RAPASTINEL

• Molecular Formula C₁₈H₃₁N₅O₆
• Average mass 413.469 Da

L-threonyl-L-prolyl-L-prolyl-L-threoninamide

(2S)-1-[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]pyrrolidine-2-carboxamide

UNII-6A1X56B95E; 117928-94-6; 6A1X56B95E

BV-102; GLYX13, GLYX-13, in phase 3 clinical trials

Originator Northwestern University

• Developer Allergan; Naurex
• Class Amides; Antidepressants; Neuropsychotherapeutics; Oligopeptides; Small molecules
• Mechanism of Action NR2B N-Methyl-D-Aspartate receptor agonists

Highest Development Phases

• Phase III Major depressive disorder
• Discontinued Bipolar depression; Neuropathic pain

Most Recent Events

• 01 Jan 2017 Allergan initiates enrolment in a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
• 21 Dec 2016 Allergan plans a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
• 01 Nov 2016 Phase-III clinical trials in Major depressive disorder (Adjunctive treatment, Prevention of relapse) in USA (IV) (NCT02951988)

It is disclosed that GLYX-13 (Rapastinel) acts as NMDA receptor partial agonist, useful for treating neurodegenerative disorders such as stroke-related brain cell death, convulsive disorders, and learning and memory. See WO2015065891 , claiming peptidyl compound. Naurex , a subsidiary of Allergan is developing rapastinel (GLYX-13) (in phase3 clinical trials), a rapid-acting monoclonal antibody-derived tetrapeptide and NMDA receptor glycine site functional partial agonist as well as an amidated form of NT-13, for treating depression.

Rapastinel (INN) (former developmental code names GLYX-13, BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder.^[1][2] It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide (Thr-Pro-Pro-Thr-NH₂) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (E_max ≈ 25%).^[1][2]The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.^[1][2]

On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.^[3] As of 2015, the drug had completed phase II clinical development for this indication.^[4] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapydesignation from the U.S. FDA for adjunctive treatment of major depressive disorder.

Rapastinel belongs to a group of compounds, referred to as glyxins (hence the original developmental code name of rapastinel, GLYX-13),^[5] that were derived via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.^[2][6][7] The glyxins were invented by Joseph Moskal, the co-founder of Naurex.^[5] Glyxins and B6B21 do not bind to the glycine site of the NMDA receptor but rather to a different regulatory site on the NMDA receptor complex that serves to allosterically modulate the glycine site.^[8] As such, rapastinel is technically an allosteric modulator of the glycine site of the NMDA receptor, and hence is more accurately described as a functional glycine site weak partial agonist.^[8]

In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.^[9] It has been shown to increase Schaffer collateral–CA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats.^[10] Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.^[11] Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at non-ataxic doses.^[12]

Apimostinel (NRX-1074), an analogue of rapastinel with the same mechanism of action but dramatically improved potency, is being developed by the same company as a follow-on compound to rapastinel.

CN 104109189,

PAPER

Tetrahedron Letters (2017), 58(16), 1568-1571

http://www.sciencedirect.com/science/article/pii/S0040403917303015

Novel silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13)

Graphical abstract

This paper reports the synthesis of silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13).

PATENT

CN 104109189

Depression is the most common neuropsychiatric diseases, seriously affecting people’s health. In China With accelerated pace of life, increasing the incidence of depression was significantly higher social pressure.

[0003] Drug therapy is the primary means of treatment of depression. The main treatment drugs, including tricyclic antidepressants such as imipramine, amitriptyline and the like; selective serotonin reuptake inhibitors such as fluoxetine, sertraline and the like; serotonin / norepinephrine dual uptake inhibitors such as venlafaxine, duloxetine. However, commonly used drugs slow onset, usually takes several weeks to months, and there is not efficient and toxicity obvious shortcomings.

[0004] GLYX-13 is a new antidepressant, Phase II clinical study is currently underway. It does this by regulating the brain NMDA (N_ methyl -D- aspartate) receptors play a role, and none of them have serious side effects such as ketamine and R-rated, such as hallucinations and schizophrenia and so on.GLYX-13 can play a strong, fast and sustained antidepressant effects, the onset time of less than 24 hours, and the sustainable average of 7 days. As a peptide drug, GLYX-13 was well tolerated and safe to use.

[0005] GLYX-13 is a tetrapeptide having the sequence structure Thr-Pro-Pro-Thr, which is a free N-terminal amino group, C terminal amide structure. GLYX-13 synthesis methods include traditional methods of two solid-phase peptide synthesis and liquid phase peptide synthesis, because of its short sequence, the amount of solid phase synthesis of amino acids, high cost, and difficult to achieve a lot of preparation. A small amount of liquid phase amino acids, high yield can be prepared in large quantities.

The present invention can be further described by the following examples.

Preparation of r-NH2; [0013] Example 1 Four peptide H-Thr-Pr〇-P; r〇-Th

[0014] 1.1 threonine carboxyl amidation (H-Thr-NH2)

[0015] 500ml three flask was added Boc-Thr (tBu) -0H20g (0.073mol), anhydrous tetrahydrofuran (THF) 150ml, stirring to dissolve the solid. Ice-salt bath cooled to -10 ° C~_15 ° C, was added N- methylmorpholine 8ml, then l〇ml isobutyl chloroformate, keeping the temperature not higher than -10 ° C, after the addition was complete retention low temperature reaction 10min, then adding ammonia 20ml, ice bath reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times.Dried over anhydrous sodium sulfate 6h. Filtered, and then the solvent was distilled off under reduced pressure to give a white solid 16. 6g, 83% yield.

[0016] The above product was dissolved in 50ml of trifluoroacetic acid or 2N hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e. amidated carboxyl threonine trifluoroacetic acid / hydrochloric acid salt H- Thr-NH 2. HC1.

[0017] 1.2 Pro – Preparation of threonine dipeptide fragment H-Pr〇-Thr-NH2 of

[0018] 500ml flask was added Boc-Pr〇 three-0H20g (0. 093mol), in anhydrous tetrahydrofuran (TH F) 200ml, stirring to dissolve solids, cooled to ice-salt bath -l〇 ° C~-15 ° C, added N- methylmorpholine 11ml, then dropwise isobutyl 13ml, keeping the temperature not higher than -10 ° C, keep it cool after the addition was complete the reaction 10min. H-Thr-NH2. HC114. 5g dissolved in 50ml of tetrahydrofuran, was added N- methyl morpholine 11ml. The above solution was added to the reaction mixture, the low temperature reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times. Dried over anhydrous sodium sulfate 6h. Filtered and then evaporated under reduced pressure to give a white solid 25.7g, 82% yield.

[0019] The above product was dissolved in 100ml of 2N trifluoroacetic acid or hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e., proline – threonine dipeptide hydrochloride salt of H-Pr〇 -Thr-NH 2. HC1.

[0020] The above product was dissolved in 100ml of pure water, sodium carbonate solution was added to adjust the PH value, the precipitated white solid was filtered and dried in vacuo to give the desired product proline – threonine dipeptide fragment H-Pr square-Thr- NH223g.

Protected threonine [0021] 1.3 – Preparation of dipeptide fragment Boc-Thr (tBu) -Pr〇-0H of

[0022] Boc-Thr (tBu) -0H20g (0 · 073mol) was dissolved in dry tetrahydrofuran (THF) 150ml, stirring to dissolve the solid.Ice-salt bath cooled to -10 G~-15 ° C, was added N- methylmorpholine 8ml, then dropwise isobutyl 10ml, maintained at a temperature no higher than -10 ° C, kept cold reaction After dropping 10min. Proline methyl ester hydrochloride

PAPER

Journal of Medicinal Chemistry (1989), 32(10), 2407-11.

Threonylprolylprolylthreoninamide (HRP-7). The synthesis of HRP-7 was begun with 3 g of p-methylbenzhydrylamine-resin containing 1.41 mmol of attachment sites. The protected tetrapeptidyl-resin (1.63 g) was subjected to HF cleavage. Radioactivity was found in the 1% acetic acid extract (77%) and in the 5% extract (24%). These solutions were combined and lyophilized. Crude peptide (309 mg, 97%) was gel filtered on Sephadex G-15 (1.1 X 100 cm). Peptide eluting between 34 and 46 mL was pooled and lyophilized to yield 294 mg (95%, overall yield 92%) of homogeneous HRP-7.

PATENT

WO 2010033757

PATENT

WO 2017136348

Process for synthesizing dipyrrolidine peptide compounds (eg GLYX-13) is claimed.

An N-methyl-D-aspartate (NMDA) receptor is a postsynaptic, ionotropic receptor that is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor (NMDAR) appears to controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel and has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. The NMDAR has been implicated, for example, in neurodegenerative disorders including stroke-related brain cell death, convulsive disorders, and learning and memory.

NMDAR also plays a central role in modulating normal synaptic transmission, synaptic plasticity, and excitotoxicity in the central nervous system. The NMDAR is further involved in Long-Term Potentiation (LTP), which is the persistent strengthening of neuronal connections that underlie learning and memory The NMDAR has been associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there are preliminary reports indicating involvement of NMDA receptors in the chronic neurodegeneration of Huntington’s, Parkinson’s, and Alzheimer’s diseases. Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures. In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself. Further, NMDA receptors have also been implicated in certain types of spatial learning.

[0003] In view of the association of NMDAR with various disorders and diseases, NMDA-modulating small molecule agonist and antagonist compounds have been developed for therapeutic use. NMDA receptor compounds may exert dual (agonist/antagonist) effect on the NMDA receptor through the allosteric sites. These compounds are typically termed “partial agonists”. In the presence of the principal site ligand, a partial agonist will displace some of the ligand and thus decrease Ca flow through the receptor. In the absence of the principal site ligand or in the presence of a lowered level of the principal site ligand, the partial agonist acts to increase Ca⁺⁺ flow through the receptor channel.

Example 2: Synthesis of GLYX-13

[00119] GLYX-13 was prepared as follows, using intermediates KSM-1 and KSM-2 produced in Example 1. The synthetic route for the same is provided in Figure 2.

Stage A – Preparation of (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide (Compound XI)

[00120] In this stage, KSM -1 was reacted with 10%Pd/C in presence of methanol to produce a compound represented by Formula XI. The reaction was optimized and performed up to 4.0 kg scale in the production plant and observed consistent quality (>80% by HPLC%PA) and yields (80% to 85%).

[00121] The reaction scheme involved in this method is as follows:

[00122] Raw materials used for this method are illustrated in Table 7 as follows:

Table 7.

[00123] In stage A, 10% Palladium on Carbon (w/w, 50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. KSM-1 was dissolved in methanol in another container and sucked into above reactor under vacuum. Hydrogen pressure was maintained at 45-60 psi at ambient temperature for over a period of 5-6 hrs. Progress of the reaction mixture was monitored by HPLC for KSM-1 content; limit is not more than 5%.

Hyflow bed was prepared with methanol (Lot-II). The reaction mass was filtered through nutsche filter under nitrogen atmosphere and bed was washed with Methanol Lot-Ill. Filtrate was transferred into the reactor and distilled completely under reduced pressure at below 50 °C (Bath temperature) to get the syrup and syrup material was unloaded into clean and dry container and samples were sent to QC for analysis.

[00124] From the above reaction(s), 1.31 kg of compound represented by Formula XI was obtained with a yield of 89.31% and with a purity of 93.63%).

Stage B – Preparation of Benzyl (2S, 3R)-l-((S)-2-((S)-2-((2S, 3R)-I-amino-3-hydroxy-I- oxobutan-2-ylcarbamoyl) pyrrolidine-! -carbonyl) pyrrolidin-1 -yl)-3-hydroxy-l -oxobutan-2- ylcarbamate (Compound XII)

[00125] In this stage the compound represented by Formula XI obtained above was reacted with KSM-2 to produce a compound represented by Formula XII. This reaction was optimized and scaled up to 3.0 kg scale in the production plant and obtained 25% to 28% yields with UPLC purity (>95%).

[00126] The reaction scheme is as follows:

[00127] Raw materials used for this method are illustrated in Table 8 as follows:

Table 8.

[00128] Stage B: ethanol was charged into the reactor at 20 to 35 °C. Compound represented by Formula XI was charged into the reactor under stirring at 20 to 35 °C and reaction mass was cooled to -5 to 0°C. EDC.HC1 was charged into the reaction mass at -5 to 0 °C and reaction mass, was maintained at -5 to 0 °C for 10-15 minutes. N-Methyl morpholine was added drop wise to the above reaction mass at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 10-15 minutes.

[00129] KSM-2 was charged into the reactor under stirring at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 3.00 to 4.00 hours. The temperature of the reaction mass was raised to 20 to 35 °C and was maintained at 20 to 35 °C for 12 – 15 hours under stirring. (Note:

Monitor the reaction mass by HPLC for Stage A content after 12.0 hours and thereafter every 2.0 hours. The content of stage A should not be more than 2.0%). Ethanol was distilled out completely under vacuum at below 50 °C (Hot water temperature) and reaction mass was cooled to 20 to 35 °C. Water Lot-1 was charged into the residue obtained followed by 10% DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-1 & Isopropyl alcohol Lot-1 prepared in a cleaned HDPE container) into the reaction mass at 20 – 35 °C.

[00130] Both the layers were separated and the aqueous layer was charged into the reactor. 10%) DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-2 & Isopropyl alcohol Lot-2 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> IDCM-isopropyl alcohol (Mixture of Dichloromethane Lot-3 & Isopropyl alcohol Lot-3 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-4 & Isopropyl alcohol Lot-4 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C and separated both the layers. The above organic layers were combined and potassium hydrogen sulfate solution (Prepare a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-1 in water Lot-2) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and charged back organic layer into the reactor. Potassium hydrogen sulfate solution (Prepared a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-2 in water Lot-3) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and the organic layer was dried over Sodium sulfate and distilled out the solvent completely under vacuum at below 45 °C (Hot water temperature).

[00131] The above crude was absorbed with silica gel (100-200mesh) Lot-1 in

dichloromethane. Prepared the column with silica gel (100-200 mesh) Lot-2, and washed the silica gel bed with from Dichloromethane Lot-5 and charged the adsorbed compound into the column. Eluted the column with 0-10% Methanol Lot-1 in Dichloromethane Lot-5 and analyzed fractions by HPLC. Solvent was distilled out completely under vacuum at below 45 °C (Hot water temperature). Methyl tert-butyl ether Lot-1 was charged and stirred for 30 min. The solid was filtered through the Nutsche filter and washed with Methyl tert-butyl ether Lot-2 and

samples were sent to QC for complete analysis. (Note: If product quality was found to be less than 95%, column purification should be repeated).

[00132] From the above reaction(s), 0.575 kg of compound represented by Formula XII was obtained with a yield of 17% and with a purity of 96.28%).

Stage C – Preparation of Benzyl (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-l- ((2R, 3R)-2-amino-3-hydroxybutanoyl) pyrrolidine-2 carbonyl) pyrrolidine-2-carboxamide (GLYX-13)

[00133] In this reaction step the compound of Formula XII obtained above was reacted with 10%oPd in presence of methanol to produce GLYX-13. This reaction was optimized and performed up to 2.8 kg scale in the production plant and got 40% to 45% of yields with UPLC purity >98%.

