AU2005230207B2 - Biologically active compounds with anti-angiogenic properties - Google Patents

Description

WO 2005/097142 PCT/AU2005/000506 1 Biologically Active Compounds With Anti-Angiogenic Properties.

FIELD OF THE INVENTION [0001] The invention provides a class of biologically active compounds with anti-angiogenic properties.

BACKGROUD OF THE INVENTION [0002] Blood vessels form the largest network in the body and are the first organ to form in the developing embryo. The formation of new blood vessels is a complex, highly regulated process that is critically important for the development and homeostasis of an organism. Disruption to the regulation of the formation of new blood vessels contributes to malignant, inflammatory, immune and infectious disorders [Angiogenesis in health and disease, Carmeliet, Nature Medicine 2003, 9 653-660].

[0003] Recent attention has been focused on the "angiogenic switch" and its role in tumorigenesis. The complex stepwise progression towards malignancy has been well described for several types of cancer, in particular colon cancer, and is known to involve various genetic and epigenetic events leading to tumorigenesis. In addition to these events during transformation is the requirement for the induction of tumour vasculature, which allows the tumour to grow and spread. The induction of this vasculature is termed the "angiogenic switch" [Tumourigenesis and the Angiogenic Switch, Bergers, G. and Benjamin, Nature Reviews in Cancer 2003, 3, 401-410].

[0004] The classical model for the molecular regulation of angiogenesis involves a balance between pro-angiogenic molecules and anti-angiogenic molecules.

There are at least twenty naturally occurring pro-angiogenic molecules identified to date including vascular endothelial growth factors (VEGFs), angiopoietins, fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), epidermal growth 3 0 factors (EGF's) and other growth factors and cytoldnes. To balance the scales there are at least thirty naturally occurring anti-angiogenic molecules identified to date.

Somatostatin receptor subtypes have also been implicated in the inhibition of angiogenesis.

WO 2005/097142 PCT/AU2005/000506 2 [0005] There is a continuing demand for the development of new and potent therapeutics for the treatment of cancer, inflammation, immune and infectious disorders. Inhibition of angiogenesis has proven to be a validated target in the treatment of these disorders. Compounds with somatostatin subtype 2 selectivity, subtype 2 3 dual selectivity and which inhibit subtypes 2, 3 and 5 have been previously identified by others as anti-angiogenic compounds. It is believed angiogenesis is associated with upregulation of the somatostatin 2 receptor [Pawlikowski, Melen-Mucha Curr. Opin. in Pharmacol. 2004, 4, 608-613].

[0006] There is a need for compounds with improved anti-angiogcnic activity.

SUMMARY OF THE INVENTION [0007] The invention provides compositions, methods, and kits for inhibition of angiogenesis, binding to somatostatin receptors, somatostatin receptor 5, and treatment of conditions for which inhibition of angiogenesis provides a therapeutic benefit.

[0008] It is a general object of the invention to provide compounds with anti-angiogenic properties, suitably, to arrest the development of malignant, inflammatory, immune and infectious disorders. In one aspect, the invention includes compounds described herein, and compositions comprising one or more of the 2 0 compounds described herein, or tautomers, esters, solvates hydrates), or pharmaceutically acceptable salts thereof. It is a further object of the invention to provide a pharmaceutical formulation comprising at least one compound as described herein or a tautomer, ester, solvate, or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

In one embodiment, a pharmaceutical composition of the invention is provided as a pharmaceutically acceptable aqueous formulation, for example for parenteral administration, intravenously, intramuscularly. In some embodiments, a unit dose comprising one or more compounds of the invention is provided in a dry powder lyophilized) form and reconstituted in a pharmaceutically acceptable carrier, such as a sterile aqueous formulation, prior to administration to an individual. In various embodiments, a pharmaceutical composition of the invention comprises one or more compounds of the invention and one or more pharmaceutical carriers, formulated for administration via a route selected from the group consisting of WO 2005/097142 PCT/AU2005/000506 3 intravenous infusion or bolus, oral administration, intramuscular injection, suppository or pessiary, implant device, in the musculature or within a tumor, intra-ocular injection, transmucosal delivery, nasal delivery, or metered pump implant.

[0009] In another aspect, the invention provides a method of inhibition of angiogenesis, in vitro or in vivo. In one embodiment, the invention provides a method for inhibiting angiogenesis, comprising contacting a receptor associated with angiogenesis, for example a somatostatin receptor, somatostatin receptor subtype with one or more compounds of the invention, wherein binding of said one or more compounds to said receptor inhibits angiogencsis.

[0010] In another embodiment, the invention provides a method for inhibiting angiogenesis, comprising contacting a sample comprising a blood vessel or a cell associated with formation of blood vessels with one or more compounds described herein, wherein contacting of said blood vessel or cell with said one or more compounds inhibits angiogenesis.

[0011] It is a further object of the invention to provide a method of treatment of a human or animal subject which method comprises administering to the human or animal subject an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, In one embodiment, the invention provides a method of inhibiting angiogenesis in an individual in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds as described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, to the individual. In some embodiments the invention provides a method for inhibiting growth of a tumor in an individual, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds as described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, to the individual. In some embodiments, the one or more compounds binds to somatostatin receptor subtype 5, thereby inhibiting angiogenesis.

DETAILED DESCRIPTION OF THE INVENTION [0012] The invention provides compounds and pharmaceutical compositions thereof that are useful for inhibition of angiogenesis both in vitro and in WO 2005/097142 PCT/AU2005/000506 4 vivo, and kits comprising compounds of the invention. The invention also provides methods for inhibiting angiogenesis and methods for inhibiting tumor growth with compounds of the invention. The invention further provides methods for inhibiting activity of somatostatin receptors, somatostatin receptor subtype 5, and complexes comprising a compound of the invention bound to a somatostatin receptor.

The invention also provides methods for inhibiting angiogenesis comprising binding of one or more compounds described herein to the somatostatin 5 receptor subtype.

[0013] We have identified compounds that interact in a biologically significant manner, with somatostatin receptors. Surprisingly, compounds exhibiting their strongest interaction with the somatostatin 5 receptor subtype also exhibited potent anti-angiogenic activity. These compounds have now been shown to be antiangiogenic in vitro, ex vivo and in vivo. A number of the compounds described herein have previously been described to interact with G protein coupled receptors (GPCRs) in PCT application no. PCT/AU2003/001347 (WO 2004/032940), which is incorporated by reference herein. As used herein, "biologically significant manner" refers to a binding interaction, a high affinity binding interaction, between a compound of the invention and a somatostatin receptor. Typically, such an interaction has an agonistic or antagonistic effect on receptor activity and/or an inhibitory effect on angiogenesis. Often, a compound of the invention interacts with somatostatin 2 0 receptor subtype 5 with an IC50 of less than about 10 micromolar.

Compositions [0014] The invention provides compounds that are useful for binding to somatostatin receptors and for inhibition of angiogenesis, and pharmaceutical compositions thereof.

Compounds of the invention [0015] In one aspect the invention provides for compounds of general formula I, that interact with one or more somatostatin receptors including somatostatin 3 0 5 in a biologically significant manner, thereby inhibiting angiogenesis, WO 2005/097142 PCT/AU2005/000506 R7 R6 O ZR 1

R

5

X'

R

4 X 3 XR 2

XR

3 General Formula I wherein the ring or any chiral center(s) may be of any configuration; Z is sulphur, oxygen, CH 2 C(O)HN, NH, NR A or hydrogen, in the case where Z is hydrogen then R 1 is not present, RA is selected from the set defined for R 1 to Rs, X and X' are independently oxygen or nitrogen providing that at least one X of General Formula I is nitrogen, X or X' may also combine independently with one of R 1 to R 5 to form an azide,

R

1 to R 5 are independently selected from the following definition which includes but is not limited to H or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear. Typical substituents include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, any of which may optionally be further substituted, and

R

6 and R 7 are hydrogen, or may combine to form a carbonyl function.

[0016] In one embodiment the invention provides for compounds of general formula II that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, WO 2005/097142 PCT/AU2005/000506

.ZR

1 HO' HR 2 General Formula II wherein R 1

R

2

R

3 Rs, and Z are defined as in General Formula I.

[0017] In another embodiment the invention provides for compounds of general formula m that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis,

R

5

X'

XR

2 General Formula III wherein A is defined as hydrogen, SRI, or OR 1 where RI is defined as in General Formula I, and X, R 2

R

3

R

4 and R 5 are defined as in General Formula 1.

[0018] In another embodiment the invention provides for compounds of General Formula IV that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, WO 2005/097142 PCT/AU2005/000506 7 MeO O O R 1 HO "NHR2 OR3 General Formula IV wherein R 1

R

2 and R 3 are defined as in General Formula I.

