HRP20191729T1 - Novi spojevi i konjugati kriptoficina, njihova priprava i njihova terapeutska uporaba - Google Patents
Novi spojevi i konjugati kriptoficina, njihova priprava i njihova terapeutska uporaba Download PDFInfo
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- HRP20191729T1 HRP20191729T1 HRP20191729T HRP20191729T1 HR P20191729 T1 HRP20191729 T1 HR P20191729T1 HR P20191729 T HRP20191729 T HR P20191729T HR P20191729 T1 HRP20191729 T1 HR P20191729T1
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- Prior art keywords
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- alkyl
- formula
- cryptophycin
- hydrogen atom
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- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 title claims 14
- 238000002360 preparation method Methods 0.000 title claims 2
- 230000001225 therapeutic effect Effects 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 27
- 229930188224 Cryptophycin Natural products 0.000 claims 26
- 108010006226 cryptophycin Proteins 0.000 claims 26
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 claims 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 22
- -1 Cryptophycin compound Chemical class 0.000 claims 17
- 229910052799 carbon Inorganic materials 0.000 claims 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 5
- 125000001424 substituent group Chemical group 0.000 claims 5
- JFCBEFFZEOHJDG-MLWJPKLSSA-N (2s)-2,6-diamino-7-oxooctanoic acid Chemical compound CC(=O)C(N)CCC[C@H](N)C(O)=O JFCBEFFZEOHJDG-MLWJPKLSSA-N 0.000 claims 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 125000003636 chemical group Chemical group 0.000 claims 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 3
- 229910006069 SO3H Inorganic materials 0.000 claims 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims 3
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 235000018417 cysteine Nutrition 0.000 claims 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000004471 Glycine Substances 0.000 claims 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 2
- 239000004472 Lysine Substances 0.000 claims 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 235000004279 alanine Nutrition 0.000 claims 2
- 235000001014 amino acid Nutrition 0.000 claims 2
- 229940024606 amino acid Drugs 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 235000013477 citrulline Nutrition 0.000 claims 2
- 229960002173 citrulline Drugs 0.000 claims 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 239000004474 valine Substances 0.000 claims 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 claims 1
- WAMWSIDTKSNDCU-UHFFFAOYSA-N 2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)C(N)C1CCCCC1 WAMWSIDTKSNDCU-UHFFFAOYSA-N 0.000 claims 1
- 239000004475 Arginine Substances 0.000 claims 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims 1
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 1
- 238000006942 Corey-Chaykovsky ring formation reaction Methods 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 claims 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims 1
- 239000004473 Threonine Substances 0.000 claims 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000003172 aldehyde group Chemical group 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 150000001408 amides Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 1
- 235000009582 asparagine Nutrition 0.000 claims 1
- 229960001230 asparagine Drugs 0.000 claims 1
- 235000003704 aspartic acid Nutrition 0.000 claims 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 1
- 229940000635 beta-alanine Drugs 0.000 claims 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims 1
- 125000000837 carbohydrate group Chemical group 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 150000001945 cysteines Chemical class 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 1
- 229960000310 isoleucine Drugs 0.000 claims 1
- 150000002576 ketones Chemical group 0.000 claims 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
- 238000005710 macrocyclization reaction Methods 0.000 claims 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229930182817 methionine Natural products 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 229960003104 ornithine Drugs 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 238000005897 peptide coupling reaction Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 1
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (32)
1. Spoj kriptoficina s formulom (I):
pri čemu:
▪ R1 predstavlja skupinu (C1-C6)alkil;
▪ R2 i R3 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil;
ili alternativno R2 i R3 tvore zajedno s ugljikovim atomom na koji su oni vezani skupinu (C3-C6)cikloalkil ili skupinu (C3-C6)heterocikloalkil;
▪ R4 i R5 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil ili skupinu (C1-C6)alkil-NH(R12) ili skupinu (C1-C6)alkil-OH ili skupinu (C1-C6)alkil-SH ili skupinu (C1-C6)alkil-CO2H;
ili alternativno R4 i R5 tvore zajedno s ugljikovim atomom na koji su oni vezani skupinu (C3-C6)cikloalkil ili skupinu (C3-C6)heterocikloalkil;
▪ R6 predstavlja vodikov atom ili skupinu (C1-C6)alkil;
▪ R7 i R8 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil ili skupinu (C1-C6)alkil-CO2H ili skupinu (C1-C6)alkil-N(C1-C6)alkil2;
ili alternativno R7 i R8 tvore zajedno s ugljikovim atomom na koji su oni vezani skupinu (C3-C6)cikloalkil ili skupinu (C3-C6)heterocikloalkil;
▪ R9 predstavlja jedan ili više supstituenata fenilne jezgre odabranih, neovisno jedan od drugoga, od: vodikovog atoma, -OH, (C1-C4)alkoksi, halogenog atoma, -NH2, -NH(C1-C6)alkil ili - N(C1-C6)alkil2 ili -NH(C1-C6)cikloalkil ili (C3-C6)heterocikloalkil;
▪ R10 predstavlja barem jedan supstituent fenilne jezgre odabran od vodikovog atoma i (C1-C4)alkila;
▪ W predstavlja
• (C1-C6)alkil-NH(R11),
• (C1-C6)alkil-OH,
• (C1-C6)alkil-SH,
• CO2H ili C(=O)NH2;
• (C1-C6)alkil-CO2H ili (C1-C6)alkil-C(=O)NH2; ili
• (C1-C6)alkil-N3.
