3-phenyl-isoquinolin-1(2H)-one derivatives as PARP-1 inhibitors

Patent metadata

Field	Value
Publication number	US-9422243-B2
Application number	US-201214358537-A
Country	US
Kind code	B2
Filing date	Nov 20, 2012
Priority date	Nov 25, 2011
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

There are provided substituted 3-phenyl-isoquinolin-1(2H)-one derivatives which selectively inhibit the activity of poly(ADP-ribose) polymerase PARP-1 with respect to poly(ADP-ribose) polymerase PARP-2. The compounds of the present invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

First claim

The invention claimed is:

1. A compound selected from the group consisting of:
4-(2-Amino-ethoxy)-3-(4-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3-bromo-4-morpholin-4-yl-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(4-chloro-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(4-bromo-phenyl)-7,8-difluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(4-chloro-3-methyl-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3,4-dichloro-phenyl)-7-fluoro-2H-isoquinolin-1-one and
4-(2-Amino-ethoxy)-7-fluoro-3-(3-fluoro-4-methoxy-phenyl)-2H-isoquinolin-1-one.

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier or diluent.

3. A pharmaceutical composition according to claim 2 , further comprising one or more chemotherapeutic agents.

4. A pharmaceutical composition according to claim 3 , wherein the chemotherapeutic agent is an alkylating agent.

5. A pharmaceutical composition according to claim 4 , wherein the alkylating agent is temozolomide.

6. A product comprising a compound 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 product according to claim 6 , wherein the chemotherapeutic agent is an alkylating agent.

8. A product according to claim 7 , wherein the alkylating agent is temozolomide.

9. A process for the preparation of a compound of formula (I)

wherein
R and R 1 are independently hydrogen or an optionally substituted group selected from linear or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and heterocyclyl, or, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycle;
R 2 is hydrogen or an optionally substituted group selected from linear or branched C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
R 3 is fluorine, chlorine, bromine, cyano, or an optionally substituted group selected from linear or branched C 1 -C 6 alkyl, C 1 -C 6 alkoxy, polyfluorinated C 1 -C 6 alkyl, polyfluorinated C 1 -C 6 alkoxy, heterocyclyl, aryloxy, arylamino, C 1 -C 6 alkylsulphonyl; or R 3 may be represented by a dioxolyl, dioxinyl or dioxepinyl ring, fused with the phenyl ring;
R 4 is hydrogen or fluorine, and
when R 4 is hydrogen, n is a number between 1 and 5;
when R 4 is fluorine, n is a number between 0 and 5;
which comprises:
step 1) protecting a compound of formula (II):

wherein R 3 and R4 and n and as defined above
with a compound of formula PG-X (III), wherein PG is a suitable protecting group and X is a suitable leaving group;
step 2) rearranging the resultant compound of formula (IV):

wherein R 3 , R 4 , n and PG are as defined above;
step 3) alkylating the resultant compound of formula (V):

wherein R 3 , R 4 , and PG are as defined above, with a compound of formula (VI):

wherein R 2 is as defined above; R′ and R 1 ′ have the same meaning of R and R 1 but can also be independently COOR 6 , wherein R 6 is an optionally substituted linear or branched C 1 -C 6 alkyl; and R 5 is a suitable group;
step 4) deprotecting the resultant compound of formula (VII):

wherein R′, R 1 ′, R 2 , R 3 , R 4 , n and PG are as defined above, so as to obtain a compound of formula (I), as defined above;
optionally converting a compound of formula (I) into a different compound of formula (I); and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into a free compound of formula (I);
moreover, optionally converting a compound of formula (II) or formula (IV) or formula (V) or formula (VII) into a corresponding compound of formula (II) or formula (IV) or formula (V) or formula (VII), respectively.

10. The process according to claim 9 , for the preparation of a compound selected from the group consisting of:
4-(2-Amino-ethoxy)-3-(4-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-7-fluoro-3-(3-trifluoromethyl-phenyl)-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3-bromo-4-morpholin-4-yl-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Aminoethoxy)-7-fluoro-3-(4-pyrrolidin-1-yl-phenyl)-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(4-chloro-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-7-fluoro-3-(4-fluoro-phenyl)-2H-isoquinolin-1-one,
3-[4-(2-Amino-ethoxy)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-3-yl]-benzonitrile,
4-(2-Amino-ethoxy)-3-(4-bromo-phenyl)-7,8-difluoro-2H-isoquinol in- 1-one,
4-(2-Amino-ethoxy)-3-(4-chloro-3-methyl-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3,4-dichloro-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3,4-difluoro-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(3-bromo-4-pyrrolidin-1-yl-phenyl)-7-fluoro-2H-isoquinolin-1-one,
4-(2-Amino-ethoxy)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-fluoro-2H-isoquinol in-1-one,
4-(2-Amino-ethoxy)-3-benzo [1,3]dioxol-5-yl-7-fluoro-2H-isoquinol in-1-one,
4-(2-Amino-ethoxy)-7-fluoro-3 -(3 -fluoro-4-methoxy-phenyl)-2H-isoquinolin- 1-one;
or a pharmaceutically acceptable salt thereof.

Assignees

• Nerviano Medical Sciences Srl
• Nerviano Medical Sciences S R L A Corp

Inventors

• Papeo Gianluca Mariano Enrico
• Cirla Alessandra
• D'Anello Matteo
• Scolaro Alessandra
• Zuccotto Fabio

Classifications

• A61K31/472

  Non-condensed isoquinolines, e.g. papaverine · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D217/24 Primary

  Oxygen atoms · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title