Title:
ANTIZYME MODULATORS AND THEIR USE
Document Type and Number:
WIPO Patent Application WO/2000/046187
Kind Code:
A2
Abstract:
The present invention is directed to agmatine and polyamine analogs and their use as drugs, as well as agricultural or environmentally useful agents. As drugs, the analogs decrease cellular polyamine levels, possibly by inducing antizyme, and can be used to treat disorders of undesired cell proliferation, including cancer, viral infections and bacterial infections. The analogs may be utilized in pharmaceutical compositions either alone or in combination with other agents, particularly other inhibitors of polyamine synthesis or transport, but including other inhibitors of cell proliferation. The analogs are not necessarily metabolized to contribute to the polyamine pool and are designed to enter cells by pathways independent of polyamine transport. The invention further defines structural elements/motifs within these analogs that are key to their induction of antizyme.
Inventors:
VERMEULIN NICOLAAS M J (US)
BURNS MARK R (US)
WEBB HEATHER K (US)
BURNS MARK R (US)
WEBB HEATHER K (US)
Application Number:
PCT/US2000/002972
Publication Date:
August 10, 2000
Filing Date:
February 04, 2000
Export Citation:
Assignee:
ORIDIGM CORP (US)
VERMEULIN NICOLAAS M J (US)
BURNS MARK R (US)
WEBB HEATHER K (US)
VERMEULIN NICOLAAS M J (US)
BURNS MARK R (US)
WEBB HEATHER K (US)
International Classes:
A61K31/132; C07D233/24; A61K31/137; A61K31/155; A61K31/16; A61K31/17; A61K31/18; A61K31/343; A61K31/381; A61K31/4168; A61K31/4178; A61K31/427; A61K31/444; A61K31/454; A61K31/4545; A61K31/473; A61P35/00; C07C211/09; C07C211/14; C07C211/15; C07C211/27; C07C211/49; C07C211/53; C07C211/54; C07C215/58; C07C217/58; C07C233/13; C07C233/36; C07C233/37; C07C237/10; C07C251/38; C07C275/28; C07C279/00; C07C279/12; C07C279/26; C07C311/05; C07C311/10; C07C311/18; C07C311/29; C07C311/41; C07D211/14; C07D211/26; C07D213/36; C07D219/04; C07D233/16; C07D233/52; C07D295/13; C07D307/91; C07D333/34; C07D401/14; C07D417/04; C40B40/04; (IPC1-7): C07C279/00
Domestic Patent References:
| WO1999003823A2 | 1999-01-28 |
Foreign References:
| US5498522A | 1996-03-12 | |||
| US5677350A | 1997-10-14 |
Other References:
CHEMICAL ABSTRACTS, vol. 129, no. 12, 21 September 1998 (1998-09-21) Columbus, Ohio, US; abstract no. 147272, SATRIANO, JOSEPH ET AL: "Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels" XP002142375 & J. BIOL. CHEM. (1998), 273(25), 15313-15316 ,
BEILSTEIN INFORMATION SERVICE FILE: XFIRE, XP002142374
BEILSTEIN INFORMATION SERVICE FILE: XFIRE, XP002142374
Attorney, Agent or Firm:
Lau, Kawai (2000 Pennsylvania Avenue N.W, Washington DC, US)
Download PDF:
Claims:
CLAIMS
| 1. | A polyamine analog of spermine comprising four amine groups capable of forming four positive charges at physiological pH, wherein the first and second amine groups, and the third and fourth amine groups, are separated by the distance of four CC and/or CN bonds and said second and third amine groups are separated by the distance of five CC and/or CN bonds or more, wherein said analog induces expression of fulllength antizyme. |
| 2. | The analog of claim 1 wherein said second and third amine groups are separated byCH2GroupCH2 wherein said Group is a C210, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; C3to alicyclic; single or multiring aromatic or aryl; aryl substituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynyl substituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphaticsubstituted aromatic; heterocyclic substituted alkyl, alkenyl or alkynyl; or alkyl, alkenyl, or alkynylsubstituted heterocyclic. |
| 3. | The analog of claim 2 wherein said Group is a single or multiring aromatic or aryl; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynylsubstituted aryl; a single or multiring heterocyclic; an aliphaticsubstituted aromatic; or alkyl, alkenyl, or alkynylsubstituted heterocyclic. |
| 4. | The analog of claim 3 wherein said Group is any one of the following wherein Gi isH; a C210, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; C310 alicyclic; single or multiring aromatic or aryl; aryl substituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynyl substituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphaticsubstituted aromatic; heterocyclic substituted alkyl, alkenyl or alkynyl; alkyl, alkenyl, or alkynylsubstituted heterocyclic; or combinations thereof. |
| 5. | The analog of claim 4 wherein G, isH,CH3,CH2CH3,CH2Ph, <BR> <BR> <BR> NH2,NHCOCH3,N3,CN,F,CL,BR,I,CF3,OCH3,OCH2Ph,COCH3, COOH,COOCH3,COOCH2CH3,COOCH2Ph,OCH2CH20,C (NH2) =NH, or combinations thereof. |
