CN101906136B - Amino acid-(3,4-dyhydroxy-Phe)-Ser-Leu false peptide, and synthesizing method and application thereof - Google Patents

Amino acid-(3,4-dyhydroxy-Phe)-Ser-Leu false peptide, and synthesizing method and application thereof Download PDF

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CN101906136B
CN101906136B CN2009100851525A CN200910085152A CN101906136B CN 101906136 B CN101906136 B CN 101906136B CN 2009100851525 A CN2009100851525 A CN 2009100851525A CN 200910085152 A CN200910085152 A CN 200910085152A CN 101906136 B CN101906136 B CN 101906136B
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leu
ser
phe
dihydroxyl
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CN101906136A (en
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赵明
彭师奇
孙丹璐
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Capital Medical University
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Abstract

The invention discloses amino acid-(3,4-dyhydroxy-Phe)-Ser-Leu false peptide, and a synthesizing method and application thereof. The synthesizing method comprises the following steps of: (1) synthesizing the protected (3,4-dyhydroxy-Phe)-Ser-Leu; and (2) condensing glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophane, serine, threonine, proline, glutamine, lysine, histidine, aspartate or glutamic acid respectively with the (3,4-dyhydroxy-Phe)-Ser-Leu protected by a protective group, and then removing the protective group to obtain the amino acid-(3,4-dyhydroxy-Phe)-Ser-Leu. The false peptide compound has favorable activity for removing NO free radical, the performance for inhibiting vasodilatation and excellent orally-taken thromobus-resisting activity, and can be used as the medicine with double activities for removing free radical and resisting thromobus.

Description

Amino acid-(3, the 4-dihydroxyl-Phe)-the pseudo-peptide of Ser-Leu and compound method and application
Technical field
The present invention relates to pseudo-peptide; Relate in particular to amino acid and (3; The aminoterminal condensation of the pseudo-tripeptides of 4-dihydroxyl-Phe)-Ser-Leu and removing radical and the pseudo-peptide of antithrombotic double activity; Compound method and they that the invention still further relates to them as the inhibitor of removing radical, suppress the application of vasodilator and pharmaceutical preparations having antithrombotic activity, belong to biomedicine field.
Background technology
The compound that contains the pyrocatechol structure has oxidation resistant ability, can remove radical.And interior free yl too much accumulation can initiation various diseases, the for example generation of cardiovascular and cerebrovascular diseases, inflammation, aging, sacred disease etc.NO can vasodilator, exists as free-radical scavengers, can suppress its vasodilator effect.Radical and hematoblastic gathering also have relation, and superoxide radical can promote hematoblastic gathering.The flavonoid compound that contains the pyrocatechol structure has the effect of removing radical, and then suppresses hematoblastic gathering.So design-series contains the pseudo-peptide of pyrocatechol structure, the effect of radical and anticoagulant is removed in performance.
Summary of the invention
One of the object of the invention provide one type water-soluble good, that biological half-life is long, remove interior free yl and the pseudo-peptide of anti thrombotic action arranged.
Two of the object of the invention provides a kind of method of synthetic above-mentioned pseudo-peptide;
The present invention seeks to realize through following technical scheme:
Amino acid-(3, the 4-dihydroxyl-Phe)-and the pseudo-peptide of Ser-Leu, its structural formula is shown in the general formula I:
Figure G2009100851525D00011
general formula I
Wherein, AA is selected from hydrogen (H), glycine residue (Gly), alanine residue (Ala), Xie Ansuan residue (Val); Leucine residue (Leu), Isoleucine residue (Ile), phenylalanine residue (Phe), tyrosine residues (Tyr); Tryptophan residue (Trp), serine residue (Ser), threonine residues (Thr), proline residue (Pro); Glutamine residue (Gln), lysine residue (Lys), histidine residues (His), asparagicacid residue (Asp) or L-glutamic acid (Glu) residue; Wherein, described amino acid or 3,4-dihydroxyl-Phe is left-handed.
Another object of the present invention provide a kind of synthetic above-mentioned amino acid-(3, the method for 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu;
A kind of synthetic above-mentioned amino acid-(3, the method for 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu comprises:
(1) synthetic protection (3,4-dihydroxyl-Phe)-Ser-Leu;
(2) with glycocoll (Gly), L-Ala (Ala), Xie Ansuan (Val), leucine (Leu), Isoleucine (Ile); Phenylalanine(Phe) (Phe), tyrosine (Tyr), tryptophane (Trp), Serine (Ser), Threonine (Thr); Proline(Pro) (Pro), Stimulina (Gln), Methionin (Lys), Histidine (His); Aspartic acid (Asp) or L-glutamic acid (Glu) respectively with protection base protection (3,4-dihydroxyl-Phe)-Ser-Leu condensation is sloughed the protection base, promptly gets.
