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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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Naloxegol


Image result for Naloxegol

Naloxegol

Movantik; NKTR-118; NKTR118; UNII-44T7335BKE; NKTR 118

854601-70-0  cas

1354744-91-4 (Naloxegol Oxalate)

(4R,4aS,7S,7aR,12bS)-7-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-prop-2-enyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol

MF C34H53NO11
MW 651.78472 g/mol
Morphinan-3,14-diol, 4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propen-1-yl)-, (5α,6α)-, ethanedioate (1:1) (salt)
Naloxegol oxalate [USAN]
UNII-65I14TNM33
AZ-13337019 oxalate
Naloxegol (oxalate)
NKTR-118 oxalate;AZ-13337019 oxalate
UNII:65I14TNM33

Naloxegol oxalate (MovantikTM, Moventig)

Image result for Naloxegol

Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherallyselective opioid antagonistdeveloped by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation.[2] It was approved in 2014 in adult patients with chronic, non-cancer pain.[3] Doses of 25 mg were found safe and well tolerated for 52 weeks.[4] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[5]

Image result for naloxegol

Naloxegol Oxalate was approved by the U.S. Food and Drug Administration (FDA) on Sept 16, 2014, then approved by European Medicine Agency (EMA) on Dec 8, 2014. It was developed and marketed as Movantik®(in the US)/Moventig®(in EU) by AstraZeneca.

Naloxegol oxalate is an antagonist of opioid binding at the mu-opioid receptor. It is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

Movantik® is available as tablets for oral use, containing 12.5 mg or 25 mg of free Naloxegol. The recommended dose is 25 mg once daily (reduce to 12.5 mg if not tolerated).

Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 5-α-hydroxyl group of α-naloxol is connected via an ether linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The “n=7” defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the “monomethoxy” indicates that the terminal hydroxyl group of the PEG is “capped” with amethyl group.[6] The pegylation of the 5-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood-brain barrier(BBB).[5] As such, it can be considered the antithesis of the peripherally-acting opiate loperamide which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.

Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids, but was recently reclassified as a prescription drug after the FDA concluded that the impermeability of the blood-brain barrier to this compound made it non-habit-forming, and so without the potential for abuse — specifically, naloxegol was officially decontrolled on 23. January 2015. [7]

Image result for Naloxegol

As an opiate antagonist, it is not expected to be capable of inducing the euphoria and anxiolytic effects which are generally cited as the desirable effects of commonly abused opiates (all of which are opiate agonists) if it were to cross the BBB; it would in fact reverse the effects of opiate drugs of abuse if it entered the central nervous system.

Naloxegol is an oral polyethylene glycol (PEG) derivative of naloxone, a peripherally acting µ-opioid receptor antagonist (PAMORA) with limited potential for interfering with centrally mediated opioid analgesia. The incorporation of a polyethylene glycol moiety aims at inhibiting naloxone’s capacity to cross the blood-brain barrier, while preserving the affinity for the µ-opioid receptor [1].

Image result for Naloxegol

Opioid-induced bowel dysfunction (OIBD) represents a broad spectrum of symptoms that result from the actions of opioids on the CNS as well as the gastrointestinal tract. The majority of gastrointestinal effects seem to be mediated by the high number of µ-receptors that are expressed in the enteric nervous system. Naloxegol was more effective than placebo in increasing the number of spontaneous bowel movements in patients with opioid-induced constipation, including those with an inadequate response to laxatives.

Recognition of Naloxegol as a useful option in the treatment of opioid-induced constipation resulted in its approval by US-FDA for adult patients with chronic, non-cancer pain in 2014.
Naloxegol oxalate (XXI) is a peripherally acting l-opioid receptor antagonist that was approved in the USA and EU for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. The drug, a pegylated version of naloxone, has significantly reduced central nervous system (CNS) penetration and works by inhibiting the binding of opioids in the gastrointestinal tract.152–154 Naloxegol oxalate was developed by Nektar and licensed to AstraZeneca. Although we were unable to find a single report in the primary or patent literature that describes the exact experimental procedures to prepare naloxegol oxalate, there havebeen reports on the preparation of closely related analogs155 with specific reports on improving the selectivity of the reduction step156 and the salt formation of the final drug substance.157 Taken together, the likely synthesis of naloxegol oxalate (XXI) is
described in Scheme 28. Naloxone (180) was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone 181. Reduction of the ketone with potassium trisec-butylborohydride exclusively provided the a-alcohol 182 in 85% yield. Alternatively, sodium trialkylborohydrides could also be used to provide similar a-selective reduction in high yield.
Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br (183) provided the pegylated intermediate 184 in 88% yield. Acidic removal of the methoxyethyl ether protecting group followed by treatment with oxalic acid and crystallization provided naloxegol oxalate (XXI) in good yield.

152. Corsetti, M.; Tack, J. Expert Opin. Pharmacol. 2015, 16, 399.
153. Garnock-Jones, K. P. Drugs 2015, 75, 419.
154. Leonard, J.; Baker, D. E. Ann. Pharmacother. 2015, 49, 360.
155. Bentley, M. D.; Viegas, T. X.; Goodin, R. R.; Cheng, L.; Zhao, X. US Patent
2005136031A1, 2005.
156. Cheng, L.; Bentley, M. D. WO Patent 2007124114A2, 2007.
157. Aaslund, B. L.; Aurell, C.-J.; Bohlin, M. H.; Sebhatu, T.; Ymen, B. I.; Healy, E. T.;
Jensen, D. R.; Jonaitis, D. T.; Parent, S. WO Patent 2012044243A1, 2012.
158. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm4183

Image result for Naloxegol

Naloxegol Synthesis

CREDIT

https://ayurajan.blogspot.in/2016/08/naloxegol.html

US20050136031A1: The patent reports detailed synthetic procedures to manufacture gram quantities of Naloxegol. The synthesis starts with Naloxone which was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone. Reduction of the ketone with potassium tri-sec-butylborohydride exclusively provided the α-alcohol in 85% yield. Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br  provided the pegylated Naloxone in 88% yield.

Identifications:

1H NMR (Estimated) for Naloxegol

Image result for Naloxegol

Image result for Naloxegol

Image result for Naloxegol

Image result for Naloxegol

PATENT

US20060182692

Figure US20060182692A1-20060817-C00004

PATENT

http://www.google.co.in/patents/WO2005058367A2?cl=en

EXAMPLE 4 SYNTHESIS OF PEG 3-NALθxoL [0211] The structure of the naloxol, an exemplary small molecule drug, is shown below.

Figure imgf000059_0001

Naloxol [0212] This molecule was prepared (having a protected hydroxyl group) as part of a larger synthetic scheme as described in Example 5.

EXAMPLE 5

Figure imgf000059_0002

[0213] α,β-PEGι-naloxol was prepared. The overview of the synthesis is provided below.

Figure imgf000060_0001

(3)

Figure imgf000060_0002

(4)

5.A. Synthesis of 3-MEM-naloxone

[0214] Diisopropylethylamine (390 mg, 3.0 mmole) was added to a solution of naloxone HCl 2H2O (200 mg, 0.50 mmole) in CH2C12 (10 mL) with stining. Methoxyethyl chloride (“MEMCl,” 250 mg, 2.0 mmole) was then added dropwise to the above solution. The solution was stined at room temperature under N2 overnight.

[0215] The crude product was analyzed by HPLC, which indicated that 3-

MEM-O-naloxone (1) was formed in 97% yield. Solvents were removed by rotary evaporation to yield a sticky oil.

5.B. Synthesis of α and β epimer mixture of 3-MEM-naloxoI (2)

[0216] 3 mL of 0.2 N NaOH was added to a solution of 3-MEM-naloxone

(1) (obtained from 5.A. above, and used without further purification) in 5mL of ethanol. To this was added a solution of NaBHLt (76 mg, 2.0 mmole) in water (1 mL) dropwise. The resulting solution was stined at room temperature for 5 hours. The ethanol was removed by rotary evaporation followed by addition of a solution of 0.1 N HCl solution to destroy excess NaBKj and adjust the pH to a value of 1. The solution was washed with CHC13 to remove excess methoxyethyl chloride and its derivatives (3 x 50 mL), followed by addition of K2OO3 to raise the pH of the solution to 8.0. The product was then extracted with CHC13 (3 x 50 mL) and dried over Na2SO4. The solvent was removed by evaporation to yield a colorless sticky solid (192 mg, 0.46 mmole, 92% isolated yield based on naloxone HCl 2H2O).

[0217] HPLC indicated that the product was an α and β epimer mixture of

3-MEM-naloxol (2).

5.C. Synthesis of α and β epimer mixture of 6-CH3-OCH2CH2-O-3-MEM- naloxol (3a).

[0218] NaH (60% in mineral oil, 55 mg, 1.38 mmole) was added into a solution of 6-hydroxyl-3-MEM-naloxol (2) (192 mg, 0.46 mmole) in dimethylformamide (“DMF,” 6 mL). The mixture was stined at room temperature under N2 for 15 minutes, followed by addition of 2-bromoethyl methyl ether (320 mg, 2.30 mmole) in DMF (1 mL). The solution was then stirred at room temperature under N2 for 3 hours.

[0219] HPLC analysis revealed formation of a mixture of α- and β-6-CH3-OCH2CH2-0-3-MEM-naloxol (3) in about 88% yield. DMF was removed by a rotary evaporation to yield a sticky white solid. The product was used for subsequent transformation without further purification.

5.D. Synthesis of α and β epimer mixture of 6-CH3-OCH2CH2-naloxoI (4)

[0220] Crude α- and β-6-CH3-OCH2CH2-O-3-MEM-naloxol (3) was dissolved in 5 mL of CH2C12 to form a cloudy solution, to which was added 5 mL of trifluoroacetic acid (“TFA”). The resultant solution was stined at room temperature for 4 hours. The reaction was determined to be complete based upon HPLC assay. CH2C12 was removed by a rotary evaporator, followed by addition of 10 mL of water. To this solution was added sufficient K2OO3 to destroy excess TFA and to adjust the pH to 8. The solution was then extracted with CHC13 (3 x 50 mL), and the extracts were combined and further extracted with 0.1 N HCl solution (3 x 50 mL). The pH of the recovered water phase was adjusted to a pH of 8 by addition of K2CO3>followed by further extraction with CHC13 (3 x 50 mL). The combined organic layer was then dried with Na2SO4. The solvents were removed to yield a colorless sticky solid.

[0221] The solid was purified by passage two times through a silica gel column (2 cm x 30 cm) using CHCl3/CH3OH (30:1) as the eluent to yield a sticky solid. The purified product was determined by 1H NMR to be a mixture of α- and β epimers of 6-CH3-OCH2CH2-naloxol (4) containing ca. 30% α epimer and ca. 70% β epimer [100 mg, 0.26 mmole, 56% isolated yield based on 6-hydroxyl-3-MEM- naloxol (2)].

[0222] 1H NMR (δ, ppm, CDC13): 6.50-6.73 (2 H, multiplet, aromatic proton of naloxol), 5.78 (1 H, multiplet, olefinic proton of naloxone), 5.17 (2 H, multiplet, olefinic protons of naloxol), 4.73 (1 H, doublet, C5 proton of α naloxol), 4.57 (1 H, doublet, C5 proton of β naloxol), 3.91 (1H, multiplet, C6 proton of naloxol), 3.51-3.75 (4 H, multiplet, PEG), 3.39 (3 H, singlet, methoxy protons of PEG, α epimer), 3.36 (3 H, singlet, methoxy protons of PEG, β epimer), 3.23 (1 H, multiplet, C6 proton of β naloxol), 1.46-3.22 (14 H, multiplet, protons of naloxol).

SYN 1

PATENT

https://www.google.com/patents/WO2012044243A1?cl=en

Naloxol-polyethylene glycol conjugates are provided herein in solid phosphate and oxalate salt forms. Methods of preparing the salt forms, and pharmaceutical compositions comprising the salt forms are also provided herein. ACKGROUND

Effective pain management therapy often calls for an opioid analgesic. In addition to the desired analgesic effect, however, certain undesirable side effects, such as bowel dysfunction, nausea, constipation, among others, can accompany the use of an opioid analgesic. Such side effects may be due to opioid receptors being present outside of the central nervous system, principally in the gastrointestinal tract. Clinical and preclinical studies support the use of mPEG7-0-naloxol, a conjugate of the opioid antagonist naloxol and polyethylene glycol, to counteract undesirable side effects associated with use of opioid analgesics. When administered orally to a patient mPEG7-0-naloxol largely does not cross the blood brain barrier into the central nervous system, and has minimal impact on opioid- induced analgesia. See, e.g., WO 2005/058367; WO 2008/057579; Webster et al., “NKTR-118 Significantly Reverses Opioid-Induced Constipation,” Poster 39, 20th AAPM Annual Clinical Meeting (Phoenix, AZ), October 10, 2009.

To move a drug candidate such as mPEG7-O-naloxol to a viable pharmaceutical product, it is important to understand whether the drug candidate has polymorphic forms, as well as the relative stability and interconversions of these forms under conditions likely to be encountered upon large-scale production, transportation, storage and pre-usage preparation. Solid forms of a drug substance are often desired for their convenience in formulating a drug product. No solid form of mPEG7-O-naloxol drug substance has been made available to date, which is currently manufactured and isolated as an oil in a free base form. Exactly how to accomplish this is often not obvious. For example the number of pharmaceutical products that are oxalate salts is limited. The free base form of mPEG7-0-naloxol has not been observed to form a crystalline phase even when cooled to -60 °C and has been observed to exist as a glass with a transition temperature of

approximately -45 °C. Furthermore, mPEG7-0-naloxol in its free base form can undergo oxidative degradation upon exposure to air. Care can be taken in handling the free base, for example, storing it under inert gas, to avoid its degradation. However, a solid form of mPEG7-0-naloxol, preferably one that is stable when kept exposed to air, is desired

a naloxol-polyethlyene glycol conjugate oxalate salt, the salt comprising ionic species of mPEG7-0-naloxol and oxalic acid. The formulas of mPEG7-0-naloxol and oxalic acid are as follows:

Figure imgf000004_0001

In certain embodiments, the methods provided comprise dissolving mPEG7-0- naloxol free base in ethanol; adding methyl t-butyl ether to the dissolved mPEG?

O-naloxol solution; adding oxalic acid in methyl t-butyl ether to the dissolved mPEG7-0-naloxol over a period of at least 2 hours to produce a slurry; and filtering the slurry to yield the naloxol-polyethlyene glycol conjugate oxalate salt in solid form.

In certain embodiments, the methods provided comprise dissolving mPEG7-0- naloxol free base in acetonitrile; adding water to the dissolved mPEG7-0-naloxol solution; adding oxalic acid in ethyl acetate to the dissolved mPEG7-0-naloxol over a period of at least 2 hours to produce a slurry; and filtering the slurry to yield the naloxol-polyethlyene glycol conjugate oxalate salt in solid form.

In some embodiments, the solid salt form of mPEG7-0-naloxol is a crystalline form.

In certain embodiments a solid crystalline salt provided herein is substantially pure, having a purity of at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

In certain embodiments, the solid salt form of mPEG7-0-naloxol is a phosphate salt.

In other embodiments, the solid mPEG7-0-naloxol salt form is an oxalate salt. For instance, in some embodiments of solid oxalate salt forms provided herein, the solid mPEG7-0-naloxol oxalate salt form is in Form A, as described herein. As another example, in some embodiments of solid oxalate salt forms provided herein, the solid mPEG7-0-naloxol oxalate salt form is in Form B, as described herein. In yet other embodiments, an oxalate salt of mPEG7-0-naloxol in solid form prepared according to the methods described herein is provided.

In yet other embodiments, an dihydrogenphosphate salt of mPEG7-0-naloxol in solid form prepared according to the methods described herein is provided.

In certain embodiments of a solid mPEG7-0-naloxol oxalate salt Form B provided herein, the salt form exhibits a single endothermic peak on differential scanning calorimetry between room temperature and about 150 °C. The single endothermic peak can occur, for instance, between about 91 °C to about 94 °C. For example, in some embodiments the endothermic peak is at about 92 °C, about 92.5 °C, or about93 °C.

PATENT

http://www.google.co.in/patents/WO2005058367A2?cl=en

PATENT

CN101033228A

PATENT

https://www.google.com/patents/CN102174049A?cl=en

References and notes

  1.  Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi; Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 14 May 2012.
  2.  “Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119”. Retrieved2012-05-14.
  3. “FDA approves MOVANTIK™ (naloxegol) Tablets C-II for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain”. 16 September 2014.
  4.  “Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation.”. Aliment Pharmacol Ther. 40: 771–9. Oct 2014.doi:10.1111/apt.12899. PMID 25112584.
  5. ^ Jump up to:a b Garnock-Jones KP (2015). “Naloxegol: a review of its use in patients with opioid-induced constipation”. Drugs. 75 (4): 419–425. doi:10.1007/s40265-015-0357-2.
  6.  Technically, the molecule that is attached via the ether link is O-methyl-heptaethylene glycol [that is, methoxyheptaethylene glycol, CH3OCH2CH2O(CH2CH2O)5CH2CH2OH], molecular weight 340.4, CAS number 4437-01-8. See Pubchem Staff (2016). “Compound Summary for CID 526555, Pubchem Compound 4437-01”. PubChem Compound Database. Bethesda, MD, USA: NCBI, U.S. NLM. Retrieved 28 January2016.
  7. ^http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0123_3.htm

1. WO2012044243A / US12015038524A1.

2. WO2005058367A2 / US7786133B2.

3. US20060182692A1 / US8067431B2.

4. CN101033228A.

5. Fudan Univ. J. Med. Sci. 2007, 34, 888-890.

WO2008057579A2 * Nov 7, 2007 May 15, 2008 Nektar Therapeutics Al, Corporation Dosage forms and co-administration of an opioid agonist and an opioid antagonist
WO2009137086A1 * May 7, 2009 Nov 12, 2009 Nektar Therapeutics Oral administration of peripherally-acting opioid antagonists
US20050136031 * Dec 16, 2004 Jun 23, 2005 Bentley Michael D. Chemically modified small molecules

Patents

7056500 United States
7662365 United States
 
8067431 United States
 
8617530 United States
 
9012469 United States

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 6
Patent 7056500
Expiration Jun 29, 2024
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
FDA Orange Book Patents: 2 of 6
Patent 7662365
Expiration Oct 18, 2022
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
 
FDA Orange Book Patents: 3 of 6
Patent 8617530
Expiration Oct 18, 2022
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
 
FDA Orange Book Patents: 4 of 6
Patent 9012469
Expiration Apr 2, 2032
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
 
FDA Orange Book Patents: 5 of 6
Patent 7786133
Expiration Dec 19, 2027
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
 
FDA Orange Book Patents: 6 of 6
Patent 8067431
Expiration Dec 16, 2024
Applicant ASTRAZENECA PHARMS
Drug Application N204760 (Prescription Drug: MOVANTIK. Ingredients: NALOXEGOL OXALATE)
Naloxegol
Naloxegol.svg
Systematic (IUPAC) name
(5α,6α)-4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propen-1-yl)morphinan-3,14-diol
Clinical data
Trade names Movantik, Moventig
AHFS/Drugs.com movantik
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding ~4.2%
Metabolism Hepatic (CYP3A)
Biological half-life 6–11 h
Excretion Feces (68%), urine (16%)
Identifiers
CAS Number 854601-70-0
ATC code A06AH03 (WHO)
PubChem CID 56959087
ChemSpider 28651656
ChEBI CHEBI:82975
Synonyms NKTR-118
Chemical data
Formula C34H53NO11
Molar mass 651.785 g/mol

//////////////Naloxegol, Movantik,  NKTR-118,  NKTR118,  UNII-44T7335BKE, NKTR 118, 854601-70-0, EU 2014, FDA 2014

COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@]2([C@H]3Cc4ccc(c5c4[C@]2([C@H]1O5)CCN3CC=C)O)O

Opicapone


STR1

Image result for Opicapone

Opicapone

2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide

BIA-9-1067; ONO-2370; BIA-91067
CAS No.923287-50-7

MF C15H10Cl2N4O6
MW: 411.9977

TRADE NAME (Ongentys®)

Approved EU 2016-06-24 BIAL PORTELA

PORTELA & CA. S.A. [PT/PT]; Av. Da Siderurgia Nacional, P-4745-457 S. Mamede do Coronado (PT)

LEARMONTH, David Alexander; (PT).
KISS, Laszlo Erno; (PT).
LEAL PALMA, Pedro Nuno; (PT).
DOS SANTOS FERREIRA, Humberto; (PT).
ARAÚJO SOARES DA SILVA, Patrício Manuel Vieira; (PT)

MOA:Catechol-O-methyl transferase (COMT) inhibitor

Indication:Parkinson’s disease (PD)

A COMT inhibitor used as adjunctive therapy for parkinson’s disease.

STR1

Opicapone was approved by European Medicine Agency (EMA) on Jun 24, 2016. It was developed and marketed as Ongentys® by Bial – Portela in EU.

Opicapone is a selective and reversible COMT inhibitor, used as adjunctive therapy for Parkinson’s disease.

Ongentys® is available as hard capsules, containing 25 mg and 50 mg of opicapone. The recommended dose is 50 mg, taken once a day at bedtime, at least one hour before or after levodopa combination medicines.

Catechol-O-methyltransferase (COMTa) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine to catecholic substrates such as endogenous catechol neurotransmitters(2)and xenobiotics including (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (l-Dopa), the gold standard drug for treatment of Parkinson’s disease (PD). Coadministration of a peripheral amino acid decarboxylase (AADC) inhibitor prevents breakdown of l-Dopa in the periphery by blocking enzymatic decarboxylation, and inhibition of COMT further improves its bioavailability by reducing the formation of 3-O-methyl-l-Dopa (3-OMD).

Abbreviations: COMT, catechol-O-methyltransferase; PD, Parkinson’s disease; AADC, amino acid decarboxylase; SAR, structure−activity relationship; ADMET, absorption, distribution, metabolism, excretion, toxicity; l-Dopa, (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid; 3-OMD, 3-O-methyl-l-Dopa.

