CN101906097B - 1,3-dioxane compounds as well as synthesizing method and medical application thereof - Google Patents
1,3-dioxane compounds as well as synthesizing method and medical application thereof Download PDFInfo
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- CN101906097B CN101906097B CN2009100851559A CN200910085155A CN101906097B CN 101906097 B CN101906097 B CN 101906097B CN 2009100851559 A CN2009100851559 A CN 2009100851559A CN 200910085155 A CN200910085155 A CN 200910085155A CN 101906097 B CN101906097 B CN 101906097B
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- tetrahydroisoquinoline
- serine
- formyl radical
- boc
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 150000000093 1,3-dioxanes Chemical class 0.000 title abstract description 4
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 16
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 12
- 150000001413 amino acids Chemical class 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 63
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 20
- 229960001153 serine Drugs 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 15
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 9
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- BWKMGYQJPOAASG-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN[C@H](C(=O)O)CC2=C1 BWKMGYQJPOAASG-VIFPVBQESA-N 0.000 claims description 5
- 229960005190 phenylalanine Drugs 0.000 claims description 5
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 4
- 229940024606 amino acid Drugs 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 61
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 abstract description 20
- 208000007536 Thrombosis Diseases 0.000 abstract description 5
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 abstract 1
- 229960004676 antithrombotic agent Drugs 0.000 abstract 1
- 238000013329 compounding Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 37
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 13
- -1 acyl Serine Chemical compound 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 5
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- 239000011780 sodium chloride Substances 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- HFPVZPNLMJDJFB-LBPRGKRZSA-N (3s)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-LBPRGKRZSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- 229910000071 diazene Inorganic materials 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
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- BNHQWMNGVIMKKZ-UHFFFAOYSA-N tert-butyl 3,4,4a,5-tetrahydro-1h-isoquinoline-2-carboxylate Chemical compound C1C=CC=C2CN(C(=O)OC(C)(C)C)CCC21 BNHQWMNGVIMKKZ-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 1
- OQGAELAJEGGNKG-QHCPKHFHSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-phenylmethoxybutanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)OCC1=CC=CC=C1 OQGAELAJEGGNKG-QHCPKHFHSA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- ZPGDWQNBZYOZTI-UHFFFAOYSA-N 1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 229940122202 Thromboxane receptor antagonist Drugs 0.000 description 1
- 108010069102 Thromboxane-A synthase Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical class Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
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- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
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Abstract
The invention discloses 1,3-dioxane compounds as well as a synthesizing method and medical application thereof. The synthesizing method comprises the following steps of: compounding tetrahydroisoquinoline and 1,3-dioxane, and then modifying the N end of the tetrahydroisoquinoline by using 20 kinds of endogenous amino acid to obtain the 1,3-dioxane compounds with excellent antithrombotic activities, which are evaluated by adopting a rat thrombus model. The experimental results indicate that the compounds all have excellent antithrombotic activities and can be clinically used as antithrombotic agents.
Description
Technical field
The present invention relates to six lopps compounds, relate in particular to and have 1 of antithrombotic acitivity, the 3-dioxanes compounds, the invention still further relates to this 1, the compound method of 3-dioxanes compounds and they belong to biomedicine field as the application of pharmaceutical preparations having antithrombotic activity.
Background technology
The M & M of cardiovascular and cerebrovascular diseases day by day rises at present.The major cause that causes cardiovascular and cerebrovascular diseases is to form thrombus in the blood vessel.Thrombocyte plays a part very crucial in the thrombotic process.Anticoagulant, and then suppress the important step that thrombosis has become the various cardiovascular disordeies of prevention.So the research to medicament for resisting platelet aggregation also receives publicity day by day.
Thromboxane (TXA
2) be arachidonic meta-bolites, be a kind of strong platelet aggregating agent, many cardiovascular disordeies and TXA
2Excessive generation relevant, so thromboxane synthetase inhibitor and thromboxane receptor antagonist be the focus of research at present, especially based on 1, the research of 3-dioxane parent nucleus.And it is reported that tetrahydroisoquinoline has good platelet aggregation inhibitory activity; The contriver recognizes that with tetrahydroisoquinoline and 1 the 3-dioxane combines, and is terminal modified to tetrahydroisoquinoline N with 20 kinds of endogenous amino acid; The antithrombotic reagent that can obtain, so the contriver proposes the present invention.
