Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2001-10-30
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S304400, C548S310400, C548S310700
Reexamination Certificate
active
06310082
ABSTRACT:
The present invention relates to certain benzimidazole 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 any forms of antitumour therapy.
In this connection, several classes of PARP inhibitors are already known, including benzamide 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 benzamide compounds as chemotherapeutic agents, various 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 benzamide compounds can also potentiate the activity of cytotoxic drugs in vivo, 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 benzamide compounds 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 vivo 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 and there remains a need to find and develop a greater range of compounds having potentially useful PARP inhibitory properties.
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 to which this invention relates comprise certain benzimidazole derivatives, more particularly benzimidazole-4-carboxamide compounds, as hereinbelow defined. By virtue of their structure it would appear that many such compounds are particularly well adapted to compete with the natural substrate NAD+ for the PARP enzyme.
More specifically, from one aspect, the invention resides in the use of a compound as herein defined for the manufacture of a medical or veterinary preparation for use in therapy for inhibiting activity of the enzyme poly(ADP-ribose)polymerase or PARP (also known as ADP-ribosyl transferase or ADPRT), such enzyme inhibition constituting an element of a therapeutic treatment, wherein said compound provides the active PARP enzyme inhibiting agent and comprises a benzimidazole-4-carboxamide having the general structural formula I
or a pharmaceutically acceptable salt and/or pro-drug form thereof, characterised in that in structural formula I
R is selected from hydrogen, alkyl, hydroxyalkyl (e.g. CH
2
CH
2
OH), acyl (e.g. acetyl or benzoyl) and an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group, and
R′ is selected from hydrogen, alkyl, hydroxyalkyl (e.g. CH
2
CH
2
OH), acyl (e.g. acetyl or benzoyl) and an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group.
The invention also provides for use in therapy, as active pharmaceutical substances, especially but not exclusively as PARP inhibitors, benzimidazole compounds having the general structural formula I
(or a pharmaceutically acceptable salt and/or pro-drug form thereof), with substituents as defined above except for provisos that R does not represent 4′-methane-sulphonyloxy-2′-methoxyphenyl or 4′-methane-sulphonylamino-2′-methoxyphenyl and does not represent a phenyl group having a substituent which is an alkylsulphenyl, alkylsulphinyl, alkanesulphonyl or alkylsulphoximino group, an alkylsulphoximino group substituted at the nitrogen atom by an alkanoyl, alkylsulphonyl or hydroxycarbonyl-alkylenecarbonyl group, an ethoxy or n-propoxy group each of which is substituted in the terminal position by an alkylsulphenyl, alkylsulphinyl, alkanesulphonyl or alkylsulphoximino group, an alkoxycarbonylamino or an N-alkylaminocarbonyl-amino group and R′ is not an optionally substituted aralkyl group and does not include a biphenyl or substituted biphenyl group.
The invention further provides novel benzimidazole compounds having the general structural formula I (or a pharmaceutically acceptable salt and/or pro-drug form thereof), with substituents as defined immediately above except for the further proviso that R does not represent an unsubstituted aryl group such as phenyl.
Alkyl groups when present as such or as a moiety in other groups will generally be composed of 1-8 carbon atoms, preferably 1-6 carbon atoms, and more usually 1-4 carbon atoms. In particular, when R and/or R′ 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. When R and/or R′ is or includes a phenyl group this may be substituted, especially in the 4 (para) position but alternatively or additionally in the 2-position and/or 3-position for instance, by various substituents including hydroxy, alkoxy (methoxy or ethoxy for example), cyano, carboxy, amide, tetrazole, amino or substituted amino, CW
3
(e.g. CF
3
) or W where W is halogen.
In cases where R′ is hydrogen or alkyl preferred compounds of structural formula I include compounds in which R is phenyl or benzyl having at least one substituent in the benzene ring which is selected from hydroxy, alkoxy, NO
2
, N
3
, NR
5
R
6
(R
5
and R
6
each being independently hydrogen, alkyl or alkoxy), NHCOR
3
(R
3
being alkyl or aryl), CO
2
R
4
(R
4
being H or alkyl), an amide (e.g. CONH
2
), tetrazole, alkyl, hydroxyalkyl, CW
3
or W (W being h
Calvert Alan H
Curtin Nicola J
Golding Bernard T
Griffin Roger J
Newell David R
Newcastle University Ventures Limited
Pillsbury & Winthrop LLP
Stockton Laura L.
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