CN102796167A - (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof - Google Patents

(S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof Download PDF

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CN102796167A
CN102796167A CN2011101393983A CN201110139398A CN102796167A CN 102796167 A CN102796167 A CN 102796167A CN 2011101393983 A CN2011101393983 A CN 2011101393983A CN 201110139398 A CN201110139398 A CN 201110139398A CN 102796167 A CN102796167 A CN 102796167A
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tetrahydrochysene
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赵明
彭师奇
孙能彪
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Capital Medical University
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Abstract

The invention discloses a compound (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and a preparation method and application thereof, namely a compound represented by a general formula I, and a preparation method and application thereof in the preparation of thrombolytic medicaments. The thrombolytic effect and the self-loading property of the compound are evaluated by a rat neck arteriovenous bypass catheterization thrombus model; an in-vitro and in-vivo thrombolytic activity experiment shows that the peptide compound represented by the general formula I has excellent thrombolytic activity and can be applied to the preparation of thrombolytic medicaments.

Description

(S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid
Technical field
The present invention relates to a kind of compound of synthetic; Particularly relate to one type of (S)-4; 5,6,7-tetrahydrochysene-3H-imidazo [4; 5-c] pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, the invention still further relates to its preparation method and the application in the preparation thrombolytic agent.
Background technology
P6A (ARPAK) is one of scleroproein β chain degradation product, has thrombus dissolving activity.In the metabolism research of P6A, found meta-bolites PAK.On rat arteriovenous shut intubate thrombus dissolving model, the thrombus dissolving activity of PAK is stronger than parent P6A.According to general understanding, polypeptide all can be degraded rapidly in vivo.Structural modification through PAK delays vivo degradation speed and improves thrombus dissolving activity, is the important channel of oligopeptides thrombolytic agent research.
Spinacine (Spinacine) has the inhibit feature of similar Ang II suppressor factor, and is closely related with the morbidity of cardiovascular disordeies such as thrombus and hypertension.According to general understanding, contain the amphipathic molecule of polypeptide, for example self-assembly can take place through intermolecular non-covalent interaction in heterocycle modified polypeptides under suitable condition, forms nanostructure.By nanostructure can improve in vivo conveying of polypeptide, delay polypeptide in vivo degradation rate and improve the activity in vivo of polypeptide.According to these understanding, the contriver has proposed the present invention.
Summary of the invention
First technical problem that the present invention will solve is that it is the compound (3a-r) of I that general formula is provided:
Figure BDA0000064088280000011
In the formula, AA is Gly, L-Val, L-Trp, L-Leu, L-Ala, L-Met, L-Tyr, L-Asp, L-Ile, L-Phe, L-Pro, L-Ser, L-Thr, L-Glu, L-Asn, L-Gln, L-Arg or L-Lys.
Compound (3a-r) to the representative of synthetic general formula I is numbered: AA is Gly among the 3a; AA is L-Val among the 3b; AA is L-Trp among the 3c; AA is L-Leu among the 3d; AA is L-Ala among the 3e; AA is L-Met among the 3f; AA is L-Tyr among the 3g; AA is L-Asn among the 3h; AA is L-Ile among the 3i; AA is L-Phe among the 3j; AA is L-Pro among the 3k; AA is L-Ser among the 3l; AA is L-Thr among the 3m; AA is L-Gln among the 3n; AA is L-Asp among the 3o; AA is L-Glu among the 3p; AA is L-Arg among the 3q; AA is L-Lys among the 3r.
More than numbering is just described for ease, does not have any limited significance to invention.
Second technical problem that the present invention will solve provides the preparation method of general formula compound 3a-r, and this method comprises:
1) Boc-Pro is Boc-Pro-Ala with the Ala condensation in anhydrous THF in the presence of NSC 57182 (DCC) and N-hydroxy-succinamide (HOSu);
2) AA-OBzl is Boc-Pro-Ala-AA-OBzl with the Boc-Pro-Ala condensation in anhydrous THF in the presence of DCC and HOBt (N-hydroxy benzo triazole);
3) slough Boc (tertbutyloxycarbonyl) at hydrogenchloride-ethyl acetate solution Boc-Pro-Ala-AA-OBzl and generate Pro-Ala-AA-OBzl;
4) (S)-3 in the presence of EDC and HOBt, 5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid is (S)-3 with the Pro-Ala-AA-OBzl condensation in anhydrous methylene chloride; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino-acid benzyl ester;
5) (S)-3 in the presence of C/Pd, 5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino-acid benzyl ester is sloughed OBzl and is generated (S)-3 in methanol solution; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid;
6) at hydrogenchloride-ETHYLE ACETATE, in the anhydrous methylene chloride mixing solutions, (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid removes Boc and generates (S)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid.
Wherein said EDC is the abbreviation of 1-ethyl-(3-dimethylaminopropyl) carbodiimide, and TLC is a thin-layer chromatography, and DCU is a NSC 30023.
This preparation method can use the route of Fig. 1 to summarize.
The 3rd technical problem that the present invention will solve provided the application of said compound in the preparation thrombolytic agent.
The 4th technical problem that the present invention will solve is on rat neck arteriovenous shut intubate thrombus model, to estimate the thrombus dissolving effect of The compounds of this invention and independently adorn performance.
Description of drawings
Fig. 1 is the synthetic route chart of The compounds of this invention 3a-r;
The transmission electron microscope photo of the nanometer ball that Fig. 2 forms in the aqueous solution for invention compound 3a.
i)DCC；ii)NaHCO 3；iii)DCC，HOBt，NMM；iv)HCHO/H 2O/H 2SO 4；v)(Boc) 2O；vi)EDC，HOBt，NMM；vii)HCl/EtOAc；viii)NaOH/MeOH；ix)Pd/C，H 2，MeOH；x)HCl/CH 2Cl 2.
