DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, this will not stop me, Only God and death can..........
DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai), INDIA, worlddrugtracker, 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.8 Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution
n, सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।...........P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
Showing posts with label PHASE 3. Show all posts
Showing posts with label PHASE 3. Show all posts

Thursday, 9 June 2016

Gilteritinib

Gilteritinib
ASP-2215
Treatment of Acute Myeloid Leukemia
6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide
C29H44N8O3, 552.71
Phase III
A FLT3/AXL inhibitor potentially for the treatment of acute myeloid leukemia.
CAS No. 1254053-43-4
Astellas Pharma  INNOVATOR
Mechanism Of ActionAxl receptor tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors, Proto oncogene protein c-kit inhibitors
Who Atc CodesL01X-E (Protein kinase inhibitors)
Ephmra CodesL1H (Protein Kinase Inhibitor Antineoplastics)
IndicationCancer, Hepatic impairment
Gilteritinib(ASP-2215) is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/<1 nM respectively; shows potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations.
IC50 value: 0.29 nM(FLT3); <1 nM(Axl kinase)
Target: FLT3/AXL inhibitor
ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.

SYNTHESIS

STR1

Patent
Compound A is 6-ethyl-3 - ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- a (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-carboxamide, its chemical structure is shown below.
[Formula 1]

Gilteritinib fumarate

1254053-84-3.png

2D chemical structure of 1254053-84-3

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

  • ASP-2215 hemifumarate
  • Molecular Formula, 2C29-H44-N8-O3.C4-H4-O4, Molecular Weight, 1221.5108

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

gilteritinib-ASP2215
TOKYO, Japan I October 28, 2015 I Astellas Pharma Inc. (TSE:4503) today announced dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215)versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).
Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.
The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.
On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.
About the Phase 3 Study
The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to www.clinicaltrials.gov, trial identifier NCT02421939.
Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.
About Acute Myeloid Leukemia
Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf” target=”_blank” rel=”nofollow”>American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.
About SAKIGAKE
The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review. Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.
About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at www.astellas.com/en.
SOURCE: Astellas Pharma
////////1254053-43-4, Gilteritinib, ASP-2215, PHASE 3, ASP 2215, Astellas Pharma, Acute Myeloid Leukemia
CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5
CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O

Thursday, 31 March 2016

Tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE)


