Quinazolinone derivatives as PARP inhibitors

Patent metadata

Field	Value
Publication number	US-10150757-B2
Application number	US-201615350663-A
Country	US
Kind code	B2
Filing date	Nov 14, 2016
Priority date	Jun 30, 2004
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The present invention provides compounds of formula (I), their use as PARP inhibitors as well as pharmaceutical compositions comprising said compounds of formula (I)

wherein R 1 , R 2 , R 3 , L, X, Y and Z have defined meanings.

First claim

The invention claimed is:

1. A compound of formula (I),

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
the dotted lines represent optional bonds;
X is >N—;
is —N—C(O)— or —N═CR 4 —, wherein R 4 is hydroxy;
L is a direct bond or a bivalent radical selected from —C(O)—, —C(O)—NH—, —NH—, —C(O)—C 1-6 alkanediyl-, —C(O)—O—C 1-6 alkanediyl- or —C 1-6 alkanediyl-;
R 1 is hydrogen, halo, C 1-6 alkyloxy or C 1-6 alkyl;
R 2 is hydrogen, hydroxy, C 1-6 alkyloxy or aminocarbonyl;
R 3 is hydrogen, or C 1-6 alkyloxy;
Z is amino, cyano or a radical selected from

wherein each R 5 and R 6 is independently selected from hydrogen, halo, amino, C 1-6 alkyl, or C 1-5 alkyloxy.

2. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .

3. A process of preparing a pharmaceutical composition as claimed in claim 2 wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 are intimately mixed.

4. A combination of a compound with a chemotherapeutic agent wherein said compound is a compound of formula (I)

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
the dotted lines represent optional bonds;
X is >N—;
is —N—C(O)— or —N═CR 4 —, wherein R 4 is hydroxy;
L is a direct bond or a bivalent radical selected from —C(O)—, —C(O)—NH—, —NH—, —C(O)—C 1-6 alkanediyl-, —C(O)—O—C 1-6 alkanediyl- or —C 1-6 alkanediyl-;
R 1 is hydrogen, halo, C 1-6 alkyloxy or C 1-6 alkyl;
R 2 is hydrogen, hydroxy, C 1-6 alkyloxy or aminocarbonyl;
R 3 is hydrogen, or C 1-6 alkyloxy;
Z is amino, cyano or a radical selected from

wherein each R 5 and R 6 is independently selected from hydrogen, halo, amino, C 1-6 alkyl, or C 1-5 alkyloxy.

5. A process for preparing a compound as claimed in claim 1 , characterized by
reacting an intermediate of formula (II) with an intermediate of formula (III), wherein W is an appropriate leaving group, with the formation of a compound of formula (I-a), wherein L 1 is —C 1-6 alkanediyl-NH— and both dotted lines can be a bond, in a reaction-inert solvent and with the addition of an appropriate base,

6. A compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

7. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 6 .

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Guillemont Jerome Emile Georges
• Kennis Ludo Edmond Josephine
• Mertens Josephus Carolus
• Van Dun Jacobus Alphonsus Josephus
• Somers Maria Victorina Francisca
• Wouters Walter Boudewijn Leopold

Classifications

• 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P37/04

  Immunostimulants · CPC title

• A61P41/00

  Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution · CPC title