Isoquinolinone derivatives

Details Isoquinolinone derivatives Isoquinolinone derivatives

2002-04-30

2003-12-16

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S141000

Reexamination Certificate

active

06664269

ABSTRACT:

The present invention relates to isoquinolinone derivatives, and their use as pharmaceuticals. In particular, the present invention relates to the use of these compounds to inhibit the activity of the enzyme poly (ADP-ribose)polymerase, also known as poly(ADP-ribose)synthase and poly ADP-ribosyltransferase, and commonly referred to as PARP.
The mammalian enzyme PARP (a 113-kDa multidomain protein) has been implicated in the signalling of DNA damage through its ability to recognize and rapidly bind to DNA single or double strand breaks (D'Amours et al, 1999, Biochem. J. 342: 249-268).
Several observations have led to the conclusion that PARP participates in a variety of DNA-related functions including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair and also effects on telomere length and chromosome stability (d'Adda di Fagagna et al, 1999, Nature Gen., 23(1): 76-80).
Studies on the mechanism by which PARP modulates DNA repair and other processes has identified its importance in the formation of poly (ADP-ribose) chains within the cellular nucleus (Althaus, F. R. and Richter, C., 1987, ADP-Ribosylation of Proteins: Enzymology and Biological Significance, Springer-Verlag, Berlin). The DNA-bound, activated PARP utilizes NAD to synthesize poly (ADP-ribose) on a variety of nuclear target proteins, including topoisomerase, histones and PARP itself (Rhun et al, 1998, Biochem. Biophys. Res. Commun., 245: 1-10)
Poly (ADP-ribosyl)ation has also been associated with malignant transformation. For example, PARP activity is higher in the isolated nuclei of SV40-transformed fibroblasts, while both leukemic cells and colon cancer cells show higher enzyme activity than the equivalent normal leukocytes and colon mucosa (Miwa et al, 1977, Arch. Biochem. Biophys. 181: 313-321; Burzio et al, 1975, Proc. Soc. Exp. Bioi. Med. 149: 933-938; and Hirai et al, 1983, Cancer Res. 43: 3441-3446).
A number of low-molecular-weight inhibitors of PARP have been used to elucidate the functional role of poly (ADP-ribosyl)ation in DNA repair. In cells treated with alkylating agents, the inhibition of PARP leads to a marked increase in DNA-strand breakage and cell killing (Durkacz et al, 1980, Nature 283: 593-596; Berger, N. A., 1985, Radiation Research, 101: 4-14).
Subsequently, such inhibitors have been shown to enhance the effects of radiation response by suppressing the repair of potentially lethal damage (Ben-Hur et al, 1984, British Journal of Cancer, 49 (Suppl. VI): 34-42; Schlicker et al, 1999, Int. J. Radiat. Bioi., 75: 91-100). PARP inhibitors have been reported to be effective in radio sensitising hypoxic tumour cells (U.S. Pat. Nos. 5,032,617; 5,215,738 and 5,041,653).
Furthermore, PARP knockout (PARP −/−) animals exhibit genomic instability in response to alkylating agents and &ggr;-irradiation (Wang et al, 1995, Genes Dev., 9: 509-520; Menissier de Murcia et al, 1997, Proc. Natl. Acad. Sci. USA, 94: 7303-7307).
A role for PARP has also been demonstrated in certain vascular diseases, septic shock, ischaemic injury and neurotoxicity (Cantoni et al, 1989, Biochim. Biophys. Acta, 1014: 1-7; Szabo, et al, 1997, J. Clin. Invest., 100: 723-735). Oxygen radical DNA damage that leads to strand breaks in DNA, which are subsequently recognised by PARP, is a major contributing factor to such disease states as shown by PARP inhibitor studies (Cosi et al, 1994, J. Neurosci. Res., 39: 38-46; Said et al, 1996, Proc. Natl. Acad. Sci. U.S.A., 93: 4688-4692). More recently, PARP has been demonstrated to play a role in the pathogenesis of haemorrhagic shock (Liaudet et al, 2000, Proc. Natl. Acad. Sci. U.S.A., 97(3): 10203-10208).
It has also been demonstrated that efficient retroviral infection of mammalian cells is blocked by the inhibition of PARP activity. Such inhibition of recombinant retroviral vector infections was shown to occur in various different cell types (Gaken et al, 1996, J. Virology, 70(6): 3992-4000). Inhibitors of PARP have thus been developed for the use in anti-viral therapies and in cancer treatment (WO91/18591)
