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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 first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease


06/22/2017

 

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection.

“The approval of Haegarda provides a new treatment option for adolescents and adults with Hereditary Angioedema,” said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research. “The subcutaneous formulation allows patients to administer the product at home to help prevent attacks.”

Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks.

The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.

The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.

The FDA granted approval of Haegarda to CSL Behring LLC.

///////////Haegarda, C1 Esterase inhibitor, CSL Behring LLC,  fda 2017, orphan drug

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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

FDA approves new combination treatment for acute myeloid leukemia, Rydapt (midostaurin)


MIDOSTAURIN

04/28/2017
The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

April 28, 2017

Release

The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute estimated that approximately 19,930 people would be diagnosed with AML in 2016 and 10,430 were projected to die of the disease.

“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment.”

Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth. If the FLT3 mutation is detected in blood or bone marrow samples using the LeukoStrat CDx FLT3 Mutation Assay, the patient may be eligible for treatment with Rydapt in combination with chemotherapy.

The safety and efficacy of Rydapt for patients with AML were studied in a randomized trial of 717 patients who had not been treated previously for AML. In the trial, patients who received Rydapt in combination with chemotherapy lived longer than patients who received chemotherapy alone, although a specific median survival rate could not be reliably estimated. In addition, patients who received Rydapt in combination with chemotherapy in the trial went longer (median 8.2 months) without certain complications (failure to achieve complete remission within 60 days of starting treatment, progression of leukemia or death) than patients who received chemotherapy alone (median three months).

Common side effects of Rydapt in patients with AML include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting, headache, spots on the skin due to bleeding (petechiae), musculoskeletal pain, nosebleeds (epistaxis), device-related infection, high blood sugar (hyperglycemia) and upper respiratory tract infection. Rydapt should not be used in patients with hypersensitivity to midostaurin or other ingredients in Rydapt. Women who are pregnant or breastfeeding should not take Rydapt because it may cause harm to a developing fetus or a newborn baby. Patients who experience signs or symptoms of lung damage (pulmonary toxicity) should stop using Rydapt.

Rydapt was also approved today for adults with certain types of rare blood disorders (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm or mast cell leukemia). Common side effects of Rydapt in these patients include nausea, vomiting, diarrhea, swelling (edema), musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, fever, headache and shortness of breath.

The FDA granted this application Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations.

The FDA granted the approval of Rydapt to Novartis Pharmaceuticals Corporation. The FDA granted the approval of the LeukoStrat CDx FLT3 Mutation Assay to Invivoscribe Technologies Inc.

MIDOSTAURIN

(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one

N-[(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide

N-((9S,10R,11R,13R)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3′,2′,1′-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-,

N-[(2R,4R,5R,6S)-5-methoxy-6-methyl-18-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14(28),15(19),20(27),21(26),22,24-nonaen-4-yl]-N-methylbenzamide hydrate

N-benzoyl staurosporine

NOVARTIS ONCOLOGY ORIGINATOR

Chemical Formula: C35H30N4O4

Exact Mass: 570.22671

Molecular Weight: 570.63710

Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22

Tyrosine kinase inhibitors

PKC 412。PKC412A。CGP 41251。Benzoylstaurosporine;4′-N-Benzoylstaurosporine;Cgp 41251;Cgp 41 251.

120685-11-2 CAS

PHASE 3

  • 4′-N-Benzoylstaurosporine
  • Benzoylstaurosporine
  • Cgp 41 251
  • CGP 41251
  • CGP-41251
  • Midostaurin
  • PKC 412
  • PKC412
  • UNII-ID912S5VON

Midostaurin is an inhibitor of tyrosine kinase, protein kinase C, and VEGF. Midostaurin inhibits cell growth and phosphorylation of FLT3, STAT5, and ERK. It is a potent inhibitor of a spectrum of FLT3 activation loop mutations.

it  is prepared by acylation of the alkaloid staurosporine (I) with benzoyl chloride (II) in the presence of diisopropylethylamine in chloroform.Production Route of Midostaurin

Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.

MIDOSTAURIN

Derivative of staurosporin, orally active, potent inhibitor of FLT3 tyrosine kinase (fetal liver tyrosine kinase 3). In addition Midostaurin inhibits further molecular targets such as VEGFR-1 (Vascular Endothelial Growth Factor Receptor 1), c-kit (stem cell factor receptor), H-and K-RAS (Rat Sarcoma Viral homologue) and MDR (multidrug resistance protein).

Midostaurin inhibits both wild-type FLT3 and FLT3 mutant, wherein the internal tandem duplication mutations (FLT3-ITD), and the point mutation to be inhibited in the tyrosine kinase domain of the molecule at positions 835 and 836.Midostaurin is tested in patients with AML.

Midostaurin, a protein kinase C (PKC) and Flt3 (FLK2/STK1) inhibitor, is in phase III clinical development at originator Novartis for the oral treatment of acute myeloid leukemia (AML).

Novartis is conducting phase III clinical trials for the treatment of aggressive systemic mastocytosis or mast cell leukemia. The National Cancer Institute (NCI) is conducting phase I/II trials with the drug for the treatment of chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS).

Massachusetts General Hospital is conducting phase I clinical trials for the treatment of adenocarcinoma of the rectum in combination with radiation and standard chemotherapy.

MIDOSTAURIN

Midostaurin (PKC412) is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus, and is active in patients with mutations of CD135 (FMS-like tyrosine kinase 3 receptor).[1]

After successful Phase II clinical trials, a Phase III trial for AML has started in 2008. It is testing midostaurin in combination with daunorubicin and cytarabine.[2] In another trial, the substance has proven ineffective in metastatic melanoma.[3]

Midostaurin has also been studied at Johns Hopkins University for the treatment of age-related macular degeneration (AMD), but no recent progress reports for this indication have been made available. Trials in macular edema of diabetic origin were discontinued at Novartis.

In 2004, orphan drug designation was received in the E.U. for the treatment of AML. In 2009 and 2010, orphan drug designation was assigned for the treatment of acute myeloid leukemia and for the treatment of mastocytosis, respectively, in the U.S. In 2010, orphan drug designation was assigned in the E.U. for the latter indication.

MIDOSTAURIN

References

  1.  Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. (2010). “Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome with Either Wild-Type or Mutated FLT3”. Journal of Clinical Oncology 28 (28): 4339–4345. doi:10.1200/JCO.2010.28.9678PMID 20733134edit
  2.  ClinicalTrials.gov NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  3.  Millward, M. J.; House, C.; Bowtell, D.; Webster, L.; Olver, I. N.; Gore, M.; Copeman, M.; Lynch, K.; Yap, A.; Wang, Y.; Cohen, P. S.; Zalcberg, J. (2006). “The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study”British Journal of Cancer 95 (7): 829–834. doi:10.1038/sj.bjc.6603331PMC 2360547PMID 16969355.
    1. Midostaurin product page, Fermentek
    2.  Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol 48 (6): 763–775. doi:10.1177/0091270008318006PMID 18508951.
    3.  Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes”Ph.D. Thesis. Massachusetts Institute of Technology.

Bioorg Med Chem Lett 1994, 4(3): 399

US 5093330

EP 0657164

EP 0711556

EP 0733358

WO 1998007415

WO 2002076432

WO 2003024420

WO 2003037347

WO 2004112794

WO 2005027910

WO 2005040415

WO 2006024494

WO 2006048296

WO 2006061199

WO 2007017497

WO 2013086133

WO 2012016050

WO 2011000811

8-1-2013
Identification of potent Yes1 kinase inhibitors using a library screening approach.
Bioorganic & medicinal chemistry letters
 
3-1-2013
Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay.
European journal of medicinal chemistry
2-23-2012
Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.
Journal of medicinal chemistry
 
1-26-2012
VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.
Journal of medicinal chemistry
1-1-2012
H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling.
PloS one
10-27-2011
Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
Journal of medicinal chemistry
 
6-1-2011
Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.
European journal of medicinal chemistry
3-1-2010
Colony stimulating factor-1 receptor as a target for small molecule inhibitors.
Bioorganic & medicinal chemistry
7-18-2012
Staurosporine Derivatives as Inhibitors of FLT3 Receptor Tyrosine Kinase Activity
6-13-2012
Crystal form of N-benzoyl-staurosporine
12-14-2011
COMPOSITIONS FOR TREATMENT OF SYSTEMIC MASTOCYTOSIS
7-6-2011
Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
7-6-2011
Staurosporine Derivatives for Use in Alveolar Rhabdomyosarcoma
12-10-2010
Pharmaceutical Compositions for treating wouds and related methods
11-5-2010
COMBINATIONS OF JAK INHIBITORS
7-23-2010
COMBINATIONS COMPRISING STAUROSPORINES
3-5-2010
COMBINATION OF IAP INHIBITORS AND FLT3 INHIBITORS
1-29-2010
ANTI-CANCER PHOSPHONATE ANALOGS
1-13-2010
Therapeutic phosphonate compounds
11-20-2009
Use of Staurosporine Derivatives for the Treatment of Multiple Myeloma
7-17-2009
KINASE INHIBITORY PHOSPHONATE ANALOGS
6-19-2009
Organic Compounds
3-20-2009
Use of Midostaurin for Treating Gastrointestinal Stromal Tumors
11-21-2008
PHARMACEUTICAL COMPOSITIONS COMPRISING A POORLY WATER-SOLUBLE ACTIVE INGREDIENT, A SURFACTANT AND A WATER-SOLUBLE POLYMER
11-19-2008
Anti-cancer phosphonate analogs
9-12-2008
Multi-Functional Small Molecules as Anti-Proliferative Agents
9-5-2008
Sensitization of Drug-Resistant Lung Caners to Protein Kinase Inhibitors
8-29-2008
Organic Compounds
8-27-2008
Kinase inhibitory phosphonate analogs
4-25-2008
Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin
12-28-2007
Pharmaceutical Uses of Staurosporine Derivatives
12-7-2007
Kinase Inhibitor Phosphonate Conjugates
8-17-2007
Combinations comprising staurosporines
10-13-2006
Staurosporine derivatives for hypereosinophilic syndrome
7-15-2005
Phosphonate substituted kinase inhibitors
10-20-2004
Staurosporin derivatives

MIDOSTAURIN HYDRATE

Midostaurin according to the invention is N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (II):

Figure US20090075972A1-20090319-C00002

or a salt thereof, hereinafter: “Compound of formula II or midostaurin”.

Compound of formula II or midostaurin [International Nonproprietary Name] is also known as PKC412.

