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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
Originator University of Munich; University of Oxford
Developer IntraBio
Class Acetamides; Amino acids; Esters; Neuroprotectants; Pentanoic acids; Small molecules; Vestibular disorder therapies
Mechanism of Action Calcium channel modulators
Orphan Drug StatusYes – Tay-Sachs disease; Niemann-Pick disease type C; Ataxia telangiectasia
Registered Niemann-Pick disease type C
Phase IIIAtaxia telangiectasia
Phase IISandhoff disease; Tay-Sachs disease
18 Mar 2025Phase-III clinical trials in Ataxia telangiectasia (In adolescents, In children, In the elderly, In adults) in Switzerland, Slovakia, Spain, Germany, USA, United Kingdom (PO) (NCT06673056)
04 Nov 2024IntraBio plans a phase III trial for Ataxia telangiectasia (In children, In adolescents, In adults, In elderly) in the US, Germany, Slovakia, Spain and Switzerland (PO, Suspension) in March 2025 (NCT06673056)
24 Sep 2024Registered for Niemann-Pick disease type C (In adolescents, In children, In adults) in USA (PO)
Levacetylleucine (N-acetyl-L-leucine), sold under the brand name Aqneursa, is a medication used for the treatment of neurological manifestations of Niemann-Pick disease type C.[1][2] Levacetylleucine is a modified version of the amino acid leucine.[1] It is the L-form of acetylleucine. It is taken by mouth.[1]
Levacetylleucine was approved for medical use in the United States in September 2024.[1][2][3] Levacetylleucine is the second medication approved by the US Food and Drug Administration (FDA) for the treatment of Niemann-Pick disease type C.[2] The FDA considers it to be a first-in-class medication.[4]
DATA
N-acetyl-D, L-leucine is the active ingredient of Tanganil ® which helps treat vertigo attacks.
N-Acetyl-D, L-leucine
Unlike the majority of chemical syntheses of active principles where it is desirable to separate the enanti omers and / or to retain the selective stereo information during the synthesis steps, the synthesis of N-acetyl-D, L-leucine is carried out from L-leucine and therefore involves a racemization step. This racemization takes place before the acetylation step, via a Schiff base formed in situ with salicylic aldehyde (Yamada et al., J. Org. Chem., 1983 48, 843- 846).
Two competitive reactions are then involved: the acetylation of leucine, the main reaction, where acetic anhydride reacts with the amine function of leucinate of sodium to give N-acetyleucinate and the hydrolysis of acetic anhydride to acetic acid, a side reaction described below.
This synthesis has a molar yield of 70%. The limiting steps are essentially the secondary reaction of hydrolysis of acetic anhydride and the step of isolation of the racemized leucine before the acetylation reaction. Indeed, on an industrial scale, the quantities of products brought into play for isolations prove to be very restrictive.
There is therefore a real need to develop a new process for the preparation of N-actéyl-D, L-leucine which is faster and more economical.
The inventors thus discovered that the racemization step could be carried out after the L-leucine acetylation step making it possible to avoid a step of isolating the intermediate product and that this process could be carried out in continuous flow. Du Vigneaud & Meyer (J. Biol Chem, 1932, 98, 295-308) had already shown that it was possible to racemize different acetylated amino acids by bringing them into the presence of acetic anhydride for several hours. However, no examples had been made with acetyl leucine. By attempting to reproduce this process with acetyl-leucine, the inventors have thus found that this racemization reaction did not give satisfactory results with acetyl-leucine because of a competitive hydrolysis reaction of acetic anhydride. used. The inventors have also surprisingly discovered that the racemization reaction of N-acetyl-L-leucine could be improved by producing it in a continuous flow. It seems indeed that the realization of this continuous flow process allows better control of the mixing of the reagents and therefore to better control the reaction. The inventors have also shown that the racemization of N-acetyl-L-Leucine in continuous flow was obtained in a very short time of the order of a few minutes.
Furthermore, there is also a need to develop a new method of acetylation of leucine for the preparation of N-actyle-leucine which is faster and more economical. The inventors have discovered that the acetylation reaction of leucine can be improved by making it in a continuous flow. The process according to the invention gives good yields, in a very short time and using fewer reagents compared to the method known hitherto.
Indeed, DeWitt et al. (J Am Chem Soc (1951) 73 (7) 3359-60) described the preparation of N-acetyl-L-Leucine by reacting L-Leucine with 3 molar equivalents of acetic anhydride and sodium hydroxide for 2 hours 20 minutes. . N-acetyl-L-leucine is then obtained in a yield of only 70-80%. In addition, the authors of this publication clearly indicated that a molar ratio between L-Leucine and acetic anhydride below 2 resulted in much lower yields.
