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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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CT 1812


img

CT-1812

Elayta

Condition(s): Alzheimer’s Disease
U.S. FDA Status: Alzheimer’s Disease (Phase 2)
Company: Cognition Therapeutics Inc.

CAS: 1802632-22-9
Chemical Formula: C24H33NO4S
Molecular Weight: 431.591

2-(tert-butoxy)-4-(3-methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol

Phenol, 4-[3-[1,3-dihydro-5-(methylsulfonyl)-2H-isoindol-2-yl]-3-methylbutyl]-2-(1,1-dimethylethoxy)-

  • Originator Cognition Therapeutics
  • Class Antidementias; Neuroprotectants; Nootropics; Small molecules
  • Mechanism of Action Sigma-2 receptor antagonists
  • Phase II Alzheimer’s disease
  • Phase I Cognition disorders
  • 21 Feb 2019 Cognition Therapeutics receives patent for a composition of matter patent covering Elayta™ in Europe
  • 19 Feb 2019 Pharmacokinetics and adverse events data from a phase I trial in Cognition disorders released by Cognition Therapeutics
  • 22 Oct 2018 CTP push 289675: Updated KDM, forwarded USA line from PI/II to PII

CT-1812 is a first-in-class, orally available sigma-2/PGRMC1 antagonist (alpha beta oligomer receptor antagonist), is being developed by Cognition. sCT-1812 is a novel therapeutic candidate for Alzheimer’s disease

SYN

BACKGROUND

CT1812 is a small-molecule antagonist of the sigma2 receptor, also known as the progesterone receptor membrane component 1. The rationale behind this therapeutic approach is that ligands for the sigma2/PGRMC1 receptor will compete with oligomeric Aβ binding to this receptor and thus interfere with Aβ-induced synaptic toxicity. CT1812 grew out of screening programs at Cognition Therapeutics. Company scientists have reported that compounds in this series not only block binding of a range of different Aβ species to this receptor but also displace it when applied after Aβ has bound (Dec 2014 conference news).

The structure of CT1812 has not been disclosed, but similar compounds in the series have been reported to enter the brain, occupy up to 80 percent of sigma2/PGRMC1 receptors, and restore behavioral deficits in APP transgenic mice (Izzo et al., 2014Izzo et al., 2014).

FINDINGS

From September 2015 to May 2016, Cognition Therapeutics ran a Phase 1 trial in 80 healthy volunteers aged 18 to 75 in Melbourne, Australia; target enrollment was originally listed as 114. Single-ascending-dose administration was followed by multiple ascending doses given once daily for two weeks. The dose range in this trial spanned 10 to 650 mg; if this would not generate data to set a maximum tolerated dose, doses up to 1,350 mg were to be tried. Outcome measures included safety, tolerability, plasma pharmacokinetics, and CSF CT1812 concentration. At the 2016 and 2017 AAIC conferences, company scientists reported that single doses up to 1,120 mg were given, as were multiple doses of up to 840 mg in young and up to 560 mg in elderly volunteers. The drug was reported to be well-tolerated, with suitable pharmacokinetics, sufficient brain penetrance and target exposure, and minimal drug-drug interactions affecting cytochrome P450 activity (Catalano et al., 2016Catalano et al., 2017).

From September 2016 to August 2017, Cognition Therapeutics ran a Phase 1/2 trial at four sites in Australia, enrolling 19 participants with mild to moderate Alzheimer’s disease supported by a recent MRI. It compared a four-week course of 90, 280, or 560 mg of CT 1812 to placebo, taken once daily, on safety and tolerability parameters. At the subsequent CTAD conference, Elayta was reported to have been generally safe and well tolerated, though there were four cases of lymphocytopenia. Exploratory measures such as ADAS-Cog14, verbal or category fluency tests recorded no difference between groups, but exploratory biomarker analyses yielded possible signals of synapse protection (Dec 2017 conference news).

In April 2018, a Phase 1/2 study started enrolling 21 people whose mild to moderate AD was confirmed by amyloid PET or CSF testing. Conducted at Yale University School of Medicine and dubbed COG0105 or SPARC, this trial will compare a six-month course of 100 or 300 mg of Elayta, or placebo. The primary outcome is cognition as assessed by the Alzheimer’s Disease Clinical Study Activities of Daily Living (ADCS-ADL), but the trial will also use the investigational PET tracer UCB-J, which binds to the synaptic vesicle glycoprotein 2A, in an attempt to monitor synapse density before and after treatment (see company press release; Jul 2016 news).

In summer 2018, a Phase 1b target engagement study at the University of Pennsylvania will start enrolling 18 people whose mild to moderate AD is confirmed by amyloid PET. Called COG0104 or SNAP, it will compare single injections of 90, 280, or 560 mg of Elayta or placebo for their ability to displace Aβ oligomers and clear them into the CSF, as measured by a CSF Aβ oligomer assay.

Also in summer 2018, a Phase 2 multi-center study is expected to begin enrolling 24 people with mild to moderate AD as confirmed by amyloid PET for a six-month course of 100 or 300 mg of Elayta, or placebo. As of May 22, 2018, this trial lists CT1812 pharmacodynamic effects on CSF biomarkers, specifically as assessed by CSF neurogranin levels, as primary outcome.

For all trials of this compound, see clinicaltrials.gov.

PATENT

WO 2015116923

https://patents.google.com/patent/WO2015116923A1

There are only five medications currently FDA-approved for the treatment of Alzheimer’s Disease (AD). Four are cholinesterase inhibitors: tacrine (COGNEX®; Sciele), donepezil (ARICEPT®; Pfizer), rivastigmine (EXELON®; Novartis), and galantamine (RAZADYNE®; Ortho-McNeil-Janssen). Donepezil, rivastigmine, and galantamine are successors to tacrine, a first generation compound rarely prescribed because of the potential for hepatotoxicity; they are roughly equally efficacious at providing symptomatic improvement of cognition and function at all stages of AD. The fifth approved medication is memantine (NAMENDA®; Forest), a low-affinity, use dependent N-methyl-D-aspartate glutamate receptor antagonist that offers similar benefits, but only in moderate to severe AD. The clinical effects of these compounds are small and impermanent, and currently available data are inconclusive to support their use as disease modifying agents. See, e.g., Kerchner et al, 2010, Bapineuzumab, Expert Opin Biol Ther., 10(7): 1121-1130. Clearly, alternative approaches to treatment of AD are required.

[004] Certain isoindoline compounds are provided that act as sigma-2 receptor functional antagonists and inhibit the deleterious effects of soluble Αβ oligomers. In some embodiments, isoindoline sigma-2 receptor antagonist compounds and compositions are used to treat or prevent synaptic dysfunction in a subject.

Example 21 illustrates representative preparation of 2-(Tert-butoxy)-

4-(3-methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol, Example Compound 62, as shown in Scheme 17.

Figure imgf000185_0001
Figure imgf000186_0001

10 Compound 62

[0534] Scheme 17: Procedure for preparation of 2-(Tert-butoxy)-4-(3- methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol, Example Compound 62.

[0535] Preparation of compound l(Scheme 17): To a glass pressure -bottle at -30 °C containing a mixture of catechol (50.0 g, 454 mmol, 1.0 eq), concentrated sulfuric acid (0.3 mL) in dichloromethane (200 mL), isobutene (152.6 g, 2.72 mol, 6.0 eq) was condensed. After sealing the pressure-bottle with a threaded Teflon cap tipped with a Teflon-protected rubber O-ring, the mixture was heated at 35 °C for 3 h until a clear solution was obtained. After cooling (-30 °C), triethylamine (1.5 mL, 10.8 mmol) was added and the mixture was concentrated. The residue was suspended in 0.5 M NaOH (1 L) and stirred for 10 min. The dark-green colored solution was washed with petroleum ether (2x 100 mL) and the washing layers were reextracted with 0.5 M NaOH (3x 100 mL). The combined aqueous layers were brought to pH 7-8 with 2 N HCl (400 mL), and extracted with ethyl acetate (2* 1 L), dried over sodium sulfate and concentrated to afford product 1 (67.7 g, 90%) as a colorless oil, which was used directly for the next step reaction without further purification. TLC: PE/EA = 50/1 ; Rf (Catechol) = 0.1 ; Rf (Compound 1) = 0.6.

[0536] Preparation of compound 2 (Scheme 17): To a stirred solution of compound 1 (1 12.2 g, 676 mmol, 1.2 eq) and potassium iodide (1 12.2 g, 676 mmol, 1.0 eq) in methanol (2 L) at 0 °C was slowly added sodium hydroxide (27.0 g, 676 mmol, 1.0 eq), followed with aqueous sodium chlorite (7% aq., 718.8 mL, 710 mmol, 1.05 eq) dropwise over 3 h while keeping the reaction below 0 °C. The mixture was stirred at 0 °C for another 30 min and neutralized by adding 2 N HCl at 0 °C till pH 7, extracted with DCM (2 x 1 L). The organic layers were dried over sodium sulfate and concentrated to afford product 2 (179.8 g, 91%). TLC: PE/EA = 50/1; Rf(Compound 1) = 0.6 ; Rf (Compound 2) = 0.6.

[0537] Preparation of compound 3(Scheme 17): To a stirred solution of compound 2 (179.8 g, 616 mmol, 1.0 eq) and triethylamine (186.6 g, 1.85 mol, 3.0 eq) in dichloromethane (2 L) at 0 °C was slowly added acetyl chloride (53.2 g, 677 mmol, 1.1 eq). The mixture was stirred at 0 °C for another 30 min, and warmed up to rt, and stirred at rt for 3 h, water (1 L) was added into the reaction mixture and the organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3 (206 g, 100%), which was used directly to the next step without further purification. TLC: PE/EA = 50/1; Rf (Compound 2) = 0.6; Rf (Compound 3) = 0.5.

[0538] Preparation of compound 4 (Scheme 17): To a stirred solution of compound 3 (206 g, 616 mmol, 1.0 eq) in triethylamine (4.0 L) was added 2- methylbut-3-yn-2-amine (102.5 g, 1.23 mol, 2.0 eq), Pd(PPh3)2Cl2 (15.1 g, 18.5 mmol, 0.03 eq) and copper(I) iodide (5.9 g, 31 mmol, 0.05 eq) and resulting mixture was stirred at rt for 17 h. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography to afford the title compound 4 (132.7 g, 74%). TLC: PE/EA = 1/1; Rf (Compound 3) = 0.9; Rf (Compound 4) = 0.3. [0539] Preparation of compound 5(Scheme 17): To a stirred solution of compound 4 (104.5 g, 0.36 mol) in ethanol (1.5 L) was added Pd/C (10% wt, 10.5 g). The mixture was stirred under hydrogen (balloon) overnight, and filtered. The filtrate was evaporated to dryness to afford compound 5 (106.3 g, 100%), which was used directly to the next step without further purification. TLC: PE/EA = 1/1; Rf(Compound 4) = 0.3 ; Rf (Compound 5) = 0.3.

[0540] Preparation of compound 6 (Scheme 17): To a solution of o-xylene

(115.7 g, 1.09 mol, 1.0 eq) in chloroform (1.0 L) at 0 °C was added C1S03H (254 g, 2.18 mol, 2.0 eq) dropwise. After the addition, the reaction mixture was stirred at room temperature for 2 days, and poured into ice. The crude mixture was extracted with dichloromethane (3 x 1.0 L). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to afford the crude compound 6 (161.5 g, 80%) as a white solid, which was used directly to the next step without further purification. TLC: PE/EA = 5/1; Rf (Compound 6) = 0.7.

[0541] General procedure for the preparation of compound 7 (Scheme

17): To a stirred solution of compound 6 (161.5 g, 0.87 mol, 1.0 eq) in saturated sodium sulfite solution (273 g, 2.17 mol, 2.5 eq, in 2.0 L of water) was added dropwise 32% NaOH (69.4 g, 1.73 mol, 2.0 eq) till the solution reached pH 9. After stirring at rt overnight, the reaction mixture was acidified with cone. HC1 in ice- cooling bath till pH 1. The precipitate was filtered, and washed with ice-water (2x), dried in vacuo to afford the crude product 7 (131 g, 88%), which was used directly for next step without further purification. TLC: PE/EA = 5/1; Rf (Compound 6) = 0.7; Rf (Compound 7) = 0.6.

[0542] Preparation of compound 8 (Scheme 17): To a stirred solution of compound 7 (130 g, 0.76 mol, 1.0 eq) and potassium carbonate (211 g, 1.53 mol, 2.0 eq) in DMF (300 mL) was added iodomethane (96 mL, 1.53 mol, 2.0 eq). The reaction was stirred at 40 °C overnight. The reaction mixture was evaporated to dryness, extracted with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and concentrated, purified by flash column chromatography (PE: EA,10: 1 ~ 5: 1) to afford compound 8 (85.2 g, 61%). TLC: PE/EA = 5/1; Rf (Compound 7) = 0.6; Rf (Compound 8) = 0.3. [0543] Preparation of compound 9 (Scheme 17):To a stirred solution of compound 8 (78.2 g, 424 mmol, 1.0 eq) in 1 ,2-dichloroethane (1.2 L), were added N-bromosuccinimide (166 g, 934 mmol, 2.2 eq) and AIBN (6.9 g, 42.4 mmol, 0.1 eq). The reaction was stirred at reflux overnight. The reaction was diluted with water and dichloromethane. The organic layer was collected, and dried over sodium sulfate and concentrated, purified by flash column chromatography to afford compound 9, which was further recrystallized from hot methanol to afford the pure product 8 (75 g, 52%). TLC: PE/EA = 5/1; Rf (Compound 8) = 0.3; Rf (Compound 9) = 0.2.

[0544] Preparation of compound 10 (Scheme 17):To a stirred solution of compound 5 (46 g, 157 mmol, 1.0 eq) and compound 9 (53.5 g, 157 mmol, 1.0 eq) in THF (460 mL) was added triethylamine (47.7 g, 472 mmol, 3.0 eq). The reaction was stirred at 40 °C overnight, filtered and the filtrate was evaporated to dryness and purified by flash column chromatography to afford compound 10 (45 g, 63%). TLC: PE/EA = 1/1; Rf (Compound 5) = 0.3; Rf (Compound 9) = 1.0; Rf (Compound 10) = 0.4.

