CN101747410A - Aminoacyl tyrosyl tryptophan tripeptide with easing pain activity and preparation method and application thereof - Google Patents

Aminoacyl tyrosyl tryptophan tripeptide with easing pain activity and preparation method and application thereof Download PDF

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CN101747410A
CN101747410A CN200810227524A CN200810227524A CN101747410A CN 101747410 A CN101747410 A CN 101747410A CN 200810227524 A CN200810227524 A CN 200810227524A CN 200810227524 A CN200810227524 A CN 200810227524A CN 101747410 A CN101747410 A CN 101747410A
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tyrosyl
tryptophan
tertbutyloxycarbonyl
benzyl ester
residue
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CN101747410B (en
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彭师奇
赵明
谭栎
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Peking University
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Peking University
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Abstract

The invention discloses an aminoacyl tyrosyl tryptophan tripeptide with easing pain activity and a preparation method and the application thereof; the structural formula of the aminoacyl tyrosyl tryptophan tripeptide is AA-Tyr-Trp, wherein AA is chosen from aminopropionic acid, aspartic acid, glutamic acid, phenylalanine, glycin, histidine, isoleucine, lysine, aminocaproic acid, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan or tyrosine ; animal experiments show that the compound in the invention has good easing pain activity and is potential pain killer clinically.

Description

The aminoacyl tyrosyl tryptophan tripeptide of tool analgesic activities and preparation method and application
Technical field
The present invention relates to tripeptides, relate in particular to the aminoacyl tyrosyl tryptophan tripeptide and the preparation method of tool analgesic activities, the invention still further relates to the purposes of this aminoacyl tyrosyl tryptophan tripeptide in the preparation analgesic, belong to biomedicine field.
Background technology
That pain is not only numerous disease and close disease, and self be counted as a class disease.On the disease aspect, the quality of life that is caused by various pain descends and has involved the crowd of maximum.Because effectively analgesic agent often interrelates with dependency, has important value so invent the analgesic agent of new no dependence.The contriver chances on discovery in polypeptide research, the oligopeptides that contains tryptophane has analgesic activities usually.According to this clue, the present invention discloses a class aminoacyl tyrosyl tryptophan tripeptide analgesic agent.
Summary of the invention
One of purpose of the present invention provides the aminoacyl tyrosyl tryptophan tripeptide that a class has analgesic activities.
Two of purpose of the present invention provides a kind of method for preparing above-mentioned aminoacyl tyrosyl tryptophan tripeptide.
Three of purpose of the present invention provide a kind of can the analgesic pharmaceutical composition.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
One class has the aminoacyl tyrosyl tryptophan tripeptide of analgesic activities, and its structure is shown in the general formula I:
AA-Tyr-Trp?I
Wherein, AA is selected from alanine residue, asparagicacid residue, glutaminic acid residue, phenylalanine residue, glycine residue, histidine residues, Isoleucine residue, lysine residue, leucine residue, methionine residues, asparagine residue, proline residue, glutamine residue, arginine residues, serine residue, threonine residues, Xie Ansuan residue, tryptophan residue or tyrosine residues.
A kind ofly prepare above-mentioned method, comprising with aminoacyl tyrosyl tryptophan tripeptide of analgesic activities:
(1) with the tyrosine and the tryptophan benzyl ester coupling connection of tertbutyloxycarbonyl protection, synthesizes tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester;
(2) slough the tertbutyloxycarbonyl of tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester, obtain tyrosyl tryptophan benzyl ester;
(3) amino acid with tyrosyl tryptophan benzyl ester and tertbutyloxycarbonyl protection carries out the coupling connection, obtains t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester;
(4) with t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester hydrogenolysis debenzylation, obtain t-butoxycarbonyl amino acyl tyrosyl tryptophan;
(5) t-butoxycarbonyl amino acyl tyrosyl tryptophan is sloughed tertbutyloxycarbonyl, promptly get the aminoacyl tyrosyl tryptophan tripeptide of general formula I.
