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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves drug to treat ALS, Radicava (Edaravone) , эдаравон, إيدارافون , 依达拉奉 ,ラジカット,


Edaravone.svg

05/05/2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

May 5, 2017

Release

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,

ChemSpider 2D Image | Edaravone | C10H10N2O

1-Phenyl-3-methyl-5-pyrazolone
3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- [ACD/Index Name]
89-25-8 [RN]
эдаравон [Russian]
إيدارافون [Arabic]
依达拉奉 [Chinese]
ラジカット,
MCI-186

Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.[1] It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis.[2][3][4] It has been marketed solely in Japan by Mitsubishi Pharma since 2001.[1] It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.

On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.

The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.

Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia.[5][6] It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.[7][8][9]

Image result for edaravone synthesis

Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.

Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

SYNTHESIS

Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:

 

Figure CN101830852BD00031

[0004] Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.

For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.

Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:

Figure CN102285920BD00031

edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.

 The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I

Edaravone synthetic route for the reaction:

Figure CN102285920BD00032

[0008] The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:

Figure CN102285920BD00041

PATENT

https://www.google.com/patents/CN101830852B?cl=en

Figure CN101830852BD00041

1 Edaravone Synthesis Example [0023] Example

[0024] (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours; [0025] ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;

[0026] (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0

2 Edaravone Synthesis Example [0027] Example

[0028] (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;

[0029] (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;

(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0

3 Edaravone Synthesis Example [0031] Example

[0032] (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;

[0033] (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;

[0034] (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0

[0035] Comparative Example

[0036] The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).

PATENT

https://www.google.com/patents/CN102285920B?cl=en

Example 1: Preparation of phenylhydrazine edaravone.

[0024] a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.

[0025] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0026] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0

[0027] Example 2: Preparation of phenylhydrazine hydrochloride edaravone.

[0028] a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.

[0029] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0030] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%. [0031] Comparative Example:

Under the [0032] state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.

Figure CN102285920BD00042

CLIP

http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849739634-chapter%204.2.3.pdf

Edaravone:

IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;

1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);

13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;

1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);

13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.

These values are in accordance with the previous published in literature1 .

In the carbon spectrum in DMSO presented in Figure SM 4.2.3.1.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 4.2.3.1.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.

1. S. Pal, J. Mareddy and N. S. Devi, J.  Braz. Chem. Soc., 2008, 19, 1207.

CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000600023

We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1Figure 2) in DMSO and 2,4-dihydro form (T-2Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27

 

 

 

5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)

mp 125-127 ºC (lit21 126-130 ºC); 

IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;

 1H NMR (400 MHz, DMSO-d6δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H); 

13C NMR (50 MHz, DMSO-d6δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9; 

Mass (CI, m/z) 175 (M+1, 100).

1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).

21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 200412, 2317.         [ Links ]

CN101830852A Mar 22, 2010 Sep 15, 2010 海南美兰史克制药有限公司 Edaravone compound synthesized by new method
CN102060771A Nov 18, 2009 May 18, 2011 南京长澳制药有限公司 Edaravone crystal form and preparation method thereof
CN102180834A Mar 24, 2011 Sep 14, 2011 江苏正大丰海制药有限公司 Preparation method for edaravone

References

  1. ^ Jump up to:a b Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
  2. Jump up^ Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
  3. Jump up^ Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
  4. Jump up^ Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
  5. Jump up^ Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC 2533664Freely accessible. PMID 18671880.
  6. Jump up^ Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
  7. Jump up^ Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
  8. Jump up^ Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
  9. Jump up^ Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.

External links

Edaravone
Edaravone.svg
Edaravone ball-and-stick model.png
Clinical data
Trade names Radicut
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Rx-only (JP)
Identifiers
Synonyms MCI-186
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.719
Chemical and physical data
Formula C10H10N2O
Molar mass 174.20 g/mol
3D model (Jmol)
////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,
O=C1CC(=NN1c1ccccc1)C
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FDA approves first treatment for a form of Batten disease, Brineura (cerliponase alfa)


Image result
04/27/2017
The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

“The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition.”

CLN2 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease. CLN2 disease is a rare inherited disorder that primarily affects the nervous system. In the late infantile form of the disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.

Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

The efficacy of Brineura was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.

The safety of Brineura was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura in clinical studies. The safety and effectiveness of Brineura have not been established in patients less than 3 years of age.

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure.

Brineura should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).

Health care providers should also monitor vital signs (blood pressure, heart rate, etc.) before the infusion starts, periodically during infusion and post-infusion in a health care setting. Health care providers should perform electrocardiogram (ECG) monitoring during infusion in patients with a history of slow heart rate (bradycardia), conduction disorder (impaired progression of electrical impulses through the heart) or structural heart disease (defect or abnormality of the heart), as some patients with CLN2 disease can develop conduction disorders or heart disease. Hypersensitivity reactions have also been reported in Brineura-treated patients. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated.

The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Brineura also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucherunder a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.

////////Brineura, cerliponase alfa, fda 2017, Batten disease, BioMarin Pharmaceutical Inc, Priority Review,  Breakthrough Therapy designations, Orphan Drug designation,

FDA approves Xermelo (telotristat ethyl) for carcinoid syndrome diarrhea


ChemSpider 2D Image | Telotristat ethyl | C27H26ClF3N6O3Image result for telotristat ethyl

 

Telotristat ethyl

Molecular Formula, C27-H26-Cl-F3-N6-O3,

Molecular Weight, 574.9884,

RN: 1033805-22-9
UNII: 8G388563M

LX 1032

(2S)-2-Amino-3-[4-[2-amino-6-[[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethyl]oxy]pyrimidin-4-yl]phenyl]propionic acid ethyl ester

Ethyl-4-(2-amino-6-{(1R)-1-[4-chlor-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluorethoxy}-4-pyrimidinyl)-L-phenylalaninat

L-Phenylalanine, 4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-4-pyrimidinyl]-, ethyl ester
SEE……………
Image result for Telotristat etiprate,LX1606 Hippurate.png
Telotristat etiprate,
(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate 2-benzamidoacetate .
CAS: 1137608-69-5 (etiprate), LX 1606
Chemical Formula: C36H35ClF3N7O6
Molecular Weight: 754.16
L-Phenylalanine, 4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-4-pyrimidinyl]-, ethyl ester, compd. with N-benzoylglycine (1:1)
  • LX 1032 hippurate
  • LX 1606
SEE ALSO………….
Telotristat, also known as LX1033, 1033805-28-5 CAS OF ACID FORM
 Arokiasamy Devasagayaraj
02/28/2017
The U.S. Food and Drug Administration today approved Xermelo (telotristat ethyl) tablets in combination with somatostatin analog (SSA) therapy for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled.
February 28, 2017
The U.S. Food and Drug Administration today approved Xermelo (telotristat ethyl) tablets in combination with somatostatin analog (SSA) therapy for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled.

Carcinoid syndrome is a cluster of symptoms sometimes seen in people with carcinoid tumors. These tumors are rare, and often slow-growing. Most carcinoid tumors are found in the gastrointestinal tract. Carcinoid syndrome occurs in less than 10 percent of patients with carcinoid tumors, usually after the tumor has spread to the liver. The tumors in these patients release excess amounts of the hormone serotonin, resulting in diarrhea. Complications of uncontrolled diarrhea include weight loss, malnutrition, dehydration, and electrolyte imbalance.

“Today’s approval will provide patients whose carcinoid syndrome diarrhea is not adequately controlled with another treatment option,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.

Xermelo, in a regimen with SSA therapy, is approved in tablet form to be taken orally three times daily with food. Xermelo inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea.

The safety and efficacy of Xermelo were established in a 12-week, double-blind, placebo-controlled trial in 90 adult participants with well-differentiated metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. These patients were having between four to 12 daily bowel movements despite the use of SSA at a stable dose for at least three months. Participants remained on their SSA treatment, and were randomized to add placebo or treatment with Xermelo three times daily. Those receiving Xermelo added on to their SSA treatment experienced a greater reduction in average bowel movement frequency than those on SSA and placebo. Specifically, 33 percent of participants randomized to add Xermelo on to SSA experienced an average reduction of two bowel movements per day compared to 4 percent of patients randomized to add placebo on to SSA.

The most common side effects of Xermelo include nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decreased appetite and fever. Xermelo may cause constipation, and the risk of developing constipation may be increased in patients whose bowel movement frequency is less than four bowel movements per day. Patients treated with a higher than recommended dosage of Xermelo developed severe constipation in clinical trials. One patient required hospitalization and two other patients developed complications of either intestinal perforation or intestinal obstruction. Patients should be monitored for severe constipation. If a patient experiences severe constipation or severe, persistent or worsening abdominal pain, they should discontinue Xermelo and contact their healthcare provider.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Xermelo is manufactured by Woodlands, Texas-based Lexicon Pharmaceuticals, Inc.

SYNTHESIS…….WO 2011100285

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011100285&recNum=142&docAn=US2011024141&queryString=((serotonin)%2520OR%2520(HT2C)%2520OR%2520(&

5.67. Synthesis of (S)-2-Amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yll- phenyll-2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl)-phenyll-propionic acid ethyl ester

The title compound was prepared stepwise, as described below:

Step 1: Synthesis of l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5°C (ice water bath) over 10 minutes. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHC03 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2- bromo-4-chloro-benzoic acid methyl ester (26 g, 99 %), which was directly used in the following step.

2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -70°C, and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added.

Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4h, after which it was stirred for 10 hours at room temperature. The reaction mixture was concentrated to give the crude [l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-l-methoxy-ethoxy]-trimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCI (100 ml) was added. The mixture was kept at 45-50°C for 12h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHC03 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). !H-NMR (300 MHz, CDC ): δ (ppm) 7.50 (d,lH), 7.65(d,lH), 7.80(s,lH).

Step 2: Synthesis of R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol. To catechol borane (1M in THF 280 ml, 280 mmol) in a 2L 3-necked RB flask was added S-2-methyl-CBS oxazaborolidine (7.76 g, 28 mmol) under nitrogen, and the resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to -78°C (dry ice/acetone bath), and 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (40 g, 139 mmol) in THF (400 ml) was added dropwise over 2 hours. The reaction mixture was allowed to warm to -36°C, and was stirred at that temperature for 24 hours, and further stirred at -32 °C for another 24h. 3N NaOH (250 ml) was added, and the cooling bath was replaced by ice-water bath. Then 30 % hydrogen peroxide in water (250 ml) was added dropwise over 30 minutes. The ice water bath was removed, and the mixture was stirred at room temperature for 4 hours. The organic layer was separated, concentrated and re-dissolved in ether (200 ml). The aqueous layer was extracted with ether (2 x 200 ml). The combined organic layers were washed with IN aq. NaOH (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave crude product which was purified by column chromatography using 2 to 5% ethyl acetate in hexane as solvent to give desired alcohol 36.2 g (90 %, e.e. >95%). The alcohol (36.2 g) was crystallized from hexane (80 ml) to obtain R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol 28.2 g (70 %; 99-100 % e.e.). !H-NMR (400 MHz, CDCIs) δ (ppm) 5.48 (m, 1H), 7.40 (d, 1H), 7.61 (d, 2H).

Step 3: Synthesis of R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyll-2.2.2-trifluoro-ethanol. R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol (15.65 g, 54.06 mmol), 3-methylpyrazole (5.33 g, 65 mmol), Cul (2.06 g, 10.8 mmol), 2CO3 (15.7 g, 113.5 mmol), (lR,2R)-N,N’-dimethyl-cyclohexane-l,2-diamine (1.54 g, 10.8 mmol) and toluene (80 ml) were combined in a 250 ml pressure tube and heated to 130°C (oil bath temperature) for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10 % ethyl acetate in hexane as solvent to get R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (13.5 g; 86 %). i-H-NMR (400 MHz, CDC ): δ (ppm) 2.30(s, 3H), 4.90(m, 1H), 6.20(s, 1H), 6.84(d, 1H), 7.20(s, 1H), 7.30(d, 1H), 7.50(d, 1H).

Step 4: Synthesis of (S)-2-Amino-3- 4-(2-amino-6-fR-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyll^^^-trifluoro-ethoxyl-pyrimidin^-yll-phenvD-propionic acid ethyl ester. R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (17.78 g, 61.17 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (20.03 g, 51 mmol), 1,4-dioxane (250 ml), and CS2CO3 (79.5 g, 244 mmol) were combined in a 3-necked 500 ml RB flask and heated to 100°C (oil bath temperature) for 12-24 hours. The progress of reaction was monitored by LCMS. After the completion of the reaction, the mixture was cooled to 60°C, and water (250 ml) and THF (400 ml) were added. The organic layer was separated and washed with brine (150 ml). The solvent was removed to give crude BOC protected product, which was taken in THF (400 ml), 3N HCI (200 ml). The mixture was heated at 35-40 °C for 12 hours. THF was removed in vacuo. The remaining aqueous layer was extracted with isopropyl acetate (2x 100 ml) and concentrated separately to recover the unreacted alcohol (3.5 g). Traces of remaining organic solvent were removed from the aqueous fraction under vacuum.

To a 1L beaker equipped with a temperature controller and pH meter, was added H3PO4 (40 ml, 85 % in water) and water (300 ml) then 50 % NaOH in water to adjust pH to 6.15. The temperature was raised to 58 °C and the above acidic aqueous solution was added dropwise into the buffer with simultaneous addition of 50 % NaOH solution in water so that the pH was maintained between 6.1 to 6.3. Upon completion of addition, precipitated solid was filtered and washed with hot water (50-60°C) (2 x 200 ml) and dried to give crude (S)-2-amino-3-[4-(2-amino-6-[R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl}^ propionic acid (26.8 g; 95 %). LCMS and HPLC analysis indicated the compound purity was about 96-97 %.

To anhydrous ethanol (400 ml) was added SOC (22 ml, 306 mmol) dropwise at 0-5°C.

Crude acid (26.8 ) from the above reaction was added. The ice water bath was removed, and the reaction mixture was heated at 40-45°C for 6-12 hours. After the reaction was completed, ethanol was removed in vacuo. To the residue was added ice water (300 ml), and extracted with isopropyl acetate (2 x 100 ml). The aqueous solution was neutralized with saturated Na2C03 to adjust the pH to 6.5. The solution was extracted with ethyl acetate (2 x 300 ml). The combined ethyl acetate layer was washed with brine and concentrated to give 24 g of crude ester (HPLC purity of 96-97 %). The crude ester was then purified by ISCO column chromatography using 5 % ethanol in DCM as solvent to give (S)-2-amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl}-propionic acid ethyl ester (20.5g; 70 %; HPLC purity of 98 %). LCMS M+l = 575. !H-NMR (400 MHz, CDsOD): δ (ppm) 1.10 (t, 3H), 2.25 (s, 3H), 2.85 (m, 2H), 3.65 (m, IH), 4.00 (q, 2H), 6.35 (s, IH), 6.60 (s, IH), 6.90 (m, IH), 7.18 (d, 2H), 7.45 (m, 2H), 7.70 (d, IH), 7.85 (m, 3H).

SYNTHESIS OF INTERMEDIATE

WO 2009048864

https://google.com/patents/WO2009048864A1?cl=en

6.15. Preparation of 6SV3-(4-(2-Amino-6-chloropyrimidin-4-yl)phenyl)-2- (fert-butoxycarbonylamino)propanoic Acid Using the Lithium Salt of (S)-2-(te^-butoxycarbonylamino)-3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoic Acid

Figure imgf000021_0001

During preparation of compound 7, the isolation of the free acid can be optionally omitted. Thus, an aqueous solution of the lithium salt of compound 7 in 100 ml water, prepared from 5.0 g of Boc-Tyr-OMe (4, 17 mmol), was mixed 2-amino-4,6- dichloropyrimidine (3.3 g, 1.2 eq), potassium bicarbonate (5.0 g, 3 eq), bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.5 mol%), and 100 ml ethanol. The resulting mixture was heated at 700C for 5 hours. Additional 2-amino-4,6- dichloropyrimidine (1.1 g, 0.4 eq) was added and heating was continued at 7O0C for an additional 2 hours. HPLC analysis showed about 94% conversion. Upon cooling and filtration, the filtrate was analyzed by HPLC against a standard solution of compound 8. The assay indicated 3.9 g compound 8 was contained in the solution (59% yield from compound 4).

6.16. Alternative Procedure for Preparation of (S)-3-(4-f2-Amino-6- chloropyrimidin-4-yl)phenyl)-2-(fe^-butoxycarbonylamino)propanoic Acid Using Potassium Carbonate as Base

Figure imgf000021_0002

The boronic acid compound 11 (Ryscor Science, Inc., North Carolina, 1.0 g, 4.8 mmol) and potassium carbonate (1.32 g, 2 eq) were mixed in aqueous ethanol (15 ml ethanol and 8 ml water). Di-ter£-butyldicarbonate (1.25 g, 1.2 eq) was added in one portion. After 30 minutes agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11. The 2-amino-4,6- dichloropyrimidine (1.18 g, 1.5 eq) and the catalyst bis(triphenylphosphine)palladium(II) dichloride (34 mg, 1 mol%) were added and the resulting mixture was heated at 65-700C for 3 hours. HPLC analysis showed complete consumption of compound 12. After concentration and filtration, HPLC analysis of the resulting aqueous solution against a standard solution of compound 8 showed 1.26 g compound 8 (67% yield).

6.17. Alternative procedure for preparation of (5)-3-(4-(2-Amino-6-

Figure imgf000022_0001

The boronic acid compound 11 (10 g, 48 mmol) and potassium bicarbonate (14.4 g, 3 eq) were mixed in aqueous ethanol (250 ml ethanol and 50 ml water). Oi-tert- butyldicarbonate (12.5 g, 1.2 eq) was added in one portion. HPLC analysis indicated that the reaction was not complete after overnight stirring at room temperature. Potassium carbonate (6.6 g, 1.0 eq) and additional di-te/t-butyldicarbonate (3.1 g, 0.3 eq) were added. After 2.5 hours agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11. The 2-amino-4,6-dichloropyrimidine (11.8 g, 1.5 eq) and the catalyst bis(triphenylphosphine)-palladium(II) dichloride (0.34 g, 1 mol%” were added and the resulting mixture was heated at 75-8O0C for 2 hours. HPLC analysis showed complete consumption of compound 12. The mixture was concentrated under reduced pressure and filtered. The filtrate was washed with ethyl acetate (200 ml) and diluted with 3 : 1 THF/MTBE (120 ml). This mixture was acidified to pH about 2.4 by 6 N hydrochloric acid. The organic layer was washed with brine and concentrated under reduced pressure. The residue was precipitated in isopropanol, filtered, and dried at 500C under vacuum to give compound 8 as an off-white solid (9.0 g, 48% yield). Purity: 92.9% by HPLC analysis. Concentration of the mother liquor yielded and additional 2.2 g off-white powder (12% yield). Purity: 93.6% by HPLC analysis

PATENT

https://www.google.com/patents/WO2013059146A1?cl=en

This invention is directed to solid pharmaceutical dosage forms in which an active pharmaceutical ingredient (API) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

(telotristat):

Figure imgf000004_0001

or a pharmaceutically acceptable salt thereof. The compound, its salts and crystalline forms can be obtained by methods known in the art. See, e.g., U.S. patent no. 7,709,493.

PATENT

http://www.google.co.in/patents/WO2008073933A2?cl=en

6.19. Synthesis of (S)-2-Amino-3-r4-q-amino-6-{R-l-r4-chloro-2-(3-methyl- Pyrazol-l-yl)-phenyll-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyll- propionic acid ethyl ester

Figure imgf000042_0001

The title compound was prepared stepwise, as described below: Step 1 : Synthesis of l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-50C (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2- bromo-4-chloro-benzoic acid methyl ester (26 g, 99 %), which was directly used in the following step.

2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -700C, and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (IM, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4h, after which it was stirred for 1Oh at room temperature. The reaction mixture was concentrated to give the crude [l-(2-bromo-4-chloro-phenyl)-2,2,2- trifluoro-l-methoxy-ethoxy]-trimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCl (100 ml) was added. The mixture was kept at 45-500C for 12h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford 1- (2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.50 (d,lH), 7.65(d,lH), 7.80(s,lH).

Step 2: Synthesis of R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol. To catechol borane (IM in THF 280 ml, 280 mmol) in a 2L 3-necked RB flask was added S-2- methyl-CBS oxazaborolidine (7.76 g, 28 mmol) under nitrogen, and the resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to -78°C (dry ice/acetone bath), and l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (40 g, 139 mmol) in THF (400 ml) was added dropwise over 2h. The reaction mixture was allowed to warm to -36°C, and was stirred at that temperature for 24 h, and further stirred at -32°C for another 24h. 3N NaOH (250 ml) was added, and the cooling bath was replaced by ice-water bath. Then 30 % hydrogen peroxide in water (250 ml) was added dropwise over 30 minutes. The ice water bath was removed, and the mixture was stirred at room temperature for 4h. The organic layer was separated, concentrated and re-dissolved in ether (200 ml). The aqueous layer was extracted with ether (2 x 200 ml). The combined organic layers were washed with IN aq. NaOH (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave crude product which was purified by column chromatography using 2 to 5% ethyl acetate in hexane as solvent to give desired alcohol 36.2 g (90 %, e.e. >95%). The alcohol (36.2 g) was crystallized from hexane (80 ml) to obtain R-l-(2-bromo-4-chloro- phenyl)-2,2,2-trifiuoro-ethanol 28.2 g (70 %; 99-100 % e.e.). 1H-NMR (400 MHz, CDCl3) δ (ppm) 5.48 (m, IH), 7.40 (d, IH), 7.61 (d, 2H). Step 3: Synthesis of R-l-r4-chloro-2-(3-methyl-pyrazol-l-vπ-phenyl1-2.2.2-trifluoro- ethanol. R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol (15.65g, 54.06 mmol), 3- methylpyrazole (5.33 g, 65 mmol), CuI (2.06 g, 10.8 mmol), K2CO3 (15.7 g, 113.5 mmol), (lR,2R)-N,N’-dimethyl-cyclohexane-l,2-diamine (1.54 g, 10.8 mmol) and toluene (80 ml) were combined in a 250 ml pressure tube and heated to 1300C (oil bath temperature) for 12 h. The reaction mixture was diluted with ethyl acetate and washed with H2O (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10 % ethyl acetate in hexane as solvent to get R-I- [4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (13.5 g; 86 %). 1H-NMR (400 MHz, CDCl3): δ (ppm) 2.30(s, 3H), 4.90(m, IH), 6.20(s, IH), 6.84(d, IH), 7.20(s, IH), 7.30(d, IH), 7.50(d, IH).

