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US 5,686,444 AGranted
Selected soluble esters of hydroxyl-containing indolocarbazoles
AssigneesCephalon, Inc., Kyowa Hakko Kogyo Co., Ltd.
InventorsJohn P. Mallamo, Robert L. Hudkins
Life of this patent
Estimating the term…
Abstract
Esters of hydroxyl-containing indolocarbazoles and acids containing selected solubilizing groups are provided. Compositions including the indolocarbazole esters and methods for the use of the indolocarbazole esters are also provided.
Claims35
An indolocarbazole ester of formula Q--L--C(.dbd.O)--A wherein:
- A is a solubilizing group selected from the group consisting of an amino acid residue, a dipeptide residue, --(CH.sub.2).sub.m Z, --(CH.sub.2).sub.m C(.dbd.O)NH(CH.sub.2).sub.m Z, --(CH.sub.2).sub.m C(.dbd.O)NH--Z, --(CH.sub.2).sub.m Z(CH.sub.2).sub.m Z, branched --(CH.sub.2).sub.n CH(CH.sub.2).sub.m Z!.sub.2, --(CH.sub.2).sub.m --Z(CH.sub.2).sub.m Z!.sub.2, --(CH.sub.2).sub.n --A.sup.1, --(CH.sub.2).sub.n -heteroaryl and --NH(CH.sub.2).sub.m N(CH.sub.3).sub.2 ;
- wherein:
- n is an integer from 0 to 5;
- m is an integer from 1-6;
- Z is selected from the group consisting of a basic group, --C(.dbd.NH)NH.sub.2, cyclic amidine, --NHC(NH.sub.2).dbd.NR.sup.11, cyclic guanidine and an acidic group;
- and
- A.sup.1 is aryl or heteroaryl substituted with one to three substituents of formula --(CH.sub.2).sub.n Z;
- L is oxygen;
- and
- Q is an indolocarbazole residue of the formula:
- ##STR9## wherein:
- R.sup.1 is hydrogen, carbamoyl, lower alkyl, amino, lower alkanoyl, --CH.sub.2 R.sup.5 or --CH.sub.2 CH.sub.2 R.sup.5 ;
- R.sup.5 is halogen, amino, di-lower alkylamino, hydroxyl, a single bond attached to --L--C(.dbd.O)--A, or lower alkylamino optionally substituted with hydroxyl or a single bond attached to --L--C(.dbd.O)--A;
- R.sup.2 and R.sup.3 are independently hydrogen, hydroxyl, cyano, lower alkoxy, halogen, hydroxymethyl, lower alkoxymethyl, lower alkylthiomethyl, lower alkylsulfinylmethyl, arylthiomethyl, heteroarylthiomethyl, arylsulfinylmethyl, heteroarylsulfinylmethyl, arylmethylthiomethyl, heteroarylmethylthiomethyl, CH.dbd.NNHC(.dbd.NH)NH.sub.2, nitro, lower alkanoyl, lower alkanoyloxy, sulfonic acid, --SO.sub.2 NR.sup.8 R.sup.9, --OC(.dbd.O)NR.sup.8 R.sup.9, --CH.dbd.NNR.sup.8 R.sup.9, --NR.sup.6 R.sup.7, --OCO.sub.2 R.sup.10, --NHC(.dbd.O)NHR.sup.11, --CH.sub.2 OC(.dbd.O)NHR.sup.11, --NHCO.sub.2 R.sup.11, lower alkyl sulfonylmethyl, (dialkylamino)alkylthiomethyl, a single bond attached to --L--C(.dbd.O)--A, or lower alkyl optionally substituted with hydroxyl or a single bond attached to --L--C(.dbd.O)--A;
- one of R.sup.6 and R.sup.7 is hydrogen and the other is hydrogen, lower alkyl, carbamoyl, lower alkylaminocarbonyl, lower alkanoyl or phenylaminocarbonyl;
- or R.sup.6 and R.sup.7 are both lower alkyl;
- R.sup.8 and R.sup.9 are independently hydrogen, lower alkyl, aryl, heteroaryl or R.sup.8 and R.sup.9, together with the nitrogen atom to which they are attached, form a heterocycle;
- R.sup.10 is lower alkyl or substituted or unsubstituted phenyl;
- R.sup.11 is hydrogen or lower alkyl;
- R.sup.4 is hydrogen, amino or --NHC(.dbd.O)NHC.sub.2 H.sub.5 ;
