TW200302833A - Tetra-, penta-, hexa-and heptapeptides having antiangiogenic activity - Google Patents

Abstract

Compounds of formula (SEQ ID NO:2) and (SEQ ID NO:3), which are useful for treating conditions that arise from or are exacerbated by angiogenesis, are described. Also disclosed are pharmaceutical compositions comprising these compounds, methods of treatment using these compounds, and methods of inhibiting angiogenesis.

Description

200302833 ⑴ 玖, 鼙 suspend; Ming (The description of the invention should state: the technical field, prior art, content, implementation and drawings of the invention are briefly explained) Crossover of related applications. The old specification is October 31, 2001 US Patent Application No. 10 / 000,07 applied for and US Patent Application No. 10 / 000,540 filed on October 31, 2001, both of which are incorporated herein by reference . TECHNICAL FIELD The present invention relates to a method for inhibiting angiogenesis, a method for treating cancer, and a compound having an activity capable of treating a condition caused or worsened by angiogenesis. A pharmaceutical composition containing the compound and a method for treating the same using the same are also disclosed. BACKGROUND OF THE INVENTION Angiogenesis is a fundamental process of new blood vessel formation and is necessary for various positive body activities (such as reproduction, development, and wound repair). Although not yet fully understood, Xianxin involves complex interactions of molecules that stimulate and inhibit endothelial cell growth. Under normal conditions, these eight or two blades seem to maintain the microvascular structure in a static state (and no capillary clothing 'test *).

Time, and this can last for weeks, in some cases even Ding Ping. However, when necessary, such as in wound repair, these same cells, ❿, 进行, are rapidly proliferated and renewed in as little as 5 days. Although angiogenesis is a highly controlled condition under normal conditions, there are end-stage diseases (characterized by "angiogenic diseases"). 7 7 is driven by uncontrolled angiogenesis. In other words The unregulated m ^^ formation may directly cause special diseases, or may worsen both the symptoms and signs. For example, it has been shown that the growth and metastasis of solid tumors are related to the blood and the formation of -6-

200302833 ⑼ Off. Based on these findings, there is a continuing need for compounds that have been shown to have anti-angiogenic activity due to their potential use in the treatment of various diseases such as cancer. Peptides with angiogenesis-inhibiting properties have been described in common WO 01/38397, WO 01/3 8347, WO 99/61476 and U.S. Patent No. 09 / 915,956. However, it is desirable to make antiangiogenic compounds with improved molecular profiles and smaller molecules. SUMMARY OF THE INVENTION The present invention relates to a new class of compounds having angiogenesis-inhibitory properties. The present invention provides tetra-, penta-, penta-, and hepeptides with enhanced angiogenesis inhibitory properties. In its specific example, the present invention proposes a compound of formula (1)

Xaai-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8 (I) (SEQ ID NO: i) or a therapeutically acceptable salt thereof, wherein

Xaai is selected from the group consisting of hydrogen and R- (CH2) nC (0)-, where η is an integer from 0 to 8, and R is selected from the group consisting of alkoxy, alkyl, amine, aryl, and several percent groups , Cyclofluorenyl, cycloalkyl and heterocyclic group;

Xaa is absent or selected from the group consisting of cold-propylamine, D-propylamine, D-biexamine S & 'D-propylglycine, D-4-lactopropylamine, D -'Amine group 'D-3 -Cyclophenylamine group' D-Local phenylamine group, D-Homoseramine group, Isolemine group, D-Isoamine group, D _Leucamine, N-methyl-D-leucine, D-n-leucine, D-n-valamine · S Shengji 'cyanamide, D-amphetamine, D-biliary Amine group, silk 200302833 _ (i) Amine test group, D-Ethyl phenylamine group and D-threonine group, Xaa3 is selected from the group consisting of D-propylamine group, D-isopropyl Amidino, besulamine, propylidene glycamine, aspartame, aspartame, glutamine, D-glutamine, N-formyl Glutamine, glutamine, N-methylglutamine, glycamine, histamine, homoseramine, D-homamine, isoleucine, D-isoleucine group, lysamine group (N-ε-ethylfluorenyl group), methionamine group, D-methionamine group, n-leucine group, D · n-leucine group, Valamine, D-orthoamine, Dproline, Inosamine, Serine, D-Seline, N-methylseramine, Threonine , D-threonium group, tryptamine group, tyrosine group and tyrosine group (0-methyl);

Xaa4 is selected from the group consisting of N-amidinopropylamine, allesamine, spermine, aspartyl, D-aspartyl, citrulyl, glutamine, D-glutamine, glutamine, glycine, homoseramine, leukoamido, D-leukoamido, lysamine (N-ε-ethylamido), Lysamine group (N-ε-nicotinylamine group), n-leucine group, n-valamine group, D-n-valamine group, N-methyl-n-valinyl group, ornithine group (N-5-ethenyl), 3-(3-ρ bisyl) propylamine, inosine, serine, D-serine, N-methylseramine, Threonium group, tryptamine group, valine group and N-methyl valine group;

Xaa $ is selected from the group consisting of propylamine's alloisoleucine * asparagine's citrulamine, glutamine, glutamine, isoleucine, D-isoleucine, N-formyl Isopropylamine, leucine, D-leucine, lysamine, lysamine (N-ε-ethyl), D-lysamine (N-ε-ethyl)醯 基), positive 200302833 (2)

In the group consisting of leucine, amphetamine S &

Xaa6 is selected from the group consisting of D-isoisoleucine, spermine, D-spermine, citrulidine, histamine, lysamine, lysamine (N-ε-isopropyl Group), ornithinofluorenyl, and 3- (3-pyridyl) propylaminofluorenyl; Xaa7f is present or selected from N-methyl-D-propylaminofluorenyl, 2-aminobutylfluorenyl '2-amine Isobutyric acid 'D-amino acid amino acid group, homoceramide amino group's light proline amino group, leucine amino group, phenylalanine group, prolyl group, D-proline group, threonine In the group consisting of amine groups and D-serine groups; and

Xaa8 is selected from the group consisting of D-propylamine fluorenylamine, azglycine fluorenylamine, glycamine fluorenylamine, hydroxy, D-lysamine fluorenyl (N-ε-ethylfluorenyl) amine, and a group represented by the fHDn-CHRiR2 formula; and a group consisting of a group represented by the -NHR3 formula, where η is an integer from 0 to 8; R1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl; R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocyclyl, and hydroxy. The limitation is that when η is 0, R2 is not alkoxy or hydroxy And R3 is selected from the group consisting of hydrogen, cyclofluorenyl, ring :): end group and meridian; and the limitation is that when Xaa6 * D-isoisoleulamino, Xaa7 is threonium and Xaa8 * Hydroxyl. In a preferred embodiment, the present invention proposes a compound of formula (II) X3.3.J-X3.3-2 " X3.3.3 " X3.2-4-X3.3.7 " X3.3-8 ( II) (SEQ ID NO: 2) or a therapeutically acceptable salt thereof, wherein

Xaai is absent or is R- (CH2) nC (0)-, where η is the number 200302833 (3) from 0 to 8, and R is selected from alkoxy, alkyl, amine, aryl, carboxyl, In the group consisting of cycloalkenyl, cycloalkyl and heterocyclic groups;

Xaa2 is selected from the group consisting of / 3-propylamine fluorenyl, D-propylamine fluorenyl, D-isopropylalanine fluorenyl, D-propylaminoglycine fluorenyl, D-4-chloroamphetamine fluorenyl, D-citramine , D-3-cyanoamphetamine, D-homoamphetamine, D-homoselamido, isoleukin, D-isoleumine, D-leucine, N-methyl -D-leucine, D-n-leucine, D-n-valinyl, D-penicillamine, D-amphetamine 'D-alkaliamine' D-serine D -p sephenylpropane

In the group consisting of amine groups and D-threonium groups;

Xaa3 is selected from the group consisting of alloxamine, aspartyl, glutamine, D-glutamine, N-methylglutamine, glycine, histamine Group, homoseramine group, isoleucine group, lysamine group (N-ε-ethylamidino group), methylthiamine group, serine group, N-methylseramine group, threonine Group, D-threonium group, tryptamine group, tyramine group and tyramine group (0-group);

Xaa4 is selected from the group consisting of N-methylpropylamine, allesamine, spermine, glutamine, D-glutamine, glycamine, homoseramine, leucamine Fluorenyl, lysamine fluorenyl (N-ε-ethylfluorenyl), n-leucine fluorenyl, n-valamine fluorenyl, D-n-valamine fluorenyl, N-fluorenyl n-valamine fluorenyl, ornithine (N-5-ethenyl), 3- (3-p ratio) propylamine, sarcosine, serine, N-methylserine, threonine, color In the group consisting of amine group, valine group and N-methyl valine group;

Xaa5 is selected from the group consisting of alaninyl group, allosamine group, aspartame group, citramine group, glutamine group, isoleusino group, D-isoleusin group, -10 200302833 (4) N-methylisoleucine, leucine, D-leucine, lysamine, lysamine (N-ε-ethylamyl), D-lysamine (N-ε-ethenyl), n-leucine, n-valinyl, phenylalanine, proline and D-proline groups;

Xaa6 is selected from the group consisting of spermine, D-spermine, citrulline, histamine, lysine, lysine (N-ε-isopropyl), ursamine, and In the group consisting of 3- (3-pyridyl) propylaminofluorenyl;

Xaa7 is absent or is selected from the group consisting of N-fluorenyl-D-propylaminofluorenyl, 2-aminobutylfluorenyl, 2-aminoisobutylfluorenyl, D-glutamine aminofluorenyl, homoproline, hydroxyproline , Leucylamine, Amphetylamine, Proline, D-Proline and D-Valamine; and

Xaa8 is selected from the group consisting of D-propylamine fluorenylamine, azglycine fluorenylamine, glycamine fluorenylamine, hydroxy, D-lysamine fluorenyl (N-ε-ethylfluorenyl) amine, and -NH ^ CHJn-CHRiR2 represents the group represented by the formula; and a group consisting of the groups represented by the -NHR3 formula, where η is an integer from 0 to 8; R1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl In the group consisting of: R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cyclofluorenyl, cycloalkyl, heterocyclyl, and hydroxyl group, and the limitation is that when η is 0, R2 is non-alkoxy Or hydroxyl; and R3 is selected from the group consisting of hydrogen, cyclofluorenyl, cycloalkyl, and hydroxyl. In a preferred embodiment, the present invention proposes a compound of formula (11) or a therapeutically acceptable salt thereof, wherein Xaa2 is selected from the group consisting of / 3-propylaminofluorenyl, D-isoisoleulamino, D-4-chlorobenzene In the group consisting of propylpropylamine, D-homoamphetamine, D-leucine, D-penicillamine and D-proline, and Xaai, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, and Xaa8 This is generally as described in formula (II). 200302833 (5) In another preferred embodiment, the present invention proposes a compound of formula (II), or a therapeutically acceptable salt thereof, wherein Xaa2 is D-isoleulamido, and 333 is-selected from Bezu Aminomethyl, Aspartame, Glutamine, Lysamine Pro. (N-ε-Ethyl), Methionamine, Serine, and Tyramine And Xaa !, Xaa4, Xaa5, Xaa6, Xaa7, and Xaa8 are as described in formula (II).

In another preferred embodiment, the present invention proposes a compound of formula (II), or a therapeutically acceptable salt thereof, wherein parent 382 is D-isoleucine, Xaa3 is threonine, and Xaa4 is selected from the group consisting of Amine group, glutamine group, D-glutamine group, n-leucine group, n-valine group, N-methyl n-valine group, serine and tryptophan And Xaai, Xaa5, Xaa6, Xaa7 & Xaa8W as described in formula (II). In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, and combined with a therapeutically acceptable carrier. In another specific example, the invention proposes a method of inhibiting angiogenesis in a mammal, wherein the animal is confirmed to require such treatment, the method comprising administering to the mammal a therapeutically acceptable dose of a compound of formula (II) or a compound thereof A therapeutically acceptable salt. In another specific example, the present invention provides a method for treating cancer in a mammal, wherein the mammal is confirmed to require such treatment, the method comprising administering to the mammal a therapeutically acceptable dose of a compound of formula (II), or A therapeutically acceptable salt. In another preferred embodiment, the present invention proposes a compound of formula (III) -12- 200302833 Χ χ3,3, ι-X3.3,2 ~ X3.3 > 3 ~ X33-4 * · X2.3-5 -X3.3.5-X3.3.7 (III) (SEQ ID NO: 3) or a therapeutically acceptable salt thereof, wherein:

Xaai does not exist, or R- (CH2) nC (〇)-, where η is an integer from 0 to 8, and R is selected from the group consisting of alkoxy, alkyl, amine, aryl, carboxy, and cycloalkenyl In the group consisting of cycloalkyl and heterocyclyl;

Xaa2 is selected from the group consisting of D-propylamine sulfonyl, D-isoisoleulam sulfonyl, alloxamine sulfonyl, alloglycine sulfonyl, aspartamine sulfonyl, aspartamine sulfonyl, glutamine

Fluorenyl, D-glutamine hydrazone, glutamine, N-fluorenylglutamine, glycamine, histamine, homoseramine, D-homoselide, iso-white Amine group, D-isoleucine group, lysamine group (N-ε-ethylamidino group), methionamine group, D-methionamine group, n-leucine group, D-n-white Amine group, n-valinyl group, D-n-valinyl group, D-proline group, inosinyl group, serine group, D-serine group, N-methylserine group , Threonium group, D-threonium group, tryptamine group, tyrosine group, and tyramine group (0 -fluorenyl group);

Xaa3 is selected from the group consisting of N-methylpropylamine, allesamine, spermine, aspartame, D-aspartyl, citramide, glutamine, D-glutamine, glutamine, glycamine, homoseramine, leucine, D-leucine, lysine (N-ε-ethyl) Lysamine group (N-ε-nicotinyl group), n-leucine group, n-valinyl group, D-n-valinyl group, N-methyl n-valinyl group, ornithine group (N-5 -ethenyl), 3- (3-p-pyridyl) propylamine, inosamine, serine, D · seramine, N-methylseramine, Threonium group, tryptamine group, val-13- 200302833 group, amine group and N-methyl valine group;

Xaa4 is selected from the group consisting of propylamine, allisopropylamine, asparagine, citrulamine, isopropylamine, D-isopropylamine, N-methylisobutylamine, white Amine group, D-leucine group, lysamine group, lysine group (N-ε-ethylfluorenyl), D-lysamine group (N-ε-ethylfluorenyl), n-valamine group In the group consisting of amine, amphetamine, proline, D-proline, and valine;

Xaa5 is selected from the group consisting of D-isoisoamidine, spermine, D-spermine, citrulidine, histamine, lysamine, and lysamine (N-ε-isopropyl Group), ornithino group, and 3- (3-pyridyl) propylamino group; Xaa6 is absent or selected from the group consisting of: N-methyl-D-propylamino group, 2-aminobutylamino group, 2 -Aminoisobutylamido, D-glutamine amidino, homoproline, hydroxyproline, leume, amphetamine, proline, D-proline, threonine In a group consisting of fluorenyl and D-serine fluorenyl; and

Xaa7 is selected from the group consisting of D-propylamine fluorenylamine, azglycine fluorenylamine, glycamine fluorenylamine, hydroxy, D-lysamine fluorenyl (N-ε-ethylfluorenyl) amine, and A group represented by NHJCHJn-CHRiR2; and a group consisting of groups represented by the formula -NHR3, where η is an integer from 0 to 8; R1 is selected from the group consisting of hydrogen, alkyl, cyclofluorenyl, and cycloalkyl In the group; R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cyclofluorenyl, cycloalkyl, heterocyclyl, and hydroxyl group, with the limitation that when η is 0, R2 is not an alkoxy group Or hydroxyl; and R3 is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and meridian; the limitation is that Dangyou & & 5 is D-isoisoamylamine, Xaa6 is threonium And Xaa7 is light base.

(δ) / In one comparison, it is therapeutically acceptable, and the sulfonyl group is composed of: in the composition group as in formula (III) 丨 in another treatment group, the composition is composed of asparagine sulfonyl group. As shown in formula (III), another vehicle can be treated with glutamine, N_thiamine, n-valamine, and Xaai can be treated with glutamine, Xaa2, xaa4, In another specific example of its therapeutically acceptable sulfonyl group: In a specific example, the present invention proposes a compound of formula (ΠI), or a salt thereof, wherein Xaa2 is selected from the group consisting of threonyl and D-threonine, and Xaa3 It is selected from the group consisting of n-valinyl and d-n-valinyl 'Xaa5 is spermine, and is defined by Xaai, Xaa4, Xaa6, and Xaa7. In a specific example, the present invention proposes a compound of the formula (〗 丨 丨), or an acceptable salt thereof, wherein Xaa2 is selected from the group consisting of alloxamine, aspartame, asosamine, and inosamine, and In the tyramine group, 'Xaas' is selected from the group consisting of n-valinyl group and £) -n-valinyl group. Xaa5 is a spermine group, and Xaai, Xaa4, Xaa6 and Xaa7 are defined. In a preferred embodiment, the present invention proposes a compound of formula (II), or a salt thereof: wherein Xaa2 is selected from the group consisting of glutamine, glutamine, glutamine, and lysamine (N-ε-ethyl In the group consisting of methylamine and tryptamine group, Xaa3 is selected from the group consisting of and ortho-amine group, Xaa5 is spermine group, Xaa4, Xaa6 & Xaa7 as shown in formula (ΠΙ) definition. In a specific embodiment, the present invention proposes a compound of formula (III), or a salt thereof, wherein Xaa3 is selected from the group consisting of glutamine and a D-group, and Xaa5 is a spermine group, and Xaai, Xaa6 'and Xaa7 are as defined in formula (III). In a preferred embodiment, the present invention proposes a compound of formula (111), or # ^ where Xaa3 is selected from the group consisting of serine amidino and D-serine group Xaa5 a spermine amidino, and Xaai, Xaa2, Xaa4, Xaa6 • 15 -200302833 (9) and Xaa7 are as defined in formula (III). In another preferred embodiment, the present invention provides a compound of formula (III), or a therapeutically acceptable salt thereof, wherein Xaa3 is selected from the group consisting of spermine, aspartame, and D-asparagine. Base, citrulamide base, glutamine base, D-leucine base, lysine base (N-ε-ethylamyl), lysamine base (N-ε-in donkey base), white In the group consisting of amine groups, N-methyl n-valinyl groups, threonium groups, and tryptamine groups, Xaa5 is a spermine group, and Xaai, Xaa2, Xaa4, Xaa6 & Xaa7 are represented by formula (III) ).

In another preferred embodiment, the present invention proposes a compound of formula (III), or a therapeutically acceptable salt thereof, wherein Xaa5 is selected from the group consisting of D-isoisoleulamido, citrulamine, and lysamine In the group consisting of Ν-ε-isopropyl), guanamine, and 3- (3-p-pyridyl) propylamino, and Xaa !, Xaa2, Xaa3, Xaa4, Xaa6 & Xaa7 is represented by formula (III ). In another specific example, the present invention provides a pharmaceutical composition containing a compound of formula (III), or a therapeutically acceptable salt thereof, and combined with a therapeutically acceptable carrier. In another specific example, the present invention proposes a method of inhibiting angiogenesis in a mammal, the mammal being confirmed to be in need of the therapy, the method comprising administering to the mammal a therapeutically acceptable dose of a compound of formula (111), Or a therapeutically acceptable salt thereof. In another specific example, the present invention provides a method for treating cancer in a mammal, the mammal being confirmed to be in need of the therapy, the method comprising administering to the mammal a therapeutically acceptable dose of a compound of formula (III) or a treatment thereof Acceptable salt. -16- 200302833 _ (10) 1 ^^^ Detailed description of the invention As used herein, the singular forms "a", '' anπ, and '' the1 'include plurals unless the context clearly indicates otherwise. As used in this specification, the following terms have the definitions shown: πalkoxy '' as used herein means that an alkyl group is attached to the parent molecular moiety and is attached via an oxygen atom. "Alkyl" as used herein represents a monovalent group derived from a straight or branched chain saturated hydrocarbon from which a hydrogen atom is removed. A preferred alkyl group for use in the present invention is an alkyl group having one to six carbon atoms (CrG Alkyl). An alkyl group (Ci-Cg alkyl) of one to three carbon atoms is preferred for the present invention. '' Alkylcarbonyl, as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group Π amino group π, as used herein, represents -NRaRb, where 113 and Rb are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. "Aryl" as used herein, represents phenyl or bicyclic Or a tricyclic fused ring system in which more than one fused ring is phenyl. Examples of bicyclic fused ring systems are a phenyl group fused to a cyclofluorenyl group (as defined herein) or a cycloalkyl group (as defined herein) or another phenyl group. Examples of tricyclic fused ring systems are: a fused ring system fused to a cyclofluorenyl group (as defined herein), a cycloalkyl group (as defined herein), or another phenyl group. Representative examples of the aryl group include the following but are not limited thereto: anthracenyl, aryl, thyryl, hydroindenyl, indenyl, fluorenyl, phenyl, and tetrahydrofluorenyl. The aryl group of the present invention may optionally be substituted by one, two, three, four or five substituents, and is independently selected from the group consisting of: alkoxy, alkyl, carboxyl, fluorene, and hydroxyl. -17- 200302833 .....-_ a (11) π carbonyl '' as represented by -c (o)-. The π carboxy '' is represented by -C02H. One

`` Cycloalkenyl '' as used herein refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, where each five-membered ring has a double bond and each six-membered ring has one Or two double bonds, each of the seven and eight member rings has one to three double bonds, and each of the nine to ten member rings has one to four double bonds. Examples of cycloalkenyl include cyclohexenyl, octahydrofluorenyl, n-sullofluorenyl and the like. The cycloalkenyl group of the present invention may be optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of oxy, alkynyl, carboxyl, carboxylic, and hydroxy. "Cycloalkyl" as used herein refers to a saturated monocyclic, bicyclic, or tricyclic hydroxyl ring system having three to twelve carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclopentyl, Bicyclo [3,1,1] heptyl, adamantyl, etc. The cycloalkyl of the present invention may be one, two, three, four or five independently selected from the group consisting of alkoxy, alkyl, carboxy , 卣 and hydroxy are substituted by a substituent. '· Halo' as used herein represents F, C1, B Γ or I.

"Heterocyclyl" as used herein refers to a five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The five-membered ring has 0 to two There are two double bonds, and the six- and seven-membered rings have 0 to three double bonds. "Heterocycles" also include bicyclic groups in which the heterocyclic ring is fused to an aryl group, as defined herein. The heterocyclic group of the present invention It can be attached via a carbon atom or a nitrogen atom in the group. Examples of the heterocyclic ring include the following but are not limited thereto: furanyl, 4-phenyl, pyrrolyl, stilbendinyl, 4-benzyl, 0-olyl, Mitoki, Mitoki, Sayaki, Misaki, Misaki, Misaki, Morioki, Thiophrynki, Phoenic, Phyto, W Base, glutenyl group and benzoxanthenyl group. Honfa-18- 200302833 (12)

The heterocyclic group of Ming is optionally substituted by one, two, three or four substituents, and the substituents are independently selected from the group consisting of alkoxy, alkyl, alkyl, halogen and hydroxyl groups. πhydroxy '' as used herein represents -0 Η.

