HRP20220311T1 - Konjugati pirolobenzodiazepina - Google Patents
Konjugati pirolobenzodiazepina Download PDFInfo
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- HRP20220311T1 HRP20220311T1 HRP20220311TT HRP20220311T HRP20220311T1 HR P20220311 T1 HRP20220311 T1 HR P20220311T1 HR P20220311T T HRP20220311T T HR P20220311TT HR P20220311 T HRP20220311 T HR P20220311T HR P20220311 T1 HRP20220311 T1 HR P20220311T1
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- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 24
- -1 methoxy, ethoxy Chemical group 0.000 claims 16
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 8
- 125000003342 alkenyl group Chemical group 0.000 claims 8
- 229910052736 halogen Inorganic materials 0.000 claims 8
- 150000002367 halogens Chemical class 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 claims 6
- 125000003118 aryl group Chemical group 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- 125000002947 alkylene group Chemical group 0.000 claims 5
- 125000000539 amino acid group Chemical group 0.000 claims 5
- 230000021615 conjugation Effects 0.000 claims 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims 5
- 125000000304 alkynyl group Chemical group 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 4
- 125000004076 pyridyl group Chemical group 0.000 claims 4
- 125000001544 thienyl group Chemical group 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 108010016626 Dipeptides Proteins 0.000 claims 3
- 235000001014 amino acid Nutrition 0.000 claims 3
- 150000001413 amino acids Chemical class 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 claims 3
- 125000000623 heterocyclic group Chemical group 0.000 claims 3
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 125000001931 aliphatic group Chemical group 0.000 claims 2
- 125000000732 arylene group Chemical group 0.000 claims 2
- 239000011230 binding agent Substances 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- IBAHLNWTOIHLKE-UHFFFAOYSA-N cyano cyanate Chemical compound N#COC#N IBAHLNWTOIHLKE-UHFFFAOYSA-N 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000005647 linker group Chemical group 0.000 claims 2
- 150000002825 nitriles Chemical group 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 125000004450 alkenylene group Chemical group 0.000 claims 1
- 125000004419 alkynylene group Chemical group 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 125000002993 cycloalkylene group Chemical group 0.000 claims 1
- 235000018417 cysteine Nutrition 0.000 claims 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
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- C07K—PEPTIDES
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
Claims (23)
1. Konjugat, naznačen time, da je predstavljen formulom I:
[image]
u kojoj
Ab je modificirano protutijelo koje ima najmanje jedno slobodno mjesto za konjugaciju na svakom teškom lancu, D predstavlja skupinu D1 ili D2:
[image]
;
crtkana linija označava opcionalnu prisutnost dvostruke veze između C2 i C3;
kada je između C2 i C3 dvostruka veza, R2 se bira iz skupine koja se sastoji od sljedećih:
(ia) C5-10 aril skupina, opcionalno supstituirana s jednim ili više supstituenata odabranih iz skupine koju čine: halogen, nitro, cijano, eter, karboksi, ester, C1-7 alkil, C3-7 heterociklil i bis-oksi-C1-3 alkilen;
(ib) C1-5 zasićeni alifatski alkil;
(ic) C3-6 zasićeni cikloalkil;
(id)
[image]
,
pri čemu se svaki od R11, R12 i R13 neovisno bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila, gdje ukupan broj atoma ugljika u skupini R2, nije veći od 5;
(ie)
[image]
pri čemu jedan od R15a i R15b jest H i preostali se bira od: fenila, gdje je fenil opcionalno supstituiran sa skupinom odabranom od halogena, metila, metoksi; piridila; i tiofenila; i
(if)
[image]