SYNTHESIS
H. D. DeWitt and A. W. Ingersoll. The Preparation of Pure N-Acetyl-L-leucine and L-Leucine. Journal of the American Chemical Society 1951 73 (7), 3359-3360. DOI: 10.1021/ja01151a108
A. L. Study of the molar ratio of acetic anhydride to leucine
The objective of this study is to define the necessary molar ratio of acetic anhydride so that the acetylation reaction with acetic anhydride is complete and is not disadvantageous by competition with the acetic anhydride hydrolysis reaction. In this study, the residence time in the reactor / exchanger (1 process plate) was set at 9 seconds, for a temperature of the reaction medium of between 25 and 30 ° C.
The ratio range studied is between 0.9 and 2.0 molar equivalents. The optimum is obtained for a ratio between 1.20 and 2.00, more particularly between 1.30 and 1.60. Below this ratio, the acetylation reaction is disadvantageous compared to the acetic hydrolysis reaction. Beyond this, the drop in pH (acid instead of base) also disadvantages the acetylation reaction.
EXAMPLES 1-10:
A solution of sodium L-leucinate, for passage in continuous flow reactor, is prepared in the following manner: 700 g of L-leucine are dissolved in a solution of 576 g of sodium hydroxide and 3.5 liters of Demineralized Water. This solution is the main fluid process. The reaction between this solution and the acetic anhydride is carried out in a continuous flow in a Boostec® reactor, made of silicon carbide. The reactor / exchanger is configured with an injection-type process plate comprised between two utility plates. The volume of the process plate is 10 mL. The temperature in the reactor is maintained by the circulation of a coolant heated by a thermostatic bath. The transformation of L-leucine to N-acetyl-L-leucine is monitored online by quantitative Raman spectroscopy. This method of analysis is calibrated beforehand with solutions of known concentration prepared with pure L-leucine and N-acetyl-L-leucine.
Example 1
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 4.06 kg.h -1 and 0.42 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 0.91 equivalents. The total flow rate is therefore 4.48 kg.h -1 , which corresponds to a residence time (equivalent to the reaction time) of 8.7 s The yield of acetyl-L-leucinate determined by Raman spectroscopy online at the outlet of the reactor is 40% Example 2:
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.95 kg · h -1 and 0.45 kg · h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.01 equivalents. The total flow rate is therefore 4.40 kg.h -1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 52.degree. %.
Example 3
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.89 kg · h -1 and 0.52 kg · h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.18 equivalents. The total flow rate is therefore 4.41 kg.h -1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 57.degree. %. Example 4
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.82 kg. h -1 and 0.57 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.32 equivalents. The total flow is therefore 4.39 kg. h “1 , which corresponds to a residence time of 8.9 S. The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 83%.
Example 5
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective rates set at 3.64 kg. h -1 and 0.55 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.34 equivalents. The total flow is therefore 4, 19 kg. h “1 , which corresponds to a residence time of 9.4 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 98%.
Example 6
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective rates set at 3.66 kg. h 1 and 0.62 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.50 equivalents. The total flow is therefore 4.28 kg. h “1 , which corresponds to a residence time of 9.2 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 96%.
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates fixed at 3.67 kg. h -1 and 0.64 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.54 equivalents. The total flow is therefore 4.31 kg. h “1 , which corresponds to a residence time of 9.1 sec The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 100%. Example 8
The temperature of the thermostated bath is set at 25 ° C. The sodium leucinate solution and pure acetic anhydride are introduced into the reactor at respective flow rates set at 3.63 kg. h -1 and 0.73 kg h -1 . These flow rates correspond to a molar ratio of acetic anhydride to leucine of 1.78 equivalents. The total flow is therefore 4.36 kg. h “1 , which corresponds to a residence time of 9.0 s The yield of acetyl-L-leucinate determined by in-line Raman spectroscopy at the outlet of the reactor is 90%.