Gly-Pro-Glu

Synonym: GPE, Glycyl-prolyl-glutamic acid, (1-3)IGF-1
Pfizer (Originator)
Neuren Pharmaceuticals (Originator)
Glypromate; glycine-proline-glutamate (neuroprotectant), Neuren
  • CAS Number 32302-76-4
  • Empirical Formula C12H19N3O6
  • Molecular Weight 301.30
  • Psychiatric Disorders (Not Specified)
    Neurologic Drugs (Miscellaneous)
    Cognition Disorders, Treatment of
    Antiepileptic Drugs
    Antidepressants Biochem/physiol Actions
Gly-Pro-Glu is a neuroprotective compound and the N-terminal tripeptide of IGF-1. Gly-Pro-Glu is neuroprotective after central administration in animal models of neurodegenerative processes, such as Huntington’s, Parkinson’s, Alzheimer’s diseases, and varies acute brain injury animal models. The neuroprotective activity is not related to its affinity to glutamate receptor. Findings indicate that GPE mimics insulin-like growth factor I effects on the somatostatin system through a mechanism independent of β-amyloid clearance that involves modulation of calcium and glycogen synthase kinase 3β signaling.
GPE is a naturally occurring peptide fragment which had been in phase III clinical trials at Neuren Pharmaceuticals for use as prophylactic neuroprotection for patients undergoing coronary artery bypass graft (CABG) and valvuloplasty surgery. Although clinical evaluation in Australia continues, phase III trials evaluating the compound in the U.S. were discontinued based on negative results. The compound is found in normal brain tissue and, when injected intravenously, has been shown to act by multiple pathways to protect brain tissue from injury. The drug was originally developed by Pfizer, but rights were transferred to Neuren pursuant to a proprietary agreement between the companies.
When amino acids join together (forming short groups called polypeptides, or much longer chains called proteins) the amine group of one amino acid joins with the carboxyl group of the next, making a peptide bond. These bonds don’t ionise at different pHs, but can be hydrolised — broken — reforming the amino acids. GPE is formed from the amino acids glycine, proline and glutamic acid:
This tripeptide has 3 pH-sensitive groups, each with its own pKa. What the university chemists needed to do was work out what form GPE is in when it is active in the brain, what parts of the molecule are critical to its effectiveness, and how to ‘tweak’ the molecule (by changing the side chains) so that it will remain in the brain for longer than the naturally-occurring substance.   They also needed to make sure the final compound passes through the blood-brain barrier (that prevents most substances in the blood from entering and affecting the brain). If possible, they also wanted a compound that could be taken in pill form without being broken down in the stomach. It was also essential that the compound was safe for people to take!
Neuren Pharmaceuticals
After initial work on GPE at the university, the research was passed to a spin-off research group called Neuren Pharmaceuticals Ltd, which takes compounds discovered by the University of Auckland and develops them into medicines. Neuren developed GPE intoGlypromate® and are working with researchers in the US (including the US Military, who have a keen interest in a medicine that will reduce brain damage after head injuries) to test the compound on patients. There is considerable interest in Glypromate® world-wide, because at present there is nothing that reduces cell death after brain injuries. The chances of winning a race are pretty high when you’re the only competitor!Glypromate® is being tested on heart-bypass patients because up to 70% of bypass patients are affected mentally after their surgery. It’s thought that tiny clots form after the heart is restarted, and that these travel to the brain and cause mini-strokes. Unlike naturally-occurring strokes, or the brain damage caused by accident or war, the bypass surgery is planned, so before and after tests can be done on the patients to see exactly what effect the treatment has. Early results look very promising.
Glypromate is just one of the compounds Neuren is working on. Others may develop into treatments for Multiple Sclerosis, Parkinson’s Disease or Alzheimer’s Disease as well as various kinds of cancer. The company’s links with overseas research groups mean that compounds developed in New Zealand are able to be tested in the US and gain the FDA approval which will allow them to be used in most countries in the world.
The tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE) is a naturally occurring peptide, which is proteolytically cleaved from insulin-like growth factor-1 (IGF-1). IGF-1 is a potent neurotrophic factor produced endogenously in damaged regions of the brain. It has been postulated that some of the neuroprotective actions of IGF-1 are mediated by GPE although the precise mechanism of action remains unclear. GPE has a different mode of action to IGF-1 as GPE does not bind to the IGF-1 receptor. Rather, GPE has been shown to bind with low affinity to the N-methyl-D-aspartate (NMDA) receptor and also elicit a biological response via other mechanisms. GPE facilitates the release of dopamine through interaction with the NMDA receptor but GPE stimulated acetylcholine release is via an unknown, non-NMDA pathway.
It has been demonstrated that GPE can act as a neuronal rescue agent following brain injury or disease, including hypoxic-ischemic brain injury, NMDA challenge, chemical toxins and in animal models of Parkinson's and Alzheimer's disease. Analogs of GPE are thus of interest in the development of novel pharmaceutical agents for the treatment of central nervous system (CNS) injuries and neurodegenerative disorders among others.
CURRENT STATUS
Neuren Pharmaceuticals was developing Glypromate (glycine-proline glutamate), a naturally occurring small-molecule neuroprotectant derived from IGF-1 which inhibits caspase III dependent apoptosis, for the potential treatment of neurodegenerative diseases by iv infusion. By June 2008, a phase III trial had begun . However, in December 2008, the company discontinued further development of the drug after it failed to show an observable effect [972907]. In November 2005, the company was seeking to outlicense the drug [771417].
Neuren is also investigating the Glypromate analog, NNZ-2566 for similar indications.
In August 2006, Neuren expected Glypromate to be eligible for Orphan Drug status for neurodegenerative diseases and planned to apply for Fast Track status for the drug.
SYDNEY, Australia, Sept. 4 /PRNewswire-FirstCall/ -- Neuren Pharmaceuticals today announced that physicians from Madigan Army Medical Center (Madigan) in Tacoma, Washington, will conduct an investigator- initiated Phase 2 trial to determine the safety and efficacy of Glypromate(R) in reducing brain injury caused by out of hospital cardiac arrest. The trial will start in mid-2007 and will be managed by The Henry M. Jackson Foundation for the Advancement of Military Medicine (Jackson Foundation) in consultation with the clinical investigators at Madigan.
The proposed study will be an investigator-initiated study which means that the Investigational New Drug (IND) application will be submitted to the FDA by the Army investigators rather than by Neuren. Neuren will provide the drug product as well as access to preclinical, clinical and regulatory documents related to Glypromate(R). The Company's only financial commitment will be compensation to the Jackson Foundation for administrative costs incurred in coordinating the study. Neuren will retain all commercial rights to Glypromate(R) in these indications.
Cardiac arrest involves the sudden, complete cessation of heart function and circulation leading rapidly to neurological and other organ system damage. Among patients who survive, the consequences of neurological damage resulting from lack of blood flow and oxygen to the brain represent the primary adverse outcomes. This occurs in up to 80% of survivors and causes cognitive impairment such as occurs in patients undergoing major cardiac surgery, the focus for Neuren's upcoming Phase 3 study with Glypromate(R). However recovery without residual neurological damage after cardiac arrest is rare.
There are no drugs approved to reduce the neurological damage caused by cardiac arrest. Neuren believes that Glypromate(R) for this indication will be eligible for Orphan Drug designation. Orphan Drug designation provides for a period of market exclusivity following approval as well as possible access to US government grants. In addition, because of the serious nature of neurological impairment resulting from cardiac arrest and the lack of available drug therapy, Neuren intends to apply for Fast Track designation which provides for accelerated clinical development and review.
While the Army's investigator-initiated trial will focus on out of hospital cardiac arrest, if this trial is successful, Neuren, the Jackson Foundation and the Army investigators are considering additional trials of Glypromate(R) to reduce brain damage resulting from related conditions including in-hospital cardiac arrest and treatment of patients with ventricular fibrillation, the heart rhythm disturbance associated with more than 75% of cardiac arrests.
Under the agreement, the Jackson Foundation will provide support to the Army investigators in clinical trial preparations, protocol development, obtaining human subjects clearance, coordination of patient enrolment, data management and analysis, and preparation of study reports.
Mr David Clarke, CEO of Neuren said: "This is a very important development for Neuren in that it reflects a growing appreciation of the potential for Glypromate(R) to reduce neurological damage. It also, of course, reinforces the value and strength of Neuren's relationship with the US Army physicians and scientists. Cardiac arrest is a devastating clinical event and one for which a drug to reduce the neurological consequences is clearly needed. The addition of this trial will now give Neuren a very strong and cost effective portfolio of clinical trials in 2007 -- a Phase 3 and a Phase 2 for Glypromate(R) and the two Phase 2 trials with NNZ-2566."
Approximately 300,000 deaths result from cardiac arrest in the US each year, making cardiac arrest one of the leading causes of death. According to the American Heart Association, each year approximately 160,000 people in the US experience sudden cardiac arrest outside of a hospital or in a hospital emergency department.
Neuren estimates that the number of patients in the US that could be treated for out of hospital cardiac arrest and related indications is approximately 400,000 which could represent a potential market of US$800 million.
About Madigan Army Medical Center
Madigan Army Medical Center, located in Tacoma, Washington, is one of the major US Army medical centers, providing clinical care to over 120,000 active, reserve and retired military personnel and dependents. The hospital has a medical staff of more than 1,000 with 200 physicians and nurses in training. Madigan's Department of Clinical Investigations, which is dedicated to writing, performing, and regulating clinical research, is conducting approximately 200 clinical trials across a wide spectrum of indications from Phase I to IV.
About the Jackson Foundation
The Jackson Foundation is a private, not-for-profit organisation that supports the US military in conducting medical research and clinical trials and has established relationships with more than 160 military medical organisations worldwide. It was founded in 1983, in part, to foster cooperative relationships between the military medical community and the private sector, including pharmaceutical sponsors. The Jackson Foundation manages Phase I - IV clinical trials utilizing an established network of military medical centers across the United States.
About Glypromate(R)
Glypromate(R) is a peptide fragment of IGF-1 and is being developed by Neuren as a potential therapeutic candidate for diseases caused by some forms of chronic or acute brain injury. Glypromate(R) has been shown to act by multiple pathways to protect brain tissue from injury. Neuren has successfully completed a Phase I safety study and a Phase IIa safety and pharmacokinetics study and plans to initiate a Phase III study in late 2006.
About Neuren Pharmaceuticals
Neuren Pharmaceuticals is a biotechnology company developing novel therapeutics in the fields of brain injury and diseases and metabolic disorders. The Neuren portfolio consists of six product families, targeting markets with large unmet needs and limited competition. Neuren has three lead candidates, Glypromate(R) andNNZ-2566, presently in the clinic in development to treat a range of acute neurological conditions, and NNZ-2591, in preclinical development for Parkinson's and other chronic conditions. Neuren has commercial and development partnerships with the US ArmyWalter Reed Army Institute of Research, Metabolic Pharmaceuticals,UCLA Medical Center and the National Trauma Research Institute in Melbourne.
For more information, please visit Neuren's website at http://www.neurenpharma.com
Company David Clarke CEO of Neuren T: 1800 259 181 (Australia) T: +64 9 3 367 7167 ext 82308 (New Zealand) M: +64 21 988 052 Media and investor relations Rebecca Piercy Buchan Consulting T: +61 9827 2800 M: +61 422 916 422
CONTACT: David Clarke, CEO of Neuren, 1-800-259-181(Australia), or
+64-9-3-367-7167 ext 82308 (New Zealand), or +64-21-988-052 (mobile); or
Media and investor relations - Rebecca Piercy of Buchan Consulting,
+61-9827-2800, +61-422-916-422 (mobile)
Web site: http://www.neurenpharma.com/
REFERENCES
1 EP 0366638
2 WO 2005042000
3 WO 2008153929
4 WO 2009033805
5 WO 2009033806
Synthesis off isotopically labelled glycyl-L-prolyl-L-glutamic acid (Glypromate(R)) and derivatives
J Label Compd Radiopharm 2006, 49(6): 571
An efficient fmoc solid-phase synthesis of an amphiphile of the neuroprotective agent glycyl-prolyl-glutamic acid
Synlett (Stuttgart) 2014, 25(15): 2221
Intracellular pathways activated by Insulin-like growth factor 1 and its derivates
40th Annu Meet Soc Neurosci (November 13-17, San Diego) 2010, Abst 167.13
EP2667715A1 *Jan 27, 2012Dec 4, 2013Neuren Pharmaceuticals LimitedTreatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
EP2667715A4 *Jan 27, 2012Jul 23, 2014Neuren Pharmaceuticals LtdTreatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
US8940732Jan 15, 2010Jan 27, 2015Massachusetts Institute Of TechnologyDiagnosis of autism spectrum disorders and its treatment with an antagonist or inhibitor of the 5-HT2c receptor signaling pathway
US9212204Jan 26, 2015Dec 15, 2015Neuren Pharmaceuticals Limited
WO2005042000A1 *22 Oct 200412 May 2005David Charles BatchelorNeuroprotective effects of gly-pro-glu following intravenous infusion
WO2005097161A2 *30 Mar 200520 Oct 2005Peter D GluckmanGpe and g-2mepe, caffeine and alkanol for treatment of cns injury
WO2006127702A2 *23 May 200630 Nov 2006Neuren Pharmaceuticals LtdAnalogs of glycyl-prolyl-glutamate
EP0366638A2 *24 Oct 19892 May 1990KabiGen ABNeuromodulatory peptide
US20020151522 *13 Mar 200217 Oct 2002Tajrena AlexiRegulation of weight
Reference
1*ALONSO DE DIEGO, SERGIO A. ET AL: "New Gly-Pro-Glu (GPE) analogues: Expedite solid-phase synthesis and biological activity" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 5, 2006, - 1392 page 1396, XP002527092
2*SARA V R ET AL: "IDENTIFICATION OF GLY-PRO-GLU (GPE), THE AMINOTERMINAL TRIPEPTIDE OF INSULIN-LIKE GROWTH FACTOR 1 WHICH IS TRUNCATED IN BRAIN, AS A NOVEL NEUROACTIVE PEPTIDE" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 165, no. 2, 15 December 1989 (1989-12-15), pages 766-771, XP000992688 ISSN: 0006-291X


