| Patent | Submitted | Granted |
|---|---|---|
| COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY AND FIBROTIC DISORDERS [US2009318455] | 2009-12-24 | |
| COMPOSITION AND METHOD FOR TREATING PROTEINURIA [US2010099719] | 2010-04-22 | |
| COMPOSITION AND METHOD FOR TREATING FIBROTIC DISEASES [US2009258911] | 2009-10-15 | |
| Composition and Method for Treating Fibrotic Diseases [US2008319027] | 2008-12-25 | |
| METHODS FOR TREATING ACUTE MYOCARDIAL INFARCTIONS AND ASSOCIATED DISORDERS [US2010190731] | 2010-07-29 | |
| Methods for Treating Acute Myocardial Infarctions and Associated Disorders [US2011218515] | 2011-09-08 | |
| METHODS OF TREATING HIV PATIENTS WITH ANTI-FIBROTICS [US2012014917] | 2012-01-19 | |
| Composition and Method for Treating Fibrotic Diseases Composition and Method for Treating Fibrotic Diseases [US2009005424] | 2007-08-30 | |
| Crystalline 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridone, the preparation methods, compositions and applications thereof [US8232408] | 2009-03-10 | 2012-07-31 |
FLAGS AND HITS
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
Join me on Linkedin
Join me on Researchgate
Join me on Facebook
FACEBOOK
...................................................................Join me on twitter
..................................................................Join me on google plus
Googleplus
FACEBOOK
...................................................................Join me on twitter
..................................................................Join me on google plus
GoogleplusMYSELF
DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai)
, INDIA
36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google,
NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64
Merck’s Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP)
Indoline 7 as in ACS MEDCHEM LETTERS, DOI: 10.1021/acsmedchemlett.5b00404
and
eg 10 as in WO2015054088
(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.
1H-Indole-1-ethanol, 2,3-dihydro-3-[3-(trifluoromethoxy)phenyl]-3-[[3-(trifluoromethoxy)phenyl]methyl]-α-(trifluoromethyl)-, (αR)-
cas 1699732-96-1 R ISOMER
MF C26 H20 F9 N O3, MW 565.43
Merck Sharp & Dohme Corp. INNOVATOR
Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from 1H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK–PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.
chemical compounds that inhibit cholesterol ester transfer protein (CETP) and are expected to have utility in raising HDL-C, lowering LDL-C, and in the treatment and prevention of atherosclerosis.
see………….http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00404
http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00404/suppl_file/ml5b00404_si_001.pdf
Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach
†Department of Medicinal Chemistry and ‡Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States
§Department of Pharmacology, ∥Department of Drug Metabolism and Pharmacokinetics, and ⊥Department of Biology, Merck Research Laboratories, Merck & Co, Inc., P.O. Box 2000, Kenilworth, New Jersey 07033, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.5b00404
Publication Date (Web): January 4, 2016
Copyright © 2016 American Chemical Society
*E-mail: jonathan_wilson@merck.com.
PATENT
Atherosclerosis and its clinical consequences, including coronary heart disease
(CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as an epidemic in obesity and diabetes continues to grow.
It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA reductase inhibitors, especially the statins, in reducing coronary events is based on the reduction of circulating low density lipoprotein cholesterol (LDL-C), levels of which correlate directly with an increased risk for atherosclerosis. More recently, epidemiologic studies have
demonstrated an inverse relationship between high density lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
Metabolic control of lipoprotein levels is a complex and dynamic process involving many factors. One important metabolic control in man is the cholesteryl ester transfer protein (CETP), a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, C.B., et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282)). Under physiological conditions, the net reaction is a heteroexchange in which CETP carries triglyceride to HDL from the apoB lipoprotein and transports cholesterol ester from HDL to the apoB lipoprotein.
In humans, CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues. Intriguingly, many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al, (1998)
Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3), 517-525). Numerous epidemiologic studies correlating the effects of natural variation in CETP activity with respect to coronary heart disease risk have been performed, including studies on a small number of known human null mutations (see Hirano, K.-L, Yamashita, S. and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies have clearly demonstrated an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu, A., et. al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologic inhibition of CETP lipid transfer activity may be beneficial to humans by increasing levels of HDL-C while lowering LDL-C.
Despite the significant therapeutic advance that statins such as simvastatin and atorvastatin represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
Currently, few pharmacologic therapies are available that favorably raise circulating levels of HDL-C. Certain statins and some fibrates offer modest HDL-C gains. Niacin provides an effective therapy for raising HDL-C but suffers from patient compliance issues, due in part to side effects such as flushing. Drugs that inhibit CETP (CETP inhibitors) have been under development with the expectation that they will effectively raise HDL cholesterol levels and also reduce the incidence of atherosclerosis in patients. Torcetrapib was the first drug that was tested in a long-term outcomes clinical trial. The clinical trial of torcetrapib was terminated early due to a higher incidence of mortality in patients to whom torcetrapib and atorvastatin were administered concomitantly compared with patients who were treated with atorvastatin alone. The cause of the increased mortality is not completely understood, but it is not believed to be associated with the CETP inhibiting effects of the drug.
Two other drug candidates, dalcetrapib and anacetrapib, are currently being tested in Phase III clinical trials, including large scale outcomes trials. Data from the recently completed DEFINE Phase III trial of anacetrapib are promising. Patients who were being treated with anacetrapib along with baseline statin therapy showed an increase of HDL-C of 138% and a decrease of LDL-C of 40%> compared with patients who were treated with just a statin. See: N. Engl. J. Med. 2010: 363: 2406-15. The data in the DEFINE trial were sufficient to indicate that an increase in mortality for patients treated with anacetrapib is unlikely. Additional drug candidates are still being sought that may have properties that are advantageous compared with the CETP inhibitors that have so far been studied or are currently being studied. Such properties may include, for example, higher potency, reduced off-target activity, better pharmacodynamics, higher bioavailability, or a reduced food effect compared with many of the highly lipophilic compounds that have so far been studied. “Food effect” refers to the variability in exposure to the active drug that occurs depending on when the patient had last eaten, whether or not the drug is administered with food, and the fat content of the food.
Example 18 as in patent
(R)- 1,1, 1 -trifluoro-3-((R)-4-(3-trifluoromethoxy)benzyl)-2-(3-(l, 1 ,2,2,-tetrafluoroethoxy)phenyl)-3,4- dihydroquinoxalin- 1 (2H)-yl)propan-2-ol
SPA: 15 nM
Example 18 was prepared from 2-bromo-l-(3-(l , 1 ,2,2,-tetrafluoroethoxy)phenyl)ethanone in three steps, using the reactions detailed in Schemes A6, A2 and Al . Spectral data are as follows: 1H NMR (400 MHz, CDC13) £2.70 (bd, J=4.1 Hz, IH), 3.24 (dd, J=l 1.3, 3.4 Hz, IH), 3.34 (dd, J=15.5, 9.7 Hz, IH), 3.58 (dd, J=l 1.3, 3.3 Hz, IH), 3.86 (d, J=15.4 Hz, IH), 4.20 (d, J=15.7 Hz, IH), 4.40 (d, J=15.8 Hz, IH), 4.46 (m, IH), 4.927 (t, J=3.3 Hz, IH), 5.90 (tt, J=53.1 , 2.7 Hz, IH), 6.59 (d, J= 7.9 Hz, IH), 6.72 (m, 2H), 6.84 (m, 2H), 6.92 (d, J=7.6 Hz, IH), 7.20 (m, 2H), 7.35 (t, J=7.9 Hz, IH), MS m/z = 613.03.
Scheme A12
Methyl 3 – { 1 – [(R)-3 ,3 ,3 -trifluoro-2-hy droxypropyl] -4- [3 -(trifluoromethoxy) benzyl]-l,2,3,4-tetrahydroquinoxalin-2-yl}benzoate (700 mg, 1.262 mmol) is made as described in Example 16 but with one stereochemical center unresolved. The compound was dissolved in MeOH (12.6mL), lithium hydroxide monohydrate (530 mg, 12.62 mmol) was added, and the reaction mixture was heated to 60°C for 4 hours. The crude mixture was dissolved in saturated ammonium chloride solution and extracted into EtOAc, the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and purified on a silica gel column with a 0-100% Hex/EtOAc gradient. The major peak was concentrated to afford 3-{l-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-l,2,3,4-tetra-hydroquinoxalin-2-yl} benzoic acid. MS m/z = 541.09.
1H and 13C NMR spectra for compound 7
(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.
Patent
WO2015054088
http://google.com/patents/WO2015054088A1?cl=en
Scheme Al
Scheme A2
Scheme A3
R = Ar, NR2l C02R, CN, S02Me
es
es
SEE EXAMPLE ………SIMILAR BUT NOT SAME
Example 1. (2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. This material was prepared according to Scheme Al, as described below.
3-(3-(trifluoromethyl)phenyl)indolin-2-one. Oxindole (1.598 g, 12 mmol), 3-bromo-a,a,a-trifluoromethyltoluene (2.009 ml, 14.40 mmol), potassium carbonate (3.32 g, 24.00 mmol), Pd2dba3 (0.220 g, 0.240 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.458 g, 0.960 mmol) were combined in THF (12 ml) and the mixture was degassed with nitrogen. The solution was then heated to 80 °C for 18h. The mixture was cooled to room temperature, filtered through silica eluting with ethyl acetate, and concentrated. The material was then purified by silica gel chromatography (Biotage lOOg SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethyl)phenyl)indolin-2-one as a white solid.
1H NMR (500 MHz) δ 8.58 (s, 1H), 7.61 (d, J=7 Hz, 1H), 7.53-7.45 (m, 3H), 7.33-7.29 (m, 1H), 7.16 (d, J=7 Hz, 1H), 7.10 (m, 1H), 7.01-6.90 (m, 1H), 4.73 (s, 1H).
3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin-2-one . 3 -Trifluoromethoxy-benzylbromide (0.204 ml, 1.255 mmol) was added to a mixture of 3-(3-(trifluoromethyl)-phenyl)indolin-2-one (290 mg, 1.046 mmol) and potassium carbonate (289 mg, 2.092 mmol) (sodium carbonate may be used in place of potassium carbonate) in DMA (2.5 ml). The mixture was stirred at r.t. for 16h. The reaction was diluted with ethyl acetate and washed with water (3×5 mL). The organic layer was dried with Na2S04, filtered, and concentrated. The products were then purified by silica gel chromatography (Biotage 50g SNAP cartridge; 0-40%> ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-2-one .
1H NMR (500 MHz) δ 7.79 (s, 1H), 7.73 (d, J=7 Hz, 1H), 7.62-7.60 (m, 2H), 7.51 (t, J=7 Hz, 1H), 7.26- 7.22 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 7.11 (m, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 6.78 (m, 1H), 6.73 (s, 1H), 3.77 (d, J=13 Hz, 1H), 3.49 (d, J=13 Hz, 1H).
LCMS m/z = 451.8 (M+H)
3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. Borane tetrahydrofuran complex (1.673 ml, 1.673 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indolin-2-one (302 mg, 0.669 mmol) in THF (1.5 ml). The mixture was heated to 70 °C for 20h. The reaction was cooled to room temperature and quenched with saturated NH4C1 solution, and this mixture was stirred vigorously for 20 minutes. The product was extracted with ethyl acetate. The extracts were dried over Na2S04, filtered, and concentrated. The product was purified by silica gel chromatography (Biotage 25g SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. This material may also be used without purification in the final step of the sequence, epoxide opening.
