Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]- heterocycles

Molecular Diversity

Volumn 12, Issue 1, 2008, Pages 1-15

  Hulme, Christopher ^a   Lee, Yeon Sun ^a  

^a UNIVERSITY OF ARIZONA   (United States)

Author keywords

Combinatorial chemistry; Imidazopyridine; Isonitrile; Multicomponent reaction; Parallel synthesis

Indexed keywords

ALPIDEM; BENZODIAZEPINE DERIVATIVE; IMIDAZO[1,2 A]PYRIDINE DERIVATIVE; ZOLPIDEM TARTRATE;

ATAXIA; ATOM; AUTOMATION; CYCLIZATION; CYCLOADDITION; DEPROTECTION REACTION; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; HUMAN; INSOMNIA; MICROWAVE RADIATION; POLYMERIZATION; PRIORITY JOURNAL; REVIEW; STRUCTURE ACTIVITY RELATION;

AUTOMATION; BICYCLO COMPOUNDS, HETEROCYCLIC; DRUG DESIGN; IMIDAZOLES;

EID: 41949142589     PISSN: 13811991     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11030-008-9072-1     Document Type: Review

References (89)

1. Ruben AJ, Kiso Y, Freire E (2006) Overcoming roadblocks in lead optimization: a thermodynamic perspective. Chem Biol Drug Des 67: 2-4
2. (a) Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529-531;
3. (b) Leeson PD, Iverson LL (1994) The Glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 37:4053-4067;
4. (c) For alternate multi-component routes to other fused imidazo systems see: (i) Adib M, Ghanbary K Mostofi M, Bijanzadeh HR (2005) Reaction between isocyanides and dialkyl acetylene dicarboxylates in the presence of 4,5-diphenyl-1,3-dihydro-2H-imidazol-2-one. One-pot synthesis of 5H-imidazo [2,1-b][1,3]oxazine derivatives. Tetrahedron 61:2645-2648;
5. (ii) Le Bas H, O'Shea DF (2005) Parallel microwave-assisted library of imidazothiazol-3-ones and imidazothiazin-4-ones. Parallel microwave-assisted library of imidazothiazol-3-ones and imidazothiazin-4-ones. J Comb Chem 7:947-951
6. Aloup J-C, Audiau F, Barreau, M, Damour D, Genevois-Borella A, Jimonet P, Mignagni S, Ribeill Y (1996) Preparation of spiro(heterocycle-imidazo(1,2-a) indeno(1,2-e)pyrazine)-4′-ones as AMPA and NMDA receptor antagonists. WO 9614318
7. (a) Fabbro D, Garcia-Echeverria C (2002) Targeting protein kinases in cancer therapy. Curr Opin Drug Discov Devel 5:701-712;
8. (b) Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934
9. Geronikaki A, Babaev E, Dearden J, Dehaen W, Filimonov D, Galaeva I, Krajneva V, Lagunin A, Macaev F, Molodavkin G, Poroikov V, Pogrebnoi S, Saloutin V, Stepanchikova A, Stingaci E, Tkach N, Vlad L, Voronina T (2004) Design, synthesis, computational and biological evaluation of new anxiolytics. Bioorg Med Chem 12: 6559-6568
10. (a) Miwa S, Mizokami A, Keller ET, Taichman R, Zhang J, Namiki M (2005) The Bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer. Cancer Res 65:8818-8825;
11. (b) Cui N, Nomura T, Noma H, Yokoo K, Takagi R, Hashimoto S, Okamoto M, Sato M, Yu G, Guo C Shibahala T (2005) Effect of YM529 on a model of mandibular invasion by oral squamous cell carcinoma in mice. Clin Cancer Res 11:2713-2719
12. Xia G, Li J, Peng A, Lai S, Zhang S, Shen J, Lui Z, Chen X, Ji R (2005) Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives. Bioorg Med Chem Lett 15: 2790-2794
13. Sablayrolles C, Cros GH, Milhavet JC, Rechencq E, Chapat JP, Boucard M, Serrano JJ, McNeill JM (1984) Synthesis of imidazo[1,2-a]pyrazine derivatives with uterine-relaxing, antibronchospastic, and cardiac-stimulating properties. J Med Chem 27: 206-212
