ZA200201298B - Integrin-mediated drug targeting. - Google Patents
Integrin-mediated drug targeting. Download PDFInfo
- Publication number
- ZA200201298B ZA200201298B ZA200201298A ZA200201298A ZA200201298B ZA 200201298 B ZA200201298 B ZA 200201298B ZA 200201298 A ZA200201298 A ZA 200201298A ZA 200201298 A ZA200201298 A ZA 200201298A ZA 200201298 B ZA200201298 B ZA 200201298B
- Authority
- ZA
- South Africa
- Prior art keywords
- radical
- bonded
- substituted
- optionally
- alkyl
- Prior art date
Links
- 102000006495 integrins Human genes 0.000 title claims description 27
- 108010044426 integrins Proteins 0.000 title claims description 27
- 239000003814 drug Substances 0.000 title claims description 5
- 229940079593 drug Drugs 0.000 title description 2
- 230000001404 mediated effect Effects 0.000 title description 2
- 230000008685 targeting Effects 0.000 title description 2
- -1 aryloxy radical Chemical class 0.000 claims description 200
- 150000003254 radicals Chemical class 0.000 claims description 148
- 239000000562 conjugate Substances 0.000 claims description 91
- 229920006395 saturated elastomer Polymers 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 46
- 230000015572 biosynthetic process Effects 0.000 claims description 32
- 125000005842 heteroatom Chemical group 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 239000000824 cytostatic agent Substances 0.000 claims description 25
- 230000001085 cytostatic effect Effects 0.000 claims description 25
- 150000005840 aryl radicals Chemical class 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 23
- 150000001413 amino acids Chemical group 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 229940024606 amino acid Drugs 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical group C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 8
- 125000002837 carbocyclic group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 4
- 229940127093 camptothecin Drugs 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 231100000433 cytotoxic Toxicity 0.000 claims description 4
- 230000001472 cytotoxic effect Effects 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002355 alkine group Chemical group 0.000 claims description 2
- 125000005156 substituted alkylene group Chemical group 0.000 claims description 2
- 125000005650 substituted phenylene group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 24
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 24
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 24
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 23
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 23
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 23
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 23
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 23
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 22
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 21
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 20
- 125000003944 tolyl group Chemical group 0.000 claims 20
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 18
- 235000001014 amino acid Nutrition 0.000 claims 16
- 238000006243 chemical reaction Methods 0.000 claims 14
- 125000004122 cyclic group Chemical group 0.000 claims 11
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 11
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 10
- 239000004471 Glycine Substances 0.000 claims 9
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 9
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 9
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 claims 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 6
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 6
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims 6
- 235000004279 alanine Nutrition 0.000 claims 6
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 6
- 229960000310 isoleucine Drugs 0.000 claims 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 6
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims 6
- 239000004474 valine Substances 0.000 claims 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 4
- 239000004475 Arginine Substances 0.000 claims 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 3
- 239000004472 Lysine Substances 0.000 claims 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 3
- 238000001212 derivatisation Methods 0.000 claims 3
- 229930195712 glutamate Natural products 0.000 claims 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 3
- 150000007530 organic bases Chemical class 0.000 claims 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims 2
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- UQIJOBDVZCNFAM-UHFFFAOYSA-N hexyl hypofluorite Chemical compound CCCCCCOF UQIJOBDVZCNFAM-UHFFFAOYSA-N 0.000 claims 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- 239000011630 iodine Substances 0.000 claims 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 229960003104 ornithine Drugs 0.000 claims 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 2
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims 1
- 101150088095 RTM2 gene Proteins 0.000 claims 1
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- 125000004188 dichlorophenyl group Chemical group 0.000 claims 1
- 208000005244 familial abdominal 2 aortic aneurysm Diseases 0.000 claims 1
- 208000002153 familial abdominal 3 aortic aneurysm Diseases 0.000 claims 1
- 208000034199 familial abdominal 4 aortic aneurysm Diseases 0.000 claims 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 1
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 229940037201 oris Drugs 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000004344 phenylpropyl group Chemical group 0.000 claims 1
- 239000007790 solid phase Substances 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 description 12
- SRIOCKJKFXAKHK-UHFFFAOYSA-N 8-amino-10h-isoindolo[1,2-b]quinazolin-12-one Chemical compound C1=CC=C2C3=NC4=CC=C(N)C=C4CN3C(=O)C2=C1 SRIOCKJKFXAKHK-UHFFFAOYSA-N 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 231100000777 Toxicophore Toxicity 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 150000001720 carbohydrates Chemical group 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 102000004856 Lectins Human genes 0.000 description 3
- 108090001090 Lectins Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002523 lectin Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 2
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- ABYZSYDGJGVCHS-ZETCQYMHSA-N (2s)-2-acetamido-n-(4-nitrophenyl)propanamide Chemical compound CC(=O)N[C@@H](C)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 ABYZSYDGJGVCHS-ZETCQYMHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 102100035140 Vitronectin Human genes 0.000 description 1
- 108010048673 Vitronectin Receptors Proteins 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000010913 antigen-directed enzyme pro-drug therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000035289 cell-matrix adhesion Effects 0.000 description 1
- 210000003570 cell-matrix junction Anatomy 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003093 intracellular space Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Description
Integrin-mediated drug targeting
The marked lectin pattern on tumour cell surfaces (Gabius; Onkologie 12, (1989), 175) opens up the fundamental possibility of addressing these specifically on tumour cells by linkage of appropriate carbohydrate units to cytostatics. This prospect is restricted - by the fact that, even in other tissues, in particular in the liver, lectins having similar carbohydrate specificities (galactose, lactose, mannose, N-acetylglucosamine, fucose etc.) occur (Ashwell et al., Annu. Rev. Biochem. 46 (1982), 531; Stahl et al. Proc. Natl.
Acad. Sci. USA 74 (1977), 1521; Hill et al., J. Biol. Chem. 262 (1986), 7433; Jansen et al., J. Biol. Chem. 266 (1991), 3343). Accordingly, a marked concentration of active compound-containing glycoconjugates in the liver and other lectin-rich organs must be expected if, in this approach, carbohydrates are used without particular modification establishing a selectivity to tumour tissue.
