| Revision as of 09:36, 3 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'StdInChI', 'StdInChIKey', 'CAS_number').← Previous edit |
Latest revision as of 18:16, 15 June 2024 edit undo2.101.54.127 (talk) →Synthesis: SIR 117 |
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{{Short description|Chemical compound}} |
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{{Confusing|date=May 2009}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 458780494 |
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| IUPAC_name = 3-(8,8-dipropyl-3-azaspirodecan-3-yl)-''N'',''N''- diethylpropan-1-amine |
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| IUPAC_name = 3-(8,8-dipropyl-3-azaspirodecan-3-yl)-''N'',''N''- diethylpropan-1-amine |
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| image = Atiprimod.svg |
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| image = Atiprimod.svg |
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| width = 250 |
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| image2 = Atiprimod molecule ball.png |
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| alt2 = Ball-and-stick model of the atiprimod molecule |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| pregnancy_category = |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = |
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| legal_status = |
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| routes_of_administration = |
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| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| bioavailability = |
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| protein_bound = |
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| protein_bound = |
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| metabolism = |
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| metabolism = |
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| elimination_half-life = |
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| elimination_half-life = |
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| excretion = |
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| excretion = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = <!-- blanked - oldvalue: 123018-47-3 --> |
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| CAS_number = 123018-47-3 |
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| ATC_prefix = none |
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| ATC_prefix = none |
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| ATC_suffix = |
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| ATC_suffix = |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = SERHTTSLBVGRBY-UHFFFAOYSA-N |
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| StdInChIKey = SERHTTSLBVGRBY-UHFFFAOYSA-N |
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| PubChem = 129869 |
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| PubChem = 129869 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 114962 |
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| ChemSpiderID = 114962 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = MG7D3QD743 |
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| UNII = MG7D3QD743 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 103735 |
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| ChEMBL = 103735 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D03003 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=22 | H=44 | N=2 |
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| C=22 | H=44 | N=2 |
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| molecular_weight = 336.598 g/mol |
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| smiles = N(CC)(CC)CCCN2CCC1(CCC(CC1)(CCC)CCC)C2 |
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| smiles = N(CC)(CC)CCCN2CCC1(CCC(CC1)(CCC)CCC)C2 |
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| InChI = 1/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 |
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| InChIKey = SERHTTSLBVGRBY-UHFFFAOYAG |
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}} |
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}} |
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'''Atiprimod''' (], codenamed '''SK&F106615'''; also known as '''azaspirane''', although this more properly refers to the class of chemicals to which atiprimod belongs) is a substance being studied in the treatment of certain ]s and other advanced ]s. Atiprimod may block the growth of tumors and the growth of ] from surrounding tissue to the ]. Atiprimod is a type of ]. It was first developed by ] (now part of ]) as a potential treatment for ].<ref>{{cite journal |url=http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=1379&aTab=0 |title=Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma |author=Jacobs GS |journal=Myeloma Today |date=Spring 2004 |volume=5 |issue=10 |publisher=International Myeloma Foundation |format={{dead link|date=January 2010}}}} Retrieved on September 14, 200.</ref> |
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'''Atiprimod''' (], codenamed '''SK&F106615''') is a substance being studied in the treatment of certain ]s and other advanced ]s. It may block the growth of tumors and the growth of ] from surrounding tissue to the ]. This drug is also being researched as a potential treatment for various ]. |
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It was first developed by ] as a potential treatment for ].<ref>{{cite journal |url=http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=1379&aTab=0 |title=Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma |author=Jacobs GS |journal=Myeloma Today |date=Spring 2004 |volume=5 |issue=10 |publisher=International Myeloma Foundation |access-date=2010-09-30 |archive-url=https://web.archive.org/web/20110718215308/http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=1379&aTab=0 |archive-date=2011-07-18 |url-status=dead }}</ref><ref name=Badger>Badger, A. M., Schwartz, D. A., Picker, D. H., Dorman, J. W., Bradley, F. C., Cheeseman, E. N., DiMartino, M. J., Hanna, N., Mirabelli, C. K. (November 1990). "Antiarthritic and supressor 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.</ref><ref>US4963557 idem Alison M. Badger, WO1989002889 (to Callisto Pharmaceuticals Inc).</ref> |
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January 7, 2008 |
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Callisto Pharmaceuticals, Inc. announced that it has restructured its license agreement with Genzyme Corporation for Atiprimod. In August 2002, Callisto’s wholly owned subsidiary, Synergy, acquired from AnorMED Inc. worldwide exclusive rights to develop, manufacture and commercialize Atiprimod. AnorMED was acquired by Genzyme in November 2006. |