Embodiment
Below in conjunction with accompanying drawing, embodiment and testing data, do more detailed explanation with other technical characterictic and advantage to the present invention is above-mentioned.
Embodiment 1 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid synthetic
10g L-His is placed the eggplant-shape bottle of 250ml,, drip the dense H of 1ml with 80ml zero(ppm) water and the dissolving of 20ml formaldehyde mixing solutions 2SO 4, oil bath 60-70 ℃ is reacted 12h, and cool to room temperature, ice bath drip strong aqua down and transfer pH to 8-9, have a large amount of colourless depositions to separate out, and filter, and get 10.5g colorless solid (yield 97%).ESI-MS(m/z)167[M+H] +
Embodiment 2 (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid synthetic
With 1.67g (10mmol) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid is dissolved in the 2N aqueous sodium hydroxide solution under condition of ice bath, get 5.23g (24mmol) Boc 2O with the dioxane dissolving, joins in the reaction solution.Stirring at room, TLC monitoring reaction raw materials point disappears, and after reaction is accomplished, filters, and filtrating is revolved dried dioxane.Water layer is used saturated KHSO 4Acidified aqueous solution is to pH=2, with ethyl acetate extraction three times, combined ethyl acetate layer, and uses the less water backwash, and organic layer is used anhydrous Na SO 4Drying is filtered, and revolves dried colorless solid, soaks with ETHYLE ACETATE and wears away, and filters, and obtains colorless solid 1.55g (yield 42%).ESI-MS(m/z)367[M+H] +
Embodiment 3 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Methionin (3a) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-L-Methionin benzyl ester (1a) synthetic
With 1.85g (5mmol) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid is with the anhydrous CH of 15ml 2Cl 2Dissolving, ice bath are stirred and are added 653mg (5mmol) HOBt and 1.0g (5mmol) EDC down, get solution A.With 2.9g (5mmol) Pro-Ala-Lys (Z)-OBzl hydrochloride with the anhydrous CH of 15ml 2Cl 2Dissolving is transferred pH 8 with NMM, gets solution B.Solution B is dropped in the solution A under the ice bath stirring, regulate pH 8-9, continue to stir 12h and disappear up to raw material point with NMM.Reaction solution is evaporated to dried; Residue dissolves with the 40ml chloroform again; Use saturated sodium bicarbonate aqueous solution (10ml * 3), 5% aqueous potassium hydrogen sulfate (10ml * 3), saturated sodium-chloride water solution (10ml * 3) collection to give a baby a bath on the third day after its birth time successively, tell chloroform layer and use anhydrous sodium sulfate drying 2h.Filter, filtrate decompression is concentrated into dried, and 200-300 order silica gel column chromatography gets colorless oil product 968mg (yield 21%).ESI-MS(m/z)888[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Methionin (2a) synthetic
With 888mg (1.0mmol) (S)-3,5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-L-Methionin benzyl ester hydrochloride places the 50ml eggplant-shape bottle; Use the 8ml dissolve with methanol, add 500mg Pd/C, drip 3 formic acid; Deflate with threeway, feed the H that is contained in the airbag 2, five times repeatedly, the final state of threeway rests on logical H 2, continue logical H 2Disappear until raw material point.Reaction mixture filters, filtering Pd/C.Filtrating is evaporated to dried with Rotary Evaporators, residue is worn away with anhydrous diethyl ether repeatedly, gets 520mg colorless solid (yield 95%).ESI-MS(m/z)315[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Methionin (3a) is synthetic
With 600mg (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Methionin is with a small amount of anhydrous CH 2Cl 2Dissolving, ice bath are stirred and are added the mixing of 4N HCl/ ethyl acetate solution down, and TLC shows that raw material point disappears; The solution with water pump is drained repeatedly, the Ex-all hydrogen chloride gas, and residue grinds with anhydrous diethyl ether repeatedly; Get colorless solid, it is used dissolved in distilled water, transfer pH=7 with saturated sodium bicarbonate solution; Walk SepHadex G10, freeze-drying gets colourless floss 373mg (yield 89%).Mp?220-221℃.
Figure BDA0000064088280000041
ESI-MS(m/z)462[M-H] -.IR(KBr)3414，3247，2951，1651，1545，1441，1229cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.626(s，1H)，8.316(d，J＝7.2Hz，1H)，8.147(d，J＝7.2Hz，1H)，4.666(dd，J＝6.1Hz，J＝12.4Hz?1H)，4.475(dd，J＝4.5Hz，J＝8.7Hz?1H)，4.213(m，3H)，3.715(m，1H)，3.596(m，1H)，3.305(dd，J＝4.2Hz，J＝17.1Hz?1H)，2.724(m，2H)，2.634(s，1H)，2.134(m，1H)，1.873(m，3H)，1.563(m，3H)，1.369(m，2H)，1.245(d，J＝6.9Hz，2H).
Embodiment 4 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) (3b) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) benzyl ester (1b) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Pro-OBzl hydrochloride are raw material, get 1.0g colorless solid (yield 30%).ESI-MS(m/z)724[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) (2b) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 725mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) benzyl ester is a raw material, gets 595mg colorless solid (yield 94%).ESI-MS(m/z)634[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) (3b) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 595mg (0.95mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-proline(Pro) is a raw material, gets 370mg colorless solid (yield 91%).Mp?223-225℃.
