CN102796167B - (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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CN102796167B
CN102796167B CN201110139398.3A CN201110139398A CN102796167B CN 102796167 B CN102796167 B CN 102796167B CN 201110139398 A CN201110139398 A CN 201110139398A CN 102796167 B CN102796167 B CN 102796167B
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imidazo
pyridine
tetrahydrochysene
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proline
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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 and its preparation method and application
Technical field
The present invention relates to compound of a kind of synthetic and its preparation method and application, particularly relate to a class (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 preparing thrombolytic agent.
Background technology
P6A (ARPAK) is one of scleroproein β chain degradation product, has thrombus dissolving activity.Found meta-bolites PAK in the metabolism research of P6A.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 by 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 inhibitor, closely related with the morbidity of the cardiovascular disordeies such as thrombus and hypertension.According to general understanding, containing the amphipathic molecule of polypeptide, self-assembly, can occur by noncovalent intermolecular interactions in polypeptide that for example heterocycle is modified under suitable condition, forms nanostructure.Can improve conveying in vivo of polypeptide, delay degradation rate in vivo of polypeptide and improve the activity in vivo of polypeptide by nanostructure.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 the compound that general formula is I (3a-r) is provided:
Figure BDA0000064088280000011
In 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 synthetic general formula I representative is numbered: in 3a, AA is Gly, in 3b, AA is L-Val, in 3c, AA is L-Trp, in 3d, AA is L-Leu, in 3e, AA is L-Ala, in 3f, AA is L-Met, in 3g, AA is L-Tyr, in 3h, AA is L-Asn, in 3i, AA is L-Ile, in 3j, AA is L-Phe, in 3k, AA is L-Pro, in 3l, AA is L-Ser, in 3m, AA is L-Thr, in 3n, AA is L-Gln, in 3o, AA is L-Asp, in 3p, AA is L-Glu, in 3q, AA is L-Arg, in 3r, AA is L-Lys.
Above numbering just for convenience of description, there is no any limited significance to invention.
Second technical problem that the present invention will solve is to provide the preparation method of general formula compound 3a-r, and the method comprises:
1) under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) existence, Boc-Pro is Boc-Pro-Ala with the Ala condensation in anhydrous THF;
2) under DCC and HOBt (N-hydroxy benzo triazole) existence, AA-OBzl is Boc-Pro-Ala-AA-OBzl with the Boc-Pro-Ala condensation in anhydrous THF;
3) slough Boc (tertbutyloxycarbonyl) at hydrogenchloride-ethyl acetate solution Boc-Pro-Ala-AA-OBzl and generate Pro-Ala-AA-OBzl;
4) (S)-3 under EDC and HOBt existence, 5-bis-(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-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino-acid benzyl ester;
5) (S)-3 under C/Pd exists, 5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino-acid benzyl ester sloughs OBzl and generates (S)-3 in methanol solution, 5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid;
6) in hydrogenchloride-ethyl acetate, in the anhydrous methylene chloride mixing solutions, (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid removes Boc and generates (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid.
The abbreviation that wherein said EDC is 1-ethyl-(3-dimethylaminopropyl) carbodiimide, TLC is thin-layer chromatography, DCU is dicyclohexylurea (DCU).
This preparation method can summarize with the route of Fig. 1.
The 3rd technical problem that the present invention will solve has been to provide the application of described compound in preparing thrombolytic agent.
The 4th technical problem that the present invention will solve is estimate the thrombus dissolving effect of the compounds of this invention and independently fill performance on rat neck arteriovenous shut intubate thrombus model.
The accompanying drawing explanation
The synthetic route chart that Fig. 1 is the compounds of this invention 3a-r;
The transmission electron microscope photo that Fig. 2 is the nanometer ball that forms in the aqueous solution of 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, above-mentionedly to the present invention with other technical characterictic and advantage, be described in more detail.
