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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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FDA approves first therapy Crysvita (burosumab) for rare inherited form of rickets, x-linked hypophosphatemia


FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia

The U.S. Food and Drug Administration today approved Crysvita (burosumab), the first drug approved to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH causes low levels of phosphorus in the blood. It leads to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a patient’s life.

April 17, 2018

Release

The U.S. Food and Drug Administration today approved Crysvita (burosumab), the first drug approved to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH causes low levels of phosphorus in the blood. It leads to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a patient’s life.

“XLH differs from other forms of rickets in that vitamin D therapy is not effective,” stated Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “This is the first FDA-approved medication for the treatment of XLH and a real breakthrough for those living with this serious disease.”

XLH is a serious disease affecting approximately 3,000 children and 12,000 adults in the United States. Most children with XLH experience bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with XLH experience persistent discomfort or complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss.

The safety and efficacy of Crysvita were studied in four clinical trials. In the placebo-controlled trial, 94 percent of adults receiving Crysvita once a month achieved normal phosphorus levels compared to 8 percent of those receiving placebo. In children, 94 to 100 percent of patients treated with Crysvita every two weeks achieved normal phosphorus levels. In both children and adults, X-ray findings associated with XLH improved with Crysvita therapy. Comparison of the results to a natural history cohort also provided support for the effectiveness of Crysvita.

The most common adverse reactions in adults taking Crysvita were back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation. The most common adverse reactions in children were headache, injection site reaction, vomiting, decreased vitamin D and pyrexia (fever).

Crysvita was granted Breakthrough Therapy designation, under which the FDA provides intensive guidance to the company on efficient drug development, and expedites its review of drugs that are intended to treat serious conditions where clinical evidence shows the drug may represent a substantial improvement over other available therapies. Crysvita also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 14th Rare Pediatric Disease Priority Review Voucher issued by the FDA since the program began.

The FDA granted approval of Crysvita to Ultragenyx Pharmaceutical Inc.

 

////////////fda 2018, Crysvita, burosumab, Breakthrough Therapy, priority review.  Ultragenyx Pharmaceutical Inc

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FDA expands approval of Blincyto (blinatumomab) for treatment of a type of leukemia in patients who have a certain risk factor for relapse


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FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse

Blincyto (blinatumomab)

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.Continue reading.

 

March 29, 2018

Release

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” 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. “Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer Institute estimates that approximately 5,960 people in the United States will be diagnosed with ALL this year and approximately 1,470 will die from the disease.

Blincyto works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved Blincyto under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Philadelphia chromosome-positive ALL.

The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia).

Blincyto carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and difficulty breathing (cytokine release syndrome) at the start of the first treatment, experienced a short period of difficulty with thinking (encephalopathy) or other side effects in the nervous system. Serious risks of Blincyto include infections, effects on the ability to drive and use machines, inflammation in the pancreas (pancreatitis), and preparation and administration errors—instructions for preparation and administration should closely be followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative free saline should be used for patients weighing less than 22 kilograms.

This new indication for Blincyto was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL.

The FDA granted this application Priority Review and it received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Blincyto to Amgen Inc.

 

//////amgen, fda 2018,  Priority Review m  Orphan Drug designation, Blincyto, blinatumomab,

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options


Image result for ibalizumab-uiykImage result for taiMed Biologics USA Corp

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk),for patients who have limited treatment options

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.

 

 

March 6, 2018

Release

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.

“While most patients living with HIV can be successfully treated using a combination of two or more antiretroviral drugs, a small percentage of patients who have taken many HIV drugs in the past have multidrug resistant HIV, limiting their treatment options and putting them at a high risk of HIV-related complications and progression to death,” said Jeff Murray, M.D., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Trogarzo is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options. New treatment options may be able to improve their outcomes.”

The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.

The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of Trogarzo in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the Trogarzo development program.

A total of 292 patients with HIV-1 infection have been exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The FDA granted this application Fast TrackPriority Review and Breakthrough Therapy designations. Trogarzo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Trogarzo to TaiMed Biologics USA Corp.

Theratechnologies Announces FDA Approval of Breakthrough Therapy, Trogarzo™ (ibalizumab-uiyk) Injection, the First HIV-1 Inhibitor and Long-Acting Monoclonal Antibody for Multidrug Resistant HIV-1


NEWS PROVIDED BY

Theratechnologies Inc. 


  •  First HIV treatment approved with a new mechanism of action in more than 10 years
  • Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
  • Trogarzo™ has no drug-drug interactions and no cross-resistance with other ARTs

MONTREALMarch 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo™ (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo™ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.1

Trogarzo™ represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo™ is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.1

“Today’s approval of Trogarzo™ by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo™, and are helping address this critical unmet medical need.”

Trogarzo™ previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.

“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”

Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.13

“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo™ patient. “Since starting treatment with Trogarzo™ six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo™ is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”

TaiMed and Theratechnologies partnered on the development of Trogarzo™ so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo™ or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support™ at 1-833-23-THERA (84372).

“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”

Clinical Trial Findings

Clinical studies show that Trogarzo™, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.

The Phase 3 trial showed:1

  • Trogarzo™ significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
  • More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log10 (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo™ and no adjustment to the failing background regimen.
  • The average viral load reduction after 24 weeks was 1.6 log10 with 43% of patients achieving undetectable viral loads.

Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm3, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.1

The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.1

About Trogarzo™ (ibalizumab-uiyk) Injection

Trogarzo™ is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo™ binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.

IMPORTANT SAFETY INFORMATION

Trogarzo™ is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.

Trogarzo™ blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.

Before you receive Trogarzo™, tell your healthcare provider if you:

  • are pregnant or plan to become pregnant. It is not known if Trogarzo™ may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Trogarzo™ passes into breast milk.

Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.

Trogarzo™ can cause serious side effects, including:

Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines.  Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time.  Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of Trogarzo™ include:

  • Diarrhea
  • Dizziness
  • Nausea
  • Rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo™. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  You may also report side effects to at 1-833-23THERA (1-833-238-4372).

 

About Theratechnologies

Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.

/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast TrackPriority Review, Breakthrough Therapy designations,  Orphan Drug designation

FDA approves new treatment Erleada (apalutamide) for a certain type of prostate cancer using novel clinical trial endpoint


FDA approves new treatment Erleada (apalutamide) for a certain type of prostate cancer using novel clinical trial endpoint

The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer. Continue reading.

February 14, 2018

Release

The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.

“The FDA evaluates a variety of methods that measure a drug’s effect, called endpoints, in the approval of oncology drugs. This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” 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. “In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.”

According to the National Cancer Institute (NCI) at the National Institutes of Health, prostate cancer is the second most common form of cancer in men in the U.S.. The NCI estimates approximately 161,360 men were diagnosed with prostate cancer in 2017, and 26,730 were expected to die of the disease. Approximately 10 to 20 percent of prostate cancer cases are castration-resistant, and up to 16 percent of these patients show no evidence that the cancer has spread at the time of the castration-resistant diagnosis.

Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.

The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or with surgery to lower the amount of testosterone in their body (surgical castration). The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.

Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).

Severe side effects of Erleada include falls, fractures and seizures.

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The sponsor for Erleada is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, certain information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.

The FDA granted the approval of Erleada to Janssen Pharmaceutical Companies.

//////////////fda 2018, Erleada, apalutamide, Priority Review, Janssen

FDA approves new treatment for certain digestive tract cancers Lutathera (lutetium Lu 177 dotatate)


Image result for lutetium Lu 177 dotatate

lutetium Lu 177 dotatate

FDA approves new treatment for certain digestive tract cancers

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs. Continue reading.\

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm?utm_campaign=01262018_PR_FDA%20approves%20new%20treatment%20for%20digestive%20cancers&utm_medium=email&utm_source=Eloqua

January 26, 2018

Release

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs.

“GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing,” 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. “This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment.”

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia).

Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

 

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Dotatate lutenium Lu-177.png

Dotatate lutenium Lu-177; 437608-50-9; DTXSID20195927

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium(3+)

Image result for lutetium Lu 177 dotatate

 

Lutetium-177

Lutetium 1777

Lutetium-177 has been quite a late addition as an isotope of significance to the nuclear medicine yet it is making big strides especially as a therapeutic radiopharmaceutical for neuroendocrine tumours in the form of 177Lu-DOTA-TATE on regular basis as described by Das & Pillai (2013). 

 
Lutetium-177 a lanthanide is an f block element that has a half-life of 6.7 days and decays mainly by beta emission to Hf-177, is accompanied by two gamma ray emissions. These radionuclide properties are very similar to those of I-131 which has long served as a therapeutic radionuclide, it was therefore not surprising that Lu-177 also emerged as a highly valuable radionuclide for similar applications,
 
There are several other upcoming applications especially for bone pain palliatiion. As a result of its convenient production logistics Lu-177 as discussed by Pillai et al (2003) is fast emerging a radionuclide of choice in radionuclide therapy (RNT).
 
Lu-177 can be prepared in a nuclear reactor by one of the two reactions given below :
176Lu(n,gamma)177Lu or
 
176Yb(n,gamma)177Yb –beta–> 177Lu
 
The former reaction has a high thermal neutron capture cross section and is presently the method adopted at our reactors in spite of the  formation of long lived Lu-177m whose yield is very much low and is considered insignificant to cause any great concern.
Lutetium-177 Impact 
Recently there has been a rush of several research reviews and articles where Lu-177 holds the centre stage, for example, Banerjee et al (2015) have reviewed the chemistry and applications of Lu-177; Dash et al (2015) reviewed its production and available options; Knapp & Pillai (2015) highlighted its usefulness in cancer treatment and chronic diseases and Pillai and Knapp (2015) have discussed the evolving role of Lu-177 in nuclear medicine with this ready availability of Lu-177. Peptide receptor radionuclide therapy is one of the upcoming field of investigation where Lu-177 holds much promise among few other radionuclides. Indeed Lutetium-177 has covered a good distance especially for Therapeutic and as a palliative radiopharmaceutical.
 
Chemistry
Das et al (2014) have described the preparation of Lu-177 EDTMP kit.
Parus et al (2015) have discussed chemistry of bifunctional chelating agents for binding Lu-177.
Gupta et al (2014) have compiled methods of labelleing antibdoies with radioiodine and radiometals. 
 
Applications
Limouris (2012) has reviewed applications in neuroendocrine tumors with focus on Liver metastasis. Das and Banerjee (2015) described the potential theranostic applications with Lu-177.
Anderson et al (1960) were among the first to use Lutetium (as chloride and citrate) in a clinical trial which were not so successful and did not encourage much promise. Keeling et al (1988) published their results with in vitro uptake of Lutetium hydroxylapatite particles. Lu-EDTMP as bone palliating agent by Ando et al (1998) soon followed,  However the greatest impact was seen with the advent of a somatostatin analogue Lu-DOTATATE for targetting neuroendocrine tumors reported by Kwekkeboom et al (2001) and reviewed recently by Bodei et al (2013).
PRRNT  – IAEA (2013) has brought out a human health series booklet on the subject with emphasis on neuroendocrine tumors.
177Lu Labelled Peptides in NET Kam et al (2012).
177Lu- DOTATATE – PRRNT – Bakker et al (2006)
177Lu-EDTMP – Bone Pain Palliation –  Bahrami-Samani et al (2012)
177Lu-EDTMP – Pharmacokinetics, dosimetry and Therapeutic efficacy – Chakraborty S et al (2015)
177Lu-Hydroxylapatite – Radiosynovectomy – Kamalleshwaran et al. (2014) Shinto et al. (2015)
117Lu- Radioimmunotherapy – Kameshwaran et al (2015) 
177Lu – Pretargeted Radioimmunotherapy (PRIT) Frost et al (2015).
 