Figure BDA0000064088280000052
ESI-MS(m/z)432[M-H] -.IR(KBr)3424，3242，2971，1647，1448，1190，653cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝12.594(s，1H)，10.194(s，1H)，9.035(s，1H)，8.326(d，J＝7.2Hz，1H)，8.144(d，J＝7.2Hz，1H)，4.718(dd，J＝3.9Hz，J＝10.5Hz?1H)，4.513(dd，J＝6.0Hz，J＝13.5Hz?2H)，4.243(m，3H)，3.705(m，1H)，3.496(m，4H)，3.344(dd，J＝3.9Hz，J＝7.2Hz?2H)，2.774(t，J＝4.2Hz?2H)，2.157(m，3H)，1.888(m，6H)，1.215(d，J＝6.9Hz，2H).
Embodiment 5 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan (3c) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan benzyl ester (1c) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Val-OBzl hydrochloride are raw material, get 1.0g colorless solid (yield 30%).ESI-MS(m/z)726[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan (2c) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 725mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan benzyl ester is a raw material, gets 600mg colorless solid (yield 94%).ESI-MS(m/z)636[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan (3c) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 600mg (0.95mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Xie Ansuan is a raw material, gets 370mg colorless solid (yield 91%).Mp?216-217℃.
Figure BDA0000064088280000061
Figure BDA0000064088280000062
ESI-MS(m/z)434[M-H] -.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝9.088(s，1H)，8.355(d，J＝7.2Hz，1H)，7.904(d，J＝5.4Hz，1H)，4.741(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.482(dd，J＝4.8Hz，J＝8.4Hz?1H)，4.376(m，3H)，4.129(m，1H)，3.718(m，2H)，3.553(m，3H)，3.386(m，3H)，2.774(t，J＝4.5Hz，2H)，1.254(d，J＝6.3Hz，2H)，0.883(d，J＝6.6Hz，6H).
Embodiment 6 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-Ala (3d) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-alanine benzyl ester (1d) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 1.89g (5mmol) Pro-Ala-Ala-OBzl hydrochloride are raw material, get 1.0g colorless solid (yield 30%).ESI-MS(m/z)697[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-Ala (2d) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 700mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-alanine benzyl ester is a raw material, gets 550mg colorless solid (yield 90%).ESI-MS(m/z)607[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-Ala (3d) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 550mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-Ala is a raw material, gets 320mg colorless solid (yield 90%).Mp?210-212℃. ESI-MS(m/z)405[M-H] -.IR(KBr)3270，2971，1653，1539，1449，1225cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.504(d，J＝7.2Hz，1H)，8.258(d，J＝5.4Hz，1H)，7.537(s，1H)，4.582(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.476(dd，J＝4.8Hz，J＝8.4Hz?1H)，4.300(m，3H)，4.129(m，3H)，3.861(m，4H)，3.512(m，2H)，2.775(t，J＝4.5Hz，2H)，1.852(m，3H)，1.249(d，J＝6.3Hz，6H).
Embodiment 7 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycocoll (3e) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycine benzyl ester (1e) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 1.80g (5mmol) Pro-Ala-Gly-OBzl hydrochloride are raw material, get 1.0g colorless solid (yield 30%).ESI-MS(m/z)684[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycocoll (2e) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 680mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycine benzyl ester is a raw material, gets 530mg colorless solid (yield 90%).ESI-MS(m/z)594[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycocoll (3e) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 530mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-glycocoll is a raw material, gets 317mg colorless solid (yield 90%).Mp?208-209℃. ESI-MS(m/z)392[M-H] -.IR(KBr)3418，2954，1652，1542，1437，1219cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.594(s，1H)，8.300(d，J＝7.5Hz，1H)，8.190(d，J＝6.0Hz，1H)，4.683(dd，J＝4.2Hz，J＝10.8Hz?1H)，4.462(dd，J＝4.8Hz，J＝8.4Hz?1H)，4.306(m，3H)，4.109(d，J＝6.9Hz，1H)，3.748(m，3H)，3.553(m，2H)，3.306(dd，J＝4.2Hz，J＝16.2Hz?1H)，2.728(t，J＝5.4Hz，1H)，2.155(m，1H)，1.905(m，3H)，1.221(d，J＝5.7Hz，3H).
Embodiment 8 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) (3f) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) benzyl ester (1f) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.30g (5mmol) Pro-Ala-Phe-OBzl hydrochloride are raw material, get 1.16g colorless solid (yield 30%).ESI-MS(m/z)773[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) (2f) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 780mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) benzyl ester is a raw material, gets 615mg colorless solid (yield 90%).ESI-MS(m/z)683[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) (3f) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 615mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-phenylalanine(Phe) is a raw material, gets 346mg colorless solid (yield 80%).Mp?200-202℃. ESI-MS(m/z)483[M+H] +.IR(KBr)3418，2955，1654，1533，1448，1225cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.189(d，J＝7.2Hz，1H)，8.026(d，J＝7.5Hz，1H)，7.636(s，1H)，7.232(m，5H)，4.687(d，J＝10.5Hz，1H)，4.379(m，3H)，4.257(dd，J＝2.7Hz，J＝7.5Hz?2H)，4.053(s，2H)，3.818(m，3H)，3.553(m，2H)，3.444(dd，J＝6.9Hz，J＝13.5Hz?1H)，3.018(m，3H)，2.694(t，J＝11.4Hz，1H)，2.085(m，1H)，1.886(m，3H)，1.198(d，J＝6.9Hz，3H).
Embodiment 9 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophane (3g) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophan benzyl ester (1g) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.50g (5mmol) Pro-Ala-Trp-OBzl hydrochloride are raw material, get 810mg colorless solid (yield 20%).ESI-MS(m/z)813[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophane (2g) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 810mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophan benzyl ester is a raw material, gets 650mg colorless solid (yield 90%).ESI-MS(m/z)723[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophane (3g) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (3a), with 650mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tryptophane is a raw material, gets 375mg colorless solid (yield 80%).Mp?213-214℃.