“First-generation” COMT inhibitors such as pyrogallol, tropolone, and gallic acid are poorly selective and have poor efficacy in vivo. “Second-generation” inhibitors are exemplified by tolcapone 1, entacapone 2,(13) and nebicapone (BIA 3-202) 3 . Structure−activity (SAR) studies exploring the position of the nitro group and various side-chain substituents have been reported. Subtle differences in the mode of COMT inhibition by 1are thought to be relevant in terms of efficacy. Entacapone 2 is a short-acting,peripherally selective inhibitor which is taken concomitantly with every dose of l-Dopa. Albeit the most widely marketed COMT inhibitor, the clinical efficacy of 2 has been questioned. Tolcapone 1 is a more potent, longer acting but nonselective inhibitor of both cerebral and peripheral COMT. Unlike2, clinical use of 1 is severely restricted due to its elevated hepatotoxicity risk, postulated to occur through uncoupling of oxidative phosphorylation. Nebicapone 3 possesses a longer duration of peripheral COMT inhibition than 2 and more limited access to the brain than 1, but due to limited clinical experience, firm conclusions concerning safety have not yet been established. Undoubtedly therefore, a requirement exists for improved COMT inhibitors to address the unmet medical needs of many PD patients.
Figure

 Chemical structures of tolcapone 1, entacapone 2, and nebicapone 3.

ChemSpider 2D Image | Opicapone | C15H10Cl2N4O6

Opicapone

A preferred method of treatment of Parkinson’s disease is the administration of a combination of levodopa and a peripherally selective aromatic amino acid decarboxylase inhibitor (AADCI) together with a catechol-O-methyltransferase (COMT) inhibitor. The currently employed COMT inhibitors are tolcapone and entacapone. However, some authorities believe that each of these COMT inhibitors have residual problems relating to pharmacokinetic or pharmacodynamic properties, or to clinical efficiency or safety. Hence, not all patients get most benefit from their levodopa/AADCI/COMT inhibitor therapy.

Favoured new COMT inhibitors were disclosed in L. E. Kiss et al, J. Med. Chem., 2010, 53, 3396-3411 (D1), WO 2007/013830 (D2) and WO 2007/117165 (D3) which are believed to have particularly desirable properties so that patients can benefit from enhanced therapy.

D1, D2 and D3 also disclosed methods of preparing the new COMT inhibitors. Those processes, although effective, would benefit from an increase in yields. Other benefits which would be appropriate include those selected from reduction in number of process steps, reduction in number of unit operations, reduction of cycle-times, increased space yield, increased safety, easier to handle reagents/reactants and/or increase in purity of the COMT inhibitor, especially when manufacture of larger quantities are envisaged. A process has now been discovered that proceeds via a new intermediate which is suitable for manufacture of commercially useful quantities of a particularly apt COMT inhibitor in good yield. Additional benefits occur such as those selected from a reduced number of process steps and number of unit operations, reduced cycle-times, increased space yield, increased safety, with easier to handle reagents/reactants, improved impurity profile and/or good purity.

CLINICAL

https://clinicaltrials.gov/show/NCT01851850

SYN1

Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

Laboratory of Chemistry
Laboratory of Pharmacology
Department of Research and Development, BIAL, À Avenida da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal
J. Med. Chem., 2010, 53 (8), pp 3396–3411
*To whom correspondence should be addressed. E-mail: Psoares.silva@bial.com. Phone: +351-22-9866100. Fax: +351-22-9866192.
Abstract Image
Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to l-Dopa therapy of Parkinson’s disease
2,5-Dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (37d). Compound 37d was synthesized by a similar procedure as described for 37a. Compound 36d (500 mg, 0.84 mmol) was reacted with BBr3 (1.05 g, 4.21 mmol) in dichloromethane (5 mL) at -78°C. Recrystallization from dichloromethane-ethanol afforded 37d (284 mg, 82%) as a yellow solid.
STR1
NMR (DMSO-d6):
1H : 11.07 (2H, br, OH), 8.11 (1H, d, J = 2 Hz, H6), 7.73 (1H, d, J = 2 Hz, H2), 2.66 (3H, s, H15),2.24 (3H, s, H14).
13C : 175.2 (C7), 164.5 (C8), 150.4 (C12), 148.7 (C3), 146.3 (C4), 139.4 (C13), 137.8 (C5), 134.1(C10), 131.1 (C11), 122.7 (C9), 116.6 (C2), 115.7 (C6), 112.7 (C1), 17.9 (C14), 16.5 (C15).
Elemental Analysis:
(C15H10Cl2N4O6) C, H, N, S: Calc: C, 43.60; H, 2.44; N, 13.56; Found: C, 44; H, 2.3; N, 13.6.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007013830&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

LEARMONTH, David Alexander; (PT).
KISS, Laszlo Erno; (PT).
LEAL PALMA, Pedro Nuno; (PT).
DOS SANTOS FERREIRA, Humberto; (PT).
ARAÚJO SOARES DA SILVA, Patrício Manuel Vieira; (PT)

PATENT

The present invention in one aspect provides 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4,oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene and salts thereof, that is the compound of the formula (I):

and salts thereof.

Most aptly the compound of formula (I) is unsalted. However, salts of the hydroxy group with metal ions such as the alkali or alkaline earth metals, particularly the sodium and potassium salts are provided as well as those of highly basic organic compounds such as guanidine or the like.

Particularly suitably the compound of formula (I) or its salt is provided in a form suitable for use as a chemical intermediate. This may be, for example, in a form at least 50% pure, in crystalline form, in solid form or in an organic solvent or the like.

The compound of formula (I) is useful as an intermediate in the preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol i.e. the compound of formula II):

The compound of formula (II) may also be referred to as opicapone or 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-[1,2,4]-oxadiazole-3-yl)-4,6-dimethylpyridine-1-oxide. Opicapone has been found to be more potent than tolcapone in inhibiting liver COMT both at 3 hours and 6 hours post oral administration to rats [ED50 in mg/kg, opicapone 0.87 at 3 hours and 1.12 at 6 hours as compared to tolcapone 1.28 at 3 hours and 2.08 at 6 hours]. Opicapone at a dose of 3 mg/kg was found to be more effective at inhibiting rat liver COMT with nearly complete inhibition occurring 2 to 6 hours post oral administration with only about 90% of enzyme activity recovered after 72 hours while tolcapone provided shorter duration of activity with about 84% recovery after only 9 hours. Both opicapone and tolcapone inhibit human recombinant S-COMT but opicapone has an inhibitory constant of 16pM being 10 fold lower than that for tolcapone. With respect to the desirable property of avoiding inhibition of COMT in the brain, opicapone following oral administration to the rat was found to be devoid of effect whereas tolcapone inhibited about 50% of enzyme activity over a period of 8 hours post administration.

Preparation 1

Cyanoacetamide (280g) was reacted with acetyl acetone (352.9g) in methanol (1015g) and morpholine (14.9g). The reaction was stirred under reflux at 65 °C until the reaction appeared complete. The resulting product suspension was filtered, washed with methanol and dried to provide the desired product about 97% yield.

Preparation 2

The product of Preparation 1 (159g) was suspended in acetonitrile (749.5g) and cooled to 0-5°C. Sulfuryl chloride (178.9g) was added and the reaction mixture warmed to room temperature and stirred until the reaction appeared complete.

The resulting suspension is cooled to 0-5°C and filtered. The solid was washed with acetonitrile, ethyl acetate and heptane. The product was then dried under vacuum at 50°C to yield the desired product (82%).

Preparation 3

Phosphoryl chloride (973.2g), tetramethylammonium chloride (67.3g) and compound of Preparation 2 (227.1g) were added to dichloromethane (500g). The suspension was heated to 85°C and stirred for 5 hours. Excess of phosphoryl chloride was removed by distillation in vacuo. The reaction mixture was cooled below 30°C and diluted with dichloromethane. The resulting solution was added to water (1350g) at room temperature and stirred for 30 minutes. The lower organic phase was separate and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with water and then treated with charcoal. The charcoal was filtered and a solvent swap to heptane was performed by distillation at atmospheric pressure. The solution was filtered at 50°C and then cooled to 30°C. On further cooling to 0°C

crystals were obtained. These were isolated by filtration, washed twice with heptane. After drying at 50°C the desired product was obtained typically at 88-91 % .

The above process was repeated with a reduction in dichloromethane during crystallisation and adding some methanol. The resulting plate-like crystals were more easily transferred for subsequent use.

Preparation 4a

Product of Preparation 3 (68.6g) and 1,10-phenanthroline monohydrate (0.9g) were suspended in methanol (240g) at room temperature. Water (518g) and a hydroxylamine solution (50% in water, 80.9g), were added and the mixture heated to 70-80°C and stirred for 5-6 hours. Water was added at 70-80 °C and the solution held for 1 hour to induce crystallization. Crystallization was completed by cooling to 15°C over 8 hours. The product was filtered off and washed twice with water and dried at 50°C under vacuum. The product was an off white to light yellow and the yield was 87.9% .

Preparation 4b

A suspension of 2,5-Dichloro-4,6-dimethyl-nicotinonitrile (45.0 kg) and 50% hydroxylamine (59.2 kg) in the presence of catalytic amount of 1,10-phenanthroline monohydrate (0.680 kg) in methanol / water (214 kg/362 kg) is heated to 70-80°C. The mixture is agitated at 70-80°C. Water (353 kg) is added slowly into the resulting solution while the temperature is maintained at > 79°C. The solution is cooled to 75 °C with stirring resulting in crystallization of (Z)-2,5-dichloro-N’-hydroxy-4,6-

dimethylnicotinimidamide. The suspension is further cooled to 20 °C, the solid is filtered off and the wet cake is washed with water (160 kg). (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide is dried under vacuum at max. 60°C until residual water level is max 0.15% (KF).

Example 1a

Preparation of 4-hydroxy-5-methoxy-3 nitrobenzoic acid

Vanillic acid (75g) was suspended in acetic acid (788g). The suspension was cooled to 10°C to 15°C and nitric acid (49g or 65% solution) was added over three hours at a rate which kept temperature between 10°C and 20°C. The resulting yellow orange was stirred for a further one hour at 18°C to 23°C. The suspension was filtered off, washed with acetic acid, then a mixture of acetic acid and water (1/2) and then water. Yield of 53% of a 87.9% pure product was obtained.

The above crude product was suspended in acetic acid and warmed to 105°C to 110°C until an orange brown solution is obtained. The solution was transferred to the crystallization vessel via a charcoal filter (or polish filtration) at a temperature above 85°C (optional step). The solution was then cooled to 80°C to 85°C. The mixture was stirred for one hour at 70°C to 80°C (optionally at 75°C) during which crystallization occurred. The product suspension was cooled to 20°C to 25°C for 17 hours or stirred for at least 12h at 20°C to 25 °C. The product suspension was filtered and washed with acetic acid, then acetic acid/ water (1/2) and finally water. The product was dried under vacuum at 50°C to 55°C. The yield of 70% corresponds to an overall yield of 44% for both parts of this preparation. The purity of the product assayed at 99.7% .

The preceding crystallization step is optional and the solution may be transferred to the crystallization vessel via polish filtration instead of via a charcoal filter.

The post crystallization suspension may be stirred for at least 12 hours at 20° C to 25 °C as an alternative to 17 hours.

Example 1b

Preparation of 4-hydroxy-5-methoxy-3 nitrobenzoic acid

A reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50°C in around 75 minutes. Temperature was set to 16°C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours.

The suspension was centrifuged whilst washed with 25 kg of acetic acid, 50 liter deionised water and 25 kg of acetic acid again. The wet crystalline material was suspended in 165 kg of acetic acid and heated at 91°C until complete dissolution. The solution was then cooled to 19.8°C and the mixture was allowed to stir for 1 hr. Centrifugation and washing with 15.2 kg acetic and 40 liter of deionised water was performed. The wet material was then dried in tray vacuum drier between 40-50°C until constant weight, for 72 hours. The dry material weight was 28.7 kg. The calculated yield was 45.4%.

Example 1c

Preparation of 4-h droxy-5-methoxy-3 nitrobenzoic acid

A suspension of vanillic acid (68.8 kg) in acetic acid (720 kg) is cooled to 17°C before an excess of a 65% nitric acid (44.0 kg) is added. After complete dosage of nitric acid the suspension is stirred for 2 hours. The suspension is filtered off and the wet cake is successively washed with acetic acid (80.0 kg), acetic acid/water (1:2 w/w – 105 kg) and finally water (80 kg – if necessary repeat). The solid is dried at 52°C for NMT 12 hours prior going to next step.

A suspension of the crude solid (650 kg) in acetic acid is warmed to 105 °C and stirred until complete dissolution of the crude solid. After polish filtration, the solution is cooled to 20°C over 3h resulting in crystallization and the suspension is stirred for 2h at 20°C. The solid is filtered off and the wet cake is successively washed with acetic acid (80 kg), acetic acid/water (1:2 w/w – 105 kg) and finally water (193 kg – if necessary repeat). 4-hydroxy-5-methoxy-3 nitrobenzoic acid pure is dried under vacuum at max. 55 °C until max 0.5% w/w residual acetic acid and max 0.2% w/w water is reached.

Example 2a

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoic acid

The process of Example la was scaled up to employ vanillic acid (375g) in acetic acid (3940g) to which was added nitric acid (65%, 245g) at 12°C over 3 hours followed by stirring for one hour. The overall yield was 40% of a 99.9% pure product.

Example 2b

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoic acid

Vanillic acid methyl ester (33g) and sodium nitrite (0.625g) are charged. Water (158mL) and 1,4-dioxane (158mL) are added at room temperature. The reaction mixture is heated to 40 °C. Nitric acid (65%) (15.75g) is added in the course of three hours and the resulting mixture is stirred for 4h after addition. The reaction mixture is sampled for completion.

The water/nitric-acid/dioxane azeotrope is distilled off in vacuum at 40 °C. The resulting product suspension is quenched by addition of sodium hydroxide solution (50% , 33.2 mL) and then stirred for 16h. The quench mixture is sampled for completion.

Then, HCl (18,5%, 70.2mL.) is added until the pH is below 1. The product is filtered off and washed with water (27.9mL). The product is then dried in vacuum at 50 °C. The overall yield was 81 % of a 97.3 % pure product.

Example 3a

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in dioxane (approx 4.5 vol) was treated with thionyl chloride (1.5 eq) and heated to 80°C. A clear solution formed at approximately 75 °C. The mixture was stirred for 3 hours at 80°C. Unreacted thionyl chloride was distilled off and after distillation the residue was cooled to 10°C.

Example 3 b

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in DCM (approx 3.4 vol) is treated with thionyl chloride (1.0 – 1.2 eq, for example 1.1 eq) and catalytic amount (0.011 eq) of DMF and the mixture is stirred for 16 h at 40°C. DCM is distilled off (approx 2.7 vol) and the residue is diluted with THF (approx 1.8 vol). The excess of thionylchloride is distilled off with THF/DCM and the residue after distillation is cooled to 10°C.

Example 3c

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of compound of Example la (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0 – 1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10°C.

The amount of DCM may be approx 3.4 as an alternative to approx 4.5 vol.

The catalytic amount of DMF may be about 0.011 eq as an alternative to 0.0055 eq.

Example 3d

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

In a reactor 68 kg dichloromethane, 20 kg 5-nitro- vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2°C.

The mixture was heated to 40°C until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40°C then the mixture was cooled to 20-25 °C and the distillation was continued until dry under vacuum at 40°C.

The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in

Example 4d.

Example 3e

Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoyl chloride

A suspension of product of example 1C (4-hydroxy-5-methoxy-3 nitrobenzoic acid -160g, 1eq) in 1,4-dioxane (720mL, 4.5vol) is treated with thionyl chloride (169.8g, 103.7mL,1.5eq) and heated to 80°C. A clear solution is formed at approx. 75 °C. The mixture is stirred at 80 °C (3 hours). Unreacted thionyl chloride is distilled off and the residue after distillation is cooled to 10°C.

Example 4a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In this example the compound of formula (IV) is reacted with the compound of formula (V) to produce the compound of the formula (III).

Compound of formula (V) (1.24 eq) was suspended in 1,4-dioxane (approximately 4.5 vol) and the suspension cooled to 10°C. The acyl chloride (compound of formula (IV)) solution of Example 3a in 1,4-dioxane was added slowly maintaining the temperature below 20°C. A clear orange solution was formed. After complete addition, the reaction mixture was stirred at 20°C for one hour. Pyridine (approximately 8eq) was added and the reaction mixture heated slowly to 115°C. The mixture was stirred for 6 hours at 115°C and then cooled to 20°C.

The dioxane/pyridine was distilled off under vacuum at 70°C. The residue was kept at 80°C and ethanol (approx 8 vol) added to induce crystallization. The resulting yellow suspension was cooled to 0°C and stirred for two hours. The product was filtered off and washed with ethanol (2.5 vol) water (3.8 vol) and ethanol 2.5 vol). The product was dried under vacuum at 50 °C. Typical yields for this process are 82 to 85%.

In an optional variant, methanol was employed in place of ethanol to induce crystallization.

Example 4b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a different reactor, compound of formula (V) (1.1 eq) is dissolved in DM Ac (approx 5.8 vol) and the solution is cooled to 5°C. The benzoyl chloride solution of Example 3b in THF/DCM is then added slowly maintaining the temperature below 10°C. After complete addition, the reaction mixture is stirred at 20 ±5°C. Pyridine (1.3 to 1.6 eq, for example 1.5 eq) is charged and the reaction mixture is heated slowly to 110±5°C removing low boiling components by distillation. The mixture is stirred for additional 3 h at 110±5°C.

In a further reactor, concentrated HCl (23.8 eq) is diluted with water (approx. 8.5 vol) and cooled to 10 °C. The reaction mixture in pyridine is dosed slowly to diluted hydrochloric acid. After complete addition, the resulting suspension is stirred for additional 2 h and the solid is filtered off. The crude solid is washed once with water and pre-dried on funnel.

The crude solid is suspended in DCM (approx. 28.6 vol) and the suspension is heated to 40°C to reach a clear solution. Resulting solution is cooled to 20°C and extracted with water. After phase separation, the aqueous phase is re-extracted with DCM and combined organic phase are washed once with water. DCM is distilled off under vacuum followed by addition of ethanol. Resulting suspension is further distilled to reduce the amount of DCM, then cooled to 5°C and stirred for additional 2 h. Finally, the product is filtered off, washed once with cold ethanol and dried under vacuum at 45°C.

Example 4c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a second reactor, compound of formula (V) (1.1 eq) is dissolved in DMAc (approx. 7 vol) and the solution is cooled to 5°C. The benzoyl chloride solution of Example 3c in THF/DCM is added slowly maintaining the temperature below 10 °C. After complete addition, the reaction mixture is stirred at 20 ± 5°C for 30 min. Pyridine (6.9 to 7.3 eq, for example 7.14 eq) is charged and the reaction mixture is heated slowly to 110°C removing low boiling components by distillation. The mixture is stirred for additional 4 h at 110°C and cooled to 20°C.

In a third reactor an emulsion of diluted hydrochloric acid (prepared from cone. HCl (19.6 eq) and approx. 7.6 vol distilled water) and DCM (approx. 25.5 vol) is cooled to about 15 °C before the reaction mixture in pyridine is dosed slowly to the emulsion. After complete addition, the organic phase is separated and washed with water before DCM is distilled off under vacuum followed by addition of ethanol. The resulting suspension is further distilled to reduce the amount of DCM, then cooled to 5°C and stirred for additional 2 h.

Finally, the product is filtered off, washed once with cold ethanol and dried under vacuum at 45 °C.

Example 4d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

140 kg Ν,Ν-dimethyl acetamide was charged into the reactor. 24.2 kg of amidoxime of Preparation 4 was dissolved in N,N-dimethyl acetamide while stirring at 21°C. The solution was cooled to 5-10°C. The THF solution of Example 3d was introduced slowly into the reaction mixture, 1.5-2 hrs, while the internal temperature was maintained at max. 9.5°C by external cooling. When the addition was complete the external cooling

was stopped. The internal temperature was allowed to raise to 21 °C in an hour. After stirring for 30 minutes, pyridine 53.0 kg was added to the mixture, while the temperature was in the range of 22.4°C – 20.6°C. Heating was started and the internal temperature raised to 105-115°C. The mixture started to reflux for 3h while the internal temperature managed to 113°C by partial distillation of some THF. The reaction mixture was then cooled and introduced to a mixture of 220 kg concentrated HCl and 170 kg of deionised water while the internal temperature was maintained between 14-16°C. The reactor was rinsed with 10 kg of Ν,Ν-dimethylacetamide and 20 kg deionised water. The rinse liquid was run to the mixture. The suspension was then further cooled to 5-10°C and stirred for 1.5-2.0 hours. The product was centrifuged and was washed 80 kg deionised water. Crude wet weight of the product was 88.6 kg.

The crude wet product, was dissolved in 460 kg (340 L) dichloromethane at max 40°C. When dissolved the temperature was set to 20-30°C and 120 kg deionised water was added. The organic phase was separated, the inorganic phase was extracted with 80 kg dichloromethane. The organic phase of 460 kg, was then washed with 200 kg deionised water and the phases were separated. The inorganic phase was extracted with the 80 kg dichloromethane and the organic phases were unified. The organic phase obtained so was concentrated in vacuum at 35°C to 200-240 Liter, then 260 kg ethanol 96% was continuously added and the evaporation was continued to a final 200-240 liter volume. Then the mixture was cooled to 5-10°C and was allowed to stir for 3 hrs. Centrifuging, washing with 20 kg ethanol resulted in 35.4 kg wet product. Vacuum drying for 16 hours at 45°C gave 34.09 kg dry product. The yield was 79.9%.

Example 4e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

In a second vessel, (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotiriimidamide (201.2g, 1.24eq) is suspended in 1,4-dioxane (720mL, 4.5vol) and the suspension is cooled to 10°C. The residue of example 3e in 1,4-dioxane is added slowly maintaining the temperature below 20°C. A clear orange solution is formed. After complete addition, the reaction mixture is stirred at 20°C for 1 hour. Pyridine (483.7mL, 8eq) is then charged and the reaction mixture is heated slowly to 115°C. The mixture is stirred at 115°C for 6 hours. The solution is then cooled to 20°C. Dioxane/pyridine is distilled off.

