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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, 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 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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Ivosidenib,  ивосидениб , إيفوزيدينيب , 艾伏尼布 , 


Ivosidenib.svg

Ivosidenib

AG-120; TIBSOVO
FDA approves first targeted treatment Tibsovo (ivosidenib) for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation
The U.S. Food and Drug Administration today approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.
“Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The use of Tibsovo is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

July 20, 2018

Release

The U.S. Food and Drug Administration today approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.

“Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The use of Tibsovo is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 19,520 people will be diagnosed with AML this year; approximately 10,670 patients with AML will die of the disease in 2018.

Tibsovo is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells. If the IDH1 mutation is detected in blood or bone marrow samples using an FDA-approved test, the patient may be eligible for treatment with Tibsovo. Today the agency also approved the RealTime IDH1 Assay, a companion diagnostic that can be used to detect this mutation.

The efficacy of Tibsovo was studied in a single-arm trial of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a median follow-up of 8.3 months, 32.8 percent of patients experienced a CR orCRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets due to AML at the start of the study, 37 percent went at least 56 days without requiring a transfusion after treatment with Tibsovo.

Common side effects of Tibsovo include fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, swelling in the arms or legs, nausea, pain or sores in the mouth or throat, irregular heartbeat (QT prolongation), rash, fever, cough and constipation. Women who are breastfeeding should not take Tibsovo because it may cause harm to a newborn baby.

Tibsovo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. The prescribing information for Tibsovo includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Signs and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

Other serious warnings include a QT prolongation, which can be life-threatening. Electrical activity of the heart should be tested with an electrocardiogram during treatment. Guillain-Barré syndrome, a rare neurological disorder in which the body’s immune system mistakenly attacks part of its peripheral nervous system, has happened in people treated with Tibsovo, so patients should be monitored for nervous system problems.

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

The FDA granted the approval of Tibsovo to Agios Pharmaceuticals, Inc. The FDA granted the approval of the RealTime IDH1 Assay to Abbott Laboratories.

ChemSpider 2D Image | ivosidenib | C28H22ClF3N6O3

ivosidenib

  • Molecular FormulaC28H22ClF3N6O3
  • Average mass582.961 Da
1448347-49-6 [RN]
2-Pyrrolidinecarboxamide, N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyano-2-pyridinyl)-N-(5-fluoro-3-pyridinyl)-5-oxo-, (2S)-
AG-120
UNII:Q2PCN8MAM6
ивосидениб [Russian] [INN]
إيفوزيدينيب [Arabic] [INN]
艾伏尼布 [Chinese] [INN]

Ivosidenib is an experimental drug for treatment of cancer. It is a small molecule inhibitor of IDH1, which is mutated in several forms of cancer. The drug is being developed by Agios Pharmaceuticals and is in phase III clinical trials. The FDA awarded orphan drug statusfor acute myeloid leukemia and cholangiocarcinoma.[1][better source needed]

It is in a phase III clinical trial for acute myeloid leukemia (AML) with an IDH1 mutation and a phase III clinical trial for cholangiocarcinoma with an IDH1 mutation.[2]

  • OriginatorAgios Pharmaceuticals
  • DeveloperAbbVie; Agios Pharmaceuticals; University of Texas M. D. Anderson Cancer Center
  • ClassAntineoplastics; Cyclobutanes; Nitriles; Pyridines; Pyrrolidines; Small molecules
  • Mechanism of ActionIsocitrate dehydrogenase 1 inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia; Cholangiocarcinoma
  • New Molecular EntityYes

Highest Development Phases

  • PreregistrationAcute myeloid leukaemia
  • Phase IIICholangiocarcinoma
  • Phase IGlioma; Myelodysplastic syndromes; Solid tumours

Most Recent Events

  • 28 Jun 2018Massachusetts General Hospital and Agios Pharmaceuticals plan a phase I trial for Acute myeloid leukaemia; Myelodysplastic syndromes and Chronic myelomonocytic leukaemia (Maintenance therapy) in USA (NCT03564821)
  • 26 Jun 2018Ivosidenib licensed to CStone Pharmaceuticals in China, Hong Kong, Macau and Taiwan
  • 14 Jun 2018Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 23rd Congress of the European Haematology Association (EHA-2018)
Ivosidenib
Ivosidenib.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C28H22ClF3N6O3
Molar mass 582.97 g·mol−1
3D model (JSmol)
///////////////Tibsovo, ivosidenib, fda 2018,  Fast Track, Priority Review ,  Orphan Drug designation, UNII:Q2PCN8MAM6, ивосидениб , إيفوزيدينيب , 艾伏尼布 ,
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BMS-978587


str1

str1

Ido-IN-4.pngFigure imgf000059_0001

BMS-978587

Molecular Formula: C26H35N3O3 CAS 1629125-65-0
Molecular Weight: 437.582

US9675571   PATENT

Inventor James Aaron Balog Audris Huang Bin Chen Libing Chen Steven P. Seitz Amy C. Hart Jay A. Markwalder

AssigneeBristol-Myers Squibb Co Priority date 2013-03-15

IDO-IN-4; 1629125-65-0; SCHEMBL17456163; AKOS030526622; ZINC521836543; CS-5086

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid

(1R,2S)-2-[4-[bis(2-methylpropyl)amino]-3-[(4-methylphenyl)carbamoylamino]phenyl]cyclopropane-1-carboxylic acid

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

BMS-978587 was discovered and developed within Bristol-Myers Squibb as a potent small molecule IDO inhibitor

Tryptophan is an amino acid which is essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine. N-formyl-kynurenine is then metabolized by mutliple steps to eventually produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be preferentially cytotoxic to T-cells. Thus an overexpression of IDO can lead to increased tolerance in the tumor microenvironment. IDO overexpression has been shown to be an independent prognostic factor for decreased survival in patients with melanoma, pancreatic, colorectal and endometrial cancers among others. Moreover, IDO has been found to be implicated in neurologic and psychiatric disorders including mood idsorders as well as other chronic diseases characterized by IDO activation and tryptophan depletiion, such as viral infections, for example AIDS, Alzheimer’s disease, cancers including T-cell leukemia and colon cancer, autimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.

Accordingly, an agent which is safe and effective in inhibiting production of IDO would be a most welcomed addition to the physician’s armamentarium

SYNTHESIS

 

PATENT

https://patents.google.com/patent/US9675571

Figure US09675571-20170613-C00026

Figure US09675571-20170613-C00027

Example 1 Method A Enantiomer 1 and Enantiomer 2 Enantiomer 1: (1R,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure US09675571-20170613-C00039

PATENT

WO2014/150677

https://patents.google.com/patent/WO2014150677A1/en

Example 1- Method A

Enantiomer 1 and Enantiomer 2

Enantiomer 1 : (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000059_0001

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000060_0001

1A. 4-bromo-N,N-diisobutyl-2-nitroaniline

4-bromo-l-fluoro-2 -nitrobenzene (7 g, 31.8 mmol) and diisobutylamine (12.23 ml, 70.0 mmol) were heated at 130 °C for 3 h. It was then cooled to RT, purification via flash chromatography gave 1A (bright red solid, 8.19 g, 24.88 mmol, 78 % yield) LC-MS Anal. Calc’d for Ci4H2iBrN202 328.08, found [M+3] 331.03, Tr = 2.63 min (Method A).

IB. N,N-diisobutyl-2-nitro-4-vinylaniline

To a solution of 1 A (1 g, 3.04 mmol) in ethanol (15.00 mL) and toluene (5 mL) (sonication to break up the solid) was added 2,4,6-trivinyl- 1 ,3 ,5 ,2,4,6-trioxatriborinane pyridine complex (0.589 g, 3.64 mmol) followed by K3PO4 (1.289 g, 6.07 mmol) and water (2.000 mL). The reaction mixture was purged with Argon for 2 min and then Pd (PPh3)4(0.351 g, 0.304 mmol) was added. It was then heated at 80 °C in an oil bath for 8 h. LC-MS indicated completion. It was diluted with EtOAc (10 mL) and water (5 mL) and filtered through a pad of Celite, rinsed with EtOAc (2×30 mL). Aqueous layer was further extracted with EtOAc (2×30 mL), the combined extracts were washed with water, brine, dried over MgS04, filtered and concentrated. Purification via fiash chromatography gave IB (orange oil, 800 mg, 2.89 mmol, 95 % yield). LC-MS Anal. Calc’d for

Ci6H24N202 276.18, found [M+H] 277.34, Tr = 2.41 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 7.73 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 5.63 (dd, J=17.6, 0.4 Hz, 1H), 5.20 (d, J=11.2 Hz, 1H), 3.00 – 2.89 (m, 4H), 1.99 – 1.85 (m, 2H), 0.84 (d, J=6.6 Hz, 12H) IC. Racemic (lR,2S)-ethyl 2-(4-(diisobutylamino)-3 nitrophenyl)

cyclopropanecarboxylate

To a solution of IB (800 mg, 2.61 mmol) in DCM (15 mL) was added rhodium(II) acetate dimer (230 mg, 0.521 mmol) followed by a slow addition of a solution of ethyl diazoacetate (0.811 mL, 7.82 mmol) in CH2CI2 (5.00 mL) over a period of 2 h via a syringe pump. The reaction mixture turned into a dark red solution and it was stirred at RT for extra 1 h. LC-MS indicated the appearance of two peaks with the desired molecular mass, the solvent was removed in vacuo and purification via flash

chromatography gave 1C (cis isomer) (yellow oil, 220 mg, 0.607 mmol, 23.30 % yield) and trans isomer (yellow oil, 300 mg, 0.828 mmol, 31.8 % yield). LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.27, Tr = 2.34 min (cis), 2.42 min (trans) (Method A), cis isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=1.8 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.86 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.53 – 2.44 (m, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.37 – 1.30 (m, 1H), 0.99 (t, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H) trans isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.43 (d, J=2.2 Hz, 1H), 7.17 – 7.11 (m, 1H), 7.08 – 7.03 (m, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.46 (ddd, J=9.2, 6.4, 4.2 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.62 – 1.54 (m, 1H), 1.34 – 1.23 (m, 4H), 0.83 (d, J=6.6 Hz, 12H)

ID. Racemic (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

To a stirred solution of 1C (cis isomer) (220 mg, 0.607 mmol) in EtOAc (6 mL) was added palladium on carbon (64.6 mg, 0.061 mmol) and the suspension was hydrogenated (1 atm, balloon) at RT for 1 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×30 mL). Combined filtrate and rinses were evaporated in vacuo. Purification via flash chromatography gave ID (light yellow oil, 140 mg, 0.421 mmol, 69.4 % yield). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.34, Tr= 2.22 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.64 – 6.59 (m, 1H), 4.06 (s, 2H), 3.87 (qd, J=7.1, 0.9 Hz, 2H), 2.56 (d, J=7.0 Hz, 4H), 2.47 (q, J=8.6 Hz, IH), 2.01 (ddd, J=9.4, 7.8, 5.7 Hz, IH), 1.78 – 1.61 (m, 3H), 1.24 (ddd, J=8.6, 7.9, 5.1 Hz, IH), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Racemic example 1. Racemic (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

To a solution of ID (140 mg, 0.421 mmol) in THF (4mL) was added 1- isocyanato-4-methylbenzene (0.079 mL, 0.632 mmol). The resulting solution was stirred at RT for 3 h. LC-MS indicated completion. The reaction mixture was concentrated and used without purification in the next step. The crude ester (180 mg, 0.387 mmol) was dissolved in THF (4 mL), NaOH (IN aqueous) (1.160 mL, 1.160 mmol) was added. Then MeOH (1 mL) was added to dissolve the precipitate and it turned into a clear yellow solution. After 60 h, reaction was complete by LC-MS. Most MeOH and THF was removed in vacuo and the crude was diluted with 2 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine, dried over Na2S04 and concentrated. Purification via flash chromatography gave racemic example 1 (yellow foam, 110 mg, 0.251 mmol, 65.0 % yield), LC-MS Anal. Calc’d for CzeHssNsOs 437.27, found [M+H] 438.29, Tr = 4.22 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 10.15 (br. s., IH), 7.42 – 7.35 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 3.22 (d, J=6.6 Hz, 4H), 2.54 (q, J=8.6 Hz, IH), 2.31 (s, 3H), 2.16 – 1.98 (m, 3H), 1.61 (dt, J=7.3, 5.6 Hz, IH), 1.40 (td, J=8.3, 5.3 Hz, IH), 1.01 (br. s., 12H)

Example 1, Enantiomer 1 and Enantiomer 2. Chiral separation of racemic example 1 (Method H) gave enantiomer 1 Tr = 9.042 min (Method J). [a]24 D = -11.11 (c 7.02 mg/mL, MeOH) and enantiomer 2 Tr = 10.400 min (Method J). [a]24 D = + 11.17 (c 7.02 mg/mL, MeOH) as single enantiomers. Absolute stereochemistry was confirmed in example 1 method B.

Enantiomer 1 : LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.25, Tr= 4.19 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.12 (d, J=1.3 Hz, IH), 7.97 (s, IH), 7.20 (d, J=8.4 Hz, 2H), 7.14 – 7.07 (m, 2H), 7.02 (t, J=7.7 Hz, 2H),

6.89 (dd, J=8.1, 1.5 Hz, IH), 2.60 (q, J=8.6 Hz, IH), 2.50 (d, J=7.0 Hz, 4H), 2.32 (s, 3H), 2.13 – 2.04 (m, 1H), 1.71 – 1.55 (m, 3H), 1.35 (td, J=8.3, 5.1 Hz, 1H), 0.76 (dd, J=6.6, 2.2 Hz, 12H)

Enantiomer 2: LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.24, Tr= 4.18 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.11 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.23 – 7.16 (m, 2H), 7.13 – 7.07 (m, 2H), 7.05 – 6.98 (m, 2H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 2.59 (q, J=8.7 Hz, 1H), 2.49 (d, J=7.3 Hz, 4H), 2.32 (s, 3H), 2.12 – 2.03 (m, 1H), 1.70 – 1.53 (m, 3H), 1.34 (td, J=8.2, 5.0 Hz, 1H), 0.75 (dd, J=6.6, 2.0 Hz, 12H) Example 1 – Method B

Enantiomer 1 and Enantiomer 2

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000063_0001

IE. 4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline

1A (10 g, 30.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(l,3,2-dioxaborinane) (7.55 g, 33.4 mmol), PdCl2(dppf)- CH2C12 adduct (0.556 g, 0.759 mmol) and potassium acetate

(8.94 g, 91 mmol) were combined in a round bottom flask, and DMSO (100 mL) was added. It was vacuated and back-filled with N2 three times, then heated at 80 °C for 8 h. Reaction was complete by LC-MS. Cooled to RT and passed through a short plug of silica gel, rinsed with a mixture of Hexane/EtOAc (5: 1) (3×100 mL). After removing the solvent in vacuo, purification via flash chromatography gave IE (orange oil, 9 g, 22.36 mmol, 73.6 % yield), LC-MS Anal. Calc’d for C19H31BN2O4 362.24, found [M+H] 295.18 (mass of boronic acid), Tr = 3.65 min (Method A). 1H NMR (400MHz,

CHLOROFORM-d) δ 8.13 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 3.75 (s, 4H), 3.00 – 2.92 (m, 4H), 1.93 (dquin, J=13.5, 6.8 Hz, 2H), 1.02 (s, 6H), 0.93 – 0.79 (m, 12H)

IF. (lS,2R)-ethyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To IE (9 g, 22.36 mmol) in a 500 mL round bottom flask was added 1,4-dioxane (60 mL). After it was dissolved, cesium carbonate (15.30 g, 47.0 mmol) was added. To the suspension was then added water (30 mL) slowly. It became an homogeneous solution. Enantiopure (lR,2R)-ethyl 2-iodocyclopropanecarboxylate (5.90 g, 24.59 mmol) (For synthesis see Organic Process Research & Development 2004, 8, 353-359 ) was then added. The resulting mixture was purged with nitrogen for 25 min. Then PdCl2(dppf)-

CH2C12 adduct (1.824 g, 2.236 mmol) was added. The reaction mixture was purged with nitrogen for another 10 min. It became dark brown colored solution. This mixture was then stirred under nitrogen at 87 °C for 22 h. LC-MS indicated product formation and depletion of starting material. It was then cooled to RT. After removing solvent under reduced pressure, it was diluted with EtOAc (50 mL) and water (50 mL). Organic layer was separated and the aqueous layer was further extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. Purification via flash chromatography gave IF (dark orange oil, 3.2 g, 8.83 mmol, 39.5 % yield), LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.3, Tr = 3.89 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) 57.65 – 7.60 (m, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.84 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.48 (q, J=8.6 Hz, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.38 – 1.28 (m, 1H), 0.99 (t, J=7.2 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H

IG. (lS,2R)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of IF (5.5 g, 15.17 mmol) in EtOAc (150 mL) was added palladium on carbon (1.615 g, 1.517 mmol) and the suspension was hydrogenated (1 atm, balloon) for 1.5 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×50 mL). Combined filtrate and rinses were concentrated under reduced pressure. Purification via flash chromatography gave 1G (yellow oil, 4.5 g, 13.53 mmol, 89 % yield). LC-MS Anal. Calc’d for

C20H32N2O2 332.25, found [M+H] 333.06, Tr = 2.88 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Example 1 enantiomer 2 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 2 Tr = 10.646 min (Method J). Absolute stereochemistry was confirmed by referring to reference: Organic Process Research & Development 2004, 8, 353-359.

Enantiomer 1 Method B: (lR,2S)-2-(4-(diisobutylamino)-3

tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000065_0001

1H. Single enantiomer (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

1H was prepared following procedures in example 1 enantiomer 2 method B utilizing enantiopure (l S,2S)-ethyl 2-iodocyclopropanecarboxylate. This was obtained through chiral resolution modifying the procedure in Organic Process Research & Development 2004, 8, 353-359, using (i?)-(+)-N-benzyl-a-methylbenzylamine instead of (S)-(-)-N-benzyl-a-methylbenzylamine). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.06, Tr = 2.88 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H).

Note: 1H was also made through chiral separation (Method I) of racemic (1R,2S)- ethyl 2-(3-amino-4-(diisobutylamino)phenyl)cyclopropanecarboxylate. Chiral analytical analysis (Method K) showed 1H as a single enantiomer (99 % ee).

Example 1 enantiomer 1 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A using 1H except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 1 with 97.8% ee (Method J).

Example 1 – Method C

Enantiomer 1

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000066_0001

II. Diastereomer 1: (R)-4-benzyl-3-((lR,2S)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one

Diastereomer 2: (R)-4-benzyl-3-((l S,2R)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one: 1C (1.2 g, 3.31 mmol) was dissolved in THF (20 mL), NaOH (IN aqueous) (8.28 mL, 8.28 mmol) was added. Saw precipitate formed, then MeOH (5.00 mL) was added and it turned into a clear yellow solution. The reaction was monitored by LC-MS. After 24 h, reaction was complete. Most MeOH and THF was removed in vacuo and the crude was diluted with 10 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×30 mL) and the combined organic phase was washed with brine, dried over Na2S04 , filtered and concentrated to give 1.1 g of desired acid as an orange foam. This was used without purification in the subsequent step. To a solution of the crude acid from the previous step (1132 mg, 3.39 mmol) in THF (15 mL) cooled in an ice-water bath was added N-methylmorpholine (0.447 mL, 4.06 mmol) followed by slow addition of pivaloyl chloride (0.500 mL, 4.06 mmol). After stirring in an ice-water bath for 30 min, the reaction mixture was then cooled to -78 °C. In a separate reaction flask, ftBuLi (1.354 mL, 3.39 mmol) was added dropwise to a solution of (R)-4- benzyloxazolidin-2-one (600 mg, 3.39 mmol) in THF (15.00 mL). After 45 min at -78 °C, the solution was cannulated into the -78 °C anhydride mixture. After 30 min, the cooling bath was removed and the solution was allowed to warm to RT. After 1 h, LC-MS indicated completion. The reaction was quenched by addition of saturated aqueous NH4C1. The solution was then partitioned between EtOAc and water. The organic phase was further extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water, brine, dried over MgS04, filtered and concentrated. Purification via flash chromatography gave II Diastereomer 1 (yellow oil, 600 mg, 1.216 mmol, 35.9 % yield). Diastereomer 2 (yellow oil, 450 mg, 0.912 mmol, 26.9 % yield) LC-MS Anal. Calc’d for C28H35N305 493.26, found: [M+H] 494.23, Tr = 5.26 min (Diastereomer 1). Tr = 5.25 min (Diastereomer 2) (Method A). Diastereomer 1 : 1H NMR (400MHz,

CHLOROFORM-d) δ 7.56 (d, J=1.8 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.18 – 7.12 (m, 2H), 7.03 (d, J=8.8 Hz, 1H), 4.37 (ddt, J=9.6, 7.3, 3.6 Hz, 1H), 4.11 – 4.06 (m, 2H), 3.48 – 3.40 (m, 1H), 3.22 (dd, J=13.4, 3.5 Hz, 1H), 2.89 (d, J=7.3 Hz, 4H), 2.77 – 2.66 (m, 2H), 1.97 – 1.81 (m, 3H), 1.52 – 1.44 (m, 1H), 0.82 (d, J=6.6 Hz, 12H); Diastereomer 2: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=2.0 Hz, 1H), 7.36 – 7.19 (m, 4H), 7.09 – 6.97 (m, 3H), 4.45 (ddt, J=10.2, 7.2, 3.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.45 – 3.36 (m, 1H), 2.80 (d, J=7.3 Hz, 4H), 2.52 (dd, J=13.3, 3.2 Hz, 1H), 2.19 (dd, J=13.2, 10.3 Hz, 1H), 2.03 (dt, J=7.2, 5.8 Hz, 1H), 1.72 (dquin, J=13.4, 6.8 Hz, 2H), 1.45 (ddd, J=8.3, 7.3, 5.3 Hz, 1H), 0.64 (dd, J=6.6, 2.0 Hz, 12H) 1 J. (lR,2S)-methyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To a solution of II Diastereomer 1 (460 mg, 0.932 mmol) in THF (6mL) at 0 °C was added hydrogen peroxide (0.228 mL, 3.73 mmol). Then a solution of lithium hydroxide monohydrate (44.6 mg, 1.864 mmol) in water (2.000 mL) was added to the cold THF solution and stirred for 6 h. LC-MS indicated completion, then 2 mL of saturated aqueous Na2S03 was added followed by 3 mL of saturated aqueous NaHC03. The mixture was concentrated to remove most of the THF. The solution was then diluted with 5 mL of water. The aqueous solution was acidified with 1 N aqueous HC1 and extracted with EtOAc (3×20 mL). The combined organic extracts was washed with water, brine, dried over MgS04, filtered and concentrated to give 300 mg acid. To a solution of the crude acid from previous step (300 mg, 0.897 mmol) in MeOH (10 mL) was added 6 drops of concentrated H2SO4. The resulting solution was stirred at 50 °C for 6 h. After LC-MS indicated completion, solvent was removed under reduced pressure. It was then diluted with 5 mL of water, the aqueous layer was then extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water, brine, dried with Na2S04, filtered and concentrated. Purification via flash chromatography gave 1J (orange oil, 260 mg, 0.746 mmol, 83 % yield). LC-MS Anal. Calc’d for Ci9H28N204 348.20, found:

[M+H] 349.31 , Tr = 3.87 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ

7.66 – 7.61 (m, 1H), 7.31 – 7.25 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.47 (s, 3H), 2.90 (d, J=7.3 Hz, 4H), 2.54 – 2.44 (m, 1H), 2.14 – 2.04 (m, 1H), 1.89 (dquin, J=13.5, 6.8 Hz, 2H),

1.67 (dt, J=7.5, 5.5 Hz, 1H), 1.42 – 1.31 (m, 1H), 0.83 (dd, J=6.6, 1.1 Hz, 12H)

IK. (lR,2S)-methyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of 1 J (100 mg, 0.287 mmol) in EtOAc (5mL) was added palladium on carbon (30.5 mg, 0.029 mmol) and the suspension was hydrogenated (1 atm, balloon) for 2 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (20 mL). Combined filtrate and rinses were concentrated. Purification via flash chromatography gave IK (yellow oil, 90 mg, 0.287 mmol, 99 % yield). LC-MS Anal. Calc’d for Ci9H3oN202 318.23, found:

[M+H] 319.31 , Tr = 2.72 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.60 (dd, J=8.1 , 1.5 Hz, 1H), 4.08 (br. s., 2H), 3.42 (s, 3H), 2.58 (d, J=7.0 Hz, 4H), 2.52 – 2.42 (m, 1H), 2.09 – 1.98 (m, 1H), 1.79 – 1.59 (m, 3H), 1.32 – 1.22 (m, 1H), 0.94 – 0.84 (m, 12H)

Enantiomer 1 was prepared following the urea formation and saponification procedure in racemic example 1 method A. Chiral analytical analysis verified it was enantiomer 1 with 98.1% ee (Method J).