Figure BDA0000064088280000101
ESI-MS(m/z)523[M+H] +.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝11.015(s，1H)，8.305(d，J＝6.9Hz，1H)，8.073(d，J＝7.5Hz，1H)，7.736(s，1H)，7.531(d，J＝7.8Hz，1H)，7.353(d，J＝8.1Hz，1H)，7.212(d，J＝7.2Hz，1H)，7.030(d，J＝6.9Hz，2H)，4.536(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.484(t，J＝4.5Hz?2H)，4.289(m，1H)，4.048(m，3H)，3.689(m，2H)，3.553(m，3H)，3.208(m，3H)，2.756(t，J＝11.1Hz，2H)，2.085(m，1H)，1.873(m，3H)，1.198(d，J＝7.2Hz，3H).
Embodiment 10 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Isoleucine (3h) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Isoleucine benzyl ester (1h) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.10g (5mmol) Pro-Ala-Ile-OBzl hydrochloride are raw material, get 740mg colorless solid (yield 20%).ESI-MS(m/z)739[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Isoleucine (2h) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-identical method of L-Methionin (2a), with 740mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-L-Isoleucine benzyl ester is a raw material, gets 580mg colorless solid (yield 90%).ESI-MS(m/z)649[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Isoleucine (3h) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 580mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Isoleucine is a raw material, gets 324mg colorless solid (yield 80%).Mp?206-207℃. ESI-MS(m/z)447[M-H] -.IR(KBr)3379，3252，2954，1648，1430，1234cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.298(d，J＝7.5Hz，1H)，7.892(d，J＝8.4Hz，1H)，7.742(s，1H)，4.582(dd，J＝4.8Hz，J＝11.1Hz?1H)，4.472(dd，J＝5.1Hz，J＝8.7Hz?1H)，4.346(m，2H)，4.149(m，3H)，3.738(m，1H)，3.533(m，2H)，3.186(m，2H)，2.724(t，J＝11.4Hz，1H)，2.149(m，1H)，1.866(m，4H)，1.233(d，J＝6.9Hz，4H)，0.819(t，J＝13.2Hz，6H).
Embodiment 11 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine (3i) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine benzyl ester (1i) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.10g (5mmol) Pro-Ala-Leu-OBzl hydrochloride are raw material, get 740mg colorless solid (yield 20%).
ESI-MS(m/z)739[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine (2i) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 740mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine benzyl ester is a raw material, gets 580mg colorless solid (yield 90%).ESI-MS(m/z)649[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine (3i) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 580mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-leucine is a raw material, gets 324mg colorless solid (yield 80%).Mp?182-183℃. ESI-MS(m/z)449[M+H] +.IR(KBr)3295，2955，1655，1542，1446，1232，691cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.966(s，1H)，8.282(d，J＝7.5Hz，1H)，8.072(d，J＝7.8Hz，1H)，4.725(d，J＝6.6Hz?1H)，4.496(d，J＝5.4Hz?1H)，4.204(m，5H)，3.553(m，5H)，2.793(t，J＝11.4Hz，2H)，2.140(m，1H)，1.859(m，3H)，1.533(m，3H)，1.230(d，J＝6.6Hz，3H)，0.876(dd，J＝6.3Hz，J＝15.0Hz，6H).
Embodiment 12 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine (3j) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine benzyl ester (1j) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Ser-OBzl hydrochloride are raw material, get 710mg colorless solid (yield 20%).ESI-MS(m/z)713[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine (2j) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 710mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine benzyl ester is a raw material, gets 561mg colorless solid (yield 90%).ESI-MS(m/z)623[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine (3j) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 561mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Serine is a raw material, gets 304mg colorless solid (yield 80%).Mp?279-280℃. ESI-MS(m/z)423[M+H] +.IR(KBr)3377，3271，2971，1655，1539，1434，1235cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.255(d，J＝7.5Hz，1H)，8.049(d，J＝7.8Hz，1H)，7.876(s，1H)，4.625(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.475(dd，J＝4.8Hz，J＝8.4Hz?1H)，4.380(m，1H)，4.286(m，1H)，4.123(m，2H)，3.708(q，J＝6.0Hz?2H)，3.586(m，3H)，3.215(dd，J＝4.5Hz，J＝16.2Hz?1H)，2.752(t，J＝12.0Hz，2H)，2.190(m，1H)，1.886(m，3H)，1.258(d，J＝7.2Hz，3H).
Embodiment 13 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Threonine (3k) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-threonine benzyl ester (1k) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.05g (5mmol) Pro-Ala-Thr-OBzl hydrochloride are raw material, get 720mg colorless solid (yield 20%).ESI-MS(m/z)727[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Threonine (2k) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 720mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-threonine benzyl ester is a raw material, gets 571mg colorless solid (yield 90%).ESI-MS(m/z)637[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Threonine (3k) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 571mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-Threonine is a raw material, gets 313mg colorless solid (yield 80%).Mp?246-248℃.
Figure BDA0000064088280000132
ESI-MS(m/z)435[M-H] -.IR(KBr)3378，3272，3066，1656，1540，1435，1235cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.469(d，J＝6.0Hz，1H)，8.342(d，J＝7.5Hz，1H)，7.657(s，1H)，4.614(d，J＝3.6Hz?1H)，4.469(m，3H)，4.350(dd，J＝4.8Hz，J＝12.0Hz?2H)，4.111(m，6H)，3.715(m，2H)，3.563(m，3H)，3.089(dd，J＝3.9Hz，J＝15.9Hz2H)，2.700(t，J＝12.0Hz，1H)，2.150(m，2H)，1.879(m，3H)，1.264(d，J＝7.2Hz，3H)，1.049(d，J＝6.0Hz，3H).