More specific applications and additional information about the highly valuable therapeutic isotope would soon be added.
 
References and Notes
Anderson J, Farmer FT, Haggith JW, Hill M. (1960). The treatment of myelomatosis with Lutetium. Br J Radiol. 33:374-378.
Ando A, Ando L, Tonami N, Kinuya S, Kazuma K, Kataiwa A, Nakagawa M, Fujita N. (1998). 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 19: 587-591.
Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. (2012). Production, Quality Control and Pharmacokinetic Studies of 177Lu-EDTMP for Human Bone Pain Palliation Therapy Trials. Iran J Pharm Res. 11:137-44.
Bakker WH, Breeman WAP, Kwekkeboom DJ, De Jong LC, Krenning EP. ((2006) Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q J Nucl Med Mol Imaging 50: 265-271.

Banerjee S, Pillai MR, Knapp FF (2015). Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry, Radiochemistry, and Practical Applications. Chem Rev. 115: 2934-2974.
 
Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ. (2013).The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013 40:800-16.
 
Chakraborty S, Balogh L, Das T, Polyák A, Andócs G, Máthé D, Király R, Thuróczy J, Chaudhari PR, Jánoki GA, Jánoki G, Banerjee S, Pillai MR (2015). Evaluation of 177Lu-EDTMP in dogs with spontaneous tumor involving bone: Pharmacokinetics, dosimetry and therapeutic efficacy. Curr Radiopharm (ahead of Pub)
Das T, Banerjee S. (2015). Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr Radiopharm. (ahead of print).
Das T , Sarma HD, Shinto A, Kamaleshwaran KK, Banerjee S. (2014). Formulation, Preclinical Evaluation, and Preliminary Clinical Investigation of an In-House Freeze-Dried EDTMP Kit Suitable for the Preparation of Lu-177-EDTMP. Cancer Biotherap Radiopharm. 29: (ahead of publication).
Das T, Pillai M.R.A. (2013).Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol. 40: 23-32.
 
Dash A, Pillai MR, Knapp FF Jr. (2015). Production of 177Lu for targeted radionuclide therapy : Available options. Nucl Med Mol Imaging. 49: 85-107. 

Frost SH, Frayo SL, Miller BW, Orozco JJ, Booth GC, Hylarides MD, Lin Y, Green DJ, Gopal AK, Pagel JM, Bäck TA, Fisher DR, Press OW. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One. 2015 Mar 18;10(3):e0120561.
 
Gupta S, Batra S, Jain M (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol. 2014;1141:147-57. 
IAEA (2013). Peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumors. IAEA Human Health Series No. 20., IAEA, Vienna. 
 
Kam BLR, Teunissen JJM, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ. (2012). Lutetium-labelled peptides for therapy of neuroendocrine tumours.  Eur J Nucl Med Mol Imaging 39 (Suppl 1):S103–S112.
 
Kamaleshwaran KK, Rajamani V, Thirumalaisamy SG, Chakraborty S, Kalarikal R, Mohanan V, Shinto AS.(2014). 

Kameshwaran M, Pandey U, Dhakan C, Pathak K, Gota V, Vimalnath KV, Dash A, Samuel G. (2015) .Synthesis and Preclinical Evaluation of (177)Lu-CHX-A”-DTPA-Rituximab as a Radioimmunotherapeutic Agent for Non-Hodgkin’s Lymphoma. Cancer Biother Radiopharm. 2015 Aug;30(6):240-6

Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JL, de Jong M, Krenning EP.. (2001). [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients.Eur J Nucl Med.  28: 1319-1325.

Parus JL, Pawlak D, Mikolajczak R, Duatti A. (2015) Chemistry and bifunctional chelating agents for binding 177Lu Curr Radiopharm (Ahead of Pub)
 
Limouris G. (2012) Neuroendocrine tumors: a focus on liver metastatic lesions. Front Oncol. 2:20 (Ahead of Pub) PMC article
Pillai MR, (Russ) Knapp FF. (2015). Evolving Important Role of Lutetium-177 for Therapeutic Nuclear Medicine Curr Radiopharm (ahead of print).
Pillai MR, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N. (2003). Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot. 59: 109-118.
 
Shinto AS, Kamaleshwaran KK, Vyshakh K, Thirumalaisamy SG, Karthik S, Nagaprabhu VN, Vimalnath KV, Das T, Chakraborty S, Banerjee S. (2015)  Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra‑Articular Administration of 177Lu‑Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience. World J Nucl Med. 14: (ahead of print).
 
Videos
DOTA-TATE
DOTATATE.svg
Names
Other names

DOTA-(Tyr3)-octreotate
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C65H90N14O19S2
Molar mass 1,435.63 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DOTA-TATEDOTATATE or DOTA-octreotate is a substance which, when bound to various radionuclides, has been tested for the treatment and diagnosis of certain types of cancer, mainly neuroendocrine tumours.

Chemistry and mechanism of action

DOTA-TATE is an amide of the acid DOTA (top left in the image), which acts as a chelator for a radionuclide, and (Tyr3)-octreotate, a derivative of octreotide. The latter binds to somatostatin receptors, which are found on the cell surfaces of a number of neuroendocrine tumours, and thus directs the radioactivity into the tumour.

Usage examples

Gallium (68Ga) DOTA-TATE (GaTate[1]) is used for tumour diagnosis in positron emission tomography (PET).[2] DOTA-TATE PET/CT has a much higher sensitivitycompared to In-111 octreotide imaging.[1]

Lutetium (177Lu) DOTA-TATE[3] has been tested for the treatment of tumors such as carcinoid and endocrine pancreatic tumor. It is also known as Lutathera.[4]

Patients are typically treated with an intravenous infusion of 7.5 GBq of lutetium-177 octreotate. After about four to six hours, the exposure rate of the patient has fallen to less than 25 microsieverts per hour at one metre and the patients can be discharged from hospital.

A course of therapy consists of four infusions at three monthly intervals.[5]

Availability

Lu177 octreotate therapy is currently available under research protocols in five different medical centers in North America: Los Angeles (CA), Quebec City, (Qc), Birmingham, AL, Edmonton, (Ab), London, (On) as Houston (Tx) on clinical trial.[6] Medical centers in Europe also offer this treatment. For instance: Cerrahpasa Hospital in TurkeyUppsala Centre of Excellence in Neuroendocrine Tumors in Sweden and Erasmus University in the Netherlands.[7] In Israel, treatment is available at Hadassah Ein Kerem Medical Center. In Australia, treatment is available at St George Hospital and Royal North Shore Hospital, Sydney;[8] the Royal Brisbane and Women’s Hospital in Brisbane [9], the Peter MacCallum Cancer Centre [1] and at the Department of Nuclear Medicine at Fremantle Hospital in Western Australia.[10] In Aarhus universitet hospital in Denmark. In the coming years such therapy will also become commercially available in Latvia, Riga – “Clinic of nuclear medicine”.

See also

  • DOTATOC or edotreotide, a similar compound

References

  1. Jump up to:a b c Hofman, M. S.; Kong, G.; Neels, O. C.; Eu, P.; Hong, E.; Hicks, R. J. (2012). “High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours”. Journal of Medical Imaging and Radiation Oncology56 (1): 40–47. doi:10.1111/j.1754-9485.2011.02327.xPMID 22339744.
  2. Jump up^ Breeman, W. A. P.; De Blois, E.; Sze Chan, H.; Konijnenberg, M.; Kwekkeboom, D. J.; Krenning, E. P. (2011). “68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives”. Seminars in Nuclear Medicine41 (4): 314–321. doi:10.1053/j.semnuclmed.2011.02.001PMID 21624565.
  3. Jump up^ Bodei, L.; Cremonesi, M.; Grana, C. M.; Fazio, N.; Iodice, S.; Baio, S. M.; Bartolomei, M.; Lombardo, D.; Ferrari, M. E.; Sansovini, M.; Chinol, M.; Paganelli, G. (2011). “Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study”. European Journal of Nuclear Medicine and Molecular Imaging38(12): 2125–2135. doi:10.1007/s00259-011-1902-1PMID 21892623.
  4. Jump up^ Radiolabeled Peptide Offers PFS Benefit in Midgut NET
  5. Jump up^ Claringbold, P. G.; Brayshaw, P. A.; Price, R. A.; Turner, J. H. (2010). “Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours”. European Journal of Nuclear Medicine and Molecular Imaging38 (2): 302–311. doi:10.1007/s00259-010-1631-xPMID 21052661.
  6. Jump up^ Clinical trial number NCT01237457 for “177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms” at ClinicalTrials.gov
  7. Jump up^ “PRRT Behandelcentrum Rotterdam”PRRT Behandelcentrum RotterdamErasmus Universiteit.
  8. Jump up^ http://www.swslhd.nsw.gov.au/liverpool/pet/PET.html
  9. Jump up^ https://agitg.org.au/control-nets-study-set-to-commence
  10. Jump up^ Turner, J. H. (2012). “Outpatient therapeutic nuclear oncology”. Annals of Nuclear Medicine26 (4): 289–97. doi:10.1007/s12149-011-0566-zPMID 22222779.

//////////////Lutathera, lutetium Lu 177 dotatate, fda 2018, PRIORITY REVIEW, ORPHAN DRUG

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(C(C)O)C(=O)O)O.[Lu+3]

TEZACAFTOR, VX 661 for treatment of cystic fibrosis disease.


ChemSpider 2D Image | Tezacaftor | C26H27F3N2O6

img

2D chemical structure of 1152311-62-0

TEZACAFTOR, VX 661

CAS : 1152311-62-0;

  • Molecular FormulaC26H27F3N2O6
  • Average mass520.498 Da

l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[l-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-l,l-dimethylethyl)-lH-indol-5-yl]-cyclopropanecarboxamide).

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

Cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-

1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide

Cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(1-((2R)-2,3-dihydroxypropyl)-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl)-

1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(1-((2R)-2,3-dihydroxypropyl)-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl)cyclopropanecarboxamide

Vertex (INNOVATOR)

UNII: 8RW88Y506K

In July 2016, this combination was reported to be in phase 3 clinical development.

Update         

Symdeko (tezacaftor/ivacaftor) ; Vertex; For the treatment of cystic fibrosis , Approved February 2018

Urology

Tezacaftor, also known asVX-661, is CFTR modulator. VX-661 is potentially useful for treatment of cystic fibrosis disease. Cystic fibrosis (CF) is a genetic disease caused by defects in the CF transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel. The most common mutation, Δ508CFTR, produces a protein that is misfolded and does not reach the cell membrane. VX-661 can correct trafficking of Δ508CFTR and partially restore chloride channel activity. VX-661 is currently under Phase III clinical trial.

VX-661 is an orally available deltaF508-CFTR corrector in phase III clinical trials at Vertex for the treatment of cystic fibrosis in patients homozygous to the F508del-CFTR mutation

Novel deuterated analogs of a cyclopropanecarboxamide ie tezacaftor (VX-661), as modulators of cystic fibrosis transmembrane conductance regulator (CFTR) proteins, useful for treating a CFTR-mediated disorder eg cystic fibrosis.

