Angiogenic inhibitory compounds

Details Angiogenic inhibitory compounds Angiogenic inhibitory compounds

1999-03-22

2002-07-30

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

C424SDIG001

Reexamination Certificate

active

06426067

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds which are effective in inhibition of angiogenesis, and accordingly can be used instead of sulfated polysaccharides such as heparin in preventing restenosis, accelerating wound healing, and in inhibiting tumor cell metastasis.
BACKGROUND OF THE INVENTION
The use of sulfated polysaccharides in the inhibition of angiogenesis and in the treatment of disorders and conditions associated with angiogenesis has been previously disclosed. Thus, International Patent Application No. PCT/GB95/00515 (WO 95/24907), the contents of which are incorporated herein by reference, discusses the use of heparin and other sulfated polysaccharides such as pentosan polysulfate and dextran sulfate in treatment of these disorders and conditions, and discloses the use of another sulfated polysaccharide, laminarin sulfate, which exhibits only about 30% of the anti-coagulant activity of heparin, in preventing restenosis by the inhibition of vascular smooth muscle cell proliferation, in accelerating wound healing by activating the release of active growth factors stored in the extra-cellular matrix, and for inhibiting tumor cell metastasis by inhibition of heparanase activity.
International Patent Application No. PCT/AU95/00350 (WO 95/34595) discloses a class of antiviral compounds comprising a dendrimer such as a polyamidoamine or polylysine dendrimer having a plurality of terminal groups, wherein at least one of the terminal groups has an anionic- or cationic-containing moiety bonded or linked thereto, particularly a sulfonic acid-containing, a carboxylic acid-containing, or a trimethyl-ammonium-containing moiety.
The present invention provides the use of polyionic materials formed by linking ionic groups to a linear non-carbohydrate polymer or a dendritic polymer in the inhibition of angiogenesis and in the treatment of related disorders and conditions.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a method of prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal patient, which comprises administration to the patient of an effective amount of a compound selected from:
(i) linear, non-carbohydrate polymers having a plurality of side chain groups wherein at least one of said side chain groups has an anionic- or cationic-containing moiety bonded or linked thereto; and
(ii) dendrimers having a plurality of terminal groups wherein at least one of said terminal groups has an anionic- or cationic-containing moiety bonded or linked thereto.
Particularly preferred compounds for use in the method of the present invention are linear polymers having sulfonic acid-containing moieties, carboxylic acid-containing moieties, phosphoric or phosphonic acid-containing moieties, boronic acid-containing moieties, neuraminic or sialic acid-containing moieties or moieties containing neuraminic or sialic acid modified in the 4- or other position thereof, linked to side chain groups thereof, and dendrimers having sulfonic acid-containing moieties, carboxylic acid-containing moieties, phosphoric or phosphonic acid-containing moieties, boronic acid-containing moieties, neuraminic or sialic acid-containing moieties or moieties containing neuraminic or sialic acid modified in the 4- or other position thereof, linked to terminal groups thereof.
The compounds used in the method of this invention are referred to herein are linear polyionic polymers or polyionic dendrimers, respectively, and these terms are used throughout this specification and the claims which follow to include not only the polymers or dendrimers per se, but also their pharmaceutically or veterinarily acceptable salts, for example the alkaline metal or alkaline earth metal salts such as the sodium, potassium or calcium salts.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds used in accordance with the present invention include (i) linear polyionic polymers of the general formula I:
wherein:
R is a non-carbohydrate monomer unit forming a linear polymer backbone;
X is an optional linking group on the side chain groups of monomer units R; and
A is an anionic-containing moiety; and (ii) polyionic dendrimers of the general formula II:
wherein:
I is an initiator core;
Z is an interior branching unit;
n is an integer which represents the number of generations of the dendrimer; and
A is an anion-containing moiety which may be linked to interior branching unit Z through an optional linking group X.
In accordance with the present invention, the preferred linear polyionic polymers are polyanionic materials formed by the conjugation of anionic moieties (A) to a linear non-carbohydrate polymer backbone (made up of a plurality of monomer units R), optionally through linking groups (X). The resultant polyanionic linear polymers have a weight range distribution of repeating units to give a desired median range of molecular weight distribution. Desirably, the median range of molecular weight distribution is from 1,000 to 1,000,000, preferably from 10,000 to 600,000.
The monomer unit R is preferably an amino or amide moiety, more preferably an amino acid moiety. A particularly preferred monomer unit is a lysine moiety. Poly-L-lysines having various molecular weight ranges are available commercially from Sigma Chemical Company.
The anionic moiety A can be linked to reactive side chain groups on the linear polymer backbone either directly or via a variety of functional linking groups X such as, but not limited to, esters, amides, ethers, thioethers, amines, ureas, thioureas, carbamates and carbonates.
The optional linking group X may also act as a spacer between the polymer and the anionic moiety A, and may consist of an alkyl chain (optionally substituted or branched), an alkoxy, polyalkoxy, alkylthio or polyalkylthio chain (optionally substituted), or an alkenyl, multiple alkenyl, alkynyl or multiple alkynyl chain (optionally substituted). Suitable spacer chains include groups of the formula —(CH
2
)
n
—Z—(CH
2
)
n
—, wherein Z is —CH
2
—, —CH═CH—, —C≡C—, —O— or —S—, and n is an integer of from 1 to 15.
Dendrimers are macromolecular highly branched compounds formed by reiterative reaction sequences starting from an initial, core molecule with successive layers or stages being added in successive “generations” to build up a three-dimensional, highly ordered polymeric compound. Dendrimers are characterised by the following features: I an initiator core(I) which may have one or more reactive sites and be point-like or of significant size so as to effect the final topology of the dendrimer; ii layers of branched repeating units (Z) attached to the initiator core; iii functional terminal groups (such as anionic moieties A) attached to the surface of the dendrimer, optionally through linking groups (such as linking groups X described above). The present invention uses dendritic structures as frameworks for the attachment of ionic moieties; the invention is not limited to the spherical dendrimers described in detail herein but can be based on any dendritic structure. The variety of dendrimers in both shape and constitution are well known to persons skilled in the art.
The preparation of dendrimers is well known, and is described by way of example in U.S. Pat. Nos. 4,289,872 and 4,410,688 (describing dendrimers based on layers of lysine units), as well as U.S. Pat. Nos. 4,507,466, 4,558,120, 4,568,737 and 4,587,329 (describing dendrimers based on other units including polyamidoamine or PAMAM dendrimers). The dendrimers disclosed in these US patents are described as being suitable for uses such as surface modifying agents, as metal chelating agents, as demulsifiers or oil/water emulsions, wet strength agents in the manufacture of paper, and as agents for modifying viscosity in aqueous formulations such as paints. It is also suggested in U.S. Pat. Nos. 4,289,872 and 4,410,688 that the dendrimers based on lysine units can be used as substrates for the preparation of pharmaceutical dosages.
International Patent Publications Nos. WO 88/01178, WO 88/01179 an

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