| 6. | The analog of any one of claims 15 futher comprising a substituent on one or more of said amine groups or on one or more adjacent carbon atoms. |
| 7. | The analog of claim 6 wherein said one or more adjacent carbon atoms are one or both of the terminal carbon atoms in spermine. |
| 8. | The analog of claim 6 or 7 wherein said substituent is a Cllo, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; C310 alicyclic; single or multiring aromatic or aryl; arylsubstituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynylsubstituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphatic substituted aromatic; heterocyclicsubstituted alkyl, alkenyl or alkynyl; or alkyl, alkenyl, or alkynylsubstituted heterocyclic. |
| 9. | The analog of claim 8 wherein said substituent is methyl, ethyl, phenyl, or CH2Ph. |
| 10. | The analog of claim 9 that is analog 1283. |
| 11. | A polyamine analog of spermidine comprising three amine groups capable of forming three positive charges at physiological pH, wherein the first and second amine groups are separated by the distance of five CC and/or CN bonds and said second and third amine groups are separated by the distance of four CC and/or CN bonds, wherein said analog induces expression of fulllength antizyme. |
| 12. | The analog of claim 11 futher comprising a substituent on one or more of said amine groups or on one or more adjacent carbon atoms. |
| 13. | The analog of claim 12 wherein said one or more adjacent carbon atoms are one or both of the terminal carbon atoms in spermine. |
| 14. | The analog of claim 12 wherein said subsituent is a carboxylic amide or sulfonamide amide on the N'position of spermine. |
| 15. | The analog of claim 14 wherein said carboxylic amide is an alkyl or aryl carboxylic substituent comprising a C210, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; ¬310 alicyclic; single or multiring aromatic or aryl; arylsubstituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynylsubstituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphaticsubstituted aromatic; heterocyclic substituted alkyl, alkenyl or alkynyl; or alkyl, alkenyl, or alkynylsubstituted heterocyclic. |
| 16. | The analog of claim 15 wherein said sulfonamide amide is an alkyl or aryl sulfonamide substituent comprising a C2io, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; C310 alicyclic; single or multiring aromatic or aryl; arylsubstituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynylsubstituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphaticsubstituted aromatic; heterocyclicsubstituted alkyl, alkenyl or alkynyl; or alkyl, alkenyl, or alkynyl substituted heterocyclic. |
| 17. | The analog of claim 15 or 16 wherein said alkyl containing substituent further contains a halide or said alkoxy moiety is methoxy, ethoxy, and substituted or unsubstituted benzyloxy. |
| 18. | The analog of claim 17 that is analog 1041. |
| 19. | A polyamine analog of putrescine comprising two amine groups capable of forming two positive charges at physiological pH, separated by the distance of five CC, CO, NO, and/or CN bonds or more, wherein said analog induces expression of fulllength antizyme and is not agmatine. |
| 20. | The analog of claim 19 futher comprising one or more substituents on one or more of said amine groups or on one or more adjacent carbon atoms. |
| 21. | The analog of claim 20 wherein said one or more substituents is a Cl , 0, straight or branched, alkyl, alkenyl, alkynyl, alkoxy, or aliphatic; C310 alicyclic; single or multiring aromatic or aryl; arylsubstituted alkyl, alkenyl or alkynyl; single or multiring aryl substituted aliphatic; aliphaticsubstituted single or multiring aromatic; alkyl, alkenyl, or alkynylsubstituted aryl; a single or multiring heterocyclic; a single or multiring heterocyclicsubstituted aliphatic; an aliphaticsubstituted aromatic; heterocyclicsubstituted alkyl, alkenyl or alkynyl; or alkyl, alkenyl, or alkynylsubstituted heterocyclic. |
| 22. | The analog of claim 21 wherein said one or more substituents isH, CH3,CH2CH3, andCH2CH2. |
| 23. | The analog of claim 22 that is 1,4diaminobutane with monomethyl or dimethyl substitutents in the 1,2,3 or 4 position; 1,4, 1,3, or 1,2 dimethyl diaminobutane; bis1, 4cyclopropyl1, 4diaminobutane; and 1,1,4,4<BR> tetramethyldiaminobutane. |
| 24. | The analog of claim 21 that is analog 1354. |
| 25. | A pharmaceutical composition comprising an analog of any one of the preceding claims. |