Step 4: Synthesis of (S)-2-Amino-3- r4-(2-amino-6- (R-I- r4-chloro-2-(3-methyl- pyrazol- 1 -ylVphenyl~|-2,2.,2-trifluoro-ethoxy| -pyrimidin-4-yl)-phenyU -propionic acid ethyl ester. R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (17.78 g, 61.17 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert- butoxycarbonylamino-propionic acid (20.03 g, 51 mmol), 1,4-dioxane (250 ml), and Cs2CO3 (79.5 g, 244 mmol) were combined in a 3-necked 500 ml RB flask and heated to 1000C (oil bath temperature) for 12-24 h. The progress of reaction was monitored by LCMS. After the completion of the reaction, the mixture was cooled to 600C, and water (250 ml) and THF (400 ml) were added. The organic layer was separated and washed with brine (150 ml). The solvent was removed to give crude BOC protected product, which was taken in THF (400 ml), 3N HCl (200 ml). The mixture was heated at 35-400C for 12h. THF was removed in vacuo. The remaining aqueous layer was extracted with isopropyl acetate (2x 100 ml) and concentrated separately to recover the unreacted alcohol (3.5 g). Traces of remaining organic solvent were removed from the aqueous fraction under vacuum.

To a IL beaker equipped with a temperature controller and pH meter, was added H3PO4 (40 ml, 85 % in water) and water (300 ml) then 50 % NaOH in water to adjust pH to 6.15. The temperature was raised to 58°C and the above acidic aqueous solution was added dropwise into the buffer with simultaneous addition of 50 % NaOH solution in water so that the pH was maintained between 6.1 to 6.3. Upon completion of addition, precipitated solid was filtered and washed with hot water (50-600C) (2 x 200 ml) and dried to give crude (S)-2- amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro- ethoxy}-pyrimidin-4-yl)-phenyl} -propionic acid (26.8 g; 95 %). LCMS and HPLC analysis indicated the compound purity was about 96-97 %. To anhydrous ethanol (400 ml) was added SOCl2 (22 ml, 306 mmol) dropwise at 0-

5°C. Crude acid (26.8 g ) from the above reaction was added. The ice water bath was removed, and the reaction mixture was heated at 40-450C for 6-12h. After the reaction was completed, ethanol was removed in vacuo. To the residue was added ice water (300 ml), and extracted with isopropyl acetate (2 x 100 ml). The aqueous solution was neutralized with saturated Na2CO3 to adjust the pH to 6.5. The solution was extracted with ethyl acetate (2 x 300 ml). The combined ethyl acetate layer was washed with brine and concentrated to give 24 g of crude ester (HPLC purity of 96-97 %). The crude ester was then purified by ISCO column chromatography using 5 % ethanol in DCM as solvent to give (S)-2-amino-3-[4-(2- amino-6- (R- 1 -[4-chloro-2-(3-methyl-pyrazol- 1 -yl)-phenyl]-2,2,2-trifluoro-ethoxy} – pyrimidin-4-yl)-phenyl} -propionic acid ethyl ester (20.5g; 70 %; HPLC purity of 98 %). LCMS M+l = 575. 1H-NMR (400 MHz, CD3OD): δ (ppm) 1.10 (t, 3H), 2.25 (s, 3H), 2.85 (m, 2H), 3.65 (m, IH), 4.00 (q, 2H), 6.35 (s, IH), 6.60 (s, IH), 6.90 (m, IH), 7.18 (d, 2H), 7.45 (m, 2H), 7.70 (d, IH), 7.85 (m, 3H).

PATENT

WO 2011056916

https://www.google.com/patents/WO2011056916A1?cl=en

PATENT

WO 2010065333

https://www.google.com/patents/WO2010065333A1?cl=en

CLIP,……..PL CHECK ERROR

CONFUSION ON CODES, CLEAR PIC BELOW……LINK
Description of Telotristat Etiprate
Telotristat etiprate is the hippurate salt of telotristat ethyl.
Telotristat ethyl, also known as LX1032, has the chemical name, CAS identifier, and chemical structure shown below:
Chemical name: (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate
CAS Registry number: 1033805-22-9
Chemical structure:
Telotristat etiprate, also known as LX1606, is the hippurate salt of telotristat ethyl, and has the chemical name, CAS identifier, and chemical structure shown below:
Chemical Name: (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate 2-benzamidoacetate
CAS Registry number: 1137608-69-5
Chemical Structure:
Description of LX1033
Telotristat, also known as LX1033, has the chemical name, CAS identifier and chemical structure shown below:
Chemical Name: (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid
CAS Registry number: 1033805-28-5
Chemical Structure:

REFERENCES

Kulke, M.H.; Hoersch, D.; Caplin, M.E.; et al.
Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome
J Clin Oncol 2017, 35(1): 14

WO2010056992A1 * Nov 13, 2009 May 20, 2010 The Trustees Of Columbia University In The City Of New York Methods of preventing and treating low bone mass diseases
US7709493 May 20, 2009 May 4, 2010 Lexicon Pharmaceuticals, Inc. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use
US20090088447 * Sep 25, 2008 Apr 2, 2009 Bednarz Mark S Solid forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use
Citing Patent Filing date Publication date Applicant Title
US9199994 Sep 5, 2014 Dec 1, 2015 Karos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors
US9512122 Sep 1, 2015 Dec 6, 2016 Karos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors

///////////telotristat ethyl, fast track designation,priority review,orphan drug designation, Xermelo ,  Woodlands, Texas-based,  Lexicon Pharmaceuticals, Inc, fda 2017, LX 1606, LX 1032

O=C(OCC)[C@@H](N)Cc1ccc(cc1)c2cc(nc(N)n2)O[C@H](c3ccc(Cl)cc3n4ccc(C)n4)C(F)(F)F

O=C(OCC)[C@@H](N)CC1=CC=C(C2=NC(N)=NC(O[C@H](C3=CC=C(Cl)C=C3N4N=C(C)C=C4)C(F)(F)F)=C2)C=C1.O=C(O)CNC(C5=CC=CC=C5)=O

Deflazacort


Deflazacort structure.svgChemSpider 2D Image | Deflazacort | C25H31NO6

Deflazacort

  • CAS 14484-47-0
  • Molecular Formula C25H31NO6
  • Average mass 441.517 Da
(11b,16b)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
11b,21-Dihydroxy-2′-methyl-5’bH-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione 21-acetate
2-[(4aR,4bS,5S,6aS,6bS,9aR,10aS,10bS)-5-Hydroxy-4a,6a,8-trimethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]oxazol-6b-yl]-2-oxoethyl acetate
  • 5’βH-Pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, 11β,21-dihydroxy-2′-methyl-, 21-acetate (8CI)
  • (11β,16β)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
  • 2H-Naphth[2′,1′:4,5]indeno[1,2-d]oxazole, 5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione deriv.
  • Azacort
  • Azacortinol
  • Calcort
  • DL 458IT
  • Deflan
Optical Rotatory Power +62.3 ° Conc: 0.5 g/100mL; Solv: chloroform (67-66-3); Wavlength: 589.3 nm

…………..REF, “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)Hoechst Marion Roussel (now Aventis Pharma) has developed and launched Deflazacort (Dezacor; Flantadin; Lantadin; Calcort) a systemic corticosteroid developed for the treatment of a variety of inflammatory conditions .

In March 1990, the drug was approved in Spain, and by January 2013, the drug had been launched by FAES Farma . By the end of 1999, the product had been launched in Germany, Italy, Belgium, Switzerland and South Korea

Deflazacort is a corticosteroid first launched in 1985 by Guidotti in Europe for the oral treatment of allergic asthma, rheumatoid arthritis, arthritis, and skin allergy.

In 2017, an oral formulation developed at Marathon Pharmaceuticals was approved by the FDA for the treatment of Duchenne’s muscular dystrophy in patients 5 years of age and older.

Deflazacort (trade name Emflaza or Calcort among others) is a glucocorticoid used as an anti-inflammatory and immunosuppressant.

In 2013, orphan drug designation in the U.S. was assigned to the compound for the treatment of Duchenne’s muscular dystrophy. In 2015, additional orphan drug designation in the U.S. was assigned for the treatment of pediatric juvenile idiopathic arthritis (JIA) excluding systemic JIA.

Also in 2015, deflazacort was granted fast track and rare pediatric disease designations in the U.S. for the treatment of Duchenne’s muscular dystrophy.

Deflazacort is a glucocorticoid used as an anti-inflammatory and immunosuppressant. It was approved in February, 2017 by the FDA for use in treatment of Duchenne muscular dystrophy (trade name Emflaza).
  • Aventis Pharma (Originator), Lepetit (Originator), Guidotti (Licensee), Shire Laboratories (Licensee)

Image result for deflazacort

February 9, 2017 FDA approved

The U.S. Food and Drug Administration today approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system.

Corticosteroids are commonly used to treat DMD across the world. This is the first FDA approval of any corticosteroid to treat DMD and the first approval of deflazacort for any use in the United States.

Image result for Deflazacort

“This is the first treatment approved for a wide range of patients with Duchenne muscular dystrophy,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We hope that this treatment option will benefit many patients with DMD.”

DMD is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between 3 and 5 years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

The effectiveness of deflazacort was shown in a clinical study of 196 male patients who were 5 to 15 years old at the beginning of the trial with documented mutation of the dystrophin gene and onset of weakness before age 5. At week 12, patients taking deflazacort had improvements in a clinical assessment of muscle strength across a number of muscles compared to those taking a placebo. An overall stability in average muscle strength was maintained through the end of study at week 52 in the deflazacort-treated patients. In another trial with 29 male patients that lasted 104 weeks, deflazacort demonstrated a numerical advantage over placebo on an assessment of average muscle strength. In addition, although not statistically controlled for multiple comparisons, patients on deflazacort appeared to lose the ability to walk later than those treated with placebo.

The side effects caused by Emflaza are similar to those experienced with other corticosteroids. The most common side effects include facial puffiness (Cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism) and excessive fat around the stomach (central obesity).

Other side effects that are less common include problems with endocrine function, increased susceptibility to infection, elevation in blood pressure, risk of gastrointestinal perforation, serious skin rashes, behavioral and mood changes, decrease in the density of the bones and vision problems such as cataracts. Patients receiving immunosuppressive doses of corticosteroids should not be given live or live attenuated vaccines.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the ninth rare pediatric disease priority review voucher issued by the FDA since the program began.

Emflaza is marketed by Marathon Pharmaceuticals of Northbrook, Illinois.

Medical uses

The manufacturer lists the following uses for deflazacort:[1]

In the United States, deflazacort is only FDA-approved for the treatment of Duchenne muscular dystrophy in people over the age of 5.

Image result for DeflazacortImage result for Deflazacort

Image result for DeflazacortImage result for Deflazacort

Adverse effects

Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushing’s-like appearance, weight gain, and increased appetite.[2]

Pharmacology

Mechanism of action

Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort.[3]

Relative potency

Deflazacort’s potency is around 70–90% that of prednisone.[4] A 2017 review found its activity of 7.5 mg of deflazacort is approximately equivalent to 25 mg cortisone, 20 mg hydrocortisone, 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone or triamcinolone, or 0.75 mg of betamethasone or dexamethasone. The review noted that the drug has a high therapeutic index, being used at initial oral doses ranging from 6 to 90 mg, and probably requires a 50% higher dose to induce the same demineralizing effect as prednisolone. Thus it has “a smaller impact on calcium metabolism than any other synthetic corticosteroid, and therefore shows a lower risk of growth rate retardation in children and of osteoporosis” in the elderly, and comparatively small effects on carbohydrate metabolism, sodium retention, and hypokalemia.[5]

History

In January 2015, the FDA granted fast track status to Marathon Pharmaceuticals to pursue approval of deflazacort as a potential treatment for Duchenne muscular dystrophy, a rare, “progressive and fatal disease” that affects boys.[6] Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017,[7][8] Marathon CEO announced on February 13, 2017 that the launch of deflazacort (Emflaza) would be delayed amidst controversy over the steep price Marathon was asking for the drug – $89,000-a-year. In Canada the same drug can be purchased for around $1 per tablet.[9] Marathon has said that Emflaza is estimated to cost $89,000/year which is “roughly 70 times” more than it would cost overseas.[10] Deflazacort is sold in the United Kingdom under the trade name Calcort;[4] in Brazil as Cortax, Decortil, and Deflanil; in India as Moaid, Zenflav, Defolet, DFZ, Decotaz, and DefZot; in Bangladesh as Xalcort; in Panama as Zamen; Spain as Zamene; and in Honduras as Flezacor.[11]

SYNTHESIS

Worlddrugtracker drew this

1 Protection of the keto groups in pregna-1,4-diene derivative  with NH2NHCOOMe using HCOOH, yields the corresponding methyl ester.

2 Cleavage of epoxide  with NH3 in DMAc/DMF gives amino-alcohol,

3 which on esterification with acetic anhydride in the presence of AcOH furnishes acetate.

4 Cyclization of amine using NaOH, Na2CO3 or K2CO3 produces oxazoline derivative ,

5 which is finally deprotected with HCl to afford Deflazacort 

SYNTHESIS FROM CHEMDRUG

The cyclization of 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione (I) by hydrogenation with H2 over Pt in methanol, followed by a treatment with 10% HCl gives 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (II), which is converted into the semicarbazone (III) by treatment with semicarbazide hydrochloride (A) and pyridine in refluxing methanol. The reduction of one ketonic group of (III) with NaBH4 in refluxing ethanol yields the dihydroxy-semicarbazone (IV), which is hydrolyzed with 10% HCl in refluxing methanol to afford the ketodiol (V). The oxidation of (V) with cyclohexanone and aluminum isopropoxide in refluxing toluene gives 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (VI). The dehydrogenation of (VI) by treatment with Br2 in dioxane-acetic acid, followed by treatment with Li2CO3 in DMF at 140 C yields the corresponding 1,4-diene derivative (VII). Finally, the reaction of (VII) with I2 by means of azobisisobutyronitrile in CH2Cl2 affords the corresponding 21-iodo compound, which is then acetylated with triethylammonium acetate in refluxing acetone.

The monoacetylation of (V) with acetic anhydride and pyridine at 100 C gives the 3-acetoxy-11-hydroxy compound (IX), which is dehydrated by treatment with methanesulfonyl chloride and then with sodium acetate yielding 3beta-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (X). The hydrolysis of (X) with KOH in refluxing methanol affords the corresponding hydroxy compound (XI), which is acetoxylated by treatment with I2 and AZBN as before giving the iodo derivative (XII), and then with triethylammonium acetate also as before, yielding 3beta-hydroxy-21-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (XIII). The oxidation of (XIII) with CrO3 in acetone yields the 3,20-diketone (XIV), which by treatment with Br2 and Li2CO3 as before is dehydrogenated affording the 1,4,9(11)-pregnatriene (XV). Finally, the reaction of (XV) with N-bromoacetamide in THF yields 9alpha-bromo-11beta-hydroxy-21-acetoxy-5alpha-pregna-1,4-dieno-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (XVI), which is then debrominated by reaction with chromous acetate and butanethiol in DMSO.

PAPER

Journal of Medicinal Chemistry (1967), 10(5), 799-802

Steroids Possessing Nitrogen Atoms. III. Synthesis of New Highly Active Corticoids. [17α,16α,-d]Oxazolino Steroids

J. Med. Chem., 1967, 10 (5), pp 799–802
DOI: 10.1021/jm00317a009

PATENT

CN 105622713

PATENT CN 106008660

MACHINE TRANSLATED FROM CHINESE may seem funny

Description of the drawings

[0007] Figure 1 is a map of the traditional method of the combination process;

Figure 2 is a two-step method of the present invention.

detailed description

[0008] In order to more easily illustrate the gist and spirit of the present invention, the following examples illustrate:

Example 1

A: Preparation of hydroxylamine

In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 30 ml of DMF, 300 ml of chloroform was added and incubated at 30-35 ° C with 8 g of ammonia gas at 1-2 atmospheres Reaction 16 ~ 20 hours, TLC detection reaction end point, after the reaction, the vacuum exhaust ammonia gas, add 3x100ml saturated brine washing 3 times, plus 10ml pure water washing times, then, under reduced pressure to chloroform to dry, add 200ml Ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 degrees, hot filter, l-2ml ethyl acetate washing carbon, combined filtrate and lotion, and then below 500C concentrated under pressure 95 % Of ethyl acetate, the system cooled to -5-0 ° C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of approved; filter cake below 70 ° C Drying, get hydroxylamine 18.2g, HPLC content of 99.2%, weight loss of 91%.

[0009] B: Preparation of terracavir

Add 10 g of hydroxylamine, 150 ml of glacial acetic acid and 150 ml of acetic anhydride in a 100 ml three-necked flask. Add 5 g of concentrated sulfuric acid under stirring at room temperature. The reaction was carried out at 30-35 ° C for 12-16 hours. TLC confirmed the end of the reaction. Add 500ml of pure water, and adjust the pH of 7.5.5 with liquid alkali, cool to 10 ~ 15 ° C, stirring crystallization 2-3 hours, filtration, washing to neutral, combined filtrate and lotion, pretreated into Waste water treatment tank, filter cake below 70 V drying, Texaco can be special crude 112.5g, HPLC content of 98.2%, the yield of 112.5% ο the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, Decolorization 1-1.5 hours, hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -5-0 ° C, frozen crystal 2-3 hours, Filtration, filter cake with 4-5ml alcohol washing, 70 ° C below drying, digoxin special product 89.2g, melting point 255.5-256.0 degrees, HPLC content of 99.7%, yield 89.2%. The mother liquor is recycled with solvent and crude.

[0010] Example II

A: Preparation of hydroxylamine

In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 120 ml of toluene was added and incubated at 30-35 ° C with 8 g of ammonia and 16 to 20 at atmospheric pressure The reaction was carried out in the presence of 3 x 50 ml of saturated brine and 50 ml of pure water was added. Then, the toluene was dried under reduced pressure to dryness, and 200 ml of ethyl acetate, Ig activated carbon was added, and the mixture was stirred. Reflux 60-90 minutes, cool to 50-55 ° C, hot filter, l2ml ethyl acetate wash carbon, combined filtrate and lotion, and then below 500C under reduced pressure 95% ethyl acetate, the system cooling To 5-0C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of the next batch; filter cake 70 ° C below drying, hydroxylamine 18.0g, HPLC content 99.1%, 90% by weight.

[0011] B: Preparation of terracavir

Add 10 g of hydroxylamine, 500 ml of chloroform and 150 ml of acetic anhydride in a 100 ml three-necked flask, add 5 g of p-toluenesulfonic acid under stirring at room temperature, and incubate at 30-35 ° C for 12-16 hours. TLC confirms the reaction end, After the addition of 500ml of pure water, and with the liquid alkali pH 7.55, down to 10 ~ 15 ° C, stirring 0.5_1 hours, separate the water layer, washed to neutral, combined with water and lotion, pretreated into Waste water treatment tank, organic layer under reduced pressure concentrated chloroform to near dry, adding 200ml hexane, reflux 0.5-1 hours, slowly cooling to -5 ~ O0C, stirring crystallization 2-3 hours, filter, filter cake with 4-5ml Alcohol washing, the filtrate and lotion combined apply to the next batch, the filter cake below 70 ° C drying, Texaco can crude 110.5g, HPLC content of 98.4%, the yield of 110.5%. The above-mentioned diltiazem crude product dissolved in 800ml alcohol, add 5g activated carbon, temperature reflux bleaching 1-1.5 hours, hot filter, 10ml alcohol washing cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol And then cooled to -500C, frozen crystallization for 2-3 hours, filtration, filter cake with 4-5ml alcohol washing, 70 ° C the following drying, digester can special products 88.6g, melting point 255.0-256.0 degrees, HPLC content of 99.5%, the yield of 88.6%. The mother liquor is recycled with solvent and crude.

[0012] Example 3

A: Preparation of hydroxylamine

Add 20 g of 16 (17) a-epoxy prednisolone to 120 ml of ethanol in a 100 ml three-necked flask and incubate at 30-35 ° C with stirring to give Sg ammonia at 16 to 20 hours , TLC test reaction end point, after the reaction, vacuum exhaust ammonia gas, concentrated ethanol to the near dry, cooling, adding 300ml chloroform, stirring dissolved residue, and then add 3x100ml saturated brine washing, plus 10ml pure water washing, washing And then concentrated to reduce the chloroform to dry, add 200ml of ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 ° C, hot filter, l2ml ethyl acetate washing carbon, combined filtrate and lotion And then concentrated below 50 ° C to 95% ethyl acetate under reduced pressure. The system was cooled to -5-0 0C, stirred for 2 to 3 hours, filtered, 0.5-l of ethyl acetate, washed and filtrate The filter cake was dried at 70 ° C, 18.6 g of hydroxylamine, 99.5% of HPLC, and 93% by weight.

[0013] B: Preparation of terracavir

In a 100ml three-necked flask, add 10g of hydroxylamine, 500ml toluene, 150ml acetic anhydride, stirring at room temperature by adding 5g concentrated sulfuric acid, insulation at 30-35 degrees stirring reaction 12-16 hours, TLC confirmed the end of the reaction, after the reaction, Add 500ml of pure water, and liquid pH adjustment pH 7.5, cooling to 1 ~ 15 ° C, stirring 0.5-1 hours, the water layer, washed to neutral, combined with water and lotion, pretreated into the wastewater The cells were dried and the organic layer was concentrated to dryness under reduced pressure. 200 ml of hexane was added and refluxed

0.5-1 hours, slowly cool to -5 ~ O0C, stirring crystallization 2-3 hours, filtration, filter cake with 4-5ml hexane, the filtrate and lotion combined apply to the next batch, filter cake below 70 ° C Drying, digoxin crude 112.5g, HPLC content of 97.4%, the yield of 112,5% ο will be the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, heating reflux bleaching 1-1.5 hours, while Hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -500C, frozen crystallization for 2-3 hours, filter, filter cake with 4-5ml alcohol Washing, 70 ° C below the dry, Diges can special products 86.2g, melting point 255.5-256.0 degrees, HPLC content of 99.8%, the yield of 86.2%. The mother liquor is recycled with solvent and crude.

PATENT

https://www.google.com/patents/CN101418032A?cl=en

Example 1

21- bromo -ll (3- hydroxy – pregna–l, 4- diene -3, 20-dione [170, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask was added 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw: 178.00; 55 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 20 ° C 0.5 h, the reaction is complete. After completion of the reaction was filtered to remove the white precipitate cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, the solvent was evaporated under reduced pressure to give a pale yellow solid 21.27 g, yield: 92%, HPLC content of greater than 95%.

Example 2

21- bromo -lip- hydroxy – pregna–l, 4- diene -3, 20-dione [17 “16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw : 178.00; 55 mmol), 150 ml of toluene; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 110 ° C 5 h, the reaction is complete. After completion of the reaction was cooled to room temperature, the white precipitate was removed by filtration cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 19.65 g, yield: 85%, HPLC content greater than 95%.

Example 3

21 Jie bromo -11 – hydroxy – pregna-1,4-diene -3, 20-dione [17a, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System Stirring was continued at reflux for 3 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.18 g, yield: 70%, HPLC content greater than 92%.

