New Drug Approvals

Home » Posts tagged 'FDA 2019'

Tag Archives: FDA 2019

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,501,310 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,354 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,354 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

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


Diaminopyridine.png

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.”

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 …

May 06, 2019

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.”

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

Advertisements

First FDA-approved vaccine Dengvaxia for the prevention of dengue disease in endemic regions


Image result for dengue

First FDA-approved vaccine for the prevention of dengue disease in endemic regions

May 01, 2019

The U.S. Food and Drug Administration announced today the approval of Dengvaxia, the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.

“Dengue disease is the most common mosquito-borne viral disease in the world and global incidence has increased in recent decades,” said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs. “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases. While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States.”

The CDC estimates more than one-third of the world’s population is living in areas at risk for infection by dengue virus which causes dengue fever, a leading cause of illness among people living in the tropics and subtropics. The first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection. A subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Symptoms may include stomach pain, persistent vomiting, bleeding, confusion and difficulty breathing. Approximately 95 percent of all severe/hospitalized cases of dengue are associated with second dengue virus infection. Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

Each year, an estimated 400 million dengue virus infections occur globally according to the CDC. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children. Although dengue cases are rare in the continental U.S., the disease is regularly found in American Samoa, Puerto Rico, Guam, the U.S. Virgin Islands, as well as Latin America, Southeast Asia and the Pacific islands.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease.”

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.

The most commonly reported side effects by those who received Dengvaxia were headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever. The frequency of side effects was similar across Dengvaxia and placebo recipients and tended to decrease after each subsequent dose of the vaccine.

Dengvaxia is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection – without actually infecting the person with wild-type dengue virus – such that a subsequent infection can result in severe dengue disease.Therefore, health care professionals should evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus. This can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing (tests using blood samples from the patient) prior to vaccination.

Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.

The FDA granted this application Priority Review and a Tropical Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of certain tropical diseases. The approval was granted to Sanofi Pasteur.

https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions?utm_campaign=050119_PR_First%20FDA-approved%20vaccine%20for%20prevention%20of%20dengue%20in%20endemic%20areas&utm_medium=email&utm_source=Eloqua

//////////fda 2019, Priority Review, Tropical Disease Priority Review Voucher , Sanofi Pasteur,  Dengvaxia, vaccine, dengue

Erdafitinib, エルダフィチニブ ,Эрдафитиниб , إيردافيتينيب , 厄达替尼 ,


Erdafitinib.svg

Erdafitinib.png

Erdafitinib

エルダフィチニブ

JNJ-42756493

CAS 1346242-81-6

MF, C25H30N6O2, MW 446.54

UNII-890E37NHMV

890E37NHMV

2019/4/12, FDA APPROVED, BALVERSA (Janssen Products LP)

Balversa

Эрдафитиниб [Russian] [INN]

إيردافيتينيب [Arabic] [INN]
厄达替尼 [Chinese] [INN]

N‘-(3,5-dimethoxyphenyl)-N‘-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine

1,2-Ethanediamine, N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]- [ACD/Index Name]
10147
1346242-81-6 [RN]
890E37NHMV
N-(3,5-dimethoxyphenyl)-N’-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
5SF
MFCD28502040
N’-(3,5-dimethoxyphenyl)-N’-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine
N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethanediamine

Image result for Erdafitinib

Erdafitinib is an orally bioavailable, pan fibroblast growth factor receptor (FGFR) inhibitor with potential antineoplastic activity. Upon oral administration, erdafitinib binds to and inhibits FGFR, which may result in the inhibition of FGFR-related signal transduction pathways and thus the inhibition of tumor cell proliferation and tumor cell death in FGFR-overexpressing tumor cells. FGFR, upregulated in many tumor cell types, is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival

Erdafitinib has been used in trials studying the basic science and treatment of Tumor or Lymphoma.

Erdafitinib[1] is a small molecule inhibitor of FGFR approved for treatment of cancer and marketed under the name Balversa. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival.[2] Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.

Researchers have investigated erdafitinib for safety and efficacy in treatment of cholangiocarcinomagastric cancernon-small cell lung cancer, and esophageal cancer.[3]

In March 2018, erdafitinib was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration for treatment of urothelial cancer.[2],

In April 2019, erdafitinib was granted approval by the FDA for treatment of metastatic or locally advanced bladder cancer with an FGFR3 or FGFR2 alteration that has progressed beyond traditional platinum-based therapies, subject to a confirmatory trial.

PATENT

WO 2011135376

https://patents.google.com/patent/WO2011135376A1/ru

STR1-1

MORE……………

STR1-1

References

  1. ^ https://searchusan.ama-assn.org/usan/documentDownload?uri=%2Funstructured%2Fbinary%2Fusan%2Ferdafitinib.pdf
  2. Jump up to:a b “Janssen Announces U.S. FDA Breakthrough Therapy Designation for Erdafitinib in the Treatment of Metastatic Urothelial Cancer – Johnson & Johnson”http://www.jnj.com.
  3. ^ “Erdafitinib – Janssen Pharmaceutica – AdisInsight”adisinsight.springer.com.
Erdafitinib
Erdafitinib.svg
Clinical data
Synonyms JNJ-42756493
Identifiers
CAS Number
PubChem CID
UNII
KEGG
ECHA InfoCard 100.235.008 Edit this at Wikidata
Chemical and physical data
Formula C25H30N6O2
Molar mass 446.555 g·mol−1
3D model (JSmol)

Patent IDTitleSubmitted DateGranted Date

US2018186775QUINOXALINE DERIVATIVES USEFUL AS FGFR KINASE MODULATORS2017-12-28

US2018127397PYRAZOLYL QUINOXALINE KINASE INHIBITORS2017-11-13

US20172601682-ARYL- AND 2-HETEROARYL-SUBSTITUTED 2-PYRIDAZIN-3(2H)-ONE COMPOUNDS AS INHIBITORS OF FGFR TYROSINE KINASES2016-10-24

US2017267684A DEUTERATED TRIAZOLOPYRIDAZINE AS A KINASE MODULATOR2015-12-03

US9464071PYRAZOLYL QUINOXALINE KINASE INHIBITORS2014-10-022015-04-16

US8895601Pyrazolyl quinoxaline kinase inhibitors2011-04-282014-11-25

US2017100406COMBINATIONS OF AN FGFR INHIBITOR AND AN IGF1R INHIBITOR2015-03-26

US9850228PYRAZOLYL QUINOXALINE KINASE INHIBITORS2016-04-28

US9902714QUINOXALINE DERIVATIVES USEFUL AS FGFR KINASE MODULATORS2015-03-26

US2018296558COMBINATIONS2018-04-17

US2018021332PHARMACEUTICAL COMPOSITIONS COMPRISING N-(3,5-DIMETHOXYPHENYL)-N’-(1-METHYLETHYL)-N-[3-(1-METHYL-1H-PYRAZOL-4-YL)QUINOXALIN-6-YL]ETHANE-1,2-DIAMINE2016-02-09

US2017119763COMBINATIONS2015-03-26

US2016090633USE OF FGFR MUTANT GENE PANELS IN IDENTIFYING CANCER PATIENTS THAT WILL BE RESPONSIVE TO TREATMENT WITH AN FGFR INHIBITOR2015-09-182016-03-31

US2016287699FGFR/PD-1 COMBINATION THERAPY FOR THE TREATMENT OF CANCER2016-03-24

/////////Erdafitinib, FDA 2019, エルダフィチニブ, BALVERSA, Janssen Products LP, JNJ-42756493, Эрдафитиниб ,  إيردافيتينيب 厄达替尼 ,

CC(C)NCCN(C1=CC2=NC(=CN=C2C=C1)C3=CN(N=C3)C)C4=CC(=CC(=C4)OC)OC

 

FDA approves first treatment for pediatric patients with lupus


The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.
“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of …

April 26, 2019

Release

The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.

