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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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(4aS,7aR)-1-[5-[(3-Fluorophenyl)ethynyl]pyridin-2-yl]hexahydrocyclopenta[d][1,3]oxazin-2(1H)-one
(4aS,7aR)-1-[5-[(3-Fluorophenyl)ethynyl]pyridin-2-yl]hexahydrocyclopenta[d][1,3]oxazin-2(1H)-one
(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one
336.35
C20 H17 F N2 O2
F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc.
mgluR5 Positive Allosteric Modulators
Signal Transduction Modulators
http://www.google.com/patents/WO2014056710A1?cl=en
Example 1
(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one
Ste 1 : ((lR,2S)-2-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester
To a well stirred suspension of 0.94 g (24.7 mmol, 2 equiv.) of L1AIH4 in 30ml of THF at 0°C was added dropwise at 0°C a solution of (lS,2R)-methyl 2-(tert-butoxycarbonylamino)- cyclopentanecarboxylate (CAS: 592503-55-4) (3.0 g, 12.3 mmol) (gas evolution, lightly exo therm). After 15 minutes at 0°C the reaction mixture was allowed to warm up to room temperature and was stirred for 2h. The mixture was cooled to 0°C and water was added dropwise. The precipitated inorganic salts were filtered through Celite and were washed with ethyl acetate. The filtrate was evaporated and the residue was purified by column
chromatography on silica gel eluting with a 0% to 50% ethyl acetate in heptane gradient to yield 1.99 g (75%) of the title compound as a crystalline white solid which was directly used in the next step. Ste 2: (4aS,7aR)-Hexahydro-cyclopenta[d][l,3]oxazin-2-one
To a solution of ((lR,2S)-2-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (1.6 g, 7.43 mmol) in THF (40 ml) was added potassium tert-butoxide (3.34 g, 29.7 mmol, 4.0 equiv.) at room temperature. After stirring for lh at 60°C the reaction was allowed to warm up to room temperature and after workup with Ethyl acetate/water, drying and concentration in vaccuo, the crude material mixture was adsorbed on silica and chromatographed over a prepacked silica column (50g, 50% to 100% EtOAc in Heptane gradient) to yield 950 mg (91%) of the title compound as a white solid, which was directly used in the next step. -Fluoro-5-phenylethynyl-pyridine
In an 100ml 2-necked round bottomed flask under Argon were dissolved 2-fluoro-5-iodopyridine (5.0 g, 22.4 mmol, 1.0 equiv.) in THF (30 ml). After 5 minutes at room temperature were added bis(triphenylphosphin)palladium(II)chloride (944 mg, 1.35 mmol, 0.06 equiv.), triethylamine (6.81 g, 9.32 ml, 67.3 mmol, 3.0 equiv.), phenyl acetylene (2.75 g, 2.95 ml, 26.9 mmol, 1.2 equiv.) and copper(I)iodide (128 mg, 0.67 mmol, 0.03 equiv.). The brown suspension was cooled with water (exothermic) to room temperature and stirred overnight. Then 200ml of diethylether were added, the mixture was filtered, washed with ether and concentrated in vacuum to yield 5.7g of a brown solid which was adsorbed on silica and was chromatographed in 2 portions over a lOOg prepacked silica column eluting with a 0-10% ethyl acetate in heptane gradient to yield 3.99g (91%) of the title compound as a light brown solid, MS: m/e = 198.1 (M+H+). Step 4: (4aS aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d][l,3]oxazin-2-one In a 10ml Round bottomed flask were dissolved (4aS,7aR)-hexahydro-cyclopenta[d]- [l,3]oxazin-2-one (80 mg, 0.57 mmol, 1.0 equiv.) and 2-fluoro-5-(phenylethynyl)pyridine (112 mg, 0.57 mmol, 1.0 equiv.) in 2ml of DMF. Sodium hydride (60%> suspension) (29.5 mg, 0.74 mmol, 1.3 equiv.) were added and the brown suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were dried, filtered and concentrated. The crude material was purified by flash chromatography over a prepacked silica column eluting with 0-50% ethyl acetae in heptane gradient to yield 42.5mg of the title compound as colorless amorphous solid, MS: m/e = 319.1 (M+H+).
Example 2
(4aS,7aR)- 1- [5-(3-Fluorophenylethynyl)-py ridin-2-yl] -hexahydro- cyclopenta[d] [l,3]oxazin-2-one
Step 1 : 2-Fluoro-5-(3-fluoro-phenylethynyl)-pyridine
The title compound was prepared in accordance with the general method of Example 1, step 3 using 3-flurorophenylacetylene instead of phenylacetylene to yield the title compound as a crystalline white solid, MS: m/e = 216.2 (M+H+).
Step 2 : (4aS ,7aR)- 1 – [5 -(3 -Fluorophenylethynyl)-pyridin-2-yl] -hexahydro- cyclopenta[d] [ 1 ,3]oxazin-2-one
The title compound was prepared in accordance with the general method of Example 1, step 4 using (4aS,7aR)-hexahydro-cyclopenta[d]-[l,3]oxazin-2-one (66 mg, 0.47 mmol) (Example 1, step 2) and 2-fluoro-5-((3-fluorophenyl)ethynyl)pyridine (100 mg, 0.47 mmol) to yield 48 mg (31%) of the title compound as a light yellow amorphous solid; MS: m/e = 337.3 (M+H+).
(3S)-3-[[2-Amino-5-(2-methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino]heptan-1-ol
COMPOUND 80 ABOVE
IN
http://www.google.com/patents/WO2014056953A1?cl=en
(3S)-3-[[2-Amino-5-(2-methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino]heptan-1-ol
TLR7 Receptor Agonists , Signal Transduction Modulators
Janssen R&D Ireland (INNOVATOR)
383.4873
C21 H29 N5 O2
HTL-9936 is a selective muscarinic M1 agonist designed to improve cognitive function in patients with AD and other diseases
(2)
GENERAL STR
HTL-9936
PRE CLINICAL
Selective muscarinic acetylcholine receptor M1 (CHRM1; HM1) agonist
MolecularTargetMuscarinic acetylcholine receptor M1 (CHRM1) (HM1)
Mechanism of ActionMuscarinic acetylcholine receptor M1 agonist
Heptares Therapeutics was founded in 2007 to develop drugs against GPCRs. Its lead candidate,HTL-9936, is a selective muscarinic M1 agonist designed to improve cognitive function in patients with AD and other diseases, which recently entered the clinic for the first time.
Heptares Therapeutics, the leading GPCR structure-guided drug discovery and development company, announces that it has initiated a Phase 1 clinical study of HTL9936, the first fully selective muscarinic M1 receptor agonist to enter clinical development. HTL9936 is an orally available, small molecule drug candidate discovered using the Heptares GPCR structure-based drug design (SBDD) platform. Heptares plans to develop HTL9936 as a novel treatment for improving cognitive function (memory and thinking abilities) in patients with Alzheimer’s disease and other diseases associated with dementia and cognitive impairment.
“We are excited to initiate clinical development of HTL9936, a first-in-class agent with the potential to become an important new medicine for improving cognitive function in patients with Alzheimer’s disease and other potential indications including schizophrenia and Lewy body dementia,” said Malcolm Weir, CEO of Heptares. “In addition, the initiation of this clinical trial with HTL9936 marks an important milestone for Heptares, as we evolve into a clinical-stage business with a rich portfolio of novel GPCR-targeted agents advancing through Phase 1 and 2a clinical trials in the near-term.”
M1 receptor agonism is a well-validated mechanism of action for treating cognitive impairment and a valuable pharmacological profile that the pharmaceutical industry has endeavored to create for decades. The principal challenge has been to engineer selective compounds that activate the M1 receptor subtype without also activating the M2 or M3 receptors, which are associated with undesirable side effects. All previous compounds have been discontinued due to inadequate selectivity. Using a new structure-guided approach, Heptares scientists determined the x-ray crystal structure of the M1 receptor for the first time and leveraged unique insights into the receptor to identify new chemistries with fully selective M1 agonist profiles.
The Phase 1 study will evaluate the safety, tolerability and pharmacokinetics of HTL9936. In addition, the clinical pharmacodynamics of the drug will be investigated in a series of studies over the next year. This study aims to recruit more than 100 healthy volunteers including elderly people at a single clinical centre in the UK. Initial results are expected in mid-2014
About Alzheimer’s Disease and Other Disorders of Cognitive Impairment
Today there is significant unmet medical need and heavy economic burden across multiple diseases characterised by cognitive impairment and dementia. In Alzheimer’s disease, currently available drugs provide limited and transient effects on cognition. Healthcare costs associated with the epidemic of AD, including nursing home care, continue to grow dramatically and new therapies with better and more durable efficacy are urgently needed. In addition, an estimated 80% of schizophrenics suffer from cognitive impairment and 1.3 million patients in the US suffer from Lewy body dementia. Currently there are no approved therapies for treating cognitive impairment in schizophrenia or for treating Lewy body dementia.
About Heptares Therapeutics
Heptares creates new medicines targeting clinically important, yet historically challenging, GPCRs (G protein-coupled receptors), a superfamily of drug receptors linked to a wide range of human diseases. Leveraging our proprietary structure-based drug design technology platform, we have built an exciting pipeline of novel drug candidates with the potential to transform the treatment of serious diseases, including Alzheimer’s disease, ADHD, diabetes, schizophrenia, and migraine. Our pharmaceutical partners include Cubist, MorphoSys, Takeda, AstraZeneca and MedImmune, and we are backed by Clarus Ventures, MVM Life Science Partners, Novartis Venture Fund, the Stanley Family Foundation and Takeda Ventures. To learn more about Heptares, please visit http://www.heptares.com
…………………….
WO 2013072705
http://www.google.com/patents/WO2013072705A1?cl=en
Scheme 3 below.
Scheme 3
………………………………………….
WO 2014045031
http://www.google.com/patents/WO2014045031A1?cl=en
Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily which mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five mAChR subtypes have been cloned, to M5. The mAChR is predominantly expressed post-synaptically in the cortex, hippocampus, striatum and thalamus; M2 mAChRs are located predominantly in the brainstem and thalamus, though also in the cortex, hippocampus and striatum where they reside on cholinergic synaptic terminals (Langmead et al., 2008 Br J
Pharmacol). However, M2 mAChRs are also expressed peripherally on cardiac tissue (where they mediate the vagal innervation of the heart) and in smooth muscle and exocrine glands. M3 mAChRs are expressed at relatively low level in the CNS but are widely expressed in smooth muscle and glandular tissues such as sweat and salivary glands (Langmead et al, 2008 Br J Pharmacol).
Muscarinic receptors in the central nervous system, especially the mAChR, play a critical role in mediating higher cognitive processing. Diseases associated with cognitive impairments, such as Alzheimer’s disease, are accompanied by loss of cholinergic neurons in the basal forebrain (Whitehouse et al, 1982 Science). In schizophrenia, which is also characterised by cognitive impairments, mAChR density is reduced in the pre-frontal cortex, hippocampus and caudate putamen of
schizophrenic subjects (Dean et al, 2002 Mol Psychiatry). Furthermore, in animal models, blockade or lesion of central cholinergic pathways results in profound cognitive deficits and non-selective mAChR antagonists have been shown to induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy has largely been based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to dose-limiting side effects resulting from stimulation of peripheral M2 and M3mAChRs including disturbed gastrointestinal motility, bradycardia, nausea and vomiting
(http ://www. d rugs . com/pro/donepezi 1. htm I ;
http://yvww.drugs.com/pro/rivastigmine.html).
Scheme 1 below.
Scheme 1
Scheme 2 below.
(1 1)
Scheme 2
REF
March 2012, data were presented at the 243rd ACS meeting in San Diego, CA
April 2013, similar data were presented at the 245th ACS Meeting in New Orleans, LA.