//////Gly-Pro-Glu, GPE, Glycyl-prolyl-glutamic acid,  32302-76-4, Tripeptide,  Glycyl-L-Prolyl-L-Glutamate, Glypromate®, (1-3)IGF-1 , PHASE 3, Glypromate,  glycine-proline-glutamate, neuroprotectant, Neuren

Neuren’s NNZ-2566 shows clinical benefit in Rett syndrome trial

FRAXA Research Foundation Logo

Promising results in Phase 2 clinical trial

by Michael Tranfaglia, MD
FRAXA Medical Director
nnz-2566This isn’t a Fragile X trial, but the Neuren compound, NNZ-2566, that is in trials now for Fragile X has shown significant positive effects in a Phase 2 trial for Rett syndrome.
The results of the trial are interesting, in that improvement was seen a Rett syndrome-specific rating scale compared to placebo, and there was also improvement noted on the CGI-I (Clinical Global Impression of Improvement) and Caregiver Top 3 Concerns. However, there was no effect seen on ABC scores (Aberrant Behavior Checklist) compared to placebo. Many in the Fragile X field have noted the inadequacies of the ABC; indeed, it was never designed or intended to be an outcome measure for clinical trials. In this case, a Rett-specific rating scale called the Motor-Behavior Assessment (MBA) showed a statistically significant and clinically meaningful treatment effect at the highest dose of the Neuren compound compared to placebo.
This is great news for those of us in the Fragile X community for several reasons:
  • It shows that this compound really does something—it seems to have useful properties in actual patients, and that’s not trivial.
  • It demonstrates that disease-specific symptoms can improve significantly on the drug, and that improvement can be measured in a relatively short clinical trial.
  • It shows that a drug can have beneficial effects on core features of a genetically based developmental disorder, even if the more general rating scales (like the ABC) show no change.