[0019] In another embodiment, the invention provides for compounds of General Formula V that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, B O A

A

0 0 O

NH

A O L

Q

General Formula V wherein the stereochemistry may be alpha or beta at the anomeric carbon, and may be axial or equatorial at the other pyranosyl ring carbons, nis 0 or 1, is selected from substituted or unsubstituted C1-C8 alkyl, hetero alkyl, cycloalkyl, aromatic or heterocyclic spacer, where typical substituents include but are not limited to nitro, chloro, fluoro, bromo, nitrile, carboxyl, -NH 2 -NHR, -NHB, C1-3 alkyl, -OR, azido, -C(O)NH 2 -C(O)NHR, -C(O)N(R) 2 WO 2005/097142 PCT/AU2005/000506 8

CF

3 -SR, wherein R are typically independently selected from a substituted or unsubstituted alkyl, aryl or heterocyclic group, L is selected from -NB 2 or guanidinium wherein B is defined as below, and additionally and can combine to form a substituted or unsubstituted nitrogen containing heterocycle, Q are independently selected from a substituted or unsubstituted monocyclic or bicyclic aromatic or hetero aromatic, where typical substituents are defined as for A are independently selected from hydrogen, chloro, fluoro or methyl, and B are independently selected from H, methyl, ethyl, propyl.

[0020] In another embodiment the invention provides for compounds of General Formula VI that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, OMe

OO

HO NH OY L o 0" Y

Q

General Formula VI where Y, L, and Q are as defined in General Formula V.

[0021] In another embodiment the invention provides for compounds of General Formula VII that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, WO 2005/097142 PCT/AU2005/000506 9 OMe O 0O HO NH 0

L

w General Formula VII wherein, may represent mono-, di-, tri-, or tetrasubstitution and may be the same or different. Similarly, in combination with the aromatic ring, may represent a substituted or unsubstituted fused ring system which may be hetero-atomic or homoatomic, and may be aromatic or aliphatic. Typical substituents include but are not limited to phenyl, C 1 4 alkyl, heterocycles, nitro, chloro, fluoro, bromo, nitrile, carboxyl, -NH2, -NHR, -NR 2

C

1 -3 alkyl, -OR, azido, -C(O)NH 2 -C(O)NHR,

C(O)N(R)

2

-CF

3 -SR, wherein R are typically independently selected from a substituted or unsubstituted alkyl, aryl or heterocyclic group, and where Y and L are as defined in General Formula V.

[0022] In a further embodiment the invention provides for compounds of General Formula VII that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, WO 2005/097142 PCT/AU2005/000506 General Formula VIII wherein, W, L and Y are as defined above; [0023] In a further embodiment the invention provides for compounds of General Formula IX that interact with one or more somatostatin receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis,

'NH

o v Y

L

General Formula IX wherein, W, L and Y are as defined above; [0024] In a further preferred embodiment the invention provides for compounds of General Formula X that interact with one or more somatostatin WO 2005/097142 PCT/AU2005/000506 11 receptors including somatostatin 5 in a biologically significant manner, thereby inhibiting angiogenesis, w General Formula X wherein, W, L and Y are as defined above.

[0025] In all embodiments described above, where a group may be optionally or further substituted, the possible substituents are selected from the group consisting of OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2 CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl. In a preferred embodiment, the substituents are selected from the group consisting of OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, WO 2005/097142 PCT/AU2005/000506 12 heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, hydroxamate, hydroxamic acid and thioalkyl.

Pharmaceutical compositions [0026] In another aspect, the invention provides pharmaceutical compositions comprising any of the compounds described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0027] In some embodiments, a pharmaceutically acceptable aqueous formulation is provided that is suitable for parenteral administration, such as, for example, intravenous injection. For preparing such an aqueous formulation, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, stabilizers, or other additives normally used in the art may be used.

[0028] A pharmaceutical composition for parenteral administration includes a physiologically acceptable diluent such as deionized water, physiological saline, 5% dextrose, water miscible solvent ethyl alcohol, polyethylene glycol, propylene glycol, etc.), non-aqueous vehicle oil such as corn oil, cottonseed oil, peanut oil, and sesame oil), or other commonly used diluent. The formulation may 2 0 additionally include a solubilizing agent such as polyethylene glycol, polypropylene glycol, or other known solubilizing agent, buffers for stabilizing the solution citrates, acetates, and phosphates) and/or antioxidants ascorbic acid or sodium bisulfite). (See, for example, U.S. Patent No. 6,143,739.) Other suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. As is known in the art, pharmaceutical preparations of the invention may also be prepared to contain acceptable levels of particulates particle-free) and to be non-pyrogenic meeting the requirements of an injectable in the U.S. Pharmacopeia).

[0029] In some embodiments, pharmaceutical compositions of the invention comprise one or more compounds described herein and a pharmaceutically acceptable carrier, suitable for administration via parenteral administration, e.g., intravenous, intramuscular, subcutaneous. In various embodiments, pharmaceutical compositions of the invention comprise one or more compounds described herein and WO 2005/097142 PCT/AU2005/000506 13 a pharmaceutically acceptable carrier, suitable for administration via a route selected from the group consisting of intravenous infusion or bolus injection, oral administration, intramuscular injection, suppository or pessiary, implant device, e.g., in the musculature or within a tumor, intra-ocular injection, transmucosal delivery, nasal delivery, or metered pump implant.

Complexes with somatostatin receptors [0030] In another aspect, the invention provides a complex between a receptor, a receptor that is involved in angiogenesis, and a bound compound as described herein. For example, a complex of the invention may comprise a compound described herein and a somatostatin receptor. In one embodiment, the complex comprises a compound described herein, and a somatostatin receptor, for example, somatostatin receptor subtype 5. In one embodiment, the complex comprises "compound 1" (described infra) and somatostatin receptor subtype Methods of the invention Methods for inhibiting angiogenesis [0031] In one aspect, the invention provides a method of inhibition of angiogenesis, in vitro or in vivo. As used herein, "inhibition of angiogenesis" refers to 2 0 inhibition of formation of new blood vessels; for example, inhibition of the proliferation, migration, and/or differentiation of cells associated with the growth and/or formation of new blood vessels endothelial cells, endothelial progenitor cells, bone marrow cells, smooth muscle cells). Inhibition of angiogenesis may be assessed by methods that are well known in the art, including those described in the Examples herein. Examples of assays for inhibition of angiogenesis include cell proliferation, migration, and differentiation assays, the rat aortic ring assay, chicken chorioalantoic membrane assay, the in vivo matarigel plug assay, and other implant assays. These assays are described in "Angiogenesis Assays: A Critical Overview" [Auerbach, et al. (2003) Clinical Chemistry 49(1):32-40] and references therein.

3 0 [0032] In one embodiment, the invention provides a method for inhibiting angiogenesis, comprising contacting a receptor associated with angiogenesis, for example a somatostatin receptor, somatostatin receptor subtype 5, with one or more compounds of the invention, wherein binding of said one or more compounds to WO 2005/097142 PCT/AU2005/000506 14 said receptor inhibits angiogenesis. As used herein, "binding" of a compound of the invention refers to a specific binding interaction between the compound and the receptor, such that the compound acts as an agonist or antagonist of the receptor.

Generally, the interaction between the compound and the receptor is of high affinity.

In some embodiments, the IC50 of a compound of the invention is less than about micromolar, 1 micromolar, or 0.5 micromolar at the somatostatin 5 receptor. As used herein, "IC50" refers to the concentration of compound required to displace 50% of the native receptor ligand. Receptor binding may be assessed according to a number of well known techniques in the art, including radio-ligand binding assays, cell based assays, and signal transduction pathway assays, as describd in Current Protocols in Pharmacology Ed., Enna, et al., published by John Wiley.& Sons.

[0033] In another embodiment, the invention provides a method for inhibiting angiogenesis, comprising contacting a sample comprising a blood vessel or a cell associated with formation of blood vessels endothelial cells, endothelial progenitor cells, bone marrow cells, smooth muscle cells) in vitro or in vivo with one or more compounds described herein, wherein contacting of said blood vessel or cell with said one or more compounds inhibits angiogenesis. In some embodiments, angiogenesis is inhibited at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% in comparison to a control sample which has not been contacted with the one or more compounds.

Methods of treatment [0034] The invention provides methods of treatment comprising administering one or more compounds of the invention to an individual in need of treatment for a condition for which inhibition of angiogenesis is therapeutically beneficial.

[0035] In one embodiment, the invention provides a method of inhibiting angiogenesis in an individual in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of one or 3 0 more compounds as described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, to the individual. In some embodiments, angiogenesis is inhibited at least about WO 2005/097142 PCT/AU2005/000506 30, 40, 50, 60, 70, 80, 90, or 95% in comparison to an individual to whom the pharmaceutical composition has not been administered.

[0036] In some embodiments the invention provides a method for inhibiting growth of a tumor in an individual, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds as described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, to the individual. In some embodiments, tumor growth is inhibited at least about 30, 40, 50, 60, 70, 80, 90, or 95% in comparison to an individual to whom the pharmaceutical composition has not been administered. In some embodiments, one or more additional therapeutic compounds is administered simultaneously or sequentially, in a combination therapy, for example, one or more chemotherapeutic substances. In one embodiment, one or more chemotherapeutic agents of the taxoid class of anti-tumor compounds, paclitaxel, docetaxel, is administered simultaneously or sequentially with one or more compounds described herein. In other embodiments, 5-fluorouracil, methotrexate, or a platinum drug, cisplatin, carboplatin, oxaliplatin, is administered simultaneously or sequentially with one or more compounds described herein. In one embodiment, the chemotherapeutic agent(s) and the compound(s) described herein act synergistically to inhibit tumor growth.

[0037] As used herein, "individual" refers to a vertebrate, typically a mammal, often a human.

