88 (br, 1H), δ4 . 60 (m, 1Η), δ2 48-2 27 (m, 2H), 52.19 (s, 6H); 13C-NMR:…. δ157 26, 5 137.21, 5 136.83, δ128 · 35, δ127 68, δ127. 52, δ127. 17, δ114. 19, δ69. 62, δ69. 13, δ67. 57,45.56.

[0057] Example 6

[0058] Following the procedure of Example 5 experiments embodiment, the shame 0! 1 (9.368,0.23111〇1) shame Alternatively 0! 1 (14.048,0.72111〇1), and NaBH4 (8. 88g, 0. 23mol) is replaced with NaBH4 (13. 32g, 0. 72mol), stirred Ih at room temperature the reaction was complete feed. Rotary evaporation, and thereto was added 60mL of water, burning 120mL dichloromethane, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry. The crude 31. 33g, yield 99%.

[0059] Example 7

Synthesis [0060] The compound of formula VII

[0061] was added (24g, 0.078 mol) compound of formula VI to a 500mL round bottom flask, 240 mL of toluene, under ice-water bath, and thereto is added thionyl chloride (10. 2g, 0. 086mol), the reaction was heated to 60 ° C 4h, cooled, stirred for about 25 ° C 2h, filtered off with suction, the filter cake washed with 30mL toluene, and drying, the product compound of formula to give an off-white VII22. 4g, 88% yield. 1H NMR (300MHz, DMS〇-d6):… Δ7 44-7 29 (m, 7H), δ7 07 (d, 2Η), δ5 12 (s, 2Η), δ4 69 (m, 1Η).. , δ3 37-3 15 (m, 2H), δ2 80 (s, 6H); 13C-NMR:…. δ158 26, 5 137.33, 5 136.71, 5 128.31, δ127 72, δ127 47, δ127… 13, δ114. 21, δ69. 62, δ67. 57, δ59. 39, δ46. 74.

[0062] Example 8

Synthesis [0063] The compound of formula VIII

[0064] Add the compound of formula ¥ 11 (218,0.064 11〇1!) Was added to a round bottom flask, 2001 ^ toluene, triethylamine (7.21 8, 0.071mol), stirred for 3h, filtered off with suction, washed with a little toluene; the 500mL three-neck flask was added to the toluene solution, cooled to -80 ° C, n-butyllithium was slowly added dropwise 35mL (2. 5mol / L), dropwise with stirring incubated 0. 5h, 9. 48g was slowly added dropwise cyclohexanone, After dropping the reaction 4h, slowly warmed to room temperature, the reaction was quenched with saturated ammonium chloride, using lmol / L sodium hydroxide to adjust pH = about 9, EA extraction, rotary evaporation, the crude product was slurried with diethyl ether, dried to obtain a compound of formula VIII19. 56g, yield 86%. 1H bandit R (300MHz, DMS0-d6): δ7 · 45-7 · 23 (πι, 7Η), S6.87 (d, 2H), S5.09 (s, 2H), S3.05 (t, 1H) , S2.75 (t, lH), δ2 · 41-2 · 34 (πι, 1Η), S2.18 (s, 6H), Sl.58-0.92 (m, 10H); 13C-Mffi:. δ157 32 , δ136. 73, δ134. 73, δ129. 11, δ128. 90, δ127. 65, δ127. 16, δ114. 23, δ73. 42, δ70. 87, δ59. 85, δ48. 52, δ47. 35, δ38 . 95, δ26. 33, δ22. 30.

[0065] Example 9

After the [0066] following the experimental procedure of Example 8, the reaction temperature is added dropwise n-butyllithium was replaced _65 ° C, to give compound VIII crude, beaten with ether and drying to give pure 15. 33g, yield 67 %.

[0067] Example 10

Synthesis [0068] The compound of formula IX

[0069] The compound of formula ¥ 111 (1 (^, 0.028111〇1) was dissolved in ^ booklet 1,501,111, was added 18 10% wet palladium on carbon, into hydrogen, I.SMPa at room temperature for 5h, filtration, rotary evaporation as a white solid compound of formula 1X6 83g, yield 92% 1HNMR (300MHz, DMSO- (I6):… δ9 13 (br, 1H), 5 6.96 (d, 2H), 5 6.64 (d, 2H), 53.01 (t, 1H), S2.72 (t, lH), δ2 · 39-2 · 35 (πι, 1Η), S2.15 (s, 6H), Sl.57-0.90 (m, 10H); 13C, MR:. δ155 56, δ131 56, δ130 04, δ114 23, δ72 52, δ60 36, δ51 57, δ45 21, δ37 11, δ32 38, δ25 67, δ21 23〇………..

[0070] Example 11

Synthesis [0071] The compounds of formula I

Under [0072] nitrogen, the compound of formula IX is added to the three-necked flask (4g, 0. 015mol), succinic acid (1.85g, 0. 015mol), IOOmL acetone / water mixed solvent = 71/19 was heated at reflux for 3h proceeds down to room temperature to crystallization under ice-cooling, filtered off with suction, 40 ° C dried to give 5. 13g as a white solid compound of formula I, yield 85%.

PATENT

https://patents.google.com/patent/WO2008090465A2/en

Desvenlafaxine (Formula I, below) is an active pharmaceutical substance with an empirical formula of C16H₂5NO₂ and a molecular weight of 263.38. Desvenlafaxine, which can also be referred to as desmethylvenlafaxine and/or O-desmethylvenlafaxine, is the major active metabolite of venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder.

U.S. Patent No. 4,535, 186 discloses the first process for preparing desvenlafaxine. In U.S. Patent No.4,535,186, desvenlafaxine is synthesized by the process illustrated in Scheme 1:

Scheme 1 Additional alternative processes for preparing desvenlafaxine are described in the literature. These alternative processes generally proceed via the demethylation of venlafaxine, see, for example, U.S. Patent Application Publication No. 2005/197392, U.S. Patent Nos. 7,026,508, and 6,689,912, and International Patent Publication No. WO07/071404. These processes make use of different demethylating agents, such as lithium diphenylphosphide, alkali metal salts of trialkylborohydrides, high molecular weight thiolate anions, and metal sulfides. However, the use of the aforementioned demethylating agents presents several drawbacks, i.e., requires extensive purification procedures aimed to isolate desvenlafaxine from said demethylating agents and/or corresponding by-products, and involve odor workups, which make these processes unsuitable for industrial implementation.

In view of the foregoing, there is a need for an alternative process for preparing desvenlafaxine from venlafaxine including, for instance, an alternative process which avoids the drawbacks of current state of the art processes (e.g., makes use of simpler and shorter purification procedures, allows an essentially odorless workup, and which is well suited for industrial implementation).

Salts of O-desmethylvenlafaxine, including the fumarate, succinate and formate salts, have been described in the literature. For example, U.S. Patent No. 4,535,186 reports the preparation of O-desmethylvenlafaxine fumarate salt. More recently, the preparation of several polymorphic forms of the succinate salt have been reported in U.S. Patent No. 6,673,838 B2. Additionally, U.S. Patent Application Publication No. 2006/0058552 discloses the preparation of the formate salt.

HPLC Method

In the examples described below, the following analytical chromatographic HPLC method was used:

The chromatographic separation was carried out in a Kromasil C8, 5 μm, 25 cm x 4.6 mm. I. D column at room temperature.

The mobile phase was prepared by mixing 1,600 g of (NH₄)H₂P(I_t buffer solution pH = 4.4 and 313.2 g of acetonitrile HPLC grade. The pH of the mixture should be 4.9, adjust if necessary.

A (NH₄)H₂PO₄ buffer solution (pH = 4.4) was prepared by dissolving 17 g of (NH₄)H₂PO₄ in 1600 mL of water and adjusting the pH = 4.4 with HaPO₄ or ammonium hydroxide.

The chromatograph was equipped with a 225 nm detector, and the flow rate was 1.2 mL per minute at room temperature. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.

In those conditions the retention time of desvanlafaxine, compound (I), is about 7 minutes, and the retention time of venlafaxine, compound (IV), is about 22 minutes.

EXAMPLE 1: Preparation of Desvenlafaxine (Le., Compound I).

This example illustrates a process for converting Compound IV into desvenlafaxine {i.e., Compound I) according to one aspect of the invention.

In a 100 mL flask 8 g (0.027 mol) of Venlafaxine free base, 13 mL of polyethylene glycol 400 (PEG400) and 6.9 g (0.041 mol) of 2-(diethylamino)ethanothiol were charged. 13.2 g (13.6 mL, 0.073 mol) of 30 % w/w solution of sodium methanolate in methanol were slowly added. The resulting suspension was heated to about 195° C and methanol was distilled off in the meantime. The stirring was continued for four hours at that temperature and then was cooled down to 20-25° C. 30 mL of 1 M hydrochloric acid were added to adjust pH to approx. 9.5. The resulting suspension was filtered at 20-25° C and the solid was dried at 50° C. The solid corresponded to desvenlafaxine (3.4 g; yield: 45 %; purity HPLC: 96.8 %).

EXAMPLE 2: Preparation of Desvenlafaxine Succinate Monohydrate.

This example illustrates a process for converting desvenlafaxine (i.e., Compound I) into desvenlafaxine succinate monohydrate according to one aspect of the invention.

Desvenlafaxine base (18.1 g, 0.069 mol) was charged into a 500 mL round bottomed flask under nitrogen atmosphere with 9.75 g (0.083 mol) of succinic acid, 135 g (170 mL) of acetone and 54 g of deionized water. The suspension was heated to reflux temperature and maintained at this temperature 30 minutes. The resulting solution was cooled to 50-55° C and filtered.

The filtered solution was cooled to 30-35° C in approximately 1 hour. In the interim, seeding was performed at approximately 40-45° C. The suspension was maintained for 3 hours at 30-35° C. Thereafter, the suspension was cooled to 20-25° C in approximately 1 hour, and maintained at this temperature for 2 hours. Then, the suspension was cooled to 10 ± 3° C in approximately 30 minutes and maintained at this temperature for 1 hour. Finally, the suspension was filtered and washed twice with 2 x 7.5 g (2 x 9.4 mL) of acetone. The wet solid was dried under vacuum at 60 ± 5° C to yield 22.96 g of desvenlafaxine succinate (yield: 83.6 %). Analytical data: HPLC Purity: 99.9 %; assay: 99.6 %.

Desvenlafaxine

- Synonyms:metabolite of Venlafaxine, O-desmethylvenlafaxine, WY-45233, DVS-233
- ATC:N06AX23
Use:antidepressant
Chemical name:4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol
Formula:C₁₆H₂₅NO₂

MW:263.38 g/mol
CAS-RN:93413-62-8
InChI Key:KYYIDSXMWOZKMP-UHFFFAOYSA-N
InChI:InChI=1S/C16H25NO2/c1-17(2)12-15(13-6-8-14(18)9-7-13)16(19)10-4-3-5-11-16/h6-9,15,18-19H,3-5,10-12H2,1-2H3

Derivatives

succinate monohydrate

Formula:C₂₀H₃₃NO₇
MW:399.48 g/mol
CAS-RN:386750-22-7

Synthesis Path

Trade Names

Country	Trade Name	Vendor	Annotation
USA	Pristiq	Wyeth ,2008

Formulations

tabl. 50 mg, 100 mg (as succinate)

References

- a EP 1 973 866 (Synthon; 1.10.2008; appl. 19.12.2006; USA-prior. 20.12.2005).
- b WO 2 008 090 465 (Medichem SA; 31.7.2008; appl. 22.1.2008; USA-prior. 22.1.2007).
- c US 7 026 508 (Wyeth; 5.5.2005; appl. 10.11.2004; USA-prior. 12.2.2001).
- d US 4 535 186 (American Home Products; 13.8.1985; appl. 26.10.1983; USA-prior. 19.4.1983).

new polymorph:
- WO 2 008 110 338 (Synthon; 18.9.2008; appl. 6.3.2008; USA-prior. 9.3.2007).

crystalline polymorphs of Desvenlafaxine succinate:
- CN 101 274 897 (Mai DE Ltd.; 1.10.2008; appl. 4.1.2008; USA-prior. 8.1.2007).
- US 20 080 188 567 (Mai DE Ltd.; 8.7.2008; USA-prior. 8.1.2006).

enantiomers of Desvenlafaxine:
- US 2 002 022 662 (American Home Products; 21.2.2002; appl. 21.9.2001; USA-prior. 15.6.1999).

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Desvenlafaxine Succinate Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 18 March 2019.
^ Jump up to:^a ^b ^c ^d “Withdrawal Assessment Report for Dessvenlafaxime” (PDF). EMA. p. 3. Retrieved 22 March 2019.
^ “Desvenlafaxine Pregnancy and Breastfeeding Warnings”. Drugs.com. Retrieved 19 March 2019.
^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018.
^ Jump up to:^a ^b “PRODUCT INFORMATION PRISTIQ® desvenlafaxine (as succinate)” (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 10 December 2012. Retrieved 8 November2013.
^ Perry, Richard; Cassagnol, Manouchkathe (2009). “Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder”. Clinical Therapeutics. 31 Pt 1: 1374–1404. doi:10.1016/j.clinthera.2009.07.012. ISSN 1879-114X. PMID 19698900.
^ Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT (March 2009). “An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder”. CNS Spectr. 14 (3): 144–54. PMID 19407711.
^ Soares CN, Kornstein SG, Thase ME, Jiang Q, Guico-Pabia CJ (October 2009). “Assessing the efficacy of desvenlafaxine for improving functioning and well-being outcome measures in patients with major depressive disorder: a pooled analysis of 9 double-blind, placebo-controlled, 8-week clinical trials”. J Clin Psychiatry. 70 (10): 1365–71. doi:10.4088/JCP.09m05133blu. PMID 19906341.
^ “DESVENLAFAXINE tablet, extended release [Ranbaxy Pharmaceuticals Inc.]”. DailyMed. Ranbaxy Pharmaceuticals Inc. March 2013. Retrieved 9 November 2013.
^ “desvenlafaxine (Rx) – Pristiq, Khedezla”. Medscape Reference. WebMD. Retrieved 9 November 2013.
^ Lemke, Thomas L.; Williams, David A. (2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 609. ISBN 978-1-60913-345-0.
^ Jump up to:^a ^b Deecher, DC; Beyer, CE; Johnston, G; Bray, J; Shah, S; Abou-Gharbia, M; Andree, TH (August 2006). “Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor” (PDF). The Journal of Pharmacology and Experimental Therapeutics. 318 (2): 657–665. doi:10.1124/jpet.106.103382. PMID 16675639.
^ Roth, BL; Driscol, J (Dec 2012). “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 7 July 2018.
^ “Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Succinate) For The Treatment Of Major Depressive Disorder” (Press release). 2007-01-23. Retrieved 2007-04-04.
^ “FDA Approves Pristiq” (Press release). Wyeth. 2008-02-29. Archived from the original on 2008-03-05. Retrieved 2008-02-29.
^ Health Canada Notice of Compliance – Pristiq^{[permanent dead link]}. February 4, 2009, retrieved on March 9, 2009.
^ “Summary Basis of Decision (SBD) ^PrPristiq™”. Health Canada. 2009-05-29. Retrieved 2016-12-30.
^ “Pristiq 100 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.
^ “Pristiq 50 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.

External links

Drug information from the NIH

Route 1

Reference：1. US4535186.

2. WO2008093142 / US2010076086.

3. WO2002064543 / US20030045583.

4. WO2003048104 / US20030105358.

5. WO2003103603 / US20030236309.

6. J. Med. Chem. 1990, 33, 2899-2905.

Route 2

Reference：1. WO2008013990 / US20080183016.

Route 3

Reference：1. WO2008015584 / US20100121108.

2. WO2009034434.

3. WO2009053731 / US20110118357.

4. US20110098506.

5. WO2009009665A2 / US20100210719.

Route 4

Reference：1. WO2008013993.