This last point is strongly reminiscent of the experience of many families and clinicians in recent Fragile X clinical trials, where the drugs showed no advantage compared to placebo based on rating scales, but genuine improvement was noted in many subjects, with significant deterioration upon discontinuation of the drugs. Thus the calls for improved rating scales which can “capture” these core, disease-specific therapeutic effects. The NeurenFragile X trial is using some Fragile X-specific outcome measures which will hopefully lead to similar positive results.
The fact that this result is good news for Neuren also means that the company should remain financially viable for longer, so that they can continue the development of this compound for a number of indications—more “shots on goal”.
Of course, the usual caveats apply: this was a small study, and these results need to be replicated in a larger Phase 3 trial. Still, there’s a realistic possibility that we may see a similar result in Fragile X!

Monday, 8 February 2016

Finerenone, BAY 94-8862

Finerenone
Finerenone; UNII-DE2O63YV8R; BAY 94-8862; DE2O63YV8R; 1050477-31-0
C21H22N4O3
MW378.42438 g/mol
(4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide
Bayer Corp
Mineralocorticoid receptor antagonist
phase III in January 2016, for treating diabetic kidney disease and chronic heart failure in patients with worsening chronic cardiac insufficiency
Used as mineralocorticoid receptor antagonist for treating heart failure and diabetic nephropathy.

SYNTHESIS


str1
Finerenone (INNUSAN) (developmental code name BAY-94-8862) is a non-steroidal antimineralocorticoid that is in phase IIIclinical trials for the treatment of chronic heart failure as of October 2015. It has less relative affinity to other steroid hormone receptors than currently available antimineralocorticoids such as eplerenone and spironolactone, which should result in fewer adverse effects like gynaecomastiaimpotence, and low sex drive.[1][2]

Pharmacology

Finerenone blocks mineralocorticoid receptors, which makes it a potassium-sparing diuretic.
This table compares inhibitory (blocking) concentrations (IC50, unit: nM) of three antimineralocorticoids. Mineralocorticoid receptor inhibition is responsible for the desired action of the drugs, whereas inhibition of the other receptors potentially leads to side effects. Lower values mean stronger inhibition.[1]
SpironolactoneEplerenoneFinerenone
Mineralocorticoid receptor2499018
Glucocorticoid receptor240022,000>10,000
Androgen receptor7721,200>10,000
Progesterone receptor74031,200>10,000
The above-listed drugs have insignificant affinity for the estrogen receptor.

Chemistry

Unlike currently marketed antimineralocorticoids, finerenone is not a steroid but a dihydropyridine derivative.

Research

The drug is also being investigated in early trials for the treatment of diabetic nephropathy.[3]

 PAPER

Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases

  1. Dr. Lars Bärfacker1,*,
  2. Dr. Alexander Kuhl1,
  3. Prof. Dr. Alexander Hillisch1,
  4. Dr. Rolf Grosser1,
  5. Dr. Santiago Figueroa-Pérez1,
  6. Dr. Heike Heckroth1,
  7. Adam Nitsche1,
  8. Dr. Jens-Kerim Ergüden1,
  9. Dr. Heike Gielen-Haertwig1,
  10. Dr. Karl-Heinz Schlemmer2,
  11. Prof. Dr. Joachim Mittendorf1,
  12. Dr. Holger Paulsen1,
  13. Dr. Johannes Platzek3 and
  14. Dr. Peter Kolkhof4
Article first published online: 12 JUL 2012
DOI: 10.1002/cmdc.201200081
ChemMedChem

ChemMedChem

Volume 7Issue 8pages 1385–1403August 2012

Abstract

Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.


