Geron Corporation

Elaine C Stracker

Federico C Gaeta

Adam Antoni Galan

Patricia A Peterli-Roth

Michael R Kozlowski

Karen R Prowse

Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds characterized by the following structure: ##STR1## and their pharmaceutically acceptable salts. Y is selected from the group consisting of oxygen, sulfur, sulfonyl, sulfinyl, and --NR.sub.7 --. R.sub.1 is --TR.sub.8, where T is --C(X.sub.1)-- or --SO.sub.2 --, and R.sub.8 is selected from the group consisting of --OR.sub.9, --NHNHSO.sub.2 R.sub.9, --NHNHC(X.sub.2)OR.sub.9, --NR.sub.9 R.sub.10, --NHNHC(X.sub.2)NR.sub.9 R.sub.10, --NHCR.sub.9 R.sub.10 C(X.sub.2)NR.sub.11 R.sub.12, --NHC(X.sub.2)NR.sub.9 R.sub.10, and the piperazinyl moiety shown below: ##STR2## where n is 0 or 1, and Q.sub.n, for n=1, is --SO.sub.2 --, --C(X.sub.2)-- or --C(X.sub.2)NR.sub.10 --. R.sub.2 -R.sub.6 are selected independently from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, halogen, cyano, nitro, alkylcarbamido, arylcarbamido, dialkylcarbamido, diarylcarbamido, alkylarylcarbamido, alkylthiocarbamido, arylthiocarbamido, dialkylthiocarbamido, diarylthiocarbamido, alkylarylthiocarbamido, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamido, arylsulfonylamido, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and arylsulfinyl. X.sub.1 and X.sub.2 are selected independently from the group consisting of oxygen, and sulfur. R.sub.7 -R.sub.12 are selected independently from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycle, and heterocyclealkyl.

Telomerase inhibitors

Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds that are derivatives of pyridine aldehydes, thioaldehyde, acetals, or thioacetals. Such compounds are characterized by the following structure: ##STR1## X.sub.1 is selected from the group consisting of oxygen, sulfur, sulfone, sulfinyl, and --NR-- where R is hydrogen, alkyl, aryl, and aralkyl. R.sub.1 is --Y.sub.n R.sub.6, in which n is an integer between 0 and 10 and each Y.sub.n for n greater than 0 independently is methylene, methine, or quarternary carbon. R.sub.6, for any value of n (i.e., n is zero or non-zero), is alkyl, aryl, heterocycle, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, aralkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aldehyde, sulfo, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, and arylsulfonyl. R.sub.6 can also be a linker L selected from the group consisting of alkyl, aryl, aralkyl, heterocycle, and heterocyclealkyl, to which linker between 1 and 3 additional compounds having the structure shown as Compound I above are attached to form thereby homogeneous or heterogeneous poly pyridine aldehydes, acetals, or thioacetals as described in greater detail below. R.sub.2 is hydrogen, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, halogen, cyano, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aldehyde, sulfo, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, or arylsulfonyl. R.sub.3 and R.sub.4 are selected independently from the group consisting of hydrogen, halogen, hydroxyl, aryloxyl, alkoxyl, lower alkyl, aryl, heteroaryl, aralkyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaralkyl, nitro, amino, alkylamino, arylamino, dialkylamino, diarylamino, and arylalkylamino. Finally, R.sub.5 is selected from the group consisting of bis(alkoxy)methyl, bis(alkylthio)methyl, and --HC.dbd.X.sub.2, where X.sub.2 is oxygen or sulfur.

Compounds for treating cancer and other diseases involving telomerase activity are characterized by the following structure: ##STR1## Such compounds include those for which X.sub.1 is oxygen, sulfur, sulfone, or sulfinyl, and R.sub.1 is --Y.sub.n R.sub.6, where n is an integer between 0 and 10 and each Y.sub.n independently is methylene, methine, or quaternary carbon. R.sub.6, is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroaralkylcarbonyl, aralkylcarbonyl, arninocarbonyl, alkylarninocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, carboxaldehyde, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl. R.sub.6 can also be a linker selected from the group consisting of alkyl, aryl, and heterocycle. R.sub.2 is hydrogen, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, halogen, cyano, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, or arylsulfonyl. R.sub.3 and R.sub.4 independently can be hydrogen, amino, alkylamino, arylamino, heterocycleamino, aralkylamino, dialkylamino, diarylamino, heterocylcealkylamino, alkylcarbonyl, arylcarbonyl, nitro, halogen, hydroxyl, aryloxyl, alkoxyl, lower alkyl, aryl, heteroaryl, aralkyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, or heteroaralkyl. R.sub.5 is selected from the group consisting of iminyl, hydroximinyl, alkyliminyl, aryliminyl, aralkyliminyl, alkoximinyl, aryloximinyl, heterocycleiminyl, and cyclic iminyl. Provided, however, that R.sub.5 is not 4-methylphenyliminyl when X.sub.1 is sulfur, n is 1, Y is methylene, R.sub.2 is cyano, R.sub.3 and R.sub.4 are hydrogen, and R.sub.6 is 4-chlorophenyl.

Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds that are derivatives of pyrido�b!thiophenes, pyrido�b!furans, pyridine ethers or pyridine thioethers. Such compounds are characterized by the following structure: ##STR1## X.sub.3 is oxygen or sulfur; and the double dashed lines between X.sub.4 and X.sub.5 indicate an optional double bond, which, when present, forms a fused, bicyclic pyrido�b!furan or pyrido�b!thiophene ring system, depending upon whether X.sub.3 is oxygen or sulfur, respectively. When the double bond is not present, the compound is a monocyclic pyridine ether or thioether, again depending upon whether X.sub.3 is oxygen or sulfur. X.sub.4 is --CH.sub.2 R.sub.21 or --CR.sub.21 --, where R.sub.21 is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroaralkylcarbonyl, aralkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylarninocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl and arylsulfonyl; and X.sub.5 is hydrogen, alkyl, hydroxyl, alkoxyl, aryloxyl, halogen, cyano, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, arylsulfonyl or --CR.sub.22 -- where R.sub.22 is selected from the group consisting of hydrogen, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, hydroxyl, halogen, cyano, carboxyl, alkoxycarbonyl and aryloxycarbonyl. When X.sub.4 is --CR.sub.21 --, X.sub.5 is --CR.sub.22 --, and X.sub.4 and X.sub.5 are joined by the above-mentioned double bond, to form thereby a fused, bicyclic pyrido�b!thiophene (X.sub.3 is sulfur) or pyrido�b!furan (X.sub.3 is oxygen) ring system. When X.sub.4 is --CH.sub.2 R.sub.21, X.sub.5 is not --CR.sub.22 --, thereby forming a pyridine ether (X.sub.3 is oxygen) or thioether (X.sub.3 is sulfur). R.sub.18 and R.sub.19 are selected independently from the group consisting of hydrogen, halogen, hydroxy, aryloxy, alkoxy, lower alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl. R.sub.20 is selected from the group consisting of alkoxymethyl, dialkoxymethyl, arylalkylaminomethyl, arylaminomethyl, alkylaminomethyl, aminomethyl, diarylaminomethyl, dialkylaminomethyl, hydroximinyl, iminyl, aldehyde, alkylcarbonyl, arylcarbonyl, alkyliminyl, aryliminyl, aralkyliminyl, alkoximinyl, aryloximinyl, heterocycleimninyl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkene, --HC.dbd.NNHR.sub.23 where R.sub.23 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl, and --C(X.sub.6)NHR.sub.24 where X.sub.6 is oxygen or sulfur and R.sub.24 is selected from the group consisting of hydrogen, aryl, arylsulfonyl, aralkyl, heterocycle and heterocyclealkyl.

Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds that are derivatives of benzo�b!thiophenes. Such compounds are characterized by the following structure: ##STR1## In this compound, R.sub.1 is selected from the group consisting of --OR.sub.7, --NR.sub.8 R.sub.9, --NHNR.sub.10 R.sub.11, --NHNHC(X.sub.2)NHR.sub.12, --NHSO.sub.2 NR.sub.8 R.sub.9, --NHNHC(O)R.sub.12, --NHNHSO.sub.2 R.sub.12 and --NHC(O)NR.sub.8 R.sub.9. R.sub.7 -R.sub.12 are selected independently from the group consisting of hydrogen, alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. X.sub.1 and X.sub.2 are selected independently from the group consisting of oxygen and sulfur. R.sub.2 is hydrogen or halogen. R.sub.3 -R.sub.6 are selected independently from the group consisting of hydrogen, halogen, hydroxyl, --NR.sub.8 R.sub.9, nitro, cyano, alkoxyl, lower alkyl, aryl and aryloxyl.

Telomerase Inhibitors

Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds characterized by the following structure: ##STR1## and its pharmaceutically acceptable salts. Z is selected from the group consisting of oxygen, sulfur, sulfone, sulfinyl and --NR--, where R selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. R.sub.1 is --Y.sub.n R.sub.6, where n is an integer between 0 and 10 and each Y.sub.n for n greater than 0 independently is methylene, methine, or quaternary carbon, and R.sub.6, for any value of n, is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroaralkylcarbonyl, aralkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl. R.sub.2 is hydrogen, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, halogen, cyano, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, or arylsulfonyl. R.sub.3 and R.sub.4 are selected independently from the group consisting of hydrogen, amino, alkylamino, arylamino, heterocycleamino, aralkylamino, heterocylcealkylamino, dialkylamino, diarylamino, arylalkylamino, nitro, halogen, hydroxyl, aryloxyl, alkoxyl, lower alkyl, aryl, heteroaryl, aralkyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and heteroaralkyl. Finally, R.sub.5 is selected from the group consisting of iminyl, hydroximinyl, alkyliminyl, aryliminyl, aralkyliminyl, alkoximinyl, aryloximinyl, heterocycleiminyl, cyclic iminyl, bis(alkylthio)methyl, bis(arylthio)methyl, bis(alkoxy)methyl, bis(aryloxy)methyl, carboxaldehyde, hydroxymethyl, alkoxymethyl, aryloxymethyl, aralkoxymethyl, heterocycleoxymethyl, heterocyclealkoxymethyl, and --HC.dbd.NNHR.sub.7 where R.sub.7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl, and --C(.dbd.X.sub.1)(X.sub.2).sub.p R.sub.8 where p is 0 or 1, X.sub.1 is oxygen or sulfur, X.sub.2 is selected from the group consisting of oxygen, sulfur, and --NR.sub.9 --, where R.sub.8 and R.sub.9 are selected independently from the group consisting of hydrogen, alkyl, aryl, aralkyl, and heterocycle.

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Vacaville, CA, United States of America

Elaine C Stracker