[0545] Preparation of Compound 62 (Scheme 17):To a stirred solution of compound 10 (45 g, 98.4 mmol) in methanol (300 mL) was added sodium methoxide (844 mg, 15.6 mmol, 0.16 eq) in one portion. The solution was stirred at rt overnight. Water (250 mL) was added dropwise into the reaction mixture over 1 h, the mixture was stirred at rt for 2 h, and filtered. The white solid was collected and dried on vacuum overnight to afford pure example Compound 62 base (38 g, 89%>). TLC: PE/EA = 1/1; Rf (Compound 10) = 0.4; Rf (Compound 62) = 0.4; ESI-MS: 432 (M+l)+; 1H NMR (400 MHz, CDC13) δ 7.80-7.78 (m, 2H). 7.40-7.38 (m, 1H), 6.87-6.79 (m, 3H), 5.58 (s, 1H), 4.11 (s, 4H), 3.05 (s, 3H), 2.61-2.57 (m, 2H), 1.76- 1.72 (m, 2H), 1.48 (s, 9H), 1.18 (s, 6H). Example 22: Preparation of (2-(4-(4-Hydroxy-3-methoxyphenyl)-2- methylbutan-2-yl)isoindolin-4-yl)(piperazin-l-yl)methanone,

REFERENCES

1: Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ,
Guttendorf R, Higgin M, Pribyl J, Mozzoni K, Safferstein H, Catalano SM. A phase
1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a
novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y).
2019 Jan 23;5:20-26. doi: 10.1016/j.trci.2018.11.001. eCollection 2019. PubMed
PMID: 30723776; PubMed Central PMCID: PMC6352291.

Paper Citations

  1. A Two-Part, Double-Blind, Placebo-Controlled, Phase 1 Study of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Ct1812 in Healthy VolunteersAlzheimer’s & Dementia, July 2016, Volume 12, Issue 7, Supplement
  2. A Phase 1 Safety Trial of the aβ Oligomer Receptor Antagonist CT1812Alzheimer’s & Dementia, July 2017, Volume 13, Issue 7
  3. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficitsPLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.
  4. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicityPLoS One. 2014;9(11):e111899. Epub 2014 Nov 12PubMed.

/////CT-1812,  CT 1812, CT1812, Alzheimers , Cognition Therapeutics, Elayta, phase 2, Cognition disorders

OC1=CC=C(CCC(C)(N2CC3=C(C=C(S(=O)(C)=O)C=C3)C2)C)C=C1OC(C)(C)C

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Dipivefrine, дипивефрин , ديبيفيفرين , 地匹福林 , ジピベフリン


Dipivefrine.svg

ChemSpider 2D Image | Dipivefrin | C19H29NO5

Dipivefrine

  • Molecular FormulaC19H29NO5
  • Average mass351.437 Da
4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diyl bis(2,2-dimethylpropanoate)
52365-63-6 [RN]
(±)-3,4-Dihydroxy-a-[(methylamino)methyl]benzyl Alcohol 3,4-Dipivalate
1-(3′,4′-Dipivaloyloxyphenyl)-2-methylamino-1-ethanol
2,2-Dimethylpropanoic acid 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-phenylene ester
дипивефрин [Russian] [INN]
ديبيفيفرين [Arabic] [INN]
地匹福林 [Chinese] [INN]
ジピベフリン
4-[1-hydroxy-2-(methylamino)ethyl]-o-phenylene divavalate
D Epifrin [Trade name]
Diopine [Trade name]
MFCD00673243 [MDL number]
Pivalephrine [Trade name]
Pro-Epinephrine
Propine [Trade name]
Thilodrin [Trade name]
ATC:S01EA02
Use:antiglaucoma

Dipivefrine hydrochloride

CAS 64019-93-8 

Dipivefrine hydrochloride

  • Formula:C19H29NO5 • HCl
  • MW:387.90 g/mol

Dipivefrine (INN) or dipivefrin (USAN), trade name Propine among others, is a prodrug of epinephrine, and is used to treat open-angle glaucoma.[1][2] It is available as a 0.1% ophthalmic solution. It is no longer available in the United States.[3]

Dipivefrin is a prodrug with little or no pharmacologically activity until it is hydrolyzed into epinephrine inside the human eye. The liberated epinephrine, an adrenergic agonist, appears to exert its action by stimulating α -and/or β2-adrenergic receptors, leading to a decrease in aqueous production and an enhancement of outflow facility. The dipivefrin prodrug delivery system is a more efficient way of delivering the therapeutic effects of epinephrine, with fewer side effects than are associated with conventional epinephrine therapy. Dipivefrin is used as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma.

Image result for dipivefrine

Contraindications

Use in narrow-angle glaucoma may be dangerous because it could make the eye susceptible to an attack of angle closure,[2] causing an increase in pressure and pain, and possibly loss of vision.

Side effects

The most common side effects of dipivefrine are burning, stinging and other irritations of the eye. Possible, but uncommon, side effects are those of epinephrine: tachycardia (fast heartbeat), hypertension (high blood pressure) and arrhythmias (irregular heartbeat).[2]

Pharmacology

Dipivefrine penetrates the cornea and is then hydrolysed to epinephrine by esterase enzymes. It increases outflow of the aqueous humour and also reduces its formation (mediated by its action on α1 and α2 receptors), thus reducing pressure inside the eye. It also increases the conductivity of trabecular filtering cells (a β2 receptor mediated action). It is preferred to epinephrine because it is longer acting, more consistent in its action and better tolerated.[1]

Patent

https://patents.google.com/patent/CN102153485A/en

Image result for dipivefrine

Example 1 [0023] Embodiment

[0024] A 600g (3. 21mol) 4_ chloroacetyl catechol, the IOL 6L methylene chloride was added 4-neck flask, the system was cooled to 5 ° C, was added 666g (6. 58mol) of triethylamine, and then was added dropwise 784g (6. 5mol) pivaloyl chloride was added dropwise and stirring was continued after the pool. Filtered off with suction, the filtrate by rotary evaporation; to give 990g yellow-brown solid, 4- (2-chloroacetyl) -1,2-pivalate phenyl ester, the content of 96.2%. [0025] The 35mol) N- methyl amine section, 370g (3. 66mol) of triethylamine, 25g (0. 15mol) KI, 3L DMF was added 4-neck flask of the IOL. Cooled to 0 ° C, was added dropwise 990g (2. 8mol) 4- (2- chloroacetyl) -I, DMF solution tank 2-phenyl pivalate ester. At room temperature was stirred for 4h.

[0026] suction filtration, washed with water IOL filtrate was added 3 times, the organic phase was separated, the organic phase by rotary evaporation to give a yellow-brown oil; frozen stirring, the precipitated solid was suction filtered to give a solid 923. Og. I.e., 1- (3,4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) -1-one content of 96.5%.

[0027] Take 625g (1. 422mol) 1_ (3,4- two pivaloyloxymethyl phenyl) _2_ (N- benzyl-methylamino) ketone, 6L IOL of absolute ethanol was added 4-neck flask. Under cooling, was added 65g (1.71mol) of sodium borohydride. At room temperature was stirred for 4h. 500mL of water was slowly added to the system, then add ethyl acetate extract products. After solvent removal to give 552. 5g of solid particles, i.e. 1_ (3, 4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) ethanol, the content of 98.2%.

[0028] 1828 was added to the beaker (0.41211101) of 1- (3,4-pivaloyloxymethyl-phenyl) -2 – (^ -benzyl methylamino) ethanol, with ethanol and dissolved IL; to 2L autoclave was charged with 13g 5% palladium on carbon, infiltration system with IOOml ethanol, then added to the solution in a closed system. Through hydrogenation under hydrogen 2MPa pool.

[0029] suction filtered to remove palladium on carbon. The filtrate was twice filtered off with suction, the filtrate by rotary evaporation to give a yellow-brown oil; standing crystallization, the precipitated pale yellow solid was suction filtered to give a solid crude product.

[0030] After the solution was washed with methanol hydrochloride salt to give an off-white solid 119. 9g, dipivefrin i.e., the content of 98.9%.

[0031] m.p. 161 ~162 ° C;

[0032] 1H NMR (CDCl3) δ: 1. 35 (s, 18Η), 2 68 (s, 3Η), 3 07-3 13 (m, 2Η), 5 36-5 39 (m….. , 1H),

[0033] 7. 06-7. 30 (m, 3H), 8. 61 (s, 1H), 9. 48 (s, 1H)

Dipivefrin prepared: Example 2 [0034] Embodiment

[0035] A 600g (3. 21mol) 4_ chloroacetyl catechol, the IOL 6L methylene chloride was added 4-neck flask, the system was cooled to 10 ° C, was added 666g (6. 58mol) of triethylamine, and then dropwise 78½ (6. 5mol) pivaloyl chloride was added dropwise and stirring was continued after the pool. Filtered off with suction, the filtrate by rotary evaporation; 978. 2g to give yellow-brown solid, 4- (2-chloroacetyl) -1,2-pivalate phenyl ester, the content of 96. 2% o

[0036] The 35mol) N- methyl amine section, 370g (3. 66mol) of triethylamine, 25g (0. 15mol) KI, 3L DMF was added 4-neck flask of the IOL. Cooled to O0C, dropwise 978. 2g (2. 77mol) 4- (2- chloroacetyl) of DMF solution tank Laid-1,2-phenyl valerate. At room temperature was stirred for 4h.

[0037] suction filtration, washed with water IOL filtrate was added 3 times, the organic phase was separated, the organic phase by rotary evaporation to give a yellow-brown oil; frozen stirring, the precipitated solid was suction filtered to give a solid 910. 2g. I.e., 1- (3,4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) -1-one content of 96.3%.

[0038] Take 625g (1. 422mol) 1_ (3,4- two pivaloyloxymethyl phenyl) _2_ (N- benzyl-methylamino) ketone, 6L IOL of absolute ethanol was added 4-neck flask. Under cooling, was added 97g (l. SOmol) potassium borohydride. Stirred cell at room temperature. 500mL of water was slowly added to the system, then add ethyl acetate extract products. After solvent removal to give 532. 7g of solid particles, i.e. 1_ (3, 4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) ethanol, the content of 98.0%.

[0039] 1828 was added to the beaker (0.41211101) of 1- (3,4-pivaloyloxymethyl-phenyl) -2 – (^ -benzyl methylamino) ethanol, with ethanol and dissolved IL; to 2L autoclave was charged with 15g 5% palladium on carbon, infiltration system with IOOml ethanol, then added to the solution in a closed system. Through hydrogenation under hydrogen 2MPa pool.

[0040] suction filtered to remove palladium on carbon. The filtrate was twice filtered off with suction, the filtrate by rotary evaporation to give a yellow-brown oil; standing crystallization, the precipitated pale yellow solid was suction filtered to give a solid crude product.

[0041] After the solution was washed with methanol hydrochloride salt to give an off-white solid was 112. 8g, i.e., dipivefrin, content 98.6%.

3 [0042] Example 2: Preparation of dipivefrin

[0043] A 600g (3. 21mol) 4_ chloroacetyl catechol, the IOL 6L methylene chloride was added 4-neck flask, the system was cooled to 5 ° C, was added 897g (6. 5mol) of potassium carbonate, and then drops was added 784g (6. 5mol) pivaloyl chloride addition was completed stirring was continued Syndrome. Filtered off with suction, the filtrate by rotary evaporation; to give 900g yellow-brown solid, 4- (2-chloroacetyl) -1,2-pivalate phenyl ester, the content of 95.6%.

[0044] A 526g (4. 35mol) N_ methylbenzylamine, 414g (3. Omol) of potassium carbonate, 25g (0. 15mol) KI, 3L DMF force Λ IOL of four port flask. Cooled to O0C, was added dropwise 900g (2. 55mol) 4- (2- chloroacetyl) of DMF solution of 1,2-Shan Laid phenyl valerate. It was stirred at room temperature Mi.

[0045] The suction filtration, washed with water IOL filtrate was added 3 times, the organic phase was separated, the organic phase by rotary evaporation to give a yellow-brown oil; frozen stirring, the precipitated solid was suction filtered to give a solid 820g. I.e., 1- (3,4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) -1-one content of 95.6%.

[0046] Take 625g (1. 42mol) 1_ (3,4- two pivaloyloxymethyl phenyl) _2_ (N- benzyl-methylamino) ketone, 6L IOL of absolute ethanol was added 4-neck flask. Under cooling, was added 65g (1.71mol) of sodium borohydride. Stirred cell at room temperature. 500mL of water was slowly added to the system, then add ethyl acetate extract products. After solvent removal to give 512. 5g of solid particles, i.e. 1_ (3, 4-pivaloyloxymethyl-phenyl) -2- (N- benzyl-methylamino) ethanol, the content of 98.0%.

[0047] 1828 was added to the beaker (0.41211101) of 1- (3,4-pivaloyloxymethyl-phenyl) -2 – (^ -benzyl methylamino) ethanol, with ethanol and dissolved IL; to 2L autoclave was charged with 16g 5% palladium on carbon, infiltration system with IOOml ethanol, then added to the solution in a closed system. Through hydrogenation under hydrogen 2MPa pool.

[0048] suction filtered to remove palladium on carbon. The filtrate was twice filtered off with suction, the filtrate by rotary evaporation to give a yellow-brown oil; standing crystallization, the precipitated pale yellow solid was suction filtered to give a solid crude product.

[0049] After the solution was washed with methanol hydrochloride salt to give an off-white solid was 109. 8g, i.e., dipivefrin, content 98.5%.

