Claims for Patent: 10,449,258

Summary for Patent: 10,449,258

Title:	Antibody drug conjugate, intermediate, preparation method, pharmaceutical composition and uses thereof
Abstract:	Disclosed are an antibody drug conjugate IB, which uses ether linkages for connection, and improves the water solubility, stability and cytotoxicity in vivo and in intro, and an intermediate, a pharmaceutical composition, and uses of the antibody drug conjugate. The antibody drug conjugate has simple synthetic steps and a high yield. ##STR00001##
Inventor(s):	Xiang; Jason Shaoyun (Shanghai, CN), Liu; Shifeng (Shanghai, CN), Yang; Hongyu (Shanghai, CN), Ma; Xingquan (Shanghai, CN)
Assignee:	XDCEXPLORER (SHANGHAI) CO., LTD. (Shanghai, CN)
Application Number:	15/580,895
Patent Claims:	1. An antibody drug conjugate, wherein (a) the antibody drug conjugate is represented by formula IB, ##STR00371## wherein, Z is a nitrogen atom, ##STR00372## or an oxygen atom, when Z is an oxygen atom, R.sup.1 is absence; when Z is ##STR00373## or a nitrogen atom, R.sup.1 is a hydrogen or a C.sub.1-C.sub.4 alkyl; R.sup.2 is a hydrogen or a halogenated C.sub.1-C.sub.4 alkyl; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Y.sub.1 is an oxygen atom, a chemical bond or ##STR00374## wherein x2 is an integer among 1-24; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.3 and R.sup.4 are independently a hydrogen, a cyano, or a substituted or unsubstituted C.sub.1-C.sub.4 alkyl; in R.sup.3 or R.sup.4, the substituent contained in the substituted C.sub.1-C.sub.4 alkyl refers to a C.sub.1-C.sub.4 alkoxy; x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Q1 is ##STR00375## wherein, R.sup.8 is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl, ##STR00376## y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y1 is 0 or 1; in R.sup.8, the substituent contained in the substituted C.sub.1-C.sub.4 alkyl refers to ##STR00377## t is 1 or 2; t1 is 0, 1, 2, 3, 4, 5 or 6; R.sup.6 is a hydrogen or an unsubstituted C.sub.1-C.sub.12 alkyl or ##STR00378## r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R.sup.7 is a hydrogen or an unsubstituted C.sub.1-C.sub.12 alkyl, an substituted C.sub.1-C.sub.12 alkoxy or ##STR00379## mAb represents a monoclonal antibody; k is a figure among 1-8; when Z is nitrogen atom, and both of R.sup.3 and R.sup.4 are the substituted or unsubstituted C.sub.1-C.sub.4 alkyl, at least one of R.sup.3 and R.sup.4 is a C.sub.1-C.sub.4 alkyl substituted by a C.sub.1-C.sub.4 alkyloxy; when Z is nitrogen atom, and one of R.sup.3 and R.sup.4 is hydrogen, the other one is the unsubstituted C.sub.1-C.sub.4 alkyl, the unsubstituted C.sub.1-C.sub.4 alkyl is n-propyl, iso-propyl, n-butyl, tert-butyl or iso-butyl; when Z is a nitrogen atom, and both of R.sup.3 and R.sup.4 are hydrogen, m is 0; when Z is ##STR00380## Y.sub.1 is an oxygen atom or ##STR00381## when Z is a nitrogen atom, p is 0, m is 1, and Q1 is ##STR00382## R.sup.8 is not ##STR00383## or, (b) the antibody drug conjugate is ##STR00384## 2. The antibody drug conjugate represented by formula TB according to claim 1, wherein, R.sup.1 is methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl or tert-butyl; R.sup.2 is a halogenated C.sub.1-C.sub.4 alkyl, the halogen contained in the halogenated C.sub.1-C.sub.4 alkyl is fluorine, chlorine, or bromine; the halogenated C.sub.1-C.sub.4 alkyl; is halogenated methyl, a halogenated ethyl, a halogenated propyl, a halogenated iso-propyl, a halogenated butyl, a halogenated iso-butyl or a halogenated tert-butyl; p is 0, 1 or 2; n is 0, 1 or 2; q is 0, 1 or 2; when Y1 is a chemical bond, the chemical bond is a single bond, or, when Y1 is ##STR00385## R.sup.3 and R.sup.4 are independently methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, tert-butyl, a substituted methyl, a substituted ethyl, a substituted propyl, a substituted butyl, a substituted iso-propyl, a substituted iso-butyl or a substituted tert-butyl; in R.sup.3 or R.sup.4, the substituent contained in the substituted or unsubstituted C.sub.1-C.sub.4 alkyl refers to methoxy, ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy, tert-butoxy; x is 0, 1 or 2; when Q1 is ##STR00386## R.sup.8 is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl, the substituted or unsubstituted C.sub.1-C.sub.4 alkyl is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted propyl, a substituted or unsubstituted iso-propyl, a substituted or unsubstituted butyl, a substituted or unsubstituted iso-butyl or a substituted or unsubstituted tert-butyl; R.sup.6 is an unsubstituted C.sub.1-C.sub.4 alkyl; R.sup.7 is an unsubstituted C.sub.1-C.sub.4 alkyl or an unsubstituted C.sub.1-C.sub.4 alkoxy; mAb represents a monoclonal antibody, or Herceptin. 