“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of improving their quality of life and lowering their risk of long-term organ damage and disability,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

While childhood-onset SLE is rare, when diagnosed, it is generally more active in children and adolescents than adult patients, particularly in how it impacts organs such as the kidneys and central nervous system. As a result of the disease starting early in life, pediatric patients with SLE are at a higher risk for developing increased organ damage and complications from the disease as well as adverse events from the life-long treatments usually required.

The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was studied over 52 weeks in 93 pediatric patients with SLE. The proportion of pediatric patients achieving the composite primary endpoint, the SLE response index (SRI-4), was higher in pediatric patients receiving Benlysta IV plus standard therapy compared to placebo plus standard therapy. Pediatric patients who received Benlysta IV plus standard therapy also had a lower risk of experiencing a severe flare, as well as longer duration of time until a severe flare (160 days versus 82 days). The drug’s safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE.

Benlysta’s doctor and patient information includes a warning for mortality, serious infections, hypersensitivity and depression, based on data from the clinical studies in adults with SLE. The drug should not be administered with live vaccines. The manufacturer is required to provide a Medication Guide to inform patients of the risks associated with Benlysta.

The most common side effects in patients included nausea, diarrhea and fever. Patients also commonly experienced infusion reactions, so healthcare professionals are advised to pre-treat patients with an antihistamine.

The FDA granted this application a Priority Review designation. The FDA granted the approval of Benlysta to GlaxoSmithKline.

////////////Benlysta, belimumab, fda 2019, Priority Review, GlaxoSmithKline

Solriamfetol hydrochloride, ソルリアムフェトル塩酸塩 , солриамфетол , سولريامفيتول , 索安非托 ,


2D chemical structure of 178429-65-7

Solriamfetol hydrochloride

FDA APPROVED 2019/3/20, Sunosi

ソルリアムフェトル塩酸塩; R228060, R 228060

Formula
C10H14N2O2. HCl
CAS
178429-65-7 HCL
Mol weight
230.6913
(2R)-2-Amino-3-phenylpropyl carbamate
(2R)-2-Amino-3-phenylpropylcarbamat
10117
178429-62-4 [RN] FREE FORM
Benzenepropanol, β-amino-, carbamate (ester), (βR)- [
солриамфетол [Russian] [INN]
سولريامفيتول [Arabic] [INN]
索安非托 [Chinese] [INN]
JZP-110
Originator SK Holdings
  • Developer Jazz Pharmaceuticals plc; SK biopharmaceuticals
  • Class Carbamates; Sleep disorder therapies; Small molecules
  • Mechanism of Action Adrenergic uptake inhibitors; Dopamine uptake inhibitors
  • Orphan Drug Status Yes – Narcolepsy
  • Registered Hypersomnia
  • Discontinued Depressive disorders
  • 26 Mar 2019 Discontinued – Phase-I for Depressive disorders (Adjunctive treatment) in USA (PO) (Jazz Pharmaceuticals pipeline, March 2019)
  • 20 Mar 2019 Registered for Hypersomnia (excessive daytime sleepiness) in patients with obstructive sleep apnoea and narcolepsy in USA (PO) – First global approval
  • 20 Mar 2019 US FDA approves solriamfetol to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnoea(OSA)
  • New Drug Application (NDA): 211230
    Company: JAZZ PHARMA IRELAND LTD

Solriamfetol, sold under the brand name Sunosi, is a medication used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea.[1]

Common side effects include headache, nausea, anxiety, and trouble sleeping.[1] It is a norepinephrine–dopamine reuptake inhibitor(NDRI). It is derived from phenylalanine and its chemical name is (R)-2-amino-3-phenylpropylcarbamate hydrochloride.[2]

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of 11 countries in Asia to Aerial Pharma in 2011.[3]

History

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of 11 countries in Asia to Aerial Pharma in 2011.[3]Aerial ran two Phase II trials of the drug in narcolepsy[4] before selling the license to solriamfetol to Jazz in 2014; Jazz Pharmaceuticalspaid Aerial $125 million up front and will pay Aerial and SK up to $272 million in milestone payments, and will pay double digit royalties to SK.[3][5]

In March 2019 the FDA accepted SK’s and Jazz’ NDA for use of solriamfetol to treat excessive sleepiness in people with narcolepsy or obstructuve sleep apnea; the drug has an orphan designation for narcolepsy.[3][6]

Names

During development it has been called SKL-N05, ADX-N05, ARL-N05, and JZP-110.[6]

Research

Solriamfetol had also been tested in animal models of depression, but as of 2017 that work had not been advanced to clinical trials.[7]

PATENT

WO 9607637

https://patents.google.com/patent/WO1996007637A1/e

Organic alkyl carbamates have been effectively used for controlling various central nervous system (CNS) disorders. For example, U.S. Pat. Nos . 2,884,444, 2,937,119 and 3,313,697 disclose function of carbamate in CNS disorders, especially as antiepileptic and centrally acting muscle relaxant.
Phenylethylamine derivatives, one important class of therapeutical medicines useful for managing CNS diseases, have been used mainly to treat obesity, narcolepsy, minimal brain dysfunction and mild depression.
Recent design of pharmacologically useful compounds has been based on amino acids or the derivatives thereof, which is mainly attributable to the fact that many of the compounds found in biological systems come from amino acids or the derivatives thereof. In addition, in most cases, the function of a pharmaceutically useful compound is effected after it binds to an enzyme or receptor, which may trigger the regulatory mechanisms of the enzyme or receptor.

