Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-10-22
2003-11-11
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S388000, C548S113000, C548S308700, C548S309100
Reexamination Certificate
active
06645950
ABSTRACT:
This application is a 371 of PCT/GB00/00099 filed Jan. 14, 2000.
This invention relates to vascular damaging agents and particularly to the use of new and known substituted benzimidazoles in the preparation of medicaments for the treatment of diseases involving neovascularisation.
Formation of new vasculature by angiogenesis is a key pathological feature of several diseases (J Folkman, New England Journal of Medicine 333, 1757-1763 (1995)). For example, for a solid tumour to grow it must develop its own blood supply upon which it depends critically for the provision of oxygen and nutrients; if this blood supply is mechanically shut off the tumour undergoes necrotic death. Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques. Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy. In all these diseases reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect.
5(6)-Substituted benzimidazole-carbamates are known and have found use as antiparasitic agents (P. J. Islip in Burgers Medicinal Chemistry (M. E. Wolff ed.), Fourth Edition, Part II, p481, (1979)). Examples of such compounds include mebendazole, fenbendazole, oxibendazole, flubendazole, albendazole, cyclobendazole, parbendazole, dribendazole, luxabendazole, and etibendazole. Their mode of action for their antiparasitic action is believed to involve selective binding to tubulin of the target parasite while having little effect due to binding tubulin of the mammalian host (Biochim. Biophys. Acta 630, 271-278, (1980)). Some of these compounds have been shown to be antimitotic for cancer cells and one particular 5(6)-substituted benzirnidazole-2-carbamate, nocodazole, has therefore been studied as an anticancer agent (Cancer Research, 36, 905-916 (1976)). No effects on neovasculature have been reported for any of these compounds.
Some structurally-unrelated compounds which bind tubulin have been shown to have anti-vascular effects when given at their maximum tolerated dose (MTD) (S. A. Hill et al. Eur. J Cancer, 29A, 1320-1324 (1993)) but other tubulin-binding agents, such as docetaxel, have no vascular-damaging activity even when administered at the MTD. The presence of tubulin-binding properties is then not predictive for antivascular activity.
According to the present invention there is provided the use of 5(6)-substituted benzimidazole-2-carbamates for the preparation of compositions for the treatment of diseases involving angiogenesis in which the 5(6)-substituted benzirnidazole carbamate has the formula
wherein
Alk is an alkyl group
X is oxygen, sulphur, sulphinyl, sulphonyl, carbonyl (CO), thiocarbonyl (CS), sulphonyloxy, NH, iminomethylene (C═NH), N-hydroxyiminomethylene, N-alkoxyimninomethylene, dialkoxymethylene, 1,3-dioxolan-2yl, 1,1-ethenyl, a group CHR
3
or a bond
R
1
is hydrogen, alkylarninocarbonyl or alkoxycarbonyl
R
2
is hydrogen, alkoxycarbonyl, cyanomethyl, cyanoethyl, alkoxymethyl or acetoxymethyl.
R
3
is hydrogen, hydroxy, alkoxy or amino
A is an optionally substituted aromatic, optionally substituted heteroaromatic, optionally substituted heterocycloalkyl, optionally substituted alkyl or optionally substituted cycloalkyl group
and the pharmaceutically acceptable salts, solvates and hydrates thereof.
Particular substituents that may be present on the group A include one or more substituents selected from a group Y, optionally substituted alkyl,(where substituents on such alkyl group may include one or more selected from hydroxy, amino, alkylamino, dialkylamino, halogen, carboxyl, SO
3
H, sulphate, phosphate, alkoxycarbonyl, aralkoxycarbonyl, alkoxycarbonylamino, aminoalkylaminocarbonyl and cyano), halogen, hydroxy, amino, alkoxy, alkylthio, cyano, nitro, sulphate, isothiocyanate, aryl, heteroaryl and heterocycloalkyl.
