MXPA99000655A - Angiogeni inhibitors compounds - Google Patents

Abstract

A method of prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal patient comprises administering to the patient an effective amount of a compound selected from: (i) linear, non-carbohydrate polymers having a plurality of chain groups where at least one of the side chain groups has an anionic or cationic containing moiety linked or bonded thereto, and (ii) dendrimers having a plurality of terminal groups wherein at least one of the terminal groups in an anionic or cationic containing portion bound or bound to the same

Description

FIELD OF THE INVENTION This invention relates to compounds that are effective in the inhibition of angiogenesis and consequently can be used in place of sulfated polysaccharides such as heparin to prevent restenosis, accelerate the healing of wounds, and inhibit tumor cell metastasis. BACKGROUND OF THE INVENTION The use of sulfated polysaccharides for the inhibition of angiogenesis and in the treatment of disorders and conditions associated with angiogenesis has been previously described. Therefore, the International Patent Application NO. PCT / GB95 / 00515 (WO 95/24907), the content of which is incorporated herein by reference, deals with the use of heparin and other sulfated polysaccharides such as pentosan polysulfate and dextran sulfate in the treatment of these disorders and conditions and describes the use of another laminarin sulphate of sulfated polysaccharides, which exhibits only about 30% of the anticoagulant activity of heparin, to prevent restenosis by the inhibition of proliferation of vascular smooth muscle cells, to accelerate wound healing by activating the release of active growth factors stored in the extracellular matrix and to inhibit the metastasis of tumor cells by inhibiting heparanase activity. International Patent Application No. PCT / AU95 / 00350 (WO 95/34595) describes a class of antiviral compounds that comprise a dendrimer such as a polyamidoamine or polylysine dendrimer having a plurality of end groups, wherein at least one of the end groups has an anionic or cationic portion bound or bound thereto, particularly, a portion containing sulfonic acid, or containing carboxylic acid, or containing trimethyl ammonium. The present invention provides the use of polyionic materials formed by linking the ionic groups to a polymer, without carbohydrate, linear, or a dendritic polymer in the inhibition of angiogenesis and in the treatment of disorders and related conditions. CO MPENDIO OF I NVENTION In accordance with 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 administering to the patient 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 the side chain groups has an anionic or cationic containing moiety attached or bonded thereto; and (ii) dendrimers having a plurality of end groups in which at least one of said end groups has an anionic or cationic containing portion bound or bound thereto.

Particularly preferred compounds for use in the method of the present invention are linear polymers having sulfonic acid-containing portions, carboxylic acid-containing portions, phosphonic or phosphonic acid-containing portions, boronic acid-containing portions, neuraminic acid-containing portions or sialic or portions containing modified neuraminic or sialic acid in position 4 or other thereof, linked to the side chain groups thereof, and dendrimers having sulfonic acid-containing portions, portions containing carboxylic acid, portions containing acid phosphoric or phosphonic, portions containing boronic acid, portions containing neuraminic acid or portions containing neuraminic or modified sialic acid in position 4 or other thereof, linked to the terminal groups thereof. The compounds used in the method of this invention are referred to herein as linear polyionic polymers or polyionic dendrimers, respectively, and these terms are used throughout this specification and the following claims to include not only polymers or dendrimers by if not also their pharmaceutically or veterinarily acceptable salts, for example the alkali 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 monomer unit without carbohydrate that forms a structure of the linear polymer base; X is an optional ligation group on the side chain groups of the R monomer units; and A is a portion containing anionic; and (ii) polyionic dendrimers of general formula I I: where: I is the initiating nucleus; Z is an indoor branching unit; n is an integer representing the generation number of the dendrimer; and A is an anionic containing portion that can be attached to the branching unit Z through an optional linker group X. According to the present invention, the preferred linear polyionic polymers are polyanionic materials formed by the conjugation of portions (A) to a polymeric base structure without linear carbohydrate (formed of a plurality of units of monomers R), optionally through linking groups (X). The resulting polyanionic linear polymers have a weight scale distribution of repeating units to give a desired median scale of molecular weight distribution. Conveniently, the average scale of molecular weight distribution is from 1,000 to 1,000,000, preferably 10,000 to 600,000. The monomer unit R preferably is an amino or amide portion, more preferably an amino acid portion. . A particularly preferred monomer unit is a lysine moiety. Poly-L-lysines having various molecular weight scales are commercially available from Sigma Chemical Company. The anionic portion can be linked to the reactive side chain groups on the linear polymer structure, either directly or via a variety of functional (X) linkages such as, but not limited to, esters, amides, ethers, thioethers, amines , ureas, thioureas, cabamates and carbonates. The optional linking group X can also act as a spacer between the polymer and the anionic portion A, and can consist of an alkyl chain (optionally substituted or branched), an alkoxy, polyalkoxy, alkylthio or polyalkathio chain (optionally substituted, or a multiple alkenyl, multiple alkenyl, alkynyl or alkynyl chain (optionally substituted) Suitable stringer chains include groups of the formula (CH2) nZ- (CH2) n-, where Z is -CH2-, -CH = CH-, -C = C, -O- or -S-, and n is an integer from 1 to 15. The dendrimers they are highly branched macromolecular compounds formed by repetitive reaction sequences that start from an initial core molecule with successive layers or stages that are added in successive "generations" to accumulate a highly ordered three-dimensional polymeric compounds. The dendrimers are characterized by the following aspects: I an initiator nucleus (I) that can have one or more reactive sites and be similar to the point or have a significant size so as to effect the final dendrimer topology; ii layers of branched repeating units (Z) attached to the initiator core; iii functional terminal groups (such as anionic portions 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 frames for the attachment of ionic portions; The invention is not limited to spherical dendrimers described in detail herein, but may be based on any dendritic structure. The variety of dendrimers in both form and constitution are well known to those skilled in the art. The dendrimer preparation is well known and is described by way of example in the Patents of E. U.A. Nos. 4,289,872 and 4,410,688 (describing dendrimers based on layers of lysine units), as well as in the Patents of E. U.A. Nos. 4,507,466, 4, 558, 120, 4, 568,737 and 4,587, 329 (which describe dendrimers based on other units including polyamidoamine or PAMAM dendrimers). The dendrimers described in these patents of E.U.A. they are described as being suitable for uses such as surface modification agents, metal chelating agents, as demulsifiers or oil / water emulsions, moisture resistance agents in papermaking and as agents for modifying viscosity in aqueous formulations such as paintings. It is also suggested in the Patents of E. U.A. Nos. 4,289,872 and 4,410,688 that dendrimers based on lysine units can be used as substrates for the preparation of pharmaceutical doses. The International Patent Publications Nos. WO 88/01 178, WO 88/01 179 and WO 88/01 180 describe conjugates in which a dendrimer is conjugated or associated with another material such as a pharmaceutical or agricultural carrier material. Besides, the International Patent Publication No. WO 95/24221 discloses conjugates of dendritic polymers composed of at least one dendrimer in association with a carrier material which may be a biological response modifier and optionally a targeting agent. These patent publications together with the patents of E. U.A. mentioned above, contain a broad description of various dendrimers and processes for the preparation thereof and the description of each of these publications is incorporated herein by reference.

The term "dendrimer", as used herein, should be understood in its broadest sense and should include within its scope all forms and compositions of these dendrimers as described in Patent Publications Nos. WO 88/01 178, WO 88/01 179 and WO 88/01 180. The term also includes dotted or dotted dendrimers as described in these patent publications. Preferred dendrimers of the present invention comprise a polyvalent core covalently linked to at least two dendritic branches and preferably extending through at least two generations. Particularly preferred dendrimers are polyamidoamine dendrimers (PAMAM), PAMAM dendrimers (E DA) and polylysine dendrimers.

According to the present invention, at least one, and preferably a substantial number of the side chain groups on the linear polymer or end groups on the surface of the dendrimer, have an anionic or cationic portion covalently attached thereto. The side chains of the linear polymer or branches of the dendrimer can terminate into amino groups or other functional reactive groups such as OH, SH, or the like, which can be subsequently reacted with the anionic or cationic portions. Where the side chain groups of the l ineal polymer or terminal groups of the dendrimer are amine groups, the portion containing anionic or cationic can be linked to the dendrimer by a variety of functional groups which include amide and thiourea ligatures. Preferred anionic or cationic containing portions that can be attached to the side chain groups of the linear polymer or terminal groups of the dendrimer include sulfonic acid-containing portions, carboxylic acid-containing portions (including portions containing neuraminic and sialic acid and portions that they contain modified neuraminic and sialic acid) portions containing boronic acid, portions containing phosphoric and phosphonic acid (including portions containing esterified phosphoric or phosphonic acid) and portions containing trimethylammonium. Suitable anionic or cationic containing moieties which can be attached or linked to the amino or other side chain or terminal groups include, by way of example, the following groups (in which n is zero or a positive integer, more particularly n is zero or an integer from 1 to 20): • NH (CH2) nS? 3- - < CH2) nS03 '-Ar (S03) n -CH2CH (Ss3 ') COOH -CH (S03-) CH2COOH -ArX (CH2) nS? 3' X »O.S. NH + - (CH2) nNMe3-NMe3) n -Ar (CH5¡ e3) n OH . SO-jNa - ArXP (= 0) (OR) 2 x = 0, CH2, CHF, CF2 R = alkyl, aryl, H, Na ^ rXP (= 0) (OR) (NR2R3) x = 0, CH2, CHF, CF2 Realkyl, aryl, H, Na R2, Realkyl, aryl -Ar [P (= 0) (OR) 2] n R = alkyl, aryl, H, Na n = 1-3 - Ar [B (OH) 2] "n = 1.3 -Ar [COOH] n n = 1-3 In addition to the foregoing, various portions containing neuraminic or sialic acid or portions containing modified neuraminic or sialic acid can be attached or linked to the side chain or terminal groups according to this invention. These portions include the various substituted N and O-acyl derivatives of neuraminic acid, particularly N and O-acyl derivatives such as N-acetyl, O-acetyl N-glycolyl derivatives, as well as portions in which the Neuraminic acid, particularly by substitution at the 4-position, with an amino, amido, cyano, azido or guanidino group. The anionic or cationic dendrimer polymers of this invention can be prepared by the normal chemists that are well known to those skilled in the art. Suitable methods are described by way of example in the following examples. As previously described, it has been found that the linear anionic or cationic polymers and dendrimers of the present invention inhibit angiogenesis. Accordingly, the method of the present invention includes an inhibition of angiogenesis in a patient, treatment of conditions wherein the development of new blood vessels is involved such as chronic inflammation, diabetic retinopathy, psoriasis and rheumatoid arthritis, as well as treatment of disorders and conditions related, including, but not limited to, prevention of restenosis by inhibition of smooth muscle cell proliferation vascular, acceleration of wound healing by activation of the factors of the release of active growth factors stored in the extracellular matrix and the inhibition of cellular metastasis by inhibition of angiogenesis. Therefore, in another aspect the present invention provides a pharmaceutical or veterinary composition for the prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal patient, comprising a linear anionic or cationic polymer or dendrimer as amply described in with at least one veterinarily acceptable pharmaceutical diluent carrier. The formulation of said compositions is well known to the person skilled in the art. Suitable pharmaceutically acceptable carriers and / or diluents include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, sotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art and is described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA. Except that any conventional medium or agent is incompatible with the active ingredient, the use thereof in the pharmaceutical compositions herein invention is contemplated. The supplementary active ingredients can be incorporated into the compositions. It is especially advantageous to formulate compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unit doses for the human subjects to be treated; each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the vehicle and / or pharmaceutical diluent required. The specifications for the novel unit dose forms of the invention are dictated by, and directly depend on, (a) the unique characteristics of the active ingredient and the particular therapeutic effect that will be achieved, and (b) the limitations inherent in the technique of forming compounds such as the active ingredient for the particular treatment. In yet another aspect, this invention provides for the use of an effective amount of a linear anionic or cationic polymer or dendrimer as widely described above in the prophylactic or therapeutic treatment of, or the manufacture of, a medicament for the prophylactic or therapeutic treatment of a human patient or non-human animal by inhibition of angiogenesis. A variety of administration routes is available. The particular mode selected will depend, of course, on the particular condition that is being treated and the dose required to therapeutic efficacy. The methods of this invention, generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces therapeutic levels of the active component of the invention without causing clinically unacceptable adverse effects. Said modes of administration include oral, rectal, topical, nasal inhalation, transdermal or parenteral routes (e.g., subcutaneous, intramuscular and intravenous). Formulations for oral administration include discrete units such as capsules, tablets, troches and the like. Other routes include intrathecal administration directly into the spinal fluid, direct introduction such as by various catheter and balloon angioplasty devices well known to those of ordinary experience in the art and intraparenchymal injection in white areas. The compositions may conveniently be present in unit dosage form and may be prepared by any of the methods well known in the pharmacy art. Said methods include the step of carrying the active component in association with a vehicle that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately carrying the active component in association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

The compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, tablets or troches, each containing a predetermined amount of the active component, in liposomes or as a suspension in aqueous liquor or a non-aqueous liquid. such as a syrup, an elixir or an emulsion. Compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active component which is preferably isotonic with the blood of the recipient. This aqueous preparation can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution or a suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in polyethylene glycol. Among the vehicles and acceptable solvents that can be used is Ringer's solution and isotonic so chloride solution in the water. In addition, fixed sterile oils are conventionally employed as a solvent or suspension me. To this end, any soft fixed oil can be employed including synthetic di-glycerides. In addition, fatty acids such as oleic acid find their use in the preparation of injectables. The active component can also be formulated to be delivered in a system designed to administer the active component intranasally or by inhalation, for example as a finely dispersed aerosol spray containing the active component. Other delivery systems may include sustained release delivery systems. Preferred sustained release delivery systems are those that can provide release of the active component from release in pellets or sustained release capsules. Many types of sustained release delivery systems are available. These include, but are not limited to: (a) erosion systems in which the active component is contained within a matrix, and (b) diffusion systems in which the active component makes it permeable to a controlled regime through a polymer. In addition, a pump-based, hard-use supply system can be used, some of which are adapted per implant. The active component is administered in prophylactically or therapeutically effective amounts. A prophylactically or therapeutically effective amount means that the amount is at least partially necessary to obtain the desired effect to delay the onset of, inhibit the progression of, or alter everything, to the beginning or progression of the particular condition that is being treated. Said amounts, of course, will depend on the particular condition being treated, the severity of the condition and the patient's individual parameters, including age, physical condition, weight and current treatment. These factors are well known to Experts in the field and can be regulated with no more than routine experimentation. It is generally preferred that a maximum dose be used, that is, the most highly safe dose according to medical judgment. It will be understood by those skilled in the art, however, that a lower dose or tolerable dose may be administered for medical reasons, physiological reasons or virtually for any other reason. Generally, daily oral doses of the active component will be from about 0.01 mg / kg per day to 1000 mg / kg per day. Small doses (0.01-1 mg) can be administered initially, followed by increasing doses to approximately 1000 mg / kg per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses for a more localized, different delivery route) may be employed to the extent that patient tolerance allows. Multiple doses per day are contemplated to achieve the appropriate systemic levels of compounds. The active component according to the invention will also be presented for use in the form of veterinary compositions, which can be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for: (a) oral administration, external application, e.g., portions (e.g., aqueous or non-aqueous solutions or suspensions); tablets or bowls; powders, granules or pellets for mixing with food products; pastes for the application to the tongue; (b) parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. , as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat; (c) topical application, e.g. , as a cream, ointment or spray applied to the skin; or (d) intravaginal mind, v.gr. , like a pessary, cream or foam.

Throughout this specification and the following claims, unless the context otherwise requires, the word "comprises", or variations of said "comprise" or "comprising", shall be understood to imply the inclusion of an integer set or group of integers but not the exclusion of any other integer or group of integers. Additional aspects of the present invention will be apparent from the following Examples which are included by way of illustration, not as limitation of the invention. In the following Examples, PAMAM dendrimers refer to polyamidoamine dendrimers based on an ammonia core as detailed in the Patents of E.U.A. Nos. 4,507,466, 4,558, 120, 4,568, 737 and 4, 587, 329; PAMAM dendrimers (EDA) refer to polyamidoamine dendrimers based on a core ethylene diamine; and the BHAIysxlysylysz dendrimers refer to non-symmetric polylysine dendrimers based on a benzohydrylamine core and lysine branching units as described in U.S. Patents. Nos. 4,289,872 and 4,410,688. The polyamidoamine dendrimers PAMAM 1.0, PAMAM 2.0, PAMAM 3.0, PAMAM 4.0, PAMAM 5.0 or higher generation PAMAM 4.0 (EDA) and polylysine dendrimers BHAIysIys2, BHAIyslys2lys4, BHAIyslys2lys4lys8 and BHAIyslys2lys4lys8lys16, BHAIyslys2lys4lys8lySi6lys32, BHAIyslys2lys4lys8lys16lys32lys6 or higher generations prepared as described in US Patents. Nos. 4289872, 4410688, 4507466, 4558120, 4568737 and 4578239 and International Patent Publications Nos. WO 88/01178, WO 88/01179, WO 88/01180 and WO 95/24221 to which reference is made above. EXAMPLE 1 Reaction of dendritic polymers with 2-acrylamido-2-methyl propane sulfonic acid to give dendrimers terminated in Su ponic acid A. PAMAM 1.0 Solid sodium carbonate (0.13 g, 1.0 mmol) was added slowly to a stirred solution of acid 2. α-α-amido-2-methyl propane sulfonic acid (0.41 g, 2.0 mmol) in water (3 ml). After the evolution of gas ceased, the pH of the solution was 8.0. A solution of PAMAM 1.0 (0.12 g, 0.33 mmol) in water (1 ml) was then added to the solution followed by the addition of four drops of a solution 40% ac. Of benzyl trimethylammonium hydroxide. The solution was then heated under nitrogen at 60 ° C for three days and then concentrated. The residue was purified by gel filtration (Sephadex G10, water) and then freeze-dried to give the sulfonated PAMAM 1.0 dendrimer as an off-white solid (0.51 g). The nmr and 13 C nmr spectra showed a dialkylated or monoalkylated PAMAM 1.0 dendrimer mixture (approx. 70:30). rmn 13C (DzO): d 31.0, 31.1, 37.1, 37.7, 41.3, 48.6, 51.5, 53.1, 53.4, 55.6, 56.2, 61.2, 61.5, 178.3, 179.0, 179.8. PAMAM 2.0 PAMAM 2.0 was reacted with 2-acrylamido-2-methyl propane sulfonic acid as described above. The crude product was purified by gel filtration (Sephadex G10, water) and then freeze-dried to give an off-white solid. The 1H and 13C nmr spectra showed a dialkylated or monoalkylated PAMAM 2.0 dendrimer mixture (approx. 65:35). rmn 13C (D20): d 31.0, 31.1, 37.1, 37.7, 41.3, 48.7, 51.5, 53.4, 55.6, 56.2, 61.2, 61.5, 178.4, 179.0, 179.1, 179.6. When the above reaction was repeated omitting the benzyltrimethylammonium hydroxide a similar result was obtained. PAMAM 3.0 BR12783 PAMAM 3.0 was reacted with 2-acrylamido-2-methyl propane sulfonic acid as before, except that a slight excess of sodium carbonate was used and the benzyltrimethylammonium hydroxide was omitted. The 1H and 13C nmr spectra showed a dialmilled or monoalkylated PAMAM 3.0 dendrimer blend (approx. 50:50). rmn 13C (DzO): d 31.0, 31.1, 36.9, 37.4, 41.1, 48.6, 51.5, 53.4, 55.7, 56.2, 61.1, 61.5, 178.2, 179.0, 179.8. PAMAM 4.0 BR12784 PAMAM 4.0 was reacted with 2-acrylamido-2-methyl propane sulfonic acid as described for PAMAM 3.0. The nmr and 13 C nmr spectra showed a dialkylated or monoalkylated PAMAM 4.0 dendrimer mixture (approx. 35:65). rmn 13C (D20): d 31.0, 31.1, 36.9, 37.3, 41.1, 48.5, 51.5, 53.5, 55.7, 56.2, 61.1, 61.5, 178.1, 178.9, 179.0, 179.8. EXAMPLE 2 Preparation of dendrimers terminated in sodium sulphoacetamide A. PAMAM 1.0 A solution of 4-nitrophenyl bromoacetate (0.40 g, 1.5 mmol) in dry DMF (1 ml) was added to a stirred solution of PAMAM 1.0 (0.18 g; mmoles) in DMF (3 ml). The resulting yellow solution was stirred for 20 hours at room temperature, when a ninhydrin test was negative. The solution was concentrated (30 ° C / 0.1 mmHg) to give a yellow oil. This oil was divided between water and chloroform and the aqueous layer was separated and washed with chloroform (2X) and finally with ethyl acetate. The aqueous solution was concentrated (35 ° C / 25 mmHg) to give the bromoacetylated PAMAM 1.0 dendrimer as a yellow oil (0.36 g, 100%). nmR 13C (D20): d 32.8, 33.3, 43.0, 43.5, 54.4, 174.5, 176.4.

A solution of sodium sulfite (0.2 g, 1.6 mmol) in water (1 ml) was added to a bromoacetylated 1.0 PAMAM dendrimer solution described above (0.36 g, 0.5 mmol) in water (5 ml) and the solution was left Stand at room temperature for eleven days. The yellow solution was concentrated to give a yellow solid (0.60 g). rmn 13C (DzO): d 34.4, 43.1, 43.4, 54.0, 61.7, 171.3, 177.2.

The above reaction sequence could be carried out without isolating the bromoacetylated dendrimer simply by adding the sodium sulfite solution to the crude aqueous extract obtained from the first reaction. PAMAM 2.0 Method 1: A solution of 4-nitrophenyl bromoacetate (0.18 g, 0.7 mmol) in dry DMF (1 ml) was added to a stirred solution of PAMAM 2.0 (0.10 g, 0.1 mmol) in DMF (3 ml). The resulting yellow solution was stirred for 20 hours at room temperature, when a ninhydrin test was negative. The solution was added with stirring to water (150 ml) and the mixture was extracted with chloroform (3X) and ethyl acetate. A solution of sodium sulfite (0.1g, 0.8mmol) in water (1ml) was added to a solution of crude bromoacetylated dendrimer and the mixture was allowed to stand for three days at room temperature. The yellowish solution was then concentrated to give a yellow solid residue, which was purified by gel filtration (Sephadex LH20, water) to give the finished PAMAM 2.0 dendrimer of sodium sulphoacetamide (103 mg). RM 3C (D20): d 33. 0, 35.7, 36.0, 37.7, 40.3, 43.0, 43.2, 53.4, 53.7, 56.0, 61.6, 171.2, 174.6, 178.5. Method 2 Solid succinimidyl acetylthioacetate (67 mg, 0.33 mmol) was added to a solution of PAMAM 2.0 (52 mg, 0.05 mmol) in dry DMF (2 ml) and the resulting solution was stirred at room temperature for two days. The mixture was then concentrated (30 ° / 10'3 mmHg) to give an oily residue. The residue was partitioned between water and chloroform and the water layer was separated and concentrated to give a viscous oil (117 mg). rmn 1H and 13C showed that the oil is a mixture of acrylated dendrimer and N-hydroxy succinimide. Gel filtration (Sephadex G10, water) provides a pure sample of the finished PAMAM 2.0 dendrimer of acetylthioacetamide (29 mg). nmR 13C (D2O): d 34.0, 34.2, 37.3, 43.0, 43.1, 43.3, 53.5, 54.0, 56.3, 175.4, 177.2, 177.5. A solution of the dendrimer functionalized at 40% in aqueous formic acid (7 ml) was then added to an ice-cold freshly prepared solution of performic acid (1.6 mmol) in formic acid (2 ml). The mixture was stirred for 1 hour at 0 ° C and then for twenty hours at room temperature. A small amount of activated charcoal was then added to decompose any excess peracid, the mixture was stirred for 30 minutes and then filtered and concentrated to give a viscous oil.