str1



str1

PATENT

WO2008104306,




EXAMPLES
Example 1
4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2-methyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide
Figure imgf000066_0001
100 mg (ca. 0:24 mmol) of the compound from Example 23A are initially charged in 3 ml DMF. Is 2.94 mg Then (0.024 mmol) of 4-N, N-dimethylaminopyridine and 340 ul of ammonia (28 wt .-% - solution in water, 2:41 mmol) and 3 h at 100 0 C temperature. After cooling, the crude product is purified directly by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 → 95: 5). There are 32 mg (37% d. Th.) The title connection receive.
LC-MS (Method 3): R, = 1:57 min; MS (EIPOS): m / z = 365 [M + H] +
1 H-NMR (300 MHz, DMSOd6): δ = 1:07 (t, 3H), 2.13 (s, 3H), 3.83 (s, 3H), 4:04 (m, 2H), 5:36 (s, IH), 6:42 (d, IH), 6.66 (br. s, 2H), 7.18 (d, IH), 7.29 (dd, IH), 7:38 (d, IH), 7.67 (d, IH), 8.80 (s, IH).
Example 2
4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,7-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide
Figure imgf000067_0001
640 mg (1.69 mmol) of the compound from Example 27A are initially charged in 30 ml of ethyl acetate, 342 mg (2.11 mmol) l, r-carbonyldiimidazole and then stirred overnight at room temperature. A TLC check (silica gel; mobile phase: cyclohexane / ethyl acetate 1: 1 or dichloromethane / methanol 9: 1) shows complete conversion. The volatile components are removed on a rotary evaporator and the residue taken up in 20 ml DMF. Subsequently, 2.36 ml of ammonia (28 wt .-% - solution in water, 16.87 mmol) was added and the reaction mixture for 8 hours at 50 0 C temperature. The solvent is distilled off under reduced pressure and the residue purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). This gives 368 mg (58% d. Th.) Of the title compound.
LC-MS (method 7): R t = 1.91 min; MS (EIPOS): m / z = 379 [M + H] +
1 H-NMR (300 MHz, DMSO-d 6): δ = 1:05 (t, 3H), 2.13 (s, 3H), 2.19 (s, 3H), 3.84 (s, 3H), 4:02 (q, 2H) , 5:32 (s, IH), 6.25 (s, IH), 6.62 (br. s, 2H), 7.16 (d, IH), 7.28 (dd, IH), 7:37 (d, IH), 8.71 (s, IH ).
Example 3
e 'f 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,7-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox- amide [(-) - enantiomer and (+) - enantiomer \
Figure imgf000068_0001
The racemate of Example 2 can be separated on a preparative scale by chiral HPLC into its enantiomers [column: Chiralpak IA, 250 mm x 20 mm; Eluent: methyl tert-butyl ether / methanol 85: 15 (v / v); Flow: 15 ml / min; Temperature: 30 0 C; UV detection: 220 Dm].
(-) - Enantiomer:
HPLC: R, = 5.28 min, ee> 98% [column: Chiralpak IA, 250 mm x 4.6 mm; Eluent: methyl tert-butyl ether / methanol 80:20 (v / v); Flow: 1 ml / min; Temperature: 25 0 C; UV detection: 220 nm];
specific optical rotation (chloroform, nm 589, 19.8 ° C, c = 0.50500 g / 100 ml): -239.3 °.
A single crystal X-ray structural analysis revealed a ^ -configuration at C * for this enantiomer - atom.
(+) - Enantiomer:
HPLC: R = 4:50 min, ee> 99% [column: Chiralpak IA, 250 mm x 4.6 mm; Eluent: methyl tert-butyl ether / methanol 80:20 (v / v); Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 220 nm];
specific optical rotation (chloroform, nm 589, 20 0 C, c = 0.51000 g / 100 ml): + 222.7 °.
Example 4
4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxamide
Figure imgf000069_0001
1:46 g (3.84 mmol) of the compound from Example 3oA are introduced into 50 ml of ethyl acetate, 777 mg (4.79 mmol) l, r-carbonyldiimidazole and then stirred overnight at room temperature. A TLC check (silica gel; eluent: ethyl acetate) shows complete conversion. The volatile components are removed on a rotary evaporator and the residue taken up in 20 ml DMF.Then 10.74 ml of ammonia (28 wt% solution in water, 76.8 mmol) was added and the reaction mixture heated for 30 minutes at 100 0 C. The solvent is distilled off under reduced pressure and the residue purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). After concentrating the product fractions, the residue in 40 ml of dichloromethane / methanol (1: 1 v / v) and treated with 100 ml of ethyl acetate. The solvent is concentrated to a volume of about 20 ml, whereupon the product crystallized. The precipitate is filtered off and washed with a little diethyl ether.After drying at 40 0 C in a vacuum oven obtained 1:40 g (96%. Th.) The title connection.
LC-MS (Method 3): R, = 1.64 min; MS (EIPOS): m / z = 379 [M + H] +
1 H-NMR (300 MHz, DMSOd6): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H) , 5:37 (s, IH), 6.60-6.84 (m, 2H), 7.14 (d, IH), 7.28 (dd, IH), 7:37 (d, IH), 7:55 (s, IH), 7.69 (s, IH ).
Example 5
e "M- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox- amide [(-) - enantiomer and (+ ) enantiomer]
Figure imgf000070_0001
The racemate of Example 4 can be separated on a preparative scale by chiral HPLC into its enantiomers [column: 680 mm x 40 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 80 ml / min; UV detection: 260 nm].
(-) - Enantiomer:
HPLC: R = 2:48 min, ee = 99.6% [column: 250 mm x 4.6 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 2 ml / min; UV detection: 260 nm];
specific optical rotation (chloroform, nm 589, 19.7 ° C, c = 0.38600 g / 100 ml): -148.8 °.
A single crystal X-ray structure analysis showed this enantiomer S configuration at C * - atom.
(+) - Enantiomer:
HPLC: R = 4:04 min, ee = 99.3% [column: 250 mm x 4.6 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide; eluent: ethyl acetate; temperature: 24 ° C; flow: 2 ml / min; UV detection: 260 nm];
specific optical rotation (chloroform, nm 589, 19.8 ° C, c = 0.36300 g / 100 ml): + 153.0 °.