1H NMR (500 MHz) δ 7.66 (s, IH), 7.59 (d, J=7 Hz, IH), 7.53 (d, J=7 Hz, IH), 7.45 (t, J=8 Hz, IH), 7.18-7.13 (m, 2H), 7.04 (d, J=8 Hz, IH), 6.98 (d, J=7 Hz, IH), 6.81 (t, J=7.5 Hz, IH), 6.71 (m, 2H), 6.60 (s, IH), 3.83 (m, IH), 3.75-3.73 (m, 2H), 3.46 (d, J=13 Hz, IH), 3.41 (d, J=13 Hz, IH).
= 437.9 (M+H)
(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. (S)-2-(trifluoromethyl)oxirane (81 μΐ, 0.933 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline (136 mg, 0.311 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (412 μΐ, 3.91 mmol). The reaction was stirred at room temperature overnight. The solvent was removed and the product was purified by silica gel chromatography (Biotage 25 g SNAP cartridge; 0-25% ethyl acetate in hexanes) to provide (2R)- 1 ,1,1 -trifluoro-3 -(3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin- 1 -yl)propan-2-ol.
1H NMR (500 MHz) (mixture of diastereomers) δ 7.72 (s, 0.5 H), 7.69 (s, 0.5 H), 7.65 (d, J=6.5 Hz, 0.5 H), 7.61 (d, J=7.5 Hz, 0.5 H), 7.56 (s, 1H), 7.50 (m, 1H), 7.25-7.17 (m, 2H), 7.07 (broad s, 2H), 6.91-6.89 (m, 1H), 6.79-6.75 (m, 1H), 6.53 (m, 2H), 4.00 (broad s, 1H), 3.83 (d, J= 9 Hz, 0.5H), 3.77 (d, J=9 Hz, 0.5H), 3.59-3.55 (m, 1H), 3.45-3.43 (m, 1H), 3.39-3.29 (m, 2H), 3.21-3.15 (m, 1H), 2.32 (m, 0.5H), 2.15 (m, 0.5H).
LCMS m/z = 549.8 (M+H)
Examples 1-25, in the table below, were prepared according to Scheme Al in a
SEE EG 10…….(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.
ABOUT AUTHOR
Jonathan Wilson
Associate Principal Scientist at Merck
https://www.linkedin.com/in/jonathan-wilson-23206523
Experience
Associate Principal Scientist
Merck
October 2013 – Present (2 years 4 months)
Senior scientist
Merck
May 2009 – October 2013 (4 years 6 months)
Postdoctoral researcher
Princeton University
October 2007 – May 2009 (1 year 8 months)
Associate Medicinal Chemist
Merck
2000 – 2002 (2 years)
Education
///////CETP inhibition, cholesterol ester transfer protein, HDL, indoline, tetrahydroquinoxaline, merck, discovery
c21ccccc1N(C[C@@]2(c3cccc(c3)OC(F)(F)F)Cc4cc(ccc4)OC(F)(F)F)C(C(F)(F)F)O
FC(F)(F)Oc1cccc(c1)C3(CN(C[C@@H](O)C(F)(F)F)c2ccccc23)Cc4cccc(OC(F)(F)F)c4
see…………http://worlddrugtracker.blogspot.in/2016/01/mercks-novel-indoline-cholesterol-ester.html
Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products
Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.
Two examples out of several in the publication discussed below……………
1 Diphenhydramine Hydrochloride
Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.
2 Olanzapine
Scheme 2. Continuous Flow Synthesis of Olanzapine
Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.
In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd2dba3 as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H2O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et3SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.
The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)4 as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.
SEE MORE IN THE PUBLICATION…………..
Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products
Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00325
Publication Date (Web): November 26, 2015
Copyright © 2015 American Chemical Society
*E-mail: maurizio.benaglia@unimi.it., *E-mail: alessandra.puglisi@unimi.it.
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Riccardo Porta
PhD Student
Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
//////////
Fluorofenidone
Fluorofenidone
1- (3-fluorophenyl) -5-methyl – 2 (1H) pyridone
2(1H)-Pyridinone, 1-(3-fluorophenyl)-5-methyl-
1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one
C12 H10 F N O, 203.2123
PRECLINICAL, IND Filing
An anti-inflammatory agent potentially for the treatment of organ fibrosis.
CAS No. 848353-85-5
Synthesis
PATENT
WO 2006108354
http://www.google.co.in/patents/WO2006108354A1?cl=en
PATENT
http://www.google.com/patents/CN102241625A?cl=zh
(Compound 1)
A. (3_ fluorophenyl) methyl pyridine _2 (IH) 1- -5_ – -one
9. 6gDMF, 45 0g (0 2mol.) Inter-fluoro-iodobenzene, 21 8g (0. 2mol) 5_ methylpyridine _2_ (IH) -.. -one, 28g of anhydrous potassium carbonate and 1. Og copper powder, 160 ° -170 °, the reaction was stirred at reflux for 20 hours, the natural cooling to 110~120 ° C, was slowly added to about 330ml 80~90 ° C hot water, cooled to 20 ° C. Suction filtered, the filter cake was washed with about 20ml of water, remove the cake, with about 300ml of ethyl acetate ultrasound 30min, suction filtered, the filter residue was washed with 20ml of ethyl acetate. The combined ethyl acetate, washed with water three times (50ml * 3), and the filtrate layers were separated and allowed to stand for 15min, ethyl acetate fraction was concentrated to a non-steamed, hot added under stirring for about 85ml of petroleum ether, cooling to 15~20 ° C insulation ~ 1.5 hours. Filtration, the filter cake was washed twice with petroleum ether (about 20ml * 2) used to give 34. 9g crude. Recrystallized from 20% ethanol to give the product 1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one as a white solid # 30. Ig0 Μ P.: 132 · 1 ~133 7 °.. C.
PATENT
http://www.google.co.in/patents/WO2009149188A1?cl=zh-CN
PATENT
CN 102241625
http://www.google.com/patents/CN102241625A?cl=zh
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009111947
PAPER
| CN1386737A * | Jun 11, 2002 | Dec 25, 2002 | 中南大学湘雅医学院 | Antifibrosis pyridinone medicine and its prepaing process |
| CN1846699A | Apr 13, 2005 | Oct 18, 2006 | 中南大学湘雅医院 | Application of 1-(substituted phenyl)-5-methyl-2-(1H)-pyridone compound in preparing medicine for anti-other organifibrosis and tissue fibrosis except renal interstitial fibrosis |
| CN101235013A* | Mar 10, 2008 | Aug 6, 2008 | 广东东阳光药业有限公司;张中能 | Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application |
| US20070203203 | May 1, 2007 | Aug 30, 2007 | Tao Li J | Composition and Method for Treating Fibrotic Diseases |
/////////
CC1=CN(C(=O)C=C1)C2=CC(=CC=C2)F
PNQ 103 from Advinus for the potential treatment of COPD,; sickle cell disease (SCD)
Formula I and Formula II
OR
PNQ 103
STRUCTURE COMING…………
for the potential treatment of COPD & sickle cell disease (SCD)
Adenosine A2b receptor antagonist
Advinus Therapeutics Ltd
KEEP WATCHING THIS POST……….
PNQ-103 is a proprietary A2B Adenosine receptor (A2BAdoR antagonist), currently in the pre-clinical development stage for the potential treatment of COPD & sickle cell disease (SCD). Advinus is looking for partnering/co-development opportunities.
A2BAdenosine Receptor (A2BAdoR) Antagonist PNQ-103 for COPD and SCD
COPD
Chronic Obstructive Pulmonary Disease (COPD) is a disease that damages lung tissue or restricts airflow through the bronchioles and bronchi, and commonly leads to chronic bronchitis and emphysema. COPD, along with asthma, forms the third leading cause of death in both developed and developing countries and an annual direct and indirect cost of healthcare of more than $50 billion in the US alone. Current therapies suffer from lack of long term efficacy, patient compliance and a narrow therapeutic index.
Adenosine is a powerful bronchoconstrictor and pro-inflammatory agent in COPD and asthma. Adenosine regulates tissue function by activating its receptors: A1AdoR and A2AAdoR are high affinity receptors and A2BAdoR and A3AdoR are low affinity receptors. During pathological conditions in lung, local adenosine concentrations rise to high levels and activate A2BAdoR. A2BAdoR agonized by adenosine induces both bronchoconstriction and pro-inflammatory effects in lung by acting on multiple cell types that lead to airway hyperreactivity and chronic inflammation. Therefore, A2BAdoR antagonists are expected to be beneficial in COPD and asthma.
PNQ-103 is a proprietary A2BAdoR antagonist, currently in the pre-clinical development stage for the potential treatment of COPD. It is a potent, selective, orally bio-available agent with low clearance and small volume of distribution. PNQ-103 is efficacious in standard rodent asthma and lung fibrosis models. PNQ-103 was found to be safe in exploratory safety studies including a Drug Matrix Screen, mini-AMES test, and a test for cardiovascular liability in dog telemetry as well as a 30- day repeat dose study in rats.
SCD
Sickle Cell Disease (SCD) affects millions of people worldwide. It is caused by an autosomal mutation in the hemoglobin gene (substitution of amino-acid valine [Hb A] for glutamic acid [Hb S]. Hb S in low O2 condition polymerizes, leading to distortion of the cell membrane of red blood cells (RBC) into an elongated sickle shape. Sickled RBCs accumulate in capillaries causing occlusions, impair circulation and cause tissue damage and severe disabilities. Unfortunately, there is no targeted therapy for SCD.
Adenosine levels are elevated in SCD patients. Activation of the A2BAdoR by adenosine increases 2,3-DPG levels in RBCs, which reduces Hb S affinity to O2 and promotes its polymerization leading to RBC sickling. A recent study published in Nature Medicine (2011; 17:79-86) demonstrated potential utility of an A2BAdoR antagonist for the treatment of SCD, through selective inhibition of 2,3-DPG production in RBCs. Therefore, PNQ-103, a selective A2BAdoR antagonist, is expected to be useful for the treatment of SCD. In support, ex vivo PoC (selective inhibition of 2,3-DPG production) has been established for PNQ-103 in RBCs from normal and SCD patients.
EXAMPLES………
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012035548
Example 1: Phosphoric acid mono-{2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyraz -4-yl]-l,6-dihydr»-purin-7-ylmethyl} ester
Step I: Synthesis of l-(3-Trifiuoroirethyl-ben:ijl)-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,354-tetrahydro-pyrimidin-5-yl)-amide
A mixture of 5,6-diamino-3-propyl-l H-pyrimidine-2,4-dione (4.25 g, 0.023 mol), l-(3-Trifluoromethyl-benzyl)-lH-pyrazole-4-carboxylic acid (6.23 g, 0.023 mol), prepared by conventional methods starting from pyrazole-4-carboxylic ester, in methanol (50 ml) were cooled to 0 °C and added EDCI.HC1 (8.82 g, 0.046 mol). The reaction mixture was stirred at 25 °C for 6 h and the organic volatiles were evaporated. To this residue water (50 ml) was added and the precipitate was filtered off, and washed with cold water (50 ml) to obtain l-(3-Trifluoromethyl-benzyl)- 1 H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (7.2 g, 72 %) as a pale yellow solid.
‘HNMR(400MHz, DMSO d6): δ 0.82 (t, J=7.6Hz, 3H); 1.46-1.51 (m, 2H); 3.64 (t, J=7.2Hz, 2H); 5.49 (s, 2H); 6.01 (s, 2H); 7.55-7.63 (m, 2H); 7.68-7.72 (m, 2H); 7.99 (s, 1H); 8.37 (s, 1H); 8.55 (s, 1H); 10.42 (s, 1H).