Wherein, preferred tyrosine of in the presence of dicyclohexyl carbonyl diimine, N-hydroxybenzotriazole, N-methylmorpholine and anhydrous tetrahydro furan, tertbutyloxycarbonyl being protected and tryptophan benzyl ester coupling connection in the step (1), synthetic tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester;
Preferably in hydrogenchloride/ethyl acetate solution, add tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester in the step (2), slough tertbutyloxycarbonyl, prepare tyrosyl tryptophan benzyl ester;
The preferred amino acid of in the presence of dicyclohexyl carbonyl diimine, N-hydroxybenzotriazole, N-methylmorpholine and anhydrous tetrahydro furan tyrosyl tryptophan benzyl ester and tertbutyloxycarbonyl being protected carries out coupling and joins in the step (3), obtains t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester; The amino acid of described tertbutyloxycarbonyl protection is preferably: the L-Ala of tertbutyloxycarbonyl protection, the aspartic acid list benzyl ester of tertbutyloxycarbonyl protection, the L-glutamic acid list benzyl ester of tertbutyloxycarbonyl protection, the phenylalanine of tertbutyloxycarbonyl protection, the glycine of tertbutyloxycarbonyl protection, the Histidine of tertbutyloxycarbonyl protection, the Isoleucine of tertbutyloxycarbonyl protection, the Methionin of the two tertbutyloxycarbonyls protection of tertbutyloxycarbonyl protection, the leucine of tertbutyloxycarbonyl protection, the methionine(Met) of tertbutyloxycarbonyl protection, the l-asparagine of tertbutyloxycarbonyl protection, the glutamine of tertbutyloxycarbonyl protection, the nitro arginine of tertbutyloxycarbonyl protection, the Serine of tertbutyloxycarbonyl protection, the Threonine of tertbutyloxycarbonyl protection, the Xie Ansuan of tertbutyloxycarbonyl protection, the tyrosine of the tryptophane of tertbutyloxycarbonyl protection or tertbutyloxycarbonyl protection;
In the step (4) preferably in the presence of palladium carbon with t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester hydrogenolysis debenzylation, prepare t-butoxycarbonyl amino acyl tyrosyl tryptophan;
In the step (5) preferably in hydrogenchloride/ethyl acetate solution t-butoxycarbonyl amino acyl tyrosyl tryptophan slough tertbutyloxycarbonyl, prepare the aminoacyl tyrosyl tryptophan tripeptide of general formula I.
Estimate the analgesic activities of The compounds of this invention on mouse whipping model, experimental result shows that compound of Formula I of the present invention has excellent analgesic activity, can be used as analgesic agent clinically and uses.On this basis, another purpose of the present invention provides a kind of medicinal compositions with analgesic activities, this medicinal compositions is gone up effective dose by treatment compound of Formula I of the present invention is with pharmaceutically acceptable excipient or assist and add agent and form, the The compounds of this invention that is about to significant quantity is with after pharmaceutically acceptable carrier or thinner cooperate, and by the formulation method of this area routine it is prepared into any one appropriate drug composition.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 The compounds of this invention of preferred 10-60% weight.
Description of drawings
Fig. 1 is the synthetic route chart of The compounds of this invention; (i) DCC, HOBt, NMM, THF; (ii) 4NHCl/EtOAc, 0 ℃, 30min; (iii) H 2/ Pd; Boc-AA is selected from L-Ala, aspartic acid list benzyl ester, L-glutamic acid list benzyl ester, phenylalanine, glycine, Histidine, the Isoleucine of tertbutyloxycarbonyl protection, Methionin, leucine, methionine(Met), l-asparagine, glutamine, nitro arginine, Serine, Threonine, Xie Ansuan, tryptophane or the tyrosine of two tertbutyloxycarbonyls protection.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall within the scope of protection of the present invention the details of technical solution of the present invention and form.
Embodiment 1 preparation Ala-Tyr-Trp (AYW)
1) preparation Boc-Tyr-Trp-OBzl
Room temperature is with Boc-Tyr-OH (20.00g, 71.17mmol) and HOBt (9.60g, 71.17mmol) be dissolved among the anhydrous THF, regulate the pH value to 8-9 with NMM under the ice bath, add with anhydrous THF dissolved DCC (14.66g, 71.17mmol), a large amount of dicyclohexylurea (DCU) (DCU) are separated out in 0 ℃ of stirring, after 15-20 minute, add H in the reaction solution 3PO 4Trp-OBzl (23.25g, 59.31mmol).The deicing of dropping back half an hour is bathed, stirring at room.Stop after 12 hours stirring, filter DCU, THF is spin-dried for as far as possible and makes yellow thick liquid.With using saturated sodium bicarbonate (200ml * 3) behind the 300ml acetic acid ethyl dissolution successively, saturated aqueous common salt (200ml * 2), 5%KHSO 4(200ml * 3), saturated aqueous common salt (200ml * 2) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure removes to desolvate and makes yellow thick liquid, adds the ether decompressing and extracting, and repeated multiple times makes faint yellow solid 36.473g (92%), is directly used in the next step without column chromatography for separation.ESI +-MS(m/e)558[M+H] +.
2) preparation HClTyr-Trp-OBzl
(10.00g 17.95mmol) is dissolved in anhydrous ethyl acetate, and 0 ℃ adds 100ml HCl/EtOAc (4N) down with Boc-Tyr-Trp-OBzl.0.5 a hour afterreaction finishes.Add sherwood oil, separate out a large amount of white powder solids.Filter, filter residue washs with ether (50ml * 3).Filtrate decompression is concentrated into dried, obtains 8.42g (95%) solid, drops into next step reaction.ESI +-MS(m/e)458[M+H] +.