Midostaurin is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 110 published on Dec. 21, 1988, as well as in U.S. Pat. No.  5093330 published on Mar. 3, 1992, and Japanese Patent No. 2 708 047.

………………….

https://www.google.co.in/patents/EP0296110B1

The nomenclature of the products is, on the complete structure of staurosporine ([storage]-NH-CH ₃derived, and which is designated by N-substituent on the nitrogen of the methylamino group

Figure imgb0028

Example 18:

     N-Benzoyl-staurospor

  • A solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropylethylamine in 2 ml of chloroform is added at room temperature with 0.035 ml (0.3 mmol) of benzoyl chloride and 10 stirred minutes.The reaction mixture is diluted with chloroform, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 30:1), mp 235-247 ° with brown coloration.
  • cut paste may not be ok below

Staurosporine the formula [storage]-NH-CH ₃ (II) (for the meaning of the rest of [storage] see above) as the basic material of the novel compounds was already in 1977, from the cultures of Streptomyces staurosporeus AWAYA, and TAKAHASHI

O ¯

Figure imgb0003

MURA, sp. nov. AM 2282, see Omura, S., Iwai, Y., Hirano, A., Nakagawa, A.; awayâ, J., Tsuchiya, H., Takahashi, Y., and Masuma, R. J. Antibiot. 30, 275-281 (1977) isolated and tested for antimicrobial activity. It was also found here that the compound against yeast-like fungi and microorganisms is effective (MIC of about 3-25 mcg / ml), taking as the hydrochloride = having a LD ₅ ₀ 6.6 mg / kg (mouse, intraperitoneal). Stagnated recently it has been shown in extensive screening, see Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y, Morimoto, M. and Tomita, F.: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986) that the compound exerts a potent inhibitory effect on protein kinase C (rat brain)

…………………

https://www.google.co.in/patents/US5093330

EXAMPLE 18 N-benzoyl-staurosporine

0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235

…………………….

Bioorg Med Chem Lett 1994, 4(3): 399

http://www.sciencedirect.com/science/article/pii/0960894X94800049

Full-size image (2 K)

……………………

http://www.google.com/patents/WO1998007415A2

A variety of PKC inhibitors are available in the art for use in the invention. These include bryostatin (U.S. Patent 4,560,774), safinogel (WO 9617603), fasudil (EP 187371), 7- hydoxystaurosporin (EP 137632B), various diones described in EP 657458, EP 657411 and WO9535294, phenylmethyl hexanamides as described in WO9517888, various indane containing benzamides as described in WO9530640, various pyrrolo [3,4-c]carbazoles as described in EP 695755, LY 333531 (IMSworld R & D Focus 960722, July 22, 1996 and Pharmaprojects Accession No. 24174), SPC-104065 (Pharmaprojects Accession No. 22568), P-10050 (Pharmaprojects Accession No. 22643), No. 4432 (Pharmaprojects Accession No. 23031), No. 4503 (Pharmaprojects Accession No. 23252), No. 4721 (Pharmaprojects Accession No. 23890), No. 4755 (Pharmaprojects Accession No. 24035), balanol (Pharmaprojects Accession No. 20376), K-7259 (Pharmaprojects Accession No. 16649), Protein kinase C inhib, Lilly (Pharmaprojects Accession No. 18006), and UCN-01 (Pharmaprojects Accession No. 11915). Also see, for example, Tamaoki and Nakano (1990) Biotechnology 8:732-735; Posada et al. (1989) Cancer Commun. 1:285-292; Sato et al. (1990) Biochem Biophys. Res. Commun. 173:1252-1257; Utz et al. (1994) Int. J. Cancer 57:104-110; Schwartz et al. (1993) J. Na . Cancer lnst. 85:402-407; Meyer et al. (1989) Int. J. Cancer 43:851-856; Akinaga et al. (1991) Cancer Res. 51:4888-4892, which disclosures are herein incorporated by reference. Additionally, antisense molecules can be used as PKC inhibitors. Although such antisense molecules inhibit mRNA translation into the PKC protein, such antisense molecules are considered PKC inhibitors for purposes of this invention. Such antisense molecules against PKC inhibitors include those described in published PCT patent applications WO 93/19203, WO 95/03833 and WO 95/02069, herein incorporated by reference. Such inhibitors can be used in formulations for local delivery to prevent cellular proliferation. Such inhibitors find particular use in local delivery for preventing rumor growth and restenosis.

N-benzoyl staurosporine is a benzoyl derivative of the naturally occurring alkaloid staurosporine. It is chiral compound ([a]D=+148.0+-2.0°) with the formula C35H30R1O4 (molecular weight 570.65). It is a pale yellow amorphous powder which remains unchanged up to 220°C. The compound is very lipophilic (log P>5.48) and almost insoluble in water (0.068 mg/1) but dissolves readily in DMSO.

……………………….

staurosporine

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment

Synthesis of Staurosporine

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.

Indolocarbazoles belong to the alkaloid sub-class of bisindoles. Of these carbazoles the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes – halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.

The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imineby enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P450enzyme to form an aromatic ring system occurs

Staurosporine 2

This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine

US4107297 * 28 Nov 1977 15 Aug 1978 The Kitasato Institute Antibiotic compound
US4735939 * 27 Feb 1987 5 Apr 1988 The Dow Chemical Company Insecticidal activity of staurosporine
ZA884238A * Title not available
////////FDA 2017, acute myeloid leukemia, Rydapt, midostaurin, Novartis Pharmaceuticals Corporation, LeukoStrat CDx FLT3 Mutation Assay,  Invivoscribe Technologies Inc, Priority Review, Fast Track, (for the mastocytosis indication, Breakthrough Therapy

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,

BLU 285


BLU-285

CAS 1703793-34-3

  • Molecular FormulaC26H27FN10
  • Average mass498.558 Da
(1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl}-5-pyrimidinyl)ethanamine
5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
  • 5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
  • Originator Blueprint Medicines
  • Class Antineoplastics; Skin disorder therapies; Small molecules
  • Mechanism of Action Platelet-derived growth factor alpha receptor modulators; Proto oncogene protein c-kit inhibitors
  • Orphan Drug Status Yes – Systemic mastocytosis; Gastrointestinal stromal tumours
  • Phase I Gastrointestinal stromal tumours; Solid tumours; Systemic mastocytosis
  • 04 Dec 2016 Proof-of-concept data from phase I trial in Systemic mastocytosis presented at the 58thAnnual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)
  • 03 Dec 2016 Pharmacodynamics data from preclinical studies in Systemic mastocytosis presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2016)
  • 03 Dec 2016 Preliminary pharmacokinetic data from a phase I trial in Systemic mastocytosis presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)

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BLU 285

(S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 44) WO2015057873

Inventors Yulian Zhang, Brian L. Hodous, Joseph L. Kim, Kevin J. Wilson, Douglas Wilson
Applicant Blueprint Medicines Corporation

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Yulian Zhang,

Yulian Zhang,

Blueprint Medicines Corporation

ΚΓΓ and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways. KIT mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make KIT function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma. As such, there is a need for therapeutic agents that inhibit ΚΓΓ, and especially agents that inhibit mutant ΚΓΓ.Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. A PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. As such, there is a need for agents that target this mutation.

CONTD………..

PATENT

WO 2015057873

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na2S04, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H3iFN10OS requires: 586, found: 587 [M + H]+.

Step 3: Synthesis of (lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

(lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C3oH35FN10OS requires: 602, found: 603 [M + H]+.

Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10 requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]+.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-1 -yl)pyrimidin- -yl)ethanamine:

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-

pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (lS,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C26H27FN10 requires: 498, found: 499 [M + H]+.

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/////////BLU-285,  1703793-34-3, PHASE 1,  Brian Hodous, BlueprintMeds,  KIT & PDGFRalpha inhibitors, Orphan Drug Status

Fc1ccc(cc1)[C@](C)(N)c2cnc(nc2)N3CCN(CC3)c4ncnn5cc(cc45)c6cn(C)nc6

Next in 1st time disclosures Brian Hodous of @BlueprintMeds will talk about KIT & PDGFRalpha inhibitors

str0

TRIENTINE HYDROCHLORIDE, 塩酸トリエンチン , 曲恩汀


Skeletal formula of triethylenetetramine

TRIENTINE

  • Molecular Formula C6H18N4
  • Average mass 146.234 Da

112-24-3 CAS

曲恩汀, KD-034, MK-0681, MK-681, TECZA, TETA, TJA-250

1,2-Ethanediamine, N1,N2-bis(2-aminoethyl)-
1,8-diamino-3,6-diazaoctane
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TRIENTINE HYDROCHLORIDE

  • Molecular Formula C6H19ClN4
  • Average mass 182.695 Da

38260-01-4 CAS

Launched – 1986 VALEANT, WILSONS DISEASE

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塩酸トリエンチン
Trientine Hydrochloride

C6H18N4▪2HCl : 219.16
[38260-01-4]

Aton Pharma, a subsidiary of Valeant Pharmaceuticals, has developed and launched Syprine, a capsule formulation of trientine hydrochloride, for treating Wilson disease.

Image result for TRIENTINE

Triethylenetetramine, abbreviated TETA and trien and also called trientine (INN), is an organic compound with the formula [CH2NHCH2CH2NH2]2. This oily liquid is colorless but, like many amines, assumes a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.[1]

Trientine hydrochloride is a metal antagonist that was first launched by Merck, Sharp & Dohme in the U.S. in 1986 under the brand name Syprine for the oral treatment of Wilson’s disease.

Orphan drug designation has also been assigned in the U.S. for the treatment of patients with Wilson’s disease who are intolerant or inadequately responsive to penicillamine and in the E.U. by Univar for the treatment of Wilson’s disease

 Trientine hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=90373

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II)

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4·2HCI with a molecular weight of 219.2. The structural formula is:

NH2(CH2)2NH(CH2)2NH(CH2)2NH2•2HCI

Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

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Production

TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, which are separated by distillation and sublimation.[2]

Uses

The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It was primarily used as a crosslinker (“hardener”) in epoxy curing.[2]

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson’s disease, particularly in those who are intolerant to penicillamine. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[3]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[4] Octahedral complexes of the type M(trien)Cl3 can adopt several diastereomeric structures, most of which are chiral.[5]

Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-l,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson’s disease.

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Trientine dihydrochloride (1)

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson’s disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer’s disease and cancer.

Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.

U.S. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. 4,550,209 and U.S. 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.

U.S. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.

The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.

CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν’-dibenzyl-,N,N’-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N’-dibenzyl-,N,N’-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N’-dibenzyl-,N,N’-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.

CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochlonde salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.

The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.

US 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.

PATENT

WO-2017046695

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EXAMPLES

Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl- 1-butyloxy carbonylamino)acetonitrile (5)

Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10°C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15°C and Boc-anhydride (762. lg) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30°C and the mass was stirred till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70°C followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

Yield: 506.8 g

% Yield: 89.9 %

Example 2: Preparation of t-butyl( N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25°C under hydrogen pressure of 2-5 Kg/cm2.

After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50°C, followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino] ethyl) carbamate.

Yield: 174 g

%Yield: 85 %

Example 3: Preparation of triethylenetetramine dihydrochloride (1)

Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl] amino] ethyl} carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30°C. The reaction mixture was heated in the temperature range of 100-105°C till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

Yield: 88.9 g, (70 %)

Purity : > 99%

Patent

https://www.google.com/patents/US8394992

Trientine was said to be used in the synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine in French Patent No. FR2810035 to Guilard et al. Cetinkaya, E., et al., “Synthesis and characterization of unusual tetraminoalkenes,” J. Chem. Soc. 5:561-7 (1992), is said to be directed to synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine from trientine, as is Araki T., et al., “Site-selective derivatization of oligoethyleneimines using five-membered-ring protection method,” Macromol., 21:1995-2001 (1988). Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in U.S. Pat. No. 2,390,766, to Zellhoefer et al.

Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide-phosphate type catalysts was reported by Vanderpool et al. in U.S. Pat. No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in U.S. Pat. No. 4,550,209, to Unvert et al. U.S. Pat. No. 5,225,599, to King et al. is said to be directed to the synthesis of linear triethylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst. Joint production of triethylenetetramine and 1-(2-aminoethyl)-aminoethyl-piperazine was proposed by Borisenko et al. in U.S.S.R. Patent No. SU1541204. U.S. Pat. No. 4,766,247 and European Patent No. EP262562, both to Ford et al., reported the preparation of triethylenetetramine by reaction of an alkanolamine compound, an alkaline amine and optionally either a primary or secondary amine in the presence of a phosphorous containing catalyst, for example phosphoric acid on silica-alumina or Group IIIB metal acid phosphate, at a temperature from about 175° C. to 400° C. under pressure. These patents indicate that the synthetic method used therein was as set forth in U.S. Pat. No. 4,463,193, to Johnson. The Ford et al. ‘247 patent is also said to be directed to color reduction of polyamines by reaction at elevated temperature and pressure in the presence of a hydrogenation catalyst and a hydrogen atmosphere. European Patent No. EP450709 to King et al. is said to be directed to a process for the preparation of triethylenetetramine and N-(2-aminoethyl)ethanolamine by condensation of an alkylenamine and an alkylene glycol in the presence of a condensation catalyst and a catalyst promoter at a temperature in excess of 260° C.

Russian Patent No. RU2186761, to Zagidullin, proposed synthesis of diethylenetriamine by reaction of dichloroethane with ethylenediamine. Ethylenediamine has previously been said to have been used in the synthesis of N-carboxylic acid esters as reported in U.S. Pat. No. 1,527,868, to Hartmann et al.

Japanese Patent No. 06065161 to Hara et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP115,138, to Larkin et al.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. U.S. Pat. No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 psig., and at a temperature of between about 200° C. to about 400° C. Templeton, et al., reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. “A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson’s disease and hygroscopicity of its capsule,” Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Preparation of triethylenetetramine salts used for the treatment of Wilson’s disease was said to be reported in “Treatment of Wilson’s Disease with Triethylene Tetramine Hydrochloride (Trientine),” Dubois, et al., J. Pediatric Gastro. & Nutrition, 10:77-81 (1990); “Preparation of Triethylenetetramine Dihydrochloride for the Treatment of Wilson’s Disease,” Dixon, et al., Lancet, 1(1775):853 (1972); “Determination of Triethylenetetramine in Plasma of Patients by High-Performance Liquid Chromatography,” Miyazaki, et al., Chem. Pharm. Bull., 38(4):1035-1038 (1990); “Preparation of and Clinical Experiences with Trien for the Treatment of Wilson’s Disease in Absolute Intolerance of D-penicillamine,” Harders, et al., Proc. Roy. Soc. Med., 70:10-12 (1977); “Tetramine cupruretic agents: A comparison in dogs,” Allen, et al., Am. J. Vet. Res., 48(1):28-30 (1987); and “Potentiometric and Spectroscopic Study of the Equilibria in the Aqueous Copper(II)-3,6-Diazaoctane-1,8-diamine System,” Laurie, et al., J.C.S. Dalton, 1882 (1976).

Preparation of Triethylenetetramine Salts by Reaction of Alcohol Solutions of Amines and acids was said to be reported in Polish Patent No. 105793, to Witek. Preparation of triethylenetetramine salts was also asserted in “Polycondensation of polyethylene polyamines with aliphatic dicarboxylic acids,” Witek, et al., Polimery, 20(3):118-119 (1975).

Baganz, H., and Peissker, H., Chem. Ber., 1957; 90:2944-2949; Haydock, D. B., and Mulholland, T. P. C., J. Chem. Soc., 1971; 2389-2395; and Rehse, K., et al., Arch. Pharm., 1994; 393-398, report on Strecker syntheses. Use of Boc and other protecting groups has been described. See, for example, Spicer, J. A. et al., Bioorganic & Medicinal Chemistry, 2002; 10: 19-29; Klenke, B. and Gilbert, I. H., J. Org. Chem., 2001; 66: 2480-2483.

FIG. 6 shows an 1H-NMR spectrum of a triethylenetetramine hydrochloride salt in D2O, as synthesized in Example 3. NMR values include a frequency of 400.13 Mhz, a 1H nucleus, number of transients is 16, points count of 32768, pulse sequence of zg30, and sweep width of 8278.15 H

Image result for TRIENTINE

CLIP

http://jpdb.nihs.go.jp/jp17e/JP17e_1.pdf

Method of purification: Dissolve Trientine Hydrochloride in water while warming, and recrystallize by addition of ethanol (99.5). Or dissolve Trientine Hydrochloride in water while warming, allow to stand after addition of activated charcoal in a cool and dark place for one night, and filter. To the filtrate add ethanol (99.5), allow to stand in a cool and dark place, and recrystallize. Dry the crystals under reduced pressure not exceeding 0.67 kPa at 409C until ethanol odor disappears.

References

  1.  “Ethyleneamines” (PDF). Huntsman. 2007.
  2. ^ Jump up to:a b Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. (2005). “Amines, Aliphatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.
  3. Jump up^ Roberts, E. A.; Schilsky, M. L. (2003). “A practice guideline on Wilson disease” (pdf). Hepatology. 37 (6): 1475–1492. doi:10.1053/jhep.2003.50252. PMID 12774027.
  4. Jump up^ von Zelewsky, A. (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
  5.  Utsuno, S.; Sakai, Y.; Yoshikawa, Y.; Yamatera, H. (1985). “Three Isomers of the Trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation”. Inorganic Syntheses. 23: 79–82. doi:10.1002/9780470132548.ch16.
Triethylenetetramine
Skeletal formula of triethylenetetramine
Ball and stick model of triethylenetetramine
Spacefill model of triethylenetetramine
Names
Other names

N,N’-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien; Trientine (INN); Syprine (brand name)
Identifiers
3D model (Jmol)
605448
ChEBI
ChemSpider
ECHA InfoCard 100.003.591
EC Number 203-950-6
27008
KEGG
MeSH Trientine
RTECS number YE6650000
UNII
UN number 2259
Properties
C6H18N4
Molar mass 146.24 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
Density 982 mg mL−1
Melting point −34.6 °C; −30.4 °F; 238.5 K
Boiling point 266.6 °C; 511.8 °F; 539.7 K
Miscible
log P 1.985
Vapor pressure <1 Pa (at 20 °C)
1.496
Thermochemistry
376 J K−1 mol−1 (at 60 °C)
Pharmacology
A16AX12 (WHO)
Hazards
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word DANGER
H312, H314, H317, H412
P273, P280, P305+351+338, P310
Corrosive C
R-phrases R21, R34, R43, R52/53
S-phrases (S1/2), S26, S36/37/39, S45
Flash point 129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
  • 550 mg kg−1 (dermal, rabbit)
  • 2.5 g kg−1 (oral, rat)
Related compounds
Related amines
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////////TRIENTINE, 112-24-3, 曲恩汀 , KD-034 , MK-0681, MK-681, TECZA, TETA, TJA-250, Orphan drug

NCCNCCNCCN

FDA approves first treatment Bavencio (avelumab)for rare form of skin cancer


 Image result for avelumab
str1
03/23/2017
The U.S. Food and Drug Administration today granted accelerated approval to Bavencio (avelumab) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy. This is the first FDA-approved treatment for metastatic MCC, a rare, aggressive form of skin cancer.

March 23, 2017

Release

The U.S. Food and Drug Administration today granted accelerated approval to Bavencio (avelumab) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy. This is the first FDA-approved treatment for metastatic MCC, a rare, aggressive form of skin cancer.

“While skin cancer is one of the most common cancers, patients with a rare form called Merkel cell cancer have not had an approved treatment option until now,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The scientific community continues to make advances targeting the body’s immune system mechanisms for the treatment of various types of cancer. These advancements are leading to new therapies—even in rare forms of cancer where treatment options are limited or non-existent.”

According to the National Cancer Institute, approximately 1,600 people in the United States are diagnosed with MCC every year. While the majority of patients present with localized tumors that can be treated with surgical resection, approximately half of all patients will experience recurrence, and more than 30 percent will eventually develop metastatic disease. In patients with metastatic MCC, the cancer has spread beyond the skin into other parts of the body.

Bavencio targets the PD-1/PD-L1 pathway (proteins found on the body’s immune cells and some cancer cells). By blocking these interactions, Bavencio may help the body’s immune system attack cancer cells.

Bavencio received an Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm Bavencio’s clinical benefit and the sponsor is currently conducting these studies.

Today’s approval of Bavencio was based on data from a single-arm trial of 88 patients with metastatic MCC who had been previously treated with at least one prior chemotherapy regimen. The trial measured the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and, for patients with a response, the length of time the tumor was controlled (duration of response). Of the 88 patients who received Bavencio in the trial, 33 percent experienced complete or partial shrinkage of their tumors. The response lasted for more than six months in 86 percent of responding patients and more than 12 months in 45 percent of responding patients.

