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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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, 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...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves treatment Inrebic (fedratinib) for patients with rare bone marrow disorder

FDA approves treatment Inrebic (fedratinib) for patients with rare bone marrow disorder

Today, the U.S. Food and Drug Administration approved Inrebic (fedratinib) capsules to treat adult patients with certain types of myelofibrosis.

“Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder. Our approval today provides another option for patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to encouraging the development of treatments for patients with rare diseases and providing alternative options, as not all patients respond in the same way.”

Myelofibrosis is a chronic disorder where scar tissue forms in the bone marrow and the production of the blood cells moves from the bone marrow to the spleen and liver, causing organ enlargement. It can cause extreme fatigue, shortness of breath, pain below the ribs, fever, night sweats, itching and bone pain. When myelofibrosis occurs on its own, it is called primary myelofibrosis. Secondary myelofibrosis occurs when there is excessive red blood cell production (polycythemia vera) or excessive platelet production (essential thrombocythemia) that evolves into myelofibrosis.

Jakafi (ruxolitinib) was approved by the FDA in 2011. The approval of Inrebic for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis was based on the results of a clinical trial where 289 patients with myelofibrosis were randomized to receive two different doses (400 mg or 500 mg daily by mouth) of fedratinib or placebo. The clinical trial showed that 35 of 96 patients treated with the fedratinib 400 mg daily dose (the dose recommended in the approved label) experienced a significant therapeutic effect (measured by greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 (week 24) as measured by an MRI or CT scan with a follow-up scan four weeks later). As a result of treatment with Inrebic, 36 patients experienced greater than or equal to a 50% reduction in myelofibrosis-related symptoms, such as night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under ribs on left side, and bone or muscle pain.

The prescribing information for Inrebic includes a Boxed Warning to advise health care professionals and patients about the risk of serious and fatal encephalopathy (brain damage or malfunction), including Wernicke’s, which is a neurologic emergency related to a deficiency in thiamine. Health care professionals are advised to assess thiamine levels in all patients prior to starting Inrebic, during treatment and as clinically indicated. If encephalopathy is suspected, Inrebic should be immediately discontinued.

Common side effects for patients taking Inrebic are diarrhea, nausea, vomiting, fatigue and muscle spasms. Health care professionals are cautioned that patients may experience severe anemia (low iron levels) and thrombocytopenia (low level of platelets in the blood). Patients should be monitored for gastrointestinal toxicity and for hepatic toxicity (liver damage). The dose should be reduced or stopped if a patient develops severe diarrhea, nausea or vomiting. Treatment with anti-diarrhea medications may be recommended. Patients may develop high levels of amylase and lipase in their blood and should be managed by dose reduction or stopping the mediation. Inrebic must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The FDA granted this application Priority Review designation. Inrebic 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 Inrebic to Impact Biomedicines, Inc., a wholly-owned subsidiary of Celgene Corporation.


///////Inrebic , fedratinib, FDA 2019, Priority Review , Orphan Drug, Biomedicines, Celgene , bone marrow disorder


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

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

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

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

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

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

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

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

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

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

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


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

FDA approves new antibiotic Xenleta (lefamulin) to treat community-acquired bacterial pneumonia

FDA approves new antibiotic  Xenleta (lefamulin) to treat community-acquired bacterial pneumonia

The U.S. Food and Drug Administration today approved Xenleta (lefamulin) to treat adults with community-acquired bacterial pneumonia.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease,” said Ed Cox, M.D., M.P.H., director of FDA’s Office of Antimicrobial Products. “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”

Community-acquired pneumonia occurs when someone develops pneumonia in the community (not in a hospital). Pneumonia is a type of lung infection that can range in severity from mild to severe illness and can affect people of all ages. According to data from the Centers from Disease Control and Prevention, each year in the United States, about one million people are hospitalized with community-acquired pneumonia and 50,000 people die from the disease.

The safety and efficacy of Xenleta, taken either orally or intravenously, was evaluated in two clinical trials with a total of 1,289 patients with CABP. In these trials, treatment with Xenleta was compared to another antibiotic, moxifloxacin with or without linezolid. The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid.

The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting. Xenleta has the potential to cause a change on an ECG reading (prolonged QT interval). Patients with prolonged QT interval, patients with certain irregular heart rhythms (arrhythmias), patients receiving treatment for certain irregular heart rhythms (antiarrhythmic agents), and patients receiving other drugs that prolong the QT interval should avoid Xenleta. In addition, Xenleta should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class, or any of the components of Xenleta. Based on findings of fetal harm in animal studies, pregnant women and women who could become pregnant should be advised of the potential risks of Xenleta to a fetus. Women who could become pregnant should be advised to use effective contraception during treatment with Xenleta and for two days after the final dose.

Xenleta received FDA’s Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, Xenleta was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Xenleta to Nabriva Therapeutics.

A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections. Among the FDA’s other efforts to address antimicrobial resistance, is the focus on facilitating the development of safe and effective new treatments to give patients more options to fight serious infections.


//////////Xenleta,  Nabriva Therapeutics, Qualified Infectious Disease Product, QIDP, fda 2019, Generating Antibiotic Incentives Now, GAIN, lefamulin, community-acquired bacterial pneumonia, antibacterial, Priority Review

AK 3280



AK 3280; GDC3280; RG 6069

C19 H15 F3 N4 O2, 388.34
CAS 1799412-33-1
4H-Benzimidazol-4-one, 1,5-dihydro-1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-5-[4-(trifluoromethoxy)phenyl]-

Ci8Hi4N502F3, mass 389.3 g/mol),


Ark Biosciences , under license from Roche , is developing AK-3280, an antifibrotic agent, for the potential oral treatment of IPF. In July 2018, Ark intended to further clinical development of the drug, for IPF. In June 2019, a phase I trial was planned in Sweden.

  • Originator Genentech
  • Mechanism of Action Undefined mechanism
  • Phase I Interstitial lung diseases
  • 19 Jun 2019Ark Biosciences plans a phase I trial for Idiopathic pulmonary fibrosis (In volunteers) in Sweden (PO, Tablet), in August 2019 , (NCT03990688)
  • 28 Sep 2018GDC 3280 is still in phase I trials for Interstitial lung diseases (Genentech pipeline, September 2018)
  • 28 Jun 2018No recent reports of development identified for phase-I development in Fibrosis(In volunteers) in United Kingdom (PO)


GDC 3280 (also known as RG 6069), an orally administered drug, is being developed by Genentech, for the treatment of interstitial lung diseases. Early stage clinical development is underway in the UK.

Company Agreements

In September 2018, Genentech licensed exclusive worldwide development and commercialisation rights of GDC 3280 to Ark Biosciences, for the treatment of idiopathic pulmonary fibrosis

Key Development Milestones

As at September 2018, GDC 3280 is still in phase I development for interstitial lung disease (Genentech pipeline, September 2018).

In December 2015, Genentech completed a phase I trial that evaluated the safety, pharmacokinetics and tolerability of GDC 3280 in healthy volunteers, compared with placebo (GB29751; EudraCT2015-000560-33; NCT02471859). The randomised, double-blind, single and multiple oral dose trial was initiated in June 2015 and enrolled eight volunteers in the UK .



Novel crystalline salt forms of 1-methyl-7-(1-methyl-lH-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (compound I; presumed to be AK-3280 ), processes for their preparation and compositions comprising them are claimed.

Compound I is an orally available small molecule having the structure:

[0004] Compound I has therapeutic value in several different indications that display fibrotic pathophysiology, including idiopathic pulmonary fibrosis (IPF).

[0005] Idiopathic pulmonary fibrosis is a disease of unknown etiology that occurs mainly in middle-aged and elderly patients, which is characterized by progressive fibrosis of the lung, leading to pulmonary insufficiency and death. Because fibrosis has long been considered to be a clinically irreversible process, treatments have traditionally been focused on managing the symptoms and complications, with little hope of significantly slowing progression of the condition. For many years, mainstay treatments have been typically anti inflammatory, immunosuppressive, and anti-oxidant agents. The effectiveness of these therapies in the treatment of IPF and other fibrotic conditions appears to be minimal and variable, and their side effects are often poorly tolerated by patients.

[0006] New treatment options have only recently become available. Both pirfenidone and nintedanib have been approved for use in the treatment of IPF. Current research efforts to develop new anti-fibrotic agents are targeting multiple mechanisms proposed to be linked to the underlying molecular pathogenic processes. This changing landscape has raised hopes and expectations for what might be achievable with new single agents or combination therapies targeting additional pathways.

Preparation of Compound I and its salts

[0045] A synthesis of Compound I and its tosylate salt is shown in the scheme below:

[0046] l-methyl-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (5) was synthesized in 4 steps, including a copper-catalyzed coupling reaction e.g., a Goldberg-Ullmann coupling reaction. In another aspect of the invention, intermediate (5) is synthesized using any transition metal-catalyzed coupling reaction. The skilled chemist would know that intermediate (5) could be synthesized from intermediate (4) and compounds


of the general formula: OCF3 , wherein the leaving group“LG” includes but is not limited to halogen, tosylate, mesylate, triflate, etc.

[0047] Compound I was synthesized in 6 steps, using a transition metal cross-coupling reaction, e.g., a Suzuki reaction. In another aspect of the invention, Compound I is synthesized using any cross -coupling reaction. Compound I is synthesized from intermediate 6 containing any leaving group. For example, the skilled chemist would use compounds of

the general formula: 
, wherein the leaving group“LG” includes but is not limited to halogen, tosylate, mesylate, triflate, etc.

An alternative synthesis of Compound I and its salts is shown in the scheme below:

Example 13 – Synthesis of Compound I Tosylate Salt

[00183] A process for the formation of mono- and di-tosylate salts of Compound I was developed and a batch was performed to successfully produce the mono-tosylate salt.

Step 1 : Synthesis of2-chloro-N-methyl-3-nitropyridin-4-amine

[00184] A reactor was charged with 2,4-dichloro-3-nitropyridine and 3.0 volumes of DMF. The solution was stirred at 20-25 °C until a clear solution was obtained. The solution was then cooled to 0-5 °C, and 2.1 equivalents of 40% methylamine in water were slowly added over at least 2 hours at 0-5 °C. The reaction mixture was stirred for at least 2 hours at 0-5 °C until conversion to the product was 95% (as measured by HPLC). The reaction mixture was diluted by slowly adding 10 volumes of water over at least 30 minutes at 0-5 °C. The obtained suspension was stirred for at least 60 minutes at 0-5 °C. The precipitate was collected by filtration, and the filter cake was rinsed via the reactor with 10 volumes of water at 0-5 °C. The damp filter cake was then dried in a flow of dry nitrogen to yield 2-chloro-A-methyl-3-nitropyridin-4-amine in 78% yield.