VX-661 (CAS #: 1152311-62-0; l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[l-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-l,l-dimethylethyl)-lH-indol-5-yl]-cyclopropanecarboxamide). VX-661 is a cystic fibrosis transmembrane conductance regulator modulator. VX-661 is currently under investigation for the treatment of cystic fibrosis. VX-661 has also shown promise in treating sarcoglycanopathies, Brody’s disease, cathecolaminergic polymorphic ventricular tachycardia, limb girdle muscular dystrophy, asthma, smoke induced chronic obstructive pulmonary disorder, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick’s disease, polyglutamine neurological disorders such as Huntington’s, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatombral pallidoluysian, and myotonic dystrophy, as well as spongifiorm encephalopathies, such as hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Gerstrnarm-Straussler-Scheinker syndrome, chronic obstructive pulmonary disorder, dry-eye disease, or Sjogren’s disease, osteoporosis, osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham’s Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter’s

syndrome type III, Dent’s disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus, and ciliary aplasia. WO 2014086687; WO2013185112.

VX-661

VX-661 is likely subject to extensive CYP45o-mediated oxidative metabolism. These, as well as other metabolic transformations, occur in part through polymorphically-expressed enzymes, exacerbating interpatient variability. Additionally, some metabolites of VX-661 may have undesirable side effects. In order to overcome its short half-life, the drug likely must be taken several times per day, which increases the probability of patient incompliance and discontinuance.Deuterium Kinetic Isotope Effect

PATENT

WO 2016109362

Scheme I

EXAMPLE 1

(R)-l-(2,2-difluorobenzo[dl[l,31dioxol-5-vn-N-(l-q,3-dihvdroxypropyn-6-fluoro-2-(l- hvdroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cvclopropanecarboxamide

(VX-661)

Methyl 2.2-difluorobenzo[dl [1.31dioxole-5-carboxylate: To a 200 mL pressure tank reactor (10 atm. in CO), was placed 5-bromo-2,2-difluoro-2H-l,3-benzodioxole (20.0 g, 84.4 mmol, 1.00 equiv), methanol (40 mL), triethylamine (42.6 g, 5.00 equiv.), Pd2(dba)3 (1.74 g, 1.69 mmol, 0.02 equiv), Pd(dppf)Cl2 (1.4 g, 1.69 mmol, 0.02 equiv.). The resulting solution was stirred at 85 °C under an atmosphere of CO overnight and the reaction progress was monitored by GCMS. The reaction mixture was cooled. The solids were filtered out. The organic phase was concentrated under vacuum to afford 17.5 g of methyl 2,2-difluoro-2H-l,3-benzodioxole-5-carboxylate as a crude solid, which was used directly in the next step. Step 2

2 step 2 3

(2.2-difluorobenzo[dl [ 1.31 dioxol-5 -vDmethanol : To a 500mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed methyl 2,2-difluoro-2H-l,3-benzodioxole-5-carboxylate (17.5 g, 81.01 mmol, 1.00 equiv.), tetrahydrofuran (200 mL). This was followed by the addition of L1AIH4 (6.81 mg, 162.02 mmol, 2.00 equiv.) at 0 °C. The resulting solution was stirred for 1 h at 25 °C and monitored by GCMS. The reaction mixture was cooled to 0 °C until GCMS indicated the completion of the reaction. The pH value of the solution was adjusted to 8 with sodium hydroxide (1 mol/L). The solids were filtered out. The organic layer combined and concentrated under vacuum to afford 13.25 g (87%) of (2,2-difluoro-2H-l,3-benzodioxol-5-yl)methanol as yellow oil.

Step 3

step 3

5-(chloromethyl)-2.2-difluorobenzo[diri.31dioxole: (2.2-difluoro-2H-1.3-benzodioxol-5-yl)methanol (13.25 g, 70.4 mmol, 1.00 equiv.) was dissolved in DCM (200 mL). Thionyl chloride (10.02 g, 1.20 equiv.) was added to this solution. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under vacuum. The residue was then diluted with DCM (500 mL) and washed with 2 x 200 mL of sodium bicarbonate and 1 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and evaporated to afford 12.36 g (85%) of 5-(chloromethyl)-2,2-difluoro-2H-l ,3-benzodioxole as yellow oil.

Step 4

step 4 5

[00160] 2-(2.2-difluorobenzordi ri .31dioxol-5-yl)acetonitrile: 5-(chloromethyl)-2,2-difluoro-2H-l,3-benzodioxole (12.36 g, 60 mmol, 1.00 equiv.) was dissolved in DMSO (120 mL). This was followed by the addition of NaCN (4.41 g, 1.50 equiv.) with the inert temperature below 40 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 300 mL of water/ice. The resulting solution was extracted with 3 x 100 mL of ethyl acetate. The organic layers combined and washed with 3 x 100 mL brine dried over anhydrous sodium sulfate and concentrated under vacuum to afford 10.84 g (92%) of 2-(2,2-difluoro-2H-l ,3-benzodioxol-5-yl)acetonitrile as brown oil.

Step 5

l -(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l -carbonitrile: To a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2-(2,2-difluoro-2H-l ,3-benzodioxol-5-yl)acetonitrile (10.84 g, 55 mmol, 1.00 equiv.),

NaOH (50%) in water), 1 -bromo-2-chloroethane (11.92g, 82.5 mmol, 1.50 equiv.), BmNBr

(361 mg, 1.1 mmol, 0.02 equiv.). The resulting solution was stirred for 48 h at 70 °C. The reaction progress was monitored by GCMS. The reaction mixture was cooled. The resulting solution was extracted with 3 x 200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 10.12g of 1 -(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carbonitrile as brown oil.

Step 6

[00162] l-(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l-carboxylic acid: To a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carbonitrile (10.12 g, 45.38 mmol, 1.00 equiv), 6 N NaOH (61 mL) and EtOH (60 mL). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled and the pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol/L) until LCMS indicated the completion of the reaction. The solids were collected by filtration to afford 9.68 g (88%) of l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxylic acid as a light yellow solid.

Step 7

[00163] l-(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l-carbonyl chloride; To a solution of l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxylic acid (687 mg, 2.84 mmol, 1.00 equiv.) in toluene (5 mL) was added thionyl chloride (1.67 g, 5.00 equiv.). The resulting solution was stirred for 3h at 65 °C. The reaction mixture was cooled and concentrated under vacuum to afford 738 mg (99%) of l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carbonyl chloride as a yellow solid.

Step 8

9 STEP 8 10

2-methyl-4-(trimethylsilyl)but-3-vn-2-ol: To a solution of ethynyltrimethylsilane (20 g, 203.63 mmol, 1.00 equiv) in THF (100 mL) was added n-BuLi (81 mL, 2.5M in THF)

dropwise with stirring at -78 °C. Then the resulting mixture was warmed to 0 °C for 1 h with stirring and then cooled to -78 °C. Propan-2-one (11.6 g, 199.73 mmol, 1.00 equiv.) was added dropwise with the inert temperature below -78 °C. The resulting solution was stirred at -78 °C for 3 h. The reaction was then quenched by the addition of 100 mL of water and extracted with 3 x 100 mL of MTBE. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 28 g (90%) of 2-methyl-4-(trimethylsilyl)but-3-yn-2-ol as an off-white solid. ¾ NMR (400 MHz, CDCh) δ: 1.50 (s, 6H), 1.16-1.14 (m, 9H).

Step 9

step 9

10

(3-chloro-3-methylbut-l-vnvntrimethylsilane: To a lOOmL round-bottom flask, was placed 2-methyl-4-(trimethylsilyl) but-3-yn-2-ol (14 g, 89.57 mmol, 1.00 equiv.), cone. HC1 (60 mL, 6.00 equiv.). The resulting solution was stirred for 16 h at 0 °C. The resulting solution was extracted with 3 x 100 mL of hexane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 8 g (51%) of (3-chloro-3-methylbut-l-yn-l-yl)trimethylsilane as light yellow oil. ¾ NMR (400 MHz, CDCh) δ: 1.84 (s, 6H), 1.18-1.16 (m, 9H).

Step 10

step 10

11 12

(4-(benzyloxy)-3.3-dimethylbut-l-vnyl)trimethylsilane: Magnesium turnings (1.32 g, 1.20 equiv) were charged to a 250-mL 3-necked round-bottom flask and then suspended in THF (50 mL). The resulting mixture was cooled to 0 °C and maintained with an inert atmosphere of nitrogen. (3-chloro-3-methylbut-l-yn-l-yl)trimethylsilane (8 g, 45.78 mmol, 1.00 equiv.) was dissolved in THF (50 mL) and then added dropwise to this mixture with the inert temperature between 33-37 °C. The resulting solution was stirred at room temperature for an addition 1 h before BnOCH2Cl (6.45 g, 41.33 mmol, 0.90 equiv.) was added dropwise with the temperature below 10 °C. Then the resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 50 mL of water and extracted with 3 x 100 mL of hexane. The combined organic layers was dried over

anhydrous sodium sulfate and concentrated under vacuum to afford 10 g (84%) of [4-(benzyloxy)-3,3-dimethylbut-l-yn-l-yl]trimethylsilane as light yellow oil. ¾ NMR (400 MHz, CDCh) δ: 7.37-7.35 (m, 5H), 4.62 (s, 2H), 3.34 (s, 2H), 1.24 (s, 6H), 0.17-0.14 (m, 9H).

Step 11

((2.2-dimethylbut-3-vnyloxy)methyl)benzene: To a solution of [4-(benzyloxy)-3,3-dimethylbut-l-yn-l-yl]trimethylsilane (10 g, 38.40 mmol, 1.00 equiv) in methanol (100 mL) was added potassium hydroxide (2.53 g, 38.33 mmol, 1.30 equiv). The resulting solution was stirred for 16 h at room temperature. The resulting solution was diluted with 200 mL of water and extracted with 3 x 100 mL of hexane. The organic layers combined and washed with 1 x 100 mL of water and then dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5 g (69%) of [[(2,2-dimethylbut-3-yn-l-yl)oxy]methyl]benzene as light yellow oil. ¾ NMR (300 MHz, D20) δ: 7.41-7.28 (m, 5H) , 4.62 (s, 2H), 3.34 (s, 2H), 2.14 (s, 1H), 1.32-1.23 (m, 9H).

Step 12

14 15

methyl 2.2-difluorobenzo[d1[1.31dioxole-5-carboxylate: To a solution of 3-fluoro-4-nitroaniline (6.5 g, 41.64 mmol, 1.00 equiv) in chloroform (25 mL) and AcOH (80 mL) was added Bn (6.58 g, 41.17 mmol, 1.00 equiv.) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 150 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10 %). The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 2 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from PE/EA (10: 1) to afford 6 g (61%) of 2-bromo-5-fluoro-4-nitroaniline as a yellow solid.

Step 13

(R)-l-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol: 2-bromo-5-fluoro-4-nitroaniline (6.00 g, 25.56 mmol, 1.00 equiv.), Zn(C104)2 (1.90 g, 5.1 mmol, 0.20 equiv.), 4A Molecular Sieves (3 g), toluene (60 mL) was stirred at room temperature for 2 h and maintain with an inert atmosphere of N2 until (2R)-2-[(benzyloxy)methyl]oxirane (1.37 g, 8.34 mmol, 2.00 equiv.) was added. Then the resulting mixture was stirred for 15 h at 85 °C. The reaction progress was monitored by LCMS. The solids were filtered out and the resulting solution was diluted with 20 mL of ethyl acetate. The resulting mixture was washed with 2 x 20 mL of Sat. NH4CI and 1 x 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (1 :5) to afford 7.5 g (70%) of N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-bromo-5-fluoro-4-nitroaniline as a yellow solid.

