CN1504480A - Endothelin receptor antagonist of tripeptide - Google Patents
Endothelin receptor antagonist of tripeptide Download PDFInfo
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- CN1504480A CN1504480A CNA031459293A CN03145929A CN1504480A CN 1504480 A CN1504480 A CN 1504480A CN A031459293 A CNA031459293 A CN A031459293A CN 03145929 A CN03145929 A CN 03145929A CN 1504480 A CN1504480 A CN 1504480A
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Abstract
The invention relates to peptides and non-peptides derivatives having endothelium essence receptor antagonizing activity, its preparing process, medicinal compositions containing them, and their use in treating diseases related to endothelium essence and prostate.
Description
Invention field
The present invention relates to have the peptide class and the non-peptide derivative of endothelin receptor antagonizing activity, its preparation method contains their pharmaceutical composition and they are in the purposes of prevention or treatment and endothelin and prostate gland diseases related.
Background technology
Endothelin (Endothelin, be called for short ET) is by the blood vessel endothelium excretory, and they are one of the strongest biotic factors of the vasoconstriction effect found so far of a class.There is the gene of three kinds of endothelin of encoding respectively in human or other mammalian genes group, and the big ET of formation changes ET-1, ET-2, ET-3 under the effect of endothelin conversion enzyme.They are 21 peptides, contain two disulfide bridge bonds.ET-1 not only is expressed in non-vascular cell, and is unique endothelin that is present in vascular endothelial cell.ET-2 and ET-3 are mainly in brain, kidney and suprarenal gland and small intestine.Special receptors bind in ET and the target cell finally produces corresponding biological effect.Three class ET acceptor, i.e. ET have been found so far
A, ET
B, and ET
CET
AMainly be distributed in aorta, the atrium, placenta is in the unstriated muscle of lung, the cerebrovascular and renal blood vessels; ET
BBe present in the neurogliocyte in the central nervous system, the arteries and veins clump epithelial cell that falls, lung, tire blood, renal glomerulus endothelium, ventricle, brain is medium, at vascular smooth muscle distribution is arranged also; ET
CThen mainly be distributed in the endotheliocyte.Three kinds of acceptors are to the avidity difference of various ET.Endothelin and acceptor have physiopathology reaction widely in human body.Participated in as hypertension, congestive heart failure, myocardial ischemia, brain suffocate, process such as shock, acute renal failure, pulmonary hypertension, vasospasm disease.Therefore the ET acceptor is considered to treat the practicable novel targets of cardiovascular and cerebrovascular diseases, and its receptor antagonist helps the preventing/treating cardiovascular disorder.
Summary of the invention
The objective of the invention is to seek new endothelin-receptor antagonists.
The inventor has now found that formula (I) peptide class and non-peptide derivative after deliberation
R-CO-AA1-AA
2-AA
3-OH (I)
Or its steric isomer has good endothelin receptor antagonizing activity, so formula (I) peptide class and non-peptide derivative or its steric isomer can be used as medicine and be used for prevention or treatment and endothelin and prostate gland diseases associated.
First aspect present invention relates to formula (I) peptide class and non-peptide derivative or its steric isomer,
R-CO-AA
1-AA
2-AA
3-OH
Formula (I)
Wherein, R is two chain hydrocarbon imido grpup, hexamethylene imine base or following groups of replacing
N in the formula
1, n
2, n
3Be 0,1,2,3 integers, n
3≠ 0,0≤n
1+ n
2≤ 4; X
1Be NH, O, S, CH
2X
2Be N, CH; Work as n
1=n
2=1, n
3=2, X
1Be CH
2, X
2Be the N atomic time, R is abbreviated as ABO;
m
1, m
2, m
3And m
4Be 0,1,2 integers, 0≤m
1+ m
2≤ 4,0≤m
3+ m
4≤ 4; y
1, y
2And y
3Be CH
2, O, S and NH, when they are NH or CH
2The time, can be used as N end structure R, form is N or CH; Work as m
1=m
2=1, m
3=m
4=2, y
1, y
2Be O atom, y
3Be the N atomic time, R is abbreviated as DAD; Work as m
1=m
2=1, m
3=m
4=2, y
3Be CH
2, y
1Be O atom, y
2Be the N atomic time, R is abbreviated as CSO;
AA
1Be L or D type Ala, Ile, Leu, MeVal, PrO, Val or other non-natural aliphatic amino acid, as β-Ala, γ-An Jidingsuan, or aminoisobutyric acid;
AA
2Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
2Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer;
AA
3Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
3Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer.
The invention still further relates to and contain at least a formula (I) peptide class and non-peptide derivative or its steric isomer,
R-CO-AA
1-AA
2-AA
3-OH formula (I)
Wherein, R is two chain hydrocarbon imido grpup, hexamethylene imine base or following groups of replacing
N in the formula
1, n
2, n
3Be 0,1,2,3 integers, n
3≠ 0,0≤n
1+ n
2≤ 4; X
1Be NH, O, S, CH
2X
2Be N, CH; Work as n
1=n
2=1, n
3=2, X
1Be CH
2, X
2Be the N atomic time, R is abbreviated as ABO;
m
1, m
2, m
3And m
4Be 0,1,2 integers, 0≤m
1+ m
2≤ 4,0≤m
3+ m
4≤ 4; y
1, y
2And y
3Be CH
2, O, S and NH, when they are NH or CH
2The time, can be used as N end structure R, form is N or CH; Work as m
1=m
2=1, m
3=m
4=2, y
1, y
2Be O atom, y
3Be the N atomic time, R is abbreviated as DAD; Work as m
1=m
2=1, m
3=m
4=2, y
3Be CH
2, y
1Be O atom, y
2Be the N atomic time, R is abbreviated as CSO.
AA
1Be L or D type Ala, Ile, Leu, MeVal, Pro, Val or other non-natural aliphatic amino acid, as β-Ala, γ-An Jidingsuan, or aminoisobutyric acid;
AA
2Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
2Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer;
AA
3Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
3Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer;
And the pharmaceutical composition of pharmaceutical carrier or vehicle.
The invention still further relates to the method for preparation formula (I) peptide derivative or its steric isomer, it comprises:
1) with compound R CO-A-OH and B-OP at DMF-DCM, NMM reacts among the DCC-HOBt, generates RCO-A-B-OP, R wherein, A, B, as definition in the claim 1, P is C
1-4Alkyl.