Step 2: Synthesis of 2-chloro-N4 -methylpyridine-3, 4-diamine

[00185] A reactor was charged with catalyst [2% Pt on charcoal, 59 %wt. water] (0.0004 equivalents Pt), damp 2-chloro-/V-methyl-3-nitropyridin-4-amine from step 1 and 9.4 volumes of THF. The solution was stirred, and then the suspension was transferred from the glass-reactor to an autoclave. The line was rinsed with 1.2 volumes of THF into the autoclave, and the autoclave was purged with nitrogen for 15 minutes at 50 rpm, followed by hydrogen for 15 minutes at 150 rpm. The autoclave was closed, and the hydrogen pressure was adjusted to 2 bar at 20-30 °C. The reaction mixture was stirred for 4-8 hours at 2 bar and 20-30 °C.

[00186] Next, the autoclave was released to atmospheric pressure and purged with nitrogen for at least 15 minutes. Conversion to the product was verified by HPLC, and then the catalyst was removed by filtration. The filtered catalyst was rinsed with 1.3 volumes of THF and the filtrates were combined. The combined filtrates were charged to a second reactor via a particle filter, and the line was rinsed with 0.5 volumes of THF. The solution was concentrated to a final volume of 2.5 volumes by distillation under reduced pressure at 40-45 °C.

[00187] The solution was then diluted with 10 volumes of THF in portions while concentrating the solution to a final volume of 2.5 volumes by distillation under reduced pressure at 45-50 °C. The reactor was purged with nitrogen to atmospheric pressure, and 5.0 volumes of heptane were added to the residue at 40-50 °C. The reaction mixture was cooled over 2 hours to 20-25 °C, and stirring was continued for 1 hour. The reaction mixture was then further cooled to 0-5 °C over 1 hour, and stirring was continued for 1 hour. The precipitated product was collected by filtration, rinsed via the reactor with 5.0 volumes of heptane, and the damp filter cake was dried in a vacuum drying oven at max. 40 °C until loss on drying was < 2 % weight, giving 2-chloro-/V4-methylpyridine-3, 4-diamine in 85% yield.

Step 3 : Synthesis of -inelhyl- 1 ,5-dihvdro-4H-iinidazoi4,5-c h yridin-4-one

[00188] A reactor was charged with 2-chloro-/V4-methylpyridine-3, 4-diamine and 4 volumes of formic acid. The reaction mixture was heated to smooth reflux within one hour, and reflux was maintained for 6 hours. The reaction mixture was then cooled to

approximately 60 °C, and conversion to the product was verified by HPLC.

[00189] The reaction mixture was then concentrated by distillation under reduced pressure at 60-80 °C to a final volume of 2 volumes. The temperature of the solution was adjusted to 60 °C, maintaining the temperature above 50 °C to avoid precipitation.

[00190] Next, a second reactor was charged with 10 volumes of acetone, and heated to gentle reflux. The product solution from the first reactor was slowly transferred to the acetone in the second reactor over 20 minutes, and the line was rinsed with approximately 0.05 volumes of formic acid. Reflux of the obtained suspension was maintained for 15 minutes. The slurry was cooled to 0 °C within 1 hour, and stirring was continued for 1 hour at that temperature. The precipitate was collected by filtration, and the filter cake was rinsed via the reactor with 3.7 volumes of cold acetone at 0-10 °C. The filter cake was dried in a flow of dry nitrogen or in a vacuum drying oven at 50 °C until loss on drying was < 2% of weight, giving 1 -methyl- 1 ,5-dihydiO-4/7-imidazo[4,5-c]pyndin-4-onc in 95% yield.

Step 4: Synthesis of l-methyl-5-(4-(trifluoromethoxy)phenyl)-J5-dihvdro-4H-imidaz.o[4,5-c]pyridin-4-one

[00191] A first reactor (Reactor A) was charged with 1 -methyl- 1 ,5-dihydro-4/7-imidazo[4,5-c]pyridin-4-one (1.0 mol equivalent), Cu(0Ac)2 H20 (0.1 mol equivalents), and K2C03 (1.1 mol equivalents). The reactor was closed and the atmosphere replaced with nitrogen.

[00192] Next, l-bromo-4-(trifluoromethoxy)benzene (1.5 mol equivalents) and N-methylpyrrolidinone (5.4 volume equivalents) were added, whereupon a suspension was formed. The suspension was stirred until the temperature had fallen again to approximately 20-25 °C and gas evolution had slowed. The reaction mixture was heated to approximately 130-150 °C at which time a blue/green color was observed, changing to dark brown after some time. The reaction was stirred at 130-150 °C for at least 40 hours. Stirring times of 40 hours up to 72 hours were required to reach an acceptable level of conversion. In general, higher reaction temperatures supported faster conversion.

[00193] Next, the reaction mixture was cooled to approximately 20-30 °C, and 25% aqueous NH3 (0.7 volume equivalents) was added, followed by water (3.5 volume equivalents). The resulting suspension was transferred into a second reactor (Reactor B). Additional water was added (18.1 volume equivalents) to the reaction mixture via Reactor A, followed by n-heptane (3.2 volume equivalents). The resulting suspension was cooled to approximately 0-5 °C, and stirred for approximately 2 hours.

[00194] The suspension was filtered, and the filter cake was washed with water (9.7 volume equivalents). The filter cake was then dissolved in dichloromethane (14.1 volume equivalents) and transferred back into reactor B. To this solution was added water (5.7 volume equivalents) via the filter, followed by 25% aq. NH3(1.6 volume equivalents). The mixture was stirred for approximately 1 hour at approximately 15-25 °C.

[00195] Next, the layers were separated, and dichloromethane was added (3.6 volume equivalents) to the aqueous layer. The biphasic mixture was stirred at approximately 15-25 °C for approximately 20-30 minutes. The layers were separated over a period of at least 1 hour, and to the combined organic layers was added a solution of NH4Cl (2.5 mol equivalents) in water (7.0 volume equivalents). The biphasic mixture was stirred at approximately 15-25 °C for about 20-30 minutes, then the layers were separated over the course of 1 hour.

[00196] The lower organic layer was filtered through a particle filter and diluted with toluene (7.1 volume equivalents) via the filter. The organic layer was concentrated under ambient pressure at approximately 80 °C, until no further liquid was seen to evaporate and a precipitate began to form. Toluene was added (16.6 volume equivalents), then concentrated in vacuo, followed by addition of more toluene (7.1 volume equivalents) and again concentrated in vacuo. The suspension was cooled to approximately 0-5 °C, stirred for approximately 2 hours, and filtered. The filter cake was washed with toluene (2.9 volume equivalents), and dried in vacuo at approximately 50 °C until the loss on drying was 0.5% of the weight to give l-methyl-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-47/-imidazo[4,5-c]pyridin-4-one as a beige-colored solid in 83.1% yield.

Step 5 : Synthesis of 7-bromo- 1 -methyl-5-(4-( trifluoromethoxy Iphenyl )- l,5- 4H- 


[00197] A first reactor (Reactor A) was charged with water (1.8 volume equivalents) and cooled to approximately 0-5 °C, to which was slowly added 96% sulfuric acid (14 mol. equivalents) at approximately 0-20 °C. The temperature of the solution was adjusted to approximately 0-5 °C, and l -mcthyl-5-(4-(tnfluoromcthoxy)phcnyl)-l ,5-dihydro-4/7-imidazo[4,5-c]pyridin-4-one (1.0 mol equivalent) was added in 3-4 portions at approximately 0-5 °C. The temperature of the mixture was adjusted to approximately 0-5 °C, and N-bromosuccinimide (1.0 mol equivalents) was slowly added in 3-4 portions, while maintaining the temperature at approximately 0-5 °C.

[00198] The reaction mixture was stirred for about 1 hour at approximately 0-5 °C, and then for an additional 4-16 hours at approximately 0-22 °C. Conversion to the product was confirmed by HPLC, then the reaction mixture was cooled to approximately 0-5 °C.

[00199] A second reactor (Reactor B) was charged with water (42.7 volume equivalents) and cooled to approximately 0-5 °C. The reaction mixture from Reactor A was transferred into the pre-cooled water in Reactor B at a temperature below 30 °C over 2 hours. The reaction was rinsed with water (1.6 volume equivalents), and 50% aqueous sodium hydroxide (25 mol. equivalents) was carefully added at approximately 0-30 °C over about 2 hours until the pH reached 2-5.

[00200] Next, MTBE (6.5 volume equivalents) was added at approximately 0-20 °C, and the mixture was stirred for about 5 minutes. Additional 50% aqueous sodium hydroxide (2 mol. equivalents) was added at approximately 0-30 °C until the pH of the solution was in the range of 10-14. The reaction was stirred for at least 1.5 hours at approximately 15-25 °C, and then the layers were allowed to separate over a period of at least 1 hour. The suspension was filtered, taking care to capture the product, which accumulated at the interface of the aqueous and organic layers. The filter cake was washed with MTBE (1.7 volume equivalents), water (3.0 volume equivalents), and then MTBE again (3.0 volume equivalents). The product was dried in vacuo at below 50 °C until the loss on drying was < 1% of the weight, giving 7-bromo-l-methyl-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-47/-imidazo[4,5-c]pyridin-4-one as a pale beige-colored solid in 97.6% yield.

Step 6: Synthesis of 1 -methyl-7 -( 1 -methyl-lH-pyraz.ol-4-yl )-5-(4-( trifluoromethoxy )pheml )-J5-dihvdro-4H-imidaz.o[4,5-c]pyridin-4-one (Compound /)

[00201] A reactor was charged with 7-bromo-l-methyl-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-4//-imidazo[4,5-c]pyridin-4-one (1.0 mol equivalents), ( 1 -methyl- 1 //-pyrazol-4-yl)boronic acid pinacol ester (l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l//-pyrazole, 1.6 mol equivalents), Pd[Ph3]4 (0.025 mol equivalents, and K2C03 (2.0 mol equivalents), to which were added acetonitrile (10.0 volume equivalents) and water (3.0 volume equivalents). The reaction mixture was stirred for approximately 10-20 minutes at about 20-25 °C to form a suspension.

[00202] The mixture was heated to slight reflux, whereupon a biphasic, yellow solution formed. The mixture was stirred at slight reflux for at least 10 hours. The reaction mixture was cooled to between 30-50 °C, then passed through a particle filter. The filter was washed with acetonitrile (2.6 volume equivalents), the filtrates were combined, and the solution was concentrated to a final volume of approximately 120 mL (4.8 volume equivalents) under reduced pressure at below 60 °C.

