Atiprimod

Atiprimod
Clinical data
ATC code	none;
Identifiers
	IUPAC name 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine;
CAS Number	123018-47-3 ;
PubChem CID	129869;
ChemSpider	114962 ;
UNII	MG7D3QD743;
KEGG	D03003 ;
ChEMBL	ChEMBL103735 ;
CompTox Dashboard (EPA)	DTXSID10153834 ;
Chemical and physical data
Formula	C22H44N2
Molar mass	336.608 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES N(CC)(CC)CCCN2CCC1(CCC(CC1)(CCC)CCC)C2;
	InChI InChI=1S/C22H44N2/c1-5-10-21(11-6-2)12-14-22(15-13-21)16-19-24(20-22)18-9-17-23(7-3)8-4/h5-20H2,1-4H3 ; Key:SERHTTSLBVGRBY-UHFFFAOYSA-N ;
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Atiprimod (INN, codenamed SK&F106615) is a substance being studied in the treatment of certain multiple myelomas and other advanced cancers. It may block the growth of tumors and the growth of blood vessels from surrounding tissue to the tumor. This drug is also being researched as a potential treatment for various autoimmune diseases.

It was first developed by GlaxoSmithKline as a potential treatment for rheumatoid arthritis.^[1]^[2]

This compound has also been shown to kill mantle cell lymphoma cells in vitro.^[3]

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.^{[citation needed]}

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).

Lednicer (unofficial) synthesis^[5]

References

^ GS J (Spring 2004). "Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma". Myeloma Today. 5 (10). International Myeloma Foundation. Archived from the original on 2011-07-18. Retrieved 2010-09-30.
^ ^a ^b Badger AM, Schwartz DA, Picker DH, Dorman JW, Bradley FC, Cheeseman EN, et al. (November 1990). "Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents". Journal of Medicinal Chemistry. 33 (11): 2963–2970. doi:10.1021/jm00173a010. PMID 2146392.
^ Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, et al. (June 2007). "Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways". Blood. 109 (12): 5455–5462. doi:10.1182/blood-2006-12-063958. PMID 17317853.
^ US 4963557, Badger AM, Cheeseman EN, DiMartino MJ, Dorman JW, Mirabelli CK, Picker DH, Schwartz DA, "Immunomodulatory azaspiranes", issued 16 October 1990, assigned to Callisto Pharmaceuticals Inc.
^ US 5952365, Dagger RE, Grady CW, "2-[2-(dimethylaminoehtyl]-8,8-diproply-2-azaspiro[4.5]decane dimaleate", issued 4 September 1999, assigned to Anormed Inc.

External links

Atiprimod entry in the public domain NCI Dictionary of Cancer Terms

This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

[1] GS J (Spring 2004). "Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma". Myeloma Today. 5 (10). International Myeloma Foundation. Archived from the original on 2011-07-18. Retrieved 2010-09-30.

[Badger_1990-2] Badger AM, Schwartz DA, Picker DH, Dorman JW, Bradley FC, Cheeseman EN, et al. (November 1990). "Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents". Journal of Medicinal Chemistry. 33 (11): 2963–2970. doi:10.1021/jm00173a010. PMID 2146392.

[3] Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, et al. (June 2007). "Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways". Blood. 109 (12): 5455–5462. doi:10.1182/blood-2006-12-063958. PMID 17317853.

[US4963557-4] US 4963557, Badger AM, Cheeseman EN, DiMartino MJ, Dorman JW, Mirabelli CK, Picker DH, Schwartz DA, "Immunomodulatory azaspiranes", issued 16 October 1990, assigned to Callisto Pharmaceuticals Inc.

[5] US 5952365, Dagger RE, Grady CW, "2-[2-(dimethylaminoehtyl]-8,8-diproply-2-azaspiro[4.5]decane dimaleate", issued 4 September 1999, assigned to Anormed Inc.

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