September 2012, preclinical data were presented at the Fourth RSC/SCI GPCRs in Medicinal Chemistry Symposium in Windlesham, UK.
Novel Oxazolidinone Antibacterial Candidate FYL-67 …..(S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide
cas no 1416314-55-0
C20 H18 F N5 O3
FYL-67 IS HYDROCHLORIDE
(S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide
N-[[(5S)-3-[3-fluoro-4-[4-(2-pyridinyl)-1H-pyrazol-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-Acetamide,
(S)-N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl) phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide.
| Inventores | Youfu LUO, 罗有福, Zhenling WANG, 王震玲,Yuquan Wei, 魏于全 |
| Requerente | Si Chuan University, 四川大学 |
The discovery and application of antibiotics is one of the greatest achievements of mankind in the 20th century, the field of medicine, called a revolution of the history of the human fight against illness. Since then, the field of medicine into a bacterial disease caused by greatly reducing the golden age. Today, however, due to the widespread use of antibiotics or even abuse, the growing problem of bacterial resistance, humans are gradually approaching the “post-antibiotic era, the efficacy of antibiotics is gradually reduced. Clinical have been found on many new drug-resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP) has seriously jeopardize the clinical treatment , the number of varieties of drugs less.
The compounds of the oxazolidinone linezolid was in the United States in 2000, mainly used in clinical acquired pneumonia, soft tissue infections, can also be used for the surgical treatment of infectious diseases, bones, lungs, cerebrospinal fluid permeability pharmacokinetic and tissue concentrations. Domestic and foreign the oxazolidinone drug development is a hot field
WO 2012171479
http://www.google.st/patents/WO2012171479A1?cl=en
The object compound (S N-{[3 – (3 – fluoro-4 – (4 – (2 – pyridyl) pyrazol-yl) phenyl) -2 – oxo-oxazol the embankment -5 – yl] methanone yl}
Weigh 150mg of the compound (26f), was dissolved with 10 ml of anhydrous THF was added under nitrogen protection, an ice water bath 154.1 mg t-BuOLi, ice-water bath after stirring for 5 minutes, 149.9 mg Compound 11, followed by ice-water bath was removed, go reaction at room temperature for 36 hours the reaction was stopped, by adding 10 mL of methylene chloride and 10 ml of water and 22μί acetic acid, stirred for 1 minute, the liquid separation, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, dried and purified by column chromatography to give the product ( 130 white solid 58 mg of yield of 38.2%.
1H-MR (400 MHz, CDC1 3): δ 8.61 (d, J = 4Hz, IH), 8.52 (d, J = 6.8Hz, 2.4H), 8.22 (s, IH), 7.94 (t, J = 8.8 Hz, IH), 7.77-7.69 (m, 2H), 7.55 (d, J = 8Hz, IH), 7.27-7.26 (m, IH), 7.18-7.15 (m, IH), 6.06 (t, J = 6Hz , IH), 4.86-4.80 (m, IH), 4.11 (t, J = 9.2Hz, IH), 3.86-3.82 (m, IH), 3.78-3.62 (m, 2H), 2.04 (s, 3H 😉 .
13 C-MR (DMSO-e): δ 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91.
ESI-MSm / z 418.08 (M + Na +).
………………….
Nanoscale (2013), 5(1), 275-283
Carrier-free nanoassemblies of a novel oxazolidinone compound FYL-67 display antimicrobial activity on methicillin-resistant Staphylococcus aureus
E-mail: luo_youfu@scu.edu.cn, wangzhenling2007@126.com;
Fax: +86-28-85164060 ;
Tel: +86-28-85164063
DOI: 10.1039/C2NR32505E
In this work, a novel oxazolidinone compound FYL-67 was synthesized, and the obtained FYL-67 could form nanoassemblies in aqueous solution by a self-assembly method without using any carrier, organic solvent, or surfactant. The prepared FYL-67 nanoassemblies had a particle size of 264.6 ± 4.3 nm. The FYL-67 nanoassemblies can be lyophilized into a powder form without any cryoprotector or excipient, and the re-dissolved FYL-67 nanoassemblies are stable and homogeneous. The in vitro release profile showed a significant difference between rapid release of free FYL-67 and much slower and sustained release of FYL-67 nanoassemblies. In vitro susceptibility tests were conducted in three strains of methicillin-susceptibleStaphylococcus aureus (MSSA) and three strains of methicillin-resistant Staphylococcus aureus(MRSA), using linezolid as a positive control. FYL-67 nanoassemblies exhibited excellent in vitro activity, with a minimum inhibitory concentration (MIC) value of 0.5 μg mL−1 against MRSA. In the in vitro post-antibiotic effect (PAE) evaluation, FYL-67 nanoassemblies showed a more powerful effect than linezolid. Besides, in vitro cytotoxicity tests indicated that FYL-67 nanoassemblies had a very low cytotoxicity on HEK293 cells and L02 cells. Furthermore, in both MSSA and MRSA systemic infection mouse models, FYL-67 nanoassemblies showed a lower ED50 than linezolid. In a murine model of MRSA systemic infection, FYL-67 nanoassemblies displayed an ED50 of less than 4.0 mg kg−1, which is 2.3-fold better than that oflinezolid. Our findings suggested that the FYL-67 nanoassemblies may be a potential drugcandidate in MRSA therapy.
 |
||
| Fig. 1 Synthetic route of the novel compound FYL-67. (i) 2-(pyridin-2-yl)malonaldehyde, p-TsOH (cat.),ethanol, reflux, 2 h; (ii) Fe, HCl, 95% ethanol, 1 h; (iii) Cbz–Cl, K2CO3, CH2Cl2, 2 h; (iv) (S)-1-acetamido-3-chloropropan-2-yl acetate, LiOt-Bu, THF, r.t.; (v) HCL (g), acetone, ethyl ether | ||
1H-NMR (400 MHz, CDCl3): δ 8.61 (d, J = 4 Hz, 1H), 8.52 (d, J = 6.8 Hz, 2.4H), 8.22 (s, 1H), 7.94 (t, J = 8.8 Hz, 1H), 7.77–7.69 (m, 2H), 7.55 (d, J = 8 Hz, 1H), 7.27–7.26 (m, 1H), 7.18–7.15 (m, 1H), 6.06 (t, J = 6 Hz, 1H), 4.86–4.80 (m, 1H), 4.11 (t, J = 9.2 Hz, 1H), 3.86–3.82 (m, 1H), 3.78–3.62 (m, 2H), 2.04 (s, 3H).
13C-NMR (DMSO-d6): δ 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43, 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91.
ESI-MS m/z418.08 (M + Na+).
1H-NMR (400 MHz, DMSO-d6) δ: 9.33 (s, 1H), 8.80 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.45 (t, J = 7.2 Hz, 1H), 8.38–8.31 (m, 2H), 7.90 (t, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.4 Hz, J = 16.4 Hz, 1H), 7.76 (t,J = 6.0 Hz, 1H); 7.55 (dd, J = 1.6 Hz, J = 8.8 Hz, 1H), 4.83–4.76 (m, 1H), 4.60 (br s, 1H), 4.20 (t, J = 8.8 Hz, 1H), 3.91–3.82 (m, 1H), 3.45 (t, J = 5.2 Hz, 2H), 1.85 (s, 3H);
13C-NMR (DMSO-d6) δ: 170.51, 154.47, 152.94, 151.26, 149.94, 139.70, 139.15, 137.43, 129.96, 125.61, 125.19, 123.42, 122.19, 120.38, 114.52, 106.68, 72.29, 47.70, 41.84, 22.91;
HR-MS(TOF) m/z calcd for C20H18FN5O3 [M + Cl−]: 430.1082, found: 430.1085; for C20H18FN5O3 [M + H+]: 396.1472, found: 396.1472.
PAPER
A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C–N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid–liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.
\
(S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (1)
-
Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E.J. Med. Chem. 1996, 39, 673– 679
-
(a) Gong, C. Y.; Yang, T.; Yang, X. Y.; Liu, Y. Y.; Ang, W.; Tang, J. Y.; Pi, W. Y.; Xiong, L.; Chang, Y.; Ye, W. W.; Wang, Z. L.; Luo, Y. F.; Zhao, X.; Wei, Y. Q. Nanoscale. 2013, 5, 275–283(b) Luo, Y. F.; Wang, Z. L.; Wei, Y. Q.; Geng, F. WO/2012/171479,2012.
WO2008143649A2 * 4 Dez 2007 27 Nov 2008 Das Jagattaran Novel oxazolidinone compounds as antiinfective agents CN1172484A * 29 Jan 1996 4 Fev 1998 法玛西雅厄普约翰美国公司 Hetero-aromatic ring substituted phenyloxazolidinone antimicrobials
Evacetrapib, LY2484595 for Treatment of high cholesterol and preventing cardiac events
Evacetrapib, LY2484595
Evacetrapib is an experimental drug being investigated to raise high-density lipoprotein cholesterol (HDL-C) via inhibition of the cholesteryl ester transfer protein (CETP)
Trans-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl-2H-tetrazol-5- yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzazepin-1-yl}methyl) cyclohexanecarboxylic acid
trans-4-[[(5S)-5-[[[3 ,5- bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2, 3,4,5- tetrahydro-7,9-dimethyl- IH- 1 -benzazepin- 1 -yl]methyl]-cyclohexanecarboxylic acid
trans-4-[5(S)-[N-[3,5-Bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylmethyl]cyclohexanecarboxylic acid
1186486-62-3 is cas
UNII-51XWV9K850
-
C31-H36-F6-N6-O2
- 638.6534
- lily……….. .innovator
Evacetrapib is a drug under development by Eli Lilly & Company (investigational name LY2484595) that inhibits cholesterylester transfer protein, which transfers and thereby increases high-density lipoprotein and lowers low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease.[1]
The first CETP inhibitor, torcetrapib, was unsuccessful because it increased levels of the hormone aldosterone and increased blood pressure,[2] which led to excess cardiac events when it was studied.[2] Evacetrapib does not have the same effect.[1] When studied in a small clinical trial in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.[3]
LY-2484595 is in phase III clinical trials at Lilly for the treatment of high-risk vascular disease and in phase II for the treatment of dyslipidemia.
Evacetrapib is one of two CETP inhibitors currently being evaluated (the other being anacetrapib).[1] Two other CETP inhibitors (torcetrapib and dalcetrapib) were discontinued during trials due to increased deaths and little identifiable cardiovascular benefit (despite substantial increases in HDL). Some hypothesize that CETP inhibitors may still be useful in the treatment of dyslipidemia, though significant caution is warranted.[2]
……………………………..
http://www.google.com/patents/WO2006002342A1?cl=en
Intermediate Preparation Scheme 1
Preparation Scheme 2
Intermediate Preparation Scheme 3
Scheme 7
Scheme 8
Scheme 11
…………………
http://www.google.com/patents/WO2011002696A1?cl=en
trans-4-[[(5S)-5-[[[3 ,5- bis(trifluoromethyl)phenyl]methyl] (2-methyl-2H-tetrazol-5-yl)amino]-2, 3,4,5- tetrahydro-7,9-dimethyl- IH- 1 -benzazepin- 1 -yl]methyl]-cyclohexanecarboxylic acid, (identified according to its Chemical Abstracts Index Name (referred to herein as BCCA) having the structure of Formula I illustrated below, and pharmaceutically acceptable salts of this compound.
I
The compound, BCCA, can be a free acid (referred to herein as BCCA free acid), or a pharmaceutically acceptable salt thereof, as a solvate (referred herein as BCCA’solvate) and a hydrate (referred to herein as BCCA ‘hydrate). The solvate molecules include water (as the hydrate), methanol, ethanol, formic acid, acetic acid, and isopropanol.