Moreover, PARP inhibition has been speculated to delay the onset of aging characteristics in human fibroblasts (Rattan and Clark, 1994, Biochem. Biophys. Res. Comm., 201 (2): 665-672). This may be related to the role that PARP plays in controlling telomere function (d'Adda di Fagagna et al, 1999, Nature Gen., 23(1): 76-80).
EP 0 355 750 discloses classes of 5-substituted isoquinolinones and dihydroisoquinolinones as PARP inhibitors. Exemplified substituents on the nitrogen containing ring, at the 3 and/or 4 position, include methyl, phenyl, bromo or amino.
WO 99/11624 discloses a number of PARP inhibitors, amongst which are some isoquinolinone derivatives.
The present inventors have now discovered that further derivatives of isoquinolinone and dihydroisoquinolinone and related compounds act as PARP inhibitors.
Accordingly, the first aspect of the present invention provides a method of treatment of a disease of the human or animal body mediated by PARP comprising administering to such a subject a therapeutically effective amount of a compound of formula:
and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein:
A and B together represent an optionally substituted, fused aromatic ring;
the dotted line between the 3 and 4 positions indicates the optional presence of a double bond;
at least one of R
C1
and R
C2
is independently represented by -L-R
L
, and if one of R
C1
and R
C2
is not represented by -L-R
L
, then that group is H, where L is of formula:
—(CH
2
)
n1
-Q
n2
-(CH
2
)
n3
—
wherein n
1
, n
2
and n
3
are each selected from 0, 1, 2 and 3, the sum of n
1
, n
2
and n
3
is 1, 2 or 3 and each Q (if n
2
is greater than 1) is selected from O, S, NR
3
, C(═O), or -cR
1
R
2
—, where R
1
and R
2
are independently selected from hydrogen, halogen or optionally substituted C
1-7
alkyl, or may together with the carbon atom to which they are attached form a C
3-7
cyclic alkyl group, which may be saturated (a C
3-7
cycloalkyl group) or unsaturated (a C
3-7
cycloalkenyl group), or one of R
1
and R
2
may be attached to an atom in R
L
to form an unsaturated C
3-7
cycloalkenyl group which comprises the carbon atoms to which R
1
and R
2
are attached in Q, —(CH
2
)
n3
— (if present) and part of R
L
, and where R
3
is selected from H or C
1-7
alkyl; and
R
L
is selected from optionally substituted C
3-20
heterocyclyl, C
5-20
aryl and carbonyl; and
R
N
is selected from hydrogen, optionally substituted C
1-7
alkyl, C
3-20
heterocyclyl, C
5-20
aryl, hydroxy, ether, nitro, amino, thioether, sulfoxide and sulfone.
A second aspect of the present invention relates to a compound of the formula:
or an isomer, salt, solvate, chemically protected form, and prodrug thereof, wherein:
A and B together represent an optionally substituted, fused aromatic ring;
the dotted line between the 3 and 4 positions indicates the optional presence of a double bond;
one of R
C1
and R
C2
is —CH
2
—R
L
, and the other of R
C1
and R
C2
is H;
R
L
is optionally substituted phenyl; and
R
N
is hydrogen.
A third aspect of the present invention relates to a pharmaceutical composition comprising a compound of the second aspect and a pharmaceutically acceptable carrier or diluent.
Further aspects of the invention provide for a method of treatment as described in the first aspect of the invention, wherein the disease mediated by PARP is: vascular disease; septic shock; ischaemic injury; neurotoxicity; haemorraghic shock; or viral infection.
A further aspect of the invention provides a method of cancer therapy for the human or animal body comprising administering to such a subject a therapeutically effective amount of a compound as described in the first aspect in combination with chemotherapy or radiation therapy.
Another further aspect of the invention provides a method of potentiating tumour cells for treatment with ionising radiation or chemotherapeutic agents comprising administering to said cells a compo

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