Step 14

[00170] (R)-l-(4-amino-2-bromo-5-fluorophenylamino)-3-(benzyloxy)propan-2-ol: To a 250-mL round-bottom flask, was placed N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-bromo-5-fluoro-4-nitroaniline (7.5 g, 18.84 mmol, 1.00 equiv.), ethanol (80 mL), water (16 mL), NH4CI (10 g, 189 mmol, 10.00 equiv.), Zn (6.11 g, 18.84 mmol, 5.00 equiv.). The resulting solution was stirred for 4 h at 85 °C. The solids were filtered out and the resulting solution was concentrated under vacuum and diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 1 x 50 mL of water and 2 x 50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (1 :3) to afford 4.16 g (60%) of l-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-bromo-5-fluorobenzene-l ,4-diamine as light yellow oil.

Step 15

TsO

(R)-4-(3-(benzyloxy)-2-hvdroxypropylamino)-5-bromo-2-fluorobenzenaminium 4-methylbenzenesulfonate: l-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-bromo-5-fluorobenzene-l ,4-diamine (2 g, 5.42 mmol, 1.00 equiv.) was dissolved in dichloromethane (40 mL) followed by the addition of TsOH (1 g, 5.81 mmol, 1.10 equiv.). The resulting mixture was stirred for 16 h at room temperature and then concentrated under vacuum to afford 2.8 g (95%) of 4-[[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino]-5-bromo-2-fluoroanilinium 4-methylbenzene-l -sulfonate as an off-white solid.

Step 16

(R)-l-(4-amino-2-(4-(benzyloxy)-3.3-dimethylbut-l-vnyl)-5-fluorophenylamino)-3-(benzyloxy)propan-2-ol: To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino]-5-bromo-2-fluoroanilinium 4-methylbenzene-l -sulfonate (2.9 g, 5.36 mmol, 1.00 equiv.), [[(2,2-dimethylbut-3-yn-l-yl)oxy]methyl]benzene (1.2 g, 6.37 mmol, 1.20 equiv.), Pd(OAc)2 (48 mg, 0.21 mmol, 0.04 equiv.), dppb (138 mg, 0.32 mmol, 0.06 equiv.), potassium carbonate (2.2 g, 15.92 mmol, 3.00 equiv.) and MeCN (50 mL). The resulting solution was stirred for 16 h at 80 °C. The solids were filtered out and the resulting mixture was concentrated under vacuum until LCMS indicated the completion of the reaction. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (1 :4) to afford 2.2 g (86%) of l-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[4-(benzyloxy)-3,3-dimethylbut-l-yn-l-yl]-5-fluorobenzene-l ,4-diamine as a light brown solid.

Step 17

l-(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l-carboxylic acid: To a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 1-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[4-(benzyloxy)-3,3-dimethylbut-l-yn-l-yl]-5-fluorobenzene-l,4-diamine (1 g, 2.1 mmol, 1.00 equiv.), MeCN (10 mL), Pd(MeCN)2Cl2 (82 mg, 0.32 mmol, 0.15 equiv.). The resulting solution was stirred for 12 h at 85 °C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum to afford 900 mg (crude) of (2R)-l-[5-amino-2-[l-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-lH-indol-l-yl]-3-(benzyloxy)propan-2-ol as a brown solid, which was used for next step without further purification.

Step 18

(R)-N-(l-(3-(benzyloxy)-2-hvdroxypropyl)-2-(l-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro- lH-indol-5-yl)- 1 -(2.2-difluorobenzo[dl [ 1.31 dioxol-5-vDcvclopropanecarboxamide: To a 40 mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (2R)-l-[5-amino-2-[l-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-lH-indol-l-yl]-3-(benzyloxy)propan-2-ol (800 mg, 1.68 mmol, 1.00 equiv.), dichloromethane (20 mL), TEA (508 mg, 5.04 mmol, 3.00 equiv.). l-(2,2-difiuoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carbonyl chloride (524 mg, 2 mmol, 1.20 equiv.) was added to this mixture at 0 °C. The resulting solution was stirred for 2 h at 25 °C. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of DCM and washed with 3 xlO mL of brine. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (1:5) to afford 400 mg (30%) of N-[l-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[l-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-lH-indol-5-yl]-l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxamide as a light yellow solid.

Step 19

(R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide: To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of H2, were placed N-[l-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-[l-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-lH-indol-5-yl]-l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxamide (400 mg, 0.77 mmol, 1.00 equiv.) dry Pd/C (300 mg) and MeOH (5 Ml, 6M HC1). The resulting mixture was stirred at room temperature for 2 h until LCMS indicated the completion of the reaction. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column 19 x 150 mm, 5um; mobile phase and Gradient, Phase A: Waters (0.1%FA ), Phase B: ACN; Detector, UV 254 nm to afford 126.1 mg (42.4%) of (R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide as a light yellow solid.

¾ NMR (400 MHz, OMSO-de) δ: 8.32 (s, 1H), 7.54 (s, 1H), 7.41-7.38 (m, 2H), 7.34-7.31 (m, 2H), 6.22 (s, 1H), 5.03-5.02 (m, 1H), 4.93-4.90 (m, 1H), 4.77-4.75 (m, 1H), 4.42-4.39 (m, 1H), 4.14-4.08 (m, 1H), 3.91 (brs, 1H) , 3.64-3.57 (m, 2H), 3.47-3.40 (m, 2H), 1.48-1.46 (m, 2H), 1.36-1.32 (m, 6H), 1.14-1.12 (m, 2H).

LCMS: m/z = 521.2[M+H]+.

PATENT

WO 2015160787

https://www.google.com/patents/WO2015160787A1?cl=en

PATENT

WO 2014014841

https://www.google.com/patents/WO2014014841A1?cl=en

All tautomeric forms of the Compound 1 are included herein. For example, Compound 1 may exist as tautomers, both of which are included herein:

Figure imgf000026_0001

Methods of Preparing Compound 1 Amorphous Form and Compound 1 Form A

Compound 1 is the starting point and in one embodiment can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 1-4.

Scheme 1. Synthesis of the acid chloride moiety.

Figure imgf000037_0001

Toluene, H20, 70 °C

Figure imgf000037_0002

Bu4NBr

1. NaOH

2. HC1

Figure imgf000037_0003

Scheme 2. Synthesis of acid chloride moiety – alternative synthesis.

Figure imgf000038_0001

1. NaCN

2. H20

Figure imgf000038_0002

SOC1,

Figure imgf000038_0003

Scheme 3. Synthesis of the amine moiety.

Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000039_0003

Scheme 4. Formation of Compound 1.

Figure imgf000040_0001

Compound 1

Methods of Preparing Compound 1 Amorphous Form

Starting from Compound 1 , or even a crystalline form of Compound 1 , Compound 1 Amorphous Form may be prepared by rotary evaporation or by spray dry methods.

Dissolving Compound 1 in an appropriate solvent like methanol and rotary evaporating the methanol to leave a foam produces Compound 1 Amorphous Form. In some embodiments, a warm water bath is used to expedite the evaporation.

Compound 1 Amorphous Form may also be prepared from Compound 1 using spray dry methods. Spray drying is a process that converts a liquid feed to a dried particulate form. Optionally, a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus. In a standard procedure, the preparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g. a cyclone). The spent air is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent. Commercially available types of apparatus may be used to conduct the spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. And Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820; US 2003/0144257).

Spray drying typically employs solid loads of material from about 3% to about 30% by weight, (i.e., drug and excipients), for example about 4% to about 20% by weight, preferably at least about 10%. In general, the upper limit of solid loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particle in the resulting powder product.

Techniques and methods for spray drying may be found in Perry’s Chemical

Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds.), McGraw-Hill book co. (1984); and Marshall “Atomization and Spray-Drying” 50, Chem. Eng. Prog. Monogr. Series 2 (1954). In general, the spray drying is conducted with an inlet temperature of from about 60 °C to about 200 °C, for example, from about 95 °C to about 185 °C, from about 110 °C to about 182 °C, from about 96 °C to about 180 °C, e.g., about 145 °C. The spray drying is generally conducted with an outlet temperature of from about 30 °C to about 90 °C, for example from about 40 °C to about 80 °C, about 45 °C to about 80 °C e.g., about 75 °C. The atomization flow rate is generally from about 4 kg h to about 12 kg/h, for example, from about 4.3 kg/h to about 10.5 kg h, e.g., about 6 kg/h or about 10.5 kg/h. The feed flow rate is generally from about 3 kg/h to about 10 kg/h, for example, from about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1 kg/h. The atomization ratio is generally from about 0.3 to 1.7, e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5.

Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C).

Synthesis of Compound 1

Acid Chloride Moiety

Synthesis of (2,2-difluoro-l,3-benzodioxol-5-yl)-l-ethylacetate-acetonitrile

Figure imgf000083_0001

ouene, 2 , CN

A reactor was purged with nitrogen and charged with 900 mL of toluene. The solvent was degassed via nitrogen sparge for no less than 16 h. To the reactor was then charged Na3P04 (155.7 g, 949.5 mmol), followed by bis(dibenzylideneacetone) palladium (0) (7.28 g, 12.66 mmol). A 10% w/w solution of tert-butylphosphine in hexanes (51.23 g, 25.32 mmol) was charged over 10 min at 23 °C from a nitrogen purged addition funnel. The mixture was allowed to stir for 50 min, at which time 5-bromo-2,2-difluoro-l,3-benzodioxole (75 g, 316.5 mmol) was added over 1 min. After stirring for an additional 50 min, the mixture was charged with ethyl cyanoacetate (71.6 g, 633.0 mmol) over 5 min followed by water (4.5 mL) in one portion. The mixture was heated to 70 °C over 40 min and analyzed by HPLC every 1 – 2 h for the percent conversion of the reactant to the product. After complete conversion was observed (typically 100% conversion after 5 – 8 h), the mixture was cooled to 20 – 25 °C and filtered through a celite pad. The celite pad was rinsed with toluene (2 X 450 mL) and the combined organics were concentrated to 300 mL under vacuum at 60 – 65 °C. The concentrate was charged with 225mL DMSO and concentrated under vacuum at 70 – 80 °C until active distillation of the solvent ceased. The solution was cooled to 20 – 25 °C and diluted to 900 mL with DMSO in preparation for Step 2. Ή NMR (500 MHz, CDC13) δ 7.16 – 7.10 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 4.63 (s, 1H), 4.19 (m, 2H), 1.23 (t, J= 7.1 Hz, 3H).

Synthesis of (2,2-difluoro-l^-benzodioxol-5-yl)-acetonitrile.

Figure imgf000084_0001

[00311] The DMSO solution of (2,2-difluoro-l,3-benzodioxol-5-yl)-l-ethylacetate-acetonitrile from above was charged with 3 N HCl (617.3 mL, 1.85 mol) over 20 min while maintaining an internal temperature < 40 °C. The mixture was then heated to 75°C over 1 h and analyzed by HPLC every 1 – 2 h for % conversion. When a conversion of > 99% was observed (typically after 5 – 6 h), the reaction was cooled to 20 – 25 °C and extracted with MTBE (2 X 525 mL), with sufficient time to allow for complete phase separation during the extractions. The combined organic extracts were washed with 5% NaCl (2 X 375 mL). The solution was then transferred to equipment appropriate for a 1.5 – 2.5 Torr vacuum distillation that was equipped with a cooled receiver flask. The solution was concentrated under vacuum at < 60°C to remove the solvents. (2,2-Difluoro-l,3-benzodioxol-5-yl)-acetonitrile was then distilled from the resulting oil at 125 – 130 °C (oven temperature) and 1.5 – 2.0 Torr. (2,2-Difluoro-l,3- benzodioxol-5-yl)-acetonitrile was isolated as a clear oil in 66% yield from 5-bromo-2,2- difluoro-l,3-benzodioxole (2 steps) and with an HPLC purity of 91.5% AUC (corresponds to a w/w assay of 95%). Ή NMR (500 MHz, DMSO) 6 7.44 (br s, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.22 (dd, J= 8.2, 1.8 Hz, 1H), 4.07 (s, 2H).  Synthesis of (2,2-difluoro- l,3-benzodioxol-5-yl)-cycIopropanecarbonitrUe.