Common side effects of Bavencio include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema). The most common serious risks of Bavencio are immune-mediated, where the body’s immune system attacks healthy cells or organs, such as the lungs (pneumonitis), liver (hepatitis), colon (colitis), hormone-producing glands (endocrinopathies) and kidneys (nephritis). In addition, there is a risk of serious infusion-related reactions. Patients who experience severe or life-threatening infusion-related reactions should stop using Bavencio. Women who are pregnant or breastfeeding should not take Bavencio because it may cause harm to a developing fetus or a newborn baby.

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

The FDA granted accelerated approval of Bavencio to EMD Serono Inc.

Image result for avelumab

Image result for avelumab

Avelumab
Monoclonal antibody
Type ?
Source Human
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG

Avelumab (MSB0010718C) is a fully human monoclonal PD-L1 antibody of isotype IgG1, currently in development by Merck KGaA, Darmstadt, Germany & Pfizer for use in immunotherapy, especially for treatment of Non-small-cell lung carcinoma (NSCLC) .[1]

Mechanism of action

Avelumab binds to the PD ligand 1 and therefore inhibits binding to its receptor programmed cell death 1 (PD-1). Formation of a PD-1/PD-L1 receptor/ligand complex leads to inhibition of CD8+ T cells, and therefore inhibition of an immune reaction. Immunotherapy aims at ceasing this immune blockage by blocking those receptor ligand pairs. In the case of avelumab, the formation of PD-1/PDL1 ligand pairs is blocked and CD8+ T cell immune response should be increased. PD-1 itself has also been a target for immunotherapy.[2] Therefore, avelumab belongs to the group of Immune checkpoint blockade cancer therapies.

Clinical trials

As of May 2015, according to Merck KGaA, Darmstadt, Germany & Pfizer, avelumab has been in Phase I clinical trials for bladder cancer, gastric cancer, head and neck cancer, mesothelioma, NSCLC, ovarian cancer and renal cancer. For Merkel-cell carcinoma, Phase II has been reached and for NSCLC there is also a study already in Phase III.[1]

Merkel-cell carcinoma

On March 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab (BAVENCIO, EMD Serono, Inc.) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).

Approval was based on data from an open-label, single-arm, multi-center clinical trial (JAVELIN Merkel 200 trial) demonstrating a clinically meaningful and durable overall response rate (ORR). All patients had histologically confirmed metastatic MCC with disease progression on or after chemotherapy administered for metastatic disease.

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR was 33% (95% confidence interval [CI]: 23.3, 43.8), with 11% complete and 22% partial response rates. Among the 29 responding patients, the response duration ranged from 2.8 to 23.3+ months with 86% of responses durable for 6 months or longer. Responses were observed in patients regardless of PD-L1 tumor expression or presence of Merkel cell polyomavirus.

Safety data were evaluated in 1738 patients who received avelumab, 10 mg/kg, every 2 weeks. The most common serious adverse reactions to avelumab are immune-mediated adverse reactions (pneumonitis, hepatitis, colitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus, and nephritis) and life-threatening infusion reactions. Among the 88 patients enrolled in the JAVELIN Merkel 200 trial, the most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. Serious adverse reactions that occurred in more than one patient in the trial were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis.

The recommended dose and schedule of avelumab is 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. All patients should receive premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.

Full prescribing information for avelumab is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf

References

  1. ^ Jump up to:a b Merck-Pfizer Alliance. “Merck-Pfizer Alliance Avelumab Fact Sheet” (PDF). Retrieved 2 December 2015.
  2. Jump up^ Hamid, O; Robert, C; Daud, A; Hodi, F. S.; Hwu, W. J.; Kefford, R; Wolchok, J. D.; Hersey, P; Joseph, R. W.; Weber, J. S.; Dronca, R; Gangadhar, T. C.; Patnaik, A; Zarour, H; Joshua, A. M.; Gergich, K; Elassaiss-Schaap, J; Algazi, A; Mateus, C; Boasberg, P; Tumeh, P. C.; Chmielowski, B; Ebbinghaus, S. W.; Li, X. N.; Kang, S. P.; Ribas, A (2013). “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma”. New England Journal of Medicine. 369 (2): 134–44. doi:10.1056/NEJMoa1305133. PMC 4126516Freely accessible. PMID 23724846.

//////////fda 2017, Bavencio, avelumab, EMD Serono Inc., Priority Review,  Breakthrough Therapy designation.  Orphan Drug designation, skin cancer

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

Lorlatinib, лорлатиниб , لورلاتينيب , 洛拉替尼 , PF-6463922


Lorlatinib.svgChemSpider 2D Image | lorlatinib | C21H19FN6O2

Lorlatinib, PF-6463922

For Cancer; Non-small-cell lung cancer

  • Molecular Formula C21H19FN6O2
  • Average mass 406.413 Da

Phase 2

WO 2013132376

Andrew James Jensen, Suman Luthra, Paul Francis RICHARDSON
Applicant Pfizer Inc.
Image result for pfizer
(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8- methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
(16R)-19-Amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10,12,14,18,20-octaene-3-carbonitrile
(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
CAS 1454846-35-5 [RN]
UNII:OSP71S83EU
лорлатиниб [Russian]
لورلاتينيب [Arabic]
洛拉替尼 [Chinese]

Ros1 tyrosine kinase receptor inhibitor; Anaplastic lymphoma kinase receptor inhibitor

useful for treating cancer mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) receptor tyrosine kinase, particularly NSCLC.  an ATP-competitive inhibitor of ROS1/ALK, for treating NSCLC. In February 2017, lorlatinib was reported to be in phase 2 clinical development.

  • Originator Pfizer
  • Developer Pfizer; The Childrens Hospital of Philadelphia; Yale University
  • Class Antineoplastics; Aza compounds; Benzoxazines; Pyrazoles; Pyrazolones; Small molecules
  • Mechanism of Action Anaplastic lymphoma kinase inhibitors; ROS1-protein-inhibitors
  • Orphan Drug Status Yes – Non-small cell lung cancer

Lorlatinib (PF-6463922) is an experimental anti-neoplastic drug in development by Pfizer. It is a orally-administered small molecule inhibitor of ROS1 and ALK.

In 2015, FDA granted Pfizer orphan drug status for lorlatinib for the treatment of non-small cell lung cancer.[1]

  • 05 Oct 2016 Massachusetts General Hospital plans a phase II trial for Non-small cell lung cancer (Late-stage disease, Metastatic disease) in USA (PO, unspecified formulation) (NCT02927340)
  • 01 Oct 2016 Pfizer completes a phase I trial in pharmacokinetic trial in Healthy volunteers in USA (NCT02804399)
  • 01 Aug 2016 Pfizer initiates a phase I drug-drug interaction trial in Healthy volunteers in Belgium (PO, unspecified formulation) (NCT02838264)

Figure

Structures of ALK inhibitors marketed or currently in the clinic

Synthesis

NEED COLOUR

Clinical studies

Several clinical trials are ongoing. A phase II trial comparing avelumab alone and in combination with lorlatinib or crizotinib for non-small cell lung cancer is expected to be complete in late 2017. A phase II trial comparing lorlatinib with crizotinib is expected to be complete in mid-2018.[2] A phase II trial for treatment of ALK-positive or ROS1-positive non-small cell lung cancer with CNA metastases is not expected to be complete until 2023.[3] Preclinical studies are investigating lorlatinib for treatment of neuroblastoma.

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Due to tumor complexity and development of resistance to treatment, disease progression is a challenge in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). A common site for progression in metastatic NSCLC is the brain. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.

ABOUT LORLATINIB

ALK in NSCLC ROS1 in NSCLC PRECLINICAL DATA CLINICAL STUDIES Originally discovered as an oncogenic driver in a type of lymphoma, ALK gene alterations were also found to be among key drivers of tumor development in cancers, such as NSCLC.1 In ALK-positive lung cancer, a normally inactive gene called ALK is fused with another gene. This genetic alteration creates the ALK fusion gene and ultimately, the production of an ALK fusion protein, which is responsible for tumor growth.1,2 This genetic alteration is present in 3-5% of NSCLC patients.3,4,5 Another gene that can fuse with other genes is called ROS1. Sometimes a ROS1 fusion protein can contribute to cancer-cell growth and tumor survival. This genetic alteration is present in approximately 1% of NSCLC patients.5 Preclinical data showed lorlatinib is capable of overcoming resistance to existing ALK inhibitors and penetrated the blood brain barrier in ALK-driven tumor models.2 Specifically, in these preclinical models, lorlatinib had activity against all tested clinical resistance mutations in ALK.

A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. • The primary objective of the Phase 1 portion was to assess safety and tolerability of single-agent lorlatinib at increasing dose levels in patients with ALK-positive or ROS1-positive advanced NSCLC.6 • Data from the Phase 1 study showed that lorlatinib had promising clinical activity in patients with ALK-positive or ROS1- positive advanced NSCLC. Most of these patients had developed CNS metastases and had received ≥1 prior tyrosine kinase inhibitor.7 o The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

PATENT

WO2014207606

This invention relates to crystalline forms of the macrocyclic kinase inhibitor, (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4, 3-?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, including crystalline solvates thereof, that may be useful in the treatment of abnormal cell growth, such as cancer, in mammals. The invention also relates to compositions including such crystalline forms, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.

Background of the Invention

The compound (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, represented by the formula (I):

(I)

is a potent, macrocyclic inhibitor of both wild type and resistance mutant forms of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) receptor tyrosine kinase. Preparation of the free base compound of formula (I) as an amorphous solid is disclosed in International Patent Publication No. WO 2013/132376 and in United States Patent Publication No. 2013/0252961 , the contents of which are incorporated herein by reference in their entirety.

Human cancers comprise a diverse array of diseases that collectively are one of the leading causes of death in developed countries throughout the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of cancers is caused by a complex series of multiple genetic and molecular events including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan & Weinberg, The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of

cancer are both diverse and complex, each cancer type has been observed to exhibit common traits and acquired capabilities that facilitate its progression. These acquired capabilities include dysregulated cell growth, sustained ability to recruit blood vessels (i.e., angiogenesis), and ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan & Weinberg 2000). Therefore, the ability to identify novel therapeutic agents that inhibit molecular targets that are altered during cancer progression or target multiple processes that are common to cancer progression in a variety of tumors presents a significant unmet need.