[00134] The reaction scheme involved in this method is as follows:

i

[00135] Raw materials used for this method are illustrated in Table 9 as follows:

Table 9.

30 Nitrogen cylinder – – – – – 31 Hydrogen cylinder – – – – –

[00136] In an exemplary embodiment of stage C, 10% Palladium Carbon (50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. Compound of Formula XII was dissolved in methanol in a separate container and sucked into the reactor under vacuum. Hydrogen pressure was maintained 45-60 psi at ambient temperature over a period of 6-8 hrs. Progress of the reaction was monitored by HPLC for stage-B (compound represented by Formula XII) content (limit is not more than 2%). If HPLC does not comply continue the stirring until it complies. Prepared the hyflow bed with methanol (Lot-II) and the reaction mass was filtered through hyflow bed under nitrogen atmosphere, and the filtrate was collected into a clean HDPE container. The bed was washed with Methanol Lot-Ill and the filtrate was transferred into the Rota Flask and distilled out the solvent completely under reduced pressure at below 50°C (Bath temperature) to get the crude product. The material was unloaded into clean HDPE container under Nitrogen atmosphere.

[00137] Neutral Alumina Lot-1 was charged into the above HDPE container till uniform mixture was formed. The neutral Alumina bed was prepared with neutral alumina Lot-2 and dichloromethane Lot-1 in a glass column. The neutral Alumina Lot-3 was charged and

Dichloromethane Lot-2 into the above prepared neutral Alumina bed. The adsorbed compound was charged into the column from op.no.11. The column was eluted with Dichloromethane Lot-2 and collect 10 L fractions. The column was eluted with Dichloromethane Lot-3 and collected 10 L fractions. The column was eluted with Dichloromethane Lot-4 and Methanol Lot-4 (1%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-5 and Methanol Lot-5 (2%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-6 and Methanol Lot-6 (3%) and collected 10 L fractions. The column was eluted with

Dichloromethane Lot-7 and Methanol Lot-7 (5%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-8 and Methanol Lot-8 (8%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-9 and Methanol Lot-9 (10%) and collected 10 L fractions. Fractions were analyzed by HPLC (above 97% purity and single max impurity >0.5% fractions are pooled together)

[00138] Ensured the reactor is clean and dry. The pure fractions were transferred into the reactor.

[00139] The solvent was distilled off completely under vacuum at below 45 °C (Hot water temperature). The material was cooled to 20 to 35°C. Charged Dichloromethane Lot- 10 and Methanol Lot- 10 into the material and stirred till dissolution. Activated carbon was charged into the above mixture at 20 to 35°C and temperature was raised to 45 to 50 °C.

[00140] Prepared the Hyflow bed with Hyflow Lot-2 and Methanol Lot-11 Filtered the reaction mass through the Hy-flow bed under nitrogen atmosphere and collect the filtrate into a clean FIDPE container. Prepared solvent mixture with Dichloromethane Lot-11 and Methanol Lot- 12 in a clean FIDPE container and washed Nutsche filter with same solvent. Charged filtrate in to Rota evaporator and distilled out solvent under vacuum at below 50°C. Dry the compound in Rota evaporator for 5 to 6 hours at 50°C, send sample to QC for Methanol content (residual solvent) which should not be more than 3000 ppm. The material was cooled to 20 to 35 °C and the solid material was unloaded into clean and dry glass bottle. Samples were sent to QC for complete analysis.

[00141] From the above reaction(s), 0.92 kg of Glyx-13 was obtained with a yield of 43.5% and with a purity of 99.73%.

See also

• List of investigational antidepressants

References

External links

• Rapastinel – AdisInsight
• Rapastinel (GLYX-13) – Naurex, Inc.
• Rapastinel Receives FDA Breakthrough Therapy Designation – Allergan plc. press release

rapastinel

Clinical data
Pregnancy category	US: N (Not classified yet)
ATC code	none
Legal status
Legal status	US: Investigational New Drug
Identifiers
IUPAC name[show]
CAS Number	117928-94-6
PubChem CID	14539800
ChemSpider	25069944
Chemical and physical data
Formula	C18H31N5O6
Molar mass	413.47 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(=O)N)N)O

/////////////RAPASTINEL, BV-102, GLYX-13, PEPTIDE, phase 3, рапастинел , راباستينيل , 雷帕替奈

CC(C(C(=O)N1CCCC1C(=O)N2CCCC2C(=O)NC(C(C)O)C(=O)N)N)O

Prexasertib

Captisol^® enabled prexasertib; CHK1 Inhibitor II; LY 2606368; LY2606368 MsOH H2O

5-(5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile

2-Pyrazinecarbonitrile, 5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]-

Name	Prexasertib
Lab Codes	LY-2606368
Chemical Name	5-({5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile
Chemical Structure
Molecular Formula	C18H19N7O2
UNII	UNII:820NH671E6
Cas Registry Number	1234015-52-1
OTHER NAMES	прексасертиб [Russian] [INN] بريكساسيرتيب [Arabic] [INN] 普瑞色替 [Chinese] [INN]
Originator	Array BioPharma
Developer	Eli Lilly, National Cancer Institute
Mechanism Of Action	Checkpoint kinase inhibitors, Chk-1 inhibitors
Who Atc Codes	L01X-E (Protein kinase inhibitors)
Ephmra Codes	L1H (Protein Kinase Inhibitor Antineoplastics)
Indication	Breast cancer, Ovarian cancer, Solid tumor, Head and neck cancer, Leukemia, Neoplasm Metastasis, Colorectal Neoplasms, Squamous Cell Carcinoma

2100300-72-7 CAS

Prexasertib mesylate hydrate
CAS#: 1234015-57-6 (mesylate hydrate)
Chemical Formula: C19H25N7O6S
Molecular Weight: 479.512, CODE LY-2940930
LY-2606368 (free base)

Prexasertib mesylate ANHYDROUS
CAS#: 1234015-55-4 (mesylate)
Chemical Formula: C19H23N7O5S
Molecular Weight: 461.497

Prexasertib dihydrochloride
1234015-54-3. MW: 438.3169

LY2606368 is a small-molecule Chk-1 inhibitors invented by Array and being developed by Eli Lilly and Company. Lilly is responsible for all clinical development and commercialization activities. Chk-1 is a protein kinase that regulates the tumor cell’s response to DNA damage often caused by treatment with chemotherapy. In response to DNA damage, Chk-1 blocks cell cycle progression in order to allow for repair of damaged DNA, thereby limiting the efficacy of chemotherapeutic agents. Inhibiting Chk-1 in combination with chemotherapy can enhance tumor cell death by preventing these cells from recovering from DNA damage.

Originator Array BioPharma; Eli Lilly

Developer Eli Lilly; National Cancer Institute (USA)

Class Antineoplastics; Nitriles; Pyrazines; Pyrazoles; Small molecules

Mechanism of Action Checkpoint kinase 1 inhibitors; Checkpoint kinase 2 inhibitors

Highest Development Phases

• Phase II Breast cancer; Ovarian cancer; Small cell lung cancer; Solid tumours
• Phase I Acute myeloid leukaemia; Colorectal cancer; Head and neck cancer; Myelodysplastic syndromes; Non-small cell lung cancer

Most Recent Events

• 10 Apr 2017 Eli Lilly completes a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Japan (NCT02514603)
• 10 Mar 2017 Phase-I clinical trials in Solid tumours (Combination therapy, Metastatic disease, Inoperable/Unresectable) in USA (IV) (NCT03057145)
• 22 Feb 2017 Khanh Do and AstraZeneca plan a phase H trial for Solid tumour (Combination therapy, Metastatic disease, Inoperable/Unresectable) in USA (NCT03057145)

Prexasertib (LY2606368) is a small molecule checkpoint kinase inhibitor, mainly active against CHEK1, with minor activity against CHEK2. This causes induction of DNA double-strand breaks resulting in apoptosis. It is in development by Eli Lilly. ^[1]

A phase II clinical trial for the treatment of small cell lung cancer is expected to be complete in December 2017.^[2]

an aminopyrazole compound, or a pharmaceutically acceptable salt thereof or a solvate of the salt, that inhibits Chkl and is useful for treating cancers characterized by defects in deoxyribonucleic acid (DNA) replication, chromosome segregation, or cell division.

Chkl is a protein kinase that lies downstream from Atm and/or Atr in the DNA damage checkpoint signal transduction pathway. In mammalian cells, Chkl is phosphorylated in response to agents that cause DNA damage including ionizing radiation (IR), ultraviolet (UV) light, and hydroxyurea. This phosphorylation which activates Chkl in mammalian cells is dependent on Atr. Chkl plays a role in the Atr dependent DNA damage checkpoint leading to arrest in S phase and at G2M. Chkl phosphorylates and inactivates Cdc25A, the dual-specificity phosphatase that normally dephosphorylates cyclin E/Cdk2, halting progression through S-phase. Chkl also phosphorylates and inactivates Cdc25C, the dual specificity phosphatase that dephosphorylates cyclin B/Cdc2 (also known as Cdkl) arresting cell cycle progression at the boundary of G2 and mitosis (Fernery et al, Science, 277: 1495-1, 1997). In both cases, regulation of Cdk activity induces a cell cycle arrest to prevent cells from entering mitosis in the presence of DNA damage or unreplicated DNA. Various inhibitors of Chkl have been reported. See for example, WO 05/066163,

WO 04/063198, WO 03/093297 and WO 02/070494. In addition, a series of aminopyrazole Chkl inhibitors is disclosed in WO 05/009435.

However, there is still a need for Chkl inhibitors that are potent inhibitors of the cell cycle checkpoints that can act effectively as potentiators of DNA damaging agents. The present invention provides a novel aminopyrazole compound, or a pharmaceutically acceptable salt thereof or solvate of the salt, that is a potent inhibitor of Chkl . The compound, or a pharmaceutically acceptable salt thereof or a solvate of the salt, potently abrogates a Chkl mediated cell cycle arrest induced by treatment with DNA damaging agents in tissue culture and in vivo. Furthermore, the compound, or a pharmaceutically acceptable salt thereof or a solvate of the salt, of the present invention also provides inhibition of Chk2, which may be beneficial for the treatment of cancer. Additionally, the lack of inhibition of certain other protein kinases, such as CDKl, may provide a -2- therapeutic benefit by minimizing undesired effects. Furthermore, the compound, or a pharmaceutically acceptable salt thereof or a solvate of the salt, of the present invention inhibits cell proliferation of cancer cells by a mechanism dependent on Chkl inhibition.

WO 2010077758

Preparation 8

tert-Butyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3- methoxyphenoxy)propylcarbamate

A solution of tert-butyl 3-(2-(3-(5-bromopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3- methoxyphenoxy)propylcarbamate (0.378 g, 0.730 mmol) and zinc cyanide (0.10 g, 0.870 mmol) in DMF (10 mL) is degassed with a stream of nitrogen for one hour and then -25- heated to 80 ⁰C. To the reaction is added Pd(Ph₃P)₄ (0.080 g, 0.070 mmol), and the mixture is heated overnight. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel chromatography (CH₂Cl₂/Me0H) to give 0.251 g (73%) of the title compound.

Preparation 12 tert-Butyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3- methoxyphenoxy)propylcarbamate

A 5 L flange-neck round-bottom flask equipped with an air stirrer rod and paddle, thermometer, pressure-equalizing dropping funnel, and nitrogen bubbler is charged with 5-(5-(2-hydroxy-6-methoxy-phenyl)-lH-pyrazol-3-ylamino)-pyrazine-2-carbonitrile (47.0 g, 152 mmol) and anhydrous THF (1.2 L). The stirred suspension, under nitrogen, is cooled to 0 ⁰C. A separate 2 L 3 -necked round-bottom flask equipped with a large -28- magnetic stirring bar, thermometer, and nitrogen bubbler is charged with triphenylphosphine (44.0 g; 168 mmol) and anhydrous THF (600 mL). The stirred solution, under nitrogen, is cooled to 0 ⁰C and diisopropylazodicarboxylate (34.2 g; 169 mmol) is added and a milky solution is formed. After 3-4 min, a solution of7-butyl-N-(3- hydroxypropyl)-carbamate (30.3 g, 173 mmol) in anhydrous THF (100 mL) is added and the mixture is stirred for 3-4 min. This mixture is then added over 5 min to the stirred suspension of starting material at 0 ⁰C. The reaction mixture quickly becomes a dark solution and is allowed to slowly warm up to room temperature. After 6.5 h, more reagents are prepared as above using PPh₃ (8 g), DIAD (6.2 g) and carbamate (5.4 g) in anhydrous THF (150 mL). The mixture is added to the reaction mixture, cooled to -5 ⁰C and left to warm up to room temperature overnight. The solvent is removed in vacuo. The resulting viscous solution is loaded onto a pad of silica and product is eluted with ethyl acetate. The concentrated fractions are separately triturated with methanol and resulting solids are collected by filtration. The combined solids are triturated again with methanol (400 mL) and then isolated by filtration and dried in vacuo at 50 ⁰C overnight to give 31.3 g of desired product. LC-ES/MS m/z 466.2 [M+ 1]⁺.

Example 2

5 -(5 -(2-(3 -Aminopropoxy)-6-methoxyphenyl)- 1 H-pyrazol-3 -ylamino)pyrazine-2- carbonitrile dihydrogen chloride salt

A 5 L flange-neck, round-bottom flask equipped with an air stirrer rod and paddle, thermometer, and air condenser with bubbler attached, is charged with tert-bvXyl 3-(2-(3- (5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3-methoxyphenoxy)propylcarbamate (30.9 g, 66.3 mmol) and ethyl acetate (3 L). The mechanically stirred yellow suspension is cooled to just below 10 ⁰C. Then hydrogen chloride from a lecture bottle is bubbled in -29- vigorously through a gas inlet tube for 15 min with the ice-bath still in place. After 5 h the mixture is noticeably thickened in appearance. The solid is collected by filtration, washed with ethyl acetate, and then dried in vacuo at 60 ⁰C overnight to give 30.0 g. ¹H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 2H), 2.96 (m, 2H), 3.81 (s, 3H), 4.12 (t, J = 5.8 Hz, 2H), 6.08 (br s, 3H), 6.777 (d, J = 8.2 Hz, IH), 6.782 (d, J = 8.2 Hz, IH), 6.88 (br s, IH), 7.34 (t, J = 8.2 Hz, IH), 8.09 (br s, IH), 8.55 (br s, IH), 8.71 (s, IH), 10.83 (s, IH), 12.43 (br s, IH). LC-ES/MS m/z 366.2 [M+lf.