Example 4

21- bromo -11 Jie – hydroxy – pregna-1,4-diene -3, 20- dione [17c, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml dichloromethane; followed by ammonium acetate (0.039 g; Fw: 77.08; 0.0005 mmol) added to the system. System Stirring was continued at reflux for 24 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.41 g, yield: 71%, HPLC content of greater than 92. / 0.

Example 5

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of sodium acetate (8.20g; Fw: 82.03; lOOmmol), 50 mL methanol was added to the system.

Then tetrabutylammonium bromide (O. 81g; Fw: 322.38; 2.5 mmol). Warmed to 50 ° C with stirring

48 h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase washed with 10% aqueous sodium carbonate paint 3 times, saturated sodium chloride once. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, purified ethyl acetate to give the product 9.93g, yield 90%, HPLC content> 990/0.

Example 6

Deflazacort Preparation –

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetone was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.

Example 7

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetonitrile was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.

Example 8

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (2.45g; Fw: 98.14; 25 mmol), the N, N- dimethylformamide, 50 mL added to the system. Followed by tetrabutylammonium iodide (O.IO g; Fw: 369.37; 0.25 mmol). Warmed to 120. C stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99o / q.

PATENT

https://www.google.com/patents/WO1997021722A1?cl=zh

compound (llβ,16β)-21-(acetyloxy)-11- hydroxy-2 ‘ -methyl-5 ‘H-pregna-1, -dieno[17 , 16-d Joxazole- 3,20-dione, also known, and hereinafter referred to, with the INN (International Nonproprietary Name) deflazacort. Deflazacort is represented by the following formula I

Figure imgf000003_0001

Deflazacort is employed in therapy aince some years as a calcium-sparing corticoid agent. This compound belongs to the more general class of pregneno-oxazolines, for which anti-inflammatory, glucocorticoid and hormone-like pharmacological activities are reported. Examples of compounds of the above class, comprising deflazacort, are disclosed in US 3413286, where deflazacort is referred to as llβ-21-dihydroxy-2 ‘ -methyl-5 ‘ βH-pregna-1,4-dieno.17 , 16- d]oxazole-3,20-dione 21-acetate.

According to the process disclosed by US 3413286, deflazacort is obtained from 5-pregnane-3β-ol-ll , 20- dione-2 ‘-methyloxazoline by 2 , -dibromination with Br2– dioxane, heating the product in the presence of LiBr- iC03 for obtaining the 1,4-diene, and converting this latter into the 21-iodo and then into the desired 21- acetyloxy compound. By hydrolysis of deflazacort, the llβ-21-dihydroxy-2 ‘ -methyl-5 ‘βH-pregna-1, -dieno[ 17 , 16- d-]oxazoline-3, 20-dione of formula II is obtained:

Figure imgf000004_0001

The compound of formula II is preferably obtained according to a fermentation process disclosed in

EP-B-322630; in said patent, the compound of formula II is referred to as llβ-21-dihydroxy-2 ‘-methyl-5 ‘ βH- pregna-1,4-dieno[17,16-d-]oxazoline-3,20-dione.

The present invention provides a new advantageous single-step process for obtaining deflazacort, by acetylation of the compound of formula II.

CLIP

Image result for Deflazacort NMR

tructure of deflazacort and its forced degradation product (A), chromatogram plot of standard deflazacort (B), contour plot of deflazacort (C). Deflazacort was found to be a stable drug under stress condition such as thermal, neutral and oxidative condition. However, the forceddegradation study on deflazacort showed that the drug degraded under alkaline, acid and photolytic conditions.

Mass fragmentation pathway for degradant product of deflazacort.

PATENT

CN 103059096

Figure CN103059096AD00051

Example 1: Protective reaction To the reaction flask was added 20 g of 1,4-diene-11? -hydroxy-16,17-epoxy_3,20-dione pregnone (Formula I) 20% of the aqueous solution of glacial acetic acid 300g, stirring 5 minutes, temperature 10 ° C ~ 15 ° C, adding ethyl carbazate 14g, temperature control 30 ° C reaction 6 hours; TLC detection reaction is complete, cooling to 0 ° C ~ 5 ° C for 2 hours, until dry, washed to neutral; 60 ° C vacuum dry to dry creatures 20. 5g; on P, oxazoline ring reaction The above protective products into the reaction bottle, add 41ml Of the DMAC dissolved, temperature 25 ~ 30 ° C, access to ammonia, to keep the reaction bottle micro-positive pressure, the reaction of 32 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes; 5 ° C, temperature 5 ~ 0 ° C by adding 5ml glacial acetic acid, then add 21ml acetic anhydride, heated to 35 ° C reaction 4 hours, the sample to confirm the reaction completely; slowly add 5% sodium hydroxide solution 610ml and heated to 60 ~ 70 ° C reaction 2 hours; point plate to confirm the end of the reaction, cooling to 50 ° C, half an hour by adding refined concentrated hydrochloric acid 40ml, insulation 50 ~ 55 ° C reaction 10 hours; to the end of the reaction temperature to room temperature, chloroform Extraction, drying and filtration, concentration of at least a small amount of solvent, ethyl acetate entrained twice, leaving a small amount of solvent, frozen crystallization filter high purity [17a, 16a-d] terfu Kete intermediate. Example 2: Protective reaction 20 g of 1,4-diene-l1-la-hydroxy-16,17-epoxy_3,20_dione progestin (Formula I) was added to the reaction flask and 15% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding methyl carbazate 12g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, Suction to dry, washed to neutral; 60 ° C vacuum drying to dry protection of 20g; on P, oxazoline ring reaction The protection of the reaction into the reaction flask, add 30ml of DMF dissolved, temperature control 25 ~ 30 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 30 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooled to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 30 ° C reaction for 5 hours to confirm the reaction is complete; slowly add 20% sodium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 4 hours, the point plate to confirm the reaction The temperature of 55 ~ 60 ° C for 10 hours; to be the end of the reaction temperature to room temperature, chloroform extraction, drying and filtration, concentration of a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues. [0024] Example 3: Protective reaction 20 g of I, 4-diene-16,17-epoxy-3,11,20-triketone pregnone (Formula I) was added to the reaction flask and 20% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding hydrazine carbamate 15g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, To the dry, washed to neutral; 60 ° C vacuum drying to dry protection of 22g; on P, oxazoline ring reaction of the protection of the reaction into the bottle, add 30ml of DMAC dissolved temperature control 35 ~ 40 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 40 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooling to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 40 ° C reaction 5 hours to confirm the reaction is complete; slowly add 20% potassium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 7 hours, the point plate to confirm the reaction The temperature of the reaction to the end of the temperature to room temperature, chloroform extraction, drying filter, concentrated to a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues.

PATENT

CN 102936274

Figure CN102936274BD00041

xample 1

[0028] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 15 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10-15 ° C), 30 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 30.6 g, 102% mass yield, product by HPLC , a purity of 95.2%.

[0029] Example 2

[0030] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mL of pyridine were mixed, added pressure reactor, stirring ammonia gas to the reactor pressure to 0. 15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 15 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 28.6 g, yield 95% by mass, product by HPLC , a purity of 94.8%.

[0031] Example 3

[0032] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction.Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31.2 g, yield 104% quality products by HPLC , a purity of 95.4%.

[0033] Example 4

[0034] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.5 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31. I g, 102% mass yield, product by by HPLC, the purity was 95.2%.

[0035] Example 5

[0036] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 60 mL of acetic acid, 15 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29. 5 g, yield 98% by mass, the product of by HPLC, purity of 95%.

[0037] Example 6

[0038] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. The reaction was complete, the material was transferred to a glass reaction flask until the material temperature drops below 10 ° C, plus acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of maleic dianhydride, the reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 30 g, 100% mass yield, product by HPLC purity of 95.2%.

[0039] Example 7

[0040] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of propionic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 27.6 g, 92% yield of quality products by HPLC , a purity of 93.5%.

[0041] Example 8

[0042] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature is controlled at 50 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29.8 g, 99% yield of quality products by HPLC , a purity of 94.8%.

References

  1. Jump up^ “Refla: deflazacort” (PDF).
  2. Jump up^http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208684s000,208685s000lbl.pdf
  3. Jump up^ Möllmann, H; Hochhaus, G; Rohatagi, S; Barth, J; Derendorf, H (1995). “Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone”. Pharmaceutical Research. 12 (7): 1096–100. PMID 7494809.
  4. ^ Jump up to:a b “Calcort”. electronic Medicines Compendium. June 11, 2008. Retrieved on October 28, 2008.
  5. Jump up^ Luca Parente (2017). “Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids”. BMC Pharmacol Toxicol. doi:10.1186/s40360-016-0111-8.
  6. Jump up^ Ellen Jean Hirst (January 19, 2015), Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016, The Chicago Tribune, retrieved February 13, 2017,has been shown to prolong lives … a progressive and fatal disease that has no drug treatment available in the US
  7. Jump up^ “FDA approves drug to treat Duchenne muscular dystrophy”. http://www.fda.gov. 2017-02-09. Retrieved 2017-02-10.
  8. Jump up^ “Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug”. http://www.wsj.com. 2017-02-10. Retrieved 2017-02-10.
  9. Jump up^ Clifton Sy Mukherjee (February 10, 2017). “Brainstorm Health Daily”. Retrieved February 13, 2017.
  10. Jump up^ Joseph Walker and Susan Pulliam (February 13, 2017), Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug After 70-Fold Increase, The Wall Street Journal, retrieved February 13, 2017,FDA-approved deflazacort treats rare type of disease affecting boys
  11. Jump up^ “Substâncias: DEFLAZACORT” (in Portuguese). Centralx. 2008. Retrieved on October 28, 2008.
Deflazacort
Deflazacort structure.svg
Clinical data
Trade names Emflaza, Calcort, others
AHFS/Drugs.com International Drug Names
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 40%
Metabolism By plasma esterases, to active metabolite
Biological half-life 1.1–1.9 hours (metabolite)
Excretion Renal (70%) and fecal (30%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.034.969
Chemical and physical data
Formula C25H31NO6
Molar mass 441.517 g/mol
3D model (Jmol)
CN102746358A * Apr 22, 2011 Oct 24, 2012 天津金耀集团有限公司 Novel technology for synthesis of pregnane 21-bit bromide
CN102746358B * Apr 22, 2011 Feb 10, 2016 天津金耀集团有限公司 一种合成孕甾21位溴化物的工艺
CN102936274A * Nov 12, 2012 Feb 20, 2013 浙江仙居君业药业有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN102936274B * Nov 12, 2012 Apr 1, 2015 江西君业生物制药有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline

///////FDA 2017, Emflaza, Calcort, Deflazacort, orphan drug designation, FAST TRACK

[H][C@@]12C[C@@]3([H])[C@]4([H])CCC5=CC(=O)C=C[C@]5(C)[C@@]4([H])[C@@]([H])(O)C[C@]3(C)[C@@]1(N=C(C)O2)C(=O)COC(C)=O

Pridopidine.svg

Pridopidine

  • Molecular Formula C15H23NO2S
  • Average mass 281.414 Da
346688-38-8  CAS FREE FORM
882737-42-0 (hydrochloride)
1440284-30-9 HBr
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidin
4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
ACR16
Huntexil
UNII-HD4TW8S2VK;
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine
ACR 16
  • ASP 2314
FR 310826

Huntingtons chorea

Dopamine D2 receptor antagonist; Opioid receptor sigma agonist 1

Neurosearch INNOVATORS, In 2012, the product was acquired by Teva

In January 2017, pridopidine was reported to be in phase 3 clinical development,  pridopidine for treating or improving cognitive functions and Alzheimer’s disease.

Teva Pharmaceutical Industries, following an asset acquisition from NeuroSearch, is developing pridopidine, a fast-off dopamine D2 receptor antagonist that strengthens glutamate function, for treating HD.
The drug holds orphan drug designation in the U.S. and the E.U. for the treatment of Huntington’s disease

PRIDOPIDINE.png

About Huntington Disease

HD is a fatal neurodegenerative disease for which there is no known cure or prevention. People who suffer from HD will likely have a variety of steadily-worsening symptoms, including uncoordinated and uncontrolled movements, cognition and memory deterioration and a range of behavioral and psychological problems. HD symptoms typically start in middle age, but the disease may also manifest itself in childhood and in old age. Disease progression is characterized by a gradual decline in motor control, cognition and mental stability, and generally results in death within 15 to 25 years of clinical diagnosis. Current treatment is limited to managing the symptoms of HD, as there are no treatments that have been shown to alter the progression of HD. Studies estimate that HD affects about 13 to 15 people per 100,000 in Caucasians, and for every affected person there are approximately three to five people who may carry the mutation but are not yet ill.

Image result for Pridopidine

Pridopidine, also known as ACR16, is a dopamine stabilizer, which improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD.

Figure

Dopamine D2 ligands. Dopamine D2 receptor agonists dopamine (1) and apomorphine (2), classical antagonists haloperidol (3) and olanzapine (4), partial agonists (−)-3-(3-hydroxyphenyl)-Nn-propylpiperidine (5), bifeprunox (6), aripiprazole (7), and 3-(1-benzylpiperidin-4-yl)phenol (9a), and dopaminergic stabilizers S-(−)-OSU6162 (8) and pridopidine (12b).

Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopa-mine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson’s disease and schizophrenia. Currently available dopaminer-gic pharmaceuticals have severe side effects, such as ex-trapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti -Parkinson ‘ s agents. Therapeutic effects are un-satisfactory in many respects. To improve efficacy and reduce side effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive do-pamine receptor blockade or excessive stimulation.
Compounds belonging to the class of substituted 4- (phenyl-N-alkyl) -piperazine and substituted 4-(phenyl-N-alkyl) -piperidines have been previously reported. Among these compounds, some are inactive in the CNS, some dis-play serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.
A number of 4-phenylpiperazines and 4 -phenyl -piperidine derivatives are known and described, for example Costall et al . European J. Pharm. 31, 94, (1975), Mewshaw et al . Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4 -phenyl -piperazine ‘ s, most of them being 2-, 3- or 4 -OH phenyl substituted and displaying DA autoreceptor agonist properties .
Fuller R. W. et al , J. Pharmacol. Exp . Therapeut . 218, 636, (1981) disclose substituted piperazines (e.g. 1- (m-trifluoro-methylphenyl) piperazine) which reportedly act as serotonin agonists and inhibit serotonin uptake.

Fuller R. W. et al , Res. Commun. Chem. Pathol . Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3 , 4-dihydroxy-phenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the compara-tive effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1- (p-chlorophenol) -piperazine .
Boissier J. et al Chem Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives , potentiators of barbitu-rates, and depressants of the central nervous system.
A number of different substituted piperazines have been published as ligands at 5-HT1A receptors, for example Glennon R.A. et al J. Med. Chem., 31, 1968, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. et al, Arch. Pharm. (Weinheim) 328, 143-148 (1995), and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A. discloses, in international patent applications WO93/00313 and WO 91/09594 various amines, among them substituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evi-dence of antipsychotic activity, or activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al , 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al , 1994, Neuropsycho-pharmacology 10:37-40) .
Further, WO 93/04684 and GB 2027703 also describe specific substituted piperazines useful in the treatment of CNS disorders

Pridopidine (Huntexil, formerly ACR16) is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. These compounds may counteract the effects of excessive or insufficient dopaminergic transmission,[1][2] and are therefore under investigation for application in neurological and psychiatric disorders characterized by altered dopaminergic transmission, such as Huntington’s disease (HD).

Pridopidine is in late-stage development by Teva Pharmaceutical Industries who acquired the rights to the product from its original developer NeuroSearch in 2012. In April 2010, NeuroSearch announced results from the largest European phase 3 study in HD carried out to date (MermaiHD). The MermaiHD study examined the effects of pridopidine in patients with HD and the results showed after six months of treatment, pridopidine improved total motor symptoms, although the primary endpoint of the study was not met. Pridopidine was well tolerated and had an adverse event profile similar to placebo.[3]

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both indicated they will not issue approval for pridopidine to be used in human patients on the basis of the MermaiHD and HART trials, and a further, positive phase 3 trial is required for approval.[4][5]

Image result for Pridopidine

Dopidines

Dopidines, a new class of pharmaceutical compounds, act as dopaminergic stabilizers, enhancing or counteracting dopaminergic effects in the central nervous system.[1][2] They have a dual mechanism of action, displaying functional antagonism of subcortical dopamine type 2 (D2) receptors, as well as strengthening of cortical glutamate and dopamine transmission.[6] Dopidines are, therefore, able to regulate both hypoactive and hyperactive functioning in areas of the brain that receive dopaminergic input (i.e. cortical and subcortical regions). This potential ability to restore the cortical–subcortical circuitry to normal suggests dopidines may have the potential to improve symptoms associated with several neurological and psychiatric disorders, including HD.

SYNTHESIS

Figure

aReagents and conditions: (a) n-butyllithium, 1-Boc-4-piperidone, THF; (b) trifluoroacetic acid, CH2Cl2, Δ; (c) triethylamine, methyl chloroformate, CH2Cl2; (d) m-CPBA, CH2Cl2; (e) Pd/C, H2, MeOH, HCl; (f) HCl, EtOH, Δ; (g) RX, K2CO3, acetonitrile, Δ.

Pharmacology

In vitro studies demonstrate pridopidine exerts its effects by functional antagonism of D2 receptors. However, pridopidine possesses a number of characteristics[1][2][6][7] that differentiate it from traditional D2 receptor antagonists (agents that block receptor responses).

  • Lower affinity for D2 receptors than traditional D2 ligands[8]
  • Preferential binding to activated D2 (D2high) receptors (i.e. dopamine-bound D2 receptors)[8]
  • Rapid dissociation (fast ‘off-rate’) from D2 receptors
  • D2 receptor antagonism that is surmountable by dopamine
  • Rapid recovery of D2-receptor-mediated responses after washout[1][2][6][7]

Pridopidine is less likely to produce extrapyramidal symptoms, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless), than dopamine antagonists (such as antipsychotics).[9] Furthermore, pridopidine displays no detectable intrinsic activity,[9][10] differentiating it from D2 receptor agonists and partial agonists (agents that stimulate receptor responses). Pridopidine, therefore, differs from D2 receptor antagonists, agonists and partial agonists.[6]

As a dopaminergic stabilizer, pridopidine can be considered to be a dual-acting agent, displaying functional antagonism of subcortical dopaminergic transmission and strengthening of cortical glutamate transmission.

Clinical development

The MermaiHD study

In 2009, NeuroSearch completed the largest European HD trial to date, the Multinational EuRopean Multicentre ACR16 study In Huntington’s Disease (MermaiHD) study.

This six-month, phase 3, randomized, double-blind, placebo-controlled trial recruited patients from Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK, and compared two different pridopidine dose regimens with placebo. Patients were randomly allocated to receive pridopidine (45 mg once daily or 45 mg twice daily) or placebo. During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two doses (one morning and one afternoon dose) until the end of the treatment period. The study had a target recruitment of 420 patients; recruitment was finalized in April 2009 with 437 patients enrolled.[14]

The purpose of the study was to assess the effects of pridopidine on a specific subset of HD motor symptoms defined in the modified motor score (mMS).[14] The mMS comprises 10 items relating to voluntary motor function from the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS—TMS).[14] Other study endpoints included the UHDRS—TMS, submotor items, cognitive function, behaviour and symptoms of depression and anxiety.

After six months of treatment, patients who received pridopidine 45 mg twice daily showed significant improvements in motor function, as measured by the UHDRS-TMS, compared with placebo. For the mMS, which was the primary endpoint of the study, a strong trend in treatment effect was seen, although statistical significance was not reached. Pridopidine was also very well tolerated, had an adverse event profile similar to placebo and gave no indication of treatment-associated worsening of symptoms.[3]

The MermaiHD study – open-label extension

Patients who completed the six-month, randomized phase of the MermaiHD study could choose to enter the MermaiHD open-label extension study and receive pridopidine 45 mg twice daily for six months. In total, 357 patients were enrolled into the MermaiHD open-label extension study and of these, 305 patients completed the entire 12-month treatment period.[15]

The objective of this study was to evaluate the long-term safety and tolerability profile of pridopidine and to collect efficacy data after a 12-month treatment period to support the safety evaluation. Safety and tolerability assessments included the incidence and severity of adverse events, routine laboratory parameters, vital signs and electrocardiogram measurements.[15]

Results from the MermaiHD open-label extension study showed treatment with pridopidine for up to 12 months (up to 45 mg twice daily for the first six months; 45 mg twice daily for the last six months) was well tolerated and demonstrated a good safety profile.[3][15]

The HART study

In October 2010, NeuroSearch reported results from their three-month, phase 2b, randomized, double-blind, placebo-controlled study carried out in Canada and the USA – Huntington’s disease ACR16 Randomized Trial (HART). This study was conducted in 28 centres and enrolled a total of 227 patients, who were randomly allocated to receive pridopidine 10 mg, 22.5 mg or 45 mg twice daily) or placebo.[14][16] During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two treatment doses (one morning and one afternoon dose) until the end of the treatment period. Study endpoints were the same as those for the MermaiHD study.

Results from the HART study were consistent with findings from the larger MermaiHD study. After 12 weeks of treatment with pridopidine 45 mg twice daily, total motor function significantly improved, as measured by the UHDRS–TMS. The primary endpoint, improvement in the mMS, was not met.[16]

In both studies, the effects on the UHDRS–TMS and the mMS were driven by significant improvements in motor symptoms such as gait and balance, and hand movements, deemed by the authors to be “clinically relevant”. However, the magnitude of the improvements was small. Pridopdiine demonstrated a favourable tolerability and safety profile, including no observations of treatment-related disadvantages in terms of worsening of other disease signs or symptoms.[15][16]

Compassionate use programme and open-ended, open-label study

To meet requests from patients and healthcare professionals for continued treatment with pridopidine, NeuroSearch has established a compassionate use programme in Europe to ensure continued access to pridopidine for patients who have completed treatment in the MermaiHD open-label extension study. The programme is active in all of the eight European countries where the MermaiHD study was conducted.

NeuroSearch has initiated an open-ended, open-label clinical study in the USA and Canada, called the Open HART study. In this study, all patients who have completed treatment in the HART study are offered the chance to restart treatment with pridopidine until either marketing approval has been obtained in the countries in question, or the drug’s development is discontinued. The first patients were enrolled in March 2011.[3]

Regulatory agency advice

The results of the MermaiHD and HART trials were presented to the American and European regulatory agencies: the FDA in March 2011 and EMA in May, 2011. Both agencies indicated insufficient evidence had been produced to allow approval in human patients, and a further phase 3 trial would be required for approval.[4][5]

PATENT

WO 2001046145

Example 6: 4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
m.p. 200°C (HCl) MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp) , 129 (20), 115 (20), 70 (25.

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2510-2520.

Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16)

NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Göteborg, Sweden
J. Med. Chem., 2010, 53 (6), pp 2510–2520
DOI: 10.1021/jm901689v
*To whom correspondence should be addressed. Phone: +(46) 31 7727710. Fax: +(46) 31 7727701. E-mail: fredrik.pettersson@neurosearch.se.

Abstract

Abstract Image

Modification of the partial dopamine type 2 receptor (D2) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D2 antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D2 in vitro, without displaying properties essential for interaction with D2 in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D2 antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D2 antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The “agonist-like” kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D2 antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique “dopaminergic stabilizer” characteristics, differentiating 12b from D2 antagonists and partial D2agonists.

4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (12b)

Purification with flash chromatography using CH2Cl2/MeOH [1:1 (v/v)] as eluent afforded pure 12b (3.28 g, 79%).
MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25).
1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.
The amine was converted to the HCl salt and recrystallized in EtOH/diethyl ether: mp 212−214 °C. Anal. (C15H24ClNO2S) C, H, N.

PATENT

WO-2017015609

Pridopidine (Huntexil®) is a unique compound developed for the treatment of patients with motor symptoms associated with Huntington’s disease. The chemical name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-l-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSED:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459. U.S. Patent No. 6,903,120 claims pridopidine for the treatment of Parkinson’s disease, dyskinesias, dystonias, Tourette’s disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington’s disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

US Patent Application Publication Nos. 20140378508 and 20150202302, describe methods of treatment with high doses of pridopidine and modified release formulations of pridopidine, respectively.

EXAMPLES

Example 1: Pridopidine-HCl synthesis

An initial process for synthesizing pridopidine HC1 shown in Scheme 1 and is a modification of the process disclosed in US Patent No. 7,923,459.

The synthesis of Compound 9 started with the halogen-lithium exchange of 3-bromothioanisole (3BTA) in THF employing n-hexyllithium (HexLi) in hexane as the lithium source. Li-thioanisole (3LTA) intermediate thus formed was coupled with 1 -propyl-4-piperidone (1P4P) forming a Li-Compound 9. These two reactions require low (cryogenic) temperature. The quenching of Li-Compound 9 was done in water HCl/MTBE resulting in precipitation of Compound 9-HCl salt. A cryogenic batch mode process for this step was developed and optimized. The 3BTA and THF were cooled to less than -70°C. A solution of HexLi in n-hexane (33%) was added at a temperature below -70°C and the reaction is stirred for more than 1 hour. An in-process control sample was taken and analyzed for completion of halogen exchange, l-propyl-4-piperidone (1P4P) was then added to the reaction at about -70°C letting the reaction mixture to reach -40°C and further stirred at this temperature for about 1 hour. An in-process sample was analyzed to monitor the conversion according to the acceptance criteria (Compound 9 not less than 83% purity). The reaction mixture was added to a mixture of 5N hydrochloric acid (HC1) and methyl teri-butyl ether (MTBE). The resulting precipitate was filtered and washed with MTBE to give the hydrochloric salt of Compound 9 (Compound 9-HCl) wet.

Batch mode technique for step 1 requires an expensive and high energy-consuming cryogenic system that cools the reactor with a methanol heat exchange, in which the methanol is circulated in counter current liquid nitrogen. This process also brings about additional problems originated from the workup procedure. The work-up starts when the reaction mixture is added into a mixture of MTBE and aqueous HC1. This gives three phases: (1) an organic phase that contains the organic solvents MTBE, THF and hexane along with other organic related materials such as thioanisole (TA), hexyl-bromide,

3-hexylthioanisole and other organic side reaction impurities (2) an aqueous phase containing inorganic salts (LiOH and LiBr), and (3) a solid phase which is mostly Compound 9-HCl but also remainders of 1P4P as an HC1 salt.

The isolation of Compound 9-HCl from the three phase work-up mixture is by filtration followed by MTBE washings. A major problem with this work-up is the difficulty of the filtration which resulted in a long filtration and washing operations. The time it takes to complete a centrifugation and washing cycle is by far beyond the normal duration of such a manufacturing operation. The second problem is the inevitable low and non-reproducible assay (purity of -90% on dry basis) of Compound 9-HCl due to the residues of the other two phases. It should be noted that a high assay is important in the next step in order to control the amount of reagents. The third problem is the existence of THF in the wet Compound 9-HCl salt which is responsible for the Compound 3 impurity that is discussed below.

Example 6.2: Pridopidine crude – work-up development

After the reduction, pridopidine HC1 is precipitated by adding HC1/IPA to the solution of pridopidine free base in ΓΡΑ in the process of Example 1. Prior to that, a solvent swap from toluene to ΓΡΑ is completed by 3 consecutive vacuum distillations. The amount of toluene in the ΓΡΑ solution affects the yield and it was set to be not more than 3% (IPC by GC method). The spontaneous precipitation produces fine crystals with wide PSD. In order to narrow the PSD, Example 1 accomplishes HC1/IPA addition in two cycles with cooling/warming profile.

The updated process is advantageous for crystallizing pridopidine free base over the procedure in Example 1 for two reasons.

First, it simplifies the work-up of the crude because the swap from toluene to PA is not required. The pridopidine free base is crystallized from toluene/n-heptanes system. Only one vacuum distillation of toluene is needed (compared to three in the work-up of Example 1) to remove water and to increase yield.

Second, in order to control pridopidine-HCl physical properties. Pridopidine free base is a much better starting material for the final crystallization step compared to the pridopidine HC1 salt because it is easily dissolved in ΓΡΑ which enables a mild absolute (0.2μ) filtration required in the final step of API manufacturing.

Crystallization of pridopidine free base in toluene/n-heptane system

First, crystallization of pridopidine free base in toluene/n-heptane mixture was tested in order to find the right ratio to maximize the yield. In order to obtain pridopidine free base, pridopidine-HCl in water/toluene system was basified with NaOH(aq) to pH>12. Two more water washes of the toluene phase brought the pH of the aqueous phase to <10. Addition of n-heptane into the toluene solution

resulted in pridopidine free base precipitation. Table 21 shows data from the toluene/n-heptane crystallization experiments.

Example 7: Development of the procedure for the purification of Compound 1 in pridopidine free base.

The present example describes lowering Compound 1 levels in pridopidine free base. This procedure involves dissolving pridopidine FB in 5 Vol of toluene at 20-30°C, 5 Vol of water are added and after the mixing phases are separated and the organic phase is washed three times with 5 Vol water. The toluene mixture is then distilled up to 2.5 Vol in the reactor and 4 Vol of heptane are added for crystallization. Experiment No. 2501 was completed using this procedure. Table 24 summarizes the results.

Example 8: Step 4 in Scheme 2: Pridopidine Hydrochloride process

This example discusses the step used to formulate pridopidine-HCl from pridopidine crude. The corresponding stage in Example 1 was part of the last (third) stage in which pridopidine-HCl was obtained directly from Compound 8 without isolation of pridopidine crude. In order to better control pridopidine-HCl physical properties, it is preferable to start with well-defined pridopidine free base which enables control on the exact amount of HC1 and IPA.

Pridopidine-HCl preparation – present procedure

Pridopidine-HCl was prepared according to the following procedure: Solid pridopidine crude was charged into the first reactor followed by 8 Vol of IPA (not more than (NMT) 0.8% water by KF) and the mixture is heated to Tr =40-45°C (dissolution at Tr = 25-28°C). The mixture was then filtered through a 0.2 μιη filter and transferred into the second (crystallizing) reactor. The first hot reactor was washed with 3.8 Vol of IPA. The wash was transferred through the filter to the second reactor. The temperature was raised to 65-67°C and 1.1 eq of IPA/HCl are added to the mixture (1.1 eq of HC1, from IPA/HCl 5N solution, 0.78 v/w). The addition of EPA HCl into the free base is exothermic; therefore, it was performed slowly, and the temperature maintained at Tr = 60-67°C. After the addition, the mixture was stirred for 15 min and pH is measured (pH<4). If pH adjustment is needed,

0.2 eq of HCl (from IPA/HC1 5 N solution) is optional. At the end of the addition, the mixture was stirred for 1 hour at Tr = 66°C to start sedimentation. If sedimentation does not start, seeding with 0.07% pridopidine hydrochloride crystals is optional at this temperature. Breeding of the crystals was performed by stirring for 2.5 h at Tr =64-67°C. The addition HCl line was washed with 0.4 Vol of ΓΡΑ to give~13 Vol solution. The mixture was cooled to Tr =0°C The solid is filtered and washed with cooled 4.6 Vol ΓΡΑ at LT 5°C. Drying as performed under vacuum (P< ) at 30-60°C to constant weight: Dried pridopidine-HCl was obtained as a white solid.

Purification of Compound 4 during pridopidine-HCl process

A relationship between high temperature in the reduction reaction and high levels of Compound 4 impurity have been observed. A reduction in 50°C leads to 0.25% of Compound 4. For that reason the process of Example 1 limits the reduction reaction temperature to 30±5°C since this is the final step and Compound 4 level should be not more than 0.15%. The present process has another crystallization stage by which Compound 4 can be purified.

PATENT

https://www.google.ch/patents/US20130150406

Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, is a drug substance currently in clinical development for the treatment of Huntington’s disease. The hydrochloride salt of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine and a method for its synthesis is described in WO 01/46145. In WO 2006/040155 an alternative method for the synthesis of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine is described. In WO 2008/127188 N-oxide and/or di-N-oxide derivatives of certain dopamine receptor stabilizers/modulators are reported, including the 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine-1-oxide.

1H NMR PREDICTIONS

ACTUAL VALUES

1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
 
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.

13C NMR PREDICTIONS

References

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  10.  Rung JP, Carlsson A, Markinhuhta KR, Carlsson ML (June 2005). “The dopaminergic stabilizers (-)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats”. Progress in Neuro-psychopharmacology & Biological Psychiatry. 29 (5): 833–9. doi:10.1016/j.pnpbp.2005.03.003. PMID 15913873.
  11.  Nilsson M, Carlsson A, Markinhuhta KR, et al. (July 2004). “The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition”. Progress in Neuro-psychopharmacology & Biological Psychiatry. 28 (4): 677–85. doi:10.1016/j.pnpbp.2004.05.004. PMID 15276693.
  12. Pettersson F, Waters N, Waters ES, Carlsson A, Sonesson C (November 7, 2002). The development of a new class of dopamine stabilizers. Society for Neuroscience Annual Conference. Orlando, FL.
  13.  Tedroff, J.; Krogh, P. Lindskov; Buusman, A.; Rembratt, Å. (2010). “Poster 20: Pridopidine (ACR16) in Huntington’s Disease: An Update on the MermaiHD and HART Studies”. Neurotherapeutics. 7: 144. doi:10.1016/j.nurt.2009.10.004.
  14.  “NeuroSearch announces results from an open-label safety extension to the Phase III MermaiHD study of Huntexil® in patients with Huntington’s disease” (Press release). NeuroSearch. 15 September 2010. Retrieved 2010-09-15.
  15.  “The HART study with Huntexil® shows significant effect on total motor function in patients with Huntington’s disease although it did not meet the primary endpoint after 12 weeks of treatment” (Press release). NeuroSearch. 14 October 2010. Retrieved 2010-10-14.

REFERENCES CITED:

U.S. Patent No. 6,903,120

U.S. Patent No. 7,923,459

U.S. Publication No. US-2013-0267552-A1

CSED:25948790, http://w .chemspider.com/Chernical-Stmcture.25948790.

CSID:7971505, http://ww.chemspider.com/Chermcal-Stmcture.7971505.html

Ebenezer et al, Tetrahedron Letters 55 (2014) 5323-5326.

REFERENCES

1: Squitieri F, de Yebenes JG. Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date. Drug Des Devel Ther. 2015 Oct 28;9:5827-33. doi: 10.2147/DDDT.S65738. eCollection 2015. PubMed PMID: 26604684; PubMed Central PMCID: PMC4629959.

2: Rabinovich-Guilatt L, Siegler KE, Schultz A, Halabi A, Rembratt A, Spiegelstein O. The effect of mild and moderate renal impairment on the pharmacokinetics of pridopidine, a new drug for Huntington’s disease. Br J Clin Pharmacol. 2016 Feb;81(2):246-55. doi: 10.1111/bcp.12792. Epub 2015 Nov 25. PubMed PMID: 26407011.

3: Shannon KM, Fraint A. Therapeutic advances in Huntington’s Disease. Mov Disord. 2015 Sep 15;30(11):1539-46. doi: 10.1002/mds.26331. Epub 2015 Jul 30. Review. PubMed PMID: 26226924.

4: Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, Dierckx RA, Elsinga PH, van Waarde A. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacology (Berl). 2015 Sep;232(18):3443-53. doi: 10.1007/s00213-015-3997-8. Epub 2015 Jul 11. PubMed PMID: 26159455; PubMed Central PMCID: PMC4537502.

5: Squitieri F, Di Pardo A, Favellato M, Amico E, Maglione V, Frati L. Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. J Cell Mol Med. 2015 Nov;19(11):2540-8. doi: 10.1111/jcmm.12604. Epub 2015 Jun 22. PubMed PMID: 26094900; PubMed Central PMCID: PMC4627560.

6: Waters S, Ponten H, Klamer D, Waters N. Co-administration of the Dopaminergic Stabilizer Pridopidine and Tetrabenazine in Rats. J Huntingtons Dis. 2014;3(3):285-98. doi: 10.3233/JHD-140108. PubMed PMID: 25300332.

7: Waters S, Ponten H, Edling M, Svanberg B, Klamer D, Waters N. The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression. J Neural Transm (Vienna). 2014 Nov;121(11):1337-47. doi: 10.1007/s00702-014-1231-1. Epub 2014 May 11. PubMed PMID: 24817271.

8: Reilmann R. The pridopidine paradox in Huntington’s disease. Mov Disord. 2013 Sep;28(10):1321-4. doi: 10.1002/mds.25559. Epub 2013 Jul 11. PubMed PMID: 23847099.

9: Gronier B, Waters S, Ponten H. The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex. J Neural Transm (Vienna). 2013 Sep;120(9):1281-94. doi: 10.1007/s00702-013-1002-4. Epub 2013 Mar 7. PubMed PMID: 23468085.

10: Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord. 2013 Sep;28(10):1407-15. doi: 10.1002/mds.25362. Epub 2013 Feb 28. PubMed PMID: 23450660.

11: Squitieri F, Landwehrmeyer B, Reilmann R, Rosser A, de Yebenes JG, Prang A, Ivkovic J, Bright J, Rembratt A. One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology. 2013 Mar 19;80(12):1086-94. doi: 10.1212/WNL.0b013e3182886965. Epub 2013 Feb 27. PubMed PMID: 23446684.

12: Ponten H, Kullingsjö J, Sonesson C, Waters S, Waters N, Tedroff J. The dopaminergic stabilizer pridopidine decreases expression of L-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model. Eur J Pharmacol. 2013 Jan 5;698(1-3):278-85. doi: 10.1016/j.ejphar.2012.10.039. Epub 2012 Nov 2. PubMed PMID: 23127496.

13: Lindskov Krog P, Osterberg O, Gundorf Drewes P, Rembratt Å, Schultz A, Timmer W. Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing. Eur J Drug Metab Pharmacokinet. 2013 Mar;38(1):43-51. doi: 10.1007/s13318-012-0100-2. Epub 2012 Sep 5. PubMed PMID: 22948856.

14: Ruiz C, Casarejos MJ, Rubio I, Gines S, Puigdellivol M, Alberch J, Mena MA, de Yebenes JG. The dopaminergic stabilizer, (-)-OSU6162, rescues striatal neurons with normal and expanded polyglutamine chains in huntingtin protein from exposure to free radicals and mitochondrial toxins. Brain Res. 2012 Jun 12;1459:100-12. doi: 10.1016/j.brainres.2012.04.021. Epub 2012 Apr 21. PubMed PMID: 22560595.

15: Helldén A, Panagiotidis G, Johansson P, Waters N, Waters S, Tedroff J, Bertilsson L. The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans. Eur J Clin Pharmacol. 2012 Sep;68(9):1281-6. doi: 10.1007/s00228-012-1248-z. Epub 2012 Mar 8. PubMed PMID: 22399238.

16: Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013 Jan;18(1):12-4. doi: 10.1038/mp.2012.3. Epub 2012 Feb 21. PubMed PMID: 22349783.

17: Neurodegenerative disease: Pridopidine for Huntington disease falls short of primary efficacy end point in phase III trial. Nat Rev Neurol. 2011 Dec 26;8(1):4. doi: 10.1038/nrneurol.2011.208. PubMed PMID: 22198402.

18: de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, Saft C, Magnet MK, Sword A, Rembratt A, Tedroff J; MermaiHD study investigators. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011 Dec;10(12):1049-57. doi: 10.1016/S1474-4422(11)70233-2. Epub 2011 Nov 7. PubMed PMID: 22071279.

19: Feigin A. Pridopidine in treatment of Huntington’s disease: beyond chorea? Lancet Neurol. 2011 Dec;10(12):1036-7. doi: 10.1016/S1474-4422(11)70247-2. Epub 2011 Nov 7. PubMed PMID: 22071278.

20: Esmaeilzadeh M, Kullingsjö J, Ullman H, Varrone A, Tedroff J. Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. Clin Neuropharmacol. 2011 May-Jun;34(3):95-100. doi: 10.1097/WNF.0b013e31821c31d8. PubMed PMID: 21586914.

US6903120 Dec 22, 2000 Jun 7, 2005 A. Carlsson Research Ab Modulators of dopamine neurotransmission
US7417043 Dec 21, 2004 Aug 26, 2008 Neurosearch Sweden Ab Modulators of dopamine neurotransmission
US7923459 Apr 10, 2007 Apr 12, 2011 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-N-propyl-piperidine
US20070238879 * Apr 10, 2007 Oct 11, 2007 Gauthier Donald R Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
US20100105736 Apr 14, 2008 Apr 29, 2010 Nsab, Filial Af Neurosearch Sweden Ab, Sverige N-oxide and/or di-n-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles
US20130150406 Dec 7, 2012 Jun 13, 2013 IVAX International GmbH Hydrobromide salt of pridopidine
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US20140088140 Sep 27, 2013 Mar 27, 2014 Teva Pharmaceutical Industries, Ltd. Combination of laquinimod and pridopidine for treating neurodegenerative disorders, in particular huntington’s disease
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CN101056854A Oct 13, 2005 Oct 17, 2007 神经研究瑞典公司 Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-N-propyl-piperidine
WO2001046145A1 Dec 22, 2000 Jun 28, 2001 A. Carlsson Research Ab New modulators of dopamine neurotransmission
WO2006040155A1 Oct 13, 2005 Apr 20, 2006 Neurosearch Sweden Ab Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
US9006445 6. Sept. 2012 14. Apr. 2015 IVAX International GmbH Polymorphic form of pridopidine hydrochloride
US9139525 11. Apr. 2008 22. Sept. 2015 Teva Pharmaceuticals International Gmbh N-oxide and/or di-N-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles
US20100105736 * 14. Apr. 2008 29. Apr. 2010 Nsab, Filial Af Neurosearch Sweden Ab, Sverige N-oxide and/or di-n-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles
US20160176821 * 18. Dez. 2015 23. Juni 2016 Teva Pharmaceuticals International Gmbh L-tartrate salt of pridopidine
USRE46117 22. Dez. 2000 23. Aug. 2016 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
WO2014205229A1 * 19. Juni 2014 24. Dez. 2014 IVAX International GmbH Use of high dose pridopidine for treating huntington’s disease
WO2015112601A1 * 21. Jan. 2015 30. Juli 2015 IVAX International GmbH Modified release formulations of pridopidine
WO2016106142A1 * 18. Dez. 2015 30. Juni 2016 Teva Pharmaceuticals International Gmbh L-tartrate salt of pridopidine
Pridopidine
Pridopidine.svg
Names
IUPAC name

4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine
Identifiers
346688-38-8 Yes
3D model (Jmol) Interactive image
ChemSpider 7971505 
KEGG D09953 
PubChem 9795739
UNII HD4TW8S2VK Yes
Properties
C15H23NO2S
Molar mass 281.41 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////pridopidine, PHASE 3, TEVA, 346688-38-8, orphan drug designation, Neurosearch, ACR16, Huntexil, ASP 2314, FR 310826, UNII-HD4TW8S2VK

CCCN1CCC(CC1)c2cccc(c2)S(C)(=O)=O

OXIDE

Example 5 – Preparation Of Compound 5 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine 1-oxide)

Pridopidine (50.0g, 178mmol, leq) was dissolved in methanol (250mL) and 33% hydrogen peroxide (20mL, 213mmol, 1.2eq). The reaction mixture was heated and kept at 40°C for 20h. The reaction mixture was then concentrated in a rotavapor to give 71g light-yellow oil. Water (400mL) was added and the suspension was extracted with isopropyl acetate (150mL) which after separation contains unreacted pridopidine while water phase contains 91% area of Compound 5 (HPLC). The product was then washed with dichloromethane (400mL) after adjusting the water phase pH to 9 by sodium hydroxide. After phase separation the water phase was washed again with dichloromethane (200mL) to give 100% area of Compound 5 in the water phase (HPLC). The product was then extracted from the water phase into butanol (lx400mL, 3x200ml) and the butanol phases were combined and concentrated in a rotavapor to give 80g yellow oil (HPLC: 100% area of Compound 5). The oil was washed with water (150mL) to remove salts and the water was extracted with butanol. The organic phases were combined and concentrated in a rotavapor to give 43g of white solid which was suspended in MTBE for lhr, filtered and dried to give 33g solid that was melted when standing on air. After high vacuum drying (2mbar, 60°C, 2.5h) 32.23g pure Compound 5 were obtained (HPLC: 99.5% area, 1H-NMR assay: 97.4%).

NMR Identity Analysis of Compound 5

Compound 5:

The following data in Tables 10 and 11 was determined using a sample of 63.06 mg Compound 5, a solvent of 1.2 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΙΠ 400 MHz.

Table 10: Assignment of ¾ NMRa,c

a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.

b Weak signal.

c Spectra is calibrated by the solvent residual peak (2.5 ppm).

Table 11: Assignment of 13C NMRa,b

a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.

b Spectra is calibrated by a solvent peak (39.54 ppm)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016003919&recNum=5&docAn=US2015038349&queryString=EN_ALL:nmr%20AND%20PA:(teva%20pharmaceutical)&maxRec=677#H3

PATENT

http://www.google.bg/patents/WO2013086425A1?cl=en&hl=bg

Preparation of pridopidine HBr

In order to prepare 33 g of pridopidine HBr, 28.5 g of free base was dissolved in 150 ml 99% ethanol at room temperature. 1 .5 equivalents of hydrobromic acid 48% were added. Precipitation occurred spontaneously, and the suspension was left in refrigerator for 2.5 hours. Then the crystals were filtered, followed by washing with 99% ethanol and ether. The crystals were dried over night under vacuum at 40°C: m.p. 196°C. The results of a CHN analysis are presented in Table 2, below.

