Fluorinated compounds in medicinal chemistry: Recent applications, synthetic advances and matched-pair analyses

Current Topics in Medicinal Chemistry

Volumn 14, Issue 7, 2014, Pages 855-864

  Barnes Seeman, David ^a   Beck, Jeremy ^a   Springer, Clayton ^a  

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Difluoroalkyl; Fluorine; Matched pairs analysis; Metabolic stability; Pentafluorosulfanyl; Trifluoromethylcyclopropyl

Indexed keywords

1 TRIFLUOROMETHYLCYCLOPROPYL; 1,1 DIMETHYL 2,2,2 TRIFLUOROETHYL; 2 TRIFLUOROMETHYLCYCLOPROPYL; ANTIBODY CONJUGATE; ARYLDIFLUOROPHOSPHONATE; BOMBESIN ANTAGONIST; CAMPTOTHECIN; CANNABINOID RECEPTOR ANTAGONIST; CYCLIN DEPENDENT KINASE 9 INHIBITOR; DHODH INHIBITOR; DIFLUOROALKYL; DIFLUOROPHOSPHONATE; FARNESOID X RECEPTOR; FLUORINE DERIVATIVE; MEFLOQUINE; MK 5046; NEUROKININ 1 RECEPTOR ANTAGONIST; PENTAFLUOROSULFANYL; POLO LIKE KINASE 1; PROSTAGLANDIN E RECEPTOR 2 ANTAGONIST; PROTEIN KINASE C; PYRAZOLE; SODIUM CHANNEL NAV1.7 BLOCKER; SODIUM CHANNEL NAV1.8 INHIBITOR; TRIFLUOROMETHYL; TRIFLUOROMETHYL DIAZOMETHANE; TRIFLUOROMETHYLCYCLOPROPYL; UNCLASSIFIED DRUG; VANILLOID RECEPTOR 1 ANTAGONIST;

AEROBIC METABOLISM; CHEMICAL ANALYSIS; CYCLOPROPANATION; DRUG SOLUBILITY; FLUORINATION; HUMAN; MATCHED PAIR ANALYSIS; MEDICAL RESEARCH; MEMBRANE PERMEABILITY; NONHUMAN; PLASMODIUM FALCIPARUM; PROTEIN PHOSPHORYLATION; REVIEW; STRUCTURE ACTIVITY RELATION;

CHEMISTRY, PHARMACEUTICAL; DRUG DISCOVERY; FLUORINE COMPOUNDS; HALOGENATION; HUMANS; MATCHED-PAIR ANALYSIS;

EID: 84897468587     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026614666140202204242     Document Type: Review

References (61)