Embodiment 1 (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid synthetic
10g L-His is placed in to the eggplant-shape bottle of 250ml, dissolves with 80ml distilled water and 20ml formaldehyde mixing solutions, drip the dense H of 1ml 2sO 4, oil bath 60-70 ℃ of reaction 12h, cool to room temperature, drip strong aqua and adjust pH to 8-9 under ice bath, a large amount of colourless Precipitations are arranged, and filters, and obtains 10.5g colorless solid (yield 97%).ESI-MS(m/z)167[M+H] +
Embodiment 2 (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid synthetic
By 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, gets 5.23g (24mmol) Boc 2o, dissolve with dioxane, joins in reaction solution.Stirring at room, TLC monitoring reaction raw materials point disappears, and after having reacted, filters, and filtrate is spin-dried for dioxane.The saturated KHSO of water layer 4acidified aqueous solution, to pH=2, is extracted with ethyl acetate three times, the combined ethyl acetate layer, and with a small amount of water backwash, organic layer anhydrous Na SO 4drying, filter, and is spin-dried for to obtain colorless solid, by ethyl acetate, soaks and wear 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-ALANINE-1B (3a) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-1B benzyl ester (1a) synthetic
By 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the anhydrous CH of 15ml for 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid 2cl 2dissolve, ice bath adds 653mg (5mmol) HOBt and 1.0g (5mmol) EDC under stirring, and obtains solution A.By the anhydrous CH of 15ml for 2.9g (5mmol) Pro-Ala-Lys (Z)-OBzl hydrochloride 2cl 2dissolve, with NMM, adjust pH 8, obtain solution B.Solution B is dropped in the solution A under the ice bath stirring, with NMM, regulate pH 8-9, continue to stir 12h until raw material point disappears.Reaction solution is evaporated to dry, residue dissolves again with the 40ml chloroform, use successively saturated sodium bicarbonate aqueous solution (10ml * 3), 5% aqueous potassium hydrogen sulfate (10ml * 3), saturated sodium-chloride water solution (10ml * 3) extraction to wash three times, separate chloroform layer anhydrous sodium sulfate drying 2h.Filter, filtrate decompression is concentrated into dry, and 200-300 order silica gel column chromatography obtains colorless oil product 968mg (yield 21%).ESI-MS(m/z)888[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-1B (2a) synthetic
By 888mg (1.0mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-1B benzyl ester hydrochloride is placed in the 50ml eggplant-shape bottle, use the 8ml dissolve with methanol, add 500mg Pd/C, drip 3 formic acid, deflate with threeway, pass into the H be contained in airbag 2, five times repeatedly, the final state of threeway rests on logical H 2, continue logical H 2until raw material point disappears.Reaction mixture filters, filtering Pd/C.Filtrate is evaporated to dry with Rotary Evaporators, residue is worn away with anhydrous diethyl ether repeatedly, obtains 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-ALANINE-1B (3a) synthetic
By 600mg (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-a small amount of anhydrous CH for 6-formyl-L-PROLINE-ALANINE-1B 2cl 2dissolve, ice bath adds 4N HCl/ ethyl acetate solution to mix under stirring, TLC shows that raw material point disappears, and the solution with water pump is drained repeatedly, the Ex-all hydrogen chloride gas, residue grinds repeatedly with anhydrous diethyl ether, obtains colorless solid, and it is dissolved with distilled water, adjust pH=7 with saturated sodium bicarbonate solution, walk SepHadex G10, freeze-drying, obtain 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-ALANINE-L-PROLINE (3b) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-PROLINE benzyl ester (1b) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Pro-OBzl hydrochloride be raw material, obtains 1.0g colorless solid (yield 30%).ESI-MS(m/z)724[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-PROLINE (2b) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 725mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-PROLINE benzyl ester is raw material, obtains 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-ALANINE-L-PROLINE (3b) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 595mg (0.95mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-PROLINE is raw material, obtains 370mg colorless solid (yield 91%).Mp?223-225℃.?
Figure BDA0000064088280000051
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?2?H)，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-ALANINE-Valine (3c) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Valine benzyl ester (1c) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Val-OBzl hydrochloride be raw material, obtains 1.0g colorless solid (yield 30%).ESI-MS(m/z)726[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Valine (2c) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 725mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Valine benzyl ester is raw material, obtains 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-ALANINE-Valine (3c) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 600mg (0.95mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Valine is raw material, obtains 370mg colorless solid (yield 91%).Mp?216-217℃.?