Step II: Preparation of l-Propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazoI-4-yl]-3,7-dihydro-purine-2,6-dione
A mixture of l-(3-Trifluoromethyl-benzyl)-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (30 g, 0.068 mol), P205(34.0g, 0.240.8 mol) and DMF (300ml) were heated at 100 °C for 30 minutes. The reaction mixture was cooled to 20-25 °C. The reaction mixture was slowly poured into water (1.5 L) with vigorous stirring. Solid material separated was filtered off, and washed with water (200ml) to obtain 1 -Propyl-8-[l -(3-trifluoromethyl-benzyl)-l H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (25 g, 88 %) as a pale yellow solid.
‘HNMR(400MHz, DMSO d6): δ 0.87 (t, J=7.2Hz, 3H); 1.53-1.60 (m, 2H); 3.98 (t, J=7.2Hz, 2H); 5.53 (s, 2H); 7.57-7.64 (m, 2H); 7.69-7.71 (m, 2H); 8.08 (s, 1H); 8.47 (s, 1H); 1 1.83 (s, 1H); 13.39 (s, 1H)
Step III: Preparation of 2-ChIoro-l-propyI-8-[l-(3-trifluoromethyI-benzyl)-lH-pyrazol-4-yl]-l,7-dihydro-purin-6-one
A mixture of l-Propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (7.2 g, 0.017 mol), NH4C1 (4.54 g, 0.085 mol) and POCl3 (220 ml) were heated at 120-125 °C for 72 h. Reaction mixture was cooled to 20-25 °C. It was then concentrated under vacuum and quenched with cold water slowly and solid material was separated. It was filtered off and washed with water. The solid material was dried under vacuum. The crude product was purified by column chromatography using silica gel (230-400 mesh) and 0.5 to 4 % methanol in chloroform as an eluent to obtain 2-Chloro-l-propyl-8-[l-(3-trifluoromethyl-benzyl)- lH-pyrazol-4-yl]-l,7-dihydro-purin-6-one (4.2 g, 58 %) as a pale yellow solid.
‘HNMR(400MHz, CD3OD): 6 1.02 (t, J=7.2Hz, 3H); 1.78-1.84 (m, 2H); 4.29 (t, J=7.6Hz,
2H); 5.52 (s, 2H); 7.56-7.57 (m, 2H); 7.63 (m, 2H); 8.12 (s, 1H); 8.35 (s, 1 H)
Step IV: Preparation of 6-Oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-6,7-dihydro-lH-purine-2-carbonitrile
A mixture of 2-Chloro-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-l H-pyrazol-4-yl]-l ,7-dihydro-purin-6-one (O. lg, 0.23 mmol), NaCN (0.016 g, 0.35 mmol), Nal (0.069g, 0.46 mmol) and DMF (2 ml) were stirred for 48 h at 65-70 °C. Reaction mixture was cooled to 20-25 °C and water was added. Solid material was separated. It was filtered off and washed with water. The product was dried under vacuum to obtain 6-Oxo-l-propyl-8-[l-(3-
trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-6,7-dihydro-lH-puriiAe-2-carbonitrile (0.075 g, 77 %) as an off white solid.
‘HNMR(400MHz, DMSO d6): δ 0.97 (t, J=7.6Hz, 3H); 1.71-1.77 (m, 2H); 4.12 (t, J=7.6Hz, 2H); 5.51 (s, 2H); 7.57-7.67 (m, 4H); 8.14 (s, 1H); 8.55 (s, 1H); 14.01 (bs, 1H)
Preparation of hosphoric acid di-tert-butyl ester chloromethyl ester:
Step I: Phosphoric acid di-tert-butyl ester
A mixture of di-tert-butylphosphite (5 g, 0.026 mol), NaHC03 (3.71 g, 0.044 mol) and water (50 ml) were taken and cooled to 0-(-5 , °C. KMn04 (6.18 g, 0.039 mol) was added to the reaction mixture in portion wise over ¾ period of 30 minutes at that temperature. The reaction mixture was allowed to warm to 20-25 °C ana stirred for 1.5 hours at that temperature. To this reaction mixture activated charcoal (25 g) was added and stirred at 55-60 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered off and washed with water (200 ml). The filtrate was concentrated to half of its volume and cooled to 0 °C. It was then acidified with con. HC1 (pH~l-2) to obtain solid. The solid material was filtered off, washed with ice cold water and dried under vacuum to obtain Phosphoric acid di-tert-butyl ester as white solid (3.44 g, 63 %).
Step II. Phosphoric acid di-tert-butyl ester chloromethyl ester
A mixture of Phosphoric acid di-tert-butyl ester (1 g, 0.0048 mol), NaHC03 (0.806 g, 0.0096 mol), tetra butyl ammonium hydrogen sulphate (0.163 g, 0.00048 mol), water (40 ml) and DCM (25 ml) were taken. The mixture was cooled to 0 °C and stirred at that temperature for 20 minutes. Chloromethyl chlorosulphatc (0.943g, 0.0057 mol) in DCM (15 ml) was added to it at 0 °C. The reaction mixture allc ed to warm to room temperature and stirred for 18 hours. The organic layer was separated and aqueous layer was extracted with DCM (30 ml). The organic layer was washed with brine (60 ml) solution and dried over Na2SC>4. The organic layer was evaporated to obtain Phosphoric acid di-tert-butyl ester chloromethyl ester as colorless oil (0.79 g, 64%).
Step I: Phosphoric acid di-tert-butyl ester 2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-l,6-dihydro-purin-7-ylmethyl ester
A mixture of 6-Oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-6,7-dihydro-lH-purine-2-carbonitrile (0.5 g, 0.0012mol), K2C03 (0.485 g, 0.0036 mol ) and acetone ( 10 ml) were taken and stirred for 20 minutes at room temperature. Nal (0.702 g, 0.0047 mol) was added and then Phosphoric acid di-ten-butyl ester chloromethyl ester (0.619 g, 0.0024 mol in 2 ml acetone) was added to the reaction mixture drop wise. The reaction mixture was heated at 45 °C for 16 h. The reaction mixture was filtered through celite and washed with acetone. The organic layer was concentrated and the residue was taken in ethyl acetate (30 ml) and saturated NaHC03 solution (20 ml). The organic layer was separated and washed with saturated sodium thiosulphate solution (20 ml). The organic layer was washed with 0.5 N HC1 solution (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate and evaporated to obtain brown colored mass. The crude product, which is a mixture of N7 and N9 isomers was purified by column chromatography (230-400 mesh silica gel and it was first treated with 5% triethyl amine in hexane) using 5-20 % acetone in hexane (with 0.5 to 1% triethyl amine) as an eluent to obtain N7 isomer (0.34g, 45 % ) and N9 isomer ( 0.1 lg, 14 % )
Phosphoric acid di-tert-butyl ester 2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-l,6-dihydro-purin-7-ylmethyl ester (N7-isomer).
Ή NMR (400MHz, DMSO d6):6 0.95 (t J=8Hz, 3H); 125 (s, 18 H); 1.75-1.80 (m, 2H); 4.18 (t, J=7.2Hz, 2H); 5.58 (s, 2H); 6.34 (d, 
2H); 7.61-7.63 (m, 2H); 7.70-7.73 (m, 2H); 8.19 (s, 1H); 8.75 (s, 1H)
Phosphoric acid di-tert-butyl ester 2-cyano-8-[l-(3-trifluoromethyI-benzyl)-lH-pyrazol-4-yl]-6-oxo-l-propyl-l,6-dihydro-purin-9-ylmethyl ester (N9-isomer)
Ή NMR (400MHz, DMSO d6): δ 0.94 (t, J=8Hz, 3H); 125 (s, 18 H); 1.74-1.78 (m, 2H); 4.21 (t, J=7.2Hz, 2H); 5.59 (s, 2H); 6.05 (d, J=10.8Hz, 2H); 7.62-7.63 (m, 2H); 7.69-7.71 (m, 2H); 8.16 (s, 1H); 8.71 (s, 1H)
Step II: Phosphoric acid mono-{2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-l,6-dihydro-purin-7-ylmethyl} ester (N7-isomer).
The above product, N7 isomer (0.34 g, 0.52 mmol) was dissolved in DCM (20 ml) and TFA (0.29 ml, 4.2 mmol) was added to it. The reaction mixture was stirred at room temperature for 7 hours. The organic volatiles were evaporated and the residue was stirred with pentane: diethyl ether (3:1, 10 ml) and the solid material obtained was filtered off and washed with 10 % diethyl ether in pentane (10 ml) to obtain Phosphoric acid mono- {2-cyano-6-oxo-l -propyls’ [ 1 -(3 -trifluoromethyl-benzyl)- 1 H-pyrazol-4-yl]- 1 ,6-dihydro-purin-7-ylmethyl } ester (0.239g, 85 %) as an off white solid.
(400MHz, DMSO d6): δ 0.96 (t, J=7.6Hz, 3H); 1.75-1.81 (m, 2H); 4.16 (t, J=7.2Hz, 2H); 5.58 (s, 2H); 6.23 (d, J=6Hz, 2H); 7.61-7.63 (m, 2H); 7.69-7.75 (m, 2H); 8.22 (s, 1 H); 8.80 (s, 1H); (M+1): 538.2
Phosphoric acid mono-{2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyl)-lH-pyrazol-4-yl]-l,6-dihydro-purin-9-ylmethyl} ester (N9-isomer, 28%)
(400MHz, DMSO d6): δ 0.93 (t, J=7.6Hz, 3H); 1.72-1.80 (m, 2H); 4.16 (t, J=7.2Hz, 2H); 5.54 (s, 2H); 5.95 (d, J=6Hz, 2H); 7.59-7.60 (m, 2H); 7.67-7.73 (m, 2H); 8.17 (s, 1H); 8.72 (s, 1H).
Step III: Phosphoric acid mon -{2-cyano-6-oxo-l-propyl-8-[l-(3-trifluoromethyl-benzyI)-lH-pyrazol-4-yl]-l,6-dihydro-purin-7-yimethyl} ester di sodium salt
The above product (0.239g, 0.44 mmol) and water (25 ml) were taken. To the suspension formed, NaHC03 solution (0.1 12g, 1.3 mmol in 20 ml water) was added. The reaction mixture was stirred at room temperature for 1.5 h and the solid material obtained was filtered off. The clear solution was passed through reverse phase column chromatography (LCMS). The fraction obtained was evaporated. It was lyophilized to obtain pure Phosphoric acid mono-{2-cyano-6-oxo- 1 -propyl-8-[ 1 -(3 -trifluoromethyl-benzyl)- 1 H-pyrazol-4-yl]- 1 ,6-dihydro-purin-7-ylmethyl} ester di sodium salt (0.208g; 80%) as an off white solid.
Ή NMR: (400MHz, D20): δ 0.97 (t, J=7.6Hz, 3H); 1.80-1.86 (m, 2H); 4.28 (t, J=7.6Hz, 2H); 5.53 (s, 2H); 6.04 (d, J=3.2Hz, 2H); 7.52-7.53 (m, 2H); 7.62-7.64 (m, 2H); 8.22 (s, 1H); 8.74 (s, 1H)
31P NMR: (400MHz, D20): δ 0.447
EXAMPLES…………..