Summary of the invention
One of the object of the invention is with tetrahydroisoquinoline and 1, and the 3-dioxane combines, and with 20 kinds of endogenous amino acid tetrahydroisoquinoline N end is modified, and obtains one type and has 1 of outstanding antithrombotic acitivity, the 3-dioxanes compounds;
Two of the object of the invention provides a kind of synthetic above-mentioned 1, the method for 3-dioxanes compounds;
Three of the object of the invention provides above-mentioned, a kind of purposes of 3-dioxanes compounds in medical science.
Above-mentioned purpose of the present invention realizes through following technical scheme:
Have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
General formula I
Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Another object of the present invention provides a kind of above-mentioned 1 of antithrombotic acitivity that has for preparing, the method for 3-dioxanes compounds, and this method may further comprise the steps:
(1) preparation N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol; (3) with 1,2,3, the two pure and mild paranitrobenzaldehyde condensations of 4-tetrahydroisoquinoline acyl Serine generate 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (4) with 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate 5-[Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane; (5) 5-(Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical)-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis promptly gets; Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Wherein, described N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol can prepare with reference to following method:
(1) at SOCl
2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine(Phe) into 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety; (3) at (Boc)
2With 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety changed N-tertbutyloxycarbonyl tetrahydroisoquinoline under O and NaOH existed; (4) L-serine methylester and the condensation of N-tertbutyloxycarbonyl tetrahydroisoquinoline generate N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester in the presence of DCC, HOBt.
Described 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol can prepare with reference to following method:
(1) at NaBH
4Following with the THF existence with N-t-butoxycarbonyl amino acyl-1,2,3, the reduction of 4-tetrahydroisoquinoline acyl serine methylester, generation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) in the presence of hydrogenchloride-THF with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydroisoquinoline acyl silk glycol generates 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol.
Estimate the antithrombotic acitivity of compound of the present invention on the rat anti thrombus model, test-results shows that chemical combination of the present invention has outstanding antithrombotic acitivity, can be used as pharmaceutical preparations having antithrombotic activity and uses.
Another purpose of the present invention provides the medicinal compsns of the above-mentioned general formula compound of a kind of the present invention of containing, and this medicinal compsns is gone up effective dose by treatment The compounds of this invention is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the The compounds of this invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
Description of drawings
The synthetic route chart of Fig. 1 The compounds of this invention; I) formaldehyde and concentrated hydrochloric acid, 80 ℃ of oil bath condensing refluxes; Ii) (Boc)
2O, the NaOH ice bath; Iii) SOCl
2, CH
3The OH cryosel is bathed iv) Ser-OMe, DCC, HoBt, NMM ice bath; V) NaBH
4, THF; Vi) vii) paranitrobenzaldehyde of 4N HCl/THF, BF
3Et
2O, CH
3The CN ice bath; Viii) Fmoc-AA, DCC, HoBt, NMM ice bath; Wherein AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr; Ix) NaOH/CH
3OH, CH
2Cl
2, ice bath; AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr.