Receptor tyrosine kinases (RTKs) play fundamental roles in cellular processes, including cell proliferation, migration, metabolism, differentiation, and survival. RTK activity is tightly controlled in normal cells. The constitutively enhanced RTK activities from point mutation, amplification, and rearrangement of the corresponding genes have been implicated in the development and progression of many types of cancer. (Gschwind et al., The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 2004; 4, 361-370; Krause & Van Etten, Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005; 353: 172-187.)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, grouped together with leukocyte tyrosine kinase (LTK) to a subfamily within the insulin receptor (IR) superfamily. ALK was first discovered as a fusion protein with nucleophosmin (NPM) in anaplastic large cell lymphoma (ALCL) cell lines in 1994. (Morris et al., Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263:1281-1284.) NPM-ALK, which results from a chromosomal translocation, is implicated in the pathogenesis of human anaplastic large cell lymphoma (ALCL) (Pulford et al., Anaplastic lymphoma kinase proteins in growth control and cancer. J. Cell Physiol., 2004; 199: 330-58). The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of ALCL have been defined (Wan et. al., Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large cell lymphoma cells. Blood, 2006; 107:1617-1623). Other chromosomal rearrangements resulting in ALK fusions have been subsequently detected in ALCL (50-60%), inflammatory myofibroblastic tumors (27%), and non-small-cell lung cancer (NSCLC) (2-7%). (Palmer et al., Anaplastic lymphoma kinase: signaling in development and disease. Biochem. J. 2009; 420:345-361 .)

The EML4-ALK fusion gene, comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the ALK gene, was first discovered in NSCLC archived clinical specimens and cell lines. (Soda et al., Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 2007; 448:561-566; Rikova et al., Cell 2007; 131 :1 190-1203.) EML4-ALK fusion variants were demonstrated to transform NIH-3T3 fibroblasts and cause lung adenocarcinoma when expressed in transgenic mice, confirming the

potent oncogenic activity of the EML4-ALK fusion kinase. (Soda et al., A mouse model for EML4-ALK-positive lung cancer. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:19893-19897.) Oncogenic mutations of ALK in both familial and sporadic cases of neuroblastoma have also been reported. (Caren et al., High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumors. Biochem. J. 2008; 416:153-159.)

ROS1 is a proto-oncogene receptor tyrosine kinase that belongs to the insulin receptor subfamily, and is involved in cell proliferation and differentiation processes. (Nagarajan et al. Proc Natl Acad Sci 1986; 83:6568-6572). ROS is expressed, in humans, in epithelial cells of a variety of different tissues. Defects in ROS expression and/or activation have been found in glioblastoma, as well as tumors of the central nervous system (Charest et al., Genes Chromos. Can. 2003; 37(1): 58-71). Genetic alterations involving ROS that result in aberrant fusion proteins of ROS kinase have been described, including the FIG-ROS deletion translocation in glioblastoma (Charest et al. (2003); Birchmeier et al. Proc Natl Acad Sci 1987; 84:9270-9274; and NSCLC (Rimkunas et al., Analysis of Receptor Tyrosine Kinase ROS1 -Positive Tumors in Non-Small Cell Lung Cancer: Identification of FIG-ROS1 Fusion, Clin Cancer Res 2012; 18:4449-4457), the SLC34A2-ROS translocation in NSCLC (Rikova et al. Cell 2007;131 :1 190-1203), the CD74-ROS translocation in NSCLC (Rikova et al. (2007)) and cholangiocarcinoma (Gu et al. PLoS ONE 201 1 ; 6(1 ): e15640), and a truncated, active form of ROS known to drive tumor growth in mice (Birchmeier et al. Mol. Cell. Bio. 1986; 6(9):3109-31 15). Additional fusions, including TPM3-ROS1 , SDC4-ROS1 , EZR-ROS1 and LRIG3-ROS1 , have been reported in lung cancer patient tumor samples (Takeuchi et al., RET, ROS1 and ALK fusions in lung cancer, Nature Medicine 2012; 18(3):378-381).

The dual ALK/c-MET inhibitor crizotinib was approved in 201 1 for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. Crizotinib has also shown efficacy in treatment of NSCLC with ROS1 translocations. (Shaw et al. Clinical activity of crizotinib in advanced rson-smali cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, June 1-5, 2012.) As observed clinically for other tyrosine kinase inhibitors, mutations in ALK and ROS1 that confer resistance to ALK inhibitors have been described (Choi et ai., EML4-ALK Mutations in Lung Cancer than Confer Resistance to ALK Inhibitors, N Engl J Med 2010; 363:1734-1739; Awad et ai., Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1, Engl J Med 2013; 368:2395-2401 ).

Thus, ALK and ROS1 are attractive molecular targets for cancer therapeutic intervention. There remains a need to identify compounds having novel activity profiles against wild-type and mutant forms of ALK and ROS1 .

The present invention provides crystalline forms of the free base of (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2, 5,1 1 ]-benzoxadiazacyclotetradecine-3-carbonitrile having improved properties, such as improved crystallinity, dissolution properties, decreased hygroscopicity, improved mechanical properties, improved purity, and/or improved stability, while maintaining chemical and enantiomeric stability.

Comparative Example 1A

Preparation of (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxadiazacyclo-tetradecine-3-carbonitrile (amorphous)

Example 1A

Step 1 :

Palladium (II) acetate (53 mg, 0.24 mmol) and cataCXium® A (180 mg, 0.5 mmol) were mixed together in toluene (1 .5 mL, de-gassed) and the resulting solution was added via pipette to a stirred solution of compound 7 (0.9 g, 2.4 mmol), compound 15 (1 .0 g, 3.0 mmol) bis-pinacolato diboron (0.9 g, 3.6 mmol) and CsF (1 .9 g, 12.6 mmol) in MeOH/H20 (9:1 , 12 mL, degassed) at 60 °C. The resulting mixture was then stirred at reflux for 3 hrs. A further portion of Palladium (II) acetate (26 mg, 0.12 mmol) and cataCXium® A (90 mg, 0.25 mmol) in toluene (1 .5 mL, de-gassed) was added, and the yellow reaction mixture stirred at 60 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (150 mL) and filtered through CELITE®. The filtrate was washed with water (100 mL), then brine (100 mL), dried (Na2S04) and evaporated. The residue was purified by flash chromatography over silica gel, which was eluted with 1 :1 EtOAc/cyclohexane, to give compound 22 as a yellow oil (570 mg, 43% yield). TLC (Rf = 0.40, 1 :1 EtOAc/cyclohexane). 1H NMR (400 MHz, CDCI3) δ 8.03 (m, 1 H), 7.65 (s, 1 H), 7.27 (dd,1 H, J = 9.9, 2.7 Hz), 7.01 (m, 1 H), 6.68 (m, 1 H), 6.40 (m, 1 H), 4.90 (br s, 2 H), 4.20 – 4.30 (m, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 2.55 – 2.85 (m, 3 H), 1 .68 (d, 3 H, J = 6.6 Hz), 1 .24 (s, 9 H). LCMS ES m/z 539 [M+H]+.

Step 2:

To a solution of compound 22 (69% purity, 0.95 g, assumed 1 .05 mmol) in MeOH (20 mL) was added a solution NaOH (1 .0 g, 25 mmol) in water (2 mL). The mixture was stirred at 40 °C for 3.5 hours. The reaction was diluted with water (80 mL), concentrated by 20 mL to remove MeOH on the rotary evaporator, and washed with MTBE (100 mL). The aqueous layer was then acidified carefully with 1 M aq HCI to approx. pH 2 (pH paper). Sodium chloride (15 g) was added to the mixture and the mixture was extracted with EtOAc (100 mL). The organic layer was separated, dried (Na2S04) and evaporated to give compound 23 as a pale yellow solid (480 mg, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.05 (m, 1 H), 7.45 (s, 1 H), 7.37 (dd,1 H, J = 10.4, 2.8 Hz), 7.10 (dt, 1 H, J = 8.5, 2.4 Hz), 6.50 – 6.60 (m, 2 H), 4.05 – 4.30 (m, 2 H), 3.99 (s, 3 H), 2.60 – 2.80 (m, 3 H), 1 .72 (d, 3 H, J = 6.5 Hz). LCMS ES m/z 525 [M+H]+.

Step 3:

A solution of HCI in dioxane (4 M, 6.0 mL) was added to a solution of compound 23

(480 mg, 0.91 mmol) in MeOH (methanol) (6 mL) and the reaction was stirred at 40 °C for 2.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was taken-up in MeOH (50 mL) and acetonitrile (100 mL) was added and the mixture was then again evaporated to dryness, to give compound 24 as an off white solid (400 mg, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.07 (dd, 1 H, J = 8.9. 5.9 Hz), 7.51 (d, 1 H, J = 1 .7 Hz), 7.42 (dd, 1 H, J = 9.8, 2.6 Hz), 7.23 (d, 1 H, J = 1 .6 Hz), 7.16 (dt, 1 H, J = 8.5, 2.7 Hz), 6.73 (dd, 1 H, J = 1 1 .9, 6.9 Hz), 4.22 (d, 1 H, J = 14.7 Hz), 4.14 (d, 1 H, J = 14.7 Hz), 4.07 (s, 3 H), 2.75 (s, 3 H), 1 .75 (d, 3 H, J = 5.5 Hz). LCMS ES m/z 425 [M+H]+.

Step 4:

A solution of compound 24 (400 mg, assumed 0.91 mmol) as the HCI salt and DIPEA

(diisopropylethylamine) (1 .17 g, 9.1 mmol) in DMF (dimethylformamide) (5.0 mL) and THF (0.5 mL) was added drop-wise to a solution of HATU (2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (482 mg, 1 .27 mmol) in DMF (10.0 mL) at 0 °C over 30 minutes. After complete addition, the mixture was stirred at 0 °C for a further 30 mins. Water (70 mL) was added and the mixture was extracted into EtOAc (2 x 60 mL). The combined organics were washed with saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried over Na2S04, and evaporated. The residue was purified by column chromatography over silica gel, which was eluted with 70% EtOAc/cyclohexane giving 205 mg of a pale yellow residue (semi-solid). The solids were dissolved in MTBE (7 mL) and cyclohexane (20 mL) was added slowly with good stirring to precipitate the product. After stirring for 30 minutes, the mixture was filtered, and Example 1A was collected as an

amorphous white solid (1 10 mg, 29% yield). TLC (Rf = 0.40, 70% EtOAc in cyclohexane). 1H NMR (400 MHz, CDCI3) δ 7.83 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 9.6, 2.4 Hz), 7.21 (dd, 1 H, J = 8.4, 5.6 Hz), 6.99 (dt, 1 H, J = 8.0, 2.8 Hz), 6.86 (d, 1 H, J = 1 .2 Hz), 5.75 – 5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, 1 H, J = 14.4 Hz), 4.35 (d ,1 H, J = 14.4 Hz), 4.07 (s, 3 H), 3.13 (s, 3 H), 1 .79 (d, 3 H, J = 6.4Hz). LCMS ES m/z 407 [M+H]+.