The crude product was dissolved in water, the pH was adjusted to 9.10 with aqueous sodium bicarbonate and the material was desalted by passing it through a Sephadex G10 column. A white solid (10 mg) was obtained; after lyophilization that was spectroscopically essential that the same as the material obtained by method 1. nmr 13C (D20): d 33.0, 38.7, 42.9, 43.0, 43.1, 53.9, 54.3, 56.5, 61.6, 171.2, 176.4, 177.0 . EXAMPLE 3 Preparation of Dendrimer Finished in Sodium Sulfosuccinic Acid A PAMAM 1.0 Solid maleic anhydride (0.11 g, 1.1 mmol) was added to a stirred solution of PAMAM 1.0 (0.12 g, 0.33 mmol) in dry DMF (3 ml). The mixture warmed a little and turned brown as the ring dissolved and the resulting solution was stirred overnight at room temperature. The solution was then concentrated (30 ° / 10"4 mmHg) to give a viscous oil.The rmn of 1H and 13C (D20) showed complete conversion of PAMAM 1.0 to trisamide together with some of the maieic acid .mRn 13C (D20) : 33.1, 42.8, 43.1, 54.3, 135.0, 137.1, 169.1, 171.9, 173.3 The crude trisamide was then dissolved in water (4 ml) and sodium sulfite (0.20g, 1.6 mmol) was added. it was allowed to stand at room temperature for four days and then it was concentrated.The rmn of 1H and 13C (D20) showed some of the PAMAM dendrimers of 1: 1 terminated in sulfosuccinamic acid. regio-isomeric sodium along with some sulfosuccinic acid. AND! crude product was purified by gel filtration (Sephadex G10; water) to give a sample of the PAMAM 1.0 dendrimers terminated in sulfosuccinnamic acid (107 mg). rmn 13C (D20): d 33.3, 39.6, 40.0, 42.9, 43.1, 54.0, 67.9, 69.4, 173.8, 176.3, 177.6, 181 .8. B PAMAM 2.0 A mixture of PAMAM 2.0 dendrimers terminated in regio-isomeric sodium sulfosuccinic acid was prepared as described above. The maleamic acid derivative of rmn 3C PAMAM 2.0 (D20): d 32.8, 33.0, 38.7, 42.9, 53.8, 54.3, 56.5, 135.2, 136.8, 169.2, 171.9, 173.5, 174.6. Derivatives of sodium sulphosuccinic acid of PAMAM nmr 3C (DzO): d 37.0, 40.1, 41.1, 43.0, 43.2, 43.9, 53.0, 53.3, 55.5, 68.0, 69.4, 173.8, 177.6, 179.1, 179.5, 179.8, 182.3. C PAMAM 4.0 BRI6038 The solid maleic anhydride (60 mg, 0.6 mmol) was added to a stirred solution of PAMAM 4.0 (51 mg, 0.01 mmol) in dry DM F (2 mL). The mixture initially turned cloudy but soon gave a clear solution which was stirred overnight at room temperature. The solution was concentrated (35 ° / 10"4 mmHg) to give a viscous oil.The rmn 1 H and 13C (D20) showed the complete conversion of PAMAM 4.0 of the polyamide together with some maleic acid.The crude polyamide was dissolved Then in water (2 ml) and a solution of sodium sulfite (126 mg, 1.0 mmoles) in water (2 ml) was added.The resulting solution was allowed to stand at room temperature two days and then concentrated. The rnH of 1H and 13C (D20) showed a mixture of PAMAM 4.0 dendrimers terminated in sodium sulfosuccinamic regio-isomeric acid together with some sulfosuccinic acid. The crude product was purified by gel filtration (Sephadex LH20, water) to give a sample of finished PAMAM 4.0 with 24 groups of sulfosuccinnamic acid regio-isomers (90 mg). rmn 1 H (D 2 O): d 2.4-2.6; 2.7-3.1; 3.2-3.4; 3.9-4.0. nmr 13C (D20): d 36.2; 39.8; 40.5; 43.0; 43.2; 53.5; 55.8; 68.1; 69.5; 173.8; 177.4; 177.6; 178.7; 182.3. EXAMPLE 4 Preparation of dendrimers terminated in sodium N- (2-sulfoethyl-succinnamide a) Preparation of N- (2-sulfoethyl) succinamic tetrabutylammonium acid Solid succinic anhydride (0.5 g, 5.0 mmol) was added to a stirred solution of tetrabutylammonium acid 2- aminoethylsulfonic (1.83g, 5.0 moles) in dry dichloromethane (30 ml) The succinic anhydride was dissolved slowly and the resulting cloudy solution was stirred overnight at room temperature, the mixture was filtered and the filtrate was concentrated to give a viscous oil. (2.41 g) The 13 C rmn showed complete conversion to the desired monoamide together with a small amount of succinic acid Repeated precipitation of the product by drip addition of a dichloromethane solution to a large excess of diethyl ether to give tetrabutylammonium acid N- (2-sulfoethyl) succinnamic as a white solid (1762 g, 76%), mp 125-127 ° C. 1H NMR (CDCl3): d 0.86 (t, 12h, 4xCH3), 1.28 (m, 8H, 4xCH2), 1.50 (m, 8H, 4xCH2), 2.33 (m, 2H, CH2COOH), 2.44 (m, 2H, CH2CONH ), 2.76 (m, 2H, CH2NHCO), 3.12 (m, 8H, 4xCH2N), 3.50 (m, 2H, CH2S03), 7.53 (br, t, 1H, NH). rmn 13C (CDCl 3): d 13.5, 19.5, 23.8, 30.1, 30.9, 35.6, 50.0, 58.5, 172.0, 174.1. b. Preparation of tetrabutylammonium 4-nitrophenyl N- (sulfoethyl) succinamate To a solution of dicyclohexylcarbodiimide (45 mg, 0.22 mmol) in dry dichloromethane (1 ml) was added to a stirred solution of N- (2-suiphenyl) succinamic tetrabutylammonium acid ( 94 mg, 0.20 mmol) in dichloromethane (2 ml) and the mixture was stirred overnight at room temperature. The resulting suspension was filtered and the filtrate was concentrated to give the crude active ester, which was used without further purification. A Preparation of PAMAM dendrimers terminated in sodium N- (2-sulfoethyl) succinamide. PAMAM 4.0 BR12786 A solution of crude tetrabutylammonium 4-nitrophenyl N- (2-sulfoethyl) succinamate (0.30 mmol) in dry DMF (1 ml) was added to a stirred solution of PAMAM 4.0 (51.5 mg, 0.01 mmol) dissolved in 50 ml. % aqueous DMF (3 ml) and the resulting yellow solution was stirred overnight at room temperature. The mixture was then concentrated (35 ° / 10"s mmHg) and the yellow residue was partitioned between water and chloroform.The water layer was separated, washed with chloroform (2X) and the ethyl acetate then concentrated to give a yellow oil (134 mg). The crude product was converted to the sodium salt by passing it through a column of Amberlite IR 120 (Na) to give 85 mg of material. This material was further purified by gel filtration (Sephadex LH20, water) to give the PAMAM 4.0 dendrimer terminated in N- (2-sulfoethyl) succinamide sodium (45 mg). rmn 13C (D20): d 33.2, 33.6, 35.5, 39.0, 39.5, 42.8, 43.2, 53.8, 54.1, 54.4, 56.6, 176.5, 176.9, 177.2, 178.9, 179.4. The corresponding dendrimers of PAMAM 1.0 and PAMAM 3.0 (BR12785) terminated with the sodium N- (2-sulfoethyl) succinamide groups are prepared in a similar manner. rm of 13C of PAMAM derivative (D20): d 33.4, 35.5, 39.0, 39.5, 42.9, 43.2, 53.8, 54.1, 54.3, 56.5, 176.4, 176.9, 177.4, 178.9, 179.4. 3M rmn of PAMAM derivative (D20): d 34.9, 35.5, 39.5, 42.9, 43.1, 53.7, 54.1, 179.0, 179.1, 179.3. B. Preparation of polylysine dendrimers terminated in sodium N- (2-sulfoethyl) succinamide. BHAIyslys2lys4lys8lys 6 BR12789 Trifluoroacetic acid (1 ml) was added to a suspension of BHAIyslys2lys4lys8DBL16 (36.5 mg, 5.0μmol) in dry dichloromethane (1ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in dry DMSO (2 ml) and the pH adjusted to 8.5 with triethylamine. A solution of 4-nitrophenyl N- (2-sulfoethyl) succinamate of tetrabutylammonium (approx., 0.2 mmol) in DMSO (1 ml) was then added dropwise and the mixture was stirred overnight at room temperature. The yellow solution was then concentrated (50 ° / 10"s mmHg) and the yellow residue was partitioned between water and chloroform.The aqueous layer was separated, washed with chloroform (3X) and ethyl acetate, and then concentrated to give an oil (99 mg) The crude product was converted to the sodium salt by passing it through a column of Amberlite IR 120 (Na) to give 81 mg of the material.This material was further purified by gel filtration (Sephadex LH20; water) to give the dendrimer BHAIysIys2lys lys8lys16 terminated in sodium N- (2-sulfoethyl) succinimide (39 mg) rmn 13C (D20) d 27.0, 32.3, . 2, 35.3, 35.6, 35.7, 39.5, 43.5, 54.1, 58.5, 131.5, 132.0, 133.3, 145. 1, 177.8, 178.0, 178.4, 178.8, 178.9, 179.2, 179.7, 179.8. The corresponding BHAIyslys2, BHAIyslys2lys4, (BRI2787) BHAIyslys2lys4iys8 (BRI2788), terminated in sodium N- (sulfoethyl) succinamide groups were prepared in a similar manner. 13C rmn of derivative of BHAIyslys2lys4lys8 (D20) d 26.9, 32. 3, 35.1, 35.3, 35.6, 35.7, 39.5, 43.5, 54.1, 58.5, 131.6, 131.9, 132. 2, 132.3, 133.2, 133.3, 145.0, 145.2, 177.2, 177.8, 177.9, 178.0, 178.0, 178.2, 178.3, 178.6, 178.6, 178.7, 178.8, 178.9, 179.2, 179.3, 179.2, 179.8. 13C rmn of derivative of BHAIyslys2lys4 (D20): d 26.9, 32.3, 35.1, 35.4, 35.7, 35.8, 39.5, 43.5, 54.1, 58.5, 61.8, 131.7, 132.2, 132. 3, 133.2, 133.3, 145.0, 145.1, 177.3, 178.0, 178.3, 178.4, 178.7, 178.9, 179.0, 179.3, 179.7, 179.8. rn of 13C of BHAIyslys2 (D20): d 26.9, 27.1, 32.2, 32.3, 34.7, 34.8, 35.1, 35.3, 35.6, 35.7, 39.5, 43.4, 54.1, 58.6, 61.8, 131.7, 131.9, 132.2, 132.3, 133.3, 144.9, 145.0, 177.7, 178.4, 178.8, 179.0, 179.3, 180.0. EXAMPLE 5 Preparation of Dendrimers Terminated in Sodium Sulfophenylthiourea A PAMAM 4.0 BRI2791 A solid sodium 4-sufophenylisothiocyanate monohydrate (500 mg, 1.96 mmol) was added to a solution of PAMAM 4.0 (300 mg, 0.0582 mmol) in water (10 ml). ) and the resulting solution was heated under nitrogen at 53 ° for two hours and then cooled. The solution was concentrated and the yellow solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined and freeze-dried to give the PAMAM 4.0 dendrimer terminated in sodium 4-sulfophenylthiourea as a fluffy white solid (370 mg). rmn 1H (D20): d 2.28; 2.52; 2.69; 3.15; 3,237; 3.60; 7.32 (d, J = 9Hz); 7.72 (d, J = 9Hz). rmn 13C (D20): d 36.9; 41.1; 43.1; 48.3; 53.6; 55.8; 129.0; 131.1; 144.4; 178.5; 179.1; 184.4. The dendrimers of PAMAM 1.0, PAMAM 2.0 (BRI2790), PAMAM 3.0 and PAMAM 5.0 (BRI2991) correspondingly terminated with 3, 6, 12, and 48 sodium 4-sulfophenylthiourea groups respectively were prepared in a similar manner. B. PAMAM 4.0 (EDA) BRI6045 Sodium 4-sulfophenylisothiocyanate monohydrate (130 mg, 0.5 mmol) was added to a solution of PAMAM 4.0 (EDA) (69 mg, 0.01 mmol) in water (4 ml) and the resulting solution was heated under nitrogen at 53 ° C. for 2 hours and then cooled. The solution was concentrated and the solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined and freeze-dried to give PAMAM 4.0 terminated with 32 sodium 4-sulfophenylthiourea groups as a flabby white solid (136 mg). rmn 1H (D20): d 2.30; 2.50; 2.70; 3.18; 3.62; 7.35 (d, J = 9Hz); 7.72 (d, J = 9Hz). nmr 13C (D 2 O): d 36.8, 41.0, 43.1, 48.4; 53.6; 55.7; 128.9; 131.0; 144.3; 178.5; 179.0; 184.5. C BHAIyslys2lys4lys8lys16 BRI2792 Trifluoroacetic acid (4ml) was added to a suspension of BHAIyslys2lys lys8lys16 (0.73g, 0.1 mmol) in dry dichloromethane (4 ml) under nitrogen. A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution was passed through a column of Amberlite IRA-401 (OH) and the filtrate was concentrated to give BHAIyslys2lys4lys8lys16 as a viscous oil (0.49 g). The oil was redissolved in water (5 ml) and a buffer solution of N, N-dimethyl-N-allylamine (pH 9.5, 3 ml) was added. Sodium 4-sulfophenylisothiocyanate monohydrate (1.30 g, 5.1 mmol) was then added and the resulting solution was heated under nitrogen at 53 ° C for two hours and then cooled. The solution is concentrated and the residue was solid coffee was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined, passed through a column of Amberlite IR 120 (Na) and freeze dried to give the dendrimer of BHAIysIys2lys4lys8lys16 terminated in sodium 4-sulfophenylthiourea as a fluffy white solid (375mg). rmn 1H (DzO): d 1.40; 1.72; 3.08; 3.42; 4.24; 4.60; 7.30 7.40 (d, J = 9Hz); 7.78 (d, J = 9Hz). nmr 13C (D2O): d 27.3; 32.5; 35.9 43.7; 48.9; 58.6; 63.3; 128.8; 131.0; 143.7; 144.7; 145.1; 177.7 178.1; 183.8; 185.2. The dendrimers BHAIyslys2lys4lysslys16lys32 (BRI2992) and BHAIyslys2lys4lys8lys16lys32lys6 (BRI2993) correspondingly terminated in 16, 64 and 68 sodium 4-sulfophenylthiourea groups respectively were prepared in a similar manner. EXAMPLE 6 Preparation of dendrimers terminated in sodium 3,6-disulfonaphthyl thiourea A PAMAM 4.0 BRI2923 3,6-Disulfonaphthyl isothiocyanate (160 mg, 0.41 mmol) was added to a solution of PAMAM 4.0 (51 mg, 0.01 mmol) in water (3 ml) and the resulting solution was heated under nitrogen at 53 ° for two hours and then cooled. The solution was concentrated and the brown solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined and concentrated to give the PAMAM 4.0 dendrimer terminated in sodium 3,6-disulfanaphthyl thiourea as a brown solid (73 mg). rmn 1H (D20): d 2.30; 2.60; 2.74; 3. twenty; 3.57; 7.75; 7.86; 8.28. rmn 13C (D20): d 35.0; 39.9; 43.1; 48.1; 53.8; 56.1; 128.4; 128.6; 129.3; 131 .0; 131 .3; 136.0; 136.8; 138.2; 145.5; 146.0; 177.2; 177.8; 185.5. The corresponding PAMAM 2.0 dendrimer terminated with 3,6-disulfonaphthylthiourea groups was prepared in a similar manner. B PAMAM 4.0 (EDA) BRI6046 Solid sodium 3,6-dihydrophenylisothiocyanate (220 mg, 0.67 mmol) was added to a solution of PAMAM 4.0 (EDA) (74 mg, 0.01 mmol) in water (4 ml) and the resulting solution heated under nitrogen at 53 ° for two hours and then cooled. The solution was concentrated and the brown solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined and concentrated