- one of W.sup.1 and W.sup.2 is hydrogen, and the other is selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower alkylthio and a single bond attached to --L--C(.dbd.O)--A, or W.sup.1 and W.sup.2 combined together are oxygen;
- X is hydrogen, --CH.sub.2 --NHC(.dbd.O)O--C.sub.6 H.sub.5, formyl, carboxyl, alkoxycarbonyl having from 2 to 13 carbons, cycloalkoxycarbonyl having from 4 to 11 carbons, --(CH.sub.2).sub.n CH.sub.2 N(R.sup.11).sub.2 wherein n is an integer from 0 to 5, --C(.dbd.O)NR.sup.12 R.sup.13, --CH.sub.2 B, --NR.sup.14 R.sup.15, --N.dbd.CHN(CH.sub.3).sub.2, --OCOCH.sub.2 CH.sub.2 CO.sub.2 H, lower alkylhydrazinocarbonyl, --CH.dbd.N--R.sup.16, --CONHR.sup.17, a group of formula:
- ##STR10## R.sup.12 and R.sup.13 are independently hydrogen, lower alkyl, phenyl, lower alkyl optionally substituted by hydroxyl or by a single bond attached to --L--C(.dbd.O)--A, or R.sup.12 and R.sup.13 are combined together to form a 3-6 carbon heterocyclic ring which optionally contains at least one O, S and/or additional N heteroatom, or R.sup.12 is hydrogen and R.sup.13 is hydroxyl, phenyl, or a single bond attached to --L--C(.dbd.O)--A;
- B is hydroxyl, lower alkoxy, lower alkanoyloxy, azido, lower alkylthio, arylthio, heteroarylthio, lower alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl or a single bond attached to --L--C(.dbd.O)--A;
- one of R.sup.14 or R.sup.15 is hydrogen and the other is hydrogen, lower alkyl, allyl, carboxyl-substituted lower alkyl, carbamoyl, lower alkyl- or aryl-substituted carbamoyl, a residue of an .alpha.-amino acid in which the carboxylate hydrogen is removed, or lower alkoxycarbonyl-substituted lower alkyl;
- or both R.sup.14 and R.sup.15 are lower alkyl or chlorine-substituted lower alkyl;
- or R.sup.14 and R.sup.15 are combined together to form --CH.sub.2 CH.sub.2 DCH.sub.2 CH.sub.2 -- wherein D is --CH.sub.2 --, --NH--, --S-- or --O--;
- R.sup.16 is hydroxyl, carbamoylamino, --NR.sup.8 R.sup.9 guanidino, 2-imidazolylamino or a single bond attached to --L--C(.dbd.O)--A;
- R.sup.17 is the residue of an .alpha.-amino acid after removal of the amino group thereof, wherein the carboxyl group of the .alpha.-amino acid is optionally esterified by a lower alkyl alcohol or benzyl alcohol;
- Y is hydroxyl, lower alkanoyloxy, carbamoyloxy, lower alkoxy, or a single bond attached to --L--C(.dbd.O)--A, or X and Y together may be --CH.sub.2 OC(CH.sub.3).sub.2 O--, O.dbd., --CH.sub.2 O--, --CH.sub.2 OCO.sub.2 --, --CH.sub.2 OC(.dbd.S)O--, --CH.sub.2 N(R.sup.18)CO.sub.2 --, --CH.sub.2 NHC(.dbd.S)O--, --CH.sub.2 OS(.dbd.O)O--, --OC(.dbd.S)NHCH.sub.2 -- or --O--C(R.sup.19).dbd.N--CH.sub.2 --;
- R.sup.18 is hydrogen, lower alkyl, allyl, formylmethyl, --CH.sub.2 CH.dbd.NNHC(.dbd.NH)NH.sub.2, --CH.sub.2 CH(--G)CH.sub.2 --J wherein G and J are independently hydroxyl or one of them is a single bond attached to --L--C(.dbd.O)--A;
- and
- R.sup.19 is lower alkyl or lower alkylthio;
- provided that one of R.sup.2, R.sup.3, R.sup.5, W.sup.1, W.sup.2, X and Y contains a single bond attached to --L--C(.dbd.O)--A;
- provided that where R.sup.1, R.sup.2, R.sup.3, R.sup.4, W.sup.1 and W.sup.2 are H, Y cannot be hydroxyl when X is --CH.sub.2 --O--C(.dbd.O)CH.sub.2 NH.sub.2 or --CH.sub.2 --O--C(.dbd.O)CH.sub.2 NH-cbz;
- and further provided that the solubilizing group A is other than 3-dimethylaminobutyric acid, lysyl-.beta.-alanine and a residue of succinic acid.