NMR 1 H NMR (DMSO-d6): 0.93 ( 3H, t), 1 .68-1 .80 ( 2H, m), 1 .99-2.10 ( 4H, m) 2.97-3.14 (5H, m), 3.24 ( 3H, s), 3.57-3.65 ( 2H, d), 7.60-7.68 (2H, m), 7.78-7.86 ( 2H, m) and 9.41 ppm (1 H, bs).

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy


Image result for Exondys 51

Image result for eteplirsen

CAS 1173755-55-9
eteplirsen, eteplirsén [Spanish], étéplirsen [French] , eteplirsenum [Latin], этеплирсен [Russian], إيتيبليرسان [Arabic]

Structure credit http://lgmpharma.com/eteplirsen-still-proves-efficacious-duchenne-drug/

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy
New therapy addresses unmet medical need

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

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Image result for Duchenne muscular dystrophy

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

September 19, 2016

Release

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects reported by participants taking Exondys 51 in the clinical trials were balance disorder and vomiting.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

The manufacturer received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.

Exondys 51 is made by Sarepta Therapeutics of Cambridge, Massachusetts.

Image result for Exondys 51 (eteplirsen) injection

ChemSpider 2D Image | eteplirsen | C364H569N177O122P30

CAS 1173755-55-9 [RN]
eteplirsén [Spanish] [INN]
étéplirsen [French] [INN]
eteplirsenum [Latin] [INN]
этеплирсен [Russian] [INN]
إيتيبليرسان [Arabic] [INN]
Eteplirsen
Systematic (IUPAC) name
(P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),5′-(P-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)carbonyl)-1-piperazinyl)-N,N-dimethylphosphonamidate) RNA
Clinical data
Routes of
administration
Intravenous infusion
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 1173755-55-9
ATC code None
ChemSpider 34983391
UNII AIW6036FAS Yes
Chemical data
Formula C364H569N177O122P30
Molar mass 10305.738

///////////Exondys 51, Sarepta Therapeutics, Cambridge, Massachusetts, eteplirsen,  Orphan drug designationPriority reviewfast track designation, Duchenne muscular dystrophy, этеплирсен ,  إيتيبليرسان ,

AMG 900, An aurora kinase (ARK) inhibitor potentially for the treatment of leukemia and solid tumours


AMG-900

N-(4-((3-(2-aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine.

N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine

Phase I

Amgen Inc. INNOVATOR

Inventors Victor J. Cee, Holly L. Deak, Bingfan Du,Stephanie D. Geuns-Meyer, Brian L. Hodous,Hanh Nho Nguyen, Philip R. Olivieri, Vinod F. Patel, Karina Romero, Laurie Schenkel,Less «
Applicant Amgen Inc.

An aurora kinase (ARK) inhibitor potentially for the treatment of leukemia and solid tumours.

CAS No. 945595-80-2

In 2014, orphan drug designation was assigned in the U.S. for the treatment of ovarian cancer

Molecular Formula: C28H21N7OS
Molecular Weight: 503.57764 g/mo
AMG 900; AMG-900; 945595-80-2; AMG900; UNII-9R2G075611; N-(4-((3-(2-aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine;

AMG 900 is a small-molecule inhibitor of Aurora kinases A, B and C with potential antineoplastic activity. Aurora kinase inhibitor AMG 900 selectively binds to and inhibits the activities of Aurora kinases A, B and C, which may result in inhibition of cellular division and proliferation in tumor cells that overexpress these kinases. Aurora kinases are serine-threonine kinases that play essential roles in mitotic checkpoint control during mitosis and are overexpressed by a wide variety of cancer cell types. Check for active clinical trials or closed clinical trials using this agent

AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor for Aurora A/B/C with IC50 of 5 nM/4 nM /1 nM;  >10-fold selective for Aurora kinases than p38α, Tyk2, JNK2, Met and Tie2.
IC50 Value: 5 nM(Aurora A); 4 nM(Aurora B); 1 nM(Aurora C)
Target: pan-Aurora
in vitro: AMG 900 is a novel class of ATP-competitive phthalazinamine small molecule inhibitors of aurora kinases. In HeLa cells, AMG 900 inhibits autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division without a prolonged mitotic arrest, which ultimately results in cell death. AMG 900 inhibits the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations (about 2- 3 nM). Furthermore, AMG 900 is active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L) [1].
in vivo: Oral administration of AMG 900 blocks the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. AMG 900 is broadly active in multiple xenograft models, including 3 multidrugresistant xenograft models, representing 5 tumor types [1]. AMG 900 exhibits a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 hours. AMG 900 is well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake has an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans are predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibits acceptable PK properties in preclinical species and is predicted to have low clearance in humans [2].

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

MG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser10, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes. (Source: Cancer Res; 70(23); 9846–54.)

Clinical Information of AMG 900

Product Name Sponsor Only Condition Start Date End Date Phase Last Change Date
AMG 900 Amgen Inc Leukemia 31-JUL-11 31-JUL-14 Phase 1 14-SEP-13
Amgen Inc Advanced solid tumor 30-APR-09 30-JUN-13 Phase 1 10-SEP-13

AMG 900.png

PATENT

WO 2007087276

http://www.google.co.in/patents/WO2007087276A1?cl=en

PATENT

WO 2015084649

https://google.com/patents/WO2015084649A1?cl=en

The compound, N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)- 4-(4-methyl-2-thienyl)-l-phthalazinamine, also chemically named as 4-((3-(2-amino- pyrimidin-4-yl)-pyridin-2-yl)oxy)phenyl-(4-(4-methyl-thiophen-2-yl)-phthalazin-l- yl)amine, and is referred to herein as “AMG 900” has a chemical structure of

AMG 900 is an ATP competitive small molecule Aurora kinase inhibitor that is highly potent and selective for Aurora kinases A, B and C. AMG 900 is disclosed in US patent publication no. 20070185111, which published on August 9, 2007 and issued as U.S. Patent No. 7,560,551. AMG 900 is further disclosed in US patent publication no.

20090163501, now US patent no 8,022,221. Various uses and applications of AMG 900 are described in patent publications US20120028917 and WO2013149026. AMG 900 is being clinically evaluated primarily for its safety, tolerability and pharmacokinetic (PK) profile in human phase I trials for (1) advanced solid tumors (US Clinical Trial Id No. NCT00858377), and (2) for acute leukemias (US Clinical Trial Id No. NCT1380756).

Different solid state forms of a given compound are typically investigated to determine whether or not a particular form possesses and/or exhibits desirable properties allowing that compound to be clinically and/or commercially developed. Such beneficial and advantageous properties, by way of example, include without limitation, crystallinity, improved thermodynamic stability, non-hygroscopicity, high purity, minimal to total absence of moisture and/or residual solvents, chemical stability, high yielding synthetic process and/or manufacturability and reproducibility, desirable biopharmaceutical properties including improved dissolution characteristics and increased bioavailability, absence or reduced toxicities due to reduced or limited exposure, rate of exposure or release, or related to counter ions, good bulk and formulation properties including good flow, bulk density, desirable particle size and the like, or a combination of the aforementioned characteristic attributes.

Generally when a compound, also referred to herein as drug substance (DS), has been identified as a developmental candidate, the DS is screened to identify potentially beneficial polymorphic, crystalline or solid state forms of the compound and/or a pharmaceutically acceptable salt thereof. X-ray diffraction, Raman, solid state NMR and a melting point temperature and/or a melting point temperature range have been typically used to monitor or screen and identify the different polymorphic form of the DS.

Different polymorphic forms of a given DS can have an impact on that compound’s solubility, stability and bioavailability. Also, it is important to monitor possible changes in polymorphic forms of the DS during stability studies.

AMG 900 was previously isolated and identified as a free base compound. This compound exhibited rather lack-luster pharmacokinetic (PK) and/or pharmacodynamic (PD) properties, including poor aqueous solubility, poor bioavailability, poor absorption, poor target exposure and overall, a not-so-attractive in-vivo efficacy profile. Thus, there is a need to address and solve the technical problem of identifying alternative forms of AMG 900 to achieve substantially the same effect or an improved effect, including improved PK and PD profiles, as that of AMG 900 known in the art.

Example 1

Synthesis of N-(4-((3-(2-amino-4-pyrimidinylN)-2-pyridinylN)oxyN)phenylN)-4-(4-methyl-2-thienvD-l-phthalazinamine (AMG 900)

Step 1 : 4-(2-chloropyridin-3-yl)pyrimidin-2 -amine

In an argon purged 500 mL round bottom flask placed in an isopropanol bath, was added sodium metal (3.40g, 148mmol) slowly to methanol (180mL). The mixture was stirred at room temperature (RT) for about 30 minutes. To this was added guanidine hydrochloride (12.0 mL, 182 mmol) and the mixture was stirred at RT for 30 minutes, followed by addition of (E)-l-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-l-one (12.0 g, 57.0 mmol), attached air condenser, moved reaction to an oil bath, where it was heated to about 50 °C for 24 hr. Approximately half of the methanol was evaporated under reduced pressure and the solids were filtered under vacuum, then washed with saturated sodium bicarbonate (NaHCO and H^O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off white solid. MS m/z = 207 [M+l]+. Calc’d for C9H7C1N4: 206.63.

Step 2: 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine

To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture was heated to 100 °C for 5 minutes, and then 4-(2-chloropyridin-3-yl)pyrimidin-2 -amine (2.5 g, 12 mmol) was added, and the reaction mixture was heated to 130 °C overnight. Upon completion, as judged by LCMS, the reaction mixture was allowed to cool to RT and diluted with water. The resulting precipitate was filtered, and the solid washed with water and diethyl ether. The solid was then taken up in 9: 1 CH2Cl2:MeOH and passed through a pad of silica gel with 9:1 CH2Cl2:MeOH as eluent. The solvent was concentrated in vacuo to provide the desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z = 280

[M+l]+. Calc’d for Ci5H13N50: 279.30.

Step 3: l-Chloro-4-(4-methylthiophen-2-yl)phthalazine

1 ,4-Dichlorophthalazine (1.40 g, 7.03 mmol), 4-methyltmophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCl2(DPPF) (721 mg, 985 μιηοΐ) were added into a sealed tube. The tube was purged with Argon. Then sodium carbonate (2.0 M in water) (7.74 ml, 15.5 mmol) and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed, stirred at RT for 5 min, and placed in a preheated oil bath at 110 °C. After 1 hr, LC-MS showed product and byproduct (double coupling), and starting material

dichlorophthalazme. The reaction was cooled to RT, filtered through a pad of celite with an aid of ethyl acetate (EtOAc), concentrated, and loaded onto column. The product was purified by column chromatography using Hex to remove the top spot, then 80:20 hexanes:EtOAc to collect the product. The product, 1 -chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained as yellow solid. LC-MS showed that the product was contaminated with a small amount of dichlorophthalazme and biscoupling byproduct. MS m/z = 261 [M+l]+. Calcd for Ci3H9ClN2S: 260.12.

Step 4: N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)- 1 -phthalazinamine

To 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2 -amine and l-chloro-4-(4-methyl-2-thienyl)phthalazine was added tBuOH. The resulting mixture was heated at 100 °C in a sealed tube for 16 hours. The rection was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-l -phthalazinamine as an off-white solid. MS m/z = 504 [M+H]+. Calc’d for C28 H21 N7 O S: 503.58.

Example 2

Alternative Synthesis of N-(4-((3-(2-amino-4-pyrimidinylN)-2-pyridinylN)oxyN)phenylN)-4-(4-methyl-2-thienvD-l-phthalazinamine (AMG 900)

Step 1 : 4-(2-chloropyridin-3-yl)pyrimidin-2 -amine

In an argon purged 500 mL round bottom flask placed in an isopropanol bath, was added sodium metal (3.40g, 148mmol) slowly to methanol (180mL). The mixture was stirred at room temperature (RT) for about 30 minutes. To this was added guanidine hydrochloride (12.0 mL, 182 mmol) and the mixture was stirred at RT for 30 minutes, followed by addition of (E)-l-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-l-one (12.0 g, 57.0 mmol), attached air condenser, moved reaction to an oil bath, where it was heated to about 50 °C for 24 hr. Approximately half of the methanol was evaporated under reduced pressure and the solids were filtered under vacuum, then washed with saturated sodium bicarbonate (NaHCO and H^O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off white solid. MS m/z = 207 [M+l]+. Calc’d for C9H7C1N4: 206.63.

Step 2: 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine

To a reaction vessel at ambient temperature was added 4-aminophenol (571 g, 5.25 mol, 1.05 equiv) followed by 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (1064g, 97 wt%, 5.00 mol, 1.0 equiv) and DMSO (7110 ml, 7820 g, 7x the volume of 4-(2-chloropyridin-3-yl)pyrimidin-2 -amine). The reaction mixture was agitated and sparged with nitrogen gas for at least 10 minutes. Then a 50 weight % aqueous KOH solution (593 g, 5.25 mol, 1.05 equiv.) was added to the mixture while keeping the reaction

mixture temperature below about 40°C. The mixture was sparged with nitrogen gas for more than 5 minutes, the sparging tube was removed, and the reaction mixture was heated to 110 +/- 10 °C for at least 1.5 hrs. Upon completion, as judged by HPLC, the reaction mixture was allowed to cool to RT and diluted with 6N HC1 (42 mL, 0.25 mol, 0.05 equiv). The desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2 -amine was not isolated. Rather, it was formed in-situ and combined with the product of step 3 below, in step 4 to form the desired product.

Step 3: l-Chloro-4-(4-methylthiophen-2-yl)phthalazine

A separate reaction vessel was fitted with a reflux condenser and an addition funnel, and 4-(4-methylthiophen-2-yl)phthalazin-l(2H)-one (1,537 mg, 6.34 mol, 1.0 equivalent) was added to the reaction vessel. Acetonitrile (7540 mL, 5859 g, 5 V), was added and the reaction vessel was agitated to allow the starting material to dissolve. The vessel was then charged with phosphorus oxychloride (709 ml, 1166 g, 7.44 mol, 1.2 equivalents) and the reaction was heated to about 75 +/- 5 °C for a least 4 hrs. The reaction was cooled to about about 25 +/- 5 °C and held there for more than 24 hrs. N,N-diisopropylethylamine (3046 g, 4100 mL, 3.8 equivalents) was added to the reaction vessel and the temperature was maintained at <30°C. Pyridine (97g, 1.24 mol, 0.2 equiv) was added in a single portion followed by water (4100 g, 2.7V) over more than 30 minutes. The reaction mixture was stirred at ambient temperature ofr about 24 hrs. the mixture was filtered through a <25uM polypropylene filter and the rsulting mother liquor was diluted with 1 : 1 ACN:water (9000 mL total) and stirred for a minimum of 2 minutes. Filter off product solids as they precipitate. Collect mother liquor and washes to obtain additional product. Dry the filter cake, and additional product crops, under a constant stream of nitrogen gas for at least 14 hrs. Unlike the previous method, the present method avoids contamination of impurities, such as dichlorophthalazine and biscoupling byproduct, as seen via LC-MS. Yield: 1537 g (97.2 weight %). MS m/z = 261 [M+l]+. Calcd for Ci3H9ClN2S: 260.12.

Step 4: N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)- 1 -phthalazinamine

To the reaction mixture was added l-chloro-4(4-methylthiophen-2-yl)phthalazine

(1450g, 97.2 wt%, 5.40 mol, 1.08 equiv) rinding the addition port with DMSO (520 ml, 572 g, 0.5x the volume of 4-(2-chloropyridin-3-yl)pyrimidin-2-amine). The reaction mixture was again agitated and sparged with nitrogen gas for at least 10 minutes. The sparging tube was removed, and the reaction mixture was heated to 80 +/- 20 °C for at least 2 hrs. Upon completion, as judged by HPLC, the reaction mixture was allowed to cool to RT and N,N-diisopropylethylamine (776 g, 1045 mL, 6.0 mol, 1.2 equiv) was added and the mixture was kept at about 80 +/- 10°C. Filter the mixture at about 80oC into a separate reactor vessel rinsing with DMSO (1030 mL, 1133 g, 1 V). Then adjust the raction mixture temperature to about 70+/-5 °C and add 2-propanol (13200 mL, 10360 g, 12.75 V) over more than 15 minutes at about 70°C. As the reaction mistreu cools, the product begins to precipitate out of solution. Add more 2-propanol (8780 mL, 6900 g, 8.5V) to the solution slowly over more then 60 minutes at about 70°C. The reactor vessel was cooled to about 20°C over more than 60 minutes and let sit for over 2 hrs. The product was filtered through an Aurora filter with a >25uM polypropylene filter cloth. Additional crops were obtained from the mother liquors by diluting with additional 2-propanol. The filter cakes were dried under a constant stream of nitrogen gas for at least 14 hrs to provide the desired product, N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-l-phthalazinamine as an off-white solid. Yield: 2831 g (88.8%); purity 99.7%. MS m/z = 504 [M+H]+. Calc’d for C28 H21 N7 O S: 503.58.

The starting material 1 used/shown in Example 2 was prepared as follows:

and starting material 3, thienyl substituted phthalazinone, shown in Example 2 was prepared as follows:

Starting material 3

Synthesis of 4-(5-methylthiophen-2-yl)phthalazin-l(2//)-one

Step 1 : 2-(Dimethylamino)isoindoline-1.3-dione

A solution of isobenzofuran-l,3-dione (5.00 g, 34 mmol) and N,N-dimethylhydrazine (2.9 ml, 37 mmol) in toluene (75 ml, 34 mmol) was added p-TsOH H20 (0.32 g, 1.7 mmol). The Dean-Stark apparatus and a condenser were attached. The mixture was refluxed. After 4 hr, LCMS showed mainly product. The reaction was cooled to rt. Toluene was removed under reduced pressure the crude was dissolved in DCM, washed with sat NaHC03, water, and brine. The organic was dried over MgS04, filtered, and concentrated. Light yellow solid was obtained. !H NMR showed mainly product, 2-(dimethylamino)isoindoline-l,3-dione. MS Calcd for C10H10N2O2: [M]+ = 190. Found: [M+H]+ = 191.

Step 2 : 2-(Dimethylamino)-3 -hydroxy-3 -(5 -methylthiophen-2 -vDisoindolin- 1 -one

A solution of 2-bromo-5-methylthiophene (0.60 mL, 5.3 mmol) in THF (11 mL) was purged with nitrogen and cooled to -78 °C. «-Butyllithium (2.2 mL, 5.5 mmol; 2.5 M in THF) was added and the mixture was stirred under nitrogen for 30 min. This solution was cannulated into a flask containing a solution of 2-(dimethylamino)isoindoline-l,3-dione (1.5 g, 7.9 mmol) in THF (16 mL) at -78 °C under nitrogen. The reaction was allowed to warm to -30 °C over an hour, at which point LCMS showed complete conversion of 2-bromo-5-methylthiophene to product. The reaction was quenched by careful addition of saturated aqueous NH4C1. The reaction mixture was diluted with dichloromethane and water, and the layers were separated. The aqueous portion was extracted with additional dichloromethane, and the combined organic layers were dried with MgS04, filtered, concentrated, and purified by silica gel chromatography eluting with 0-2% MeOH in dichloromethane to provide intermediate A, as a light yellow solid, 2-(dimethylamino)-3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin-l-one (1.2 g, 80% yield). !H NMR (400 MHz, DMSO-4) δ 7.68-7.65 (m, 1H). 7.63-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.37 (d, 1H, J=8), 7.09 (s, 1H), 6.69-6.66 (m, 1H), 6.65-6.62 (m, 1H), 2.81 (s, 6H), 2.40 (s, 3H). 13C NMR (400 MHz, DMSO-de) δ 165.0, 147.3, 141.6, 139.3, 132.7, 129.49, 129.46, 125.0, 124.7, 123.0, 122.1, 88.4, 44.7, 14.9. FT-IR (thin film, cm ) 3347, 3215, 1673. MS Calcd for Ci2H7ClN2S: [M]+ = 288. Found: [M+H]+= 289.

HRMS Calcd for Ci5H16N202S: [M+H]+= 288.1005, [M+Na]+ = 311.0825. Found:

[M+H]+ = 289.1022, [M+Na]+= 311.0838. mp = 138-140 °C.

Step 3: 4-(5-Methylthiophen-2-yl)phthalazin-l(2//)-one

2-(Dimethylamino)-3 -hydroxy-3 -(5 -methylthiophen-2-yl)isoindolin- 1 -one (1.1 g, 0.40 mmol), EtOH (4.0 mL), and hydrazine (0.19 mL, 59 mmol) were added into a RBF fitted with a reflux condenser. A nitrogen balloon was attached on top of the condenser. After refluxing overnight, the reaction was cooled to room temperature. An off-white solid precipitated. After cooling to 0 °C, water was added. The solid was filtered off with an aid of water and dried under vacuum to afford a white solid, 4-(5-methylthiophen-2-yl)phthalazin-l(2//)-one (0.82 g, 85% yield).

!H NMR (400 MHz, CDC13) δ 10.57 (s, 1H), 8.50-8.39 (m, 1H), 8.14-8.04 (m, 1H), 7.83- 7.69 (m, 2H), 7.20-7.17 (m, 1H), 6.82-6.71 (m, 1H), 2.47 (s, 3H). 13C NMR (400 MHz,

CDC13) 8 159.9, 142.5, 141.1, 134.3, 133.7, 131.7, 129.4, 128.8, 128.3, 127.1, 126.6,

125.8, 15.4. FT-IR (thin film, cm“1) 2891, 1660, 1334. MS Calcd for Ci3H10N2OS: [M]+

= 242. Found: [M+H]+= 243. HRMS Calcd for Ci3H10N2OS: [M+H]+= 243.0587. Found:

[M+H]+ = 243.0581. mp = 191-194 °C.

Alternatively, starting material 3 was prepared as follows:

The above scheme depicts the process by which intermediate-scale synthesis of thiophene-phthalazinone 5 (shown above) was prepared. Treatment of 50 grams of 3-methylthiophene with z-PrMgCl at 66 °C in the presence of catalytic TMP-H resulted in 98% conversion to the reactive species lb with a >40:1 regioisomeric ratio. After cooling to 20 °C, this mixture was added dropwise to a -20 °C slurry of phthalic anhydride in THF to provide keto acid 3 in 94% assay yield. While this intermediate could be crystallized from toluene/heptane, the crude reaction mixture was taken directly in a through -process conversion to the phthalazinone 5. To that end, removal of THF, MTBE, and residual 3-methylthiophene was accomplished through a distillative solvent switch into ethanol. The resulting solution of 3 was exposed to aqueous hydrazine at 80 °C. After 18 hours, the reaction was cooled and the precipitated product was filtered directly at 20 °C. This process provided 82.7 grams of 98.6 wt % thiophene-phthalazinone 5 in a weight-adjusted 85% yield over the two steps.