Figure imgf000085_0001

MTBE

A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-l,3- benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0 °C was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by l-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a % conversion > 99 % was observed (typically after 2.5 – 3 h), the reaction mixture was cooled to 10 °C and was charged with water (461 mL) at such a rate as to maintain a temperature < 25 °C. The temperature was adjusted to 20 – 25 °C and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HC1 (163mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro- 1,3 -benzodioxol-5-yl)- cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40 – 50 °C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50 – 60 °C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50 – 60 °C. The resulting mixture was cooled to 20 – 25 °C and diluted with ethanol to 266 mL in preparation for the next step. lH NMR (500 MHz, DMSO) 6 7.43 (d, J= 8.4 Hz, 1H), 7.40 (d, J= 1.9 Hz, 1H), 7.30 (dd, J= 8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H). [00314] Synthesis of l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid.

Figure imgf000086_0001

The solution of (2,2-difluoro-l ,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6 N NaOH (277 mL) over 20 min and heated to an internal temperature of 77 – 78 °C over 45 min. The reaction progress was monitored by HPLC after 16 h. Note: the consumption of both (2,2-difluoro-l,3-benzodioxol-5-yl)- cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2-difluoro- l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a % conversion > 99 % was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25 °C and charged with ethanol (41 mL) and DCM (164 mL). The solution was cooled to 10 °C and charged with 6 N HC1 (290 mL) at such a rate as to maintain a temperature < 25 °C. After warming to 20 – 25 °C, the phases were allowed to separate. The bottom organic phase was collected and the top aqueous phase was back extracted with DCM (164 mL). Note: the aqueous phase was somewhat cloudy before and after the extraction due to a high concentration of inorganic salts. The organics were combined and concentrated under vacuum to 164 mL. Toluene (328 mL) was charged and the mixture condensed to 164 mL at 70 – 75 °C. The mixture was cooled to 45 °C, charged with MTBE (364 mL) and stirred at 60 °C for 20 min. The solution was cooled to 25 °C and polish filtered to remove residual inorganic salts. MTBE (123 mL) was used to rinse the reactor and the collected solids. The combined organics were transferred to a clean reactor in preparation for the next step.

Isolation of l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecar boxy lie acid.

Figure imgf000086_0002

The solution of l-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid from the previous step is concentrated under vacuum to 164 mL, charged with toluene (328 mL) and concentrated to 164 mL at 70 – 75 °C. The mixture was then heated to 100 – 105 °C to give a homogeneous solution. After stirring at that temperature for 30 min, the solution was cooled to 5 °C over 2 hours and maintained at 5 °C for 3 hours. The mixture was then filtered and the reactor and collected solid washed with cold 1 :1 toluene/n-heptane (2 X 123 mL). The material was dried under vacuum at 55 °C for 17 hours to provide l-(2,2-difluoro-l,3-benzodioxol-5-yl)- cyclopropanecarboxylic acid as an off-white crystalline solid. l-(2,2-difluoro-l,3-benzodioxol- 5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-l,3- benzodioxol-5-yl)-acetonitrile (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS m/z calc. 242.04, found 241.58 (M+l)+; Ή NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.17 (dd, J= 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H).

Alternative Synthesis of the Acid Chloride Moiety [00319] Synthesis of (2,2-ditluoro-l,3-benzodioxol-5-yl)-methanol.

1. Vitride (2 equiv)

PhCH3 (10 vol)

Figure imgf000087_0001

[00320] Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 °C. At the end of addition the temperature is increased to 40 °C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 °C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 °C. The organic phase is cooled to 20 °C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-l,3-benzodioxol-5-yl)-methanol that is used directly in the next step.

Synthesis of 5-chloromethyl-2,2-difluoro-l,3-benzodioxole.

1. SOCl2 (1.5 equiv)

DMAP (0.01 equiv)

Figure imgf000087_0002

(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-methanol ( 1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and S0C12 (1.2 eq) is added via addition funnel. The S0C12 is added at a rate to maintain the temperature in the reactor at 15-25 °C. The temperature is increased to 30 °C for 1 hour then cooled to 20 °C then water (4 vol) is added via addition funnel maintaining the temperature at less than 30 °C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO_ , filtered, and concentrated to afford crude 5-chloromethyl- 2,2-difluoro-l,3-benzodioxole that is used directly in the next step.

Synthesis of (2,2-difluoro-l,3-benzodioxol-5-yl)-acetonitrile.

Figure imgf000088_0001

A solution of 5-chloromethyl-2,2-difluoro- 1 ,3-benzodioxole ( 1 eq) in DMSO ( 1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1,8 vol), dried (Na2S04), filtered, and concentrated to afford crude (2,2-difluoro-l,3-benzodioxol-5-yl)-acetonitrile (95%) that is used directly in the next step.

The remaining steps are the same as described above for the synthesis of the acid moiety.

Amine Moiety

Synthesis of 2-bromo-5-fluoro-4-ntroaniline.

Figure imgf000088_0002
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50 °C overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di- bromo adduct (1.1% AUC). Ή NMR (500 MHz, DMSO) δ 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).

Synthesis of benzyIglycoIated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt.

1) l ^OBn

cat. Zn(C104)2-2H20 ®

Figure imgf000089_0001

DCM

A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wt% based on 2-bromo-5-fluoro-4-nitroaniline), 2-Bromo-5- fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol%), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80 °C (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4-nitroaniline was <5%AUC.

The reaction was cooled to room temperature and Celite (50 wt%) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20% w/v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5% w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator.

The hydrogenator was charged with 5wt% Pt(S)/C (1.5 mol%) and the mixture was stirred under N2 at 30 °C (internal temperature). The reaction was flushed with N2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness.

The resulting residue was dissolved in dichloromethane (10 vol). jP-Toluenesulfonic acid monohydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to drying trays and into a vacuum oven and dried at 45 °C with N2 bleed until constant weight was achieved. Benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt was isolated as an off-white solid.

Chiral purity was determined to be >97%ee.

[00334] Synthesis of (3-Chloro-3-methylbut-l-ynyl)trimethylsilane.

Figure imgf000090_0001

[00335] Propargyl alcohol (1.0 equiv) was charged to a vessel. Aqueous hydrochloric acid (37%, 3.75 vol) was added and stirring begun. During dissolution of the solid alcohol, a modest endotherm (5-6 °C) is observed. The resulting mixture was stirred overnight (16 h), slowly becoming dark red. A 30 L jacketed vessel is charged with water (5 vol) which is then cooled to 10 °C. The reaction mixture is transferred slowly into the water by vacuum, maintaining the internal temperature of the mixture below 25 °C. Hexanes (3 vol) is added and the resulting mixture is stirred for 0.5 h. The phases were settled and the aqueous phase (pH < 1) was drained off and discarded. The organic phase was concentrated in vacuo using a rotary evaporator, furnishing the product as red oil. [00336] Synthesis of (4-(Benzyloxy)-3,3-dimethylbut-l-yttyl)trimethylsiIane.

Figure imgf000091_0001

[00337] Method A

[00338] All equivalent and volume descriptors in this part are based on a 250g reaction.

Magnesium turnings (69.5 g, 2.86 mol, 2.0 equiv) were charged to a 3 L 4-neck reactor and stirred with a magnetic stirrer under nitrogen for 0.5 h. The reactor was immersed in an ice- water bath. A solution of the propargyl chloride (250 g, 1.43 mol, 1.0 equiv) in THF (1.8 L, 7.2 vol) was added slowly to the reactor, with stirring, until an initial exotherm (-10 °C) was observed. The Grignard reagent formation was confirmed by IPC usingΉ-NMR spectroscopy. Once the exotherm subsided, the remainder of the solution was added slowly, maintaining the batch temperature <15 °C. The addition required ~3.5 h. The resulting dark green mixture was decanted into a 2 L capped bottle.

[00339] All equivalent and volume descriptors in this part are based on a 500g reaction. A 22 L reactor was charged with a solution of benzyl chloromethyl ether (95%, 375 g, 2.31 mol, 0.8 equiv) in THF (1.5 L, 3 vol). The reactor was cooled in an ice-water bath. Two Grignard reagent batches prepared as described above were combined and then added slowly to the benzyl chloromethyl ether solution via an addition funnel, maintaining the batch temperature below 25 °C. The addition required 1.5 h. The reaction mixture was stirred overnight (16 h).

[00340] All equivalent and volume descriptors in this part are based on a 1 kg reaction. A solution of 15%» ammonium chloride was prepared in a 30 L jacketed reactor (1.5 kg in 8.5 kg of water, 10 vol). The solution was cooled to 5 °C. Two Grignard reaction mixtures prepared as described above were combined and then transferred into the ammonium chloride solution via a header vessel. An exotherm was observed in this quench, which was carried out at a rate such as to keep the internal temperature below 25 °C. Once the transfer was complete, the vessel jacket temperature was set to 25 °C. Hexanes (8 L, 8 vol) was added and the mixture was stirred for 0.5 h. After settling the phases, the aqueous phase (pH 9) was drained off and discarded. The remaining organic phase was washed with water (2 L, 2 vol). The organic phase was concentrated in vacuo using a 22 L rotary evaporator, providing the crude product as an orange oil.

[00341] Method B

[00342] Magnesium turnings (106 g, 4.35 mol, 1.0 eq) were charged to a 22 L reactor and then suspended in THF (760 mL, 1 vol). The vessel was cooled in an ice-water bath such that the batch temperature reached 2 °C. A solution of the propargyl chloride (760 g, 4.35 mol, 1.0 equiv) in THF (4.5 L, 6 vol) was added slowly to the reactor. After 100 mL was added, the addition was stopped and the mixture stirred until a 13 °C exotherm was observed, indicating the Grignard reagent initiation. Once the exotherm subsided, another 500 mL of the propargyl chloride solution was added slowly, maintaining the batch temperature <20 °C. The Grignard reagent formation was confirmed by IPC using Ή-NMR spectroscopy. The remainder of the propargyl chloride solution was added slowly, maintaining the batch temperature <20 °C. The addition required -1.5 h. The resulting dark green solution was stirred for 0.5 h. The Grignard reagent formation was confirmed by IPC using Ή-NMR spectroscopy. Neat benzyl

chloromethyl ether was charged to the reactor addition funnel and then added dropwise into the reactor, maintaining the batch temperature below 25 °C. The addition required 1.0 h. The reaction mixture was stirred overnight. The aqueous work-up and concentration was carried out using the same procedure and relative amounts of materials as in Method A to give the product as an orange oil.

[00343] Syntheisis of 4-Benzyloxy-3,3-dimethylbut-l-yne.

Figure imgf000092_0001

2 steps

[00344] A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5 °C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20 °C exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25 °C. A solution of 4-benzyloxy-3,3-dimethyl-l-trimethylsilylbut-l-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25 °C is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. Ή NMR (400 MHz, C6D6) δ 7.28 (d, 2 H, J = 7.4 Hz), 7.18 (t, 2 H, J= 7.2 Hz), 7.10 (d, 1H, J= 7.2 Hz), 4.35 (s, 2 H), 3.24 (s, 2 H), 1.91 (s, 1 H), 1.25 (s, 6 H).