33 more elements
An indolocarbazole ester of formula Q--L--C(.dbd.O)--A wherein:
- A is 3-dimethylaminobutyric acid or lysyl-.beta.-alanine;
- L is oxygen;
- and
- Q is an indolocarbazole residue of the formula:
- ##STR11## wherein:
- R.sup.1 is --CH.sub.2 R.sup.5 ;
- R.sup.5 is halogen, amino, di-lower alkylamino, hydroxyl, a single bond attached to --L--C(.dbd.O)--A, or lower alkylamino optionally substituted with hydroxyl or a single bond attached to --L--C(.dbd.O)--A;
- R.sup.2 and R.sup.3 are independently hydrogen, hydroxyl, cyano, lower alkoxy, halogen, hydroxymethyl, lower alkoxymethyl, lower alkylthiomethyl, lower alkylsulfinylmethyl, arylthiomethyl, heteroarylthiomethyl, arylsulfinylmethyl, heteroarylsulfinylmethyl, arylmethylthiomethyl, heteroarylmethylthiomethyl, CH.dbd.NNHC(.dbd.NH)NH.sub.2, nitro, lower alkanoyl, lower alkanoyloxy, sulfonic acid, --SO.sub.2 NR.sup.8 R.sup.9, --OC(.dbd.O)NR.sup.8 R.sup.9, --CH.dbd.NNR.sup.8 R.sup.9, --NR.sup.6 R.sup.7, --OCO.sub.2 R.sup.10, --NHC(.dbd.O)NHR.sup.11, --CH.sub.2 OC(.dbd.O)NHR.sup.11, --NHCO.sub.2 R.sup.11, lower alkyl sulfonylmethyl, (dialkylamino)alkylthiomethyl, a single bond attached to --L--C(.dbd.O)--A, or lower alkyl optionally substituted with hydroxyl or a single bond attached to --L--C(.dbd.O)--A;
- one of R.sup.6 and R.sup.7 is hydrogen and the other is hydrogen, lower alkyl, carbamoyl, lower alkylaminocarbonyl, lower alkanoyl or phenylaminocarbonyl;
- or R.sup.6 and R.sup.7 are both lower alkyl;
- R.sup.8 and R.sup.9 are independently hydrogen, lower alkyl, aryl, heteroaryl or R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached, form a heterocycle;
- R.sup.10 is lower alkyl or substituted or unsubstituted phenyl;
- R.sup.11 is hydrogen or lower alkyl;
- R.sup.4 is hydrogen, amino or --NHC(.dbd.O)NHC.sub.2 H.sub.5 ;
- one of W.sup.1 and W.sup.2 is hydrogen, and the other is selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower alkylthio and a single bond attached to --L--C(.dbd.O)--A, or W.sup.1 and W.sup.2 combined together are oxygen;
- X is hydrogen, --CH.sub.2 --NHC(.dbd.O)O--C.sub.6 H.sub.5, formyl, carboxyl, alkoxycarbonyl having from 2 to 13 carbons, cycloalkoxycarbonyl having from 4 to 11 carbons, --(CH.sub.2).sub.n CH.sub.2 N(R.sup.11).sub.2 wherein n is an integer from 0 to 5, --C(.dbd.O)NR.sup.12 R.sup.13, --CH.sub.2 B, --NR.sup.14 R.sup.15, --N.dbd.CHN(CH.sub.3).sub.2, --OCOCH.sub.2 CH.sub.2 CO.sub.2 H, lower alkylhydrazinocarbonyl, --CH.dbd.N--R.sup.16, --CONHR.sup.17, a group of formula:
