Conjugates useful in the treatment of prostate cancer
First Claim
1. A conjugate which is useful for the treatment of prostate cancer which comprises a cytotoxic agent attached to an oligopeptide, wherein the oligopeptide comprises a sequence of amino acids that is selectively proteolytically cleaved by free prostate specific antigen and wherein the means of attachment is a covalent bond or through a chemical linker, said sequence of amino acids which comprises at least one cyclic amino acid having a hydrophilic substituent;
- or the pharmaceutically acceptable salt thereof.
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Abstract
Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA) and known cytotoxic agents are disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).
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Citations
38 Claims
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1. A conjugate which is useful for the treatment of prostate cancer which comprises a cytotoxic agent attached to an oligopeptide, wherein the oligopeptide comprises a sequence of amino acids that is selectively proteolytically cleaved by free prostate specific antigen and wherein the means of attachment is a covalent bond or through a chemical linker, said sequence of amino acids which comprises at least one cyclic amino acid having a hydrophilic substituent;
or the pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 19, 20, 21, 22, 23, 27, 31, 35, 36, 37, 38)
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10. A conjugate which is useful for the treatment of prostate cancer of the formula I:
- ##STR52## wherein;
oligopeptide is an oligopeptide which is selectively recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen, wherein the oligopeptide comprises a cyclic amino acid of the formula;
##STR53## and wherein the C-terminus carbonyl is covalently bound to the amine of doxorubicin;R is selected from ##STR54## R1 and R2 are independently selected from;
hydrogen, OH, C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 aralkyl and aryl;R1a is C1 -C6 -alkyl, hydroxylated aryl, polyhydroxylated aryl or aryl, R5 is selected from HO-- and C1-C6 alkoxy; R6 is selected from hydrogen, halogen, C1 -C6 alkyl, HO-- and C1 -C6 alkoxy; and n is 1, 2, 3 or 4; p is zero or an integer between 1 and 100; q is 0 or 1, provided that if p is zero, q is 1; r is an integer between 1 and 10; and t is 3 or 4; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18, 24, 25, 26, 28, 29, 30, 32, 33, 34)
- ##STR52## wherein;
Specification