SYN

Dipivefrin
CAS Registry Number: 52365-63-6
CAS Name: 2,2-Dimethylpropanoic acid 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-phenylene ester
Additional Names: (±)-3,4-dihydroxy-a-[(methylamino)methyl]benzyl alcohol 3,4-dipivalate; 1-(3¢,4¢-dipivaloyloxyphenyl)-2-methylamino-1-ethanol; dipivalyl epinephrine; DPE
Molecular Formula: C19H29NO5
Molecular Weight: 351.44
Percent Composition: C 64.93%, H 8.32%, N 3.99%, O 22.76%
Literature References: Dipivalyl ester of epinephrine, q.v. Prepn: D. Henschler et al., DE 2152058eidem, US 4085270 (1973, 1978 both to Klinge); A. Hussain, J. E. Truelove, DE 2343657eidem, US 3809714 and US 3839584 (all 1974 to Interx). In vitrostudy: A. H. Neufeld, E. D. Page, Invest. Ophthalmol. Visual Sci. 16, 1118 (1977). Pharmacology: B. C. Wang et al., J. Pharmacol. Exp. Ther. 203, 442 (1977). Effects on intraocular pressure in dogs: R. M. Gwin et al., Am. J. Vet. Res. 39, 83 (1978). Metabolism: I. Abramovsky, J. S. Mindel, Arch. Ophthalmol. 97, 1937 (1979). Clinical study: M. A. Kass et al., ibid. 1865. General pharmacology, toxicology and clinical experience in glaucoma: D. A. McClure, ACS Symp. Ser. 14, 224-235 (1975). Comprehensive description: G. M. Wall, T. Y. Fan, Anal. Profiles Drug Subs. Excip. 22, 229-262 (1993).
Properties: Crystals from ether, mp 146-147°.
Melting point: mp 146-147°
Derivative Type: Hydrochloride
CAS Registry Number: 64019-93-8
Trademarks: Diopine (Allergan); d Epifrin (Allergan); Diphemin (Alcon); Pivalephrine (Santen); Propine (Allergan)
Molecular Formula: C19H29NO5.HCl
Molecular Weight: 387.90
Percent Composition: C 58.83%, H 7.80%, N 3.61%, O 20.62%, Cl 9.14%
Properties: Crystals from ethyl acetate, mp 158-159°. Sol in water and ethanol. pKa 8.40.
Melting point: mp 158-159°
pKa: pKa 8.40
Therap-Cat: Adrenergic (ophthalmic); antiglaucoma.
Keywords: a-Adrenergic Agonist; Antiglaucoma.

SYN

2-chloro-3′,4′-dihydroxyacetophenone, 99-40-1

3′,4′-dihydroxy-2-methylaminoacetophenone, 99-45-6

2,2-dimethylpropanoic acid 4-[(methylamino)acetyl]-1,2-phenylene ester, 52245-00-8

Pivaloyl chloride, 3282-30-2

Trimethylacetyl chloride, 3282-30-2

1-(3,4-dipivaloyloxyphenyl)-2-(benzylmethylamino)ethan-1-one, 42146-03-2

SPECTROSCOPY

infrared spectral assignments for dipiveh hydrochloride
Wavelength (cm-1) Assignment

3255,2804,2475, 2397 RflHz+-NH stretch

2974-2875 sp3 C-H stretch
1273, 1258-1163 C-0-C stretch

3600-3400 0-H stretch

phenyl ester C=O stretch 1761
aromatic C-C stretch 1614, 1595, 1562, 1504
sp3 C-H bending and scissoring 1481, 1461, 1441, 1397
tert-butyl C-H bending1368, 1332
secondary alcohol C-0 stretch 1 124- 1028
out-of-plane bending for 1,substituted benzene ring 3,4  891,842

Ultraviolet absorption of dipivefrin hydrochloride
E (176, 1 cm)
Solvent              210 nm                   264 Nn                    270 nm
Acetonitrile         267.3                    14.8                          13.4
Ethanol              246.8                    14.5                          13.1
pH 3 Buffer        266.7                     12.4                          10.4
pH 7 Buffer        257.6                      10.8                         8.9
Water                278.0                     18.0                          16.2

References

  1. Jump up to:a b KD Tripari. Essentials of Medical Pharmacology (5 ed.). Jaypee Brothers Medical Publishers(P) Ltd. p. 88. ISBN 81-8061-187-6.
  2. Jump up to:a b c Dipivefrin FDA Professional Drug Information.
  3. ^ Zhang L, Weizer JS, Musch DC (2017). “Perioperative medications for preventing temporarily increased intraocular pressure after laser trabeculoplasty”Cochrane Database Syst Rev2: CD010746. doi:10.1002/14651858.CD010746.pub2PMC 5477062PMID 28231380.
    • Hussain, A.; Truelove, J.E.: J. Pharm. Sci. (JPMSAE) 65, 1510 (1976).
    •  US 3 839 584.
    • a DOS 2 343 657 (Interx Res. Corp.; appl. 30.8.1973; USA-prior. 31.8.1972).
    •  US 3 809 714 (Interx; 7.5.1974; prior. 31.8.1972) also racemate resolution.
    • b DOS 2 152 058 (Klinge; appl. 19.10.1971).
Dipivefrine
Dipivefrine.svg
Clinical data
Trade names Propine, Pivalephrine
Synonyms Dipivefrin
AHFS/Drugs.com International Drug Names
MedlinePlus a686005
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
Eye drops
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H29NO5
Molar mass 351.437 g/mol g·mol−1
3D model (JSmol)

//////////дипивефрин ديبيفيفرين 地匹福林 Dipivefrine, antiglaucoma, GENERIC, ジピベフリン

Etosalamide, этосаламид , إيتوسالاميد , 依托柳胺 ,


img

Image result for Etosalamide

Etosalamide

ethosalamide

Cas 15302-15-5
Chemical Formula: C11H15NO3
Molecular Weight: 209.245

o-(2-Ethoxyethoxy)benzamide

1585
1PU994YJUH
этосаламид [Russian] [INN]
إيتوسالاميد [Arabic] [INN]
依托柳胺 [Chinese] [INN]

Etosalamide, also known as Ethosalamide, is an antipyretic and analgesics agent

SYN

str1

OR

str1

CAS:592-55-2, 2-Bromoethyl ethyl ether

Cas, 611-20-1, 2-Hydroxybenzonitrile

PATENT

DE 1013643

PATENT

GB 774635

PATENT

US2822391

78 – 79 MP

PAPER

Journal of Chemical and Engineering Data (1962), 7, 265-6

70 – 71.5 MP

PATENT

WO 2004003198

US 20100226943

/////////Etosalamideэтосаламид إيتوسالاميد 依托柳胺 ethosalamide

O=C(N)C1=CC=CC=C1OCCOCC

FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


Diaminopyridine.png

FDA approves first treatment Ruzurgi (amifampridine)  for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with …

May 06, 2019

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. LEMS can occur at any age. The prevalence of LEMS specifically in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide.

Use of Ruzurgi in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of the drug in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients and safety data from pediatric patients 6 to less than 17 years of age.

The effectiveness of Ruzurgi for the treatment of LEMS was established by a randomized, double-blind, placebo-controlled withdrawal study of 32 adult patients in which patients were taking Ruzurgi for at least three months prior to entering the study. The study compared patients continuing on Ruzurgi to patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients that continued on Ruzurgi experienced less impairment than those on placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients switched to placebo.

The most common side effects experienced by pediatric and adult patients taking Ruzurgi were burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Patients should inform their health care professional immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Fast Track designations. Ruzurgi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical Company, Inc.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-lambert-eaton-myasthenic-syndrome-rare-autoimmune-disorder?utm_campaign=050619_PR_FDA%20approves%20first%20treatment%20for%20children%20with%20LEMS&utm_medium=email&utm_source=Eloqua

/////////////////FDA 2019, Ruzurgi, amifampridine,  Lambert-Eaton myasthenic syndrome, LEMS,  RARE DISEASES, CHILDREN, Jacobus Pharmaceutical Company, Priority Review,  Fast Track designations, Orphan Drug designation

Beperminogene perplasmid, ベペルミノゲンペルプラスミド


1gctgcttcgc gatgtacggg ccagatatac gcgttgacat tgattattga
51ctagttatta atagtaatca attacggggt cattagttca tagcccatat
101atggagttcc gcgttacata acttacggta aatggcccgc ctggctgacc
151gcccaacgac ccccgcccat tgacgtcaat aatgacgtat gttcccatag
201taacgccaat agggactttc cattgacgtc aatgggtgga gtatttacgg
251taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc
301ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt
351acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc
401atcgctatta ccatggtgat gcggttttgg cagtacatca atgggcgtgg
451atagcggttt gactcacggg gatttccaag tctccacccc attgacgtca
501atgggagttt gttttggcac caaaatcaac gggactttcc aaaatgtcgt
551aacaactccg ccccattgac gcaaatgggc ggtaggcgtg tacggtggga
601ggtctatata agcagagctc tctggctaac tagagaaccc actgcttact
651ggcttatcga aattaatacg actcactata gggagaccca agctggctag
701cgtttaaact taagcttggt accgagctcg gatccgccag cccgtccagc
751agcaccatgt gggtgaccaa actcctgcca gccctgctgc tgcagcatgt
801cctcctgcat ctcctcctgc tccccatcgc catcccctat gcagagggac
851aaaggaaaag aagaaataca attcatgaat tcaaaaaatc agcaaagact
901accctaatca aaatagatcc agcactgaag ataaaaacca aaaaagtgaa
951tactgcagac caatgtgcta atagatgtac taggaataaa ggacttccat
1001tcacttgcaa ggcttttgtt tttgataaag caagaaaaca atgcctctgg
1051ttccccttca atagcatgtc aagtggagtg aaaaaagaat ttggccatga
1101atttgacctc tatgaaaaca aagactacat tagaaactgc atcattggta
1151aaggacgcag ctacaaggga acagtatcta tcactaagag tggcatcaaa
1201tgtcagccct ggagttccat gataccacac gaacacagct ttttgccttc
1251gagctatcgg ggtaaagacc tacaggaaaa ctactgtcga aatcctcgag
1301gggaagaagg gggaccctgg tgtttcacaa gcaatccaga ggtacgctac
1351gaagtctgtg acattcctca gtgttcagaa gttgaatgca tgacctgcaa
1401tggggagagt tatcgaggtc tcatggatca tacagaatca ggcaagattt
1451gtcagcgctg ggatcatcag acaccacacc ggcacaaatt cttgcctgaa
1501agatatcccg acaagggctt tgatgataat tattgccgca atcccgatgg
1551ccagccgagg ccatggtgct atactcttga ccctcacacc cgctgggagt
1601actgtgcaat taaaacatgc gctgacaata ctatgaatga cactgatgtt
1651cctttggaaa caactgaatg catccaaggt caaggagaag gctacagggg
1701cactgtcaat accatttgga atggaattcc atgtcagcgt tgggattctc
1751agtatcctca cgagcatgac atgactcctg aaaatttcaa gtgcaaggac
1801ctacgagaaa attactgccg aaatccagat gggtctgaat caccctggtg
1851ttttaccact gatccaaaca tccgagttgg ctactgctcc caaattccaa
1901actgtgatat gtcacatgga caagattgtt atcgtgggaa tggcaaaaat
1951tatatgggca acttatccca aacaagatct ggactaacat gttcaatgtg
2001ggacaagaac atggaagact tacatcgtca tatcttctgg gaaccagatg
2051caagtaagct gaatgagaat tactgccgaa atccagatga tgatgctcat
2101ggaccctggt gctacacggg aaatccactc attccttggg attattgccc
2151tatttctcgt tgtgaaggtg ataccacacc tacaatagtc aatttagacc
2201atcccgtaat atcttgtgcc aaaacgaaac aattgcgagt tgtaaatggg
2251attccaacac gaacaaacat aggatggatg gttagtttga gatacagaaa
2301taaacatatc tgcggaggat cattgataaa ggagagttgg gttcttactg
2351cacgacagtg tttcccttct cgagacttga aagattatga agcttggctt
2401ggaattcatg atgtccacgg aagaggagat gagaaatgca aacaggttct
2451caatgtttcc cagctggtat atggccctga aggatcagat ctggttttaa
2501tgaagcttgc caggcctgct gtcctggatg attttgttag tacgattgat
2551ttacctaatt atggatgcac aattcctgaa aagaccagtt gcagtgttta
2601tggctggggc tacactggat tgatcaacta tgatggccta ttacgagtgg
2651cacatctcta tataatggga aatgagaaat gcagccagca tcatcgaggg
2701aaggtgactc tgaatgagtc tgaaatatgt gctggggctg aaaagattgg
2751atcaggacca tgtgaggggg attatggtgg cccacttgtt tgtgagcaac
2801ataaaatgag aatggttctt ggtgtcattg ttcctggtcg tggatgtgcc
2851attccaaatc gtcctggtat ttttgtccga gtagcatatt atgcaaaatg
2901gatacacaaa attattttaa catataaggt accacagtca tagctgttaa
2951cccgggtcga agcggccgct cgagtctaga gggcccgttt aaacccgctg
3001atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct
3051cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc
3101taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat
3151tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca
3201atagcaggca tgctggggat gcggtgggct ctatggcttc tactgggcgg
3251ttttatggac agcaagcgaa ccggaattgc cagctggggc gccctctggt
3301aaggttggga agccctgcaa agtaaactgg atggctttct tgccgccaag
3351gatctgatgg cgcaggggat caagctctga tcaagagaca ggatgaggat
3401cgtttcgcat gattgaacaa gatggattgc acgcaggttc tccggccgct
3451tgggtggaga ggctattcgg ctatgactgg gcacaacaga caatcggctg
3501ctctgatgcc gccgtgttcc ggctgtcagc gcaggggcgc ccggttcttt
3551ttgtcaagac cgacctgtcc ggtgccctga atgaactgca agacgaggca
3601gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagctgtgct
3651cgacgttgtc actgaagcgg gaagggactg gctgctattg ggcgaagtgc
3701cggggcagga tctcctgtca tctcaccttg ctcctgccga gaaagtatcc
3751atcatggctg atgcaatgcg gcggctgcat acgcttgatc cggctacctg
3801cccattcgac caccaagcga aacatcgcat cgagcgagca cgtactcgga
3851tggaagccgg tcttgtcgat caggatgatc tggacgaaga gcatcagggg
3901ctcgcgccag ccgaactgtt cgccaggctc aaggcgagca tgcccgacgg
3951cgaggatctc gtcgtgaccc atggcgatgc ctgcttgccg aatatcatgg
4001tggaaaatgg ccgcttttct ggattcatcg actgtggccg gctgggtgtg
4051gcggaccgct atcaggacat agcgttggct acccgtgata ttgctgaaga
4101gcttggcggc gaatgggctg accgcttcct cgtgctttac ggtatcgccg
4151ctcccgattc gcagcgcatc gccttctatc gccttcttga cgagttcttc
4201tgaattatta acgcttacaa tttcctgatg cggtattttc tccttacgca
4251tctgtgcggt atttcacacc gcatcaggtg gcacttttcg gggaaatgtg
4301cgcggaaccc ctatttgttt atttttctaa atacattcaa atatgtatcc
4351gctcatgaga caataaccct gataaatgct tcaataatag cacgtgctaa
4401aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat
4451ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga
4501ccccgtagaa aagatcaaag gatcttcttg agatcctttt tttctgcgcg
4551taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt
4601ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag
4651cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc
4701accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc
4751ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt
4801ggactcaaga cgatagttac cggataaggc gcagcggtcg ggctgaacgg
4851ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg
4901agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag
4951aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca
5001cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg
5051tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg
5101gcggagccta tggaaaaacg ccagcaacgc ggccttttta cggttcctgg
5151ccttttgctg gccttttgct cacatgttct t