Example 1

Preparation of crystalline hydrate of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo- 10,15,16,17-tetrahvdro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxa-diazacyclo-tetradecine-3-carbonitrile (Form 1)

Example 1A Example 1

(amorphous) (Form 1 }

Amorphous (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2,5,11 ]benzoxa-diazacyclo-tetradecine-3-carbonitrile free base, prepared as described in Example 1A (and Example 2 of United States Patent Publication No. 2013/0252961), was dissolved in 1 .0 : 1 .1 (v:v) H20:MeOH at a concentration of 22 mg/mL at 50°C, then allowed to cool to room temperature . This slurry was granulated for approximately 72 hours. The solids were isolated by filtration and vacuum dried overnight at 60°C to produce crystalline hydrate Form 1 of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-/?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile.

Example 4

Alternative preparation of crystalline acetic acid solvate of (10 ?)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahvdro-2H-8,4-(metheno)pyrazolo[4,3- ?U2,5, 1 1 lbenzoxa-diazacyclotetradecine-3-carbonitrile (Form 3)

Step 1 :

To a reaction vessel under N2 were charged compound 9 (9.97 kg, 17.95 mol), compound 21 (3.52 kg, 18.85 mol) and 2-methyltetrahydrofuran (97 L). Triethylamine (7.45 kg, 73.6 mol) was added while keeping the internal temperature below 35°C. The reaction mixture was held for 30 min and n-propylphosphonic anhydride (T3P), 50% solution in ethyl acetate (22.85 kg, 35.9 mol) was charged slowly, maintaining the internal temperature below 25°C. The reaction mixture was held at 20°C for at least 2 h until reaction was deemed complete. Ethyl acetate (35 L) and water (66 L) were added followed by 0.5N Hydrochloric acid solution (80 L). The aqueous layer was removed and the organic layer was washed with brine solution (80 L). The organic layer was concentrated and solvent exchanged with 2-methyl-2-butanol (80 L) give compound 25 (23 wt/wt%) solution in 2-methyl-2-butanol . This solution was carried forward to the next step directly in three batches, assuming 12.00 kg (100% yield) from this step.

Step 2:

2-Methyl-2-butanol (100 L) was combined with potassium acetate (1 .8 kg, 18.34 mol), palladium(ll) acetate (0.10 kg, 0.46 mol) and water (0.10 kg, 5.73 mol). The resulting mixture was purged with nitrogen. Di(1 -adamantyl)n-butylphosphine (0.23 kg, 0.43 mol) was added. An amount of 20% of compound 25 (3.97 kg active or 17.3 L of step 1 solution in 2-methyl-2-butanol) was added, and the resulting reaction mixture was heated at reflux for 2 h. The remaining solution of compound 25 in 2-methyl-2-butanol was subsequently added to the reaction over a period of 5 h. The resulting mixture was heated until the reaction was deemed complete (typically 16 – 20 h). This reaction step was processed in three batches, and the isolation was done in one single batch. Thus, the combined three batches were filtered through CELITE® to remove insoluble materials. The filtrate was concentrated to a low volume (approximately 20 L). Acetonitrile (60 L) was added. The resulting mixture was heated to reflux for 2 – 4 h, then cooled to RT for granulation. The resulting slurry was filtered to give compound 26 as a crude product. The crude product was combined with ethyl acetate (80 L) and Silicycle thiol (5 kg). The resulting mixture was heated for 2 h, cooled to RT and filtered. The filtrate was concentrated to approx. 20 L, and the resulting slurry was granulated and filtered. The filter cake was rinsed with ethyl acetate (4 L) and dried in a vacuum oven to give compound 26 as a pure product (4.74 kg, 43.5% overall last two steps). 1H NMR (CDCI3) δ 8.25 – 8.23 (m, 1 H), 7.28 (1 H, dd, 2.76 and 9.79 Hz), 7.22 (1 H, dd, 5.52 and 8.53 Hz), 7.18 (1 H, d, J = 1 .76 Hz), 7.01 (1 H, dt, J = 2.50 and 8.03 Hz), 5.78 – 5.70 (m, 1 H), 4.76 (1 H, d, J = 14.3 Hz), 4.13 (s, 3H), 3.16 (s, 3H), 1 .78 (d, 3H, J = 6.02 Hz), 1 .45 (s, 18H); 13C NMR (CDCI3) δ 167.0, 162.9, 160.4, 148.7, 146.3, 143.0, 140.7, 139.9, 135.5, 129.9, 129.8, 126.1 , 123.8, 123.5, 1 19.7, 1 13.8, 1 13.5, 1 1 1 .6, 108.1 , 81 .1 , 70.1 , 45.5, 37.0, 29.7, 26.0, 20.7; LCMS (M+1)+ 607.3, 507.1 , 451 .2.

Step 3:

To a reactor under N2 was added compound 26 (4.74 kg, 7.82 mol) and ethyl acetate (54 L). Hydrochloric acid 37% (5.19 L, 63.2 mol) was charged slowly while keeping the internal temperature below 25°C. The reaction mixture was stirred for 24 – 48 h until the reaction was complete. Ethyl acetate (54L) and water (54 L) were added. The reaction mixture was then treated with triethylamine until pH 8 – 9 was reached. The aqueous layer was removed and then the organic layer was washed water (2 x 54 L). The organic layer was concentrated under reduced pressure to approx. 54 L to give compound 27 (unisolated).

Step 4:

Acetic acid (1 .0 kg, 16.6 mol) was added to the organic layer containing compound 27. The reaction mixture was concentrated and then held for at least 3 h with stirring at RT. The resulted slurry was filtered. The filter cake was washed with ethyl acetate (2 L) and dried under vacuum to give 3.20 kg (87.8% yield) of Example 4 acetic acid solvate (Form 3). The spectroscopic data of this material was identical to that of an authentic sample of the crystalline acetic acid Form 3 of (10R)-7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]-benzoxadiazacyclo-tetradecine-3-carbonitrile prepared according to Example 3.

Preparation of Synthetic Intermediates

7 6 5

Step 1 :

A solution of (-)-DIPCI ((-)-B-chlorodiisopinocampheylborane) (57.1 g, 178 mmol) in THF

(tetrahydrofuran) (100 ml) was cooled to -20 to -30 °C. A solution of compound 1 (31 .3 g, 1 19 mmol) in THF (100 ml) was then added dropwise, via addition funnel (30 min addition). The reaction was left to warm up to room temperature (RT). After 2 h, the reaction was cooled to -30 °C and another portion of (-)-DIPCI (38.0 g, 1 19 mmol) was added. After 30 min, the reaction was allowed to warm to RT and after 1 h, the solvents were removed in vacuo and the residue re-dissolved in MTBE (methyl tertiary-butyl ether) (200 ml). A solution of diethanolamine (31 g, 296 mmol) in ethanol/THF (15 ml/30 ml) was added via addition funnel, to the reaction mixture under an ice bath. The formation of a white precipitate was observed. The suspension was heated at reflux for 2 hours then cooled to room temperature, filtered and the mother liquids concentrated in vacuo. The residue was suspended in heptane/EtOAc (7:3, 200 ml) and again

filtered. This procedure was repeated until no more solids could be observed after the liquids were concentrated. The final yellow oil was purified by column chromatography (eluent: cyclohexane/EtOAc 99:1 to 96:4). The resulting colorless oil was further purified by recrystallization from heptanes, to give alcohol compound 2 (25 g, 80% yield, 99% purity and 96% ee) as white crystals. 1H NMR (400 MHz, CDCI3) δ 7.73 (dd, 1 H), 7.32 (dd, 1 H), 6.74 (ddd, 1 H), 4.99 – 5.04 (m, 1 H), 2.01 (d, 1 H), 1 .44 (d, 3 H). LCMS-ES: No ionization, Purity 99%. Chiral GC (column CP-Chirasil-DexnCB): 96% ee; Rt (minor) 17.7 minutes and Rt (major) 19.4 minutes.

Step 2:

A solution of compound 2 (22 g, 83 mmol) in MTBE (350 mL) was cooled under an ice bath and triethylamine (23 mL, 166 mmol) followed by mesyl chloride (9.6 mL, 124 mmol) were added drop-wise. The reaction was then warmed to RT and stirred for 3 h. The reaction mixture was filtered and the solids washed with EtOAc. The mother liquids were concentrated in vacuo to give compound 3 (35 g, 80% yield) as a pale yellow oil. This material was taken into the following step without further purification. 1H NMR (400 MHz, CDCI3) δ 7.78 (dd, 1 H), 7.24 (dd, 1 H), 6.82 (ddd, 1 H), 2.92 (s, 3 H), 1 .64 (d, 3 H). LCMS-ES no ionization.

Step 3:

A suspension of Cs2C03 (65 g, 201 mmol) and compound 4 (13.3 g, 121 mmol) in 2-CH3-THF (2-methyitetrahydrofuran) (600 mL) and acetone (300 mL) was stirred at RT for 30 minutes then heated at 40 °C before drop-wise addition of a solution of compound 3 (34.4 g, 80 mmol) in 2-CH3-THF (300 mL) via addition funnel. The resulting mixture was left stirring at 75 -80 °C for 24 h. The reaction was then filtered through CELITE® with MTBE, the solvents removed in vacuo and the residue purified by column chromatography over silica gel which was eluted with cyclohexane/EtOAc (9:1 to 1 :1) to give compound 5 (14.3 g, 39 % yield, 90% ee) as a white solid. The solids were then re crystallized from heptane/EtOAc to give compound 5 (10.8 g, 37% yield, 95% ee). 1H NMR (400 MHz, CDCI3) 5 7.38 (dd, 1 H), 7.62 (dd, 1 H), 7.10 (dd, 1 H), 6.75 (ddd, 1 H), 6.44 – 6.51 (m, 2 H), 5.34 – 5.39 (m, 1 H), 4.73 (br s, 2 H), 1 .61 (d, 3 H). LCMS-ES m/z 359 [M+H]+. HPLC (Chiralpak IC 4.6 x 250 mm): 95% ee; Rt (minor) 10.4 minutes; Rt (major) 14.7 minutes; eluent: Heptane 80%/IPA 20% with 0.2% DEA, 0.7 mL/min. Step 4:

Compound 5 (20 g, 57 mmol) was dissolved in methanol (300 mL), and sequentially treated with triethylamine (TEA) (15.4 mL, 1 13 mmol) and PdCI2(dppf) (1 ,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ) (4.1 g, 5.7 mmol). This mixture was heated at 100 °C for 16 hours, under a 100 psi carbon monoxide atmosphere. LCMS indicated consumption of starting material. The reaction mixture was filtered through a pad of CELITE®, and the filtrate evaporated to a brown oil. The crude product was purified by flash

chromatography over silica gel which was eluted with 50% to 75% ethyl acetate in cyclohexane, affording the pure product 6 as a brick-red solid (13.0 g, 79% yield). 1H NMR (400 MHz, CDCI3) δ 1 .65 (d, 3 H), 3.94 (s, 3 H), 4.75 (br s, 2 H), 6.32 (q, 1 H), 6.42 (dd, 1 H), 6.61 (dd, 1 H), 7.00 (ddd, 1 H), 7.28 (dd, 1 H), 7.60 (dd, 1 H), 8.03 (dd, 1 H). LCMS ES m/z 291 for [M+H]+.

