CN101519427A - Peptide derivative with endothelin receptor antagonizing activity, drug composition and application thereof - Google Patents

Peptide derivative with endothelin receptor antagonizing activity, drug composition and application thereof Download PDF

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CN101519427A
CN101519427A CN200810007611A CN200810007611A CN101519427A CN 101519427 A CN101519427 A CN 101519427A CN 200810007611 A CN200810007611 A CN 200810007611A CN 200810007611 A CN200810007611 A CN 200810007611A CN 101519427 A CN101519427 A CN 101519427A
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hyp
trp
phe
dba
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CN101519427B (en
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刘克良
杨菁
梁远军
许笑宇
宫泽辉
董华进
孔令雷
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to a novel-structure compound with endothelin receptor antagonizing activity, a preparation method thereof, and drug composition comprising the compound and the application of the compound on treating or preventing the illness related with endothelin effects.

Description

Peptide derivative and pharmaceutical composition and purposes with endothelin receptor antagonizing activity
Technical field
The present invention relates to have the peptide derivative of endothelin receptor antagonizing activity, its preparation method contains their pharmaceutical composition and their purposes in prevention or treatment and endothelin and prostate gland diseases associated.
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. ETA, ETB and ETC have been found so far.ETA mainly is distributed in the unstriated muscle of aorta, atrium, placenta, lung, the cerebrovascular and renal blood vessels; It is medium that ETB is present in fall clump epithelial cell, lung, tire blood, renal glomerulus endothelium, ventricle, brain of neurogliocyte, arteries and veins in the central nervous system, at vascular smooth muscle distribution arranged also; ETC then mainly is 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 and cerebrovascular diseases.
Summary of the invention
The objective of the invention is to seek new peptide-like endothelin receptor antagonist.
The inventor has now found that formula (I) or formula (II) peptide derivative after deliberation
R-(CH 2) i-CO-(CH 2) j-AA 1-AA 2-AA 3-OH formula (I)
R-(CH 2) i-CO-(CH 2) j-AA 1(M)-AA 2-AA 3-OH formula (II)
Or its steric isomer or its pharmaceutical salts have good endothelin receptor antagonizing activity, so formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts 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 derivative or its steric isomer or its pharmaceutical salts,
R-(CH 2) i-CO-(CH 2) j-AA 1-AA 2-AA 3-OH formula (I)
Wherein, R is hexamethylene imine base or following group:
Figure A200810007611D00181
(structural formula 1) (structural formula 2) (structural formula 3) (structural formula 4)
In the structural formula 1, n 1, n 2And n 3Be integer 0,1 independently, 2 or 3, and n wherein 3≠ 0,0≤n 1+ n 2≤ 4; X 1Be NH, O, S or CH 2X 2Be N or 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;
In the structural formula 2, m 1, m 2, m 3And m 4Be integer 0,1 or 2 independently, and 0≤m wherein 1+ m 2≤ 4,0≤m 3+ m 4≤ 4; y 1And y 3Be CH independently 2, O, S or NH, y 2Be N or CH; Work as m 1=m 2=1, m 3=m 4=2, y 1, y 3Be O atom, y 2Be 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;
In the structural formula 3, z is N or CH, and k is N or Ck 1(k 1Be H, CH 3Or CH 2CH 3), t is H, CH 3, CH 2CH 3Or CH 1(CH 3) 2Perhaps z is O or S, and k is N or Ck 1(k 1Be H, CH 3Or CH 2CH 3), t and connecting key thereof do not exist; Work as z=N, k=N, during t=H, R is a piperazinyl; Work as z=O, k=N, when t and connecting key thereof did not exist, R was a morpholinyl;
In the structural formula 4, a and b are integer 0,1 independently, 2 or 3; P is the N atom; Work as a=3, during b=3, R is abbreviated as DBA;
AA 1For L or D type Ser, Thr, Phe, Cys, Gln, Asn, Ala, Ile, Leu, Nle, Val, other L or D type aliphatics alpha-non-natural amino acid, as β-Ala, γ-An Jidingsuan or aminoisobutyric acid;
AA 2Be L or D type Trp, Pro, aromatic amino acid, cis or trans Hyp or following cis or trans Hyp derivative (structural formula 5):
(structural formula 5)
In the structural formula 5, R 1Be linking group, can be-O-,-NH-,-NH-CO-,-O-CO-,-CH 2-,-NH-CO-O-,-O-CO-NH-,-NH-CO-NH-or-NH-SO 2-.R 2Be aryl, virtue is amino, aryl-short chain alkylamino; aryl-sulfo-, aryl-short-chain alkyl-sulfo-, aryloxy; aryl-short chain alkoxyl group, aryl-short-chain alkyl, aryl-sulfinyl; heteroaryl, heteroaryl-oxo, heteroaryl-amino; heteroaryl-sulfo-, heteroaryl-short-chain alkyl, heteroaryl-sulfinyl; heterocyclic radical, heterocyclic radical-short chain alkoxyl group, heterocyclic radical-oxo; heterocyclic radical-amino, heterocyclic radical-short chain alkylamino, heterocyclic radical-sulfo-; heterocyclic radical-short-chain alkyl-sulfo-, heterocyclic radical-short-chain alkyl, heterocyclic radical-sulfinyl; cycloalkyl; cycloalkyl-oxo, cycloalkyl-short chain alkoxyl group, cycloalkyl-amino; cycloalkyl-short chain alkylamino; cycloalkyl-sulfo-, cycloalkyl-short-chain alkyl sulfo-, cycloalkyl-short-chain alkyl or cycloalkyl-sulfinyl.
AA 3Be non-natural aromatic amino acid, tryptophane, phenylglycocoll or the non-amino acid of D type, wherein the phenyl in the aromatic nucleus can be selected from halogen on 2,3,4 or 5, nitro, and urea groups, methoxyl group, the substituting group list of carboxyl and short-chain alkyl replace or two replacements.
0≤i≤4; 0≤j≤4; Wherein when i=0 and j=0, AA 2Be L or D type cis or trans Hyp derivative only;
Work as AA 2When only being L or D type cis or trans Hyp derivative, AA 3Can lack.