3) preparation Boc-Ala-Tyr-Trp-OBzl
(403mg, 2.13mmol), (280mg 2.07mmol) is dissolved in the anhydrous dimethyl formamide (DMF) HOBt, under 0 ℃, regulates the pH value to 8-9 with NMM, adds that (483mg 2.13mmol), reacted 20 minutes with dry DMF dissolved DCC with Boc-Ala.Add then compound H ClTyr-Trp-OBzl (1.0g, 2.07mmol).0.5 a hour recession deicing is bathed stirring at room.Stop after 12 hours stirring, filter DCU, filtrate decompression concentrate yellow thick liquid.Residue is used saturated sodium bicarbonate (30ml * 3), saturated aqueous common salt (30ml * 2), 5%KHSO after with the 50ml acetic acid ethyl dissolution successively 4The aqueous solution (30ml * 3), saturated aqueous common salt (30ml * 2) washing, anhydrous sodium sulfate drying, filtration, filtrate decompression concentrate 973mg (80%) title compound, be yellow solid.ESI +-MS(m/e)629[M+H] +.
4) preparation Ala-Tyr-Trp
Boc-Ala-Tyr-Trp-OBzl (500mg) is dissolved in methyl alcohol, adds 15%Pd/C, logical hydrogen 48 hours, filtering palladium carbon, filtrate decompression concentrate.Residue adds 5ml 4N HCl/EtOAc, 0 ℃ and stirs 0.5 hour, filtration, filtrate decompression and concentrate.Residue washs (30ml * 3) with anhydrous diethyl ether.Obtain 240mg (79%) title compound, be colourless powder.Mp.122-123C；[α] D 25＝16.6(c＝1.23，CH 3OH)，ESI +-MS(m/e)439[M+H] +； 1HNMR(BHSC-300Hz，DMSO-d 6)，10.82(s，1H)，8.37(d，J＝8.0Hz，1H)，8.08(d，J＝7.5Hz，1H)，7.58(d，J＝7.5Hz，1H)，7.31(d，J＝7.5Hz，1H)，6.98(m，5H)，6.64(d，J＝8.4，2H)，3.55(q，J＝6.9Hz，J＝14.1Hz，1H)，3.10(m，4H)，2.09(s，1H)，1.20(d，J＝7.5Hz，3H)。
Embodiment 2 preparation Cys-Tyr-Trp (CYW)
1) preparation Boc-Asp (OBzl)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 870mg (79%) title compound, is colorless solid.ESI +-MS(m/e)763[M+H] +。
2) preparation Asp-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 100mg (60%) title compound, is pale yellow powder.Mp：189-191C；[α] D 25＝38.7(c＝1.08，CH 3OH)；ESI +-MS(m/e)483[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.83(s，1H)，8.35(d，J＝8.0Hz，1H)，7.98(d，J＝7.5Hz，1H)，7.56(d，J＝7.5Hz，1H)，7.32(d，J＝7.5Hz，1H)，7.19(s，1H)，7.03(m，4H)，6.62(d，J＝8.4Hz，2H)，4.34(m，2H)，3.72(m，1H)，3.22(m，4H)，2.77(d，J＝6.5Hz，2H)，2.09(s，1H)。
Embodiment 3 preparation Glu-Tyr-Trp (EYW)
1) preparation Boc-Glu (OBzl)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 760mg (79%) title compound, is colorless solid.ESI +-MS(m/e)777[M+H] +。
2) preparation Glu-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 242mg (88%) title compound, is pale yellow powder.Mp：154-155C；[α] D 25＝52.6(c＝1.21，CH 3OH)；ESI +-MS(m/e)497[M+H] +； 1HNMR(BHSC-300Hz，DMSO-d 6)，10.87(s，1H)，9.24(s，2H)，8.57(d，J＝8Hz，1H)，8.47(d，J＝7.5Hz，1H)，7.55(d，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.18(s，1H)，7.08(m，4H)，6.65(d，J＝8.4Hz，2H)，4.50(m，2H)，3.74(m，1H)，2.98(m，2H)，2.75(m，2H)，2.40(d，J＝7Hz，2H)，2.10(s，1H)，1.98(m，2H)。
Embodiment 4 preparation Phe-Tyr-Trp (FYW)
1) preparation Boc-Phe-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 580mg (47%) title compound, is colorless solid.ESI +-MS(m/e)727[M+Na] +。
2) preparation Phe-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 308mg (69%) title compound, is colourless powder.Mp：148-149C；[α] D 25＝1.3(c＝1.08，CH 3OH)；ESI +-MS(m/e)514.9[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，12.68(s，1H)，10.93(s，1H)，9.25(s，1H)，8.83(d，J＝8Hz，1H)，8.81(d，J＝7.5Hz，1H)，8.11(s，2H)，7.57(d，J＝7.5Hz，1H)，7.36(d，J＝7.5Hz，1H)，7.21(m，8H)，7.08(d，J＝8.4Hz，2H)，6.65(d，J＝8.4Hz，2H)，4.55(m，2H)，4.00(s，1H)，3.35(d，J＝7Hz，2H)，3.15(m，4H)。
Embodiment 5 preparation Gly-Tyr-Trp (GYW)