The heterocyclic amine batracylin (1) shows a good antitumour action in various stom- ach cancer models (US-4 757 072). oo
Oo
H,N
P :
N
(1)
Peptide conjugates of (1) having good in-vitro action and more favourable solubility properties (US-4 180 343) are more poorly tolerable in animal experiments than free batracylin. The fucose conjugates of batracylin (1) described in EP-A-0 501 250 disad- vantageously concentrate very strongly in the liver.
Quinolone-a (2), 7-[(32-R,S, 4-R,S, 7a-S,R)-4-amino-1,3,3a,4,7,7a-hexahydro-iso-in- dol-2-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, also shows, in addition to its outstanding antibacterial activity, a very good activ- ] ity against various tumour cell lines (EP-A-0 520 240, JP-4 253 973). However, con-
siderable toxicological problems face it (e.g. genotoxicity, bone marrow toxicity, high acute toxicity in vivo etc.). : o sees an : z N N
OL
¥ : (2) (quinolone-a) 20(S)-Camptothecin is a pentacyclic alkaloid which was isolated in 1966 by Wall et al. (J. Am. Chem. Soc. 88, 3888 (1966)). It has a high active antitumour potential in numerous in-vitro and in-vivo tests. Unfortunately, however, the realization of the promising potential in the clinical investigation phase failed because of toxicity and solubility problems.
By opening of the E ring lactone and formation of the sodium salt, a water-soluble compound was obtained which is in a pH-dependent equilibrium with the ring-closed form. Here too, clinical studies have not led to success as yet. oo Oo OH
AANA 4 Ae NaOH - 13 N 2 3 he 2 O N Pas Oo
H,C,, OH H,C OH
About 20 years later, it was found that the biological activity is to be attributed to enzyme inhibition of topoisomerase I. Since then, the research activities have again been increased in order to find a camptothecin derivative which is more tolerable and which is active in vivo.
For improvement of the water solubility, salts of A ring- and B ring-modified camp- tothecin derivatives and of 20-O-acyl derivatives with ionizable groups have been described (Vishnuvajjala et al. US 4 943 579). The latter prodrug concept was later also transferred to modified camptothecin derivatives (Wani et al. WO 9602546).
The described 20-O-acyl prodrugs, however, have a very short half-life in vivo and are very rapidly cleaved to give the parent structure.
WO 96/31532 describes carbohydrate-modified cytostatics in which both serum stabil- ity and release of the cytostatic within the tumour cells and a specific concentration of the cytostatic in tumour tissue is achieved by a novel linkage of selectively modified carbohydrates to cytostatics (for example batracylin, quinolone-a, camptothecin) via preferred spacer and linker groups. .
Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix.
They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix via the RGD sequence occurring in these proteins (RGD is the single-letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also called the a8; receptor, or alternatively the a.,85 receptor or the GplIIb/HIa receptor play an important part in biological processes such as cell migration, angiogenesis and cell-matrix adhesion and thus for diseases in which these processes are crucial : steps. Cancer, osteoporosis, arteriosclerosis, restenosis and ophthalmia may be men- tioned by way of example.
The a.,8; receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. The , j3receptor thus plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumour growth and metastasis formation in carci- nomatous disorders.
It was possible to show that the blockade of the abovementioned receptors is an im- portant starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their corresponding integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Angiogenesis therefore does not occur, which leads to a stoppage or regression of tumour growth (cf., for example, Brooks et al.,
Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumour cells and thus their capability to form metastases markedly decrease when their a,B3 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
WO 98/10795 describes conjugates in which a molecule adding to tumours is linked to a functional unit such as, for example, a cytostatic or a detectable label such as, for example, a radioactive nuclide. Inter alia, integrin antagonists such as, for example, peptides having the RGD sequence described above are described as molecules add- ing to tumours. Doxorubicin is described as an example of a cytostatic which is linked to a molecule of this type addressing tumours.
In the case of the compounds of WO 98/10795, the linkage is carried out such that the molecule addressing a tumour and the functional unit are directly bonded to one another with retention of their respective properties (cf., for example, p. 56, 1. 17, to p- 58, 1. 10, and Ex. 6). This has the result that these compounds are indeed selec- tively concentrated in the immediate vicinity of tumour cells by binding of the entity addressing a tumour (in the case of a radical having 83 integrin-antagonistic action "by binding to the a8; integrin receptor which, in particular, is expressed on endothelial cells newly formed by angiogenesis), but on account of the direct combination the functional unit such as, for example, a cytostatic cannot be released into the intracellu- lar space of the tumour tissue.
Fundamentally, the conjugate which on the one hand is selectively concentrated in tumour tissue by the effect of a part addressing 83 or a8 integrin receptors found in the conjugate, but on the other hand comprises a cytostatic which can be released from the conjugate, should have an increased toxophoric effect on tumour tissue due to the possibility of the more direct action of the cytostatic on the tumour cells compared "with the conjugates described in WO 98/10795.
It was therefore the object of the present invention to develop conjugates which com- prise a moiety addressing o.,83 or a, 85 integrin receptors and a cytostatic which can be released from the conjugate, where the moiety in the conjugate addressing a, 8; or o,8s integrin receptors retains its ability to bind to the 0.83 or 8s integrin receptor.
The above object is achieved by conjugates which comprise a non-peptide moiety ad- dressing a8; or a.Bs integrin receptors, a cytostatic and a linking unit which is enzy- matically or hydrolytically cleavable with release of the cytostatic. Conjugates having a : non-peptide moiety addressing «83 integrin receptors are particularly preferred here.
In principle, medicament-containing conjugates are complex, difficult-to-prepare com- pounds, as is explained, for example, in Anti-Cancer Drug Design 10 (1995), 1-9, in particular p. 1. In this article, conjugates of the cytostatic methotrexate, an oligopeptide spacer and a protein (human serum albumin) are described. However, it is also pointed out (cf. p. 7, first paragraph) that the nature of the linking unit and the type of linkage of this unit to the toxophore and the carrier (for example an antibody) can affect the cleav- age of the linking unit. This article therefore teaches that the linkage presented there cannot be transferred to other conjugate systems without difficulty. In particular, noth- ing is said about whether moieties addressed also to a.,83 or a,8s integrin receptors in this manner can be linked to toxophores without the moiety addressing a8; or a, Bs integrin receptors by this means losing its ability to bind to a.83 or a,Bs integrin re- ceptors.
The linking units disclosed in WO 96/31532 are used specifically for the linkage of a toxophore to an oligosaccharide radical. Nothing is said about whether moieties ad- dressed also to a8; or a, 85 integrin receptors can be linked to toxophores in this man- ner, without, by this means, the moiety addressing o,8; or a,8s integrin receptors los- ing its ability to bind to a, 83 or a,B85 integrin receptors.