3. The antibody drug conjugate represented by formula TB according to claim 2, wherein, when R.sup.2 is a halogenated methyl, the halogenated methyl is ##STR00387## when R.sup.3 and R.sup.4 are independently a substituted methyl, the substituted methyl is ##STR00388## when Q1 is ##STR00389## and R8 is a substituted propyl, the substituted propyl is ##STR00390## R.sup.6 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl; R.sup.7 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy or tert-butoxy. 4. The antibody drug conjugate represented by formula IB according to claim 1, having a structure of formula Ib or Ib1, ##STR00391## in the antibody drug conjugate represented by formula Ib or Ib1, each letters and groups is defined as that defined in claim 1; Y is an oxygen atom or a chemical bond; Y.sub.2 is ##STR00392## wherein x2 is an integer among 1-24; Q2 is ##STR00393## t1 is 0, 1, 2, 3, 4, 5 or 6. 5. The antibody drug conjugate according to claim 1 which is selected from the group consisting of ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## 6. An intermediate, wherein (a) the intermediate is represented by formula IA: ##STR00401## Z is a nitrogen atom, ##STR00402## or an oxygen atom, when Z is an oxygen atom, R.sup.1 is absence; when Z is ##STR00403## or a nitrogen atom, R.sup.1 is a hydrogen or a C.sub.1-C.sub.4 alkyl: R.sup.2 is a hydrogen or a halogenated C.sub.1-C.sub.4 alkyl; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Y.sub.1 is an oxygen atom, a chemical bond or ##STR00404## wherein x2 is an integer among 1-24; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.3 and R.sup.4 are independently a hydrogen, a cyano, or a substituted or unsubstituted C.sub.1-C.sub.4 alkyl; in R.sup.3 or R.sup.4, the substituent contained in the substituted C.sub.1-C.sub.4 alkyl refers to a C.sub.1-C.sub.4 alkoxy; x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.6 is a hydrogen or an unsubstituted C.sub.1-C.sub.12 alkyl or ##STR00405## r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12: R.sup.7 is a hydrogen or an unsubstituted C.sub.1-C.sub.12 alkyl, an unsubstituted C.sub.1-C.sub.12 alkoxy or ##STR00406## when Z is nitrogen atom, and both of R.sup.3 and R.sup.4 are the substituted or unsubstituted C.sub.1-C.sub.4 alkyl, at least one of R.sup.3 and R.sup.4 is a C.sub.1-C.sub.4 alkyl substituted by a C.sub.1-C.sub.4 alkyloxy; when Z is nitrogen atom, and one of R.sup.3 and R.sup.4 is hydrogen, the other one is the unsubstituted C.sub.1-C.sub.4 alkyl, the unsubstituted C.sub.1-C.sub.4 alkyl is n-propyl, iso-propyl, n-butyl, tert-butyl or iso-butyl; when Z is a nitrogen atom, and both of R.sup.3 and R.sup.4 are hydrogen, m is 0: when Z is ##STR00407## Y.sub.1 is an oxygen atom or ##STR00408## Q is ##STR00409## t is 1 or 2; t1 is 0, 1, 2, 3, 4, 5 or 6; R.sup.51 is H, a C.sub.1-C.sub.4 alkyl, ##STR00410## or a halogen; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.9 is H or a C.sub.1-C.sub.4 alkyl; when Z is a nitrogen atom, p is 0, m is 1, both of R.sup.3 and R.sup.4 are hydrogen or both of R.sup.3 and R.sup.4 are unsubstituted C.sub.1-C.sub.4 alkyl, and Q.sub.3 is ##STR00411## R.sup.51 is ##STR00412## or a halogen; y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.9 is H or a C.sub.1-C.sub.4 alkyl; or, (b) the intermediate is: ##STR00413## ##STR00414## 7. The intermediate represented by formula IA according to claim 6, wherein, R.sup.51 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, F, Cl, Br or I; R.sup.9 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl. 8. The intermediate represented by formula IA according to claim 6, having a structure of formula Ia or Ia1: ##STR00415## wherein in the intermediate represented by formula Ia or Ia1, each letters and groups is defined as that in claim 6; in the intermediate represented by formula Ia, R.sup.5 is a hydrogen or a C.sub.1-C.sub.4 alkyl; or the C.sub.1-C.sub.4 alkyl-in R.sup.5 is methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl or tert-butyl, ##STR00416## y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; y1 is 0 or 1; R.sup.9 is a hydrogen or a C.sub.1-C.sub.4 alkyl, or, the C.sub.1-C.sub.4 alkyl in R.sup.9 is methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl or tert-butyl; in the intermediate represented by formula Ia1, R.sup.52 is a hydrogen or a halogen, or, the halogen in R.sup.52 is F, Cl, Br, or I. 9. The intermediate according to claim 6 is selected from the group consisting of ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## 10. A process for preparing the antibody drug conjugate represented by formula IB according to claim 1, comprising in an organic solvent, under the condition of pH 6-8, conjugating the intermediate IA with a monoclonal antibody to deliver the antibody drug conjugate represented by formula IB; ##STR00432## in the compound represented by formula IA or IB, each letters and groups is defined as that in claim 1. 11. A method for treating breast cancer in a subject in need thereof, comprising: administering an effective amount of the antibody drug conjugate according to claim 1 to the subject. 