Route 5

Reference：1. WO2009084037.

Route 6

Reference：1. WO2008013994 / US20080177110.

Update Date：2015-08-31

China

Patent

Publication numberPriority datePublication dateAssigneeTitle

WO2008093142A1 *2007-01-312008-08-07Generics [Uk] LimitedProcess for the preparation of o-desmethyl venlafaxine

WO2010028130A2 *2008-09-032010-03-11Concert Pharmaceuticals, Inc.Antidepressant compounds

CN101781221A *2010-02-112010-07-21上海凯米侬医药科技有限公司Preparation method of O-desmethylvenlafaxine

CN102249936A *2010-05-192011-11-23江苏豪森医药研究院有限公司Hydrate of O-desmethylvenlafaxine hydrochloride and preparation method thereof

Title

FUJII, TOZO等: “Quinolizidines. XXII. An extension of the “3-acetylpyridine route” to the syntheses of 9-hydroxy-10-methoxy- and 10-hydroxy-9-methoxybenzo[a]quinolizidine-type Alangium alkaloids”, 《CHEMICAL & PHARMACEUTICAL BULLETIN》, vol. 35, no. 9, 31 December 1987 (1987-12-31), XP002311646 *

周金培等: “抗抑郁药文拉法辛的合成研究”, 《中国药科大学学报》, vol. 30, no. 4, 31 December 1999 (1999-12-31) *

///////DVS-233 , PF-05212375 , WY-45233, DESVENLAFAXINE SUCCINATE, WYETH

METHYL DOPA

October 3, 2019 10:20 am / Leave a comment

ChemSpider 2D Image | L-Methyldopa | C10H13NO4

L-Methyldopa

Molecular FormulaC₁₀H₁₃NO₄
Average mass211.214 Da

Name	:	Methyldopa
Synonym	:	3-hydroxy-alpha-methyl-L-tyrosine
Mol Formula	:	C10H13NO4
CAS	:	555-30-6

(S)-(-)-α-Methyldopa

L-Methyldopa

(-)-Methyldopa

(-)-α-Methyldopa

(S)-(-)-a-Methyldopa

(S)-a-Methyldopa

1110

209-089-2 [EINECS]

2417244

3-(3,4-Dihydroxyphenyl)-2-methyl-L-alanine

3-Hydroxy-α-methyl-L-tyrosine

555-30-6 [RN],

Alanine, 3- (3,4-dihydroxyphenyl)-2-methyl-, L-

Synthesis ReferenceVincenzo Cannata, Giancarlo Tamerlani, Mauro Morotti, “Process for the synthesis of the levodopa.” U.S. Patent US4962223, issued December, 1986.

US4962223

Methyldopa USP is the L-isomer of alpha-methyldopa. Its chemical name is levo-3-(3,4-dihydroxyphenyl)- 2-methylalanine sesquihydrate. Its structural formula is:

C 10H13NO4 • 1 1/2 H2O M.W. 238.24

Levodopa is a prodrug of dopamine that is administered to patients with Parkinson’s due to its ability to cross the blood-brain barrier^Label. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrier^Label,1. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson’s^Label. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 1975^1,7.

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.^[1] It is one of the preferred treatments for high blood pressure in pregnancy.^[1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.^[1] It can be given by mouth or injection into a vein.^[1] Onset of effects is around 5 hours and they last about a day.^[1]

Common side effects include sleepiness.^[1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.^[1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication.^[1] It works by stimulating the brain to decrease the activity of the sympathetic nervous system.^[1]

Methyldopa was discovered in 1960.^[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] The wholesale cost in the developing world is about US$4.31–9.48 per month.^[4] In the United States it costs less than $25 per month.^[5]

Medical uses

Methyldopa is used in the clinical treatment of the following disorders:

Hypertension (or high blood pressure)
Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia

Side effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.^[6] Side effects may include:

Psychological
- Depression or even suicidal ideation, as well as nightmares
- Apathy or anhedonia, as well as dysphoria
- Anxiety, especially of the social anxiety variant
- Decreased alertness, awareness, and wakefulness
- Impaired attention, focus, and concentration
- Decreased desire, drive, and motivation
- Fatigue or lethargy or malaise or lassitude
- Sedation or drowsiness or somnolence or sleepiness
- Agitation or restlessness
- Cognitive and memory impairment
- Derealization or depersonalization, as well as mild psychosis
- Sexual dysfunction including impaired libido, desire, and drive
Physiological
- Dizziness, lightheadedness, or vertigo
- Miosis or pupil constriction
- Xerostomia or dry mouth
- Gastrointestinal disturbances such as diarrhea or constipation
- Headache or migraine
- Myalgia or muscle aches, arthralgia or joint pain, or paresthesia (“pins and needles”)
- Restless legs syndrome (RLS)
- Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability
- Akathisia, ataxia, dyskinesia as well as even tardive dyskinesia, or dystonia
- Bell’s palsy or facial paralysis
- Sexual dysfunction consisting of impaired erectile dysfunction or anorgasmia
- Hyperprolactinemia or excess prolactin, gynecomastia/breast enlargement in males, or amenorrhoea or absence of menstrual cycles in females
- Bradycardia or decreased heart rate
- Hypotension or decreased blood pressure (though this may also be considered a therapeutic benefit)
- Orthostatic hypotension (also known as postural hypotension)
- Hepatitis, hepatotoxicity, or liver dysfunction or damage
- Pancreatitis or inflammation of the pancreas
- Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs)
- Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia or blood platelet deficiency or leukopenia or white blood cell (WBC) deficiency
- Hypersensitivity such as lupus erythematosus, myocarditis, or pericarditis
- Lichenoid reactions such as skin lesions or rashes
- Pallor

Rebound/withdrawal

Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.^[7]

Mechanism of action

Methyldopa has a dual mechanism of action:

It is a competitive inhibitor of the enzyme DOPA decarboxylase, also known as aromatic L-amino acid decarboxylase, which converts L-DOPA into dopamine. Dopamine is a precursor for norepinephrine (noradrenaline) and subsequently epinephrine (adrenaline). This inhibition results in reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system. This effect may lower blood pressure and cause central nervous system effects such as depression, anxiety, apathy, anhedonia, and parkinsonism. In addition, decreased dopamine may reduce its inhibitory effect on prolactin leading to signs and symptoms of hyperprolactinemia.
It is converted to α-methylnorepinephrine by dopamine beta-hydroxylase (DBH). α-Methylnorepinephrine is an agonist of presynaptic central nervous system α₂ adrenergic receptors. Activation of these receptors in the brainstem appears to inhibit sympathetic nervous system output and lower blood pressure. This is also the mechanism of action of clonidine.

Pharmacokinetics

Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.

History

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.^[8] Nonetheless, one of methyldopa’s still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

PATENT

https://patents.google.com/patent/CN105693541B/en

L-methyldopa an α2 receptor agonistic cardiovascular drugs. The structural formula is as follows:

[0003]

[0004] The product produced methyl α- demethylated metabolite of norepinephrine, blockade of central α receptor, thereby inhibiting the heart, kidney and peripheral vascular sympathetic drive output at the same time, peripheral vascular resistance in vivo and plasma renin activity is reduced, and thus decrease blood pressure. It can be used for treating hypertension, nephropathy, including hypertension time.This product is safe, is the preferred treatment during pregnancy with hypertension drugs.

[0005] In the prior art, methyldopa synthesis are the following:

[0006] 1 to veratridine-one was synthesized by the synthesis of L-hydantoin intermediate methyldopa:

[0007]

[0008] 2 to veratridine-one was synthesized by the synthesis of L-amino nitrile intermediate methyldopa:

[0009]

[0010] 3, eugenol synthesized from L-methyldopa

[0011]

[0012] The plurality of reaction have their own advantages, but in general, the reaction need to use highly toxic cyanide, have a certain impact on the environment and operating conditions.

SUMMARY

[0013] The present invention discloses a method for synthesizing methyldopa, the synthetic route without using highly toxic substances, the advantage of having a clean environment and efficient.

[00 M] methyldopa synthesis method disclosed in the present invention, is 3,4-dimethoxybenzaldehyde with 2-acetylamino-propionic acid methyl ester as a starting material synthesized by condensation, reduction, deprotection to give the crude product methyldopa, methyldopa and then purified to give pure product.Scheme with easy operation, high yield, etc. cleaning process.

[0015] The scheme is as follows:

[0016]

Example 1

[0034] (A) Weigh 3,4_-dimethoxybenzaldehyde 16.6g (0. Imol), sodium methoxide 5.4g (0. Imol), into dried dimethylformamide (150ml), stirring dissolution was complete, the reactor was placed in a cold water bath controlled at a temperature of about 20 ° C, weighed 2-acetamido-methyl 14.5g (0. Imol), successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes plus complete. After all was added, maintaining the reaction temperature for 1.5h.After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0035] (B) Intermediate (A) obtained was transferred to the reactor, 150ml of dichloromethane was added to dissolve, was added p-toluenesulfonyl chloride 19. Ig (0. Imol), triethylamine reactor after 10. Ig (0. Imol), the reaction was stirred for 2h, sodium boron hydride was added 4g, reaction was continued for lh. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0036] (C) Intermediate (B) obtained was transferred to the reactor was added 150ml 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about IlOml, filtered, the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Filtered and the solid washed with a little cold methylene chloride to give 20.8 g of crude product methyldopa, yield 98.5%.

[0037] (D) The crude product take methyldopa, add 30ml 0. Imo 1 / L dilute hydrochloric acid, an Ig activated carbon, heated, stirred until dissolution methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give 17.7 g methyldopa pure, a yield of 85.0%. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.6%.

[0038] Example 2

[0039] (A) Weigh 166kg of 3,4-dimethoxybenzaldehyde, 54kg sodium methoxide, into dried dimethylformamide 500L stirred to dissolve completely, the reactor was placed in a cold water bath controlled temperature of about 20 ° C, 2-acetamido-Weigh 145kg methyl, successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes the addition was completed. After all was added, maintaining the reaction temperature for 2 h. After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0040] (B) Intermediate (A) obtained was transferred to the reactor, 500L of methylene chloride was added to dissolve, was added p-toluenesulfonyl chloride 19Ikg, triethylamine 10Ikg into the reactor, the reaction was stirred for 2.5h , sodium borohydride was added 4kg, reaction was continued for 1.3h. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0041] (C) Intermediate (B) obtained was transferred to the reactor, was added 500L 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about 375L, filtered, and the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Centrifuged, and the solid washed with a little cold water to give the crude product methyldopa 200kg, 94.7% yield.

[0042] (D) The crude product take methyldopa, add 300L O.lmol / L dilute hydrochloric acid, 10 kg activated carbon, heating and stirring until dissolved methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give pure methyldopa 177kg, 88.5% yield. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.7%.

CLIP

Exists as the sesquihydrate.

Prepn: Pfister, Stein, US 2868818 (1959 to Merck & Co.). D. F. Reinhold and M. Sletzinger, GB 936074 eidem U.S. Patent 3,344,023 (1963 to Merck and Co.)

Resolution: Jones et al., US 3158648 (1964 to Merck & Co.); cf. Slates et al., J. Org. Chem. 29, 1424 (1964). Resolution and configuration: Tristram, ibid. 2053.

Synthesis from asymmetric intermediates: Reinhold et al., J. Org. Chem. 33, 1209 (1968).

Prepn of the ethyl ester hydrochloride: FR M2153 (1963 to Merck & Co.);

of pharmaceutical dosage forms: Marcus, US 3230143 (1966 to Merck & Co.).

CLIP

Reactions of D-glucose with phenolic amino acids: further insights into the competition between Maillard and Pictet-Spengler condensation pathways
Carbohydrate Research (2005), 340, (18), 2719-2727

Methyldopa

- ATC:C02AB01
Use:antihypertensive
Chemical name:3-hydroxy-α-methyl-l-tyrosine
Formula:C₁₀H₁₃NO₄

MW:211.22 g/mol
CAS-RN:555-30-6
InChI Key:CJCSPKMFHVPWAR-JTQLQIEISA-N
InChI:InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1
EINECS:209-089-2

Synthesis

References

- Tristram, E.W. et al.: J. Org. Chem. (JOCEAH) 29, 2053 (1964).
- B Stein, G.A. et al.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
- Chem. Eng. from 8.11.1965; p. 247.
- C Reinhold, D.F. et al.: J. Org. Chem. (JOCEAH) 33, 1209 (1968).
- A US 2 868 818 (Merck & Co.; 13.1.1959; prior. 15.12.1953).
- GB 936 074 (Merck & Co.; appl. 18.10.1960; USA-prior. 8.4.1960, 24.8.1960).
- DE 1 171 931 (Merck & Co.; prior. 6.10.1960).
- US 3 158 648 (Merck & Co.; 24.11.1964; prior. 11.7.1961, 9.4.1962).
- FR 1 492 765 (Merck & Co.; appl. 10.10.1963; USA-prior. 11.10.1962, 19.9.1963).

similar method via l-α-acetylamino-α-vanillylpropionitrile:
- GB 1 142 595 (Merck & Co.; appl. 23.5.1967, 12.2.1969).

alternative syntheses:
- D a Steinetal, G.A.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
- US 3 366 679 (Merck & Co.; 30.1.1968; prior. 11.10.1962, 19.9.1963).
- DOS 2 302 937 (Tanabe; appl. 22.1.1973; J-prior. 22.1.1972).
- US 3 517 057 (Merck & Co.; 23.6.1970; appl. 21.9.1967).
- DE 1 235 946 (Boehringer Mannh.; appl. 8.8.1964).
- DE 1 235 947 (Bayer; appl. 16.1.1963).
- DE 1 258 416 (Knoll; appl. 9.10.1964).
- DE 1 269 622 (Knoll; appl. 22.12.1966).
- DOS 2 406 898 (BASF; appl. 14.2.1974).
- AT 250 936 (Egyesült; appl. 3.11.1964; HU-prior. 18.11.1963).
- FR 1 502 972 (Merck & Co.; appl. 21.10.1966; USA-prior. 22.10.1965).
- FR 1 531 877 (Sankyo; appl. 18.7.1967; J-prior. 11.8.1966, 21.2.1967).
- GB 1 321 802 (D.D.S.A.; appl. 5.2.1971).
- b GB 2 059 955 (Merck & Co.; appl. 9.9.1980; USA-prior. 13.9.1979, 28.9.1979).

medical use:
- US 3 344 023 (Merck & Co.; 12.4.1983; prior. 8.4.1960, 24.8.1960, 1.2.1963; reexamination request 21.12.1981).
References
1. ^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “Methyldopa”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
2. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592. Archived from the original on 2016-09-14.
3. ^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
4. ^ “Methyldopa”. International Drug Price Indicator Guide. Retrieved 8 December 2016.
5. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 140. ISBN 9781284057560.
6. ^ British National Formulary 56. September 2008. pp. 95–96. ISBN 978-0-85369-778-7.
7. ^ Methyldopa (PIM 342) Archived 2008-03-13 at the Wayback Machine
8. ^ Mah GT, Tejani AM, Musini VM. Methyldopa for primary hypertension. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003893. DOI: 10.1002/14651858.CD003893.pub3.
External links