According to a preferred embodiment of the present invention, the linking unit can be cleaved by tumour-associated enzymes. This leads to a further increase in the tissue specificity of the conjugates according to the invention and thus to an additional de- crease of the conjugates according to the invention in other tissue types.
According to a further preferred embodiment of the invention, the linking unit can be cleaved by enzymes which are coupled to antibodies with selectivity for tumour tissue and are thus addressed to tumour tissue. This is also called the ADEPT approach. This likewise leads to a further increase in the tissue specificity of the conjugates according to the invention and thus to an additional decrease of the conjugates according to the invention in other tissue types.
Particularly preferred conjugates according to the present invention are those of the general formula (I)
CT-AAl1-AA2-AA3-AA4-Sp-1A 0) in which
CT denotes a cytotoxic radical or a radical of a cytostatic or of a cytostatic derivative, which can additionally carry a hydroxyl, carboxyl or amino group,
AAl is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp‘,
-AA2 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp®,
AA3 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp*,
AA4 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp‘, in which
Sp* is an arylaminocarbonyl or an arylaminothio- carbonyl radical having 7-11 carbon atoms,
Sp is absent, is an arylaminocarbonyl! or an arylaminothiocarbonyl radical having 7-11 carbon atoms or is an alkanedicarboxylic acid radical having 3 to 8 carbon atoms or a carbonyl or a thio- carbonyl radical, with the proviso that at least one of the radicals AA to AA4 and/or Sp is present, 1A is a non-peptide radical addressing an a.,B; integrin receptor, which is selected from the group consisting of
A) a radical of the formula (II) o) 3 u N R*
Ny SV—A—B—WT Ne” (n
: in which
R' is OH, a substituted or unsubstituted alkoxy or cyclo- alkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substi- tuted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of O,
N and S, via which the radical of the formula (II) is bonded to the rest of the conjugate;
R? is hydrogen, a substituted or unsubstituted alkyl or cy- cloalkyl radical, a substituted or unsubstituted aryl radi- : cal, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical or an optionally substituted alkinyl radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate, or is -NR”, -
NR¥SO,R?", -NR*COOR”", -NR*COR*, -NR*CO-
NR?; or -NR?CSNR?;; in which
R¥ independently of one another is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substi- - tuted or unsubstituted aryl radical or a saturated or un- saturated, optionally substituted heterocyclic radical, or optionally represents a direct bond, via which the radi- cal of the formula (IT) is bonded to the rest of the con- jugate;
~R¥ is a substituted or unsubstituted alkyl or cycloalkyl } radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted hetero- cyclic radical, via which the radical of the formula (I) 1s optionally bonded to the rest of the conjugate;
U is a direct bond or a substituted or unsubstituted alkylene group, via which the radical of the formula (II) _ 1s optionally bonded to the rest of the conjugate;
Vv 1s a substituted or unsubstituted alkylene group, “NR*CO- or -NR?'SO; -, via which the radical of the formula (II) is optionally bonded to the rest of the con-
Jjugate; : A and B each independently of one another is a 1,3- or 1,4- bridged, optionally additionally substituted phenylene group; | Ww is a direct bond or a substituted or unsubstituted alkylene group;
C is absent or is NT ;
Co ls :
RS _X R'm
R? 1s hydrogen, a substituted or unsubstituted alkyl or cy- cloalkyl radical, a substituted or unsubstituted aryl radi- : cal, a saturated or unsaturated, optionally substi-tuted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R*, Y, R® or
RS, if present, with formation of an optionally substi- tuted heterocyclic ring system which includes the nitro- gen atom to which R? is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
Co : R* is hydrogen, a substituted or unsubstituted alkyl or cy- cloalkyl radical, a substituted or unsubstituted aryl radi- cal, a saturated or unsaturated, optionally substi-tuted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R?, Y, R® or
RS, if present, with formation of an optionally substi- tuted heterocyclic ring system which includes the nitro- gen atom to which R* is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond, via which the radi- cal of the formula (II) is bonded to the rest of the con- jugate;
X isO,NorS; m isOorl;
Y is a direct bond or an optionally substituted alkylene or alkine group;
R® isabsent, -NO,, -CN, -COR*, -COOR?®, or is bonded to one of R3, Y, Ror RS, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or un- saturated and/or can contain further heteroatoms;
: R® is hydrogen, a substituted or unsubstituted alkyl or cy- : cloalkyl radical, a substituted or unsubstituted aryl radi- cal or a saturated or unsaturated, optionally substi-tuted heterocyclic radical which can be saturated or unsatu- rated and/or can contain further heteroatoms;
R® 1s hydrogen, a substituted or unsubstituted alkyl or cy- cloalkyl radical, a substituted or unsubstituted aryl radi- cal, a saturated or unsaturated, optionally substi-tuted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R®, R*, Y or
R®, if present, with formation of an optionally substi- tuted heterocyclic ring system which includes the nitro- gen atom to which R® is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; or
B) a radical of the formula (III)
R"2 rR" 12 oO SN i R*
N rR’ A
RS R? L If p R 17 . : R'® R rs” (ny in which Co
R’ is OH, a substituted or unsubstituted alkoxy or cyclo- alkoxy radical, a substituted or unsubstituted aryloxy radical or a saturated or unsaturated, optionally substi-
tuted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N,
O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate;
R® is hydrogen, a substituted or unsubstituted alkyl or cy- : cloalkyl radical, a substituted or unsubstituted aryl radi- cal, a saturated or unsaturated, optionally substi-tuted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hy- droxyl radical or an alkoxy radical or is bonded to R® ~ with formation of an optionally substi-tuted carbocyclic or heterocyclic ring system which includes the carbon atom to which R® is bonded and can optionally contain heteroatoms;
R® is hydrogen, a substituted or unsubstituted alkyl or cy- cloalkyl radical, a substituted or unsubstituted aryl radi- cal, a saturated or unsaturated, optionally substi-tuted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hy- droxyl radical or an alkoxy radical or is bonded to R® with formation of an optionally substi-tuted carbocyclic or heterocyclic ring system which includes the carbon atom to which R? is bonded and can optionally contain _ heteroatoms;
RY is -SOR', -COOR'”, -COR'®, -CONR'”; or -CS-NR'",, or represents a direct bond via which the radical of the formula (II) is optionally bonded to the - rest of the conjugate;
Claims (24)
1. Conjugate, comprising a) a non-peptide moiety addressing a3; or a.Bs integrin receptors, b) a linking unit which can be cleaved enzymatically or hydrolytically with release of the cytotoxic radical or of the radical of a cytostatic or of a cytostatic derivative, and c) a cytostatic radical or a radical of a cytostatic or -of a cytostatic : derivative.
