Patent EA-002745-B1 (EA)
Title: Conjugates useful in the treatment of prostate cancer
Inventor: BRADY STEPHEN F
IPC: A61K47/48
Filed: 1998-11-25
Abstract: 1. A conjugate of the formula I:   wherein: oligopeptide is an oligopeptide which is specifically 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, XL is a bond; R is selected from a) hydrogen, b) -(CO)R<la> c)   d)   e)   f) ethoxysquarate; and g) cotininyl; R<1> and R<2> are independently selected from: hydrogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 aralkyl and aryl; R<1a> is C1-C6-alkyl, hydroxylated C3-C8-cycloalkyl, polyhydroxylated C3-C8-cycloalkyl, hydroxylated aryl, polyhydroxylated aryl or aryl, R<9> is hydrogen, (C1-C3 alkyl)-CO, or chloro-substituted (C1-C3 alkyl)-CO; 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 1,2 or 3; t is 3 or 4; or a pharmaceutically acceptable salt or optical isomer thereof. 2. The conjugate according to Claim 1 wherein oligopeptide is an oligomer that comprises an amino acid sequence selected from: a) AsnLysIleSerTyrGln|Ser (SEQ.ID.NO. 1), b) LysIleSerTyrGln|Ser (SEQ.ID.NO. 2), c) AsnLysIleSerTyrTyr|Ser (SEQ.ID.NO. 3), d) AsnLysAlaSerTyrGln|Ser (SEQ.ID.NO. 4), e) SerTyrGln|SerSer (SEQ.ID.NO. 5), f) LysTyrGln|SerSer (SEQ.ID.NO. 6), g) hArgTyrGln|SerSer  (SEQ.ID.NO. 7), h) hArgChaGln|SerSer (SEQ.ID.NO. 8), i) TyrGln|SerSer (SEQ.ID.NO. 9), j) TyrGln|SerLeu (SEQ.ID.NO. 10), k) TyrGln|SerNle (SEQ.ID.NO. 11), l) ChgGln|SerLeu (SEQ.ID.NO. 12), m) ChgGln|SerNle (SEQ.ID.NO. 13), n) SerTyrGln|Ser (SEQ.ID.NO. 14), o) SerChgGln|Ser (SEQ.ID.NO. 15), p) SerTyrGln|SerVal (SEQ.ID.NO. 16), q) SerChgGln|SerVal (SEQ.ID.NO. 17), r) SerTyrGln|SerLeu (SEQ.ID.NO. 18), s) SerChgGln|SerLeu (SEQ.ID.NO. 19), t) HaaXaaSerTyrGln|Ser (SEQ.ID.NO. 20), u) HaaXaaLysTyrGln|Ser (SEQ.ID.NO. 21), v) HaaXaahArgTyrGln|Ser (SEQ.ID.NO. 22), w) HaaXaahArgChaGln|Ser (SEQ.ID.NO. 23), x) HaaTyrGln|Ser (SEQ.ID.NO. 24), y) HaaXaaSerChgGln|Ser (SEQ.ID.NO. 25), z) HaaChgGln|Ser (SEQ.ID.NO. 26), wherein Haa is a cyclic amino acid substituted with a hydrophilic moiety, hArg is homoarginine, Xaa is any amino acid, Cha is cyclohexylalanine and Chg is cyclohexylglycine; or an optical isomer thereof. 3. The conjugate according to Claim 2 wherein Haa is trans-4-hydroxy-L-proline; or an optical isomer thereof. 4. The conjugate according to Claim 1 wherein the oligopeptide - R is selected from: Ac-4-trans-L-HypSerSerChgGlnSerSerPro; (SEQ.ID.NO. 84) Ac-4-trans-L-HypSerSerChgGlnSerGly; (SEQ.ID.NO. 85) Ac-4-trans-L-HypSerSerChgGlnSerSerSar; (SEQ.ID.NO. 86) Ac-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro; (SEQ.ID.NO. 87) Ac-4-trans-L-Hyp-Ser-Ser-Chg-Gln-SerVal; (SEQ.ID.NO. 