Example 3 5 -(5 -(2-(3 -Aminopropoxy)-6-methoxyphenyl)- 1 H-pyrazol-3 -ylamino)pyrazine-2- carbonitrile

5-(5-(2-(3-Aminopropoxy)-6-methoxyphenyl)-lH-pyrazol-3-ylamino)pyrazine-2- carbonitrile dihydrogen chloride salt (3.0 g, 6.84 mmol) is suspended in 200 mL of CH₂Cl₂. 1 N NaOH is added (200 mL, 200 mmol). The mixture is magnetically stirred under nitrogen at room temperature for 5 h. The solid is collected by filtration and washed thoroughly with water. The filter cake is dried in vacuo at 50 ⁰C overnight to give 2.26 g (90%) of the free base as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.81 (m, 2H), 2.73 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 4.09 (t, J = 6.2 Hz, 2H), 6.76 (t, J = 8.2 Hz, 2H), 6.93 (br s, IH), 7.31 (t, J = 8.2 Hz, IH), 8.52 (br s, IH), 8.67 (s, IH). LC- MS /ES m/z 366.2 [M+ 1]⁺.

Example 4

5 -(5 -(2-(3 -Aminopropoxy)-6-methoxyphenyl)- 1 H-pyrazol-3 -ylamino)pyrazine-2- carbonitrile methanesulfonic acid salt -30-

5-(5-(2-(3-aminopropoxy)-6-methoxyphenyl)-lH-pyrazol-3-ylamino)pyrazine-2- carbonitrile (1.0 g, 2.74 mmol) is suspended in MeOH (100 mL). A I M solution of methanesulfonic acid in MeOH (2.74 mL, 2.74 mmol) is added to the mixture dropwise with stirring. The solid nearly completely dissolves and is sonicated and stirred for 15 min, filtered, and concentrated to 50 mL. The solution is cooled overnight at -15 ⁰C and the solid that forms is collected by filtration. The solid is dried in a vacuum oven overnight to give 0.938 g (74%) of a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.97 (m, 2H), 2.28 (s, 3H), 2.95 (m, 2H), 3.79 (s, 3H), 4.09 (t, J = 5.9 Hz, 2H), 6.753 (d, J = 8.4 Hz, IH), 6.766 (d, J = 8.4 Hz, IH), 6.85 (br s, IH), 7.33 (t, J = 8.4 Hz, IH), 7.67 (br s, 3H), 8.49 (br s, IH), 8.64 (s, IH), 10.70 (s, IH), 12.31 (s, IH). LC-ES/MS m/z 366.2 [M+l]⁺.

Preparation 18 tert-Butyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3- methoxyphenoxy)propylcarbamate

5-(5-(2-Hydroxy-6-methoxyphenyl)-lH-pyrazol-3-ylamino)pyrazine-2- carbonitrile (618 g, 1.62 mol) is slurried in tetrahydrofuran (6.18 L, 10 volumes) and chilled to -5 to 0 ⁰C with an acetone/ice bath. Triethylamine (330 g, 3.25 mol) is added through an addition funnel over 30 – 40 min at -5 to 5 ⁰C. The resulting slurry is stirred at -5 to 5 ⁰C for 60 – 90 min. The insoluble triethylamine hydrochloride is filtered and the solution of the phenol ((5-(2-hydroxy-6-methoxyphenyl)-lH-pyrazol-3- ylamino)pyrazine-2-carbonitrile) collected in an appropriate reaction vessel. The cake is rinsed with THF (1.24 L). The THF solution of the phenol is held at 15 to 20 ⁰C until needed.

Triphenylphosphine (1074 g, 4.05 mol) is dissolved at room temperature in THF (4.33 L). The clear colorless solution is cooled with an acetone/ice bath to -5 to 5 ⁰C. Diisopropylazodicarboxylate (795 g, 3.89 mol) is added dropwise through an addition funnel over 40 – 60 min, keeping the temperature below 10 ⁰C. The resulting thick white slurry is cooled back to -5 to 0 ⁰C. tert-Butyl 3-hydroxypropylcarbamate (717g, 4.05 moles) is dissolved in a minimum of THF (800 mL). The tert-butyl 3- hydroxypropylcarbamate/THF solution is added, through an addition funnel, over 20 – 30 -35- min at -5 to 5 ⁰C to the reagent slurry. The prepared reagent is stirred in the ice bath at -5 to 0 ⁰C until ready for use.

The prepared reagent slurry (20%) is added to the substrate solution at 15 to 20 ⁰C. The remaining reagent is returned to the ice bath. The substrate solution is stirred at ambient for 30 min, then sampled for HPLC. A second approximately 20% portion of the reagent is added to the substrate, stirred at ambient and sampled as before. Addition of the reagent is continued with monitoring for reaction completion by HPLC. The completed reaction is concentrated and triturated with warm methanol (4.33 L, 50 – 60 ⁰C) followed by cooling in an ice bath. The resulting yellow precipitate is filtered, rinsed with cold MeOH (2 L), and dried to constant weight to provide 544 g (72%) of the title compound, mp 214 – 216 ⁰C; ES/MS m/z 466.2 [M+l]⁺.

Example 5

2-Pyrazinecarbonitrile, 5-[[5-[-[2-(3-aminopropyl)-6-methoxyphenyl]-lH-pyrazol-3- yl]amino] monomesylate monohydrate (Chemical Abstracts nomenclature)

tert-Butyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3- methoxyphenoxy)propylcarbamate (1430 g, 3.07 mol) is slurried with acetone (21.5 L) in a 30 L reactor. Methanesulfonic acid (1484 g, 15.36 mol) is added through an addition funnel in a moderate stream. The slurry is warmed to reflux at about 52 ⁰C for 1 to 3 h and monitored for reaction completion by HPLC analysis. The completed reaction is cooled from reflux to 15 to 20 ⁰C over 4.5 h. The yellow slurry of 2-pyrazinecarbonitrile, 5-[[5-[-[2-(3-aminopropyl)-6-methoxyphenyl]-lH-pyrazol-3-yl]amino] dimesylate salt is filtered, rinsed with acetone (7 L) and dried in a vacuum oven. The dimesylate salt, (1608 g, 2.88 mol) is slurried in water (16 L). Sodium hydroxide (aqueous 50%, 228 g, 2.85 mol) is slowly poured into the slurry. The slurry is -36- heated to 60 ⁰C and stirred for one hour. It is then cooled to 16 ⁰C over 4 h and filtered. The wet filter cake is rinsed with acetone (4 L) and dried to constant weight in a vacuum oven at 40 ⁰C to provide 833 g (94%) of 2-pyrazinecarbonitrile, 5-[[5-[-[2-(3- aminopropyl)-6-methoxyphenyl]-lH-pyrazol-3-yl]amino] monomesylate monohydrate. mp 222.6 ⁰C; ES/MS m/z 366.2 [M+l]⁺.

Example 5a

2-Pyrazinecarbonitrile, 5-[[5-[-[2-(3-aminopropyl)-6-methoxyphenyl]-lH-pyrazol-3- yl] amino] monomesylate monohydrate (Chemical Abstracts nomenclature)

Crude 2-pyrazinecarbonitrile, 5 -[ [5 – [- [2-(3 -aminopropyl)-6-methoxyphenyl]- IH- pyrazol-3-yl] amino] monomesylate monohydrate is purified using the following procedure. The technical grade 2-pyrazinecarbonitrile, 5-[[5-[-[2-(3-aminopropyl)-6- methoxyphenyl]-lH-pyrazol-3-yl] amino] mono mesylate mono hydrate (1221 g, 2.55 mol) is slurried in a solvent mixture of 1: 1 acetone/water (14.7 L). The solid is dissolved by warming the mixture to 50 – 55 ⁰C. The solution is polish filtrated while at 50 – 55 ⁰C through a 0.22μ cartridge filter. The solution is slowly cooled to the seeding temperature of about 42 – 45 ⁰C and seeded. Slow cooling is continued over the next 30 – 60 min to confirm nucleation. The thin slurry is cooled from 38 to 15 ⁰C over 3 h. A vacuum distillation is set up and the acetone removed at 110 – 90 mm and 20 – 30 ⁰C. The mixture is cooled from 30 to 15 ⁰C over 14 h, held at 15 ⁰C for 2 h, and then filtered. The recrystallized material is rinsed with 19: 1 water/acetone (2 L) and then water (6 L) and dried to constant weight in a vacuum oven at 40 ⁰C to provide 1024 g (83.9%) of the title compound, mp 222.6 ⁰C; ES/MS m/z 366.2 [M+l]⁺. X-ray powder diffraction (XRPD) patterns may be obtained on a Bruker D8

Advance powder diffractometer, equipped with a CuKa source (λ=l.54056 angstrom) operating at 40 kV and 40 mA with a position-sensitive detector. Each sample is scanned between 4° and 35° in °2Θ ± 0.02 using a step size of 0.026° in 2Θ ± 0.02 and a step time of 0.3 seconds, with a 0.6 mm divergence slit and a 10.39 mm detector slit. Primary and secondary Soller slits are each at 2°; antiscattering slit is 6.17 mm; the air scatter sink is in place. -37-

Characteristic peak positions and relative intensities:

Differential scanning calorimetry (DSC) analyses may be carried out on a Mettler- Toledo DSC unit (Model DSC822e). Samples are heated in closed aluminum pans with pinhole from 25 to 350 ⁰C at 10 °C/min with a nitrogen purge of 50 mL/min. Thermogravimetric analysis (TGA) may be carried out on a Mettler Toledo TGA unit (Model TGA/SDTA 85Ie). Samples are heated in sealed aluminum pans with a pinhole from 25 to 350 ⁰C at 10 ⁰C /min with a nitrogen purge of 50 mL/min.

The thermal profile from DSC shows a weak, broad endotherm form 80 – 140⁰C followed by a sharp melting endotherm at 222 ⁰C, onset (225 ⁰C, peak). A mass loss of 4% is seen by the TGA from 25 – 140 ⁰C.

PATENT

US 20110144126

WO 2017015124

WO 2017100071

WO 2017105982

WO 2016051409

Clip

science 2017, 356, 1144

Kilogram-Scale Prexasertib Monolactate Monohydrate Synthesis under Continuous-Flow CGMP Conditions

  

References

REFERENCES

1: Zeng L, Beggs RR, Cooper TS, Weaver AN, Yang ES. Combining Chk1/2 inhibition with cetuximab and radiation enhances in vitro and in vivo cytotoxicity in head and neck squamous cell carcinoma. Mol Cancer Ther. 2017 Jan 30. pii: molcanther.0352.2016. doi: 10.1158/1535-7163.MCT-16-0352. [Epub ahead of print] PubMed PMID: 28138028.

2: Ghelli Luserna Di Rorà A, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, Guadagnuolo V, Robustelli V, Parisi S, Sartor C, Abbenante MC, Paolini S, Martinelli G. Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. Oncotarget. 2016 Aug 16;7(33):53377-53391. doi: 10.18632/oncotarget.10535. PubMed PMID: 27438145; PubMed Central PMCID: PMC5288194.

3: King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. PubMed PMID: 26141948.
4: Hong D, Infante J, Janku F, Jones S, Nguyen LM, Burris H, Naing A, Bauer TM, Piha-Paul S, Johnson FM, Kurzrock R, Golden L, Hynes S, Lin J, Lin AB, Bendell J. Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer. J Clin Oncol. 2016 May 20;34(15):1764-71. doi: 10.1200/JCO.2015.64.5788. PubMed PMID: 27044938.

Prexasertib

Clinical data
Pregnancy category	IV
ATC code	none
Identifiers
IUPAC name[show]
CAS Number	1234015-52-1
ChemSpider	32738771
UNII	820NH671E6
Chemical and physical data
Formula	C18H19N7O2
Molar mass	365.40 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] C1=C(C(=C(C=C1)OC)C1=CC(=NN1)NC1=NC=C(N=C1)C#N)OCCCN

////////////Prexasertib, прексасертиб , بريكساسيرتيب , 普瑞色替 , PHASE 2, LY-2606368, LY 2606368

Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India

Speaking at World health congress 2017….JNTUH Hyderabad 22 aug 2017

Tozadenant

RO-449351
SYN-115

• Molecular Formula C₁₉H₂₆N₄O₄S
• Average mass 406.499 Da

A2 (3); A2a-(3); RO4494351; RO4494351-000; RO4494351-002; SYN-115

Phase III clinical trials at Biotie Therapies for the treatment of Parkinson’s disease as an adjunctive therapy with levodopa

• Originator Roche
• Developer Acorda Therapeutics
• Class Amides; Antiparkinsonians; Benzothiazoles; Carboxylic acids; Morpholines; Piperidines; Small molecules
• Mechanism of Action Adenosine A2A receptor antagonists

Highest Development Phases

• Phase III Parkinson’s disease
• Phase I Liver disorders

Most Recent Events

• 30 Jun 2017 Biotie Therapies plans a phase I trial in Healthy volunteers in Canada (NCT03200080)
• 30 Jun 2017 Phase-I clinical trials in Liver disorders (In volunteers) in USA (PO) (NCT03212313)
• 27 Apr 2017 Acorda Therapeutics initiates enrolment in a phase III trial for Parkinson’s disease in Germany (EudraCT2016-003961-25)(NCT03051607)

Biotie Therapies Holding , under license from Roche , is developing tozadenant (phase 3, as of August 2017) for the treatment of Parkinson’s disease.

SYN-115, a potent and selective adenosine A2A receptor antagonist, is in phase III clinical trials at Biotie Therapeutics for the treatment of Parkinson’s disease, as an adjunjunctive therapy with levodopa. Phase 0 trials were are underway at the National Institute on Drug Abuse (NIDA) for the treatment of cocaine dependency, but no recent development has been reported.

The A2A receptor modulates the production of dopamine, glutamine and serotonin in several brain regions. In preclinical studies, antagonism of the A2A receptor resulted in increases in dopamine levels, which gave rise to the reversal of motor deficits.

Originally developed at Roche, SYN-115 was acquired by Synosia in 2007, in addition to four other drug candidates with potential for the treatment of central nervous system (CNS) disorders. Under the terms of the agreement, Synosia was responsible for clinical development and in some cases commercialization, while Roche retained the right to opt-in to two preselected programs.

In 2010, the compound was licensed to UCB by Synosia Therapeutics for development and commercialization worldwide.

In February 2011, Synosia (previously Synosis Therapeutics) was acquired by Biotie Therapeutics, and in 2014, Biotie regained global rights from UCB.

Representative examples of A_2AAdoR antagonists.

Tozadenant, also known as 4-hydroxy-N-(4-methoxy-7-(4-morpholinyl)benzo[d]thiazol-2-yl)-4-methylpiperidine-l-carboxamide or SYN115, is an adenosine A2A receptor antagonist. The A2A receptor modulates the production of

dopamine, glutamine and serotonin in several brain regions. In preclinical studies, antagonism of the A2A receptor resulted in increases in dopamine levels, which gave rise to the reversal of motor deficits.

Tozadenant is currently phase III clinical trials for the treatment of Parkinson’s disease as an adjunctive therapy with levodopa. It has also been explored for the treatment of cocaine dependency.