to give finished PAMAM 4.0 with sodium 3,6-disulfonaphthyl thiourea groups as a tan solid (148 mg). rmn 1 H (D20): d 2.30; 2.80; 3.20; 3.54; 7.74; 7.85; 8.25. rmn 13C (D20): d 36.0; 40.8; 43.1; 48.3; 53.6; 55.9; 128.5; 129.4; 131 .0; 131 .3; 136.0; 136.8; 138.3; 145.5; 146.0; 178.2; 185.6. C B HAIyslys2lys4lys8lys 16 BRI2999 Trifluoroacetic acid (2ml) was added to a suspension of BHAIyslys2lys lys8DBL? 6 (0.73g, 0.01 mmol) in dry dichloromethane (2 ml) under nitrogen. A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution was passed through a column of Amberlite I RA-401 (OH) and the filtrate was filtered. concentrated to give BHAIyslys2lys4lys8lys16 as a viscous oil. The oil was redissolved in water (5 ml) and a buffer solution of N, N-dimethy-N-allylamine (pH 9.5, 3 ml) was added. Then, solid sodium 3,6-disulfonaphthylisothiocyanate (2.34 mg) 0.60 mol) was added and the resulting solution was heated under nitrogen at 53 ° for two hours and then cooled. The solution was concentrated and the brown solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined, passed through a column of Amberlite IR 120 (Na) and freeze-dried to give BHAiyslys2lys4lys8lys16 terminated in 32 sodium 3,6-disulfonaphthylthiourea groups as a flabby off-white solid (119 mg). rmn 1H (D20): d 1.0-2.0; 3.18; 3.43, 4.31; 7.22; 7.80; 7.89; 8.25. rmn 13C (D20): d 27.2; 32.4; 35.3; 43.7; 49.0; 58.5; 63.6; 128.4; 129.1; 131.4; 136.1; 136.6; 138.6; 139.0; 145.1; 145.6; 178.4; 184.8; 186.7. EXAMPLE 7 Preparation of finished dendrimers of sodium 4-sulfonaphthylthiourea PAMAM 4.0 BRI2997 Sodium 4-sulfonaphthyl isothiocinate (180 mg, 0.5 mmol) was added to a solution of PAMAM 4.0 (51 mg, 0.01 mmol) in water (5 ml) and the The mixture was heated under nitrogen at 53 ° C for two hours and then cooled. The water was distilled under reduced pressure from the resulting suspension and the off-white solid residue was purified by gel filtration (Sephadex LH20, water). The pure fractions are combined and freeze-dried to give the PAMAM 4.0 dendrimer terminated in sodium 4-sulfonaphthylthiourea as a solid flabby bank (60 mg). rmn 1H (D20): d 2.20; 2.60; 3.14; 3.48; 7.23; 7.47; 7.56; 7.77; 7.93 (d, J = 6Hz); 8.56 (d, J = 6Hz). nmr 13C (DzO): d 35.8, 40.5; 43.1, 48.4; 53.6; 55.9; 127.6, 128.6; J30-3; 131.9; 132.5; 133.5; 134.7; 140.5; 142.7; 177.8; 178.0; 185.4. EXAMPLE 8 Preparation of dendrimers terminated in sodium 3,5-disulfonphenylthiourea PAMAM 4.0 BRI6039 Solid sodium 3,5-disulfophenylisothiocyanate (110mg; 0. 32 mmoles) was added to a solution of PAMAM 4.0 (63 mg, 0.012 mmol) in water (3 ml) and the resulting solution was heated under nitrogen to water. 53 ° for two hours and then cooled. The solution was concentrated and the brown solid residue was purified by gel filtration (Sephadex G25; Water). The pure fractions were combined and concentrated to give finished PAMAM 4.0 with 24 groups of sodium 3,5-disulfophenylthiourea as an off-white solid (110 mg). rmn 1H (D20): d 2.53; 3.08; 3.36; 3.66; 7.90, 7.95. nmr 13C (DzO): d 34.8; 41.0; 43.1; 48.0; 53.7, 56.2; 124.1; 128.6; 143.5; 148.8; 177.6; 185. 0. EXAMPLE 9 Preparation of dendrimers terminated in 3,6,8-trisulfonaphthylthiourea sodium PAMAM 4.0 BRI2998 Solid sodium 3,6,8-trisulfonaphthylisothiocyanate (250 mg, 0.5 mmol) was added to a solution of PAMAM 4.0 (51 mg, 0.01 mmol) and N, N-dimethyl-N-allylamine buffer (pH 9.5; ml) in water (2 ml) and the mixture was heated under nitrogen at 53 ° for two hours and then cooled. The mixture was concentrated under reduced pressure to give an orange solid. The residual solid was dissolved in water (2 ml) and passed through a short column of Amberlite IR-120 (Na). The filtrate was then concentrated and the residue was purified by gel filtration (Sephadex LH20, water). The pure fractions were combined and freeze-dried to give the PAMAM 4.0 dendrimer terminated in 3,6,8-trisuI-phalonaphthylthiourea sodium as an off-white solid (102 mg). rmn 1H (DzO): d 2.65; 3.02; 3.30; 3.66; 8.05; 8.42; 8.59; 8.67. nmr 13C (D20): d 33.2; 38.7; 43.2; 43.7; 47.8; 54.0; 54.3; 56.7; 131.0, 131.3; 131.9; 135.9; 138.0; 139.6; 143.8; 144.1; 145.6; 176.2; 176.5; 186.0. EXAMPLE 10 Preparation of dendrimers terminated in sodium 4- (sulfomethyl) benzamide PAMAM 4.0 BRI6040 Solid 4-nitrophenyl 4- (chloromethyl) benzoate (200 mg, 0.68 mmol) was added to a stirred solution of PAMAM 4.0 (70 mg, 0.014). mmoles) in dry DMSO (4ml) and the resulting yellow solution was stirred at room temperature for two hours. The solution was concentrated (10"4 mmHg, 40 °) and the residue was extracted with the mixture of water and dichloromethane (1: 1) .The remaining solid material was dissolved in DMSO (5ml) and a solution of sodium sulfite (130 mg, I mmoles) in water (3ml) was added. The resulting slightly cloudy mixture was allowed to stand for four days, after which time the addition of more water (2 ml) resulted in the formation of a clear homogenous yellow solution. The solution was then concentrated, first at 25 mmHg and 40 ° then at 10"4 mmHg and 50 ° to give the crude product.The crude product was purified by gel filtration (Sephadex G25, water) to give PAMAM 4.0 finished with 24 groups of sodium 4- (sulfomethyl) benzamide (24 mg), rmn 1 H (D20): d 2.25, 2.66, 3.08, 3.20, 3.33, 3.38, 4.01, 7.40 (br d), 7.62 (br d). 13C (D20): d 36.7; 40.9; 43.0; 43.6; 53.5; 55.5; 61.0; 131.6; 135.0; 137.2; 140.4; 174.5; 178.6; 179.2 EXAMPLE 1 1 Preparation of thermionized dendrimers in 4-su lfobenzamide PAMAM 4.0 (EDA) BRI61 16 Solid potassium N-hydroxysuccinimidyl-4-sulfobenzoate (100 mg, 0.3 mmol) was added to a solution of PAMAM 4.0 (EDA) (35 mg, 0.005 mmol) in 0.1 M borate buffer solution. pH 8.5 (5ml) and the solution was stirred at room temperature for two hours.The milky solution resulting in this step had a pH of 4.5.The 1M sodium carbonate solution (1ml) was then added to give a solution. transparent n that the solid product as a white solid concentrated. The crude product was purified by gel filtration (Sephadex G25, water) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfobenzamide groups (47mg). rmn 1H (D20): d 2.25; 2.42; 2.63; 3.05; 3.18; 3.31; 3.38; 7.72 (d, J = 8Hz); 7. 78 (d, J = 8Hz). rmn 13C (D20): d 36.0; 40.4; 43.0; 43.7; 53.7; 55.8; 130. 2; 132.2; 140.4; 150.1; 173.6; 178.0; 178.5. EXAMPLE 12 Preparation of Sodium N- (4-sulfophenyl) propanamide-terminated dendrimers: PAMAM 4.0 (EDA) BRI6117 Solid sodium N- (4-sulfophenyl) acrylamide (250 mg, 1 mmol) and sodium carbonate were added. solid (106 mg, Immoles) successively to a stirred solution of PAMAM 4.0 (EDA) (78 mg; 0. 011 mmol) in water (4ml). The resulting solution was stirred under nitrogen for four days and then freeze dried to give a flabby white solid. The crude product was purified by gel filtration (Sephadex LH20, water) to give PAMAM 4.0 (EDA) terminated with 64 groups of sodium N- (4-sulfophenyl) propioamide (206 mg). The 13C NMR showed small traces of what was taken as the monoalkylated amino groups. rmn 1H (D20): d 2.10; 2. 48; 2.58; 2.79; 3.20; 7.42 (d, J = 7Hz); 7.65 (d, J = 7Hz). rmn 13C (DzO): d 36.5; 37.9, 41.1; 53.4; 55.6; 124.8; 130.9; 143.0; 144.2; 177.4; 178.5. EXAMPLE 13 Preparation of dendrimers terminated in 4-sulfophenylurea of Sodium PAMAM 4.0 (EDA) BRI6115 A solution of sodium sulphanilic acid (195 mg, 1 mmol) in dry DMSO (3 ml) was added dropwise to a solution of N, N'-disucinimidyl carbonate (530 mg, 2 mmol) in dry DMSO (4 ml). and the resulting coffee solution was stirred at room temperature for 20 hours. A solution of PAMAM (4.0) (EDA) (75 mg, 0.011 mmol) in dry DMSO (1 ml) was added and the solution was stirred for 18 hours. The solution was concentrated under high vacuum (10"5 mmHg, 35 °) to give a yellow semi-solid The crude product was dissolved in DMSO (4 ml) and the solution was added to 200 ml of well-stirred ethyl acetate. White precipitated solid was recovered by filtration and washed with ethyl acetate (2X) and ether (2X), then dried to give a white powder (275 mg) This material was then purified by gel filtration (Sephadex LH20; ) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfophenylurea groups (106 mg), rmn 1H (D20): d 2.31, 2.55, 2.75, 3.19, 7.32 (d, J = 9Hz), 7.63 (d) , J = 9Hz) .mRn 13C (D20): d 36.3; 40.7; 43.3; 43.8; 53.7; 55.7; 123.3; 130.9; 140.9; 146.0; 161.4; 178.2; 178.6 EXAMPLE 14 Preparation of dendrimers terminated in N-chloride, N, N-trimethylglycinamide BHAIyslys2lys4lys8 BRI2922 Trifluoroacetic acid (4ml) was added to a suspension of BHAIyslys2lys4lys8lys16 (220mg; 30μl) in dry dichloromethane (2ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated. The residue dissolved in Dry DMSO (5 ml) and the pH was adjusted to 8.5 with triethylamine. Sodium 4-nitrophenyl N, N, N-trimethylglycinate chloride (0.50 g, 1.8 mmol) was then added and the mixture was stirred overnight at room temperature. The nebulous solution was then concentrated (50 ° / 10"mm Hg) and the residue was partitioned between water and dichloromethane.The aqueous layer was separated, washed with dichloromethane (3X) and ethyl acetate and then concentrated to give an oil (1.128g) The crude product was purified by gel filtration (Sephadex LH20; water) to give the dendrimer of BHAIyslys2lys4lys8lys1s terminated in N, N, N-trimethylglycinamide (116 mg), rmn 13C (D20): d 25.5, 30.5 , 30.8, 33.4, 42.1, 56.5, 57.1, 67.5, 68.1, 166.7, 167.0, 167.1, 176.0, 176.2 EXAMPLE 15 Preparation of Dendrimers of 4-Trimethylammoniobenzamide PAMAM 4.0 BRI6043 Added 1, 1'-Carbonyldiimidazole (85 mg, 0.52 mmoles) was added to a solution of trimethylammoniobenzoic acid iodide (154 mg, O.dmmoles) in dry DMF (4 ml) and the mixture was stirred at room temperature under argon for two hours, during which time a white solid separated from the solution. A solution of PAMAM 4.0 (58 mg, 0.011 mmol) in dry DMF (2 ml) was added and the The mixture was stirred overnight at room temperature. After this time most of the precipitate dissolved and a ninhydrin test of the solution was negative. The mixture was concentrated (10 * 4 mmHg, 30 °) to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; 10% AcOH) to give PAMAM 4.0 finished with 24 groups of 4-trimethylammoniobenzamide as the acetic acid salt (89 mg). rmn 1H (D20): d 1.96; 2.65-2.85; 3.25-3.55; 3.64; 7.92. rmn 13C (D20): d 25.8; 33.1; 33.5; 38.7; 43.1; 43.5; 53.5; 54.1; 56.4; 61.2; 124.8; 133.6; 139.9; 153.2; 173.2; 176.3; 176.8; 182.6. The corresponding PAMAM 2.0 dendrimer terminated with 6 groups of 4-trimethylammoniobenzamide was prepared in a similar manner. EXAMPLE 16 Preparation of finished dendrimers of 4- (T rimet Mamon i ometil) benzamide PAMAM 4.0 BRI6044 Solid 4-nitrophenyl 4- (chloromethyl) benzoate was added (150 mg, 0.5 mmol) to a stirred solution of PAMAM 4.0 (52 mg, 0.01 mmol) in dry DMSO (3 mL). The resulting yellow solution was stirred at room temperature for 20 hours, when the ninhydrin test was negative (pH each 8.5). The solution was then concentrated (10"smmHg, 40 °) and the residue was stirred with a mixture of water and dichloromethane (1: 1). The insoluble gel-like material was recovered by filtration, washed with water (2X) and dichloromethane (2X) and then dried with air The dendrimer terminated in crude 4- (chloromethyl) -banzamide was dissolved in 25% aqueous trimethylamine (20 ml) and the yellow solution was allowed to stand overnight. concentrated, the residue was dissolved in water (5 ml) and the solution was passed through a column of Amberlite IRA-401 (OH) The colorless filtrate was concentrated to a viscous oil which was purified by gel filtration (Sephadex G10; 10% AcOH) to give PAMAM 4.0 finished with 24 groups of 4- (tpmethylammoniomethyl) benzamide (90 mg). rmn 1H (D20): d 1.88; 2.65-2.80; 2.98; 3.10-3.60; 7.52 (br d, J = 9 Hz); 7.72 (br d, J = 9 Hz). nmr 13C (D20): d 26.6, 33.4; 38.8; 43.2; 43.5; 53.6; 53.6; 54.1; 56.8; 62.8; 73.0; 132.1; 135.3; 137.5; 140.0; 176.4; 176.9; 183.6. EXAMPLE 17 Preparation of dendrimers terminated in N- (2-Acetoxyethyl) -N, N- (dimethylammonium) m ethylcarboxamide PAMAM 4.0 Solid 1,1'-carbonyldiimidazole (85 mg, 0.52 mmol) was added to a solution of bromide. N- (2-acetoxyethyl) -N- (carboxymethyl) -N, N-dimethylammonium (135 mg, O.dmmoles) in dry DMF (3 ml) and the resulting solution was stirred under nitrogen for two hours. A solution of PAMAM 4.0 (60 mg, 0.012 mmol) in DMF (2 ml) was then added, which caused the immediate formation of a flocculent precipitate that slowly redissolved. The mixture was stirred for two days and then concentrated (10"4mmHg, 40 °) to give a viscous oil.The crude product was purified by gel filtration (Sephadex G10; 10% AcOH) to give PAMAM 4.0 finished with 24 groups N- (2-Acetoxyethyl) -N, N- (dimethylammonium) methylcarboxyamide (64mg) rmn 1H (D20): d 1.93, 2.05; 2.70; 3.10-3.60; 3.28; 3.93 (m); 4.14; 4.48 (m) ) rmn 13C (D20): 24.6, 26.2, 33.2, 38.7, 42.8, 42.9, 53.9, 57.4, 62.6, 67.3, 67.5, 168.9, 176.4, 176.8, 177.3, 183.2.