pri čemu se R14 bira od: H; C1-3 zasićenog alkila; C2-3 alkenila, C2-3 alkinila; ciklopropila; fenila, gdje je fenil opcionalno supstituiran sa skupinom odabranom od halogena, metila, metoksi; piridila; i tiofenila;
kada je između C2 i C3 jednostruka veza,
R2 se bira od H, OH, F, diF i
[image]
gdje se R16a i R16b neovisno biraju od H, F, C1-4 zasićenog alkila, C2-3 alkenila, pri čemu su alkil i alkenil skupine opcionalno supstituirane sa skupinom odabranom od sljedećih: C1-4 alkil amido i C1-4 alkil ester; ili
kada jedan od R16a i R16b jest H, preostali se bira od nitrila i C1-4 alkil estera;
D' predstavlja skupinu D'1 ili D'2:
[image]
pri čemu crtkana linija označava opcionalnu prisutnost dvostruke veze između C2' i C3';
kada je između C2' i C3' dvostruka veza, R22 se bira iz skupine koja se sastoji od sljedećih:
(iia) C5-10 aril skupina, opcionalno supstituirana s jednim ili više supstituenata odabranih iz skupine koju čine: halogen, nitro, cijano, eter, karboksi, ester, C1-7 alkil, C3-7 heterociklil i bis-oksi-C1-3 alkilen;
(iib) C1-5 zasićeni alifatski alkil;
(iic) C3-6 zasićeni cikloalkil;
(iid)
[image]
gdje se R31, R32 i R33 neovisno biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila, gdje ukupni broj atoma ugljika u skupini R22, nije veći od 5;
(iie)
[image]
pri čemu jedan od R25a i R25b jest H i preostali se bira od: fenila, gdje je fenil opcionalno supstituiran sa skupinom koja se bira od halogena, metila, metoksi; piridila; i tiofenila; i
(iif)
[image]
gdje se R24 bira od: H; C1-3 zasićenog alkila; C2-3 alkenila; C2-3 alkinila; ciklopropila; fenila, gdje je fenil opcionalno supstituiran sa skupinom koja se bira od halogena, metila, metoksi; piridila; i tiofenila;
kada je između C2' i C3' jednostruka veza,
R22 se bira od H, OH, F, diF i
[image]
gdje se R26a i R26b neovisno biraju od: H, F, C1-4 zasićenog alkila, C2-3 alkenila, dok su alkil i alkenil skupine opcionalno supstituirane sa skupinom odabranom od sljedećih: C1-4 alkil amido i C1-4 alkil ester; ili
kada jedan od R26a i R26b jest H, preostali se bira od nitrila i C1-4 alkil estera;
R6 i R9 se neovisno biraju od H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn i halogena;
pri čemu se R i R' neovisno biraju od opcionalno supstituiranih C1-12 alkila, C3-20 heterociklila i C5-20 aril skupina;
R7 se bira od H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn i halogena;
R'' je C3-12 alkilen skupina, čiji lanac može biti prekinut s jednim ili više heteroatoma, primjerice O, S, NRN2,
gdje RN2 je H ili C1-4 alkil, i/ili aromatski prstenovi, primjerice benzen ili piridin;
Y i Y' se biraju od O, S ili NH;
R11a se bira od OH, ORA, gdje RA jest C1-4 alkil;
R6', R7', R9' i R11a' se biraju iz istih skupina kao R6, R7, R9 i R11a, prema odgovarajućem poretku;
i
RLL1 i RLL2 su poveznici koji su spojeni s protutijelom na različitim mjestima i koji neovisno imaju formulu IIIa':
[image]
,
u kojoj
Q jest:
[image]
gdje QX je takav da Q je aminokiselinski ostatak, dipeptidni ostatak ili tripeptidni ostatak;
X jest:
[image]
gdje a = 0 do 5, b = 0 do 16, c = 0 ili 1, d = 0 do 5;
GLL se bira od:
[image]
gdje Ar predstavlja C5-6 arilen skupinu, primjerice fenilen i X predstavlja C1-4 alkil; gdje CBA predstavlja sredstvo za vezanje stanice koje je modificirano protutijelo s najmanje jednim slobodnim mjestom konjugacije na svakom teškom lancu;
pri čemu izraz alkil uključuje podrazrede alkenila, alkinila i cikloalkila, izraz alkilen uključuje podrazrede alkenilena, alkinilena, cikloalkilena, izraz alkenil pripada u alkilnu skupinu koja ima jednu ili više dvostrukih veza ugljik-ugljik i izraz alkinil pripada u alkilnu skupinu koja ima jednu ili više trostrukih veza ugljik-ugljik.
2. Konjugat prema patentnom zahtjevu 1, naznačen time, da:
a) Y i Y' su oba O; i/ili
b) R'' je C3-7 alkilen ili skupina s formulom:
[image]
,
gdje r je 1 ili 2; i/ili
c) R9 je H; i/ili
d) R6 je H; i/ili
e) R7 se bira od H, OH, OR ili C1-4 alkiloksi skupine.
