New Drug Approvals

Home » rheumatoid arthritis

Category Archives: rheumatoid arthritis

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 3,338,865 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,604 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,604 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Iguratimod


Iguratimod.svg
ChemSpider 2D Image | Iguratimod | C17H14N2O6S

Iguratimod

  • Molecular FormulaC17H14N2O6S
  • Average mass374.368 Da
  • UNII-4IHY34Y2NVигуратимодإيغوراتيمود艾拉莫德

123663-49-0[RN]

3-Formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one

4IHY34Y2NV8176IGU
Methanesulfonamide, N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-
N-(3-Formamido-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide

product patent US4954518 

Research Code:T-614

Trade Name:Iremod® / Kolbet® / Careram®

MOA:Nuclear factor NF-κB activation inhibitor

Indication:Rheumatoid arthritis

Status:Approved

Company:Simcere (Originator) , Taisho Toyama,EisaiSales:ATC Code:

Approved Countries or Area

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2012-06-29Marketing approvalCareramRheumatoid arthritisTablet, Film coated25 mgEisai 
2012-06-29Marketing approvalKolbetRheumatoid arthritisTablet, Film coated25 mgToyama Chemical, Taisho Toyama 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2011-08-15Marketing approval艾得辛/IremodRheumatoid arthritisTablet, Film coated25 mgSimcere

Iguratimod was first approved by China Food and Drug Administration (CFDA) on August 15, 2011, then approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on June 29, 2012. It was developed by Simcere and marketed as 艾得辛®/Iremod® by Simcere and as Kolbet® by Taisho Toyama and by Eisai in Japan.

Iguratimod is a nuclear factor NF-κB activation inhibitor used in the treatment of rheumatoid arthritis.

Iremod® is available as tablet for oral use, containing 25 mg of free Iguratimod, and the recommended dose is 25 mg once daily or 25 mg at a time, twice daily.

Iguratimod: (Iremod)-First approval: 2009

Iguratimod is a disease-modifying antirheumatic drug (DMARD) that was approved for use in rheumatoid arthritis (RA) patients in China and Japan in 2009

Toyama Chemical , Taisho Toyama Pharmaceutical , Eisai , Simcere and Tianjin Institute of Pharmaceutical Research have codeveloped and launched iguratimod, an inflammatory cytokine and IL-6 gene inhibiting compound that also inhibits immunoglobulin production in B cells. Iguratimod is indicated for the oral treatment of rheumatoid arthritis. 

Iguratimod is an anti-inflammatory small molecule drug used for the treatment of rheumatoid arthritis, together with methotrexate in Japan and China.[1] As of 2015 the biological target was not known, but it prevents NF-κB activation and subsequently selectively inhibits COX-2 and several inflammatory cytokines.[1]

Adverse effects include elevated transaminases, nausea, vomiting, stomach pain; rashes, and itchiness.[1]

It is a derivative of 7-methanesulfonylamino-6-phenoxychromones and is a chromone with two amide groups; it was first published in 2000.[1][2] It was submitted for regulatory approval in Japan in 2003; the application was withdrawn in 2009, and it was resubmitted with additional data in 2011 and approved for marketing in Japan in 2012.[1] Eisai and Toyama Chemical market it in Japan.[3] Approval was obtained in China in 2011 by Simcere, independently of the Japanese originators.[1][4]

During discovery and development it was called T-614 and it is marketed under the names Careram and Kolbet.[5]

Syn

Indian Pat. Appl., 2014MU01507

SYN

Route 1

Reference:1. US4954518.Route 2

Reference:1. Chem. Pharm. Bull. 2000, 48, 131-139.

2. Chin. J. New. Drugs. 200615, 2042-2044.

3. Shanghai Chem. Ind. 200732, 22-24.Route 3

Reference:1. CN1462748A.

2. Chem. Pharm. Bull. 200048, 131-139.

SYN

AU 8823489; CH 679397; FR 2621585; GB 2210879; JP 1995267943; US 4954518

The reduction of 3-nitro-4-phenoxyphenol (I) with Fe, aqueous HCl gives 3-amino-4-phenoxyphenol (II), which is acylated with methanesulfonyl chloride by means of pyridine in dichloromethane affording 3-(methylsulfonamido)-4-phenoxyphenol (III). The condensation of (III) with 3-chloropropionic acid (IV) by means of NaOH in water gives 3-[3-(methylsulfonamido)-4-phenoxyphenoxy]propionic acid (V), which is cyclized by means of polyphosphoric acid at 65-70 C yielding 7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VI). The bromination of (VI) with Br2 in CHCl3 affords 3-bromo-7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VII), which is treated with sodium azide in DMF at 70-75 C giving 3-amino-7-(methylsulfonamido)-6-phenoxy-2H-1-benzopyran-4-one (VIII). Finally, this compound is formylated with formic acid in acetic anhydride.

SYN

Chem Pharm Bull 2000,48(1),131

A preparative-scale synthetic route for T-614 has been reported: The reaction of 4-chloro-3-nitroanisole (I) with potassium phenolate in hot DMF gives 4-phenoxy-3-nitroanisole (II), which is reduced to the corresponding 3-amino compound (III) by treatment with Fe and HCl. The reaction of (III) with mesyl chloride in pyridine affords the sulfonamide (IV), which is acylated with 2-aminoacetonitrile (V) and AlCl3 in nitrobenzene/HCl giving the 2-aminoacetophenone (VI). Formylation of (VI) at the NH2 with acetic formic anhydride yields the formamide (VII), which is demethylated with AlCl3 and NaI in acetonitrile affording the phenol (VIII). Finally, this compound is cyclized with dimethylformamide dimethylacetal in DMF.

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0968089614001230

Synthetic approaches to the 2012 new drugs

Hong X. Ding, … Christopher J. O’Donnell, in Bioorganic & Medicinal Chemistry, 2014

13 Iguratimod (Careram®, Iremod®)

Iguratimod, which was discovered by Toyama Pharmaceuticals and jointly co-developed with Eisai in Japan, was approved by the PMDA (Pharmaceuticals and Medical Devices Agency) of Japan on June 29, 2012 for the treatment of rheumatoid arthritis.83 This drug was also independently developed by Simcere Pharmaceutical Group and is marketed as Iremod® in China. The drug exhibited inhibitory effects on granuloma inflammation, and was shown to be efficacious for the prevention of joint destruction in adjuvant arthritis.84,85 While several synthesis of iguratimod have been published,86 the most likely scale synthesis, which does not require chromatographic purification, is described in Scheme 14.87

The synthesis began with commercially available 3-nitro-4-chloro anisole (78) which was reacted with potassium phenoxide (generated from phenol and potassium t-butoxide at 110 °C) to provide the corresponding nitrophenyl ether which was subsequently reduced and sulfonylated to furnish sulfonamide 79. Next, this diphenyl ether was submitted to a Friedel–Crafts reaction with aminoacetonitrile hydrochloride which gave rise to aminomethylacetophenone 80 in 90% yield. This aminoketone was then formylated with formic trimethylacetic anhydride 81 at room temperature to afford formamide 82 in 91% yield, and this material was immediately subjected to O-demethylation conditions with aluminum trichloride and sodium iodide in acetonitrile to give the phenol 83 in 95% yield. Finally, treatment of the aminomethyl acetophenone phenol 83 with N,N-dimethylformamide dimethylacetal in DMF at low temperatures furnished iguratimod (XII) in 87% yield

83. Eisai and Toyama Chemical Receive Approval to Market Anti-rheumatic Agent Iguratimod in Japan, 2012, http://www.eisai.com/news/news201239.html, [Access Date: 2012-July-29].

84. Tanaka, K.; Shimotori, T.; Makino, S.; Aikawa, Y.; Inaba, T.; Yoshida, C.; Takano, S. Arzneim.-Forsch. 1992, 42, 935.

85. Tanaka, K.; Makino, S.; Shimotori, T.; Aikawa, Y.; Inaba, T.; Yoshida, C. Arzneim.-Forsch. 1992, 42, 945.

86. Takano, S.; Yoshida, C.; Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Shimotori, T.; Makino, S. US Patent 4954518 A, 1990.

87. Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Yoshida, C.; Takano, S. Chem. Pharm. Bull. 2000, 48, 131.

