Apafant
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| ECHA InfoCard | 100.220.442 |
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| Formula | C22H22ClN5O2S |
| Molar mass | 455.96 g·mol−1 |
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Apafant (WEB-2086, LSM-2613) is a drug which acts as a potent and selective inhibitor of the phospholipid mediator platelet-activating factor (PAF). It was developed by structural modification of the thienotriazolodiazepine sedative drug brotizolam and demonstrated that PAF inhibitory actions could be separated from activity at the benzodiazepine receptor. Apafant was investigated for several applications involving inflammatory responses such as asthma and conjunctivitis but was never adopted for medical use, however it continues to be used in pharmacology research.[1][2][3][4]
Synthesis
The chemical synthesis of Apafant was reported:[5][6] Precursor:[7] Dan’s book said there is keto present but absent in the database and the patent.
Reaction of the Diethyl 2-(4-oxobutyl)propanedioate, PC88403880 (1) with the 2-Chlorobenzoylacetonitrile [609-772-9] (2) in the presence of sulfur leads to formation of the aminothiophene, Diethyl 2-(5-amino-4-(2-chlorobenzoyl)thiophen-2-ylmethyl)malonate, PC13670761 (3). Saponification of the esters with caustic potash is accompanied by decarboxylation. The re-esterification of the monoacid with methanol then gives 2-Amino-3-(2-chlorobenzoyl)-5-(2-carbomethoxyethyl)thiophene [100827-77-8] (4). Construction of the diazepine ring starts by alkylation of the amino group with bromoacetamide in the presence of base to afford, Methyl 3-[5-[(2-aminoacetyl)amino]-4-(2-chlorobenzoyl)thiophen-2-yl]propanoate, PC13670766 (5). Heating with silica causes the side-chain amide nitrogen to react with the ketone to form a cyclic imine affording 7-(2-Carbomethoxyethyl)-5-(2-chlorophenyl)-thieno-1,4-diazepin-2-one [100827-80-3] (6). The amide carbonyl is converted to a thioamide with phosphorus pentoxide giving, Methyl 3-[5-(2-chlorophenyl)-2-sulfanylidene-1,3-dihydrothieno[2,3-e][1,4]diazepin-7-yl]propanoate, PC136015497 (7). Reaction of this last intermediate with hydrazine gives a cyclic aminoamidine (8). Condensation of that product with orthoacetic acid ester leads to 4-(2-Chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-2-propanoic Acid Methyl Ester, [100827-83-6] (9). Ester–amide interchange of this last product with morpholine completes the synthesis of apafant (10).
References
- ^ Casals-Stenzel J (December 1991). "Thieno-triazolo-1,4-diazepines as antagonists of platelet-activating factor: present status". Lipids. 26 (12): 1157–1161. doi:10.1007/BF02536522. PMID 1668111. S2CID 4053407.
- ^ Brecht HM, Adamus WS, Heuer HO, Birke FW, Kempe ER (January 1991). "Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man". Arzneimittel-Forschung. 41 (1): 51–59. PMID 1646613.
- ^ Ikegami K, Hata H, Fuchigami J, Tanaka K, Kohjimoto Y, Uchida S, Tasaka K (June 1997). "Apafant (a PAF receptor antagonist) suppresses the early and late airway responses in guinea pigs: a comparison with antiasthmatic drugs". European Journal of Pharmacology. 328 (1): 75–81. doi:10.1016/s0014-2999(97)83031-2. PMID 9203572.
- ^ Kato M, Imoto K, Miyake H, Oda T, Miyaji S, Nakamura M (August 2004). "Apafant, a potent platelet-activating factor antagonist, blocks eosinophil activation and is effective in the chronic phase of experimental allergic conjunctivitis in guinea pigs". Journal of Pharmacological Sciences. 95 (4): 435–442. doi:10.1254/jphs.fp0040265. PMID 15286429. S2CID 34872524.
- ^ Lednicer, D., Mitscher, L. A. (2008). The organic chemistry of drug synthesis. 7. Wiley. ISBN 9780470107508.
- ^ Weber, K. H. (1988). "WEB 2086". Drugs of the Future. 13 (3): 242. doi:10.1358/dof.1988.013.03.62409. ISSN 0377-8282.
- ^ Warner, D. T., Moe, O. A. (October 1948). "1,4-Addition Reactions. II. Addition of Ethyl Malonate to Acrolein 1". Journal of the American Chemical Society. 70 (10): 3470–3472. doi:10.1021/ja01190a076.