After distillation, the pit is kept at 80 °C and ethanol (1.28L, 8vol) is added at this temperature to induce crystallization. The resulting yellow suspension is cooled to 75 °C and stirred for 1h at this temperature to allow crystal growth. The product suspension is then cooled to 0 °C and stirred for 2h at this temperature. The product is filtered off and washed subsequently with ethanol (400mL, 2.5vol), water (608mL, 3.8vol) and ethanol (400mL, 2.5vol). The product is dried under vacuum at 50°C until LOD is max 1% w/w.

Example 4f

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

A mixture of compound of formula (V) (11.7g, 50 mmol, 1.25eq), methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10g, 40 mmol, leq) and a catalytic amount of p-toluenesulfonic acid (0.76g, 4mmol, 0.1eq) in dimethyl acetamide was heated to 80°C. The reaction was followed by HPLC. After 23h, 6% of conversion was obtained.

Example 4g

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-y1]-2-hydroxy-3-methoxy-1-nitrobenzene

A mixture of compound of formula (V) (11.7g, 50 mmol, 1.25eq), methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10g, 40 mmol, 1eq) and a catalytic amount of aluminum chloride (0.53g, 4mmol, 0.1eq) in dimethyl acetamide was heated to 80°C. The reaction was followed by HPLC. After 20h, 10% of conversion was obtained.

Example 5a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

A solution of the product of Example 4a (24g) was dissolved in dichloromethane (388g) at 20-40°C. The yellow solution was cooled to 5°C and urea hydrogen-peroxide (UHP) (17.6g) and trifluoroacetic acid anhydride (37g) added and stirring continued for 12hr at 5°C. The reaction mixture was warmed to room temperature over one hour and stirring continued for a further five hours. The precipitate that formed was filtered off and washed with dichloromethane. The combined filtrates were diluted further with dichloromethane, all washed and concentrated at atmospheric pressure. Toluene was added and the resulting suspension concentrated under vacuum, to remove residual dichloromethane. Further toluene was added and the mixture checked to ensure less than 0.5% dichloromethane and less than 0.1% water was present. Formic acid was added to provide a 10-12% formic acid in toluene mixture. The resulting suspension was warmed to 90°C and stirred until complete dissolution of solid. Crude product was obtained by cooling the solution to 5-10°C until crystallization commenced. The suspension was agitated at 5-10°C until crystallization appeared complete. The solid was filtered off, washed with toluene and dried under a stream of nitrogen.

The crude product was suspended in 10-12% wt/wt solution of formic acid in toluene and warmed to 90°C until dissolution of the solid. The solution was cooled to 5°C and stirred at 5°C until crystallisation occurred. The solid was obtained by filtration and washed with toluene. This recrystallization was repeated until the product tested as containing less than 0.1 % of starting material. The pure product was dried under vacuum at 50°C.

Example 5b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4b (24g) in DCM (388g) at 20-40°C the yellow solution is cooled to 5°C before the temperature controlled addition of urea hydrogen peroxide complex (UHP)(17.6) and trifluoroacetic anhydride (TFAA) (37g). After addition of TFAA is complete stirring is continued for 12h at 5°C before the reaction mixture is warmed to room temperature (RT) within 1 h and stirring is continued for additional 5 h. The precipitate formed during the reaction is filtered and washed with DCM on the funnel filter. The combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure. DCM is replaced by toluene (170g) and the resulting suspension is concentrated again under vacuum to remove surplus DCM. Distillates are replaced by fresh toluene as before and the mixture is analyzed for residual water and DCM (Residual DCM after solvent switch max. 0.5%; residual water after solvent switch max. 0.1 %). Formic acid (24g) is charged resulting in an approx. 10-12 % w/w formic acid in toluene solvent mixture The resulting suspension is warmed to 90°C and stirred until compete dissolution of the solid is achieved. The crude product is crystallized by cooling of this solution to 5-10°C and subsequent agitation of the resulting suspension at 5-10°C. The solid is filtered of washed with toluene and then dried in a stream of nitrogen gas.

The crude product so obtained is suspended in an approx. 10-12 %w/w solution (176g) of formic acid in toluene. The suspension is warmed to 90°C and stirred until all product is dissolved. After cooling of this solution to 5°C and subsequent stirring at 5°C, crude product is isolated by filtration and subsequent washing of the wet product with toluene.

The re-crystallization of crude product is repeated (2 or more times). The pure product (11.8g) is dried at 50°C under vacuum.

Example 5c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4c (24g) in DCM (388g) at 20-40°C the yellow solution is cooled to 5°C prior to the temperature controlled addition of urea hydrogen peroxide complex (UHP) (17.6g) and trifluoroacetic acid anhydride (TFAA) (37g). After addition of TFAA is complete stirring is continued for 12h at 5°C before the reaction mixture is warmed to RT within 1 h and stirring is continued for additional 5 h. The precipitate formed during the reaction is filtered and the filter cake is washed with DCM. The combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure. DCM is replaced by toluene (170g) and the resulting suspension is concentrated again in vacuum in order to remove surplus DCM and water. Distillates are replaced by fresh toluene followed by addition of formic acid (24g). The resulting suspension is warmed to 80°C and stirring is continued in order to dissolve the solid. The product is crystallized by cooling of this solution to 5°C and subsequent agitation of the resulting suspension at 5°C. The solid is filtered, washed with toluene and then dried in a stream of nitrogen gas.

The product is suspended in a formic acid / toluene (18g/158g) mixture followed by warming of the reaction mixture to 80°C. After dissolution of the product the solution is cooled to 5°C whereby the product precipitates. After additional stirring at 5°C the suspension is filtered and the filter cake is washed with toluene.

The re-crystallization of the product is repeated. The product is used as a wet material in the next process step (12.1g product obtained if dried at max. 60°C).

Example 5d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yI]-2-hydroxy-3-mefhoxy-1-nitrobenzene

550 kg (420 L) Dichloromethane was charged into a reactor. 34 kg of product of example 4d was added to in a short period at 20°C internal temperature. The solution was cooled to 6.5°C then 24.9 kg urea hydrogen peroxide complex (UHP) was added over a period of 20-40 minutes between 5-10°C. Stirring was continued for additional 20 minutes between 6.5-7.5°C. Trifluoroacetic anhydride, 53 kg, was administered into the reaction mixture, starting and maintaining the temperature at 6-7°C over a period of 2-3 hours. When the administration was complete the mixture was stirred for additional 30 minutes. Then the internal temperature was allowed to rise to a maximum of 25°C over a period of 1.5 hours. The internal temperature was maintained between 20-25°C and the mixture was allowed to react for additional 18-20 hrs. The reaction mixture was centrifuged and the fuge was washed with 45 kg dichloromethane. To the separated dichloromethane solution 460 kg (350 L) dichloromethane and 190 kg deionised water was added. The mixture was stirred for 10 minutes and the phases were separated for 30 minutes. The organic phase was washed again with 2×190 kg deionised water and separated as previously. Evaporation of the unified organic solution at max 35 °C under vacuum was done to a final volume of 100-120 L. Then a total of 105 kg acetonitrile was administered into the system while the distillation was continued to keep the volume at 100-120 L. When complete an additional 170 kg (220 L) acetonitrile was added to the mixture at normal pressure. This suspension was heated to 70-80°C at normal pressure while dichloromethane was distilled off continuously. The mixture was then kept stirred for an hour. The suspension was cooled to 20-25°C and was stirred for an additional 30 minutes. The suspension was then centrifuged and was washed with 30 kg acetonitrile. The wet material, 29.7 kg, was vacuum dried for 16 hrs at 30°C. Dried product yield was 81.5%.

27.7 kg product, 240 kg toluene and 29.2 kg formic acid was charged into reactor then heated to 90°C for complete dissolution for 1 hour. Then the solution was cooled to 7°C and then the suspension was kept at 7°C for additional 2 hrs. If necessary seeding was applied with 3-5 grams of pure product. The suspension was then centrifuged for 1 hour whilst washing with 28 kg cold toluene. The product was suspended in 225 kg toluene and 27.2 kg formic acid was charged. The mixture then was heated to 90°C for complete dissolution for 1 hour. Then the solution was cooled to 20-25 °C, then the suspension was kept between 15-25°C for additional 2 hrs, seeded if necessary. The suspension then was centrifuged for 60 minutes whilst washed with 28 kg cold toluene. The recrystallization process may be repeated 2-3 more times.

Drying for 24 hrs at 38-41°C under vacuum was conducted until constant weight. This resulted in 16.34 kg (58.8%) dry material.

Example 5e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene

After dissolution of the product of Example 4e (150g) in DCM (2.43kg) at reflux, the yellow solution is cooled to 5°C prior to the temperature controlled addition of carbamide peroxide (UHP – urea hydrogen peroxide) ( 110g) and trifluoroacetic acid anhydride (TFAA) (155.1 ml in 4 portions within 2 hours). The mixture is stirred for 12h at 5°C then the reaction mixture is warmed to 25 °C over 1.5 hours and stirred for 5 hours. The precipitate formed during the reaction is filtered and the filter cake is washed with DCM (0.36 kg). The combined filtrates are warmed to 30°C and diluted with water (300g). 10% sodium hydroxide is added until pH= 4 is reached. The biphasic system is stirred for 10 minutes at 30°C and the mixture is then allowed to separate. The organic layer is then successively washed with a mixture water (750g) and 10% sodium hydroxide (7.5g) (until pH=4), 3.2% HCl solution (300g). DCM is distilled at atmospheric pressure and then replaced by toluene (1035g) applying vacuum (150mbar) and keeping internal temperature at 45°C. Formic acid (300g) and toluene (900g) are added keeping the internal temperature above 40°C. The resulting solution is distilled under vacuum (150 mbar, 45°C internal temperature) until distillation ceases. After seeding at 45°C, the slurry is stirred for 1 hour at 45°C then is cooled to 5°C over 2 hours. The suspension is stirred for at least 2 hours at 5°C and then filtered. The wet cake is washed with toluene (195g) and dried in a stream of nitrogen gas (Chemical purity of crude product min. 92 % area).

A suspension of crude product in formic acid (388g, 2wt) is warmed to 55°C and stirred until complete dissolution of the crude product. Toluene (1242g, 6.4wt) is added maintaining the internal temperature above 50 °C. The reaction is stirred at 150mBar and internal temperature 45 °C until distillation ceases. The vacuum and distillation is stopped and then seed is added at 45°C. The slurry is stirred for 1 hour at 45°C and cooled to 5°C in 2 hours. The resulting suspension is stirred for at least 2 hours at 5°C then filtered. The wet cake is washed with toluene (260g, 1.34wt). The wet cake is collected and charged into the reactor. This procedure is repeated at least twice until 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-y1]-2-hydroxy-3-methoxy-1-nitrobenzene level max is 0.1 % (a/a) prior to dry at 25°C max under vacuum.

Example 6

Example 5a was repeated on a larger scale employing product of Example 3 (82g), dichloromethane (1325g), urea peroxide (60.1g) and trifuoroacetic acid anhydride

(128g).

Example 7a

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

(Π)

Product of Example 6 (15g) was suspended in N-methyl pyrrolidone (NMP) (131.5g) and cooled to 5°C. Aluminium chloride (6.2g) and pyridine (12g) were added while maintaining the temperature at 5°C. After the addition of pyridine was complete the reaction mixture was warmed to 60 °C and maintained for 2 hours. After confirmation that less than 0.5 starting material remained, the reaction mixture was cooled, and aqueous HCl (water 233g, HCl 123g, 37%) added. The resulting yellow solid was isolated by suction filtration. The resulting wet product was washed with water and propan-2-ol (67g) and dried under vacuum.

Optionally, the crude product was suspended in ethanol (492g) and warmed to reflux. The suspension was stirred for 1 hour under reflux and then cooled to room temperature. The solid was obtained by filtration, washed with ethanol and dried under vacuum at 50°C. A typical yield of 85% was achieved.

If desired either the final ethanol crystallised material or the initially produced product after washing with propan-2-ol may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7b

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-y1)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

An approx. 11 % w/w suspension of the product of example 5b (20g) in NMP (150g) is cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (8g) and pyridine (15.3g). After addition of pyridine is complete the reaction mixture is warmed to 60°C followed by additional 2 h reaction time. After complete conversion of the product of example 5b the reaction mixture is cooled before an aqueous diluted hydrochloric acid (water 293g, HCl 177g, 34%) is dosed. By addition of the hydrochloric acid, crude product precipitates from the NMP/water matrix as a yellow solid which is isolated by suction filtration. The resulting wet product is washed with water and 2-propanol in a replacement wash followed by drying of the wet crude product under vacuum.

The crude product is suspended in ethanol (282g) followed by warming of the mixture to reflux. The suspension is stirred for 1 h at reflux conditions followed by cooling to room temperature. The product is isolated by filtration of the suspension. The wet product is washed with ethanol and subsequently dried in vacuo at approx 50°C (typically weight corrected yield was 85%).

The product (20g) is suspended in formic acid (725g) before the resulting suspension is warmed to max. 67°C. Stirring is continued until complete dissolution of the product is achieved. The hot solution is filtered and the filtrate is cooled to 40 – 45°C before the product is precipitated first by concentration of the solution to approx. 40% (v/v) of its original volume followed by addition of the anti solvent 2-propanol (390g). After addition of 2-propanol is finished the resulting suspension is kept at 55-60°C for crystal ripening followed by cooling to RT and filtration. The filter cake is washed with 2-propanol followed by drying of the material at max. 58°C until loss on drying (LOD) max. 0.5% . Typically, a yield of 97-98% was obtained.

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7c

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

A suspension of the product of example 5c (20g) or of example 6 (20g) in NMP (153g) is cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (8.2g) and pyridine (15.4g). After addition of pyridine is complete the reaction mixture is warmed to 60°C followed by additional 3 h reaction time. After complete conversion of the product of example 5c or of example 6 the crude product is

precipitated by a temperature controlled addition of an aqueous hydrochloric acid solution (water 296g, HCl 179g, 34%). Filtration of the solid followed by washing of the wet filter cake with water and 2-propanol yields a crude product wet material which is immediately dissolved in formic acid (536g). After polish filtration the filtrate is concentrated under vacuum followed by addition of the anti-solvent 2-propanol (318g). After aging of the resulting suspension at 55-60°C the suspension is cooled to RT and filtered. The wet filter cake is washed with 2-propanol. The wet product is dried under vacuum at max. 58°C until LOD max. 0.5%. The yield was in the range of 70-95%

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7d

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

132 kg (147 L) N-methylpyrrolidone was charged into a 1000 L reactor. 16.3 kg of product of example 5d was then added. The suspension was cooled to 5-7°C and 6.5 kg of sublimed aluminium chloride was added in portions keeping the internal temperature between 5-10°C. The mixture was stirred for 10 minutes then 12.6 kg pyridine was added maintaining the internal temperature between 5-10°C. The mixture was warmed with water in the jacket to 20-25°C and the mixture was stirred for 30 minutes. Then the mixture is heated to 58-62 °C and reacted for around 2 hours. In a separate reactor a mixture of 240.5 kg deionised water and 146.4 kg concentrated HCl was mixed. This was cooled to 15-20°C. The reaction mixture from the demethylation was introduced into the diluted hydrochloric acid between 20-25°C. Optionally, 51.2 kg dichloromethane was added to the suspension, stirred for 30 minutes and was centrifuged, washed with 60 kg deionised water and 20 kg isopropanol. Drying gave 15.9 kg of product.

The product was suspended in 185.3 kg of ethanol. The mixture was then stirred at 78°C for an hour, then cooled to 20-25°C and stirred for 1 hour. The suspension was then centrifuged and the filtercake was washed with 44.5 kg ethanol, 96% . The solid material was dried at 50°C in vacuum in a stainless steel tray drier. 14.35 kg (90.3% yield) dry product was obtained.

A reactor was charged with 317.2 kg formic acid and dry product. The mixture was heated to 65 °C until all the solid dissolves. The hot solution was then filtered to an empty 1000 L reactor, was rinsed with 20 kg formic acid, then the formic acid solution was distilled partially off under vacuum to around 80-100L. 260 kg isopropanol was then introduced at 50-60°C and stirred for 30-35 minutes. The mixture was then cooled to 20-25°C with water in the jacket and was allowed to stir min 2 hours. The suspension was then centrifuged and was washed with 25 kg isopropanol. The wet material was removed from the fuge and was transferred into vacuum tray drier and was dried until constant weight under vacuum at 45-50°C resulting in 13.6 kg product, with a yield of 95.3% .

If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.

Example 7e

Preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

A suspension of product of Example 5e (34.1kg) in N-Methyl pyrrolidone (NMP) (182kg) is warmed to 50 °C until dissolution and then cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (9.8 kg) and pyridine (18.2kg). After addition of pyridine is complete the reaction mixture is warmed to 60°C and stirred for at least 2 hours. The reaction mixture is cooled to 10-16°C (e.g. 11, 13, 15°C) before an aqueous diluted hydrochloric acid (4M solution, 283L) is dosed maintaining the temperature below 25 °C. During the addition of the hydrochloric acid the crude product is precipitated from the NMP/water matrix as a yellow solid. The yellow solid is filtered and subsequently washed with water (179kg), 2-propanol (105kg). The wet solid is dried under vacuum at 55°C.

A suspension of wet product (25.1kg) in formic acid (813kg) is warmed to max. 67°C. The mixture is stirred at 67°C until complete dissolution of the product is achieved. The hot solution is filtered and the filtrate is cooled to 40 – 45°C before the product is precipitated first by concentration of the solution to approx. 40% (v/v) of its original volume followed by addition of the anti solvent 2-propanol (380kg). After addition of 2-propanol the resulting suspension is stirred at 55-60°C for crystal ripening followed by cooling to RT and filtration. The filter cake is washed with 2-propanol (38kg) and then dried at max. 58°C until LOD max. 0.5%). The product may be milled (for example using the method of Example 8).

Example 8

Micronization of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol with MC JETMILL® type 200 milling equipment (micronization through spiral jet mills)

Equipment:

Mill: MC JETMILL® 200

Dosing unit: K-Tron T 35

Cyclone: type 600

Each micronization trial was performed on at least 2 kg of 5-(3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

The following working parameters have been defined for the micronization:

Feed rate range: 24.0-48.0 kg/h (200-400 g/30sec.)

Mill pressure range: 3.0-4.0 bar

Venturi pressure range: 3.0-4.0 bar; preferably the Venturi pressure is the same as the mill pressure

Using the above equipment and working parameters the microparticles of 5-(3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol comply with the following particle size specification (particle size determined by optical microscopy): D10 (EDC) is not less than 4 or 5 μm (for example not less than 5 μm), the D50 (EDC) is 10-45 or 15-30 μm (for example 15-30 μm) and the D95 (EDC) is not more than 60 or 70 μm (for example not more than 60 μm).

Example 9 (Figure 5)

2,5-Dichloro-4,6-dimethyl-nicotinonitrile is reacted with hydroxylamine in the presence of catalytic amounts of 1,10-phenanthroline monohydrate to yield the aldoxime (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide which represents the first coupling partner towards the synthesis of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene. The second coupling partner 5-nitro-vanillic acid pure is synthesized from vanillic acid by nitration with 65 % nitric acid followed by re-crystallization of the crude 5-nitro-vanillic acid intermediate from acetic acid. The convergent assembly of the oxadiazole moiety in 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene is achieved by first activation of 5-nitro-vanillic acid as its acid chloride and subsequent coupling with the aldoxime (Z)-2,5-dichloro-N’-hydroxy-4,6-dimethylnicotinimidamide. Cyclisation of the initially formed coupling product is achieved thermally to give the oxadiazole moiety by elimination of water. The reaction

mixture of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene, after ring closure reaction, is concentrated and product isolated from 1,4-dioxane/ethanol mixture in one step. Oxidation of the pyridine ring to the corresponding aryl-N-oxide (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene) is achieved with trifluoroperoxoacetic acid which is formed in situ from UHP (Urea hydrogen peroxide complex) and trifluoroacetic acid anhydride. Unreacted 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene is subsequently removed from 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene by repeated re-crystallisation from formic acid/toluene. The analogue intermediate 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene pure with a level of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene below 0.10 %area is converted to 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol crude analogue by ether cleavage in the presence of a stoichiometric amount of aluminium chloride and pyridine. After completion of the reaction, the crude product is isolated by precipitation with an aqueous hydrochloric acid followed by dissolution of the precipitate in formic acid. After polish filtration of the resulting solution and partial solvent switch from formic acid to isopropanol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol is crystallized from the resulting formic acid/IPA crystallization matrix and finally optionally milled to the desired particle size.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012107708

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007117165

scheme 1 depicts example how to produce a compound of the general formula IIB from a compound of the general formula IVB:

iii.

HB IVB
Scheme 1. Reagents: i. Piperidine, ethanol, reflux; ii. SO2Cl2, CCl4, reflux; iii. POCI3, 120 0C, 18 h; iv. 50% H2NOH, MeOH-H20, 1.25 mol % 1,10-phenanthroline hydrate.

The following reaction scheme 2 depicts an example how to produce certain compounds of general formula III:

I, R8 = methyl III, R8 = R9 = H
iv.
R9 = H

III, R8 = R9 = benzyl

Scheme 2. Reagents: i. 65 % HNO3, AcOH; ii. 48 % HBr (aq), 140 0C; iii. MeOH, HCl(g); iv. BnBr, K2CO3, CH3CN, reflux; v. 3N NaOH, MeOH/H2O.