Embodiment
In order further to set forth the present invention, provide a series of instances below.These instances are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
In 4.0g (24.2mmol) L-phenylalanine(Phe), dropwise add 21.6ml formaldehyde earlier, dropwise add 36ml 35% concentrated hydrochloric acid again.The suspension oil bath that obtains is heated to 2 two hours phenylalanine(Phe)s of 80-90 ℃ of stirring and dissolves fully, reacts after 2.5 hours, begins to have colourless deposition to generate, and reacts TLC (CHCl 7 hours
3/ CH
3OH=5/1) show that the L-phenylalanine(Phe) disappears, suction filtration gets the 4.2g colorless solid, and the gained colorless solid is joined in the 86ml ethanol (80%) 80 ℃ of oil baths heating 9 hours; Dissolve to colorless solid; Be cooled to room temperature, slowly drip 1ml (1.376g Pottasium Hydroxide is dissolved in 1ml zero(ppm) water) potassium hydroxide solution, have colourless deposition to separate out; Cross and filter 4.02g (94%) title compound, be colorless solid.MP:302.1-302.5 ℃, [α]
D 25=-68 (c 1 methyl alcohol); ESI-MS (m/z) 176 [M-1]
-
The following 2.49g of ice bath (62.15mmol) sodium hydroxide dissolves in 62.2ml water, adds 10g (56.49mmol) then (3S)-1,2,3, and 4-tetrahydroisoquinoline-3-carboxylic acid is processed suspension.With 40ml THF dissolving 14.8g (67.8mmol) (Boc)
2O adds in the suspension.Reaction mixture stirred 48 hours, the solution becomes clarification, and TLC (ethyl acetate/petroleum ether: 1: 3) shows (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid disappears, and stops reaction.The reaction mixture concentrating under reduced pressure is removed THF, and the oily matter that obtains is used acetic acid ethyl dissolution.The solution that obtains is used 5%KHSO successively
4Wash with the saturated NaCl aqueous solution.Organic layer is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression, the oily matter that obtains stirred 24 hours with ethyl acetate/petroleum ether (1: 10), and the colorless solid that obtains filters, and obtains 12.5g (79.9%) title compound.ESI-MS (m/z) 278.2 [M+1]
+, [α]
D 25=-6.78 (c1 methyl alcohol);
The 50ml anhydrous methanol is dripping thionyl chloride 3.75ml (0.050mol) under ice bath, adds L-Serine 5g (0.042mol) behind the 30min, and stirring at room 24h, TLC monitor to raw material disappearance termination reaction.Water pump is taken the intact sulfur oxychloride SOCl of unreacted away
2And HCl, with sherwood oil grind repeatedly white solid 7.34g (productive rate 99%), Mp:161 ℃-162 ℃
Embodiment 4 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester (3)
Ice bath down with anhydrous THF with 5.54g (20mmol) (3S)-N-Boc-1,2,3; 4-tetrahydroisoquinoline-3-carboxylic acid dissolving; Add 2.8g (21mmol) N-hydroxy benzo triazole (HOBt), the dissolving back adds 4.9g (24mmol) dicyclohexyl carbonyl diimine (DCC), obtains reaction solution (I).Be suspended in 2.6g (16.7mmol) HClSer-OMe among the anhydrous THF, add N-methylmorpholine (NMM) and transfer pH value 8~9, get reaction solution (II).Add (I) in (II), stirring at room 12h, TLC (petrol ether/ethyl acetate, 3: 1) show that HClSer-OMe disappears.Leach NSC 30023 (DCU), filtrate decompression is concentrated into dried, and residue is used the 80ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, 5%KHSO
4The aqueous solution, the saturated NaCl aqueous solution, saturated NaHCO
3The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior.Ethyl acetate layer is used anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate 5.68g (90%) title compound, be colorless solid
Embodiment 5 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (4)
With 5 dissolvings of 0.378g (1mmol) compound, ice bath adds 0.152g (4mmol) NaBH following minute three times with THF
4, behind the reaction 12h, TLC (CHCl
3/ CH
3OH, 10: 1) show that raw material disappears.With the HCl aqueous solution adjust pH 5-6 of 2N, concentrating under reduced pressure is removed THF under the ice bath vigorous stirring, and residue is used EtOAc/H
2O dissolving, separatory, water layer are used the EtOAc extracted twice, and the ester layer is with 5% KHSO