Y is a group selected from phosphate, alkylphosphate, C(O)R
4
, OC(O)R
4
, SO
2
R
4
, NHC(O)R
4
, NR
5
C(O)R
4
, SR
4
, S(O)R
4
, OSO
2
R
4
, NHSO
2
R
4
, NR
5
SO
2
R
4
, SO
3
H, CO
2
H and CO
2
R
5
where R
4
is a group selected from hydrogen, R
5
, OR
5
, NHR
5
, NR
5
R
6
, aryl, heteroaryl or heterocycloalkyl such aryl, heteroaryl or heterocycloalkyl groups being optionally substituted with one or more substituents selected from alkyl, heterocycloalkyl, haloalkyl, hydroxy, nitro, cyano, amino, alkylamino, dialkylamino, halogen, carboxyl, SO
3
H, sulphate and phosphate. R
5
and R
6
, which may be the same or different, are each an alkyl group optionally substituted with one or more substituents selected from hydroxy, amino, alkylamino, dialkylamino, guanidino, halogen, carboxyl, SO
3
H, sulphate, phosphate, aryl and heteroaryl.
Some of the compounds usable in the invention are known, for example the following compounds within the following formula:
These compounds are
X
A
Fenbendazole
S
Ph
Mebendazole
CO
Ph
Albendazole
S
nPr
Oxibendazole
O
nPr
Nocodazole
CO
2-thienyl
Certain of these compounds are novel. In one embodiment the novel compounds are those of formula I in which at least one of the substituents on the group A is a group Y where Y is as hereinbefore defined. Particularly preferred are compounds defined by the formula
wherein
alk is an alkyl group
B is an aromatic or heteroaromatic ring
X is oxygen, sulphur, sulphinyl, sulphonyl, carbonyl (CO), thiocarbonyl (CS), sulphonyloxy, NH, iminomethylene (C═NH), N-hydroxyiminomethylene, N-alkoxyiminomethylene, dialkoxymethylene, 1,3-dioxolan-2yl, 1,1-ethenyl, a group CHR
3
or a bond
R
1
is hydrogen, alkylaminocarbonyl or alkoxycarbonyl
R
2
is hydrogen, alkoxycarbonyl, cyanomethyl, cyanoethyl, alkoxymethyl or acetoxymethyl
R
3
is hydrogen, hydroxy, alkoxy or amino
Y is as hereinbefore defined
R
7
and R
8
are each independently H, alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy, alkylthio, cyano, nitro, or trifluoromethyl
with the proviso that Y is not NHC(O)Me and when B is a thiophene ring then Y is not C(O)CF
3
and when B is a 5(6)-benzimidazole ring then Y is not NHCO
2
Me or NHCO
2
Et
and the pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof.
As used herein the term “alkyl”, alone or in combinations, means a straight or branched-chain alkyl group containing from one to seven, preferably a maximum of four, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy. The term “halogen” means fluorine, chlorine, bromine or iodine. The term “aryl” as used herein unless otherwise stated includes reference to a C
6-10
aryl group which may, if desired, carry one or more substituents selected from halogeno, alkyl, haloalkyl, alkoxy, hydroxy, amino, nitro and cyano. The term “aralkoxy” means an alkoxy group substituted with an aryl group.
The term heteroaryl is defined herein as a mono- or bi-cyclic aromatic group containing one to four heteroatoms selected in any combination from N, S or O atoms and a maximum of 9 carbon atoms. Examples of heteroaryl groups include pyridyl, pyrimidyl, furyl, thienyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl, benzothienyl, benzothiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, quinolyl and isoquinolyl groups.
The term heterocycloalkyl includes heterocycloalkyl groups containing 3-6 carbon atoms and one or two oxygen, sulphur or nitrogen atoms. Particular examples of such groups include azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl or thiomorpholinyl groups.
The term cycloalkyl means a cycloaliphatic group containing 3-10 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
One particularly preferred group of compounds are those of formula II in which Y is a phosphate group.
Another particularly preferred group of compounds are those of formula II in which Y is a group NR
5
C(
Angiogene Pharmaceuticals Ltd.
Stockton Laura L.
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