REACTION SCHEME I

REACTION SCHEME II

REACTION SCHEME III

EXAMPLE I
Preparation of N-Benzyloxycarbonyl-D-phenylalaninol

In a 500 mL RB flask equipped with a mechanical stirrer and a dropping funnel, D-phenylalaninol (45.4 g, 300 mmol) was dissolved in 220 mL of distilled water, and cooled in an ice-bath. The pH of the solution was adjusted with 50 % sodium hydroxide to 14. Benzyl chloroformate (49.3 mL, 345 mmol) was charged into the dropping funnel and added slowly to the well stirred solution over 0.5 hr. After the completion of the addition, the reaction mixture was stirred for 1 hr. at 0 *C. The product precipitated from the reaction mixture as a white solid. It was collected by filtration and washed completely with distilled water. After being dried in vacuo, the solid thus obtained weighed 104 grams without any further purification: 99.8% Yield.
Melting point = 90 – 92 *C
[α]D20 = + 43.4 (c = 1.0, EtOH)
Analysis calc: C, 71.56; H, 6.71; N,4.91
Found: C, 71.35; H, 6.71; N,4.91

EXAMPLE II
Preparation of N-Benzyloxycarbonyl-D-phenylalaninol
carbamate

In a 500 mL RB flask, N-benzyloxycarbonyl-D- phenylalaninol (13.56 g, 50 mmol) was charged with antipyrine (11.29 g, 60 mmol) in 250 mL of dry THF under a nitrogen atmosphere. The reaction mixture was cooled in an ice-bath and phosgene (30.3 mL of 1.93 M solution in toluene, 58.5 mmol) was added quickly while vigorously stirring. After stirring for 1 hr. , the formation of a corresponding chloroformate from the starting material was monitored by TLC. The chloroformate solution thus prepared, was slowly added to a well stirred and ice-chilled aqueous ammonium hydroxide solution (75 mL, 28-30 %, 1,190 mmol) via cannula over 0.5 hr. The resulting reaction mixture was stirred for an extra 0.5 hr. The organic phase separated was collected. The aqueous phase was extracted twice with methylene chloride (100 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield 17.8 g (113%) of foamy solid. It was purified a flash column chromatography to give 14.8 g of the title compound, white solid: 94% Yield.
Melting point = 121 – 125 *C
[α]D20 = + 28.6 (c = 2.0, EtOH)
Analysis calc. : C, 65.84; H, 6.14; N, 8.53
Found: C, 66.68; H, 6.21; N, 7.80

EXAMPLE III
Preparation of D-Phenylalaninol carbamate hydrochloric
acid salt In a 160 mL Parr reactor, N-benzyloxycarbonyl-D-phenylalaninol carbamate (9.43 g) was added with 75 mL of anhydrous methanol and 10 % palladium on charcoal (0.32 g). Then, the reactor was closed and purged with hydrogen for 1 in. The reaction was completed in 2 hrs . under 40 psi pressure of hydrogen at 45 #C. The catalyst was filtered off. Thereafter, the organic layer was concentrated into 5.97 g (102 %) of pale yellow thick liquid. The liquid was poured in 50 mL of anhydrous THF and cooled to 0 “C. Anhydrous hydrogen chloride gas was then purged through the solution with slowly stirring for

0.5 hr. 50 mL of anhydrous ether was added, to give a precipitate. Filtration with THF-ether (1:1) mixture provided 6.1 g of the title compound as a white solid: 88 % Yield.
Melting point = 172 – 174 “C
[α]D20 = – 12.9 (c = 2.0, H20)
Analysis calc. : C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.90; H, 6.60; N, 12.15; Cl ,

15.52

EXAMPLE IV
Preparation of N-benzyloxγcarbonyl-L-Phenγlalaninol

The title compound was prepared in the same manner as that of Example I, except that (L)-phenylalaninol was used as the starting material.
Melting point = 90 – 92 *C
[α]D20 = – 42.0 (c = 1.0, EtOH)
Analysis calc. : C, 71.56; H, 6.71; N,4.91
Found: C, 70.98; H, 6.67; N,4.95

EXAMPLE V
Preparation of -N-benzyloxycarbonyl-L-Phenylalaninol
carbamate

The title compound was prepared in the same manner as that of Example II, except that N-benzyloxycarbonyl-L-phenylalaninol was used as the starting material.
Melting point = 121 – 128 ‘C
[α]D20 = – 28.9 (c = 2.0, EtOH)
Analysis calc: C, 65.84; H, 6.14; N, 8.53
Found: C, 65.45; H, 6.15; N, 8.32

EXAMPLE VI
Preparation of L-Phenylalaninol carbamate hydrochloric
acid salt

The title compound was prepared in the same manner as that of Example III, except that N-benzyloxycarbonyl-L-phenylalaninol carbamate was used as the starting material.
Melting point = 175 – 177 *C [α]D20 = + 13.1 (c = 1.0, H20)
Analysis calc : C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.95; H, 6.58; N, 12.09; Cl , 15.37

EXAMPLE VII
Preparation of N-benzyloxycarbonyl-D,L-Phenylalaninol

The title compound was prepared in the same manner as that of Example I, except that (D,L)-phenylalaninol was used as the starting material.
Melting point = 72 – 75 #C
Analysis calc: C, 71.56; H, 6.71; N,4.91
Found: C, 71.37; H, 6.74; N,4.84

EXAMPLE VIII
Preparation of N-benzyloxycarbonyl-D,L-Phenylalaninol
carbamate

The title compound was prepared in the same manner as that of Example II, except that N-benzyloxycarbonyl-D,L-phenylalaninol was used as the starting material.
Melting point = 130 – 133 *C
Analysis calc: C, 65.84; H, 6.14; N, 8.53
Found: C, 65.85; H, 6.14; N, 8.49 EXAMPLE IX
Preparation of D,L-Phenylalaninol carbamate hydrochloric
acid salt

The title compound was prepared in the same manner as that of Example III, except that N-benzyloxycarbonyl-D,L-phenylalaninol carbamate was used as the starting material.
Melting point = 163 – 165 *C
Analysis calc: C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.92; H, 6.56; N, 11.95; Cl , 15.82

PATENT

US 20050080268

PATENT

WO 2018133703

https://patents.google.com/patent/WO2018133703A1/en

Excessive daytime sleepiness (Excessive Daytime Sleepiness, EDS) or pathological somnolence refers to excessive daytime sleep and wakefulness associated with various sleep disorders. These disorders can be the basis for a sleep disorder or sleep have side effects caused by some other medical conditions. Excessive daytime sleep, also known as narcolepsy, sleep clinics is seen mainly in patients with disease that affects 12% of the general population. EDS patients may be manifested as mental distress, poor work or school performance, increasing the risk of accidents, the impact of EDS can debilitating, even life-threatening.

R228060, also known JZP-110, is a selective dopamine and norepinephrine reuptake inhibitor, originally developed by R & D, SK biopharmaceutical, 2014 Sir ownership of the pharmaceutical compound. R228060 has the potential to treat narcolepsy and sleep apnea syndrome, in three multi-center study in two global reached the primary endpoint, and achieved positive results, significantly improved adult obstructive sleep apnea patients excessive sleepiness in patients with narcolepsy and excessive sleep problems.