Example 1 – Method C Enantiomer 2

(lS,2R)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000069_0001

Example 1 Enantiomer 2 was prepared following the procedure for Example 1 enantiomer 1 method C using diastereomer 2 instead of diastereomer 1. Chiral analytical analysis verified it was enantiomer 2 with 94.0% ee (Method J).

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00171

Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid

 Chemical Development and API SupplyBiocon Bristol-Myers Squibb Research and Development CenterBiocon Park, Jigani Link Road, Bommasandra IV, Bangalore-560099, India
 Chemical and Synthetic DevelopmentBristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00171
*E-mail: vaidy@bms.com.
Abstract Image

A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography.

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid (1)

………… afford 1 as a white solid (510 g, 99.05 HPLC area % purity, 96.0% potency, 60% yield; Pd content: <10 ppm).
1H NMR (300 MHz, DMSO-d6) 11.83 (br s, 1H), 9.30 (s, 1H), 7.90 (d, 1H, J = 1.5 Hz), 7.82 (s, 1H), 7.35–7.37 (d, 2H, J = 8.1 Hz), 7.06–7.10 (q, 3H, J = 2.1, 6.3, and 2.1 Hz), 6.78–6.80 (t, 1H, J = 6.3 and 1.8 Hz), 2.50–2.72 (m, 4H), 2.25 (s, 3H), 1.934–2.01 (m, 1H), 1.59–1.65 (m, 2H), 1.20–1.41 (m, 2H), 0.81(m, 13H);
13C NMR (100 MHz, DMSO-d6) 172.2, 153.0, 139.0, 137.8, 135.2, 133.1, 131.2, 129.6, 123.0, 122.1, 121.4, 119.4, 63.6, 26.3, 25.3, 21.9, 21.6, 20.8, 11.4.
HRMS (ESI) m/zcalcd for C26H36N3O3 [M + H]+ 438.2757, found 438.2714.

REF

(a) Balog, J. A.Huang, A.Chen, B.Chen, L.Seitz, P.Hart, A. C.Markwalder, J. A. Preparation of cycloalkylaryl amide compounds as indoleamine 2,3-dioxygenase and therapeutic uses thereof, PCT Int. Appl. 2014WO 2014150677A1 20140925.

(b) Balog, J. A.Cherney, E. C.Guo, W.Huang, A.Markwalder, J. A.Seitz, S. P.Shan, W.Williams, D. K.Murugesan, N.Nara, S.Jethanand; Preparation of benzenediamine derivatives as inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer, PCT Int. Appl. 2016WO 2016161269A1 20161006.

(c) Markwalder, J. A.Seitz, S. P.Hart, A.Nation, A.Balog, A.Vite, G.Borzilleri, R.Jure-Kunkel, M.Chen, B.Chen, L.Newitt, J.Lu, H.Abell, L.Lin, T.-A.Covello, K.Hunt, J.D’Arienzo, C.Fargnoli, J.Ranasinghe, A.Traeger, S. C. Manuscript in preparation.
D
Swift, E. C.Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocentersTetrahedron 2013695799– 5817DOI: 10.1016/j.tet.2013.05.001
E
Proceedings of the National Academy of Sciences of the United States of America2018vol. 115  13p. 3249 – 3254

////////////BMS-978587, IDO-IN-4, 1629125-65-0,  CS-5086, BMS978587, BMS 978587

OC(=O)[C@@H]3C[C@@H]3c2cc(NC(=O)Nc1ccc(C)cc1)c(cc2)N(CC(C)C)CC(C)C

FDA approves first cancer drug Kisqali (ribociclib) through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug


FDA approves first cancer drug through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug

The U.S. Food and Drug Administration today approved Kisqali (ribociclib) in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The FDA also approved Kisqali in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

July 18, 2018

Release

The U.S. Food and Drug Administration today approved Kisqali (ribociclib) in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The FDA also approved Kisqali in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

This is the first approval that FDA has granted as a part of two new pilot programs announced earlier this year that collectively aim to make the development and review of cancer drugs more efficient, while improving FDA’s rigorous standard for evaluating efficacy and safety. With this real-time review, the FDA was able to start evaluating the clinical data as soon as the trial results become available, enabling FDA to be ready to approve the new indication upon filing of a formal application with the Agency.

The first new program, called Real-Time Oncology Review, allows for the FDA to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA. This allows the FDA to begin its analysis of the data earlier, and provide feedback to the sponsor on how they can most effectively analyze the data to answer key regulatory questions. The pilot focuses on early submission of data that are the most relevant to assessing safety and effectiveness of the product. Then, when the sponsor submits the application with the FDA, the review team will already be familiar with the data and in a better position to conduct a more efficient, timely, and thorough review.

The second program is a new templated Assessment Aid that the applicant uses to organize its submission into a structured format to facilitate FDA’s review of the application. By using a structured template, the FDA is able to layer its assessment into the same file submitted by the sponsor, allowing this annotated application to serve as the document that contains the FDA review. This voluntary submission form provides for a more streamlined approach to reviewing data and illustrating FDA’s analysis. It allows for drug reviewers to focus on the key benefit-risk and labeling issues rather than administrative issues.

“With this approval, we’ve demonstrated some of the benefits of the new programs that we’re piloting for our review of cancer drugs, to improve regulatory efficiency while enhancing the process for evaluating the data submitted to us. This shows that, with smart policy approaches, we can gain efficiency while also improving the rigor of our process. These new programs were designed to reduce some of the administrative issues that can add to the time and cost of the review process, including the staffing burdens on the FDA. For example, by analyzing data earlier in the process, before formal submission to the FDA, and evaluating submissions in a structured template, we can make it easier to identify earlier when applications are missing key analysis or information that can delay reviews,” said FDA Commissioner Scott Gottlieb, M.D. “With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information. This enabled our approval less than one month after the June 28 submission date and several months ahead of the goal date.”

These new processes are good for patients, good for health care providers, good for product developers, and good for the FDA, by allowing our staff to have more time to engage with product developers and focus on the key aspects of drug reviews. We can improve efficiency and solidify our gold standard for review.”

Currently the two pilot programs are being used for supplemental applications for already-approved cancer drugs and could later be expanded to original drugs and biologics.

Kisqali was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative breast cancer in post-menopausal women whose cancer is advanced or has spread to other parts of the body.

“The approval adds a new treatment choice for patients with breast cancer,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to bring more treatment options to patients.”

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 266,120 women will be diagnosed with breast cancer this year and 40,920 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The efficacy of Kisqali in combination with an AI for pre/perimenopausal women was demonstrated in a clinical trial of 495 participants who received either Kisqali and an AI or placebo and an AI. All pre- or peri-menopausal patients on this study received ovarian suppression with goserelin. The trial measured progression-free survival (PFS), which is generally the amount of time after the start of this treatment during which the cancer does not substantially grow and the patient is alive. PFS was longer for patients taking Kisqali plus an AI (median PFS of 27.5 months) compared to patients who received placebo plus an AI (median PFS of 13.8 months).

The efficacy of Kisqali in combination with fulvestrant in treating advanced or metastatic breast cancer was demonstrated in a clinical trial that included 726 participants who received either Kisqali and fulvestrant or placebo and fulvestrant. The trial measured PFS, which was longer for patients taking Kisqali plus fulvestrant (median PFS of 20.5 months) compared to patients who received placebo plus fulvestrant (median PFS of 12.8 months).

The common side effects of Kisqali are infections, abnormally low count of a type of white blood cell (neutropenia), a reduction in the number of white cells in the blood (leukopenia), headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash.

Warnings include the risk of a heart problem known as QT prolongation that can cause an abnormal heartbeat and may lead to death, serious liver problems, low white blood cell counts that may result in infections that may be severe, and fetal harm.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

Mercaptamine bitartrate, システアミン , меркаптамин , 巯乙胺


Cysteamine bitartrate.pngImage result for mercaptamine bitartrate

Image result for mercaptamine bitartrate

Mercaptamine bitartrate

2-aminoethanethiol;2,3-dihydroxybutanedioic acid

Molecular Formula: C6H13NO6S
Molecular Weight: 227.231 g/mol

Cystagon; Cysteamine – Mylan/Orphan Europe; Cysteamine bitartrate

Procysbi; CYSTEAMINE BITARTRATE; 27761-19-9; CHEBI:50386; (+/-)-Tartaric Acid

INGREDIENT UNII CAS
Cysteamine Bitartrate QO84GZ3TST 27761-19-9
Cysteamine Hydrochloride IF1B771SVB 156-57-0

Cysteamine bitartrate is a mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.

Cysteamine Bitartrate is an aminothiol salt used in the treatment of nephropathic cystinosis. Cysteamine bitartrate enters the cell and reacts with cystine producing cysteineand cysteinecysteamine mixed disulfide compound, both of which, unlike cystine, can pass through the lysosomal membrane. This prevents the accumulation of cystinecrystals in the lysosomes of patients with cystinosis, which can cause considerable damage and eventual destruction of the cells, particularly in the kidneys. (NCI05)

Cysteamine is a simple aminothiol molecule that is used to treat nephropathic cystinosis, due to its ability to decrease the markedly elevated and toxic levels of intracellular cystine that occur in this disease and cause its major complications. Cysteamine has been associated with serum enzyme elevations when given intravenously in high doses, but it has not been shown to cause clinically apparent acute liver injury.

Given intravenously or orally to treat radiation sickness. The bitartrate salts (Cystagon® and Procysbi) have been used for the oral treatment of nephropathic cystinosis and cystinurea. The hydrochloride salt (Cystaran™) is indicated for the treatment of corneal cystine crystal accumulation in cystinosis patients.

  • OriginatorMylan
  • DeveloperAlphapharm; Mylan
  • ClassMercaptoethylamines; Small molecules; Sulfhydryl compounds
  • Mechanism of ActionGlutathione synthase stimulants

Highest Development Phases

  • MarketedNephropathic cystinosis
  • DiscontinuedUnspecified

Most Recent Events

  • 09 Apr 2018Mercaptamine bitartrate licensed to Recordati worldwide
  • 26 Oct 2017Chemical structure information added
  • 31 Dec 2008Mercaptamine bitartrate oral is still in phase II/III trials for Undefined indication in European Union

DESCRIPTION: CYSTAGON® (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON® is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C2H7NS · C4H6O6. It has the following chemical structure:

str1

Cysteamine is a medication intended for a number of indications, and approved by the FDA to treat cystinosis.

It is stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups. Cysteamine is a white, water-soluble solid. It is often used as salts of the ammonium derivative [HSCH2CH2NH3]+[1] including the hydrochloride, phosphocysteamine, and bitartrate.[2]

Cysteamine molecule is biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermedia pantetheineis broken down into cysteamine and pantothenic acid.[2] It is the biosynthetic precursor to the neurotransmitter hypotaurine.[3][4]

Medical uses

Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.[5][6][7][8][9]

Adverse effects

Topical use

The most important adverse effect related to topical use might be skin irritation.

Oral use

The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levelselevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.[6]

The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levelselevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.

Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.[6]

The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.[7][8]

For eye drops, the most common adverse effects are sensitivity to light, redness, and eye pain, headache, and visual field defects.[8]

Interactions

There are no drug interactions for normal capsules or eye drops,[7][8] but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly.[6] It doesn’t inhibit any cytochrome P450 enzymes.[6]

Pharmacology

People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells.[5] Cysteamine enters lysosomes and converts cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome.[6]

Biological function

Cysteamine also promotes the transport of L-cysteine into cells, that can be further used to synthesize glutathione, which is one of the most potent intracellular antioxidants.[4]

Cysteamine is used as a drug for the treatment of cystinosis; it removes cystine that builds up in cells of people with the disease.[10]

History

First evidence regarding the therapeutic effect of cysteamine on cystinosis dates back to 1950s. Cysteamine was first approved as a drug for cystinosis in the US in 1994.[6] An extended release form was approved in 2013.[11]

Society and culture

It is approved by FDA and EMA.[5][6]

In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year.[11]

Research

It was studied in in vitro and animal models for radiation protection in the 1950s, and in similar models from the 1970s onwards for sickle cell anemia, effects on growth, its ability to modulate the immune system, and as a possible inhibitor of HIV.[2]

In the 1970s it was tested in clinical trials for Paracetamol toxicity which it failed, and in clinical trials for systemic lupus erythematosus in the 1990s and early 2000s, which it also failed.[2]

Clinical trials in Huntington’s disease were begun in the 1990s and were ongoing as of 2015.[2][12]

As of 2013 it was in clinical trials for Parkinson’s diseasemalaria, radiation sickness, neurodegenerative disorders, neuropsychiatric disorders, and cancer treatment.[10][2]

It has been studied in clinical trials for pediatric nonalcoholic fatty liver disease[13]

Horizon Pharma , following the acquisition of Raptor Pharmaceuticals (previously through its Bennu Pharmaceuticals subsidiary, and following its acquisition of Encode Pharmaceuticals , which licensed the drug from the University of California )) has developed and launched DR Cysteamine (EC Cysteamine; Procysbi), a methyl-CpG binding protein 2 (MECP2) gene modulating, oral delayed-release (DR), enteric-coated (EC), bitartrate salt formulation of mercaptamine (cysteamine).

PRODUCT PATENT, WO2007089670 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007089670

hold SPC protection in most of the EU states until September 2028, and expire in the US in July 2037. In July 2018, the US FDA’s Orange Book was seen to list a patent covering product ( US8026284 and US9173851 ) of cysteamine bitartrate, that is due to expire in September 2027 and December 2034, respectively.

Cystinosis is a rare, autosomal recessive disease caused by intra-lysosomal accumulation of the amino acid cystine within various tissues, including the spleen, liver, lymph nodes, kidney, bone marrow, and eyes. Nephropathic cystinosis is associated with kidney failure that
necessitates kidney transplantation. To date, the only specific treatment for nephropathic cystinosis is the sulfhydryl agent, cysteamine. Cysteamine has been shown to lower intracellular cystine levels, thereby reducing the rate of progression of kidney failure in children.
[0004] Cysteamine, through a mechanism of increased gastrin and gastric acid production, is ulcerogenic. When administered orally to children with cystinosis, cysteamine has also been shown to cause a 3 -fold increase in gastric acid production and a 50% rise of serum gastrin levels. As a consequence, subjects that use cysteamine suffer
gastrointestinal (GI) symptoms and are often unable to take cysteamine regularly or at full dose .

[0005] To achieve sustained reduction of leukocyte cystine levels, patients are normally required to take oral cysteamine every 6 hours, which invariably means having to awaken from sleep. However, when a single dose of
cysteamine was administered intravenously the leukocyte cystine level remained suppressed for more than 24 hours, possibly because plasma cysteamine concentrations were higher and achieved more rapidly than when the drug is administered orally. Regular intravenous administration of cysteamine would not be practical. Accordingly, there is a need for formulations and delivery methods that would result in higher plasma, and thus intracellular, concentration as well as decrease the number of daily doses and therefore improve the quality of life for patients.

PATENT

US-20180193292

Process for the preparation of cysteamine bitartrate . Represents the first patenting to be seen from Lupin Limited on cysteamine bitartrate.

Cysteamine bitartrate (I) is a cystine depleting agent which lower the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport, it is indicated for the management of nephropathic cystinosis in children and adults. Cysteamine bitartrate (I) is simplest stable aminothiol salt and has the following structural formula:

 The application WO 2014204881 provides pharmaceutical composition of cysteamine bitrate and another application WO 2007089670 provides method of administrating cysteamine and pharmaceutically salts and method of treatment thereof.

Examples

1. Preparation of Cysteamine Bitartrate.

 A mixture of ethanol (1000 ml), butylated hydroxy anisole (1 g) and cysteamine hydrochloride (100 g) was stirred and cooled to 5 to 10° C. To this mixture a solution of ethanol (500 ml) and sodium hydroxide (352 g) was added over a period of 30 minutes.
The mixture was stirred at a temperature of 10 to 15° C. for 45 minutes. The mixture was filtered through celite. The filtrate was added to a mixture of ethanol (1250 ml), butylated hydroxy anisole (1 g) and L-(+)-tartaric acid (132 g) at a temperature of 55-60° C. The reaction mixture was stirred at 70-75° C. for 45 minutes. The mixture was cooled to 20-30° C. The solid was filtered, washed with ethanol and dried under vacuum.

2. Purification of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (100 g) and ethanol (5000 ml) was heated to a temperature of 77-82° C. The solution was filtered and the filtrate was cooled to 20 to 30° C. and stirred for 40 minutes. The solid was filtered, washed with ethanol and dried under vacuum. Yield: 80 g; HPLC purity: 99.90%.

3. Preparation of Crystalline Form L1 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −5 to −25° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and dried under vacuum. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 1 was obtained.

4. Preparation of Crystalline Form L2 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g), butylated hydroxy anisole (1.3 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −25 to −30° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and the solid was dried under 800-900 mm/Hg of vacuum at 35-40° C. for 5 hours. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 2 was obtained.

PATENT

WO 2014204881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014204881

PATENTS
EP3308773A1 *2016-10-112018-04-18Recordati Industria Chimica E Farmaceutica SPAFormulations of cysteamine and cysteamine derivatives
Family To Family Citations
JP2016523364A *2013-06-172016-08-08ラプター ファーマシューティカルズ インコーポレイテッドシステアミン組成物の分析方法
WO2017087532A1 *2015-11-162017-05-26The Regents Of The University Of CaliforniaMethods of treating non-alcoholic steatohepatitis (nash) using cysteamine compounds
WO2017157922A12016-03-182017-09-21Recordati Industria Chimica E Farmaceutica S.P.A.Prolonged release pharmaceutical composition comprising cysteamine or salt thereof, 
KR20167000255A2014-06-17서방성 시스테아민 비드 투약 형태
JP2016521489A2014-06-17
CN 2014800346472014-06-17延迟释放型半胱胺珠粒调配物,以及其制备及使用方法
EP201408131322014-06-17Delayed release cysteamine bead formulation
CA 29147702014-06-17Delayed release cysteamine bead formulation, and methods of making and using same

References

  1. Jump up^ Reid, E. Emmet (1958). Organic Chemistry of Bivalent Sulfur1. New York: Chemical Publishing Company, Inc. pp. 398–399.
  2. Jump up to:a b c d e f Besouw, M; Masereeuw, R; van den Heuvel, L; Levtchenko, E (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today18 (15–16): 785–92. doi:10.1016/j.drudis.2013.02.003PMID 23416144.
  3. Jump up^ Singer, Thomas P (1975). “Oxidative Metabolism of Cysteine and Cystine”. In Greenberg, David M. Metabolic pathways Vol. 7. Metabolism of sulfur compounds (3rd ed.). New York: Academic Press. p. 545. ISBN 9780323162081.
  4. Jump up to:a b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003ISSN 1878-5832PMID 23416144.
  5. Jump up to:a b c Nesterova, Galina; Gahl, William A. (October 6, 2016). “Cystinosis”GeneReviews. University of Washington, Seattle.
  6. Jump up to:a b c d e f g h “US Label: Cysteamine bitartrate delayed-release capsules” (PDF). FDA. August 2015.
  7. Jump up to:a b c “US Label: Cysteamine bitartrate capsules” (PDF). FDA. June 2007.
  8. Jump up to:a b c d “US Label: Cysteamine ophthalmic solution” (PDF). FDA. October 2012.
  9. Jump up^ Shams, F; Livingstone, I; Oladiwura, D; Ramaesh, K (10 October 2014). “Treatment of corneal cystine crystal accumulation in patients with cystinosis”Clinical ophthalmology (Auckland, N.Z.)8: 2077–84. doi:10.2147/OPTH.S36626PMC 4199850Freely accessiblePMID 25336909.
  10. Jump up to:a b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”Drug Discovery Today18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003ISSN 1878-5832PMID 23416144.
  11. Jump up to:a b Pollack, Andrew (30 April 2013). “F.D.A. Approves Raptor Drug for Form of Cystinosis”The New York Times.
  12. Jump up^ Shannon, KM; Fraint, A (15 September 2015). “Therapeutic advances in Huntington’s Disease”. Movement disorders : official journal of the Movement Disorder Society30 (11): 1539–46. doi:10.1002/mds.26331PMID 26226924.
  13. Jump up^ Mitchel, EB; Lavine, JE (November 2014). “Review article: the management of paediatric nonalcoholic fatty liver disease”Alimentary pharmacology & therapeutics40 (10): 1155–70. doi:10.1111/apt.12972PMID 25267322.
ysteamine
Cysteamine-2D-skeletal.png
Cysteamine 3D ball.png

