Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-24
2001-11-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S287000, C544S289000
Reexamination Certificate
active
06316455
ABSTRACT:
The present invention relates to benzamide analogues, especially certain 3-substituted benzamide compounds and related quinazolinone compounds that are of interest as being at least potentially useful chemotherapeutic agents by virtue of an ability to inhibit the activity of the enzyme poly ADP-ribosyltransferase (EC 2.4.2.30), also known as poly(ADP-ribose) polymerase, commonly referred to as ADPRT or PARP. In general, the latter abbreviation, PARP, will be used throughout the present specification.
BACKGROUND
At least in higher organisms, the enzyme poly ADP-ribosyltransferase is known to catalyse a transfer of the ADP-ribose moiety from the oxidized form NAD
+
of nicotinamide adenine dinucleotide to nuclear acceptor proteins so as to form homo ADP-ribose polymers, and this process has been implicated in a number of cellular events such as, for example, repair of DNA damage, development of cellular differentiation, transformation of cells by oncogenes, and gene expression. A common feature in a number of these processes is the formation and repair of DNA strand breaks and the stage which involves the PARP enzyme appears to be that of DNA ligase II-mediated strand rejoining. In the majority of cases a role for poly ADP-ribosylation has been implicated by the use of inhibitors of the PARP enzyme, and this has led to suggestions that such inhibitors, by interfering with the intracellular DNA repair mechanism, may have a useful chemotherapeutic role insofar as they should be able to modify treatment resistance characteristics and potentiate or enhance the effectiveness of cytotoxic drugs in chemotherapy or of radiation in radiotherapy where a primary effect of the treatment is that of causing DNA damage in target cells, as for example in many forms of antitumour therapy.
In this connection, several classes of PARP inhibitors are already known, including benzamide itself and various nicotinamide and benzamide analogues, especially 3-substituted benzamides with small substituent groups such as 3-amino, 3-hydroxy and 3-methoxy. PARP inhibitory activity of certain N-substituted benzamides has also been reported in EP-A-0305008 wherein it has also been proposed to use these compounds in medicine for increasing the cytotoxicity of radiation or of chemotherapeutic drugs.
Regarding this use of benzamides as chemotherapeutic agents, a number of studies on such compounds that are known to exhibit PARP inhibitory activity have confirmed that they can potentiate the cytoxicity of a range of antitumour agents in vitro, for example, bleomycin and methylating drugs. More limited data has further indicated that such benzamides can also potentiate the activity of cytotoxic drugs in viva, although the dose requirements have appeared to be rather high (e.g. in the region of 0.5 g kg
−1
per dose for 3-aminobenzamide) and there may be associated problems in preparing satisfactory pharmaceutical formulations and in avoiding toxicity limitations. Furthermore, a number of the known benzamides have also been shown clearly to have potential as radiosensitizers, increasing for example ionising radiation-induced tumour cell kill both in vitro and in vivo, and it is believed that in many cases this effect is related to these compounds acting as PARP inhibitors and interfering with DNA repair.
However, notwithstanding the existing data from in vitro and in viva studies suggesting that PARP inhibitors have considerable potential as useful chemotherapeutic agents which merit further clinical evaluation, for instance in connection with cancer therapy, currently available known PARP inhibitors are not considered as yet to be entirely suitable to represent candidate drugs. Accordingly, there is a need to find and develop a greater range of compounds having potentially useful PARP inhibitory proper ties.
DISCLOSURE OF THE INVENTION
The present invention identifies a new range or ranges of compounds of interest as PARP inhibitors that can be useful in medicine, especially when administered in conjunction with at least certain cytotoxic drugs or with radiotherapy for increasing the cytotoxic effectiveness thereof. In general, the compounds of this invention as hereinbelow defined comprise novel 3-substituted benzamide compounds, especially 3-oxybenzamide compounds, or analogues, of which many include relatively large or bulky 3-position substituents or include 3-position substituents linked in a ring structure with substituents in the 2-position. The compounds also include certain quinazolinones of which at least some may be formed by molecular rearrangement of related benzamide compounds. By virtue of their structure in general such compounds are adapted to act as an alternative substrate to NAD
+
for the PARP enzyme.
More specifically, from one aspect, the invention provides novel compounds selected from: (A), a 3-substituted benzamide compound having the general structural formula I
or a pharmaceutically acceptable salt thereof, and
(B), a quinazolinone compound having the general structural formula II
or a pharmaceutically acceptable salt thereof,
characterised in that in structural formula I
(i) Y is hydrogen, and
X is —CH
2
-Z
wherein
Z represents alkyl, an optionally substituted aralkyl group, —CH═CHR (where R is H, alkyl or an optionally substituted phenyl group), cyclohexyl, or a group having the structural formula III
where R
1
is selected from H, alkoxy, NO
2
, N
3
, NH
2
, NHCOR
3
(R
3
being alkyl or aryl), CO
2
R
4
(R
4
being H or alkyl), alkyl, hydroxyalkyl, CW
3
or W (W being halide), and CN,
and where
R
2
is H,
or where R
1
and R
2
together represent a group —O—CHR
5
—O— bridging adjacent ring C's with R
5
being H, alkyl or an optionally substituted aralkyl or aryl group
or
ii) Y is hydrogen, and
X is —(CH
2
)
n
-Z
wherein n is in the range of 5 to 12, and
Z is halide or a purin-9-yl moiety,
or
iii) Y and X together form a bridge —Y—X— that represents the grouping
where R
5
is as specified above,
and in structural formula II
X′ represents hydroxyl, alkyl, alkoxy or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl) group,
and
Y′ represents hydrogen, alkyl or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl) group.
Alkyl groups when present as such or as a moiety in other groups such as alkoxy, excluding in some cases the methylene chain —(CH
2
)
n
specified above, will generally be composed of 1-8 carbon atoms, preferably 1-6 carbon atoms, and more usually 1-4 carbon atoms.
One very important group of compounds of special interest from the point of view of PARP-inhibitory activity comprises benzoxazole-4-carboxamide compounds, i.e. compounds represented by the formula IV
where R
5
, if not H, is preferably alkyl, phenyl or another aryl group such as naphthyl or pyridyl. When R
5
is an alkyl group this will generally be C
1-6
alkyl, such as for example methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or cyclohexyl. However, it may in some cases be larger, such as in adamantyl for instance. When R
5
is a phenyl group this may be substituted, especially in the 4 (para) position but alternatively perhaps in the 2-position or 3-position, by substituents such as alkoxy for example. Within this group of benzoxazole compounds preferred members which are of particular interest include
2-methylbenzoxazole-4-carboxamide,
2-t-butylbenzoxazole-4-carboxamide,
2-phenylbenzoxazole-4-carboxamide,
2-(4-methoxyphenyl)benzoxazole-4-carboxamide.
In the above-mentioned compounds of formula IV, wherein there is an electron-rich aromatic ring, it is believed that the carboxamide group is constrained in a fixed conformation, particularly favourable for presenting the compound as an alternative substrate to NAD
+
for the PARP enzyme, by an intramolecular hydrogen bond between the ring nitrogen atom and one of the hydrogen atoms of the carboxamide group. A similar, although probably somewhat weaker effect may also occur in other compounds of formula I where the X and Y substituents f
Calvert Alan Hilary
Curtin Nicola Jane
Golding Bernard Thomas
Griffin Roger John
Newell David Richard
Newcastle University Ventures Limited
Pillsbury & Winthrop LLP
Raymond Richard L.
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