QUINOLINE DERIVATIVES FOR MODULATING DNA METHYLATION
First Claim
1. A compound of formula (I), or a physiologically acceptable salt or a phosphate prodrug, or a carboxylic acid or aminoacid ester prodrug thereof, wherein G1, G2, G3, and G4 are each independently C, N, or N+ (where an R6-R9 is attached to N);
- G5 and G6 are each independently CH or N;
G7 and G8 are each independently CH, C (where an R2 is attached to C), N, or N+ (where an R2 is attached to N),D1 and D2 are each separately CH, C (where R3 attached to C), N, or N+ (where an R3 is attached to N).R6, R7, R8, and R9 are each separately H, halogen, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2, or CH2R4, wherein R4 and R5 are each independently H, lower C1-C6 alkyl or cycloalkyl optionally substituted with amino, hydroxyl or methoxy groups, or with one or more oxygen or nitrogen atoms as part of the cycloalkyl structure which may represent morpholine, pyrrolidine, piperidine, imidazole or 4-methylpiperazine, or may be substitution of a —
CH═
ring carbon by —
N═
,R2 and R3 are each independently H, NHR4, NR4R5, OR4, NO2 or CH2R4, wherein R4 and R5 are defined as above,X may be H or C1-C6 alkyl optionally substituted with amino, hydroxyl or methoxy groups, or with one or more oxygen or nitrogen atoms as part of a cycloalkyl structure which may represent azetidine, pyrrolidine, piperidine, piperazine, or morpholine;
Y may be CONR4, NR4CO, O, S(O)n [n=0 to 2], (CH2)k [k=1 to 6], —
CH═
CH—
, NR4, or a direct link between the two aromatic rings (i.e., a C—
C bond between the two aromatic rings), wherein R4 and R5 are defined as above;
o, m and p represent positions of attachment of the moiety Z;
Z may be one of the groups Q1-Q43 represented in formula (II);
wherein A is O or NR4, wherein R4 is defined as above, G9-G13 are each independently C, N, or N+ (where an R10-R13 is attached to N);
but at least three of G9-G13 are C; and
R10, R11, R12, R13, and R14 are each separately H, halogen, alkyl, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2 or CH2R4, wherein R4 and R5 are as defined above.
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Accused Products
Abstract
Quinoline derivatives, particularly 4-anilinoquinoline derivatives, are provided. Such quinoline derivatives can be used for modulation of DNA methylation, such as effective inhibition of methylation of cytosine at the C-5 position, for example via selective inhibition of DNA methyltransferase DNMT1. Methods for synthesizing numerous 4-anilinoquinoline derivatives and for modulating DNA methylation are provided. Also provided are methods for formulating and administering these compounds or compositions to treat conditions such as cancer and hematological disorders.
49 Citations
35 Claims
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1. A compound of formula (I), or a physiologically acceptable salt or a phosphate prodrug, or a carboxylic acid or aminoacid ester prodrug thereof,
wherein G1, G2, G3, and G4 are each independently C, N, or N+ (where an R6-R9 is attached to N); - G5 and G6 are each independently CH or N;
G7 and G8 are each independently CH, C (where an R2 is attached to C), N, or N+ (where an R2 is attached to N),D1 and D2 are each separately CH, C (where R3 attached to C), N, or N+ (where an R3 is attached to N). R6, R7, R8, and R9 are each separately H, halogen, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2, or CH2R4, wherein R4 and R5 are each independently H, lower C1-C6 alkyl or cycloalkyl optionally substituted with amino, hydroxyl or methoxy groups, or with one or more oxygen or nitrogen atoms as part of the cycloalkyl structure which may represent morpholine, pyrrolidine, piperidine, imidazole or 4-methylpiperazine, or may be substitution of a —
CH═
ring carbon by —
N═
,R2 and R3 are each independently H, NHR4, NR4R5, OR4, NO2 or CH2R4, wherein R4 and R5 are defined as above, X may be H or C1-C6 alkyl optionally substituted with amino, hydroxyl or methoxy groups, or with one or more oxygen or nitrogen atoms as part of a cycloalkyl structure which may represent azetidine, pyrrolidine, piperidine, piperazine, or morpholine; Y may be CONR4, NR4CO, O, S(O)n [n=0 to 2], (CH2)k [k=1 to 6], —
CH═
CH—
, NR4, or a direct link between the two aromatic rings (i.e., a C—
C bond between the two aromatic rings), wherein R4 and R5 are defined as above;o, m and p represent positions of attachment of the moiety Z; Z may be one of the groups Q1-Q43 represented in formula (II); wherein A is O or NR4, wherein R4 is defined as above, G9-G13 are each independently C, N, or N+ (where an R10-R13 is attached to N);
but at least three of G9-G13 are C; andR10, R11, R12, R13, and R14 are each separately H, halogen, alkyl, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2 or CH2R4, wherein R4 and R5 are as defined above. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)
- G5 and G6 are each independently CH or N;
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2. A compound of formula (III),
or a pharmaceutically acceptable salt, a phosphate prodrug, or a carboxylic acid or amino acid ester prodrug thereof, wherein R6, R7, R8, and R9 are each separately H, halogen, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2 or CH2R4, wherein R4 and R5 are each independently H, C1-C6 alkyl, or cycloalkyl that is optionally substituted with one or more amino, hydroxyl or methoxy groups; -
X is H, or C1-C6 alkyl that is optionally substituted with one or more amino, hydroxyl or methoxy groups; Y is CONR4, NR4CO, O, S(O)n (n=0 to
2), (CH2)k (k=1 to
6), —
CH═
CH—
, or NR4, where R4 and R5 are defined as above;G7 and G8 are each independently CH or N, D1 and D2 are each independently CH or N, o, m and p represent positions of attachment of the moiety Z; Z is one of the groups Q1-Q43 represented in formula (II) above, wherein, A is O or NR4, where R4 is defined as above; G9-G13 are each independently C, N, or N+ (where an R10-R13 is attached to N), but at least three of G9 G13 are C, R10, R11, R12, R13, and R14 are each separately H, halogen, alkyl, CF3, OCF3, CN, CONHR4, CONR4R5, SO2Me, SO2NHR4, SO2NR4R5, NHCOR4, NHR4, NR4R5, OR4, NO2 or CH2R4, and wherein R4 and R5 are as defined above.
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Specification