Skeletal formula (top)
Ball-and-stick model of the cysteamine
Clinical data
Synonyms 2-Aminoethanethiol
β-Mercaptoethylamine
2-Mercaptoethylamine
Decarboxycysteine
Thioethanolamine
Mercaptamine
License data
Identifiers
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.421 Edit this at Wikidata
Chemical and physical data
Formula C2H7NS
Molar mass 77.15 g·mol−1
Melting point 95 to 97 °C (203 to 207 °F)
Title: Cysteamine
CAS Registry Number: 60-23-1
CAS Name: 2-Aminoethanethiol
Additional Names: mercaptamine; b-mercaptoethylamine; 2-aminoethyl mercaptan; thioethanolamine; decarboxycysteine; MEA; mercamine
Manufacturers’ Codes: L-1573
Trademarks: Becaptan (Labaz); Lambratene (formerly) (Cilag Italiano)
Molecular Formula: C2H7NS
Molecular Weight: 77.15
Percent Composition: C 31.14%, H 9.15%, N 18.16%, S 41.56%
Line Formula: HSCH2CH2NH2
Literature References: A sulfhydryl compound with a variety of biological effects. Prepn: Gabriel, Leupold, Ber. 31, 2837 (1898); Knorr, Rössler, ibid. 36, 1281 (1903); Mills, Jr., Bogart, J. Am. Chem. Soc. 62, 1173 (1940); Wenker, ibid. 57, 2328 (1935); D. A. Shirley, Preparation of Organic Intermediates (Wiley, New York, 1951) p 189. Use in treatment of paracetamol (acetaminophen) poisoning: L. F. Prescott et al., Lancet 2, 109 (1976); A. L. Harris, Br. Med. J. 284, 825 (1982). Effects in nephropathic cystinosis: M. Yudkoff et al., N. Engl. J. Med. 304, 141 (1981). Radioprotective effects: R. P. Bird, Radiat. Res. 72, 290 (1980); C. J. Koch, R. L. Howell, ibid. 87, 265 (1981). Cysteamine has been shown to be a duodenal ulcerogen in rats: H. Selye, S. Szabo, Nature 244,458 (1973); S. Szabo, Am. J. Pathol. 93, 273 (1978); P. Kirkegaard et al., Scand. J. Gastroenterol. 15, 621 (1980). Review: S. Szabo, Lab. Invest. 51, 121 (1984). It has also been found to deplete somatostatin concentration: S. Szabo, S. Reichlein, Endocrinology 109, 2255 (1981); S. M. Sagar et al., J. Neurosci. 2, 225 (1982). In pituitary tissue, cysteamine is a potent depletor of prolactin concentrations in vivo and in vitro: W. J. Millard et al., Science 217, 452 (1982). Toxicity studies: E. Beccari et al.,Arzneim.-Forsch. 5, 421 (1955); D. L. Klayman et al., J. Med. Chem. 12, 510 (1969); P. K. Srivastava, L. Field, ibid. 18, 798 (1975).
Properties: Crystals by sublimation in vacuo. Disagreeable odor. mp 97-98.5°. Oxidizes to cystamine on standing in air. Freely sol in water, alkaline reaction. LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field).
Melting point: mp 97-98.5°
Toxicity data: LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field)
Derivative Type: Hydrochloride
Molecular Formula: C2H7NS.HCl
Molecular Weight: 113.61
Percent Composition: C 21.14%, H 7.10%, N 12.33%, S 28.22%, Cl 31.21%
Properties: Crystals from alc, mp 70.2-70.7°. Sol in water, alcohol. LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari).
Melting point: mp 70.2-70.7°
Toxicity data: LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari)
Use: Experimentally as a radioprotective agent and to produce acute and chronic duodenal ulcers in rats.
Therap-Cat: Antidote to acetaminophen.
Keywords: Antidote (Acetaminophen Poisoning)

///////////Mercaptamine bitartrate, Cystagon, Cysteamine,  Cysteamine bitartrate, Mercaptamine,, システアミン , меркаптамин ,  巯乙胺

C(CS)N.C(C(C(=O)O)O)(C(=O)O)O

National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India


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DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

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////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO

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FDA approves the first drug TPOXX (tecovirimat) with an indication for treatment of smallpox


WATCH OUT FOR CORRECT FORMATTING TEXT AND STRUCTURE BOTH IN 2-3 DAYS

ChemSpider 2D Image | Tecovirimat | C19H15F3N2O3

FDA approves the first drug with an indication for treatment of smallpox

The U.S. Food and Drug Administration today approved TPOXX (tecovirimat), the first drug with an indication for treatment of smallpox. Though the World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980, there have been longstanding concerns that smallpox could be used as a bioweapon.
“To address the risk of bioterrorism, Congress has taken steps to enable the development and approval of countermeasures to thwart pathogens that could be employed as weapons. Today’s approval provides an important milestone in these efforts. This new treatment affords us an additional option should smallpox ever be used as a bioweapon,” said FDA Commissioner Scott Gottlieb, M.D. “This is the first product to be awarded a Material Threat Medical Countermeasure priority review voucher.  Today’s action reflects the FDA’s commitment to ensuring that the U.S. is prepared for any public health emergency with timely, safe and effective medical products.”

July 13, 2018

Release

The U.S. Food and Drug Administration today approved TPOXX (tecovirimat), the first drug with an indication for treatment of smallpox. Though the World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980, there have been longstanding concerns that smallpox could be used as a bioweapon.

“To address the risk of bioterrorism, Congress has taken steps to enable the development and approval of countermeasures to thwart pathogens that could be employed as weapons. Today’s approval provides an important milestone in these efforts. This new treatment affords us an additional option should smallpox ever be used as a bioweapon,” said FDA Commissioner Scott Gottlieb, M.D. “This is the first product to be awarded a Material Threat Medical Countermeasure priority review voucher. Today’s action reflects the FDA’s commitment to ensuring that the U.S. is prepared for any public health emergency with timely, safe and effective medical products.”

Prior to its eradication in 1980, variola virus, the virus that causes smallpox, was mainly spread by direct contact between people. Symptoms typically began 10 to 14 days after infection and included fever, exhaustion, headache and backache. A rash initially consisting of small, pink bumps progressed to pus-filled sores before finally crusting over and scarring. Complications of smallpox could include encephalitis (inflammation of the brain), corneal ulcerations (an open sore on the clear, front surface of the eye) and blindness.

TPOXX’s effectiveness against smallpox was established by studies conducted in animals infected with viruses that are closely related to the virus that causes smallpox, and was based on measuring survival at the end of the studies. More animals treated with TPOXX lived compared to the animals treated with placebo. TPOXX was approved under the FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support an FDA approval when it is not feasible or ethical to conduct efficacy trials in humans.

The safety of TPOXX was evaluated in 359 healthy human volunteers without a smallpox infection. The most frequently reported side effects were headache, nausea and abdominal pain.

The FDA granted this application Fast Track and Priority Review designations. TPOXX also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases and a Material Threat Medical Countermeasure Priority Review Voucher, which provides additional incentives for certain medical products intended to treat or prevent harm from specific chemical, biological, radiological and nuclear threats.

The FDA granted approval of TPOXX to SIGA Technologies Inc.

TPOXX was developed in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA).

Tecovirimat

Tecovirimat.svg

 

Figure US08802714-20140812-C00014

Tecovirimat

4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop(f)isoindol-2(1H)-yl)-benzamide

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

4 -trifluoromethyl -N- (3, 3a, 4, 4a, 5, 5a, 6, 6a- octahydro-1, 3 -dioxo-4, 6 -ethenocycloprop [f] isoindol -2 ( 1H) -yl ) – benzamide

Details

NDA FILED IN  US

2006 ORPHAN DRUG DESIGNATION IN US FOR SMALL POX

2010 ORPHAN DRUG DESIGNATION IN US FOR ORTHOPOX VIRUS

A core protein cysteine protease inhibitor potentially for treatment of smallpox infection.

SIGA TECHNOLOGIES INNOVATOR
SIGA-246; ST-246

CAS No. 869572-92-9

C19H15F3N2O3,

376.32921 g/mol

The Orthopox genus (Orthopoxyiridae) is a member of the Poxyiridae family and the Choropoxivirinae subfamily. The genus consists of numerous viruses that cause significant disease in human and animal populations. Viruses in the orthopox genus include cowpox, monkeypox, vaccina, and variola (smallpox), all of which can infect humans.

The smallpox (variola) virus is of particular importance. Recent concerns over the use of smallpox virus as a biological weapon has underscored the necessity of developing small molecule therapeutics that target orthopoxviruses. Variola virus is highly transmissible and causes severe disease in humans resulting in high mortality rates (Henderson et al. (1999) JAMA. 281:2127-2137). Moreover, there is precedent for use of variola virus as a biological weapon. During the French and Indian wars (1754-1765), British soldiers distributed blankets used by smallpox patients to American Indians in order to establish epidemics (Stern, E. W. and Stern A. E. 1945. The effect of smallpox on the destiny of the Amerindian. Boston). The resulting outbreaks caused 50% mortality in some Indian tribes (Stern, E. W. and Stern A. E.). More recently, the soviet government launched a program to produce highly virulent weaponized forms of variola in aerosolized suspensions (Henderson, supra). Of more concern is the observation that recombinant forms of poxvirus have been developed that have the potential of causing disease in vaccinated animals (Jackson et al. (2001) J. Virol., 75:1205-1210).

The smallpox vaccine program was terminated in 1972; thus, many individuals are no longer immune to smallpox infection. Even vaccinated individuals may no longer be fully protected, especially against highly virulent or recombinant strains of virus (Downie and McCarthy. (1958) J. Hyg. 56:479-487; Jackson, supra). Therefore, mortality rates would be high if variola virus were reintroduced into the human population either deliberately or accidentally.

Variola virus is naturally transmitted via aerosolized droplets to the respiratory mucosa where replication in lymph tissue produces asymptomatic infection that lasts 1-3 days. Virus is disseminated through the lymph to the skin where replication in the small dermal blood vessels and subsequent infection and lysis of adjacent epidermal cells produces skin lesions (Moss, B. (1990) Poxyiridae and Their Replication, 2079-2111. In B. N. Fields and D. M. Knipe (eds.), Fields Virology. Raven Press, Ltd., New York). Two forms of disease are associated with variola virus infection; variola major, the most common form of disease, which produces a 30% mortality rate and variola minor, which is less prevalent and rarely leads to death (<1%). Mortality is the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse, that can be exacerbated by clotting defects in the rare hemorrhagic type of smallpox (Moss, supra).

A recent outbreak of monkeypox virus underscores the need for developing small molecule therapeutics that target viruses in the orthpox genus. Appearance of monkeypox in the US represents an emerging infection. Monkeypox and smallpox cause similar diseases in humans, however mortality for monkeypox is lower (1%).

Vaccination is the current means for preventing orthopox virus disease, particularly smallpox disease. The smallpox vaccine was developed using attenuated strains of vaccinia virus that replicate locally and provide protective immunity against variola virus in greater than 95% of vaccinated individuals (Modlin (2001) MMWR (Morb Mort Wkly Rep) 50:1-25). Adverse advents associated with vaccination occur frequently (1:5000) and include generalized vaccinia and inadvertent transfer of vaccinia from the vaccination site. More serious complications such as encephalitis occur at a rate of 1:300,000, which is often fatal (Modlin, supra). The risk of adverse events is even more pronounced in immunocompromised individuals (Engler et al. (2002) J Allergy Clin Immunol. 110:357-365). Thus, vaccination is contraindicated for people with AIDS or allergic skin diseases (Engler et al.). While protective immunity lasts for many years, the antibody response to smallpox vaccination is significantly reduced 10 to 15 years post inoculation (Downie, supra). In addition, vaccination may not be protective against recombinant forms of ortho poxvirus. A recent study showed that recombinant forms of mousepox virus that express IL-4 cause death in vaccinated mice (Jackson, supra). Given the side effects associated with vaccination, contraindication of immunocompromised individuals, and inability to protect against recombinant strains of virus, better preventatives and/or new therapeutics for treatment of smallpox virus infection are needed.

Vaccinia virus immunoglobulin (VIG) has been used for the treatment of post-vaccination complications. VIG is an isotonic sterile solution of immunoglobulin fraction of plasma derived from individuals who received the vaccinia virus vaccine. It is used to treat eczema vaccinatum and some forms of progressive vaccinia. Since this product is available in limited quantities and difficult to obtain, it has not been indicated for use in the event of a generalized smallpox outbreak (Modlin, supra).

Cidofovir ([(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine][HPMPC]) is a nucleoside analog approved for treatment of CMV retinitis in AIDS patients. Cidofovir has been shown to have activity in vitro against a number of DNA containing viruses including adenovirus, herpesviruses, hepadnaviruses, polyomaviruses, papillomaviruses, and ortho poxviruses (Bronson et al. (1990) Adv. Exp. Med. Biol. 278:277-83; De Clercq et al. (1987) Antiviral Res. 8:261-272; de Oliveira et al. (1996) Antiviral Res. 31:165-172; Snoeck et al. (2001) Clin Infect. Dis. 33:597-602). Cidofovir has also been found to inhibit authentic variola virus replication (Smee et al. (2002) Antimicrob. Agents Chemother. 46:1329-1335).

However, cidofovir administration is associated with a number of issues. Cidofovir is poorly bioavailable and must be administered intravenously (Lalezari et al. (1997) Ann. Intern. Med. 126:257-263). Moreover, cidofovir produces dose-limiting nephrotoxicity upon intravenous administration (Lalezari et al.). In addition, cidofovir-resistance has been noted for multiple viruses. Cidofovir-resistant cowpox, monkeypox, vaccinia, and camelpox virus variants have been isolated in the laboratory by repeated passage in the presence of drug (Smee, supra). Cidofovir-resistance represents a significant limitation for use of this compound to treat orthopoxvirus replication. Thus, the poor bioavailability, need for intravenous administration, and prevalence of resistant virus underscores the need for development of additional and alternative therapies to treat orthopoxvirus infection

In addition to viral polymerase inhibitors such as cidofovir, a number of other compounds have been reported to inhibit orthopoxvirus replication (De Clercq. (2001) Clin Microbiol. Rev. 14:382-397). Historically, methisazone, the prototypical thiosemicarbazone, has been used in the prophylactic treatment of smallpox infections (Bauer et al. (1969) Am. J. Epidemiol. 90:130-145). However, this compound class has not garnered much attention since the eradication of smallpox due to generally unacceptable side effects such as severe nausea and vomiting. Mechanism of action studies suggest that methisazone interferes with translation of L genes (De Clercq (2001), supra). Like cidofovir, methisazone is a relatively non-specific antiviral compound and can inhibit a number of other viruses including adenoviruses, picornaviruses, reoviruses, arboviruses, and myxoviruses (Id.).

Another class of compounds potentially useful for the treatment of poxviruses is represented by inhibitors of S-adenosylhomocysteine hydrolase (SAH). This enzyme is responsible for the conversion of S-adenosylhomocysteine to adenosine and homocysteine, a necessary step in the methylation and maturation of viral mRNA. Inhibitors of this enzyme have shown efficacy at inhibiting vaccinia virus in vitro and in vivo (De Clercq et al. (1998) Nucleosides Nucleotides. 17:625-634.). Structurally, all active inhibitors reported to date are analogues of the nucleoside adenosine. Many are carbocyclic derivatives, exemplified by Neplanacin A and 3-Deazaneplanacin A. While these compounds have shown some efficacy in animal models, like many nucleoside analogues, they suffer from general toxicity and/or poor pharmacokinetic properties (Coulombe et al. (1995) Eur. J. Drug Metab Pharmacokinet. 20:197-202; Obara et al. (1996) J. Med. Chem. 39:3847-3852). It is unlikely that these compounds can be administered orally, and it is currently unclear whether they can act prophylactically against smallpox infections. Identification of non-nucleoside inhibitors of SAH hydrolase, and other chemically tractable variola virus genome targets that are orally bioavailable and possess desirable pharmicokinetic (PK) and absorption, distribution, metabolism, elimination (ADME) properties would be a significant improvement over the reported nucleoside analogues. In summary, currently available compounds that inhibit smallpox virus replication are generally non-specific and suffer from use limiting toxicities and/or questionable efficacies.

In U.S. Pat. No. 6,433,016 (Aug. 13, 2002) and U.S. Application Publication 2002/0193443 A1 (published Dec. 19, 2002) a series of imidodisulfamide derivatives are described as being useful for orthopox virus infections.

Synthesis
str2

RAW MATERIAL

Key RM is, 4,6-Etheno-1H-cycloprop[f]isobenzofuran-1,3(3aH)-dione, 3a,4,4a,5,5a,6-hexahydro-, (3aR,4R,4aR,5aS,6S,6aS)-rel

cas  944-41-2, [US7655688]

SCHEMBL3192622.png

Molecular Formula: C11H10O3
Molecular Weight: 190.1953 g/mol
  • 4,6-Etheno-1H-cycloprop[f]isobenzofuran-1,3(3aH)-dione, 4,4a,5,5a,6,6a-hexahydro-, (3aα,4β,4aα,5aα,6β,6aα)-
  • Tricyclo[3.2.2.02,4]non-8-ene-6,7-dicarboxylic anhydride, stereoisomer (8CI)
  • 3,6-Cyclopropylene-Δ4-tetrahydrophthalic anhydride

MP 94-96 °C

Ref, Dong, Ming-xin; European Journal of Medicinal Chemistry 2010, V45(9), Pg 4096-4103

SMILES……….

O=C1OC(=O)[C@H]4[C@@H]1[C@H]3C=C[C@@H]4[C@@H]2C[C@@H]23

SYNTHESIS CONTINUED…….

ST-246

Patent

WO2014028545
 
 
 

The present invention provides a process for making ST-246 outlined in Scheme 1

P = Boc

Scheme 1

The present invention also provides a process for making ST-246 outlined in, Scheme 2

Scheme 2

The present invention further provides a process for making ST-246 outlined in Scheme 3

ST-246

P = Boc

Scheme 3

P = Boc

Scheme 4

The present invention further provides a process for making ST-246 outlined in

Scheme 5

Scheme 5

 

Example 1 : Synthetic Route I:

P = Boc

Scheme 1

Step A. Synthesis of Compound 6 (P = Boc)

To a mixture of compound 3 (5.0 g, 26.3 mmol, synthesized according to WO041 12718) in EtOH (80 mL, EMD, AX0441 -3) was added terf-butyl carbazate 5 (3.65 g, 27.6 mmol, Aldrich, 98%). The reaction mixture was heated to reflux for 4 h under nitrogen atmosphere. LC-MS analysis of the reaction mixture showed less than 5% of compound 3 remained. The reaction mixture was evaporated under reduced pressure. The residue was recrystallized from EtOAc – hexanes, the solid was filtered, washed with hexanes (50 mL) and dried under vacuum to afford compound 6 (3.1 g, 39% yield) as a white solid. The filtrate was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to give an additional 3.64 g (46% yield) of compound 6 as a white solid. Total yield: 6.74 g (84% yield). 1H NMR in CDCI3: δ 6.30 (br s, 1 H), 5.79 (t, 2H), 3.43 (s, 2H), 3.04 (s, 2H), 1 .46 (s, 9H), 1 .06-1 .16 (m, 2H), 0.18-0.36 (m, 2H); Mass Spec: 327.2 (M+Na)+

Step B. Synthesis of Compound 7 (HCI salt)

Compound 6 (3.6 g, 1 1 .83 mmol) was dissolved in /-PrOAc (65 mL, Aldrich, 99.6%). 4M HCI in dioxane (10.4 mL, 41 .4 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight (18 h) under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (15 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .9 g, 67% yield) as a white solid. The filtrate was concentrated to 1/3 its volume and stirred at 10 – 15 °C for 30 min. The solid was filtered, washed with minimal volume of /-PrOAc and dried to afford additional 0.6 g (21 % yield) of compound 7. Total yield: 2.5 g (88% yield). 1 H NMR in DMSO-d6: δ 6.72 (br s, 3H), 5.68 (m, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 1 .07-1 .17 (m, 2H), 0.18-0.29 (m, 1 H), -0.01 -0.07 (m, 1 H); Mass Spec: 205.1 (M+H)+

Step C. Synthesis of ST-246

To a mixture of compound 7 (0.96 g, 4 mmol) in dry dichloromethane (19 mL) was added triethylamine (1 .17 mL, 8.4 mmol, Aldrich) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minutes at 15 – 20 °C, to it was added drop-wise 4-(trifluoromethyl)benzoyl chloride 8 (0.63 mL, 4.2 mmol, Aldrich, 97%) and the reaction mixture was stirred at room temperature overnight (18 h). LC-MS and TLC analysis showed the correct molecular weight and Rf value of ST-246 but the reaction was not complete. Additional 0.3 mL (2 mmol, 0.5 eq) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C. The reaction was then stirred at room temperature overnight (19 h). LC-MS analysis indicated ca. 5% of starting material 7 still remained. The reaction was stopped and dichloromethane (30 mL) was added. The organic phase was washed with water (30 mL), saturated aqueous NH CI (30 mL), water (15 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 -50% EtOAc in hexanes to afford ST-246 (0.34 g, 23% yield) as an off-white solid. Analytical data (1H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent.

Example 2: Synthetic Route II

Scheme 2

Step A. Synthesis of Compound 9

A mixture of compound 4 (2.0 g, 9.8 mmol) and maleic anhydride 2 (0.96 g, 9.8 mmol, Aldrich powder, 95%) in o-xylene (100 mL, Aldrich anhydrous, 97%) was heated to reflux using a Dean-Stark trap apparatus overnight. After 18 h, LC-MS analysis at 215 nm showed the desired product 9 (86%), an uncyclized product (2.6%) and a dimer by-product (1 1 .6%).

Uncyclized product (MS = 303) Dimer by-product (MS = 489)

The reaction mixture was cooled to 45 °C and evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the insoluble solid (mostly uncyclized product) was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 50% EtOAc in hexanes to yield compound 9 (1 .5 g, 54% yield) as an off-white solid. 1 H NMR in CDCI3: δ 8.44 (s, 1 H), 7.91 (d, 2H), 7.68 (d, 2H), 6.88 (s, 2H); Mass Spec: 285.1 (M+H)+

Step B. Synthesis of ST-246 (Route II)

A mixture of compound 9 (0.97 g, 3.4 mmol) and cycloheptatriene 1 (0.51 mL, 4.42 mmol, distilled before use, Aldrich tech 90%) in toluene (50 mL, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 1 .5 h at 95 °C, LC-MS analysis at 254 nm showed 29% conversion to the desired product (endo:exo = 94:6). The resulting solution was continued to be heated at same temperature overnight. After 18 h at 95 °C, LC-MS analysis indicated 75% conversion with an endo:exo ratio of 94:6. The reaction temperature was increased to 1 10 °C and the reaction was monitored. After heating at 1 10 °C for 7 h, LC-MS analysis at 254 nm showed 96.4% conversion to the desired product (endo:exo = 94:6). The volatiles were removed by evaporation under reduced pressure and the reside was purified by column chromatography eluting with 30% EtOAc in hexanes to afford ST-246 (0.29 g, 22.6% yield, HPLC area 99.7% pure and 100% endo isomer) as a white solid. Analytical data (1H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent. An additional 0.5 g of ST-246 (38.9% yield, endo:exo = 97: 3) was recovered from column chromatography. Total Yield: 0.84 g (65.4% yield). 1H NMR of ST-246 exo isomer in CDCI3: δ 8.62 (s, 1 H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1 .17 (s, 2H), 0.24 (q, 1 H), 0.13 (m, 1 H); Mass Spec: 377.1 (M+H)+

Example 3: Synthetic Route III

ST-246 9

P = Boc

Scheme 3

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (15.2 g, 155 mmol, Aldrich powder 95%) and terf-butyl carbazate 5 (20.5 g, 155 mmol, Aldrich, 98%) in anhydrous toluene (150 mL, Aldrich anhydrous) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (20% by HPLC area), imine byproduct (18%) and disubstituted by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to afford compound 10 (5.98 g, 18% yield, HPLC area >99.5% pure) as a white solid. 1 H NMR in DMSO-d6: δ 9.61 (s, 1 H), 7.16 (s, 2H), 1 .42 (s, 9H); Mass Spec: 235.1 (M+Na)+.

duct

C9H12N204 C14H22N405

Mol. Wt.: 212.2 Mol. Wt.: 326.35

Step B. Synthesis of Compound 11 (HCI salt)

Compound 10 (3.82 g, 18 mmol) was dissolved in /-PrOAc (57 mL, Aldrich, 99.6%). 4M HCI in dioxane (15.8 mL, 63 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (24 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (10 mL) and dried at 45 °C under vacuum for 1 h to afford HCI salt of compound 11 (2.39 g, 89% yield) as a white solid. 1 H NMR in CD3OD: δ 6.98 (s, 2H); Mass Spec: 1 13.0 (M+H)+

Step C. Synthesis of Compound 9 (Route III)

To a mixture of compound 11 (1 .19 g, 8 mmol) in dry dichloromethane (24 mL) was added diisopropylethylannine (2.93 mL, 16.8 mmol, Aldrich redistilled grade) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minute at 15 – 20 °C and to it was added 4-(trifluoromethyl)benzoyl chloride 8 (1 .31 mL, 8.8 mmol, Aldrich, 97%) drop-wise. The reaction was stirred at room temperature for 5 h. LC-MS analysis showed the correct MW but the reaction was not complete. Additional 0.48 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C and the reaction mixture was stirred at room temperature overnight (21 h). The reaction was stopped and dichloromethane (50 mL) was added. The organic phase was washed with water (50 mL), saturated aqueous NH4CI (50 mL), water (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford compound 9 (0.8 g, 35% yield) as a light pink solid. Analytical data (1H NMR and LC-MS) were consistent with those of compound 9 obtained in Synthetic Route II.

