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CN-117024438-B - Esatitecan derivative and application thereof

CN117024438BCN 117024438 BCN117024438 BCN 117024438BCN-117024438-B

Abstract

The invention provides an isatecan derivative with a novel structure, pharmaceutically acceptable salt, stereoisomer or prodrug thereof and application thereof in the field of anti-tumor, wherein the isatecan derivative has a structure shown in a formula (I).

Inventors

  • HUANG YUNSHENG
  • JIN XUE
  • XU ZHENJIANG
  • LI YAOWU
  • WU KAI
  • ZHANG SHIYI
  • Fan Wange
  • LU YAO
  • LI DELIANG
  • WANG XIAOBEI
  • DAI QING

Assignees

  • 杭州爱科瑞思生物医药有限公司

Dates

Publication Date
20260505
Application Date
20230616
Priority Date
20220729

Claims (12)

  1. 1. A compound of formula (I): In the formula, R is selected from-Z-R 1 , wherein Z is a single bond or c=o; R 1 is selected from -NHNH 2 、-N(CH 3 )NH 2 、-N(CH 3 )NHCH 3 、-C(O)NHNH 2 、-C(O)N(CH 3 )NH 2 、-CH 2 NHOH、-CH 2 NHOCH 3 、-CH 2 ONHCH 3 、-CH 2 NCH 3 NH 2 、-CH 2 N(CH 3 )NHCH 3 、-CH 2 N(CH 3 )OH、-CH 2 NHOCH 2 CH 3 ; Provided that-Z-R 1 is not-NH 2 、-CH 2 OH、-CH 2 NH 2 or-CH 2 OCH 2 NH 2 .
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic) or (Id): In formula (Ia), R 1 is-NHNH 2 or-N (CH 3 )NH 2 ; in formula (Ib), R 2 is selected from -NHOH、-NHOCH 3 、-ONHCH 3 、-NCH 3 NH 2 、-N(CH 3 )NHCH 3 、-N(CH 3 )OH or-NHOCH 2 CH 3 ; In formula (Ic), R a 、R b is not simultaneously H; -NR a R b is selected from-NHNH 2 、-N(CH 3 )NH 2 or-N (CH 3 )NHCH 3 ).
  3. 3. The following compounds or pharmaceutically acceptable salts thereof:
  4. 4. A process for the preparation of a compound according to any one of claims 1 to 3, selected from the following schemes: scheme 1: Reacting irinotecan with N, N' -carbonyl diimidazole, and then reacting with hydrazine or substituted hydrazine to obtain the corresponding N-semicarbazide irinotecan derivative; Scheme 2: Reacting the substituted hydrazine with oxalyl chloride, and then reacting with the isartan to obtain a corresponding oxamide hydrazine isartan derivative; scheme 3: Reacting the irinotecan with bromoacetic acid to obtain bromoacetyl irinotecan, and condensing the bromoacetyl irinotecan with amine compounds to obtain corresponding amide irinotecan derivatives; Scheme 4: and (3) directly reacting the irinotecan with carboxylic acid compounds to obtain the corresponding amide irinotecan derivative.
  5. 5. A drug-linker compound represented by formula (II): Wherein R is as defined in formula (I) of claim 1; l is-L 1 -Q-L 2 , R is connected with L 1 part; Wherein L 1 is Wherein, the The positions shown represent the attachment to the R group, The indicated positions represent links to the Q group; l 2 is Q is selected from Val-Cit, gly-Gly-Phe-Gly, (CH 2 ) 2 O(CH 2 ) 2 , or (CH 2 ) 6 ).
  6. 6. A drug-antibody conjugate compound represented by formula (III): Wherein R is as defined for the compound of formula (I) in claim 1 and L is as defined for the compound of formula (II) in claim 5; Ab is tumor-associated antigen antibody, and n is an integer selected from 1-8.
  7. 7. The drug-antibody conjugate compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein the tumor associated antigen is selected from Her2, trop2, 5T4, ROR1, or B7-H3.
  8. 8. A drug-antibody conjugate compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  9. 9. the drug-antibody conjugate compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, a drug-linker compound according to claim 5 or a pharmaceutically acceptable salt thereof, or an antibody drug conjugate according to claims 6 to 9, and a pharmaceutically acceptable adjuvant.
  11. 11. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, a drug-linker compound according to claim 5 or a pharmaceutically acceptable salt thereof, an antibody drug conjugate according to claims 6 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of cancer.
  12. 12. The use of claim 11, wherein the cancer comprises gastric cancer, esophageal cancer, breast cancer, and lung adenocarcinoma.