[00203] To the resulting suspension was added water (1.9 volume equivalents), methanol (26 mL, 1.0 volume equivalents), and dichloromethane (14.8 volume equivalents). The mixture was warmed to about 30-35 °C and stirred until two clear layers were observed. The layers were allowed to separate without stirring at about 30-35 °C, and additional dichloromethane (3.7 volume equivalents) was added to the aqueous layer. The mixture was warmed to approximately 30-35 °C and stirred for about 5 minutes, and then the layers were allowed to separate at approximately 30-35 °C.

[00204] To the combined organic layers was added water (1.9 volume equivalents), and the mixture was warmed to approximately 30-35 °C and stirred for about 5 minutes. The layers were separated at approximately 30-35 °C. Charcoal was added to the combined organic layers and stirred for 30-60 minutes at approximately 30-35 °C. The charcoal was removed by filtration, and the filter was washed with dichloromethane (39 mL, 1.6 volume equivalents).

[00205] The solution was concentrated to approximately 4.0 volume equivalents at ambient pressure and at below 50 °C, then diluted with methanol (5.0 volume equivalents). The solution was again concentrated to approximately 4.0 volume equivalents at ambient pressure and below 60 °C, diluted with methanol (5.0 volume equivalents), and concentrated to a final volume of approximately 3.0 volume equivalents under reduced pressure below 60 °C.

[00206] To the resulting suspension was added methanol (2.9 volume equivalents), and the suspension was warmed to approximately 45-55 °C and stirred for about 1 hour. The suspension was cooled to approximately 0-5 °C within approximately 1 hour, stirred for 1 hour at approximately 0-5 °C, and then filtered. The filter cake was washed with cold methanol (pre-cooled to approximately 0-10 °C, 2.9 volume equivalents), and the product was dried under a stream of nitrogen and in vacuo at below 60 °C until the loss on drying was < 1% by weight, giving Compound I (l-methyl-7-(l-methyl-l -pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-4//-imidazo[4,5-c]pyridin-4-one) as a white solid in 88.5% yield.

Step 7: Recrystallization of 1 -methyl-7 -(1 -methyl- lH-pyraz.ol-4-yl)-5-( 4-(trifluoromethoxy)phenyl)-J5-dihvdro-4H-imidaz.o[4,5-c]pyridin-4-one (Compound /)

[00207] A reactor was charged with crude l-methyl-7-(l -methyl- l//-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-47/-imidazo[4,5-c]pyridin-4-one from step 6, and to this was added glacial acetic acid (1.5 volume equivalents). The suspension was warmed to approximately 50-60 °C and stirred until a clear solution was obtained, approximately 10-20 minutes. The warm solution was passed through a particle filter into a second reactor.

[00208] To this solution was added ethanol (10.0 volume equivalents) at approximately 45-55 °C over 2 hours. The suspension was stirred for approximately 30 minutes at approximately 45-55 °C, then cooled to approximately 0-5 °C over about 4 hours. The suspension was then stirred for approximately 4-16 hours at about 0-5 °C.

[00209] Next, the suspension was filtered and the filter cake was washed with cold isopropanol (4.2 volume equivalents) at approximately 0-20 °C. The product was dried under a nitrogen stream and in vacuo at below 60 °C until the loss on drying was < 1% by weight, giving Compound I ( 1 – mcthyl-7-( 1 -methyl- 1 /7-pyrazol-4-yl)-5-(4-(tnfluoromcthoxy)phcnyl)-l,5-dihydro-47/-imidazo[4,5-c]pyridin-4-one) as a white solid in 93.0% yield.

Step 8 : Synthesis of 1 -methyl-7 -( 1 -methyl- 1 H-pyrazol-4-yl )-5-(4-( trifluoromethoxy )phenyl )- 1 ,5-dihvdro-4H-imidaz.oi 4,5-clpyridin-4-one, mono – mono -tosylate


[00210] A reactor was charged with Compound I ( 1 -mcthyl-7-( 1 -methyl- 1 /7-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-4//-imidazo[4,5-c]pyridin-4-one, 1.00 mol equivalent), para-toluenesulfonic acid monohydrate (1.05 mol equivalents), acetone (6.75 volume equivalents), and water (0.75 volume equivalents). The mixture was stirred at 15-25 °C until a clear solution formed, and then this solution was filtered through a particle filter into a second reactor.

[00211] The filter was washed with acetone (2.5 volume equivalents), and to the combined filtrates was added MTBE (7.5 volume equivalents) at 15-25 °C and Compound I mono-tosylate seeding crystals (0.001 mol equivalents).

[00212] The resulting suspension was stirred at 15-25 °C for approximately 30-60 minutes, and MTBE was added (22.5 volume equivalents) at 15-25 °C during a period of

approximately 30 minutes. Stirring was continued at 15-25 °C for approximately 30-60 minutes, and then the suspension was filtered. The filter was washed with MTBE (2.5 volume equivalents), and the material was dried in vacuo at below 55 °C to give Compound I mono-tosylate salt (l-methyl-7-(l-methyl-l//-pyrazol-4-yl)-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-47/-imidazo[4,5-c]pyridin-4-one, mono-tosylate salt) as a white, crystalline solid in 93% yield.


WO2018102323 ,

claiming use of a specific compound, orally administered, in combination with food (eg low, medium or high fat meal) for treating fibrotic, inflammatory or autoimmune disorders eg idiopathic pulmonary fibrosis IPF, assigned to Genentech Inc ,


  1. Roche licenses IPF candidate to Ark Biosciences. Internet-Doc 2019;.

    Available from: URL:

  2. Roche Q3 2018. Internet-Doc 2018;.

    Available from: URL:

  3. A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending, Single- and Multiple-Oral-Dose, Safety, Tolerability, and Pharmacokinetic Study of GDC-3280 in Healthy Subjects


// AK-3280,  AK 3280, AK3280,  GDC 3280, RG 6069, PHASE 1, Idiopathic pulmonary fibrosis

Novobiocin, ノボビオシン;


ChemSpider 2D Image | novobiocin | C31H36N2O11



  • Molecular FormulaC31H36N2O11
  • Average mass612.624 Da
(3R,4S,5R,6R)-5-hydroxy-6-(4-hydroxy-3-(4-hydroxy-3-(3-methylbut-2-enyl)benzamido)-8-methyl-2-oxo-2H-chromen-7-yloxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name) [ACD/IUPAC Name]
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
1476-53-5 [RN]
216-023-6 [EINECS]
224-321-2 [EINECS]
Albamycin[Trade name]
CAS number303-81-1
WeightAverage: 612.6243
Monoisotopic: 612.231910004
Chemical FormulaC31H36N2O11
For the treatment of infections due to staphylococci and other susceptible organisms
CAS Registry Number: 303-81-1
CAS Name: N-[7-[[3-O-(Aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-b-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]-4-hydroxy-3-(3-methyl-2-butenyl)benzamide
Additional Names: crystallinic acid; streptonivicin
Manufacturers’ Codes: PA-93; U-6591
Molecular Formula: C31H36N2O11
Molecular Weight: 612.62
Percent Composition: C 60.78%, H 5.92%, N 4.57%, O 28.73%
Literature References: Antibiotic substance produced by Streptomyces spheroides: Kaczka et al., J. Am. Chem. Soc. 77, 6404 (1955); Wolf, US 3000873 (1961 to Merck & Co.); Stammer, Miller; Miller; Wallick, US 3049475US 3049476US 3049534 (all 1962 to Merck & Co.). By Streptomyces niveus: Hoeksema et al., J. Am. Chem. Soc. 77, 6710 (1955); Antibiot. Chemother. 6, 143 (1956); French, US 3068221 (1962 to Upjohn). Structure: Shunk et al., J. Am. Chem. Soc. 78, 1770 (1956); Hoeksema et al., ibid.2019; Walton et al., ibid. 82, 1489 (1960). Conformation: Golding, Richards, Chem. Ind. (London) 1963, 1081. Revised configuration: O. Achmatowicz et al., Tetrahedron 32, 1051 (1976). Synthesis: Stammer, US 2925411 (1960); Walton, Spencer, US2966484 (1960 to Merck & Co.); Vaterlaus et al., Helv. Chim. Acta 47, 390 (1964). Conversion of isonovobiocin to novobiocin: Caron et al., US 2983723 (1961 to Upjohn). Antiviral activity: Chang, Weinstein, Antimicrob. Agents Chemother. 1970, 165. Efficacy in canine respiratory infections: B. W. Maxey, Vet. Med. Small Anim. Clin. 75, 89 (1980). Mechanism of action studies: Smith, Davis, J. Bacteriol. 93, 71 (1967); H. T. Wright et al., Science 213, 455 (1981); I. W. Althaus et al., J. Antibiot. 41, 373 (1988). Review: Brock in Antibiotics vol. 1, R. Gottlieb, P. Shaw, Eds. (Springer-Verlag, New York, 1967) pp 651-665; M. J. Ryan, ibid. vol. 5(pt. 1), F. E. Hahn, Ed. (1979) pp 214-234.
Properties: Pale yellow orthorhombic crystals from ethanol. Sensitive to light. d 1.3448. Dec at 152-156° (a rarer modification dec 174-178°). Acid reaction: pKa1 4.3; pKa2 9.1. [a]D24 -63.0° (c = 1 in ethanol). uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.). Sol in aq soln above pH 7.5. Practically insol in more acidic solns. Sol in acetone, ethyl acetate, amyl acetate, lower alcohols, pyridine. Additional soly data: Weiss et al., Antibiot. Chemother.7, 374 (1957).
pKa: pKa1 4.3; pKa2 9.1
Optical Rotation: [a]D24 -63.0° (c = 1 in ethanol)
Absorption maximum: uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.)
Density: d 1.3448
Derivative Type: Monosodium salt
CAS Registry Number: 1476-53-5
Trademarks: Albamycin (Pharmacia & Upjohn)
Molecular Formula: C31H35N2NaO11
Molecular Weight: 634.61
Percent Composition: C 58.67%, H 5.56%, N 4.41%, Na 3.62%, O 27.73%
Properties: Minute crystals, dec 220°. [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water). Freely sol in water. A 100 mg/ml soln has a pH of 7.5 and a half-life of ~30 days at 25° and several months at 4°. Soly data: Weiss et al., loc. cit. Properties: Birlova, Traktenberg, Antibiotiki 13, 997 (1968).
Optical Rotation: [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water)
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antimicrobial.
Novobiocin sodium Q9S9NQ5YIY 1476-53-5 WWPRGAYLRGSOSU-RNROJPEYSA-M

Reata Pharmaceuticals Inc

Abgentis is investigating a novobiocin analog, GYR-12 (discovery), as a re-engineered, previously-marketed-but-uncompetitive (undisclosed) antibacterial compound inhibiting ATPase activity of DNA supercoiling GyrB/ParE, for the potential broad-spectrum treatment of bacterial infections, including multi-drug resistant Gram-negative infections. In April 2017, development was underway [1924695].

Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides[1] a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.[2] Novobiocin was first reported in the mid-1950s (then called streptonivicin).[3][4]

It is active against Staphylococcus epidermidis and may be used to differentiate it from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture.

Novobiocin was licensed for clinical use under the tradename Albamycin (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials.[5][6] The oral form of the drug has since been withdrawn from the market due to lack of efficacy.[7] Novobiocin is an effective antistaphylococcal agent used in the treatment of MRSA.[8]

Mechanism of action

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.[2][9][10][11][12] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.

Novobiocin has been shown to weakly inhibit the C-terminus of the eukaryotic Hsp90 protein (high micromolar IC50). Modification of the novobiocin scaffold has led to more selective Hsp90 inhibitors.[13] Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC.[14][15]


Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.[9] X-ray crystallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.[16] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.[17]

Structure–activity relationship

In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.[17]


This aminocoumarin antibiotic consists of three major substituents. The 3-dimethylallyl-4-hydroxybenzoic acid moiety, known as ring A, is derived from prephenate and dimethylallyl pyrophosphate. The aminocoumarin moiety, known as ring B, is derived from L-tyrosine. The final component of novobiocin is the sugar derivative L-noviose, known as ring C, which is derived from glucose-1-phosphate. The biosynthetic gene cluster for novobiocin was identified by Heide and coworkers in 1999 (published 2000) from Streptomyces spheroidesNCIB 11891.[18] They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.

The biosynthesis of ring A (see Fig. 1) begins with prephenate which is a derived from the shikimic acid biosynthetic pathway. The enzyme NovF catalyzes the decarboxylation of prephenate while simultaneously reducing nicotinamide adenine dinucleotide phosphate (NADP+) to produce NADPH. Following this NovQ catalyzes the electrophilic substitution of the phenyl ring with dimethylallyl pyrophosphate (DMAPP) otherwise known as prenylation.[19] DMAPP can come from either the mevalonic acid pathway or the deoxyxylulose biosynthetic pathway. Next the 3-dimethylallyl-4-hydroxybenzoate molecule is subjected to two oxidative decarboxylations by NovR and molecular oxygen.[20] NovR is a non-heme iron oxygenase with a unique bifunctional catalysis. In the first stage both oxygens are incorporated from the molecular oxygen while in the second step only one is incorporated as determined by isotope labeling studies. This completes the formation of ring A.

Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)

The biosynthesis of ring B (see Fig. 2) begins with the natural amino acid L-tyrosine. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by ATPand NovH itself.[21] NovI then further modifies this PCP bound molecule by oxidizing the β-position using NADPH and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase.[22] This process uses NADP+ as a hydride acceptor in the oxidation of the β-alcohol. This ketone will prefer to exist in its enol tautomer in solution. Next a still unidentified protein catalyzes the selective oxidation of the benzene (as shown in Fig. 2). Upon oxidation this intermediate will spontaneously lactonize to form the aromatic ring B and lose NovH in the process.

Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B)

The biosynthesis of L-noviose (ring C) is shown in Fig. 3. This process starts from glucose-1-phosphate where NovV takes dTTP and replaces the phosphate group with a dTDP group. NovT then oxidizes the 4-hydroxy group using NAD+. NovT also accomplishes a dehydroxylation of the 6 position of the sugar. NovW then epimerizes the 3 position of the sugar.[23] The methylation of the 5 position is accomplished by NovU and S-adenosyl methionine (SAM). Finally NovS reduces the 4 position again to achieve epimerization of that position from the starting glucose-1-phosphate using NADH.

Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C)

Rings A, B, and C are coupled together and modified to give the finished novobiocin molecule. Rings A and B are coupled together by the enzyme NovL using ATP to diphosphorylate the carboxylate group of ring A so that the carbonyl can be attacked by the amine group on ring B. The resulting compound is methylated by NovO and SAM prior to glycosylation.[24] NovM adds ring C (L-noviose) to the hydroxyl group derived from tyrosine with the loss of dTDP. Another methylation is accomplished by NovP and SAM at the 4 position of the L-noviose sugar.[25] This methylation allows NovN to carbamylate the 3 position of the sugar as shown in Fig. 4 completing the biosynthesis of novobiocin.

Figure 4. Completed biosynthesis of novobiocin from ring systems AB, and C.







Novel co-crystal forms of novobiocin and its analogs and proline, processes for their preparation and compositions comprising them are claimed. Also claims are methods for inhibiting heat shock protein 90 and treating or preventing neurodegenerative disorders, such as diabetic peripheral neuropathy.


  1. ^ Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J (May 2002). “The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus”. International Journal of Systematic and Evolutionary Microbiology52 (Pt 3): 823–9. doi:10.1099/ijs.0.02008-0PMID 12054245.
  2. Jump up to:a b Alessandra da Silva Eustáquio (2004) Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production. DISSERTATION
  3. ^ Hoeksema H.; Johnson J. L.; Hinman J. W. (1955). “Structural studies on streptonivicin, a new antibiotic”. J Am Chem Soc77 (24): 6710–6711. doi:10.1021/ja01629a129.
  4. ^ Smith C. G.; Dietz A.; Sokolski W. T.; Savage G. M. (1956). “Streptonivicin, a new antibiotic. I. Discovery and biologic studies”. Antibiotics & Chemotherapy6: 135–142.
  5. ^ Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP (November 1995). “Antibiotics and prevention of microbial colonization of catheters”Antimicrobial Agents and Chemotherapy39 (11): 2397–400. doi:10.1128/aac.39.11.2397PMC 162954PMID 8585715.
  6. ^ Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S (January 1998). “A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2”. Cancer82 (2): 403–11. doi:10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0PMID 9445199.
  7. ^ “Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness”The Federal Register. 19 January 2011.
  8. ^ Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D (June 1993). “Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome”Antimicrobial Agents and Chemotherapy37 (6): 1334–42. doi:10.1128/aac.37.6.1334PMC 187962PMID 8328783.
  9. Jump up to:a b Maxwell A (August 1993). “The interaction between coumarin drugs and DNA gyrase”. Molecular Microbiology9 (4): 681–6. doi:10.1111/j.1365-2958.1993.tb01728.xPMID 8231802.
  10. ^ Maxwell A (February 1999). “DNA gyrase as a drug target”. Biochemical Society Transactions27 (2): 48–53. doi:10.1042/bst0270048PMID 10093705.
  11. ^ Lewis RJ, Tsai FT, Wigley DB (August 1996). “Molecular mechanisms of drug inhibition of DNA gyrase”. BioEssays18 (8): 661–71. doi:10.1002/bies.950180810PMID 8760340.
  12. ^ Maxwell A, Lawson DM (2003). “The ATP-binding site of type II topoisomerases as a target for antibacterial drugs”. Current Topics in Medicinal Chemistry3 (3): 283–303. doi:10.2174/1568026033452500PMID 12570764.
  13. ^ Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS (September 2005). “Hsp90 inhibitors identified from a library of novobiocin analogues”. Journal of the American Chemical Society127 (37): 12778–9. doi:10.1021/ja0535864PMID 16159253.
  14. ^ Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D (June 2018). “Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport”Journal of the American Chemical Society140 (22): 6749–6753. doi:10.1021/jacs.8b02283PMC 5990483PMID 29746111.
  15. ^ May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D (December 2017). “The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport”Journal of the American Chemical Society139 (48): 17221–17224. doi:10.1021/jacs.7b07736PMC 5735422PMID 29135241.
  16. ^ Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O’Brien R, Ladbury JE, Wigley DB (May 1997). “The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin”. Proteins28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>;2-bPMID 9144789.
  17. Jump up to:a b Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A (April 2006). “Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis”Antimicrobial Agents and Chemotherapy50 (4): 1136–42. doi:10.1128/AAC.50.4.1136-1142.2006PMC 1426943PMID 16569821.
  18. ^ Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L (May 2000). “Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891”Antimicrobial Agents and Chemotherapy44 (5): 1214–22. doi:10.1128/AAC.44.5.1214-1222.2000PMC 89847PMID 10770754.
  19. ^ Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L (March 2003). “CloQ, a prenyltransferase involved in clorobiocin biosynthesis”Proceedings of the National Academy of Sciences of the United States of America100 (5): 2316–21. Bibcode:2003PNAS..100.2316Pdoi:10.1073/pnas.0337708100PMC 151338PMID 12618544.
  20. ^ Pojer F, Kahlich R, Kammerer B, Li SM, Heide L (August 2003). “CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis”. The Journal of Biological Chemistry278 (33): 30661–8. doi:10.1074/jbc.M303190200PMID 12777382.
  21. ^ Chen H, Walsh CT (April 2001). “Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI”. Chemistry & Biology8 (4): 301–12. doi:10.1016/S1074-5521(01)00009-6PMID 11325587.
  22. ^ Pacholec M, Hillson NJ, Walsh CT (September 2005). “NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis”. Biochemistry44 (38): 12819–26. CiteSeerX 16171397.
  23. ^ Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK (April 2005). “Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides”. Archives of Biochemistry and Biophysics436 (1): 161–7. doi:10.1016/ 15752721.
  24. ^ Pacholec M, Tao J, Walsh CT (November 2005). “CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis”. Biochemistry44 (45): 14969–76. doi:10.1021/bi051599oPMID 16274243.
  25. ^ Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT (January 2004). “Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring”. Angewandte Chemie43 (1): 67–70. doi:10.1002/anie.200352626PMID 14694473.