Step D. Synthesis of ST-246 (Route III)

A mixture of compound 9 (0.5 g, 1 .76 mmol) and cycloheptatriene 1 (0.33 mL, 3.17 mmol, distilled before to use, Aldrich tech 90%) in toluene (10 mL, Aldrich anhydrous) was heated at 1 10 – 1 15 °C under nitrogen atmosphere. After 6 h, LC-MS analysis at 254 nm showed 95% conversion to the desired product (endo:exo = 94:6). The resulting solution was heated at same temperature overnight (22 h). LC-MS analysis at 254 nm showed no starting material 9 remained and the desired product (endo:exo = 93:7). The reaction mixture was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (0.39 g, HPLC area >99.5% pure with a ratio of endo:exo = 99:1 ) as a white solid. Analytical data (1 H NMR, LC-MS and HPLC by co-injection) were compared with those of ST-246 synthesized according to WO041 12718 and were found to be consistent. An additional 0.18 g of ST-246 (HPLC area >99.5% pure, endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 0.57 g (86% yield).

Example 4 ; Synthetic Route IV:

P = Boc

Scheme 4

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (3.4 g, 34.67 mmol, Aldrich powder, 95%) and terf-butyl carbazate 5 (4.6 g, 34.67 mmol, Aldrich, 98%) in anhydrous toluene (51 ml_, Aldrich) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2.5 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (19% HPLC area), imine by-product (18%) and another by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 30% EtOAc in hexanes to afford compound 10 (1 .0 g, 13.6% yield, HPLC area >99% pure) as a white solid. Analytical data (1H NMR and LC-MS) were consistent with those of compound 10 obtained in Synthetic Route III.

Im ine by-product

Mol. Wt.: 212.2

Step B. Synthesis of Compound 6

A mixture of compound 10 (4.4 g, 20.74 mmol) and cycloheptatriene 1 (3.22 mL, 31 .1 mmol, distilled before to use, Aldrich tech 90%) in toluene (88 mL, 20 volume, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 15 h at 95 °C, LC-MS analysis showed 83% conversion to the desired product. The reaction mixture was heated at 105 °C overnight. After total 40 h at 95 – 105 °C, LC-MS analysis at 254 nm showed -99% conversion to the desired product (endo:exo = 93:7). The reaction mixture was concentrated and the crude was purified by column chromatography eluting with 25 – 50 % EtOAc in hexanes to afford compound 6 (2.06 g, 32.6% yield, HPLC area 99.9% pure and 100% endo isomer) as a white solid. 1 H NMR and LC-MS were consistent with those of compound 6 obtained in Synthetic Route I. An additional 4.0 g of 6 (63.4% yield, HPLC area 93% pure with a ratio of endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 6.06 g (96% yield).

Step C. Synthesis of Compound 7 (HCI salt)

Compound 6 (2.05 g, 6.74 mmol) was dissolved in /-PrOAc (26 mL, Aldrich, 99.6%). 4M HCI in dioxane (5.9 mL, 23.58 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (18 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (5 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .57 g, 97% yield) as a white solid. Analytical data (1 H NMR and LC-MS) were consistent with those of compound 7 in Synthetic Route I.

Step D. Synthesis of ST-246 (Route IV)

To a mixture of compound 7 (0.84 g, 3.5 mmol) in dichloromethane (13 mL) was added diisopropylethylamine (1 .34 mL, 7.7 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minutes. 4-(Trifluoromethyl)benzoyl chloride 8 (0.57 mL, 3.85 mmol, Aldrich, 97%) was added to above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature for 2 h. Additional 0.2 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction keeping the temperature below 20 °C. The reaction was stirred at room temperature overnight (24 h). The reaction mixture was diluted with dichloromethane (20 mL). The organic phase was washed with water (20 mL), saturated aqueous NH4CI (20 mL), water (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford ST-246 (0.25 g, 19% yield, HPLC area >99.5% pure) as a white solid. Analytical data (1H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

Example 5: Synthetic Route V:

Scheme 5

Step A. Synthesis of Compound 13

To a mixture of compound 7 (1 .6 g, 6.65 mmol, synthesized according to Synthetic Route I) in dichloromethane (80 ml_,) was added triethylamine (2.04 ml_, 14.63 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minute. 4-lodobenzoyl chloride 12 (1 .95 g, 7.31 mmol, 1 .1 equiv, Aldrich) was added portion-wise under nitrogen atmosphere to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight. After 17 h and 19 h, additional 0.35 g (0.2 equiv) of acid chloride 12 was added to the reaction keeping the temperature below 20 °C. After 24 h, additional 0.18 g (0.1 equiv, used total 1 .6 equiv) of acid chloride 12 was added and the reaction was continued to stir at room temperature overnight (total 43 h). LC-MS analysis at 215 nm showed 43% of the desired product (13) and -5% of compound 7. The reaction was diluted with dichloromethane (100 ml_). The organic phase was washed with saturated aqueous NH4CI (100 ml_), water (100 ml_) and saturated aqueous NaHCO3 (100 ml_). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 25 – 50% EtOAc in hexanes to afford compound 13 (1 .63 g, 57% yield, HPLC area 93% pure) as a white solid. 1 H NMR in DMSO-d6: δ 1 1 .19 and 10.93 (two singlets with integration ratio of 1 .73:1 , total of 1 H, same proton of two rotamers), 7.93 (d, 2H), 7.66 (d, 2H), 5.80 (s, 2H), 3.36 (s, 2H), 3.27 (s, 2H), 1 .18 (s, 2H), 0.27 (q, 1 H), 0.06 (s,1 H); Mass Spec: 435.0 (M+H)+

Step B. Synthesis of ST-246 (Route V)

Anhydrous DMF (6 ml_) was added to a mixture of compound 13 (0.2 g, 0.46 mmol), methyl 2, 2-difluoro-2-(fluorosulfonyl)acetate (0.44 ml_, 3.45 mmol, Aldrich) and copper (I) iodide (90 mg, 0.47 mmol). The reaction mixture was stirred at -90 °C for 4 h. LC-MS analysis at 254 nm indicated no starting material 13 remained and showed 48% HPLC area of ST-246. The reaction mixture was cooled to 45 °C and DMF was removed under reduced pressure. The residue was slurried in EtOAc (30 mL) and insoluble solid was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (55

mg, 32% yield, 95% pure by HPLC at 254 nm) as off-white solid. Analytical data (1H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

PAPER

N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides:  Identification of Novel Orthopoxvirus Egress Inhibitors

ViroPharma Incorporated, 397 Eagleview Boulevard, Exton, Pennsylvania 19341, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, Maryland 21702, University of Alabama, Birmingham, Alabama 35294, and SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, Oregon 97333

J. Med. Chem.200750 (7), pp 1442–1444

DOI: 10.1021/jm061484y

Abstract Image

A series of novel, potent orthopoxvirus egress inhibitors was identified during high-throughput screening of the ViroPharma small molecule collection. Using structure−activity relationship information inferred from early hits, several compounds were synthesized, and compound 14was identified as a potent, orally bioavailable first-in-class inhibitor of orthopoxvirus egress from infected cells. Compound 14 has shown comparable efficaciousness in three murine orthopoxvirus models and has entered Phase I clinical trials.

http://pubs.acs.org/doi/suppl/10.1021/jm061484y/suppl_file/jm061484ysi20070204_060607.pdf

General Procedure for synthesis of compounds 2-14, 16-18.

N-(3,3a,4,4a,5,5a,6,6aoctahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-4- (trifluoromethyl)benzamide (14).

A mixture of 2.00 g (9.8 mmol) of 4-(trifluoromethyl) benzoic acid hydrazide, 1.86 g (9.8 mmol) of 4,4a,5,5a,6,6a-hexahydro-4,6-etheno-1Hcycloprop[f]isobenzofuran-1,3(3aH)-dione, and one drop of diisopropylethylamine in 40 mL of absolute ethanol was refluxed for 4.5 h. Upon cooling to rt, 4 mL of water was added, and the product began to crystallize. The suspension was cooled in an ice bath, and the precipitate collected by filtration. The crystalline solid was air-dried affording 3.20 g (87%) of the product as a white solid;

Mp 194-195 ºC. 1 H NMR, (300 MHz, d6 -DMSO) δ 11.20, 11.09 (2 brs from rotamers, 1H), 8.06 (d, J= 7.8 Hz, 2H), 7.90 (d, J= 7.8 Hz, 2H), 5.78 (m, 2H), 3.26 (m, 4H), 1.15 (m, 2H), 0.24 (dd, J= 7.2, 12.9 Hz, 1H), 0.04 (m, 1H).

Anal. calcd. for C19H15F3N2O3● 0.25H2O: %C, 59.92; %H, 4.10; %F, 14.97; %N, 7.36; %O, 13.65. Found: %C, 59.97; %H, 4.02; %F, 14.94; %N, 7.36; %O, 13.71.

CLICK ON IMAGE

PATENT

US20140316145

CLICK ON IMAGE

http://www.google.com/patents/US8802714

Example 1

Preparation of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide

a. Preparation of Compounds 1(a) and 1(b).

Figure US08802714-20140812-C00010

A mixture of cycloheptatriene (5 g, 54.26 mmol) and maleic anhydride (6.13 g, 62.40 mmol) in xylenes (35 mL) was heated at reflux under argon overnight. The reaction was cooled to room temperature and a tan precipitate was collected by filtration and dried to give 2.94 grams (28%) of the desired product, which is a mixture of compounds 1(a) and 1(b). Compound 1(a) is normally predominant in this mixture and is at least 80% by weight. The purity of Compound 1(a) may be further enhanced by recrystallization if necessary. Compound 1(b), an isomer of compound 1(a) is normally less than 20% by weight and varies depending on the conditions of the reaction. Pure Compound 1(b) was obtained by concentrating the mother liquid to dryness and then subjecting the residue to column chromatography. Further purification can be carried out by recrystallization if necessary. 1H NMR (500 MHz) in CDCl3: δ 5.95 (m, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 1.12 (m, 2H), 0.22 (m, 1H), 0.14 (m, 1H).

b. Preparation of N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. desired

A mixture of compound 1(a) (150 mg, 0.788 mmol) and 4-trifluoromethylbenzhydrazide (169 mg, 0.827 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed by rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate provided 152 mg (51%) of the product as a white solid.

c. Preparation of N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. UNWANTED

N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]4-(trifluoromethyl)-benzamide was prepared and purified in the same fashion as for N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide by replacing 1(a) with 1(b) and was obtained as a white solid. 1H NMR (300 MHz) in CDCl3: δ 8.62 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1.17 (s, 2H), 0.24 (q, 1H), 0.13 (m, 1H); Mass Spec: 377.1 (M+H)+.

FINAL COMPD SYNTHESIS

TABLE 1
Example **Mass
Number R6 *NMR Spec Name
 1 1H NMR in DMSO-d6: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H) 375 (M − H)− N-[(3aR,4R,4aR,5aS,6S, 6aS)-3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6-ethenocycloprop[f] isoindol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

TABLE 1 EXAMPLE 1

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

1H NMR in DMSO-d6: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H), 375 (M − H)

EXAMPLE 42 Characterization of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (“ ”)

In the present application, ST-246 refers to: N-[(3aR,4R,4aR,5aS,65,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide.

Physico-Chemical Properties

Appearance: ST-246 is a white to off-white powder.

Melting Point: Approximately 196° C. by DSC.

Permeability: The calculated log P is 2.94. Based on the partition coefficient, ST-246 is expected to have good permeability.

Particle Size: The drug substance is micronized to improve its dissolution in the gastrointestinal fluids. The typical particle size of the micronized material is 50% less than 5 microns.

Solubility: The solubility of ST-246 is low in water (0.026 mg/mL) and buffers of the gastric pH range. Surfactant increases its solubility slightly. ST-246 is very soluble in organic solvents. The solubility data are given in Table 5.

CLICK ON IMAGE

PATENT

http://www.google.com/patents/CN101445478A?cl=en

Tecovirimat (ST-246) is an antiviral with activity against orthopoxviruses such as smallpox and is currently undergoing clinical trials. It was previously owned by Viropharma and discovered in collaboration with scientists at USAMRIID. It is currently owned and is synthesized by Siga Technologies, a drug development company in the biodefense arena. It works by blocking cellular transmission of the virus, thus preventing the disease. Tecovirimat has been effective in laboratory testing, with no serious side effects reported to date. Despite not yet having FDA approval for medical use, tecovirimat is stockpiled in the US Strategic National Stockpile as a defense against a smallpox outbreak.[1]

Clinical study

The results of clinical trials involving tecovirimat supports its use against smallpox and other related orthopoxviruses. It has shown potential for a variety of uses including prophylaxis, as a post-exposure therapeutic, as a therapeutic and an adjunct to vaccination.[2]

Tecovirimat can be taken orally and has recently been granted permission to conduct Phase II trials by the U.S. Food and Drug Administration (FDA). In phase I trials tecovirimat was generally well tolerated with no serious adverse events.[3] Due to its importance for biodefense, the FDA has designated tecovirimat for ‘fast-track’ status, creating a path for expedited FDA review and eventual regulatory approval.

Tecovirimat is an orthopoxvirus egress inhibitor. Tecovirimat appears to target the V061 gene in cowpox, which is homologous to the vaccinia virus F13L. By targeting this gene, tecovirimat inhibits the function of a major envelope protein required for the production of extracellar virus. Thus the virus is prevented from leaving the cell, and the spread of the virus within the body is prevented.[4]

 

References

  1. Damon, Inger K.; Damaso, Clarissa R.; McFadden, Grant (2014). “Are We There Yet? The Smallpox Research Agenda Using Variola Virus”. PLoS Pathogens 10 (5): e1004108.doi:10.1371/journal.ppat.1004108PMID 24789223.
  2. Siga Technologies
  3. Jordan, R; Tien, D; Bolken, T. C.; Jones, K. F.; Tyavanagimatt, S. R.; Strasser, J; Frimm, A; Corrado, M. L.; Strome, P. G.; Hruby, D. E. (2008). “Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor”Antimicrobial Agents and Chemotherapy 52 (5): 1721–1727. doi:10.1128/AAC.01303-07PMC 2346641PMID 18316519.
  4. Yang, G; Pevear, D. C.; Davies, M. H.; Collett, M. S.; Bailey, T; Rippen, S; Barone, L; Burns, C; Rhodes, G; Tohan, S; Huggins, J. W.; Baker, R. O.; Buller, R. L.; Touchette, E; Waller, K; Schriewer, J; Neyts, J; Declercq, E; Jones, K; Hruby, D; Jordan, R (2005). “An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge”Journal of Virology 79 (20): 13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005PMC 1235851PMID 16189015.

Referenced by
Citing Patent Filing date Publication date Applicant Title
CN101912389A * Aug 9, 2010 Dec 15, 2010 中国人民解放军军事医学科学院微生物流行病研究所 Pharmaceutical composition containing ST-246 and preparation method and application thereof
CN102406617A * Nov 30, 2011 Apr 11, 2012 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN102406617B Nov 30, 2011 Aug 28, 2013 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN103068232B * Mar 23, 2011 Aug 26, 2015 西佳科技股份有限公司 多晶型物形式st-246和制备方法
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

Patent Citations
Cited Patent Filing date Publication date Applicant Title
US20070287735 * Apr 23, 2007 Dec 13, 2007 Siga Technologies, Inc. Chemicals, compositions, and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US20090011037 * Apr 23, 2008 Jan 8, 2009 Cydex Pharmaceuticals, Inc. Sulfoalkyl Ether Cyclodextrin Compositions and Methods of Preparation Thereof
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases
Classifications
Tecovirimat
Tecovirimat.svg
Systematic (IUPAC) name

N-{3,5-Dioxo-4- azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4- yl}-4-(trifluoromethyl)benzamide

Identifiers
UNII F925RR824R Yes
ChEMBL CHEMBL1242629 Yes
Synonyms ST-246
Chemical data
Formula C19H15F3N2O3
Molecular mass base: 376.3 g/mol

//////////////////Tecovirimat, FDA 2018, ORPHAN DRUG DESIGNATION,  TPOXX, SIGA Technologies Inc,  Fast TrackPriority Review

FC(F)(F)c1ccc(cc1)C(=O)NN1C(=O)C2C(C3C=CC2C2CC32)C1=O

Acamprosate calcium, アカンプロセート


Acamprosate CalciumSkeletal formula of acamprosateThumb

ChemSpider 2D Image | Acamprosate | C5H11NO4SAcamprosate.pngImage result for Acamprosate synthesis

Acamprosate calcium

Molecular Formula: C10H20CaN2O8S2
Molecular Weight: 400.474 g/mol

3-acetamidopropane-1-sulfonic acid

Campral [Trade name]
Ethanimidic acid, N-(3-sulfopropyl)-, (1Z)- [ACD/Index Name]
N4K14YGM3J
N-Acetylhomotaurine
アカンプロセート
INGREDIENT UNII CAS fre form

Cas 77337-76-9

181.21

C5H11NO4S

Acamprosate Calcium 59375N1D0U 77337-73-6

Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.[1][2]

Acamprosate, also known by the brand name Campral™, is a drug used for treating alcohol dependence. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. Certain serious side effects include allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Acamprosate should not be taken by people with kidney problems or allergies to the drug.

Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal.[3] When used alone, acamprosate is not an effective therapy for alcoholism in most individuals;[4] however, studies have found that acamprosate works best when used in combination with psychosocial support since it facilitates a reduction in alcohol consumption as well as full abstinence.[2][5][6]

Serious side effects include allergic reactionsabnormal heart rhythms, and low or high blood pressure, while less serious side effects include headachesinsomnia, and impotence.[7] Diarrhea is the most common side-effect.[8] Acamprosate should not be taken by people with kidney problems or allergies to the drug.[9]

Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US.

Medical uses

Acamprosate is useful when used along with counselling in the treatment of alcohol dependence.[2] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol.[2] It appears to work as well as naltrexone.[2]

Contraindications

Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearancebetween 30 mL/min and 50 mL/min).[1][10] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.[10]

Adverse effects

The US label carries warnings about increased of suicidal behavior, major depressive disorder, and kidney failure.[1]

Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.[1]

Other frequent adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.[1]

Pharmacology

Acamprosate calcium

Pharmacodynamics

The pharmacodynamics of acamprosate is complex and not fully understood;[11][12][13] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors.[12][13]

Ethanol and benzodiazepines act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).[12][4] In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).[4] When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;[4] since GABA normally inhibits neural firing, GABAA receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABAA receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate’s mechanisms of action is the enhancement of GABA signaling at GABAA receptors via positive allosteric receptor modulation.[12][13] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.[medical citation needed]

In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs).[14][15] Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremensand excitotoxic neuronal death.[16] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.[17] Acamprosate reduces this glutamate surge.[18] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal[19] and from glutamate exposure combined with ethanol withdrawal.[20]

Pharmacokinetics

Acamprosate is not metabolized by the human body.[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.[13]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA.[21] and was approved for marketing in Europe in 1989.[citation needed]

In October 2001 Forest Laboratories acquired the rights to market the drug in the US.[21][22]

It was approved by the FDA in July 2004.[23]

The first generic versions of acamprosate were launched in the US in 2013.[24]

As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.[25]

Society and culture

“Acamprosate” is the INN and BAN for this substance. “Acamprosate calcium” is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.