2) with 1) middle products therefrom saponification in 1M alkali/alcoholic solution, use acidifying then, generate RCO-A-B-OH,
3) with 2) in product RCO-A-B-OH and C-OP at DMF-DCM, NMM reacts among the DCC-HOBt, generation RCO-A-B-C-OP, wherein P is C
1-4Alkyl, products therefrom is as 2) described in carry out saponification reaction, production (I) RCO-A-B-C-OH,
4) with 2) in product RCO-A-B-OH in THF, NMM with isobutyl chlorocarbonate reaction 5-10 minute, add C-ONa again, generate RCO-A-B-C-ONa, use acidifying then, production (I) RCO-A-B-C-OH.
The invention still further relates to the preparation method of the non-peptide derivative of formula (I) or its steric isomer derivative, by means known in the art and the preparation of improvement Szelke literature method, detailed step is referring to embodiment 3.
The invention still further relates to formula (I) peptide class and non-peptide derivative or its steric isomer purposes in the medicine of prevention or treatment and endothelin and prostate gland diseases related or symptom.
Term used herein " formula (I) peptide class and non-peptide derivative steric isomer " is meant its corresponding D-or L-steric configuration.
According to this invention, formula (I) peptide class and non-peptide derivative or its steric isomer can be selected from following compound:
1?ABO-CO-NH-CH2-CH
2-CO-D-Trp-D-Trp-OH
2?ABO-CO-GABA-D-Trp-D-Trp-OH
3?ABO-CO-NH-C(CH
3)
2-CO-D-Trp-D-Trp-OH
4?ABO-CO-Leu-D-Trp-D-Phe(2-F)-OH
5?ABO-CO-Leu-D-Trp-D-Phe(3-F)-OH
6?ABO-CO-Leu-D-Trp-D-Phe(4-F)-OH
7?ABO-CO-Leu-D-Trp-D-Phe(2-Cl)-OH
8?ABO-CO-Leu-D-Trp-D-Phe(3-Cl)-OH
9?ABO-CO-Leu-D-Trp-D-Phe(4-Cl)-OH
10?ABO-CO-Leu-D-Trp-D-Phe(4-Br)-OH
11?ABO-CO-Leu-D-Trp-D-Phe(3-NO
2)-OH
12?ABO-CO-Leu-D-Trp-D-Phe(3-COOH)-OH
13?ABO-CO-Leu-D-Trp-D-Phe(4-COOH)-OH
14?ABO-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
15?ABO-CO-Leu-D-Trp-D-Phe(2，4-Cl
2)-OH
16?ABO-CO-Leu-D-Trp-D-Phe(2，5-Cl
2)-OH
17?ABO-CO-Leu-D-Trp-D-Phe(2-CH
3-3-Cl)-OH
18?ABO-CO-Leu-D-Trp-D-Mob-OH
19?ABO-CO-Leu-D-Trp-D-Phg(4-F)-OH
20?ABO-CO-Leu-D-Phe(2-F)-D-Trp-OH
21?ABO-CO-Leu-D-Phe(3-F)-D-Trp-OH
22?ABO-CO-Leu-D-Phe(4-F)-D-Trp-OH
23?ABO-CO-Leu-D-Phe(4-Br)-D-Trp-OH
24?ABO-CO-Leu-D-Phe(3-NO
2)-D-Trp-OH
25?ABO-CO-Leu-D-Phe(4-F-3-Cl)-D-Trp-OH
26?ABO-CO-Leu-D-Phe(3-CO-D-Trp-OH)-D-Trp-OH
27?ABO-CO-Leu-D-Phe(4-CO-D-Trp-OH)-D-Trp-OH
28?ABO-CO-Leu-D-Phe(2-CH
3-3-Cl)-D-Trp-OH
29?ABO-CO-Leu-D-Mob-D-Trp-OH
30?ABO-CO-Leu-D-Phg(4-F)-D-Trp-OH
31?ABO-CO-Leu-D-Trp-D-Trp-OH
32?HIM-CO-Leu-D-Trp-D-Mob-OH
33?HIM-CO-Leu-D-Mob-D-Trp-OH
34?HIM-CO-Leu-D-Trp-D-Phg(4-F)-OH
35?HIM-CO-Leu-D-Phg(4-F)-D-Trp-OH
36?DAD-CO-Leu-D-Trp-D-Phe(4-F)-OH
37?DAD-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
38?DAD-CO-Leu-D-Trp-D-Mob-OH
39?CSO-CO-Leu-D-Trp-D-Phe(4-F)-OH
40?CSO-CO-Leu-D-Trp-D-Phe(3，4-Cl
2)-OH
41?CSO-CO-Leu-D-Trp-D-Mob-OH
42?ENP002
According to the present invention, formula (I) peptide derivative or its steric isomer can by means known in the art, literature method or following shown in reaction scheme 1 preparation:
Reaction scheme 1
At reaction scheme 1 Chinese style R-CO-AA
1-OH compound (R wherein, AA
1As above define) and AA
2-OP (AA wherein
2As above definition, P is C
1-4Alkyl, it can be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, preferable methyl and ethyl) at DMF-DCM, NMM reacts among the DCC-HOBt, generates R-CO-AA
1-AA
2-OP compound (R wherein, AA
1, AA
2, P as above defines).With R-CO-AA
1-AA
2Hcl acidifying is used in the saponification in 1M NaOH/ methanol solution of-OP compound then, generates R-CO-AA
1-AA
2-OH compound (R wherein, AA
1, AA
2As above definition).With formula R-CO-AA
1-AA
2-OH and AA
3-OP (AA wherein
3, P as above defines) and at DMF-DCM, NMM reacts among the DCC-HOBt, production R-CO-AA
1-AA
2-AA
3-OP (R wherein, AA
1, AA
2, AA
3, P as above defines) and compound.Then with gained R-CO-AA
1-AA
2-AA
3Hcl acidifying is used in-OP saponification in 1M NaOH/ methanol solution then, production (I) R-CO-AA
1-AA
2-AA
3-OH.Perhaps with compound R-CO-AA
1-AA
2-OH reacts with isobutyl chlorocarbonate in THF, NMM, again with AA
3-ONa generates R-CO-AA
1-AA
2-AA
3-ONa uses hcl acidifying then, production (I) R-CO-AA
1-AA
2-AA
3-OH tripeptide derivative or its steric isomer.
According to this invention, formula (I) peptide derivative steric isomer is meant its corresponding D-or L-steric configuration.
According to this invention, formula (I) peptide class and non-peptide derivative and steric isomer thereof demonstrate excellent results in the anti-ET1 receptor model of animal, and therefore can be used as cardiovascular drug is used for animal, is preferred for Mammals, particularly the people.
Therefore the present invention also relates to and containing as at least a formula (I) the peptide class of the effective dose of activeconstituents and the pharmaceutical composition of non-peptide derivative and/or its steric isomer and conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains formula (I) peptide class and non-peptide class and/or its steric isomer of 0.1-90%.Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, formula (I) peptide class and non-peptide derivative and/or its steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make the suitable administration form or the dosage form that can be used as human.