Beperminogene perplasmid

ベペルミノゲンペルプラスミド

HGF plasmid

  • DNA (human hepatocyte growth factor plasmid pVAX1 cDNA)
  • DNA (plasmid pVAX1HGF/MGBI)
  • AMG-0001
    DS-992

Nucleic Acid Sequence

Sequence Length: 51811342 a 1223 c 1314 g 1302 t

APPROVED, japan 2019, Collategene, 2019/3/29

Antiparkinsonian, Angiogenesis inducing agent

CAS: 627861-07-8

  • Originator AnGes MG
  • Developer AnGes MG; Osaka University Hospital
  • Class Antiparkinsonians; Gene therapies; Ischaemic heart disorder therapies; Vascular disorder therapies
  • Mechanism of Action Angiogenesis inducing agents; Gene transference; Hepatocyte growth factor expression stimulants
  • Available For Licensing Yes – Ischaemic heart disorders; Lymphoedema; Parkinson’s disease
  • Registered Peripheral arterial disorders
  • Phase I/II Lymphoedema
  • No development reported Arteriosclerosis obliterans; Ischaemic heart disorders; Parkinson’s disease; Thromboangiitis obliterans
  • 26 Mar 2019 Registered for Peripheral arterial disorders in Japan (IM)
  • 21 Feb 2019 The Pharmaceutical Affairs and Food Sanitation Council recommends conditional and time-limited approval of beperminogene perplasmid for the improvement of ulcers associated with chronic peripheral arterial disease
  • 21 Feb 2019 AnGes plans a clinical study to assess the efficacy of beperminogene perplasmid in improvement of pain at rest in chronic peripheral arterial disorders
  • In 2010, the product received fast track designation in the U.S. for the treatment of critical limb ischemia

HGF Plasmid (Beperminogene Perplasmid)Critical Limb Ischemia (Arteriosclerosis Obliterans & Buerger’s Disease) AMG0001 Injection, JAPAN AND US  ALLIANCE Mitsubishi Tanabe Pharma

PATENT

WO 2017126488

US 20170283446

Expert Review of Cardiovascular Therapy (2014), 12(10), 1145-1156.

////////////Beperminogene perplasmid,  japan 2019, ベペルミノゲンペルプラスミド , AnGes MG, Osaka University Hospital, Critical Limb Ischemia, Arteriosclerosis Obliterans,  Buerger’s Disease, AMG0001, AMG-0001, DS-992 , HGF plasmid ,  fast track designation

BI-882370


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BI-882370

XP-102

N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide

CAS 1392429-79-6
Chemical Formula: C28H33F2N7O2S
Molecular Weight: 569.68
Elemental Analysis: C, 59.03; H, 5.84; F, 6.67; N, 17.21; O, 5.62; S, 5.63

N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide

N-(3-{5-[(1-Ethylpiperidin-4-Yl)(Methyl)amino]-3-(Pyrimidin-5-Yl)-1h-Pyrrolo[3,2-B]pyridin-1-Yl}-2,4-Difluorophenyl)propane-1-Sulfonamide

N-[3-[5-[(1-ethylpiperidin-4-yl)-methylamino]-3-pyrimidin-5-ylpyrrolo[3,2-b]pyridin-1-yl]-2,4-difluorophenyl]propane-1-sulfonamide

BI 882370 is a highly potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of the BRAF kinase. BI 882370 inhibits proliferation of human BRAF-mutant melanoma cells with 100× higher potency (1-10 nmol/L) than vemurafenib.

Xynomic, under license from Boehringer Ingelheim , is investigating for treating BRAF mutant cancers, including colorectal cancer and melanoma; in October 2017, preclinical data were reported in the melanoma and colorectal cancer settings.

  • Originator Boehringer Ingelheim
  • Developer Boehringer Ingelheim; Xynomic Pharmaceuticals
  • Class Antineoplastics; Piperidines; Pyridines; Pyrimidines; Pyrroles; Small molecules
  • Mechanism of Action Proto oncogene protein b raf inhibitors
  • Preclinical Colorectal cancer; Malignant melanoma
  • 20 Dec 2018 Xynomic Pharma plans a phase Ib trial for Colorectal cancer (in combination with BI 860585) in third quarter of 2019
  • 01 Jun 2018 Xynomic Pharmaceuticals plans a phase I trial for Colorectal cancer and Malignant melanoma in 2018 or 2019
  • 06 Nov 2017 Chemical structure information added
  • US8889684

PATENT

WO2012104388

PATENT

WO-2019084459

Novel crystalline salts (monosuccinate salt), designated as Form A, of BI-882370 and their substantially anhydrous and non-solvated, processes for their preparation and compositions comprising them. Also claimed are their use as a RAF kinase Inhibitor, for the treatment of cancers and other diseases, such as infections, inflammations and autoimmune diseases.

The compound N-(3-(5-((l -ethylpiperidin-4-yl)(methyl)andno)-3-(pyrimidin-5-yl)-lH-pyrrolo [3, 2-Z>]pyri din- l-yl)-2,4-difluorophenyl)propane-l -sulfonamide (BI 882370), having Formula I:

I

is a RAF kinase inhibitor useful in the treatment of various diseases including cancer. The compound of Formula I, as well as its preparation and use, have been described in

WO/2012/104388, which is incorporated herein by reference in its entirety.

The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a critical role in transmitting proliferation signals generated by the cell surface receptors and cytoplasmic signaling elements to the nucleus. Constitutive activation of this pathway is involved in malignant transformation by several oncogenes. Activating mutations in RAS

occur in approximately 15 % of cancers, and recent data has shown that B-RAF is mutated in about 7% of cancers (Wellbrock et al, “The RAF proteins take centre stage”, Nature Rev. Mol. Cell Biol., 2004, 5, 875-885), identifying it as another important oncogene in this pathway. In mammals, the RAF family of serine/threonine kinases comprises three members: A-RAF, B-RAF and C-RAF. However, activating mutations have so far been only identified in B-RAF underlining the importance of this isoform. It is believed that B-RAF is the main isoform that couples RAS to MEK, and that C-RAF and A-RAF signal to ERK only to fine-tune cellular responses (Wellbrock et al. Nature Rev. Mol. Cell Biol, 2004, 5, 875-885). The most common cancer mutation in B-RAF results in a valine to glutamic acid exchange at position 600 of the protein (V600E), which dramatically enhances B-RAF activity, presumably because its negative charge mimics activation loop phosphorylation (Wan et al , “Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF”, Cell, 2004, 116, 855-867). The highest incidence of B-RAF V600 mutations occurs in malignant melanoma (39%), thyroid cancer (46%), colorectal cancer (10%), biliary tract cancer (10%), prostate cancer (4%), ovary cancer (3%) and non-small cell lung cancer (2%), but they also occur at a low frequency in a wide variety of other cancers (frequencies of mutations according to COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v.53, 15th May 2011 ;

http://www.sanger.ac.uk/genetics/CGP/cosmic/). Literature supported the hypothesis that B-RA 600E mutated tumor cells seem to rely heavily on the continued activation of this pathway – a phenomenon termed “oncogene addiction” – whereas normal B-RAFwt cells use a broader range of signals. This provides an Achilles’ heel that can be exploited

therapeutically by treating patients with somatically mutated B-RAFV600E using orally available B-RAF inhibitors.

The key role of B-RAF V600E in aberrant ERK signaling and consequently oncogenesis has been demonstrated in several independent experimental approaches such as

overexpression of oncogenic/mutated B-RAF in vitro and in vivo (Wan et al., Cell, 2004, 116, 855-867; Wellbrock et al, Cancer Res. 2004, 64: 2338-2342), siRNA knock-down in vitro (Karasarides et al., Oncogene, “V599EB-RAF is an oncogene in melanocytes”, 2004, 23, 6292-6298) or in inducible short-hairpin RNA xenograft models where gain-of-function B-RAF signaling was found to be strongly associated with in vivo tumorigenicity (Hoeflich et al, “Oncogenic BRAF is required for tumor growth and maintenance in melanoma models”, Cancer Res., 2006, 66, 999-1006).

Treatment of B-RAFV600E mutated melanoma or colon carcinoma cells induces a B-RAF inhibition phenotype (e.g. reduction of phospho-MEK and phospho-ERK levels, reduction of cyclin D expression and induction of p27 expression). Consequently, these cells are locked in the Gl -phase of the cell cycle and do not proliferate.

Clinical proof of mechanism and proof of concept has been established for treating in cancer in B-RAFV600E mutated melanoma patients treated with Zelboraf®, B-RAF inhibitor (PLX-4032, vemurafenib, from Plexxikon/Daiichi Sankyo/Roche. Bollag et al., “Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma”, Nature, 2010, 467(7315), 596-9.; Flaherty et al, New Engl. J. Med., “Inhibition of Mutated, Activated BRAF in Metastatic Melanoma”, 2010, 363, 809-819; Chapman et al. “Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation”, New Engl. J. Med, 2011, 364:2507-2516. Favorable response rates were observed in both Phase I and Phase III clinical trials. It was reported, that melanoma patients carrying a B-RAFV600K mutation also do respond to therapy (Rubinstein et al, “Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032”, J. Transl. Med , 2010, 8, 67).

The most frequent B-RAF mutation is the exchange at amino acid position 600 from valine to glutamate with more than 90% frequency of all B-RAF mutations (Wellbrock et al. Nature Rev. Mol. Cell Biol, 2004, 5, 875-885), the second most frequent mutation is an alteration from valine to lysine, other mutations were found with lower frequency at that position (Wellbrock et al. Nature Rev. Mol. Cell Biol, 2004, 5, 875-885 and frequencies of mutations according to COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v53, 15th May 2011 ;

http://www.sanger.ac.uk/genetics/CGP/cosmic/). Additional mutations were found at e.g. the glycine rich loop (Wellbrock et al. Nature Rev. Mol. Cell Biol, 2004, 5, 875-885). Not all of these rather rare mutations seem to lead to direct activation of B-RAF (Wan et al. ,

“Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF”, Cell, 2004, 116, 855-867).

The compound of Formula I is a highly potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of the B-RAF kinase. The compound inhibited proliferation of human B-RAF-mutant melanoma cells with 100 times higher potency (1-10 nmol/L) than vemurafenib, whereas wild-type cells were not affected at 1,000 nmol/L. A solution of the compound administered orally was efficacious in mouse models of B-RAF-mutant melanomas and colorectal carcinomas, and at 25 mg/kg twice daily showed superior efficacy compared with vemurafenib, dabrafenib, or trametinib. The compound was also active in A375 melanoma-bearing mice that were resistant to vemurafenib, particularly when dosed in combination with trametinib. Mice treated with the compound did not show any body weight loss or clinical signs of intolerability, and no pathologic changes were observed in several major organs investigated, including skin. Furthermore, in a pilot study in rats (up to 60 mg/kg daily for 2 weeks), the compound lacked toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics. These results are described in Waizenegger et al., Mol. Cancer Ther., 2016, 75(3); 354-65, which is incorporated herein by reference in its entirety.

For the manufacture, purification, and formulation of a drug, it may be advantageous to employ a form of the drug having superior stability or other desirable formulation property exhibited by, for example, one or more salt or crystalline forms of the drug. Formation of salts of basic or acidic drugs can sometimes provide forms of the drug that have

advantageous properties such as solubility, non-hygroscopicity, crystallinity, and other physical properties that advantageous for formulating the drug. On the other hand, discovering a suitable salt or other crystalline form that is suitable for formulation is difficult, since there are numerous variables in the formation of a salt or crystalline form. These include the existence of numerous possible acids and bases that might be used as a counter-ion, various stoichiometric ratios that may be possible for combining a given basic or acid drug with an acid or base counter-ion, a wide variety of solvents and solvent systems

(including combinations of solvents) that potentially can be used to attempt to form salts or crystalline forms, and a variety of conditions (such as temperature or heating or cooling conditions) under which salts or crystalline forms may be generated. All of these variables of which may affect the properties of the salts or crystalline forms that might be obtained. Salts or solid forms may also have a variety of properties that render them unsuitable for drug development and formulation such as lack of crystallinity (amorphous forms), the presence or formation of multiple crystalline forms, which may interconvert and/or have different properties (polymorphism), lack of aqueous solubility, hygroscopicity, or stickiness of the solid. Furthermore, the formation of salts and crystalline forms and their properties are generally very unpredictable.

Accordingly, the crystalline salt forms of the compound of Formula I provided herein help satisfy the ongoing need for the development of a RAF kinase inhibitor for the treatment of serious diseases.

Preparation of A^-(3-(5-((l-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-lH-pyrrolo[3,2-Z>]pyridin-l- amide (BI 882370)

Step 1. 4-(6-Methyl-5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyi ester

(3)

1 2 3

DIPEA (62.82 mL, 0.435 mol) is added to the solution of 6-chloro-3-nitro-2-methylpyridine (1) (50 g, 290 mmol) and N-Boc-piperazine (2) (53.95 g, 290 mmol) in dry MeCN (200 mL) and stirred for 4 h at 50 °C. After the reaction is finished the reaction mixture is diluted with MeCN and water and stirred for 30 min. The precipitated product is collected by filtration, washed with water and the solid is dried in vacuo.

Step 2. 4- [6-((£’)-2-Dimethylamino-vinyl)-5-nitro-pyridin-2-yl] -piperazine- 1-carboxylic acid

To a stirred solution of 4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine- 1-carboxylic acid tert-butyl ester (3) (13 g, 40.3 mmol) in DMF (35 mL) is added N,N-dimethylformamide dimethylacetal (14.47 g, 121 mmol) and stirred in argon atmosphere for 36 h at 90 °C.