1. Purser, S.; Moore, P. R.; Swallow, S; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev., 2008, 37 (2), 320-330.
2. Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature, 2011, 473, 470-477.
3. Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Direct synthesis of fluorinated heteroarylether bioisosteres. Angew. Chem. Int. Ed., 2013, 52 (14), 3949-52.
4. Fujiwara Y.; Dixon J. A.; Rodriguez R. A.; Baxter R. D.; Dixon D. D.; Collins M. R.; Blackmond D. G.; Baran P. S. A new reagent for direct difluoromethylation. J. Am. Chem. Soc., 2012, 134, 1494-1497.
5. Fujiwara Y.; Dixon J. A.; O'Hara F.; Funder E. D.; Dixon D. D.; Rodriguez R. A.; Baxter R. D.; Herlé B.; Sach N.; Collins M. R.; Ishihara Y.; Baran P. S. Practical and innate carbon-hydrogen functionalization of heterocycles. Nature, 2012, 492, 95-99.
6. O'Hara F.; Blackmond D. G.; Baran P. S. Radical-based regioselective C-H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability. J. Am. Chem. Soc., 2013, 135(32), 12122-12134.
7. Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Innate C-H trifluoromethylation of heterocycles. Proc. Nat. Acad. Sci., 2011, 108(35), 14411-14415.
8. Langlois, B. R.; Laurent, E.; Roidot, N. Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. Tetrahedron Lett., 1991, 32(51), 7525-7528.
9. Nagib D. A.; MacMillan D. W. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature, 2011, 480, 224-228.
10. Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Innate and Guided C-H Functionalization Logic. Acc. Chem. Res., 2012, 45(6), 826-839.
11. Studer A. A "Renaissance" in radical trifluoromethylation. Angew. Chem. Int. Ed., 2012, 51(36), 8950-8958.
12. Duncton M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal chemists. Med. Chem. Comm., 2011, 2, 1135-1161.
13. Zhou Q.; Gui J.; Pan C. M.; Albone E.; Cheng X.; Suh E. M.; Grasso L.; Ishihara Y.; Baran P. S. Bioconjugation by native chemical tagging of C-H bonds. J. Am. Chem. Soc., 2013, 135(35), 12994-12997.
14. Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.-H.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically Stable tert-Butyl Replacement. ACS Med. Chem. Lett., 2013, 4(6), 514-516.
15. Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity. ACS Med. Chem. Lett., 2011, 2(1), 43-47.
16. Reitman, M. L.; Dishy, V.; Moreau, A.; Denney, W. S.; Liu, C.; Kraf, W. K.; Mejia, A. V.; Matson, M. A.; Stoch, S. A.; Wagner, J. A.; Lai, E. Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients. J. Clin. Pharmacol., 2012, 52(9), 1306-1316.
17. Lee, S. H.; Seo, H. J.; Lee, S.-H.; Jung, M. E.; Park, J.-H.; Park, H.-J.; Yoo, J.; Yun, H.; Na, J.; Kang, S. Y.; Song, K.-S.; Kim, M.-a.; Chang, C.-H.; Kim, J.; Lee, J. Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity. J. Med. Chem., 2008, 51 (22), 7216-7233.
18. Phillips, D. J.; Davenport, R. J.; Demaude, T. A.; Galleway, F. P.; Jones, M. W.; Knerr, L.; Perry, B. G.; Ratcliffe, A. J. Imidazopyridines as VLA-4 integrin antagonists. Bioorg. Med. Chem. Lett., 2008, 18 (14), 4146-4149.
19. Guo, C.; McAlpine, I.; Zhang, J.; Knighton, D. D.; Kephart, S.; Johnson, M. C.; Li, H.; Bouzida, D.; Yang, A.; Dong, L.; Marakovits, J.; Tikhe, J.; Richardson, P.; Guo, L. C.; Kania, R.; Edwards, M. P.; Kraynov, E.; Christensen, J.; Piraino, J.; Lee, J.; Dagostino, E.; Del-Carmen, C.; Deng, Y.-L.; Smeal, T.; Murray, B. W. Discovery of pyrroloaminopyrazoles as novel PAK inhibitors. J. Med. Chem., 2012, 55 (10), 4728-4739.
20. Lazerwith, S. E.; Bahador, G.; Canales, E.; Cheng, G.-F.; Chong, L.; Clarke, M. O.; Doerffler, E.; Eisenberg, E. J.; Hayes, J.; Lu, B.; Liu, Q.; Matles, M.; Mertzman, M.; Mitchell, M. L.; Morganelli, P.; Murray, B. P.; Robinson, M.; Strickley, R. G.; Tessler, M.; Tirunagari, N.; Wang, J.-H.; Wang, Y.-J.; Zhang, J. R.; Zheng, X.-B.; Zhong, W.-D.; Watkins, W. J. Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors. ACS Med. Chem. Lett., 2011, 2(10), 715-719.
