Antibody Conjugates (ADCS) - Active principle of KSP inhibitors with anti tweakr

摘要

This application relates to conjugated Linker - Active Principle (ADCS), active Metabolites of these ADCS, procedures for preparing these ADCS,The use of these ADCS for Treatment and Prevention of diseases, as well as the use of these ADCS for the preparation of drugs for the treatment and / or prevention of diseasesIn particular, angiogenic and / or hyperproliferative diseases such as cancer.These treatments can be performed as monotherapy or in combination with other medications and other Therapeutic measures.Claim 1: Conjugate of an Antibody with one or more Molecules of the active principle of the formula (2),Where represents a Linker Antibody anti tweakr agonist agonist Action moderately or not or one of its Fragments Binding to Antigen; l represents a Linker; n is a number1 to 1.2 to 20 and 50, preferably with Special preference, 2 to 8; and KSP is a compound of the formula (1), where ru00b9 represents - H, - L - # Mod 1, - O - (chu2082) u2080u208bu2083z, where z represents h,- nhyu00b3, oyu00b3 syu00b3 halogen -, -, - C (= o) - nyu00b9yu00b2 or - C (= o) - oyu00b3; yu00b9 and yu00b2 represent, independently of each other, - H, - nhu2082, - (chu2082chu2082o) u2080u208bu2083 - (chu2082) u2080u208bu2083z '(e.g.- (chu2082) u2080u208bu2083z ') or CH (chu2082w) Z'; or (chu2082 represents - H OR - '' represents u2080u208bu2083z); Z - H, - nhu2082, - COOH, - sou2083h,- NH - C (= o) - chu2082 - chu2082 - COOH and - ch (nhu2082) (CO NH - chyu2074) u2081u208bu2083cooh; W represents H or Oh; yu2074 cu2081u208bu2086 represents linear or branched alkyl, optionally substituted with - NH - C (= o) - nhu2082,Or - or benzyl aryl optionally replaced with nhu2082; Ru00b2 represents h, mod -, - C (= o) - O - (chyu2074 - nhyu2075 u2080u208bu2083z chu2082), where z represents h, halogen, oyu00b3 syu00b3 -, -, - nhyu00b3,- C (= o) - nyu00b9yu00b2 or - C (= o) - oyu00b3; yu00b9 and yu00b2 represent, independently of each other, - H, - or - nhu2082 (chu2082 represents u2080u208bu2083z '); or - H OR - (chu2082) u2080u208bu2083z' represents'; Z - H, - sou2083h,- nhu2082 or - COOH; yu2074 cu2081u208bu2086 represents linear or branched alkyl, optionally substituted with - NH - C (= o) - nhu2082,Or optionally substituted aryl or benzyl yu2075 represents nhu2082 with - and - H OR - C (= o) - chyu2076 - nhu2082; yu2076 represents linear or branched alkyl cu2081u208bu2086; ru2074 represents # - H, - L - 1, - sgu2097u02b8u209b - (c = o) - u2080u208bu2081 ru2074 ',- C (= o) - O - (chyu2074 - nhyu2075 chu2082) u2080u208bu2083z, Where Where sgu2097u02b8u209b represents a Group cleavable by lysosomal Enzymes, particularly a group composed of a Di - or tripeptide,Where ru2074 'cu2081u208bu2081u2080 represents an alkyl, aryl or cu2085u208bu2081u2080 aralquilo cu2086u208bu2081u2080, heteroalquilo cu2085u208bu2081u2080, alkyl - or aryl - cu2081u208bu2081u2080 cu2086u208bu2081u2080, heterocicloalquilo cu2085u208bu2081u2080 heteroaryl heteroaryl alkyl,,,Heteroaryl - alkoxy -, alkoxy cu2081u208bu2081u2080, ariloxi cu2086u208bu2081u2080 or aralcoxi cu2086u208bu2081u2080, heteroaralcoxi cu2085u208bu2081u2080 cu2081u208bu2081u2080, alkyl - or - ariloxi cu2086u208bu2081u2080, heterocicloalcoxi cu2085u208bu2081u2080, which can be polisustituido with mono - or - nhu2082,- NH - N - alkyl (alkyl) u2082, - NH - C (= o) - alkyl (alkyl) - N - C (= o) - sou2083h alkyl -, - S - (= o) u2082 nhu2082, S (= o) - (alkyl) - n u2082 u2082, - COOH, - C (= o) - nhu2082, - C (= o) - (alkyl) - n u2082 or Oh.