14. Gehlert DR, Cippitelli A, Thorsell A, Le A-D, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M (2007) 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6- dimethyl-imi- dazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci 27: 2718-2726
15. For a recent excellent review on IMCRs see Domling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17-89
16. Curtin ML, Davidsen SK, Heymman R, Garland RB, Sheppard GS, Florjancic AS, Lianhong X, Carrera GM, Seinman DH, Trautmann JA, Albert DH, Magoc TJ, Tapang P, Rhein DA, Conway RG, Luo G, Denissen JF, Marsh KC, Morgan DW, Summers JB (1998) Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists. J Med Chem 41: 74-95
17. (a) Harrison TS, Keating GM (2005) Zolpidem: a review of its use in the management of insomnia. CNS Drugs 19:65-89;
18. (b) Mereu G, Carcangiu G, Concas A, Passino N, Biggio G (1990) Reduction of reticulata neuronal activity by Zolpidem and Alpidem, two imidazopyridines with high affinity for type I benzodiazepine receptors. Eur J Pharmacol 179:339-345
19. Anzini M, Cappelli A, Vomero S, Giorgi G, Langer T, Bruni G, Romeo R, Basile AS (1996) Molecular basis of peripheral vs. central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem. J Med Chem 39: 4275-4284
20. Crestani F, Martin JR, Mohler H, Rudolph U (2000) Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 131: 1251-1254
21. Musch B, Morselli PL, Priore P (1988) Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences. Pharmacol Biochem Behav 29: 803-806
22. Georges GJ, Vercauteren DP, Evrard GH, Durant FV, George PG, Wick A (1993) Characterization of the physico-chemical properties of the imidazopyridine derivative Alpidem. Comparison with Zolpidem. Eur J Med Chem 28: 323-335
23. Almirante L, Mugnaini A, Rugarli P, Gamba A, Zefelippo E, De Toma N, Murmann WJ (1969) Derivatives of imidazole. III. Synthesis and pharmacological activities of nitriles, amides, and carboxylic acid derivatives of imidazo[1,2-a]pyridine. J Med Chem 12: 122-126
24. Klupsch F, Houssin R, Humbert L, Imbenotte M, Henichart J-P, Lhermitte M (2006) Major metabolites of Zolpidem: expeditious synthesis and mass spectra. Chem Pharmacol Bull 54: 1318-1321
25. (a) Blackburn C, Guan B, Fleming P, Shiosaki, K, Tsai S (1998) Parallel synthesis of 3-aminoimidazo[1,2-a]pyridines and pyrazines by a new three-component condensation. Tetrahedron Lett 39:3635-3638;
26. (b) Bienayme H, Bouzid K (1998) A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles. Angew Chem Int Ed 37:2234-2237;
27. (c) Groebke K, Weber L, Mehlin. F (1998) Synthesis of imidazo[1,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation. Synlett 6:661-663
28. (a) All topologically feasible combinations of bi-functional parent compounds which can lead to constrained structures are theoretically exemplified in this review: Domling A, Ugi I (2000) Multicomponent reactions with isocyanides. Angew Chem Int Ed 39:3168-3210;
29. (b) Isenring HP, Hofheinz W (1981) A simple two-step synthesis of diphenylmethyl esters of 2-oxo-1-azetidineacetic acids. Synthesis 5:385-387;
30. (c) Harriman GCB (1997) Synthesis of small and medium sized 2,2-disubstituted lactams via the "intramolecular" three component Ugi reaction. Tetrahedron Lett 38:5591-5594;
31. (d) Hanusch-Kompa C, Ugi I (1998) Multi-component reactions 13: synthesis of γ-lactams as part of a multi-ring system via Ugi-4-centre-3-component reaction. Tetrahedron Lett 39:2725-2728;