21. Williams, B. S.; Felix, J. P.; Priest, B. T.; Brochu, R. M.; Dai, K.; Hoyt, S. B.; London, C.; Tang, Y. S.; Duffy, J. L.; Parsons, W. H.; Kaczorowski, G. J.; Garcia, M. L. Characterization of a New Class of Potent Inhibitors of the Voltage-Gated Sodium Channel Nav1. 7. Biochemistry, 2007, 46(50), 14693-14703.
22. Nielsen, F. E.; Ebdrup, S.; Jensen, A. F.; Ynddal, L.; Bodvarsdottir, T. B.; Stidsen, C.; Worsaae, A.; Boonen, H. C. M.; Arkhammar, P. O. G.; Fremming, T.; Wahl, P.; Korno, H. T.; Hansen, J. B. New 3-Alkylamino-4H-thieno-1, 2, 4-thiadiazine 1, 1-Dioxide Derivatives Activate ATP-Sensitive Potassium Channels of Pancreatic Beta Cells. J. Med. Chem., 2006, 49(14), 4127-4139.
23. Tanaka, H.; Shishido, Y. Synthesis of aromatic compounds containing a 1, 1-dialkyl-2-trifluoromethyl group, a bioisostere of the tert-alkyl moiety Bioorg. Med. Chem. Lett., 2007, 17(22), 6079-6085.
24. Duncton, M. A. J.; Singh, R. Synthesis of trans-2-(Trifluoromethyl)cyclopropanes via Suzuki Reactions with an NMethyliminodiacetic Acid Boronate. Org. Lett., 2013, 15(17), 4284-4287.
25. Duncton, M.; Singh, R. Preparation of cyclopropylboronic acid Nmethyliminodiacetic acid (MIDA) ester. WO 2012075316, Jun 7, 2012.
26. Gillis, E. P.; Burke, M. D. A Simple and Modular Strategy for Small Molecule Synthesis: Iterative Suzuki-Miyaura Coupling of BProtected Haloboronic Acid Building Blocks. J. Am. Chem. Soc., 2007, 129(21), 6716-6717.
27. Gillis, E. P.; Burke, M. D. Iterative cross-coupling with MIDA boronates: towards a general-strategy for small-molecule synthesis. Aldrichimica Acta, 2009, 42(1), 17-27.
28. Risse, J.; Fernández-Zúmel, M. A.; Cudré, Y.; Severin, K. Synthesis of trifluoromethyl-substituted cyclopropanes via sequential Kharasch-dehalogenation reactions. Org. Lett., 2012, 14(12), 3060-3063.
29. Morandi, B.; Cheang, J.; Carreira, E. M. Iron-Catalyzed Preparation of Trifluoromethyl Substituted Vinyl-and Alkynylcyclopropanes. Org. Lett., 2011, 13(12), 3080-3081.
30. Morandi, B.; Carreira, E. M. Iron-Catalyzed Cyclopropanation with Trifluoroethylamine Hydrochloride and Olefins in Aqueous Media: In Situ Generation of Trifluoromethyl Diazomethane. Angew. Chem. Int. Ed., 2010, 49(5), 938-941.
31. Morandi, B.; Mariampillai, B.; Carreira, E. M. Enantioselective Cobalt-Catalyzed Preparation of Trifluoromethyl-Substituted Cyclopropanes. Angew. Chem. Int. Ed., 2011, 50(5), 1101-1104.
32. Grygorenko, O. O.; Artamonov, O. S.; Komarov, I. V.; Mykhailiuk, P. K. Trifluoromethyl-substituted cyclopropanes Tetrahedron, 2011, 67(5), 803-823.
33. Tully, D. C.; Rucker, P. V.; Alper, P. B.; Mutnick, D.; Chianelli, D. Nortropine derivatives as farnesoid X receptor modulators and their preparation and use for treatment of farnesoid X receptor-mediated diseases. WO 2012087519, Jun 28, 2012.
34. Holland, S.; Kolluri, R.; Alvarez, S.; Duncton, M.; Singh, R.; Zhang, J.; Masuda, E. Preparation of pyrimidinediamine compounds as protein kinase C inhibitors. WO 2012012619, Jan 26, 2012.
35. Duncton, M. A. J.; Ayala, L.; Kaub, C.; Janagani, S.; Edwards, W. T.; Orike, N.; Ramamoorthy, K.; Kincaid, J.; Kelly, M. G. Dibutyl 2-(trifluoromethyl)cyclopropylboronate as a useful (trifluoromethyl) cyclopropyl donor: application to antagonists of TRPV1. Tetrahedron Lett., 2010, 51(7), 1009-1011.
36. Kelly, M. G.; Kincaid, J.; Janagani, S.; Duncton, M. Preparation of cyclopropyl(hetero)arylamides as vanilloid VR1 receptor antagonists. US 20060205773, Sep 14, 2006.
37. Welch, J. T.; Lim D. S. The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine. Bioorg. Med. Chem., 2007, 15(21), 6659-6666.
38. 5) organic molecules. J. Fluorine Chem., 2012, 143, 57-93.
39. Welch, J. T. Applications of pentafluorosulfanyl substitution in life sciences research. Mol. Med. Medicin. Chem., 2012, 6 (Fluorine in Pharmaceutical and Medicinal Chemistry), 175-207.