[00345] Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-l,l-dimethylethyl)-6- fluoroindole.

[00346] Method A

[00347] Synthesis of Benzylglycolated 4-Amino-2-(4-benzyloxy-3,3-dimethyIbut- l-ynyl)-5- fluoroaniline.

Figure imgf000093_0001

[00348] Benzylglycolated 4-ammonium-2-bromo-5-flouroaniline tosylate salt was freebased by stirring the solid in EtOAc (5 vol) and saturated NaHCC>3 solution (5 vol) until clear organic layer was achieved. The resulting layers were separated and the organic layer was washed with saturated NaHC03 solution (5 vol) followed by brine and concentrated in vacuo to obtain benzylglocolated 4-ammonium-2-bromo-5-flouroaniline tosylate salt as an oil.

[00349] Then, a flask was charged with benzylglycolated 4-ammonium-2-bromo-5- flouroaniline tosylate salt (freebase, 1.0 equiv), Pd(OAc) (4.0 mol%), dppb (6.0 mol%) and powdered K2CO3 (3.0 equiv) and stirred with acetonitrile (6 vol) at room temperature. The resulting reaction mixture was degassed for approximately 30 min by bubbling in N2 with vent. Then 4-benzyloxy-3,3-dimethylbut-l-yne (1.1 equiv) dissolved in acetonitrile (2 vol) was added in a fast stream and heated to 80 °C and stirred until complete consumption of 4-ammonium-2- bromo-5-flouroaniline tosylate salt was achieved. The reaction slurry was cooled to room temperature and filtered through a pad of Celite and washed with acetonitrile (2 vol). Filtrate was concentrated in vacuo and the residue was redissolved in EtOAc (6 vol). The organic layer was washed twice with NH4CI solution (20% w/v, 4 vol) and brine (6 vol). The resulting organic layer was concentrated to yield brown oil and used as is in the next reaction.

[00350] Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-l,l-dimethylethyl)-6- fluoroindole.

Figure imgf000094_0001

[00351] Crude oil of benzylglycolated 4-amino-2-(4-benzyloxy-3,3-dimethylbut-l-ynyl)-5- fluoroaniline was dissolved in acetonitrile (6 vol) and added (MeCN)2PdCl2 (15 mol%) at room temperature. The resulting mixture was degassed using N2 with vent for approximately 30 min. Then the reaction mixture was stirred at 80 °C under N2 blanket overnight. The reaction mixture was cooled to room temperature and filtered through a pad of Celite and washed the cake with acetonitrile (1 vol). The resulting filtrate was concentrated in vacuo and redissolved in EtOAc (5 vol). Deloxane-II THP (5 wt% based on the theoretical yield of N-benzylglycolated-5-amino-2- (2-benzyloxy-l,l-dimethylethyl)-6-fluoroindole) was added and stirred at room temperature overnight. The mixture was then filtered through a pad of silica (2.5 inch depth, 6 inch diameter filter) and washed with EtOAc (4 vol). The filtrate was concentrated down to a dark brown residue, and used as is in the next reaction.

[00352] Repurification of crude N-benzylglycolated-5-amino-2-(2-benzyloxy- 1,1- dimethylethyl)-6-fluoroindole:

[00353] The crude N-benzylglycolated-5-amino-2-(2-benzyloxy- 1 , l-dimethylethyl)-6- fluoroindole was dissolved in dichloromethane (~1.5 vol) and filtered through a pad of silica initially using 30% EtOAc/heptane where impurities were discarded. Then the silica pad was washed with 50% EtO Ac/heptane to isolate N-benzylglycolated-5-amino-2-(2-benzyloxy-l,l- dimethylethyl)-6-fluoroindole until faint color was observed in the filtrate. This filtrate was concentrated in vacuo to afford brown oil which crystallized on standing at room temperature. Ή NMR (400 MHz, DMSO) 6 7.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J= 12.8 Hz), 6.77 (d, 1H, J= 9.0 Hz), 6.06 (s, 1 H), 5.13 (d, 1H, J = 4.9 Hz), 4.54 (s, 2 H), 4.46 (br. s, 2 H), 4.45 (s, 2 H), 4.33 (d, 1 H, J= 12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J= 9.2 Hz), 3.56 (d, 1H, J= 9.2 Hz), 3.49 (dd, 1H, J= 9.8, 4.4 Hz), 3.43 (dd, 1H, J= 9.8, 5.7 Hz), 1.40 (s, 6 H).

[00354] Synthesis of N-benzyIglycolated-5-amino-2-(2-benzyIoxy-l,l-diniethylethyl)-6- fluoroindole.

[00355] Method B

Figure imgf000095_0001

2. (MeCN)2PdCl2

MeCN, 80 <€

3. Silica gel filtration

[00356] Palladium acetate (33 g, 0.04 eq), dppb (94 g, 0.06 eq), and potassium carbonate (1.5 kg, 3.0 eq) are charged to a reactor. The free based oil benzylglocolated 4-ammonium-2-bromo- 5-flouroaniline (1.5 kg, 1.0 eq) was dissolved in acetonitrile (8.2 L, 4.1 vol) and then added to the reactor. The mixture was sparged with nitrogen gas for NLT 1 h. A solution of 4-benzyloxy- 3,3-dimethylbut-l-yne (70%), 1.1 kg, 1.05 eq) in acetonitrile was added to the mixture which was then sparged with nitrogen gas for NLT 1 h. The mixture was heated to 80 °C and then stirred overnight. IPC by HPLC is carried out and the reaction is determined to be complete after 16 h. The mixture was cooled to ambient temperature and then filtered through a pad of Celite (228 g). The reactor and Celite pad were washed with acetonitrile (2 x 2 L, 2 vol). The combined phases are concentrated on a 22 L rotary evaporator until 8 L of solvent have been collected, leaving the crude product in 7 L (3.5 vol) of acetonitrile. [00357] 5 s-acetonitriledichloropalladium ( 144 g, 0.15 eq) was charged to the reactor. The crude solution was transferred back into the reactor and the roto-vap bulb was washed with acetonitrile (4 L, 2 vol). The combined solutions were sparged with nitrogen gas for NLT 1 h. The reaction mixture was heated to 80 °C for NLT 16 h. In process control by HPLC shows complete consumption of starting material. The reaction mixture was filtered through Celite (300 g). The reactor and filter cake were washed with acetonitrile (3 L, 1.5 vol). The combined filtrates were concentrated to an oil by rotary evaporation. The oil was dissolved in ethyl acetate (8.8 L, 4.4 vol). The solution was washed with 20% ammonium chloride (5 L, 2.5 vol) followed by 5% brine (5 L, 2.5 vol). Silica gel (3.5 kg, 1.8 wt. eq.) of silica gel was added to the organic phase, which was stirred overnight. Deloxan THP II metal scavenger (358 g) and heptane (17.6 L) were added and the resulting mixture was stirred for NLT 3 h. The mixture was filtered through a sintered glass funnel. The filter cake was washed with 30% ethyl acetate in heptane (25 L). The combined filtrates were concentrated under reduced pressure to give N- benzylglycolated-5-amino-2-(2-benzyloxy-l,l-dimethylethyl)-6-fluoroindole as a brown paste ( 1.4 kgl.Svnthesis of Compound 1

[00358] Synthesis of benzyl protected Compound 1.

Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000096_0003

[00359] 1 -(2,2-difluoro- 1 ,3 -benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on l-(2,2-difluoro-l,3-benzodioxol-5-yi)- cyclopropanecarboxylic acid) and the mixture was heated to 60 °C. SOCl2 (1.7 equiv) was added via addition runnel. The resulting mixture was stirred for 2 hr. The toluene and the excess

SOCI2 were distilled off using rotavop. Additional toluene (2.5 vol, based on l-(2,2-difluoro- l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-l,l-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3 °C (internal temperature). The resulting mixture was stirred at 0 °C for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt% K2CO3 (4 vol x 2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected Compound 1 as a thick brown oil, which was purified further using silica pad filtration.

[00360] Silica gel pad filtration: Crude benzyl protected Compound 1 was dissolved in ethyl acetate (3 vol) in the presence of activated carbon Darco-G (10wt%, based on theoretical yield of benzyl protected Compound 1) and stirred at room temperature overnight. To this mixture was added heptane (3 vol) and filtered through a pad of silica gel (2x weight of crude benzyl protected Compound 1). The silica pad was washed with ethyl acetate/heptane (1:1, 6 vol) or until little color was detected in the filtrate. The filtrate was concentrated in vacuo to afford benzyl protected Compound 1 as viscous reddish brown oil, and used directly in the next step.

[00361] Repurification: Benzyl protected Compound 1 was redissolved in dichloromethane (1 vol, based on theoretical yield of benzyl protected Compound 1) and loaded onto a silica gel pad (2x weight of crude benzyl protected Compound 1). The silica pad was washed with

dichloromethane (2 vol, based on theoretical yield of benzyl protected Compound 1) and the filtrate was discarded. The silica pad was washed with 30% ethyl acetate/heptane (5 vol) and the filtrate was concentrated in vacuo to afford benzyl protected Compound 1 as viscous reddish orange oil, and used directly in the next step. [00362] Synthesis of Compound 1.

Figure imgf000098_0001

OBn 4 steps

Figure imgf000098_0002

[00363] Method A

[00364] A 20 L autoclave was flushed three times with nitrogen gas and then charged with palladium on carbon (Evonik E 101 NN/W, 5% Pd, 60% wet, 200 g, 0.075 mol, 0.04 equiv). The autoclave was then flushed with nitrogen three times. A solution of crude benzyl protected Compound 1 (1.3 kg, ~ 1.9 mol) in THF (8 L, 6 vol) was added to the autoclave via suction. The vessel was capped and then flushed three times with nitrogen gas. With gentle stirring, the vessel was flushed three times with hydrogen gas, evacuating to atmosphere by diluting with nitrogen. The autoclave was pressurized to 3 Bar with hydrogen and the agitation rate was increased to 800 rpm. Rapid hydrogen uptake was observed (dissolution). Once uptake subsided, the vessel was heated to 50 °C.

[00365] For safety purposes, the thermostat was shut off at the end of every work-day. The vessel was pressurized to 4 Bar with hydrogen and then isolated from the hydrogen tank.

[00366] After 2 full days of reaction, more Pd / C (60 g, 0.023 mol, 0.01 equiv) was added to the mixture. This was done by flushing three times with nitrogen gas and then adding the catalyst through the solids addition port. Resuming the reaction was done as before. After 4 full days, the reaction was deemed complete by HPLC by the disappearance of not only the starting material but also of the peak corresponding to a mono-benzylated intermediate. [00367] The reaction mixture was filtered through a Celite pad. The vessel and filter cake were washed with THF (2 L, 1.5 vol). The Celite pad was then wetted with water and the cake discarded appropriately. The combined filtrate and THF wash were concentrated using a rotary evaporator yielding the crude product as a black oil, 1 kg.

[00368] The equivalents and volumes in the following purification are based on 1 kg of crude material. The crude black oil was dissolved in 1 :1 ethyl acetate-heptane. The mixture was charged to a pad of silica gel (1.5 kg, 1.5 wt. equiv) in a fritted funnel that had been saturated with 1 :1 ethyl acetate-heptane. The silica pad was flushed first with 1 :1 ethyl acetate-heptane (6 L, 6 vol) and then with pure ethyl acetate (14 L, 14 vol). The eluent was collected in 4 fractions which were analyzed by HPLC.