Formula of the present invention (I) peptide class and non-peptide derivative and steric isomer thereof or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. for example.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.About the example of carrier, as thinner and absorption agent, as starch, dextrin, lactose, N.F,USP MANNITOL, sucrose, glucose, calcium sulfate, sodium-chlor, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent is as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; The disintegration inhibitor is as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer is as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant is as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent such as gum arabic, tragacanth gum, gelatin, ethanol, honey, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, effective constituent formula (I) peptide class and non-peptide derivative or its steric isomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard capsule or soft capsule.Also effective constituent formula (I) peptide class and non-peptide derivative or its steric isomer can be made microcapsule, be suspended in and make suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, as water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of the isooctadecanol of ammediol, ethoxylation, polyoxy baseization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The dosage of formula of the present invention (I) peptide class and non-peptide derivative or its steric isomer depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, in, four dosage form administrations.
Embodiment
The abbreviation of Shi Yonging in the present invention has following implication:
The Ala-L-Ala,
The Gly-glycine,
The GABA-γ-An Jidingsuan,
The Ile-Isoleucine,
The Leu-leucine,
Mob-β-piperonyl L-Ala
The Phe-phenylalanine,
The Phg-phenylglycocoll,
The Pro-proline(Pro),
Pya-β-pyridyl L-Ala,
The Trp-tryptophane,
The Val-Xie Ansuan,
The MeVal-methylvaline
The HIM-hexamethylene imine,
HMPA-hexamethyl phosphonic amide
The NMM-N-methylmorpholine,
The TEA-triethylamine,
The DCM-methylene dichloride,
The DMF-dimethyl formamide,
The DCC-dicyclohexylcarbodiimide,
The HOBt-1-hydroxybenzotriazole,
The THF-tetrahydrofuran (THF).
Among the present invention, all amino acid configurations are the L-type except that being labeled as the D-type.
Embodiment
Below example and biological activity test be used for further specifying the present invention, but this and do not mean that any limitation of the invention.
The embodiment melting point compound is measured by RY-1 type fusing point instrument, and temperature is not calibrated;
1H NMR collection of illustrative plates is measured by Bruker ARX 400 types or US Varian Unity Inova 600 type nuclear magnetic resonance spectrometers; The FAB mass spectrum is measured by Zabspect high resolution magnetic mass spectrometer; Ultimate analysis is measured by Carlo Erba1106 type elemental analyser; UV spectrum is measured by the UV-260 ultraviolet-visible pectrophotometer; Infrared spectra is by Magna IR
TM550 infrared instrument are measured.Embodiment prepares used reaction reagent and is commercial prod.
The preparation of embodiment 1:HIM-CO-Leu-D-Trp-D-Mob-OH
1.1 the preparation of piperitol (3,4-methylenedioxybenzyl alcohol):
15.0 gram (0.1mol) piperonylaldehyde is dissolved in 20 ml methanol, adds 12 milliliter 37% formaldehyde (0.12mol), stirring, and mixture heating up to 65 ℃ makes its whole dissolvings.After it dissolves fully, stop heating immediately, water-bath is cooled off, and adds the solution of 12 gram sodium hydroxide/12 ml waters (0.3mol) rapidly, and temperature sharply raises, heating, warm 70 ℃ of stirring reactions are 40 minutes in keeping, and temperature rising reflux is 20 minutes then.Cooling adds 30 ml waters, and with benzene extraction (15 milliliters * 4), united extraction liquid, washing twice, the benzene layer is with anhydrous sodium sulfate drying.The benzene layer concentrates, and gets oily liquids 14.8 grams (97.4%), Rf=0.30 (petroleum ether-ethyl acetate=1: 1).
1.2 the preparation of piperonyl chlorine methane (3,4-methylenedioxybenzyl chloride) mixes 68.4 gram piperitols (0.45mol) with 110 milliliters of concentrated hydrochloric acids (1.35mol), high degree of agitation, solid dissolving.After treating all dissolvings, with the benzene extraction, the benzene layer is used anhydrous sodium sulfate drying after washing with water, saturated sodium bicarbonate solution, saturated nacl aqueous solution.Concentrate the benzene layer, get pale yellow oily liquid body 76.1 grams, the oil pump underpressure distillation, the fraction of collection 100-120 ℃/5 mmhg gets 66.2 grams (86.3%).
1.3 the preparation of N-acetyl-(2-piperonyl) diethyl malonate
Sodium 9.0 (0.388mol) gram is refluxed (98 ± 3 ℃) in 600 milliliters of absolute dehydrated alcohols, dissolve fully to sodium.After being cooled to room temperature (for white casse liquid), add acetamino diethyl malonate 84.29 grams (0.388mol), stirring and dissolving.Piperonyl chlorine methane 66.2 grams (0.388mol) that add above-mentioned preparation, reaction solution gradual change muddiness, oil bath backflow (100 ℃ ± 3) 3 hours.Decompression steams ethanol, gets faint yellow oily thing, slowly solidifies, and with the benzene dissolving, the benzene layer is used anhydrous sodium sulfate drying after respectively washing twice with 10% yellow soda ash, water.Concentrate, cooling gets colourless plate crystal 107.95 grams (79.3%), m.p.109-110 ℃.TLC detects: sherwood oil: ethyl acetate (1: 1), Rf=0.33.
1.4 the preparation of N-acetyl-(2-piperonyl) monoethyl malonate:
N-acetyl-(2-piperonyl) diethyl malonate 25.45 grams (0.0725mol), with 250 milliliters of dissolve with ethanol, room temperature drips 21.75 milliliters in 6N sodium hydroxide, and TLC monitors to initial reactant disappearance (2.5 hours).Under the ice-water bath condition, drip 6N hydrochloric acid (about 21.75 milliliters) and transfer to about pH3, get white suspension.Concentrate, add 180 ml waters, suction filtration gets white powdery solid, drying at room temperature.Weigh 22.3 the gram (95.2%).
1.5 the preparation of N-acetyl-(2-piperonyl) alanine ethyl ester:
N-acetyl-(2-piperonyl) monoethyl malonate 22.3 grams (0.069mol) dissolve oil bath backflow (108 ℃ ± 3) 3.5 hours with 210 milliliters of dioxane.Reaction solution concentrates, and resistates washes twice with saturated sodium bicarbonate, saturated sodium-chloride respectively with 150 milliliters of acetic acid ethyl dissolutions, the ethyl acetate layer anhydrous sodium sulfate drying.Filtering siccative, filtrate are concentrated into about 15 milliliters, add ether, place, and the adularescent crystallization is separated out.Filter is assembled brilliant, and sherwood oil washes twice, drying at room temperature.Weigh 14.6 the gram (76.9%), m.p.85-87 ℃.TLC detects: sherwood oil: ethyl acetate (1: 2), Rf=0.63.
1.6 the fractionation of N-acetyl-(2-piperonyl) alanine ethyl ester:
Weighing N-acetyl-(2-piperonyl) alanine ethyl ester 11.16 grams (40.0mmol) are ground into fine powder in mortar, be suspended in 280 milliliters of phosphate buffer solns water-bath (37 ℃ ± 1), the solution suspendible shape that is white in color.Add about 2.0 milligrams of subtilopeptidase A, the pH value descends rapidly, keeps about pH7.60 with 0.5N sodium hydroxide.5.5 after hour, it is constant that the pH value keeps substantially, continues to stir 1.0 hours.(till λ=254nm) nothing absorbed, ethyl acetate layer washed twice with saturated sodium-chloride to reaction solution, anhydrous sodium sulfate drying to ultraviolet lamp with ethyl acetate extraction.The filtering siccative, filtrate concentrates, and gets colourless block crystallization 5.45 gram (97.7%) (D-N-acetyl-(2-piperonyl) alanine ethyl ester); Water layer is transferred about pH2 with concentrated hydrochloric acid in ice-water bath, uses ethyl acetate extraction, and ethyl acetate layer washes twice with saturated sodium-chloride, anhydrous sodium sulfate drying.The filtering siccative, filtrate concentrates, and gets colourless block crystallization 4.70 gram (93.6%) (L-N-acetyl-(2-piperonyl) L-Ala).
1.7 hydrolysis:
Above-mentioned gained (L)-N-acetyl-(2-piperonyl) L-Ala, (D)-N-acetyl-(2-piperonyl) alanine ethyl ester with 10% hydrochloric acid reflux hydrolysis, are obtained (L)-(2-piperonyl) L-Ala hydrochloride m.p.235-237 ℃ (decomposition), [α]
D 20=-13.4 ° (C=1.45,1M HCl) be the L-Ala hydrochloride (D)-(2-piperonyl), and m.p.235-237 ℃, [α]
D 20=+13.1 ° (C=1.47,1M HCl).
IR：3080-3020，2560，2480，2040(NH
3 +)，1600(NH
3 +，COO
-)，1040(-O-CH
2-O)；
1HNMR(D
2O)：δ3.1-3.3(2H，-CH
2Ar)，4.25(1H，-CHCOOH)，5.90(s，2H，-O-CH
2-O)，7.27-6.8-6.9(m，3H，Ar-H)；
1.8 the preparation of HIM-CO-Leu-D-Trp-D-Mob-OH
With 127 milligrams of D-tryptophan methyl ester hydrochlorides (0.5mmol), be dissolved among 2 milliliters of DMF, add N-methylmorpholine 55 microlitres (0.5mmol), make its dissolving, add hexa-methylene amine 128 milligrams of leucines of formyl (0.5mmol), with 2 milliliters of DCM dissolvings.Add HOBt 71 milligrams of (0.525mmol) and 108 milligrams of DCC (0.525mmol) under the condition of ice bath.Continue to keep ice bath after 0.5 hour, room temperature reaction 6 hours.Concentrate, add ethyl acetate, after the washing once, it is inferior respectively to give a baby a bath on the third day after its birth with 10% citric acid, saturated sodium bicarbonate and saturated sodium-chloride respectively, and ethyl acetate layer is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.This oily matter is dissolved with 2 ml methanol, in ice-water bath, add 1.25 milliliters of 1M sodium hydroxide, stir under the room temperature, TLC detects, question response fully after, with 10% citric acid acidifying to the pH3.0, separate out solid, ethyl acetate extraction after the saturated nacl aqueous solution washing, is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, and filter collects the dry 180 milligrams of solids that get.This solid is dissolved among 2 milliliters of THF, cryosel is bathed cooling, add 55 microlitre NMM and 68 milliliters of isobutyl chlorocarbonates, react after 5 minutes, add 10% the sodium carbonate solution (1 milliliter) that contains 122.75 milligrams of D-piperonyl L-Ala hydrochlorides prepare in advance, cryosel was bathed reaction after 30 minutes, room temperature reaction 1.5 hours, concentrating under reduced pressure adds 10 ml waters, the ether extraction insolubles, water layer with 10% citric acid acidifying to the pH3.0, ethyl acetate extraction (3 * 15 milliliters), united extraction liquid was with anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate obtains 290 milligrams of white solids (91.6%).MS：[M+H]
+＝634.2，[M+Na]
+＝656.4。
TLC detects: chloroform: methyl alcohol: Glacial acetic acid (16: 1: 0.5), Rf=0.68.
The preparation of embodiment 2:ABO-CO-Leu-D-Trp-D-Phe (3-Cl-4-F)-OH
With 127 milligrams of D-tryptophan methyl ester hydrochlorides (0.5mmol), be dissolved among 2 milliliters of DMF, add N-methylmorpholine 55 microlitres (0.5mmol), make its dissolving, add 134 milligrams of ABO-CO-Leu-OH (0.5mmol), with 2 milliliters of DCM dissolvings.Add HOBt 71 milligrams of (0.525mmol) and 108 milligrams of DCC (0.525mmol) under the condition of ice bath.Continue to keep ice bath after 0.5 hour, room temperature reaction 6 hours.Concentrate, add ethyl acetate, after the washing once, it is inferior respectively to give a baby a bath on the third day after its birth with 10% citric acid, saturated sodium bicarbonate and saturated sodium-chloride respectively, and ethyl acetate layer is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.This oily matter is dissolved with 2 ml methanol, in ice-water bath, add 1.25 milliliters of 1M sodium hydroxide, stir under the room temperature, TLC detects, question response fully after, with 10% citric acid acidifying to the pH3.0, separate out solid, ethyl acetate extraction after the saturated nacl aqueous solution washing, is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry 226 milligrams of solids (100%) that get of filter collection.This solid is dissolved among 2 milliliters of DCM, adds 134 milligrams of D-3-chloro-4-fluorophenylalanine methyl ester hydrochlorides,, add N-methylmorpholine 55 microlitres (0.5mmol) again with 2 milliliters of DMF dissolvings.Add HOBt 71 milligrams of (0.525mmol) and 108 milligrams of DCC (0.525mmol) under the condition of ice bath.Continue to keep ice bath after 0.5 hour, room temperature reaction 6 hours.Concentrate, add ethyl acetate, after the washing once, it is inferior respectively to give a baby a bath on the third day after its birth with 10% citric acid, saturated sodium bicarbonate and saturated sodium-chloride respectively, and ethyl acetate layer is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.This oily matter is dissolved with 2 ml methanol, in ice-water bath, add 1.25 milliliters of 1M sodium hydroxide, stir under the room temperature, TLC detects, question response fully after, with 10% citric acid acidifying to the pH3.0, separate out solid, ethyl acetate extraction after the saturated nacl aqueous solution washing, is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry 310 milligrams of solids (95.2%) that get of filter collection.MS：[M+H]
+＝654.8。TLC detects: chloroform: methyl alcohol: Glacial acetic acid (16: 1: 0.5), Rf=0.52.
