CN1639188A - Hepta-, octa- and nonapeptides having antiangiogenic activity - Google Patents

Hepta-, octa- and nonapeptides having antiangiogenic activity Download PDF

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CN1639188A
CN1639188A CNA028258991A CN02825899A CN1639188A CN 1639188 A CN1639188 A CN 1639188A CN A028258991 A CNA028258991 A CN A028258991A CN 02825899 A CN02825899 A CN 02825899A CN 1639188 A CN1639188 A CN 1639188A
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ile
arg
gln
gly
thr
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F·哈维夫
M·F·布拉德利
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Abbott Laboratories
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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    • A61K38/08—Peptides having 5 to 11 amino acids
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Abstract

Compounds of formula (SEQ ID NO:1), 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

Have seven of anti-angiogenic activity-, eight-and nine-peptide
Technical field
The compound that the present invention relates to suppress vascularization method, treatment cancer method and can be used for treating illness that cause by vascularization or aggravation.Also openly contain simultaneously this compounds pharmaceutical composition, use the methods of treatment of this compounds.
Background of the present invention
Vascularization is the primary process that generates new blood vessel, and it is most important to multiple normal physiological activity (as reproduction, growth and trauma repair).Although this process also is not distinct fully, it is believed that it relates to intermolecular complicated interaction that not only stimulates but also suppress endothelial cell growth, wherein endotheliocyte is the main cell of capillary vessel.Under normal circumstances, as if these molecules keep microvasculature to remain static (being a kind of state that does not have the capillary vessel growth) sustainable a few weeks longer, or in some cases, keep this state many decades.But in case of necessity, during wound repair, these cells but can experience fast breeding and renewal within short five days.
Although vascularization is a process that quilt is highly regulated and control under normal operation, the vascularization out of control that numerous disease (being characterized as " vascularization disease ") is continued promotes.In other words, vascularization out of control perhaps may directly cause certain disease or increase the weight of existing illness.For example, the growth of solid tumor and shift the verified vascularization of depending on.Find that based on these continuous demand of compound of pair anti-angiogenic activity is just arranged, because they have the potentiality of treatment various diseases such as cancer.Peptide class with vascularization inhibition activity was introduced in the WO 01/38397 that owns together, WO 01/38347, WO 99/61476 and U.S. Patent Application Serial Number 09/915956.But, be necessary to prepare and have active anti-angiogenic formation compounds higher, more small molecules characteristics.
The present invention's general introduction
In its main embodiment, the invention provides upward acceptable salt of formula (I) compound or its treatment:
Xaa 1-Xaa 2-Xaa 3-Xaa 4-Xaa 5-Xaa 6-Xaa 7-Xaa 8-Xaa 9-Xaa 10(I), (SEQ IDNO:1), wherein:
Xaa 1Be selected from hydrogen and R-(CH 2) n-C (O)-, wherein n is 0 to 8 integer, and R is selected from alkoxyl group, alkyl, amino, aryl, carboxyl, cycloalkenyl group, cycloalkyl and heterocycle;
Xaa 2Be selected from alanyl, D-alanyl, (1S, 3R)-1-Aminocyclopentane-3-carbonyl, (1S, 4R)-1-amino cyclopentyl-2-alkene-4-carbonyl, (1R, 4S)-and 1-amino cyclopentyl-2-alkene-4-carbonyl, asparagyl, 3-cyano group phenylalanyl, 4-cyano group phenylalanyl, 3,4-dimethoxy phenylalanyl, 4-fluorobenzene alanyl, 3-(2-furyl) alanyl, glutaminyl, D-glutaminyl, glycyl, lysyl (N-ε ethanoyl), 4-methylbenzene alanyl, norvalyl and sarcosyl;
Xaa 3Be selected from alanyl, (1R, 4S)-1-amino cyclopentyl-2-alkene-4-carbonyl, arginyl, asparagyl, the D-asparagyl, t-butyl glycyl, the melon aminoacyl, the cyclohexyl glycyl, glutaminyl, the D-glutaminyl, glutamyl, glycyl, histidyl-, isoleucyl, leucyl, lysyl (N-ε-ethanoyl), methionyl, norvalyl, phenylalanyl, N-methylbenzene alanyl, prolyl, seryl, 3-(2-thienyl alanyl), Threonyl, valyl and the N-methyl is valyl;
Xaa 4Be selected from that D-alanyl, the other isoleucyl of D-, D-allyl group glycyl, D-4-chlorobenzene alanyl, D-melon aminoacyl, D-3-cyano group phenylalanyl, the high phenylalanyl of D-, homoseryl, isoleucyl, D-isoleucyl, D-leucyl, N-methyl D-leucyl, D-norleueyl-, D-are norvalyl, Beracilline acyl group, D-phenylalanyl, D-prolyl, D-seryl, D-thienyl alanyl and Threonyl;
Xaa 5Be selected from other Threonyl, aspartoyl, glutaminyl, D-glutaminyl, N-methyl glutaminyl, N-methyl glutamyl, glycyl, histidyl-, homoseryl, isoleucyl, lysyl (N-ε-ethanoyl), methionyl, seryl, N-methyl seryl, Threonyl, D-Threonyl, tryptophyl (tryptyl), tyrosyl and tyrosyl (O-methyl);
Xaa 6Be selected from alanyl, N-methyl-prop aminoacyl, other Threonyl, glutaminyl, glycyl, homoseryl, leucyl, lysyl (N-ε-ethanoyl), norleueyl-, norvalyl, D-is norvalyl, the N-methyl is norvalyl, the octyl group glycyl, ornithyl (N-δ-ethanoyl), 3-(3-pyridyl) alanyl, sarcosyl, seryl, N-methyl seryl, Threonyl, tryptophyl (tryptyl), valyl and the N-methyl is valyl;
Xaa 7Be selected from alanyl, other isoleucyl, aspartoyl, melon aminoacyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl (N-ε-ethanoyl), D-lysyl (N-ε-ethanoyl), N-methyl isoleucyl, norvalyl, phenylalanyl, prolyl and D-prolyl;
Xaa 8Be selected from arginyl, D-arginyl, melon aminoacyl, glutaminyl, histidyl-, high arginyl, lysyl, lysyl (N-ε-sec.-propyl), ornithyl and 3-(3-pyridyl) alanyl;
Xaa 9Do not exist or to be selected from the amino butyryl radicals of N-methyl D-alanyl, 2-, D-glutaminyl, high prolyl, hydroxyl prolyl, leucyl, prolyl, D-prolyl and D-valyl; With
Xaa 10Be selected from D-alanimamides, azepine G-NH2 (azaglycylamide), G-NH2, N-ε-ethanoyl-D-lysyl amine, formula-NH-(CH 2) n-CHR 1R 2The group and the formula-NHR of representative 3The group of representative, wherein n is the integer of 0-8; R 1Be selected from hydrogen, alkyl, cycloalkenyl group and cycloalkyl; R 2Be selected from hydrogen, alkoxyl group, alkyl, aryl, cycloalkenyl group, cycloalkyl, heterocycle and hydroxyl, precondition is when n is 0, R 2Be not alkoxyl group or hydroxyl; And R 3Be selected from hydrogen, cycloalkenyl group, cycloalkyl and hydroxyl.
In a preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be selected from alanyl, D-alanyl, asparagyl, 4-cyano group phenylalanyl, 4-toluene alanyl and norvalyl; And Xaa 1, Xaa 3, Xaa 4, Xaa 5, Xaa 6, Xaa 7, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In a further preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be selected from glutaminyl and D-glutaminyl, and Xaa 1, Xaa 3, Xaa 4, Xaa 5, Xaa 6, Xaa 7, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In a further preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be glycyl; Xaa 3Be selected from arginyl, asparagyl, D-asparagyl, melon aminoacyl, lysyl (N-ε-ethanoyl) and histidyl-; And Xaa 1, Xaa 4, Xaa 5, Xaa 6, Xaa 7, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In a further preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be glycyl; Xaa 3Be selected from valyl and N-methyl valyl group; Xaa 6Be selected from norvalyl norvalyl with the N-methyl; And Xaa 1, Xaa 4, Xaa 5, Xaa 7, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In a further preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be glycyl; Xaa 3Be selected from valyl valyl with the N-methyl; Xaa 6Be selected from glutaminyl, seryl and Threonyl; And Xaa 1, Xaa 4, Xaa 5, Xaa 7, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In a further preferred embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be glycyl; Xaa 3Be selected from glutaminyl, D-glutaminyl, phenylalanyl and N-methylbenzene alanyl; Xaa 7Be isoleucyl; And Xaa 1, Xaa 4, Xaa 5, Xaa 6, Xaa 8, Xaa 9And Xaa 10With formula (I) introduce identical.
In another embodiment, the invention provides formula (I) compound or its treatment upward acceptable salt, wherein Xaa 2Be glycyl; Xaa 3Be selected from glutaminyl, D-glutaminyl and phenylalanyl; Xaa 7Be selected from D-isoleucyl, lysyl (N-ε-ethanoyl) and D-prolyl; And Xaa 1, Xaa 4, Xaa 5, Xaa 6, Xaa 8, Xaa 9And Xaa 10With formula (1) introduce identical.
In another embodiment, the invention provides and comprise formula (I) compound or its treatment and go up the pharmaceutical composition that acceptable carrier is gone up in acceptable salt and treatment.
In another embodiment, the invention provides and a kind ofly when thinking that Mammals needs this treatment, suppress the angiopoietic method of Mammals, but described method comprises that formula (I) compound of receiving amount or its treatment are gone up in treatment goes up acceptable salt and give described Mammals use.
In another embodiment, the invention provides a kind of when thinking that Mammals needs this treatment the method for treatment mammalian cancer, but described method comprises that formula (I) compound of receiving amount or its treatment are gone up in treatment goes up acceptable salt and use for described Mammals.
The present invention describes in detail
Singulative used herein " a kind of ", " being somebody's turn to do (described) " comprise plural form, except that this paper clearly refers else.