(F. Hoffmann-La Roche AG)

Claus Riemer

Sonia Poli

Lucinda Steward

PhD

Principal Scientist

PAPER

Fredriksson, Kai; Lottmann, Philip; Hinz, Sonja; Onila, Iounut; Shymanets, Aliaksei; Harteneck, Christian; Müller, Christa E.; Griesinger, Christian; Exner, Thomas E. – Angewandte Chemie – International Edition, 2017, vol. 56, 21, pg. 5750 – 5754, Angew. Chem., 2017, vol. 129, pg. 5844 – 5848,5

PAPER

Mancel, Valérie; Mathy, François-Xavier; Boulanger, Pierre; English, Stephen; Croft, Marie; Kenney, Christopher; Knott, Tarra; Stockis, Armel; Bani, Massimo – Xenobiotica, 2017, vol. 47,  8, pg. 705 – 718

Paper

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A_2A Receptor Antagonists and Their Biological Evaluation

Sujay Basu^* , Dinesh A. Barawkar, Sachin Thorat, Yogesh D. Shejul, Meena Patel, Minakshi Naykodi, Vaibhav Jain, Yogesh Salve, Vandna Prasad, Sumit Chaudhary, Indraneel Ghosh, Ganesh Bhat, Azfar Quraishi, Harish Patil, Shariq Ansari, Suraj Menon, Vishal Unadkat, Rhishikesh Thakare, Madhav S. Seervi, Ashwinkumar V. Meru, Siddhartha De, Ravi K. Bhamidipati, Sreekanth R. Rouduri, Venkata P. Palle, Anita Chug, and Kasim A. Mookhtiar

Drug Discovery Facility, Advinus Therapeutics Ltd., Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India

J. Med. Chem., 2017, 60 (2), pp 681–694

DOI: 10.1021/acs.jmedchem.6b01584

* Phone: +91 20 66539600. Fax: +91 20 66539620. E-mail: sujay.basu@advinus.com.

Patent

https://www.google.com/patents/US20050261289

• Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzyme A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
• [0003]
  The adenosine receptors have been classified as A₁, A_2A, A_2B and A₃receptors, belonging to the family of G protein-coupled receptors. Activation of aderosine receptors by adenosine initiates signal transduction mechanisms. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtypes has been classically characterized by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The A₁and A₃ receptors, coupled with G_i proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A_2A and A_2Breceptors couple to G_s proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A₁receptor system activates phospholipase C and modulates both potassium and calcium ion channels. The A₃ subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and activates calcium ion channels.
• [0004]
  The A₁ receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A_2Areceptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A_2B receptor (332 amino acids) was cloned from human and mouse and shows 45% homology with the human A₁ and A_2A receptors. The A₃ receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
• [0005]
  The A₁ and A_2A receptor subtypes are proposed to play complementary roles in adenosine’s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A₁) or increase the oxygen supply (A_2A) and so reinstate the balance of energy supply: demand within the tissue. The actions of both subtypes is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischemia, hypotension and seizure activity.
• [0006]
  Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A₃ receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A₃ receptor plays a role in mediating asthmatic attacks and other allergic responses.
• [0007]
  Adenosine is a neurotransmitter able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington’s disease), Alzheimer’s disease, depression, schizophrenia, or addiction. An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A₁agonists mimic the central inhibitory effects of adenosine and may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Furthermore, adenosine antagonists have proven to be effective as cognition enhancers. Selective A_2A antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer’s disease, and of neurodegenerative disorders, e.g. stroke. Adenosine A_2A receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, and cannabinoids). Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder).
• [0008]
  An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). By acting at the A₁ receptor, adenosine A₁ agonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating influence of A_2Areceptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A_2Aantagonists may be of therapeutic benefit in situations in which an enhanced anti-adrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A_2A Areceptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias.
• [0009]
  Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds which antagonize the renal affects of adenosine have potential as renal protective agents. Furthermore, adenosine A₃ and/or A_2Bantagonists may be useful in the treatment of asthma and other allergic responses or and in the treatment of diabetes mellitus and obesity.
• [0010]

  Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:

  • • Bioorganic & Medicinal Chemistry, 6, (1998), 619-641,
    • Bioorganic & Medicinal Chemistry, 6, (1998), 707-719,
    • J. Med. Chem., (1998), 41, 2835-2845,
    • J. Med. Chem., (1998), 41, 3186-3201,
    • J. Med. Chem., (1998), 41, 2126-2133,
    • J. Med. Chem., (1999), 42, 706-721,
    • J. Med. Chem., (1996), 39, 1164-1171,
    • Arch. Pharm. Med. Chem., 332, 39-41, (1999),
    • Am. J. Physiol., 276, H1113-1116, (1999) or
    • Naunyn Schmied, Arch. Pharmacol. 362,375-381, (2000)

EXAMPLE 14-Hydroxy-4-methyl-piperidine-1-carboxylic acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (I)
• [0065]
  To a solution of (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid phenyl ester (3.2 g, 8.3 mmol) and N-ethyl-diisopropyl-amine (4.4 ml, 25 mmol) in trichloromethane (50 ml) is added a solution of 4-hydroxy-4-methyl-piperidine in trichloromethane (3 ml) and tetrahydrofurane (3 ml) and the resulting mixture heated to reflux for 1 h. The reaction mixture is then cooled to ambient temperature and extracted with saturated aqueous sodium carbonate (15 ml) and water (2×5 ml). Final drying with magnesium sulphate and evaporation of the solvent and recrystallization from ethanol afforded the title compound as white crystals (78% yield), mp 236° C. MS: m/e=407(M+H⁺).

PATENT

WO-2017136375

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017136375&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated forms of tozadenant are claimed. Also claimed are compositions comprising them and method of modulating the activity of adenosine A2A receptor (ADORA2A), useful for treating Parkinson’s diseases. Represents new area of patenting to be seen from CoNCERT Pharmaceuticals on tozadenant. ISR draws attention towards WO2016204939 , claiming controlled-release tozadenant formulations.

This invention relates to deuterated forms of morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an adenosine A2A receptor antagonist.

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co- administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.

Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable 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 ADME 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.

[7] 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, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] 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.

///////////////TOZADENANT, phase III,  clinical trials,  Parkinson’s disease ,  adjunctive therapy,  levodopa, RO-449351, SYN-115

CC1(CCN(CC1)C(=O)NC2=NC3=C(C=CC(=C3S2)N4CCOCC4)OC)O

Benznidazole

Clinical data
Trade names	Rochagan, Radanil[1]
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	by mouth
ATC code	P01CA02 (WHO)
Pharmacokinetic data
Bioavailability	High
Metabolism	Liver
Biological half-life	12 hours
Excretion	Kidney and fecal
Identifiers
IUPAC name[show]
CAS Number	22994-85-0
PubChem CID	31593
ChemSpider	29299
UNII	YC42NRJ1ZD
KEGG	D02489
ChEBI	CHEBI:133833
ChEMBL	CHEMBL110
ECHA InfoCard	100.153.448
Chemical and physical data
Formula	C12H12N4O3
Molar mass	260.249 g/mol
3D model (JSmol)	Interactive image
Melting point	188.5 to 190 °C (371.3 to 374.0 °F)

Benznidazole is an antiparasitic medication used in the treatment of Chagas disease.^[2] While it is highly effective in early disease this decreases in those who have long term infection.^[3] It is the first line treatment given its moderate side effects compared to nifurtimox.^[1] It is taken by mouth.^[2]

Side effects are fairly common. They include rash, numbness, fever, muscle pain, loss of appetite, and trouble sleeping.^[4][5] Rare side effects include bone marrow suppression which can lead to low blood cell levels.^[1][5] It is not recommended during pregnancy or in people with severe liver or kidney disease.^[4][3]Benznidazole is in the nitroimidazole family of medication and works by the production of free radicals.^[5][6]

Benznidazole came into medical use in 1971.^[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[7] It is not commercially available in the United States, but can be obtained from the Centers of Disease Control.^[2] As of 2012 Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer.^[8]

Medical uses

Benznidazole has a significant activity during the acute phase of Chagas disease, with a therapeutical success rate up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of T. cruzi from the body) in pediatric and young patients during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%.^[6]

However, some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure, because it reduces electrocardiographic changes and a delays worsening of the clinical condition of the patient.^[6]

Benznidazole has proven to be effective in the treatment of reactivated T. cruzi infections caused by immunosuppression, such as in people with AIDS or in those under immunosuppressive therapy related to organ transplants.^[6]

Children

Benznidazole can be used in children and infants, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections.^[9] Children are found to be at a lower risk of adverse events compared to adults, possibly due to increased hepatic clearance of the drug. The most prevalent adverse effects in children were found to be gastrointestinal, dermatologic, and neurologic in nature. However, the incidence of severe dermatologic and neurologic adverse events is lower in the pediatric population compared to adults.^[10]

Pregnant women

Studies in animals have shown that benznidazole can cross the placenta.^[11] Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended.^[9]

Side effects

Side effects tend to be common and occur more frequently with increased age.^[12] The most common adverse reactions associated with benznidazole are allergic dermatitis and peripheral neuropathy.^[1] It is reported that up to 30% of people will experience dermatitis when starting treatment.^[11][13] Benznidazole may cause photosensitization of the skin, resulting in rashes.^[1] Rashes usually appear within the first 2 weeks of treatment and resolve over time.^[13] In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever.^[13] Peripheral neuropathy may occur later on in the treatment course and is dose dependent.^[1] It is not permanent, but takes time to resolve.^[13]

Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysguesia, and bone marrow suppression.^[1] Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time.^[13] Bone marrow suppression has been linked to the cumulative dose exposure.^[13]

Contraindications

Benznidazole should not be used in people with severe liver and/or kidney disease.^[12] Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity.^[11]

Pharmacology

Mechanism of action

Benznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypanosoma cruzi, commonly referred to as Chagas disease.^[11] Like other nitroimidazoles, benznidazole’s main mechanism of action is to generate radical species which can damage the parasite’s DNA or cellular machinery.^[14] The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present.^[15] This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.^[16]

Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species.^[14] The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead.^[15] The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates.^[14] In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form.^[14] This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).^[15]

In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as “futile cycling“.^[14] In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species.^[15] The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells’ ability to detoxify superoxide radicals and other reactive oxygen species.^[15] In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited direct toxicity to human cells.^[15] In Trypanosoma species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasite’s cellular machinery.^[15]

Pharmacokinetics

Oral benznidazole has a bioavailability of 92%, with a peak concentration time of 3–4 hours after administration.^[17] 5% of the parent drug is excreted unchanged in the urine, which implies that clearance of benznidazole is mainly through metabolism by the liver.^[18] Its elimination half-life is 10.5-13.6 hours.^[17]

Interactions

Benznidazole and other nitroimidazoles have been shown to decrease the rate of clearance of 5-fluorouracil (including 5-fluorouracil produced from its prodrugs capecitabine, doxifluridine, and tegafur).^[19]While co-administration of any of these drugs with benznidazole is not contraindicated, monitoring for 5-fluorouracil toxicity is recommended in the event they are used together.^[20]

The GLP-1 receptor agonist lixisenatide may slow down the absorption and activity of benznidazole, presumably due to delayed gastric emptying.^[21]

Because nitroimidazoles can kill Vibrio cholerae cells, use is not recommended within 14 days of receiving a live cholera vaccine.^[22]

Alcohol consumption can cause a disulfiram like reaction with benznidazole.^[1]

References

External links

• “Rochagan [Patient Information]” (PDF) (in Portuguese). Hoffmann-La Roche. Retrieved 2006-11-27.

////////////benznidazole, Chemo Research, Tropical Disease Priority Review Voucher, Chagas disease, rare disease, FDA 2017

Meropenem

/////////////Kymriah, Novartis Pharmaceuticals Corp, Actemra, Genentech Inc., gene therapy, fda 2017

 

Vaborbactam 
RN: 1360457-46-0
UNII: 1C75676F8V

Molecular Formula. C12-H16-B-N-O5-S

Molecular Weight. 297.1374

1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-((2-(2-thienyl)acetyl)amino)-, (3R,6S)-

B1([C@H](CC[C@H](O1)CC(=O)O)NC(=O)Cc2cccs2)O

RPX7009

A beta-lactamase inhibitor.

Treatment of Bacterial Infection

{(3R,6S)-2-Hydroxy-3-[(2-thienylacetyl)amino]-1,2-oxaborinan-6-yl}acetic acid

2-[(3R,6S)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid

1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-, (3R,6S)-

Ваборбактам [Russian]

فابورباكتام [Arabic]

法硼巴坦 [Chinese]

• Originator Rempex Pharmaceuticals
• Developer The Medicines Company; US Department of Health and Human Services
• Class Antibacterials; Pyrrolidines; Small molecules; Thienamycins
• Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

• Registered Urinary tract infections
• Phase III Bacteraemia; Gram-negative infections; Pneumonia; Pyelonephritis

Most Recent Events

• 29 Aug 2017 Registered for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) – First global approval
• 29 Aug 2017 Updated efficacy and safety data from a phase III trial in Gram-negative infections released by The Medicines Company
• 09 Aug 2017 Planned Prescription Drug User Fee Act (PDUFA) date for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) is 2017-08-29

 

Rapidly rising resistance to multiple antimicrobial agents in Gram-negative bacteria, commonly related to healthcare-associated infections, is an emerging public health concern in U.S. hospitals. While the cephalosporin class of β-lactams was the mainstay of treatment in the 1980s, the dissemination of extended-spectrum β-lactamases (ESBLs) over the past 2 decades has dramatically weakened the utility of this class and brought about a corresponding reliance on the carbapenems.(1) Although carbapenems are widely recognized as a safe and effective class of antimicrobials, carbapenem-resistant Enterobacteriaceae (CRE) due to the Klebsiella pneumoniaecarbapenemase (KPC) and other β-lactamases now threatens the usefulness of all β-lactam antibiotics.(2) The Centers for Disease Control (CDC) considers CRE to be an urgent antimicrobial resistance threat that now has been detected in nearly every U.S. state, with an alarming increase in incidence over the past 5 years.(3) The failure to develop antimicrobial agents to manage CRE threatens to have a catastrophic impact on the healthcare system.(4)

A proven strategy to overcome resistance to β-lactam antibiotics has been to restore their activity by combining them with an inhibitor of the β-lactamase enzymes responsible for their degradation. Examples of clinically important β-lactamase inhibitors (Figure 1) include clavulanic acid (combined with amoxicillin), sulbactam (with ampicillin), and tazobactam (with piperacillin). The KPC β-lactamase is poorly inhibited by these β-lactamase inhibitors, and thus, they have no usefulness in the treatment of infections due to CRE. More recently, the diazabicyclooctane inhibitors avibactam (NXL-104)(5) and relebactam (MK-7655)(6) have entered clinical development, in combination with ceftazidime and imipenem, respectively. Both compounds display a broad spectrum of β-lactamase inhibition that includes the KPC enzyme.

Next generation β-lactamase inhibitors recently approved or in clinical trials. A. Avibactam. B. Relebactam. C. Vaborbactam.

Vaborbactam (INN)^[1] is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the beta-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.^[2]

According to a Medicines Company press release, as of June 2016 a combination of vaborbactam with the carbapenem antibiotic meropenem had met all pre-specified primary endpoints in a phase III clinical trial in patients with complicated urinary tract infections.^[3] The company planned to submit an NDA to the FDAin early 2017.