The following reaction scheme 3 depicts an example how to produce the compound A, by activation of a compound according to general formula III followed by cyclisation involving condensation with a compound according to formula HB, dehydration and deprotection of the methyl residue protecting the hydroxyl group;

0C

compound A

Cited Patent Filing date Publication date Applicant Title
WO2007013830A1 Jul 26, 2006 Feb 1, 2007 Portela & Ca. S.A. Nitrocatechol derivatives as comt inhibitors
WO2007117165A1 Apr 10, 2007 Oct 18, 2007 Bial – Portela & Ca, S.A. New pharmaceutical compounds
WO2008094053A1 * Oct 10, 2007 Aug 7, 2008 Bial-Portela & Ca, S.A. Dosage regimen for comt inhibitors
WO2012107708A1 * Oct 21, 2011 Aug 16, 2012 Bial – Portela & Ca, S.A. Administration regime for nitrocatechols
US20100168113 * Apr 10, 2007 Jul 1, 2010 David Alexander Learmonth Pharmaceutical Compounds
Reference
1 * [1,2,4]-oxadiazolyl nitrocatechol derivatives“, IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 3 May 2012 (2012-05-03), XP013150541, ISSN: 1533-0001
2 * KISS L E ET AL: “Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase“, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 53, no. 8, 22 April 2010 (2010-04-22), pages 3396 – 3411, XP002594266, ISSN: 0022-2623, [retrieved on 20100324], DOI: 10.1021/JM1001524
3 L. E. KISS ET AL., J. MED. CHEM., vol. 53, 2010, pages 3396 – 3411
4 * RASENACK N ET AL: “MICRON-SIZE DRUG PARTICLES: COMMON AND NOVEL MICRONIZATION TECHNIQUES“, PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, NEW YORK, NY, US, vol. 9, no. 1, 1 January 2004 (2004-01-01), pages 1 – 13, XP009055393, ISSN: 1083-7450, DOI: 10.1081/PDT-120027417

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2: Devos D, Moreau C. Opicapone for motor fluctuations in Parkinson’s disease. Lancet Neurol. 2015 Dec 22. pii: S1474-4422(15)00346-4. doi: 10.1016/S1474-4422(15)00346-4. [Epub ahead of print] PubMed PMID: 26725545.

3: Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P; Bi-Park 1 investigators. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2015 Dec 22. pii: S1474-4422(15)00336-1. doi: 10.1016/S1474-4422(15)00336-1. [Epub ahead of print] PubMed PMID: 26725544.

4: Rascol O, Perez-Lloret S, Ferreira JJ. New treatments for levodopa-induced motor complications. Mov Disord. 2015 Sep 15;30(11):1451-60. doi: 10.1002/mds.26362. Epub 2015 Aug 21. Review. PubMed PMID: 26293004.

5: Gonçalves D, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. Development of a liquid chromatography assay for the determination of opicapone and BIA 9-1079 in rat matrices. Biomed Chromatogr. 2016 Mar;30(3):312-22. doi: 10.1002/bmc.3550. Epub 2015 Aug 17. PubMed PMID: 26147707.

6: Ferreira JJ, Rocha JF, Falcão A, Santos A, Pinto R, Nunes T, Soares-da-Silva P. Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson’s disease. Eur J Neurol. 2015 May;22(5):815-25, e56. doi: 10.1111/ene.12666. Epub 2015 Feb 4. PubMed PMID: 25649051.

7: Bonifácio MJ, Torrão L, Loureiro AI, Palma PN, Wright LC, Soares-da-Silva P. Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat. Br J Pharmacol. 2015 Apr;172(7):1739-52. doi: 10.1111/bph.13020. Epub 2015 Jan 20. PubMed PMID: 25409768; PubMed Central PMCID: PMC4376453.

8: Kiss LE, Soares-da-Silva P. Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility. J Med Chem. 2014 Nov 13;57(21):8692-717. doi: 10.1021/jm500572b. Epub 2014 Sep 2. PubMed PMID: 25080080.

9: Rocha JF, Falcão A, Santos A, Pinto R, Lopes N, Nunes T, Wright LC, Vaz-da-Silva M, Soares-da-Silva P. Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. Eur J Clin Pharmacol. 2014 Sep;70(9):1059-71. doi: 10.1007/s00228-014-1701-2. Epub 2014 Jun 14. PubMed PMID: 24925090.

10: Rocha JF, Santos A, Falcão A, Lopes N, Nunes T, Pinto R, Soares-da-Silva P. Effect of moderate liver impairment on the pharmacokinetics of opicapone. Eur J Clin Pharmacol. 2014 Mar;70(3):279-86. doi: 10.1007/s00228-013-1602-9. Epub 2013 Nov 24. PubMed PMID: 24271646.

11: Bonifácio MJ, Sutcliffe JS, Torrão L, Wright LC, Soares-da-Silva P. Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor. Neuropharmacology. 2014 Feb;77:334-41. doi: 10.1016/j.neuropharm.2013.10.014. Epub 2013 Oct 19. PubMed PMID: 24148813.

12: Gonçalves D, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. An HPLC-DAD method for the simultaneous quantification of opicapone (BIA 9-1067) and its active metabolite in human plasma. Analyst. 2013 Apr 21;138(8):2463-9. doi: 10.1039/c3an36671e. PubMed PMID: 23476919.

13: Rocha JF, Almeida L, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ, Wright LC, Nunes T, Soares-da-Silva P. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013 Nov;76(5):763-75. doi: 10.1111/bcp.12081. PubMed PMID: 23336248; PubMed Central PMCID: PMC3853535.

14: Almeida L, Rocha JF, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ, Wright LC, Nunes T, Soares-da-Silva P. Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7. PubMed PMID: 23248072.

15: Palma PN, Bonifácio MJ, Loureiro AI, Soares-da-Silva P. Computation of the binding affinities of catechol-O-methyltransferase inhibitors: multisubstate relative free energy calculations. J Comput Chem. 2012 Apr 5;33(9):970-86. doi: 10.1002/jcc.22926. Epub 2012 Jan 25. PubMed PMID: 22278964.

16: Gonçalves D, Alves G, Soares-da-Silva P, Falcão A. Bioanalytical chromatographic methods for the determination of catechol-O-methyltransferase inhibitors in rodents and human samples: a review. Anal Chim Acta. 2012 Jan 13;710:17-32. doi: 10.1016/j.aca.2011.10.026. Epub 2011 Oct 20. Review. PubMed PMID: 22123108.

17: Kiss LE, Ferreira HS, Torrão L, Bonifácio MJ, Palma PN, Soares-da-Silva P, Learmonth DA. Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase. J Med Chem. 2010 Apr 22;53(8):3396-411. doi: 10.1021/jm1001524. PubMed PMID: 20334432.

////////BIA-9-1067,  ONO-2370,  BIA-91067, 923287-50-7, Opicapone, Catechol-O-methyl transferase, COMT inhibitor, Parkinson’s disease, PD, BIA 9-1067,  BIA 91067,  BIA-91067,  BIA91067, EU 2016

OC1=CC(C2=NC(C3=C(Cl)[N+]([O-])=C(C)C(Cl)=C3C)=NO2)=CC([N+]([O-])=O)=C1O

RPL 554


STR1

RPL554.png

ChemSpider 2D Image | RPL-554 | C26H31N5O4

UNII-3E3D8T1GIX.png

RPL-554

  • Molecular FormulaC26H31N5O4
  • Average mass477.555
RPL 554
Urea, N-[2-[(2E)-6,7-dihydro-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl]ethyl]-
(2-[(2E)-9,10-DIMETHOXY-4-OXO-2-[(2,4,6-TRIMETHYLPHENYL)IMINO]-2H,3H,4H,6H,7H-PYRIMIDO[4,3-A]ISOQUINOLIN-3-YL]ETHYL)UREA
2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea
{2-[(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H,3H,4H,6H,7H-pyrimido[4,3-a]isoquinolin-3-yl]ethyl}urea
2-[4-keto-9,10-dimethoxy-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea
2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea
298680-25-8  CAS
UNII:3E3D8T1GIX

CFTR stimulator; PDE 3 inhibitor; PDE 4 inhibitor

RPL-554 is a mixed phosphodiesterase (PDE) III/IV inhibitor in phase II clinical development at Verona Pharma for the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD) and inflammation.

RPL-554 is expected to have long duration of action and will be administered nasally thereby preventing gastrointestinal problems often resulting from orally administered PDE4 antiinflammatory drugs.

The company is now seeking licensing agreements or partnerships for the further development and commercialization of the drug.

RPL-554 (LS-193,855) is a drug candidate for respiratory diseases. It is an analog of trequinsin, and like trequinsin, is a dual inhibitor of the phosphodiesterase enzymes PDE-3 and PDE-4.[1] As of October 2015, inhaled RPL-554 delivered via a nebulizer was in development for COPD and had been studied in asthma.[2]

PDE3 inhibitors act as bronchodilators, while PDE4 inhibitors have an anti-inflammatory effect.[1][3]

RPL554 was part of a family of compounds invented by Sir David Jack, former head of R&D for GlaxoSmithKline, and Alexander Oxford, a medicinal chemist; the patents on their work were assigned to Vernalis plc.[4][5]:19-20

In 2005, Rhinopharma Ltd, acquired the rights to the intellectual property from Vernalis.[5]:19-20 Rhinopharma was a startup founded in Vancouver, Canada in 2004 by Michael Walker, Clive Page, and David Saint, to discover and develop drugs for chronic respiratory diseases,[5]:16 and intended to develop RPL-554, delivered with an inhaler, first for allergic rhinitis, then asthma, then forCOPD.[5]:16-17 RPL554 was synthesized at Tocris, a contract research organization, under the supervision of Oxford, and was studied in collaboration with Page’s lab at King’s College, London.[1] In 2006 Rhinopharma recapitalized and was renamed Verona Pharma plc.[5]

This was first seen in April 2015 when it was published as a France national. Verona Pharma (formerly Rhinopharma), under license from Kings College via Vernalis, is developing the long-acting bronchodilator, RPL-554 the lead in a series dual inhibitor of multidrug resistant protein-4 and PDE 3 and 4 inhibiting trequinsin analogs which included RPL-565, for treating inflammatory respiratory diseases, such as allergic rhinitis, asthma, and COPD.

RPL554

Verona Pharma’s lead drug, RPL554, is a “first-in-class” inhaled drug under development for chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. The drug is an inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes, two enzymes known to be of importance in the development and progression of immunological respiratory diseases. The drug has the potential to act as both a bronchodilator and an anti-inflammatory which would significantly differentiate it from existing drugs.

RPL554 was selected from a class of compounds co-invented by Sir David Jack, the former Director of Research at Glaxo who led the team that discovered many of the commercially successful drugs in the respiratory market.

Verona Pharma has successfully completed two double-blind placebo controlled randomised Phase 2b studies of RPL554: one in mild to moderate asthma and another in mild to moderate COPD. The drug was found to be well tolerated, free from drug-related adverse effects (especially cardiovascular and gastro-intestinal effects) and generated significant bronchodilation.  Additionally, double-blind placebo controlled exploratory studies in healthy volunteers challenged with an inhaled irritant also generated consistent, clinically meaningful anti-inflammatory effects.

Verona Pharma is also carrying out exploratory studies to investigate the potential of RPL554 as a novel treatement for cystic fibrosis. In November 2014, the Company received a Venture and Innovation Award from the UK Cystic Fibrosis Trust to further such studies.

For further information on the potential of RPL554 for the treatment of respiratory diseases, refer to the peer-reviewed paper available on-line in the highly-respected medication journal, The Lancet Respiratory Medicine, entitledEfficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials”.

The competitive advantages of RPL554 include the following:
  • combining bronchodilator (PDE 3) and anti-inflammatory actions (PDE 4) in a single drug, something that is currently only achieved with a combination LABA and glucocorticosteroid inhaler,
  • unique in not using steroids or beta agonists, which have known side effects,
  • planned to be administered by nasal inhalation, thereby reducing the unwanted gastrointestinal side effects of many orally administered drugs.
History of Clinical Trials
  • Following completion in May 2008 of toxicological studies of RPL554, the Company commenced in February 2009 a Phase I/IIa clinical trial of the drug at the Centre for Human Drug Research (CHDR) at Leiden in the Netherlands. In September 2009, the Company announced that it had successfully completed the trial, demonstrating that RPL554 has a good safety profile and has beneficial effects in terms of bronchodilation and bronchoprotection in asthmatics and a reduction in the numbers of inflammatory cells in the nasal passages of allergic rhinitis patients.
  • In November 2010, the Company successfully completed a further trial that examined the safety and bronchodilator effectiveness of the drug administered at higher doses.
  • In August 2011, the Company demonstrated that bronchodilation is maintained over a period of 6 days with daily dosing of RPL554 in asthmatics.
  • In November 2011, the Company successfully demonstrated safety and bronchodilation of RPL554 in patients with mild to moderate forms of COPD.
  • In March 2013, the Company demonstrated positive airway anti-inflammatory activity with respect to COPD at a clinical trial carried out at the Medicines Evaluation Unit (MEU) in Manchester, UK.

Synthesis

WO 2000058308

STR1

Cyclization of 1-(3,4-dimethoxyphenethyl)barbituric acid  in refluxing POCl3 produces the pyrimidoisoquinolinone , which is further condensed with 2,4,6-trimethylaniline  in boiling isopropanol to afford the trimethylphenylimino derivative . Subsequent alkylation of with N-(2-bromoethyl)phthalimide in the presence of K2CO3 and KI, followed by hydrazinolysis of the resulting phthalimidoethyl compound  yields the primary amine . This is finally converted into the title urea RPL 554 by reaction with sodium cyanate in aqueous HCl.

Example 1 : 9 Λ 0-Dimethoxy-2-(2.4-6-trimethy-phen yliminoY-3-(N-carbamoyl-2- aminoethylV3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

Figure imgf000029_0001

Sodium cyanate (6.0g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7- tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0g, 0.046 mol) in water (600 ml) and IN ΗC1 (92 ml) at 80°C. After stirring for 2h at 80°C the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3 x 200 ml) and the combined extract was dried (MgSO- ) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2CI2 / MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9g, 54%.

M.p.: 234-236°C m/z: C26H31N5O4 requires M=477 found (M+l) = 478

HPLC: Area (%) 99.50 Column ODS (150 x 4.6 mm)

MP pH3 KH2PO4 / CH3CN (60/40)

FR (ml/min) 1.0 RT (min) 9.25 Detection 250 nm

lK NMR (300 MHz, CDCI3): δ 1.92 (1H, br s, NH), 2.06 (6H, s, 2xCH3), 2.29 (3H, s, CH3), 2.92 (2H, t, CH2), 3.53 (2H, m, CH2), 3.77 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.05 (2H, t, CH2), 4.40 (2H, t, CH2), 5.35 (2H, br s, NH2), 5.45 (1H, s, C=CH), 6.68 (1H, s, ArH), 6.70 (1H, s, ArH), 6.89 (2H, s, 2xArH).

Preparation 1 : Synthesis of 2-Chloro-6.7-d-hydro-9.10-Dimethoxy-4H-pyrimido- [6,l-a]isoquinoHn-4-one (shown as (1) in Figure 1

Figure imgf000027_0001

A mixture of l-(3,4-dimethoxyphenyl) barbituric acid (70g, 0.24mol), prepared according to the method described in B. Lai et al. J.Med.Chem. 27 1470-1480 (1984), and phosphorus oxychloride (300ml, 3.22mol) was refluxed for 2.5h. The excess phosphorous oxychloride was removed by distillation (20mmHg) on wa ming. After cooling the residue was slurried in dioxan (100ml) and cautiously added to a vigorously stirred ice/water solution (11). Chloroform (11) was added and the resulting mixture was basified with 30% sodium hydroxide solution. The organic layer was separated and the aqueous phase further extracted with chloroform (2x750ml). The combined organic extracts were washed with water (1.51), dried over magnesium sulphate and concentrated in vacuo to leave a gummy material (90g). This was stirred in methanol for a few minutes, filtered and washed with methanol (200ml), diethyl ether (2x200ml) and dried in vacuo at 40°C to yield the title compound as a yellow/orange solid. 47g, 62%

(300MHz, CDCI3) 2.96(2H, t, C(7) H2); 3.96(6H, s, 2xOCH3; 4.20(2H, t, C(6) H2); 6.61(1H, s, C(1) H); 6.76(1H, s, Ar-H); 7.10(1H, s, Ar-H). Preparation 2: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3.4.6.7- tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one (shown as (2) in Figure 1

2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5g, 0.13 mol) and 2,4,6-trimethylaniline (52.7g, 0.39 mol) in propan-2-ol (3 1) was stirred and heated at reflux, under nitrogen, for 24h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CΗ2CI2 /

MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, (just above the product on tic). Yield 34.6g, 67%.

Preparation 3: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3-(2-N- phthalimidoethyπ-3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

(shown as (3 in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H- pyrimido[6,l-a]isoquinolin-4-one (which was prepared according to Preparation 2) (60.0g, 0.153 mol), potassium carbonate (191g, 1.38 mol), sodium iodide (137g, 0.92 mol) and N-(2-bromoethyl)phthalimide (234g, 0.92 mol) in 2-butanone (1500 ml) was stirred and heated at reflux, under nitrogen, for 4 days. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo. The residue was treated with methanol (1000 ml) and the solid filtered off, washed with methanol and recrystallised from ethyl acetate to obtain the title compound as a pale yellow solid in yield 40. Og, 46%. Evaporation of the mother liquor and column chromatography of the residue on silica gel (CΗ2C-2 / MeOH 95:5) provided further product 11.7g, 13.5%. Preparation 4: 9.10-Dimethoxy-2-(2A6-trimethylphenylimino)-3-(2-arninoethyO- 3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquino-in-4-one (shown as (4) in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-N- phthalimidoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one (22. Og, 0.039 mol), prepared according to Preparation 3, and hydrazine hydrate (11.3g, 0.195 mol) in chloroform (300 ml) and ethanol (460 ml) was stined at room temperature, under nitrogen, for 18h. Further hydrazine hydrate (2.9g, 0.05 mol) was added and the mixture was stirred a further 4h. After cooling in ice / water, the solid was removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in dichloromethane and the insoluble material was removed by filtration. The fitrate was dried (MgSO-i) and evaporated in vacuo to afford the title compound as a yellow foam in yield 16.2g, 96%.

PATENT

WO-2016128742

Novel crystalline acid addition salts forms of RPL-554 are claimed, wherein the salts, such as ethane- 1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. .

RPL554 (9, 10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(/V-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6, l-a]isoquinolin-4-one) is a dual PDE3/PDE4 inhibitor and is described in WO 00/58308. As a combined PDE3/PDE4 inhibitor, RPL554 has both antiinflammatory and bronchodilatory activity and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of RPL554 is shown below.

Owing to its applicability in the treatment of respiratory disorders, it is often preferable to administer RPL554 by inhalation. Franciosi et al. disclose a solution of RPL554 in a citrate-phosphate buffer at pH 3.2 (The Lancet: Respiratory Medicine 11/2013; l(9):714-27. DOI: 10.1016/S2213-2600(13)70187-5). The preparation of salts of RPL554 has not been described.

PATENT

http://www.google.ch/patents/WO2000058308A1?cl=en&hl=de

PATENT

http://www.google.ch/patents/WO2012020016A1?cl=en

U.S. Pat. No. 6,794,391, 7,378,424, and 7,105,663, which are each incorporated herein by reference, discloses compound RPL-554 (N-{2-[(2iT)-2-(mesityiimino)-9,10- dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,l-a]-isoquinolin-3 4H)-yl]ethyl}urea).

Figure imgf000003_0001

It would be beneficial to provide a composition of a stable polymorph of RPL-554, that has advanrtages over less stable polymorphs or amorphous forms, including

stability, compressibility, density, dissolution rates, increased potency or. lack toxicity.

WO2000058308A1 * Mar 29, 2000 Oct 5, 2000 Vernalis Limited DERIVATIVES OF PYRIMIDO[6,1-a]ISOQUINOLIN-4-ONE
US6794391 Sep 26, 2001 Sep 21, 2004 Vernalis Limited Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US7105663 Feb 24, 2004 Sep 12, 2006 Rhinopharma Limited Derivatives of pyrimido[6,1-a]isoquinolin-4-one
US7378424 Feb 24, 2004 May 27, 2008 Verona Pharma Plc Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
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US7378424 2008-05-27 Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
US7105663 2006-09-12 Derivatives of pyrimido[6, 1-a]isoquinolin-4-one
US6794391 2004-09-21 Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US2004001895 2004-01-01 Combination treatment for depression and anxiety
US2003235631 2003-12-25 Combination treatment for depression and anxiety
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US2015210655 2015-07-30 CERTAIN (2S)-N-[(1S)-1-CYANO-2-PHENYLETHYL]-1, 4-OXAZEPANE-2-CARBOXAMIDES AS DIPEPTIDYL PEPTIDASE 1 INHIBITORS
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References

  1. Boswell-Smith V et al. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. PMID 16682455
  2.  Nick Paul Taylor for FierceBiotech. October 1, 2015 Verona sets sights on PhIIb after COPD drug comes through early trial
  3.  Turner MJ et al. The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia. Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1):L59-70. PMID 26545902
  4. Jump up^ see US20040171828, identified in the citations of PMID 16682455
  5. ISIS Resources, PLC. August 23, 2006 Proposed Acquisition of Rhinopharma

REFERENCES

1: Calzetta L, Cazzola M, Page CP, Rogliani P, Facciolo F, Matera MG. Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways. Pulm Pharmacol Ther. 2015 Jun;32:15-23. doi: 10.1016/j.pupt.2015.03.007. Epub 2015 Apr 18. PubMed PMID: 25899618.

2: Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker MJ, Page CP. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013 Nov;1(9):714-27. doi: 10.1016/S2213-2600(13)70187-5. Epub 2013 Oct 25. PubMed PMID: 24429275.

3: Wedzicha JA. Dual PDE 3/4 inhibition: a novel approach to airway disease? Lancet Respir Med. 2013 Nov;1(9):669-70. doi: 10.1016/S2213-2600(13)70211-X. Epub 2013 Oct 25. PubMed PMID: 24429260.

4: Calzetta L, Page CP, Spina D, Cazzola M, Rogliani P, Facciolo F, Matera MG. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther. 2013 Sep;346(3):414-23. doi: 10.1124/jpet.113.204644. Epub 2013 Jun 13. PubMed PMID: 23766543.