LCMS Method:

Samples were run on a Agilent model- 1100 LC-MSD system with an Agilent Technologies XDB-C8 (3.5 μ) reverse phase column (4.6 x 75 mm) at 30 °C. The flow rate was constant and ranged from about 0.75 mL/min to about 1.0 mL/min.

The mobile phase used a mixture of solvent A (H2O/0.1% HO Ac) and solvent B

(AcCN/O.1 HOAc) with a 9 min time period for a gradient from 10%> to 90%> solvent B. The gradient was followed by a 0.5 min period to return to 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) of the column.

Other methods may also be used to synthesize AMG 900. Many synthetic chemistry transformations, as well as protecting group methodologies, useful in synthesizing AMG 900, are known in the art. Useful organic chemical transformation literature includes, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); A. Katritzky and

A. Pozharski, Handbook of Heterocyclic Chemistry, 2nd edition (2001); M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, Springer- Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd edition, Wiley- VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

AMG 900 was tested for its ability to reduce or inhibit tumor progression in various cell lines (in-vitro) and multiple solid tumor types (in-vivo), some of which have previously been exposed to and developed resistance to standard-of-care antimitotic agents, including taxanes and vinca alkaloids, as well as to other chemotherapeutic agents. The following Examples and resulting data will illustrate the ability of AMG 900 to treat cancer, including cancer resistant to the presently standard-of-care therapies, including antimitotic agents, such as paclitaxel, and other drugs used in conjunction with chemotherapy, such as doxorubicin. Unless otherwise indicated, the free base form of AMG 900 was used in the Examples described hereinbelow.

The following Examples describe the efforts of identifying and characterizing various crystalline solid state forms of various salts of AMG 900. Some attempts at forming a solid state crystalline form of a given salt failed, as shown in table 1 hereinbelow. To this end, synthesizing and/or forming &isolating a crystalline solid state form of AMG 900 was not, in any way, straightforward or routine. Rather, the ability to prepare and identify a crystalline solid state form of AMG 900 depended upon the particular salt of AMG 900 and/or the crystallization conditions employed.

PAPER

Journal of Medicinal Chemistry (2015), 58(13), 5189-5207

Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

Departments of Medicinal Chemistry, Pharmaceutical Research and Development, §Pharmacokinetics and Drug Metabolism, Molecular Structure, and Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States, and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
J. Med. Chem., 2015, 58 (13), pp 5189–5207
DOI: 10.1021/acs.jmedchem.5b00183
*Phone: 617-444-5041. E-mail: MeyerS@amgen.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Abstract Image

Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.

N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (23r)

Applying similar SNAr conditions as for 23b, reaction of 22r and 20a in 2-butanol provided the title compound (2.08 g, 49%) as an off-white solid; mp (DSC) 216 °C.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1 H) 8.64–8.69 (m, 1 H) 8.41–8.44 (m, 1 H) 8.36–8.40 (m, 1 H) 8.35 (d, J = 5.2 Hz, 1 H) 8.23 (dd, J = 4.8, 2.0 Hz, 1 H) 8.00–8.10 (m, 2 H) 7.91–7.97 (m, 2 H) 7.52 (d, J = 1.0 Hz, 1 H) 7.26–7.33 (m, 3 H) 7.16–7.22 (m, 2 H) 6.74 (br s, 2 H) 2.34 (br s, 3 H).
13C NMR (150 MHz, DMSO-d6) δ 163.81, 160.72, 160.67, 158.68, 151.64, 148.50, 148.36, 147.14, 139.86, 139.24, 137.72, 137.10, 132.61, 131.74, 130.24, 125.27, 124.89, 122.92, 122.83, 122.44, 121.56, 121.52, 119.11, 118.23, 109.93, 15.6
HRMS m/z [M + H]+ Calcd for C28H21N7OS: 504.1601. Found: 504.1607.
Table 1. Aurora Kinase Inhibitors with Known Structures That Have Entered Clinical Trials

ID, compd name AKa AK cell assayb (nM) most potently inhibited non-AKs (nM)c [total kinases in panel] admin route
1 (MK-0457/VX-680/tozasertib)(7) A/B MDA-MB-231 p-HH3(12) 43 FLT3 (6), PLK4 (9), ABL (13), MLCK (15), RET (28); [317](16) IV
2 (PHA-739358/danusertib)(8) A/B MDA-MB-231 p-HH3(12) 49 ABL (25), RET (31), TrkA (31), FGFR1 (47); [35](17) IV
3a(AZD1152/barasertib)d,(9) B MDA-MB-231 p-HH3(12) 16 FLT3 (8), cKIT (17), PDGFRA (38), PDGFRB (41), RET (80); [317](16) IV
4 (AT9283)(18) A/B HCT-116 DNA ploidy ∼30 JAK2 (1), JAK3 (1) Abl (T315I) (4), 9 others ≤10 nM; [230] IV
5 (SNS-314)(19) A/B HCT-116 DNA ploidy(20) 9 TrkB (5), TrkA (12), FLT4 (14), Fms (15), DDR2 (82), Axl (84); [219] IV
6 (GSK1070916)(21) B HCT-116 p-HH3(22) 20 FLT1 (42), TIE2 (59), SIK (70), FLT4 (74), FGFR (78); [328](22) IV
7 (ENMD-2076)(23) A HCT-116 p-AurA 130 FLT3 (2), RET (10), FLT4 (16), SRC (20), TrkA (24), Fms (25); [100] PO
8 (CYC116)(24) A/B A549 p-HH3 480 VEGFR2 (44), FLT3 (44), CDK2 (390); [23] PO
9 (ABT-348)(25) A/B HCT-116 p-HH3 21 VEGFR1 (1), FLT3 (1), VEGFR2 (2), CSF-1R (3), PDGFR-α (11); [128] PO
10 (AS703569/R763)(26) A/B A549 p-HH3 14 cell-based assays: VEGFR2 (11), FLT3 (27), AMPK (201); [10] PO
11 (PF-03814735)(27) A/B MDA-MB-231 p-HH3 ∼50 FLT1 (10), FAK (22), TrkA (30), 17 others ≥90% inh@100 nM; [220] PO
12 (MK-5108)(28) A HeLa S3 ↑p-HH3+ cells <1000 TrkA (2), ABL (8), FLT4 (12), TrkB (13), VEGFR2 (30); [233] PO
13a (MLN8054)(29) A HCT-116 p-AurA 34 DRAK2 (8), BLK (68), DRAK1 (190), FGR (220); [317](16) PO
13b (MLN8237/alisertib)(30) A HeLa p-AurA 7 %inh@1 μM: EphA2 (111), FGR (97), CAMK2A (95), EphA4 (94); [220] PO

a

AK = Aurora kinase family member(s) inhibited (AurA and/or AurB; AurC potency not listed).

b

Cell line; substrate or phenotype detected.

c

Kinase activities of greatest potency listed in published literature.

d

Listed enzyme and cellular potency data is for 3b, the parent of prodrug 3a.

References on AMG 900

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///////////945595-80-2, AMG 900,  aurora kinase (ARK) inhibitor,  treatment of leukemia and solid tumours, AMGEN, 2014, orphan drug designation,  U.S. for the treatment of ovarian cancer

CC1=CSC(=C1)C2=NN=C(C3=CC=CC=C32)NC4=CC=C(C=C4)OC5=C(C=CC=N5)C6=NC(=NC=C6)N

INCB24360 (epacadostat)


ChemSpider 2D Image | epacadostat | C11H13BrFN7O4S

Epacadostat
(Z)-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboxamidine
1,2,5-Oxadiazole-3-carboximidamide, 4-[[2-[(aminosulfonyl)amino]ethyl]amino]-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-
1204669-58-8
INCB024360
N-(3-Brom-4-fluorphenyl)-N’-hydroxy-4-{[2-(sulfamoylamino)ethyl]amino}-1,2,5-oxadiazol-3-carboximidamid
UNII 71596A9R13
(Z)-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-4-(2-(sulfamoylamino)ethylamino)-1,2,5-oxadiazole-3-carboximidamide
1,2,5-Oxadiazole-3-carboximidamide, 4-[[2-[(aminosulfonyl)amino]ethyl]amino]-N’-(3-bromo-4-fluorophenyl)-N-hydroxy-

Molecular Formula, C11H13BrFN7O4S

Average mass438.233 Da

cas 1204669-58-8 (or 1204669-37-3)

Synonym: IDO1 inhibitor INCB024360
indoleamine-2,3-dioxygenase inhibitor INCB024360
Code name: INCB 024360
INCB024360
Chemical structure: 1,2,5-Oxadiazole-3-carboximidamide, 4-((2-((Aminosulfonyl)amino)ethyl)amino)-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-, (C(Z))-
Company Incyte Corp.
Description Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor
Molecular Target Indoleamine 2,3-dioxygenase 1 (IDO1)
Mechanism of Action Indoleamine 2,3-dioxygenase (INDO) inhibitor
Therapeutic Modality Small molecule

 

  • OriginatorIncyte Corporation
  • DeveloperFred Hutchinson Cancer Research Center; Incyte Corporation; Merck AG
  • ClassAmides; Antineoplastics; Imides; Oxadiazoles; Small molecules
    • Phase IIFallopian tube cancer; Malignant melanoma; Non-small cell lung cancer; Ovarian cancer; Peritoneal cancer; Solid tumours

    Most Recent Events

    • 15 Jan 2016Phase-II clinical trials in Solid tumours (Combination therapy, Late-stage disease, Second-line therapy or greater) in USA (PO)
    • 11 Jan 2016Phase-II clinical trials in Non-small cell lung cancer (Combination therapy, Late-stage disease, Second-line therapy or greater) in USA (PO)
    • 11 Jan 2016The US FDA and Health Canada approve IND application and Clinical Trial Application, respectively, for a phase Ib trial in Ovarian cancer (Combination therapy, Recurrent, Second-line therapy or greater)

In 2016, orphan drug designation was assigned to the compound in the US. for the treatment of stage IIB-IV melanoma

EpacadostatAn orally available hydroxyamidine and inhibitor of indoleamine 2,3-dioxygenase (IDO1), with potential immunomodulating and antineoplastic activities. epacadostat targets and binds to IDO1, an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, epacadostat increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), NK cells, and T-lymphocytes, as well as interferon (IFN) production, and a reduction in tumor-associated regulatory T cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may inhibit the growth of IDO1-expressing tumor cells. IDO1 is overexpressed by a variety of tumor cell types and DCsINCB24360 (epacadostat), An Agent For Cancer Immunotherapy

Incyte and Merck Expand Clinical Collaboration to Include Phase 3 Study Investigating the Combination of Epacadostat with Keytruda® (pembrolizumab) as First-line Treatment for Advanced Melanoma

Pivotal study to evaluate Incyte’s IDO1 inhibitor in combination with Merck’s anti-PD-1 therapy in patients with advanced or metastatic melanoma

WILMINGTON, Del. and KENILWORTH, N.J. — October 13, 2015 — Incyte Corporation (Nasdaq: INCY) and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the expansion of the companies’ ongoing clinical collaboration to include a Phase 3 study evaluating the combination of epacadostat, Incyte’s investigational selective IDO1 inhibitor, with Keytruda® (pembrolizumab), Merck’s anti-PD-1 therapy, as first-line treatment for patients with advanced or metastatic melanoma. The Phase 3 study, which is expected to begin in the first half of 2016, will be co-funded by Incyte and Merck.

“We are very pleased to expand our collaboration with Merck and to move the clinical development program for epacadostat in combination with Keytruda into Phase 3,” said Hervé Hoppenot, President and Chief Executive Officer of Incyte. “We believe the combination of these two immunotherapies shows promise and, if successfully developed, may help to improve clinical outcomes for patients with metastatic melanoma.”

“The initiation of this large Phase 3 study with Incyte in the first-line advanced melanoma treatment setting is an important addition to our robust immunotherapy clinical development program for Keytruda,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “We continue to explore the benefit that Keytruda brings to patients suffering from advanced melanoma when used alone, and we are pleased to be able to add this important combination study with epacadostat to our Keytruda development program.”

Under the terms of the agreement Incyte and Merck have also agreed, for a period of two years, not to initiate new pivotal studies of an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist as first-line therapy in advanced or metastatic melanoma with any third party. During this time, the companies will each offer the other the opportunity to collaborate on any new pivotal study involving an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist for types of melanoma and lines of therapy outside of the current collaboration agreement.

The agreement is between Incyte and certain subsidiaries and Merck through its subsidiaries.

Epacadostat and Keytruda are part of a class of cancer treatments known as immunotherapies that are designed to enhance the body’s own defenses in fighting cancer; the two therapies target distinct regulatory components of the immune system. IDO1 is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Preclinical evidence suggests that the combination of these two agents may lead to an enhanced anti-tumor immune response compared with either agent alone.

Safety and efficacy data from the ongoing Phase 1/2 study evaluating the combination of epacadostat with Keytruda in patients with advanced malignancies is scheduled to be highlighted as a late-breaking oral presentation (Abstract #142) at the upcoming Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting & Associated Programs, November 4–8, 2015 at the Gaylord National Resort & Convention Center in National Harbor, MD.

Metastatic Melanoma

Melanoma, the most serious form of skin cancer, strikes adults of all ages and accounts for approximately five percent of all new cases of cancer in the United States each year. The number of new cases of melanoma continues to rise by almost three percent each year which translates to 76,000 new cases yearly in the U.S. alone.[i] The 5-year survival rate for late-stage or metastatic disease is 15 percent.[ii] 

About Epacadostat (INCB024360)

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Epacadostat is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. Epacadostat has shown proof-of-concept clinical data in patients with unresectable or metastatic melanoma in combination with the CTLA-4 inhibitor ipilimumab, and is currently in four proof-of-concept clinical trials with PD-1 and PD-L1 immune checkpoint inhibitors in a variety of cancer histologies.

PATENT

WO 2014066834

https://www.google.com/patents/WO2014066834A1?cl=en

EXAMPLE 1

4-({2-[(Aminosulfonyl)amino]ethyl}amino)- V-(3-bromo-4-fluorophenyl)- V -hydroxy- l,2,5-oxadiazole-3-carboximidamide

Figure imgf000055_0001

Step 1: 4-Amino-N’-hydroxy-l,2,5-oxadiazole-3-carboximidamide

[00184] Malononitrile (320.5 g, 5 mol) was added to water (7 L) preheated to 45 °C and stirred for 5 min. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 °C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction ensued with the temperature reaching 16 °C. After 15 min the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18 °C. The reaction mixture was cooled to 13 °C and 50% aqueous hydroxylamine (990 g, 15 mol) was added all at once. The temperature rose to 26 °C. When the exothermic reaction subsided the cold bath was removed and stirring was continued for 1 hr at 26-27 °C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and 6 N hydrochloric acid (800 mL) was added in portions over 40 min to pH 7.0. Stirring was continued in the ice bath at 5 °C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 °C) to give the desired product (644 g, 90%). LCMS for C3H6N5O2

(M+H)+: m/z = 144.0. 13C MR (75 MHz, CD3OD): δ 156.0, 145.9, 141.3. Step 2: 4-Amino-N-hydroxy-l,2,5-oxadiazole-3-carboximidoyl chloride [00185] 4-Amino-N,-hydroxy-l ,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 Ν hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42 – 45 °C until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0 °C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15 °C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl i-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45 °C) to give the desired product (256 g, 53.4%). LCMS for C3H4CIN4O2 (M+H)+: m/z = 162.9. 13C NMR (100 MHz, CD3OD): 5 155.8, 143.4, 129.7.

Step 3: 4-Amino-N’-hydroxy-N-(2-methoxyethyl)-l,2,5-oxadiazole-3-carboximidamide [00186] 4-Amino-N-hydroxy-l ,2,5-oxadiazole-3-carboximidoyl chloride (200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). At 0-5 °C 2-methoxyethylamine [Aldrich, product # 143693] (119.0 mL, 1.35 mol) was added in one portion while stirring. The reaction temperature rose to 41 °C. The reaction was cooled to 0 – 5 °C. Triethylamine (258 mL, 1.84 mol) was added. After stirring 5 min, LCMS indicated reaction completion. The reaction solution was washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to give the desired product (294 g, 1 19%) as a crude dark oil.

LCMS for C6Hi2 503 (M+H)+: m/z = 202.3. 1H NMR (400 MHz, DMSO- ): δ 10.65 (s, 1 H), 6.27 (s, 2 H), 6.10 (t, J = 6.5 Hz, 1 H), 3.50 (m, 2 H), 3.35 (d, J = 5.8 Hz, 2 H), 3.08 (s, 3 H).

Step 4: N’-Hydroxy-4-[(2-methoxyethyl)amino]-l,2,5-oxadiazole-3-carboximidamide

[00187] 4-Amino-N-hydroxy-N-(2-methoxyethyl)-l,2,5-oxadiazole-3- carboximidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed at 100 °C overnight (15 hours). TLC with 50% ethyl acetate (containing 1% ammonium hydroxide) in hexane indicated reaction completed (product Rf = 0.6, starting material Rf = 0.5). LCMS also indicated reaction completion. The reaction was cooled to room temperature and extracted with ethyl acetate (3 x 1 L). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (201 g, 81%) as a crude off-white solid. LCMS for C6H12N5O3 (M+H)+: m/z = 202.3 LH NMR (400 MHz, OMSO-d6): δ 10.54 (s, 1 H), 6.22 (s, 2 H), 6.15 (t, J = 5.8 Hz, 1 H), 3.45 (t, J= 5.3 Hz, 2 H), 3.35 (m, 2 H), 3.22 (s, 3 H). Step 5: N-Hydroxy-4-[(2-methoxyethyl)amino]-l,2,5-oxadiazole-3-carboximidoyl chloride

[00188] At room temperature N’-hydroxy-4-[(2-methoxyethyl)amino]- 1 ,2,5- oxadiazole-3-carboximidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M hydrochloric acid aqueous solution (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). At 3-5 °C a previously prepared aqueous solution (100 mL) of sodium nitrite (15.0 g, 0.217 mol) was added slowly over 1 hr. The reaction was stirred at 3 – 8 °C for 2 hours and then room temperature over the weekend. LCMS indicated reaction completed. The reaction solution was extracted with ethyl acetate (2 x 200 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (49.9 g, 126%) as a crude white solid. LCMS for

C6HioClN403 (M+H)+: m/z = 221.0. !H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1 H), 5.85 (t, J= 5.6 Hz, 1 H), 3.50 (t, J= 5.6 Hz, 2 H), 3.37(dd, J= 10.8, 5.6 Hz, 2 H), 3.25 (s, 3 H).

Step 6 : N-(3-Bromo-4-fluorophenyl)-N’-hydroxy-4- [(2-methoxyethyl)amino] – 1 ,2,5- oxadiazole-3-carboximidamide [00189] N-Hydroxy-4-[(2-methoxyethyl)amino]- 1 ,2,5-oxadiazole-3-carboximidoyl chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60 °C. 3-Bromo-4-fluoroaniline [Oakwood products, product # 013091] (43.6 g, 0.229 mol) was added and stirred for 10 min. A warm sodium bicarbonate (26.3 g, 0.313 mol) solution (300 mL water) was added over 15 min. The reaction was stirred at 60 °C for 20 min. LCMS indicated reaction completion. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2 x 300 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (76.7 g, 98%) as a crude brown solid. LCMS for Ci2Hi4BrF503 (M+H)+: m/z = 374.0, 376.0. 1H NMR (400 MHz, DMSO- tf): δ 11.55 (s, 1 H), 8.85 (s, 1 H), 7.16 (t, J= 8.8 Hz, 1 H), 7.08 (dd, J= 6.1, 2.7 Hz, 1 H), 6.75 (m, 1 H), 6.14 (t, J= 5.8 Hz, 1 H), 3.48 (t, J = 5.2 Hz, 2 H), 3.35 (dd, J= 10.8, 5.6 Hz, 2 H), 3.22 (s, 3 H).

Step 7: 4-(3-Bromo-4-fluorophenyl)-3-{4- [(2-methoxyethyl)amino]-l,2,5-oxadiazol-3- yl}-l,2,4-oxadiazol-5(4H)-one

[00190] A mixture of N-(3-bromo-4-fluorophenyl)-N’-hydroxy-4-[(2- methoxyethyl)amino]-l,2,5-oxadiazole-3-carboximidamide (76.5 g, 0.204 mol), 1,1 ‘- carbonyldiimidazole (49.7 g, 0.307 mol), and ethyl acetate (720 mL) was heated to 60 °C and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N HC1 (2 x 750 mL), dried over sodium sulfate, and concentrated to give the desired product (80.4 g, 98%) as a crude brown solid. LCMS for

Figure imgf000058_0001

(M+H)+: m/z = 400.0, 402.0. 1H NMR (400 MHz, DMSO-c½): δ 7.94 (t, J = 8.2 Hz, 1 H), 7.72 (dd, J = 9.1, 2.3 Hz, 1 H), 7.42 (m, 1 H), 6.42 (t, J= 5.7 Hz, 1 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.36 (t, J= 5.8 Hz, 2 H), 3.26 (s, 3 H).

Step 8: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-l,2,5-oxadiazol-3- yl}-l,2,4-oxadiazol-5(4H)-one

[00191] 4-(3-Bromo-4-fluoroplienyl)-3-{4-[(2-metlioxyethyl)amino]-l,2,5-oxadiazol- 3-yl}-l,2,4-oxadiazol-5(4H)-one (78.4 g, 0.196 mol) was dissolved in dichloromethane (600 mL). At -67 °C boron tribromide (37 mL, 0.392 mol) was added over 15 min. The reaction was warmed up to -10 °C in 30 min. LCMS indicated reaction completed. The reaction was stirred at room temperature for 1 hour. At 0 – 5 °C the reaction was slowly quenched with saturated sodium bicarbonate solution (1.5 L) over 30 min. The reaction temperature rose to 25 °C. The reaction was extracted with ethyl acetate (2 x 500 mL, first extraction organic layer is on the bottom and second extraction organic lager is on the top). The combined organic layers were dried over sodium sulfate and concentrated to give the desired product (75 g, 99%) as a crude brown solid. LCMS for Ci2HioBrFN504 (M+H)+: m/z = 386.0, 388.0.

1H NMR (400 MHz, DMSO-^): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.70 (m, 1 H), 7.68 (t, J = 8.7 Hz, 1 H), 6.33 (t, J = 5.6 Hz, 1 H), 4.85 (t, J= 5.0 Hz, 1 H), 3.56 (dd, J= 10.6, 5.6 Hz, 2 H), 3.29 (dd, J= 11.5, 5.9 Hz, 2 H).

Step 9 : 2-({4- [4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl] – l,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate

[00192] To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]- l,2,5-oxadiazol-3-yl}-l,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35 °C. After 2 h, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield) as a tan solid. LCMS for C HnBrFNsOeS a (M+Na)+: m/z = 485.9, 487.9. !H NMR (400 MHz, DMSO- d6): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.75 (t, J = 5.9 Hz, 1 H), 4.36 (t, J = 5.3 Hz, 2 H), 3.58 (dd, J = 11.2, 5.6 Hz, 2 H), 3.18 (s, 3 H).

