Functionalized thieno-indole derivatives for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9561290-B2
Application number	US-201314390216-A
Country	US
Kind code	B2
Filing date	Mar 28, 2013
Priority date	Apr 5, 2012
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R 1 and R 2 taken together form a group (D) or (G): wherein R 5 is hydrogen or C 1 -C 4 alkyl; R 3 and R 4 are independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl; n is 0, 1 or 2; each of X is independently —O—, —S— or —NR 4 —; each of Y is independently —CH═ or —N═; R 7 and R 8 are independently hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, cyano, —NHCOOR 3 , —C(NH)NH 2 or —NR 3 R 4 ; A is —O—, —NH— or —CO—; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R 6 is a leaving group; A 1 is null or A; L 1 is hydrogen or L.

First claim

The invention claimed is:

1. A compound of formula (II)

wherein
R 1 and R 2 taken together form a group (D) or (G):

wherein R 5 is hydrogen or linear or branched C 1 -C 4 alkyl;
R 3 and R 4 are, each independently, hydrogen, linear or branched C 1 -C 4 alkyl or linear or branched C 1 -C 4 hydroxyalkyl;
n is 0, 1 or 2;
each of X is independently —O—, —S— or —NR 4 —, wherein R 4 is as defined above;
each of Y is independently —CH═ or —N═;
R 7 and R 8 are independently hydrogen, halogen, hydroxy, linear or branched C 1 -C 4 alkoxy, cyano, —NHCOOR 3 , —C(NH)NH 2 or —NR 3 R 4 , wherein R 3 and R 4 are as defined above;
L is null or a group selected from:
—NHCOR 9 (IIIa); —NHCONHR 9 (IIIb); —NHCOOR 9 (IIIc); —NHR 9 (IIId);

wherein:
R 9 and R 10 are, each independently, a point of attachment, 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 sulthydrylalkyl and linear or branched C 1 -C 4 aminoalkyl;
n 1 is an integer from 0 to 4 and n is as defined above;
W is null or one or groups independently selected from

wherein
one of R 9 and R 10 is null and the other is as defined above;
R 11 and R 12 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 2 is —CH 2 , —CH 2 NR 12 or —NR 12 — wherein R 12 is as defined above;
Z is null or a linker (Z 1 ), a linker (Z 2 ) or a linker (Z 3 ), wherein
Z 1 is a single amino acid, a dipeptide, a tripeptide, a tetrapeptide, or an oligopeptide moiety wherein the amino acids are selected from natural L-amino acids, unnatural D-amino acids, synthetic amino acids, or any combination thereof;
Z 2 is a group selected from:

wherein one of R 9 and R 10 is a point of attachment and the other is as defined above; and p is an integer from 1 to 20; and
Z 3 has the general formula Z 1 -Z 2 or Z 2 -Z 1 where Z 1 and Z 2 are as defined above;
RM is null or a group selected from

wherein R 13 is a C 1 -C 3 alkyl or an electron withdrawing group selected from —NO 2 and —CN groups;
r is an integer from 0 to 7; and R 11 and R 12 are as defined above;
R 6 is a leaving group;
A 1 is null or —O—, —NH— or —CO;
L 1 is hydrogen or L, wherein L is as defined above;
or the pharmaceutically acceptable salts thereof,
provided that
1) when L 1 is hydrogen, then A 1 is —O—, —NH— or —CO—;
2) when A 1 is null, then RM is not null.

2. A compound of formula (II) according to claim 1 wherein:

R 1 and R 2 taken together are (D)

R 5 is methyl,
R6 is chlorine,
R 3 , R 4 , R 7 , R 8 and L 1 are hydrogen,
n is 0 or 1,
X is —NH—,
Y is —CH═,
A 1 is A and A is —O— or —NH—;
L is null or

W is null or

Z is null or

RM is null or

3. A Compound of formula (II) according to claim 1 wherein

R 1 and R 2 taken together are (D)

R 5 is methyl,
R 6 is chlorine,
R 3 , R 4 , R 7 , and R 8 are hydrogen,
n is 0 or 1,
X is —NH—,
Y is —CH═,
A 1 is A, and A is —O— or —NH;
L is null or

L 1 is L, wherein L is as defined in claim 1 ;
W is null or

Z is null or

RM is null or

4. A compound, or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
(8S)-8-(chloromethyl)-6-[(5-{[(5-{[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-1 H-indol-2-yl)carbonyl]amino}-1H-indol-2-yl)carbonyl]-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl 4-methylpiperazine-1-carboxylate,
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-5-carbamoyl-N-(4-{[({2-[(2-{[(8S)-8-(chloromethyl)-1-methyl-4-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)carbamoyl]1H-indol-5-yl}carbamoyl)oxy]methyl}phenyl)-L-ornithinamide,
(8S)-8-(chloromethyl)-6-({5-[(1H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methyl 7,8-dihydro-6H-thieno[3,2-e]indol-4-yl 4-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]piperazine-1-carboxylate,
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-5-carbamoyl-N-{4-[({[4-({[(8S)-8-(chloromethyl)-6-({5-[(1H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-L-ornithinamide,
(8R)-8-(chloromethyl)-6-[(5-{[(5-{[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-1 H-indol-2-yl)carbonyl]amino}-1H-indol-2-yl)carbonyl]-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl 4-methylpiperazine-1-carboxylate,
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-5-carbamoyl-N-(4-{[({2-[(2-{[(8R)-8-(chloromethyl)-1-methyl-4-{[(4-methylpiperazin-1-yl)carbonyl]oxy}-7,8-dihydro-6H-thieno[3,2-e]indol-6-yl]carbonyl}-1H-indol-5-yl)carbamoyl]-1H-indol-5-yl}carbamoyl)oxy]methyl}phenyl)-L-ornithinamide,
(8R)-8-(chloromethyl)-6-({5-[(1H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl 4-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]piperazine-1-carboxylate,
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-5-carbamoyl-N-{4-[({[4-({[(8R)-8-(chloromethyl)-6-({5-[(H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-yl]oxy}carbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-L-ornithinamide,
N-[6-(2,5-dioxo-2,5-dihydro-1

Assignees

• Nerviano Medical Sciences Srl

Inventors

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

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K45/06 Primary

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

• C07K5/0812

  and aromatic or cycloaliphatic · CPC title