Below clear and definite in this explanation the implication of used term:
Term used herein " alkoxyl group " expression alkyl joins by Sauerstoffatom and parent molecular moiety.
The univalent perssad that term used herein " alkyl " expression produces by a hydrogen atom of removing on the straight or branched saturated hydrocarbyl.Preferred alkyl of the present invention is the alkyl (C with 1-6 carbon atom 1-C 6Alkyl).The present invention is the alkyl (C of 1-3 carbon atom more preferably 1-C 3Alkyl).
Term used herein " alkyl-carbonyl " expression alkyl joins by carbonyl and parent molecular moiety.
Term used herein " amino " expression-NR aR b, R wherein aAnd R bIndependently be selected from hydrogen, alkyl and alkyl-carbonyl.
Term used herein " aryl " expression phenyl group or wherein one or more fused rings are the dicyclo or the tricyclic condensed ring system of phenyl.The example of bicyclic condensed ring system is that phenyl is fused to cycloalkenyl group (this paper definition), cycloalkyl (this paper definition) or another phenyl.The example of tricyclic condensed ring system is that the cycloalkenyl group of bicyclic condensed ring system and this paper definition, cycloalkyl or another phenyl of this paper definition condense.The representative instance of aryl includes but not limited to anthryl, Azulene base, fluorenyl, 2,3-indanyl, indenyl, naphthyl, phenyl and tetralyl.Aryl among the present invention can be chosen wantonly by 1,2,3,4,5 substituting group that independently is selected from alkoxyl group, alkyl, carboxyl, halogen and hydroxyl and replace.
Term used herein " carbonyl " representative-C (O)-.
Term used herein " carboxyl " representative-CO 2H.
Term used herein " cycloalkenyl group " refers to contain 1-3 non-aromatic ring or the bicyclic ring system of encircling of 3-10 carbon atom, wherein each five-ring has a two key, each six-ring has the two keys of 1-2, and each seven yuan and octatomic ring have 1-3 two keys, and each nine yuan and pick up unit's ring 1-4 two keys are arranged.The example of cycloalkenyl group comprises cyclohexenyl, octalin base, norbornene etc.Cycloalkenyl group among the present invention can be chosen wantonly by 1,2,3,4 or 5 substituting group that independently is selected from alkoxyl group, alkyl, carboxyl, halogen and hydroxyl and replace.
Term used herein " cycloalkyl " refers to the saturated monocyclic, bicyclic or tricyclic alkyl ring system that contains 3-12 carbon atom.The example of cycloalkyl comprises cyclopropyl, cyclopentyl, dicyclo [3.1.1] heptyl, adamantyl (adamantyl) etc.Cycloalkyl among the present invention can be chosen wantonly by 1,2,3,4 or 5 substituting group that independently is selected from alkoxyl group, alkyl, carboxyl, halogen and hydroxyl and replace.
F, Cl, Br or I represented in term used herein " halogen ".
Term used herein " heterocycle " refers to contain 1,2 or 3 heteroatomic five yuan, hexa-atomic or seven-membered ring that independently is selected from nitrogen, oxygen and sulphur.Five-ring can not contain two keys or contain 1-2 two keys and six-ring and seven-membered ring can not contain two keys or contain 1-3 two keys.Term " heterocycle " also comprises heterocycle and aryl (wherein defining) condensed bicyclic radicals.Can interconnect by carbon atom on the group or nitrogen-atoms between the heterocyclic group among the present invention.The heterocyclic example includes but are not limited to furyl, thienyl, pyrryl, pyrrolidyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, isoxazolyl, isothiazolyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, pyridyl, indyl, indolinyl, benzothienyl etc.Heterocyclic group among the present invention can be chosen wantonly by 1,2,3 or 4 substituting group that independently is selected from alkoxyl group, alkyl, carboxyl, halogen and hydroxyl and replace.
Term used herein " hydroxyl " representative-OH.
The salt of term used herein " acceptable salt in the treatment " expression The compounds of this invention or the zwitterionic form of The compounds of this invention, they are water-soluble, oil solubles or dispersible, and they are fit to the treatment disease and do not have tangible toxicity, stimulation and anaphylaxis; They have rational risk/benefit ratio, and effective on the purposes of its expection.Described salt prepares in the time of can in the end separating with the described compound of purifying, or passes through in addition amino with suitable acid-respons preparation.Representational acid salt comprises acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, formate, prolong carboxylate salt recklessly, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, 1,3,5-tri-methyl p-toluenesulfonate salt, mesylate, naphthylidene sulfonate, nicotinate, the 2-naphthalenesulfonate, oxalate, embonate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphoric acid salt, glutaminate, supercarbonate, right-tosylate and undecylate.The amino of The compounds of this invention also can be quaternized by following material: the muriate of methyl, ethyl, propyl group and butyl, bromide, iodide; The sulfuric ester of dimethyl, diethyl, dibutyl and diamyl; The muriate of decyl, lauryl, tetradecyl and steryl, bromide, iodide; And benzyl and styroyl bromination thing.Can be used for forming the example that to accept the acid of additive salt in the treatment and comprise mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; With organic acid such as oxalic acid, toxilic acid, succsinic acid and citric acid.
Unless refer else, " D " prefix, for example D-Ala or NMe-D-lle, the stereochemistry of the amino acid in the peptide of representing to introduce in this specification sheets and the appended claims and the alpha-carbon of aminoacyl residue is native configurations or " L " configuration.Stereochemistry with chiral centre in the concrete acyl substituent of Cahn-Ingold-Prelog " R " and " S " symbolic representation peptide N-of the present invention end.The racemic mixture of two enantiomorphs of designator " R, S " expression.This nomenclature is followed R.S.Cahn, etc.; Angew.Chem.Int.Ed.Engl., 5, the rule that 385-415 (1966) introduces.
All peptide order is write by the convention of generally acknowledging, so α--terminal amino acid residue is positioned at the left side, and its α-C-terminal is positioned at the right side.Term used herein " α-N-terminal " refers to the free alpha-amino group of peptide upper amino acid, and term " α-C-terminal " refers to the free α-carboxylic acid end of peptide upper amino acid.
In most of the cases; " nomenclature of a-amino acid (suggestion; 1974) " biological chemistry of announcing in the relevant biological chemical name method with the IUPAC-IUB council of organic chemistry nomenclature of IUPAC council recommendation is followed in name natural or non-natural aminoacyl residue used herein; 14 (2), (1975).The amino acid in this explanation and the affiliated claim and the name and the abbreviation of aminoacyl residue are different from described suggestion to a certain extent, and difference will clearly be pointed out the reader.Following table 1 has provided the abbreviation definition of using among the present invention.
Table 1
Abbreviation Definition
Ala Alanyl
AlaNH 2 Alanimamides
aIle Other isoleucyl
alloThr Other Threonyl
alloThr(t-Bu) Other Threonyl (O-t-butyl)
Arg Arginyl
Arg(Pmc) Arginyl (N G-2,2,5,7,8-pentamethyl-benzo dihydropyrane-6-alkylsulfonyl)
Fmoc-Arg(Pbf)-OH N-Fmoc-N G-(2,2,4,6,7-pentamethyl-Dihydrobenzofuranes-5-alkylsulfonyl) arginine
Asn Asparagyl
Asn(Trt) Asparagyl (trityl)
Asp Aspartyl
Asp(Ot-Bu) Aspartyl (O-t-butyl)
Cit The melon aminoacyl
Fmoc 9-fluorenyl methyl oxygen base carbonyl
Gln Glutaminyl
Gln(Trt) Glutaminyl (trityl)
Glu Glutamyl
NMeGlu N-methyl glutamyl
NMeGlu(t-Bu) N-methyl glutamyl (t-butyl)
Gly Glycyl
His Histidyl-
His(Trt) Histidyl-(trityl)
Hser Homoseryl
Ile Isoleucyl
Leu Leucyl
Lys(Ac) Lysyl (N-ε-ethanoyl)
Met Methionyl
6-Me-nicotinyl 6-methyl nicotinoyl
Nle Norleueyl-
Nva Norvalyl
NMeNva The N-methyl is norvalyl
Orn(Ac) Ornithyl (N-δ-ethanoyl)
Pen The Trolovol acyl group
Phe Phenylalanyl
(4-CH 3)Phe 4-methylbenzene alanyl
(4-CN)Phe 4-cyano group phenylalanyl
NMePhe N-methylbenzene alanyl
Pro Prolyl
ProNHCH 2CH 3 The prolyl ethanamide
3-Pal 3-(3-pyridyl) alanyl
Sar Sarcosyl
Ser Seryl
Ser(t-Bu) Seryl (O-t-butyl)
Thr Threonyl
Thr(t-Bu) Threonyl (O-t-butyl)
Trp Tryptophyl
Trp(Boc) Tryptophyl (t-butoxy carbonyl)
Tyr Tyrosyl
Tyr(t-Bu) Tyrosyl (O-t-butyl)
Val Valyl
NMeVal The N-methyl is valyl
If abridge at the compound that last table can not find out, can be with reference to Calbiochem-Novabiochem Corp, name and abbreviation in " the solid phase synthesis instrument 1998-1999 catalogue of peptide " of 1999 Catalog and Peptide Synthesis Handbook or Chem-Impex International company.