| 26. | A method of inducing fulllength antizyme expression comprising contacting an antizyme expression system with an analog of any one of the preceding claims. |
| 27. | A method of inhibiting cell growth comprising contacting said cell with an analog of any one of the preceding claims. |
Description:
INTERNATIONALSEARCHREPORT IMPcrti'lonal ApplicationNo PCT/US00/02972 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindication,whereappropnate,of
therelevantpassagesRelevanttoclaimNo. ACHEMICALABSTRACTS,vol.129,no.12,1-27 21September1998(1998-09-21) Columbus,Ohio,US; abstractno.147272, SATRIANO,JOSEPHETAL:"Agmatine suppressesproliferationbyframeshift inductionofantizymeandattenuationof cellularpolyaminelevels" XP002142375 abstract &J.BIOL.CHEM.(1998),273(25), 15313-15316, XBEILSTEININFORMATIONSERVICEFILE:19-23 XFIRE,XP002142374 seeBRN:1719247,1735364,1732596, 1735401 1 . mabonal applicabonNo. INTERNATIONALSEARCHREPORTPCT/US00/02972 Box I Observationswherecertainclaimswerefoundunsearchable(Continua
tionofitem1offirstsheet) ThisInternationalSearchReporthasnotbeenestablishedinrespecto
fcertainclaimsunderArticle17(2)(a)forthefollowingreasons: 1.iClaims Nos.: becausetheyrelatetosubjectmatternotrequiredtobesearchedbythi
sAuthority,namely: Althoughclaims26and27aredirectedtoamethodoftreatmentofthe human/animalbody,thesearchhasbeencarriedoutandbasedonthealle
ged effectsofthecompound/composition. 2.EClaimsNos.:1-27partially becausetheyrelatetopartsoftheinternationalApplicationthatdon
otcomplywiththeprescribedrequirementstosuch anextentthatnomeaningfulinternationalSearchcanbecarriedout,s
pecifically: seeFURTHERINFORMATIONsheetPCT/ISA/210 3.QClaimsNos.: becausetheyaredependentclaimsandarenotdraftedinaccordancewit
hthesecondandthirdsentencesofRule6.4(a). BoxliObservationswhereunityofinventionislacking(Continuation
ofitem2offirstsheet) ThisinternationalSearchingAuthorityfoundmultipleinventionsin
thisinternationalapplication,asfollows: 1. 12 As allrequiredadditionalsearchfeesweretimelypaidbytheapplicant,
thisInternationalSearchReportcoversall searchableclaims. 2.2 Asallsearchableclaimscouldbesearchedwithouteffortjustifyinga
nadditionalfee,thisAuthoritydidnotinvitepayment ofanyadditionalfee. 3.As onlysomeoftherequiredadditionalsearchfeesweretimelypaidbythe
applicant,thisInternationalSearchReport covers onlythoseclaimsforwhichfeeswerepaid,specificallyclaimsNos.: 4.No requiredadditionalsearchfeesweretimefypaidbytheapplicant.Con
sequently,thisinternationalSearchReportis restrictedtotheinventionfirstmentionedintheclaims;itiscovere
dbyclaimsNos.: RemarkonProtestThe additionalsearchfeeswereaccompaniedbytheapplicant'sprotest. u Noprotestaccompaniedthepaymentofadditionalsearchfees. u FURTHER INFORMAMON CONTINUED FROM PCT/ISA/210 Continuation of Box 1.2 Claims Nos.: 1-27 partially 1. The wording"wherein said analog induces expression of full-length antizyme"renders the scope of present claims 1 to 24 unclear. Such an intended definition for a compound is to be regarded as a mere result to be achieved and not as a feature characterizing a compound.
Due to this definition it is not clear neither from the claims nor from the description, if the application is directed to the compounds per se or to the use of the compounds for induction of expression of full-length antizyme.
It is further noticed that such a use (induction of expression of full-length antizyme) in itself is no clear medical use.
2. Present claims 1-9,11-17,19-22 relate to an extremely large number of possible compounds. Support within the meaning of Article 6 PCT and/or disclosure within the meaning of Article 5 PCT is to be found, however, for only a very small proportion of the compounds claimed. In the present case, the claims so lack support, and the application so lacks disclosure, that a meaningful search over the whole of the claimed scope is impossible. In particular due to the unclear definitton wanalogw as well as to the unlimited definitions of the possible groups and substituents ('substituted alkyl, alkenyl, multi-ring substituted aliphaticw etc. a meaningful search is impossible.
The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. INTERNATIONALSEARCHREPORT * « A_No PCT/US00/02972 Patentdocument PubHcaOon Pttttnttanxty PuMioMton a<ed) nseatchn) pMt date nwtOefts) date WO9903823A28-01-1999AU8496898A10-02-1999 EP1001927A24-05-2000 US5498522A12-03-1996CA2094341A29-10-1993 EP0568338A03-11-1993 JP6062896A08-03-1994 US5677350A14-10-1997AU6381996A30-12-1996 WO9640096A19-12-1996 i
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