3. Konjugat prema patentnom zahtjevu 1 ili 2, naznačen time, da D je D1, između C2 i C3 je dvostruka veza, i R2 je:
a) C5-7 aril skupina gdje R2 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili
b) C8-10 aril skupina gdje R2 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili
c) C1-5 zasićena alifatska alkil skupina, opcionalno gdje R2 je metil, etil ili propil; ili
d) skupina s formulom:
[image]
,
dok opcionalno pritom:
i) ukupni broj atoma ugljika u skupini R2, nije veći od 4;
ii) jedan od R11, R12 i R13 je H, s preostale dvije skupine koje se biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili
iii) dva od R11, R12 i R13 su H, s preostalom skupinom koja se bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili
e) skupina s formulom:
[image]
;
ili
f) skupina:
[image]
;
ili
g) skupina s formulom:
[image]
;
ili
h) C3-6 zasićena cikloalkil skupina, opcionalno pritom R2 je ciklopropil.
4. Konjugat prema patentnom zahtjevu 1 ili 2, naznačen time, da D je D1, između C2 i C3 je jednostruka veza, i R2 je:
a) H; ili
b)
[image]
i R16a i R16b su oba H; ili
c)
[image]
,
i R16a i R16b su oba metil; ili
d)
[image]
,
jedan od R16a i R16b je H, i preostali se bira od C1-4 zasićenog alkila, C2-3 alkenila, gdje su alkil i alkenil skupine opcionalno supstituirane.
5. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da D' je D'1, između C2' i C3' je dvostruka veza, i R22 je:
a) C5-7 aril skupina gdje R22 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili
b) C8-10 aril skupina gdje R22 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili
c) C1-5 zasićena alifatska alkil skupina; ili
d) C3-6 zasićena cikloalkil skupina; ili
e) skupina s formulom:
[image]
u kojoj:
i) ukupni broj atoma ugljika u skupini R22, nije veći od 4; ili
ii) jedan od R31, R32 i R33 je H, s preostale dvije skupine koje se biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili
iii) dva od R31, R32 i R33 su H, s preostalom skupinom koja se bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili
f) skupina s formulom:
[image]
;
ili
g) skupina:
[image]
;
ili
h) skupina s formulom:
[image]
gdje se R24 bira od H, metila, etila, etenila i etinila.
6. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da D' je D'1, između C2' i C3' je jednostruka veza, i R22 je:
a) H; ili
b)
[image]
i oba R26a i R26b su H; ili
c)
[image]
,
i oba R26a i R26b su metil; ili
d)
[image]
,
jedan od R26a i R26b je H; i preostali se bira od C1-4 zasićenog alkila, C2-3 alkenila, gdje su alkil i alkenil skupine opcionalno supstituirane.
7. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R11a je:
a) OH; ili
b) ORA, gdje RA jest C1-4 alkil.
8. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, da:
a) R6' se bira iz istih skupina kao R6, R7' se bira iz istih skupina kao R7, R9' se bira iz istih skupina kao R9, R11a' se bira iz istih skupina kao R11a i Y' se bira iz istih skupina kao Y; i/ili
b) R6' je ista skupina kao R6, R7' je ista skupina kao R7, R9' je ista skupina kao R9, R11a' je ista skupina kao R11a i Y' je ista skupina kao Y; i/ili
c) R22 je ista skupina kao R2.
9. Konjugat prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom Ia-1, Ia-2 ili Ia-3:
[image]
[image]
[image]
pri čemu su R2a i R22a isti i biraju se od:
(a)
[image]
(b)
[image]
(c)
[image]
(d)
[image]
(e)
[image]
(f)
[image]
(g)
[image]
;
i
(h)
[image]
R1a se bira od metila i benzila;
RLL1, RLL2 i R11a su kao što su definirani u patentnom zahtjevu 1.
10. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da RLL1 je predstavljen formulom IIIa', i Qx je:
a) aminokiselinski ostatak odabran od Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg i Trp; ili
b) dipeptidni ostatak odabran od:
CO-Phe-Lys-NH,
CO-Val-Ala-NH,
CO-Val-Lys-NH,
CO-Ala-Lys-NH,
CO-Val-Cit-NH,
CO-Phe-Cit-NH,
CO-Leu-Cit-NH,
CO-Ile-Cit-NH,
CO-Phe-Arg-NH, i
CO-Trp-Cit-NH; ili
c) tripeptidni ostatak.
11. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, da RLL1 je predstavljen formulom IIIa', i:
a) a je 0 do 3; i/ili
b) b je 0 do 12; i/ili
c) d je 0 do 3.
12. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da RLL1 je predstavljen formulom IIIa', i a je 0, c je 1 i d je 2, i b je od 0 do 8, opcionalno b je 0, 4 ili 8.
13. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da RLL2 je predstavljen formulom IIIa', i Qx je:
a) aminokiselinski ostatak odabran od Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg i Trp; ili
b) dipeptidni ostatak odabran od:
CO-Phe-Lys-NH,
CO-Val-Ala-NH,
CO-Val-Lys-NH,
CO-Ala-Lys-NH,
CO-Val-Cit-NH,
CO-Phe-Cit-NH,
CO-Leu-Cit-NH,
CO-Ile-Cit-NH,
CO-Phe-Arg-NH, i
CO-Trp-Cit-NH; ili
c) tripeptidni ostatak.
14. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 13, naznačen time, da RLL2 je predstavljen formulom IIIa', i:
a) a je 0 do 3; i/ili
b) b je 0 do 12; i/ili
c) d je 0 do 3.
15. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 13, naznačen time, da RLL2 je predstavljen formulom IIIa', i a je 0, c je 1 i d je 2, i b je od 0 do 8.
16. Konjugat prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom Id:
[image]
gdje je m cijeli broj od 2 do 8.
17. Konjugat prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da:
a) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, je IgG1, IgG2, IgG3 ili IgG4 protutijelo; i opcionalno
b) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, jest ljudsko protutijelo; ili
c) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, jest humanizirano protutijelo.
18. Konjugat prema patentnom zahtjevu 17, naznačen time, da:
a) modificirano protutijelo je modificirano tako, da cisteinski ostaci prirodnog međulanca supstituiraju aminokiselinskeostatke kojima nedostaju tiol skupine; i/ili
b) modificirano protutijelo sadrži najmanje jednu dodatnu supstituciju u svakom teškom lancu aminokiselinskog ostatka, pri čemu dodatno supstituirana aminokiselina je cistein ili neprirodna aminokiselina; i/ili
c) modificirano protutijelo je modificirano tako, da ima najmanje jednu dodatnu supstituciju u svakom teškom lancu aminokiseline, gdje je pozicija koja se supstituira, odabrana iz onih koje su dolje prikazane:
[image]
19. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, naznačen time, da je za uporabu u liječenju.
20. Farmaceutski pripravak, naznačen time, da sadrži konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, i farmaceutski prihvatljiv razrjeđivač, nosač ili pomoćno sredstvo.
21. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, ili farmaceutski pripravak prema patentnom zahtjevu 20, naznačen time, da je za uporabu u liječenju proliferativne bolesti kod pojedinca, opcionalno gdje bolest koja se liječi, jest rak.
22. Spoj, naznačen time, da je predstavljen formulom II:
[image]
i njegove soli i solvati,
pri čemu su D, R2, R6, R7, R9, R11a, Y, R'', Y', D', R6', R7', R9', R11a' i R12 (uključujući prisutnost ili odsutnost dvostrukih veza između C2 i C3 odnosno C2' i C3'), kao što su definirani u bilo kojem od patentnih zahtjeva 1 do 9;
RL1 i RL2 su poveznice za spajanje na sredstvo za vezanje stanice, gdje su neovisno predstavljeni formulom IIIa:
[image]
pri čemu su Q i X kao što su definirani u bilo kojem od patentnih zahtjeva 1, 10 do 12 i 13 do 15 i GL se bira od:
[image]
[image]
gdje Ar predstavlja C5-6 arilen skupinu, primjerice fenilen, i X predstavlja C1-4 alkil.
23. Spoj prema patentnom zahtjevu 22, naznačen time, da je spoj predstavljen formulom Id':
[image]
u kojoj je m cijeli broj od 2 do 8.
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