Embodiment 14 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine (3l) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine benzyl ester (1l) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.30g (5mmol) Pro-Ala-Tyr-OBzl hydrochloride are raw material, get 787mg colorless solid (yield 20%).
ESI-MS(m/z)789[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine (2l) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 787mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine benzyl ester is a raw material, gets 630mg colorless solid (yield 90%).ESI-MS(m/z)699[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine (3l) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 630mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-tyrosine is raw material, gets 360mg colorless solid (yield 80%).Mp?213-215℃.
Figure BDA0000064088280000141
ESI-MS(m/z)499[M+H] +.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.497(d，J＝6.9Hz，1H)，8.222(d，J＝7.5Hz，1H)，7.416(s，1H)，6.889(d，J＝8.1Hz，1H)，6.590(d，J＝8.1Hz，1H)，4.536(m，1H)，4.337(t，J＝4.2Hz?1H)，4.065(m，1H)，3.894(m，2H)，3.718(m，4H)，3.005(dd，J＝4.8Hz，J＝13.2Hz?2H)，2.863(dd，J＝4.2Hz，J＝13.2Hz?2H)，1.942(m，5H)，1.193(d，J＝6.9Hz，3H).
Embodiment 15 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid (3m) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6, the two benzyl esters (1m) of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.60g (5mmol) Pro-Ala-Glu (OBzl)-OBzl hydrochloride are raw material, get 840mg colorless solid (yield 20%).
ESI-MS(m/z)845[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid (2m) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 840mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; The two benzyl esters of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid are raw material, get 598mg colorless solid (yield 90%).ESI-MS(m/z)665[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid (3m) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 598mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-L-glutamic acid is raw material, gets 335mg colorless solid (yield 80%).Mp?184-185℃.
Figure BDA0000064088280000151
ESI-MS(m/z)463[M-H] -.IR(KBr)3424，2945，1652，1538，1436，1220cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.445(s，1H)，8.232(d，J＝3.0Hz，1H)，8.133(d，J＝6.0Hz，1H)，4.657(dd，J＝4.2Hz，J＝10.5Hz?1H)，4.479(dd，J＝4.5Hz，J＝8.7Hz?1H)，4.261(m，3H)，4.062(dd，J＝6.9Hz，J＝14.1Hz?1H)，3.518(m，8H)，2.774(t，J＝6.0Hz，2H)，2.264(m，2H)，1.842(m，5H)，1.231(d，J＝3.9Hz，3H).
Embodiment 16 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid (3n) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6, the two benzyl esters (1n) of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.55g (5mmol) Pro-Ala-Asp (OBzl)-OBzl hydrochloride are raw material, get 830mg colorless solid (yield 20%).ESI-MS(m/z)831[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid (2n) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 830mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; The two benzyl esters of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid are raw material, get 585mg colorless solid (yield 90%).ESI-MS(m/z)651[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid (3n) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 585mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-aspartic acid is a raw material, gets 325mg colorless solid (yield 80%).Mp?245-246℃.
Figure BDA0000064088280000161
ESI-MS(m/z)449[M-H] -.IR(KBr)3297，2965，1655，1540，1430，1216cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.252(d，J＝7.8Hz，1H)，8.146(d，J＝7.8Hz，1H)，8.036(s，1H)，4.628(dd，J＝4.5Hz，J＝11.1Hz?1H)，4.534(dd，J＝6.0Hz，J＝12.0Hz?2H)，4.295(m，1H)，4.150(s，3H)，3.737(m，2H)，3.533(m，3H)，3.263(dd，J＝4.2Hz，J＝15.9Hz?2H)，2.673(t，J＝6.3Hz，3H)，2.145(m，1H)，1.861(m，3H)，1.234(d，J＝6.9Hz，2H).
Embodiment 17 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) (3o) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) benzyl ester (1o) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.25g (5mmol) Pro-Ala-Met-OBzl hydrochloride are raw material, get 750mg colorless solid (yield 20%).ESI-MS(m/z)757[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) (2o) synthetic
With 750mg (1mmol) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) benzyl ester is used CH 3OH dissolving, ice bath are stirred and are slowly dripped 2NNaOH/H down 2O solution, ice bath are kept reacting liquid temperature at 0 ℃, and TLC shows that raw material point disappears.Reaction solution is used KHSO 4/ H 2O transfers to neutrality, and evaporated under reduced pressure is worn away with small amount of methanol to solid, filters, and revolves dried methyl alcohol, adds small amount of methanol again and wears away, and filters, and revolves dried methyl alcohol, and the methanol crystallization gets 595mg colorless solid (yield 90%).ESI-MS(m/z)667[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) (3o) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 595mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-methionine(Met) is a raw material, gets 335mg colorless solid (yield 80%).Mp?205-206℃. ESI-MS(m/z)467[M+H] +.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.340(s，1H)，8.282(d，J＝4.5Hz，1H)，8.153(d，J＝7.8Hz，1H)，4.668(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.485(dd，J＝5.1Hz，J＝8.4Hz?1H)，4.372(m，2H)，4.200(m，2H)，3.733(m，1H)，3.553(m，1H)，3.279(dd，J＝4.5Hz，J＝16.2Hz?1H)，2.774(t，J＝14.4Hz，1H)，2.172(m，1H)，2.009(s，3H)，1.892(m，4H)，1.221(d，J＝7.5Hz，3H).