It is sold under the brand name Campral.[1]

Research

In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity).[18][26]

References

  1. Jump up to:a b c d e f g h i j k l m “Campral label” (PDF). FDA. January 2012. Retrieved 27 November2017. For label updates see FDA index page for NDA 021431
  2. Jump up to:a b c d e Plosker, GL (July 2015). “Acamprosate: A Review of Its Use in Alcohol Dependence”. Drugs75 (11): 1255–68. doi:10.1007/s40265-015-0423-9PMID 26084940.
  3. Jump up^ Williams, SH. (2005). “Medications for treating alcohol dependence”American Family Physician72 (9): 1775–1780. PMID 16300039.
  4. Jump up to:a b c d Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). “Chapter 16: Reinforcement and Addictive Disorders”. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706It has been hypothesized that long-term ethanol exposure alters the expression or activity of specific GABAA receptor subunits in discrete brain regions. Regardless of the underlying mechanism, ethanol-induced decreases in GABAA receptor sensitivity are believed to contribute to ethanol tolerance, and also may mediate some aspects of physical dependence on ethanol. … Detoxification from ethanol typically involves the administration of benzodiazepines such as chlordiazepoxide, which exhibit cross-dependence with ethanol at GABAA receptors (Chapters 5 and 15). A dose that will prevent the physical symptoms associated with withdrawal from ethanol, including tachycardia, hypertension, tremor, agitation, and seizures, is given and is slowly tapered. Benzodiazepines are used because they are less reinforcing than ethanol among alcoholics. Moreover, the tapered use of a benzodiazepine with a long half-life makes the emergence of withdrawal symptoms less likely than direct withdrawal from ethanol. … Unfortunately, acamprosate is not adequately effective for most alcoholics.
  5. Jump up^ Mason, BJ (2001). “Treatment of alcohol-dependent outpatients with acamprosate: a clinical review”. The Journal of Clinical Psychiatry. 62 Suppl 20: 42–8. PMID 11584875.
  6. Jump up^ Nutt, DJ (2014). “Doing it by numbers: A simple approach to reducing the harms of alcohol”. JOURNAL OF PSYCHOPHARMACOLOGY28: 3–7. doi:10.1177/0269881113512038PMID 24399337.
  7. Jump up^ “Acamprosate”. drugs.com. 2005-03-25. Archived from the original on 22 December 2006. Retrieved 2007-01-08.
  8. Jump up^ Wilde, MI; Wagstaff, AJ (June 1997). “Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification”. Drugs53(6): 1038–53. doi:10.2165/00003495-199753060-00008PMID 9179530.
  9. Jump up^ “Acamprosate Oral – Who should not take this medication?”. WebMD.com. Retrieved 2007-01-08.
  10. Jump up to:a b Saivin, S; Hulot, T; Chabac, S; Potgieter, A; Durbin, P; Houin, G (Nov 1998). “Clinical Pharmacokinetics of Acamprosate”. Clinical Pharmacokinetics35 (5): 331–345. doi:10.2165/00003088-199835050-00001PMID 9839087.
  11. Jump up^ “Acamprosate: Biological activity”IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017Due to the complex nature of this drug’s MMOA, and a paucity of well defined target affinity data, we do not map to a primary drug target in this instance.
  12. Jump up to:a b c d “Acamprosate: Summary”IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017Acamprosate is a NMDA glutamate receptor antagonist and a positive allosteric modulator of GABAA receptors.
    Marketed formulations contain acamprosate calcium
  13. Jump up to:a b c d e f “Acamprosate”DrugBank. University of Alberta. 19 November 2017. Retrieved 26 November 2017Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. … The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. in vitro and in vivostudies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance. It seems to inhibit NMDA receptors while activating GABA receptors.
  14. Jump up^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN 9780071481274.
  15. Jump up^ Möykkynen T, Korpi ER (July 2012). “Acute effects of ethanol on glutamate receptors”. Basic & Clinical Pharmacology & Toxicology111 (1): 4–13. doi:10.1111/j.1742-7843.2012.00879.xPMID 22429661.
  16. Jump up^ Tsai, G; Coyle, JT (1998). “The role of glutamatergic neurotransmission in the pathophysiology of alcoholism”. Annual Review of Medicine49: 173–84. doi:10.1146/annurev.med.49.1.173PMID 9509257.
  17. Jump up^ Tsai, GE; Ragan, P; Chang, R; Chen, S; Linnoila, VM; Coyle, JT (1998). “Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal”The American Journal of Psychiatry155 (6): 726–32. doi:10.1176/ajp.155.6.726PMID 9619143.
  18. Jump up to:a b De Witte, P; Littleton, J; Parot, P; Koob, G (2005). “Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action”. CNS Drugs19 (6): 517–37. doi:10.2165/00023210-200519060-00004PMID 15963001.
  19. Jump up^ Mayer, S; Harris, BR; Gibson, DA; Blanchard, JA; Prendergast, MA; Holley, RC; Littleton, J (2002). “Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus”. Alcoholism: Clinical and Experimental Research26 (10): 1468–78. doi:10.1097/00000374-200210000-00003PMID 12394279.
  20. Jump up^ Al Qatari, M; Khan, S; Harris, B; Littleton, J (2001). “Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain”. Alcoholism: Clinical and Experimental Research25(9): 1276–83. doi:10.1111/j.1530-0277.2001.tb02348.xPMID 11584146.
  21. Jump up to:a b Berfield, Susan (27 May 2002). “A CEO and His Son”Bloomberg Businessweek.
  22. Jump up^ “Press release: Forest Laboratories Announces Agreement For Alcohol Addiction Treatment”Forest Labs via Evaluate Group. October 23, 2001.
  23. Jump up^ “FDA Approves New Drug for Treatment of Alcoholism”FDA Talk PaperFood and Drug Administration. 2004-07-29. Archived from the original on 2008-01-17. Retrieved 2009-08-15.
  24. Jump up^ “Acamprosate generics”. DrugPatentWatch. Retrieved 27 November 2017.
  25. Jump up^ “Acamprosate – Confluence Pharmaceuticals – AdisInsight”. AdisInsight. Retrieved 27 November 2017.
  26. Jump up^ Mann K, Kiefer F, Spanagel R, Littleton J (July 2008). “Acamprosate: recent findings and future research directions”. Alcohol. Clin. Exp. Res32 (7): 1105–10. doi:10.1111/j.1530-0277.2008.00690.xPMID 18540918.
Title: Acamprosate Calcium
CAS Registry Number: 77337-73-6
CAS Name: 3-(Acetylamino)-1-propanesulfonic acid calcium salt (2:1)
Additional Names: calcium acetyl homotaurinate; Ca-AOTA; calcium bisacetyl homotaurine
Trademarks: Aotal (Merck KGaA); Campral (Merck Sant?
Molecular Formula: C10H20CaN2O8S2
Molecular Weight: 400.48
Percent Composition: C 29.99%, H 5.03%, Ca 10.01%, N 6.99%, O 31.96%, S 16.01%
Literature References: GABA (g-aminobutyric acid, q.v.) agonist. Prepn: J. P. Durlach, DE 3019350idem, US 4355043 (1980, 1982 both to Lab. Meram). Physicochemical and pharmacological study: C. Chabenat et al., Methods Find. Exp. Clin. Pharmacol.10, 311 (1988). Pharmacology: J. Durlach et al., ibid. 437; A. Guiet-Bara et al., Alcohol 5, 63 (1988). Suppression of ethanol intake in rats: F. Boismare et al., Pharmacol. Biochem. Behav. 21, 787 (1984); J. Le Magnen et al., Alcohol 4, 97 (1987). Evaluation of abuse potential: K. A. Grant, W. L. Woolverton, Pharmacol. Biochem. Behav. 32, 607 (1989). HPLC determn in plasma: C. Chabenat et al., J. Chromatogr. 414, 417 (1987). Clinical evaluation in relapse prevention in weaned alcoholics: J. P. L’Huintre et al., Lancet 1, 1014 (1985); J. P. L’Huintre et al., Alcohol Alcohol. 25, 613 (1990). Review of clinical efficacy in maintenance of abstinence in alcoholics: L. J. Scott et al., CNS Drugs 19, 445-464 (2005); of mechanism of action: P. De Witte et al., ibid. 517-537.
Properties: Colorless crystalline powder, mp 270°. uv max (water): 192 nm (e 7360). Freely sol in water. Practically insol in absolute ethanol, dichloromethane. LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982).
Melting point: mp 270°
Absorption maximum: uv max (water): 192 nm (e 7360)
Toxicity data: LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982)
Therap-Cat: In treatment of alcoholism.
Keywords: Alcohol Dependence Treatment.

 Acamprosate calcium

    • ATC:N07BB03
  • Use:alcohol-abuse deterrent
  • Chemical name:3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1)
  • Formula:C10H20CaN2O8S2
  • MW:400.49 g/mol
  • CAS-RN:77337-73-6
  • EINECS:278-665-3
  • LD50:>10 g/kg (M, p.o.)

Derivatives

free acid

  • Formula:C5H11NO4S
  • MW:181.21 g/mol
  • CAS-RN:77337-76-9
  • EINECS:278-667-4

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN Formula Chemical Name CAS Index Name
3687-18-1 C3H9NO3S 3-aminopropane-1-sulfonic acid 1-Propanesulfonic acid, 3-amino-
156-87-6 C3H9NO 3-amino-1-propanol 1-Propanol, 3-amino-

Trade Names

Country Trade Name Vendor Annotation
D Campral Merck
F Aotal Merck Lipha
GB Campral EC Merck Serono
USA Campral Forest

Formulations

  • tabl. 50 mg, 100 mg, 333 mg

References

    • DE 3 019 350 (Lab. Meram; appl. 21.5.1980; F-prior. 23.5.1979).
    • US 4 355 043 (Lab. Meram; 19.10.1982; F-prior. 23.5.1979).
  • synthesis of 3-aminopropane-1-sulfonic acid:

    • Fujii, A. et al.: J. Med. Chem. (JMCMAR) 18, 502 (1975).
    • JP 46 002 012 (Kowa; appl. 19.1.1971).
    • WO 8 400 958 (Mitsui; appl. 15.3.1984; J-prior. 7.9.1982, 19.7.1983, 8.9.1982).
Acamprosate
Skeletal formula of acamprosate
Ball-and-stick model of the acamprosate molecule
Clinical data
Trade names Campral EC
Synonyms N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS)
Pregnancy
category
Routes of
administration
Oral [1]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 11%[1]
Protein binding Negligible[1]
Metabolism Nil[1]
Elimination half-life 20 h to 33 h[1]
Excretion Renal[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.071.495 Edit this at Wikidata
Chemical and physical data
Formula C5H11NO4S
Molar mass 181.211 g/mol
3D model (JSmol)
 NoYes (what is this?)  (verify)

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size.Image result for Acamprosate nmr

////////////////Acamprosate calcium, アカンプロセート

CC(=O)NCCCS(O)(=O)=O

CC(=O)NCCCS(=O)(=O)[O-].CC(=O)NCCCS(=O)(=O)[O-].[Ca+2]

DOCONEXENT, доконексен, دوكونيكسانت , 二十二碳六烯酸


ThumbImage result for doconexent

ChemSpider 2D Image | Docosahexaenoic acid | C22H32O2(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid.png

Image result for doconexentDocosahexaenoic Acid

Doconexent

CAS 6217-54-5

WeightAverage: 328.4883
Chemical FormulaC22H32O2

4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-

Doconexent sodium 295P7EPT4C 81926-93-4  2D chemical structure of 81926-93-4
  • (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
  • 22:6-4, 7,10,13,16,19
  • 22:6(n-3)
  • 4,7,10,13,16,19-docosahexaenoic acid
  • 4,7,10,13,16,19-Docosahexaenoic acid
  • all-cis-4,7,10,13,16,19-docosahexaenoic acid
  • all-cis-DHA
  • cervonic acid
  • DHA
  • docosa-4,7,10,13,16,19-hexaenoic acid
  • Docosahexaenoic acid
  • Ropufa 60
  • S.Presso
  • all-Z-Docosahexaenoic acid
  • all-cis-4,7,10,13,16,19-Docosahexaenoic acid
  • Δ4,7,10,13,16,19-Docosahexaenoic acid
  • 4,7,10,13,16,19-Docosahexaenoic acid, (all-Z)- (8CI)
  • Docosahexaenoic acid (6CI)
    • (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid
    • (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
    • (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexenoic acid
    • (all-Z)-4,7,10,13,16,19-Docosahexaenoic acid
    • 4-cis,7-cis,10-cis,13-cis,16-cis,19-cis-Docosahexaenoic acid
Docosahexaenoic acid (22:6(n-3))
ZAD9OKH9JC
доконексент [Russian] [INN]
دوكونيكسانت [Arabic] [INN]
二十二碳六烯酸 [Chinese] [INN]
(4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid [ACD/IUPAC Name]
(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid
(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
(all-Z)- 4,7,10,13,16,19-Docosahexaenoic Acid
(all-Z)-4,7,10,13,16,19-Docosahexaenoic acid
4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-
all-Z-Docosahexaenoic acid
cis-4, cis-7, cis-10, cis-13, cis-16, cis-19-docosahexaenoic acid
cis-4,7,10,13,16,19-Docosahexaenoic acid
D4,7,10,13,16,19-Docosahexaenoic Acid
A mixture of fish oil and primrose oil; used as a high-docosahexaenoic acid fatty acid supplement.

A mixture of fish oil and primrose oil, doconexent is used as a high-docosahexaenoic acid (DHA) supplement. DHA is a 22 carbon chain with 6 cis double bonds with anti-inflammatory effects. It can be biosythesized from alpha-linolenic acid or commercially manufactured from microalgae. It is an omega-3 fatty acid and primary structural component of the human brain, cerebral cortex, skin, and retina thus plays an important role in their development and function. The amino-phospholipid DHA is found at a high concentration across several brain subcellular fractions, including nerve terminals, microsomes, synaptic vesicles, and synaptosomal plasma membranes

Image result for doconexent

Synthesis , By Farmer, Ernest H.; Van den Heuvel, Frantz A., From Journal of the Chemical Society (1938), 427-30.

ALSO

Title: Docosahexaenoic Acid
CAS Registry Number: 6217-54-5
CAS Name: (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid
Additional Names: cervonic acid; doconexent; DHA
Molecular Formula: C22H32O2
Molecular Weight: 328.49
Percent Composition: C 80.44%, H 9.82%, O 9.74%
Literature References: Omega-3 fatty acid found in marine fish oils and in many phospholipids. Major structural component of excitable membranes of the retina and brain; synthesized in the liver from a-linolenic acid, q.v. Isoln from oil of Sardina ocellata J. and structure: J. M. Whitcutt, Biochem. J. 67, 60 (1957). Improved isoln from cod liver oil: S. W. Wright et al., J. Org. Chem. 52,4399 (1987). Effect on brain and behavioral development: P. E. Wainwright, Neurosci. Biobehav. Rev. 16, 193 (1992). Review of uptake and metabolism by retinal cells: N. G. Bazan, E. B. Rodriguez de Turco, J. Ocul. Pharmacol. 10, 591-603 (1994). Review of clinical studies in infant formula supplementation: M. Makrides et al., Lipids 31, 115-119 (1996).
Properties: Clear, faintly yellow oil, mp -44.7 to -44.5°. n26D 1.5017.
Melting point: mp -44.7 to -44.5°
Index of refraction: n26D 1.5017
Use: Nutritional supplement.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human braincerebral cortexskin, and retina. It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fish oil, or algae oil.[1]

DHA’s structure is a carboxylic acid (-oic acid) with a 22-carbon chain (docosa- derives from the Ancient Greek for 22) and six (hexa-cis double bonds (-en-);[2] with the first double bond located at the third carbon from the omega end.[3] Its trivial name is cervonic acid, its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its shorthand name is 22:6(n−3) in the nomenclature of fatty acids.

Most of the DHA in fish and multi-cellular organisms with access to cold-water oceanic foods originates from photosynthetic and heterotrophic microalgae, and becomes increasingly concentrated in organisms the further they are up the food chain. DHA is also commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus Schizochytrium.[4] DHA manufactured using microalgae is vegetarian.[5]

In strict herbivores, DHA is manufactured internally from α-linolenic acid, a shorter omega-3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants), while omnivores and carnivores primarily obtain DHA from their diet.[6] Limited amounts of eicosapentaenoic and docosapentaenoic acids are possible products of α-linolenic acid metabolism in young women[7] and men.[6] DHA in breast milk is important for the developing infant.[8] Rates of DHA production in women are 15% higher than in men.[9]

DHA is a major fatty acid in brain phospholipids and the retina. While the potential roles of DHA in the mechanisms of Alzheimer’s disease are under active research,[10] studies of fish oil supplements, which contain DHA, have failed to support claims of preventing cardiovascular diseases.[11][12][13]

Image result for doconexent

Central nervous system constituent

DHA is the most abundant omega-3 fatty acid in the brain and retina. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of the weight of a neuron‘s plasma membraneis composed of DHA.[14]

DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles, among many other functions.[15]

DHA deficiency is associated with cognitive decline.[16] Phosphatidylserine (PS) controls apoptosis, and low DHA levels lower neural cell PS and increase neural cell death.[17] DHA levels are reduced in the brain tissue of severely depressed patients.[18][19]

Image result for DOCONEXENT NMR

Metabolic synthesis

In humans, DHA is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3) via docosapentaenoic acid (DPA, 22:5 ω-3) as an intermediate.[7][6] This synthesis had been thought to occur through an elongation step followed by the action of Δ4-desaturase.[6] It is now considered more likely that DHA is biosynthesized via a C24 intermediate followed by beta oxidation in peroxisomes. Thus, EPA is twice elongated, yielding 24:5 ω-3, then desaturated to 24:6 ω-3, then shortened to DHA (22:6 ω-3) via beta oxidation. This pathway is known as Sprecher’s shunt.[20][21]

In organisms such as microalgae, mosses and fungi, biosynthesis of DHA usually occurs as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. A common pathway in these organisms involves:

  1. a desaturation at the sixth carbon of alpha-linolenic acid by a Δ6 desaturase to produce stearidonic acid,
  2. elongation of the stearidonic acid by a Δ6 elongase to produce to eicosatetraenoic acid,
  3. desaturation at the fifth carbon of eicosatetraenoic acid by a Δ5 desaturase to produce eicosapentaenoic acid,
  4. elongation of eicosapentaenoic acid by a Δ5 elongase to produce docosapentaenoic acid, and
  5. desaturation at the fourth carbon of docosapentaenoic acid by a Δ4 desaturase to produce DHA.[22]

Metabolism

DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others.[23]

The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]).[24]

Potential health effects

Neurological research

While one human trial of 402 subjects lasting 18 months concluded that DHA did not slow decline of mental function in elderly people with mild to moderate Alzheimer’s disease,[25] a similar trial of 485 subjects lasting 6 months concluded that algal DHA of 900 mg per day taken decreased heart rate and improved memory and learning in healthy, older adults with mild memory complaints.[26]

In another early-stage study, higher DHA levels in middle-aged adults was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary.[27]

One study found that the use of DHA-rich fish oil capsules did not reduce postpartum depression in mothers or improve cognitive and language development in their offspring during early childhood.[28] Another systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa.[29] A 2017 pilot study found that fish oil supplementation reduced the depression symptoms emphasizing the importance of the target DHA levels.[30]

Pregnancy and lactation

It has been recommended to eat foods which are high in omega-3 fatty acids for women who want to become pregnant or when nursing.[31] A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study.[32] Despite these recommendations, recent evidence from a trial of pregnant women randomized to receive supplementation with 800 mg/day of DHA versus placebo, showed that the supplement had no impact on the cognitive abilities of their children at up to seven years follow-up.[33]

Other research

In one preliminary study, men who took DHA supplements for 6–12 weeks had lower blood markers of inflammation.[34]

Nutrition

Algae-based DHA supplements

Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams.[35] Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring(1105 mg per 100 grams).[35] Brains from mammals are also a good direct source, with beef brain, for example, containing approximately 855 mg of DHA per 100 grams in a serving.[36]

Discovery of algae-based DHA

In the early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights. Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid,[37] present in some health supplements.

Use as a food additive

DHA is widely used as a food supplement. It was first used primarily in infant formulas.[38] In 2004, the US Food and Drug Administration endorsed qualified health claims for DHA.[39]

Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega-3s such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.[40]

Studies of vegetarians and vegans

Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA.[41] In preliminary research, algae-based supplements increased DHA levels.[42]While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the developing fetus.[41]

DHA and EPA in fish oils

Fish oil is widely sold in capsules containing a mixture of omega-3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA.[43][44]

Hypothesized role in human evolution

An abundance of DHA in seafood has been suggested as being helpful in the development of a large brain,[45] though other researchers claim a terrestrial diet could also have provided the necessary DHA.[46]

Patent

CN 106190872

https://patents.google.com/patent/CN106190872A/zh

PATENT

WO 2017038860

https://patents.google.com/patent/WO2017038860A1/en

[Example 1]
The raw EPA ethyl ester 1 of Comparative Example 1 containing EPA 96.7%, except for changing the temperature of the alkaline hydrolysis in 6 ° C., in the same manner as in Comparative Example 1 was alkaline hydrolysis.
That is, the starting EPA ethyl ester 1 2.50 g, ethanol 6.25 mL (4.92 g, 14.11 equivalents relative fatty acid), water 1.00 mL, 48 wt% sodium hydroxide aqueous solution 0.76 g ( 1.20 equivalents of base) was added a sample solution 3 was prepared against fatty acids. In sample liquid 3, moisture 1.40 g, i.e., was 10.27 equivalents relative fatty acid. The sample liquid 3, stirred for 24 hours 6 ° C., was subjected to hydrolysis treatment. Confirmed the completion of the reaction of the hydrolysis treatment, returned to the sample liquid 3 after treatment at room temperature, after transferred to a separatory funnel, and hexane was added 3.13 mL, purified water 2.50mL the sample liquid 3. When further adding 2.25g of hydrochloric acid, the sample solution 3 was separated into two layers of hexane and aqueous layers. The pH of the aqueous layer was 1.0.

The sample liquid 3 was stirred, then the mixture was allowed to stand, after removing the aqueous layer from the sample liquid 3, was further stirred with purified water 3.75mL the sample liquid 3 after removal. Hydrochloric acid was added small amount to adjust the pH of the aqueous layer to 1.0. Thereafter, the aluminum plate was washed with the same amount of purified water as rinsing liquid. Rinsing liquid is recovered after washing with water was repeatedly washed with water until neutral pH 6.0 ~ 7.0. The hexane layer was recovered from the sample liquid 3 after washing with water, the recovered hexane layer, the hexane was removed with an evaporator and vacuum, the EPA3 a composition containing free EPA was obtained 2.14 g.
Against EPA3, it was evaluated in the same manner as EPA1. The results are shown in Table 1 and Table 4.
The recovery was 93.8%. The resulting Gardner color of EPA3 is 2-, AnV 1.3, ethyl ester (EE) content 2790Ppm, conjugated diene acid content was 0.47%. Conjugated unsaturated fatty acids other than the conjugated diene acid was not detected. These physical property values are shown in Table 1. Note that the conjugated unsaturated fatty acids, only the conjugated diene acid shown in Table 1.

PATENT

WO-2018120574

Process for production of docosahexaenoic acid (DHA), by microbial fermentation of Schizochytrium limacinum . Discloses use of DHA for treating cardiovascular diseases, infertility or neurological diseases. See CN106635405 , claiming method for separating DHA from powder DHA grease by supercritical extraction method. Kingdomway lists that it produces DHA by microorganism fermentation.

DHA, the full name doc-4,7,10,13,16,19-docosahexaenoic acid, DHA, is a polyunsaturated fatty acid. The human body is difficult to synthesize itself and must be taken from the outside world. DHA is one of the essential fatty acids in the human body. It has important physiological regulation functions and health care functions. When it is lacking, it will cause a series of diseases, including growth retardation, skin abnormalities, scales, infertility, mental retardation, etc. In addition, there are cardiovascular diseases. Special preventive and therapeutic effects. Studies have also shown that DHA can act on many different types of tissues and cells, inhibit inflammation and immune function, including reducing the production of inflammatory factors, inhibit lymphocyte proliferation, etc. DHA also has multiple effects in preventing Alzheimer’s disease and neurological diseases. .

The current commercial sources of DHA are mainly fish oil and microalgae. DHA extracted from traditional deep-sea fish oil is unstable due to the variety, season and geographical location of fish, and the content of cholesterol and other unsaturated fatty acids is high. The difference in length and degree of unsaturation of fatty acid chains is large, resulting in limited production and content of DHA. It is not high, it is difficult to separate and purify, and the cost is high. With the growing shortage of fish oil raw materials, it is difficult to achieve the widespread use of DHA, a high value-added product in the food and pharmaceutical industries. The production of DHA by microbial fermentation can overcome the defects of traditional fish oil extraction, can be used for mass production of DHA, continuously meet people’s needs, has broad application prospects, and has attracted the attention of scholars at home and abroad. The microbial fermentation method uses fermented microorganisms such as fungi and microalgae to produce DHA-containing algal oil, and refined to obtain essential oil with high DHA content. DHA-producing strains approved by the Ministry of Health include Schizochytrium sp., Ulkenia amoeboida, and Crypthecodinium cohnii.