Step 5:

Compound 6 (13.0 g, 45 mmol) was dissolved in acetonitrile (195 mL), and cooled to <10 °C in an ice water bath. NBS (N-bromosuccinimide) (7.9 g, 45 mmol) was added drop-wise to the cooled reaction mixture as a solution in acetonitrile (195 mL), monitoring the internal temperature to ensure it did not rise above 10 °C. After addition was complete, the mixture was stirred for 15 minutes. Thin layer chromatography (TLC) (1 :1 cyclohexane/ethyl acetate) showed consumption of starting material. The reaction mixture was evaporated, and the residue redissolved in ethyl acetate (400 mL), and washed with 2M aqueous NaOH (2 x 300 mL), and 10% aqueous sodium thiosulfate solution (300 mL). The organic extracts were dried over MgS04, and evaporated to a red oil (17.6 g). The crude product was purified over silica gel, which was eluted with 10% to 50% ethyl acetate in cyclohexane, which gave compound 7 (12.0 g, 73% yield). 1H NMR (400 MHz, CDCI3) δ 1 .65 (d, 3 H), 3.96 (s, 3 H), 4.74 – 4.81 (br s, 2 H), 6.33 (q, 1 H), 6.75 (d, 1 H), 7.03 (ddd, 1 H), 7.25 (dd, 1 H), 7.66 (d, 1 H), 8.06 (dd, 1 H). LCMS ES m/z 369/371 [M+H]+. A Chiralpak AD-H (4.6 x 100 mm, 5 micron) column was eluted with 10% MeOH (0.1 % DEA) in C02 at 120 bar. A flow rate of 5.0 mL/min gave the minor isomer Rt 0.6 minutes and the major isomer Rt 0.8 minutes (99% ee). Optical rotation: [ ]d20 = -92.4 deg (c=1 .5, MeOH).

Preparation of (/?)-methyl 2-(1 -((N,N-di-Boc-2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoic acid (9)

7

Step 1 :

To a solution of compound 7 (2000 g, 5.4 mol) in dry DCM (dichloromethane) (32000 mL) was added DIPEA (N.N-dsisopropyleibylamine) (2100 g, 16.28 mol) and DMAP (4-dimethylaminopyridine) (132 g, 1 .08 mol). Then Boc20 (di-tert-butyl-dicarbonate) (3552 g, 16.28 mol) was added to the mixture in portions. The reaction was stirred at RT for overnight. TLC (petroleum ether/EtOAc =5:1) show the reaction was complete, the mixture was washed with sat. NH4CI (15 L) two times, then dried over Na2S04and concentrated to give a crude product which was purified by column (silica gel, petroleum ether/EtOAc from 20:1 to 10:1) to give compound 8 (2300 g, 75%) as a white solid.

Step 2:

Compound 8 (50 g, 87.81 mmol, 100 mass%) was charged to a round bottom flask (RBF) containing tetrahydrofuran (12.25 mol/L) in Water (5 mL/g, 3060 mmol, 12.25 mol/L) and sodium hydroxide (1 mol/L) in Water (1 .5 equiv., 131 .7 mmol, 1 mol/L). The biphasic mixture was stirred at RT for 14 hours. 1 N HCI was added to adjust pH to < 2. THF was then removed by vacuum distillation. The product precipitated out was collected by filtration. The filter cake was rinsed with water, pulled dried then dried in vacuum oven to constant weight (48 h, 55°C, 25 mbar). 48.3g isolated, 99% yield. 1H NMR (CDCI3, 400MHz) δ 8.24 (1 H, dd, 1 H, J = 5.76 and 3.0 Hz), 8.16 (1 H, d, J = 2.0 Hz), 7.37 (1 H, dd, J = 2.5 and 9.8 Hz), 7.19 (1 H, d, J = 2 Hz), 7.14 – 7.06 (1 H, m), 6.50 (1 H, q, J = 6.3 Hz), 1 .67 (3H, d, J = 8.4 Hz), 1 .48 (18H, s). 13C NMR (CDCI3, 100 MHz), δ 170.1 , 169.2, 167.6, 165.1 , 150.6, 149.2, 148.6, 141 .4, 140.7, 135.2, 135.1 , 124.2, 122.2,122.1 , 1 19.9, 1 15.4, 1 15.1 , 1 13.4, 1 13.2, 100.0, 83.4, 73.3, 27.9, 23.9. LCMS (M+ +1) 557.2, 555.3, 457.1 , 455.1 , 401 , 0, 399.0.

Step 1 :

Ethyl 1 ,3-dimethylpyrazole-5-carboxylate (5.0 g, 30 mmol) was dissolved in 1 ,2-dichloroethane (200 mL), followed by addition of NBS (5.3 g, 30 mmol) and dibenzoyi peroxide (727 mg, 3.0 mmol), in small portions and stirred at 85 °C for 2 hours. The mixture was allowed to cool, diluted to 400 mL with dichloromethane, and washed with water (2 x 200 mL). The organic layer was dried over MgS04, and evaporated to give compound 10 (4.1 g, 42% yield). TLC (EtOAc/Cyclohexane; 1 :10; KMn04): Rf~0.3. 1H NMR (400 MHz, CDCI3) δ 4.47 (s, 2 H), 4.41 (q, 2 H), 4.15 (s, 3 H), 1 .42 (t, 3 H). LCMS ES m/z 324/326/328 [M+H]+.

Step 2:

Compound 10 (3.0 g, 9.2 mmol) was dissolved in methylamine solution (33% solution in ethanol, 70 mL), and stirred at RT for 16 hours. The mixture was evaporated to give compound 11 (1 .8 g, 71 % yield). 1H NMR (400 MHz, CDCI3) δ 4.39 (q, 2 H), 4.14 (s, 3 H), 4.05 (s, 2 H), 2.62 (d, 3 H), 1 .41 (t, 3 H). LCMS ES m/z 276/278 [M+H]+.

Step 3:

Compound 11 (1 .8 g, 6.5 mmol) was dissolved in dichloromethane (20 mL), and the mixture cooled to 0 °C. A solution of di(fe/?-butyl) dicarbonate (1 .75 g, 8 mmol) in dichloromethane (17.5 mL) was added dropwise. The ice bath was removed and the mixture stirred for 18 hours at room temperature. The mixture was diluted to 100 mL with dichloromethane, and washed with water (2 x 50 mL). Organic extracts were dried over magnesium sulfate, and evaporated to give compound 12 (1 .8 g, 72% yield). 1H NMR (400 MHz, CDCI3) δ 4.48 – 4.44 (m, 2 H), 4.41 (q, 2 H), 4.12 (s, 3 H), 2.82 – 2.79 (m, 3 H), 1 .47 (s, 9 H), 1 .41 (t, 3 H). LCMS ES m/z 376/378 [M+H]+ and 276/278 [M-BOC]+.

Step 4:

Compound 12 (4 g, 1 1 mmol) was dissolved in dioxane (43 mL). Sodium amide (1 g, 27 mmol) was added in one portion. The reaction mixture was stirred at 100 °C for 24 h. After this time, the solvent was removed under reduced pressure to give a white solid. The material was suspended in EtOAc (100 mL) and washed with 5% citric acid solution (100 mL). The organic phase was separated and washed with water (100 mL), dried over MgS04, filtered and the solvent removed in vacuo to give compound 13 as a yellow gum (3.1 g, 84% yield). 1H NMR (400 MHz, DMSO-c/6) δ 4.27 (s, 2 H), 3.92 (s, 3 H), 2.70 (s, 3 H), 1 .40 (s, 9 H). LCMS ES m/z 348/350 [M+H]+ and 248/250 [M-BOC]+.

Step 5:

Compound 13 (3 g, 8.6 mmol) was dissolved in DMF (43 mL, 0.2 M). HOBt (1 .2 g, 8.6 mmol) was added, followed by ammonium chloride (0.9 g, 17.2 mmol). EDCI (2.5 g, 13 mmol) was then added, followed by TEA (2.4 mL, 17 mmol). The reaction mixture was stirred at room temperature. After 18h, the solvent was removed under reduced pressure to give a yellow oil

(8.0 g). The residue was dissolved in EtOAc (75ml_). The organic phase was washed with NaHC03 (sat. solution, 70 ml_) and then brine (100 ml_). The combined organic layers were dried over MgS04 and the solvent removed in vacuo to give compound 14 as a dark yellow oil (2.7 g, 91 % yield). This material was used directly in the next step without further purification. 1H NMR (400 MHz, CDCI3) δ 6.74 (br s, 1 H), 5.95 (br s, 1 H), 4.49 (br s, 2 H), 4.16 (s, 3 H), 2.81 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 347/349 [M+H]+ and 247/249 [M-BOC]+.

Step 6:

Compound 14 (2.7 g, 7.9 mmol) was dissolved in DCM (80 ml_, 0.1 M). TEA (3.3 ml_, 23.8 mmol) was then added and the reaction mixture cooled down to -5 °C. Trifluoroacetic anhydride (2.2 ml_, 15.8 mmol) in DCM (15 ml_) was added dropwise over 30 min. After addition, the reaction mixture was stirred at 0 °C for 1 h. After this time, the solvents were removed under reduced pressure to give a dark yellow oil. This residue was diluted in DCM (100 ml_), washed with 5% citric acid, sat. NaHC03and brine, dried over MgS04, filtered and the solvents removed in vacuo to give a dark yellow oil (2.6 g). The crude product was purified by reverse phase chromatography to give compound 15 as a yellow oil (2.3 g, 87% yield). 1H NMR (400 MHz, CDCI3) δ 4.46 (br s, 2 H), 4.01 (s, 3 H), 2.83 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 331 /329 [M+H]+ and 229/231 [M-BOC]+ as the base ion.