2. Conjugate according to Claim 1, characterized in that the linking unit can be cleaved by tumour-associated enzymes. :
3. Conjugate according to Claim 1, characterized in that the linking unit can be cleaved by enzymes which are coupled to antibodies with selectivity for tumour tissue and thus are addressed to tumour tissue. CC
4, Conjugate according to one of the preceding claims, characterized by the formula (I) CT-AAl —AA2 —AA3-AA4-Sp-]A 4) : in which CT denotes a cytotoxic radical or a radical of a cytostatic or of a cytostatic derivative, which can additionally carry a hydroxyl, carboxyl or amino group,
AAl is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp*, AA2 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp*, AA3 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp‘, AA4 is absent or is an amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp‘, in which Sp‘ is an arylaminocarbonyl or an arylaminothiocarbonyl radical having 7-11 carbon atoms, Sp is absent, is an arylaminocarbonyl or an arylaminothiocarbonyl radical having 7-11 carbon atoms or is an alkanedicarboxylic acid radical "having 3 to 8 carbon atoms or a carbonyl or a thiocarbony! radical, with the proviso that at least one of the radicals AAl to AA4 and/or Sp is : present, IA isa non-peptide radical addressing an a.f3; integrin receptor, which is selected from the group consisting of A) a radical of the formula (II)
0) il Ny Usv—a—s-w Ne” Re 0) . Rr? . in which’ R! is OH, a substituted or unsubstituted alkoxy or cycloalkoxy : radical, a substituted or unsubstituted aryloxy radical or a satu- rated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (IT) is bonded to the rest of the conjugate;
R? is hydrogen, a substituted or unsubstituted alkyl! or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl! radical or an optionally substi- tuted alkinyl radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate, or is -NR?, -NR¥SO,;R?", -NR¥COOR?", -NR*COR?, -NR*CONR?*) or
-NR¥CSNR?;
: in which B R* independently of one another is hydrogen, a substituted or un- substituted alkyl or cycloalkyl radical, a substituted or unsub- stituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, or optionally represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate;
: R¥ is a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or un- saturated, optionally substituted heterocyclic radical, via which the radical of the formula (II) is optionally bonded to the rest - of the conjugate;
U is a direct bond or a substituted or unsubstituted alkylene group, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate;
:
\' is a substituted or unsubstituted alkylene group, -NR*CO- or -NR*SO; -, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate;
A and B each independently of one another is a 1,3- or 1,4-bridged, optionally additionally substituted phenylene group; \"4 is a direct bond or a substituted or unsubstituted alkylene group;
C is absent or is St : 6 ’ RS AX R°/m
R? is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R%, Y, R® or RS, if present, with formation of an optionally substituted heterocyclic ring system, which includes the nitrogen atom to which R® is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; R* is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R®, Y, R® or RS, if present, with formation of an optionally - substituted heterocyclic ring system which includes the nitrogen atom to which R* is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate; X isO,NorS; m isQorl; Y is a direct bond or an optionally substituted alkylene or alkine group; R? is absent, -NO,, -CN, -COR?, -COOR’ or is bonded to one of R?, Y, Ror RS, if present, with formation of an optionally sub- stituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms; : R* is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical which can be saturated or unsaturated and/or can contain fur- ther heteroatoms; RS is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl Co radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical or is bonded to one of R} R*, Y or R’, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitro- gen atom to which R® is bonded and can be saturated or un- saturated and/or can contain further heteroatoms; or B) a radical of the formula (III) R'Q_ _R" R™2 0 N RM east {1 I) rR R® £7 ; R R16 R' . ya R in which
R’ is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a satu- rated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate;
R® is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl } radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hydroxy! radical or an alkoxy radical or is bonded to R® with formation of an optionally substituted carb- ocyclic or heterocyclic ring system which includes the carbon atom to which R® is bonded and can optionally contain hetero- atoms;
R® | is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl
: radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, a hydroxyl radical or an alkoxy radical or is bonded to R® with formation of an optionally substituted carb- ocyclic or heterocyclic ring system which includes the carbon atom to which R’ is bonded and can optionally contain hetero- atoms;
R' is-SOR'?, -COOR'", -COR'?, -CONR'?; or -CS-NR'?, or represents a direct bond via which the radical of the formula (111) is optionally bonded to the rest of the conjugate;
R'" independently of one another is hydrogen, a substituted or un- substituted alkyl or cycloalkyl radical, a substituted or un- substituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical, via which the radical of the formula (III) is optionally bonded to the rest of the conjugate;
R'is a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or un- saturated, optionally substituted heterocyclic radical, via which the radical of the formula (IIT) is optionally bonded to the rest of the conjugate;
R'" is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical or a substituted or unsubstituted aryl radical,
R'® is hydrogen, CN, a substituted or unsubstituted alkyl or cyclo- alkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;
R" is hydrogen, CN, a substituted or unsubstituted alkyl or cyclo-
alkyl radical, a substituted or unsubstituted alkoxy radical or a halogen atom;
L is -(CH2)s2NHSO,(CH3),-, -(CH;)»SO;NH(CH,),-, -(CHz2),NH-CO(CHz),-, +(CH2).CONH(CH),-,
-(CH;)yOCH2(CH,),-, -(CH2).CH;0(CH,),-,
: -(CH2),COO(CH>)o-, -(CH2),O0C-(CHa)o-, -(CH2)nCH,CO(CH;)o-, -CH;),COCH2(CHa),-, -NHCONH-, -(CH;)»SCH2(CH,)o-, -(CH3).CH,S(CHa)o-, -(CH,),CH;SO(CHa).-, -(CH),SOCH(CHa).-,
-(CH2),CH2S02(CH3)o- or -(CH2)aSO,CH2(CH,)o-, where n'and o each is an integerof Oor 1 andn +0 <1;
R!? is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R'?, R" or R'%, if present, with formation of an optionally substituted heterocyclic ring system which in- cludes the nitrogen atom, to which R'? is bonded and can be saturated or unsaturated and/or can contain further hetero- atoms; :