5: Gross N. The COPD pipeline XX. COPD. 2013 Feb;10(1):104-6. doi: 10.3109/15412555.2013.766103. PubMed PMID: 23413896.

6: Gross NJ. The COPD Pipeline XIV. COPD. 2012 Feb;9(1):81-3. doi: 10.3109/15412555.2012.646587. PubMed PMID: 22292600.

7: Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6, 7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquino lin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. Epub 2006 May 8. PubMed PMID: 16682455.

RPL-554
RPL554.png
Systematic (IUPAC) name
N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea
Identifiers
PubChem CID 9934746
ChemSpider 8110374 Yes
Synonyms 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one
Chemical data
Formula C26H31N5O4
Molar mass 477.554 g/mol

///////////RPL-554, LS-193,855, 298680-25-8, UNII:3E3D8T1GIX, RPL554, RPL 554, phase 2, Chronic Obstructive Pulmonary Diseases , COPD, Allergic Rhinitis, Asthma Therapy, Cystic Fibrosis, Inflammation, Bronchodilators

Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O

ACT-334441, Cenerimod an S1P receptor 1 agonist


img

ACT-334441

Cenerimod

UNII-Y333RS1786; Y333RS1786

S1P receptor 1 agonist

CAS 1262414-04-9
Chemical Formula: C25H31N3O5
Exact Mass: 453.22637

Actelion Pharmaceuticals Ltd.

Martin Bolli, Cyrille Lescop, Boris Mathys,Keith Morrison, Claus Mueller, Oliver Nayler,Beat Steiner,

(S)-3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propane-1,2-diol

(2S)-3-[4-[5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl]-2-ethyl-6-methylphenoxy]propane-1,2-diol

(S)-3-{4-[5-(2-Cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol

Mechanism Of Action Sphingosine 1 phosphate receptor modulator
Who Atc Codes L03A-X (Other immunostimulants)
Ephmra Codes L3A (Immunostimulating Agents Excluding Interferons)
Indication Systemic Lupus Erythematosus

Cenerimod is a potent and orally active immunomodulator, exhibited EC50 value of 2.7 nM. Cenerimod is an agonist for the G protein-coupled receptor S1 P1/EDG1 and has a powerful and long-lasting immunomodulating effect which is achieved by reducing the number of circulating and infiltrating T- and B-lymphocytes, without affecting their maturation, memory, or expansion. Cenerimod may be useful for prevention or treatment of diseases associated with an activated immune system

CENERIMOD

ACT-334441; lysosphingolipid receptor agonist – Actelion; S1P1 receptor modulator – Actelion; Second selective S1P1 receptor agonist – Actelion; Sphingosine 1 phosphate receptor modulators – Actelion; Sphingosine 1-phosphate receptor 1 agonists – Actelion

  • Mechanism of Action Lysosphingolipid receptor agonists
  • Highest Development Phases
  • Phase I/II Systemic lupus erythematosus

Most Recent Events

  • 09 Jun 2016 Actelion terminates a phase I drug interaction trial for Systemic lupus erythematosus (In volunteers) in France (NCT02479204)
  • 22 Dec 2015 Phase-I/II clinical trials in Systemic lupus erythematosus in Ukraine, Belarus (PO) (NCT02472795)
  • 24 Sep 2015 Phase-I/II clinical trials in Systemic lupus erythematosus in USA (PO) (NCT02472795)
# Nct Number Title Recruitment Conditions Interventions Phase
1 NCT02472795 Clinical Study to Investigate the Biological Activity, Safety, Tolerability, and Pharmacokinetics of ACT-334441 in Subjects With Systemic Lupus Erythematosus Recruiting Systemic Lupus Erythematosus Drug: ACT-334441|Drug: Placebo Phase 2 Actelion
2 NCT02479204 Drug Interaction Study of ACT-334441 With Cardiovascular Medications in Healthy Subjects Suspended Healthy Subjects Drug: ACT-334441 2 mg|Drug: ACT-334441 4 mg|Drug: placebo|Drug: atenolol|Drug: diltiazem ER Phase 1 Actelion

str1

UNII-Y333RS1786.png

STR2 STR3

The human immune system is designed to defend the body against foreign micro-organisms and substances that cause infection or disease. Complex regulatory mechanisms ensure that the immune response is targeted against the intruding substance or organism and not against the host. In some cases, these control mechanisms are unregulated and autoimmune responses can develop. A consequence of the uncontrolled inflammatory response is severe organ, cell, tissue or joint damage. With current treatment, the whole immune system is usually suppressed and the body’s ability to react to infections is also severely compromised. Typical drugs in this class include azathioprine, chlorambucil, cyclophosphamide, cyclosporin, or methotrexate. Corticosteroids which reduce inflammation and suppress the immune response, may cause side effects when used in long term treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, however, they exhibit considerable side effects. Alternative treatments include agents that activate or block cytokine signaling.

Orally active compounds with immunomodulating properties, without compromising immune responses and with reduced side effects would significantly improve current treatments of uncontrolled inflammatory diseases.

In the field of organ transplantation the host immune response must be suppressed to prevent organ rejection. Organ transplant recipients can experience some rejection even when they are taking immunosuppressive drugs. Rejection occurs most frequently in the first few weeks after transplantation, but rejection episodes can also happen months or even years after transplantation. Combinations of up to three or four medications are commonly used to give maximum protection against rejection while minimizing side effects. Current standard drugs used to treat the rejection of transplanted organs interfere with discrete intracellular pathways in the activation of T-type or B-type white blood cells. Examples of such drugs are cyclosporin, daclizumab, basiliximab, everolimus, or FK506, which interfere with cytokine release or signaling; azathioprine or leflunomide, which inhibit nucleotide synthesis; or 15-deoxyspergualin, an inhibitor of leukocyte differentiation.

The beneficial effects of broad immunosuppressive therapies relate to their effects; however, the generalized immunosuppression which these drugs produce diminishes the immune system’s defense against infection and malignancies. Furthermore, standard immunosuppressive drugs are often used at high dosages and can cause or accelerate organ damage.

SYNTHESIS

STR1

PATENT

https://www.google.com/patents/WO2011007324A1?cl=zh

The human immune system is designed to defend the body against foreign microorganisms and substances that cause infection or disease. Complex regulatory mechanisms ensure that the immune response is targeted against the intruding substance or organism and not against the host. In some cases, these control mechanisms are unregulated and autoimmune responses can develop. A consequence of the uncontrolled inflammatory response is severe organ, cell, tissue or joint damage. With current treatment, the whole immune system is usually suppressed and the body’s ability to react to infections is also severely compromised. Typical drugs in this class include azathioprine, chlorambucil, cyclophosphamide, cyclosporin, or methotrexate. Corticosteroids which reduce inflammation and suppress the immune response, may cause side effects when used in long term treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, however, they exhibit considerable side effects. Alternative treatments include agents that activate or block cytokine signaling.

Orally active compounds with immunomodulating properties, without compromising immune responses and with reduced side effects would significantly improve current treatments of uncontrolled inflammatory diseases.

In the field of organ transplantation the host immune response must be suppressed to prevent organ rejection. Organ transplant recipients can experience some rejection even when they are taking immunosuppressive drugs. Rejection occurs most frequently in the first few weeks after transplantation, but rejection episodes can also happen months or even years after transplantation. Combinations of up to three or four medications are commonly used to give maximum protection against rejection while minimizing side effects. Current standard drugs used to treat the rejection of transplanted organs interfere with discrete intracellular pathways in the activation of T-type or B-type white blood cells. Examples of such drugs are cyclosporin, daclizumab, basiliximab, everolimus, or FK506, which interfere with cytokine release or signaling; azathioprine or leflunomide, which inhibit nucleotide synthesis; or 15-deoxyspergualin, an inhibitor of leukocyte differentiation.

The beneficial effects of broad immunosuppressive therapies relate to their effects; however, the generalized immunosuppression which these drugs produce diminishes the immune system’s defense against infection and malignancies. Furthermore, standard immunosuppressive drugs are often used at high dosages and can cause or accelerate organ damage.

Description of the invention

The present invention provides novel compounds of Formula (I) that are agonists for the G protein-coupled receptor S1 P1/EDG1 and have a powerful and long-lasting immunomodulating effect which is achieved by reducing the number of circulating and infiltrating T- and B-lymphocytes, without affecting their maturation, memory, or expansion. The reduction of circulating T- / B-lymphocytes as a result of S1 P1/EDG1 agonism, possibly in combination with the observed improvement of endothelial cell layer function associated with S1 P1/EDG1 activation, makes such compounds useful to treat uncontrolled inflammatory diseases and to improve vascular functionality. Prior art document WO 2008/029371 discloses compounds that act as S1 P1/EDG1 receptor agonists and show an immunomodulating effect as described above. Unexpectedly, it has been found that the compounds of the present invention have a reduced potential to constrict airway tissue/vessels when compared to compounds of the prior art document WO 2008/029371. The compounds of the present invention therefore demonstrate superiority with respect to their safety profile, e.g. a lower risk of bronchoconstriction.

Examples of WO 2008/029371 , which are considered closest prior art analogues are shown in Figure 1.

Figure imgf000004_0001

Figure 1 : Structure of Examples of prior art document WO 2008/029371 , which are considered closest analogues to the compounds of the present invention.

The data on the constriction of rat trachea rings compiled in Table 1 illustrate the superiority of the compounds of the present invention as compared to compounds of prior art document WO 2008/029371.

For instance, the compounds of Example 1 and 6 of the present invention show a significantly reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 222 and 226 of WO 2008/029371 , respectively. Furthermore, the compounds of Example 1 and 6 of the present invention also show a reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 196 and 204 of WO 2008/029371 , respectively. These data demonstrate that compounds wherein R1 represents 3-pentyl and R2 represents methoxy are superior compared to the closest prior art compounds of WO 2008/029371 , i.e. the compounds wherein R1 represents an isobutyl and R2 represents methoxy or wherein R1represents methyl and R2 represents 3-pentyl. Moreover, also the compound of Example 16 of the present invention, wherein R1 is 3-methyl-but-1-yl and R2 is methoxy, exhibits a markedly reduced potential to constrict rat trachea rings when compared to its closest analogue prior art Example 226 of WO 2008/029371 wherein R1 is isobutyl and R2 is methoxy.

The unexpected superiority of the compounds of the present invention is also evident from the observation that the compounds of Example 2 and 7 of the present invention show a markedly reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 229 and 233 of WO 2008/029371 , respectively. This proves that compounds wherein R1represents cyclopentyl and R2 represents methoxy are superior compared to the closest prior art compounds of WO 2008/029371 , i.e. the compounds wherein R1 represents methyl and R2 represents cyclopentyl.

Also, the compound of Example 3 of the present invention exhibits the same low potential to constrict rat trachea rings as its S-enantiomer, i.e. the compound of Example 2 of the present invention, indicating that the configuration at this position has no significant effect on trachea constriction. Furthermore, also Example 21 of the present invention exhibits the same low potential to constrict rat trachea rings as present Example 2, which differs from Example 21 only by the linker A (forming a 5-pyridin-4-yl-[1 ,2,4]oxadiazole instead of a 3- pyridin-4-yl-[1 ,2,4]oxadiazole). This indicates that also the nature of the oxadiazole is not critical regarding trachea constriction.

Table 1 : Rat trachea constriction in % of the constriction induced by 50 mM KCI. n.d. = not determined. For experimental details and further data see Example 33.

Figure imgf000005_0001
Figure imgf000006_0002

result obtained at a compound concentration of 300 nM.

The compounds of the present invention can be utilized alone or in combination with standard drugs inhibiting T-cell activation, to provide a new immunomodulating therapy with a reduced propensity for infections when compared to standard immunosuppressive therapy. Furthermore, the compounds of the present invention can be used in combination with reduced dosages of traditional immunosuppressant therapies, to provide on the one hand effective immunomodulating activity, while on the other hand reducing end organ damage associated with higher doses of standard immunosuppressive drugs. The observation of improved endothelial cell layer function associated with S1 P1/EDG1 activation provides additional benefits of compounds to improve vascular function.

The nucleotide sequence and the amino acid sequence for the human S1 P1/EDG1 receptor are known in the art and are published in e.g.: HIa, T., and Maciag, T., J. Biol

Chem. 265 (1990), 9308-9313; WO 91/15583 published 17 October 1991 ; WO 99/46277 published 16 September 1999. The potency and efficacy of the compounds of Formula (I) are assessed using a GTPγS assay to determine EC5O values and by measuring the circulating lymphocytes in the rat after oral administration, respectively (see in experimental part). i) In a first embodiment, the invention relates to pyridine compounds of the Formula (I),

Figure imgf000006_0001

Formula (I)

PATENT

WO 2013175397

https://www.google.com/patents/WO2013175397A1?cl=en

Pyridine-4-yl derivatives of formula (PD),

Figure imgf000002_0001

Formula (PD) A represents

Figure imgf000002_0002

(the asterisks indicate the bond that is linked to the pyridine group of Formula (PD));

Ra represents 3-pentyl, 3-methyl-but-1-yl, cyclopentyl, or cyclohexyl;

Rb represents methoxy;

Rc represents 2,3-dihydroxypropoxy, -OCH2-CH(OH)-CH2-NHCO-CH2OH,

-OCH2-CH(OH)-CH2N(CH3)-CO-CH2OH, -NHS02CH3, or -NHS02CH2CH3; and

Rd represents ethyl or chloro.)

disclosed in WO201 1007324, have immunomodulating activity through their S1 P1/EDG1 receptor agonistic activity. Therefore, those pyridine-4-yl derivatives are useful for prevention and / or treatment of diseases or disorders associated with an activated immune system, including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host diseases brought about by stem cell transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis such as Hashimoto’s thyroiditis, uveo-retinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; type I diabetes; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancers and tumor metastasis. 2-Cyclopentyl-6-methoxy-isonicotinic acid, which is also disclosed in WO201 1007324, is a useful intermediate for the synthesis of the pyridine-4-yl derivatives of formula (PD), wherein Ra is a cyclopentyl group.

In the process described in WO201 1007324, 2-cyclopentyl-6-methoxy-isonicotinic acid was prepared according to the following reaction scheme 1 :

Figure imgf000003_0001

Compound D Compound E

Rieke Zinc: cyclopentylzinc bromide;

PdCI2(dppf)dcm: 1 ,1 ‘-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride

dichloromethane complex

However, the abovementioned process has drawbacks for larger scale, i.e. industrial scale synthesis of 2-cyclopentyl-6-methoxy-isonicotinic acid, for the following reasons:

a) The commercially available starting material, 2,6-dichloro-isonicotinic acid (Compound A) is expensive.

b) The conversion of Compound C to Compound D is cost-intensive. The reaction has to be performed under protective atmosphere with expensive palladium catalysts and highly reactive and expensive Rieke zinc complex. Such synthesis steps are expensive to scale up and it was therefore highly desired to find alternative synthesis methods.

Even though Goldsworthy, J. Chem. Soc. 1934, 377-378 discloses the preparation of 1 -cyclopentylethanone, which is a key building block in the new process of the present invention, by using ethyl 1 -acetoacetate as a starting material, this synthesis was far from being suitable in an industrial process. The reported yield was low (see also under “Referential Examples” below). Scheme 2

Figure imgf000004_0001

ethyl 1 -acetylcyclo- 1-cyclopentyl- pentanecarboxylate ethanone

Besides the early work by Goldsworthy there are several recent examples for the preparation of 1 -cyclopentylethanone described in the literature. Such examples include:

1 ) Addition of methyl lithium to a N-cyclopentanecarbonyl-N,0-dimethylhydroxylamine at -78°C in a yield of 77%. US2006/199853 A1 , 2006 and US2006/223884 A1 , 2006.

2) Addition of methyl lithium to a cyclopentyl carboxylic acid in diethylether at -78°C in a yield of 81 %. J. Am. Chem. Soc, 1983, 105, 4008-4017.

3) Addition of methylmagnesiumbromide to cyclopentanecarbonitrile.

Bull. Soc. Chim. Fr., 1967, 3722-3729.

4) Oxidation of 1 -cyclopentylethanol with chromtrioxide. US5001 140 A1 , 1991.

WO2009/71707 A1 , 2009.

5) Addition of cyclopentylmagnesium bromide to acetic anhydride at -78 °C with a yield of 54%. WO2004/74270 A2, 2004.

6) Synthesis of 1-cyclopentylethanone in 5 steps from cyclopentanone. Zhang, Pang; Li, Lian-chu, Synth. Commun., 1986, 16, 957-966.

However, the processes described in the above-listed publications are not efficient for scale-up since they require cryogenic temperatures, expensive starting materials, toxic reagents or many steps. The lack of an efficient process to manufacture 1 -cyclopentylethanone is further also mirrored by the difficulty in sourcing this compound on kilogram scale for a reasonable price and delivery time. Therefore, the purpose of the present invention is to provide a new, efficient and cost effective process for the preparation of 2-cyclopentyl-6-methoxy-isonicotinic acid, which is suitable for industrial scale synthesis.

Patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US133347630&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Disclosed in WO2011007324, have immunomodulating activity through their S1P1/EDG1 receptor agonistic activity. Therefore, those pyridine-4-yl derivatives are useful for prevention and/or treatment of diseases or disorders associated with an activated immune system, including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host diseases brought about by stem cell transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis such as Hashimoto’s thyroiditis, uveo-retinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; type I diabetes; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancers and tumor metastasis. 2-Cyclopentyl-6-methoxy-isonicotinic acid, which is also disclosed in WO2011007324, is a useful intermediate for the synthesis of the pyridine-4-yl derivatives of formula (PD), wherein Ra is a cyclopentyl group.

      In the process described in WO2011007324, 2-cyclopentyl-6-methoxy-isonicotinic acid was prepared according to the following reaction scheme 1:

Rieke Zinc: cyclopentylzinc bromide;
PdCl2(dppf)dcm: 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

EXAMPLES

Example 1a

1-Cyclopentylethanone


      A mixture of 1,4 dibromobutane (273 g, 1 eq.), tetrabutylammonium bromide (20 g, 0.05 eq.) in 32% NaOH (1 L) was heated to 50° C. Tert.-butyl acetoacetate (200 g, 1 eq.) was added keeping the maximum internal temperature below 55° C. The mixture was stirred for 5 h at 50° C. The stirrer was stopped and the org. layer was separated. The org. layer was washed with 1N HCl (500 mL). The org. layer was added to 32% HCl (300 mL) at an external temperature of 60° C. The mixture was stirred at 60° C. for 3.5 h and cooled to 40° C. The mixture was washed with brine (60 mL). The org. layer was washed with brine (150 mL) and dried with magnesium sulphate (8 g). The mixture was filtered and the product was purified by distillation (distillation conditions: external temperature: 70° C., head temperature: 40-55° C., pressure: 30-7 mbar) to obtain a colourless liquid; yield: 107 g (75%). Purity (GC-MS): 99.8% a/a; GC-MS: tR=1.19 min, [M+1]+=113. 1H NMR (CDCl3): δ=2.86 (m, 1H), 2.15 (s, 3H), 1.68 (m, 8H).

Example 1 b

1-Cyclopentylethanone

      Tert-butyl 1-acetylcyclopentanecarboxylate (723 g, 3.41 mol) was added to 32% HCl (870 mL) at an internal temperature of 80° C. over a period of 2 h. The mixture was stirred at 80° C. for 1 h and cooled to 50° C. The stirrer was stopped and the org. layer was separated. The org. layer was washed with water (250 mL) and dried with magnesium sulphate (24 g). The mixture was filtered and the product was purified by distillation to obtain a colourless liquid; yield: 333.6 g (87%). Purity (GC-MS): 97.3% a/a; GC-MS: tR=1.19 min, [M+1]+=113.

Example 1c

1-Cyclopentylethanone

      Tert-butyl 1-acetylcyclopentanecarboxylate (300 g, 1.41 mol) was added to 5 M HCl in isopropanol (600 mL) at an internal temperature of 60° C. over a period of 25 min. The mixture was stirred at 60° C. for 18 h and cooled to 20° C. Water (1 L) was added, the stirrer was stopped and the org. layer was separated. The org. layer was washed with water (500 mL). The crude product was purified by distillation to obtain a colourless liquid; yield: 115 g (72%). Purity (GC-MS): 87.2% a/a; GC-MS: tR=1.19 min, [M+1]+=113.

Example 1d

1-Cyclopentylethanone

      Tert-butyl 1-acetylcyclopentanecarboxylate (514 g, 2.42 mol) was added to TFA (390 mL) at an internal temperature of 60° C. More TFA (200 mL) was added and the temperature was adjusted to 65° C. The mixture was stirred at 65° C. for 1 h. The reaction mixture was concentrated at 45° C. and 20 mbar. The residue was added to TBME (500 mL), ice (200 g) and 32% NaOH (300 mL). The aq. layer was separated and extracted with TBME (500 mL). The combined org. layers were concentrated to dryness to yield the crude 1-cyclopentylethanone. The crude product was purified by distillation to yield a colorless liquid: 221.8 g (82%). Purity (GC-MS): 90.2% a/a; GC-MS: tR=1.19 min, [M+l]+=113.

Example 1e

1-Cyclopentylethanone

      Tert-butyl 1-acetylcyclopentanecarboxylate (534 g, 2.52 mol) was added to 50% H2SO4 (300 mL) at an internal temperature of 100° C. over a period of 40 min. The mixture was stirred at 120° C. for 2 h and cooled to 20° C. The stirrer was stopped and the org. layer was separated. The org. layer was washed with saturated NaHCO3 solution (250 mL). The crude product was purified by distillation to obtain a colourless liquid; yield: 177 g (63%). Purity (GC-MS): 99.9% a/a; GC-MS: tR=1.19 min, [M+1]+=113.