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-ALANINE-ALANINE (3d) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ALANINE benzyl ester (1d) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 1.89g (5mmol) Pro-Ala-Ala-OBzl hydrochloride be raw material, obtains 1.0g colorless solid (yield 30%).ESI-MS(m/z)697[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ALANINE (2d) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 700mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ALANINE benzyl ester is raw material, obtains 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-ALANINE-ALANINE (3d) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 550mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ALANINE is raw material, obtains 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-ALANINE-glycine (3e) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-glycine benzyl ester (1e) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 1.80g (5mmol) Pro-Ala-Gly-OBzl hydrochloride be raw material, obtains 1.0g colorless solid (yield 30%).ESI-MS(m/z)684[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-glycine (2e) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 680mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-glycine benzyl ester is raw material, obtains 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-ALANINE-glycine (3e) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 530mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-glycine is raw material, obtains 317mg colorless solid (yield 90%).Mp?208-209℃.?
Figure BDA0000064088280000081
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-ALANINE-L-Phe (3f) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Phe benzyl ester (1f) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.30g (5mmol) Pro-Ala-Phe-OBzl hydrochloride be raw material, obtains 1.16g colorless solid (yield 30%).ESI-MS?(m/z)773[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Phe (2f) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 780mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Phe benzyl ester is raw material, obtains 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-ALANINE-L-Phe (3f) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 615mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Phe is raw material, obtains 346mg colorless solid (yield 80%).Mp?200-202℃.?
Figure BDA0000064088280000091
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-ALANINE-L-Trp (3g) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Trp benzyl ester (1g) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.50g (5mmol) Pro-Ala-Trp-OBzl hydrochloride be raw material, obtains 810mg colorless solid (yield 20%).ESI-MS(m/z)813[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Trp (2g) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 810mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Trp benzyl ester is raw material, obtains 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-ALANINE-L-Trp (3g) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (3a), with 650mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Trp is raw material, obtains 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-ALANINE-ILE (3h) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ILE benzyl ester (1h) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.10g (5mmol) Pro-Ala-Ile-OBzl hydrochloride be raw material, obtains 740mg colorless solid (yield 20%).ESI-MS(m/z)739[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ILE (2h) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-ALANINE-1B (2a), with 740mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-ILE benzyl ester is raw material, obtains 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-ALANINE-ILE (3h) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 580mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-ILE is raw material, obtains 324mg colorless solid (yield 80%).Mp?206-207℃.?
Figure BDA0000064088280000111
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-ALANINE-L-Leu (3i) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Leu benzyl ester (1i) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.10g (5mmol) Pro-Ala-Leu-OBzl hydrochloride be raw material, obtains 740mg colorless solid (yield 20%).
ESI-MS(m/z)739[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Leu (2i) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 740mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Leu benzyl ester is raw material, obtains 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-ALANINE-L-Leu (3i) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 580mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Leu is raw material, obtains 324mg colorless solid (yield 80%).Mp?182-183℃.?
Figure BDA0000064088280000121
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-ALANINE-Serine (3j) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Serine benzyl ester (1j) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.0g (5mmol) Pro-Ala-Ser-OBzl hydrochloride be raw material, obtains 710mg colorless solid (yield 20%).ESI-MS(m/z)713[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Serine (2j) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 710mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Serine benzyl ester is raw material, obtains 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-ALANINE-Serine (3j) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 561mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-Serine is raw material, obtains 304mg colorless solid (yield 80%).Mp?279-280℃.?
Figure BDA0000064088280000131
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-ALANINE-L-threonine (3k) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-threonine benzyl ester (1k) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.05g (5mmol) Pro-Ala-Thr-OBzl hydrochloride be raw material, obtains 720mg colorless solid (yield 20%).ESI-MS(m/z)727[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-threonine (2k) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 720mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-threonine benzyl ester is raw material, obtains 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-ALANINE-L-threonine (3k) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 571mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-threonine is raw material, obtains 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-ALANINE-TYR (3l) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-TYR benzyl ester (1l) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.30g (5mmol) Pro-Ala-Tyr-OBzl hydrochloride be raw material, obtains 787mg colorless solid (yield 20%).