Description

Esatitecan derivative and application thereof Technical Field The invention relates to the field of biological medicine, in particular to an isatecan derivative and application thereof. Background Irinotecan (Exatecan) is a fully synthesized natural product camptothecine derivative, has extremely strong inhibition activity on topoisomerase Top1, can promote tumor cell apoptosis, and has broad-spectrum anti-tumor activity. The application of the isatecan in the field of anti-tumor medicaments is greatly limited due to the toxic and side effects of the isatecan, and an antibody coupling medicament DS-8201a (anti-body-drugconjugate, ADC) formed by taking a hydroxyacetamide derivative (Dxd) of the isatecan as toxin and trastuzumab (Herceptin) has a very good therapeutic effect on Her 2-expressed tumors. DS-8201a is an ADC anti-tumor drug with excellent performance. In addition to Herceptin, ADC drugs against other antigens such as B7-H3, trop2, etc. are also being widely studied. The invention carries out the derivatization of hydroxylamine and hydrazine on the irinotecan on the basis of maintaining the pharmacodynamic skeleton of the irinotecan to form a series of irinotecan derivatives with coupling sites, and the compounds have the characteristics of high anti-tumor activity, low toxic and side effects and easy water dissolution, and have potential application value as anti-tumor single drugs or antibody coupling drugs. Disclosure of Invention The invention provides an isatecan derivative with a novel structure, pharmaceutically acceptable salt, stereoisomer or prodrug thereof, and application thereof in the field of anti-tumor. In one aspect of the invention, there is provided a compound of formula (I): In the formula, R is selected from-Z-R 1, wherein Z is a single bond or c=o; R 1 is selected from -(CH2)nNRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb or-R 3, n is selected from 0, 1, 2 or 3; R a、Rb is each independently selected from hydrogen, hydroxy, amino, C 1-C6 alkyl, C 1-C6 alkylamino, aminoC 1-C6 alkyl or C 1-C6 alkoxy; r 3 is selected from 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl containing N, O, or S heteroatom, R 3 is optionally further substituted with R c; r c is selected from hydrogen, hydroxy, amino, C 1-C6 alkyl, C 1-C6 alkylamino or C 1-C6 alkoxy; Provided that-Z-R 1 is not-NH 2、-CH2OH、-CH2NH2 or-CH 2OCH2NH2. In one embodiment, R 1 is not-CH 2ONH2 or hydroxy oxetanyl. In one embodiment, R 1 is selected from -NRaRb、-CH2NRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb or-R 3. Preferably, R 1 is selected from -NRaRb、-C(O)NRaRb、-CH2NRaRb、-CH2ONRaRb or-R 3. In one embodiment, each R a、Rb is independently selected from hydrogen, hydroxy, amino, C 1-C6 alkyl, C 1-C6 alkylamino, or C 1-C6 alkoxy. Preferably, each R a、Rb is independently selected from hydrogen, hydroxy, amino, methyl, methylamino or methoxy. In one embodiment, R 3 is selected from 3 to 6 membered heterocycloalkyl containing N, O, or S heteroatoms, R 3 is optionally further substituted with R c, said R c is selected from hydrogen, hydroxy, amino, C 1-C6 alkyl, C 1-C6 alkylamino, or C 1-C6 alkoxy. In one embodiment, R 1 is selected from -NHNH2、-N(CH3)NH2、-N(CH3)NHCH3、-C(O)NHNH2、-C(O)N(CH3)NH2、-CH2NHOH、-CH2NHOCH3、-CH2ONH2、-CH2ONHCH3、-CH2NCH3NH2、-CH2N(CH3)NHCH3、-CH2N(CH3)OH、-CH2NHOCH2CH3、 hydroxy oxetanylAmino oxetanyl group In one embodiment, R 1 is selected from -NHNH2、-N(CH3)NH2、-N(CH3)NHCH3、-C(O)NHNH2、-C(O)N(CH3)NH2、-CH2NHOH、-CH2NHOCH3、-CH2ONHCH3、-CH2NCH3NH2、-CH2N(CH3)NHCH3、-CH2N(CH3)OH、-CH2NHOCH2CH3、 aminooxetanyl In one embodiment, the compound of formula (I) is a compound of formula (Ia): wherein R 1 is as defined for the compound of formula (I). Preferably, R 1 is-NHNH 2 or-N (CH 3)NH2). In one embodiment, the compound of formula (I) is a compound of formula (Ib): In the formula, R 2 is selected from the group consisting of-NHOH, -ONH 2、-NHO(C1-C3 alkyl, -ONH (C 1-C3 alkyl), -N (C 1-C3 alkylamino), -N-N (C 1-C3 alkyl) NH (C 1-C3 alkyl), -N (C 1-C3 alkyl) OH or-NHO (C 1-C3 alkyl). Preferably, R 2 is selected from -NHOH、-NHOCH3、ONH2、-ONHCH3、-NCH3NH2、-N(CH3)NHCH3、-N(CH3)OH or-NHOCH 2CH3. In one embodiment, R 2 is selected from the group consisting of-NHOH, -NHO (C 1-C3 alkyl), -ONH (C 1-C3 alkyl), -N (C 1-C3 alkylamino), -N-N (C 1-C3 alkyl) NH (C 1-C3 alkyl), -N (C 1-C3 alkyl) OH or-NHO (C 1-C3 alkyl). Preferably, R 2 is selected from -NHOH、-NHOCH3、-ONHCH3、-NCH3NH2、-N(CH3)NHCH3、-N(CH3)OH or-NHOCH 2CH3. In one embodiment, the compound of formula (I) is a compound of formula (Ic): Wherein R a、Rb is as defined for the compound of formula (I), provided that R a、Rb is not simultaneously H. Preferably, each R a、Rb is independently selected from hydrogen, amino, C 1-C3 alkyl, C 1-C3 alkylamino. Preferably, -NR aRb is selected from-NHNH 2、-N(CH3)NH2 or-N (CH 3)NHCH3). In one embodiment, the compound of formula (I) is a compound of formula (Id): wherein X is CH 2, NH, O or S. Preferably, X is CH 2 or O, more preferably X is O. In one embodiment,