R228060 chemical name is O- carbamoyl – (D) – phenylalaninol, as shown in the structural formula of formula (I):

Figure PCTCN2018071889-appb-000001

Solid Form different chemicals, can cause varying their solubility and stability, and thus affects the absorption and bioavailability of the drug, and can lead to differences in clinical efficacy. Improve the candidate compound has a solubility by salt way become an important means of drug development. Compared to the free form of the drug, suitable pharmaceutically acceptable salts can improve the solubility of the drug type, increased physical and chemical stability, and also to improve the drug-salt having a melting point, hygroscopicity, crystal type and other physical properties, further development of the pharmaceutical dosage form It plays an important role. Patent Document WO1996007637A1 discloses R228060 hydrochloride and its preparation method, and other characteristics of the obtained having a melting point of 172-174 deg.] C as a white solid, the solid was not given in the text data. Further, the present inventors found no other relevant R228060 hydrochloride polymorph or patent literature. Accordingly, the present need in the art to develop a comprehensive system R228060 hydrochloride polymorph, found to be suitable to the development of crystalline form. The present inventors after many experiments, found that polymorph CS1 R228060 hydrochloride CS2 and a melting point polymorph, Form CS1 and CS2 is Form 183 ℃, much higher than the melting point disclosed in prior art solid. It provides a better alternative preparation of pharmaceutical preparations containing R228060 is, has very important implications for drug development.

PATENT

WO 2019027941

https://patentscope2.wipo.int/search/en/detail.jsf;jsessionid=15B8F200BCC820C3761C600EA64A2018?docId=WO2019027941&recNum=4220&office=&queryString=&prevFilter=%26fq%3DOF%3AWO&sortOption=Pub+Date+Desc&maxRec=3471866

(i?)-2-amino-3-phenylpropyl carbamate (APC) is a phenylalanine analog that has been demonstrated to be useful in the treatment of a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, and others. See, for example, US Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290; and U.S. Publication Nos. 2012/0004300 and 2015/0018414. Methods for producing APC (which also has other names) and related compounds can be found in US Patent Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of the above patents and applications are hereby incorporated by reference in their entireties for all purposes.

EXAMPLE 1

Synthesis of Compounds

Compound 8 (110CR002)

1 B 110CR002

[0083] tert- utyl (if)-(l-(Carbamothioyloxy)-3-phenylpropan-2-yl)carbamate (IB): A

60% dispersion of sodium hydride (0.36 g, 4.78 mmol, 1.2 equiv) in mineral oil was added in portions to compound 1A (1.0 g. 3.98 mmol, 1 equiv) in THF (20 mL) at 0 °C. After stirring for 1 hour, carbon disulfide (0.191 g, 4.78 mmol, 1.2 equiv) was added at 0 °C. After an additional hour of stirring, methyl iodide (0.3 mL, 4.78 mmol, 1.2 equiv) was added and the reaction was warmed to room temperature. After stirring two additional hours, concentrated ammonium hydroxide (1.6 mL, 7.98 mmol, 2 equiv) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude compound IB. The solid was triturated in diethyl ether (20 mL) to give compound IB (0.17 g, 14% yield) as a light yellow solid.

[0084] (R)-0-(2-Amino-3-phenylpropyl) carbamothioate dihydrochloride (110CR002):

4M HCI in dioxane (0.68 mL, 2.74 mmol, 5 equiv) was added to neat compound IB (0.17 g, 0.548 mmol, 1 equiv) and the reaction was stirred overnight. The solution was diluted with diethyl ether (20 mL) and the resulting suspension was filtered. The solid was triturated in diethyl ether (20 mL) and the filtered solid was dried under vacuum at room temperature for two hours to give compound 110CR003 (140 mg, 93% yield, 96.9% purity) as a white solid.

Compound 9 (110CR003)

Scheme 2

2A 2B 110CR003

[0085] (R)-2-((ter^Butoxycarbonyl)amino)-3-phenylpropyl sulfamate (2B): A solution of sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added dropwise to a solution of compound 2 A (1.0 g, 3.98 mmol, 1 equiv) and triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) in N,N-dimethylacetamide (20 mL) at 0 °C. After stirring at room temperature for 4 hours, additional triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) and sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added at 0 °C. The reaction was stirred at room temperature overnight, at which point LCMS indicated a 3 :2 mixture of product to starting material. Additional triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) and sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added at 0 °C and the reaction was stirred at room temperature for an additional 6 hours. LCMS indicated a 4: 1 mixture of product to starting material. The reaction was quenched with saturated sodium bicarbonate (5 mL) and stirred for an additional hour at room temperature. The reaction was diluted with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The product still contained unreacted starting material which could not be easily separated. Sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added dropwise to a solution of crude compound 2B (0.9 g) and triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) in N,N-dimethylacetamide (20 mL) at 0 °C. After stirring at room temperature for two hours, the reaction was quenched with saturated sodium bicarbonate (5 mL) and the reaction was stirred for an additional hour at room temperature. The reaction was diluted with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (Redisep 24 g silica gel column), eluting with a gradient of 25 to 50% ethyl acetate in heptanes, to give compound 2B (0.37 g, 28% yield) as a white solid.

[0086] (R)-2-Amino-3-phenylpropyl sulfamate hydrochloride (110CR003): 4M HC1 in dioxane (1.4 mL, 5.6 mmol, 5 equiv) was added to neat compound 2B (0.37 g, 1.12 mmol, 1 equiv) and the reaction was stirred overnight. The solution was diluted with diethyl ether (20 mL) and the resulting suspension was filtered. The solid was triturated in diethyl ether (20 mL) and the filtered solid was dried under a vacuum at room temperature for two hours to give compound 110CR003 (250 mg, 84% yield, 97.8% purity) as a white solid.

Com ound 3 (110CR007)

[0087] (Benzyl (R)-(l-phenyl-3-ureidopropan-2-yl)carbamate) (3B): Concentrated hydrochloric acid (0.06 mL, 0.68 mmol, 0.12 equiv) was added to a solution of benzyl (ft)-(l -amino-3-phenylpropan-2-yl)carbamate ( 1.5 g, 5.28 mmol, 1 equiv) and urea (1.26 g, 21.21 mmol, 4 equiv) in toluene (150 mL) under nitrogen. After refluxing overnight, LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure, diluted with water (150 mL) and stirred for 30 minutes. The resulting solid was filtered and washed with water (25 mL) to give crude compound 3B (1.4 g, 4.27 mmol, 80% yield) as a white solid, which was used sequentially.

[0088] ((R)-l-(2-mino-3-phenylpropyl)urea) (3C): Compound 3B (0.5 g, 1.5 mmol, 1 equiv) and 10% palladium on carbon (0.09 g) in methanol (60 mL) was hydrogenated at 30 psi for 1 hour at which time LC-MS determined that the reaction was incomplete. The solution was filtered and fresh catalyst (0.09 g) was added. The solution was hydrogenated at 30 psi for an additional 45 minutes resulting in complete conversion. Two identical scale reactions were run for 105 minutes each, both resulting in complete conversion. The three runs were combined and filtered through celite, which was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give crude compound 3C (0.9 g), which was used sequentially.

[0089] (R)-l-(2-Amino-3-phenylpropyI)urea hydrochloride (110CR007): Compound 3C (0.88 g, 4.58 mmol, 1 equiv) was dissolved diethyl ether (10 mL) and 4 N HCl in dioxane (2.31 mL, 9.27 mmol, 2 equiv) was added. The reaction was stirred overnight and then concentrated under reduced pressure to give crude 110CR007 as a white solid. The material was twice recrystallized from 10% methanol in ethanol (30 mL) to give 110CR007 (0.163 g, 16 % yield, 93.7 % purity) as a white solid.