Patent
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009118759
Example Al: 1, 3-Dipropyl-8-[l-(3-p-tolyl-prop-2ynyl)-lH-pyrazol-4-yI]-3, 7-dihydro-purine-2, 6-dione
Step I: l-(3-p-ToIyl-prop-2-ynyl)-lH-pyrazole-4-carboxylic acid ethyl ester
A mixture of l-prop-2-ynyl-lH-pyrazole-4-carboxylic acid ethyl ester obtained as given in example Bl (0.20Og, l.lmmol), 4-iodo toluene (0.254g, 1.1 mol), copper iodide (0.021g, O.l lmmol), dichlorobis (triphenylphosphine)-palladium (II) (39mg, O.Oόmmol), triethylamine (2ml), DMF (2ml) was degassed for lOmin. and stirred for 20hrs at 25-25 0C. Reaction mixture was diluted with water (10ml) and extracted with
• ethyl acetate. Organic layer was washed with brine solution and dried over Na2SO4.
The solvent was evaporated and crude product was purified by column chromatography
(Ethyl acetate: hexane-12:78) to obtain pure l-(3-p-tolyl-prop-2-ynyl)-lH-pyrazole-4- carboxylic acid ethyl ester compound (0.226g, 75%). 1HNMR^OOMHZ, CDCl3): δ 1.35 (t, J=6.8Hz, 3H); 2.37 (s, 3H); 4.31 (q, J=6.8Hz, 2H); 5.18 (s, 2H); 7.16 (d, J=7.6Hz, 2H); 7.38 (d, J=8Hz, 2H); 7.95 (s, IH); 8.21 (s, IH)
Step II: l-(3-p-Tolyl-prop-2-ynyl)-lH-pyrazole-4-carboxy!ic acid l-(3-p-Tolyl-prop-2-ynyl)-lH-pyrazole-4-carboxylic acid ethyl ester (0.226g, 0.84 mmol) was dissolved in a mixture of solvents THF: methanol: water (3:1:1, 10ml) and LiOH (0.07 Ig, 1.7mol) was added to the reaction mixture with stirring. The reaction mixture was then stirred at 20-25 0C for 2 hours. Solvents were evaporated and the residue was diluted with water (0.5 ml) and acidified with dil. HCl, filtered and dried to obtain off white precipitate, l-(3-p-Tolyl-prop-2-ynyl)-lH-pyrazole-4-carboxylic acid (0.182g, 90%).
1HNMR^OOMHZ, CDCl3): δ 2.37 (s, 3H); 5.2 (s, 2H); 7.16 (d, J=7.6Hz, 2H); 7.38 (d, J=8Hz, 2H); 8.01 (s, IH); 8.29 (s, IH) Step III: 1, 3-Dipropyl-8-[l-(3-p-tolyl-prop-2ynyl)-lH-pyrazol-4-yI]-3, 7-dihydro-‘ purine-2, 6-dione
A mixture of 5,6-diamino-l,3-dipropyl-lH-pyrimidine-2,4-dione (0.075g, 0.33 mmol), l-(3-p-tolyl-prop-2-ynyl)-lH-pyrazole-4-carboxylic acid (0.080gm, 0.33mmol), methanol (5ml), EDCI (0.089g, 0.46mmol) were taken and stirred for 12 hours at 20-25 0C. The reaction mixture was concentrated to obtain intermediate l-(3-p-tolyl-prop-2-ynyl)-lH-pyrazole-4-carboxylic acid (6-amino-2, 4-dioxo-l, 3-dipropyl)-l, 2, 3, 4-tetrahydro-pyrimidine-5yl) amide (50mg, 34%) which was dissolved in hexamethyldisilazane (HMDS). To this reaction mixture ammonium sulphate (0.01 Og) was added. The reaction mixture was refluxed at 140 0C for 18hrs. The organic volatiles were evaporated and the residue was treated with crushed ice, the precipitate formed was filtered off. The product was then purified by column chromatography (l%MeOH in CHCl3) to obtain 1, 3-dipropyl-8~[l-(3-p-tolyl-prop-2ynyl)-lH-pyrazol-4-yl]-3, 7-dihydro-purine-2, 6-dione (0.035g, 92%). ‘HNMR(400MHz, DMSO d6): δ 0.76-0.87 (m, 6H); 1.51-1.57 (m, 2H); 1.68-1.74 (m, 2H); 2.29 (s, 3H); 3.82 (t, J=7.2Hz, 2H); 3.95 (t, J=7.2Hz, 2H); 5.36 (s, 2H); 7.18 (d, J=8Hz, 2H); 7.35 (d. J=8Hz, 2H); 8.08 (s, IH); 8.49 (s, IH); 13.9 (bs,lH)
Happy new year wishes 2016
/////////
PNQ 201 from Advinus for for potential treatment of IBD.
formula I
PNQ 201
STRUCTURE COMING……
Adenosine A2b receptor antagonist
Advinus Therapeutics Ltd
KEEP WATCHING THIS POST……………
PNQ-201 is a proprietary orally active A2B Adenosine receptor (A2BAdoR) antagonist, currently in pre-clinical development for potential treatment of IBD. Advinus is looking for partnering/co-development opportunities.
A2BAdenosine Receptor (A2BAdoR) Antagonist PNQ-201 for IBD
Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease of an etiology not fully understood. It includes chronic inflammation of the gut, characterized by dysfunction of mucosal immunity. Current oral therapies are ineffective, non-specific, and have significant adverse effects. As such, there is a large unmet medical need for the development of new and specific therapies for IBD.
Adenosine is a stimulator of pro-inflammatory effects in the gastro-intestinal tract. Adenosine regulates tissue function by activating its receptors: A1AdoR and A2AAdoR are high affinity receptors and A2BAdoR and A3AdoR are low affinity receptors. A2BAdoR is highly expressed in cecum and colon, with expression increased even further in epithelial cells in human and murine colitis. A2BAdoR, agonized by adenosine induces cytokine secretion at the mucosal surface, inflammatory cell infiltration into intestinal wall, focal crypt damage and ulceration. Therefore, A2BAdoR antagonists are expected to be beneficial in IBD patients.
PNQ-201 is a proprietary orally active A2BAdoR antagonist, currently in pre-clinical development for the potential treatment of IBD. PNQ-201 is a potent and selective A2B antagonist. It is selected for development on the basis of poor systemic bioavailability and high exposure in colon/cecum. Negligible systemic bioavailability and maximum exposure at the sites of action in the lower gastrointestinal tract is expected to offer maximum therapeutic benefits while minimizing potential side effects. PNQ-201 has shown a robust efficacy profile in standard models of IBD, namely, the mouse DSS-induced colitis model and the rat TNBS-induced colitis model. PNQ-201 was found to be safe in exploratory safety studies including a Drug Matrix Screen, mini-AMES test, and a 14- day repeat dose toxicology study in rats.
PATENT
Example 1 : 8-(l-Benzyl~lH-pyrazol-4-yl)-l-propyl-l,4,5,7-tetrahydro-purin-6-one
Step 1: l-Benzyl-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-pyrimidin-5-yl)-amide
A mixture of 5,6-diamino-3-propyl-lH-pyrimidine-2,4-dione (1.6g, 8.55mmol), 1-benzyl-lH-pyrazole-4-carboxylic acid (1.75g, 8.65mmol) in methanol (10ml) were cooled to 0 0C and added EDCLHCl (2.32g, 12.11mmol). The reaction mixture was stirred at 25 0C for 20 hours and the solvents were removed under reduced pressure. To this residue water (10ml) was added and the precipitate was filtered off, and was washed sequentially with cold water (20ml) and DCM (25ml) to obtain l-Benzyl-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3 -propyl- 1 ,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (1.5 g, 47 %) as a pale yellow solid.
1HNMR^OOMHZ5 DMSO d6): δ 0.82 (t, J=7.6Hzs 3H); 1.46-1.51 (m, 2H); 3.64 (t, J=7.2Hz, 2H);^5.36 (s, 2H); 6.01 (s, 2H); 7.26-7.38 (m, 5H); 7.96 (s, IH); 8.31 (s, IH); 8.54 (s, IH); 10.43 (s, IH).
Step 2 : 8-(l-Benzyl-lH-pyrazol-4-yl)-2-chloro-l-propyH,7-dihydro-purin-6-one A mixture of l-benzyl-lH-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-ρyrimidin-5-yl)-amide (0.5g, 13.5mmol)s POCl3 (10ml) and DMF (0.1ml) were heated at 125-130 0C for 20 hours. Reaction mixture was cooled to 20-25 0C. It was then concentrated under vacuum. The residue was triturated with diethyl ether, dried. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4 % methanol in DCM as an eluent to obtain 8-( 1 -Benzyl- 1 H-pyrazol-4-yl)-2-chloro-l -propyl- l,7-dihydro-purin-6-one (0.04g, 8%) as a pale brown solid.
1HNMR^OOMHZ5 DMSO d6): δ 0.93 (t, J=7.6Hz, 3H); 1.67-1.73 (m, 2H); 4.15 (t, J=7.6Hz, 2H); 5.42 (s, 2H); 7.29-7.39 (m, 5H); 8.14 (s, IH); 8.49 (s, IH); 13.68 (bs, IH). Step 3: 8-(l-Benzyl-lH-pyrazol-4-yl)-l-propyl-l,7-dihydro-purin-6-one
A mixture of 8-(l -benzyl- lH-pyrazol-4-yl)-2-chloro-l -propyl- l,7-dihydro-purin-6-one (0.035 g, 0.094 mmol), Pd\C (10%) (0.025g), in ethanol (20ml) were stirred under hydrogen atmosphere for 20 hours. Reaction mixture was filtered through celite bed washed with methanol (20ml), and the solvents were removed under vacuum. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4 % methanol in DCM as an eluent to obtain 8-(l-Benzyl-lH-pyrazol-4-yl)-l-propyl-l,7-dihydro-purin-6-one (0.012g, 39%) as off white solid.
1HNMR^OOMHZ, DMSO d6): δ 0.89 (t, J=7.2Hz, 3H); 1.66-1.72 (m, 2H); 3.94 (t, J=7.6Hz, 2H); 5.41 (s, 2H); 7.302-7.38 (m, 5H); 8.03 (s, IH); 8.16 (s, IH); 8.34 (s, IH).
PATENT
WO 2011055391
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011055391
Preparation 1: 2-chloro-8-cyclopentyl-l-propyI-l, 7-dihydro-purin-6-one:
Step 1: Cyclopentane carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetra hydro-pyriniidin-S-y -amide
To a solution of 5, 6-diamino-3-propyI-lH-pyrimidine-2, 4-dione (0.6 g, 2.72 mmol) in methanol (50 ml) was added cyclopentane carboxylic acid (0.310 g, 2.72 mmol). The reaction mixture was cooled to 0°C and then l-ethyl-3(3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HC1) (0.78 g, 4.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water. The solid was filtered and washed thoroughly with water followed by diethyl ether. The product obtained was dried under high vacuum. The crude product (0.40 g) was used for the next step without further purification.
Step 2: Preparation of 8-cyclopentyI-2-chloro-l-propyl-l, 7-dihydro-purin-6-one
To a suspension of cyclopentanecarboxylic acid (6-amino-2,4-dioxo-3-propyl- 1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.40 g, crude) obtained from step 1 in phosphorus oxychloride (25 ml) was added phosphorus pentachloride (0.10 g) and the resulting reaction mixture was refluxed overnight. Phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly quenched with water. Ethyl acetate was added and the organic layer was separated and washed thoroughly with water followed by brine. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using dichloromethane, methanol (9:1) as the solvent system to give 0.075 g (19% over two steps) of the product as a white solid.