ESI-MS(m/z)789[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-TYR (2l) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 787mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-TYR benzyl ester is raw material, obtains 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-ALANINE-TYR (3l) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 630mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-TYR is raw material, obtains 360mg colorless solid (yield 80%).Mp?213-215℃.? 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-ALA-GLU (3m) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the two benzyl esters (1m) of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALA-GLU synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(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 be raw material, obtains 840mg colorless solid (yield 20%).
ESI-MS(m/z)845[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALA-GLU (2m) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 840mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] the two benzyl esters of pyridine-6-formyl-L-PROLINE-ALA-GLU are raw material, obtain 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-ALA-GLU (3m) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 598mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALA-GLU is raw material, obtains 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-ALANINE-L-Aspartic acid (3n) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the two benzyl esters (1n) of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Aspartic acid synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(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 be raw material, obtains 830mg colorless solid (yield 20%).ESI-MS(m/z)831[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Aspartic acid (2n) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 830mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] the two benzyl esters of pyridine-6-formyl-L-PROLINE-ALANINE-L-Aspartic acid are raw material, obtain 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-ALANINE-L-Aspartic acid (3n) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 585mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Aspartic acid is raw material, obtains 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-ALANINE-L-Methionine (3o) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Methionine benzyl ester (1o) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.25g (5mmol) Pro-Ala-Met-OBzl hydrochloride be raw material, obtains 750mg colorless solid (yield 20%).ESI-MS(m/z)757[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Methionine (2o) synthetic
By 750mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Methionine benzyl ester CH 3oH dissolves, and ice bath stirs the lower 2NNaOH/H that slowly drips 2o solution, ice bath maintains reacting liquid temperature at 0 ℃, and TLC shows that raw material point disappears.Reaction solution KHSO 4/ H 2o is adjusted to neutrality, and evaporated under reduced pressure, to solid, is worn away with a small amount of methyl alcohol, filters, and is spin-dried for methyl alcohol, then adds a small amount of methyl alcohol and wear away, and filters, and is spin-dried for methyl alcohol, and the methanol/ether crystallization, obtain 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-ALANINE-L-Methionine (3o) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 595mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-Methionine is raw material, obtains 335mg colorless solid (yield 80%).Mp?205-206℃.?
Figure BDA0000064088280000171
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-ALANINE-L-arginine (3p) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-NG-nitro-L-arginine benzyl ester (1p) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with (S)-3 of 1.85g (5 mmol), 5-bis-(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 raw material, obtains 828mg colorless solid (yield 20%).ESI-MS(m/z)828[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-arginine (2p) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 830mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-NG-nitro-L-arginine benzyl ester is raw material, obtains 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-ALANINE-L-arginine (3p) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 630mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-L-arginine is raw material, obtains 335mg colorless solid (yield 80%).Mp?205-206℃.?
Figure BDA0000064088280000181
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-ALANINE-altheine (3q) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-altheine benzyl ester (1q) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.15g (5mmol) Pro-Ala-Asn-OBzl hydrochloride be raw material, obtains 741mg colorless solid (yield 20%).ESI-MS(m/z)740[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-L-Ala-altheine (2q) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 741mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-altheine benzyl ester is raw material, obtains 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-ALANINE-altheine (3q) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 585mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-altheine is raw material, obtains 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-L-Ala-L-Gln (3r) synthetic
1) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Ala-L-Gln benzyl ester (1r) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Leu-N-carbobenzoxy-(Cbz)-identical method of 1B benzyl ester (1a), with 1.85g (5mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid and 2.25g (5mmol) Pro-Ala-Gln-OBzl hydrochloride be raw material, obtains 751mg colorless solid (yield 20%).ESI-MS(m/z)754[M+H] +.
2) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Ala-L-Gln (2r) synthetic
Adopt and preparation (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (2a), with 751mg (1mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Ala-L-Gln benzyl ester is raw material, obtains 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-L-Ala-L-Gln (3r) synthetic
Adopt and preparation (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-identical method of 6-formyl-L-PROLINE-L-Leu-1B (3a), with 595mg (0.9mmol) (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6, the 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-L-Ala-L-Gln is raw material, obtains 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).