The present invention has combined following understanding or foundation to accomplish technique scheme.Radical level rising in vivo can cause the generation such as diseases such as tumor disease, autoimmunization obstacle, aging, rheumatoid arthritis, cardiovascular disorder and nerve move back, and inhibitor can be removed radical, keeps the normal physiological function of human body.A lot of natural compoundss all possess the pyrocatechol structure, are the excellent antioxidation agent.Flavonoid compound is exactly one type of inhibitor that contains the pyrocatechol structure, can effectively remove radical, and the activity of its platelet aggregation-against of experiment proof is arranged.And 3,4-dihydroxyl-Phe contains the pyrocatechol structure, has the radical of removing ability; Add its structure and amino acids seemingly, can be used as amino acid analogue and be condensed in the small-molecular peptides, bring into play the activity that it removes radical on the one hand; In the protection of its aminoterminal and carboxyl terminal, whole macromolecule water-solubility is increased on the other hand, be difficult for 3 in the compound; 4-dihydroxyl-Phe part metabolism has improved bioavailability.
The inventor is based on above-mentioned cognition; 16 seed amino acids and (3; The ammonia end condensation of the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu makes the molecule that makes obtain four kinds of performances, promptly depend on peptide good water-solubility, depend on 3; The oxidation-resistance of the pyrocatechol structure in 4-dihydroxyl-Phe structure and the ability of removing radical ability and platelet aggregation-against and depend on AA and the Ser-Leu dipeptides to 3, the provide protection of 4-dihydroxyl-Phe structure.So, (3, the molecule that the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu and 16 seed amino acid condensations make just becomes water-soluble good, stable performance removing radical and antithrombotic reagent in vivo.
The evaluation that forms on the model at rat suppository shows that free-radical scavengers of the present invention has the excellent oral antithrombotic acitivity, can be used as pharmaceutical preparations having antithrombotic activity and uses; The clearance test result that ESR (ESR spectrum) method is measured radical shows that the pseudo-peptide of the present invention has the ability of outstanding removing radical, can be used as free-radical scavengers; Suppress rat chest aorta arterial ring diastole experiment, show that the pseudo-peptide of the present invention has the vasodilative activity of outstanding inhibition.
Another purpose of the present invention provides the pharmaceutical composition of the pseudo-peptide compounds of a kind of the present invention of containing, and the pseudo-peptide compounds of the present invention that this pharmaceutical composition is gone up effective dose by treatment is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the The compounds of this invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the pseudo-peptide compounds of the present invention of preferred 10-60% weight.
Description of drawings
The synthetic route chart of the pseudo-peptide of Fig. 1 the present invention.I) DCC, HOBt, NMM; Ii) hydrogenchloride/ethyl acetate solution (4N); Iii) 10% palladium carbon and hydrogen (0.02Mba). AA=glycocoll (Gly) wherein, L-Ala (Ala), Xie Ansuan (Val), leucine (Leu); Isoleucine (Ile), phenylalanine(Phe) (Phe), tyrosine (Tyr), tryptophane (Trp); Serine (Ser), Threonine (Thr), proline(Pro) (Pro), Stimulina (Gln); Methionin (Lys), Histidine (His), aspartic acid (Asp), L-glutamic acid (Glu) residue.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 1 (3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4q)
1) preparation of Boc-Ser-Leu-OBzl
4.00g (10.18mmol) Leu-OBzl, 1.90g (9.25mmol) Boc-Ser and 1.44g (10.69mmol) HOBt are placed 100mL eggplant bottle; Add 50mLTHF; Splash into about 20 N methylmorpholines under the condition of ice bath; Treat the solution clarification, drip the solution that the anhydrous THF of 2.28g (11.12mmol) DCC and 15mL constitutes.In the solution that obtains, splash into about 20 adjust pHs 8～9 of NMM again.Reaction mixture stirs after 10 minutes for 0 ℃, removes ice bath, suction filtration after reacting 4 hours under the room temperature, and filtrate decompression is concentrated into dried.The resistates that obtains with the 70mL acetic acid ethyl dissolution, place the 100mL separating funnel, wash (20mL * 3), saturated sodium-chloride water solution with 5% sodium bicarbonate aqueous solution successively and wash (20mL * 3), 5% aqueous potassium hydrogen sulfate and wash (20mL * 3), saturated sodium-chloride water solution and wash that (20mL * 3), 5% sodium bicarbonate aqueous solution are washed (20mL * 3), saturated sodium-chloride water solution is washed (20mL * 3).Ethyl acetate layer concentrates the oily matter that obtains and, wears away and obtain 3.62g (96.02%) title compound after immersion for some time with sherwood oil with anhydrous sodium sulfate drying, filtration, filtrate decompression, be colorless solid.ESI +-MS(m/e)409[M+H] +.