1) preparation Boc-Gly-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 990mg (88%) title compound, is colorless solid.ESI +-MS(m/e)634[M+Na] +。
2) preparation Gly-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 320mg (89%) title compound, is pale yellow powder.Mp：164-167?C；[α] D 25＝19.6(c＝1，CH 3OH)；ESI +-MS(m/e)425.3[M+H] +； 1HNMR(BHSC-300Hz，DMSO-d 6)，12.68(s，1H)，10.94(s，1H)，9.24(s，2H)，8.57(d，J＝8.7Hz，1H)，8.51(d，J＝7.5Hz，1H)，8.05(s，2H)，7.56(d，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.19(s，1H)，7.02(m，2H)，6.95(d，J＝8.4Hz，2H)，6.63(d，J＝8.4Hz，2H)，4.53(m，2H)，3.74(m，1H)，3.57(s，2H)，3.20(s，2H)，3.00(m，4H)，2.08(s，1H)。
Embodiment 6 preparation His-Tyr-Trp (HYW)
1) preparation Boc-His (Boc)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 433mg (26%) title compound, is colorless solid.ESI +-MS(m/e)795[M+H] +。
2) preparation His-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 430mg (80%) title compound, is pale yellow powder.Mp：118-120C；[α] D 25＝32.6(c＝1.04，CH 3OH)；ESI +-MS(m/e)505[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，11.01(s，1H)，9.40(s，1H)，8.99(d，J＝8Hz，1H)，8.93(s，1H)，8.31(d，J＝8.0Hz，1H)，7.58(d，J＝7.5Hz，1H)，7.41(s，1H)，7.32(d，J＝7.5Hz，1H)，7.16(s，1H)，7.14(d，J＝8.4Hz，2H)，7.04(t，J＝7.4Hz，1H)，6.97(t，J＝7.4Hz，1H)，6.64(d，J＝8.4Hz，2H)，4.42(m，2H)，3.30(m，1H)，3.07(m，1H)，2.95(m，2H)，2.78(m，2H)，2.08(s，1H)。
Embodiment 7 preparation Ile-Tyr-Trp (IYW)
1) preparation Boc-Ile-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 806mg (84%) title compound, is colorless solid.ESI +-MS(m/e)691[M+Na] +。
2) preparation Ile-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 290mg (88%) title compound, is pale yellow powder.Mp：168-169C；[α] D 25＝37.1(c＝0.97，CH 3OH)；ESI +-MS(m/e)481[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.88(s，1H)，9.24(s，1H)，8.53(d，J＝8.1Hz，1H)，8.43(d，J＝7.5Hz，1H)，7.53(d，J＝7.5Hz，1H)，7.34(d，J＝7.5Hz，1H)，7.17(s，1H)，7.08(t，J＝7.4Hz，1H)，7.06(d，J＝8.4Hz，2H)，6.97(t，J＝7.4Hz，1H)，6.64(d，J＝8.4Hz，2H)，4.50(m，2H)，3.17(m，2H)，2.92(m，2H)，2.68(m，1H)，2.10(s，1H)，1.09(m，2H)，0.89(d，J＝7.0Hz，3H)，0.8(t，J＝7.3Hz，3H)。
Embodiment 8 preparation Lys-Tyr-Trp (KYW)
1) preparation Boc-Lys (Z)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 640mg (40%) title compound, is colorless solid.ESI +-MS(m/e)787[M+H] +。
2) preparation Lys-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 280mg (79%) title compound, is pale yellow powder.Mp：131-132C；[α] D 25＝30.4(c＝1.24，CH 3OH)；ESI +-MS(m/e)496[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，12.68(s，1H)，10.96(s，1H)，9.25(s，1H)，8.73(d，J＝8.2Hz，1H)，8.46(d，J＝7.5Hz，1H)，8.23(s，2H)，8.03(s，2H)，7.54(d，J＝7.5Hz，1H)，7.36(d，J＝7.5Hz，1H)，7.23(s，1H)，7.09(t，J＝7.4Hz，1H)，7.06(d，J＝8.4Hz，2H)，7.00(t，J＝7.4Hz，1H)，6.65(d，J＝8.4Hz，2H)，4.50(m，2H)，3.45(m，1H)，3.15(m，2H)，2.90(m，2H)，2.09(s，3H)，1.75(m，2H)，1.56(m，2H)，1.47(m，2H)。
Embodiment 9 preparation Leu-Tyr-Trp (LYW)
1) preparation Boc-Leu-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 1002mg (83%) title compound, is colorless solid.ESI +-MS(m/e)671[M+H] +。
2) preparation Leu-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 190mg (50%) title compound, is pale yellow powder.Mp：147-149C；[α] D 25＝44.0(c＝1.07，CH 3OH)；ESI +-MS(m/e)481.3[M+H] +； 1HNMR(BHSC-300Hz，DMSO-d 6)，10.84(s，1H)，9.20(s，1H)，8.63(d，J＝8Hz，1H)，8.53(d，J＝7.5Hz，1H)，7.55(d，J＝7.5Hz，1H)，7.38(d，J＝7.5Hz，1H)，7.17(s，1H)，7.08(t，J＝7.4Hz，1H)，7.00(d，J＝8.4Hz，2H)，6.97(t，J＝7.4Hz，1H)，6.65(d，J＝8.4Hz，2H)，4.50(m，2H)，3.45(m，1H)，3.20(m，4H)，2.09(s，1H)，2.00(m，1H)，1.64(m，2H)。
Embodiment 10 preparation Met-Tyr-Trp (MYW)
1) preparation Boc-Met-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 780mg (80%) title compound, is colorless solid.ESI +-MS(m/e)711[M+Na] +。