- H OR - represents a Group ou02e3 - (chu2082chu2082o) u02b8 - ru2074 ', where X is 0 OR 1, where V represents a number from 1 to 10, where ru2074' represents h, alkyl (alkyl preferably cu2081u208bu2081u2082) - chu2082 - COOH,Chu2082 chu2082 - COOH and - - - - - chu2082 chu2082 nhu2082; where z represents h, halogen, oyu00b3 syu00b3 nhyu00b3 -, -, - C (= o) - nyu00b9yu00b2 or - C (= o) - oyu00b3, where yu00b9 and yu00b2 represent, independently of each other, - H nhu2082, - O - (chu2082) u2080u208bu2083z ',Where is or - H OR - (chu2082) u2080u208bu2083z ', where z represents sou2083h' - H, - or - COOH, - nhu2082; where yu2074 represents linear or branched alkyl cu2081u208bu2086,Optionally replaced with - NH - C (= o) - nhu2082 or aryl benzyl or optionally substituted with - nhu2082,Where yu2075 represents - H OR - C (= o) - chyu2076 - nhu2082 and where yu2076 represents linear or branched alkyl cu2081u208bu2086; or Ru00b2 and ru2074 represent Together (with formation of a pyrrolidine Ring chu2082 chru00b9u00b9) - - - - - - or chru00b9u00b9 chu2082,Where ru00b9u00b9 represents - H, - nhu2082 sou2083h, - SH, - COOH, - Halogen (F, CL, or in Special cu2081u208bu2084 haloalquilo cu2081u208bu2084) alkyl, alkoxy, substituted with alkyl cu2081u208bu2084, cu2081u208bu2084 hydroxylCoo (cu2081u208bu2084 or alkyl) - Oh, - C (= o) - (= o) - S, - S, - u2082 (= o) -, S - (= o) - (u2082nh or - C = N - nhu2082); ru00b3 represents # - L - 1, - mod or an alkyl group, cycloalkyl, aryl, heteroaryl, heteroalquilo,Heterocicloalquilo optionally replaced, preferably # - L - 1 or an aryl or alkyl group cu2081u208bu2081u2080, cu2086u208bu2081u2080 aralquilo cu2086u208bu2081u2080, heteroalquilo cu2085u208bu2081u2080,Cu2081u208bu2081u2080 alkyl - or aryl - or cu2086u208bu2081u2080 heterocicloalquilo cu2085u208bu2081u2080, which in each case may be substituted with groups 1 - 3 - 1 - 3 Halogen Atoms.1 - 3 (Halogenated alkyl groups present in each case 1 - 3 Halogen Atoms), 1 - 3 - alkyl groups or - SH groups, 1 - 3, 1 - 3 - alkyl groups, groups 1 - 3 or - C (= o) - alkyl1 - 3 Groups - or - C (= o) - alkyl - NH - NH groups, 1 - 3 - C (= o) - alkyl groups 1 - 3, - NH - C (= o) - NH - alkyl groups, 1 - 3 - S (= o) - alkyl u2099, 1 - 3 Groups - S (= o) - alkyl u2082 - NH - NH groups, 1 - 3 - alkyl1 - 3 groups (alkyl) - n u2082, 1 - 3 - 1 - 3 nhu2082 groups or groups (u2080u208bu2083z chu2082), where n represents 0, 1 or 2; Z represents h, halogen - oyu00b3 syu00b3 nhyu00b3, -, -, - C (= o) - O - nyu00b9yu00b2 C (= o) - oyu00b3 yu00b9 yu00b2 represent; and,Independently of each other, - H, - or - nhu2082 (chu2082 represents u2080u208bu2083z '); or - H, - (chu2082 u2080u208bu2083 - ch (NH) - C (= o) - chu2083) Z' - (chu2082) u2080u208bu2083 - ch (nhu2082) Z - (chu2082 