Additional 1.5 eq. of N^V-dimethylformamide dimethylacetal is added and stirred for 12 h at 90 °C. The reaction mixture is poured into water and extracted with DCM. The combined organic layers are washed with water, dried over anhydrous Na2S04 and concentrated in vacuo. The residue is used without further purification for the next step.

Step -(lH-pyrrolo[3,2-Z>]pyridin-5-yl)piperazine-l-carboxylic acid tert-butyl ester (5)

4 5

4-[6-((i?)-2-Dimethylairdno-vinyl)-5-nitro-pyridin-2-yl]-piperazine-l-carboxylic acid tert-butyl ester (36.4 g, 96 mmol) is taken up in MeOH, Pd/C (0.56 g, 10 %) is added and the mixture is hydrogenated in an autoclave at 60 psi for 16 h. The reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by column chromatography viaNP MPLC. The product containing fractions of compound (5) (HPLC-MS method B: tRet. = 1.55 min.; MS (M+H)+ = 303) are combined and evaporated in vacuo.

Step 4. N- -Amino-2,6-difluorophenyl)acetamide (7)

6 7

Compound (6) (55.0 g, 254 mmol) is taken-up in MeOH (1.0 L). Pd/C (10.0 g, 10 %) is added and the mixture is hydrogenated in an autoclave at 200 psi for 3 h. The reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by NP-MPLC on silica gel using DCM/MeOH (96:4) as eluent. The product containing fractions of the aniline intermediate (HPLC-MS method B: tRet. = 0.25 min.; MS (M-H) = 185) are combined and evaporated.

Step 5. N- -Difluoro-3-(propylsulfonamido)phenyl)acetamide (9)

To the aniline intermediate (35.0 g, 188 mmol) in DCM (100 mL) pyridine (6.6 mL, 75 mmol) and ^-propane sulfonyl chloride (8) (29.5 mL, 263 mmol) are added and the mixture is stirred at rt for 16 h. The reaction mixture is diluted with EtOAc (200 mL), washed with H2O and HC1 (aq., 1 N) and the layers are separated, dried over MgS04 and evaporated to yield the sulfonamide (9) which was used without further purification.

Step 6. N-

9 10

The sulfonylated aniline (9) (38.0 g, 130 mmol) is taken-up in EtOH (250 mL), H2O (200 mL) and concentrated hydrochloric acid (200 mL) and heated to 80 °C for 2 h. The reaction mixture is concentrated under reduced pressure, aqueous NaOH (4 N) is added until pH = 6 is reached and the mixture is extracted 2 x with DCM. The combined organic layer is washed with brine, dried over MgS04, filtered and evaporated to yield the deacylated aniline (10) (HPLC-MS method B: tRet. = 0.22 min.; MS (M-H) = 249) as a hydrochloride which was used without further purification.

Step 7. N-(2 -Difluoro-3-iodophenyl)propane-l-sulfonamide (11)

10 11

The hydrochloride of compound (10) is taken-up in DCM and extracted with NaHCCb solution. The organic layer is dried over MgSCn, filtered and evaporated. To the free base (10) (3.55 g, 14.21 mmol) in TFA (80 mL) at 0 °C is added NaNC (1.96 g, 28.4 mmol) in small portions and the mixture is stirred for 30 min. KI (23.83 g, 142 mmol) is added and stirring is continued for additional 15 min. The reaction mixture is diluted with Et^O and stirred for 1 h. Na2S203 solution (semiconc.) is added and the mixture is extracted 3 x with Et20. The combined organic layer is dried over MgSCn, filtered and concentrated in vacuo. The residue is purified by column chromatography via NP-MPLC. The product containing fractions of compound (11) (HPLC-MS method A: tRet. = 1.58 min.; MS (M-H) = 360) are combined and evaporated in vacuo.

Step 8. 4-((l-(2,6-Difluoro-3-(propylsulfonamido)phenyl)-lH-pyrrolo [3,2-b] pyridin-5-yl)

12

The lH-pyrrolo [3,2-*] pyridine (5) (10.0 g, 30.27 mmol), sulfonamide (11) (16.4 g,

45.4 mmol), Cul (576 mg, 3.03 mmol), ^^-(l ^^^-^N’-bismethyl-l^-cyclohexandiamine

(1.91 mL, 12.1 mmol) and CS2CO3 (29.6 g, 90.85 mmol) are taken-up in dry toluene (3 mL) and the resulting mixture is flushed with argon and stirred for 16 h at 120 °C. After the addition of further Cul (576 mg, 3.03 mmol), trans-(\R,2R)-N,N’-bismet y 1-1,2-cyclohexandiamine (1.91 mL, 12.1 mmol) and CS2CO3 (20.0 g, 60.0 mmol) the reaction mixture is stirred for further 24 h. The solvent is removed in vacuo, the residue is taken up in DCM and extracted with NaHCC solution (semiconc). The organic layer is dried over MgS04, filtered, the solvent is removed in vacuo and the residue is purified viaNP-MPLC. The product containing fractions of (12) (HPLC-MS method C: teet. = 1.62 mia; MS (M+H)+ = 564) are combined and the solvent is removed in vacuo.

Step 9. 4-((l-(2,6-Difluoro-3-(propylsulfonamido)phenyl)-3-iodo-lH-pyrrolo[3,2-b]pyridin-5 3)

To a solution of sulfonamide (12) (1.078 g, 1.9 mmol) in DMF (4 mL)/THF (100 μί) is added NIS (474 mg, 2.1 mmol) and the mixture is stirred for 1 h at rt. The reaction mixture is diluted with 30 mL DCM and extracted with NaHCCb solution (semiconc). The combined organic layer is dried over MgSCn, filtered and concentrated under reduced pressure. The residue is purified by column chromatography via RP HPLC. The product containing fractions of (13) (HPLC-MS method B: tRet. = 2.035 mia; MS (M+H)+ = 688) are freeze dried.

Step 10. 4-((l-(2,6-Difluoro-3-(propylsulfonamido)phenyl)-3-(pyrimidin-5-yl)-lH-pyrrolo[3,2-b]pyridin-5-yl)(methyl)amino)piperidine-l-carboxylic acid tert-butyi ester (15)

13 15

Sulfonamide (13) (770 mg, 1.12 mmol), pyrimidin-5-yl-boronic acid (14) (194 mg, 1.57 mmol), Pd(dppf)Cl2 (82 mg, 0.11 mmol), LiCl (142 mg, 3.35 mmol) and Na2C03 (294 mg, 2.8 mmol) are taken-up in dioxane/LhO (2: 1 mixture, 12 mL), and the resulting mixture is flushed with argon and stirred for 1 h at 100 °C. The reaction mixture is diluted with DCM and extracted with NaHCCb solution (semi-concentrated). The organic layer is dried over MgS04, filtered, Isolute® is added, the solvent is removed in vacuo and the residue is purified via RP HPLC. The product containing fractions of (15) (HPLC-MS method C: tRet. = 2.149 min.; MS (M+H)+ = 642) are freeze dried.

Step 11. N-(2,4-Difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)- 1H-pyrrolo[3,2-b]pyridin-l-yl)phenyl)propane-l-sulfonamide

15 16

To a solution of example compound (15) (154 mg, 0.24 mmol) in DCM/MeOH (1 : 1, 4 mL) is added HC1 (in dioxane, 4 N, 2 mL) and the mixture is stirred for 3 h at rt. The solvent is removed in vacuo. Obtained compound (16) (HPLC-MS method B: tRet. = 1.02 min.; MS (M+H)+ = 542) is used without further purification.

Step 12. ^-(3-(5-((l-Ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-lH-pyrrolo [3,2-Z>] pyridin- l-yl)-2,4-diflu

Compound I was obtained from compound (16) by reductive alkylation with acetaldehyde (40% in iPrOH) in the presence of 1.5 eq. sodium acetoxyborohydride in iPrOH. The crude product was recrystallized from ethanol to obtain the title compound in 84% yield.

Scale-Up Synthesis of A/-(3-(5-((l-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-lH-pyrrolo[3,2-Z>]pyridin-l-yl)-2,4-difluorophenyl)propane- 1-sulfonamide (BI 882370)

Step 1. N-(2,4-Difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-(pyrimidin-5-yl)-lH-pyrrolo[

15 16

Isopropanol (8.83 kg) and compound (15) (1.80 kg, 2.8 mol) were added into a reactor, and the mixture was stirred and heated to 55-60 °C. Concentrated hydrochloric acid (2.76 kg, 28 mol) was dropped into the reactor over than 20 min. at 60-65 °C. Then, the reaction mass was heated to 60-70 °C and held for 1 h. The conversion was monitored by HPLC, and reached about 99.5% after about 1 h.

The reaction mass was cooled and the isopropanol was removed by distillation under reduced pressure at not more than 50 °C. A brown oil was obtained, dissolved into water (6.75 kg) and washed by extraction with ethyl acetate (2.02 kg) at 20-30 °C. The water-phase was cooled to 15-20 °C. The pH was adjusted to 8.0-8.5 with 10% aqueous NaOH solution (-8.0 kg) at 20-30°C. The mixture was stirred for 3-4h at 20-30°C with the pH adjusted to 8.0-8.5 by addition of 10% NaOH solution every half-hour. The product was isolated by filtration and the cake washed with water (3.6 kg). The solid was dried under vacuum at 45-50 until the water content was not more than 5.5%. This provided about 1.64 kg of crude compound (16) (yield 108% of theoretical; the crude product containing water and NaCl detected). The crude product was used directly).

Step 12. ^-(3-(5-((l-Ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-lH-pyrr -Z>] pyridin- l-yl)-2,4-difluorophenyl)propane- 1-sulfonamide (I)

Bl 878426 Bl 882370 

Process:

Dichloromethane (19.88 kg) and compound (16) (1.5kg, 2.77mol) were added into a reactor, and the mixture was stirred and cooled to 0-10°C under a nitrogen atmosphere. Sodium triacetoxyborohydride (95%, 0.93 kg, 4.16 mol) was added into the mixture at 0-10°C. The mixture was stirred for 20-30 min. at 0- 10°C. Acetaldehyde in DCM (40%,

1.07 kg, 9.71 mol) added into the mixture slowly over 2 h at 0-10 °C. The reaction mixture was stirred at 0-10 °C under a nitrogen atmosphere for 0.5-lh. The conversion was monitored by HPLC, and reached about 99.5% after about 0.5-1 h.

Water (15 kg) was added into the reaction mass at a temperature below 15 °C. The mixture was stirred at 15-30 °C for 20-30 min. Aqueous ammonia (25%, 1.13 kg, 16.61 mol) was added into the mixture and the mixture was then stirred for 0.5 h. The organic phase was separated and then washed by extraction with water (15 kg) at 20-25 °C. Activated charcoal (0.15 kg) was added into the organic phase. The mixture was stirred for 1 h and then filtered. The filtrate was concentrated under reduced pressure at not more than 40°C, and compound (I) (1.58 kg, 100% yield) was obtained as a foamy solid.

Investigation of the Crystallinity of iV-(3-(5-((l-Ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)- lH-pyrrolo [3,2-Z>] pyridin- l-yl)-2,4-difluorophenyl)propane- 1-sulfonamide Free Base

Investigation of the crystallinity of N-(3-(5-((l-ethylpiperidin-4-yl)(methyl)amino)-3-(py rimidin-5-y 1)- lH-pyrrolo[3 ,2-b] pyridin- 1 -y l)-2,4-difluoropheny l)propane- 1 -sulfonamide free base, obtained by recrystallization from aqueous ethanol, which was used as a starting material to investigate salt formation showed that the compound had low crystallinity, as seen in FIG. 1.

Investigation of Salt forms of iV-(3-(5-((l-Ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)- lH-pyrrolo [3,2-Z>] pyridin- l-yl)-2,4-difluorophenyl)propane- 1-sulfonamide

The compound N-(3-(5-((l-ethylpiperidin-4-yl)(methyl)andno)-3-(pyrimidin-5-yl)-lH-pyrrolo [3 ,2-Z>]pyri din- l-yl)-2,4-difluorophenyl)propane-l -sulfonamide was combined with various acids in various solvent systems.

A 96-well master plate was charged by dosing compound in MeOH (stock solution) with a concentration of approx. 40 mg/mL. This plate was placed in a vacuum oven for liquid removal to obtain the same amount of solid material in each well. Subsequently different solvents/solvent mixtures and the acids were added to the solid material in each well (approx. 500μί) and the whole plate was heated up to 50 °C for 2 hours while stirring (using a small stirring bar added to each well).

The acids used were as shown in Table 1. The solvents used were as shown in Table 2. Crystallinity of salts obtained either by the slurry experiment or crystallization by evaporation.

To investigate crystal formation by a slurry experiment, the plate was allowed to cool and the crystallinity of the resulting salts was investigated by XRPD. An image of the master plate showing the salts obtained is shown in FIG. 2A and images of XRPD performed on the salt from each of the master plate wells, showing the crystallinity of the salts formed, is shown in FIG. 2B.

To investigate crystal formation by an evaporation experiment, after the heating period, the solutions were filtered at the same temperature (50 °C) using a preheated filter plate to ensure that no non-dissolved material can be transferred into the other crystallization plates. The filtrate was dispensed into an evaporation plate (approx.. 200μί). The solvents were allowed to evaporate, and the crystallinity of the resulting salts was investigated by XRPD. An image of the master plate showing the salts obtained is shown in FIG. 3A and images of XRPD performed on the salt from each of the evaporation plate wells, showing the crystallinity of the salts formed, is shown in FIG. 3B.

Table 1. Salts Used for Salt Form Investigation

Table 2. Solvents Used for Salt Form Investigation

REFERENCES

1: Waizenegger IC, Baum A, Steurer S, Stadtmüller H, Bader G, Schaaf O, Garin-Chesa P, Schlattl A, Schweifer N, Haslinger C, Colbatzky F, Mousa S, Kalkuhl A, Kraut N, Adolf GR. A Novel RAF Kinase Inhibitor with DFG-Out-Binding Mode: High Efficacy in BRAF-Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation. Mol Cancer Ther. 2016 Mar;15(3):354-65. doi: 10.1158/1535-7163.MCT-15-0617. Epub 2016 Feb 25. PubMed PMID: 26916115.

/////////////// BI-882370,  BI 882370,  BI882370, XP-102, Boehringer Ingelheim, Xynomic Pharmaceuticals, Preclinical,  Colorectal cancer, Malignant melanoma

CCN1CCC(CC1)N(C)c3ccc4n(cc(c2cncnc2)c4n3)c5c(F)ccc(NS(=O)(=O)CCC)c5F

ACLIMOSTAT


img

Image result for Aclimostat

Aclimostat
CAS: 2082752-83-6
Chemical Formula: C26H42N2O6
Molecular Weight: 478.63
Elemental Analysis: C, 65.25; H, 8.85; N, 5.85; O, 20.06

ZGN-1061; ZGN1061; ZGN 1061; Aclimostat,

UNII-X150A3JK8R

X150A3JK8R

(3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3- methylbut-2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl 3-[2-(morpholin-4-yl)ethyl]azetidine-1-carboxylate

1-Azetidinecarboxylic acid, 3-[2-(4-morpholinyl)ethyl]-, (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-buten-1-yl)-2-oxiranyl]-1-oxaspiro[2.5]oct-6-yl ester

3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-(2-morpholinoethyl)azetidine-1-carboxylate

ZAFGEN,  PHASE 2,  DIABETES

Aclimostat, also known as ZGN-1061, is an anti-diabetic, anti-obesity MetAP2 inhibitor.

Over 1.1 billion people worldwide are reported to be overweight. Obesity is estimated to affect over 90 million people in the United States alone. Twenty-five percent of the population in the United States over the age of twenty is considered clinically obese. While being overweight or obese presents problems (for example restriction of mobility, discomfort in tight spaces such as theater or airplane seats, social difficulties, etc.), these conditions, in particular clinical obesity, affect other aspects of health, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. The estimated mortality from obesity-related conditions in the United States is over 300,000 annually (O’Brien et al. Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science, 280:1371). [0003] There is no curative treatment for being overweight or obese. Traditional pharmacotherapies for treating an overweight or obese subject, such as serotonin and noradrenergic re-uptake inhibitors, noradrenergic re-uptake inhibitors, selective serotonin re- uptake inhibitors, intestinal lipase inhibitors, or surgeries such as stomach stapling or gastric banding, have been shown to provide minimal short-term benefits or significant rates of relapse, and have further shown harmful side-effects to patients. [0004] MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J. Proteome Res.7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci.9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).

[0005] Such MetAP2 inhibitors may be useful as well for patients with excess adiposity and conditions related to adiposity including type 2 diabetes, hepatic steatosis, and

cardiovascular disease (via e.g. ameliorating insulin resistance, reducing hepatic lipid content, and reducing cardiac workload). Accordingly, compounds capable of modulating MetAP2 are needed to address the treatment of obesity and related diseases as well as other ailments favorably responsive to MetAP2 modulator treatment.

Synthesis

CONTD……………….

contd………………….

Tetrahedron, 73(30), 4371-4379; 2017

WO 2017027684

PATENT

WO 2017027684

https://patents.google.com/patent/WO2017027684A1/en

Example 1

(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-(2-morpholinoethyl)azetidine-1-carboxylate

Figure imgf000117_0001

[00312] To a mixture of 4-(2-(azetidin-3-yl)ethyl)morpholine, trifluoroacetate (2.33 g, 3.7 mmol) in CH3CN (150 mL) was added DIPEA (2.9 mL, 17 mmol) drop-wise at 0-5oC. The mixture was then stirred at 0-5oC for 10 min, and carbonate Intermediate 1 (1.3 g, 2.9 mmol) was added to the mixture in portions at 0oC under a N2atmosphere. The reaction mixture was stirred at 25oC for 16 hrs. TLC (PE : EtOAc = 3 : 1) showed that the reaction was complete. The solvent was removed under vacuum below 40oC. The residue was diluted with DCM (60 mL), and the DCM solution was washed with ammonium acetate buffer (pH~4, 15 mL x 2). The combined aqueous layers were back-extracted with DCM (20 mL x 2). The combined organic layers were washed with aq. NaHCO3 solution (15 mL x 2, 5% wt), dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (DCM: MeOH=100: 0~60: 1), followed by preparative HPLC (Method A, H2O (0.1% FA) / CH3CN) gave the title compound (1.15 g) as a light yellow syrup. LC-MS: m/z = 479 [M+H]+1H-NMR (400 MHz, CDCl3) δ 5.43 (br, 1H), 5.13 (t, J = 7.6 Hz, 1H), 3.87-4.15 (m, 2H), 3.63-3.65 (m, 4H), 3.52- 3.56 (m, 3H), 3.49 (s, 3H), 2.90 (d, J = 4.4 Hz, 1H), 2.46-2.54 (m, 3H), 2.19-2.36 (m, 7H), 1.97-2.13 (m, 2H), 1.78-1.89 (m, 5H), 1.73 (s, 3H), 1.62 (s, 3H), 1.13 (s, 3H), 0.99 (d, J = 13.6 Hz, 1H).

REFERENCES

1: Malloy J, Zhuang D, Kim T, Inskeep P, Kim D, Taylor K. Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes Metab. 2018 Aug;20(8):1878-1884. doi: 10.1111/dom.13305. Epub 2018 Apr 23. PubMed PMID: 29577550; PubMed Central PMCID: PMC6055687.

2: Burkey BF, Hoglen NC, Inskeep P, Wyman M, Hughes TE, Vath JE. Preclinical Efficacy and Safety of the Novel Antidiabetic, Antiobesity MetAP2 Inhibitor ZGN-1061. J Pharmacol Exp Ther. 2018 May;365(2):301-313. doi: 10.1124/jpet.117.246272. Epub 2018 Feb 28. PubMed PMID: 29491038.

//////////////Aclimostat, ZGN-1061, ZAFGEN,  PHASE 2,  DIABETES

 O=C(N1CC(CCN2CCOCC2)C1)O[C@H](CC3)[C@@H](OC)[C@H]([C@@]4(C)O[C@@H]4C/C=C(C)\C)[C@]53CO5

SRT 1720


img

SRT-1720 diHCl

CAY10559

CAS: 1001645-58-4 (di HCl) , 925434-55-5 (free base)   1001645-58-4 (HCl)
Chemical Formula: C25H25Cl2N7OS
Molecular Weight: 542.483
Elemental Analysis: C, 55.35; H, 4.65; Cl, 13.07; N, 18.07; O, 2.95; S, 5.91

SRT-1720 HCl, SRT-1720 hudrochloride; SRT1720; SRT-1720; SRT 1720; CAY10559; CAY-10559; CAY 10559; SIRT-1933; SIRT 1933; SIRT1933.

 N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide dihydrochloride

SRT1720.svg

  • Molecular FormulaC25H23N7OS
  • Average mass469.561 Da

SRT-1720, also known as CAY10559 and is a drug developed by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. It has similar activity in the body to the known SIRT1 activator resveratrol, but is 1000x more potent. In animal studies it was found to improve insulin sensitivity and lower plasma glucose levels in fat, muscle and liver tissue, and increased mitochondrial and metabolic function. A study of SRT1720 conducted by the National Institute on Aging found that the drug may extend the lifespan of obese mice by 44% .

SRT1720 is an experimental drug that was studied by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuinsubtype SIRT1. The compound has been studied in animals, but safety and efficacy in humans have not been established.

Animal research

In animal models of obesity and diabetes SRT1720 was found to improve insulin sensitivity and lower plasma glucose levels in fat, muscle and liver tissue, and increase mitochondrial and metabolic function.[1] In mice rendered obese and diabetic by feeding a high-fat, high-sugar diet, a study performed at the National Institute of Aging found that feeding chow infused with the highest dose of SRT1720 beginning at one year of age increased mean lifespan by 18%, and maximum lifespan by 5%, as compared to other short-lived obese, diabetic mice; however, treated animals still lived substantially shorter lives than normal-weight mice fed normal chow with no drug.[2] In a later study, SRT1720 increased mean lifespan of obese, diabetic mice by 21.7%, similar to the earlier study, but there was no effect on maximum lifespan in this study.[3] In normal-weight mice fed a standard rodent diet, SRT1720 increased mean lifespan by just 8.8%, and again had no effect on maximum lifespan.[3]

Since the discovery of SRT1720, the claim that this compound is a SIRT1 activator has been questioned[4][5][6] and further defended.[7][8]

Although SRT1720 is not currently undergoing clinical development, a related compound, SRT2104, is currently in clinical development for metabolic diseases.[9]

PAPER

Letters in Drug Design & Discovery, 10(9), 793-797; 2013

The Identification of the SIRT1 Activator SRT2104 as a Clinical Candidate

Author(s): Pui Yee Ng, Jean E. Bemis, Jeremy S. Disch, Chi B. Vu, Christopher J. Oalmann, Amy V. Lynch,David P. Carney, Thomas V. Riera, Jeffrey Song, Jesse J. Smith, Siva Lavu, Angela Tornblom, Meghan Duncan, Marie Yeager, Kristina Kriksciukaite, Akanksha Gupta, Vipin Suri, Peter J. Elliot, Jill C. Milne, Joseph J. Nunes, Michael R. Jirousek, George P. Vlasuk, James L. Ellis, Robert B. Perni.

Journal Name: Letters in Drug Design & Discovery

Volume 10 , Issue 9 , 2013

Paper

Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; Bemis, J.E.; Xie, R.; Disch, J.S.; Ng, P.Y.; Nunes, J.J.; Lynch, A.V.; Yang, H.; Galonek, H.; Israelian, K.; Choy, W.; Iffland, A.; Lavu, S.; Medvedik, O.; Sinclair, D.A.; Olefsky, J.M.; Jirousek, M.R.; Elliott, P.J.; Westphal, C.H.
Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
Nature 2007, 450(7170): 712

PATENT

WO 2007019417

WO 2007019416

WO 2007019345

WO 2007019344

WO 2007019346

WO 2008115518

PAPER

Vu, Chi B.; Journal of Medicinal Chemistry 2009, VOL 52(5), PG 1275-1283 

https://pubs.acs.org/doi/abs/10.1021/jm8012954

Abstract Image

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD+-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.

Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators

Sirtris Pharmaceuticals, 200 Technology Square, Cambridge, Massachusetts 02139
J. Med. Chem.200952 (5), pp 1275–1283
DOI: 10.1021/jm8012954

* To whom correspondence should be addressed. Phone: (617)-252-6920, extension 2129. Fax: (617)-252-6924. E-mail: cvu@sirtrispharma.com., †

Present address: Department of Medicine, Division of Endocrinology and Metabolism, University of California—San Diego, 9500 Gilman Drive, La Jolla, CA 92093.

Preparation of N-(2-(3-(Piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide (29)

Essentially the same procedure as detailed in the preparation of 3,4,5-trimethoxy-N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)benzamide was employed except that 2-quinoxaloyl chloride was used.
Mp: dec (HCl salt), 221.4 °C (freebase).
 1H NMR (300 MHz, DMSO-d6) δ 9.60 (br s, 1 H), 8.88 (d, 1 H, J = 8 Hz), 8.60 (br s, 1 H), 8.50 (s, 1 H), 8.0−8.30 (m, 5 H), 7.78 (d, 1 H, J = 8 Hz), 7.10−7.33 (m, 4 H), 3.90 (br s, 2 H), 3.00−3.10 (m, 4H), 2.60−2.80 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ 47.49, 49.88, 111.45, 120.47, 121.84, 124.02, 127.04, 128.10, 129.20, 129.23, 131.39, 132.15, 135.39, 139.54, 143.03, 143.80, 144.36, 144.62, 147.76, 161.57.
High resolution MS, calcd for C25H23N7OS [M + H]+ 470.1763; found, 470.1753.

References

  1. ^ Milne JC; Lambert PD; Schenk S; Carney DP; Smith JJ; Gagne DJ; Jin L; Boss O; Perni RB; Vu CB; Bemis JE; Xie R; Disch JS; Ng PY; Nunes JJ; Lynch AV; Yang H; Galonek H; Israelian K; Choy W; Iffland A; Lavu S; Medvedik O; Sinclair DA; Olefsky JM; Jirousek MR; Elliott PJ; Westphal CH (November 2007). “Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes”Nature450(7170): 712–6. doi:10.1038/nature06261PMC 2753457PMID 18046409.
  2. ^ Minor RK; Baur JA; Gomes AP; Ward TM; Csiszar A; Mercken EM; Abdelmohsen K; Shin YK; Canto C; Scheibye-Knudsen M; Krawczyk M; Irusta PM; Martín-Montalvo A; Hubbard BP; Zhang Y; Lehrmann E; White AA; Price NL; Swindell WR; Pearson KJ; Becker KG; Bohr VA; Gorospe M; Egan JM; Talan MI; Auwerx J; Westphal CH; Ellis JL; Ungvari Z; Vlasuk GP; Elliott PJ; Sinclair DA; de Cabo R (Aug 2011). “SRT1720 improves survival and healthspan of obese mice”Scientific Reports1 (70): 70. doi:10.1038/srep00070PMC 3216557PMID 22355589. Retrieved 1 March 2014.
  3. Jump up to:a b Mitchell SJ; Martin-Montalvo A; Mercken EM; et al. (Feb 2014). “The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet”Cell Reports6 (4): 836–43. doi:10.1016/j.celrep.2014.01.031PMC 4010117PMID 24582957. Retrieved 1 March 2014.
  4. ^ Pacholec M; Chrunyk BA; Cunningham D; Flynn D; Griffith DA; Griffor M; Loulakis P; Pabst B; Qiu X; Stockman B; Thanabal V; Varghese A; Ward J; Withka J; Ahn K (January 2010). “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1”J Biol Chem285 (11): 8340–8351. doi:10.1074/jbc.M109.088682PMC 2832984PMID 20061378.
  5. ^ Beher D; Wu J; Cumine S; Kim KW; Lu SC; Atangan L; Wang M (December 2009). “Resveratrol is not a direct activator of SIRT1 enzyme activity”. Chem Biol Drug Des74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.xPMID 19843076.
  6. ^ Zarse, K.; Schmeisser, S.; Birringer, M.; Falk, E.; Schmoll, D.; Ristow, M. (2010). “Differential Effects of Resveratrol and SRT1720 on Lifespan of AdultCaenorhabditis elegans”. Hormone and Metabolic Research42 (12): 837–839. doi:10.1055/s-0030-1265225PMID 20925017.
  7. ^ Callaway E (2010-08-16). “GlaxoSmithKline strikes back over anti-ageing pills: Drugs do work as thought, says pharmaceutical giant”Naturedoi:10.1038/news.2010.412.
  8. ^ Dai H; Kustigian L; Carney D; Case A; Considine T; Hubbard BP; Perni RB; Riera TV; Szczepankiewicz B; Vlasuk GP; Stein RL (August 2010). “SIRT1 activation by small molecules – kinetic and biophysical evidence for direct interaction of enzyme and activator”J Biol Chem285 (43): 32695–32703. doi:10.1074/jbc.M110.133892PMC 2963390PMID 20702418.
  9. ^ “Sirtuin Pipeline”Sirtris Pharmaceuticals.
SRT1720
SRT1720.svg
Identifiers
PubChem CID
IUPHAR/BPS
ChemSpider
CompTox Dashboard(EPA)
Chemical and physical data
Formula C25H23N7OS
Molar mass 469.560 g/mol g·mol−1
3D model (JSmol)

////////////SRT-1720 DI HCl, obesity, diabetes, SRT 1720,  Sirtris Pharmaceuticals,  CAY10559,  CAY 10559, Preclinical

O=C(NC1=CC=CC=C1C2=CN3C(SC=C3CN4CCNCC4)=N2)C5=NC6=CC=CC=C6N=C5.[H]Cl.[H]Cl

KETOROLAC


KetorolacKetorolac.svg

Ketorolac

  • Molecular FormulaC15H13NO3
  • Average mass255.269 Da
1H-Pyrrolizine-1-carboxylic acid, 5-benzoyl-2,3-dihydro-
413572 [Beilstein]
5-(Phenylcarbonyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
5-Benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
74103-06-3 [RN]
 Ketorolac
CAS Registry Number: 74103-06-3
CAS Name: 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
Additional Names: 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid
Manufacturers’ Codes: RS-37619
Molecular Formula: C15H13NO3
Molecular Weight: 255.27
Percent Composition: C 70.58%, H 5.13%, N 5.49%, O 18.80%
Literature References: Prostaglandin biosynthesis inhibitor. Prepn and separation of isomers: BE 856681; J. M. Muchowski, A. F. Kluge, US 4089969 (both 1978 to Syntex). Alternate processes: J. M. Muchowski, R. Greenhouse, US 4347186 (1982 to Syntex); F. Franco et al., J. Org. Chem. 47, 1682 (1982); J. B. Doherty, US 4496741 (1985 to Merck & Co.). Absolute configuration: A. Guzman et al., J. Med. Chem. 29, 589 (1986). Structure-activity relationships: J. M. Muchowski et al., ibid. 28, 1037 (1985). Pharmacology and analgesic, anti-inflammatory profile of ketorolac and its tromethamine salt: W. H. Rooks et al., Agents Actions12, 684 (1982); eidem, Drugs Exp. Clin. Res. 11, 479 (1985). Clinical comparison with acetaminophen in post-operative pain: H. J. McQuay et al., Clin. Pharmacol. Ther. 39, 89 (1986).
Properties: Crystals from ethyl acetate + ether, mp 160-161°. uv max in methanol: 245, 312 nm (e 7080, 17400). pKa 3.49 ±0.02. LD50 orally in mice: ~200 mg/kg (Rooks).
Melting point: mp 160-161°
pKa: pKa 3.49 ±0.02
Absorption maximum: uv max in methanol: 245, 312 nm (e 7080, 17400)
Toxicity data: LD50 orally in mice: ~200 mg/kg (Rooks)
Derivative Type: (±)-Form tromethamine salt
CAS Registry Number: 74103-07-4
Trademarks: Acular (Allergan); Dolac (Syntex); Lixidol (Farmitalia); Tarasyn (Syntex); Toradol (Syntex); Toratex (Syntex)
Molecular Formula: C19H24N2O6
Molecular Weight: 376.40
Percent Composition: C 60.63%, H 6.43%, N 7.44%, O 25.50%
Derivative Type: (+)-Form
Properties: Crystals from hexane + ethyl acetate, mp 174° (Guzman); also reported as mp 154-156° (Muchowski, Kluge). [a]D+173° (c = 1 in methanol).
Melting point: mp 174° (Guzman); mp 154-156° (Muchowski, Kluge)
Optical Rotation: [a]D +173° (c = 1 in methanol)
Derivative Type: (-)-Form
Properties: Crystals from hexane + ethyl acetate, mp 169-170° (Guzman); also reported as mp 153-155° (Muchowski, Kluge). [a]D-176° (c = 1 in methanol).
Melting point: mp 169-170° (Guzman); mp 153-155° (Muchowski, Kluge)
Optical Rotation: [a]D -176° (c = 1 in methanol)
Therap-Cat: Analgesic; anti-inflammatory.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylcarboxylic Acids.

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.[1]Specifically it is recommended for moderate to severe pain.[2] Recommended duration of treatment is less than six days.[1] It is used by mouth, by injection into a vein or muscle, and as eye drops.[1][2] Effects begin within an hour and last for up to eight hours.[1]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.[1] Serious side effects may include stomach bleedingkidney failureheart attacksbronchospasmheart failure, and anaphylaxis.[1] Use is not recommended during the last part of pregnancy or during breastfeeding.[1] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2) thereby decreasing prostaglandins.[1][3]

Ketorolac was patented in 1976 and approved for medical use in 1989.[4][1] It is avaliable as a generic medication.[2] In the United Kingdom it costs the NHS less than a £ per injectable dose as of 2019.[2] In the United States the wholesale cost of this amount is about 1.50 USD.[5] In 2016 it was the 296th most prescribed medication in the United States with more than a million prescriptions.[6]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain.[7]It is usually not prescribed for longer than five days.[8][9][10][11] Ketorolac is effective when administered with paracetamol to control pain in neonates because it does not depress respiration as do opioids.[12] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[11] Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[13]

Ketorolac is used for short-term pain control not lasting longer than five days, and can be administered orally, by intramuscular injection, intravenously, and by nasal spray.[8] Ketorolac is initially administered by intramuscular injection or intravenously.[7] Oral therapy is only used as a continuation from the intramuscular or intravenous starting point.[8][12]

Ketorolac is used during eye surgery help with pain.[14] Ketorolac is effective in treating ocular itching.[15] The ketorolac ophthalmic formulation is associated with a decreased development of macular edema after cataract surgery and is more effective alone rather than as an opioid/ketorolac combination treatment.[16][17] Ketorolac has also been used to manage pain from corneal abrasions.[18]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects and side effects. Lab tests, such as liver function tests, bleeding time, BUNserum creatinine and electrolyte levels are often used and help to identify potential complications.[8][9]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polypsangioedema, and asthma.[8][9] Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failurecoagulation disorders, renal impairment, and hepatic impairment.[8][9]

Adverse effects

Though uncommon, potentially fatal adverse effects are strokemyocardial infarctionGI bleedingStevens-Johnson Syndrometoxic epidermal necrolysis and anaphylaxis. A less serious and more common (>10%) side effect is drowsiness. Infrequent (<1%) side effects are paresthesia, prolonged bleeding timeinjection site pain, purpurasweatingabnormal thinking, increased production of tearsedemapallordry mouthabnormal tasteurinary frequencyincreased liver enzymesitching and others. Ketorolac can cause premature constriction of the ductus arteriosis in an infant during the third trimester of pregnancy.[8][9] Platelet function is decreased related to the use of ketorolac.[19]

The practice of restricting treatment with ketorolac is due to its potential to cause kidney damage.[20]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction or experiencing a side effect when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDS, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrelcefoperazonevalproic acidcefotetaneptifibatidetirofiban, and copidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.[8][9]

Interactions with ketorolac exist with some herbal supplements. The use of Panax ginsengclovegingerarnicafeverfewdong quaichamomile, and Ginkgo biloba increases the risk of bleeding.[8][9]

Mechanism of action

The primary mechanism of action responsible for ketorolac’s anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[21] Ketorolac has been assessed to be a relatively higher risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[13] It is considered a first-generation NSAID.[19]

History

In the US, ketorolac was the only widely available intravenous NSAID for many years; an IV form of paracetemol, which is not an NSAID, became available in Europe in 2009 and then in the US.[12]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular around 2006.[citation needed]

In 2007, there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital, although this was not designed to exclude its use in prehospital care and mountain rescue settings.[7] Dosing guidelines were published at that time.[22]

Concerns over the high incidence of reported side effects with ketorolac trometamol led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.[23]

The eye-drop formulation was approved by the FDA in 1992.[24] An intranasal formulation was approved by the FDA in 2010[25] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Synthesis

DOI: 10.1021/jo00348a014

Image result for Ketorolac SYNTHESIS

1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ketorolac

2-Methylthiopyrrole (I) is benzoylated with N,N-dimethylbenzamide (II) to produce 5-benzoyl-2-methylthiopyrrole (III) in the presence of POCl3 in refluxing CH2Cl2, and the yielding product is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) in the presence of NaH in DMF giving compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol.Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

SYN

DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075

The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol – water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol – water.

SYN2

The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

References

  1. Jump up to:a b c d e f g h i “Ketorolac Tromethamine Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  2. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
  3. ^ “DailyMed – ketorolac tromethamine tablet, film coated”dailymed.nlm.nih.gov. Retrieved 14 April 2019.
  4. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 521. ISBN 9783527607495.
  5. ^ “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  6. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December 2018.
  7. Jump up to:a b c Mallinson, Tom (2017). “A review of ketorolac as a prehospital analgesic”Journal of Paramedic Practice9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
  8. Jump up to:a b c d e f g h i Vallerand, April H. (2017). Davis’s Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
  9. Jump up to:a b c d e f g Physician’s Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S–474–5. ISBN 9781563638381.
  10. ^ “Ketorolac-tromethamine”The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  11. Jump up to:a b Henry, p. 291.
  12. Jump up to:a b c Martin, Lizabeth D; Jimenez, Nathalia; Lynn, Anne M (2017). “A review of perioperative anesthesia and analgesia for infants: updates and trends to watch”F1000Research6: 120. doi:10.12688/f1000research.10272.1ISSN 2046-1402PMC 5302152PMID 28232869.
  13. Jump up to:a b Schwier, Nicholas; Tran, Nicole (2016). “Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis”Pharmaceuticals9 (2): 17. doi:10.3390/ph9020017ISSN 1424-8247PMC 4932535PMID 27023565.
  14. ^ Saenz-de-Viteri, Manuel; Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guiaro-Navarro, María Concepción (2016). “Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac”Patient Preference and Adherence10: 1795–1801. doi:10.2147/PPA.S90468ISSN 1177-889XPMC 5029911PMID 27695298.
  15. ^ Karch, Amy (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
  16. ^ Lim, Blanche X; Lim, Chris HL; Lim, Dawn K; Evans, Jennifer R; Bunce, Catey; Wormald, Richard; Wormald, Richard (2016). “Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery”Cochrane Database Syst Rev11: CD006683. doi:10.1002/14651858.CD006683.pub3PMID 27801522.
  17. ^ Sivaprasad, Sobha; Bunce, Catey; Crosby-Nwaobi, Roxanne; Sivaprasad, Sobha (2012). “Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery”. Cochrane Database Syst Rev (2): CD004239. doi:10.1002/14651858.CD004239.pub3PMID 22336801.
  18. ^ Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N (2017). “Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions”. Cochrane Database Syst Rev5: CD009781. doi:10.1002/14651858.CD009781.pub2PMID 28516471.
  19. Jump up to:a b Henry, p. 279.
  20. ^ Henry, p. 280.
  21. ^ Lee, I. O.; Seo, Y. (2008). “The Effects of Intrathecal Cyclooxygenase-1, Cyclooxygenase-2, or Nonselective Inhibitors on Pain Behavior and Spinal Fos-Like Immunoreactivity”. Anesthesia & Analgesia106 (3): 972–977, table 977 contents. doi:10.1213/ane.0b013e318163f602PMID 18292448.
  22. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
  23. ^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance:June 1993; Volume 19 (pages 5-8).
  24. ^ “Ketorolac ophthalmic medical facts from”. Drugs.com. Retrieved 2013-10-06.
  25. ^ “Sprix Information from”. Drugs.com. Retrieved 2013-10-06.

Bibliography

External links

Ketorolac
Ketorolac.svg
Ketorolac ball-and-stick.png
Clinical data
Trade names Toradol, Acular, Sprix, others
Synonyms Ketorolac tromethamine
AHFS/Drugs.com Monograph
MedlinePlus a693001
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
By mouth, IMIV, eye drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (All routes)
Metabolism Liver
Elimination half-life 3.5 h to 9.2 h, young adults;
4.7 h to 8.6 h, elderly (mean age 72)
Excretion Kidney: 91.4% (mean)
Biliary: 6.1% (mean)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.314 Edit this at Wikidata
Chemical and physical data
Formula C15H13NO3
Molar mass 255.27 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

//////////Ketorolac,

Cavosonstat (N-91115)


Cavosonstat.png

Cavosonstat (N-91115)

CAS 1371587-51-7

C16H10ClNO3, 299.71 g/mol

UNII-O2Z8Q22ZE4, O2Z8Q22ZE4, NCT02589236; N91115-2CF-05; SNO-6

3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

Treatment of Chronic Obstructive Pulmonary Diseases (COPD), AND Cystic fibrosis,  Nivalis Therapeutics, phase 2

The product was originated at Nivalis Therapeutics, which was acquired by Alpine Immune Sciences in 2017. In 2018, Alpine announced the sale and transfer of global rights to Laurel Venture Capital for further product development.

In 2016, orphan drug and fast track designations were granted to the compound in the U.S. for the treatment of cystic fibrosis.