External links

Space-filling model of the novobiocin molecule
Clinical data
AHFS/ International Drug Names
Routes of
ATCvet code
Pharmacokinetic data
Bioavailability negligible oral bioavailability
Metabolism excreted unchanged
Elimination half-life 6 hours
Excretion renal
CAS Number
PubChem CID
CompTox Dashboard(EPA)
ECHA InfoCard 100.005.589 Edit this at Wikidata
Chemical and physical data
Formula C31H36N2O11
Molar mass 612.624 g·mol−1
3D model (JSmol)

Novobiocin calcium.png

4309-70-0  CAS


///////// Novobiocin, ノボビオシン  , Antibacterial, Antimicrobial,  crystallinic acid, streptonivicin,

Manufacturers’ Codes: PA-93; U-6591


Novobiocin is a coumarin antibiotic obtained from Streptomyces niveus and other Streptomyces species. Novobiocin is useful primarily in infections involving staphylococci, and other gram-positive organisms. It acts by inhibiting the initiation of DNA replication in bacterial and mammanlian cells. Evidences indicated that Novobiocin blocks prokaryotic DNA gyrase and eukaryotic II topoisomerase, enzymes that relax super-coiled DNA and are crucial for DNA replication.1


UIPAC Name 4-Hydroxy-3-4-hydroxy-3-(3-methylbut-2-enyl)benzamido-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-l-lyxofuranoside
CAS Number 303-81-1
Molecular Mass 612.624 g / mol
Chemical Formular C31H36N2O11


The substituted coumarin (ring B, red) and the 4-OH benzoyl moiety (ring A, aqua) in novobiocin were derived from Image-Tyr based on earlier labeling studies. β-OH-Tyr is proposed to be a common intermediate in these two biosynthetic pathways.2

NovH is a Image-Tyr specific didomain NRPS that generates the Image-tyrosyl-S-NovH intermediate. NovH, isolated from E. coli is primed by a PPTase with CoA. The A domain activates Image-Tyr as Image-tyrosyl-AMP and then transfers the Image-tyrosyl group to the HS-pant-PCP domain of NovH through thioester formation.3

Image-tyrosyl-S-NovH is then function as a cytochrome P450 monooxygenase that hydroxylates the β-carbon of the tethered Image-tyrosyl group on NovH. While the substrate Image-tyrosyl-S-NovH provides two electrons for a single round of the hydroxylation reaction, the other two electrons needed to reduce the oxygen atom are provided by NADPH via two-electron transfer effected by electron transfer proteins ferrodoxin (Fd) and ferrodoxin reductase (Fd Red).3 The electron transfer route is from NADPH→FAD in Fd Red→Fe–S center in Fd→Heme in NovI→oxygen.

Both NovJ and NovK are similar to 3-keto-ACP reductase and they may form a heterodimer and operate in the reverse direction to oxidize 3-OH to 3-keto. NovO is similar to some quinone C-methyltransferases 3 but the timing of methylation is not clear. NovC resembles flavin-dependent monooxygenases (35 and 32% similarity to dimethylaniline and cyclohexanone monooxygenases, respectively) 3 and is proposed to hydroxylate the ortho position of the phenyl ring. The nucleophilic attack of the ortho hydroxyl group on the thioester carbonyl center would release the coumarin ring and regenerate NovH. Ring B is then synthesized.


Mechanism of action

E.Coli DNA gyrase utilizes ATP to catalyze the negative supercoiling, or under-twisting, of duplex DNA. The energy coupling components of the supercoiling reaction includes 1) the DNA-dependent hydrolysis that converts ATP to ADP and Pi, and 2) the gyrase cleavage reaction that targets the specified DNA site. The two activities are induced by treating the stable gyrase-DNA complex trapped by the inihibitor oxolinic acid with sodium dodecyl sulfate (SDS or Sulphate). 4 Novobiocin competes with ATP in the ATPase and supercoiling assays, hence Novobiocin prevents the ATP from shifting the primary cleavage site on ColE1 DNA by places the site of action of the antibiotics at a reaction step prior to ATP hydrolysis and blocks the binding of ATP. 4 Such a simple mechanism of action represents for all effects of the drugs on DNA gyrase.

Clinical Use

Due to factors as low solubility, poor pharmacokinetics, and limited activity agasinst Gram-negative bacteria, the clinical usage of Novobiocin is not achieved. 5 Therefore, it is of interest to study the novobiocin biosynthetic pathway in order to generate analogs with enhanced solubility and pharmacokinetic properties while maintaining the gyrase inhibitory properties.


1 J.C. D’Halluin, M. Milleville, and P. Boulanger. “Effect of Novobiocin on adenovirus DNA synthesis and encapsidation”. Nucleic Acids Research 1980; 8: 1625-1641

2 M. Steffensky, S.M. Li and L. Heide, “Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides ” NCIB 11891. J. Biol. Chem. 275 (2000), pp. 21754–21760.

3 Huawei Chen and Christopher T. Walsh, “Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI” Chemistry and Biology; 2001; 8: 301-312

4 K. Scheirer and N. P. Higgins. “The DAN Cleavage Reaction of DNA Gyrase ” The Journal of Biological Chemistry; 1997; 272 (43): 27202-27209

5 N Pi, C. L. F. Meyers, M. Pacholec, C. T. Walsh, and J. A. Leary. “Mass spectrometric characterization of a three-enzyme tandem reacton for assembly and modification of the novobiocin skeleton” PNAS 2004;101;10036-10041

Imipenem, イミペネム水和物


ChemSpider 2D Image | Imipenem hydrate | C12H19N3O5S




Cas 74431-23-5

  • Molecular FormulaC12H19N3O5S
  • Average mass317.361 Da

(5R,6S)-3-((2-(Formimidoylamino)ethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid monohydrate

1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-, (5R,6S)-, monohydrate
264-734-5 [EINECS]
74431-23-5 [RN]
N-Formimidoylthienamycin Monohydrate
Primaxin monohydrate
Tienam monohydrate
(5R,6S)-3-((2-Formimidamidoethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate
(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and hydrate
8174596 [Beilstein]
imipemide monohydrate

Antibacterial, Cell wall biosynthesis inhibitor

CAS Registry Number: 74431-23-5; 64221-86-9 (anhydrous)
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate
Additional Names: N-formimidoylthienamycin monohydrate; imipemide
Manufacturers’ Codes: MK-787
Molecular Formula: C12H17N3O4S.H2O
Molecular Weight: 317.36
Percent Composition: C 45.41%, H 6.03%, N 13.24%, O 25.21%, S 10.10%
Literature References: Extremely broad-spectrum semi-synthetic antibiotic; first stable derivative of thienamycin, q.v. Prepn: W. J. Leanza et al., J. Med. Chem. 22, 1435 (1979); T. W. Miller, EP 6639 (1980 to Merck & Co.), C.A. 93, 155845y (1980); B. G. Christensen et al., US 4194047 (1980 to Merck & Co.). Totally synthetic prepn without formation of thienamycin: I. Shinkai et al.,Tetrahedron Lett. 23, 4903 (1982). HPLC determn in serum: C. M. Myers, J. L. Blumer, Antimicrob. Agents Chemother. 26, 78 (1984). Series of articles on in vitro activity, pharmacokinetics, clinical efficacy of combination with cilastatin sodium, q.v., a renal dehydropeptidase I inhibitor: J. Antimicrob. Chemother. 12, Suppl. D, 1-155 (1983); Rev. Infect. Dis. 7, Suppl. 3, S389-S536 (1985); Am. J. Med. 78, Suppl. 6A, 1-167 (1985); Infection 14, Suppl. 2, S111-S180 (1986). Comprehensive description: E. R. Oberholtzer, Anal. Profiles Drug Subs. 17, 73-114 (1988).
Properties: Crystals from water-ethanol. [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7). pKa1 ~3.2, pKa2 ~9.9. uv max (water): 299 nm (e 9670, 98% NH2OH ext). Soly (mg/ml): water 10, methanol 5, ethanol 0.2, acetone <0.1, dimethylformamide <0.1, dimethylsulfoxide 0.3.
pKa: pKa1 ~3.2, pKa2 ~9.9
Optical Rotation: [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7)
Absorption maximum: uv max (water): 299 nm (e 9670, 98% NH2OH ext)
Derivative Type: Combination with cilastatin sodium
CAS Registry Number: 85960-17-4
Trademarks: Imipem (Neopharmed); Primaxin (Merck & Co.); Tenacid (Sigma-Tau); Tienam (Merck & Co.); Zienam (Merck & Co.)
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics); ?Lactams; Carbapenems.

Imipenem (Primaxin among others) is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s.[1] Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria,[2] thus play a key role in the treatment of infections not readily treated with other antibiotics.[3]

Imipenem was patented in 1975 and approved for medical use in 1985.[4] It was discovered via a lengthy trial-and-error search for a more stable version of the natural product thienamycin, which is produced by the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but is unstable in aqueous solution, so impractical to administer to patients.[5] Imipenem has a broad spectrum of activity against aerobic and anaerobicGram-positive and Gram-negative bacteria.[6] It is particularly important for its activity against Pseudomonas aeruginosa and the Enterococcus species. It is not active against MRSA, however.

Medical uses

Spectrum of bacterial susceptibility and resistance

Acinetobacter anitratusAcinetobacter calcoaceticusActinomyces odontolyticusAeromonas hydrophilaBacteroides distasonisBacteroides uniformis, and Clostridium perfringens are generally susceptible to imipenem, while Acinetobacter baumannii, some Acinetobacter spp., Bacteroides fragilis, and Enterococcus faecalis have developed resistance to imipenem to varying degrees. Not many species are resistant to imipenem except Pseudomonas aeruginosa (Oman) and Stenotrophomonas maltophilia.[7]

Coadministration with cilastatin

Imipenem is rapidly degraded by the renal enzyme dehydropeptidase 1 when administered alone, and is almost always coadministered with cilastatin to prevent this inactivation[8]

Adverse effects

Common adverse drug reactions are nausea and vomiting. People who are allergic to penicillin and other β-lactam antibiotics should take caution if taking imipenem, as cross-reactivity rates are high. At high doses, imipenem is seizurogenic.[9]

Mechanism of action

Imipenem acts as an antimicrobial through inhibiting cell wall synthesis of various Gram-positive and Gram-negative bacteria. It remains very stable in the presence of β-lactamase (both penicillinase and cephalosporinase) produced by some bacteria, and is a strong inhibitor of β-lactamases from some Gram-negative bacteria that are resistant to most β-lactam antibiotics.


By reaction of thienamycin (I) with methyl formimidate (II) by means of NaOH in water.

DE 2652679; FR 2332012; GB 1570990; NL 7612939


WO 0294828

The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.


Tetrahedron Lett 1982,23(47),4903

The condensation of 7-oxo-6-(1-hydroxyethyl)-3-(diphenoxyphosphate)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrophenyl ester (I) with the bis(trimethylsilyl) derivative of 2-(iminomethylamino)ethanethiol (II) in the presence of base gives p-nitrophenyl ester of MK-0787, protected with a trimethylsilyl group (III), which is finally deprotected by hydrogenolysis.