Methyldopa
Clinical data


Trade names	Aldomet, Aldoril, Dopamet, others
Synonyms	L-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/Drugs.com	Monograph
MedlinePlus	a682242
Pregnancy category	AU: A US: B (No risk in non-human studies)
Routes of administration	by mouth, IV
ATC code	C02AB01 (WHO) C02AB02 (WHO) (racemic)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	approximately 50%
Metabolism	Liver
Onset of action	4 to 6 hrs^[1]
Elimination half-life	105 minutes
Duration of action	10 to 48 hrs^[1]
Excretion	Kidney for metabolites
Identifiers
IUPAC name [show]
CAS Number	555-30-6
PubChem CID	38853 40175
IUPHAR/BPS	5217
DrugBank	DB00968
ChemSpider	35562
UNII	56LH93261Y
ChEMBL	ChEMBL459
CompTox Dashboard (EPA)	DTXSID5023295
ECHA InfoCard	100.008.264
Chemical and physical data
Formula	C₁₀H₁₃NO₄
Molar mass	211.215 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N
InChI [hide] InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1 Key:CJCSPKMFHVPWAR-JTQLQIEISA-N

Other Names

Alanine, 3-(3,4-dihydroxyphenyl)-2-methyl-, L- (8CI)
3-Hydroxy-α-methyl-L-tyrosine
(-)-Methyldopa
(-)-α-Methyl-3,4-dihydroxyphenylalanine
(-)-α-Methyldopa

(2S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
(S)-(-)-α-Methyldopa
(S)-α-Methyldopa
2-Methyl-3-(3,4-dihydroxyphenyl)alanine
AMD
Aldochlor
Aldomet
Aldometil
Aldomin
Aldomine
Alpha medopa
Alphamethyldopa
Bayer 1440L
Baypresol
Dopamet
Dopatec
Dopegyt
Elanpres
Equibar
L-(-)-α-Methyl-β-(3,4-dihydroxyphenyl)alanine
L-(-)-β-(3,4-Dihydroxyphenyl)-α-methylalanine
L-2-Amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid
L-3,4-Dihydroxy-α-methylphenylalanine
L-3,4-Dihydroxyphenyl-2-methylalanine
L-Methyldopa
L-α-Methyl-3,4-dihydroxyphenylalanine
L-α-Methyl-3-(3,4)-dihydroxyphenylalanine
L-α-Methyldopa
Lederdopa
Levo-3-(3,4-Dihydroxyphenyl)-2-methylalanine
MK 351
Medomet
Medopa
Medopren
Methoplain
Methyl-L-dopa
Methyldopa
NSC 169916
Nr.C 2294
Presinol
Presolisin
Sembrina
l-3-(3,4-Dihydroxyphenyl)-2-methylalanine
l-α-Methyldopa
α-Methyl-L-3,4-dihydroxyphenylalanine
α-Methyl-L-dopa
α-Methyldopa

General References

Djamshidian A, Poewe W: Apomorphine and levodopa in Parkinson’s disease: Two revolutionary drugs from the 1950’s. Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S9-S12. doi: 10.1016/j.parkreldis.2016.12.004. Epub 2016 Dec 22. [PubMed:28012951]
Meiser J, Weindl D, Hiller K: Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34. doi: 10.1186/1478-811X-11-34. [PubMed:23683503]
Elroby SA, Makki MS, Sobahi TR, Hilal RH: Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes. Int J Mol Sci. 2012;13(4):4321-39. doi: 10.3390/ijms13044321. Epub 2012 Apr 2. [PubMed:22605980]
Robertson DR, Wood ND, Everest H, Monks K, Waller DG, Renwick AG, George CF: The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989 Jul;28(1):61-9. [PubMed:2775615]
Abrams WB, Coutinho CB, Leon AS, Spiegel HE: Absorption and metabolism of levodopa. JAMA. 1971 Dec 27;218(13):1912-4. [PubMed:5171067]
Fanali G, Rampoldi V, di Masi A, Bolli A, Lopiano L, Ascenzi P, Fasano M: Binding of anti-Parkinson’s disease drugs to human serum albumin is allosterically modulated. IUBMB Life. 2010 May;62(5):371-6. doi: 10.1002/iub.317. [PubMed:20225277]
FDA Approved Drug Products: Sinemet [Link]
Sinemet FDA Label [File]

/////////Methyl-L-dopa, Methyldopa, NSC 169916

N[C@@H](CC1=CC(O)=C(O)C=C1)C(O)=O

Nilotinib ニロチニブ;

September 27, 2019 9:38 am / Leave a comment

ChemSpider 2D Image | Nilotinib | C28H22F3N7O

NILOTINIB

ニロチニブ;

Molecular FormulaC₂₈H₂₂F₃N₇O
Average mass529.516 Da

4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide

4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)benzamide

4-Methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide

4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluormethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzolcarboxamid

4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}benzamide

4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide

641571-10-0 [RN]

8654

Benzamide, 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-

Nilotinib (AMN107, trade name Tasigna^[2]), in the form of the hydrochloride monohydrate salt, is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia.^[3] Structurally related to imatinib,^[4] it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.^[5]^[6]^[7] Nilotinib is a selective Bcr-Abl tyrosine kinase inhibitor^[5]^[6] that is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.^[4]^[6]^[7]^[8] Nilotinib was developed by Novartis and is sold under the trade name Tasigna.^[9]

Medical uses

Crystal structure of Abl kinase domain(blue) in complex with nilotinib (red)

It is FDA– (29 October 2007),^[10] EMA– (29 September 2009),^[11] MHRA– (19 November 2007)^[12] and TGA– (17 January 2008)^[13] approved for use as a treatment for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia.^[1]

The drug carries a black box warning for possible heart complications.^[14]^[15]

Clinical trials

CML

In June 2006, a phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib, another tyrosine kinase inhibitor currently used as a first-line treatment.^[16] In that study 92% of patients (already resistant or unresponsive to imatinib) achieved normal white blood cell counts after five months of treatment.^[17]

Contraindications

Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.^[1]^[13]

Cautions include:^[1]

Myelosuppression
Tumour lysis syndrome
Liver impairment
History of pancreatitis
Check serum lipase periodically in order to detect pancreatitis
Total gastrectomy
Avoid pregnancy or impregnating women

Dose reduction of nilotinib has been recommended in hepatically impaired population which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.^[18]

Adverse effects

Nilotinib has a number of adverse effects typical of anti-cancer drugs. These include headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain, rash and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as hypertension (high blood pressure), various types of arrhythmia, and prolonged QT interval. Nilotinib can also affect the body’s electrolyte and glucosebalance.^[10] Though pulmonary-related adverse effects are rare when compared with imatinib and dasatinib, there is a case report of acute respiratory failure from diffuse alveolar hemorrhage in a patient taking nilotinib.^[19]

Interactions

Nilotinib has been reported as a substrate for OATP1B1 and OATP1B3. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.^[18] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.^[20]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors^[21] will increase its action and inducers like St. John’s wort^[22] will decrease it. Patients report that pomegranates and starfruit may also interfere.

Food should not be eaten two hours before or one hour afterwards because it unpredictably increases its bioavailability, approximately doubling it.

Pharmacology

Nilotinib inhibits the kinases BCR-ABL,^[23] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.^[24]

Research

Parkinson’s disease

There is weak evidence that nilotinib may be beneficial with Parkinson’s Disease (PD), with a small clinical trial suggesting it might halt progression and improve symptoms.^[25]However, there were significant side effects including infection, liver function tests abnormalities, hallucinations and heart attack, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson’s.^[26]Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson’s due to the significant media hype surrounding the small and early clinical trial.^[27]^[28]

Other

Novartis announced on April 11, 2011 that it was discontinuing a phase III trial of Tasigna (nilotinib) for investigational use in the first-line treatment of gastrointestinal stromal tumor(GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Novartis’s Gleevec (imatinib)*, the current standard of care in this setting.^[29]

Low dose nilotinib is also being investigated for use for and Alzheimer’s disease, as well as for ALS, dementia and Huntington’s disease.^[30]

Patent

WO 2016024289, NILOTINIB, New Patent by SUN

SUN PHARMACEUTICAL INDUSTRIES LTD [IN/IN]; 17/B, Mahal Industrial Estate, Off Mahakali Caves Road, Andheri (east), Mumbai 400093 (IN)

THENNATI, Rajamannar; (IN).
KILARU, Srinivasu; (IN).
VALANCE SURENDRAKUMAR, Macwan; (IN).
SHRIPRAKASH DHAR, Dwivedi; (IN)

The present invention provides novel salts of nilotinib and polymorphs thereof. The acid addition salts of nilotinib with benzenesulfonic acid, butanedisulfonic acid, 1-5- naphthalenedisulfonic acid, naphthalene-1-sulfonic acid and 1-hydroxynaphthoic acid; hydrates and anhydrates thereof.

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.

WIPO publication 2014059518A1 discloses crystalline forms of nilotinib hydrochloride and methods of the preparation of various crystalline solvates of nilotinib hydrochloride including benzyl alcohol, acetic acid and propylene glycol.

WIPO publication 2011033307A1 discloses nilotinib dihydrochloride and its hydrates and method for their preparation.

WIPO publication 2011163222A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts of nilotinib disclosed are hydrochloride, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, p-toluenesulfonate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate and malonate.

WIPO publication number 2011086541A1 discloses a nilotinib monohydrochloride monohydrate salt and methods for preparing.

WIPO publication number 2010054056A2 describes several crystalline forms of nilotinib hydrochloride.

WIPO publication number 2007/015871A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts are mixtures of nilotinib and one acid wherein the acids are selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sul- fonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.

WIPO publication number 2007015870A2 discloses several nilotinib salts including amorphous and crystalline forms of nilotinib free base, nilotinib HC1 and nilotinib sulfate along with their hydrate and solvates.

EXAMPLES:

Example 1: Preparation of nilotinib benzenesulfonate crystalline Form I

Nilotinib base (1 g) was suspended in water (20 ml). A solution of benzenesulfonic acid (0.4 g) in water (3ml) was added and the content was heated at 60 °C for 2-3 h. The mixture was cooled to 25-30 °C, filtered, washed with water (3 x 5 ml) and dried under vacuum for 2 h at 50-55 °C.

1H NMR (500 MHz, DMSO-d6) δ 2.40 (s,3H), 2.42 (s,3H), 7.35-7.37 (m,3H), 7.51-7.66 (m,5H),7.83 (d,lH), 7.96 (s,lH),8.08 (s,lH),8.30 (s,lH) 8.39 (s,lH),8.54 (d,lH), 8.61 (d,lH), 8.64 (s,lH), 8.75 (d,lH), 9.25 (s,lH), 9.34 (d,lH), 9.61 (s,lH), 10.84 (s,lH).

The salt provides an XRPD pattern substantially same as set forth in FIG. 1.

Example 2: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (100 g) was dissolved in 20 % water in THF solution (2000 ml) at 60-65 °C and insoluble matter was filtered. The filtrate was concentrated under vacuum below 60 °C. Filtered water (1000 ml) was added to the reaction mixture and it was heated at 50-55 °C, followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution (28.6 ml) at same temperature. The content was stirred at 50-55 °C for 2-3h. Reaction mixture as cooled to 25-30 °C and product was filtered, washed with water (200 ml x 2) and dried in air oven at 50-55 °C (yield: 115 g).

Purity (by HPLC):99.76%

1H NMR (400 MHz,DMSO-d6) δ 1.63-1.66(m,2H), 2.40(d,3H),2.42(s,3H),2.43-2.47(m,2H), 7.51-7.62(m,3H),7.85(dd,lH),7.96(s,lH),8.08(s,lH),8.34(s,lH),8.38(d,lH),8.52-8.55(m,lH), 8.60-8.62 (m,2H), 8.75(d,lH), 9.25(S,1H),9.34(S,1H),9.59(S,1H),10.86(S,1H)

Water content: 7.95 %.

The salt has a XRPD pattern substantially same as set forth in FIG. 2.

Example 3: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (300 g) was suspended in methanol (3000 ml) and aqueous hydrochloric acid was added to get pH less than 2. Reaction contents were heated at reflux and was filtered and washed with methanol (100 ml). 5% (w/w) NaOH (1200 ml) solution was added at 40-45 °C within 15 min, reaction mixture was stirred for 2h. Product was filtered, washed with water

(300 ml x 3) and dried for lh. Wet material was suspended in water (3000 ml), heated at 50- 55 °C followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution. The reaction mixture was stirred at 50-55°C for 2hrs. Product was filtered at room temperature, washed with water (500 ml x 2) and dried in air oven at 50-55 °C (yield: 293 g).

Purity (by HPLC): 99.88 %

¹H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.75-1.78(m,2H), 2.36(d,3H),2.38(s,3H),2.69- 2.72(m,2H),7.45(d,lH),7.68(d,lH),7.83(s,lH),7.88(dd,lH),7.97(s,lH),8.16-8.19(m,lH), 8.35

(s,2H), 8.63(d,lH),8.68(d,lH),9.04(d,lH),9.21(d,lH),9.53(br s,lH),9.69(d,lH)10.80 (s,lH)

Water content: 6.44 %

Example 4: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form III

Nilotinib butanedisulfonate (210g) was dissolved in acetic acid water mixture (50:50) (2520 ml) at 75-80 °C and was filtered to remove insoluble matter and washed with acetic acid water mixture (50:50) (210 ml). Water (3150ml) was added to the filtrate and stirred first at room temperature and then at 0-5 °C. Product was filtered and washed with water. Material was dried in air oven at 70-75 °C. Dried material was leached with methanol (3438 ml) at reflux temperature, filtered and dried in air oven 70-75°C (yield: 152.6 g)

Purity (by HPLC): 99.89 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.73-1.77(m,2H), 2.40(s,6H),2.67-2.70(m,2H), 7.50 (d,lH), 7.70(d,lH), 7.88-7.92(m,2H), 8.07(s,lH),8.23 (dd,lH), 8.34(s,2H), 8.67 (d,lH), 8.72 (d,lH), 9.09(d,lH), 9.23 (s,lH), 9.54(d,lH), 9.74(d,lH), 10.86(s,lH).

Water content: 0.61 %

The salt provides an XRPD pattern substantially same as set forth in FIG. 3.

Example 5: Preparation of crystalline form of nilotinib butanedisulfonate (2: 1)

Crystalline Nilotinib butanedisulfonate (1 g) of Example 2 was suspended in methanol (20 ml) and was stirred at reflux for 60 min. The mixture was cooled to room temperature. Solid was filtered, washed with methanol (2 ml x 3) and dried in air oven at 70-75°C (yield: 0.8 g)

Example 6: Preparation of nilotinib butanedisulfonate (1: 1) crystalline Form IV

Nilotinib base (20 g) was suspended in methanol (800 ml) and 1,4-butanedisulfonic acid -60

% aqueous solution (6 ml) was added at 50-55 °C, and was filtered to remove insoluble matter. Filtrate was stirred at room temperature for 2-3 h. Product formed was filtered, washed with methanol (20 ml x 2) and dried the product in air oven at 70-75 °C (yield: 18.4 g).

Purity (by HPLC):99.86 %

1H NMR (400 MHz,DMSO-d6) δ 1.64-1.68(m,4H), 2.47-2.5 l(m,4H), 2.41(s,3H), 2.42(d,3H), 7.52(d,lH), 7.83-7.89(m,2H), 7.99(s,lH), 8.15(s,lH), 8.36 (d,lH), 8.39(s,lH), 8.65-8.66(m,2H), 8.79(d,lH), 8.89(br s,lH), 9.36(s,lH), 9.41(br s,lH), 9.74(d,lH), 10.91(s,lH).

The salt has XRPD pattern substantially same as set forth in FIG. 4.

Example 7: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (2: 1) crystalline Form V

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.4 g; 0.6 eq.) in water (5ml) was added and the content was heated at 50-55 °C for lh. The mixture was cooled to 25-30 °C, filtered and washed with water (10 ml). The product was dried in air oven at 50-55°C (yield: 1.2 g).

1H NMR (400 MHz,DMSO-d6) δ 2.39 (s,3H), 2.42 (s,3H), 7.45-7.61 (m,4H),7.84 (d,lH), 7.97(s,2H),8.08 (m,lH),8.31 (s,lH) 8.38 (s,lH),8.55 (d,lH), 8.63 (s,2H), 8.75 (s,lH), 8.92 (d,lH), 9.26 (s, 1H), 9.34 (s,lH),9.62 (s,lH), 10.85 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 5.

Example 8: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (1: 1) crystalline Form VI

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.8 g; 1.2eq) in water (5 ml) was added and the content was heated at 50-55 °C for 1 h. The mixture was cooled to 25-30 °C, filtered, washed with water (10 ml) and dried in air oven at 50-55 °C (yield: 1.4g).

1H NMR(400 MHz,DMSO-d6) δ 2.40 (s,3H),2.41 (s,3H), 7.43-7.52 (m,3H),7.61 (d,lH), 7.85-7.99(m,5H),8.11 (s,lH),8.34 (s,2H), 8.64-8.67 (m,2H), 8.89-8.92 (m,4H),9.40(d,2H), 9.72 (s,lH), 10.87 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 6.

Example 9: Preparation of nilotinib napthalene-1- sulfonic acid salt crystalline Form VII Nilotinib base (1 g) was suspended in water (10 ml) and heated to 50-55 °C. A solution of napthelene-1 -sulfonic acid and methanol (10 ml) was added to it and heated at 70-75 °C for 30 min. The mixture was cooled to 25-30 °C and stirred for 10 min. The product was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1-2 h at 50-55 °C.

1H NMR (400 MHz,DMSO-d6) δ 2.41 (s,3H),2.42 (s,3H), 7.46-7.58 (m,5H), 7.70-8.00 (m,7H)8.11(s,lH)8.31(s,lH),8.37(s,lH),8.63-8.66 (m,3H), 8.81-8.89 (m,2H), 9.31 (s,lH), 9.37 (d,lH), 9.71 (d,lH), 10.86 (s,lH)

The salt has a XRPD pattern substantially same as set forth in FIG. 7.

Example 10: Preparation of nilotinib l-hydroxy-2-napthoic acid salt crystalline Form VIII Nilotinib base (1 g) was suspended in water (20 ml) and heated to 50-55 °C. l-Hydroxy-2-napthoic acid was added to it and the content was heated at 50-55 °C for 1 h. Methanol (5 ml) was added to the mixture and stirred for 30 min. The content was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1 h at 50-55 °C.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s,3H), 2.41 (s,3H), 7.40-7.92 (m,l lH), 8.23-8.73 (m,8H), 9.24 (s,lH), 9.34(s,lH), 10.70 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 8.

PATENT

https://patents.google.com/patent/WO2010009402A2/en

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-

(trifluoromethyl)phenyl] -3 – [ [4-(3 -pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot tolerate other therapies that included imatinib. Nilotinib is administered as a hydrochloride salt in forms of capsules that are marketed in the USA and the EU under the name Tasigna®.

[0004] US patent no. 7,169,791 (“US 791”) and its parallel PCT publication WO

2004/005281, the journal article in Synthesis, 2007, vol 14, pp 2121-2124, as well as PCT publication nos.: WO 2006/135640, WO 2006/135641 (“WO “641”), WO 2007/018325 and WO 2007/017734, report processes for preparing Nilotinib intermediate, 3-(trifluoromethyl)- 5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I

I by reacting 3-bromo-5-trifluoromethylaniline of formula II and 4-methylimidazole of formula III in the presence of a non-alkaline hydroxide inorganic base, such as potassium carbonate, cesium carbonate and sodium hydride, a copper (I) salt, such as copper iodide and a complexing amine ligand, such as ethylene diamine. The process can be illustrated by the following scheme:

Il ‘

Scheme 1

[0005] The journal article in Synthesis, 2007, VoI 14, pp 2121-2124, describes a purification process of 3-(trifluoromethyl-5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I.

[0006] US 791 describes processes for preparing Nilotinib and its different intermediates, using di-ethyl cyano phosphate, as described in the following scheme:

[0007] WO ‘641 further describes a process for preparing Nilotinib according to the following scheme:

Scheme 3

[0008] The present invention provides improved processes to prepare and/or purify 3-

(trifluoromethyl)-5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I without requiring the use of column chromatography, and thus can be easily applied to large scale manufacture, as well as new intermediates of Nilotinib, which result in higher yields in the preparation of Nilotinib.

[0009] PCT publications WO 2007/015870 (“WO ‘870”) and WO 2007/015871

(“WO ‘871”) describe several Nilotinib salts including crystalline forms of nilotinib free base, Nilotinib hydrochloride and Nilotinib Sulfate.

[0010] The present invention also relates to the solid state physical properties of

Nilotinib^»3HCl, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3- [[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide trihydrochloride. These properties can be influenced by controlling the conditions under which Nilotinib-3HC1 is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.

[0011 ] Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient’s bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability. [0012] These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x-ray crystallography, solid state ¹³C NMR spectroscopy, and infrared spectrometry.

[0013] Generally, a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability.

[0014] The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

[0015] There is a need in the art for new intermediates of Nilotinib and processes for their preparation, new processes for preparing Nilotinib and new crystalline forms of Nilotinib^»3HCl salt and processes for the preparation thereof.

xample 1: Preparation of 3-(ϊrifluoromethyl)-5-(4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I

[00245] 200Og of 3-bromo-5- trifluoromethylaniline of formula II, 1368g of 4- methylimidazole of formula III , 181g of 8-hydroxyquinoline, 238g of CuI, 666.6g of NaOH, 933g of CaO and 7000ml of DMSO were loaded into a 1OL of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 12O⁰C for 69 hours while monitoring for the consumption of 3-bromo-5- trifluoromethy aniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline / 4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-5O⁰C and poured into a 5OL reactor. 8.4L of 14% ammonia was added dropwise and then stirred for lhour at 45-5O⁰C. The mixture was cooled down to room temperature.16.8L of water and 1OL of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate.

The combined organic layer was washed with 5L*3 of 5% of brine for three times. The upper organic layer was separated and dried over lkg of anhydrous Na₂SO₄overnight. The mixture was filtered and concentrated to obtain 2.3kg of solid. The residue was dissolved in 2L of ethyl acetate at 45⁰C. To the solution was then added 8L of petroleum ether dropwise at 45⁰C. The mixture was cooled down slowly to 0-15⁰C and stirred for lhour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2L of ethyl acetate at 45⁰C. The solution was then added 8L of petroleum ether dropwise at 45⁰C. The mixture was cooled down slowly to 15-O⁰C and stirred for lhour. A large precipitate was formed and filtered. The filter cake was dried at 45⁰C and 954g of 3-(trifluoromethyl)-5-(4-methyl-lH- imidazole-l-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity.

Example 2: Recrystallization of 3-ftrifluoromethyl)-5-f4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I from IPA/water

[00246] A 5OmL flask was charged with Ig of the compound of Formula I crude

(purity of 82.5%) and 3.5mL of IPA. The mixture was heated to 45°C under stirring until the entire solid dissolved. At 45°C, 6mL of water was added drop-wise. The mixture was stirred for lOmin and cooled slowly to 0~10°C. The mixture was stirred at 0~10°C for 10 min and filtered to obtain the recrystallized compound of Formula I having a purity of 98%.

Example 3: Recrystallization of 3-ftrifluoromethyl)-5-f4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I from Ethanol/water

[00247] A 5OmL flask was charged with 2g of the compound of Formula I crude

(purity of 83.1%) and 4mL of Ethanol. The mixture was heated to reflux under stirring until the entire solid dissolved. While refluxing, 1OmL of water was added drop-wise. The mixture was cooled slowly to 25±5°C. The mixture was filtered and washed with a mixture of ethanol/water to obtain the recrystallized compound of Formula I having a purity of 86.5%.

[00248] The purification factor can be seen in the following table:

Example 4: Preparation of compound of formula IV

[00249] The compound of formula X (31.Og, 0.1 Omol) was suspended in 310ml toluene, and SOCl₂ (47.6g, 0.40mol) was added to the mixture under the protection of N₂. The formed mixture was reacted at 5O⁰C for 2 h. The solvent was evaporated completely, and a compound of formula (X-Cl) was obtained as yellow solid. The compound of formula (X- Cl) was then added to a THF solution of the compound of formula II (27.Og, 0.1 lmol), DIPEA (15.Og, 0.12mol) and DMAP (0.5g, 4.0mmol). The reaction mixture was reacted at 3O⁰C for 12 h, and then quenched with 8% solution of sodium bicarbonate (620ml). The mixture was filtered, and washed with H₂O, then dried in vacuum. The solid was re-slurried with MTBE, and dried in vacuum again. 49.5g of the compound of formula IV were obtained as light yellow powder. The yield is about 93.7% by weight. The purity of the isolated product is 98% (% on area by HPLC).

Example 5: Preparation of compound of formula IV

[00250] To a 50ml 3-neck flask was charged compound of formula X 3. Ig and 21ml of toluene. The suspension was charged 5.1g dichlorosulfoxide (SOCl₂) under nitrogen protection. The reaction mixture was heated to 5O⁰C and reacted for 2hrs. The reaction was then concentrated to dry. To another 100ml 3-neck flask was charged 2.7g of compound of formula II, 1.5g of DIPEA, O.lg of DMAP and 30ml of THF. To the mixture was charged the above concentrated residue. The reaction mixture was stirred at 25±5°C overnight. The mixture was charged 45ml of ethyl acetate and 20ml of water. The mixture was then stirred at 25±5°C for lOmin, filtered and the filtrate was phase separated. The organic layer was washed by water 10ml twice. Then the organic layer was concentrated to dry. The residue was combined with the filter cake and slurried in MTBE. The mixture was filtered and dried under vacuum at 5O⁰C. The water layer was adjusted pH to 8 with NaHCO₃solution. The second crop 0.5g was thus precipitated out. Total yield was 94%.

Example 6: Preparation of compound of formula IV

[00251] To a 50ml 3-neck flask was charged compound of formula X 3. Ig, 20 mL of toluene and 18ml of dichlorosulfoxide (SOCl₂) under nitrogen protection. The reaction mixture was heated to 5O⁰C and reacted overnight. The reaction was then concentrated to dry and co-evaporated with 20ml of toluene of once. To another 100ml 3-neck flask was charged 2.7g of compound of formula II, 1.5g OfK₂CO₃, O.lg of DMAP and toluene. To the mixture was charged the above concentrated residue. The reaction mixture was stirred at 5O⁰C overnight. The mixture was charged 30ml of half saturated NaHCO₃ solution, 15ml of MTBE and stirred for lOmin. Large amount of solid was precipitated out and filtered. The filter cake was washed with MTBE and fired under vacuum at 55 ⁰C. The resulted product was of 81% of purity. There were about 9% of the compound of formula X.

Example 7: Preparation of compound of formula IV [00252] The compound of formula X (50 g), HOBt (26.5 g)/ EDCI (37.5 g) and DMF

(500 mL) were loaded into a reactor at 25±5°C. After being reacted for 3h, the compound of formula II (39 g) was added to the reactor. The reaction mixture was stirred at 80⁰C for about 18 hours while monitoring for the consumption of active ester by HPLC. After being cooled to 25±5°C, the mixture was dropped to a solution of half-saturated aqueous solution of sodium hydrogen carbonate, and the product was precipitated as canary yellow solid. [00253] The yield of this step was about 29.0% by weight. The purity of the isolated product was 95% (% on area by HPLC method described in Appendix 1).

Example 8: Preparation of Nilotinib

[00254] The compound of formula IV (21.Og, 39.7mmol), NaI (12.Og, 79.8mmol), CuI

(1.3g, β.Ommol) and N,N-Dimethylethylenediamine (1.Ig, 12.0mmol) were dissolved in DMF (105ml) under the protection of N₂. The formed solution was reacted at 12O⁰C for 24h. The temperature of the above solution was decreased to 6O⁰C.

[00255] 8-Hydroxyquinoline (1.8g, 1 l.βmmol), CuI (1.3g, β.Ommol), the compound of formula III (4.6g, 56.3mmol) and DBU (9.Og, 59.3mmol) were added to the above solution under the protection of N₂. The formed solution was reacted at 12O⁰C for 48h. After the reaction was competed (detected by the consumption of the compound of formula IV, HPLC), the reaction solution was dropped to a mixture of saturated solution of NaHCO₃ (15ml) and water (300ml) at 25±5°C. The mixture was then filtered, and the filter cake was washed with water. 26.9g crude product was obtained as pale brown powder with 69% purity after drying in vacuum.

[00256] The crude product was added to 3.8 vol. DMF, and heated to dissolution. The solution was filtered through Celite, and the filter cake was washed with 0.5 vol. DMF. 3.5 vol. of methanol/H₂O (3:1) was added to the above solution at 6O⁰C. The formed solution was stirred at 25±5°C overnight and at ice bath for 2h. The mixture was filtered, and the filter cake was washed with methanol (0.05 vol^χ3). The first round re-crystallization solid was obtained after drying in vacuum. The above solid was added to 2.9 vol DMF, and heated to dissolution. Then filtered, and the filter cake was washed with 0.1vol. DMF. The resulting solution was stirred at 25±5°C for 0.5 h, and at ice bath for 2 h. The mixture was filtered, and the cake was washed with methanol (0.05vol^χ3). 9.1g solid was obtained with 99.1% purity after drying in vacuum. The total yield was about 43.5% by weight. The purity of the isolated product is 99.1% (% on area by HPLC). Example 9: Preparation of Nilotinib

[00257] The compound of formula IV, the compound of formula III, CS2CO3, CuI , 8- hydroxyquinoline and CaO were loaded into a reactor at 25±5°C under the protection of N₂. The reaction mixture was then stirred at 120⁰C for about 24 hours while monitoring for the consumption of the compound of formula IV by HPLC. After cooled to 25±5°C, the mixture was treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate, then dried by Na₂SO₄. After concentration, the crude product was obtained as yellow solid. Then the solid was dissolved by CH₂CVMeOH (10 equ., 3:2), and the mixture was washed three times with water. After a period of time, the product would be crystallized from the organic solvent (purity: 95%, detected by HPLC). Few minutes later, the product would precipitate as yellow solid. Then the product was stirred in the solvent of CH₂Cl₂/Me0H (5 equ., 5:1) at 40⁰C for 1 hour. After that, the mixture would be filtered. The solid we got was dried in vacuum, and the product with 98% purity was obtained by this means.

[00258] The yield of this step was about 31.1% by weight. The purity of the isolated product was 98% (% on area by HPLC method described in Appendix 1).

Example 10: Preparation of Nilotinib:

[00259] To 250 mL glass reactor was added the compound 4-methyl-3-{[4-(pyridin-3- yl)pyrimidin-2-yl] amino} benzoic acid of formula X (10.0 g, 0.032 mol), a compound of formula I (8.7 g, 0.036 mol), SOCl₂ (7.5 mL, 0.103 mol) and N-Methyl-pyrrolidone (100 mL). The reaction mixture was stirred and heated to 90⁰C for 5 h. The reaction was then cooled to 50⁰C and an aqueous NaOH solution was added (12 g in 72 mL H₂O) until pH 10- 11. Then, the suspension was cooled to room-temperature, stirred for 30 minutes at this temperature, filtered under reduced pressure and washed with 30 mL H₂O to yield a beige solid. This material was dried under vacuum at 50⁰C and 8.2 g of Nilotinib base was obtained. To the mother-liquor was added H₂O (300 mL), and the mixture was stirred for 15 hours at room-temperature. A precipitate was formed and filtered under vacuum. The solid so-obtained was washed with H₂O (20 mL), and dried in vacuum oven at 50⁰C to yield additional 5.9 g of Nilotinib base. The total amount of Nilotinib base was 14.1 g in 81% yield. Example 11: Preparation of Nilotinib:

[00260] To 250 mL glass reactor was added the compound of formula 4-methyl-3- {[4-

(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid of formula X (20.0 g, 0.065 mol), a compound of formula I (17.3 g, 0.072 mol), SOCl₂ (15 mL, 0.206 mol) and N-Methyl- pyrrolidone (100 mL). The reaction mixture was stirred and heated to 90⁰C for 3 h. The reaction was filtered under reduced pressure and washed with NMP (10 mL) and H₂O (10 mL). The filtrate was then cooled to 70⁰C and a 47% NaOH solution (30 mL) was added and stirred for 30 minutes until pH 11-12. Then, the suspension was cooled to 5°C during 3 hours, stirred at this temperature for 10 hours room-temperature, filtered under reduced pressure and washed with 100 mL H₂O to yield a beige solid. This material was dried under vacuum at 50⁰C and 27.1 g of Nilotinib base was obtained with 76% yield. (97.2% assay, 99.17% purity).

Example 12: Preparation of Nilotinib:

[00261] To IL glass reactor was added the compound of formula 4-methyl-3-{[4-

(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid of formula X (80.0 g, 0.26 mol), and N- Methyl-pyrrolidone (400 mL). The mixture was heated to 60⁰C, then SOCl₂ (24 mL, 0.33 mol) was added during 15 minutes. The resulted mixture was stirred at 60⁰C for 1 h. A compound of formula I (69.2 g, 0.29 mol) was added and the reaction mixture was stirred and heated to 90⁰C for 3 h. Water (500 mL) was added and the solution was heated to 80⁰C. NaOH 47% solution (65 mL) was added until pH 11-12. Then, the suspension was cooled to 40⁰C and stirred at this temperature for 2 hours, filtered under reduced pressure at 40⁰C, and washed with 500 mL H₂O to yield a beige solid. This material was slurried in water (1 L) at 40⁰C for 1 h, filtered, washed with water (500 mL), and dried under vacuum at 50⁰C to obtain 135.25 g of Nilotinib base with 94% yield. (95.8% assay, 99.46% purity).

Example 13: Preparation of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride, dihydrochloride of the formula (X-C1)*2HC1:

[00262] Thionyl chloride (1400ML) was added to 3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylbenzoic acid of formula X (39 gms). This mixture was heated to 60-70⁰C and stirred for 10-12 hours. The reaction mixture was then cooled to 30-27⁰C. The obtained slurry was filtered and the solid was washed with dichloromethane. The wet product was dried at 55-60⁰C under reduced pressure.

Dry wt: 140gm

Yield: 95.4

Purity: above 98% by HPLC

Hydrochloride content (by Argentometry titration): 27.48%

Example 14: Preparation of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride, dihydrochloride of the formula (X-ClWHCl:

[00263] Thionyl chloride (1000ML) was added to 3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylbenzoic acid of formula X (100 gms). This mixture was heated to 60-70⁰C and stirred for 5-6 hours. The reaction mixture was then cooled to 30-35⁰C. Dichloromethane

(1000ML) was then added to the recation mixture and stirred for 10-15 minutes. The obtained slurry was filtered and the solid was washed with dichloromethane. The wet product was dried at 55-60⁰C under reduced pressure.

Dry wt: 100-106gm

Purity: above 98% by HPLC

Example 15: Preparation of Nilotinib*3HCl (crude):

[00264] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride dihydrochloride of formula (X-C1)-2HC1 (105 gms) was added to dichloromethane (1000ml) and 3-(trifluoromethyl)-5-(4-methyl-lH-imidazol-l-yl)benzenamine of formula I (71 gms) at

25-40⁰C. The temperature was raised to reflux point and was stirred at this temperature for

10-12 Hours. The reaction mixture was then cooled to 30-20⁰C. The obtained slurry was filtered and the solid was washed with dichloromethane (200ml). The wet product was dried at 40-60 ⁰C under reduced pressure.

[00265] The X-ray powder diffraction of the obtained product is shown in Figure 3.

The X-ray powder diffraction of the obtained product after exposure to 100% humidity for

96% is shown in Figure 4.

Yield: 90-92%

Purity: 85-90%

Hydrochloride content (by Argentometry titration): 16.8%.

Example 16: Preparation of Nilotinib^«3HCl: [00266] Methanol (50ml) was cooled to 0-5⁰C and acetyl chloride (2.29gm) was slowly added to it. To this mixture, 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3- (trifluoromethyl)-5-(4-methyl-lH-imidazol-l-yl)phenyl)-4-methyl benzamide (Nilotinib free base) (5.00 gms) was added slowly and mixture was stirred for 2 hours. Acetone (50ml) was then added and mixture was stirred for 60 minutes. Reaction mass was filtered and washed with acetone (10ml). The obtained product was dried at 55-60⁰C. Dry wt: 4.5gm Yield: 75% Purity: 95-98%

Example 17: Purification of Nilotinib^«3HCl (Pure):

[00267] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide tri hydrochloride (5gm) and water (25ml) were added and the mass was heated to 60-70⁰C. The mass was charcoalized (0.5gm carbon) and filtered through celite bed. Methanol (50ml) was added to the filtrate. The mixture was heated to 50-60⁰C and acetone (100ml) was added. It was then cooled to 30-27⁰C and stirred for 2hours. The obtained product was filtered and dried at 50-55⁰C for 12 hours under vacuum. The X-ray powder diffraction of the obtained product is shown in Figure 5. Dry wt 3.5gm Yield 0.7w/w Purity: 95-98%

Example 18: Preparation of Nilotinib:

[00268] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide tri hydrochloride (185gms) was dissolved in 825ml water and heated to 45-55°C. A methanolic solution of sodium hydroxide (35.9gm Sodium hydroxide dissolve in 1800 ml methanol) was added to the reaction mixture over a period of 1-2 hours. The suspension was heated to 65-70⁰C for 5-6 hours and the slurry was cooled to 35-30⁰C. The solid was filtered and washed with equal amount of water: methanol mixture 200ml. The wet product was dried at 45-55°C under reduced pressure. Yield: 90% Purity: 99.5% Example 19: Purification of Nilotinib:

[00269] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide (140gm) was taken into methanol (1.41it) and sodium hydroxide (14gm). The mixture was heated to reflux and stirred for 3-4 hours. The mixture was the cooled to 40-35⁰C and filtered. The product was washed with methanol (2X50ml) and dried at 50-60⁰C for 12 hours under vacuum. Dry wt. 120gm Yield: 0.85w/w

PAPER

https://pubs.rsc.org/en/content/articlelanding/2013/ob/c2ob27003j/unauth#!divAbstract

Graphical abstract: The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib

Image result for nilotinib synthesis

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 25 January 2014.
^ Official Manufacturer Website http://www.tasigna.com
^ “Cancer Drug Information: Nilotinib”.
^ Jump up to:^a ^b Manley, P.; Cowan-Jacob, S.; Mestan, J. (2005). “Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia”. Biochimica et Biophysica Acta. 1754 (1–2): 3–13. doi:10.1016/j.bbapap.2005.07.040. PMID 16172030.
^ Jump up to:^a ^b Manley, P.; Stiefl, N.; Cowan-Jacob, S.; Kaufman, S.; Mestan, J.; Wartmann, M.; Wiesmann, M.; Woodman, R.; Gallagher, N. (2010). “Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib”. Bioorganic & Medicinal Chemistry. 18 (19): 6977–6986. doi:10.1016/j.bmc.2010.08.026. PMID 20817538.
^ Jump up to:^a ^b ^c Jabbour, E.; Cortes, J.; Kantarjian, H. (2009). “Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review”. Core Evidence. 4: 207–213. doi:10.2147/CE.S6003. PMC 2899790.
^ Jump up to:^a ^b Olivieri, A.; Manzione, L. (2007). “Dasatinib: a new step in molecular target therapy”. Annals of Oncology. 18 Suppl 6: vi42–vi46. doi:10.1093/annonc/mdm223. PMID 17591830.
^ Breccia, M.; Alimena, G. (2010). “Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia”. Leukemia Research. 34 (2): 129–134. doi:10.1016/j.leukres.2009.08.031. PMID 19783301.
^ https://www.cancer.gov/about-cancer/treatment/drugs/fda-nilotinib
^ Jump up to:^a ^b “Complete Nilotinib information from Drugs.com”. Drugs.com. Retrieved 25 January2014.
^ “Tasigna : EPAR – Product Information” (PDF). European Medicines Agency. Novartis Europharm Ltd. 18 October 2013. Retrieved 25 January 2014.
^ “Tasigna 150mg Hard Capsules – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. Novartis Pharmaceuticals UK Ltd. 9 September 2013. Retrieved 25 January 2014.
^ Jump up to:^a ^b “TASIGNA® nilotinib” (PDF). TGA eBusiness Services. 21 October 2013. Retrieved 25 January 2014.
^ “FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia”. U.S. Food and Drug Administration. 2007-10-30. Retrieved 2009-08-04.
^ “Prescribing information for Tasigna (nilotinib) Capsules” (PDF). NDA 022068. U.S. FDA. 2007-10-29. Retrieved 2009-08-04.
^ Kantarjian H; Giles, Francis; Wunderle, Lydia; Bhalla, Kapil; O’Brien, Susan; Wassmann, Barbara; Tanaka, Chiaki; Manley, Paul; Rae, Patricia; Mietlowski, William; Bochinski, Kathy; Hochhaus, Andreas; Griffin, James D.; Hoelzer, Dieter; Albitar, Maher; Dugan, Margaret; Cortes, Jorge; Alland, Leila; Ottmann, Oliver G.; et al. (2006). “Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL”. N Engl J Med. 354 (24): 2542–51. doi:10.1056/NEJMoa055104. PMID 16775235.
^ “Patients with treatment-resistant leukemia achieve high responses to Tasigna (nilotinib) in first published clinical trial results”. MediaReleases. Novartis. 2006-06-14. Retrieved 2009-08-04.
^ Jump up to:^a ^b Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors”. Drug Metabol Drug Interact. 29 (3): 179–90. doi:10.1515/dmdi-2013-0062. PMC 4407685. PMID 24643910.
^ Donatelli, Christopher; Chongnarungsin, Daych; Ashton, Rendell (2014). “Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage”. Leukemia & Lymphoma. 55 (10): 1–6. doi:10.3109/10428194.2014.887714. PMID 24467220.
^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors”. Drug Metabol Drug Interact. 29 (4): 249–59. doi:10.1515/dmdi-2014-0014. PMC 4407688. PMID 24807167.
^ Bailey, David G; Malcolm, J; Arnold, O; David Spence, J (1998-08-01). “Grapefruit juice–drug interactions”. British Journal of Clinical Pharmacology. 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. ISSN 0306-5251. PMC 1873672. PMID 9723817.
^ Komoroski, Bernard J.; Zhang, Shimin; Cai, Hongbo; Hutzler, J. Matthew; Frye, Reginald; Tracy, Timothy S.; Strom, Stephen C.; Lehmann, Thomas; Ang, Catharina Y. W. (2004-05-01). “Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures”. Drug Metabolism and Disposition. 32 (5): 512–518. doi:10.1124/dmd.32.5.512. ISSN 0090-9556. PMID 15100173.
^ Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (June 2006). “AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL”. Br. J. Cancer. 94 (12): 1765–9. doi:10.1038/sj.bjc.6603170. PMC 2361347. PMID 16721371.
^ Manley, PW; Drueckes, P; Fendrich, G; Furet, P; Liebetanz, J; Martiny-Baron, G; Mestan, J; Trappe, J; et al. (2010). “Extended kinase profile and properties of the protein kinase inhibitor nilotinib”. Biochimica et Biophysica Acta. 1804 (3): 445–53. doi:10.1016/j.bbapap.2009.11.008. PMID 19922818.
^ Pagan, F.; Hebron, M.; Valadez, E. H.; Torres-Yaghi, Y.; Huang, X.; Mills, R. R.; Wilmarth, B. M.; Howard, H.; Dunn, C.; Carlson, A.; Lawler, A.; Rogers, S. L.; Falconer, R. A.; Ahn, J.; Li, Z.; Moussa, C. (2016). “Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies”. Journal of Parkinson’s Disease. 6 (3): 503–17. doi:10.3233/JPD-160867. PMC 5008228. PMID 27434297.
^ Dash, Deepa (2019). “Anticancer Drugs for Parkinson’s Disease: Is It a Ray of Hope or Only Hype?”. Annals of Indian Academy of Neurology. 22 (1): 13–16. doi:10.4103/aian.AIAN_177_18. PMC 6327695. PMID 30692753.
^ Robledo, I.; Jankovic, J. (2017). “Media hype: Patient and scientific perspectives on misleading medical news”. Movement Disorders. 32 (9): 1319–1323. doi:10.1002/mds.26993. PMID 28370445.
^ Wyse, R. K.; Brundin, P.; Sherer, T. B. (2016). “Nilotinib – Differentiating the Hope from the Hype”. Journal of Parkinson’s Disease. 6 (3): 519–22. doi:10.3233/JPD-160904. PMC 5044778. PMID 27434298.
^ “Global Novartis News Archive”.
^ “Cancer drug prevents build-up of toxic brain protein”. MedicalXpress.com. 10 May 2013. Retrieved 11 April 2017.

External links

Discovery and development of Bcr-Abl tyrosine kinase inhibitors
New drug information/Abbreviated Scientific Narrative
Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
Summary of Product Characteristics Nilotinib (November 2007) Novartis AG (Europe)

Nilotinib
Clinical data


Trade names	Tasigna
AHFS/Drugs.com	Monograph
MedlinePlus	a608002
License data	EU EMA: by INN US FDA: Nilotinib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
ATC code	L01XE08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	30%^[1]
Protein binding	98%^[1]
Metabolism	Hepatic (mostly CYP3A4-mediated)^[1]
Elimination half-life	15-17 hours^[1]
Excretion	Faeces (93%)^[1]
Identifiers
IUPAC name [show]
CAS Number	641571-10-0 (base)
PubChem CID	644241
IUPHAR/BPS	5697
DrugBank	DB04868
ChemSpider	559260
UNII	F41401512X
KEGG	D08953
ChEBI	CHEBI:52172
ChEMBL	ChEMBL255863
PDB ligand	NIL (PDBe, RCSB PDB)
CompTox Dashboard(EPA)	DTXSID5042663
ECHA InfoCard	100.166.395
Chemical and physical data
Formula	C₂₈H₂₂F₃N₇O
Molar mass	529.5245 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F
InChI [hide] InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37) Key:HHZIURLSWUIHRB-UHFFFAOYSA-N

Nilotinib

- Synonyms:AMN-107
- ATC:L01XE08
Use:antineoplastic, kinase inhibitor
Chemical name:4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide
Formula:C₂₈H₂₂F₃N₇O

MW:529.53 g/mol
CAS-RN:641571-10-0
InChI Key:HHZIURLSWUIHRB-UHFFFAOYSA-N
InChI:InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)

Derivatives

Hydrochloride monohydrate

Formula:C₂₈H₂₂F₃N₇O • HCl • H₂O
MW:586.01 g/mol
CAS-RN:923288-90-8

Synthesis

Trade Names

Country	Trade Name	Vendor
D	Tasigna	Novartis ,2008
F	Tasigna	Novartis
GB	Tasigna	Novartis
I	Tasigna	Novartis
USA	Tasigna	Novartis ,2007
J	Tasigna	Novartis ,2010

Formulations

cps. 150 and 200 mg as hydrochloride monohydrate

References

- a WO 2004 005281 (Novartis; 15.1.2004; GB-prior. 5.7.2002).
- US 7 169 791 (Novartis; 30.1.2007; appl. 4.7.2003; GB-prior. 5.7.2002).
- US 7 569 566 (Novartis; 4.8.2009; GB-prior. 5.7.2002, 20.12.2002).
- WO 2006 135641 (Novartis; 21.12.2006; USA-prior. 4.8.2005).
- US 7 956 053 (Novartis; 7.6.2011; appl. 22.6.2009; GB-prior. 5.7.2002).

