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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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CK-101

August 30, 2019 2:30 pm / Leave a comment

N-[3-[2-[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]quinazolin-8-yl]phenyl]prop-2-enamide.png

CK-101, RX-518

CAS 1660963-42-7

MF C₂₉ H₂₈ F₂ N₆ O₂

MW 530.57

2-Propenamide, N-[3-[2-[[2,3-difluoro-4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-8-quinazolinyl]phenyl]-

N-[3-[2-[[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]amino]quinazolin-8-yl]phenyl]acrylamide

N-(3-(2-((2,3-Difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide

EGFR-IN-3

UNII-708TLB8J3Y

708TLB8J3Y

AK543910

Suzhou NeuPharma (Originator)
Checkpoint Therapeutics

Non-Small Cell Lung Cancer Therapy
Solid Tumors Therapy

PHASE 2 Checkpoint Therapeutics, Cancer, lung (non-small cell) (NSCLC), solid tumour

RX518(CK-101) is an orally available third-generation and selective inhibitor of certain epidermal growth factor receptor (EGFR) activating mutations, including the resistance mutation T790M, and the L858R and exon 19 deletion (del 19) mutations, with potential antineoplastic activity.

In August 2019, Suzhou Neupharma and its licensee Checkpoint Therapeutics are developing CK-101 (phase II clinical trial), a novel third-generation, covalent, EGFR inhibitor, as a capsule formulation, for the treatment of cancers including NSCLC and other advanced solid tumors. In September 2017, the FDA granted Orphan Drug designation to this compound, for the treatment of EGFR mutation-positive NSCLC; in January 2018, the capsule was being developed as a class 1 chemical drug in China.

CK-101 (RX-518), a small-molecule inhibitor of epidermal growth factor receptor (EGFR), is in early clinical development at Checkpoint Therapeutics and Suzhou NeuPharma for the potential treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and other advanced solid malignancies.

In 2015, Suzhou NeuPharma granted a global development and commercialization license to its EGFR inhibitor program, excluding certain Asian countries, to Coronado Biosciences (now Fortress Biotech). Subsequently, Coronado assigned the newly acquired program to its subsidiary Checkpoint Therapeutics.

In 2017, the product was granted orphan drug designation in the U.S. for the treatment of EGFR mutation-positive NSCLC.

There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

[0003] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0004] The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial.

[0005] While such compounds are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance, such as a kinase inhibitor, can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties

can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Thus, there still remains a need for polymorphs of kinase inhibitors. The present disclosure addresses this need and provides related advantages as well.

PATENT

WO2015027222

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027222

PATENT

WO-2019157225

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019157225&tab=PCTDESCRIPTION&_cid=P10-JZNKMN-12945-1

Crystalline form II-VIII of the compound presumed to be CK-101 (first disclosed in WO2015027222 ), for treating a disorder mediated by epidermal growth factor receptor (EGFR) eg cancer.

SCHEME A

Scheme B

General Procedures

Example 1: Preparation of the compound of Formula I (N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide)

[0253] To a solution of l,2,3-trifluoro-4-nitrobenzene (2.5 g, 14 mmol, 1.0 eq.) in DMF (20 mL) was added K₂C0₃ (3.8 g, 28 mmol, 2.0 eq.) followed by 2-(piperazin-l-yl)ethanol (1.8 g, 14 mmol, 1.0 eq.) at 0 °C and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (200 mL), filtered and dried in vacuo to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 67.5%).

[0254] To a solution of 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 9.0 mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting mixture was stirred at r.t.

overnight. The Pd/C was removed by filtration and the filtrate was concentrated to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (2.39 g, 99% yield) as off-white solid.

[0255] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6 mmol, 1 eq. ) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1 eq.) in dioxane/H₂0 (200 mL/20 mL) was added Na₂C0₃ (13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl₂ (2.6 g, 3.2 mmol, 0.05 eq.) under N₂, then the mixture was stirred at 80 °C for 12 h. Then the solution was cooled to r.t.,

concentrated and the residue was purified via column chromatography (PE/EA=3 :2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as yellow solid (8.7 g, 53.7% yield).

[0256] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g, 34 mmol, 1 eq.) in DCM ( 200 mL ) cooled in ice-bath was added TEA (9.5 mL, 68 mmol, 2 eq. ), followed by acryloyl chloride (4.1 mL, 51 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t. for 1 h, then washed with brine, dried over anhydrous N₂S0₄ concentrated and the residue was purified via column chromatography (PE/EA=l : 1, v:v) to afford N-(3-(2-chloroquinazolin-8-yl)phenyl)acryl amide as yellow solid(6.6 g, 65% yield).

[0257] To a suspension of 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (83 mg,

0.32 mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol, 1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and the resulting mixture was stirred at 90 °C overnight. The mixture was concentrated, diluted with DCM (20 mL) , washed with Na₂C0₃ solution (20 mL), dried over anhydrous Na₂S0₄, concentrated and the residue was purified via column chromatography (MeOH/DCM=l/30, v:v) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide as a yellow solid(l6.3 mg, 9.5% yield). LRMS (M+H⁺) m/z calculated 531.2, found 531.2. 1H NMR

(CD₃OD, 400 MHz) d 9.21 (s, 1 H), 7.19-8.01 (m, 10 H), 8.90 (s, 1 H), 6.41-6.49 (m, 3 H), 5.86 (m, 1 H), 3.98-4.01 (m, 3 H), 3.70-3.76 (m, 3 H), 3.40-3.49 (m, 2 H), 3.37-3.39 (m, 4 H), 3.18 (m, 2H).

Example 2. Preparation of Form I of the compound of Formula I

[0258] Crude compound of Formula I (~30 g, 75% of weight based assay) was dissolved in ethyl acetate (3 L) at 55-65 °C under nitrogen. The resulting solution was filtered via silica gel pad and washed with ethyl acetate (3 L><2) at 55-65 °C. The filtrate was concentrated via vacuum at 30-40 °C to ~2.4 L. The mixture was heated up to 75-85 °C and maintained about 1 hour.

Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and the mixture was then cooled down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with ethyl acetate (60 mL><2). The wet cake was dried via vacuum at 30-40 °C to get (about 16 g) of the purified Form I of the compound of Formula I.

Example 3. Preparation of Form III of the compound of Formula I

[0259] The compound of Formula I (2 g) was dissolved in EtOH (40 mL) at 75-85 °C under nitrogen. n-Heptane (40 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 75-85 °C for 1 hour. Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with EtOH/n-Heptane (1/1, 5 mL><2). The wet cake was dried via vacuum at 30-40 °C to get the purified Form III of the compound of Formula I (1.7 g).

Example 4. Preparation of Form IV of the compound of Formula I The crude compound of Formula I (15 g) was dissolved in ethyl acetate (600 mL) at 75-85 °C under nitrogen and treated with anhydrous Na₂S0₄, activated carbon, silica metal scavenger for 1 hour. The resulting mixture was filtered via neutral Al₂0₃ and washed with ethyl acetate (300 mL><2) at 75-85 °C. The filtrate was concentrated under vacuum at 30-40 °C and swapped with DCM (150 mL). n-Heptane (75 mL) was added into this DCM solution at 35-45 °C, and then the mixture was cooled down to 20-30 °C slowly. The resulting mixture was filtered and washed with DCM/n-Heptane (2/1, 10 mL><3). The wet cake was dried via vacuum at 35-40 °C to get the purified Form IV of the compound of Formula I (9.6 g).

Example 5. Preparation of Form V of the compound of Formula I

[0260] Polymorph Form III of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form V.

Example 6. Preparation of Form VI of the compound of Formula I

[0261] The compound of Formula I (1 g) was dissolved in IPA (20 mL) at 75-85 °C under nitrogen. n-Heptane (20 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 45-55 °C for 16 hours. Then heated up to 75-85 °C and maintained about 0.5 hour.

Then cooled down to 45-55 °C for 0.5 hour and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. Filtered and washed with IPA/n-Heptane (1/1, 3 mL><2). The wet cake was dried via vacuum at 75-80 °C for 2 hours to get the purified Form VI of the compound of Formula I.

Example 7. Preparation of Form VIII of the compound of Formula I

[0262] The polymorph Form VI of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form VIII.

Example 8. X-ray powder diffraction (XRD)

[0263] X-ray powder diffraction (XRD) patterns were obtained on a Bruker D8 Advance. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 40 mA scans each sample between 4 and 40 degrees 2-theta. The step size is 0.05°C and scan speed is 0.5 second per step.

Example 9. Thermogravimetric Analyses (TGA)

[0264] Thermogravimetric analyses were carried out on a TA Instrument TGA unit (Model TGA 500). Samples were heated in platinum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 60mL/min (sample purge) and 40mL/min (balance purge). The TGA temperature was calibrated with nickel standard, MP=354.4 °C. The weight calibration was performed with manufacturer-supplied standards and verified against sodium citrate dihydrate desolvation.

Example 10. Differential scanning calorimetry (DSC)

[0265] Differential scanning calorimetry analyses were carried out on a TA Instrument DSC unit (Model DSC 1000 or 2000). Samples were heated in non-hermetic aluminum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 50mL/min. The DSC temperature was calibrated with indium standard, onset of l56-l58°C, enthalpy of 25-29J/g.

Example 11. Hygroscopicity (DVS)

[0266] The moisture sorption profile was generated at 25°C using a DVS Moisture Balance Flow System (Model Advantage) with the following conditions: sample size approximately 5 to 10 mg, drying 25°C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes.

Example 12: Microscopy

[0267] Microscopy was performed using a Leica DMLP polarized light microscope equipped with 2.5X, 10X and 20X objectives and a digital camera to capture images showing particle shape, size, and crystallinity. Crossed polars were used to show birefringence and crystal habit for the samples dispersed in immersion oil.

Example 13: HPLC

[0256] HPLCs were preformed using the following instrument and/or conditions.