The market share of DHA produced by microbial fermentation is increasing rapidly year by year. There is a trend to replace DHA of fish oil, improve the production technology and quality of microalgae DHA, and the prospect of entering the microalgae DHA market is broad.

The publication No. CN103882072A discloses a method for producing docosahexaenoic acid by using Schizochytrium, and the highest yield disclosed is a cell dry weight of 61.2 g/L, a DHA content of 55.07%, and a DHA yield of 22.17 g. /L. The publication No. CN101812484A discloses a method for fermenting DHA by high-density culture of Schizochytrium, which discloses a dry cell weight of 120-150 g/L and a DHA yield of 26-30 g/L, which is also reported. The highest production level of DHA produced by Schizochytrium sp. Although the DHA productivity has been greatly improved compared with the previous research, the industrial production of docosahexaenoic acid by using microalgae greatly reduces the production cost, increases the unit yield, and enables the method of microbial fermentation to produce DHA. Promotion and popularization are still far from enough.

There are three main methods for extracting DHA from the fermentation liquid of Schizochytrium, one is centrifugation, the other is organic solvent extraction, and the third is supercritical extraction. Centrifugation, such as the publication No. CN101817738B, discloses a method for extracting DHA from algae and fungal cells by separating the microalgae or fungal fermentation broth after fermentation by a separation system, and adjusting the pH of the sludge with an acid. 2.0-4.0, then control the temperature of the slime at 10 °C-20 °C, add anti-oxidant in the slime, and then carry out high-pressure homogenization and breaking through the high-pressure homogenizer; add the broken mud to the water, stir and feed The liquid was separated by a three-phase separator to obtain DHA grease. The invention adopts physical wall breaking and physical extraction methods, has simple process, high cell breakage, low temperature treatment of bacteria sludge and antioxidant treatment, can effectively protect the biological activity of algae and fungal cells, and the product is green and non-toxic. Residue. However, the quality of the oil layer after centrifugation of the invention is poor. In addition to the oil, it also contains impurities such as water, medium components and cell debris, which is not conducive to subsequent refining. In addition, the wastewater layer after centrifugation contains a large amount of slag and has a high COD. Difficult to handle or process is extremely costly. The organic solvent extraction method, such as the publication No. CN101824363B, discloses a method for extracting docosahexaenoic acid oil: the fermentation liquid containing docosahexaenoic acid is subjected to enzymatic breaking, and then an organic solvent is used first. The first stage water is divided, the cells are enriched, and the organic solvent is used for secondary extraction to obtain a crude oil. The method is simple in operation and low in equipment investment, but the method uses organic solvent for extraction, and the final product may have solvent residue, and the extraction process has safety hazards such as flammability and explosion. The supercritical extraction method, as disclosed in the publication No. CN102181320B, discloses a method for extracting bio-fermented DHA algae oil, comprising the following steps: a) drying the solid matter obtained by solid-liquid separation of the microalgae fermentation liquid to obtain a dried bacterial cell; b) extracting the dried cells with supercritical carbon dioxide as an extractant to obtain a carbon dioxide fluid; c) separating the carbon dioxide fluid under reduced pressure to obtain DHA algae oil. Experiments show that the DHA content of DHA algae oil obtained by the method provided by the invention is more than 40%, the extraction yield is only 85.23%, and the need to add ethanol as the extracting agent has certain safety risks and supercritical. The equipment is expensive and the extraction yield is not high.

In the prior art, the refining of DHA hair oil is mostly carried out by chemical refining technology, and the DHA hair oil is degummed, alkali refining, decolorized and deodorized to obtain DHA essential oil. Inevitably, there are some problems in the process technology. For example, in order to achieve the requirement of controlling low acid value, alkali refining usually adds excessive alkali, and some triglycerides are inevitably saponified; high COD wastewater produced by alkali refining will pollute the environment; Alkali refining requires high temperature treatment for a long time, which is easy to cause the product’s peroxide value and anisidine value to increase; the deodorization temperature is high, and the long time is easy to produce trans fatty acids.

Currently, there is still a need to develop new DHA production processes.
Fermentation culture
In the following Examples 1-13, unless otherwise specified, the seed medium formulations used were: glucose 3%, peptone 1%, yeast powder 0.5%, sea crystal 2%, and pH natural (the rest being water). The fermentation medium formula is: glucose 12%, peptone 1%, yeast powder 0.5%, sea crystal 2% (the rest is water).
Example 1
The Schizochytrium sp. ATCC 20888, Schizochytrium limacinum Honda et Yokochi ATCCMYA-1381, and Schizochytrium sp. CGMCC No. 6843 slope-preserved strains were respectively inserted into 400 mL of medium. The 2L shake flask was cultured at a temperature of 25 ° C at a rotation speed of 200 rpm for 24 hours to complete the activated culture of the strain. According to the inoculation amount of 0.4%, the shake flask seed solution was connected to the first-stage seed tank containing the sterilized medium, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 50 rpm for 30 hours to complete the first stage. Seeds are expanded and cultured. The seed liquid of the primary seed tank was connected to the secondary seed tank containing the sterilized medium according to the inoculation amount of 3%, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 75 rpm for 24 hours. Complete secondary seed expansion culture. The seed solution of the secondary seed tank was connected to a fermentor containing the sterilized medium according to a 3% inoculum.
The fermentation process has a culture temperature of 28 ° C, aeration of 1 vvm, a can pressure of 0.02 MPa, a stirring speed of 75 rpm, a carbon source containing 30% of the pretreated crude glycerin, a glucose concentration of 5 g/L, and a nitrogen source. Fermentation culture. During the fermentation process, the glucose concentration, pH, bacterial biomass, crude oil production and DHA yield of the fermentation broth were measured.
After 96 hours of culture, the fermentation was terminated. Table 1 below shows the biomass, crude oil production, DHA production and DHA productivity of the three strains cultured in the original culture mode. Table 2 below shows the mixed fat and fatty acid composition of the gas obtained after fermentation. Analysis results. The biomass, crude oil production and DHA production of CGMCC No.6843 are also shown in Figure 3.
Table 1: Fermentation results of different strains in the original culture mode
Table 2: 100m 3 fermenter original culture method
It can be seen from Table 1 and Table 2 that the yield and fatty acid composition of the three strains are different in the original culture mode, and the Schizochytrium sp. CGMCC No. 6843 is superior to the other two strains. Schizochytrid sp. (Schizochytrium sp. CGMCC No. 6843) was used as the starting strain to optimize the different culture methods.

PATENT

CN106635405

https://patents.google.com/patent/CN106635405A/zh

PATENT

WO2012153345

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012153345

PAPER

NMR

Organic Chemistry 2014 vol. 2014  21 pg. 4548 – 4561

Patent

WO 2015162265

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015162265&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

1 H NMR (500 MHz; CDCI3) δΗ 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH2 bis-allylic), 2.42-2.40 (m, 4H, CH2-C=0, CH2 allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH2 allylic), 0.98 (t, J = 7.5 Hz, 3H, CH3)

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Patent

Publication numberPriority datePublication dateAssigneeTitle
JPS60133094A *1983-12-211985-07-16Nisshin Oil Mills LtdManufacture of high purity eicosapentaenoic acid
JPH07242895A *1993-03-161995-09-19Ikeda Shiyotsuken KkEicosapentaenoic acid of high purity and isolation and purification of lower alcohol ester thereof
JPH09238693A *1996-03-071997-09-16Maruha CorpPurification of highly unsaturated fatty acid
JPH10139718A *1996-11-071998-05-26Kaiyo Bio Technol Kenkyusho:KkProduction of eicosapentaenoic acid
JP2004089048A *2002-08-302004-03-25National Institute Of Advanced Industrial & TechnologyNew labyrinthulacese microorganism and method for producing 4,7,10,13,16-docosapentaenoic acid therewith
JP2007089522A *2005-09-292007-04-12Hisahiro NagaoMethod for producing fatty acid composition containing specific highly unsaturated fatty acid in concentrated state
WO2013172346A1 *2012-05-142013-11-21日本水産株式会社Highly unsaturated fatty acid or highly unsaturated fatty acid ethyl ester with reduced environmental pollutants, and method for producing same
Family To Family Citations
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References

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  2. Jump up^ “Archived copy”. Archived from the original on 2013-07-07. Retrieved 2012-04-21.
  3. Jump up^ The omega end is the one furthest from the carboxyl group.
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  12. Jump up^ O’Connor, Anahad (March 30, 2015). “Fish Oil Claims Not Supported by Research”New York Times. Retrieved October 11, 2015.
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  45. Jump up^ Crawford, M; et al. (2000). “Evidence for the unique function of docosahexaenoic acid (DHA) during the evolution of the modern hominid brain”. Lipids34 (S1): S39–S47. doi:10.1007/BF02562227PMID 10419087.
  46. Jump up^ Carlson BA, Kingston JD (2007). “Docosahexaenoic acid biosynthesis and dietary contingency: Encephalization without aquatic constraint”. Am. J. Hum. Biol19 (4): 585–8. doi:10.1002/ajhb.20683PMID 17546613.

External links

REFERENCE

  1. Calder PC: Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74. doi: 10.3390/nu2030355. Epub 2010 Mar 18. [PubMed:22254027]
  2. Kim HY: Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem. 2007 Jun 29;282(26):18661-5. Epub 2007 May 8. [PubMed:17488715]
  3. Picq M, Chen P, Perez M, Michaud M, Vericel E, Guichardant M, Lagarde M: DHA metabolism: targeting the brain and lipoxygenation. Mol Neurobiol. 2010 Aug;42(1):48-51. doi: 10.1007/s12035-010-8131-7. Epub 2010 Apr 28. [PubMed:20422316]
  4. Butovich IA, Lukyanova SM, Bachmann C: Dihydroxydocosahexaenoic acids of the neuroprotectin D family: synthesis, structure, and inhibition of human 5-lipoxygenase. J Lipid Res. 2006 Nov;47(11):2462-74. Epub 2006 Aug 9. [PubMed:16899822]
  5. Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA: Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006 Feb 1;176(3):1848-59. [PubMed:16424216]
  6. Mas E, Croft KD, Zahra P, Barden A, Mori TA: Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin Chem. 2012 Oct;58(10):1476-84. Epub 2012 Aug 21. [PubMed:22912397]
  7. Chen CT, Kitson AP, Hopperton KE, Domenichiello AF, Trepanier MO, Lin LE, Ermini L, Post M, Thies F, Bazinet RP: Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain. Sci Rep. 2015 Oct 29;5:15791. doi: 10.1038/srep15791. [PubMed:26511533]
  8. Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr: Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J Lipid Res. 2001 Aug;42(8):1257-65. [PubMed:11483627]
  9. Pawlosky RJ, Hibbeln JR, Salem N Jr: Compartmental analyses of plasma n-3 essential fatty acids among male and female smokers and nonsmokers. J Lipid Res. 2007 Apr;48(4):935-43. Epub 2007 Jan 17. [PubMed:17234605]
  10. Cederholm T, Salem N Jr, Palmblad J: omega-3 fatty acids in the prevention of cognitive decline in humans. Adv Nutr. 2013 Nov 6;4(6):672-6. doi: 10.3945/an.113.004556. eCollection 2013 Nov. [PubMed:24228198]
  11. Guesnet P, Alessandri JM: Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) – Implications for dietary recommendations. Biochimie. 2011 Jan;93(1):7-12. doi: 10.1016/j.biochi.2010.05.005. Epub 2010 May 15. [PubMed:20478353]
  12. Kelley DS, Siegel D, Fedor DM, Adkins Y, Mackey BE: DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr. 2009 Mar;139(3):495-501. doi: 10.3945/jn.108.100354. Epub 2009 Jan 21. [PubMed:19158225]
  13. Arterburn LM, Hall EB, Oken H: Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1467S-1476S. [PubMed:16841856]
Docosahexaenoic acid
DHA numbers.svg
Docosahexaenoic-acid-3D-balls.png
Docosahexaenoic-acid-3D-sf.png
Names
IUPAC name

(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid
Other names

cervonic acid
DHA
doconexent (INN)
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.118.398
PubChem CID
UNII
Properties
C22H32O2
Molar mass 328.488 g/mol
Density 0.943 g/cm3
Melting point −44 °C (−47 °F; 229 K)
Boiling point 446.7 °C (836.1 °F; 719.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////Docosahexaenoic acid (22:6(n-3)), ZAD9OKH9JC, доконексен, دوكونيكسانت 二十二碳六烯酸 Doconexent, 6217-54-5, cervonic acid, DHA, doconexent, 81926-93-4

 

  • all-Z-Docosahexaenoic acid
  • AquaGrow Advantage
  • CCRIS 7670
  • Cervonic acid
  • DHA
  • Doconexent
  • Doconexento
  • Doconexento [INN-Spanish]
  • Doconexentum
  • Doconexentum [INN-Latin]
  • Docosahexaenoic acid (all-Z)
  • Doxonexent
  • Efalex
  • Marinol D 50TG
  • Martek DHA HM
  • Monolife 50
  • Ropufa 60
  • UNII-ZAD9OKH9JC

CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O

6
Promega
308064-99-5
2D chemical structure of 308064-99-5
MW: 644.9746
7
4,7,10,13,16,19-Docosahexaenoic acid, (4E,7E,10E,13E,16E,19E)-
391921-09-8
2D chemical structure of 391921-09-8
MW: 328.4928
8
Algal DHA
2D chemical structure of A320050000
MW: 328.4928
9
Omega-3 Fatty Acids
2D chemical structure of F005100000
MW: 909.3808
4,7,10,13,16,19-Docosahexaenoic acid
2091-24-9
2D chemical structure of 2091-24-9
MW: 328.493
2
Doconexent [INN]
6217-54-5
2D chemical structure of 6217-54-5
MW: 328.4928
3
Docosahexaenoic acid, (Z,Z,Z,Z,Z,Z)-
32839-18-2
2D chemical structure of 32839-18-2
MW: 328.493
4
Doconexent sodium
81926-93-4
2D chemical structure of 81926-93-4
MW: 350.4749
5
(14C)Docosahexaenoic acid
93470-46-3
2D chemical structure of 93470-46-3
MW: 328.493

CH4630808


str1

RZHKGHCZVMTIDL-XSRFUOEWSA-N.png

CH4630808, CH-4630808, NA-808

(2S)-2-[(E,2S)-1-[[(1S)-2-(4-but-2-ynoxyphenyl)-1-carboxyethyl]amino]-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioic acid

Molecular Formula: C35H49NO10
Molecular Weight: 643.774 g/mol

Cas 827034-92-4  DOUBLE BOND E, SP ROT (-)

CAS 744208-75-1  E Z NOT DEFINED

  • D-erythro-Pentonic acid, 5-[[(1S)-2-[4-(2-butynyloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecenyl]- (9CI)
  • 5-[[(1S)-2-[4-(2-Butyn-1-yloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecen-1-yl]-D-erythro-pentonic acid
  • D-erythro-Pentonic acid, 5-[[(1S)-2-[4-(2-butyn-1-yloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecen-1-yl]-

Chugai Pharmaceutical (Originator)

str1

Trisodium Der ,CAS 1799542-36-1,  SP ROT (-), MW 709.7097, MF C35 H46 N O10 . 3 Na, Trisodium (2S)-2-[(2S,3E)-1-([(1S)-2-[4-(but-2-yn-1-yloxy)phenyl]-1-carboxylatoethyl]amino)-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioate

SIMILAR

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X12013741

Bioorganic & Medicinal Chemistry Letters

Volume 23, Issue 1, 1 January 2013, Pages 336-339
str1

Image result for CH4630808.

Image result for CH4630808

Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt; (b) n-BuLi, (CH2O)n, THF; (c) Red-Al, 0 C, then I2, THF 40 C; (d) DHP, PPTS, DCM, rt; (e) n-BuLi, (CH2O)n, THF, 78 C to 0 C; (f) TBDPSCl, imidazole, DMF, rt; (g) PPTS, EtOH. 28.6% over 7 steps; (h) L-(+)-DET, Ti(Oi-Pr)4, TBHP, DCM, 97%, >95% ee; (i) Terminal alkyne 7 in Scheme 2, Cp2ZrClH, MeMgCl, CuI, THF, 20 C, 91% yield⁄ ; (j) 2,2-dimethoxypropane, PPTS, DCM, 85% yield⁄ ; (k) TBAF, AcOH, THF, 89% yield⁄ ; (l) oxalyl chloride, DMSO, triethylamine, DCM, 78 C; (m) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O; (n) N,N-dimethylformamide di-tert-butyl acetal, 58% yield in 3 steps⁄ ; (o) 80% AcOH, THF, rt, 90% yield⁄ ; (p) Jones reagent, aqueous acetone, 10 C, 80% yield⁄ ; (q) the corresponding amine, HATU, Hunig base, 85% yield⁄ ; (r) TFA, anisole, DCM, 90% yield⁄ ; (s) H2-Pd/C, EtOH, 80%; (t) NaBH4, THF, MeOH, 93% yield. ⁄ yields when n = 5 and R1 = n-C7H15.

Paper

Development of a Kilogram-Scale Synthesis of a Novel Anti-HCV Agent, CH4930808

CH4630808 corrected

 Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
 Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan
§ Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
Org. Process Res. Dev.201822 (2), pp 236–240
DOI: 10.1021/acs.oprd.7b00383
*E-mail: haneishitys@chugai-pharm.co.jp. Tel.: +81-550-87-9102. Fax: +81-550-87-5326.

Abstract

Abstract Image

Herein, we report the kilogram-scale synthesis of CH4930808 (1) CH 4630808 CORRECTED, a novel anti-hepatitis C virus agent. While pursuing improved productivity using many through-process strategies, we conducted scrupulous impurity control. Finally, we successfully developed a practical and scalable process for the synthesis of (1·1.5Na·2.5H2O), by which we prepared 3.28 kg of the active pharmaceutical ingredient for clinical studies

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00383/suppl_file/op7b00383_si_001.pdf

1H-NMR and 13C-NMR spectra of compound 5·HCl S 3– S 4

1H-NMR spectra of compound 1·1.5 Na·2.5 H2O S 5

13C-NMR spectra compound 1·1.5 Na·2.5 H2O S 6

1H-COSY spectra of compound 1·1.5 Na·2.5 H2O S 7 – S 8

DEPT spectra of compound 1·1.5 Na·2.5 H2O S 9 – S 10

HMBC spectra of compound 1·1.5 Na·2.5 H2O S 11 – S 17

MASS

PATENT

WO 2004071503

WO 2005005372

WO 2006016657

WO 2006088071

WO 2007000994

WO 2007132882

WO 2009154248

WO 2014027696

PAPER

Angewandte Chemie, International Edition (2012), 51(17), 4218-4222, S4218/1-S4218/77.

Bioorganic & Medicinal Chemistry Letters (2013), 23(1), 336-339

PAPER

Organic & Biomolecular Chemistry (2017), 15(31), 6632-6639.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/OB/C7OB01608E#!divAbstract

10.1039/C7OB01608E

Stereoselective synthesis of the viridiofungin analogue NA808 from a chiral tetrahydrofuran-carboxylic acid

 Author affiliations

Abstract

The viridiofungin analogue NA808 was synthesized by the stereoselective Ireland–Claisen rearrangement of dienylmethyl ester, regioselective bromolactonization of β-divinylpropanoic acid and retro-bromolactonization.

Graphical abstract: Stereoselective synthesis of the viridiofungin analogue NA808 from a chiral tetrahydrofuran-carboxylic acid
http://www.rsc.org/suppdata/c7/ob/c7ob01608e/c7ob01608e1.pdf
str1 str2 str3
PATENT
https://patents.google.com/patent/WO2004071503A1/ar

The number of people infected with hepatitis C virus (HCV) is estimated at 1 to 200 million people worldwide, and over 2 million people in Japan. Approximately 50% of these patients migrate to chronic hepatitis, of which approximately 20% become liver cirrhosis, liver cancer after more than 30 years after infection. About 90% of liver cancer is said to be hepatitis C cause. In Japan, more than 20,000 patients die every year from liver cancer associated with HCV infection.

HCV was discovered in 1989 as a major causative virus of non-A non-B hepatitis after transfusion. HCV is an enveloped RNA virus whose genome

It consists of single-stranded (+) RNA and is classified as a genus Hepacivirus of Flaviviridae.

Since HCV avoids the immune mechanism of the host due to a cause which is still unclear, persistent infection is often established even when infected with an adult with developed immune mechanism, progresses to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, surgery It is also known that many patients have liver cancer recurrence due to inflammation that continues to occur in non-cancerous areas.

Therefore, establishment of an effective therapy for hepatitis C is desired, and among them, apart from coping therapy that suppresses inflammation by anti-inflammatory agents, development of a drug that reduces or eradicates HCV in the affected liver It is strongly desired.

Interferon treatment is currently known as the only effective treatment for HCV elimination. However, the number of patients with interferon effective is about one third of all patients. In particular, interferon response to HCV genotype 1 b is very low. Therefore, development of anti-HCV drugs that can replace or be used in combination with interferon is strongly desired.

In recent years, Ribavirin (1 – 3 – D – lipofuranosyl – 1 H – 1, 2, 4 – triazole – 3 – carboxamide) is commercially available as a therapeutic agent for hepatitis C by combining with interferon, Is still low, further new treatment for hepatitis C is desired. In addition, attempts have been made to eliminate viruses by enhancing the immune system of patients, such as interferon agonists, interleukin-12 agonists, etc. However, no effective drug has yet been found.

Since the HCV gene has been cloned, molecular biological analysis of the mechanism and function of viral genes, functions of proteins of each virus and the like has been accompanied by rapid development of forces, replication of virus in host cells, persistent infection, pathogenesis The mechanism such as sexuality has not been sufficiently elucidated, and at the present time, an HCV infection experiment system using reliable cultured cells has not been constructed. Conventionally, when evaluating anti-HCV drugs, alternative alternative virus method using other closely related viruses had to be used.

In recent years, however, it became possible to observe in vitro HCV replication using the nonstructural region part of HCV, so that anti-HCV drugs could be easily evaluated by the replicon assay method (Non-Patent Document 1). The mechanism of H CV RN A replication in this system is believed to be identical to the replication of the full-length HCV RNA genome infected with hepatocytes. Therefore, this system can be said to be a cell-based approach system useful for identifying compounds that inhibit the replication of HCV.

The compounds claimed in this patent are compounds that inhibit the replication of HCV found by the replicon astrocyte method. These inhibitors are considered highly likely to be therapeutic agents for HCV.

Non-Patent Document 1

B. Roman et al., Science (Science), 1999, 285, 110 – 113

Example 14

– 1 (Step 1 1)

According to the method described in the literature (J. Org. Chem. 1989, 45, 5522, BE Marron, et al)

TBDPSO.

a on

Of compound a (7.0 1 g) was synthesized, and anhydrous ethyl ether of this compound a

(700 ml) was cooled to 0 ° C. and bis (2-methoxyethoxy) aluminum hydride (414 mmol, 218 ml, 70% toluene solution) was added slowly. Five minutes after adding the reagent, the ice bath was removed and stirring was continued for 1 hour at room temperature. The reaction solution was cooled to 0 ° C and anhydrous ethyl acetate (1 9.8 ml, 203 mmol) was added slowly. After stirring at the same temperature for 10 minutes, it was cooled to 1 78 ° C., and iodine (76.1 g,

300 thigh 0 1) was added. The temperature was gradually raised to room temperature over 2 hours to complete the reaction. To the reaction solution was added aqueous sodium bisulfite solution, and ethyl acetate was added. The reaction solution was filtered with suction through celite, the organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (100 g) as a light brown oily substance. The obtained crude product was directly used for the next reaction.