"Therapeutic acceptable salt" as used herein represents a salt of the compound of the present invention or a zwitterionic form, which may be water or oil-soluble or dispersible, without undue toxicity, irritant and allergic reactions It is suitable for the treatment of diseases; it has a reasonable reasonable benefit / risk ratio and is effective for its intended use. The preparation of the salt can be carried out during the final isolation and purification of the compound, or it can be separately reacted by an amine group with a suitable acid Representative acid addition salts include acetate, ferrate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate Salt, camphor salt, camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide Compounds, 2-hydroxyethane sulfonate, lactate, maleate, mesitylene sulfonate, pristane sulfonate, peptone sulfonate, nicotinate, 2-peptone sulfonate , Oxalate, dihydroxygallate, pectate, persulfate, 3-phenyl Acid salt, picrate, trimethyl acetate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- Tosylate and undecanoate. At the same time, the amine group in the compound of the present invention can be quaternized in the following four ways, such as: methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dimethyl, diethyl, dibutyl and dipentyl sulfate; decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and fluorenyl and phenethyl-19 200302833 〇3)

Based bromide. Examples of acids that can be used to form therapeutically acceptable 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. Unless otherwise indicated by the "Dn" prefix, such as D-Ala or NMe-D-Ile, the α-carbons of the amino acids and amino sulfonyl residues in the peptides described in this specification and the appended patent applications The stereochemistry is in the natural or "L" configuration. The Cahn-Ingold-Prelog "R" and "S · 'designations can be used to show clearly that some of the fluorenyl substituents on the N-terminus of the peptide of the present invention are opposite the palm center. Stereochemistry. The designation ', R, S' represents a racemic mixture of two enantiomeric forms. All peptide sequences are written according to generally accepted conventions, with the α-N-terminal amino acid residue on the left, and The a-C-terminus is on the right. As used herein, π α-N-terminus ”refers to the free state of the amino acid in the peptide, α-amino group, and π a -C-terminus refers to the free state of the amino acid in the peptide. α-carboxyl terminus. For the most part, the names of naturally occurring and non-naturally occurring amino group residues used here follow the IUPAC Commission on the

Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature. To the extent that the names and abbreviations of the amino acid and amino fluorenyl residues used in this specification and the scope of the attached patent application are different from their suggestions, they can be explained in more detail to the reader. Certain abbreviations that can be used to describe the invention are defined in Table 1 below. -20- 200302833 (14) Table 1 Definition of 1 words N-Ac N-B Hall: Ala propylamine S & b Ala / 3 · Alanamine AlaNH2 Alanamine Amine alle Allyl isopropylamine alloThr Other Threonyl alloThr (O-tBu) alloThryl (0-third butyl) AllyGly AllylGlycinyl Arg Spermine Glycine Arg (Pmc) Spermine Glycine (NG-2,2 , 5,7,8-pentamethylchroman-6-sulfonyl) Fmoc-Arg (Pbf) -OH N-Fmoc-NG- (2,2,4,6,7-pentamethyldihydrobenzene Benzofuran-5-Transferyl) Aspartic Acid Asn Asparagine Asn (Trt) Aspartame Amidino (trityl) Asp Asparagine Asp (O-tBu) Asparagine Fluorenyl (0-third butyl) Cit Citrullamine Fmoc 9-thylmethoxycarbonyl Gin Glutamine Amidino Gln (Trt) Glutamine Amidino (trityl) Glu Glutamine Glu (O-tBu) glutamine (0-third butyl) NMeGlu N-methylglutamine

-21-200302833 (15)

Gly Glycinol His Histamine Histidine His (Trt) Histamine Heptyl (triphenylfluorenyl) Hphe Sulphenylanine Hser Nanseramine S & Hser (Trt) Homoseramine (Triphenylmethyl) Group) lie isoleucine si group Leu leucamine group Lys (Ac) lysamine group (N-ε-ethylfluorenyl group) Lys (Boc) lysamine group (N-ε-third butoxycarbonyl group) Lys (Isp) Lysamine group (N-ε-isopropyl) Lys (Nic) Lysamine group (N-ε-nicotinyl group) Met Methionamine group N-3Mev N-3-methylvaleryl Amine group N- (6MeNic) 6-methylnicotinyl group Nle n-Leucylamine Nva n-Valamine group, NMeNva N-methyl-n-Valamine group Orn Ornithine Orn (Ac) ornithine Fluorenyl (N-ε-Ethylfluorenyl) Orn (Boc) Ornithinofluorenyl (third butoxycarbonyl) 3-Pal 3- (3-pyridyl) propylaminofluorenyl Pen Penicillinamine Pen (Trt) Penicillamine (Trityl)

-22- 200302833 (16) 4ClPhe 4-chlorophenylpropylamine amidino Phe Phenylpropylamine amidino Pro Proline amidino ProNHCH (CH3) 2 Proline amidinoisopropyl amidin ProNHCH2CH3 Proline amidinoethyl amidamine 3-Pal 3- (3-0 specific amidinyl) alaninyl Sar Sarinosinyl Ser Seranine (O-tBu) seramine (0-third butyl) Thr threonine Thr (O-tBu) Threonyl (0-third butyl) Trp Tryptophanyl Trp (Boc) Tryptophanyl (N-third butoxycarbonyl) Tyr Tyr (O-tBu) Tyramine (0-third butyl) Val Valamine base composition

The compounds of the invention, including but not limited to those shown in the examples, have anti-angiogenic activity. As an anti-angiogenesis inhibitor, this compound can be used to treat primary and metastatic solid tumors including the following cancers: breast, colon, rectum, lung, oropharynx, ingestion, stomach, pancreas, liver, gallbladder and biliary tract , Small intestine, urethra (including kidney, bladder and bladder epithelium), female reproductive tract (including cervix, uterus and ovary, choriocarcinoma and trophoblastic disease of pregnancy), male reproductive tract (including prostate, seminal vesicles, testes and blastoma -23- 200302833 (17)

Tumors), endocrine glands (including thyroid, adrenal and pituitary glands) and skin, as well as hemangiomas, melanoma, sarcomas (including those generated from bone and soft tissue and Kaposi's sarcoma), and brain, nerve, and eye And meningeal tumors (including astrocytoma, glioma, glioblastoma, retinoblastoma, neuroma, neuroblastoma, schwannomas, and meningiomas). This compound is also useful in the treatment of solid tumors originating from hematopoietic malignancies, such as leukemia (ie, green tumors, plasmacytomas, and mycosis plaques and tumors and keratinous T-cell lymphoma / leukemia) as well as lymphomas (Including Hodgkin's and non-Hodgkin's lymphoma). In addition, these compounds can be used for the metastasis of the aforementioned tumors, either alone or in combination with radiation therapy and / or other chemotherapeutic agents. Further uses include the treatment and prevention of autoimmune diseases such as rheumatoid, immune and degenerative arthritis; various ophthalmic diseases such as diabetic retinopathy, premature retinopathy, corneal graft rejection, posterior lens fibrosis, new Angiogenic glaucoma, redness of the skin, neoretinal angiogenesis due to plaque degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neoangiogenic conditions in the eye; skin diseases Such as psoriasis; vascular diseases such as hemangioma, and hair vessel proliferation in atherosclerotic plaques; Osler-Webber syndrome; myocardial angiogenesis; plaque neoangiogenesis; capillary dilatation; hemophilic joint hemorrhage; angiofibroma; And granulation of the wound. Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endothelial cells, including but not limited to the following. This: Intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and scar hypertrophy, ie keloids. Another use is as a fertility control agent, which inhibits ovulation and the development of the placenta. The compounds of the present invention can also be used to treat diseases in which angiogenesis is a pathological cause and effect, such as Rochele minutesalia * quintosa and ulcers (Helicobacter pylori). The compound of the present invention can also be used to reduce the bleeding before administration, especially in the treatment of resectable tumors. 0 The compound of the present invention can be combined with other compositions and steps when treating diseases. For example, tumors can be treated conventionally by surgery, irradiation or chemotherapy, plus a combination of the peptides of the invention, and the peptides of the invention are then re-administered to the patient

To prolong the quiescence of micrometastases and stabilize and inhibit the growth of any residual primary% tumors. In addition, the compounds of the present invention may be combined with pharmaceutically acceptable excipients and a matrix that is continuously released as needed, such as a biodegradable polymer, to form a therapeutic composition. The continuous release matrix used in this case is usually a matrix made of a polymer, which can be degraded by enzymes, acid-base hydrolysis or dissolution. Once in the body, the matrix can be acted upon by enzymes and body fluids. The matrix for sustained release is desirably selected from biocompatible materials such as liposomes, polylactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide ( Copolymer of lactic acid and glycolic acid), polyanhydrides, poly (ortho) esters, peptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids Amino acids such as phenylalanine, tyrosine, isoleucine, polynuclear acid, polypropylene, polyvinylpyrrolidone, and polysiloxane. A preferred biodegradable matrix is a matrix of any one of polylactide, polyglycolide, or polylactide co-glycolide (a copolymer of lactic acid and glycolic acid). In the application of the above or other treatments, the treatment of one of the compounds of the present invention -25- 200302833 (19)

The effective dose can be applied in pure form or when a therapeutically acceptable salt form is present. The "therapeutically effective dose" of the compound of the present invention means that at a reasonable benefit / risk ratio applicable to any medical treatment, it can treat angiogenic diseases / so restrict tumor growth or slow or block tumor metastasis A sufficient dose of the compound. However, it should be understood that the total daily dose of the compounds and compositions of the present invention should be determined by the attending physician in the professional medical judgment. The specific therapeutically effective dose for any particular patient depends on various factors, including : The severity of the disease and disorder to be treated; the activity of the special compound applied; the special composition applied, the patient's age, weight, general health status, gender, and diet; the frequency of administration, the path, and the particular application The excretion rate of the compound; the duration of the treatment period; the drug used in combination with the particular compound; and similar factors well known in medical technology. For example, the skilled artist knows that the initial dose of the compound should be lower than the dose required to achieve the desired therapeutic effect The dose level, and then gradually increase the dose until the desired effect is achieved Only.

In addition, the compound of the present invention may be administered in the form of a medical composition containing a key compound and combined with more than one pharmaceutically acceptable excipient. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating substance or any type of adjuvant. The composition can be administered parenterally, intraluminally, intravaginally, intraperitoneally, topically (for example, as a powder, ointment, drop, or transdermal patch), transanally, or transbuccally. The term "parenteral" refers to the mode of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarterial injection and infusion. Pharmaceutical compositions for parenteral injection include pharmaceutically acceptable Accepted Sterile-26- 200302833 (20) Aqueous or non-aqueous solutions, dispersants, suspensions or emulsions, and sterile powders can be reconstituted into sterile injectable solutions or dispersions and reconstituted before use. Suitable aqueous Examples of non-aqueous carriers, diluents, solvents or solvents include: water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive Oil), and injectable organics such as Bole oleate. To maintain moderate fluidity, coating materials such as lecithin can be used, and in the case of dispersants, the necessary particle size is maintained, and used Surfactants. These compositions may also contain adjuvants such as preservatives, moisturizers, emulsifiers, and dispersants. To prevent microbial effects, various antibacterial and antifungal agents can be incorporated to ensure this. Such as p-benzoic acid, chlorobutanol, g, ascorbic acid, etc. It can also be included isotonic agents such as sugar, steel chloride, etc. Injectable pharmaceutical types can be included to extend the absorption delaying effect, such as single Aluminum stearate and injectable storage types are prepared by forming the drug into a microcapsule matrix in a biodegradable polymer such as polylactide-polyglycolide, poly (orthoester), Polyanhydride, and polyglycol, such as PEG. Depending on the ratio of pharmacy to polymer and the nature of the particular polymer used, the drug release rate can be controlled. Storage-type injectable blends can also be used by the drug Prepared by trapping in liposomes or microemulsions, both of which are compatible with body tissues. Injectable blends can be sterilized, such as filtration through a bacterial filter, or they will be in the form of a sterile solid composition Sterilizer is included, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. -27- 200302833 (21) Topical administration includes administration to the skin or mucous membranes, including the lungs and the eye surface For local investment The composition includes inhalables, which can be made into a dry powder form, compressed or uncompressed. In an uncompressed powder composition, the active ingredient in a finely divided form can be combined with larger particles of a pharmaceutically acceptable Inert carriers, where the particle diameter of the latter can even be as high as 100 microns. Suitable inert carriers such as sugars (lactose as an example). It is desirable that at least 95% or more of the active ingredient particles have a weight of 0.01 to 10 microns. Effective particles.

Alternatively, the composition is compressible and contains a compressed gas such as nitrogen or a liquefied gas propellant. This should be the case with the liquefied propellant medium and, more preferably, the complete composition, so that the active ingredient will not be substantially dissolved therein. The compressed composition may also contain a surfactant, and a liquid or solid non-ionic surfactant, or a solid anionic surfactant. It is preferable to use a solid anionic surfactant in the form of a sodium salt.

A further form of topical administration is to the eye. The compound of the present invention can be delivered in a pharmaceutically acceptable ophthalmic vehicle, so that the compound can be kept in contact with the eye surface for a sufficient time to allow the compound to penetrate the cornea and internal areas of the eye, such as the anterior chamber, posterior chamber, vitreous body, and body fluid , Vitreous fluid, cornea, iridescent / ciliary body, crystalline lens, choroid / omentum and sclera. Pharmaceutically acceptable ophthalmic vehicles can be, for example, ointments, vegetable oils or encapsulated substances. In addition, the compound of the present invention can be directly injected into a vitreous body and a body fluid. The composition for rectal or vaginal administration is preferably a suppository, which is prepared by mixing the compound of the present invention with a suitable non-irritating excipient or vehicle such as cocoa butter, polyethylene glycol or suppository wax, which is used in It is solid at room temperature and liquid at body temperature, so it can melt in the rectum or vaginal cavity and release life-28- 200302833 (22)

Sexual compounds. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are often derived from phospholipids or other lipids. Liposomes are formed from single or multiple parallel hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition in the form of a liposome may contain a stabilizer, a preservative, an excipient and the like in addition to the compound of the present invention. Preferred lipids are phospholipids and phospholipids and choline (ovlinyl lipids), which can be natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Velume, XIV, Academic Press, New York N.Y. (1976), p33 See below. Although the compounds of the present invention can be administered in the form of a single active pharmaceutical agent, they can also be used in combination with more than one agent conventionally used to treat vascular diseases. For example, the compounds of the invention are effective in a short time because they make tumors more sensitive to traditional cytotoxic therapies, such as chemical agents and radiation therapy. The compounds of the present invention can also enhance the effectiveness of existing anti-cancer therapies with cytotoxicity. The compounds of the present invention can also be combined with other anti-angiogenic agents to enhance their effectiveness, or they can be 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 present invention can be administered with: IL-1 2, retinoic acid, interferon, angiostatin, endostatin, thalidomide Thrombin spondin-l, Thrombin spondin-l, Thrombin spondin-2, Captopryl 'Angioinhibins, TNP-470' Pentosan sulfate, Platelet factor 4, LM -609, SU-5416, CM-101, -29- 200302833 (23) Tecogalan, plasminogen k-5, vasostatin, vitaxin, Vasculostatin, squalamine, marimastat or other MMP inhibitors, anti-neoplastic agents such as interferon alpha, COMP (cyclophosphamide, vinpocetine, amine methylacetate) And prednisone), etoposide, mBACOD (methotrine, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone, PRO-MACE / MOPP (prednisone, methotrexate (W / leucovin rescue), doxorubicin, cyclophosphamide, Shun Ming, Taxol, Yitopou 1 / nitrogen chloride (mechlorethamine), vincent test, prednisone and procarbazine), vincent test, vinblastine, etc., and can cooperate with radiation The total daily dose when the composition of the present invention is administered to a human or other mammalian host in single or divided doses may be from 0.0001 to 300 mg / kg body weight (per day), and more usually from 1 to 300 mg / kg body weight It should be understood that when inhibiting, treating or preventing angiogenic diseases, the agents that can be combined with the compounds of the present invention are not limited to those listed above, and in principle include any agents that can be used to treat or prevent angiogenic diseases. In-tube analysis of deciding on angiogenesis and living 4 days according to SS Tolsma, OV Volpert, DJ Good. WF Frazier, PJ Polverini and N. Bouck, JL Cell · Biol. 1993, 122, 497-511 Microvascular endothelial (HMVEC) migration analysis. HMVEC migration analysis is performed using human microvascular endothelial cells-dermis (single-donor) and human vascular endothelial cells (newborn). HMV EC cells-30- 200302833 (24) Cells containing 0.01% bovine serum albumin (BSA) were trypsin harvested and suspended in DME with 0.01% BSA at a concentration of 1.5 x 1 per ml 06 cells. Cells are modified into 48 holes

The bottom of the Boyden chamber (Nucleopore corporation, Cabin John, MD). The chamber was reassembled and inverted, and the cells were allowed to adhere to the polycarbonate chemotactic membrane (5 micron pore size) at 37 ° C for 2 hours, while the latter was soaked in 0.01% gelatin overnight and then dried. The chamber was then inverted, and the test substance (50 microliters) was added to the hole above the chamber, which included an activator, namely 5 nanograms / ml of bFGF / VEGF. The entire device was incubated at 37 ° C for 4 hours. Recover the membrane, fix and stain (Ditt Quick, Fisher Scientific) and count the number of cells transferred to the upper chamber under 3 high power electric fields. The background value of transfer to DME + 〇1 BSA is subtracted, and the number of cells transferred per 10 high-power electric fields (400 times under magic) is reported, or when the result is a combination of multiple experiments, the Compared with the positive control group, the percentage of inhibition of migration is expressed. _ The representative compounds of Examples 1 to 154, in the above analysis, inhibited the migration of human endothelial cells by at least 55% when tested at a concentration of ιn nM. The preferred compound inhibits human endothelial cell migration. When tested at a concentration of nM, it can reach about 80% to ㈣ ', while the best compound inhibits human migration at 0.001 nM, and cell migration can reach about 55% to 7G%. As shown by these results, the present compound has been shown to have stronger strength than the previously described anti-angiogenic peptides. The present invention includes compounds of formulae, which are metabolized by synthetic steps Arrow. The preparation of the compounds of the present invention through metabolic processes includes processes that occur in humans-31-200302833 (25) or in animals (in vivo) or in test tubes. The synthesis of the polypeptides of the present invention can be made by skilled artisans Many known technologies For solid phase peptide synthesis, an overview of many technologies can be found in: JM Stewart and JD Young, Solid Phase Peptide Synthesis, WH Freeman Co. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins and Peptide, vol. 2 p. 46 Academic Press, (New York), 1973. For typical solution synthesis, see G. Schroder and K. Lupke, The Peptides, vol. 1,

Academic Press (New York), 1965. Reagents, resins, amino acids and amino acid derivatives are commercially available and can also be purchased from Chem-Impex International, Inc. (Wood Dale, IL. USA) or Calbiochem-Novabiochem Corp. (San Diego, CA, USA) unless otherwise indicated.

Generally, these methods include the sequential addition of more than one amino acid or appropriately protected amino acid to a growing peptide chain. Usually, the amine or carboxyl group of the first amino acid is protected with a suitable protecting group. The protected or derivatized amino acid is then adhered to an inert solid support or used in a solution. The next amino acid can be added to the sequence where the complementary group (amino or carboxyl) is properly protected, under conditions It is suitable for the formation of amidine chain. The protecting group is then removed from the newly added amino acid residue, and then the next amino acid (appropriately protected) is added, and so on. Once all the desired amino acids have been linked in the appropriate sequence, any protecting groups (and any solid support) left behind are removed sequentially or simultaneously to generate the final polypeptide. This general process is modified purely, and more than one amino acid can be added at a time, such as coupling a protected tripeptide with a properly protected peptide (in the center of the palm that does not racemize -32- 200302833

mmmm I), a pentapeptide can be formed after deprotection. A particularly preferred method for preparing the compounds of the present invention involves solid-phase peptide synthesis. In this particularly preferred method, the? -Amine functional group is protected with an acid or base sensitive group. Such protecting groups should be stable under the conditions of peptide chain formation, and can be easily removed without damaging the growing peptide chain, or racemizing any palm center contained therein. Suitable protecting groups are: 9-thiylmethoxycarbonyl (Fmoc), tertiary butoxyl (Boc), ethoxycarbonyl (Cbz), biphenyl isopropyl monooxycarbonyl, third pentyloxycarbonyl , Isofluorenyloxycarbonyl, (α, α) -dimethyl-3,5-dioxofluorenyloxycarbonyl, 0-nitrophenylsulfenylfluorenyl, 2-cyano-tertiary butoxycarbonyl ,and others. A 9-Czechyl methoxycarbonyl (Fmoc) protecting group is preferred. Particularly preferred side-chain protecting groups are: arginine: > ^-2,2,5,7,8-pentamethyl-6-sulfonyl (Pmc), and 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfofluorenyl (Pbf); asparagine: trityl (Trt); aspartic acid: third butyl (t-Bu); In glutamine: third butyl ester (O-tBu); in glutamine: trityl (Ti: t); in N-methylglutamine: third butyl (t-Bu) ); In homoserine: trityl (Trt); in histidine ·· trityl (Trt); in lysine: third butoxycarbonyl (Boc); in ornithine: Tributoxycarbonyl (Boc); in penicillamine: trityl (Trt); in serine: tertiary butyl (t-Bu); in threonine and allothuronic acid: third butyl ( t-Bu); in tryptophan: third butoxycarbonyl (Boc); in tyrosine: third butyl (t-Bu). In the solid phase peptide synthesis method, the C-terminal amino acid is adhered to a suitable solid phase support or resin. Suitable solid phase support system for the above synthesis -33- 200302833

(27) Agents and substances which are inert in the reaction conditions of the stepwise condensation-deprotection reaction, and are insoluble in the medium used. It is preferred for the synthesis of C-terminal carboxyl peptides. The solid support is Sieber fluorene resin or Sieber ethyl fluoramine resin. The preferred solid phase carrier for terminal amine peptides is Sieber Ethyl Ammonium Resin, available from Novabiochem Corporation. The coupling of the 0 C-terminal amino acid to the resin uses the following mediators, including: Ν, Ν ·- Dicyclohexylcarbodiimide (DCC), N, N, -diisopropylcarbodiimide (DIC), [0- (7-Azolobenzotriazol-1-yl) -1,1, 3,3-tetrafluorenyl tungsten hexafluorophosphate] (HATU), or 0-benzotristetra-1 -yl-N, N, N ', N, -tetramethyl_tungsten hexaphosphate (HBTU) ), With or without 4-dimethylamino p ratio (DMAP), 1-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM), benzotriazol-1-yloxy -Tris (diamido) phosphonium hexafluorophosphate (BOP) or bis (2-keto-2-3-oxazolidinyl) phosphine chloride (BOPC1), at 10 ° C -50 At a temperature between ° C and about 1 to about 24 hours, the solvent is dichloromethane or DMF. When the solid support is Sieberamine or Sieber's ethylamine resin, the Fmoc group can be dissociated with a secondary amine, preferably hexahydropyridine, and coupled with the c-terminal acrime as described above. In 4- (2,4, -dimethoxyphenyl-Fmoc-aminomethyl) phenoxyacetamidoethyl resin coupled to deprotection, the preferred reagent is 0-benzotris Azole-1-yl-N, N, N ,, N, -tetramethyltungsten hexafluorophosphate (HBTU, 1 equivalent) plus 1-hydroxybenzotriazole (HOBT, 1 equivalent), or [0- (7-Azbenzotriazol-1-yltetramethyltungsten hexafluorophosphate) · (HATU, 1 equivalent) plus N-fluorenylmorpholine (1 equivalent) in DMF.. Protected amine Sequential coupling of amino acids can be performed in an automated peptide synthesizer at -34-200302833 (28), as is well known in the art. In a preferred embodiment, in the amino acids of a growing peptide chain, the α-amino group The functional group can be protected by Fmn & c. The removal of the Fmoc protecting group from the N-terminal side of the elongating peptide can be completed by secondary amine treatment, preferably hexahydropyridine. Each protected amino acid is about 3 times more The molar concentration is excessively introduced, and the coupling is preferably performed in DMF. The coupling agent is usually 0_benzotriazole_byl-N, N, N ,, N, -tetramethyltungsten hexafluorophosphate ( HBTU, 1 equivalent), or [0- (7-azibenzotriazol-1-yl) -1,1, 3,3-tetrafluorenyl tungsten hexafluorophosphate] (HATU, 1 equivalent), and the presence of N-methylmorpholine (NMM, 1 equivalent). At the end of solid-phase synthesis, 'polypeptide is shifted from the resin' Remove and deprotect, either sequentially or in a single operation. Removal and deprotection of the polypeptide can be performed in a single operation, that is, the resin-bound polypeptide is treated with a dissociation reagent, such as trifluoroacetic acid containing anisole , Water, or ethanedithiol. In the case where the C-terminus of the polypeptide is carbamoylamine, the dissociation of the resin is amine hydrolysis with an alkylamine. In addition, the peptide can be removed by transesterification, If you use methanol, then perform the ammonolysis or direct transaminization. The protected peptide can be purified at this point, or go directly to the next step. The removal of the side chain protecting group can use the above-mentioned dissociation blending 1 Completely deprotected peptides can be purified using a sequence of chromatographic steps, using all or any of the following steps: · Ion exchange on weakly acetic resins in the acetate form; on underivatized polybenzene Hydrophobic Absorption on Ethyl-Diethylbenzene (eg AMBERLITE® XAD) Chromatography; silica gel adsorption chromatography; ion exchange chromatography on methylcellulose; such as partition chromatography on SEPHADEX® G-25, LH-20, or countercurrent distribution; high performance liquid chromatography 200302833 ( 29) (HPLC), especially reverse-phase HPLC, is performed on octyl- or octadecylsilyl · crushed stone bonded phase column packing. The above examples can better understand the above, which only describes that it can be performed according to the present invention. The compounds and methods do not limit the scope of the invention in any respect. The abbreviations used in the following examples are as follows: DMF in N, N-dimethylformamide; 1 ^ but 11 in 0-benzotriazole -: 1-yl- ^ 1 ^ 3, tetramethyl tungsten hexafluorophosphate; NMM in N-methylmorpholine; TFA in trifluoroacetic acid; NMP in N_methylpyrrolidone; and HATU in [0 -(7-Acryltriazole-; [-yl) -1,1,3,3-tetramethyltungsten hexafluoroscale salt]. Example 1 N-_Ac-D-Ile ^ T_hr-Nva ^ Ile-Arg-ProNHCH1CH1 In the reaction tank of the Rainin peptide synthesizer, put FmoC-Pro-Sieber ethylammonium resin (0.25 g, 0.4 mmol Ear / gram loading; ^ Resin was solvated with DMF, and amino acids were coupled in sequence according to the following synthesis cycle: (1) Washed with DMF for 3 x 1.5 minutes; (2) 2 X 1 for 5 minutes using 20% hexahydro Pyridine deprotected; (3) 6x3 minutes washing with DMF; _ (4) adding amino acid (5) activating amino acid with 0.4 M HBTU / NMM and coupling; (6) 3 × 1.5 minutes with DMF Washed. The protected amino acid is coupled to the resin in the following order: Protected amino acid coupling time Fmoc-Arg (Fmc) 30 minutes Fmoc-Ile 30 minutes -36- 200302833

(30) Fmoc-Nva 30 minutes Fmoc-Thr (O-tBu) 30 minutes Fmoc-D-Ile 30 minutes Acetic acid 30 minutes Once the synthesis is complete, the peptide is taken from the resin using TFA / anisole / water: 2 · 5: 2 · 5) The mixture was dissociated for 3 hours. The peptide solution was concentrated under vacuum, precipitated with diethyl ether, and collected by filtration. The crude peptide was purified by HPLC using a C-18 column and a solvent mixture-a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA) over 50 minutes. Pure fractions were freeze-dried to produce N-AC-D-Ile-Thr_NVa-Ile-Arg-PrOHNHCH2CH3 as trifluoroacetate; Rt = 3.38 minutes (gradient change from 20% to 80% acetonitrile / water (containing TFA) for 10 minutes); MS (ESI) m / e 767 (M + H) +; amino acid analysis: 2.06 lie; 0.58 Thr; 1.01 Nva; 0.98 Arg; 1.04 PΓ0 〇 Example 2 Wanted The product was prepared by replacing Fmoc-D-aIle with lie. After the treatment, the crude peptide was purified by HPLC purifying agent mixture at 5% to 100% acetonitrile / water (containing a change history of 50 minutes. Pure fractions were cold; East drying could generate Fmc in Generation Example 1) e_D_ 'Utilization C-18 column and gradient of 0.1% TFA) N-Ac-D-alle-Thr-

Nva-Ile-Arg-ProNHCH2CH3 ， was trifluor private jealous # 气 vine 故 盐; Rtd U minutes (gradient change over 10 minutes, from 20% to 80% Acetone / u, human & / water (containing 0.01% TFA)); MS (ESI) m / e 767 (Μ + Η) +; amino acid analysis · 0.99 Nva; 1.03 Arg; 1.02 Pro. 2.11 lie; 0.43 Thr; Example 3 -37 · 200302833

(31) N-Ac-D-Ile-alloThr-Nva-lie-Arg-ProNHCHiCH! The desired product was prepared by replacing Fmoc-alloThr (O-tBu) with Fmoc-Thr (O-tBu) in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and solvent mixture over a 50-minute change on a gradient of 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.56 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 767 (M + H) +; amino acid analysis: 2.02 lie; 0.51 Thr; 0.96 Nva; 1.03 Arg; 1.07 Pro. Example 4 N-Ac-D-lie-Thr-Gin-lie-Arg-ProNHCH ^ CH ^ The desired product was prepared by replacing Fmoc-Nva in Example i with Fmoc-Gln (Trt). After processing, the crude peptide was purified by HPLC, using a C-18 column and solvent mixture for 50 minutes, on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). The crude fraction was freeze-dried to produce Ile-Thi > Gln-Ile-Arg-PrOHNHCH2CH3 as a trifluoroacetate; Rt == 1 79 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 〇i% TFA)); MS (ESI) m / e 796 (M + H) +; amino acid analysis: 2.05 Iie; 〇44