PATENT

The present invention relates to a novel and improved process for preparing 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carbox- amide of formula (I)
as well as the preparation and use of crystalline modification I of (4S) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3- carbox-amide of formula (I).
The compound of formula (I) acts as a non-steroidal mineralocorticoid receptor antagonist and can be used as agents for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.
The compound of formula (I) and their preparation process are described in WO 2008/104306 and ChemMedChem 2012 7, described in 1385, in both publications a detailed discussion of research synthesis is disclosed. A disadvantage of the synthesis described there is the fact that this synthesis is not suitable for another large-scale process, since many steps in very high dilution, at very high reagent surpluses and thus run on a relatively low overall yield. Furthermore, many chromatographic cleanings are necessary, which are usually very expensive and require a high consumption of solvents, are costly and which should therefore be avoided if possible.Some stages can not be realized due to safety and procedural difficulties.
There is therefore a need for an industrially viable synthesis, reproducible in high overall yield, low production costs and high purity provides the compound of formula (I) and complies with all regulatory requirements in order to supply the clinical trials on drug and for subsequent regulatory submission to be used.
With the present invention a very efficient synthesis has been found, which allows to meet the above requirements.
In the publication ChemMedChem 2012 7, in which the research synthesis of the compound of formula (I) disclosed in 1385, the compound of formula (I), starting from vanillin prepared in 10 steps with an overall yield of 3.76% of theory , The compound of formula (I) was obtained by evaporation of the chromatography fractions as an amorphous solid, a defined process Kristalhsations- the stage for polymorphism-setting has not been described.
The following Scheme 1 shows the known process for preparing the compound of formula (I).
(II) (HI) (IV)
(V) (VI)
(XIII) (I)
Scheme 1: synthesis research of the compound of formula (I)
There are used 3 chromatographic purifications, and a chiral chromatography step to separate the enantiomers of the racemate of formula (XIII). The steps run partially in very high dilution and using very large amounts of reagent.
Thus, in particular the sequence of the preparation of the nitrile aldehyde intermediate (VI), which occupies a central role in the synthesis of atom not economically acceptable.
Furthermore, not to apply this process to an industrial scale, since [=> (IV) (III)] and excesses of acrylic acid tert-butyl ester are used for a very expensive reagents such as trifluoromethanesulfonic anhydride. When upscaling the Heck reaction (IV) => (V) formed in the boiler, a plastic similar residue resulting from the polymerization of acrylic acid tert.butyl ester used in excess. This is not acceptable in the technical implementation, there is a risk that there may be a Rührerbruch and it would lead to strong to remove residues in the agitators.
The subsequent cleavage of the double bond with sodium and the highly toxic osmium tetroxide is to be avoided since there is a delay of reaction and thereby caused to a strongly exothermic and connected with that comes a runaway under the test conditions described.
Scheme 2 illustrates the new process of the invention that the compound of formula (I) in 9 levels in 27.7% d. Th. Total yield without a chromatographic
Purification of intermediates supplies.
Scheme 2: According to the Invention for preparing the compound of formula (I).
Examples
example 1
Methyl 4-bromo-2-methoxybenzoate (XV)
3.06 kg (22.12 mol) potassium carbonate are placed in 1 acetone 3.6 and heated to reflux. To this suspension is metered in 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol) suspended in 7.8 1 of acetone and rinsed with 0.6 1 acetone. The mixture is heated for one hour under reflux (vigorous evolution of gas!). is boiled for 2.65 kg (21.01 mol) Dimethylsufat over 4 hours then metered. 2.5 hours then is stirred under reflux. The solvent is distilled off to a large extent (up to the stirrability) and returns to 12 1 toluene, then the remaining acetone is distilled off at 110 ° C. There are about 3 1 distillate distilled, these are supplemented by the addition of a further 3 1 toluene to approach. Allow to cool to 20 ° C and are 10.8 1 water were added and agitated vigorously. The organic phase is separated and the aqueous phase extracted again with 6.1 1 of toluene. The combined organic phases are washed with 3 1 of saturated sodium chloride solution, and the toluene phase is concentrated to about 4 first A quantitative analysis by evaporating a subset results converted a yield 1.306 kg (96.4% of theory). The solution is used directly in the next stage.
HPLC method A: RT about 11.9 min.
MS (EIPOS): m / z = 245 [M + H] +
H NMR (400 MHz, CD 2 C1 2 ): δ = 3.84 (s, 3H), 3.90 (s, 3H), 7:12 to 7:20 (m, 2H), 7.62 (d, 1H).
example 2
4-bromo-2-methoxybenzaldehyde (XVI)
It puts 1.936 kg (6.22 mol) 65% Red- Al solution in toluene with 1.25 1 of toluene at -5 ° C before. To this solution was dosed 0.66 kg (6.59 mol) of 1-methylpiperazine and rinsed with 150 ml of toluene, the temperature keeps you here from -7 to -5 ° C.. It is allowed for 30 minutes at 0 ° C. for. This solution is then dosed to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 1 of toluene, the temperature is maintained at - 8-0 ° C. Rinse twice with 0.7 1 of toluene and stirred for 1.5 hours at 0 ° C to. For working up, dosed to a 0 ° C cold aqueous sulfuric acid (12.5 1 water + 1.4 kg of conc. Sulfuric acid). The temperature should rise to a maximum of 10 ° C (slow dosage). The pH is, if necessary, by addition of further sulfuric acid to a pH of the first The organic phase is separated and extracted the aqueous phase with 7.6 1 of toluene. The combined organic phases are washed with 5.1 1 of water and then substantially concentrated and the residue taken up with 10 1 DMF. The mixture is concentrated again to about 5 1 volume. A quantitative analysis by evaporating a subset results converted a yield 1.041 kg (94.1% of theory). The solution is used directly in the next stage.
HPLC method A: RT approximately 12.1 min.
MS (EIPOS): m / z = 162 [M + H] +
X H-NMR (CDCl, 400MHz): δ = 3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10:40 (1H, s)
example 3
4-formyl-3-methoxybenzonitrile (VI)
719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 1 of DMF with 313 g (0.74 mol) of potassium hexacyanoferrate (K4 [Fe (CN) 6]) and 354 g submitted (3.34 mol) of sodium carbonate and a further 1.2 1 of DMF and 3.8 g (0.017 mol) of palladium acetate. It is stirred for 3 hours at 120 ° C. Allow to cool to 20 ° C and are 5.7 1 water to approach. It is extracted with 17 1 ethyl acetate, and the aqueous phase is washed again with 17 1 of ethyl acetate to. The organic phases are combined and substantially concentrated with 5 1 of isopropanol was added and concentrated to about 2 1st The mixture is heated to boiling and dripping 2 1 of water.Allow to cool to 50 ° C and are again added 2 1 water. It is cooled to 3 ° C and stirred for one hour at this temperature. The product is filtered and washed with water (2 times 1.2 1) washed. It is dried at 40 ° C under vacuum.
Yield: 469 g (87% of theory.) Of a beige solid.
HPLC method A: RT about 8.3 min.
MS (EIPOS): m / z = 162 [M + H] +
1H-NMR (300 MHz, DMSO-d6): δ = 3.98 (s, 3H), 7:53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10:37 (s, 1H).
example 4
2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-l, 4,5,6-tett ^
din-3-carboxylate (X)
option A
1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg (8.028 mol) of 2-Cyanefhyl 3-oxobutanoate, 54.6 g (0.642 mol) of piperidine and 38.5 g (0.642 mol) of glacial acetic acid are heated under reflux on a water in 10 1 dichloromethane 6.5 hours. Allow to cool to room temperature and the organic phase was washed 2 times with 5 1 water. Subsequently, the dichloromethane phase is concentrated under atmospheric pressure and the still stirrable residue with 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridone added. The residual dichloromethane is distilled off until an internal temperature of 98 ° C is reached. Then, 20 hours, heated under reflux. It is cooled to 0 ° C, can be 4 hours at this temperature is stirred and filtered off the product. It is dried at 40 ° C under vacuum to the carrier gas.
Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridone, since this component is used in deficiency) of a slightly yellowish colored solid.
HPLC method A: RT about 9.7 min.
MS (EIPOS): m / z = 405 [M + H] +
Ή-NMR (300 MHz, DMSO-d 6 ): δ = 2:03 (s, 3H), 2:35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4:04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7:28 to 7:33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H) ,
variant B
1.344 kg (8.34 mol) of 4-formyl-3-methoxy-benzonitrile (VI), 71 g (0.834 mol) piperidine and 50.1 g (0.834 mol) of glacial acetic acid are introduced into 6 1 of isopropanol at 30 ° C within 3 hours, a solution of 1.747 kg (11.26 mol) of 2-cyanoethyl 3-oxobutanoate metered in 670 ml of isopropanol. Stirring an hour after at 30 ° C. It is cooled to 0-3 ° C and stirred at 0.5 hours. the product is filtered off and washed 2 times with 450 ml of cold isopropanol to. For yield determination is under vacuum at 50 ° C. (2.413 kg, 97% of theory..); but it is usually due to the high yield continued to work directly with the isopropanol-moist product. For this, the product is taken up with 29 1 of isopropanol and 1.277 kg (7.92