[00369] The equivalents and volumes in the following purification are based on 0.6 kg of crude material. Fraction 3 was concentrated by rotary evaporation to give a brown foam (600 g) and then redissolved in MTBE (1.8 L, 3 vol). The dark brown solution was stirred overnight at ambient temperature, during which time, crystallization occurred. Heptane (55 mL, 0.1 vol) was added and the mixture was stirred overnight. The mixture was filtered using a Buchner funnel and the filter cake was washed with 3:1 MTBE-heptane (900 mL, 1.5 vol). The filter cake was air-dried for 1 h and then vacuum dried at ambient temperature for 16 h, furnishing 253 g of Compound 1 as an off-white solid.

[00370] The equivalents and volumes for the following purification are based on 1.4 kg of crude material. Fractions 2 and 3 from the above silica gel filtration as well as material from a previous reaction were combined and concentrated to give 1.4 kg of a black oil. The mixture was resubmitted to the silica gel filtration (1.5 kg of silica gel, eluted with 3.5 L, 2.3 vol of 1 :1 ethyl acetate-heptane then 9 L, 6 vol of pure ethyl acetate) described above, which upon concentration gave a tan foamy solid (390 g).

[00371] The equivalents and volumes for the following purification are based on 390 g of crude material. The tan solid was insoluble in MTBE, so was dissolved in methanol (1.2 L, 3 vol). Using a 4 L Morton reactor equipped with a long-path distillation head, the mixture was distilled down to 2 vol. MTBE (1.2 L, 3 vol) was added and the mixture was distilled back down to 2 vol. A second portion of MTBE (1.6 L, 4 vol) was added and the mixture was distilled back down to 2 vol. A third portion of MTBE (1.2 L, 3 vol) was added and the mixture was distilled back down to 3 vol. Analysis of the distillate by GC revealed it to consist of -6% methanol. The thermostat was set to 48 °C (below the boiling temp of the MTBE-methanol azeotrope, which is 52 °C). The mixture was cooled to 20 °C over 2 h, during which time a relatively fast crystallization occurred. After stirring the mixture for 2 h, heptane (20 mL, 0.05 vol) was added and the mixture was stirred overnight (16 h). The mixture was filtered using a Buchner funnel and the filter cake was washed with 3:1 MTBE-heptane (800 mL, 2 vol). The filter cake was air- dried for 1 h and then vacuum dried at ambient temperature for 16 h, furnishing 130 g of Compound 1 as an off-white solid.

[00372] Method B

[00373] Benzyl protected Compound 1 was dissolved in THF (3 vol) and then stripped to dryness to remove any residual solvent. Benzyl protected Compound 1 was redissolved in THF (4 vol) and added to the hydrogenator containing 5 wt% Pd/C (2.5 mol%, 60% wet, Degussa E5 El 01 N /W). The internal temperature of the reaction was adjusted to 50 °C, and flushed with N2 (x5) followed by hydrogen (x3). The hydrogenator pressure was adjusted to 3 Bar of hydrogen and the mixture was stirred rapidly (>1100 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with THF (1 vol). The filtrate was concentrated in vacuo to obtain a brown foamy residue. The resulting residue was dissolved in MTBE (5 vol) and 0.5N HC1 solution (2 vol) and distilled water (1 vol) were added. The mixture was stirred for NLT 30 min and the resulting layers were separated. The organic phase was washed with 10wt% K2CO3 solution (2 vol x2) followed by a brine wash. The organic layer was added to a flask containing silica gel (25 wt%), Deloxan-THP II (5wt%, 75% wet), and

Na2S04 and stirred overnight. The resulting mixture was filtered through a pad of Celite and washed with 10%THF/MTBE (3 vol). The filtrate was concentrated in vacuo to afford crude Compound 1 as pale tan foam.

[00374] Compound 1 recovery from the mother liquor: Option A.

[00375] Silica gel pad filtration: The mother liquor was concentrated in vacuo to obtain a brown foam, dissolved in dichloromethane (2 vol), and filtered through a pad of silica (3x weight of the crude Compound 1). The silica pad was washed with ethyl acetate/heptane (1 :1, 13 vol) and the filtrate was discarded. The silica pad was washed with 10% THF/ethyl acetate (10 vol) and the filtrate was coiicentraied in vacuo to afford Compound 1 as pale tan foam. The above crystallization procedure was followed to isolate the remaining Compound 1.

{00376] Compound 1 recovery from the mother liquor: Option B,

[00377] Silica gel column chromatography: After chromatography on silica gel (50% ethyl acetate/hexaties to 100% ethyl acetate), the desired compound was isolated as pale tan foam. The above crystallization procedure was followed to isolate the remaining Compound 1.

{003781 Additional Recrystaliization of Compound 1

[ 0379j Solid Compound 1 (135 kg) was suspended in IPA (5.4 L, 4 vol) and then heated to 82 °C. Upon complete dissolution (visual), heptane (540 mL, 0.4 vol) was added slowly. The mixture was cooled to 58 °C The mixture was then cooled slowly to 51 °C, during which time crystallization occurs. The heat source was shut down and the recrystalfeation mixture was allowed to cool naturally overnight. The mixture was filtered using a benchtop Buclmer funnel and the filter cake was washed with IPA (2.7 L, 2 vol). The filler cake was dried in the tunnel under air flow for 8 h and then was oven-dried in vacuo at 45-50 °C overnight to give 1.02 kg of recrystallized Compound 1 ,

100380] Compound 1 may also be prepared by one of several synthetic routes disclosed in US published patent application U S20090131 92, incorporated herein by reference.

{003811 Table 6 below recites analytical data for Compound 1.

Table 6.

Figure imgf000101_0001

 Synthesis of Compound 1 Amorphous Form [00383] Spray-Dried Method

[00384] 9.95g of Hydroxypropylmethylcellulose acetate succinate HG grade (HPMCAS-HG) was weighed into a 500 ml beaker, along with 50 mg of sodium lauryl sulfate (SLS). MeOH (200 ml) was mixed with the solid. The material was allowed to stir for 4 h. To insure maximum dissolution, after 2 h of stirring the solution was sonicated for 5 mins, then allowed to continue stirring for the remaining 2 h. A very fin suspension of HPMCAS remained in solution. However, visual observation determined that no gummy portions remained on the walls of the vessel or stuck to the bottom after tilting the vessel.

[00385] Compound 1 (1 Og) was poured into the 500 ml beaker, and the system was allowed to continue stirring. The solution was spray dried using the following parameters:

Formulation Description: Compound 1 Form A/HPMCAS/SLS (50/49.5/0.5)

Buchi Mini Spray Dryer

T inlet (setpoint) 145 °C

T outlet (start) 75 °C

T outlet (end) 55 °C

Nitrogen Pressure 75 psi

Aspirator 100 %

Pump 35 %

Rotometer 40 mm

Filter Pressure 65 mbar

Condenser Temp -3 °C

Run Time l h

REFERENCES

1: Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE, Hegedus T, Verkman AS, Lukacs GL. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med. 2014 Jul 23;6(246):246ra97. doi: 10.1126/scitranslmed.3008889. PubMed PMID: 25101887.

2: Pettit RS, Fellner C. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11. PubMed PMID: 25083129; PubMed Central PMCID: PMC4103577.

3: Norman P. Novel picolinamide-based cystic fibrosis transmembrane regulator modulators: evaluation of WO2013038373, WO2013038376, WO2013038381, WO2013038386 and WO2013038390. Expert Opin Ther Pat. 2014 Jul;24(7):829-37. doi: 10.1517/13543776.2014.876412. Epub 2014 Jan 7. PubMed PMID: 24392786.

//////TEZACAFTOR, VX 661, PHASE 3, 1152311-62-0, UNII: 8RW88Y506K,  deltaF508-CFTR corrector, Vertex,  treatment of cystic fibrosis in patients homozygous to the F508del-CFTR mutation

CC(C)(CO)C1=CC2=CC(=C(C=C2N1CC(CO)O)F)NC(=O)C3(CC3)C4=CC5=C(C=C4)OC(O5)(F)F

CC(C)(CO)c1cc2cc(c(cc2n1C[C@H](CO)O)F)NC(=O)C3(CC3)c4ccc5c(c4)OC(O5)(F)F

GS 9883, Bictegravir an HIV-1 integrase inhibitor


UNII-8GB79LOJ07.png

GS 9883, bictegravir

CAS 1611493-60-7

PHASE 3

HIV-1 integrase inhibitor

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluoroheoctahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide

MF  C21H18F3N3O5,

 MW 449.37993 g/mol

 UNII-8GB79LOJ07; 8GB79LOJ07

 

2D chemical structure of 1611493-60-7

BICTEGRAVIR

 

  • 16 Nov 2015 Phase-III clinical trials in HIV-1 infections (Combination therapy, Treatment-naive) in USA (PO) (Gilead Pipeline, November 2015)
  • 01 Jul 2015 Gilead Sciences completes a phase I trial in HIV-1 infections in USA and New Zealand (NCT02400307)
  • 01 Apr 2015 Phase-I clinical trials in HIV-1 infections (In volunteers) in New Zealand (PO) (NCT02400307)

UPDATE       Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide); Gilead; For the treatment of HIV-1 infection in adults, Approved February 2018

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV and that minimize PXR activation when co-administered with other drugs.

Certain polycyclic carbamoylpyridone compounds have been found to have antiviral activity, as disclosed in PCT/US2013/076367. Accordingly, there is a need for synthetic routes for such compounds.

 

SYNTHESIS

WO 2014100323

PATENTS

WO2014100323

xample 42

Preparation of Compound 42

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorohe

octahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide


42

Step 1

l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l ,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesuffhnic acid (0.195 mL, 3 mmol) and placed in a 75 deg C bath. The reaction mixture was stirred for 7 h, cooled and stored at -10 °C for 3 days and reheated to 75 °C for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (lR,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85 °C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HQ (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichloimethane:hexanes afforded the desired intermediate 42 A: LC S-ESI (m/z): [M+H]+ calculated for Ci5Hi7N206: 321.1 1 ; found: 321.3.

Step 3

Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethyiammo)- V,A/-dimethyi(3H-[l ,2,3]triazolo[4,5-&]pyridm~3-yiox.y)methammimum hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LfJMS-ESlT (m/z): [M+H calculated for (\ ,l l.,, i \\:0< : 464.14; found: 464.2.

Step 4

To the crude reaction mixture of the previous step was added MgBr2

(0.258 g, 1.40 mmol). The reaction mixture was stirred at 50 °C for 10 minutes, acidified with 10% aqueous HC1, and extract twice with dichloromethane. The combined organic phases were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN H2O with 0.1 % TFA modifier) to afford compound 42: 1H~ M (400 MHz, DMSO-</6) δ 12.43 (s, 1H), 10.34 (t, J = 5.7 Hz, IH), 8.42 (s, 1H), 7.19 (t, J = 8.7 Hz, 2H), 5.43 (dd, ./’ 9.5, 4.1 Hz, I H), 5.08 (s, i l l ). 4.66 (dd, ./ 12.9, 4.0 Hz, IH), 4.59 (s, 1 1 1 ). 4.56 4.45 (m, 2H), 4.01 (dd, J = 12.7, 9.7 Hz, IH), 1.93 (s, 4H), 1.83 (d, J —— 12.0 Hz, I H),

1.56 (dt, J = 12.0, 3.4 Hz, I H). LCMS-ESI+ (m/z): [M+H]+ calculated for { · Ί ί ] ΝΓ :Χ.¾ϋ : 450.13; found: 450.2.