40. Wipf, P.; Mo, T.; Geib, S. J.; Caridha, D.; Dow, G. S.; Gerena, L.; Roncal, N.; Milner, E. E. Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine. Org. Biomol. Chem., 2009, 7(20), 4163-4165.
41. Welch, J. T.; Lim, D. S. Pentafluorosulfanyl serotonin analogs: synthesis, characterization, and biological activity. ACS Symposium Series, 2009, 1003 (Fluorinated Heterocycles), 165-181.
42. Stump, B.; Eberle, C.; Schweizer, W. B.; Kaiser, M.; Brun, R.; Krauth-Siegel, R. L.; Lentz, D.; Diederich, F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem., 2009, 10(1), 79-83.
43. Bagal, S. K.; Kemp, M. I.; Miller, D. C.; Murata, Y. Imidazoles as Nav1. 8 inhibitors and their preparation and use in the treatment of pain. WO 2013061205, May 2, 2013.
44. Luecking, U.; Kosemund, D.; Scholz, A.; Lienau, P.; Siemeister, G.; Boemer, U.; Bohlmann, R. Preparation of disubstituted 5-fluoropyrimidine derivatives containing a sulfoximine group as CDK inhibitors. WO 2013037894, Mar 21, 2013.
45. Haerter, M.; Beck, H.; Thierauch, K.-H.; Ellinghaus, P.; Greschat, S.; Schuhmacher, J. Preparation of 3-(fluorovinyl)pyrazoles and use thereof in the treatment of hyperproliferative and angiogenic diseases. WO 2013011033, Jan 24, 2013.
46. Braeuer, N.; Mengel, A.; Roehn, U.; Rotgeri, A.; Buchmann, B.; Lindenthal, B.; Ter Laak, A. Preparation of novel 2H-indazoles as EP2 receptor antagonists. WO 2013079425, June 6, 2013.
47. Savoie, P. R.; Welch, J. M.; Higashiya, S.; Welch, J. T.; Control of hydroxyl group conformation by the pentafluorosulfanyl group. J. Fluorine Chem., 2013, 148, 1-5.
48. Vintonyak, V. V.; Waldmann, H.; Rauh, D. Using small molecules to target protein phosphatases. Bioorg. Med. Chem., 2011, 19(7), 2145-2155.
49. Turcheniuk, K. V.; Kukhar, V. P.; Röschenthaler, G.-V.; Aceña, J. L.; Soloshonokcd V. A.; Sorochinsky, A. E. Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids. RSC Adv., 2013, 3(19), 6693-6716.
50. Otaka, A.; Miyoshi, K.; Burke, T. R., Jr.; Roller, P. P.; Kubota, H.; Tamamura, H.; Fujii, N. Synthesis and application of N-Boc-L-2-amino-4-(diethylphosphono)-4, 4-difluorobutanoic acid for solidphase synthesis of nonhydrolyzable phosphoserine peptide analogs. Tetrahedron Lett., 1995, 36(6), 927-30.
51. Otaka, A.; Miyoshi, K.; Kaneko, M.; Burke, T. R. Jr.; Roller, P. P.; Tamamura, H.; Fujii, N. Peptide Chemistry, 1995, 32, 9-12.
52. Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activity. Chemistry & Biology, 2012, 19(6), 764-71.
53. Burke, T. R.; Qian, W.; Liu, F.; Lee, K. S.; Park, J.-E. Preparation of antitumor peptide mimetic ligands of polo-like kinase 1 polo box domain. WO 2012142245 Oct 18, 2012.
54. Hayashi, R.; Tanoue, K.; Durell, S. R.; Chatterjee, D. K.; Miller Jenkins, L. M.; Appella, D. H.; Appella, E. Optimization of a Cyclic Peptide Inhibitor of Ser/Thr Phosphatase PPM1D (Wip1). Biochemistry, 2011, 50(21), 4537-4549.
55. Madela, K.; McGuigan, C. Progress in the development of antihepatitis C virus nucleoside and nucleotide prodrugs. Future Med. Chem., 2012, 4(5), 625-650.
56. Hussain, J.; Rea, C. Computationally efficient algorithm to identify matched molecular pairs (MMPs) in large data sets. J. Chem. Inf. Model., 2010, 50, 339-348.
57. RDKit: Open-source Cheminformatics. http://www. rdkit. org.
58. Morgan, H. L. The Generation of a Unique Machine Description for Chemical Structures-A Technique Developed at Chemical Abstracts Service. J. Chem. Mod., 1965, 5, 107-113.
59. Rooted Morgan Fingerprint calculated using the chiral Morgan Fingerprint (bit vector representation) implemented in RDKit's rdMolDescriptors module, with the root specified using the fromAtoms option.
60. Butina, D. Unsupervised Data Base Clustering Based on Daylight's Fingerprint and Tanimoto Similarity: A Fast and Automated Way to Cluster Small and Large Data Sets. J. Chem. Inf. Comput. Sci., 1999, 39, 747-750. Butina algorithm implemented in rdkit. ML. Cluster. Butina module.
61. Smart, B. E. Fluorine substituent effects (on bioactivity). J. Fluorine Chem., 2001, 109(1), 3-11.