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TIDEGLUSIB ..An NSAID and neuroprotective agent.
Tideglusib
M.Wt: 334.39
Formula: C19H14N2O2S
CAS No.: 865854-05-3
4-Benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione
Glycogen Synthase Kinase 3 beta (GSK-3beta; tau Protein Kinase I) Inhibitors
Treatment of Neurologic Drugs (Miscellaneous)
Alzheimer’s Dementia, Treatment ofCerebrovascular Diseases, NP031112; NP-031112, Nypta Zentylor
- NP 031112
- NP-12
- NP031112
- Tideglusib
- UNII-Q747Y6TT42
Noscira (Originator)
Tideglusib (NP-12, NP031112) is a potent, selective and irreversible[1] small molecule non-ATP-competitive GSK3 inhibitor that has been investigated as a potential treatment for Alzheimer’s disease and paralysis supranuclear palsy in Phase IIa[2] and IIb clinical trials.[3][4][5][6] The first clinical trial conducted with tideglusib to be published (in English, at least) was phase II and demonstrated that overall tideglusib was well tolerated, except for some moderate, asymptomatic, fully reversible increases in liver enzymes (≥2.5xULN; where ULN=Upper Limit of Normal).[4]
tideglusib
NP-031112 is an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta) in early clinical development for the oral treatment of Alzheimer’s disease. The compound had been in phase II clinical trials for the treatment of progressive supranuclear palsy and for the treatment of Alzheimer’s disease; however the development was discontinued in 2011 and 2012 respectively, due to lack of efficacy.
The neuroprotective effects demonstrated in animal studies have also suggested its potential use in stroke and other brain disorders. It is being developed by Noscira (formerly known as NeuroPharma). In 2009, orphan drug designation was received in the E.U. and the U.S. for the treatment of progressive supranuclear palsy. In 2010, fast track designation was assigned in the U.S. by Noscira for this indication.
Fast Track status is granted to facilitate development and expedite the review of a drug for a serious or potentially fatal illness and to meet an unmet medical need
The Phase II trial for Progressive Supranuclear Palsy (PSP) commenced in December 2009 and is currently in progress
Belen Sopesen, CEO of Noscira: ‘Fast Track status is very positive for the company and is an incentive to continue advancing in the clinical development of Tideglusib (ZentylorTM) in Progressive Supranuclear Palsy’
Overexpression of GSK-3 leads to hyperphosphorylation of the tau protein, an anomaly which occurs in a number of neurodegenerative diseases known collectively as tauopathies, which include Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP) and Pick disease. NP-12 is a GSK-3 inhibitor with oral bioavailability and great therapeutic potential as a disease-modifying treatment for Alzheimer’s.
NP-12 is currently undergoing clinical trials for Alzheimer’s disease in the EU. NP-12, the only GSK-3 inhibitor under clinical development for AD, has proven to be capable of acting on all of the histopathological lesions associated with the disease in experimental models: it reduces phosphorylation of the tau protein and hippocampal and entorhinal cortex neuron loss, improves spatial memory deficits and significantly reduces the accumulation of amyloid plaques in the brain. NP-12 also provides neuroprotection in vivo and has a potent anti-inflammatory effect in a range of animal models.
About Progressive Supranuclear Palsy
PSP is a neurodegenerative disease characterized by oculomotor disturbances, specifically difficulties in moving the eye vertically, falling down and Parkinsonian symptoms.
The disease affects an estimated 5-6.4 out of every 100,000 people.
There is currently no treatment capable of delaying or altering the progression of the illness.
TIDEGLUSIB
- Domínguez, JM; Fuertes, A; Orozco, L; del Monte-Millán, M; Delgado, E; Medina, M (January 2012). “Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib”. The Journal of Biological Chemistry 287 (2): 893–904.doi:10.1074/jbc.M111.306472. PMC 3256883. PMID 22102280.
- Teodoro Del Ser (2010). “Phase IIa clinical trial on Alzheimer’s disease with NP12, a GSK3 inhibitor”. Alzheimer’s & Dementia 6 (4): S147. doi:10.1016/j.jalz.2010.05.455.
- Eldar-Finkelman, H; Martinez, A (2011). “GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS”. Frontiers in Molecular Neuroscience 4: 32.doi:10.3389/fnmol.2011.00032. PMC 3204427. PMID 22065134.
- Del Ser, T; Steinwachs, KC; Gertz, HJ; Andrés, MV; Gómez-Carrillo, B; Medina, M; Vericat, JA; Redondo, P et al. (2013). “Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study”. Journal of Alzheimer’s disease 33 (1): 205–15.doi:10.3233/JAD-2012-120805. PMID 22936007.
- “FDA Grants Fast Track Status to Tideglusib (ZentylorTM) for Progressive Supranuclear Palsy”. PR Newswire Europe Including UK Disclose. 10 September 2010. Retrieved 11 August 2013.
- Dominguez, JM; Fuertes, A; Orozco, L; Del Monte-Millan, M; Delgado, E; Medina, M (2011). “Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib”. Journal of Biological Chemistry 287 (2): 893–904.doi:10.1074/jbc.M111.306472. PMC 3256883. PMID 22102280.
- WO 2005097117
- WO 2006045581
- WO 2006084934
- WO 2008057933
- WO 2011151359
- Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.
Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M.
J Biol Chem. 2012 Jan 6;287(2):893-904. doi: 10.1074/jbc.M111.306472. Epub 2011 Nov 18
13. MARTINEZ A ET AL.: “First Non-ATP Competitive Glycogen Synthase Kinase 3.beta. (GSK-3.beta.) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer’s Disease” JOURNAL OF MEDICINAL CHEMISTRY, vol. 45, no. 6, 2002, pages 1292-1299
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GSK-3 Inhibitors
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5-13-2009
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GSK-3 inhibitors
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6-27-2008
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Use Of Heterocyclic Compounds As Neurogenic Agents
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CLINICAL TRIALS
http://clinicaltrials.gov/search/intervention=NP+031112
http://clinicaltrials.gov/show/NCT01350362
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http://www.google.com/patents/WO2005097117
For example, the following procedure can be used to produce 4-N-benzyl substituted thiadiazolidinones :
The general experimental procedure of Scheme 1 is described for example in Slomczynska,
U.; Barany, G., “Efficient Synthesis of l,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl- amines) and observations on formation of l,2,4-Thiadiazolidine-3,5-dione by related
Chemistry”, J. Heterocyclic Chem., 1984, 21, 241-246.
For example, sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, preferably at low temperature, preferably at about 5 °C, to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in a suitable solvent such as hexane, ether or THF. When the addition is finished, the mixture is left to react, for example by stirring for 20 hours at room temperature. After this time, the resulting product is isolated by conventional methods such as suction filtration or solvent evaporation and then, the purification is performed (e.g. by recristallization or silica gel column chromatography using the appropriate eluent). Other alternative procedures will be apparent to the person skilled in the art, such as the use of any other chlorinating agent instead of sulfuryl chloride, variations in the order of addition of the reactants and reaction conditions (solvents, temperature, etc).
Example 2
4-Benzyl-2-naphthalen-l-yl-[l,2,4]thiadiazolidine-3,5-dione (2)
Reagents: Benzyl-isothiocianate (13 mmol, 1.72 mL), 1-naphthyl-isocyanate (13 mmol, 1.9 mL) and SO2CI2 (13 mmol, 1.04 mL) in hexane (50 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from EtOH. Yield: 3.8 g (87%), white needles. mp= 150 °C
1H-RMN (CDC13): 4.9 (s, 2H, CH2PI1); 7.3-7.9 (m, 12Η, arom.) 13C-RMN (CDCI3): 46.5 (CH2Ph); 128.3; 128.6; 129.0; 135.0 (C arom, Ph); 122.0; 125.3; 126.8; 127.2; 127.5; 128.5; 130.8; 134.4 (C arom, naphthyl); 152.2 (3-00); 165.9 (5- C=O).
Anal (C19H14N2O2S), C, H, N, S
Sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, at 5 °C to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in hexane, ether or THF. When the addition is finished, the mixture is stirred for 20 hours at room temperature. After this time, the resulting product is isolated by suction filtration or by solvent evaporation and then, the purification is performed by recristallization or silica gel column chromatography using the appropriate eluent. More details can be found in Slomczynska, U.; Barany, G., “Efficient Synthesis of l,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl-amines) and observations on formation of l,2,4-Thiadiazolidine-3,5-dione by related Chemistry”, J Heterocyclic Client., 1984, 21, 241-246.
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| WO2006045581A1 * | Oct 21, 2005 | May 4, 2006 | Neuropharma Sa | The use of 1, 2, 4-thiadiazolidine-3, 5-diones as ppar activators |
| WO2011151359A1 | Jun 1, 2011 | Dec 8, 2011 | Noscira, S.A. | Combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative |
| WO2013124413A1 | Feb 22, 2013 | Aug 29, 2013 | Noscira, S.A. | Thiadiazolidinediones as gsk-3 inhibitors |
| EP2177510A1 | Oct 17, 2008 | Apr 21, 2010 | Universität des Saarlandes | Allosteric protein kinase modulators |
| EP2527323A1 | May 24, 2011 | Nov 28, 2012 | Noscira, S.A. | Urea carbonyl disulfide derivatives and their therapeutic uses |
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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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MIDAZOLAM
MIDAZOLAM
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
59467-70-8 CAS NO OF FREE BASE
59467-94-6 MALEATE, Launched – 1982, Roche (Originator)
59467-96-8 (HCl)
A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.
Midazolam (/mɪˈdæzəlæm/, marketed in English-speaking countries and Mexico under the trade names Dormicum, Hypnovel, andVersed,) is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potentanxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties.[6][7][8] Midazolam has a fast recovery time and is the most commonly used benzodiazepine as a premedication for sedation; less commonly it is used for induction and maintenance of anesthesia.Flumazenil, a benzodiazepine antagonist drug, can be used to treat an overdose of midazolam, as well as to reverse sedation.[7] However, flumazenil can trigger seizures in mixed overdoses and in benzodiazepine-dependent individuals, so is not used in most cases.[9][10]
midazolam
Administration of midazolam by the intranasal or the buccal route (absorption via the gums and cheek) as an alternative to rectally administereddiazepam is becoming increasingly popular for the emergency treatment of seizures in children. Midazolam is also used for endoscopyprocedural sedation and sedation in intensive care. The anterograde amnesia property of midazolam is useful for premedication before surgery to inhibit unpleasant memories. Midazolam, like many other benzodiazepines, has a rapid onset of action, high effectiveness and low toxicity level. Drawbacks of midazolam include drug interactions, tolerance, and withdrawal syndrome, as well as adverse events including cognitive impairment and sedation. Paradoxical effects occasionally occur, most commonly in children and the elderly, particularly after intravenous administration. The drug has also recently been hastily introduced for use in executions in the USA in combination with other drugs.
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of one to four hours; however, in the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally with only 50 percent of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, hypnotic, anxiolytic, anterograde amnesia, muscle relaxation and anti-convulsant.Midazolam maleate is a benzodiazepine that is commercialized by Astellas Pharma and Roche as an intravenous or intramuscular injection for the long-term sedation of mechanically ventilated patients under intensive care. The drug is also available in a tablet formulation, and is currently distributed in various markets, including Germany, Japan, Switzerland and the U.K. In March 2002, two lots of a syrup formulation were recalled in the U.S. due to the potential presence of a crystalline precipitate of an insoluble complex of midazolam and saccharin. Subsequently, the injection and syrup formulations of the product were both withdrawn from the U.S. market. In 2010, a Pediatric Use Marketing Authorization (PUMA) was filed for approval in the E.U. by ViroPharma for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents, from 3 months to less than 18 years. In 2011, a positive opinion was assigned to the PUMA and final approval was assigned in June 2011. The product was launched in the U.S. in November 2011. This product was filed for approval in Japan in 2013 by Astellas Pharma for the conscious sedation in dentistry and dental surgery. In the same year the product was approved for this indication.
In terms of clinical development, a nasal formulation of the drug is in phase III clinical trials at Upsher-Smith for rescue treatment of seizures in patients on stable anti-epileptic drug regimens who require control of intermittent bouts of increased seizure activity (seizure clusters). The Hopitaux de Paris had been developing a sublingual tablet formulation of midazolam to be used in combination with morphine for the treatment of pain in children following bone fractures; however, no recent development has been reported for this indication. NovaDel Pharma had been developing the compound preclinically for the treatment of generalized anxiety, however no recent developments have been reported.
Midazolam achieves its therapeutic effect through interaction with the gamma-aminobutyric acid benzodiazepine (GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and post-synaptic neurons, opening ion channels and bringing about a hyperpolarization via either chloride or potassium ion flow.