Step 10: 3-{4-[(2-Azidoethyl)amino]-l,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one

To a solution of 2-({4-[4-(3-bromo-4-f uorophenyl)-5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl]-l ,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 50 °C for 6 h, poured into ice/water (8 L), and extracted with 1 : 1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for CnHgBrFNsOs a

(M+Na)+: m/z = 433.0, 435.0. !H NMR (400 MHz, DMSO-J6): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J= 8.7 Hz, 1 H), 6.75 (t, J = 5.7 Hz, 1 H), 3.54 (t, J = 5.3 Hz, 2 H), 3.45 (dd, J= 1 1.1 , 5.2 Hz, 2 H).

Step 11: 3-{4-[(2-Aminoethyl)amino]-l,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-

1.2.4- oxadiazol-5(4H)-one hydrochloride

[00194] Sodium iodide (1080 g, 7.2 mol) was added to 3-{4-[(2-azidoethyl)amino]-

1.2.5- oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one (500 g, 1.22 mol) in methanol (6 L). The mixture was allowed to stir for 30 min during which time a mild exotherm was observed. Chlorotrimethylsilane (930 mL, 7.33 mol) was added as a solution in methanol (1 L) dropwise at a rate so that the temperature did not exceed 35 °C, and the reaction was allowed to stir for 3.5 h at ambient temperature. The reaction was neutralized with 33 wt% solution of sodium thiosulfate pentahydrate in water (-1.5 L), diluted with water (4 L), and the pH adjusted to 9 carefully with solid potassium carbonate (250 g – added in small portions: watch foaming). Di-ieri-butyl dicarbonate (318 g, 1.45 mol) was added and the reaction was allowed to stir at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 h to ensure that the pH was still at or above 9. After stirring at room temperature overnight, the solid was filtered, triturated with water (2 L), and then MTBE (1.5 L). A total of 11 runs were performed (5.5 kg, 13.38 mol). The combined solids were triturated with 1 : 1 THF:dichloromethane (24 L, 4 runs in a 20 L rotary evaporator flask, 50 °C, 1 h), filtered, and washed with dichloromethane (3 L each run) to afford an off- white solid. The crude material was dissolved at 55 °C tetrahydrofuran (5 mL/g), treated with decolorizing carbon (2 wt%) and silica gel (2 wt%), and filtered hot through celite to afford the product as an off-white solid (5122 g). The combined MTBE, THF, and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 kg silica gel, heptane with a 0-100% ethyl acetate gradient, 30 L) to afford more product (262 g). The combined solids were dried to a constant weight in a convection oven (5385 g, 83%).

In a 22 L flask was charged hydrogen chloride (4 N solution in 1 ,4-dioxane, 4 L, 16 mol). tert-Butyl [2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl]-l ,2,5-oxadiazol-3-yl}amino)ethyl]carbamate (2315 g, 4.77 mol) was added as a solid in portions over 10 min. The slurry was stirred at room temperature and gradually became a thick paste that could not be stirred. After sitting overnight at room temperature, the paste was slurried in ethyl acetate (10 L), filtered, re-slurried in ethyl acetate (5 L), filtered, and dried to a constant weight to afford the desired product as a white solid (combined with other runs, 5 kg starting material charged, 41 13 g, 95%). LCMS for

Ci2HnBrFN603 (M+H)+: m/z = 384.9, 386.9. 1H NMR (400 MHz, DMSO-^): δ 8.12 (m, 4 H), 7.76 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.78 (t, J = 6.1 Hz, 1 H), 3.51 (dd, J = 1 1.8, 6.1 Hz, 2 H), 3.02 (m, 2 H).

Step 12: tert-Butyl ({[2-({4-[4-(3-bromo-4-nuorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl]-l,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate

A 5 L round bottom flask was charged with chlorosulfonyl isocyanate [Aldrich, product # 142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) and cooled using an ice bath to 2 °C. teri-Butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate so that the temperature did not exceed 10 °C. The resulting solution was stirred at room temperature for 30-60 min to provide tert-bvAy\ [chlorosulfonyl]carbamate.

A 22 L flask was charged with 3- {4-[(2-aminoethyl)amino]- 1 ,2,5-oxadiazol-3- yl}-4-(3-bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to -15 °C with an ice/salt bath, the solution oi tert- Vmtvl i Vi 1 r>rosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed -10 °C (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed -5 °C (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10 °C, split into two portions, and neutralized with 10% cone HC1 (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (-25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off- white solid. The solid was triturated with MTBE (2 x 1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-^): δ 10.90 (s, 1 H), 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J = 8.6 Hz, 1 H), 6.58 (t, J = 5.7 Hz, 1 H), 3.38 (dd, J= 12.7, 6.2 Hz, 2 H), 3.10 (dd, J= 12.1 , 5.9 Hz, 2 H), 1.41 (s, 9 H).

Step 13: N-[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide

[00198] To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-bvXyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40- 50 °C, the solvents removed in vacuo, and chased with dichloromethane (3 x 2 L). The resulting white solid was dried in a vacuum drying oven at 50 °C overnight. A total of 5409 g was processed in this manner (4990 g, quant, yield). LCMS for C12H12BrFN705S (M+H)+: m/z = 463.9, 465.9. 1H NMR (400 MHz, DMSO- ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J= 8.7 Hz, 1 H), 6.67 (t, J = 5.9 Hz, 1H), 6.52 (t, J= 6.0 Hz, 1 H), 3.38 (dd, J = 12.7, 6.3 Hz, 2 H), 3.11 (dd, J = 12.3, 6.3 Hz). Step 14: 4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N’- hydroxy-l,2,5-oxadiazole-3-carboximidamide

Figure imgf000063_0001

[00199] To a crude mixture of N-[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl]-l,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (2.4 mol) containing residual amounts of trifluoroacetic acid stirring in a 22 L flask was added THF (5 L). The resulting solution was cooled to 0 °C using an ice bath and 2 N NaOH (4 L) was added at a rate so that the temperature did not exceed 10 °C. After stirring at ambient temperature for 3 h (LCMS indicated no starting material remained), the pH was adjusted to 3-4 with concentrated HC1 (-500 mL). The THF was removed in vacuo, and the resulting mixture was extracted with ethyl acetate (15 L). The organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford a solid. The solid was triturated with MTBE (2 x 2 L), combined with three other reactions of the same size, and dried overnight in a convection oven to afford a white solid (3535 g). The solid was recrystallized (3 x 22 L flasks, 2:1 watenethanol, 14.1 L each flask) and dried in a 50 °C convection oven to a constant weight to furnish the title compound as an off-white solid (3290 g, 78%). LCMS for CnHnBrF yC S (M+H)+: m/z = 437.9, 439.9. i NMR (400 MHz, DMSO-J^): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J= 8.8 Hz, 1 H), 7.11 (dd, J= 6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J = 6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J= 6.1 Hz, 1 H), 3.35 (dd, J= 10.9, 7.0 Hz, 2 H), 3.10 (dd, J= 12.1, 6.2 Hz, 2 H).

PATENT

WO 2010005958

https://www.google.com/patents/WO2010005958A2?cl=en

EXAMPLES Example 1

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-7V-(3-bromo-4-fluorophenyl)-iV’-hydroxy- l,2,5-oxadiazole-3-carboximidamide

Figure imgf000043_0001

Step A: 4-Amino-N’-hydroxy-l,2,5-oxadiazole-3-carboximidamide

Figure imgf000043_0002

Malononitrile [Aldrich, product # M1407] (320.5 g, 5 mol) was added to water (7 L) preheated to 45 0C and stirred for 5 min. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 0C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction ensued with the temperature reaching 16 0C. After 15 min the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18 0C. The reaction mixture was cooled to 13 0C and 50% aqueous hydroxylamine (990 g, 15 mol) was added all at once. The temperature rose to 26 0C. When the exothermic reaction subsided the cold bath was removed and stirring was continued for 1 hr at 26-270C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and 6 N hydrochloric acid (800 mL) was added in portions over 40 min to pH 7.0. Stirring was continued in the ice bath at 5 0C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 0C) to give the desired product (644 g, 90%). LCMS for C3H6N5O2 (M+H)+: m/z = 144.0. 13C NMR (75 MHz, CD3OD): δ 156.0, 145.9, 141.3. Step B: 4-Amino-N-hydroxy-l,2,5-oxadiazole-3-carboximidoyl chloride

Figure imgf000044_0001

4-Amino-N’-hydroxy-l,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 Ν hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42 – 45 0C until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0 0C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15 0C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl f-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45 0C) to give the desired product (256 g, 53.4%). LCMS for C3H4ClN4O2(M+H)+: m/z = 162.9. 13c NMR (100 MHz, CD3OD): δ 155.8, 143.4, 129.7.

Step C: 4-Amino-N’-hydroxy-N-(2-methoxyethyl)- 1 ,2,5-oxadiazole-3-carboximidamide

Figure imgf000044_0002

4-Amino-N-hydroxy-l,2,5-oxadiazole-3-carboximidoyl chloride (200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). At 0-50C 2-methoxyethylamine [Aldrich, product # 143693] (119.0 mL, 1.35 mol) was added in one portion while stirring. The reaction temperature rose to 41 0C. The reaction was cooled to 0 – 5 °C. Triethylamine (258 mL, 1.84 mol) was added. After stirring 5 min, LCMS indicated reaction completion. The reaction solution was washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to give the desired product (294 g, 119%) as a crude dark oil. LCMS for C6Hi2N5O3 (M+H)+: m/z = 202.3. 1H NMR (400 MHz, DMSO-J6): δ 10.65 (s, 1 H), 6.27 (s, 2 H), 6.10 (t, J= 6.5 Hz, 1 H), 3.50 (m, 2 H), 3.35 (d, J= 5.8 Hz, 2 H), 3.08 (s, 3 H).

Step D: N’-Hydroxy-4-[(2-methoxyethyl)amino]-l ,2,5-oxadiazole-3-carboximidamide

Figure imgf000045_0001

4-Amino-N’-hydroxy-N-(2-methoxyethyl)-l,2,5-oxadiazole-3-carboximidaniide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed at 100 0C overnight (15 hours). TLC with 50% ethyl acetate (containing 1% ammonium hydroxide) in hexane indicated reaction completed (product Rf= 0.6, starting material Rf = 0.5). LCMS also indicated reaction completion. The reaction was cooled to room temperature and extracted with ethyl acetate (3 x 1 L). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (201 g, 81%) as a crude off-white solid. LCMS for C6H12N5O3 (M+H)+: m/z = 202.3 1H NMR (400 MHz, DMSO-Gk): δ 10.54 (s, 1 H), 6.22 (s, 2 H), 6.15 (t, J= 5.8 Hz, 1 H), 3.45 (t, J= 5.3 Hz, 2 H), 3.35 (m, 2 H), 3.22 (s, 3 H).

Step E: N-Hydroxy-4-[(2-methoxyethyl)amino]-l,2,5-oxadiazole-3-carboximidoyl chloride

Figure imgf000045_0002

Ν. ,Ν O

At room temperature N’-hydroxy-4-[(2-methoxyethyl)amino]-l,2,5-oxadiazole-3- carboximidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M hydrochloric acid aqueous solution (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). At 3-5 0C a previously prepared aqueous solution (100 mL) of sodium nitrite (15.0 g, 0.217 mol) was added slowly over 1 hr. The reaction was stirred at 3 – 8 0C for 2 hours and then room temperature over the weekend. LCMS indicated reaction completed. The reaction solution was extracted with ethyl acetate (2 x 200 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (49.9 g, 126%) as a crude white solid. LCMS for C6Hi0ClN4O3 (M+H)+: m/z = 221.0. 1H NMR (400 MHz, DMSO-J6): δ 13.43 (s, 1 H), 5.85 (t, J= 5.6 Hz, 1 H), 3.50 (t, J= 5.6 Hz, 2 H), 3.37(dd, J= 10.8, 5.6 Hz, 2 H), 3.25 (s, 3 H).

Step F: N-(3-Bromo-4-fluorophenyl)-N’-hydroxy-4-[(2-methoxyethyl)amino]- 1 ,2,5- oxadiazole-3 -carboximidamide

Figure imgf000046_0001

N-Hydroxy-4-[(2-methoxyethyl)amino]-l,2,5-oxadiazole-3-carboximidoyl chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60 °C. 3-Bromo-4- fluoroaniline [Oakwood products, product # 013091] (43.6 g, 0.229 mol) was added and stirred for 10 nrnn. A warm sodium bicarbonate (26.3 g, 0.313 mol) solution (300 mL water) was added over 15 min. The reaction was stirred at 60 0C for 20 min. LCMS indicated reaction completion. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2 x 300 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (76.7 g, 98%) as a crude brown solid. LCMS for Ci2Hi4BrFN5O3 (M+H)+: m/z = 374.0, 376.0. 1H NMR (400 MHz, DMSO-J6): δ 11.55 (s, 1 H), 8.85 (s, 1 H), 7.16 (t, J= 8.8 Hz, 1 H), 7.08 (dd, J= 6.1, 2.7 Hz, 1 H), 6.75 (m, 1 H), 6.14 (t, J= 5.8 Hz, 1 H), 3.48 (t, J= 5.2 Hz, 2 H), 3.35 (dd, J= 10.8, 5.6 Hz, 2 H), 3.22 (s, 3 H).

Step G: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-l,2,5-oxadiazol-3-yl}- 1 ,2,4-oxadiazol-5(4H)-one

Figure imgf000046_0002

A mixture of N-(3-bromo-4-fluorophenyl)-N’-hydroxy-4-[(2-methoxyethyl)amino]-l,2,5- oxadiazole-3-carboximidamide (76.5 g, 0.204 mol), l,r-carbonyldiimidazole (49.7 g, 0.307 mol), and ethyl acetate (720 mL) was heated to 60 0C and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 Ν HCl (2 x 750 mL), dried over sodium sulfate, and concentrated to give the desired product (80.4 g, 98%) as a crude brown solid. LCMS for C13H12BrFN5O4 (M+H)+: m/z = 400.0, 402.0. 1H NMR (400 MHz, OMSO-d6): δ 7.94 (t, J= 8.2 Hz, 1 H), 7.72 (dd, J= 9.1, 2.3 Hz, 1 H), 7.42 (m, 1 H), 6.42 (t, J= 5.7 Hz, 1 H), 3.46 (t, J= 5.4 Hz, 2 H), 3.36 (t, J= 5.8 Hz, 2 H), 3.26 (s, 3 H).

Step H: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-liydroxyethyl)amino]-l,2,5-oxadiazol-3-yl}- 1 ,2,4-oxadiazol-5(4H)-one

Figure imgf000047_0001

4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyetliyl)amino]-l,2,5-oxadiazol-3-yl}-l,2,4- oxadiazol-5(4H)-one (78.4 g, 0.196 mol) was dissolved in dichloromethane (600 mL). At -67 0C boron tribromide (37 mL, 0.392 mol) was added over 15 min. The reaction was warmed up to -10 0C in 30 min. LCMS indicated reaction completed. The reaction was stirred at room temperature for 1 hour. At 0 – 5 0C the reaction was slowly quenched with saturated sodium bicarbonate solution (1.5 L) over 30 min. The reaction temperature rose to 25 0C. The reaction was extracted with ethyl acetate (2 x 500 mL, first extraction organic layer is on the bottom and second extraction organic lager is on the top). The combined organic layers were dried over sodium sulfate and concentrated to give the desired product (75 g, 99%) as a crude brown solid. LCMS for C12H10BrFN5O4 (M+H)+: m/z = 386.0, 388.0. 1H NMR (400 MHz, DMSO-^6): δ 8.08 (dd, J= 6.2, 2.5 Hz, 1 H), 7.70 (m, 1 H), 7.68 (t, J= 8.7 Hz, 1 H), 6.33 (t, J= 5.6 Hz, 1 H), 4.85 (t, J= 5.0 Hz, 1 H), 3.56 (dd, J= 10.6, 5.6 Hz, 2 H), 3.29 (dd, J= 11.5, 5.9 Hz, 2 H).

Step I: 2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]-l,2,5- oxadiazol-3-yl}amino)ethyl methanesulfonate

Figure imgf000047_0002

To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-l,2,5-oxadiazol- 3-yl}-l,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35 0C. After 2 h, the reaction mixture was washed with water (5 L), brine (I L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield) as a tan solid. LCMS for

Ci3HnBrFN5O6SNa (M+Na)+: m/z = 485.9, 487.9. 1H NMR (400 MHz, DMSCW6): δ 8.08 (dd, J= 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J= 8.7 Hz, 1 H), 6.75 (t, J- 5.9 Hz, 1 H), 4.36 (t, J= 5.3 Hz, 2 H), 3.58 (dd, J= 11.2, 5.6 Hz, 2 H), 3.18 (s, 3 H).

Step J: 3-{4-[(2-Azidoethyl)amino]-l,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)- 1 ,2,4-oxadiazol-5(4H)-one

Figure imgf000048_0001

To a solution of 2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 500C for 6 h, poured into ice/water (8 L), and extracted with 1 : 1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for C12H8BrFN8O3Na (M+Na)+: m/z =

433.0, 435.0. 1H NMR (400 MHz, DMSO-*/*): δ 8.08 (dd, J= 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J= 8.7 Hz, 1 H), 6.75 (t, J= 5.7 Hz, 1 H), 3.54 (t, J= 5.3 Hz, 2 H), 3.45 (dd, J= 11.1, 5.2 Hz, 2 H).

Step K: 3-{4-[(2-Aminoethyl)amino]-l,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)- 1 ,2,4-oxadiazol-5(4H)-one hydrochloride

Figure imgf000049_0001

Sodium iodide (1080 g, 7.2 mol) was added to 3-{4-[(2-azidoethyl)amino]-l,2,5-oxadiazol-3- yl}-4-(3-bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (500 g, 1.22 mol) in methanol (6 L). The mixture was allowed to stir for 30 min during which time a mild exotherm was observed. Chlorotrimethylsilane (930 mL, 7.33 mol) was added as a solution in methanol (1 L) dropwise at a rate so that the temperature did not exceed 35 0C, and the reaction was allowed to stir for 3.5 h at ambient temperature. The reaction was neutralized with 33 wt% solution of sodium thiosulfate pentahydrate in water (~1.5 L), diluted with water (4 L), and the pΗ adjusted to 9 carefully with solid potassium carbonate (250 g – added in small portions: watch foaming). Di-fe/t-butyl dicarbonate (318 g, 1.45 mol) was added and the reaction was allowed to stir at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 h to ensure that the pΗ was still at or above 9. After stirring at room temperature overnight, the solid was filtered, triturated with water (2 L), and then MTBE (1.5 L). A total of 11 runs were performed (5.5 kg, 13.38 mol). The combined solids were triturated with 1 : 1 TΗF:dichloromethane (24 L, 4 runs in a 20 L rotary evaporator flask, 50 0C, 1 h), filtered, and washed with dichloromethane (3 L each run) to afford an off- white solid. The crude material was dissolved at 55 0C tetrahydrofuran (5 mL/g), treated with decolorizing carbon (2 wt%) and silica gel (2 wt%), and filtered hot through celite to afford the product as an off-white solid (5122 g). The combined MTBE, THF, and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 kg silica gel, heptane with a 0-100% ethyl acetate gradient, 30 L) to afford more product (262 g). The combined solids were dried to a constant weight in a convection oven (5385 g, 83%).

In a 22 L flask was charged hydrogen chloride (4 N solution in 1,4-dioxane, 4 L, 16 mol). fert-Butyl [2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl]carbamate (2315 g, 4.77 mol) was added as a solid in portions over 10 min. The slurry was stirred at room temperature and gradually became a thick paste that could not be stirred. After sitting overnight at room temperature, the paste was slurried in ethyl acetate (10 L), filtered, re-slurried in ethyl acetate (5 L), filtered, and dried to a constant weight to afford the desired product as a white solid (combined with other runs, 5 kg starting material charged, 4113 g, 95%). LCMS for C12HnBrFN6O3 (M+H)+: m/z

= 384.9, 386.9. 1H NMR (400 MHz, DMSO-J6): δ 8.12 (m, 4 H), 7.76 (m, 1 H), 7.58 (t, J= 8.7 Hz, 1 H), 6.78 (t, J= 6.1 Hz, 1 H), 3.51 (dd, J= 11.8, 6.1 Hz, 2 H), 3.02 (m, 2 H).

Step L: tert-Butyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-diliydro-l,2,4-oxadiazol- 3-yl]-l,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate

Figure imgf000050_0001

A 5 L round bottom flask was charged with chlorosulfonyl isocyanate [Aldrich, product #

142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) and cooled using an ice bath to 2 0C. tert-Butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate so that the temperature did not exceed 10 0C. The resulting solution was stirred at room temperature for 30-60 min to provide tert-butyl [chlorosulfonyljcarbamate.

A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-l,2,5-oxadiazol-3-yl}-4-(3- bromo-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to -15 0C with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed -10 0C (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed -5 0C (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10 0C, split into two portions, and neutralized with 10% cone HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (~25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2 x 1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). *Η NMR (400 MHz, OMSO-d6): δ 10.90 (s, 1 H), 8.08 (dd, J= 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J= 8.6 Hz, 1 H), 6.58 (t, J= 5.7 Hz, 1 H), 3.38 (dd, J= 12.7, 6.2 Hz, 2 H), 3.10 (dd, J = 12.1, 5.9 Hz, 2 H), 1.41 (s, 9 H). Step M: N-[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dmydro-l ,2,4-oxadiazol-3-yl]- l,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide

Figure imgf000051_0001

To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-butyl ({[2- ({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-diliydro-l,2,4-oxadiazol-3-yl]-l,2,5-oxadiazol-3- yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40-50 0C, the solvents removed in vacuo, and chased with dichloromethane (3 x 2 L). The resulting white solid was dried in a vacuum drying oven at 50 0C overnight. A total of 5409 g was processed in this manner (4990 g, quant, yield). LCMS for C]2H12BrFN7O5S (M+H)+: m/z = 463.9, 465.9.

1H NMR (400 MHz, OM$>O-d6): δ 8.08 (dd, J= 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J= 8.7 Hz, 1 H), 6.67 (t, J= 5.9 Hz, IH), 6.52 (t, J= 6.0 Hz, 1 H), 3.38 (dd, J= 12.7, 6.3 Hz, 2 H), 3.11 (dd, J= 12.3, 6.3 Hz).