u2080u208bu2083z 'Or') 'h; Z represents sou2083h -, - or - COOH, - nhu2082; ru2075 represents h,- nhu2082, - nou2082 (in particular, halogen (F, CL, BR), - CN, - cfu2083, ocfu2083 chu2082f chu2082f, -, -, or - SH (chu2082) u2080u208bu2083z, where z represents oyu00b3 - H, -, - syu00b3, halogen, nhyu00b3 -, - C (= o) - nyu00b9yu00b2 or - C (= o) - oyu00b3, yu00b9 and yu00b2 representIndependently of each other, - H, - or - nhu2082 (chu2082 u2080u208bu2083z '); or (chu2082 represents - H OR -' ') u2080u208bu2083z; Z represents sou2083h - H, -, - and - COOH or nhu2082; ru2076 ru2077 represent, independently of each other, - H, cyano,Cu2081u208bu2081u2080 fluoro alkyl, alkyl cu2081u208bu2081u2080, alquenilo cu2082u208bu2081u2080, fluoro alquenilo cu2082u208bu2081u2080, alquinilo cu2082u208bu2081u2080 alquinilo cu2082u208bu2081u2080, fluoro -, hydroxy - nou2082 nhu2082, - COOH, - ru2078 represents alkyl or Halogen; cu2081u208bu2081u2080,Fluoro alkyl cu2081u208bu2081u2080, alquenilo cu2082u208bu2081u2080, fluoro alquenilo cu2082u208bu2081u2080, alquinilo cu2082u208bu2081u2080, fluoro alquinilo cu2082u208bu2081u2080, cycloalkyl or cycloalkyl cu2084u208bu2081u2080 cu2084u208bu2081u2080, fluoro - (chu2082) u2080u208bu2082 - (hzu00b2)That may be mono - or di, identical or different, - Oh, - COOH and - nhu2082 and where hzu00b2 represents a heterocycle of 4 to 7 members with up to two heteroatoms selected from N,O and S; ru2079 represents - H, - F, - chu2083, cfu2083 chu2082f -, - or - chfu2082; where one of the substituents ru00b9, ru00b3 and ru2074 represents # - L - 1,L represents a Linker and # 1 represents the link with the Antibody; mod represents - (nru00b9u2070) u2099 - (gu00b9) u2092 - G - gu00b3, where ru00b9u2070 represents H or alkyl cu2081u208bu2083; gu00b9 represents - NHC (= o) -,- C (= o) - NH - (which is when gu00b9 - NHC (= o) - then ru00b9u2070 is not nhu2082); n is 0 OR 1; or is 0 OR 1; and G is a linear or branched Hydrocarbon chain with 1 to 10 carbon ATOMS,That can be interrupted once or several times by one or several of the groups - O -, - S - S - (= o) - O - (= o) - - - u2082, nru02b8, nru02b8c (= o) -, - C (= o) - - - - nru02b8, nru02b8nru02b8 - S, - nru02b8nru02b8 u2082 (= o) -, - C (= o) - nru02b8nru02b8 -- Where ru02b8 represents h, alkyl, phenyl or cu2081u208bu2081u2080, alquenilo cu2082u208bu2081u2080 alquinilo cu2082u208bu2081u2080, which may be mono - or polisustituidos, identical or different, with - NH - C (= o) - nhu2082, - COOH, - Oh, - nhu2082, - NH - cnnhu2082,Sulfonamide and sulfonic acid sulfoxide, sulfone, and / or may be one or several times interrupted by the same or different, - C (= o) - O - N - cru02e3 =, where represents ru02e3 - HCu2081u208bu2083 alkyl or phenyl, and where the Hydrocarbon Chain including an alkyl group cu2081u208bu2081u2080 optionally substituted Hydrocarbon Group as in the side chainCan be replaced with - NH - C (= o) - nhu2082, - COOH, - Oh, - nhu2082, - NH - cnnhu2082, sulfonamide, sulphoneSulfoxide or sulfonic acid; gu00b3 represents - H OR - COOH Group; and where the mod is preferably at least a - COOH Group; as well as their salts, solvates, Salts and solvates of the epu00edmeros.