Image result for imipenem synthesis

Synthesis Path


  1. ^ U.S. Patent 4,194,047
  2. ^ Clissold, SP; Todd, PA; Campoli-Richards, DM (Mar 1987). “Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy”. Drugs33 (3): 183–241. doi:10.2165/00003495-198733030-00001PMID 3552595.
  3. ^ Vardakas, KZ; Tansarli, GS; Rafailidis, PI; Falagas, ME (Dec 2012). “Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis”. The Journal of Antimicrobial Chemotherapy67 (12): 2793–803. doi:10.1093/jac/dks301PMID 22915465.
  4. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 497. ISBN 9783527607495.
  5. ^ Kahan, FM; Kropp, H; Sundelof, JG; Birnbaum, J (Dec 1983). “Thienamycin: development of imipenen-cilastatin”. The Journal of Antimicrobial Chemotherapy. 12 Suppl D: 1–35. doi:10.1093/jac/12.suppl_d.1PMID 6365872.
  6. ^ Kesado, Tadataka; Hashizume, Terutaka; Asahi, Yoshinari (1980). “Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics”Antimicrobial Agents and Chemotherapy17 (6): 912–7. doi:10.1128/aac.17.6.912PMC 283902PMID 6931548.
  7. ^ “Imipenem spectrum of bacterial susceptibility and Resistance” (PDF). Retrieved 4 May 2012.
  8. ^ “IMIPENEM/CILASTATIN” Retrieved 2019-03-08.
  9. ^ Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A. (2014-08-01). “The risk of seizures among the carbapenems: a meta-analysis”Journal of Antimicrobial Chemotherapy69 (8): 2043–2055. doi:10.1093/jac/dku111ISSN 0305-7453.

Further reading

External links

Imipenem ball-and-stick.png
Clinical data
Trade names Primaxin
AHFS/ International Drug Names
MedlinePlus a686013
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 20%
Metabolism Renal
Elimination half-life 38 minutes (children), 60 minutes (adults)
Excretion Urine (70%)
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.058.831 Edit this at Wikidata
Chemical and physical data
Formula C12H17N3O4S
Molar mass 299.347 g/mol g·mol−1
3D model (JSmol)
    • Synonyms:Imipemide
    • ATC:J01DH51
  • Use:carbapenem antibiotic
  • Chemical name:[5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Formula:C12H17N3O4S
  • MW:299.35 g/mol
  • CAS-RN:64221-86-9
  • InChI:InChI=1S/C12H17N3O4S/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)/t6-,7-,9-/m1/s1
  • EINECS:264-734-5
  • LD50:1660 mg/kg (M, i.v.); >5 g/kg (M, p.o.);
    1972 mg/kg (R, i.v.); >5 g/kg (R, p.o.)

Derivatives, monohydrate

  • Formula:C12H17N3O4S • H2O
  • MW:317.37 g/mol
  • CAS-RN:74431-23-5
    • Leanza, W.J. et al.: J. Med. Chem. (JMCMAR) 22, 1435 (1979).
    • a Salzmann, T.L. et al.: J. Am. Chem. Soc. (JACSAT) 102, 6161-6163 (1980).
    •  Reider, P.J.; Grabowski, E.J.J.: Tetrahedron Lett. (TELEAY) 23, 2293-2296 (1982).
    •  Grabowski, E.J.J.: Chirality (CHRLEP) 17, 249-259 (2005).
    • US 4 194 047 (Merck & Co.; 18.3.1980; prior. 21.11.1975).
    • DOS 2 652 679 (Merck & Co.; appl. 19.11.1976; USA-prior. 21.11.1975).
    • b US 5 998 612 (Merck & Co.; 7.12.1999; appl. 12.6.1992; prior. 23.10.1981).
    • c US 4 981 992 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
    •  US 5 204 460 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
    •  US 5 204 462 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
    •  US 5 712 388 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
    •  US 5 081 239 (Takasago; 14.1.1992; appl. 29.11.1989; J-prior. 29.11.1988).
  • Acetoxylation of 2-azetidinones in 4-position:
    • Noyori, R. et al.: J. Am. Chem. Soc. (JACSAT) 111, 9134-9135 (1989).
    • Noyori, R. et al.: Angew. Chem. (ANCEAD) 114, 2108-2123 (2002).
    • US 5 288 862 (Takasago; 22.2.1994; appl. 16.4.1992; J-prior. 18.4.1991).
    • US 5 606 052 (Takasago; 25.2.1997; appl. 16.4.1992; J-prior. 18.4.1991).
  • Noyori-catalyst:
    • US 4 739 084 (Takasago; 19.4.1988; appl. 15.4.1987; J-prior. 13.5.1986).
  • d process of Nippon Soda (Nisso):
    • US 5 026 844 (Suntory & Nippon Soda; 25.6.1991; appl. 13.10.1989; J-prior. 19.10.1988).
    • US 5 792 861 (Tanabe Seiyaku & Nippon Soda; 11.8.1998; appl. 29.6.1994, 4.11.1996; J-prior. 30.6.1993).
    • US 5 808 055 (Suntory & Nippon Soda; 15.9.1998; appl. 30.3.1993, 5.7.1995; J-prior. 30.3.1993).
    • e US 4 791 198 (Kanegafuchi; 13.12.1988; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1986).
    •  US 4 861 877 (Kanegafuchi; 29.8.1989; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1985, 14.1.1986).
    •  US 5 061 817 (Kanegafuchi; 29.10.1991; appl. 1.7.1985, 6.1.1987, 31.5.1988; J-prior. 5.7.1984, 14.1.1986).
    •  US 4 914 200 (Kanegafuchi; 3.4.1990; appl. 28.4.1987, 14.2.1989; J-prior. 30.4.1986, 13.11.1986, 9.2.1987).
  • Enzymatic reduction of alkyl-2-(N-benzoylamino)methyl-3-oxobutyrates with bakers yeast:
    • US 5 463 047 (Ciba-Geigy; 31.10.1995; appl. 15.9.1994; CH-prior. 4.5.1987).
  • Further synthesis processes of Merck & Co. for thienamycin:
    • Johnston, D.B.R. et al.: J. Am. Chem. Soc. (JACSAT) 100, 313-315 (1978).
    • Mellilo, D.G. et al.: Tetrahedron Lett. (TELEAY) 21, 2783 (1980).
    • Melillo, D.G. et al.: J. Org. Chem. (JOCEAH) 51, 1498-1504 (1986).
    • Karady, S. et al.: J. Am. Chem. Soc. (JACSAT) 103, 6765-6767 (1981).
    • US 4 269 772 (Merck & Co.; 26.5.1981; appl. 14.1.1980).
    • US 4 282 148 (Merck & Co.; 4.8.1981; appl. 14.1.1980).
    • US 4 287 123 (Merck & Co.; 1.9.1981; appl. 14.1.1980).
    • US 4 290 947 (Merck & Co.; 22.9.1981; appl. 29.5.1980).
    • US 4 360 684 (Merck & Co.; 23.11.1982; appl. 8.4.1981).
    • US 4 206 219 (Merck & Co.; 3.6.1980; appl. 24.10.1978).
    • US 4 348 320 (Merck & Co.; 7.9.1982; appl. 20.8.1980; USA-prior. 19.11.1976).
    • US 4 460 507 (Merck & Co.; 17.7.1984; appl. 29.4.1982; USA-prior. 10.10.1980).
    • US 5 055 573 (Merck & Co.; 8.10.1991, appl. 24.8.1990; USA-prior. 19.11.1976).
    • US 5 037 974 (Merck & Co.; 6.8.1991; appl. 14.8.1990; prior. 23.5.1988, 10.4.1990).
  • Review of thienamycin syntheses:
    • Nicolaou, K.C.; Sorensen, E.J.: Classics in Total Synthesis, VCH 1996, Weinheim & New York, chapter 16, p. 249-263.
    • Berks, A.H.: Tetrahedron (TETRAB) 52, 331-375 (1996).
  • Alternative 2-azetidinone ring closure with chlorosulfonyl isocyanate:
    • US 4 350 631 (Merck & Co.; 21.9.1982; appl. 18.3.1981; prior. 18.12.1980).
  • Thienamycin (by fermentation of S. cattleya):
    • US 3 950 357 (Merck & Co.; 13.4.1976; appl. 25.11.1974).
    • DOS 2 552 638 (Merck & Co.; appl. 24.11.1975; USA-prior. 25.11.1974).
  • Combination with cilastatin:
    • EP 48 301 (Merck & Co.; appl. 24.9.1980).

/////////////Imipenem, イミペネム水和物  , MK-787,

SK1-I , BML 258



SK1-I , BML 258

Sphingosine kinase 1 (SphK1) inhibitor; antiproliferative

  • (1E)-1,2,4-Trideoxy-4-(methylamino)-1-(4-pentylphenyl)-D-erythro-pent-1-enitol
  • (E,2R,3S)-2-(Methylamino)-5-(4-pentylphenyl)pent-4-ene-1,3-diol
  • D-erythro-Pent-1-enitol, 1,2,4-trideoxy-4-(methylamino)-1-(4-pentylphenyl)-, (1E)-
Name: (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol . HCl
Formula: C17H27NO. HCl
MW: 313.9
CAS: 1072443-89-0


  • Originator Enzo Biochem; Virginia Commonwealth University
  • Developer Enzo Biochem
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Sphingosine kinase inhibitors
  • Preclinical Autoimmune hepatitis; Haematological malignancies; Liver cancer; Solid tumours
  • 07 May 2019 Preclinical trials in Liver cancer in USA (unspecified route)
  • 03 Dec 2018 SK1 I is available for licensing as of 03 Dec 2018.
  • 03 Dec 2018 Enzo Biochem has patent pending for SK1 I worldwide

SK1 I, a small molecule that specifically inhibits sphingosine kinase 1, is being developed by Enzo Biochem for the treatment of cancer and autoimmune diseases. Preclinical development is underway for the treatment of solid tumours, liver cancer, haematological malignancies and autoimmune hepatitis in the US.

As at December 2018, Enzo Biochem seeks partners for the development of SK1

SK1-I is a sphingosine analog and a sphingosine competitive inhibitor specific for sphingosine kinase 1 (SK1), with ki~10µM and excellent water solubility. It is not to be confused with SKI-I, 5-naphthalen-2-yl-2H-pyrazole-3-carboxylic acid (2-hydroxy-naphthalen-1-ylmethylene)-hydrazide, CAS 306301-68-8, a noncompetitive inhibitor of both SK1 and SK2 with poor water solubility (K.J. French, et al., 2006; N.J. Pyne and S. Pyne, 2010). SK1-I does not inhibit SK2, PKCα, PKCδ, PKA, AKT1, ERK1, EGFR, CDK2, IKKβ or CamK2β. Not only does it decrease sphingosine-1-phosphate levels, it also causes an accumulation of its proapoptotic precursor ceremide. Inhibits tumor cell growth in vitro and in vivo.


US 20100035959

WO 2010127093

US 20100278741

WO 2011025545



This patent was granted in July 30, 2019 and set to expire on October 24, 2038. Claims methods for synthesizing the compound (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol (also known as SK1-I and BML-258 (as HCl salt)) and its intermediates.