Step N: 4-( {2-[(Aminosulfonyl)amino]ethyl} amino)-N-(3-bromo-4-fluorophenyl)-N- hydroxy-l,2,5-oxadiazole-3-carboximidamide

To a crude mixture of N-[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl]-l,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (2.4 mol) containing residual amounts of trifluoroacetic acid stirring in a 22 L flask was added THF (5 L). The resulting solution was cooled to 0 °C using an ice bath and 2 Ν NaOH (4 L) was added at a rate so that the temperature did not exceed 10 0C. After stirring at ambient temperature for 3 h (LCMS indicated no starting material remained), the pH was adjusted to 3-4 with concentrated HCl (-500 mL). The THF was removed in vacuo, and the resulting mixture was extracted with ethyl acetate (15 L). The organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford a solid. The solid was triturated with MTBE (2 x 2 L), combined with three other reactions of the same size, and dried overnight in a convection oven to afford a white solid (3535 g). The solid was recrystallized (3 x 22 L flasks, 2: 1 water: ethanol, 14.1 L each flask) and dried in a 50 0C convection oven to a constant weight to furnish the title compound as an off-white solid (3290 g, 78%). LCMS for CnH14BrFN7O4S (M+H)+: m/z = 437.9, 439.9. 1H NMR (400 MHz, DMSO-J6): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J= 8.8 Hz, 1 H), 7.11 (dd, J= 6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J= 6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J= 6.1 Hz, 1 H), 3.35 (dd, J= 10.9, 7.0 Hz, 2 H), 3.10 (dd, J= 12.1, 6.2 Hz, 2 H).

The final product was an anhydrous crystalline solid. The water content was determined to be less than 0.1% by Karl Fischer titration.

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INCB24360
Company:Incyte Corp.
Target: IDO1
Disease: Cancer

Incyte’s Andrew P. Combs presented the company’s clinical candidate for cancer immunotherapy. The basic tenet of this burgeoning field is that the human body’s immune system is a tremendous resource for fighting disease; scientists just need to figure out how to unleash it. One target that’s proven to be particularly attractive for this purpose in recent years is indoleamine-2,3-dioxygenase-1, or IDO1 (C&EN, April 6, page 10).

IDO1 plays a role in signaling the immune system to stand down from attacking foreign bodies it might otherwise go after, such as fetuses. Tumors also produce IDO1 to evade the immune system, so molecules that can inhibit this enzyme could bring the full force of the body’s defenses to bear on these deadly invaders.

Incyte’s search for an IDO1 inhibitor began with a high-throughput screen, which led to a proof-of-concept compound. But the compound had poor oral bioavailability. What’s more, the molecule and its analogs underwent glucuronidation during its metabolism: Enzymes tacked on a glucuronic acid group to the structure’s amidoxime, which was key to its activity.

The chemists reasoned they could block this metabolism by sterically hindering that position. Making such molecules proved to be more difficult than they expected. But then they unearthed a Latvian paper from 1993 that gave them the synthetic method they needed to make the series of compounds that would lead to their clinical candidate INCB24360 (epacadostat).

With its furazan core, as well as its amidoxime, bromide, and sulfuric diamide functional groups, INCB24360 is something of an odd duck, Combs acknowledged. “Some of you in the audience may be looking at this and saying, ‘That molecule does not look like something I would bring forward or maybe even make,’ ” he said, noting that the structure breaks many medicinal chemistry rules. “We’re a data-centric company, and we followed the data, not the rules,” Combs told C&EN.

The compound has completed Phase I clinical trials and is now being used in collaborative studies with several other pharmaceutical companies that combine INCB24360 with other cancer immunotherapy agents.

09338-scitech1-Incytecxd
TEAMWORK
Incyte’s team (from left): Andrew Combs, Dilip Modi, Joe Glenn, Brent Douty, Padmaja Polam, Brian Wayland, Rick Sparks, Wenyu Zhu, and Eddy Yue.
Credit: Incyte
WO2007113648A2 * Mar 26, 2007 Oct 11, 2007 Pfizer Products Inc. Ctla4 antibody combination therapy
US20070185165 * Dec 19, 2006 Aug 9, 2007 Combs Andrew P N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20100055111 * Feb 14, 2008 Mar 4, 2010 Med. College Of Georgia Research Institute, Inc. Indoleamine 2,3-dioxygenase, pd-1/pd-l pathways, and ctla4 pathways in the activation of regulatory t cells
US20120058079 * Nov 11, 2011 Mar 8, 2012 Incyte Corporation, A Delaware Corporation 1,2,5-Oxadiazoles as Inhibitors of Indoleamine 2,3-Dioxygenase

REFERENCES

1: Vacchelli E, Aranda F, Eggermont A, Sautès-Fridman C, Tartour E, Kennedy EP, Platten M, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014 Dec 15;3(10):e957994. eCollection 2014 Nov. Review. PubMed PMID: 25941578; PubMed Central PMCID: PMC4292223.

2: Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010 Apr 29;115(17):3520-30. doi: 10.1182/blood-2009-09-246124. Epub 2010 Mar 2. PubMed PMID: 20197554.

3: Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. 2010 Feb;9(2):489-98. doi: 10.1158/1535-7163.MCT-09-0628. Epub 2010 Feb 2. PubMed PMID: 20124451.

//////////1204669-58-8 , INCB024360, INCB24360, epacadostat, PHASE 2, CANCER, orphan drug designation
Fc1ccc(cc1Br)N/C(=N\O)c2nonc2NCCNS(N)(=O)=O

ONL 1204 a small molecule peptide


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ONL 1204

CAS 1349038-53-4

(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[2-[(3R)-3-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-2-oxopiperidin-1-yl]acetyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]propanoic acid

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

ONL Therapeutics Inc.

Fas receptor (CD95)

Peptide, Retinal detachment, OPTHALMIC DRUGS

C71 H100 N18 O16, 1461.66

L-Histidyl-L-histidyl-L-isoleucyl-L-tyrosyl-L-leucylglycyl-L-alanyl-L-valyl-L-asparaginyl-L-tyrosyl-L-isoleucyl-L-tyrosinamide

RFVTGHFXGL YPA

ORPHAN DRUG DESIGNATION DATA

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

01/13/2016

Treatment of retinal detachment

ONL Therapeutics, Inc
1600 Huron Parkway
Second Floor
Ann Arbor, Michigan 48109…….http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=501215

ONL1204, ONL’s lead therapeutic candidate, is a first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, against the apoptosis (programmed cell death) that occurs in a range of retinal diseases and conditions. It is this death of these retinal cells that is the root cause of vision loss and the leading cause of blindness.

Researchers have shown that ONL1204 effectively inhibits the Fas pathway; one of the body’s primary mechanisms for inducing programmed cell death (apoptosis). Specifically, the compound’s activity inhibits the Fas receptor, blocks the activation of the Fas pathway, and prevents the apoptosis cascade which results in the death of key retinal cells, including photoreceptor.

While initial development efforts for ONL1204 are focused on retinal detachment, preclinicalin vivo data, along with a growing body of literature, support potential application in age-related macular degeneration (AMD) and other chronic retinal diseases. Combined, the estimated market for the initial indications that ONL plans to target is >$12 billion globally.

ONL Therapeutics, Inc., a biopharmaceutical company developing novel therapies for preserving sight in a range of retinal diseases, today announced that the United States Food and Drug Administration (FDA) has granted orphan drug designation to ONL1204 for the treatment of retinal detachment. ONL1204 is a novel, first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, from cell death that occurs in a range of retinal diseases and conditions. Death of these retinal cells is the root cause of vision loss and the leading cause of blindness. ONL expects to advance ONL1204 into clinical trials for retinal detachment patients in 2016.

Retinal detachment occurs when the retina is separated from the underlying layer of cells called the retinal pigment epithelium (RPE). The RPE provides nutritional support to the highly-active photoreceptors in the retina. When there is a detachment, the photoreceptors no longer receive these nutrients and undergo cell death processes that dramatically impact a patient’s vision. Retinal detachments occur in approximately 50,000 people each year in the United States and affect people of all ages, although risk increases as people reach fifty years of age.

Patients experiencing a retinal detachment are normally treated by surgical reattachment of the retina to reconnect the photoreceptors with the RPE and prevent additional loss of vision. However, these procedures do not address the photoreceptor death and vision loss, which can be significant, that occurs prior to surgery. ONL1204 will be delivered to patients upon diagnosis and is intended to block photoreceptor cells from dying until surgery can be completed.

“When retinal detachments involve the center of vision called the macula, more than a third of patients have final best corrected vision of 20/60 or worse after successful surgery,” said David Zacks, M.D., Ph.D., co-founder and chief science officer of ONL Therapeutics. “Those are truly poor outcomes from successful surgeries. We are very pleased the FDA has recognized this need and that ONL is the only company to have received an orphan designation for this disease. It reinforces our belief that ONL1204 can play a key role in preventing vision loss in these patients by protecting their photoreceptors.”

The FDA’s Orphan Drug Designation program provides certain incentives for companies developing therapeutics to treat rare diseases or conditions that affect less than 200,000 individuals in the US. A drug candidate and its developer must meet several key criteria in order to qualify for, and obtain, orphan drug status. Once a drug has received orphan drug designation, the developer qualifies for a range of benefits, including federal grants, tax credits, reduction in certain regulatory fees, and the potential for seven years of market exclusivity for the drug following FDA marketing approval.

About ONL Therapeutics

ONL Therapeutics (ONL) is a biopharmaceutical company committed to protecting and improving the vision of patients with retinal disease. By advancing a novel breakthrough technology designed to protect key retinal cells from Fas-mediated cell death, ONL is pioneering an entirely new approach to preserving sight. The death of key retinal cells is the root cause of vision loss and leading cause of blindness, and is implicated in a wide range of retinal diseases, including retinal detachment and both the wet and dry forms of age related macular degeneration (AMD).

read

FDA grants orphan status for ONL Therapeutics’ ONL1204 to treat retinal detachment
The US Food and Drug Administration (FDA) has granted orphan drug designation for ONL Therapeutics’ first-in-class small molecule peptide, ONL1204, for the treatment of retinal detachment.

 

SEE………http://www.allfordrugs.com/2016/02/17/onl-1204-a-small-molecule-peptide-for-treatment-of-retinal-detachment/

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Use smiles

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OR

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VAL-083


VAL-083

(1R,2S)-1-((R)-oxiran-2-yl)-2-((S)-oxiran-2-yl)ethane-1,2-diol

Galactitol, 1,​2:5,​6-​dianhydro-

  • 1,2:5,6-Dianhydrodulcitol
  • 1,2:5,6-Dianhydrogalactitol
  • 1,2:5,6-Diepoxydulcitol

Dianhydrodulcitol; Dianhydrogalactitol; VAL083; VAL 083, Dulcitol diepoxide, NSC 132313

CAS 23261-20-3

MF C6H10O4, MW 146.14

VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused apoptosis

VAL-083 is a bi-functional alkylating agent, with potential antineoplastic activity. Upon administration, VAL-083 crosses the blood brain barrier (BBB) and appears to be selective for tumor cells. This agent alkylates and crosslinks DNA which ultimately leads to a reduction in cancer cell proliferation. In addition, VAL-083 does not show cross-resistance to other conventional chemotherapeutic agents and has a long half-life in the brain. Check for active clinical trials or closed clinical trials using this agent

Currently, VAL-083 is approved in China to treat chronic myelogenous leukemia and lung cancer, while the drug has also secured orphan drug designation in Europe and the US to treat malignant gliomas.

LAUNCHED CHINA FOR Cancer, lung

Del Mar Pharmaceuticals Inc……..Glioblastoma…………..PHASE2

DelMar and MD Anderson to accelerate development of anti-cancer drug VAL-083
DelMar Pharmaceuticals has collaborated with the University of Texas MD Anderson Cancer Center (MD Anderson) to speed up the clinical development of its VAL-083 anti-cancer drug.

VAL-083 is a BI-Functional alkylating agent; INHIBIT U251 and SF188 Cell Growth in monolayer Better than TMZ and Caused apoptosis. IC50 Value : 5 uM (INHIBIT U251, SF188, T98G Cell Growth in monolayer after 72h) [1]. in vitro :.. VAL-083 INHIBITED U251 and SF188 Cell Growth in monolayer and as neurospheres Better than TMZ and Caused apoptosis after 72 hr Formation Assay In the colony, VAL-083 (5 uM) SF188 Growth suppressed by about 95% are T98G cells classically TMZ-resistant and express MGMT, but VAL-083 inhibited their growth in monolayer after 72 hr in a dose-dependent manner (IC50, 5 uM). VAL-083 also inhibited the growth of CSCs (BT74, GBM4, and GBM8) . by 80-100% in neurosphere self-Renewal assays Conversely, there was minimal normal Effect on Human Neural stem cells [1]. in Vivo : Clinical Trial : Safety Study of VAL-083 in Patients With Recurrent Malignant glioma or Secondary Progressive Brain Tumor. Phase 1 / Phase 2

VAL-083 has demonstrated activity in cyclophosphamide, BCNU and phenylanine mustard resistant cell lines and no evidence of cross-resistance has been encountered in published clinical studies. Based on the presumed alkylating functionality of VAL-083, published literature suggests that DNA repair mechanisms associated with Temodar and nitrosourea resistance, such as 06-methylguanine methyltransferace (MGMT), may not confer resistance to VAL-083.  VAL-083 readily crosses the blood brain barrier where it maintains a long half-life in comparison to the plasma. Published preclinical and clinical research demonstrates that VAL-083 is selective for brain tumor tissue.  VAL-083 has been assessed in multiple studies as chemotherapy in the treatment of newly diagnosed and recurrent brain tumors. In published clinical studies, VAL-083 has previously been shown to have a statistically significant impact on median survival in high grade gliomas when combined with radiation vs. radiation alone. The main dose-limiting toxicity related to the administration of VAL-083 in previous clinical studies was myelosuppression

Glioblastoma is the most common form of primary brain cancer

DelMar Pharmaceuticals has collaborated with the University of Texas MD Anderson Cancer Center (MD Anderson) to speed up the clinical development of its VAL-083 anti-cancer drug.

VAL-083 is a small-molecule chemotherapeutic designed to treat glioblastoma multiforme (GBM), the most common and deadly cancer that starts within the brain.

Under the deal, MD Anderson will begin a new Phase II clinical trial with VAL-083 in patients with GBM at first recurrence / progression, prior to Avastin (bevacizumab) exposure.

During the trial, eligible patients will have recurrent GBM characterised by a high expression of MGMT, the DNA repair enzyme implicated in drug-resistance, and poor patient outcomes following current front-line chemotherapy.

” … Our research shows that VAL-083 may offer advantages over currently available chemotherapies in a number of tumour types.”

The company noted that MGMT promoter methylation status will be used as a validated biomarker for enrollment and tumours must exhibit an unmethylated MGMT promoter for patients to be eligible for the trial.

DelMar chairman and CEO Jeffrey Bacha said: “The progress we continue to make with our research shows that VAL-083 may offer advantages over currently available chemotherapies in a number of tumour types.

“This collaboration will allow us to leverage world-class clinical and research expertise and a large patient population from MD Anderson as we extend and accelerate our clinical focus to include GBM patients, following first recurrence of their disease.

“We believe that VAL-083’s unique cytotoxic mechanism offers promise for GBM patients across the continuum of care as a potential superior alternative to currently available cytotoxic chemotherapies, especially for patients whose tumours exhibit a high-expression of MGMT.”

The deal will see DelMar work with the scientists and clinicians at MD Anderson to accelerate its research in order to transform the treatment of patients whose cancers fail or are unlikely to respond to existing treatments.

In more than 40 clinical trials, VAL-083 showed clinical activity against several cancers including lung, brain, cervical, ovarian tumours and leukemia both as a single-agent and in combination with other treatments.

PATENT

WO 2012024368

https://www.google.com/patents/WO2012024368A3?cl=en

Dianhydrogalactitol (DAG or dianhydrodulcitol) can be synthesized from dulcitol which can be produced from natural sources (such as Maytenus confertiflora) or commercial sources.The structure of DAG is given below as Formula (I).

Figure imgf000006_0001

One method for the preparation of dulcitol from Maytenus confertiflora is as follows: (1) The Maytenus confertiflora plant is soaked in diluted ethanol (50-80%) for about 24 hours, and the soaking solution is collected. (2) The soaking step is repeated, and all soaking solutions are combined. (3) The solvent is removed by heating under reduced pressure. (4) The concentrated solution is allowed to settle overnight and the clear supernatant is collected. (5) Chloroform is used to extract the supernatant. The chloroform is then removed under heat and reduced pressure. (6) The residue is then dissolved in hot methanol and cooled to allow crystallization. (7) The collected crystals of dulcitol are filtered and dried under reduced pressure. The purified material is dulcitol, contained in the original Maytenus confertiflora plant at a concentration of about 0.1% (1/1000).

DAG can be prepared by two general synthetic routes as described below:

Route 1 :

Dulcitol DAG

Route 2. Dulcitol

Figure imgf000006_0002

In Route 1 , “Ts” represents the tosyl group, or p-toluenesulfonyl group. PATENT

However, the intermediate of Route 1, 1,6-ditosy)dulcitol, was prepared with low yield (~36%), and the synthesis of 1,6-ditosyldulcitol was poorly reproducible. Therefore, the second route process was developed, involving two major steps: (1) preparation of dibromodulcitol from dulcitol; and (2) preparation of dianhydrodulcitol from dibromodulcitol.

Dibromodulcitol is prepared from dulcitol as follows: (1) With an aqueous HBr solution of approximately 45% HBr concentration, increase the HBr concentration to about 70% by reacting phosphorus with bromine in concentrated HBr in an autoclave. Cool the solution to 0° C. The reaction is:

2P+3Br2→2PBr3+H20→HBr†+H3P04. (2) Add the dulcitol to the concentrated HBr solution and reflux at 80° C to complete the reaction. (3) Cool the solution and pour the mixture onto ice water. Dibromodulcitol is purified through recrystallization.

The results for the preparation of dibromodulcitol (DBD) are shown in Table 1, below.

TABLE 1

Figure imgf000007_0001

For the preparation of DAG from DBD, DBD was poorly dissolved in methanol and ethanol at 40° C (different from what was described in United States PATENT

Patent No. 3,993,781 to Horvath nee Lengyel et al., incorporated herein by this reference). At refluxing, DBD was dissolved but TLC showed that new impurities formed that were difficult to remove from DBD.

The DBD was reacted with potassium carbonate to convert the DBD to dianhydrogalactitol.

The results are shown in Table 2, below.

TABLE 2

Figure imgf000008_0001

In the scale-up development, it was found the crude yield dropped significantly. It is unclear if DAG could be azeotropic with BuOH. It was confirmed that t-BuOH is essential to the reaction. Using MeOH as solvent would result in many impurities as shown spots on TLC. However, an improved purification method was developed by using a slurry with ethyl ether, which could provide DAG with good purity. This was developed after a number of failed attempts at recrystallization of DAG.

str1

Bromination of dulcitol with HBr at 80°C gives dibromodulcitol , which upon epoxidation in the presence of K2CO3 in t-BuOH or NaOH in H2O  or in the presence of ion exchange resin Varion AD (OH) (4) affords the target dianhydrogalactitol .

 

PATENT

US 20140155638

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SCHEME 5

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PATENT

CN 103923039

http://www.google.com/patents/CN103923039A?cl=en

The resulting Dulcitol 9g and 18ml mass percent concentration of 65% hydrobromic acid at 78 ° C under reflux for 8 hours to give 1,6-dibromo dulcitol, and the product is poured into ice crystals washed anhydrous tert-butyl alcohol, and dried to give 1,6-dibromo dulcitol crystal, then 10.0gl, 6- dibromo dulcitol sample is dissolved in t-butanol, adding solid to liquid 2 % obtained through refining process 1,6_ dibromo dulcitol seed stirred and cooled to 0 ° C, allowed to stand for seven days to give 1,6_ dibromo dulcitol crystal, anhydrous t-butanol, dried to give 1,6-dibromo dulcitol. 5g of the resulting 1,6_ dibromo Euonymus dissolved in 50ml tert-butanol containing 5g of potassium carbonate, the elimination reaction, at 80 ° C under reflux time was 2 hours, the resulting product was dissolved in t-butanol, Join I% stock solution to the water quality of 1,2,4,5_ two Dulcitol including through a purification step to get less than 1% of 1,2,5,6_ two to water Dulcitol seeded stirring, cooling to 0 ° C, allowed to stand for I-day, two to go get 1,2,5,6_ water Dulcitol crystals washed anhydrous tert-butyl alcohol, and dried to give 1,2,5,6 two to crystalline water Dulcitol and lyophilized to give two to water Dulcitol lyophilized powder, containing I, 2,4,5- two to water Dulcitol less than 0.3%.

PATENT

WO 2005030121

PATENT

US 20140066642

  • DAG can be prepared by two general synthetic routes as described below:
  • Figure US20140066642A1-20140306-C00002
  • In Route 1, “Ts” represents the tosyl group, or p-toluenesulfonyl group.
  • However, the intermediate of Route 1, 1,6-ditosyldulcitol, was prepared with low yield (˜36%), and the synthesis of 1,6-ditosyldulcitol was poorly reproducible. Therefore, the second route process was developed, involving two major steps: (1) preparation of dibromodulcitol from dulcitol; and (2) preparation of dianhydrodulcitol from dibromodulcitol.
  • Dibromodulcitol is prepared from dulcitol as follows: (1) With an aqueous HBr solution of approximately 45% HBr concentration, increase the HBr concentration to about 70% by reacting phosphorus with bromine in concentrated HBr in an autoclave. Cool the solution to 0° C. The reaction is: 2P+3Br2→2PBr3+H2O→HBr↑+H3PO4. (2) Add the dulcitol to the concentrated HBr solution and reflux at 80° C. to complete the reaction. (3) Cool the solution and pour the mixture onto ice water. Dibromodulcitol is purified through recrystallization.

PATENT

US 20150329511

 PAPER

Molecules 2015, 20(9), 17093-17108; doi:10.3390/molecules200917093
Article

Antibacterial and Anti-Quorum Sensing Molecular Composition Derived from Quercus cortex (Oak bark) Extract

Microbiological Department, Orenburg State University, 13 Pobedy Avenue, Orenburg 460018, Russia
* Author to whom correspondence should be addressed.
1,2: 5,6-dianhydrogalactitol ** in table 1
Paper
Takano, Seiichi; Iwabuchi, Yoshiharu; Ogasawara, Kunio
Journal of the American Chemical Society, 1991 ,  vol. 113,   7  pg. 2786 – 2787
str1

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Currently, VAL-083 is approved in China to treat chronic myelogenous leukemia and lung cancer, while the drug has also secured orphan drug designation in Europe and the US to treat malignant gliomas.

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[2]. Fotovati A, Hu KJ, Wakimoto H, VAL-083, A NOVEL AGENT N7 alkylating, SURPASSES temozolomide Inhibits TREATMENT ACTIVITY AND STEM CELLS, PROVIDING A NEW TREATMENT OPTION FOR POTENTIAL glioblastoma multiforme. Neuro-oncology, 2012, 14, AbsET-37, Suppl. 6

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