In the definition of formula (I), except as otherwise noted, the word short chain is meant the straight or branched group with 1 to 7 carbon atom, preferentially has 1 to 4 carbon atom.The example of short-chain alkyl and short chain alkoxyl group is a methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, methoxyl group, oxyethyl group, propoxy-, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.The example of short chain thiazolinyl and short chain alkynyl is a vinyl, propenyl, butenyl, 2-methylpropenyl, ethynyl, proyl, butynyl, pentynyl, 2-methylpent alkynyl.The word cycloalkyl is meant the saturated cyclic hydrocarbons that contains 3 to 7 carbon atoms, as cyclopropyl, and cyclobutyl, cyclopentyl, cyclohexyl, suberyl, and have short-chain alkyl, hydroxyl-short-chain alkyl, amino-short-chain alkyl, the substituting group of short chain alkoxyl group-short-chain alkyl.Not saturated or unsaturated (but not being aromatic) four that the word heterocyclic radical is meant, five, six or seven-membered ring, wherein contain one or two identical or different nitrogen, oxygen or sulphur atom, and these are four years old, five, six or seven-membered ring can suitably have short-chain alkyl, the substituting group of short chain alkoxyl group, piperidyl for example, morpholinyl, thio-morpholinyl, piperazinyl, THP trtrahydropyranyl, dihydro pyranyl, 1, the 4-alkyl dioxin, pyrrolidyl, the Pyrrolidine base, the pyrrolin base, the glyoxalidine base, pyrazolidyl and have above-mentioned substituent these heterocyclic substitutive derivatives.The word heteroaryl is meant the six-ring that contains one to four nitrogen-atoms, the benzo six-ring that contains one to three nitrogen-atoms, five yuan of aromatic rings that contain a Sauerstoffatom or a nitrogen-atoms or a sulphur atom, the five-membered ring fused benzene that contains a Sauerstoffatom or a nitrogen-atoms or a sulphur atom, contain a Sauerstoffatom and five yuan of aromatic rings of a nitrogen-atoms and benzo derivative thereof, the five yuan of aromatic rings and the benzo derivative thereof that contain a sulphur atom and a nitrogen-atoms, the five yuan of aromatic rings and the benzo derivative thereof that contain two nitrogen-atoms, the five yuan of aromatic rings and the benzo derivative thereof that contain three nitrogen-atoms, or tetrazolium basic ring, furyl for example, thienyl, pyrryl, pyridyl, pyrimidyl, indyl, quinolyl, isoquinolyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl oxazolyl isoxazolyl, 5-oxygen-1,2,4-oxadiazole base, 5-oxygen-1,2, the 4-thiadiazolyl group, 5-sulphur-1,2,4-oxadiazole base, 2-oxygen-1,2,3,5-Evil thiadiazolyl group, wherein above-mentioned ring can have the substituting group short-chain alkyl, the short chain thiazolinyl, amino, amino-short-chain alkyl, halogen, hydroxyl, the short chain alkoxyl group, trifluoromethoxy, carboxyl, amido, thio acylamino, amidino groups, short chain alkoxyl group-carbonyl, cyano group, hydroxyl-short-chain alkyl, short chain alkoxyl group-short-chain alkyl or another aromatic nucleus or heterocyclic ring.The word aryl is meant does not have aromatic ring such as phenyl ring or naphthalene nucleus substituted radical or that have one, two or three substituent 6 to 10 carbon atom, and described substituted radical is aryl, halogen, hydroxyl, short-chain alkyl, short chain thiazolinyl, short chain alkynyl, short chain alkoxyl group, short chain alkynyl-short chain alkoxyl group, hydroxyl-short-chain alkyl, hydroxyl-short chain thiazolinyl, hydroxyl-short-chain alkyl-short chain alkynyl, short chain alkoxyl group-short-chain alkyl, short chain alkoxyl group-short chain alkoxyl group, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxyl-cycloalkyl, heterocyclic radical or heteroaryl.
Second aspect present invention relates to formula (II) peptide derivative or its steric isomer or its pharmaceutical salts,
R-(CH 2) i-CO-(CH 2) j-AA 1(M)-AA 2-AA 3-OH formula (II)
R wherein, AA 1, AA 2, AA 3, i, j is with the definition in the above-mentioned formula (I), and M is as AA 1Modification group in the structure on the N atom, can be short-chain alkyl, short chain thiazolinyl, short chain alkynyl, short chain alkyloyl, short chain alkoxyl group ,-CO 2Short-chain alkyl ,-short-chain alkyl-CO 2Short-chain alkyl ,-CONH 2,-CONH short-chain alkyl ,-the CON[short-chain alkyl] 2Wherein word short chain alkyloyl is meant ethanoyl, propionyl, butyryl radicals, isobutyryl.
The invention still further relates to formula (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts as the application of treatment with the medicine of endothelin effect diseases related.
Term used herein " peptide derivative steric isomer " is meant its corresponding D-or L-steric configuration.
Formula (I) compound can be by scheme 1, and scheme 2 or scheme 3 methods are synthetic:
Figure A200810007611D00211
i：DMF-DCM，NMM，DCC-HOBt，ii：1M?NaOH/MeOH，
The iii:10% citric acid
Scheme 1
In scheme 1, R-CO-AA 1-OH compound (R wherein, AA 1As above define) and AA 2-OP (AA wherein 2Be cis or trans Hyp derivative, P is C 1-4Alkyl, it can be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, preferable methyl and ethyl) at DMF-DCM, react among NMM and the DCC-HOBt, generate R-CO-AA 1-AA 2-OP compound (R wherein, AA 1, P as above defines, AA 2Be cis or trans Hyp derivative).With R-CO-AA 1-AA 210% citric acid acidifying is used in the saponification in 1M NaOH/MeOH 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, react production R-CO-AA among NMM and the DCC-HOBt 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 3-OP saponification in 1M NaOH/MeOH solution is used 10% citric acid acidifying, production R-CO-AA then 1-AA 2-AA 3-OH.
Figure A200810007611D00221
I:Et 3N, ii:DCM, iii:1M NaOH/MeOH, the iv:10% citric acid,
v：DCM，DMF，DCC/HOBt，NMM
Scheme 2
In scheme 2, AA 1-OP compound (AA wherein 1As above definition, P is C 1-4Alkyl, it can be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, preferable methyl and ethyl) with bromoacetyl bromide at Et 3Generate compd B r-CH among N and the DCM 2-CO-AA 1-OP (AA wherein 1, P as above defines).With compd B r-CH 2-CO-AA 1-OP and R-H (R as above defines) are at Et 3Generate compound R-CH among N and the DCM 2-CO-AA 1-OP (AA wherein 1, P, R as above defines).With compound R-CH 2-CO-AA 110% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-AA 1-OH (AA wherein 1, R as above defines).With compound R-CH 2-CO-AA 1-OH and AA 2-OP (AA wherein 2As above definition) at DMF-DCM, reacts among NMM and the DCC-HOBt, generate compound R-CH 2-CO-AA 1-AA 2-OP (R wherein, AA 1, AA 2, P as above defines).With compound R-CH 2-CO-AA 1-AA 210% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-AA 1-AA 2-OH (R wherein, AA 1, AA 2As above definition).With compound R-CH 2-CO-AA 1-AA 2-OH and AA 3-OP (AA wherein 3, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-AA 1-AA 2-AA 3-OP (R wherein, AA 1, AA 2, AA 3, P as above defines).Then with gained R-CH 2-CO-AA 1-AA 2-AA 310% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates R-CH 2-CO-AA 1-AA 2-AA 3-OH.
Figure A200810007611D00231
I:Et 3N, ii:DCM, iii:NaOH/MeOH, the iv:10% citric acid, v: acid anhydrides,
vi：DCM，DMF，DCC-HOBt，NMM
Scheme 3
Compound R-H in scheme 3 (wherein R as above defines) and bromoacetyl bromide are at Et 3Generate compd B r-CH among N and the DCM 2-CO-R (AA wherein 1, R as above defines).With compd B r-CH 2-CO-R and AA 1-OP (AA wherein 1, P as above defines) and at Et 3Generate compound R-CO-CH among N and the DCM 2-AA 1-OP (AA wherein 1, P, R as above defines).With compound R-CO-CH 2-AA 1The citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CO-CH 2-AA 1-OH (AA wherein 1, R as above defines).With compound R-CO-CH 2-AA 1-OH and acid anhydrides (as two-tertiary butyl carbonic anhydride) generate R-CO-CH under alkaline condition 2-(K) AA 1-OH (AA wherein 1, R as above defines, and K is an amino protecting group, as Boc etc.).With R-CO-CH 2-(K) AA 1-OH and AA 2-OP (AA wherein 2, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CO-CH 2-(K) AA 1-AA 2-OP (R wherein, AA 1, AA 2, K, P as above defines).With compound R-CO-CH 2-(K) AA 1-AA 210% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(K) AA 1-AA 2-OH (R wherein, AA 1, AA 2, K as above defines).With compound R-CH 2-CO-(K) AA 1-AA 2-OH and AA 3-OP (AA wherein 3, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(K) AA 1-AA 2-AA 3-OP (R wherein, AA 1, AA 2, AA 3, P, M as above defines).With gained R-CH 2-CO-(K) AA 1-AA 2-AA 310% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(K) AA 1-AA 2-AA 3-OH.Then with compound R-CH 2-CO-(K) AA 1-AA 2-AA 3Obtain compound R-CH after the-OH deprotection 2-CO-AA 1-AA 2-AA 3-OH.
And the preparation method of Hyp derivative is as follows:
Figure A200810007611D00241
R wherein ABe amino protecting group, P is a carboxyl-protecting group, and itself and formula (6) compound make structural formula (5).
G-W-R 2Formula (6)
Wherein G is a reactive residue, preferred halogen atom; W is-CO--CH 2-,-CO-NH-; R 2Define as structural formula (5).
The preparation method of another kind of Hyp derivative:
Figure A200810007611D00242
Formula (7)
Hydroxyl is converted to amino reaction reference literature [1] (Ko, S.Y.J.Org.Chem.2002, method 67:2689), wherein R ABe amino protecting group, P is a carboxyl-protecting group, and formula (7) makes structural formula (5) with formula (8) compound.
G-Z-R 2Formula (8)
Wherein G is a reactive residue, preferred carboxyl, sulfonic group, halogen atom; Z is-O--NH-,-CH 2-, a key; R 2Define as structural formula (5).
Formula (II) compound can be by scheme 4, and scheme 5 or scheme 6 methods are synthetic:
Figure A200810007611D00251
I:Et 3N, ii:DCM, iii:NaOH/MeOH, the iv:10% citric acid,
v：DCM，DMF，DCC-HOBt，NMM
Scheme 4
In scheme 4, (M) AA 1-OP compound (AA wherein 1As above definition, P is C 1-4Alkyl, it can be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, preferable methyl and ethyl, M are AA 1Amido modified group, can be C 1-4Alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, preferable methyl, ethyl) with bromoacetyl bromide at Et 3Generate compd B r-CH among N and the DCM 2-CO-(M) AA 1-OP (AA wherein 1, P, M as above defines).With compd B r-CH 2-CO-(M) AA 1-OP and R-H (R as above defines) are at Et 3Generate compound R-CH among N and the DCM 2-CO-(M) AA 1-OP (AA wherein 1, P, R, M as above defines).With chemical combination R-CH 2-CO-(M) AA 110% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-OH (AA wherein 1, P, R, M as above defines).With compound R-CH 2-CO-(M) AA 1-OH and AA 2-OP (AA wherein 2As above definition) at DMF-DCM, reacts among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(M) AA 1-AA 2-OP (AA wherein 1, AA 2, P, R, M as above defines).With compound R-CH 2-CO-(M) AA 1-AA 210% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-AA 2-OH (R wherein, AA 1, AA 2, M as above defines).With compound R-CH 2-CO-(M) AA 1-AA 2-OH and AA 3-OP (AA wherein 3, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(M) AA 1-AA 2-AA 3-OP (R wherein, AA 1, AA 2, AA 3, P, M as above defines).Then with gained R-CH 2-CO-(M) AA 1-AA 2-AA 310% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates R-CH 2-CO-(M) AA 1-AA 2-AA 3-OH.
Figure A200810007611D00261
I:Et 3N, ii:DCM, iii:NaOH/MeOH, the iv:10% citric acid,
V: acid anhydrides or carboxylic acid halides, vi:DCM, DMF, DCC-HOBt, NMM
Scheme 5
In scheme 5, compound R-H (wherein R as above defines) and bromoacetyl bromide are at Et 3Generate compd B r-CH among N and the DCM 2-CO-R (AA wherein 1, R as above defines).With compd B r-CH 2-CO-R and AA 1-OP (AA wherein 1, P as above defines) and at Et 3Generate compound R-CO-CH among N and the DCM 2-AA 1-OP (AA wherein 1, P, R as above defines).With compound R-CO-CH 2-AA 1The citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CO-CH 2-AA 1-OH (AA wherein 1, R as above defines).With compound R-CO-CH 2-AA 1-OH and acid anhydrides or carboxylic acid halides generate R-CO-CH under alkaline condition 2-(M) AA 1-OH (AA wherein 1, R as above defines, and this moment, M was selected from ethanoyl, propionyl, butyryl radicals, isobutyryl, preferred ethanoyl, propionyl).With R-CO-CH 2-(M) AA 1-OH and AA 2-OP (AA wherein 2, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CO-CH 2-(M) AA 1-AA 2-OP (R wherein, AA 1, AA 2, M, P as above defines).With compound R-CO-CH 2-(M) AA 1-AA 210% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-AA 2-OH (R wherein, AA 1, AA 2, M as above defines).With compound R-CH 2-CO-(M) AA 1-AA 2-OH and AA 3-OP (AA wherein 3, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(M) AA 1-AA 2-AA 3-OP (R wherein, AA 1, AA 2, AA 3, P, M as above defines).With gained R-CH 2-CO-(M) AA 1-AA 2-AA 310% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-AA 2-AA 3-OH.
Figure A200810007611D00271
I:Et 3N, ii:DCM, iii:NaOH/MeOH, the iv:10% citric acid,
v：DCM，DMF，DCC-HOBt，NMM
Scheme 6
In scheme 6, compound R-H (wherein R as above defines) and bromoacetyl bromide are at Et 3Generate compd B r-CH among N and the DCM 2-CO-R.With compd B r-CH 2-CO-R and (M) AA 1-OP (AA wherein 1, P as above defines, and this moment, M was C 1-4Alkyl, it can be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, preferable methyl, ethyl) at Et 3Generate compound R-CH among N and the DCM 2-CO-(M) AA 1-OP.With compound R-CH 2-CO-(M) AA 1The citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-OH.With R-CH 2-CO-(M) AA 1-OH and AA 2-OP (AA wherein 2, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(M) AA 1-AA 2-OP (R wherein, AA 1, AA 2, M, P as above defines).With compound R-CH 2-CO-(M) AA 1-AA 210% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-AA 2-OH.With compound R-CH 2-CO-(M) AA 1-AA 2-OH and AA 3-OP (AA wherein 3, P as above defines) at DMF-DCM, react among NMM and the DCC-HOBt, generate compound R-CH 2-CO-(M) AA 1-AA 2-AA 3-OP (R wherein, AA 1, AA 2, AA 3, P, M as above defines).With gained R-CH 2-CO-(M) AA 1-AA 2-AA 310% citric acid acidifying is used in-OP saponification in 1M NaOH/MeOH solution then, generates compound R-CH 2-CO-(M) AA 1-AA 2-AA 3-OH.
According to the present invention, formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts comprise following sequence:
Sequence 1:R-CH 2-CO-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00281
Figure A200810007611D00282
Sequence 2:R-CH 2-CO-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00283
Figure A200810007611D00284
Figure A200810007611D00291
Sequence 3:R-CO-CH 2-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00292
Figure A200810007611D00293
Sequence 4:R-CO-CH 2-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00294
Figure A200810007611D00295
Sequence 5:R-CO-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝
Figure A200810007611D00302
Sequence 6:R-CO-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝
Figure A200810007611D00303
Figure A200810007611D00304
Sequence 7:R-CH 2-CO-(M) AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、ALa、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00306
Figure A200810007611D00311
Sequence 8:R-CH 2-CO-(M) AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611D00312
Figure A200810007611D00313
Sequence 9:R-CO-CH 2-(M) AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH-、CH 3CO-，CH 3CH 2CO-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Sequence 10:R-CO-CH 2-(M) AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH-、CH 3CO-，CH 3CH 2CO 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
According to the present invention, the steric isomer of formula (I) or formula (II) peptide derivative is meant its corresponding D-or L-steric configuration.
According to the present invention, formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts demonstrate excellent results in the anti-ET1 receptor model of animal, and therefore can be used as cardiovascular and cerebrovascular medicine is used for animal, is preferred for Mammals, are more preferably to be used for the people.