Compound 4 (110CR009)

Scheme 4

[0090] Ethyl (R^)-4-((tert-butoxycarbonyI)amino)-5-phenylpent-2-enoate (4B): A solution of compound 4A (4.0 g, 16.1 mmol, 1 equiv) and ethyl (triphenylphos-phoranylidene)acetate (5.6 g, 16.1 mmol, 1 equiv) in dichloromethane (40 mL) was stirred at room temperature overnight. The reaction was concentrated under reduce pressure to remove the organic solvent and the resulting residue was purified on an AnaLogix automated system (40 g Sorbtech silica gel column), eluting with gradient of 50 to 100% ethyl acetate in heptanes, to give compound 4B (4.8 g, 94% yield) as a white solid.

[0091] (R^E)-4-((te *i-ButoxycarbonyI)amino)-5-phenylpent-2-enoic acid (4C): Lithium hydroxide (1.4 g, 60 mmol, 4 equiv) in water (15 mL) was added to compound 4B (4.8 g, 15 mmol, 1 equiv) in THF (60 mL) at room temperature and the reaction was stirred overnight. After 16 hours, the reaction was adjusted to pH 4 with IN hydrochloric acid. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers was washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give compound 4C (4.2 g, 97% yield) as a light cream solid, which was used subsequently.

[0092] Methyl (R E)-4-((½ -i-butoxycarbonyl)amino)-5-phenylpent-2-enoate (4D1):

Isobutyl chloro formate (1.3 mL, 10 mmol, 1 equiv) in THF (4 mL) was added dropwise to a solution of compound 4C (3.0 g, 10 mmol, 1 equiv) and N-methyl-morpholine (1.1 mL, 10 mmol, 1 equiv) in THF (12 mL) at -15 °C. After 30 minutes of stirring, LCMS indicated complete conversion to the anhydride intermediate. 2M Ammonia in methanol (5 mL, 10 mmol, 1 equiv) was added dropwise over 20 minutes, keeping the internal temperature between -25 to -15 °C. After 30 minutes of stirring, the reaction was warmed to room

temperature and stirred overnight. The reaction mixture was concentrated at reduced pressure to remove the organic solvent. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (80 g Sorbtech silica gel column), eluting with a gradient of 25 to 50% ethyl acetate in heptanes, to give compound 4D1 (1.1 g, 35 % yield) as a white solid.

[0093] Methyl (S)-4-((te^-butoxycarbonyl)amino)-5-phenylpentanoate (4D2): A mixture of compound 4D1 (1.1 g, 3.6 mmol, 1 equiv) and 10% palladium on carbon (0.33 g, 50% wet) in methanol (40 mL) was hydrogenated at 40 psi at room temperature for 4 hours. The mixture was filtered through celite, which was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give compound 4D2 (1.1 g, 99% yield) as a white solid.

[0094] (S)-4-((ii? i-Butoxycarbonyl)amino)-5-phenylpentanoic acid (4D3): Lithium hydroxide (73 mg, 3 mmol, 1.5 equiv) in water (1 mL) was added to compound 4B (0.6 g, 2 mmol, 1 equiv) in THF (9 mL) at room temperature. After stirring overnight, the reaction was adjusted to pH 4 with IN hydrochloric acid. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers was washed with saturated brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure to give compound 4D3 (0.56 g, 98% yield) as a white solid, which was used subsequently.

[0095] tert-Butyl (S)-(5-amino-5-oxo-l-phenylpentan-2-yl)carbamate (4E): Isobutyl chloroformate (0.23 mL, 1.8 mmol, 1 equiv) in THF (0.5 mL) was added drop-wise to a solution of compound 4C (0.54 g, 1.8 mmol, 1 equiv) and N-methylmorpholine (0.2 mL, 1.8 mmol, 1 equiv) in THF (1 mL) at -15 °C. After 20 minutes of stirring, LCMS indicated complete conversion to the anhydride intermediate. 0.4M Ammonia in THF (9 mL, 3.6 mmol, 2 equiv) was added drop-wise over 20 minutes, keeping the internal temperature between -25 to -15 °C. After 30 minutes of stirring the reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in ethyl acetate (25 mL) and washed with water (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under

reduced pressure to give compound 4E (0.5 g, 93% yield) as a white solid, which was used subsequently.

[0096] (S)-4-Amino-5-phenylpentanamide hydrochloride (110CR009): 4M HC1 in dioxane (6 mL, 25 mmol, 10 equiv) was added to compound 4E (0.73 g, 1.12 mmol, 1 equiv) After stirring overnight at room temperature, the reaction was diluted with diethyl ether (20 mL) and stirred for 6 hours. The resulting suspension was filtered and the solid was washed with diethyl ether (20 mL). The filtered solid was dried under vacuum at room temperature for two hours to give compound 110CR009 (340 mg, 60% yield, 97.9 % purity) as a white solid.

Compound 10 (110CR012)

[0097] tert-Butyl (R)-(l-(carbamoylthio)-3-phenyIpropan-2-yI)carbamate (5B):

Compound 5 A (0.15 g, 0.56 mmol, 1 equiv) was dissolved in THF (8 mL) and sparged with nitrogen for 15 minutes. Trichloroacetyl isocyanate (0.1 mL, 0.84 mmol, 1.5 equiv) was added and the solution stirred for 3 hours, at which point TLC (30% ethyl acetate in heptane) indicated absence of starting material. The reaction was cooled to 0°C and concentrated ammonium hydroxide (0.15 mL) was added. After stirring overnight at room temperature, TLC indicated that the reaction was complete. The reaction was washed with a 10% ammonium hydroxide (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (12 g silica gel column), eluting with a gradient of 0 to 30% ethyl acetate in heptane, to give compound 5B. This reaction was repeated an additional two times 0.15 g and 0.18 g). The products were to give compound 5B (0.35 g, 1.12 mmol, 62.2% yield) as a white solid.

[0098] (R)-S-(2-Amino-3-phenylpropyl) carbamothioate hydrochloride (110CR012):

Compound 5B (0.35 g, 1.12 mmol, 1 equiv) was dissolved in 4N HCI in dioxane (2 mL). The reaction was stirred for two hours and then concentrated under reduced pressure to give crude 110CR012 as a white solid. The material was triturated in diethyl ether (15 mL) to give 110CR012 (0.215 g, 78 % yield, 98.0 % purity) as a white solid.