2) preparation of HClSer-Leu-OBzl
1gBoc-Ser-Leu-OBzl (2.45mmol) is placed 50mL eggplant bottle, with it dissolving, drip the about 5mL of 4N HCl/EtOAc under the condition of ice bath, dropwise and add a cover drying tube, remove ice bath, make to react under the room temperature and carry out with about 6mL anhydrous diethyl ether.After about ten minutes, observe reaction solution and separate out white solid, promptly reaction solution becomes muddiness by clarification, and afterreaction finished in 1.5 hours.In reaction solution, add about 10mL anhydrous diethyl ether, be evaporated to dried.Add anhydrous diethyl ether again and stir, leave standstill, the supernatant that inclines, repeatable operation 3 times, the deposition decompressing and extracting obtains 0.80g (95.24%) title compound, is colorless solid.ESI +-MS(m/e)309[M+H] +
3) Boc-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (1)
(3,4-dihydroxyl-Phe)-OH gets 4.11g (93%) title compound, is faint yellow solid by 3.44g (9.99mmol) Ser-Leu-OBzl and 2.70g (9.08mmol) Boc-according to the preparation method of Boc-Ser-Leu-OBzl.Mp 130-132 ℃; ESI +-MS (m/e) 588 [M+H] +[α] D 20=-31.48 (c=0.115, methyl alcohol).
4) HClH-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (2)
Preparing method according to HClSer-Leu-OBzl gets 1.65g (92.43%) title compound by 2g (3.41mmol) 1, is colorless solid.ESI +-MS(m/e)488[M+H] +.
5) (3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4q)
89mg (17.0 μ mol) 2 is placed 25mL eggplant bottle, with it dissolving, adds 10% palladium carbon 10mg with 8mL methyl alcohol, to be mixed evenly after, with threeway reaction flask, vacuum pump, hydrogen bag are linked to each other, vacuumize with vacuum pump earlier, feed H again 2, repeatable operation 3～4 times makes to be full of H in the reaction flask 2, about 8 hours of room temperature reaction, with the reaction solution filtration under diminished pressure, filtrate decompression concentrates, and ether is separated out solid after soaking for some time, the supernatant that inclines, the deposition vacuum is removed ether and is obtained about 65mg (96.31%) title compound, is 150-151 ℃ of colorless solid Mp; ESI -MS (m/e) 396 [M-H] -[α] D 20=-5.40 (c=0.115, methyl alcohol).
Embodiment 2Gly-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4a)
1) Boc-Gly-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3a)
Preparing method according to Boc-Ser-Leu-OBzl gets 1.73g (93.61%) title compound by 1.5g (2.865mmol) 2,0.55g (3.15mmol) Boc-Gly, is 107-108 ℃ of colorless solid Mp; ESI +-MS (m/e) 646 [M+H] +, 668 [M+Na] +[α] D 20=-30.43 (c=0.100, methyl alcohol).
2) Gly-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4a)
100mg (15.5 μ mol) 3a is placed 25mL eggplant bottle, with it dissolving, adds 10% palladium carbon 10mg with 8mL methyl alcohol, to be mixed evenly after, with threeway reaction flask is vacuumized, feed H again 2, repeatable operation 3～4 times makes to be full of H in the reaction flask 2, about 8 hours of room temperature reaction, with the reaction solution filtration under diminished pressure, filtrate decompression concentrates, and ether is separated out solid after soaking for some time, the supernatant that inclines, the deposition vacuum is removed ether and is obtained colorless solid.Under the condition of ice bath, in this pressed powder, slowly drip 4mL 4N HCl/ ETHYLE ACETATE, add a cover drying tube, remove ice bath, the suspendible reaction is 2 hours under the room temperature.After reaction finishes, add the 8mL anhydrous diethyl ether, concentrating under reduced pressure obtains solid and soaks with anhydrous diethyl ether, the supernatant that inclines, and repeatable operation 3 times, the solid vacuum that obtains are removed ether and are obtained about 67mg (94.97%) title compound, are 162-164 ℃ of colorless solid Mp; ESI -MS (m/e) 454 [M-H] -[α] D 20=-12.09 (c=0.115, methyl alcohol).
Embodiment 3Ala-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4b)
1) Boc-Ala-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3b)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.70g (90.17%) title compound by 0.60g (3.15mmol) Boc-Ala, is colorless solid.Mp 107-108 ℃; ESI +-MS (m/e) 658 [M+H] +[α] D 20=-31.48 (c=0.115, methyl alcohol).
2) Ala-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4b)
According to the preparation method of 4a, make 68mg (95.61%) title compound by 100mg (15.2 μ mol) 3b, be colorless solid.Mp 163-165 ℃; ESI --MS (m/e) 467 [M-H] -[α] D 20=-4.25 (c=0.105, methyl alcohol).