[0038] As used herein, "therapeutically effective amount" refers to the amount of a compound that will render a desired therapeutic outcome inhibition of angiogenesis or reduction of tumor growth). A therapeutically effective amount may be administered in one or more doses. A therapeutically effective dosage of a compound described herein is sometimes about 1 tg/kg to about 100 mg/kg, sometimes about 50 jxg/kg to about 25 mg/kg.

[0039] Administration may be via any route suitable for the condition being treated. For example, administration may be parenteral, intravenous (infusion or bolus injection), intramuscular, subcutaneous, or may be via suppository or pessiary, implantable device, for example intramuscular or within a tumor, intra- WO 2005/097142 PCT/AU2005/000506 16 ocular injection, trasmucosal, transdermal, or nasal administration, or via a metered pump implant.

[0040] Compounds described herein are useful for treatment of conditions for which inhibition of angiogenesis is therapeutically beneficial. For example, compounds described herein may be used for treatment of type I or type II diabetes mellitus, including complications thereof, angiopathy, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy, neuropathy and dawn phenomenon, and other metabolic disorders related to insulin or glucagon release, obesity, for example morbid obesity or hypothalamic or hyperinsulinemic obesity. Compounds described herein may also be used for the prevention or treatment of angiogenesis and inflammatory disorders including inflammatory eye diseases, macular edema, cystoid macular edema, idiopathic cystoid macular edema, exudative age-related macular degeneration, choroidal neovascularization related disorders and proliferative retinopathy. The compounds described herein may also be used in the treatment of enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, inflammatory diseases, Grave's disease, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, dumping syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal bleeding, variceal 2 0 oesophagial bleeding. Compounds described herein may also be used in the treatment of tumors and malignant cell proliferative diseases, for example, gastrointestinal hormone secreting tumors GEP tumors, for example vipomas, glucagonomas, insulinomas, carcinoids), lymphocyte malignancies, lymphomas, leukemias, hepatocellular carcinoma, colon and bowel, liver, breast, prostate, lung, stomach, pancreas, or other GI tract cancers.

Kits [0041] The invention also provides kits for use in methods of the invention. The kits include one or more compounds described herein. A kit may include a pharmaceutical composition as described herein, for example including at least one therapeutically effective dose of at least one compound of the invention, and optionally instructions for use, for example, instructions providing information to a health care provider regarding usage in a method of the invention as described above.

WO 2005/097142 PCT/AU2005/000506 17 Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. In some embodiments, the kit comprises a compound described herein as a sterile aqueous pharmaceutical composition or as dry powder lyophilized) composition.

[0042] Suitable packaging is provided. As used herein, "packaging" refers to a solid matrix or material customarily used in a system and capable of holding within fixed limits a composition suitable for administration to an individual.

Such materials include glass and plastic polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.

[0043] Kits may also optionally include equipment for administration of a pharmaceutical composition, such as, for example, syringes or equipment for intravenous administration, and/or a sterile solution, a diluent, for preparing a dry powder lyophilized) composition for administration.

[0044] The following Examples are intended to illustrate, but not limit, the invention.

EXAMPLES OF THE INVENTION Example 1. Ex ovo determination of antiangiogenic effects using the early chicken embryo chorioallantoic membrane (earlvCAM) [0045] "Compound 1" was assayed to determine its anti-angiogenic characteristics ex vivo according to a previously published method [A novel early chorioallantoic membrane assay demonstrates quantitative and qualitative changes caused by antiangiogenic substances, Hazel, JLab Clin Med, 2003, 141, 217-28].

Vein Diameter [0046] Vein diameter was included as a measure of vessel growth. Where there was more than one major vein branch, the diameters of both were added together WO 2005/097142 PCT/AU2005/000506 18 to give a total vein diameter. In the control CAM there were two well developed vein branches of similar diameter. In contrast, in the treated CAM there was a single major vein branch. Total vein diameter is 239 pixels in the control CAM, and only 107 pixels in the treated CAM.

Octeotride [0047] As a comparison, octeotride was tested in the earlyCAM assay. At a dose of 10 nmol octeotride did not appear to have any significant effect on the CAM vasculature.

1C General Results [0048] When "compound 1" was applied to the CAM, there were dose responsive reductions in CAM growth and vasculature. The effects on CAM growth and vessel parameters were expressed as pixel measures (Table 1) and also as a percentage of the vehicle treated control group (Figure Vein lengths were reduced at all dose levels of "compound both in pixel and percentage terms, with a reduction to 67% of control at 5 nmol In contrast the artery lengths were not reduced as much, with a maximal reduction to 86% of control at 1 nmol. When artery and vein lengths were combined to give total vessel length there was a significant 2 0 reduction at the 5 nmol level (Figure 1; p<0.05). A strong trend to reduced CAM growth with increasing doses of "compound 1" was also present. Hence, when vessel lengths were expressed relative to the CAM size, relative vessel lengths were not significantly changed with "compound 1" treatment.

[0049] Vein diameter was also reduced in a dose dependent manner, from 215 pixels in the vehicle control group to 157 pixels in the 5 nmol group (p 0.057).

This represents an approximately 25% reduction in vein diameter in the 5 nmol group versus control.

[0050] In the vehicle control the vessels were well developed and regularly organised. Following treatment with 1 nmol of "compound 1" there was some distortion of the CAM, but the vessels were still reasonably well developed.

However, in the CAM treated with 5 nmol of "compound 1" there was a single attenuated major vein branch and far fewer vessels. In the higher magnification image WO 2005/097142 WO 205/07142PCT/A1J20051000506 19 the avascular areas between the vessels were apparent, and the major vessel branches are relatively thin compared with the control CAM.

Table 1: Effects of "compound 1" on vessel parameters in the earlyCAM assay.

Mean SEM; n--8.

Vehicle 0.2 nmol 1 nmol 5 nrnol CAM increase 11.1±0.7 9.9 ±0.9 9.9 ±0.8 8.9 ±0.8 (fold) Vein length 2158±158 1628 ±183' 1625 ±1661 1429 ±1411 (pixels) Artery length 1922±156 1870 ±109 1544 ±214 1510 ±196 (pixels) Total vessel 4080± 289 3498 ±222 3169 341 2939 ±292' length Relative vein 42.8 1.9 36.9 3.4 36.5 2.4 35.1 2.6 length Relative artery 38.0 ±1.4 43.0 ±3.7 34.7 ±4.7 36.4 length Relative total 80.8 ±2.1 79.9 ±5.8 71.3 ±6.3 71.6 ±3.7 vessel length *I Vein diametera 215±9 191 ±10 187 ±15 157 ±23 (pixels) *Relative vessel length =absolute vessel length (pixels)/ CAM area (pixels) 1: p<0.05 vs vehicle a: 0 5 7 WO 2005/097142 PCT/AU2005/000506 0 °0.2 nmol SInmol nmol Bo p<0.05 vs vehicle 0 Fig. 1: Effects of "compound 1" on vessel parameters as a percentage of the vehicle control in the earlyCAM assay.

Example 2. In vivo pharmacokinetic evaluation of "compound 1" after i.v. and p.o. administration to rats.

Experimental conditions [0051] Intravenous infusion of "compound 1" (2 mg/Kg) over 5 minutes to two rats and arterial blood sampled up to 24 hours.

Oral administration of "compound 1" (25 mg/Kg as HPMC suspension) via oral gavage to two rats and arterial blood sampled up to 24 hours.

-Plasma concentrations of "compound 1" determined by MS (LOQ 0.01 pM) [0052] Calculations: CLtotaI Dose i AUCjv V CLtota AUCoral Dosev Vd 3AUC DBA(%)eor VP- AUG, Dose ora CLtotai total plasma clearance after IV administration WO 2005/097142 PCT/AU2005/000506 21 Vd/ volume of distribution during the elimination phase after IV administration BA oral bioavailability AUCiv area under the plasma concentration versus time profile from time zero to infinity after IV administration AUCorai area under the plasma concentration versus time profile from time zero to infinity after oral administration f terminal elimination rate constant after IV administration Summary [0053] Following an I.V. dose, the elimination half-life of "compound 1" was approx 4.6 h. The clearance and volume of distribution values were 8.20 mL/min/Kg and 3.30 L/Kg, respectively. The bioavailability of "compound 1" following oral dosing was approximately 5.2 This is based on the AUC from 0 to 480 min.

Table 2: Pharmacokinetic parameters following I.V. and oral administration of "compound 1" to rats.

Mean Parameter Rat 1 Rat 2 Mean ±SD Rat 3 Rat4 IV IV PO PO Measured 28 Dose 2.66 2.67 2.67 0.01 27.17 29.64 (mg/Kg) 7 31.87 69 4.95 Cmax 30.26 33.48 6.95 2.94 2.27 2.84 Tmax (min) 20 20 t 1 2 4.45 4.76 4.60 0.22 n.d. n.d. n.d.

(lt o /tala 7.53 8.86 8.20 0.94 (ml/min/Kg) VdB (L/Kg) 2.90 3.69 3.29 0.56 4.95 5.38 5.16 0.30 WO 2005/097142 PCT/AU2005/000506 Total plasma clearance Oral BA calculated using AUCO- 480 not determined rat 030304-A IV rat 030304-B IV rat 030307-B Oral 2 10 a- rat 030307-0 Oral 0 c 3 o 1 E 9 0.3 0.1 0.05 0 100 200 300 400 500 Time (min) Fig. 2: Dose normalized plasma concentration of "compound 1" following I. V (2mg/kg) and oral (25 mg/kg) administration in rats.