References

  1. Jump up to:a b “SUNOSI™ (solriamfetol) Tablets, for Oral Use. Full Prescribing Information” (PDF). Jazz Pharmaceuticals. 2019. Retrieved 21 March2019.
  2. ^ Abad, VC; Guilleminault, C (2017). “New developments in the management of narcolepsy”Nature and Science of Sleep9: 39–57. doi:10.2147/NSS.S103467PMC 5344488PMID 28424564.
  3. Jump up to:a b c d Ji-young, Sohn (5 March 2018). “SK Biopharmaceuticals’ narcolepsy drug on track to hitting US market”The Korea Herald.
  4. ^ Sullivan, SS; Guilleminault, C (2015). “Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy”. Expert Opinion on Emerging Drugs20 (4): 571–82. doi:10.1517/14728214.2015.1115480PMID 26558298.
  5. ^ Garde, Damian (January 14, 2014). “Jazz bets up to $397M on Aerial’s narcolepsy drug”FierceBiotech.
  6. Jump up to:a b “Solriamfetol – Jazz Pharmaceuticals/SK Biopharmaceuticals”. AdisInsight. Retrieved 15 April 2018.
  7. ^ de Biase, S; Nilo, A; Gigli, GL; Valente, M (August 2017). “Investigational therapies for the treatment of narcolepsy”. Expert Opinion on Investigational Drugs26 (8): 953–963. doi:10.1080/13543784.2017.1356819PMID 28726523.
Solriamfetol
Solriamfetol.svg
Clinical data
Trade names Sunosi
Synonyms SKL-N05, ADX-N05, ARL-N05, and JZP-110; (R)-2-amino-3-phenylpropylcarbamate hydrochloride
Routes of
administration
By mouth
ATC code
Pharmacokinetic data
Bioavailability ~95%
Protein binding 13.3–19.4%
Metabolism negligible
Elimination half-life ~7.1 h
Excretion urine (95% unchanged)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C10H14N2O2
Molar mass 194.234 g/mol g·mol−1
3D model (JSmol)

///////////Solriamfetol hydrochloride, Solriamfetol, ソルリアムフェトル塩酸塩; солриамфетол , سولريامفيتول 索安非托 JZP-110, Orphan Drug, fda 2019, R228060, R 228060

Cladribine, クラドリビン


Cladribine.svgChemSpider 2D Image | Cladribine | C10H12ClN5O3

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 lymphocytesnatural 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.

Figure imgb0001

[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-Op-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.

Figure imgb0002
[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, 6379-6382US4760137 EP0173059 ) provided an improved method in which the sodium salt of 2,6-dichloropurine was coupled with 1-chloro-2-deoxy-3,5-di-Op-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 SN2 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 SN2 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.

Figure imgb0003
[0006]

Gerszberg and Alonso (Gerszberg S. and Alonso, D. WO0064918 , and US20020052491 ) also utilised an SN2 approach with 1-chloro-2-deoxy-3,5-di-Op-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.

Figure imgb0004
[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 SN2 reaction using the anomerically pure α-anomer, 1-chloro-2-deoxy-3,5-di-Op-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.

Figure imgb0005
[0008]

More recently Robins et al. (Robins, M. J. et al., J. Org. Chem. 2006, 71, 7773-7779US20080207891 ) 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-Op-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.

Figure imgb0006
[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

Image result for cladribine

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

clip
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

  1. ^ Drugs.com International trade names for Cladribine Page accessed Jan 14, 2015
  2. 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.
  3. ^ Liliemark, Jan (1997). “The Clinical Pharmacokinetics of Cladribine”. Clinical Pharmacokinetics32 (2): 120–131. doi:10.2165/00003088-199732020-00003PMID 9068927.
  4. Jump up to:a b “European Medicines Agency – – Litak”http://www.ema.europa.eu.
  5. Jump up to:a b “Leustat Injection. – Summary of Product Characteristics (SPC) – (eMC)”http://www.medicines.org.uk.
  6. ^ Leist, TP; Weissert, R (2010). “Cladribine: mode of action and implications for treatment of multiple sclerosis”. Clinical Neuropharmacology34 (1): 28–35. doi:10.1097/wnf.0b013e318204cd90PMID 21242742.
  7. Jump up to:a b c d Cladribine label, last updated July 2012. Page accessed January 14, 2015
  8. ^ https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634837.htm
  9. ^ Histiocytosis Association Erdheim-Chester Disease Page accessed Aug 20, 2016
  10. ^ Aricò M (2016). “Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy”. Br J Haematol173 (5): 663–70. doi:10.1111/bjh.13955PMID 26913480The combination of cytarabine and cladribine is the current standard for second-line therapy of refractory cases with vital organ dysfunction.
  11. 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 Medicine362 (5): 416–26. doi:10.1056/NEJMoa0902533PMID 20089960.
  12. ^ Johnston, JB (June 2011). “Mechanism of action of pentostatin and cladribine in hairy cell leukemia”. Leukemia & Lymphoma. 52 Suppl 2: 43–5. doi:10.3109/10428194.2011.570394PMID 21463108.
  13. ^ 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 & Lymphoma5 (1): 1–8. doi:10.3109/10428199109068099PMID 27463204.
  14. ^ 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”EBioMedicine16: 41–50. doi:10.1016/j.ebiom.2017.01.042PMC 5474520PMID 28161400.
  15. ^ 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 & Neuroinflammation4 (4): e360. doi:10.1212/NXI.0000000000000360PMC 5459792PMID 28626781.
  16. 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 Neurology265 (5): 1199–1209. doi:10.1007/s00415-018-8830-yPMC 5937883PMID 29550884.
  17. Jump up to:a b Marshall A. Lichtman Biographical Memoir: Ernest Beutler 1928–2008 National Academy of Sciences, 2012
  18. ^ Staff, The Pink Sheet Mar 8, 1993 Ortho Biotech’s Leustatin For Hairy Cell Leukemia
  19. Jump up to:a b EMA 2004 Litak EMA package: Scientific Discussion
  20. ^ EMA 2004 Litak: Background Information one the Procedure
  21. ^ 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
  22. ^ Tortorella C, Rovaris M, Filippi M (2001). “Cladribine. Ortho Biotech Inc”. Curr Opin Investig Drugs2 (12): 1751–6. PMID 11892941.
  23. 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
  24. ^ Reuters. Dec 4, 2000. Ivax to Develop Cladribine for Multiple Sclerosis
  25. ^ Jennifer Bayot for the New York Times. July 26, 2005 Teva to Acquire Ivax, Another Maker of Generic Drugs
  26. ^ Teva Press Release, 2006. Teva Completes Acquisition of Ivax
  27. ^ Staff, First Word Pharma. Sept 21, 2006 Merck KGaA to acquire Serono
  28. Jump up to:a b c EMA. 2011 Withdrawal Assessment Report for Movectro Procedure No. EMEA/H/C/001197
  29. 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
  30. 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
  31. ^ Connolly, Allison (24 April 2012). “Merck KGaA to Close Merck Serono Site in Geneva, Cut Jobs”Bloomberg.
  32. ^ Pakpoor, J; et al. (December 2015). “No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine”Neurology: Neuroimmunology & Neuroinflammation2 (6): e158. doi:10.1212/nxi.0000000000000158PMC 4592538PMID 26468472.
  33. ^ Press release
  34. ^ Merck. “Cladribine Tablets Receives Positive CHMP Opinion for Treatment of Relapsing Forms of Multiple Sclerosis”http://www.prnewswire.co.uk. Retrieved 2017-08-22.
  35. ^ Cladribine approved in Europe, Press Release
  36. 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:10.1177/1352458517727603PMID 28870107.
  37. ^ “Sustained Efficacy – Merck Neurology”Merck Neurology. Retrieved 28 September2018.
  38. ^ 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 Management13: 871–879. doi:10.2147/TCRM.S134398PMC 5522829PMID 28761351.
  39. ^ 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 Neurology74 (8): 961–969. doi:10.1001/jamaneurol.2017.0676PMC 5710323PMID 28604916.
  40. ^ “Cladribine tablets for treating relapsing–remitting multiple sclerosis”National Institute for Clinical Excellence. Retrieved 23 September 2018.
  41. ^ 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 Medicine7 (293): 293ra102. doi:10.1126/scitranslmed.aaa5079ISSN 1946-6234PMC 4807901PMID 26109102.
Cladribine
Cladribine.svg
Clinical data
Trade names Leustatin, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a693015
License data
Pregnancy
category
  • AU:D
  • US:D (Evidence of risk)
Routes of
administration
Intravenoussubcutaneous(liquid)
ATC code
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 intracellularkinases; 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
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.164.726Edit this at Wikidata
Chemical and physical data
Formula C10H12ClN5O3
Molar mass 285.687 g/mol g·mol−1
3D model (JSmol)
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 173059eidem, 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
NC1=C2N=CN([C@H]3C[C@H](O)[C@@H](CO)O3)C2=NC(Cl)=N1

