Functionalized 9-bromo-camptothecin derivatives

Patent metadata

Field	Value
Publication number	US-9556192-B2
Application number	US-201314439020-A
Country	US
Kind code	B2
Filing date	Oct 29, 2013
Priority date	Oct 30, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present disclosure is directed to a compound of formula (I)

wherein L is null or a conditionally-cleavable moiety; W is null or a self-immolative system, 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 that can be attached to one or more of L, W or Z groups, or RM is attached to oxygen when L, W and Z are all null; provided that at least one of L, W, Z and RM is not null; or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
L is null or a group selected from:

wherein:
R1, R2 and R3 are, each independently, null, 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, linear or branched C 1 -C 4 aminoalkyl, linear or branched C 1 -C 4 alkylcarbonyl and linear or branched C 1 -C 4 alkoxycarbonyl;
each of n is independently an integer from 0 to 2; and
n1 is an integer from 0 to 5;

W is null or a group selected from:

wherein:
one of R1 and R2 is null and the other is as defined above;
R3 is as defined above;
R4 and R5 are, each independently, halogen, methyl, ethyl or linear or branched C 1 -C 4 hydroxyalkyl;
m is an integer from 0 to 3;
A is C 1 -C 3 alkyl, CH 2 NH, NH or N—R4, wherein R4 is as defined above; and
R12 and R13 are, each independently, hydrogen, halogen, methyl, ethyl, linear or branched C 1 -C 4 hydroxyalkyl, linear or branched C 1 -C 4 haloalkyl, or R12 and R13, taken together, form a 3- to 6-membered carbocycle;

Z is independently null or
Z1, wherein Z1 is a dipeptide or a tripeptide, linked via its C-terminus to W, or to L when W is null, or to oxygen when W and L are both null, wherein the C-terminal aminoacid residue of the dipeptide or of the tripeptide is selected from glycine, leucine, alanine, arginine and citrulline; and the N-terminal aminoacid residue is selected from any natural or unnatural aminoacid; and, in the case of the tripeptide, the middle aminoacid residue is selected from alanine, valine, leucine, isoleucine, methionine, phenylalanine and proline;
Z2, wherein Z2 is a group selected from:

wherein
one of R1 and R2 is null and the other is as defined above, and
p is an integer from 1 to 20;
Z1-Z2, wherein Z1 and Z2 are as defined above;

RM is a group selected from:

wherein R4 and R5 are as defined above;
R6 is C 1 -C 3 alkyl or an electron-withdrawing group, comprising NO 2 and CN group;
r is an integer from 0 to 7;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein Z is a group selected from:

wherein
one of R1 and R2 is null and the other is as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2 -b]quinolin-4-yl N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-phenylalanyl-L -leucylglycinate;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[({[4-({[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}carbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-N 5 -carbamoyl-L-omithinamide;
(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-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-[4-({[{2-[({[(4S)-10-bromo -4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}carbonyl) (methyl)amino]ethyl} (methyl)carbamoyl] oxy}methyl)phenyl]-N 5 -carbamoyl -L-omithinamide;
N-[6-(2,5-dioxopyrrolidin-1-yl)hexanoyl]-L-valyl-N-[4-({[(5-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl] oxy}-2,2-difluoro-5-oxopentyl)carbamoyl]oxy}methyl)phenyl]-N 5 -carbamoyl-L-omithinamide;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-(5-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-difluoro-5-oxopentyl)-N 5 -carbamoyl-L-omithinamide;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{[1-(2-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2-oxoethyl)cyclohexyl]methyl}-N 5 -carbamoyl-L-omithinamide;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-(4-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-dimethyl-4-oxobutyl)-N 5 -carbamoyl-L-omithinamide;
N-(3-carboxypropanoyl)-L-valyl-N-(5-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-difluoro-5-oxopentyl)-N 5 -carbamoyl-L-omithinamide;
N-(3-carboxypropanoyl)-L-valyl-N-{[1-(2-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2-oxoethyl)cyclohexyl]methyl}-N 5 -carbamoyl-L-omithinamide;
N-(3-carboxypropanoyl)-L-valyl-N-(4-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-dimethyl-4-oxobutyl)-N 5 -carbamoyl-L-omithinamide;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-phenylalanyl-N-(5{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-difluoro-5-oxopentyl)-L-leucinamide;
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-phenylalanyl-N-{[1-(2-{[(4S)-10-bromo-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2-oxoethyl)cyclohexyl]methyl}-L-leucinamide; and
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-phenylalanyl-N-(4-{[(4S)-10-bromo -4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-2,2-dimethyl-4-oxobutyl)-L-leucinamide.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier or diluent.

5. A pharmaceutical composition according to claim 4 further comprising one or more chemotherapeutic agents.

6. A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

7. A method for treating ovarian cancer, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 .

8. A method according to claim 7 , wherein the mammal in need thereof is a human.

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Beria Italo
• Caruso Michele
• Salsa Matteo
• Faiardi Daniela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/496

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