Embodiment 4Val-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4c)
1) Boc-Val-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3c)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.78g (90.56%) title compound by 0.68g (3.15mmol) Boc-Val, is colorless solid.Mp 84-86 ℃; ESI +-MS (m/e) 687 [M+H] +, 709 [M+Na] +, 725 [M+K] +[α] D 20=-41.44 ° (c=0.130, methyl alcohol).
2) Val-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4c)
Preparing method according to 4a makes 66mg (91.28%) title compound by 100mg (14.9 μ mol) 3c, is colorless solid.Mp 155-157 ℃; ESI --MS (m/e) 495 [M-H] -[α] D 20=17.20 (c=0.125, methyl alcohol).
Embodiment 5Leu-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4d)
1) Boc-Leu-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3d)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.82g (90.74%) title compound by 0.73g (3.15mmol) Boc-Leu, is colorless solid.Mp 132-134 ℃; ESI +-MS (m/e) 701 [M+H] +[α] D 20=-42.77 (c=0.135, methyl alcohol).
2) Leu-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4d)
Preparing method according to 4a makes 67mg (91.96%) title compound by 100mg (14.3 μ mol) 3d, is colorless solid.Mp 145-147 ℃; ESI --MS (m/e) 509 [M-H] -[α] D 20=-16.38 ° (c=0.105, methyl alcohol).
Embodiment 6Ile-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4e)
1) Boc-Ile-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3e)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.78g (88.75%) title compound by 0.73g (3.15mmol) Boc-Ile, is colorless solid.Mp 68-70 ℃; ESI +-MS (m/e) 701 [M+H] +, 723 [M+Na] +, 739 [M+K] +[α] D 20=-38.06 (c=0.120, methyl alcohol).
2) Ile-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4e)
Preparing method according to 4a makes 64mg (87.84%) title compound by 100mg (14.3 μ mol) 3e, is colorless solid.Mp 148-149 ℃; ESI --MS (m/e) 509 [M-H] -[α] D 20=7.30 ° (c=0.115, methyl alcohol).
Embodiment 7Phe-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4f)
1) Boc-Phe-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3f)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.92g (91.29%) title compound by 0.84g (3.15mmol) Boc-Phe, is colorless solid.Mp 173-175 ℃; ESI +-MS (m/e) 735 [M+H] +[α] D 20=-35.91 (c=0.110, methyl alcohol)
2) Phe-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4f)
According to the preparation method of 4a, make 70mg (94.45%) target compound by 100mg (15.2 μ mol) 3f, be colorless solid.Mp 143-145 ℃; ESI --MS (m/e) 543 [M-H] -[α] D 20=-9.57 (c=0.115, methyl alcohol).
Embodiment 8Tyr-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4g)
1) Boc-Tyr-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3g)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.95g (90.74%) title compound by 0.89g (3.15mmol) Boc-Tyr, is colorless solid.Mp 153-154 ℃; ESI +-MS (m/e) 751 [M+H] +, 773 [M+Na] +[α] D 20=-35.19 (c=0.115, methyl alcohol).
2) Tyr-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4g)
According to the preparation method of 4a, make 69mg (92.41%) title compound by 100mg (13.3 μ mol) 3g, be colorless solid.Mp 151-153 ℃; ESI --MS (m/e) 559 [M-H] -[α] D 20=-23.01 (c=0.125, methyl alcohol).
Embodiment 9Trp-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4h)
1) Boc-Trp-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3h)
By making 2.00g (90.30%) title compound, be colorless solid according to the preparation method of Boc-Ser-Leu-OBzl by 0.96g (3.15mmol) Boc-Trp.Mp 160-162 ℃; ESI +-MS (m/e) 774 [M+H] +[α] D 20=-37.07 (c=0.100, methyl alcohol).
2) Trp-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4h)
According to the preparation method of 4a, make 70mg (92.81%) title compound by 100mg (12.9 μ mol) 3h, be colorless solid.Mp 169-171 ℃; ESI --MS (m/e) 582 [M-H] -[α] D 20=-10.43 (c=0.100, methyl alcohol).
Embodiment 10Ser-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4i)
1) Boc-Ser-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3i)
By making 1.80g (93.20%) title compound, be colorless solid according to the preparation method of Boc-Ser-Leu-OBzl by 0.65g (3.15mmol) Boc-Ser.Mp 93-95 ℃; ESI +-MS (m/e) 675 [M+H] +[α] D 20=-37.16 (c=0.115, methyl alcohol).
2) Ser-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4i)
According to the preparation method of 4a, make 66mg (91.91%) title compound by 100mg (14.8 μ mol) 3i, be colorless solid.Mp 149-151 ℃; ESI --MS (m/e) 483 [M-H] -[α] D 20=-16.97 (c=0.110, methyl alcohol).