///////////////CK-101 , CK 101 , CK101 , phase II , Suzhou Neupharma, Checkpoint Therapeutics , Orphan Drug designation, EGFR mutation-positive NSCLC, NSCLC, CANCER, SOLID TUMOUR, China, RX-518, AK543910

OCCN1CCN(CC1)c5ccc(Nc2nc3c(cccc3cn2)c4cccc(NC(=O)C=C)c4)c(F)c5F

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor

August 20, 2019 10:25 am / Leave a comment

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” 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. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority Review, Breakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority Review, Breakthrough Therapy, Orphan Drug designation, fda 2019, Genentech, cancer

SELPERCATINIB

July 9, 2019 9:56 am / Leave a comment

SELPERCATINIB

LOXO 292

CAS: 2152628-33-4
Chemical Formula: C29H31N7O3
Molecular Weight: 525.613

CEGM9YBNGD

UNII-CEGM9YBNGD

6-(2-hydroxy-2-methylpropoxy)-4-(6-{6-[(6-methoxypyridin- 3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Selpercatinib is a tyrosine kinase inhibitor with antineoplastic properties.

A phase I/II trial is also under way in pediatric patients and young adults with activating RET alterations and advanced solid or primary CNS tumors.

Loxo Oncology (a wholly-owned subsidiary of Eli Lilly ), under license from Array , is developing selpercatinib, a lead from a program of RET kinase inhibitors, for treating cancer, including non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma and soft tissue sarcoma

In 2018, the compound was granted orphan drug designation in the U.S. for the treatment of pancreatic cancer and in the E.U. for the treatment of medullary thyroid carcinoma.

Trk is a high affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophic factor (NT). The Trk receptor family has three members, namely TrkA, TrkB and TrkC. Among the neurotrophic factors are (1) nerve growth factor (NGF) which activates TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5 which activate TrkB, and (3) NT3 which activates TrkC. Trk is widely expressed in neuronal tissues and is involved in the maintenance, signaling and survival of neuronal cells.

The literature also shows that Trk overexpression, activation, amplification and/or mutations are associated with many cancers including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma. And medulloblastoma, glioma, melanoma, thyroid cancer, pancreatic cancer, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophin pathway have been shown to be effective in a variety of preclinical animal models for the treatment of pain and inflammatory diseases.

The neurotrophin/Trk pathway, particularly the BDNF/TrkB pathway, has also been implicated in the pathogenesis of neurodegenerative diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The modulating neurotrophic factor/Trk pathway can be used to treat these and related diseases.

It is believed that the TrkA receptor is critical for the disease process in the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts. Therefore, TrkA inhibitors can be used to treat Chagas disease and related protozoal infections.

Trk inhibitors can also be used to treat diseases associated with imbalances in bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastasis. Bone metastases are a common complication of cancer, up to 70% in patients with advanced breast or prostate cancer and about 15 in patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney cancer Up to 30%. Osteolytic metastases can cause severe pain, pathological fractures, life-threatening hypercalcemia, spinal cord compression, and other neurostress syndromes. For these reasons, bone metastases are a serious cancer complication that is costly. Therefore, an agent that can induce apoptosis of proliferating bone cells is very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, almost all osteoblast apoptosis agents are very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, localization of NGF was observed in almost all osteoblasts. Recently, it was demonstrated that pan-Trk inhibitors in human hFOB osteoblasts inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors. This data supports the theory of using Trk inhibitors to treat bone remodeling diseases, such as bone metastases in cancer patients.

Developed by Loxo Oncology, Larotrectinib (LOXO-101) is a broad-spectrum antineoplastic agent for all tumor patients expressing Trk, rather than tumors at an anatomical location. LOXO-101 chemical name is (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)pyrazolo[1,5-a] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the structural formula is as follows. LOXO-101 began treatment of the first patient in March 2015; on July 13, 2016, the FDA granted a breakthrough drug qualification for the inoperable removal or metastatic solid tumor of adults and children with positive Trk fusion gene mutations; Key entry was completed in February 2017; in November 2018, the FDA approved the listing under the trade name Vitrakvi.

Poor absorption, distribution, metabolism, and/or excretion (ADME) properties are known to be the primary cause of clinical trial failure in many drug candidates. Many of the drugs currently on the market also limit their range of applications due to poor ADME properties. The rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body. Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.

Although LOXO-101 is effective as a Trk inhibitor in the treatment of a variety of cancers and the like, it has been found that a novel compound having a good oral bioavailability and a drug-forming property for treating a cancer or the like is a challenging task. Thus, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics for Trk kinase mediated diseases useful as therapeutic agents, and the present invention provides such compounds.

SYN

WO 2018071447

PATENT

WO2018071447

PATENT

US 20190106438

PATENT

WO 2019075108

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019075108&tab=PCTDESCRIPTION

Compounds of Formula I-IV, 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III); and 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV) are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases, including cancers.

[0007] Accordingly, provided herein is a compound of Formula I-IV:

and pharmaceutically acceptable salts, amorphous, and polymorph forms thereof.

PATENT

WO 2019075114

PATENT

WO-2019120194

Novel deuterated analogs of pyrazolo[1,5-a]pyrimidine compounds, particularly selpercatinib , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating pain, inflammation, cancer and certain infectious diseases.

Example 2(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl-2,3,3-d 3)-pyrazolo[ 1,5-a] pyrimidin-3-yl) -3-hydroxypyrazole prepared pyrrolidine-1-carboxamide (compound L-2) a.

[0163]

[0164]

Use the following route for synthesis:

[0165]

Patent ID	Title	Submitted Date
US10137124	Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors	2018-01-03
US10172851	Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors	2018-01-03
US10112942	Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors	2017-12-29

/////////////SELPERCATINIB, non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma, soft tissue sarcoma, LOXO, ELI LILY, ARRAY, LOXO 292, orphan drug designation

N#CC1=C2C(C3=CC=C(N4CC(C5)N(CC6=CC=C(OC)N=C6)C5C4)N=C3)=CC(OCC(C)(O)C)=CN2N=C1

FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

May 10, 2019 10:07 am / Leave a comment

FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

May 06, 2019

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. LEMS can occur at any age. The prevalence of LEMS specifically in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide.

Use of Ruzurgi in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of the drug in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients and safety data from pediatric patients 6 to less than 17 years of age.

The effectiveness of Ruzurgi for the treatment of LEMS was established by a randomized, double-blind, placebo-controlled withdrawal study of 32 adult patients in which patients were taking Ruzurgi for at least three months prior to entering the study. The study compared patients continuing on Ruzurgi to patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients that continued on Ruzurgi experienced less impairment than those on placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients switched to placebo.

The most common side effects experienced by pediatric and adult patients taking Ruzurgi were burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Patients should inform their health care professional immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Fast Track designations. Ruzurgi 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 Ruzurgi to Jacobus Pharmaceutical Company, Inc.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-lambert-eaton-myasthenic-syndrome-rare-autoimmune-disorder?utm_campaign=050619_PR_FDA%20approves%20first%20treatment%20for%20children%20with%20LEMS&utm_medium=email&utm_source=Eloqua

/////////////////FDA 2019, Ruzurgi, amifampridine, Lambert-Eaton myasthenic syndrome, LEMS, RARE DISEASES, CHILDREN, Jacobus Pharmaceutical Company, Priority Review, Fast Track designations, Orphan Drug designation

Cladribine, クラドリビン

April 1, 2019 2:15 pm / Leave a comment

Cladribine

クラドリビン

Leustatin

クラドリビン

RWJ 26251 / RWJ-26251

Molecular FormulaC₁₀H₁₂ClN₅O₃
Average mass285.687 Da

2-chloro-6-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine

2-Chlorodeoxyadenosine

4291-63-8 [RN]

6997

adenosine, 2-chloro-2′-deoxy- [ACD/Index Name]

AU7357560

CDA

(2R,3S,5R)-5-(6-Amino-2-chlor-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol

Leustatin (Trade name)

Litak (Trade name)

MLS000759397

Movectro (Trade name)

Mylinax

QA-1968

LAUNCHED, 1993, USA Ortho Biotech, Janssen Biotech

Cladribine, sold under the brand name Leustatin and Mavenclad among others, is a medication used to treat hairy cell leukemia(HCL, leukemic reticuloendotheliosis), B-cell chronic lymphocytic leukemia and relapsing-remitting multiple sclerosis.^[4]^[5] Its chemical name is 2-chloro-2′-deoxyadenosine (2CdA).

Cladribine, a deoxyadenosine derivative developed by Ortho Biotech (currently Janssen), was first launched in the U.S. in 1993 as an intravenous treatment for hairy cell leukemia

Cladribine has been granted orphan drug designation in the U.S. in 1990 for the treatment of acute myeloid leukemia (AML) and hairy cell leukemia

As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes and selectively suppresses the immune system. Chemically, it mimics the nucleoside adenosine. However, unlike adenosine it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in cells and interfere with the cell’s ability to process DNA. Cladribine is taken up cells via a transporter. Once inside a cell cladribine is activated mostly in lymphocytes, when it is triphosphorylated by the enzyme deoxyadenosine kinase (dCK). Various phosphatases dephosphorylate cladribine. Activated, triphosphorylated, cladribine is incorporated into mitochondrial and nuclear DNA, which triggers apoptosis. Non-activated cladribine is removed quickly from all other cells. This means that there is very little non-target cell loss.^[4]^[6]

Medical uses

Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous or subcutaneous infusion.^[5]^[7]

Since 2017, cladribine is approved as an oral formulation (10 mg tablet) for the treatment of RRMS in Europe, UAE, Argentina, Chile, Canada and Australia. Marketing authorization in the US was obtained in March 2019^[8].

Some investigators have used the parenteral formulation orally to treat patients with HCL. It is important to note that approximately 40% of oral cladribine in bioavailable orally. It used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease^[9] and Langerhans cell histiocytosis,^[10]

Cladribine can cause fetal harm when administered to a pregnant woman and is listed by the FDA as Pregnancy Category D; safety and efficacy in children has not been established.^[7]

Adverse effects

Injectable cladribine suppresses the body’s ability to make new lymphocytes, natural killer cells and neutrophils (called myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.^[7]

At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.^[7]

In comparison, in MS, cladribine is associated with a 6% rate of severe lymphocyte suppression (lymphopenia) (levels lower than 50% of normal). Other common side effects include headache (75%), sore throat (56%), common cold-like illness (42%) and nausea (39%)^[11]

Mechanism of Action

As a purine analogue, it is taken up into rapidly proliferating cells like lymphocytes to be incorporated into DNA synthesis. Unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase (ADA). In cells it is phosphorylated into its toxic form, deoxyadenosine triphosphate, by the enzyme deoxycytidine kinase (DCK). This molecule is then incorporated into the DNA synthesis pathway, where it causes strand breakage. This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis).^[12] This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment^[13]

Within the lymphocyte pool, cladribine targets B cells more than T cells. Both HCL and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers. In MS, its effectiveness may be due to its ability to effectively deplete B cells, in particular memory B cells^[14] In the pivotal phase 3 clinical trial of oral cladribine in MS, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40-50% of total T cells.^[15] More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.^[16]

Another family of enzymes, the 5´nucleotidase (5NCT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtype of this group appears to be 5NCT1A, which is cytosolically active and specific for purine analogues. When DCK gene expression is expressed as a ratio with 5NCT1A, the cells with the highest ratios are B cells, especially germinal centre and naive B cells.^[16] This again helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis.

Although cladribine is selective for B cells, the long term suppression of memory B cells, which may contribute to its effect in MS, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department. However, while naive B cells rapidly move from lymphoid organs, the memory B cell pool repopulates very slowly from the bone marrow.

History

Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognized that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas. Carson then synthesized cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia (HCL). No pharmaceutical companies were interested in selling the drug because HCL was an orphan disease, so Beutler’s lab synthesized and packaged it and supplied it to the hospital pharmacy; the lab also developed a test to monitor blood levels. This was the first treatment that led to prolonged remission of HCL, which was previously untreatable.^[17]^:14–15

In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladrabine was approved by the FDA in 1993 for HCL as an orphan drug,^[18] and was approved in Europe later that year.^[19]^:2

The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialized by Lipomed GmbH in the 2000s.^[19]^:2^[20]

Multiple sclerosis

In the mid-1990s Beutler, in collaboration with Jack Sipe, a neurologist at Scripps, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug’s immunosuppressive effects. Sipe’s insight into MS, and Beutler’s interest in MS due to his sister’s having had it, led a very productive collaboration.^[17]^:17^[21] Ortho-Clinical, a subsidiary of J&J, filed an NDA for cladribine for MS in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.^[22]^[23]

Ivax acquired the rights for oral administration of cladribine to treat MS from Scripps in 2000,^[24] and partnered with Serono in 2002.^[23] Ivax was acquired by Teva in 2006,^[25]^[26] and Merck KGaA acquired control of Serono’s drug business in 2006.^[27]

An oral formulation of the drug with cyclodextrin was developed^[28]^:16 and Ivax and Serono, and then Merck KGaA conducted several clinical studies. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.^[28]^:4–5 Likewise Merck KGaA’s NDA with the FDA rejected in 2011.^[29] The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators.^[28]^:54–55 The failures with the FDA and the EMA were a blow to Merck KGaA and were one of a series of events that led to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.^[30]^[31] However, several MS clinical trials were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.^[29] A meta-analysis of data from clinical trials showed that cladiribine did not increase the risk of cancer at the doses used in the clinical trials.^[32]

In 2015 Merck KGaA announced it would again seek regulatory approval with data from the completed clinical trials in hand,^[30] and in 2016 the EMA accepted its application for review.^[33] On June 22, 2017, the EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.^[34]

Finally, after all these problems it was approved in Europe on August 2017 for highly active RRMS.^[35]

Efficacy

Cladribine is an effective treatment for relapsing remitting MS, with a reduction in the annual rate of relapses of 54.5%.^[11] These effects may be sustained up to 4 years after initial treatment, even if no further doses are given.^[36] Thus, cladribine is considered to be a highly effective immune reconstitution therapy in MS. Similar to alemtuzumab, cladribine is given as two courses approximately one year apart. Each course consists of 4-5 tablets given over a week in the first month, followed by a second dosing of another 4-5 tablets the following month^[37] During this time and after the final dose patients are monitored for adverse effects and signs of relapse.

https://www.merckneurology.co.uk/wp-content/uploads/2017/08/mavenclad-table-1.jpg

Safety

Compared to alemtuzumab, cladribine is associated with a lower rate of severe lymphopenia. It also appears to have a lower rate of common adverse events, especially mild to moderate infections^[11]^[36] As cladribine is not a recombinant biological therapy, it is not associated with the development of antibodies against the drug, which might reduce the effectiveness of future doses. Also, unlike alemtuzumab, cladribine is not associated with secondary autoimmunity.^[38]

This is probably due to the fact cladribine more selectively targets B cells. Unlike alemtuzumab, cladribine is not associated with a rapid repopulation of the peripheral blood B cell pool, which then ´overshoots´ the original number by up to 30%.^[39] Instead, B cells repopulate more slowly, reaching near normal total B cells numbers at 1 year. This phenomenon and the relative sparing of T cells, some of which might be important in regulating the system against other autoimmune reactions, is thought to explain the lack of secondary autoimmunity.

Use in clinical practice

The decision to start cladribine in MS depends on the degree of disease activity (as measured by number of relapses in the past year and T1 gadolinium-enhancing lesions on MRI), the failure of previous disease-modifying therapies, the potential risks and benefits and patient choice.

In the UK, the National Institute for Clinical Excellence (NICE) recommends cladribine for treating highly active RRMS in adults if the persons has:

rapidly evolving severe relapsing–remitting multiple sclerosis, that is, at least 2 relapses in the previous year and at least 1 T1 gadolinium-enhancing lesion at baseline MRI or

relapsing–remitting multiple sclerosis that has responded inadequately to treatment with disease-modifying therapy, defined as 1 relapse in the previous year and MRI evidence of disease activity.^[40]

People with MS require counselling on the intended benefits of cladribine in reducing the risk of relapse and disease progression, versus the risk of adverse effects such as headaches, nausea and mild to moderate infections. Women of childbearing age also require counselling that they should not conceive while taking cladribine, due to the risk of harm to the fetus.

Cladribine, as the 10 mg oral preparation Mavenclad, is administered as two courses of tablets approximately one year apart. Each course consists of four to five treatment days in the first month, followed by an additional four to five treatment days in the second month. The recommended dose of Mavenclad is 3.5 mg/kg over 2 years, given in two treatment courses of 1.75 mg/kg/year. Therefore, the number of tablets administered on each treatment day depends on the person’s weight. A full guide to the dosing strategy can be found below:

https://www.merckneurology.co.uk/mavenclad/mavenclad-efficacy/

After treatment, people with MS are monitored with regular blood tests, looking specifically at the white cell count and liver function. Patients should be followed up regularly by their treating neurologist to assess efficacy, and should be able to contact their MS service in the case of adverse effects or relapse. After the first two years of active treatment no further therapy may need to be given, as cladribine has been shown to be efficacious for up to last least four years after treatment. However, if patients fail to respond, options include switching to other highly effective disease-modifying therapies such as alemtuzumab, fingolimod or natalizumab.

Research directions

Cladribine has been studied as part of a multi-drug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukemia.^[41]

REF

A universal biocatalyst for the preparation of base- and sugar-modified nucleosides via an enzymatic transglycosylation
Helv Chim Acta 2002, 85(7): 1901

Synthesis of 2-chloro-2′-deoxyadenosine by microbiological transglycosylation
Nucleosides Nucleotides 1993, 12(3-4): 417

Synthesis of 2-chloro-2′-deoxyadenosine by washed cells of E. coli
Biotechnol Lett 1992, 14(8): 669

Efficient syntheses of 2-chloro-2′-deoxyadenosine (cladribine) from 2′-deoxyguanosine
J Org Chem 2003, 68(3): 989

WO 2004028462

Synthesis of 2′-deoxytubercidin, 2′-deoxyadenosine, and related 2′-deoxynucleosides via a novel direct stereospecific sodium salt glycosylation procedure
J Am Chem Soc 1984, 106(21): 6379

WO 2011113476

A stereoselective process for the manufacture of a 2′-deoxy-beta-D-ribonucleoside using the vorbruggen glycosylation
Org Process Res Dev 2013, 17(11): 1419

A new synthesis of 2-chloro-2′-deoxyadenosine (Cladribine), CdA)
Nucleosides Nucleotides Nucleic Acids 2011, 30(5): 353

A dramatic concentration effect on the stereoselectivity of N-glycosylation for the synthesis of 2′-deoxy-beta-ribonucleosides
Chem Commun (London) 2012, 48(56): 7097

CN 105367616

PATENT

https://patents.google.com/patent/EP2891660A1/en

Previously Robins and Robins (Robins, M. J. and Robins, R. K., J. Am. Chem. Soc. 1965, 87, 4934-4940) reported that acid-catalyzed fusion of 1,3,5-tri-O-acety-2-deoxy-D-ribofuranose and 2,6-dichloropurine gave a 65% yield of an anomeric mixture 2,6-dichloro-9-(3′,5′-di-O-acetyl-2′-deoxy-α-,β-D-ribofuranosyl)-purines from which the α-anomer was obtained as a pure crystalline product by fractional crystallization from ethanol in 32% yield and the equivalent β-anomer remained in the mother liquor (see Scheme 1). The β-anomer, which could have been used to synthesize cladribine, wasn’t isolated further. The α-anomer was treated with methanolic ammonia which resulted in simultaneous deacetylation and amination to give 6-amino-2-chloro-9-(2′-deoxy-α-D-ribofuranosyl)-purine, which is a diastereomer of cladribine.