Thr »0.94 Glu, 1.02 Arg * 0.99 Pro ° Example 5

NjLAc ^ D.aIle > Ser-Ser ^ Ile > Arg-ProNHCH1rR3 k The product is prepared by replacing Fmoc-D-Iie with Fmoc-D-alle, and replacing Fmoc-Thr (0-tBu) with Fmoc-Ser (CMBu). And Fmoc-Nva, in Example i. After the treatment ', the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture -38- (32) 200302833, and the substance change history was 50 minutes (/ π I (0.01% TFA)). Pure fractions can be freeze-dried to produce N. Wang Feng N-Ac-D-alle-Ser-Ser-Ile-Arg-ProNHCi ^ CH3 'Trifluoroacetate; production scale 39 minutes (gradient change 10 minutes By 20 / 0-80% acetonitrile / water (containing 0.001% TFA)); ms (2) m / e 74i (M + ΗΓ; amino acid analysis: 2.13 Ile; 〇48 —; ι 〇2 Heart; 1.04 Pro 〇 ± J ^ L6 N-Ac-D-alle-TJiL-SerJLI ^^. ProNHppTi Preparation of the desired product is to replace Fmoc-D-Ile in Example i with Fm0C-D-aIle, and Fm〇C -Ser (0-tBii) replaced Fmoc-Nva. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent mixture, and the change was performed over 50 minutes at 5% -100% acetonitrile / water ( Contains 〇〇〇〇 / 〇TFA). Pure fractions are cold; East drying can generate N-AdaIle-ThpSe: r_Ile_Ai * g • PfoNHCH ^ H3 'is trifluoroacetate; Rt = 173 minutes (gradient change history 10 minutes' from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 755 (M + H) +; amino acid analysis: 2.10ne; 〇49 Thr; 〇21 Ser; 104 Arg; 1.02 Pro 0 N > Ac ~ D-ane > TYr-NvaIT [e.Arg.proNHCH? CH1 Preparation of desired product Fmoc-D-aiie was used to replace Fmoc-D-Ile, and Fmoc-Tyir (O-tBu) was used to replace Fmoc-Thr (CMBu) in Example 1. After processing, the crude peptide was purified by HPLC using a C -1 8-column And solvent mixture for 50 minutes, on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure flow typhoid / East drying can produce N-Ac-D-alle-Tyr- Nva-Ile-Arg · -39. 200302833

(33)

ProNHCHWH3, trifluoroacetate; Rt = 2.89 minutes (gradient change over 10 minutes' from 20% -80% acetonitrile / water (containing 0.01% tfa)); MS (ESI) m / e 829 (M + H) +; amino acid analysis: 2.06 Ile; 0.99 Tyr; 1.03 Nva; 1.01

Arg; 1 · 00 Pro ο Example i

NjiAc-D-alle-Ser ^ XhMle-Arg-ProNHCH ^ CHi The desired product is prepared by replacing Fmoc-D-Ile of Example 1 with Fmoc-D-alle, and Fmoc-Ser (O-tBu) replacing Fmoc-Thr (O -tBu) and Fmoc-Thr (O-tBu) replace Fmoc-Nva. After processing, the crude peptide was purified by HPLC, using a C-18 column and solvent mixture for 50 minutes, on a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions are cold; dry in the east can produce N-Ac-D-alle-Ser-Thr-Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate; Rt = 1.40 minutes (gradient change history 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 755 (M + H) +; amino acid analysis: 2.10 lie; 0.19 Ser; 0.52 Thr; 1.02 Arg 1 · 01 Pro 〇 Example 9 N- (6-MeNic) -D-Ile-Thr-Nva-Ile > Arg-ProNHCH1CH1 The desired product was prepared by replacing the acetic acid of Example 1 with 6-methylnicotinic acid. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent mixture for 50 minutes, on a gradient of 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-(6-Me -nicotinylfluorenyl) -D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3, showing trifluoroacetate; Rt = 1.96 minutes (gradient change history 10 Minutes, from 20% -80% acetonitrile / water (with 0.01% TFA)); MS (ESI) m / e 844 (M + H) +; amino acid analysis: 2.06 -40- 200302833 (34) lie ; 0.50 Thr; 1.02 Nva; 1.04 Arg; 〇99 Pro 〇 Example 1Q_ N- Ac.D.Pro_Thr.Nva_Ile-Arg-ProjsJHCH, CH7 The preparation of the desired product is Fmoc-D-Pro instead of Fmoc of Example i -D-Ile. After treatment, the crude peptide was purified by HPLC using a c-18 column and the solvent mixture for 50 minutes on a gradient from 5% to 100% acetonitrile / water (containing 0.010 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = i 62 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 751 (M + H) +; amino acid analysis: 1.01 Ile; 49 Thr; 0.98 Nva; 1.00 Arg; 2.08 Pro ο Example 1 1 N-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNTffr ^ / fj H The desired product was prepared by replacing Fmoc-ne of Example 1 with Fmoc-Pro. After processing, the 'crude peptide was purified by HPLC' using a C-18 column and solvent mixture for 50 minutes on a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Nva-PiO-Arg-ProNHCI ^ CH3, which is trifluoroacetate; Rt = 1 49 minutes (gradient change over 10 minutes, from 20% -80 % Acetonitrile / water (containing 0.001 / 〇1ΤΑ)); MS (ESI) m / e 751 (M + ΗΓ; amino acid analysis: Ile; 〇54 Tlu; i ⑻ Νν &; 1.00 Arg; 2.03 Pro 0

Example U

HcUe-Thr-Nva-Il ^^ p-proNHCl ^ r ^ The desired product was prepared by using FmCD-PrO-Sieber ethylamidoamine resin instead of 200302833 (35) Fmoc-Pro-Sieber ethyl of Example 1 Lamine. After treatment, the crude peptide was purified by HPLC using a c-18 column and solvent mixture over a period of 50 minutes on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be cold-rolled and dried to produce N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH2CH3, which is trifluoroacetate; R cadaver 2.59 minutes (gradient change over 10 minutes, from 20% -80 % Eyre cream / water (containing 0.001 / 10/0 TFA)); MS (ESI) m / e 767 (M + H) +; amino acid analysis: 2.04 lie; 0.47 Thr; 1.02 Nva; 1.06 Arg 1.01 Pro. Example 1 3 N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH1CH1 The desired product was prepared by replacing Fmoc-Ter (O-tBu) and Fmoc-Thr of Example 1 with Fmoc-Ser (O-tBu), and Fmoc- Gln (Trt) replaces Fmoc-Nva. After treatment, the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture, and the gradient was changed from 5% to 100% acetonitrile / water (containing 0.01% TFA) over a period of 50 minutes. Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Ser-Gln-Ile_Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 1.28 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water ( Contains 0.01% TFA)); MS (ESI) m / e 782 (M + H) +; amino acid analysis 2.07 lie; 0.22 Ser; 0.97 Glu; 1.03 Arg; 1.04 Pro o Example 1 4 N-Ac- D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH, the desired product was prepared by replacing Fmoc-Nva of Example 1 with Fmoc-Ser (O-tBu), and Fmoc-D-Ala-Sieber amine The resin replaced Fmoc-Pro-Sieber Ethylamine Resin 'and was coupled with Fmoc-Pro in Example 1 before coupling with Fmoc-Arg (Pmc). After treatment, the crude peptide was purified by HPLC using C-1 8 -42- 200302833

(36) The column and the solvent mixture were changed for 50 minutes in a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH2, which is trifluoroacetate; Rt = 1.35 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 798 (M + H) +; amino acid analysis: 2.02 lie; 0.43 Thr; 0.24 Ser; 1.01 Arg; 0 · 99 Pro 1.02 Ala. Example 1 5 N-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH, the preparation of the desired product is to replace Fmoc-Thr (O-tBu) and Fmoc with Fmoc-Ser (O-tBu) -D-Ala-Sieber amidine resin replaced Fmoc-Pro-Sieber ethylamidine resin, and coupled with Fmoc-Arg (Pmc) in Example 1 before coupling with Fmoc-Pro. After processing the crude peptide, it was purified by HPLC using a C-18 column and solvent mixture for 50 minutes at a gradient of 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce

Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH2, as trifluoroacetate; Rt = 2.60 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA) ); MS (ESI) m / e 796 (M + H) +; amino acid analysis 2.03 Ile; 019 Ser; 1.00 Nva; 1.001 Arg; 0.998 Pro; 1.02 Ala. Example 1 6 N-Ac-D-Ile-Ser-GIn-D-Ile-Arg-ProNHCH ^ CHi The desired product was prepared by replacing Fmoc-Sei: (0-tBi〇 in Example 1

Fmoc-Thr (O-tBu), Fmoc-Gln (Trt) replaces Fmoc-Nva 'and Fmoc-D-Ile replaces Fmoc-Ile. After processing, the crude peptide was purified by HPLC using a c-1 8 column and solvent mixture for 50 minutes, and 0.01% in 5% -100% acetonitrile / water (containing -43- 200302833 "One" (37) TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 1.28 minutes (gradient change history is 10 minutes, from 20%- 80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 782 (M + H) +; amino acid analysis: 2.05 lie; 0.29 Ser; 1.02 Gin; 1.03 Arg; 1.02 Pro. Example 1 7 N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH ^ CH: For the preparation of the desired product, Fmoc-Gln (Trt) was used instead of Fmoc-Thr (O-tBu) of Example 1. After treatment, the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture for 50 minutes, on a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 1.45 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.00% TFA)); MS (ESI) m / e 794 (M + H) +; amino acid analysis: 2.10 lie; 1.01 Glu; 1.02 Nva; 0.999 Arg; 0.98 Pro ο Example 1 8 N ^ Ac-D-Ilc-Thr-Nv ^ -Ilc-Arg-Pro-D ^ AldNH? The desired product is prepared by replacing Fmoc-D-Ala-SieberS & amine resin with Fmoc-Pro of Example 1. -Sieber ethylamidamine resin, and coupled with Fmoc-Pro before coupling with Fmoc-Arg (Pmc). After processing, the crude peptide was purified by HPLC using a C.18 column and a solvent mixture over a 50 minute gradient over a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Nva-Ile-Arg-PrO-D-AlaNH2, which is a trifluoroacid salt; Rt = 2.10 minutes (gradient change over 10 minutes, from 20 % _80% acetonitrile / -44- 200302833 (38) water (containing 0.01% TFA)); MS (ESI) m / e 10 (M + H) +; amino acid analysis: 2.10 Ile; 0.49 Thr; 0 99 Nva; 1.00 Arg; 0.98 Pr0; 1.02 Ala. Example 19 9 N-Ac-D-Leu-Thr-Nva-Ile-Arg-ProNHdPjj ^ Fmoc-D-Leu was used to replace Fmoc-D-❿ in Example i. After treatment, the crude peptide was purified by HPLC using a C8 column and a solvent mixture for 50 minutes at a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N_AdLeu 矸 hr_Nva_ Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate; Rt = 2 57 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.0%). 1% TFA)); ms (esi) m / e 767 (M + H glutamic acid analysis: Leu; 〇51 Thr; 〇〇_; 1.04 lie; 1.02 Arg; 1.04 Pro. What is the case? And N ^ Ac-D-Leu-Ser-NvazIle ^ Arg-ProNHrH1rR1 The preparation of the desired product is to replace Fm〇c_D ne with Fm〇c_D Leu and

Fmoc-Ser (0-tBu) replaces Fmoc_Thr (0_tBu) in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent mixture, and the gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure cold; dry and dry in the east can generate N_Ac_D_Leu_Ser_Nva_ne_Arg_

ProMHChCH3 'is trifluoroacetate; Rt = 25 minutes (gradient change over 10 minutes, from 20% -80% ethane / water (containing 〇i% tfa)); Ms (Esi) m / e 753 (M + H glutamic acid analysis: 101Leu; 〇23Ser: 〇3_: 1.02 lie; 1.02 Arg; 〇99 Pro 〇-45. 200302833 (39) The preparation of the desired product is Fmoc-D-Leii Replace Fmoc-ne of Example i. After treatment, the crude peptide was purified by HPLC using a c-18f column and a solvent mixture. The material was changed for 50 minutes at 5% to 100% acetonitrile / water (containing 0.01% tfa). ) Gradient. Pure fraction cold / east drying can produce N-Ac-D-Ile-Thr-Nva-D-Leu -Arg-PrOHNHCH2CH3 'as trifluoroacid salt; 2.71 minutes (gradient change Over 10 minutes' by 20% -80 ° / 〇acetonitrile / water (containing 0.001 / .TFA)); MS (ESI) m / e 767 (M + H) +; amino acid analysis: 1.02 Ile; 〇55 Thr; i 〇1 Nva; 1.00 Leu; 1.01 Arg; 1.0. Pro. Example 27 N-Ac-D-Ile >, Thr > NyarD ^ j ^ LArg.pr〇NHCH ^ CH ^ Product desired It was prepared by replacing Fmoc_Ile of Example i with FmooD-Ile. After processing, the crude peptide was purified by HPLC using a C-1 8 column and solvent mixture. After 50 minutes, it is on a gradient of 5% -100% acetonitrile / water (containing 0.001% TFA). Pure fractions are cold; dry in the east can generate N-Ac-D-Ile-Thr * -Nva -D-Ile ~ Ai * g -ProNHCH2CH3, as trifluoroacetate; Rt = 2.61 minutes (gradient change over 10 minutes from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 767 (M + H) +; Amino acid analysis: 2.04 lie; 0.42 Thr; 1.02 Nva; 1.00 Arg; 1.03 Pro 0 Example 23 N > Ac-D-Ile-Tvr-Nva-D > Ile-Arg-ProNHCH1CH1 The desired product was prepared by replacing Fmoc-Tyr (O-tBu) with Fmoc-Tyr (O-tBu) in Example 1, and Fmoc-D-lie instead of Fmoc-lie. After processing, the crude peptide was analyzed by HPLC Purification, using C-1 8 column and solvent mixture, change history • 46- 200302833

(40) 50 minutes on a gradient of 5% to 100% acetonitrile / water (containing 0.01 / 0.0 TFA). Pure fractions are freeze-dried to produce N-Ac-D-Ile-Tyir-Nva-D-Ile-Arg-Pi :. · NHCF ^ CH3, as difluoroacetate; Rt = 2.94 minutes (gradient change time 10 minutes-minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 829 (M + H), amino acid analysis2.09 lie; 0.96 Tyr; 1.03 Nva; 0.97 Arg; 1.001 Pro 0 Example 24

I ^ Ac-D-Ile-Thr ^ r ^ D.iie-Arg ^ ProNHrH1rH1 The desired product was prepared by replacing Fmoc-Nva with Fmoc-Trp (Boc), and replacing Fmoc-Ile with Fmoc-D-Ile in Example 1. . After processing, the "crude peptide was purified by HPLC" using a C-18 column and a solvent mixture, which were changed for 50 minutes over a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate; Rt = 3.17 minutes (gradient change over 10 minutes, from 2 % -80% acetonitrile / water (containing 0.0001 / 0 TFA)); MS (ESI) m / e 854 (M + H) +. Example 2 5 ijiAc-D'alle-Thr-Trp-Ile-Arg-ProNHCH ^ CF ^ Preparation of the desired product is to replace Fmoc-D-Ile with Fmoc-D-aIle and Fmoc-Nva to Fmoc-Tfp (Boc)于 例 1。 In Example 1. After treatment, the crude peptide was purified by HPLC using a c-8 column and a solvent mixture, which were changed over a period of 50 minutes on a gradient of 5%] 00% acetonitrile / water (containing 0.01% TFA). Pure fractions can be cold-rolled and dried to form N-Ac-D-aIle-Thr-Trp-Ile-Arg-PrOHNHCH2CH3, which is trill acetate; Ri = 3 06 minutes (gradient change over 10 minutes, from 2 % _80 / 0 acetonitrile / water (containing 0 01 // TFA)); MS (ESI) m / e 854 (M + H) +. -47- 200302833

(41) Example 2 6 N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-zUaNH: Preparation of the desired product is to replace Fmoc-Nva with Fmoc-Trp (Boc) and Fmoc-D -Ala-Sieber acid amine resin replaces Fmoc-Pro-Sieber ethyl amine resin 'and add coupling with Fmoc-Pro before coupling with Fmoc-Arg (Pmc), as in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and solvent mixture over a period of 50 minutes on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH2 5 as trifluoroacetate; Rt = 2.97 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 897 (M + H) +. Example 27 N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-LvsfAcINH: The desired product was prepared by replacing Fmoc-Pro-Sieber with Fmoc-D-Lys (Ac) -Sieber amine resin Based on ammonium amine resin and coupled with Fmoc-Pro before coupling with Fmoc-Arg (Pmc), as in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and solvent mixture over a period of 50 minutes on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions are cold / east-dried to produce N-Ac-D-Ile-Thr-Nva-Ile-Arg-PrO-D-Lys (Ac) NH2 'three-speaking acetate; 32 minutes (gradient change calendar 1 〇minutes, from 20% -80% acetonitrile / water (containing 〇〇〇 / 。TFA)); milk (ESI) m / e 909 (M + H) + 〇f Example 2 8 N two Ac-D-Ile ^ jQy-Glii-Ile-Arg-Pro-D-AlaNH, 200302833 (42) The preparation of the desired product is to replace Fmoc-Nva with Fmoc-Gln (Trt) and Fmoc-Pro with Fmoc-D-Ala-Sieber6i amine resin -Sieber ethylammonium resin, coupled with Fmoc-Pro before coupling with Fmoc-Arg (Pmc). After treatment, the crude peptide was purified by HPLC using a C-18 column and solvent mixture for 50 minutes at a gradient of 5% to 100% acetonitrile / water (containing 0.001 0/0 TFA). Pure fractions freeze-dried to produce N-Ac-D-Ile-Thr-

Gln-Ile-Arg-Pro-D-AlaNH2, as a trifluoroacetate salt; Rt = 1.34 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.1% TFA)); MS (ESI) m / e 839 (M + H) +. Example 2 9

N-Ac-D-Ile-Thr-Nva-D-Lvs (AcVArg-PrOHNHCHOC: H? The desired product was prepared by replacing Fmoc-Ile with Fmoc-D-Lys (Ac) in Example 1. After treatment. The crude peptide was purified by HPLC using a C.18 column and solvent mixture for 50 minutes at a gradient of 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried. Generates N-Ac-D-Ile-Thr-Nva-D

-Lys (Ac) -Arg-ProNHCH2CH3, as trifluoroacetate; Rt = i. 58 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 824 (M + H) +. Example 3 0 N-Ac-D-Ile-Thr ^ Nva-LvsfAcVArg-ProNHCH ^ CH ^ The desired product was prepared by replacing Fmoc-Ile with Fmoc-Lys (Ac), as in Example 1. After treatment, the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture, and changed for 50 minutes on a gradient of 5% to 100% acetonitrile / water (containing 0.01% / 0 TFA). Pure fractions freeze-dried to produce N-Ac-D-Ile-Thr-Nva- -49- 200302833 (43)

Lys (Ac) -Arg-PrOHNHCH2CH3, as a trifluoroacetate; Rt = 1.51 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (containing 0.001% tfa)) ; MS (ESI) m / e 824 (M + H) +. Example 3 1 • N-Ac-D-Ile-LvsiAcVNva-Ile-Arg-ProNHnr ^

The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Lys (Ac) in Example 1. After the treatment, the crude peptide was purified by HPLC using a c-18 column and solvent mixture for 50 minutes on a gradient of 5% to 10d% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Lys (Ac) -Nva-Ile-Ai * g-PrOHNHCH2CH3, showing trifluoroacetate; Rt = 2.51 minutes (gradient change over 10 minutes, 20% -80% acetonitrile / water (containing 0.01% / ο TFA)); MS (ESI) m / e 836 (M + H) +. Example 3 2 N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH ^ C%

The desired product was prepared by replacing Fmoc-His (Trt) with Fmoc-Arg (Pmc) in Example 1. After treatment, the crude product was purified by HPLC using a C-18 column and a solvent mixture for 50 minutes at a gradient of 5%-100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to produce N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH2CH3, which was trifluoroacetate; Rt = 2.45 minutes (gradient change over 10 minutes, from 20%-80% % Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 748 (M + H) +. Example 3 3 N-Ac-D-Hphe-Thr-Nva-Ile-Arp-ProNHCHiCHi The desired product was prepared by replacing Fmoc- -50- 200302833 of Example 1 with Fmoc-D-Hphe (44)

D-Ile. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent mixture for 50 minutes on a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.12 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% tfa)); MS (ESI) m / e 815 (M + H) +. Example 3 4 N-Ac-D-4ClPhe-Thr-Nva-Ile-Arg-PrNTmcHq The desired product is prepared by replacing Fmoc-D-Ile with Fmoc-D-4ClPhe, as in Example 1. After treatment, the crude peptide was purified by HPLC using a C-8 column and solvent mixture for 50 minutes at a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-4C1Phe · Thr-Nva-Ile-Arg-ProNHCH2CH3 1 as trifluoroacetate; Rt = 3.28 minutes (gradient change over 10 minutes, from 20% -8 0% Acetonitrile / water (containing 0.001% TFA)); MS (ESI) m / e 835 (M + H) + 〇 Example 3 5 N-Ac-D-Pen-Thr_Nva-Ile · Αγ2 · ΡγοΝΗΓΗ, ΓΤΤ: Request The product was prepared by replacing Fmoc-D-Ile with FmCD-Pen (Trt) in Example 1. After the treatment, the crude peptide was purified by HPLC using a C-8 column and solvent mixture for 50 minutes at a gradient of 5% to 100% acetonitrile / water (containing 10,000 / 0 TFA). Pure fraction cold / east drying can produce N-Ac-D-Pen-Thr-Nva · Ile-Arg-ProNHCH2CH3, showing trifluoroacetate; Rt == 2.41 minutes % Acetonitrile / water (containing 0.01% TFA)); ms (esi) m / e 785 (M + H) +. 200302833

(45) Example 36 6 N-Ac-D-Ile-Met >Nva-Ile-Arg-PrOHNHCH7CH; The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Met in Example 1. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent mixture, and the gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.000 / 0 TFA). Pure fractions were freeze-dried to produce N-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH2CH3 as trifluoroacetate; Rt = 3.11 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) τη / e 797 (M + H) +. Example 3 7 N-Ac-D-Ile-AsD-Nva-Ile-Arg> ProNHCH1CH1 The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Asp (O-tBu) in Example 1. After processing, the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture, and changed for 50 minutes on a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Asp_Nva-iie-Ai: g-Pi * oNHCH2CH3, which is trifluoroacetate;

Rt = 2.32 minutes (gradient change over 10 minutes, from 20% · 80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 781 (M + H) +. Example 3 8 H-Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH ^ CHi Preparation of the desired product is to replace Fmoc-Ai * g (Pmc) with Fmoc-3-Pal in Example 1 after treatment The crude peptide was purified by HPLC using a C-18 column and a solvent / quinone compound. The gradient was changed over a period of 50 minutes at a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Nva-Ile- -52- 200302833 (46) 3-Pal-ProNHCH2CH3, showing trifluoroacetate; Rt = 2.45 minutes (gradient change over 10 minutes By 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 759 (M + H) +. Example 3 9 N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH ^ CH ^ The desired product was prepared by replacing Fmoc-Arg (Pmc) with Fmoc-D-Arg (Pmc) in Example 1. After processing, the crude peptide was purified by HPLC, using a C-18 column and a solvent mixture, which were changed for 50 minutes on a gradient of 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.71 minutes (gradient change over 10 minutes, from 20% -80% Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 767 (M + H) + 〇 Example 40 N-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH ^ rH? Want product It was prepared by replacing Fmoc-Nva with Fmoc-Nle in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent mixture on a gradient from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Nle-Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate; Rt = 2.82 minutes (gradient change over 10 minutes, from 20% -80% Acetonitrile / water (containing 0.001 / 0 TFA)); MS (ESI) m / e 781 (M + H) +. Example 4 1 Ν-Ac-D-Ile-Thr-D-Gln-Ile-Arg-ProNHrHfHi The desired product was prepared by replacing Fmoc-Nva of Example 1 with FmOC-D-Gln (Trt). After processing, the crude peptide was purified by HPLC using a C-1 8 column and • 53- 200302833

(47) The solvent mixture was changed over a period of 50 minutes in a gradient of 5% to 100% acetonitrile / water (containing 0.001 TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile_ThpD_ Gln-Ile-Arg-ProNHCE ^ CH; 'Trifluoroacetate; Rt = i 60 minutes (gradient change over 10 minutes') from 20% -80% Bet / water (containing 0.01% butyl pA >) · MS (ESI) m / e 796 (M + H) +. Example 42 N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH ^ rTj ^ The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-alloThr (O-tBu) and Fmoc-Ile by Fmoc-Pro, after Example 1. After processing, the crude peptide was purified by HPLC using C- 18-column column and solvent mixture were changed over 50 minutes in a gradient of 5%-100% acetonitrile / water (containing 0.000 / 〇 丁丁). Pure fractions were cold-beam dried to produce N-AoD- Ile.alloThir.Nva.Pro.Arg-Pi ·. NHCHzCH3 'Main difluoroacetate fe: salt; Rt = i. 52 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (containing 〇〇. 1% TFA)); MS (ESI) m / e 751 (M + H) +. N-Ac-Ihj ^ Nva-I.le-Aj ^^^ g ^ j ^^ cHy SEq id NO: 4) in In a reaction container of the Rainin peptide synthesizer, Fmoc-PrO-Sieber ethylammonium resin (0.25 g, 0.4 mmol / g loading) was charged. The resin was solvated with DMF, and the amino acid was coupled sequentially in accordance with the following synthesis cycle: (1) Washing the strips with 0 "? For 3 \ 1.5 minutes; (2) Deprotection with 20% hexahydropyridine for 2 x 15 minutes; ( 3) Wash with DMF for 6x3 minutes; (4) Add amino acid; -54- 200302833 (48) (5) Activate amino acid with 0.4M HBTU / NMM and couple; (6) 3χ 1.5 minutes DMF wash. Protected amino acids are coupled to the resin in the following order: Protected amino acid coupling time Fmoc-Arg (Pmc) 30 minutes Fmoc-Ile 30 minutes Fmoc-Nva 30 minutes Fmoc-Thr (O-tBu) 30 minutes acetic acid 30 minutes Once synthesis was completed, the peptide was dissociated from the resin using a mixture of TFA / anisole / water (95: 25 · 25) for 3 hours. The peptide solution was concentrated under vacuum, then precipitated with diethyl ether and filtered Collected. The crude peptide was purified by HPLC using a C-18 column and the solvent mixture was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to produce N. -Ac-Thr-Nva-Ile-Arg-ProNHCH2CH3, as trifluoroacetate; minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 654 (M + H) +; amino acid analysis: 0 49 Thr; 1.02 Nva; 0.99 lie; 1.01 Arg; 1.04 Pro. Example 44 N Ac alloThr-Nva- He-Arg-ProNHCH ^ CH ^ SEP ID NO: 5) Fmoc-alloThr (O-tBu) was used to replace Fmoc-Thr (O-tBu) in Example 43. The crude peptide was purified by HPLC after processing. Using a C -18 column and a solvent mixture, the gradient was changed on a gradient of 5% -100% acetonitrile / water (containing 0.00% /. TFA) for 50 minutes. Pure fractions were freeze-dried to produce -55- 200302833 (49)