▪ R11 i R12 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil.
2. Spoj kriptoficina s formulom (I) prema patentnom zahtjevu 1, naznačen time što ima slijedeću strukturu:
3. Spoj kriptoficina s formulom (I) prema bilo kojem patentnom zahtjevu 1 ili 2, naznačen time što R1 predstavlja metilnu skupinu.
4. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time što:
- svaki od R2 i R3 predstavlja vodikov atom, ili
- jedan od R2 i R3 predstavlja metilnu skupinu i drugi predstavlja vodikov atom, ili
- R2 i R3 tvore zajedno s ugljikovim atomom na koji su oni vezani ciklopropilnu skupinu.
5. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time što svaki od R4 i R5 predstavlja metilnu skupinu.
6. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time što R6 predstavlja vodikov atom.
7. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time što R7 i R8 predstavljaju neovisno jedan od drugoga vodikov atom ili skupinu (C1-C6)alkil.
8. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time što R9 predstavlja dva supstituenta izabrana od metoksi skupine i klorovog atoma.
9. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 8, naznačen time što R10 predstavlja vodikov atom.
10. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time što:
▪ R1 predstavlja (C1-C6)alkil;
▪ svaki od R2 i R3 predstavlja vodikov atom;
▪ R6 predstavlja vodikov atom;
▪ R9 predstavlja dva supstituenta izabrana od metoksi skupine i klorovog atoma; i R10 predstavlja vodikov atom.
11. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time što:
▪ R1 predstavlja (C1-C6)alkil;
▪ R2 i R3 predstavljaju (C1-C6)alkil, i drugi predstavlja vodikov atom;
▪ R6 predstavlja vodikov atom;
▪ R9 predstavlja dva supstituenta izabrana od metoksi skupine i klorovog atoma; i
▪ R10 predstavlja vodikov atom.
12. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time što W je odabran od (C1-C6)alkil-NHR11, (C1-C6)alkil-OH, (C1-C6)alkil-SH i (C1-C6)alkil-CO2H, poželjno W predstavlja skupinu CH2-NH2 ili skupinu CH2-OH.
13. Spojevi kriptoficina s formulom (I) prema patentnom zahtjevu 1 naznačeni time što su odabrani sa sljedećeg popisa:
14. Korisni dio kriptoficina s formulom (II):
pri čemu
R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 su kako je definirano u zahtjevu 1 do 11, i
▪ Y je odabran od skupine (C1-C6)alkil-NR11, (C1-C6)alkil-O, (C1-C6)alkil-S, C(=O)O, C(=O)NH, (C1-C6)alkil-C(=O)O, (C1-C6)alkil-C(=O)NH ili (C1-C6)alkil-triazol;
▪ R11 predstavlja vodikov atom ili skupinu (C1-C6)alkil;
▪ L predstavlja poveznicu;
▪ RCG1 predstavlja reaktivnu kemijsku skupinu koja je prisutna na kraju poveznice, te
L ima formulu (IV):
u kojoj:
▪ L1 predstavlja
▪ jednostruku vezu ili skupinu NR16(hetero)aril-CR15R14O-C(=O) ako Y = (C1-C6)alkil-N(R11);
▪ skupinu NR18-(C2-C6)alkil-NR17-C(=O) ili skupinu NR16(hetero)aril-CR15R14-O-C(=O)-NR18-(C2-C6)alkil-NR17-C(=O) ako Y = (C1-C6)alkil- O ili (C1-C6)alkil- S;
▪ skupinu NR16(hetero)aril-CR15R14- ako Y = C(=O)O, C(=O)NH, (C1-C6)alkil-C(=O)O ili (C1-C6)alkil-C(=O)NH;