•H MR (400 MHz, DMSO d6): δ 0.9 (t, J = 8 Hz, 3H), 1.59-1.82 (m, 8H), 1.99 (m, 2H), 3.15 (t, J = 8 Hz, 1H), 4.12 (t, J = 8 Hz, 2H).
Preparations 2 to 7 were prepared following the experimental procedure as given for Preparation 1.
Preparation 2: 2-Chloro-8-cyclohexyl- 1 -propyl- 1 ,7-dihydro-purin-6-one,
Preparation 3: 2-Chloro-8-cyclopropyl-l -propyl- 1 ,7-dihydro-purin-6-one,
Preparation^ 2-Chloro-8-(hexahydro-2,5-methano-pentalen-3a-yl)-l -propyl- 1,7- dihydro-purin-6-one,
Preparation 5: 8-Bicyclo-[2.2.1]-hept-2-yl-2-chloro-l -propyl- 1, 7-dihydro-purin-6- one,
Preparation 6: 8-Adamantan-2-yl-2-chloro-l -propyl- 1, 7-dihydro-purin-6-one, Preparation7:3-[4-(2-Chloro-6-ox0-l-propyl-6,7-dihydro-lH-purin-8-yl)- bicyclo[2.2.2]oct-l-yl]-propionic acid.
Example 1: 8-Cyclopentyl-2-(3, 4-difluoro-phenoxy)-l-propyl-l, 7-dihydro-purin- 6-one:
To a solution of 8-cyclopentyl-2-chloro- 1 -propyl- l,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-2-pyrrolidone (0.2 ml) was added K2CO3 (0.044g, 0.32 mmol) followed by 3, 4-difluoro phenol and the reaction mixture was heated at 130 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and ethyl acetate layer was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 3% methanol in DCM to give the product (0.015 g, 19 %) as a white solid.
‘HNMR (400 MHz, DMSO d6): δ 0.94 (t, J = 8 Hz, 3H), 1.59-1.74 (m, 6H), 1.94 (br.s, 2H), 3.12 (m, 2H), 4.09 (br. s, 2H), 7.21 (d, J = 8 Hz, 1H), 7.53-7.65 (m, 2H), 12.74 (br.s, 1H).
PNQ 370 useful in treating Parkinson’s disease from ADVINUS
2016
PNQ 370
Advinus Therapeutics Ltd
Adenosine A2a receptor antagonist
for treating disease or disorder susceptible to improvement by antagonism of A2A receptor.
Advinus Therapeutics is investigating PNQ-370, presumed to be lead from a series of small molecule therapeutics including PD-2 and PD-3, as adenosine A2a receptor antagonist, for the potential treatment of Parkinson’s disease . In November 2012, this drug was in preclinical development .
KEEP WATCHING THIS POST AS I ARRIVE AT THE STRUCTURE…………..
ONE OF THE ABOVE OR SIMILAR
INTRODUCTION
The effects of adenosine are mediated through at least four specific cell membrane receptors so far identified and classified as Ai, A2A, A2B and A3 belonging to G protein-coupled receptor family. The Ai and A3 receptors down-regulate cellular cAMP levels through their coupling to G protein, which inhibit adenylate cyclase. In contrast, A2A and A2B receptors couple to G protein that activate adenylate cyclase and increase intracellular levels of cAMP. Through these receptors, adenosine regulates the wide range of physiological functions.
Advances in understanding the role of adenosine and its receptors in physiology and pathophysiology, as well as new developments in medicinal chemistry of these receptors have identified potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson’s Disease (PD).
Happy new year wishes 2016
Movement disorder constitutes a serious health problem, especially among the elderly. These movement disorders can often be the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson’s disease, Huntington’s chorea and Wilson’s disease. Tremor, rigidity, akinesia and postural changes are four classic symptoms of Parkinson’s disease, it is also associated with depression, dementia and overall cognitive decline. Parkinson’s disease has a prevalence of 1 per 1000 of the total population and increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurons in the substantia nigra and the subsequent reductions in the interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson’s disease. About 80% of cells from the substantia nigra can be destroyed before the clinical symptoms of Parkinson’s disease become apparent
PD is a progressive, incurable disorder with no definite preventive treatment, although drugs are available to alleviate the symptoms and/or slow down the progress of the disease. Current therapy is based on dopamine replacement therapy, the most common drug treatments being dopaminomimetic agents, including L-DOPA, a dopamine precursor, as well as direct or indirect dopamine receptor agonists. L-DOPA is the mainstay in the treatment of PD, but because of tolerance problems and a wide range of adverse reactions, including involuntary movements and vomiting, a strong demand for new therapies exists. Among the various strategies, A2A AR blockers are considered a potential approach to treatment of the disease. Within the brain A2A ARs are richly expressed in the striatum, nucleus accumbens, and olfactory tubercle. A coexpression of A2A with D2 dopamine receptors has been reported in the GABAergic striatopallidal neurons where adenosine and dopamine agonists exert antagonistic effects in the regulation of locomotor activity. Activation of A2A ARs in striatopallidal neurons decreases the affinity of D2 receptors for dopamine, antagonizing the effects of D2 receptors.
The negative interaction between A2A and D2 receptors is at the basis of the use of A2A antagonists as a novel therapeutic approach in the treatment of PD. (Pharmacol. Ther. 2005, 105, 267). The recent discovery that the A2A can form functional heteromeric receptor complexes with other Gprote in-coupled receptors such as D2 and the mGlu5 receptors has also suggested new opportunities for the potential of A2A antagonists in PD. (J. Mol. Neurosci. 2005, 26, 209).
A2A knockout (KO) mice transient focal ischemia caused less neuronal damage in comparison to their wild-type (WT) littermates (J. Neurosci. 1999, 19, 9192.). Therefore, it seems that tonic activation of A2A ARs may be responsible for dangerous signal during injury, in contrast to the neuroprotective effects induced by endogenous Al activation. Recently, selective inactivation or reconstitution of A2A ARs in bone-marrow cells revealed their contribution to the development of ischemic brain injury (J.F. Nat. Med. 2004, 10, 1081) Blockade of A2A ARs has recently been implicated in the treatment of movement disorders such as Parkinson’s disease (Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Life Sci. 1994, 55, 61-65).
The potential utility of A2A AR antagonists in the treatment of Parkinson’s disease has been reviewed (CNS drugs, 1998, 10, 31 1-320). One advantage of A2A AR antagonist therapy is that the underlying neurodegenerative disorder may also be treated ((Ann. N. Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 3048). In particular, blockade of A2A AR function confers neuroprotection against MPTP-induced neurotoxicity in mice (Neurosci. 2001, 21, RC143).
Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system manifested by cognitive and memory deterioration, a variety of neuropsychiatric symptoms, behavioral disturbances, and progressive impairment of daily life activities. Recent research suggests that adenosine receptors play important roles in the modulation of cognitive function. Epidemiological studies have found an association between coffee (a nonselective adenosine receptor antagonist) consumption and improved cognitive function in AD patients and in the elderly. Long-term administration of caffeine in transgenic animal models showed a reduced amyloid burden in brain with better cognitive performance.
Advinus’ Pharma Development Bangalore operation, located on a 8-acre campus with 220,000 sq ft of modern facilities, offers end-to-end pre-clinical to early clinical development platform for pharma product development
Antagonists of adenosine A2A receptors mimic these beneficial effects of caffeine on cognitive function. Neuronal cell cultures with amyloid beta in the presence of an A2A receptor antagonist completely prevented amyloid beta-induced neurotoxicity. These findings suggest that the adenosinergic system constitutes a new therapeutic target for AD, and caffeine and A2A receptor antagonists may have promise to manage cognitive dysfunction in AD (Curr Neuropharmacol. 2009 September; 7(3): 207-216).
High expression of A2A ARs has been found in platelets, leukocytes, vascular smooth muscle, and endothelial cells with important implications in the regulation of inflammatory responses. It is now well established that stimulation of the A2A AR in immune cells induces anti-inflammatory effects, mostly due to its ability to increase cAMP levels, which has strong immunosuppressive effects (Trends Immunol. 2005, 26, 299). Stimulation of A2A ARs inhibits neutrophil adherence to the endothelium, degranulation of activated neutrophils and monocytes, plus superoxide anion generation. A2A ARs have been recently defined as sensors and terminators of proinflammatory activities. The strongest evidence for the key role of A2A in inflammation is derived by the elegant study using mice deficient in A2A ARs (Nature 2001, 414, 916).
The state-of-the-art facility in Pune, Advinus Drug Discovery, develops its own drug candidates to out-license them at preclinical or clinical stages
In this model the lack of A2A subtype leads to increased tissue inflammation and damage, thus suggesting a negative and nonredundant regulatory role for the A2A AR. This model permits one to appreciate that adenosinergic regulation of immune cells is fundamental in normal physiological control of inflammation in vivo in spite of the fact that other Gs-protein-coupled receptors and cAMP elevating ligands are present, such as cathecolamines, prostaglandins, dopamine, and histamine (Trends Immunol. 2005, 26, 299). Interestingly, the A2A AR has been demonstrated to be involved in promotion of wound healing and angiogenesis in healing wounds (Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 289, R283).
Moreover, it plays an active role in the pathogenesis of dermal fibrosis, suggesting a role for antagonists as novel therapeutic approach in the treatment and prevention of dermal fibrosis in diseases such as scleroderma (Arthritis Rheum. 2006, 54, 2632) as well as hepatic fibrosis (Br. J. Pharmacol. 2006 Aug; 148(8): 1 144-55). Studies also suggest that A2A receptor antagonists may be beneficial for social memory impairment and hypertension (Behav Brain Res. 2005 Apr 30;159(2):197-205), sepsis (J Immunol. 2006 May 1 ; 176(9): 5616-26), spinal cord injury and neuroprotection (J Neuroinflammation. 201 1 Apr 12;8:31), retinopathy (IVOS, Jan. 2000, vol. 41 (1), 230-243, depression (Neurology. 2003 Dec 9;61(1 1 Suppl 6):S82-7), narcolepsy and other sleep related disorders (Prog Neurobiol. 2007 Dec;83(5):332-47), attention-deficit hyperactivity disorder (ADHD) (Behav Pharmacol. 2009 Mar;20(2): 134-45; Clinical Genetics (2000), 58(1), 31-40 and references therein),
Dr Rashmi Barbhaiya, CEO & Managing Director
… Dr Rashmi Barbhaiya, CEO & Managing Director and Dr Kasim Mookthiar, Chief Scientific Officer and SVP, Drug Discovery, Advinus Therapeutics …
Antagonists of the A2A receptor are potentially useful therapies for the treatment of addiction. Major drugs of abuse (opiates, cocaine, ethanol, and the like) either directly or indirectly modulate dopamine signaling in neurons particularly those found in the nucleus accumbens, which contain high levels OfA2A adenosine receptors. Dependence has been shown to be augmented by the adenosine signaling pathway, and it has been shown that administration of an A2A receptor antagonist redues the craving for addictive substances (“The Critical Role of Adenosine A2A Receptors and Gi βγ Subunits in Alcoholism and Addiction: From Cell Biology to Behavior”, by Ivan Diamond and Lina Yao, (The Cell Biology of Addiction, 2006, pp 291-316) and “Adaptations in Adenosine Signaling in Drug Dependence: Therapeutic Implications”, by Stephen P. Hack and Macdonald J. Christie, Critical Review in Neurobiology, Vol. 15, 235-274 (2003)). See also Alcoholism: Clinical and Experimental Research (2007), 31(8), 1302-1307.
