JP-2022533215-A5 -

Dates

Publication Date

20230526

Application Date

20200519

Description

The examples and embodiments described herein are for illustrative purposes only, and it is understood that various modifications or variations thereof are suggested to those skilled in the art and are included in the spirit and scope of this application and the appended claims.The invention described in the original claims of this application is listed below.[1] Equation (I):(In the formula,R1It is a reactive group,L1This is a cross-linking spacer,Lp is a divalent peptide spacer,G-L2- A is a self-sacrificing spacer,R2This is the hydrophilic part,L2is a bond, methylene, neopentylene or C2~C3It is alkenylene,A is a bond, -OC (=O)-*,, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3) C (Ra)2C(Ra)2N(CH3)C(=O)-*, where each RaThese are H and C, independently.1~C6Alkyl or C3~C8Selected from cycloalkyl groups, and the asterisk (*) in A indicates the bond site to D.L3This is the spacer part, andD is a drug portion containing N or O, where D is bonded to A via a direct bond from A to the drug portion, or to the N or O.A compound of or a pharmaceutically acceptable salt thereof.[2] R1It is a reactive group,L1This is a cross-linking spacer,Lp is a divalent peptide spacer containing 1 to 4 amino acid residues.The basis is,Selected from, here,The asterisk (*) indicates the bonding point of the drug portion to N or O.The *** indicates the binding point to Lp.R2This is the hydrophilic part,L2is a bond, methylene, neopentylene or C2~C3It is alkenylene,A is a bond, -OC (=O)-*,, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3) C (Ra)2C(Ra)2N(CH3)C(=O)-*, where each RaThese are H and C, independently.1~C6Alkyl or C3~C8Selected from cycloalkyl groups, and the asterisk (*) in A indicates the bond site to D.L3This is the spacer part, andD is a pharmaceutical portion containing N or O, wherein D is bonded to A via a direct bond from A to the pharmaceutical portion, or a pharmaceutically acceptable salt thereof, of the compound of formula (I) described in [1] or a pharmaceutically acceptable salt thereof.[3] Compounds of formula (II) or pharmaceutically acceptable salts thereof:(In the formula,R1It is a reactive group,L1This is a cross-linking spacer,Lp is a divalent peptide spacer containing 1 to 4 amino acid residues.R2This is the hydrophilic part,A is a bond, -OC (=O)-*,, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3) C (Ra)2C(Ra)2N(CH3)C(=O)-*, where each RaThese are H and C, independently.1~C6Alkyl or C3~C8Selected from cycloalkyl groups, and the asterisk (*) in A indicates the bond site to D.L3This is the spacer part, andD is a drug portion containing N or O, where D is bonded to A via a direct bond from A to the drug portion (N or O).[4] R1teeth,And,L1is *-C(=O)(CH2)I understandO(CH2)I understand-**;*-C(=O)((CH2)I understandO)t(CH2)n-**;*-C(=O)(CH2)I understand-**;*-C(=O)NH((CH2)I understandO)t(CH2)n-**;*-C(=O)O(CH2)I understandSSC(R3)2(CH2)I understandC(=O)NR3(CH2)I understandNR3C(=O)(CH2)I understand-**;*-C(=O)O(CH2)I understandC(=O)NH(CH2)I understand-**;*-C(=O)(CH2)I understandNH(CH2)I understand-**;*-C(=O)(CH2)I understandNH(CH2)nC(=O)-**;*-C(=O)(CH2)I understandX1(CH2)I understand-**;*-C(=O)((CH2)I understandO)t(CH2)nX1(CH2)n-**;*-C(=O)(CH2)I understandNHC(=O)(CH2)n-**;*-C(=O)((CH2)I understandO)t(CH2)nNHC(=O)(CH2)n-**;*-C(=O)(CH2)I understandNHC(=O)(CH2)nX1(CH2)n-**;*-C(=O)((CH2)I understandO)t(CH2)nNHC(=O)(CH2)nX1(CH2)n-**;*-C(=O)((CH2)I understandO)t(CH2)nC(=O)NH(CH2)I understand-**;*-C(=O)(CH2)I understandC(R3)2-** or *-C (=O) (CH2)I understandC(=O)NH(CH2)I understand-** and here, L1The asterisk (*) indicates the binding point to Lp, and L1** is R1The connection points are shown,R2This includes polyethylene glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide, polysarcosine, or 1 to 3C substituted with a group2~C6The hydrophilic portion is selected from alkyl groups.Each R3H and C are independent of each other.1~C6Selected from alkyl groups,R4It is 2-pyridyl or 4-pyridyl,Each R5These are H and C, independently.1~C6Selected from alkyl, F, Cl and -OH,Each R6These are H and C, independently.1~C6Alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2-CN, -NO2Selected from and -OH,Each R7H and C are independent of each other.1~6Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH1-4C substituted with alkoxy and -C(=O)OH1-4Selected from alkyl groups,X1teeth,And,Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.Each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.Lp is a divalent peptide spacer containing 1 to 4 amino acid residues independently selected from glycine, valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.A is a bond, -OC (=O)-*,, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3) C (Ra)2C(Ra