[0004]

Broom et al. (Christensen, L. F., Broom, A. D., Robins, M. J., and Bloch, A., J. Med. Chem. 1972, 15, 735-739) adapted Robins et al.’s method by treating the acetylated mixture (viz., 2,6-dichloro-9-(3′,5′-di-O-acety-2′-deoxy-α,β-D-ribofuranosyl)-purine) with liquid ammonia and reacylating the resulting 2′-deoxy-α-and –β-adenosines with p-toluoyl chloride (see Scheme 2). The desired 2-chloro-9-(3′,5′-di-O–p-toluoyl-2′-deoxy-β-D-ribofuranosyl)-adenine was then separated by chromatography and removal of the p-toluoyl group resulted in cladribine in 9% overall yield based on the fusion of 1,3,5-tri-O-acety-2-deoxy-D-ribofuranose and 2,6-dichloropurine.

[0005]

To increase the stereoselectivity in favour of the β-anomer, Robins et al.(Robins, R. L. et al., J. Am. Chem. Soc. 1984, 106, 6379-6382, US4760137 , EP0173059 ) provided an improved method in which the sodium salt of 2,6-dichloropurine was coupled with 1-chloro-2-deoxy-3,5-di-O–p-toluoyl-α-D-ribofuranose in acetonitrile (MeCN) to give the protected β-nucleoside in 59% isolated yield, following chromatography and crystallisation, in addition to 13% of the undesired N-7 regioisomer (see Scheme 3). The apparently higher selectivity in this coupling reaction is attributed to it being a direct S_N2 displacement of the chloride ion by the purine sodium salt. The protected N-9 2′-deoxy-β-nucleoside was treated with methanolic ammonia at 100°C to give cladribine in an overall 42% yield. The drawback of this process is that the nucleophilic 7- position nitrogen competes in the S_N2 reaction against the nucleophilic 9- position, leading to a mixture of the N-7 and N-9 glycosyl isomers as well as the need for chromatography and crystallisation to obtain the pure desired isomer.

[0006]

Gerszberg and Alonso (Gerszberg S. and Alonso, D. WO0064918 , and US20020052491 ) also utilised an S_N2 approach with 1-chloro-2-deoxy-3,5-di-O–p-toluoyl-α-D-ribofuranose but instead coupled it with the sodium salt of 2-chloroadenine in acetone giving the desired β-anomer of the protected cladribine in 60% yield following crystallisation from ethanol (see Scheme 4). After the deprotection step using ammonia in methanol (MeOH), the β-anomer of cladribine was isolated in an overall 42% yield based on the 1-chlorosugar, and 30% if calculated based on the sodium salt since this was used in a 2.3 molar excess.

[0007]

To increase the regioselectivity towards glycosylation of the N-9 position, Gupta and Munk recently ( Gupta, P. K. and Munk, S. A., US20040039190 , WO2004018490 and CA2493724 ) conducted an S_N2 reaction using the anomerically pure α-anomer, 1-chloro-2-deoxy-3,5-di-O–p-toluoyl-α-D-ribofuranose but coupling it with the potassium salt of a 6-heptanoylamido modified purine (see Scheme 5). The bulky alkyl group probably imparted steric hindrance around the N-7 position, resulting in the reported improved regioselectivity. Despite this, following deprotection, the overall yield of cladribine based on the 1-chlorosugar was 43%, showing no large improvement in overall yield on related methods. Moreover 2-chloroadenine required prior acylation with heptanoic anhydride at high temperature (130°C) in 72% yield, and the coupling required cryogenic cooling (-30°C) and the use of the strong base potassium hexamethyldisilazide and was followed by column chromatography to purify the product protected cladribine.

[0008]

More recently Robins et al. (Robins, M. J. et al., J. Org. Chem. 2006, 71, 7773-7779, US20080207891 ) published a procedure for synthesis of cladribine that purports to achieve almost quantitative yields in the N-9-regioselective glycosylation of 6-(substituted-imidazol-1-yl)-purine sodium salts with 1-chloro-2-deoxy-3,5-di-O–p-toluoyl-α-D-ribofuranose in MeCN/dichloromethane (DCM) mixtures to give small or no detectable amounts of the undesired α-anomer (see Scheme 6). In actuality this was only demonstrated on the multi-milligram to several grams scale, and whilst the actual coupling yield following chromatography of the desired N-9-β-anomer was high (83% to quantitative), the protected 6-(substituted-imidazol-1-yl)-products were obtained in 55% to 76% yield after recrystallisation. Following this, toxic benzyl iodide was used to activate the 6-(imidazole-1-yl) groups which were then subsequently displaced by ammonia at 60-80°C in methanolic ammonia to give cladribine in 59-70% yield following ion exchange chromatography and multiple crystallisations, or following extraction with DCM and crystallisation. Although high anomeric and regioselective glycosylation was demonstrated the procedure is longer than the prior arts, atom uneconomic and not readily applicable to industrial synthesis of cladribine such as due to the reliance on chromatography and the requirement for a pressure vessel in the substitution of the 6-(substituted-imidazole-1-yl) groups.

[0009]

Therefore, there is a need for a more direct, less laborious process, which will produce cladribine in good yield and high purity that is applicable to industrial scales.

EXAMPLE 1 Preparation of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine

[0052]
2-Chloroadenine (75 g, 0.44 mol, 1.0 eq.), MeCN (900 mL, 12 P), and BSTFA (343.5 g, 1.33 mol, 3.0 eq.) were stirred and heated under reflux until the mixture was almost turned clear. The mixture was cooled to 60°C and TfOH (7.9 mL, 0.089 mol, 0.2 eq.) and then 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose (III; 200.6 g, 1.0 eq.) were added into the mixture, and then the mixture was stirred at 60°C. After 1 hour, some solid precipitated from the solution and the mixture was heated for at least a further 10 hours. The mixture was cooled to r.t. and stirred for 2 hours. The solid was filtered and dried in vacuo at 60°C to give 180.6 g in 64% yield of a mixture of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]-purine (IVa) with 95.4% HPLC purity and its non-silylated derivative 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) with 1.1 % HPLC purity.

EXAMPLE 2 Preparation of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine by isomerisation of a mixture of 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-α,β-D-ribofuranosyl]-purine mixture

[0053]
50.0 g of 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-α,β-D-ribofuranosyl]-purine as a 0.6:1.0 mixture of the β-anomer IVb and α-anomer Vb(83.16 mmol, assay of α-anomer was 58.6% (52.06 mmol) and β-anomer was 34.3% (31.10 mmol, 17.15 g)), 68.6 g BSTFA (266.5 mmol) and 180 mL of MeCN (3.6 P) were charged into a dried 4-necked flask. The mixture was heated to 60°C under N₂ for about 3 h and then 2.67 g of TfOH (17.8 mmol) was added. The mixture was stirred at 60°C for 15 h and was then cooled to about 25°C and stirred for a further 2 h, and then filtered. The filter cake was washed twice with MeCN (20 mL each) and dried at 60°C in vacuo for 6 h to give 24 g of off-white solid (the assay of 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-α-D-ribofuranosyl]-purine was 1.4% (0.60 mmol, 0.34 g),
2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine was 8.4% (3.18 mmol, 2.02 g) and
2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine was 86.6% (32.73 mmol, 20.78 g)).
Analysis of the 274.8 g of the mother liquor by assay showed that it in addition to the α-anomer it contained 0.5% (1.37 g, 2.43 mmol) of
2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine and 0.01% (0.027 g, 0.05 mmol) of
2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine.

EXAMPLE 3 Preparation of 2-chloro-2′-deoxy-adenosine (cladribine)

[0054]
To the above prepared mixture of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]- purine (IVa) and 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (179 g, >95.4% HPLC purity) in MeOH (895 mL, 5 P) was added 29% MeONa/MeOH solution (5.25 g, 0.1 eq.) at 20-30°C. The mixture was stirred at 20-30°C for 6 hours, the solid was filtered, washed with MeOH (60 mL, 0.34 P) and then dried in vacuo at 50°C for 6 hour to give 72 g white to off-white crude cladribine with 98.9% HPLC purity in ca. 93% yield.

EXAMPLE 4 Recrystallisation

[0055]
Crude cladribine (70 g), H₂O (350 mL, 5 P), MeOH (350 mL, 5 P) and 29% MeONa/MeOH solution (0.17 g) were stirred and heated under reflux until the mixture turned clear. The mixture was stirred for 3 hour and was then filtered to remove the precipitates at 74-78°C. The mixture was stirred and heated under reflux until the mixture turned clear and was then cooled. Crystals started to form at ca. 45°C. The slurry was stirred for 2 hour at the cloudy point. The slurry was cooled slowly at a rate of 5°C/0.5 hour. The slurry was stirred at 10-20°C for 4-8 hours and then filtered. The filter cake was washed three times with MeOH (50 mL each) and dried at 50°C in vacuo for 6 hours to give 62.7 g of 99.9% HPLC pure cladribine in ca. 90% yield.

EXAMPLE 5 Preparation of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine

[0056]
2-Chloroadenine (2.2 Kg, 13.0 mol, 1.0 eq.), MeCN (20.7 Kg, 12 P), and BSTFA (10.0 Kg, 38.9 mol, 3.0 eq.) were stirred and heated under reflux for 3 hours and then filtered through celite and was cooled to about 60°C. TfOH (0.40 Kg, 2.6 mol, 0.2 eq.) and 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose (III; 5.87 Kg, 13.0 mol, 1.0 eq.) were added into the filtrate and the mixture was stirred at about 60°C for 29.5 hours. The slurry was cooled to about 20°C and stirred for 2 hours. The solids were filtered and washed with MeCN (2.8 Kg) twice and dried in vacuo at 60°C to give 5.17 Kg with a 96.5% HPLC purity in 62% yield of a mixture of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]-purine (IVa), and non-silylated derivative 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb).