Physicochemical properties of compound b

Molecular weight 466

FAB-MS (positive mode, matrix m-NBA) 467 (M + H + ).

Chemical shift value of X H-NMR (in heavy chloroform) δ:

J = 6 Hz), 3.80 (2H, t, J = 6 Hz), 4.18 (2H, t, J = 5 Hz), 2.73 (2H, t, J = 6 Hz), 1.49 Hz, 5.91 (1 H, t, J = 5 Hz), 7.35 – 7.46 (6 H, m), 7.65 – 7.69 (4 H, m)

1 -2 (Step 1 – 2)

TBDPS

Dichloro port methane solution of compound b obtained in the above reaction (300 ml) was cooled to 0 ° C, dihydropyran (22. 7 ml, 248删0 plus 1). Pyridinium paratoluenesulfonic acid (260 mg, 1 mol) was added to this solution. After 1 hour sodium bicarbonate water was added to stop the reaction. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound c (108 g) thus obtained was directly used for the next reaction.

Physicochemical properties of compound c

Molecular weight 550

FAB-MS (positive mode, matrix m-NBA) 551 (M + H + )

Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:

3.46-3.58 (2H, m), 3.76 (2H, t, J = 6 Hz), 3.82 (2H, t, J = 6 Hz), 1.04 (9H, s), 1.49-1.91 J = 13, 6 Hz), 4.65 (1 H, t, J = 3 Hz), 5.91 (1 H, t (s)), 4.93 (1 H, m), 4.06 (1 H, dd, J = 13, 6 Hz) , J = 5 Hz) 7.35 – 7.43 (6 H, m), 7.65 – 7.69 (4 H, m)

1-3 (Step 1- 3)

The crude compound c (4. 73 g) was dissolved in anhydrous ethyl ether (30 ml) and cooled to 1 78 ° C. Tert-butyllithium (1 7. 2 mol, 1 0.7 ml, 1.6 N pentane solution) was added slowly. After stirring at the same temperature for 1 hour, paraformaldehyde (1 8.9 mraol, 570 mg) was added and the mixture was warmed to 0 ° C. for 30 minutes at the same temperature and stirred for 1 hour. An aqueous solution of salthyanmonium was added to stop the reaction, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 4: 1) to give compound d (1. 635 g) as a colorless oily substance.

Physicochemical properties of compound d

Molecular weight 454

FAB-MS (positive mode, matrix m-NBA) 455 (M + H + )

^ – NMR (chemical shift value in heavy chloroform) δ:

J = 6 Hz), 3.03 (1 H, t, J = 6 Hz), 3.47 – 3.58 (2 H, m), 3.75 – 3.92 (2 H, (3 H, m), 4.08 – 4.26 (4 H, m), 4.68 (1 H, t, 3 Hz),

5.53 (1 H, t, J = 7 Hz) 7.35 – 7.47 (6 H, m), 7.64 – 7.68 (4 H, m)

1 -4 (Step 1 – 4)

An anhydrous N, N-dimethylformamide solution (2 ml) of the compound d (34 mg, 0. 76 mmol) and imidazole (71 mg, 1.14 mmol) was cooled to 0 ° C and tert- Chlorosilane (0: 2 ml, 0. 76 mmol) was capped and stirred for 2 hours. An ammonium chloride aqueous solution was added to stop the reaction, and the mixture was extracted with hexane. The organic layer was washed with water twice, followed by saturated brine and dried over anhydrous sodium sulfate. And concentrated under reduced pressure to obtain crude compound e (554 mg) as a colorless oily substance.

Physicochemical properties of compound e

FAB-MS (positive mode, matrix m-NBA) 715 (M + Na + )

Chemical shift value of ‘1 H-NMR (in heavy mouth formium) δ:

(4H, m), 1.00 J = 7 Hz), 5.43 (1 H, t, J = 7 Hz), 7.29 – 7.48 (12 H, m), 4.00 – 4.09 (1 H, m), 4.14 , 7.57 – 7.78 (8 H, m)

1-5 (Step 1- 5)

f

Pyridinium paratoluenesulfonic acid (9 O mg, 0.36 mmol) was added to an ethanol solution (6 ml) of the compound e (1. 16 g, 1. 67 mmol), and the mixture was stirred at 60 ° C. for 3.5 hours. After cooling the solution to room temperature, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound f (825 mg, 81%) as a colorless oily substance.

Physicochemical properties of compound f

Molecular weight 608

FAB-MS (positive mode, matrix m-NBA) 631 (M + Na + )

^ – NMR (chemical shift value in heavy chloroform) δ:

(2H, t, J = 7 Hz), 3.75 (2H, t, J = 7 Hz), 3.90 (2H, t, J = 7 Hz), 1.01 (9H, s), 1.01 , 7.59-7.47 (12 H m), 7.57-7.75 (8 H, m), 4.14 (2 H, s), 5 47 (1 H, t, J =

1-6 (Step 1-6)

9

The round bottom flask containing the rotor was heated and dried under reduced pressure and then purged with nitrogen, and anhydrous

Dichloromethane (60 ml) was added and cooled to _20 ° C. Titanium tetraisopropoxide (2.3 3 ml, 7.8 8 mmol), L 1 (+) – Jetyl tartrate (1.6 2 ml, 9. 4 6 min. 0 1) was added successively, and after stirring for 15 minutes, compound f (4.80 g, 7. 88 mmol) in dichloromethane (30 ml), and the mixture was stirred for 15 minutes. Cool to _ 25 ° C and add tert-butyl hydroperoxide (5. 25 ml,

15. 8 mmol, 3 N dichloromethane solution) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 2 hours, dimethylsulfide (1.1 ml) was added, and the mixture was further stirred at the same temperature for 1 hour. A 10% aqueous solution of tartaric acid was added to the reaction solution and the mixture was stirred for 30 minutes, and then stirred at room temperature for 1 hour. The organic layer was separated, the aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained was concentrated under reduced pressure, and purified by force RAM chromatography (silica gel, hexane / monoacetic acid ethyl 9: 1). Compound g (4. 78 g, 97%) was obtained as a colorless oily substance. The asymmetric yield (> 95% ee) was determined by NMR analysis of the corresponding MT PA ester.

Physicochemical properties of compound g

Molecular weight 624

F AB-MS (positive mode, matrix m-NBA) 647 (M + Na + )

– Chemical shift value of NMR (in heavy chloroform) δ:

J = 14, 7 Hz), 2.23 (1 H, dt, J = 14, 1 H), 1.02 (9 H, s), 1.03 (9 H, s), 1.72 (6H, m), 7.32-7.45 (12H, m), 7.60- 7.65 (8H, m), 6.5 Hz), 3.17 (1H, dd, J = 6, 5 Hz), 3.55-3.79

1 – 7 (Step 1 – 7)

To a solution (100 ml) of the compound α (10. 45 g, 37.2 mmol) produced in the step 2-3 of Production Example 1 described below in an anhydrous tetrahydrofuran solution (100 ml) under a nitrogen atmosphere was added biscyclopentadienylzirconium hydride chloride (10. lg, 37.2 mol) was added at room temperature and stirred for 30 minutes. The resulting solution was cooled to 1780C and methyl magnesium chloride (24.7 ml, 74 mmol, 3 N tetrahydrofuran

Furan solution), and the mixture was stirred for 5 minutes. Monovalent copper iodide (500 mg, 7.2 mM) was added to this solution and the temperature was gradually raised to _ 30 ° C. An anhydrous tetrahydrofuran solution (70 ml) of the compound g (4. 49 g) was added over 20 minutes, and after completion of the dropwise addition, the mixture was stirred at 25 ° C. overnight. The saturated ammonium chloride aqueous solution was slowly added, the reaction was stopped, and the temperature was gradually raised to room temperature. The mixture was stirred at room temperature for 10 hours and the resulting white solid was filtered off through celite. The celite was washed thoroughly with ethyl acetate and the organic layer was separated. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate. Concentrated under reduced pressure and the obtained crude product was purified by column chromatography (silica gel, hexyl acetate

20: 1 to 9: 1) to give compound h (5. 96 g, 91%) as a pale yellow oily substance.

Physicochemical properties of compound h

Molecular weight 907

F AB – MS (negative mode, matrix πι – Α Β A) 906 (Μ – Η + )

Chemical shift value of 1 H-NMR (in heavy chloroform) δ:

0.88 (3H, t, 
0.99 (9H, s), 1.04 (9H, s), 1.18-1.63 (22H, m), 1.78-2.01 (4H, m), 2.44-2.57 (1H, m), 3.00 (1H, t, J = 6 Hz), 3.59-3.92 (10H, m), 4.28 (1H, s), 5.37-5.55 (2H, m), 7.29-7.65 (20H, m)

1-8 (Step 1-8)

Compound h (5.30 g, 5.84 dragon ol) was dissolved in dichloromethane (200 ml) and 2, 2-dimethoxypropane (150 ml), pyridinium paratoluenesulfonic acid (15 mg, 0.058 mmol) was added , And the mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 20: 1). Compound i (4. 69 g, 86%) was obtained as a pale yellow oily substance.

Physicochemical properties of Compound i

Molecular weight 947

F AB-MS (negative mode, matrix m-NBA) 946 (M – H + )

Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:

(1 H, m), 0.88 (3H, t, J = 6 Hz), 1.02 (9H, s), 1.05 (9H, s), 1.14-1.63 (28H, m), 1. 2.16 (2H, m), 7.28 – 7.47 (12H, m), 7.61 – 7.69 (1H, d, J = 10 Hz), 3.64-3.86 (6H, m 3.92 (s, 4H), 5.36-5.42 8 H, m) 1 – 9 (Step 1 – 9)

A tetrahydrofuran solution (50 ml) of the compound i (4. 39 g, 4. 64 mmol) was cooled to 0 ° C., tetrabutylammonium fluoride (10. 2 ml, 10, 2 difficulty, 1 M tetrahydrofuran solution) and Acetic acid (0. 53 ml, 9. 27 mmol) was added. The temperature was gradually raised to room temperature and stirred for 2 days. A saturated ammonium chloride aqueous solution was added and the mixture was extracted twice with dichloromethane. The combined organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 3: 2) to obtain the compound〗 (1. 73 g, 81%) Was obtained as a pale yellow oily substance.

Physicochemical properties of compound j

Molecular weight 470

F AB-MS (positive mode, matrix m-NBA) 493 (M + Na + )

Chemical shift value of X H-NMR (in heavy chloroform) δ:

2.73 (1H, dt, J = 6, 10 Hz), 2.95 (3H, t, J = 6 Hz), 1.17-1.73 (26H, m), 1.91-2.16 (4H, m), 2.4 J = 15, 7 Hz (1 H, dt, J = 15 Hz), 3.48 (1 H, d, J = 1 Hz), 3.63-4.01 (m, 10 H), 5.15 )

1-10 (Step 1- 10)

Under an atmosphere of nitrogen, a solution of oxalyl chloride (0. 575 ml, 6. 6 mol) in anhydrous dichloromethane (17 ml) was cooled to 178 ° C. and dimethyl sulfoxide

(0. 9 36 ml, 1 3 2 minol) in dichloromethane (1 ml) was added dropwise and the mixture was stirred for 15 minutes. Dichloromethane solution (5 ml) of compound j (388 mg, 0. 824 aura) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, then terethylamine (3 ml, 21.4fflmol) was added and the mixture was stirred for 30 minutes. The cooling bath was removed and a low-boiling compound was removed by blowing a nitrogen gas stream to the solution, followed by drying under reduced pressure. Jether ether (15 ml) was added to the residue, and insoluble matter was filtered off and concentrated. After this operation was carried out twice, the obtained residue was immediately used for the next reaction.

The crude dialdehyde was dissolved in 2-methyl-2-propanol (24 ml) and 2-methyl-2-butene (6 ml) and cooled to about 5 to 7 ° C. To this solution was added sodium chlorite (745 mg, 8. 24 mmol) and sodium dihydrogenphosphate

(745 mg, 6. 2 l mmol) in water (7. 45 ml) was slowly added dropwise. After 2 hours the mixture was cooled to 0 ° C. and aqueous sodium hydrogenphosphate solution was added to adjust PH to approximately 5. The mixture was extracted three times with dichloromethane, and the combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure afforded a pale yellow oily residue which was immediately used for the next reaction without further purification.

The crude dicarboxylic acid was dissolved in N, N-dimethylformamide di tert-butylacetal (4. 5 ml) and stirred at 70 ° C. for 1 hour. The low boiling point compound was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound k (340 mg, 60%) as a pale yellow oily substance.

Physicochemical properties of compound k

Molecular weight 6 10

FAB-MS (positive mode, matrix m-NBA) (M + H + ) 611, (M + Na + ) 633

^ – NMR (chemical shift value in heavy chloroform) δ:

(2H, ABq, J = 15, 18 Hz), 2.93 (1 H, q, J = 6 Hz), 1.18 J = 7 Hz), 3.82-3.88 (2H, m), 3.92 (4H, s), 5.51-5.69 (2H, m)

1- 11 (Step 1 – 1 1)

Compound k (34 mg, 0. 556 mmol) was dissolved in tetrahydrofuran (1 ml), 80% acetic acid aqueous solution (10 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was slowly added into a saturated aqueous solution of sodium bicarbonate to neutralize acetic acid and then extracted twice with ethyl acetate. Drying over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure to give compound t

(290 mg, 99%) as a pale yellow oil.

Physicochemical properties of compound f

Molecular weight 526

FAB – MS (positive mode, matrix m – NBA) (M + H + ) 527,

(M + Na + ) 549

Chemical shift value of iH-NMR (in heavy chloroform) δ:

(2H, Q 
, 2.25-2.41 (5H, m), 1.99 (1H, d, J = 7 Hz), 2.04 (1H, d (1H, t, 7 Hz), 1.18- 1.68 (36H, ra), 2.01 J = 7 Hz), 5.58 (1 H, dt, J = 16, 6 Hz), 3.62 (3H, m), 3.99 (1H, s), 5.42

1-12 (Step 1 – 12)

Acetone (45 ml) was cooled to 0 ° C. and Jyones reagent (0.48 ml, 0.9 mmol, 1.8 9 N) was added. An acetone solution (3 ml) of the compound (216 mg, 0, 41) was slowly added dropwise to this mixture. Stirring at the same temperature for 1 hour

After stirring, the reaction was stopped by adding an aqueous sodium bisulfite solution until the yellow color of the reaction disappeared and a dark green precipitate appeared. A saturated saline solution (20 ml) was added thereto, and the mixture was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane monomethanol 50: 1 to 20: 1) to give compound m (198 mg, 89%) as a pale yellow oily substance.

Physicochemical properties of compound m

Molecular weight 541

ESI (L CZMS positive mode) (M + H + ) 542

Chemical shift value of 1 H – NMR (in heavy mouth formium) δ:

J = 8 Hz), 2.70 (1 H, t, J = 6 Hz), 1.16 – 1.67 (36 H, m), 1.99 (2 H, J = 15, 5 Hz), 2.68 (1 H, d, J = 9 Hz), 3.28 )

1 – 13 (Step 1 – 13)

A solution of the compound m (6. 4 mg, 0.12 mmol), a solution of (S) -4- (2-butynyloxy) phenylalanine t-butyl ester hydrochloride (4.6 mg, 0.114 mmol) in N, N-dimethylformamide lml) was cooled to 110 ° C and N, N-diisopropylethylamine (0 ° 5 ml, 0.026 mmol), O- (7-azobenzotriazole 1- 1, N, N, N ‘, N’ – tetramethyluronium hexafluorophosphate (7.0 mg, 0.17 mmol) was added sequentially. The temperature was raised to room temperature with stirring and stirred overnight. An aqueous ammonium chloride solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by thin layer silica gel thin layer chromatography (hexane / ethyl acetate 7: 3) to obtain compound n

(8. 4 mg, 88%) as a colorless solid.

Physicochemical properties of compound n

^ – NMR (chemical shift value in heavy chloroform) δ:

J = 1.9 Hz), 1.90-2.03 (2H, m), 2.29 – 2.43 (4H, t, J = 6.9 Hz), 1 .12-1.68 (45H, m), 1.85 (3H, m), 4.22 (1 H, s), 4.57 – 4.74 (3H, d, J = 16.5 Hz) J = 8.6 Hz), 7.01 (1 H, d, J = 8.6 Hz), 5.46 (1 H, dd J = 9.2, 15.2 Hz), 5.64 (1 H, dt, J = 6.6, 15.2 Hz) 7.9 Hz), 7.13 (2H, d, J – 8.6 Hz)

1-14 (Step 1 – 14)

Dichloromethane solution (3 ml) of compound n (8.4 mg) was cooled to 0 ° C and anisanol (0.01 ml) and trifluoroacetic acid (1 ml) were sequentially added. Slowly warmed to room temperature and stirred overnight. After concentrating the reaction solution under reduced pressure and azeotropically twice with benzene, the residue was purified with megabond-1-butanediol (500 mg, Parian) (dichloromethane-methanol = 20: 1) to obtain Compound 21 (5. 3 mg, 80% As a colorless solid.

Physicochemical properties of compound 21 ‘

Molecular weight 643

ESI (LC / MS positive mode) 644 (M + H +)

Chemical shift value of 1 H – NMR (in methanol d – 4) δ:

0.90 (3 H, t, J = 7 Hz), 1.19 – 1.38 (1 m), 1.42 – 1.60 (cm), 1.82 (3 H, t,

J = 2 Hz), 2.8 – 2.98 (2 H, m), 3.09 – 3.23 (2 H, m), 2.8 (2H, d, J = 9 Hz) 7 7.13 (2H, d, J = 9 Hz), 4.53 – 4.67 (3H, m), 5.39-5.61 (2H, m), 6.83

Patent ID

Patent Title

Submitted Date

Granted Date

US2011098477 Method Of Producing Compound Having Anti-Hcv Activity
2011-04-28
US2010152457 Intermediate compound for synthesis of viridiofungin a derivative
2010-06-17
US8030496 Intermediate compound for synthesis of viridiofungin a derivative
2010-06-17
2011-10-04
US7897783 Intermediate compound for synthesis of viridiofungin a derivative
2008-11-27
2011-03-01
Patent ID

Patent Title

Submitted Date

Granted Date

US2011160252 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OR PREVENTION OF HBV INFECTION
2011-06-30
US2010274026 Virus therapeutic drug
2010-10-28
US7776918 Remedy for viral disease
2006-09-28
2010-08-17
US7378446 Compound having anti-hcv activity and process for producing the same
2006-08-31
2008-05-27
US9266853 ORALLY AVAILABLE VIRIDIOFUNGIN DERIVATIVE POSSESSING ANTI-HCV ACTIVITY
2013-08-16
2015-07-30

References

Discovery of NA808: A novel host targeting anti-HCV agent
237th Am Chem Soc (ACS) Natl Meet (March 22-26, Salt Lake City) 2009, Abst MEDI 14

///////////////CH4630808, CH 4630808, NA 808

Viridiofungin A.png

Viridiofungin A

CCCCCCCC(=O)CCCCCCC=CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)O)C(CC(=O)O)(C(=O)O)O

TITLE COMPD

O=C(O)[C@](O)(CC(=O)O)[C@H](\C=C\CCCCCCC(=O)CCCCCCC)C(=O)N[C@@H](Cc1ccc(OCC#CC)cc1)C(=O)O

BMS-986169


imgUNVYDSCXINFREZ-BHDDXSALSA-N.pngBDBM198728.png

BMS-986169

CAS 1801151-08-5 Related CAS : 1801151-09-6   1801151-08-5
Chemical Formula: C23H27FN2O2
Molecular Weight: 382.4794
Elemental Analysis: C, 72.23; H, 7.12; F, 4.97; N, 7.32; O, 8.37

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

(3R)-3-[(3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl]-1-[(4-methylphenyl)methyl]pyrrolidin-2-one

Preclinical

BMS-986169 is a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder. BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets.

Chemical structures of BMS-986169 and the phosphate prodrug BMS-986163.

Chemical structures of BMS-986169 and the phosphate prodrug BMS-986163. 
Image result for BMS-986169

 

PAPER

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

 Discovery Chemistry and Molecular TechnologiesBristol-Myers Squibb Research and Development, Princeton, New Jersey 08540, United States
 Drug Product Science & Technology, Materials Science & EngineeringBristol-Myers Squibb Research and Development, Princeton, New Jersey 08540, United States
§ Department of Discovery SynthesisBiocon Bristol-Myers Squibb Research Center (BBRC), Bangalore 560099, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00120
Abstract Image

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor 1 (BMS-986169), which relies upon a stereospecific SN2 alkylation strategy and a robust process for the preparation of its phosphate prodrug 28 (BMS-986163) from parent 1 using POCl3. A deoxyfluorination reaction employing bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00120/suppl_file/op8b00120_si_001.pdf

PAPER

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.8b00080

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder

 Bristol-Myers Squibb Research and Development5 Research Parkway, Wallingford, Connecticut 06492, United States
 Biocon Bristol-Myers Squibb Research Center, Bangalore, India
§ Bristol-Myers Squibb Research and Development3551 Lawrenceville Road, Princeton, New Jersey 08648, United States
ACS Med. Chem. Lett.20189 (5), pp 472–477
DOI: 10.1021/acsmedchemlett.8b00080
*Phone 203-677-6701. E-mail: lawrence.marcin@bms.com.