(2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I and BML-258 (as HCl salt), is a pharmaceutical inhibitor of sphingosine kinase 1 initially described in Paugh et al., Blood. 2008 Aug. 15; 112(4): 1382-1391. An existing method for synthesizing SK1-I is disclosed in U.S. Pat. No. 8,314,151.


    The invention provides methods and intermediate compounds for synthesizing the compound (2R,3 S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I, and related compounds. The structure of SK1-I is shown below.
      A step-wise synthesis of SK1-I according to the invention is exemplified as follows.

N-Boc-(D)-Serine Methyl Ester

      To an ice-cooled suspension of the (D)-Serine methyl ester hydrochloride (62.24 g, 0.4 mol) in dichloromethane (600.0 mL), triethylamine (40.4 g, 0.4 mol) was added. After the mixture was stirred for 30 min, Boc anhydride (96.0 g, 0.44 mol) in dichloromethane (100 mL) was added dropwise with vigorous stirring over 30 min. The reaction mixture was stirred for 16 hours at room temperature. Water (600 mL) was added. The organic layer was separated. The aqueous layer was extracted with 2×200 mL of dichloromethane. The combined organic layer was washed with water (2×400 mL) and dried (Na 2SO 4). The solution was filtered, concentrated under reduced pressure to give an oil 93.36 g (˜100% yield), which was used directly in the next step without further purification.

Protection of N-Boc-(D)-Serine Methyl Ester

      Boc-Serine methyl ester from above (93.0 g, 0.42 mol) and catalyst p-toluenesulfonic acid (9.3 g) were dissolved in dichloromethane (500 mL) and 2,2-dimethoxypropane (500 mL). The mixture was stirred at room temperature for 20 hours with a drying tube. Saturated sodium bicarbonate (600.0 mL) was added. The mixture was then stirred vigorously for 30 min. The organic layer was separated, washed with bicarbonate (2×400.0 mL), water (400.0 mL), saturated NaCl (400.0 mL) and dried (Na 2SO 4). The solution was filtered and concentrated under vacuum to give 87.22 g oil (84% yield for two steps), which was used directly in the next step without further purification.

(R)—Garner Aldehyde

      To a cooled solution of the ester (87.0 g, 0.336 mol) in anhydrous toluene (690.0 mL, −78° C., acetone/dry ice bath), DIBAL in toluene (1.49 M in toluene, 392 mL, 585.0 mmol) was added dropwise under argon in such a way that the internal temperature did not rise above −70° C. After the addition, the reaction mixture was stirred for an additional 4 hours at −78° C. Methanol (128 mL) was added to the mixture to quench the reaction. The mixture was poured slowly into an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate; 1.2 M, 660 g/1949 mL water) with vigorous stirring. The mixture was stirred at room temperature until clear separation into two layers. The aqueous layer was extracted with diethyl ether (2×300.0 mL). The combined organic layer was washed with water (2×800 mL) and brine (800 mL), then dried with anhydrous Na 2SO 4. The solvent was evaporated under vacuum to give aldehyde as a pale yellow oil (68.59 g, 89%), which was used without further purification.

Addition of 4-Pentylphenyl Acetylene to the Above Aldehyde

      To a cooled (−20° C.) solution of 4-n-pentylphenylacetylene (51.68 g, 300 mmol) in dry THF (400 mL), n-BuLi solution (2.5 M in hexane, 120 mL, 300 mmol) was added dropwise under argon. After 2 hours, the mixture was cooled to −78° C., followed by the addition of HMPA (hexmethylphosphoramide, 64.5 g, 360 mmol). After the mixture was stirred at −78° C. for an additional 30 mins, methyl (R)-(+)-3-(t-butoxycarbonyl)-2,2-dimethyl-4-oxazolidinecarboxaldehyde (58.0 g, 248.3 mmol) in anhydrous THF (tetrahydrofuran; 100 mL) was added dropwise (maintaining the temperature below −60° C.). The mixture was stirred for an additional 5 hours at −78° C., then quenched by saturated ammonium chloride solution (1000 mL). The aqueous layer was extracted with ethyl ether (3×400 mL). The combined organic layer was washed with 0.5 N HCl (2×400 mL) and brine (400 mL), then dried with anhydrous sodium sulfate. The solvent was removed under vacuum to give a yellow oil (104.04 g, ˜100% yield), which was used without further purification.

Deprotection of the Above Oxazolidine

      To an ice cooled solution of Boc-oxazolidine (103.0 g, 257.0 mmol) in methanol (1000 mL), was added conc. HCl (43.5 mL, pre-cooled to 0° C.). The mixture was stirred at room temperature overnight and then extracted with hexane (3×400 mL). The pH of the methanol solution was adjusted with solid sodium bicarbonate to 8.0. Boc anhydride (53.94 g, 245.92 mmol) was added and the mixture was stirred at room temperature for 1-4 hours until the disappearance of formed intermediate free amine. The solvent was removed under vacuum. The residue was redissolved in water (300 mL) and diethyl ether (300 mL). The ethyl ether layer was dried with anhydrous sodium sulfate and then evaporated to give a brown oil (87.54 g, 94%), which was used without further purification.

Reduction of the Above Alcohol

      To an ice-cooled solution of the above acetylene (87.0 g, 241.0 mmol) in THF (800 mL), Red-Al (Sodium bis(2-methoxyethoxy)aluminum dihydride; 60% w/w in toluene, 392 mL; 1.205 mol) was added dropwise over 1 hour under argon with stirring. The solution was then stirred at room temperature for 36 hours. The reaction mixture was cooled in an ice bath and then poured carefully into a pre-cooled solution of Rochelle salt in water (700 g in 2200 mL of water). The mixture was vigorously stirred until two layers were visible and well separated. The aqueous layer was extracted with 2×600 mL of toluene. The combined toluene layer was washed with water (2×800 mL) and saturated sodium chloride (800 mL) and dried (Na 2SO 4). The solvent was removed under vacuum to give a yellowish semi solid, which was recrystallized with hexane (200 mL) to give a white solid 43.3 g (purity: >98%; yield: 49%)

Deprotection to SK1-I (BML-258)

      To a solution of Boc protected amine (15 g, 41.3 mmol) in anhydrous THF (300 mL), DIBAL (25% w/w in toluene, 1.49 M, 278 mL, 413 mmol) was added at room temperature under argon. The mixture was refluxed until the starting material disappeared. The mixture was cooled to room temperature and poured into Rochelle salt (340 g/1000 mL water) containing sodium hydroxide (50 g, ˜5%). The mixture was stirred vigorously for 1 hour. The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water (1000 mL) and brine (1000 mL) and dried with anhydrous sodium sulfate. The solvent was removed under vacuum to afford yellowish oil, which turned into a pale solid after storing at −20° C. overnight. To a cold solution (ice bath) of this solid in ethyl ether (400 mL), was added 1M HCl in ethyl ether (50 mL). The white precipitate was collected by filtration and washed with ethyl ether (2×50 mL), and then dried under vacuum to give product as a white solid (8.11 g, 63% yield).


WO2018237379 ,

claiming sphingosine pathway modulating compounds for the treatment of cancers, assigned to Enzo Biochem Inc , naming different team

Sphingosine- 1 -phosphate (SIP) was discovered to be a bioactive signaling molecule over 20 years ago. Studies have since identified two related kinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I” and “type II” respectively, and SphKl and SphK2 respectively), which catalyze the phosphorylation of sphingosine to SIP. Extracellular SIP can bind to and activate each of five S IP-specific, G protein-coupled receptors (designated S IPR1-5) to regulate cellular and physiological processes in an autocrine or paracrine manner. Selective inhibitors of each of sphingosine kinase 1 and 2, as well as both nonselective and selective agonists of SlPRs, have been developed and are known in the art.

Product Literature References

Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer: M.A. Maczis, et al.; J. Lipid Res. 59, 2297 (2018), AbstractFull Text
TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition: S. Lima, et al.; Autophagy 11, 1 (2018), Abstract;
A novel E2F/Sphingosine kinase 1 axis regulates anthracycline response in squamous cell carcinoma: M. Hazar-Rethinam, et al.; Clin. Cancer Res. 21, 417 (2015), Application(s): Inhibition of Sphingosine kinase 1 in doxorubicin-treated SCC cells and in vivo., Abstract;
Inhibition of Sphingosine Kinase 1 Ameliorates Angiotensin II-induced Hypertension and Inhibits Transmembrane Calcium Entry via Store-Operated Calcium Channel: P. C. Wilson, et al.; Mol. Endocrinol. 29, 896 (2015), Application(s): Cell Culture, AbstractFull Text
Sphingosine Kinases Signalling in Carcinogenesis: G. Marfe, et al.; Mini Rev. Med. Chem. 15, 300 (2015), Application(s):Inhibition of Sphingosine kinase 1, Abstract;
K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5.: K. B. Harikumar, et al.; Nat. Immunol. 15, 231 (2014), Application(s): Inhibition of Sphingosine kinase 1 in primary human astrocytes and mice, AbstractFull Text
LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling: J. J. C. Sheu, et al.; Oncogene 33, 1375 (2014), Application(s): Inhibition of Sphingosine kinase 1 in head and neck cancer TW06 cells, Abstract;
Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching: E. Y. Kim, et al.; FASEB J. 28, 4347 (2014), Application(s): Inhibition of Sphingosine kinase 1 in human tonsil B cells, mouse splenic B cells and in mice, Abstract;
Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-κB pathway in human non–small cell lung cancer: L. Song et al.; Clin. Cancer Res. 17, 1839 (2011), Abstract;
Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts: D. Kapitonov et al.; Cancer Res. 69, 6915 (2009), Abstract;
A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia: S.W. Paugh et al.; Blood 112, 1382 (2008), Abstract;

General Literature References

Sphingosine-1-phosphate and cancer: N.J. Pyne & S. Pyne; Nat. Rev. Cancer 10, 489 (2010), Abstract;
Antitumor Activity of Sphingosine Kinase Inhibitors: K.J. French, et al.; J. Pharmacol. Exp. Ther. 318, 596 (2006), AbstractFull Text

/////////SK1-I , SK1I , SK1 I , BML 258, Enzo Biochem,  Virginia Commonwealth, Preclinical, solid tumours, liver cancer, haematological malignancies, autoimmune hepatitis, 


PF 04965842, Abrocitinib

PF-04965842, >=98% (HPLC).png


2D chemical structure of 1622902-68-4


PF 04965842, Abrocitinib


CAS Number 1622902-68-4, Empirical Formula  C14H21N5O2S, Molecular Weight 323.41



1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-


PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor


In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD


In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD


Pub. No.: WO/2014/128591 International Application No.: PCT/IB2014/058889
Publication Date: 28.08.2014 International Filing Date: 11.02.2014

EXPIRY  Roughly 2034

form powder
color white to beige
solubility DMSO: 10 mg/mL, clear
storage temp. room temp
    Biochem/physiol Actions
    • PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
  • Originator Pfizer
  • Class Skin disorder therapies; Small molecules
  • Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

  • Phase IIIAtopic dermatitis
  • DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

  • 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
  • 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
  • 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

Image result for PF-04965842

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).


Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018


CN 105732637


CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

Image result for PF-04965842

Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis

Wednesday, February 14, 2018 8:30 am EST



Public Company Information:

“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the J AK1 A topic D ermatitis E fficacy and Safety (JADE) global development program.

“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1

About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership

PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:

  • PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
  • PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
  • PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis

Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at In addition, to learn more, please visit us on and follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedInYouTube and like us on Facebook at

DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at  and .

Image result for PF-04965842

# # # # #

1 Food and Drug Administration Fact Sheet Breakthrough Therapies at on January 25, 2018


CA 2899888


WO 2014128591;jsessionid=6767BBB5964A985E88C9251B6DF3182B.wapp2nB?docId=WO2014128591&recNum=233&maxRec=8235&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3Apfizer&tab=PCTDescription

PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)

BROWN, Matthew Frank; (US).
FENWICK, Ashley Edward; (US).
FLANAGAN, Mark Edward; (US).
GONZALES, Andrea; (US).
JOHNSON, Timothy Allan; (US).
KAILA, Neelu; (US).
MITTON-FRY, Mark J.; (US).
STROHBACH, Joseph Walter; (US).
TENBRINK, Ruth E.; (US).
TRZUPEK, John David; (US).
UNWALLA, Rayomand Jal; (US).
VAZQUEZ, Michael L.; (US).
PARIKH, Mihir, D.; (US)



Example 2 : N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane- l -sulƒonamide

This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93 : 7) to afford the title compound as a tan sol id (78% yield). 1NMR (400 MHz, DMSO-d6): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d, 1 H), 6.61 (d, 1 H), 4.81-4.94 (m, 1 H), 3.47-3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 2.14-2.27 (m, 2 H) 1.60- 1.73 (m, 2 H) 0.96 (t, 3 H). LC/MS (exact mass) calculated for C14H21N5O2S;

323.142, found (M + H+); 324.1.


 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

Abstract Image

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (25)

Compound 48a·2HBr …………..was collected by filtration, washed with 2:1 EtOH/H2O (100 mL), and again dried overnight in a vacuum oven at 40 °C.
1H NMR (400 MHz, DMSO-d6): 11.64 (br s, 1H), 8.12 (s, 1 H), 7.50 (d, J = 9.4 Hz, 1H), 7.10–7.22 (m, 1H), 6.65 (dd, J= 1.8, 3.3 Hz, 1H), 4.87–4.96 (m, 1H), 3.53–3.64 (m, 1H), 3.27 (s, 3H), 2.93–2.97 (m, 2H), 2.57–2.64 (m, 2H), 2.20–2.28 (m, 2H), 1.65–1.74 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.

SchmiederG.DraelosZ.PariserD.BanfieldC.CoxL.HodgeM.KierasE.Parsons-RichD.MenonS.SalganikM.PageK.PeevaE. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study Br. J. Dermatol. 2017DOI: 10.1111/bjd.16004

Compound 25N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).


1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012

 2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

  • Originator Pfizer
  • Class Anti-inflammatories; Antipsoriatics; Pyrimidines; Pyrroles; Skin disorder therapies; Small molecules; Sulfonamides
  • Mechanism of Action Janus kinase 1 inhibitors
  • Phase III Atopic dermatitis
  • Discontinued Lupus vulgaris; Plaque psoriasis
  • 21 May 2019Pfizer initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03937258)
  • 09 May 2019 Pfizer plans a phase I pharmacokinetic and drug-drug interaction trial in healthy volunteers in May 2019 (NCT03937258)
  • 30 Apr 2019 Pfizer completes a phase I trial (In volunteers) in USA (PO) (NCT03626415)

/////////PF 04965842, Abrocitinib, Phase III,  Atopic dermatitis, pfizer




Image result for PF-06651600

Image result for PF-06651600

Image result for PF-06651600


CAS 1792180-81-4

C₁₅H₁₉N₅O, 285.34, UNII-2OYE00PC25


Image result for PF-06651600

 1-[(2S,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-piperidinyl]-2-propen-1-one malonate

PF-06651600 malonate
CAS: 2140301-97-7 (malonate)
Chemical Formula: C18H23N5O5

Molecular Weight: 389.412

PHASE 2  alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.

PF-06651600 is a potent and selective JAK3 inhibitor. PF-06651600 is a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor PF-06651600 led to its evaluation in several human clinical studies. JAK3 was among the first of the JAKs targeted for therapeutic intervention due to the strong validation provided by human SCID patients displaying JAK3 deficiencies

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitors in development as potential medicines. PF-06651600 is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile, and ADME properties, this JAK3-specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Supported by positive results from a Phase 2 study, 1 was granted Breakthrough Therapy designation by the FDA on Sept. 5, 2018 for treatment of alopecia areata.



J. Med. Chem. 201760 (5), 19711993DOI: 10.1021/acs.jmedchem.6b01694


Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600, 

Yong Tao*

Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX

Publication Date:July 19, 2019

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate (1·TsOH)

1·TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. Mp 199 °C. Rotomers observed for NMR spectroscopies. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.68 (brs, 1H), 9.22 (brs, 1H), 8.40 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1.2 Hz, 1H), 6.84 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1.91–1.72 (m, 4H), 1.24–1.17 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51, 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41, 25.22, 21.28, 16.97, 15.51. HRMS (ESI) m/z: calculated for C15H20N5O [M + H]+286.1668; observed 286.1692.


Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.


WO 2015083028


1: D’Amico F, Fiorino G, Furfaro F, Allocca M, Danese S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin Investig Drugs. 2018 Jul;27(7):595-599. doi: 10.1080/13543784.2018.1492547. Epub 2018 Jul 6. Review. PubMed PMID: 29938545.

2: Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, Colonna M. Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunol. 2018 Jan;11(1):50-60. doi: 10.1038/mi.2017.38. Epub 2017 May 17. PubMed PMID: 28513593; PubMed Central PMCID: PMC5693788.

3: Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem. 2017 Mar 9;60(5):1971-1993. doi: 10.1021/acs.jmedchem.6b01694. Epub 2017 Feb 16. PubMed PMID: 28139931.

4: Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. Epub 2016 Nov 10. PubMed PMID: 27791347.

5: Walker G, Croasdell G. The European League Against Rheumatism (EULAR) – 17th Annual European Congress of Rheumatology (June 8-11, 2016 – London, UK). Drugs Today (Barc). 2016 Jun;52(6):355-60. doi: 10.1358/dot.2016.52.6.2516435. PubMed PMID: 27458612.

////////////PF-06651600, PF 06651600, PF06651600, Breakthrough Therapy designation, PHASE 2,   alopecia areata, rheumatoid arthritis, Crohn’s disease,  ulcerative colitis,


SYN 01

SYN-01, SYN-510

Synthena AG


Synthena , presumed to be under license from  University of Bern , is investigating (presumably SYN-01 ), a lead from the tricyclo(tc)-DNA based antisense oligonucleotides (AON) developed using its proprietary tricyclo-DNA technology platform, for the treatment of Duchenne muscular dystrophy. In January 2017, the drug was listed as being in preclinical development.



Process for preparing tricyclo-deoxyribonucleic acid (tc-DNA) which may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Antisense technology is an effective means for reducing the expression of specific gene products and can therefore be useful in therapeutic, diagnostic, and research applications.

Generally, the principle behind antisense technology is that an antisense oligomeric compound (a sequence of nucleotides or analogues thereof) hybridizes to a target nucleic acid and modulates gene expression activities or function, such as transcription and/or translation.

[003] Antisense oligomeric compounds may be prepared from chemically-modified antisense oligonucleotides, which may include a variety of different structural variations depending upon the therapeutic strategy. For example, tricyclo-deoxyribonucleic acids (tc-DNA) are conformationally constrained DNA analogs.

[004] There is a need in the field for processes that allow for the bulk preparation of tc-DNA nucleoside precursors that may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Example 4 – Cvclopropanation of Compound 17 with Carbenoid Prepared from CH2I2 and Et2Zn in the Absence of Additives

[00127] According to the following scheme, compound 17 was converted to tc-DNA Nucleoside Precursor 18 using the cyclopropanation conditions set forth in Examples 4 to 7 :

[00128] 1.07 g purified a-anomer (3.736 mmol) 17 was dissolved in 37 ml of dry CH2C12 and cooled to 0 °C (ice). Subsequently, 22.3 ml (22.3 mmol, 6 eq.) Et2Zn 1.0 M in hexane (Aldrich) were added dropwise and stirred under Ar for 30 min at 0 °C. Then, 3.02 ml (37.2 mmol, 10 eq.) of CH2I2 were added dropwise over 15 min at the same temperature and stirred for further 2 h at 0 °C. Afterwards the cooling bath was removed and the mixture was stirred for additional 21 h at ambient temperature. TLC showed substantial amount of unreacted a- 17. It was diluted by addition of EtOAc and quenched with 50 mL of sat. aqueous NH4Cl. Extractive work-up provided 1.79 g of crude which was purified by chromatography on silica-gel giving 0.43 g (39%) of 18 and 0.49 g of mixture of compound 17 and 18 (approximately 20:80).



claiming a composition comprising an oligomeric compound having tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a lipid moiety.


Inventive compositions for the treatment of Duchenne muscular dystrophy

Evaluation of efficacy

[00464] Adult mdx mice were treated weekly over 4 weeks with intravenous injections of different 13-mer AONs targeting the donor splice site of exon 23 of the dystrophin pre-mRNA (M23D: +2-11), namely with either SY-0308, SY-0210 and the inventive SY-0299, SY-0343, SY-0442 and SY-0455. SY-0308 (also named “tcDNA-PO M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: l, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorodiester linkage groups, and p being a phosphate moiety at the 5′ end. SY-0210 (also named “tcDNA-PS M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: 1, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorothioate linkage groups, and p being a phosphate moiety at the 5′ end. The inventive composition SY-0343 is herein interchangeably referred to as “Palm-2PS-tcDNA-PO M23D” which is depicted in the following:

[00465] The inventive composition SY-0442 is herein interchangeably referred to as “Palm-lPS-tcDNA-PO M23D” which is depicted in the following:

[00466] The inventive composition SY-0299 is herein interchangeably referred to as “Palm-2PO-tcDNA-PO M23D” which is depicted in the following:

//////////////////SYN-01, SYN 01, SYN01, preclinical , Duchenne muscular dystrophy, University of Bern,

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