3 . - X isN,QorS; p isOorl; R!® is absent, is -H, a substituted or unsubstituted alkyl or cyclo- alkyl radical, -NO,, -CN, -COR'*, -COOR'?, or is bonded to one of R'2, R' or R'’ with formation of an optionally substi- - tuted heterocyclic ring system which includes X* and can be saturated or unsaturated and/or can ‘contain further hetero- atoms; R'is hydrogen, a substituted or unsubstitutéd alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, optionally substituted heterocyclic radical which can be saturated or unsaturated and/or can contain further heteroatoms; Y* isNorS; R'" is absent, hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R'?, R" or RY, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R'* is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; R' is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated or unsaturated, optionally substituted heterocyclic radical or is bonded to one of R'?, R" or R'*, if present, with formation of an optionally substituted heterocyclic ring system which in- cludes the nitrogen atom to which R!® is bonded and can be saturated or unsaturated and/or can contain further hetero- : atoms, or optionally represents a direct bond via which the radical of the formula (II) is bonded to the rest of the con- jugate; or C) aradical of the formula (IV) 0 NH BQ RY N : .~ Rr NY N74 ] R'™® © i (iv) in which R'® is OH, a substituted or unsubstituted alkoxy or cycloalkoxy radical, a substituted or unsubstituted aryloxy radical or a satu- rated or unsaturated, optionally substituted heterocyclyloxy radical, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (IV) is bonded to the rest of the conjugate;
q isOorl; R' is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl radical, a substituted or unsubstituted aryl radical, a saturated : or unsaturated, optionally substituted heterocyclic radical, an alkylamine radical, an alkylamide radical, or optionally repre- sents a direct bond, via which the radical of the formula (IV) is bonded to the rest of the conjugate; and their physiologically acceptable salts and stereoisomers.
5. Conjugate according to Claim 4, characterized in that CT is camptothecin or 9-aminocamptothecin, which can be bonded to the rest of the conjugate via the C20-OH group or, in the case of 9-amino- camptothecin, via the free amino group; AAl is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine; AA2 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of lysine, glutamate, histidine, glycine, arginine, ornithine and leucine, and can optionally carry protective groups or a radical Sp*, AA3 is absent or is a naturally occurring amino acid in the D or L configu- ration, which is selected from the group consisting of glycine, alanine, | valine, leucine, isoleucine and phenylalanine;
AA4 is absent or is a naturally occurring amino acid in the D or L con- figuration, which can optionally carry protective groups or a radical Sp*, in which
Sp‘ is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical, Sp is absent, is a phenylaminocarbonyl or a phenylaminothiocarbonyl radi- cal or is an alkanedicarboxylic acid radical having 3 to 6 carbon atoms : _ oris a carbonyl or a thiocarbony] radical, : with the proviso that at least one of the radicals AA1 to AA4 and/or Sp is present, IA denotes a non-peptide radical of the formula (II) addressing an af integrin receptor, N in which R! is OH, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t- butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, cyclopropoxy, cyclopropylmethoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, : phenoxy, benzyloxy, tolyloxy or a substituted derivative thereof, or optionally represents a direct bond or an atom from the group con- sisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate; R? is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl] radical or an optionally sub-
stituted alkinyl radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate, or is -NR%), -NR¥SO,R*, -NR¥COOR?', -NR¥*COR?,-NR*CONR*, or -NR*CSNR?,,
: . in which R¥ independently of one another is hydrogen, methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, or optionally represents a direct bond via which the radical of the formula (II) is bonded to the rest of the conjugate; : R¥" is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, iso- pentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, -C¢H2(CHs)3, 3-aminophenyl, 4-aminophenyl, 2-chlorophenyl, 4- chlorophenyl, 4-methoxyphenyl, 2,5-dichlorophenyl, 4-trifluorometh- ylphenyl, camphor-10-yl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3- chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluorometh- ylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-meth- ylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimeth- oxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2- alkylsulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-meth- oxy)aniline or 8-quinolinyl, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate; : U is a direct bond,
\% is an optionally substituted C,.s-alkylene group, via which the radical of the formula (I) is optionally bonded to the rest of the conjugate; A is a 1,3- or 1,4-bridged phenylene group which is unsubstituted or contains at least one alkoxy radical; B is a 1,3- or 1,4-bridged phenylene group which is unsubstituted or contains at least one alkyl radical; Co w is a direct bond or an optionally substituted C;4-alkylene group; Nr C is a direct bond or I le R R? is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-tri- methylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, Cj4-alkylamino-C,4-alkyl, C,4-dialkyl- amino-C;4-alkyl, amino-C;4-alkyl, C; s-alkyloxy-C;4-alkyl,
[1 Na Eo (CN BS J) )— N © SN" So or Do + HN (a1) (2 (a (ad) (a5)
N . eo] * NA Np” ’ ps ’ So ’ N N Eh (a6) (a7 (a8) (a9) (a10) NZ NC NNW CONN Ny (a11) (a12) (a13) (a14) (a15)
"NO, Me
0.0.0.0. C3 N EN Me (216) (a7) (a18) (a19) (a20) } A Me Et— ) N ALC OCD ] N N (a21) (a22) (a23) (a24) Me ’ AN CL CO OU A N ' : ae N ~ (a25) (a26) (a27) (a28) or is bonded to one of R*, Y, Ror RS, if present, with formation of an _optionally substituted heterocyclic 4- to 6-membered ring system, -- which includes the nitrogen atom to which R? is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; R* is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-tni- methylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substi- tuted derivative thereof, C,s-alkylamino-C,4-alkyl, C;4-dialkyl- amino-C, 4-alkyl, amino-C,4-alkyl, C,4-alkyloxy-C,.-alkyl, one of the radicals (al) to (a28) or is bonded to one of R? Y, R® or R®, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R* is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond via which the radical of the formula (IT) is bonded to the rest of the conjugate; X 1sO,NorS; Y is a direct bond or a substituted or unsubstituted methylene or methine group; : R® is absent, is -NO,, -CN, -COR*, -COOR®’ or is bonded to one of R}, Y, R* or RS, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which in- cludes X and which can be saturated or unsaturated and/or can contain further heteroatoms; R* is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof; R® is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-tr- methylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substi- : tuted derivative thereof, C,s-alkylamino-C,4-alkyl, C,4-dialkyl- amino-C;4-alkyl, amino-C;4-alkyl, C;4-alkyloxy-C,4-alkyl, one of the radicals (al) to (a28) or is bonded to one of R? Y, Ror RS, if present, with formation of an optionally substituted heterocyclic 4- to : 6-membered ring system which includes the nitrogen atom to which
RS is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
6. Conjugate according to Claim 5, characterized in that R’ represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate; : 10 and the other radicals of the formula (II) are as defined in Claim 5.