Example 3. In vivo efficacy evaluation of "compound 1" in a nude mouse model of human PC-3 prostate tumours.

[0054] Initial Maximum Tolerated Dose (MTD) studies were done in male nude mice to determine the appropriate intravenous dosing regimen for the PC-3 human prostate tumour model. A range of doses between 0 and 50 mg/Kg for 28 days (qdx28) were tested. Mice were randomized into groups with 5 animals per group including vehicle control. Animals were weighed twice weekly starting on day one and observed daily for adverse reactions or toxicity due to the agent. MTD studies determined the selection of 20 mg/kg and 35 mg/kg for intravenous dosing once per day for 28 days in the PC-3 human prostate tumour xenograft model.

WO 2005/097142 PCT/AU2005/000506 23 [0055] Male nude mice (nu/nu) between 5 and 6 weeks of age weighing approximately 25 g were implanted subcutaneously by trocar with fragments of PC-3 human tumour carcinomas harvested from s.c growing tumours in host mice.

PC-3, is a metastatic human prostate adenocarcinoma cell line originating from a 62 year old Caucasian male. When tumours reached approximately 36 mm 3 in size animals were pair matched into treatment and control groups with 10 mice in each group. Each mouse was tagged and followed individually throughout the experiment.

[0056] "Compound 1" was administered i.v. in a saline vehicle from day one. Vehicle control group animals were administered saline i.v. There were two treatment groups, one group received 20 mg/kg of "compound 1" i.v. and the second group received 35mg/kg of "compound 1" i.v. These 3 groups were treated daily for 29 days. A fourth positive control group of animals were given the standard chemotherapeutic agent Taxotere® i.v on days 1, 3 and 5 of the study.

[0057] Mice were weighed twice weekly and tumour measurements were obtained using calipers twice weekly. Collection of measurements started on day 1.

Tumour measurements were converted into tumour volume (mm 3 using the standard formula (W 2 x L) x 0.52.

[0058] At the end of the treatment period the mice were weighed and sacrificed. Each tumour was excised and weighed and a mean actual tumour weight (mg) per group was calculated along with the mean actual volume (mm 3 Mice having a tumour with less volume than on day 1 were classified as having partial tumour regression. Mean tumour regression was determined using the formula [1- (mean actual tumour weightFINAL/mean tumour weightDAY 1) x 100%].

[0059] Tumour growth inhibition (TGT) was calculated for each group containing treated animals that did not demonstrate tumour regression using the formula [1-(mean actual tumour weightFNAL(treated) mean tumour weightDAYl (treated) mean actual tumour weightFINAL(vehicle control) mean tumour weightDAYI(vehicle control)) X 100%].

3 0 Results [0060] In these studies, "compound 1" was found to result in TGI of 34% at both doses tested.

WO 2005/097142 PCT/AU2005/000506 24 Example 4. In vitro determination of human hepatocyte microsomal degradation half-life.

General experimental protocol [0061] -"Compound 1" (in 50% acetonitrile) was added to a microsomal incubation mixture (1:50 dilution) to achieve a final concentration that was less than the compound's solubility limit in pH 7.4 phosphate buffer, -the final concentration ofACN in the microsomal incubation was 1%, -samples were incubated in a water bath at 37 0 C, and -45 tL aliquots were taken over 2 hr, quenched with ACN, placed on ice for 30 min to precipitate proteins and assayed by LC/MS/MS using either the Quattro Ultima Pt, LCT or Q-Tof instruments.

Results Table 3 Compound Degradation Predicted Predicted Pr Predicted tl/2 CLint CLblood (min) (mL/min/kg) (mL/min/kg) 1 32.2 62.2 15.5 0.75 Example 5. In vitro determination of toxicity using the ActiveTox® suite of assays [0062] Compounds were analyzed in eight separate assays at concentrations of 10 and 100 M in quadruplicate. Compounds were assayed for toxicity via LDH release, inhibition of proliferation, ATP content, caspase 3/7 activation. Compounds were assayed for induction of cyplA and P-glycoprotein inhibition. Compounds were also assayed for cyp3A induction under conditions which favor activation via the pregnane receptor (PXR) or the glucorticord receptor Appropriate positive and negative controls were included in each case.

"Compound 1" showed no statistical effects in any of the above assays from the ActiveTox® suite.

WO 2005/097142 PCT/AU2005/000506 Example 6. In vitro cell proliferation measurements as an indicator of compound toxicity [0063] A simple cell proliferation assay was used to determine the in vitro cytotoxicity of "compound Selected cell lines were cultured according to their specific requirements. The optimal cell density required for each cell line was determined. All compounds were tested at a single concentration in triplicate. Cell viability was determined using the CellTiter 969 AQueous One reagent from Promega Corporation.

[0064] Assays are performed by adding the test compound to the cells in culture and incubating the cells for a fixed period. The number of viable cells remaining after the incubation period is determined by adding a small amount of the CellTiter 96® AQueous One Solution Reagent directly to culture wells, incubating for 1-4 hours and then recording absorbance at 490 nm with a 96 well plate reader.

[0065] Controls in the assay include untreated cells, wells without cells and cells treated with know cytotoxic agents. Data is presented as inhibition of cell proliferation. "Compound 1" showed no inhibitory effect on cell proliferation of 3T3, MCF_7, or Jurkat cell lines at 100 tM.

Example 7. In vitro determination of absorption of "compound 1" by determination of transport across a Caco-2 cell monolayer [0066] The Caco-2 assay was performed according to the procedure described in the following cited article [Caco-2 Monolayers in Experimental and Theoretical Predictions of Drug Transport, Artursson P, Palm K, Luthman Adv.

Drug Deliv. Rev., 2001, 46, 27-43]. "Compound 1" was shown to have a Papp of 1.04 x 10 6 cm/sec relative to mannitol at 8.13 x 10 7 cm/sec.

WO 2005/097142 PCT/AU2005/000506 26 Example 8. Solubility Data Table 4: Solubility Data for Salts of "Compound 1" Salt Water (mg/mL) a (mg/mL) b Free Base 0.

0.2 (Compound 1) TFA 3.64 5.27 Citrate 4.54 Acetate 6.96 Methanesulphonate 5.17 Hydrochloride 7.87 6.30 Succinate 8.52 4.98 *-Not Examined a-overnight b-Day 3 Example 9. In vitro screening of compounds against somatostatin subtypes SSTR-1 to General method [0067] Receptor membrane preparations containing the desired cloned receptor (for example cloned human somatostatin receptor subtype 5, SSTR5) and radio-labeled ligand (for example 3-[ 1 25 I]iodotyrosyl Somatostatin-14)) were diluted at the concentration required for testing and according to the specific parameters associated with the selected receptor-ligand combination, including receptor Bmax, ligand Kd and any other parameters necessary to optimize the experimental conditions.

2 0 When tested for competition activity to the reference ligand, "compound 1" was mixed with membrane suspension and the radiolabeled reference ligand (with or without an excess of cold ligand to the receptor for determination of non-specific binding) and incubated at the temperature required by internal standard operating procedures. Following incubation, the binding reaction was stopped by the addition of ice-cold washing buffer and filtered on appropriate filters, which are then counted.

Data analysis and curve-fitting was performed with XLfit (IDBS).

WO 2005/097142 PCT/AU2005/000506 27 Preparation of compounds [0068] 10mM solutions of test compounds in 100% DMSO were prepared. ~160 pl was used for each dilution (20 pl/well in triplicate).

A 1.25 mM assay stock was prepared by making a 1:8 dilution of the 10 mM solution. (To 3 pL of the 10 mM solution was added 210 pL milli-Q H 2 0. A dilution series in milli-Q H 2 0 was then prepared.

Final concentration Final concentration concentration in SST4 assay in SST5 assay A. 240 [L of 1.25 mM 0.25 mM 0.125 mM B. 48 pL A 192 pL mQ 0.05 mM 0.025 mM C. 24 L B 192 pL mQ 0.01 mM 0.005 mM etc [0069] Assays were performed in triplicate at each concentration within the 1:5 dilution series: 250|pM, 50p-M, 10 pM, 2mM, 0.4p-M, 0.08pM, 0.016[pM, 0.0032 pM, etc. (for SST4 assay) and 125pM, 10pM, 2pM, 1pM, 0.5. pM, etc (for assay).

Filter plate assay for SST5 receptor 2 0 [0070] Human SST5 somatostatin receptor was transfected into HEK- 293 EBNA cells. Membranes were suspended in assay buffer (50 mM Tris-HC1, 1 mM EGTA, 5 mM MgC12, 10% sucrose, pH The receptor concentration (Bmax) was 0.57 pmol/mg proteinKd for 1 2 5 I]SST-14 Binding 0.31 nM,volume 0.4 ml per vial (400 microassays/vial), and protein concentration 1.03 mg/ml.

[0071] After thawing the frozen receptor preparation rapidly, receptors were diluted with binding buffer, homogenized, and kept on ice.

1. Use Multiscreen glass fiber filter plates (Millipore, Cat No precoated with o.5 PEI for 2hr at 40C. Before use add 200 pl/well assay buffer and filter using Multiscreen Separation System.

2. Incubate 5.5 pg of membranes (40 p/ of a 1:40 dilution), buffer and [1251]SST-14 (4 nM, -80 000 cpm, 2000 Ci/mmol) in a total volume of 200 pl for 60 min at 250C. Calculate IC50 for SST-14 (a truncated WO 2005/097142 PCT/AU2005/000506 28 version of the natural ligand SST-28) (Auspep, Cat No 2076) and SST- 28 (Auspep, Cat No 1638). Prepare serial dilutions of compounds, as described above and instead of adding SST-14 in well, add 20 i1 of compounds (Table 1).

3. Filter using Multiscreen Separation System with 5 x 0.2 ml ice-cold Assay buffer.

4. Remove the plastic underdrain and dry plate in oven for 1 hr at 40 0

C.

Seal tape to the bottom of the plate.

6. Add 50 il/well scintillant (Supermix, Wallac, Cat No 1200-439).

7. Seal and count in the BJET, program 2.

Table Volume (ul); Membranes (5.5 pg/well) Hot label 80 000 epm, 4nM) Cold hormone mQH z

O

Compounds Assay buffer ,NSB Compounds testing 40 i40 100 'Total volume 200 200 200 TB: total binding NSB: non-specific binding [0072] In primary screening experiments compounds were tested in duplicate for a particular concentration. When determination of IC5o values was required ten concentrations of the compounds were tested in duplicate such that the concentration range covered several log units above and below the expected [0073] Membranes were contacted with a test compound and a radioactive ligand (SST-14) versus a blank with radioactive ligand only and no test compound. The percentage of displaced radioactive ligand in the test samples relative to the blank, at two concentrations of each test compound, is represented as inhibition of binding in Table 6 below.

WO 2005/097142 WO 205/07142PCT/A1J20051000506

'NH

Scaffold type A Table 6.

Scaffold type B Inhibition of binding of SST-14 to Scaffold Type X R1 R2 R3 R4 Inhib Inhib l0uM 17' B 0 .Me2Nap PrG MePh4CI Me 98 84 18 B 0 MePh EtN Me2Nap Me 98 19 A 0 MePh4CI PrN Me2Nap Me 98 88 B 0 Me2Nap PrN MePh4CI Me 97 76 21 -B 0 Me2Nap EtN MePh Me 97 81 22 B 0 MePh EtN MePh4CI Me 96 23 A 0 Me2Nap PrG MePh4Cl Me 96 24 B 0 MePh4CI PrN Me2Nap Me 96 67 A 0 Me2Nap PrN MePh4Ph Me 96 77 26 B 0 Me2Nap EtN MePh4Ph Me 96 77 27 B 0 MePh4CI PrN MePh4Ph Me 96 74 28 B 0 EtPh PrN Me2Nap Me 96 29 A 0 Me2Nap PrN MePh4Ph Me 96 77 A 0 MePh4GI PrN MePh4Ph Me 96 31 A 0 MePh4Ph PrN MePh4Ph Me 96 32 A 0 MePh PrN Me2Nap Me 95 33 A 0 MePh4CI PrN MePh4CI Me 95 88- 34 B 0 EtPh EtN MePh4GI Me 95 61 B 0 Me2Nap EtG MePh4CI Me 95 WO 2005/097142 WO 205/07142PCT/A1J20051000506 36 Me2Nap MePh4Ph IMe 95 1 67 37 B 0 MePh EtN Me2Nap Me 95 81 38 A 0 MePh4Ph PrN Me2Nap Me 95 79 39 B 0 MePh4GI EtN MePh4CI Me 95 74 A 0 MePh4GI PrN Me MePh4Ph 95 6 41 B 0 MePh4CI PrN MePh4CI Me 94 63 42 A 0 EtPh PrN MePh4CI Me 94 77 43 B 0 Me2Nap PrN MePh4Ph Me 94 68 44 A 0 EtPh PrN Me2Nap Me 94 78 B S Me MeG MePh4CI MePh 93 71 46 B 0 MePh PrN MePh4Ph Me 93 71 47 A 0 Me2Nap PrN MePh4CI Me 93 68 48 A 0 MePh4CI PrN Me2Nap Me 92 66 49 B S Me PrG Me2Nap MePh4CI 92 B 0 MePh4CI EtG Me2Nap Me 92 74 51 A 0 MePh4Ci 2THPI Me Me2Nap 92 76 52 A 0 Me2Nap EtG MePh4Ph Me 92 69 53 B 0 MePh EtG Me2Nap Me 91 58 54 B 0 MePh EtN MePh4Ph Me 91 A 0 MePh4Ph PrG MePh4Ph Me 91 71 56 A 0 MePh4GI PrG MePh4CI Me 91 57 57 B 0 Me2Nap EtG Me2Nap Me 91 64 58 A 0 MePh4Ph PrG MePh4Ph Me 91 59 B 0 MePh PrN MePh4CI Me 90 66 B 0 Me2Nap PrG Me2Nap Me 90 57 61 A 0 Me2Nap PrN MePh4CI Me 90 61 62 B 0 EtPh PrG MePh4CI Me 90 61 63 A 0 MePh4Ph PrN MePh4CI Me 90 64 B 0 Me2Nap PrG MePh Me 90 57 A 0 EtPh PrN MePh4Ph Me 90 61 66 B S Me EtN Me2Nap MePh4Ph 89 61 67 A 0 MePh4CI PrG Me MePh4Ph 89 48 68 A 0 Me2Nap PrN MePh Me 89 46 69 B 0 MePh4GI 3PipG Me Me2Nap 89 67 WO 2005/097142 WO 205/07142PCT/A1J20051000506 0 1MePh4Ph 31 MeG MePh4Ph F 89 18 71 B 0 MePh4CI EtG MePh4CI Me 89 49 72 B S Me MeG Me2Nap MePh 89 51 73 A 0 EtPh PrN Me2Nap Me 89 56 74 A 0 MePh4Ph PrN MePh4CI Me 89 64 A 0 Me2Nap PrG Me2Nap M e 89 61 76 B 0 MePh PrN Me2Nap Me 88 51 77 A 0 MePh4Ph PrG MePh4Ph Me 88 78 A 0 MePh4Ph EtG Me MePh4CI 86 43 79 A 0 MePh4CI 4PipG Me Me2Nap 88 A 0 MePh4Ph PrN MePh4Ph Me 88 44 81 A 0 Me2Nap PrN Me Me2Nap 87 82 A 0 Me2Nap PrN MePh3OH Me 87 48 83 B S Me MeN MePh4Ph MePh4GI 87 61 84 A S Me Ph MePh3N MePh 87 B 0 Me2Nap EtG MePh Me 87 54 86 A 0 Me2Nap EtG MePh4Ph Me 87 58 87 B 0 MePh EtG MePh4Ph Me 86 43 88 A 0 Me2Nap MeG MePh4Ph Me 86 63 89 B S Me EtG MePh Me2Nap 86 58 A 0 MePh4CI PrN MePh4Ph Me 86 52 91 B S Me PrG Me2Nap MePh 86 53 92 B 0 Me2Nap PrN MePh Me 86 52 93 A 0 MePh4Ph PrG MePh4CI Me 86 47 94 B S Me PrN MePh4Ph MePh 86 A 0 MePh PrN MePh4Ph Me 85 44 96 A 0 MePh4CI PrG MePh4Ph Me 85 43 97 B S Me MeN MePh4Ph Me2Nap 85 41 98 A 0 EtPh PrG MePh4CI Me 84 99 B 0 MePh4CI EtG MePh4Ph Me 84 43 100 B 0 MePh PrG Me2Nap Me 84 59 101 A 0 MePh4CI EtG MePh4Ph Me 84 102 B 0 MePh EtG MePh4CI Me 84 42 103 A 0 Me2Nap PrG MePh4CI Me 84 48 WO 2005/097142 WO 205/07142PCT/A1J20051000506 Me2Nap Me2Nap 84 105 B S Me EtN MePh Me2Nap 83 44 106 B 0 EtPh EtN MePh Me83 53 107 A 0 MePh4Ph PrG Me2Nap M4 e 83 54 108 A 0 MePh4Ph EtO MePh4CI Me 83 47 109 B S Me EtN Me2Nap Mie Ph 83 44 110 A 0 MePh PrN MePh4CI Me83 il1 B S Me MeG MePh4Ph -MePh4CI 83 T36 112 B 0 MePh EtG MePh Me 83 58 113 A 0 MePh4CI PrN MePh3OH Me 83 114 B S Me EtG Me2Nap Me2Nap 82 47 115 A 0 Me2Nap EtG Me Me2Nap 82 116 B S Me MeG MePh4CI Me2Nap 82 42 117 B 0 MePh4CI PrN MePh Me 82 46 118 B S Me EtG MePh4CI MePh 81 37 119 B 0 MePh MeG MePh4Ph Me 81 37 120 A 0 MePh4Ph PrG MePh4Ci Me 81 46 121 A 0 MePh4CI PrN Me Me2Nap 81 32 122 A 0 MePh4CI PrN Me MePh4CI 81 39 123 A 0 MePh4CI EtG MePh4CI Me 81 124 B H EtN MePh4CI MePh4Ph 80 125 B S Me EtG Me2Nap MePh4CI 80 34 126 A 0 Me2Nap MeG Me Me2Nap 80 57 127 B S Me PrN Me2Nap MePh4Ph 80 48 128 B S Me EtG Me2Nap MePh 80 28 129 A 0 MePh4Ph MeG MePh4Ph Me 80 36 130 A 0 MePh4Ph PrG MePh4Ph Me 80 131 B S Me MeG Me2Nap Me2Nap 80 52 132 A 0 EtPh PrG MePh4Ph Me 80 39 133 B 0 Me2Nap MeG MePh4CI Me 80 24 134 A 0 Me2Nap PrG Me MePh4CI 79 135 A 0 Me2Nap PrG MePh Me 79 136 A 0 MePh4Ph EtG Me MePh4Ph 79 26 137 A 0 Me2Nap MeG Me2Nap Me 79 43 WO 2005/097142 WO 205/07142PCT/A1J20051000506 0 MePh 33 PrG MePh4CI 79 139 B S Me MeG Me2Nap MePh4Ph 79 34 140 A 0 EtPh PrN Me Me2Nap 78 38 141 A 0 EtPh PrN Me MePh4CI 78 36 142 B S Me EtG MePh MePh4CI 78 44 143 A 0 Me-2Nap PrN Me MePh4Ci 78 144 A 0 MePh PrN MePh3OH Me 78 145 A 0 EtPh PrN MePh4CI Me 78 146 A 0 Me2Nap PrN MePh3OH Me 77 147 A 0 EtPh PrN MePh3OH Me 77 148 B S Me PrN MePh4CI MePh4Ph 76 38 149 B S Me MeG MePh4Ph MePh 76 150 B S Me MeG Me2Nap MePh4CI 76 42 151 A 0 Me2Nap EtG Me2Nap Me 76 36 152 A 0 MePh4CI EtG Me MePh4CI 76 47 153 B S Me PrN Me2Nap MePh4CI 76 34 154 B 0 MePh PrN MePh Me 76 33 155 B S Me PrG MePh4Ph MePh 76 46 156 B S Me PrN Me2Nap MePh 76 157 A 0 MePh4Ph PrG Me MePh4Ph 75 158 B S Me EtN MePh4CI Me2Nap 75 36 159 B 0 MePh4CI MeG Me2Nap Me 75 31 160 A 0 MePh4CI PrG Me2Nap Me 74 161 A 0 Me2Nap PrN Me MePh4Ph 74 51 162 B 0 MePh MeG Me2Nap Me 74 163 B 0 MePh EtN MePh Me 73 34 164 A 0 MePh4CI PrN MePh Me 73 39 165 A 0 MePh PrG MePh4Ph Me 73 37 166 A 0 EtPh EtG MePh4CI Me 73 36 167 B S Me MeN Me2Nap MePh4CI 73 43 168 A 0 EtPh PrG MePh4CI Me 72 47 169 A 0 Me2Nap EtG Me MePh4Ph 72 27 170 A 0 Me2Nap EtG MePh Me 72 29 171 A 0 MePh PrG Me MePh4Ph 72 44 WO 2005/097142 WO 205/07142PCT/A1J20051000506 34 172 A 0 1MePh EtG MePh4Ph Me 72 21 173 A 0 MePh4CI MeG Me Me2Nap 71 47 174 B 0 Me2Nap MeG Me2Nap Me 71 31 175 A N 2Nap PrG MePh4CI Me 71 29 176 B 0 MePh4CI PrG MePh Me 71 37 177 A 0 MePh4CI MeG Me MePh4Ph 71 47 178 A 0 MePh4Ph PrG Me2Nap Me 71 39 179 A 0 MePh4Ph PrN Me MePh4Ph 70 29 [0074] Where scaffold type A is of the D-gluco configuration as shown and type B is of the D-Allo configuration as shown. X may be either Sulfur Oxygen or an amide funictionality in which the nitrogen is bound to the anomeric position of the carbohydrate ring.

[00751 The substituents at Ri, R3 and R4 are described as: Me is methyl (043); MePh is benzyl; MePh4Cl is p-chlorobenzy1; MePh4Ph is p-phenylbenzyl; Me2Nap is beta-napthylmethyl; MePh3OH is m.-hydroxybenzyl; MePh3N is mnaminobenzyl; EtPh is phenethyl or ethyiphenyl; [0076] The substituents at R2 are described as: MeN is methylamino

CH

2

-NH

2 EtN is ethylamino -CH 2

-CH

2

-NH

2 PrN is n-propylamino, -CH 2

-CH

2

-CH

2

NH-

2 MeG in methylguanidinium -C11 2

-NH-C(=NH)-NH

2 EtG is ethylguanidinium

-CH

2

-CH

2 -NfI-C(=NHE)-NH 2 PrG is propylguanidinium -CH 2

-CH

2

-CH

2

-NH-

C(=Ni)-N11 2 3-PipG is WO 2005/097142 WO 205/07142PCT/A1J20051000506 I N,

NH

NH,

4-PipG is; N NH 2THPI is

H

N

Table 7. Binding of "Compound 1" to Somatostatin Receptor Subtypes SSTRI SSTR2 ISSTR3 SSTR4 "Cmond 1" >12.5 LLM 7.5 M 18.5 4M >12.5 L 322 nM Hilislope ND' 11.2 11.04 ND 0.71 selectivity ND 23.3 126.4 ND 1 SST-28 control 1C50 5.137 nM 1.09 nM 12.49 nM 12.074 nM 0.66 nM Hillslope -1.42 -2.03 1-1.49 -1.23 selectivity 7.8 1.6 13.7 18 I 1C50 represents the concentration of compound required to displace 50% of the competitive radioligand.

Selectivity is the nornialized 1C50: that is the lowest IC50 for a compound is assigned a value of 1 and each other IC50 is some multiple of that number.

SST-28 is the natural ligand and is a positive control for this experiment.

WO 2005/097142 PCT/AU2005/000506 36 Table 8. Ki Values for Compounds 2-16 Compound SSTR1 SSTR2 SSTR3 SSTR4 2 2280 728 203 3258 353 3 NoModel NoModel 3732 1230 (127) 4578 (147) 4 1595 842 188 1424 530 2547 1572 285 8542 153 6 NoModel NoModel >10000 (29247) (206) >10000 151 7 6092 498 131 9133 22 8 3092 2009 599 2774 598 9 NoModel NoModel >10000 490 463 (1.1) NoModel >10000 726 (228) noModel 220 11 NoModel NoModel 9221 4846 3984 (3) 12 NoModel >10000 5060 (429) >10000 46 13 NoModel >10000 >10000 (476) >10000 62 14 >10000 1210. 340 >10000 549 1956 1038 792 2257 73 16 2369 860 441 4378 Ki is expressed in nM concentration. Where Ki could not be detennined, the corresponding IC50 in nanomolar concentration is shown in parentheses. Ki is defined by the Michaelis-Menten kinetic equation as described in "Biochemistry" by A. Lehninger.

No Model indicates the slope of the curve is such that a reasonable Ki could not be extracted.

WO 2005/097142 PCT/A1J20051000506 37 Example 10. Endothelial cell proliferation assays cI H2 HH H 0~ NH, 4 0

H

'1 7 0

H

2

H

0 NH 2 8 0 0 'N N J NHz N) H 10 0 cdH 0 1 WO 2005/097142 PCT/AU2005/000506 0--j 'Ne MeO 0

H

16 [0077] Human Umbilical Vein Endothelial Cells (HUVEC from Clonetics) were plated in 96 well plates at 1000 cell per well in EGM-2 medium (Clonetics). Cells were grown overnight at 37°C in 5% CO 2 Fresh EGM-2 medium containing compound at the desired concentration was added to the wells and the cells allowed to grow for a further 48hrs. A MTS (Promega) colorimetric assay was performed after 48hrs to determine cell growth according to the manufacturers instructions. Results are presented in terms of percentage growth.

Table 9 Growth Compound Number 125uM 250uM 2 -83 -91 3 -75 -39 4 -98 -89 -57 6 24 -78 7 -81 -63 8 66 -18 9 -86 -78 -85 -63 11 29 -53 12 -95 -71 13 58 14 -95 -78 -67 1 69 17 WO 2005/097142 PCT/AU2005/000506 39 Example 11. In vivo efficacy evaluation of "compound 1" in a nude mouse model of human MV522 non-small cell lung cancer (NSCLC) tumours [0078] Initial Maximum Tolerated Dose (MTD) studies were done in male nude mice to determine the appropriate intravenous dosing regimen for the MV522 human NSCLC tumour model. A range of doses between 0 and 50 mg/Kg for 28 days (qdx28) were tested. Mice were randomized into groups with 5 animals per group including vehicle control. Animals were weighed twice weekly starting on day one and observed daily for adverse reactions or toxicity due to the agent. MTD studies determined the selection of 20 mg/kg and 35 mg/kg for intravenous dosing once per day for 28 days in the MV522 human NSCLC tumour xenograft model.

[00791 Male nude mice (nu/nu) between 5 and 6 weeks of age weighing approximately 20 g were implanted subcutaneously by trocar with fragments of MV522 human tumour carcinomas harvested from s.c growing tumours in host mice.

MV-522 is a metastatic human lung adenocarcinoma line. When tumours reached approximately 72mg in size animals were pair matched into treatment and control groups with 10 mice in each group. Each mouse was tagged and followed individually throughout the experiment.

[00801 "Compound 1" was administered i.v. in a saline vehicle from day one. Vehicle control group animals were administered saline i.v. There were nine treatment groups including the vehicle control group. Group one animals received saline, i.v. qdx28; group 2 received "compound 1" 20 mg/kg, i.v. qdx28; group 3 received "compound 1" 35mg/kg i.v. qdx28; group four received paclitaxel 8mg/kg i.p. qdx5; group five received paclitaxel 16mg/kg i.p. qdx5; group six received mg/kg of "compound 1" i.v. qdx28 and paclitaxel 8mg/kg i.p. qdx5; group seven received 20 mg/kg of "compound 1" i.v. qdx28 and paclitaxel 16 mg/kg i.p. group eight received 35 mg/kg of "compound 1" i.v. qdx28 and paclitaxel 8mg/kg i.p.

group nine received 35 mg/kg of "compound 1" i.v. qdx28 and paclitaxel 16mg/kg i.p. [0081] Mice were weighed twice weekly and tumour measurements were obtained using calipers twice weekly. Collection of measurements started on day 1.

WO 2005/097142 PCT/AU2005/000506 Tumour measurements were converted into tumour volume (mm 3 using the standard formula [(W 2 x L) [0082] At the end of the treatment period the mice were weighed and sacrificed. Each tumour was excised and weighed and a mean actual tumour weight (mg) per group was calculated along with the mean actual volume (mm 3 Mice having a tumour with less volume than on day 1 were classified as having partial tumour regression. Mean tumour regression was determined using the formula [1- (mean actual tumour weightFINAL/mean tumour weightDAY 1) x 100%].

[0083] Tumour growth inhibition (TGI) was calculated for each group containing treated animals that did not demonstrate tumour regression using the formula [1-(mean actual tumour weightFINAL(treated) mean tumour weightDAl(treated) mean actual tumour weightFAL(vehicle control) mean tumour weightDAYI(vehicle control)) X 100%].

Results [0084] In these studies TGI was found in group five group seven and group nine (75.1%) Example 12. Tube formation assays [0085] HUVEC (Clonetics) were plated in 96 well plates in EGM-2 media (Clonetics) at 2,5 to 3 x 104 cells per well. Cells of less than 6 passages were used in all studies. Wells were precoated with 50tL growth factor containing Matrigel (Becton Dickinson). HUVEC were allowed to fonn tubes by incubation at 37 0 C in

CO

2 for 22 hrs. In test wells compound was added in the desired concentration.

Photographic images of the wells x4 magnification were used to determine size of the tubes, length of tubes and number of junctions using image analysis software. This data was used to determine if matrigel tube formation was disrupted in the presence of test compounds and in some cases to calculate the concentration of compound that resulted in 50% inhibition of tube formation (EC 5 o).

WO 2005/097142 WO 205/07142PCT/A1J20051000506 41 Table 10: Matrigel tube formation disruption Compound 125uM 250uM 2 Y 3 Y Y 4 Y

Y

6 Y 7 Y Y 16 Y Y 8 Y 9 Y Y Y Y 11 Y 12 Y 13 Y 14 Y Y Y Y 1 Y Table 11: IC50 determination of selected compounds from above set.

in Matrigel Compound Number assay 1 250 uM 7 beta 7 alpha 3 beta 9OuM 3 alpha 16 alpha 125uM 9 14 mixture 155uM 14 single anomer 155uM Example 13. Preparation of "Compound 1" [0086] Methods that can be used in the preparation of "compound 1 are described in Aichenia patent application PCT AU03/0 1008 (WO 2004/014929) which is hereby incorporated by reference to this application.

WO 2005/097142 PCT/AU2005/000506 42 [0087] The preparation of "compound 1" is also described in scheme 1 below. Thus, in a typical experiment, D-GluNAc (115,15g) was suspended in 2phenylethanol (375ml) and heated at 120 0 C. Acetyl chloride (3.7ml) was added and the mixture refluxed for -3hrs. The reaction mixture was cooled to RT and poured into ether (2L) to ppt A 146g A (142.99g) in acetonitrile (574mL) was treated with p-methoxybenzaldehyde dimethylacetal (112mL) and N-camphor sulphonic acid (2.26g) at 60 0 C for 5hrs. The mixture was cooled to RT and treated with Et3N (-8mL) and evaporated to dryness to give a brown solid. The solid was triturated with petrol to give a yellow brown solid and filtered to give B (21 1g). B (203.26g) was treated with diethylene glycol methyl ether (800mL) and a solution of KOH (257g) and heated at 120 0 C for 5hrs, cooled, then poured into water (4L) and extracted with chloroform (4L and 2L). The combined organics where washed with brine (2L) and the organics evaporated to dryness. The residue was stirred with water filtered and washed with water (500mL). The solid product was dried under high vacuum and azeotroped with toluene until dry to give C (189g). C (89.5g) in MeOH (560mL) was treated with a solution of CuSO4.5H20 (1.32g) in water (2mL) with stirring. Triflic azide was added and the mixture stirred at room temperature for 4hr. The reaction is then quenched with n-butylamine (15mL) and was filtered through a celite pad and evaporated. The residue was dissolved in EtOH/water and cooled to 0°C. The 2 0 product was filtered, washed and dried to give D (141.4g). To a stirred suspension of NaH 8.42g; 0.21mol) in dry DMF(100mL) was added a solution of D 59.67g) in dry DMF (100mL) over 30min and then stirred at OoC for a further 30min. 2- (bromomethyl)naphthalene (37.09g) in dry DMF (50mL) was then added drop wise over 30mins and then stirred for a further Ihr. The reaction was quenched with methanol (10mL) until no further hydrogen evolution and the mixture evaporated to dryness under high vacuum. He crude residue was dissolved in DCM (1000mL) and washed with water (500mL), 10% HC1 (500mL), NaHCO3 (500mL) and brine The organic layer was evaporated and azeotroped with toluene to give dark yellow solid. The residue was dissolved in EtOAc (300mL) and precipitated with petroleum 3 0 ether (4L) to give E. [0088] To a solution of E (34.6g) in DCM (350mL) at 0 5oC, was added 1M BH3 in THF (91.53g; 91.53mmol, 1.5eq) over 30 min. After an additional of stirring, Bu2BOTf (6.10mL; 6.1mmol; 0.1eq) was added slowly to the mixture.

WO 2005/097142 PCT/AU2005/000506 43 The ice bath was removed and the reaction stirred at RT for 2hr. The reaction was quenched by slow addition of MeOH and the diluted with DCM (1500mL). The organic mixture was washed with sat. NaHCO3 (200mL), dried MgSO4 and evaporated to give a glassy solid. The crude product was chromatographed with Tol: EtOAc eluant mixes from silica to yield F (23.3g). F (20g; 35.15mmol) dissolved in dry DMF (55mL) and cooled in an ice bath (0-5 0 C) and treated with NaH Methyl iodide (3.32mL) was added drop wise and stirred at RT for 4hr. The reaction quenched with methanol and diluted with DCM (2L) and washed with water (1L. The aqueous layer wash back extracted with DCM (2 x 100mL). The combined organics were dried (MgSO4) and evaporated to give G (19.6g). G (23.4g) in a mixture of DMF (54.6mL) and MeOH (155mL) was treated with a solution of NH4Cl (10.73g), followed by activated zinc dust (13.1g) and stirred at RT for lhr. The mixture was diluted with DCM (2L) and filtered through a celite pad. The DCM layer was washed with sat NaHCO3 solution dried MgSO4 and evaporated to give H (20.7g). To a solution of 4-Boc-NH-butyric acid 11.974g) in dry DMF was added HBTU (21.465g) and DIPEA (8.783g) with stirring at room temperature. The resulting solution was stirred at RT for 20min and then added to a solution of H (25.24g) in DMF (200mL). The reaction was stirred at RT for lhr and quenched with 1N NaOH The reaction was diluted with DCM (2L) and washed with 0.5N NaOH (800mL). The organic layer was dried (MgSO4) and evaporated to dryness to give I (30.8g). I (15g) in dry DCM (200mL) was treated with Et3SiH (20mL) and then TFA and stirred at RT for 2hr. The reaction was evaporated to dryness (water bath at 25oC) and the residue taken up into DCM (500mL) and basified with 25% solution (90mL) and again evaporated to dryness. The residue was dissolved in DCM (500mL) and washed with water (200mL) and 1N NaOH (1OOmL). The organic layer was washed with brine (100mL), dried MgSO4 and evaporated to give J g).

Example 14. Preparation of compounds 2-179 [0089] Methods suitable for the preparation of compounds 2 to 179 are described in Alchemia patent application PCT AU03/01008 (WO 2004/014929) which is hereby incorporated by reference to this application. The materials used in these studies were prepared by the solid phase methods described in PCT AU03/01008.

WO 2005/097142 WO 205/07142PCTAJ2005OOO506 44 Table 12: Mass Spectral Data for Compounds 1-16 M+H

M

compound observed Calculated 1 523.321 2 570.071 568.19 3 529.099 528.2 4 586.151 584.24 510.03 508.26 6 495.192 494.24 7 529.277 528.2 8 587.33 586.28 9 545.209 544.18 561.311 560.23 11 559.322 558.27 12 543.34 542.22 13 543.341 542.22 14 611t359 610.26 545.31 544.26 18 545.121 544.26, Scheme 1 synthesis of "compound 1"

OH

OH 0 OH

NH

NHAc Ph

A

D-GluNAc PMP-,\050: o

PMP-,

0 a HO HO P 0 NH)--.Ph

N

c D PMPXV, O 0 0

B

PMP- 0 r0 N 3

P

Napth

E

HO OMe O-Me PMBO PMBO- 0 PMBO 00 0 Ph0--/ri~.W Ph 0 N P K N 3 pth N3 N 0 ,/p NathNapth Napt F 1 W~e OMe PMBO HO KH HN Ph Napth 0Napth 0 1 J NHBoc

NH,

WO 2005/097142 PCT/AU20051000506 46 [0090] Throughout the specification and the claims (if present), unless the context requires otherwise, the term "comprise", or variations such as "comprises" or "comprising," will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0091] Throughout the specification and claims (if present), unless the context requires otherwise, the term "substantially" or "about" will be understood to not be limited to the value for the range qualified by the terms.

[0092] Although the foregoing invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced without departing from the spirit and scope of the invention. Therefore, the description should not be construed as limiting the scope of the invention.

[0093] All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be so incorporated by reference.

Throughout the specification and the claims (if present), unless the context requires otherwnvise, the term "comprise", or variations such as "comprises" or "comprising", will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers.

Throughout the specification and claims (if present), unless the context requires otherwise, the term "substantially" or "about" will be understood to not be limited to the value for the range qualified by the terms.

Claims (17)

1. A method for inhibiting angiogenesis in a subject comprising administering to the subject at least one compound of General Formula I R7 R6 ZR 1 RSX' R 4 X XR 2 XR 3 General Formula I wherein the ring or any chiral center(s) may be of any configuration; Z is sulphur, oxygen, CH 2 C(O)HN, NH, NRA or hydrogen, in the case where Z is hydrogen then R 1 is not present, R A is selected from the set defined for R 1 to R 5 X and X' are independently oxygen or nitrogen providing that at least one X of General Formula I is nitrogen, X or X' may also combine independently with one of R 1 to R 5 to form an azide, R 1 to R 5 are independently selected from the following definition which includes but is not limited to H or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear, and R 6 and R 7 are hydrogen, or may combine to form a carbonyl function.

2. The method of claim 1, wherein angiogenesis is inhibited by contacting a receptor associated with angiogenesis with at least one said compound.

3. The method of claim 2, wherein the receptor is a somatostatin receptor.

4. The method of claim 3, wherein the receptor is somatostatin receptor subtype The method of claim 1, wherein the at least one compound comprises a compound of WO 2005/097142 PCT/AU2005/000506 General Formula II HO" NHR 2 1R 3 General Formula II wherein R 1 R 2 R 3 R 5 and Z are defined as in General Formula I.

6. The method of claim 1, wherein the at least one compound comprises a compound of General Formula If General Formula III wherein A is defined as hydrogen, SRI, or OR 1 where R 1 is defined as in General Formula I, and X, R 2 R 3 R 4 and R 5 are defined as in General Formula I.

7. The method of claim 1, wherein the at least one compound comprises a compound of General Formula IV WO 2005/097142 PCT/AU2005/000506 MeO OR 1 HR 2 General Formula IV wherein RI, R 2 and R 3 are defined as in General Formula I.

8. The method of claim 1, wherein the at least one compound comprises a compound of General Formula V 'NH O- General Formula V wherein the stereochemistry may be alpha or beta at the anomeric carbon, and may be axial or equatorial at the other pyranosyl ring carbons, n is 0 or 1, is selected from substituted or unsubstituted C1-C8 alkyl, hetero alkyl, cyclo-alkyl, aromatic or heterocyclic spacer, where typical substituents include but are not limited to nitro, chloro, fluoro, bromo, nitrile, carboxyl, -NH 2 -NHR, -NHB, C 1 -3 alkyl, -OR, azido, WO 2005/097142 PCT/AU2005/000506 C(O)NH 2 -C(O)NHR, -C(O)N(R) 2 -CF 3 -SR, wherein R are typically independently selected from a substituted or unsubstituted alkyl, aryl or heterocyclic group, L is selected from -NB 2 or guanidinium wherein B is defined as below, and additionally 'Y' and can combine to form a substituted or unsubstituted nitrogen containing heterocycle, Q are independently selected from a substituted or unsubstituted monocyclic or bicyclic aromatic or hetero aromatic, where typical substituents are defined as for A are independently selected from hydrogen, chloro, fluoro or methyl, and B are independently selected from H, methyl, ethyl, propyl.

9. The method of claim 8, wherein the at least one compound comprises a compound of General Formula VI General Formula VI where Y, L, and Q are as defined in General Formula V. The method of claim 8, wherein the at least one compound comprises a compound of General Formula VII WO 2005/097142 PCT/AU2005/000506 51 OMe o 0 -W HO NH O L W General Formula VII wherein, may represent mono-, di-, tri-, or tetrasubstitution and may be the same or different. Similarly, in combination with the aromatic ring, may represent a substituted or unsubstituted fused ring system which may be hetero-atomic or homo-atomic, and may be aromatic or aliphatic. Typical substituents include but are not limited to phenyl, C 1 4 alkyl, heterocycles, nitro, chloro, fluoro, bromo, nitrile, carboxyl, -NH 2 -NHR, -NR 2 C-3 alkyl, OR, azido, -C(O)NH 2 -C(O)NHR, -C(O)N(R) 2 -CF 3 -SR, wherein R are typically independently selected from a substituted or unsubstituted alkyl, aryl or heterocyclic group, and where Y and L are as defined in General Formula V.

11. The method of claim 10, wherein the at least one compound comprises a compound of General Formula VIII WO 2005/097142 PCT/AU2005/000506 I L Y General Formula VIII wherein, W, L and Y are as defined in General Formula VII.

12. The method of claim 1, wherein the at least one compound comprises a compound of General Formula IX General Formula IX wherein, W, L and Y are as defined in General Formula VII.

13. The method of claim 1, wherein the at least one compound comprises a WO 2005/097142 PCT/AU2005/000506 compound of General Formula X General Formula X wherein, W, L and Y are as defined in General Formula VII.

14. The method of claim 1, wherein the substituents are selected from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, any of which may optionally be further substituted with at least one moiety of the group. The method of claim 1, wherein the at least one compound comprises WO 2005/097142 WO 205/07142PCT/A1J20051000506 ""NH The method of claim 1, wherein the at least one compound comprises which is in the D-gluco configuration, Wherein; X is Sulfur Oxygen or an amide functionality in which the nitrogen is bound to the anomeric position of the carbohydrate ring, Ri, R3 and R4 are selected from the group consisting of methyl; benzyl; p-chlorobenzyl; p- phenylbenzyl; beta-napthylmethyl; m-hydroxybenzyl; m-aminobenzyl; phenethyl or ethyiphenyl, R2 is selected from the group consisting of methylamino -CH 2 -NI{ 2 ethylamino -CH 2 CH 2 -N11 2 n-propylamino -CH 2 -CH 2 -CH 2 -N1 2 methylguanidinium -CI1 2 -NIIi-C(=NII)- Nil 2 ethylguanidinium -CH 2 Cf 2 -Ml-C(=N{-NH 2 propylguanidinium -CH 2 -CH 2 -CH 2 NH-C(=N)-NH 2 and WO 2005/097142 PCT/AU2005/000506 H NThe method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises which is of the D-Allo configuration, Wherein; X is Sulfur Oxygen or an amide functionality in which the nitrogen is bound to the anomeric position of the carbohydrate ring, WO 2005/097142 WO 205/07142PCT/A1J20051000506 56 RI, R3 and R4 are selected from the group consisting of methyl; benzyl; p-chlorobenzyl; p- phenylbenzyl; beta-niapthylmeothyl; m-hydroxybenzyl; m-aminobenzyl; phenethyl or ethyiphenyl, R2 is selected from the group consisting of methylamino -C1 2 -N1 2 ethylamino -CH2- CH 2 -NH 2 n-propylamino -CH 2 -CH 2 -CH 2 -NH 2 methylguanidiniuam -CH 2 -NH-C(=NH)- NI-i 2 ethylguanidinium -CH 2 -CH 2 -NH-C(=NH)-NH 2 propylguanidinium -CH 2 -CH 2 CH 2 NI{-C(=NH)-N1 2 and N NH NH 2 ,0 N NH NH 2 H N

18. The method of claim 1, wherein the at least one compound comprises WO 2005/097142 PCT/AU2005/000506 HOP 0 a The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises WO 2005/097142 PCTIAU2005/000506 58 H

22. The method of claim 1, wherein the at least one compound comprises S hm 20

23. The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises WO 2005/097142 PCT/AU2005/000506 MoH2 The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises WO 2005/097142 PCT/AU2005/000506 The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises 00 (N 1 o O- 14 The method of claim 1, wherein the at least one compound comprises The method of claim 1, wherein the at least one compound comprises

33. A method for inhibiting angiogenesis, comprising contacting a sample comprising a blood vessel or a cell associated with formation of blood vessels with at least one compound as claimed in claim 1, wherein contacting of said blood vessel or cell with said at least one compound inhibits angiogenesis.

34. Use of a compound as claimed in claim 1 for the manufacture of a 00 medicament for inhibiting angiogenesis. (N A compound as claimed in claim 1 used to bind to a somatostatin receptor and for inhibition of angiogenesis. t ALCHEMIA LIMITED JULY 2008.