2) preparation Met-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 480mg (80%) title compound, is pale yellow powder.Mp：151-152C；[α] D 25＝20.7(c＝1.05，CH 3OH)；ESI +-MS(m/e)499[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.78(s，1H)，9.21(s，2H)，8.03(d，J＝7.5Hz，2H)，7.55(d，J＝7.5Hz，1H)，7.32(d，J＝7.5Hz，1H)，7.13(s，1H)，7.04(t，J＝7.4Hz，1H)，6.97(m，3H)，6.61(d，J＝8.4Hz，2H)，4.45(m，1H)，4.35(m，1H)，3.56(m，1H)，3.23(m，2H)，3.06(m，2H)，2.39(t，J＝6.7Hz，2H)，2.05(m，2H)，1.98(s，3H)。
Embodiment 11 preparation Asn-Tyr-Trp (NYW)
1) preparation Boc-Asn-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 876mg (78%) title compound, is colorless solid.ESI +-MS(m/e)672[M+H] +。
2) preparation Asn-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 403mg (82%) title compound, is pale yellow powder.Mp：122-123C；[α] D 25＝22.4(c＝1.04，CH 3OH)；ESI +-MS(m/e)483[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.88(s，1H)，9.44(s，1H)，8.65(d，J＝8.0Hz，1H)，8.50(d，J＝7.5Hz，1H)，8.25(s，2H)，7.60(d，J＝7.5Hz，1H)，7.33(d，J＝7.5Hz，1H)，7.20(s，2H)，7.12(d，J＝8.4Hz，2H)，7.00(m，3H)，6.69(d，J＝8.4Hz，2H)，4.50(m，2H)，3.00(m，6H)，2.09(s，1H)。
Embodiment 12 preparation Pro-Tyr-Trp (PYW)
1) preparation Boc-Pro-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 1321mg (92%) title compound, is colorless solid.ESI +-MS(m/e)655[M+H] +。
2) preparation Pro-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 300mg (82%) title compound, is pale yellow powder.Mp：160-161C；[α] D 25＝-12.5(c＝1.12，CH 3OH)；ESI+-MS(m/e)466[M+H] +； 1HNMR(BHSC-300Hz，DMSO-d 6)，10.91(s，1H)，9.21(s，1H)，8.72(d，J＝8.1Hz，1H)，8.40(d，J＝7.8Hz，1H)，7.55(d，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.20(s，1H)，7.03(d，J＝8.4Hz，2H)，6.99(m，2H)，6.64(d，J＝8.4Hz，2H)，4.50(m，2H)，4(m，1H)，3.12(m，4H)，2.95(m，1H)，2.68(m，1H)，2.09(s，1H)，1.78(m，4H)。
Embodiment 13 preparation Gln-Tyr-Trp (QYW)
1) preparation Boc-Gln-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 730mg (72%) title compound, is colorless solid.ESI +-MS(m/e)706[M+Na] +。
2) preparation Gln-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 322mg (83%) title compound, is pale yellow powder.Mp：128-130C；[α] D 25＝31.5(c＝1.08，CH 3OH)；ESI +-MS(m/e)496[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.88(s，1H)，9.18(s，1H)，8.26(d，J＝7.7Hz，1H)，7.95(d，J＝8.8Hz，1H)，7.77(s，1H)，7.55(d，J＝7.5Hz，1H)，7.33(d，J＝7.5Hz，1H)，7.17(s，2H)，7.08(t，J＝7.4Hz，2H)，7.00(m，3H)，6.58(d，J＝8.4Hz，2H)，4.50(m，2H)，3.20(dd，J＝5.0Hz，J＝15.0Hz，2H)，3.09(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.92(dd，J＝5.0Hz，J＝15.0Hz，1H)，2.68(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.02(m，1H)。
Embodiment 14 preparation Arg-Tyr-Trp (RYW)
1) preparation Boc-Arg (NO 2)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 988mg (86%) title compound, is colorless solid.ESI +-MS(m/e)759[M+H] +。
2) preparation Arg-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 530mg (50%) title compound, is pale yellow powder.Mp：174-176C；[α] D 25＝45.2(c＝1.05，CH 3OH)；ESI +-MS(m/e)524[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.90(s，1H)，9.28(s，1H)，8.85(d，J＝8.1Hz，1H)，8.52(s，2H)，8.04(d，J＝7.5Hz，1H)，7.60(d，J＝7.5Hz，1H)，7.37(s，1H)，7.36(d，J＝7.5Hz，1H)，7.16(s，1H)，7.06(m，3H)，6.97(t，J＝7.4Hz，1H)，6.62(d，J＝8.4Hz，2H)，4.35(m，2H)，3.73(t，J＝6.0Hz，1H)，3.15(m，2H)，2.90(m，2H)，2.65(m，2H)，1.91(s，1H)，1.85(m，2H)，1.55(m，2H)。
Embodiment 15 preparation Ser-Tyr-Trp (SYW)
1) preparation Boc-Ser (OBzl)-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 654mg (34%) title compound, is colorless solid.ESI +-MS(m/e)645[M+H] +。