SYN

Image result for iguratimod synthesis

https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/slct.202003553A Convenient Synthesis of Iguratimod‐Amine Precursor via NHC‐Catalyzed Aldehyde‐Nitrile Cross Coupling ReactionNithya MurugeshProf. Ramasamy KarvembuDr. Seenuvasan VedachalamFirst published: 24 November 2020https://doi.org/10.1002/slct.202003553

A protocol for the synthesis of iguratimod‐amine precursor has been developed using N‐heterocyclic carbene (NHC)‐catalyzed aldehyde‐nitrile cross coupling reaction with overall atom efficiency of 71 %. The first step involves a nucleophilic aromatic substitution (SNAr) of 1‐chloro‐4‐methoxy‐2‐nitrobenzene (1) with phenol to produce 4‐methoxy‐2‐nitro‐1‐phenoxybenzene (2) which further undergoes nitro reduction followed by mesylation to produce N‐(5‐methoxy‐2‐phenoxyphenyl)methanesulfonamide (4). Furthermore, it was subjected to Vilsmeier‐Haack formylation and demethylation (using BBr3) to produce N‐(4‐formyl‐5‐hydroxy‐2‐phenoxyphenyl)methanesulfonamide (6). Subsequently, O‐alkylation followed by NHC‐catalyzed aldehyde‐nitrile cross coupling yields the amine precursor of iguratimod (8).

N-(3-Amino-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide (8):4=4. S. Vedachalam, J. Zeng, B. K. Gorityala, M. Antonio, X.-W. Liu, Org. Lett. 2010, 12, 352–355.

Compound 7 (290 mg, 0.83 mmol) and triazolium carbene catalyst (34 mg, 0.1245 mmol) were dissolved in dry CH2Cl2 under N2 atmosphere. To this, DBU (24.7 µL, 0.16 mmol) was added at room temperature, and the mixture was stirred for 12 h. After the completion of reaction, the reaction mixture was dried, and the residue was purified by column chromatography to yield compound 8. Yield: 200 mg, 70 %; m. p. 162 ℃; 1H NMR (500 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.25–7.21 (m, 3H), 7.16 (s, 1H), 4.91 (s, 2H), 3.23 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 171.2, 155.0, 152.1, 150.4, 137.9, 133.0, 132.8, 131.0 (2C), 125.9, 122.4, 121.1 (2C), 117.2, 110.0, 39.0; FTIR (KBr): v 3423, 3347, 1620, 1592, 1487, 1342, 1210, 1155, 970, 757 cm-1 ; HR-MS (ESI): m/z calcd. for C16H15N2O5S 347.0702, found 347.0714 [M+H]+ …..https://chemistry-europe.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fslct.202003553&file=slct202003553-sup-0001-misc_information.pdf

Patent

WO 2021020481

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021020481&tab=FULLTEXT&_cid=P11-KKXGLE-06477-1The following formula (1)

[Chemical 1]

Iguratimod (chemical name: N- [3- (formylamino) -4-oxo-6-phenoxy-4H-chromen-7-yl] methanesulfonamide), which is indicated by, has excellent anti-inflammatory and antipyretic and analgesic effects. It is a very useful compound as a therapeutic agent exhibiting anti-arthritis and anti-allergic effects (see Patent Document 1). 
 A plurality of synthetic routes are known for the method for producing iguratimod and its derivatives (hereinafter, may be referred to as iguratimod derivatives as a term meaning both iguratimod and its derivatives), and all of them use intermediates of iguratimod derivatives. This is a stepwise manufacturing method. The present inventors have studied the stepwise production of intermediates of iguratimod derivatives of formulas (II) to (XI) by the following synthetic route to synthesize the iguratimod derivatives represented by formula (XII). doing. 
[Chemical formula 2]
1 = hydroxyl protecting group, R 2 = amino protecting group, Ar = aromatic ring group which may have a substituent, X 2 = halogen atom.[Chemical 3]
Ms = methylsulfonyl group[Chemical 4]
Production Example 1
(Production of igratimodo: Patent Documents 3 and 4)
N, N-dimethylformamide 150 mL, N, N-dimethylformamide dimethyl acetal 40.9 g (N, N-dimethylformamide dimethyl acetal ) in a 1000 mL four-necked flask equipped with two stirring blades having a diameter of 10 cm ( 343 mmol) was added, and the mixture was cooled to 10 ° C. with stirring. 8.2 g (137 mmol) of glacial acetic acid and 50.0 g (137 mmol) of formylaminomethyl (2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl) ketone were sequentially added thereto, and the temperature was raised to 20 ° C. The reaction was carried out at the same temperature for 5 hours. 250 mL of methylene chloride was added to the reaction suspension, and 500 mL of water was added dropwise to the obtained solution. After adjusting the pH to 5 with a 10% aqueous hydrochloric acid solution, the mixture was stirred at 20 ° C. for 1 hour. The obtained precipitated crystals were separated, washed successively with 50 mL of methylene chloride, 50 mL of water and 50 mL of ethanol, and then dried at 50 ° C. for 12 hours. Next, the obtained crystals were dissolved in a mixed solvent of 7.7 g (137 mmol) of potassium hydroxide, 750 mL of water and 750 mL of acetone, and then neutralized with 2N hydrochloric acid water, and the obtained precipitated crystals were separated. Then, after washing with 50 mL of water, it was dried at 50 ° C. for 12 hours to obtain 42.8 g of iguratimod (iguratimod purity: 99.72%, N-methyl compound: 0.23%).

References

  1. Jump up to:a b c d e f Tanaka K, Yamaguchi T, Hara M (May 2015). “Iguratimod for the treatment of rheumatoid arthritis in Japan”. Expert Review of Clinical Immunology11 (5): 565–73. doi:10.1586/1744666X.2015.1027151PMID 25797025S2CID 25134255.
  2. ^ Inaba T, Tanaka K, Takeno R, Nagaki H, Yoshida C, Takano S (January 2000). “Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models”Chemical & Pharmaceutical Bulletin48 (1): 131–9. doi:10.1248/cpb.48.131PMID 10705489.
  3. ^ Bronson J, Dhar M, Ewing W, Lonberg N (2012). “Chapter Thirty-One – To Market, To Market—2011”. Annual Reports in Medicinal Chemistry47: 499–569. doi:10.1016/B978-0-12-396492-2.00031-X.
  4. ^ “Iguratimod – Simcere”. AdisInsight. Retrieved 27 May 2018.
  5. ^ “Iguratimod – Toyama Chemical”. AdisInsight. Retrieved 27 May 2018.
Clinical data
Trade namesCareram; Kolbet
Other namesT-614
ATC codeNone
Identifiers
IUPAC name[show]
CAS Number123663-49-0
PubChem CID124246
ChemSpider110694
UNII4IHY34Y2NV
ChEMBLChEMBL2107455
CompTox Dashboard (EPA)DTXSID0048971 
ECHA InfoCard100.236.037 
Chemical and physical data
FormulaC17H14N2O6S
Molar mass374.37 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=S(=O)(Nc3c(Oc1ccccc1)cc2c(O/C=C(\C2=O)NC=O)c3)C
InChI[hide]InChI=1S/C17H14N2O6S/c1-26(22,23)19-13-8-15-12(17(21)14(9-24-15)18-10-20)7-16(13)25-11-5-3-2-4-6-11/h2-10,19H,1H3,(H,18,20)Key:ANMATWQYLIFGOK-UHFFFAOYSA-N

////////////IGURATIMOD, UNII-4IHY34Y2NV , игуратимод , إيغوراتيمود , 艾拉莫德 , T-614, T 614, Kolbet, Careram, Rheumatoid arthritis, JAPAN 2012, CHINA 2011

CS(=O)(=O)NC1=C(C=C2C(=C1)OC=C(C2=O)NC=O)OC3=CC=CC=C3

WXFL-10203614


(7R)-7-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile.png

WXFL-10203614

CAS 2054932-34-0 R isomer, (S isomer 2054932-33-9 )

C15 H15 N7, 293.33

(7R)-7-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile

  • (7R)-5,6,7,8-Tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)imidazo[1,2-a]pyridine-2-carbonitrile
  • Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-

Wuxi Fortune Pharmaceutical Co Ltd

Jak1 tyrosine kinase inhibitor

Wuxi Fuxin Pharmaceutical Research and Development , in collaboration with  Wuxi Apptec , is investigating a tablet formulation of WXFL-10203614 , a JAK1 tyrosine kinase inhibitor, for the oral treatment of rheumatoid arthritis. In January 2019, a phase I trial was planned.

  • Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-, 4-methylbenzenesulfonate, hydrate (1:1:1)
  • cas 2226936-85-0

  • Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-, 2,2,2-trifluoroacetate (1:1)
  • cas 2226936-87-2

syn

PATENT

WO2018095345  claiming novel crystalline salt forms of similar compound

PATENT

WO 2016192563

PATENT

US-20190218231

https://patentscope.wipo.int/search/en/detail.jsf?docId=US248874703&tab=PCTDESCRIPTION&_cid=P11-JYF9EY-53753-1

Novel crystalline forms of 7h-pyrrolo[2,3-D]pyrimidine compounds (designated as forms A to E) useful as JAK1 and JAK2 inhibitors for treating arthritis, inflammation and autoimmune diseases.

 JAK belongs to the family of tyrosine kinases involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, impaired cartilage turnover-related diseases, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6. The present invention also provides a method for preparing the compound or a pharmaceutical composition comprising the compound, and a method for preventing and/or treating inflammation, autoimmune diseases, proliferative diseases, transplant rejection, impaired cartilage turnover-related diseases, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6 by administrating the compound of the present invention.

Janus kinase (JAK) is a cytoplasmic tyrosine kinase that transduces a cytokine signal from a membrane receptor to an STAT transcription factor. The prior art has described four members of the JAK family: JAK1, JAK2, JAK3 and TYK2. When cytokines bind to their receptors, JAK family members are auto-phosphorylated and/or trans-phosphorylated from each other, followed by STATs phosphorylation, and then are migrated into the cell nucleus to regulate the transcription. JAK-STAT intracellular signal transduction is suitable for interferons, most interleukins, as well as various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al. (2008)).

A combinatorial study of a genetic model and a small molecule JAK inhibitor has revealed the therapeutic potential of several JAKs. It has been confirmed by mouse and human genetics that JAK3 is an immunosuppressive target (O’Shea J. et al. (2004)). A JAK3 inhibitor has been successfully used in clinical development. At first, it was used in organ transplant rejection, and later also used in other immunoinflammatory indications such as rheumatoid arthritis (RA), psoriasis and Crohn’s disease (http://clinicaltrials.gov/). It has been confirmed by human genetics and mouse knockout studies that TYK2 is a potential target for immunoinflammatory diseases (Levy D. and Loomis C. (2007)). JAK1 is a new target in the field of immunoinflammatory diseases. The heterodimerization of JAK1 and other JAKs arouses a transduction of cytokine-driven pro-inflammatory signaling. Thus, it is expected that inhibition of JAK1 and/or other JAKs has a therapeutic benefit for a series of inflammatory diseases and other diseases driven by JAK-mediated signal transduction.


transduction.

Example 1: Preparation of Compound 1

Step 1: 2-chloro-4-nitro-1-oxo-pyridin-1-ium (40.0 g, 229.2 mmol) and (4-methoxyphenyl)methylamine (63 g, 458.4 mmol) were dissolved in EtOH (400 mL), and the resulting solution was stirred at reflux for 5 hours. TLC (PE:EA=2:1) showed that the reaction was complete. The EtOH was concentrated to half of its volume and was cooled in an ice bath for 2-3 hours. The resulting cold mixture was filtered, and the isolated solid was washed with PE (60 mL*3) and ice water (60 mL*3), respectively. Drying in vacuum given an orange solid, N-[(4-methoxyphenyl)methyl]-4-nitro-1-oxo-pyridin-1-ium-2-amine (2) (38.6 g, 140.2 mmol, with a yield of 61.2%). MS (ESI) calcd. For r C 13133[M+H] 275, found 276.

Step 2: to a solution of N-[(4-methoxyphenyl)methyl]-4-nitro-1-oxo-pyridin-1-ium-2-amine (5.0 g, 18.16 mmol) in CHCI (50 mL) was dropwise added PCI (8.4 g, 60.8 mmol) at 0° C. After the addition, the reaction mixture was heated to 25° C. and stirred vigorously for 16 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The reaction mixture was filtered, and the resulting solid was washed with PE (30 mL*3) to give a yellow solid compound, N-[(4-methoxyphenyl)methyl]-4-nitro-pyridin-2-amine (3) (4.2 g, a crude product) which was directly used in the next step without further purification. MS (ESI) calcd. For C 1518[M+H] +259, found 260.

Step 3: to a solution of N-[(4-methoxyphenyl)methyl]-4-nitro-pyridin-2-amine (4.2 g, 16.2 mmol) in toluene (10 mL) was dropwise added TFA (5.0 mL) at atmospheric temperature. Then, the mixture was stirred at 80° C. for 2 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H 2O (50 mL), and its pH was adjusted to be neutral with solid NaHCO 3. The aqueous phase was extracted with EA (50 mLE*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1/0-1:1) to obtain an orange solid compound, 4-nitropyridine-2-amine (4) (700 mg, 5.0 mmol, with a yield of 31.1%). MS (ESI) calcd. For C 553[M+H] 139, found 140.

Step 4: to a solution of 4-nitropyridine-2-amine (200 mg, 1.4 mmol) in DME (5 mL) was added 3-bromo-2-oxo-propanoate (280 mg, 1.4 mmol) at atmospheric temperature. The resulting mixture was stirred at 25° C. for 1 hour, and then was concentrated under reduced pressure to remove the solvent. The residue was dissolved with EtOH (10 mL); and then was refluxed for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was basified with saturated NaHCO aqueous solution (25 mL). The aqueous phase was extracted with DCM (15 mL*3); and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EA:PE=10-60%) to obtain a light yellow solid compound, ethyl 7-nitroimidazo[1,2-]pyridin-2-carboxylate (5) (302 mg, with a yield of 88.9%). MS (ESI) calcd. For C 1093[M+H] 235, found 236.

Step 5: a solution of ethyl 7-nitroimidazo[1,2-a]pyridin-2-carboxylate (150 mg, 637.8 mmol) in ethanol (20 mL) was added HCl (7 mg, 0.2 mmol) and PtO (15 mg, 0.6 mmol) at atmospheric temperature. The reaction system was repeatedly vacuumed and filled with N for three times, then filled with H 2(50 psi), and was stirred at 50° C. for 16 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The reaction mixture was concentrated to half of its volume, and filtered to obtain a white solid compound, ethyl 7-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate hydrochloride (6) (120 mg, a crude product). MS (ESI) calcd. For C 10153[M+H] 209, found 210.

Step 6: ethyl 7-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate hydrochloride (100 mg, 0.4 mmol) and 4-chloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (137 mg, 0.4 mmol) were dissolved in n-BuOH (5 mL), and DIEA (158 mg, 1.2 mmol) were added to the above solution. The resulting mixture was stirred under reflux for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with H 2O (10 mL). The aqueous phase was extracted with EA (20 mL*3); and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (PE:EA=0:1) to obtain a light yellow solid compound, ethyl 7-[[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl] amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxylate (7) (55 mg, 0.11 mmol, with a yield of 28.1%). MS (ESI) calcd. For C 232464S [M+H] 480, found 481.

Step 7: to a solution of ethyl 7-[[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxylate (3.0 g, 6.2 mmol) in THF (150 mL) was added NaH (499 mg, 12.5 mmol) in portions under N atmosphere at 0° C. The mixture was stirred at that temperature for 1 hour, and then was dropwise added MeI (7.1 g, 50.2 mmol). After the addition, the mixture was stirred at atmospheric temperature for 1 hour. TLC showed that the reaction was complete. The reaction was quenched by the addition of saturated NH 4Cl (10 mL), and then was diluted by the addition of ice water (50 mL). The aqueous phase was extracted with a mixed solvent of DCM/MeOH (3:1, 50 mL*3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (DCM:MeOH=10:1) to obtain a light yellow solid, ethyl 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate (8) (1.5 g, with a yield of 45%). MS (ESI) calcd. For C 242664S [M+H] 494, found 495.

Step 8: to a solution of 7-[methyl-[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate (4.0 g, 8.1 mmol) in THF (40 mL) and H 2O (8 mL) was added LiOH.H 2O (509 mg, 12.1 mmol), and the mixture was stirred at 20° C. for 10 hours. TLC showed that the reactants were completely consumed. THF in the reaction mixture was removed under reduced pressure; and the pH of the residue was adjusted to 2-3 with 2M HCl (4 mL) to form a white solid. The solid was filtered out, and was concentrated under reduced pressure to obtain 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxylic acid (9) as a white solid (3.6 g, with a yield of 95.4%). MS (ESI) calcd. For C 222264S [M+H] 466, found 467.

Step 9: to a solution of 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxylic acid (1.8 g, 3.9 mmol) in DMF (20 mL) was added CDI (751 mg, 4.6 mmol) at 0° C. The reaction solution was heated to 25° C. and stirred for 2 hours, and after that, solid ammonium chloride (2.1 g, 38.6 mmol) was added, and then the reaction was kept overnight at atmospheric temperature. LC-MS showed that the reactants were completely consumed. The reaction mixture was poured into ice water (50 mL), and a white solid was precipitated. The solid was filtered out, washed with water (20 mL), and was dried under reduced pressure in a rotating manner to obtain 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxamide (10) as a white solid (2.5 g, a crude product) which product was directly used in the next step. MS (ESI) calcd. For C 222373S [M+H] 465, found 466.

Step 10: 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxamide (2.5 g, 5.4 mmol) was dissolved in a mixture of THF (20 mL), MeOH (10 mL) and H 2O (6 mL), and NaOH (429.6 mg, 10.7 mmol) was added. The mixture was heated to 60° C. and stirred for 30 minutes. LC-MS showed that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure to obtain 7-[methyl-[heptahydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxamide (11) as a white solid (2.5 g, a crude product) which was directly used in the next step. MS (ESI) calcd. For C 15177O [M+H] 311, found 312.

Step 11: to a solution of 7-[methyl-[heptahydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxamide (2.0 g, 6.4 mmol) and triethylamine (3.9 g, 38.5 mmol) in THF (20 mL) was dropwise added TFAA (4.1 g, 19.3 mmol) at 0° C. After the addition, the reaction solution was stirred at atmospheric temperature for 30 minutes. LC-MS showed the starting materials were completely consumed. The reaction mixture was poured into ice water (20 mL), and extracted with DCM/MeOH (5:1, 100 mL*2). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (DCM/MeOH=40/1 to 20:1) to obtain 7-[methyl-[7-hydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-nitrile (12,378 mg, with a yield of 19.8%). MS (ESI) calcd. For C 1515[M+H] 293, found 294. 1H NMR (400 MHz, DMSO-d6) 11.44-11.71 (m, 1H), 7.99-8.17 (m, 2H), 7.11-7.20 (m, 1H), 6.63 (dd, J=1.76, 3.26 Hz, 1H), 5.33 (br. s., 1H), 4.21-4.21-4.31 (m, 1H), 4.13 (dt, J=4.14, 12.49 Hz, 1H), 3.27 (s, 3H), 2.91-3.11 (m, 2H), 2.31-2.44 (m, 1H), 2.07 (d, J=11.54 Hz, 1H).

Step 12: racemic 7-[methyl-[7-hydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-nitrile (30 mg, 102.3 umol) was separated by a chiral column to obtain the compound 1 (10 mg, with a yield of 32.8%).

Compound 1: retention time 6.407 min; MS (ESI) calcd. For C 1515[293, found 294 M+H]+. Purity 98.8%, e.e. was 98.9%; [α] D 20=+78.4° (c=0.6, DMSO). MS ESI calcd. For C 1515[M+H] 294, found 294. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.02-2.15 (m, 1H) 2.39 (qd, J=12.42, 5.90 Hz, 1H) 2.92-3.12 (m, 2H) 3.28 (s, 3H) 4.05-4.36 (m, 2H) 5.20-5.45 (m, 1H) 6.64 (dd, J=3.39, 1.88 Hz, 1H) 7.17 (dd, J=3.26, 2.51 Hz, 1H) 8.02-8.17 (m, 2H) 11.69 (br s, 1H).

//////////WXFL-10203614, WXFL 10203614 , WXFL10203614, Wuxi Fuxin, arthritis, inflammation, autoimmune diseases, Wuxi Apptec, JAK1,  JAK2 inhibitors

N#Cc1cn2CC[C@H](Cc2n1)N(C)c4ncnc3nccc34

Piclidenoson, иклиденозон , بيكليدينوسون , 匹利诺生 ,


img

Thumb

ChemSpider 2D Image | Piclidenoson | C18H19IN6O4

DB05511.png

CF 101, Piclidenoson

ALB-7208

CAS 152918-18-8
Chemical Formula: C18H19IN6O4
Molecular Weight: 510.28

(2S,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(3-iodobenzyl)amino]-9H-purin-9-yl}-N-methyltetrahydro-2-furancarboxamide

N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide

β-D-Ribofuranuronamide, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-

1-Deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide

10136
1-Deoxy-1-[6-[((3-Iodophenyl)methyl)amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide
30679UMI0N
UNII-30679UMI0N
Пиклиденозон [Russian] [INN]
بيكليدينوسون [Arabic] [INN]
匹利诺生 [Chinese] [INN]

CF 101 (known generically as IB-MECA) is an anti-inflammatory drug for rheumatoid arthritis patients. Its novel mechanism of action relies on antagonism of adenoside A3 receptors. CF101 is supplied as an oral drug and has an excellent safety profile. It is also being considered for the treatment of other autoimmune-inflammatory disorders, such as Crohn’s disease, psorasis and dry eye syndrome.

Image result for CF 101, Piclidenoson

  • Originator Can-Fite BioPharma
  • Class Amides; Anti-inflammatories; Antineoplastics; Antipsoriatics; Antirheumatics; Eye disorder therapies; Iodobenzenes; Neuroprotectants; Purine nucleosides; Ribonucleosides; Small molecules
  • Mechanism of Action Adenosine A3 receptor agonists; Immunosuppressants; Interleukin 23 inhibitors; Interleukin-17 inhibitors
  • Phase III Plaque psoriasis; Rheumatoid arthritis
  • Phase II Glaucoma; Ocular hypertension
  • Phase I Uveitis
  • Preclinical Osteoarthritis
  • Discontinued Colorectal cancer; Dry eyes; Solid tumours
  • 05 Feb 2019 Can-Fite BioPharma receives patent allowance for A3 adenosine receptor (A3AR) agonists in USA
  • 05 Feb 2019 Can-Fite BioPharma receives patent allowance for A3 adenosine receptor (A3AR) agonists in North America, South America, Europe and Asia
  • 21 Aug 2018 Phase-III clinical trials in Plaque psoriasis (Monotherapy) in Israel (PO)

Piclidenoson, also known as CF101, is a specific agonist to the A3 adenosine receptor, which inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. CF101 has been shown to downregulate PKB/Akt and NF-κB protein expression level. CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.

Piclidenoson is known to be a TNF-α synthesis inhibitor and a neuroprotectant. use as an A3 adenosine receptor agonist, useful for treating rheumatoid arthritis (RA), psoriasis, osteoarthritis and glaucoma.

Can-Fite BioPharma , under license from the National Institutes of Health (NIH), is developing a tablet formulation of CF-101, an adenosine A3 receptor-targeting, TNF alpha-suppressing low molecular weight molecule for the potential treatment of psoriasis, RA and liver cancer. The company is also investigating a capsule formulation of apoptosis-inducing namodenoson, the lead from a program of adenosine A3 receptor agonist, for treating liver diseases, including hepatocellular carcinoma (HCC). In January 2019, preclinical data for the treatment of obesity were reported. Also, see WO2019105217 , WO2019105359 and WO2019105082 , published alongside.

PATENT

WO-2019105388

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019105388&tab=FULLTEXT&maxRec=1000

Novel crystalline forms of CF-101 (also known as piclidenoson; designated as Forms CS1, CS2 and CS3), processes for their preparation, compositions comprising them and their use as an A3 adenosine receptor agonist for treating rheumatoid arthritis, psoriasis, osteoarthritis and glaucoma are claimed

CF-101 was developed by Kan-Fete Biomedical Co., Ltd. By the end of 2018, CF-101 is in clinical phase III for the treatment of autoimmune diseases such as rheumatoid arthritis, osteoarthritis and psoriasis, as well as glaucoma. CF-101 is an A3 adenosine receptor (A3AR) agonist, and adenosine plays an important role in limiting inflammation through its receptor. Adenosine can produce anti-inflammatory effects by inhibiting TNF-a, interleukin-1, and interleukin-6. Studies have shown that A3AR agonists are in different experimental autoimmune models, such as rheumatoid arthritis, Crohn’s disease, and silver swarf. In the disease, it acts as an anti-inflammatory agent by improving the inflammatory process.
The chemical name of CF-101 is: 1-deoxy-I-(6-{[(3-iodophenyl)methyl]amino}-9H-fluoren-9-yl)-N-methyl-bD-ribofuranose Carbonamide (hereinafter referred to as “Compound I”) has the following structural formula:
A crystal form is a solid in which a compound molecule is orderedly arranged in a microstructure to form a crystal lattice, and a drug polymorphism phenomenon means that two or more different crystal forms of a drug exist.
Due to different physical and chemical properties, different crystal forms of drugs may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent; especially for poorly soluble solid drugs, the crystal form will have greater influence. Therefore, the drug crystal form is inevitably an important part of drug research and an important part of drug quality control. Most importantly, the study of crystal forms is beneficial to find a crystal form that is clinically therapeutically meaningful and has stable and physicochemical properties.
There are no reports of CF-101 related crystal forms so far. Amorphous is generally not suitable as a medicinal form, and the molecules in the amorphous material are disorderly arranged, so they are in a thermodynamically unstable state. Amorphous solids are in a high-energy state, and generally have poor stability. During the production and storage process, amorphous drugs are prone to crystal transformation, which leads to the loss of consistency in drug bioavailability, dissolution rate, etc., resulting in changes in the clinical efficacy of the drug. In addition, the amorphous preparation is usually a rapid kinetic solid precipitation process, which easily leads to excessive residual solvents, and its particle properties are difficult to control by the process, making it a challenge in the practical application of the drug.
Therefore, there is a need to develop a crystalline form of CF-101 that provides a usable solid form for drug development. The inventors of the present application have unexpectedly discovered the crystalline forms CS1, CS2 and CS3 of Compound I, which have melting point, solubility, wettability, purification, stability, adhesion, compressibility, fluidity, dissolution in vitro and in vivo, and biological effectiveness. There is an advantage in at least one of the properties and formulation processing properties. Crystalline CS1 has advantages in physical and chemical properties, especially physical and chemical stability, low wettability, good solubility and good mechanical stability. It provides a new and better choice for the development of drugs containing CF-101, which is very important. The meaning.
Figure 7 is a 1 H NMR spectrum of the crystalline form CS3 obtained according to Example 7 of the present invention
The nuclear magnetic data of the crystalline form CS3 obtained in Example 7 was: { 1 H NMR (400 MHz, DMSO) δ 8.82 – 8.93 (m, 1H), 8.53 – 8.67 (m, 1H), 8.45 (s, 1H), 8.31 ( s, 1H), 7.73 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 5.98 ( d, J = 7.4 Hz, 1H), 5.74 (s, 1H), 5.56 (s, 1H), 4.64 (d, J = 29.3 Hz, 3H), 4.32 (s, 1H), 4.15 (s, 1H), 2.71 (d, J = 4.6 Hz, 3H), 1.91 (s, 3H).}. Form CS3 has a single peak at 1.91, corresponding to the hydrogen chemical shift of the acetic acid molecule. According to the nuclear magnetic data, the molar ratio of acetic acid molecule to CF-101 is 1:1, and its 1 H NMR is shown in FIG.7

PAPER

Journal of medicinal chemistry (1994), 37(5), 636-46

https://pubs.acs.org/doi/pdf/10.1021/jm00031a014

PAPER

Journal of medicinal chemistry (1998), 41(10), 1708-15

https://pubs.acs.org/doi/abs/10.1021/jm9707737

PAPER

Bioorganic & Medicinal Chemistry (2006), 14(5), 1618-1629

PATENT

WO 2015009008

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015009008

Example 1
Preparation Example 1: Synthesis of Compound (5) (S) -2 – ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin- Hydroxyethoxy) -3-hydroxy-N-methylpropanamide)
Scheme 1
Step 1: A solution of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro-9H- purin-9- yl) tetrahydrofuran- Preparation of benzoate (7)
Starting material A mixture of (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran-3,4-diyldibenzoate (7.5 g, 14.9 mmol) (3.09 g, 16.4 mmol) was dissolved in acetonitrile (50 mL), and a solution of N, O-bis (trimethylsilyl) acetamid (8.9 mL, 36.4 mmol) was slowly added dropwise for 10-15 minutes Then, the mixture is stirred at 60 DEG C for 30 minutes. After cooling the reaction solution to -30 ° C, TiCl 4 (60 mL, 1 M methylene chloride solution, 59.5 mmol) is added dropwise, and the mixture is stirred at 60-65 ° C for 20 minutes. After confirming the completion of the reaction, methylene chloride (500 mL) and saturated sodium hydrogencarbonate solution (500 mL) are added. The reaction solution was stirred at 0 ° C for 30 minutes, and the organic layer was extracted and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro- Yl) tetrahydrofuran-3,4-diyl dibenzoate (9.3 g, 98.8%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm 4.71-4.74 (dd, J = 12.22, 3.91 Hz, 1H), 4.85-4.93 (m, 2H), 6.12-6.14 (t, J = 4.89 Hz, 1H) (M, 1H), 6.16-6.19 (t, J = 5.38 Hz, 1H), 6.47-6.48 (d, J = 5.38 Hz, 1H), 7.35-7.38 4H), 7.54-7.61 (m, 3H), 7.92-7.93 (d, J = 7.33 Hz, 2H), 8.02-8.06 (m, 4H), 8.28 (s, 1H); 13C NMR (125 MHz; CDCl 3 ) δ 63.50, 71.59, 74.33, 81.56, 87.05, 128.14, 128.59 (3), 128.63 (2), 128.73 (2), 129.10, 129.63 (2), 129.88 (2), 129.92 (2), 131.38, 133.63, 133.87, 133.98, 143.81, 152.36, 152.64, 153.51, 165.13, 165.29, 166.03; mp = 76-80 [deg.] C.
Step 2: (2R, 3S, 4S, 5R) -2- (Benzoyloxymethyl) -5- (2-chloro-6- (3-iodobenzylamino) -9H- purin-9-yl) tetrahydrofuran -3,4-diyl dibenzoate (8)
The intermediate compound (204 mg, 0.32 mmol) and 3-iodobenzylamine hydrochloride (113 mg, 0.41 mmol) prepared in the above step 1 were dissolved in anhydrous ethanol (5 mL) under a nitrogen atmosphere, triethylamine (0.13 mL, 0.96 mmol) is stirred at room temperature for 24 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by column chromatography to obtain the intermediate compound (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-3,4-diyldibenzoate (230 mg, 86.14%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm 4.71-4.90 (m, 5H), 6.13-6.17 (m, 2H), 6.33 (.. Br s, 1H), 6.43-6.44 (d, J = 4.89 Hz (M, 4H), 7.31-7.33 (m, 6H), 7.33-7.46 (m, 6H) 7.70-7.71 (t, J = 1.46 Hz, 1H), 7.88 (s, 1H), 7.94-7.96 (m, 2H), 7.99-8.01 (m, 2H), 8.07-8.09 (m, 2H); 13 C NMR (125 MHz; CDCl 3) δ 43.91, 63.79, 71.56, 74.43, 80.97, 86.40, 94.49, 119.07, 127.14, 128.40, 128.52 (3), 128.62 (2), 128.71, 129.32, 129.68 (3), 129.86 (2), 129.93 (2), 130.39 (2), 133.41, 133.69, 133.78, 136.72, 136.80, 138.39, 140.20, 150.05, 155.00, 165.17, 165.31, 166.11; mp = 80-84 [deg.] C.
Step 3: ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2- dimethyltetrahydrofur [3,4-d] [1,3] dioxol-4-yl) methanol (9)
The intermediate compound (20 g, 24.09 mmol) prepared in the above step 2 was dissolved in methanolic ammonia (1 L) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain a triol intermediate. The triol intermediate thus obtained (20 g, 38.63 mmol) was dissolved in anhydrous acetone (400 mL), and 2,2-dimethoxypropane (23.68 mL, 193.15 mmol) and p-toluenesulfonic acid monohydrate (7.34 g, 38.63 mmol) was added dropwise thereto, followed by stirring at room temperature for 12 hours. After confirming the completion of the reaction, saturated sodium hydrogencarbonate solution (400 mL) was added thereto. The reaction mixture was concentrated under reduced pressure. The organic layer was extracted with chloroform (4 x 250 mL), washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated under reduced pressure, and the obtained residue was then separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) Yl] -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methanol (12 g, 89.35%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 )? Ppm 1.36 (s, 3H), 1.62 (s, 3H), 3.77-3.80 (dd, J = 12.71, 1.95 Hz, 1H), 3.95-3.98 12.71, 1.95 Hz, 1H), 4.48-4.49 (d, J = 1.46 Hz, 1H), 4.68 (br. s., 1H, exchangeable with d 2 O, OH), 4.74 (br. s., 2H), (D, J = 5.86, 1.46 Hz, 1H), 5.15-5.17 (t, J = 5.38 Hz, 1H), 5.77-5.78 (d, J = 4.40 Hz, 1H), 6.81 (br s. , 1H, exchangeable with d 2 O, NH), 7.03-7.06 (t, J = 7.82 Hz, 1H), 7.30-7.31 (d, J = 7.33 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz , & Lt; / RTI & gt; 1H), 7.67 (s, 1H), 7.70 (s, 1H); 13 C NMR (125 MHz; CDCl 3) [delta] 25.26, 27.63, 43.93, 63.37, 81.52, 82.98, 86.12, 93.89, 94.55, 114.18, 120.09, 127.19, 130.44, 136.86 (2), 139.93, 140.01, 148.80, 154.50, 155.14; mp = 82-86 [deg.] C.
Step 4: (2S, 5R) -5- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -3,4- dihydroxy- -2-carboxamide & lt; / RTI & gt; (10)
The intermediate compound (15 g, 26.89 mmol) prepared in step 3 was dissolved in a solution of acetonitrile-water (130 mL, 1: 1) and then (diacetoxy iodo) -benzene (19 g, 59.16 mmol) 2,2,6,6-Tetramethyl 1-piperidinyloxyl (840 mg, 5.37 mmol) was added dropwise, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain an acid intermediate without purification. The obtained intermediate (15 g, 26.23 mmol) was dissolved in anhydrous ethanol (500 mL) under a nitrogen stream, cooled to 0 ° C, thionyl chloride (9.52 mL, 131.17 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain an ethyl ester intermediate without purification. Methylamine (750 mL, 2 N THF solution) was added dropwise to the resulting ethyl ester intermediate (15.5 g, 25.84 mmol) and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -5- (2-Chloro-6- (3- -9-yl) -3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide (5 g, 31.80%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 )? Ppm 2.72-2.73 (d, J = 3.91 Hz, 3H), 4.17 (brs, 1H), 4.33 (s, 1H), 4.55-4.56 (D, J = 6.35 Hz, 1H, exchangeable with D 2 O, 2′-OH), 5.71-5.72 d, J = 3.91 Hz, 1H, exchangeable with d 2 O, 3′-OH), 5.92-5.93 (d, J = 7.33 Hz, 1H), 7.11-7.14 (t, J = 7.82 Hz, 1H), 7.35 (D, J = 6.84 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.75 (s, 1H), 8.27-8.28 exchangeable with D 2 O, NH), 8.48 (s, 1 H), 8.98-8.99 (br. t, J = 5.86 Hz, 1H, exchangeable with D 2 O, N 6 H); 13 C NMR (125 MHz; DMSO-d 6) [delta] 26.07, 43.02, 72.79, 73.42, 84.95, 88.10, 95.12, 119.46, 127.31, 130.99, 136.06, 136.51, 141.57, 142.23, 150.00, 153.44, 155.31, 170.14; mp = 207-209 [deg.] C.
Step 5: (S) -2 – ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2-hydroxyethoxy) -3 – & lt; / RTI & gt; hydroxy-N-methylpropanamide (5)
The intermediate compound (2.0 g, 3.67 mmol) prepared in step 4 was dissolved in water / methanol (210 mL, 1: 2), cooled to 0 ° C and then sodium per iodate (1.57 g, 7.34 mmol) And then stirred at the same temperature for 2 hours. After completion of the reaction was confirmed, sodium borohydride (694 mg, 18.35 mmol) was added and stirred for 1 hour. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was concentrated under reduced pressure using toluene (3 x 50 mL). The residue was separated by column chromatography to obtain the title compound (1.58 g, 79%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 ) δ ppm 2.40 (.. Br s, 3H), 3.53-3.60 (m, 1H), 3.71-3.73 (d, J = 10.27 Hz, 1H), 3.85 (br . s., 1H), 3.95 (br. s., 2H), 4.60 (br. s., 2H), 4.98-5.00 (t, J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.19 -5.20 (t, J = 5.86 Hz, 1H, exchangeable with D 2 O, OH), 5.78-5.80 (t, J = 5.38 Hz, 1H), 7.10-7.13 (t, J = 7.82Hz, 1H), 7.35 -7.36 (d, J = 6.84Hz, 1H), 7.59-7.60 (d, J = 5.86 Hz, 2H, exchangeable with D 2 O, NH), 7.73 (br. s., 1H), 8.30 (s, 1H ), 8.85 (br s, 1H, exchangeable with D 2 O, NH); 13 C NMR (125 MHz; DMSO-d 6) [delta] 25.59, 42.98, 62.02, 62.25, 80.43, 84.90, 95.11, 118.57, 127.27, 130.96, 136.03, 136.45, 140.78, 142.34, 150.69, 153.53, 155.17, 169.31; HRMS (FAB) m / z calcd for C 18 H20 ClIN 6 O 4 [M + Na] + 546.0279, found 569.0162; mp = 226-229 [deg.] C.
Example 2
Preparation Example 2: Synthesis of Compound (11) ((R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9-yl) -2- hydroxyethoxy) Propane-1,3-diol)
Scheme 2
The intermediate compound (230 mg, 0.27 mmol) prepared in Step 2 of Example 1 was dissolved in methanolic ammonia (25 mL) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain a triol intermediate. The obtained triol intermediate (248 mg, 0.47 mmol) was treated in the same manner as in Step 5 of Example 1 to obtain the desired compound (109 mg, 75.69%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 )? Ppm 3.13-3.17 (m, 1H), 3.22-3.26 (m, 1H), 3.43-3.47 (m, 2H), 3.54-3.56 (Br s, 2H), 4.41-4.42 (br t, J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 4.60 , J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.13 (br. s., 1H, exchangeable with D 2 O, OH), 5.80-5.82 (t, J = 4.89 Hz, 1H), 7.11 (D, J = 7.33 Hz, 1H), 7.36-7.37 (d, J = 7.33 Hz, 1H), 7.59-7.60 s, 1 H), 8.82 (br s, 1H, exchangeable with D 2 O, NH); 13 C NMR (125 MHz; DMSO-d 6) [delta] 43.01, 61.12, 61.23, 62.64, 80.90, 84.53, 95.12, 118.56, 127.36, 130.99, 136.04, 136.58, 140.68, 142.44, 150.73, 153.40, 155.12; HRMS (FAB) m / z calcd for C 17 H 19 ClIN 5 O 4 [M + Na] + 519.0170, found 542.0054; mp = 170-172 [deg.] C.
Example 3
Preparation Example 3: Synthesis of Compound (12) ((S) -3-Hydroxy-2 – ((R) -2-hydroxy- 1- (6- (3-iodobenzylamino) -9H- Yl) ethoxy) -N-methylpropanamide & lt; / RTI & gt;
Scheme 3
Step 1: ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4 d] [1,3 ] Dioxol-4-yl) methanol (14)
(Hydroxymethyl) tetrahydrofuran-3,4-diol (4.8 g, 16.74 mmol) and 2,2 & lt; RTI ID = 0.0 & -Dimethoxypropane (10.26 mL, 83.71 mmol) was dissolved in anhydrous acetone (120 mL) under a nitrogen stream, p-toluenesulfonic acid monohydrate (3.18 g, 16.74 mmol) was added dropwise and the mixture was stirred at room temperature for 4 hours . After confirming the completion of the reaction, the reaction is terminated with a saturated sodium hydrogencarbonate solution. The reaction solution was concentrated under reduced pressure, and the organic layer was extracted with chloroform (4 x 20 mL), washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- 3,4-d] [1,3] dioxol-4-yl) methanol (4.87 g, 89.03%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 )? Ppm 1.38 (s, 3H), 1.65 (s, 3H), 3.80-3.83 (dd, J = 12.22, 1.46 Hz, 1H), 3.95-3.98 (Dd, J = 5.86, 1.46 Hz, 1H), 5.19 (d, J = 8.6 Hz, 1H), 4.53-4.55 5.21 (dd, J = 5.86, 4.40 Hz, 1H), 5.99-6.00 (d, J = 4.89 Hz, 1H), 8.25 (s, 1H), 8.75 (s, 1H); 13 C NMR (125 MHz; CDCl 3 )? 25.22, 27.55, 63.22, 81.51, 83.35, 86.43, 94.02, 114.51, 133.25, 144.73, 150.50, 151.71, 152.31; mp = 146-150 [deg.] C.
Step 2: ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4- d] 3] dioxol-4-yl) methyl benzoate (15)
The intermediate compound (2.8 g, 8.56 mmol) prepared in Step 1 was dissolved in anhydrous methylene chloride (100 mL), and then cooled to 0 ° C. Triethylamine (3.6 mL, 25.70 mmol) and dimethylaminopyridine (21 mg, 0.17 mmol). Benzoyl chloride (1.5 mL, 12.85 mmol) is slowly added dropwise at the same temperature and then stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction is terminated with a saturated sodium hydrogencarbonate solution. The reaction solution was concentrated under reduced pressure, the organic layer was extracted with methylene chloride, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- 3,4-d] [1,3] dioxol-4-yl) methyl benzoate (3.68 g, 99.72%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm 1.40 (s, 3H), 1.62 (s, 3H), 4.42-4.46 (dd, J = 11.73, 3.9 Hz, 1H), 4.61-4.64 (m, 2H) (D, J = 7.33 Hz, 2H), 5.51-5.13 (d, J = 2.93 Hz, 1H), 5.53-5.54 7.47-7.50 (t, J = 7.33 Hz, 1 H), 7.79-7.81 (d, J = 7.82 Hz, 2H), 8.21 (s, 1H), 8.64 (s, 1H); 13 C NMR (125 MHz; CDCl 3 ) δ 25.36, 27.15, 63.99, 81.42, 84.07, 85.04, 91.87, 114.92, 128.31 (2), 129.07, 129.39 (2), 132.42, 133.33, 144.10, 150.79, 151.40, 152.02 , 165.80; mp = 50-54 [deg.] C.
Step 3: ((3aR, 4R, 6R, 6aR) -6- (6- (3-Iodobenzylamino) -9H- purin- 9-yl) -2,2 dimethyltetrahydrofuro [3,4 -d] [1,3] dioxol-4-yl) methyl benzoate (16)
The intermediate compound (1.24 g, 2.87 mmol) prepared in the above step 2 was prepared in the same manner as in step 2 of Example 1 to give the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6- Yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl benzoate (1.73 g, 96.11 %).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 )? Ppm 1.42 (s, 3H), 1.63 (s, 3H), 4.45-4.59 (m, 1H), 4.59-4.61 (m, 2H), 4.80 (br s. J = 5.38 Hz, 1H), 5.17 (d, J = 3.43 Hz, 1H), 5.58-5.59 , 7.32-7.05 (t, J = 7.33 Hz, 2H), 7.49-7.52 (t, J = = 7.33 Hz, 1 H), 7.58-7.60 (d, J = 7.33 Hz, 1 H), 7.71 (s, (br. s., 1 H); 13 C NMR (125 MHz; CDCl 3 ) δ 25.47, 27.21, 43.81, 64.35, 81.71, 84.21, 85.03, 91.38, 94.55, 114.61, 120.52, 126.85, 128.32 (3), 129.43, 129.62 (2), 130.34, 133.18 , 136.53, 139.16, 140.99, 148.68, 153.34, 154.60, 166.02; mp = 68-72 [deg.] C.
Step 4: ((2R, 3R, 4R, 5R) -3,4-Bis (tert- butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H-purin- ) Tetrahydrofuran-2-yl) methyl benzoate (17)
The intermediate compound (4.93 g, 7.85 mmol) prepared in the above step 3 was dissolved in 80% acetic acid (250 mL), and the mixture was refluxed at 100 ° C for 12 hours. After completion of the reaction was confirmed, the reaction solution was concentrated under reduced pressure, toluene (4 x 50 mL) was added, and the filtrate was concentrated under reduced pressure to obtain a diol intermediate without purification. The obtained diol intermediate (8.5 g, 14.47 mmol) was dissolved in anhydrous pyridine (250 mL), followed by addition of tetrabutyldimethylsilyl triflate (TBDMSOTf) (13.3 mL, 57.88 mmol) followed by stirring at 50 ° C for 5 hours. After confirming the completion of the reaction, the reaction solution was partitioned into methylene chloride / water. The organic layer was washed with water, saturated sodium hydrogencarbonate solution and saturated saturated sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -9H-purin-9-yl) tetrahydrofuran-2-yl) methylbenzoate (4.47 g, 69.73%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm -0.17 (s, 3H), 0.01 (s, 3H), 0.1 (s, 3H), 0.12 (s, 3H), 0.83 (s, 9H), 0.93 ( (t, J = 4.40 Hz, 1H), 4.74-4.78 (dd, J = J = 4.40 Hz, 1H), 4.82 (br s, 2H), 5.07-5.09 (t, J = 4.40 Hz, 1H), 5.88-5.89 (d, J = 7.82 Hz, 1H), 7.31-7.33 (d, J = 7.82 Hz, 1H), 7.38-7.41 (t, J = 7.82 Hz, 1H) , 7.52-7.55 (t, J = 7.82 Hz, 1H), 7.59-7.60 (d, J = 7.82 Hz, 1H), 7.72 (s, 1H), 7.84 dd, J = 8.31, 0.97 Hz, 2H), 8.32 (s, 1H); 13 C NMR (125 MHz; CDCl 3)? -0.00, 0.11, 0.26, 0.54, 30.63 (3), 34.61 (2), 49.19, 68.45, 77.09, 79.28, 87.24, 94.71, 99.46, 125.63, 131.74, 133.32 , 134.59, 135.23, 138.10, 141.41, 141.46, 144.66, 145.99, 153.87, 157.99, 159.53, 171.15; mp = 68-70 [deg.] C.
Step 5: ((2R, 3R, 4R, 5R) -3,4-Bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H-purin- ) Tetrahydrofuran-2-yl) methanol (18)
The intermediate compound (1.28 g, 1.56 mmol) prepared in step 4 was dissolved in anhydrous methanol (100 mL), 25% sodium methoxide / methanol (15 mL) was added, and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by column chromatography to obtain the intermediate compound ((2R, 3R, 4R, 5R) -3,4- bis (tert- butyldimethylsilyloxy) Yl) tetrahydrofuran-2-yl) methanol (960 mg, 86.48%) was obtained as a pale-yellow amorphous solid.
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm -0.58 (s, 3H), -0.13 (s, 3H), 0.11-0.13 (d, J = 7.33 Hz, 6H), 0.74 (s, 9H), 0.95 (s, 9H), 3.68-3.71 (d, J = 12.71 Hz, 1H), 3.92-3.95 (d, J = 12.71 Hz, (D, J = 7.33, 4.40 Hz, 1H), 5.75-5.77 (d, J = 7.82 Hz, 1H), 6.39 (br s). J = 7.82 Hz, 1H), 7.30-7.32 (d, J = 7.82 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.70 (s, 1H), 7.76 (br s, 1H), 8.35 (br s, 1H); 13 C NMR (125 MHz; CDCl 3 ) δ 0.00, 1.30, 1.35, 1.38, 31.62 (3), 31.75 (3), 35.61 (2), 49.54, 68.95, 79.91, 79.96, 95.50, 96.96, 100.51, 127.37, 132.70, 136.30, 142.42, 142.57, 146.54, 146.61, 153.78, 158.46, 160.79; mp = 82-86 [deg.] C.
Step 6: (2S, 5R) -3,4-Bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Preparation of tetrahydrofuran-2-carboxamide (19)
The intermediate compound (450 mg, 0.63 mmol) prepared in Step 5 and pyridinium dichromate (5.47 g, 14.54 mmol) were dissolved in DMF (50 mL) under a nitrogen stream, followed by stirring at room temperature for 12 hours. After confirming completion of the reaction, the resulting solid was washed with water to obtain an acid intermediate. The obtained intermediate (450 mg, 0.62 mmol) was dissolved in anhydrous ethanol (10 mL) under a nitrogen stream, cooled to 0 ° C, thionyl chloride (0.25 mL, 3.10 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 5 hours Lt; / RTI & gt; After completion of the reaction was confirmed, the reaction solution was concentrated under reduced pressure, and the residue was partitioned into ethyl acetate / water. The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, an intermediate ethyl ester was obtained. The ethyl ester thus obtained is added with a methylamine / 2N-THF solution under a nitrogen stream, followed by stirring at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide (400 mg, 85.65%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm -0.61 (s, 3H), -0.16 (s, 3H), 0.15 (s, 3H), 0.25 (s, 3H), 0.71 (s, 9H), 0.97 (s, 9H), 2.93-2.94 (d, J = 4.40 Hz, 3H), 4.33-4.34 (d, J = 3.42 Hz, (D, J = 7.33 Hz, 1H), 6.42 (br s, 1H), 7.03-7.06 (t, J = 7.82 Hz, 1H), 7.30-7.32 ), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.70 (s, 1H), 7.75 (s, 1H), 8.36 , 1H); 13 C NMR (125 MHz; CDCl 3 ) δ 0.00, 1.19, 1.21, 1.40, 23.71, 24.00, 31.53 (3), 31.58, 31.78 (2), 35.64, 49.60, 78.09, 81.25, 92.53, 95.48, 100.56, 127.30 , 132.72, 136.34, 142.44, 142.61, 146.64, 146.79, 154.27, 158.70, 160.96, 175.92; mp = 80-84 [deg.] C.
Step 7: (2S, 5R) -3,4-Dihydroxy-5- (6- (3-iodobenzylamino) -9H- purin-9- yl) -N- methyltetrahydrofuran- Manufacture of Radiate (20)
The intermediate compound (65 mg, 0.08 mmol) prepared in Step 6 was dissolved in anhydrous THF under a nitrogen stream, and then tetrabutylammonium fluoride (TBAF) (0.44 mL, 0.43 mmol, (1 M solution THF) Stir at room temperature for 1 hour. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide (52 mg, 95.45%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 ) δ ppm 2.70-2.71 (d, J = 4.40 Hz, 3H), 4.14-4.16 (t, J = 3.91 Hz, 1H), 4.31 (s, 1H), 4.57 (D, J = 4.40 Hz, 1H), 4.67 (d, 1H), 5.96-5.97 (d, J = 7.33 Hz, 1H), 7.09-7.12 (t, J = 7.82 Hz, 1H), 7.35-7.36 (d, J = 7.82 Hz, 1H), 7.56-7.58 1H, J = 7.82 Hz, 1H), 7.72 (s, 1H), 8.29 (s, 1H), 8.42 (s, 1H), 8.53 (br s., 1H), 8.85-8.86 (m, 1H); 13 C NMR (125 MHz; DMSO-d 6 )? 25.81, 42.74, 72.56, 73.49, 85.09, 88.26, 95.06, 120.42, 127.11, 130.95, 135.86, 136.13, 141.17, 143.10, 148.70, 152.94, 154.86, 170.34; mp = 178-182 [deg.] C.
Step 8: (S) -3-Hydroxy-2 – ((R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H- purin- Preparation of N-methylpropanamide (12)
The intermediate compound (52 mg, 0.10 mmol) prepared in the above Step 7 was treated in the same manner as in Step 5 of Example 1 to obtain the title compound (35 mg, 83.33%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 .) Δ ppm 2.35 (s, 3H), 3.5-3.6 (m, 1H), 3.72-3.74 (d, J = 9.29 Hz, 1H), 3.86 (br s. 2H), 4.99 (br s, 1H, exchangeable with D2O, OH), 5.21 (br. S., 1H), 4.00 (d, J = (d, J = 6.84 Hz, 1H), 7.56 d, J = 6.35 Hz, 2H, exchangeable with D 2 O, NH), 7.71 (s, 1H), 8.22 (s, 1H), 8.30 (s, 1H), 8.37 (br. s., 1H, exchangeable with D2O, NH); 13 C NMR (125 MHz; DMSO-d 6 ) δ 25.53, 42.81, 61.98, 62.26, 80.30, 84.62, 95.09, 119.43, 127.11, 130.91, 135.81, 136.16, 140.19, 143.31, 149.79, 152.98, 154.66, 169.42; HRMS (FAB) m / z calcd for C 1821 IN 6 O 4 [M + Na] +512.0669, found 535.0578; mp = 176-182 [deg.] C.
Example 4
Production Example 4: Synthesis of Compound (21) ((R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H- purin- 3-diol)
Scheme 4
Step 1: ((3aR, 4R, 6R, 6aR) -6- (6- (3-Iodobenzylamino) -9H-purin-9- yl) -2,2-dimethyltetrahydrofuro [ 4-d] [1,3] dioxol-4-yl) methanol (22)
The intermediate compound (1.73 g, 2.75 mmol) prepared in the step 2 of Example 1 was treated in the same manner as in the step 5 of Example 3 with (3aR, 4R, 6R, 6aR) -6- L, 3-dioxol-4-yl) methanol (1.04 g, 93.69 & lt; RTI ID = 0.0 & gt; %).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CDCl 3 ) δ ppm 1.36 (s, 3H), 1.63 (s, 3H), 3.75-3.80 (t, J = 11.24 Hz, 1H), 3.95-3.97 (d, J = 12.71 Hz , 5.19 (br, s, 2H), 5.10-5.11 (d, J = 4.89 Hz, 1H), 5.19 = 3.91 Hz, 1H), 6.58 (br s, 2H), 7.01-7.04 (t, J = 7.82 Hz, 1H), 7.29-7.30 (d, J = 6.84 Hz, 1H), 7.58-7.59 , J = 7.33 Hz, 1H), 7.69 (br s, 2H), 8.33 (br s, 1H); 13 C NMR (125 MHz; CDCl 3 ) δ 25.24, 27.66, 29.65, 63.36, 81.68, 83.03, 86.12, 94.26, 94.54, 113.93, 121.24, 126.80, 130.32, 136.52, 136.58, 139.71, 140.72, 147.66, 152.73, 154.94 ; mp = 72-76 [deg.] C.
Step 2: (2R, 3S, 4R, 5R) -2- (hydroxymethyl) -5- (6- (3-iodobenzylamino) -9H- purin-9- yl) tetrahydrofuran- – Preparation of diol (23)
The intermediate compound (250 mg, 0.47 mmol) prepared in the above step 1 was dissolved in 80% acetic acid (250 mL), and the mixture was heated under reflux at 100 ° C for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, toluene (4 x 50 mL) was added, and the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the intermediate (2R, 3S, 4R, Methyl) -5- (6- (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-3,4-diol (177 mg, 76.95%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; DMSO-d 6 )? Ppm 3.56 (br s, 1H), 3.67-3.69 (d, J = 10.27 Hz, 1H), 3.97 ), 4.61-4.67 (m, 3H), 5.17 (d, J = 2.93 Hz, 1H, exchangeable with D 2 O, OH), 5.35-5.36 (t, J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.43-5.44 (d, J = 5.38 Hz, 1H, exchangeable with d 2O, OH), 5.89-5.90 (d, J = 4.89 Hz, 1H), 7.09-7.11 (t, J = 7.33 Hz, 1H), 7.35-7.36 (d, J = 6.84 Hz, 1H), 7.56-7.58 (d, J = 7.33 Hz, 1H), 7.72 ), 8.45 (br s, 1H, exchangeable with D 2 O, NH); 13 C NMR (125 MHz; DMSO-d 6) [delta] 42.69, 62.08, 71.06, 73.97, 86.32, 88.42, 95.09, 120.24, 127.08, 130.91, 135.81, 136.16, 140.47, 143.22, 149.00, 152.76, 154.79; mp = 174-178 [deg.] C.
Step 3: (R) -2- (2-Hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane- )
The intermediate compound (77 mg, 0.15 mmol) prepared in the above Step 2 was treated in the same manner as in Step 5 of Example 1 to obtain the desired compound (62 mg, 80.51%).
The analytical data of the obtained compound are as follows.
1 H NMR (500 MHz; CD 3 OD)? Ppm 3.42 – 3.44 (d, J = 5.38 Hz, 2H), 3.54-3.58 (m, 1H), 3.65-3.68 ), 3.75-3.78 (dd, J = 11.73,4.44 Hz, 1H), 4.01-4.02 (d, J = 5.38 Hz, 2H), 4.53 (s, 2H), 6.04-6.06 J = 7.82 Hz, 1H), 7.76 (s, 1H), 7.07-7.10 (t, J = 7.82 Hz, 1H), 7.38-7.40 (d, J = 7.82 Hz, 1H), 7.59-7.60 ), 8.27 (s, 1 H), 8.29 (s, 1 H); 13 C NMR (125 MHz; CD 3 OD)? 42.88, 60.80, 61.25, 62.76, 80.26, 84.02, 93.52, 119.00, 126.44, 129.93, 135.90, 136.10, 139.65, 141.72, 148.97, 152.52, 154.53; HRMS (FAB) m / z calcd for C 17 H 20 IN 5 O 4 [M + H] +485.0560, found 486.0625; mp = 72-76 [deg.] C.

PATENT

WO 2008111082

REFERENCES

1: Avni I, Garzozi HJ, Barequet IS, Segev F, Varssano D, Sartani G, Chetrit N, Bakshi E, Zadok D, Tomkins O, Litvin G, Jacobson KA, Fishman S, Harpaz Z, Farbstein M, Yehuda SB, Silverman MH, Kerns WD, Bristol DR, Cohn I, Fishman P. Treatment of Dry Eye Syndrome with Orally Administered CF101 Data from a Phase 2 Clinical Trial. Ophthalmology. 2010 Mar 19. [Epub ahead of print] PubMed PMID: 20304499.

2: Bar-Yehuda S, Rath-Wolfson L, Del Valle L, Ochaion A, Cohen S, Patoka R, Zozulya G, Barer F, Atar E, Piña-Oviedo S, Perez-Liz G, Castel D, Fishman P. Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis Rheum. 2009 Oct;60(10):3061-71. PubMed PMID: 19790055.

3: Borea PA, Gessi S, Bar-Yehuda S, Fishman P. A3 adenosine receptor: pharmacology and role in disease. Handb Exp Pharmacol. 2009;(193):297-327. Review. PubMed PMID: 19639286.

4: Moral MA, Tomillero A. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Mar;30(2):149-71. PubMed PMID: 18560631.

5: Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial. J Rheumatol. 2008 Jan;35(1):41-8. Epub 2007 Nov 15. PubMed PMID: 18050382

/////////////CF 101, Piclidenoson, CF101, CF-101, CF 101, ALB-7208,  ALB 7208, ALB7208,  IB MECA, Phase III,  Plaque psoriasis, Rheumatoid arthritis, UNII-30679UMI0N, Пиклиденозон بيكليدينوسون 匹利诺生 , Can-Fite BioPharma

CNC(=O)[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC2=C(NCC3=CC(I)=CC=C3)N=CN=C12

%d bloggers like this: