MXPA98009612A - Antiangiogenic drug to treat cancer, arthritis and retinopathy - Google Patents

Abstract

Peptides having the formula:T-Gly-Val-D-Ile-Thr-Arg-Ile-U, V-Gly-D-Val-Ile-D-Thr-D-Arg-D-Ile-W, X-D-Arg-D-Ile-D-Arg-D-Thr-Ile-D-Val-Y, and Z-Gly-Val-Ile-Thr-Arg-Ile-U wherein T is absent oris selected from N-protecting group and a polypeptide of up to 12 amino acid residues optionally terminated with an N-protecting group;U is selected from Arg and Arg-NR1R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms;V is absent or an N-protecting group;W is selected from D-Arg and D-Arg-NR1R2;X is absent or an N-protecting grou;Y is selected from Gly and Gly-NR1R2;and Z is 1-12 amino acid residues optionally terminated with an N-protecting group wherein at least one of the amino acid residues is a D-amino acid residue inhibit angiogenesis and are useful in the treatment of disease states such as cancer, arthritis, macular degeneration and diabetic retinopathy in which angiogenesis plays a role.

Description

Antiangiogenic drug to treat cancer, arthritis and retinopathy Technical Field The present invention relates to compounds useful for treating disease states, which arise or are exacerbated by angiogenesis. More particularly, the invention relates to certain peptides which inhibit angiogenesis, to pharmaceutical compositions comprising these compounds and to a method that inhibits angiogenesis.

BACKGROUND OF THE INVENTION Angiogenesis is the fundamental process by which new blood vessels are formed and is essential for a variety of normal bodily activities (such as reproduction, development and wound healing). Although the process is not fully understood, it is thought to involve a complex interaction of molecules, which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules seem to maintain the microvasculature in a state of rest (ie, one of non-capillary growth) for prolonged periods, which can last as long as weeks or in some cases, decades. However, when necessary (such as during wound healing), these same cells may experience rapid proliferation and change within a period of 5 days. (Folkman, J. and Shing, Y., The Journal of Biological! Chemistry, 267 (16): 10931-10934, 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 managed by persistent unregulated angiogenesis. Stated differently, 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 approxily 20 eye diseases. Under certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy the cartilage. In diabetes, capillaries formed in the retina invade the vitreous, bleed and cause blindness. The 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 that enlarge to more than 2 mm must obtain their own blood supply and in doing so they induce the growth of new capillary blood vessels. Once these new blood vessels are embedded in the tumor, they provide a means for tumor cells to enter the circulation and spread to distant sites, such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324 (1): 1-8 (1991)).

Thrombospondin-1 (TSP1, MW 450,000) is a large modular ix protein that inhibits neovascularization in vivo (Good, et al., Proc. Nati, Acad. Sci. USA, 87, 6624 (1980)). The majority of the antiangionic activity of TSP1 resides in the central 70-kD cell region. Synthetic peptides were prepared, which simulate the sequences found in the repeat region as properdin 1 of the central stack region of the TSP1 molecule. One of these peptides, the so-called Malll, is a 19-mer of the formula Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-lle-Thr-Arg -lle-Arg (Tolsma, et al., J. Cell, Biol., 122, 497 (1993)). Peptide Mall l blocked neovascularization in vivo in the rat cornea and inhibited the migration of cultured endothelial cells with an EDso of approxily 1 μM. Although the various angiogenesis inhibitors are currently under development to be used to treat angiogenic diseases (Gasparini, G. and Harris, A.L., J Clin Oncol 13 (3): 765-782, (1995)), there are disadvantages associated with several of these compounds. For example, suramin is a potent inhibitor of angiogenesis, but causes (at the doses required to achieve antitumor activity) severe systemic toxicity in humans. Other compounds, such as retinoids, interferons and antiestrogens are safe for human use but only have a weak anti-angiogenic effect. Still other compounds can be difficult or expensive to make. Short peptides are relatively simple to make and represent an effective cost method for treating disease diseases in which angiogenesis plays a role and for designing targeted angiogenesis inhibitors.

BRIEF DESCRIPTION OF THE INVENTION In this main embodiment, the present invention provides a peptide, or a pharmaceutically acceptable salt thereof, selected from the group consisting of T-Gly-Val-D-lle-Thr-Arg-lle-U, I. and Z-Gly-Val-lle-Thr-Arg-lle-U IV Where T is absent or selected from an N-protecting group and a polypeptide of up to 12 amino acid residues optionally ending with an N-protecting group; U is selected from Arg and Arg-NR1 R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms; and Z is 1 -12 amino acid residues optionally terminated with an N-protecting group, wherein at least one of the amino acid residues is a D-amino acid residue. Preferred compounds of the present invention have the formula T-Gly-Val-D-lle-Thr-Arg-lle-U, wherein T is absent or selected from the N-protecting group and a polypeptide of up to 12 amino acid residues optionally covered with an N-protecting group and U is selected from Arg and Arg-NR1 R2. The most preferred compounds are those of the formula T-Gly-Val-D-lle-Thr-Arg-lle-U, wherein T is absent or is acetyl and U is selected from the group consisting of Arg, Arg-NH2 and Arg-NHCH2CH3.

In another embodiment, the present invention provides retro isomers of the above peptides, or retro-inverso isomers of the above peptides, or pharmaceutically acceptable salts thereof.

Examples of retro and retro-inverse isomers are selected from the group consisting of VD-Gly-D-Val-lle-D-Thr-D-Arg-D-lle-W and II XD-Arg-D-lle-D- Arg-D-Thr-lle-D-Val-Y, III wherein V is absent or is an N-protecting group; W is selected from D-Arg and D-Arg-NR1 R2; X is absent or is an N-protective group; and Y is selected from Gly and Gly-NR1 R2. In another embodiment, the present invention provides a composition for treating a patient in need of anti-angiogenesis therapy comprising a peptide defined above in combination with a pharmaceutically acceptable carrier. In still another embodiment, the present invention provides a method for treating a patient in need of anti-angiogenesis therapy comprising administering to the patient a therapeutically effective amount of a peptide as defined above. In still another embodiment, the present invention provides a composition for the treatment of a disease selected from the group consisting of cancer, arthritis, psoriasis, angiogenesis of the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy, comprising a peptide such as defined above, in combination with a pharmaceutically acceptable carrier.

In still another embodiment, the present invention provides a treatment for a disease selected from the group consisting of cancer, arthritis, macular degeneration and diabetic retinopathy, comprising administering to the patient a therapeutically effective amount of a peptide as defined above. In still another embodiment, the present invention provides a method for isolating the TSP-1 receptor from endothelial cells comprising ligating a peptide of Formulas I and IV to the receptor, isolating the peptide receptor complex and purifying the receptor.

DETAILED DESCRIPTION The term "alkyl" refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n-e / so-propyl, n-, sec-, iso- and fer-butyl, and the like. The term "N-protecting group", as used herein, refers to an easily removable group, which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of N-protecting groups is well known in the art to protect groups against undesirable reactions during a synthetic process, and many such protective groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & amp; amp;; Sons, New York (1991). Examples of N-protecting groups include, but are limited to, acyl groups including acetyl, trifluoroacetyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy groups, including t-butyloxycarbonyl (BOC) and carbobenzyloxy, and the like. The term "retro isomer", as used herein, refers to a peptide in which amino acids L and D of Formulas I and IV have been inverted, i.e., amino acids L have been substituted by amino acids D and amino acids D have been replaced by amino acids L. An example of retro isomer is of formula II. The term "retro isomers" includes fragments of such isomers "The term" retro-inverse isomer ", as used herein, refers to a peptide in which (i) amino acids L and D of Formulas I and IV have been inverted as in the retro isomer, and (ii) the sequence, when read from the N-terminus to the C-terminus, is inverted.An example of retro-inverted isomer is of formula III.The term "retro-inverted isomers" includes fragments of such isomers By "pharmaceutically acceptable salt" is meant salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and they are commensurate with a reasonable risk / benefit ratio Pharmaceutically acceptable salts are well known in the art For example, SM Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical S Ciences, 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 salts of acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, comforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, 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, and the like. The alkali metal salts or. Representative alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium cations, quaternary ammonium and amine, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and similar. As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that readily break down in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl portion conveniently has no more than 6 carbon atoms. Examples of particular esters include formats, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of medical judgment, suitable for use in contact with human and lower animal tissues with undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk / benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug 2" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formula, for example by hydrolysis in the blood.A full discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Deliverv Systems, Volume 14 of ACS SYMPOSIUM SERIES, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference. otherwise by a "D" prefix, the stereochemistry of the α-carbon of the amino acid and aminoacyl residues in peptides described in this specification and the appended claims is the natural configuration or "L." The designations "R" and "S" "of Cahn-Ingold-Prelog are used to specify the stereochemistry of chiral centers in certain of the acetyl substituents at the N-terminus of the peptides of this invention. , S "is to indicate a racemic mixture of the two enantiomeric forms. This nomenclature follows that described in R.S. Cahn, et al. Angew Chem. Int. Ed. Engl., 5, 385-415 (1966). For the most part, the names of aminoacyl residues that occur naturally and occur unnaturally used in the present follow the naming conventions suggested by the IUPAC Commission in Organic Chemistry Nomenclature and the IUPAC-IUB Commission in Nomenclature. Biochemistry as set forth in "Nomenclature of a-Amino Acids (Recommendations, 1974)" Biochemistry, 14 (2), (1975). To the extent that the names and abbreviations of amino acid and aminoacyl residues used in this specification and appended claims differ from those suggestions, they will be clarified to the reader by the following. It is well known in the art that modifications and changes in the structure of a polypeptide can be made without substantially altering the biological function of that peptide. For example, certain amino acids may be substituted for other amino acids in a given polypeptide without any appreciable loss of function. In making these changes, substitutions of similar amino acid residues may be made in the base of relative similarity of side chain substituents, eg, their size, charge, hydrophobicity, hydrophilicity, and the like. As detailed in U.S. Patent No. 4,554,101, incorporated herein by reference, the following hydrophilicity values have been assigned to amino acid residues: Arg (+3.0); Lys (+3.0); Asp (+3.0); Glu (+3.0); Ser (+0.3); Asn (+0.2); Gln (+0.2); Gly (0); Pro (+0.5); Thr (-0.4); Ala (-0.5); His (-0.5); Cys (-1.0); Met (-1.3); Val (-1.5); Leu (-1.8); lie (-1 .8); Tyr (-2.3); Phe (-2.5); and Trp (-3.4). It is understood that an amino acid residue can be substituted by another having a similar hydrophilicity value (eg, within a value of plus or minus 2.0) and still obtain a biologically equivalent polypeptide. In a similar way, substitutions can be made on the base of similarity in hydropathic index. A hydropathic index has been assigned to each amino acid residue based on its hydrophobicity and charge characteristics. These hydropathic index values are: He (+4.5); Val (+4.2); Leu (+3.8); Phe (+2.8); Cys (+2.5); Met (+1 .9); Ala (+1 .8); Gly (-0.4); Thr (-0.7); Ser (-0.8); Trp (-0.9); Tyr (-1 .3); Pro (-1.6); His (-3.2); Glu (-3.5); Gln (-3.5); Asp (-3.5); Asn (-3.5); Lys (-3.9); and Arg (-4.5). When making a substitution based on the hydropathic index, a value within plus or minus 2.0 is preferred. Compounds contemplated as falling within the scope of the present invention include, but are not limited to: Gly-Val-D-Ue-Thr-Arg-He-Arg, Gly-V __-D-ne-Thr-Arg-ne- Arg-N-_2. Gly-Val-D-pe-thr-Arg-Ile-Arg-N? CH2CH3, Ac-Gly-Val-D-Ile-Thr-Arg-pe-Arg, Ac-GIy-Val-D-Ile-Thr- Arg-Ue-Arg-N? 2, Ac-Gly-Val-D-pe-Thr-Arg-_le-Arg-NHCH2CH3, Tyr-Gly-Val-D-pe-Thr-Arg-Ile-Arg, Tyr- Gly-Val-D-pe-Thr-Arg-_le-Arg-NH2, tvr-Gly-Val-D-_le-Thr-Arg-pe-Arg-NHCH2CH3, Ac-Tyr-Gly-Val-D-Ile- Thr-Axg-ne-Arg, Ac-Tyr-Gly-Val-D-pe-thr-Axg-Ile-Arg-NÍ-2. Ac-Tyr-Gly-Val-D-pe-Thr-Arg-Ile-Arg-NHCH2CH3, D-Tyt-Gly-Val-D-pe-Thr-Arg-Ile-Arg, D-Tyr-Gly-Val- D-pe-thr-Arg-Ile-Arg-NH2. D-Tvr-Gly-Val-D-pe-Thr-Arg-Ile-A_-g-NHCH2CH3, | Ac-D-Tyr-Gly-Val-D-He-Thr-Arg-pe-Arg. I Ac-D-Tyr-Gly-Val-D-Ile-Thr-Arg-_le-Arg-NH2, Ac-D-Tyr-Gly-Val-D-Ile-TÍr-Arg-pe-Arg-NHCH2CH3, Gly -Asp-GIy-Val-D-lle-Thr-Arg-Ile-Arg, Gly-Asp-Gly-VaI-D-Ile-Thr-Arg-Ile-Arg-NH2. Gly-Asp-Gly-V_l-D-pe-tr_r-Arg-pe-Arg-NHCH2CH3, Ac-Gly-Asp-Gly-Val-D-pe-Thr-Arg-Ile-Arg, Ac-Gly-Asp- Gly-Val-D-Ile-thr-Arg-Ile-Arg-NH2 »Ac-Gly-Asp-Gly-V_J-D-pe-Thr-Arg-pe-Arg-NHCH2CH3, Ser-Pro-Tf-Ser- Ser-AIa-Ser-V_a-- _.- A_a - ^ Ser-Pro-Tf-Ser-Se.-Ala-Ser-V_l-T __.- Ate ^ Ser-Pro-T ?? Ser-Ser-Ala-Ser-V_J-Thr-Ala-Gly-Asp-Gly-Val-I ne-Thr-Arg-Ile-Arg-NHCH2CH3. Ac-Ser-Prc ^ Tf-Ser-Ser-A-a-Ser-V -Or-AJa-Gly-Asp-Gly-Vai-D-ne-Thr-Arg-Ile-Arg. Ac-Ser-Pro-Tf-Ser-Ser-AJa-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-NH2, Ac-Ser-E ^ o-Tf-Ser-Ser-AJa-Ser-Val-T r-AJa-Gly-Ap-Gly-VaJ-D-Ile-Thr-Arg-Ile-Arg-NHCH 2 CH 3, Gly-D-Val-pe-D -Thr-D-Arg-D-ne-D-Arg, Gly-D-Val-De-D-Thr-D-Arg-D-pe-D-Arg-NH2, Gly-D-Val-pe-D -Thr-D-Arg-D-pe-D-Arg-NHCH2CH3, Ac-Gly-D-Val-Ile-D-Thr-D-Arg-D-pe-D-Arg, Ac-Gly-D-Val -pe-D-Thr-D-Arg-D-Ile-D-Arg-NH2 Ac-Gly-D-Val-ne-D-Thr-D-Arg-D-pe-D-Arg-NHCH2CH3, D- Axg-D-pe-D-Arg-D-Thr-Ile-D-Val-GIy, D-Arg-D-pe-D-Arg-D-Thr-Ile-D-Val-Gly-NH2, D- Arg-D-pe-D-Arg-D-Thr-Ile-D-Val-Gly-NHCH2CH3, Ac-D-Arg-D-pe-D-Arg-D-Thr-Ile-D-Val-Gly, Ac-D-Arg-D-pe-D-Arg-D-Thr-ue-D-Val-Gly-NH2, Ac-D-Arg-D-pe-D-Arg-D-Thr-pe-D- VaI-Gly-i HCH2CH3. Gly-Val-D-rie-Lys-Arg-Ile-Arg, Ac-Gly-Val-D-Ile-Lys-Arg-Ile-Arg, Gly-Val-D-pe-Lys-Arg-Ile-Arg- N? 2, Ac-Gly-Val-D-Ce-Lys-Arg-Ile-Arg-NH2, Gly-Val-D-pe-Lys-Arg-pe-Arg-NHCH2CH3, Ac-Giy-Val-D- Ile-Lys-Ars-Ile-Arg-NHCH2CH3, Gly-Val-D-Ile-Lys-Arg-Ser-Arg, Ac-Gly-Val-D-ne-Lys-Axg-Ser-Axg, Gly-Val- D-ne-Lys-Arg-Ser-Arg-NH2. Ac-Gly-Val-D-Ile-Lys-Arg-Ser-Arg-NH2. Gly-Val-D-ne-Lys-Arg-Ser-Arg-NHCH2CH3. Ac-Gly-Val-D-Ile-Lys-Axg-Ser-Arg-NHCH2CH3. Gly-Val-D-Ile-Thr-Arg-Ser-Arg, Ac-Gly-Val-D-Ue-Thr-Arg-Ser-Arg, Gly-V_l-D-pe-Thr-Axg-Ser-Arg- NH2. Ac-Gly-Val-D-Ile-thr-Arg-Ser-Arg-NHz, Gly-Val-D-ne-Thr-Arg-Ser-Arg-? Ffl [CH2CH3, Ac-Gly-Val-D-pe -Thr-Arg-Ser-Arg-NHCH2CH3. Gly-Val-D-IIe-Tyr-Arg-Ile-Arg, Ac-Gly-Val-D-Ile-Tyr-Arg-Ile-Arg, Gly-Val-D-Ile-Tyr-Arg-Ile-Arg- N_-2. Ac-Gly-Val-D-Ile-Tyr-Arg-Ue-Arg-NH2, Gly-Val-D-pe-Tyr-Arg-Ile-Arg-M? CH2CH3. Ac-Gly-Val-D-Ile-Tyr-A_-g-pe-Arg-NHCH2CH31 Gly-Val-D-Ile-Tyr-Arg-Asn-Arg, Ac-Gly-Val-D-Ile-Tyr-Arg-Asn-Arg, Gly-Val-D-lle-Tyr-Arg-Asn-Arg-NH2, Ac-Gly-Val-D-Ile-Tyr-Arg -Asn-Arg-NH2, Gly-Val-D-IIe-Tyr-Arg-Asn-Arg-NHCH2CH3, Ac-Gly-Val-D-Ile-Tyr-Arg-Asn-Arg-I ^? CH2CH3, Gly- Val-D-Ile-Thr-Arg-Asp-Arg, Ac-Gly-Val-D-Ile-Thr-Arg-Asn-Arg, Gly-VaI-D-pe-Thr-Arg-Asn-Arg-NH2, Ac-Gly-Val-D-Ile-Thr-Arg-Asn-Arg-NH2, Gly-Val-D-Ile-Thr-Arg-An-Arg-N? CH2CH3, Ac-Gly-VaJ-D-Ile- Thr-Axg-Asn-Arg-NHCH2CH3, Ser-Prc-tf-Ser-D-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-Ile-Thr-Arg-ne- Arg, Ser -_ ^ o-tf-Ser-D-Ser-AIa-Ser-V_l-Thr-Ala-Gly-Asp-Gly-Val-D-Ile-Thr-Arg-ne-Arg-NH2, Ser- Pro-tf-Ser-D-Ser-Ala-Ser-Val-TTir-Ala-Gly-Asp-Gly-Val-D-ne-Thr-Arg-pe-Arg-NHCH2CH3 Ac-Ser-Pro-Tf-Ser-D-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-pe-Thr-Arg-Ile-Arg, Ac-Ser-_- o-tf-Ser-D-Ser-AJa-Ser-VaJ-Tr_-Ala-Gly-Asp-Gly-V_l-D-pe-Thr-Arg-Ile-Arg-NH2, Ac-Ser-Prx -Tf- Ser-D-Ser-Ala-Ser-Val-Tl r-Ala-Gly-Asp-GIy-Val-D-ne-Thr-Arg-Ile-Atg-NHCH2CH3, Ser-Pro-Tf-Ser-D-Ser -AIa ~ Ser-V_l-Tl? R-AIa-Gly-A_p-Gly-V_l-pe-Thr-Arg-_le- I Axg, Ser-Pro-Tf-Ser-D -__ 2r-Ala-Ser-Val-_ r-A __? - Gly-A_ip-Gly-V_l-pe- - u - Arg-Ile-Arg-NH2. Ser-Pro-Trp-Ser-I Ser-Ala-Ser-V_d-T? R-AIa-Gly-Asp-Gly-Val-Ile-? R-Arg-Ile-Arg-NHCH2CH3. Ac -_ ^ r-_ or-Tf-Ser-I Ser-AIa-_ r-V_d-?? r-Ala-Gly-Asp-Giy-V_I-pe-Thr-Arg-Ile-Arg, > Ac-Ser-Pro-Tf-Ser-D-Ser-AJa-Ser-Val-thr-Ala-Gly-Asp-Gly-Val-pe-Thr-Axg- _le-Arg-NH2, Ac -_ ^ r- - ^ o-Tf-Ser-D-Ser-AJa-Ser-Val-Tr? r-Ala-GIy-Asp-Gly-V_l-De-Thr-Arg-Ile-Arg-NHCH2CH3, Ser-Pro-Tf- D-Ser-Ser-Ala-Ser-Val-T ^ r-Ala-Gly-Asp-Gly-Val-pe-Thr-Arg-Ile-Arg, Ser-Pro-tf-D-Ser-Ser-Ala- Ser-V_J-Tl r-A_a-Gly-Asp-GIy-Val-pe-Thr-Arg-Ile-Arg-NH2, Ser-- or-Tf-D-Ser-Ser-Ala-Ser-Val-Thr- Ala-Gly-Asp-Gly-Val-Ile-thr-Arg-Ile-Arg-NHCH2CH3, Ac-Ser-Pro-Tf-D-Ser-Ser-Ala-Ser-Val-thr-Ala-Gly-Asp- Gly-Val-pe-T r-Arg-Herg, Ac-Ser-Pro-Tf-D-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-pe-Thr -Arg- De-Arg-NH2.

Ac-Ser-l ^ o-tf-D-Ser-Ser-AJa-Ser-Val-thr-Ala-Gly-Asp-Gly-Val-Ile-Thr-Arg-Ile-Arg-NHCH2CH3.

Effect of the compounds of the invention on the migration of endothelial cells The effect of the peptides of the invention on the migration of endothelial cells was determined in vitro using the endothelial cell migration assay. This test was performed essentially as described by Polverini, P.J. et al., Methods Enzymol, 198: 440-450 (1991). Briefly, endothelial cells (bovine capillaries (adrenal) (BCE, supplied by Judah Folkman, Harvard University Medical School) were exposed overnight in DMEM containing 0.1% bovine serum albumin (BSA) .The cells were then collected with trypsin and resuspended in DMEM with 0.1% BSA at a concentration of 1.5 x 106 cells / ml. The cells were added to the bottom of a modified 48-cavity Boyden chamber (Nucleopore Corporation, Cabin John, MD), the chamber was mounted and inverted, and the cells were allowed to bind for 2 hours at 37 ° C to polycarbonate chemotaxis membranes (5 μm pore size) had been soaked in 0.1% gelatin overnight and dried. The chamber was then inverted again and the test compounds were added to the cavities of the upper chamber (at a total volume of 50 μl); the apparatus was then incubated for 4 hours at 37 ° C. The membranes were recovered, fixed and stained (DiffQuick, Fisher Scientific, Pittsburgh, PA) and the number of cells that had migrated to the upper chamber was counted by 10 high energy fields. Support migration to DMEM + 9.1% BSA was subtracted and the data reported as the number of cells that migrated through 10 high energy fields (400X), or when the results of multiple experiments were combined, such as the percentage of the Maximum migration compared with a simultaneous positive control. The compounds of the invention inhibit cell migration as shown in Table 1.

Table 1 Effect of the compounds of the invention on endothelial cell migration The inhibition of angiogenesis in vivo was measured using a rat corneal neovascularization assay. According to this, 6% of hydron pellets containing peptide alone or in combination with 0.15 μM bFGF were implanted in rat corneas 1 -1.5 mm from the limbus. At 7 days, the rats were sacrificed, they were diffused with colloidal carbon to visualize the vessels and the corneas were extracted. The vigorous inward growth of vessels was recorded as a positive angiogenic response. The induction control indicates the response to 0.15 μM of bFGF alone. Negative controls were made against 0.1% BSA, which did not induce inward vessel growth. The inhibition of neovascularization by compounds of the invention is shown in Table 2.

Table 2 Inhibition of neovascularization of rat cornea by the compounds of the invention The compounds of the invention, including but not limited to those specified in the examples, possess anti-angiogenic activity. As inhibitors of angiogenesis, such compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of the breast, coloh, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gall bladder and bile ducts, intestine. thin, urinary tract (including, kidney, bladder, and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, cell tumor tests and germ), endocrine glands (including the pituitary, adrenal and thyroid glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and brain tumors, nerves , eyes, and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neurons, neuroblastomas, schwannomas, and meningiom ace). Such compounds may also be useful for creating solid tumors arising from hematopoietic malignancies, such as leukemias (ie, chloromas, plasmacytomas and plaques and tumors of mycosis fungoides and cutaneous T cell lymphoma / leukemia), as well as in the treatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas). In addition, these compounds or genes which encode their expression may be useful in the prevention of metastasis of the tumors described above, either when used alone or in combination with radiotherapy and / or other chemotherapeutic agents. Additional uses include the treatment and prophylaxis of autoimmune diseases, such as rheumatoid, immune and degenerative arthritis; various ocular diseases, such as diabetic retinopathy, premature retinopathy, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other conditions of abnormal neovascularization of the eye; skin diseases such as psoriasis; diseases of blood vessels such as hemangiomas, and capillary proliferation within the atherosclerotic plaques; Osler-Webber syndrome; myocardial angiogenesis; plate neovascularization; telangiectasia; hemophilic joints; angiofibroma, and wound granulation. Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endothelial cells, including but not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars, ie, keloids. Another use is as a birth control agent, by inhibiting ovulation and establishment of the placenta. The compounds of the invention are also useful in the treatment of diseases having angiogenesis as a pathological consequence, such as cat scratch disease (Táchele minalia quintosa) and ulcers (Helicobacter pylori). The compounds of the invention are also useful for reducing bleeding by administration prior to surgery, especially for the treatment of resectable tumors. The compounds of the invention can be used in combination with other compositions and methods for the treatment of diseases. For example, a tumor can be conventionally treated with surgery, radiation or chemotherapy in combination with a peptide of the present invention, and then a peptide of the present invention can be subsequently administered to the patient to extend the inactivity of micrometastasis and to stabilize and inhibit the growth of any residual primary tumor. Additionally, the compounds of the invention can be combined with pharmaceutically acceptable excipients, and optionally 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, which are degradable by acid-base or enzymatic hydrolysis or by dissolution. Once inserted into the body, the matrix is activated by enzymes and body fluids. A sustained release matrix is desirably chosen from biocompatible materials, such as liposomes, polylactides (polylactide acid), polyglycolide (glycolide 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, soleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone and silicone. A preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactic co-glycolide (copolymers of lactic acid and glycolic acid). 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. By a "therapeutically effective amount" of the compound is meant a sufficient amount of the compound to treat an angiogenic disease (eg, to limit the growth of a tumor or to decrease or block tumor metastasis) at a risk / benefit ratio reasonable applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition used, the age, body weight, general health, sex and diet of the patient; the administration time, the route of administration and rate of excretion of the specific compound employed; the duration of the treatment; medications used in combination or that match the specific compound used; and similar factors well known in the medical arts. For example, it is known that within the ability of the technique to start with doses 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 compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camforate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (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. Dispersible or soluble products in oil or water are obtained with them. Examples of acids, which can be employed to form pharmaceutically acceptable acid addition salts, include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic base. Preferred salts of the compounds of the invention include phosphate, tris and acetate. The total daily dose of the compounds of this invention administered to a human or lower animal, can vary from about 0.001 to about 1 mg / kg body mass of the patient / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, single dose compositions may contain such amounts or submultiples thereof to make the daily dose.

Alternatively, a compound of the present invention can be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. A "pharmaceutically acceptable carrier or excipient" refers to a non-toxic filler, diluent, encapsulant or formulation aid, solid, semi-solid or liquid, non-toxic, of any type. The compositions can be administered parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), rectally or buccally. The term "parenteral" as used herein refers to modes of administration which include infusion and intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection. Pharmaceutical compositions for parenteral injection comprise sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions pharmaceutically acceptable, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions just before use. Examples of suitable non-aqueous and aqueous carriers, diluents, solvents or 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 injectable organic esters 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 auxiliaries 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, for example, paraben, chlorobutane, phenol sorbic acid and the like. It may also be convenient to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that retard absorption, such as aluminum monostearate and gelatin. Injectable depot forms are made by forming microencapsulated matrices of the drug in the biodegradable polymers, such as polylactide-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 prepared by trapping the drug in liposomes or microemulsions, which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial retention 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 medium just before to be used.

Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those by inhalation, can be prepared as a 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 include sugars such as lactose. Conveniently 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 microns. Alternatively, the composition can be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and indeed the total composition, is preferably so that the active ingredient does not dissolve therein to any substantial degree. The pressurized composition may also contain an active surface agent, such as a solid or liquid nonionic surface active agent, or it 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. An additional form of topical administration is to the eye. A compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such 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 inner regions of the eye, as per example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary, crystalline, choroid / retina and sclera. The pharmaceutically acceptable ophthalmic vehicle can, for example, be an ointment, vegetable oil or an encapsulating material. Alternatively, the compounds of the invention can be injected directly into the vitreous and aqueous humor. Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at temperature environment but liquid at body temperature and therefore fuse in the rectum or vaginal cavity and release the active compound. 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. Liposomes are formed 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 phosphatidylcholines (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), p. 33 et seq. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more agents, which are conventionally administered to patients to treat angiogenic diseases. For example, the compounds of the invention are effective over the short term to make tumors more sensitive to traditional cytotoxic therapies, such as chemicals and radiation. The compounds of the invention also enhance the effectiveness of existing cytotoxic auxiliary anti-cancer therapies. The compounds of the invention can also be combined with other anti-angiogenic agents to enhance their effectiveness, or combined with other anti-angiogenic agents and administered together with other cytotoxic agents. In particular, when used in the treatment of solid tumors, the compounds of the invention can be administered with IL-12, retinoids, interferons, angiostatin, endostatin, thalidomide, thrombospondin-1 -, thrombospondin-2, captopril, anticancer agents. neoplastic drugs such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (w / salvage leucovin) , doxorubicin, cyclophosphamide, taxol, etoposide / meclorotamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibines, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101 , Techgalan, Thalidomide, SP-PG and the like, as well as with radiation The total daily dose of the compositions of the invention to be administered to a human or other mammalian host in single or divided doses can be in amounts, for example, from 0.0001 to 300 mg / kg of body weight daily and more usually 1 to 300 mg / kg of body weight.

It will be understood that agents that can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of angiogenic diseases are not limited to those listed above, but include in principle any agent useful for the treatment or prophylaxis of angiogenic diseases. The peptides of the invention can be used for the development of affinity columns for isolation of receptors relevant to the antiangiogenic activity of the peptide of the invention, for example TSP-1 receptor in, for example, cultured endothelial cells. As is known in the art, the isolation and purification of the receptor can be followed by amino acid sequencing to identify and isolate polynucleotides which encode the receptor. Recombinant expression of this receptor would allow larger amounts of receptor to be produced, for example, to produce an amount sufficient to be used in high throughput screening assays to identify other angiogenesis inhibitors. The peptides of the present invention can be chemically coupled to isotopes, enzymes, carrier proteins, cytotoxic agents, fluorescent, chemiluminescent, bioluminescent molecules and other compounds for a variety of applications. For example, a peptide can be labeled to facilitate testing for its ability to bind antisera or to detect cell types, which possess a relevant receptor. The coupling technique is generally chosen on the basis of the functional groups available on the peptide amino acids including, but not limited to amino, sulfhydral, carboxyl, amide, phenol and imidazole. Various reagents used to effect such couplings include, among others, glutaraldehyde, diazodized benzidine, carbodiimide, and p-benzoquinone. The efficiency of the coupling reaction is determined using different techniques appropriate for the specific reaction. For example, the radiolabelling of the peptide with I125 can be achieved using chloramine T and Nal125 of high specific activity. The reaction is terminated with sodium metabisulfite and the mixture is desalted in disposable columns. The labeled peptide is levigated from the column and the fractions are collected. The aliquots are removed from each fraction and the radioactivity is measured in a gamma counter. In this form, a labeled peptide can be obtained, which is free of unreacted Nal125. The peptides of the present invention can be used as antigens to generate polyclonal or monoclonal antibodies. Such antibodies can be used in diagnostic methods and kits to detect or quantify the peptide of the invention, or peptides related thereto, in a body fluid or tissue. The results of these tests can be used to diagnose or determine the prognostic relevance of such peptides. The use of the peptides of the present invention generate monoclonal antibodies in animals such as mouse, rabbit or sheep, following techniques well known in the art. If desired, the antibodies can then be used to make anti-idiotype antibodies, which in turn, can be humanized as is known in the art to prevent immune responses. Humanized antibodies can be used to inhibit angiogenesis or to make pools to detect the receptor as described herein. For the production of polyclonal antisera in rabbits, sheep, goats or other animals, the peptides of the invention are coupled, for example, via lysine residues, to purified bovine serum albumin using glutaraldehyde. The efficiency of this reaction can be determined by measuring the incorporation of radiolabelled peptide. The unreacted glutaraldehyde and the peptide can be separated by dialysis and the conjugate stored for subsequent use. Serum samples from the generation of polyclonal antisera or media samples from the production of monoclonal antisera can be analyzed for antibody titre determination and in particular, for the determination of high titer antisera. Subsequently, antisera of higher titre can be tested to establish the following: a) dilution of optimal antiserum for higher specific antigen binding and lower non-specific binding, b) ability to bind increasing amounts of peptide in a standard displacement, c) potential cross-reactivity with immunologically related peptides and proteins (including plasminogen, TSP-1 and TSP-1 of related species), and d) ability to detect the peptide of the invention in extracts of plasma, urine, tissues and media of cell culture. The titer can be established through various means known in the art, such as "dot blot" analysis and density, and also by precipitation of radiolabeled peptide-antibody complexes using protein A, secondary antisera, cold ethanol or carbon-dextran followed by Measurement of activity with a gamma counter. If desired, antisera of higher titers can be purified on affinity columns. For example, the peptides of the invention can be coupled to a commercially available resin and used to form an affinity column. The antiserum samples can then be passed through the column such that antibodies to the peptides of the invention are linked (via the peptide) to the column. These ligated antibodies are subsequently levigated, harvested and evaluated for the determination of titer and specificity. Sets for the measurement of the compounds of the invention are also contemplated as part of the present invention. Antisera possessing the highest titer and specificity and capable of detecting the peptides of the invention in extracts of plasma, urine, tissues and cell culture media, can be used to establish test sets for rapid measurement, reliable, sensitive and specific and location of peptides of the invention. These test sets can be used (but are not limited to) the following techniques: competitive and non-competitive assays, radioimmunoassay (RIA), bioluminescence and chemiluminescence assays, fluorometric assays, sandwich assays, immunoradiometric assays, dot blots, assays enzyme linked, including ELISA, microtiter plates, strips covered by antibodies or dipsticks for rapid monitoring of urine or blood, and immunocytochemistry. For each set, the range, sensitivity, accuracy, reliability, specificity and reproducibility of the assay are established by means well known to those skilled in the art. The test set described above would provide instructions, antisera, one or more peptides of the invention and possibly radiolabelled peptides of the invention and / or reagents for the precipitation of bound peptide / antibody complexes. Such a pool would be useful for the measurement of the peptide of the invention in biological fluids and tissue extracts from animals and humans with and without tumors, as is well known in the art. Another set can be used to visualize or locate the peptide of the invention in tissues and cells. Immunohistochemistry techniques and kits, for example, which employ such techniques, are well known to those of ordinary skill in the art. Such a kit provides antisera to the peptide of the invention, and possibly blocking serum and secondary antiserum bound to a fluorescent molecule, such as fluorescein isothiocyanate, or some other reagent used to visualize the primary antiserum. Using this methodology, tumors with biopsies can be examined for peptide production sites or for peptide receptor sites. Alternatively, a pool can deliver radiolabelled nucleic acids for use in in situ hybridization to probe a messenger RNA, which encodes the compound of the invention.

Synthesis of the peptides The peptides of the present invention can be synthesized by any technique that is known to those skilled in the art. For peptide synthesis solid phase, you may be a summary of the many techniques J.M Stewart and J. D. Young, Solid Phase Peptide Synthesis, W. H. Freeman Co. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins and Peptides, vol. 2 P. 46, Academic Press (New York), 1973. For classical solution synthesis, see G. Schroder and K. Lupke, The Peptides, vol. 1, Academic Press (New York), 1965. In general, these methods comprise the sequential addition of one or more amino acids or amino acids suitably protected to a growing peptide chain. Normally, either the amino or carboxyl group of the first amino acid is protected by a suitable protecting group. The protected amino acid or derivative can then be either bound to an inert solid support or be used in solution by adding the next amino acid in the sequence having the complementary group (amino or carboxyl) suitably protected, under suitable conditions to form the amide bond. The protecting group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is then added, and so on. After all the desired amino acids have been linked in the proper sequence, any remaining protecting group (and any solid support) are removed sequentially or concurrently, to provide the final polypeptide. By simple modification of this general procedure, it is possible to add more than one amino acid at a time to a growing chain, for example, by coupling (under conditions which do not racemize the chiral centers) a protected tripeptide with a protected dipeptide to form, after deprotection, a pentapeptide. A particularly preferred method for preparing compounds of the present invention involves solid phase peptide synthesis. In this particularly preferred method, the alpha-amino function is protected by a group sensitive to the acid or base. Such protecting groups must have the properties to be stable to the conditions of peptide bond formation, while being easily removable without the destruction of the growing peptide chain or racemization of any of the chiral centers contained therein. Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), f-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, r-amyloxycarbonyl, isobroniloxicarbonilo, (,) dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2-cyano -i-butyloxycarbonyl, and the like. The protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) is preferred.

The protecting side chain groups are particularly preferred for amino groups and side chain lysine and arginine: 2,2,5,7, 8-pentamethylchroman-6-sulfonyl (pmc), nitro, p-toluenesulfonyl, 4-methoxybenzenesulfonyl , Bcz, Boc, and adamantyloxycarbonyl; for tyrosine: benzyl, o-bromobenzyloxycarbonyl, 2,6-dichlorobenzyl, isopropyl,.-butyl (t-Bu), cyclohexyl, cyclopenyl and acetyl (Ac); for serine: -butyl, benzyl and tetrahydropyranyl; for histidine: trityl, benzyl, Cbz, p-toluenesulfonyl and 2,4-dinitrophenyl; for tryptophan: formyl. In the solid phase peptide synthesis method, the c-terminal amino acid is attached to a suitable solid support or resin. Suitable solid supports useful for the above synthesis are those materials which are inert to the reagents and reaction conditions of the condensation-deprotection reactions in steps, as well as being insoluble in the media used. The preferred solid support for the synthesis of the C-terminal carboxy peptides is 4-hydroxymethylphenoxymethyl-copoly (styrene-1% divinylbenzene). The preferred solid support for peptide C-terminal amide is deprotected 4- (2 \ 4'-dimethoxyphenyl-Fmoc-aminomethyl) phenoxyacetamidoethyl available from Applied Biosystems [city, state]. The C-terminal amino acid is coupled to the resin by means of ? /, '-dicyclohexylcarbodiimide (DCC),? /,? /' - diisopropylcarbodiimide (DIC) or O-benzotriazol-1 -yl -? /,? ,? / ',? /' - tetramethyluronium hexafluorophosphate (H BTU), with or without 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-fr-s (dimethylamino) f osf oniohexaf luorof osf ato (BOP) or chloride / s (2-oxo-3-oxazoIidinyl) phosphino (BOPCI), mediating the coupling for from about 1 to about 24 hours at a temperature of between 10 ° and 50 ° C in a solvent, such as dichloromethane or DMF. When the solid support is the resin of 4- (2 ', 4'-dimethoxyphenyl-Fmoc-aminomethyl) phenoxyacetamidoethyl, the Fmoc group is cut with a secondary amine, preferably piperidine, before coupling with the C-terminal amino acid as described before. The preferred method for coupling to the resin of deprotected 4- (2 ', 4'-dimethoxyphenyl-Fmoc-aminomethyl) phenoxyacetamidoethyl is O-benzotriazole-1-yl-? ,? , / V ',? '-tetra meti I u ron iohexaf luorof osfato (HBTU, 1 equiv.) and 1-hydroxybenzotriazole (HOBT, 1 equiv.) in DMF. The coupling of successive protected amino acids can be performed in an automatic polypeptide synthesizer as is well known in the art. In a preferred embodiment, the a-amino function in the amino acids of the growing peptide chain is protected with Fmoc. Removal of the Fmoc protecting group from the N-terminal side of the growing peptide is achieved by treatment with a secondary amine, preferably piperidine. Each protected amino acid is then introduced in about 3 times of molar excess and the coupling is preferably carried out in DMF. The coupling agent is usually O-benzotriazole-1-yl-? /,?.,? / ',? F-tetramethyluronium hexafluorophosphate (HBTU, 1 equiv.) And 1-hydroxybenzotriazole (HOBT, 1 equiv.). At the end of the solid phase synthesis, the polypeptide is removed from the resin and deprotected, either successively or in a simple operation. Removal of the polypeptide and deprotection can be achieved in a simple operation by treating the polypeptide linked to the resin with a cutting reagent, for example tianisol, water, ethanedithiol and trifluoroacetic acid. In cases where the C-terminus of the polypeptide is an alkylamide, the resin is cut by aminolysis with an alkylamine. Alternatively, the peptide can be removed by transesterification, for example with methanol, followed by aminolysis or by direct transamidation. The protected peptide can be purified at this point or taken to the next step directly. The removal of the side chain protecting groups is achieved using the cutting cocktail described above. The completely deprotected peptide is purified by a sequence of chromatographic steps employing any or all of the following types: exchange of ions in a weakly basic resin in the acetate form; hydrophobic adsorption chromatography on polystyrene-divinylbenzene without derivatization (e.g., AMBERLITE® XAD); silica gel adsorption chromatography; ion exchange chromatography on carboxymethylcellulose; partition chromatography, for example in SEPHADEX® G-25, LH-20 or countercurrent distribution; high performance liquid chromatography (HPLC), especially reversed-phase HPLC in phase column packing bound to octyl- or octadecylsilyl-silica. The following examples will serve to further illustrate the preparation of the novel compounds of the invention.

Preparation of the cutting reagent The cutting reagent (2 ml) is prepared by mixing, in the following order, thioanisole (100 μl), water (50 μl), ethanedithiol (50 μl) and trifluoroacetic acid (1.8 ml). The freshly prepared mixture is cooled to -5 ° C to -10 ° C and used as described below.

Cutting procedure A mixture of polypeptide bound to the resin and cutting reagent is stirred at 0 ° C for 10-15 minutes and then at room temperature for an additional 75 hours. The amount of time is increased by 0.5 hours for each additional arginine up to a total of three hours. The amount of cutting reagent used is determined using the following formula: Resin weight (mg) Amount of cutting reagent (ul) 0-10 100 10-25 200 25-50 400 50-100 700 100-200 1200 The resin was filtered and rinsed with pure trifluoroacetic acid. The filtrate is then added in 0.5 ml portions to a centrifuge tube containing approximately 8 ml of cold diethyl ether. The suspension is then centrifuged and the supernatant is decanted. The pellet was resuspended in approximately 8 ml of ether, another 0.5 ml of the filtrate is added, and the process is repeated until all the peptide is precipitated. The precipitated filtrate is then washed with ether, dried and lyophilized. If the peptide is not precipitated on addition to ether, the mixture is stirred with 30% aqueous acetic acid. The organic phase is then extracted twice with 30% aqueous acetic acid and the combined aqueous extracts are lyophilized.

EX EMPLO 1 Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg In the position of the peptide synthesis column of a SYNERGY® peptide synthesizer from Perkin Elmer / Applied Biosynthesis a synthesis column is placed of peptide Arg (Pmc) (25 μM of amino acid; Applied Biosystems). The amino acids are added sequentially according to the following synthetic cycle: 0. Soil the resin using DMF for about 5 minutes; 1 . Unblock to remove the Fmoc group from the α-amino acid function using piperidine in DMF for approximately 15 minutes; 2. Wash with DMF for approximately 5 minutes; 3. Activate the incoming protected amino acid Fmoc (75 μM) using a 0.2 M solution of HBTU (75 μM) and HOBT (75 μM) in DMSO-NMP (N-methylpyrrolidone) and a 0.4 M solution of diisopropylethylamine (150 μM) in DMSO-N MP; 4. Coupling using a solution in DMF of the activated amino acid Fmoc activated prepared in step 3 above for approximately 30 minutes; and 5. Wash with DMF for 5 minutes.

The amino acids are coupled to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes 7. Fmoc-Asp (O-tBu) 30 minutes 8. Fmoc-Gly 30 minutes Upon completion of the synthesis, the resin is washed with THF for about 5 minutes to remove DMF and shrink the resin. The resin is then dried with gas with argon for about 10 minutes and nitrogen for an additional 10 minutes to give the peptide bound to the resin (80 mg). The cut is achieved using the procedure described above (40 mg of peptide bound to the dried resin, 700 μl of cutting reagent, cutting time 2.5 hours) to give the crude peptide (14 mg). Purification by HPLC using a Symmetry Prep C18 column of 7 μm (7.8x300 mm) with solvent mixtures varying in a gradient from 5% to 100% acetonitrile-water with 0.1% by volume of trifluoroacetic acid over a period of 50 minutes followed by lyophilization of Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg (5 mg). MS (FAB) m / z 986 (M + H) +.

EXAMPLE 2 Ac-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired peptide is prepared by placing 40 mg of the peptide linked to the resin prepared in Example 1 on the peptide synthesizer and repeating in steps 3-5 above, except that acetic acid (87 μM) is replaced by the protected amino acid Fmoc and using 87 μM each of HBTU and HOBT. Cutting and purification of HPLC (gradient from 15% to 100% acetonitrile-water) as described in Example 1 gave Ac-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg (4 mg).

EXAMPLE 3 Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NH2 The desired compound is prepared according to the method of Example 1, except that an amide synthesis resin is used in the synthesis column of the peptide synthesizer. The amino acids are coupled to the resin using the indicated conditions.

#Amino acid Coupling. Fmoc-Arg (Pmc) 30 minutes. Fmoc-lle 30 minutes. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Thr (t-Bu) 30 minutes. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes. Fmoc-Gly 30 minutes. Fmoc-Asp (O-tBu) 30 minutes 9. Fmoc-Gly 30 minutes EXAMPLE 4 Ac-Gly-Asp-Giy-Val-D-lle-Thr-Arg-lle-Arg-N Hz The desired compound is prepared according to the method of Example 2 using the peptide bound to the resin prepared in Example 3 .

EXAMPLE 5 Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCHaCHs Step 1 Gly-Asp (Pmc) -Gly-VaI-D-lle-Thr (t-Bu) -Arg (Pmc) -lle-Arg (Pmc) -N HCH2CH3 A mixture of resin bound to peptide prepared as in Example 1 and ethylamine in a bottle and stirred for 4 hours. The ethylamine is then evaporated and the methanol is added to the residue. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is taken up in methanol-water (3: 7) and lyophilized to give the protected peptide.

Step 2 Gly-Asp-Gly-Val-D-lle-Thr-Arg-ile-Arg-NHCHzCHs The desired compound is prepared by deprotection of the peptide prepared in step 1 using the cutting reagent and procedure described above EXAMPLE 6 Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 when coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes EXAMPLE 7 Ac-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 2, except using the peptide bound to the resin prepared as in example 6. MS (FAB) ) m / z 856 (M + H) +.

EXAMPLE 8 Gly-Val-D-lle-Thr-Arg-lle-Arg-NH2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes 6. Fmoc Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 9 Ac-Gly-Val-D-lle-Thr-Arg-lle-Arg-NH2 The desired compound is prepared according to the method of Example 2, except that the resin bound peptide prepared as in Example is used. 8. MS (FAB) m / z 855 (M + H) +, 877 (M + Na) +.

EXAMPLE 10 Gly-Val-Dl le-Thr-Arg-lle-Arg-NHCH2CH3 The desired peptide is prepared according to the method of Example 5, except that the peptide bound to the resin of Example 6 is replaced by the peptide linked to the resin of Example 1.

EXAMPLE 1 1 Ac-Gly-VaI-D-lle-Thr-Arg-lle-Arg-NHCH2CH3 The desired compound is prepared from Ac-Gly-Val-D-lle-Thr-Arg-lle-Arg linked to the resin of Example 7 using the method of Example 5. MS (FAB) m / z 883 (M + H) +.

EXAMPLE 12 Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Thr (t-Bu) 30 minutes. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes. Fmoc-Gly 30 minutes. Fmoc-Tyr (tBu) 30 minutes EXAMPLE 13 Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-NH2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes 6. Fmoc Val 30 minutes 7. Fmoc-Gly 30 minutes 8. Fmoc-Tyr (tBu) 30 minutes EXAMPLE 14 Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCH 2 CH 3 The desired compound is prepared from the peptide linked to the resin of Example 12 using the method of Example 5.

EXAMPLE 15 Ac-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared from the peptide linked to the resin of Example 12 according to the method of Example 2.

EXAMPLE 16 Ac-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHz The desired compound is prepared from the peptide linked to the resin of Example 13 according to the method of Example 2. MS (FAB) ) m / z 1018 (M + H) +.

EXAMPLE 17 Ac-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCHzCHs The desired compound is prepared from Ac-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg bound to the resin using the method of Example 5.

EXAMPLE 18 Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 when coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes 7. Fmoc-Asp (O-tBu) 30 minutes 8. Fmoc-Gly 30 minutes 9. Fmoc-Ala 30 minutes 10. Fmoc-Thr (t-Bu) 30 minutes 1 1. Fmoc-Val 30 minutes 12. Fmoc-Ser (tBu) 30 minutes 13. Fmoc-Ala 30 minutes 14. Fmoc-Ser (tBu) 30 minutes 15. Fmoc-Ser (tBu) 30 minutes 16. Fmoc-Trp 30 minutes 17 Fmoc-Pro 30 minutes 18. Fmoc-Ser (tBu) 30 minutes EXAMPLE 19 Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr .la-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NH2 The desired compound is prepared in accordance to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Acor. . 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D -fill 30 meters 6. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes 8. Fmoc-Asp (O-tBu) 30 minutes 9. Fmoc-Gly 30 minutes 10. Fmoc-Ala 30 m ñutos 1 1. Fmoc-Thr (t-Bu) 30 minutes 12. Fmoc-Val 30 minutes 13. Fmoc-Ser (tBu) 30 minutes 14. Fmoc-Ala 30 m inutes 15. Fmoc-Ser (tBu) 30 m inutes 16 Fmoc-Ser (tBu) 30 m inutes 17. Fmoc-Trp 30 m inutes 18. Fmoc-Pro 30 m inutes 19. Fmoc-Ser (tBu) 30 minutes EXAMPLE 20 Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCH2CH3 The desired peptide is prepared from of the peptide bound to the resin of Example 19 using the procedure of Example 5.

EXAMPLE 21 Ac-Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared Starting from the peptide bound to the resin of Example 18 using the procedure of Example 2.

EXAMPLE 22 Ac-Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NH 2 The desired compound is prepared from the peptide bound to the resin of Example 19 using the procedure of Example 2.

EXAMPLE 23 Ac-Ser-Pro-Trp-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCH2CH3 The desired compound is prepared from the peptide bound to the resin of Example 21 using the procedure of Example 5.

EXAMPLE 24 D-Tyr-Gly-Val-D-IIe-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes 7. Fmoc-D-Tyr (tBu) 30 minutes EXAMPLE 25 D-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-N H2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions.

#Amino acid Coupling. Fmoc-Arg (Pmc) 30 minutes. Fmoc-lle 30 minutes. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Thr (t-Bu) 30 minutes. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes. Fmoc-Gly 30 minutes 8. Fmoc-D-Tyr (tBu) 30 minutes EXAMPLE 26 D-Tyr-gly-Val-D-lle-Thr-Arg-lle-Arg-NHCH2CH3 The desired compound is prepared from the peptide bound to the resin of Example 24 using the method of Example 5.

EXAMPLE 27 Ac-D-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared from the peptide bound to the resin of Example 24 according to the method of Example 2.

EXAMPLE 28 Ac-D-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-N H2 The desired compound is prepared from the peptide bound to the resin of Example 25 according to the method of Example 2 MS (FAB) m / z 1018 (M + H) +.

EXAMPLE 29 Ac-D-Tyr-Gly-Val-D-lle-Thr-Arg-lle-Arg-NHCH 2 CH 3 The desired compound is prepared from Ac-D-Tyr-Gly-Val-D-lle-Thr- Arg-lle-Arg bound to the resin of Example 27 using the method of Example 5.

EXAMPLE 30 Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg The desired peptide is prepared according to the method of Example 3, except that 4-hydroxymethyl phenoxymethyl resin is used (Applied Biosystems) and the amino acids are attached to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-D-Arg (Pmc) 30 minutes 2. Fmoc-D-lle 30 minutes 3. Fmoc-D-Arg (Pmc) 30 minutes 4. Fmoc-D-Thr (t-Bu) 30 minutes 5. Fmoc-lle 30 minutes 6. Fmoc-D-Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 31 Gly-D-Val-lle-D-Thr-D-Arg-lle-D-Arg-NH2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin as described in Example 30.

EXAMPLE 32 Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg-NHCHzCHa The desired peptide is prepared from the peptide bound to the resin of Example 30 using the method of Example 5.

EXAMPLE 33 Ac-Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg The desired peptide is prepared from the peptide bound to the resin of Example 30 according to the method of Example 2 .

EXAMPLE 34 Ac-GIy-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg-NH2 The desired compound is prepared from Gly-D-Val-He-D-Thr-D -Arg-D-lle-D-Arg-NH2 bound to the resin of Example 31 using the method of Example 2.

EXAMPLE 35 Ac-Gly-D-Val-lle-D-Thr-D-Arg-D-Ile-D-Arg-N HCH2CH3 The desired compound is prepared from Ac-Gly-D-Val-lle-D -Thr-D-Arg-D-lie-D-Arg bound to the resin of Example 33 using the method of Example 5. MS (FAB) m / e 855 (M + H) +.

EXAMPLE 36 D-Arg-D-IIe-D-Arg-D-Thr-lle-D-Val-Gly The desired peptide is prepared according to the method of Example 1 using a Gly peptide synthesis column and coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-D-Val 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-D-Thr (t-Bu) 30 minutes 4. Fmoc-D-Arg (Pmc) 30 minutes 5. Fmoc-D-lle 30 minutes 6 Fmoc-D-Arg (Pmc) 30 minutes EXAMPLE 37 D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly-NH 2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the Next order using the indicated conditions. # amino acid Coupling 1. Gly 30 minutes 2. Fmoc-D-Val 30 minutes. Fmoc-lle 30 minutes. Fmoc-D-Thr (t-Bu) 30 minutes 5. Fmoc-D-Arg (Pmc) 30 minutes. Fmoc-lle 30 minutes 7. Fmoc-Arg (Pmc) 30 minutes EXAMPLE 38 D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly-NHCHzCHs The desired peptide is prepared from the peptide bound to the resin of Example 36 using the method of Example 5 .

EXAMPLE 39 Ac-D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly The desired peptide is prepared from the peptide bound to the resin of Example 36 according to the method of Example 2 .

EXAMPLE 40 Ac-D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly-N H2 The desired compound is prepared from D-Arg-D-lle-D-Arg- D-Thr-lle-D-Val-Gly-NH2 bound to the resin of Example 37 using the method of Example 2.

EXAMPLE 41 Ac-D-Arg-D-lie-D-Arg-D-Thr-lle-D-Val-Gly-N HCH2CH3 The desired compound is prepared from Ac-D-Arg-D-lle-D- Arg-D-Thr-lle-D-Val-Gly bound to the resin of Example 36 using the method of Example 5. MS (FAB) m / e 855 (M + H) +.

EXAMPLE 42 Gly-Val-D-lle-Lys-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Lys (Boc) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes EXAMPLE 43 Ac-Gly-Val-D-lle-Lys-Arg-lle-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 42 is used.

EXAMPLE 44 Gly-Val-D-lle-Lys-Arg-lle-Arg-NH2 The compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Lys (Boc) 30 minutes 5. Fmoc-D-lle 30 minutes 6. Fmoc-Val 30 7. Fmoc-Gly minutes 30 minutes EXAMPLE 45 Ac-Gly-Val-D-lle-Lys-Arg-lle-Arg-N H2 The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 44 EXAMPLE 46 Gly-Val-D-lle-Lys-Arg-lle-Arg-N HCHzCHs The desired peptide is prepared according to the method of Example , except that the peptide bound to the resin of Example 42 is substituted for the peptide linked to the resin of Example 1.

EXAMPLE 47 Ac-Gly-Val-D-lle-Lys-Arg-1 le-Arg-N HCH 2 CH 3 The desired compound is prepared from bound Ac-Gly-Val-D-lle-Lys-Arg-lle-Arg to the resin of Example 43 using the method of Example 5.

EXAMPLE 48 Gly-Val-D-lle-Lys-Arg-Ser-Arg The desired compound is prepared according to the method of Example 1 when coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Ser (tBu) 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Lys (Boc) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes EXAMPLE 49 Ac-Gly-Val-D-lle-Lys-Arg-Ser-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 48 is used.

EXAMPLE 50 Gly-Val-D-lle-Lys-Arg-Ser-Arg-NH2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-Ser (tBu) 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Lys (Boc) 30 minutes 5. Fmoc-D-lle 30 minutes 6. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 51 Ac-GIy-Val-D-lle-Lys-Arg-Ser-Arg-N H2 The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example is used. fifty.

EXAMPLE 52 Gly-Val-D-lle-Lys-Arg-Ser-Arg-NHCH2CH3 The desired peptide is prepared according to the method of Example 5, except that the peptide bound to the resin of Example 48 is replaced by the peptide linked to the resin of Example 1.

EXAMPLE 53 Ac-Gly-Val-D-lle-Lys-Arg-Ser-Arg-N HCH2CH3 The desired compound is prepared from Ac-Gly-Val-D-lle-Lys-Arg-Ser-Arg linked to the resin of Example 49 using the method of Example 5.

EXAMPLE 54 Gly-Val-D-lle-Thr-Arg-Ser-Arg The desired compound is prepared according to the method of Example 1 when coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Ser (tBu) 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc Gly 30 minutes EXAMPLE 55 Ac-Gly-Val-D-lle-Thr-Arg-Ser-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example is used. 54 EXAMPLE 56 Gly-Val-D-lle-Thr-Arg-Ser-Arg-N H2 The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-Ser (tBu) 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes 6 Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 57 Ac-Gly-Val-D-lle-Thr-Arg-Ser-Arg-NH2 The desired compound is prepared according to the method of Example 2, except that the resin bound peptide prepared as in Example 56 is used. .

EXAMPLE 58 Gly-Val-D-lle-Thr-Arg-Ser-Arg -? \ I HCH2CH3 The desired peptide is prepared according to the method of Example 5, except that the peptide bound to the resin of Example 54 is replaced by the peptide bound to the resin of Example 1.

EXAMPLE 59 Ac-Gly-Val-D-lle-Thr-Arg-Ser-Arg-NHCH 2 CH 3 The desired compound is prepared from Ac-Gly-Val-D-lle-Thr-Arg-Ser-Arg bound to the resin of Example 55 using the method of Example 5.

EXAMPLE 60 Gly-Val-D-lle-Tyr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Thr (t-Bu) 30 minutes. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes. Fmoc-Gly 30 minutes EXAMPLE 61 Ac-Gly-Val-D-lle-Tyr-Arg-lle-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 60 is used.

EXAMPLE 62 Gly-Val-D-lle-Tyr-Arg-lle-Arg-NH2 The desired compound is prepared according to the method of Example 3, ai coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-lle 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes 6. Fmoc Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 63 Ac-Gly-Val-D-lle-Tyr-Arg-lle-Arg-N Hz The desired compound is prepared according to the method of Example 2, except that it is used the peptide linked to the resin prepared as in Example 62.

EXAMPLE 64 Gly-Val-D-lle-Tyr-Arg-lle-Arg-NHCHzCHs The desired peptide is prepared according to the method of Example , except that the peptide bound to the resin of Example 60 is replaced by the peptide bound to the resin of Example 1.

EXAMPLE 65 Ac-Gly-Val-D-Ile-Tyr-Arg-lle-Arg-NHCH 2 CH 3 The desired compound is prepared from Ac-Gly-Val-D-lle-Tyr-Arg-lle-Arg bound to the resin of Example 61 using the method of Example 5.

EXAMPLE 66 Gly-Val-D-IIe-Tyr-Arg-Asn-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Asn (trt) 30 minutes. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Tyr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes EXAMPLE 67 Ac-Gly-Val-D-lle-Tyr-Arg-Asn-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 66 is used.

EXAMPLE 68 Gly-Val-D-lle-Tyr-Arg-Asn-Arg-N Hz The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes 2. Fmoc-Asn (Trt) 30 minutes 3. Fmoc-Arg (Pmc) 30 minutes 4. Fmoc-Tyr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 69 Ac-Gly-Val-D-lle-Tyr-Arg-Asn-Arg-NHz The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example is used. 68 EXAMPLE 70 Gly-Val-D-1 le-Tyr-Arg-Asn-Arg-NHCH 2 CH 3 The desired peptide is prepared according to the method of Example , except that the peptide bound to the resin of Example 66 is replaced for the peptide bound to the resin of Example 1.

EXAMPLE 71 Ac-Gly-Val-D-lle-Tyr-Arg-Asn-Arg-NHCHzCH3 The desired compound is prepared from Ac-Gly-Val-D-lle-Tyr-Arg-Asn-Arg of Example 67 using the method of Example 5.

EXAMPLE 72 Gly-Val-D-lle-Thr-Arg-Asn-Arg The desired compound is prepared according to the method of Example 1 by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Asn (Trt) 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc Gly 30 minutes EXAMPLE 73 Ac-Gly-Val-D-lle-Thr-Arg-Asn-Arg The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example 72 is used.

EXAMPLE 74 Gly-Val-D-lle-Thr-Arg-Asn-Arg-NHz The desired compound is prepared according to the method of Example 3, by coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Asn (trt) 30 minutes. Fmoc-Arg (Pmc) 30 minutes. Fmoc-Thr (t-Bu) 30 minutes 5. Fmoc-D-lle 30 minutes. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes EXAMPLE 75 Ac-Gly-Val-D-lle-Thr-Arg-Asn-Arg-N Hz The desired compound is prepared according to the method of Example 2, except that the peptide bound to the resin prepared as in Example is used 74 EXAMPLE 76 Gly-Val-D-lle-Thr-Arg-Asn-Arg-NHCH2CH3 The desired peptide is prepared according to the method of Example , except that the peptide bound to the resin of Example 72 is replaced by the peptide linked to the resin of Example 1.

EXAMPLE 77 Ac-Gly-Val-D-lle-Thr-Arg-Asn-Arg-N HCH2CH3 The desired compound is prepared from Ac-Gly-Val-D-lle-Thr-Arg-Asn-Arg linked to the resin of Example 73 using the method of Example 5.

EXAMPLE 78 Ser-Pro-Trp-Ser-D-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-lle-Thr-Arg-lle-Arg The desired compound is prepared according to the method of Example 1 and coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes 7. Fmoc-Asp (O-tBu) 30 minutes 8. Fmoc-Gly 30 minutes 9. Fmoc-Ala 30 minutes 10. Fmoc-Thr (t-Bu) 30 minutes 1 1. Fmoc-Val 30 minutes 12. Fmoc-Ser (tBu) 30 minutes 13. Fmoc-Ala 30 minutes 4. Fmoc-D-Ser (tBu) 30 minutes 5. Fmoc-Ser (tBu) 30 minutes 16. Fmoc-Trp 30 minutes 7. Fmoc-Pro 30 minutes 18. Fmoc-Ser (tBu) 30 minutes EXAMPLE 79 Ser-Pro-Trp-Ser-D-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg-lle-Arg The desired compound is prepared in accordance to the method of Example 1 and coupling the amino acids to the resin in the following order using the indicated conditions. # amino acid Coupling 1. Fmoc-lle 30 minutes 2. Fmoc-Arg (Pmc) 30 minutes 3. Fmoc-Thr (t-Bu) 30 minutes 4. Fmoc-D-lle 30 minutes 5. Fmoc-Val 30 minutes 6. Fmoc-Gly 30 minutes 7. Fmoc-Asp (O-tBu) 30 minutes 8. Fmoc-Gly 30 minutes 9. Fmoc-Ala 30 minutes 10. Fmoc-Thr (t-Bu) 30 minutes 1 1. Fmoc-Val 30 minutes 12. Fmoc-Ser (tBu) 30 minutes 13. Fmoc-Ala 30 minutes 14. Fmoc-D-Ser (tBu) 30 minutes 15. Fmoc-Ser (tBu) 30 minutes 16. Fmoc-Trp 30 minutes 17. Fmoc-Pro 30 minutes 18. Fmoc-Ser (tBu) 30 minutes EXAMPLE 80 Ser-Pro-Trp-D-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-D-lle-Thr-Arg--. The desired compound was prepared according to the method of Example 79 but substituting Fmoc-D-Ser (tBu) for amino acid number 15 and substituting Fmoc-Ser (tBu) for amino acid number 14.

Claims (20)

1. CLAIMS 1 . A peptide or pharmaceutically acceptable salt thereof selected from the group consisting of T-Gly-Val-D-lle-Thr-Arg-1 le-U, V-Gly-D-Val-lle-D-Thr-D-Arg -D-lle-W, XD-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Y, and Z-Gly-Val-lle-Thr-Arg-lie-U where T is absent or is selected from an N-protecting group and a polypeptide of up to 12 amino acid residues optionally terminated with an N-protecting group; U is selected from Arg and Arg-NR1 R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms; V is absent or is an N-protective group; W is selected from D-Arg and D-Arg-NR1 R2; X is absent or is an N-protective group; And it is selected from Gly and Gly-N R1 R2; and Z is 1 -12 amino acid residues optionally terminated with an N-protecting group wherein at least one of the amino acid residues is a D-amino acid residue.
2. 2. A peptide or pharmaceutically acceptable salt thereof as defined by claim 1 of the formula T-Gly-Val-D-lle-Thr-Arg-1 le-U.
3. 3. A peptide or pharmaceutically acceptable salt thereof as defined by claim 2, wherein U is selected from Arg and Arg-NHCHzCH.
4. 4. A pharmaceutically acceptable salt peptide thereof as defined by claim 2, wherein where T is absent.
5. 5. A peptide or pharmaceutically acceptable salt thereof as defined by claim 2, wherein T is acetyl.
6. 6. A peptide or pharmaceutically acceptable salt thereof as defined by claim 2, wherein T is a peptide of up to 12 amino acid residues optionally capped with acetyl.
7. 7. A peptide or pharmaceutically acceptable salt thereof as defined by claim 6, wherein T is Gly-Asp- optionally terminated with acetyl.
8. 8. A peptide or pharmaceutically acceptable salt thereof as defined by claim 2, selected from the group consisting of Gly-Val-D-Ile-Thr-Arg-Ile-Arg, Gly-Val-D-pe-Thr-Arg-Ile-Arg-NH2. Gly-Val-D-pe-Thr-Arg-pe-Arg-NHCH2CH3, Ac-Gly-Val-D-pe-Thr-Arg-Ue-Arg, Ac-Gly-Val-D-pe-Thr-Arg- _le-Arg- H2. Ac-Gly-Val-D-Ue-Thr-Axg-pe-Arg-HCH2CH3, | Tyr-GIy-Val-D-pe-Thr-Arg-Ile-Arg, Tyr-Gly-Val-D-pe-Thr-Arg-pe-Arg-NH2, I Tyr-Gly-Val-D-Ile-Thr-Arg-p_-Arg-N? CH2CH3, Ac-Tyr-Gly-Val-D-pe-Thr-Arg-He-Arg, Ac-tyr-Gly-V_l- D-pe-Thr-Arg-He-Arg-NH2. Ac-Tyr-Gly-Val-D-ue-Thr-Arg-pe-Axg-NHCH2CH3, D-Tyr-Gly-Val-D-Ile-Thr-Arg-Ile-Arg, D-Tyr-Gly-Val- D-pe-Thr-Arg-Ile-Arg-NH2, D-Tyr-Gly-Val-D-pe-T r-Arg-pe-Arg-NHCH2CH3, Ac-D-Tyr-Gly-Val-D-pe -Thr-Arg-pe-Arg, Ac-D-Tyr-Gly-V_J-D-pe-Thr-Arg-? E-Arg-NH2. Ac-D-Tyr-Gly-Val-D-ne-Thr-Arg.-pe-Arg-NHCH2CH3, Gly-Asp-Gly-Val-D-Ile-Thr-Arg-Ile-Arg, Gly-Asp-Gly -Val-D-Ile-Thr-Arg-Ile-Arg-NH2, Gly-Asp-GIy-Val-D-ne-Thr-Arg-? E-Arg-N HCH2CH3. Ac-Gly-Asp-Gly-Val-D-Ile-Thr-Arg-Ile-Arg, Ac-Gly-Asp-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-NH2. Ac-Gly-Asp-Gly-Val-D-ne-Thr-Arg-pe-Arg-NHCH2CH3, Ser-F-or-Tf-Ser-Ser-Ala-Ser-V_J-Tr? R-Ala-Gly -Asp-Gly-V_l-D-ne-Thr-Arg-_le-Arg, Ser-Pro-Tr ^ Ser-Ser-A_a- & sr-V_l- - _r- ^ NH2. Ser-E-or-Tf-Ser-Ser-AJa-Ser-VaJ-Tr-r-Ala-Gly-Asp-Gly-Val-D-pe-Thr-Arg-Ile-Arg-NHCH2CH3, Ac-Ser- _ ^ o-Tr ^ Ser-Ser-A_a-Ser-V_l-Tr_r-Ala-Gly-A_p-Gly-Val-D-ne-_ -r-Arg-IIe-Arg, Ac-_ter-Pro-Tf-Ser -Ser-Ala-Ser-Val-T -_.- Ala-Gly-Asp-Gly-V_l-D-Ile-T-_r-Axg-I_e- Arg-NH2 Ac-Ser-PrcHTf-Se_-Se-- A_a-Ser-V __- T ^ Arg-NHCH2CH3.
9. 9. A pharmaceutically acceptable peptide or sai thereof according to claim 1, having the formula V-Gly-D-Val-lle-D-Thr-D-Arg-D-ile-W.
10. 10. A peptide or pharmaceutically acceptable salt thereof as defined by claim 9 selected from the group consisting of Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg, Gly-D-Val-l le-D-Thr-D-Arg-D-lle-D-Arg-NH2 , Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg-NHCH2CH3, Ac-Gly-D-Val-IIe-D-Thr-D-Arg-D-lle-D -Arg, Ac-Gly-D-Val-lle-D-Thr-D-Arg-D-lle-D-Arg-N Hz and, Ac-Gly-D-Val-lle-D-Thr-D-Arg -D-lle-D-Arg-NHCHzCHs. eleven .
11. A peptide or pharmaceutically acceptable salt thereof as defined by claim 1 having the formula X-D-Arg-D-lle-D-Arg-D-Thr-IIe-D-Val-Y.
12. 12. A peptide or pharmaceutically acceptable salt thereof as defined by claim 1 selected from the group consisting of D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly, D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly-NH2, D-Arg-D-lle-D-Arg-D-Thr-lle-D-Val-Gly-NHCHzCHs, Ac-D-Arg-D-lie-D-Arg-D-Thr-lle-D-Val- Gly, Ac-D-Arg-D-ile-D-Arg-D-Thr-lle-D-Val-Gly-N Hz and Ac-D-Arg-D-lle-D-Arg-D-Thr-lle -D-Val-Gly-NHCH2CH3.
13. 13. A composition for treating a patient in need of anti-angiogenesis therapy comprising the peptide of claim 1 in combination with a pharmaceutically acceptable carrier.
14. A method for treating a patient in need of anti-angiogenesis therapy comprising administering to the patient a therapeutically effective amount of the peptide of claim 1.
15. 15. A composition for the treatment of a disease selected from the group consisting of cancer, arthritis, psoriasis, angiogenesis in the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy, the peptide of claim 1 comprising in combination with a carrier pharmaceutically acceptable.
16. 16. A method for treating a disease selected from the group consisting of cancer, arthritis, psoriasis, angiogenesis in the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy, comprising administering to the patient a therapeutically effective amount of the peptide of claim 1.
17. 17. A peptide or pharmaceutically acceptable salt thereof as defined by claim 2 selected from the group consisting of Ser-Pro-tf-Ser-D-Ser-Ala-Ser-Val-Tnr-Ala-Gly-Ap-Gly-VaJ-D-Ile-Thr-Arg-Ile-Arg, xScr-Pro-Trp-Sür- D-Scr-Ala-Scr-Va thr-Ala-Gly-Asp-G y-Val-D-Ile-Thr-Arg-Ile-Arg-NH2. Ser -_ ^ o-Tf-Ser-D-Ser-Ala-Ser-Val-TT? R-Ala-GYy-Asp-Gly-VaI-D-Ile-Thr-Arg-Ile- Arg-NHCH2CH3. Ac-Ser-Pro-Trt Ser-D-Ser-Ala-Ser-VaJ-Thr-AJa-Gly-Asp ^ Gly-Val-D-pe-Thr-Arg-He-Arg, Ac-Ser-Pro-Tf -Ser-D-Ser-AIa-Ser-Val-T -r-Ala-Gly-Asp-Gly-V_l-D-ile-Thr-Arg-Ile-Arg-N_-2, Ac-Ser-Pro-Tr- Ser-D-Ser-Ala-Ser-Val-Thr-Ala-GIy-Asp-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-NHCH2CH3.
18. 18. A peptide or pharmaceutically acceptable salt thereof as defined by claim 1 of formula Z-Gly-Val-lie-Thr-Arg-IIe-U.
19. 19. A peptide or pharmaceutically acceptable salt thereof as defined by claim 18, wherein U is selected from Arg, Arg-N H2, and Arg-N HCH2CH3 and Z is optionally terminated with an N-protecting group.
20. 20. A peptide or pharmaceutically acceptable salt thereof as defined by claim 18 selected from the group consisting of Ser-Pro-Tf-_rer-D-Ser-AIa-Ser-V_l-Tl? R-Ala-Gly-Asp-GIy-V_a-pe-Tl _-- Arg-Ile- I Arg, Ser-Pr_-Tf- & rD-Ser-Ala-Ser-V_l-T ^ Arg-NH2, SCT-Pro-Trp-Ser-D-Ser-AIa-Ser-V_d ^ 'NHCH2CH3, Ac-Ser-Pro-Tf-Ser-D Ser-Ala-Ser-VJT ^^ i De-Arg, Ac- &r-Pr-HTf-_fc_r-_ Ser-Ala -_ ^ De-Arg-NH2. Ac-Ser-- -o-Tf-Ser-D-Ser-AIa-Ser-Val-?? r-AJa-Gly-Asp-Gly-VaJ-ne-Tltr-Arg-pe- 'Arg-NHCH2CH3, Ser -_ ^ o-Tf-D-Ser-Ser-Ala-Ser-V -Thr-Ala-GIy-A_p-Gly-V_l-pe-Thr-Arg-Ile-Arg, Ser-Pro-Tf-D-Ser -Ser-Ala-Ser-VJ-? Ir-Ala-Gly-Asp-Gly-Val-pe-Thr-Arg-pe- Arg-NH2. Ser-F_-or-Tf-D-Ser-Ser-AJa-Ser-Val-Tr-r-AJa-Gly-A_! P-Gly-Val-Ile-Thr-Arg-pe-Arg-NHCH2CH3. Ac-Ser-Pro-Tf-D-Ser-Ser-Ala-Ser-Val-Thr-Ala-Gly-Asp-Gly-Val-Ile-T r-Arg-Ile-Arg, Ac-Ser - ^ o -Tf-D-Ser-Ser-Ala-Ser-V_J-Thr-Ala-Gly-Asp-Gly-Val-ne-Thr-Arg-Ac-Ser-Pro-tf-D-Ser-Ser-AJa-Ser -Val-Thr-Ala-Gly-Asp-Gly-Val-pe-Thr-Arg-pe-Arg-NHCH2CH3.