Preparation of III:
- b Huang, W.-S., Shakesperare, W.C., Synthesis (SYNTBF) (2007) 14, 2121.
- c WO 2010 060074 (Teva Pharms.; 27.5.2010; appl. 24.11.2009; USA-prior. 24.11.2008).
- d Ueda, S. et al., J. Med. Chem. Soc., (2012) 134(1), 700-706.
- US 8 017 621 (Novartis; 13.9.2011; appl. 17.11.2007; USA-prior. 18.11.2003).
- WO 2006 135619 (Novartis; 21.12.2006; USA-prior. 6.9.2005).
- e EP 2 626 355 (Natco Pharma; 14.8.2013; appl. 9.2.2012).

Inhibitors of mutant form of KIT:
- US 8 017 621 (Novartis; 13.9.2011; appl. 17.11.2004; USA-prior. 18.11.2003).

Salts of Nilotinib:
- US 8 163 904 (Novartis; 24.4.2012; appl. 18.7.2006; USA-prior. 20.7.2005).
- US 8 389 537 (Novartis; 5.3.2013; appl. 13.3.2012; USA-prior. 20.7.2005).

Pharmaceutical compositions:
- US 8 293 756 (Novartis; 23.10.2012; appl. 25.9.2007; EP-prior. 27.9.2006).
- US 8 501 760 (Novartis; 6.8.2013; appl. 21.9.2012; EP-prior. 27.9.2006).

Crystalline forms:
- US 8 343 984 (Novartis; 1.1.2013; appl. 18.7.2006; USA-prior. 20.7.2005).
- US 8 415 363 (Novartis; 9.4.2013; appl. 3.8.2012; USA-prior. 20.7.2005).

//////////Nilotinib, AMN107, Tasigna, ニロチニブ,

LENALIDOMIDE, レナリドミド, леналидомид , ليناليدوميد , 来那度胺 ,

September 27, 2019 9:35 am / Leave a comment

Lenalidomide

ChemSpider 2D Image | Lenalidomide | C13H13N3O3

LENALIDOMIDE

Molecular FormulaC₁₃H₁₃N₃O₃
Average mass259.261 Da

レナリドミド;

леналидомид , ليناليدوميد , 来那度胺 ,

191732-72-6 [RN]

1-Oxo-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole

2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-

3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-piperidinedione

3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-2,6-dion

3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione

3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione

3-(7-amino-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione

8505

E3 Ligase ligand

IMiD3

CAS Registry Number: 191732-72-6

CAS Name: 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione

Additional Names: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

Manufacturers’ Codes: CC-5013

Trademarks: Revimid (Celgene); Revlimid (Celgene)

Molecular Formula: C13H13N3O3

Molecular Weight: 259.26

Percent Composition: C 60.22%, H 5.05%, N 16.21%, O 18.51%

Literature References: Immunomodulatory drug; analog of thalidomide, q.v. Prepn: G. W. Muller et al., US 5635517 (1997 to Celgene); and in vitro TNF-a inhibition: eidem, Bioorg. Med. Chem. Lett. 9, 1625 (1999). LC-MS determn in plasma: T. M. Tohnya et al., J. Chromatogr. B 811, 135 (2004). Clinical evaluation in multiple myeloma: P. G. Richardson et al., Blood 100, 3063 (2002); in myelodysplastic syndromes: A. List et al., N. Engl. J. Med. 352, 549 (2005). Review of development, pharmacology and therapeutic potential: J. B. Bartlett et al., Nature Rev. 4, 314-322 (2004); C. S. Mitsiades, N. Mitsiades, Curr. Opin. Invest. Drugs 5, 635-647 (2004).

Therap-Cat: Immunomodulator.

Keywords: Immunomodulator.

191732-72-6
SYP-1512
LENALIDOMIDE [VANDF]
LENALIDOMIDE [WHO-DD]
LENALIDOMIDE [EMA EPAR]
LENALIDOMIDE [MI]
LENALIDOMIDE [MART.]
LENALIDOMIDE [ORANGE BOOK]
LENALIDOMIDE [USAN]
LENALIDOMIDE [INN]
CDC-501
REVLIMID
LENALIDOMIDE
3-(4-AMINO-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PIPERIDINE-2,6-DIONE
2,6-PIPERIDINEDIONE, 3-(4-AMINO-1,3-DIHYDRO-1-OXO-2H-ISOINDOL-2-YL)-
CC-5013

Lenalidomide (trade name Revlimid) is a derivative of thalidomide approved in the United States in 2005.^[1]

It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Along with several other drugs developed in recent years, lenalidomide has significantly improved overall survival in myeloma (which formerly carried a poor prognosis), although toxicity remains an issue for users.^[2] It costs $163,381 per year for the average patient.^[3]

It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[4]

Medical uses

Multiple myeloma

Multiple myeloma is a cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow.^[5] Lenalidomide is one of the novel drug agents used to treat multiple myeloma. It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis.^[6]^[7]^[8]

Compared to placebo, lenalidomide is effective at inducing a complete or “very good partial” response as well as improving progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma were neutropenia (a decrease in the white blood cell count), deep vein thrombosis, infections, and an increased risk of other hematological malignancies.^[9] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.^[10] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.^[6]

On 29 June 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.^[11] On 22 February 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for patients with multiple myeloma following autologous stem cell transplant.^[12]

On 23 April 2009, The National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination (FAD) approving lenalidomide, in combination with dexamethasone, as an option to treat patients with multiple myeloma who have received two or more prior therapies in England and Wales.^[13]

On 5 June 2013, the FDA designated lenalidomide as a specialty drug requiring a specialty pharmacy distribution for “use in mantle cell lymphoma (MCL) in patients whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.” Revlimid is only available through a specialty pharmacy, “a restricted distribution program in conjunction with a risk evaluation and mitigation strategy (REMS) due to potential for embryo-fetal risk.”^[14]

Myelodysplastic syndromes

With myelodysplastic syndromes (MDS), the best results of lenalidomide were obtained in patients with the Chromosome 5q deletion syndrome (5q- syndrome).^[15] The syndrome results from deletions in human chromosome 5 that remove three adjacent genes, granulocyte-macrophage colony-stimulating factor, Platelet-derived growth factor receptor B, and Colony stimulating factor 1 receptor.^[16]^[17]

It was approved by the FDA on 27 December 2005, for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. A completed Phase II, multi-centre, single-arm, open-label study evaluated the efficacy and safety of Revlimid monotherapy treatment for achieving haematopoietic improvement in red blood cell (RBC) transfusion dependent subjects with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.

63.8% of subjects had achieved RBC-transfusion independence accompanied by a median increase of 5.8 g/dL in blood Hgb concentration from baseline to the maximum value during the response period. Major cytogenetic responses were observed in 44.2% and minor cytogenetic responses were observed in 24.2% of the evaluable subjects. Improvements in bone marrow morphology were also observed. The results of this study demonstrate the efficacy of Revlimid for the treatment of subjects with Low- or Intermediate-1-risk MDS and an associated del 5 cytogenetic abnormality.^[15]^[18]^[19]

Lenalidomide was approved on 17 June 2013 by the European Medicines Agency for use in low- or intermediate-1-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q cytogenetic abnormality and no other cytogenetic abnormalities, are dependent on red blood cell transfusions, and for whom other treatment options have been found to be insufficient or inadequate.^[20]

Mantle cell lymphoma

Lenalidomide is approved by FDA for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies.^[1] One of these previous therapies must have included bortezomib.

Other cancers

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin’s lymphoma,^[21] as well as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.^[22] One Phase 3 clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.^[23]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide also carries Black Box Warnings for hematologic toxicity (including significant neutropenia and thrombocytopenia) and venous/arterial thromboembolisms.^[1]

Serious potential side effects are thrombosis, pulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is contrary to experience with thalidomide.^[24] Lenalidomide may also be associated with adverse effects including second primary malignancy, severe cutaneous reactions, hypersensitivity reactions, tumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism. ^[1]

Teratogenicity

Lenalidomide is related to thalidomide which is known to be teratogenic. Tests in monkeys have suggested lenalidomide is also teratogenic.^[25] It therefore has the pregnancy category X and cannot be prescribed for women who are pregnant or who may become pregnant during therapy. For this reason, the drug is only available in the United States(under the brand name Revlimid) through a restricted distribution system called RevAssist. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.^[1]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. Bennett et al. have reviewed incidents of lenalidomide-associated VTE among patients with multiple myeloma.^[26] They have found that there are high rates of VTE when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin. When lenalidomide and dexamethasone are used to treat multiple myeloma, a median of 14% of patients had VTE (range,3-75%). In patients who took prophylaxis to treat lenalidomide-associated VTE, such as aspirin, thromboembolism rates were found to be lower than without prophylaxis, frequently lower than 10%. Clearly, thromboembolism is a serious adverse drug reaction associated with lenalidomide, as well as thalidomide. In fact, a black box warning is included in the package insert for lenalidomide, indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism.

Currently,^[when?] clinical trials are under way to further test the efficacy of lenalidomide to treat multiple myeloma, and to determine how to prevent lenalidomide-associated venous thromboembolism.^{[citation needed]}

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. The drug is being investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening condition affecting the skin.^[27]

FDA ongoing safety review

As of 2011, the FDA has initiated an ongoing review which will focus on clinical trials which found an increased risk of developing cancers such as acute myelogenous leukemia (AML) and B-cell lymphoma,^[3] though the FDA is currently advising all people to continue their treatment.^[28]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.^[when?] There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.^[29] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulation. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon^[30] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.^[31] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.

Research

The low level of research that continued on thalidomide, in spite of its scandalous history of teratogenicity, unexpectedly showed that the compound affected immune function. The drug was, for example, recently approved by the FDA for treatment of complications from leprosy; it has also been investigated as an adjunct for treating some malignancies. Recent research on related compounds has revealed a series of molecules which inhibit tumor necrosis factor (TNF-α).^{[citation needed]}

Price

Lenalidomide costs $163,381 per year for the average person in the United States.^[3] Lenalidomide made almost $9.7bn for Celgene in 2018.^[32]

In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for “use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)” in England and Scotland, arguing that Celgene “did not provide enough evidence to justify the £3,780 per month (USD$5746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)”.^[33]

SYN

https://link.springer.com/article/10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

SYN

EP 0925294; US 5635517; WO 9803502

Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).

SYN

Bioorg Med Chem Lett 1999,9(11),1625

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.

Lenalidomide

- Synonyms:CC-5013, CDC 501
- ATC:L04AX04
Use:myelodysplastic syndrome (MDS)
Chemical name:3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione
Formula:C₁₃H₁₃N₃O₃

MW:259.27 g/mol
CAS-RN:191732-72-6
InChI Key:GOTYRUGSSMKFNF-JTQLQIEISA-N
InChI:InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)/t10-/m0/s1

Synthesis

Trade Names

Country	Trade Name	Vendor
D	Revlimid	Celgene
GB	Revlimid	Celgene
USA	Revlimid	Celgene ,2005

Formulations

cps. 5 mg, 10 mg

References

- WO 9 803 502 (Celgene; 29.1.1998; USA-prior. 24.7.1996).
- WO 2 006 028 964 (Celgene; 16.3.2006; USA-prior. 3.9.2004).
- US 5 635 517 (Celgene; 3.6.1997; USA-prior. 24.7.1996).

medical use for treatment of certain leukemias:
- US 2 006 030 594 (Celgene; 9.2.2006; USA-prior. 4.10.2005).

alternative preparation of III:
- WO 2 005 005 409 (Siegfried Ltd.; 20.1.2005; CH-prior. 9.7.2003).

References

^ Jump up to:^a ^b ^c ^d ^e REVLIMID [package insert]. Summit, NJ: Celgene Corporation; 2017. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s055lbl.pdf on 14 September 2018.
^ McCarthy PL, Owzar K, Hofmeister CC, et al. (2012). “Lenalidomide after stem-cell transplantation for multiple myeloma”. N. Engl. J. Med. 366 (19): 1770–81. doi:10.1056/NEJMoa1114083. PMC 3744390. PMID 22571201.
^ Jump up to:^a ^b ^c Badros AZ (10 May 2012). “Lenalidomide in Myeloma — A High-Maintenance Friend”. N Engl J Med. 366 (19): 1836–1838. doi:10.1056/NEJMe1202819. PMID 22571206.
^ “World Health Organization model list of essential medicines: 21st list 2019”. 2019. hdl:10665/325771.
^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”. Journal of Clinical Pharmacy and Therapeutics. 33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.x. PMID 18452408.
^ Jump up to:^a ^b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Curr Opin Oncol. 22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752c. PMID 20689431.
^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents Med. Chem. 11 (3): 315–26. doi:10.2174/187152011795347487. PMID 21426296.
^ Kotla V, Goel S, Nischal S, et al. (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”. J Hematol Oncol. 2: 36. doi:10.1186/1756-8722-2-36. PMC 2736171. PMID 19674465.
^ Yang B, Yu RL, Chi XH, et al. (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”. PLoS ONE. 8 (5): e64354. doi:10.1371/journal.pone.0064354. PMC 3653900. PMID 23691202.
^ Dimopoulos MA, Richardson PG, Brandenburg N, et al. (22 March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”. Blood. 119 (12): 2764–7. doi:10.1182/blood-2011-08-373514. PMID 22323483.
^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”. Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.
^ “Approved Drugs – Lenalidomide (Revlimid)”. Food and Drug Administration (FDA).
^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”. Reuters. 23 April 2009.
^ Ness, Stacey (13 March 2014). “New Specialty Drugs”. Pharmacy Times. Retrieved 5 November 2015.
^ Jump up to:^a ^b List A, Kurtin S, Roe DJ, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine. 352 (6): 549–57. doi:10.1056/NEJMoa041668. PMID 15703420.
^ “PDGFRB platelet derived growth factor receptor beta [Homo sapiens (human)] – Gene – NCBI”.
^ Nimer SD (2006). “Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q”. Journal of Clinical Oncology. 24 (16): 2576–82. doi:10.1200/JCO.2005.03.6715. PMID 16735711.
^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology. 32 (4 Suppl 5): S31–5. doi:10.1053/j.seminoncol.2005.06.020. PMID 16085015.
^ List A, Dewald G, Bennett J, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine. 355 (14): 1456–65. doi:10.1056/NEJMoa061292. PMID 17021321.
^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
^ “Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin’s Lymphoma”. ClinicalTrials.gov. US National Institutes of Health. February 2009.
^ “276 current clinical trials world-wide, both recruiting and fully enrolled, as of 27 February 2009”. ClinicalTrials.gov. US National Institutes of Health. February 2009.
^ “Celgene Discontinues Phase 3 Revlimid Study after ‘Imbalance’ of Deaths”. Nasdaq. 18 July 2013.
^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy. 64 (17): 1799–807. doi:10.2146/ajhp070029. PMID 17724360.
^ “Revlimid Summary of Product Characteristics. Annex I” (PDF). European Medicines Agency. 2012. p. 6.
^ Bennett CL, Angelotta C, Yarnold PR, et al. (December 2006). “Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer”. JAMA: The Journal of the American Medical Association. 296 (21): 2558–60. doi:10.1001/jama.296.21.2558-c. PMID 17148721.
^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”. Food and Drug Administration (FDA). March 2008.
^ “FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies”. Food and Drug Administration(FDA). April 2011.
^ Vallet S, Palumbo A, Raje N, et al. (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma. 49 (7): 1238–45. doi:10.1080/10428190802005191. PMID 18452080.
^ Zhu YX, Braggio E, Shi CX, et al. (2011). “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide”. Blood. 118 (18): 4771–9. doi:10.1182/blood-2011-05-356063. PMC 3208291. PMID 21860026.
^ Stewart AK (2014). “Medicine. How thalidomide works against cancer”. Science. 343(6168): 256–7. doi:10.1126/science.1249543. PMC 4084783. PMID 24436409.
^ “Top 10 Best-Selling Cancer Drugs of 2018”. Genetic Engineering and Biotechnology News. 22 April 2019. Retrieved 25 April 2019.
^ “Revlimid faces NICE rejection for use in rare blood cancer Watchdog’s draft guidance does not recommend Celgene’s drug for NHS use in England and Wales”. Pharma News. 11 July 2013. Retrieved 5 November 2015.

External links

Official website Includes list of adverse reactions
Prescribing Information
International Myeloma Foundation article on Revlimid
multiplemyeloma.org Revlimid April 2007 Summary

Lenalidomide
Clinical data

Pronunciation	/ˌlɛnəˈlɪdoʊmaɪd/
Trade names	Revlimid
AHFS/Drugs.com	Monograph
MedlinePlus	a608001
License data	EU EMA: by INN
Pregnancy category	AU: X (High risk) US: X(Contraindicated)
Routes of administration	Oral (capsules)
ATC code	L04AX04 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Undetermined
Protein binding	30%
Metabolism	Undetermined
Elimination half-life	3 hours
Excretion	Renal (67% unchanged)
Identifiers
IUPAC name [show]
CAS Number	191732-72-6
PubChem CID	216326
IUPHAR/BPS	7331
DrugBank	DB00480
ChemSpider	187515
UNII	F0P408N6V4
KEGG	D04687
ChEMBL	ChEMBL848
CompTox Dashboard(EPA)	DTXSID8046664
ECHA InfoCard	100.218.924
Chemical and physical data
Formula	C₁₃H₁₃N₃O₃
Molar mass	259.261 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES [hide] O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
InChI [hide] InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18) Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N

//////////LENALIDOMIDE, レナリドミド ,REVLIMID, Celgene Corporation, леналидомид , ليناليدوميد , 来那度胺 ,

CANERTINIB

September 12, 2019 3:27 am / Leave a comment

Canertinib

ChemSpider 2D Image | Canertinib | C24H25ClFN5O3

CANERTINIB

Canertinib

CAS Registry Number: 267243-28-7

CAS Name: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-2-propenamide

Additional Names: N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]acrylamide

Molecular Formula: C24H25ClFN5O3

Molecular Weight: 485.94

Percent Composition: C 59.32%, H 5.19%, Cl 7.30%, F 3.91%, N 14.41%, O 9.88%

Literature References: Irreversible pan-erbB tyrosine kinase inhibitor. Prepn: A. J. Bridges et al., WO 0031048; eidem, US 6344455 (2000, 2002 both to Warner-Lambert); J. B. Smaill et al., J. Med. Chem. 43, 1380 (2000). Clinical pharmacokinetics in patients with solid malignancies: E. Calvo et al., Clin. Cancer Res. 10, 7112 (2004); and tolerability in refractory cancer: J. Nemunaitis et al., ibid. 11, 3846 (2005). Review of pharmacology and mechanism of action: L. F. Allen et al., Semin. Oncol. 30, Suppl. 16, 65-78 (2003); of development and clinical experience: C. M. Galmarini, IDrugs 7, 58-63 (2004).

Properties: Crystals from methanol, mp 188-190°.

Melting point: mp 188-190°

Canertinib dihydrochloride, CI-1033, PD-183805(free base)

Derivative Type: Dihydrochloride

CAS Registry Number: 289499-45-2

Manufacturers’ Codes: CI-1033

Molecular Formula: C24H25ClFN5O3.2HCl

Molecular Weight: 558.86

Percent Composition: C 51.58%, H 4.87%, Cl 19.03%, F 3.40%, N 12.53%, O 8.59%

Properties: Sol in water.

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Tyrosine Kinase Inhibitors.

267243-28-7 [RN]

2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]- [ACD/Index Name]

8256

C78W1K5ASF

Canertinib [INN] [Wiki]

N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl}acrylamide

Canertinib (CI-1033) is an experimental drug candidate for the treatment of cancer. It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC₅₀ 0.8 nM), HER-2 (IC₅₀ 19 nM) and ErbB-4 (IC₅₀ 7 nM).^[1]^[2] By 2015, Pfizer had discontinued development of the drug.^[3]

Canertinib has been reported as a substrate for OATP1B3. Interaction of canertinib with OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.^[4] Also, canertinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.^[5]

SYN

J Med Chem 2000,43(7),1380

EP 1131304; US 6344455; WO 0031048

4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.

PATENT

https://patents.google.com/patent/CN103242244A/en

canertinib (Canertinib, I), chemical name 4- (3-chloro-4-fluoroanilino) -7- [3- (4_-morpholinyl) propoxy] -6-propylene quinazoline amide group, and by the US Pfizer Warner Lambert developed jointly an irreversible epidermal growth factor receptor (pan-ErbB) selective inhibitor, which is capable of binding to the cell surface of all members of the ErbB family adenosine triphosphate binding site, thereby inhibiting the activation of these receptors and their downstream mitogenic signal transduction pathways. Clinical studies show that the product has good resistance, can be effective in treating metastatic breast cancer, ovarian cancer, cervical cancer and other tumors, and can be combined with a variety of antineoplastic agents exhibit a synergistic effect.

[0004]

[0005] China Patent No. CN1160338C, CN1438994A and No. No. CN1745073A reported the preparation of canertinib: A nucleus 4- [(3-chloro-4-fluorophenyl) amino] -6-nitro 7-fluoro-quinazoline (VIII) as a starting material, under basic conditions with 3- (4-morpholinyl) -1-propanol 7-position substitution reaction occurs to give 4- [(3-chloro – 4-fluorophenyl) amino] -6-nitro-7- [3- (4-morpholinyl) -1-propoxy] quinazoline (IX); intermediate (IX) through the 6-position nitro reduction, to give the corresponding amino compound (X); amino compound (X) to give canertinib acylation reaction (I) with acrylic acid or acryloyl chloride occurs.

[0006] In addition, “Qilu Pharmaceutical Affairs” 30, 2011, Vol. 10, page 559, and “China Industrial Medicine” 2010 Volume 41, No. 6, pp. 404 also reported an improved method of the above-prepared and studied method from 7-fluoro-quinazolin-3-one (V) via nitration, chloro and condensation reaction of the preparation of intermediate (VIII) is.

[0007]

[0008] This shows that the current Kanai prepared for Nepal is mainly the 4-position through an intermediate (VII), respectively, a functional transformation of the 6-position and 7-position achieved. Since the intermediate (VII) a fluorine-containing compounds, materials are not readily available, many steps, and many steps are required to be isolated and purified by column chromatography, which is not required for industrialization.

Example a:

[0023] at room temperature, to a three-necked flask was added diisopropyl azodicarboxylate (3mL, 15mmol) and tetrahydrofuran 5mL, dropwise addition of triphenylphosphine (4.0g, 15mmol) in tetrahydrofuran 25mL solution at room temperature, kept at room temperature for 2 hours. Under nitrogen, 3- (4-morpholinyl) -1_-propanol (0.49g, 3.4mmol) in 5mL of tetrahydrofuran was added dropwise to the reaction system after the dropwise addition is complete, 6-amino – 7-hydroxy-3,4-dihydro-quinazolin-4-one (II) (0.53g,

3.0mmol), stirred at room temperature for 4 hours. Solution of 3- (4-morpholinyl) -1-propanol (0.38g, 2.6mmol) in 5mL of tetrahydrofuran was continued at room temperature for 2 hours, the end of the reaction was monitored TLC. Recovery of the solvent by distillation under reduced pressure, the residue was treated with dilute hydrochloric acid, pH = 5-6, extracted with ethyl acetate, the organic phase was washed with saturated sodium carbonate adjusted pH = 10-11. The aqueous phase was freeze-dried in vacuo to give an off-white solid 6-amino-7- [3- (4-morpholinyl) propoxy] _3,4- dihydroquinazolin-4-one (111) 0.80g yield 87.7%.

[0024] Example II:

[0025] to a three-neck flask was added 6-amino-7- [3- (4_ morpholino) propoxy] quinazolin-dihydro _3,4_ one _4_

(III) (0.76g, 2.5mmol), triethylamine (0.25g, 2.5mmol) and dichloromethane 20mL, warmed to 40-45 ° C, stirred until homogeneous dissolution system. Dropped below 10 ° C, was slowly added dropwise acryloyl chloride (0.25g, 2.8mmol) in dichloromethane IOmL solution dropwise at room temperature after continued for 6 h, TLC detection reaction was completed. The reaction solution was respectively 10% sodium bicarbonate solution and water, dried over anhydrous sodium sulfate. Recovery of the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to give a white solid 7- [3- (4-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazoline – 4-one (IV) 0.81g, 90.5% yield.

[0026] Example III:

Under [0027] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-_3,4- dihydroquinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium iron hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL. Under stirring, a solution of 1,8-diazabicyclo [5.4.0] ^ a-7-ene (DBU) (2.28g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran IOOmL, 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g, 13mmol), was heated to 50 ° C, reaction was stirred for 5 hours, the end of the reaction was monitored TLC. Quenched with saturated brine the reaction, the organic phase was separated, dried, evaporated under reduced pressure to recover the solvent to give an off-white solid. Recrystallized from ethanol to give an off-white solid canertinib (I) 4.05g, yield 83.5%.

[0028] Example IV:

Under [0029] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium iron hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile lOOmL. Under stirring, dropwise power port I, 5- diazabicyclo [4.3.0] – non-5-ene (DBN) (1.86g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran IOOmL, 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g, 13mmol), was heated to 50 ° C, reaction was stirred for 5 hours, the end of the reaction was monitored TLC. Quenched with saturated brine the reaction, the organic phase was separated, dried, evaporated under reduced pressure to recover the solvent to give an off-white solid. Recrystallized from ethanol to give an off-white solid canertinib (I) 3.85g, yield 79.4%. ·

[0030] Example Five:

Under [0031] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate gun (BOP) (6.63g, 15mmol), 4_-chloro-3-fluoroaniline ( 1.89g, 13mmol) and N, N- dimethylformamide lOOmL. Under stirring, a solution of I, 8- diazabicyclo [5.4.0] – ^ a _7_ ene (DBU) (2.28g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to give an off-white solid canertinib (1) 2.32g, yield 47.8%.

Figure CN103242244AD00043

References

GW; Loo, JA; Greis, KD; Chan, OH; Reyner, EL; Lipka, E; Showalter, HD; et al. (2000). “Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido3,2-dpyrimidine-6-acrylamides bearing additional solubilizing functions”. Journal of Medicinal Chemistry. 43 (7): 1380–97. doi:10.1021/jm990482t. PMID 10753475.

^ CI-1033 (Canertinib), Selleck Chemicals
^ http://adisinsight.springer.com/drugs/800012072
^ Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors”. Drug Metabol Drug Interact. 29 (3): 1–11. doi:10.1515/dmdi-2013-0062. PMC 4407685. PMID 24643910.
^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors”. Drug Metabol Drug Interact. 29 (4): 1–11. doi:10.1515/dmdi-2014-0014. PMC 4407688. PMID 24807167.

Canertinib
Names

IUPAC name N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide
Other names CI-1033; PD-183805
Identifiers
CAS Number	267243-28-7
3D model (JSmol)	Interactive image
ChEBI	CHEBI:61399
ChEMBL	ChEMBL31965 ChEMBL545315
ChemSpider	137741
IUPHAR/BPS	5675
PubChem CID	156414
UNII	C78W1K5ASF
CompTox Dashboard (EPA)	DTXSID8048943
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₄H₂₅ClFN₅O₃
Molar mass	485.94 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////CANERTINIB

C=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4

DICYCLOPLATIN

September 5, 2019 10:10 am / Leave a comment

ChemSpider 2D Image | Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2) | C12H20N2O8Pt

Dicycloplatin

Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2)

Molecular FormulaC₁₂H₂₀N₂O₈Pt
Average mass515.380 Da
287402-09-9

Has antineoplastic activity; a supramolecular complex of 1,1-cyclobutane dicarboxylic acid and cis-diammine(1,1-cyclobutane dicarboxylate)platinum (II).

1,1-Cyclobutanedicarboxylic acid, ammonium platinum(2+) salt (2:2:1) [ACD/Index Name]

Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2)

287402-09-9 [RN]

DICYCLOPLATIN

UNII:0KC57I4UNB

Dicycloplatin is a chemotherapy medication used to treat a number of cancers which includes the Non-small-cell lung carcinoma and prostate cancer.^[1]

Some side effects which are observed from the treatment by dicycloplatin are nausea, vomiting, thrombocytopenia, neutropenia, anemia, fatigue, loss of appetite, liver enzyme elevation and alopecia. The drugs is a form of Platinum-based antineoplastic and it works by causing the mitochondrial dysfunction which leads to the cell death.^[2]

Dicycloplatin was developed in China and it was used for phase I human trial clinical in 2006. The drug was approved for chemotherapy by the Chinese FDA in 2012.^[3]

Image result for DICYCLOPLATIN SYNTHESIS

Medical uses

Dicycloplatin can inhibit the proliferation of tumor cells via the induction of apoptosis . It is used to treat a number types of cancer which are Non-small-cell lung carcinoma and prostate cancer.^[4]

Side effects

Similar to cisplatin and carboplatin, dicycloplatin also contains some side effects, which are nausea, vomiting, thrombocytopenia, neutropenia, anemia, fatigue, anorexia, liver enzyme elevation, and alopecia. However, with doses up to 350 mg/m(2), there is no significant toxicity; these effects are observed only at higher doses. Furthermore, the nephrotoxicity of dicycloplatin is reported to be less than that of cisplatin, and its myelosuppressive potency is similar to that of carboplatin.^[5]

Chemical structure

Dicycloplatin consists of carboplatin and cyclobutane-1,1-dicarboxylic acid (CBDC) linked by the hydrogen bond. In the structure of dicycloplatin, there are two types of bond: O-H…O is the bond between the hydroxyl group of CBDC with carboxyl oxygen atom. It creates the one-dimensional polymer chain of carboplatin and CBDC. The second one is N-H…O which links between the ammoniagroup of carboplatin and oxygen of CBDC. It forms the two-dimensional polymer chain of carboplatin and CBDC. In aqueous solution, the 2D-hydrogen bonded polymeric structure of dicycloplatin is destroyed. Firstly, the bond between ammonia group of carboplatin and oxygen of CBDC breaks, thus inducing the formation of one-dimensional dicycloplatin. After that, the strong hydrogen bond breaks and creates an intermediate state of dicycloplatin. Finally, the rearrangement of different orientation of carboplatin and CBDC leads to the formation of intramolecular hydrogen bond and a supramolecule of dicycloplatin with two O-H…O and N-H…O is created.^[6]

Mechanism of action

Similar to carboplatin, dicycloplatin inhibits the proliferation of cancer cells by inducing cell apoptosis. When treated with dicycloplatin, some changes in the properties of Hep G2 cells are observed: the declination of Mitochondria Membrane Potential, the release of cytochrome c from mitocondria to cytosol, the activation of caspase-9, caspase-3 and the decrease of Bcl-2.^[4] Those phenomena indicate the role of mitochondrial in the apoptosis by intrisic way.^[7] Furthermore, the increase in caspase-8 activation is also observed. This can stimulate the apoptosis by activating downstream caspase-3 ^[8] or by cleaving Bid.^[9] As a result, the cleavage of Bid (tBid) transfers to the mitochondria and induce mitochondrial dysfunction which promotes the release of cytochrome c from mitochondria to cytosol.^[10] From the dicycloplatin-treated Hep G2 cell, an excessive amount of reactive oxygen species was detected,^[4] which plays an important role in the release of cytochrome c. In the mitochondria, the release of hemoprotein happens through 2-step process: Firstly, the dissociation of cytochrome c from its binding to cardiolipin happens. Due to the reactive oxygen species, the cardiolipin is oxidized, thus reducing the cytochrome c binding and increase the concentration of free cytochrome c ^[11]

PATENT

WO2018171371

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018171371

Since the FDA approved cisplatin as an anticancer drug in 1978, the mortality rate of testicular cancer patients has been reduced from 100% to less than 10%. For patients with early detection, the cure rate can reach 100%, making cisplatin An outstanding representative of anticancer drugs. In 1986, the FDA approved the second-generation platinum anticancer drug carboplatin. Its anticancer spectrum is similar to that of cisplatin, but it has good water solubility and light toxicity. In 2002, the FDA approved the third-generation platinum anticancer drug oxaliplatin to enter clinical treatment of colorectal cancer. Its anticancer spectrum is different from cisplatin, and it does not produce cross-resistance with cisplatin.