Example 1f

Tert-butyl 1-acetylcyclopentanecarboxylate


      To a mixture of potassium carbonate (1 kg, 7.24 mol) and tetrabutylammonium iodide (10 g, 0.027 mol) in DMSO (3 L) was added a mixture of 1,4-dibromobutane (700 g, 3.24 mol) and tert.-butyl acetoacetate (500 g, 3.16 mol). The mixture was stirred at 25° C. for 20 h. To the reaction mixture was added water (4 L) and TBME (3 L). The mixture was stirred until all solids dissolved. The TBME layer was separated and washed with water (3×1 L). The org. layer was concentrated and the crude product was purified by distillation (distillation conditions: external temperature: 135° C., head temperature: 105-115° C., pressure: 25-10 mbar) to obtain a colourless liquid; yield: 537.6 g (80%). Purity (GC-MS): 90.5% a/a; GC-MS:
      tR=1.89 min, [M+1]+=213. 1H NMR (CDCl3): δ=2.16 (s, 3H), 2.06 (m, 4H), 1.63 (m, 4H), 1.45 (s, 9H).

Example 1 g

Tert-butyl 1-acetylcyclopentanecarboxylate

      A mixture of 1,4 dibromobutane (281 g, 1 eq.) and tetrabutylammonium bromide (15 g, 0.05 eq.) in 50% NaOH (1 L) was heated to 50° C. Tert.-butyl acetoacetate (206 g, 1 eq.) was added keeping the maximum internal temperature below 55° C. The mixture was stirred for 5 h at 50° C. The stirrer was stopped and the org. layer was separated. The org. layer was washed with 1N HCl (500 mL). The crude product was purified by distillation to obtain a colourless liquid; yield: 199 g (72%). Purity (GC-MS): 97.8% a/a; GC-MS: tR=1.89 min, [M+1]+=213.

Example 2

2-Cyclopentyl-6-hydroxyisonicotinic acid


      A 10 L reactor was charged with potassium tert.-butylate (220 g, 1.1 eq.) and THF (3 L). The solution was cooled to −20° C. A mixture of diethyloxalate (260 g, 1 eq.) and 1-cyclopentylethanone (200 g, 1.78 mol, 1 eq.) was added at a temperature below −18° C. The reaction mixture was stirred at −10° C. for 30 min and then warmed to 15° C. To the mixture was added cyano acetamide (180 g, 1.2 eq.). The mixture was stirred for 20 h at 22° C. Water (600 mL) was added and the reaction mixture was concentrated at 60° C. under reduced pressure on a rotary evaporator. 3.4 L solvent were removed. The reactor was charged with 32% HCl (5 L) and heated to 50° C. The residue was added to the HCl solution at a temperature between 44 and 70° C. The mixture was heated to 100° C. for 22 h. 2.7 L solvent were removed at 135° C. external temperature and a pressure of ca. 400 mbar. The suspension was diluted with water (2.5 L) and cooled to 10° C. The suspension was filtered. The product cake was washed with water (2.5 L) and acetone (3 L). The product was dried to obtain an off white solid; yield: 255 g (69%); purity (LC-MS): 100% a/a; LC-MS: tR=0.964 min, [M+1]+=208; 1H NMR (deutero DMSO): δ=12.67 (br, 2H), 6.63 (s, 1H), 6.38 (s, 1H), 2.89 (m, 1H), 1.98 (m, 2H), 1.63 (m, 6H).

Example 3

Methyl 2-cyclopentyl-6-hydroxyisonicotinate


      2-Cyclopentyl-6-hydroxyisonicotinic acid (1520.5 g, 7.3 mol, 1 eq.), methanol (15.2 L), trimethylorthoformiate (1.56 L, 2 eq.) and sulphuric acid (471 mL, 1.2 eq.) were mixed at 20° C. and heated to reflux for 18 h. 10 L solvent were removed at 95° C. external temperature and a pressure of ca. 800 mbar.
      The mixture was cooled to 20° C. and added to water (7.6 L) at 50° C. The suspension was diluted with water (3.8 L), cooled to 10° C. and filtered. The cake was washed with water (3.8 L). The product was dried to obtain a yellowish solid; yield: 1568 g (97%); purity (LC-MS): 100% a/a; LC-MS: tR=1.158 min, [M+1]+=222; 1H NMR (deutero DMSO) δ=11.98 (br, 1H), 6.63 (m, 1H), 6.39 (s, 1H), 3.83 (s, 3H), 2.91 (m, 1H), 1.99 (m, 2H), 1.72 (m, 2H), 1.58 (m, 4H).

Example 4a

Methyl 2-chloro-6-cyclopentylisonicotinate


      Methyl 2-cyclopentyl-6-hydroxyisonicotinate (50 g, 0.226 mol, 1 eq.) and phenylphosphonic dichloride (70 mL, 2 eq.) were heated to 130° C. for 3 h. The reaction mixture was added to a solution of potassium phosphate (300 g) in water (600 mL) and isopropyl acetate (600 mL) at 0° C. The mixture was filtered over kieselguhr (i.e. diatomite, Celite™) (50 g). The aq. layer was separated and discarded. The org. layer was washed with water (500 mL). The org. layer was concentrated to dryness at 65° C. and reduced pressure to obtain a black oil; yield: 50.4 g (93%); purity (LC-MS): 94% a/a.
      The crude oil was purified by distillation at an external temperature of 130° C., head temperature of 106° C. and oil pump vacuum to yield a colourless oil; yield: 45.6 g (84%); purity (LC-MS): 100% a/a; LC-MS: tR=1.808 min, [M+1]+=240; 1H NMR (CDCl3) δ=7.69 (s, 1H), 7.67 (s, 1H), 3.97 (s, 3H), 3.23 (m, 1H), 2.12 (m, 2H), 1.80 (m, 6H).

Example 4b

Methyl 2-chloro-6-cyclopentylisonicotinate

      2-Cyclopentyl-6-hydroxyisonicotinic acid (147 g, 0.709 mol, 1 eq.) and phosphorous oxychloride (647 mL, 10 eq.) were heated to 115° C. for 4 h. The mixture was concentrated at normal pressure and an external temperature of 130-150° C. At 20° C. DCM (250 mL) was added. The solution was added to MeOH (1000 mL) below 60° C. The mixture was concentrated under reduced pressure at 50° C. DCM (1 L) was added to the residue and the mixture was washed with water (2×500 mL). The org. layer was concentrated to dryness under reduced pressure at 50° C. to obtain a black oil; yield: 181.7 g (107%); purity (LC-MS): 97% a/a. The product was contaminated with trimethyl phosphate.

Example 5

2-Cyclopentyl-6-methoxyisonicotinic acid


      Methyl 2-chloro-6-cyclopentylisonicotinate (40 g, 0.168 mol, 1 eq.) and 5.4 M NaOMe in MeOH (320 mL, 10 eq.) were heated to reflux for 16 h. Water (250 mL) was added carefully at 80° C. external temperature. Methanol was distilled off at 60° C. and reduced pressure (300 mbar). The residue was acidified with 32% HCl (150 mL) and the pH was adjusted to 1. The mixture was extracted with isopropyl acetate (300 mL). The aq. layer was discarded. The org. layer was washed with water (200 mL). The org. solution was concentrated to dryness under reduced pressure at 60° C. to obtain a white solid; yield: 35.25 g (95%). The crude product was crystallized from acetonitrile (170 mL) to obtain a white solid; 31 g (84%); purity (LC-MS): 97.5% a/a.
      LC-MS: tR=1.516 min, [M+1]+=222; 1H NMR (deutero DMSO) δ=13.50 (br s, 1H), 7.25 (s, 1H), 6.98 (s, 1H), 3.88 (s, 3H), 3.18 (m, 1H), 2.01 (m, 2H), 1.72 (m, 6H).

Example 6

Ethyl 4-cyclopentyl-2,4-dioxobutanoate


      A solution of 20% potassium tert-butoxide in THF (595 mL, 1.1 eq.) and THF (400 mL) was cooled to −20° C. A mixture of diethyloxalate (130 g, 1 eq.) and 1-cyclopentylethanone (100 g, 0.891 mol, 1 eq.) was added at a temperature below −18° C. The reaction mixture was stirred at −10° C. for 30 min and then warmed to 15° C. To the mixture was added 2 M HCl (1 L) and TBME (1 L). The org. layer was separated and washed with water (1 L). The org. layer was evaporated to dryness on a rotary evaporator to obtain an oil; yield: 171 g (91%); purity (GC-MS): 97% a/a; GC-MS: tR=2.50 min, [M+1]+=213;1H NMR δ: 14.55 (m, 1H), 6.41 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.91 (m, 1H), 1.79 (m, 8H), 1.40 (t, J=7.1 Hz, 3H).

Example 7

Ethyl 3-cyano-6-cyclopentyl-2-hydroxyisonicotinate


      Triethylamine (112 mL, 1 eq.) and cyanoacetamide (67.9 g, 1 eq.) was heated in ethanol to 65° C. Ethyl 4-cyclopentyl-2,4-dioxobutanoate (171 g, 0.807 mol, 1 eq.) was added to the mixture at 65° C. The mixture was stirred for 3 h at 65° C. The mixture was cooled to 20° C. and filtered. The product was washed with TBME (2×200 mL).
      The product was dried to obtain a yellow solid; yield: 85 g (40%); purity (LC-MS): 97% a/a; LC-MS: tR=1.41 min, [M+1]+=261; 1H NMR (CDCl3) δ: 12.94 (m, 1H), 6.70 (s, 1H), 4.50 (q, J=7.1 Hz, 2H), 3.11 (m, 1H), 2.21 (m, 2H), 1.96 (m, 2H), 1.78 (m, 4H), 1.48 (t, 3H).

REFERENTIAL EXAMPLES


      Original process described by Goldsworthy in J. Chem. Soc. 1934, 377-378.
      According to Goldsworthy the ketonic ester (ethyl 1-acetylcyclopentanecarboxylate) (19.5 g) was refluxed for 24 h with a considerable excess of potash (19 g) in alcohol (150 cc), two-thirds of the alcohol then distilled off, the residue refluxed for 3 h, the bulk of the alcohol finally removed, saturated brine added, and the ketone extracted with ether. The oil obtained from the extract distilled at 150-160°/760 mm and yielded nearly 4 g of a colourless oil, b.p. 153-155°/760 mm, on redistillation. The semicarbazone, prepared from the ketone and a slight excess of equivalent amounts of semicarbazide and sodium acetate in saturated solution, alcohol just sufficient to clear the solution being finally added, rapidly separated; m.p. 145° after recrystallisation from acetone (Found: N, 24.5. C8H15ON3 requires N, 24.8%).
      The process described by Goldsworthy has been reproduced using K2CO3 in the absence (Referential Example 1) and presence (Referential Example 2) of water.

Referential Example 1

      Ethyl 1-acetylcyclopentanecarboxylate (19.5 g, 0.106 mol) was refluxed for 24 h with K2CO3 (19 g, 0.137 mol, Aldrich: 347825) in ethanol (150 mL). GC-MS indicated a conversion to 3% of the desired product. The solvent was removed and the residue was extracted with ether and brine. Evaporation of solvent yielded 28.5 g of a yellow oil. GC-MS indicated ca. 86% a/a starting material, 3% a/a product.

Referential Example 2

      Ethyl 1-acetylcyclopentanecarboxylate (19.5 g, 0.106 mol) was refluxed for 24 h with K2CO3 (19 g, 0.137 mol, Aldrich: 347825) in ethanol (150 mL) in the presence of water (1.91 g, 1 eq.). GC-MS indicated a conversion to 17% of the desired product. The reaction mixture was discarded.

PATENT

US8658675

https://www.google.com/patents/US8658675

Martin Bolli, Cyrille Lescop, Boris Mathys,Keith Morrison, Claus Mueller, Oliver Nayler,Beat Steiner,

novel compounds of Formula (I) that are agonists for the G protein-coupled receptor S1P1/EDG1 and have a powerful and long-lasting immunomodulating effect which is achieved by reducing the number of circulating and infiltrating T- and B-lymphocytes, without affecting their maturation, memory, or expansion. The reduction of circulating T-/B-lymphocytes as a result of S1P1/EDG1 agonism, possibly in combination with the observed improvement of endothelial cell layer function associated with S1P1/EDG1 activation, makes such compounds useful to treat uncontrolled inflammatory diseases and to improve vascular functionality. Prior art document WO 2008/029371 discloses compounds that act as S1P1/EDG1 receptor agonists and show an immunomodulating effect as described above. Unexpectedly, it has been found that the compounds of the present invention have a reduced potential to constrict airway tissue/vessels when compared to compounds of the prior art document WO 2008/029371. The compounds of the present invention therefore demonstrate superiority with respect to their safety profile, e.g. a lower risk of bronchoconstriction.

Examples of WO 2008/029371, which are considered closest prior art analogues are shown in FIG. 1.

Figure US08658675-20140225-C00002
Figure US08658675-20140225-C00003

The data on the constriction of rat trachea rings compiled in Table 1 illustrate the superiority of the compounds of the present invention as compared to compounds of prior art document WO 2008/029371.

For instance, the compounds of Example 1 and 6 of the present invention show a significantly reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 222 and 226 of WO 2008/029371, respectively. Furthermore, the compounds of Example 1 and 6 of the present invention also show a reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 196 and 204 of WO 2008/029371, respectively. These data demonstrate that compounds wherein R1 represents 3-pentyl and R2represents methoxy are superior compared to the closest prior art compounds of WO 2008/029371, i.e. the compounds wherein R1 represents an isobutyl and R2represents methoxy or wherein R1 represents methyl and R2 represents 3-pentyl. Moreover, also the compound of Example 16 of the present invention, wherein R1is 3-methyl-but-1-yl and R2 is methoxy, exhibits a markedly reduced potential to constrict rat trachea rings when compared to its closest analogue prior art Example 226 of WO 2008/029371 wherein R1 is isobutyl and R2 is methoxy.

The unexpected superiority of the compounds of the present invention is also evident from the observation that the compounds of Example 2 and 7 of the present invention show a markedly reduced potential to constrict rat trachea rings when compared to the compounds of prior art Examples 229 and 233 of WO 2008/029371, respectively. This proves that compounds wherein R1 represents cyclopentyl and R2 represents methoxy are superior compared to the closest prior art compounds of WO 2008/029371, i.e. the compounds wherein R1represents methyl and R2 represents cyclopentyl.

Preparation of Intermediates2-Chloro-6-methyl-isonicotinic acid

The title compound and its ethyl ester are commercially available.

2-(1-Ethyl-propyl)-6-methoxy-isonicotinic acid

a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34° C.) and is then heated to 70° C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60° C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.

b) To a suspension of 2-chloro-6-methoxy-isonicotinic acid (244 g, 1.30 mol) in methanol (2.5 L), H2SO4 (20 mL) is added. The mixture is stirred at reflux for 24 h before it is cooled to 0° C. The solid material is collected, washed with methanol (200 mL) and water (500 mL) and dried under HV to give 2-chloro-6-methoxy-isonicotinic acid methyl ester (165 g) as a white solid; LC-MS: tR=0.94 min, [M+1]+=201.89.

c) Under argon, Pd(dppf) (3.04 g, 4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (50 g, 0.248 mol) in THF (100 mL). A 0.5 M solution of 3-pentylzincbromide in THF (550 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 18 h before it is cooled to rt. Water (5 mL) is added and the mixture is concentrated. The crude product is purified by filtration over silica gel (350 g) using heptane:EA 7:3 to give 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (53 g) as a pale yellow oil; 1H NMR (CDCl3): δ0.79 (t, J=7.5 Hz, 6H), 1.63-1.81 (m, 4H), 2.47-2.56 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 7.12 (d, J=1.0 Hz, 1H), 7.23 (d, J=1.0 Hz, 1H).

d) A solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (50 g, 0.211 mol) in ethanol (250 mL), water (50 mL) and 32% aq. NaOH (50 mL) is stirred at 80° C. for 1 h. The mixture is concentrated and the residue is dissolved in water (200 mL) and extracted with TBME. The org. phase is separated and washed once with water (200 mL). The TBME phase is discarded. The combined aq. phases are acidified by adding 25% aq. HCl and then extracted with EA (400+200 mL). The combined org. extracts are concentrated. Water (550 mL) is added to the remaining residue. The mixture is heated to 70° C., cooled to rt and the precipitate that forms is collected and dried to give the title compound (40.2 g) as a white solid; LC-MS: tR=0.95 min, [M+1]+=224.04; 1H NMR (D6-DMSO): δ 0.73 (t, J=7.3 Hz, 6H), 1.59-1.72 (m, 4H), 2.52-2.58 (m, 1H), 3.88 (s, 3H), 7.00 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H).

2-Methoxy-6-(3-methyl-butyl)-isonicotinic acid

The title compound is prepared in analogy to 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid; LC-MS: tR=0.94 min, [M+1]+=224.05; 1H NMR (D6-DMSO): δ 0.92 (d, J=5.8 Hz, 6H), 1.54-1.62 (m, 3H), 2.70-2.76 (m, 2H), 3.88 (s, 3H), 6.99 (s, 1H), 7.25 (s, 1H), 13.52 (s).

2-Cyclopentyl-6-methoxy-isonicotinic acid

The title compound is prepared in analogy to 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid; LC-MS: tR=0.93 min, [M+1]+=222.02; 1H NMR (CDCl3): δ 1.68-1.77 (m, 2H), 1.81-1.90 (m, 4H), 2.03-2.12 (m, 2H), 3.15-3.25 (m, 1H), 3.99 (s, 3H), 7.18 (d, J=1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H).

2-Cyclohexyl-6-methoxy-isonicotinic acid

The title compound is prepared in analogy to 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid; LC-MS: tR=0.98 min, [M+1]+=236.01; 1H NMR (D6-DMSO): δ 1.17-1.29 (m, 1H), 1.31-1.43 (m, 2H), 1.44-1.55 (m, 2H), 1.67-1.73 (m, 1H), 1.76-1.83 (m, 2H), 1.84-1.92 (m, 2H), 2.66 (tt, J=11.3, 3.3 Hz, 1H), 3.88 (s, 3H), 7.00 (d, J=1.0 Hz, 1H), 7.23 (d, J=1.0 Hz, 1H).

2-Cyclopentyl-N-hydroxy-6-methoxy-isonicotinamidine

a) A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (3.19 g, 13.6 mmol) in 7 N NH3 in methanol (50 mL) is stirred at 60° C. for 18 h. The solvent is removed in vacuo and the residue is dried under HV to give crude 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g) as a pale yellow solid; LC-MS**: tR=0.57 min, [M+1]+=221.38.

b) Pyridine (8.86 g, 91.3 mmol) is added to a solution of 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g, 15.2 mmol) in DCM (100 mL). The mixture is cooled to 0° C. before trifluoroacetic acid anhydride (9.58 g, 45.6 mmol) is added portionwise. The mixture is stirred at 0° C. for 1 h before it is diluted with DCM (100 mL) and washed with sat. aq. NaHCO3 solution (100 mL) and brine (100 mL). The separated org. phase is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g) as pale yellow oil; LC-MS**: tR=0.80 min, [M+1]+=not detectable; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.16 (quint, J=7.8 Hz, 1H), 3.89 (s, 3H), 7.15 (s, 1H), 7.28 (s, 1H).

c) To a solution of 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g, 10.3 mmol) in methanol (100 mL), hydroxylamine hydrochloride (2.15 g, 31.0 mmol) and NaHCO3 (3.04 g, 36.2 mmol) are added. The mixture is stirred at 60° C. for 18 h before it is filtered and the filtrate is concentrated. The residue is dissolved in EA (300 mL) and washed with water (30 mL). The washings are extracted back with EA (4×100 mL) and DCM (4×100 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried under HV to give the title compound (2.74 g) as a white solid; LC-MS**: tR=0.47 min, [M+1]+=236.24; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.92-2.01 (m, 2H), 3.04-3.13 (m, 1H), 3.84 (s, 3H), 5.90 (s, 2H), 6.86 (s, 1H), 7.13 (s, 1H), 9.91 (s, 1H).

2-Cyclopentyl-6-methoxy-isonicotinic acid hydrazide

a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as pale yellow oil; LC-MS**: tR=0.74 min, [M+1]+=369.69; 1H NMR (D6-DMSO): δ 1.62-1.83 (m, 6H), 1.95-2.05 (m, 2H), 3.10-3.21 (m, 1H), 3.88 (s, 3H), 5.13 (s, 2H), 6.97 (s, 1H), 7.23 (s, 1H), 7.28-7.40 (m, 5H), 9.45 (s, 1H), 10.52 (s, 1H).

b) Pd/C (500 mg, 10% Pd) is added to a solution of N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g, 7.42 mmol) in THF (50 mL) and methanol (50 mL). The mixture is stirred at rt under 1 bar of H2 for 25 h. The catalyst is removed by filtration and the filtrate is concentrated and dried under HV to give the title compound (1.58 g) as an off-white solid; LC-MS**: tR=0.51 min, [M+1]+=236.20; 1H NMR (D6-DMSO): δ 1.60-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.08-3.19 (m, 1H), 3.86 (s, 3H), 4.56 (s br, 2H), 6.93 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H), 9.94 (s, 1H).

3-Ethyl-4-hydroxy-5-methyl-benzonitrile

The title compound is prepared from 3-ethyl-4-hydroxy-5-methyl-benzaldehyde following literature procedures (A. K. Chakraborti, G. Kaur, Tetrahedron 55 (1999) 13265-13268); LC-MS: tR=0.90 min; 1H NMR (CDCl3): δ1.24 (t, J=7.6 Hz, 3H), 2.26 (s, 3H), 2.63 (q, J=7.6 Hz, 2H), 5.19 (s, 1H), 7.30 (s, 2H).

3-Chloro-4-hydroxy-5-methyl-benzonitrile

The title compound is prepared from commercially available 2-chloro-6-methyl-phenol in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.85 min. 1H NMR (CDCl3): δ2.33 (s, 3H), 6.10 (s, 1H), 7.38 (s, 1H), 7.53 (d, J=1.8 Hz, 1H).