- ##STR12## R.sup.12 and R.sup.13 are independently hydrogen, lower alkyl, phenyl, lower alkyl optionally substituted by hydroxyl or by a single bond attached to --L--C(.dbd.O)--A, or R.sup.12 and R.sup.13 are combined together to form a 3-6 carbon heterocyclic ring which optionally contains at least one O, S and/or additional N heteroatom, or R.sup.12 is hydrogen and R.sup.13 is hydroxyl, phenyl, or a single bond attached to --L--C(.dbd.O)--A;
- B is hydroxyl, lower alkoxy, lower alkanoyloxy, azido, lower alkylthio, arylthio, heteroarylthio, lower alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl or a single bond attached to --L--C(.dbd.O)--A;
- one of R.sup.14 or R.sup.15 is hydrogen and the other is hydrogen, lower alkyl, allyl, carboxyl-substituted lower alkyl, carbamoyl, lower alkyl- or aryl-substituted carbamoyl, a residue of an .alpha.-amino acid in which the carboxylate hydrogen is removed, or lower alkoxycarbonyl-substituted lower alkyl;
- or both R.sup.14 and R.sup.15 are lower alkyl or chlorine-substituted lower alkyl;
- or R.sup.14 and R.sup.15 are combined together to form --CH.sub.2 CH.sub.2 DCH.sub.2 CH.sub.2 -- wherein D is --CH.sub.2 --, --NH--, --S-- or --O--;
- R.sup.16 is hydroxyl, carbamoylamino, --NR.sup.8 R.sup.9 guanidino, 2-imidazolylamino or a single bond attached to --L--C(.dbd.O)--A;
- R.sup.17 is the residue of an .alpha.-amino acid after removal of the amino group thereof, wherein the carboxyl group of the .alpha.-amino acid is optionally esterified by a lower alkyl alcohol or benzyl alcohol;
- Y is hydroxyl, lower alkanoyloxy, carbamoyloxy, lower alkoxy, or a single bond attached to --L--C(.dbd.O)--A, or X and Y together may be --CH.sub.2 OC(CH.sub.3).sub.2 O--, O.dbd., --CH.sub.2 O--, --CH.sub.2 OCO.sub.2 --, --CH.sub.2 OC(.dbd.S)O--, --CH.sub.2 N(R.sup.18)CO.sub.2 --, --CH.sub.2 NHC(.dbd.S)O--, --CH.sub.2 OS(.dbd.O)O--, --OC(.dbd.S)NHCH.sub.2 -- or --O--C(R.sup.19).dbd.N--CH.sub.2 --;
- R.sup.18 is hydrogen, lower alkyl, allyl, formylmethyl, --CH.sub.2 CH.dbd.NNHC(.dbd.NH)NH.sub.2, --CH.sub.2 CH(--G)CH.sub.2 --J wherein G and J are independently hydroxyl or one of them is a single bond attached to --L--C(.dbd.O)--A;
- and
- R.sup.19 is lower alkyl or lower alkylthio;
- provided that one of R.sup.2, R.sup.3, R.sup.5, W.sup.1, W.sup.2, X and Y contains a single bond attached to --L--C(.dbd.O)--A.
- and further provided that where R.sup.1, R.sup.2, R.sup.3, R.sup.4, W.sup.1 and W.sup.2 are H, Y cannot be hydroxyl when X is --CH.sub.2 --O--C(.dbd.O)CH.sub.2 NH.sub.2 or --CH.sub.2 --O--C(.dbd.O)CH.sub.2 NH-cbz.
26 more elements
Dependencies are inferred from the claim text.