▪ R11, R14, R15, R16, R17 i R18 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil;
▪ (AA)w predstavlja sekvencu od w amino kiselina AA povezanu zajedno putem peptidnih veza;
▪ w predstavlja cijeli broj u rasponu od 1 do 12;
▪ L2 predstavlja jednostruku vezu ili skupinu (C1-C6)alkil ili skupinu (C1-C6)alkil-(OCH2CH2)i ili skupinu (C1-C6)alkil-(OCH2CH2)i-O(C1-C6)alkil ili skupinu (CH2CH2O)i(C1-C6)alkil ili skupinu CH(SO3H)-(C1-C6)alkil ili skupinu (C1-C6)alkil-CH(SO3H) ili skupinu (C1-C6)alkil-cikloheksil ili skupinu NR19-(C1-C6)alkil ili skupinu NR20-(CH2CH2O)i(C1-C6)alkil ili skupinu NR21-aril ili skupinu NR21-heteroaril ili skupinu (C1-C6)alkil-NR22C(=O)-(C1-C6)alkil ili skupinu (C1-C6)alkil-NR22C(=O)-(C1-C6)alkil-(OCH2CH2)i;
▪ R19, R20, R21 i R22 predstavljaju, neovisno jedan od drugoga, vodikov atom ili skupinu (C1-C6)alkil;
▪ i predstavlja cijeli broj između 1 i 50 ;
AA označava prirodnu ili neprirodnu aminokiselinu konfiguracije D ili L, izabranu između: alanina (Ala), β-alanina, γ-aminomaslačne kiseline, 2-amino-2-cikloheksiloctene kiseline, 2-amino-2-feniloctene kiseline, arginina (Arg), asparagina (Asn), asparaginske kiseline (Asp), citrulina (Cit), cisteina (Cys), α,α-dimetil-γ-aminomaslačne kiseline, β,β-dimetil-γ-aminomaslačne kiseline, glutamine (Gln), glutaminske kiseline (Glu), glicina (Gly), histidina (His), izoleucina (Ile), leucina (Leu), lizina (Lys), ε-acetil-lizina (AcLys), metionina (Met), ornitina (Orn), fenilalanina (Phe), prolina (Pro), serina (Ser), treonin (Thr), triptofana (Trp), tirozine (Tyr), valina (Val).
15. Korisni dio kriptoficina s formulom (II) prema patentnom zahtjevu 14, naznačen time što ima slijedeću strukturu:
16. Korisni dio kriptoficina s formulom (II) prema bilo kojem patentnom zahtjevu 14 ili 15, naznačen time što Y predstavlja (C1-C6)alkil-NR11, poželjno Y predstavlja CH2-NH.
17. Korisni dio kriptoficina s formulom (II) prema patentnom zahtjevu 14, naznačen time što sekvenca (AA)w ima formulu:
u kojoj R23 predstavlja bočni lanac AA.
18. Korisni dio kriptoficina s formulom (II) prema bilo kojem patentnom zahtjevu 14 ili 17, naznačen time što sekvenca AA predstavlja alanin (Ala), citrulin (Cit), glutamin (Gln), glicin (Gly), ε-acetil-lizin (AcLys), valin (Val).
19. Korisni dio kriptoficina s formulom (II) prema bilo kojem od patentnih zahtjeva 14 do 18, naznačen time što je RCG1 odabran od:
- skupine -C(=O)-ZaRa za koju
▪ Za predstavlja jednostruku vezu, O ili NH, i
▪ Ra predstavlja H ili skupinu (C1-C6)alkil, (C3-C7)cikloalkil, (C5-C10)aril, (C5-C10)heteroaril ili (C3-C7)heterocikloalkil ili skupinu sukcinimidil;
- jedne od sljedećih reaktivnih skupina: maleimidne
skupine; haloacetamido
skupine gdje R13 predstavlja vodikov atom ili skupinu (C1-C6)alkil; -Cl; -N3; - OH; -SH; -NH2;
-C≡CH, skupinu ili skupinu O-(C1-C6)alkil hidroksilamin.
20. Korisni dio kriptoficina s formulom (II) prema bilo kojem od patentnih zahtjeva 14 do 18, naznačen time što L2 predstavlja skupinu (C1-C6)alkil ili skupinu (C1-C6)alkil-(OCH2CH2)i ili skupinu CH(SO3H)-(C1-C6)alkil.