PATENT

WO2015177537

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015177537&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

WO2015196116

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196116&redirectedID=true

PATENT

WO2015196137

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196137&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

http://www.google.com/patents/US20140221356

Example 42 Preparation of Compound 42 (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

  • 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL, 3 mmol) and placed in a 75 deg C. bath. The reaction mixture was stirred for 7 h, cooled and stored at −10° C. for 3 days and reheated to 75° C. for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

  • Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85° C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HCl (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichlormethane:hexanes afforded the desired intermediate 42A: LCMS-ESI+ (m/z): [M+H]+ calculated for C15H17N2O6: 321.11; found: 321.3.

Step 3

  • Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LCMS-ESI+ (m/z): [M+H]+ calculated for C22H21F3N3O5: 464.14; found: 464.2.

Step 4

  • To the crude reaction mixture of the previous step was added MgBr2 (0.258 g, 1.40 mmol). The reaction mixture was stirred at 50° C. for 10 minutes, acidified with 10% aqueous HCl, and extract twice with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN/H2O with 0.1% TFA modifier) to afford compound 42: 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.34 (t, J=5.7 Hz, 1H), 8.42 (s, 1H), 7.19 (t, J=8.7 Hz, 2H), 5.43 (dd, J=9.5, 4.1 Hz, 1H), 5.08 (s, 1H), 4.66 (dd, J=12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 4.56-4.45 (m, 2H), 4.01 (dd, J=12.7, 9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J=12.0 Hz, 1H), 1.56 (dt, J=12.0, 3.4 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calculated for C21H19F3N3O5: 450.13; found: 450.2.

 

 

PATENT

WO-2015195656

 

General Scheme I:

General Scheme II:

General Scheme II

General Scheme III:

General Scheme III

General Scheme IV:

G-1

 

General Scheme V:

II

 

EXAMPLES

In order for this invention to be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating embodiments, and are not to be construed as limiting the scope of this disclosure in any way. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.

In one embodiment, a multi-step synthetic method for preparing a compound of Formula I is provided, as set forth below. In certain embodiments, each of the individual steps of the Schemes set forth below is provided. Examples and any combination of two or more successive steps of the below Examples are provided.

A. Acylation and amidation of Meldrum ‘s acid to form C-la:

[0520] In a reaction vessel, Meldrum’s acid (101 g, 1.0 equivalent) and 4-dimethylaminopyridine (1.8 g, 0.2 equivalents) were combined with acetonitrile (300 mL). The resulting solution was treated with methoxyacetic acid (6.2 mL, 1.2 equivalents). Triethylamine (19.4 mL, 2.0 equivalents) was added slowly to the resulting solution, followed by pivaloyl chloride (9.4 mL, 1.1 equivalents). The reaction was then heated to about 45 to about 50 °C and aged until consumption of Meldrum’s acid was deemed complete.

A separate reaction vessel was charged with acetonitrile (50 mL) and J-la (13.4 g, 1.2 equivalents). The resulting solution was treated with trifluoroacetic acid (8.0 mL, 1.5 equivalents), and then this acidic solution was added to the acylation reaction in progress at about 45 to about 50 °C.

The reaction was allowed to age for at least 18 hours at about 45 to about 50 °C, after which time the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL), and the organic layer was washed with water. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, and the combined bicarbonate washes were back extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified twice via silica gel chromatography to yield C-la.

lH NMR (400 MHz, CDC13): δ 7.12 (br, 1H), 6.66 (app t, J= 8.1 Hz, 2H), 4.50 (app d, J= 5.7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). 13C NMR (100 MHz, CDC13): δ 203.96, 164.90, 162.37 (ddd, J= 250.0, 15.7, 15.7 Hz), 161.71 (ddd, J = 250.3, 14.9, 10.9 Hz), 110.05 (ddd, J= 19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J= 3.5 Hz). LCMS, Calculated: 275.23, Found: 275.97 (M).

I l l

B. Alkylation of C-la to form E-la:

A solution of C-la (248 mg, 1.0 equivalent) and 2-methyl tetrahydrofuran (1.3 niL) was treated with N,N-dimethylformamide dimethylacetal (0.1 mL, 1.1 equivalent) and stirred at room temperature overnight (~14 hours). The reaction was treated with aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalents), and was allowed to age for about 2 hours, and then was quenched via the addition of 2 Ν HC1

(1.5 mL).

The reaction was diluted via the addition of ethyl acetate, and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield E-la.

1H NMR (400 MHz, CDC13): δ 10.85 (s, 1H), 9.86 (s, 1H), 8.02 (d, J= 13.1 Hz, 1H), 6.65 (dd, J= 8.7, 7.7 Hz, 2H), 4.53 (d, J= 3.9 Hz, 2H), 4.40 (t, J= 5.1 Hz, 1H), 4.18 (s, 2H), 3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H). 13C MR (100 MHz, CDC13): δ 193.30, 169.15, 162.10 (ddd, J= 248.9, 15.5, 15.5 Hz), 161.7 (ddd, J =

250.0, 14.9, 1 1.1 Hz), 161.66, 1 11.08 (ddd J= 19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, J= 28.1, 17.7, 2.3 Hz), 76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J= 3.3 Hz). LCMS, Calculated: 390.36, Found: 390.92 (M).

c. Cyclization of E-la to form F-la:

E-1a F-1a

] E-la (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalents) and methanol (1.5 mL) were combined and cooled to about 0 to about 5 °C. Sodium methoxide (0.2 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly while keeping the internal temperature of the reaction below about 10 °C throughout the addition. After the addition was completed the reaction was heated to about 40 to about 50 °C for at least 18 hours.

After this time had elapsed, the reaction was diluted with 2 N HC1 (1.5 mL) and ethyl acetate (2 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and solvent was removed under reduced pressure. The resulting crude oil was purified via silica gel chromatography to afford F-la.

lR NMR (400 MHz, CDC13): δ 10.28 (t, J= 5.5 Hz, 1H), 8.38 (s, 1H), 6.66 – 6.53 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.00 (d, J= 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). 13C NMR (100 MHz, CDC13): δ 173.08, 163.81, 162.17, 162.14 (ddd, J= 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J= 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 1 10.53 (ddd, J= 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15 (M+H).

D. Alkylation and cyclization of C-la to form F-la:

1 . DMFDMA

C-1a NaOMe, MeOH, 40 °C F-1a

To a reaction vessel were added C-la (245 mg, 1.0 equivalent) and N,N-dimethylformamide dimethylacetal (0.5 mL, 4.3 equivalent). The reaction mixture was agitated for approximately 30 minutes. The reaction was then treated with 2-methyl tetrahydrofuran (2.0 mL) and aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent). The reaction was allowed to age for several hours and then solvent was removed under reduced pressure.

The resulting material was dissolved in methanol and dimethyl oxalate was added (0.3 g, 2.5 equivalents). The reaction mixture was cooled to about 0 to about 5 °C, and then sodium methoxide (0.4 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly. After the addition was completed the reaction was heated to about 40 to about 50 °C.

After this time had elapsed, the reaction was cooled to room temperature and quenched via the addition of 2 Ν HC1 (1.5 mL). The reaction was then diluted with ethyl acetate, and the resulting phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield F-la.

lR NMR (400 MHz, CDC13): δ 10.28 (t, J= 5.5 Hz, 1H), 8.38 (s, 1H), 6.66 – 6.53 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.00 (d, J= 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). 13C NMR (100 MHz, CDC13): δ 173.08, 163.81, 162.17, 162.14 (ddd, J= 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J= 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 1 10.53 (ddd, J= 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15 (M+H).

E. Condensation of F-la with N-la to form G-la:

K2C03, MeCN, 75 °C

To a reaction vessel were added F-la (202 mg, 1.0 equivalent) and acetonitrile (1.4 mL). The resulting solution was treated with glacial acetic acid (0.2 mL, 6.0 equivalents) and methane sulfonic acid (0.01 mL, 0.3 equivalents). The reaction was then heated to about 70 to about 75 °C.

After 3 hours, a solid mixture of N-la (0.128g, 1.5 equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was introduced to the reaction at about 70 to about 75 °C. After the addition was completed, the reaction was allowed to progress for at least about 1 hour.

After this time had elapsed, water (1.4 mL) and dichloromethane (1.4 mL) were introduced to the reaction. The phases were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, then were filtered and concentrated under reduced pressure. The resulting crude material was purified via silica gel chromatography to obtain G-la.

lR NMR (400 MHz, CDC13): δ 10.23 (t, J= 5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J= 8.1 Hz, 2H), 5.29 (dd, J= 9.5, 3.7 Hz, 2H), 4.57 (d, J= 5.4 Hz, 3H), 4.33 (dd, J = 12.8, 3.8 Hz, 1H), 4.02 – 3.87 (m, 1H), 3.94 (s, 3H), 2.06 – 1.88 (m, 4H), 1.78 (dd, J = 17.2, 7.5 Hz, 1H), 1.55 – 1.46 (m, 1H). 13C MR (100 MHz, CDC13): δ 174.53, 163.75, 162.33 (dd, J= 249.4, 15.7, 15.7 Hz), 161.86 (ddd, J= 250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75, 1 18.88, 1 10.58 (ddd, J= 19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, Calculated: 463.14, Found: 464.15 (M+H).

Γ. Deprotection of G-la to form a compound of Formula la:

G-la (14 g) was suspended in acetonitrile (150 mL) and dichloromethane (150 mL). MgBr2 (12 g) was added. The reaction was heated to 40 to 50 °C for approximately 10 min before being cooled to room temperature. The reaction was poured into 0.5M HC1 (140 mL) and the layers separated. The organic layer was washed with water (70 mL), and the organic layer was then concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane up to 6% ethanol/dichloromethane) to afford la.

 

REFERENCES

Patent Submitted Granted
POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE [US2014221356] 2013-12-19 2014-08-07
US9216996 Dec 19, 2013 Dec 22, 2015 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections

see full gravir series at…………..http://medcheminternational.blogspot.in/p/ravir-series.html

//////////

C1CC2CC1N3C(O2)CN4C=C(C(=O)C(=C4C3=O)O)C(=O)NCC5=C(C=C(C=C5F)F)F

OR

c1c(cc(c(c1F)CNC(=O)c2cn3c(c(c2=O)O)C(=O)N4[C@H]5CC[C@H](C5)O[C@@H]4C3)F)F

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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR 

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed.  Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11b is independently hydrogen or deuterium; provided that if each Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, and Y11 is hydrogen, then Y11b is deuterium.

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Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

 [75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and/or Y11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y3=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d1 (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y3=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y3 position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y3.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl2 in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y9=Y10a=Y10b=H). Replacing acetaldehyde with acetaldehyde-d1, acetaldehyde-2,2,2-d3, or acetaldehyde-d4 (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y9=D, Y10a=Y10b=H), 4c (Y9=H,

Y10a=Y10b=D) and 4d (Y9=Y10a=Y10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y9, Y10a, and Y10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y9, Y10a, and/or Y10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

 [85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b=Y8=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b= Y8=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d6 and performing the penultimate hydrogenation with D2 in place of H2. Cyclopentadiene-d6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl3 then affords the D1-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D2-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D2-diol is then converted to 9c (Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=H, Y6=Y8=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=D, Y6=Y8=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D2O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and Y8 positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and/or Y8.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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