Spliceostatin analogs and methods for their preparation

Patent metadata

Field	Value
Publication number	US-9504669-B2
Application number	US-201514818455-A
Country	US
Kind code	B2
Filing date	Aug 5, 2015
Priority date	Nov 5, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present invention is directed to novel cytotoxic spliceostatin analogs and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.

First claim

We claim:

1. A method for treating cancer comprising administering to a patient an amount of a compound of formula (I):

wherein:
a dashed line represents an optional bond;
each X 1 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X 2 is independently selected from the group consisting of: —O—, —S— and —NR—;
R 1 is selected from the group consisting of: —R, —OR, —OCOR 13 , —OCONR 14 R 15 , —OCON(R 14 )NR(R 15 ), ═O (double bond to oxygen) and —NR 14 R 15 ;
R 2 and R 3 are independently selected from the group consisting of: hydrogen and C 1-6 alkyl;
R 4 and R 5 are independently selected from the group consisting of: hydrogen, —OR, —NR 14 R 15 and oxo;
R 6 and R 7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen,
R 6 and R 7 , together with the carbon atom to which they are bound, form a C 2-5 alkylidene optionally substituted with 1-3 substituents independently selected from R,
R 6 and R 7 together are oxo, or
R 6 and R 7 , together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R;
R 8 is hydrogen, C 1-6 alkyl or —OR;
R 9 is independently selected from —(C(R) 2 ) m —C(O)OR, —(C(R) 2 ) m —C(O)NR 14 R 15 , —(C(R) 2 ) m —NR 14 R 15 , —(C(R) 2 ) m —N(R)COR 13 , —(C(R) 2 ) m —C(O)—SR, —(C(R) 2 ) m —C(O)NR 14 N(R)R 15 , —(C(R) 2 ) m —NR—C(O)—NR 14 R 15 and (C(R) 2 ) m —NR 14 N(R)R 15 ;
R 13 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, C 3-8 heterocyclyl, C 1-6 alkyl-C 6-14 aryl, C 1-6 alkyl-O 5-14 heteroaryl, wherein R 13 is optionally substituted with —NRR or —SO 2 NRR;
each R 14 and R 15 is independently selected from the group consisting of: hydrogen, hydroxyl, —NRR, —NRNR 2 , —C 3-10 carbocyclyl, —C 1-6 alkylene-C 3-10 carbocyclyl, —C 3-10 heterocyclyl, —C 1-6 alkylene-C 3-10 heterocyclyl, —(CH 2 CH 2 O) 1-6 CH 2 CH 2 C(O)OR, —(CH 2 CH 2 O) 1-6 CH 2 CH 2 NRR, —C 1-6 alkyl, C 6-14 aryl, —C 1-6 alkylene-C 6-14 aryl and —C 5-14 heteroaryl;
or R 14 and R 15 , together with the atom or atoms to which they are joined, form a C 3-10 heterocyclyl ring,
wherein R 14 , R 15 , or both, or a ring formed with R 14 and R 15 , are optionally substituted with —(C(R) 2 ) m —R 18 where each R 18 is independently selected from (i) —NRR, (ii) —C(NRR)(C(O)OR), (iii) —S—R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, —CF 3 , —(C(R) 2 ) m —NRR or —(C(R) 2 ) m —SO 2 NRR, (v) —SO 2 R, (vi) —S—S—C 1-6 alkyl-C(O)OR, (vii) —SO 2 NRR, (viii) —C(O)NRR, (ix) —C(O)OR, (x) —C 4-6 cycloalkyl optionally substituted with —NRR, —SO 2 NRR or —NR—C(O)(CH 2 ) 0-6 NRR, (xi) —R, (xii) —OR, (xiii) —N(R)NRR, (xiv) —C(O)N(R)NRR, —(C(R) 2 ) m —O—NRR and —S—S—C 1-6 alkyl-NRR;
each R is independently selected from the group consisting of: hydrogen and —C 1-6 alky; and
each m is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, said amount being effective to that cancer.

2. The method of claim 1 where said cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes, leukemias and lymphomas.

3. The method of claim 2 wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. A method for treating cancer comprising administering to a patient an amount of a compound having the formula III:
(AB)-(L-P) b   (III)

or a pharmaceutically acceptable salt thereof, wherein:
L is the linker moiety L 1 -L 2 -L 3 , where L 3 is bound to P;
P is a radical of formula (I):

wherein:
a dashed line represents an optional bond;
AB is an antibody;
each X 1 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X 2 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X′ is CR or N;
each X″ is CH—, CR—(C(R) 2 ) m —NR—, CR—(C(R) 2 ) m —O—; CR—(C(R) 2 ) m —C(O)NR—, CR—(C(R) 2 ) m —C(O)NR—NR—, CR—(C(R) 2 ) m —SO 2 NR—, CR—(C(R) 2 ) m —NR—NR—, CR—(C(R) 2 ) m —NR—C(O)— or N— if X″ binds to L 2 or an additional L 3 , or otherwise is O, S, CRR, CR—(C(R) 2 ) m —NRR or NRR;
each X′″ is —(C(R) 2 ) m —NR— or CR—(C(R) 2 ) m —O— if X′″ binds to L 2 , or otherwise is R;
Y is —C(R) 2 —, —O—, —NR— or —S—;
R 1 is selected from the group consisting of: —R, —OR, —OCOR 13 , —OCONR 14 R 15 , —OCON(R 14 )NR(R 15 ), ═O (double bond to oxygen) and —NR 14 R 15 ;
R 2 and R 3 are independently selected from the group consisting of: hydrogen and C 1-6 alkyl;
R 4 and R 5 are independently selected from the group consisting of: hydrogen, —OR, —NR 14 R 15 and oxo;
R 6 and R 7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen,
R 6 and R 7 , together with the carbon atom to which they are bound, form a C 2-5 alkylidene optionally substituted with 1-3 substituents independently selected from R,
R 6 and R 7 together are oxo, or
R 6 and R 7 , together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R;
R 8 is hydrogen, C 1-6 alkyl or —OR;
R 9 is —(C(R) 2 ) m —C(O)— or —(C(R) 2 ) m —;
L 1 is selected from: a bond to AB, —NR-(bond to AB) and

Assignees

• Pfizer

Inventors

• Subramanyam Chakrapani
• Koehn Frank Erich
• Dirico Kenneth John
• Eustaquio Alessandra S
• Green Michael Eric
• He Haiyin
• He Min
• O'Donnell Christopher John
• Puthenveetil Sujiet
• Ratnayake Anokha
• Teske Jesse Alexander
• Yang Hui Yu

Classifications

• A61K31/35

  having six-membered rings with one oxygen as the only ring hetero atom · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title