4The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, and the ester layer is used anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate 0.210g (60%) title compound, be colorless solid [α]
D 25=-8.67 (c 0.65CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 351 [M+H]
+
Embodiment 6 preparation N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (5)
With a small amount of anhydrous THF dissolving of 0.210g (0.6mmol) compound 4 usefulness, ice bath drips 2ml 4N HCl/THF solution down, stirring reaction, and behind about 2h, TLC (CHCl
3/ CH
3OH, 10: 1) show that raw material disappears, in reaction solution, pour a large amount of ether into, there is colorless solid to separate out, leave standstill, inclining supernatant, and solid adds diethyl ether and takes out three times, gets oily matter, directly is used for step reaction down.ESI-MS(m/z):251[M+H]
+
Embodiment 7 preparation 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyls-1,3-dioxane (6)
In 0.287g (1mmol) compound 5, add the 2ml acetonitrile and suspend, add 0.302g (2mmol) paranitrobenzaldehyde, ice bath stirs down, slowly drips 0.25ml BF
3Et
2O, reaction solution becomes clarification, and along with reaction, reaction solution becomes the jelly shape.TLC (CHCl
3/ CH
3OH, 10: 1) monitoring, initial point does not have colour developing, filters, and filter cake is washed till white with EtOAc, and filter cake is transferred in the 100ml eggplant bottle, adds saturated NaHCO
3The aqueous solution, adjust pH to 8 stirs half a hour, filters, and gets title compound, colorless solid 0.214g (56%); Mp:217-217.4 ℃; [α]
D 25=-53.23; (c 0.65 CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 384.2 [M+H]
+
Embodiment 8 preparation 5-[(3S)-and N-Fmoc-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7a)
Ice bath dissolves 0.289g (0.85mmol) Fmoc-Val with anhydrous THF down; Add 0.1g (0.74mmol) N-hydroxy benzo triazole (HOBt); The dissolving back adds 0.175g (0.85mmol) dicyclohexyl carbonyl diimine (DCC) and obtains reaction solution (I); Be suspended in 0.272g (0.71mmol) compound 6 in the dry DMF, add N-methylmorpholine (NMM) and transfer pH value 8~9, get reaction solution (II).Add in (II) stirring at room 24h, TLC (CH to (I)
2Cl
2/ CH
3OH, 20: 1) show that compound 8 disappears.Leach NSC 30023 (DCU), filtrating dries up, and residue is used the 10ml acetic acid ethyl dissolution.Filter, the solution that obtains is used 5%NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, it is inferior respectively to give a baby a bath on the third day after its birth.Ethyl acetate layer is used anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate, through silica gel column chromatography obtain 0.3g (60%) title compound (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), be colorless solid; Mp:108.2-109.6 ℃; [α]
D 25=-67.33 (C 0.65; CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 727.3 [M+Na]
+
Embodiment 9 preparation 5-[(3S)-and N-Fmoc-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7b)
According to the operation of preparation 7a, get 0.312g (43%) title compound, (CH from 0.414g (1.23mmol) Fmoc-Leu and 0.392g (1.02mmol) compound 6
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp:118.2-120.0℃[α]
D 25=-63.88(C?0.55?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):719.2[M+H]
+
Embodiment 10 preparation 5-[(3S)-and N-Fmoc-Ile-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7c)
According to the operation of preparation 7a, 0.221g (0.63mmol) Fmoc-Ile and 0.2g (0.52mmol) compound 6 get 0.242g (65%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp:101.9-102.5°C;[α]
D 25=-56.10(C?0.7?CH
2Cl
2/CH
3O?1∶1?V/V);ESI-MS(m/z)719.2[M+H]
+
Embodiment 11 preparation 5-[(3S)-and N-Fmoc-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7d)
According to the operation of preparation 7a, 0.279g (0.94mmol) Fmoc-Gly and 0.3g (0.78mmol) compound 6 get 0.3g (58%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.20), colorless solid.Mp:128.3-128.9℃[α]
D 25=-64.67(C?0.2?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):663.2[M+H]
+,685.2[M+Na]
+
Embodiment 12 preparation 5-[(3S)-and N-Fmoc-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7e)