EXAMPLE 18 Preparation of Guanidino-terminated dendrimers PAMAM 4.0 BRI6042 A solution of PAMAM 4.0 (63 mg, 0.012 mmol) and methylthiopseudourea sulfate (170 mg, 0.61 mmol) in water (5 mL) (pH 10.5) was heated under nitrogen to 80 ° C for two hours. The solution was then concentrated and the residue was purified by gel filtration (Sephadex G10; 10% AcOH) to give finished PAMAM 4.0 with 24 guanidino groups as acetate salt (107mg). rmn 1H (D20): d 2.00; 2.80 (br t), 3.09 (br t), 3.32; 3.45 (br t); 3.60 (br t). nmr 13C (D20): d 25.2; 33.2; 33.4; 38.7; 41.2; 42.6; 43.4; 44.7; 53.5; 54.0; 56.3; 176.7; 176.9; 181.6. The corresponding PAMAM 2.0 dendrimer terminated with 6 guanidino groups was prepared in a similar manner. EXAMPLE 19 Preparation of dendrimers terminated in 4 - ([1,4,8-11-tetraazaci c otetra deca no] meti I) benzamide PAMAM 4.0 BRI6041 A solution of tetrahydrochloride of 1- (4-carboxyphenyl) methyl-1, 4,8,11-tetraazacycotetradecane (120mg, 0.25mmol), N-hydroxysuccinimide (60mg, 0.52mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250mg, 1.3mmol) in phosphate buffer pH 7 (10ml) was allowed to stand at room temperature for one hour and then a solution of PAMAM 4.0 (32mg, O.OOdmmoles) in buffer solution was added. of phosphate pH 7 (10ml). The mixture was allowed to stand for two days and then concentrated. The residue was purified by gel filtration (Sephadex LH20; 10% AcOH) to give PAMAM 4.0 finished with each. 12 groups of 4 - ([1, 4,8,11-tetraazacyclotetradecane] methyl) -benzamide as determined by rmn of 1H and 13C (80mg). The product was then dissolved in water and passed through a column of Amberlite IRA-401 (Cl) and then concentrated. The residue was dissolved in water (1 ml), concentrated HCl (1 ml) was added and the solution was diluted with ethanol (30 ml) to precipitate a solid bench. The solid was recovered by filtration (68 mg). Again the rmn of 1H and 13C showed a functionalization of almost 50% of the terminal amino groups, rmn 1H (D20): d 2.17; 2.36; 2.50; 2.78; 2.85; 3.25; 3.40; 3. fifty; 3.60; 3.62; 4.49; 7.63 (br d); 7.78 (br d). rmn 13C (D20): d 22.7; 23. 1; 33.2; 38.8; 39.9; 40.2; 40.3; 41.0, 41.2; 42.0; 42.9; 43.2; 43.6; 45.5; 46.1; 49.1; 52.2; 53.9; 54.3; 56.6; 62.7; 132.5; 135.7; 137.1; 139. 7; 174.3; 176.2; 176.3; 176.7; 177.0; 178.2; 178.5. EXAMPLE 20 Preparation of dendrimers terminated in 4-Carboxy-3-hydroxybenzylamine PAMAM 4.0 (EDA) BRI6119 Sodium cyanoborohydride (32 mg, O.dmmoles) was added to a mixture of PAMAM 4.0 (EDA) (69mg, O.OImmoles), acid 4-formyl-2-hydroxybenzoic acid (83mg, 0.5mmol) and sodium hydrogen carbonate (42mg, O.dmmoles) in water (4ml). The inhomogeneous orange mixture was stirred for four hours at room temperature, during that time it became homogeneous. The orange solution was then concentrated and the residue was purified by gel filtration (Sephadex LH20, water) to give PAMAM 4.0 (EDA) terminated with ca. 32 groups of 4-carboxy-3-hydroxybenzylamine (91mg). The rnH of 1H and 13C (D20) shows almost all mono alkylation but with some signs of dialkylation of the amino terminal groups, but the spectrum showed broad peaks, nmr 13C (D20): d 37.0; 41.1; 50.9; 53.4; 55.5; 55.8; 61.5; Í20.9; 122.2; 122.4; 132.3; 132.7; 135.0; 135.8; 163.5; 163.7, 169.0; 178.6; 179.3. rmn 1H (D20): d 2.20; 2.35; 2.60; 3.15; 3.30; 3.55, 4.25; 6.68; 7.12; 7.55. EXAMPLE 21 Preparation of finished dendrimers of 4-Carboxyphenylamine PAMAM 4.0 (EDA) Solid 4-carboxyphenylisothiocyanate (86 mg, 0.48 mmol) was added to a solution of PAMAM 4.0 (EDA) (69 mg, 0.01 mmol) in water (20 ml). The pH of the resulting cloudy solution was adjusted to 9 with saturated NaHCO 3 solution and allowed to stir at room temperature for 24 hours. The reaction mixture was then filtered and the filtrate was concentrated to give a white solid residue, which was purified by gel filtration (Sephadex LH20, water) and then freeze dried to give the product as a white fluffy solid (68mg). ). EXAMPLE 22 Preparation of dendrimers terminated in 3,5-Dicarboxyphenylamide PAMAM 4.0 (EDA) Solid 3,5-dicarboxyphenylisothiocyanate (112mg, O.dmmoles) was added to a solution of PAMAM 4.0 (EDA) (70mg, O.OImmoles) in water (5ml). The pH of the resulting nebulized solution was adjusted to 10 with a 1M Na 2 CO 3 solution and heated under nitrogen at 53 ° C for 2 hours. The reaction mixture was then filtered and the filtrate was then concentrated to give a brown solid residue, which was purified by gel filtration (Sephadex LH20, water) and then freeze dried to give the product as a pale brown solid ( 112 mg). EXAMPLE 23 Preparation of Dendrimers Terminated in 4- Sodium Phosphonoxyphenylthiourea PAMAM 4.0 (EDA) Solid sodium 4-phosphonoxyphenylisothiocyanate (251mg) was added to a solution of PAMAM 4.0 (EDA) (69mg, O.OImmoles) in water (20ml). The resulting solution (pH 9) was stirred for 24 hours at room temperature under nitrogen. The reaction mixture was then concentrated to give a white solid residue, which was purified by gel filtration (Sephadex LH20, water) and then freeze dried to give the product as a fluffy white solid (86mg). EXAMPLE 24 Preparation of dendrimers terminated in sodium 4- (phosphonomethyl) phenylthiourea PAMAM 4.0 (EDA) Solid sodium 4- (phosphonomethyl) phenylisothiocyanate (97mg) was added to a solution of PAMAM 4.0 (EDA) (69mg, O.Ommoles) in water (30ml). The resulting solution was stirred for 3 days at room temperature under nitrogen, maintaining the pH at 8 with periodic addition of saturated NaHC 3 solution. The reaction mixture was then concentrated to give a white solid residue, which was purified by gel filtration (Sephadex LH20, water) and then freeze dried to give the product as a fluffy white solid (102mg). EXAMPLE 25 Preparation of thermionized dendrimers in Ethyl 4- (phosphono methyl) phen ilthiourea PAMAM 4.0 (EDA) Solid sodium 4- (phosphonomethyl) phenylisothiocyanate (109 mg) was added to a solution of PAMAM 4.0 (EDA) (69mg; O.OI mmoles) in dry DMF (20 ml). The resulting solution was stirred for 17 hours at room temperature under nitrogen, maintaining the pH at 8 with periodic addition of saturated NaHCO 3 solution. The reaction mixture was then concentrated to give a white solid residue, which was purified by gel filtration (Sephadex LH20, water) and then freeze dried to give the product as a fluffy white solid (30mg). EXAMPLE 26 Preparation of Polylysines Terminated in 4-Sulfophenyl Tioriorurea PAMAM 4.0 (EDA) 4-Sulfophenylisothiocyanate monohydrate (2.55g; l Ommoles) was added to a solution of poly-L-lysine (15-30K) (Sigma Chemical Company) (1.0g) in a mixture of water (20ml) and buffer solution. N, N-dimethyN-allylamine (pH 9.5, 15ml). The resulting mixture was heated under nitrogen at 53 ° C for 3 hours, when a ninhydrin test came out negative. The cooled mixture was filtered and the filtrate was concentrated to give a gray solid residue. The solid residue was redissolved in water and passed through a column of Amberlite I R 120 (Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20, water) and freeze dried to give poly-L-lysine BRI2995 terminated in sodium 4-sulfophenylthiourea as a white flabby solid (1.25g). Similarly, polylysines terminated in 4-sulfophenylthiourea of molecular weight fraction 1-4K BRI2994, 4-15K, BRI2967, 150-300K BR12996 were prepared. EXAMPLE 27 Preparation of Terminated Polyvinides in Sodium 3,6-Disu-L-Phonaphthylthiourea. Solid sodium 3,6-disulfonaphthylisothiocyanate (200 mg, 0.51 mmol) was added to a solution of poly-L-lysine (15-30K) (50mg) in a mixture of water (2ml) and N, N-dimethyl regulatory solution. -N-allylamine (pH 9.5, 2ml). The resulting mixture was heated under nitrogen at 53 ° C for 3 hours, when a ninhydrin test came out negative. The cooled mixture was filtered and the filtrate was concentrated to give a brown solid residue. The solid residue is redissolved in water and passed through a column Amberlite I R 120 (Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20; water) and freeze-dried to give poly-L-lysine BRI6047 terminated in sodium 3,6-disulfonaphthyl thiourea as a white flabby solid (87 mg). EXAMPLE 28 Preparation of dendrimers and l inenal polymers terminated in 2-thiosaloside bonded from Cn alkyl. 5-Acetamido-4,7,8-9-tetra-O-acetyl-3,5-dideoxy-2-thio-D was prepared. Methyl 8-octanoic acid N-hydroxysuccinimide ester-glycerol-aD-galacto-2-nonulpyranoside] nate by the following procedure. To a solution of N-ester 5-acetamido-4,7,8-9-tetra-0-actyl-3,5-dideoxy-2-thio-D-glycerol-aD-galacto-2-nonulpyranoside] onate. hydroxysuccinimide of 8-octanoic acid [Hasegawa et al., 1986) (100mg) in dry dimethylformamide (1 ml) was added 8-bromo-octanoic acid (41 mg) and diethylamine (280mg) and the solution was stirred at 20 ° C for 17 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and 5% hydrochloric acid cooled on ice. The organic layer was washed with water, dried over sodium sulfate and evaporated to give a residue (130 mg). This was dissolved in ethyl acetate and hydroxysuccinimide (26mg) and dicyclohexylcarbodiimide (46mg) were added. The mixture was stirred at 20 ° C for 17 hours then the white precipitate was filtered. The filtrate was concentrated and purified by flash chromatography on a silica eluting with ethyl acetate. The fractions containing products were combined and evaporated to give 97 mg a white foam. 71%. Similarly prepared were: 5-acetamido-4,7,8-9-tetra-0-acetyl-3,5-dideoxy-2-thio-D-glycero-aD-galacto-2-nonulopyranosid] nato ester of N- Hydroxysuccimide of methyl 11-undecanoic acid. 5-Acetamido-4,7,8-9-tetra-0-acetyl-3,5-dideoxy-2-thio-D-glycero-aD-galacto-2-nonulopyranoside] -acetic ester of N-hydroxysuccinimide acetic acid of methyl. 5-Acetamido-4, 7, 8-9-tetra-0-acetyl-3, 5-d-deoxy-2-thio-D-glycoxylate N-hydroxysuccimide ester of N-hydroxysuccimide ester-D-galacto-2-nonulopyranoside] methyl 4-butanoic acid. 5-Acetamido-4,7,8-9-tetra-0-acetyl-3,5-dideoxy-2-thio-D-gIicero-aD-galacto-2-nonulopyranosid] N-hydroxysuccinimide ester ester of N-hydroxysuccinimide methyl-methylbenzoic acid. A. PAMAM [EDA] 4.0 [(8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-D-ga-Iacto-2-nonulopyranosidoic acid] 32 BRI 6112 To a solution of PAMAM [EDA] 4.0 (50mg) in dry dimethyl sulfoxide (4ml) under an inert atmosphere was added 5- acetamido-4,7,8-9-tetra-0-acetyl-3,5- N-hydroxysuccimide methyl 8-octanoic acid ester dideoxy-2-thio-D-glycero-aD-galacto-2-nonulopyranoside] -natoate (300 mg) and the solution was stirred for 60 hours at 20 ° C. The solvent was removed under vacuum and the residue was dissolved in methanol (2ml). This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with methanol. Upon evaporation of the solvent, the product, PAMAM [EDA] 4.0 of [(8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-giicero-D-galacto-2-nonulopyranosidoic acid] 32 It was obtained as a white powder. 182 mg. 93% This was converted to the free siaioside by the following method: To a solution of PAMAM [EDA] 4.0 [(8-octamido) -5-acetamido-4,7,8,9-tetra-0-acetyl-3,5- acid] methyl deoxy-2-thio-D-glycero-α-D-galacto-2-nonylpyranosyl] -etonate] (32 mg) in dry methanol (3 ml) under argon at 20 ° C was added a freshly prepared 0.19 M solution. of sodium methoxide in methanol (7ml) and the mixture was stirred for 2.5 hours. The solvent was evaporated and the residue was dissolved in water (10ml) and stirred for 3 hours. This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with water. When freeze dried the product PAMAM [EDA] 4.0 of [(8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-aD-galacto-2-nonulopyranoside] 32 was obtained as a pale lemon powder 110mg. 77%. By a similar procedure, they were prepared: PAMAM [EDA] 4.0 of [(11-undecanamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid] 32 BRI6147 PAMAM [EDA] 4.0 of [acid (acetamido) -5-acetamido-3,5-d-deoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic] 32 BRI 6121 PAMAM [EDA] 4.0 of [(4-methylbenzamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid] 32 BRI6120 PAMAM [EDA] 4.0 of [(8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid] 32 BRI 6169 A solution of BHA lyslys2lys4lys8lys? 6 (t-Boc) 32 (20.3mg) in a mixture of trifluoroacetic acid (2ml) and dichloromethane (2ml) was stirred at 20 ° C for 2 hours then the solvent was removed under vacuum. The residue was dissolved in dry dimethyl sulfoxide (1 ml) and di-isopropylethylamine (25 mg) and 5-acetamido-4,7,8-9-tetra-O-acetyl-3,5-d idesoxy-2-thio were added. - N-hydroxysuccimide methyl-8-octanoic acid (78mg) ro-D-galacto-2-nonulopyran- sidic acid ester. The mixture was stirred under argon at 20 ° C for 60 hours then the solvent was removed under vacuum. The residue was dissolved in a freshly prepared 0.1M sodium methoxide solution in methanol (2.5ml) and the mixture was stirred for 3 hours under argon at 20 ° C. The solvent was evaporated and the residue was dissolved in water (1 ml) and stirred for 17 hours. This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with water. After lyophilization, the BHA product Iyslys2lys4lys8lys16 of [(8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid] 32 was obtained as a white powder 44mg. 86% C Poly-L-lysyl [8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-aD-galacto-2-nonulopyranosidoic acid] n BRI 6150 To a solution of poly- L-lysine H Br PM 1 50-300Kd (22mg) in dry dimethyl sulfoxide (1 ml) were added di-isopropylethylamine (15mg) and 5-acetamido-4,7,8,9-tetra-0-acetyl-3, 5 N-hydroxysuccimide ester of methyl 8-octanoic acid (90mg) -d idesoxy-2-thio-D-glycero- -D-galacto-2-nonulopyranosid] onate. The mixture was stirred under argon at 20 ° C for 60 hours then the solvent was removed under vacuum. The residue was dissolved in a fresh 0.5M solution of sodium methoxide in methanol (4ml) and the mixture was stirred for 48 hours under argon at 20 ° C. The solvent was evaporated and the residue was dissolved in water (1.5 ml) and stirred for 24 hours. This solution was subjected to size exclusion chromatography during in Sephadex LH20 eluting with water. After lyophilization, the polylysyl product of [(8- octamido) -5-acetamido-3, 5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonuiopyranosidoic] n as a white powder. 49mg 94% EXAMPLE 29 Preparation of Dendritic Sialosides Modified in the 4-Position of Sialic Acid 4-Azido-5-acetamido-7,8,9-tri-0-acetyl-2-S-acetyl, 3,4,5-trideoxy- Methyl 2-thio-D-glycerol-aD-galacto-2-nonulopyranosonate by the following procedure. To a solution of methyl 4-azido-5-acetamido-7,8,9-tri-0-acetyl-2-chloro-3,4,5-tridesoxy-Dg licero-β-D-galacto-2-nonulopyranosonate (Sabesan, 1994) (5g) in dry dichloromethane (150ml) finely powdered fine potassium thiolacetate (5.8g) was added and the suspension was stirred vigorously at 20 ° C for 48 hours. The mixture was filtered and evaporated to give a clear brown foam (5.2g). The required product was isolated by preparative reverse phase HPLC [C? 8, 30% acetonitrile / water] as a white 3.9g foam. 72%. 