In addition to the above three products, four products, including Nida Platinum, Shuplatin, Lobaplatin and Miplatin, have been listed in different countries and are the first in other countries.

In CN1311183A, Yang Xuqing et al. designed and prepared a new class of platinum antitumor drugs, diammonium platinum dichloride (II) derivatives, based on the abnormal changes in the spatial configuration of cancer cells DNA and RNA. A typical representative drug is bicycloplatinum. Bicycloplatinum in English is called Dicycloplatin, which is called bis(1,1-cyclobutanedicarboxylic acid) diammine platinum (II) (English name [Bis-(1,1-cyclobutane dicarboxylic acid)]diammine platinum(II) ), the structural formula is:

It is a supramolecular compound composed of carboplatin and 1,1-cyclobutanedicarboxylic acid through four hydrogen bonds. It is the first self-developed platinum antitumor drug in China with broad spectrum, low toxicity and high efficiency. It does not produce cross-resistance and good penetrability.

Bicycloplatinum is usually obtained by reacting carboplatin with 1,1-cyclobutanedicarboxylic acid. The prior art discloses various preparation methods, but both have the problems of complicated preparation process and low product purity.

CN1311183A As the earliest publication of bicycloplatin and its preparation method, it is disclosed that bicycloplatinum is prepared by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-cyclobutanedicarboxylic acid is added. After the reaction was completed, it was evaporated to dryness, washed with ethanol, and then recrystallized from distilled water. This method is cumbersome in operation due to the need for evaporation and recrystallization steps, and the yield of bicycloplatinum is low.

CN104693245A discloses a preparation method of bicyclo platinum, which is prepared by using carboplatin as a raw material in a ratio of 1:11 to 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1, and is protected from light at 0-60 ° C. After -9 days, the excess water is removed by concentration under reduced pressure or freeze-drying to obtain a bicyclic platinum product. Although according to reports, the HPLC purity of the product is more than 99%, it requires a long standing process, is inefficient, and greatly increases the risk of carboplatin decomposition, especially for the process of amplification; The heating and concentration in the final process makes the bicyclic platinum product exist in the higher temperature aqueous solution for a long time, and the product has a high risk of degradation, and the quality stability is inevitably affected. In fact, bicycloplatinum with the reported yield and purity was not obtained according to this method.

CN106132408A discloses a process for the preparation of another bicyclic platinum in which carboplatin is mixed with a corresponding ratio of 1,1-cyclobutanedicarboxylic acid and a solvent to form a suspension, and the precipitated solid formed is separated from the suspension. Although the report states that the obtained product does not contain XRPD detectable amount of carboplatin, the suspension method uses a small amount of solvent, so that the product formed during the reaction is also precipitated as a solid, which is mixed with the unreacted raw material solid. This prevents the reaction from proceeding and makes the purification of the product more difficult. Especially in the case where the product is coated with carboplatin, the carboplatin can hardly be removed by purification. Therefore, the suspension method has the disadvantages of difficulty in control, poor operability, and incapability of industrial scale-up production. In fact, bicycloplatinum with the reported yield and purity cannot be obtained according to this method as well.

1 is a nuclear magnetic resonance-hydrogen spectrum of the bicyclic platinum product of Example 1.

2 is a nuclear magnetic resonance-carbon spectrum of the bicyclic platinum product of Example 1.

Drawing

[ figure 1]

[ figure 2]

Preparation Example 1:

Take 20.0 g of cis-diiododiammine platinum (II), add 600 ml of purified water, stir well and heat to 80 ° C in water bath, then add 14.1 g of silver 1,1-cyclobutanedicarboxylate, after reacting for 30 minutes. The AgI slag was filtered off, and the filtrate was concentrated under reduced pressure to a residue of about 50 ml, cooled to room temperature, and the precipitated product was filtered. After recrystallization, the mixture was dried at 60 ° C to obtain 11.26 g of carboplatin, and the yield was 69.88%.

Example 1

32.0 g (222.2 mmol) of 1,1-cyclobutanedicarboxylic acid was taken, and 260 ml of water was added thereto, and the mixture was heated to 80 ° C in a water bath. Add 10.0 g (26.95 mmol) of carboplatin, stir for 40 minutes, cool at 10 ° C for 8 hours, filter the precipitated solid, wash the filter cake with appropriate amount of purified water, drain the washing water, and dry at 40 ° C under reduced pressure to obtain bicyclo platinum 9.32 g. The yield is 67.15% and the content is 99.78%. The obtained products were characterized by elemental analysis, negative ion electrospray mass spectrometry, nuclear magnetic resonance-hydrogen spectroscopy, nuclear magnetic resonance-carbon spectroscopy and X-ray diffraction. The content of bicycloplatin was measured by high performance liquid chromatography.

The test results are shown in Figure 1. The attribution of each peak is as follows:

The peak of chemical shift 1.7159-1.7793ppm is H _a , the actual number of hydrogen nuclei is 2, and it is divided into 5 heavy peaks by 4 H _b on both sides ; the peak of chemical shift 1.8281-1.8928ppm is H _c , actual hydrogen the number of cores 2, a total of four sides by H _D impact crack 5 doublet; 2.3965-2.4288ppm peak chemical shift of H _B , the actual number of hydrogen nuclei to 4, were subjected to unilateral 2 H _a of Effect split into three doublet; 2.7140-2.7457ppm peak chemical shift of H _D , the actual number of hydrogen nuclei is 4, were subjected to unilateral 2 H _Caffected divided into three split doublet; chemical shifts of the peaks 4.0497ppm is H _E , the actual number of hydrogen nuclei 6 as broad singlet; due to D ₂ exchange interaction of O, carboxy FIG active hydrogen protons H does not appear _f peaks. 4. Nuclear Magnetic Resonance – Carbon Spectrum (D ₂ O, 500MHz)

The test results are shown in Figure 2, where the peaks are as follows:

The peak of chemical shift 15.25ppm is C _a ; the peak of chemical shift 15.39ppm is C _h ; the peak of chemical shift 28.60ppm is C _b ; the peak of chemical shift 31.02ppm is C _g ; the peak of chemical shift 52.93ppm is C _c ; The peak of chemical shift 56.19 ppm is C _f ; the peak of chemical shift 176.11 ppm is C _d ; the peak of chemical shift 181.85 ppm is C _e .

PATENT

WO-2019161526

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019161526&tab=FULLTEXT&_cid=P20-K0667C-67730-1

One-pot method for preparing twin dicarboxylic acid diamine complex platinum (II) derivatives ( dicycloplatin ) comprising the separation of intermediate carboplatin or carboplatin analogue.

For the preparation of bicycloplatin, CN1311183A, as the earliest publication of bicycloplatin and its preparation method, discloses the preparation of bicycloplatinum by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-ring is added. Butane dicarboxylic acid was evaporated to dryness after completion of the reaction, washed with ethanol, and recrystallized from distilled water. The method needs to completely evaporate the solvent water, which increases the risk of degradation of the bicyclic platinum, and also introduces more impurities into the crude bicycloplatinum. Therefore, ethanol washing and recrystallization are required, and the operation is cumbersome, and the yield of the bicyclic platinum is low.

[0015]

CN104693245A discloses a preparation method of bicyclo platinum, which is prepared by using carboplatin as a raw material in a ratio of 1:11 to 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1, and is protected from light at 0-60 ° C. After -9 days, the excess water is removed by concentration under reduced pressure or freeze-drying to obtain a bicyclic platinum product. Although according to reports, the HPLC purity of the product is more than 99%, it requires a long standing process, is inefficient, and greatly increases the risk of carboplatin decomposition, especially for the process of amplification; In the final process, the solvent water is completely evaporated to make the bicyclic platinum product exist in a relatively high temperature aqueous solution for a long time, and the product has a high risk of degradation, and the quality stability is inevitably affected. In fact, bicycloplatinum with the reported yield and purity was not obtained according to this method.

[0016]

CN106132408A also discloses a process for the preparation of another bicyclic platinum in which carboplatin is mixed with a corresponding ratio of 1,1-cyclobutanedicarboxylic acid and a solvent to form a suspension, and the precipitated solid formed is separated from the suspension. Although the report states that the obtained product does not contain XRPD detectable amount of carboplatin, the suspension method uses a small amount of solvent, so that the product formed during the reaction is also precipitated as a solid, which is mixed with the unreacted raw material solid. This prevents the reaction from proceeding and makes the purification of the product more difficult. Especially in the case where the product is coated with carboplatin, the carboplatin can hardly be removed by purification. Therefore, the suspension method has the disadvantages of difficulty in control, poor operability, and incapability of industrial scale-up production. In fact, bicycloplatinum with the reported yield and purity cannot be obtained according to this method as well.

Notes

^ D., Zhao; Y., Zhang; C., Xu; C., Dong; H., Lin; L., Zhang; C., Li; S., Ren; X., Wang; S., Yang; D., Han; X., Chen (February 2012). “Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding Study of Platinum Originating from Dicycloplatin, a Novel Antitumor Supramolecule, in Rats and Dogs by ICP-MS”. Biological Trace Element Research. 148 (2): 203–8. doi:10.1007/s12011-012-9364-2. PMID 22367705.
^ G.Q., Li; X.G., Chen; X.P., Wu; J.D., Xie; Y.J., Liang; X.Q., Zhao; W.Q, Chen; L.W., Fu (November 2012). “Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis”. PLOS ONE. 7 (11): e48994. Bibcode:2012PLoSO…748994L. doi:10.1371/journal.pone.0048994. PMC 3495782. PMID 23152837.
^ J.J, Yu; X.Q, Yang; Q.H, Song; M. D., Mueller; S. C., Remick (2014). “Dicycloplatin, a Novel Platinum Analog in Chemotherapy: Synthesis of Chinese Pre-clinical and Clinical Profile and Emerging Mechanistic Studies”. Anticancer Research. 34: 455–464.
^ Jump up to:^a ^b ^c Guang-quan, Li; Xing-gui, Chen; Xing-ping, Wu; Jing-dun, Xie; Yong-ju, Liang; Xiao-qin, Zhao; Wei-qiang, Chen; Li-wu, Fu (November 2012). “Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis”. PLOS ONE. 7 (11): e48994. Bibcode:2012PLoSO…748994L. doi:10.1371/journal.pone.0048994. PMC 3495782. PMID 23152837.
^ Li.S; Huang H; Liao H; Zhan J; Guo Y; Zou BY; Jiang WQ; Guan ZZ; Yang XQ (2015). “Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results”. International Journal of Clinical Pharmacology and Therapeutics. 51 (2): 96–105. doi:10.5414/CP201761. PMID 23127487.
^ Y., Xu Qing; J., Xiang Lin; S., Q.; TANG, Ka Luo; Y., Zhen Yun; Z., Xiao Feng; T., You Qi (June 2010). “Structural studies of dicycloplatin, an antitumor supramolecule”. Science China Chemistry. 53 (6): 1346–1351. doi:10.1007/s11426-010-3184-z.
^ R., Kumar; P.E., Herbert; A.N., Warrens (September 2005). “An introduction to death receptors in apoptosis”. International Journal of Surgery. 3 (4): 268–77. doi:10.1016/j.ijsu.2005.05.002. PMID 17462297.
^ Yang, BF; Xiao, C; Li, H; Yang, SJ (2007). “Resistance to Fas-mediated apoptosis in malignant tumours is rescued by KN-93 and cisplatin via downregulation of cFLIP expression and phosphorylation”. Clinical and Experimental Pharmacology and Physiology. 34 (12): 1245–51. doi:10.1111/j.1440-1681.2007.04711.x. PMID 17973862.
^ Blomgran, R; Zheng, L; Stendahl, O (2007). “Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization”. Journal of Leukocyte Biology. 81 (5): 1213–23. doi:10.1189/jlb.0506359. PMID 17264306.
^ Yin, XM (2006). “Bid, a BH3-only multi-functional molecule, is at the cross road of life and death”. Gene. 369: 7–19. doi:10.1016/j.gene.2005.10.038. PMID 16446060.
^ Ott, M; Gogvadze, V; Orrenius, S; Zhivotovsky, B (May 2007). “Mitochondria, oxidative stress and cell death”. Apoptosis. 12 (5): 913–22. doi:10.1007/s10495-007-0756-2. PMID 17453160.

Dicycloplatin
Clinical data
Chemical structure of Dicycloplatin
Trade names	Dicycloplatin
Synonyms	Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2), 1,1-Cyclobutanedicarboxylic acid, compd. with (sp-4-2)-diammine(1,1-cyclobutanedi(carboxylato-kappaO)(2-))platinum (1:1)
Routes of administration	Intravenous
Pharmacokinetic data
Bioavailability	100% (IV)
Protein binding	< 88.7%
Elimination half-life	24.49 – 108.93 hours
Excretion	Renal
Identifiers
IUPAC name [show]
CAS Number	287402-09-9
ChemSpider	8476840
UNII	0KC57I4UNB
Chemical and physical data
Formula	C₁₂H₂₀N₂O₈Pt
Molar mass	515.382 g/mol
3D model (JSmol)	Interactive image coordination form: Interactive image
SMILES [hide] C1CC(C1)(C(=O)O)C(=O)O.C1CC(C1)(C(=O)[O-])C(=O)[O-].N.N.[Pt+2] coordination form: C0CCC0C4[C-]1O[H+]O[C-](O[H+][NH2+]2)C0(CCC0)[C-](O[H+][NH2+]3)O[H+]O[C-]4O[Pt-2]23O1
InChI [hide] InChI=InChI=1S/2C6H8O4.2H3N.Pt/c27-4(8)6(5(9)10)2-1-3-6;;;/h21-3H2,(H,7,8)(H,9,10);2*1H3;/q;;;;+2/p-2 Key:IIJQICKYWPGJDT-UHFFFAOYSA-L

/////////////Dicycloplatin

C1CC(C1)(C(=O)O)C(=O)O.C1CC(C1)(C(=O)[O-])C(=O)[O-].N.N.[Pt+2]

	DR ANTHONY MELVIN CR… on AK 3280
	DR ANTHONY MELVIN CR… on Novobiocin, ノボビオシン;
	DR ANTHONY MELVIN CR… on CT 1812
	DR ANTHONY MELVIN CR… on ACLIMOSTAT
	DR ANTHONY MELVIN CR… on SRT 1720

No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Salt	CN1501909A	CN100567253C	Granted	2002/2/11	2022/2/11
2	Preparation	CN101671260A		Withdrawn	2002/2/11
3	Combination	CN1705474A		Withdrawn	2003/10/15
4	Combination	CN1705484A		Withdrawn	2003/10/15
5	Combination	CN101146539A		Withdrawn	2006/2/16
6	Formulation	CN101304734A		Withdrawn	2006/9/6
7	Combination	CN101410112A		Withdrawn	2007/3/23
8	Others	CN101528667A		Withdrawn	2007/10/24

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