21. Korisni dijelovi kriptoficina s formulom (II) prema patentnom zahtjevu 14, naznačeni time što su odabrani sa sljedećeg popisa:
22. Konjugat s formulom (III):
naznačen time što
▪ R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 su kako je definirano u zahtjevu 1 do 11;
▪ Y i L su kako je definirano u zahtjevima 14 do 18;
▪ G predstavlja produkt reakcije između RCG1, reaktivne skupine prisutne na kraju poveznice i RCG2, ortogonalne reaktivne skupine prisutne na Ab;
▪ Ab predstavlja protutijelo.
23. Konjugat s formulom (III) prema patentnom zahtjevu 22 naznačeni time što ima slijedeću strukturu:
24. Konjugat s formulom (III) prema bilo kojem patentnom zahtjevu 22 ili 23, naznačen time što je RCG2 odabrana od:
• ε-amino skupina lizina koje nose bočni lanci lizinskih ostataka koji su prisutni na površini protutijela;
• α-amino skupina N- terminalnih aminokiselina teških i lakih lanaca protutijela;
• saharidnih skupina zglobne regije;
• tiola cisteina stvoreni redukcijom disulfidnih veza unutar lanca ili tiola dizajniranih cisteina;
• amidnih skupina koje nose bočni lanci nekih glutaminskih ostataka koji su prisutni na površini protutijela;
• aldehidnih skupina uvedenih korištenjem enzima koji stvara formilglicin.
25. Konjugat s formulom (III) prema bilo kojem patentnom zahtjevu 22 ili 23, naznačen time što:
• kada RCG1 predstavlja N-hidroksisukcinimidil ester, RCG2 predstavlja skupinu -NH2;
• kada RCG1 predstavlja maleimido ili haloacetamido funkciju ili skupinu -Cl, RCG2 predstavlja skupinu -SH;
• kada RCG1 predstavlja skupinu -N3, RCG2 predstavlja skupinu -C≡CH ili aktivirani C≡C;
• kada RCG1 predstavlja skupinu -OH ili -NH2, RCG2 predstavlja karboksilnu kiselinu ili amidnu funkciju;
• kada RCG1 predstavlja skupinu -SH, RCG2 predstavlja maleimido ili haloacetamido funkciju;
• kada RCG1 predstavlja -C≡CH funkciju ili aktivirani C≡C, RCG2 predstavlja skupinu -N3;
• kada RCG1 predstavlja O-alkil hidroksilaminsku funkciju ili Pictet-Spengler reakcijski supstrat, RCG2 predstavlja aldehidnu ili ketonsku funkciju.
26. Konjugat s formulom (III) prema bilo kojem od patentnih zahtjeva 22 do 25, naznačen time što je G odabran od:
27. Postupak za pripremanje spoja kriptoficina s formulom (I) koji sadrži korak:
naznačen time što:
- korak (i) je peptidno spajanje između fragmenata AD3 i alternativno BC u prisutnosti reagenasa za spajanje;
- korak (ii) je makrociklizacija metatezom zatvaranja prstena u prisutnosti katalizatora;
- korak (iii) je uklanjanje zaštite p-metoksibenzil etera u kiselim uvjetima;
- korak (iv) je oksidacija alkohola primjenom oksidirajućeg sredstva;
- korak (v) je uvođenje epoksida asimetričnom Corey-Chaykovsky reakcijom primjenom odgovarajuće supstituiranog izotiocineolom-dobivenog kiralnog sulfonija u prisutnosti baze;
- korak (vi) je redukcija azido skupine.
28. Postupak za pripremanje konjugata s formulom (III) koji sadrži korake:
(i) dovođenje u kontakt i ostavljanje da reagiraju:
- po izboru puferirane vodene otopine protutijela, proizvoljno modificirane pomoću sredstva za modificiranje,
i
- otopine korisnog dijela kriptoficina s formulom (II) kako je definirano u jednom od zahtjeva 14 do 21,
kemijska skupina RCG1 korisnog dijela kriptoficina s formulom (II) je reaktivna prema kemijskim skupinama RCG2 prisutnima na protutijelu, posebno prema amino skupinama prisutnim na protutijelima, pri čemu su navedene kemijske skupine RCG2, gdje je prikladno, uvedene, pomoću sredstva za modificiranje,
tako da se korisni dio kriptoficina s formulom (II) veže na protutijelo stvaranjem kovalentne veze;
(ii) i zatim, prema potrebi, odvajanje konjugata nastalog u koraku (i) iz korisnog dijela kriptoficina s formulom (II) i/ili iz nereagiranog protutijela i/ili iz bilo kojeg agregata koji je možda nastao.