N-Ac-alloThr-Nva-Ile-Arg-ProNHCH2CH3 »Trifluoroacetate; R t = 1.07 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 654 (M + H) +; amino acid analysis: 0.57 Thr; 1.00 Nva; 1.02 lie; 0.98 Arg; 1.04 Pro 〇 Example 4 5

Ac-Thr:, Gl, n-Ile-Arg > ProNHCH ^ H ^ πη ID NO: 6) In the preparation of the desired product, Fmoc-Gln (Trt) was used in place of Fmoc-Nva in Example 43. After treatment, the peptide was purified by HPLC, using a c-8 column and a solvent system, and the gradient was changed from 5% to 100% acetonitrile / water (containing 0.01% TFA) over 50 minutes & Cold / East drying of fractions can produce N-Ac-Thr-Gln-Ile-Arg-Pro NHCHzCH3 'trifluoroacetate; Rt = 10 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 0.001% TFA)); MS (ESI) 683.5 (M + H) +; amino acid analysis: 0.49 Thr; 101 Glu; 〇% ne; i 〇5 Arg; 1.00 Pro 0 Lesson 4 6

Nr (6-MeNic) -Thr ~ Nva> Ile ^ Arg.prONHCHir: HirSFn id NO: 7) The preparation of the desired product was replaced by 6, methyl nicotinic acid in Example 43. After treatment, the crude skin was purified by HPLC using a C-18 column and solvent system 'on a gradient of 5% to 100% acetonitrile / water (containing 0.001 / 0 TFA) over 50 minutes. Pure fractions are cold; dry in the east to produce N- (6MeNic) -Thr-Nva-Ile-Arg-ProNHCH2CH3, as a difluoroacrylate; = 〇94 minutes (gradient change over 10 minutes' from 20% -80% Acetonitrile / water (containing 0.001% TFA)); ms (ESI) m / e 731.5 (M + H), amino acid analysis · 〇51 Thr; i 〇〇Nva;} 〇1 Ile; 1 · 10 Arg; 1.03 Pro 〇200302833 (50)

Example 47 N-Ac-Ser-Ser-Ile-Arg-ProNHCH, CHJSEO ID NO: 8) Fmoc-Ser (O-tBu) was used instead of Fmoc-Thr (O-tBu), and Fmoc-Nva was prepared for the desired product. , In Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed from a gradient of 5% to 100% acetonitrile / water (containing 0.01% TFA) over a period of 50 minutes. Pure fractions can be freeze-dried to produce N-Ac-Ser'Ser-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.34 minutes (gradient change over 10 minutes, 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 628.3 (M + H) +; amino acid analysis: 0.43 Ser; 0.96 lie; 1.00 Arg; 1.04 Pro. Example 48

Ac-Thr-Ser-Ile-Arg-ProNHCH ^ H ^ SFO ID NO: 9) Fmoc-Ser (O-tBu) was used instead of Fmoc-Nva in the preparation of the desired product, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Ser-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.52 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water ( Contains 0.011 // TFA)); MS (ESI) m / e 642.3 (M + H) +; amino acid analysis: 0.55 Thr; 0.23 Ser; 0.96 lie; 0.98 Arg; 1 · 04 Pro.

Example 4 Q N-Ac-TyrrNva> IlezArg.Pro-D> A1aNH1 Preparation of the desired product is to replace Fmoc-Pro-Sieber ethylamine resin with Fmoc-D-Ala-Sieber ethylamine resin, and -Arg (Pmc) coupling-57- 200302833

(51) Ke, coupled with Fmoc-Pro, in Example 43. After the treatment, the crude peptide was purified by HPLC 'using a C-18 column and a solvent system with a gradient change of 50 minutes' from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to produce N-Ac-Thr-Nva-Ile-Arg-Pro-D-AlaNH2, which was trifluoroacetate; Rt = 3.94 minutes (gradient change over 10 minutes, from 20% -8 〇% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 697 · 3 (M + H) +; amino acid analysis: 0.56 Thr; 0.92 Nva; 0.97 Ile; 0.85 Arg 1.09 Pro; 1.09 Ala. tExample 50

NiAc-Thr-Nva-D.Ile .. Arg-ProNHCH1CH1 ‘The product is prepared by replacing Fmoc-Ile with Fmoc-D-Ile. After treatment, the crude peptide was purified by HPLC using a C-18 tube and solvent system. The gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to produce N-Ac-Thr-Nva-D-Ile-Arg-ProNHCH2CH3 as trifluoroacetate; Rt = 4 59 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 654.4 (M + H) +; amino acid analysis: 0.5 Thr; 0.84 Nva; 1.03 lie; 0.97 Arg; 1.01 Pro ο Example 51 N-Ac-Thr-NMeNva-ne-Arg-ProNHrf ^ CHJSEO ID NO: 10) The preparation of the desired product is to replace Fmoc-Nva with Fmoc-NMeNva, and use HATU as Example 43 Activator in Fmoc-NMeNva coupling. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Thr-NMeNva-Ile-Arg- -58- 200302833 (52)

ProNHCH2CH3, as trifluoroacetate; Ri = 4 305 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water (containing 〇〇〇〇 ／ 〇TFA)); MS (ESI) m / e 668.4 (M + H) +; Amino acid analysis: 0.22 Thr; 1.01 lie; 0.95 Arg; 1.03 Pro o N-Ac-Thr-Gln > Ile-Arg-Pro-n-A1 ^ NW1 It was prepared by replacing Fmoc-Nva with Fmoc-Gln (Tre), Fmoc-D-Ala-Sieber amine resin instead of Fmoc-PrO-Sieber ethylamine resin, and Fmoc-Arg (Pmc) ) Coupling with Fmoc-Pr0 before coupling. After the treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system, and the gradient was changed for 50 minutes from 5% .. 00% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Thr-Gln-Ile-Arg-

Pro-D-AlaNH2, trifluoroacetate; Rt = 3.375 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0 01〇 / 〇TFA)); MS (ESI) m / e726 · 4 (M + H), amino analysis: 0.51 Thr; 0.55 Glu; 0.96 lie; 0.82

Arg; 1.11 Pro; 1.12 Ala. Duplicate example 53 N-Ac-Tyr-Nva-.ne ^ Arg ^ PrgNHCH ^ H ^ sEQ iNO: 11) Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-Tyr (O-tBu)于 例 43。 In Example 43. After processing, the crude peptide was purified by HPLC using a c-18 column and a solvent system. The gradient was changed from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Tyr-Nva-Ile-Arg-Pro NHCH2CH3 King Difluoroacetate; Rt = 4.845 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water ( Contains 〇01〇 / 〇TFA)); MS (ESI) m / e • 59- 200302833

(53) 716.4 (M + H) +; Amino acid analysis: 〇94 Tyr; 〇85 Nva; 〇96 Ile;! 〇2 Arg; 1.02 Pro of Example 54 N ^ Ac ^ Ser-Glu-Ile ^ Arg-ProNHCH ^ H ^ SEO ID NO: 12) Fmoc-Ser (CMBu) replaced Fmoc-Thr (0-tBu), and Fmoc-Gln (Trt) replaced Fmoc-Nva. . After the treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system, and the gradient was changed for 50 minutes' from 5% to 100%. Acetonitrile / water (containing 0.001 /. TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-Glu-Ile-Arg-ProNHCH2CH3 as a trifluoroacetate salt; Rt = 3.377 minutes (gradient change over a period of 10 minutes, from 20% to 80 / 0acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 669.3 (M + H) +; amino acid analysis · 0.14 Ser; 0.79 Glu; 0.93 lie; 0.98 Arg; 1.04 Pro. Example 55] Ac-Thr-NvaJ.ys (Ac) -Arg-ProNHCH1rj ^ {^ Fn ID NO: 13) The desired product was prepared by replacing Fmoc-Ile with Fmoc-Lys (Ac), as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Lys (Ac ^ Arg-ProNHCHAH3, which is trifluoroacetate; Rt = 3 556 minutes (gradient change over 10 minutes, from 20% -8 0% acetonitrile / Water (containing 0.01% TFA)); Ms (ESI) m / e 711.4 (M + Η) +; amino acid analysis 0.52 Thr; 0.84 Nva; 1.02 Lys; 0.97 Arg; 1.01 Pro 〇

Ii: Ac-Ser-Thr-Ile-^! R: Pro ^ || £ || ^^ (sEQ ID NO: 14) 200302833 (54) Fmoc-Ser (CMBu) is used instead of Fmoc-Thr for the preparation of the desired product (O-tBu), and Fmoc-Thr (O-tBu) replaced FmOC-Nva in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.10 / 0 TFA). Pure fractions are freeze-dried to produce N-Ac-Ser-Thr-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.388 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water (Containing 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 642.3 (M + H) +; amino acid analysis: 0.43 Thr; 0.19 Ser; 0.98 lie; 0.97 Arg; 1.06 Pro 0 Example 57 N-Ac-Tyr-Nva-D-Ile-Arg-PrQNHCH1rN1 The desired product is prepared by replacing Fmoc-Tyr (O-tBu) with Fmoc-Thr (O-tBu), and Fmoc-D-Ile replacing Fmoc-Ile,于 例 43。 In Example 43. After the treatment, the crude peptide was purified by HPLC 'using a C-18 column and a solvent system, and the gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 100/0 tfA). Pure " Watt / j cold; East drying can generate N-Ac-Tyr-Nva-D-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 5.103 minutes (gradient change over 10 minutes, from 20%- 80% acetonitrile / water (containing 0.005 / 0 TFA)); MS (ESI) m / e 716.4 (M + H) +; amino acid analysis: 0.94 Tyr; 0.85 NVa; 1.00 lie; 1.04

Arg; 1.02 Pro o Example 58 ID NO: 15) Fmoc-NMeGlu (t-Bu) was used instead of Fmoc-Thr (O-tBu), and HATU was used as Fmoc-NMeGlu (t-Bu) in Example 43 ) Coupling activator in 200302833. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed for 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-NMeGlu-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 4.51 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 〇 〇1% TFA)); MS (ESI) m / e 696.4 (M + H) + 0 Example 59

N-Ac-Met-Nva-Ile-Arg ^ ProNHCH ^ CH ^ SEO ID NO: 16) Fmoc-Met was used instead of Fmoc-Thr (O-tBu) in the preparation of the desired product, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Met-Nva-Ile-Arg-ProNHCH2CH3, which is trilactate; Rt = 4.913 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01 % TFA)); MS (ESI) m / e 684.4 (M + H) +; amino acid analysis: 0.91 Met; 0.90 Nva; 1.01 lie; 1.03 Arg; 1.05 Pro o Example 6 0

N-Ac-LvsiAcVNva-Ile-Arg-ProNHCHiCHySEO ID NO: 17) The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Lys (Ac) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed from 5% to 100% acetonitrile / water (containing 0.01% TFA) over a 50-minute gradient. Pure fractions can be freeze-dried to produce N-Ac-Lys (Ac) · Nva-Ile-Arg-Pi: oNHCH2CH3 as trifluoroacetate; Rt = 4.328 minutes (gradient change over 10 minutes, from 20% -80% Acetonitrile / water (containing 0.01% TFA)); • 62-200302833 (56) MS (ESI) m / e 723.5 (M + H) +; amino acid analysis: ι · 2〇Lys; 0.89 Nva; 1.02 lie; 0.97 Arg; 1.00 Pro. Example 61 N-Ac-Gln-Nva-Ile-ArR-ProNHCH ^ rH ^ SFO ID NO: 18) The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Gln (Trt) in Example 43. After delivery, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to produce N-Ac-Gln-Nva-Ile-Arg-ProNHCH2CH3 as trifluoroacetate; Rt = 3.993 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water ( Contains 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 681.4 (M + H) +; amino acid analysis: 1.01 Glu; 0.90 Nva; 1.01 lie; 0.97 Arg; 1.01 Pro o Example 62 N -Ac-alloThr-Ser-Ile-Arg-ProNHCH ^ CH ^ SFO ID NO: 19) Fmoc-alloThr (O-tBu) instead of Fmoc-Thr (O-tBu) and Fmoc-Ser (O -tBu) replaces Fmoc-Nva in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.10 / 0 TFA). Pure fractions are cold and dried in the east to produce N-Ac-alloThr-Ser-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.507 minutes (gradient change over 10 minutes, from 20% -8 0% acetonitrile / water (Contains 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 642.3 (M + H) +; amino acid analysis 0.40 Thr; 0.09 Ser; 1.00 lie; 0.96 Arg; 1 05 Pro ο Example 6 3 -63- 200302833 (57) N-Ac> Thr-Nva ^ T1e.Arg.D.pr〇NHCH1CH1 The preparation of the desired product is to replace Fmoc with Dmoc-D-Pro-Sieber ethylammonium resin -Pro-Sieber amine resin, in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100 ° /. Acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Ile-Ai * gD-ProNHCH2CH3, which is trifluoroacetate; Rt = 4.232 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (Contains 0.01% TFA)); MS (ESI) m / e 654.3 (M + H) +; amino acid analysis: 0.39 Thr; 0.91 Nva; 1.01 Ile; 0.98 Arg; 1.01 Pro. Example 64 N ^ Ac ^ alloThr ^ Nva-Pro-Arg-ProNHCH ^ CH ^ SRO ID NO: 20) Fmoc-alloThr (O-tBu) was used instead of Fmoc-Thr (〇-tBu) 'and Fmoc to prepare the desired product. -Pro replaces Fmoc-Ile, in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient of 50/0 to 100/50. Acetonitrile / water (containing 0.001 / 〇 TFA). Pure fractions can be freeze-dried to produce N-Ac-alloThr-Nva-Pro-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.586 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 638.3 (M + H) +; amino acid analysis: 043 Thr; 0.88 Nva; 1.00 Arg; 2.00 Pro. Example 65 H ^ Ac-Trp-Nva-Ile-Arg-ProNHCH2 ^ CMjU (S; FQ ID NO: 21) The desired product was prepared by replacing Fmoc-Trp (Boc) with Fmoc-Thr (O-tBu) in Example 43 . After processing, the crude peptide was purified by HPLC, using a C-18 column and a dropping system, and the gradient was changed over 50 minutes.

(58) 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Trp-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 5.861 minutes (gradient change calendar; 10 minutes, 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 739.5 (Μ + Η) +; amino acid analysis: 0.22 Trp; 0.90 Nva; 0.95 lie; 1.03 Arg; 1.03 Pro 0 Examples 66 N-Ac-Thr-Nle-Ile-Arg-ProNHCH ^ CHdSEO ID NO: 22) Fmoc-Nle was used instead of Fmoc-Nva in the preparation of the desired product, as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.005 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-Th, Nle-Ile-Arg-ProNHC & CH3, which is trifluoroacetate; Rt = 4 544 minutes (gradient change over 10 minutes, from 20% -8 0% acetonitrile / Water (containing 0.001% TFA)); MS (ESI) m / e 666.4 (M + H) +; amino acid analysis: 〇41 Thr; 〇1 Ile; 〇99 Arg; 〇〇Pro o N: 4g:! hr-D-ij ^ jj ^ Arg_pr_NHCHiC The preparation of the desired product is based on Fmoc-Nva, as in Example 43. After the treatment, the crude peptide was purified by HPLC using a dagger 18 column and a solvent system. The gradient was changed over 50 minutes from 5% "00% acetonitrile / water (containing 0.01% TFA). Pure fractions were cold; Generate N-Ac-Thr-D ^ va-iie-Arg-

ProNHCH2CH3 'king difluoroacetate; ι = 4.373 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water (containing 0.01% TFA)); Ms (esi) _ 654.4 (M + (H), amino acid analysis: 0.40 Thr; 〇89 Nva; i 〇3 Ile; 098-65. 200302833 (59)

Arg; 1.00 Pro 0 Example 68 N-Ac-Thr-Trp-Ile-Arg-Pro-D ^ AInNH ^ The preparation of the desired product is to replace Fmoc-Pro-Sieber ethyl with Fmoc-D-Ala-Sieber Amidine, and Fmoc-Trp (Boc) replaced Fmoc-Nva, and the coupling with Fmoc-Pro was added before Example 43 was coupled with Fmoc-Arg (Pmc). After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system.

The gradient changed from 5% to 100% acetonitrile / water (containing 0.01% TFA) for 50 minutes. Pure fractions can be freeze-dried to produce N-Ac-Thr-Trp-Ile-Arg-Pro-D-AlaNH2, which is trifluoroacetate; Rt = 4.927 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 784 · 5 (M + H) +; amino acid analysis: 0.39 Thr; 0.10 Trp; 1.04 lie; 0.91 Arg; 1 · 03 Pro; 1.02 Ala. Example 69

NrAc-Thr ^ Ser-Ile > Arg-Pro-D.AlaNH1 The desired product is prepared by replacing Fmoc-D-Ala-Sieber fluorene resin with Fmoc-Pro-Sieber ethyl amine resin, and FmoC-Ser (0- tBu) replaced Fmoc-Nva and was coupled with Fmoc-Pro before coupling with Fmoc-Arg (Pmc) in Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 50/0 to 100% acetonitrile / water (containing 0.00% TFA). Pure flow typhoid / East drying can generate N-Ac-Thr-Ser-Ile-Arg-Pro-D · AlaNH2, which is a trifluoroacid salt; Rt = 3 322 minutes (gradient change time 丨 0 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) 685 4 (M + H) +; amino acid analysis: 0.37 Thr; 0.110 Ser; 1.01 lie; 0.92 Arg -66- 200302833 (60) 1.07 Pro; 1 · 01 Ala. Example 70 N-Ac-Thr: .DzGln ^ Ile-Arg-ProNHCHICH1 The desired product was prepared by replacing Fmoc-Nva with Fmoc-D-Gln (Trt), as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-D-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.292 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 683.4 (M + H) +. Example 71 N-Ac-Ser-Ser-Ile-Arg-Pfo-D-AlaNl · ^ Preparation of the desired product is to replace Fmoc-D-Ala-Sieber amine resin with Fmoc-Pro-Sieber ethyl amine resin, Fmoc -Ser (O-tBu) replaces Fmoc-Thr (O-tBu) and Fmoc-Nva, and before Example 43 is coupled with Fmoc-Arg (Pmc), a coupling with Fmoc-Pro is added. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.10 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-Ser-Ile-Arg-Pro-D-AlaNH2 as trifluoroacetate; Rt = 3.107 minutes (gradient change over 10 minutes, from 20% to 80% Yiyue f / water (containing 0.01% TFA)); MS (ESI) m / e 671.3 (M + H) +. Example 72 N-Ac-Thr-Nva-Pro-Arg-ProNHCI ^ CHySEO ID NO: 23) Fmoc-Pro was used instead of Fmoc-Ile in the preparation of the desired product, as in Example 43. -67- 200302833

(61) After processing, the crude peptide was purified by HPLC, using a C-18 column and a solvent system, and the gradient was changed over 50 minutes from 5% to 10 0% yueyue cream / water (containing 0.01% TFA). . Cold fraction drying of pure fractions can produce N-Ac-Thr-Nva-Pro-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.654 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 638.4 (M + H) +. Example 73 N-Ac-Ser-Gln-D-Ile-Arg-ProNHCH, CH; Fmoc-Ser (O-tBu) is used instead of Fmoc-Thr (O-tBu), Fmoc-Gln (Trt ) Replace Fmoc-Nva, and Fmoc-D-Ile replace Fmoc-Ile, as in Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5%] 00/0 acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac_Ser_Gln-IMle-Arg-proNHCH2CH3, which is trifluoroacetate; Rt = 3 382 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA) ); MS (ESI) m / e 669.4 (M + H) +. Example 74 R'Ac-Thr-Jxp-D-Ile-Arg-ProNHCHfl · ^ The preparation of celebrity seeking products was to replace Fmoc-Nva with Fmoc-Trp (O-tBu), and Fmoc-Ile with Fmnile. η. After the treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system, and the gradient was changed over 50 minutes. Jiangli 'was made from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Trp-D-Ile-Arg-PrOHNHCH2CH3 as trifluoroacetate; Rt = 5.422 minutes (gradient change over 10 minutes, from 20% to 8%). % Acetonitrile / -68- 200302833 (62) water (containing 0.01% TFA)); MS (ESI) m / e 741.5 (M + H) +. Example 75 N-Ac-Ser-Gln-LvsiAcVArg-ProNHCt ^ CHySEO ID NO: 24) Fmoc-Ser (O-tBu) was used instead of Fmoc-Thr (O-tBu), Fmoc-Gln (Trt) Replace Fmoc-Nva, and Fmoc-Lys (Ac) replace Fmoc-Ile, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5%-100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Ser-

Gln-Lys (Ac) -Arg-ProNHCH2CH3, as trifluoroacetate; Rt = 2.710 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (containing 0.001 〇 / 〇TFA )); MS (ESI) m / e 726.4 (M + H) + 〇 Example 76

N-Ac-Ser-Gln-Ile-Arg-Pro-D-AlaNHi The preparation of the desired product is to replace Fmoc-D-Ala-Sieber fluorene resin with Fmoc-Pro-Sieber ethyl amine resin, Fmoc-Ser (O -tBu) replaces Fmoc-thr (O-tBu) 'Fmoc-Gln (Trt) replaces Fmoc-Nva, and before coupling with Example 43 Fmoc-Arg (Pmc), add a coupling with Fmoc-pr0. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-Gln-Ile-Arg-Pro-D-AlaNH2, which is trifluoroacetate; Rt = 3.004 minutes (gradient change over 10 minutes, from 20% -80〇 / 〇 Acetonitrile / water (containing 0.001 / 0 TFA)); MS (ESI) m / e 712.4 (M + H) +. Example 77 iirAg-pyridyl Glv-Gln-Arg-PfoNHCI ^ CHySEO ID NO: 25) -69- 200302833 (63) The preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-methylpropyl Gly, And Fmoc-Gln (Trt) replaced Fmoc-Nva Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac- 晞 propyl Gly-Gln-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 4.015 minutes (gradient change over 10 minutes, from

20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 679.3 (M + H) +. Example 78 N-Ac-Thr-Nva-Lys-Arg-ProNHCH ^ H ^ SFQ ID NO: 26) Fmoc-Lys (Boc) was used instead of Fmoc-Ile in the preparation of the desired product, as described in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Lys-Arg-Pro NHCH2CH3 as trifluoroacetate; Rt = 2.872 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water ( Contains 0.01% TFA)); MS (ESI) m / e 669.3 (M + H) + 0 t Example 79 N-A c: Ser,: ,, D-G1 ιι ^ χΐ e > Arg-ProNHCH1rH1 The product was prepared by replacing Fmoc-Ser (O-tBu) with Fmoc-Thr (O-tBu) and Fmoc-D-Gln (Trt); pmoc-Nva, in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes' from 5% to 100/0 acetonitrile / water (containing 0.001 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-D-Gin ne Arg Pr0-70- 200302833 (64) NHCHWH3, showing trifluoroacetate; Rt = 3.276 minutes (gradient change over 10 minutes' by 20% -80% acetonitrile / water (containing 0.01 / tfa)); MS (ESI) m / e 669.3 (M + H) +. Example 80 N-Ac-D-Ile-Thr-Arg-I1e-Arg-NHCH1CH1 The desired product was prepared by replacing Fmoc-Nva with Fmoc-Arg (Pmc), and the coupling of Fmoc-Pro in Example 1 was omitted. After treatment, the crude peptide was purified with hplC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% tfa). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Arg-Ile-Ai: g-NHCH2CH3, which is trifluoroacetate; Rt = 1.05 minutes (gradient change over 10 minutes, from 20% -8 〇% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 727.4 (M + H) +; amino acid analysis: 2.01 lie, 0.56 Thr, 2.31 Arg 〇 Example 81

ijzAc-D-aIle-Ser-Ser-Lvs (AcVArg-ProNHCH1CHi 4 The preparation of the product is Fmoc-D-alle instead of Fmoc-D-Ile, Fmoc-Ser (O-tBu) instead of Fmoc-Thr (O-tBu ) And Fmoc-Nva, and Fmoc-Lys (Ac) instead of Fmoc-Ile in Example 1. After processing, the crude peptide was purified by HPLC using a C-1 8 column and solvent system. The gradient was changed over 50 minutes. 5% -100% acetonitrile / water (containing 0.00% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-ane-Ser-Ser-Lys (Ac) -Arg-ProNHCH2CH3, which is trifluoroacetic acid. Salt; Rt = 3.671 minutes (10 minutes of gradient change from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 798.7 (M + H) +; amino acid analysis : 0.19 Ser; 0.92 lie; 0.98 Lys; 0.74 Arg; 1.0 Pro. -71- 200302833 (65) f Example 82 N-Ac > D-aIle-Ser-Ser-Nle-Arg-ProNHCH1CH1 Preparation system of the desired product Fmoc-D-alle replaced Fmoc-D-Ile, Fmoc-Ser (O-tBu) replaced Fmoc-Thr (O-tBu) and Fmoc-Nva, and Fmoc-Nle replaced Fmoc-Ile, after Example 1. After treatment. The crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TF). A). Pure fractions can be freeze-dried to produce N-Ac-D-alle- Ser-Ser-Nle-Arg-ProNHCH2CH3 ^ trifluoroacetate; Rt = 4.394 minutes (gradient change over 10 minutes, from 20% -80 % Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 741.6 (M + H) +; amino acid analysis: 0.34 Ser; 0.99 lie; 0.96 Nle; 0.99 Arg; 1.05 Pro 〇Example 83 N-Ac-D-alle-Ser-Ser-Pro-Arg-ProNHCH ^ CH ^ For the preparation of the desired product, Fmoc-D-alle was used instead of Fmoc-D-Ile, and Fmoc-Ser (O-tBu) Replace Fmoc-Thr (O-tBu) and Fmoc-Nva, and Fmoc-Pro replace Fmoc-lie, as in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-alle- Ser-Ser-Pro-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.37 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 725.5 (M + H) +; amino acid analysis · 0.18 Ser; 1.00; 0.87 Arg; 2.13 Pro. Example 84 N-Ac-D-alle-Ser-Ser-Nva-Arg-ProNHCHiCHi -72- 200302833 (66) Preparation of the desired product is to replace Fmoc-D-Ile with Fmoc-D-alle,; pm () c- Ser (O-tBu) replaced Fmoc-Thr (O-tBu) and Fmoc-Nva, and FmOC-Nva replaced Fmoc-Ile in Example 1. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a dropping system 'for a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Ser-Ser-Nva-Arg-Pi * oNHCH2CH3, which is trifluoroacetate; Rt = 3.938 minutes (gradient change over 10 minutes, from 20% -80% Acetonitrile / water (containing 001〇 / 〇TFA)); MS (ESI) m / e 727.5 (M + H) +; amino acid analysis: 0.30Ser; 1.03 Nva; 1.04 lie; 0.94 Arg; 1 · 03 Pro. Example 85 N-Ac-D-Ile-Thr-Nva-Ile-Arg-NHCI ^ CHi The desired product was prepared without the coupling with Fmoc-Pro in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be cold-rolled and dried to form N-Ac-D-Ile-Thr-Nva-Ile-Arg-NHCH2CH3, which is trifluoroacetate; Rt = 2.15 minutes (gradient change over 10 minutes, from 20% -8 0% Azulene / water (containing 0.01% TFA)); MS (ESI) m / e 670.3 (M + H) +; amino acid analysis: 0.55 Thr; 1.02 Nva; 2.02 lie; 1 · 21 Arg. Example 86 N-Ac-D-alle-Ser-Ser-Lvs-Arg-ProNHCH2_CHj_ Preparation of the desired product is to use Fmoc-D-alle instead of Fmoc-D-Ile, and Fmoc-Ser (O-tBu) to replace Fmoc-Thr ( O-tBu), Fmoc-Nva, and Fmoc-Lys (Boc) instead of Fmoc-Ile. After treatment in the example, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes. -73- 200302833

(67) 5% -100% acetonitrile / water (containing 0.00% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH2CH3 'as trifluoroacetate; 1 = 3.272 minutes (gradient change over 10 minutes, from 20% to 80% Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 756 · 5 (M + H) +. Example 87

Ac-D-alle-Ser-Ser-Ile-Arg-ProNHCHfCHOo. Fmoc-D-alle is used instead of Fmoc-D-Ile, Fmoc-Pro- [4- (4-N-isopropylamino) Methyl-3-methoxyphenoxy] butylammonium AM is intended to replace Fmoc-Pro-Sieber acetic acid amine resin, and Fmoc-Ser (O-tBu) replaces Fmoc-Thr (O-tBu) and Fmoc- Nva is in Example 1. After processing, the crude peptide was purified by HPLC using a c-18 column and a solvent system with a gradient change of 50 minutes from 5% · 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH (CH3) 2, which is trifluoroacetate; Rt = 3.04 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 755.5 (M + H) +. Example 88

N-Ac-D-alle-Ser-Ser-Gln-Arg-ProNHCHiCH! The preparation of the desired product is to replace Fmoc-D-Ile with Fmoc-D-alle, Fmoc-Thr (O-tBu) instead of Fmoc-Thr (O -tBu) and Fmoc-Nva, and Fmoc-Gln (Trt) replace Fmoc-lie, as in Example 1. After treatment, the crude peptide was purified by HPLC using a CM 8 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100% ethane f / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Ser, Ser-Gln-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.〇39 minutes (gradient change over 10 minutes, from 20% -80 % Acetonitrile / water (containing 0.01% -74- 200302833 (68) TFA)); MS (ESI) m / e 756.5 (M + H) + 0 Example 89 N-Ac-D-alle-Ser-Ser -Cit-Arg-ProNHCHiCHi Preparation of desired product is Fmoc-D-alle instead of Fmoc-D-Ile, Fmoc-Ser (O-tBu) instead of Fmoc-Thr (O-tBu) and Fmoc-Nva, and Fmoc-Cit Replace Fmoc-lie in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D · aIle-Ser-Ser-Cit-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.796 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (with 0.01% TFA)); MS (ESI) m / e 785.5 (M + H) +. Example 9 0 N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH ^ CHi Preparation of the desired product is to use Fmoc-Met instead of Fmoc-Thr (O-tBu) and Fmoc-Gln (Trt) to replace Fmoc- Nva is in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system, and the gradient was changed for 50 minutes' from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 4.49 minutes (gradient change over 10 minutes, from 20% to 80%). 0 / () acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 826.5 (M + H). Example 91 The desired product was prepared by replacing Fmoc_Ile with Fmoc_D_Lys (Ac), as in Example 43. After treatment ’, it was purified by HPLC using a C_18 column and a solvent system, -75- 200302833 (69)

The gradient was changed over a period of 50 minutes from 5% · 1000 / 〇acetonitrile / water (containing 10000 / 〇 TFA). Pure " W 1¾ Cold / East drying can produce N-Ac-Thr-Nva-D-Lys (Ac) -Arg-ProNHCi ^ CH3, which is trifluoroacetate; Κί = 〇.81 minutes (gradient change history 1〇 Min. From 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 711.5 (M + H) +. —Example 92 N ^ Ac-ThL-Nva-Ile ^ Orn-ProNHCH ^ H ^ SEO ID NO: 27) Fmoc-Orn (Boc) was used instead of Fmoc-Arg (Pmc) in the preparation of the desired product, as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Ile-Orn-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.494 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (Containing 0.01% TFA)); MS (ESI) m / e 612 · 4 (M + H) +; amino acid analysis: 0.525 Thr; 1.007 Nva; 1.01 lie; 1.013 Orn; 0.999 Pro 〇 Example 93 N-Ac-Glu-Nva-Ile-Arg-ProNHCHiCHySEO ID NO: 28) The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-Glu (O-tBu) in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Glu-Nva-Ile-Arg-ProNHCH2CH3, which is trilactate; Rt = 3.676 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / water ( Contains 0.001% TFA)); MS (ESI) m / e 682.4 (M + H) +; amino acid analysis: 1.014 Glu; 1.003 Nva; 1.007 lie; 200302833 (70) 0.964 Arg; 1.015 Pro 0 Example 94 N-Ac-Ajin-Nva-IlezArg ^ ProNHCH ^ H ^^ Fn ID NO: 29) The preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-Asn (Trt) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fraction cold; Donggan :) ¾ can produce N-Ac-Asn-Nva-Ile-Arg-proNHCI ^ Ci ^, showing trifluoroacetate; Rt = 3.579 minutes (gradient change history 10 minutes, from 20% -8 0% acetonitrile / water (containing 〇〇〇〇〇 / 0 TFA)); MS (ESI) m / e 667 · 4 (M + H) +; amino acid analysis: 1.018 Asp; 1 · 〇52 Nva; 1.047 Lie; 0.998 Arg; 0.938 Pro ο Example 95 N-Ac-Hser-Nva-Ile-Arg-ProNHCH ^ CH ^ SF.O ID NO: 30) The preparation of the desired product is Fmoc-Hser (Trt) instead of Fmoc-Thr (O-tBu), as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Hser-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = i. 35 minutes (gradient change over 10 minutes, from 20 ° / 〇- 80 % Acetonitrile / water (containing 0.001% TFA)); MS (ESI) m / e 654.5 (M + H) +; amino acid analysis: ι · 35 Hser; 1.052 Nva; 1.002 lie; 0.972 Arg; 1.026 Pro. Example 96 N-Ac-Sar-Nva-Ile-Arg-ProNHCt ^ CH ^ / SFQ ID NO: 31) Fmoc-Sar was used instead of Fmoc-Thr (O-tBu) in the preparation of the desired product. 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Sar-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.60 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01 % TFA)); MS (ESI) m / e 624.4 (M + H) +; amino acid analysis: 0.835 Sar; 1.035 Nva; 0.986 lie; 0.8980 Arg; 1.034 Pro.

Example 9 7 N-Ac-Asp-Nva-ne-Arg-ProNHCH ^ CH ^ / SEO ID NO: 32) Fmoc-Asp (O-tBu) was used instead of Fmoc-Thr (O-tBu) to prepare the desired product.于 例 43。 In Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile /

Water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Asp-Nva-Ile-Arg-PrOHNHCH2CH3 as trifluoroacetate; Rt = 3.622 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water ( Contains 0.01% TFA)); MS (ESI) m / e 668 · 4 (M + H) +; amino acid analysis: 1.036 Asp; 1.054 Nva; 1.045 lie; 〇 · 982 Arg; 0.937 Pro 0 Example 98 H ^ A ^ Ser-Gln-Nva-Arg-ProNHCH, CHJSEO ID NO: 33) Fmoc-Ser (O-tBu) instead of Fmoc-Thr (O-tBu) 'Fmoc-Gln (Trt) Fmoc-Nva, and Fmoc-Nva replace Fmoc-Ile, in Example a. After treatment, the crude peptide was purified with hplC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Ser- -78- 200302833

(72)

Gln-Nva-Arg-ProNHCH2CH3 'is trifluoroacetate; Rt = 3.253 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 655.4 (M + H), amino acid analysis: 224 Ser; 1.046 Glu; 0.845 Nva; 0.969 Arg; 0.985 Pro 〇 Example 99 N ~ Ac-Ser-Gln-Ile-Cit-ProNHCH ^ CHj (q ID NO : 34) The preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-Ser (〇_tBu), Fmoc-Gln (Trt) instead of Fmoc-Nva, and Fmoc-Cit instead of Fmoc-Arg (Pmc) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-Gln-Ile-Cit-ProNHCH2CH3 as trifluoroacetate; Rt = 3.253 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01 % TFA)); MS (ESI) m / e 655.4 (M + H) +; amino acid analysis: 0.273 Ser; 1.012 Glu; 0.939 lie; 1.043 Cit; 1.04 Pro ^ Example 100

N-Ac-Ser-Gln-Ile ^ Pal-ProNHCH ^ H ^ SEO ID NO: 35) The preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-Ser (O-tBu), and Fmoc-Gln ( Trt) replaced Fmoc-Nva, and Fmoc-3Pal replaced Fmoc-Arg (Pmc) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-Ser-Gln-Ile-3Pal-ProNHCH2CH3, which is trifluoroacetate; Rt = 4.031 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 〇 〇1% -79- 200302833 (73)

TFA)); MS (ESI) m / e 661.3 (M + H) +; amino acid analysis 0.23 Ser; 1.012 Glu; 1.025 lie; 0.793 3Pal; 0.963 Pro. Example 101 N ^ Ac-Thr-Gln-Nva-Arg-ProNHCH ^ CH ^ SEO ID NO: 36) The preparation of the desired product is to replace Fmoc-Nva with Fmoc-Gln (Trt) and Fmoc-Ile to Fmoc-Nva,于 例 43。 In Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Gln-Nva-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.4 minutes (gradient change over 10 minutes, from 20%-80% acetonitrile / water (Containing 0.01% TFA)); MS (ESI) m / e 669.4 (M + H) +; amino acid analysis: 0.535 Thr; 1.023 Glu; 1.09 Nva; 1.013 Arg; 0.964 Pro 0 Example 102 N ^ Aj ^ Thr-Asn-IlerArg-ProNHCH ^ CH ^^ FO ID NO: 37) Fmoc-Asn (Trt) was used instead of Fmoc-Nva in the preparation of the desired product, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure " tile typhoon / east drying can produce N-Ac-Thr-Asn-Ile-Arg · ProNHCI ^ CH3, which is trifluoroacetate; Rt = 3 4 minutes (gradient change over 10 minutes' from 20%- 80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 669.4 (M + H) +; amino acid analysis: 0.591 Thr; 1.02 Asp; ι · 〇〇3 lie; 1.005 Arg; 0.972 Pro ο 103 N-Ac-Thr > DA ^ nzr [e-Arg-ProNHCH1rH1 200302833 (74) The preparation of the product is replaced by Fmoc-D-Asn (Trt). 43. After treatment, the crude peptide was purified by HPLC using a 018 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr_DLIle-Arg · ProNHCi ^ CH3, which is trifluoroacetate; Rt = 3 615 minutes (gradient change over 10 minutes' from 20% -80% acetonitrile / water (containing 〇〇. 1〇 / 〇TFA)); MS (ESI) m / e 669.4 (M + H), amino acid analysis: 〇62 Thr; 〇09〇8 ASp; 〇995 Ile; 1.044 Arg; 1.053 Pro °

Example 104 NJhr-Nva-Pro-Arg-ProNHCH ^ CH ^ SF.O ID NO: 38) Fmoc-Pro was used in place of Fmoc-Ile in the preparation of the desired product, and the final acetylation step in Example 43 was omitted. After treatment, the crude peptide was purified with jjpLC, using a C-18 column and a solvent system, with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce

N-Thr-Nva-Pro-Arg-ProNHCH2CH3, as trifluoroacetate; Rt = 3.30 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI ) m / e 596.4 (M + H) +; Amino acid analysis: 0.604 Thr; L20 Nva; 0.955 Arg; 2.045 Pro ° Example 105 N-Ac-D-Thr ^ Nva-Pro-Arg-ProNHCH1CH1 Want product It was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Thr (O-tBu) and Fmoclle by Fmoc-Pro 'in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fraction cold • 81-200302833 (75) beam drying can generate N-Ac-D-Thr-Nva-Pro-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.82 minutes (gradient change over 10 minutes, from 20 % -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 638.5 (M + H) +; amino acid analysis: 0.568 Thr; 1.17 Nva; 0.997 Arg; 2.003 Pro. Example 106 N-Ac-Thr-Nva-D-Pro-Arg-ProNHCK ^ Cl · ^ The desired product was prepared by replacing Fmoc-Ile with Fmoc-D-Pro, as in Example 43. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system 'gradient over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-D-Pro-Arg-ProNHCH2CH3 as a trifluoroacetate; Rt = 3.45 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water ( Contains 0.01% τρΑ)); MS (ESI) m / e 638.4 (M + H) +; amino acid analysis: 0.6 Thr; 1.195 Nva; 1.073 Arg; 1.927 Pro. Example 107 N-Ac ^ Nv .az, Gln-Ile > Arg-PrOHNHCH1CH1rSRO ID NO: 39) Fmoc-Nva is used to replace Fmoc-Thr (O-tBu) and Fmoc-Gln (Trt) is used to replace Fmoc-Nva, as in Example 43 . After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 cycles from 5% to 100% acetonitrile / water (containing 0.001 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-Nva-Gln-Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate 'Rt = 3.822 minutes (gradient change over 10 minutes, from 20% -8〇 / (Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 681.5 (M + H) +. ^ J ^ L108-82- 200302833 (76) N-Ac-D-Nva'Pro-Ile-Arg-ProNHCHiCHi The preparation of the desired product is to replace Fmoc-Thr (O-tBu) and Fmoc with Fmoc-D-Nva -Pro replaces Fmoc-Nva, in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Pr〇-Ile-Arg-PrOHNHCH2CH3 as trifluoroacetate; Rt = 5.008 minutes (gradient change over 10 minutes, from 20% to 80% Acetonitrile / water (containing 0.01% TFA)), MS (ESI) m / e 638.4 〇

Example 109 N-Acr.Thr-Arg-Ile-Cit-ProNHCH ^ CH ^ SEO ID NO: 40) Fmoc-Arg (Pmc) is used to replace Fmoc-Nva and Fmoc-Arg is replaced by Fmoc-Cit ( Pmc), in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Arg-ne-Cit-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.868 minutes (gradient change over 10 minutes, from 200 / 〇_80% acetonitrile / water (Containing 0.01% TFA)), MS (ESI) m / e 712.5. Example 110 N-Ac-JLbj-Qln-LysfAcVAfg-ProNHrH / H / SFO ID NO: 41) The preparation of the desired product is to replace Fmoc-Nva with Fmoc-Gln (Trt), and

Fmoc-Lys (Ac) replaces Fmoc-Ile in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Thr-Gln-Lys (Ac) -Arg-ProNHCH2CH3 as trifluoroacetic acid • 83-200302833

(77) Salt; Rt = 2.334 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 740 · 5. Example 111 N-Ac-Buthr-Nva-Pro-Arg-Pro-D-AlaNHi The desired product was prepared by replacing Fmoc-D-Ala-Sieber ethylamine resin with Fmoc-Pro-Sieber ethylamine resin. Fmoc-Arg (Pmc) coupling is preceded by a coupling with Fmoc-Pro, and Fmoc-Pro replaces Fmoc-Ile coupling, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Pro-Arg-Pro-D-AlaNH2, which is trifluoroacetate; Rt = 2.943 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 68 1 · 5. Example 112 N ^ Ac-Thr-Ser-LysiAc ^ -Arg-ProNHCH ^ H ^^ FO ID NO: 42) Fmoc-Ser (O-tBu) was used instead of Fmoc-Nva and Fmoc-Lys for the preparation of the desired product. (Ac) replaces Fmoc-Ile in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.00 %% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Ser-Lys (Ac) -Arg-ProNHCH2CH3 as trifluoroacetate; Rt = 2.428 minutes (gradient change over 10 minutes, from 200 / 〇-80 % Acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 699.5. Example 113 N-Ac-Thr-Ser-Pro-Arg > Pro-D-AlaNH7 -84- 200302833

(78) The preparation of the desired product is replaced by Fmoc-D-Ala-Sieber amine resin

Fmoc-Pro-Sieber Ethyl Amine Resin ’is coupled with Fmoc-Pro before coupling with Fmoc · Arg (Pmc) and replaced with Fmoc-Ser (O-tBu)

Fmoc-Nva, and Fmoc-Pro replace Fmoc_lie, in Example 4 3. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be cold rolled and dried to form N-Ac-Thr-Ser-Pro-Arg-Pro-D-AlaNH2, which is trifluoroacetate; Rt = 2.028 minutes (gradient change over 10 minutes, from 20% -80% Acetonitrile / water (containing 0.01 / 0 TFA)); MS (ESI) m / e 669.3. Example 114 N-Ac-Thr-Cit-Arg-ProNHCH ^ CHySFO ID NO: 43) k Fmoc-Cit was used in place of Fmoc-Nva in the preparation of the product. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.001 〇 / 〇 TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Cit-Ile-Arg-ProNHCH ^ CH3, which is trifluoroacetate; Rt = 2.839 minutes (gradient change over 10 minutes' from 20% -80% acetonitrile / water ( Contains 0.005% TFA)); ms (ESI) m / e 712.5. Example 11 5 Hm-Gln-Tle-Aq-ProNHCH ^ CHi (SEQ ID NO: 44) of methylpentamidine is prepared by replacing Fmoc-Nva with Fmoc_Gln (Trt) and Valproic acid replaces acetic acid, as in Example 43. After processing, the crude peptide was purified by hPLC 'using a C-1 8 column and solvent system. The gradient was changed over 50 minutes, -85- 200302833 (79) from 5%-100% acetonitrile / water (containing 001 % TFA). Pure fractions can be freeze-dried to produce N_ (3-methylpentanyl) -Thr-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetic acid's salt 'Rt = 4.501 minutes (gradient change over 10 minutes, from 20%). % -8〇 (% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 739.5. Example 116 K _- (3-methylpentyl) -Thr-Nva-Ile-Arg-ProNHCH, C! H, — -G3 ---- 3. (SEQ ID NO: 45) For the preparation of the product, 3-methylvaleric acid was used instead of acetic acid, as in Example 43. After treatment, the crude peptide was purified with hPlc and used C-1 8-column column and solvent system 'gradient change over 50 minutes, freeze-dried from 5% -100% acetonitrile / water (containing 〇i% TFA) ° Pure fractions can produce ν · (3-methyl Pentamyl) -Th Nva-Ile-Arg-ProNHCHAH3, as trifluoroacetate; Rt = 4 82 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 〇〇〇〇〇 / 0 TFA)); ms (ESI) m / e 710.5 ο Example 117 i ^ Ac-Ser > TrBJQe ^ Arg--ProNHCH1CH1rSKO ID NO: 46) k The preparation of the product was replaced by Fmoc-Ser (O-tBu) Fmoc -Thr (O-tBu) 'and FmOC-TrP (BOC) in place of Fmoc-Nva, as in Example 43. After treatment, the crude peptide was purified by HPLC, using a c-18 column and a solvent system, and the gradient was changed over 50 minutes from 50 / 0-100 / 0 acetonitrile / water (containing 0.001 / 0 butane FA). ). Pure fraction cooling / east drying can produce N-Ac-Se, Trp-ne-Arg Pr0NHCH2CH3, which is trifluoroacetate; Rt = 4 539 minutes (gradient change calendar 丨 0 minutes, from 20% to 80% Acetonitrile / water (containing 0.01 / TFA)); ESI (m / e) 727.4. Example 118 -86-200302833 (80)

N-Aj ^ ThrJrp-Ile-Arg-ProNHCH ^ rH ^ ID NO: 47) Fmoc-Trp (Boc) was used instead of Fmoc-Nva in the preparation of the desired product, in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 tube and solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Trp-Ile-Arg-PfONHCH2CH3 as a trifluoroacetate; Rt =: 4 589 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (with 0.01% TFA)); MS (ESI) m / e 741.5. Example 119

N ^ Ac > D-Nva-Gln > Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-Nva and Fmoc-Nva instead of Fmoc-Gln (Trt), as in Example 43 . After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.005% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.692 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (With 0.01% TFA)); MS (ESI) m / e 681.4. Example 120 N-Ac-Thr-LvsfAcVIle-Arg-ProNHCH ^ H ^ SEO ID NO: 48) The desired product was prepared by replacing Fmoc-Nva with Fmoc-Lys (Ac) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-Thr-Lys (Ac) _Iie_Ai: g_

ProNHCH2CH3, as trifluoroacetate; Rt = 3.3 · 11 minutes (gradient change calendar-87- 200302833 (81) 10 minutes, from 20% to 80% acetonitrile / water (containing 0.01% TFA)); MS ( ESI) m / e 725.5 0 Example 121 N-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH1Cjj1 (SFQ ID NO: 49) Preparation of the desired product is performed by coupling with Fmoc- / 3-propylamine before coupling with acetic acid Acid coupling. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.625 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (Containing 0.00% TFA)); MS (ESI) m / e 725.5. Example 122 N-Ac-bAla-Thr-Gln-Ile-Arg ^ ProNHCH ^ CH ^ SRO ID NO: 50) The desired product was prepared by replacing Fmoc-Nva with Fmoc-Gln (Trt), and before coupling with the acid Add a coupling with Fmoc-/ 3 -alanine, as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-bAla-Thr-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.844 minutes (gradient change over 10 minutes, from 20% -8 0% acetonitrile / water (With 0.01% TFA)); MS (ESI) m / e 754.5. Example 123 N-Ac-Ser-D-Gln ^ Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr with Fmoc-Ser (O-tBu) -88- 200302833 (82) (O-tBu), and Fmoc -Gln (Trt) replaces Fmoc-Nva, as in Example 43. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 10,000 / .TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-D-Gln-Ile-Arg-ProNHCHAH3, which is trifluoroacetate; Rt = 2.542 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (Containing 〇〇〇 / 〇TFA)); ms (ESI) m / e 712.4. N > Ac-D-LeurAsp-I ^^ iie, Arp.pr〇NHCH ^ CHi Preparation of the desired product is to replace Fmoc-D-Ile with Fmoc-D-Leu, and

Fmoc-Asp (O-tBu) replaces Fmoc-Thr (O-tBu) in Example 1. After treatment, the crude peptide was purified by HPLC 'using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 1.86 minutes (gradient change over 10 minutes, from 20% to 80%) 〇acetonitrile / water (containing 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 781.6 (M + H) +; amino acid analysis: 1.01 Leu; 0.97 Asp; i.oo Nva; 1.03 lie 1.10 Arg; 1.006 Pro o 125 NTAc-D:, IIe> Glji ^ .Arg.prQNHCHiCHl The preparation of the desired product is to replace Fmoc-Thr (O-tBu) and Fmoc-Gln (Trt) with Fmoc-D-Ile Replace Fmoc-Nva in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes' from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fraction freeze-drying • 89-200302833 (83) Drying can generate N-Ac-D-Ile-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.73 minutes (gradient change over 10 minutes, from 20 % -80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 695.4 (M + H) +. f Example 126 N-Ac-D-Ala-Gln-Ile-Arg-ProNHCH ^ CH ^

The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Ala and Fmoc-Nva by Fmoc-Gln (Trt), as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N_Ac-D-Ala-Gln-Ile-Arg-Pi * oNHCH2CH3, which is trifluoroacetate; Rt = 2.981 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water ( Contains 0.01% TFA)); MS (ESI) m / e 653.4. Example 127 N-Ac-D> Thr-Gln-Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-Thr (O-tBu), and Fmoc-Gln (Trt) Replace Fmoc-Nva in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.005% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Thr-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 2.927 minutes (gradient change over 10 minutes, from 20% -8 0% acetonitrile / water (Contains 〇〇〇〇 / 0 TFA)); MS (ESI) m / e 683.4 〇t Example 128 N-Ac-D-Ser-gjsDrg-ProNHCHn -90- 200302833

(84) The desired product was prepared by replacing Fmoc-Dhr (O-tBu) with Fmoc-Thr (O-tBu) and Fmoc-Gln (Trt) in place of Fmoc-Nva, as in Example 43. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system. The gradient was changed over a period of 50 minutes' from 5% to 100% acetonitrile / water (containing 0.001 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ser-Gln-Ile-Arg-ProNHCH2CH3 as trifluoroacetate; Rt = 2.763 minutes (gradient change over 10 minutes, from 20% to 80% acetonitrile / Water (containing 0.00 / 0 TFA)); MS (ESI) m / e 669.3. Example 129 N-Ac-D > Pro-Gln-Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-Pro and

Fmoc-Gln (Trt) replaces Fmoc-Nva in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.005 / 0 tfA). Pure fractions can be freeze-dried to produce N-Ac-D-PrO-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.376 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / Water (containing 0.01% TFA)); MS (ESI) m / e 679.4. Example 130 N-Ac-D-alle-Gln-Ile-Arg-ProNHCI ^ CHi The preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-alle and Fmoc-Gln (Trt) to replace Fmoc- Nva, in Example 43. After treatment, the crude Yuetai was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate; Rt = 3.778 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile-91- 200302833 (85) / water (containing 0.01% TFA)); MS (ESI) m / e 695.4. Example 131 N-Ac-D-Nv—a-Asn-Ile-Arg-ProNHCH ^ CI ^

For product preparation, Fmoc-D-Nva was used in place of Fmoc-Thr (O-tBu) and Fmoc-Asn (Trt) was used in place of Fmoc-Nva, as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.000 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Asn-Ile-Arg-PrOHNHCH2CH3 as a trifluoroacetate. 1 case 132

NrAc-D ^ Nva-Arg-Ile-Arg-ProNHCH1CH1 For the preparation of the desired product, Fmoc-D-Nva was used in place of Fmoc-Thr (O-tBu) and Fmoc-Arg (Pmc) was used in place of Fmoc-Nva, as in Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Arg-Ile-Arg-PrOHNHCH2CH3 as a trifluoroacetate.

NzAc-D> Nva-ThrrIle ^ Arg-ProNHCH1CH1 Preparation of the desired product 'Fmoc-D-Nva instead of Fmoc-Thr (O-tBu)' and Fmoc-Thr (O-tBu) instead of Fmoc-Nva. 43. After treatment, the crude peptide was purified by HPLC using a c-18 column and a solvent system. The gradient was changed over 50 minutes from 50/0 to 100% acetonitrile / water (containing 0.000 / 0 TFA). Pure fractions freeze-dried to produce N_Ac-D-Nva-Thr-Ile-Arg- -92-

200302833 (86)

ProNHCH2CH3 is trifluoroacetate. Example 134

N-Ac-D-Nva-Ser-Ile-Arg-ProNHCHiCHi The desired product is prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Nva and Fmoc-Nva by Fmoc-Ser (O-tBu),于 例 43。 In Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-D-Nva-Ser-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate. Example 135 N ~ Ac-D-Nva-Glu> Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-Nva and Fmoc-Ser (O-tBu) to replace Fmoc- Nva, in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over a period of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Glu-Ile-Arg-ProNHCH2CH3, which is trifluoro

Example 136 N-Ac-D-Met-Gln-Ile-Arg-ProNHCHiCHi The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Met and Fmoc-Nva by Fmoc-Gln (Trt),于 例 43。 In Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-D-Met-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetic acid -93- 200302833

(87) Acid salt. Example 137 N-Ac-D-Hser-Gln-Ile-Arg > ProNHCH ^ CH3 ¥ The preparation of the desired product was to replace Fmoc-Thr (O-tBu) with Fmoc-D-Hser (Trt), and Fmoc-Gln ( Trt) in place of Fmoc-Nva, in Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 100% TFA). Pure fractions can be freeze-dried to form N-Ac-D-Hser-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate. Example 138 N > Ac > D-Nva-Lys (NicVIle-Arg-ProNHCH1CH1 The preparation of the desired product was replaced by Fmoc-D-Nva for Fmoc-Thr (O-tBu) and Fmoc-Lys (Nic) for Fmoc-Nva. Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were frozen Drying can produce N-Ac-D-Nva-Lys (Nic) -Ile-Arg-ProNHCH2CH3 as a trifluoroacetate. Example T39 N-Ac-D-Nva-Gln-Lvs (^ cVArg > ProNHCH1CH1 Preparation of the desired product Replace Fmoc-Thr (O-tBu) with Fmoc-D-Nva,

Fmoc-Gln (Trt) replaces Fmoc-Nva in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.00% Tfa). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Gln-Lys (Ac) -Arg-ProNHCH2CH3, which is trifluoro-94- 200302833 (88) acetate. Example 14 (^ N-Ac-D-NvaJ ^ hL: ile-Arg-.ProNHrH:;, rH1 Preparation of the desired product 'is the replacement of Fmoc-Pro-Sieber ethyl with Fmoc-D-Ala-Siebei · amidamine resin Amine resin, coupled with Fmoc-Pro before coupling with Fmoc-Arg (pmc), and Fmoc-Thr (O-tBu) replaced with Fmoc-D-Nva, and Fmoc-Gln (Trt) replaced Fmoc-Nva, in Example 43. After treatment, the crude peptide was purified by HPLC 'using a c-18 column and solvent system with a gradient change over 50 minutes' from 5% -100% acetonitrile / water (containing 0.01 / 〇TFA). Pure fractions can be freeze-dried to form N-Ac-D-Nva-Gln-Ile-Arg-Pro-D-AlaNH2, which is trifluoroacetate. Example 141

N-Ac-D-Nva-Gln-Ile-Cit-ProNHCHiCHi Preparation of the desired product is Fmoc-D-Nva instead of Fmoc-Thr (O-tBu), Fmoc-Gln (Trt) instead of Fmoc-Nva, and Fmoc- Cit replaces Fmoc-Arg (Pmc) in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-D-Nva-Gln-Ile-

Cit-ProNHCH2CH3 is a trigas acetate. Example 142 N-Ac-D-Nva-Gin-Pro-Arg-ProNHCHiC The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Nva, replacing Fmoc-Nva with Fmoc-Gln (Trt), and Fmoc-Pro replaces Fmoc-Ile in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and -95- 200302833 (89) solvent system with a gradient change of 50 minutes from 5%-100% acetonitrile / water (containing 0.01% TFA) . N-Ac-D-Nva-Gln-Pro-

Arg-ProNHE, as trifluoroacetate. Example 143

N ~ Ac-D-Nva-Gln-Ile-Lys (Isp) > ProNHCH1CHJ The preparation of the desired product is to use Fmoc-D-Nva instead of Fmoc-Thr (O-tBu), and Fmoc-Gln (Trt) to replace Fmoc-Nva And Fmoc-Lys (Isp) instead of Fmoc-Arg (Pmc), as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-D-Nva-

Gln-Ile-Lys (Isp) -PrOHNHCH2CH3 is trifluoroacetate. Example 144 N > Ac-D-Nlv-Gln-Ile-Arg-ProNHCH1CH1 The desired product was prepared by replacing Fmoc-Thr (O-tBu) with Fmoc-D-Nva and Fmoc-Nva by Fmoc-Gln (Trt). Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.005 / 0 TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nle-Gln-Ile-Arg-ProNHCH2CH3 as a trifluoroacetate. Example 145 N ^ Ac-Nle-Gln-Ile-Arg-ProNHCH ^ H ^ SKO ID NO : 51) Fmoc-Nle is used instead of Fmoc-Thr (O-tBu) for the preparation of the desired product, and

Fmoc-Gln (Trt) replaces Fmoc-Nva in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 -96- 200302833 (90) minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-Nle-Gln-Ile-Arg-PrOHNHCH2CH3 as a trifluoroacetate. Example 146 N-Ac-D-Nva ^ Gln-Ile-Arg-ProNHCH (< CH1) 1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-D-Nva, Fmoc-Gln (Trt) Replaces Fmoc-Nva, and Fmoc-Pro- [4- (4-N-isopropylamino) methyl-3-methoxyphenoxy] butanol-based AM resin instead of Fmoc-Pro-Sieber ethylammonium resin , In Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Nva-Gln-Ile-Arg-ProNHIsp, which is trifluoro1 acetate 0 Example 147 N- (6MeNicVD-Nva-Gln-Ile-Arg-ProNHCH1CH1 Preparation of desired product Fmoc-D-Nva was used to replace Fmoc-Thr (O-tBu), Fmoc-Gln (Trt) was used to replace Fmoc-Nva, and 6-methylnicotinic acid was used to replace acetic acid, as in Example 43. After treatment, the crude peptide was analyzed by HPLC. Purification, using C-18 column and solvent system, gradient change over 50 minutes, from 5%-100% acetonitrile / water (containing 0.01% TFA). N- (6MeNic) -D can be produced by freeze-drying pure fractions -Nva-Gln-Ile-Arg-ProNHCH2CH3, which is trifluoroacetate. Example 148 ^ ~ Ac-Is [va ~ D ~ Gln * Il € -Arg ~ ProNHCH Η ^ Fmoc-Nva is used instead of Fmoc -Thr (O-tBu), and Fmoc-D-Gln (Trt) instead of Fmoc-Nva, as in Example 43. After processing, the crude -97 · 200302833_ (91) peptide was purified by HPLC using a C-1 8 column And solvent system, the gradient changes over 50 minutes, from 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Nva-D-Gln-Ile-Arg-ProNHCH2CH3, showing Trifluoroacetate. Example 14 9

N-Ac-Nva-D-Asn ^ Ile-Arp ^ ProNHCH1CH1 Preparation of the desired product is to use Fmoc-Nva instead of Fmoc-Thr (O-tBu), and Fmoc-D-Asn (Trt) to replace Fmoc-Nva. 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.005% TFA). Pure fractions can be freeze-dried to produce N-Ac-Nva-D-Asn-Ile-Arg-ProNHCH2CH3 as a trifluoroacetate. Example 150 N > Ac-Nva-D-Ser-Ile-Arg-ProNHCH1CH1 Preparation of the desired product is to replace Fmoc-Thr (O-tBu) with Fmoc-Nva and Fmoc-D-Ser (O-tBu) Nva, in Example 43. After processing, coarse

The peptide preparation was purified by HPLC, using a C-18 column and a solvent system, and the gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.005 TFA). Pure fractions can be freeze-dried to produce N-Ac-Nva-D-Ser-Ile-Arg-PrOHNHCH2CH3, which is trifluoroacetate. Example 1 5 1 N-Ac-Nva-B-Leu-Ile-Arg-ProNHrH ^ rf ^ Fmoc-Nva is used to replace Fmoc-Thr (O-tBu), and Fmoc-D-Leu is used to replace Fmoc- Nva, in Example 43. After processing, the crude peptide was -98- 200302833 (92)

Purified by HPLC, using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Nva-D-Leu-Ile-Ai: g-PrONHCH2CH3 as trifluoroacetate. Example 152

N-Ac-Sar-GlY.Va1-D-aTle-Thr-OH Put H-Thr (0-tBu) -2-chlorotrityl resin (0.2 g, 0.52) in the reaction tank of Rainin peptide synthesizer亳 Mol / g filler). The resin was solvated with DMF 'and the amino acid was coupled in sequence according to the following synthesis cycle: (1) 3x1.5 minutes, DMF strip washing; (2) 2 X 15 minutes, deprotection of 20% pyridine; 3) Wash with DMF for 6x3 minutes; (4) Add amino acid; (5) Activate and couple amino acid with 0.4 M HBTU / NMM; (6) Wash the strip with DMF for 3x1.5 minutes.

Protected amino acid coupling with protected amino acid coupling time__ Fmoc-D-alle 30 minutes Fmoc-Val 30 minutes Fmoc-Gly 30 minutes Fmoc-Sar 30 minutes acetic acid 30 minutes Synthesis can be carried out using a mixture of TFA / anisole / water (95: 2.5: 2.5) for 3 hours and dissociated from the resin. The peptide solution was concentrated under vacuum, and then -99-200302833 (93) was precipitated with diethyl ether and collected by filtration. The crude peptide was purified by HPL (: using a C-18 column and a solvent mixture with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions were freeze-dried to generate N-Ac -Sar-Gly-Val-D-alle-Thr-OH: Rt = 0.60 minutes (gradient change over 10 minutes' from 20% -80% acetonitrile / water (containing 0.000 / 〇TFA)); ms (ESI) m / e 502.28 (M + H) +. i Example 153 N_-Ac-Thr-Gln] le-Arg-following CHiCHySEO ID NO: 52) The desired product is prepared by Fmoc-Arg (Pbf)- [4- (4-N-Ethyl) methyl-3 -methoxyphenoxy] Butylenyl AM resin Ethylamidoamine resin replaces Fmoc-Pro-Sieber Ethylamidoamine resin, Fmoc-Gln (Trt) replaces Fmoc-Nva, and omit the coupling with Fmoc-Airg (Pmc), in Example 43. After the treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0 01〇 / 〇 TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Gln-Ile-Arg-NHCH2CH3 as a trifluoroacetate; Rt = 2.771 minutes (gradient change over 10 minutes, from 20% _80% acetonitrile / water (containing 0.01% TFA)); MS (ESI) m / e 586.3. Example 154 N-Ac-Thr-Nva-Ile ^ Arg ^ NHCH ^ H ^ SEO ID NO: 53) Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl -3-Methoxyphenoxy] butylammonium ammonium resin ethylammonium resin replaces Fmoc-Pro-Sieber ethylammonium resin, and the coupling with Fmoc-Arg (Pmc) is omitted, as in Example 43. After processing, the crude peptide was purified by HPLC using a C -18 column and a solvent system. The gradient was changed over 50 minutes from 5% -100% acetonitrile / -100- 200302833 (94) water (containing 0.01% TFA ). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Ile-Arg-NHCH2CH3 as a trifluoroacetate; Rt = 3.586 minutes (gradient change over 10 minutes, from 20% -80% acetonitrile / water (containing 〇 .〇i〇 / 〇TFA)); MS (ESI) m / e 557.3 0 Example 1 5 5

N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCK ^ CHi Preparation of the desired product is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -fluorene Phenoxy] butylammonium AM resin ethyl amidamine resin replaces Fmoc-Pro-Sieber ethyl donkey amine resin, Fmoc-Gln (Trt) replaces Fmoc-Nva, and the coupling with Fmoc-Arg (Pmc) is omitted. Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 156

N > Ac-D-Ile-Thr-Nva-Lvs (Ac > > > Arg-NHCH1CH1 The preparation of the desired product is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl- 3-Methoxyphenoxy] butylammonium AM resin ethylammonium resin replaces Fmoc-Pro-Sieber ethylammonamine resin, Fmoc-Lys (Ac) replaces Fmoc-lie, and omits with Fmoc-Arg (Pmc) The coupling was performed in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure flow Freeze-drying can produce N-Ac-D-Ile-Thr-Nva-Lys (Ac) -Arg-NHCH2CH3, which is trifluoroacetate. -101-

200302833 (95) Example 157 N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH7CHU The desired product is prepared by Fmoc-Arg (Pbf)-[4- (4-N-ethyl) fluorenyl- 3-Methoxyphenoxy] butylammonium AM resin ethylammonium resin replaced Fmoc-Pro-Sieber ethylammonium resin, Fmoc-Ser (O-tBu) replaced Fmoc-Thr (O-tBu), and omitted Coupling with Fmoc-Arg (Pmc), in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 158 N-Ac-D-aIle > Ser-Ser-Ile > Arg > NHCH1CH1 The desired product was prepared by Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxy Phenoxy] butylammonium AM resin ethyl amidamine resin replaces Fmoc-Pro-Sieber ethyl amine resin, Fmoc-D-alle replaces Fmoc-D-Ile 'Fmoc- Ser (O-tBu) replaces Fmoc-Thr ( O-tBu) and Fmoc-Nva, and the coupling with Fmoc-Arg (Pmc) is omitted, as in Example 1. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-aIle-Ser-Ser-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 159 N-Ac-D-alle-Thr-Nva-Ile-Arg-NUCH, the preparation of the desired product is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-102- 200302833 (96)

-3 -Methoxyphenoxy] Butylenyl AM Resin Ethyl Ammonium Resin Replaces Fmoc-Pro-Sieber Ethyl Ammonium Resin ’Fmoc-D-alle Replacement

Fmoc-D-Ile, and omit the coupling with Fmoc-Arg (Pmc), in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fraction cold beam drying can produce N-Ac-D-alle-Thr-Nva-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 160

N-Ac-D-Ile-Thr> Gln-Lvs (Ac) -Arg-NHCH1CH1 The preparation of the desired product is Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3-form Oxyphenoxy] Butylenyl AM resin Ethylamidoamine resin replaces Fmoc-Pro-Sieber Ethylamine resin, Fmoc-Gln (Trt) replaces Fmoc-Nva, Fmoc-Lys (Ac) replaces Fmoc-lie, and Decoupling with Fmoc-Arg (Pmc), as in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-D-Ile-Thr-Gln-Lys (Ac) -Afg-NHCH2CH3, which is trifluoroacetate. Example 161 N-Ac-D> aIle-Ser-Nva-Lvs (Ac) -Arg-NHCH1CH1 Preparation of the desired product is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl- 3 -methoxyphenoxy] butylammonium AM resin ethyl amidamine resin replaces Fmoc-Pro-Sieber ethyl amine resin, Fmoc-D-alle replaces Fmoc-Ile, Fmoc-Ser (O-tBu) replaces FmocThr ( O-tBu), Fmoc-Lys (Ac) replaces Fmoc-Ile, and the coupling with Fmoc-Arg (Pmc) is omitted. Handling -103- 200302833 (97)

The crude peptide was then purified by HPLC using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions are cold; dry in the east can produce N-Ac-D-aIle-Ser-Nva-Lys (Ac) -Arg-; NHCH2CH3, which is trifluoroacetate. Example 162 N-Ac-D ^ Ile-Thr-Ser-Ile-Arg-NHCH1CH1 The desired product was prepared by Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxy Phenoxy] butylammonium AM resin ethyl amidamine resin replaces g Fmoc-Pro-Sieber ethyl amidamine resin, Fmoc-Ser (O-tBu) replaces Fmoc-Nva, and omits with Fmoc-Arg (Pmc) Coupling, in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ile-Thr-Ser-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 163

N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH1CH1 The preparation of the desired product is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxybenzene Oxy] butylammonium AM resin ethyl amidamine resin replaces Fmoc-Pro-Sieber ethyl alcohol amine resin, Fmoc-NMeNva replaces Fmoc-Nva, the coupling with Fmoc-Arg (Pmc) is omitted, and the N-methyl Replace HATB with HATU in amino acid coupling, as in Example 1. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of ~ 50 minutes from 5% -100% acetonitrile / water (containing 0.01% TFA). Pure fractions freeze-dried to produce N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH2CH3, shown as • 104- 200302833 (98)

Fluoroacetate. Example 164 N-Ac-Ser-GhMle ^ Arg-NHCH ^ H ^ SEP ID NO: 54) Preparation of the desired product 'is based on Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl- 3-Methoxy + oxy] Butyl-based AM resin Ethylamine resin replaces Fmoc-Pro-Sieber Ethylamine resin, Fmoc-Ser (O-tBu) replaces Fmoc-Thr (O-tBu), Fmoc -Gln (Trt) replaces Fmoc-Nva and omits coupling with Fmoc-Arg (Pmc), as in Example 43. After the treatment, the crude peptide was purified by HPLC using a C.18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Ser-Gln-Ile-Arg-NHCH2CH3 as a trifluoroacetate. Example 165 N-Ac-Ser-SePlle-Arg-NHCH ^ CH ^ SEO ID NO: 55) The product was prepared by replacing Fmoc-Pro-Sieber with Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxyphenoxy] butylammonium AM resin and ethylammonium resin. Ethylamine resin, Fmoc-Ser (O-tBu) replaced Fmoc-Thr (O-tBu), and Fmoc-Nva, and the coupling with Fmoc-Arg (Pmc) was omitted, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Cold fraction drying of pure fractions can produce N-Ac-Ser-Ser-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 166 N-Ac-Thr-Nva-LvsiAcVArg-NHCH ^ CHYSEO ID NO: 56) The desired product was prepared using Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl 200302833 (99) -3 -methoxyphenoxy] butylammonium AM resin ethylamine resin replaces Fmoc-Pro-Sieber ethylammonium resin, Fmoc-Lys (Ac) replaces Fmocc "le, and omits Fm O-Arg (PmC) coupling, as in Example 43. After the treatment, the crude peptide was purified by HPLC 'using a C-18 column and a solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Nva-Lys (Ac) -Arg-NHCH2CH3 as a trifluoroacetate. f Example 167 N-Ac-Thr-Gln ^ LysfAc ^ rg ^ NHCHoCH ^ SEO ID NO: 57) Fm0C-Arg (Pbf)-[4- (4-N-ethyl) methyl- 3-Methoxyphenoxy] butylammonium ammonium resin, ethylammonium resin replace Fmoc-Pro-Sieber ethylammonium resin, Fmoc-Gln (Trt) replaces Fmoc-Nva 'Fmoc-Lys (Ac) replaces Fmoc-Ile And omit the coupling with Fmoc-Arg (Pmc), as in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Thr-Gln-Lys (Ac) -Arg-NHCH2CH3 'as trifluoroacetate 0 Example 168 N ^ Ac-Thr ^ Ser-Ile-Arg-NHCH ^ H ^ SEQ ID NO: 58) The preparation of the desired product is to replace Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxyphenoxy] butylammonium ammonium ethyl resin with Fmoc-Arg (Pbf)-[4] -Pro-Sieber ethylamidamine resin, Fmoc-Met replaces Fmoc-Thr (O-tBu), and the coupling with Fmoc-Arg (Pmc) is omitted, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system. The ladder-106-200302833 (100) degree was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-Thr-Ser-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 169

N-Ac-Met-Nva-Ile-Arg-NHCH ^ H ^ SEQ ID NO: 59) The desired product is prepared by Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -Methoxyphenoxy] Butylenyl AM resin Ethyl Ammonium resin replaces Fmoc-Pro-Sieber Ethylamine resin and Fmoc-Met replaces Fmoc-Thr (O-tBu), and eliminates the need for Fmoc-Arg ( Pmc) coupling, in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-Met-Nva-Ile-Arg-NHCH2CH3 as a trifluoroformate. Example 170 N-Ac-Thr-NMeNva-Ile-Arg-NHCH ^ CHySEO ID NO: 60)

For the preparation of the product, Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3-methoxyphenoxy] butylammonium AM resin ethylammonium resin is used instead of Fmoc-Pro- Sieber ethylammonium resin, Fmoc-NMeNva instead of Fmoc-Nva, the coupling with Fmoc-Arg (Pmc) was omitted, and HATU was used instead of HBTU in the coupling with N-methylamino acid, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and solvent system. The gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Thr-NMeNva-Ile-Arg-NHCH2CH3, which is trifluoroacetate. -107- 200302833 (101)

Example 171 N-Ac-D-Nva-Gln-Ile-Arg-NHCH ^ CH ^ The desired product was prepared by Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -formaldehyde Ethoxyphenoxy] Butylenyl AM Resin Ethyl Ammonium Resin Replaces Fmoc-Pro-Sieber Ethyl Ammonium Resin, Fmoc-D-Nva Replaces Fmoc-

Thr (O-tBu), Fmoc-Gln (Trt) replaced Fmoc-Nva, and the coupling with Fmoc-Arg (Pmc) was omitted, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-D-Nva-Gln-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 172 N-Ac-Ser-Nva-Ile-Arg-NHCH ^ CHJSEO ID NO: 61) The desired product was prepared using Fmoc-Arg (Pbf)-[4- (4-N-ethyl) fluorenyl-3 -Methoxyphenoxy] butylammonium AM resin ethyl amidamine resin replaces Fmoc-Pro-Sieber ethyl amidamine resin, Fmoc-Ser (O-tBu) replaces Fmoc-

Thr (O-tBu), and omit the coupling with Fmoc-Arg (Pmc), in Example 43. After treatment, the crude peptide was purified by HPLC using a C-18 column and a solvent system 'for a gradient change of 50% from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to form N-Ac-Ser-Nva-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 173 N-Ac-D-Thr-Gln-Ile-Arg-NHCHiCHi The desired product was prepared using Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -methoxybenzene Oxy] butylammonium AM resin ethyl amidamine resin replacement -108- 200302833 (102)

Fmoc-Pro-Sieber Ethyl Ammonium Resin '^^^^^^^-But Dagger-Replace ... Replace Fmoc-Thr (O-tBu), Fmoc-Gln (Trt) Replace Fmoc-Nva' and omit ? 111〇 (:-Baqiao (? 1) 1〇) Coupling 'in Example 43. After treatment, the crude skin was purified with 1 ·!?! ^, Using a C-18 column and a solvent system, and the gradient was changed over 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Thr-Gln-Ile-Arg-NHCH2CH3, which is trifluoroacetate. Example 174 N ~ Ac-D ^ Ser-Gln-Ile> Arg-NHCH1CH1 The desired product was prepared by using Fmoc-Arg (Pbf)-[4- (4-N-ethyl) methyl-3 -fluorenyl + Oxy] Butyl-based AM resin Ethylamine resin replaces Fmoc-Pro-Sieber Ethylamidamine resin, Fmoc-D-Ser (O-tBu) replaces Fmoc-Thr (O-tBu), Fmoc-Gln (Trt ) Instead of Fmoc-Nva, and the coupling with Fmoc-Arg (Pmc) is omitted, as in Example 43. After processing, the crude peptide was purified by HPLC using a C-18 column and a solvent system with a gradient change of 50 minutes from 5% to 100% acetonitrile / water (containing 0.01% TFA). Pure fractions can be freeze-dried to produce N-Ac-D-Ser-Gln-Ile, Arg_NHCH2CH3, which is trifluoroacetate. It will be apparent to those skilled in the art that the present invention is not limited to the above-mentioned illustrative examples, and there may be specific examples in other special types as long as it does not deviate from its basic contribution. Therefore, the examples are intended to be illustrative and not restrictive in all respects. Reference is made to the scope of the attached patent application, not the foregoing examples, and all changes within the same scope as the definition and scope of the patent application are included. -109- 200302833 SEQUENCE LIST < 110〉 Abbott Laboratories Haviv, Fortuna Bradley, Michael F. < 120 > Seven, Eight & Nine Peptides with Anti-angiogenic Properties < 130〉 6854.US.P1 < 140〉 091132161 ,

< 141〉 2002/10/30 < 150 > 10 / 000,540 < 151〉 2001-10-31 < 150〉 10 / 000,007 < 151 > 2001-10-31 < 160〉 61 < 170〉 FastSEQ for Windows Version 4.0 < 210> 1 < 211> 8 < 212 > PRT < 213> Artificial sequence < 220 > < 22 3> Anti-angiogenic peptide < 221 > Variant < 222 > (1) ... (1) < 223> Xaa = hydrogen or R- (CH2) nC (0)-, where η is an integer from 0 to 8, R is alkoxy, alkyl, amino , Aryl, carboxyl, cycloalkenyl, cycloalkyl and heterocyclic, at the 1 position 200302833

< 221〉 Variant < 222〉 (2) ... (2) &223; Xaa = bAla and lie in 2 positions < 221 > Variation < 222〉 (3) ... (3) < 223> Xaa = All Thr, Allyl Gly, Asn, Asp, Gin, N-methylglutamine §1 Amino group, Glu, N-methylglutamine S & group, Gly, His, Hser, lie, Lys (Ac), Met, Nle, Nva, Sar, Ser, N-methylseramine, Thr, Trp and Tyr, at position 3 < 221 > variant < 222 > (3) ... (3) ) < 223 > 3 (continued)

Xaa = Tyramine (O-methyl), at the 3 position < 221 > Variation < 222〉 (4) ... (4) < 223〉 Xaa = N-fluorenylpropylamine Thr, Arg, Asn, Cit, Gin, Glu, Gly, Hser, Leu, Lys (Ac), Lys (Nic), Nle, Nva, NMeNva, Orn (Ac), 3-Pal, Sar, Ser, N- Methylseramine, Thr, Trp, Val, and N-methylvalinyl, at 4 position < 221 > Variation < 222〉 (5) ... (5) &223; Xaa = Ala , Alle, Asp, Cit, Gin, lie, N-methylisoleucine, Leu, Lys, Lys (Ac), Nle, Nva, Phe, Pro and Val at 5 positions

200302833 < 221 > Variation < 222〉 (6) ... (6) < 223〉 Xaa = Arg, Cit, His, Lys, Lys (Isp), Orn and 3-Pal in 6 positions < 221 〉 Variations < 222 > (7) ... (7) < 223> Xaa = 2-aminobutyridinyl, 2-aminoisobutyridyl, homoproline, hydroxyproline, Leu, Phe, Pro and Thr, at position 7 < 221 > Variation < 222 > (8) ... (8) < 223> Xaa = Acrylamine fluorenyl ammonium amine, glycamine fluorenyl amine, hydroxyl, -1 ^ 11-((: 112) 11-CHR1R2, -NHR3, where η is an integer from 0 to 8, R1 is hydrogen, alkyl, cyclofluorenyl, and cycloalkyl at the 8 position < 221 > variant < 222 > (8) ... (8) < 223〉 8 (continued)

Xaa = R2 is hydrogen, alkoxy, alkyl, aryl, cyclofluorenyl, cycloalkyl, heterocyclic, and hydroxyl, with the limitation that when η is 0, R2 is not alkoxy or hydroxyl, at position 8 < 221> Variations < 222 > (8) ... (8) < 223> 8 (continued) are chlorine, cyclohexyl, cycloalkynyl and #stem base, the limitation is when it is D-allisobar Amine group, Xaa7 is threonyl group and Xaa8 is a hydroxyl group, at 8

200302833 in position < 400〉 1

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 < 210 > 2 < 211〉 8 < 212 > PRT < 213> Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > Variation <; 222〉 (1) ... (1) < 223〉 Xaa = hydrogen or R- (CH2) nC (0)-, where η is an integer from 0 to 8, R is alkoxy, alkyl, Amine, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocyclic ring at 1 position

< 221 > Variation < 222 > (2) ... (2) < 223 > Xaa = bAla and lie in 2 position < 221 > Variation < 222 > (3) ... (3) < 223> Xaa = Both Thr, Asp, Gin, N-methylglutamine and amidino, Gly, His, Hser, lie, Lys (Ac), Met, Set, N-methylseramine, Thr, Ti * ρ, Tyr, and Tyramine (O-methyl) at the 3 position < 221 > Variation < 222 > (4) ... (4) -4-

200302833 < 223> Xaa = N-methylpropylamine, other Thr, Arg, Gin, Gly, Hser, Leu, Lys (Ac), Nle, Nva, NMeNva, Orn (Ac), 3-Pal, Sar, Ser, N-methylseramine group, Thr, Trp, Val and N-methylvaleramine group at position 4 < 221 > Variation < 222〉 (5) ... (5) < 223> Xaa = Ala, alle, Asp, Cit, Gin, lie, N-methylisoleucine donkey, Leu, Lys, Lys (Ac), Nle, Nva, Phe, and Pro at 5 position < 221 > variant < 222> (6) ... (6) < 223 > Xaa = Arg, Cit, His, Lys, Lys (Isp), Orn and 3-Pal at 6 positions < 221 > Variation < 222 > (7 ) ... (7) < 223> Xaa = 2-aminobutyryl, 2-aminoisobutyryl, homoprolyl, hydroxyprolyl, Leu, Phe, and Pro at 7 position < 221 〉 Modifications < 222〉 (8) ... (8) < 223> Xaa = Acrylamine fluorenyl ammonium amine, glycamine fluorenyl amine, hydroxyl group,-> ^-((: 112) 11- CHR1R2, -NHR3, where η is an integer from 0 to 8, R1 is hydrogen, alkyl, cycloalkenyl, and cycloalkyl, at position 8 < 221〉 variant < 222〉 (8) ... ( 8) < 223〉 8 (continued)

Xaa = R2 is hydrogen, alkoxy or alkyl, aryl, cyclofluorenyl, cycloalkyl, hetero

200302833 Ring and hydroxyl group at position 8 < 221> Variation < 222 > (8) ... (8) < 223 > 8 (continued)

Xaa = The limiting condition is that when n = 0, R2 is not an alkoxy group and a hydroxyl group at the 8 position < 221〉 Variation < 222 > (8) ... (8) < 223> 8 (continued)

Xaa = R3 is hydrogen, cyclofluorenyl, cycloalkyl, and hydroxyl, at position 8 < 400 > 2

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 < 210 > 3 < 211〉 7 < 212 > PRT < 213〉 Artificial sequence < 220 > < 223〉 Anti-angiogenic peptide < 221〉 Variant < 222 > (1) ... (1) < 223 > Xaa = hydrogen or R- (CH2) nC (0)-, where η is an integer from 0 to 8, R is alkoxy, alkyl, Amino group, aryl group, carboxyl group, cycloalkenyl group, cycloalkyl group and heterocyclic ring at position 1 < 221 > Variation < 222 > (2) ... (2) 200302833

< 223> Xaa = Both Thr, Glycyl Gly, Asn, Asp, Gin, Glu, N-methylglutamine, Gly, His, Hiser, lie, Lys (Ac), Met, Nle, Nva, Sar, Ser, N-methylseramine, Thr, Trp, Tyr, and enzymatic amine (0-) methyl at 2 position < 221 > Variation < 222 > (3) ... (3) < 223> Xaa = N-methylpropylamine, other Thr., Arg, Asn, Cit, Gin, Glu, Gly, Hser, Leu, Lys (Ac), Lys (Nic), Nle, Nva, NMeNva, Orn (Ac), 3-Pal, Sar, and Ser in 3 positions < 221 > Variation < 222 > (3) ... (3) < 223 > 3 (continued)

Xaa = N-methylseramine group, Thr, Trp, Val and N-methylvaleramine group at 3 positions < 221〉 Variation < 222〉 (4) ... (4) < 223> Xaa = Ala, alle, Asp, Cit, lie, N-methylisoleucine, Leu, Lys, Lys (Ac), Nva, Phe, Pro and Val at 4 positions < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = Arg, Cit, His, Lys, Lys (Isp), Orn and 3-Pal at 5 positions < 221 > Variation < 222 > (6) .. (6) < 223> Xaa = 2-aminobutyridinyl, 2-aminoisobutyridinyl, homoproline, hydroxyl 200302833

Proline methyl group, Leu, Phe, Pro and Thr at 6 position < 221> Variation < 222 > (7) ... (7) < 223> Xaa = 1; Glycinylamine, hydroxyl, -1 ^ 11-((1; 112) 11-CHR1R2, -NHR3, where η is an integer from 0 to 8, R1 is hydrogen, alkyl, cycloalkenyl, and cycloalkane Base at 7 position < 221〉 variant < 222〉 (7) ... (7) < 223 > 7 (continued)

Xaa = R2 is hydrogen, alkoxy or alkyl, aryl, cycloalkenyl, cycloalkyl, heterocyclic and hydroxyl at the 7 position < 221 > Variation < 222〉 (7) ... (7) < 223 > 7 (continued)

Xaa = The limiting condition is that when n = 0, R2 is not an alkoxy group and a hydroxyl group at the 7 position < 221〉 Variant < 222〉 (7) ... (7) < 223 > 7 (continued)

Xaa = R3 is hydrogen, cycloalkenyl, cycloalkyl, and hydroxy. The limitation is that when Xaa5 is D-isoisoamidofluorenyl, Xaa6 is threonamido, and Xaa7 is hydroxyl, at position 7 < 400 > 3

Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 < 210 > 4

200302833 < 211> 5 < 212> PRT < 213 > Artificial sequence < 220> < 223> Anti-angiogenic peptide < 221> Variant < 222 > (2) ... (2) < 223> Xaa = Nva, at position 2 < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = proline amidinoethylethylamine, at position 5 < 400 > 4

Thr Xaa lie Arg Xaa 1 5 < 210 > 5 < 211> 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > variant < 222 > (1) ... (1) < 223 > Xaa = Don't Thr in position 1 < 221 > Variation < 222 > (2) ... (2)

200302833 < 223〉 Xaa = Nva in 2 position < 221〉 Variant < 222〉 (5) ... (5) < 223〉 Xaa = Proline amidinoethylethylamine, in 5 position < 400 > 5

Xaa Xaa lie Arg Xaa 1 5

< 210 > 6 < 211 > 5 < 212 > PRT < 213> Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > Variation < 222 > (5) ... (5) ... 5)

< 22 3> Xaa = proline amidinoethylamidine at the 5 position < 400 > 6

Thr Gin He Arg Xaa 1 5 < 210 > 7 < 211〉 6 < 212〉 PRT < 213 > Artificial sequence < 220 > < 223> Antiangiogenic peptide -10- 200302833

< 221〉 Variation < 222 > (1) ... (1) < 223 > Xaa = N- (6-methylnicotinylfluorenyl) at 1 position < 221> Variation < 222 > (3 ) ... (3)

< 223> Xaa = Nva in 3 position < 221 > Variation < 222 > (6) ... (6) < 223> Xaa = Proline amidinoethylethylamine in 6 position < 400 > 7

Xaa Thr Xaa lie Arg Xaa 1 5 < 210〉 8 < 211〉 5

< 212 > PRT < 213> Artificial sequence < 220> < 223> Anti-angiogenic peptide < 221> Variant < 222 > (5) ... (5) < 223> Xaa = proline Amidinoethylamidine, at 5 position < 400 > 8

Ser Ser lie Arg Xaa 1 5 < 210 > 9 -11-200302833 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221〉 variant < 222 > (5) ... (5) < 223 > Xaa = proline methyl ethyl amine, at position 5 < 400 > Thr Ser 1 9 lie Arg Xaa 5 < 210> 10 < 211> 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221 > Variation < 222 > (2) ... (2) < 223 > Xaa = NMeNva in 2 position < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = Proline ethyl ethyl amine, in position 5 < 400 > 10 Thr Xaa lie Arg Xaa 1 5

-12- 200302833 < 210〉 11 < 211〉 5 < 212〉 PRT < 213〉 artificial sequence < 220 >

< 223 > Anti-angiogenic peptide < 221 > Variation < 222 > (2) ... (2) < 223 > Xaa = Nva at 2 position < 221> Variation < 222 > (5). .. (5) < 223 > Xaa = proline amidinoethylamidine, at position 5 < 400 > 11

Tyr Xaa lie Arg Xaa 1 5

< 210 > 12 < 211 > 5 < 212 > PRT < 213 > artificial sequence < 220 > < 223> antiangiogenic peptide < 221 > variant < 222 > (5) ... 5) < 223> Xaa = proline amidinoethylethylamine, at position 5-13-13200302833 < 400 > 12 Ser Gin lie Arg Xaa 1 5 < 210> 13 < 211> 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221〉 Variation < 222〉 (2) ... (2) < 223 > Xaa = Nva in 2 position < 221> Variations < 222 > (3) ... (3) < 223> Xaa = Lys (Ac) in 3 positions < 221 > Variations < 222 > (5) ... (5) < 223 > Xaa = Proline Proethyl Ethylamine < 400 > 13 Thr Xaa Xaa Arg Xaa in 5 position 1 5 < 210〉 14 < 211〉 5 < 212〉 PRT < 213 > Artificial Sequence < 220 >

-14-

200302833 < 223 > Anti-angiogenic peptide < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = Proline amidinoethylamidine, at position 5 < 400 > 14

Ser Thr lie Arg Xaa 1 5 < 210〉 15

< 211〉 5 < 212 > PRT < 213 > artificial sequence < 220〉 < 223〉 anti-angiogenic peptide < 221 > variant < 222 > (1) ... (1)

< 223〉 Xaa = NMeGlu in 1 position < 221〉 Variation < 222 > (2) .., (2) < 223 > Xaa = Nva in 2 position < 221 > Variation < 222〉 (5) ... (5) < 223> Xaa = proline amidinoethylamidine, at position 5 < 400 > 15

Xaa Xaa lie Arg Xaa 1 5 -15-

200302833 < 210 > 16 < 211〉 5 < 212〉 PRT < 213〉 artificial sequence < 220 >

< 223> Anti-angiogenic peptide < 221 > variant < 222 > (2) ... (2) < 223 > Xaa = Nva at 2 position < 221 > variant < 222 > (5). .. (5) < 223> Xaa = proline amidinoethylethylamine, at position 5 < 400 > 16

Met Xaa lie Arg Xaa

1 5 < 210 > 17 < 211 > 5 < 212 > PRT < 213 > artificial sequence < 220〉 < 223〉 antiangiogenic peptide < 221> variant < 222 > (1) " . (1) < 223 > Xaa = Lys (Ac) in position 1 < 221 > variant • 16 ·

200302833 < 222〉 (2) ... (2) < 223〉 Xaa = Nva in 2 position < 221〉 Variation &222; (5) ... (5) &223; Xaa = proline Amidinoethylamidine, 5 position < 400 > 17

Xaa Xaa lie Arg Xaa 15

< 210〉 18 < 211〉 5 < 212 > PRT < 213〉 artificial sequence < 220〉

< 223> Anti-angiogenic peptide < 221> Variation < 222 > (2) ... (2) < 223 > Xaa = Nva at 2 position < 221 > Variation < 222 > (5). .. (5) < 223 > Xaa = proline amidinoethylamidine, at position 5 < 400 > 18

Gin Xaa lie Arg Xaa 1 5 < 210> 19 < 211 > 5 -17- 200302833

< 212〉 PRT < 213〉 Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > Variation < 222〉 (1) ... (1)

< 223 > Xaa = Don't Thr at 1 position < 221〉 Variation < 222 > (5) ... (5) < 223> Xaa = Proline amidinoethylethylamine, at 5 position

< 400 > 19

Xaa Ser lie Arg Xaa 1 5 < 210 > 20 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > variant < 222> (1) ... (1) < 223〉 Xaa = Don't Thr in position 1 < 221〉 Variation < 222〉 (2) ... (2) < 223〉 Xaa = Nva in position 2-18 -200302833

< 221 > Variation < 222 > (5) ... (5) < 223> Xaa = Proline Si-ethyl ethyl amine, at position 5 < 400 > 20

Xaa Xaa Pro Arg Xaa 1 5 < 210〉 21 < 211〉 5

< 212〉 PRT < 213〉 Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > Variation < 222〉 (2) ... (2)

< 223 > Xaa = Nva in 2 position < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = Proline aminoethyl amine, in position 5 < 400 > twenty one

Trp Xaa lie Arg Xaa 1 5 < 210 > 22 < 211〉 5 < 212 > PRT < 213〉 artificial sequence -19-

200302833 < 220 > < 223> Anti-angiogenic peptide < 221 > Variation < 222 > (2) ... (2) < 223> Xaa = Nva at 2 position < 221> Variation < 222 〉 (5) ... (5)

< 223> Xaa = proline amidinoethylamidine, at position 5 < 400 > 22

Thr Xaa lie Arg Xaa 1 5 < 210 > 23 < 211〉 5 < 212 > PRT < 213> artificial sequence < 220 >

< 223> Anti-angiogenic peptide < 221> Variation < 222 > (2) ... (2) < 223> Xaa = Nva at 2 position < 221 > Variation < 222 > (5). .. (5) < 223 > Xaa = proline amidinoethylamidine, at position 5 < 400 > 23

Thr Xaa Pro Arg Xaa 1 5 -20- 200302833 < 210〉 24 < 211 > 5 < 212〉 PRT < 213 > Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > variant < 222 > (3) ... (3) < 223 > Xaa = Lys (Ac) in 3 position < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = Proline ethyl ethyl amine < 400 > 24 Ser Gin Xaa Arg Xaa in 5 position 1 5 < 210 > 25 < 211 > 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > Variation < 222 > (1) ... (1) < 223 > Xaa = Hydroxypropyl Gly at 1 position-21 200302833

< 221 > Variation < 222〉 (5) ... (5) < 223〉 Xaa = proline amidinoethylamidine, at position 5 < 400 > 25

Xaa Gin lie Arg Xaa 1 5 < 210〉 26 < 211〉 5

< 212 > PRT < 213〉 Artificial sequence < 220 > < 223〉 Anti-angiogenic peptide < 221〉 Variation < 222〉 (2) ... (2)

< 223> Xaa = Nva at 2 position < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = Proline amidinoethylethylamine, at 5 position < 400 > 26

Thr Xaa Lys Arg Xaa 1 5 < 210 > 27 < 211〉 5 < 212 > PRT < 213 > Artificial Sequence-22- 200302833 < 220> < 223 > Anti-angiogenic peptide < 221 > variant < 222〉 (2) ... (2) < 223 > Xaa = Nva at 2 position < 221〉 Variation < 222 > (4) ... (4) < 223 > Xaa = Orn at 4 Position < 221 > Variant < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 27 Thr Xaa lie Xaa Xaa 1 5 < 210 > 28 < 211 > 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221〉 Variation < 222 > (2) ... (2) < 223 > Xaa = Nva In 2 position < 221 > variant < 222 > (5) ... (5)

-23- 200302833 < 223 > Xaa = proethylamide in 5 position < 400 > 28 Glu Xaa lie Arg Xaa 1 5 < 210 > 29 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 〉 ≪ 223〉 Antiangiogenic peptide < 221 > Variation < 222 > (2) ... (2) < 223〉 Xaa = Nva at 2 position < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = proethylamide in 5 position < 400 > 29 Asn Xaa lie Arg Xaa 1 5 < 210 > 30 < 211 > 5 < 212> PRT < 213 > Artificial sequence <; 220 > < 223> antiangiogenic peptide

-24- 200302833 < 221 > Variation < 222 > (1) ... (1) < 223〉 Xaa = Hser in 1 position < 221> Variation < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 position < 221 > Variation < 222 > (5) ... (5) < 223> Xaa = proethylamide in 5 position < 400> 30

Xaa Xaa Ike Arg Xaa 1 5 < 210 > 31 < 211〉 5 < 212 > PRT < 213 > < 220 > Artificial sequence < 223 > Anti-angiogenic month month < 221 > variant < 222 & gt (1) ... (1) < 223 > Xaa = Sar in 1 position < 221 > Variation < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 position < 221 > Variation 200302833 < 222〉 (5) ... (5) < 223〉 Xaa = proethylamide at 5 position < 400 > 31 Xaa Xaa lie Arg Xaa 1 5 < 210 > 32 < 211〉 5 < 212> PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221 > Variant < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 Position < 221 > Variation < 222〉 (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 32 Asp Xaa lie Arg Xaa 1 5 < 210〉 33 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 >

26- 200302833 < 223〉 Anti-angiogenic peptide < 221〉 Variation < 222〉 (3) ... (3) &223; Xaa = Nva in 3 position < 221 > Variation < 222 > ( 5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 33 Ser Gin Xaa Arg Xaa 1 5 < 210 > 34 < 211 > 5 < 212 > PRT < 213 > manual Sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > variant < 222 > (4) ... (4) < 223 > Xaa = Cit < 221 > variant < 222 > (5 ) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 34 Ser Gin lie Xaa Xaa 1 5

-27- 200302833 < 210〉 35 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221 > Variant < 222 > (4) ... (4) < 223 > Xaa = 3Pal in 4 position < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 35 Ser Gin lie Xaa Xaa 1 5 < 210 > 36 < 211 > 5 < 212〉 PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221〉 Variant < 222〉 ( 3) ... (3) < 223 > Xaa = Nva in 3 position < 221 > variant

-28- 200302833 < 222〉 (5) ... (5) < 223〉 Xaa = proethylamide in 5 position < 400 > 36 Thr Gin Xaa Arg Xaa 1 5 < 210 > 37 < 211〉 5 < 212> PRT < 213> Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221〉 Variation < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 37 Thr Asn lie Arg Xaa 1 5 < 210> 38 < 211 > 5 < 212 > PRT < 213 > artificial sequence < 220 > < 223 > antiangiogenic peptide < 221 > variants < 222 > (2) ... (2)

-29- 200302833

< 223 > Xaa = Nva in 2 position < 221〉 Variation < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400> 38 Thr Xaa Pro Arg Xaa 1 5 < 210> 39 < 211 > 5 < 212> PRT < 213> Artificial sequence < 220> < 223 > Anti-angiogenic peptide < 221 > Variation < 222 > ⑴ ·· ⑴ < 223〉 Xaa = Nva in 1 position < 221 > Variation < 222〉 (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 39 Xaa Gin lie Arg Xaa 1 5 < 210 > 40 < 211 > 5 < 212 > PRT

-30- 200302833 < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221 > Variant < 222〉 (4) ... (4) < 223 > Xaa = Cit in 4 Position < 221 > Variant < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position &400; 40 Thr Arg lie Xaa Xaa 1 5 < 210 > 41 < 211 > 5 < 212 > PRT < 213〉 Artificial sequence < 220> < 223 > Antiangiogenic peptide < 221 > Variant < 222 > (3) ... (3) < 223> Xaa = Lys (Ac) in 3 position < 221 > variant < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 41

-31-200302833

Thr Gin Xaa Arg Xaa 1 5 < 210 > 42 < 211〉 5 < 212 > PRT < 213〉 Artificial sequence < 220> < 223 > Anti-angiogenic peptide < 221 > Variant < 222 > (3) ... (3) < 223> Xaa = Lys (Ac) in 3 position < 221〉 Variation < 222 > (5) ... (5) < 223> Xaa = proethylaxnide in 5 position < 400〉 42 Thr Ser Xaa Arg Xaa 1 5 < 210〉 43 < 211〉 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > Variations < 222 > (2) ... (2)

-32-

200302833 < 223〉 Xaa = Cit in 2 position < 221 > Variation < 222〉 (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 43

Thr Xaa lie Arg Xaa

1 5 < 210 > 44 < 211> 6 < 212 > PRT < 213 > artificial sequence < 220> < 223> antiangiogenic peptide < 221 > variant < 222 > (1) .. . (1) < 223 > Xaa = N-3Mev in 1 position < 221 > Variation < 222 > (6) ... (6) < 223 > Xaa = proethylamide in 6th place < 400> 44 Xaa Thr Gin lie Arg Xaa 1 5 < 210 > 45 < 211 > 6 < 212〉 PRT -33-200302833 < 213 > Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221 > variant < 222〉 ⑴ ... (1) < 223> Xaa = N-3Mev in 1 position < 221 > Variation < 222 > (3) ... (3) < 223> Xaa = Nva in 3 position < 221〉 Variations < 222 > (6) ... (6) < 223 > Xaa = proethylamide in 6 position < 400 > 45 Xaa Thr Xaa lie Arg Xaa 1 5 < 210〉 46 < 211 > 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221〉 Variation < 222 > (5) ... (5) < 223> Xaa = proethylamide in 5 position < 400> 46

-34- 200302833

Ser Trp lie Arg Xaa 1 5 < 210〉 47 < 211〉 5 < 212〉 PRT < 213〉 Artificial sequence < 220〉 < 223 > Antiangiogenic peptide < 221 > Variant < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400〉 47 Thr Trp lie Arg Xaa 1 5 < 210〉 48 < 211〉 6 < 212 > PRT < 213 > Artificial sequence < 220> < 223 > Antiangiogenic peptide < 221> Variation < 222 > (2) ... (2) < 223 > Xaa = Lys (Ac) in 2 position < 221 > Variations < 222 > (5) ... (5)

-35-

200302833 < 223〉 Xaa = proethylamide in 5 position

< 400 > 48 Thr Xaa lie Arg Xaa 1 5 < 210 > 49 < 211 > 6 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221 > Variation < 222> (1) ... (1) < 223 > Xaa = bAla in 1 position < 221 > Variation < 222 > (3) ... (3) < 223 > Xaa = Nva in 3 position < 221 > variant < 222〉 (6) ... (6) < 223 > Xaa = proethylamide in 6 position < 400 > 49 Xaa Thr Xaa lie Arg Xaa 1 5 < 210> 50 < 211 > 6 < 212 > PRT

-36- 200302833 < 213 > Artificial sequence < 220 > < 223〉 Antiangiogenic peptide < 221〉 Variation < 222 > (1) ... (1) < 223 > Xaa = bAla in 1 Position < 221 > Variation < 222 > (6) ... (6) < 223 > Xaa = proethylamide in 6 position < 400 > 50 Xaa Thr Gin lie Arg Xaa 1 5 < 210 > 51 < 211 > 5 < 212 > PRT < 213 > artificial sequence < 220 > < 223 > antiangiogenic peptide < 221 > variant < 222 > (1) ... (1) < 223> Xaa = Nle in 1 position < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = proethylamide in 5 position < 400 > 51

-37- 200302833

Xaa Gin lie Arg Xaa 1 5 < 210 > 52 < 211〉 5 < 212〉 PRT < 213 > Artificial sequence < 220〉 < 223〉 Antiangiogenic peptide < 221 > Variant < 222 > (5) ... (5) < 223〉 Xaa = NHCH2CH3 in 5 position < 400〉 52 Thr Gin lie Arg Xaa 1 5 < 210〉 53 < 211 > 5 < 212〉 PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > Variation < 222 > (2) ... (2) < 223 > Xaa = Nva at 2 position < 221 > Variation < 222〉 (5) ... (5)

-38- 200302833 < 223〉 Xaa = NHCH2CH3 in 5 position < 400 > 53 Thr Xaa lie Arg Xaa 1 5 < 210〉 54 < 211〉 5 < 212〉 PRT < 213 > Artificial sequence < 220 〉 ≪ 223 > Antiangiogenic peptide < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = NHCH2CH3 at 5 position < 400 > 54 Ser Gin lie Arg Xaa 1 5 < 210 > 55 < 211 > 5 < 212 > PRT < 213 > artificial sequence < 220 > < 223 > antiangiogenic peptide < 221 > variant < 222 > (5) ... ( 5) < 223 > Xaa = NHCH2CH3 is in 5 position

-39- 200302833 < 400 > 55 Ser Ser lie Arg Xaa 1 5 < 210 > 56 < 211 > 5 < 212 > PRT < 213〉 Artificial sequence < 220 > < 223> Anti-angiogenic peptide < 221> Variation < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 position < 221 > Variation < 222〉 (3) ... (3) < 223 > Xaa = Lys (Ac) in 3 position < 221 > Variant < 222 > (5) ... (5) < 223 > Xaa = NHCH2CH3 in 5 position < 400> 56 Thr Xaa Xaa Arg Xaa 1 5 < 210 > 57 < 211 > 5 < 212〉 PRT < 213〉 artificial sequence

-40- 200302833 < 220 > < 223> Anti-angiogenic peptide < 221 > variant < 222 > (3) ... (3) < 223 > Xaa = Lys (Ac) in 3 position < 221〉 Variations < 222 > (5) ... (5) < 223 > 5 position < 400 > 57 Thr Gin Xaa Arg Xaa 1 5 < 210 > 58 < 211 > 5 < 212 > PRT < 213 > Artificial sequence < 220 > < 223 > anti-angiogenic peptide < 221 > variant < 222 > (5) ... (5) < 223 > Xaa = NHCH2CH3 at 5 position < 400 > 58 Thr Ser lie Arg Xaa 1 5 < 210 > 59 < 211〉 5

• 41 · 200302833 < 212 > PRT < 213 > artificial sequence < 220 > < 223> antiangiogenic peptide < 221 > variant < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 position < 221 > Variation < 222〉 (5) ... (5) < 223 > Xaa = NHCH2CH3 in 5 position < 400〉 59 Met Xaa lie Arg Xaa 1 5 < 210〉 60 < 211> 5 < 212> PRT < 213 > Artificial sequence < 220 > < 223 > Anti-angiogenic peptide < 221 > Variation < 222> (2) ... (2) < 223〉 Xaa = NMeNva in 2 position < 221〉 Variation < 222 > (5) ... (5) &223; Xaa = NHCH2CH3 in 5 position

-42- 200302833 < 400 > 60 Thr Xaa lie Arg Xaa 1 5 < 210 > 61 < 211〉 5 < 212 > PRT < 213> Artificial sequence < 220 > < 223 > Antiangiogenic peptide < 221> Variation < 222 > (2) ... (2) < 223 > Xaa = Nva in 2 position < 221 > Variation < 222 > (5) ... (5) < 223 > Xaa = NHCH2CH3 in 5 position < 400 > 61 Ser Xaa lie Arg Xaa 1 5

-43-

Claims (1)

200302833 Patent application scope 1. A compound of formula (II) X3, E {-X3.3-2-X3.2-3-X3.3-4-X3-3-5 " X3.3-6-X2 . ^ 7 ~ X2,2,8 (II) (SEQ ID NO: 2) or a therapeutically acceptable salt thereof, wherein Xaai is selected from the group consisting of hydrogen and R- (CH2) nC (0)-, where η is an integer from 0 to 8, and R is selected from the group consisting of alkoxy, alkyl, amine, aryl, carboxyl, cyclofluorenyl, A group consisting of cycloalkyl and heterocyclic ring; Xaa2 is selected from the group consisting of cold-propylaminofluorenyl, D-propylaminofluorenyl, D-isoisoleulamido, D-fluorenylglycinamido, D-4 -chlorobenzene Propylpropylamine, D-citrulamine, D-3-cyanophenylpropylamine, D-homophylpropylamine, D-homoselamide, isoleucine, D-isoleucine Fluorenyl, D-leucine fluorenyl, N-fluorenyl-D-leucine fluorenyl, D-n-leucine fluorenyl, D-n-valamine fluorenyl, D-penicillamine, D-phenylpropylamine fluorenyl Consisting of D-proline, D-serine, D-thienylpropylamino, and D-threonyl Xaa3 is selected from the group consisting of alloxamine, aspartyl, glutamine, D-glutamine, N-methylglutamine, glycine, Histamine group, homoseramine group, isoleucine group, lysamine group (N-ε-ethylamidino group), methionamine group, serine group, N-methylserine group, Threonium, D-threonium, tryptamine, tyramine, and tyramine (0-methyl) groups; Xaa4 is selected from N-fluorenylpropylamine, alloxamine Fluorenyl, spermine fluorenyl, glutamine fluorenyl fluorenyl, D-glutamine fluorenyl fluorenyl, glycamine fluorenyl, high 200302833 Seramine, leucine, lysine Si (N-ε-ethyl fluorenyl), n-leucine fluorenyl, n-valamine fluorenyl, D-valamine fluorenyl, N-methyl valencer Amidino, ornithino (N-5 -ethenyl), 3- (3-pyridyl) propylamino, inosinyl, serine, N-methylserine, threonine Amine group, tryptophan group, valine group and N-methyl valine group; 乂 & & 5 is selected from the group consisting of propylamino group, allo-isopropylamine group, aspartame group , Citrulamine, glutamine, hydrazone, isoleucine, D-isoleucine, N-methylisoleucine, leucine, D-leucine Amine group, lysine group (N-ε-ethenyl), D-lysine group (N-ε-ethenyl), n-leucine, n-valine, amphetamine St group, A group consisting of a proline group and a D-proline group; Xaa6 is selected from the group consisting of spermine group, D-spermine group, citrulline group, histamine group, lysine group, lysine group ( Ν-ε-isopropyl), ornithinofluorenyl, and 3- (3-pyridyl) propylaminofluorenyl; Xaa7 is absent or selected from the group consisting of N-methyl-D-propyl Aminomethyl, 2-aminobutylamidino, 2-aminoisobutylamidino, D-glutamine aminoamido, homoproline, hydroxyproline, leukoamido, amphetamine, and proline A group consisting of D-proline fluorenyl and D-valinyl fluorenyl; and Xaa8 is selected from the group consisting of D-propylamine fluorenyl fluorenyl, azglycin fluorenyl fluorenyl amine, glycamine fluorenyl fluorenyl amine, hydroxyl, D- Lysamine (N-ε-ethenyl) fluorenamide, a group represented by the formula -NHJCHJn-CHRiR2; and a group consisting of groups represented by the formula -NHR3, where η is a group of 0 to 8 Integer; R1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl and cycloalkyl; R2 is selected from the following including hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, 200302833 A group consisting of a heterocyclic ring and a hydroxyl group, with the limitation that when η is 0, R2 is not an alkoxy group or a peptyl group; and R3 is selected from the group consisting of hydrogen, a cyclofluorenyl group, a cycloalkyl group, and a light group. 2. The compound according to item 1 of the scope of patent application, wherein Xaa2 is selected from the group consisting of / 3 -propylamine, D-4 -chloroamphetamine, D-homamphetamine, D-leucine, D-penicillamine And D-proline groups. 3. The compound according to item 2 of the scope of patent application, which is selected from: N-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-.D-Leu-Thr-Nva-Ile- Arg-ProNHCH2CH3; N-Ac-D-Leu-Ser-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-Hphe-Thr-Nva-Ile-Arg-.ProNHCH2CH3; N-Ac-D-4ClPhe-Thr -Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-Pen-Thr-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-bAla-Thr.Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 49); A group consisting of N-Ac.bAla-Thr-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 50); and N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH2CH3. 4. The compound according to item 1 of the scope of patent application, wherein Xaa2 is a D-isoisoamidofluorenyl group. 5. The compound according to item 4 of the scope of patent application, which is selected from: N-Ac-D-aIle-Thr-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Ile-Arg -ProNHCH2CH3; N-Ac-D-aIle-Thr-Ser-Ile-Arg-ProNHCH2CH3; N-Ac-D-alle-Tyr-Nva-Ile-Arg-ProNHCH2CH3; 200302833 N-Ac-D-aIle-Ser-Thr-Ile-Arg-ProNHCH2CH3; N-Ac-D-aIle-Thr-Trp-Ile-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Lys ( Ac) -Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Nle-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Pro-Arg-ProNHCH2CH3; N-Ac-D-aIle -Ser-Ser-Nva-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH (CH3) 2 ; N-Ac-D-aIle-Ser-Ser-Gln-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Cit-Arg-ProNHCH2CH3; N-Ac-D-aIle-Ser-Ser-Ile -Arg-NHCH2CH3; N-Ac-D-aIle-Thr-Nva-Ile-Arg-NHCH2CH3; and N-Ac-D-aIle-Ser-Nva-Lys (Ac) -Arg-NHCH2CH3. 6. The compound according to item 1 of the scope of patent application, wherein Xaa2 is D-isoleucine fluorenyl. 7. The compound according to item 6 of the scope of patent application, wherein Xaa3 is selected from the group consisting of besulamine, aspartame, glutamine, lysine (N-ε-ethylamyl), and formazan The group consisting of thiaminyl, seramine, and tyramine groups. The compound according to item 7 of the application, which is selected from the group consisting of: N-Ac-D-Ile-alloThr-Nva-Ile-Arg -ProNHCH2CH3; N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH2 > 200302833 N-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Tyr-Nva- D-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Lys (Ac) -Nva-Arg-ProNHCH2CH3; N-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D -Ile-Asp-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH2CH3; N-Ac-D-Ile-Met-Gln-Ile-Arg-Pi * oNHCH2CH3 And a group consisting of N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH2CH3. 9. The compound according to item 6 of the application, wherein Xaa3 is threonium. 10. The compound according to item 9 of the scope of patent application, wherein Xaa4 is selected from the group consisting of spermine, glutamine, glutamine, D-glutamine, phosphonium, n-leucine, and N-methyl-n-valamine. A group consisting of fluorenyl, serine fluorenyl and tryptamine. 11. The compound according to item 10 of the scope of patent application, which is selected from: N-Ac-D-Ile-Thr-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Ser-Ile- Arg-Pro-D-AlaNH2 »N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH2» N-Ac-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH2 »N-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr- D-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Arg-Ile-ArgNHCH2CH3; 200302833 N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH2CH3; N-Ac-D-Ile-Thr-Gln-Lys (Ac) -Arg-NHCH2CH3; N-Ac-D-Ile-Thr-Ser -Ile-Arg-NHCH2CH3; and N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH2CH3. 12. The compound according to item 9 of the scope of patent application, wherein Xaa4 is n-valamine. 13. The compound according to item 12 of the scope of patent application, which is selected from: N-Ac-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3; N- (6-Me-Nic) -D-Ile- Thr-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH2CH3; N- Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2 »N-Ac-D-Ile-Thr-Nva-D-Leu-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr- Nva-D-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-Lys (Ac) NH2 »N-Ac-D-Ile-Thr-Nva-D- Lys (Ac) -Arg-ProNHCH2CH3; N-Ac-D «Ile-Thr-Nva-Lys (Ac) -Arg« ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH2CH3; N- Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH2CH3; N-Ac-D-Ile-Thr-Nva- Ile-ArgNHCH2CH3; and N-Ac-D-Ile-Thr-Nva-Lys (Ac) -Arg-NHCH2CH3. 14. A pharmaceutical composition comprising a compound according to item 1 of the scope of patent application, or a therapeutically acceptable salt thereof, combined with a therapeutically accessible 200302833 Affected by the vehicle. 15. A method for inhibiting angiogenesis in a mammal, which mammal is confirmed to require such therapy, which method comprises administering to the mammal a therapeutically acceptable dose of a compound according to item 1 of the scope of patent application, or A therapeutically acceptable salt. 16. A method of treating a mammal with cancer, the mammal being confirmed to require such therapy, the method comprising administering a therapeutically acceptable dose of a compound according to item 1 of the scope of the patent application, or A therapeutically acceptable salt. 17 · —Specific compounds of formula (III) X3,3.1-X3,3.2 " * X2.2.3-X3.3-4-X3- & 5-X3.2-7 (III) (SEQ ID NO: 3) Or a therapeutically acceptable salt thereof: Xaai is selected from the group consisting of hydrogen and R- (CH2) nC (0)-, where η is an integer from 0 to 8, and R is selected from the group consisting of alkoxy, alkyl, amine, aryl, carboxy, and ring Alkenyl, cycloalkyl, and heterocyclic groups; Xaa2 is selected from the group consisting of D-propylaminofluorenyl, D-isoisoamine, alloxamine, allylglycine, aspartame Base, asparagine, glutamine, glutamine, D-glutamine, glutamine, N-methylglutamine, glycine, histamine, and nan Amine group, D-homoseramine group, isoleucine group, D-isoleucine group, lysamine group (N-ε-ethyl fluorenyl group), methionamine group, D-methylthioamine Fluorenyl, n-leucine fluorenyl, D-leucine fluorenyl, n-valine fluorenyl, D-n-valine fluorenyl, D-proline fluorenyl, inosamine fluorenyl, serine fluorenyl, D-silk Amine group, N-methyl 200302833 Seramine group, threonyl group, D-threonine group, tryptophan group, amine group, and tyrosine group (0-methyl); Xaa3 is selected from N-methyl group Alanine, besulamine, spermine, aspartame, D-aspartame, citramide, glutamine, siamine, and D-glutamine Base, glutamine base, glycamine base, homoseramine base, leucine base, D-leucine base, lysine base (N-ε-ethylamyl), lysamine base (N- ε-nicotine fluorenyl), n-leucine fluorenyl, N-Valaminomethyl, D-aminovalinomethyl, N-methyl-aminovalinomethyl, guanamine (N-5-ethylamino), 3- (3-ρ biphenyl) propylamine Fermenting group, inosamine group, serine group, D-serine group, N-methylserine group, threonium group, tryptamine group, valinyl group and valine group Group consisting of Xaa4 is selected from the group consisting of propylamine, allo-isoleucine, aspartame, citrulamine, isoleucine, D-isoleucine, N-methylisoleucine, white Amine group, D-leucine group, lysamine group, lysine group (N-ε-ethylfluorenyl), D-lysamine group (N-ε-ethylfluorenyl), n-valinyl group Group consisting of phenylalanine, proline fluorenyl, D-proline fluorenyl, and valine fluorenyl; Xaa5 is selected from the group consisting of D-isoisoamine sulfonyl, spermine fluorenyl, D-spermine Composition of fluorenyl, citramine, histamine, lysamine, lysamine (N-ε-isopropyl), ornithine, and 3- (3-pyridyl) propylamine Group; Xaa6 * is present or selected from the group consisting of N-methyl-D-propylaminomethyl, 2-aminobutylmethyl, 2-aminoisobutylmethyl, D-glutamine, methylamino, homoproline 200302833 Group, via prolyl group, leucine group, amphetamine group, proline group, D-proline group, threonium group and D-serine group; and Xaa7 is selected from the group consisting of D- Propylamine sulfonium amine, azglycinamine fluorenylamine, glycamine fluorenylamine, hydroxy, D-lysamine fluorenyl (N-ε-ethylfluorenyl) fluorene, by the formula -NH-CCHJn-CHRiR2 Representative groups; and groups consisting of groups represented by -NHR3, where η is an integer from 0 to 8; R1 is selected from the group consisting of hydrogen, alkyl, cyclofluorenyl, and cycloalkyl R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cyclofluorenyl, cycloalkyl, heterocyclic and hydroxyl, with the limitation that when η is 0, R2 is not alkoxy or hydroxyl; R3 is selected from the group consisting of hydrogen, cyclofluorenyl, cycloalkyl, and hydroxyl; the limitation is that when Xaa5 is D-isoisoleulamino, Xaa6 is threonium, and 乂 & & 7 is hydroxyl . 18. The compound according to claim 17 in which Xaa5 is a spermine group. 19. The compound according to item 18 of the scope of patent application, wherein Xaa3 is selected from the group consisting of n-valinyl group and D-n-valinyl group. 20. The compound according to item 19 of the application, wherein Xaa2 is selected from the group consisting of threonyl and D-threonyl. 21. The compound according to item 20 of the scope of patent application, which is selected from: N-Ac-Thr-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 4); N- (6-MeNic) -Thr-Nva- Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 200302833 N-Ac-Thr-Nva-Ile-Arg-Pro-D-AlaNH2! N-Ac-Thr-Nva-D-Ile-Arg-ProNHCH2CH3; N-Ac-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3 (SEQ ID NO: 13); N-Ac-Thr-Nva-Ile-Arg-D-ProNHCH2CH3; N-Ac-Thr-D-Nva-Ile-Arg-ProNHCH2CH3; N-Ac-Thr-Nva-Pro-Arg-ProNHCH2CH3 (SEQ ID NO: 23); N-Ac-Thr-Nva-Lys-Arg-ProNHCH2CH3 (SEQ ID NO: 26); N-Ac-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3; N-Thr-Nva-Pro-Arg -ProNHCH2CH3 (SEQ ID NO: 38); N-Ac-D-Thr-Nva-Pro-Arg-ProNHCH2CH3; N-Ac-Thr-Nva-D-Pro-Arg-ProNHCH2CH3; N-Ac-Thr-D- Nva-Pro-Arg-ProNHCH2CH3; N-Ac-Thr-Nva-Pro-Arg-Pro-D-AlaNH2 »N-3Mev-Thr-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 45); A group consisting of N-Ac_Thr-Nva-Ile-Arg-NHCH2CH3 (SEQ ID NO: 53); and N-Ac-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3 (SEQ ID NO: 56). 22. The compound according to item 19 of the scope of patent application, wherein 乂 332 is selected from the group consisting of allosamine, aspartame, aspartame, homoseramine, inosamine, and tyramine A group of 醯 基. 23. The compound according to item 22 of the scope of patent application, which is selected from: N-Ac-alloThr-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 5); N-Ac-Tyr-Nva-Ile.Arg- ProNHCH2CH3 (SEQ ID NO: 11); -10- 200302833 N-Ac-Tyr-Nva-D-Ile-Arg-ProNHCH2CH3; N-Ac-alloThr-Nva-Pro-Arg-ProNHCH2CH3 (SEQ ID NO: 20); N-.Ac-Asn-Nva-Ile-Arg- ProNHCH2CH3 (SEQ ID NO: 29); N-Ac-Hser-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 30); N-Ac-Sar-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 31) ; And N-Ac-Asp-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 32) group Into groups. 24. The compound according to item 19 of the scope of patent application, wherein 乂 & & 2 is selected from the group consisting of glutamine, glutamine, N-methylglutamine, and lysamine (N -ε -ethenyl), methionamine, serine, and tryptamine. 25. The compound according to item 24 of the scope of patent application, which is selected from: N-Ac-NMeGlu-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 15); N-Ac-Met-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 16); N-Ac-Lys (Ac) -Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 17); N-Ac-Gln -Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 18); N-Ac-Trp-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 21); N-Ac-Glu-Nva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 28); N-Ac-Met-Nva-Ile-Arg-NHCH2CH3 (SEQ ID NO: 59); and N-Ac-Ser-Nva-Ile-Arg-NHCH2CH3 (SEQ ID NO: 61) Group of people. -11- 200302833 26. The compound according to item 18 of the scope of patent application, wherein Xaa3 is selected from the group consisting of glutamine and D-glutamine. 27. The compound according to item 26 of the application, which is selected from the group consisting of: N-Ac-Thr-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 6); N-Ac-Thr-Gln-Ile-Arg -Pro-D-AlaNH2 »N-Ac-Ser-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 12); N-Ac-Thr-D-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Ser- Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Ser-Gln-Lys (Ac) -Arg-ProNHCH2CH3 (SEQ ID NO: 24); N-Ac-Ser-Gln-Ile-Arg-Pro-D-AlaNH2; N-Ac-AllyGly-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 25); N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Ser-Gln-Nva-Arg-ProNHCH2CH3 (SEQ ID NO: 33); N-Ac-Thr-Gln-Nva-Arg-ProNHCH2CH3 (SEQ ID NO: 36); N-Ac-Nva-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 39); N-Ac-Thr-Gln-Lys (Ac) -Arg-ProNHCH2CH3 (SEQ ID NO: 41); N-3Mev-Thr-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 44); N-Ac-D -Nva-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ile-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Ala -Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Thr-Gln-Ile-Arg-ProNHCH2CH3; -12- 200302833 _ N-Ac-D-Ser-Gln-Ile-Arg-ProNHCH2CH3; N-Ac- DP ro-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-aIle-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Met-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Hser- Gln-Ile-Arg-ProNHCH2CH3; N-Ac-D-Nva-Gln-Lys (Ac) -Arg-ProNHCH2CH3; N-Ac-D-Nva-Gln-Ile-Arg-Pro-D-AlaNH2 »N-Ac-D-Nva-Gln-Pro-Arg-ProNHCH2CH3; N-Ac-D-Nle-Gln-Ile-Arg- ProNHCH2CH3; N-Ac-Nle-Gln-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 51); N-Ac-D.Nva-Gln-Ile-Arg-ProNHCH (CH3) 2; N (6MeNic) -D- Nva-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Nva-D-Gln-Ile-Arg-ProNHCH2CH3; N-Ac-Thr-Gln-Ile-Arg-NHCH2CH3 (SEQ ID NO: 52); N-Ac -Ser-Gln-Ile-Arg-NHCH2CH3 (SEQ ID NO: 54); N-Ac-Thr-Gln-Lys (Ac) -Arg-NHCH2CH3 (SEQ ID NO: 57); N-Ac-D-Nva- Gln-Ile-Arg-NHCH2CH3; N-Ac-D-Thr-Gln-Ile-Arg-NHCH2CH3; and N-Ac-D-Ser-Gln-Ile-Arg-NHCH2CH3. 28. The compound according to item 18 of the scope of application, wherein Xaa3 is selected from the group consisting of seramine and D-serine. 29. The compound according to item 28 of the scope of patent application, which is selected from: N-Ac-Ser-Ser-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 8); N-Ac-Thr-Ser-Ile-Arg -ProNHCH2CH3 (SEQ ID NO: 9); -13- 200302833 N-Ac-alloThr-Ser-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 19); N-Ac-Thr-Ser-Ile-Arg-Pro-D-AlaNH2 »N-Ac-Ser-Ser-Ile-Arg -Pro-D-AlaNH2 »N-Ac-Thr-Ser-Lys (Ac) -Arg-ProNHCH2CH3 (SEQ ID NO: 42); N-Ac-Thr-Ser-Pro-Arg-Pro-D-AlaNH2» N -Ac-D-Nva-Ser-Ile-Arg-ProNHCH2CH3; N-Ac-Nva-D-Ser-Ile-Arg-ProNHCH2CH3; N-Ac'Ser-Ser-Ile-Arg-NHCH2CH3 (SEQ ID NO: 55); and N-Ac-Thr-Ser-Ile-Arg- The group consisting of NHCH2CH3 (SEQ ID NO: 58) 0 30. The compound according to item 18 of the scope of patent application, wherein Xaa3 is selected from the group consisting of spermine si, asparagine, D-asparagine, Citrullinyl, glutamine Si, D-leucine, lysamine (N-ε-ethyl), lysamine (N-ε-nicotinyl), n-leucine N-methyl-n-valerium A group consisting of amine groups, threonium groups and tryptamine groups. 31. The compound according to item 30 of the scope of patent application, which is selected from: N-Ac-Thr-NMeNva-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 10); N-Ac.Ser-Thr-Ile-Arg -ProNHCH2CH3 (SEQ ID NO: 14); N-Ac-Thr-Nle-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 22); N-Ac-Thr-Trp-lie-Arg-Pro-DA laNH2; N- Ac-Thr-Trp-D-Ile-Arg-ProNHCH2CH3; N-Ac-Thr-Asn-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 37); -14- 200302833 N-Ac-Thr-D-Asn-Ile-Arg-ProNHCH2CH3; N-Ac-Thr-Cit-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 43); N-Ac-Ser-Trp-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 46); N-Ac-Thr-Trp-Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 47); N-Ac-Thr-Lys (Ac) -Ile-Arg-ProNHCH2CH3 (SEQ ID NO: 48); N-Ac-D-Nva-Asn-Ile-Arg-ProNHCH2CH3; N-Ac-D-Nva-Arg-Ile-Arg-ProNHCH2CH3; N-Ac-D-Nva-Thr-Ile-Arg-ProNHCH2CH3 ; N-Ac-D-Nva-Glu-Ile-Arg-ProNHCH2CH3; N-Ac-D-Nva-Lys (Nic) -Ile-Arg-ProNHCH2CH3; N-Ac-Nva-D-Asn-Ile-Arg- ProNHCH2CH3; N-Ac-Nva-D-Leu-Ile-Arg-ProNHCH2CH3; and N-Ac-Thr-NMeNva-Ile-Arg-NHCH2CH3 (SEQ ID NO: 60). 32. The compound according to item 17 of the scope of patent application, wherein Xaa5 is selected from the group consisting of D-isoisoleulamino, citrulamine, lysamine (N-ε-isopropyl), ornithine, and A group consisting of 3- (3-pyridyl) propylamine groups. 33. The compound according to item 32 of the scope of patent application, which is selected from: N-Ac-Thr-Nva-Ile-Orn-ProNHCH2CH3 (SEQ ID NO: 27); N-Ac-Ser-Gln-Ile-Cit -ProNHCH2CH3 (SEQ ID NO: 34); N-Ac-Ser-Gln-Ile-3Pal-ProNHCH2CH3 (SEQ ID NO: 35); N-Ac-Thr-Arg-Ile-Cit-ProNHCH2CH3 (SEQ ID NO: 40) ); N-Ac-D-Nva-Gln ~ Ile-Cit-ProNHCH2CH3; and N-Ac-D-Nva-Gln-Ile-Lys (Isp) -ProNHCH2CH3. -15- 200302833 34. A compound which is N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH2CH3. 35. A compound which is N-Ac-Thr-Gln-Ile-Ai: g-ProNHCH2CH3 (SEQ ID NO: 6). 36. A compound which is N-A c-S ar-G1 y-V a 1-D-a 11 e-T hr-〇 〇 〇 37.-a pharmaceutical composition, comprising the first The compound of item 7, or a therapeutically acceptable salt thereof, combined with a therapeutically acceptable carrier. 38. A method for inhibiting angiogenesis in a mammal, wherein the mammal has confirmed the need for such therapy, the method comprising administering to the mammal a therapeutically acceptable dose of a compound according to item 17 of the scope of patent application, or Its therapeutically acceptable salts. 39. A method for treating a mammal having cancer, wherein the mammal has been confirmed to require the therapy, the method comprising administering to the mammal a therapeutically acceptable dose according to item 17 of the scope of the patent application φ compounds, or their therapeutically acceptable salts. -16- 200302833 Lu, (a), the designated representative of this case is: Figure __ (b), the representative symbol of this representative diagram is briefly explained: 柒, if there is a chemical formula in this case, please disclose the one that can best show the characteristics of the invention Formula (II)-X3.2,2 ~ X3.2.3 ~ X3.3.4-XS3.5--X3.E7-X3,3.g (II),