2) preparation Ser-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 290mg (85%) title compound, is no yellow powder.Mp：121-122C；[α] D 25＝9.8(c＝1.09，CH 3OH)；ESI +-MS(m/e)455[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，12.78(s，1H)，10.91(s，1H)，9.22(s，1H)，8.60(d，J＝8.1Hz，1H)，8.42(d，J＝7.5Hz，1H)，8.13(s，2H)，7.53(d，J＝7.5Hz，1H)，7.34(d，J＝7.5Hz，1H)，7.20(s，1H)，7.05(d，J＝8.4Hz，1H)，6.98(m，4H)，6.64(d，J＝8.4Hz，2H)，5.50(s，1H)，4.50(m，2H)，3.78(m，2H)，3.09(m，2H)，2.09(s，1H)。
Embodiment 16 preparation Thr-Tyr-Trp (TYW)
1) preparation Boc-Thr-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 876mg (87%) title compound, is colorless solid.ESI +-MS(m/e)651[M+H] +。
2) preparation Thr-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 400mg (90%) title compound, is no yellow powder.Mp：114-115C；[α] D 25＝4.7(c＝1.04，CH 3OH)；ESI +-MS(m/e)469[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.96(s，1H)，8.66(d，＝8.1Hz，1H)，8.52(d，J＝7.5Hz，1H)，8.18(s，2H)，7.54(d，J＝7.8Hz，1H)，7.35(d，J＝7.8Hz，1H)，7.22(s，1H)，7.06(m，3H)，6.98(t，J＝7.4Hz，1H)，6.65(d，J＝8.4Hz，2H)，4.55(m，3H)，3.91(m，1H)，3.65(m，1H)，3.21(dd，J＝5.0Hz，J＝15.0Hz，1H)，3.08(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.95(dd，J＝5.0Hz，J＝15.0Hz，1H)，2.72(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.10(s，1H)，1.10(d，J＝6.3Hz，3H)。
Embodiment 17 preparation Val-Tyr-Trp (VYW)
1) preparation Boc-Val-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 789mg (82%) title compound, is colorless solid.ESI +-MS(m/e)657[M+H] +。
2) preparation Val-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 288mg (89%) title compound, is no yellow powder.Mp：153-155C；[α] D 25＝7.3(c＝0.96，CH 3OH)；ESI +-MS(m/e)467[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.89(s，1H)，9.24(s，2H)，8.55(d，J＝7.5Hz，1H)，8.43(d，J＝7.5Hz，1H)，8.08(s，2H)，7.53(d，J＝7.5Hz，1H)，7.33(d，J＝7.5Hz，1H)，7.16(s，1H)，7.06(m，3H)，6.97(t，J＝7.4Hz，1H)，6.61(d，J＝8.4Hz，2H)，4.55(m，2H)，3.21(dd，J＝5.5Hz，J＝15.0Hz，1H)，3.10(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.92(dd，J＝5.5Hz，J＝15.0Hz，1H)，2.75(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.13(m，1H)，2.10(s，1H)，1.07(d，J＝7.0Hz，6H)。
Embodiment 18 preparation Trp-Tyr-Trp (WYW)
1) preparation Boc-Trp-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 1098mg (91%) title compound, is colorless solid.ESI +-MS(m/e)745[M+H] +。
Boc-Trp-Tyr-Trp-OBzl(3s)
2) preparation Trp-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 340mg (88%) title compound, is no yellow powder.Mp：171-172C；[α] D 25＝6.2(c＝1.03，CH 3OH)；ESI +-MS(m/e)554[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，11.00(s，1H)，10.95(s，1H)，9.24(s，1H)，8.85(d，J＝7.9Hz，1H)，8.51(d，J＝7.5Hz，1H)，8.00(s，2H)，7.57(d，J＝7.5Hz，2H)，7.35(d，J＝7.5Hz，2H)，7.24(s，1H)，7.22(s，1H)，7.08(d，J＝8.4Hz，2H)，7.00(t，J＝7.4Hz，2H)，6.93(t，J＝7.4Hz，2H)，6.65(d，J＝8.4Hz，2H)，4.55(m，2H)，4.00(s，1H)，3.25(dd，J＝5.0Hz，J＝15.0Hz，2H)，3.15(dd，J＝7.8Hz，J＝15.0Hz，1H)，2.97(dd，J＝5.0Hz，J＝15.0Hz，2H)，2.75(dd，J＝7.8Hz，J＝15.0Hz，1H)。
Embodiment 19 preparation Tyr-Tyr-Trp (YYW)
1) preparation Boc-Tyr-Tyr-Trp-OBzl
Operation according to preparation Boc-Ala-Tyr-Trp-OBzl obtains 694mg (80%) title compound, is colorless solid.ESI +-MS(m/e)722[M+H] +。
2) preparation Tyr-Tyr-Trp
Operation according to preparation Ala-Tyr-Trp obtains 548mg (88%) title compound, is no yellow powder.Mp：126-127C；[α] D 25＝10.5(c＝1.06，CH 3OH)；ESI +-MS(m/e)531[M+H] +； 1HNMR(BHSC-500Hz，DMSO-d 6)，10.92(s，1H)，9.35(s，1H)，9.30(s，1H)，8.78(d，J＝8.0Hz，1H)，8.48(d，J＝8.5Hz，1H)，7.97(s，2H)，7.57(d，J＝7.5Hz，2H)，7.35(d，J＝7.5Hz，2H)，7.21(s，1H)，7.06(m，6H)，6.99(t，J＝7.4Hz，2H)，6.69(d，J＝8.4Hz，2H)，6.64(d，J＝8.4Hz，2H)，4.55(m，2H)，3.15(dd，J＝5.0Hz，J＝15.0Hz，1H)，3.00(dd，J＝7.8Hz，J＝15.0Hz，2H)，2.92(dd，J＝5.0Hz，J＝15.0Hz，1H)，2.68(dd，J＝7.8Hz，J＝15.0Hz，2H)。
The analgesic activity evaluation experimental of experimental example 1 The compounds of this invention