  • Originator N30 Pharma
  • Developer Nivalis Therapeutics
  • Class Small molecules
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator modulators; Glutathione-independent formaldehyde dehydrogenase inhibitors; Nitric oxide stimulants
  • Orphan Drug Status Yes – Cystic fibrosis
  • 20 Jul 2018 Laurel Venture Capital acquires global rights for cavosonstat from Alpine Immune Sciences
  • 20 Jul 2018 Laurel Venture Capital plans a phase II trial for Asthma
  • 24 Jun 2018 Biomarkers information updated

 Cavosonstat, alos known as N91115) an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

cavosonstat-n91115Cavosonstat (N91115) was an experimental therapy being developed by Nivalis Therapeutics. Its primary mechanism of action was to inhibit the S-nitrosoglutathione reductase (GSNOR) enzyme and to stabilize cystic fibrosis transmembrane regulator (CFTR) protein activity. A press release published in February announced the end of research for this therapy in cystic fibrosis (CF) patients with F508del mutations. The drug, which did not meet primary endpoints in a Phase 2 trial, had been referred to as the first of a new class of compounds that stabilizes the CFTR activity.

History of cavosonstat

During preclinical studies, N91115 (later named cavosonstat) demonstrated an improvement in cystic fibrosis transmembrane regulator (CFTR) stability.

Phase 1 study was initiated in 2014 to evaluate the safety, tolerability, and pharmacokinetics (how a drug is processed in the body) of the drug in healthy volunteers. Later that year, the pharmacokinetics of the drug were assessed in another Phase 1 trial involving CF patients with F508del mutation suffering from pancreatic insufficiency. Results were presented a year later by Nivalis, revealing good tolerance and safety in study participants.

A second, much smaller Phase 2 study (NCT02724527) assessed cavosonstat as an add-on therapy to ivacaftor (Kalydeco). This double-blind, randomized, placebo-controlled study included 19 participants who received treatment with cavosonstat (400 mg) added to Kalydeco or with placebo added to Kalydeco. The primary objective was change in lung function from the study’s start to week 8. However, the treatment did not demonstrate a benefit in lung function measures or in sweat chloride reduction at eight weeks (primary objective). As a result, Nivalis decided not to continue development of cavosonstat for CF treatment.

The U.S. Food and Drug Administration (FDA) had granted cavosonstat both fast track and orphan drug designations in 2016.

How cavosonstat works

The S-nitrosoglutathione (GSNO) is a signaling molecule that is present in high concentrations in the fluids of the lungs or muscle tissues, playing an important role in the dilatation of the airways. GSNO levels are regulated by the GSNO reductase (GSNOR) enzyme, altering CFTR activity in the membrane. In CF patients, GSNO levels are low, causing a loss of the airway function.

Cavosonstat’s mechanism of action is achieved through GSNOR inhibition, which was presumed to control the deficient CFTR protein. Preclinical studies showed that cavosonstat restored GSNO levels.

PATENT
WO 2012083165

The chemical compound nitric oxide is a gas with chemical formula NO. NO is one of the few gaseous signaling molecules known in biological systems, and plays an important role in controlling various biological events. For example, the endothelium uses NO to signal surrounding smooth muscle in the walls of arterioles to relax, resulting in vasodilation and increased blood flow to hypoxic tissues. NO is also involved in regulating smooth muscle proliferation, platelet function, and neurotransmission, and plays a role in host defense. Although NO is highly reactive and has a lifetime of a few seconds, it can both diffuse freely across membranes and bind to many molecular targets. These attributes make NO an ideal signaling molecule capable of controlling biological events between adjacent cells and within cells.

[0003] NO is a free radical gas, which makes it reactive and unstable, thus NO is short lived in vivo, having a half life of 3-5 seconds under physiologic conditions. In the presence of oxygen, NO can combine with thiols to generate a biologically important class of stable NO adducts called S-nitrosothiols (SNO’s). This stable pool of NO has been postulated to act as a source of bioactive NO and as such appears to be critically important in health and disease, given the centrality of NO in cellular homeostasis (Stamler et al., Proc. Natl. Acad. Sci. USA, 89:7674-7677 (1992)). Protein SNO’s play broad roles in the function of cardiovascular, respiratory, metabolic, gastrointestinal, immune, and central nervous system (Foster et al., Trends in Molecular Medicine, 9 (4): 160-168, (2003)). One of the most studied SNO’s in biological systems is S-nitrosoglutathione (GSNO) (Gaston et al., Proc. Natl. Acad. Sci. USA 90: 10957-10961 (1993)), an emerging key regulator in NO signaling since it is an efficient trans-nitrosating agent and appears to maintain an equilibrium with other S-nitrosated proteins (Liu et al., Nature, 410:490-494 (2001)) within cells. Given this pivotal position in the NO-SNO continuum, GSNO provides a therapeutically promising target to consider when NO modulation is pharmacologically warranted.

[0004] In light of this understanding of GSNO as a key regulator of NO homeostasis and cellular SNO levels, studies have focused on examining endogenous production of GSNO and SNO proteins, which occurs downstream from the production of the NO radical by the nitric oxide synthetase (NOS) enzymes. More recently there has been an increasing understanding of enzymatic catabolism of GSNO which has an important role in governing available concentrations of GSNO and consequently available NO and SNO’s.

[0005] Central to this understanding of GSNO catabolism, researchers have recently identified a highly conserved S-nitrosoglutathione reductase (GSNOR) (Jensen et al., Biochem J., 331 :659-668 (1998); Liu et al., (2001)). GSNOR is also known as glutathione-dependent formaldehyde dehydrogenase (GSH-FDH), alcohol dehydrogenase 3 (ADH-3) (Uotila and Koivusalo, Coenzymes and Coƒactors., D. Dolphin, ed. pp. 517-551 (New York, John Wiley & Sons, (1989)), and alcohol dehydrogenase 5 (ADH-5). Importantly GSNOR shows greater activity toward GSNO than other substrates (Jensen et al., (1998); Liu et al., (2001)) and appears to mediate important protein and peptide denitrosating activity in bacteria, plants, and animals. GSNOR appears to be the major GSNO-metabolizing enzyme in eukaryotes (Liu et al., (2001)). Thus, GSNO can accumulate in biological compartments where GSNOR activity is low or absent (e.g. , airway lining fluid) (Gaston et al., (1993)).

[0006] Yeast deficient in GSNOR accumulate S-nitrosylated proteins which are not substrates of the enzyme, which is strongly suggestive that GSNO exists in equilibrium with SNO-proteins (Liu et al., (2001)). Precise enzymatic control over ambient levels of GSNO and thus SNO-proteins raises the possibility that GSNO/GSNOR may play roles across a host of physiological and pathological functions including protection against nitrosative stress wherein NO is produced in excess of physiologic needs. Indeed, GSNO specifically has been implicated in physiologic processes ranging from the drive to breathe (Lipton et al., Nature, 413: 171-174 (2001)) to regulation of the cystic fibrosis transmembrane regulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001)), to regulation of vascular tone, thrombosis, and platelet function (de Belder et al., Cardiovasc Res.; 28(5):691-4 (1994)), Z. Kaposzta, et al., Circulation; 106(24): 3057 – 3062, (2002)) as well as host defense (de Jesus-Berrios et al., Curr. Biol., 13: 1963-1968 (2003)). Other studies have found that GSNOR protects yeast cells against nitrosative stress both in vitro (Liu et al., (2001)) and in vivo (de Jesus-Berrios et al., (2003)).

[0007] Collectively, data suggest GSNO as a primary physiological ligand for the enzyme S-nitrosoglutathione reductase (GSNOR), which catabolizes GSNO and

consequently reduces available SNO’s and NO in biological systems (Liu et al., (2001)), (Liu et al., Cell, 116(4), 617-628 (2004)), and (Que et al., Science, 308, (5728): 1618-1621 (2005)). As such, this enzyme plays a central role in regulating local and systemic bioactive NO. Since perturbations in NO bioavailability has been linked to the pathogenesis of numerous disease states, including hypertension, atherosclerosis, thrombosis, asthma, gastrointestinal disorders, inflammation, and cancer, agents that regulate GSNOR activity are candidate therapeutic agents for treating diseases associated with NO imbalance.

[0008] Nitric oxide (NO), S-nitrosoglutathione (GSNO), and S-nitrosoglutathione reductase (GSNOR) regulate normal lung physiology and contribute to lung pathophysiology. Under normal conditions, NO and GSNO maintain normal lung physiology and function via their anti-inflammatory and bronchodilatory actions. Lowered levels of these mediators in pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) may occur via up-regulation of GSNOR enzyme activity. These lowered levels of NO and GSNO, and thus lowered anti-inflammatory capabilities, are key events that contribute to pulmonary diseases and which can potentially be reversed via GSNOR inhibition.

[0009] S-nitrosoglutathione (GSNO) has been shown to promote repair and/or regeneration of mammalian organs, such as the heart (Lima et al., 2010), blood vessels (Lima et al., 2010) skin (Georgii et al., 2010), eye or ocular structures (Haq et al., 2007) and liver (Prince et al., 2010). S-nitrosoglutathione reductase (GSNOR) is the major catabolic enzyme of GSNO. Inhibition of GSNOR is thought to increase endogenous GSNO.

[0010] Inflammatory bowel diseases (IBD’s), including Crohn’s and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal (GI) tract, in which NO, GSNO, and GSNOR can exert influences. Under normal conditions, NO and GSNO function to maintain normal intestinal physiology via anti-inflammatory actions and maintenance of the intestinal epithelial cell barrier. In IBD, reduced levels of GSNO and NO are evident and likely occur via up-regulation of GSNOR activity. The lowered levels of these mediators contribute to the pathophysiology of IBD via disruption of the epithelial barrier via dysregulation of proteins involved in maintaining epithelial tight junctions. This epithelial barrier dysfunction, with the ensuing entry of micro-organisms from the lumen, and the overall lowered anti-inflammatory capabilities in the presence of lowered NO and GSNO, are key events in IBD progression that can be potentially influenced by targeting GSNOR.

[0011] Cell death is the crucial event leading to clinical manifestation of

hepatotoxicity from drugs, viruses and alcohol. Glutathione (GSH) is the most abundant redox molecule in cells and thus the most important determinant of cellular redox status. Thiols in proteins undergo a wide range of reversible redox modifications during times of exposure to reactive oxygen and reactive nitrogen species, which can affect protein activity. The maintenance of hepatic GSH is a dynamic process achieved by a balance between rates of GSH synthesis, GSH and GSSG efflux, GSH reactions with reactive oxygen species and reactive nitrogen species and utilization by GSH peroxidase. Both GSNO and GSNOR play roles in the regulation of protein redox status by GSH.

[0012] Acetaminophen overdoses are the leading cause of acute liver failure (ALF) in the United States, Great Britain and most of Europe. More than 100,000 calls to the U.S. Poison Control Centers, 56,000 emergency room visits, 2600 hospitalizations, nearly 500 deaths are attributed to acetaminophen in this country annually. Approximately, 60% recover without needing a liver transplant, 9% are transplanted and 30% of patients succumb to the illness. The acetaminophen-related death rate exceeds by at least three-fold the number of deaths due to all other idiosyncratic drug reactions combined (Lee, Hepatol Res 2008; 38 (Suppl. 1):S3-S8).

[0013] Liver transplantation has become the primary treatment for patients with fulminant hepatic failure and end-stage chronic liver disease, as well as certain metabolic liver diseases. Thus, the demand for transplantation now greatly exceeds the availability of donor organs, it has been estimated that more than 18 000 patients are currently registered with the United Network for Organ Sharing (UNOS) and that an additional 9000 patients are added to the liver transplant waiting list each year, yet less than 5000 cadaveric donors are available for transplantation.

[0014] Currently, there is a great need in the art for diagnostics, prophylaxis, ameliorations, and treatments for medical conditions relating to increased NO synthesis and/or increased NO bioactivity. In addition, there is a significant need for novel compounds, compositions, and methods for preventing, ameliorating, or reversing other NO-associated disorders. The present invention satisfies these needs.

Schemes 1-6 below illustrate general methods for preparing analogs.

[00174] For a detailed example of General Scheme 1 see Compound IV-1 in Example 1.

[00175] For a detailed example of Scheme 2, A conditions, see Compound IV-2 in Example 2.

[00176] For a detailed example of Scheme 2, B conditions, see Compound IV-8 in Example 8.

[00177] For a detailed example of Scheme 3, see Compound IV-9 in Example 9.

[00178] For a detailed example of Scheme 4, Route A, see Compound IV-11 in Example 11.

[00179] For a detailed example of Scheme 4, Route B, see Compound IV-12 in Example 12.

[00180] For a detailed example of Scheme 5, Compound A, see Compound IV-33 in Example 33.

[00181] For a detailed example of Scheme 5, Compound B, see Compound IV-24 in Example 24.

[00182] For a detailed example of Scheme 5, Compound C, see Compound IV-23 in Example 23.

Example 8: Compound IV-8: 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

[00209] Followed Scheme 2, B conditions:

[00210] Step 1: Synthesis of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid:

[00211] A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3(369 mg, 2.70 mmol) in DEGME / H2O (7.0 mL / 2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2(dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110 °C for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.

[00212] Step 2: Synthesis of Compound IV-8: To a suspension of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, 0.479 mmol) in anhydrous CH2Cl2 (5 mL) was added AlCl3 (320 mg, 2.40 mmol). The reaction mixture was refluxed overnight. The mixture was quenched with saturated NH4Cl (10 mL) and the aqueous layer was extracted with CH2Cl2 / MeOH (v/v=10: l, 30 mL x3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive) to give 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (25 mg, yield 18%). 1H NMR (DMSO, 400 MHz): δ 10.20 (brs, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.10-8.00 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), MS (ESI): m/z 299.9 [M+H]+.

PATENT
WO 2012048181
PATENT
WO 2012170371

REFERENCES

1: Donaldson SH, Solomon GM, Zeitlin PL, Flume PA, Casey A, McCoy K, Zemanick ET,
Mandagere A, Troha JM, Shoemaker SA, Chmiel JF, Taylor-Cousar JL.
Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic
fibrosis adults homozygous for F508DEL-CFTR. J Cyst Fibros. 2017 Feb 13. pii:
S1569-1993(17)30016-4. doi: 10.1016/j.jcf.2017.01.009. [Epub ahead of print]
PubMed PMID: 28209466.

//////////Cavosonstat, N-91115, Orphan Drug Status, NCT02589236, N91115-2CF-05,  SNO-6, PHASE 2, N30 Pharma, Nivalis Therapeutics, CYSTIC FIBROSIS, FAST TRACK

O=C(O)C1=CC=C(C2=NC3=CC=C(O)C=C3C=C2)C(Cl)=C1

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