Scheme 1
(MeO) SO
Scheme 2
Scheme 3 : Alternate method for preparing BCCA
Preparation 11 Preparation 12
Preparation 13 Preparation 14 Preparation 15
Preparation 16
Preparation 17
Example 16
Scheme 4
………….
http://www.google.com/patents/US8299060
formula III below
with
Preparation 10 (Trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (12)
Charge a flask equipped with an overhead stirrer, temperature probe, nitrogen inlet with (S)—N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine (5 g, 10.03 mmoles) and sodium triacetoxyborohydride (3.19 g, 15.05 mmoles) and acetonitrile (40 mL). Immerse the flask in an ice bath to cool the slurry to below about 5° C., then add (trans)-methyl 4-formylcyclohexanecarboxylate (2.99 g, 17.57 mmoles, prepared essentially according to the procedures in Houpis, I. N. et al, Tetrahedron Let. 1993, 34(16), 2593-2596 and JP49048639) dissolved in THF (10 mL) via a syringe while maintaining the reaction mixture at or below about 5° C. Allow the reaction to warm to RT and stir overnight. Add NH4Cl (25 mL, 50% saturated aqueous solution) and separate the aqueous layer from the organic layer. The pH of the organic layer should be about 5.5. Warm the organic layer to about 45° C. and add water (16 mL). Add a seed crystal of the titled compound and cool to about 35° C. Collect the resulting solid by filtration and rinse with ACN. Dry to provide 5.80 g of the title compound.
………….
Evacetrapib
http://www.platinummetalsreview.com/article/56/4/229-235/
…………………….paper
THE ESTER OF EVACETRAPIB
http://pubs.acs.org/doi/abs/10.1021/op500025v
Development of a Hydrogenative Reductive Amination for the Synthesis of Evacetrapib: Unexpected Benefits of Water
References
- Cao G, Beyer TP, Zhang Y, et al. (December 2011). “Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure”. J. Lipid Res. 52 (12): 2169–76.doi:10.1194/jlr.M018069. PMID 21957197.
- Joy T, Hegele RA (July 2009). “The end of the road for CETP inhibitors after torcetrapib?”. Curr. Opin. Cardiol. 24 (4): 364–71.doi:10.1097/HCO.0b013e32832ac166. PMID 19522058.
- Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE (2011). “Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol”. JAMA 306 (19): 2099–109.doi:10.1001/jama.2011.1649.
Glenmark’s novel molecule ‘GRC 27864’ for chronic inflammatory diseases including pain entering human trials
Glenmark’s novel molecule ‘GRC 27864’ for chronic inflammatory diseases including pain entering human trials
- GRC 27864 is a potent, selective, orally bioavailable inhibitor of mPGES-1
- The molecule has successfully completed pre-clinical and Phase 1 enabling studies. Regulatory submission has been filed for Phase 1 trial (first-in-human)with MHRA, UK
- mPGES-1 inhibitors selectively block the production of PGE2 while sparing other prostanoids of physiological importance
- With this announcement, Glenmark has reaffirmed its position globally in the development of novel pain therapies
Mumbai, India: April 3, 2014: Glenmark Pharmaceuticals today announced that its Novel Chemical Entity (NCE) ‘GRC 27864’ is entering human trials. This NCE program targets Microsomal Prostaglandin E synthase-1 (mPGES-1) as a novel therapeutic target in pain management. Selective mPGES-1 inhibitors are expected to inhibit increased prostaglandin E2 (PGE2) production in the disease state without affecting other prostanoid metabolites and, consequently, may be devoid of the GI(gastrointestinal) and cardiovascular side effects seen with NSAIDs and COX-2 inhibitors, respectively.
Glenmark has completed preclinical studies and Phase 1 enabling GLP studies for its selected lead molecule, GRC 27864 and has filed a Phase 1 application forfirst-in-human trial with the MHRA, UK. The Phase 1 studies are to be initiated soon and are likely to get completed by January 2015. Following this, Glenmark will also be initiating a proof of concept study in patients with acute pain.
ACH-702 the isothiazoloquinolone in preclinical from Achillion Pharmaceuticals (USA)
ACH-702
7-[3(R)-(2-Aminopropan-2-yl)pyrrolidin-1-yl]-9-cyclopropyl-6-fluoro-8-methoxy-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione
(7^-7-[3-(1-AMrNO-I-METHYLETHYL)PYRROLiDiN-I-YL]-P-CYCLOPROPYL-6-FLUORO-8-METHOXY-PH-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4-DIONE
(R)- 7-[3-(l-amino-l-methyl-ethyl)-pyrrolidin-l-yl]-9-cyclopropyl-6-fluoro-8-methoxy- 9H-isothiazolo[5, 4-b] -quinoline-3, 4-dione
922491-46-1 free base
922491-09-6 (hydrochloride)468.973, C21 H25 F N4 O3 S . Cl H
ACH-0139586
ACH-702
Achillion Pharmaceuticals (USA)
pre clinical
Achillion Pharmaceuticals is working on the discovery of compounds in a new subclass of quinolones, the isothiazoloquinolones. The most advanced compound is ACH-702, which is at the pre-clinical stage of development [1-3].
ACH 702
The utility of isothiazoloquinolines as pharmaceutical agents has been discussed in the literature. For example, Pinol, et al discussed the use of isothiazoloquinolines as medical bactericides in US Patent 5,087,621, including
The Proctor & Gamble Company discussed antimicrobial quinolones including the following compound:
in published application no. US 2003008894.
The use of isothiazoloquinoline compounds as TNF production inhibitors has also been discussed, for example by Sankyo Co., Ltd. in JPl 010149, which includes the following compound
Bayer Aktiengesellschaft has discussed bicycle[3.3.0]oct-7-yl containing compounds useful for treating H. pylori infections in WO 98/26768, including isothiazoloquinolines, having the general structure shown below in which Y may be sulfur joined to the carboxamide group to form a 5-membered ring
Otsuka Pharmaceutical Co., Ltd. has discussed the use of isothiazoloquinolines as antibacterial agents in JP 01193275, including the following carbamate-containing compound
Abbott Laboratories has discussed the use of isothiazoloquinolines as antineoplastic agents in US Patent No. 5,071,848 and has discussed the use of tricyclic quinolones as antibacterial agents in US 4,767,762. The Abbott compounds have hydrogen, halogen, or lower alkyl as substituents at the 6- and 8- positions of the isothiazoloquinoline core.
………………
Synthesis
WO2008021491A2
http://www.google.com/patents/WO2008021491A2?cl=en
EXAMPLE 1. SYNTHESIS OF (7^-7-[3-(1-AMrNO-I-METHYLETHYL)PYRROLiDiN-I-YL]-P-
CYCLOPROPYL-6-FLUORO-8-METHOXY-PH-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4-DIONE (5). Step 1. Ethyl l-cyclopropyl-6, 7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-l,4-dihydro- quinoline-3-carboxylate (6)
Oxonβ®
MeOHZH2O
6
Water (180 mL), followed by Oxone® (Dupont Specialty Chemicals) (170 g, 277 mmol), is added to a suspension of 1 in MeOH (510 mL). The reaction mixture is heated with stirring at 55-60 0C for 3 h. The reaction mixture is cooled to room temperature, diluted with water (40 mL), and stirred at 5 0C (ice bath) for 30 min. The resulting crystals are collected by filtration, washed with water (2 x 100 mL), and dried to afford 6 (13.8 g). This material was used in the next step without further purification, mp 177-178 0C. 1H NMR (DMF-^7): J0.62 (m, IH), 1.11 (m, 2H), 1.29 (m, IH), 1.32 (t, JH-H = 7.0 Hz, 3H), 3.76 (s, 3H), 4.18 (m, IH), 4.21 (d, JH-F = 2.0 Hz, 3H), 4.33 (q, JH–H = 7.0 Hz, 2H), 7.64 (dd, JH-F = 10.0 Hz, 8.5 Hz, IH). Step 2 (R)- 7-[3-(l-amino-l-methyl-ethyl)-pyrrolidin-yl]-l-cyclopropyl-6-fluoro-2- methanesulfonyl-8-methoxy-4-oxo-l , 4-dihydro-quinoline-3-carboxylic acid ethyl ester (7)
10 6 7
A mixture containing compound (6) (3.88 g, 9.67 mmol), compound 10 (1.64 g, 12.8 mmol), anhydrous DIEA (5.05 g, 39.1 mmol, dried over 4A sieves), and anhydrous DMF (40 mL) is heated at 70 0C under an atmosphere of argon gas. After heating for 4.5 h (LC-MS analysis shows ~7% compound (6) remained), the reaction mixture is cooled to room temperature, diluted with EtOAc (200 mL), and washed with water (100 mL). The aqueous layer is extracted with EtOAc (100 mL), and the combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (100 mL). The organic layer is diluted with water (100 mL) and treated with an aqueous solution of HCl (4 N) until the aqueous layer is acidic (pH 2—3 after shaking the mixture vigorously). The organic layer is separated, and this process is repeated. The combined aqueous layers are diluted with EtOAc (100 mL) and treated with an aqueous solution of sodium hydroxide (6 N) until the aqueous layer is basic (pH ~8 after shaking the mixture vigorously). The aqueous layer is separated, and this process is repeated. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving an orange solid (3.27 g of an~80:20 mixture of compound (7) and impurity B). This solid is recrystallized from hot EtOAc (~60 mL) furnishing 2.18 g (44% yield) of pure compound 7 as a bright yellow solid. LC-MS mlz calcd for C24H32FN3O6S 509 ([M+]); found 510 ([M + H]+).
This reaction should not be allowed to proceed for more than a few hours (not overnight) as prolonged reaction time can lead to the formation of more side products. The product should be —95% pure (based on HPLC), with only a trace amount of impurity B. Step 3. (R)-7-[3-(l-amino-l-methyl-ethyl)-pyrrolidin-yl]-l-cyclopropyl-6-fluoro-2-mercapto-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid ethyl ester (8)
7 8
Compound 7 (1.04 g, 2.04 mmol) is partially dissolved in DME (40 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich, 72.6% by titration, 465 mg, 6.02 mmol) in water (3.0 mL) is added to this solution. The resulting mixture is sparged slowly with argon for 30 min.
The progress of the reaction is monitored by HPLC-MS, and judged to be complete (<2% of 7 remains) after 11.5 h. Excess sodium hydrosulfide is quenched upon addition of aq HCl (4.5 mL, 4 N).
The resulting orange solution (pH ~2) is sparged with argon (30 min) to remove the generated hydrogen sulfide. Step. 4 (R)- 7-[3-(l-amino-l-methyl-ethyl)-pyrrolidin-l-yl]-9-cyclopropyl-6-fluoro-8-methoxy- 9H-isothiazolo[5, 4-b] -quinoline-3, 4-dione (5)
A solution of potassium carbonate (4.26 g, 30.8 mmol) in water (25 mL) is next added to this solution to give a clear yellow solution (pH 9-10). The clear yellow solution is then sparged with argon for ~5 min. Finally, hydroxylamine-0-sulfonic acid (0.93 g, 8.2 mmol) is added portionwise as a solid, with immediate evolution of gas and formation of the product as a yellow precipitate. After stirring for 16 h, the reaction mixture (pH 10.2) is acidified with aq HCl to pH 8.3 (the approximate isoelectric point of 5) causing additional product to precipitate from solution. The reaction mixture is concentrated under reduced pressure (final volume -40 mL). The yellow precipitate is collected by centrifugation, washed with water (3 x 40 mL, with sonication), and lyophilized to give 0.80 g of 5.
……………………..
WO2007014308A1
http://www.google.com/patents/WO2007014308A1?cl=en
EXAMPLE 5. SYNTHESIS OF I-METHYL-I-PYRROLIDIN-3-YL ETHYLAMINE (5)
1 -Methyl- l-pyrrolidin-3-yl-ethylamine is prepared in accordance with the synthetic scheme below.
N O
5 P
Step 1. Synthesis of (S)-l-benzylpyrrolidin-3-yl methanesulfonate (N).
Methanesulfonyl chloride (15 mL, 0.19 mol) is added to a cooled (0 0C) solution of toluene (300 mL) containing (5)-l-benzylpyrrolidin-3-ol (24.5 g, 0.14 mol) and triethylamine (80 mL, 0.57 mol). The resulting mixture is stirred at 0 °C for 15 min, and allowed to warm to room temperature with stirring for 2h. The mixture is quenched with a 5% aqueous solution of sodium bicarbonate (250 mL). The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2 x 250 mL), washed with water (I x 250 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N (35.1 g, 99 %) as an orange oil. 1H NMR (300 MHz, CDCl3): £2.07 (m, IH), 2.30 (m, IH), 2.49 (m, IH), 2.75-2.90 (m, 3H), 2.98 (s, 3H), 3.61 (d, J= 13.0 Hz, IH), 3.68 (d, J= 13.0 Hz, IH), 5.18 (m, IH), 7.15-7.30 (m, 5H). LCMS mlz calcd for C12H17NO3S 255 ([M+]); found 256 ([M + H]+, 100%), 160 (40%). Steps 2 and 3. Syntheses of(R)-l-benzylpyrrolidine-3~carbonitrile (O) and 2-((R)-I- benzylpyrrolidin-3-yl)propan-2-amine (P).
The syntheses of O and P are described previously by Fedij et al. (Fedij, V.; Lenoir, E. A., Ill; Suto, M. J.; Zeller, J. R.; Wemple, J. Tetrahedron: Asymmetry 1994, J, 1131- 1134). Step 4. Synthesis ofl-((R)-Methyl~l-pyrrolidin-3-yl)-ethylamine (5).
A mixture containing P (7.4 g), 20% palladium hydroxide on carbon (7.5 g), and ethanol (75 niL) is stirred under an atmosphere of hydrogen gas (50 psi) at 45 °C for 24 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to give 5 (4.1 g, 95 %) as a yellow oil. This material is stored under an atmosphere of argon gas. 1H NMR (300 MHz, CDCl3): J1.09 (s, 6H), 1.51 (m, IH), 1.64 (br s, 3H), 1.81 (m, IH), 2.06 (apparent pentet, J= 8.5 Hz, IH), 2.69 (dd, J= 11.0 Hz, J= 8.5 Hz, IH), 2.94 (m, 2H), 3.00 (dd, J= 11.0 Hz, J= 8.5 Hz, IH). LCMS mlz calcd for C7H16N2 128 ([M+]); found 129 ([M + H]+, 60%), 112 (100%).
EXAMPLE 6. GENERAL METHOD FOR THE FINAL AMINE-COUPLING STEP: SYNTHESIS OF 7-((R)-3-
(2-AMINOPROPAN-2-YL)PYRROLIDIN- 1 -YL)-9-CYCLOPROPYL-6-FLUORO-8- METHOXYISOTHIAZOLO[5,4-B]QUINOLINE-3 ,4(2H,9H)-DIONE HYDROCHLORIDE
[0261 ] 7-((R)-3-(2-Aminopropan-2-yl)pyrrolidin- 1 -yl)-9-cyclopropyl-6-fluoro-8- methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione hydrochloride is prepared in accordance with the synthetic scheme below.
Synthesis ofJ-ffRJS-^-aminopropan^-ylJpyrrolidin-l-ylJ-P-cyclopropyl-o-fluoro-S- methoxyisothiazolofS, 4-bJguinoline-3,4(2H, 9H)-dione hydrochloride (6).
Under an atmosphere of argon, a reaction vessel is charged with 5 (206.0 mg, 1.6 mmol), 3 (328.6 mg, 1.0 mmol), dimethyl sulfoxide (4.5 mL), and ΛζN-diisopropylethylamine (750 μL, 4.3 mmol). The resulting mixture is irradiated with microwaves (CEM Discover) at 125 0C for 1 h (conventional heating may also be used — 115 °C in an oil bath for 14 h), allowed to cool, and evaporated to dryness under reduced pressure (-70 °C/2-3 mm Hg). The oily residue is triturated with ethyl acetate (15 mL) and the resulting powder is collected by centrifugation. This solid is purified using preparative HPLC to give the desired product. Preparative HPLC is performed using a YMC Pack Pro C18 150 x 30.0 mm 5//m column coupled to a YMC Pack Pro 50 x 20 mm 5/an column with an isocratic elution of 0.37 min at 95:5 H2OiCHsCN containing 0.1% TFA followed by a 15.94 min linear gradient elution from 95:5 to 25:75, followed by a 0.69 min linear gradient from 25:75 to 5:95 at a flow rate of 30.0 mL/min with UV detection at 254. The crude material is loaded as a solution containing acetic acid (~2 mL), methanol (~1 mL), and water (~1 mL). The purified product is isolated as the TFA salt and is converted to the corresponding hydrochloride salt by addition of a solution of hydrogen chloride (~1.25 M in methanol) followed by evaporation; this process is repeated twice to give a yellow solid. Purity by HPLC: >99%; tR = 10.08 min. 1H NMR (300 MHz, TFA-d): δ 1.28 (m, 2H), 1.53 (m, 2H), 1.66 (s, 6H), 2.43 (m, IH), 2.57 (m, IH), 3.35 (m, IH), 3.97 (s, 3H), 4.01-4.38 (m, 5H), 8.17 (d, J= 12.0 Hz, IH, aromatic). 19F(1H) (282 MHz, TFA-J): δ-\ 18.0 (s). 13C(1H) (75 MHz, TFA-d): £13.5, 13.9, 25.0, 25.1, 29.1, 39.7, 49.6, 59.4 (br, W1/2 « 14 Hz), 59.8 (br, W1/2 « 14 Hz), 60.0, 66.8, 106.0, 112.1 (dJc_F = 23.0 Hz), 137.5 (br m, W1/2 « 24 Hz), 138.4, 144.8 (br, W1/2 » 10 Hz), 155.3 (dJc_F = 255.0 Hz), 169.8, 170.1, 171.5 (br, W1/2 « 9 Hz). LCMS mlz calcd for C21H25FN4O3S 432 ([M+]); found 433 ([M + H]+). Anal. Calcd for C21H25FN4O3S-l.5HCM.5H2O: C, 49.05; H, 5.78; N, 10.90; Cl, 10.34. Found: C, 49.30; H, 5.60; N, 10.83; Cl, 10.00.
EXAMPLE 3. SYNTHESIS OF 9-CYCLθPRθPYL-6,7-DiFLUθRθ-8-METHθχγ-9H-isoτHiAzθLθ[5,4- 5]QUlNOLlNE-3,4-DIONE (Compound 3).
9-Cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo[5,4-&]quinoline-3,4-dione (3) is prepared in accordance with the synthetic scheme below.
Step 1. Synthesis of 2,4, 5-trifluoro-3-methoxybenzoyl chloride (A)
A mixture of 2,4,5-trifluoro-3-methoxybenzoic acid (154 mg, 0.75 mmol) and thionyl chloride (8 mL) is refluxed for 4 h. Excess thionyl chloride is removed in vacuo, and the remaining residue is used directly in the next synthetic step. Step 2. Synthesis of (Z)-ethyl 3-hydroxy-3-(2,4,5-trifluoro-3-methoxyphenyl)aaγlate (B).
Compound B is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chein. (1979) 44: 310-311). H-Butyllithium (1.6 M in hexanes) is added to a cooled (-78 °C) solution of tetrahydrofliran (10 mL) containing ethyl hydrogen malonate (180 juL, 1.50 mmol) and 2,2′-bipyridyl (~1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. -5 0C during the addition of n- butyllithium. Sufficient n-butyllithium (2.8 mL, 4.48 mmol) is added until a pink color persists at -5 0C for 5-10 min. A solution of 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.75 mmol, vide supra) in tetrahydrofuran (~3 mL) is added in one portion to the reaction mixture that had been recooled to -78 0C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (50 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2 x 30 mL), followed by brine (2 x 50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure B as a white solid. 1H NMR (300 MHz, CDCl3): (enol, predominant tautomer, >90%) δ 1.32 (t, JH–H = 7.0 Hz, 3H, CO2CH2CH3), 4.02 (apparent t, JH–F = 1.0 Hz, 3H, OCH3), 4.25 (q, JH–H = 7.0 Hz, 2H, CO2CH2CH3), 5.79 (s, IH, CH3C(OH)=CH- CO2CH2CH3), 7.39 (ddd, JH_F= 11.0 Hz, 8.5 Hz, 6.5 Hz, IH, aromatic), 12.68 (s, IH, OH). 19F(1H) NMR (282 MHz, CDCl3): <5-146.8 (dd, JF_F = 21.5 Hz, 10.5 Hz, IF), -140.2 (dd, JF_F = 21.5 Hz, 13.5 Hz, IF), -131.3 (dd, JF_F = 13.5 Hz, 10.5 Hz, IF).
Step 3. Synthesis ofζEyethy^-^ZJ-N-cyclopropy^methylthioJcarbonoimidoylJS-hydroxyS- (2, 4, 5-trifluoro-3-methoxyphenyl)acrylate (C)
Sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) is added portionwise to a cooled (0 °C) solution containing B (200 mg, 0.73 mmol), cyclopropyl isothiocyanate (120 /JL, 1.2 mmol), and dimethylformamide (2 mL). The resulting mixture is allowed to warm to room temperature with stirring overnight (18 h). Methyl iodide (80 juL, 1.2 mmol) is added to the resulting solution and stirred for an additional 4 h (until TLC indicated the complete consumption of B). The reaction mixture is diluted with ethyl acetate (100 mL) and quenched by addition of a saturated aqueous solution of ammonium chloride (30 mL). The organic layer is washed with brine (4 x 30 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 40% v/v ethyl acetate in hexanes) to give C as a yellow oil. 1H NMR (300 MHz, CDCl3): (50.86 (m, 2H, cyclopropyl CH2), 0.97 (m, 5H), 2.52 (s, 3H, SCH3), 3.00 (m, IH, cyclopropyl CH), 3.96 (q, JH–H = 7.0 Hz, 2H, CO2CH2CH3), 4.02 (apparent t, JH–F = 1.0 Hz, 3H, OCH3), 6.96 (m, IH, aromatic), 11.71 (s, IH). 19F(1H) NMR (282 MHz, CDCl3): £-149.9 (br, IF), -141.4 (br, IF), -135.7 (br, IF).
Step 4. Synthesis of ethyl l-cyclopropyl-6,7-difluoro-8-methoxy-2-(methylthio)-4-oxo-l,4- dihydroquinoline-3-carboxylate (D)
Sodium hydride (60% in mineral oil, 82 mg, 2.1 mmol) is added portionwise to a solution of C (760 mg, 1.95 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture is heated at 80 0C for 3 d (until TLC indicates the complete consumption of B), cooled to room temperature, and quenched by addition of a saturated aqueous solution of ammonium chloride (10 mL). The mixture is extracted with ethyl acetate (3 x 50 mL). The combined organic extracts are washed with brine (4 x 30 mL), dried over sodium sulfate, and evaporated under reduced pressure to give crude D. This material is purified by flash column chromatography (eluting with 30% v/v ethyl acetate in hexanes) to D as a pale yellow oil.1H NMR (300 MHz, CDCl3): £0.73 (m, 2H, cyclopropyl CH2), 1.19 (m, 2H, cyclopropyl CH2), 1.38 (t, JH–H = 7.0 Hz, 3H, CO2CH2CH3), 2.66 (s, 3Η, SCH3), 3.74 (m, IH, cyclopropyl CH), 4.08 (d, JH–F = 2.5 Hz 3H, OCH3), 4.40 (q, JH_H = 7.0 Hz, 2H, CO2CH2CH3), 7.76 (dd, JH_F = 10.5 Hz, 8.5 Hz IH, aromatic). 19F(1H) NMR (282 MHz, CDCl3): £-146.8 (d, JF_F = 21.0 Hz, IF), – 137.7 (d, JF–F = 21.0 Hz, IF). LCMS mlz calcd for C17H17F2NO4S 369 ([M+]); found 370 ([M + H]+).
Step 5. Synthesis of ethyl l-cyclopropyl-6,7-difluoro-8-methoxy-2-(methylsulfinyl)-4-oxo-l,4- dihydroquinoline-3-carboxylate (E)
m-Chloroperoxybenzoic acid (<77%, 34 mg, 0.15 mmol) is added in one portion to a solution of D (50 mg, 0.14 mmol) in methylene chloride (3 mL) at room temperature. The reaction mixture is stirred for 1 h, diluted with ethyl acetate (20 mL), and washed with a 5% aqueous solution of sodium bicarbonate (2 x 10 mL). The organic layer is dried over sodium sulfate and evaporated under reduced pressure to give the crude product. This material is purified by preparative thin-layer chromatography (eluting with 10% v/v hexanes in ethyl acetate) to give pure E as a white solid. 1H NMR (300 MHz, CDCl3): £0.62 (m, IH, cyclopropyl CH2), 1.00 (m, IH, cyclopropyl CH2), 1.13 (m, IH, cyclopropyl CH2), 1.29 (m, IH, cyclopropyl CH2), 1.36 (t, JH_H = 7.5 Hz, 3H, CO2CH2CH3), 3.22 (s, 3Η, S(O)CH3), 3.85 (m, IH, cyclopropyl CH), 4.09 (d, JH-F = 2.5 Hz, 3H, OCH3), 4.37 (q, JH–H = 7.5 Hz, 2H, CO2CH2CH3), 7.75 (dd, JH–F = 10.0, 8.0 Hz, IH, aromatic). 19F(1H) NMR (282 MHz, CDCl3): £-145.2 (d, JF_F = 21.0 Hz, IF), -136.2 (d, JF_F = 21.0 Hz, IF). LCMS mlz calcd for C17H17F2NO5S 385 ([M+]); found 386 ([M + H]+).
Step 6. Synthesis of ethyl l-cyclopropyl-βJ-difluoro-l-mercaptoS-methoxy-^oxo-lA- dihydroquinoline-3-carboxylate (F).
Anhydrous sodium hydrogen sulfide (Alfa Aesar, 20 mg, 0.36 mmol) is added in one portion to a solution of DMF (6 mL) containing E (93 mg, 0.24 mmol) at room temperature. The resulting solution is heated at 40 0C for 2-3 h (until TLC indicated complete consumption of E) and allowed to cool to room temperature. The reaction mixture is quenched by addition of a 5% aqueous solution of hydrochloric acid (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts are washed with brine (4 x 25 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to give crude F in quantitative yield. This material is used directly in the next synthetic step to prevent its oxidative degradation. LCMS mlz calcd for C16H15F2NO4S 355 ([M+]); found 356 ([M + H]+) Step 7. Synthesis of9-cyclopropyl-6,7-difluoro-8-methoxyisothiazolo[5,4-b]quinoline- 3,4(2H,9H)-dione (3).
A solution of sodium bicarbonate (820 mg, 9.8 mmol) in water (14 mL) is added to a solution of F (348 mg, 0.98 mmol) in tetrahydrofuran (10 mL) at room temperature. Hydroxylamine-O-sulfonic acid (465 mg, 4.1 mmol) is added in one portion to this mixture. The reaction mixture is stirred at room temperature for ~3 h and quenched by addition of an aqueous solution of 5% hydrochloric acid (100 mL). The precipitate that formed is collected by filtration, washed with water (3 x 5 mL), and dried in vacuo to give 3 as a white solid. This product is of sufficient purity (>95% by 1H NMR spectroscopy) to use directly in the final amine-coupling step. 1HNMR (300 MHz, DMSO-J6): Jl.12 (m, 4H, cyclopropyl CH2), 3.85 (m, IH, cyclopropyl CH), 4.01 (d, JH–F= 1.5 Hz, 3H, OCH3), 7.85 (dd, JH_F = 11.0 Hz, 9.0 Hz, IH, aromatic). 19F(1H) NMR (282 MHz, DMSO-J6): £-146.4 (d, JF_F = 23.0 Hz, IF), -140.2 (d, JF_ F = 23.0 Hz, IF). LCMS mlz calcd for C14H10F2N2O3S 324 ([M*]); found 325 ([M + H]+).
REFERENCES
- Achillion Pharmaceuticals. About ACH-702. Available online: http://www.achillion.com/PL/pdf/04_ach_702_bg.pdf (accessed on 2 May 2013).
- Pucci, M.J.; Podos, S.D.; Thanassi, J.A.; Leggio, M.J.; Bradbury, B.J.; Deshpande, M. In vitro and in vivoprofiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens. Antimicrob. Agents Chemother. 2011, 55, 2860–2871, doi:10.1128/AAC.01666-10.
- Achillion Pharmaceuticals, Inc. SEC filling form 10-Q quarterly report filed August 7, 2013. Available online: http://ir.achillion.com/secfiling.cfm?filingID=1193125–13–324297 (accessed on 28 September 2013).
- An efficient method for the synthesis of (R)-3-(1-amino-1-methylethyl)pyrrolidines for the antiinfective agent, PD 138312
Tetrahedron Asymmetry 1994, 5(7): 1131 - WO 2007014308
- WO 2008021491
-
WO2011031745A1 Sep 8, 2010 Mar 17, 2011 Achaogen, Inc. Antibacterial fluoroquinolone analogs -
HASHIMOTO, A. ET AL.: “Practical synthesis and molecular structure of a potent broad-spectrum antibacterial isothiazoloquinolone” ORG. PROCESS RESEARCH & DEVELOPMENT, vol. 11, 16 March 2007 (2007-03-16), pages 389-398, XP002465315 2 * WANG, Q. ET AL.: “Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains: Effects of Structural Modifications at the 6-, 7-, and 8-Positions” J. MED. CHEM., vol. 50, 2007, pages 199-210, XP002465316 -
WO2005019228A1 * Aug 4, 2004 Mar 3, 2005 Achillion Pharmaceuticals Inc Isothiazoloquinolones and related compounds as anti-infective agents WO2006118605A2 * Nov 10, 2005 Nov 9, 2006 Achillion Pharmaceuticals Inc 8a, 9-dihydro-4a-h-isothiazolo[5,4-b] quinoline-3, 4-diones and related compounds as anti-infective agents WO2007014308A1 * Jul 27, 2006 Feb 1, 2007 Achillion Pharmaceuticals Inc 8-methoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents -
Citing Patent Filing date Publication date Applicant Title WO2008021491A2 * Aug 16, 2007 Feb 21, 2008 Achillion Pharmaceuticals Inc Method for synthesis of 8-alkoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones WO2011031745A1 Sep 8, 2010 Mar 17, 2011 Achaogen, Inc. Antibacterial fluoroquinolone analogs EP2488532A2 * Oct 15, 2010 Aug 22, 2012 Rib-X Pharmaceuticals, Inc. Antimicrobial compounds and methods of making and using the same US7902365 Aug 16, 2007 Mar 8, 2011 Achillion Pharmaceuticals, Inc. Method for synthesis of 8-alkoxy-9H-isothiazolo[5,4-B]quinoline-3,4-diones US8138346 Mar 4, 2011 Mar 20, 2012 Achillion Pharmaceuticals, Inc. Method for synthesis of 8-alkoxy-9H-isothiazolo[5,4-B]quinoline-3,4-diones
MG 96077 in Pre-Clinical for Gram-negative bacteria
MG 96077
poster
MG96077 – MethylGene
………..http://methylgene.solocom.biz/files/2011/10/poster102.pdf ……………..lot of data presented
Mirati Therapeutics (USA)
Pre-Clinical for Gram-negative bacteria
Beta-Lactamase Inhibitors—Non-beta-Lactam Phosphonate-Based
Mirati Therapeutics is seeking partners to continue the development of the compound MG96077, a non-beta-lactam phosphonate-based beta-lactamase inhibitor that has shown an inhibitory profile for both class A and class C beta-lactamase enzymes [1,2].
Potent, irreversible inhibitor of serine β-lactamases that efficiently protects βlactams from hydrolysis in a variety of class
A- and class C-producing organisms-
 |
September 14, 2009 13:23 ET
MethylGene Presents Preclinical Data for Its Beta-Lactamase Inhibitor, MG96077, at the 49th Annual ICAAC Meeting
MONTREAL, QUEBEC–(Marketwire – Sept. 14, 2009) – MethylGene Inc. (TSX:MYG) today disclosed preclinical data for MG96077, a novel, broad spectrum, non-beta-lactam beta-lactamase inhibitor (BLI). MG96077 possesses a broad-spectrum inhibitory profile for both class A and class C beta-lactamase enzymes, including extended spectrum beta-lactamases (ESBLs). In addition, the compound overcomes resistance in beta-lactam-resistant organisms such as Pseudomonas aeruginosa. The data were presented in a poster session at the 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Annual Meeting in San Francisco, California.
Poster C1-1373: Novel Beta-Lactamase Inhibitor Potentiates and Extends the Antibacterial Activity of Imipenem against Beta-Lactam-Resistant P. aeruginosa and K. pneumoniae
MG96077 was tested in combination with imipenem, a commonly-used antibiotic agent for a variety of serious infections.
A series of in vitro and in vivo preclinical studies focused on comparing the combination of MG96077 and imipenem to imipenem alone, or imipenem plus currently approved BLIs, were performed. Greater than 90 percent of imipenem-resistant clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae were rendered susceptible with the addition of MG96077 to imipenem. The combination of imipenem and any of the three currently approved BLIs did not achieve greater than 61 percent coverage.
Furthermore, the combination of imipenem and MG96077 in vivo demonstrated 3-6 log reduction in colony forming units (CFU) and a 100 percent survival rate in combating imipenem-resistant P. aeruginosa infections of mouse spleen and lung. The pharmacokinetic properties of MG96077 were similar to imipenem in preclinical studies with no observable drug-drug interactions.
Thus, MG96077 is a novel beta-lactamase inhibitor that restores efficacy to imipenem against a high percentage of imipenem-resistant Pseudomonas and Klebsiella strains and, therefore, may address the clinical need for antibacterial therapies with more potent coverage of resistant gram-negative organisms.
MethylGene retains exclusive rights to MG96077 and a series of related molecules. Additional data has been developed regarding MG96077 compared to other beta-lactam antibiotics, as well as other compounds in the series paired with various beta-lactam antibiotics.
“Antibiotic resistance rates are increasing among several problematic gram-negative pathogens, including P. aeruginosa, K. pneumoniae, Acinetobacter spp. and Enterobacteriaceae that are often responsible for serious hospital-acquired infections. In these studies, MG96077 appears to demonstrate activity in a variety of organisms and we look forward to further evaluation of this compound in what is a growing antibiotic market in need of novel treatments,” said Donald F. Corcoran, President and Chief Executive Officer of MethylGene.
About MethylGene
MethylGene Inc. (TSX:MYG) is a publicly-traded, clinical stage, biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics with a focus on cancer. The Company’s product candidates include: MGCD265, an oral, multi-targeted kinase inhibitor targeting the c-Met, VEGF, Ron and Tie-2 receptor tyrosine kinases that is in Phase I and Phase II clinical trials for cancers; MGCD290, a fungal Hos2 inhibitor being developed for use in combination with fluconazole for serious fungal infections that is in Phase I clinical studies; and MGCD0103, an oral, isoform-selective HDAC inhibitor which has been in multiple clinical trials for solid tumors and hematological malignancies and is licensed to Taiho Pharmaceutical Co. Ltd. A fourth compound discovered using MethylGene’s HDAC platform, EVP-0334 – a potential cognition enhancing agent, is in a Phase I study sponsored by EnVivo Pharmaceuticals Inc. MethylGene also has a funded collaboration with Otsuka Pharmaceutical Co. Ltd. for applications in ocular diseases using the Company’s proprietary kinase inhibitor chemistry. Please visit our website at www.methylgene.com.
- Martell, L.A.; Rahil, G.; Vaisburg, A.; Young, K.; Hickey, E.; Hermes, J.; Dininno, F.; Besterman, J.M. A Novel Beta-Lactamase Inhibitor Potentiates and Extends the Antibacterial Activity of Imipenem against β-Lactam-Resistant P. aeruginosa and K. pneumoniae. In Proceedings of 49th ICAAC Annual Meeting, San Francisco, CA, USA, 14 September 2009.
- Mirati Therapeutics. MG96077. Available online: http://mirati.com/other-pipeline-assets/mg96077(accessed on 9 July 2013).
- 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Annual Meeting in San Francisco, California.
Poster C1-1373: Novel Beta-Lactamase Inhibitor Potentiates and Extends the Antibacterial Activity of Imipenem against Beta-Lactam-Resistant P. aeruginosa and K. pneumoniae
FALDAPREVIR
FALDAPREVIR
801283-95-4
(1R,2S)-1-{[(2S,4R)-4-[{8-bromo-7-methoxy-2-[2-(2-methylpropanamido)-1,3-thiazol-4-yl]quinolin-4-yl}oxy]-1-[(2S)-2-{[(cyclopentyloxy)carbonyl]amino}-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamido]-2-ethenylcyclopropane-1-carboxylic acid
Boehringer Ingelheim (Originator)
BI-201335 is an HCV NS3 protease inhibitor awaiting approval in the E.U. by Boehringer Ingelheim for the treatment of chronic hepatitis C, in combination with pegylated Interferon and ribavirin.
Faldaprevir (formerly BI 201335) is an experimental drug for the treatment of hepatitis C. It is being developed by Boehringer-Ingelheim and is currently in Phase III trials.[1]
Faldaprevir is a hepatitis C virus protease inhibitor.
Faldaprevir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including BI 207127.
Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of faldaprevir, BI 207127, and ribavirin performed well in HCV genotype 1b patients.[2] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.
- Efficacy and Safety of BI 201335 (Faldaprevir) in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients (STARTverso 1). Cliicaltrials.gov. March 6, 2013.
- Interferon-free hepatitis C treatment with faldaprevir proves safe and effective in people with cirrhosis. Alcorn, K. Aidsmap.com. 20 November 2012.
Phase II clinical trials are also ongoing for the treatment of patients with chronic genotype-1a hepatitis C virus (HCV) infection, in combination with PPI-668 and BI-207127.
In 2007, fast track designation was assigned to the compound in the U.S. for the treatment of chronic genotype-1 hepatitis C (HCV).
Protease inhibitors that are active against NS3/4a are a fertile area of research, not least because of the early promise shown by the two already-approved agents
FaldaprevirProtease inhibitors that are active against NS3/4a are a fertile area of research. Boehringer Ingelheim’s compound faldaprevir is currently in Phase III trials.1 In one 24-week trial in 429 treatment-naïve patients with genotype-1 hepatitis C infection, subjects were given standard peg-interferon and ritonavir therapy plus placebo, or standard therapy plus either 120mg or 240mg of faldaprevir either with or without a three day lead-in of standard therapy alone, or standard therapy plus the higher dose of faldaprevir.
ADDN LIT
Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)
J Med Chem 2010, 53(17): 6466
WO 2010033444
WO 2004103996
| US6323180 | Aug 5, 1999 | Nov 27, 2001 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| US7514557 * | May 23, 2005 | Apr 7, 2009 | Boehringer Ingelheim International Gmbh | Process for preparing acyclic HCV protease inhibitors |
| US7585845 * | May 20, 2004 | Sep 8, 2009 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
| US20050020503 * | May 20, 2004 | Jan 27, 2005 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
| US20120059033 | Mar 9, 2011 | Mar 8, 2012 | Boehringer Ingelheim International Gmbh | Crystalline Salts of a Potent HCV Inhibitor |
| USRE40525 | Sep 30, 2005 | Sep 30, 2008 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor tri-peptides |
| WO2000009543A2 | Aug 9, 1999 | Feb 24, 2000 | Boehringer Ingelheim Ca Ltd | Hepatitis c inhibitor tri-peptides |
| WO2004087741A1 | Mar 25, 2004 | Oct 14, 2004 | Boehringer Ingelheim Int | Crystalline phases of a potent hcv inhibitor |
| WO2004103996A1 | May 19, 2004 | Dec 2, 2004 | Boehringer Ingelheim Int | Hepatitis c inhibitor compounds |
| WO2011112761A1 | Mar 10, 2011 | Sep 15, 2011 | Boehringer Ingelheim International Gmbh | Crystalline salts of a potent hcv inhibitor |
………………………………………….
EXAMPLES Example 1 Preparation of Quinoline Starting Material Compound 11
Step 1
The dianion of amide 1 (prepared exactly as described above, from 1.00 g amide 1) was cooled to −78° C., then 2.19 mL perfluorooctyl bromide (8.46 mmol, 1.75 eq.) was added dropwise via syringe over 5 minutes. The dark-colored reaction mixture was then placed in a −10° C. bath. After two hours, 10 mL 1N HCl was cautiously added, and the mixture extracted with EtOAc (2×25 mL), dried (MgSO4), and the solvents removed in vacuo. The residue was then chromatographed on silica gel eluting with 4:1 Hexane:EtOAc to give 1.13 g bromoamide 5 (81%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 8.12 (br s, 1H), 8.04 (dd, J=1.3, 8.4 Hz, 1H), 7.24 (t, J=8.3 Hz, 1H), 6.63 (dd, J=1.3, 8.3 Hz, 1H), 3.87 (s, 3H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 176.57 (s), 155.74 (s), 136.98 (s), 128.34 (d), 113.63 (d), 106.86 (d), 103.07 (s), 56.26 (q), 40.20 (s), 27.45 (q).
Step 2
0.25 g bromoamide 5 (0.87 mmol, 1 eq.), 2.0 mL con. HCl (24 mmol, 28 eq.), and 1.0 mL diglyme were heated at 100° C. for 24 hours. The mixture was then cooled and filtered (product). The filtrate was evaporated in vacuo using H2O to azeotropically remove all solvents. The residue was triturated with EtOAc to cause precipitation of additional product, which was also filtered. The combined solids were dried to give 0.16 g (77%) of bromoaniline 6.HCl as a light brown solid. 1H NMR (400 MHz, CDCl3) δ: 7.09 (t, J=8.1 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H), 3.84 (br s, 2H), 3.77 (s, 3H).
Step 3
Bromoanisidine.HCl (5.73 g, 24.0 mmol), Aluminumtrichloride (3.52 g) and chlorobenzene (15.0 mL) are charged into an oven dried 100 mL three necked flask at rt (temperature rise to 30° C.). The resulting mixture is then stirred for 10 min then cooled to 0-5° C. followed by slow addition of acetonitrile (1.89 mL, 36.0 mmol) followed by addition of BCl3 (2.82 g), transferred as gas (or liquid) into the reaction mixture, keeping the temperature below 5° C. The resulting mixture is then stirred at rt for 20 min then heated to 85-100° C. for 16 h. HPLC indicate completion of the reaction (SM<0.5% at 220 nm). The mixture is cooled down to 50° C. then Toluene (15 mL) was added followed by slow addition of IPA (11.1 mL) then slow addition of water (32 mL) at 50° C. The resulting mixture stirred for additional 2 h at this temperature then 3 g Celite was added and the stirred mixture cooled to rt. Filtration then wash of the organic fraction with water 1×15 mL, 2×15 m: 5% NaHCO3, 1×15 mL water then concentration under reduced pressure provided 3.92-4.4 g of the desired product in 68-72% isolated yield. 1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J=9.0 Hz, 1H), 7.1 (br s, 2H), 6.28 (d, J=9.1 Hz, 1H), 3.94 (s, 3H), 2.55 (s, 3H).
Step 4
Oxalyl chloride (8.15 mL) is added dropwise to the cold mixture (10±5° C.) of Thiazole acid 8 (20.18 g) is dissolved in THF (300 mL) and DMF (300 μL) over a period of ˜5 min keeping the internal temperature at 10±5° C. The reaction mixture becomes yellow and homogenous. The cooling bath is removed and the mixture is allowed to reach ambient temperature over a period of ˜30 min. Gas evolution is observed. The mixture is stirred at ambient temperature for 30 min to 1 hour. A solution of aniline 7 (19.8 g), DMAP (140 mg) and THF (35 mL) was added at 10±5° C. Et3N (13.2 mL) was added in portions at 10±5° C. over a period of 10 min. The ice bath was removed and mixture was heated to 65±2° C. and stirred overnight (18 h). The mixture was allowed to reach ambient temperature, diluted with EtOAc (150 mL) and washed with water (150 mL). NaHCO3(5%, 225 mL) was added to the organic portion and the mixture was stirred at ambient temperature for 30 min. The organic portion was concentrated under reduced pressure at approx. 40° C. EtOAc (150 mL) was added to the resulting material and the residual water was removed and the mixture was concentrated under reduced pressure at approx. 40° C. (to azeotrope water). EtOAc (94 mL) was added and the resulting slurry was stirred for 2-6 h and filtered. The solid was washed with EtOAc (30 mL) followed by heptane (30 mL) and air dried for 1 h to give the desired product in 70% yield.
1H NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=7.8 Hz), 2.58 (s, 3H), 2.65-2.72 (m, 1H), 3.98 (s, 3H), 6.83 (d, 1H, J=8.7 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.86 (s, 1H), 8.98 (bs, 1H), 10.13 (bs, 1H).
Step 5
In a 2 L flask was placed potassium t-butoxide (112 g). Dry DME was added at room temperature (exothermic: temperature went up to 35° C.). The resultant solution was heated to ca. 80° C., and amide (88 g) was added in 10 portions slowly so temperature was kept between 80-85° C. Upon completion, reaction mixture was stirred at 85° C. for 2 hours. Solid precipitated during the reaction. HPLC analysis indicated that the reaction was completed at this point (conversion: 100%). The reaction mixture was cooled to room temperature and then to 10° C. with a cool bath. Aqueous 2N HCl solution (ca. 500 ml) was added slowly so temperature was kept under 25° C. to quench the reaction mixture. pH was adjusted to 4-5. About 100 ml of water was added (Note: amount of water may need adjustment to facilitate filtration), and the resulting suspension was stirred at room temperature for 5-10 hours. Product was isolated by filtration, washing with THF and drying under vacuum. Yield: 81 g, 96% yield.
1H-NMR (400 M Hz, DMSO-d6): 1.14 (6H, d, J=6.8 Hz, i-Pr), 2.48 (1H, hept., J=6.8 Hz, i-Pr), 3.99 (3H, s, MeO), 6.75 (1H, s, H-3), 7.24 (1H, d, J=8.5 Hz, H-6), 8.10 (1H, d, J=8.5 Hz, H5), 8.22 (1H, s, H-5′), 9.87 (1H, s, OH), 12.40 (1H, s, amide NH).
Step 6
In a 100 ml flask was placed starting material quinoline (4.22 g) and dioxane (40 ml). POCl3 (4.6 g) was added, and the mixture was heated to 75° C. After 2 hours, HPLC showed the reaction finished (99.7% conversion). Reaction mixture was cooled to room temperature, and then poured to 100 ml saturated NaHCO3 solution and 20 ml EtOAc. The resulting suspension was stirred for 3 hours. Product was isolated by filtration, washing with EtOAc and drying under vacuum. Yield: 4.0 g, 90.9%.
1H-NMR (400 M Hz, CDCl3): 1.14 (6H, d, J=6.8 Hz, i-Pr), 2.76 (1H, hept., J=6.8 Hz, i-Pr), 4.05 (3H, s, MeO), 7.68 (1H, d, J=8.5 Hz, H-6), 8.07 (1H, s, H-3), 8.13 (1H, s, H-5′), 8.20 (1H, d, J=8.5 Hz, H5), 12.30 (1H, s, amide NH).
Example 2 Preparation of Dipeptide Acid Compound 13 Starting Material
A 250 mL 3-neck flask with a thermocouple, nitrogen inlet, and magnetic stir bar was charged with N-cyclopentyloxy carbonyl-tert-L-leucine (20.0 g, 82.2 mmol, 1.0 eq.), 1-hydroxy-benzotriazole (12.73 g, 90.42 mmol, 1.1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.33 g, 90.42 mmol, 1.1 eq.) The flask was purged with nitrogen, and the stiffing started. Anhydrous DMF (62 mL) was added to the flask and the mixture was stirred for 20 minutes at room temperature (about 24° C.). The reaction was mildly exothermic, the internal temperature rose to 29° C. Solid trans-4-hydroxyproline methyl ester HCl (14.93 g, 82.2 mmol, 1.0 eq) was added to the reaction in one portion. Using a syringe, diisopropyl ethyl amine (14.36 mL, 82.2 mmol, 1.0 eq) was added to the reaction dropwise over 25 min. The internal temperature rose to 34.5° C. from 29° C. The reaction was stirred for 1.75 h, forming 12. The reaction was then quenched with 0.1 M HCl (100 mL), the internal temperature rose to 34° C. The reaction was extracted three times with 75 mL of ethyl acetate, and the organic layers were combined. The organic layer was washed with 75 mL H2O, and 2×75 mL of sat. NaHCO3. The organic layer (about 235 mL) was transferred to a 500 mL flask fitted with a mechanical stirrer, shortpath distillation head, internal and external thermocouples, and distilled to minimal stirrable volume under house vacuum (˜110 mm Hg) below 35° C. internal temperature with an oil bath temperature of 40° C. To this crude mixture of 12 was then added tetrahydrofuran (150 mL) and it was distilled to minimum stirrable volume. Tetrahydrofuran (100 mL) was added to the flask, and it was again distilled to minimum stirrable volume. The distillation head was replaced with an addition funnel. Tetrahydrofuran, (100 mL) and methanol (50 mL) were added to the flask, and the solution stirred for about 15 minutes. A 3.2 M solution of LiOH (77 mL, 246.6 mmol, 3 eq.) was charged to the addition funnel, and added over 45 minutes. The temperature rose from 22° C. to 29° C., and the reaction mixture became slightly cloudy. The mixture was cooled in a cold water bath, then the reaction was quenched by slow (45 min.) addition of 4 M HCl (58-65 mL) to adjust the pH to 3.5, causing a slight increase in temperature to 27° C. The flask was fitted with a distillation head, and the methanol and tetrahydrofuran were removed by distillation at reduced pressure, with a bath temperature of 40° C., internal temperature below 30° C. The mixture was extracted twice with 150 mL of MTBE. The MTBE solution was concentrated at reduced pressure, (350 mmHg) to minimum stirrable volume. 50 mL of MTBE was added, it was removed by distillation, internal temp below 35° C. The reaction was a clear viscous liquid, 20 mL of MTBE was added, the mixture was heated to 50° C., solution was clear, the oil bath was turned off, and the solution cooled to rt, ˜24° C. over 1.5 h. To the resultant slurry was then added 60 mL MTBE, stirred 2 h, then the slurry was filtered, using ˜20 mL MTBE to transfer the mixture. The solid was then dried under vacuum at 35° C. to constant weight, 16.4 g (52%), to give the ⅓ MTBE solvate compound 13 as a colorless solid, m.p. 117-124° C.; αD=−58.6 (c 2.17, MeOH); 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 6.76 (d, J=9.3 Hz, 1H), 5.15 (s, 1H), 4.92 (m, 1H), 4.31 (br s, 1H), 4.26 (t, J=8.3 Hz, 1H), 4.19 (d, J=9.3 Hz, 1H), 3.63 (m, 2H), 3.06 (s, 1H, (MTBE)), 2.08 (m, 1H), 1.87-1.48 (m, 9H), 1.09 (s, 3H, (MTBE)), 0.92 (s, 9H).
Example 3 Preparation of Tripeptide Acid Compound 16 Starting Material
In a 25 ml flask 14 was dissolved in 3 ml DMF. HOBt (149 mg, 1.1 mmol), EDC (211 mg, 1.1 mmol), 13 (290 mg, 1.0 mmol) and i-Pr2NEt (129 mg, 1.0 mmol) were added in the given order at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 15 ml aqueous NaHCO3 and extracted with ethyl acetate (20 ml). The organic layer was washed with HCl (0.5 N, 2×10 ml) and saturated aqueous NaHCO3 (10 ml). After removal of solvent by rotary evaporation, 15 was obtained as a white solid. 0.46 g (95% yield). 1H-NMR (400 M Hz, CDCl3): 0.96 (s, 9H), 1.35 (1H, dd, J=3.0, 4.5 Hz), 1.45-1.90 (m, 9H), 1.77 (1H, dd, J=3.0, 4.0 Hz), 2.00-2.09 (1H, m), 2.45-2.52 (1H, m), 3.02 (1H, br), 3.50 (1H, dd, J=11.0, 3.0 Hz), 3.58 (3H, s), 3.99 (1H, d, J=11.0 Hz), 4.18 (1H, d, J=9.0 Hz), 4.43 (1H, br), Hz), 4.63 (1H, t, J=8.0 Hz), 4.93-5.00 (1H, m), 5.04 (1H, dd, J=10.5, 2.0 Hz), 5.20 (1H, d, J=18.0 Hz), 5.20-5.25 (1H, m), 5.65-5.77 (1H, ddd, J=18.0, 10.5, 2.0 Hz), 7.78 (1H, br) ppm.
320 mg ester 15 (0.667 mmol, 1 eq.) was dissolved in 6.7 mL THF+3.4 mL MeOH at ambient temperature under N2. To this solution was then added 3.34 mL 1.6 M LiOH (5.34 mmol, 8 eq.) dropwise over 5 minutes. After 1.5 hours, the solvents were removed in vacuo, and the residue diluted with 15 mL EtOAc+10 mL sat’d NaCl, then 1N HCl was added until pH 3.45 was reached. The phases were separated and the aqueous phase reextracted with 15 mL EtOAc. The combined EtOAc layers were washed with H2O (1×50 mL), dried (MgSO4), and the solvents removed in vacuo to give an oil. The oil was azeotroped with MTBE (1×15 mL), and the residue dried under high vacuum to give 320 mg of 16 (100%) as a colorless foam. Exact mass calc’d for C23H35N3O7: 465.25. Found (ES−): 464.29; 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 12.40 (br s, 1H), 8.49 (s, 1H), 6.77 (d, J=8.2 Hz, 1H), 5.71 (m, 1H), 5.22-4.85 (m, 4H), 4.36-4.10 (m, 3H), 3.80-3.21 (m, 4H), 2.00-1.42 (m, 11H), 0.92 (s, 9H).
Example 4 Dipeptide SNAr Approach to Amorphous Compound (1)
SNAr Protocol 1: A 100 mL 3-neck round bottom flask was charged with 1.93 g 13 (5.00 mmol, 1 eq.), then evacuated/Ar filled (3×), then 17.0 mL DMSO was added via syringe to give a clear, colorless solution. The flask was again evacuated/Ar filled (3×), then 2.53 g t-BuOK (22.5 mmol, 4.5 eq.) was added neat, at once. An exotherm to a maximum of 31.5° C. was observed. The flask was evacuated/Ar filled (3×), then stirred under house vacuum (˜60 mm) for one hour, and some foaming (-t-BuOH) was observed. The vacuum was relieved to Ar, then 2.20 g 11 (5.00 mmol, 1 eq.) was added neat, at once. An exotherm to 28.6° C. was observed. The flask was evacuated/Ar filled (3×), then stirred under house vacuum protected from light at ambient temperature. After 6.5 h the vacuum was relieved to Ar and a sample removed for HPLC, which showed <2% unreacted 11. The flask was then cooled in a cold water bath to 18° C., and 1.72 mL glacial HOAc (30 mmol, 6 eq.) was then added via syringe over ˜10 minutes. An exotherm to 20.5° C. was observed. The mixture was stirred for 10 minutes, then added dropwise over 15 minutes into a second flask containing a well-stirred solution of 30 mL pH 3.5H2O (˜0.001M HCl) at 18° C., causing a precipitate to form immediately, and giving an exotherm to 21.0° C. 2.0 mL DMSO was used to wash the residue into the aqueous mixture, followed by a wash of 5.0 mL ˜0.001M HCl. The resulting suspension was stirred for 15 minutes, then 30 mL of a 1:1 mixture of EtOAc:MTBE was added, and the mixture agitated vigorously for 15 minutes. Agitation was stopped and the phases were allowed to separate. Rapid phase separation and formation of 2 clear phases with no rag layer was seen. The lower aqueous phase was then reextracted with 30 mL of 1:1 EtOAc:MTBE (same fast separation), and the organic extracts were combined and saved. The aqueous phase was discarded as waste.
The organic solution was then washed with H2O (3×30 mL), again all extractions gave rapid separation of phases and no rag layer, then the EtOAc was distilled to minimal stirrable volume. The residue was then azeotroped with 30 mL THF (2×), again distilling to minimal stirrable volume. The resultant slurry of crude 18 was used immediately in the peptide coupling. Exact mass calc’d for C34H42BrN5O8S: 759.19. Found (MS−): 757.92.
SNAr Protocol 2: 1.00 g 13 (2.59 mmol, 1 eq.) and 1.35 g 11 (2.59 mmol, 1 eq.) were charged to a dry flask. The flask was then evacuated/Ar filled (3×), then 10 mL dry DMSO was added via syringe. The flask was again evacuated/Ar filled (3×), then cooled to 19° C. with a cold water bath. To this mixture was then added a 2M solution of KDMO/heptane (5.71 mL, 11.7 mmol, 4.5 eq.) dropwise over 30 minutes. After six hours, HPLC showed the reaction as complete. The reaction was quenched with 0.89 mL HOAc (6 eq.), and added slowly to 25 mL stirring H2O, causing a precipitate to form. The mixture was then extracted with IPAc (2×25 mL). The combined IPAc phases were washed with H2O (1×25 mL), dried (MgSO4), and the solvents removed in vacuo to give a solid, which was azeotroped with MeCN (1×25 mL), and then diluted with heptane to give a slurry. The slurry was filtered and dried to give 1.80 g 18 (91%).
Peptide Coupling Protocol 1: To the THF slurry of crude 18 from SNAr Protocol 1 (taken as 5.00 mmol, 1 eq.) under Ar at ambient temperature in a flask protected from light was added 1.72 g 14 (5.5 mmol, 1.1 eq.) and 25 mL THF. The solution was then cooled to 5° C. under Ar, then 0.958 mL DIEA (5.50 mmol, 1.1 eq.) was added dropwise via syringe over 5 minutes. 5 minutes after the DIEA addition was completed, 0.85 g HOBT hydrate (6.00 mmol, 1.2 eq.), and 1.05 g EDC (5.50 mmol, 1.1 eq.) was then added neat, at once. The flask was then removed from the cold bath and the resultant mixture was then stirred at ambient temperature under Ar for 4 hours. A sample was withdrawn for HPLC which showed <2% unreacted 18 remained. The mixture was cooled to 5° C., then 40 mL 0.1N HCl was added dropwise via addition funnel over 5 minutes, followed by 40 mL EtOAc. The mixture was well agitated for 15 minutes, then agitation was stopped and the phases were allowed to separate. The lower aqueous phase was then reextracted with 40 mL EtOAc and the organic phases were combined and saved. The aqueous phase was discarded as waste. The organic solution was then washed with H2O (1×40 mL), sat’d NaHCO3 (2×40 mL), and again H2O (1×40 mL), then distilled to minimal stirrable volume. The residue was then azeotroped with MTBE (2×40 mL), and again distilled to minimal stirrable volume. The residue was dried under high vacuum to give 4.70 g of crude 19 as an orange solid, with HPLC purity of 78.3%. This material was then chromatographed on silica gel eluting with 2:1 EtOAc:Hexane to give 3.01 g (68% over 2 steps) pure 19 as a yellow powder. Exact mass calc’d for C41H51BrN6O9S: 882.26, MS+: 883.30. 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 12.32 (s, 1H), 8.69 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 5.65 (m, 1H), 5.40 (s, 1H), 5.20 (dd, J=1.5, 17 Hz, 1H), 5.06 (dd, J=1.6, 10.2 Hz, 1H), 5.56 (s, 1H), 4.46 (m, 1H), 4.37 (d, J=9 Hz, 1H), 4.08 (m, 1H), 3.99 (s, 3H), 3.90 (m, 1H), 3.56 (s, 3H), 2.81 (m, 1H), 2.51 (m, 1H), 2.25 (m, 1H), 2.07 (m, 1H), 1.70-1.32 (m, 7H), 1.30 (m, 3H), 1.15 (d, J=8.1 Hz, 6H), 0.95 (s, 9H).
Peptide Coupling Protocol 2: A 5 L 4-neck RBF fitted with mech. stirrer, addition funnel, and thermocouple was charged with 69.57 g 14 (222 mmol, 1.3 eq.), then evacuated/Ar filled (3×). To this was then added a 200 mL THF solution of 18 (contains 129.85 g 171 mmol, 1 eq.), then 523 mL THF was charged to bring the final THF volume to 1 L. The mixture was then cooled to 4.0° C. under Ar. 38.67 mL DIEA (222 mmol, 1.3 eq.) was then added dropwise via addition funnel over 10 minutes, as the internal temperature fell to 2.4° C. The mixture was aged 5 minutes, then 29.98 g HOBT H2O (222 mmol, 1.3 eq.) was added, followed by 42.57 g EDC (222 mmol, 1.3 eq.). The internal temperature was then 3.6° C. The bath was then removed. The internal temperature rose to 20.5° C. over 90 minutes. 4 h after the EDC addition was completed, HPLC showed the reaction was complete. The mixture was cooled to 4.0° C., then 750 mL 0.1N HCl was added over 30 minutes via addition funnel, giving an exotherm to 9.5° C. To this mixture was then added 250 mL sat’d NaCl, followed by 1 L IPAc. After 5 min. vigorous stirring, the mixture was added to a separatory funnel, and the phases were separated. The lower aq. phase was then reextracted with 500 mL IPAc, and the IPAc phases combined. These were then washed successively with H2O (1×1 L), sat’d NaHCO3 (1×1 L), and then H2O (1×1 L). The mixture was then mech. stirred for 12 h to precipitate quinoline 7. The mixture was then filtered through a medium-fritted funnel, and the filtrate distilled until minimal stirrable volume was reached. The residue was then azeotroped with MTBE (2×400 mL), and again distilled to minimal stirrable volume. The residue was dried under high vacuum to give 128 g of 19 as a yellow solid, with HPLC purity of 89%.
140 mg 19 (0.158 mmol, 1 eq.) was dissolved in 1.6 mL THF+0.80 mL MeOH at ambient temperature under N2. To this solution was then added 0.79 mL 1.6 M LiOH (1.27 mmol, 8 eq.) dropwise over 5 minutes. After 1.5 h, the organic solvents were removed in vacuo, and the residue diluted with 10 mL EtOAc+10 mL sat’d NaCl. The pH was then adjusted to 5.75 with 1N HCl. The mixture was agitated vigorously for one hour, then the phases were separated. The aqueous phase was reextracted with 10 mL EtOAc. The combined EtOAc phases were then washed with H2O (2×25 mL), dried (MgSO4, and the solvents removed in vacuo to give 125 mg of Compound (1) (91%) as an amorphous yellow powder.
Example 5 Tripeptide SNAr Approach to Amorphous Compound (1)
233 mg tripeptide acid 16 (0.50 mmol) was charged to a flask, then the flask was evacuated/Ar filled (3×). 1.7 mL DMSO was then added, and the mixture evacuated/Ar filled (3×). The mixture was then cooled in a cold water bath, then 317 mg t-BuOK (2.82 mmol, 5.63 eq.) were added. The flask was again evacuated/Ar filled (3×), then stirred under 60 mm vacuum for one hour. 220 mg quinoline 11 (0.50 mmol, 1 eq.) was then added, and the flask evacuated/Ar filled (3×), then stirred under 60 mm vacuum in the dark at ambient temperature for 3 hours. 0.30 mL HOAc was then added, then the resulting solution was added to 25 mL 0.001 M HCl, causing a precipitate to form. The slurry was filtered, washing the solids with 25 mL H2O. The solid was dried under N2 for 2 hours, then chromatographed on silica gel eluting with EtOAc to give 226 mg (52%) of Compound (1) as an amorphous yellow solid.
Additional methods for preparing amorphous Compound (1) can be found in U.S. Pat. Nos. 6,323,180, 7,514,557 and 7,585,845, which are herein incorporated by reference.
Example 6 Preparation of Type A of Compound (1)
Amorphous Compound (1) (Batch 7, 13.80 g) was added to a 1000 ml three neck flask. Absolute ethanol (248.9 g) was added to the flask. While stirring, the contents of the flask were heated at 60 degrees C./hr to ˜74 degrees C. (Solids do not dissolve at 74 degrees C.). Water (257.4 g) was then added linearly over 4 hr to the resulting slurry while stirring and maintaining the temperature at 74 degrees C. After the water addition was complete, the temperature was reduced linearly to ambient temperature at 8 degrees C./hr and then held at ambient temperature for 6 hrs while stiffing. The resulting solids were collected by filtration and washed with 50 ml of 1/1 (w/w) EtOH/Water. The wet solids were dried on the funnel for 30 minutes by sucking N2 through the cake. (XRPD analysis on this sample indicates that the pattern is similar to the EtOH solvate). The solids were then dried at 65-70 degrees C. under vacuum (P=25 in Hg) and a nitrogen bleed for 1.5 hr. The resulting solids (12.6 g, 95.5% corrected yield) were confirmed by XRPD as being Type A Compound (1).
The unique XRPD pattern and DSC curve of Type A Compound (1) is shown in FIGS. 1 and 2.
Example 7 Preparation of the Sodium Salt of Compound (1)—Method 1
2.1 g of amorphous sodium salt of Compound (1) and 8.90 g of acetone was added to a vial and stirred at ambient temperature for 3 hr. The slurry was filtered off mother liquors and the resulting solids were dried for 20 minutes under nitrogen flow for 20 minutes. 1.51 g of crystalline sodium salt of Compound (1) as solids was collected.
Example 8 Preparation of the Sodium Salt of Compound (1)—Method 2
15.6 g of Type A of Compound (1), 175 ml of acetone and 3.6 ml of water was added to a 250 ml reactor and heated to 53 degrees C. to dissolve the solids. 900 ul of 10.0 N NaOH was added to reactor and the solution was seeded with Type A. The seeded solution was stirred at 53 degrees C. for 10 minutes. A second 900 ul portion of 10.0 N NaOH was added and the system was stirred at 53 degrees C. for 30 minutes over which a slurry developed. The slurry was cooled to 19 degrees C. at a cooling rate of 15 degrees C. per hour and held overnight at 19 degrees C. The final resulting slurry was filtered and the wet solids were washed with 15 ml of acetone. Dried solids for 1 hr at 52 degrees C. under vacuum with a nitrogen flow and then exposed the solids to lab air for one hour. Collected 12.1 g of Compound (1) crystalline sodium salt solids.
Example 11 Preparation of the Sodium Salt of Compound (1)—Method 5
At room temperature a solution of sodium ethoxide in ethanol (21 weight %; 306 ml) was added to a solution of Compound (1) (745 g) in THF (2000 ml) and water (76.5 ml) while stiffing. After stiffing for 30 minutes, the mixture was filtered and the filter was washed with THF (85 ml). The resulting solution was warmed to 65° C. and treated with filtered butyl acetate (6640 ml, optionally pre-warmed to 65° C.) within 30 minutes. Seeding crystals (0.50 g) were added, and the mixture was stirred at 65° C. for 2 hours, while crystallization starts after about 30 minutes. The suspension was cooled to 50° C. within 1 hour and stirred at this temperature for an additional hour. The title compound was isolated by filtration, washed with filtered butyl acetate (765 ml, optionally pre-warmed to 50° C.) and dried at 65° C. for about 16 h giving Compound (1) crystalline sodium salt (˜725 g).
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| Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US8399484 | Sep 16, 2009 | Mar 19, 2013 | Boehringer Ingelheim International Gmbh | Combination therapy for treating HCV infection |
| US8530497 | Mar 9, 2011 | Sep 10, 2013 | Boehringer Ingelheim International Gmbh | Crystalline salts of a potent HCV inhibitor |
| WO2013144193A1 | Mar 27, 2013 | Oct 3, 2013 | Boehringer Ingelheim International Gmbh | Combination therapy for treating hcv infection in specific patient subgenotype sub-population |
Pimavanserin …New Drug Shows Early Promise in Treating Parkinson’s Psychosis
Pimavanserin, ACP 103
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide, 706779-91-1 cas
 706782-28-7 (tartrate) |
THURSDAY Oct. 31, 2013 — Many people living with Parkinson’s disease suffer from hallucinations and delusions, but an experimental drug might offer some relief without debilitating side effects.
READ ALL AT
http://www.drugs.com/news/new-shows-early-promise-treating-parkinson-s-psychosis-48630.html
The drug — pimavanserin — appears to significantly relieve these troubling symptoms, according to the results of a phase 3 trial to test its effectiveness.
Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6]
3-D MODEL OF DRUG PIMAVANSERIN, THE DEVELOPMENT OF WHICH HAS BEEN EXPEDITED BY THE FDA
- Friedman, JH (October 2013). “Pimavanserin for the treatment of Parkinson’s disease psychosis”. Expert Opinion on Pharmacotherapy 14 (14): 1969–1975.doi:10.1517/14656566.2013.819345. PMID 24016069.
- ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Retrieved 2009-04-11.[dead link]
- “ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
- Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. J Pharmacol Exp Ther 322 (2): 862–70.doi:10.1124/jpet.107.121715. PMID 17519387.
- Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacol Biochem Behav 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670.PMID 18534670.
- Abbas A, Roth BL (December 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opin Pharmacother9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345.
Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.
“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”
Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.
HERBERT MELTZER, MD, DESIGNED ACADIA PHARMACEUTICAL’S INITIAL PROOF OF CONCEPT TRIAL OF THE DRUG PIMAVANSERIN TO TREAT PARKINSON’S DISEASE PSYCHOSIS.
“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”
Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.
24 YEARS IN THE MAKING
The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.
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New Drug Approvals 