A2A receptors may be beneficial for the treatment or prevention of disorders such as a movement disorder, for example, Parkinson’s disease or progressive supernuclear palsy, Restless leg syndrome, nocturnal myoclonus, cerebral ischaemia, Huntington’s disease, multiple system atrophy, corticobasal degeneration, Wilson’s disease or other disorders of basal ganglia which results in dyskinesias, post traumatic stress disorder. See for example WO200013682, WO200012409, WO2009156737, WO20091 1442, WO2008121748, WO2001092264, WO2007038284, WO2008002596, WO20091 1 1449, WO20091 1 1442, WO2008121748, WO2009156737, WO2003022283, WO2005044245, WO2008077557, WO20091 1 1449, WO2009705138, WO20091 1 1442, WO2007035542, WO20080870661, WO2008070529, WO20051 16026, WO2009055548, WO2007133983, WO2010045006, WO2010045015, WO2010045008 WO2009015236.
centre: Mr Ratan Tata, Chairman, Tata Sons, flanked by Dr Rashmi Barbhaiya (left), Managing Director and CEO, Advinus, and Mr R. Gopalakrishnan, …
ONE EXAMPLE………..
COMPD A1
MF C26 H31 N9 O4
2H-[1,2,4]Triazolo[5,1-i]purin-2-one, 5-amino-8-(2-furanyl)-1,3-dihydro-3-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]-1-methyl-
mw 533.58
cas 1367365-26-1
| Molecular Formula: | C26H31N9O4 |
|---|---|
| Molecular Weight: | 533.58224 g/mol |
A15-amino-8-(furan-2-yl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one
Example Al :
5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one
5-Amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-
5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one
Step-1 : 2-[(2,5-Diamino-6-chloro-pyrimidin-4-yI)amino]ethanol
A mixture of 4,6-dichloropyrimidine-2,5-diamine (28g, 156mmol), ethanolamine (18ml, 312mmol) and ethanol (250ml) were heated at 100-1 10 °C for 16 hours. The mixture was cooled and solvent was removed. To the residue methanol (100ml) was added and stirred for 20 minutes. The solid was filtered off to obtain 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (22.0g, 70%).
‘H MR(400MHz, DMSO d6): δ 3.36-3.40 (m, 2H); 3.50-3.54 (m, 2H); 3.88 (bs, 2H); 4.74 (t, J=5.6Hz, 1H); 5.63 (bs, 2H); 6.51 (t, J=5.6Hz, 1H)
Step-2: 2-Amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one
A mixture of 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol obtained in step 1 (l O.Og, 49.26mmol) in acetonitrile (400ml) were cooled to 0 °C. To this reaction mixture K2C03 (20.39gm, 147.7mmol) and 4-nitrophenyl chloroformate (19.8g, 98.52mmol)was added and stirred at 25-27 °C for 24 hours. This reaction mixture was filtered and washed with acetonitrile (300ml) and diethyl ether (300ml) respectively. Solid obtained was dried to obtain crude 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one as a yellow solid. Small amount of crude material was purified by column chromatography to obtain pure product. ‘HNMR(400MHz, DMSO d6): δ 3.61-3.66 (m, 2H); 3.72-3.75 (m, 2H); 4.85 (t, J=6Hz, 1H); 6.60 (s, 2H); 1 1.21 (s, 1 H)
Step-3: 2-Amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one obtained in step 2 (13g, 56.7mmol) , K2C03 (1 1.5g, 84mmol), methyl iodide (12g, 85.15mmol) and DMF (130ml) were stirred at 25-30 °C for 16 hours. The reaction mixture was concentrated and purified by column chromatography using 60-120 silica gel and 4% methanol in DCM as an eluent to obtain 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one (8g, 58%) as an off white solid.
‘HNMR(400MHz, DMSO d6): δ 3.42 (s, 3H); 3.65 (t, J=5.6Hz, 2H); 3.78 (t, J=5.6Hz, 2H); 4.85 (t, J=5.6Hz, 1H); 6.69 (bs, 2H).
Step-4: 2-Amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyI-purin-8-one
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one obtained in step 3 (8g, 32.9mmol) , Hydrazine hydrate (16ml ,32.9mmol) and ethanol (300ml) were heated at 100-1 10 °C for 16 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (7g, 89 %) as an off white solid.
‘HNMR(400MHz, DMSO d6): δ 3.37 (s, 3H); 3.58-3.61 (m, 2H); 3.71 (t, J=6Hz, 2H); 4.29 (bs, 2H); 4.87 (t, J=5.6Hz, 1H), 6.00 (bs, 2H); 7.63 (s, 1H).
Step-5: N’-[2-Amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide
2-amino-6-hydrazino-9-(2-hydroxyethyl)-7-methyl-purin-8-one (4.5g, 18.18mmol) obtained in step 4, 2-furoic acid (2.53g, 22.5mmol), HOBT (2.53g, 18.8 mmol) and N-methylmorpholine were taken in dimethylformamide (40ml). l-Ethyl-3(3′-dimethylaminopropryl)carbodiimide hydrochloride (EDCI.HCl) (5.4g, 28.2mmol) was added to the reaction mixture and stirred at 25-27 °C for 14 hours. The reaction mixture was evaporated and residue was purified by column chromatography to obtain N’-[2-amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide (5.3g, 84%) as an off white solid.
‘HNMR (400MHZ, DMSO d6): δ 3.43 (s, 3H); 3.59-3.63 (m, 2H); 3.74 (t, J=6Hz, 2H); 4.88 (t, J=5.6Hz, 1H); 5.98 (bs, 2H); 6.67 (bs, 1H); 7.25 (d, J=3.2Hz, 1H); 7.90 (s, 1H); 8.35 (s, 1H); 10.28 (s, lH).
Step-6: 5-Amino-8-(2-furyl)-3-(2-hydroxyethyl)-l-methyl-[l^,4]triazolo[5,l-flpurin-2-one
A mixture of N’-[2-amino-9-(2-hydroxyethyl)-7-methyl-8-oxo-purin-6-yl]furan-2-carbohydrazide obtained in step 5 (5.3g, 15.9mmol), Ν,Ο-bistrimethylsilylacetamide (27ml, 1 1 1.4mmol) and hexamethyldisilazane (83ml, 397mmol) were heated at 1 10-120 °C for 16 hours. The reaction mixture was quenched with methanol (100ml) and water (100ml) and organic volatiles were evaporated. The solid obtained was filtered off and washed with water (30ml) followed by diethyl ether (100ml) to obtain 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-l-methyl-[l,2,4]triazolo[5,l-f]purin-2-one (3.50g, 71%) as an off white solid.
‘HNMR (400MHZ, DMSO d6): δ 3.56 (s, 3H); 3.67-3.70 (m, 2H); 3.84-3.87 (m, 2H); 4.88 (t, J=5.6Hz, 1H); 6.73 (bs, 1H); 7.20 (bs, 1H); 7.79 (bs, 2H); 7.94 (bs, 1H).
Step-7: 2-[5-Amino-8-(2-furyl)-l-methyl-2-oxo-[l,2,4]triazolo[5,l-fJpurin-3-yl]ethyl 4-methylbenzenesulfonate
A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-l -methyl-[l,2,4]triazolo[5, l-fJpurin-2-one obtained in step 6 (3.5g, l lmmol), p-toluene sulphonylchloride (5.2 g, 27mmol) were taken in pyridine (30ml)and stirred at 25-27 °C for 16 hours. To the reaction mixture hexane (100ml) was added and solid obtained was filtered off and washed with water (100ml) followed by hexane (100ml) to obtain 2-[5-amino-8-(2-furyl)-l-methyl-2-oxo-[l,2,4]triazolo[5, l-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1g, 78%) as a brown solid. ‘HNMR (400MHz, DMSO d6): δ 2.02 (s, 3H); 3.49 (s, 3H); 3.99 (t, J=4.8Hz, 2H); 4.71 (t, J=4.8Hz, 2H); 6.73-6.75 (m, 1H); 7.01 (d, J=8Hz, 2H); 7.23 (d, J=3.2Hz, 1H); 7.41 (d, J=8.4Hz, 2H); 7.78 (bs, 2H); 7.96 (d, J=1.2Hz, 1H).
Step-8: : 5-Amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methyl-[l,2,4]triazolo[5,l-f)purin-2-one
A mixture of 2-[5-amino-8-(2-furyl)-l-methyl-2-oxo-[l ,2,4]triazolo[5, l-f]purin-3-yl]ethyl 4-methylbenzenesulfonate obtained in step 7 (0.25g, 0.533mmol), l-[4-(2-Methoxy-ethoxy)-phenyl]-piperazine (0.188g, 0.799mmol) and DIPEA (0.27ml, 1.599mmol) were taken in DMF (5ml) and stirred at 80 °C for 16 hours. To the reaction mixture water (100ml) was added and solid obtained was filtered off. The crude product was purified by column chromatography to obtain 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl]ethyl]- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one (0.135g, 47%) as an off white solid
‘HNMR (400MHz, DMSO d6): δ 2.60 (bs, 4H); 2.68 (t, J=6.4Hz, 2H); 2.96 (bs, 4H); 3.29 (s, 3H); 3.56 (s, 3H); 3.59-3.62 (m, 2H); 3.94-4.00 (m, 4H); 6.71 -6.73 (m, 1H); 6.79-6.86 (m, 4H); 7.19 (dd, J=3.2Hz, 1.2Hz, 1H); 7.80 (bs, 2H); 7.94 (bs, 1H).
ANOTHER……..
Example Gl: 5-Amino-l-ethyl-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-[l,2,4]triazolo[5,l-i]purin-2-one
Step-1 : 2-Amino-6-chloro-7-ethyl-9-(2-hydroxyethyl)purin-8-one
(Procedure is same as step-3 in example Al)
‘HNMR (400MHz, DMSO d6): δ 1.21 (t, J=7.2Hz, 3H); 3.64 (s, 2H); 3.78 (t, J=6Hz, 2H);
3.92 (q, J=7.2Hz, 2H); 4.92 (bs, I H); 6.7 (bs, 2H).
Step-2 : 2-Amino-7-ethyl-6-hydrazino-9-(2-hydroxyethyl)purin-8-one
(Procedure is same as step-4 in example Al)
‘ HNMR (400MHz, DMSO d6): δ 1.07 (t, J=6.8Hz, 3H); 3.59 (q, J=6Hz, 2H); 3.72 (t, J=6Hz,
2H); 3.91 (q, J=6.8Hz, 2H); 4.32 (bs, 2H); 4.86 (t, J=5.6Hz, IH); 5.99 (bs, 2H), 7.55 (bs, IH).
Step-3: N’-[2-Amino-7-ethyl-9-(2-hydroxyethyl)-8-oxo-purin-6-yl]furan- 2carbohydrazide (Procedure is same as step-5 in example Al)
Crude product was used in next step
Step-4: 5-Amino-l-ethyI-8-(2-furyl)-3-(2-hydroxyethyl)-[l,2,4]triazolo[5,l-flpurin-2-one
(Procedure is same as step-6 in example Al)
‘H MR (400MHZ, DMSO d6): δ 1.34 (t, J=7.2Hz, 3H); 3.67 (q, J=5.6Hz, 2H); 3.84 (t, J=5.6Hz, 2H); 4.01 (q, J=7.2Hz, 2H); 4.87 (t, J=6Hz, IH); 6.70 (bs, IH); 7.17 (d, J=2.8Hz, I H); 7.18 (bs, 2H); 7.92 (bs, IH).
Step-5: 2-[5-Amino-l-ethyl-8-(2-furyl)-2-oxo-[l,2,4]triazoIo[5,l-f|purin-3-yl]ethyl 4- methylbenzenesulfonate (procedure is same as step-7 in example Al)
lHNMR (400MHz, DMSO d6): δ 1.35 (t, J=7.2Hz, 3H); 2.00 (s, 3H); 3.95-4.00 (m, 4H); 4.47 (bs, 2H); 6.74 (s, IH); 7.00 (d, J=7.6Hz, 2H); 7.22 (s, IH); 7.42 (d, J=7.6Hz, 2H); 7.78 (bs, 2H); 7.97 (bs, IH).
Step-6: 5-Amino-l-ethyl-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyi]piperazin-l- yl]ethyl]-[l,2,4]triazolo[5,l-f]purin-2-one (procedure is same as step-8 in example Al)
HNMR(400MHz, DMSO d6): δ 1.35 (t, J=7.2Hz, 3H); 2.60 (bs, 4H); 2.68 (t, J=6.8Hz, 2H); 2.95 (bs, 4H); 3.28(s, 3H);3.61 (t, J=4.4Hz, 2H); 3.94-4.04 (m, 6H); 6.72 (dd, J=2Hz, 3.6Hz, I H); 6.78-6.85 (m, 4H); 7.19 (d, J=3.2Hz, IH); 7.81(bs, 2H); 7.94 (s, IH).
Representative compounds of the present disclosure were tested and had micromolar to nanomolar activity.
A1 ABOVE
A7 ABOVE
A9 ABOVE
A13 ABOVE
A31 ‘HNMR (400MHz, DMSO d6): δ 2.62 (bs,4H); 2.68 (t, J=6.8Hz, 2H); 2.85 (bs, 4H); 3.28 (s, 3H); 3.57 (s, 3H); 3.59-3.62 (m, 2H); o 3.95 (t, J=6.8Hz, 2H); 4.01-4.04 (m, 2H);
5-Amino-3-[2-[4-[2-fluoro-4-(2- 6.66-6.68 (m, 1H); 6.72 (dd, J=2 Hz,3.6Hz, methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-8- 1H); 6.79 (dd, J=2.8Hz, 14Hz, 1H); 6.92 (t, (2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -f|purin-2- J=9.6Hz, 1H); 7.19 (d, J=3.2Hz, 1 H); 7.93 one (bs, 2H); 7.93-7.94 (m, 1H).
A31 ABOVE
A32 HNM (400MHz, DMSO d6): δ 2.59 (bs,
4H); 2.68(t, J=6.4Hz, 2H); 3.27(t, J=4.8Hz, 4H); 3.56 (s, 3H); 3.96 (t, J=6.4Hz, 2H);
0 6.72(dd, J=2Hz, 3.6Hz, 1H); 6.99 (d, J=8.8Hz,
4-[4-[2-[5-Amino-8-(2-furyl)-l-methyl-2-oxo- 2H); 7.19 (d, J=3.6Hz, 1H);7.56 (d, J=8.8Hz, [ 1 ,2,4]triazolo[5, 1 -f]purin-3-yl]ethyl]piperazin- 2H); 7.80 (bs, 2H); 7.93 (bs, lH).
l-yl]benzonitrile
A32 ABOVE
A36 ‘HNMR(400MHz, CDCI3): δ θ.09 (d,
J=4.4Hz, 2H); 0.50 (d, J=6.8Hz, 2H); 0.82- 0.89 (m, 1H); 2.24 (d, J=6.0Hz, 2H): 2.52- 2.72 (m, 8H); 2.80 (t, J=6.4Hz, 2H); 3.76 (s,
5-Amino-3-[2-[4-(cyclopropylmethyl)piperazin- 3H); 4.07 (t, J=6.8Hz, 2H); 5.89 (bs, 2H); l -yl]ethyl]-8-(2-furyl)-l-methyl- 6.61 (bs, 1H); 7.22 (d, J=2.4Hz, 1H); 7.64 (s, [ 1 ,2,4]triazolo[5, 1 -f]purin-2-one 1H).
A36 ABOVE
A38 ‘HNMR(400MHz, CDCI3): δ 2.62 . (t,
J=4.4Hz, 4H); 2.79 (t, J=6.4Hz, 2H); 2.81 (s, 6H); 3.22 (t, J=4.4Hz, 4H): 3.77 (s, 3H); 4.06 (t, J=6.8Hz, 2H); 5.74 (bs, 2H); 6.60 (dd,
4-[2-[5-Amino-8-(2-fiiryl)- 1 -methyl-2-oxo- J=2.0Hz, 3.2Hz, 1H); 7.24 (d, J=3.6Hz, 1H);
[ 1 ,2,4]triazolo[5, 1 -f]purin-3-yl]ethyl]-N,N- 7.65 (s, 1H).
dimethy l-piperazine- 1 -sulfonamide
A38 ABOVE
A39 ‘HNMR(400MHZ, DMSO d6): δ 1.89-1.94
im, 1H); 2.09-2.18 .(m, 1 H); 2.60 (bs, 4H); 2.67 (t, J=6.4Hz, 2H); 2.96 (bs, 4H); 3.56 (s, 3H); 3.69-3.85 (m, 4H); 3.95 (t, J=6.4Hz,
2H); 4.89 (bs, 1H); 6.72 (dd, J=2.0, 3.2Hz,
5-Amino-8-(2-furyl)-l -methyl-3-[2-[4-(4- 1H); 6.78 (d, J=9.2Hz, 2H); 6.85 (d, J=9.2Hz, tetrahydrofuran-3-yloxyphenyl)piperazin- 1 – 2H): 7.20 (d, J=3.2Hz, 1 H); 7.80 (bs, 2H); yl]ethyl]-[l ,2,4]triazolo[5,l-f]purin-2-one
7.93 (s, 1H).
A39 ABOVE
A42 ‘HNMR(400MHz, CDCI3): δ
2.26 (s,3H); 2.94-2.97 (m, 6H); 3.72 (s, 2H); 3.75 (s, 3H); 4.17 (t, J=6.4Hz, 2H); 5.74 (bs, 2H); 6.59 (dd, J=1.6Hz, 3.6Hz, 1H);7.13 (s, J=3.6Hz, IH); 7.21-7.24 (m, IH); 7.63 (s,
5-Amino-8-(2-furyl)-l-methyl-3-[2-(3-methyl- IH); 8.20 (bs, IH),
7,8-dihydro-5H- 1 ,6-naphthyridin-6-yl)ethyl]- [ 1 ,2,4]triazolo[5, 1 -f]purin-2-one
A42 ABOVE
A57 HNMR(400MHz, DMSO d6): δ 2.95 (t,
J=8Hz, 2H); 3.52 (s, 3H); 3.69 (s, 3H ), 3.97 (t, J=8Hz, 2H); 6.71 (dd, J=2Hz, 3.6Hz, I H );
5-Amino-8-(2-furyl)-3-[2-(4- 6.80 (dd, J=2Hz, 6.8Hz, 2H); 7.10 (d, methoxyphenyl)ethyl]- 1 -methyl- J=8.8Hz, 2H); 7.18 (dd, J=0.8Hz, 3.2Hz, I H );
[ 1 ,2,4]triazolo[5, 1 -f]purin-2-one 7.80 (bs, 2H), 7.94 (dd, J=lHz, 2Hz, I H ).
A57 ABOVE
A58 HNMR(400MHz, DMSO d6): δ 2.61 (bs,
4H); 2.68 (bs, 2H); 3.05(bs, 4H); 3.57 (s, 3H ), 3.96 (bs, 2H); 6.72 (bs, IH); 6.92 (d, J=8Hz, 2H); 7.01 (d, J=10Hz, 2H );7.03(d, J=148Hz, IH); 7.19 (bs , 1 H); 7.80 (bs, 2H); 7.94 (s,
5-amino-3-[2-[4-[4- IH).
(difluoromethoxy)phenyl]piperazin-l-yl]ethyl]- 8-(2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fjpurin- 2-one
A58 ABOVE
A62 O ‘HNMR (400MHz, DMSO d6): δ 0.66-0.70
(m, 4H); 1.90-1.94 (m, lH); 2.41 (bs, 4H); 2.65 (t, J=6Hz, 2H); 3.38 (bs, 2H); 3.56 (bs, 5H); 3.93 (t, J=6.4 Hz, 2H); 6.71 (bs, 1H );
5-Amino-3-[2-[4- 7.19 (d, J=2.4Hz, 1H); 7.79 (bs, 2H); 7.93 (bs,
(cyclopropanecarbonyl)piperazin- 1 -yl]ethyl]-8- 1H).
(2-furyl)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fjpurin-2- one
A62 ABOVE
A63 ‘HNMR (400MHz, DMSO d6): δ 0.07-0.10
(m, 2H); 0.40-0.44 (m, 2H); 0.88-0.94 (m,lH); 2.21 (d, J=6.4Hz, 2H); 2.41-2.45 (m, 4H); 2.64 (t, J=6.4Hz, 2H); 3.38 (bs,4H); 3.56
5-Amino-3-[2-[4-(2- (s, 3H); 3.93 (t, J=6.4Hz, 2H); 6.72 (dd, cyclopropylacetyl)piperazin-l -yl]ethyl]-8-(2- J=2Hz,3.6 Hz, 1H); 7.19-7.20 (m, 1H); 7.80 fury 1)- 1 -methyl-[ 1 ,2,4]triazolo[5, 1 -fJpurin-2- (bs, 2H); 7.93 (d, J=0.8 Hz, 1H).
one
A63 ABOVE
C1 ABOVE
E1 ABOVE
D3 ABOVE
G1 ABOVE
G2
H2
M1
M2
M3
M6
ETC AS IN TABLE……………..
Dr Kasim Mookthiar, CSO & Executive VP (Drug Discovery),
Dr Nimish Vachharajani, Senior VP & Head (Pharmaceuticals & Agrochemical Development),
/////////
n21c(nc4c(c1nc(n2)c3occc3)N(C(N4CCN5CCN(CC5)c6ccc(cc6)OCCOC)=O)C)N
CN1C2=C(N=C(N3C2=NC(=N3)C4=CC=CO4)N)N(C1=O)CCN5CCN(CC5)C6=CC=C(C=C6)OCCOC
CE-224535 for the treatment of rheumatoid arthritis and osteoarthritis
CE-224535
2-(4-Chloro-3-(3-(1-hydroxycycloheptyl)propanoyl)phenyl)-4-((2R)-2-hydroxy-3-methoxy-propyl)-1,2,4-triazine-3,5-dione
Benzamide, 2-chloro-5-(4,5-dihydro-4-((2R)-2-hydroxy-3-methoxypropyl)-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-n-((1-hydroxycycloheptyl)methyl)-
2-chloro-N-[(1-hydroxycycloheptyl)methyl]-5-[4-[(2R)-2-hydroxy-3-methoxypropyl]-3,5-dioxo-1,2,4-triazin-2-yl]benzamide
Phase III
A P2X7 receptor antagonist potentially for the treatment of rheumatoid arthritis and osteoarthritis.
CE-224535
CAS No. 724424-43-5
mw 480.9, C22H29ClN4O6
DETAILS COMING…………….