The external thrombolytic experiment of embodiment 21
experiment material
Urokinase (UK, Beijing SaiSheng pharmacy Co., Ltd produces, 100,000 units/propping up), physiological saline (Cologne, Sichuan medicine company), distilled 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
By internal diameter 4mm, external diameter 5.5mm, one section Glass tubing of length 18mm is placed on a 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 in Glass tubing, screw diameter 1mm, length 20mm, the long hook of 2mm that comprises an end, blood be set in the stainless steel spiral around, while weighing, thrombus can be hung up, when hatching, thrombus can be hung in the solution of reaction flask, do not encounter wall, in order to avoid the damage thrombus.
(2) making of reaction flask
With the 10ml cillin bottle with rubber plug, wear a Stainless Steel Wire on rubber plug, an end in bottle curves hook, thrombus hangs on 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 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 may about 8ml can touch thrombus, therefore add 8ml solution to be measured in reaction flask, at 37 ℃ of constant-temperature tables, hatches.
(3) preparation of thrombus
By 20% urethane (6ml/kg for the 350-400g male SD rat, i.p.), anesthesia, lie on the back fixing, separates right common carotid artery, 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, immediately the blood of emitting is injected one by one and prepares the Glass tubing that thrombus is used with the 5ml syringe of silanization, the stainless steel spiral is put at once.Standing 40min makes thrombosis, afterwards Glass tubing is carefully taken off from base, with fine needle, thrombus surrounding and Glass tubing inwall is separated, removal of thromboses hangs on the rubber plug of reaction flask, add 8ml distilled water in reaction flask, thrombus is suspended in water to standing 1 hour, remove the floating blood in thrombus surface.After 1 hour, suck the moisture on thrombus surface with filter paper, accurately weigh one by one.
(4) measure the external thrombolysis activity of compound
Refill the solution of testing compound 3a-r in each reaction flask, using physiological saline as blank, UK (100IU/ml) is as positive control, then thrombus hung in the solution of testing compound, and 37 ℃ of constant-temperature table 70rpm are 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
For the assessing compound fibrinolytic, using physiological saline as blank, the positive contrast of 100000IU/1UK, carry out external thrombolysis activity experiment to compound, and data are as follows:
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 physiological saline group; C) P>0.05. that compares with the physiological saline group
Result shows, to concentration, is 100nM, 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 relatively arranged.The thrombolysis loss of weight of positive control is 83.35 ± 2.31mg.And the carboxyl terminal of working as peptide is to contain the amino acid of phenyl ring as Phe, during Tyr, do not present external thrombolysis activity.
Thrombolytic 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 company limited), urokinase (Beijing match crude drug industry), physiological saline (Cologne, Sichuan medicine company).Retaining plate, bulldog clamp, curved hemostat, straight mosquito forceps, Cyphophthalmi tweezer, straight ophthalmic tweezers, 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 intubation model
(1) prepare thrombus
The 200-220g male SD rat is anaesthetized with 20% urethane solution (6ml/kg, i.p.).The anesthetized rat dorsal position is fixed, and separates right common carotid artery, in proximal part folder bulldog clamp, proximal part and distal end penetrate respectively surgical thread, 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.Past vertical fixing Glass tubing (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 pipe.This thrombus Stainless Steel Wire that fixedly spiral is 0.2mm with diameter is coiled into, the long 12mm of spiral part, and containing 15 bung flanges, the diameter of bung flange is 1.0mm, and the holder handle is connected with spiral, and long 7.0mm, be question mark type.After 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) prepare the bypass intubate
The bypass intubate forms by 3 sections, and stage casing is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, two ends are identical polyethylene tube, long 100mm, internal diameter 1mm, external diameter 2mm, one end of this pipe pulls into point pipe (for inserting 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, in the polyethylene rubber tube that inserts stage casing).The equal silanization of the inwall of 3 sections pipes.The thrombus that thrombus is wrapped up fixedly spiral is put into the stage casing polyethylene rubber tube, and the two ends of sebific duct are nested with two poly butt ends that add respectively.With syringe by sharp pipe end by filling with heparin-saline solution (50IU/kg) in pipe, standby.