EXAMPLE 6 Preparation of 2-chloro-2′-deoxy-adenosine (cladribine)

[0057]
To a mixture of 25% sodium methoxide in MeOH (0.11 Kg, 0.5 mol, 0.1 eq.) and MeOH (14.8 Kg, 5 P) at about at 25°C was added 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]-purine (IVa) and non-silylated derivative 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (3.70 Kg, combined HPLC purity of >96.3%) and the mixture was agitated at about 25°C for 2 hours. The solids were filtered, washed with MeOH (1.11 Kg, 0.4 P) and then dried in vacuo at 60°C for 4 hours to give 1.43 Kg of a crude cladribine with 97.8% HPLC purity in ca. 87% yield.

EXAMPLE 7 Recrystallisation of crude cladribine

[0058]
A mixture of crude cladribine (1.94 Kg, >96.0% HPLC purity), MeOH (7.77 Kg, 5 P), process purified water (9.67 Kg, 5 P) and 25% sodium methoxide in MeOH (32 g, 0.15 mol) were stirred and heated under reflux until the solids dissolved. The solution was cooled to about 70°C and treated with activated carbon (0.16 Kg) and celite for 1 hour at about 70°C, rinsed with a mixture of preheated MeOH and process purified water (W/W = 1:1.25, 1.75 Kg). The filtrate was cooled to about 45°C and maintained at this temperature for 1 hours, and then cooled to about 15°C and agitated at this temperature for 2 hours. The solids were filtered and washed with MeOH (1.0 Kg, 0.7 P) three times and were then dried in vacuo at 60°C for 4 hours giving API grade cladribine (1.5 Kg, 5.2 mol) in 80% yield with 99.84% HPLC purity.

EXAMPLE 8 Recrystallisation of crude cladribine

[0059]
A mixture of crude cladribine (1.92 Kg, >95.7% HPLC purity), MeOH (7.76 Kg, 5 P), process purified water (9.67 Kg, 5 P) and 25% sodium methoxide in MeOH (36 g, 0.17 mol) were stirred and heated under reflux until the solids dissolved. The solution was cooled to about 70°C and treated with activated carbon (0.15 Kg) and celite for 1 hour at about 70°C, rinsed with a mixture of preheated MeOH and process purified water (1:1.25, 1.74 Kg). The filtrate was cooled to about 45°C and maintained at this temperature for 1 hour, and then cooled to about 15°C and agitated at this temperature for 2 hours. The solids were filtered and washed with MeOH (1.0 Kg, 0.7 P) three times and were giving damp cladribine (1.83 Kg). A mixture of this cladribine (1.83 Kg), MeOH (7.33 Kg, 5 P) and process purified water (9.11 Kg, 5 P) were stirred and heated under reflux until the solids dissolved and was then cooled to about 45°C and maintained at this temperature for 1 hours. The slurry was further cooled to about 15°C and agitated at this temperature for 2 hours. The solids were filtered and washed with MeOH (0.9 Kg, 0.7 P) three times and were then dried in vacuo at 60°C for 4 hours giving API grade cladribine (1.38 Kg, 4.8 mol) in 75% yield with 99.86% HPLC purity.

SYN

Cladribine can be got from 2-Deoxy-D-ribose. The detail is as follows:

Production of Cladribine

SYN

https://www.tandfonline.com/doi/abs/10.1080/15257770.2015.1071848?journalCode=lncn20

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FDA approves new oral treatment for multiple sclerosis, Mavenclad (cladribine)

The U.S. Food and Drug Administration today approved Mavenclad (cladribine) tablets to treat

relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease. Mavenclad is not recommended for MS patients with clinically isolated syndrome. Because of its safety profile, the use of Mavenclad is generally recommended for patients who have had an inadequate response to…

March 29, 2019

Release

The U.S. Food and Drug Administration today approved Mavenclad (cladribine) tablets to treat relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease. Mavenclad is not recommended for MS patients with clinically isolated syndrome. Because of its safety profile, the use of Mavenclad is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

“We are committed to supporting the development of safe and effective treatments for patients with multiple sclerosis,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “The approval of Mavenclad represents an additional option for patients who have tried another treatment without success.”

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communications between the brain and other parts of the body. Most people experience their first symptoms of MS between the ages of 20 and 40. MS is among the most common causes of neurological disability in young adults and occurs more frequently in women than in men.

For most people, MS starts with a relapsing-remitting course, in which episodes of worsening function (relapses) are followed by recovery periods (remissions). These remissions may not be complete and may leave patients with some degree of residual disability. Many, but not all, patients with MS experience some degree of persistent disability that gradually worsens over time. In some patients, disability may progress independent of relapses, a process termed secondary progressive multiple sclerosis (SPMS). In the first few years of this process, many patients continue to experience relapses, a phase of the disease described as active SPMS. Active SPMS is one of the relapsing forms of MS, and drugs approved for the treatment of relapsing forms of MS can be used to treat active SPMS.

The efficacy of Mavenclad was shown in a clinical trial in 1,326 patients with relapsing forms of MS who had least one relapse in the previous 12 months. Mavenclad significantly decreased the number of relapses experienced by these patients compared to placebo. Mavenclad also reduced the progression of disability compared to placebo.

Mavenclad must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Mavenclad has a Boxed Warning for an increased risk of malignancy and fetal harm. Mavenclad is not to be used in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, health care professionals should evaluate the benefits and risks of the use of Mavenclad on an individual patient basis. Health care professionals should follow standard cancer screening guidelines in patients treated with Mavenclad. The drug should not be used in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during treatment and for six months after the course of therapy because of the potential for fetal harm. Mavenclad should be stopped if the patient becomes pregnant.

Other warnings include the risk of decreased lymphocyte (white blood cell) counts; lymphocyte counts should be monitored before, during and after treatment. Mavenclad may increase the risk of infections; health care professionals should screen patients for infections and treatment with Mavenclad should be delayed if necessary. Mavenclad may cause hematologic toxicity and bone marrow suppression so health care professionals should measure a patient’s complete blood counts before, during and after therapy. The drug has been associated with graft-versus-host-disease following blood transfusions with non-irradiated blood. Mavenclad may cause liver injury and treatment should be interrupted or discontinued, as appropriate, if clinically significant liver injury is suspected.

The most common adverse reactions reported by patients receiving Mavenclad in the clinical trials include upper respiratory tract infections, headache and decreased lymphocyte counts.

The FDA granted approval of Mavenclad to EMD Serono, Inc.

