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US 2006/0142238 A1Published application
Chemical compounds
AssigneeCardiff Protides Limited
InventorChristopher McGuigan
Life of this patent
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Abstract
Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The a-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.
Claims40
A chemical compound having formula I:
- wherein:
- R is selected from the group comprising alkyl, aryl and alkylaryl;
- R′ and R″ are independently selected from the group comprising H, alkyl and alkylaryl, or R′ and R″ together form an alkylene chain so as to provide, together with the C atom to which they are attached, a cyclic system;
- Q is selected from the group comprising —O— and —CH2—;
- X and Y are independently selected from the group comprising H, F, Cl, Br, I, OH and methyl (—CH3);
- Ar is a monocyclic aromatic ring moiety or a fused bicyclic aromatic ring moiety, either of which said ring moieties is carbocyclic or heterocyclic and is optionally substituted;
- Z is selected from the group comprising H, alkyl and halogen;
- and
- n is 0 or 1,
- wherein when n is 0, Z′ is —NH2 and a double bond exists between position 3 and position 4, and
- when n is 1, Z′ is ═O;
- or a pharmaceutically acceptable derivative or metabolite of a compound of formula I;
- with the proviso that, except where R is 2-Bu (—CH2—CH(CH3)2) and one of R′ and R″ is H and one of R′ and R″ is methyl (—CH3), when n is 1 and X and Y are both H, then Ar is not unsubstituted phenyl (—C6H5).
10 more elements
A chemical compound having formula II:
- wherein n, Q, R, R′, R″, X, Y, Z and Z′ Q 5is selected from the group comprising —O— and —CH2—, R is selected from the group comprising alkyl, aryl and alkylaryl, and H, R′ and R″ are independently selected from the group comprising H, alkyl and alkylaryl, or
- R′ and R″ together form an alkylene chain so as to provide, together with the C atom to which they are attached a cyclic system, X and Y are independently selected from the group comprising Hz F, Cl, Br, I, OH and
- methyl (—CH3) with provisos that:
- when n is 1, X and Y are both H, R is methyl (—CH3), one of R′ and R″ is H and one of R′ and R″ is methyl (—CH3), then Z is not —CH═CHBr;
- when n is 1, X and Y are both H, R is methyl (—CH3), one of R′ and R″ is H and one of R′ and R″ is phenylethyl, phenylmethyl, indol-3-ylmethyl or indol-3-ylethyl, then Z is not F;
- and
- when n is 0, X is not H.
4 more elements
A compound selected from the group comprising:
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 3)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 2)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 5)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 6)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 7)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 10)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 9)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 8)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[para-(trifluoromethyl)-phenyl-(methoxy-L-alaninyl)]-phosphate (CPF 15)
- (E)-5-(2-bromoyinyl)-2′-deoxyuridine-5′-[para-(trifluoromethyl)-phenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 25)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-trifluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 4)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 13)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 12)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 12)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[phenyl-(methoxy-ana-dimethylglycinyl)]-phosphate (CPF 26)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[phenyl-(ethoxy-a,a-dimethylglycinyl)]-phosphate (CPF 27)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[phenyl-(benzoxy-α,α-dimethylglycinyl)]-phosphate (CPF 14)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-nitrophenyl-(methoxy-α,α-dimethylglycinyl)]-phosphate (CPF 45)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-nitrophenyl-(ethoxy-α,α-dimethylglycinyl)]-phosphate (CPF 46)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-nitrophenyl-(benzoxy-α,α-dimethylglycinyl)]-phosphate (CPF 47)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(methoxy-α,α-dimethylglycinyl)]-phosphate (CPF 42)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(ethoxy-α,α-dimethylglycinyl)]-phosphate (CPF 43)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[4-chlorophenyl-(benzoxy-α,α-dimethylglycinyl)]-phosphate (CPF 44)
- (E)-5-(2-bromovinyl)-2′-deoxyuridine-5′-[para-(trifluoromethyl)-phenyl-(benzoxy-α,α-dimethylglycinyl)]-phosphate (CPF 48)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(methoxy-α,α-cycloleucinyl)]-phosphate (CPF 16)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(ethoxy-α,α-cycloleucinyl)]-phosphate (CPF 17)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(benzoxy-α,α-cycloleucinyl)]-phosphate (CPF 18)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(methoxy-α,α-cycloleucinyl)]-phosphate (CPF 19)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(ethoxy-α,α-cycloleucinyl)]-phosphate (CPF 20)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(benzoxy-α,α-cycloleucinyl)]-phosphate (CPF 21)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(methoxy-α,α-cycloleucinyl)]-phosphate (CPF 22)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(ethoxy-α,α-cycloleucinyl)]-phosphate (CPF 23)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-fluorophenyl-(benzoxy-α,α-cycloleucinyl)]-phosphate (CPF 24)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-chlorophenyl-(methoxy-α,α-cycloleucinyl)]-phosphate (CPF 32)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-chlorophenyl-(ethoxy-α,α-cycloleucinyl)]-phosphate (CPF 33)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(methoxy-L-phenylalaninyl)]-phosphate (CPF 36)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-chlorophenyl-(benzoxy-α,α-cycloleucinyl)]-phosphate (CPF 34)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-trifluorophenyl-(methoxy-α,α-cycloleucinyl)]-phosphate (CPF 28)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-trifluorophenyl-(ethoxy-α,α-cycloleucinyl)]-phosphate (CPF 29)
- (E)-5 -(2-Bromovinyl)-2′-deoxyuridine-5′-[para-trifluorophenyl-(benzoxy-α,α-cycloleucinyl)]-phosphate (CPF 30)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(methoxy-L-phenylalaninyl)]-phosphate (CPF 36)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(methoxy-L-leucinyl)]-phosphate (CPF 35)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 37)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-nitrophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 38)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[para-chlorophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 39)
- (E)-5-(2-Bromovinyl)-2′-deoxyuridine-5′-[phenyl-(2-butyl-L-alaninyl)]-phosphate
- Gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 31)
- Gemcitabine-[para-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 40) and
- Gemcitabine-[para-chlorophenyl-(benzoxy-α,α-dimethylglycinyl)]-phosphate (CPF 41).
46 more elements
Dependencies are inferred from the claim text.