 

Abstract Image

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 56, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Image result for BMS-986169

Image result for BMS-986169

 

 

(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-
methylbenzyl)pyrrolidin-2-one (compound 23) and (R)-3-((3S,4S)-3-fluoro-4-(4-
hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169, compound
5)……https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.8b00080/suppl_file/ml8b00080_si_001.pdf

Analytical data for BMS-986169 (compound 5): LCMS (C23H27FN2O2, MW 382.2, ESAPI),
observed 383.2 m/z (M+H)+; []D20 = +6.09 (c = 1.15, MeOH); Anal. Calcd for
C23H27FN2O2 (382.21): C, 72.22; H, 7.12; N, 7.32. Found: C, 72.26; H, 7.05; N, 7.31; HRMS
(ESI) Calcd for C23H27N2O2, 383.2118. Found, 383.2129;

13C NMR (126 MHz, chloroformd)
172.4, 155.0, 137.5, 133.0, 132.8, 129.4, 128.6, 128.2, 115.6, 91.6 (d, J=173.5 Hz),
65.0, 54.5 (d, J=25.4 Hz), 48.3, 47.7 (d, J=17.3 Hz), 46.7, 43.6, 31.5, 21.1, 19.2;(500 MHz, chloroform-d) 7.23 – 7.11 (m, 5H), 6.92 (d, J=8.5 Hz, 2H), 6.18 (br. s., 1H),
4.79 – 4.55 (m, 1H), 4.57 – 4.33 (m, 2H), 3.72 (t, J=8.7 Hz, 1H), 3.46 – 3.30 (m, 1H), 3.30 –
3.09 (m, 2H), 2.82 (d, J=8.5 Hz, 1H), 2.73 – 2.56 (m, 2H), 2.49 (d, J=2.5 Hz, 1H), 2.36 (s,
3H), 2.21 – 1.98 (m, 2H), 1.87 (br. s., 2H). The corresponding 1H NMR spectrum for
compound 5 is shown below

1H NMR

 

PATENT

https://patents.google.com/patent/US9221796B2/und

InventorDalton KingLorin A. Thompson, IIIJianliang ShiSrinivasan ThangathirupathyJayakumar Sankara WarrierImadul IslamJohn E. Macor

Current Assignee Bristol-Myers Squibb Co

https://patents.google.com/patent/WO2015105772A1/und

N-Methyl-D-aspartate (NMDA) receptors are ion channels which are gated by the binding of glutamate, an excitatory neurotransmitter in the central nervous system. They are thought to play a key role in the development of a number of neurological diseases, including depression, neuropathic pain, Alzheimer’s disease, and Parkinson’s disease. Functional NMDA receptors are tetrameric structures primarily composed of two NRl and two NR2 subunits. The NR2 subunit is further subdivided into four individual subtypes: NR2A, NR2B, NR2C, and NR2D, which are differentially distributed throughout the brain. Antagonists or allosteric modulators of NMDA receptors, in particular NR2B subunit-containing channels, have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437).

The NR2B receptor contains additional ligand binding sites in additon to that for glutamate. Non-selective NMDA antagonists such as Ketamine are pore blockers, interfering with the transport of Ca++ through the channel. Ketamine has demonstrated rapid and enduring antidepressant properties in human clinical trials as an i.v. drug. Additionally, efficacy was maintained with repeated, intermittent infusions of Ketamine (Zarate et al., 2006, Arch. Gen. Psychiatry 63: 856-864). This class of drugs, though, has limited therapeutic value because of its CNS side effects, including dissociative effects.

An allosteric, non-competitive binding site has also been identified in the N-terminal domain of NR2B. Agents which bind selectively at this site, such as

Traxoprodil, exhibited a sustained antidepressant response and improved side effect profile in human clinical trials as an i.v. drug (Preskorn et al., 2008, J. Clin.

PsychopharmacoL, 28: 631-637, and F. S. Menniti, et al, 1998, CNS Drug Reviews, 4, 4, 307-322). However, development of drugs from this class has been hindered by low bioavailability, poor pharmacokinetics, and lack of selectivity against other pharmacological targets including the hERG ion channel. Blockade of the hERG ion channel can lead to cardiac arrythmias, including the potentially fatal Torsades de pointe, thus selectivity against this channel is critical. Thus, in the treatment of major depressive disorder, there remains an unmet clinical need for the development of effective NR2B-selective negative allosteric modulators which have a favorable tolerability profile.

NR2B receptor antagonists have been disclosed in PCT publication WO 2009/006437.

The invention provides technical advantages, for example, the compounds are novel and are ligands for the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

Synthetic Scheme 1

The l-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V may be reacted with (4-oxy-phenyl)cyclic amines VI in the presence of base to produce protected products VII, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products I, which may be separated into individual enantiomers/diastereomers I*, as shown in synthetic scheme 2.

Synthetic Scheme 2

I I*

Compounds la may be prepared by condensing l-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with substituted 4(4-oxyphenyl)piperidines Vllla-c to generate protected intermediates IX, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products la, which may be separated into individual enantiomers/diastereomers la*, as shown in synthetic scheme 3.

Synthetic Scheme 3

The 4(4-oxyphenyl)piperidines Vllla-c may be synthesized in turn by a sequence starting with a protected tetrahydropiperidine X, which can be hydroxylated via hydroboration/oxidation to give the protected hydroxypiperidine XI, which may be either directly transformed into the protected fluoropiperidine XII by treatment with DAST or oxidized into the protected 3-oxopiperidine XIII, which may be further transformed into protected 3,3-difluoropiperidines XIV via treatment with DAST. XI, XII, and XIV may be transformed into Villa, Vlllb, and VIIIc, respectively, by employing cleaving conditions appropriate for the protecting group (PG2), as shown in synthetic scheme 3 a.

S nthetic scheme 3 a

Chiral

Cleavage Individual enantiomers/

G2P-N diastereomers

separation

conditions

OH 
Villa*

Villa

XI

Chiral

Cleavage Individual enantiomers/

HN

G2P-N diastereomers

%_\J> PQ separation

PG1 conditions

R F

F Vlllb*

Vlllb

XII

Chiral

Individual enantiomers/

G2P- diastereomers separation

Vlllc*

For tetrahydropyridines X which are not commercially available may be synthesized by coupling protected bromophenols XV with protected unsaturated

piperidineboronic acids XVI, as shown in synthetic scheme 4a.

Synthetic scheme 4a:

For tetrahydropyridines X which are not commercially available may be synthesized by adding the anion generated from protected bromophenols XV to a protected 4-piperidinone XVII to yield 4-phenyl-4-piperidinol XVIII, which may be dehydrated under acid conditions to yield the desired X, as shown in synthetic scheme 4b.

Synthetic scheme 4b:

l-Phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V may be condensed with isolated individual enantiomers VIIIa-c*, which results in diastereomers 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones IX*, which may be deprotected and separated to give final products la*, as shown in scheme 5.

Alternatively, the backbone scaffold may be synthesized by condensing 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with hydroxypiperidines Villa to yield the protected 3-fluoropiperidines IXa, which may themselves be converted to the protected 3-fluoropiperidines IXb or oxidized to the ketones XIX, which may be converted to the 3,3-difluoropiperidines Ixc, as shown in scheme 6. The final compounds can then be isolated after the deprotection of IXa-c.

Scheme 6

Example 46, P-1 Example 46, P-2

(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one.

Example 46, P-3 Example 46, P-4

Step A. (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol.

To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0 °C under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl- 4-(4-methoxyphenyl)-l,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added

sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30%> hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na2S04, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69%> yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H+).

Step B. (±)-re -(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol.

To a solution of (±)-re/-(35′,45)-l-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10 % Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-de) δ ppm 7.10 – 7.15 (m, 2 H) 6.80 – 6.86 (m, 2 H) 4.30 (d, J=5.27 Hz, 1 H) 3.37 – 3.43 (m, 1 H) 3.04 (dd, J=11.58, 4.36 Hz, 1 H) 2.86 (d, J=12.17 Hz, 1 H) 2.43 (td, J=12.09, 2.67 Hz, 1 H) 2.22 – 2.35 (m, 2 H) 1.57 – 1.63 (m, 1 H) 1.43 – 1.54 (m, 1 H).

To a solution of (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7 mmol) in DCM (150 mL) at -10°C under nitrogen was added a 1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The reaction mixture was allowed to warm to rt, stired for 2 h, and then rechilled to 0 °C and quenched by the addition of a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was washed with 250 mL of DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred for an additional 2 h. The mixture was then extracted with 200 mL ethyl acetate and the organic layer was separated, dried over Na2S04,filtered, and evaporated under reduced pressure to (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 12 mmol, 56 % yield) which was used without further purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H+ -2 t-butyl), 370; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J=8.66 Hz, 2 H) 7.08 (d, J=8.66 Hz, 2 H) 4.85 (d, J=5.65 Hz, 1 H) 4.13 (d, J=8.41 Hz, 1 H) 3.97 (d, J=10.48 Hz, 1 H) 3.45 (tt, J=10.27, 5.19 Hz, 1 H) 1.67 (d, J=3.39 Hz, 1 H) 1.50 – 1.59 (m, 1 H) 1.49 (s, 11 H).

Step D. (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

To a solution of (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between IN HC1 (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na2S04 and evaporated under reduced pressure to give (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (5 g, 15 mmol, 92 % yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H+ – 1-butyl), 279 (M+H+ – t-butyl+CH3CN), 1H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (d, J=8.53 Hz, 2 H) 6.66 (d, J=8.53 Hz, 2 H) 4.70 (d, J=5.02 Hz, 1 H) 4.09 (br. s., 1 H) 3.94 (d, J=11.55 Hz, 1 H) 3.35 – 3.41 (m, 1 H) 2.66 – 2.77 (m, 1 H) 2.29 – 2.39 (m, 1 H) 1.63 (dd, J=13.30, 3.26 Hz, 1 H) 1.44 – 1.52 (m, 1 H) 1.42 (s, 9 H).

Step E. (3S,4S)-tert-Butyl 3 -hydroxy-4-(4-hydroxyphenyl)piperidine-l -carboxylate and (3R, -tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

E-1 E-2

(±)-rel-(3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine- 1 -carboxylate (5 g, 17 mmol, from step D) was subjected to chiral SFC separation (method C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0 % yield) and E-2 (2.4 g, 8.18 mmol, 48.0 % yield). Data for E-1 : chiral HPLC (method A5 ) retention time 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2 min.

Step F. (3R,4R)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate.

A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydous Na2S04, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l -carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z = 310 (M+H+ – t-butyl -water), 328 (M+H+ -t-butyl).

Step G. (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride.

A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCI in dioxane was stirred at rt for 2h. The reaction was then evaporated to dryness to yield 550 mg of (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H+).

Step H. 3-((3i?,4i?)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-l -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .

A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3i?,4i?)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60 °C for lh, 80 °C for 1 h, 100 °C for 1 h and 120 °C for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3 ?,4i?)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H+).

Step I. 3-((3R, 4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .

A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0 °C was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3i?,4i?)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H+).

Step J. 3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)-l -(4-methylbenzyl)pyrrolidin-2-one .

A mixture of 3-((Ji?,4i?)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cm2 hydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((Ji?,4i?)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H+).

Step K. (5)-3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl>

methylbenzyl)pyrrolidin-2-one and (i?)-3-((3i?,4i?)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

The diastereomeric mixture from step J was separated by SFC method C-7 to yield homochiral Examples 46 P-l (29.3 mg) and P-2 (32.8 mg). Data for P-l (S)-3-((3R, 4R)-3 -fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC (method C-6) RT 4.1 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.76 – 1.86 (m, 2 H) 2.07 (d, J=8.53 Hz, 1 H) 2.13 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.43 (s, 0 H) 2.55 – 2.60 (m, 1 H) 2.65 – 2.70 (m, 1 H) 2.75 (br. s., 1 H) 3.20 – 3.30 (m, 2 H) 3.38 – 3.45 (m, 1 H) 3.70 (t, J=8.78 Hz, 1 H) 4.44 (t, J=79.81 Hz, 3 H) 4.63 – 4.71 (m, 1 H) 6.70 – 6.80 (m, 2 H) 7.07 – 7.15 (m, 2 H) 7.07 – 7.12 (m, 1 H) 7.13 – 7.22 (m, 4 H); 19F NMR δ ppm -184.171. Data for P-2: (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method C-6) RT 6.92 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.80 – 1.90 (m, 2 H) 2.07 (d, J=8.03 Hz, 1 H) 2.19 (s, 1 H) 2.34 (s, 3 H) 2.41 – 2.48 (m, 1 H) 2.66 (d, J=4.52 Hz, 2 H) 2.95 – 3.03 (m, 1 H) 3.10 – 3.18 (m, 1 H) 3.20 – 3.30 (m, 2 H) 3.68 – 3.78 (m, 1 H) 4.38 (s, 1 H) 4.51 (d, J=14.56 Hz, 2 H) 6.70 – 6.80 (m, 2 H) 7.05 – 7.13 (m, 2 H) 7.13 – 7.22 (m, 4 H); 19F NMR δ ppm -184.311.

(3S,4S)-tert-Butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-l from step E) in DCM (5 mL) cooled to 0 °C was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2h. The reaction was slowly quenched with 50 mL of a 10%> aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layerss were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of {3S,4S)-tert-bvXy\ 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-

carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m z 240.1(M+H+).

Step M. 4-((3S’,4S)-3-Fluoropi ridin-4-yl)phenol hydrochloride.

A mixture of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate (390 mg, 1.3 mmol) and 4M HC1 in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirred at rt for 2 hr. It was then concentrated to dryness, washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was isolated by filtration. Yield: 260 mg of 4-((J£4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS

(method Q) RT 0.46 min, mz 196.1(M+H+) 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (br. s., 4 H), 8.92 – 8.68 (m, 1 H), 7.14 (d, J= 8.5 Hz, 1 H), 7.06 (d, J= 8.5 Hz, 2 H), 6.82 – 6.73 (m, 2 H), 5.07 – 4.85 (m, 1 H), 3.77 – 3.36 (m, 9 H), 3.32 – 3.22 (m, 2 H), 3.13 – 2.85 (m, 5 H), 2.06 – 1.88 (m, H).

Step N. 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120 °C in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3 4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H+).

Step O. (5)-3-((3lS,45)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one and (i?)-3-((35,,45)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

A portion of the diasteromer mixture from step N (130 mg) was subjected to chiral purification via SFC (method C-7) to give homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3 (S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT = 2.10 min, m/z 383.2 (M+H+); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min;1H NMR (400 MHz, methanol-d4) δ ppm 1.76 – 1.86 (m, 2 H) 2.06 (d, J=8.53 Hz, 1 H) 2.10 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.40 – 2.48 (m, 1 H) 2.53 – 2.60 (m, 1 H) 2.61 – 2.70 (m, 2 H) 2.95 -3.01 (m, 1 H) 3.01 (s, 2 H) 3.10 – 3.16 (m, 1 H) 3.18 – 3.28 (m, 2 H) 3.72 (s, 1 H) 4.35 – 4.41 (m, 1 H) 4.46 – 4.70 (m, 2 H) 6.72 – 6.80 (m, 2 H) 7.05 – 7.23 (m, 6 H). Data for P-4 (R)-3-((3S,4S)-3-fiuoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H+);; HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2 H) 2.06 (d, J=9.04 Hz, 2 H) 2.33 (s, 3 H) 2.43 (s, 1 H) 2.55 (br s, 1 H) 2.66 (d, J=40.16 Hz, 2 H) 2.75 – 2.80 (m, 1 H) 2.96 – 3.10 (m, 2 H) 3.20 – 3.28 (m, 2 H) 3.41 (d, J=5.52 Hz, 1 H) 3.66 – 3.75 (m, 1 H) 4.31 – 4.41 (m, 1 H) 4.46 – 4.71 (m, 2 H) 6.76 (d, J=8.53 Hz, 2 H) 7.05 – 7.23 (m, 6 H).

PATENT

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Example 46 (Peak-1, Peak-2, Peak-3, Peak-4)

(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


Step A. (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol

      To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30% hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69% yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H+).

Step B. (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol


      To a solution of (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.15 (m, 2H) 6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H) 3.04 (dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17 Hz, 1H) 2.43 (td, J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m, 1H) 1.43-1.54 (m, 1H).

Step C. (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate


 (
      To a solution of (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7 mmol) in DCM (150 mL) at −10° C. under nitrogen was added a 1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The reaction mixture was allowed to warm to rt, stirred for 2 h, and then rechilled to 0° C. and quenched by the addition of a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was washed with 250 mL of DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred for an additional 2 h. The mixture was then extracted with 200 mL ethyl acetate and the organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 12 mmol, 56% yield) which was used without further purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H+-2 t-butyl), 370; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J=8.66 Hz, 2H) 7.08 (d, J=8.66 Hz, 2H) 4.85 (d, J=5.65 Hz, 1H) 4.13 (d, J=8.41 Hz, 1H) 3.97 (d, J=10.48 Hz, 1H) 3.45 (tt, J=10.27, 5.19 Hz, 1H) 1.67 (d, J=3.39 Hz, 1H) 1.50-1.59 (m, 1H) 1.49 (s, 11H).

Step D. (±)-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate


      To a solution of (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between 1N HCl (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na2SOand evaporated under reduced pressure to give (±)-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 15 mmol, 92% yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H+-t-butyl), 279 (M+H+-t-butyl+CH3CN), 1H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (d, J=8.53 Hz, 2H) 6.66 (d, J=8.53 Hz, 2H) 4.70 (d, J=5.02 Hz, 1H) 4.09 (br. s., 1H) 3.94 (d, J=11.55 Hz, 1H) 3.35-3.41 (m, 1H) 2.66-2.77 (m, 1H) 2.29-2.39 (m, 1H) 1.63 (dd, J=13.30, 3.26 Hz, 1H) 1.44-1.52 (m, 1H) 1.42 (s, 9H).

Step E. (3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate


      (±)-rel-(3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 17 mmol, from step D) was subjected to chiral SFC separation (method C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0% yield) and E-2 (2.4 g, 8.18 mmol, 48.0% yield). Data for E-1: chiral HPLC (method A5) retention time 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2 min.

Step F. (3R,4R)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate


      A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z=310 (M+H+-t-butyl -water), 328 (M+H+-t-butyl).

Step G. (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride


      A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCl in dioxane was stirred at rt for 2 h. The reaction was then evaporated to dryness to yield 550 mg of (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H+).

Step H. 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


      A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60° C. for 1 h, 80° C. for 1 h, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H+).

Step I. 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin-1l-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


      A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0° C. was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H+).

Step J. 3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


      A mixture of 3-((3R,4R)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cmhydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H+).

Step K. (S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

      The diastereomeric mixture from step J was separated by SFC method C-7 to yield homochiral Examples 46 P-1 (29.3 mg) and P-2 (32.8 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC (method C-6) RT 4.1 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.76-1.86 (m, 2H) 2.07 (d, J=8.53 Hz, 1H) 2.13-2.21 (m, 1H) 2.34 (s, 3H) 2.43 (s, 0H) 2.55-2.60 (m, 1H) 2.65-2.70 (m, 1H) 2.75 (br. s., 1H) 3.20-3.30 (m, 2H) 3.38-3.45 (m, 1H) 3.70 (t, J=8.78 Hz, 1H) 4.44 (t, J=79.81 Hz, 3H) 4.63-4.71 (m, 1H) 6.70-6.80 (m, 2H) 7.07-7.15 (m, 2H) 7.07-7.12 (m, 1H) 7.13-7.22 (m, 4H); 19F NMR δ ppm −184.171. Data for P-2: (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H+), 405.2 (M+Na+); HPLC (method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method C-6) RT 6.92 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.80-1.90 (m, 2H) 2.07 (d, J=8.03 Hz, 1H) 2.19 (s, 1H) 2.34 (s, 3H) 2.41-2.48 (m, 1H) 2.66 (d, J=4.52 Hz, 2H) 2.95-3.03 (m, 1H) 3.10-3.18 (m, 1H) 3.20-3.30 (m, 2H) 3.68-3.78 (m, 1H) 4.38 (s, 1H) 4.51 (d, J=14.56 Hz, 2H) 6.70-6.80 (m, 2H) 7.05-7.13 (m, 2H) 7.13-7.22 (m, 4H); 19F NMR δ ppm −184.311.

Step L. (3S,4S)-tert-Butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate


      To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-1 from step E) in DCM (5 mL) cooled to 0° C. was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2 h. The reaction was slowly quenched with 50 mL of a 10% aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layers were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m/z 240.1 (M+H+).

Step M. 4-((3S,4S)-3-Fluoropiperidin-4-yl)phenol hydrochloride


      A mixture of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (390 mg, 1.3 mmol) and 4M HCl in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirred at rt for 2 hr. It was then concentrated to dryness, washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was isolated by filtration. Yield: 260 mg of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS (method Q) RT 0.46 min, mz 196.1 (M+H+)1H NMR (400 MHz, DMSO-d6) δ=9.57 (br. s., 4H), 8.92-8.68 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.82-6.73 (m, 2H), 5.07-4.85 (m, 1H), 3.77-3.36 (m, 9H), 3.32-3.22 (m, 2H), 3.13-2.85 (m, 5H), 2.06-1.88 (m, H).

Step N. 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one


      A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120° C. in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3S,4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H+).

Step O. (S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

      A portion of the diastereomer mixture from step N (130 mg) was subjected to chiral purification via SFC (method C-7) to give homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3 (S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT=2.10 min, m/z 383.2 (M+H+); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.76-1.86 (m, 2H) 2.06 (d, J=8.53 Hz, 1H) 2.10-2.21 (m, 1H) 2.34 (s, 3H) 2.40-2.48 (m, 1H) 2.53-2.60 (m, 1H) 2.61-2.70 (m, 2H) 2.95-3.01 (m, 1H) 3.01 (s, 2H) 3.10-3.16 (m, 1H) 3.18-3.28 (m, 2H) 3.72 (s, 1H) 4.35-4.41 (m, 1H) 4.46-4.70 (m, 2H) 6.72-6.80 (m, 2H) 7.05-7.23 (m, 6H). Data for P-4 (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H+); HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; 1H NMR (400 MHz, methanol-d4) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2H) 2.06 (d, J=9.04 Hz, 2H) 2.33 (s, 3H) 2.43 (s, 1H) 2.55 (br s, 1H) 2.66 (d, J=40.16 Hz, 2H) 2.75-2.80 (m, 1H) 2.96-3.10 (m, 2H) 3.20-3.28 (m, 2H) 3.41 (d, J=5.52 Hz, 1H) 3.66-3.75 (m, 1H) 4.31-4.41 (m, 1H) 4.46-4.71 (m, 2H) 6.76 (d, J=8.53 Hz, 2H) 7.05-7.23 (m, 6H).

ADDITIONAL INFORMATION

Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

ADDITIONAL INFORMATION

Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

 

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10.1124/jpet.117.242784. Epub 2017 Sep 27. PubMed PMID: 28954811.

2. BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
Lawrence R. Marcin, Jayakumar Warrier, Srinivasan Thangathirupathy, Jianliang Shi, George N. Karageorge, Bradley C. Pearce, Alicia Ng, Hyunsoo Park, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Aliphedi B. Reddy, G. Nagaraju, Gopikishan Tonukunuru, Grandhi V. R. K. M. Gupta, Manjunatha Kamble, Raju Mannoori, Srinivas Cheruku, Srinivas Jogi, Jyoti Gulia, Tanmaya Bastia, Charulatha Sanmathi, Jayant Aher, Rajareddy Kallem, Bettadapura N. Srikumar, Kumar Kuchibhotla Vijaya, Pattipati S. Naidu, Mahesh Paschapur, Narasimharaju Kalidindi, Reeba Vikramadithyan, Manjunath Ramarao, Rex Denton, Thaddeus Molski, Eric Shields, Murali Subramanian, Xiaoliang Zhuo, Michelle Nophsker, Jean Simmermacher, Michael Sinz, Charlie Albright, Linda J. Bristow, Imadul Islam, Joanne J. Bronson, Richard E. Olson, Dalton King, Lorin A. Thompson, and John E. Macor
Publication Date (Web): April 13, 2018 (Letter)
DOI: 10.1021/acsmedchemlett.8b00080

Patent ID

Patent Title

Submitted Date

Granted Date

US9221796 Selective NR2B antagonists
2015-01-05
2015-12-29

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 O=C1N(CC2=CC=C(C)C=C2)CC[C@H]1N3C[C@@H](F)[C@H](C4=CC=C(O)C=C4)CC3

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