Embodiment 18 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-l-arginine (3p) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-NG-nitro-L-arginine benzyl ester (1p) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a); With 1.85g (5mmol) (S)-3,5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.55g (5mmol) Pro-Ala-Arg (NO 2)-OBzl hydrochloride is a raw material, gets 828mg colorless solid (yield 20%).ESI-MS(m/z)828[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-l-arginine (2p) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 830mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-NG-nitro-L-arginine benzyl ester is a raw material, gets 635mg colorless solid (yield 90%).ESI-MS(m/z)693[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-l-arginine (3p) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 630mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-l-arginine is a raw material, gets 335mg colorless solid (yield 80%).Mp?205-206℃. ESI-MS(m/z)467[M+H] +.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.355(d，J＝7.2Hz，1H)，7.904(d，J＝5.4Hz，1H)，7.488(s，1H)，4.741(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.482(dd，J＝4.8Hz，J＝8.4Hz?1H)，4.376(m，3H)，4.129(m，1H)，3.718(m，2H)，3.553(m，3H)，3.386(m，3H)，2.774(t，J＝4.5Hz，2H)，1.254(d，J＝6.3Hz，2H)，0.883(d，J＝6.6Hz，6H).
Embodiment 19 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine (3q) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine benzyl ester (1q) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.15g (5mmol) Pro-Ala-Asn-OBzl hydrochloride are raw material, get 741mg colorless solid (yield 20%).ESI-MS(m/z)740[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine (2q) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 741mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine benzyl ester is a raw material, gets 585mg colorless solid (yield 90%).ESI-MS(m/z)650[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine (3q) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 585mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-altheine is a raw material, gets 320mg colorless solid (yield 80%).Mp?145-146℃.
Figure BDA0000064088280000191
ESI-MS(m/z)450[M+H] +.IR(KBr)3408，3252，2965，1658，1537，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝8.582(s，1H)，8.295(d，J＝7.5Hz，1H)，8.069(d，J＝8.1Hz，1H)，7.519(s，1H)，6.948(s，1H)4.693(dd，J＝4.5Hz，J＝10.8Hz?1H)，4.499(m，2H)，4.313(m，3H)，4.058(dd，J＝6.3Hz，J＝7.5Hz?1H)，3.749(m，2H)，3.574(m，3H)，3.296(dd，J＝4.2Hz，J＝16.2Hz?2H)，2.673(t，J＝10.8Hz，1H)，2.145(m，1H)，1.861(m，3H)，1.234(d，J＝7.2Hz，3H).
Embodiment 20 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate (3r) synthetic
1) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate benzyl ester (1r) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-N-carbobenzoxy-(Cbz)-identical method of L-Methionin benzyl ester (1a), with 1.85g (5mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.25g (5mmol) Pro-Ala-Gln-OBzl hydrochloride are raw material, get 751mg colorless solid (yield 20%).ESI-MS(m/z)754[M+H] +.
2) (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate (2r) synthetic
Adopt and preparation (S)-3,5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (2a), with 751mg (1mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate benzyl ester is a raw material, gets 595mg colorless solid (yield 90%).ESI-MS(m/z)664[M+H] +.
3) (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate (3r) is synthetic
Adopt and preparation (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4, the 5-c] pyridine-6-formyl-L-proline(Pro)-L-leucine-identical method of L-Methionin (3a), with 595mg (0.9mmol) (S)-3; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-L-glutaminate is a raw material, gets 333mg colorless solid (yield 80%).Mp?133-134℃.
Figure BDA0000064088280000201
ESI-MS(m/z)464[M+H] +.IR(KBr)3490，3272，2905，1648，1586，1442，1222cm -1. 1HNMR(300MHz，DMSO-d 6)δ/ppm＝9.087(s，1H)，8.319(d，J＝7.2Hz，1H)，8.131(d，J＝7.5Hz，1H)，6.822(s，1H)4.737(dd，J＝6.0Hz，J＝10.8Hz?1H)，4.483(dd，J＝4.8Hz，J＝8.4Hz，2H)，4.303(m，5H)，4.077(dd，J＝2.7Hz，J＝7.2Hz?1H)，3.736(m，1H)，3.579(m，3H)，3.383(dd，J＝4.8Hz，J＝16.8Hz?2H)，2.797(t，J＝12.9Hz，1H)，2.146(m，3H)，1.861(m，5H)，1.241(d，J＝7.2Hz，3H).
Embodiment 21 external thrombolysis experiments
Experiment material
Urokinase (UK, the Beijing SaiSheng pharmacy Co., Ltd produces, 100,000 units/prop up), saline water (Cologne, Sichuan medicine company), zero(ppm) water.DZP-102 vibrator (Chinese Harbin Donglian Electronic & Technology Development Co., Ltd.).Male SD rat, 200-400g, Beijing Vital River Experimental Animals Technology Co., Ltd..
Experimental technique
(1) making of thrombosis device
With internal diameter 4mm, external diameter 5.5mm, one section Glass tubing of length 18mm is placed on the quick detachable base of plastics, and the seam crossing of Glass tubing and plastic feet seals with one section emulsion tube.Place a Stainless Steel Wire spiral, screw diameter 1mm, length 20mm in the Glass tubing; The long hook of 2mm that comprises an end; Blood promptly be set in the stainless steel spiral around, can thrombus be hung up when weighing, when hatching, can thrombus be hung in the solution of reaction flask; Do not run into wall, in order to avoid the damage thrombus.
(2) making of reaction flask
10ml cillin bottle with the band rubber plug; On rubber plug, wear a Stainless Steel Wire, the end in bottle curves hook, and thrombus hangs on the hook; Be suspended in bottle interior testing compound solution; Stainless Steel Wire can move up and down on rubber plug, regulates the height of thrombus in solution, and it just is immersed in the solution to be measured.The simulation of internal milieu: estimate that according to the rat mean body weight every rat has 13ml blood, if rat thrombus in vivo model, blood that maybe about 8ml can touch thrombus, so adding 8ml solution to be measured in the reaction flask is hatched at 37 ℃ of constant temperature shaking tables.
