Chemistry:Tirilazad

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Tirilazad is a drug that has been proposed to treat acute ischaemic stroke. When tested on animal models, tirilazad protects brain tissue, and reduces brain damage. However, the drug fails to treat, and even worsens a stroke when studied on a human being.[1]

Tirilazad is a 21-aminosteroid and belongs to the "Lazaroid" family of agents. The metabolite of tirilazad is called U-89678 [157744-31-5]. Other known lazaroids found in the data base include the following list of agents: U-74389G [153190-29-5], U-74500 [111640-85-8], U-75412E [130590-09-9] & U-87999 [177949-23-4]. The name comes from Lazarus — the biblical figure raised from the dead — because these compounds were thought to “bring cells back to life” after oxidative injury.

More recently Tirilazad has shown some promising results in treating traumatic brain inhury (TBI).[2]

Synthesis

The chemical synthesis has been reported:[3][4]
Patent (Example 83; S22 page 59, A22 page 47):[5] Precursor patent:[6]

File:Tirilazad synthesis.svg
  • The starting material is called 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate [37413-91-5] (1). Soft addition of methylmagnesium chloride in the presence copper propionate (c.f. Gilman reagent), followed by saponification of the ester group furnished 21-Hydroxy-16alpha-methylpregna-1,4,9(11)-triene-3,20-dione [56016-90-1] (2). FGI of the hydroxy group to the tosyl leaving group, followed by displacement with sodium iodide led to 21-Iodo-16alphamethylpregna-1,4,9(11)-triene-3,20-dione, PC14878745 (3).
  • The reaction of 2,4,6-Trichloropyrimidine [3764-01-0] (4) with 2 equivalents of Pyrrolidine [123-75-1] (5) gave 4-chloro-2,6-di(pyrrolidin-1-yl)pyrimidine [111669-15-9] (6). Further reaction of the remaining halogen with piperidine [110-89-4] (7) yielded 4-(Piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine [111641-17-9] (8).
  • Convergent synthesis between 3 and 8 completed the synthesis of tirilazad (9).

N.B The precursor 4-chloro-2,6-di(pyrrolidin-1-yl)pyrimidine [111669-15-9] (6) finds dual use in the synthesis of 2-MAC (U-78517F) [122003-11-6] as well as for U-83836E (aka PNU-83836E or GNF-Pf-3881) [137018-55-4]. These agents show similar antiinflammatory/antioxidant activity to lazaroids but are not related to steroid hormones.

References

  1. ↑ "Tirilazad for acute ischaemic stroke". The Cochrane Database of Systematic Reviews (4). 2001. doi:10.1002/14651858.CD002087. PMID 11687138. 
  2. ↑ "Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury". Neuropharmacology 145 (Pt B): 247–258. February 2019. doi:10.1016/j.neuropharm.2018.08.005. PMID 30086292. 
  3. ↑ The Organic Chemistry of Drug Synthesis. 5. Wiley. 1995. ISBN 978-0-471-58959-4. 
  4. ↑ "Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma". Journal of Medicinal Chemistry 33 (4): 1145–1151. April 1990. doi:10.1021/jm00166a010. PMID 2319560. 
  5. ↑ Mc Call JM, Ayer DE, Jacobsen EJ, Van Doornik FJ, Palmer JR, Karnes HA, "C20 through c26 amino steroids", WO patent 1987/001706, published 26 March 1987
  6. ↑ Mendelsohn H, Smith LL, Origoni VE, "Pregnatetraenes and method of preparing the same", patent2864834 US patent patent 2864834, issued 16 December 1958



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