Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ether doai
Reexamination Certificate
2000-01-05
2002-07-23
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ether doai
C514S721000, C514S729000, C568S733000, C568S660000
Reexamination Certificate
active
06423753
ABSTRACT:
This invention relates to vascular damaging agents and particularly to use in the preparation of agents for treatment of neovascularisation of a group of colchinol derivatives some of which are new compounds.
Formation of new vasculature by angiogenesis is a key pathological feature of several diseases (J Folkman, New England Journal of Medicine 333, 1757 (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 i diabetic retinopathy. In all these diseases reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect.
Colchinol derivatives for example N-acetyl-colchinol are known. Anti-tumour effects have been noted on animal models (see for example—JNCI (Journal National Cancer Institute) Page 379-392 1952, Vol 13). However, the effect studied was that of gross damage (haemorrhage, softening and necrosis) and there is no suggestion of treatment of inappropriate angiogenesis by destruction of neovasculature.
A search of Chemical Abstracts (post 1955) based on the substructure
revealed a number of colchinol related structures.
To the extent that any of these compounds have been studied for anti-cancer activity it is because tubulin binding agents might be expected to be anti-mitotic and therefore to have a direct effect on tumour cells.
In the course of the work on the present invention, the issue of the relevance of tubulin-binding properties to possible effectiveness as anti-vascular agent was studied but no predictability was found. Thus docetaxel (Lancet, 344, 1267-1271, 1994), which is a tubulin-binding agent, had no vascular-damaging effects even when administered at its Maximum Tolerated Dose. Even when the present inventors tested some compounds structurally related to the present invention, the therapeutic window (ratio of MTD (Maximum tolerated dose) to MED (Minimum effective dose)) was found to be too small for potential clinical effectiveness.
According to the present invention there is provided the use of colchinol derivatives for the preparation of compositions for the treatment of diseases involving angiogenesis in which the colchinol derivative has the formula
wherein
R
1
, R
2
, R
3
and R
5
are each independently H. optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, alkanoyl, PO
3
H
2
;
X is carbonyl (CO), thiocarbonyl (CS), methylene (CH
2
) or a group CHR
4
R
4
is OH, O-alkyl or NR
8
R
9
;
R
5
and R
7
are each independently H, alkyl, halogen, hydroxy, alkoxy, nitro or amino;
R
8
is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl;
and R
9
is H, alkyl or cycloalkyl
and the pharmaceutically acceptable salts, solvates, and hydrates thereof.
It is believed, though this is not limiting on the invention, that the use of compounds of the invention damages newly-formed vasculature, for example the vasculature of tumours, thus effectively reversing the process of angiogenesis as compared to known anti-angiogenic agents which tend to be less effective once the vasculature has formed.
Certain of these compounds are novel. In one embodiment the novel compounds are those of formula I in which at least one of R
1
, R
2
, R
3
, R
6
is PO
3
H
2
. In a particular preferred embodiment R
6
is PO
3
H
2
. Particularly preferred are compounds defined by the formula
wherein
R
1
, R
2
and R
3
are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, alkanoyl, or PO
3
H
2
;
R
6
is PO
3
H
2
;
R
4
is H or NR
8
R
9
;
R
5
and R
7
are each independently H, alkyl, halogen, alkoxy, nitro or amino;
R
8
is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl;
and R
9
is H, alkyl or cycloalkyl,
and the pharmaceutically acceptable salts, solvates and hydrates thereof.
In another aspect of the invention the novel compounds are of formula
wherein
R
1
, R
2
and R
3
are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, alkanoyl or PO
3
H
2
;
R
6
is H, optionally substituted alkyl, cycloalkyl, alkenyl, akynyl or PO
3
H
2
;
R
4
is H or NR
8
R
9
;
R
5
and R
7
are each independently H, alkyl halogen, nitro or amino;
R
8
is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl;
and R
9
is H, alkyl or cycloalkyl, with the proviso that, when R
1
, R
2
and R
3
are all methyl groups and R
4
is hydrogen, acetylamino, acetylmethylamino, amino, methylamino or dimethylamino then R
6
is not hydrogen, methyl or hydroxyethyl, or acetoxyethyl,
and the pharmaceutically acceptable salts, solvates and hydrates thereof.
Preferred compounds used in the invention and of the invention are those in which R
1
, R
2
and R
3
are alkyl and those in which R
4
is acylamino.
As used herein the term “alkyl”, (including any aliphatic structure chain related to alkyl) means a straight or branched-chain 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. Optional substituents which may be present on the alkyl groups include one or more substituents selected from halogen, amino, monoalkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkylsulphonyl, acylamino, alkoxycarbonylamino, alkanoyl, acyloxy, carboxyl, sulphate or phosphate groups. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy. The term “halogen” means fluorine, chlorine, bromine or iodine.
An alkenyl group is an olefinic group containing from two to seven carbon atoms for example methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene and t-butylene. An alkynyl group is of a group of 2-7 carbon atoms for example ethynyl, propynyl or butynyl group.
The term aryl alone or in combination means an unsubstituted phenyl group or a phenyl group carrying one or more, preferably one to three, substituents examples of which are halogen, alkyl, haloalkyl, hydroxy, nitro, cyano, amino and alkoxy. A haloalkyl group can carry one or more halogen atoms with the examples of such groups being trifluoromethyl and dichloromethyl.
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 aralkyl is defined herein as an alkyl group, as previously defined, in which one of the hydrogen atoms is replaced by an aryl or heteroaryl group as defined herein.
Where one or more functional groups in compounds of formulae I, II, IIA are sufficiently basic or acidic the formation of salts
Angiogene Pharmaceuticals Ltd.
Lambkin Deborah C.
Morgan & Lewis & Bockius, LLP
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