Preparation o/: 1 -methyl-3-((methylamino)methyl)-1 H-pyrazole-5-carbonitrile (21)

Step 1 :

To /V-benzylmethylamine (2.40 kg, 19.8 mol) and ethyldiisopropylamine (2.61 kg, 20.2 mol) in acetonitrile (6 L) at 16°C was added chloroacetone (1 .96 kg, 21 .2 mol) over 60 mins [exothermic, temp kept <30°C]. The mixture was stirred at 22°C for 18 hours then concentrated to an oily solid. The residue was triturated with MTBE (5 L), and then filtered through a pad of CELITE® (600 g, top) and silica (1 .5 kg, bottom), washing with MTBE (8 L). The filtrate was evaporated to afford compound 16 (3.35 kg, 18.9 mol, 95%) as a brown oil.

Step 2:

Compound 16 (1 .68 kg, 9.45 mol), Boc-anhydride (2.1 kg, 9.6 mol) and 20wt% Pd/C (50% H20, 56 g) in ethanol (5 L) were hydrogenated in an 1 1 -L autoclave at 50 psi [exotherm to 40°C with 20°C jacket]. The atmosphere became saturated with carbon dioxide during the reaction and so needed to be vented and de-gassed twice to ensure sufficient hydrogen uptake and completion of the reaction. The total reaction time was ~1 .5 hours. Two runs (for a total of 18.9 mol) were combined and filtered through a pad of SOLKA-FLOC®, washing with methanol. The filtrate was treated with DMAP (45 g, 0.37 mol) and stirred at room temperature overnight to destroy the excess Boc-anhydride. The mixture was then concentrated to dryness, dissolved in MTBE (6 L) and filtered through a pad of magnesol (1 kg), washing with MTBE (4 L). The filtrate was evaporated to afford compound 17 (3.68 kg, ~95 wt%, 18.7 mol, 99%) as an orange-brown oil.

Step 3:

To compound 17 (3.25 kg, -95 wt%, 16.5 mol) and diethyl oxalate (4.71 kg, 32.2 mol) in methanol (12 L) at 15°C was added 25 wt% sodium methoxide in methanol (6.94 kg, 32.1 mol) over 25 mins [temp kept <25°C]. The mixture was stirred at 20°C for 16 hours then cooled to -37°C and 37% hydrochloric acid (3.1 kg, 31 mol) was added over 5 mins [temp kept <-10°C]. The mixture was cooled to -40°C and methylhydrazine (1 .42 kg, 30.8 mol) was added over 7 mins [temp kept <-17°C]. The mixture was warmed to 5°C over 90 minutes, then re-cooled to 0°C and quenched by addition of 2.4M KHS04 (6.75 L, 16.2 mol) in one portion [exotherm to 27°C]. The mixture was diluted with water (25 L) and MTBE (15 L), and the layers separated. The organic layer was washed with brine (7 L) and the aqueous layers then sequentially re-extracted with MTBE (8 L). The combined organics were evaporated and azeotroped with toluene (2 L) to afford crude compound 18. Chromatography (20 kg silica, 10-40% EtOAc in hexane) afforded compound 18 (3.4 kg, ~95 wt%, 11 .4 mol, 69%) as an orange oil.

Step 4:

Ammonia (3 kg, 167 mol) was bubbled in to cooled methanol (24 L) [temp kept <18°C]. A solution of compound 18 (4.8 kg, ~95 wt%, 16.1 mol) in methanol (1 .5 L) was added over 30 minutes and the mixture stirred at 25°C for 68 hours and then at 30°C for 24 hours. Two runs (from a total of 9.68 kg of ~95 wt% Step 3) were combined and concentrated to ~13 L volume. Water (30 L) was slowly added over 80 minutes, keeping the temperature 30 to 40°C. The resulting slurry was cooled to 20°C, filtered, washed with water (12 L) and pulled dry on the filter overnight. The solids were triturated in MTBE (8 L) and hexane (8 L) at 45°C then re-cooled to 15°C, filtered, washed with hexane (4 L) and dried under vacuum to afford compound 19 (7.95 kg, 29.6 mol, 90%) as an off-white solid.

Step 5:

To compound 19 (7.0 kg, 26.1 mol) in DCM (30 L) at 0°C was added triethylamine (5.85 kg, 57.8 mol). The mixture was further cooled to -6°C then trifluoroacetic anhydride (5.85 kg, 27.8 mol) added over 90 minutes [temp kept 0 to 5°C]. TLC assay showed the reaction was incomplete. Additional triethylamine (4.1 kg, 40.5 mol) and trifluoroacetic acid (4.1 kg, 19.5 mol) were added over 2 hours until TLC showed complete reaction. The reaction mixture was quenched in to water (40 L) [temp to 23°C]. The layers were separated and the aqueous re-extracted with DCM (8 L). The organic layers were sequentially washed with brine (7 L), filtered through a pad of silica (3 kg) and eluted with DCM (10 L). The filtrate was evaporated and chromatographed (9 kg silica, eluent 10-30% EtOAc in hexane). Product fractions were evaporated and azeotroped with IPA to afford compound 20 (6.86 kg, -94 wt%, 25.8 mol, 99%) as an orange oil.

Step 6:

To compound 20 (6.86 kg, -94 wt%, 25.8 mol) in IPA (35 L) at 17°C was added 37% hydrochloric acid (6.4 L, 77.4 mol). The mixture was heated to 35°C overnight then concentrated to a moist solid and residual water azeotroped with additional IPA (8 L). The resulting moist solid was triturated with MTBE (12 L) at 45°C for 30 minutes then cooled to 20°C and filtered, washing with MTBE (5 L). The solids were dried under vacuum at 45°C to afford compound 21 (4.52 kg, 24.2 mol, 94%) as a white solid. 1H-NMR was consistent with desired product; mp 203-205°C; HPLC 99.3%. 1H NMR (CD3OD, 400 MHz) δ 7.12 (1 H, s), 4.28 (2H, s), 4.09 (3H, s), 2.77 (3H, s). 13C NMR (CD3OD, 100 MHz) δ 144.5, 177.8, 1 14.9, 110.9, 45.9, 39.0, 33.2. LCMS (M++1) 151 .1 , 138.0, 120.0.

PATENT

WO2013132376

PATENT

WO 2016089208

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017021823&redirectedID=true

Preparation of the free base of lorlatinib as an amorphous solid is disclosed in

International Patent Publication No. WO 2013/132376 and in United States Patent No. 8,680,1 1 1 . Solvated forms of lorlatinib free base are disclosed in International Patent Publication No. WO 2014/207606.

Example 1

Lab Scale Preparation of Form 7 of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 l lbenzoxadiazacyclotetra-decine- -carbonitrile (lorlatinib) Free Base

[AcOH solvate]

Form 7 of lorlatinib free base was prepared by de-solvation of the acetic acid solvate of lorlatinib (Form 3), prepared as described in International Patent Publication No. WO 2014/207606, via an intermediate methanol solvate hydrate form of lorlatinib (Form 2).

The acetic acid solvate of lorlatinib (Form 3) (5 g, 10.72 mmol) was slurried in methanol

(10 mL/g, 1235.9 mmol) at room temperature in an Easymax flask with magnetic stirring to which triethylamine (1 .2 equiv., 12.86 mmol) was added over 10 minutes. The resulting solution was heated to 60°C and water (12.5 mL/g, 3469.3 mmol) was added over 10 minutes, while maintaining a temperature of 60°C. Crystallization was initiated by scratching the inside of the glass vessel to form a rapidly precipitating suspension which was triturated to make the system mobile. The suspension was then cooled to 25°C over 1 hour, then cooled to 5°C and granulated for 4 hours. The white slurry was filtered and washed with 1 mL/g chilled

water/methanol (1 :1) then dried under vacuum at 50°C overnight to provide the methanol solvate hydrate Form 2 of lorlatinib.

Form 7 was then prepared via a re-slurry of the methanol solvate hydrate Form 2 of lorlatinib in heptane. 100 mg of lorlatinib Form 2 was weighed into a 4-dram vial and 3 mL of heptane was added. The mixture was slurried at room temperature on a roller mixer for 2 hours. Form conversion was confirmed by PXRD revealing complete form change to Form 7 of lorlatinib free base.

Paper

http://pubs.acs.org/doi/abs/10.1021/jm500261q

*E-mail: ted.w.johnson@pfizer.com. Phone: (858) 526-4683., *E-mail: paul.f.richardson@pfizer.com. Phone: (858) 526-4290.

Abstract Image

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States
J. Med. Chem., 2014, 57 (11), pp 4720–4744
DOI: 10.1021/jm500261q
(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (8k)
white solid:
TLC Rf = 0.40 (70% EtOAc in cyclohexane);
LC–MS (ESI), m/z 407.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 9.6, 2.4 Hz, 1 H), 7.21 (dd, J = 8.4, 5.6 Hz, 1 H), 6.99 (dt, J = 8.0, 2.8 Hz, 1 H), 6.86 (d, J = 1.2 Hz, 1 H), 5.75–5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, J = 14.4 Hz, 1 H), 4.35 (d, J = 14.4 Hz, 1 H), 4.07 (s, 3 H), 3.13 (s, 3 H), 1.79 (d, J = 6.4 Hz, 3 H).

References

1H NMR PREDICT

13C NMR PREDICT

Lorlatinib
Lorlatinib.svg
Clinical data
Routes of
administration
PO
Legal status
Legal status
  • experimental
Identifiers
CAS Number 1454846-35-5
ChemSpider 32813339
Chemical and physical data
Formula C22H20FN5O2
Molar mass 405.43 g·mol−1
3D model (Jmol) Interactive image

///////////////////Lorlatinib, PF-6463922,  anti-neoplastic,  Pfizer,  ROS1,  ALK, phase 2, UNII:OSP71S83EU, лорлатиниб لورلاتينيب 洛拉替尼 Orphan Drug, PF 6463922

Fc2ccc3C(=O)N(C)Cc1nn(C)c(C#N)c1c4cc(O[C@H](C)c3c2)c(N)nc4

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