Form
The compounds of this invention includes but are not limited to the compound that embodiment introduces, and they have anti-angiogenic activity.As angiogenesis inhibitor, this compound is all effective on former of treatment and transfer solid tumor, comprises mammary cancer, colorectal carcinoma, the rectum cancer, lung cancer, the oropharynx cancer, the hypopharynx cancer, the esophageal carcinoma, cancer of the stomach, carcinoma of the pancreas, liver cancer, carcinoma of gallbladder and cholangiocarcinoma, carcinoma of small intestine, the urinary tract cancer (comprises renal cancer, bladder cancer and urothelial cancer), the female genital tract cancer (comprises cervical cancer, uterus carcinoma, ovarian cancer and choriocarcinoma and pregnant trophoblastic disease), male genetic road cancer (comprises prostate cancer, seminal fluid capsule cancer, carcinoma of testis and germinoma), internal secretion gland cancer (comprises thyroid carcinoma, adrenal carcinoma, pituitary carcinoma); Skin carcinoma; Vascular tumor, melanoma, sarcoma (comprising bone and soft tissue sarcoma and Kaposi sarcoma); The tumour of brain, nerve, eyes and brain (comprising star-like glucagonoma, neurospongioma, glioblastoma, retinoblastoma, neuroma, neuroblastoma, schwannoma and meningioma).Described compound (is a chlorosarcoma at the solid tumor of treatment hematopoiesis malignant tumor such as leukemia generation; Plasmoma; Mycosis fungoides and cutaneous T cell lymphoma/leukemic scab and tumour) and lymphoma (comprising He Jiejinshi and non_hodgkin lymphoma) also effective.In addition, use separately or use with radiotherapy and/or other chemotherapy drugs in combination, described compound can prevent the transfer of above-mentioned tumour.
Other purposes comprise treatment and prevention autoimmune disease such as rheumatic, immunity and degenerated sacroiliitis; Various ophthalmic diseasess are diabetic retinopathy for example, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, flush, the retinal vessel regeneration that macular degeneration causes, histanoxia, infect or surgical operation with intraocular vascularization and other revascularization venereal disease diseases; Tetter such as ox-hide moss; Capillary proliferation in vascular disease such as vascular tumor and the atherosclerotic plaque; The Osler-Webber syndromes; The vascularization of cardiac muscle; The revascularization of patch; Telangiectasis; Bleeders' joint; Hemangiofibroma; The wound granulationization.Other purposes comprise the treatment of diseases that is characterized as excessive or abnormal stimulation endotheliocyte, include but not limited to intestinal adhesion, regional ileitis, atherosclerosis, scleroderma and hypertrophic scar (being keloid).Another purposes is as the Birth control medicine, and its mechanism of action is for suppressing ovulation and placentation.The compounds of this invention also can be used for treating the angiopoietic disease as pathological examination, as cat scratcs disease (Rochele minutesalia quintosa) and ulcer (Helicobacter pylori).By use this compound before operation, described compound can reduce hemorrhage, but is particularly useful for the treatment tumor resection.
The compounds of this invention can be united use with the treatment disease with other compositions and method.For example, certain tumour can use operation, radiation or chemotherapy to treat in conjunction with peptide of the present invention routinely, can use peptide of the present invention with resting stage that prolongs micrometastasis and the growth of stablizing and suppress any remaining primary tumo(u)r to patient then.In addition, The compounds of this invention can combine with pharmaceutically acceptable vehicle and the sustained-release matrix of choosing wantonly (as biological degradation polyalcohol) and form therapeutic composition.
Sustained-release matrix used herein is normally made by polymkeric substance, and it can be by enzyme or acid-alkali hydrolysis or dissolving and degrades.In case enter in the body, this matrix is acted on by enzyme and body fluid.The sustained-release matrix that is fit to is selected from biocompatible material such as liposome, polylactide (poly(lactic acid)), polyglycolide (polymkeric substance of oxyacetic acid), polylactide copolymerization glycollide (multipolymer of lactic acid and oxyacetic acid) polyanhydride, poly-(ortho acid) ester, polypeptide, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acid, lipid acid, phosphatide, polysaccharide, nucleic acid, polyamino acid, amino acid is (as phenylalanine, tyrosine, Isoleucine), polynucleotide, polyethylene propylene, polyvinylpyrrolidone and silicone resin.Preferred biodegradable matrix is that polylactide, polyglycolide or polylactide copolymerization glycollide (multipolymer of lactic acid and oxyacetic acid) are wherein a kind of.
When being used for above-mentioned or during other treatment, effective therapeutic dose of a kind of compound in the The compounds of this invention can use by pure product, if or this form exist, use with pharmacy acceptable salt.The implication of " effectively therapeutic dose " of The compounds of this invention is the described compounds for treating vascularization disease with sufficient dosage, and (for example, restriction tumor growth or slow down or block metastases) has the rational benefit/risk ratio of suitable therapeutic treatment.But, will be appreciated that the use total amount of compound of the present invention and composition every day will be determined by the doctor in charge in the scope of rational medical judgment.Concrete therapeutically effective dosage level to arbitrary specific patient depends on multiple factor, comprises disease and the disease severity that will treat; The activity of the specific compound that uses; The concrete composition that uses, patient's age, body weight, general health state, sex and diet; The discharge rate of the approach of time of administration, administration and the specific compound of use; The treatment time length; The medicine that is used in combination or uses simultaneously with employed particular compound; And the well-known similar factor of medical field.For example, art technology technician knows very well, brings into use the dosage level of described compound lower than reaching the needed dosage level of result of treatment, little by little increases dosage up to producing a desired effect.
As selection, the medicinal compositions that The compounds of this invention also can comprise described purpose compound and one or more pharmaceutically acceptable vehicle uses.Pharmaceutically acceptable carrier or vehicle are meant that non-toxic solid, semisolid or liquid filling agent, thinner, packing form the preparation auxiliary of thing or any kind.Described composition can parenteral, in the pond, intravaginal, intraperitoneal, part (as powder, ointment, drops or transdermal patch), rectum or mouthful cheek use.Term used herein " parenteral " is meant the mode of administration, comprises intravenously, muscle, intraperitoneal, intrathoracic, subcutaneous and intra-articular injection and infusion medication.
The medicinal compositions of parenteral injection comprises pharmaceutically acceptable aseptic aqueous solution or non-aqueous solution, dispersion liquid, suspension or emulsion and is facing the sterilized powder that is formulated as aseptic injectable solution or dispersion liquid with preceding.Water-soluble or the non-water-soluble carrier, thinner, solvent or the solvent that are fit to comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), carboxymethyl cellulose and suitable mixture, vegetables oil (sweet oil) and injectable organic ester such as ethyl oleate thereof.Can keep suitable flowability, for example, guarantee particle diameter scope up to specification during dispersion liquid by using coating material such as Yelkin TTS, and by using tensio-active agent.
These compositions also can contain adjuvant such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can guarantee the prophylaxis of microbial effect by including various antibiotic or anti-mycotic agents, for example p-Hydroxybenzoate, trichloro-butyl alcohol, phenol Sorbic Acid etc.May need also to comprise that isotonic agent is as sugar, sodium-chlor etc.Prolong the material that absorbs by it is contained,, the absorption of described injectable pharmaceutical dosage form is prolonged as aluminum monostearate and gelatin.
Prolonged action preparation for injection can be used Biodegradable polymeric such as polylactide-polyglycolide, gathers (former ester), gather (acid anhydride) and (gathering) di-alcohols (as polyoxyethylene glycol) preparation.The character that depends on medicine and polymer ratio and the concrete polymkeric substance that uses, the may command release rate of drugs.Long acting injection also can by described pharmaceutical pack is rolled in the liposome of bodily tissue compatibility or microemulsion in prepare.
Injection formulations can be sterilized, and for example filter by strainer and hold back bacterium, or by add sterilizing agent in aseptic solid composite, described composition can be before use with sterilized water or other injectable medium dissolves or dispersion.
Topical comprises skin or mucosa delivery, comprises lung and ocular surface.Topical drug delivery composition comprises composition for inhalation, can be prepared into compressible or incompressible dry powder.In incompressible powder composition, particulate type activeconstituents can form mixture with the pharmaceutically acceptable inert support of comparatively large vol, and for example wherein particle diameter is up to 100 microns.The inert support that is fit to comprises sugar, for example lactose.Preferably the effective size of grain of the active ingredient particle of at least 95% (weight) is at the 0.01-10 micron.
On the other hand, described composition is constrictive and contains pressurized gas, as nitrogen or liquefied gas casting charge.Described liquefaction casting charge medium and the real preferably combination of whole composition are the dissolvings that described activeconstituents does not have any substantial extent therein.Described compressed compositions also can contain tensio-active agent, as liquid or solid nonionogenic tenside or solid anion surfactant.The preferred solid anion surfactant that uses sodium-salt form.
Another form of topical is an ophthalmic administration.The compounds of this invention is carried with pharmaceutically acceptable ophthalmic medicine carrier, described like this compound can keep contacting the sufficiently long time so that described compound sees through the interior region of cornea and eye, for example anterior chamber, back room, vitreum, aqueous humor liquid, vitreum liquid, cornea, iris/ciliary body, lens, choroid/retina and sclera with the eye surface.Described pharmaceutically acceptable eye vector for example can be ointment, vegetables oil or cover material.Perhaps, The compounds of this invention can directly inject vitreum and aqueous humor liquid.
The composition of rectum and vagina administration is preferably suppository, the preparation of suppository can be The compounds of this invention is mixed with the non-irritating excipient or the carrier that are fit to, as cocoa butter, polyoxyethylene glycol or suppository wax, described carrier at room temperature is a solid, be liquid under body temperature, therefore described composition can discharge active compound at rectum or vaginal canal thawing.
The compounds of this invention also can the liposome form administration.As known in the art, liposome generally is derived from phosphatide or other lipid matters.Liposome is by brilliant formation of single or multiple lift aqua liquid that is dispersed in the aqueous medium.Can use any nontoxic physiologically acceptable and metabolizable lipid that can form liposome.Except that The compounds of this invention, liposome composition of the present invention also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide and phosphatidylcholine (Yelkin TTS), and natural and synthetic all is fit to.The method for preparing liposome is known in the art.Referring to for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33 and following document etc.
Though the active medicine that The compounds of this invention can be independent uses, they also can use the medication combined use of treatment vascularization disease usually with one or more to the patient.For example, The compounds of this invention can make tumour responsive more to traditional cytotoxic treatments such as chemotherapy and radiation in a short time.The compounds of this invention also strengthens the curative effect of the cell toxicant adjuvant of existing antineoplaston.The compounds of this invention also can combine with other anti-angiogenic formation medicines and improve its curative effect, or with other anti-angiogenic formation medicines in conjunction with and with other cell toxicity medicament administrations.Particularly, when being used for the treatment of solid tumor, The compounds of this invention can with IL-12, retinoids, Interferon, rabbit, the vascularization chalone, endostatin, Thalidomide, thrombin-sensitive protein-1, thrombin-sensitive protein-2, captopril (captopryl), the vascularization statin, TNP-470, poly sulfuric acid piperylene, platelet factor 4, LM-609, SU-5416, CM-101, but for the Garland, Profibrinolysin-K-5, angiostatin (vasostatin), integral protein is disturbed body (vitaxin), angiostatin (vasculostatin), squalamine, Marimastat or other MMP inhibitor; Antitumor drug such as alpha-interferon, COMP (endoxan, vincristine(VCR), methotrexate and prednisone), Etoposide, mBACOD (methotrexate, bleomycin, Dx, endoxan, vincristine(VCR) and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin redemption)), Dx, endoxan, cis-platinum, taxol, Etoposide/mustargen, vincristine(VCR), prednisone and Procarbazine), vincristine(VCR), vinealeucoblastine(VLB) etc. and with the radiotherapy coupling.
Give one day the total dose of the present composition that people or other mammalian hosts use (can by single dose or divided dose administration) 0.0001-300mg/kg body weight/every day for example, and be more typically the 1-300mg/kg body weight.
Know to combine with The compounds of this invention to be used to suppress, treat or to prevent the medicine of vascularization disease to be not limited only to above cited, comprise that in principle all are to treatment or the effective medicine of prevention vascularization disease.
Biological activity determination
Extracorporeal blood vessel forms determination of activity
(HMVEC) migration of human microvascular endothelial is measured according to S.S.Tolsma, O.V.Volpert, and D.J.Good, W.F.Frazier, P.J.Polverini and N.Bouck, J.CellBiol.1993,122, the method for 497-511 is carried out.
Carrying out described HMVEC migration with human microvascular endothelial skin cells (single donor) and human microvascular endothelial cell (newborn infant) measures.Described HMVEC cell hunger in the DME that contains 0.01% bovine serum albumin (BSA) is spent the night.Be 1.5 * 10 with pancreas egg enzyme harvested cell and with concentration then 6Cell/ml is resuspended in cell among the DME that contains 0.01%BSA.Cell put into 48 hole Boyden of improvement pore chamber bottom (Nucleopore Corporation, CabinJohn, MD).Install and also to be inverted pore chamber, allow cell in 37 ℃ following 2 hours, make it be attached to polycarbonate taxis film (aperture 5 μ m), described film is put into 0.01% gelatin soaked overnight and dry before use.And then described pore chamber refunded original position, and with tester (cumulative volume 50 μ l), comprising activator, 15ng/ml bFGF/VEGF adds described pore chamber top.These cell plate are incubated 4 hours at 37 ℃, film (Diff Quick reclaims, fixes, dyes, Fisher Scientific), add up the cell number of moving to the upper strata in per 3 high power fields again, deduct the background migration among the DME+0.1BSA, with the number of per 10 high power fields (400X) migrating cell as report data, or the result that obtains of comprehensive test of many times, the percentage that relatively suppresses with positive control as migration.
During with the 0.1nM concentration determination, representation compound suppresses human endothelial cell migration rate and reaches 50% at least in above-mentioned test.With the 1nM concentration determination, the about 65%-90% of the human endothelial cell migration rate of the inhibition of preferred compound, and most preferred is pressed the 1nM concentration determination, suppresses the about 50%-95% of human endothelial cell migration rate.Show that by these results the The compounds of this invention proof has enhancing usefulness.
Synthesizing of peptide
The present invention includes formula (I) compound by synthetic method or metabolic approach preparation.That the The compounds of this invention of metabolic approach preparation is included in that (in vivo) produces in human body or the animal body or in external generation.
Polypeptide of the present invention can be synthetic by a lot of technology that those skilled in the art have known.For the solid-phase peptide preparation method, at J.M.Stewart and J.D.Young, Solid PhasePeptide Synthesis, W.H.Freeman Co. (San Francisco), 1963 and J.Meienhofer, Hormonal Proteins and Peptides, Vol.2, p.46, AcademicPress (New York), 1973 can see the summary of a lot of technology.See G.Schroder and K.Lupke for classical solution synthesis method, The Peptides, vol.1, AcademicPress (New York), 1965.
Reagent, resin, amino acid and amino acid derivative all have commercially available, can be from Chem-ImpexInternational, Inc. (Wood Dale, IL, U.S.A.) or Calbiochem-NovabiochemCorp. (San Diego, CA U.S.A.) buys.
Generally speaking, these methods comprise and one or more amino-acid sequences are added on the ever-increasing peptide chain or the amino acid of due care is added on the ever-increasing peptide chain.Usually, first amino acid whose amino or carboxyl group are protected with a suitable blocking group, the amino acid of protected or derivation can be connected on the inert solid carrier then; Or be fit to form under the condition of amido linkage, add the amino acid of the next correspondence group (amino or carboxyl) that contains due care and in solution, use by order.Remove described blocking group and increase next amino acid (being fit to protect) etc. from initiate amino-acid residue then.After all amino acid that need are all with correct being linked in sequence, all remaining blocking groups (with all solids carrier) order removed or removed simultaneously, so that final polypeptide to be provided.By simple modifications to described whole flow process; it is possible increasing more than one amino acid to growing chain at one time; for example; by the dipeptides coupling (under the condition that the chiral centre racemization does not take place) that makes a shielded tripeptides and a due care, go to protect the back to form a pentapeptide.
It is synthetic that the particularly preferred method of preparation The compounds of this invention relates to solid-phase peptide.In this elite method, the alpha amino function base is by acid or the protection of alkali sensitive group.This blocking group should have the condition that peptide bond is formed and keep stable character, can remove described blocking group easily not destroying under the situation that described growing chain or wherein contained any chiral centre do not produce racemization simultaneously.The blocking group that is fit to is 9-fluorenyl methyl oxygen base carbonyl (Fmoc), t-butoxy carbonyl (Boc), benzyl oxygen base carbonyl (Cbz), xenyl sec.-propyl oxygen base carbonyl, t-amyl group oxygen base carbonyl, isobornyl oxygen base carbonyl, (α; α)-and dimethyl-3,5-dimethoxy-benzyl oxygen base carbonyl, O-nitrophenyl sulfenyl, 2-cyano group-t-butyl oxygen base carbonyl etc.Preferred 9-fluorenyl methyl oxygen base carbonyl (Fmoc) is as blocking group.
Preferred especially side chain blocking group is as follows: arginic blocking group is: 2,2,5,7, and 8-pentamethyl-benzo dihydropyrane-6-alkylsulfonyl (Pmc) and 2,2,4,6,7-pentamethyl-Dihydrobenzofuranes-S-alkylsulfonyl (Pbf); The blocking group of l-asparagine is: trityl (Trt); The blocking group of aspartic acid is: t-butyl (t-Bu); The blocking group of glutamine is: trityl (Trt); The blocking group of N-methyl L-glutamic acid is: t-butyl (t-Bu); The blocking group of Histidine is: trityl (Trt); The blocking group of Methionin is: t-butoxy carbonyl (Boc); The blocking group of seryl is: t-butyl (t-Bu); The blocking group of Threonine and allothreonine is: t-butyl (t-Bu); The blocking group of tryptophane is: t-butoxy carbonyl (Boc); And the blocking group of tyrosine is: t-butyl (t-Bu).
In the solid-phase peptide synthetic method, the C-end amino acid is connected on the suitable solid carrier or resin.To the above-mentioned synthetic useful solid carrier that is fit to is those to the reaction reagent and the apparent inert material of reaction conditions of condensation-deprotection progressively, and is insoluble to the medium of use.The preferred solid carrier of synthetic C-terminal carboxyl peptide is Sieber amide resins or Sieber ethanamide resin.The preferred solid carrier of synthetic C-terminal amidated peptide is a Sieber ethanamide resin, and Novabiochem Corporation is on sale.
By by N, N '-dicyclohexylcarbodiimide (DCC), N, N '-DIC (DIC), [O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate] (HATU), or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU), contain or do not contain 4-dimethylaminopyridine (DMAP), I-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM), the coupling of benzotriazole-Ji oxygen base-three (dimethylamino) phosphorus-hexafluorophosphate (BOP) or the mediation of two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (BOPCI), at 10 ℃-50 ℃, the about 1-of insulation is about 24 hours in solvent such as methylene dichloride or DMF, and the C-end amino acid is coupled on the resin.
When solid carrier is Sieber acid amides or Sieber ethanamide resin, with the coupling of aforesaid C-terminal amino acid before, disconnect the Fmoc group with secondary amine, preferred piperidines.In coupling, be used for deprotection 4-(2 '; 4 '-Dimethoxyphenyl-Fmoc-amino methyl) preferred reagent of phenoxy group kharophen ethylamide resin is O-benzotriazole-1-base-N, N, N '; N '-tetramethyl-urea hexafluorophosphate (HBTU; or [O-(7-azepine benzo triazol-1-yl)-1 1 equivalent) and 1-hydroxy benzo base triazole (HOBT, 1 equivalent); 1; 3,3-tetramethyl-urea hexafluorophosphate] the DMF solution of (HATU, 1 equivalent) and N-methylmorpholine (1 equivalent).
The protected amino acid whose coupling of successive can be finished in the known automatic Peptide synthesizer in this area.In an embodiment preferred, the alpha amino function base on the amino acid of described growth peptide chain is protected with Fmoc.Can handle from the terminal side chain of the N-of growing chain by secondary amine, preferred piperidines and remove the Fmoc blocking group.Introduce each protected amino acid with about 3 times of molar excess concentration then, and coupling is finished in DMF preferably.Described coupling reagent is generally O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU, 1 equivalent) or [O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate] (HATU, 1 equivalent), wherein there is N-methylmorpholine (NMM, 1 equivalent).
When solid phase synthesis finishes, remove polypeptide and slough protection from described resin, described step can be continuously or separate operation.By can once finishing, for example with the trifluoroacetic acid that contains thia methyl-phenoxide (thianisole), water or dithioglycol with separation agent process resin bonding polypeptide isolated polypeptide and deprotection.
When the C-of polypeptide end is alkylamide, it is dissociated by separating described resin with alkylamine ammonia.Also can select, for example use methyl alcohol by transesterify, separate by ammonia then or directly transmidation remove described polypeptide.Can or directly enter next step at the protected peptide of this purifying.Can remove the blocking group of side chain with the above-mentioned combined method of dissociating.
The peptide of being protected fully is by using following arbitrary or all types chromatogram sequential steps purifying: carry out ion-exchange in the acetate mode on weak base resin; Polystyrene-divinylbenzene (for example, AMBERLITES in not derivation XAD) carry out hydrophilic adsorption chromatography on; Silica gel adsorption chromatography; On carboxymethyl cellulose, carry out ion-exchange chromatography; Distribution chromatography for example, at SEPHADEX G-25, the last or adverse current distribution of LH-20; High performance liquid chromatography (HPLC), particularly octyl group or octadecyl silyl-silicon bonding phase column is filled reversed-phase HPLC.
Said process is better understood with reference to embodiment, and no matter the method that described embodiment is used for introducing compound and uses by the present invention does not constitute limitation of the scope of the invention what.
Being abbreviated as that following examples are used: DMF represents N, dinethylformamide; HBTU represents O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate; NMM represents N-methylmorpholine; And TFA represents trifluoroacetic acid.
Embodiment 1
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
In the reaction tubes of Rainin peptide synthesizer, put into Fmoc-Pro-Sieber ethanamide resin and (add 0.25g, 0.4mmol/g).With the described resin of DMF solvation, again by following synthesis cycle order couping amino acids:
(1) with DMF washing 3 * 1.5 minutes;
(2) with 20% piperidines deprotection 2 * 15 minutes;
(3) with DMF washing 6 * 3 minutes;
(4) add amino acid;
(5) activate amino acid and coupling with 0.4M HBTU/NMM;
(6) with DMF washing 3 * 1.5 minutes.
By following order described protected amino acid is coupled on the resin:
Shielded amino acid The coupling time
????Fmoc-Arg(Pmc) 30 minutes
????Fmoc-Ile 30 minutes
????Fmoc-Nva 30 minutes
????Fmoc-Thr(t-Bu) 30 minutes
????Fmoc-D-Ile 30 minutes
????Fmoc-Val 30 minutes
????Fmoc-Gly 30 minutes
Acetate 30 minutes
Behind the described end of synthesis,, described polypeptide is dissociated from described resin with TFA/ methyl-phenoxide/water mixture (95: 2.5: 2.5) with 3 hours.The described peptide solution of vacuum concentration is used ether sedimentation then, filters.With the thick peptide of HPLC purifying gained, described HPLC uses the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=3.16 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 923 (M+H) +Amino acid analysis: 0.96Gly; 1.01Val; 1.98Ile; 0.46Thr; 0.94Nva; 1.03Arg; 0.98Pro.
Embodiment 2
N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-D-Ile with Fmoc-D-aIle alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.97 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e923.7 (M+H) +Amino acid analysis: 0.94Gly; 0.98Val; 2.06Ile; 0.51Thr; 1.04Nva; 1.00Arg; 0.97Pro.
Embodiment 3
N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH 2CH 3
By with Fmoc-alloThr (T-Bu) alternative embodiment 1 Fmoc-Thr (t-Bu) prepare needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.95 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 923.7 (M+H) +Amino acid analysis: 1.01Gly; 0.92Val; 2.03Ile; 0.58Thr; 0.99Nva; 1.05Arg; 0.97Pro.
Embodiment 4
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-Nva with Fmoc-Gln (Ttr) alternative embodiment 1.After described peptide dissociates from resin, with HPLC purifying gained crude product, described HPLC uses the C-18 post, the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, the solvent gradient time is that 50 minutes solvent systems gradients are the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.48 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 952.7 (M+H) +Amino acid analysis: 1.03Gly; 1.00Val; 2.10Ile; 0.53Thr; 0.90Glu; 0.95Arg; 1.03Pro.
Embodiment 5
N-6-Me-nicotinyl-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-
ProNHCH 2CH 3
Prepare needed product by acetate with 6-methylnicotinic acid alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-6-Me-nicotinyl-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.62 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e1000.6 (M+H) +Amino acid analysis: 1.01Gly; 0.94Val; 2.13Ile; 0.55Thr; 1.00Nva; 1.01Arg; 1.04Pro.
Embodiment 6
N-Ac-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Phe, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.15 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1014.6 (M+H) +Amino acid analysis: 1.01Gly; 0.97Phe; 2.03Ile; 0.43Thr; 1.03Nva; 1.11Arg; 0.99Pro; 0.93Ala.
Embodiment 7
N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-D-Ile with Fmoc-D-aIle; Fmoc-Thr (t-Bu) and Fmoc-Nva with Fmoc-Ser (t-Bu) alternative embodiment 1 prepare needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.32 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 897.5 (M+H) +Amino acid analysis: 0.96Gly; 0.91Val; 2.11Ile; 0.59Ser; 1.06Arg; 1.04Pro.
Embodiment 8
N-Ac-Gly-Val-D-aIle-Thr-Ser-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-D-Ile with Fmoc-D-aIle; Fmoc-Nva with Fmoc-Ser (t-Bu) alternative embodiment 1 prepares needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Thr-Ser-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.35 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 911.5 (M+H) +Amino acid analysis: 0.98Gly; 1.03Val; 2.09Ile; 0.48Thr; 0.27Ser; 1.05Arg; 1.01Pro.
Embodiment 9
N-Ac-Gly-Val-D-aIle-Ser-Thr-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); The Fmoc-Nva that reaches with Fmoc-Thr (t-Bu) alternative embodiment 1 prepares needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Thr-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.36 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 911.5 (M+H) +Amino acid analysis: 0.96Gly; 0.93Val; 2.04Ile; 0.31Ser; 0.50Thr; 1.04Arg; 0.99Pro.
Embodiment 10
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); The Fmoc-Nva that reaches with Fmoc-Gln (Trt) alternative embodiment 1 prepares needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.39 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 938.5 (M+H) +Amino acid analysis: 1.00Gly; 0.95Val; 2.10Ile; 0.33Ser; 1.04Glu; 1.02Arg; 1.04Pro.
Embodiment 11
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate; R t=1.42 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e995.5 (M+H) +Amino acid analysis: 1.01Gly; 1.03Glu; 2.03Ile; 0.51Thr; 1.01Nva; 1.05Arg; 0.97Pro; 1.04Ala.
Embodiment 12
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-Val with Fmoc-Gln (Trt); Fmoc-Ile with Fmoc-D-Ile alternative embodiment 1 prepares needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=1.98 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 952.5 (M+H) +Amino acid analysis: 1.03Gly; 0.99Glu; 2.09Ile; 0.53Thr; 0.98Nva; 1.03Arg; 0.98Pro.
Embodiment 13
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-Ile with Fmoc-D-Ile alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=3.04 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e923.5 (M+H) +Amino acid analysis: 0.99Gly; 1.02Val; 2.12Ile; 0.51Thr; 0.98Nva; 1.04Arg; 1.07Pro.
Embodiment 14
N-Ac-Gly-Val-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3
By replacing Fmoc-D-Ile with Fmoc-Ile; Fmoc-Ile with Fmoc-D-Ile alternative embodiment 1 prepares needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.71 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 923.5 (M+H) +Amino acid analysis: 0.97Gly; 1.03Val; 2.10Ile; 0.55Thr; 0.93Nva; 1.02Arg; 0.95Pro.
Embodiment 15
N-Ac-Gly-Val-D-Ile-Thr-Nva-Pro-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-Ile with Fmoc-Pro alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-Pro-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.45 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e907.5 (M+H) +Amino acid analysis: 1.05Gly; 1.00Val; 1.10Ile; 0.49Thr; 1.01Nva; 1.04Arg; 2.12Pro.
Embodiment 16
N-Ac-Gly-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-Ile with Fmoc-Lys (Ac) alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-Lys (Ac)-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.39 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 980.5 (M+H) +Amino acid analysis: 0.97Gly; 1.02Val; 1.08He; 0.49Thr; 1.04Nva; 0.89Lys; 1.01Arg; 1.03Pro.
Embodiment 17
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
Prepare needed product by Fmoc-Val with Fmoc-Gln (Trt) alternative embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.02 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e952.5 (M+H) +Amino acid analysis: 0.94Gly; 1.04Glu; 2.07Ile; 0.43Thr; 1.01Nva; 1.10Arg; 0.97Pro.
Embodiment 18
N-AC-Gly-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.20 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.5 (M+H) +
Embodiment 19
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide, and the step of adding and Fmoc-Pro coupling with the Fmoc-D-Ala-Sieber amide resins, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=2.34 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 966.7 (M+H) +
Embodiment 20
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Pro-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Ile with Fmoc-D-Pro, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Pro-Arg-Pro-D-AlaNH 2Trifluoroacetate: Rt=1.05 minute (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 979.6 (M+H) +
Embodiment 21
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Nva and adding and Fmoc-Pro coupling with Fmoc-Gln (Trt), and then with Fmoc-Arg (Pmc) coupling of elder generation and embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.65 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e995.7 (M+H) +
Embodiment 22
N-Ac-Gly-Gln-D-Ile-alloThr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-alloThr (t-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-alloThr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.24 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA): MS (ESI) m/e 995.7 (M+H) +
Embodiment 23
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Fmoc-Lys (Ac) replaces Fmoc-Ile, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-Lys (Ac)-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=0.94 minute (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1052.7 (M+H) +
Embodiment 24
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Nva with Fmoc-Ser (t-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=0.92 minute (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 983.6 (M+H) +
Embodiment 25
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); With Fmoc-D-Ile replace Fmoc-Ile and with earlier with the Fmoc-Pro coupling again with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Tbr-Nva-D-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.41 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.7 (M+H) +
Embodiment 26
N-Ac-Gly-D-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-D-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent systems gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-D-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.14 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.5 (M+H) +
Embodiment 27
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Gly with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=2.71 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e1037.6 (M+H) +Amino acid analysis: 0.89Glu; 1.01Val; 2.05Ile; 0.54Thr; 0.98Nva; 0.99Arg; 1.01Pro; 1.01Ala.
Embodiment 28
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method of using embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With gained pure component freeze-drying N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=2.86 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 994.6 (M+H); Amino acid analysis: 0.96Glu; 1.02Val; 1.98Ile; 0.59Thr; 1.01Nva; 1.06Arg; 0.99Pro.
Embodiment 29
N-Ac-(4-CH 3)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; With Fmoc-(4-CH 3) Phe replaces Fmoc-Gly; Replace Fmoc-Val with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then prepare described title product with Fmoc-Arg (Pmc) coupling of embodiment 1.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-(4-CH 3) Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.19 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1099.7 (M+H) +Amino acid analysis: 1.00Glu; 2.03Ile; 0.51Thr; 1.03Nva; 1.02Arg; 1.10Pro; 1.02Ala.
Embodiment 30
N-Ac-(4-CN)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Gly with Fmoc-(4-CN) Phe; Replace Fmoc-Val with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-(4-CN) Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=2.88 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1110.6 (M+H) +Amino acid analysis: 0.97Glu; 2.11Ile; 0.49Thr; 1.01Nva; 0.95Arg; 1.04Pro; 1.01Ala.
Embodiment 31
N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Asn (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=1.75 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e981.6 (M+H) +Amino acid analysis: 0.99Gly; 0.96Asp; 2.05Ile; 0.55Thr; 1.02Nva; 1.01Arg; 1.00Pro; 1.02Ala.
Embodiment 32
N-Ac-Gly-Cit-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Cit, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Cit-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.08 minutes (the gradient scope variation contains 0.015TFA from the 20%-80% acetonitrile/water more than 10 minutes); MS (ESI) m/e1024.6 (M+H) +Amino acid analysis: 1.03Gly; 0.94Cit; 2.07Ile; 0.53Thr; 1.00Nva; 0.99Arg; 0.97Pro; 1.01Ala.
Embodiment 33
N-Ac-Gly-Lys(Ac)-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Lys (Ac), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Lys (Ac)-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.16 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1037.7 (M+H) +
Embodiment 34
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method that use is introduced at embodiment 1, but replace Fmoc-Val with Fmoc-His (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=3.88 minutes (gradient scope changes from 20%-80% acetonitrile/water 0.01%TFA more than 10 minutes); MS (ESI) m/e 961.6 (M+H) +
Embodiment 35
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-His (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.70 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1004.6 (M+H) +
Embodiment 36
N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method that use is introduced at embodiment 1, but to use Fmoc-Asn (Trt) to replace Fmoc-Val.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=3.88 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e938.7 (M+H) +
Embodiment 37
N-Ac-Gly-D-Asn-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3
The method that use is introduced at embodiment 1, but replace Fmoc-Val with Fmoc-D-Asn (Trt); Replace Fmoc-Ile with Fmoc-Lys (Ac).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-D-Asn-D-Ile-Thr-Nva-Lys (Ac)-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=3.65 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.6 (M+H) +
Embodiment 38
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH 2CH 3
The method of using embodiment 1 to introduce, but replace Fmoc-Val with Fmoc-Gln (Trt); And use Fmoc-Tyr (t-Bu) to replace Fmoc-Thr (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=4.43 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1014.5 (M+H) +
Embodiment 39
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Pro-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Ile with Fmoc-Pro, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-Pro-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.74 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 979.5 (M+H) +
Embodiment 40
N-Ac-Gly-Gln-D-Ile-Met-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-Met,,, thereby make needed product again with Fmoc-Arg (Pmc) coupling of embodiment 1 earlier with the Fmoc-Pro coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Met-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.48 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1025.5 (M+H) +
Embodiment 41
N-Ac-Gly-Gln-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val and Fmoc-Nva with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.75 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1024.6 (M+H) +
Embodiment 42
N-Ac-Gly-Arg-D-Ile-Thr-Nva-Ile-Gln-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide, replace Fmoc-Val with Fmoc-Arg (Pmc) with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Arg (Pmc) with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Arg-D-Ile-Thr-Nva-Ile-Gln-Pro-D-AlaNH 2Trifluoroacetate: R t=3.96 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.6 (M+H) +
Embodiment 43
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-Tyr (t-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.41 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1057.5 (M+H) +
Embodiment 44
N-Ac-Gly-Gln-D-Leu-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-Leu, and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Leu-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.00 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 995.6 (M+H) +
Embodiment 45
N-Ac-Gly-Gln-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-Leu; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.05 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e981.5 (M+H) +
Embodiment 46
N-Ac-Gly-Gln-D-aIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt), replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Nva with Fmoc-Ser (t-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-aIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.55 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e983.5 (M+H) +
Embodiment 47
N-Ac-Gly-Gln-D-aIle-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Ile with Fmoc-Lys (Ac), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-aIle-Thr-Nva-Lys (Ac)-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.70 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1009.6 (M+H) +
Embodiment 48
N-Ac-Gly-Gln-D-Ile-Asp-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-Asp (Ot-Bu), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Asp-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.00 minutes (gradient scope variation from 20% to 80% acetonitrile/water contains 0.01%TFA more than 10 minutes); MS (ESI) m/e 1009.5 (M+H) +
Embodiment 49
N-Ac-Gly-Gln-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Nva with Fmoc-Trp (Boc), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.46 minutes (gradient scope variation from 20% to 80% acetonitrile/water contains 0.01%TFA more than 10 minutes); MS (ESI) m/e 1082.5 (M+H) +
Embodiment 50
N-Ac-Gln-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Gly and Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-lle with Fmoc-Lys (Ac), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Gln-D-Ile-Thr-Nva-Lys (Ac)-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.965 minutes (gradient scope variation from 20% to 80% acetonitrile/water contains 0.01%TFA more than 10 minutes); MS (ESI) m/e1067.8 (M+H) +
Embodiment 51
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method of using embodiment 1 to introduce, but replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-Gly with Fmoc-Ala.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=4.215 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 966.6 (M+H) +
Embodiment 52
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Gly with Fmoc-Asn (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=4.4155 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e1023.6 (M+H) +
Embodiment 53
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2
By replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-Gly with Fmoc-Ala; Replace Fmoc-Val with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate: R t=3.995 minutes (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 1009.6 (M+H) +
Embodiment 54
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method of using embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Asn (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate: R t=4.62 minutes (gradient scope variation from 20% to 80% acetonitrile/water contains 0.01%TFA more than 10 minutes); MS (ESI) m/e 980.7 (M+H) +
Embodiment 55
N-Ac-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 56
N-Ac-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the method for introducing at embodiment 1, but replace Fmoc-D-Ile with Fmoc-D-Leu; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 57
N-Ac-Gly-Phe-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Val with Fmoc-Phe; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Phe-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 58
N-Ac-Gly-Val-D-aIle-Ser-Gln-Lys(Ac)-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt); Replace Fmoc-Ile with Fmoc-Lys (Ac).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Gln-Lys (Ac)-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 59
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH(CH 3) 2
The method that can use embodiment 1 to introduce, but replace Fmoc-D-Ile with Fmoc-D-aIle, replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu), replace Fmoc-Nva with Fmoc-Gln (Trt), with Fmoc-Pro-[4-(4-N-sec.-propyl amino) methyl-3-methoxyl group phenoxy group] butyryl AM resin replacement Fmoc-Pro-Sieber ethanamide resin.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH (CH 3) 2Trifluoroacetate.
Embodiment 60
N-Ac-Gly-Val-D-aIle-Tyr-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the introduction method of embodiment 1, but replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Tyr (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Tyr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 61
N-Ac-Gly-Gln-D-aIle-Ser-Nva-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Val with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-aIle-Ser-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 62
N-Ac-Gly-Gln-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the method for introducing at embodiment 1, but replace Fmoc-Val and Fmoc-Nva, replace Fmoc-D-Ile with Fmoc-D-aIle with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 63
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-D-AlaNH 2
Can be by replacing the Fmoc-Pro-Sieber ethanamide with the Fmoc-D-Ala-Sieber amide resins; Replace Fmoc-D-Ile with D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt), and the step of adding and Fmoc-Pro coupling, and then with Fmoc-Arg (Pmc) coupling of embodiment 1, thereby make needed product.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-D-AlaNH 2Trifluoroacetate.
Embodiment 64
N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the introduction method of embodiment 1, but replace Fmoc-D-Ile with Fmoc-D-aIle; And use Fmoc-Gln (Trt) to replace Fmoc-Nva.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 65
N-Ac-Gly-His-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the introduction method of embodiment 1, but replace Fmoc-Val with Fmoc-His (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-His-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 66
N-(6-Me-nicotinyl)-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
Can use the introduction method of embodiment 1, but replace acetate with 6-methyl-nicotinic acid; Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Fmoc-Gln (Trt) replaces Fmoc-Nva.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-(6-Me-nicotinyl)-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 67
N-Ac-Gly-NMeVal-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
Can use the introduction method of embodiment 1, but replace Fmoc-Va, in the coupling of N-methylamino acid, replace HBTU with HATU with Fmoc-NMeVal.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-NMeVal-D-Ile-Thr-NVa-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 68
N-Ac-Gly-NMePhe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method of using embodiment 1 to introduce, but replace Fmoc-Val with Fmoc-NMePhe, in the coupling of N-methylamino acid, replace HBTU with HATU.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-NMePhe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 69
N-Ac-Gly-Val-D-Ile-Thr-NMeNva-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Nva with Fmoc-NMeNva, in the coupling of N-methylamino acid, replace HBTU with HATU.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-NMeNva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 70
N-Ac-Gly-Val-D-Ile-NMeGlu-Nva-Ile-Arg-ProNHCH 2CH 3
Can be used on the method that embodiment 1 introduces, but must replace Fmoc-Thr (t-Bu), in the coupling of N-methylamino acid, replace HBTU with HATU with Fmoc-NMeGlu (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-NMeGlu-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 71
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-ProSieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Nva with Fmoc-Gln (Trt); Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-D-Ile with Fmoc-D-aIle, and save embodiment 1 and step Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3Trifluoroacetate.R t=0.83 minute (10 minutes graded is the 20%-80% acetonitrile/water that contains 0.01%TFA); MS (ESI) m/e 841.6 (M+H) +
Embodiment 72
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but must replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin, and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 73
N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
Can use the method for introducing at embodiment 1, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin, replace acetate with the 6-methylnicotinic acid, and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-NVa-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 74
N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-ArgNHCH 2CH 3
Can use the method for introducing at embodiment 1, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Thr (t-Bu) with Fmoc-alloThr (t-Bu), and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 75
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Val with Fmoc-Gln (Trt), and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate
Embodiment 76
N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but with Fmoc-Arg (Pbf-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin replacement Fmoc-Pro Sieber ethanamide resin; Replace Fmoc-D-Ile with Fmoc-D-aIle, and save embodiment 1 and step Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 77
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) and Fmoc-Nva with Fmoc-Ser (t-Bu), and save embodiment 1 and step Fmoc-Arg (Pmc) coupling, after described peptide dissociates from resin, with HPLC purifying gained crude product, described HPLC uses the C-18 post, the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 78
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Nva with Fmoc-Gln (Trt), and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 79
N-Ac-Gly-Val-D-Ile-Thr-Ser-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Nva with Fmoc-Ser (t-Bu), and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Ser-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 80
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Ile with Fmoc-D-Ile, and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 81
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Gly with Fmoc-Gln (Trt), and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 82
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Gly with Fmoc-Nva, and save the step of embodiment 1 with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 83
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Nva.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 84
N-Ac-D-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-D-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-D-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 85
N-Ac-D-Gln-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but must replace Fmoc-Gly with Fmoc-D-Gln (Trt), and replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-D-Gln-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 86
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Gln (Trt), replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) and replace Fmoc-Nva with Fmoc-Ser (t-Bu) with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 87
N-Ac-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3
Can use the method for introducing at embodiment 1, but must replace Fmoc-Gly with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) and Fmoc-Nva with Fmoc-Ser (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 88
N-Ac-D-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-D-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) and Fmoc-Nva with Fmoc-Ser (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-D-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 89
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Gly with Fmoc-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle, replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva and save step with Fmoc-Arg (Pmc) coupling with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 90
N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but with Fmoc-Arg (Pbf-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin replacement Fmoc-Pro Sieber ethanamide resin; Replace Fmoc-Gly with Fmoc-D-Gln (Trt); Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt), and save the step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 91
N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin, replace Fmoc-Gly with Fmoc-Gln (Trt), replace Fmoc-Ile with replacing Fmoc-Pro, and save step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 92
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Gly with Fmoc-Ala; Replace Fmoc-Val with Fmoc-Gln (Trt), and save step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 93
N-Ac-D-Ala-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-D-Ala; Replace Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-D-Ala-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 94
N-Ac-Ala-Gln-D-Ile-Thr-Set-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly and replace Fmoc-Val with Fmoc-Gln (Trt) with Fmoc-Ala, Fmoc-Nva replaced with Fmoc-Ser (t-Bu).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Gln-D-Ile-Thr-Ser-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 95
N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Ala; Replace Fmoc-D-Ile with Fmoc-D-aIle; Replace Fmoc-Thr (t-Bu) and replace Fmoc-Nva with Fmoc-Ser (t-Bu) with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 96
N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-Arg-NHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace Fmoc-Gly with Fmoc-Ala; Replace Fmoc-DIle with Fmoc-D-aIle; Replace Fmoc-Thr-(t-Bu) with Fmoc-Ser (t-Bu); Replace Fmoc-Nva with Fmoc-Gln (Trt), and save the step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 97
N-Ac-(4CH 3)Phe-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but with Fmoc-Arg (Pbf-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin replacement Fmoc-Pro Sieber ethanamide resin; With Fmoc-(4CH 3) Phe replaces Fmoc-Gly; Replace Fmoc-Val with Fmoc-Gln (Trt), and save the step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-(4CH 3) Phe-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
Embodiment 98
N-Ac-(4CH 3)Phe-Gln-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but with Fmoc-(4CH 3) Phe replaces Fmoc-Gly; Replace Fmoc-Val and Fmoc-Nva with Fmoc-Gln (Trt).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-(4CH 3) Phe-Gln-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 99
N-Ac-Gln-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Gly with Fmoc-Gln (Trt), replace Fmoc-Ile with Fmoc-Lys (Ac).After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-Gln-Val-D-Ile-Thr-Nva-Lys (Ac)-Arg-ProNHCH 2CH 3Trifluoroacetate.
Embodiment 100
N-Ac-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3
The method that can use embodiment 1 to introduce, but replace Fmoc-Pro Sieber ethanamide resin with Fmoc-Arg (Pbf)-[4-(4-N-ethyl) methyl-3-methoxyl group phenoxy group] butyryl AM resin; Replace acetate with 6-methyl-nicotinic acid, and save the step with Fmoc-Arg (Pmc) coupling.After described peptide dissociated from resin, with HPLC purifying gained crude product, described HPLC used the C-18 post, and the solvent mixture gradient is the 5%-100% acetonitrile/water that contains 0.01%TFA, and the solvent gradient time is 50 minutes.With the freeze-drying of gained pure component, obtain N-Ac-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3Trifluoroacetate.
For a person skilled in the art, the invention is not restricted to above-mentioned indicative embodiment obviously, only otherwise depart from its essential characteristic, described invention also can show as other particular forms.Therefore it is indicative and nonrestrictive to be noted that embodiment should be regarded as in every respect, must be with appended claims benchmark as a reference, and can not make benchmark with the above embodiments, so any change of the implication of claim and its equivalent scope also will comprise wherein.
Sequence table
<110>Abbott?Laboratories
Haviv，Fortuna
Bradley，Michael?F.
＜120〉have seven of anti-angiogenic activity-, eight-and nine-peptide
<130>6853.WO.01
＜140〉do not give application number
<141>2002-10-30
<150>10/263,812
<151>2002-10-04
<150>10/000,681
<151>2001-10-31
<160>1
<170>FastSEQ?for?Windows?Version?4.0
<210>1
<211>10
<212>PRT
＜213〉artificial sequence
<220>
＜223〉anti-angiogenic formation peptide
＜221〉varient
<222>(1)...(1)
＜223〉1 Xaa=hydrogen or R-(CH2) n-C (O)-, wherein n is
The integer of 0-8, R are alkoxyl group, alkyl, and amino,
Aryl, carboxyl, cycloalkenyl group, cycloalkyl and heterocycle
＜221〉varient
<222>(2)...(2)
＜223〉2 Xaa=Ala, (1S, 3R)-1-Aminocyclopentane-3-carbonyl,
(1S, 4R)-1-amino cyclopentyl-2-alkene-4-carbonyl,
(1R, 4S)-1-amino cyclopentyl-2-alkene-4-carbonyl and Asn
＜221〉varient
<222>(2)...(2)
＜223〉2 (before continuous)
2 Xaa=3-cyano group phenylalanyls, 4-cyano group phenylalanyl,
3,4-dimethoxy phenylalanyl and 4-fluorobenzene alanyl
＜221〉varient
<222>(2)...(2)
＜223〉2 (before continuous)
2 Xaa=3-(2-furyl) alanyl, Gln, Gly, Lys (Ac),
4-methylbenzene alanyl, Nva and Sar
＜221〉varient
<222>(3)...(3)
＜223〉3 Xaa=Ala, (1R, 4S)-1-amino cyclopentyl-2-alkene-4-carbonyl, Arg,
Asn, t-butyl glycyl, Cit and cyclohexyl glycyl
＜221〉varient
<222>(3)...(3)
＜223〉3 (before continuous)
3 Xaa=Gln, Glu, Gly, His, Ile, Leu, Lys (Ac), Met,
Nva, Phe, NMePhe, Pro, Ser, 3-(2-thienyl alanyl),
Thr, Val and N-methyl are valyl
＜221〉varient
<222>(4)...(4)
＜223〉4 Xaa=Ile
＜221〉varient
<222>(5)...(5)
＜223〉5 Xaa=alloThr, Asp, Gln, N-methyl glutaminyl,
NMeGlu，Gly，His，Hser，Ile，Lys(Ac)，Met，Ser，
N-methyl seryl, Thr, Trp, Tyr, or tyrosyl (O-methyl)
＜22l〉varient
<222>(6)...(6)
＜223〉6 Xaa=Ala, N-methyl-prop aminoacyl, alloThr, Gln, Gly,
Hser, Leu, Lys (Ac), Nle, Nva, NMeNva, the octyl group glycyl,
Orn (Ac), 3-Pal, Sar, Ser, N-methyl seryl, Thr, Trp,
Val and N-methyl are valyl
＜221〉varient
<222>(7)...(7)
＜223〉7 Xaa=Ala, aIle, Asp, Cit, Ile, Leu, Lys (Ac),
N-methyl isoleucyl, Nva, Phe and pro
＜221〉varient
<222>(8)...(8)
＜223〉8 Xaa=Arg, Cit, Gln, His, high arginyl, Lys,
Lysyl (N-ε-sec.-propyl), orn and 3-Pal
＜221〉varient
<222>(9)...(9)
＜223〉9 amino butyryl radicalies of Xaa=2-, high prolyl, the hydroxyl prolyl,
Leu and Pro
＜221〉varient
<222>(10)...(10)
＜223〉10 Xaa=azepine G-NH2s, G-NH2,
-NH-(CH2) n-CHR1R2 ,-NHR3, wherein n is the 0-8 integer
R1 is hydrogen, alkyl, cycloalkenyl group and cycloalkyl
＜221〉varient
<222>(10)...(10)
＜223〉10 (before continuous)
10 Xaa=R2 are hydrogen, alkoxyl group, and alkyl, aryl,
Cycloalkenyl group, cycloalkyl, heterocycle and hydroxyl
＜221〉varient
<222>(10)...(10)
＜223〉10 (before continuous)
10 Xaa=preconditions are when n is 0, and R2 is not alkoxyl group or hydroxyl
＜221〉varient
<222>(10)...(10)
＜223〉10 (before continuous)
10 Xaa=R3 are hydrogen, cycloalkenyl group, and cycloalkyl, or
Hydroxyl
<400>1
Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa?Xaa
1???????????????5???????????????????10

Claims (22)

1. acceptable salt is gone up in following formula (I) compound or its treatment:
Xaa 1-Xaa 2-Xaa 3-Xaa 4-Xaa 5-Xaa 6-Xaa 7-Xaa 8-Xaa 9-Xaa 10(I)，(SEQ?IDNO：1)
Wherein
Xaa 1Be selected from hydrogen and R-(CH 2) n-C (O)-, wherein n is the integer of 0-8; And R is selected from alkoxyl group, alkyl, amino, aryl, carboxyl, cycloalkenyl group, cycloalkyl and heterocycle;
Xaa 2Be selected from alanyl, D-alanyl, (1S, 3R)-1-Aminocyclopentane-3-carbonyl, (1S, 4R)-1-amino cyclopentyl-2-alkene-4-carbonyl, (1R, 4S)-and 1-amino cyclopentyl-2-alkene-4-carbonyl, asparagyl, 3-cyano group phenylalanyl, 4-cyano group phenylalanyl, 3,4-dimethoxy phenylalanyl, 4-fluorobenzene alanyl, 3-(2-furyl) alanyl, glutaminyl, D-glutaminyl, glycyl, lysyl (N-ε ethanoyl), 4-methylbenzene alanyl, norvalyl and sarcosyl;
Xaa 3Be selected from alanyl, (1R, 4S)-1-amino cyclopentyl-2-alkene-4-carbonyl, arginyl, asparagyl, the D-asparagyl, t-butyl glycyl, the melon aminoacyl, the cyclohexyl glycyl, glutaminyl, the D-glutaminyl, glutamyl, glycyl, histidyl-, isoleucyl, leucyl, lysyl (N-ε-ethanoyl), methionyl, norvalyl, phenylalanyl, N-methylbenzene alanyl, prolyl, seryl, 3-(2-thienyl alanyl), Threonyl, valyl and the N-methyl is valyl;
Xaa 4Be selected from that D-alanyl, the other isoleucyl of D-, D-allyl group glycyl, D-4-chlorobenzene alanyl, D-melon aminoacyl, D-3-cyano group phenylalanyl, the high phenylalanyl of D-, D-homoseryl, isoleucyl, D-isoleucyl, D-leucyl, N-methyl D-leucyl, D-norleueyl-, D-are norvalyl, Beracilline acyl group, D-phenylalanyl, D-prolyl, D-seryl, D-thienyl alanyl and D-Threonyl;
Xaa 5Be selected from other Threonyl, aspartyl, glutaminyl, D-glutaminyl, N-methyl glutaminyl, N-methyl glutamyl, glycyl, histidyl-, homoseryl, isoleucyl, lysyl (N-ε-ethanoyl), methionyl, seryl, N-methyl seryl, Threonyl, D-Threonyl, tryptophyl, tyrosyl and tyrosyl (O-methyl);
Xaa 6Be selected from alanyl, N-methyl-prop aminoacyl, other Threonyl, glutaminyl, glycyl, homoseryl, leucyl, lysyl (N-ε-ethanoyl), norleueyl-, norvalyl, D-is norvalyl, the N-methyl is norvalyl, the octyl group glycyl, ornithyl (N-δ-ethanoyl), 3-(3-pyridyl) alanyl, sarcosyl, seryl, N-methyl seryl, Threonyl, tryptophyl, valyl and the N-methyl is valyl;
Xaa 7Be selected from alanyl, other isoleucyl, aspartyl, melon aminoacyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl (N-ε-ethanoyl), D-lysyl (N-ε-ethanoyl), N-methyl isoleucyl, norvalyl, phenylalanyl, prolyl and D-prolyl;
Xaa 8Be selected from arginyl, D-arginyl, melon aminoacyl, glutaminyl, histidyl-, high arginyl, lysyl, lysyl (N-ε-sec.-propyl), ornithyl and 3-(3-pyridyl) alanyl;
Xaa 9Do not exist or to be selected from the amino butyryl radicals of N-methyl D-alanyl, 2-, D-glutaminyl, high prolyl, hydroxyl prolyl, leucyl, prolyl, D-prolyl and D-valyl;
Xaa 10Be selected from D-alanimamides, azepine G-NH2, G-NH2, N-ε-ethanoyl-D-lysyl amine, formula NH-(CH 2) n-CHR 1R 2The group and the formula-NHR of representative 3The group of representative, wherein n is 0 to 8 integer; R 1Be selected from hydrogen, alkyl, cycloalkenyl group and cycloalkyl; R 2Be selected from hydrogen, alkoxyl group, alkyl, aryl, cycloalkenyl group, cycloalkyl, heterocycle and hydroxyl, precondition is when n is 0, R 2Be not alkoxyl group or hydroxyl; And R 3Be selected from hydrogen, cycloalkenyl group, cycloalkyl and hydroxyl.
2. the compound of claim 1, wherein Xaa 2Be selected from alanyl, D-alanyl, asparagyl, 4-cyano group phenylalanyl, 4-methylbenzene alanyl and norvalyl.
3. the compound of claim 2, it is selected from:
N-Ac-(4CH 3)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-(4CN)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-DAla-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Ala-Gln-D-Ile-Thr-Ser-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3；
N-Ac-(4CH 3) Phe-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3With
N-Ac-(4CH 3)Phe-Gln-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3。
4. the compound of claim 1, wherein Xaa 2Be selected from glutaminyl and D-glutaminyl.
5. the compound of claim 4, it is selected from:
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-Arg-Pro-D-AIaNH 2；
N-Ac-Gln-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2；
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-D-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-D-Gln-Val-DIle-Thr-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3；
N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3；
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2CH 3；
N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-ArgNHCH 2CH 3With
N-Ac-Gln-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3
6. the compound of claim 1, wherein Xaa 2Be glycyl.
7. the compound of claim 6, wherein Xaa 3Be selected from arginyl, asparagyl, D-asparagyl, melon aminoacyl, lysyl (N-ε-ethanoyl) and histidyl-.
8. the compound of claim 7, it is selected from:
N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Cit-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Lys(Ac)-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-D-Asn-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Arg-D-Ile-Thr-Nva-Ile-Gln-Pro-D-AlaNH 2With
N-Ac-Gly-His-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3。
9. the compound of claim 6, wherein Xaa 3Be selected from valyl valyl with the N-methyl.
10. the compound of claim 9, wherein Xaa 6Be selected from norvalyl norvalyl with the N-methyl.
11. the compound of claim 10, it is selected from:
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-Pro-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-NMeVal-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-NMeNva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-NMeGlu-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-ArgNHCH 2CH 3With
N-(6Me-nicotinyl)-Gly-Val-DIle-Thr-Nva-Ile-ArgNHCH 2CH 3。
12. the compound of claim 9, wherein Xaa 6Be selected from glutaminyl, seryl and Threonyl.
13. the compound of claim 12, it is selected from:
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Thr-Ser-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Thr-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Gln-Lys(Ac)-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-alle-Ser-Gln-Ile-Arg-ProNHCH(CH 3) 2；
N-Ac-Gly-Val-D-aIle-Tyr-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH 2CH 3；
N-6MeNic-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Val-D-alle-Ser-Gln-Ile-ArgNHCH 2CH 3；
N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-ArgNHCH 2CH 3；
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH 2CH 3With
N-Ac-Gly-Val-D-Ile-Thr-Ser-Ile-ArgNHCH 2CH 3。
14. the compound of claim 6, wherein Xaa 3Be selected from glutaminyl, D-glutaminyl, phenylalanyl and N-methylbenzene alanyl.
15. the compound of claim 14, wherein Xaa 7Be isoleucyl.
16. the compound of claim 15, it is selected from:
N-Ac-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-alloThr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-D-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Gln-D-Ile-Met-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Leu-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-aIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Asp-Nva-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Phe-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Gln-D-aIle-Ser-Nva-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Gln-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-NMePhe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2CH 3With
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH 2CH 3。
17. the compound of claim 14, wherein Xaa 7Be selected from D-isoleucyl, lysyl (N-ε ethanoyl) and D-prolyl.
18. the compound of claim 17, it is selected from:
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2CH 3；
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Pro-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2；
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-Pro-D-AlaNH 2With
N-Ac-Gly-Gln-D-aIle-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH 2
19. a compound, it is N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2CH 3
20. a medicinal compositions, it comprises the compound of claim 1 or acceptable salt is gone up in its treatment and acceptable carrier is gone up in treatment.
21. an inhibition need to be considered to the mammiferous angiopoietic method of this treatment, but this method comprises that the compound of claim 1 of receiving amount or its treatment are gone up in treatment goes up acceptable salt and give described Mammals.
22. a treatment need to be considered to the mammiferous method for cancer of this treatment, but this method comprises that the compound of claim 1 of receiving amount or its treatment are gone up in treatment goes up acceptable salt and give described Mammals.
CNA028258991A 2001-10-31 2002-10-30 Hepta-, octa- and nonapeptides having antiangiogenic activity Pending CN1639188A (en)

Applications Claiming Priority (4)

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US10/000,681 2001-10-31
US10/000,681 US20030125259A1 (en) 2001-10-31 2001-10-31 Octa- and nonapeptides having antiangiogenic activity
US10/263,812 US20030096758A1 (en) 2001-10-31 2002-10-04 HEPTA-, OCTA- and nonapeptides having antiangiogenic activity
US10/263,812 2002-10-04

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