7. Conjugate according to Claim 5, characterized in that R* represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate; and the other radicals of the formula (II) are as defined in Claim 5.
8. Conjugate according to Claim 5, characterized in that the radical of the formula (I) is linked to the rest of the conjugate via a radical in the a- or p- : position relative to the carboxyl group, and the other radicals of the formula (II) are as defined in Claim 5.
9. Conjugate according to Claim 4, characterized in that CT is camptothecin or 9-aminocamptothecin, which can be linked to the rest of the conjugate via the C20-OH group or, in the case of 9-amino- camptothecin, via the free amino group;
AAl is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine,
+ alanine, valine, leucine, isoleucine and phenylalanine; : AA2 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of lysine, glutamate, histidine, glycine, arginine, omithine and leucine, and can optionally carry protective groups or a radical Sp°,
AA3 is absent or is a naturally occurring amino acid in the D or L ’ configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;
AA4 is absent or is a naturally occurring amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp’, in which
Sp¢ is a phenylaminocarbonyl or a phenylaminothiocarbony! radical,
Sp is absent, is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical or an alkanedicarboxylic acid radical having 3 to 6 carbon atoms or a carbonyl or a thiocarbony] radical, :
with the proviso that at least one of the radicals AA1 to AA4 and/or Sp is present,
IA is a non-peptide radical of the formula (II) addressing an o,f; integrin receptor,
in which R' is OH, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso- butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, cyclopropoxy, cyclopropylmethoxy, cyclobutoxy, cyclo-pent- oxy, cyclohexoxy, phenoxy, benzyloxy, tolyloxy or a sub- stituted. derivative thereof, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via : which the radical of the formula (II) is bonded to the rest of the conjugate; R? is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl], isopentyl, neopenty], hexyl, cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-amino- benzyl, tolyl, phenylethyl, a substituted derivative such as 4- aminobenzyl or a saturated or unsaturated, optionally substi- tuted heterocyclic analogue thereof, an optionally substituted alkenyl radical, an optionally substituted alkinyl radical, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate; uU is a direct bond or an optionally Substituted Cy.3-alkylene group such as —CH(Cgl-3-NH)- or -CH(CgHs-4-NH)-, via which the radical of the formula (II) is optionally bonded to the rest of the conjugate; V is-NR?CO- or -NR¥SO;-; R?® is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
benzyl, tolyl, phenylethyl, phenylpropyl, phenoxyethyl or a substituted derivative thereof; A is a 1,3- or 1,4-bridged phenylene group which is unsubstituted or contains at least one alkoxy radical; B is a 1,3- or 1,4-bridged phenylene group which is unsubstituted or contains at least one alkyl radical; w is a direct bond or an optionally substituted C;_;-alkylene group; NY C is le RS _X R R} is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl- cyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C;4- alkylamino-C; 4-alkyl, C,4-dialkylamino-C;4-alkyl, amino-C;. s-alkyl, C,s-alkyloxy-C;4-alkyl, one of the radicals (al) to (a28) or is bonded to one of RY, Y or RS, if present, with : formation of an optionally substituted heterocyclic 4- to 6- membered ring system, which includes the nitrogen atom to which R? is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms; R* is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-
propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl- cyclohexyl, 3,3,5-trimethylcyclohexyl, S-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C.4- alkylamino-C,; 4-alkyl, C,4-dialkylamino-C,; 4-alkyl, amino- Ci4-alkyl, C,4-alkyloxy-C,4-alkyl, one of the radicals (al) to (a28) or is bonded to one of R?, Y or RS, if present, with formation of an optionally substituted heterocyclic 4- to 6- membered ring system, which includes the nitrogen atom to : which R* is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, or optionally represents a direct bond via which the radical of the formula (II) is bonded to the rest of the conjugate; X isOorS;
Y 1s a direct bond or a substituted or unsubstituted methylene or methine group; ’ R® is absent;
R® is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- we propylmethyl], cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl- h cyclohexyl, 3,3,5-trimethylcyclohexyl, S-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C;4- alkylamino-C,4-alkyl, C,4-dialkylamino-C,4-alkyl, amino- Ci4-alkyl, C,4-alkyloxy-C;4-alkyl, one of the radicals (al) to (a28) or is bonded to one of R’, Y or RY, if present, with formation of an optionally substituted heterocyclic 4- to 6- membered ring system which includes the nitrogen atom to
. which R® is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms.
10. Conjugate according to Claim 9, characterized in that R! represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate; and the other radicals of the formula (II) are as defined in Claim 9S.
11. Conjugate according to Claim 9, characterized in that R* represents a direct bond, via which the radical of the formula (II) is bonded to the rest of the conjugate; and the other radicals of the formula (II) are as defined in Claim 9.
12. Conjugate according to Claim 9, characterized in that the radical of the formula (II) is linked to the rest of the conjugate via a radical in the a- or B-position relative to the carboxyl group; and the other radicals of the formula (II) are as defined in Claim 9.