References

^ Drugs.com International trade names for Cladribine Page accessed Jan 14, 2015
^ Jump up to:^a ^b ^c ^d “PRODUCT INFORMATION LITAK© 2 mg/mL solution for injection” (PDF). TGA eBusiness Services. St Leonards, Australia: Orphan Australia Pty. Ltd. 10 May 2010. Retrieved 27 November 2014.
^ Liliemark, Jan (1997). “The Clinical Pharmacokinetics of Cladribine”. Clinical Pharmacokinetics. 32 (2): 120–131. doi:10.2165/00003088-199732020-00003. PMID 9068927.
^ Jump up to:^a ^b “European Medicines Agency – – Litak”. http://www.ema.europa.eu.
^ Jump up to:^a ^b “Leustat Injection. – Summary of Product Characteristics (SPC) – (eMC)”. http://www.medicines.org.uk.
^ Leist, TP; Weissert, R (2010). “Cladribine: mode of action and implications for treatment of multiple sclerosis”. Clinical Neuropharmacology. 34 (1): 28–35. doi:10.1097/wnf.0b013e318204cd90. PMID 21242742.
^ Jump up to:^a ^b ^c ^d Cladribine label, last updated July 2012. Page accessed January 14, 2015
^ https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634837.htm
^ Histiocytosis Association Erdheim-Chester Disease Page accessed Aug 20, 2016
^ Aricò M (2016). “Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy”. Br J Haematol. 173 (5): 663–70. doi:10.1111/bjh.13955. PMID 26913480. The combination of cytarabine and cladribine is the current standard for second-line therapy of refractory cases with vital organ dysfunction.
^ Jump up to:^a ^b ^c Giovannoni, G; Comi, G; Cook, S; Rammohan, K; Rieckmann, P; Soelberg Sørensen, P; Vermersch, P; Chang, P; Hamlett, A; Musch, B; Greenberg, SJ; CLARITY Study, Group. (4 February 2010). “A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis”. The New England Journal of Medicine. 362 (5): 416–26. doi:10.1056/NEJMoa0902533. PMID 20089960.
^ Johnston, JB (June 2011). “Mechanism of action of pentostatin and cladribine in hairy cell leukemia”. Leukemia & Lymphoma. 52 Suppl 2: 43–5. doi:10.3109/10428194.2011.570394. PMID 21463108.
^ Beutler, E; Piro, LD; Saven, A; Kay, AC; McMillan, R; Longmire, R; Carrera, CJ; Morin, P; Carson, DA (1991). “2-Chlorodeoxyadenosine (2-CdA): A Potent Chemotherapeutic and Immunosuppressive Nucleoside”. Leukemia & Lymphoma. 5 (1): 1–8. doi:10.3109/10428199109068099. PMID 27463204.
^ Baker, D; Marta, M; Pryce, G; Giovannoni, G; Schmierer, K (February 2017). “Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis”. EBioMedicine. 16: 41–50. doi:10.1016/j.ebiom.2017.01.042. PMC 5474520. PMID 28161400.
^ Baker, D; Herrod, SS; Alvarez-Gonzalez, C; Zalewski, L; Albor, C; Schmierer, K (July 2017). “Both cladribine and alemtuzumab may effect MS via B-cell depletion”. Neurology: Neuroimmunology & Neuroinflammation. 4 (4): e360. doi:10.1212/NXI.0000000000000360. PMC 5459792. PMID 28626781.
^ Jump up to:^a ^b Ceronie, B; Jacobs, BM; Baker, D; Dubuisson, N; Mao, Z; Ammoscato, F; Lock, H; Longhurst, HJ; Giovannoni, G; Schmierer, K (May 2018). “Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells”. Journal of Neurology. 265 (5): 1199–1209. doi:10.1007/s00415-018-8830-y. PMC 5937883. PMID 29550884.
^ Jump up to:^a ^b Marshall A. Lichtman Biographical Memoir: Ernest Beutler 1928–2008 National Academy of Sciences, 2012
^ Staff, The Pink Sheet Mar 8, 1993 Ortho Biotech’s Leustatin For Hairy Cell Leukemia
^ Jump up to:^a ^b EMA 2004 Litak EMA package: Scientific Discussion
^ EMA 2004 Litak: Background Information one the Procedure
^ Eric Sauter and Mika Ono for Scripps News and Views. Vol 9. Issue 18. June 1, 2009 A Potential New MS Treatment’s Long and Winding Road
^ Tortorella C, Rovaris M, Filippi M (2001). “Cladribine. Ortho Biotech Inc”. Curr Opin Investig Drugs. 2 (12): 1751–6. PMID 11892941.
^ Jump up to:^a ^b Carey Sargent for Dow Jones Newswires in the Wall Street Journal. Oct. 31, 2002 Serono Purchases Rights To Experimental MS Drug
^ Reuters. Dec 4, 2000. Ivax to Develop Cladribine for Multiple Sclerosis
^ Jennifer Bayot for the New York Times. July 26, 2005 Teva to Acquire Ivax, Another Maker of Generic Drugs
^ Teva Press Release, 2006. Teva Completes Acquisition of Ivax
^ Staff, First Word Pharma. Sept 21, 2006 Merck KGaA to acquire Serono
^ Jump up to:^a ^b ^c EMA. 2011 Withdrawal Assessment Report for Movectro Procedure No. EMEA/H/C/001197
^ Jump up to:^a ^b John Gever for MedPage Today June 22, 2011 06.22.2011 0 Merck KGaA Throws in Towel on Cladribine for MS
^ Jump up to:^a ^b John Carroll for FierceBiotech Sep 11, 2015 Four years after a transatlantic slapdown, Merck KGaA will once again seek cladribine OK
^ Connolly, Allison (24 April 2012). “Merck KGaA to Close Merck Serono Site in Geneva, Cut Jobs”. Bloomberg.
^ Pakpoor, J; et al. (December 2015). “No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine”. Neurology: Neuroimmunology & Neuroinflammation. 2 (6): e158. doi:10.1212/nxi.0000000000000158. PMC 4592538. PMID 26468472.
^ Press release
^ Merck. “Cladribine Tablets Receives Positive CHMP Opinion for Treatment of Relapsing Forms of Multiple Sclerosis”. http://www.prnewswire.co.uk. Retrieved 2017-08-22.
^ Cladribine approved in Europe, Press Release
^ Jump up to:^a ^b Giovannoni, G; Soelberg Sorensen, P; Cook, S; Rammohan, K; Rieckmann, P; Comi, G; Dangond, F; Adeniji, AK; Vermersch, P (1 August 2017). “Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study”. Multiple Sclerosis (Houndmills, Basingstoke, England): 1352458517727603. doi:10.1177/1352458517727603. PMID 28870107.
^ “Sustained Efficacy – Merck Neurology”. Merck Neurology. Retrieved 28 September2018.
^ Guarnera, C; Bramanti, P; Mazzon, E (2017). “Alemtuzumab: a review of efficacy and risks in the treatment of relapsing remitting multiple sclerosis”. Therapeutics and Clinical Risk Management. 13: 871–879. doi:10.2147/TCRM.S134398. PMC 5522829. PMID 28761351.
^ Baker, D; Herrod, SS; Alvarez-Gonzalez, C; Giovannoni, G; Schmierer, K (1 August 2017). “Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab”. JAMA Neurology. 74 (8): 961–969. doi:10.1001/jamaneurol.2017.0676. PMC 5710323. PMID 28604916.
^ “Cladribine tablets for treating relapsing–remitting multiple sclerosis”. National Institute for Clinical Excellence. Retrieved 23 September 2018.
^ Hasanali, Zainul S.; Saroya, Bikramajit Singh; Stuart, August; Shimko, Sara; Evans, Juanita; Shah, Mithun Vinod; Sharma, Kamal; Leshchenko, Violetta V.; Parekh, Samir (24 June 2015). “Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia”. Science Translational Medicine. 7 (293): 293ra102. doi:10.1126/scitranslmed.aaa5079. ISSN 1946-6234. PMC 4807901. PMID 26109102.

Cladribine
Clinical data

Trade names	Leustatin, others^[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a693015
License data	EUEMA: by INN
Pregnancy category	AU:D US:D (Evidence of risk)
Routes of administration	Intravenous, subcutaneous(liquid)
ATC code	L01BB04 (WHO) (parenteral) L04AA40 (WHO) (oral for MS)
Legal status
Legal status	AU:S4 (Prescription only) CA: ℞-only UK:POM (Prescription only)
Pharmacokinetic data
Bioavailability	100% (i.v.); 37 to 51% (orally)^[3]
Protein binding	25% (range 5-50%)^[2]
Metabolism	Mostly via intracellular kinases; 15-18% is excreted unchanged^[2]
Elimination half-life	Terminal elimination half-life: Approximately 10 hours after both intravenous infusion an subcutaneous bolus injection^[2]
Excretion	Urinary^[2]
Identifiers
IUPAC name [show]
CAS Number	4291-63-8
PubChemCID	20279
IUPHAR/BPS	4799
DrugBank	DB00242
ChemSpider	19105
UNII	47M74X9YT5
KEGG	D01370
ChEBI	CHEBI:567361
ChEMBL	ChEMBL1619
ECHA InfoCard	100.164.726
Chemical and physical data
Formula	C₁₀H₁₂ClN₅O₃
Molar mass	285.687 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Clc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)C3)CO)N
InChI [hide] InChI=1S/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5+,6+/m0/s1 Key:PTOAARAWEBMLNO-KVQBGUIXSA-N

Cladribine

CAS Registry Number: 4291-63-8

CAS Name: 2-Chloro-2¢-deoxyadenosine

Additional Names: 2-chloro-6-amino-9-(2-deoxy-b-D-erythro-pentofuranosyl)purine; 2-chlorodeoxyadenosine; 2-CdA; CldAdo

Manufacturers’ Codes: NSC-105014-F

Trademarks: Leustatin (Ortho Biotech)

Molecular Formula: C10H12ClN5O3

Molecular Weight: 285.69

Percent Composition: C 42.04%, H 4.23%, Cl 12.41%, N 24.51%, O 16.80%

Literature References: Substituted purine nucleoside with antileukemic activity. Prepn as intermediate in synthesis of 2-deoxynucleosides: H. Venner, Ber. 93, 140 (1960); M. Ikehara, H. Tada, J. Am. Chem. Soc. 85, 2344 (1963); eidem, ibid. 87, 606 (1965). Synthesis and biological activity: L. F. Christensen et al., J. Med. Chem. 15, 735 (1972). Stereospecific synthesis: Z. Kazimierczuk et al., J. Am. Chem. Soc. 106, 6379 (1984); R. K. Robins, G. R. Revankar, EP 173059; eidem, US 4760137 (1986, 1988 both to Brigham Young Univ.). Specific toxicity to lymphocytes: D. A. Carson et al., Proc. Natl. Acad. Sci. USA 77, 6865 (1980); eidem, Blood 62, 737 (1983). Mechanism of action: S. Seto et al., J. Clin. Invest. 75, 377 (1985). Clinical evaluation in chronic lymphocytic leukemia: L. D. Piro et al., Blood 72, 1069 (1988); in hairy cell leukemia: eidem, N. Engl. J. Med. 322, 1117 (1990).

Properties: Crystals from water, softens at 210-215°, solidifies and turns brown (Christensen). Also reported as crystals from ethanol, mp 220° (softens), resolidifies, turns brown and does not melt below 300° (Kazimierczuk). [a]D25 -18.8° (c = 1 in DMF). uv max in 0.1N NaOH: 265 nm; in 0.1N HCl: 265 nm.

Melting point: mp 220° (softens), resolidifies, turns brown and does not melt below 300°

Optical Rotation: [a]D25 -18.8° (c = 1 in DMF)

Absorption maximum: uv max in 0.1N NaOH: 265 nm; in 0.1N HCl: 265 nm

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Antimetabolites; Purine Analogs.