Biochemistry

Carbapenemases are a family of β-lactamase enzymes distinguished by their broad spectrum of activity and their ability to degrade carbapenem antibiotics, which are frequently used in the treatment of multidrug-resistant gram-negative infections.^[4] Carbapenemases can be broadly divided into two different categories based on the mechanism they use to hydrolyze the lactam ring in their substrates. Metallo-β-lactamases contain bound zinc ions in their active sites and are therefore inhibited by chelating agents like EDTA, while serine carbapenemases feature an active site serine that participates in the hydrolysis of the substrate.^[4] Serine carbapenemase-catalyzed hydrolysis employs a three-step mechanism featuring acylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral transition state.^[4][5]

Boronic acids are unusual in their ability to reversibly form covalent bonds with alcohols such as the active site serine in a serine carbapenemase. This property enables them to function as transition state analogs of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes. Based on data from Hecker et al., vaborbactam is a potent inhibitor of a variety of β-lactamases, exhibiting a 69-nanomolar {\displaystyle K_{i}} against the KPC-2 carbapenemase and even lower inhibition constants against CTX-M-15 and SHV-12.^[2]

Given their mechanism of action, the possibility of off-target effects brought about through inhibition of endogenous serine hydrolases is an obvious possible concern in the development of boronic acid β-lactamase inhibitors, and in fact boronic acids like bortezomib have previously been investigated or developed as inhibitors of various human proteases.^[2] Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an IC₅₀ >> 1 mM against all human serine hydrolases against which it has been tested.^[2] Consistent with its high in vitro specificity, vaborbactam exhibited a good safety profile in human phase I clinical trials, with similar adverse events observed in both placebo and treatment groups.^[6] Hecker et al. argue this specificity results from the higher affinity of human proteases to linear molecules; thus it is expected that a boron heterocycle will have zero effect on them.

PATENT

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

5

[0192] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6-yl)acetic acid 5. 1H NMR (CD₃OD) δ ppm 0.97-1.11 (q, IH), 1.47-1.69 (m, 2H), 1.69-1.80 (m, IH), 2.21-2.33 (td, IH), 2.33-2.41 (dd, IH), 2.58-2.67 (m, IH), 3.97 (s, 2H), 4.06-4.14 (m, IH), 6.97-7.04 (m, IH), 7.04-7.08 (m, IH), 7.34-7.38 (dd, IH); ESIMS found for Ci₂Hi₆BN0₅S m/z 28 -H₂0)⁺.

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

5

[0175] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6- yl)acetic acid 5. 1H NMR (CD₃OD) δ ppm 0.97-1.11 (q, 1H), 1.47-1.69 (m, 2H), 1.69-1.80 (m, 1H), 2.21-2.33 (td, 1H), 2.33-2.41 (dd, 1H), 2.58-2.67 (m, 1H), 3.97 (s, 2H), 4.06-4.14 (m, 1H), 6.97-7.04 (m, 1H), 7.04-7.08 (m, 1H), 7.34-7.38 (dd, 1H); ESIMS found for Ci₂Hi₆BN0₅S m/z 280 (100%) (M-H₂0)⁺.

References

Vaborbactam

Clinical data
Routes of administration	IV
ATC code	None
Identifiers
IUPAC name[show]
CAS Number	1360457-46-0
PubChem CID	56649692
ChemSpider	35035409
UNII	1C75676F8V
Chemical and physical data
Formula	C12H16BNO5S
Molar mass	297.13 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] B1([C@H](CC[C@H](O1)CC(=O)O)NC(=O)CC2=CC=CS2)O

FDA approves new antibacterial drug Vabomere (meropenem, vaborbactam)

Meropenem

Moxalactam synthesis

Latamoxef (or moxalactam)

http://www.wikiwand.com/en/Latamoxef

////////////////RPX7009, RPX 7009, VABORBACTAM, Vaborbactam, Ваборбактам ,   فابورباكتام ,   法硼巴坦 , FDA 2017

Riamilovir, Triazavirin

Riamilovir sodium dihydrate, CAS 928659-17-0,
Riamilovir CAS: 123606-06-4
Chemical Formula: C5H4N6O3S
Molecular Weight: 228.19

[1,2,4]Triazolo[5,1-c][1,2,4]triazin-4(1H)-one, 7-(methylthio)-3-nitro- (9CI)

7-(Methylthio)-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-4(6H)-one

1,2,4]Triazolo[5,1-c][1,2,4]triazin-4(6H)-one, 7-(methylthio)-3-nitro-

7-(methylsulfanyl)-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin- 4(1H)-one

7-thio-substituted-3-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4(1H)-one

Riamilovir sodium CAS 116061-59-7

Riamilovir sodium dihydrate, CAS 928659-17-0, Triazavirin

Flavivirus infection; Zika virus infection

Zika virus

Flavivirus

Anti-viral drug

http://apps.who.int/medicinedocs/documents/s23256en/s23256en.pdf

Triazavirin (TZV) is a broad-spectrum antiviral drug developed in Russia through a joint effort of Ural Federal University, Russian Academy of Sciences, Ural Center for Biopharma Technologies and Medsintez Pharmaceutical.

It has an azoloazine base structure, which represents a new structural class of non-nucleoside antiviral drugs.^[1]

It was originally developed as a potential treatment for pandemic influenza strains such as H5N1, and most of the testing that has been done has focused on its anti-influenza activity.^[2][3][4]

However triazavirin has also been found to have antiviral activity against a number of other viruses including tick-borne encephalitis,^[5]and is also being investigated for potential application against Lassa fever and Ebola virus disease.^{[6][7][8][9][10]}

Ebola virus

Yunona Holdings, was investigating riamilovir sodium dihydrate (triazavirin), a novel nucleoside inhibitor of human influenza virus A and B replication, for the potential oral treatment of influenza virus infection.

In November 2009, the company was seeking to outlicense the drug for development in the EU, presumed to be for use as a prescription medicine .

The Ural Branch of the Russian Academy of Sciences had previously developed, and Yunona Holdings registered and launched, triazavirinin in Russia as an OTC product .

Negative-sense, single-stranded RNA viruses (ssRNA), such as ssRNA viruses belonging to the Order Mononegavirales such as viruses in the Rhabdoviridae family, in particular the Rabies virus, the Filoviridae family, in particular the Ebolavirus, and the Paramyxoviridae family, in particular the Measles virus, other ssRNA viruses belonging to unassigned families such as notably the

Arenaviridae family, the Bunyaviridae family and the Orthomyxoviridae family and other unassigned ssRNA viruses such as notably the Deltavirus, cause many diseases in wildlife, domestic animals and humans. These ssRNA viruses belonging to different families are genetically and antigenically diverse, exhibiting broad tissue tropisms and a wide pathogenic potential.

For example, the Filoviridae viruses belonging to the Order

Mononegavirales, in particular the Ebolaviruses and Marburgviruses, are among the most lethal and most destructive viruses in the world. Filoviridae viruses are of particular concern as possible biological weapons since they have the potential for aerosol dissemination and weaponization.

The Ebolavirus includes five species: the Zaire, Sudan, Reston, Ta^‘i Forest and Bundibugyo Ebolaviruses. In particular the Zaire, Sudan and Bundibugyo Ebolavirus cause severe, often fatal, viral hemorraghic fevers in humans and nonhuman primates.

For more than 30 years, the Ebolavirus has been associated with periodic episodes of hemorrhagic fever in Central Africa that produce severe disease in

infected patients. Mortality rates in outbreaks have ranged from 50% for the Sudan species of the Ebolavirus to up to 90% for the Zaire species of the Ebolavirus ((Sanchez et al., Filoviridae: Marburg and Ebola Viruses, in Fields Virology, pages 1409-1448 (Lippincott Williams & Wilkins, Philadelphia)). In November 2007, during an outbreak in the Bundibugyo district of Uganda, near the border with the Democratic Republic of the Congo the fifth species of the Ebolavirus was discovered, the Bundibugyo species. Said outbreak resulted in a fatality rate of about 25% (Towner et al., PLoS Pathog., 4(11 ) :e1000212 (2008)). The Zaire species of the Ebolavirus has also decimated populations of wild apes in this same region of Africa (Walsh et al., Nature, 422:611-614 (2003)).

When infected with the Ebolavirus, the onset of illness is abrupt and is characterized by high fever, headaches, joint and muscle aches, sore throat, fatigue, diarrhea, vomiting, and stomach pain. A rash, red eyes, hiccups and internal and external bleeding may be seen in some patients. Within one week of becoming infected with the virus, most patients experience chest pains and multiple organ failure, go into shock, and die. Some patients also experience blindness and extensive bleeding before dying.

Another example of a negative sense single-stranded RNA envelope virus is the Morbilllivirus such as the Measles virus which is associated with Measles and the Lyssavirus such as the Rabies virus.

The Lyssavirus, belonging to the family Rhabdoviridae, includes eleven recognized species, in particular the Rabies virus which is known to cause Rabies. Rabies is an ancient disease with the earliest reports possibly dated to the Old World before 2300 B.C and remains a world health threat due to remaining lack of effective control measures in animal reservoir populations and a widespread lack of human access to vaccination. The Rabies virus is distributed worldwide among mammalian reservoirs including carnivores and bats. Each year there are many reported cases of transmission of the Rabies virus from animals to humans (e.g. by an animal bite). More than 50,000 people annually die of Rabies, particularly in Asia and Africa.

Thus, there remains a need for antiviral compounds which are effective for use in the treatment of the ssRNA virus infections different from the Influenza A and Influenza B virus infections

SYNTHESIS CONTRUCTED WITH 3 ARTICLES AS BELOW

RU 2340614 C2 20081210,

e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-7; 2009,

European Journal of Medicinal Chemistry, 113, 11-27; 2016

Khimiya Geterotsiklicheskikh Soedinenii (1989), (2), 253-7.

Khimiya Geterotsiklicheskikh Soedinenii (1992), (11), 1555-9.

Zhurnal Organicheskoi Khimii (1996), 32(5), 770-776

PAPER

Russian Journal of Organic Chemistry (Translation of Zhurnal Organicheskoi Khimii) (2002), 38(2), 272-280.

https://link.springer.com/article/10.1023%2FA%3A1015538322029

PATENT

RU 2340614 C2 20081210,

PAPER

Russian Chemical Bulletin (2010), 59(1), 136-143.

PATENT

WO 2015117016

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015117016&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PAPER

Chemistry of Heterocyclic Compounds (New York, NY, United States) (2015), 51(3), 275-280.

https://link.springer.com/article/10.1007%2Fs10593-015-1695-4

The nucleophilic susbstitution of nitro group in [1,2,4]triazolo[5,1-c][1,2,4]triazinones upon treatment with cysteine and glutathione was studied as a model for the interaction with thiol groups of virus proteins, which mimics the metabolic transformations of antiviral drug Triazavirin® and its derivatives.

PATENT

WO 2017144709

Example 1 : One pot synthesis of the sodium salt of 7-methylthio-3-nitro [1 ,

2, 4] triazolo [5,1 -c] [1, 2, 4] triazin -4 (1H)-one

Step 1 : Diazotization of compound (B): A solution (solution [1], herein after) was prepared of 5.8 g (0.05 ) of 5-amino-3-mercapto-1 ,2,4-triazole in 6.7 ml of nitric acid (15 M) and 12 ml of water. Said solution [1] was refrigerated to -7°C . Then a 40% sodium nitrite solution was added to the solution [1] in portions of 0.5 mL to obtain a total amount of sodium nitrite equal to 3.8 g in the mixture.

Step 2: Condensation of diazonium compound with an a-nitroester:

To the resulting diazonium salt of step 1 , 8.54 ml of diethyl nitromaionate was added. After holding for five minutes, a cooled solution of sodium hydroxide was slowly added dropwise to the reaction mixture until the pH was between pH 9 and pH 10 (solution [2], herein after). The resulting solution [2] was stirred at 0°C for 1 hour and at room temperature for 2 hours.

Step 3: alkylation: To the solution [2] of step 2, 6.23 ml (0.1 moi) of methyl iodide was added. The mixture was stirred for 1 hour at room temperature and filtered. The resulting precipitate was successively crystallized from water and dried in air. The reaction scheme is depicted below in Scheme 1.

SCHEME 1

The yield was 9.87 g (69%).

Physical and chemical characteristics of the sodium salt of 7-methylthio-3-nitro

[1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt: yellow crystalline powder, soluble in water, acetone, dimethylsulfoxide, dimethylformamide. insoluble in chloroform; T_melt = 300°C, H NMR spectrum, δ, ppm, solvent DMSO-d₆: 2.62 (3H, s, SCH₃); IR spectrum, n, cm^“1: 3535 (OH), 1649 (C=0), 1505 (N0₂), 1367 (N0₂); found.. %: C – 20.86, H 2.51 , N 29.28;

C₅H;N₆Na0₅S; Calculated, %: C – 20.98, H 2.47, N 29.36.

Example 2: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt

In this example the synthesis comprises 3 steps: in the first step 5-amino-3-mercapto-1.2,4-triazole (i.e. compound (B)) was prepared by condensation of aminoguanidine with a thio-derivative (thio ester) of formic acid, HC(=0)S-R, wherein -R was: methyl. In the second step 5-amino-3-mercapto-1 , 2,4-triazole was converted to the corresponding diazonium salt. In the third step this diazonium salt was reacted with an a-nitroester, 2-nitroacetoacetic ester, to form the 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one. The different steps are explained in more detail below.

Step 1 : Synthesis of compound (B): In a reaction flask equipped with a stirrer, reflux condenser, under inert gas (nitrogen, argon), 20 g (0.1 mol) of aminoguanidine and 7.6 g (0.1 mol) methylthio-formate was added to 400 ml of absolute pyridine. The reaction mixture was boiled for 4 hours at 115°C.

Subsequently the reaction mixture was transferred into distilled water and washed several times with water. The washed mixture was dried over a Nutsche filter under vacuum. Recrystallization was carried out from ethanol. The reaction scheme is depicted below in Scheme 2.

SCHEME 2

The yield was 19.3 g (70%)

Step 2: Diazotation of compound (B): A solution (solution [3], herein after) was prepared of 26 g (0.1 mol) of 5-amino-3-mercapto-1 ,2,4-triazole (as obtained in step 1) in 32 ml of nitric acid (0.1 mol) and 200 ml of water. The solution was mixed and cooled to -5°C. In a separate recipient, a 0.1 M solution of sodium nitrite was prepared by dissolving 16 g of sodium nitrite in 100 ml of water. The sodium nitrite solution was put in the freezer until there was ice formation and subsequently the ice was crushed. Thereafter, the solution [3] and the sodium nitrite crushed ice were transferred into a 1 L reactor and stirred for 1 hour while the reactor temperature was kept at 0°C. The low temperature and the fact that the two reaction components are in different phases (i.e. liquid and solid) ensured a slow gradual progress of diazotization reaction at the phase interface. The end of the diazotization process was controlled by a iodine starch test (proof of the absence of sodium nitrite in a free state).