4- azi do- 5- ace tam id-7,8, 9-tri-O-aceti 1-3, 4, 5-trideoxy-2-ti o- D-glyceryl-aD-galacto-2-nonuopyranoside] N-hydroxysuccinimide ester onate of methyl 8-octanoic acid was prepared by the following procedure. To a solution of 4-azido-5-acetamido-7, 8, 9-tri-O-aceti lo-2-S-acetyl-3,4,5-tridesoxy-2-thio-d-glycero-aD-galacto Methyl-2-nonulopyran-sonate (300 mg) in dry dimethylformamide (3.5 ml) was added 8-bromooctanoic acid (155 mg) and diethylamine (1.2 ml) and The solution was stirred at 20 ° C for 17 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and 10% hydrochloric acid cooled on ice. The organic layer was washed with water, dried over sodium sulfate and evaporated to give a yellow foam (385 mg). This was dissolved in ethyl acetate (20ml) and N-hydroxysuccinimide (95mg) and dicyclohexycarbodiimide (175mg) were added. The mixture was stirred at 20 ° C for 17 hours then the white precipitate was filtered. The filtrate was concentrated and purified by preparative reverse phase HPLC [C18, 30% acetonitrile / water] to give a white 340mg foam. 83%. A PAMAM [EDA] 4.0 of [(8-octamido) -5-acetamido-3,5-tridesoxy-2-thio-D-gIicero-D-galacto-2-nonulopyranosidoic acid] 32 BRI 6146 To a solution of PAMAM [EDA] 4.0 (72 mg) in dimethyl sulfoxide (5 ml) under an inert atmosphere was added 4-azido-5-acetamido-7,8,9-tri-O-aceti 1-3 , 4, 5-tridesoxy-2-thio- D-glycole N-hydroxysuccinimide 8-octanoic acid methyl ester N-hydroxysuccinimide ro-aD-galacto-2-nonulopyranoside] monate (318mg) and the solution was stirred for 60 hours at 20 ° C. C. The solvent was removed under vacuum and the residue was dissolved in methanol (2ml). This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with methanol. Upon evaporation of the solvent, the product, PAMAM [EDA] 4.0 from 4-azido-5-acetamido-7,8-9-tri-0-acetyl-2-S-acetyl-3,4,5-trideoxy-2- dude-D- Methyl glycero-D-galacto-2-nonulopyranoside] onato32 was obtained as a white foam. 225mg 81%. The free sialoside was obtained by the following method: To a solution of PAMAM [EDA] 4.0 of [8-octanamido) 4-azido-5-acetamido-7,8,9-tri-O-acetyl-2-S-acetyl -3,4,5-tridesoxy-2-thio-d-glycero-aD-galacto-2-nonulopyranod] onate] 32 methyl (215 mg) in dry methanol (1 ml) under argon at 20 ° C was added a solution freshly prepared 1M sodium methoxide in methanol (1ml) and the mixture was stirred for 3 hours. The solvent was evaporated and the residue was dissolved in water (2 ml) and stirred for 17 hours. This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with water. By lyophilization, the product PAMAM [EDA] of PAMAM [EDA] 4.0 of [8-octanamido acid] 4-azido-5-acetamido-7,8,9-tri-0-acetyl-2-S-acetyl-3, 4,5-trideoxy-2-thio-d-glycero-D-galacto-2-nonulopyranosidoic acid] 32 methyl was obtained as a fluffy white powder 160mg. 90% PAMAM [EDA] 4.0 of [8-octanamido acid] 4-azido-5- to ce-7,8,9- tri-O- to cetyl o-2-Sa cetyl-3,4,4,5 -2-thio-d-glycero-aD-gaIacto-2-nonulopiranosidoico] 32 of methyl BRI 6149 A slow stream of hydrogen sulphide gas was passed in a PAMAM [EDA] 4.0 solution of [8-octanamido acid] 4 -azido- 5-acetamido-7,8,9-tri-O-acetyl-2-S-acetyl-3,4,5-trideoxy-2-thio-d-glycero-aD-galacto-2-nonulopyranosidoic acid ] 32 methyl (25mg) in a mixture of pyridine (40ml) and water (20ml) at 20 ° C for 5 days. The The solution was then bubbled with nitrogen for 2 hours to remove excess hydrogen sulphide. The solution was evaporated to dryness and the residue was absorbed in water (5ml) and filtered through a 0.45μm membrane filter to remove sulfur. When lyophilized, the product, PAMAM [EDA] 4.0 of [8-octanamido acid] 4-azido-5-acetam id o-7,8, 9-tri-O-aceti I o-2-S-aceti 1-3 , 4, 5-tridioxy-2-thio-d-glycero-aD-galacto-2-nonulopyranosidoic acid] 32 was obtained as a fluffy white powder 23mg. 96%. EXAMPLE 30 Preparation of dendrimers terminated in boronic acid N-hydroxysuccinimide ester of 4-carboxyphenylboronic acid To a solution of 4-carboxyphenylboronic acid (500mg) in dry dimethylformamide (5ml) were added N-hydroxysuccinimide (380mg) and dicyclohexylcarbodiimide (680mg) ). The mixture was stirred at 20 ° C for 64 hours then the white precipitate was filtered. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (100ml). This solution was washed with water, dried over sodium sulfate and evaporated to give a white solid which was crystallized with acetonitrile / water as fine needles 730mg. 92% PAMAM [EDA] 4.0 [4-benzamidoboronic acid] 32 BRI 6160 To a solution of PAMAM [EDA] 4.0 (69mg) in dry dimethyl sulfoxide (5ml) under an inert atmosphere was added N-hydroxysuccinimide ester of 4-acid. carboxyphenylboronic acid (130mg) and the solution was stirred for 65 hours at 20 ° C. The thick grout is added a 1M sodium carbonate solution (1ml) and the clear solution was stirred an additional 24 hours. The solvent was removed under vacuum and the residue was dissolved in a 10% ammonia solution (5 ml). This solution was subjected to size exclusion chromatography on Sephadex LH20 eluting with 10% ammonia solution. Upon evaporation of the solvent, the product, PAMAM [EDA] 4.0 of [4-benzamidoboronic acid] 32 was obtained as a white flabby solid. 110mg 94% EXAMPLE 31 Preparation of dendrimers terminated in 3,5-disulfonaphthylthiourea of Sodium BHA Iyslys2lys4lys8lysi6lys32 Trifluoroacetic acid (2ml) was added to a stirred suspension of BHAIyslys2lys4lys8lys? 6DBL32 (147mg) in dry dichloromethane (2ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in N, N-dimethyl-N-allylamine buffer solution (pH 9.5, 5 ml) and then solid 3,6-disulfonaphthyl isothiocyanate (400 mg) was added. The pH of the mixture was then adjusted to 9.5 by the addition of 1M sodium carbonate and the solution was heated at 53 ° C for three hours under nitrogen. The reaction mixture was concentrated and the residue was redissolved in water and the solution was passed through a column of Amberlite IR 120 (Na). The filtrate was concentrated to give the crude product, which was purified by gel filtration (Sephadex LH20; water) to give BHAIyslys2lys4lysslys16lys32 with 64 sodium 3,6-disulfonaphthylurea groups as a white flabby solid (175mg). EXAMPLE 32 Preparation of dendrimers terminated in Sodium 3,5-disulfophenylthiourea BHAIyslys2lys lys8lys16lys32 Trifluoroacetic acid (3ml) was added to a stirred suspension of BHAIyslys2lys4lys8lys16DBL32 (300mg, 0.02mmol) in dry dichloromethane (3ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in water and the solution was passed through a column of Amberlite IRA 401 (OH) and the filtrate was concentrated to give a viscous oil (187mg). The oil was dissolved in a 1: 1 mixture of pyridine / water (8ml) and sodium 3,5-disulfophenyl sothiocyanate (680mg, 2mmol) was added. The resulting solution was heated at 53 ° C for three hours. The solution was concentrated to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give BHAIyslys2lys lys8lys? 6lys32 with 64 sodium 3,6-disulfophenylurea groups as a white flabby solid. EXAMPLE 33 Preparation of Dendrimers Terminated in Sodium 3,5-Dicarboxyphenylthiourea BHAIyslys2lys4lys8lys16lys32 Trifluoroacetic acid (3ml) was added to a stirred suspension of BHAiyslys2lys4lys8lys1 6DBL32 (300mg, 0.02 mmol) in dry dichloromethane (3ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in water and the solution was passed through a column of Amberlite I RA 401 (OH) and the filtrate was concentrated to give a viscous oil (186 mg). The oil was dissolved in a 1: 1 mixture of pyridine / water (8 ml) and 3, 5-disulfophenyl sodium isothiocyanate (450 mg, 2 mmol) was added. The resulting solution was heated at 53 ° C for 13 hours. The solution was concentrated to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give BHAIyslys2lys lys8lys16lys32 with 64 sodium 3,6-dicarboxyphenylurea groups as a white flabby solid. EXAMPLE 34 Preparation of Dendrimers Terminated in Sodium 3,5-Phosphonooxifen Sodium BHAIyslys2lys4lys8lys16lys32 Trifluoroacetic acid (2ml) was added to a stirred suspension of BHAIyslys2lys lys8lys16DBL32 (147mg, OO I mmol) in dry dichloromethane (2ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated to give a viscous oil. The oil was dissolved in N, N-dimethyl-N-allylamine buffer solution (pH 9.5, 5 ml) and solid 4-phosphonooxyphenyl isothiocyanate. The pH of the solution The resultant was adjusted to 10 with 1M sodium carbonate and the mixture was heated at 53 ° C for three hours under nitrogen. The solution was then concentrated to give a white solid residue. The residue was redissolved in water and the solution was passed through a column of Amberlite IR 120 (Na) and the filtrate was concentrated. The residue was then purified by gel filtration (Sephadex LH20; water) to give BHAIyslys2lys lys8lys16lys32 with 64 sodium 3,6-phosphonooxyphenylurea groups as a white flabby solid (150mg). EXAMPLE 5 Preparation of dendrimers terminated in 4-phosphonophenylthiourea Sodium BHAIyslys2Iys lys8lys16lys32 Trifluoroacetic acid (2ml) was added to a stirred suspension of BHAIyslys2lys4lys8lys16DBL32 (147mg, O.OImmoles) in dry dichloromethane (2ml) and the resulting solution was stirred at room temperature under nitrogen for two hours and then concentrated to give a viscous oil. The oil was dissolved in N, N-dimethyl-N-allylamine buffer solution (pH 9.5, 5ml) and solid 4-phosphonophenyl isothiocyanate (250mg) was added. The pH of the resulting solution was adjusted to 9 with saturated sodium bicarbonate solution and the mixture was heated at 53 ° C for three hours under nitrogen. The solution was then concentrated to give a white solid residue. The residue was redissolved in water and the solution was passed through a column of Amberlite IR 120 (Na) and the filtrate was concentrated. The residue was then purified by gel filtration (Sephadex LH20; water) to give BHAIyslys2lys lys8lys16lys32 with 64 groups of 4-phosphonophenylurea sodium BRI 6196 as a white flabby solid (152mg) after freeze drying. EXAMPLE 36 Preparation of dendrimers terminated in 4,6-difosf or nonaf ti Iti ou rea PAMAM 4.0 A solution of 4,6-diphosphonaphthaphthyl sodium isothiocyanate (165mg) in water (2ml) was added to a PAMAM 4.0 solution ( 51mg; O.OImmoles) in water (2ml). The pH of the mixture was adjusted to 9.5 with saturated sodium bicarbonate solution and the mixture was stirred vigorously for one hour at room temperature and then heated at 53 ° C for three hours under nitrogen. The mixture was then filtered and the filtrate was concentrated to give a brown solid residue. The crude product was purified by gel filtration (Sephadex G25; water) to give PAMAM 4.0 terminated with 24 sodium 4,6-diphosphonaphthylthiourea groups as a brown solid (81mg) after freeze drying. EXAMPLE 37 Preparation of finished dendrimers in Fluoresceinatiourea PAMAM 4.0 (EDA) Solid fluorescein isothiocyanate (188 mg) was added to a solution of PAMAM 4.0 (EDA) (74mg, O.OImmoles) in water (3ml). The saturated sodium bicarbonate solution was added to adjust the pH to 9 and the resulting homogeneous solution was stirred overnight at room temperature and then concentrated. The orange residue was purified by gel filtration (Sephadex LH20, water) to give PAMAM 4.0 (EDA) terminated with 21 fluoresceinurea groups as a fluffy orange solid (193mg) after freeze drying. EXAMPLE 38 Preparation of dendrimers terminated in (Phenyl-3-boronic acid) - Sodium PharaAM 4.0 (EDA) - Solid isothiocyanate (phenyl-3-boronic acid) was added (100mg, O.dmmoles) to a solution of PAMAM 4.0 (EDA) (69mg, O.OImmoles) in water (5ml). The 1M sodium carbonate was added to the dissolved isothiocyanate (pH ca.10). The mixture was then heated at 53 ° C for two hours under nitrogen and then filtered and the filtrate was concentrated to give a brown solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with 32 groups of (phenyl-3-boronic acid) thiourea as a white flabby solid (87mg) after freeze drying. EXAMPLE 39 Preparation of Polylysines Terminated in Sodium 3,5-Dicarboxyphenylthiourea A solution of poii-L-lysine bromohydrate (4-15K) (Sigma Chemical Company) (50mg) in water (2ml) was added to a solution of isothiocyanate of 3,5-dicarboxyphenyl sodium (305mg) in water (3ml) and the pH of the resulting solution was adjusted to 9 with aqueous sodium bicarbonate. The solution was then heated at 53 ° C under nitrogen for 4 hours. The solution was cooled and filtered and the filtrate was concentrated to give an off-white solid residue. The crude product was purified by gel filtration (Sephadex LH20, water) and freeze-dried to give poly-L-lysine terminated in 3,5-dicarboxyphenylthiourea as a white flabby solid (71 mg). EXAMPLE 40 Preparation of Polylysines Terminated in Sodium 4- (Phosphonomethyl) Phenylthiourea Solid 4- (phosphonomethyl) phenyl isothiocyanate (231 mg, LOmmoles) was added to a poly-L-lysine bromohydrate solution (30-70K) (Sigma Chemical Company) (50mg) in a 1: 1 mixture of pyridine / water. The pH was adjusted to 9 with 1 M sodium carbonate and the solution was heated overnight at 53 ° C under nitrogen. The mixture was cooled and filtered and the filtrate was concentrated to give a brown solid residue. The crude product was purified by filtration of (Sephadex LH20, water) to give a brown solid (82mg). EXAMPLE 41 Preparation of poly-isine terminated in 1-phosphono-oxyphenyl-4-thiourea To a solution of poly-L-lysine hydrobromide (50 mg; Sigma P2636, 30-70 kilodaltons) in water (10 ml), heated and stirred 53 ° C, 4-phosphonooxyphenyl isothiocyanate (153mg) was added and the pH of the mixture was adjusted to 9.5-10 with carbonate solution. 1 M sodium. The mixture was heated and stirred at 53 ° C for 5 hours and then filtered. The clear solution was purified by gel filtration on Sephadex LH20 eluting with water. The eluent was lyophilized to give the product as a white foam. 77mg. 94% EXAMPLE 42 Preparation of poly-L-lysine terminated in benzo-mido-4-boronic acid To a solution of poly-L-lysine bromohydrate (50mg; Sigma P2636, 30-70 kilodaltons) in DMSO (10ml), under an inert atmosphere , N-hydroxysuccinimide ester of 4-carboxyphenylboronic acid (90mg) and 1M sodium carbonate solution (2ml) were added and the mixture was stirred at 20 ° C for 60 hours. The solvent was removed in vacuo and the residue was dissolved in water (5 ml) and filtered. The clear solution was purified by gel filtration on Sephadex LH20 eluting with water. The eluent was lyophilized to give the product as a white foam. 50mg 90% EXAMPLE 43 I. Corioalantioic membrane (CAM) analysis The model of CAM angiogenesis in vivo, initially described by Folkman (1985) and modified by Maragoudakis et al. (1988) was used. In short, freshly fertilized eggs were incubated for 4 days at 37 ° C when a window was opened in the egg shell exposing CAM. The sale was covered with a cellophane lid and the eggs were returned to the incubator until day 9 when the test compounds were applied. The compounds of Test were placed on plastic discs (10mm) and allowed to dry under sterile conditions. The control discs (containing PBS) were placed in CAM 1cm away from the discs containing the test material. A sterile solution of cortisone acetate (100ug / disc, Sigma) was incorporated into all the discs in order to avoid the inflammatory response. The loaded and dried discs were inverted and placed in the CAM, the windows were covered and the eggs were incubated until day 11 when the angiogenesis was evaluated. Morphological evaluation of angiogenesis in the CAM analysis. For the morphological evaluation, the eggs were treated as before. On day 11 the eggs were submerged in 10% regulated formalin (Janssen Chimica, Geel, Belguim), the plastic discs were removed and the eggs were kept at room temperature for at least 4 hours. A large area around the disc was cut and placed on a glass plate and the vascular density index (expressed as numbers of blood vessels) is measured by the method of Harris-Hooker et al. (1983). II. Aortic analysis in rats The aortic ring model was used in rats, initially described by Nicosia et al. (1990). Briefly, a sterile 1.5% agarose solution (Pharmacia Biotech AB, Upppsala, Sweden) was poured into the culture plates and allowed to gel. The agarose rings were obtained by punching two concentric circles, with a diameter of 10 and 17mm, respectively, on the agarose gel. The excess agarose inside and outside the rings was removed. The rings were transferred to a 6-well plate (Nuncion, Roskilde Denmark), each well containing three rings. The thoracic aortas were obtained from three-month-old male Wistar rats. The aortas were immediately transferred to a culture dish with minimal serum essential medium (M EM). The fibroadipose tissue around the aorta was carefully removed in order to damage the aortic wall. Thin sections (0.5 nm thickness) of aortic rings were sectioned and extensively rinsed in 12 consecutive washes of serum free medium. Before transferring the aortic rings to the culture rings in the culture dish, the bottom of the agarose well was coated with 150 ul of coagulating fibrinogen. After the fibrin gel formed, the aortic annulus was transferred to the agarose well and placed in the center of the agarose well. Then the agarose wells were completely filled with coagulating fibrinogen. The partially purified bovine fibrinogen (Sigma) was dissolved in serum-free medium in order to obtain a concentration of 3mg / ml. The coagulant was obtained by adding 20ul of a 50μl / ml bovine thrombin solution (Sigma) to 1 ml of fibrinogen solution. The fibrin gel formed within 30 seconds at room temperature. After fibrin gelation, 6ml of MEM medium, supplemented with 20% FCS (Gibco), 10mM Hepes (Gibco) and 1mM L-glutamine (Gibco), were added to each well of the 6 well plate and the Test compound was added to the medium at the appropriate concentration.

