Mioflazine

Last updated

Mioflazine
Mioflazine.svg
Clinical data
Other namesR 51469
Identifiers
  • 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-(2,6-dichloroanilino)-2-oxoethyl]piperazine-2-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C29H30Cl2F2N4O2
Molar mass 575.48 g·mol−1
3D model (JSmol)
  • C1CN(C(CN1CC(=O)NC2=C(C=CC=C2Cl)Cl)C(=O)N)CCCC(C3=CC=C(C=C3)F)C4=CC=C(C=C4)F
  • InChI=1S/C29H30Cl2F2N4O2/c30-24-4-1-5-25(31)28(24)35-27(38)18-36-15-16-37(26(17-36)29(34)39)14-2-3-23(19-6-10-21(32)11-7-19)20-8-12-22(33)13-9-20/h1,4-13,23,26H,2-3,14-18H2,(H2,34,39)(H,35,38)
  • Key:VWXFUOAKGNJSBI-UHFFFAOYSA-N

Mioflazine (R 51469) is a compound that has garnered attention due to its potential protective effects against myocardial ischemia. Primarily acting as a nucleoside transport inhibitor, [1] mioflazine has been shown in preclinical studies to improve cardiac survival during ischemic episodes, modulate the dynamics of nucleoside accumulation during reperfusion, and exhibit unique pharmacological properties without significant inotropic effects. [2]

Mioflazine is a member of diphenylbutylpiperazine class. Other members of this class include lidoflazine, draflazine, and soluflazine. R57974 [3] has the same structure as mioflazine but is based on a 5,5-bis(4-fluorophenyl)pentyl] pendant sidechain. [4]

Synthesis

A patented procedure for mioflazine was released, [5] and described in a book: [6]

Mioflazine synthesis.svg

(Ex XXV inter. 83; Ex XXXI inter. 115; Ex XXXIII inter. 125; Ex XXXV cmp. 27).

The first step involves reacting Piperazine-2-carboxamide [84501-64-4] (1) with acetone to form a cyclic aminal protecting group thus forming hexahydro-3,3-dimethylimidazo(1,5-a)pyrazin-1(5H)-one [83898-63-9] (2). The vacant piperazine secondary nitrogen is reacted with 2-Chloro-N-(2,6-dichlorophenyl)acetamide [3644-56-2] (3) giving N-(2,6-dichlorophenyl)hexahydro-3,3-dimethyl-1-oxoimidazo[1,5-a]pyrazine-7(1H)-acetamide [83898-62-8] (4). Acid hydrolysis removal of the cyclic aminal protecting group gives 3-Carbamoyl-N-(2,6-dichlorophenyl)piperazine-1-acetamide [83863-78-9] (5). The unmasked remaining piperazine secondary nitrogen is alkylated with 1,1'-(4-Iodobutylidene)bis(4-fluorobenzene) [51787-79-2] (6), completing the synthesis of mioflazine (7).

References

  1. ↑ Baer HP, Haq A, el-Soofi A, Serignese V, Paterson AR (May 1990). "Potencies of mioflazine and its derivatives as inhibitors of adenosine transport in isolated erythrocytes from different species". The Journal of Pharmacy and Pharmacology. 42 (5): 367–369. doi:10.1111/j.2042-7158.1990.tb05432.x. PMID   1976791.
  2. ↑ Morton IK, Hall JM (1999). "M". Concise Dictionary of Pharmacological Agents. Springer Netherlands. pp. 171–188. doi:10.1007/978-94-011-4439-1_12. ISBN   978-94-010-5907-7.
  3. ↑ "4-[5,5-Bis(4-fluorophenyl)pentyl]-1-[2-(2,6-dichloroanilino)-2-oxoethyl]piperazine-2-carboxamide". PubChem. U.S. National Library of Medicine.
  4. ↑ Baer HP, Serignese V, Moorji A, Van Belle H (April 1991). "In vivo effectiveness of several nucleoside transport inhibitors in mice and hamsters". Naunyn-Schmiedeberg's Archives of Pharmacology. 343 (4): 365–369. doi:10.1007/BF00179040. PMID   1852220.
  5. ↑ EP0068544 idem Georges Van Daele, US4766125 (1983 to Janssen Pharmaceutica NV).
  6. ↑ The organic chemistry of drug synthesis, volume 4, Dan Lednicer & Lester Mitscher with Gunda Georg, Page 119.
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