The preparation of embodiment 3:ENP002
Preparation
With 10.24 gram (0.04mol) HIM-CO-Leu-OH, be dissolved in 150 milliliters of ether, add TEA5.55 milliliter (0.04mol), make its dissolving, logical nitrogen protection.Add 5.71 milliliters of isobutyl chlorocarbonates under the cryosel bath condition, reacted 15 minutes.Under this temperature, slowly add 200 milliliters of diethyl ether solutions containing 3 grammes per square metre n-formyl sarcolysine alkane, reacted 3 hours.Concentrate, add ethyl acetate, after the washing once, wash twice with saturated sodium bicarbonate solution, ethyl acetate layer is used anhydrous magnesium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets solid product A 5.03 grams (90%).MS：[M+H]
+＝281.4。TLC detects: Rf=0.70 (ethyl acetate: sherwood oil=1: 2).
1HNMR (CDCl
3): δ 0.93 (t, 6H ,-CH (CH
3)
2), 1.42-1.80 (t, 11H, 3H on 8H and the leucine side chain on the HIM ring), 3.20 (4H, 4H on the HIM ring), 4.20 (brq, 1H ,-CHN
2), 4.95 (brd, 1H, α-H), 5.48 (s, 1H ,-NH).
Preparation
4.2 gram (0.015mol) above-mentioned product A are dissolved among 45 milliliters of THF, and cryosel is bathed cooling, slowly drips 20 milliliters of dioxane solution that contain 1.34 gram hydrogen bromides, reacts 3 hours.Concentrating under reduced pressure with 50 milliliters of acetic acid ethyl dissolutions, washes twice with saturated sodium bicarbonate solution, and ethyl acetate layer is used anhydrous magnesium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets white solid product B 4.6 grams (92.2%).MS：[M+H]
+＝334.5。TLC detects: Rf=0.65 (ethyl acetate: sherwood oil=1: 5).
1HNMR (CDCl
3): δ 0.93 (t, 6H ,-CH (CH
3) 2), 1.32-1.80 (t, 11H, 3H on 8H and the leucine side chain on the HIM ring), 3.15 (4H, 4H on the HIM ring), 4.07 (s, 2H ,-CH
2Br), 4.55 (brd, 1H, α-H), 5.08 (s, 1H ,-NH).
Preparation
Pretreated sodium hydride 0.29 gram (60%) is suspended among 5.0 milliliters of DMF; add 7.2 milliliters of HMPA, logical nitrogen protection slowly drips 4 milliliters of DMF solution that contain 2.08 gram (7.2mmol) 3-indoles methylene radical substituted diethyl malonates; stirring at room reaction 40 minutes forms a mixed solution.In another there-necked flask, add 2.0 gram (6.0mmol) above-mentioned product B, with 6 milliliters of DMF dissolvings, add 1 milliliter of HMPA, slowly drip the mixed liquid of above-mentioned formation, stirring at room 3 hours, to react mixed liquid pours in 400 milliliters of frozen water, with ethyl acetate extraction, the ethyl acetate layer water is given a baby a bath on the third day after its birth inferior, anhydrous magnesium sulfate drying.Filtering siccative, concentrated filtrate, product get crude product 2.9 grams after saponification, decarboxylation, separate through post, get pure product C 0.85 gram (31.8%).MS：[M+H]
+＝442.6。TLC detects: Rf=0.59 (chloroform: methyl alcohol=6: 1).
3.4 the preparation of ENP002
221 milligrams of (0.5mmol) above-mentioned product C are dissolved among 2 milliliters of DCM, add 117 milligrams of (0.5mmol) D-4-fluorophenylalanine methyl ester hydrochlorides,, add N-methylmorpholine 55 microlitres (0.5mmol) again with 2 milliliters of DMF dissolvings.Add HOBt71 milligram (0.525mmol) and 108 milligrams of DCC (0.525mmol) under the condition of ice bath.Continue to keep ice bath after 0.5 hour, room temperature reaction 6 hours.Concentrate, add ethyl acetate, after the washing once, it is inferior respectively to give a baby a bath on the third day after its birth with 10% citric acid, saturated sodium bicarbonate and saturated sodium-chloride respectively, and ethyl acetate layer is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.This oily matter is dissolved with 2 ml methanol, in ice-water bath, add 1.25 milliliters of 1M sodium hydroxide, stir under the room temperature, TLC detects, question response fully after, with 10% citric acid acidifying to the pH3.0, separate out solid, ethyl acetate extraction after the saturated nacl aqueous solution washing, is used anhydrous sodium sulfate drying 5 hours.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry 280 milligrams of solids (92.4%) that get of filter collection.MS：[M+H]
+＝607.5。TLC detects: Rf=0.80 (chloroform: methyl alcohol: Glacial acetic acid=16: 1: 0.5).
Method according to embodiment 2 and embodiment 3 has been synthesized following compound
Sequence number primary structure molecular weight purity (%)
1 ABO-CO-NH-CH
2-CH
2-CO-D-Trp-D-Trp-OH 598 92
2 ABO-CO-GABA-D-Trp-D-Trp-OH 612 90
3 ABO-CO-NH-C(CH
3)
2-CO-D-Trp-D-Trp-OH 612 96
4 ABO-CO-Leu-D-Trp-D-Phe(2-F)-OH 619 95
5 ABO-CO-Leu-D-Trp-D-Phe(3-F)-OH 619 95
6 ABO-CO-Leu-D-Trp-D-Phe(4-F)-OH 619 93
7 ABO-CO-Leu-D-Trp-D-Phe(2-Cl)-OH 635.5 87
8 ABO-CO-Leu-D-Trp-D-Phe(3-Cl)-OH 635.5 91
9 ABO-CO-Leu-D-Trp-D-Phe(4-Cl)-OH 635.5 98
10 ABO-CO-Leu-D-Trp-D-Phe(4-Br)-OH 680 90
11 ABO-CO-Leu-D-Trp-D-Phe(3-NO
2)-OH 646 95
12 ABO-CO-Leu-D-Trp-D-Phe(3-COOH)-OH 645 82
13 ABO-CO-Leu-D-Trp-D-Phe(4-COOH)-OH 645 85
14 ABO-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH 653.5 92
15 ABO-CO-Leu-D-Trp-D-Phe(2，4-Cl2)-OH 670 94
16 ABO-CO-Leu-D-Trp-D-Phe(2，5-Cl
2)-OH 670 94
17 ABO-CO-Leu-D-Trp-D-Pbe(2-CH
3-3-Cl)-OH 649.5 97
18 ABO-CO-Leu-D-Trp-D-Mob-OH 645 90
19 ABO-CO-Leu-D-Trp-D-Phg(4-F)-OH 605 92
20 ABO-CO-Leu-D-Phe(2-F)-D-Trp-OH 619 97
21 ABO-CO-Leu-D-Phe(3-F)-D-Trp-OH 619 95
22 ABO-CO-Leu-D-Phe(4-F)-D-Trp-OH 619 96
23 ABO-CO-Leu-D-Phe(4-Br)-D-Trp-OH 680 90
24 ABO-CO-Leu-D-Phe(3-NO
2)-D-Trp-OH 646 97
25 ABO-CO-Leu-D-Phe(4-F-3-Cl)-D-Trp-OH 653.5 89
26 ABO-CO-Leu-D-Phe(3-CO-D-Trp-OH)-D-Trp-OH 831 82
27 ABO-CO-Leu-D-Phe(4-CO-D-Trp-OH)-D-Trp-OH 831 80
28 ABO-CO-Leu-D-Phe(2-CH
3-3-Cl)-D-Trp-OH 649.5 97
29 ABO-CO-Leu-D-Mob-D-Trp-OH 645 98
30 ABO-CO-Leu-D-Phg(4-F)-D-Trp-OH 605 97
31 ABO-CO-Leu-D-Trp-D-Trp-OH 640 95
32 HIM-CO-Leu-D-Trp-D-Mob-OH 633 92
33 HIM-CO-Leu-D-Mob-D-Trp-OH 633 93
34 HIM-CO-Leu-D-Trp-D-Phg(4-F)-OH 593 93
35 HIM-CO-Leu-D-Phg(4-F)-D-Trp-OH 593 98
36 DAD-CO-Leu-D-Trp-D-Phe(4-F)-OH 651 94
37 DAD-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH 685.5 92
38 DAD-CO-Leu-D-Trp-D-Mob-OH 677 95
39 CSO-CO-Leu-D-Trp-D-Phe(4-F)-OH 649 85
40 CSO-CO-Leu-D-Trp-D-Phe(3，4-Cl
2)-OH 700 87
41 CSO-CO-Leu-D-Trp-D-Mob-OH 675 84
42 ENP002 606 85
All the other compounds also can be synthetic according to method and the approach of embodiment 2 and embodiment 3.
Biological activity
Experiment material
Wistar rat: Military Medical Science Institute's Experimental Animal Center
Desk-top self-balancing recorder: the big magnificent instrument plant in Shanghai
ET-1： American?peptide?company
10% salt of wormwood autogamy
Improvement Kreb ' s-Ringer damping fluid: autogamy
Experimental technique
The preparation of sample solution:
Quantitatively take by weighing sample (compound of embodiment 1-35) 2 * 10
-6Mole adds 120 microlitres, 10% alkaline carbonate and 80 microlitre DMSO dissolving, and with improvement Kreb, s-Ringer damping fluid quantitatively dilution is 5.0 milliliters, as preserving in the stock solution refrigerator.With the damping fluid dilution is 10
-6, 10
-7, 10
-8With 10
-9Four concentration of mole.
The extracorporeal blood vessel experiment:
With the rat sacrificed by decapitation, open chest rapidly, win aorta, place the culture dish that fills vascular nutrition liquid, remove blood stains, careful separating blood vessel surrounding tissue, being cut into the arterial ring that is about 3 millimeters, is respectively that 0.1 millimeter stainless steel steel wire carefully penetrates with two diameters, makes the triangle ring-type.With being placed in 37 ℃ of thermostatic baths that fill 10 milliliters of vascular nutrition liquid, the lower end is fixed, and the upper end is logical moves tonotransducer and be connected in desk-top self-balancing recorder, continues to feed 95% oxygen and 5% carbon dioxide mix gas.Arterial ring load 0.5 gram begins administration after stablizing.
Antagonistic experiment
Earlier bring out vascular circle and shrink with the ET-1 of 10nM amount, about about 10 minutes, reach platform after, give 10
-9The M sample is observed the antagonism shrinking effect.When lower concentration was not imitated, concentration to 10 gradually raise
-6M.
The result
According to the method described above, determination of activity the results are shown in following table
The pharmacologically active result
Sequence number primary structure antagonistic activity (M)
10
-8 10
-9
4 ABO-CO-Leu-D-Trp-D-Phe(2-F)-OH ++
15 ABO-CO-Leu-D-Trp-D-Phe(2，4-Cl
2)-OH ++
18 ABO-CO-Leu-D-Trp-D-Mob-OH ++
31 ABO-CO-Leu-D-Trp-D-Trp-OH +
32 HIM-CO-Leu-D-Trp-D-Mob-OH ++
36 DAD-CO-Leu-D-Trp-D-Phe(4-F)-OH ++
37 DAD-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH ++
38 DAD-CO-Leu-D-Trp-D-Mob-OH ++
39 CSO-CO-Leu-D-Trp-D-Phe(4-F)-OH ++
42 ENP002 ++
++: antagonistic activity is very strong+: antagonistic activity is medium-: do not show antagonistic activity
Claims (8)
1, formula (I) peptide class and non-peptide derivative or its steric isomer R-CO-AA
1-AA
2-AA
3-OH formula (I)
Wherein, R is two chain hydrocarbon imido grpup, hexamethylene imine base or following groups of replacing
N in the formula
1, n
2, n
3Be 0,1,2,3 integers, n
3≠ 0,0≤n
1+ n
2≤ 4; X
1Be NH, O, S, CH
2X
2Be N, CH; Work as n
1=n
2=1, n
3=2, X
1Be CH
2, X
2Be the N atomic time, R is abbreviated as ABO;
m
1, m
2, m
3And m
4Be 0,1,2 integers, 0≤m
1+ m
2≤ 4,0≤m
3+ m
4≤ 4; y
1, y
2And y
3Be CH
2, O, S and NH, when they are NH or CH
2The time, can be used as N end structure R, form is N or CH; Work as m
1=m
2=1, m
3=m
4=2, y
1, y
2Be O atom, y
3Be the N atomic time, R is abbreviated as DAD; Work as m
1=m
2=1, m
3=m
4=2, y
3Be CH
2, y
1Be O atom, y
2Be the N atomic time, R is abbreviated as CSO;
AA
1Be L or D type Ala, Ile, Leu, MeVal, Pro, Val or other non-natural aliphatic amino acid, as β-Ala, γ-An Jidingsuan, or aminoisobutyric acid;
AA
2Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements, works as AA
2Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer;
AA
3Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
3Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer.
2, the peptide class of claim 1 and non-peptide derivative or its steric isomer, it is selected from following compound:
1?ABO-CO-NH-CH
2-CH
2-CO-D-Trp-D-Trp-OH
2?ABO-CO-GABA-D-Trp-D-Trp-OH
3?ABO-CO-NH-C(CH
3)
2-CO-D-Trp-D-Trp-OH
4?ABO-CO-Leu-D-Trp-D-Phe(2-F)-OH
5?ABO-CO-Leu-D-Trp-D-Phe(3-F)-OH
6?ABO-CO-Leu-D-Trp-D-Phe(4-F)-OH
7?ABO-CO-Leu-D-Trp-D-Phe(2-Cl)-OH
8?ABO-CO-Leu-D-Trp-D-Phe(3-Cl)-OH
9?ABO-CO-Leu-D-Trp-D-Phe(4-Cl)-OH
10?ABO-CO-Leu-D-Trp-D-Phe(4-Br)-OH
11?ABO-CO-Leu-D-Trp-D-Phe(3-NO
2)-OH
12?ABO-CO-Leu-D-Trp-D-Phe(3-COOH)-OH
13?ABO-CO-Leu-D-Trp-D-Phe(4-COOH)-OH
14?ABO-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
15?ABO-CO-Leu-D-Trp-D-Phe(2，4-Cl
2)-OH
16?ABO-CO-Leu-D-Trp-D-Phe(2，5-Cl
2)-OH
17?ABO-CO-Leu-D-Trp-D-Phe(2-CH
3-3-Cl)-OH
18?ABO-CO-Leu-D-Trp-D-Mob-OH
19?ABO-CO-Leu-D-Trp-D-Phg(4-F)-OH
20?ABO-CO-Leu-D-Phe(2-F)-D-Trp-OH
21?ABO-CO-Leu-D-Phe(3-F)-D-Trp-OH
22?ABO-CO-Leu-D-Phe(4-F)-D-Trp-OH
23?ABO-CO-Leu-D-Phe(4-Br)-D-Trp-OH
24?ABO-CO-Leu-D-Phe(3-NO
2)-D-Trp-OH
25?ABO-CO-Leu-D-Phe(4-F-3-Cl)-D-Trp-OH
26?ABO-CO-Leu-D-Phe(3-CO-D-Trp-OH)-D-Trp-OH
27?ABO-CO-Leu-D-Phe(4-CO-D-Trp-OH)-D-Trp-OH
28?ABO-CO-Leu-D-Phe(2-CH
3-3-Cl)-D-Trp-OH
29?ABO-CO-Leu-D-Mob-D-Trp-OH
30?ABO-CO-Leu-D-Phg(4-F)-D-Trp-OH
31?ABO-CO-Leu-D-Trp-D-Trp-OH
32?HIM-C?O-Leu-D-Trp-D-Mob-OH
33?HIM-CO-Leu-D-Mob-D-Trp-OH
34?HIM-CO-Leu-D-Trp-D-Phg(4-F)-OH
35?HIM-CO-Leu-D-Phg(4-F)-D-Trp-OH
36?DAD-CO-Leu-D-Trp-D-Phe(4-F)-OH
37?DAD-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
38?DAD-CO-Leu-D-Trp-D-Mob-OH
39?CSO-CO-Leu-D-Trp-D-Phe(4-F)-OH
40?CSO-CO-Leu-D-Trp-D-Phe(3，4-Cl
2)-OH
41?CSO-CO-Leu-D-Trp-D-Mob-OH
42?ENP002
3, the peptide class of claim 1 and non-peptide derivative or its steric isomer, wherein said non-peptide compound are the following formula: compound of ENP002 representative:
4, pharmaceutical composition, it comprises at least a formula (I) peptide class and non-peptide derivative or its steric isomer and pharmaceutical carrier or vehicle
R-CO-AA
1-AA
2-AA
3-OH formula (I)
Wherein, R is two chain hydrocarbon imido grpup, hexamethylene imine base or following groups of replacing
N in the formula
1, n
2, n
3Be 0,1,2,3 integers, n
3≠ 0,0≤n
1+ n
2≤ 4; X
1Be NH, O, S, CH
2X
2Be N, CH; Work as n
1=n
2=1, n
3=2, X
1Be CH
2, X
2Be the N atomic time, R is abbreviated as ABO.
m
1, m
2, m
3And m
4Be 0,1,2 integers, 0≤m
1+ m
2≤ 4,0≤m
3+ m
4≤ 4; y
1, y
2And y
3Be CH
2, O, S and NH, when they are NH or CH
2The time, can be used as N end structure R, form is N or CH; Work as m
1=m
2=1, m
3=m
4=2, y
1, y
2Be O atom, y
3Be the N atomic time, R is abbreviated as DAD; Work as m
1=m
2=1, m
3=m
4=2, y
3Be CH
2, y
1Be O atom, y
2Be the N atomic time, R is abbreviated as CSO.
AA
1Be L or D type Ala, Ile, Leu, MeVal, Pro, Val or other non-natural aliphatic amino acid, as β-Ala, γ-An Jidingsuan, or aminoisobutyric acid;
AA
2Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
2Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer;
AA
3Be non-natural aromatic amino acid, phenylglycocoll or non-amino acid, wherein the phenyl in the aromatic nucleus can be selected from halogen, nitro, urea groups, methoxyl group, carboxyl or C on 2,3,4 or 5
1-C
4The alkyl list replaces or two replacements.Work as AA
3Be non-amino acid, particularly connect amino-acid residue-among the CONH--NH quilt-CH
2-,-S-, when-O-etc. replaced, formula (1) was non-peptide derivative or its steric isomer.