19 compounds of 1, test-compound: embodiment of the invention 1-19 preparation;
2, experimental technique:
Male ICR mouse, body weight (22 ± 2g), illumination every day 12 hours, room temp is 20-24 ℃, humidity remains on 45-65%, competent food and water.Experiment begins fasting the day before yesterday raises, and mouse put between experimental implementation conforms, and every mouse only participates in once testing.
During experiment mouse packed in the special stationary magazine creel, outside afterbody is exposed to, 75% alcohol carries out disinfection, / 3rd places under the light beam irradiates mouse tail that produces with special spot light lamp when surveying the threshold of pain, use manual time-keeping, meter begins latent period to whipping reaction from irradiation, and (tail flick latency is TFL) as the threshold of pain.To irritate the comparatively sensitive TFL of intensity be 2-6s from making to regulate spot light lamp and mouse back range.Survey 3 times earlier during the experiment beginning, each 5min at interval gets average as the basic threshold of pain.Test-compound is suspended in respectively in 0.5% Xylo-Mucine (CMC-Na) aqueous solution, and gastric infusion is that 0.2ml and 0.13mmol/kg dosage are regulated suspension concentration by each filling stomach dosage.Each test is established the 0.5%CMC-Na group and is made parallel control.For preventing skin scald, illumination 10s dead line, 30min repetition measurement TFL is to observe medicine analgesia time-effect relationship at interval.Evaluate medicine analgesia intensity with threshold of pain raising rate: threshold of pain raising rate=(threshold of pain after the administration-basic threshold of pain) ÷ basis threshold of pain.The result who obtains lists table 1 in, and the result shows that The compounds of this invention has clear and definite analgesic activity.
The analgesic activities experimental result of table 1 The compounds of this invention
Annotate: threshold of pain raising rate is represented with mean ± SD%, n=10, dosage 0.13mmol/kg;
A) compare P＜0.05 with the CMC-Na group;
B) compare P＜0.01 with the CMC-Na group;
C) compare P＜0.001 with the CMC-Na group.
The analgesic activities of experimental example 2 various dose AYW and KYW
1) test-compound: compd A YW and KYW that the embodiment of the invention is prepared;
2) experimental technique: adopt experimental example 1 the hot whipping model evaluation of mouse optical radiation the analgesic activity of test-compound under 0.13mmol/kg, 0.08mmolmol/kg and three kinds of dosage of 0.05mmol/kg.The result lists table 2 in.Experimental result shows that test-compound all shows analgesic activity in dosage dependence ground.
The analgesic activity of table 2 different dosing dosage AYW and KYW
Annotate: raising rate in the threshold of pain is used
Figure G2008102275249D0000142
Expression, n=10; A) compare P＜0.05 with the 0.08mmol/kg group; B) compare P＜0.05 with the 0.05mmol/kg group.

Claims (10)

1. the aminoacyl tyrosyl tryptophan tripeptide that has analgesic activities, its structural formula are shown in the general formula I:
AA-Tyr-Trp?I
Wherein, AA is selected from alanine residue, asparagicacid residue, glutaminic acid residue, phenylalanine residue, glycine residue, histidine residues, Isoleucine residue, lysine residue, leucine residue, methionine residues, asparagine residue, proline residue, glutamine residue, arginine residues, serine residue, threonine residues, Xie Ansuan residue, tryptophan residue or tyrosine residues.