32. (e) Short KM, Mjalli AMM (1997) A solid-phase combinatorial method for the synthesis of novel 5- and 6-membered ring lactams. Tetrahedron Lett 38:359-362;
33. (f) Zhang J, Jacobsen A Rusche JR, Herlihy W (1999) Unique structures generated by Ugi 3CC reactions using bifunctional starting materials containing aldehyde and carboxylic acid. J Org Chem 64:1074-1076;
34. (g) Ilyn AP, Loseva MV, Vvedensky VY, Putsykina EB, Tkachenko SE, Kravchenko DV, Khvat AV, Krasavin MY, Ivachtchenko AV (2006) One-step assembly of carbamoyl-substituted heteroannelated [1,4]thiazepines. J Org Chem 71:2811-2819
35. Hulme C, Gore V (2003) Multi-component reactions: emerging chemistry in drug discovery from Xylocain to Crixivan. Curr Med Chem 10:51-80 & references therein
36. Trost BM (1991) The atom economy-a search for synthetic efficiency. Science 254: 1471-1477
37. Hulme C, Nixey T (2003) Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions. Curr Opin Drug Discov Devel 6: 921-929
38. 50)/#HA (HA = Number of heavy atoms in lead), where greater Ligand Efficiency (when applied in context with other filters i.e. toxicological and pharmacokinetic) is preferred in lead selection (LE > 0.3 is optimal). Thus, during development the chemist has ample room to optimize potency and pharmacokinetic profiles by increasing molecular weight and lipophilicity. Previous to this quantification, non-empirical judgement calls of the medicinal chemist were employed to rank lead starting points and were often simply potency driven.
39. This concept also encompasses and further justifies the exploding field of fragment based drug discovery (see Carr RAE, Congreve M, Murray CW, Rees DC (2005) Drug Discov Today 10:987-992). Simply put, very low molecular weight weak binders are often highly efficient ligands, giving the medicinal chemist ample room to dial in desired potency and ADME/PK properties
40. (a) Bienayme H, Hulme C, Oddon G, Schmitt P (2000) Maximizing synthetic efficiency: multi-component transformations lead the way. Chem Eur J 6:3321-3329;
41. (b) Akritopoulou-Zanze I Whitehead A, Waters J, Henry RF, Djuric, SW (2007) Synthesis of substituted 3,4-dihydroquinolin-2(1H)-one derivatives by sequential Ugi/acrylanilide [6π]-photocyclizations. Tetrahedron Lett. 48:3549-3552;
42. (c) Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RF, Djuric SW (2007) Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2+2] ene-enone photocycloadditions. Org Lett 9:1299-1302
43. (d) Gracias V, Gasiecki A, Pagano TG, Djuric SW (2006) Synthesis of fused imidazole rings by sequential van Leusen/C-H bond activation. Tetrahedron Lett 47:8873-8876
44. (a) Grieco PA, Bahsas A (1988) Role reversal in the cyclocondensation of cyclopentadiene with heterodienophiles derived from aryl amines and aldehydes: synthesis of novel tetrahydroquinolines. Tetrahedron Lett 29:5855-5858;
45. (b) Mellor JM, Merriman G Rataj H, Reid G (1996) Direct synthesis of 3,4-dihydro-2H-pyrido [1,2-a]pyrimidines, by addition reactions with 2-aminopyridines. Tetrahedron Lett 37:2615-2618 and references therein
46. Hulme C, Bienayme H, Nixey T, Chenera B, Jones W, Tempest P, Smith A (2003) Library generation via postcondensation modifications of isocyanide-based multicomponent reactions. Methods Enzymol 369: 469-496
47. See www.priaton.com
48. Ghose AK, Herbertz T, Salvino JM, Mallamo JP (2006) Knowledge based Chemoinformatics approaches to drug discovery. Drug Discov Today 11: 110-118