(3) preparation of thrombus
(6ml/kg i.p.), anaesthetizes with 20% urethane with the 350-400g male SD rat; It is fixing to lie on the back, and separates RCCA, and the bulldog clamp folder closes proximal part; The long polyethylene tube of 30mm is inserted in the bulldog clamp top, emits about 3-4ml blood at every turn, approximately can put 2-3 time; 5ml syringe with silylanization injects the Glass tubing that the preparation thrombus is used with the blood of emitting immediately one by one, the stainless steel spiral is put at once.Leave standstill 40min and make thrombosis, afterwards Glass tubing is carefully taken off from base, with fine needle with separating with the Glass tubing inwall around the thrombus; Removal of thromboses hangs on the rubber plug of reaction flask; Add 8ml zero(ppm) water in the reaction flask, thrombus is suspended on leaves standstill 1 hour in the water, remove thrombus surface floating blood.After 1 hour, inhale the moisture on the bolt surface of dehematizing, accurately weigh one by one with filter paper.
(4) measure the external thrombolysis activity of compound
In each reaction flask, refill the solution of testing compound 3a-r, as blank, UK (100IU/ml) hangs on thrombus in the solution of testing compound as positive control again with saline water, and 37 ℃ of constant temperature shaking table 70rpm were hatched 2 hours.After hatching end, draw surface water with filter paper and accurately weigh one by one again, calculate thrombus at the weight difference that adds solution to be measured front and back, the external thrombolysis activity of statistical appraisal compound.
Experimental result
Be the assessing compound fibrinolytic, as blank, the positive contrast of 100000IU/1UK is carried out external thrombolysis activity experiment to compound with saline water, and data are following:
The external thrombolysis activity of table 13a-r a
Figure BDA0000064088280000211
A) n=6, urokinase concentration is 100IU/ml, 3a-r concentration is 100nM; B) P＜0.01 of comparing with the saline water group; C) P＞0.05. that compares with the saline water group
The result shows, is 100nM to concentration, and the thrombolysis loss of weight of compound is 21.70 ± 2.63mg～35.13 ± 2.89mg, with blank 20.11 ± 1.31mg significant difference (p＜0.05) is arranged relatively.The thrombolysis loss of weight of positive control is 83.35 ± 2.31mg.And the carboxyl terminal of working as peptide is amino acid such as the Phe that contains phenyl ring, during Tyr, does not present external thrombolysis activity.
Thrombolysis experiment in embodiment 22 bodies
Experiment material
Urethane (Shanghai Tian Lian Fine Chemical Co., Ltd), heparin sodium (Beijing extensive and profound in meaning star biotechnology responsibility ltd), urokinase (Beijing match crude drug industry), saline water (Cologne, Sichuan medicine company).Retaining plate, bulldog clamp, curved hemostat, straight mosquito forceps, Cyphophthalmi tweezer, straight ophthalmology tweezer, syringe, surgical thread, rubber band, 1mlEP pipe, bypass intubate, scissors, thrombus holder, thrombus screw, balance, silicone oil.Male SD rat, 200-220g, Beijing Vital River Experimental Animals Technology Co., Ltd..
Experimental technique: rat neck arteriovenous shut intubate model
(1) preparation thrombus
(6ml/kg i.p.) anaesthetizes with 20% urethane solution with the 200-220g male SD rat.The anesthetized rat dorsal position is fixed, and separates RCCA, in proximal part folder bulldog clamp; Proximal part and distal end penetrate surgical thread respectively, the surgical thread of distal end are clamped with mosquito forceps in fur, in the distal end intubate; Unclamp bulldog clamp, emit about 1ml arterial blood, be contained in the 1mlEP pipe.The Glass tubing of past vertical fixing (long 15mm, internal diameter 2.5mm, external diameter 5.0mm, the pipe end, seal with plug) and the middle 0.1ml of injection rat artery blood, the rapid thrombus standing bolt that inserts a stainless steel material in past the pipe.This thrombus fixedly spiral uses the Stainless Steel Wire coiled of diameter as 0.2mm, and the long 12mm of spiral part contains 15 bung flanges, and the diameter of bung flange is 1.0mm, and the holder handle links to each other with spiral, and long 7.0mm is the question mark type.Behind the blood coagulation 15min, open the plug of Glass tubing bottom, with the fixing fixing holder handle of spiral of thrombus of tweezers, the thrombus that taking-up is wrapped up by thrombus from Glass tubing is spiral fixedly, accurately weighs.
(2) preparation bypass intubate
The bypass intubate constitutes by 3 sections, and the stage casing is a polyethylene rubber tube, long 60mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, long 100mm, internal diameter 1mm; External diameter 2mm, an end of this pipe pull into point pipe (being used to insert rat carotid artery or vein), external diameter 1mm; The outer cover one segment length 7mm of the other end, the polyethylene tube of external diameter 3.5mm (overstriking is used to insert in the polyethylene rubber tube in stage casing).The equal silylanization of the inwall of 3 sections pipes.With the thrombus of thrombus parcel fixedly spiral put into the stage casing polyethylene rubber tube, the two ends of sebific duct are nested with two poly butt ends that add respectively.Fill with heparin-saline solution (50IU/kg) in will managing through sharp pipe end with syringe, subsequent use.
(3) carry out intubate
The left external jugular vein of isolated from rat; Proximal part and distal end penetrate surgical thread respectively; On the left external jugular vein that exposes, cut an angle carefully; The point pipe of the bypass duct that above-prepared is good inserts the proximal part of left external jugular vein opening by angle, simultaneously away from the fixing holder handle of spiral of the interior thrombus in bypass tube stage casing (containing fixedly spiral of the thrombus of accurately weighing).Push the heparin-saline (50IU/kg) of accurate amount with syringe through the point pipe of the other end, this moment, syringe was not withdrawn polyethylene tube, clamped the flexible pipe between syringe and the polyethylene tube with mosquito forceps.Proximal part at RCCA stops blooding with bulldog clamp, RCCA is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use 4 trumpeter's art sutures and arteriovenous to fix.