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It also had application in the treatment of hyperlipidæmia:<ref>Alison Mary Badger, WO1994025024 (to SmithKline Beecham Corp).</ref> |
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The restructured agreement eliminates all milestone payments and reduces royalties owed to Genzyme to single digits. In return for the reduced future payments to Genzyme, Callisto is paying an upfront fee in 2008 |
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This compound has also been shown to kill ] cells '']''.<ref>{{cite journal | vauthors = Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, Samaniego F, Romaguera J, Yi Q | display-authors = 6 | title = Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways | journal = Blood | volume = 109 | issue = 12 | pages = 5455–5462 | date = June 2007 | pmid = 17317853 | doi = 10.1182/blood-2006-12-063958 | doi-access = free }}</ref> |
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==Mechanism of action== |
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Atiprimod has been shown to inhibit ] (growth of blood vessels) in a blood vessel model using chicken eggs. It is thought to inhibit the secretion of ] (VEGF), a growth factor that promotes angiogenesis.{{cn|date=February 2023}} |
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==Chemistry== |
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Atiprimod is an ] compound and a ] at neutral ]. |
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The harbinger for Atipromod was obviously ] . |
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The substance is an example of an ]. |
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Synergy Pharmaceuticals, Inc. (a wholly owned subsidiary of Callisto) entered into a license agreement with AnorMED Inc. to license Atiprimod from AnorMED. Atiprimod is a macrophage-targeting oral cytokine inhibitor which is being developed by AnorMED as a potential treatment for rheumatoid arthritis and other autoimmune diseases. Phase I trials have been successfully completed and Phase II multicenter trials have been approved by the FDA. The compound was discovered in a joint research and development program with SmithKline and French (now SmithKline Beecham, SB) but following acceptance of the Phase II protocol by the FDA, SB decided not to proceed with further development of atiprimod as a result of an internal restructuring program. All rights to atiprimod and other azaspiranes developed in this program have reverted to AnorMED. The compound was originally disclosed in European patent, EP-00310321, entitled 'Preparation of N-aminoalkyl-2-azaspirodecanes and analogs as immunosuppressants', while a cost-effective, efficacious pilot plant synthesis has also been described. |
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==Synthesis== |
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==Synthesis== |
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The first part of the synthesis uses protocols that were used for ] and agents including ]. |
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] |
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The second half of the synthesis shares features that are consonant with |
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[[File:Atiprimod synthesis.svg|thumb|center|500px|Synthesis:<ref name=Badger/> Patent:<ref>US4963557 idem Alison M. Badger, WO1989002889 (to Callisto Pharmaceuticals Inc). |
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</ref>]] |
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The Johnson–Corey–Chaykovsky reaction on 4-Heptanone (1) gives 2,2-dipropyloxirane (2). Treatment with Boron trifluoride etherate gave 2-Propylpentanal (3). Upon acid treatment with Methyl vinyl ketone (4) this led to 4,4-Dipropylcyclohex-2-enone (5). Catalytic hydrogenation of the enone olefin yielded 4,4-Dipropylcyclohexanone (7). The Knoevenagel condensation with ethyl 2-cyanoacetate (8) led to Cyano-(4,4-dipropyl-cyclohexylidene)-acetic acid ethyl ester (8). |
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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 (10). Treatment with acetic anhydride gave 8,8-Dipropyl-2-oxaspirodecane-1,3-dione (11). Condensation with 3-Diethylaminopropylamine (12) gave the imide and hence, 2--8,8-dipropyl-2-azaspirodecane-1,3-dione, PC15634126 (13). Finally reduction of both carbonyl groups with lithium aluminium hydride completed the synthesis of Atiprimod (14). |
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-8,8-diproply-2-azaspirodecane dimaleate | assign1 = Anormed Inc. | inventor = Dagger RE, Grady CW | gdate = 4 September 1999 }}</ref>]] |
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Dagger, R. E.; Grady, C. W.; 1999, {{US Patent|5,952,365}}. |
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==References== |
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==References== |
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{{Reflist}} |
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<references/> |
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==Further reading== |
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==Further reading== |
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{{refbegin}} |
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*{{cite journal |author=Hamasaki M, Hideshima T, Tassone P, ''et al.'' |title=Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro 4.5 decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo |journal=] |volume=105 |issue=11 |pages=4470–6 |year=2005 |month=June |pmid=15705788 |doi=10.1182/blood-2004-09-3794 |pmc=1895034}} {{PMC|1895034}} |
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* {{cite journal |vauthors=Hamasaki M, Hideshima T, Tassone P |title=Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro 4.5 decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo |journal=] |volume=105 |issue=11 |pages=4470–6 |date=June 2005 |pmid=15705788 |doi=10.1182/blood-2004-09-3794 |pmc=1895034|display-authors=etal }} |
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{{refend}} |
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==External links== |
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==External links== |
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* entry in the public domain NCI Dictionary of Cancer Terms |
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* entry in the public domain NCI Dictionary of Cancer Terms |
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{{NCI-cancer-dict}} |
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{{NCI-cancer-dict}} |
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{{Cytokine receptor modulators}} |
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{{antineoplastic-drug-stub}} |
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