49. Blackburn C (1998) A three-component solid-phase synthesis of 3-aminoimidazo[1,2-a]azines. Tetrahedron Lett 39: 5469-5472
50. Blackburn C, Guan B (2000) A novel dealkylation affording 3-aminoimidazo[1,2-a]pyridines: access to new substitution patterns by solid-phase synthesis. Tetrahedron Lett 41: 1495-1500
51. Almirante L, Mugnaini A, De Toma N, Murmann W (1971) Imidazole derivatives. V. Synthesis and pharmacological activity of alkylimidazo[1,2- α]pyridines. Boll Chim Farma 110: 317-321
52. See www.thalesnano.com/Hcubeapplications for a comprehensive survey of the technology
53. (a) Keating TA, Armstrong RW (1996) Postcondensation modifications of Ugi four-component condensation products: 1-isocyanocyclohexene as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 118:2574-2583;
54. (b) Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/ Cyclization (UDC) strategy to access carboxylic acids, 1,4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones. Tetrahedron Lett 39:7227-7230;
55. (c) Linderman RJ, Binet S, Petrich SR (1999) Enhanced diastereoselectivity in the asymmetric Ugi reaction using a new "convertible" isonitrile. J Org Chem 64:336-337
56. Ugi I (1962) The α-Addition of immonium ions and anions to isonitriles accompanied by secondary reactions. Angew Chem 74: 9-22
57. Hulme C, Tang S-Y, Burns CJ, Morize I, Labaudiniere R (1998) Improved procedure for the solution phase preparation of 1,4-benzodiazepine-2,5-dione libraries via Armstrong's convertible isonitrile and the Ugi reaction. J Org Chem 63: 8021-8023
58. (a) Hulme C, Cherrier MP (1999) Novel applications of ethyl glyoxalate with the Ugi MCR. Tetrahedron Lett 40:5295-5299;
59. (b) Hulme C, Ma L, Romano J, Morrissette M (1999) Remarkable three-step-one-pot solution phase preparation of novel imidazolines utilizing a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Lett 40:7925-7928
60. Chen JJ, Golebiowski A, McClenaghan J, Klopfenstein SR, West L (2001) Universal Rink-isonitrile resin: application for the traceless synthesis of 3-acylamino imidazo[1,2-a]pyridines. Tetrahedron Lett 42: 2269-2271
61. Habashita H, Kokubo M, Hamano S-I, Hamanaka N, Toda M, Shibayama S, Tada H, Sagawa K, Fukushima D, Maeda K, Mitsuya H (2006) Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists. J Med Chem 49: 4140-4152
62. Varma RS, Kumar D (1999) Microwave-accelerated three-component condensation reaction on clay: solvent-free synthesis of imidazo[1,2-a] annulated pyridines, pyrazines and pyrimidines. Tetrahedron Lett 40: 7665-7669
63. DeLaude L, Laszlo P (1996) A novel oxidizing reagent based on potassium ferrate(VI). J Org Chem 61: 6360-6370
64. Ireland SM, Tye H, Whittaker M (2003) Microwave-assisted multi-component synthesis of fused 3-aminoimidazoles. Tetrahedron Lett 44: 4369-4371
65. (a) Tye H (2004) Application of statistical 'design of experiments' methods in drug discovery. Drug Discov Today 9:485-491;
66. (b) Tye H Whittaker M (2004) Use of a Design of experiments approach for the optimization of a microwave assisted Ugi reaction. Org Biomol Chem 2:813-815
67. Kremsner JM, Stadler A, Kappe CO (2007) High-throughput microwave-assisted organic synthesis: moving from automated sequential to parallel library-generation formats in silicon carbide microtiter plates. J Comb Chem 9: 285-291
68. (a) Gladysz JA, Curran DP, Horvath IT (eds) (2004) The handbook of fluorous chemistry. Wiley-VCH, Weinheim;