(4) extracorporeal circulation
With scalp acupuncture with saline water (3ml/kg); Thrust away from the fixing nearly vein place of spiral of thrombus in the stage casing of the physiological salt soln of physiological salt soln of urokinase (20000IU/kg) or different concns compound through bypass tube (containing fixedly spiral of the thrombus of accurately weighing), opens bulldog clamp; Make blood flow flow to vein from artery through bypass duct; This is a rat arteriovenous shut Thrombolysis Model, slowly the liquid in the syringe is injected into (about 6min) in the blood, makes saline water (blank); Urokinase (positive control) or compound are through blood circulation, and the sequential action of pressing vein-heart-artery is to thrombus.Timing during from start injection, behind the 1h from bypass duct the fixing spiral of removal of thromboses, accurately weigh.Calculate fixedly of poor quality before and after the spiral administration of thrombus in every rat bypass duct, thrombolysis activity in the body of statistics and assessing compound.
Experimental result
Adopting rat neck arteriovenous shut intubate model, is blank with saline water, the positive contrast of UK (20000IU/kg), thrombolysis activity in the body of assessing compound.Data are following:
Table 23a-r is to the influence of rat suppository loss of weight a
Figure BDA0000064088280000231
Figure BDA0000064088280000241
A) n=10, urokinase dosage are 20000IU/kg, and 3a-r dosage is 10nmol/kg; B) compare p＜0.01. with the saline water group
The result shows, is 10nmol/kg to concentration, and the thrombolysis loss of weight of compound is 16.99 ± 0.59mg～22.5 ± 1.43mg, with NS significant difference (12.84 ± 0.86mg, p＜0.01) is arranged relatively, and the thrombolysis loss of weight of positive control is 21.5 ± 1.73mg.
The thrombus dissolving dose-effect relationship of embodiment 233a intravenous administration
With the method for experimental example 20, choose the best 3a of thrombolysis effect and investigate the thrombolysis activity under 10nmol/kg, 1nmol/kg, three kinds of dosage of 0.1nmol/kg.The result shows, thrombolytic effect show dose dependency (table 3) in the body of 3a.
The dosage of table 33a is to the influence of rat suppository loss of weight a
Figure BDA0000064088280000242
A) n=10; B) compare p＜0.01 with saline water, 1nmol/kg and 0.1nmol/kg group; C) compare p＜0.01 with saline water and 0.1nmol/kg group; D) compare p＜0.01. with the saline water group
The nanostructure of experimental example 243a-r
1) particle diameter of 3a-r nanometer ball in the aqueous solution
On Nano-ZS90 nano particle size determinator, measured 3a-r 10 in continuous 8 days -5The particle diameter of M.The result shows that 3a-r can be assembled into nanometer ball in the aqueous solution, and particle diameter is all between 168 to 300nm (table 4).
The median size of nanometer ball in 8 days that table 43a-r assembles in the aqueous solution
Figure BDA0000064088280000243
2) form of the nanometer ball of 3a-r
It is 1 * 10 that 3a-r is made into concentration -10The aqueous solution of mol/ml, then with this drips of solution on copper mesh, observe down the form of nanometer ball behind the dried solvent that volatilizees at transmission electron microscope (TEM).Mensuration shows, the nanometer ball of 3a-r formation rule.The transmission electron microscope photo of 3a is described with Fig. 2 as representative.
Above-described embodiment describes preferred implementation of the present invention; Be not that scope of the present invention is limited; Design under the prerequisite of spirit not breaking away from the present invention; Various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.

Claims (3)

1. compound that general formula is I:
In the formula, AA is Gly, L-Val, L-Trp, L-Leu, L-Ala, L-Met, L-Tyr, L-Asp, L-Ile, L-Phe, L-Pro, L-Ser, L-Thr, L-Glu, L-Asn, L-G1n, L-Arg or L-Lys.
2. method for preparing the described compound of claim 1 is characterized in that may further comprise the steps:
1) Boc-Pro is Boc-Pro-Ala with the Ala condensation in anhydrous THF in the presence of NSC 57182 (DCC) and N-hydroxy-succinamide (HOSu);
2) in anhydrous THF, be Boc-Pro-Ala-AA-OBzl at AA-OBzl in the presence of DCC and the HOBt with the Boc-Pro-Ala condensation;
3) slough Boc at hydrogenchloride-ethyl acetate solution Boc-Pro-Ala-AA-OBzl and generate Pro-Ala-AA-OBzl;
4) (S)-3 in the presence of EDC and HOBt, 5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid is (S)-3 with the Pro-Ala-AA-OBzl condensation in anhydrous methylene chloride; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino-acid benzyl ester;
5) (S)-3 in the presence of C/Pd, 5-two (tertbutyloxycarbonyl)-4,5; 6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino-acid benzyl ester is sloughed OBzl and is generated (S)-3 in methanol solution; 5-two (tertbutyloxycarbonyl)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid;
6) at hydrogenchloride-ETHYLE ACETATE, in the anhydrous methylene chloride mixing solutions, (S)-3,5-two (tertbutyloxycarbonyl)-4; 5,6,7-tetrahydrochysene-3H-imidazo [4; 5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid removes Boc and generates (S)-4,5,6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-proline(Pro)-L-L-Ala-amino acid promptly gets.
3. the described compound of claim 1 is in the purposes of preparation in the thrombolytic agent.
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CN106349332A (en) * 2015-07-13 2017-01-25 首都医科大学 Imidazo pyridine acyl-KRGDV, synthesis thereof, antithrombus activity and application
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