////////////fda 2019, Mavenclad, cladribine, multiple sclerosis, EMD Serono, クラドリビン , Leustatin, クラドリビン , orphan drug designation

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634837.htm?utm_campaign=032919_PR_FDA%20approves%20new%20drug%20for%20multiple%20sclerosis&utm_medium=email&utm_source=Eloqua

NC1=C2N=CN([C@H]3C[C@H](O)[C@@H](CO)O3)C2=NC(Cl)=N1

Macimorelin acetate

February 17, 2019 12:40 pm / Leave a comment

ChemSpider 2D Image | Macimorelin | C26H30N6O3

Macimorelin

Molecular FormulaC₂₆H₃₀N₆O₃
Average mass474.555 Da

CAS 381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

2-Methylalanyl-N-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]-D-tryptophanamide

381231-18-1 [RN]

8680B21W73

9073

D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-

CAS 945212-59-9 (Macimorelin acetate)

(2R)-2-(2-amino-2-methylpropanamido)-3-(1H-indol-3-yl)-N-[(1R)-2-(1H-indol-3-yl)-1-formamidoethyl]propanamide; acetic acid

AEZS-130
ARD-07
D-87875
EP-01572
EP-1572
JMV-1843

USAN (ab-26)
MACIMORELIN ACETATE

AQZ1003RMG

ARD 07

D-87575

D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1) [ACD/Index Name]

EP 1572

THERAPEUTIC CLAIM
Diagnostic agent for adult growth hormone deficiency (AGHD)
CHEMICAL NAMES
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate

MOLECULAR FORMULA
C26H30N6O3.C2H4O2
MOLECULAR WEIGHT
534.6

SPONSOR
Aeterna Zentaris GmbH
CODE DESIGNATIONS
D-87575, EP 1572, ARD 07
CAS REGISTRY NUMBER
945212-59-9

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures. read at

http://www.drugs.com/nda/macimorelin_acetate_131105.html

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

Macimorelin (INN), or Macrilen (trade name) is a drug being developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist.^[1]Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

As of January 2014, it was in Phase III clinical trials.^[2] The phase III trial for growth hormone deficiency is expected to be complete in December 2016.^[3]

As of December 2017, it became FDA-approved as a method to diagnose growth hormone deficiency.^[4] Traditionally, growth hormone deficiency was diagnosed via means of insulin tolerance test (IST) or glucagon stimulation test (GST). These two means are done parenterally, whereas Macrilen boasts an oral formulation for ease of administration for patients and providers.

Macimorelin is a growth hormone secretagogue receptor (ghrelin receptor) agonist causing release of growth hormone from the pituitary gland.^[5]^[6]^[7]

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels ^[3]. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer.

Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function ^[5]. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies ^[3]. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test ^[3]. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability ^[3].

Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820

PAPER

J Med Chem 2003, 46(7): 1191

http://pubs.acs.org/doi/full/10.1021/jm020985q

Abstract Image

Synthetic Pathway for JMV 1843 and Analogues^a

^a Reagents and conditions: (a) IBCF, NMM, DME, 0 °C; (b) NH₄OH; (c) H₂, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc₂O, DMAP cat., anhydrous CH₃CN; (f) BTIB, pyridine, DMF/H₂O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. ¹H NMR (400 MHz, DMSO-d₆) + correlation ¹H−¹H: δ 1.21 (s, 3H, CH₃ (Aib)), 1.43 (s, 3H, CH₃(Aib)), 2.97 (m, 2H, (CH₂)_β), 3.1 (m, 2H, (CH₂)_β_‘), 4.62 (m, 1H, (CH)α_A and (CH)α_B), 5.32 (q, 0.4H, (CH)α‘_B), 5.71 (q, 0.6H, (CH)α‘_A), 7.3 (m, 4H, H₅ and H₆(2 indoles)), 7.06−7.2 (4d, 2H, H_2A and H_2B (2 indoles)), 7.3 (m, 2H, H₄ or H₇ (2 indoles)), 7.6−7.8 (4d, 2H, H_4A and H_4B or H_7A and H_7B), 7.97 (s, 3H, NH₂ (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH_1B (diamino)), 8.3 (m,1H, NH_A and NH_B), 8.5 (d, 0.6H, NH_1A (diamino)), 8.69 (d, 0.6H, NH_2A (diamino)), 8.96 (d, 0.4H, NH_2B(diamino)), 10.8 (s, 0.6H, N¹H_1A (indole)), 10.82 (s, 0.4H, N¹H_1B (indole)), 10.86 (s, 0.6H, N¹H_2A (indole)), 10.91 (s, 0,4H, N¹H_2B (indole)). MS (ES), m/z: 475 [M + H]⁺, 949 [2M + H]⁺. HPLC t_R: 16.26 min (conditions A).

PATENTS

http://www.google.com/patents/US8192719

The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH₂CH₃. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:

PATENT

http://www.google.com/patents/US6861409

H-Aib-D-Trp-D-gTrp-CHO:

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):

Z-D-Tr-NH₂

Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NH₂precipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.

Yield=98%.

C₁₉H₁₉N₃O₃, 337 g.mol⁻¹.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (250 MHZ, DMSO-d⁶): δ 2.9 (dd, 1H, H_β, J_ββ′=14.5 Hz; J_βα=9.8 Hz); 3.1 (dd, 1H, H_β′, J_β′β=14.5 Hz; J_β′α=4.3 Hz); 4.2 (sextuplet, 1H, H_α); 4.95 (s, 2H, CH₂(Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H²); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N¹H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]⁺, 360 [M+Na]⁺, 675 [2M+H]⁺, 697 [2M+Na]⁺.

Boc-D-Trp-D-Trp-NH₂

Z-D-Trp-NH₂(3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH₂as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH₂(8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH₂as a white solid.

Yield=85%.

C₂₇H₃₁N₅O₄, 489 g.mol⁻¹.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH₂)_β; 4.14 (m, 1H, CH_α); 4.52 (m, 1H, CH_α′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH₂, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N¹H); 10.85 (d, 1H, J=2 Hz, N¹H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]⁺, 512 [M+Na]⁺, 979 [2M+H]⁺.

Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH₂

Boc-D-Trp-D-Trp-NH₂(3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH₂as a white solid.

Yield=60%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.6 (m, 1H, CH_α); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH₂(amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺, 1401 [2M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H

Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NⁱBoc)Trp-D-g(NⁱBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C₃₆H₄₇N₅O₇, 661 g.mol⁻¹.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH₂(amine)); 3.1-2.8 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.85 (m, 1H, CH_α); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]⁺, 684 [M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO as a white solid.

Yield=70%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH₂)_β); 4.25 (m, 1H, (CH)α_A&B); 5.39 (m, 0.4H, (CH)α′_B); 5.72 (m, 0.6H, (CH)α′_A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺.

Boc-Aib-D-Trp-D-gTrp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.

Yield=70%.

C₃₁H₃₈N₆O₅, 574 g.mol⁻¹.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.21 (s, 6H, 2 CH₃(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH₂)_β); 4.47 (m, 1H, (CH)α_A&B); 5.2 (m, 0.4H, (CH)α′_B); 5.7 (m, 0.6H, (CH)α′_A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N¹H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]⁺, 597 [M+Na]⁺, 1149 [2M+H]⁺, 1171 [2M+Na]⁺.

H-Aib-D-Trp-D-gTrT-CHO

Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

Yield=52%.

C₂₆H₃₀N₆O₃, 474 g.mol⁻¹.

¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ 1.21 (s, 3H, CH₃(Aib)); 1.43 (s, 3H, CH₃(Aib)); 2.97 (m, 2H, (CH₂)_β); 3.1 (m, 2H, (CH₂)_β′); 4.62 (m, 1H, (CH)α_A&B); 5.32 (q, 0.4H, (CH)α′_B); 5.71 (q, 0.6H, (CH)α′_A); 7.3 (m, 4H₅and H₆(2 indoles)); 7.06-7.2 (4d, 2H, H_2Aet H_2B(2 indoles)); 7.3 (m, 2H, H₄or H₇(2 indoles)); 7.6-7.8 (4d, 2H, H_4Aand H_4Bor H_7Aet H_7B); 7.97 (s, 3H, NH₂(Aib) and CHO (Formyl));8.2 (d, 0.4H, NH_1B(diamino)); 8.3 (m,1H, NH_A&B); 8.5 (d, 0.6H, NH_1A(diamino)); 8.69 (d, 0.6H, NH₂A (diamino)); 8.96 (d, 0.4H, NH_2B(diamino)); 10.8 (s, 0.6H, N¹H_1A(indole)); 10.82 (s, 0.4H, N¹H_1B(indole)); 10.86 (s, 0.6H, N¹H₂A (indole)); 10.91 (s, 0.4, N¹H_2B(indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]⁺, 949 [2M+H]⁺.

CLIP

UPDATED INFO AS ON JAN 6 2014

Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.

References

^ “Macrilen Prescribing Information” (PDF). Retrieved 2018-07-25.
^ “Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA”. Wall Street Journal. January 6, 2014.
^ https://clinicaltrials.gov/ct2/show/NCT02558829
^ Research, Center for Drug Evaluation and. “Drug Approvals and Databases – Drug Trials Snapshots: Marcrilen”. http://www.fda.gov. Retrieved 2018-07-25.
^ “Macimorelin”. NCI Drug Dictionary. National Cancer Institute.
^ Koch, Linda (2013). “Growth hormone in health and disease: Novel ghrelin mimetic is safe and effective as a GH stimulation test”. Nature Reviews Endocrinology. 9 (6): 315. doi:10.1038/nrendo.2013.89.
^ Garcia, J. M.; Swerdloff, R.; Wang, C.; Kyle, M.; Kipnes, M.; Biller, B. M. K.; Cook, D.; Yuen, K. C. J.; Bonert, V.; Dobs, A.; Molitch, M. E.; Merriam, G. R. (2013). “Macimorelin (AEZS-130)-Stimulated Growth Hormone (GH) Test: Validation of a Novel Oral Stimulation Test for the Diagnosis of Adult GH Deficiency”. Journal of Clinical Endocrinology & Metabolism. 98 (6): 2422. doi:10.1210/jc.2013-1157. PMC 4207947.