69. (b) Zhang W (2004) Fluorous synthesis of heterocyclic systems. Chem Rev 104:2531-2556
70. Lu Y, Zhang W (2004) Microwave-assisted synthesis of a 3-aminoimidazo[1,2-a]-pyridine/pyrazine library by fluorous multicomponent reactions and subsequent cross-coupling reactions. QSAR Comb Sci 23: 827-835
71. DiMauro EF, Kennedy JM (2007) Rapid synthesis of 3-amino-imidazopyridines by a microwave assisted four-component coupling in one pot. J Org Chem 72: 1013-1016
72. Lyon MA, Kercher TS (2004) Glyoxylic acid and MP-glyoxylate: efficient formaldehyde equivalents in the 3-CC of 2-aminoazines, aldehydes, and isonitriles. Org Lett 6: 4989-4992
73. (a) Lumma WC Jr, Springer JP (1981) Novel condensation of 2,3-epoxybutanal with 2-aminopyridine and 2-aminopyrazine. Synthesis and stability of 3-(1-hydroxyethyl)imidazo[1,2-a]. J Org Chem 46:3735-3736;
74. (b) Gudmundsson KS, Drach JC, Townsend LB (1997) Synthesis of imidazo[1,2-a]pyridine C-nucleosides with an unexpected site of ribosylation. J Org Chem 62:3453-3459
75. Schwerloske J, Masquelin T, Perun T, Hulme C (2005) New multi-component reaction accessing 3-aminoimidazo[1,2-a]pyridines. Tetrahedron Lett 46: 8355-8357
76. See www.biotage.com for references to dedicated microwave instruments
77. Strecker A (1850) Ann Chem Pharm 75
78. Masquelin T, Bui H, Brickley B, Stephenson G, Schwerkoske J, Hulme C (2006) Sequential Ugi/Strecker reactions via microwave assisted organic synthesis: novel 3-center-4-component and 3-center-5-component multi-component reactions. Tetrahedron Lett 47: 2989-2991
79. Murthy AK, Sailaja S, Rajanarendar E, Rao CJ (1983) Chemistry of heterocycles; 7. Synthesis of isoxazolopyridines by 6pi-electrocyclization. Synthesis 10: 839-840
80. Williams RM, Hendrix JA (1992) Asymmetric synthesis of arylglycines. Chem Rev 92: 889-917
81. Mandair GS, Light M, Russell A, Hursthouse M, Bradley M (2002) Re-evaluation of the outcome of a multiple component reaction 2- and 3-amino-imidazo[1,2-a]pyrimidines. Tetrahedron Lett 43: 4267-4269
82. Parchinsky VZ, Shuvalova O, Ushakova O, Kravchenko DV, Krasavin M (2006) Multi-component reactions between 2-aminopyrimidine, aldehydes and isonitriles: the use of a nonpolar solvent suppresses formation of multiple products. Tetrahedron Lett 47: 947-951
83. N Ar-based cycloetherification. Org Lett 3: 4079-4082
84. Carballares S, Cifuentes MM, Stephenson GA (2007) Regioselective two step synthesis of 3-substituted 2-aminoimidazo[1,2-a]pyrimidines. Tetrahedron Lett 48: 2041-2045
85. (a) Jacquier R, Lopez H, Mary GJ (1973) Intermediates in the Dimroth rearrangement of imidazo[1,2-a]pyridines. J Heterocycl Chem 10:755-762;
86. (b) Guerret P, Jacquier R, Maury GJ (1971) Minimal structural conditions for the Dimroth-type rearrangement in the polyazaindolizine series. J Heterocycl Chem 8:643-650;
87. (c) Jensen MS, Hoerrner RS, Li W, Nelson DP, Javadi GJ, Dormer PG, Cai D, Larsen DR (2005) Efficient synthesis of a GABAA α2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling. J Org Chem 70:6034-6039;
88. (d) Chezal JM, Moreau E, Delmas G, Gueiffer A, Blache Y, Grassy G, Lartigue C, Chavignon O, Teulade JC (2001) Heterocyclization of functionalized vinylic derivatives of imidazo[1,2-a]. J Org Chem 66:6576-6584
89. Parchinsky VZ, Koleda VV, Shuvalova O, Kravchenko DV, Krasavin M (2006) Air-oxidized products of multi-component reactions between 3-amino-1,2,4- triazole, aromatic aldehydes and isonitriles. Tetrahedron Lett 47: 6891-6894