Quantification of angiogenesis for the rat aortic ring analysis. Cultures were examined daily and classified under an inverted microscope. Microvessel growth was represented by a microvascular growth curve. The formation of more than 200 to 250 microvessels is common (Nicosia et al. 1990) due to the three-dimensional complexity of the microvascular network. The margin of error of the observer who is counting the microvessels is high: therefore, the microvessels formed were classified on a scale of 0 (without glasses) to 10 (number of glasses maximum). RESULTS I. CAM analysis BRI6112 number BRI2923 BRI2995 BR12784 BRI6039 egg (25μg / cam) (25μg / cam) (25μg / cam) (25μg / cam) (25μg / cam) 1 - . 1 - 11% -45% -36% 0 + 11% 2 -13% -17% -22% -7% -33% 3 -26% -35% -54% -36% -9% 4 + 11% -87% -73% + 10% -34% 5 -42% -48% -55% -40% -26% 6 -41% -8% -43% -27% -27% 7 -32% -57 % -34% 0 -12% 8 -15% -20% -27% -18% 9 0 -22% -36% -63% 10 -57% -88% -54% -53% 11 + 23% 0 -16% 12 -30% -57% + 43% 13 0 X = -22.6 + 20.9 -42.4 + 26.2 -34.9 + 29.3 -22.8 ± 22.8 -19.8 ± 27.8 P = O.01 P = O .05 P = O.01 P = O.05 P < 0.05 • Higher concentrations (50μg / cam) of BRI2995 and BRI6112 have been evaluated: BRI2995 causes 50% death in embryos. The surviving eggs showed a 73% inhibition of vascular density. No toxicity was found for BRI6112 in this concentration. However only a slight inhibition of vascular density (-16%) was observed.

TNP-470 (50μ / cam) and Pentosan Polysulfate (PPS) (50μg), two compounds that are in the clinical trial, were included as reference compounds. They produced vascular density respectively by 21% ± 15 and 42% ± 28. PPS, however, caused the death of 80% of embryos at this concentration. II. Analysis of Aorta in Rats BRI2995, BRI2996 and BRI2999 (almost) completely inhibited the formation of microvessels at concentrations of 20μg / ml and 100μg / ml. BRI6196 gave almost complete inhibition at 20μg / ml and 100μg / ml, and also gave inhibition at 4μg / ml.

BRI2923 and BR16039 reduced the growth of microvessels at a concentration of 100μg / ml.

REFERENCES 1. Folkman J. (1985) J. Biol. Chem. 267: 10931-10934. 2. Harris-Hooker S.A. and others (1983) J. Cell. Physiol. 114: 302-310. 3. Hasegawa A. and others (1986) J. Carbohydrate Chemistry. 5 (1): 11- 19. 4. Maragoudakis M.E. and others (1988) Tissue Cell. 20: 531-539. 5. Nicosia R.F. and Ottinetti A. (1990) Cell Dev. Bio. 26: 119-128. Sebesan S. (1994) Bio-Organic and Medicinal Chemistry Letters. 4 (20): 2457-2460.

Claims (28)

1. REIVI NDICATIONS 1. A method of prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal patient, which comprises administering to the patient an effective amount of a compound selected from: (i) linear non-carbohydrate polymers having a plurality of groups of side chain wherein at least one of the side chain groups has an anionic or cationic containing moiety attached or bound thereto; and (i) dendrimers having a plurality of end groups in which at least one of said terminal groups has a portion containing anionic or cationic linked or bound thereto.
2. 2. A method according to claim 1, wherein the compound is a linear polyionic polymer of the general formula I: where R is a monomer unit without carbohydrate that forms a structure of the linear polymeric base; X is an optional ligation group on the side chain groups of the R monomer units; and A is an anionic containing portion.
3. 3. A method according to claim 2, wherein the linear polymer has an average scale of molecular weight distribution of from 1,000 to 1,000,000.
4. 4. A method according to claim 3, wherein the linear polymer has an average scale of molecular weight distribution of from 10,000 to 600,000.
5. A method according to claim 2, wherein in the linear polymer the monomer unit R is an amine or an amide.
6. 6. A method according to claim 5, wherein in the linear polymer the monomeric unit R is a lysine or other amino acid portion.
7. A method according to claim 2, wherein in the linear polymer the linking group X, when present, is a functional linking group selected from the group consisting of esters, amides, ethers, thioethers, amines, ureas , thioureas, carbamates and carbonates.
8. 8. A method according to claim 2, wherein in the linear polymer the linking group X, when present, is a separating group selected from the group consisting of alkyl which may optionally be substituted or branched; alkoxy, polyalkoxy, alkylthio or polyalkatio chains which may be optionally substituted multiple alkenyl, alkenyl, alkynyl or alkynyl or alkynyl chains which may be optionally substituted and groups of the formula - (CH2) nZ- (CH2) n- where Z is - CH2-, CH = CH-, -C = C-, -O- or -S-, and n is an integer from 1 to 15.
9. 9. A method according to claim 1, wherein the compound is a dendrimer comprising a polyvalent core attached to at least two dendritic branches and extending through at least two generations.
10. 10. A method according to claim 9, wherein the dendrimer is a polyamidoamine dendrimer based on an ammonia core.
11. 11. A method according to claim 9. wherein the dendrimer is a polyamidoamine dendrimer based on an ethylene diamine core.
12. 12. A method according to claim 9, wherein the dendrimer is a polylysine dendrimer based on a benzohydrylamine core or other suitable.
13. 13. A method according to claim 9, wherein the compound is a polyionic dendrimer of the general formula II: where: l is the initiating nucleus; Z is an indoor branching unit; n is an integer representing the generation number of the dendrimer; and A is an anionic containing portion that can be linked to the branching unit Z through an optional linking group X.
14. 14. A method according to any of claims 1 to 13, wherein in the compound the anionic or cationic containing portion (s) is attached to the amine, sulfohydryl, hydroxy or other reactive functional side chain or groups terminals of the linear polymer or dendrimer by the amide or thiourea linkages.
15. 15. A method according to any of claims 1 to 14, wherein in said compound the anionic containing portions are selected from the group consisting of portions containing sulfonic acid, portions containing carboxylic acid (including portions containing neuraminic and sialic acid and portions containing modified neuraminic and sialic acid) portions containing boronic acid and portions containing phosphoric and phosphonic acid (including portions containing esterified phosphoric and phosphonic acid).
16. 16. A method according to any of claims 1 to 15, wherein in the compound the portion or portions that bind to the amino groups or other reactive functional side chain reactants or end groups of the linear polymer or dendrimer are selected of the following groups, in which n is zero or a positive integer: -NH (CH2) nS? 3- (CH2) nS03- -Ar (S03) n -CH2CH (S03") COOH -CH { S03- CH2COOH -ArX (CH2> nS? 3 'X - OS NH - (CHzJnNMej -A? - (N e3) n -Ar (CHaNMe3) n -ArXP (= 0) (0R) 2 x = 0, CH2, CHF, CF2 R = alkyl, aryl, H, Na -ArXP (= 0) (OR1) (NR2R3) x = 0, CH2, CHF, CF2 Realkyl, aryl, H, Na R2, Realkyl, aryl -Ar [P (= 0) (OR) 2] n R = alkyl, aryl, H, Na n = 1-3 - Ar [B (OH) 2] "n = 1.3 -Ar [COOH] n n = 1-3
17. 17. A method according to claim 1 or claim 2, wherein the compound is selected from the group consisting of: i. Poly-L-lysines, 4-sulfophenylthiorurea; ii. Poly-L-lysines terminated in 3,6-disulfonaphthylthiourea; iii. Poly-L-lysines terminated in (8-octamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; iv. Poly-L-lysines terminated in 3,5-dicarboxyphenylthiourea; v. Poly-L-lysines terminated in 4- (phosphonomethyl) phenylthiourea; saw. Poly-L-lysines terminated in 1-phosphonooxyphenyl-4-thiourea; and vii. Poly-L-lysines terminated in benzamido-4-boronic acid.
18. 18. A method according to claim 1 or claim 9, wherein the compound is selected from the group consisting of: i. Dendrimers terminated in alkylsulfonic acid; ii. Dendrimers ending in sulfoacetamide; iii. Dendrimers ending in sulfosuccinamic acid; iv. Dendrimers terminated in N- (2-sulfoethyl) succinamide; v. Dendrimers ending in 4-sulfophenylthiourea; saw. Dendrimers terminated in 3,6-di-sulfonaphthylthiourea; vii. Dendrimers ending in 4-sulfonaphthylthiourea; viii. Dendrimers terminated in 3,5-di-sulfophenylthiourea; ix. Dendrimers terminated in 3,6,8-tri-sulfonaphthylthiourea; x. Dendrimers ending in 4- (sulfomethyl) benzamide; xi. Dendrimers ending in 4-sulfobenzamide; xii. Finished dendrimers in N- (4-sulfophenyl) propanamide; xiii. Dendrimers terminated in 4-sulfophenylurea; xiv. Dendrimers ending in N, N, N-tri-methylglycinamide; xv. Dendrimers terminated in 4-trimethylammonium benzamide; xvi. Dendrimers ending in 4- (trimethylammoniomethyl) benzamide; xvü. Dendrimers terminated in N- (2-acetoxyethyl) -N, N- (d-imeti-lamonium) methyl-carboxyl-ida; xviii. Dendrimers finished in guanidino; xix. Finished dendrimers in 4 - ([1, 4, 8, 1 1 -tetraazacyclotetradecane] methyl) benzamide; xx. Thermionized dendrimers in 4-carboxy-3-hydroxy-benzylamine; xxi. Dendrimers terminated in 4-carboxyphenylamide; xxii. Dendrimers terminated in 3,5-dicarboxyphenylamide; xxiii. Dendrimers ending in 4-phosphonooxyphenylthiourea; xxiv. Dendrimers ending in 4- (phosphonomethyl) phenylthiourea; xxv. Dendrimers terminated in ethyl-4- (phosphonomethyl) phenylthiourea; xxvi. Dendrimers terminated in (8-octanamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; xxvii. Dendrimers terminated in (11-undecanamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; xxix. Dendrimers terminated in (4-butanamido) -5-acetamido-3,5-dideoxy-2-thio-D-gIicero-a-D-gIacto-2-nonulopiranosidoico; xxx Dendrimers terminated in (4-methylbenzamido) -5-acetmido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; xxxi. Dendrimers terminated in (8-octanamido) 4-azido-5-acetamido-3,4,5-trideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; xxxii. Finished dendrimers of (8-octanamido) -4-amino-5-acetamido-3,4,5-trideoxy-2-thio-D-glycero-D-galacto-2-nonulopyranosidoic acid; xxxiii. Dendrimers ending in 4-benzamidoboronic acid; xxxiv. Dendrimers ending in 3,5-dicarboxyphenylthiourea; xxxv Dendrimers ending in 4-phosphonophenylthiourea; xxxvi. Dendrimers terminated in 4,6-diphosphonaphthiylthiourea; xxxvii Finished dendrimers fluoresceinothiourea; and xxxviii. Dendrimers terminated in (phenyl-3-boronic acid) thiourea;
19. 19. A method according to any of claims 1 to 18, wherein the treatment comprises the inhibition of angiogenesis in a patient, treatment of chronic inflammation, diabetic retinopathy, psoriasis and rheumatoid arthritis and other conditions where the growth of new blood is involved, prevention of restenosis by inhibition of proliferation of vascular smooth muscle cells, acceleration of wound healing by activation of the release of growth in the extracellular matrix and inhibition of tumor cell metastasis by inhibition of angiogenesis.
20. 20. A pharmaceutical or veterinary composition for prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal, comprising a linear anionic or cationic polymer or a dendrimer as defined in any of claims 1 to 18, in association with at least one pharmaceutically or veterinarily acceptable diluent carrier.
21. 21. Use of a linear anionic or cationic polymer or dendrimer as defined in any of claims 1 to 18, in, or in the manufacture of a medically prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal.
22. 22. A compound comprising a dendrimer having a plurality of terminal groups, wherein at least one of the terminal groups has an anionic containing portion attached or bonded thereto, the anionic containing portion being selected from the group consisting of : i. Servings containing neuraminic and sialic acid, other than the 2-thiosialic acid moiety; ii. Servings containing modified neuraminic and sialic acid; iii. Servings containing boronic acid; and iv. Portions containing phosphoric and phosphonic acid, including portions containing esterified phosphoric and phosphonic acid.
23. 23. A compound according to claim 22, wherein the dendrimer comprises a polyvalent core covalently linked to at least two dendritic branches and extending through at least two generations.
24. 24. A compound according to claim 22 or claim 23, wherein the dendrimer is a polyamidoamine dendrimer based on an ammonia core.
25. 25. A compound according to claim 22 or claim 23, wherein the dendrimer is a polyamidoamine dendrimer based on an ethylene diamine core.
26. 26. A compound according to claim 22 or claim 23, wherein the dendrimer is a polylysine dendrimer based on benzidrylamine or another suitable core.
27. 27. A compound according to any of claims 22 or 28, wherein the anionic-containing portion is attached to the terminal amine, sulfohydride, hydroxy or other reactive dendrimer reactive functional groups by avidity or thiourea ligatures.
28. 28. A compound according to claim 22, which is selected from the group consisting of: i. Dendrimers terminated in 4-phosphoonoxyphenitiourea; ii. Dendrimers ending in 4- (phosphonomethyl) phenylthiourea; iii. Dendrimers terminated in ethyl-4- (phosphonomethyl) phenylthiourea; iv. Dendrimers terminated in (8-octanamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; saw. Dendrimers terminated in acid (acetamido) -d-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; vii. Dendrimers terminated in (4-butanamido) -5-acetamido-3,5-d idesoxy-2-thio-D-g-lice r-a-D-galacto-2-nonulopyranosidoic acid; viii. Dendrimers terminated in (4-methylbenzoamido) -5-acetamido-3,5-dideoxy-2-thio-D-glycero-a-D-galacto-2-nonuiopyranosidoic acid; ix. Dendrimers terminated in (8-octamido) -4-azido-5-acetamido-3,4,5-trideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; x. Dendrimers terminated in (8-octanamido) -4-amino-5-acetamido-3,4,5-trideoxy-2-thio-D-glycero-a-D-galacto-2-nonulopyranosidoic acid; XI. Dendrimers ending in 4-benzamidoboronic acid; xii. Finished dendrimers in 4-phosphonophenylthiourea; xiii. Dendrimers terminated in 4,6-diphosphonaphthiylthiourea; and xiv. Dendrimers ending in (phenyl-3-boronic acid) -thiourea. RESU M IN A method of prophylactic or therapeutic inhibition of angiogenesis in a human or non-human animal patient, comprises administering to the patient an effective amount of a compound selected from: (i) linear, non-carbohydrate polymers having a plurality of of side chain groups wherein at least one of the side chain groups has an anionic or cationic containing moiety attached or bonded thereto; and (ii) dendrimers having a plurality of terminal groups in which at least one of the terminal groups has an anionic or cationic containing portion bound or bound thereto.