Embodiment 11T-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4j)
1) Boc-Thr-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3j)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.83g (92.83%) title compound by 0.69g (3.15mmol) Boc-Thr, is colorless solid.Mp 123-125 ℃; ESI +-MS (m/e) 689 [M+H] +[α] D 20=-37.90 (c=0.100, methyl alcohol).
2) Thr-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4j)
According to the preparation method of 4a, make 67mg (92.56%) title compound by 100mg (14.5 μ mol) 3j, be colorless solid.Mp 148-150 ℃; ESI --MS (m/e) 497 [M-H] -[α] D 20=-10.18 (c=0.110, methyl alcohol).
Embodiment 12P-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4k)
1) Boc-Pro-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3k)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.78g (90.82%) title compound by 0.68g (3.15mmol) Boc-Pro, is colorless solid.Mp 81-83 ℃; ESI +-MS (m/e) 685 [M+H] +[α] D 20=-27.96 (c=0.095, methyl alcohol).
2) Pro-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4k)
According to the preparation method of 4a, make 69mg (95.54%) title compound by 100mg (14.6 μ mol) 3k, be colorless solid.Mp 135-137 ℃; ESI --MS (m/e) 493 [M-H] -[α] D 20=-44.09 (c=0.110, methyl alcohol).
Embodiment 13Gln-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4l)
1) Boc-Gln-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3l)
Preparing method according to Boc-Ser-Leu-OBzl makes 1.87g (91.28%) title compound by 0.78g (3.15mmol) Boc-Gln, is colorless solid.Mp 168-169 ℃; ESI +-MS (m/e) 716 [M+H] +[α] D 20=-37.68 (c=0.105, methyl alcohol).
2) Gln-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4l)
According to the preparation method of 4a, make 67mg (91.25%) title compound by 100mg (14.00 μ mol) 3l, be colorless solid.Mp 150-152 ℃; ESI --MS (m/e) 524 [M-H] -[α] D 20=-1.26 (c=0.095, methyl alcohol).
Embodiment 14Lys-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4m)
1) Boc-Lys (Boc)-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3m)
Preparing method according to Boc-Ser-Leu-OBzl makes 2.07g (88.64%) title compound by 1.09g (3.15mmol) Boc-Lys (Boc), is colorless solid.Mp 106-108 ℃; ESI +-MS (m/e) 816 [M+H] +[α] D 20=-31.48 (c=0.115, methyl alcohol).
2) Lys-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu
According to the preparation method of 4a, make 60mg (93.14%) title compound by 100mg (12.3 μ mol) 3m, be colorless solid.Mp 162-163 ℃; ESI --MS (m/e) 524 [M-H] -[α] D 20=-21.24 (c=0.110, methyl alcohol).
Embodiment 15His-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4n)
1) Boc-His (Boc)-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3n)
Preparing method according to Boc-Ser-Leu-OBzl makes 2.18g (92.33%) title compound by 1.12g (3.15mmol) Boc-His (Boc), is colorless solid.Mp 115-117 ℃; ESI +-MS (m/e) 825 [M+H] +[α] D 20=-26.79 (c=0.105, methyl alcohol).
2) His-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4n)
According to the preparation method of 4a, make 59mg (91.04%) title compound by 100mg (12.1 μ mol) 3n, be colorless solid.Mp 151-153 ℃; ESI --MS (m/e) 533 [M-H] -[α] D 20=-16.23 (c=0.115, methyl alcohol).
Embodiment 16Asp-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4o)
1) Boc-Asp (OBzl)-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3o)
Preparing method according to Boc-Ser-Leu-OBzl makes 2.06g (89.20%) title compound by 1.06g (3.15mmol) Boc-Asp (OBzl), is colorless solid.Mp 136-138 ℃; ESI +-MS (m/e) 807 [M+H] +, 829 [M+Na] +[α] D 20=-35.23 (c=0.095, methyl alcohol).
2) Asp-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4o)
According to the preparation method of 4a, make 62mg (95.91%) title compound by 100mg (12.6 μ mol) 3o, be colorless solid.Mp 147-149 ℃; ESI --MS (m/e) 511 [M-H] -[α] D 20=21.68 (c=0.125, methyl alcohol).
Embodiment 17Glu-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4p)
1) Boc-Glu (OBzl)-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu-OBzl (3p)
Preparing method according to Boc-Ser-Leu-OBzl makes 2.11g (92.98%) title compound by 1.02g (3.15mmol) Boc-Glu (OBzl), is colorless solid.Mp 67-68 ℃; ESI +-MS (m/e) 793 [M+H] +[α] D 20=-38.06 (c=0.120, methyl alcohol).