100gL-leucine adds 1000ML2NNaOH rising temperature for dissolving, adds 1ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add 160ML HCl and adjust PH 2.5, be cooled to 4 degree, suction filtration, the 118g. of oven dry
Example 2:
100gL-leucine adds 1200ML 2NNaOH rising temperature for dissolving, adds 3ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add the 3.0. that 180ML HCl adjusts PH, be cooled to 4 degree, suction filtration, the 110g. of oven dry
Example 3:
100gL-leucine adds 1000ML 2NNaOH rising temperature for dissolving, adds 2ML salicylic aldehyde, 95 degree of insulations of intensification 3 hours, recording optically-active is 0, be cooled to 5 degree and keep, dripping 80ML diacetyl oxide, dropwise maintenance 0.5 hour, be warmed up to 60 degree, add proper amount of active carbon decolouring, add 180ML HCl and adjust PH 3.0, be cooled to 4 degree, suction filtration, the 120g. of oven dry
Medical uses
Levacetylleucine is indicated for the treatment of neurological manifestations of Niemann-Pick disease type C in people weighing at least 15 kilograms (33 lb).[1][2]
Adverse effects
The most common side effects include abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting.[2]
Levacetylleucine may cause embryo-fetal harm if used during pregnancy.[1][2]
History
The safety and efficacy of levacetylleucine for the treatment of Niemann-Pick disease type C were evaluated in a randomized, double-blind, placebo-controlled, two-period, 24-week crossover study.[2] The duration was twelve weeks for each treatment period.[2] The study enrolled 60 participants.[2] To be eligible for the study participants had to be four years of age or older with a confirmed diagnosis of Niemann-Pick disease type C and at least mild disease-related neurological symptoms.[2] Participants could receive miglustat, an enzyme inhibitor, as background treatment in the study.[2]
^ Passmore P (15 April 2014). A clinical trial to test amlodipine as a new treatment for vascular dementia. ISRCTN registry (Report). doi:10.1186/isrctn31208535.
^ Strupp M, Bayer O, Feil K, Straube A (February 2019). “Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series”. Journal of Neurology. 266 (2): 525–529. doi:10.1007/s00415-018-9155-6. PMID30547273. S2CID56148131.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, et al. (February 2024). “Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C”. The New England Journal of Medicine. 390 (5): 421–431. doi:10.1056/NEJMoa2310151. PMID38294974.
Tifft CJ (February 2024). “N-Acetyl-l-Leucine and Neurodegenerative Disease”. The New England Journal of Medicine. 390 (5): 467–470. doi:10.1056/NEJMe2313791. PMID38294981.
External links
Clinical trial number NCT05163288 for “A Pivotal Study of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C” at ClinicalTrials.gov
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannova S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K: Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. [Article]
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M: N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. [Article]
FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
FDA News Release: FDA Approves New Drug to Treat Niemann-Pick Disease, Type C [Link]
Arimoclomol maleate is in a phase III clinical trials by Orphazyme for the treatment of Niemann-Pick disease type C (NP-C). It is also in phase II clinical studies for the treatment of amyotrophic lateral sclerosis (ALS).
Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[1] The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[2][3]
Fig. 1 Structures of (±)-bimoclomol (1) and (R)-(+)-arimoclomol (2).
The present disclosure provides an optimized four-step process for preparing an ultra-pure composition comprising arimoclomol citrate, i.e. N-{[(2R)-2-hydroxy-3-piperidin-l-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate. The optimized process comprises a plurality of optimized sub-steps, each contributing to an overall improved process, providing the ultra-pure composition comprising arimoclomol citrate. The ultra-pure composition comprising arimoclomol citrate meets the medicines agencies’ high regulatory requirements. An overview of the four-steps process is outlined below:
Step 1: Overview of process for preparing ORZY-01
Step 2: Overview of process for preparing ORZY-03
Step 4: Overview of process for preparing BRX-345 (ORZY-05)
The previously reported two-step synthesis of ORZY-01 as shown below includes a 2 hour reflux in step 1A, followed by purification of intermediate compound (V) to increase the batch quality.
(R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide1 – (R)-(+)-Arimoclomol – 2 A solution of (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carbamimidoyl)pyridine-1-oxide 12 (205 mg, 0.70 mmol) in conc. hydrochloric acid (1.1 mL, 13.9 mmol) and water (3 mL) was cooled to -5 °C for 15 minutes. Sodium nitrite (63 mg, 0.91 mmol) in water (0.5 mL) was then added dropwise to the reaction mixture and the reaction was stirred at -5 °C for 2.5 hours. The reaction mixture was made alkaline with NaOH (7 M, 3 mL). An additional 10 mL of water was added followed by DCM (30 mL) containing EtOAc (5 mL) and the organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on Biotage Isolera using Biotage SNAP 10 g Si cartridge eluting with gradient elution 0-30% MeOH:DCM both containing 0.1% Et3N to afford the title compound (160 mg, 73% yield) as a colourless semi-solid. Analytical data was consistent with literature values. See ESI section SFC traces for specific enantiomeric ratios of 2 synthesised under the various methodologies quoted in the text. Optical rotation was not determined as it was determined in the ultimate product of this 2·citrate and comparative run times on SFC. 1H NMR (600 MHz, CDCl3) δ: 8.63 (t, J = 1.4 Hz, 1H), 8.16 (ddd, J = 6.4, 1.6, 0.9 Hz, 1H), 7.66 – 7.62 (m, 1H), 7.25 (dd, J = 8.0, 6.6 Hz, 1H), 4.26 (qd, J = 11.3, 5.2 Hz, 2H), 4.07 (dd, J = 9.2, 4.7 Hz, 1H), 2.62 (s, 2H), 2.47 – 2.31 (m, 4H), 1.65 – 1.51 (m, 4H), 1.42 (s, 2H); 13C NMR (151 MHz, CDCl3) δ: 140.3, 137.7, 133.1, 132.5, 125.7, 123.9, 78.7, 64.9, 60.9, 54.8, 25.8, 24.0.