88) Ac-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-4-trans-L-Hyp; (SEQ.ID.NO. 89) Ac-Abu-Ser-Ser-Chg-Gln-Ser-Pro; (SEQ.ID.NO. 90) hydroxyacetyl Abu-Ser-Ser-Chg-Gln-Ser-Pro; (SEQ.ID.NO. 91) acetyl 3-PALSer-Ser-Chg-Gln-Ser-Ser-Pro; (SEQ.ID.NO. 92) Ac-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Val; (SEQ.ID.NO. 93) Ac-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Leu; (SEQ.ID.NO. 94) Ac-4-trans-L-HypSerSerChgGlnSerSer4-trans-L-Hyp; (SEQ.ID.NO. 95) Ac-4-trans-L-HypSerSerChgGlnSerPro; (SEQ.ID.NO. 96) Ac-SerSerChgGlnSerGly; (SEQ.ID.NO. 98) Ac-SerSerChgGlnSerSer-4-trans-L-Hyp; (SEQ.ID.NO. 99) Ac-SerSerChgGlnSerSerPro; (SEQ.ID.NO. 100) Ac-4-trans-L-HypSerSerChgGlnSerAla; (SEQ.ID.NO. 103) Ac-4-trans-L-HypSerSerChgGlnSerChg; (SEQ.ID.NO. 104) Ac-4-trans-L-HypSerSerChgGlnSerSerSar; (SEQ.ID.NO. 105) Ac-SerSerChgGlnSerSerHyp; (SEQ.ID.NO. 106) Ac-4-trans-L-HypSerSerChgGlnSerSerPro; (SEQ.ID.NO. 107) Ac-AbuSerSerChgGlnSer(dSer)Pro; (SEQ.ID.NO. 108) Ac-AbuSerSerChgGlnSerSerPro; (SEQ.ID.NO. 109) Ac-SerSerChgGlnSerSerPro; (SEQ.ID.NO. 111) Ac-4-trans-L-HypSerSerChg(dGln)SerSerPro; (SEQ.ID.NO. 114) Ac-4-trans-L-HypSerSerChg(dGln)(dSer)SerPro; (SEQ.ID.NO. 115) Ac-SerChgGln-SerSerPro; (SEQ.ID.NO. 116) Ac-SerChgGlnSerSer-4-trans-L-Hyp; (SEQ.ID.NO. 117) Ac-SerChgGlnSerSerSar; (SEQ.ID.NO. 118) Ac-SerChgGlnSerSerAibPro; (SEQ.ID.NO. 119) Ac-SerChgGlnSerSerN-Me-Ala; (SEQ.ID.NO. 120) Ac-4-trans-L-HypSerSerChgGlnSerSerPip; (SEQ.ID.NO. 124) Ac-SerChgGlnSerSerN-Me-dA; (SEQ.ID.NO. 125) wherein Abu is aminobutyric acid, 4-trans-L-4-Hyp is 4-trans-L-4-hydroxyproline, Pip is pipecolinic acid, 3,4-DiHyp is 3,4-dihydroxyproline, 3-PAL is 3-pyridylalanine, Sar is sarcosine and Chg is cyclohexylglycine. 5. The conjugate according to Claim 1 which is selected from:   wherein X is         or a pharmaceutically acceptable salt or optical isomer thereof. 6. The conjugate according to Claim 1 which is:   or a pharmaceutically acceptable salt or optical isomer thereof. 7. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a conjugate of Claim 1. 8. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a conjugate of Claim 5. 9. A method for treating prostate cancer which method comprises administering to a mammal a therapeutically effective amount of a conjugate of Claim 7. 10. A method for treating prostate cancer which method comprises administering to a mammal a therapeutically effective amount of a composition of Claim 8. 11. A method for treating benign prostatic hyperplasia which method comprises administering to a mammal a therapeutically effective amount of a composition of Claim 8. 12. A process for making a pharmaceutical composition comprising combining a conjugate of Claim 1 and a pharmaceutically acceptable carrier.