Certolizumab pegol, セルトリズマブペゴル (遺伝子組換え)


Image result for certolizumab pegol

>Amino acid sequence of the light chain
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence of the heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY
ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA

Certolizumab pegol

CAS: 428863-50-7

セルトリズマブペゴル (遺伝子組換え)

CDP 870 / CDP-870 / CDP870 / PHA-738144

Formula
C2115H3252N556O673S16
Cas
428863-50-7
Mol weight
47748.8128

Reducing signs and symptoms of Crohn’s disease and treatment of moderately to severely active rheumatoid arthritis (RA).

Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). Polyethylene glycol helps to delay the metabolism and elimination of the drugs. Chemically, the light chain is made up of 214 amino acid residues while the heavy chain is composed of 229 amino acid residues. The molecular mass of the Fab’ antibody fragment itself is 47.8 kDa. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008

Certolizumab pegol (CDP870, tradename Cimzia) is a biologic medication for the treatment of Crohn’s disease,[1][2] rheumatoid arthritispsoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha(TNF-α) and is manufactured by UCB.[3][4][5]

Image result for certolizumab pegol

Medical uses

Crohn’s Disease
On April 22, 2008, the U.S. FDA approved Cimzia for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.[4][6][7]
Rheumatoid arthritis
On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.[8]
Psoriatic arthritis
On September 27, 2013, the U.S. FDA approved Cimzia for the treatment of adult patients with active psoriatic arthritis.[9]

Method of action

Certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fabfragment of a humanized TNF inhibitor monoclonal antibody.[10]

Clinical trials

Crohn’s disease
Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease.[1][10][11][12]
Axial spondyloarthritis
In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive results in patient self-reported questionnaires, with rapid improvement of function and pain reduction, in patients with axial spondyloarthritis.[13]
Rheumatoid arthritis
Certolizumab appears beneficial in those with rheumatoid arthritis.[14]

Side effects

Significant side effects occur in 2% of people who take the medication.[14]

References

  1. Jump up to:a b Sandborn WJ, Feagan BG, Stoinov S, et al. (July 2007). “Certolizumab pegol for the treatment of Crohn’s disease”N. Engl. J. Med357 (3): 228–38. doi:10.1056/NEJMoa067594PMC 3187683PMID 17634458.
  2. ^ Goel, Niti; Sue Stephens (2010). “Certolizumab pegol”mAbs2 (2): 137–147. doi:10.4161/mabs.2.2.11271PMC 2840232PMID 20190560.
  3. ^ Kaushik VV, Moots RJ (April 2005). “CDP-870 (certolizumab) in rheumatoid arthritis”. Expert Opinion on Biological Therapy5 (4): 601–6. doi:10.1517/14712598.5.4.601PMID 15934837.
  4. Jump up to:a b index.cfm?fuseaction=Search.Label_ApprovalHistory “Cimzia Label and Approval History” Check |url= value (help)Drugs@FDAU.S. Food and Drug Administration(FDA). Retrieved 2009-11-15.
  5. ^ “Cimzia Prescribing Information” (PDF). US Food and Drug Administration (FDA). April 2016. Retrieved 2016-08-21.
  6. ^ UCB press release – Cimzia Approved in the US for the Treatment of Moderate to Severe Crohn’s Disease. Retrieved April 22, 2008.
  7. ^ Waknine, Yael (May 1, 2008). “FDA Approvals: Patanase, Actonel, Cimzia”Medscape. Retrieved 2008-05-01.
  8. ^ “Cimzia European Public Assessment Report”European Medicines Agency. Retrieved November 15, 2009.
  9. ^ “Cimzia (certolizumab pegol) approved by the U.S. FDA for treatment of adult patients with active psoriatic arthritis”. Archived from the original on October 1, 2013. Retrieved October 1, 2013.
  10. Jump up to:a b Schreiber S. et al., Certolizumab pegol, a humanised anti-TNF pegylated FAb’ fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn’s disease: a phase 3 study (precise), Gut, 2005, 54, suppl7, A82
  11. ^ Sandborn et al., Certolizumab pegol administered subcutaneously is effective and well tolerated in patients with active Crohn’s disease: results from a 26-week, placebo-controlled Phase 3 study (PRECiSE 1), Gastroenterology, 2006, 130, A107
  12. ^ “New Analysis Shows Cimzia (Certolizumab Pegol) Maintained Remission and Response in Recent Onset Crohn’s Disease” (Press release). UCB. October 23, 2006. Retrieved 2009-11-15.
  13. ^ Sieper J, Tubergen A, Coteur G, Woltering F, Landewe R (May 2013). “PMS50 – Rapid Improvements In Patient-Reported Outcomes With Certolizumab Pegol In Patients With Axial Spondyloarthritis, Including Ankylosing Spondylitis And Non-Radiographic Axial Spondyloarthritis: 24-Week Results Of A Phase 3 Double Blind Randomized Placebo-Controlled Study”. Value in Health16 (3): A227. doi:10.1016/j.jval.2013.03.1150.
  14. Jump up to:a b Ruiz Garcia, V; Jobanputra, P; Burls, A; Vela Casasempere, P; Bort-Marti, S; Bernal, JA (Sep 8, 2017). “Certolizumab pegol (CDP870) for rheumatoid arthritis in adults”(PDF)The Cochrane Database of Systematic Reviews9: CD007649. doi:10.1002/14651858.CD007649.pub4PMID 28884785.

External links

FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis

March 28, 2019

Release

The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.

“Today’s approval of Cimzia fulfills an unmet need for patients suffering from non-radiographic axial spondyloarthritis as there has been no FDA-approved treatments until now,” said Nikolay Nikolov, M.D., associate director for rheumatology of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms. There is no visible damage seen on x-rays, so it is referred to as non-radiographic.