2) Glu-(3, the preparation of 4-dihydroxyl-Phe)-Ser-Leu (4p)
According to the preparation method of 4a, make 63mg (96.54%) title compound by 100mg (12.4 μ mol) 3p, be colorless solid.Mp 133-135 ℃; ESI --MS (m/e) 525 [M-H] -[α] D 20=-5.64 (c=0.115, methyl alcohol).
The antithrombotic acitivity test of Test Example 1 The compounds of this invention oral administration
1) rat operation and apparatus
(male, 220～230g) press 10nmolkg to the SD rat -1Oral dose compound of the present invention is pressed 1200mg-kg behind the 30min -1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates RCCA, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, and preparation is in the distal end intubate.
2) intubate
Intubate is the polyethylene rubber tube that silylanization is crossed, and divides three sections, and the stage casing is a polyethylene rubber tube, long 60.0mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, and pipe range 100.0mm, the end that internal diameter 1.0mm, external diameter 2.0mm should manage pull into point pipe (being used to insert rat carotid artery or vein), and external diameter is 1.0mm.Be respectively charged into the long black surgical thread of 6cm in the clean penicillium mould bottle with the number of finishing, weigh; Take out silk thread then, put into the thicker intubate in stage casing of ready intubate according to numbering.
Open rat right side bulldog clamp, fill with heparin-saline solution (50IUkg in will managing through sharp pipe end with syringe -1), then the arterial end of intubate is inserted the rat right carotid, the heparin of calculated amount is slowly injected in the rat body.
3) give drug solns
Medicine: saline water (3mlkg -1, orally give), the physiological salt soln of Asprin (dosage is 30mg/kg, gives by the method vein of Test Example 1), the physiological salt soln of The compounds of this invention (dosage is 10nmol/kg, orally give).
4) thrombus is weighed
Timing is cut off venous incubation after beginning 15 minutes, stops circulation, carefully takes out silk thread with the ophthalmology tweezer, on filter paper, dips in drop of blood gently, puts into the penicillium mould bottle of weighing in advance, accurately weighs and record.Calculate the weight in wet base of thrombus.Each medicine repeats 11 administrations.The wet weight of thrombus of each group of statistics (X ± SD), and do the t check.
5) result
The oral administration administration, compound of the present invention all has good anti-thrombus activity.The result lists table 2 in.
The antithrombotic acitivity of table 1. compound oral administration of the present invention administration
Figure G2009100851525D00111
Figure G2009100851525D00121
N=10; NS=saline water; The ASP=Frosst); A. compare P＜0.01 with saline water.
The dose-effect relationship of Test Example 2 The compounds of this invention 4i oral administrations
1) rat operation and apparatus
(male, 220～230g) press 10nmolkg to the SD rat -1, 1nmolkg -1And 0.1nmolkg -1Oral dose 4i presses 1200mg-kg behind the 30min -1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates RCCA, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, and preparation is in the distal end intubate.
2) intubate
Intubate is the polyethylene rubber tube that silylanization is crossed, and divides three sections, and the stage casing is a polyethylene rubber tube, long 60.0mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, and pipe range 100.0mm, the end that internal diameter 1.0mm, external diameter 2.0mm should manage pull into point pipe (being used to insert rat carotid artery or vein), and external diameter is 1.0mm.Be respectively charged into the long black surgical thread of 6cm in the clean penicillium mould bottle with the number of finishing, weigh; Take out silk thread then, put into the thicker intubate in stage casing of ready intubate according to numbering.
Open rat right side bulldog clamp, fill with heparin-saline solution (50IUkg in will managing through sharp pipe end with syringe -1), then the arterial end of intubate is inserted the rat right carotid, the heparin of calculated amount is slowly injected in the rat body.
3) give drug solns
Medicine: 4i is pressed 10nmolkg -1, 1nmolkg -1And 0.1nmolkg -1Dosage configuration physiological salt soln, for oral administration.
4) thrombus is weighed
Timing is cut off venous incubation after beginning 15 minutes, stops circulation, carefully takes out silk thread with the ophthalmology tweezer, on filter paper, dips in drop of blood gently, puts into the penicillium mould bottle of weighing in advance, accurately weighs and record.Calculate the weight in wet base of thrombus.Each medicine repeats 11 administrations.The wet weight of thrombus of each group of statistics (X ± SD), and do the t check.
5) result
The oral administration administration is at 10nmolkg -1, 1nmolkg -1, 0.1nmolkg -1Under the dosage, 4i relies on ground performance anti thrombotic action.The result lists table 3 in.