In 2008, fast track designation was assigned to midazolam maleate in the U.S. for the treatment of seizure disorders.
In 2009, Orphan Drug Designation was received in the U.S. by for the treatment of seizure disorders in patients who require control of intermittent bouts of increased seizure activity (e.g. acute repetitive seizures, seizure clusters). This designation was assigned in the U.S. for the treatment of nerve agent-induced seizures.
In 2010, midazolam maleate was licensed to Upsher-Smith by Ikano Therapeutics for the treatment of acute repetitive seizure in patients with epilepsy. However, in 2010, Ikano closed and dissolved its business. Previously, Ikano had transferred to Upsher-Smith ownership of it nasal midazolam maleate program.
Midazolam is among about 35 benzodiazepines which are currently used medically, and was synthesised in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States.Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs.The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site.Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility.
Midazolam is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride equivalent to 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride and 0.01% edetate disodium with 1% benzyl alcohol as preservative, and sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 2.9-3.7.
Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H– imidazo[1,5-a] [1,4] benzodiazepine hydrochloride. Midazolam hydrochloride has the molecular formula C18H13ClFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula:
 |
In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.
midaolam hydrochloride NDA 018654, 075154
REF
U.S. Pat. No. 4,280,957
U.S. Pat. No. 5,693,795
U.S. Pat. No. 6,512,114
Midazolam Maleate
Drugs Fut 1978, 3(11): 822
Bioorganic and Medicinal Chemistry, 2012 , vol. 20, 18 pg. 5658 – 5667
Journal of Heterocyclic Chemistry, 1983 , vol. 20, 3 pg. 551 – 558.. 32 maleate
WO 2001070744
WO 2001002402
WO 2012075286
US2011/275799 A1… no 5
Journal of Organic Chemistry, 1978 , vol. 43, p. 936,942, mp free base, nmr
| US4280957 | May 15, 1978 | Jul 28, 1981 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| US6262260 * | Mar 23, 2000 | Jul 17, 2001 | Abbott Laboratories | Process for the preparation of midazolam |
| US6512114 | Jun 30, 1999 | Jan 28, 2003 | Abbott Laboratories | Process for the preparation of Midazolam |
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introduction
4H-imidazo[1,5-a][1,4]benzodiazepines or, more simply, imidazobenzodiazepines, are a class of benzodiazepines having the general formula (I),
wherein the 1,4-diazepine ring is fused with a 1,3-imidazole ring. The main compounds part of the 4H-imidazo[1,5-a][1,4]benzodiazepines are Midazolam of formula (IV):
an active ingredient currently commercially available as a hydrochloride salt under the name of Versed or Hypnovel for anaesthetic and sedative use and the maleate salt currently commercially available under the name Dormicum or Flormidal.
Other important compounds are Climazolam of formula (VII):
Imidazenil of formula (VIII):
1-Hydroxymidazolam of formula (IX):
and Desmethyl midazolam of formula (X):
all these being biologically active substances and having psychotropic and sedative action.
The synthesis of the Midazolam as described in U.S. Pat. No. 4,280,957 of Hoffmann-La Roche provides for the decarboxylation reaction of the 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of formula (VI) according to the following scheme:
The process for preparing the intermediate (VI) via basic hydrolysis of the corresponding ester is described in such patent publication and it is well known in the art.
The thermal decarboxylation reaction in high boiling solvent such as mineral oil at 230° C. for 5 min results in a mixture of products of Midazolam of formula (IV) and of Isomidazolam of formula (IV-bis), a non-pharmacologically active isomer, at a 80:20 ratio. The two products are separated by chromatography.
At industrial level, the formation of the Isomidazolam isomer impurity requires a further isomerisation reaction performed on the mixture of the two compounds to convert the isomer into the active product. The reaction mixture obtained from the thermal decarboxylation is thus subjected to basic treatment under the action of KOH in EtOH followed by an acid treatment which thus provides a mixture of Midazolam-Isomidazolam at a 95:5 ratio. The final removal of the Isomidazolam impurity from the product occurs through crystallisation of the product from AcOEt and EtOH. In order to limit this isomerisation treatment, in the subsequent U.S. Pat. No. 5,693,795 of Hoffmann-La Roche dated 1999, there is described a process for performing the decarboxylation of the compound of formula (VI) in n-butanol in a continuous tubular reactor with a 4 minutes permanence period with a yield between 47-77%. However, the reaction, performed at high temperature and pressure (280° C., 100 bars) results in the formation of a considerable percentage of Isomidazolam (85:15 Midazolam/Isomidazolam ratio) which still requires the basic isomerisation step.
Lastly, in U.S. Pat. No. 6,512,114 of Abbott Laboratories there is described the decarboxylation of the compound of formula (VI) in mineral oil or in N,N-Dimethylacetamide (DMA) at 160-230° C. for at least 3 hours obtaining a 3/1 to 6/1 Midazolam/Isomidazolam ratio with a yield of isolated product equal to just 54%.
Though performed using dedicated apparatus and in extreme conditions, the prior art processes do not allow selectively performing the decarboxylation reaction of the intermediate (VI) to Midazolam thus requiring a further synthetic passage followed by crystallisation with ensuing reduction of the overall yield.
Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine) is represented by the following structural formula (I):
Midazolam is a central nervous system (CNS) depressant, used for short term treatment of insomnia. Like other benzodiazepines, midazolam binds to benzodiazepine receptors in the brain and spinal cord and is thus used as a short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is currently used in dentistry, cardiac surgery, endoscopic procedures, as a preanesthetic medication, as an adjunct to local anesthesia and as a skeletal muscle relaxant. Depending on the pH value, midazolam can exist in solution as a closed ring form (I) as well as an open ring form (IA), which are in equilibrium, as shown in Scheme 1:
The amount of the open ring form (IA) is dependent upon the pH value of the solution. At a pH value of about 3, the content of the open ring form (IA) can be 40%, while at pH value of 7.5, the closed ring form (I) can be more than 90%.
Clinical studies have demonstrated that there are no significant differences in the clinical activity between midazolam hydrochloride and midazolam maleate, however the use of intravenous midazolam hydrochloride has been associated, in some cases, with respiratory depression and arrest.
U.S Pat. No. 4,280,957 (hereinafter the ‘957 patent) describes a synthetic process for preparing midazolam, which is depicted in Scheme 2 below. This process includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) with acetic anhydride in dichloromethane to produce 2-acetamido-methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (III). The latter is heated with polyphosphoric acid at 150° C. to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine of formula (IV), which is purified by column chromatography. Compound IV is then mixed with toluene and manganese dioxide and heated to reflux to afford midazolam base, which is crystallized from ether to yield a product with mp of 152-154° C.
The ‘957 patent further describes an alternative process which includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) (optionally as a dimaleate salt) with triethylorthoacetate in ethanol and in the presence of p-toluenesulfonic acid to afford 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (IV). This product is dissolved in xylene and treated with activated manganese dioxide to afford the crude base, which is reacted in situ with maleic acid in ethanol and crystallized by addition of ether to produce the midazolam maleate having melting point of 148-151° C. The process is depicted in Scheme 3 below.
The preparation of midazolam maleate from the isolated midazolam base is also described in a further example of the ‘957 Patent, wherein a warm solution of midazolam base in ethanol is combined with a warm solution of maleic acid in ethanol. The mixture is diluted with ether and at least part of the solvents is evaporated using a steam bath to obtain crystalline midazolam maleate having melting point of 148-151° C. The yield and the purity of the obtained midazolam maleate are not disclosed.
U.S. Pat. No. 6,512,114 (hereinafter the ‘114 patent) describes another synthetic process for preparing midazolam, which is depicted in Scheme 4 below. According to this Process, the starting material 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (V) is heated in mineral oil for 3 hours at 230° C. until it is decarboxylated, followed by treatment with potassium tert-butoxide, to afford midazolm (I), isomidazolam (VI) and a midazolam dimmer (VII). Midazolam base is obtained in 54.5% yield after two re-crystallizations from ethyl acetate and heptane; however, the purity of the product is not disclosed.
The preparation of midazolam by conventional routes is liable to produce impurities such as isomidazolam (VI) and a midazolam dimmer (VII), and possibly other impurities. There is, therefore, a need in the art for a midazolam purification process that will provide highly pure midazolam containing minimal amounts of impurities produced. The present invention provides such a process.
This example describes the preparation of midazolam base as taught in the ‘957 patent.
16 g (0.03 mol) of 2-aminomethyl-7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-bezodiazepine dimaleate was dissolved in 200 ml of toluene and 10 ml of 25% ammonium hydroxide solution was added and mixing was maintained for an hour. Then, the phases were separated and the toluene phase was dried by azeotropic distillation using a Dean Stark apparatus. 7 ml (0.038 mol) of triethylorthoacetate was added and the solution was heated to reflux for 4 hours, after which time the solution was left to cool to ambient temperature. 25 ml of methyl tert-butyl ether was added and the mixture was cooled overnight to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, which was isolated by filtration. The product was mixed with 200 ml of toluene and dried by azeotropic distillation using a Dean Stark apparatus. Then, 30 g of manganese dioxide was added and the mixture was heated to reflux for two hours. The excess manganese dioxide was filtered off to afford a solution of midazolam base in toluene, which was evaporated to obtain a product having 97.9% purity and containing 0.44% of impurity VIII and 1.14% of impurity IX (according to HPLC).
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EXAMPLE 28
2-Aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate
A suspension of 17 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide in 200 ml of tetrahydrofuran and 100 ml of methanol was hydrogenated in presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hrs. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 ml of 2-propanol and warmed on the steambath. A warm solution of 17 g of maleic acid in 60 ml of ethanol was added and the salt was allowed to crystallize by cooling in the ice bath. The final product consisted of yellow crystals with mp 196
EXAMPLE 14
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
Acetic anhydride, 7 ml., was added to a solution of 6.16 g. of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml. of methylene chloride. The solution was layered with 200 ml. of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave 6.2 g. resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was heated with 40 g. of polyphosphoric acid at 150 water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g.) was chromatographed over 120 g. of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[ 1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml. of toluene and 30 g. of manganese dioxide was heated to reflux for 11/2 hours. The manganese dioxide was separated by filtration over celite. The filtrate was evaporated and the residue was crystallized from ether to yield a product with m.p. 152 was recrystallized from methylene chloride/hexane
EXAMPLE 49
8-Chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine
Potassium t-butoxide, 0.625 g. (5.5 mmol), was added to a solution of 1.625 g. (5 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 20 ml. of dimethylformamide cooled to -30 nitrogen for 10 min. at -30 ml. of glacial acetic acid and was then partitioned between aqueous bicarbonate and toluene/methylene chloride (3:1 v/v). The organic layer was separated, dried and evaporated. The residue was chromatographed over 60 g. of silica gel using 25% (v/v) methylene chloride in ethyl acetate. The less polar product was eluted first and was crystallized from ethylacetate/hexane to yield product with m.p. 180
EXAMPLE 50
8-Chloro-6-(2-fluorphenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
Potassium t-butoxide, 0.125 g. (1.1 mmol) was added to a solution of 0.325 g. (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine in 20 ml. of dimethylformamide cooled to -30 -30 by addition of 0.2 ml. of glacial acetic acid and was partitioned between aqueous sodium bicarbonate and methylene chloridetoluene (1:3). The organic phase was washed with water, dried and evaporated. The residue was chromatographed over 20 g. of silica gel using ethyl acetate for elution. After elution of starting material, product was collected and crystallized from ether/hexane, m.p. 156
hyd and dihydrochloride
EXAMPLE 24
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine dihydrochloride
A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 5 ml of ethanol was treated with excess ethanolic hydrogen chloride. The salt was crystallized by addition of 2-propanol and ether. The colorless crystals were collected, washed with ether and dried to leave a final product with mp 290
EXAMPLE 258-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride
A solution of 0.325 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) of the dihydrochloride of this compound in 5 ml of ethanol. After filtration, the solution was treated with ether and heated on the steambath for 5 min to crystallize. The crystals were collected, washed with ether and dried to leave the monohydrochloride with mp 295
maleate
EXAMPLE 22
8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate
A warm solution of 6.5 g (0.02 m) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 m) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 min. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield a final product with mp 148
…
Synthesis
Midazolam, can be described according to scheme 4 indicated below:
was prepared according to processes known in the art (e.g. U.S. Pat. No. 4,280,957) which comprise the basic hydrolysis of the corresponding ester.For the reactions performed in the microreactor, the solutions containing the substrates to be decarboxylated were loaded into 5 and 10 mL gastight glass syringes (Hamilton, item n. 81527, 81627) mounted on syringe pumps (KD Scientifics, model KDS100). A pipe made of PTFE® (OD=1.58 mm, ID=0.8 mm, Supelco, item n. 58696-U) was used for making the reaction channel.A counterpressure valve sold by Swagelok (item n. SS-SS1-VH) was used for regulating the flow within the channel.Example 1Synthesis of the Compound of Formula (V)—Example of the Invention
50 g (0.135 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid of formula (VI) and 250 mL of ethanol were loaded into a two-neck 500 mL flask, equipped with a magnetic stirrer. 40 mL of an aqueous solution of 1 M HCl are dripped in about 10 minutes. The open di-hydrochloride intermediate of formula (V) starts precipitating into the reaction environment already after 3 minutes from the beginning of the addition of the acid solution. The mixture is maintained stirred at RT for 3 hrs and then it is filtered on buckner washing the solid with ethanol. The moist product is dried in an oven under vacuum at 60° C. up to reaching a constant weight. A light yellow crystalline product is obtained (51.5 g, 83% yield). The crude product was used for the decarboxylation without further purifications.
