MXPA00011497A - Antiangiogenic drug to treat cancer, arthritis and retinopathy - Google Patents

Abstract

Compounds having Formula (I), or pharmaceutically acceptable salts or prodrugs 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 FOR TREATING CANCER, ARTHRITIS AND RETINOPATHY Technical Field The present invention relates to compounds that are useful for treating disease states arising from or exacerbated by angiogenesis, with pharmaceutical compositions comprising these compounds, and with methods for inhibiting angiogenesis in a mammal. BACKGROUND OF THE INVENTION Angiogenesis, the polymer by which new blood vessels are formed, is essential for normal body activities including reproduction, growth and wound repair. Although the polymer is not completely understood, it is believed to involve a complex set of molecules that regulate the growth of endothelial cells (the major cells of capillary blood vessels). Under normal conditions, these molecules seem to keep the microvasculature in a still state (ie, one without capillary growth) for prolonged periods, which may last as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and recover within a period of five days (Folman, 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 polymer under normal conditions, many diseases (characterized as angiogenesis) are driven by unregulated persistent angiogenesis.In other words, unregulated angiogenesis can 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 the cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors also depend 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 that grow more than 2 millimeters must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels.When these new blood vessels are immersed in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as the liver, lung, or bone (Weidner, N., et al., The New England Journal of Medicine, 324 (1), 1- 8 (1991) Several angiogenesis inhibitors are currently in development for their use to treat angiogenic diseases (Gasparini, G., and Harris, AL, J. Clin. Oncol., 13 (3): 765-782, (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 anti-angiogenic effects. Irsogladine, an antitumor drug with low toxicity, has only one week anti-angiogenic effects. Thus there is still a need for compounds useful for treating angiogenic diseases in mammals. SUMMARY OF THE INVENTION In one embodiment of the present invention, compounds represented by Formula I are described I, or a pharmaceutically acceptable salt or prodrug thereof, wherein RA and RB are hydrogen or taken together are = 0; Rc and RD are hydrogen or taken together are = 0; RE and pR are hydrogen or taken together are = 0; RG and RH are hydrogen or taken together are = 0; W X, Y, Z are independently selected from (1) hydrogen and (2) alkyl of one to six carbon atoms, with the proviso that when X, Y, Z are hydrogen then at least one of RA and RB or RC and RD or RE and RF is different from = 0; R is selected from (1) hydrogen and (2) an amino protecting group; R 2 and Br 1 are independently selected from (1) hydrogen and (2) alkyl of one to six carbon atoms wherein the alkyl group is substituted with -NLJL 2 wherein L 1 and L 2 are independently selected from (a) hydrogen, ( b) alkyl of one to six carbon atoms, and (c) an amino protecting group; R and are independently selected from (1) hydrogen (2) alkyl of one to six carbon atoms, and (3) cycloalkyl of three to twelve carbon atoms; R6 and R7 are independently selected from (1) hydrogen, (2) alkyl of one to six carbon atoms, and (3) alkyl of one to six carbon atoms 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 wherein L3 is alkyl of one to six carbon atoms, (iii) alkyl of one to six carbon atoms, (iv) halogen, (v) -N02, and (vi) -NL ^ 2; or R and R ^ are independently selected from (1) hydrogen (2) alkyl of one to six carbon atoms, and (3) -CH2 (CH2) mC? 2L4 wherein L4 is selected from (a) hydrogen and (b) ) alkyl of one to six carbon atoms and m is an integer from 0 to 4; R10 is selected from (1) -OL5 wherein L5 is selected from (a) hydrogen, (b) alkyl of one to six carbon atoms, (c) cycloalkyl of three to six carbon atoms, and (d) alkyl of one to six carbon atoms substituted with 1 or 2 substituents independently selected from (i) cycloalkyl of three to six carbon atoms, (ii) aryl, and (iii) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from -OH, -OL3 wherein L3 is alkyl of one to six carbon atoms, alkyl of one to six atoms of carbon, halogen, -N02, and -NL! L2 and (2) -NHL5. In another embodiment of the invention methods for treating diseases comprising administering an effective amount of a compound having Formula I are described.

In yet another embodiment of the invention, pharmaceutical compositions containing the compounds of Formula I are described. Compounds of the invention include, but are not limited to, (4S, 7S, IOS, 13S) -4- (aminobutyl) -13 - (aminocarbonyl) -10- (4-hydroxybenzyl) -7- isobutyl-9- (- 1-1,5,8, 11-tetraoxo-3, 6,9, 12-tetra-azapentadecane-15-oico; acid (2S) -2- ( { (2S) -2- [((2S) -2- { [(2S) -2- (acetylamino) -6-aminohexanoyl] amino.} -4-methylpentanoyl ) (methyl) amino] -3-phenylpropanoyl.} amino) utanedioic acid; (2S) -2- acid. { [(2S, 5S, 8S¡) - 8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3,6,12,16-tetramethyl-4,7,10-trioxoyl- oxa-3, 6, 9-triazatridec-l-anonyl] amino} butanedioic; (2S) -2- [[(2S, 5S, 8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3, 12, 12-trimet and 1-4, acid , 10-trioxo-l-oxa-3, 6, 9-triazatridec-l-anoyl] (methyl) amino] butanedioic acid; lying (2S) -2-. { [(2S, 5S, 8S) -8- (4-aminobutyl) -2-benzyl-5-isobutyl-12,12-dimethyl-7,10-dioxo-l-oxa-3, 6,9-triazatridec-1 -anoyl] amino} utanedioic DETAILED DESCRIPTION OF THE INVENTION Definition of terms The term "alkyl" refers to a monovalent straight or branched chain group of 1 to 12 carbon atoms derived from saturated hydrocarbon by removal of hydrogen atom. The alkyl groups of this invention can optionally be substituted.

The term "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can be fused with a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of this invention can optionally be substituted. The term "amino" refers to -NH2. The term "cycloalkyl" refers to a monovalent group of 3 to 12 carbon atoms derived from a saturated cyclic or bicyclic hydrocarbon by the removal of a hydrogen 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 that protects the 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 esters, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- ( trimethylsilyl) -ethoxymethyl, and triphenylmethyl; esters of substituted ethyl, for example, 2, 2, 2-trichloroethyl and t-butyl; tetrahydropyranyl esters; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; esters, for example, format, 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 protection groups are described in Greene, T.W., & Wuts, P.G.M. (199 L). Protective Groups In Qrganic Synthesis (2nd ed.). New York: John Wiley & Sons. The term "protected amino N" or "amino protecting group" refers to groups that are intended to protect an amino group against undesirable reactions during synthetic procedures. The commonly used protection groups N are described in Greene, T.W., & Wuts, P.G.M. (1991). Protective Groups In Organic Synthesis (2nd ed.). New York: John Wiley & Sons. Preferred protecting groups N are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cb). The term "pharmaceutically acceptable prodrugs" means those prodrugs of the compounds of the present invention that are, within the scope of the medical cure judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit / risk portion, and effective for their intended use, as well as zwitterionic forms, when possible, of the compounds of the invention. The term "pharmaceutically acceptable salt" means those salts that are, within the scope of deep medical judgment, suitable for use in contact with human and lower animal tissues and undue toxicity, irritation, allergic response and the like, and are compared to 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. Phaxpiaceutical Sciences, 1977, 66: 1-19. The salts can be prepared in situ during the isolation and final purification of the compounds of the invention, or separately by reacting the function of the free phase with a convenient organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, canfersulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate. , hexanoate, hydrobromide, hydrochloride, iodohydrate, 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, succinat, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic 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 that are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.

A full discussion is provided in T. Higuchi and VEC "0R Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C.S. Symposium Series, and in Edward B. Roche, e., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference. Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols "R" or "S", depending on the configuration of the substituents 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 (±). The individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by the preparation of racemic mixtures followed by the resolution well known to those skilled in the art. These resolution methods 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 release of the optically pure product from the auxiliary or (2) direct separation of the the mixture of enantiomers in chiral chromatographic columns. Determination of biological activity Endothelial cell migration assay The endothelial cell migration assay was performed essentially as described by Polverini, P.J. et al., Methods Enzymol, 198: 440-450 (1991). In summary, human microvascular endothelial cells (HMVEC) were harvested overnight in DMEM containing 0. 1 percent bovine serum albumin (BSA). Cells were cultured with trypsin and resuspended in DMEM with C.l percent BSA at a concentration of 1.5 x 10 cells / milliliter. The cells were added to the bottom of a modified 48-well Boyden chamber (Nucleopore Corporation, Cabin John, MD). The chamber was assembled and inverted, and the cells were allowed to bind for 2 h at 37 ° C to polycarbonate chemotaxis membranes (5 micron pore size) that had been soaked in 0.1 percent gelatin overnight and dry. The chamber was reinvested and the basic fibroblast growth factor (bFGF) was added and test substances were added to the wells of the upper chamber (up to a total volume of 50 microliters); the apparatus was incubated for 4 hours at 37CC.

The membranes were recovered, fixed and stained (DiffQuick, Fisher Scientific, Pittsburgh, PA) and the number of cells that migrated to the upper chamber by 10 high power fields were counted. Background migration of DMEM + 0.1 percent BSA was subtracted and the data reported as the number of cells migrated by power fields of 10 (400X) or when the results of multiple experiments were combined, such as percent inhibition of migration compared to a positive control. The results are shown in Table 1.

Table 1 Inhibitory potencies against migration of human microvascular endothelial cells from representative compounds The compound of the invention, including but not limited to those specified in the examples, possesses anti-angiogenic activity. As inhibitors of angiogenesis, these compounds are useful in the treatment of both primary and metastatic solid tumors and carcinomas of the roof, -colon, -recto; lung; oropharynx; hypopharynx; esophagus; pancreas; liver; gallbladder, - bile ducts; small intestine; urinary tract including kidney, bladder and urothelium; 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 hemangiomeis, melanomas, sarcomas arising from bone or soft tissues such as Kaposi's sarcoma; brain tumors, nerves, eyes, and meninges including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, schwannomas, and meningiomas, - solid tumors arising from hematopoietic malignancies such as leukemias including chloromas, plasmacytomas, plaques, and mycosis fungoides tumors and cutaneous, T-cell lymphoma leukemia, lymphomas including both Hodgkin's and non-Hodgkin's lymphomas; prophylaxis of autoimmune diseases including rheumatoid, immune and degenerative arthritis; ocular diseases including diabetic retinopathy, retinopathy of prematurity, rejection of corneal graft, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration and hypoxia, - conditions of abnormal neovascularization of the eye; skin diseases including psoriasis; diseases of the blood vessels including hemangiomas and capillary proliferation with 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, scleroderm and hypertrophic lesions (ie, keloids) and diseases having angiogenesis as a pathological consequence including cat scratch disease (. Rochele minalia fifths) and ulcers. { Helicobacter pylori). Another use is as a birth control agent that inhibits ovulation and establishment of the placenta. The compounds of the present invention may also be useful for the prevention of metastasis of the tumors described above either when used alone: or in combination with radio therapy and / or other chemotherapeutic treatments conventionally administered to pacient.es to treat the Cancer. For example, when used in the treatment of solid tumors, the compounds of the present invention can be administered with chemotherapeutic agents, such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methortrexat.o, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (with / rescue of leucovine), doxorubicin, cyclophosphamide, taxol, etoposide / mechlorethamine, vincristine, prednisone and procarbacine), vincristine, vinblastine, angioinhibines , TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Tecgalan, thalidomide, P-PG and the like. Other chemotherapeutic agents include alkylating agents such as nitrogen mostases which include mecloethamine, melfan, chlorambucil, cyclophosphamide and ifosfamide, - nitrosureas including carmustine, lomustir.a, semustine and streptozocin; alkyl sulfonates including busultan, - triazines including decarbazine; etienimines that include thiotepa and hexamethylmelamine; folic acid analogues including methotrexate; pyrimidine analogs including 5-fluorouracil, cystosine arabinoside, purine analogs including 6-mercaptopurine and 6-thioguanine, antitumor antibiotics including actinomycin D; the anthracyclines that include doxorubicin, bleomycin, mitomycin C and metramycin; hormones and hormone antagonists that include tamoxifen and corticosteroids and miscellaneous agents that include cisplatin and brequinar. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic acids or organic acids. "Pharmaceutically acceptable salt" means those salts that are within the scope of deep medical judgment, convenient for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response and the like and are compared 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 and sequential. The salts can be prepared on site during the isolation and final purification of the compounds of the invention or separately by reacting a free base function with a convenient acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide. , iodohydrate, 2-hydroxyethanesulfonate (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, basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides.; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. Dispersible or water-soluble or oil-soluble products are obtained thereby. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.

The basic addition salts can be prepared on site during the final isolation and purification of the compound of this invention by reacting a carboxylic acid-containing fraction with a convenient base such as a hydroxy, carbonate or bicarbonate of a metal cation. pharmaceutically acceptable or with ammonia or with a primary, secondary or tertiary organic amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and non-toxic 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, ethanolamipa, diethanolamine, piperidine, piperazine and the like. Preferred salts of the compounds of the invention include phosphate, tris and acetate. The compounds of this invention can be combined with pharmaceutically acceptable sustained release matrices, such as biodegradable polymers, to form therapeutic compositions. A sustained release matrix, as used herein, is a matrix made of materials, usually polymers, that are degradable by enzymatic hydrolysis or acid-base or by dissolution. When inserted into the body, the matrix is activated under enzymes and body fluids. A sustained release matrix is desirably chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (glycolic acid polymer), 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, polyvinyl pyrrolidone and silicone. A preferred biodegradable matrix is a matrix of either polylactide, polyglycolide, or co-glycol polylactide (copolymers of lactic acid and glycolic acid). The compounds of this invention or combinations thereof can be combined with pharmaceutically acceptable carriers or excipients to form therapeutic compositions. A pharmaceutically acceptable carrier or excipient refers to a non-toxic, semi-solid or liquid solid encapsulating material, diluent, filler or auxiliary formulation of any kind. The compositions can be administered parenterally, sublingually, intracisternally, intravaginally, intraperitoneally, rectally, buccally or topically (as by powder, ointment, drops, transdermal patch or iontophoresis device). The term "parenteral," as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion. Pharmaceutical compositions for parenteral injection comprise sterile aqueous or non-aqueous pharmaceutically acceptable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just before use. Examples of suitable carriers, diluents, solvents or aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like.), Carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and organic esters. injectables such as ethyl oleate. The proper fluidity can 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. The prevention of the action of microorganisms can 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 of the pharmaceutically injectable form can be carried out approximately by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactic-polyglycolide, poly (orthoesters) and poly (anhydrides). Depending on 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 trapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilizable, for example, by filtration through the filter that retains bacteria or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or in other sterile injectable medium. before use Topical administration includes administration to the skin, mucosa and surfaces of the lung and eye. ^ güs? riiiÉB Compositions for topical administration include those for inhalation, they can be prepared as dry powder which can be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form can be used in admixture with an inert pharmaceutically acceptable carrier of larger size comprising particles having a size, for example, up to 100 microns in diameter. Suitable inert carriers have sugars such as lactose. Desirably, at least 95 percent by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 microns. For topical administration to the eye, a compound of the invention is administered in a pharmaceutically acceptable ophthalmic vehicle so that the compound is kept in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and regions. internal of the eye, as, for example, the anterior chamber, the posterior chamber, the vitreous body, the aqueous humor, the vitreous humor, the cornea, iris / cilari, 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 can be injected directly into the vitreous and aqueous humor. The composition can be pressurized and contain a compressed gas such as nitrogen or a liquefied gas propellant. The liquefied propulsion medium and undoubtedly the total composition is preferably such that the active ingredient does not dissolve therein to a substantial degree. The pressurized composition may also contain an active agent on the surface such as liquid or liquid or nonionic solid surface active agent or it may be an active agent on the anionic solid surface. It is preferred to use active agent on the solid anionic surface in the form of the sodium salt. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature or liquid at room temperature. body and therefore melt in the rectum or vagiral cavity and release the active component. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. The liposomes are fopran by mono- or multi-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 phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), page 33 et seg. , which is 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 can be used in pure form or, when this form exists, in a pharmaceutically acceptable 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 (eg, to limit tumor growth or to decrease or block tumor metastasis) at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope and depth of medical judgment. The specific therapeutically effective level of doeis for any particular patient will depend on the variety of factors including the problem being treated and the severity of the problem, - the activity of the specific compound used; the specific composition used, - the age, body weight, health in genere.l, sex and diet of the patient, - and time of administration, - the route of administration; the rate of excrescence c'.the specific compound employed; the duration of the treatment; they are used in combination or in coincidence with the specific compound employed and similar factors well known in the medical art. For example, it is well within the skill of the art to initiate dose of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention to be administered locally or systemically to a human or other mammalian host in single or divided doses may be in amounts, for example, from 0.01 to 200 milligrams / kilogram of body weight daily and more usually from 1 to 300 milligrams / kilogram of body weight. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Accordingly, the single dose compositions may contain amounts or submultiples thereof to form the daily dose. It will be understood that the agents can be combined with the compound of the present invention for inhibition, prophylactic treatment of angiogenic diseases are not limited to those listed above, but include, in principle, any agent useful for the treatment of prophylaxis of angiogenic diseases. Preparation of the compounds of the invention Abbreviations The abbreviations that have been used in the description of the scheme of the following examples are: NMM for 4-methylmorpholine; EDC1 for l-ethyl-3- (3- (dimethylamino) propyl] -carbodimide hydrochloride; HOBT by hydroxybenzotriazole; TFA by trifluoroacetic acid; THF by tetrahydrofuran; DMF by dimethylformamide. Synthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes illustrating the methods by which the compounds of the invention can be prepared. The compounds of this invention can be prepared by a variety of synthetic routes. The representative procedures are outlined in Scheme 1 and Scheme 2 where W, X, Y, Z, R, RB pC D pE pF pG H pl p2 p3 p4 p5 6 p7 p8 p "v R are defined as previously unless otherwise indicated. Depending on the nature of W, X, Y, Z, RA, RB, RC, RD, RE, RF, RG, RH, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, the protection and subsequent deprotection of other reactive groups may be required to successfully complete the synthetic sequences described. Commonly used protection groups are described 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 someone skilled in the art to review the synthetic route depicted below that other compounds within Formula I can be synthesized by substituting suitable reagents and agents in the synthesis shown below. Scheme 1 M HCI dioxane HCI dioxane As exemplified in Scheme 1, N-methyl tyrosine was converted to an ester. The amino protecting group of the tyrosine was removed and the free amine was coupled with leucine. The amino protecting group in leucine was removed and the free amine was coupled with lysine. The ester on tyrosine was saponified and the carboxylic acid was coupled with aspartic acid amide. The amino protecting group in lysine was removed and the free amine was acetylated with acetic anhydride. The oxygen protection group on tyrosine was removed with hydrogen gas in the presence of palladium on carbon. Scheme 2 NHCBZ As exemplified in Scheme 2, leucine was converted to leucine and then allowed to undergo reductive amination with phenylalanine. The amino protecting group was removed with trifluoroacetic acid and the free amine was coupled with lysine. The ester was saponified with sodium hydroxide and the carboxylic acid was coupled with aspartic acid. 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 to be an illustration and not a limitation on the scope of the invention as defined in the appended claims.

Example 1 Acid (4S, 7S, IOS, 13S) -4 - (aminobutyl) -13 - (aminocarbonyl) -10- (4-hydroxybenzyl) -7-isobutyl-9-methyl -2, 5. 8, ll- tetraoxo-3. 6. 9. 12 - tetra-azapentadecane-15-oico. Example 1A (2S) -3- \ 4 - (benzyloxy) phenyl 1 - 2 - \ (tert-butoxycarbonyl) (methyl) aminolpropanoate methyl A solution of N- (tert-butoxycarbonyl) -N-methyl-0-benzyl- L-benzyl-L-tyrosine (3.855 g, 10 mmol) and Cs2CO3 (10 mmol) in methanol / water was stirred at room temperature for 5 minutes, concentrated by rotary evaporation, then resuspended in DMF (10 milliliters). Methyl iodide was added (0.933 milliliters, 15 mmol) and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (100 milliliters) then washed sequentially with brine and NaHCO 3, dried (MgSO 4), and concentrated to give a colorless oil (4.01 gram). Example IB (2S) -3- T4- (benzyloxy) phenyl -2- (methylamino) propanoate methyl A solution of the product of Example 1A (4.0 g, 10 mmol), in 1,4-dioxane saturated with hydrogen chloride ( 30 milliliters) was stirred at room temperature for one hour, evaporated to dryness, suspended in ethyl ether, then concentrated and dried in vacuo to give a white solid (3.35 grams).

Use 1C (2S) -3- Í4- (benzyloxy) phenyl -2-rf (2S) -2-r (tert-butoxycarbonyl) aminol -4-methylpentanoyl} (methyl) methyl aminol propanoate A solution of the product of Example IB (3.35 g, 10 mmol), N- (tert-butoxycarbonyl) -L-leucine (2.99 g, 12 branch).), EDC1 (2.11 g, 11 mmol ), HOBT (1.69 g, 11 mmol) and NMM (1.21 mL, 11 mmol) in CH2C12 (50 milliliters) was stirred at 0 ° C for 90 minutes, then at room temperature for 16 hours, evaporated to dryness, redissolved in ethyl acetate (70 milliliters) then subsequently washed with brine, 10 percent aqueous KHS0, brine, aqueous NaHCO3, and brine, dried (MgSO4), and concentrated to give an viscous oil (3.98 grams). MS (DC1-NH3) m / e 513: (M + H) +, 530 (M + NH4) +. Example ID (2S) -2- rf (2S) -2-amino-4-methylpentanoyl (methyl) aminol -3- [4 - (benzyloxy) phenyl methyl methoxylate Example 1C was processed as Example IB to provide the dipeptide . Example 1E (9S.12S.15S) -15- f4- (benzyloxy) benzyl-9-r (tert-butoxycarbonyl) aminol-12-isobutyl-14-methyl -3.10.13-trioxo-1-phenyl-2-oxa -4,14,14-triazahexadecane-16-methyl oat The product of Example ID and N-alpha- (tert-butoxycarbonyl) -N-epsilon- (carbonylbenzyloxy) -L-lysine were processed as in Example 1C to provide the tripeptide . Example 1F (9S, 12S.15S) -15- Í4- (benzyloxy) benzyl-9-r (tert-butoxycarbonyl) aminol-12-isobutyl-14-methyl-3, 10.13-trioxo-l-phenyl-2-o >;: a-4, 11, l4-triazahexadecane-16-methyl oate A solution of the product of Example 1E (0.747 g, 0.96 mmol), and NaOH (0.06 g, 1.5 mmol) in methanol (9 milliliters) and water ( 2.5 milliliters) was stirred at room temperature for 2.5 hours, diluted with water (5 milliliters), reduced in volume to 6 milliliters by rotary evaporation, and washed three times with ethyl ether. The aqueous phase was acidified, extracted three times with ethyl acetate, and the combined organic extracts were dried (MgSO 4), and concentrated to give a viscous oil (0.347 grams). Example 1G (9S, 12S.15S, 18S) -18- (aminocarbonyl) -15- f4- (benzyloxy) benzyl-9-y (tert-butoxycarbonyl) aminol-12-isobutyl-14-metyl-3, 10, 13, 16-Tetraoxo-l-phenyl-2-oxa-4,11,14,17-tetra-azaicosan-20-tert-butyl oleate The product of Example 1F and L-aspartamide hydrochloride of beta-tert-butyl ester were processed as in Example 1C to provide a white powder (0.434 grams). Example 1 H (9S, 12S, 15S, 18S) -9-amino-18- (aminocarbonyl) -15- T4- (benzyloxy) benzyl-12-isobutyl-14-methyl-3, 10, 13, 16-tetraoxo-1 phenyl-2-oxa-4,11,14,17-tetra-azaicosan-20-tert-butyl oleate The product of Example 1G was processed as Example IB to provide the tetrapeptide. Example II Acid (9S, 12S, 15S, 18S) -9- (acetylamino) -18- (aminocarbonyl) -15- \ 4 - (benzyloxy) benzyl-12-isobutyl-14-methyl-3.10.13, 16-tetraoxo -l-phenyl-2-oxa-4.11, 14.17-tetra-azaicosan-20-oico A solution of Example 1H (0.37 g, 0.43 mmol), acetic anhydride (101 milliliters, 1.08 mmol) and triethylamine (210 milliliters, 1.5 mmol) in CH2C12 (6 milliliters) was stirred at room temperature for 48 hours, evaporated to dry, redissolved in ethyl acetate then sequentially washed with aqueous NaHCO3, brine, 10% KHS04. percent aqueous and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silicon oxide gel with 50 percent ethyl acetate / toluene to give the acetylated tetrapeptide (0.180 grams). Example 1J Acid (4S, 7S, IOS, 13S) -4- (4-aminobutyl) -13- (aminocarbonyl) -10- (4-hydroxybenzyl) -7-isobutyl-9-methyl -2.5.8.11-tetraoxo-3 , 6.9. 12-Tetra-Azaicosan-15-Oico A solution of the product from Example II (0.180 g, 0.25 mmol), and 10 percent palladium in carbon (0.18 g) in methanol (10 milliliters) was stirred for 18 hours under 4 atmospheres of hydrogen. The catalyst was filtered and the mixture was concentrated to give the title compound as a white powder (0.10 grams). MS (ESI + Q1MS) m / e 593 (M + N) +, 615 (M + Na) +; Example 2 (2S) -2- (((2S) -2-r ((2S) -2-p (2S) -2- (acetylamino) -6-aminohexanoylol aminol -4-methylpentanoyl) (methyl) amino acid] 3-F-enylpropanoyl.) Amino) butanedioic Example 2 A (2S) -2- ( { (2S) -2- i (tert-butoxycarbonyl) (methyl) aminol-3-p-enylpropanoyl} amino) N- (tert-Butoxycarbonyl) -N-methyl-L-phenylalanine dibenzyl butanedioate and L-aspartic ester dibenzyl ester were processed as in Examples 1C and IB to provide the dipeptide Example 2B (2S) -2- (( (2S) -2- Ti (2S) -2- [(tert-butoxycarbonyl) aminol-4-methylopentanoyl} - (methyl) aminol-3-f-enylpropanoyl} amino) butanediic acid dibenzyl The product of Example 2A and N- (tert-butoxycarboni) -L-leucines were processed as in Examples 1C and IB to provide the tripeptide, eg 2C (2S) -2- ( { (2S, 5S, 8S) -8- (4-aminobutyl) -2-benzyl-5-isobutyl-3, 12, 12-trimethyl-4, 7, 10-trioxo-l-oxa-3.6, 9-triazatridec-1-anoyl] aminol butanediic acid dibenzyl The product of Example 2B and N-alpha- (tert-butoxycarbonyl) -N-epsilon- (carbonylbenzyloxy) -L-lysine were processed as in Examples 1C and IB to provide the tetrapeptide. * H NMR (300 MHz, DMS0-d6) 6 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, 20H), 5.23 (m, 1H), 5.11 (s, 2H), 5.10-5.06 (m, 4H), 5.00 (d, 2E), 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 (2S) -2- ( { (2S) -2-r ((2S) -2- (r (2S) -2- (acetylamino) -6-amino hexanoyl 1 amino.} -4 - methylapentanoyl) (methyl) aminol -3-phenylpropanoyl.} dibenzyl butanedioate The product of Example 2C was processed as in Examples 1C and II to provide the acetylated tetrapeptide Example 2E Acid (2S) -2 - ((( 2S) -2-r ((2S) -2- { R (2S) -2- (acetylamino) -6-aminohexanoylol amino} - 4-methylopentanoyl) (methyl) aminol -3-phenylpropanoyl. amino) butanedioic 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 Acid (2S) -2- { (2S, 5S.8S) -8- (4- aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3.6, 12, 12-tetramethyl-4,7,1-trioxo-l-oxa-3,6,9-triazatridec-1-anoyl amino}. butanedioate Example 3A (9S.12S.15S) -15- Í4- (benzyloxy) encyl -9-? (tert-butoxycarbonyl) aminol-12-isobutyl-ll.14-dimethyl-3, 10, 13-trioxo-l- Phenyl-2-oxa-4,14,14-triazahexadecane-16-methoxymethyl N- (tert-Butoxycarbonyl) -N-methyl-L-leucine and methyl ester of O-benzyl-L-tyrosine were processed as in Examples 1C and IB to provide the dipeptide Example 3B Acid (9S.12S.15S) -15- - (benzyloxy) encyl 1 -9- \ (tert-butoxycarbonyl) aminol-12-isobutyl-11,14-dimethyl -3.10, 13-trioxo-l-phenyl-2-oxa-4, 11. l4-triazahexadecane-16-oico The product of Example 3A and N-alpha- (tert-butoxycarbonyl) -N-epsilon- (carbonylbenzyloxy) ) -L-lysine were processed as in Examples 1C and 1F to provide the tripeptide Example 3C (2S) -2- (((2S.5S.8 S) -2- Í4- (benzyloxy) benzyl -8- \ (tert-butoxycarbonyl) aminol -5-isobutyl-3.6-dimethyl-4.7, 14-trioxo-l 6-phenyl-15-oxa-3.6, 13-triazahexadec-1-anoyl} amino) dibenzyl butanedioate The product of Example 3B and dibenzyl ester of L-aspartic acid were processed as in Examples 1C and 1F to provide the tetrapeptide. 3D Example Acid (2S) -2-. { [(2S, 5S, 8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3.6.12.12-tetramet-il-4,7.10-trioxo-ll-oxa-3, 6.9- triazatridec-1-anoyl amino} butanedioic The product from Example 3C was processed as in Example 1J to provide title compound. Example 4 (2S) -2- (2S.5S.8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3.12.12-trimethyl-4.7.10-trioxo- acid 11-oxa-3,6,9-triazatridec-1-anoyl (methyl) aminol butanedioic The product of Example 1F and dibenzyl ester of N-methyl-L-aspartic acid were processed as in Examples 1C and 1J to provide the title compound . Example 5 Acid (2S) -2-. { f (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 Example 5 A (9S.12S.15S) - 15 -benzyl-9 - (tert-butoxycarbonyl) aminol-12-isobutyl-3,10-dioxo-l-enyl-2-oxa-4.11.14-triazahexadecane-6-oate of methyl H-Leuy (CH2NH) Phe-OMe prepared as described in Bravo et al., J. Chem. Soc. Perkin Trans. I (19S1) 3117 and N-a 1 fa - (tert-bu t oxicar on i 1) -N-ep if 1 on - (carbonylbenzyloxy) -L-lysine is processed as in Examples 1C and 1F to provide the tripeptide. Example 5B Acid (2S) -2-. { r (2S.5S.8S) -8- (4-aminobutyl) -2-benzyl-5-isobutyl-12,12-dimethyl-7,10-dioxo-l-oxa-3.6.9-triazatridec-l-anoill Not me} butanedioic The product of Example 5A and L-aspartic acid dibenzyl ester were processed as Examples 1C and 1J to provide the title compound.

Claims (12)

CLAIMS A compound of Formula I
1. I. or a pharmaceutically acceptable salt or prodrug thereof, wherein R and R are hydrogen or taken together are = 0; R ^ and R are hydrogen or taken together are = 0; RE and pR are hydrogen or taken together are = 0; RG and RH are hydrogen or taken together are = 0; W, X, Y, Z are independently selected from (1) hydrogen and (2) alkyl of one to six carbon atoms, with the proviso that when X, Y, Z are hydrogen then at least one of R and R or R and R or R and R is different from = 0; R 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 carbon atoms wherein the alkyl group is substituted with -NL 1L 7 wherein L11 and L2 are independently selected from (a) hydrogen, ( b) alkyl of one to six carbon atoms, and (c) an amino protecting group; R and R5 are independently selected from (1) hydrogen (2) alkyl of one to six carbon atoms, and (3) cycloalkyl of three to twelve carbon atoms; Rf and R7 are independently selected from (1) hydrogen, (2) alkyl of one to six carbon atoms, and (3) alkyl of one to six carbon atoms 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, (11) -0LJ wherein LJ is alkyl of one to six carbon atoms, (iii) alkyl of one to six carbon atoms, (iv) halogen, (v) -N02, and (vi) -NL ^ 2; R8 and R9 are independently selected from (1) hydrogen (2) alkyl of one to six carbon atoms, and (3) -CH2 (CH2) mC02L4 wherein L4 is selected from (a) hydrogen and (b) alkyl of one to six carbon atoms and m is an integer of 0 to 4 RJQ is selected from (1) -OL5 wherein L5 is selected from (a) hydrogen, (b) alkyl of one to six carbon atoms, (c) cycloalkyl from three to six carbon atoms, and (d) alkyl of one to six carbon atoms substituted with 1 or 2 substituents independently selected from (i) cycloalkyl of three to six carbon atoms, (ii) aryl, and (iii) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from -OH, -OL3 wherein L3 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms, halogen, -N02, and -NL * L2 and (2) -NHL5.
2. 2. A compound according to claim 1 of
3. Formula II p. 3. A compound according to claim 2 wherein X and Z are hydrogen, Y is alkyl of one to six carbon atoms, and RA and RB, RC and RD, and RE and RF are = 0.
4. 4. A compound according to claim 3 selected from the group consisting of (4S, 7S, IOS, 13S) -4- (4-aminobutyl) -13- (aminocarbonyl) -10- (4-hydroxybenzyl) -7 acid. - isobutyl-9-methyl-2, 5,8, 11-tetraoxo-3, 6,9, 12-tetra-azapenta-decane-15-oic acid and (2S) -2- (. {(2S) - 2- [((2S) -2- { [(2S) -2- (acetylamino) -6-aminohexanoyl] amino.} -4-methylpentanoyl) (met Ll) amino] -3-phenylpropanoyl}. amino) butanedioic acid.
5. 5. A compound according to claim 2 wherein Y and Z are hydrogen, X is alkyl of one to six carbon atoms, and RA and RB, RC and RD, and RE and RF are = 0.
6. 6. A compound according to claim 5 which is (2S) -2- acid. { [(2S, 5S, 8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3, 6, 12, 12-tetramethyl-4,7,1-trioxo-l-oxa -3,6,9-triazatridec-l-anonyl] amino} butanedioic
7. 7. A compound according to claim 2 wherein X is hydrogen, Y and Z are alkyl of one to six carbon atoms, and RA and RB, RC and RD, and RE and RF are = 0.
8. 8. A compound according to claim 7 which is (2S) -2- [_L (2S, 5S, 8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl- 3, 12, 12 -trimethyl-4,7,1-trioxo-Il-oxa-3, 6,9-triazatridec-1-anonyl] (methyl) amino} butanedioic
9. 9. A compound according to claim wherein X, Y, Z and Rc and RD are hydrogen, and RA and RB, and RE and RF are = 0.
10. 10. A compound according to claim 9 which is (2S) -2- acid. { [(2S, 5S, 8S) -8- (4-aminobutyl) -2-benzl-5-isobutyl-12,12-dimethyl-7,10-dioxo-11-oxa-3, 6,9-triazatridec- l-anonyl] aminojbutanedioic acid.
11. 11. A method for treating a patient in need of antiangiogenesis therapy comprising administering to the patient a therapeutically effective amount of the compound according to claim 1.
12. 12. A compound according to claim 1 selected from the group consisting of (4S, 7S) acid. , IOS, 13S) -4- (4-aminobutyl) -13- (aminocarbonyl) -10- (4-hydroxybenzyl) -7-isobutyl-9-methyl-2,5,8,11-tetraoxo-3,6, 9, 12-tetra-azapentadecane-15-oico, 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-4,7,1-trioxo-l-oxa -3,6,9-triazatridec-l-anonyl] amino} butanedioic acid (2S) -2- [[(2S, 5S, 8S) -8- (4-aminobutyl) -2- (4-hydroxybenzyl) -5-isobutyl-3,12,1,5-trimethyl-4,7 , 10-trioxo-l-oxa-3, 6, 9-triazatridec-l-anoyl] (methyl) amino] butanedioic, and (2S) -2- acid. { [(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