3-Ethyl-4,N-dihydroxy-5-methyl-benzamidine

The title compound is prepared from 3-ethyl-4-hydroxy-5-methyl-benzonitrile or from commercially available 2-ethyl-6-methyl-phenol following literature procedures (G. Trapani, A. Latrofa, M. Franco, C. Altomare, E. Sanna, M. Usala, G. Biggio, G. Liso, J. Med. Chem. 41 (1998) 1846-1854; A. K. Chakraborti, G. Kaur, Tetrahedron 55 (1999) 13265-13268; E. Meyer, A. C. Joussef, H. Gallardo, Synthesis 2003, 899-905); LC-MS: tR=0.55 min; 1H NMR (D6-DMSO): δ 9.25 (s br, 1H), 7.21 (s, 2H), 5.56 (s, 2H), 2.55 (q, J=7.6 Hz, 2H), 2.15 (s, 3H), 1.10 (t, J=7.6 Hz, 3H).

3-Chloro-4,N-dihydroxy-5-methyl-benzamidine

The title compound is prepared from commercially available 2-chloro-6-methyl-phenol in analogy to literature procedures (e.g. B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); 3-chloro-4-hydroxy-5-methyl-benzaldehyde: LC-MS: tR=0.49 min, [M+1]+=201.00; 1H NMR 82.24 (s, 2H), 2.35 (s, 4H), 5.98 (s br, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 9.80 (s, 1H); 3-chloro-4,N-dihydroxy-5-methyl-benzamidine: 1H NMR (D6-DMSO): δ 2.21 (s, 3H), 5.72 (s br, 2H), 7.40 (s, 1H), 7.48 (s, 1H), 9.29 (s br, 1H), 9.48 (s br, 1H).

(R)-4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine

a) To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (2.89 g, 17.9 mmol) in THF (80 mL), (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (2.84 g, 21.5 mmol) followed by triphenylphosphine (5.81 g, 21.5 mmol) is added. The mixture is cooled with an ice-bath before DEAD (9.36 g, 21.5 mmol) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 85:15 to give (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g) as a pale yellow oil; LC-MS**: tR=0.75 min, [M+1]+=not detected; 1H NMR (CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 2.65-2.77 (m, 2H), 3.80-3.90 (m, 2H), 3.94-4.00 (m, 1H), 4.21 (t, J=7.3 Hz, 1H), 4.52 (quint, J=5.8 Hz, 1H), 7.35 (s, 1H), 7.38 (s, 1H).

b) To a mixture of (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g, 16.2 mmol) and NaHCO3 (4.75 g, 56.6 mmol) in methanol (30 mL), hydroxylamine hydrochloride (3.37 g, 48.5 mmol) is added. The mixture is stirred at 60° C. for 18 h before it is filtered and the solvent of the filtrate is removed in vacuo. The residue is dissolved in EA and washed with a small amount of water and brine. The org. phase is separated, dried over MgSO4, filtered, concentrated and dried to give the title compound (5.38 g) as a white solid; LC-MS**: tR=0.46 min, [M+1]+=309.23; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 1.33 (s, 3H), 1.38 (s, 3H), 2.25 (s, 3H), 2.57-2.69 (m, 2H), 3.73-3.84 (m, 3H), 4.12 (t, J=7.0 Hz, 1H), 4.39-4.45 (m, 1H), 5.76 (s br, 2H), 7.34 (s, 1H), 7.36 (s, 1H), 9.47 (s, 1H).

(R)-3-Chloro-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-5-methyl-benzamidine

The title compound is obtained as a colorless oil (1.39 g) in analogy to (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-α,β-isopropyliden glycerol; LC-MS: tR=0.66 min, [M+H]+=314.96.

(S)-4-(3-Amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile

a) To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (5.06 g, 31.4 mmol) in THF (80 mL), PPh3 (9.06 g, 34.5 mmol) and (R)-glycidol (2.29 mL, 34.5 mmol) are added. The mixture is cooled to 0° C. before DEAD in toluene (15.8 mL, 34.5 mmol) is added. The mixture is stirred for 18 h while warming up to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-ethyl-5-methyl-4-oxiranylmethoxy-benzonitrile (5.85 g) as a yellow oil; LC-MS: tR=0.96 min; [M+42]+=259.08.

b) The above epoxide is dissolved in 7 N NH3 in methanol (250 mL) and the solution is stirred at 65° C. for 18 h. The solvent is evaporated to give crude (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6.23 g) as a yellow oil; LC-MS: tR=0.66 min; [M+1]+=235.11.

N—((S)-3-[2-Ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide

a) To a solution of (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6.23 g, 26.59 mmol) in THF (150 mL), glycolic acid (2.43 g, 31.9 mmol), HOBt (4.31 g, 31.9 mmol), and EDC hydrochloride (6.12 g, 31.9 mmol) are added. The mixture is stirred at rt for 18 h before it is diluted with sat. aq. NaHCO3 and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC with DCM containing 8% of methanol to give (S)—N-[3-(4-cyano-2-ethyl-6-methyl-phenoxy)-2-hydroxy-propyl]-2-hydroxy-acetamide (7.03 g) as a yellow oil; LC-MS: tR=0.74 min, [M+1]+=293.10; 1H NMR (CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.48-3.56 (m, 3H), 3.70-3.90 (m, 3H), 4.19 (s, br, 3H), 7.06 (m, 1H), 7.36 (s, 1H), 7.38 (s, 1H).

b) The above nitrile is converted to the N-hydroxy-benzamidine according to literature procedures (e.g. E. Meyer, A. C. Joussef, H. Gallardo, Synthesis 2003, 899-905); LC-MS: tR=0.51 min, [M+1]+=326.13; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.4 Hz, 3H), 2.24 (s, 3H), 2.62 (q, J=7.4 Hz, 2H), 3.23 (m, 1H), 3.43 (m, 1H), 3.67 (m, 2H), 3.83 (s, 2H), 3.93 (m, 1H), 5.27 (s br, 1H), 5.58 (s br, 1H), 5.70 (s, 2H), 7.34 (s, 1H), 7.36 (s, 1H), 7.67 (m, 1H), 9.46 (s br, 1H).

(S)—N-(3-[2-Chloro-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide

The title compound is obtained as a beige wax (1.1 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile; LC-MS: tR=0.48 min, [M+H]+=331.94.

3-Chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine

a) A mixture of 4-amino-3-chloro-5-methylbenzonitrile (155 mg, 930 μmol) and methanesulfonylchloride (2.13 g, 18.6 mmol, 1.44 mL) is heated under microwave conditions to 150° C. for 7 h. The mixture is cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC using heptane:EA 1:1 to give N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg) as an orange solid; LC-MS**: tR=0.48 min; 1H NMR (CDCl3): δ2.59 (s, 3H), 3.18 (s, 3H), 6.27 (s, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H).

b) Hydroxylamine hydrochloride (60 mg, 858 μmol) and NaHCO3 (72 mg, 858 μmol) is added to a solution of N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg, 429 μmol) in methanol (10 mL). The mixture is stirred at 65° C. for 18 h. The solvent is removed in vacuo and the residue is dissolved in a small volume of water (2 mL) and extracted three times with EA (15 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give the title compound (118 mg) as a white solid; LC-MS**: tR=0.19 min, [M+1]+=277.94; 1H NMR (CDCl3): δ2.57 (s, 3H), 3.13 (s, 3H), 6.21 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz).

3-Ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine

a) In a 2.5 L three-necked round-bottom flask 2-ethyl-6-methyl aniline (250 g, 1.85 mol) is dissolved in DCM (900 mL) and cooled to 5-10° C. Bromine (310.3 g, 1.94 mol) is added over a period of 105 min such as to keep the temperature at 5-15° C. An aq. 32% NaOH solution (275 mL) is added over a period of 10 min to the greenish-grey suspension while keeping the temperature of the reaction mixture below 25° C. DCM (70 mL) and water (100 mL) are added and the phases are separated. The aq. phase is extracted with DCM (250 mL). The combined org. phases are washed with water (300 mL) and concentrated at 50° C. to afford the 4-bromo-2-ethyl-6-methyl-aniline (389 g) as a brown oil; 1H NMR (CDCl3): δ 1.27 (t, J=7.3 Hz, 3H), 2.18 (s, 3H), 2.51 (q, J=7.3 Hz, 2H), 3.61 (s br, 1H), 7.09 (s, 2H).

b) A double-jacketed 4 L-flask is charged with 4-bromo-2-ethyl-6-methyl-aniline (324 g, 1.51 mol), sodium cyanide (100.3 g, 1.97 mol), potassium iodide (50.2 g, 0.302 mol) and copper(I)iodide (28.7 g, 0.151 mol). The flask is evacuated three times and refilled with nitrogen. A solution of N,N′-dimethylethylenediamine (191.5 mL, 1.51 mol) in toluene (750 mL) is added. The mixture is heated to 118° C. and stirred at this temperature for 21 h. The mixture is cooled to 93° C. and water (1250 mL) is added to obtain a solution. Ethyl acetate (1250 mL) is added at 22-45° C. and the layers are separated. The org. phase is washed with 10% aq. citric acid (2×500 mL) and water (500 mL). The separated org. phase is evaporated to dryness to afford 4-amino-3-ethyl-5-methyl-benzonitrile (240 g) as a metallic black solid; 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.19 (s, 3H), 2.52 (q, J=7.3 Hz, 2H), 4.10 (s br, 1H), 7.25 (s, 2H).

c) The title compound is then prepared from the above 4-amino-3-ethyl-5-methyl-benzonitrile in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine; LC-MS**: tR=0.26 min, [M+1]+=272.32.

3-Chloro-4-ethanesulfonylamino N-hydroxy-5-methyl-benzamidine

The title compound is prepared in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine using ethanesulfonylchloride; LC-MS**: tR=0.27 min, [M+1]+=292.13; 1H NMR (D6-DMSO): δ 1.36 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 3.22 (q, J=7.5 Hz), 5.88 (s, 2H), 7.57 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 9.18 (s, 1H), 9.78 (s, 1H).

4-Benzyloxy-3-ethyl-5-methyl-benzoic acid

a) To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol, prepared from 2-ethyl-6-methyl-phenol according to the literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) in MeCN (350 mL), K2CO3 (58.7 g, 0.425 mol) and benzylbromide (36.4 g, 0.213 mol) are added. The mixture is stirred at 60° C. for 2 h before it is cooled to rt, diluted with water and extracted twice with EA. The org. extracts are washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (45 g) as an orange oil. 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 4.90 (s, 2H), 7.31-7.52 (m, 5H), 7.62 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 9.94 (s, 1H).
b) To a mixture of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (132 g, 0.519 mol) and 2-methyl-2-butene (364 g, 5.19 mol) in tert.-butanol (1500 mL), a solution of NaH2PO4 dihydrate (249 g, 2.08 mol) in water (1500 mL) is added. To this mixture, NaClO2 (187.8 g, 2.08 mol) is added in portions. The temperature of the reaction mixture is kept below 30° C., and evolution of gas is observed. Upon completion of the addition, the orange bi-phasic mixture is stirred well for 3 h before it is diluted with TBME (1500 mL). The org. layer is separated and washed with 20% aq. NaHS solution (1500 mL) and water (500 mL). The org. phase is then extracted three times with 0.5 N aq. NaOH (1000 mL), the aq. phase is acidified with 25% aq. HCl (500 mL) and extracted twice with TBME (1000 mL). These org. extracts are combined and evaporated to dryness to give the title compound; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.31 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 4.86 (s, 2H), 7.34-7.53 (m, 5H), 7.68 (s, 2H), 12.70 (s, 1H).

Example 1 (S)-3-(2-Ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenoxy)-propane-1,2-diol

a) To a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (190 mg, 732 μmol) in THF (10 mL) and DMF (2 mL), DIPEA (190 mg, 1.46 mmol) followed by TBTU (235 mg, 732 μmol) is added. The mixture is stirred at rt for 10 min before (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine 226 mg, 732 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The org. phase is separated and concentrated. The remaining residue is dissolved in dioxane (10 mL) and heated to 105° C. for 18 h. The mixture is cooled to rt, concentrated and the crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give 4-{3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-(1-ethyl-propyl)-6-methoxy-pyridine (256 mg) as a yellow oil; LC-MS: tR=1.28 min, [M+H]+=496.23.

b) A solution of 4-{3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-(1-ethyl-propyl)-6-methoxy-pyridine (250 mg, 504 μmol) in 4 M HCl in dioxane (10 mL) is stirred at rt for 90 min before it is concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (76 mg) as a pale brownish solid; LC-MS: tR=1.12 min, [M+H]+=456.12; 1H NMR (CDCl3): δ0.85 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.0 Hz, 3H), 1.70-1.89 (m, 4H), 2.42 (s, 3H), 2.61-2.71 (m, 1H), 2.78 (q, J=7.3 Hz, 2H), 3.82-4.00 (m, 4H), 4.04 (s, 3H), 4.14-4.21 (m, 1H), 7.34 (s, 1H), 7.46 (s, 1H), 7.86-7.91 (m, 2H).

Example 2 (S)-3-{4-[5-(2-Cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol

The title compound is prepared in analogy to Example 1 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid; LC-MS: tR=1.14 min, [M+H]+=454.16; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.72-1.78 (m, 2H), 1.85-1.94 (m, 4H), 2.03-2.15 (m, 2H), 2.41 (s, 3H), 2.72 (d, J=5.3 Hz, 1H), 2.77 (q, J=7.5 Hz, 2H), 3.19-3.28 (m, 1H), 3.81-3.94 (m, 2 H), 3.95-3.98 (m, 2H), 4.02 (s, 3H), 4.14-4.21 (m, 1H), 7.31 (d, J=1.3 Hz, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.88 (d, J=1.8 Hz), 7.89 (d, J=2.0 Hz, 1H).

PAPER

Abstract Image

A practical synthesis of S1P receptor 1 agonist ACT-334441 (1) through late-stage convergent coupling of two key intermediates is described. The first intermediate is 2-cyclopentyl-6-methoxyisonicotinic acid whose skeleton was built from 1-cyclopentylethanone, ethyl oxalate, and cyanoacetate in a Guareschi–Thorpe reaction in 42% yield over five steps. The second, chiral intermediate, is a phenol ether derived from enantiomerically pure (R)-isopropylidene glycerol ((R)-solketal) and 3-ethyl-4-hydroxy-5-methylbenzonitrile in 71% yield in a one-pot reaction. The overall sequence entails 18 chemical steps with 10 isolated intermediates. All raw materials are cheap and readily available in bulk quantities, the reaction conditions match with standard pilot plant equipment, and the route reproducibly afforded 3–20 kg of 1 in excellent purity and yield for clinical studies.

Practical Synthesis of a S1P Receptor 1 Agonist via a Guareschi–Thorpe Reaction

Chemistry Process R&D, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00210
*E-mail: stefan.abele@actelion.com. Telephone: +41 61 565 67 59.
 (1H NMR): 99.40% w/w; er (HPLC method 2): (S):(R) = 99.7:0.3, tR 10.70 min (S-isomer), 14.5 min (R-isomer);
mp 80 °C (DSC);
1H NMR (d6-DMSO): δ 7.78 (s, 2 H), 7.53 (s, 1 H), 7.26 (s, 1 H), 4.98 (d, J = 4.6 Hz, 1 H), 4.65 (s, 1 H), 3.94 (s, 3 H), 3.86 (m, 2 H), 3.75 (m, 1 H), 3.50 (t, J = 5.4 Hz, 2 H), 3.28 (m, 1 H), 2.75 (d, J = 7.5 Hz, 2 H), 2.35 (s, 3 H), 2.03 (m, 2 H), 1.81 (m, 4 H), 1.69 (m, 2 H), 1.22 (t, J = 7.5 Hz, 3 H).
13C NMR (CDCl3): δ 174.3, 168.9, 165.8, 164.4, 157.4, 137.7, 133.6, 131.7, 128.4, 126.7, 122.5, 112.0, 106.0, 73.9, 71.1, 63.8, 53.7, 47.5, 33.3, 25.9, 22.9, 16.4, 14.8.
Patent ID Date Patent Title
US2015133669 2015-05-14 NEW PROCESS FOR THE PREPARATION OF 2-CYCLOPENTYL-6-METHOXY-ISONICOTINIC ACID
US8658675 2014-02-25 Pyridin-4-yl derivatives
//////////ACT-334441, ACT 334441, ACT334441, CENERIMOD, S1P receptor 1 agonist, Systemic lupus erythematosus, UNII-Y333RS1786  Y333RS1786, phase 2, Actelion Pharmaceuticals Ltd.Martin Bolli, Cyrille Lescop, Boris Mathys,Keith Morrison, Claus Mueller, Oliver Nayler,Beat Steiner,
OC[C@H](O)COC1=C(C)C=C(C2=NOC(C3=CC(C4CCCC4)=NC(OC)=C3)=N2)C=C1CC

Is AQL Testing required within the 100% Visual Inspection?


DRUG REGULATORY AFFAIRS INTERNATIONAL

Is AQL Testing required within the 100% Visual Inspection?
One of the most frequently asked questions is whether an additional testing based on samples is required after the 100% visual inspection of parenterals. The answer is: basically, “yes”.

http://www.gmp-compliance.org/enews_05496_Two-new-FDA-Warning-Letters-for-API-Manufacturers-in-China_15488,15484,Z-QCM_n.html

One of the most frequently asked questions is whether an additional AQL testing based on samples is required after the 100% visual inspection of parenterals. The background for that question is the probabilistic nature of visual inspection. It is known that the discovery of defects (like for example particulates) is a matter of detection probability. In other words, visual inspection cannot exclude that defective containers may still be in the batch which hasn’t been sorted out. This applies to manual, semi-automatic and also automatic visual inspection.

The American Pharmacopoeia has reacted to that and has integrated AQL testing in the monograph Visible Particulates in Injections. Here, the value 0.65 has been…

View original post 203 more words

Two new FDA Warning Letters for API Manufacturers in China


DRUG REGULATORY AFFAIRS INTERNATIONAL

Two new FDA Warning Letters for API Manufacturers in China

In June 2016, two API manufacturers in China received a Warning Letter from the FDA. Both companies had major deficiencies regarding data integrity. For instance, manipulations were found in HPLC analyses as well as in GC analyses. You will find more information on the current FDA Warning Letters for Chongqing Lummy and Shanghai Desano here. http://www.gmp-compliance.org/enews_05496_Two-new-FDA-Warning-Letters-for-API-Manufacturers-in-China_15488,15484,Z-QCM_n.html
The Chinese Company Chongqing Lummy Pharmaceutical Co., Ltd. received a Warning Letter from the FDA on June 21, 2016. This Warning Letter referred to both the FDA inspection from March 14-16, 2016 and the response which the API manufacturer had sent to the FDA on March 31, 2016.

It was claimed that Chongqing Lummy Pharmaceuticals had no adequate control in place to prevent data manipulation or deletion. The FDA investigator’s review of the audit trail revealed that an analyst had manipulated the computerized gas…

View original post 425 more words

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WHAT ARE SUPERGENERICS


Osanetant , SR-142,801


Osanetant.png

Osanetant (SR-142,801)

160492-56-8 CAS

: MW 605.257582985
Chemical Formula C35H41Cl2N3O2

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide

Osanetant (SR-142,801) was a neurokinin 3 receptor antagonist developed by Sanofi-Synthélabo, which was being researched for the treatment of schizophrenia, but was discontinued.[1][2] It was the first non-peptide NK3 antagonist developed in the mid-1990s,[3][4] Other potential applications for osanetant is in the treatment of drug addiction, as it has been found to block the effects ofcocaine in animal models.[5][6]

Developed by Sanofi-Aventis (formerly Sanofi-Synthelabo), osanetant (SR-142801) is an NK3 receptor antagonist which was under development for the treatment of schizophrenia and other Central Nervous System (CNS) disorders. In a review of its R&D portfolio, the company announced in August 2005 that it would cease any further development ofosanetant. This follows an earlier decision to discontinue development of eplivanserin for schizophrenia

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide and to a process for their preparation. (R)-(+)-N-[[3-[1-Benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide, hereinafter denoted by its International Non-proprietary Name “osanetant”, is the first antagonist of the NK-3 receptor described in the literature, the preparation of which, in particular in the hydrochloride form, is illustrated in EP-A-673 928.
Osanetant.png
According to this document, osanetant is prepared by reacting N-methyl-N-(4-phenylpiperidin-4-yl)acetamide with 1-benzoyl-3-(3,4-dichlorophenyl)-3-(methanesulfonyloxyprop-1-yl)piperidine and by converting the osanetant thus obtained to its hydrochloride. It has been found that osanetant hydrochloride is isolated in the form of an amorphous solid which is difficult to purify. This product comprises impurities originating from the preceding synthetic stages.
Preparative chromatography starting from osanetant base can be used to obtain osenetant in the pure form.
Osanetant is a neurokinin (NK3) receptor antagonist under development by Sanofi-Synthélabo (formerly Sanofi) as a potential treatment for schizophrenia . Sanofi was originally investigating its potential use as a treatment for psychosis and anxiety . Following phase IIa clinical trials , osanetant entered phase IIb development in February 2001 . Osanetant was the first potent and selective non-peptide antagonist described for the NK3 tachykinin receptor . It has a higher affinity for human and guinea pig NK3 receptors than for rat NK3 receptors . In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011 .
Sanofi-Aventis CEO, Chris Vihebacher,
PATENT
EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316
N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).
Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.
WO 9805640
Bioorg Med Chem Lett 1996,6(19),2307
In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) –prepared by protection of 3-bromopropanol (XXI) with dihydropyran– to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported. The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI), followed by treatment with Boc2O to yield (XXXVII). Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII). Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX). This was then alkylated with mesylate (XXVII), and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.
In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.
Bioorg Med Chem Lett 1997,7(5),555
A new method has been reported. Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane. Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI), which was converted to acetamide (XLIV) by treatment with acetyl chloride. Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X). Finally, alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.
Cited Patent Filing date Publication date Applicant Title
US5741910 * Feb 29, 1996 Apr 21, 1998 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US5942523 * Feb 29, 1996 Aug 24, 1999 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US6040316 * Sep 2, 1997 Mar 21, 2000 Warner-Lambert Company 3-alkyl-3-phenyl-piperidines
US6124316 * May 7, 1999 Sep 26, 2000 Sanofi Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
Citing Patent Filing date Publication date Applicant Title
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US7662845 Aug 7, 2006 Feb 16, 2010 Astrazeneca Ab 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12
US7666892 May 5, 2008 Feb 23, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7700604 Dec 14, 2005 Apr 20, 2010 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7754750 Jul 13, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7989620 Aug 2, 2011 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US8153673 Jan 26, 2010 Apr 10, 2012 Astrazeneca Ab Metalloproteinase inhibitors
US8183251 Nov 28, 2007 May 22, 2012 Astrazeneca Ab Hydantoin compounds and pharmaceutical compositions thereof
US20080032997 * Dec 14, 2005 Feb 7, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080064710 * Jul 4, 2005 Mar 13, 2008 Astrazeneca Ab Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
US20080221139 * Nov 28, 2007 Sep 11, 2008 David Chapman Novel Compounds
US20080262045 * May 5, 2008 Oct 23, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20080293743 * Dec 14, 2005 Nov 27, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080306065 * May 6, 2008 Dec 11, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20100144771 * Dec 2, 2009 Jun 10, 2010 Balint Gabos Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
WO2007106022A2 * Mar 15, 2007 Sep 20, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.
WO2007106022A3 * Mar 15, 2007 Nov 1, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.