The rea

SCHEME 3

Step 3: Condensation of the diazonium compound with an α-nitroester: A solution (solution [4], herein after) was prepared by mixing 17.5 g of methyl 2- nitro-acetoacetate in 300 mL of isopropanoi. The solution [4] was mixed with the diazonium salt of step 2. The mixture was cooled to 0°C. At 0°C, a 10% sodium hydroxide solution was added to the reaction mixture (to neutralize residual nitrite and acetate) until there was a marked alkaline reaction (pH between 8 and 9). The temperature was controlled and was kept below +5°C. The resulting mixture was stirred for 1 hour. The precipitate was filtered off and dried in air. The yield was 78%.

The reaction scheme is depicted in Scheme 4

SCHEME 4

Example 3: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one

The synthesis of the sodium salt of 7-methylthio-3-nitro-1 ,2,4-triazolo [5,1-c]-1 ,2,4-triazin-7-one may be carried out as in Example 2, only in step 2 the aqueous alcohol solution is replaced by an alcohol with alkali (such as sodium hydroxide). The yield of the antiviral compound (A) (sodium salt of 7-methylthio-3-nitro [1 2, 4] triazolo [5,1-c] [1 , 2. 4] triazin -4 (1 H)-one) may increase to 83%. The reaction scheme is depicted below in Scheme 5:

SCHEME 5

PATENT

WO2017144708

Process for the preparation of 7-thio-substituted-3-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4(1H)-one i.e. riamilovir sodium dihydrate is claimed. Also claimed are use of triazolo compounds for the treatment of ssRNA virus infections such as Zika virus and flavivirus, ssRNA viruses different from the Influenza A and Influenza B viruses and compositions comprising them. Along with concurrently published WO2017144709 claiming similar derivatives. Represents new area of interest from Doring International Gmbh and the inventors on this moiety.

Example 1 : One pot synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1 -cj [1, 2, 4] triazin -4 (1H)-one

Step 1: Diazotization of compound (B): A solution (solution [1], herein after) was prepared of 5.8 g (0.05 M) of 5-amino-3-mercapto-1 ,2,4-triazole in 6.7 ml of nitric acid (15 M) and 12 ml of water. Said solution [1] was refrigerated to -7°C . Then a 40% sodium nitrite solution was added to the solution [1] in portions of 0.5 mL to obtain a total amount of sodium nitrite equal to 3.8 g in the mixture.

Step 2: Condensation of diazonium compound with an a-nitroester: To the resulting diazonium salt of step 1 , 8.54 ml of diethyl nitromalonate was added. After holding for five minutes, a cooled solution of sodium hydroxide was slowly added dropwise to the reaction mixture until the pH was between pH 9 and pH 10 (solution [2], herein after). The resulting solution [2] was stirred at 0°C for 1 hour and at room temperature for 2 hours.

Step 3: alkylation: To the solution [2] of step 2, 6.23 ml (0.1 mol) of methyl iodide was added. The mixture was stirred for 1 hour at room temperature and

filtered. The resulting precipitate was successively crystallized from water and dried in air. The reaction scheme is depicted below in Scheme 1.

SCHEME 1

The yield was 9.87 g (69%).

Physical and chemical characteristics of the sodium salt of 7-methylthio-3-nitro

[1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt: yellow crystalline powder, soluble in water, acetone, dimethylsulfoxide, dimethylformamide, insoluble in chloroform; T_mei, = 300°C, ¹H NMR spectrum, δ, ppm, solvent DMSO-d₆: 2.62 (3H, s, SCH₃); IR spectrum, n, cm^“1: 3535 (OH), 1649 (CO), 1505 (N0₂), 1367 (N0₂); found, %: C – 20.86, H 2.51 , N 29.28; C₅H₇N₆Na0₅S; Calculated, %: C – 20.98, H 2.47, N 29.36.

Example 2: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2,

4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt

In this example the synthesis comprises 3 steps: in the first step 5-amino-3-mercapto-1 ,2,4-triazole (i.e. compound (B)) was prepared by condensation of aminoguanidine with a thio-derivative (thio ester) of formic acid, HC(=0)S-R, wherein -R was: methyl. In the second step 5-amino-3-mercapto-1 ,2,4-triazole was converted to the corresponding diazonium salt. In the third step this diazonium salt was reacted with an a-nitroester, 2-nitroacetoacetic ester, to form the 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one. The different steps are explained in more detail below.

Step 1 : Synthesis of compound (B): In a reaction flask equipped with a stirrer, reflux condenser, under inert gas (nitrogen, argon), 20 g (0.1 mo!) of

aminoguanidine and 7.6 g (0.1 mol) methylthio-formate was added to 400 ml of absolute pyridine. The reaction mixture was boiled for 4 hours at 115°C. Subsequently the reaction mixture was transferred into distilled water and washed several times with water. The washed mixture was dried over a Nutsche filter under vacuum. Recrystallization was carried out from ethanol. The reaction scheme is depicted below in Scheme 2.

SCHEME 2

The yield was 19.3 g (70%)

Step 2: Diazotation of compound (B): A solution (solution [3], herein after) was prepared of 26 g (0.1 mol) of 5-amino-3-mercapto-1 ,2,4-triazole (as obtained in step 1 ) in 32 ml of nitric acid (0.1 mol) and 200 ml of water. The solution was mixed and cooled to -5°C. In a separate recipient, a 0.1 M solution of sodium nitrite was prepared by dissolving 16 g of sodium nitrite in 100 ml of water. The sodium nitrite solution was put in the freezer until there was ice formation and subsequently the ice was crushed. Thereafter, the solution [3] and the sodium nitrite crushed ice were transferred into a 1 L reactor and stirred for 1 hour while the reactor temperature was kept at 0°C. The low temperature and the fact that the two reaction components are in different phases (i.e. liquid and solid) ensured a slow gradual progress of diazotization reaction at the phase interface. The end of the diazotization process was controlled by a iodine starch test (proof of the absence of sodium nitrite in a free state).

The rea

SCHEME 3

Step 3: Condensation of the diazonium compound with an a-nitroester: A solution (solution [4], herein after) was prepared by mixing 17.5 g of methyl 2-nitro-acetoacetate in 300 mL of isopropanol. The solution [4] was mixed with the diazonium salt of step 2. The mixture was cooled to 0°C. At 0°C, a 10% sodium hydroxide solution was added to the reaction mixture (to neutralize residual nitrite and acetate) until there was a marked alkaline reaction (pH between 8 and 9). The temperature was controlled and was kept below +5°C. The resulting mixture was stirred for 1 hour. The precipitate was filtered off and dried in air. The yield was 78%.

The reaction scheme is depicted in Scheme 4

SCHEME 4

Example 3: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one

The synthesis of the sodium salt of 7-methy I th io-3-nitro- 1 ,2, 4-triazolo [5,1-c]-1 ,2,4-triazin-7-one may be carried out as in Example 2, only in step 2 the aqueous alcohol solution is replaced by an alcohol with alkali (such as sodium hydroxide). The yield of the antiviral compound (A) (sodium salt of 7-methylthio-3-nitro [1 2, 4] triazolo [5,1-c] [1 , 2, 4] triazin -4 (1 H)-one) may increase to 83%.

The reaction scheme is depicted below in Scheme 5:

SCHEME 5

References

Triazavirin

Legal status
Legal status	US: Investigational New Drug
Identifiers
IUPAC name[show]
CAS Number	928659-17-0
PubChem CID	3113817
ChemSpider	2367718
ECHA InfoCard	100.217.074
Chemical and physical data
Formula	C5H4N6O3S
Molar mass	228.189
3D model (JSmol)	Interactive image
SMILES[hide] CSc1[nH]n2c(=O)c(nnc2n1)[N+](=O)[O-]

///////////riamilovir sodium dihydrate, Riamilovir , ANTIVIRAL, Triazavirin, Flavivirus infection,  Zika virus infection

O=C1N2C(NN=C1[N+]([O-])=O)=NC(SC)=N2

Funapide TV 45070,  XEN-402,  Funapide, (+)-

• Molecular FormulaC₂₂H₁₄F₃NO₅
• Average mass429.345 Da

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one

Spiro(furo(2,3-F)-1,3-benzodioxole-7(6H),3′-(3H)indol)-2′(1’H)-one, 1′-((5-(trifluoromethyl)-2-furanyl)methyl)-, (3’S)-

(3’S)-1′-((5-(Trifluoromethyl)furan-2-yl)methyl)-2H,6H-spiro(furo(2,3-F)(1,3)benzodioxole-7,3′-indol)-2′(1’H)-one

Phase II clinical trials for Postherpetic neuralgia (PHN)

Treatment of Neuropathic Pain

• Originator Xenon Pharmaceuticals
• Developer Teva Pharmaceutical Industries; Xenon Pharmaceuticals
• Class Benzodioxoles; Fluorobenzenes; Furans; Indoles; Non-opioid analgesics; Small molecules; Spiro compounds
• Mechanism of Action Nav1.7-voltage-gated-sodium-channel-inhibitors; Nav1.8 voltage-gated sodium channel inhibitors

• Orphan Drug Status Yes – Erythromelalgia

Highest Development Phases

• Phase II Erythromelalgia; Postherpetic neuralgia
• No development reported Dental pain; Pain
• Discontinued Musculoskeletal pain

Most Recent Events

• 09 May 2017 Teva Pharmaceutical Industries completes a phase IIb trial for Postherpetic neuralgia in USA (Topical) (NCT02365636)
• 26 Sep 2016 Adverse events data from a phase II trial in Musculoskeletal pain presented at the 16^th World Congress on Pain (PAN – 2016)
• 19 Aug 2015 No recent reports of development identified – Phase-I for Pain (In volunteers) in Canada (PO)

MP 100 – 102 DEG CENT EP2538919

S ROT  ALPHA 0.99 g/100ml, dimethyl sulfoxide, 14.04, US 20110087027

Funapide (INN) (former developmental code names TV-45070 and XEN402) is a novel analgesic under development by Xenon Pharmaceuticals in partnership with Teva Pharmaceutical Industries for the treatment of a variety of chronic pain conditions, including osteoarthritis, neuropathic pain, postherpetic neuralgia, and erythromelalgia, as well as dental pain.^[1][2][3][4] It acts as a small-moleculeNa_v1.7 and Na_v1.8 voltage-gated sodium channel blocker.^[1][2][4] Funapide is being evaluated in humans in both oral and topicalformulations, and as of July 2014, has reached phase IIb clinical trials.^[1][3]

Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short-term, first-line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities.

There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708 discloses certain spiro-oxindole compounds. These compounds are disclosed therein as being useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease;

cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT

Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708.

Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd)

Eluent: Acetonitrile/Water (60/40, v/v, isocratic)

Flow rate: 10 mL/min

Run time: 60 min

Loading: 100 mg of compound of formula (I) in 1 mL of acetonitrileTemperature: Ambient

Under the above chiral HPLC conditions, the (R)-enantiomer of the compound of formula (I), i.e., (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)>99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02 (ABq, J_AB=16.4 Hz, 2H), 4.82, 4.72 (ABq, J_AB=9.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]_D−17.46° (c 0.99, DMSO).

The (S)-enantiomer of the compound of formula (I), i.e., (S)-1′-{[5-(trifluoromethypfuran-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was isolated as the second fraction as a white solid; ee >99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, J_AB=16.4 Hz, 2H), 4.82, 4.72 (ABq, J_AB=9.4 Hz, 2H); ¹³C NMR (75MHz, CDCl₃) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]_D+14.04° (c 0.99, DMSO)

Synthetic Example 3Resolution of Compound of Formula (I) by SMB Chromatography

The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by SMB chromatography under the following conditions:

Extract: 147.05 mL/min, Raffinate: 76.13 mL/min Eluent: 183.18 mL/min Feed: 40 mL/min Recycling: 407.88 mL/min Run Time: 0.57 min Temperature: 25° C. Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobile phase (25:75:0.1 (v:v:v) mixture of acetonitrile/methanol/trifluoroacetic acid)) was injected continuously into the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD as stationary phase. The first eluting enantiomer (the (R)-enantiomer of the compound of formula (I)) was contained in the raffinate stream and the second eluting enantiomer (the (S)-enantiomer of the compound of formula (I)) was contained in the extract stream. The characterization data of the (S)-enantiomer and the (R)-enantiomer obtained from the SMB resolution were identical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into its constituent enantiomers on a Waters preparative LCMS autopurification system. The first-eluting enantiomer from the chiral column was brominated (at a site well-removed from the stereogenic centre) to give the corresponding 5′-bromo derivative, which was subsequently crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first-eluting enantiomer was obtained and its absolute configuration was found to be the same as the (R)-enantiomer of the invention. Hence, the second-eluting enantiomer from the chiral column is the (S)-enantiomer of the invention. Moreover, the material obtained from the extract stream of the SMB resolution had a specific optical rotation of the same sign (positive, i.e. dextrorotatory) as that of the material obtained from the aforementioned LC resolution.

Patent

WO 2013154712

EXAMPLE 8

Synthesis of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yllmethylJspirotfurop.S-flll .Sl enzoclioxole-y.S’-indoll-Zil ‘Wi-one

Compound of formula (ia1 )

To a cooled (0 °C) solution of (3S)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 7 (16.4 mmol) and 2- (diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous tetrahydrofuran (170 mL) was added di-ferf-butylazodicarboxylate (4.5 g, 20 mmol). The mixture was stirred for 2 h at 0 °C, then the reaction was diluted with ethyl acetate (170 mL), washed with 3 N hydrochloric acid (7 x 50 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (80 mL), decolorizing charcoal (15 g) was added and the mixture was heated at reflux for 1 h. The mixture was filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated in a mixture of diethyl ether/hexanes to afford (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3-/][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (1.30 g) as a colorless solid in 18% yield. The mother liquor from the trituration was concentrated in vacuo, trifluoroacetic acid (20 mL) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride (100 mL), 3 N hydrochloric acid (4 x 60 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (2.6 g) as a colorless solid (37% yield, overall yield 55% over 2 steps): H NMR (300 MHz, CDCI₃) £7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert- butyl ether).

EXAMPLE 9

Synthesis of 1-(diphenylmethyl)-1 H-indole-2,3-dione

Compound of formula (15a)

A. To a suspension of hexanes-washed sodium hydride (34.0 g, 849 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) at 0 °C was added a solution of isatin (99.8 g, 678 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) dropwise over 30 minutes. The reaction mixture was stirred for 1 h at 0 °C and a solution of benzhydryl bromide (185 g, 745 mmol) in anhydrous N-dimethylformamide (100 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and heated at 60 °C for 2 h. The mixture was cooled to 0 °C and water (500 mL) was added. The mixture was poured into water (2 L), causing a precipitate to be deposited. The solid was collected by suction filtration and washed with water (2000 mL) to afford 1-(diphenylmethyl)-1H-indole-2,3- dione (164 g) as an orange solid in 77% yield.