29. Lijek, naznačen time što sadrži konjugat s formulom (III) prema bilo kojem od patentnih zahtjeva 22 do 26.
30. Farmaceutski pripravak, naznačen time što sadrži konjugat s formulom (III) prema bilo kojem od patentnih zahtjeva 22 do 26, i također barem jednu farmaceutski prihvatljivu pomoćnu tvar.
31. Spoj kriptoficina s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 13 naznačen time što je za uporabu u liječenju raka.
32. Konjugat s formulom (III) prema bilo kojem od patentnih zahtjeva 22 do 26 naznačen time što je za uporabu u liječenju raka.
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| EP15306751 | 2015-11-05 | ||
| PCT/EP2016/076603 WO2017076998A1 (en) | 2015-11-05 | 2016-11-03 | Novel cryptophycin compounds and conjugates, their preparation and their therapeutic use |
| EP16791017.3A EP3371179B1 (en) | 2015-11-05 | 2016-11-03 | Novel cryptophycin compounds and conjugates, their preparation and their therapeutic use |
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| US (2) | US10941139B2 (hr) |
| EP (1) | EP3371179B1 (hr) |
| JP (1) | JP6929292B2 (hr) |
| KR (1) | KR20180073678A (hr) |
| CN (1) | CN108349960B (hr) |
| AR (1) | AR106604A1 (hr) |
| AU (1) | AU2016347724B2 (hr) |
| CA (1) | CA3003085A1 (hr) |
| CL (1) | CL2018001210A1 (hr) |
| CO (1) | CO2018004581A2 (hr) |
| CR (1) | CR20180256A (hr) |
| CY (1) | CY1122441T1 (hr) |
| DK (1) | DK3371179T3 (hr) |
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| PL (1) | PL3371179T3 (hr) |
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| TWI714661B (zh) * | 2015-11-05 | 2021-01-01 | 法商賽諾菲公司 | 新穎念珠藻素化合物及接合物、其製備與其治療用途 |
| CN107043380A (zh) | 2016-02-05 | 2017-08-15 | 正大天晴药业集团股份有限公司 | 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e、制备方法和用途 |
| JP2020519610A (ja) | 2017-05-10 | 2020-07-02 | サノフイＳａｎｏｆｉ | 治療において有用な、ペプチド性リンカーおよびクリプトフィシンコンジュゲート、ならびにこれらの製造 |
| CN108107103B (zh) * | 2017-12-14 | 2020-10-16 | 华中师范大学 | 谷氨酸受体的质谱探针及其在脑组织中的空间分布规律检测方法 |
| MX2021010603A (es) | 2019-03-07 | 2022-01-31 | Conatus Pharmaceuticals Inc | Inhibidores de caspasa y metodos de uso de los mismos. |
| WO2021067460A1 (en) | 2019-09-30 | 2021-04-08 | The Regents Of The University Ofmichigan | Biocatalytic synthesis of cryptophycin anticancer agents |
| EP4046996A1 (en) | 2021-02-19 | 2022-08-24 | Universität Bielefeld | Cryptophycin compounds and conjugates thereof |
| WO2023161291A1 (en) | 2022-02-22 | 2023-08-31 | Araris Biotech Ag | Peptide linkers comprising two or more payloads |
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| WO1995017093A1 (en) * | 1993-12-21 | 1995-06-29 | University Of Hawaii | New cryptophycins |
| US20020128185A1 (en) * | 1998-02-25 | 2002-09-12 | Chuan Shih | Pharmaceutical compounds |
| US7230101B1 (en) | 2002-08-28 | 2007-06-12 | Gpc Biotech, Inc. | Synthesis of methotrexate-containing heterodimeric molecules |
| US20050175619A1 (en) | 2004-02-05 | 2005-08-11 | Robert Duffy | Methods of producing antibody conjugates |
| WO2007127440A2 (en) | 2006-04-27 | 2007-11-08 | Intezyne Technologies, Inc. | Heterofunctional poly(ethylene glycol) containing acid-labile amino protecting groups and uses thereof |
| CA2658276A1 (en) | 2006-07-18 | 2008-01-24 | Sanofi-Aventis | Antagonist antibody for the treatment of cancer |
| FR2947269B1 (fr) * | 2009-06-29 | 2013-01-18 | Sanofi Aventis | Nouveaux composes anticancereux |
| AR078470A1 (es) | 2009-10-02 | 2011-11-09 | Sanofi Aventis | Anticuerpos que se unen especificamente al receptor epha2 |
| TWI714661B (zh) | 2015-11-05 | 2021-01-01 | 法商賽諾菲公司 | 新穎念珠藻素化合物及接合物、其製備與其治療用途 |
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