References

  1.  “osanetant Sanofi-Aventis discontinued, France.”. Highbeam.
  2. Kamali, F (July 2001). “Osanetant Sanofi-Synthélabo”. Current opinion in investigational drugs (London, England : 2000). 2 (7): 950–6.PMID 11757797.
  3.  Emonds-Alt, X; Bichon, D; Ducoux, JP; Heaulme, M; Miloux, B; Poncelet, M; Proietto, V; Van Broeck, D; et al. (1995). “SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor”. Life Sciences. 56 (1): PL27–32. doi:10.1016/0024-3205(94)00413-M.PMID 7830490.
  4.  Quartara L, Altamura M (August 2006). “Tachykinin receptors antagonists: from research to clinic”. Current Drug Targets. 7 (8): 975–92.doi:10.2174/138945006778019381. PMID 16918326. Retrieved 2011-04-14.
  5.  Desouzasilva, M; Mellojr, E; Muller, C; Jocham, G; Maior, R; Huston, J; Tomaz, C; Barros, M (May 2006). “The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys”. European Journal of Pharmacology. 536 (3): 269–78.doi:10.1016/j.ejphar.2006.03.010. PMID 16603151.
  6.  Jocham, Gerhard; Lezoch, Katharina; Müller, Christian P.; Kart-Teke, Emriye; Huston, Joseph P.; De Souza Silva, M. AngéLica (September 2006). “Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core”. European Journal of Neuroscience. 24 (6): 1721–32. doi:10.1111/j.1460-9568.2006.05041.x.PMID 17004936.
X Emonds-Alt et al. SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 1995, 56(1), PL27-32.
F Kamali. Osanetant Sanofi-Synthélabo. Curr. Opin. Invest. Drugs. 2001, 2(7), 950-956.
L Quartara and M Altamura. Tachykinin receptors antagonists: from research to clinic. Curr. Drug Targets. 2006, 7(8), 975-992.
MA De Souza Silva et al. The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys. Eur. J. Pharmacol. 2006, 536(3), 269-278.
G Jocham et al. Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core. Eur. J. Neurosci. 2006, 24(6), 1721-1732.
Osanetant
Osanetant.png
Systematic (IUPAC) name
N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl}-4-phenylpiperidin-4-yl]-N-methylacetamide
Identifiers
CAS Number 160492-56-8 Yes
ATC code none
PubChem CID 219077
IUPHAR/BPS 2110
ChemSpider 189901 
UNII K7G81N94DT Yes
ChEMBL CHEMBL346178 
Chemical data
Formula C35H41Cl2N3O2
Molar mass 606.625 g/mol

///////Osanetant , SR-142,801, 

CC(=O)N(C)C1(CCN(CC1)CCC[C@@]2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5

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AZD-1236 Revisited


Figure imgf000002_0001

AZD1236

CAS 459814-89-2,
MF C15 H19 Cl N4 O5 S.  MW402.85
2,4-Imidazolidinedione, 5-[[[4-[(5-chloro-2-pyridinyl)oxy]-1-piperidinyl]sulfonyl]methyl]-5-methyl-, (5S)-
(5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione
(S)-5-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-suIfonylmethyl]-5-methyl- imidazoIidine-2,4-dione
UNII-B4OQY51WZS; B4OQY51WZS; (S)-5-(((4-((5-Chloropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)methyl)-5-methylimidazolidine-2,4-dione; AZD1236; AZD-1236;
Piperidine, 4-[(5-chloro-2-pyridinyl)oxy]-1-[[[(4S)-4-methyl-2,5-dioxo-4-imidazolidinyl]methyl]sulfonyl]- (9CI)(5S)-5-[[[4-[(5-Chloro-2-pyridinyl)oxy]-1-piperidinyl]sulfonyl]methyl]-5-methyl-2,4-imidazolidinedione

Mechanism of Action: Matrix metalloproteinase 9 & 12 (MMP9,12) inhibitor MMP9 MMP12i

Anders Eriksson, Matti Lepistö, Michael Lundkvist, af Rosenschöld Magnus Munck,Pavol Zlatoidsky,

Astrazeneca Ab INNOVATOR

UNII-B4OQY51WZS.png

  • OriginatorAstraZeneca
  • Class
  • Mechanism of ActionMatrix metalloproteinase inhibitors
  • Highest Development Phases
  • DiscontinuedChronic obstructive pulmonary disease

Most Recent Events

  • 29 Jul 2010Discontinued – Phase-II for Chronic obstructive pulmonary disease in Europe (PO)
  • 29 Jul 2010Discontinued – Phase-I for Chronic obstructive pulmonary disease in Japan (PO)
  • 29 Jul 2010Discontinued – Phase-I for Chronic obstructive pulmonary disease in Japan (PO)

AZD1236 is a selective MMP-9 and MMP-12 inhibitor (IC50 4.5 and 6.1nM) from Astrazeneca that, since it failed biomarker endpoints for COPD is included in the AZ Open Innovation 2014 set for repurposing. Pending any published link the structure identification is tenatative but seems likely to be the structure crystalised in WO2007106022.

Matrix metallopeptidase 9 and 12 (MMP9|MMP12) inhibitor http://www.ncbi.nlm.nih.gov/gene/4318; http://www.ncbi.nlm.nih.gov/gene/4321 Preclinical Pharmacology AZD1236 is a potent and reversible inhibitor of human MMP9 and MMP12 (IC50’s = 4.5 and 6.1nM, respectively), with 10 – 15-fold selectivity to MMP2 and MMP13 and >350-fold selectivity to other members of the enzyme family. Its activity is approximately 20- to 50-fold lower at the rat, mouse, and guinea pig orthologues. In acute models of lung injury, AZD1236 inhibited the hemorrhage and inflammation induced by instillation of human MMP12 into rat lungs by ~80% at 0.81 mg/kg, and also abolished macrophage infiltration into BAL fluid induced by tobacco smoke inhalation in the mouse. Safety and Tolerability In healthy human volunteers, AZD1236 was well tolerated in single doses from 2 to 1500 mg and in multiple doses of 15, 75 and 500 mg for periods of up to 13 days. AZD1236 was also well tolerated in COPD patients with moderate to severe disease when given at 75 mg BID for 6 weeks. Pre-clinical toxicology studies of up to 12 month duration have been performed. Toxicologically important findings mainly relate to chronic treatment and included: diffuse eye lens opacities after 6 months administration to rats and fibrodysplasia in the subcutis after 12 months to dogs. Clinical Pharmacology Target coverage data to date have been mixed. In healthy subjects, single dose of 30 or 75 mg inhibited ex vivo zymosanstimmulated whole blood MMP activity (the 75 mg dose yielding plasma compound levels at Cmax steady state of ~120 x IC50). In contrast, 75 mg BID for 6 wks in COPD patients compared to placebo did not identify any significant change in whole blood MMP activity.

STR1

PATENT

WO 2002074750 

WO 02/074767 further discloses a specific metalloproteinase inhibitor compound identified therein as (5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione (page 65, lines 15 to 27; and page 120, lines 23 to 29). This compound is designated herein as compound (I).

Figure imgf000002_0001

(I)

WO 02/074767 further discloses processes for the preparation of compound (I). Thus, in one embodiment, compound (I) is prepared by a route analogous to that shown in the following Scheme (WO 02/074767; pages 87, 113 and 120) but substituting the appropriate amine in step (d):

Scheme 1

Figure imgf000003_0001
Figure imgf000003_0002

Reagents and conditions for Scheme 1: a) KCN, (NHLj)2CO3, EtOHTH2O, +900C, 3h;. b) Chiral separation, CHIRALPAK AD, methanol as eluent;. c) Cl2 (g), AcOH/H2O, <+15 0C, 25min; d) Diisopropylethylamine, THF. -20 0C, 30 min.

The obtained compound (I) is then purified either by precipitation and washing with ethanol/water or by preparative HPLC. In a second embodiment, the racemate of compound (I), (5RS)-5-[4-(5-chloro-pyridin-2- yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione, was prepared by reacting l-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one with an excess of potassium cyanide and ammonium carbonate in ethanol, and isolating the product by precipitation. Compound (I), the (5S)-enantiomer, was then obtained by chiral HPLC (WO 02/074767; pages 55 and 65).

No crystalline forms of compound (I) are disclosed in WO 02/074767.

Compound (I) is a potent metalloproteinase inhibitor, particularly a potent inhibitor of

MMP 12, and as such is useful in therapy. However, when made according to the processes described in WO 02/074767, compound (I) exhibits unpredictable solid state properties with respect to thermodynamic stability. To prepare pharmaceutical formulations containing compound (I) for administration to humans in accordance with the requirements of U.S. and other international health registration authorities, there is a need to produce compound (I) in a stable form, such as a stable crystalline form, having constant physical properties.

str2

PATENT

WO  2007106022

WO 02/074767 further discloses a specific metalloproteinase inhibitor compound identified therein as (5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione (page 65, lines 15 to 27; and page 120, lines 23 to 29). This compound is designated herein as compound (I).

Figure imgf000002_0001

(I)

WO 02/074767 further discloses processes for the preparation of compound (I). Thus, in one embodiment, compound (I) is prepared by a route analogous to that shown in the following Scheme (WO 02/074767; pages 87, 113 and 120) but substituting the appropriate amine in step (d):

Scheme 1

Figure imgf000003_0001
Figure imgf000003_0002

Reagents and conditions for Scheme 1: a) KCN, (NHLj)2CO3, EtOHTH2O, +900C, 3h;. b) Chiral separation, CHIRALPAK AD, methanol as eluent;. c) Cl2 (g), AcOH/H2O, <+15 0C, 25min; d) Diisopropylethylamine, THF. -20 0C, 30 min.

The obtained compound (I) is then purified either by precipitation and washing with ethanol/water or by preparative HPLC. In a second embodiment, the racemate of compound (I), (5RS)-5-[4-(5-chloro-pyridin-2- yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione, was prepared by reacting l-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one with an excess of potassium cyanide and ammonium carbonate in ethanol, and isolating the product by precipitation. Compound (I), the (5S)-enantiomer, was then obtained by chiral HPLC (WO 02/074767; pages 55 and 65).

No crystalline forms of compound (I) are disclosed in WO 02/074767.

Compound (I) is a potent metalloproteinase inhibitor, particularly a potent inhibitor of

MMP 12, and as such is useful in therapy. However, when made according to the processes described in WO 02/074767, compound (I) exhibits unpredictable solid state properties with respect to thermodynamic stability. To prepare pharmaceutical formulations containing compound (I) for administration to humans in accordance with the requirements of U.S. and other international health registration authorities, there is a need to produce compound (I) in a stable form, such as a stable crystalline form, having constant physical properties.

A preferred process for the synthesis of compound (I) is shown in Scheme 2.

Figure imgf000022_0001

Scheme 2

KCN, (NH4)2CO3

(H) 2-propanol

Figure imgf000022_0002

Chromatography KOBu’

Figure imgf000022_0003

Cl2

AcOH AcOH, H2O

Figure imgf000022_0004

Compound (I)

Figure imgf000022_0005

Recrystallisation EtOH, H2O

Compound (I) Form G

Figure imgf000022_0006

Example 5

(S)-5-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-suIfonylmethyl]-5-methyl- imidazoIidine-2,4-dione Process 1

I5 a) 5-Chloro-2-(piperidin-4-yloxy)-pyridine

5-Chloro-2-(piperidin-4-yloxy)-pyridine acetate (40 g, 0.146 mol) was slurried in iso- PrOAc (664 mL) at 300C. To this slurry was added Na2CO3 (1.5 mol per litre; 196 mL, 2 mol eq.). The slurry was then rapidly stirred at 30 0C for 15 minutes. The biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded.

20 The above base washing procedure was repeated twice more. The organic phase was then washed once with water (200 mL). The resulting iso-VxOAc solution was reduced in volume to approximately 300 mL by distillation under reduced pressure. The solution was then diluted with zsø-PrOAc (400 mL) and again distilled down to approximately 300 mL. This procedure was repeated once more. A sample was removed for analysis of 5-chloro-

25 2-(piperidm-4-yloxy)-pyridine content and water content. The weight or the volume of the solution was measured in order to calculate the concentration of 5-chloro-2-(piperidin-4- yloxy)-pyridme in the Z-PrOAc solution.

fr) rSV5-r4-(5-Chloro-pyridin-2-yloxyVpiperidine-l-sulfonylmethvn-5-methyl- 30 imidazolidine-2 ,4-dione Diisopropylethylamine (24.3 mL, 0.139 mol, 1 mol eq.) was added to the iso-PrOAc solution prepared in part (a) [ca. 300 mL; equivalent to 31.2 g, 0.146 mol, 1.05 mol eq. of 5-chloro-2-(piperidin-4-yloxy)-pyridine] in one portion at RT. The solution was then cooled to -15 °C.

((S)-4-Methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonyl chloride (31.65 g, 0.139 mol, 1 mol eq.) was dissolved in dry THF (285 mL) at RT with stirring. The resulting solution was then added to the iso-PrOAc solution of 5-chloro-2-(piperidin-4-yloxy)- pyridine dropwise at -15 0C over about 1.5 h. A precipitate was seen on addition of the ((S)-4-methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonyl chloride. At the end of the addition, dry THF (32 mL) was added to the reaction mixture to wash the line and the mixture was stirred for 1 h at — 15 0C. It was then warmed to 20 °C over 1 h and stirred at 20 °C for 1 h further. The reaction was quenched with 10 wt% NaHSO4 (157 mL) with rapid stirring. After about 15 minutes, the biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded. This acid wash procedure was repeated once more. The organic phase was then washed with water (157 mL) using rapid stirring and allowing complete phase separation before partitioning. The reaction solution was then warmed to 40 °C and washed again with water (157 mL). THF (95 mL) was added to the organic layer that was then warmed to 40 0C and filtered at 400C to remove any particulate matter. The solvent volume was then reduced to about 157 mL by reduced pressure distillation with the jacket temperature at 55 °C. zso-PrOAc (317 mL) was then added and the volume was again reduced to about 157 mL. Two more put-and-takes of zsø-PrOAc (317 mL) were carried out. Solids began to precipitate out during the distillations and a suspension resulted. The volume was reduced to about 157 mL each time and after the final distillation a small sample of solvent was then removed from the reaction mixture for residual THF analysis. The 1H NMR showed no THF peaks. The contents of the reaction were then cooled to 0 °C and the product was collected by filtration. The reaction vessel was washed with zsø-PrOAc (63 mL) and this rinse was used to wash the product on the filter. The product was dried overnight in a vacuum oven at 40 °C. The required (S)-5-[4- (5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyhnethyl]-5-methyl-imidazolidine-2,4-dione was isolated as a white solid in 71% yield (41.8 g).

1H NMR (300MHz, d6-DMSO) δ 10.74 (IH, s), 8.20 (IH, d), 8.01 (IH, s), 7.81 (IH, dd), 6.87 (IH, d), 5.09 (IH, m), 3.52-3.35 (4H, m), 3.13 (2H, m), 2.02 (2H, m), 1.72 (2H, m), 1.33 (3H, s).

Example 6

(S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl- imidazolidine-2,4-dione Process 2 a) 5-Chloro-2-(piperidm-4-yloxy)-pyridine

5-Chloro-2-(piperidm-4-yloxy)-pyridine acetate (70 g, 257 mmol) was slurried in toluene

(560 mL) at RT. IM NaOH (420 mL) was added and the slurry was then rapidly stirred at RT for 15 min. The biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded. The organic phase was then washed with water (2 x 420 mL). A sample was removed from the organic phase and assayed for 5-chloro-2-(piperidin-

4-yloxy)-pyridine.

The resulting toluene solution was then reduced in volume by distillation at reduced pressure, down to approximately 168 mL (2.4 vol eq. with respect to 5-chloro-2-(piperidin-

4-yloxy)-pyridine acetate charge). The solution was then diluted with toluene (420 mL) and again distilled down to approx 168 mL (2.4 vol eq.). A sample was removed for analysis of water content.

b*) (S)-5-r4-r5-Chloro-pyridm-2-yloxy)-piperidine-l-sulfonylmethvH-5-methyl- imidazolidine-2 ,4-dione

Diisopropylethylamine (38.4 mL, 220 mmol) was added to the toluene solution of 5-chloro-2-(piperidin-4-yloxy)-pyridine obtained in step (a) (containing 236 mmol) in one portion followed by dry THF (151 mL) as a line wash. ((S)-4-Methyl-2,5-dioxo- imidazolidin-4-yl)-methanesulfonyl chloride (48.7 g, 215 mmol) was dissolved in dry THF (352 mL) at RT with stirring. The resulting solution of the sulfonyl chloride was then added dropwise to the toluene/THF solution of 5-chloro-2-(piperidin-4-yloxy)-pyridine and diisopropylethylamine at RT over 1 to 2 h. A precipitate was seen on addition of the sulfonyl chloride. At the end of the addition, dry THF (50 mL) was added to the reaction 5 mixture as a line wash. After the addition was complete, the reaction was stirred for about 30 min at RT.

The reaction was quenched with 10 wt% NaHSO4 (251 mL) with rapid stirring for approx 15 min. The biphasic mixture was allowed to settle, when the bottom aqueous phase was io separated and discarded. This acid wash procedure was repeated once more. The solvent volume was then reduced to about 220 mL by reduced pressure distillation. Toluene (300 mL) was then added and the volume was reduced to about 245 mL Solids begin to precipitate during the distillations and a suspension resulted. After the final distillation, a small sample of solvent was then removed from the reaction mixture for residual THF i5 analysis.

The contents of the reaction mixture were then cooled to 0 °C, stirred for about 30 minutes at this temperature and the product was collected by filtration. The reaction vessel was washed with toluene (100 mL) and this rinse was used to wash the product on the filter. 20 The product was dried in a vacuum oven at 40 0C to constant weight. (S)-5-[4-(5-Chloro- pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione was isolated as a white solid in typically 85 to 88% yield over the two steps.

Aerial view of Mölndal

Patent

WO 2003106689

Paul Hudson, President, AstraZeneca U.S. and Executive Vice President, North America, joined by AstraZeneca volunteers to celebrate the AstraZeneca Hope Lodge’s fifth birthday.

Paul Hudson, President, AstraZeneca U.S. and Executive Vice President, North America, joined by AstraZeneca volunteers to celebrate the AstraZeneca Hope Lodge’s fifth birthday.

CLIPS

STR3

STR4

Astra boss Pascal Soriot

STR1

STR3

Massachusetts Economic Development Secretary Jay Ash (left) congratulates Kumar Srinivasan, Head of AstraZeneca R&D Boston (right), at a ceremony to launch AstraZeneca’s Gatehouse Park BioHub.

Massachusetts Economic Development Secretary Jay Ash (left) congratulates Kumar Srinivasan, Head of AstraZeneca R&D Boston (right), at a ceremony to launch AstraZeneca’s Gatehouse Park BioHub.

STR1

str2

STR1

str2

References
1. AstraZeneca. 
AZD1236.
Accessed on 31/10/2014. Modified on 31/10/2014. Open Innovation, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd1236/
2. Dahl R, Titlestad I, Lindqvist A, Wielders P, Wray H, Wang M, Samuelsson V, Mo J, Holt A. (2012)
Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.
Pulm Pharmacol Ther25 (2): 169-77. [PMID:22306193]

https://ncats.nih.gov/files/AZD1236.pdf

AZD1236

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Reference
1 * HIRRLINGER B. ET AL.: ‘Purification and properties of an amidase from Rhodococcus erythropolis MP50 which enantioselectively hydrolyzes 2-arylpropionamides‘ JOURNAL OF BACTERIOLOGY vol. 178, no. 12, June 1996, pages 3501 – 3507, XP001174103
2 * See also references of EP2064202A2
Citing Patent Filing date Publication date Applicant Title
US7625934 Dec 1, 2009 Astrazeneca Ab Metalloproteinase inhibitors
US7772403 Mar 15, 2007 Aug 10, 2010 Astrazeneca Ab Process to prepare sulfonyl chloride derivatives
Patent ID Date Patent Title
US2011003853 2011-01-06 Metalloproteinase Inhibitors
US7754750 2010-07-13 Metalloproteinase Inhibitors
US7625934 2009-12-01 Metalloproteinase Inhibitors
US7427631 2008-09-23 Metalloproteinase inhibitors
US2004147573 2004-07-29 Metalloproteinase inhibitors

US20110038532011-01-06Metalloproteinase InhibitorsUS77547502010-07-13Metalloproteinase InhibitorsUS76259342009-12-01Metalloproteinase InhibitorsUS20092216402009-09-03Novel Crystal ModificationsUS74276312008-09-23Metalloproteinase inhibitorsUS20041475732004-07-29Metalloproteinase inhibitors

///////AZD1236,  AZD-1236, AZD 1236,

O=S(=O)(C[C@@]1(C)NC(=O)NC1=O)N3CCC(Oc2ccc(Cl)cn2)CC3

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