The dose-effect relationship of table 2 orally give 4i
Dosage Wet weight of thrombus (
Figure G2009100851525D00122
±SD?mg)
10nmol/Kg/3ml 8.41±4.12
1nmol/Kg/3ml 19.75±5.46
0.1nmol/Kg/3ml 31.48±4.41
Test Example 3 compounds of the present invention detect with the ESR method and remove the NO radical
A. the preparation of solution:
1. the preparation of MGD solution: get 7.325mg MGD and be dissolved in the 1mL pure water, making concentration is the MGD solution of 25mM;
2. FeSO 4The preparation of solution: get FeSO 47H 2O 3.475mg is dissolved in the 1mL pure water, makes the FeSO that concentration is 12.5mM 4Solution;
3. the preparation of SNAP solution: SNAP 25mg is dissolved in the 1mL pure water, obtains the mother liquor that concentration is 110 μ M (green), get 10 μ L mother liquors, be diluted to 1mL, making concentration is the SNAP solution of 1 μ M;
4. the preparation of sample solution: get about 1mg testing sample and be dissolved in the 1mL pure water, obtain the sample solution that concentration is 1mM.
The b.ESR parameter setting:
Table 3ESR parameter setting
Figure G2009100851525D00131
Figure G2009100851525D00141
C. data determination:
(1) will be 1. and 2. 1: 1 by volume uniform mixing, make brown [(MGD) 2-Fe 2+] complexing 5.;
(2) successively will be 5., 4., 3. equal proportion is mixed, and wherein, 4. blank control group replaces with the pure water of equal volume;
(3) with mixed solution after hatching 30min under 37 ℃, draw each mixed solution with the 2mm silica tube, place the resonator cavity of ESR spectrometer to measure.
D. to the percentile calculating of the removing of NO radical:
The pH value (peak intensity) at first peak in three main peaks in the record spectrogram, blank control group (pure water group) is designated as PH BLANK, the testing compound group is PH Drug, according to formula " the removing percentage=(PH of radical BLANK-PH Drug)/PH BLANK* 100% " calculates the removing percentage (n=3) of testing compound to the NO radical.
E. experimental result: The compounds of this invention all has the ability of good removing NO radical
Table 4ESR measures compound to the removing percentage of NO radical (X ± SD)
Figure G2009100851525D00142
Figure G2009100851525D00151
Wherein, compound concentrations is 10 -3Mo1/L (n=3); Statistical method: t method of inspection
aThe expression compound is to the removing percentage and 3 of NO radical, and 4-dihydroxyl-Phe compares, P＜0.05; bThe expression compound is to the removing percentage and 3 of NO radical, and 4-dihydroxyl-Phe compares, P＜0.01; cThe expression compound is compared P＜0.05 with 4q to the removing percentage of NO radical; dThe expression compound is compared P＜0.01 with 4q to the removing percentage of NO radical.
Test Example 4 compounds of the present invention suppress rat chest aorta ring diastole experiment
1, experiment is prepared:
A. instruments: eye scissors (directly), ophthalmology tweezer (directly), ophthalmology tweezer (bending), 16cm operating scissors, watch-glass
B. instrument: LMS-2B type two road physiographs (Chengdu Instruement Factory);
Muscle tone transverter (Beijing newly navigate industrial scientific & trading Co., Ltd.);
THS-15 type numerical control super constant temperature trough (the permanent instrument plant in sky, Ningbo).
C. reagent: NE, Ach (Shanghai reagent three factories)
NaCl, CaCl 2, NaHCO 3, NaH 2PO 4, MgC 126H 2O, EDTA-2Na (Beijing Chemical Plant)
KCl (Beijing Yili Fine Chemicals Co., Ltd.)
Dextrose anhydrous (Chemical Reagent Co., Ltd., Sinopharm Group)
A. laboratory animal: healthy SD male rat (laboratory animal portion of the Capital University of Medical Sciences, about 200g)
2, experimental procedure:
The preparation of a.Krebs-Henseleit (K-H) liquid:
1. salt storing solution: NaCl 95.5g+KCl 5.5g+MgCl 26H 2O 3.3g+CaCl 23.7g with 1000mL H 2O mixes, ultrasonic dissolution.
2. sodium dihydrogen phosphate: NaH 2PO 41.56g with 100mL H 2O mixes, ultrasonic dissolution.
3. disodium ethylene diamine tetra-acetic acid solution: EDTA-2Na 1.12g and 100mLH 2O mixes, ultrasonic dissolution.
4. K-H liquid: NaHCO 35.04g+ dextrose anhydrous 6.00g+1500mL H 2O+36mL is 3. 1. solution+1236mLH of solution+225mL of solution+3mL 2. 2O
Wherein, H 2O is a zero(ppm) water, and 3. 2. 1. solution all will keep in Dark Place; 4. must prepare in order, per step guarantees that solid dissolves fully, and will prepare the same day, and used the same day.Every kind of solution all will guarantee to dissolve clear fully.