13. Conjugate according to Claim 4, characterized in that CT is camptothecin or 9-aminocamptothecin, which can be linked to the rest of the conjugate via the C20-OH group or, in the case of 9-amino- camptothecin, via the free amino group;
AA1l is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;
AA2 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of lysine, glutamate, histidine, glycine, arginine, ornithine and leucine, and can optionally carry protective groups or a radical Sp‘,
AA3 is absent or is a naturally occurring amino acid in the D or L configuration, which is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine;
AA4 is absent or is a naturally occurring amino acid in the D or L configuration, which can optionally carry protective groups or a radical Sp, in which
Sp‘ is a phenylaminocarbonyl or a phenylaminothiocarbony! radical,
Sp is absent, is a phenylaminocarbonyl or a phenylaminothiocarbonyl radical or is an alkanedicarboxylic acid radical having 3 to 6 carbon atoms or a carbonyl or a thiocarbony] radical,
with the proviso that at least one of the radicals AAl to AA4 and/or Sp is present, ’
IA - is a non-peptide radical of the formula (IIT) addressing an a.,B3 integrin receptor,
in which rR’ is OH, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso- butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, 3 cyclopropoxy, cyclopropylmethoxy, cyclobutoxy, cyclo- pentoxy, cyclohexoxy, phenoxy, benzyloxy, tolyloxy or a substituted derivative thereof, or optionally represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (III) is bonded to the rest of the conjugate; RS is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, C15 tolyl or a substituted derivative thereof, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, benzyloxy or is bonded to R’ with formation of an optionally substituted 3- to 6-mem- bered carbocyclic or heterocyclic ring system, which includes the carbon atom to which R? is bonded and can optionally con- tain heteroatoms; “va . R® is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy or is bonded to R® with : formation of an optionally substituted 3- to 6-membered carbo- cyclic or heterocyclic ring system which includes the carbon atom to which R® is bonded and can optionally contain hetero- atoms;
RY is SOR'®, -COOR'®", -COR'”, -CONR'®; or -CSNR""; or represents a direct bond, via which the radical of the formula (11) is optionally bonded to the rest of the conjugate;
: R'" is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof, -CsH,(CHa)s, -Cs(CH3)s, -CH2CeH2(CH,)3, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,6-
oo dichlorophenyl, 4-chlorophenylmethyl, 2,4-dichloro-phenyl-
methyl, 2,6-dichlorophenylmethyl, 3-aminophenyl, 4-amino- phenyl, 2-methoxycarbonylphenylmethyl, 3-trifluoromethyl-
phenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluorometh- yl)phenyl, 4-trifluoromethoxyphenyl, phenylmethyl, 2- acetamido-4-methylthiazol-5-yl, phenylethyl, 1-phenylpropyl,
(S)-(+)-camphor-10-yl, (R)-(-)-camphor-10-yl, 2-phenylethen-
yl, 2-thiophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3-
methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-propylphen- yl, 2,5-dimethylphenyl, 2-methoxy-S-methylphenyl, 2,3,5,6-
tetramethylphenyl, 1-naphthyl, 2-naphthyl, 4-fluoro-phenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-
fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-
chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkyl- sulphonylphenyl, 2-arylsulphonylphenyl, 3-(N-acetyl-6-meth-
oxy)aniline, 4-acetamidophenyl, 2,2,2-triflucroethyl, 5-chloro-
3-methylbenzothiazol-2-yl, N-meth-oxycarbonyl-piperidin-3-
yl, thiophen-2-yl, isoxazol-5-yl, ethoxy, 2-chloropyridin-3-yl,
pyridin-3-yl, benzyloxy, 5-methylisoxazol-3-yl, 1-adamantyl, 4-chlorophenoxymethyl, 2,2-dimethylethenyl, 2-chloropyr-
idine-5-methyl, 5,7-dimethyl-1,3,4-triazaindolizin-2-yl, (S)- . camphan-1-yl, (R)-camphan-1-y! or 8-quinolinyl; R'is a C,¢-alkyl radical, a Cs.5-cycloalkyl radical, a substituted or unsubstituted aryl radical or a saturated or unsaturated, op- tionally substituted heterocyclic radical, via which the radical
) of the formula (III) is optionally bonded to the rest of the conjugate;
R'" is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, 4-methylcyclohexyl, 3,3,5-tnmethylcyclohexyl, 5-
methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C;4-alkylamino-C;s-alkyl, C,4-dialkyl- amino-Cj4-alkyl, amino-C,4-alkyl, C,4-alkyloxy-C,4-alkyl, dialkylamino-C;4-alkyl, amino-Ci4-alkyl, C,4-alkyloxy-C4- alkyl or
J = 7 Co BS PN (a1) (a2) (a3) (a4) (as) N + 0 CN eT Zz pp El " (6) (aT) (a8) (a9) (a10) NZ NP . NZ , NZ : NZ 5 (att) (12) "(a13) (214) (a15)
NO, Me
» 0.0.0. 0 EIN OMe (816) (a1?) (@18) (a19) (a20) A Me Et—
AO. Cn Co- o N (a21) (a22) (a23) (a24) Me Or N ' o® ' 9 ' PEN ' (a25) (226) (a27) (828) R'® is hydrogen, CN, methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, meth- oxy, trifluoromethoxy, ethoxy, propoxy, butoxy, pentoxy or “< hexoxy, fluorine, chlorine, bromine or iodine; ’ RY is hydrogen, CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, meth- oxy, trifluoromethoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, fluorine, chlorine, bromine or iodine;
L is -NHSO;-, -CH,NHSO,-, -NHSO,CH-, -SO;NH-, -CH,SO;NH-, -SO,NHCH,-, -NHCO-, -CH;NHCO-, -NHCOCH;-, -CONH-, -CH,CONH-, -CONHCH,-, -OCH;-, -CH,0CH,, -OCH,CH,-, -CH;0- or -CH,CH,0-;
5 . R'2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- : butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5- methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted : derivative thereof, C,s-alkylamino-C;4-alkyl, C;4-dialkyl- amino-Cy4-alkyl, amino-C,4-alkyl, C4-alkyloxy-Cis-alkyl, one of the radicals (al) to (a28) or is bonded to one of R'?, R' or R', if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R!? is bonded and can be saturated or unsaturated and/or can contain further heteroatoms; X* isN,OorS;
p. isOorl; oo ) . R!? is absent, is -H, methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclo- : propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, -NO,, -CN, -COR”', -COOR”, or is connected to one of R'2, R' or R'S with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X* and can be saturated or unsaturated and/or can contain further heteroatoms;
R™ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
Y’ isNorS;
R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclo-
propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, 4-methylcyciohexyl, 3,3,5-trimethylcyciohexyl, 5- methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C;4-alkylamino-C,4-alkyl, C,.-dialkyl- amino-C,4-alkyl, amino-C,4-alkyl, C,4-alkyloxy-C,4-alkyl,
one of the radicals (al) to (a28), or is bonded to one of R'2, R" or R', if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R'* is bonded and can be saturated or : unsaturated and/or can contain further heteroatoms; and
R'®* is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl; fSopentyl, neoperityl, hexyl, cyclopropyl, cyclo- propylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-
methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C,4-alkylamino-C;4-alkyl, C,s-dialkyl- amino-C;4-alkyl, amino-C,4-alkyl, C,4-alkyloxy-C,4-alkyl, one of the radicals (al) to (a28) or is bonded to one of R'%, R"? or R', if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the
: nitrogen atom to which R'® is bonded and can be saturated or unsaturated and/or can contain further heteroatoms, and or optionally represents a direct bond via which the radical of the formula (III) is bonded to the rest of the conjugate.