The present invention also relates on the other hand and containing as at least a formula (I) of the effective dose of activeconstituents or (II) pharmaceutical composition of peptide derivative and/or its steric isomer and/or its pharmaceutical salts and conventional medicine vehicle or assistant agent.Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, can with formula (I) or (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts and one or more solids or liquid medicine vehicle and/or assistant agent combine, make the suitable administration form or the dosage form that can be used as human.
The present invention relates to the method for prevention or treatment and endothelin and prostate gland diseases associated on the other hand, and this method comprises formula (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts that gives the patient treatment significant quantity.
The present invention also relates to formula (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts on the other hand and is used for preventing or the purposes of the medicine of treatment and endothelin and prostate gland diseases associated in preparation.
Formula of the present invention (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts or contain their 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, with effective constituent formula (I) or (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts mix with above-mentioned various carriers, and the mixture that will obtain thus places hard capsule or soft capsule.Also can with effective constituent formula (I) or (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts make 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) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts 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, three, four dosage form administrations.
The abbreviation of Shi Yonging in the present invention has following implication:
The Ala L-Ala,
The Asn l-asparagine,
DAD 1,4-dioxy-8-azaspiro [4,5] decane,
The DBA Di-n-Butyl Amine,
DIC N, N '-di-isopropyl carbimide
The DCM methylene dichloride,
The DMF dimethyl formamide,
Diox 1, the 4-dioxane
Et 3The N triethylamine,
The GABA γ-An Jidingsuan,
The Gly glycine,
The Gln glutamine,
The Hyp oxyproline
The HIM hexamethylene imine,
HMPA hexamethyl phosphonic amide,
The HOBt I-hydroxybenzotriazole,
The Ile Isoleucine,
The Leu leucine,
The MeVal methylvaline,
The Nle nor-leucine
Mob β-piperonyl L-Ala,
MOP morphine quinoline,
NMM N-methylmorpholine,
The Phe phenylalanine,
The Phg phenylglycocoll,
The Pro proline(Pro),
Pya β-pyridyl L-Ala,
The Ser Serine,
The TFA trifluoroacetic acid
The Thr Threonine,
The Trp tryptophane,
The Val Xie Ansuan,
Among the present invention, all amino acid configurations are the L-type except that being labeled as the D-type.
Embodiment
Embodiment
The following examples and biological activity test are 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 CarloErba 1106 type elemental analysers; UV spectrum is measured by the UV-260 ultraviolet-visible pectrophotometer; Infrared spectra is measured by Magna IRTM 550 infrared instrument.Embodiment prepares used reaction reagent and is commercial prod.
Embodiment 1:DBA-CH 2-CO-Leu-D-Trp-D-Phe (4-Cl)-OH
Figure A200810007611D00361
1.1?Br-CH 2-CO-LeuOCH 3(aa 1)
Bromoacetyl bromide 1.00ml (11.56mmol) is dissolved among the 5ml DCM as in the 50ml there-necked flask nitrogen protection.Under-78 ℃ of stirrings, slowly drip DCM (20ml) solution of 2.00g (11.01mmol) leucine methyl ester hydrochloride and 3.13ml (22.57mmol) triethylamine.-78 ℃ of stirring reaction 45min, stirring at room 30min.Solution is poured in the frozen water, uses the separating funnel layering, tell the DCM layer of lower floor, again with 1M HCl washing 2 times, anhydrous MgSO is used in saturated NaCl washing 3 times 4Dry.The filtering siccative is spin-dried for solvent, gets faint yellow oily thing 2.93g.
1.2?DBA-CH 2-CO-LeuOH(aa 2)
With 2.93g (11.56mmol) AA 1Be dissolved in the 50ml acetonitrile, ice bath adds 1.95ml (11.56mmol) Di-n-Butyl Amine and 1.60ml (11.56mmol) triethylamine down, is heated to 40 ℃ of reactions, and TLC detects, and after question response is complete, is spin-dried for solvent, adds DCM, washes saturated NaHCO with water 1 time 3Wash 3 times, anhydrous MgSO is used in saturated common salt water washing 2 times 4Dry.The filtering siccative is spin-dried for solvent, and product separates (DCM:MeOH=100:1) through silica gel chromatographic column and gets pale brown look oily matter 2.08g.With this oily matter 25ml dissolve with methanol, in ice-water bath, add 14.55ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 1.89g that gets of filter collection.
1.3?DBA-CH 2-CO-Leu-D-Trp-D-Phe(4-Cl)-OH
With 1.89g (6.29mmol) AA 2Be dissolved among the 10ml DCM, add 1.60g (6.29mmol) D-tryptophan methyl ester hydrochloride,, add 0.89g HOBt (6.60mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.69ml (6.28mmol) and 0.83g DIC (6.60mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 2.83g.With this white solid 25ml dissolve with methanol, in ice-water bath, add 11.59ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 2.61g that gets of filter collection.This solid is dissolved among the 10ml DCM, adds 1.34g (5.36mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.76g HOBt (5.63mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.59ml (5.36mmol) and 0.71g DIC (5.63mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains white solid 3.15g.With this white solid 25ml dissolve with methanol, in ice-water bath, add 9.46ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=30:1) through silica gel chromatographic column, gets white solid 2.72g.
MS：[M+H]＝668.3。
Embodiment 2:DBA-CO-CH 2-Leu-D-Trp-D-Phe (4-Cl)-OH
Figure A200810007611D00381
2.1?DBA-CO-CH 2-Br(bb1)
Bromoacetyl bromide 2.56ml (29.69mmol) is dissolved among the 10ml DCM as in the 100ml there-necked flask nitrogen protection.Under-78 ℃ of stirrings, DCM (50ml) solution of slow Dropwise 5 ml (29.69mmol) Di-n-Butyl Amine and 8.44ml (60.83mmol) triethylamine.-78 ℃ of stirring reaction 45min, stirring at room 30min.Solution is poured in the frozen water, uses the separating funnel layering, tell the DCM layer of lower floor, again with 1M HCl washing 2 times, anhydrous MgSO is used in saturated NaCl washing 3 times 4Dry.The filtering siccative is spin-dried for solvent, gets faint yellow oily thing 6.45g.
2.2?DBA-CO-CH 2-(Boc)Leu-OH(bb2)
6.45g (25.78mmol) bb2 is dissolved in the 100ml acetonitrile, ice bath adds 4.68g (25.78mmol) leucine methyl ester hydrochloride and 7.34ml (52.85mmol) triethylamine down, be heated to 40 ℃ of reactions, TLC detects, after question response is complete, be spin-dried for solvent, add DCM, wash saturated Na HCO with water 1 time 3Wash 3 times, anhydrous MgSO is used in saturated common salt water washing 2 times 4Dry.The filtering siccative is spin-dried for solvent, and product separates (DCM:MeOH=100:1) through silica gel chromatographic column and gets pale brown look oily matter 2.43g.With this oily matter 25ml dissolve with methanol, in ice-water bath, add 15.84ml 1M sodium hydroxide, stir under the room temperature, TLC detects, and after question response was complete, ice bath added 2.16g (11.59mmol) Boc down 2O, room temperature is kept the pH=9 reaction, and TLC detects, and the complete back of question response adds ethyl acetate extraction, saturated NaCl washing 3 times, product separates (PE:EtOAc=5:1) through silica gel chromatographic column, gets white solid 2.47g.
2.3?DBA-CO-CH 2-Leu-D-Trp-D-Phe(4-Cl)-OH
2.47g (6.18mmol) bb2 is dissolved among the 10ml DCM, adds 1.57g (6.18mmol) D-tryptophan methyl ester hydrochloride,, add 0.88g HOBt (6.49mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.68ml (6.18mmol) and 0.82g DIC (6.49mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=6:1) through silica gel chromatographic column, obtains white solid 3.34g.With this white solid 25ml dissolve with methanol, add 11.40ml 1M sodium hydroxide in ice-water bath, stir under the room temperature, TLC detects, after question response is complete, to pH about 7, revolve methyl alcohol with the acidifying of 1%-30% citric acid, use the acidifying of 1%-30% citric acid again to pH 2-3, separate out solid, DCM extracts, and behind the saturated NaCl solution washing, uses anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 3.18g that gets of filter collection.This solid is dissolved among the 20ml DCM, adds 1.36g (5.42mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.77g HOBt (5.69mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.60ml (5.42mmol) and 0.72g DIC (5.69mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains white solid 3.73g.With this white solid 30ml dissolve with methanol, in ice-water bath, add 10.0ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 7, revolve methyl alcohol, use the acidifying of 1%-30% citric acid to pH 2-3 again, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 3.29g that gets of filter collection.To add under the solid ice bath in 35ml trifluoroacetic acid and the 35ml meta-cresol in batches, stirring at room, TLC detects, and after question response was complete, trifluoroacetic acid was removed in decompression, adds DCM and water, uses Na 2CO 3Adjust pH is 7.Divide ester output layer drying, the filtering siccative, concentrated filtrate gets incarnadine oily matter, and product separates (DCM:MeOH=40:1) through silica gel chromatographic column, obtains white solid 2.23g.
MS：[M+H]＝668.6。
Embodiment 3:DBA-CO-CH 2-Leu (CH 3)-D-Trp-D-Phe (4-Cl)-OH
Figure A200810007611D00401
3.1?(CH 3)LeuOCH 3·HCl(cc1)
5g (0.02mol) tertbutyloxycarbonyl leucine is dissolved among 50ml tetrahydrofuran (THF) and the 5ml DMF, adds 2.75g NaH (70%) under the ice bath in batches, behind the stirring 30min, add the 10ml methyl iodide, be heated to 80 ℃ and stir 24h.Tetrahydrofuran (THF) is removed in decompression, adds ethyl acetate, washes saturated NaHCO with water 1 time 3Wash saturated NaCl washing 1 time 1 time.With anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (PE:EtOAc=25:1) through silica gel chromatographic column, gets colorless oil 4.1g.Will be under this oily matter condition of ice bath add 50ml 4M HCl/Diox solution, stirring at room, TLC detects, question response fully after, HCl/Diox solution is removed in decompression, with methyl alcohol-ether recrystallization, white crystal 2.93g.
3.2?DBA-CO-CH 2-(CH 3)Leu-OH(cc2)
2.93g (14.97mmol) cc1 and 3.75g (14.97mmol) bb1 are dissolved in the 50ml acetonitrile, and ice bath adds 4.26ml (30.69mmol) triethylamine, 40 ℃ of stirrings down, TLC detects, and after question response was complete, acetonitrile was removed in decompression, add DCM, wash saturated NaHCO with water 1 time 3Wash 3 times, anhydrous MgSO is used in saturated common salt water washing 2 times 4Dry.The filtering siccative is spin-dried for solvent, and product separates (DCM:MeOH=100:1) through silica gel chromatographic column and gets pale brown look oily matter 1.62g.With this oily matter 30ml dissolve with methanol, in ice-water bath, add 10.0ml1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=100:1) through silica gel chromatographic column, gets colorless oil 1.38g.
3.3?DBA-CO-CH 2-(CH 3)Leu-D-Trp-D-Phe(4-Cl)-OH
With 1.38g (4.39mmol) cc2 be dissolved among the 10ml DCM, add 1.12g (4.39mmol) D-tryptophan methyl ester hydrochloride, with 1ml DMF dissolving, add 0.63g HOBt (4.61mmol) again.Add N-methylmorpholine 0.48ml (4.39mmol) and 0.58g DIC (4.61mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 1.74g.With this white solid 20ml dissolve with methanol, in ice-water bath, add 6.93ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 1.62g that gets of filter collection.This solid is dissolved among the 10ml DCM, adds 0.81g (3.24mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.46g HOBt (3.40mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.36ml (3.24mmol) and 0.43g DIC (3.40mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 1.91g.With this white solid 15ml dissolve with methanol, in ice-water bath, add 5.60ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=30:1) through silica gel chromatographic column, gets solid 1.46g.
MS：[M+H]＝682.5。
Embodiment 4:DBA-CO-CH 2-(Ac) Leu-D-Trp-D-Phe (4-Cl)-OH
Figure A200810007611D00421
With 3.1g (10mmol) DBA-CO-CH 2-LeuOCH 3(preparation method sees embodiment 2) uses the 50ml dissolve with methanol, adds 20.5ml 1M sodium hydroxide in ice-water bath, stirs under the room temperature, and TLC detects, and after question response was complete, ice bath added 1.40ml (15mmol) Ac down 2O, room temperature is kept the pH=9 reaction, and the TLC detection after question response is complete, is acidified to pH about 1 with concentrated hydrochloric acid, revolves methyl alcohol, adds ethyl acetate extraction, saturated NaCl washing 3 times, product separates (PE:EtOAc=5:1) through silica gel chromatographic column, gets oily matter 2.05g.This oily matter is dissolved among the 20mlDCM, adds 0.74g (2.93mmol) D-tryptophan methyl ester hydrochloride,, add 0.42g HOBt (3.07mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.32ml (2.93mmol) and 0.39g DIC (3.07mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=6:1) through silica gel chromatographic column, obtains white solid 1.56g.With this white solid 15ml dissolve with methanol, in ice-water bath, add 5.74ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to the pH 2-3, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 1.49g that gets of filter collection.This solid is dissolved among the 20ml DCM, adds 0.69g (2.75mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.39g HOBt (2.88mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.30ml (2.75mmol) and 0.36g DIC (2.88mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains white solid 1.79g.With this white solid 15ml dissolve with methanol, in ice-water bath, add 5.0ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to the pH 2-3, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=40:1) through silica gel chromatographic column, obtains white solid 1.40g.
MS：[M+H]＝710.7。
Embodiment 5:DBA-CH 2-CO-(CH 3) Leu-D-Trp-D-Phe (4-Cl)-OH
Figure A200810007611D00431
5.1?Br-CH 2-CO-(CH 3)LeuOCH 3(dd1)
Bromoacetyl bromide 4.3ml (25.6mmol) is dissolved among the 10ml DCM as in the 100ml there-necked flask nitrogen protection.Under-78 ℃ of stirrings, DCM (50ml) solution of slow Dropwise 5 .00g (25.6mmol) cc1 and 7.28ml (52.48mmol) triethylamine.-78 ℃ of stirring reaction 45min, stirring at room 30min.Solution is poured in the frozen water, uses the separating funnel layering, tell the DCM layer of lower floor, again with 1M HCl washing 2 times, anhydrous MgSO is used in saturated NaCl washing 3 times 4Dry.The filtering siccative is spin-dried for solvent, gets faint yellow oily thing 8g.
5.2?DBA-CH 2-CO-(CH 3)Leu-OH(dd2)
With 8g (28.6mmol) AA 1Be dissolved in the 60ml acetonitrile, ice bath adds 4.8ml (28.6mmol) Di-n-Butyl Amine and 3.97ml (28.6mmol) triethylamine down, is heated to 40 ℃ of reactions, and TLC detects, and after question response is complete, is spin-dried for solvent, adds DCM, washes saturated NaHCO with water 1 time 3Wash 3 times, anhydrous MgSO is used in saturated common salt water washing 2 times 4Dry.The filtering siccative is spin-dried for solvent, and product separates (DCM:MeOH=100:1) through silica gel chromatographic column and gets pale brown look oily matter 7.47g.With this oily matter 120ml dissolve with methanol, in ice-water bath, add 46.61ml1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=20:1) through silica gel chromatographic column and gets solid 4.86g.
5.3?DBA-CH 2-CO-(CH 3)Leu-D-Trp-D-Phe(4-Cl)-OH
2g (6.36mmol) dd2 is dissolved among the 10ml DCM, adds 1.62g (6.36mmol) D-tryptophan methyl ester hydrochloride,, add 0.90g HOBt (6.68mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.70ml (6.36mmol) and 0.84g DIC (6.68mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash with water once after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 2.90g.With this white solid 25ml dissolve with methanol, in ice-water bath, add 11.55ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 2.53g that gets of filter collection.This solid is dissolved among the 10ml DCM, adds 1.67g (5.07mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.72g HOBt (5.32mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.56ml (5.07mmol) and 0.67g DIC (5.32mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains white solid 3.10g.With this white solid 25ml dissolve with methanol, in ice-water bath, add 9.0ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=30:1) through silica gel chromatographic column, gets white solid 2.10g.
MS：[M+H]＝681.5。
Embodiment 6:
Figure A200810007611D00451
6.1
Figure A200810007611D00452
Synthesizing (ee1)
The trans tertbutyloxycarbonyl oxyproline of 5g (20.39mmol) methyl esters is dissolved among the 100ml DCM, adds 1.97ml (24.47mmol) pyridine, ice bath stirs and adds 4.66g (24.47mmol) down in batches.Keep the ice bath reaction, TLC detects, and after question response was complete, DCM was removed in decompression, adds ethyl acetate, uses the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=10:1) through silica gel chromatographic column, obtains white solid 6.83g.This white solid is dissolved among the 50ml DMF, add 1.29g (19.82mmol) sodiumazide, be heated to 50 ℃ of stirrings, TLC detects, and after question response was complete, DMF was removed in decompression, add ethyl acetate, wash with water 2 times, saturated NaCl washing 1 time, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets the 4.29g colorless oil.This oily matter is dissolved in the 20ml ethyl acetate, add 0.25gPd-C, to the logical hydrogen stirring at room of reaction system, stir 10h, filter out Pd-C, wash with water 1 time, transfer pH about 3 with 0.2M HCl,, transfer pH about 9 then with the intact raw material of ether extraction unreacted, extract product with DCM, get oily matter 2.56g.This oily matter is dissolved among the 10ml DCM, adds 1.84g (10.48mmol) 3-indolyl acetic acid,, add 1.49g HOBt (11.00mmol) again with 1ml DMF dissolving.Add 1.39g DIC (11.00mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash with water once after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets incarnadine oily matter, and ice bath adds sherwood oil down, separates out solid, the dry solid 3.49g that gets of filter collection.To add under the solid ice bath in 20ml trifluoroacetic acid and the 20ml meta-cresol in batches, stirring at room, TLC detects, and after question response was complete, trifluoroacetic acid was removed in decompression, adds DCM and water, uses Na 2CO 3Adjust pH is 9.Divide ester output layer drying, the filtering siccative, concentrated filtrate gets incarnadine oily matter, and product separates (DCM:MeOH=40:1) through silica gel chromatographic column, obtains white solid 1.31g.
6.2
Figure A200810007611D00461
Synthesizing (ee2)
1.31g (4.35mmol) ee1 is dissolved among the 10ml DCM, adds 1.25g (4.35mmol) DBA-CO-Leu-OH,, add 0.62g HOBt (4.57mmol) again with 1ml DMF dissolving.Add 0.58g DIC (4.57mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 1.73g.With this white solid 15ml dissolve with methanol, in ice-water bath, add 6.5ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to the pH 2-3, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (DCM:MeOH=30:1) through silica gel chromatographic column, obtains white solid 1.01g.
MS：[M+H]＝556.7。
Embodiment 7:
0.50g (0.90mmol) ee2 is dissolved among the 5ml DCM, adds 0.20g (0.90mmol) D-4-chlorophenylalanine methyl ester hydrochloride,, add 0.13g HOBt (0.95mmol) again with 0.5ml DMF dissolving.Add N-methylmorpholine 0.10ml (0.90mmol) and 0.12g DIC (0.95mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 0.60g.With this white solid 5ml dissolve with methanol, in ice-water bath, add 1.5ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to the pH 2-3, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (DCM:MeOH=30:1) through silica gel chromatographic column, obtains white solid 0.45g.
MS：[M+H]＝737.7。
Embodiment 8:
Figure A200810007611D00481
8.1
Figure A200810007611D00482
Synthesizing (ff1)
With D-cis tertbutyloxycarbonyl oxyproline methyl esters is raw material, and corresponding operating is with embodiment 6.
8.2 Synthesizing (ff2)
0.87g (2.90mmol) ff1 is dissolved among the 10ml DCM, adds 0.90g (2.90mmol) AA 2,, add 0.50g HOBt (3.50mmol) again with 1ml DMF dissolving.Add 0.40g DIC (3.50mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 1.43g.With this white solid 15ml dissolve with methanol, in ice-water bath, add 5ml1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (DCM:MeOH=20:1) through silica gel chromatographic column, obtains white solid 1.11g.
MS：[M+H]＝570.6。
Embodiment 9:
Figure A200810007611D00491
With ff2 is raw material (preparation method sees embodiment 8), and corresponding operating is with embodiment 1.
MS：[M+H]＝751.8。
Embodiment 10:
Figure A200810007611D00492
1.60g (5.30mmol) ff1 is dissolved among the 50ml DCM, adds 2.10g (5.30mmol) bb2,, add 0.90g HOBt (6.40mmol) again with 1ml DMF dissolving.Add 0.80g DIC (6.40mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use the 1%-30% citric acid respectively, saturated NaHCO 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains incarnadine solid 3.25g.With this white solid 25ml dissolve with methanol, add 9.7ml 1M sodium hydroxide in ice-water bath, stir under the room temperature, TLC detects, after question response is complete, to pH about 7, revolve methyl alcohol with the acidifying of 1%-30% citric acid, use the acidifying of 1%-30% citric acid again to pH 2-3, separate out solid, DCM extracts, and behind the saturated NaCl solution washing, uses anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate, ice bath add sherwood oil down, separate out solid, the dry solid 3.06g that gets of filter collection.To add under the solid ice bath in 60ml trifluoroacetic acid and the 60ml meta-cresol in batches, stirring at room, TLC detects, and after question response was complete, trifluoroacetic acid was removed in decompression, adds DCM and water, uses Na 2CO 3Adjust pH is 7.Divide ester output layer drying, the filtering siccative, concentrated filtrate gets incarnadine oily matter, and product separates (DCM:MeOH=20:1) through silica gel chromatographic column, obtains white solid 1.56g.
MS：[M+H]＝570.7。
Embodiment 11:
Figure A200810007611D00501
Figure A200810007611D00502
Shown in compound be raw material (preparation method sees embodiment 10), corresponding operating is with embodiment 2.
MS：[M+H]＝751.8。
Embodiment 12:
Figure A200810007611D00511
12.1
Figure A200810007611D00512
Synthesizing (gg1)
The trans tertbutyloxycarbonyl oxyproline of 5g (20.39mmol) methyl esters is dissolved in the 100ml tetrahydrofuran (THF), adds 1.40g (40.78mmol) NaH (70%) under the ice bath in batches, behind the stirring 1h, add 3.48g (20.39mmol) pepper methyl chloride, room temperature reaction 24h.Tetrahydrofuran (THF) is removed in decompression, adds ethyl acetate, washes with water 1 time, saturated NaCl washing 1 time.With anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (PE:EtOAc=25:1) through silica gel chromatographic column, gets colorless oil 3.78g.To add 25ml 4M HCl/Diox solution under this oily matter condition of ice bath, stirring at room, TLC detects, after question response was complete, HCl/Diox solution was removed in decompression, adds water, with the little impurity of ether extraction polarity, transfer pH=9, extract, divide ester output layer drying with DCM, the filtering siccative, concentrated filtrate, product separates (DCM:MeOH=40:1) through silica gel chromatographic column, obtains white solid 1.67g.
12.2
Figure A200810007611D00513
Synthesizing (gg2)
With gg1 is raw material, and corresponding operating is with embodiment 6.
MS：[M+H]＝532.4。
Embodiment 13:
Figure A200810007611D00521
With gg2 is raw material, and corresponding operating is with embodiment 7.
MS：[M+H]＝715.8。
Embodiment 14:
Figure A200810007611D00522
With gg1 is raw material, and corresponding operating is with embodiment 8.
MS：[M+H]＝548.4。
Embodiment 15:
With embodiment 14 products is raw material, and corresponding operating is with embodiment 1.
MS：[M+H]＝729.3。
Embodiment 16:
Figure A200810007611D00531
With gg1 is raw material, and corresponding operating is with embodiment 10.
MS：[M+H]＝548.4。
Embodiment 17:
Figure A200810007611D00532
With
Figure A200810007611D00533
Shown in structure be raw material (preparation method sees embodiment 16), corresponding operating is with embodiment 2.
MS：[M+H]＝729.2。
Embodiment 18:DBA-CH 2-CO-Leu-D-Trp-D-Trp-OH
Figure A200810007611D00541
With 1.00g (3.33mmol) aa2 is that raw material is dissolved among the 5ml DCM, adds 0.85g (3.33mmol) D-tryptophan methyl ester hydrochloride, with 0.5ml DMF dissolving, adds 0.47gHOBt (3.49mmol) again.Add N-methylmorpholine 0.37ml (3.33mmol) and 0.44g DIC (3.49mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=3:1) through silica gel chromatographic column, obtains white solid 1.51g.TLC detects: (methylene dichloride: Rf=0.3 methyl alcohol 20:1).With this white solid 10ml dissolve with methanol, in ice-water bath, add 6ml1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Ice bath adds sherwood oil down, separates out solid, the dry solid 1.43g that gets of filter collection.This solid is dissolved among the 10ml DCM, adds 0.75g (2.94mmol) D-tryptophan methyl ester hydrochloride,, add 0.35g HOBt (2.61mmol) again with 1ml DMF dissolving.Add N-methylmorpholine 0.27ml (2.49mmol) and 0.33g DIC (2.61mmol) under the condition of ice bath.Continue to keep ice bath after 0.1-5 hour, room temperature reaction 1-10 hour.Concentrate, add ethyl acetate, wash 1 time with water after, use saturated NaHCO respectively 3Respectively wash 3 times with saturated NaCl, ethyl acetate layer is used anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil, and product separates (PE:EtOAc=4:1) through silica gel chromatographic column, obtains white solid 1.80g.TLC detects: (methylene dichloride: Rf=0.5 methyl alcohol 20:1).With this white solid 25ml dissolve with methanol, in ice-water bath, add 5.50ml 1M sodium hydroxide, stir under the room temperature, TLC detects, after question response is complete, with the acidifying of 1%-30% citric acid to pH about 6, revolve methyl alcohol, separate out solid, DCM extracts, behind the saturated NaCl solution washing, use anhydrous sodium sulfate drying 3-6 hour.The filtering siccative, concentrated filtrate gets colorless oil.Product separates (DCM:MeOH=30:1) through silica gel chromatographic column, gets white solid 1.60g.
MS：[M+H]＝673.3。
Embodiment 19
Figure A200810007611D00551
With gg2 and tryptophan methyl ester hydrochloride is raw material, and the preparation method presses embodiment 13.
MS：[M+H]＝720.6。
Embodiment 20:
Evaluated biological activity: adopt anti-ET-1 to cause the isolated rat aortic annulus and shrink experiment
(1) 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:sigma company
10% salt of wormwood autogamy
Improvement Kreb ' s-Ringer damping fluid: autogamy
(2) experimental technique
The preparation of sample solution:
Quantitatively take by weighing sample 2 * 10 -6Mol adds 120 μ l, 10% alkaline carbonate and 1-80 μ l DMSO dissolving, quantitatively dilutes with improvement Kreb ' s-Ringer damping fluid to be 5.0ml, as preserving in the stock solution refrigerator.With the damping fluid dilution is 10 -6, 10 -7, 10 -8With 10 -9Four concentration of M.
The extracorporeal blood vessel preparation:
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, be cut into the arterial ring that is about 3mm, the stainless steel steel wire that is 0.1mm with two diameters carefully penetrates respectively, makes the triangle ring-type.With being placed in 37 ℃ of thermostatic baths that fill 10ml 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 0.5g 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:
NO IC 50(M) ET-1 Ki
Positive control BQ-485 1.23E-07 1.00E-08 2.37E-08
1 7.35E-08 1.00E-08 1.41E-08
2 6.74E-08 1.00E-08 1.29E-08
3 6.58E-08 1.00E-08 1.26E-08
4 3.74E-08 1.00E-08 7.18E-09
5 6.30E-08 1.00E-08 1.21E-08
6 5.11E-08 1.00E-08 9.82E-09

Claims (8)

1, formula (I) peptide derivative or its steric isomer or its pharmaceutical salts
R-(CH 2) i-CO-(CH 2) j-AA 1-AA 2-AA 3-OH formula (I)
Wherein, R is hexamethylene imine base or following group:
Figure A200810007611C00021
(structural formula 1) (structural formula 2) (structural formula 3) (structural formula 4)
In the structural formula 1, n 1, n 2And n 3Be integer 0,1 independently, 2 or 3, and n wherein 3≠ 0,0≤n 1+ n 2≤ 4; X 1Be NH, O, S or CH 2X 2Be N or 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;
In the structural formula 2, m 1, m 2, m 3And m 4Be integer 0,1 or 2 independently, and 0≤m wherein 1+ m 2≤ 4,0≤m 3+ m 4≤ 4; y 1And y 3Be CH independently 2, O, S or NH, y 2Be N or CH; Work as m 1=m 2==1, m 3=m 4=2, y 1, y 3Be O atom, y 2Be 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;
In the structural formula 3, z is N or CH, and k is N or Ck 1(k 1Be H, CH 3Or CH 2CH 3), t is H, CH 3, CH 2CH 3Or CH 1(CH 3) 2Perhaps z is O or S, and k is N or Ck 1(k 1Be H, CH 3Or CH 2CH 3), t and connecting key thereof do not exist; Work as z=N, k=N, during t=H, R is a piperazinyl; Work as z=O, k==N, when t and connecting key thereof did not exist, R was a morpholinyl;
In the structural formula 4, a and b are integer 0,1 independently, 2 or 3; P is the N atom; Work as a=3, during b==3, R is abbreviated as DBA;
AA 1For L or D type Ser, Thr, Phe, Cys, Gln, Asn, Ala, Ile, Leu, Nle, Val, other L or D type aliphatics alpha-non-natural amino acid, as β-Ala, γ-An Jidingsuan or aminoisobutyric acid;
AA 2Be L or D type Trp, Pro, aromatic amino acid, cis or trans Hyp or following cis or trans Hyp derivative (structural formula 5):
Figure A200810007611C00031
(structural formula 5)
In the structural formula 5, R 1Be linking group, can be-O-,-NH-,-NH-CO-,-O-CO-,-CH 2-,-NH-CO-O-,-O-CO-NH-,-NH-CO-NH-or-NH-SO 2-; R 2Be aryl, virtue is amino, aryl-short chain alkylamino, aryl-sulfo-, aryl-short-chain alkyl-sulfo-, aryloxy, aryl-short chain alkoxyl group, aryl-short-chain alkyl, aryl-sulfinyl, heteroaryl, heteroaryl-oxo, heteroaryl-amino, heteroaryl-sulfo-, heteroaryl-short-chain alkyl, heteroaryl-sulfinyl, heterocyclic radical, heterocyclic radical-short chain alkoxyl group, heterocyclic radical-oxo, heterocyclic radical-amino, heterocyclic radical-short chain alkylamino, heterocyclic radical-sulfo-, heterocyclic radical-short-chain alkyl-sulfo-, heterocyclic radical-short-chain alkyl, heterocyclic radical-sulfinyl, cycloalkyl, cycloalkyl-oxo, cycloalkyl-short chain alkoxyl group, cycloalkyl-amino, cycloalkyl-short chain alkylamino, cycloalkyl-sulfo-, cycloalkyl-short-chain alkyl sulfo-, cycloalkyl-short-chain alkyl or cycloalkyl-sulfinyl;
AA 3Be non-natural aromatic amino acid, tryptophane, phenylglycocoll or the non-amino acid of D type, wherein the phenyl in the aromatic nucleus can be selected from halogen on 2,3,4 or 5, nitro, and urea groups, methoxyl group, the substituting group list of carboxyl and short-chain alkyl replace or two replacements;
0≤i≤4; 0≤j≤4; Wherein when i=0 and j=0, AA 2Be L or D type cis or trans Hyp derivative only;
Work as AA 2When only being L or D type cis or trans Hyp derivative, AA 3Can lack.
