Atiprimod

Mechanism of action

Atiprimod has been shown to inhibit angiogenesis (growth of blood vessels) in a blood vessel model using chicken eggs. It is thought to inhibit the secretion of vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis.

Chemistry

Atiprimod is an amphiphilic compound that exists as a cation at neutral pH and belongs to the heterocyclic class of azaspiranes.

Synthesis

The first part of the synthesis uses protocols that were used for Pramiverine and agents including SIR 117. The second half of the synthesis shares features that are consonant with RS 86

The Johnson–Corey–Chaykovsky reaction on 4-Heptanone [123-19-3] (1) gives 2,2-dipropyloxirane [98560-25-9] (2). Treatment with Boron trifluoride etherate [109-63-7] gave 2-Propylpentanal [18295-59-5] (3). Upon acid treatment with Methyl vinyl ketone [78-94-4] (4) this led to 4,4-Dipropylcyclohex-2-enone [60729-41-1] (5). Catalytic hydrogenation of the enone olefin yielded 4,4-Dipropylcyclohexanone [123018-62-2] (7). The Knoevenagel condensation with ethyl 2-cyanoacetate [1187-46-8] (8) led to Cyano-(4,4-dipropyl-cyclohexylidene)-acetic acid ethyl ester [130065-93-9] (8). Conjugate addition of cyanide anion led to ethyl 2-cyano-2-(1-cyano-4,4-dipropylcyclohexyl)acetate, PC45358714 (9). Acid hydrolysis of both the nitrile groups to acids, saponification of the ester, and decarboxylation of the geminal diacid gave 1-(carboxymethyl)-4,4-dipropylcyclohexane-1-carboxylic acid [130065-94-0] (10). Treatment with acetic anhydride gave 8,8-Dipropyl-2-oxaspiro[4.5]decane-1,3-dione [123018-64-4] (11). Condensation with 3-Diethylaminopropylamine [104-78-9] (12) gave the imide and hence, 2-[3-(diethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane-1,3-dione, PC15634126 (13). Finally reduction of both carbonyl groups with lithium aluminium hydride completed the synthesis of Atiprimod (14).

References

References

1. (Spring 2004). "Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma". International Myeloma Foundation.
2. (November 1990). "Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents". Journal of Medicinal Chemistry.
3. (June 2007). "Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways". Blood.
4. "Immunomodulatory azaspiranes".
5. (1995). "SK&F-106615". Drugs of the Future.
6. "2-[2-(dimethylaminoehtyl]-8,8-diproply-2-azaspiro[4.5]decane dimaleate".