B. the preparation of rat chest aorta ring:
Male SD rat disconnected neck in the 200g left and right sides is put to death, cuts off breastbone, exposes heart, is picked up heart, takes off thoracic aorta along thoracic vertebrae with tweezers.Immediately in the K-H damping fluid with thoracic aorta and other separate tissue, and keep blood vessel endothelium complete.It is for use in the K-H damping fluid, to be cut into several sections wide vascular circles of 2mm to thoracic aorta.
Go up the counterweight that hangs a 1g, the lattice number that record pointer moves at muscle tone transverter (range 5g).Hang on thoracic aortic ring on the muscle tone transverter, immerse and continue logical oxygen (95%O 2+ 5%CO 2) bath in, the tension force of regulating thoracic aortic ring makes the mobile lattice number of pointer identical with the lattice number that extension 1g counterweight moves.
C. target compound 4a-q suppresses the active mensuration of vascular strip Ach diastole
After the baseline of treating the 1g pretension is walked to put down, in bath, add NE (0.2mg/mL, 10 μ L, final concentration 0.1 μ mol/L); Vascular strip shrinks, and after stablizing, adds the aqueous solution (1mg/mL, the 15 μ L of target compound 4a-q; Final concentration 1 μ mol/L) and Ach (1mg/mL, 15 μ L, final concentration 5 * 10 -5Mol/L) diastole is steadily write down the result in the back.With the K-H damping fluid with aorta washing-round 3-5 time.Repeated experiments.
3, suppressing the diastole percentage calculates:
The diastole lattice that Ach causes are counted L Ach, the diastole lattice that adding testing compound and Ach cause are counted L Drug, the contraction lattice that NE causes are counted L NE" suppress diastole percentage=(L according to formula Ach-L Drug)/L NE* 100% " calculates the inhibition percentage (n=3) of the vascular strip diastole that testing compound causes Ach.
4, experimental result: experimental result shows that The compounds of this invention all has the vasodilative activity of good restraining
The vasodilative inhibition percentage that table 5 The compounds of this invention causes Ach
Wherein, the final concentration of compound is 10 -6Mol/L (n=3); Statistical method: t method of inspection
aThe vasodilative inhibition percentage and 3 that the expression compound causes Ach, 4-dihydroxyl-Phe compares, P＜0.01; bThe vasodilative inhibition percentage that the expression compound causes Ach is with (3,4-dihydroxyl-Phe)-Ser-Leu compares P＜0.01.

Claims (8)

  1. Amino acid-(3, the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu, its structural formula is shown in the general formula I:
    Figure FSB00000838993800011
    general formula I
    Wherein, AA is hydrogen (H), glycine residue (Gly), alanine residue (Ala), Xie Ansuan residue (Val); Leucine residue (Leu), Isoleucine residue (Ile), phenylalanine residue (Phe), tyrosine residues (Tyr); Tryptophan residue (Trp), serine residue (Ser), threonine residues (Thr), proline residue (Pro); Glutamine residue (Gln), lysine residue (Lys), histidine residues (His), asparagicacid residue (Asp) or L-glutamic acid (Glu) residue.
  2. The said amino acid of synthetic claim 1-(3, the method for 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu may further comprise the steps:
    (1) synthetic protection (3,4-dihydroxyl-Phe)-Ser-Leu;
    (2) with glycocoll, L-Ala, Xie Ansuan, leucine, Isoleucine; Phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine; Proline(Pro), Stimulina, Methionin, Histidine; Aspartic acid or L-glutamic acid respectively with protection base protection (3,4-dihydroxyl-Phe)-Ser-Leu condensation is sloughed the protection base, promptly gets.
  3. 3. remove the radical pharmaceutical composition for one kind, it is characterized in that: go up by treatment or prevention that the described amino acid of claim 1 of significant quantity-(3, at least a and pharmaceutically acceptable carrier or auxiliary material in 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu are formed.
  4. 4. anti-angiogenic vasodilator compositions is characterized in that: gone up by treatment or prevention that the described amino acid of claim 1 of significant quantity-(3, at least a and pharmaceutically acceptable carrier or auxiliary material in 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu are formed.
  5. 5. antithrombotic pharmaceutical composition is characterized in that: gone up by treatment or prevention that the described amino acid of claim 1 of significant quantity-(3, at least a and pharmaceutically acceptable carrier or auxiliary material in 4-dihydroxyl-Phe)-pseudo-peptide of Ser-Leu are formed.
  6. 6. the described amino acid of claim 1-(3, the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu is removed the purposes in the radical medicine in preparation.
  7. The described amino acid of claim 1-(3, the purposes of the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu in the anti-angiogenic diastole medicine of preparation.
  8. 8. the described amino acid of claim 1-(3, the pseudo-peptide of 4-dihydroxyl-Phe)-Ser-Leu is in the purposes of preparation antithrombotic reagent.
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