ESI-MS [MeCN+0.1% HCOOH]: m/z 388 (V); 370 (VI).
1H-NMR (250 MHz, CD3OD): 2.52 (s, 3H); 4.27-4.41 (m, 2H); 7.22-8.1 (m, 7H). M.p.: 217° C.
Example 2
Synthesis of Midazolam of Formula (IV)—Performed in Batch—Example of the Invention
30 g (0.065 mol) of 5-(aminomethyl)-1-{(4-chloro-2-[(2-fluorophenyl)carbonyl]phenyl}-2-methyl-1H-imidazole-4-carboxylic acid dihydrochloride of formula (V) and 90 mL of NMP are loaded into a three-neck 250 mL flask, equipped with a magnetic stirrer and coolant. The mass is heated using an oil bath at T=195-203° C. for one hour. Thus, 1 mL of solution is collected for performing HPLC analysis. The reaction product is Midazolam having 82% titre (w/w) (determined via HPLC titre correcting it using the solvent) and it contains 1% of Isomidazolam. The product is extracted using Isopropyl acetate after raising the pH to 10 by adding aqueous Na2CO3.
Example 3
Synthesis of Midazolam of Formula (IV)—Performed in a Micro-Reactor—Example of the Invention
3.22 g (7 mmol) of 5-(aminomethyl)-1-{4-chloro-2-[(2-fluorophenyl)carbonyl]phenyl}-2-methyl-1H-imidazole-4-carboxylic acid dihydrochloride of formula (V) and 10 mL of NMP are loaded into a 10 mL flask equipped with a magnetic stirrer. In order to facilitate the complete solubilisation of the substrate, it is necessary to slightly heat the reaction mixture (about 40° C.) for a few minutes. The solution thus obtained is transferred into a 10 mL gastight glass syringe mounted on a KDS100 syringe pump (FIG. 1) and the flow is regulated at 1.0 mL/h so as to set a residence period of 30 minutes at 200° C. The reaction product is Midazolam having an 89% titre (w/w) (determined via HPLC titre correcting it using the solvent) and containing 3% (w/w) of Isomidazolam.
Example 4Synthesis of Midazolam of formula (IV)—Comparison of the InventionA table is reported which summarises the results of the decarboxylation of the compound of formula (V) and (V-bis) (for the latter see Examples 6 and 7) obtained according to some embodiments of the invention and those obtained by way of experiment through the decarboxylation of the intermediate of formula (VI) (process of the prior art) both performed in 3 volumes of NMP at 200° C., both in batch method (Example 4) and in continuous method with the microreactor (MR) made of PTFE of FIG. 1. (Examples 4-1, 4-2, 4-3).
| Example | substrate | Mode | Solv. | T° C. | t min. | Midazolam (p/p) | Isomidaz. (P/P) |
| 2 | (V) | Batch | NMP | 200 | 60 | 82 | 1 |
| 3 | (V) | MR | NMP | 200 | 30 | 89 | 3 |
| 7 | (V-bis) | Batch | NMP | 200 | 60 | 68 | 3 |
| 4 | (VI) | Batch | NMP | 200 | 60 | 78 | 18 |
| 4-1 | (VI) | MR | NMP | 200 | 38 | 81 | 17 |
| 4-2 | (VI) | MR | NMP | 200 | 20 | 77 | 18 |
| 4-3 | (VI) | MR | NMP | 200 | 15 | 58 | 22 |
| U.S. Pat. No. | (VI) | Tubular | n-BuOH | 290 | 4 | 85 * | 15 * |
| 5,693,795 | reactor | ||||||
| U.S. Pat. No. | (VI) | Batch | Olio | 230 | 180 | 75 * | 25 * |
| 6,512,114 | min. | 87.5 * | 12.5 * | ||||
| or DMA | |||||||
| * = Midazolam/Isomidazolam ratio only (other impurities not considered). | |||||||
The product of the comparative experiments 4, 4-1, 4-2, 4-3 and of the two USA patents should be subjected to a further isomerisation process to reduce the high amount of Isomidazolam so as to be able to obtain Midazolam free of Isomidazolam after further crystallization, which would not be required for the product obtained according to the invention (examples 2 and 3).
A 4-neck RBF was charged under nitrogen flow with: 10 g of Midazolam (IV) (prepared according to example 2) and 40 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. In an other flask was prepared the following solution: 3.72 g of maleic acid are dissolved in 15 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. The maleic acid solution is dropped in 30/40 minutes and keeping T=25/30° C. into the solution containing Midazolam. The slurry was cooled down at −15° C. in one hour and kept at that temperature for at least 2 hours. The slurry was then filtered and the cake was washed with 40 mL of cool Ethanol. The filter was discharged and the product was dried at 40° C. under vacuum for 2 hours and then at 60° C. for 8 hours. 12.8 g of Midazolam Maleate as white solid were collected (Molar yield=94.5%). m.p.=149-152° C. (by DSC).
A 4-neck RBF was charged under nitrogen flow with: 1 g of Midazolam (IV) (prepared according to example 2) and 15 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. 5 mL of a ethanolic solution of Hydrochloric acid 2N were slowly added. 20 mL of Isopropanol were added over 30 minutes at RT. The slurry was cooled down at −15° C. in one hour and kept at that temperature for at least 2 hours. The slurry was then filtered and the cake was washed with 10 mL of cool isopropanol. The filter was discharged and the product was dried at 40° C. under vacuum for 2 hours and then at 60° C. for 8 hours. Midazolam dihydrochloride as white solid was collected.
MIDAZOLAM HYDROCHLORIDE
Example 10
Preparation of 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride (Midazolam hydrochloride)
A 4-neck RBF was charged under nitrogen flow with: 1 g of Midazolam (IV) (prepared according to example 2) and 10 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. In an other flask was prepared the following suspension: 1.22 g of Midazolam dihydrochloride (prepared according to example 9) and 15 mL of Ethanol. The Midazolam ethanolic solution was added to the Midazolam dihydrochloride suspension. After filtration, the solution was treated with MTBE and heated at 60° C. until crystallization. After cooling to RT, the slurry was filtered, the cake washed with MTBE and the product was dried to provide Midazolam (mono)hydrochloride as a white solid.
…..
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DAPAGLIFLOZIN…FDA approves AZ diabetes drug Farxiga
DAPAGLIFLOZIN, BMS-512148
The US Food and Drug Administration has finally approved AstraZeneca’s diabetes drug Farxiga but is insisting on six post-marketing studies, including a cardiovascular outcomes trial.
The approval was expected given that the agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 last month that the benefits of Farxiga (dapagliflozin), already marketed in Europe as Forxiga, outweigh identified risks. The FDA rejected the drug in January 2012 due to concerns about possible liver damage and the potential link with breast and bladder cancer.
Orphan Drugs: FDA PDUFA Dates January – February 2014
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Investors and traders will be watching several orphan drug FDA PDUFA dates in January and February 2014.
FDA PDUFA Dates January – February 2014
| Generic Name | Trade Name | Sponsor | Indication | 2014 PDUFA Date |
| Tasimelteon | Hetlioz | Vanda Pharmaceuticals | Non-24 Hour Sleep/Wake Disorder in Blind Individuals Without Light Perception | 01/31 |
| Droxidopa * | Northera | Chelsea Therapeutics | Symptomatic Neurogenic Orthostatic Hypotension For Patients With Primary Autonomic Failure | 02/14 |
| Metreleptin | Bristol-Myers Squibb | Lipodystrophy | 02/27 | |
| Elosulfase Alfa ** | Vimizim | BioMarin Pharmaceutical | Mucopolysaccharidosis Type IV A (Morquio A Syndrome) | 02/28 |
| Ibrutinib | Imbruvica | Pharmacyclics | Chronic/Small-Cell Lymphocytic Leukemia | 2/28 |
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* Resubmission
** Priority Review
Please note the links for the following 2 chart columns above :
1) “Generic Name” Column Link = Is a source for the FDA PDUFA Date
2) “Indication” Column Link = Is the FDA Orphan Drug Product Designation Database Link.
Please…
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AVOSENTAN
AVOSENTAN
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide
5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4-yl]-amide,
5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide,
Endothelin ETA Receptor Antagonists
M.Wt: 479.51
Formula: C23H21N5O5S
Roche (Originator)
CAS No.: 290815-26-8
- RO 67-0565
- SPP 301
- UNII-L94KSX715K
PHASE 3
CLINICAL TRIALS
http://clinicaltrials.gov/search/intervention=spp301+OR+Avosentan
SPP-301 is an oral, once-daily, second-generation endothelin ETA receptor antagonist which had been in phase III clinical development at Speedel for the treatment of diabetic nephropathy. In December 2006, the company reported that the phase III trial had been stopped based on the recommendation from the trial’s Data Safety Monitoring Board (DSMB) to stop the trial following incidence of a significant imbalance in fluid retention in patients in the study arms. Speedel reported that the compound will be evaluated for potential new clinical development for the treatment of diabetic kidney disease and other indications.
Originally developed by Roche and specifically optimized for improved liver safety, SPP-301 was licensed to Speedel in October 2000. In 2003, Speedel exercised its option to license from Roche all rights to SPP-301, including exclusive worldwide rights for the full development and commercialization of the ETA antagonist. SPP-301 has fast track designation and has undergone a special protocol assessment (SPA) by the FDA. Speedel had been studying the drug for the treatment of hypertension.
AVOSENTAN
290815-26-8 CAS
PATENTS
2. WO 2004078104
3. WO 2005113543
4. WO 2007031501
5. WO 2008077916
Dutzler R, Ernstb B, Hediger MA, Keppler D, Mohr P, Neidhart W, Märki HP.Chimia (Aarau). 2010;64(9):662-6.
………………………
INTRODUCTION
-
5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide corresponding to the formula
is an inhibitor of endothelin receptors. WO00/52007 describes the preparation of said compound which is crystallized from Me2Cl2.
-
Own investigations have shown that there exist two distinct crystalline forms, hereinafter referred to as form A and form B, as well as a number of further solvates, in particular the methanol, ethanol, isopropanol, dichloromethane, acetone, methyl ethyl ketone and tetrahydrofuran solvates.
-
It was further surprisingly found that the thermodynamically stable crystalline form – form B – can be prepared under controlled conditions and that said form B can be prepared with a reliable method in an industrial scale, which is easy to handle and to process in the manufacture and preparation of formulations.
………………..
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine (described in EP 0 799 209) can be transformed to the intermediate of formula (III)—according to scheme 1—on reaction with an appropriate sulfonamide of formula (II), wherein R1 is as defined in claim 1, in a suited solvent such as DMSO or DMF at room temperature or at elevated temperature and in the presence of a suited base such as potassium carbonate.
EXAMPLE 1
[0064] a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).
[0065] C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83
[0066] Preparation of the starting material:
[0067] b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 19.66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60° C. for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide ( CHLORO STARTING MATERIAL) as yellow crystals. Melting point 177-179° C. ISN mass spectrum, m/e 482.2 (M-1 calculated for C22H18ClN5O5S1: 482).
……………………………….
http://www.google.com/patents/US6417360
EXAMPLE 1
a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).
C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83
Preparation of the starting material:
b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 19.66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60° C. for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as yellow crystals. Melting point 177-179° C. ISN mass spectrum, m/e 482.2 (M-1 calculated for C22H18ClN5O5S1: 482).