Patent ID	Title	Submitted Date	Granted Date
US2015099709	GHRELIN RECEPTOR AGONISTS FOR THE TREATMENT OF ACHLORHYDRIA	2013-05-27	2015-04-09
US2013060029	QUINAZOLINONE DERIVATIVES USEFUL AS VANILLOID ANTAGONISTS	2012-09-12	2013-03-07
US8835444	Cyclohexyl amide derivatives as CRF receptor antagonists	2011-01-31	2014-09-16
US8163785	PYRAZOLO[5, 1B]OXAZOLE DERIVATIVES AS CRF-1 RECEPTOR ANTAGONISTS	2011-08-04	2012-04-24

Patent ID	Title	Submitted Date	Granted Date
US7297681	Growth hormone secretagogues	2004-11-18	2007-11-20
US2018071367	METHODS OF TREATING COGNITIVE IMPAIRMENTS OR DYSFUNCTION	2016-03-08
US2012295942	Pyrazolo[5, 1b]oxazole Derivatives as CRF-1 Receptor Antagonists	2011-01-28	2012-11-22
US8349852	Quinazolinone Derivatives Useful as Vanilloid Antagonists	2010-08-05
US2017266257	METHODS OF TREATING TRAUMATIC BRAIN INJURY	2015-08-18

Patent ID	Title	Submitted Date	Granted Date
US2015265680	THERAPEUTIC AGENT FOR AMYOTROPHIC LATERAL SCLEROSIS	2013-10-23	2015-09-24
US2011201629	CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS	2011-08-18
US8614213	Organic compounds	2011-06-23
US7994203	Organic compounds	2010-02-11	2011-08-09
US8273900	Organic compounds	2010-02-11

Patent ID	Title	Submitted Date	Granted Date
US6861409	Growth hormone secretagogues	2002-11-07	2005-03-01
US8192719	Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds	2009-12-10	2012-06-05
US2017121385	METHODS OF TREATING NEURODEGENERATIVE CONDITIONS	2016-10-28
US2017281732	METHODS OF TREATING MILD BRAIN INJURY	2015-08-18
US2014088105	Cyclohexyl Amide Derivatives and Their Use as CRF-1 Receptor Antagonists	2013-11-22	2014-03-27

Macimorelin
Names

IUPAC name 2-Amino-N-[(2R)-1-[[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]amino]-3-1H-indol-3-yl)-1-oxopropan-2-yl]-2-methylpropanamide
Other names Aib-Trp-gTrp-CHO; AEZS-130; JMV 1843; Macimorelin acetate
Identifiers
CAS Number	381231-18-1 945212-59-9 (acetate)
3D model (JSmol)	Interactive image
ChemSpider	7980698
KEGG	D10563
PubChem CID	9804938
UNII	8680B21W73
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₆H₃₀N₆O₃
Molar mass	474.565 g·mol⁻¹
Pharmacology
ATC code	V04CD06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000ChemR.pdf

///////////macimorelin, FDA 2017, Aeterna Zentaris, AEZS-130, ARD-07, D-87875, EP-01572, EP-1572, JMV-1843, USAN (ab-26), MACIMORELIN ACETATE, orphan drug designation

CC(O)=O.CC(C)(N)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)NC=O

Caplacizumab-yhdp, カプラシズマブ

February 8, 2019 11:25 am / Leave a comment

FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

Release

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm630851.htm?utm_campaign=020919_PR_FDA%20approves%20therapy%20for%20treatment%20of%20adult%20patients%20with%20rare%20blood%20clotting%20disorder&utm_medium=email&utm_source=Eloqua

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” 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. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Cablivi 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 Cablivi to Ablynx.

EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP 1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP 2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

1 http://hugin.info/152918/R/2213684/863478.pdf

2 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA

51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG

101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR

151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT

201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG

251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

1: PN: WO2011067160 SEQID: 1 claimed protein
98: PN: WO2006122825 SEQID: 98 claimed protein
ALX 0081
ALX 0681
Caplacizumab

FORMULA	C1213H1891N357O380S10
CAS	915810-67-2
MOL WEIGHT	27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.^[1]^[2]

This drug was developed by Ablynx NV.^[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.^[4]

It is an anti-von Willebrand factor humanized immunoglobulin.^[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.^[5] Results of the phase II TITAN trial have been reported.^[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. ^[6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type	Single domain antibody
Source	Humanized
Target	VWF
Clinical data
Synonyms	ALX-0081
ATC code	B01AX07 (WHO)
Identifiers
CAS Number	915810-67-2
DrugBank	DB06081
ChemSpider	none
UNII	2R27AB6766
KEGG	D11160
Chemical and physical data
Formula	C₁₂₁₃H₁₈₉₁N₃₅₇O₃₈₀S₁₀
Molar mass	27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).³⁹Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):511–22; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref], [PubMed], [Web of Science ®], , [Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

^ Statement On A Nonproprietary Name Adopted By The USAN Council – Caplacizumab, American Medical Association.
^ World Health Organization (2011). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 106”(PDF). WHO Drug Information. 25 (4).
^ A Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES)
^ European Medicines Agency. “An overview of Cablivi and why it is authorised in the EU” (PDF). Retrieved 1 October 2018.
^ Jump up to:^a ^b ^c Immune Drug Tackles Microvascular Thrombosis Disorder. Feb 2016
^ “FDA approved caplacizumab-yhdp”. 2019-02-07.

///////////////caplacizumab, Cablivi, Ablynx, Priority Review, Orphan Drug designation, fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ , PEPTIDE, ALX 0081

Tagraxofusp タグラクソフスプ

January 11, 2019 6:28 am / Leave a comment

MGADDVVDSS KSFVMENFSS YHGTKPGYVD SIQKGIQKPK SGTQGNYDDD WKGFYSTDNK
YDAAGYSVDN ENPLSGKAGG VVKVTYPGLT KVLALKVDNA ETIKKELGLS LTEPLMEQVG
TEEFIKRFGD GASRVVLSLP FAEGSSSVEY INNWEQAKAL SVELEINFET RGKRGQDAMY
EYMAQACAGN RVRRSVGSSL SCINLDWDVI RDKTKTKIES LKEHGPIKNK MSESPNKTVS
EEKAKQYLEE FHQTALEHPE LSELKTVTGT NPVFAGANYA AWAVNVAQVI DSETADNLEK
TTAALSILPG IGSVMGIADG AVHHNTEEIV AQSIALSSLM VAQAIPLVGE LVDIGFAAYN
FVESIINLFQ VVHNSYNRPA YSPGHKTRPH MAPMTQTTSL KTSWVNCSNM IDEIITHLKQ
PPLPLLDFNN LNGEDQDILM ENNLRRPNLE AFNRAVKSLQ NASAIESILK NLLPCLPLAT
AAPTRHPIHI KDGDWNEFRR KLTFYLKTLE NAQAQQTTLS LAIF
(disulfide bridge: 187-202, 407-475)

Image result for Tagraxofusp US FDA APPROVAL

methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,https://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf

Tagraxofusp

タグラクソフスプ

CAS:	2055491-00-2

C2553H4026N692O798S16, 57694.4811

FDA 2018/12/21, Elzonris APPROVED

Antineoplastic, Immunotoxin, Peptide

DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401

UNII8ZHS5657EH

Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)

FDA approves first treatment for rare blood disease

>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF

December 21, 2018

Release

The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.

“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” 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.

BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.

The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignation. Elzonris 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 Elzonris to Stemline Therapeutics.

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.^[4] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.^[6, 7] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.^[3] This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status.^[2] Tagraxofusp has been designed as an orphan drug in EU since November 2015.^[7]

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.^[2]

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.^[1] A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.^[6]

Associated Conditions

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.^[6] One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.^[5]

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.^[2]

Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).^[5] To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.^[4,6]

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.^[6]

Absorption

The reported Cmax in clinical trials was of around 23 ng/ml.^[6] After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.^[Label]

Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.^[Label]

Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.^[6]

MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.^[6]

ClearanceThe clearance of tagraxofusp was reported to fit a mono-exponential model.^[6] The reported clearance rate is reported to be of 7.1 L/h.^[Label]

ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.^[Label]

Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
FDA news [Link]
FDA approvals [Link]
Oncology nursing news [Link]
Stemline therapeutics news [Link]
Blood journal [Link]
NHS reports [Link]

FDA label, Download (455 KB)

/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ , Stemline Therapeutics, Breakthrough Therapy, Priority Review designation, Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 , Molecule 129 , Molecule-129 , SL-401,

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

November 30, 2018 12:58 am / Leave a comment

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

November 28, 2018

Release

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse 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 Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review, Breakthrough Therapy, Firdapse, Orphan Drug designation, fda 2018, amifampridine

Caplacizumab, カプラシズマブ Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

October 29, 2018 10:44 am / Leave a comment

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

1 http://hugin.info/152918/R/2213684/863478.pdf

2 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

More………….

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA

51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG

101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR

151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT

201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG

251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

1: PN: WO2011067160 SEQID: 1 claimed protein
98: PN: WO2006122825 SEQID: 98 claimed protein
ALX 0081
ALX 0681
Caplacizumab

Formula	C1213H1891N357O380S10
CAS	915810-67-2
Mol weight	27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.^[1]^[2]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

References

Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – Caplacizumab, American Medical Association.
Jump up^ World Health Organization (2011). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 106”(PDF). WHO Drug Information. 25 (4).
Jump up^ A Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES)
Jump up^ European Medicines Agency. “An overview of Cablivi and why it is authorised in the EU” (PDF). Retrieved 1 October 2018.
^ Jump up to:^a ^b ^c Immune Drug Tackles Microvascular Thrombosis Disorder. Feb 2016

Caplacizumab
Monoclonal antibody
Type	Single domain antibody
Source	Humanized
Target	VWF
Clinical data
Synonyms	ALX-0081
ATC code	none
Identifiers
CAS Number	915810-67-2
ChemSpider	none
KEGG	D11160
Chemical and physical data
Formula	C₁₂₁₃H₁₈₉₁N₃₅₇O₃₈₀S₁₀
Molar mass	27.88 kg/mol

/////////////eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ , PEPTIDE, ALX 0081

	DR ANTHONY MELVIN CR… on ADAFOSBUVIR, адафосбувир , أدا…
	DR ANTHONY MELVIN CR… on AK 3280
	DR ANTHONY MELVIN CR… on Novobiocin, ノボビオシン;
	DR ANTHONY MELVIN CR… on CT 1812
	DR ANTHONY MELVIN CR… on ACLIMOSTAT

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FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

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Leustatin

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Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

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FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ , for the treatment of adult patients with a rare blood clotting disorder

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