14. Conjugate according to Claim 13, characterized in that R’ represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (II) is bonded to the rest of the conjugate; and the other radicals of the formula (III) are as defined in Claim 13.
15. Conjugate according to Claim 13, characterized in that R'> represents a direct bond, via which the radical of the formula (III) is bonded to the rest of the conjugate; and the other radicals of the formula (III) are as defined in Claim 13.
16. Conjugate according to Claim 13, characterized in that the radical of the formula (III) is linked to the rest of the conjugate via a radical in the a.- or B-position relative to the carboxyl group, and the other radicals of the formula (III) are as defined in Claim 13.
17. Conjugate according to Claim 4, characterized in that IA is a non-peptide radical of the formula (IV) addressing an a,f; integrin receptor,
wherein R'® represents a direct bond or an atom from the group consisting of N, O and S, via which the radical of the formula (IV) is bonded to the rest of the conjugate; and the other radicals are as defined in Claim 4. : 18. Conjugate according to Claim 4, characterized in that : 1A is a non-peptide radical of the formula (IV) addressing an a, integrin receptor, wherein RY represents a direct bond, via which the radical of the formula (IV) is bonded to the rest of the conjugate; and the other radicals are as defined in Claim 4.
19. Process for the preparation of conjugates according to Claim 4, comprising [A] the reaction of a compound from the group of compounds of the formulae (II), (IIT) and (IV), which has a free or optionally activated carboxyl function, with a compound of the formula (Ia) which has a free primary or secondary amino group CT-AA1-AA2-AA3-AA4-Sp (Ia) -
PE in which all radicals have the meaning indicated in Claim S, in the presence of a base;
or
[B] the reaction of a compound from the group of compounds of the formulae (II), (IIT) and (IV), which has a free primary or secondary amino function, with a carbonic acid derivative such as, for example, phosgene, thio- phosgene or a chloroformic acid ester, if appropriate in the presence of a base,
followed by the reaction with a compound of the formula (la) which has a free primary or secondary amino group
CT-AA1-AA2-AA3-AA4-Sp (Ta)
in which all radicals have the meaning indicated in Claim 5, and if appropriate the removal of protective groups and/or derivatization of nitrogen atoms and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic base or acid;
[C] the reaction of a cytotoxic compound or of a cytostatic or of a cytostatic derivative CT which contains a free primary or secondary amino group,
AMENDED SHEET with a carbonic acid derivative such as, for example, phosgene, thio- phosgene or a chloroformic acid ester in the presence of a base,
followed by the reaction with a compound from the group of compounds of the formulae (II), (III) and (IV), which has a free primary or secondary amino function, and if appropriate the removal op protective groups and/or derivatization of nitrogen atoms and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic base or acid;
or [D] the reaction of a compound from the group of compounds of the formulae (II), (III) and (IV), which contains a free primary or secondary amino function, with a compound of the formula (Ia) which contains a free or optionally activated carboxyl function CT-AAAI1-AAA2-AAA3-AAA4-Sp (Ia) in which all radicals have the meaning indicated in claim 5, in the presence of a base; and AMENDED SHEET if appropriate the removal of protective groups and/or derivatization of nitrogen atoms and/or conversion of the compound obtained into the free acid and/or conversion of the compound obtained into one of its physiological salts by reaction with an inorganic or organic or organic base or acid.
20. Process according to Claim 19, characterized in that all steps of the process are carried out on a solid phase.
21. Medicament, comprising at least one of the conjugates according to one of Claims 1 to 18.
22. Use of compounds according to one of Claims 1 to 18 for the production of medicaments for the treatment of carcinomatous disorders.
23. Conjugates as defined in any one of examples 3.2 to 3.5 and 3.12 to 3.14.
24. Process for the preparation of conjugates substantially as herein described and as exemplified with reference to any one of examples 3.2 to 3.5 and 3.12 to
3.14. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39216799A | 1999-09-08 | 1999-09-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200201298B true ZA200201298B (en) | 2003-03-12 |
Family
ID=27805346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200201298A ZA200201298B (en) | 1999-09-08 | 2002-02-15 | Integrin-mediated drug targeting. |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200201298B (en) |
-
2002
- 2002-02-15 ZA ZA200201298A patent/ZA200201298B/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2005232371B2 (en) | Polymeric prodrug with a self-immolative linker | |
| Calderón et al. | Development of enzymatically cleavable prodrugs derived from dendritic polyglycerol | |
| CA2613208C (en) | N, n-bis- (2-hydroxyethyl) glycine amide as linker in polymer conjugated prodrugs | |
| Papot et al. | Design of selectively activated anticancer prodrugs: elimination and cyclization strategies | |
| US7705045B2 (en) | Prodrugs built as multiple self-elimination-release spacers | |
| Tranoy-Opalinski et al. | Design of self-immolative linkers for tumour-activated prodrug therapy | |
| US20090203706A1 (en) | Lysine-based polymeric linkers | |
| WO1997040854A2 (en) | Polypeptide conjugates for transporting substances across cell membranes | |
| US20080188399A1 (en) | Drug-Polymer Conjugates Coupled to a Peptidic Carrier | |
| JP6539729B2 (en) | Peptide-drug complex | |
| Wierzba et al. | Vitamin B12 suitably tailored for disulfide-based conjugation | |
| CN109152846B (en) | Conjugates and conjugation reagents | |
| EP1235595B8 (en) | Integrin-mediated drug targeting | |
| US7304037B2 (en) | Cytostatic conjugates with integrin ligands | |
| US6653331B2 (en) | Targeted drug delivery using sulfonamide derivatives | |
| ZA200201298B (en) | Integrin-mediated drug targeting. | |
| WO2002051444A1 (en) | Conjugates of integrin receptor antagonists and a cytostatic agent having specifically cleavable linking units | |
| Vittur | Synthesis, Characterization, and Applications of a Melamine Based Dendrimer with Twelve Cysteine Groups on the Periphery |