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http://www.google.com/patents/EP0799209B1
SYNTHESIS OF
4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine
A BASIC STARTING MATERIAL FOR AVOSENTAN
- Preparation of the starting material
-
- b) 53.1 g of 4-cyano-pyridine (98%) are added all at once to a solution of 1.15 g of sodium in 200 ml of abs. MeOH. After 6 hours 29.5 g of NH4Cl are added while stirring vigorously. The mixture is stirred at room temperature overnight. 600 ml of ether are added thereto, whereupon the precipitate is filtered off under suction and thereafter dried at 50°C under reduced pressure. There is thus obtained 4-amidino-pyridine hydrochloride (decomposition point 245-247°C).
- c) 112.9 g of diethyl (2-methoxyphenoxy)malonate are added dropwise within 30 minutes to a solution of 27.60 g of sodium in 400 ml of MeOH. Thereafter, 74.86 g of the amidine hydrochloride obtained in b) are added all at once. The mixture is stirred at room temperature overnight and evaporated at 50°C under reduced pressure. The residue is treated with 500 ml of ether and filtered off under suction. The filter cake is dissolved in 1000 ml of H2O and treated little by little with 50 ml of CH3COOH. The precipitate is filtered off under suction, washed with 400 ml of H2O and dried at 80°C under reduced pressure. There is thus obtained 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (or tautomer), melting point above 250°C.
- d) A suspension of 154.6 g of 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (or tautomer) in 280 ml of POCl3 is heated at 120°C in an oil bath for 24 hours while stirring vigorously. The reaction mixture changes gradually into a dark brown liquid which is evaporated under reduced pressure and thereafter taken up three times with 500 ml of toluene and evaporated. The residue is dissolved in 1000 ml of CH2Cl2, treated with ice and H2O and thereafter adjusted with 3N NaOH until the aqueous phase has pH 8. The organic phase is separated and the aqueous phase is extracted twice with CH2Cl2. The combined CH2Cl2 extracts are dried with MgSO4, evaporated to half of the volume, treated with 1000 ml of acetone and the CH2Cl2remaining is distilled off at normal pressure. After standing in a refrigerator for 2 hours the crystals are filtered off under suction and dried at 50°C overnight. There is thus obtained 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine, melting point 178-180°C.
…………………………
http://www.google.com/patents/WO2000052007A1
Preparation of the starting material:
5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2- methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide IE THE 6 CHLORO COMPD
b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 1 .66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40°C until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60 °C for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2- methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide as yellow crystals. Melting point 177-179 °C. ISN mass spectrum, m/e 482.2 (M-l calculated for C22Hi8ClN5O5Sι: 482).
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NEXT
Example 1AVOSENTAN
a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of
5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl] -amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg SO , concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120 °C to give the desired 5-methyl-pyridine-2-sulfonic acid [6- methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide as white crystals. Melting point 225-226 °C. ISN mass spectrum, m/e 478.2 (M-l calculated for
C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83
…………………………………………….
IS DESCRIBED IN
http://www.google.com/patents/EP2331513A1?cl=en
ALSO
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Diabetic nephropathy is the principle cause of end stage renal disease in the western world. It is a major cause of morbidity and mortality in Type-I Diabetes, but is an increasing problem in Type-II Diabetes and because the incidence of this is five times that of Type-I Diabetes, it contributes at least 50% of diabetics with end stage renal disease.
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The initial stage of subtle morphologic changes in the renal glomeruli is followed by microalbuminuria. This is associated with a modestly rising blood pressure and an increased incidence of cardiovascular disease. There follows a continued increase in urinary protein excretion and declining glomerular filtration rate. Diabetic nephropathy has many possible underlying pathophysiological causes including metabolic, glycosylation of proteins, haemodynamics, altered flow/pressure in glomeruli, the development of hypertension and cytokine production; all of these are associated with the development of extracellular matrix and increased vascular permeability leading to glomerular damage and proteinuria.
| WO2005113543A1 * | May 12, 2005 | Dec 1, 2005 | Alexander Bilz | Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists |
| WO2007031501A2 * | Sep 11, 2006 | Mar 22, 2007 | Speedel Pharma Ag | Pyridylsulfonamidyl-pyrimidines for the prevention of blood vessel graft failure |
| WO2008077916A1 * | Dec 21, 2007 | Jul 3, 2008 | Ovidiu Baltatu | Pharmaceutical composition using aliskiren and avosentan |
| EP1454625A1 * | Mar 6, 2003 | Sep 8, 2004 | Speedel Development AG | Pyridylsulfonamidyl-pyrimidines for the treatment of diabetic nephropathies |
| EP1595880A1 * | May 13, 2004 | Nov 16, 2005 | Speedel Pharma AG | Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists |
| EP1938812A1 * | Dec 22, 2006 | Jul 2, 2008 | Speedel Pharma AG | Pharmaceutical composition using aliskiren and avosentan |
| US6951856 | Jul 10, 2001 | Oct 4, 2005 | Actelion Pharmaceuticals Ltd. | Arylethene-sulfonamides |
| US7402587 | May 12, 2005 | Jul 22, 2008 | Speedel Pharma Ag | Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists |
| WO1996019459A1 * | Dec 8, 1995 | Jun 27, 1996 | Volker Breu | Novel sulfonamides |
| EP0713875A1 * | Nov 13, 1995 | May 29, 1996 | F. Hoffmann-La Roche AG | Sulfonamides |
| EP0897914A1 * | Aug 10, 1998 | Feb 24, 1999 | F. Hoffmann-La Roche Ag | Process for the preparation of 2,5-disubstitued pyridines |
READ MORE ON SNTAN SERIES……http://medcheminternational.blogspot.in/p/sentan-series.html
TEGOBUVIR ..IN PHASE II FOR HEPATITIS C
TEGOBUVIR
A non-structural protein 5B polymerase inhibitor
for Treatment of chronic hepatitis C
5-[6-[2,4-Bis(trifluoromethyl)phenyl]pyridazin-3-ylmethyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
CHEMICAL NAMES
1. 5H-Imidazo[4,5-c]pyridine, 5-[[6-[2,4-bis(trifluoromethyl)phenyl]-3-pyridazinyl]methyl]-
2-(2-fluorophenyl)-
2. 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-
imidazo[4,5-c]pyridine
MOLECULAR FORMULA C25H14F7N5
MOLECULAR WEIGHT 517.4
MANUFACTURER Gilead Sciences, Inc.
CODE DESIGNATION
- GS 333126
- GS 9190
- GS-333126
- GS-9190
- Tegobuvir
- UNII-5NOK5X389M
CAS REGISTRY NUMBER 1000787-75-6
GS-9190, an RNA-directed RNA polymerase (NS5B) inhibitor, is in phase II clinical evaluation at Gilead for the treatment of hepatitis C virus (HCV) infection. A clinical trial with GS-9190 in combination with peginterferon alfa-2a and ribavirin and with GS-9451 or with GS-9256 in treatment-naive subjects with chronic genotype 1 HCV infection was discontinued due to serious adverse events.
Gilead (Originator)
Katholieke Universiteit Leuven (Originator)
……………………………………….
tegobuvir
PATENTS
WO 2005063744
WO 2008005519
WO 2009009001
WO 2010151488
WO 2010151487
WO 2010151472
WO 2011072370
WO 2011156757
WO 2012087596
WO 2013101550
Hebner CM, Han B, Brendza KM, Nash M, Sulfab M, Tian Y, Hung M, Fung W, Vivian RW, Trenkle J, Taylor J, Bjornson K, Bondy S, Liu X, Link J, Neyts J, Sakowicz R, Zhong W, Tang H, Schmitz U.
PLoS One. 2012;7(6):e39163. doi: 10.1371/journal.pone.0039163. Epub 2012 Jun 13.
Wong KA, Xu S, Martin R, Miller MD, Mo H.
Virology. 2012 Jul 20;429(1):57-62. doi: 10.1016/j.virol.2012.03.025. Epub 2012 Apr 28.
Zeuzem S, Buggisch P, Agarwal K, Marcellin P, Sereni D, Klinker H, Moreno C, Zarski JP, Horsmans Y, Mo H, Arterburn S, Knox S, Oldach D, McHutchison JG, Manns MP, Foster GR.
Hepatology. 2012 Mar;55(3):749-58. doi: 10.1002/hep.24744.
Shih IH, Vliegen I, Peng B, Yang H, Hebner C, Paeshuyse J, Pürstinger G, Fenaux M, Tian Y, Mabery E, Qi X, Bahador G, Paulson M, Lehman LS, Bondy S, Tse W, Reiser H, Lee WA, Schmitz U, Neyts J, Zhong W.
Antimicrob Agents Chemother. 2011 Sep;55(9):4196-203. doi: 10.1128/AAC.00307-11. Epub 2011 Jul 11.
- ……………………..
- http://www.google.com/patents/WO2013040492A2
- ompound 1 can be prepared using synthetic methods and intermediates like those described in US 7,754,720. Compound 1 can also be prepared as described in the following Example.
- Compound 1 is:
Compound 1 may also be referred to as 5-((6-(2,4-bis(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine, 5-[[6-[2,4-bis (trifluoromethyl)phenyl]pyridazin=3-yl]methyl]-2-(2-fluorophenyl).
- Example 1 : 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H- imidazo[4,5-c]pyridi
Compound 103 was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid 105 and a 2N aq. Na2C03 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80°C for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6g Si02 using MeOH/CH2CI2 to elute compound. The compound thus obtained was contaminated with PPh3(0). The product was repurified on a 1 mm Chromatotron plate with 0 to 5%
MeOH/CH2CI2 in 1 % steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound 1 was obtained with no PPh3 contamination. 1H NMR (300MHz,CD3OD) δ 6.20 (s, 2), 7.32 (m, 3), 7.52 (m, 1 ), 7.78 (d, 1), 7.89 (d, 1), 7.95 (s, 2), 8.15 (m, 3), 8.35 (d, 1), 9.12 (s, 1); LC/MS M+H = 518.
The intermediate compound 104 was prepared as follows, a. Preparation of Compound 10
101 102
To a solution of the commercially available starting material 101 in CHCI3, trichloroisocyanuric acid (TCCA) was added at 60°C. Then the solution was stirred for 1.5 hrs, cooled, and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g of compound 102. b. Preparation of Compound 104.
102 104
To a solution of compound 103 in DMF (dimethylformamide), NaOH was added.
Compound 102 was dissolved in DMF (20 mL) and added to the solution slowly. The reaction was stirred for 3 hrs, was diluted with water and extracted with EtOAc. The organic layer was dried with Na2S0 . The solvent was removed and the product recrystallized with
dichloromethane. The yield was 5.7 g of compound 103.
- ……………………………
- US7754720
- Example 1a Synthesis of 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridineIn this method, dimethoxyethane or its related solvents, all having the general formula R1OR2O(R4O)aR3 wherein each of R1, R2, R3 and R4 are independently selected from C1-C6 alkyl and a is 0 or 1, have been found to be particularly advantageous over the conventional solvent DMF. Typically, each of R1, R2, R3 and R4 are independently C1-C2 alkyl and usually a is 0. C1-C6 alkyl includes fully saturated primary, secondary or tertiary hydrocarbon groups with 1 to 6 carbon atoms and thereby includes, but is not limited to methyl, ethyl, propyl, butyl, etc.Step 1
Compound MW Amount mmoles Equivalents SM 128.56 5 g 38.9 1 TCCA 232.41 3.62 g 15.6 0.4 CHCl3 130 ml To a solution of the commercially available starting material (SM) in CHCl3, trichloroisocyanuric acid (TCCA) was added at 60° C. Then the solution was stirred for 1.5 hrs., cooled down and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g.
Step 2
Compound MW Amount mmoles Equivalents S.M. 163 5.073 g 31.12 1 Core 213.2 6.635 g 31.12 1 NaOH (10%) 40 1.245 g 31.12 1 DMF 320 ml To a solution of core (obtained as described in literature in DMF (dimethylformamide), NaOH was added. Then SM for this step (obtained from step 1) was dissolved in DMF (20 ml) and added to the solution slowly. The reaction was stirred for 3 hrs, was diluted with water and extracted with EtOAc. The organic layer was dried with Na2SO4. The solvent was removed and the product recrystallized with DCM (dichloromethane). The yield was 5.7 g.
Step 3
Compound MW Amount Moles Equivalents A 453.79 95 mg 0.209 1 DME 500 ul 2 N aq. Na2CO3 313ul 0.626 3 2,4-bisCF3– 257.93 80.9 mg 0.313 1.5 phenylboronic acid Pd(PPh3)4 1155 12 mg 0.0104 0.05 Compound A was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid and a 2N aq. Na2CO3 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80° C. for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6 g SiO2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Cl2 in 1% steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound (1) was obtained with no PPh3 contamination.
1H NMR (300 MHz, CD3OD)
6.20 (s, 2)
7.32 (m, 3)
7.52 (m, 1)
7.78 (d, 1)
7.89 (d, 1)
7.95 (s, 2)
8.15 (m, 3)
8.35 (d, 1)
9.12 (s, 1)
LC/MS M+H=518
Example 1b Synthesis of 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridineThis example is directed to an additional method for making compound (1), employing the following schemes.
Methanesulfonic acid was added to 2-fluorobenzoic acid in a reactor with active cooling keeping T≦50° C. 3,4-Diaminopyridine was then added portionwise to this cooled slurry, keeping T≦35° C. The contents of the reactor were then heated to 50° C. Phosphorus pentoxide was added in a single charge. The reaction was then heated at 90-110° C. for at least 3 hours. The reaction was sampled for completion by HPLC analysis. The reaction was cooled to ambient temperature and water was added portionwise slowly to quench the reaction. The reaction was then diluted with water. In solubles were removed by filtration. The pH of the filtrate was adjusted to 5.5-5.8 with ammonium hydroxide. The reaction was allowed to self-seed and granulate for ˜4 hours at ambient temperature. The pH was then adjusted to 8.0-9.3 with ammonium hydroxide. The slurry was held at ambient temperature for at least 2 hours. The solids were isolated by filtration and washed with water, followed by IPE. The wet cake was dried in vacuo at not more than 60° C. until ≦1% water remains. The dry product is core (2).
Summary of Materials M.W. Wt. Ratio Mole ratio 3,4-Diaminopyridine 109.13 1.0 1.0 2-Fluorobenzoic acid 140.11 1.4 1.1 Methanesulfonic acid 96.1 7.0 8.0 Phosphorus pentoxide 141.94 1.3 1.0 Water 18.02 40 — Isopropyl ether 102.17 5.0 — Ammonium hydroxide 35.09 ~10 — 
A solution of compound (2a) in 1,2-dichloroethane was heated to 40-45° C. Trichloroisocyanuric acid was added and the mixture was heated at 60-70° C. for at least 2 hours. The reaction was sampled for completion by HPLC analysis. The reaction was cooled to ambient temperature. Celite was added to absorb insolubles, then solids were removed by filtration. The filtrate was washed with 0.5 N sodium hydroxide solution. The organic layer was concentrated to lowest stirrable volume and displaced with DMF. Core (2) and 10% aqueous sodium hydroxide solution were added. The reaction was stirred at ambient temperature for at least 8 hours. The reaction was sampled for completion by HPLC analysis. An additional 10% charge of 10% sodium hydroxide solution was added to the reaction. The reaction was then charged into water to isolate the crude product. After granulating for at least 1 hour, the solids were isolated and washed with water and isopropyl ether. Ethyl acetate was added and refluxed (internal T=70-77° C.) for 1-5 hours to dissolve product, then cooled to 18-23° C. slowly over 4-8 hours. The reactor contents were agitated at 18-23° C. for 8-20 hours and solids collected by filtration and rinsed with ethyl acetate. Low melt (i.e., DSC about 220 degrees C.) amorphous compound (1) was discharged. Amorphous compound (1) was dissolved in ethyl acetate by heating at reflux (internal T=70-77° C.) for 1-5 hours. Water content is controlled to about 0.2% by azeotropically removing water (with ethyl acetate the upper limit on water content is about 0.6% by weight; at about 0.9% by weight water the amorphous material will reprecipitate and crystals will not be obtained). The reactor contents are cooled slowly to 18-23° C. over 4-8 hours, then agitated at 18-23° C. for 8-20 hours and solids collected by filtration. The solids were rinsed with ethyl acetate and dried in vacuo at not more than 60° C. to obtain the dry crystalline compound (1).
Summary of Materials M.W. Wt. Ratio Mole ratio 3-chloro-6-methylpyridazine 128.56 1.0 1.0 2,4bis(trifluromethyl)phenylboronic 257.93 4.0 2.0 acid X-Phos 476.72 0.18 0.05 Palladium acetate 224.49 0.04 0.025 1,2-Dimethoxyethane 90.12 16.7 — Potassium carbonate 138.21 2.15 2.0 Water 18.02 7.8 — Copper iodide 190.45 0.037 0.025 Celite — 0.25 — Heptane 100.2 22.4 — Nuclear Magnetic Resonance (1H-, 13C-, and 19F-NMR) SpectraNuclear magnetic resonance (NMR) spectra of compound (1) is consistent with the proposed structure. The 13C, 19F, and 1H-NMR spectra of compound (1) in DMSO-d6 were measured using a Varian UnityInova-400 FT-NMR spectrometer. Spectra are shown in the table below. The NMR chemical shift assignments were established using 2D correlation experiments (COSY, HSQC, HMBC and HSQCTOCSY).
1H- and 13C-NMR Chemical Shift Assignments for Compound (1) Reference Standard
Atom δC/ppm (DMSO-d6) δF/ppm (DMSO-d6) δH/ppm (DMSO-d6) 1A 140.16 2A 128.32 (qa, JCF = 32 Hz) 3A 123.61, m 8.24 (m, 1 H) 4A 130.27 (q, JCF = 34 Hz) 5A 129.54 (q, JCF = 3 Hz) 8.22 (m, 1 H) 6A 133.36 7.88 (m, 1 H) 7A 123.20 (q, JCF = 273 Hz) −56.4b 8A 123.02 (q, JCF = 275 Hz) −62.0b 1B 158.76 2B 128.16 8.01 (d, 1 H, J = 8.4 Hz) 3B 126.20 7.95 (d, 1 H, J = 8.8 Hz) 4B 157.70 5B 60.49 6.17 (s, 2 H) 2C 131.86 8.31 (m, 1 H) 3C 112.63 7.86 (m, 1 H) 4C 155.44 6C 168.11 (d, JCF = 6 Hz) 8C 145.08 9C 133.06 9.25 (s, 1 H) 1D 123.11 (d, JCF = 10 Hz) 2D 160.46 (d, JCF = 254 Hz) −111.7 3D 116.59 (d, JCF = 22 Hz) 7.29 (m, 1 H) 4D 130.84 (d, JCF = 8 Hz) 7.46 (m, 1 H) 5D 124.13 (d, JCF = 4 Hz) 7.31 (m, 1 H) 6D 131.72 (d, JCF = 2 Hz) 8.35 (m, 1 H) amultiplicity, s: singlet, d: doublet, q: quartet, m: multiplet binterchangeable signals 
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TELMISARTAN ..Actavis’ Generic Version of Micardis Receives FDA Approval
DUBLIN, Jan. 8, 2014 /PRNewswire/ — Actavis plc today announced that it has received approval from the U.S. Food and Drug Administration (FDA) on its Abbreviated New Drug Application (ANDA) for Telmisartan Immediate-Release Tablets, 20 mg, 40 mg and 80 mg, a generic equivalent to Boehringer Ingelheim’s Micardis. Actavis intends to launch the product immediately.
DANOPREVIR (ITMN-191) …..a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV)
Danoprevir
Danoprevir(ITMN-191) is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM, inhibition effect for HCV genotypes 1A/1B/4/5/6 is ~10-fold higher than 2B/3A. Phase 2.
Array BioPharma (Originator)
| RG7227 |
| ITMN-191 |
| RO5190591 |
2H-Isoindole-2-carboxylic acid, 4-fluoro-1,3-dihydro-, (2R,6S,12Z,13aS,14aR,16aS)-
14a-[[(cyclopropylsulfonyl)amino]carbonyl]-6-[[(1,1-dimethylethoxy)carbonyl]amino]-
1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-5,16-
dioxocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl ester
2. (2R,6S,12Z,13aS,14aR,16aS)-14a-[(cyclopropylsulfonyl)carbamoyl]-6-{[(1,1-
dimethylethoxy)carbonyl]amino}-5,16-dioxo-
1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-
a][1,4]diazacyclopentadecin-2-yl 4-fluoro-1,3-dihydro-2H-isoindole-2-carboxylate
Treatment of hepatitis C
MOLECULAR FORMULA C35H46FN5O9S
MOLECULAR WEIGHT 731.8
MANUFACTURER Genentech
CODE DESIGNATION R05190591
CAS REGISTRY NUMBER 850876-88-9, 916881-67-9
Danoprevir(ITMN-191) is a peptidomimetic
ITMN-191 (R-7227), a macrocyclic protease inhibitor, is in phase II clinical evaluation for the treatment of chronic hepatitis C virus (HCV) infection as monotherapy and in combination with Pegasys(R) (pegylated interferon alpha-2a) and Copegus(R) (ribavirin). The product candidate is also being evaluated in combination with R-7128 in treatment-naive patients infected with HCV genotype 1.
Danoprevir (ITMN-191; RG-7227), under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure.
In 2006, originator InterMune and licensee Roche entered into an exclusive worldwide collaboration agreement to develop and commercialize products from InterMune’s hepatitis C (HCV) protease inhibitor program, including ITMN-191. In 2010, the licensing agreement was terminated. Also in 2010, Roche acquired worldwide development and commercialization rights to R-7227 from InterMune. Preclinical pharmacokinetic results support the exploration of twice-daily oral dosing in HCV.
A phase Ib, ‘IFN-free’ clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naïve patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns. In a phase IIb trial in treatment-naïve patients with HCV-1 infection, danoprevir plus pegylated IFNalpha2a and ribavirin resulted in undetectable levels of HCV-RNA in the majority of patients, without any evidence of viral resistance; however, the high-dose danoprevir arm was prematurely terminated because of grade 4 ALT elevations. Phase I trials have also demonstrated that ritonavir boosting improved the pharmacokinetic profile of danoprevir; therefore, at the time of publication, a phase IIb trial to evaluate ritonavir-boosted, low-dose danoprevir in combination with RG-7128 was planned. (source:
inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM, inhibition effect for HCV genotypes 1A/1B/4/5/6 is ~10-fold higher than 2B/3A. Phase 2.
SODIUM SALT
HERAPEUTIC CLAIM Treatment of hepatitis C
CHEMICAL NAMES
1. 2H-Isoindole-2-carboxylic acid, 4-fluoro-1,3-dihydro-, (2R,6S,12Z,13aS,14aR,16aS)-
14a-[[(cyclopropylsulfonyl)amino]carbonyl]-6-[[(1,1-dimethylethoxy)carbonyl]amino]-
1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-5,16-dioxocyclopropa
[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl ester, sodium salt (1:1)
2. sodium (cyclopropylsulfonyl){[(2R,6S,12Z,13aS,14aR,16aS)-6-{[(1,1-dimethylethoxy)
carbonyl]amino}-2-{[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-5,16-dioxo-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-
a][1,4]diazacyclopentadecine-14a(5H)-yl]formyl}azanide
MOLECULAR FORMULA C35H45FN5NaO9S
MOLECULAR WEIGHT 753.8
SPONSOR Genentech
CODE DESIGNATION
- Danoprevir sodium
- ITMN-191
- R 7227 sodium
- R7227
- RO 5190591-001
- RO5190591-001
- UNII-217RJI972K
CAS REGISTRY NUMBER 916826-48-7
DANOPREVIR SODIUM
The HCV protease mediates the cleavage of the HCV polyprotein to release the functional proteins that are essential for viral propagation. The inhibition of the HCV protease activity is expected to block HCV replication in infected host cells. Numberous HCV protease inhibitors have been identified. Non- limiting examples of HCV protease inhibitors are described in U.S. Patent Application Pub. Nos. 20040106559, 20040180815, 20040266668, 2004038872, 20050090432, 20050267018, 20070054842, 20070281885, 2007299078, 20080032936, 20080125444, 20080279821, 20090111757, 20090148407, 20090202480, 20090269305, 20090285773, 20090285774, 20100081700, 20100144608, 2010018355, 20100183551, 20100221217, 20100260710, 20100286185 and 20110135604, and U.S. Patent Nos. 6608027, 6767991, 7091184, 7119072, 7544798, 7642235 and 7829665, as well as WO2007014919, WO2007014926, WO2008046860, WO2008095058,
………………………………
danoprevir
patents and journal ref
1. WO 2005037214..
2. WO 2005095403
3. WO 2007015824..
4. WO 2008128921
5. WO 2009080542
6. WO 2009142842
7. WO 2010015545
8. WO 2013079424
9. WO 2012062685
10.WO 2013106631
11. Concise asymmetric synthesis of a (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester
Org Biomol Chem 2013, 11(39): 6796http://pubs.rsc.org/en/content/articlelanding/2013/ob/c3ob41394b/unauth#!divAbstract
12.J. Med. Chem., Article ASAP,DOI: 10.1021/jm400164c
Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
J Med Chem. 2012 Apr 12;55(7):3021-6. doi: 10.1021/jm201278q. Epub 2012 Apr 3.
14 . Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Bioorg Med Chem Lett. 2012 Apr 15;22(8):2993-6. doi: 10.1016/j.bmcl.2012.02.039. Epub 2012 Feb 22.
……………….
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-Butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (49)
For certain NS3 inhibitors shown in this section, additional chemical transformations are utilized to obtain the final products. The preparations of two such examples are described for compounds 153 and 154 below:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-botoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-α][1,4]dizacyclopentadecine-14a-carboxylic acid (0.10 g, 0.16 mmol) and TEA (0.024 mL, 0.18 mmol) in THF (5 mL) was added ethyl carbonochlridate (0.016 mL, 0.17 mmol) at 0° C. The reaction was stirred at 0° C. for 2 hrs. Sodium boronhydride (0.012 g, 0.32 mmol) was added and the reaction was stirred at rt for 3 days. Water (5 mL) and ethyl acetate (10 mL) were added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography (ethyl acetate) to give the product (0.060 g, 61.4%) as white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.47 (b, 1H), 7.35 (m, 1H), 7.10-7.20 (m, 2H), 7.03 (m, 1H), 5.47 (m, 1H), 5.28 (b, 1H), 4.98 (m, 1H), 4.67 (b, 4H), 4.56 (m, 1H), 4.46 (m, 1H), 4.26 (m, 1H), 3.92 (m, 1H), 3.66 (m, 2H), 3.16 (m, 1H), 2.67 (m, 1H), 2.21 (m, 2H), 1.80 (m, 1H), 1.68 (m, 1H), 1.30 (m, 8H), 1.11-1.20 (m, 9H), 0.85 (m, 1H), 0.77 (m, 1H).
A solution of oxalyl chloride 90.045 mL, 0.089 mmol) in DCM (5 mL) at −78° C. was added a solution of DMSO (0.015 g, 0.020 mmol) in DCM (2 mL) dropwise over 2 ninytes. The reaction was stirred at −78° C. for 10 minutes and the a solution of (2R,6S,13aS,14aR,16aS,Z)-6-(tert-botoxycarbonylamino)-14a-(hydroxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-α][1,4]dizacyclopentadecin-2-yl-4-fluoroisoindoline-2-carboxylate (0.050 g, 0.081 mmol) in DCM (2 mL) was added. After stirred at −78° C. for 40 min, TEA (0.051 mL, 0.37 mmol) was added. The reaction was warmed to rt, water (5 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was dissolved in MeOH (5 mL) and ammonium hydroxide (0.085 g, 2.45 mmol) and acetic acid (0.014 mL, 0.25 mmol) were added. The reaction stirred at rt for 3 minutes. NaCNBH3 90.015 g, 0.245 mmol) was added and stirred at rt for 30 minutes. The MeOH was removed. DCM (20 mL) and saturated sodium bicarbonate (5 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was dissolved in DCM (5 mL). TEA (0.017 mL, 0.122 mmol) was added and followed by the cyclopropanesulfonyl chloride (0.015 g, 0.098 mmol). The reaction was stirred at rt for 5 hrs. The solvent was removed. The residue was purified by column chromatography (ethyl acetate) to give the product (0.017 g, 28.2%) as white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.52 (m, 1H), 7.35 (m, 1H), 7.02-7.20 (m, 4H), 5.56 (m, 1H), 4.99 (m, 1H), 4.97 (m, 1H), 4.67 (m, 2H), 4.66 (s, 2H), 4.46 (m, 1H), 4.24 (m, 1H), 3.92 (m, 1H), 3.67 (m, 1H), 3.46 (m, 1H), 2.74 (m, 1 h), 2.67 (m, 1H), 2.22 (m, 2H), 1.84 (m, 1H), 1.68 (m, 1H), 1.08-1.36 (m, 20H), 0.89 (m, 2H), 0.81 (m, 2H).
Hoffmann-La Roche and Genentech’s danoprevir/r (RG7227) is a twice-daily, ritonavir-boosted HCV protease inhibitor with activity against HCV genotypes 1, 4 and 6. DAUPHINE, an ongoing phase II trial in 421 treatment-naive people with HCV genotypes 1 and 4, is comparing doses (200, 100, and 50 mg danoprevir, boosted with 100 mg ritonavir, twice-daily) and response-guided therapy with danoprevir/r plus PEG-IFN/RBV. At 12 weeks after treatment completion, HCV RNA was undetectable in 86% of the highest-dosing arm, 77% of the 100 mg arm, and 65% of the 50 mg arm.
Response to treatment in the 200 mg dosing arm did not differ according to HCV subtype or IL28B genotype; at 12 weeks after treatment completion, 88% of people with HCV subtype 1a and an IL28B non-CC genotype had undetectable HCV RNA. Across all dosing arms, HCV RNA remained undetectable 12 weeks after treatment completion in 100% of people with HCV genotype 4.
In the response-guided therapy arm, 76% of early responders (who were treated for 12 weeks) and 67% of late responders (treated for 24 weeks) maintained undetectable HCV RNA 12 weeks after treatment completion, bringing the overall total to 72%.
One death occurred during the trial—from sudden heart attack, in a participant with preexisting diabetes and hypertension—it was considered unrelated to study drugs. Adverse events were reported in virtually all study participants. Side effects from ritonavir, which is used to boost danoprevir levels, increased the likelihood of more than one serious adverse event among people in the danoprevir/r arms (range 4–9% vs. 1% for placebo). The rate of danoprevir/r-related treatment discontinuations was similar to the rate of PEG-IFN/RBV-associated discontinuations (3–7%, and 3–8%, respectively).
Common side effects (experienced by more than 15% of study participants) included fatigue, fever, chills, weakness, nausea, diarrhea, itching, rash, hair loss, headache, aching muscles and joints, insomnia, cough, and appetite loss. Diarrhea was the only side effect associated with danoprevir/r. Adding danoprevir/r did not increase rates of rash or anemia (known side effects of other HCV protease inhibitors). Most grade 3 and grade 4 lab abnormalities were neutropenia, reported in 22% to 38% of study participants.
Interferon-free DAA Combinations
Danoprevir/r and Mericitabine, plus Ribavirin (HCV Genotypes 1 and 4)
Roche’s phase IIb study, INFORM-SVR, is combining response-guided therapy with danoprevir/r, a twice-daily ritonavir-boosted HCV protease inhibitor, and mericitabine, a twice-daily nucleoside polymerase inhibitor, with or without ribavirin for 12 to 24 weeks in non-cirrhotic people with HCV genotype 1. The original study design was modified after high relapse rates were observed in the 12-week treatment and ribavirin-free arms. Treatment was extended to 24 weeks, and ribavirin was given to all participants.
The majority of INFORM-SVR participants were male, had HCV genotype 1a, and non-CC genotypes. Of the 64 people treated for 24 weeks with all three drugs, 41% experienced SVR-12. People with HCV genotype 1b were more likely to achieve SVR-12 (71% versus 26% in HCV genotype 1a). In contrast, SVR-12 was more likely among people with non-CC genotypes (32% for CC versus 44% for non-CC), although only 4 people had HCV genotype 1b and CC genotype. Breakthrough rates were higher in people who did not receive ribavirin, and in HCV genotype 1a versus 1b. Resistance to danoprevir/r was observed in all patients who experienced viral breakthrough; mericitabine resistance was found in one person.
Almost all participants had more than one adverse event; a total of 567 mild-to-moderate events were reported among 83 people. The most common side effects, occurring in >10% of people were headache, fatigue, nausea, diarrhea, colds, insomnia, itching, weakness, dizziness, irritability, shortness of breath, cough, upset stomach, painful joints, and vomiting. As for laboratory abnormalities, one person experienced grade 3 anemia, four people had grade 3 lipid elevations, and one case each of grade 3 elevations in phosphate and lipase were observed.
A single serious adverse event, multiple myeloma, occurred 53 days after treatment completion and one person discontinued due to pain in the back of the throat (it was not specified whether or not this was a treatment-related adverse event).
- Everson G, Cooper C, Shiffman ML, et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEG-IFNa-2A/RBV in HCV genotype 1 or 4 patients: Dauphine week 36 interim analysis (Abstract 1177). Paper presented at: 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain. Available from: http://mobile.ilcapp.eu/EASL_161/poster_24544/program.aspx. (Accessed 2012 June 25)
- Gane EJ, Pockros P, Zeuzem S, et al. Interferon-free treatment with combination of mericitabine and danoprevir/r with or without ribavirin in treatment-naïve HCV genotype-1 infected patients (Abstract 1412). 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain. Available from:http://mobile.ilcapp.eu/EASL_161/poster_24848/program.aspx. (Accessed 2012 June 25)
Non- limiting examples of suitable HCV protease inhibitors include ACH-1095
(Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), boceprevir, danoprevir, GS- 9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX- 320 (Idenix), MK-5172 (Merck), narlaprevir, PHX-1766 (Phenomix), telaprevir, TMC-435 (Tibotec), vaniprevir, VBY708 (Virobay), VX-500 (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combination thereof. Non-limiting examples of suitable HCV polymerase inhibitors include ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (Glaxo SmithKline), BCX-4678 (BioCryst), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination thereof. A polymerase inhibitor may be a nucleotide polymerase inhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination therefore. A polymerase inhibitor may also be a non- nucleoside polymerase inhibitor, such as ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof. Non-limiting examples of suitable NS5A inhibitors include GSK62336805 (Glaxo SmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052 (BMS), BMS- 824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio), or a combination thereof. Non-limiting examples of suitable cyclophilin inhibitors include alisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis), or a combination thereof. Non-limiting examples of suitable HCV entry inhibitors include ITX-4520 (iTherx), ITX-5061 (iTherx), or a combination thereof.
WO 2007015824WO 2003053349WO 2005095403WO 2005037214WO 2005095403WO 2005037214WO 2003053349WO 2007015824WO 2008128921
| US8048862 | 14 Apr 2009 | 1 Nov 2011 | Intermune, Inc. | Macrocyclic inhibitors of hepatitis C virus replication |
| US8119592 | 10 Oct 2006 | 21 Feb 2012 | Intermune, Inc. | Compounds and methods for inhibiting hepatitis C viral replication |
| US8232246 | 30 Jun 2009 | 31 Jul 2012 | Abbott Laboratories | Anti-viral compounds |
| US8299021 | 19 Apr 2012 | 30 Oct 2012 | Intermune, Inc. | Macrocyclic inhibitors of hepatitis C virus replication |
| US8420596 | 10 Sep 2009 | 16 Apr 2013 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
| WO2013106631A1 | 11 Jan 2013 | 18 Jul 2013 | Abbvie Inc. | Processes for making hcv protease inhibitors |
Danoprevir Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators |
Start Date | Phases |
|---|---|---|---|---|---|
| NCT01331850 | Completed | Hepatitis C, Chronic | Hoffmann-La Roche | 2011-05 | Phase 2 |
| NCT01531647 | Completed | Healthy Volunteer | Hoffmann-La Roche | 2012-01 | Phase 1 |
| NCT01588002 | Completed | Healthy Volunteer | Hoffmann-La Roche | 2012-04 | Phase 1 |
| NCT01592318 | Active, not recruiting | Healthy Volunteer | Hoffmann-La Roche | 2012-05 | Phase 1 |
| NCT01749150 | Recruiting | Hepatitis C, Chronic | Hoffmann-La Roche | 2013-04 | Phase 2 |
WANT TO KNOW ABOUT VIR SERIES CLICK
click
http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html
AND
http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html
APREMILAST, … ORALLY ACTIVE PDE4 INHIBITOR
APREMILAST
PDE4 inhibitor
N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
(+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl]-4-acetylaminoisoindolin-l,3-dione,
(S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
Molecular Formula: C22H24N2O7S Molecular Weight: 460.50016
608141-41-9 CAS NO
Celgene (Originator)
CC-10004 (apremilast) is an oral compound that is being studied in multiple Phase III clinical trials for the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. We successfully completed our early stage studies, demonstrating clinical activity and tolerability and meeting safety endpoints in a placebo controlled proof-of mechanism trial in moderate-to-severe psoriasis and psoriatic arthritis. With the initiation of six multi-center international clinical trials, we are advancing the clinical development of CC-10004.
CC-10004, , Apremilast (USAN), SureCN302992, Apremilast (CC-10004), QCR-202,
- Apremilast
- CC 10004
- CC-10004
- CC10004
- UNII-UP7QBP99PN
- CLINICAL TRIALS….http://clinicaltrials.gov/search/intervention=Apremilast+OR+CC-10004
Apremilast is an orally available small molecule inhibitor of PDE4 being developed byCelgene for ankylosing spondylitis, psoriasis, and psoriatic arthritis.[1][2] The drug is currently in phase III trials for the three indications. Apremilast, an anti-inflammatory drug, specifically inhibits phosphodiesterase 4. In general the drug works on an intra-cellular basis to moderate proinflammatory and anti-inflammatory mediator production.
APREMILAST
Apremilast is being tested for its efficacy in treating “psoriasis, psoriatic arthritis and other chronic inflammatory diseases such as ankylosing spondylitis, Behcet’s disease, and rheutmatoid arthritis.
“Apremilast is Celgene’s lead oral phosphodiesterase IV inhibitor and anti-TNF alpha agent in phase III clinical studies at Celgene for the oral treatment of moderate to severe plaque-type psoriasis and for the oral treatment of psoriatic arthritis.
Early clinical development is also ongoing for the treatment of acne, Behcet’s disease, cutaneous sarcoidosis, prurigo nodularis, ankylosing spondylitis, atopic or contact dermatitis and rheumatoid arthritis. No recent development has been reported for research for the treatment of skin inflammation associated with cutaneous lupus erythematosus.
In 2011, Celgene discontinued development of the compound for the management of vision-threatening uveitis refractory to other modes of systemic immunosuppression due to lack of efficacy.
Celgene had been evaluating the potential of the drug for the treatment of asthma; however, no recent development has been reported for this research. The drug candidate is also in phase II clinical development at the William Beaumont Hospital Research Institute for the treatment of chronic prostatitis or chronic pelvic pain syndrome and for the treatment of vulvodynia (vulvar pain).
In 2013, orphan drug designations were assigned to the product in the U.S. and the E.U. for the treatment of Behcet’s disease.
Celgene Corp has been boosted by more impressive late-stage data on apremilast, an oral drug for psoriatic arthritis, this time in previously-untreated patients.
The company is presenting data from the 52-week PALACE 4 Phase III study of apremilast tested in PsA patients who have not taken systemic or biologic disease modifying antirheumatic drugs (DMARDs) at the American College of Rheumatology meeting in San Diego. The results from the 527-patient trial show that at week 16, patients on 20mg of the first-in-class oral inhibitor of phosphodiesterase 4 (PDE4) achieved an ACR20 (ie a 20% improvement in the condition) response of 29.2% and 32.3% for 30mg aapremilast, compared with 16.9% for those on placebo.
After 52 weeks, 53.4% on the lower dose and 58.7% on 30mg achieved an ACR20 response. ACR50 and 70 was reached by 31.9% and 18.1% of patients, respectively, for apremilast 30mg. The compound was generally well-tolerated and discontinuation rates for diarrhoea and nausea were less than 2% over 52 weeks.
Commenting on the data, Alvin Wells, of the Rheumatology and Immunotherapy Center in Franklin, Wisconsin, noted that apremilast demonstrated long-term safety and tolerability and significant clinical benefit in treatment-naive patients. He added that “these encouraging results suggest that apremilast may have the potential to be used alone and as a first-line therapy”. Celgene is also presenting various pooled data from the first three trials in the PALACE programme which, among other things, shows that apremilast significantly improves swollen and tender joints.
Treatment for PSA, which affects about 30% of the 125 million people worldwide who have psoriasis, currently involves injectable tumour necrosis factor (TNF) inhibitors, notably AbbVie’s Humira (adalimumab) and Pfizer/Amgen’s Enbrel (etanercept), once patients have not responded to DMARDs (at least in the UK). While the biologics are effective, the side effect profile can be a concern, due to the risk of infection and tuberculosis and many observers believe that apremilast will prove popular with patients and doctors due to the fact that it is oral, not injectable.
Apremilast was filed for PsA with the US Food and Drug Administration in the first quarter and will be submitted on both sides of the Atlantic for psoriasis before year-end. The European filing will also be for PsA.
Apremilast impresses for Behcet’s disease
Celgene has also presented promising Phase II data on apremilast as a treatment for the rare inflammatory disorder Behcet’s disease. 71% of patients achieved complete response at week 12 in clearing oral ulcers
APREMILAST
- “Apremilast Palace Program Demonstrates Robust and Consistent Statistically Significant Clinical Benefit Across Three Pivotal Phase III Studies (PALACE-1, 2 & 3) in Psoriatic Arthritis” (Press release). Celgene Corporation. 6 September 2012. Retrieved 2012-09-10.
- “US HOT STOCKS: OCZ, VeriFone, Men’s Wearhouse, AK Steel, Celgene”. The Wall Street Journal. 6 September 2012. Retrieved 2012-09-06.
- Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor.
Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW.
J Med Chem. 2009 Mar 26;52(6):1522-4. doi: 10.1021/jm900210d.
- Therapeutics: Silencing psoriasis.Crow JM.Nature. 2012 Dec 20;492(7429):S58-9. doi: 10.1038/492S58a. No abstract available.
- NMR…http://file.selleckchem.com/downloads/nmr/S803401-Apremilast-HNMR-Selleck.pdf
- WO 2003080049
- WO 2013126495
- WO 2013126360
- WO 2003080049
- WO 2006065814
- US2003/187052 A1 …..MP 144 DEG CENT
- US2007/155791
-
J. Med. Chem., 2008, 51 (18), pp 5471–5489DOI: 10.1021/jm800582j
-
J. Med. Chem., 2011, 54 (9), pp 3331–3347DOI: 10.1021/jm200070e
…………………………………………
INTRODUCTION
2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione is a PDE4 inhibitor that is currently under investigation as an anti-inflammatory for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, psoriasis and other allergic, autoimmune and rheumatologic conditions. S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.
Existing methods for synthesizing (S)-aminosulfone 1 involve resolution of the corresponding racemic aminosulfone by techniques known in the art. Examples include the formation and crystallization of chiral salts, and the use of chiral high performance liquid chromatography. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). In one example, as depicted in Scheme 1 below, (5)-aminosulfone 1 is prepared by resolution of racemic aminosulfone 3 with N-Ac-L-Leu. Racemic aminosulfone 3 is prepared by converting 3-ethoxy-4-methoxybenzonitrile 4 to enamine intermediate 5 followed by enamine reduction and borate hydrolysis. This process has been reported in U.S. Patent
Application Publication No. 2010/0168475.
CH2CI2, NaOH
Scheme 1
The procedure for preparing an enantiomerically enriched or enantiomerically pure aminosulfone, such as compound 1, may be inefficient because it involves the resolution of racemic aminosulfone 3. Thus, a need exists as to asymmetric synthetic processes for the preparation of an enantiomerically enriched or enantiomerically pure aminosulfone, particularly for manufacturing scale production. Direct catalytic asymmetric hydrogenation of a suitable enamine or ketone intermediate is of particular interest because it eliminates the need for either classic resolution or the use of stoichiometric amount of chiral auxiliary, and thus, may be synthetically efficient and economical.
……………………………………….
SYNTHESIS OF KEY INTERMEDIATE
Example 1
Synthesis of 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine
[00232] A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treated with a
1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at 0 – 5 °C. The resulting mixture was agitated for 1 hour then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) was added at 0 – 5 °C. The mixture was agitated at 0 – 5 °C for 0.5 hour, warmed to 25 – 30 °C over 0.5 hour and then agitated for 1 hour. Water (1.4 L) was added at 25 – 30 °C and the reaction mass was agitated overnight at room temperature (20 – 30 °C). The solid was filtered and subsequently washed with a 2: 1 mixture of water :THF (200 ml), water (200 ml) and heptane (2 x 200 ml). The solid was dried under reduced pressure at 40 – 45 °C to provide the product as a white solid (102 g, 83% yield); 1H NMR (DMSO-d6) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz, 1H), 7.09 – 7.22 (m, 2H).
Example 2
Synthesis of (R)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine
[00233] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (36 mg, 0.074 mmol) and (i?)-l-[(5)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (40 mg, 0.074 mmol) in 25 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. The mixture was evaporated and the residue was purified by chromatography on a CI 8 reverse phase column using a water-acetonitrile gradient. The appropriate fractions were pooled and evaporated to -150 mL. To this solution was added brine (20 mL), and the resulting solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and evaporated to provide the product as a white crystalline solid (1.4 g, 70% yield); achiral HPLC (Hypersil BDS C8, 5.0 μπι, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 9.11 (99.6%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 7.32 (97.5%), 8.26 (2.47%); 1H NMR (DMSO-de) δ 1.32 (t, J= 7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J= 3.6, 14.4 Hz, 1H), 3.41 (dd, J= 9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 7.0 Hz, 2H), 4.26 (dd, J= 3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); 13C NMR (DMSO-d6) δ 14.77, 41.98, 50.89, 55.54, 62.03, 63.68, 111.48, 111.77, 118.36, 137.30, 147.93, 148.09. Example 3
Synthesis of (6 -l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-Ac-L-Leu salt
[00234] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (5)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55 °C, and a solution of N- acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22 °C over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2 x 5 mL), and dried under vacuum at 45 °C to provide the product as a white solid (2.6 g, 80% yield); achiral HPLC (Hypersil BDS Cg, 5.0 μιη, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.57 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 8.35 (99.6%); 1H NMR (DMSO-<¾) δ 0.84 (d, 3H), 0.89 (d, J= 6.6 Hz, 3H), 1.33 (t, J= 7.0 Hz, 3H), 1.41 – 1.52 (m, 2H), 1.62 (dt, J= 6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J= 4.0, 14.4 Hz, 1H), 3.44 (dd, J= 9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 6.9 Hz, 2H), 4.18 (q, J= 7.7 Hz, 1H), 4.29 (dd, J= 4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J= 7.9 Hz, 1H); Anal. (C20H34N2O7S) C, H, N. Calcd C, 53.79; H, 7.67; N 6.27. Found C, 53.78; H, 7.57; N 6.18.
SUBSEQUENT CONVERSION
S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.
……………………………………
APREMILAST
GENERAL SYNTHESIS AND SYNTHESIS OF APREMILAST
(apremilast)
[0145] Preparation of 3-Ethoxy-4-methoxybenzonitrile (Compound 2). 3-Ethoxy-
4-methoxybenzaldehyde (Compound 1, 10.0 gm, 54.9 mmol, Aldrich) and hydroxylamine hydrochloride (4.67 gm, 65.9 mmol, Aldrich) were charged to a 250 mL three-necked flask at room temperature, followed by the addition of anhydrous acetonitrile (50 mL). The reaction mixture was stirred at room temperature for thirty minutes and then heated to reflux (oil bath at 85 °C). After two hours of reflux, the reaction mixture was cooled to room temperature, and added 50 mL of deionized water. The mixture was concentrated under reduced pressure to remove acetonitrile and then transferred to a separatory funnel with an additional 80 mL of deionized water and 80 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed successively with water (80 mL) and saturated sodium chloride (80 mL). The organic layer was dried over anhydrous sodium sulfate (approximately 20 gm). The organic layer was filtered and concentrated under reduced pressure to give a yellow oil. Purification by silica gel chromatography (0 to 1 % MeOH/DCM ) afforded 3-Ethoxy-4-methoxybenzonitrile
(Compound 2) as a white solid (7.69 gm, 79 % yield). MS (ESI positive ion) m/z 178.1 (M + 1). HPLC indicated >99% purity by peak area. 1H-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 3.83 (s, 3H), 4.05 (q, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 2.0 Hz, 1H).
[0146] Preparation of l-(3-Ethoxy-4-methoxyphenyi)-2-
(niethylsulfonyl)ethanamine (Compound 3). Dimethyl sulfone (2.60 gm, 27.1 mmol, Aldrich) and tetrahydrofuran (10 mL, Aldrich) were charged to a 250 mL three-necked flask at room temperature. The mixture was cooled to 0 – 5 °C, and the solution gradually turned white. n-Butyllithium (10.8 mL, 27.1 mmol, 2.5 M solution in hexanes, Aldrich) was added to the flask at a rate such that the reaction mixture was maintained at 5 – 10 °C. The mixture was stirred at 0 – 5 °C for one hour, turning light-yellow. 3-Ethoxy-4-methoxybenzonitrile (Compound 2, 4.01 gm, 22.5 mmol) in tetrahydrofuran (8 mL) was then charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for another 15 minutes. After warming to room temperature, the reaction mixture was stirred for another 1.5 hours and then transferred to a second 250 mL three-necked flask containing a suspension of sodium borohydride (1.13 gm, 29.3 mmol, Aldrich) in
tetrahydrofuran (1 1 mL), maintained at – 5 – 0 °C for 30 minutes. Trifluoroacetic acid (“TFA,” 5.26 mL, 68.3 mmol, Aldrich) was charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for 40 minutes and an additional 17 hours at room temperature. The reaction mixture was then charged with 2.7 mL of deionized water over five minutes at room temperature. The mxiture was stirred at room temperature for 15 hours. Aqueous NaOH (10 N, 4.9 mL) was charged to the flask over 15 minutes at 45 °C. The mixture was stirred at 45 °C for two hours, at 60 °C for 1.5 hours, and at room temperature overnight. After approximately 17 hours at room temperature the mixture was cooled to 0 °C for thirty minutes and then concentrated under reduced pressure. The residual material was charged with deionized water (3 mL) and absolute ethanol (3 mL) and stirred at 0 – 5 °C for 2 hours. The mixture was filtered under vacuum, and the filtered solid was washed with cold absolute ethanol (3 x 5 mL), followed by deionized water until the pH of the wash was about 8. The solid was air dried overnight, and then in a vacuum oven at 60 °C for 17 hours to afford Compound 3 as a white solid (4.75 gm, 77 %). MS (ESI positive ion) m/z 274.1 (M + 1). Ή-NMR (500 MHz, DMSO-c¾): δ ppm 1.32 (t, J = 7.0 Hz, 3H), 2.08 (bs, 2H), 2.95 (s, 3H), 3.23 (dd, J = 4.0 Hz, 1H), 3.40 (dd, J = 9.5 Hz, 1H), 3.72 (s, 3H), 4.01 (q, J = 7.0 Hz, 2H), 4.25 (dd, J = 3.5 Hz, 1H), 6.88 (s, 2H), 7.02 (s, 1H).
[0147] Preparation of 4-Nitroisobenzofuran-l,3-dione (Compound 5). Into a 250 mL round bottom flask, fitted with a reflux condenser, was placed 3-nitrophthalic acid (21.0 gm, 99 mmol, Aldrich) and acetic anhydride (18.8 mL, 199 mmol, Aldrich). The solid mixture was heated to 85 °C, under nitrogen, with gradual melting of the solids. The yellow mixture was heated at 85 °C for 15 minutes, and there was noticeable thickening of the mixture. After 15 minutes at 85 °C, the hot mixture was poured into a weighing dish, and allowed to cool. The yellow solid was grinded to a powder and then placed on a cintered funnel, under vacuum. The solid was washed with diethyl ether (3 x 15 mL), under vacuum and allowed to air dry overnight, to afford 4-nitroisobenzofuran-l ,3-dione, Compound 5, as a light-yellow solid (15.8 gm, 82 %). MS (ESI positive ion) m/z 194.0 (M + 1). TLC: Rf = 0.37 (10% MeOH/DCM with 2 drops Acetic acid) Ή-NMR (500 MHz, DMSO-i¾: δ ppm 8.21 (dd, J = 7.5 Hz, 1H), 8.39 (dd, J = 7.5 Hz, 1H), 8.50 (dd, J = 7.5 Hz, 1 H).
[0148] Preparation of 2-(l-(3-Ethoxy-4-methoxyphenyI)-2-
(methylsulfonyl)ethyl)-4-nitroisoindoline-l,3-dione (Compound 6). Into a 2 – 5 mL microwave vial was added 4-nitroisobenzofuran-l ,3-dione (Compound 5, 0.35 gm, 1.82 mmol), the amino-sulfone intermediate (Compound 3, 0.50 gm, 1.82 mmol) and 4.0 mL of glacial acetic acid. The mixture was placed in a microwave at 125 °C for 30 minutes. After 30 minutes the acetic acid was removed under reduced pressure. The yellow oil was taken up in ethyl acetate and applied to a 10 gm snap Biotage samplet. Purification by silica gel chromatography (0 to 20 % Ethyl Acetate/Hexanes) afforded Compound 6 as a light-yellow solid (0.67 gm, 82 %). MS (ESI positive ion) m/z 449.0 (M + 1). TLC: Rf = 0.19
(EtOAc:Hexanes, 1 : 1). HPLC indicated 99% purity by peak area. Ή-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 2.99 (s, 3H), 3.73 (s, 3H), 4.02 (m, 2H), 4.21 (dd, J = 5.0 Hz, 1H), 4.29 (dd, J = 10.0 Hz, 1H), 5.81 (dd, J = 5.0 Hz, 1H), 6.93 (d, J – 8.5 Hz, 1H), 7.00 (dd, J = 2.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 8.07 (t, J = 15.5 Hz, 1H), 8.19 (dd, J = 8.5 Hz, 1H), 8.30 (dd, J = 9.0 Hz, 1H).
[0149] Preparation of 4-Amino-2-(l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl)isoindoline-l,3-dione (Compound 7). Compound 6 (0.54 gm, 1.20 mmol) was taken up in ethyl acetate / acetone (1 : 1 , 24 mL) and flowed through the H-cube™ hydrogen reactor using a 10 % Pd/C CatCart™ catalyst cartridge system (ThalesNano, Budapest Hungary). After eluting, the yellow solvent was concentrated under reduced pressure to give Compound 7 as a yellow foam solid (0.48 gm, 95 %). MS (ESI positive ion) m/z 419.1 (M + 1). 1H-NMR (500 MHz, DMSO-<¾): δ ppm 1.31 (t, J = 7.0 Hz, 3H), 2.99 (s, 3H), 3.72 (s, 3H), 4.04 (q, J = 7.0 Hz, 2H), 4.09 (m, 1H), 4.34 (m, 1H), 5.71 (dd, J = 5.5 Hz, 1H), 6.52 (bs, 2H), 6.92-6.98 (m, 3H), 7.06 (bs, 1 H), 7.42 (dd, J = 7.0 Hz, 1H).
[0150] Preparation of N-(2-(l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsuIfonyl)ethyl)-l,3-dioxoisoindolin-4-yl)acetamide (Apremilast, Compound 8).
Into a 2-5 mL microwave vial was placed Compound 7 (0.18 gm, 0.43 mmol), acetic anhydride (0.052 mL, 0.53 mmol) and acetic acid (4 mL). The microwave vial was placed into a Biotage microwave and heated to 125 °C for 30 minutes. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (0 to 5% MeOH/DCM) to afford apremilast (Compound 8) as a yellow oil (0.14 gm, 71%). HPLC indicated 94.6% purity by peak area.
1H-NMR (500 MHz, DMSO-c 6): δ ppm 1.31 (t, 3H), 2.18 (s, 3H), 3.01 (s, 3H), 3.73 (s, 3H), 4.01 (t, J = 7.0 Hz, 2H), 4,14 (dd, J = 4.0 Hz, 1H), 4.33 (m, 1H), 5.76 (dd, J = 3.0 Hz, 1H), 6.95 (m, 2H), 7.06 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 9.72 (bs, 1H).
……………………..
SYNTHESIS
5. EXAMPLES
Certain embodiments provided herein are illustrated by the following non-limiting examples.
5.1 PREPARATION OF (+)-2-[l-(3-ETHOXY-4-METHOXYPHENYL)-2- METHANESULFONYLETHYLJ-4- ACETYL AMINOISOINDOLIN-1,3- DIONE (APREMILAST)
5.1.1 Preparation of 3-aminopthalic acid
10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacua to a constant weight, affording 54 g (84%> yield) of 3-aminopthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). 13C-NMR(DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
5.1.2 Preparation of 3-acetamidopthalic anhydride
A I L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5. degree. C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCI3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
5.1.3 Resolution of 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)- ethyl-2-amine
A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30°C. to a constant weight, yielding 49.6 g (90%> recovery) of (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine-N-acety 1-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2P04 @pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.times.4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%)
5.1.4 Preparation of (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl] -4-acetylaminoisoindolin- 1 ,3-dione
A 500 mL 3 -necked round bottom flask was equipped with a mechanical stirrer,
thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50°C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x
2), saturated aqeous NaHC03 (250 mL.times.2), brine (250 mL.times.2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL.times.2). The product was dried in vacuo at 60°C. to a constant weight, affording 19.4 g (75% yield) of Compound 3 APREMILAST with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2P04 @pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%).
1H-NMR (CDC13) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H).
13C-NMR(DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
…………………………………..
NMR
1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
…………….
aReagents and conditions: (a) LiN(SiMe3)2, then Me2SO2/n-BuLi/BF3Et2O, −78 °C; (b) N-Ac-l-leucine, MeOH; (c) HOAc, reflux.
……………………
SARCOIDOSIS
Sarcoidosis is a disease of unknown cause. Sarcoidosis is characterized by the presence of granulomas in one or more organ systems. The most common sites of involvement are the lungs and the lymph nodes in the mediastinum and hilar regions. However, sarcoidosis is a systemic disease and a variety of organ systems or tissues may be the source of primary or concomitant clinical manifestations and morbidity. The clinical course of sarcoidosis is extremely variable, and ranges from a mild or even asymptomatic disease with spontaneous resolution to a chronic progressive disease leading to organ system failure and, in 1-5% of cases, death. See Cecil
Textbook of Medicine, 21st ed. (Goldman, L., Bennett, J. C. eds), W. B. Saunders Company, Philadelphia, 2000, p. 433-436.
While the cause of sarcoidosis is unknown, a substantial body of information suggests that immune mechanisms are important in disease pathogenesis. For example, sarcoidosis is
characterized by enhanced lymphocyte and macrophage activity. See Thomas, P.D. and
Hunninghake, G.W., Am. Rev. Respir. Dis., 1987, 135: 747-760. As sarcoidosis progresses, skin rashes, erythema nodosum and granulomas may form. Granulomas or fibrosis caused by sarcoidosis can occur throughout the body, and may affect the function of vital organs such as the lungs, heart, nervous system, liver or kidneys. In these cases, the sarcoidosis can be fatal. See
http://www.nlm.nih.gov/medlineplus/sarcoidosis.html (accessed November 12, 2009).
Moreover, a variety of exogenous agents, both infectious and non-infectious, have been hypothesized as a possible cause of sarcoidosis. See Vokurka et ah, Am. J. Respir. Crit. Care Med., 1997, 156: 1000-1003; Popper et al, Hum. Pathol, 1997, 28: 796-800; Almenoff et al, Thorax, 1996, 51 : 530-533; Baughman et al., Lancet, 2003, 361 : 1111-1118. These agents include mycobaceria, fungi, spirochetes, and the agent associated with Whipple’s disease. Id.
Sarcoidosis may be acute or chronic. Specific types of sarcoidosis include, but are not limited to, cardiac sarcoidosis, cutaneous sarcoidosis, hepatic sarcoidosis, oral sarcoidosis, pulmonary sarcoidosis, neurosarcoidosis, sinonasal sarcoidosis, Lofgren’s syndrome, lupus pernio, uveitis or chronic cutaneous sarcoidosis.
As the lung is constantly confronted with airborne substances, including pathogens, many researchers have directed their attention to identification of potential causative transmissible agents and their contribution to the mechanism of pulmonary granuloma formation associated with sarcoidosis. See Conron, M. and Du Bois, R.M., Clin. Exp. Allergy, 2001, 31 : 543-554; Agostini et al, Curr. Opin. Pulm. Med. , 2002, 8: 435-440.
Corticosteroid drugs are the primary treatment for the inflammation and granuloma formation associated with sarcoidosis. Rizatto et al. , Respiratory Medicine, 1997, 91 : 449-460. Prednisone is most often prescribed drug for the treatment of sarcoidosis. Additional drugs used to treat sarcoidosis include methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, minocycline, doxycycline and chloroquin. TNF-a blockers such as thalidomide and infliximab have been reported to be effective in treating patients with sarcoidosis. Baughman et al, Chest, 2002, 122: 227-232; Doty et al, Chest, 2005, 127: 1064-1071. Antibiotics have also been studied for the treatment of sarcoidosis, such as penicillin antibiotics, cephalosporin antibiotics, macrolide antibiotics, lincomycin antibiotics, and tetracycline antibiotics. Specific examples include minocycline hydrochloride, clindamycin, ampicillin, or clarithromycin. See, e.g., U.S. Patent Publication No. 2007/0111956.
There currently lacks a Food and Drug Administration-approved therapeutic agent for the treatment of sarcoidosis, and many patients are unable to tolerate the side effects of the standard corticosteroid therapy. See Doty et al, Chest, 2005, 127: 1064-1071. Furthermore, many cases of sarcoidosis are refractory to standard therapy. Id. Therefore, a demand exists for new methods and compositions that can be used to treat patients with sarcoidosis.
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PATENTS
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8-15-2012
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PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS
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11-4-2011
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HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
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5-27-2011
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Nanosuspension of a Poorly Soluble Drug via Microfluidization Process
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5-28-2010
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METHODS AND COMPOSITIONS USING PDE4 INHIBITORS FOR THE TREATMENT AND MANAGEMENT OF CANCERS
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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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