B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol), cesium carbonate (177 g, 543 mmol) and A/./V-dimethylformamide (270 mL) at 80 °C was added dropwise a solution of benzhydryl bromide (149 g, 544 mmol) in N,N- dimethyiformamide (200 mL) over 30 minutes. The reaction mixture was heated at 80 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was rinsed with ethyl acetate (1000 mL). The filtrate was washed with saturated aqueous ammonium chloride (4 x 200 mL), 1 N

hydrochloric acid (200 mL) and brine (4 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1 -(diphenylmethyl)-1 H-indole-2,3-dione (59.1 g) as an orange solid in 69% yield. The mother liquor from the trituration was concentrated in vacuo and the residue triturated in diethyl ether to afford a further portion of 1-(diphenylmethyl)-1 H- indole-2,3-dione (8.2 g) in 10% yield: ¹H NMR (300 MHz, CDCI₃) £7.60 (d, J = 7.4 Hz, 1 H), 7.34-7.24 (m, 1 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and anhydrous N,N- dimethylformamide (3.5 L) was stirred at 15-35 °C for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was added and the mixture stirred at 55-60 °C for 1 h. A solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous N, A/-dimethylformamide (1.5 L) was added and the resultant mixture stirred at 80-85 °C for 1 h, allowed to cool to ambient temperature and filtered. The filter cake was washed with ethyl acetate (12.5 L). To the combined filtrate and washes was added 1 N hydrochloric acid (5 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with 1 N hydrochloric acid (2 * 2.5 L) and brine (3 ^χ 2.5 L) and concentrated in vacuo to a volume of approximately 750 mL. Methyl ferf-butyl ether (2 L) was added and the mixture was cooled to 5-15 °C, causing a solid to be deposited. The solid was collected by filtration, washed with methyl ferf- butyl ether (250 mL) and dried in vacuo at 50-55 °C for 16 h to afford 1- (diphenylmethyl)-1 H-indole-2,3-dione (715 g) as an orange solid in 67% yield: ¹H NMR (300 MHz, CDCI₃) 7.60 (d, J = 7.4 Hz, H), 7.34-7.24 (m, 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

EXAMPLE 10

Synthesis of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3- dihydro-2H-indol-2-one

Compound of formula (16a1 )

A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous

tetrahydrofuran (500 mL) at 0 °C was added dropwise a 2 M solution of

isopropylmagnesium chloride in tetrahydrofuran (104 mL, 208 mmol), followed by 1 – (diphenylmethyl)-1H-indole-2,3-dione (50.0 g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was stirred at ambient temperature for 5 h, diluted with ethyl acetate (1500 mL), washed with saturated aqueous ammonium chloride (400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford 1- (diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-in

2- one (70.7 g) as a colorless solid in 98% yield: ¹H NMR (300 MHz, CDCI₃) <59.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56- 6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

B. Alternatviely, a mixture of sesamol (0.99 kg, 7.2 mol) and anhydrous tetrahydrofuran (18 L) was stirred at 15-35 °C for 0.5 h and cooled to -5-0 °C.

Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was added, followed by 1-(diphenylmethyl)-1 H-indole-2,3-dione (1.50 kg, 4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture was stirred at 15-25 °C for 5 h. Ethyl acetate (45 L) and saturated aqueous ammonium chloride (15 L) were added. The mixture was stirred at 15-25 °C for 0.5 h and was allowed to settle for 0.5 h. The phases were separated and the organic phase was washed with brine (2.3 L) and concentrated in vacuo to a volume of approximately 4 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 4 L. Heptane (6 L) was added and the mixture was stirred at 15-25 °C for 2 h, causing a solid to be deposited. The solid was collected by filtration, washed with methyl tert- butyl ether (0.3 L) and dried in vacuo at 50-55 °C for 7 h to afford 1-(diphenylmethyl)-3- hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield: ¹H NMR (300 MHz, CDCI₃) 9.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56-6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

EXAMPLE 1 1

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one

Compound of formula (17a1)

A. A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70 mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous N,N- dimeihylformamide (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the solid was washed with /V,A/-dimethylformamide (100 mL). The filtrate was poured into water (1000 mL) and the resulting precipitate was collected by suction filtration and washed with water to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol- 5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield: ¹H NMR (300 MHz, CDCI₃) 7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10- 6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1), 523.9 (M – 17).

B. Alternatively, to a solution of 1-(diphenylmethyl)-3-hydroxy-3-(6- hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous A/,A/-dimethylformamide (8.4 L) at 20-30 °C was added potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide (0.58 L, 4.8 mol). The mixture was stirred at 20-30 °C for 80 h and filtered. The filter cake was washed with

A/,/V-dimethylformamide (0.4 L) and the filtrate was poured into water (75 L), causing a solid to be deposited. The mixture was stirred at 15-25 °C for 7 h. The solid was collected by filtration, washed with water (2 L) and dried in vacuo at 50-60 °C for 48 h to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one (2.1 1 kg) as an off-white solid in 84% yield; ¹H NMR (300

MHz, CDCI₃) £7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1 ).

EXAMPLE 12

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H- indol-2-one

Compound of formula (18a1 )

A. To a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL) followed by triethylsilane (50 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyi acetate (250 mL), washed with saturated aqueous ammonium chloride (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5- yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (19.0 g) as a colorless solid in 61 % yield: ¹H NMR (300 MHz, CDCI₃) 7.31 -7.23 (m, 15H), 7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

B. Alternatively, to a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in

dichloromethane (7 L) at 20-30 °C was added trifluoracetic acid (2.5 L), followed by triethylsilane (3.1 L). The mixture was stirred at 15-35 °C for 4 h and concentrated in vacuo to dryness. To the residue was added ethyl acetate (16 L) and the mixture was stirred at 15-35 °C for 0.5 h, washed with saturated aqueous ammonium chloride (3 x 7 L) and brine (3 ^χ 7 L) and concentrated in vacuo to a volume of approximately 7 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 9 L and stirred at 10-20 °C for 2.5 h, during which time a solid was deposited. The solid was collected by filtration, washed with methyl te/t-butyl ether (0.4 L) and dried in vacuo at 50-55 °C for 7 h to afford 3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1 .26 kg) as an off-white solid in 65% yield: ¹H NMR (300 MHz, CDCI₃) £7.31 -7.23 (m, 15H), 7.10- 6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

EXAMPLE 13

Synthesis of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 –

(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one

Compound of formula (19a1 )

A. To a nitrogen-degassed mixture of 50% w/w aqueous potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and (9S)-1 -(anthracen-9- ylmethyl)cinchonan-1 -ium-9-ol chloride (0.50 g, 0.95 mmol) cooled in an ice/salt bath to an internal temperature of -18 °C was added a nitrogen-degassed solution of 3-[6- (benzyloxy)-l ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H-indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9 mL, 21 mmol) in

toluene/tetrahydrofuran (1 :1 v/v, 80 mL) dropwise over 1 h. The reaction mixture was stirred for 3.5 h and diluted with ethyl acetate (80 mL). The organic phase was washed with 1 N hydrochloric acid (3 x 150 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (12.6 g) as a colorless solid in quantitative yield: ¹H NMR (300 MHz, CDCI₃) 7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83- 5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, a mixture of 50% w/v aqueous potassium hydroxide (4.2 kg), toluene (12 L) and (9S)-1 -(anthracen-9-ylmethyl)cinchonan-1 -ium-9-ol chloride (0.06 kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to -22 °C. To this mixture was added a cold (-18 to -22 °C), nitrogen-degassed solution of 3-[6-

(benzyloxy)-l ,3-benzodioxol-5-yl]-1 ~(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43 kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to 22 °C over 3 h. The mixture was stirred at -18 to -22 °C for 5 h, allowed to warm to ambient temperature and diluted with ethyl acetate (10 L). The phases were separated and the organic layer was washed with 1 N

hydrochloric acid (3 ^χ 8 L) and brine (2 ^χ 12 L) and concentrated in vacuo to dryness to afford (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1- (diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless solid in quantitative yield: ¹H NMR (300 MHz, CDCI₃) £7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83-5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17- 4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, ChiralPak IA). EXAMPLE 14

Synthesis of (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1 ,3-dihydro-2/-/-indol-2-one

Compound of formula (20a1)

A. A mixture of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3- [(benzyloxy)methyl]-1 -(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (8.8 g, 14 mmol), 10% w/w palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and acetic acid (3.9 ml_, 68 mmol) in a nitrogen-degassed mixture of ethanol/tetrahydrofuran (1 : 1 v/v, 140 mL) was stirred under hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3- dihydro-2H-indol-2-one as a colorless solid that was carried forward without further purification: H NMR (300 MHz, CDCI₃) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15- 7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl ie t-butyl ether).

B. Alternatively, a glass-lined hydrogenation reactor was charged with (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 -(diphenylmethyl)- 1 ,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol), tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and 20% w/w palladium (li) hydroxide on carbon (0.04 kg). The reactor was purged three times with nitrogen. The reactor was then purged three times with hydrogen and was then pressurized to 50-55 lb/in² with hydrogen. The mixture was stirred at 20-30 °C for 5 h under a 50-55 lb/in² atmosphere of hydrogen. The reactor was purged and the mixture was filtered. The filtrate was concentrated in vacuo to a volume of approximately 0.2 L and methyl te/t-butyl ether (0.4 L) was added. The mixture was concentrated in vacuo to a volume of approximately 0.2 L and methyl ie/t-butyl ether (0.2 L) was added, followed by heptane (0.25 L). The mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.05 L) and dried in vacuo at a temperature below 50 °C for 8 h to afford (3S)-1 -(diphenylmethyl)-3-(6-hydroxy- 1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in 95% yield: ¹H NMR (300 MHz, CDCI₃) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15-7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 91% (HPLC, ChiralPak IA).

EXAMPLE 15

Synthesis of (7S)-1′-(diphenylmethyl)spiro[furo[2,3-/][1 ,3]benzodioxole-7,3′-indol]-

2′(1 ‘tf)-one

Compound of formula (21 a1 )

A. To a cooled (0 °C) solution of (3S)-1 -(diphenylmethyl)-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 14 (13.6 mmol) and 2-

(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate (3.8 g, 17 mmol). The reaction mixture was stirred at 0 °C for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N

hydrochloric acid (6 * 50 mL) and brine (2 ^χ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (4.55 g) as a colorless solid in a 75% yield over 2 steps: ¹H NMR (300 MHz, CDCI₃) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1); ee

(enantiomeric excess) 93% (HPLC, Chiraipak IA, 2.5% acetonitrile in methyl te/f-butyl ether).

B. Alternativel, to a cooled (0-5 °C) solution of (3S)-1-(diphenylmethyl)-3- (6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2 -/-indol-2-one (1 .0 kg, 2.1 mol) and 2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous tetrahydrofuran (20 L) was added over 2 h a solution of di-terf-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous tetrahydrofuran (5 L). The mixture was stirred for 4 h at 0-5 °C and was allowed to warm to ambient temperature. The mixture was diluted with ethyl acetate (20 L), washed with 3 N hydrochloric acid (6 * 8 L) and brine (2 x 12 L) and concentrated in vacuo to a volume of approximately 1.5 L. Methyl rert-butyl ether (4 L) was added and the mixture concentrated in vacuo to a volume of

approximately 1.5 L. Methyl terf-butyl ether (2 L) and heptane (2 L) were added and the mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.5 L) and dried in vacuo below 50 °C for 8 h to afford (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (0.76 kg) as a colorless solid in 79% yield: ¹H NMR (300 MHz, CDCI₃) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99- 6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1 ); ee (enantiomeric excess) 92% (HPLC, ChiralPak IA).

EXAMPLE 16

Synthesis of (7S)-spiro[furo[2,3-f][1 ,3]benzodioxole-7,3′-indol]-2′(1 ‘H)-one

Compound of formula (22a1)

A. To a solution of (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 ml_) was added triethylsilane (7 ml_). The reaction mixture was heated at reflux for 2.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford

(7S)-spiro[furo[2,3-/][1 ,3]benzodioxole-7,3^,-indol]-2′(1’W)-one (2.30 g) as a colorless solid in 80% yield: ¹H NMR (300 MHz, CDCI₃) £8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1 ); ee (enantiomeric excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl fert-butyl ether). B. Alternatively, a mixture of (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- /Kl^benzodioxole^-indol^ r^-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and triethylsilane (1.1 L) was heated at reflux under nitrogen atmosphere for 3 h, allowed to cool to ambient temperature and concentrated in vacuo to dryness. To the residue was added ethyl acetate (0.3 L), methyl fert-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration, taken up in dichloromethane (3 L), stirred at ambient temperature for 1 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was taken up in ethyl acetate (0.3 L), methyl ferf-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration and dried in vacuo below 50 °C for 8 h to afford (7S)-spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘ -/)-one (0.40 kg) as a colorless solid in 91 % yield: ¹H NMR (300 MHz, CDCI₃) 8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1); ee (enantiomeric excess) 98.6% (HPLC, ChiralPak IA).

EXAMPLE 17

Synthesis of of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yl]methyl}spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(rH)-one

Compound of formula (Ia1)

A. To a mixture of (7S)-6H-spiro[[1 ,3]dioxolo[4,5-f]benzofuran-7,3′-indolin]- 2′-one (1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate (3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for 2 h and filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford (7S)-1′-{[5- (trifluoromethyOfuran^-yllmethy^spiroIfurop.S- ltl .Slbenzodioxole^.S’-indol^ rH)- one (2.71 g) as a colorless solid in quantitative yield (97% purity by HPLC). The product was crystallized from a mixture of methanol and hexanes to afford (7S)-1 ‘-{[5- (trifluoromethy furan^-yllmethylJspirotfuro^.S- lfl .Slbenzodioxole^.S’-indoll^ rH)- one (1.46 g) as colorless needles in 53% yield. The mother liquor was concentrated in vacuo and subjected to a second crystallization in methanol and hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-/][1 ,3]benzodioxole- 7,3’-indol]-2′(1 ‘H)-one (0.469 g) as a colorless solid in 17% yield (total yield 70%): ¹H NMR (300 MHz, CDCI₃) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, to a solution of (7S)-spiro[furoI2,3-f][1 ,3]benzodioxole-7,3′- indol]-2′(1’H)-one (0.40 kg, 1.4 mol) in anhydrous N, W-dimethylformamide (5 L) was added cesium carbonate (1.2 kg, 3.4 mol), followed by 2-(bromomethyl)-5- (trifluromethyl)furan (0.24 L, 1.7 mol). The mixture was heated at 80-85 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (8 L). The combined filtrate and washes were washed with water (4 L), saturated aqueous ammonium chloride (2 * 4 L) and brine (2 * 4 L) and concentrated in vacuo to dryness. The residue was purified by recrystallization from te/t-butyl methyl ether (0.4 L) and heptane (0.8 L), followed by drying of the resultant solid in vacuo at 40-50 °C for 8 h to afford (7S)-1 ‘-{[5- (trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)- one (0.37 kg) as a colorless solid in 61% yield: ¹H NMR (300 MHz, CDCI₃) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz,1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) > 99% (HPLC, Chiralpak IA).

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Na_v1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

The First Asymmetric Pilot-Scale Synthesis of TV-45070

Joseph A. Sclafani^*†§ , Jian Chen†∥, Daniel V. Levy†§, Harlan Reese†⊥, Mina Dimitri†, Partha Mudipalli†, Michael Christie†, Christopher J. Neville‡, Mark Olsen‡, and Roger P. Bakale†#

^†Chemical Process Research and Development, ^‡Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00237

Publication Date (Web): September 8, 2017

Copyright © 2017 American Chemical Society

*E-mail: jasclafan@yahoo.com.

