CA2332772A1 - Antiangiogenic drug to treat cancer, arthritis and retinopathy - Google Patents

Abstract

Compounds having Formula (I), or pharmaceutically acceptable salts or prodru gs thereof, are useful for treating pathological states which arise from or are exacerbated by angiogenesis. The invention also relates to pharmaceutical compositions comprising these compounds and to methods of inhibiting angiogenesis in a mammal.

Description

ANTIANGIOGENIC DRUG TO TREAT CANCER ARTHRITIS AND RETINOPATHY
s Technical Field The present invention relates to compounds which are useful for treating pathological states which arise from or are exacerbated by angiogenesis, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting angiogenesis in a mammal.
Background of the Invention Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair.
Although the process is not completely understood. it is believed to involve a complex interplay of ~5 molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and 2o turnover within a 5 day period (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267(16), 10931-10934, (1992) and Folkman, J. and Klagsbrun, M., Science, 235, 442-447 ( 1987).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are driven by persistent unregulated 'S angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and dominates approximately twenty eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In 3o diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J., Cancer Research, 46, 467-473 ( 1986), Folkman, J., Journal of the National Cancer Institute, 82, 4-6 ( 1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing 35 the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, N., et ai., The New England Journal of Medicine, 324( 1 ), 1-8 ( 1991 ).
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparini, G. and Harris, A. L., J. Clin. Oncol., 13(3):
765-782, s (1995), but there are disadvantages associated with these compounds.
Suramin, for example, is a potent angiogenesis inhibitor but causes severe systemic toxicity in humans at doses required for antitumor activity. Compounds such as retinoids, interferons and antiestrogens are relatively safe for human use but have weak antiangiogenic effects.
Irsogladine, an anti-tumor drug with low toxicity, has only weak anti-angiogenic effects.
Thus there is still a need for compounds useful in treating angiogenic diseases in mammals.
Summary of The Invention In one embodiment of the present invention are disclosed compounds represented by Formula I
R2 Rs X Rc Ro Rs R~ Z R~ RH
R\ ~ N
~N ~ ~ R,o W RA RB R4 RS Y R RF Re R9 I, or a pharmaceutically acceptable salt or prodrug thereof, where RA and RB are hydrogen or taken together are =O;
RC and RD are hydrogen or taken together are =O;
RE and RF are hydrogen or taken together are =O;
RG and RH are hydrogen or taken together are =O;
W, X, Y, and Z are independently selected from 3o ( 1 ) hydrogen and (2} alkyl of one to six carbons, provided that when X, Y, and Z are hydrogen then, at least one of RA and RB or RC and RD or RE and RF is other than =O;

Rl is selected from (1) hydrogen and (2) an amino .protecting group;
R2 and R3 are independently selected from ( 1 ) hydrogen and (2) alkyl of one to six carbons where the alkyl group is substituted with -NL 1 L2 where L 1 and L2 are independently selected from to (a) hydrogen, (b) alkyl of one to six carbons, and (c) an amino protecting group;
R4 and RS are independently selected from (1) hydrogen (2) alkyl of one to six carbons, and (3) cycloalkyl of three to twelve carbon atoms;
R6 and R~ are independently selected from ( 1 ) hydrogen, (2) alkyl of one to six carbons, and (3) alkyl of one to six carbons substituted with 1 or 2 substituents independently selected from (a) aryl and (b) aryl substituted with 1, 2, 3, 4, or ~ substituents independently selected from (i) -OH, (ii) -OL3 where L3 is alkyl of one to six carbons, (iii) alkyl of one to six carbons, (iv) halogen, {v) -N02, and (vi) -Nl-1L2;
Rg and R9 are independently selected from (1) hydrogen, (2) alkyl of one to six carbons, and (3) -CH2(CH2)mC02L4 where L4 is selected from (a) hydrogen and (b) alkyl of one to six carbons and m is an integer from 0 to 4;
s Rip is selected from ( 1 ) -OLS where LS is selected from (a) hydrogen, (b) alkyl of one to six carbons, (c) cycloalkyl of three to six carbons, and to (d) alkyl of one to six carbons substituted with 1 or 2 substituents independently selected from (i) cycloalkyl of three to six carbons, (ii) aryl, and (iii) aryl substituted with 1, 2, 3, 4, or ~ substituents independently selected from -OH, -OL3 where L3 is alkyl of one to six carbons, alkyl of one to six carbons, halogen, 20 -N02, and -NL 1 L2 and (2) -NHLS.
In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I.
25 In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of this invention include, but are not limited to, (4S,7S, l OS,13S)-4-(4-aminobutyl)-13-(aminocarbonyl)-10-(4-hydroxybenzyl)-7-isobutyl-9-methyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecan-15-oic acid, 30 (2S)-2-({(2S)-2-[((2.5~-2-{((2S)-2-(acetylamino)-6-aminohexanoyl]amino}-4-methylpentanoyl)(methyl)amino]-3-phenylpropanoyl } amino)butanedioic acid, (2S)-2-{ [(2S,SS,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,6,12,12-tetramethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino}butanedioic acid, (2,5~-2-[[(2S,SS,BS)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,12,12-trimethyl-35 4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl](methyl)amino]butanedioic acid, and (2S)-2- { [(2S,SS,BS)-8-(4-aminobutyl)-2-benzyl-5-isobutyl-12,12-dimethyl-7,10-dioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino}butanedioic acid.

Detailed Description of The Invention Definition of Terms The term "alkyl" refers to a monovalent straight or branched chain group of one to twelve carbons derived from a saturated hydrocarbon by the removal of a hydrogen atom.
The alkyl groups of this invention can be optionally substituted.
The term "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of this invention can be optionallty 1o substituted.
The term "amino" refers to -NH2.
The term "cycloalkyl" refers to a monovalent group of three to twelve carbons derived from a saturated cyclic or bicyclic hydrocarbon by the removal of a hv_ droeen atom. The cycloalkyl groups of this invention can be optionally substituted.
The term "halogen" refers to F, Cl, Br and I.
The term "hydroxy-protecting group" or "oxygen-protecting group" refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures. Examples of hydroxy-protecting groups include, but are not limited to, ethers, for example, methyl, ethyl, t-butyl, benzyl and allyl; substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl, and triphenylmethyl; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; tetrahydropyranyl ethers; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; esters, for example, formate, acetate, trifluoroacetate, pivalate, benzoate, and adamantoate; carbonates.
for example.
methyl, ethyl, isobutyl, t-butyl, vinyl, allyl, and benzyl; sulfonates, for example.
methanesulfonate, benzylsulfonate and p-toluenesulfonate. Commonly used hydroxy-protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. (i991).
Protectective Groups In Or anic S nthesis (2nd ed.). New York: John Wiley & Sons.
The term "N-protected amino" or "amino protecting group" refers to groups 3o intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. ( 1991 ). Protectective Groups In Organic Synthesis (2nd ed.). New York: John Wiley & Sons. Preferred N-protecting groups are fonmyl, acetyl, benzoyl, pivaloyl, t butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
The term "pharmaceutically acceptable prodrugs" represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irntation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "pharmaceutically acceptable salt" represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like. and are commensurate with a reasonable benefitlrisk ratio.
Pharmaceutically acceptable salts are well known in the art . For example, S. M. Berge, et al.
describe to pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 - 19 .
The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, giycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
The term "prodrug" represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
A
thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Compounds of the present invention can exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbols "R" or "S,"
depending on the configuration of substitiuents around the chiral carbon atom.
The present invention contemplates various stereoisomers and mixtures thereof.
Stereoisomers include enantiomers and diastereomers, and equal mixtures of enantiomers are designated ( ~ ). Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of enantiomers on chiral chromatographic columns.
to Determination of Biological Activity Endothelial Cell M~ration Assay The endothelial cell migration assay was performed essentially as described by Polverini, P.J. et al., Methods Enzymol, 198: 440-450 ( 1991 ). Briefly, Human Microvascular Endothelial Cells (HMVEC) were starved overnight in DMEM
containing 0.1% bovine serum albumin (BSA). Cells were then harvested with trypsin and resuspended in DMEM with 0. I % BSA at a concentration of 1.5 x 106 cells/mL.
Cells were added to the bottom of a 48-well modified Boyden chamber (Nucleopore Corporation, Cabin John, MD). The chamber was assembled and inverted, and cells were allowed to attach for 2 hours at 37 °C to polycarbonate chemotaxis membranes (5 Nm pore 2o size) that had been soaked in 0.1 % gelatin overnight and dried. The chamber was then reinvented and basic fibroblast growth factor (bFGF) and test substances were added to the wells of the upper chamber (to a total volume of 50 ESL); the apparatus was then incubated for 4 hours at 37 °C. Membranes were recovered, fixed and stained (DiffQuick, Fisher Scientific, Pittsburgh, PA) and the number of cells that had migrated to the upper chamber per 10 high power fields were counted. Background migration to DMEM + 0. I %
BSA
was subtracted and the data reported as the number of cells migrated per 10 high power fields (400X) or when results from multiple experiments were combined, as the percent inhibition of migration compared to a positive control. The results are shown in Table i.
_7_ Table 1 Inhibitory Potencies Against Human Microvascular Endothelial Cell Migration of Representative Compounds Example lo inhibition at 10 nM
test com ound The compounds of the invention, including but not limited to those specified in the examples, possess anti-angiogenic activity. As angiogenesis inhibitors, such compounds are useful in the treatment of both primary and metastatic solid tumors and carcinomas of the breast; colon; rectum; lung; oropharynx; hypopharynx; esophagus; stomach;
pancreas;
liver; gallbladder; bile ducts; small intestine; urinary tract including kidney, bladder and io urotheiium: female genital tract including cervix, uterus, ovaries, choriocarcinoma and gestational trophoblastic disease; male genital tract including prostate, seminal vesicles, testes and germ cell tumors; endocrine glands including thyroid, adrenal, and pituitary;
skin including hemangiomas, melanomas, sarcomas arising from bone or soft tissues and Kaposi's sarcoma; tumors of the brain, nerves, eyes, and meninges including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas and meningiomas; solid tumors arising from hematopoietic malignancies such as leukemias and including chloromas, plasmacytomas, plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia; lymphomas including both Hodgkin's and non-Hodgkin's lymphomas; prophylaxis of autoimmune diseases including rheumatoid, 2o immune and degenerative arthritis; ocular diseases including diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration and hypoxia;
abnormal neovascularization conditions of the eye; skin diseases including psoriasis;
blood vessel diseases including hemagiomas and capillary proliferation within atherosclerotic plaques; Osler-Webber Syndrome; myocardial angiogenesis;
plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; wound granulation;
diseases characterized by excessive or abnormal stimulation of endothelial cells including intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma and hypertrophic scars (i.e. keloids) and diseases which have angiogenesis as a pathologic consequence including 3o cat scratch disease (Rochele minalia quintosa) and ulcers (Helicobacter pylori). Another use is as a birth control agent which inhibits ovulation and establishment of the placenta.
The compounds of the present invention may also be useful for the prevention of metastases from the tumors described above either when used alone or in combination _g_ with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating cancer. For example, when used in the treatment of solid tumors, compounds of the present invention may be administered with chemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, t0 LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG and the like. Other chemotherapeutic agents include alkylating agents such as nitrogen mustards including mechloethamine, melphan, chlorambucil, cyclophosphamide and ifosfamide;
nitrosoureas including carmustine, lomustine, semustine and streptozocin; alkyl sulfonates including busuiian: triazines including dacarbazine; ethyenimines including thiotepa and hexamethylmelamine; folic acid analogs including methotrexate; pyrimidine analogues including 5-fluorouracil, cytosine arabinoside; purine analogs including 6-mercaptopurine and 6-thioguanine; antitumor antibiotics including actinomycin D; the anthracyclines including doxorubicin, bleomycin, mitomycin C and methramycin; hormones and hormone antagonists including tamoxifen and cortiosteroids and miscellaneous agents including cisplatin and brequinar.
The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. By "pharmaceutically acceptable salt" is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower ~5 animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;
arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, malefic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, canons based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like. Preferred salts of the compounds of the invention include phosphate, tris and acetate.
Compounds of this invention may be combined with pharmaceutically acceptable sustained-release matrices, such as biodegradable polymers, to form therapeutic pocompositions. A sustained-release matrix, as used herein, is a matrix made of materials.
usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix is desirably chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), poiyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. A preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).

Compounds of this invention or combinations thereof may be combined with pharmaceutically acceptable excipients or carriers to form therapeutic compositions. A
pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The compositions may be administered parenterally, sublingually, intracisternally, intravaginally, intraperitoneally, rectally, bucally or topically (as by powder, ointment, drops, transdermal patch or iontophoresis device).
The term "parenteral," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and 1o intraarticular injection and infusion. Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
Prolonged absorption ~5 of the injectable pharmaceutical form may be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming nucroencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
Topical administration includes administration to the skin, mucosa and surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, may be prepared as a dry powder which may be pressurized or non-pressurized.
In non-pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. For topical administration to the eye, a compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the to compound to penetrate the corneal and internal regions of the eye, as, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material. Alternatively, a compound of the invention may be injected directly into the t5 vitreous and aqueous humor.
The composition may be pressurized and contain a compressed gas such as nitrogen or a liquified gas propellant. The liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surface active 2o agent such as a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable non-25 irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solids at room temperature but liquids at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or 30 other lipid substances. Liposomes are formed by mono- or mufti-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
The present compositions in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the 35 phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods _ I 2_ in Cell Biolo~v, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., which is hereby incorporated herein by reference.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. A "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat an angiogenic disease (for example, to limit tumor growth or to slow or block tumor metastasis) at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient;
the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the 2o compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Total daily dose of compounds of this invention to be administered locally or systemically to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.01 to 200 mg/kg body weight daily and more usually I to 300 mg/kg body weight. If desired, the ?5 effective daily dose may be divided into multiple doses for purposes of administration.
Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
It will be understood that agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of angiogenic diseases are 30 not limited to those listed above, but include, in principle, any agents useful for the treatment or prophylaxis of angiogenic diseases.

Preparation of Compounds of the Invention Abbreviations Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: NMM for 4-methylmorpholine; EDCI for 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; HOBT for hydroxybenztriazole;
TFA for trifluoroacetic acid; THF for tetrahydrofuran; DMF for dimethylformamide.
Synthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in Scheme 1 and Scheme 2 where W, X, Y, Z, RA, RB, RC, RD, RE, RF. RG, RH. R1, R2, R3, R4, R~, R6, R~, Rg, R9, and R1~ are defined previously unless indicated ~s otherwise. Depending on the nature of W, X, Y, Z, RA, RB, RC, RD, RE, RF, RG, RH, R1. R2, R3, R4, R5, R6, R~, Rg, R9, and Rl~, protection and subsequent deprotection of other reactive groups can be required to successfully complete the described synthetic sequences. Commonly used protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," 2nd edition, (John Wiley & Sons, New York ( 1991 )), which is incorporated herein by reference. It will be readily apparent to one of ordinary skill in the art reviewing the synthetic route depicted below that other compounds within Formula I
can be synthesized by the substitution of appropriate reactants and agents in the synthesis shown below.

Scheme 1 p I O
t-Bu0 N~ t-Bu0 N
OH Cs2C0~ ~ OCH; 4 M HCI
O Mel 0 dioxane / ~ /
Bn0 Bn0 I ~ I
HN ~
HCI OCH 3 BOC-LeuOH t-Bu0" H N ~OCHy 4 M HCI
EDCI. HOST. dioxane NMM O
Bn0 Bn0 JO~ O O
H2N v 'OCH BOC-(CBZ)Lys-OH t-Bu0 N- J~ J~
a EDCI, HOBT, ~H~H I v 'OCH3 O NMM O 0 NaOH
HCI
Bn0 NHCBZ BnO
O
O O
t-Bu0 N ~ N O i O Ot-Bu O OH t-BuO~N~N N~N NH=
- H-(Ot-Bu)Asp-NHS IIO
/ EDCI, HOST, H O 4 M HCI
NMM dioxane NHCBZ Bn0 NHCBZ Bn0 SUBSTITUTE SHEET (RULE 26~

I O O
HCI O I O ~OH H O I O OOH
H2N~,~ N~N NH= ~N~N N~N NH2 H O H O E30. IO' H O H O
H2, Pd/C
/ ~ /
NHCBZ gn0 NHCBZ Bn0 H~ I O OH
N N~ NH2 O H O H O

.-~i exemplified in Scheme 1. \-methyl tyrosine was converted into an ester.
The amino protecting group on tyrosine was removed and the free amine was coupled to leucine.
The amino protecting group on leucine was removed and the free amine was coupled to lysine. The ester on tyrosine was saponified and the carboxylic acid coupled to aspartic acid amide. The amino protecting group on lysine was removed and the free amine was acetylated with acetic anhydride. The oxygen protecting group on tyrosine was removed by hydrogen gas in the presence of palladium on carbon.
~~~T' (RItL.E 2~1 i 2 O O
BuO~N~OH ~t-guO~N~H H2N~OCH3 NaBHaCN. ZnCl2 O O O
t-BuO~H Nv 'OCH3 TFA/H20 H2N N~OCH
d O O
BOC-(CBZ)Lys-OH H ~ H
NMM~ HOBT, ~O O N N
OCH3 NaOH
NHCBZ
O
O N ~ N H Oll H O OBn OBn H OH O~N~N NV 'N
H-(OBn)Asp-OBn ~ O H H
_ O
EDCI. HOBT.
/ NMM
NHCBZ NHCBZ
O
H2, Pd/C p N ~ N N ~ N \OH
H H O

SUBSTITUTE SHEET (RULE 26~

As exemplified in Scheme 2, leucine was convened to leucinal and then was allowed to undergo a reductive amination with phenylalanine The amino protecting group was removed with trifluoroacetic acid and the free amine was coupled to lysine. The ester was saponified with sodium hydroxide and the carboxylic acid was coupled to aspartic acid. The benzyl esters on aspartic acid were removed with hydrogen gas in the presence of palladium on carbon.
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.
Example 1 (4S.7S.lOS,l3S)-4-(4-aminobutyl)-13-(aminocarbon~rl) 10 (4 hydroxybenzyl) 7 isobuty_1 9-methyl-2.5,8,11-tetraoxo-3 6 9 12-tetraazapentadecan-1S-oic acid Example 1 A
methyl (2S)-3-f4-(benzyloxy)phenyll-2-f(tert-butoxycarbonyl)(methyl)aminolpropanoate A solution of N-(tert-butoxycarbonyl)-N-methyl-O-benzyl-L-tyrosine (3.855 g, mmol) and Cs2C03 ( 10 mmol) in methanol/water was stirred at ambient temperature for 5 minutes, concentrated by rotary evaporation, then resuspended in DMF ( 10 mL).
Methyl iodide (0.933 mL, 15 mmol) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with ethyl acetate ( 100 mL) then washed sequentially with brine and aqueous NaHC03, dried (MgS04), and concentrated to give a colorless oil (4.01 g).
Example 1 B
methyl (2S)-3-14-(benzyloxy)phenyll-2-(meth lamino)propanoate A solution of the product of example lA (4.01 g, 10 mmol), in 1,4-dioxane saturated with hydrogen chloride (30 mL) was stirred at ambient temperature for 1 hour, evaporated to dryness, suspended in ethyl ether then concentrated and vacuum dried to give a white solid (3.35 g).
Example 1 C
methyl (2S)-3-f4-(benzyloxy)nhenyll-2-(((2S)-2-f(tert butoxycarbonyl)aminol 4 methvlpentanoyl ) (methyl)aminolnronanoate A solution of the product of example 1B (3.35 g, 10 mmol), N-(tert-butoxycarbonyl)-L-leucine (2.99 g, 12 mmol), EDCI (2.11 g, 11 mmol), HOBT ( 1.69 g, 1 I
mmol) and NMM ( 1.21 mL, 11 mmol) in CH2Cl2 (50 mL) was stirred at 0 °C
for 90 _~8_ minutes, then at ambient temperature for 16 hours, evaporated to dryness, redissolved in ethyl acetate (70 mL) then washed sequentially with brine, 10% aqueous KHS04, brine, aqueous NaHC03, and brine, dried (MgS04), and concentrated to give a viscous oil (3.98 g)~
M.S (DCI-NH3) m/e 513: (M+ H)+, 530 (M+ NH4)+.
Example 1 D
methyl (2S)-2-ff(2S)-2-amino-4-methylpentanoyll(methvl)aminol 3 f4 (benzyloxy)phenyllpropanoate to Example 1C was processed as in example 1B to provide the dipeptide.
Example 1 E
methyl (9S,125,15S)-15-f4-(benzyloxy)benzyll 9 f (tert butoxvcarbonyl)aminol 1 ~
isobutvl-14-methyl-3 10 13-trioxo-I-phenyl-2-oxa-4 11 14 triazahexadecan 16-oate The product of example 1D and N-alpha-(tert-butoxycarbonyl)-N-epsilon-(carbonylbenzyloxy)-L-lysine were processed as in example IC to provide the tripeptide.
Example 1 F
methyl (9S.12S,15S)-15-f4-(benzyloxy)benzyll 9 f(tert butoxycarbonyl)amino] 12 2o isobutvl-14-methyl-3 10 13-trioxo-1-phenyl-2-oxa 4 11 14 triazahexadecan 16 oate A solution of the product of example lE (0.747 g, 0.96 mmol), and NaOH (0.06 g, 1.5 mmol) in methanol (9 mL) and water (2.5 mL) was stirred at ambient temperature for 2.5 hours, diluted with water (5 mL), reduced in volume to 6 mL by rotary evaporation, then washed three times with ethyl ether. The aqueous phase was acidified, extracted three times with ethyl acetate, and the combined organic extracts were dried (MgS04), and concentrated to give a viscous oil (0.347 g).
Example 1 G
tert-butyl (9S,12S 15S 18S)-18-(anunocarbonyl) 15 f4 (benzyloxy)benzyll 9 f(tert butoxycarbonvl)aminol-12-isobutyl-14-methyl-3 10 13 16 tetraoxo 1 phenyl 2 oxa 4,11,14,17-tetraazaicosan-20-oate The product of example 1F and L-aspartamide beta-tent-butyl ester hydrochloride were processed as in example 1C to provide a white powder (0.434 gj.
Example 1 H
tert-butyl (9S,12S 15S 18S)-9-anuno-18-(aminocarbonyl) 15 f 4 (benzyloxy)benzyll 12 isobutvl-14-methyl-3 1013 16-tetraoxo-1- hen I-2-oxa-41i 14,17-tetraazaicosan-20-oate The product of example 1G was processed as in example 1B to provide the tetrapeptide.
Example lI
(9S,12S,15S,18S)-9-(acetylamino)-18-(aminocarbonyl) 15 f4 (benzyloxy)benzyil isobutyl-14-methyl-3 10 13 16-tetraoxo-1-phenyl 2 oxa-4. 11 14 I7 tetraazaicosan 20 oic acid A solution of example IH (0.37 g, 0.43 mmol), acetic anhydride (101 mL, 1.08 mmol) and triethylamine (210mL, 1.5 mmol) in CH2C12 (6 mL) was stirred at ambient 1o temperature for 48 hours, evaporated to dryness, redissolved in ethyl acetate then washed sequentially with aqueous NaHC03, brine, 10% aqueous KHS04 and brine, dried (MgS04), and concentrated. The residue was purified by flash chromatography on silica gel with 50% ethyl acetate/toluene to provide the acetylated tetrapeptide (0.180 g).
I S Example I J
(4S,7S,lOS,I3S)-4-(4-aminobutyl)-13-(aminocarbon 1 10 (4 hydroxybenzyl) 7 isobutyl 9-methyl-2,5,8.11-tetraoxo-3 6 9 12-tetraazapentadecan 15 oic acid A solution of the product of example lI (0.180 g, 0.25 mmol), and 10%
palladium on charcoal (0.18 g) in methanol ( 10 mL) was shaken for 18 hours under 4 atmospheres of 20 hydrogen. The catalyst was filtered off and the mixture concentrated to give the title compound as a white powder (0.10 g).
MS (ESI+Q1MS) m/e 593 (M+H)+, 615 (M+Na)+;
Example 2 25 (2S)-2-( ( (2S)-2-f((2S)-2-( f (2S)-2-(acetylamino)-6 aminohexanovllamino ]

methylnentanoyl)(methyl)aminol-3-phenvlnropanoyl ~ amino)butanedioic acid Example 2A
dibenzyl (2S)-2-(((2S)-2-f(tert-butoxycarbonyl)(methyl)aminol 3 30 phenylnronanoyl ) amino)butanedioate N-(tert-Butoxycarbonyl)-N-methyl-L-phenylalanine and L-aspartic acid dibenzyl ester were processed as in examples 1C and 1B to provide the dipeptide.
Example 2B
35 dibenzyl (2S)-2-( ( (2S)-2-f ( (2S)-2-f(tert-butoxycarbonyl)aminol 4 methylpentanoyl ~ (methvl)aminol-3-phenvl~ropanoyl ] amino)butanedioate The product of example 2A and N-(tert-butoxycarbonyl)-L-leucine were processed as in examples 1C and 1B to provide the tripeptide.
Example 2C
dibenzvl (2S)-2-( f(2S,SS 8S)-8-(4-aminobutyl)-2-benzyl 5 isobutyl 3 12 12 trimethy_1 4,7,10-trioxo-11-oxa-3 6 9-triazatridec-1-anoyllanunolbutanedioate The product of example 2B and N-alpha-(tert-butoxycarbonyl)-N-epsilon-(carbonylbenzyloxy)-L-lysine were processed as in examples 1C and 1B to provide the tetrapeptide.
to 1H NMR (300 MHz, DMSO-d6) 8 8.59 (d, 1H), 8.42 (d, 1H), 8.16 (s, 1H), 8.06 (d, 1H), 7.68 (d, 1H), 7.39-7.11 (complex, 24H), 5.23 (m, 1H), 5.11 (s, 2H), 5.10-5.06 (m, 4H), 5.00 (d, 2H), 4.77 (m, 2H), 4.63 (m, 1H), 3.81 (m, 2H), 3.16 (dd, 1H), 3.10-2.85 (m, 8H), 2.82 (s, 3H), 1.39 (s, 9H), 0.82 (d, 3H), 0.58 (dd, 3H).
Example 2D
dibenzvl (2S)-2-(((2S)-2-f((2S)-2-lf(2S1 2 (acetylamino) 6 aminohexano~rllamino? 4 methvlnentanoyh(methvl)aminol-3-phenylpropanovl 1 amino)butanedioate The product of example 2C was processed as in examples 1C and lI to provide the acetylated tetrapeptide.
Example 2E
(2S)-2-( ( (2S)-2-f ((2S)-2-( f (2S)-2-(acetylamino) 6 aminohexanoyllamino 1-4 methylnentanoyl)(methyl)aminol-3-phenylnropanoyl l amino)butanedioic acid The product of example 2D was processed as in Example 1J to provide the title compound.
MS (ESI+Q1MS) m/e 578 {M+H)+, 600 (M+Na)+.
Example 3 (25~-2- f f (2S,5S.8S)-8-(4-aminobutyl)-2-(4-hvdroxybenzyl) 5 isobutvl 3,6,12,12-tetramethyl-4,7,10-trioxo-11-oxa-3 6 9-triazatridec 1 anoyllamino)butanedioic acid Example 3A
methyl (9S 12S 15S)-15-f4-(benzyloxy)benzyll 9 1(tert butoxycarbonyl)aminol 12 isobutvl-11,14-dimethyl-3 10 13-trioxo-1-nhenyl 2 oxa-4 11 14 triazahexadecan 16 oate N-(tert-Butoxycarbonyl)-N-methyl-L-leucine and O-benzyl-L-tyrosine methyl ester are processed as in examples 1C and 1B to provide the dipeptide.
-2 t-Example 3B
(9S,12S,15S)-15-f4-(benzyloxy)benzyll-9-f(tert-butoxycarbonyl)aminol 12 isobuty_1 11.14-dimethyl-3.10.13-trioxo-l-phenyl-2-oxa-4 11 14 triazahexadecan 16 oic acid The product of example 3A and N-alpha-(tert-butoxycarbonyI)-N-epsilon-(carbonylbenzyloxy)-L-lysine are processed as in examples 1 C and 1 F to provide the tripeptide.
Example 3C
dibenzyl (2S)-2-( ( (2S SS 8S)-2-f4-(benzyloxy)benzyl~ 8 f (tert butoxycarbonvl)aminol-5-t0 isobutyl-3.6-dimethyl-4 7 14-trioxo-16-phenyl 15 oxa 3 6 13 triazahexadec 1 anoyl 1 amino)butanedioat_e The product of example 3B and L-aspartic acid dibenzyl ester are processed as in examples 1C and 1F to provide the tetrapeptide.
Example 3D
(2S)-2-( f (2S,SS,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl) 5 isobutyl 3 6 12 tetramethvl-4,7,10-trioxo-11-oxa-3 6 9-triazatridec 1 anoyllaminolbutanedioic acid The product of example 3C is processed as in Example 1J to provide the title compound.
Example 4 (2S)-2-f f (2S,5S,8S)-8-(4-aminobutyl)-2-(4-h d~oxybenzyl) 5 isobutyl 3 12 12-trimethyl 4,7,10-trioxo-11-oxa-3 6 9-triazatridec-1-anoyll(methyl)anunolbutanedioic acid The product of example 1 F and N-methyl-L-aspartic acid dibenzyl ester are processed as in examples 1 C and 1 J to provide the title compound.
Example 5 (2S)-2-1f(2S,SS,8S)-8-(4-aminobutyl)-2-benzyl-5 isobutyl 12 12 dimethyl 7 10 dioxo 11 oxa-3,6,9-triazatridec-1-anoyllamino)butanedioic acid Example SA
methyl (9S,125,15S)-15-benzyl-9-f (tert-butoxycarbonyl)aminol 12 isobutyl 3 10 dioxo 1 phenyl-2-oxa-4 11 14-triazahexadecan-16 oate H-Leuy(CH2NH)Phe-OMe prepared as described in Bravo et al. J. Chem. Soc.
Perkin Trans. I ( 1991 ) 3117 and N-alpha-(tert-butoxycarbonyl)-N-epsilon-(carbonylbenzyloxy)-L-lysine are processed as in examples 1C and 1F to provide the tripeptide.
Example SB
O2S)-2-~f(2S,SS,8S)-8-(4-aminobutyl)-2-benzyl-5-isobutyl-12 12 dimethyl 7 10 dioxo 11 oxa-3,6,9-triazatridec-1-anoyllaminolbutanedioic acid The product from example SA and L-aspartic acid dibenzyl ester are processed as in examples 1 C and 1 J to provide the title compound.

Claims (12)

WHAT IS CLAIMED IS:

1. A compound of Formula I
or a pharmaceutically acceptable salt or prodrug thereof where R A and R B are hydrogen or taken together are =O;
R C and R D are hydrogen or taken together are =O;
R E and R F are hydrogen or taken together are =O;
R G and R H are hydrogen or taken together are =O;
W, X, Y, and Z are independently selected from (1) hydrogen and (2) alkyl of one to six carbons, provided that when X, Y, and Z are hydrogen then at least one of R A and R B
or R C and R D or R E and R F is other than =O;
R1 is selected from (1) hydrogen and (2) an amino protecting group;
R2 and R3 are independently selected from (1) hydrogen and (2) alkyl of one to six carbons where the alkyl group is substituted with -NL1L2 where L1 and L2 are independently selected from (a) hydrogen, (b) alkyl of one to six carbons, and (c) an amino protecting group;

R4 and R5 are independently selected from (1) hydrogen (2) alkyl of one to six carbons, and (3) cycloalkyl of three to twelve carbon atoms;
R6 and R7 are independently selected from (1) hydrogen, (2) alkyl of one to six carbons, and (3) alkyl of one to six carbons substituted with 1 or 2 substituents independently selected from (a) aryl and (b) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from (i) -OH, (ii) -OL3 where L3 is alkyl of one to six carbons, (iii) alkyl of one to six carbons, (iv) halogen, (v) -NO2, and (vi) -NL1L2;
R8 and R9 are independently selected from (1) hydrogen, (2) alkyl of one to six carbons, and (3) -CH2(CH2)mCO2L4 where L4 is selected from (a) hydrogen and (b) alkyl of one to six carbons and m is an integer from 0 to 4;
R10 is selected from (1) -OL5 where L5 is selected from (a) hydrogen, (b) alkyl of one to six carbons, (c) cycloalkyl of three to six carbons, and (d) alkyl of one to six carbons substituted with 1 or 2 substituents independently selected from (i) cycloalkyl of three to six carbons, (ii) aryl, and (iii) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from -OH, -OL3 where L3 is alkyl of one to six carbons, alkyl of one to six carbons, halogen, -NO2, and -NL1L2 and (2) -NHL5.

2. A compound according to claim 1 of Formula II

3. A compound according to claim 2 where X and Z are hydrogen, Y is alkyl of one to six carbons, and R A and R B, R C and R D, and R E and R F are =O.

4. A compound according to claim 3 selected from the group consisting of (4S,7S,10S,13S)-4-(4-aminobutyl)-13-(aminocarbonyl)-10-(4-hydroxybenzyl)-7-isobutyl-9-methyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecan-15-oic acid and (2S)-2-([(2S)-2-[((2S)-2-[[(2S)-2-(acetylamino)-6-aminohexanoyl]amino}-4-methylpentanoyl)(methyl)amino]-3-phenylpropanoyl}amino)butanedioic acid.

5. A compound according to claim 2 where Y and Z are hydrogen, X is alkyl of one to six carbons, and R A and R B, R C and R D, and R E and R F are =O.

6. A compound according to claim 5 which is (2S)-2-{[(2S,5S,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,6,12,12-tetramethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino}butanedioic acid.

7. A compound according to claim 2 where X is hydrogen, Y and Z are alkyl of one to six carbons, and R A and R B, R C and R D, and R E and R F are =O.

8. A compound according to claim 7 which is (2S)-2-[[(2S,5S,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,12,12-trimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl](methyl)amino]butanedioic acid.

9. A compound according to claim 2 where X, Y, Z, and R C and R D are hydrogen, and R A and R B and R E and R F are =O.

10. A compound according to claim 9 which is (2S)-2-{[(2S,5S,8S)-8-(4-aminobutyl)-2-benzyl-5-isobutyl-12,12-dimethyl-7,10-dioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino}butanedioic acid.

11. A method of treating a patient in need of anti-angiogenesis therapy comprising administering to the patient a therapeutically effective amount of the compound according to claim 1.

12. A compound according to claim 1 selected from the group consisting of (4S,7S,10S,13S)-4-(4-aminobutyl)-13-(aminocarbonyl)-10-(4-hydroxybenzyl)-7-isobutyl-9-methyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecan-15-oic acid, (2S)-2-({(2S)-2-[((2S)-2-{[(2S)-2-(acetylamino)-6-aminohexanoyl] amino]-4-methylpentanoyl)(methyl)amino]-3-phenylpropanoyl]amino)butanedioic acid, (2S)-2-{[(2S,5S,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,6,12,12-tetramethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino}butanedioic acid, (2S)-2-[[(2S,5S,8S)-8-(4-aminobutyl)-2-(4-hydroxybenzyl)-5-isobutyl-3,12,12-trimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl](methyl)amino)butanedioic acid, and (2S)-2-{[(2S,5S,8S)-8-(4-aminobutyl)-2-benzyl-5-isobutyl-12,12-dimethyl-7,10-dioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino)butanedioic acid.