12. A pharmaceutical composition, comprising the antibody drug conjugate according to claim 1, as well as one or more than one pharmaceutically acceptable excipients. 13. The antibody drug conjugate represented by formula TB according to claim 4, wherein, in the antibody drug conjugate represented by formula Ib or Ib1, R.sup.1 is methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl or tert-butyl; R.sup.2 is a halogenated C.sub.1-C.sub.4 alkyl, the halogen contained in the halogenated C.sub.1-C.sub.4 alkyl is fluorine, chlorine, or bromine; the halogenated C.sub.1-C.sub.4 alkyl is a halogenated methyl, a halogenated ethyl, a halogenated propyl, a halogenated iso-propyl, a halogenated butyl, a halogenated iso-butyl or a halogenated tert-butyl; p is 0, 1 or 2; n is 0, 1 or 2; q is 0, 1 or 2; when Y is a chemical bond, the chemical bond is a single bond, when Y2 is ##STR00433## x2 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.3 and R.sup.4 are independently methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, tert-butyl, a substituted methyl, a substituted ethyl, a substituted propyl, a substituted butyl, a substituted iso-propyl, a substituted iso-butyl or a substituted tert-butyl; in R.sup.3 or R.sup.4, the substituent contained in the substituted or unsubstituted C.sub.1-C.sub.4 alkyl refers to methoxy, ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy, tert-butoxy; x is 0, 1 or 2; when R.sup.8 is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl, the substituted or unsubstituted C.sub.1-C.sub.4 alkyl is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted so-propyl, a substituted or unsubstituted iso-propyl, a substituted or unsubstituent contained butyl, a substituted or unsubstituted iso-butyl or a substituted or unsubstituted tert-butyl; R.sup.6 is an unsubstituted C.sub.1-C.sub.4 alkyl; R.sup.7 is an unsubstituted C.sub.1-C.sub.4 alkyl or an unsubstituted C.sub.1-C.sub.4 alkoxy; mAb represents a monoclonal antibody, or Herceptin. 14. The antibody drug conjugate represented by formula IB according to claim 13, wherein, in the antibody drug conjugate represented by formula Ib or Ib1, when R.sup.2 is a halogenated methyl, the halogenated methyl is ##STR00434## when R.sup.3 and R.sup.4 are independently a substituted methyl, the substituted methyl is ##STR00435## when R.sup.8 is a substituted propyl, the substituted propyl is ##STR00436## R.sup.6 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl; R.sup.7 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy or tert-butoxy. 15. An intermediate represented by formula IA according to claim 6, wherein, in formula IA, R.sup.1 is methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl or tert-butyl; R.sup.2 is a halogenated C.sub.1-C.sub.4 alkyl, the halogen contained in the halogenated C.sub.1-C.sub.4 alkyl is fluorine, chlorine, or bromine; the halogenated C.sub.1-C.sub.4 alkyl is a halogenated methyl, a halogenated ethyl, a halogenated propyl, a halogenated iso-propyl, a halogenated butyl, a halogenated iso-butyl or a halogenated tert-butyl; p is 0, 1 or 2; n is 0, 1 or 2; q is 0, 1 or 2; when Y1 is a chemical bond, the chemical bond is a single bond, when Y1 is ##STR00437## x2, is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R.sup.3 and R.sup.4 are independently methyl, ethyl, propyl, butyl iso-propyl, iso-butyl, tert-butyl, a substituted methyl, a substituted ethyl, a substituted propyl, a substituted butyl, a substituted iso-propyl, a substituted iso-butyl or a substituted tert-butyl; in R.sup.3 or R.sup.4, the substituent contained in the substituted or unsubstituted C.sub.1-C.sub.4 alkyl refers to methoxy, ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy, tert-butoxy; x is 0, 1 or 2; R.sup.6 is an unsubstituted C.sub.1-C.sub.4 alkyl; R.sup.7 is an unsubstituted C.sub.1-C.sub.4 alkyl or an unsubstituted C.sub.1-C.sub.4 alkoxy. 16. An intermediate represented by formula IA according to claim 15, wherein, in formula IA, when R.sup.2 is a halogenated methyl, the halogenated methyl is ##STR00438## when R.sup.3 and R.sup.4 are independently a substituted methyl, the substituted methyl is ##STR00439## R.sup.6 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert-butyl; R.sup.7 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy or tert-butoxy. 17. A method for treating breast cancer in a subject in need thereof, comprising: administering an effective amount of the intermediate according to claim 6 to the subject. 18. A pharmaceutical composition, comprising the intermediate according to claim 6, as well as one or more than one pharmaceutically acceptable excipients.

Details for Patent 10,449,258

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-06-09
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-06-09