Thieno-indole moieties and methods of treating using the same

Patent metadata

Field	Value
Publication number	US-9527863-B2
Application number	US-201314390644-A
Country	US
Kind code	B2
Filing date	Mar 28, 2013
Priority date	Apr 5, 2012
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The present invention relates to a novel class of alkylating agents comprising a thieno-indole moiety linked to a DNA-binding moiety, which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical composition containing them. The invention also relates to the use of this novel class of alkylating agents in the preparation of conjugates.

First claim

The invention claimed is:

1. A compound of formula (II)

wherein R1 and R2 taken together form a group (D) or (G):

wherein R5 is hydrogen, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 hydroxyalkyl or linear or branched C 1 -C 4 aminoalkyl;
R3 and R4 are, each independently, hydrogen or a group selected from an optionally substituted linear or branched C 1 -C 4 alkyl and linear or branched C 1 -C 4 hydroxyalkyl;
R6 is a leaving group;
T is null or N;
BM of formula (V):

wherein:
X is null, linear or branched C 1 -C 4 alkyl, linear or branched C 2 -C 4 alkenyl or linear or branched C 2 -C 4 alkynyl;
Y is an optionally substituted aryl or heteroaryl selected from the group consisting of

Y′ is an optionally substituted aryl or heteroaryl selected from

wherein R15, R16 and R20 are independently hydrogen, halogen, hydroxy, NO 2 , an optionally substituted linear or branched C 1 -C 6 alkyl or C 1 -C 6 alkoxy, cyano, —COOH, —CONH—R3, —N—C(O)O—R3, —C(NH)—NH 2 or —NR3R4, and R3 and R4 are as defined above;
U is a moiety of formula (VI) or (VII):

wherein R3 is as defined above;
q is an integer from 0 to 4;
L1 is hydrogen or L, wherein L is null or a moiety selected from NHCO—R9 (Xa); —NHCONH—R9 (Xb); —NHCOO—R9 (Xc); —NH—R9 (Xd);

wherein
R9 and R10 are, each independently, hydrogen, hydroxy or an optionally substituted group selected from linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 hydroxyalkyl, linear or branched C 1 -C 4 sulfhydrylalkyl and linear or branched C 1 -C 4 aminoalkyl, when W1 and Z1 are null, or
R9 and R10 are null when at least one of W1 and Z1 is not null,
n is an integer from 0 to 2 and
n1 is an integer from 0 to 4;
W1 is null or a system comprising one or more groups independently selected from

wherein
one of R9 and R10 is null and the other is as defined above,
R11 and R12 are, each independently, hydrogen, halogen, methyl, ethyl or linear or branched C 1 -C 4 hydroxymethyl,
m is an integer from 0 to 3, and
A 1 is CH 2 , CH 2 N—R12 or N—R12, wherein R12 is as defined above;
Z1 is null or a peptidic linker (Z a ), a non peptidic linker (Z b ) or hybrid linker(Z c ), wherein
Z a is selected from a single amino acid, a dipeptide, a tripeptide, a tetrapeptide and an oligopeptide moiety comprising natural L-amino acids, unnatural D-amino acids, synthetic amino acids or any combination thereof;
Z b is selected from

wherein
one of R9 and R10 is null and the other is as defined above and p is an integer from 1 to 20; and
Z c is a group of formula
Z a —Z b or Z b —Z a

wherein Z a and Z b are as defined above;
provided that a compound of formula (II) wherein L1 is hydrogen is excluded when
1) both T and X are null, q is 0 and
Y′ is an heterocyclyl moiety of formula (VIII), (VIII)′ or (VIII)″:

or
2) both T and X are null, q is 1, U is a group of formula (VII),
Y is an heterocyclyl moiety of formula (IX)

and
Y′ is an heterocyclyl moiety of formula (VIII)′″

wherein Q is —NH— or O, and R21 is hydrogen or a group selected from —N(C 2 H 5 ) 2 and —C(NH)NH 2 ;
with the proviso that in a compound of formula (II) when L1 is L, at least one among L, W1 and Z1 is not null;
or
the pharmaceutically acceptable salts thereof.

2. The compound of formula (II) according to claim 1 , wherein R1 and R2 taken together form a group (D)

wherein R5 is linear or branched C 1 -C 4 alkyl.

3. The compound of formula (II) according to claim 2 , wherein
R6 is halogen,
W1 and Z1 are null, and
L1 is hydrogen or a moiety of formula (Xj)

wherein R9 is hydrogen, hydroxy or an optionally substituted group selected from linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 hydroxyalkyl, linear or branched C 1 -C 4 sulfhydrylalkyl and linear or branched C 1 -C 4 aminoalkyl.

4. A compound of formula (III) or (IV)

wherein R1 and R2 taken together form a group (D) or (G):

wherein R5 is hydrogen, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 hydroxyalkyl or linear or branched C 1 -C 4 aminoalkyl;
R3 and R4 are, each independently, hydrogen or a group selected from an optionally substituted linear or branched C 1 -C 4 alkyl and linear or branched C 1 -C 4 hydroxyalkyl;
R6 is a leaving group;
T is null or N;
BM is of formula (V)′:

wherein:
X is null, linear or branched C 1 -C 4 alkyl, linear or branched C 2 -C 4 alkenyl or linear or branched C 2 -C 4 alkynyl,
Y is an optionally substituted aryl or heteroaryl selected from the group consisting of

Y′ is an optionally substituted aryl or heteroaryl selected from

wherein R15, R16 and R20 are independently hydrogen, halogen, hydroxy, NO 2 , an optionally substituted linear or branched C 1 -C 6 alkyl or C 1 -C 6 alkoxy, cyano, —COOH, —CONH—R3, —N—C(O)O—R3, —C(NH)—NH 2 or —NR3R4, and R3 and R4 are as defined above,
U is a moiety of formu

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Beria Italo
• Caruso Michele
• Lupi Vittoria
• Orsini Paolo
• Salsa Matteo
• Panzeri Achille

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K45/06

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