The efficacy of Cimzia for the treatment of nr-axSpA was studied in a randomized clinical trial in 317 adult patients with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein (CRP) levels and/or sacroiliitis (inflammation of the sacroiliac joints) on MRI. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score, a composite scoring system that assesses disease activity including patient-reported outcomes and CRP levels. Responses were greater for patients treated with Cimzia compared to patients treated with placebo. The overall safety profile observed in the Cimzia treatment group was consistent with the known safety profile of Cimzia.

The prescribing information for Cimzia includes a Boxed Warning to advise health care professionals and patients about the increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis (infection in the blood steam), invasive fungal infections (such as histoplasmosis, an infection that affects the lungs), and other infections. Cimzia should be discontinued if a patient develops a serious infection or sepsis. Health care providers are advised to perform testing for latent TB and, if positive, to start treatment for TB prior to starting Cimzia. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative. The Boxed Warning also advises that lymphoma (cancer in blood cells) and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which Cimzia is a member. Cimzia is not indicated for use in pediatric patients. Cimzia must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Cimzia was originally approved in 2008 and is also indicated for adult patients with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The FDA granted the approval of Cimzia to UCB.

Certolizumab pegol
Syringe with Certolizumab pegol-1800.jpg

Syringe with 200mg Certolizumab pegol
Monoclonal antibody
Type Fab’ fragment
Source Humanized (from mouse)
Target TNF alpha
Clinical data
Trade names Cimzia
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a608041
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life about 11 days
Excretion Renal (PEG only)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C2115H3252N556O673S16
Molar mass 47,750 g/mol g·mol−1

///////////////FDA 2019, Cimzia, certolizumab pegol, inflammatory arthritis, UCB

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634671.htm?utm_campaign=032819_PR_FDA%20approves%20treatment%20for%20patients%20with%20a%20type%20of%20inflammatory%20arthritis&utm_medium=email&utm_source=Eloqua

FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis


FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis

March 28, 2019

Release

The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.

“Today’s approval of Cimzia fulfills an unmet need for patients suffering from non-radiographic axial spondyloarthritis as there has been no FDA-approved treatments until now,” said Nikolay Nikolov, M.D., associate director for rheumatology of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms. There is no visible damage seen on x-rays, so it is referred to as non-radiographic.

The efficacy of Cimzia for the treatment of nr-axSpA was studied in a randomized clinical trial in 317 adult patients with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein (CRP) levels and/or sacroiliitis (inflammation of the sacroiliac joints) on MRI. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score, a composite scoring system that assesses disease activity including patient-reported outcomes and CRP levels. Responses were greater for patients treated with Cimzia compared to patients treated with placebo. The overall safety profile observed in the Cimzia treatment group was consistent with the known safety profile of Cimzia.

The prescribing information for Cimzia includes a Boxed Warning to advise health care professionals and patients about the increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis (infection in the blood steam), invasive fungal infections (such as histoplasmosis, an infection that affects the lungs), and other infections. Cimzia should be discontinued if a patient develops a serious infection or sepsis. Health care providers are advised to perform testing for latent TB and, if positive, to start treatment for TB prior to starting Cimzia. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative. The Boxed Warning also advises that lymphoma (cancer in blood cells) and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which Cimzia is a member. Cimzia is not indicated for use in pediatric patients. Cimzia must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Cimzia was originally approved in 2008 and is also indicated for adult patients with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The FDA granted the approval of Cimzia to UCB.

 

///////////////FDA 2019, Cimzia, certolizumab pegol, inflammatory arthritis, UCB

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634671.htm?utm_campaign=032819_PR_FDA%20approves%20treatment%20for%20patients%20with%20a%20type%20of%20inflammatory%20arthritis&utm_medium=email&utm_source=Eloqua

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


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.

////////////fda 2019, Mavenclad, cladribine, multiple sclerosis, EMD Serono,

FDA approves new oral testosterone capsule for treatment of men with certain forms of hypogonadism


FDA approves new oral testosterone capsule (testosterone undecanoate) for treatment of men with certain forms of hypogonadism

March 27, 2019

Release

The U.S. Food and Drug Administration today approved Jatenzo (testosterone undecanoate), an oral testosterone capsule to treat men with certain forms of hypogonadism. These men have low testosterone levels due to specific medical conditions, such as genetic disorders like Klinefelter syndrome or tumors that have damaged the pituitary gland. Jatenzo should not be used to treat men with “age-related hypogonadism,” in which testosterone levels decline due to aging, even if these men have symptoms that appear to be related to low testosterone. Jatenzo’s benefits do not outweigh its risks for that use.

“Jatenzo’s oral route of administration provides an important addition to current treatment options available for men with certain hypogonadal conditions who up until now have most commonly been treated with testosterone products that are applied to the skin or injected,” said Hylton V. Joffe, M.D, M.M.Sc., director of the Division of Bone, Reproductive and Urologic Products in the FDA’s Center for Drug Evaluation and Research. “But it’s important to emphasize that this drug should not, like other testosterone treatments, be used to treat older men with ‘age-related hypogonadism.’ The benefits of testosterone therapy, including Jatenzo, have not been established for this use, and Jatenzo’s effects on raising blood pressure can increase the risks of heart attack, stroke and cardiovascular death in this population.”

The efficacy of Jatenzo was demonstrated in a four-month clinical trial involving 166 men with hypogonadism. Study participants initially were given Jatenzo at a dose of 237 mg twice per day, and the dose was adjusted downward or upward to a maximum of 396 mg twice per day on the basis of testosterone levels. Eighty-seven percent of Jatenzo-treated men achieved an average testosterone level within the normal range, which was the primary study endpoint.

Jatenzo contains a boxed warning on its labeling stating that the drug can cause blood pressure to rise, increasing the risk of heart attack, stroke and cardiovascular death. Health care providers should consider a patient’s individual heart disease risks and ensure that blood pressure is adequately controlled before prescribing Jatenzo; they should also periodically monitor patient blood pressure during treatment. Jatenzo is currently one of two testosterone products that have this boxed warning. The FDA is requiring all testosterone product manufacturers to conduct blood pressure postmarketing trials to more clearly address whether these products increase blood pressure.

Common side effects, occurring in more than 2 percent of patients in the Jatenzo clinical trial, included headache, an increase in hematocrit (red blood cell count), a decrease in high-density lipoprotein cholesterol (“good” cholesterol), high blood pressure and nausea. An increase in prostate specific antigen (PSA) was also observed. Patients should have their hematocrit, cholesterol and PSA monitored regularly to check for changes. Those with benign prostate hyperplasia should be monitored for worsening of symptoms.

The FDA granted the approval of Jatenzo to Clarus Therapeutics.

//////////FDA 2019, Jatenzo, Clarus Therapeutics, (testosterone undecanoate,

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634585.htm?utm_campaign=032719_PR_FDA%20approves%20new%20oral%20testosterone%20capsule&utm_medium=email&utm_source=Eloqua

%d bloggers like this: