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BMS 986236

April 15, 2019 9:35 am / Leave a comment

BMS-986236

CAS 2058035-15-5

MW C₂₂ H₂₅ N₉ O

MF 431.49

1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

1H-Pyrazolo[3,4-b]pyridine-5-carbonitrile, 1-[5-[4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl]-4-[(1-methylethyl)amino]-2-pyridinyl]-

1-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]pyrazolo[3,4-b]pyridine-5-carbonitrile

The present invention generally relates to heteroaryl substituted aminopyridine compounds useful as kinase inhibitors, including the modulation of IRAK-4. Provided herein are heteroaryl substituted aminopyridine compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to kinase modulation and methods of inhibiting the activity of kinases, including IRAK-4 in a mammal.

Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll like receptor (TLR) family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Members of the IRAK family of serine/threonine kinases are recruited to the receptor via interactions with MyD88. The family consists of four members. Several lines of evidence indicate that IRAK4 plays a critical and non-redundant role in initiating signaling via MyD88 dependent TLRs and IL-1R family members. Structural data confirms that IRAK4 directly interacts with MyD88 and subsequently recruits either IRAK1 or IRAK2 to the receptor complex to facilitate downstream signaling (Lin, S. et al., Nature, 465:885-890 (2010)). IRAK4 directly phosphorylates IRAK1 to facilitate downstream signaling to the E3 ubiquitin ligase TRAF6, resulting in activation of the serine/threonine kinase TAK1 with subsequent activation of the NFκB pathway and MAPK cascade (Flannery, S. et al., Biochem. Pharmacol., 80:1981-1991 (2010)). A subset of human patients was identified who lack IRAK4 expression (Picard, C. et al.,Science, 299:2076-2079 (2003)). Cells from these patients fail to respond to all TLR agonists with the exception of TLR3 as well as to members of the IL-1 family including IL-113 and IL-18 (Ku, C. et al., J. Exp. Med., 204:2407-2422 (2007)). Deletion of IRAK4 in mice results in a severe block in IL-1, IL-18 and all TLR dependent responses with the exception of TLR3 (Suzuki, N. et al., Nature, 416:750-754 (2002)). In contrast, deletion of either IRAK1 (Thomas, J. A. et al., J. Immunol., 163:978-984 (1999); Swantek, J. L. et al., J. Immunol., 164:4301-4306 (2000) or IRAK2 (Wan, Y. et al., J. Biol. Chem., 284:10367-10375 (2009)) results in partial loss of signaling. Furthermore, IRAK4 is the only member of the IRAK family whose kinase activity has been shown to be required for initiation of signaling. Replacement of wild type IRAK4 in the mouse genome with a kinase inactive mutant (KDKI) impairs signaling via all MyD88 dependent receptors including IL-1, IL-18 and all TLRs with the exception of TLR3 (Koziczak-Holbro, M. et al., J. Biol. Chem., 282:13552-13560 (2007); Kawagoe, T. et al., J. Exp. Med., 204:1013-1024 (2007); and Fraczek, J. et al., J. Biol. Chem., 283:31697-31705 (2008)).

As compared to wild type animals, IRAK4 KDKI mice show greatly reduced disease severity in mouse models of multiple sclerosis (Staschke, K. A. et al., J. Immunol., 183:568-577 (2009)), rheumatoid arthritis (Koziczak-Holbro, M. et al., Arthritis Rheum., 60:1661-1671 (2009)), atherosclerosis (Kim, T. W. et al., J. Immunol., 186:2871-2880 (2011) and Rekhter, M. et al., Biochem. Biophys. Res. Comm., 367:642-648 (2008)), and myocardial infarction (Maekawa, Y. et al., Circulation, 120:1401-1414 (2009)). As described, IRAK4 inhibitors will block all MyD88 dependent signaling. MyD88 dependent TLRs have been shown to contribute to the pathogenesis of multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel diseases including Crohn’s disease and ulcerative colitis, autoimmune uveitis, asthma, allergy, type I diabetes, and allograft rejection (Keogh, B. et al., Trends Pharmacol. Sci., 32:435-442 (2011); Mann, D. L., Circ. Res., 108:1133-1145 (2011); Horton, C. G. et al., Mediators Inflamm., Article ID 498980 (2010), doi:10.1155/2010/498980; Goldstein, D. R. et al., J Heart Lung Transplant., 24:1721-1729 (2005); and Cario, E., Inflamm. Bowel Dis., 16:1583-1597 (2010)). Oncogenically active MyD88 mutations in diffuse large B cell lymphomas have been identified that are sensitive to IRAK4 inhibition (Ngo, V. N. et al., Nature, 470:115-121 (2011)). Whole genome sequencing also identified mutations in MyD88 associated with chronic lymphatic leukemia suggesting that IRAK4 inhibitors may also have utility in treating leukemia (Puente, X. S. et al., Nature, 475:101-105 (2011)).

In addition to blocking TLR signaling, IRAK4 inhibitors will also block signaling by members of the IL-1 family. Neutralization of IL-1 has been shown to be efficacious in multiple diseases including gout; gouty arthritis; type 2 diabetes; auto-inflammatory diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult onset stills; systemic onset juvenile idiopathic arthritis; stroke; Graft-versus-Host Disease (GVHD); smoldering multiple myeloma; recurrent pericarditis; osteoarthritis; emphysema (Dinarello, C. A., Eur. J. Immunol., 41:1203-1217 (2011) and Couillin, I. et al., J Immunol., 183:8195-8202 (2009)). In a mouse model of Alzheimer’s disease, blockade of IL-1 receptor improved cognitive defects, attenuated tau pathology and reduced oligomeric forms of amyloid-β (Kitazawa, M. et al., J. Immunol., 187:6539-6549 (2011)). IL-1 has also been shown to be a critical link to adaptive immunity, driving differentiation of the TH17 effector T cell subset (Chung, Y. et al., Immunity, 30:576-587 (2009)). Therefore, IRAK4 inhibitors are predicted to have efficacy in TH17 associated diseases including multiple sclerosis, psoriasis, inflammatory bowel diseases, autoimmune uveitis, and rheumatoid arthritis (Wilke, C. M. et al., Trends Immunol., 32:603-661 (2011)).

WO2013/106612, WO2013/106614, WO2013/106641, WO2014/074657, and WO2014/074675 disclose substituted pyridyl compounds useful as kinase inhibitors, including the modulation of IRAK4.

In view of the conditions that may benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as IRAK-4 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of heteroaryl substituted aminopyridine compounds found to be effective inhibitors of protein kinases including IRAK-4. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

PATENT

US2018186799

https://patentscope.wipo.int/search/en/detail.jsf?docId=US222843237&tab=PCTDESCRIPTION&maxRec=1000

(MOL) (CDX)

PATENT

Gardner, D. S.; Santella, J. B.; Paidi, V. R.; Wu, H.; Duncia, J. V.; Nair, S. K.; Hynes, J. (BMS, USA). Heteroaryl Substituted Aminopyridine Compounds. PCT Int. Appl. WO/2016/210034 A1, 2016.

https://patents.google.com/patent/WO2016210034A1/en

Clip

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00023

Development of a Scalable Synthesis for the Potent Kinase Inhibitor BMS-986236; 1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile

Pirama Nayagam Arunachalam^†, Prakasam Kuppusamy^†, Sivakumar Ganesan^†, Suresh Krishnamoorthy^†, Roshan Y. Nimje^†, Lokesh Babu Jarugu^†, Nanjundaswamy Kanikahalli Chikkananjaiah^†, China Anki Reddy^†, Prakash Anjanappa^†, Murali Botlagunta^†, Sridhar Vanteru^†, Nageswararao Maddala^†, Muniyappa Shankar^†, Satheesh Nair^†, John Hynes, Jr.^‡, Joseph B. Santella, III^‡, Percy H. Carter^‡

, Richard Rampulla^‡, Muthalagu Vetrichelvan *^†

, Anuradha Gupta^†

, Arun Kumar Gupta^†, and Arvind Mathur^‡

^† Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore-560 099, India

^‡ Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-4000, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.9b00023

*E-mail: muthalagu.vetrichelvan@syngeneintl.com.

A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1, BMS-986236) was developed by incorporating an alternate azide intermediate following safety-driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed in the first-generation synthesis has been overcome.

1 (92.5 g, 73% yield, 99.5% purity by HPLC) as a cream-colored solid.

¹H NMR (400 MHz, DMSO-d₆) δ = 9.21–8.86 (m, 2H), 8.66 (s, 1H), 8.45–8.24 (m, 2H), 7.49 (s, 1H), 6.57 (d, J = 7.5 Hz, 1H), 4.33 (s, 1H), 3.83 (d, J = 7.0 Hz, 1H), 2.91–2.72 (m, 2H), 1.97–1.68 (m, 2H), 1.24 (d, J = 6.5 Hz, 12H).

¹³C NMR (100 MHz, DMSO) δ = 151.7, 150.8, 149.8, 147.9, 147.7, 143.7, 136.8, 136.3, 122.9, 118.9, 117.6, 116.0, 102.8, 99.4, 68.4, 43.6, 42.7, 29.2, 21.7, 20.2.

HRMS [M + H]⁺ calcd for C₂₂H₂₅N₉O 432.2255, found 432.2259.

//////// BMS-986236, BMS 986236

CC(C)(O)CCc1cn(nn1)c2cnc(cc2NC(C)C)n4ncc3cc(cnc34)C#N

TAK-981

April 12, 2019 9:40 am / 2 Comments on TAK-981

TAK-981

C25 H28 Cl N5 O5 S2, 578.103

[(1R,2S,4R)-4-[(5-[4-[(1R)-7-Chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl)amino]-2-hydroxycyclopentyl]methyl sulfamate

[(1R,2S,4R)-4-[[5-[4-[(1R)-7-Chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-thiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxy-cyclopentyl]methyl sulfamate

Sulfamic acid, [(1R,2S,4R)-4-[[5-[[4-[(1R)-7-chloro-1,2,3,4-tetrahydro-1-isoquinolinyl]-5-methyl-2-thienyl]carbonyl]-4-pyrimidinyl]amino]-2-hydroxycyclopentyl]methyl ester

CAS 1858276-04-6 FREE

CAS 1858279-63-6 HYDRATE

578.103

Originator Takeda Oncology
Class Antineoplastics
Mechanism of Action Small ubiquitin-related modifier protein inhibitors

Phase I Lymphoma; Solid tumours

01 Oct 2018 Phase-I clinical trials in Solid tumours (Late-stage disease, Metastatic disease) and and Lymphoma (Refractory metastatic disease, Second-line therapy or greater) in USA (IV) (NCT03648372)
03 Sep 2018 Takeda Oncology plans a phase I trial for Solid tumours (Late-stage disease, Metastatic disease) and Lymphoma (Refractory metastatic disease, Second-line therapy or greater) in September 2018 (IV) (NCT03648372)
03 Sep 2018 Preclinical trials in Lymphoma in USA (IV) prior to September 2018 (NCT03648372)

Takeda is evaluating TAK-981, a SUMO-Activating Enzyme (SAE) inhibitor, in early clinical trials for the treatment of adult patients with advanced or metastatic solid tumors or with relapsed or refractory lymphomas.

Small ubiquitin-like modifier (SUMO) is a member of the ubiquitin-like protein (Ubl) family that is covalently conjugated to cellular proteins in a manner similar to Ub-conjugation (Kerscher, O., Felberbaum, R., and Hochstrasser, M. 2006. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22: 159-80). Mammalian cells express three major isoforms: SUMO l , SUM02 and SUM03. SUM02 and SUM03 share -95% amino acid sequence homology but have -45% sequence homology with SUMO l (Kamitani, T., Kito, K., Nguyen, H. P., Fukuda-Kamitani, T., and Yeh, E. T. 1998. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 273( 18): 1 1349-53). SUMO proteins can be conjugated to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation). Only SUM02/3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., Hay, R. T. 2001. Polymeric chains of SUMO-2 and SUM 0-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 276(38):35368-74). An additional isoform, SUM04, is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can be conjugated to cellular proteins.

[0003] SUMO l , SUM02 and SUM03 are activated in an ATP-dependent manner by the SUMO-activating enzyme (SAE). SAE is a heterodimer that consists of SAE 1 (SUMO-activating enzyme subunit 1) and SAE2 (UBA2). SAE, like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO. In a second step, a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2. Next, SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9. Unlike the Ub pathway that contains many E2 enzymes, Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl , SUM02 and SUM03 proteins. SUMO proteins are then conjugated to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein. Several SUMO E3 ligases, including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A. 2001. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell. 106(6):735-44; Pichler, A., Gast, A., Seeler, J. S., Dejean, A.; Melchior, F. 2002. The nucleoporin RanBP2 has SUMOl E3 ligase activity. Cell. 108(1): 109-20; Kagey, M. H., Melhuish, T. A., and Wotton, D. 2003. The polycomb protein Pc2 is a SUMO E3. Cell. 1 13(1): 127- 37). Once attached to cellular targets, SUMO modulates the function, subcellular localization, complex formation and/or stability of substrate proteins (Miiller, S., Hoege, C, Pyrowolakis, G., and Jentsch, S. 2001. SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol. 2(3):202-10). SUMO- conjugation is reversible through the action of de-sumoylating enzymes called SENPs (Hay, R. T. 2007. SUMO-specific proteases: a twist in the tail. Trends Cell Biol. 17(8):370-6) and the SUMO proteins can then participate in additional conjugation cycles.

[0004] SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T. 2005. SUMO: a history of modification. Mol Cell. 18( 1): 1 -12; Gill, G. 2004. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18(17):2046-59). For example, SUMO- conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. 1997. A small ubiquitin-related polypeptide involved in targeting RanGAPl to nuclear pore complex protein RanBP2. Cell. 88(1):97- 1070). Sumoylation counteracts ubiquitination and subsequently blocks the degradation of Ι Β, thereby negatively regulating NF-κΒ activation (Desterro, J. M., Rodriguez, M. S., Hay, R. T. 1998. SUMO- 1 modification of IkappaB alpha inhibits NF-kappaB activation. Mol Cell. 2(2):233-9). Sumoylation has been reported to play an important role in transcription exhibiting both repressive and stimulatory effects. Many of the transcriptional nodes that are modulated play important roles in cancer. For example, sumoylation stimulates the transcriptional activities of transcription factors such as p53 and HSF2 (Rodriguez, M. S., Desterro, J. M., Lain, S., Midgley, C. A., Lane, D. P., and Hay, R. T. 1999. SUMO- 1 modification activates the transcriptional response of p53. EMBO J. 18(22):6455-61 ; Goodson, M. L., Hong, Y., Rogers, R., Matunis, M. J., Park-Sarge, O. K., Sarge, K. D. 2001. Sumo- 1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. J Biol Chem. 276(21 ): 18513-8). In contrast, SUMO-conjugation represses the transcriptional activities of transcription factors such as LEF (Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F., Grosschedl, R. 2001. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15(23):3088- 103) and c-Myb (Bies, J., Markus, J., and Wolff, L. 2002. Covalent attachment of the SUMO- 1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity. / Biol Chem. 277( 1 1):8999-9009). Thus, SUMO-conjugation controls gene expression and growth control pathways that are important for cancer cell survival.

[0005] Altered expression of SAE pathway components have been noted in a variety of cancer types: (Moschos, S. J., Jukic, D. M., Athanassiou, C., Bhargava, R., Dacic, S., Wang, X., Kuan, S. F., Fayewicz, S. L., Galambos, C., Acquafondata, M., Dhir, R., and Becker, D. 2010. Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol. 41(9): 1286-980); including multiple myeloma (Driscoll, J. J., Pelluru, D., Lefkimmiatis, K., Fulciniti, M., Prabhala, R. H., Greipp, P. R., Barlogie, B., Tai, Y. T., Anderson, K. C, Shaughnessy, J. D. Jr., Annunziata, C. M., and Munshi, N. C. 2010. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 1 15(14):2827-34); and breast cancer (Chen, S. F., Gong, C, Luo, M., Yao, H. R., Zeng, Y. J., and Su, F. X. 201 1. Ubc9 expression predicts chemoresistance in breast cancer. Chin J Cancer. 30(9):638-44), In addition, preclinical studies indicate that Myc-driven cancers may be especially sensitive to SAE inhibition (Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., Skinner, S. O., Xu, Q., Li, M. Z., Hartman, Z. C, Rao, M., Yu, P., Dominguez-Vidana, R., Liang, A. C, Solimini, N. L., Bernardi, R. J., Yu, B., Hsu, T., Golding, I., Luo, J., Osborne, C. K., Creighton, C. J., Hilsenbeck, S. G., Schiff, R., Shaw, C. A., Elledge, S. J., and Westbrook, T. F. 2012. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 335(6066):348-53; Hoellein, A., Fallahi, M., Schoeffmann, S., Steidle, S., Schaub, F. X., Rudelius, M., Laitinen, I., Nilsson, L., Goga, A., Peschel, C, Nilsson, J. A., Cleveland, J. L., and Keller, U. 2014. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood. 124( 13):2081 -90). Since SUMO-conjugation regulates essential cellular functions that contribute to the growth and survival of tumor cells, targeting SAE could represent an approach to treat proliferative disorders such as cancer.

[0006] SAE inhibitors may also be applicable for the treatment of other diseases and conditions outside of oncology. For example, SUMO modifies proteins that play important roles in neurodegenerative diseases (Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C, Slepko, N., Hies, K., Lukacsovich, T., Zhu, Y. Z., Cattaneo, E., Pandolfi, P. P., Thompson, L. M., Marsh, J. L. 2004. SUMO modification of Huntington and Huntington’s disease pathology. Science. 304(5667): 100-4); Dorval, V., and Fraser, P. E. 2006. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem. 281 ( 15):9919-24; Ballatore, C, Lee, V. M., and Trojanowski, J. Q. 2007. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 8(9):663-72). Sumoylation also has been reported to play important role in pathogenic viral infection, inflammation and cardiac function (Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S., and Ahn, J. H. 2004. Ability of the human cytomegalovirus ΓΕ1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells. / Virol. 78(12):6527-42; Liu, B., and Shuai, K. 2009. Summon SUMO to wrestle with inflammation. Mol Cell. 35(6):731-2; Wang, J., and Schwartz, R. J. 2010. Sumoylation and regulation of cardiac gene expression. Circ Rei. l07( l): 19-29). [0007] It would be beneficial therefore to provide new SAE inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative disorders.

PATENT

WO 2016004136

https://patents.google.com/patent/WO2016004136A1/en

Example 133: [(lR,2S,4R)-4-[[5-[4-[(lR)-7-Chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl- thiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxy-cyclopentyl]methyl sulfamate I-263a

Step 1: 7-Chloro-l-[5-(l,3-dioxolan-2-yl)-2-methyl-3-thienyl]-l,2,3,4-tetrahydroisoquinoline

[00714] An oven-dried 2-neck 250 mL round bottom flask under nitrogen was charged with THF (40 mL) and cooled to -74 °C . Added 2.50 M ra-BuLi in hexane (6.92 mL, 17.3 mmol). Added a solution of Int-1 (4.00 g, 16.0 mmol) in THF (60 mL) slowly keeping the internal temperature less than -70 °C . Stirred with cooling 5 min. A second oven-dried 250 mL round bottom flask under nitrogen was charged with THF (60 mL) and Int-50 (2.04 g, 12.4 mmol) and the resulting solution was cooled to 0 °C . Added boron trifluoride diethyl ether complex ( 1.71 mL, 13.6 mmol) slowly and cooled to -30 °C . The contents of the first flask were transferred via cannula to the second flask. Reaction was quenched with saturated aqueous NaHC0₃ and warmed to rt. Water was added, and the mixture was extracted three times with EtOAc. Combined organic portions were washed with brine, dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo. Residue was purified via flash column chromatography eluting with a hexane / EtOAc gradient (0 to 100% EtOAc) to afford the title compound as a white solid ( 1.88g, 45%). Ή NMR (400 MHz, Chloroform-d) δ 7.17 – 7.01 (m, 2H), 6.83 – 6.61 (m, 2H), 5.92 (s, 1H), 5.09 (s, 1H), 4.17 – 4.04 (m, 2H), 4.03 – 3.92 (m, 2H), 3.37 – 3.25 (m, 1H), 3.13 – 2.91 (m, 2H), 2.82 – 2.69 (m, 1H), 2.46 (s, 3H). LCMS: (AA) M+l 336.1

Step 2: ieri-Butyl 7-chIoro-l-[5-(l,3-dioxolan-2-yl)-2-methyl-3-thienyl]-3,4-dihydroisoquinoIine -2(lH)-carboxyIate [00715] A 50 mL round bottom flask under nitrogen was charged with 7-chloro-l -[5-(l ,3-dioxolan-2- yl)-2-methyl-3-thienyl]- l ,2,3,4-tetrahydroisoquinoline (5.67 g, 16.9 mmol) and DCM ( 100 mL), to which was added triethylamine (4.71 mL, 33.8 mmol), di-ieri-butyldicarbonate (4.61 g, 21.1 mmol), and N,N-dimethylaminopyridine (23 mg, 0.18 mmol). Reaction was stirred for 1 h at rt and then poured into saturated NaHC0₃ solution. Mixture was extracted three times with DCM, and the combined organic portions were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford 6.96g (95%) of the title compound. LCMS: (AA) M+ l 436.1

Step 3: tert-Butyl 7-chloro-l-(5-formyl-2-methyl-3-thienyl)-3,4-dihydroisoquinoline -2(1H)- carboxylate

[00716] A 1 L round bottom flask was charged with ferf-butyl 7-chloro-

1 -[5-( 1 ,3-dioxolan-2-yl)-2-methyl-3-thienyl]-3 ,4-dihydroisoquinoline-2( 1 H)-carboxylate (7.30 g, 16.7 mmol), methanol (200 mL), and water (20 mL), to which was added a solution of 12M HC1 (4.00 mL, 130 mmol) in methanol (200 mL), and the reaction was stirred at rt for 1 h. Reaction was quenched via addition of 50mL of saturated NaHC0₃ and stirred for 5 min. Methanol was removed in vacuo, and the resulting aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (4.55g, 70%). Ή NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1 H), 7.27 – 7.15 (m, 2H), 7.12 (s, 1 H), 6.98 – 6.94 (m, 1 H), 6.34 (m, l H), 4.15 (s, 1 H), 3.18 – 3.06 (m, 1 H), 3.05 – 2.93 (m, 1H), 2.82 – 2.73 (m, 1 H), 2.69 (s, 3H), 1.50 (s, 9H). LCMS: (AA) M+Na 414.2

Step 4: tert-Butyl 7-chIoro-l-{5-[(4-chloropyrimidin-5-yl)(hydroxy)methyI]-2-methyl-3-thienyl}- 3,4-dihydroisoquinoline-2(lH)-carboxylate

[00717] An oven-dried 500 mL 3-neck round bottom flask under nitrogen was charged with 4-chloro- 5-iodopyrimidine (4.08 g, 17.0 mmol) and 2-methyltetrahydrofuran ( 150 mL). An addition funnel containing a solution of rert-butyl 7-chloro- l -(5-formyl-2-methyl-3-thienyl)-3,4- dihydroisoquinoline-2(l H)-carboxylate (4.75 g, 12.1 mmol) in 2-methyltetrahydrofuran (50 mL) was attached, and the contents of the reaction flask were cooled to -75 °C . 2.50 M n-BuLi in hexane ( 14.1 mL, 35.2 mmol) was added in small portions keeping the internal temperature less than -70 °C , at which point the contents of addtion funnel were added in a single portion. Upon completion of addition, the reaction was quenched by adding 20 mL of saturated NaHC0₃ in small portions and warmed to rt. The aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (4.85g, 79%). LCMS: (AA) M+Na 528.1

Step 5: tert-Butyl 7-chloro-l-{5-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]-2-methyl-3-thienyl}- 3,4- dihydroisoquinoline-2(lH)-carboxylate

[00718] A 1 L round bottom flask was charged with fe/Y-butyl 7-chloro- l – { 5-[(4-chloropyrimidin-5- yl)(hydroxy)methyl]-2-methyl-3-thienyl}-3,4-dihydroisoquinoline-2(l H)-carboxylate (4.85 g, 9.58 mmol) and DCM (300 mL). Manganese (IV) oxide (14.2 g, 163 mmol) was added and the reaction was stirred at rt for 18 h. Mixture was filtered through Celite, and the filter cake was rinsed with hot EtOAc. Filtrate was concentrated in vacuo to afford the title compound (4.47g , 93%). Ή NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1 H), 8.70 (s, 1 H), 7.24 – 7.16 (m, 1 H), 7.16

– 7.07 (m, 1 H), 7.00 – 6.90 (m, 2H), 6.32 (s, 1 H), 4.28 – 3.97 (m, 1H), 3.14 – 2.89 (m, 2H), 2.78

– 2.65 (m, 4H), 1 .53 – 1.43 (m, 9H).

Step 6: tert-Butyl (lR)-7-chloro-l-[5-[4-[[(lR,3R,4S)-3-(hydroxymethyl)-4-triisopropylsiIyloxy- cyclopentyl]amino]pyrimidine-5-carbonyl]-2-methyl-3-thienyl]-3,4-dihydro-lH-isoquinoline-2- carboxylate

[00719] A 1 L round bottom flask under nitrogen was charged with iert-butyl 7-chloro- l – { 5-[(4- chloropyrimidin-5-yl)carbonyI]-2-methyl-3-thienyl }-3,4-dihydroisoquinoline-2( l H)-carboxylate (4.47 g, 8.86 mmol), DMF (20.0 mL, 258 mmol), Int-259 (3.06 g, 10.6 mmol), and triethylamine (3.09 mL, 22.2 mmol) and the mixture was stirred at rt for 18 h. Reaction mixture was poured into water and saturated NaHC0₃, and then extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a 70/30 to 60/40 hexane/EtOAc gradient to afford 0.56g of first-eluting diastereomer 1 (not pictured), 4.3 l g of a mixture of diastereomers, and 1.1 lg ( 17%) of second-eluting diastereomer 2 (the title compound). The mixture of diastereomers thus obtained was resubjected to the described chromatography conditions two additional times to afford a total of 2.62 g of the desired diastereomer. Ή NMR (400 MHz, Methanol-d4) δ 8.54 – 8.46 (m, 2H), 7.27 – 7.19 (m, 2H), 7.09 – 6.99 (m, 2H), 6.37 (s, 1H), 4.87 – 4.75 (m, 1H), 4.38 – 4.29 (m, 1H), 4.20 – 4.09 (m, 1H), 3.66 – 3.52 (m, 2H), 3.28- 3.14 (m, 2H), 3.02 – 2.89 (m, 1 H), 2.89 – 2.78 (m, 1 H), 2.68 (s, 3H), 2.54 – 2.41 (m, 1 H), 2.22 – 2.09 (m, 2H), 1.86 – 1.73 (m, 1H), 1.50 (s, 8H), 1.39 – 1.23 (m, 2H), 1.15 – 1.04 (m, 20H).

LCMS: (AA) M+ 1 755.3

Step 7: tert-Butyl (lR)-7-chloro-l-[2-methyl-5-[4-[[(lR,3R,4S)-3-(sulfamoyloxymethyl)-4- triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-3-thienyl]-3,4-dihydro-lH- isoquinoline-2-carboxylate [00720] A solution of ie/t-butyl (lR)-7-chloro-l-[5-[4-[[( lR,3R,4S)-3-(hydroxymethyl)-4- triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-2-methyl-3-thienyl]-3,4-dih lH-isoquinoline-2-carboxylate (2.46 g, 3.26 mmol) in 2-methyltetrahydrofuran (25 mL), and DMF (25 mL) was cooled to 0 °C. Triethylamine ( 1.82 mL, 13.0 mmol) and chlorosulfonamide (1.50 g, 13.0 mmol) were added and the reaction was stirred for 10 min. Added methanol (0.53 mL, 13.0 mmol) and stirred for 15 min. Reaction mixture was poured into saturated NaHC0₃, extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (2.41g, 89%). Ή NMR (400 MHz, Methanol-d4) δ 8.58 – 8.45 (m, 2H), 7.29 – 7.17 (m, 2H), 7.1 1 – 6.98 (m, 2H), 6.36 (s, 1 H), 4.84 – 4.73 (m, 1H), 4.44 – 4.33 (m, 1H), 4.21 – 4.08 (m, 4H), 3.27- 3.17 (m, 1 H),3.02 – 2.89 (m, 1 H), 2.88 – 2.78 (m, 1 H), 2.67 (s, 3H), 2.57 – 2.47 (m, 1 H), 2.41 – 2.30 (m, 1 H), 2.23 – 2.13 (m, 1 H), 1.87- 1.78 (m, 1 H), 1.50 (s, 9H), 1.43 – 1 .33 (m, 1 H), 1 .17 – 1.04 (m, 20H). LCMS: (AA) M+l 834.3

Step 8: [(lR,2S,4R)-4-[[5-[4-[(lR)-7-Chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl- thiophene-2-carbonyl]pyrimidin-4-yI]aniino]-2-hydroxy-cyclopentyl]methyl sulfamate

[00721] A solution of f«?r/-butyl ( l R)-7-chloro- l -[2-methyl-5-[4-[[( l R,3R,4S)-3-

(sulfamoyloxymethyl)-4-triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-3- thienyl]-3,4-dihydro- l H-isoquinoline-2-carboxylate (2.41 g, 2.89 mmol) in CH₃CN ( 10 mL) was cooled in an ice bath to + 1 °C . Phosphoric acid ( 10 mL, 200 mmol) was added dropwise and the reaction was stirred with ice bath cooling for 60 min. The mixture was warmed to rt and stirred for an additional 3 h. Reaction was poured into a stirring mixture of 50 mL water and 50 mL EtOAc, and the the pH was adjusted to ~9 by slowly adding 200 mL of saturated NaHC0₃ with stirring. Resulting aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a gradient that began with 100% DCM and increased in polarity to 80% DCM / 20% methanol / 2% ammonium hydroxide gradient to afford the title compound (1.50 g, 90%). Ή NMR (400 MHz, Methanol-d4) δ 8.61 (s, 1H), 8.52 (s, 1 H), 7.27 (s, 1 H), 7.18 – 7.13 (m, 2H), 6.73 – 6.68 (m, 1 H), 5.23 (s, 1H), 4.81 – 4.70 (m, 1 H), 4.26 – 4.10 (m, 3H), 3.29 – 3.23 (m, 2H), 3.1 1 – 2.96 (m, 2H), 2.87 – 2.76 (m, 1H), 2.60 (s, 3H), 2.55 – 2.42 (m, 1 H), 2.33 – 2.19 (m, 1H), 2.18 – 2.07 (m, 1H), 1.95 – 1.81 (m, 1H), 1.47 – 1.35 (m, 1 H). LCMS: (AA) M+l 580.0

CLIP

Candidate: TAK-981

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Credit: Tien Nguyen/C&EN

Presenter: Steven Paul Langston, associate director at Takeda Pharmaceuticals International

Target: Sumo activating enzyme

Disease: Solid tumors

Reporter’s notes: Langston gave the last talk of the morning session, placing him in the “precarious position of being between you and lunch,” he said. Takeda acquired this drug development program, falling under the umbrella of immuno-oncology, along with Millenium Pharmaceuticals in 2008. The team targeted a pathway known as SUMOylation, a protein post translation modification that is implicated in a number of cellular processes including immune response. In SUMOylation, enzymes attach a small protein to another protein. They found that inhibiting this pathway activates a type I interferon response in immune cells. How the molecule, TAK-981, inhibits this pathway is quite complicated, Langston said. TAK-981 forms an adduct with a small ubiquitin like modifier (SUMO) to inhibit a SUMO activating enzyme that catalyzes SUMOylation. While the synthesis of TAK-981 is fairly short, it requires a nonideal chiral chromatography separation after the first step. TAK-981 is in Phase I clinical trials as an intravenous infusion for patients with metastatic solid tumors or lymphomas.

Patent ID	Title	Submitted Date	Granted Date
US2018311239	HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME	2018-03-16
US9962386	HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME	2017-04-17
US9683003	HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME	2015-06-30	2016-01-14

//////////TAK-981, TAK 981, Phase I, Lymphoma, Solid tumours, TAKEDA,

Cc3sc(cc3[C@@H]1NCCc2ccc(Cl)cc12)C(=O)c5cncnc5N[C@@H]4C[C@H](COS(N)(=O)=O)[C@@H](O)C4

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

BIIB-095

April 10, 2019 10:08 am / Leave a comment

BIIB-095

ROTATION (+)

1493790-64-9 CAS free form,

1493772-48-7 cas Hcl salt

cas 1493790-65-0, 1496563-32-6 ,SULPHATE ???

cas 1496563-31-5 SULFATE 1;1

cas 1496563-32-6 SULFATE HYDRATE 1;1;1

(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1 ,7-diazaspiro[4.4]nonan-6-one

1,7-Diazaspiro[4.4]nonan-6-one, 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]-2-pyrimidinyl]-, (2R,5S)-

C₂₀ H₂₁ F₃ N₄ O, 390.40

Originator Biogen
Class Analgesics
Mechanism of Action Nav1.7 voltage-gated sodium channel inhibitors

Phase I Neuropathic pain

29 Mar 2018 Phase-I clinical trials in Neuropathic pain (In volunteers) in United Kingdom (PO) (NCT03454126)
05 Mar 2018 Biogen plans a phase I trial for Pain, including Neuropathic pain (In volunteers) in USA (PO) (NCT03454126)
05 Mar 2018 Preclinical trials in Neuropathic Pain in USA (PO), before March 2018

In March 2018, a randomized, double blind, placebo controlled, single and multiple-ascending dose, dose-escalation phase I study ( NCT03454126; 255HV101; 2017-003982-90) was initiated in the UK in healthy subjects (expected n = 80) to evaluate the safety, tolerability and pharmacokinetics of BIIB-095. At that time, the trial was expected to complete in December 2018

Biogen is developing BIIB-095, a voltage-gated sodium channel 1.7 inhibitor, for the potential oral treatment of neuropathic pain [2027279], [2027426]. In March 2018, a phase I trial was initiated in healthy subjects

Biogen is developing oral agent BIIB-095 for the treatment of chronic pain, including neuropathic pain. A phase I clinical trial is under way in healthy volunteers.

The compound was first claimed in WO2013175205 , for treating schizophrenia, assigned to subsidiary Convergence Pharmaceuticals Limited , naming some of the inventors. This might present the structure of BIIB-095 , a voltage-gated sodium channel 1.7 inhibitor, being developed by Biogen for the oral treatment of neuropathic pain; in March 2018, a phase I trial was initiated in healthy subjects.

PATENT

WO2013175205

CONTD………………

INTERMEDIATE

WO 2013175206

US 20150119404

https://patents.google.com/patent/US20150119404

Patent

WO-2019067961

https://patentscope2.wipo.int/search/en/detail.jsf;jsessionid=4E8EDA900F4ACD794E922F827F6F20D5?docId=WO2019067961&tab=PCTDESCRIPTION&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=&recNum=7931&maxRec=74545645

Novel salts (citrate, mesylate, hydrosulfate, saccharinate and oxalate) forms of 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one, processes for their preparation and compositions comprising them are claimed. Also claimed are their use for treating diseases and conditions mediated by modulation of voltage-gated sodium channels.

Voltage-gated sodium channels are responsible for the initial phase of the action potential, which is a wave of electrical depolarisation usually initiated at the soma of the neuron and propagated along the axon to the terminals. At the terminals, the action potential triggers the influx of calcium and the release of neurotransmitter. Drugs, such as lidocaine, that block voltage-gated sodium channels are used as local anaesthetics. Other sodium channel blockers, such as lamotrigine and carbamazepine are used to treat epilepsy. In the latter case, partial inhibition of voltage-gated sodium channels reduces neuronal excitability and reduces seizure propagation. In the case of local anaesthetics, regional block of sodium channels on sensory neurons prevents the conduction of painful stimuli. A key feature of these drugs is their state-dependent mechanism of action. The drugs are thought to stabilise an inactivated conformation of the channel that is adopted rapidly after the channel opens. This inactivated state provides a refractory period before the channel returns to its resting (closed) state ready to be reactivated. As a result, state-dependent sodium channel blockers inhibit the firing of neurons at high frequency, for example in response to painful stimuli, and will help to prevent repetitive firing during periods of prolonged neuronal depolarisation that might occur, for example, during a seizure. Action potentials triggered at lower frequencies, for example in the heart, will not be significantly affected by these drugs, although the safety margin differs in each case, since at high enough concentrations each of these drugs is capable of blocking the resting or open states of the channels.

The voltage-gated sodium channel family is made up of 9 subtypes, four of which are found in the brain, NaV1.1 , 1.2, 1.3 and 1.6. Of the other subtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific to cardiac muscle, and NaV1.7, 1.8, and 1.9 are found

predominantly in sensory neurons. The hypothesised binding site for state-dependent sodium channel blockers is the local anaesthetic (LA) binding site in the inner vestibule of the pore on transmembrane S6 of domain IV. Critical residues are located in a highly conserved region among the different subtypes, thus presenting a challenge for the design of new subtype selective drugs. Drugs such as lidocaine, lamotrigine and carbamazepine do not distinguish between the subtypes. However, selectivity can be achieved, and can be further enhanced functionally, as a result of the different frequencies at which the channels operate.

Drugs that block voltage-gated sodium channels in a state-dependent manner are also used in the treatment of bipolar disorder, either to reduce symptoms of mania or depression, or as mood stabilisers to prevent the emergence of mood episodes. Clinical and preclinical evidence also suggests that state-dependent sodium channel blockers may help to reduce the symptoms of schizophrenia. For example, lamotrigine has been shown to reduce symptoms of psychosis induced by ketamine in healthy human volunteers, and furthermore, studies in patients suggest that the drug can augment the antipsychotic efficacy of some atypical antipsychotic drugs, such as clozapine or olanzapine. It is hypothesised that efficacy in these psychiatric disorders may result in part from a reduction of excessive glutamate release. The reduction in glutamate release is thought to be a consequence of sodium channel inhibition in key brain areas, such as the frontal cortex. However, interaction with voltage-gated calcium channels may also contribute to the efficacy of these drugs.

WO 2013/175205 (Convergence Pharmaceuticals Limited) describes (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1 ,7-diazaspiro[4.4]nonan-6-one hydrochloride, sulfuric acid salt and sulfuric acid salt hydrate which are claimed to be modulators of voltage-gated sodium channels. The object of the invention is to identify alternative salts of said compound which have advantageous properties.

Example 1

(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-

To a solution of (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1 ,7-diazaspiro[4.4]nonan-6-one (which may be prepared in accordance with the procedure described in Example 1 of WO 2013/175205) (4.45g, 0.0114 mol) dissolved in absolute ethanol (66.82 ml, 15 vol) at 45 °C was added a solution of citric acid in ethanol (1 M, 1.05 equiv. 12 ml) over a period of 2-3 minutes. The solution was aged at 45 °C for a period of 1 hour. After 30 minutes a seed of citrate salt (0.1 wt%) was added and the mixture allowed to cool over approximately 2 hours and mature for 18 hours at ambient temperature (approximately 10-15 °C). Following maturation the salt was noted to be a very thick suspension (white) that required mobilisation with 20 ml additional ethanol and a further maturation period of 2 hours at ambient temperature. Filtration was carried out under vacuum and the vessel and cake rinsed with 15 ml ethanol. The de-liquored cake was dried further in a vacuum oven at 50 °C to provide 6.0 g of crystalline white solid (91 % yield).

H NMR (400MHz, DMSO-D6): δ_Η 1.90-2.05 (2H, m), 2.10-2.20 (2H, m,), 2.20-2.30 (1 H, m), -2.50 (1 H, m, partially masked by solvent)), 2.55-2.68 (4H, m), 2.56 (3H, s), 2.79 (3H, s),

3.28-3.40 (2H, m), 4.79 (1 H, t, J= 8.0 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.03 (1 H, s), 8.45 (2H, d, J= 8.8Hz) ppm, (exchangeables not reported)

Characterisation of Example 1

The XRPD of Example 1 is presented in FIG. 1 and the DSC/TGA of Example 1 is presented in FIG. 2. The citrate salt of Example 1 displayed the following characteristics:

1 endotherm onset: 171.82°C

peak maximum: 174.55°C

There was an endotherm post the main endotherm.

There was no weight reduction until ca 168°C had been reached. The weight reduction commenced with the start of the main endotherm and coincided with the endotherm post the main endotherm which indicated that this thermal event was the onset of compound decomposition and loss of citric acid. Thermal events >220°C were due to compound decomposition.

The XPRD data in FIG. 1 demonstrated that under different extremes of humidity indicate a stable crystalline form of the citrate salt of Example 1 with no tendency to form hydrates. This is supported by DSC/TGA data in FIG. 2 which show clear transitions and no evidence of solvates.

Aqueous solubility of the citrate salt (Example 1) = 22mg/ml (25°C).

Example 2

(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one ) salt (E2)

To a solution of (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1 ,7-diazaspiro[4.4]nonan-6-one (which may be prepared in accordance with the procedure described in Example 1 of WO 2013/175205) (4.45g, 0.0114 mol) dissolved in absolute ethanol (66.82 ml, 15 vol) at 45 °C was added a solution of methanesulfonic acid in ethanol (1 M, 1.05 equiv. 12 ml) over a period of 2-3 minutes. The solution was aged at 45 °C for a period of 1 hour. After 10 minutes nucleation and gradual crystallisation was noted to afford a thick mixture. Additional ethanol was added (10 ml) to mobilise the suspension that was then allowed to cool over approximately 2 hours and mature for 18 hours at ambient temperature (approximately 10-15 °C). Following maturation the salt was noted to be a thin, mobile suspension (white) that was filtered under vacuum and the vessel and cake rinsed with 15 ml ethanol. The de-liquored cake was dried further in a vacuum oven at 50 °C to provide 4.0 g of crystalline white solid (72% yield).

H NMR (400MHz, DMSO-D6): δ_Η 2.1-2.45 (4H, m), 2.27 (3H, s), 2.50-2.75 (2H, m), 2.61 (3H, s), 2.86 (3H, s), 3.35-3.50 (2H, m), 5.20 (1 H, t, J = 8 Hz), 7.96 (2H, d, J = 8.8 Hz), 8.17 (1 H, s), 8.51 (2H, d, J = 8.4Hz), 9.45 (1 H, br), 10.16 (1 H, br) ppm.

Characterisation of Example 2

The XRPD of Example 2 is presented in FIG. 3 and the DSC/TGA of Example 2 is presented in FIG. 4. The DSC thermograph of the methanesulfonate (mesylate) (Example 2) displayed the following characteristics:

One distinct endotherm onset: 247.34°C

peak maximum: 250.34°C

The TGA thermograph showed no weight reduction until ca 250°C had been reached. The weight reduction commenced with the start of the main endotherm and indicated that this thermal event was the onset of compound decomposition. There is no evidence of entrapped solvents or water.

The XPRD data in FIG. 3 demonstrated that under different extremes of humidity indicate a stable crystalline form of the mesylate salt of Example 2 with no tendency to form hydrates. This is supported by DSC/TGA data in FIG. 4 which show clear transitions and no evidence of solvates.

Aqueous solubility of the mesylate salt (Example 2) = 65mg/ml (25°C).

Example 3

Preparation of (2R,5S)-7-methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonan-6-one hydrosulfate single crystals: 25.0 mg of (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluorome

one hydrosulfate was added to 4 mL vial. 1.000 mL of anhydrous EtOH was added, and the sample was filtered. Anhydrous hexanes were added dropwise until the solution neared the precipitation point. The vial was sealed and left undisturbed for 24 hr, after which time a crop of single crystals was evident. The sample was sent for single crystal analysis and confirmed as the anhydrous (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one hydrosulfate form (FIGs. 5A-5B).

Example 4

Preparation of (2R,5S)-7-methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonan-6-one freebase: 8.00 g of (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one hydrosulfate (JM Lot R-2017-4323 D 301) was added to a 1 L Erlenmeyer flask and suspended and stirred vigorously in 400 mL of THF. 20% K2C03 (250 mL) was added and dissolved. The mixture was transferred to 1 L sep. funnel. 100 mL EtOAc was added and the aqueous and organic layers were separated. The aqueous layer was re-extracted with 50 mL of EtOAc and the combined organics were back-extracted with brine (100 mL) and water (100 mL). Due to fairly poor separation, a significant quantity of MgSCU was required to dry the solution. The solution was reduced via Rotavap (45 °C) to -50 mL, transferred to a 100 mL RB flask, reduced down to -10 mL, transferred to 20 mL scintillation vial and continued to be reduced to a thick oil. The oil was left on the Rotavap for another hour and a “wet” solid was obtained. Loosened solids on the bottom of the vial were left on the Rotavap for 1 hr with no heat applied to obtain a chunky solid. The contents was transferred to a mortar and pestle, ground to powder and fine granules, placed back in a 20 mL scintillation vial and left on a Rotavap overnight to obtain a dry solid (5.1 g). The XRPD pattern of (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one freebase is shown in FIG. 6.

Example 5

Preparation of (2R,5S)-7-methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonan-6-one saccharinate: 199.7 mg of (2R,5S)-7-Methyl-2-(4-

methyl-6-(4-(trifluoromethyl)phenyl)pyrirnidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one free base (0.5115 mmol) was dissolved in 4.2 mL of 2-Me-THF. 98.1 mg of saccharin (0.5106 mmol) was dissolved in 4.2 mL of 2-Me-THF. Saccharin was added to the freebase, and after 15 seconds the mixture began to precipitate and solidify. 10 mL of 2-Me-THF was added and stirred at max rpm as to provide a thick white suspension in 10 min. The suspension was filtered, air dried under vacuum for 10 min on frit, then dried under a stream of nitrogen for 30 min resulting in 215 mg of white solid product. The XRPD pattern for (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one saccharinate is shown in FIG. 7.

Example 6

Preparation of (2R,5S)-7-methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,7-diazaspiro[4.4]nonan-6-one oxalate: 403 mg of (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one freebase was dissolved in 4.03 mL EtOH. 1.000 mL of this solution was added to a 4 mL vial. 23.8 mg of oxalic acid was dissolved in 1.000 mL of EtOH and added dropwise to the stirring (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one freebase solution. After 5 min, a white precipitate was evident and 2.000 mL of EtOH was added to the slurry to aid stirring. The resulting suspension was stirred overnight. The following day the suspension was filtered and dried on a frit under vacuum for 10 min yielding 106 mg of white solid. The XRPD pattern for (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one oxalate is shown in FIG. 8.

Example 7

The single crystal structural information and refinement parameters for (2R,5S)-7-Methyl-2-(4-methyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[4.4]nonan-6-one hydrosulfate are shown in Table 1.

Table 1.

Largest peak, hole / e A^-3 0.363, -0.264

The most prominent XRPD diffraction peaks were (2Θ): 7.8±0.2°, 8.1±0.2°, 12.6±0.2°, 14.3±0.2°, 16.5±0.2°, 18.5±0.2°, 19.6±0.2°, 24.8±0.2° and 25.3±0.2°.

PATENTS

US2018360833NOVEL PYRIMIDINYL-DIAZOSPIRO COMPOUNDS2018-06-27

Patent ID	Title	Submitted Date	Granted Date
US2017304303	Novel Pyrimidinyl-DiazoSpiro Compounds	2017-07-11
US9737536	Novel Pyrimidinyl-DiazoSpiro Compounds	2016-05-25	2016-09-15
US2016184306	Novel Pyrimidinyl-DiazoSpiro Compounds	2016-02-15	2016-06-30
US9309254	NOVEL COMPOUNDS	2013-05-22	2015-04-30
US9376445	NOVEL COMPOUNDS	2013-05-22	2015-06-18

////////////////BIIB-095, BIIB095, BIIB 095, PHASE 1

CC1=NC(=NC(=C1)C2=CC=C(C=C2)C(F)(F)F)C3CCC4(N3)CCN(C4=O)C

VNRX-7145

April 9, 2019 10:02 am / 1 Comment on VNRX-7145

CAS 1842399-68-1

MF C₁₉ H₂₆ B N O₇

MW 391.22

2H-1,2-Benzoxaborin-8-carboxylic acid, 3,4-dihydro-2-hydroxy-3-[(1-oxopropyl)amino]-, (2-ethyl-1-oxobutoxy)methyl ester, (3R)-

The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

VNRX-7145

PATENT

WO 2015191907

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015191907

ntibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins, cephalosporins, and carbapenems) is widely used because they have a strong bactericidal effect and low toxicity.

[0005] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as“serine” or“metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

SCHEME 1

SCHEME 2

SCHEME 3

[00390] Alternatively, (II) can be obtained by treatment of (I) with hydrochloric acid (around 3-5 Molar in dioxane) in an alcohol solvent such as methanol, ethanol, or n-butanol at a temperature between room temperature and 120 ^ºC (SCHEME 4).

SCHEME 4

SCHEME 5

EXAMPLE 62: (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid

Step 1. Synthesis of 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester.

[00540] Prepared from [(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronic acid (+) pinanediol ester and propionic acid following the procedure in Step 2 of Example 1. The crude product was purified by flash chromatography on silica gel (25-100% EtOAc/Hexane). ESI-MS m/z 486 (MH)⁺.

Step 2. Synthesis of (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid.

[00541] Prepared from 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester following the procedure described in Step 3 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 264 (MH)⁺

CLIP

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Candidate: VNRX-7145

Credit: Tien Nguyen/C&EN

Presenter: Christopher John Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamases

Disease: Resistant urinary tract infections

Reporter’s notes: Having unveiled an antibacterial candidate at last spring’s first time disclosures session, Burns was back with another, this time the molecule can be taken orally. Both VenatoRx (pronounced Ven-a-tor-ix) compounds resuscitate the activity of β-lactam drugs, which make up more than 60% of all antibiotics prescribed. Unfortunately, many bacteria have grown resistant to these antibiotics. The new compounds rescue the old antibacterials by inhibiting β-lactamases, enzymes that chew up the antibiotics. To test the activity of new β-lactamase-targeting compounds, the researchers settled on several “sentinel” bacteria strains. Then to find a candidate with oral bioavailability, the team focused on molecules with low polarity and low molecular weight. They found VNRX-7145, developed as a prodrug in which esterases in the liver clip off the tips of the molecule to reveal the active drug. VNRX-5133, disclosed at last year’s meeting, had to be delivered intravenously along with another IV-antibiotic Cefepime, and targeted serine and metallo β-lactamases. The new oral candidate VNRX-7145 inhibits serine β-lactamases with Ceftibuten as its partner. The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

////////////VNRX-7145, VNRX7145, VNRX 7145, Phase I, VenatoRx

CCC(CC)C(=O)OCOC(=O)c1cccc2C[C@H](NC(=O)CC)B(O)Oc12

Acefylline

April 9, 2019 9:54 am / 1 Comment on Acefylline

Acefylline

Molecular FormulaC₉H₁₀N₄O₄
Average mass238.200 Da

(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetic acid

1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic Acid

1,3-Dimethylxanthine-7-acetic acid

211-490-2 [EINECS]

652-37-9 [RN]

7-(Carboxymethyl)theophylline

7H-Purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-

CAS Registry Number: 652-37-9

CAS Name: 1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-acetic acid

Additional Names: carboxymethyltheophylline; 7-theophyllineacetic acid

Molecular Formula: C9H10N4O4

Molecular Weight: 238.20

Percent Composition: C 45.38%, H 4.23%, N 23.52%, O 26.87%

Literature References: Prepn: DE 352980 (1922 to E. Merck); Frdl. 14, 1320; S. M. Ride et al., Pharmazie 32, 672 (1977). Prepn of salts: J. Baisse, Bull. Soc. Chim. Fr. 1949, 769; M. Milletti, F. Virgili, Chimica 6, 394 (1951), C.A. 46, 8615h (1952). GC determn in urine: J. Zuidema, H. Hilbers, J. Chromatogr. 182, 445 (1980). HPLC determn in serum and pharmacokinetics: S. Sved et al.,Biopharm. Drug Dispos. 2, 177 (1981).

Properties: Crystals from water, mp 271°.

Melting point: mp 271°

Derivative Type: Sodium salt

CAS Registry Number: 837-27-4

Molecular Formula: C9H9N4NaO4

Molecular Weight: 260.18

Percent Composition: C 41.55%, H 3.49%, N 21.53%, Na 8.84%, O 24.60%

Properties: Silky needles, mp >300°.

Melting point: mp >300°

Derivative Type: Compd with piperazine

Additional Names: Acefylline piperazine; acepifylline

Trademarks: Dynaphylline (Welcker-Lyster); Etaphylline (Delalande); Etafillina (Delalande)

Properties: Undefined mixture of the 1:1 and 2:1 salts; contains 75-78% theophylline acetic acid and 22-25% anhydrous piperazine.

Therap-Cat: Bronchodilator.

Keywords: Bronchodilator; Xanthine Derivatives.

Acefylline (INN),^[1] also known as acetyloxytheophylline, is a stimulant drug of the xanthine chemical class. It acts as an adenosine receptor antagonist. It is combined with diphenhydramine in the pharmaceutical preparation etanautine to help offset diphenhydramine induced drowsiness.^[2]

Synthesis

DE 352980 (1922 to E. Merck); Frdl. 14, 1320; S. M. Ride et al., Pharmazie 32, 672 (1977).

Acefylline

Use:cardiotonic, diuretic, antispasmodic, bronchodilator
Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid
Formula:C₉H₁₀N₄O₄

MW:238.20 g/mol
CAS-RN:652-37-9
EINECS:211-490-2
LD₅₀:1180 mg/kg (M, i.p.); 2733 mg/kg (M, p.o.)

Acepifylline

Use:
Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with piperazine
Formula:C₉H₁₀N₄O₄ • xC₄H₁₀N₂

MW:unspecified
CAS-RN:18833-13-1
EINECS:242-614-3

Acefylline heptaminol

Use:
Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with 6-amino-2-methyl-2-heptaminol (1:1)
Formula:C₉H₁₀N₄O₃ • C₈H₁₉NO

MW:367.45 g/mol
CAS-RN:59989-20-7
EINECS:262-012-4

References

^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 21” (PDF). World Health Organization. Retrieved 29 December 2016.
^ Zuidema, Jan. (1978). “Biofarmaceutische en farmacokinetische aspecten van theofylline en acefylline”. Thesis (doctoral)–Universiteit van Amsterdam. References

Baisse, J.: Bull. Soc. Chim. Fr. (BSCFAS) 1949, 769.

DE 352 980 (E. Merck; 1922).

Acefylline
Clinical data


ATC code	R03DA09 (WHO) (acefylline piperazine)
Identifiers
IUPAC name [show]
CAS Number	652-37-9
PubChemCID	69550
ChemSpider	62754
UNII	M494UE2YEP
ChEMBL	ChEMBL70246
ECHA InfoCard	100.010.447
Chemical and physical data
Formula	C₉H₁₀N₄O₄
Molar mass	238.20 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C2N(c1ncn(c1C(=O)N2C)CC(=O)O)C
InChI [hide] InChI=1S/C9H10N4O4/c1-11-7-6(8(16)12(2)9(11)17)13(4-10-7)3-5(14)15/h4H,3H2,1-2H3,(H,14,15) Key:HCYFGRCYSCXKNQ-UHFFFAOYSA-N

////////Acefylline

LHC 165

April 8, 2019 10:10 am / Leave a comment

LHC165

3-[5-amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]benzo[f][1,7]naphthyridin-8-yl]propanoic acid

C₂₉H₃₂F₂N₃O₇P, 603.56 g/mol

CAS 1258595-14-0

5-Amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]benzo[f][1,7]naphthyridine-8-propanoic acid

Benzo[f][1,7]naphthyridine-8-propanoic acid, 5-amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]-

Originator Novartis
Class Antineoplastics
Mechanism of Action
Undefined mechanism

Phase I Solid tumours

31 Jan 2018 Phase-I clinical trials in Solid tumours (Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Belgium, Italy, Japan (Intratumoural) (NCT03301896)
31 Jan 2018 Phase-I clinical trials in Solid tumours (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater) in USA, Japan, Italy, Belgium (Intratumoural) (NCT03301896)
10 Oct 2017 Novartis plans a phase I trial for Solid tumours (Monotherapy, Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Belgium, Canada, France, Germany, Italy, South Korea and Spain in November 2017 (Intratumoural) (NCT03301896)

PATENT

WO 2010144734

PATENT

US 20110053893

PATENT

WO 2011130379

PATENT

WO 2011027222

Scheme (III)

Scheme (IV)

Scheme (V)

Example 19 (Table 1: Compound 19): Synthesis of ^‘3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1, 7]naphthyridin-8-yl)propanoic acid (19)

Scheme 6

Step 1: (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3)

[517] To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K₂C0₃ (2.0 equiv.). The reaction was degassed and flushed with N , then added (E)-ethyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The reaction was flushed again with N₂ and stirred at 100 °C overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1 : 1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid.

Step 2: ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4)

[518] To a solution of (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) (1.0 equiv.) in ethyl acetate/ethanol (1 : 1 , 0.3 M) was added Wilkinson’s catalyst (0.10 equiv.).

Hydrogen gas was introduced via a ballon, and the reaction was stirred at room temperature for 24 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated in vacuo and purified by Combiflash using 0-10% ethyl acetate in hexane to give ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) as a solid.

Step 3: ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5)

[519] A solution of ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) (1 .0 equiv.), 4,4,4^,,4′,5,5,5′,5′-octamethyl-2,2′-bi(l ,3,2-dioxaborolane) (2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.20 equiv.), and potassium acetate (2.0 equiv.) in 1 ,4-dioxane (0.2 M) was degassed and stirred at 100 °C overnight. After cooling to ambient temperature, the reaction content was concentrated in vacuo. The crude material was purified by Combiflash using 0-50% ethyl acetate in hexane to afford ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5) as a brown oil. The product was stored at -20°C and used within a month of synthesis.

Step 4: l-bromo-4-(methoxymethoxy)-2-methylbenzene (6-7)

[520] To a solution of 4-bromo-3-methylphenol (6-6) (1.0 equiv.) in DMF (0.5 M) at 0 °C was added portionwise 60% wt NaH (1.5 equiv.). The addition was controlled such that internal reaction temperature never went above 10 °C. The reaction was stirred at room temperature for 45 minutes, then a solution of chloro(methoxy)methane (1.2 equiv.) in DMF (3 M) was added dropwise via additional funnel. The reaction was stirred at room temperature for 3.5 hours, and then quenched by pouring into ice. The resulting mixture was stirred at room temperature for 1 hour. Ether was added, and the two layers were separated. The aqueous layer was extracted (lx) with ether. The combined organic layers were washed with water (2x), brine, dried over MgS0₄, and concentrated to give 1 -bromo-4-(methoxymethoxy)-2-methylbenzene (6-7) as a colorless oil. The crude material was used in the next step without further purification.

Step 5: triethylf (4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane

[521] A solution of l -bromo-4-(methoxymethoxy)-2-methylbenzene (1.0 equiv.), triethylamine (5.0 equiv.) in DMF (0.5 M) was degassed and flushed with nitrogen. To the reaction was added TES-acetylene (1.05 equiv.), Cul (0.098 equiv.), and Pd(PPh₃)₂Cl₂ (0.098 equiv.). The reaction was heated to 60 °C and stirred overnight. After cooling to room temperature, water and ether were added. The layers were separated, and the organic layer was washed with water (2x). The organic layer was separated and passed through a pad of silica (packed with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated to give triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane as a black oil. The crude material was used in the next step without further purification.

Step 6: l-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8)

[522] To a solution of triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane (1.0 equiv.) at

0 °C was slowly added tetrabutylammonium fluoride (1M solution in THF, 0.20 equiv.). At this

point, the ice-bath was removed and the reaction mixture was allowed to stir at room temperature for 45 minutes. The reaction mixture was then passed through a pad of silica (packed with hexane) and eluted with 20% EtOAc in Hexanes to remove insoluble salts. The crude product was then purified by Combiflash using 0-10% EtOAc in Hexanes to give 1 -ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) as a slightly brown liquid.

Step 7: 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10)

[523] A solution of l -ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1 .0 equiv.), 3,5-dichloropicolinonitrile (6-9) (0.90 equiv.), Cul (0.10 equiv.), and Pd(PPh₃)₂CI₂ (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60 °C and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2x). The combined organic layers were washed with 10% aq NH₄OH (2x), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0- 10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.

Step 8: ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-ben∑o fJfl, 7J

naphthyridin-8-yl)propanoate (6-11)

[524] A solution of 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) (1 .0 equiv.), ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5) (1.25 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.10 equiv.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.20 equiv.), and sodium bicarbonate (3.0 equiv.) in «-butanol /H₂0 (5: 1 , 0.2 M) was degassed and stirred at 100 °C overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS0₄, and concentrated in vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (1SCO) using 0-40% ethyl acetate in DCM first to remove the impurity, then 0-4% MeOH in DCM to give ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][l ,7]naphthyridin-8-yl) propanoate (6-11). Further purification was accomplished by precipitating and washing in hot ether.

Step 9: ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[fl[l ]naphthyridin-8-yl)propanoate (6-12)

[525] A solution of ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-11) (1.0 equiv.) in EtOH/THF (3: 1 , 0.16 M) was flushed with nitrogen. Then, 10% wt Pd/C (0.20 equiv. by weight) was added. The reaction was flushed with hydrogen (2x) and stirred under a hydrogen balloon. After 24 hours, the reaction was filtered through a pad of celite, washing with 5%MeOH in DCM. The filtrate was checked for the presence of starting material using LCMS. The hydrogenation reaction was repeated until no more

of the alkyne starting material or alkene intermediate was detected. The crude product was purified by Combiflash using 0-4% eOH in DCM to give ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-12) as a white solid.

Step 10: ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fl[l ]naphthyridin-8-yl)propanoate (6-13)

[526] Ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[fJ[l ,7]naphthyridin-8-yl)propanoate (6-12) (1 .0 equiv.) was dissolved in EtOH (0.2 M), then added a solution of 4M HC1 in dioxane (0.2 M). The product precipitated out as a yellow salt. After stirring for 3 hours, the reaction was poured into a stirring solution of ether. The mixture was stirred for 10 minutes, then filtered and washed with ether. Ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fJ[l ,7]naphthyridin-8-yl)propanoate (6-13) was obtained as a yellow solid which was dried on vacuum overnight (bis-HCl salt). Alternatively, the crude product was purified by Combiflash using 0-5% MeOH in DCM to give the free base.

Step 11: ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f] [1 , 7]naphthyridin-8-yl)propanoate ( 6-15)

[527] To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fJ [ l ,7]naphthyridin-8-yl)propanoate (6-13) (1.0 equiv.) dissolved in DMF (0.14 M) was added a solution of diethyl 3-(2-bromoethoxy)-l ,l -difluoropropylphosphonate (6-14: described in Example 7 – Step 1) (1 .3 equiv.) in DMF (0.7 M) and cesium carbonate (4 equiv.). The reaction was stirred at 60 °C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5%MeOH in DCM to give ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[fJ

[1 ,7]naphthyridin-8-yl)propanoate (6-15) as an oil which upon standing became a white solid.

Step 12: 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphompropoxy)ethoxy)-2-methylphenethyl)be o[f]

[1, 7]naphthyridin-8-yl)propanoic acid (19)

[528] To a solution of ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-15) (1.0 equiv.) in DCM (0.16 M) at 0 °C was added slowly TMSBr (10 equiv.). The reaction was stirred at room temperature overnight. Additional TMSBr (5.0 equiv.) was added at 0 °C, and the reaction was again stirred at room temperature overnight. The solvent was removed by evaporation and the crude orange solids dried on hi-vac briefly. The solids were suspended in EtOH (0.5 M) and added 2.5 N

NaOH (10.0 equiv.). The reaction was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 9 to 10 and directly purified on RP-HPLC using a CI 8 column, eluting with 10-40% 95:5 (MeCN/5mM NH₄OAc) in l OmM NH₄OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo. The resulting white gel was dissolved in refluxing 1 :1 EtOH/water (0.04 M) with the addition of a few drops of ammonium hydroxide. While hot, the mixture was slowly poured into a stirring hot solution of acetone (0.009

M) preheated at 50 °C. The acetone suspension was slowly cooled to room temperature for 15 minutes with continued stirring, and then sat in an ice bath for 10 minutes. The solids were filtered and washed successively with acetone (2x) and ether (2x). The solids were dried on hi-vac overnight to give the 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [fj[l ,7]naphthyridin-8-yl)propanoic acid (19) as a solid. Ή NMR (Dimethylsulfoxide-d6): δ 9.02 (s, 1 H), 8.82 (s, 1H), 8.55 (d, 1H, J = 8.4 Hz), 7.58 (s, 1H), 7.48 (d, 1 H, J = 8.4 Hz), 7.07 (d, 1H, J = 8.4 Hz), 6.75 (s, 1 H), 6.68 (d, 1H, J = 8.4 Hz), 4.03-4.00 (m, 2H), 3.72-3.68 (m, 4H), 3.16-3.12 (m, 2H), 3.03-2.96 (m, 4H), 2.67-2.64 (m, 2H), 2.33-2.32 (m, 2H), 2.26 (s, 3H). LRMS [M+H] = 604.2

PATENT

US 20120237546

PATENT

WO 2012031140

PATENT

WO 2018211453

Toll-like receptors (TLRs) are pattern recognition receptors which play an essential role in the innate immunity, by recognizing invasion of microbial pathogens and initiating intracellular signal transduction pathways to trigger expression of genes, the products of which can control innate immune responses. Specifically, Toll like receptor (TLR) agonists activate innate immune cells through the TLR-MyD88-NFk and IRF3/7 pathways. TLR7, TLR8, and TLR9 belong to a subfamily of TLRs based on their genomic structure, sequence similarities, and homology. TLR7, TLR8, and TLR9 are located in intracellular endolysosomal compartments and show a unique pattern of cell type-specific expression that is thought to be responsible for different pathogen response profiles.

Small molecule agonists of TLR7 and/or TLR8 have been reported and shown to activate innate immune responses by inducing selected cytokine biosynthesis, the induction of co-stimulatory molecules, and by increased antigen-presenting capacity. Such compounds include imidazoquinoline amine derivatives (U.S. Patent No. 4689338), imidazopyridine amine derivative (U.S. Patent No. 5446153), imidazonaphthyridine derivative (U.S. Patent No.

6194425), oxazoloquinoline amine derivatives (U.S. Patent No. 61 10929); thiazoloquinoline amine derivatives (U.S. Patent No. 61 10929), selenazoloquinoline amine derivatives (U.S. Patent No. 61 10929), pyrazolopyridine derivatives (U.S. Patent No. 9145410), and

benzonaphthyridine amine derivatives (U.S. Patent Nos. 8466167 and 9045470).

The synthetic TLR7 agonist, Imiquimod (1 -(2-methylpropyl)-1 H-imidazo[ 4,5-c]quinolin-4-amine) is FDA-approved in a cream formulation for the topical treatment of cutaneous basal cell carcinoma, actinic keratosis and genital warts, and has limited activity against cutaneous melanoma and breast tumors (J. Immunol. 2014, 193(9) : 4722^1-731 ). Systemic administration of Imiquimod, and structurally similar Resiquimod, is limited by cytokine- mediated adverse effects including severe flu-like symptoms (Expert Opin. Emerging Drugs (2010), 15:544-555). Consequently, Imiquimod is used exclusively in topical applications and is not used to treat deep, non-cutaneous tumors such as melanoma or solid tumors.

An injectable lipid modified imidazoquinoline (TLR7/8 dual agonist) that forms a tissue depot with gradual, sustained release which allows for local TLR triggering activity without systemic cytokine release has been reported (J. Immunol. 2014, 193(9): 4722^731 ). However, this compound was shown to be ineffective for large tumors and in addition the serum concentration of this compound 24 hours post subcutaneous administration decreased by approximately 50% (Journal for ImmunoTherapy of Cancer, 2014, 2:12). Therefore, there remains a need for intratumor administration of a TLR7 agonist with prolonged sustained release, which may benefit the treatment of large tumors.

clip

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Candidate: LHC165

Credit: Tien Nguyen/C&EN

Presenter: Alex Cortez, senior Investigator I at the Genomics Institute of the Novartis Research Foundation

Target: Toll-like receptor 7 (TLR7)

Disease: Solid tumors

Reporter’s notes: Cortez shared another story in the realm of immuno-oncology, although the program that yielded this compound actually started in the world of vaccines. Cortez’s team had been focusing on vaccine adjuvants, small molecules that turn on the immune system to enhance a vaccine’s effect. They developed one such class of compound that activates toll-like receptor 7 (TLR7), a protein in the immune system that recognizes dangerous-looking molecules and can trigger the release of infection-clearing proteins. After observing TLR7 agonists’ ability to induce an immune response with vaccines, the researchers wondered whether the molecules could also be effective in immuno-oncology.

They found that LHC165 adsorbed to aluminum hydroxide reduced tumor growth in mice and, intriguingly, showed signs of an abscopal effect, in which untreated tumors shrink concurrently with treated tumors. The implication is that if the immune system recognizes one tumor site, it can recognize others. As with several of the candidates presented throughout the day, LHC165 bears a phosphate group and is injected into the tumor. It’s currently in Phase I trials in patients with advanced malignancies, which means they’ve already tried second and third line therapies, as a single agent and in combination with the checkpoint inhibitor PDR001.

US9618508FLOW CYTOMETRY ANALYSIS OF MATERIALS ADSORBED TO METAL SALTS2011-12-142013-12-12

US2014112950COMBINATION VACCINES WITH LOWER DOSES OF ANTIGEN AND/OR ADJUVANT2012-03-022014-04-24

Patent ID	Title	Submitted Date	Granted Date
US9597326	BENZONAPTHYRIDINE COMPOSITIONS AND USES THEREOF	2011-04-13	2013-05-16
US9950062	COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS	2010-09-01	2012-09-20
US9517263	BENZONAPHTHYRIDINE-CONTAINING VACCINES	2010-06-10	2012-10-18
US2015225432	COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS	2015-04-24	2015-08-13
US9315530	ADSORPTION OF IMMUNOPOTENTIATORS TO INSOLUBLE METAL SALTS	2011-09-01

Patent ID	Title	Submitted Date	Granted Date
US2016213776	ADSORPTION OF IMMUNOPOTENTIATORS TO INSOLUBLE METAL SALTS	2016-04-07	2016-07-28
US2012177681	Formulation of immunopotentiators	2011-09-01	2012-07-12
US9045470	COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS	2011-03-03
US2018169204	COMBINATION VACCINES WITH LOWER DOSES OF ANTIGEN AND/OR ADJUVANT	2018-02-02
US9375471	ADJUVANTED FORMULATIONS OF BOOSTER VACCINES	2013-03-08	2013-09-12

//////LHC165, LHC 165, LHC -165, Phase I, Solid tumours, novartis

O=P(O)(O)C(F)(F)CCOCCOc4ccc(CCc1cc2c3ccc(CCC(=O)O)cc3nc(N)c2nc1)c(C)c4

CC1=C(C=CC(=C1)OCCOCCC(F)(F)P(=O)(O)O)CCC2=CN=C3C(=C2)C4=C(C=C(C=C4)CCC(=O)O)N=C3N

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AB 680

April 8, 2019 10:04 am / Leave a comment

AB 680

C₂₀H₂₄ClFN₄O₉P₂, 580.827 g/mol

Cas 2105904-82-1

1H-Pyrazolo[3,4-b]pyridin-4-amine, 6-chloro-N-[(1S)-1-(2-fluorophenyl)ethyl]-1-[5-O-[hydroxy(phosphonomethyl)phosphinyl]-β-D-ribofuranosyl]-

[[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1S)-1-(2-fluorophenyl)ethyl]amino]pyrazolo[3,4-b]pyridin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid

[({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid

Originator C
Class Antineoplastics; Small molecules
Mechanism of Action 5-nucleotidase inhibitors; Adenosine A2 receptor antagonists

Phase I Cancer

19 Nov 2018 Arcus Biosciences plans to initiate a clinical trial in Cancer in first half of 2019
16 Oct 2018 Phase-I clinical trials in Cancer (In volunteers) in Australia (IV) (NCT03677973)
30 Sep 2018 Preclinical pharmacodynamics data in Cancer presented at 4th CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CRI-CIMT-EATI-AACR – 2018)

Clip

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Credit: Tien Nguyen/C&EN

Presenter: Kenneth V. Lawson, senior scientist at Arcus Biosciences

Target: Ecto-5’-nucleotidase (CD73)

Disease: Cancer

Reporter’s notes: In the first talk of the day, Lawson introduced the idea of cancer drugs that target the host’s immune system. “Checkpoint inhibitors changed the way we think of treating cancer,” he said. These drugs successfully disrupt the binding interaction between a protein and a checkpoint protein that stops immune T cells from killing cancer cells. As a result, these drugs turn immune cells loose to attack tumor cells. But the drugs work only in about 30-40% of patients—an issue pharmaceutical companies like Arcus hope to address with new immunotherapies that can be taken in combination with checkpoint inhibitors.

Lawson’s team set out to inhibit an enzyme commonly found in tumors called CD73, the second of two enzymes which break down extracellular adenosine trisphosphate (ATP) to adenosine. Adenosine then binds to immunosuppressive receptors on immune cells and shuts them down. Yet developing a small molecule inhibitor of CD73 proved challenging, Lawson said. After striking out with high-throughput screening, the team turned to CD73’s natural substrate for inspiration. However, the molecule possessed more than one phosphate group, which is notoriously a liability for drug molecules because small molecules with such negative changes struggle to cross cell membranes. The team’s goal was to remove the phosphate groups, Lawson says, but things didn’t exactly go according to plan. After showing the audience a series of compounds from structure-activity relationship (SAR) studies—slides no medicinal chemistry talk would be complete without—Lawson revealed the structure of their final clinical compound AB680 as the sound of people flipping notebook sheets rippled across the room. Synthesized in 34% overall yield, the candidate ultimately included two phosphate groups—a feature that surprised audience members.

Tests revealed that AB680 can be given intravenously but the compound also showed moderate oral bioavailability. Lawson suggested a possible route for how the molecule might pass from the digestive tract to the bloodstream, a paracellular mechanism by which molecules cross the epithelium by passing through the space between cells. AB680 showed “extraordinary potency,” inhibiting CD73 in human T-cells at a concentration of 0.008 nM. The compound has a 4 day half-life, which means it could be dosed every two weeks, coinciding with the dosing schedule for patients who receive a checkpoint inhibitor. AB680 is currently in Phase 1 clinical trials with healthy patients.

PATENT

US2017267710

https://patentscope.wipo.int/search/en/detail.jsf?docId=US204141996&tab=PCTDESCRIPTION&maxRec=1000

Purinergic signaling, a type of extracellular signaling mediated by purine nucleotides and nucleosides such as ATP and adenosine, involves the activation of purinergic receptors in the cell and/or in nearby cells, resulting in the regulation of cellular functions. Most cells have the ability to release nucleotides, which generally occurs via regulated exocytosis (see Praetorius, H. A.; Leipziger, J. (1 Mar. 2010) Ann Rev Physiology 72(1): 377-393). The released nucleotides can then be hydrolyzed extracellularly by a variety of cellular membrane-bound enzymes referred to as ectonucleotidases.

Ectonucleotides catalyze the conversion of ATP to adenosine, an endogenous modulator that impacts multiple systems, including the immune system, the cardiovascular system, the central nervous system, and the respiratory system. Adenosine also promotes fibrosis in a variety of tissues. In the first step of the production of adenosine, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as CD39 (Cluster of Differentiation 39), hydrolyzes ATP to ADP, and then ADP to AMP. In the next step, AMP is converted to adenosine by 5′-nucleotidase, ecto (NT5E or 5NT), also known as CD73 (Cluster of Differentiation 73).

The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to various cells (e.g., immune cells). Alteration of these enzymatic activities can change the course or dictate the outcome of several pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury, suggesting that these ecto-enzymes represent novel therapeutic targets for managing a variety of disorders.

CD73 inhibition with monoclonal antibodies, siRNA, or small molecules delays tumor growth and metastasis (Stagg, J. (2010) PNAS U.S.A. 107:1547-52). For example, anti-CD73 antibody therapy was shown to inhibit breast tumor growth and metastasis in animal models (Stagg, J. (26 Jan. 2010) PNAS U.S.A, 107(4):1547-52). In addition, the use of antibodies that specifically bind CD73 has been evaluated for the treatment of bleeding disorders (e.g., hemophilia) (U.S. Pat. No. 9,090,697). Recently, there have been several efforts to develop therapeutically useful CD73 small molecule inhibitors. For example, Bhattarai et al. ((2015) J Med Chem 58:6248-63) have studied derivatives and analogs of α,β-Methylene-ADP (AOPCP), one of the most metabolically stable, potent and selective CD73 inhibitors known, and purine CD73 derivatives have been reported in the patent literature (WO 2015/164573). However, the development of small molecules has been hampered due to, for example, less than ideal metabolic stability.

In view of the role played by CD73 in cancer, as well as a diverse array of other diseases, disorders and conditions, and the current lack of CD73 inhibitors available to medical practitioners, new CD73 inhibitors, and compositions and methods associated therewith, are needed.

Example 92

Synthesis of [({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid

The title compound was synthesized in similar fashion to Example 87. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.28-9.15 (m, 1H), 8.33 (dd, J=1.5, 0.7 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.29 (dd, J=7.8, 5.6 Hz, 1H), 7.23-7.08 (m, 2H), 6.00 (d, J=4.2 Hz, 1H), 5.65-5.51 (m, 1H), 4.48 (t, J=4.9 Hz, 1H), 4.26 (t, J=4.5 Hz, 1H), 4.05 (dq, J=10.1, 5.9, 5.2 Hz, 2H), 3.88 (dt, J=11.3, 6.0 Hz, 1H), 2.29-2.08 (t, J=20.4 Hz, 2H), 1.53 (d, J=6.8 Hz, 3H). ESI MS [M+H] ⁺ for C ₁₉H₂₄ClFN ₅O ₉P ₂, calcd 582.1. found 582.1.

PATENT

WO 2017120508

////////////////ARCUS, AB 680, AB680, AB-680, PHASE 1

https://www.arcusbio.com/wp-content/uploads/2018/04/AACR_AB680_1756_final_90x42-abstract-4886.pdf

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Fc1ccccc1[C@H](C)Nc4cc(Cl)nc3c4cnn3[C@@H]2O[C@H](COP(=O)(O)CP(=O)(O)O)[C@@H](O)[C@H]2O

CC(C1=CC=CC=C1F)NC2=CC(=NC3=C2C=NN3C4C(C(C(O4)COP(=O)(CP(=O)(O)O)O)O)O)Cl

Solriamfetol hydrochloride, ソルリアムフェトル塩酸塩 , солриамфетол , سولريامفيتول , 索安非托 ,

April 6, 2019 1:20 pm / Leave a comment

2D chemical structure of 178429-65-7

Solriamfetol hydrochloride

FDA APPROVED 2019/3/20, Sunosi

ソルリアムフェトル塩酸塩; R228060, R 228060

Formula	C10H14N2O2. HCl
CAS	178429-65-7 HCL
Mol weight	230.6913

(2R)-2-Amino-3-phenylpropyl carbamate

(2R)-2-Amino-3-phenylpropylcarbamat

10117

178429-62-4 [RN] FREE FORM

Benzenepropanol, β-amino-, carbamate (ester), (βR)- [

солриамфетол [Russian] [INN]

سولريامفيتول [Arabic] [INN]

索安非托 [Chinese] [INN]

JZP-110

Originator SK Holdings

Developer Jazz Pharmaceuticals plc; SK biopharmaceuticals
Class Carbamates; Sleep disorder therapies; Small molecules
Mechanism of Action Adrenergic uptake inhibitors; Dopamine uptake inhibitors

Orphan Drug Status Yes – Narcolepsy

Registered Hypersomnia
Discontinued Depressive disorders

26 Mar 2019 Discontinued – Phase-I for Depressive disorders (Adjunctive treatment) in USA (PO) (Jazz Pharmaceuticals pipeline, March 2019)
20 Mar 2019 Registered for Hypersomnia (excessive daytime sleepiness) in patients with obstructive sleep apnoea and narcolepsy in USA (PO) – First global approval
20 Mar 2019 US FDA approves solriamfetol to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnoea(OSA)
New Drug Application (NDA): 211230
Company: JAZZ PHARMA IRELAND LTD

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Solriamfetol hydrochloride	K7RO88SP7A	178429-65-7	KAOVAAHCFNYXNJ-SBSPUUFOSA-N

Solriamfetol, sold under the brand name Sunosi, is a medication used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea.^[1]

Common side effects include headache, nausea, anxiety, and trouble sleeping.^[1] It is a norepinephrine–dopamine reuptake inhibitor(NDRI). It is derived from phenylalanine and its chemical name is (R)-2-amino-3-phenylpropylcarbamate hydrochloride.^[2]

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of 11 countries in Asia to Aerial Pharma in 2011.^[3]

History

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of 11 countries in Asia to Aerial Pharma in 2011.^[3]Aerial ran two Phase II trials of the drug in narcolepsy^[4] before selling the license to solriamfetol to Jazz in 2014; Jazz Pharmaceuticalspaid Aerial $125 million up front and will pay Aerial and SK up to $272 million in milestone payments, and will pay double digit royalties to SK.^[3]^[5]

In March 2019 the FDA accepted SK’s and Jazz’ NDA for use of solriamfetol to treat excessive sleepiness in people with narcolepsy or obstructuve sleep apnea; the drug has an orphan designation for narcolepsy.^[3]^[6]

Names

During development it has been called SKL-N05, ADX-N05, ARL-N05, and JZP-110.^[6]

Research

Solriamfetol had also been tested in animal models of depression, but as of 2017 that work had not been advanced to clinical trials.^[7]

PATENT

WO 9607637

https://patents.google.com/patent/WO1996007637A1/e

Organic alkyl carbamates have been effectively used for controlling various central nervous system (CNS) disorders. For example, U.S. Pat. Nos . 2,884,444, 2,937,119 and 3,313,697 disclose function of carbamate in CNS disorders, especially as antiepileptic and centrally acting muscle relaxant.
Phenylethylamine derivatives, one important class of therapeutical medicines useful for managing CNS diseases, have been used mainly to treat obesity, narcolepsy, minimal brain dysfunction and mild depression.
Recent design of pharmacologically useful compounds has been based on amino acids or the derivatives thereof, which is mainly attributable to the fact that many of the compounds found in biological systems come from amino acids or the derivatives thereof. In addition, in most cases, the function of a pharmaceutically useful compound is effected after it binds to an enzyme or receptor, which may trigger the regulatory mechanisms of the enzyme or receptor.

REACTION SCHEME I

REACTION SCHEME II

REACTION SCHEME III

EXAMPLE I
Preparation of N-Benzyloxycarbonyl-D-phenylalaninol

In a 500 mL RB flask equipped with a mechanical stirrer and a dropping funnel, D-phenylalaninol (45.4 g, 300 mmol) was dissolved in 220 mL of distilled water, and cooled in an ice-bath. The pH of the solution was adjusted with 50 % sodium hydroxide to 14. Benzyl chloroformate (49.3 mL, 345 mmol) was charged into the dropping funnel and added slowly to the well stirred solution over 0.5 hr. After the completion of the addition, the reaction mixture was stirred for 1 hr. at 0 ^*C. The product precipitated from the reaction mixture as a white solid. It was collected by filtration and washed completely with distilled water. After being dried in vacuo, the solid thus obtained weighed 104 grams without any further purification: 99.8% Yield.
Melting point = 90 – 92 ^*C
[α]_D²⁰ = + 43.4 (c = 1.0, EtOH)
Analysis calc: C, 71.56; H, 6.71; N,4.91
Found: C, 71.35; H, 6.71; N,4.91

EXAMPLE II
Preparation of N-Benzyloxycarbonyl-D-phenylalaninol
carbamate

In a 500 mL RB flask, N-benzyloxycarbonyl-D- phenylalaninol (13.56 g, 50 mmol) was charged with antipyrine (11.29 g, 60 mmol) in 250 mL of dry THF under a nitrogen atmosphere. The reaction mixture was cooled in an ice-bath and phosgene (30.3 mL of 1.93 M solution in toluene, 58.5 mmol) was added quickly while vigorously stirring. After stirring for 1 hr. , the formation of a corresponding chloroformate from the starting material was monitored by TLC. The chloroformate solution thus prepared, was slowly added to a well stirred and ice-chilled aqueous ammonium hydroxide solution (75 mL, 28-30 %, 1,190 mmol) via cannula over 0.5 hr. The resulting reaction mixture was stirred for an extra 0.5 hr. The organic phase separated was collected. The aqueous phase was extracted twice with methylene chloride (100 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield 17.8 g (113%) of foamy solid. It was purified a flash column chromatography to give 14.8 g of the title compound, white solid: 94% Yield.
Melting point = 121 – 125 ^*C
[α]_D²⁰ = + 28.6 (c = 2.0, EtOH)
Analysis calc. : C, 65.84; H, 6.14; N, 8.53
Found: C, 66.68; H, 6.21; N, 7.80

EXAMPLE III
Preparation of D-Phenylalaninol carbamate hydrochloric
acid salt In a 160 mL Parr reactor, N-benzyloxycarbonyl-D-phenylalaninol carbamate (9.43 g) was added with 75 mL of anhydrous methanol and 10 % palladium on charcoal (0.32 g). Then, the reactor was closed and purged with hydrogen for 1 in. The reaction was completed in 2 hrs . under 40 psi pressure of hydrogen at 45 ^#C. The catalyst was filtered off. Thereafter, the organic layer was concentrated into 5.97 g (102 %) of pale yellow thick liquid. The liquid was poured in 50 mL of anhydrous THF and cooled to 0 “C. Anhydrous hydrogen chloride gas was then purged through the solution with slowly stirring for

0.5 hr. 50 mL of anhydrous ether was added, to give a precipitate. Filtration with THF-ether (1:1) mixture provided 6.1 g of the title compound as a white solid: 88 % Yield.
Melting point = 172 – 174 “C
[α]_D²⁰ = – 12.9 (c = 2.0, H₂0)
Analysis calc. : C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.90; H, 6.60; N, 12.15; Cl ,

15.52

EXAMPLE IV
Preparation of N-benzyloxγcarbonyl-L-Phenγlalaninol

The title compound was prepared in the same manner as that of Example I, except that (L)-phenylalaninol was used as the starting material.
Melting point = 90 – 92 ^*C
[α]_D²⁰ = – 42.0 (c = 1.0, EtOH)
Analysis calc. : C, 71.56; H, 6.71; N,4.91
Found: C, 70.98; H, 6.67; N,4.95

EXAMPLE V
Preparation of -N-benzyloxycarbonyl-L-Phenylalaninol
carbamate

The title compound was prepared in the same manner as that of Example II, except that N-benzyloxycarbonyl-L-phenylalaninol was used as the starting material.
Melting point = 121 – 128 ‘C
[α]_D²⁰ = – 28.9 (c = 2.0, EtOH)
Analysis calc: C, 65.84; H, 6.14; N, 8.53
Found: C, 65.45; H, 6.15; N, 8.32

EXAMPLE VI
Preparation of L-Phenylalaninol carbamate hydrochloric
acid salt

The title compound was prepared in the same manner as that of Example III, except that N-benzyloxycarbonyl-L-phenylalaninol carbamate was used as the starting material.
Melting point = 175 – 177 ^*C [α]_D²⁰ = + 13.1 (c = 1.0, H₂0)
Analysis calc : C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.95; H, 6.58; N, 12.09; Cl , 15.37

EXAMPLE VII
Preparation of N-benzyloxycarbonyl-D,L-Phenylalaninol

The title compound was prepared in the same manner as that of Example I, except that (D,L)-phenylalaninol was used as the starting material.
Melting point = 72 – 75 ^#C
Analysis calc: C, 71.56; H, 6.71; N,4.91
Found: C, 71.37; H, 6.74; N,4.84

EXAMPLE VIII
Preparation of N-benzyloxycarbonyl-D,L-Phenylalaninol
carbamate

The title compound was prepared in the same manner as that of Example II, except that N-benzyloxycarbonyl-D,L-phenylalaninol was used as the starting material.
Melting point = 130 – 133 ^*C
Analysis calc: C, 65.84; H, 6.14; N, 8.53
Found: C, 65.85; H, 6.14; N, 8.49 EXAMPLE IX
Preparation of D,L-Phenylalaninol carbamate hydrochloric
acid salt

The title compound was prepared in the same manner as that of Example III, except that N-benzyloxycarbonyl-D,L-phenylalaninol carbamate was used as the starting material.
Melting point = 163 – 165 ^*C
Analysis calc: C, 52.60; H, 6.55; N, 12.14; Cl, 15.37
Found: C, 51.92; H, 6.56; N, 11.95; Cl , 15.82

PATENT

US 20050080268

PATENT

WO 2018133703

https://patents.google.com/patent/WO2018133703A1/en

Excessive daytime sleepiness (Excessive Daytime Sleepiness, EDS) or pathological somnolence refers to excessive daytime sleep and wakefulness associated with various sleep disorders. These disorders can be the basis for a sleep disorder or sleep have side effects caused by some other medical conditions. Excessive daytime sleep, also known as narcolepsy, sleep clinics is seen mainly in patients with disease that affects 12% of the general population. EDS patients may be manifested as mental distress, poor work or school performance, increasing the risk of accidents, the impact of EDS can debilitating, even life-threatening.

R228060, also known JZP-110, is a selective dopamine and norepinephrine reuptake inhibitor, originally developed by R & D, SK biopharmaceutical, 2014 Sir ownership of the pharmaceutical compound. R228060 has the potential to treat narcolepsy and sleep apnea syndrome, in three multi-center study in two global reached the primary endpoint, and achieved positive results, significantly improved adult obstructive sleep apnea patients excessive sleepiness in patients with narcolepsy and excessive sleep problems.

R228060 chemical name is O- carbamoyl – (D) – phenylalaninol, as shown in the structural formula of formula (I):

Solid Form different chemicals, can cause varying their solubility and stability, and thus affects the absorption and bioavailability of the drug, and can lead to differences in clinical efficacy. Improve the candidate compound has a solubility by salt way become an important means of drug development. Compared to the free form of the drug, suitable pharmaceutically acceptable salts can improve the solubility of the drug type, increased physical and chemical stability, and also to improve the drug-salt having a melting point, hygroscopicity, crystal type and other physical properties, further development of the pharmaceutical dosage form It plays an important role. Patent Document WO1996007637A1 discloses R228060 hydrochloride and its preparation method, and other characteristics of the obtained having a melting point of 172-174 deg.] C as a white solid, the solid was not given in the text data. Further, the present inventors found no other relevant R228060 hydrochloride polymorph or patent literature. Accordingly, the present need in the art to develop a comprehensive system R228060 hydrochloride polymorph, found to be suitable to the development of crystalline form. The present inventors after many experiments, found that polymorph CS1 R228060 hydrochloride CS2 and a melting point polymorph, Form CS1 and CS2 is Form 183 ℃, much higher than the melting point disclosed in prior art solid. It provides a better alternative preparation of pharmaceutical preparations containing R228060 is, has very important implications for drug development.

PATENT

WO 2019027941

https://patentscope2.wipo.int/search/en/detail.jsf;jsessionid=15B8F200BCC820C3761C600EA64A2018?docId=WO2019027941&recNum=4220&office=&queryString=&prevFilter=%26fq%3DOF%3AWO&sortOption=Pub+Date+Desc&maxRec=3471866

(i?)-2-amino-3-phenylpropyl carbamate (APC) is a phenylalanine analog that has been demonstrated to be useful in the treatment of a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, and others. See, for example, US Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290; and U.S. Publication Nos. 2012/0004300 and 2015/0018414. Methods for producing APC (which also has other names) and related compounds can be found in US Patent Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of the above patents and applications are hereby incorporated by reference in their entireties for all purposes.

EXAMPLE 1

Synthesis of Compounds

Compound 8 (110CR002)

1 B 110CR002

[0083] tert- utyl (if)-(l-(Carbamothioyloxy)-3-phenylpropan-2-yl)carbamate (IB): A

60% dispersion of sodium hydride (0.36 g, 4.78 mmol, 1.2 equiv) in mineral oil was added in portions to compound 1A (1.0 g. 3.98 mmol, 1 equiv) in THF (20 mL) at 0 °C. After stirring for 1 hour, carbon disulfide (0.191 g, 4.78 mmol, 1.2 equiv) was added at 0 °C. After an additional hour of stirring, methyl iodide (0.3 mL, 4.78 mmol, 1.2 equiv) was added and the reaction was warmed to room temperature. After stirring two additional hours, concentrated ammonium hydroxide (1.6 mL, 7.98 mmol, 2 equiv) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude compound IB. The solid was triturated in diethyl ether (20 mL) to give compound IB (0.17 g, 14% yield) as a light yellow solid.

[0084] (R)-0-(2-Amino-3-phenylpropyl) carbamothioate dihydrochloride (110CR002):

4M HCI in dioxane (0.68 mL, 2.74 mmol, 5 equiv) was added to neat compound IB (0.17 g, 0.548 mmol, 1 equiv) and the reaction was stirred overnight. The solution was diluted with diethyl ether (20 mL) and the resulting suspension was filtered. The solid was triturated in diethyl ether (20 mL) and the filtered solid was dried under vacuum at room temperature for two hours to give compound 110CR003 (140 mg, 93% yield, 96.9% purity) as a white solid.

Compound 9 (110CR003)

Scheme 2

2A 2B 110CR003

[0085] (R)-2-((ter^Butoxycarbonyl)amino)-3-phenylpropyl sulfamate (2B): A solution of sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added dropwise to a solution of compound 2 A (1.0 g, 3.98 mmol, 1 equiv) and triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) in N,N-dimethylacetamide (20 mL) at 0 °C. After stirring at room temperature for 4 hours, additional triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) and sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added at 0 °C. The reaction was stirred at room temperature overnight, at which point LCMS indicated a 3 :2 mixture of product to starting material. Additional triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) and sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added at 0 °C and the reaction was stirred at room temperature for an additional 6 hours. LCMS indicated a 4: 1 mixture of product to starting material. The reaction was quenched with saturated sodium bicarbonate (5 mL) and stirred for an additional hour at room temperature. The reaction was diluted with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The product still contained unreacted starting material which could not be easily separated. Sulfamoyl chloride (1.15 g, 9.95 mmol, 2.5 equiv) in acetonitrile (2 mL) was added dropwise to a solution of crude compound 2B (0.9 g) and triethylamine (2.1 mL, 14.95 mmol, 3.75 equiv) in N,N-dimethylacetamide (20 mL) at 0 °C. After stirring at room temperature for two hours, the reaction was quenched with saturated sodium bicarbonate (5 mL) and the reaction was stirred for an additional hour at room temperature. The reaction was diluted with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (Redisep 24 g silica gel column), eluting with a gradient of 25 to 50% ethyl acetate in heptanes, to give compound 2B (0.37 g, 28% yield) as a white solid.

[0086] (R)-2-Amino-3-phenylpropyl sulfamate hydrochloride (110CR003): 4M HC1 in dioxane (1.4 mL, 5.6 mmol, 5 equiv) was added to neat compound 2B (0.37 g, 1.12 mmol, 1 equiv) and the reaction was stirred overnight. The solution was diluted with diethyl ether (20 mL) and the resulting suspension was filtered. The solid was triturated in diethyl ether (20 mL) and the filtered solid was dried under a vacuum at room temperature for two hours to give compound 110CR003 (250 mg, 84% yield, 97.8% purity) as a white solid.

Com ound 3 (110CR007)

[0087] (Benzyl (R)-(l-phenyl-3-ureidopropan-2-yl)carbamate) (3B): Concentrated hydrochloric acid (0.06 mL, 0.68 mmol, 0.12 equiv) was added to a solution of benzyl (ft)-(l -amino-3-phenylpropan-2-yl)carbamate ( 1.5 g, 5.28 mmol, 1 equiv) and urea (1.26 g, 21.21 mmol, 4 equiv) in toluene (150 mL) under nitrogen. After refluxing overnight, LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure, diluted with water (150 mL) and stirred for 30 minutes. The resulting solid was filtered and washed with water (25 mL) to give crude compound 3B (1.4 g, 4.27 mmol, 80% yield) as a white solid, which was used sequentially.

[0088] ((R)-l-(2-mino-3-phenylpropyl)urea) (3C): Compound 3B (0.5 g, 1.5 mmol, 1 equiv) and 10% palladium on carbon (0.09 g) in methanol (60 mL) was hydrogenated at 30 psi for 1 hour at which time LC-MS determined that the reaction was incomplete. The solution was filtered and fresh catalyst (0.09 g) was added. The solution was hydrogenated at 30 psi for an additional 45 minutes resulting in complete conversion. Two identical scale reactions were run for 105 minutes each, both resulting in complete conversion. The three runs were combined and filtered through celite, which was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give crude compound 3C (0.9 g), which was used sequentially.

[0089] (R)-l-(2-Amino-3-phenylpropyI)urea hydrochloride (110CR007): Compound 3C (0.88 g, 4.58 mmol, 1 equiv) was dissolved diethyl ether (10 mL) and 4 N HCl in dioxane (2.31 mL, 9.27 mmol, 2 equiv) was added. The reaction was stirred overnight and then concentrated under reduced pressure to give crude 110CR007 as a white solid. The material was twice recrystallized from 10% methanol in ethanol (30 mL) to give 110CR007 (0.163 g, 16 % yield, 93.7 % purity) as a white solid.

Compound 4 (110CR009)

Scheme 4

[0090] Ethyl (R^)-4-((tert-butoxycarbonyI)amino)-5-phenylpent-2-enoate (4B): A solution of compound 4A (4.0 g, 16.1 mmol, 1 equiv) and ethyl (triphenylphos-phoranylidene)acetate (5.6 g, 16.1 mmol, 1 equiv) in dichloromethane (40 mL) was stirred at room temperature overnight. The reaction was concentrated under reduce pressure to remove the organic solvent and the resulting residue was purified on an AnaLogix automated system (40 g Sorbtech silica gel column), eluting with gradient of 50 to 100% ethyl acetate in heptanes, to give compound 4B (4.8 g, 94% yield) as a white solid.

[0091] (R^E)-4-((te *i-ButoxycarbonyI)amino)-5-phenylpent-2-enoic acid (4C): Lithium hydroxide (1.4 g, 60 mmol, 4 equiv) in water (15 mL) was added to compound 4B (4.8 g, 15 mmol, 1 equiv) in THF (60 mL) at room temperature and the reaction was stirred overnight. After 16 hours, the reaction was adjusted to pH 4 with IN hydrochloric acid. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers was washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give compound 4C (4.2 g, 97% yield) as a light cream solid, which was used subsequently.

[0092] Methyl (R E)-4-((½ -i-butoxycarbonyl)amino)-5-phenylpent-2-enoate (4D1):

Isobutyl chloro formate (1.3 mL, 10 mmol, 1 equiv) in THF (4 mL) was added dropwise to a solution of compound 4C (3.0 g, 10 mmol, 1 equiv) and N-methyl-morpholine (1.1 mL, 10 mmol, 1 equiv) in THF (12 mL) at -15 °C. After 30 minutes of stirring, LCMS indicated complete conversion to the anhydride intermediate. 2M Ammonia in methanol (5 mL, 10 mmol, 1 equiv) was added dropwise over 20 minutes, keeping the internal temperature between -25 to -15 °C. After 30 minutes of stirring, the reaction was warmed to room

temperature and stirred overnight. The reaction mixture was concentrated at reduced pressure to remove the organic solvent. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (80 g Sorbtech silica gel column), eluting with a gradient of 25 to 50% ethyl acetate in heptanes, to give compound 4D1 (1.1 g, 35 % yield) as a white solid.

[0093] Methyl (S)-4-((te^-butoxycarbonyl)amino)-5-phenylpentanoate (4D2): A mixture of compound 4D1 (1.1 g, 3.6 mmol, 1 equiv) and 10% palladium on carbon (0.33 g, 50% wet) in methanol (40 mL) was hydrogenated at 40 psi at room temperature for 4 hours. The mixture was filtered through celite, which was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give compound 4D2 (1.1 g, 99% yield) as a white solid.

[0094] (S)-4-((ii? i-Butoxycarbonyl)amino)-5-phenylpentanoic acid (4D3): Lithium hydroxide (73 mg, 3 mmol, 1.5 equiv) in water (1 mL) was added to compound 4B (0.6 g, 2 mmol, 1 equiv) in THF (9 mL) at room temperature. After stirring overnight, the reaction was adjusted to pH 4 with IN hydrochloric acid. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers was washed with saturated brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure to give compound 4D3 (0.56 g, 98% yield) as a white solid, which was used subsequently.

[0095] tert-Butyl (S)-(5-amino-5-oxo-l-phenylpentan-2-yl)carbamate (4E): Isobutyl chloroformate (0.23 mL, 1.8 mmol, 1 equiv) in THF (0.5 mL) was added drop-wise to a solution of compound 4C (0.54 g, 1.8 mmol, 1 equiv) and N-methylmorpholine (0.2 mL, 1.8 mmol, 1 equiv) in THF (1 mL) at -15 °C. After 20 minutes of stirring, LCMS indicated complete conversion to the anhydride intermediate. 0.4M Ammonia in THF (9 mL, 3.6 mmol, 2 equiv) was added drop-wise over 20 minutes, keeping the internal temperature between -25 to -15 °C. After 30 minutes of stirring the reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in ethyl acetate (25 mL) and washed with water (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under

reduced pressure to give compound 4E (0.5 g, 93% yield) as a white solid, which was used subsequently.

[0096] (S)-4-Amino-5-phenylpentanamide hydrochloride (110CR009): 4M HC1 in dioxane (6 mL, 25 mmol, 10 equiv) was added to compound 4E (0.73 g, 1.12 mmol, 1 equiv) After stirring overnight at room temperature, the reaction was diluted with diethyl ether (20 mL) and stirred for 6 hours. The resulting suspension was filtered and the solid was washed with diethyl ether (20 mL). The filtered solid was dried under vacuum at room temperature for two hours to give compound 110CR009 (340 mg, 60% yield, 97.9 % purity) as a white solid.

Compound 10 (110CR012)

[0097] tert-Butyl (R)-(l-(carbamoylthio)-3-phenyIpropan-2-yI)carbamate (5B):

Compound 5 A (0.15 g, 0.56 mmol, 1 equiv) was dissolved in THF (8 mL) and sparged with nitrogen for 15 minutes. Trichloroacetyl isocyanate (0.1 mL, 0.84 mmol, 1.5 equiv) was added and the solution stirred for 3 hours, at which point TLC (30% ethyl acetate in heptane) indicated absence of starting material. The reaction was cooled to 0°C and concentrated ammonium hydroxide (0.15 mL) was added. After stirring overnight at room temperature, TLC indicated that the reaction was complete. The reaction was washed with a 10% ammonium hydroxide (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified on an AnaLogix automated system (12 g silica gel column), eluting with a gradient of 0 to 30% ethyl acetate in heptane, to give compound 5B. This reaction was repeated an additional two times 0.15 g and 0.18 g). The products were to give compound 5B (0.35 g, 1.12 mmol, 62.2% yield) as a white solid.

[0098] (R)-S-(2-Amino-3-phenylpropyl) carbamothioate hydrochloride (110CR012):

Compound 5B (0.35 g, 1.12 mmol, 1 equiv) was dissolved in 4N HCI in dioxane (2 mL). The reaction was stirred for two hours and then concentrated under reduced pressure to give crude 110CR012 as a white solid. The material was triturated in diethyl ether (15 mL) to give 110CR012 (0.215 g, 78 % yield, 98.0 % purity) as a white solid.

References

^ Jump up to:^a ^b “SUNOSI™ (solriamfetol) Tablets, for Oral Use. Full Prescribing Information” (PDF). Jazz Pharmaceuticals. 2019. Retrieved 21 March2019.
^ Abad, VC; Guilleminault, C (2017). “New developments in the management of narcolepsy”. Nature and Science of Sleep. 9: 39–57. doi:10.2147/NSS.S103467. PMC 5344488. PMID 28424564.
^ Jump up to:^a ^b ^c ^d Ji-young, Sohn (5 March 2018). “SK Biopharmaceuticals’ narcolepsy drug on track to hitting US market”. The Korea Herald.
^ Sullivan, SS; Guilleminault, C (2015). “Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy”. Expert Opinion on Emerging Drugs. 20 (4): 571–82. doi:10.1517/14728214.2015.1115480. PMID 26558298.
^ Garde, Damian (January 14, 2014). “Jazz bets up to $397M on Aerial’s narcolepsy drug”. FierceBiotech.
^ Jump up to:^a ^b “Solriamfetol – Jazz Pharmaceuticals/SK Biopharmaceuticals”. AdisInsight. Retrieved 15 April 2018.
^ de Biase, S; Nilo, A; Gigli, GL; Valente, M (August 2017). “Investigational therapies for the treatment of narcolepsy”. Expert Opinion on Investigational Drugs. 26 (8): 953–963. doi:10.1080/13543784.2017.1356819. PMID 28726523.

Solriamfetol
Clinical data

Trade names	Sunosi
Synonyms	SKL-N05, ADX-N05, ARL-N05, and JZP-110; (R)-2-amino-3-phenylpropylcarbamate hydrochloride
Routes of administration	By mouth
ATC code	N06BA14 (WHO)
Pharmacokinetic data
Bioavailability	~95%
Protein binding	13.3–19.4%
Metabolism	negligible
Elimination half-life	~7.1 h
Excretion	urine (95% unchanged)
Identifiers
IUPAC name [show]
CAS Number	178429-62-4
PubChem CID	10130337
ChemSpider	8305853
UNII	939U7C91AI
KEGG	D11315
Chemical and physical data
Formula	C₁₀H₁₄N₂O₂
Molar mass	194.234 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1=CC=C(C=C1)C[C@H](COC(=O)N)N
InChI [hide] InChI=1S/C10H14N2O2/c11-9(7-14-10(12)13)6-8-4-2-1-3-5-8/h1-5,9H,6-7,11H2,(H2,12,13)/t9-/m1/s1 Key:UCTRAOBQFUDCSR-SECBINFHSA-N

///////////Solriamfetol hydrochloride, Solriamfetol, ソルリアムフェトル塩酸塩; солриамфетол , سولريامفيتول , 索安非托 , JZP-110, Orphan Drug, fda 2019, R228060, R 228060

UPDATE MAR 2022

Solriamfetol, sold under the brand name Sunosi, is a medication used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea.^[1] It is derived from d-phenylalanine and its chemical name is (R)-2-amino-3-phenylpropylcarbamate hydrochloride.^[3] It is a norepinephrine–dopamine reuptake inhibitor (NDRI). Common side effects include headache, nausea, anxiety, and trouble sleeping.^[1]

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of eleven countries in Asia to Aerial Pharma in 2011.^[4]

Synthetic Description

Reference: Choi, Yong-Moon; Kim, Min Woo. Process for preparing O-carbamoyl amino alcohols by treatment of amino alcohols with cyanates in the presence of acid. US 20050080268. (2005).

SYN

https://www.researchgate.net/figure/Synthesis-of-solriamfetol-173_fig37_344079894

Synthesis of solriamfetol (173)

SYN

Cite this article

Yin, Z., Hu, W., Zhang, W. et al. Tailor-made amino acid-derived pharmaceuticals approved by the FDA in 2019. Amino Acids 52, 1227–1261 (2020). https://doi.org/10.1007/s00726-020-02887-4

Solriamfetol (Sunosi™) Solriamfetol (Sunosi™) (173), formerly known as JZP-110, is a selective dopamine and norepinephrine reuptake inhibitor (DNRI) (Fig. 23). It was discovered by SK Biopharmaceuticals and developed by Jazz Pharmaceuticals (Markham 2019c). The afnity of solriamfetol for these monoamine transporters dopamine transporter (DAT, Ki=14.2 μM), norepinephrine transporter (NET, Ki=3.7 μM), and serotonin transporter (SERT, Ki=81.5 μM) was lower than that of cocaine in transfected cells and inhibits dopamine and norepinephrine reuptake with low potency (IC50=2.9 and 4.4 μM, respectively) (Baladi et al. 2018). In 2019, US FDA approved solriamfetol for using as an oral drug to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnoea (OSA). It was granted as an orphan drug (Schweitzer et al. 2019). The systematic name of solriamfetol is (R)-2-amino3-phenylpropylcarbamate hydrochloride, which contains a phenylalanine (171)-derived (R)-2-amino-3-phenylpropan1-ol (172) moiety (Fig. 23). Some alkyl carbamates have been introduced for controlling various central nervous system (CNS) disorders. Phenylethylamine derivatives are one of the important class of therapeutical medicines, useful for managing CNS diseases. After an intensive research, these two skeletons were combined to produce solriamfetol (173) as a drug for the treatment of CNS disorder, especially for depression. The compound 174 with a (S) carbon center showed almost no activity at all, which the racemic compound 175 displayed a half potency of the activity (Fig. 24) (Yang and Gao 2019; Choi and Byun 1996). Solriamfetol (173) was discovered and patented by SK Biopharmaceuticals in 1996 (Choi and Byun 1996). The synthesis of solriamfetol using (D)-phenylalaninol (176) as a starting material is highlighted in Scheme 21. (D)-Phenylalaninol (176) was frst converted to Cbz-protected D-phenylalaninol 177 by reacting with benzyl chloroformate. Carbamoylation of 177 with phosgene followed by ammonolysis with excess of concentrated ammonium hydroxide aqueous solation aforded (D)-O-carbamoyl-N-benzyloxycarbonylphenylalaninol 178. Hydrogenolysis removal of the Cbz protection group gave solriamfetol 173 which was treated

with HCl (gas) to provide (D)-O-carbamoylphenylalaninol hydrochloride salt. In 2020, the Zhang lab reported a method of Ni-catalyzehd asymmetric hydrogenation of 2-amidoacrylates for making solriamfetol (173) (Hu et al. 2020). In this method, o-methoxybenzoyl chloride reacted with glycine methyl ester hydrochloride 179 under a base condition and then hydrolysised in the presence of NaOH to aford desired o-methoxyhippuric acid 180. The one-step construction of oxazolone 181 was accomplished by cyclization and condensation of 180 with benzaldehyde in acetic anhydride and PPh3. Oxazolone 181 was then treated with MeOH and NaOMe to aford 2-amidoacrylate 182. Hydrogenation of 182 using Ni salt and ligand (S)-DM-MeO-BIPHEP gave product 183 in 92% ee. The reduction of 183 with LiBH4 followed by hydrolysised in the presence of NaOH provided intermediate (D)-phenylalaninol 184. Then, (D)-phenylalaninol 184 was reacted with NaOCN yielded solriamfetol (173) in 91% ee (Scheme 22). As a general comment related to this and other chiral compounds discussed here, we would like to emphasize the growing awareness about the Self-Disproportionation of Enantiomers (SDE) phenomenon and the problems related to accurate determination of the stereochemical outcome of enantioselective catalytic reactions (Han et al. 2018, 2019b, 2011a; Soloshonok et al. 2017; Sorochinsky et al. 2013c,

2013d). It was demonstrated that the SDE phenomenon is ubiquitous, being manifested virtually by all types of chiral compounds subjected to physicochemical phase transfer under totally achiral conditions (Han et al. 2019b; Sorochinsky et al. 2013c, d). One of the most frequent cases is a separation of more and less enantiomerically enriched fractions as compared with the original enantiomeric purity of a chiral compound. Consequently, to ensure the accuracy in the %ee determination, it was suggested to perform SDE tests, in particular, under the conditions of achiral column chromatography (Soroshinsky et al. 2013c) and sublimation (Han et al. 2011a).

(Soroshinsky et al. 2013c) Sorochinsky AE, Katagiri T, Ono T, Wzorek A, Aceña JL, Soloshonok VA (2013c) Optical purifcations via self-disproportionation of enantiomers by achiral chromatography; case study of a series of α-CF3-containing secondary alcohols. Chirality 25:365–368

SYN

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name
63-91-2	C₉H₁₁NO₂	D-Phenylalanine
5267-64-1	C₉H₁₃NO	D-Phenylalaninol
75-44-5	CCl₂O	phosgene

SYN

European Journal of Medicinal Chemistry

Volume 205, 1 November 2020, 112667

Solriamfetol (Sunosi). Solriamfetol is a norepinephrine-dopamine reuptake inhibitor (NDRI) that was developed by SK Biopharmaceuticals [124]. This drug was approved by the FDA for the treatment of EDS associated with obstructive sleep apnea (OSA) and narcolepsy [125]. In 12-week Phase III trials in this patient population, solriamfetol (75 mg or 150 mg once daily) could provide significantly great improvement [126]. Furthermore, solriamfetol was evaluated in more than 900 adults with EDS, and was maintained its effect relative to placebo after six months of use. The specific mechanism is still unknown, possibly through inhibiting dopamine and norepinephrine reuptakes [127,128].

A single-step kilogram-scale synthetic approach to solriamfetol is depicted in Scheme 21 [129]. D-Phenylalaninol 136 reacted with sodium cyanate in the presence of acid to give solriamfetol (XVI) in 89% yield.

[124] P.J. Strollo, J. Hedner, N. Collop, D.G. Lorch, D. Chen, L.P. Carter, Y. Lu, L. Lee, J. Black, J.L. Pepin, S. Redline, Solriamfetol for the treatment of excessive sleepiness in OSA: a placebo-controlled randomized withdrawal study, Chest 155 (2019) 364-374.

[125] A. Markham, Solriamfetol: first global approval, Drugs 79 (2019) 785-790.

[126] A. Malhotra, C. Shapiro, J.L. Pepin, J. Hedner, M. Ahmed, N. Foldvary-Schaefer, P.J. Strollo, G. Mayer, K. Sarmiento, M. Baladi, P. Chandler, L. Lee, R. Schwab, Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea, Sleep 43 (2020) 220-230.

[127] M.J. Thorpy, C. Shapiro, G. Mayer, B.C. Corser, H. Emsellem, G. Plazzi, D. Chen, L.P. Carter, H. Wang, Y. Lu, J. Black, Y. Dauvilliers, A randomized study of solriamfetol for excessive sleepiness in narcolepsy, Ann. Neurol. 85 (2019) 359-370.

[128] P.K. Schweitzer, R. Rosenberg, G.K. Zammit, M. Gotfried, D. Chen, L.P. Carter, H. Wang, Y. Lu, J. Black, A. Malhotra, K.P. Strohl, Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3). A randomized controlled trial, Am. J. Respir. Crit. Care Med. 199 (2019) 1421-1431.

[129] Y.M. Choi, M.W. Kim, Process of preparing o-carbamoyl compounds in the presence of active amine group, 2005. WO2005033064.

Pharmacology

Pharmacodynamics

Solriamfetol is a norepinephrine–dopamine reuptake inhibitor (NDRI).^[1] It binds to the dopamine transporter and the norepinephrine transporter with affinities (K_i) of 14.2 μM and 3.7 μM, respectively).^[1] It inhibits the reuptake of dopamine and norepinephrine with IC₅₀ values of 2.9 μM and 4.4 μM, respectively.^[1] It has weak affinity for the serotonin transporter (K_i = 81.5 μM) and does not appreciably inhibit serotonin reuptake (IC₅₀ > 100 μM).^[1] Solriamfetol has no appreciable affinity for a variety of other targets, including the dopamine, serotonin, adrenergic, GABA, adenosine, histamine, orexin, benzodiazepine, and acetylcholine receptors.^[1]

Pharmacokinetics

The elimination half-life of solriamfetol is about 7.1 hours.^[1]

History

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of eleven countries in Asia to Aerial Pharma in 2011.^[4] Aerial ran two Phase II trials of the drug in narcolepsy^[5] before selling the license to solriamfetol to Jazz in 2014; Jazz Pharmaceuticals paid Aerial $125 million up front and will pay Aerial and SK up to $272 million in milestone payments, and will pay double-digit royalties to SK.^[4]^[6]

In 2019, solriamfetol was approved in the United States to improve wakefulness in adults with narcolepsy or obstructive sleep apnea (OSA).^[7]^[8] It was granted orphan drug designation.^[9]

The U.S. Food and Drug Administration (FDA) approved solriamfetol based primarily on evidence from five clinical trials (Trial 1/NCT02348593, Trial 2/NCT02348606, Trial 3/NCT02348619, Trial 4/NCT02348632, Trial 5 NCT01681121) of 622 patients with narcolepsy or obstructive sleep apnea (OSA).^[7] The trials were conducted in Canada, Europe, and the United States.^[7]

Solriamfetol was approved for medical use in the European Union in January 2020.^[2]

Society and culture

Names

During development it has been called SKL-N05, ADX-N05, ARL-N05, and JZP-110.^[10]

Legal status

In the United States, solriamfetol is a Schedule IV controlled substance,^[1] meaning that it has an accepted medical use and a low potential for abuse, but that abuse may lead to physical or psychological dependence.^[11] A prescription is required, and can only be refilled up to five times in a six-month period.^[12] In countries of the European Union, a prescription is required.^[2]

Research

A case report of solriamfetol for the treatment of attention deficit hyperactivity disorder (ADHD) exists.^[13]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “Sunosi – solriamfetol tablet, film coated”. DailyMed. 16 October 2019. Retrieved 24 November 2019.
^ Jump up to:^a ^b ^c “Sunosi EPAR”. European Medicines Agency (EMA). 12 November 2019. Retrieved 26 September 2020.
^ Abad VC, Guilleminault C (2017). “New developments in the management of narcolepsy”. Nature and Science of Sleep. 9: 39–57. doi:10.2147/NSS.S103467. PMC5344488. PMID 28424564.
^ Jump up to:^a ^b ^c Ji-young S (5 March 2018). “SK Biopharmaceuticals’ narcolepsy drug on track to hitting US market”. The Korea Herald.
^ Sullivan SS, Guilleminault C (2015). “Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy”. Expert Opinion on Emerging Drugs. 20 (4): 571–82. doi:10.1517/14728214.2015.1115480. PMID 26558298. S2CID 7951307.
^ Garde D (14 January 2014). “Jazz bets up to $397M on Aerial’s narcolepsy drug”. FierceBiotech.
^ Jump up to:^a ^b ^c “Drug Trials Snapshots: Sunosi”. U.S. Food and Drug Administration (FDA). 16 April 2019. Archived from the original on 28 September 2019. Retrieved 24 November 2019.This article incorporates text from this source, which is in the public domain.
^ “Drug Approval Package: Sunosi”. U.S. Food and Drug Administration (FDA). 29 April 2019. Retrieved 24 November 2019.This article incorporates text from this source, which is in the public domain.
^ “Solriamfetol Orphan Drug Approval”. U.S. Food and Drug Administration (FDA). Retrieved 24 November 2019.This article incorporates text from this source, which is in the public domain.
^ “Solriamfetol – Jazz Pharmaceuticals/SK Biopharmaceuticals”. AdisInsight. Retrieved 15 April 2018.
^ 21 U.S.C.§ 812 – Schedules of controlled substances
^ “Manuals – Practitioner’s Manual – Section V”. Retrieved 2014-01-07
^ Naguy A, El-Sheshaie A, Elsori DH, Alamiri B (April 2021). “Solriamfetol for attention deficit hyperactivity disorder”. CNS Spectr: 1–2. doi:10.1017/S1092852921000328. PMID 33870884.

External links

“Solriamfetol”. Drug Information Portal. U.S. National Library of Medicine.
* “Solriamfetol hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.

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N[C@@H](COC(N)=O)CC1=CC=CC=C1

DESLORATADINE, デスロラタジン

April 4, 2019 9:37 am / Leave a comment

Desloratadine

Molecular FormulaC₁₉H₁₉ClN₂
Average mass310.821 Da

100643-71-8 [RN]

5H-Benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-

7817

Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

Desloratadine (trade name Clarinex and Aerius) is a tricyclic H₁-antihistamine that is used to treat allergies. It is an active metaboliteof loratadine.

It was patented in 1984 and came into medical use in 2001.^[1]

Medical uses

Desloratadine is used to treat allergic rhinitis, nasal congestion and chronic idiopathic urticaria (hives).^[2] It is the major metabolite of loratadine and the two drugs are similar in safety and effectiveness.^[2] Desloratadine is available in many dosage forms and under many trade names worldwide.^[3]

An emerging indication for desloratadine is in the treatment of acne, as an inexpensive adjuvant to isotretinoin and possibly as maintenance therapy or monotherapy.^[4]^[5]

Side effects

The most common side-effects are fatigue, dry mouth, and headache.^[2]

Interactions

A number of drugs and other substances that are prone to interactions, such as ketoconazole, erythromycin and grapefruit juice, have shown no influence on desloratadine concentrations in the body. Desloratadine is judged to have a low potential for interactions.^[6]

Pharmacology

Pharmacodynamics

Desloratadine is a selective H₁–antihistamine which functions as an inverse agonist at the histamine H₁ receptor.^[7]

At very high doses, is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug’s action at therapeutic doses.^[8]

Pharmacokinetics

Desloratadine is well absorbed from the gut and reaches highest blood plasma concentrations after about three hours. In the bloodstream, 83 to 87% of the substance are bound to plasma proteins.^[6]

Desloratadine is metabolized to 3-hydroxydesloratadine in a three-step sequence in normal metabolizers. First, n-glucuronidation of desloratadine by UGT2B10; then, 3-hydroxylation of desloratadine N-glucuronide by CYP2C8; and finally, a non-enzymatic deconjugation of 3-hydroxydesloratadine N-glucuronide.^[9] Both desloratadine and 3-hydroxydesloratadine are eliminated via urine and feces with a half-life of 27 hours in normal metabolizers.^[6]^[10]

3-Hydroxydesloratadine, the main metabolite

It exhibits only peripheral activity since it does not readily cross the blood-brain barrier; hence, it does not normally cause drowsiness because it does not readily enter the central nervous system.^[11]

Desloratadine does not have a strong effect on a number of tested enzymes in the cytochrome P450 system. It was found to weakly inhibit CYP2B6, CYP2D6, and CYP3A4/CYP3A5, and not to inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2C19. Desloratadine was found to be a potent and relatively selective inhibitor of UGT2B10, a weak to moderate inhibitor of UGT2B17, UGT1A10, and UGT2B4, and not to inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, UGT1A7, and UGT1A8.^[9]

Pharmacogenomics

2% of Caucasian people and 18% of people from African descent are desloratadine poor metabolizers. In these people, the drug reaches threefold highest plasma concentrations six to seven hours after intake, and has a half-life of about 89 hours. However, the safety profile for these subjects is not worse than for extensive (normal) metabolizers.^[6]^[10]

Clip

https://www.beilstein-journals.org/bjoc/articles/9/265

The value of substituted 3-picoline precursors is illustrated in the synthesis of clarinex (1.22, Desloratadine, Scheme 5), a dual antagonist of platelet activating factor (PAF) and of histamine used in the treatment of allergies. This compound consists of a highly functional tricyclic core with an unsaturated linkage to a pendant piperidine ring. The picoline derivative 1.23 is first treated with two equivalents of n-butyllithium (n-BuLi) followed by alkylation with benzyl chloride to give the chain elongated adduct [27]. The tert-butylamide 1.24 is then dehydrated with phosphorous oxychloride at elevated temperatures to yield the nitrile derivative 1.25. Introduction of the piperidine ring is achieved by utilisation of the appropriately substituted Grignard reagent 1.26. A Friedel–Crafts type acylation promoted by either triflic acid or polyphosphoric acid (PPA) furnishes the tricyclic structure 1.28 which upon N-demethylation affords clarinex (1.22).

CLIP

FTIR

SYN

Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.

SYN

Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).

SYN

Syn

2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

SYN

1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

SYN

The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I), which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V). Finally, this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.

SPECTROSCOPY

[0052] Table 1, desloratadine sample IH-NMR data of the DMS0_d6

[0055] The desloratadine 1H spectra of the samples were assigned:
[0056] (I) 1H spectra show that there are 10 groups of hydrogen from low field to high field integral hydrogen ratio was 1: 1: 1: 1: 1: 1: 2: 4:
2: 4, and desloratadine structure match.
[0057] (2) δ 8.334 处 hydrogen as a set of double doublet, number of protons is I, attributed to two hydrogen;
[0058] (3) δ 7.560 处 hydrogen as a set of double doublet, number of protons is I, attributed to four hydrogen;
[0059] (4) δ 7.282 处 doublet hydrogen as a group, the number of protons is I, 12 attributed to hydrogen.
[0060] (5) δ 7.198 处 hydrogen as a set of double doublet, number of protons is I, 14 attributed to hydrogen;
[0061] (6) δ 7.174 处 hydrogen as a set of double doublet, number of protons is I, attributed to three hydrogen;
[0062] (7) δ 7.064 处 doublet hydrogen as a group, the number of protons is I, 15 attributed to hydrogen;
[0063] (8) δ 3.314 处 hydrogen as a group multiplet, 2 protons attributable to 10 hydrogen;
[0064] (9) δ 2.831,2.554 hydrogen groups at multiplet, protons of 4, 18, 20, the home position is hydrogen;
[0065] (10) δ 2.819 处 hydrogen as a group multiplet, 2 protons attributable to 11 hydrogen;
[0066] (11) δ 2.108 处 hydrogen as a single peak, the number of protons is I, home to 19 active hydrogen;
[0067] (12) δ 2.205, 2.002 处 two hydrogen multiplet, protons of 4, 17, 21 bits attributed to hydrogen; [0068] From the foregoing, 1H-NMR spectrum data and the resulting product in this embodiment is of he will be loratadine same structure as the target product.

http://www.google.com/patents/CN103755682A?cl=en

References

^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 549. ISBN 9783527607495.
^ Jump up to:^a ^b ^c See S (2003). “Desloratadine for allergic rhinitis”. Am Fam Physician. 68 (10): 2015–6. PMID 14655812.
^ Drugs.com Desloratadine entry at drugs.com international Page accessed May 4, 2015
^ Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, Im M (2014). “Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study”. J Eur Acad Dermatol Venereol. 28 (12): 1654–60. doi:10.1111/jdv.12403. PMID 25081735.
^ Layton AM (2016). “Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris”. Dermatol Clin. 34 (2): 147–57. doi:10.1016/j.det.2015.11.008. PMID 27015774.
^ Jump up to:^a ^b ^c ^d “Aerius: EPAR – Product Information” (PDF). European Medicines Agency. 2017-06-07.
^ Canonica GW, Blaiss M (2011). “Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence”. World Allergy Organ J. 4 (2): 47–53. doi:10.1097/WOX.0b013e3182093e19. PMC 3500039. PMID 23268457.

Desloratadine
Clinical data


Trade names	Clarinex (US), Aerius, Dasselta, Deslordis (EU), others
AHFS/Drugs.com	Monograph
MedlinePlus	a602002
License data	EU EMA: by INN US FDA: Desloratadine
Pregnancy category	AU: B1 US: C (Risk not ruled out)
Routes of administration	Oral (tablets, solution)
ATC code	R06AX27 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy only) CA: OTC UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Rapidly absorbed
Protein binding	83 to 87%
Metabolism	UGT2B10, CYP2C8
Metabolites	3-Hydroxydesloratadine
Onset of action	within 1 hour
Elimination half-life	27 hours
Duration of action	up to 24 hours
Excretion	40% as conjugated metabolites into urine Similar amount into the feces
Identifiers
IUPAC name [show]
CAS Number	100643-71-8
PubChem CID	124087
IUPHAR/BPS	7157
DrugBank	DB00967
ChemSpider	110575
UNII	FVF865388R
KEGG	D03693
ChEBI	CHEBI:291342
ChEMBL	ChEMBL1172
ECHA InfoCard	100.166.554
Chemical and physical data
Formula	C₁₉H₁₉ClN₂
Molar mass	310.82 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Clc4cc2c(C(/c1ncccc1CC2)=C3/CCNCC3)cc4
InChI [hide] InChI=1S/C19H19ClN2/c20-16-5-6-17-15(12-16)4-3-14-2-1-9-22-19(14)18(17)13-7-10-21-11-8-13/h1-2,5-6,9,12,21H,3-4,7-8,10-11H2 Key:JAUOIFJMECXRGI-UHFFFAOYSA-N

//////////Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117

CMX-8521, CMX-521

April 3, 2019 10:17 am / Leave a comment

CMX-8521, CMX-521

MF C₁₃ H₁₇ N₅ O_{5, MW 323.30}

CAS Number 2077178-99-3

7H-Pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-2-methyl-7-β-D-ribofuranosyl-

Nucleoside analogs (oral, norovirus infection), Chimerix

Image result for chimerix

4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-methylpyrrolo[2,3-d]pyrimidine-5-carboxamide

CMX8521 is a nucleoside analog that inhibits the norovirus RNA polymerase. CMX8521 has in vitro activity against mouse and human norovirus.Where possible, Chimerix uses its lipid conjugate technology to build nucleoside-analog antivirals that are orally absorbed and have favorable tissue penetration.

CMX-8521 (presumed to be CMX-521) being developed by Chimerix for treating norovirus infection. In June 2018, a phase II efficacy trial was planned in 2019.

In January 2016, preclinical data were presented at the 34th Annual JP Morgan Healthcare Conference in San Francisco, CA. CMX-8521 had in vitro activity against mouse and human norovirus (EC50 = 2.1; CC50 = 114 microM). A 7-day non GLP toxicology/toxicokinetic study was completed in-life with no clinical or gross post mortem signs of toxicity. No off-target pharmacology was observed in vitro when screened against a panel of 87 receptors, transporters and enzymes associated with adverse pharmacology

PATENT

WO2017024310

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017024310

Scheme 1: General Synthesis of Compounds of the Invention

Scheme 2: General Synthesis of Compounds of the Invention

Example 7– Synthesis of Compound 1

[00315] Step 1 (Protocol #1): To a 100-L jacketed reactor were charged 4-amino-6- bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (3.00 kg), (3R,4R,5R)-2-acetoxy-5- ((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate (6.60 kg) and DCE (18.89 kg). Stirring was started and DBU (3.61) kg was added. Over a period of 03 h and 14 min, TMSOTf (8.01 kg) was added between 30.6 °C and 37.3 °C. IPC after 01 h and 30 min at approx.32 °C showed 4% of 4-amino-6-bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (3.00 kg),

(3R,4R,5R)-2-acetoxy-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate remaining. IPC after 03h and 16 min at approx.32 °C showed 2% 4-amino-6-bromo-2-methyl-7H- pyrrolo[2,3-d]pyrimidine-5-carbonitrile (3.00 kg), (3R,4R,5R)-2-acetoxy-5- ((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate remaining (spec:≤3%). The reaction mixture was diluted with DCM (39.81 kg) and quenched with potable water (15.02 kg) over an 11 min period between 9.5 °C and 15.6 °C. The extractive work-up (at approx.22 °C) was completed by a back extraction of the aqueous phase with DCM (19.90 kg), a wash with sat NaHCO₃ (1.3 kg NaHCO₃ in 14.9 kg potable water), a back extraction of the bicarbonate phase with DCM (19.71 kg) and a wash with brine (4.5 kg NaCl in 14.9 kg potable water). Note: the reactor was cleaned with potable water, acetone and DCM after each wash/back extraction.

[00316] The drummed organic phase containing the product was charged to the 100-L jacketed reactor through an in-line filter followed by a DCM rinse of the drum and filter with DCM (2.48 kg). The contents of the reactor were distilled to 31 L with the aid of vacuum over a period of 06 h and 04 min with a maximum temperature of 50.1 °C. At this point a thick suspension had formed. Next, over a period of 39 min, IPAc (41.88 kg) was added between 44.5 °C and 49.5 °C and the contents of the reactor were heated to 76.9 °C over a period of 01 h and 25 min. Next, the contents of the reactor were cooled to 9.9 °C over a period of 04 h and 21 min and stirred for 12 h and 26 min with a minimum temperature of 1.6 °C.

[00317] Step 1 (Protocol # 2): To a 100-L jacketed reactor were charged 4-amino-6- bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (3.00 kg), (3R,4R,5R)-2-acetoxy-5- ((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate (6.60 kg) and DCE (18.80 kg). Stirring was started and DBU (3.59) kg was added. Over a period of 01 h and 46 min, TMSOTf (7.90 kg) was added between 30.4 °C and 34.2 °C. IPC after 02 h and 49 min at approx.34 °C showed 1% of 4-amino-6-bromo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile remaining (spec: ≤3%). The reaction mixture was diluted with DCM (40/70 kg) and quenched with potable water (14.97 kg) over an 04 min period between 9.9 °C and 18.0 °C. The extractive work-up (at approx.22 °C) was completed by a back extraction of the aqueous phase with DCM (20.34 kg), a wash with sat NaHCO₃ (1.30 kg NaHCO₃ in 14.90 kg potable water), a back extraction of the bicarbonate phase with DCM (20.65 kg) and a wash with brine (4.50 kg NaCl in 14.96 kg potable water). Note: the reactor was cleaned with potable water, acetone and DCM after each wash/back extraction.

[00318] The drummed organic phase containing the product was charged to the 100-L jacketed reactor through an in-line filter followed by a DCM rinse of the drum and filter with DCM (1.49 kg). The contents of the reactor were distilled to with the aid of vacuum over a period of 04 h and 49 min with a maximum temperature of 45.6 °C. At this point a thick suspension had formed. Next, over a period of 27 min, IPAc (41.70 kg) was added between 45.6 °C and 48.2 °C and the contents of the reactor were heated to 75.7 °C over a period of 01 h and 20 min. Next, the contents of the reactor were cooled to 9.4 °C over a period of 04 h and 15 min and stirred overnight with a minimum temperature of 2.3 °C.

[00319] Step 2: To the reactor were charged (2R,3R,4R,5R)-2-(4-amino-6-bromo-5- cyano-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4- diyl dibenzoate (10.0 kg), 10% Pd on C (Degussa, Type E101NE/W), trimethylamine (7.3 kg) and THF (44.5 kg). Hydrogen was submitted to the reactor and the mixture was stirred for 03 h and 54 min between 24.7 °C and 19.6 °C at approx.30.8 psig. IPC (HPLC) showed that

(2R,3R,4R,5R)-2-(4-amino-6-bromo-5-cyano-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate could no longer be detected.

[00320] The reaction mixture was filtered over Celite (7.2 kg) and a polish filter and the filter residue was washed with THF (5.2 kg). The combined filtrate and wash was transferred to a 100-L jacketed reactor with the aid of a THF wash (2.12 kg). The contents of the reactor were vacuum distilled with a maximum batch temperature of 30.0 °C over a period of 05 h and 38 min to a final volume of 27 L. IPA (31.48 kg) was charged over a 40 min period to the reactor between 39.7 °C and 53.2 °C. The contents of the reactor were vacuum distilled with a maximum batch temperature of 53.2 °C over a period of 03 h and 02 min to a final volume of 33 L. IPA (48.99 kg) was charged over a 43 min period to the reactor between 53.1 °C and 57.1 °C. The contents of the reactor were heated to 60.2 °C, agitated for 12 min and cooled over a period of 04 and 28 min to 5.4 °C. Cold stirring was continued for a period of 08 h and 55 min with a minimum temperature of 1.1 °C. The slurry was filtered and washed with IPA (9.41 kg, at approx.4.5 °C). The residue was dried under vacuum with a nitrogen bleed for a period of 11 h and 44 min at a maximum temperature of 44.0 °C to provide an LOD of 0.36%. Yield: 6.58 kg (73.9 %).¹H NMR confirms structure. Purity: 97.78 % (HPLC, AUC).

[00321] Step 3:

1100 g NaOH dissolved in potable water to a total volume of 1 L; ² Diluted 500 mL conc. HCl in 2 L total with potable water [00322] A solution of (2R,3R,4R,5R)-2-(4-amino-5-cyano-2-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate and THF was heated to 54 °C and the addition of 2.5 M NaOH was started. The initial addition gave a biphasic mixture and endothermic response (the temperature dropped to 50 °C) but as the addition continued a single phased, clear solution formed which was accompanied by a fast exotherm to 61 °C; the reaction temperature was maintained at 60 °C to 61 °C during the rest of the addition and for an additional 2 ½ h. IPC showed that no (2R,3R,4R,5R)-2-(4-amino-5-cyano-2-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate was left.

[00323] The reaction mixture was cooled to 21 °C and neutralized with 3 N HCl with external cooling to pH = 7.06 (Denver Instrument UB-10 pH meter equipped with a Sartorius P- P11 pH electrode, the electrode was checked with buffer solutions of pH = 4.00 and pH = 7.00); the mixture continued to cool to 8°C. The resulting neutralized mixture was distilled under vacuum with a pot temperature of 45 °C to 50 °C until the emergence of solids were observed in the pot. The suspension was cooled and stirred for 2 h at 2 °C. The beige suspension was filtered to afford a dark filtrate; the off-white residue was washed once with cold water (500 mL, 5 °C). A first LOD after 16 h gave a value of 18.73 %. HPLC) of the drying material showed the presence of 1.6% benzoate.

[00324] A brief rework study for compound 1, (containing 1.6% benzoic acid per AUC, HPLC) was executed in 10 vol of water (1 g in 10 mL):

● 3 h slurry at ambient

● 3h slurry at 50 °C

● 24 h slurry at ambient

[00325] All three experiments gave compound 1 with less than 0.1 % benzoic acid (UAC, HPLC). The slurries were fluid, were easily stirred and filtration was fast. Short term drying on the filter gave a powder-like solid indicating that a displacement wash with an organic solvent is not needed. Without wishing to be bound by theory, a loss of NMT than 1% is expected

(solubility 1 mg/mL).HPLC data for compound 1 were obtained with a method suitable for polar compounds using a Zorbax Eclipse Plus C18 column (water / ACN / TFA, 97.5 / 2.5 / 0.05). This is the same column used for steps 1 and 2.

[00326] The cold product suspension was filtered and the reactor and residue were washed with cold IPAc (approx.7.5 °C, 13.16 kg and 13.62 kg) until a colorless filtrate had been obtained. The residue was dried under vacuum and a nitrogen bleed≤ 45 °C for a period of 65 h and 19 min to an LOD of 0 %. Yield: 5.87 kg (70.7 %), ¹H NMR confirmed identity; HPLC purity 98.84% (AUC). EQUIVALENTS

[0001] The disclosure can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

PATENT

WO-2019060692

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019060692&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline forms of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and their stable hemihydrate crystalline forms (designated as Form A-G), processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating viral infection.

Viral infections can have serious adverse effects on individuals and society as a whole. In addition to fatal viral infections such as Ebola, even non-fatal infections can have serious societal and economic consequences. For example, human noroviruses (NV) are the most common cause of epidemic acute gastroenteritis worldwide with an estimated 19-21 million cases each year in the United States including 56,000-71,000 hospitalizations and 570-800 deaths (Hall et al., Emerg.Infect.Dis. 2013 Aug; 19(8): 1198-205).

[0004] 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo [2,3-d]pyrimidine-5-carboxamide (Compound 1) is an antiviral drug.

Formula 1

[0065] As used herein, “Formula I” is understood to encompass all diastereomers of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, and pharmaceutically acceptable salts and solvates thereof. The structure of Formula I is shown below:

(Formula I).

[0066] In some embodiments, a compound of Formula I can be 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (“Compound 1”), or a pharmaceutically acceptable salt solvate, or isomers (e.g., enantiomers and diastereomers) thereof. The structure of Compound 1 is shown below:

atent ID	Title	Submitted Date	Granted Date
US9701706	Pyrrolopyrimidine nucleosides and analogs thereof	2016-11-22	2017-07-11
US9708359	PYRROLOPYRIMIDINE NUCLEOSIDES AND ANALOGS THEREOF	2016-08-08
US2017253628	PYRROLOPYRIMIDINE NUCLEOSIDES AND ANALOGS THEREOF	2017-05-18

///////////CMX-8521, CMX 8521, CMX-521, PHASE 1

NC(=O)c2cn([C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c3nc(C)nc(N)c23

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Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

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Acepifylline

Acefylline heptaminol

References

Baisse, J.: Bull. Soc. Chim. Fr. (BSCFAS) 1949, 769.

DE 352 980 (E. Merck; 1922).

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Example 92

Synthesis of [({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid

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