5, the pharmaceutical composition of claim 4, its Chinese style (I) peptide class and non-peptide derivative or its steric isomer are selected from:
1?ABO-CO-NH-CH
2-CH
2-CO-D-Trp-D-Trp-OH
2?ABO-CO-GABA-D-Trp-D-Trp-OH
3?ABO-CO-NH-C(CH
3)
2-CO-D-Trp-D-Trp-OH
4?ABO-CO-Leu-D-Trp-D-Phe(2-F)-OH
5?ABO-CO-Leu-D-Trp-D-Phe(3-F)-OH
6?ABO-CO-Leu-D-Trp-D-Phe(4-F)-OH
7?ABO-CO-Leu-D-Trp-D-Phe(2-Cl)-OH
8?ABO-CO-Leu-D-Trp-D-Phe(3-Cl)-OH
9?ABO-CO-Leu-D-Trp-D-Phe(4-Cl)-OH
10?ABO-CO-Leu-D-Trp-D-Phe(4-Br)-OH
11?ABO-CO-Leu-D-Trp-D-Phe(3-NO
2)-OH
12?ABO-CO-Leu-D-Trp-D-Phe(3-COOH)-OH
13?ABO-CO-Leu-D-Trp-D-Phe(4-COOH)-OH
14?ABO-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
15?ABO-CO-Leu-D-Trp-D-Phe(2，4-Cl
2)-OH
16?ABO-CO-Leu-D-Trp-D-Phe(2，5-Cl
2)-OH
17?ABO-CO-Leu-D-Trp-D-Phe(2-CH
3-3-Cl)-OH
18?ABO-CO-Leu-D-Trp-D-Mob-OH
19?ABO-CO-Leu-D-Trp-D-Phg(4-F)-OH
20?ABO-CO-Leu-D-Phe(2-F)-D-Trp-OH
21?ABO-CO-Leu-D-Phe(3-F)-D-Trp-OH
22?ABO-CO-Leu-D-Phe(4-F)-D-Trp-OH
23?ABO-CO-Leu-D-Phe(4-Br)-D-Trp-OH
24?ABO-CO-Leu-D-Phe(3-NO
2)-D-Trp-OH
25?ABO-CO-Leu-D-Phe(4-F-3-Cl)-D-Trp-OH
26?ABO-CO-Leu-D-Phe(3-CO-D-Trp-OH)-D-Trp-OH
27?ABO-CO-Leu-D-Phe(4-CO-D-Trp-OH)-D-Trp-OH
28?ABO-CO-Leu-D-Phe(2-CH
3-3-Cl)-D-Trp-OH
29?ABO-CO-Leu-D-Mob-D-Trp-OH
30?ABO-CO-Leu-D-Phg(4-F)-D-Trp-OH
31?ABO-CO-Leu-D-Trp-D-Trp-OH
32?HIM-CO-Leu-D-Trp-D-Mob-OH
33?HIM-CO-Leu-D-Mob-D-Trp-OH
34?HIM-CO-Leu-D-Trp-D-Phg(4-F)-OH
35?HIM-CO-Leu-D-Phg(4-F)-D-Trp-OH
36?DAD-CO-Leu-D-Trp-D-Phe(4-F)-OH
37?DAD-CO-Leu-D-Trp-D-Phe(3-Cl-4-F)-OH
38?DAD-CO-Leu-D-Trp-D-Mob-OH
39?CSO-CO-Leu-D-Trp-D-Phe(4-F)-OH
40?CSO-CO-Leu-D-Trp-D-Phe(3，4-Cl
2)-OH
41?CSO-CO-Leu-D-Trp-D-Mob-OH
42?ENP002。
6, biological or its steric isomer of the peptide class of the arbitrary requirement of claim 1-3 and non-peptide method is used for preventing or the medicine purposes of treatment and endothelin and prostate gland diseases related in preparation.
7, the preparation method of formula (I) peptide derivative or its steric isomer derivative, it comprises:
1) with compound R-CO-AA
1-OH and AA
2-OP is at DMF-DCM, and NMM reacts among the DCC-HOBt, generates R-CO-AA
1-AA
2-OP, R wherein, AA
1, AA
2, as definition in the claim 1, P is C
1-4Alkyl;
2) with 1) middle products therefrom saponification in the 1MNaOH/ methanol solution, use hcl acidifying then, generate R-CO-AA
1-AA
2-OH;
3) with 2) middle product R-CO-AA
1-AA
2-OH and AA
3-OP is at DMF-DCM, and NMM reacts among the DCC-HOBt, generates R-CO-AA
1-AA
2-AA
3-OP, wherein P is C
1-4Alkyl.Hcl acidifying is used in products therefrom saponification in the 1MNaOH/ methanol solution then, production (I) R-CO-AA
1-AA
2-AA
3-OH;
4) with 2) middle product R-CO-AA
1-AA
2-OH reacted 5-10 minute with isobutyl chlorocarbonate in THF, NMM, added AA again
3-ONa generates R-CO-AA
1-AA
2-AA
3-ONa uses hcl acidifying then, production (I) R-CO-AA
1-AA
2-AA
3-OH.
8, the preparation method of the non-peptide derivative of formula (I) or its steric isomer derivative, by the Szelke literature method preparation of means known in the art and improvement, detailed step is referring to embodiment 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031459293A CN1504480A (en) | 2002-11-28 | 2003-07-17 | Endothelin receptor antagonist of tripeptide |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02149192.5 | 2002-11-28 | ||
| CN02149192 | 2002-11-28 | ||
| CNA031459293A CN1504480A (en) | 2002-11-28 | 2003-07-17 | Endothelin receptor antagonist of tripeptide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1504480A true CN1504480A (en) | 2004-06-16 |
Family
ID=34276073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031459293A Pending CN1504480A (en) | 2002-11-28 | 2003-07-17 | Endothelin receptor antagonist of tripeptide |
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| Country | Link |
|---|---|
| CN (1) | CN1504480A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007045184A1 (en) * | 2005-10-20 | 2007-04-26 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | The peptides essence receptor antagonist which 2-site containing proline or crico-amino acid |
| WO2010142058A1 (en) * | 2009-06-09 | 2010-12-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Peptide derivatives with endothelin receptor antagonizing activity, pharmaceutical compositions and uses thereof |
| CN101519427B (en) * | 2008-02-29 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Peptide derivative with endothelin receptor antagonizing activity, drug composition and application thereof |
-
2003
- 2003-07-17 CN CNA031459293A patent/CN1504480A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007045184A1 (en) * | 2005-10-20 | 2007-04-26 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | The peptides essence receptor antagonist which 2-site containing proline or crico-amino acid |
| CN100500691C (en) * | 2005-10-20 | 2009-06-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Peptide-like endothelin receptor antagonist with proline or cyclic amino acid on 2-postion |
| CN101519427B (en) * | 2008-02-29 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Peptide derivative with endothelin receptor antagonizing activity, drug composition and application thereof |
| WO2010142058A1 (en) * | 2009-06-09 | 2010-12-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Peptide derivatives with endothelin receptor antagonizing activity, pharmaceutical compositions and uses thereof |
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