(3) carry out intubate
The left external jugular vein that separates rat, proximal part and distal end penetrate respectively surgical thread, cut carefully an angle on the left external jugular vein exposed, the sharp pipe of the bypass duct for preparing is above inserted to 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 the fixing spiral of the thrombus of accurately weighing).Push the heparin-saline (50IU/kg) of accurate amount by the sharp pipe of the other end with syringe, now syringe is not withdrawn polyethylene tube, with mosquito forceps, clamps the flexible pipe between syringe and polyethylene tube.Proximal part in right common carotid artery stops blooding with bulldog clamp, from bulldog clamp, right common carotid artery is being cut to an angle carefully nearby.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted to 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 by physiological saline (3ml/kg), the stage casing of the normal saline solution of the normal saline solution of urokinase (20000IU/kg) or different concns compound by bypass tube (containing the fixing spiral of the thrombus of accurately weighing), thrust away from the fixing nearly vein place of spiral of thrombus, open bulldog clamp, make blood flow flow to vein by bypass duct from artery, this is rat arteriovenous shut Thrombolysis Model, slowly the liquid in syringe is injected into to (about 6min) in blood, make physiological saline (blank), urokinase (positive control) or compound are by blood circulation, press the sequential action of vein-heart-artery to thrombus.Timing during from start injection, after 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 assessing compound.
experimental result
Adopt rat neck arteriovenous shut intubation model, take physiological saline as blank, the positive contrast of UK (20000IU/kg), thrombolysis activity in the body of assessing compound.Data are as follows:
The impact of table 23a-r on the rat suppository loss of weight a
Figure BDA0000064088280000241
A) n=10, urokinase dosage is 20000IU/kg, 3a-r dosage is 10nmol/kg; B) compare p<0.01. with the physiological saline group
Result shows, to concentration, is 10nmol/kg, 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 relatively arranged, 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
By the method for experimental example 20, choose the best 3a of thrombolytic effect and investigate the thrombolysis activity under 10nmol/kg, 1nmol/kg, 0.1nmol/kg Three doses.Result shows, thrombolytic effect show dose dependency (table 3) in the body of 3a.
The impact of the dosage of table 33a on the rat suppository loss of weight a
Figure BDA0000064088280000242
A) n=10; B) compare p<0.01 with physiological saline, 1nmol/kg and 0.1nmol/kg group; C) compare p<0.01 with physiological saline and 0.1nmol/kg group; D) compare p<0.01. with the physiological saline group
The nanostructure of experimental example 243a-r
1) particle diameter of 3a-r nanometer ball in the aqueous solution
Within continuous 8 days on Nano-ZS90 nano particle size determinator, measure 3a-r 10 -5the particle diameter of M.Result shows, 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
Figure BDA0000064088280000251
2) form of the nanometer ball of 3a-r
It is 1 * 10 that 3a-r is made into to concentration -10the aqueous solution of mol/ml, then drop in this solution on copper mesh, observes the form of nanometer ball after the dry solvent that volatilizees under transmission electron microscope (TEM).Mensuration shows, the nanometer ball of 3a-r formation rule.The transmission electron microscope photo of 3a, as representative, is described with Fig. 2.
Above-described embodiment is described the preferred embodiment of the present invention; not 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 the claims in the present invention book.

Claims (3)

1. the compound that general formula is I:
In 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. a method for preparing compound claimed in claim 1 is characterized in that comprising the following steps:
1) under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) existence, Boc-Pro is Boc-Pro-Ala with the Ala condensation in anhydrous THF;
2) under DCC and HOBt existence, AA-OBzl is Boc-Pro-Ala-AA-OBzl with the Boc-Pro-Ala condensation in anhydrous THF;
3) slough Boc at hydrogenchloride-ethyl acetate solution Boc-Pro-Ala-AA-OBzl and generate Pro-Ala-AA-OBzl;
4) (S)-3 under EDC and HOBt existence, 5-bis-(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-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino-acid benzyl ester;
5) (S)-3 under C/Pd exists, 5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino-acid benzyl ester sloughs OBzl and generates (S)-3 in methanol solution, 5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid;
6) in hydrogenchloride-ethyl acetate, in the anhydrous methylene chloride mixing solutions, (S)-3,5-bis-(tertbutyloxycarbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid removes Boc and generates (S)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-PROLINE-ALANINE-amino acid, obtain.
3. the purposes of compound claimed in claim 1 in preparing thrombolytic agent.
CN201110139398.3A 2011-05-26 2011-05-26 (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 Expired - Fee Related CN102796167B (en)

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