2, formula (II) peptide derivative or its steric isomer or its pharmaceutical salts
R-(CH 2) i-CO-(CH 2) j-(M) AA 1-AA 2-AA 3-OH formula (II)
R wherein, AA 1, AA 2, AA 3, i, j is with the definition in claim 1 Chinese style (I), and M is as AA 1Modification group in the structure on the N atom, can be short-chain alkyl, short chain thiazolinyl, short chain alkynyl, short chain alkyloyl, short chain alkoxyl group ,-CO 2Short-chain alkyl ,-short-chain alkyl-CO 2Short-chain alkyl ,-CONH 2,-CONH short-chain alkyl ,-the CON[short-chain alkyl] 2
3, claim 1 or 2 described formulas (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts, wherein said formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts are selected from:
Sequence 1:R-CH 2-CO-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00041
Sequence 2:R-CH 2-CO-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C0004101411QIETU
Sequence 3:R-CO-CH 2-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00052
Sequence 4:R-CO-CH 2-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00053
Figure A200810007611C00054
Sequence 5:R-CO-AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝
Figure A200810007611C00055
Figure A200810007611C00061
Sequence 6:R-CO-AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝
Figure A200810007611C00063
Sequence 7:R-CH 2-CO-(M) AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-TrD、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00064
Figure A200810007611C00065
Sequence 8:R-CH 2-CO-(M) AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00071
Figure A200810007611C00072
Sequence 9:R-CO-CH 2-(M) AA 1-AA 2-D-Phe (4-Cl)-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH-、CH 3CO-，CH 3CH 2CO-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2=D-Trp, D-Pro, D-cis-Hyp, D-tran-Hyp, L-cis-Hyp, L-tran-Hyp,
Figure A200810007611C00073
With
Sequence 10:R-CO-CH 2-(M) AA 1-AA 2-D-Trp-OH
R＝DBA，ABO，DAD，HIM，MOP；
M＝CH 3-、CH 3CH-、CH 3CO-，CH 3CH 2CO 2-；
AA 1＝Ser、Thr、Phe、Cys、Gln、Asn、Ala、Ile、Leu、Nle、Val；
AA 2＝D-Trp、D-Pro、D-cis-Hyp、D-tran-Hyp、L-cis-Hyp、L-tran-Hyp、
Figure A200810007611C00081
Figure A200810007611C00082
4, claim 1 or 2 described formulas (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts, wherein said formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts are selected from:
Compound 1:DBA-CH 2-CO-Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 2:DBA-CO-CH 2-Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 3:DBA-CO-CH 2-Leu (CH 3)-D-Trp-D-Phe (4-Cl)-OH;
Compound 4:DBA-CO-CH 2-(Ac) Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 5:DBA-CH 2-CO-(CH 3) Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 6:
Figure A200810007611C00083
Compound 7:
Figure A200810007611C00091
Compound 8:
Compound 9:
Figure A200810007611C00093
Compound 10:
Figure A200810007611C00094
Compound 11:
Figure A200810007611C00101
Compound 12:
Figure A200810007611C00102
Compound 13:
Figure A200810007611C00103
Compound 14:
Figure A200810007611C00104
Compound 15:
Figure A200810007611C00111
Compound 16:
Figure A200810007611C00112
Compound 17:
Figure A200810007611C00113
Compound 18:DBA-CH 2-CO-Leu-D-Trp-D-Trp-OH; With
Compound 19:
Figure A200810007611C00114
5, pharmaceutical composition, it comprises at least a claim 1 or 2 described formulas (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts and pharmaceutical carrier or vehicle.
6, the pharmaceutical composition of claim 5, wherein said formula (I) or formula (II) peptide derivative or its steric isomer or its pharmaceutical salts are selected from:
Compound 1:DBA-CH 2-CO-Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 2:DBA-CO-CH 2-Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 3:DBA-CO-CH 2-Leu (CH 3)-D-Trp-D-Phe (4-Cl)-OH;
Compound 4:DBA-CO-CH 2-(Ac) Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 5:DBA-CH 2-CO-(CH 3) Leu-D-Trp-D-Phe (4-Cl)-OH;
Compound 6:
Figure A200810007611C00121
Compound 7:
Figure A200810007611C00122
Compound 8:
Figure A200810007611C00123
Compound 9:
Figure A200810007611C00131
Compound 10:
Figure A200810007611C00132
Compound 11:
Figure A200810007611C00133
Compound 12:
Figure A200810007611C00141
Compound 13:
Figure A200810007611C00142
Compound 14:
Figure A200810007611C00143
Compound 15:
Figure A200810007611C00144
Compound 16:
Compound 17:
Figure A200810007611C00152
Compound 18:DBA-CH 2-CO-Leu-D-Trp-D-Trp-OH; With
Compound 19:
Figure A200810007611C00153
7, claim 1 or 2 described formulas (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts are used for preventing or the purposes of the medicine of treatment and endothelin and prostate gland diseases associated in preparation.
8, the method for prevention or treatment and endothelin and prostate gland diseases associated, this method comprise formula (I) or formula (II) peptide derivative and/or its steric isomer and/or its pharmaceutical salts that gives the patient treatment significant quantity.
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JP2013216656A (en) * 2011-11-09 2013-10-24 Kyushu Univ Amide derivative
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US8951486B2 (en) 2011-11-09 2015-02-10 Kyushu University, National University Corporation Valuable metal extraction agent and valuable metal extraction method using said extraction agent
US9011804B2 (en) 2011-11-09 2015-04-21 Sumitomo Metal Mining Co., Ltd. Cobalt extraction method
US9481638B2 (en) 2012-03-13 2016-11-01 Kyushu University, National University Corporation Scandium extraction method
US9803262B2 (en) 2012-08-20 2017-10-31 Kyushu University, National University Corporation Gallium extraction agent and gallium extraction method
US9725786B2 (en) 2012-12-12 2017-08-08 Kyushu University, National University Corporation Nickel extraction method
US9458526B2 (en) 2013-03-18 2016-10-04 Kyushu University, National University Corporation Method for separating impurities from an acidic solution containing nickel and cobalt and/or scandium
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