US7407956
https://www.google.com.ar/patents/US7407956
compounds of the formula I may be prepared according to the following reaction schemes and discussion. Unless otherwise indicated R1 through R7 in the reaction schemes and discussion that follows are as defined above.
| Patent | Submitted | Granted |
|---|---|---|
| Methods for preparing P2X7 inhibitors [US2005288288] | 2005-12-29 | |
| Combination therapies utilizing benzamide inhibitors of the P2X7 receptor [US2006018904] | 2006-01-26 | |
| Methods for preparing P2X7 inhibitors [US7235657] | 2005-12-29 | 2007-06-26 |
| Benzamide inhibitors of the P2X7 receptor [US7176202] | 2006-02-23 | 2007-02-13 |
| Benzamide Inhibitors of the P2X7 Receptor [US7671053] | 2009-02-12 | 2010-03-02 |
| Benzamide inhibitors of the P2X7 Ereceptor [US6974812] | 2004-09-16 | 2005-12-13 |
| Benzamide Inhibitors of The P2X7 Receptor [US7407956] | 2007-12-06 | 2008-08-05 |
/////////CE-224535, CE 224535
COC[C@@H](Cn1c(=O)cnn(c1=O)c2ccc(c(c2)C(=O)NCC3(CCCCCC3)O)Cl)O
GS 9883, Bictegravir an HIV-1 integrase inhibitor
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)-
(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
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
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
PATENT
WO2015196116
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196116&redirectedID=true
PATENT
WO2015196137
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
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
BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA
WO2018005328) DEUTERATED BICTEGRAVIR
CONCERT PHARMACEUTICALS, INC.
TUNG, Roger, D.; (US)
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.
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
//////////////////
FDA approves new orphan drug Uptravi (selexipag) to treat pulmonary arterial hypertension
KEEPING WATCHING THIS POSTS FOR SYNTHESIS UPDATES
12/22/2015
On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.
December 22, 2015
On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.
“Uptravi offers an additional treatment option for patients with pulmonary arterial hypertension,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “The FDA supports continued efforts to provide new treatment options for rare diseases.”
PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath, among other more serious complications.
Uptravi belongs to a class of drugs called oral IP prostacyclin receptor agonists. The drug acts by relaxing muscles in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs.
Uptravi’s safety and efficacy were established in a long-term clinical trial of 1,156 participants with PAH. Uptravi was shown to be effective in reducing hospitalization for PAH and reducing the risks of disease progression compared to placebo. Participants were exposed to Uptravi in this trial for a median duration of 1.4 years.
Common side effects observed in those treated with Uptravi in the trial include headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing.
Uptravi was granted orphan drug designation. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.
Uptravi is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc.
Selexipag, Uptravi
475086-01-2 CAS
(C26H32N4O4S, Mr = 496.6 g/mol)
A prostacyclin receptor (PGI2) agonist used to treat pulmonary arterial hypertension (PAH).
NIPPON SHINYAKU….INNOVATOR
Selexipag (brand name Uptravi) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (MRE-269) (the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.[1]
The US FDA granted it Orphan Drug status[2] (for PAH). It was approved by the U.S. FDA on 22 December 2015.[2]
ACT-333679 or MRE-269, the active metabolite of selexipag
PATENT
US2012/101276
http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en
The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).
BACKGROUND OF THE INVENTION
Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).
Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).
In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).
Production of Compound A
Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.
Step 1:
6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.
Step 2:
5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.
Step 3:
Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.
The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.
PATENT
WO 2002088084
and
http://www.google.fm/patents/WO2009157398A1?cl=en
PAPER
Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 21 p. 6692 – 6704
compd 31
PAPER
Bioorganic and Medicinal Chemistry, 2007 , vol. 15, 24 p. 7720 – 7725
2a isthe drug
N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.
http://www.sciencedirect.com/science/article/pii/S0968089607007614
PATENT
Example 1 t- butylamine Form I crystal of the salt
Compound A (40 mg) with 0.5mL dimethoxyethane (hereinafter, referred to as. “DME”) was dissolved in, and t- butylamine (1.1 eq) were added, 25 1 ° C. at 8 it was stirred for hours. Thereafter, the reaction solution was added t- butyl methyl ether (1mL), at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, I-form crystals of t- butylamine salt ( 3 to afford 9.9mg). B Powder X-ray diffraction spectrum of type I crystal obtained t- butylamine salt using the apparatus shown in Figure 1.
Melting point: 152.5 ℃
elemental analysis (C 3 0 H 4 3 N 5 O 4 S + 0.0 3 H 2 as O)
calculated value (%) C: 6 3 .1 8 H: 7 . 6 1 N: 12 .2 8 measured value (%) C: 6 2. 8 5 H: 7 . 6 4 N: 12.52 1 H-NMR (DMSO-D 6 ): delta 8 .15 (s, 1H), 7 .55 – 7 . 8 0 (M, 2H), 7 .10- 7 . .45 (M, 10H), 4 7 . 0-4 8 5 (M, 1H), 3 . 6 6 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 3 (s, 3 H), 1.50-1. 7 5 (M, 4H), 1.2 3 (s, 9H), 1.22 (D, 6 H)
Example 2 I-form crystal of the potassium salt
Compound A tetrahydrofuran with (40mg) 12mL (hereinafter, referred to as. “THF”) was dissolved in, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added, 40 ℃ It was heated and stirred in for 15 minutes. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. After repeated two more times this step, at -20 ° C. 3 and held hours. The resulting precipitated crystals were collected by filtration under reduced pressure, and dried to obtain Form I crystal of the potassium salt. B Powder X-ray diffraction spectrum of type I crystal of the obtained potassium salt using the apparatus shown in Fig. 1 H-NMR (DMSO-D 6 ): delta 8 .14 (s, 1H), 7 .1 8 – 7 . 3 8 . (M, 10H), 4 7 . 2-4 8 4 (M, 1H) , 3 . 6 5 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 2 (s, 3 H), 1.55-1. 7 0 ( M, 4H), 1.2 3 (D, 6 H)
Example 3 II-form crystals of the potassium salt
Compound A with (40mg) was dissolved in THF and 12mL, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added and heated with stirring for 15 min at 40 ℃. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. This operation was repeated two more times, at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, after drying, 40 ℃, relative humidity 7 while 5% of thermo-hygrostat 7 left for days to give crystalline Form II of the potassium salt. B Powder X-ray diffraction spectrum of crystalline Form II of the resulting potassium salt using the apparatus Fig 3 is shown in.
Example 4 III type crystal of the potassium salt
Compound A , in addition to (100mg) acetonitrile (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (1.1 eq) was added and stirred for 200 minutes at 20 ℃. While stirring the mixture 7 after a heated stirring for 1 hour to 0 ° C., and then cooled to 10 ℃ over 10 hours. Further heated while the mixture 6 is heated to 0 ℃, t- butyl methyl ether (0. 3 after adding mL), cooled to 20 ℃ over 10 hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, III type crystal of the potassium salt ( 7 to afford 5mg). The powder X-ray diffraction spectrum of the type III crystal of the obtained potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, of about 7 endothermic peak was observed at around 4 ° C..
Elemental analysis (C 2 6 H 3 1 N 4 O 4 . SK + 0 7 8 H 2 as O)
calculated value (%) C: 5 6 .91 H: 5.9 8 N: 10.21
measured value (%) C: 5 6 . 6 1 H: 5.55 N:. 10 3 6
EXAMPLE 5 IV-type crystal of the potassium salt
Compound A , in addition to (50mg) and ethyl acetate (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (2.2 eq) was added and 2 at 20 ° C. 3 and stirred for hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried to obtain Form IV crystal of the potassium salt (41mg). The powder X-ray diffraction spectrum of crystalline Form IV of the resulting potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, an endothermic peak was observed at around approximately 91 ℃.
Selexipag (C26H32N4O4S, Mr = 496.6 g/mol) ist ein Diphenylpyrazin-Derivat. Es wird in der Leber zum aktiven Metaboliten ACT-333679 (MRE-269) biotransformiert. Selexipag unterscheidet sich strukturell von Prostazyklin und anderen Prostazylin-Rezeptor-Agonisten.
References
- 1 Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
- 2 New Drug Approved for Rare Lung Disorder. PPN. 23 Dec 2015 Has link to GRIPHON study results
- Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
- Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
- Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
- Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
- Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812. PMID 23204120.
| Patent | Submitted | Granted |
|---|---|---|
| Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof [US8877710] | 2009-12-30 | 2014-11-04 |
| Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same [US8791122] | 2010-06-25 | 2014-07-29 |
| COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2015057325] | 2013-03-26 | 2015-02-26 |
| INHIBITION OF NEOVASCULARIZATION BY SIMULTANEOUS INHIBITION OF PROSTANOID IP AND EP4 RECEPTORS [US2014275200] | 2014-03-05 | 2014-09-18 |
| INHIBITION OF NEOVASCULARIZATION BY INHIBITION OF PROSTANOID IP RECEPTORS [US2014275238] | 2014-03-05 | 2014-09-18 |
| Fibrosis inhibitor [US8889693] | 2014-04-10 | 20 |
| Patent | Submitted | Granted |
|---|---|---|
| Heterocyclic compound derivatives and medicines [US7205302] | 2004-05-27 | 2007-04-17 |
| METHODS OF IDENTIFYING CRITICALLY ILL PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ORGAN FAILURE AND COMPOUNDS FOR THE TREATMENT HEREOF [US2014322207] | 2014-07-11 | 2014-10-30 |
| THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2014329824] | 2014-07-18 | 2014-11-06 |
| Sustained Release Composition of Prostacyclin [US2014303245] | 2012-08-10 | 2014-10-09 |
| COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2013261177] | 2011-09-30 | 2013-10-03 |
| METHODS OF TREATMENT OF PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ISCHEMIC EVENTS AND COMPOUNDS HEREOF [US2013040898] | 2011-04-29 | 2013-02-14 |
| Substituted Diphenylpyrazine Derivatives [US2013005742] | 2010-08-06 | 2013-01-03 |
| USE OF FORM-I CRYSTAL OF 2–N-(METHYLSULFONYL)ACETAMIDE [US2014148469] | 2014-01-22 | 2014-05-29 |
| CRYSTALS OF 2- {4- [N- (5,6-DIPHENYLPYRAZIN-2-YL) -N-ISOPROPYLAMINO]BUTYLOXY}-N- (METHYLSULFONYL) ACETAMIDE [US2014155414] | 2014-01-22 | 2014-06-05 |
| PROSTACYCLIN AND ANALOGS THEREOF ADMINISTERED DURING SURGERY FOR PREVENTION AND TREATMENT OF CAPILLARY LEAKAGE [US2014044797] | 2012-03-30 | 2014-02-13 |
 |
|
| Names | |
|---|---|
| IUPAC name
2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
|
|
| Other names
ACT-293987, NS-304
|
|
| Identifiers | |
475086-01-2  |
|
| ChEMBL | ChEMBL238804  |
| ChemSpider | 8089417 |
| 7552 | |
| Jmol interactive 3D | Image |
| KEGG | D09994 |
| PubChem | 9913767 |
| UNII | P7T269PR6S |
| Properties | |
| C26H32N4O4S | |
| Molar mass | 496.6 g·mol−1 |
SEE……….http://apisynthesisint.blogspot.in/2015/12/fda-approves-new-orphan-drug-uptravi.html
//////////
CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3
New Drug Approvals blog by Dr Anthony Crasto hits ten lakh views in 211 countries
New Drug Approvals hits ten lakh views in 211 countries
|
 THANKS AND REGARD’S MOBILE-+91 9323115463
GLENMARK SCIENTIST , INDIA
web link 
|
//////////
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
Read all about Organic Spectroscopy on
ORGANIC SPECTROSCOPY INTERNATIONAL
New Drug Approvals 