Colchinol derivatives as angiogenesis inhibitors

Details Colchinol derivatives as angiogenesis inhibitors Colchinol derivatives as angiogenesis inhibitors

2003-01-07

2004-04-13

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S154000, C544S380000, C548S338100, C564S157000, C558S172000, C514S237800

Reexamination Certificate

active

06720323

ABSTRACT:

The present invention relates to vascular damaging agents, to the use of compounds of the invention in the manufacture of medicaments for use in the production of antiangiogenic effects in warm-blooded animals such as humans, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds as active ingredient, to methods for the treatment of disease states associated with angiogenesis and to the use of such compounds as medicaments.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). 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.
Reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect. The present invention is based on the discovery of tricyclic compounds that surprisingly specifically damage newly formed vasculature without affecting the normal, established vascular endothelium of the host species, a property of value in the treatment of disease states associated with angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
Compounds of the present invention are colchinol derivatives. Colchinol derivatives for example N-acetyl-colchinol are known. Anti-tumour effects have been noted on animal models (see for example—Jnl. Natl. Cancer Inst. 1952, 13, 379-392). 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.
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.
According to one aspect of the present invention there is provided a compound of the formula (I):
wherein:
R
1
, R
2
and R
3
are each independently hydroxy, phosphoryloxy (—OPO
3
H
2
), C
1-4
alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R
1
, R
2
and R
3
are C
1-4
alkoxy;
A is —CO—, —C(O)O—, —CON(R
8
)—, —SO
2
— or —SO
2
N(R
8
)— (wherein R
8
is hydrogen, C
1-4
alkyl, C
1-3
alkoxyC
1-3
alkyl, aminoC
1-3
alkyl or hydroxyC
1-3
alkyl);
a is an integer from 1 to 4 inclusive;
R
a
and R
b
are independently selected from hydrogen, hydroxy and amino;
B is —O—, —CO—, —N(R
9
)CO—, —CON(R
9
)—, —C(O)O—, —N(R
9
)—, —N(R
9
)C(O)O—, —N(R
9
)CON(R
10
)—, —N(R
9
)SO
2
—, —SO
2
N(R
9
)— or a direct single bond (wherein R
9
and R
10
are independently selected from hydrogen, C
1-4
alkyl, C
1-3
alkoxyC
1-3
alkyl, aminoC
1-3
alkyl and hydroxyC
1-3
alkyl);
b is 0 or an integer from 1 to 4 inclusive, (provided that when b is 0, B is a single direct bond);
D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino,
N
—(C
1-4
alkyl)amino,
N,N
-di(C
1-3
alkyl)amino or of the formula —Y
1
—(CH
2
)
c
R
11
or —NHCH(R
12
)COOH; [wherein Y
1
is a direct single bond, —O—, —C(O)—, —N(R
13
)—, —N(R
13
)C(O)— or —C(O)N(R
13
)— (wherein R
13
is hydrogen, C
1-4
alkyl, C
1-3
alkoxyC
2-3
alkyl, aminoC
2-3
alkyl hydroxyC
2-3
alkyl); c is 0 or an integer from 1 to 4 inclusive; R
11
is a
5-6
-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O, S and N, or a 5-6-membered unsaturated or partially unsaturated heteroaryl group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently form O, S and N, which heterocyclic group or heteroaryl group may bear 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C
1-4
alkyl, C
2-4
alkanoyl, carbamoyl,
N
—(C
1-4
alkyl)carbamoyl,
N
,
N
-di-(C
1-4
alkyl)carbamoyl, hydroxyC
1-4
alkyl, C
1-4
alkoxy, cyanoC
1-3
alkyl, carbamoylC
1-3
alkyl, carboxyC
1-4
alkyl, aminoC
1-4
alkyl,
N
—C
1-4
alkylaminoC
1-4
alkyl, di-
N,N
—(C
1-4
alkyl)aminoC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl, C
1-4
alkylsulphonylC
1-4
alkyl and R
14
(wherein R
14
is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted by 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxyC
1-4
alkyl and C
1-4
alkylsulphonylC
1-4
alkyl);
R
12
is an amino acid side chain;
R
5
is C
1-4
alkoxy;
R
4
and R
6
are each independently selected from: hydrogen, fluoro, nitro, amino, N—C
1-4
alkylamino, N,N-di-(C
1-4
alkyl)amino, hydroxy, C
1-4
alkoxy and C
1-4
alkyl;
R
7
is hydrogen, C
1-4
alkyl, C
1-3
alkoxyC
1-3
alkyl, aminoC
1-3
alkyl or hydroxyC
1-3
alkyl; or a pharmaceutically-acceptable salt, solvate or pro-drug thereof.
In another aspect, the invention relates to a compound of the formula (I) as hereinabove defined or to a pharmaceutically-acceptable salt thereof.
In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only. An analogous convention applies to other generic terms.
R
12
is an amino acid side chain. This includes side chains from natural and non-natural amino acids and includes the possibility of R
12
joining to the NH group so as to form a ring as in the amino acid proline. It includes &agr;-amino acids &bgr;-amino acids and &ggr;-amino acids. In addition, the amino acids may be L-isomers or D-isomers, but preferably L-isomers. Preferred amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, &bgr;-alanine and ornithine. More preferred amino acids include glutamic acid, serine, threonine, arginine, glycine, alanine, &bgr;-alanine and lysine. Especially preferred amino acids include glutamic acid, serine, threonine, arginine, alanine and &bgr;-alanine. Specific values for R
12
include hydrogen, C
1-4
alkyl, C
1-4
alkylthioC
1-4
alkyl, hydroxyC
1-4
alkyl, thioC
1-4
alkyl, phenylC
1-4
alkyl (optionally substituted by hydroxy), guanidinoC
1-4
alkyl, carboxyC
1-4
alkyl, carbamoylC
1-4
alkyl, aminoC
1-4
alkyl and imidazolyl C
1-4
alkyl and R
12
forming a pyrrolidinyl ring with the NH group. Preferred values for R
12
include hydrogen, C
1-4
alkyl, C
1-4
alkylthioC
1-4
alkyl, hydroxyC
1-4
alkyl, thioC
1-4
alkyl, guanidinoC
1-4
alkyl, carboxyC
1-4
alkyl, carbamoylC
1-4

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