(R)-(+)- Arimoclomol citrate – 2·citrate (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide (159 mg, 0.51 mmol) was dissolved in acetone (3 mL) and citric acid (97 mg, 0.51 mmol) was added. The reaction mixture was left to stir at room temperature for 18 hours. After this time the mixture was sonicated and the precipitate was filtered, rinsed with cold acetone (1 mL) and dried under vacuum to afford the title compound (165 mg, 64% yield) as a white amorphous solid. Analytical data was consistent with literature values. m.p. 161-162 °C, Acetone (lit. 163-165 °C, EtOH); [α]D 20 +8.0 (c=1, H2O); IR νmax (neat): 3423, 3228, 2949, 2868, 1722, 1589, 1483, 1433, 1307, 1128, 972, 829 cm-1; 1H NMR (600 MHz, d6-DMSO) δ: 8.54 (t, J = 1.5 Hz, 1H), 8.39 – 8.35 (m, 1H), 7.72 – 7.68 (m, 1H), 7.55 (dd, J = 8.0, 6.5 Hz, 1H), 4.28 (ddd, J = 17.6, 13.3, 7.4 Hz, 3H), 3.35 (br. s, 2H), 3.13 – 2.74 (m, 6H), 2.59 (d, J = 15.2 Hz, 2H), 2.56 – 2.51 (m, 2H), 1.77 – 1.61 (m, 4H), 1.48 (s, 2H); 13C NMR (151 MHz, d6-DMSO) δ: 176.6, 171.3, 140.5, 136.4, 132.7, 131.5, 126.8, 123.3, 77.8, 71.4, 63.8, 58.7, 53.1, 44.0, 30.7, 23.0, 21.9; HRMS (m/z TOF MS ES+) for C14H20ClN3O3 [M+H]+ calc. 314.1271, observed 314.1263; SFC er purity R:S >99:1
Procedure for the conversion of (R)-(+)-Bimoclomol 1 into (R)-(+)-Arimoclomol 2 To a solution of (R)-(+)-bimoclomol (61 mg, 0.21 mmol) in acetone (2 mL) was added benzenesulfonic acid (33 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. Separately to a suspension of hydrogen peroxide-urea adduct (39 mg, 0.41 mmol) in acetonitrile (6 mL) at -5°C (ice-salt bath) was added trifluoroacetic anhydride (58 μL, 0.41 mmol) dropwise. A suspension of (R)-(+)-bimoclomol, 1, benzenesulfonic acid salt, as made above, in acetonitrile (3 mL) was then added dropwise to this solution. The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. Aqueous Na2S2O5 solution (0.5 M, 1 mL) was added and the reaction mixture stirred for 1 hour. The reaction mixture was made alkaline with NaOH (7 M) and extracted with DCM (2 x 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on a Biotage Isolera using Biotage SNAP 10g Si cartridge eluting with gradient elution 0-35% MeOH in DCM to afford the title compound (35 mg, 55% yield) as a colourless semi-solid. Analytical data of the products was consistent with literature and/or previous samples synthesised above.
Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.
Arimoclomol has been shown to extend life in an animal model of ALS[11] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[12]
Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy’s Disease).[13]
Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[14][15] and diabetic complications such as retinopathy, neuropathy and nephropathy. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003.
^ Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (April 2004). “Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice”. Nat. Med. 10 (4): 402–5. doi:10.1038/nm1021. PMID15034571. S2CID2311751.
^ Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G (December 2003). “The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury”. Exp. Neurol. 184 (2): 636–47. doi:10.1016/S0014-4886(03)00343-1. PMID14769355. S2CID5316222.
^ Rakonczay Z, Iványi B, Varga I, et al. (June 2002). “Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats”. Free Radic. Biol. Med. 32 (12): 1283–92. doi:10.1016/S0891-5849(02)00833-X. PMID12057766.
^ Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L (July 2002). “Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats”. Exp. Neurol. 176 (1): 87–97. doi:10.1006/exnr.2002.7945. PMID12093085. S2CID16071543.
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