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one (1)

¹H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J= 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H).

¹³C NMR (100 MHz, DMSO-d₆): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, J_CF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, J_CF = 266.4 Hz), 114.01 (q, J_CF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

Funapide

Clinical data
Routes of administration	By mouth, topical
ATC code	None
Identifiers
IUPAC name[show]
CAS Number	1259933-16-8
PubChem CID	49836093
ChemSpider	34500834
UNII	E3COJ2T10W
Chemical and physical data
Formula	C22H14F3NO5
Molar mass	429.34547 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] C1C2(C3=CC=CC=C3N(C2=O)CC4=CC=C(O4)C(F)(F)F)C5=CC6=C(C=C5O1)OCO6

CARMUSTINE

Molecular Formula: C5H9Cl2N3O2
Molecular Weight: 214.046 g/mol

CAS 154-93-8

Brain tumor; Hodgkins disease; Multiple myeloma; Non-Hodgkin lymphoma

1,3-bis(2-chloroethyl)-3-nitrosourea

• Urea, 1,3-bis(2-chloroethyl)-1-nitroso- (8CI)
• N,N’-Bis(2-chloroethyl)-N-nitrosourea
• 1,3-Bis(2-chlorethyl)-1-nitrosourea
• 1,3-Bis(2-chloroethyl)-1-nitrosourea
• 1,3-Bis(2-chloroethyl)nitrosourea

• 1,3-Bis(β-chloroethyl)-1-nitrosourea
• BCNU
• Becenun
• BiCNU
• Carmubris
• Carmustin
• Carmustine
• DTI 015
• FDA 0345
• Gliadel
• Gliadel Wafer
• NSC 409962
• Nitrumon
• SK 27702
• SRI 1720

A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)
It has the appearance of an orange-yellow solid.Carmustine (bis-chloroethylnitrosourea, BCNU, BiCNU) is a medication used mainly for chemotherapy and sometimes for immunosuppression before organ transplantation. It is a nitrogen mustard β-chloro-nitrosourea compound used as an alkylating agent. As a dialkylating agent, BCNU is able to form interstrand crosslinks in DNA, which prevents DNA replication and DNA transcription.

Carmustine for injection was earlier marketed under the name BiCNU by Bristol-Myers Squibb^[2] and now by Emcure Pharmaceuticals.^[3] In India it is sold under various brand names, including Consium.

It is disclosed that carmustine is useful for treating brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas. In September 2017, Newport Premium™ reports that MSN laboratories is potentially interested in carmustine and holds an active US DMF for the drug. Represents new area of patenting to be seen from MSN lab on Carmustine . Supratek was investigating SP-1009C , carmustine formulated in the company’s Biotransport carrier technology, for the potential treatment of glioblastoma. However, no further development has been reported since 2000 , and as of February 2004, SP-1009C was no longer listed on Supratek’s pipeline.

Uses

It is used in the treatment of several types of brain cancer (including glioma, glioblastoma multiforme, medulloblastoma and astrocytoma), multiple myeloma and lymphoma (Hodgkin’s and non-Hodgkin). BCNU is sometimes used in conjunction with alkyl guanine transferase (AGT) inhibitors, such as O⁶-benzylguanine. The AGT-inhibitors increase the efficacy of BCNU by inhibiting the direct reversal pathway of DNA repair, which will prevent formation of the interstrand crosslinkbetween the N¹ of guanine and the N³ of cytosine.

It is also used as part of a chemotherapeutic protocol in preparation for hematological stem cell transplantation, a type of bone marrow transplant, in order to reduce the white blood cell count in the recipient (patient). Use under this protocol, usually with Fludarabine and Melphalan, was coined by oncologists at the University of Texas MD Anderson Cancer Center.

Implants

In the treatment of brain tumours, the U.S. Food and Drug Administration (FDA) approved biodegradable discs infused with carmustine (Gliadel).^[4] They are implanted under the skull during a surgery called a craniotomy. The disc allows for controlled release of carmustine in the extracellular fluid of the brain, thus eliminating the need for the encapsulated drug to cross the blood-brain barrier.^[5]

Reference:

Synthesis, , # 11 p. 1027 – 1029

Celaries, Benoit; Parkanyi, Cyril Synthesis, 2006 , # 14 p. 2371 – 2375

PAPER

Pharmaceutical Chemistry Journal, 2001, vol. 35, vol 2, pg. 108 – 111

10.1023/A:1010485224267

PATENT

EP 3214075

EP 902015

CA1082223

US 523334

SYNTHESIS

PATENT

http://www.google.co.in/patents/US4028410

The Urea. This material is used in good grades, preferably CP, and the amount of urea utilized is the base on which the amounts of nitrosating agent are calculated. The starting material 1,3-bis(2-chloroethyl)urea is commercially available and also may be prepared readily from phosgene and ethyleneimine.

Dinitrogen trioxide (N₂ O₃). Efficacy of reaction has been observed where this nitrosation agent was utilized in preference to the prior use of aqueous NaNO₂. It has also been found for stoichiometric reasons that an excess of the nitrosating agent ranging from 10-200% and preferably 10-20% based on urea is necessary to force the reaction to the right and obtain satisfactory completion. Furthermore, it is known from the literature art, Cotton, Advanced Inorganic Chemistry, Interscience, 1972, page 357, that this oxide exists in a pure state only at low temperatures and, therefore, reaction is conducted at nitrosation temperatures of about 0° C. to -20° C.

The Solvent. In contrast to prior art methods, the present reaction is conducted in an organic milieu. The preferred non-aqueous solvent is of the chlorinated variety; i.e., methylene dichloride. Other preferred compounds include related halogenated compounds such as ethylene dichloride, nitro-compounds such as nitromethane, acetonitrile, and simple ethers such as ethyl ether. Other less preferred but operable compounds include esters such as ethyl acetate, simple ketones such as acetone, and chloroform. Solvents to be avoided are olefins, unsaturated ethers and other unsaturated compounds, amines, malonate esters, acid anhydrides, and solvents which would interact with the reactant N₂ O₃ and the urea as well as the product nitrosourea. In general, the solvent should be low boiling (b.p. less than 120° C. and preferably less than 100° C.).

BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea is one of a group of relatively recent drugs used against cancer and since 1972 has been charted by the National Cancer Institute for utilization against brain tumors, colon cancer, Hodgkins disease, lung cancer, and multiple myeloma. The modus of action of BCNU (NSC 409962) is as an alkylating agent. Such an alkylating agent is injurious to rapidly proliferating cells such as are present in many tumors and this action is known as antineoplastic activity.

EXAMPLE 1 1,3-Bis(2-chloroethyl)-1-nitrosourea

A suspension of 1.11 mmole (0.205 g) of 1,3-bis(2-chloroethyl)urea in 8 ml methylene dichloride at -10° C. was saturated with dinitrogen trioxide in 20% excess of theoretical. The heterogeneous mixture gradually changed to a green homogeneous solution. The methylene dichloride was evaporated, and the residue was extracted with 3× 10 ml hexane. Evaporation of the hexane gave 0.1773 g of oil which was the crude BCNU (NSC 409962). The hexane insoluble portion, 0.0649 g, when treated with benzene, gave 0.020 g of 1,3-bis(2-chloroethyl)urea which was benzene insoluble. The benzene solubles were processed through a silica column (1× 10 cm) and 0.0245 g of crude BCNU was obtained. The combined fractions of crude product amounted to 0.2018 g (85.1%).

In order to evaluate the product, the above crude was recrystallized from hexane to yield a first crop and from this first crop the ir spectrum was identical to that of known BCNU. A tlc (benzene on sillica) gave a single spot R_f 0.35 (blue, 254 mμ).

EXAMPLE 2 Comparative

A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.

EXAMPLE 3

A cold slurry at -15° C. of the 1,3-bis(2-chloroethyl)urea (2.0 mmole) in 8 ml methylene dichloride was treated with a small excess of N₂ O₃. The 1,3-bis(2-chloroethyl)urea is almost insoluble in the cold methylene dichloride, whereas the BCNU product is quite soluble. Thus, treatment of the urea with the N₂ O₃ changed the slurry to a homogeneous solution. Evaporation of the methylene dichloride gave a quantitative yield of crude BCNU. Purification by silica column chromatography gave 93.4% yield and recrystallization from benzene-heptane gave 85.2% yield of pure BCNU.

PAPER

Journal of Medicinal Chemistry (1963), 6(6), 669-81.

SPECTROSCOPY

Chloroform-d, Nitrogen-15 NMR Spectrum,  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21

1H NMR

WO-2017154019

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=103D413664C194D84095110F1084E521.wapp2nA?docId=WO2017154019&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for preparing 1,3-bis(2-chloroethyl)-1- nitrosourea (also known as carmustine) and its intermediate 1,3-bis(2-chloroethyl)urea is claimed. Also claimed are composition comprising them and novel crystalline polymorphic form of carmustine.

,3-bis(2-chloroethyl)-l -nitrosourea is known as Carmustine and is approved in USA under the brand names of BICNU for the treatment of chemotherapy of certain neoplastic diseases such as brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas & Gliadel for the treatment of newly-diagnosed high-grade-malignant glioma as an adjunct to surgery and radiation, recurrent glioblastoma multiforme as an adjunct to surgery.

Journal of Medicinal Chemistry 1963, 6, 669-681 firstly disclosed process for the preparation of l,3-bis(2-chloroethyl)-l-nitrosourea.

US2288178 patent disclosed the process for the preparation of the compound of formula-2 from aziridine and phosgene. J. Med. Chem., 1979, 22 (10), pp 1193-1198 disclosed the process for the preparation of the compound of formula-2 using 2-chloroethanamine and 2-chloroisocyanoethane.

Prior disclosed processes for the preparation of the compound of formula-2 are used hazardous reagents which were difficult to handle in the laboratory. The present inventors have developed an improved process for the preparation of the compound of formula-2 by using easily available raw materials and usage of that compound in the preparation of the compound of formula- 1 to get good yield and having high purity.

he present invention is schematically represented in the scheme- 1.

Scheme-1

Examples:

Example-1: Preparation of l,3-bis(2-chloroethyl)urea compound of formula-2

2-chloroethanamine hydrochloride (429.19 gm) was added to the mixture of carbonyldiimidazole (200 gm) and tetrahydrofuran (1000 ml) at 25-30°C and stirred the reaction mixture for 5 minutes. Heated the reaction mixture to 65-70°C and stirred for 14 hours at the same temperature. Cooled the reaction mixture to 25-30°C and water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with isopropanol. Isopropanol (100 ml) was added to the obtained compound and stirred the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred the reaction mixture for 10 minutes at the same temperature.

Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 1 10 gm; M.P: 121-125°C.

Example-2: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (50 gm) was added to the mixture of dilute hydrochloric acid (16 ml) and acetic acid (205 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Sodium nitrite (46.6 gm) was added to the reaction mixture in lot-wise over the period of 3 hours at 0-5 °C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched into pre-cooled water at 0-5°C and stirred it for 30 minutes at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (100 ml) at 0-5°C. The reaction mixture was added to pre-cooled n-heptane (250 ml) at 0-5°C and stirred for 1 ½ hour at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 28 gm.

Example-3: Preparation of l,3-bis(2-chloroethyl)urea compound of formuIa-2

Carbonyldiimidazole (8 kg) was slowly added to the pre-cooled mixture of 2-chloroethanamine hydrochloride (14.31 kg) and tetrahydrofuran (40 lit) at 0-5°C in lot-wise under nitrogen atmosphere and stirred the reaction mixture for 5 minutes. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 36 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the obtained compound at 25-30°C and stirred it for I hour at the same temperature. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water at 25-30°C, filtered and washed with water. Methanol was added to the obtained compound at 25-30°C and stirred it for 1 hour at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 6 kg; PXRD of the obtained compound is shown in figure-3.

Example-4: Preparation of l,3-bis(2-ch!oroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (6 kg) was added to the mixture of dilute hydrochloric acid (1.9 lit) and acetic acid (24.5 lit) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (5.59 kg) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (24 lit) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (3 kg) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (12 lit) was added to the obtained compound and stirred it for at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (60 lit) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure.

Yield: 4.5 kg; MR: 30-32°C;

Purity by HPLC: 99.97%; Impurity at RRT -0.08: 0.01%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

PXRD of the obtained compound is shown in figure- 1 and IR shown in figure-2.

Example-5: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (150 gm) was added to the mixture of dilute hydrochloric acid (48 ml) and acetic acid (612 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (139.8 gm) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water.

Purity by HPLC: 95.1 1%, Impurity at RRT -0.08: 4.17%, Impurity at RRT -0.13: 0.63%.

Example 6: Purification of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1

Dissolved the compound of formula 1 obtained in example-5 in dichloromethane (600 ml) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (75 gm) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (300 ml) was added to the obtained compound and stirred it for 10-15 min at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (1500 ml) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure. Yield: HO gm; MR: 30-32°C;

Purity by HPLC: 99.96%, Impurity at RRT -0.08: 0.02%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

References

External links

• MedlinePlus DrugInfo medmaster-a682060
• BiCNU package insert, U.S.
• Idis press release for EU

1.  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21 
2.  Barcelo, Gerard; Synthesis 1987, (11), P1027-9 
3.  Barcelo, Gerard; FR 2589860 A1 1987 
4.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
5.  Xu, Longji; International Journal of Pharmaceutics 2008, V355(1-2), P249-258 
6.  Xu, Xiuling; Journal of Controlled Release 2006, V114(3), P307-316 
7.  Lown, J. William; Journal of Organic Chemistry 1982, V47(5), P851-6 
8. “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)

Carmustine

Names
IUPAC name 1,3-Bis(2-chloroethyl)-1-nitrosourea[1]
Other names N,N’-Bis(2-chloroethyl)-N-nitrosourea
Identifiers
CAS Number	154-93-8
3D model (JSmol)	Interactive image
ChEBI	CHEBI:3423
ChemSpider	2480
DrugBank	DB00262
ECHA InfoCard	100.005.309
EC Number	205-838-2
KEGG	D00254
MeSH	Carmustine
PubChem CID	2578
RTECS number	YS2625000
UNII	U68WG3173Y
UN number	2811
InChI[show]
SMILES[show]
Properties
Chemical formula	C5H9Cl2N3O2
Molar mass	214.05 g·mol−1
Appearance	Orange crystals
Odor	Odourless
Melting point	30 °C (86 °F; 303 K)
log P	1.375
Acidity (pKa)	10.194
Basicity (pKb)	3.803
Pharmacology
ATC code	L01AD01 (WHO)
Hazards
GHS pictograms
GHS signal word	DANGER
GHS hazard statements	H300, H350, H360
GHS precautionary statements	P301+310, P308+313
Lethal dose or concentration (LD, LC):
LD50 (median dose)	20 mg kg−1 (oral, rat)
Related compounds
Related ureas	Dimethylurea
Related compounds	Noxytiolin 1,1,3,3-Tetramethylguanidine Metformin Allantoic acid Buformin
Except where otherwise noted, data are given for materials in their standa