mol) of 4-amino-5-methylpyridone added, followed by 24 internal temperature under about 1.4 bar overpressure in the closed vessel is heated at 100 ° C h. It is cooled by a ramp within 5 h at 0 ° C. stirred for 3 hours at 0 ° C. It is filtered off and washed with 2.1 1 of cold isopropanol. It is dried under vacuum at 60 ° C.
Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridone, since this component is used in deficiency) of a slightly yellowish colored solid.
HPLC method A: RT about 9.7 min.
MS (EIPOS): m / z = 405 [M + H] +
Ή-NMR (300 MHz, DMSO-d 6 ): δ = 2:03 (s, 3H), 2:35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4:04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7:28 to 7:33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H) ,
example 5
2- cyanoethyl-4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI)
2.142 kg (5.3 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimefhyl-5-oxo-l, 4,5,6-tetrahydro-l, 6-naphthyridin-3 carboxylate (X) and 4.70 kg (29 mol) of triethyl orthoacetate are dissolved in 12.15 1 of dimethylacetamide and 157.5 grams of concentrated sulfuric acid was added. The mixture is heated for 1.5 hours at 115 ° C and then cooled to 50 ° C. At 50 ° C are added dropwise to 30 minutes 12.15 1 water. After complete addition the Titelbelbindung (XI) is treated with 10 g seeded and further added dropwise to 12.15 1 of water over 30 minutes at 50 ° C. It is cooled to 0 ° C (ramp, 2 hours) and stirred for 2 hours at 0 ° C to. The product is filtered, washed 2 times each with 7.7 1 of water and dried in vacuo at 50 ° C.
Yield: 2114.2 g (92.2% of theory) of a slightly yellowish colored solid.
HPLC Method B: RT 10,2 min.
MS (EIPOS): m / z = 433 [M + H] +
X H-NMR (300 MHz, DMSO-d 6 ): δ = 1.11 (t, 3H), 2.16 (s, 3H), 2:42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H) , 4:01 to 4:13 (m, 4H), 5:37 (s, 1H), 7.25 (d, 1H), 7:28 to 7:33 (m, 2H), 7.60 (s, 1H), 8:35 (s, 1H).
Alternatively, the reaction in NMP (l-methyl-2-pyrrolidone) may be carried out
2- cyanoethyl-4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI)
2.142 kg (5.3 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-l, 4,5,6-tetrahydro-l, 6-naphthyridin-3 carboxylate (X) and 2.35 kg (14.5 mol) of triethyl orthoacetate are in 3.21 kg NMP (l-methyl-2-pyrrolidone) and dissolved 157.5 g of concentrated sulfuric acid was added. The mixture is heated for 1.5 hours at 115 ° C and then cooled to 50 ° C. At 50 ° C are added dropwise to 30 minutes 2.2 1 water. After complete addition the Titelbelbindung (XI) is treated with 10 g seeded and dropped further 4.4 1 of water over 30 minutes at 50 ° C. It is cooled to 0 ° C (ramp, 2 hours) and stirred for 2 hours at 0 ° C to. The product is filtered off, washed 2 times each with 4 1 of water and dried under vacuum at 50 ° C.
Yield: 2180.7 g (95.1% of theory) of a slightly yellowish colored solid.
HPLC Method B: RT 10,2 min.
example 6
4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carboxylic acid IXM
2.00 kg (4.624 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI ) are dissolved in a mixture of 12 1 THF and 6 1 of water and cooled to 0 ° C. To this solution, a sodium hydroxide solution is added in drops within 15 minutes at 0 ° C (prepared from 0.82 kg 45% aqueous. NaOH (9.248 mol) and 4.23 1 of water and stirred for 1.5 hours at 0 ° C to . The mixture is extracted 2 times with each 4.8 1 methyl tert-butyl and once with 4.8 1 of ethyl acetate. The aqueous solution is at 0 ° C with dilute hydrochloric acid (prepared from 0.371 kg 37% HCl and 1.51 1 water ) adjusted to pH 7. the mixture is allowed to warm to 20 ° C and adding an aqueous solution of 2.05 kg of ammonium chloride in 5.54 1 water. the mixture is stirred 1 hour at 20 ° C, the product filtered and 2 times with each each 1.5 1 water and washed once with 4 1 acetonitrile. It is dried at 40 ° C under vacuum to the carrier gas.
Yield: 1736.9 g (99% of theory..) Of an almost colorless powder (very slight yellow tinge).
HPLC Method C: RT: about 6.8 min.
MS (EIPOS): m / z = 380 [M + H]
X H-NMR (300 MHz, DMSO-d 6 ): δ = 1.14 (t, 3H), 2.14 (s, 3H), 2:37 (s, 3H), 3.73 (s, 3H), 4:04 (m, 2H) , 5:33 (s, 1H), 7.26 (m, 2H), 7:32 (s, 1H), 7:57 (s, 1H), 8.16 (s, 1H), 11:43 (br. s, 1H).
Alternative workup with toluene for extraction:
4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylic-isäure (XII)
2.00 kg (4.624 mol) of 2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylate (XI ) are dissolved in a mixture of 12 1 THF and 6 1 of water and cooled to 0 ° C. To this solution, a sodium hydroxide solution is added in drops within 15 minutes at 0 ° C (prepared from 0.82 kg 45% aqueous. NaOH (9.248 mol) and 4.23 1 of water and stirred for 1.5 hours at 0 ° C to . Add 5 L of toluene and 381.3 g Natiumacetat added and stirred vigorously. Allow to settle the phases and the organic phase is separated. the aqueous phase is adjusted with 10% hydrochloric acid to pH 6.9 (at about pH 9.5 is inoculated with 10 g of the title compound of). After completion of the precipitation of the product for one hour at 0 ° C is stirred and then filtered and washed twice with 4 1 of water and twice with 153 ml of toluene. the mixture is dried at 40 ° C under vacuum to carrier gas (nitrogen, 200 mbar. yield:.. 1719.5 g (98% of theory) of an almost colorless powder (very slight yellow tinge).
HPLC Method C: RT: about 6.8 min).
example 7
4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- 1, 6-naphthyridine-3-carboxamide
1.60 kg (4.22 mol) of 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylic-isäure ( XII) and 958 g (5.91 mol) of 1,1-carbodiimidazole be presented in 8 1 of THF and at 20 ° C 51 g (0.417 mol) of DMAP was added. Stirring for one hour at 20 ° C (gas evolution!) And then heated 2.5 hours 50 ° C. are added to this solution 2.973 kg (18.42 mol) of hexamethyldisilazane and boil for 22 hours under reflux. Man admits further 1.8 1 THF and cooled to 5 ° C. A mixture is prepared from 1.17 1 of THF and 835 g of water is metered in over 3 hours, so that the temperature is between 5 and 20 ° C remains. Then boiled for one hour under reflux, then cooled via a ramp (3 hours) at 0 ° C. and stirred for one hour at this temperature. The product is filtered off and washed 2 times with 2.4 1 THF and twice with 3.2 1 water. It is dried under vacuum at 70 ° C under a carrier gas.
Yield: 1.501 kg (. 94% of theory) of an almost colorless powder (very slight yellow tinge).
HPLC Method B: RT about 6.7 min.
MS (EIPOS): m / z = 379 [M + H]
Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).
example 8
(4S) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy
carbox-amide (I) as a solution in acetonitrile / Methariol 40:60
Enantiomeric separation on a SMB unit
As a feed solution a solution corresponding to a concentration is used consisting of 50 g racemic 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridin-3 -carbox-amide (XIII) dissolved in 1 liter of a mixture of methanol / acetonitrile 60:40.
There is a SMB unit on a stationary phase: 20 chromatographed μιη Chiralpak AS-V. The pressure is 30 bar, as the eluent a mixture of methanol / acetonitrile 60:40 is used.
9.00 kg of 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (XII) are dissolved in 180 1 a mixture dissolved consisting of methanol / acetonitrile 60:40 and chromatographed by SMB. After concentrating the product-containing fractions, 69.68 liters of a 6.2% solution (corresponding to 4.32 kg (4S) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl- 1, 4-dihydro- 1, 6-naphthyridine-3-carbox-amide (I) as a solution in acetonitrile / methanol 40:60).
Yield: 4.32 kg (48% of theory.) Dissolved in 69.68 liters of acetonitrile / methanol 40:60 as a colorless fraction.
Enantiomeric purity:> 98.5% ee (HPLC, method D)
A sample is concentrated in vacuum to give: MS (EIPOS): m / z = 379 [M + H] +
Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).
example 9
(4S) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (I)
Crystallization and Polymorphism setting
64.52 liters of a 6.2% solution of Example 8 in a mixture Acetonitiril / methanol 40:60 (equal 4.00 kg of compound 1) (1.2 .mu.m) via a filter cartridge and then concentrated at 250 mbar applicable so that the solution is still stirrable. It added 48 1 of ethanol denatured with toluene and distilled again at 250 mbar to stirrability from (Umdestillation on ethanol). They gave an additional 48 1 of ethanol denatured with toluene and then distilled at atmospheric pressure to a total volume of about 14 1 from (jacket temperature 98 ° C). The mixture was cooled via a ramp (4 hours) to 0 ° C, stirred for 2 hours at 0 ° C and filtered by the product from. It was washed twice with 4 1 of cold ethanol and then dried in vacuo at 50 ° C.
Yield: 3.64 kg (91% of theory.) Of a colorless, crystalline powder
Enantiomeric purity: "99% ee (HPLC method D); Retention times / RRT: (4S) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (1) ca. 11 min. RRT: 1.00; (4R) - 4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carbox-amide (I) is about 9 min ,RRT: 0.82
Purity:> 99.8% (HPLC method B) RT: about 6.7 min.
Content: 99.9% (against an external standard)
specific rotation (chloroform, 589 nm, 19.7 ° C, c = 0.38600 g / 100 ml): - 148.8 °.
MS (EIPOS): m / z = 379 [M + H] +
Ή-NMR (300 MHz, DMSO-d 6 ): δ = 1:05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H ), 5:37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7:37 (d, 1H), 7:55 (s, 1H), 7.69 (s, 1H).
Melting point: 252 ° C (compound of formula (I) in crystalline form of modification I)
Physico-chemical characterization of compound of formula (I) in crystalline form of modification I
Compound of formula (I) melts in crystalline form of modification I at 252 ° C, ΔΗ = 95 -113 Jg 1 (heating rate 20 K min 1 , Figure 1).
A depression of the melting point was observed as a function of the heating rate.
The melting point decreases at a lower heating rate (eg 2 K min "1 ) because decomposition occurs. There were no other phase transitions. A mass loss of about 0.1% was observed up to a temperature of 175 ° C.