2. one kind prepares the described method with aminoacyl tyrosyl tryptophan tripeptide of analgesic activities of claim 1, comprising:
(1) with the tyrosine and the tryptophan benzyl ester coupling connection of tertbutyloxycarbonyl protection, synthesizes tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester;
(2) slough the tertbutyloxycarbonyl of tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester, obtain tyrosyl tryptophan benzyl ester;
(3) amino acid with tyrosyl tryptophan benzyl ester and tertbutyloxycarbonyl protection carries out the coupling connection, obtains t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester;
(4) with t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester hydrogenolysis debenzylation, obtain t-butoxycarbonyl amino acyl tyrosyl tryptophan;
(5) t-butoxycarbonyl amino acyl tyrosyl tryptophan is sloughed tertbutyloxycarbonyl, promptly get the aminoacyl tyrosyl tryptophan tripeptide of general formula I.
3. in accordance with the method for claim 2; it is characterized in that: tyrosine of in the presence of dicyclohexyl carbonyl diimine, N-hydroxybenzotriazole, N-methylmorpholine and anhydrous tetrahydro furan, tertbutyloxycarbonyl being protected in the step (1) and tryptophan benzyl ester coupling connection, synthetic tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester.
4. in accordance with the method for claim 2, it is characterized in that: in hydrogenchloride/ethyl acetate solution, add tertbutyloxycarbonyl tyrosyl tryptophan benzyl ester in the step (2), slough tertbutyloxycarbonyl, prepare tyrosyl tryptophan benzyl ester.
5. in accordance with the method for claim 2; it is characterized in that: in the presence of dicyclohexyl carbonyl diimine, N-hydroxybenzotriazole, N-methylmorpholine and anhydrous tetrahydro furan, the amino acid of tyrosyl tryptophan benzyl ester and tertbutyloxycarbonyl protection is carried out the coupling connection in the step (3), obtain t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester.
6. it is characterized in that in accordance with the method for claim 2; The amino acid of the tertbutyloxycarbonyl protection described in the step (3) is selected from the L-Ala of tertbutyloxycarbonyl protection; the aspartic acid list benzyl ester of tertbutyloxycarbonyl protection; the L-glutamic acid list benzyl ester of tertbutyloxycarbonyl protection; the phenylalanine of tertbutyloxycarbonyl protection; the glycine of tertbutyloxycarbonyl protection; the Histidine of tertbutyloxycarbonyl protection; the Isoleucine of tertbutyloxycarbonyl protection; the Methionin of the two tertbutyloxycarbonyls protection of tertbutyloxycarbonyl protection; the leucine of tertbutyloxycarbonyl protection; the methionine(Met) of tertbutyloxycarbonyl protection; the l-asparagine of tertbutyloxycarbonyl protection; the glutamine of tertbutyloxycarbonyl protection; the nitro arginine of tertbutyloxycarbonyl protection; the Serine of tertbutyloxycarbonyl protection; the Threonine of tertbutyloxycarbonyl protection; the Xie Ansuan of tertbutyloxycarbonyl protection; in the tyrosine of the tryptophane of tertbutyloxycarbonyl protection or tertbutyloxycarbonyl protection any one.
7. in accordance with the method for claim 2, it is characterized in that: in the step (4) in the presence of palladium carbon with t-butoxycarbonyl amino acyl tyrosyl tryptophan benzyl ester hydrogenolysis debenzylation, prepare t-butoxycarbonyl amino acyl tyrosyl tryptophan.
8. it is characterized in that in accordance with the method for claim 2: in the step (5) in hydrogenchloride/ethyl acetate solution t-butoxycarbonyl amino acyl tyrosyl tryptophan slough tertbutyloxycarbonyl.
9. pharmaceutical composition for the treatment of pain is made up of the described aminoacyl tyrosyl tryptophan tripeptide of the claim 1 of significant quantity and pharmaceutically acceptable carrier or auxiliary material.
10. the described aminoacyl tyrosyl tryptophan tripeptide of claim 1 is in the purposes of preparation in the analgesic.
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CN104817625A (en) * 2014-01-30 2015-08-05 陈光健 Oligopeptide CD03, and preparation method and application thereof
CN104817622A (en) * 2014-01-30 2015-08-05 陈光健 Oligopeptide CD04, and preparation method and application thereof
CN107501391A (en) * 2016-06-14 2017-12-22 首都医科大学 Formyl Trp Trp AA OBzl of 1 substituted beta carboline 3, its synthesis, activity and application

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YU42401A (en) * 1998-12-14 2003-12-31 Ortho-Mcneil Pharmaceuticals Inc. Substituted heterociclic acyl-tripeptides useful as thrombin receptor modulators
CA2432932A1 (en) * 2001-02-16 2002-08-29 Mark A. Scialdone Angiogenesis-inhibitory tripeptides, compositions and their methods of use

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Publication number Priority date Publication date Assignee Title
CN104817625A (en) * 2014-01-30 2015-08-05 陈光健 Oligopeptide CD03, and preparation method and application thereof
CN104817622A (en) * 2014-01-30 2015-08-05 陈光健 Oligopeptide CD04, and preparation method and application thereof
CN107501391A (en) * 2016-06-14 2017-12-22 首都医科大学 Formyl Trp Trp AA OBzl of 1 substituted beta carboline 3, its synthesis, activity and application

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