References

  1.  Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Herbst 2015 (German)
  2.  Pitt, B; Anker, S. D.; Böhm, M; Gheorghiade, M; Køber, L; Krum, H; Maggioni, A. P.; Ponikowski, P; Voors, A. A.; Zannad, F; Nowack, C; Kim, S. Y.; Pieper, A; Kimmeskamp-Kirschbaum, N; Filippatos, G (2015). "Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): A randomized study of finerenone vs. Eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease". European Journal of Heart Failure 17 (2): 224–32.doi:10.1002/ejhf.218PMID 25678098.
  3.  Bakris, G. L.; Agarwal, R; Chan, J. C.; Cooper, M. E.; Gansevoort, R. T.; Haller, H; Remuzzi, G; Rossing, P; Schmieder, R. E.; Nowack, C; Kolkhof, P; Joseph, A; Pieper, A; Kimmeskamp-Kirschbaum, N; Ruilope, L. M.; Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group (2015). "Effect of Finerenone on Albuminuria in Patients with Diabetic Nephropathy: A Randomized Clinical Trial". JAMA 314 (9): 884–94. doi:10.1001/jama.2015.10081PMID 26325557.
Finerenone.svg
Systematic (IUPAC) name
(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide
Clinical data
Legal status
  • Investigational
Routes of
administration
Oral
Identifiers
CAS Number1050477-31-0
ATC codeNone
PubChemCID 60150535
ChemSpider28669387
UNIIDE2O63YV8R
KEGGD10633
ChEMBLCHEMBL2181927
SynonymsBAY 94-8862
Chemical data
FormulaC21H22N4O3
Molar mass378.42 g/mol


////Finerenone , BAYER, PHASE 3, BAY 94-8862
CCOC1=NC=C(C2=C1C(C(=C(N2)C)C(=O)N)C3=C(C=C(C=C3)C#N)OC)C