According to the operation of preparation 7a, 0.298g (0.95mmol) Fmoc-Ala-OH and 0.306g (0.80mmol) compound 6 get 0.3g (55%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid; Mp169.9-171.8 ℃ [α]
D 25=-52.53 (C 0.5 CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 699 [M+Na]
+
Embodiment 13 preparation 5-[(3S)-and N-Fmoc-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7f)
According to the operation of preparation 7a, 0.511g (1.20mol) Fmoc-Trp and 0.383g (1mmol) compound 6 get 0.352g (45%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.22), yellow solid.Mp:129.4-130.5℃[α]
D 25=-16.29(C?0.8?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):792[M+H]
+;814.5[M+Na]
+
Embodiment 14 preparation 5-[(3S)-and N-Fmoc-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7g)
According to the operation of preparation 7a, 0.260g (0.76mmol) Fmoc-Thr and 0.244g (0.63mmol) compound 6 get 0.204g (46%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.18), colorless solid.Mp:98.5-100.1℃;[α]
D 25=-40.85(C?0.9CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):729.5[M+Na]
+
Embodiment 15 preparation 5-[(3S)-and N-Fmoc-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7h)
According to the operation of preparation 7a, 0.387g (1.04mmol) Fmoc-Met and 0.333g (0.87mmol) compound 6 get 0.278g (43%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.23), colorless solid.Mp:195.2-196.2℃;[α]
D 25=-59.95(C?0.7?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):759.6[M+Na]
+。
Embodiment 16 preparation 5-[(3S)-and N-Fmoc-Asp (OBzl)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7i)
According to the operation of preparation 7a, 0.62g (1.39mmol) Fmoc-Asp (OBzl) and 0.445g (1.16mmol) compound 6 get 0.48g (51%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp:102.4-103.8℃;[α]
D 25=-20.88(C?0.9?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):833.8[M+Na]
+
Embodiment 17 preparation 5-[(3S)-and N-Fmoc-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7j)
According to the operation of preparation 7a, 0.351g (1.04mmol) Fmoc-Pro and 0.333g (0.87mmol) compound 6 get 0.353g (58%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.21), colorless solid.Mp:116.7-118.4℃;[α]
D 25=-55.70(C?1?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):725.5[M+H]
+
Embodiment 18 preparation 5-[(3S)-and N-Fmoc-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7k)
According to the operation of preparation 7a, 0.403g (1.04mmol) Fmoc-Phe and 0.333g (0.87mmol) compound 6 get 0.340g (52%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.24), colorless solid.Mp:186-186.8℃;[α]
D 25=-51.68(C?1.05?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):775.4[M+23]
+
Embodiment 19 preparation 5-[(3S)-N-(Fmoc)
2-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7l)
According to the operation of preparation 7a, 0.708g (1.20mmol) (Fmoc)
2-Lys and 0.383g (1.00mmol) compound 6 gets 0.45g (47%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid.Mp:107.8-108.9℃;[α]
D 25=-33.76(C?0.7?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):978.4[M+23]
+
Embodiment 20 preparation 5-[(3S)-and N-Fmoc-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7m)
According to the operation of preparation 7b, 0.241g (0.6mmol) Fmoc-Tyr and 0.191g (0.5mmol) compound 6 get 0.17g (44%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid.Mp:128.3-130.2℃;[α]
D 25=-43.71(C?0.35?CH2Cl2/CH3OH?1∶1?V/V);ESI-MS(m/z):791.5[M+Na]
+
Embodiment 21 preparation 5-[(3S)-and N-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8a)
0.25g 7a is used a small amount of CH
2Cl
2Dissolving.Drip the NaOH/CH of 0.25N
3OH solution, pH value about 11, ice bath is reaction 6h down, and the TLC detection reaction is complete, (CH
2Cl
2: CH
3OH=20: 1), be evaporated to driedly, solid is worn away three times with ether, again with a small amount of washing, title compound 0.12g (71%); Mp:89.2-91.0 ℃; [α]
D 25=-21.24 (C 0.75 CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 483 [M+H]
+
Embodiment 22 preparation 5-[(3S)-and N-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (8b)
Operation according to preparation 8a gets 0.172g (83%) title compound (colorless solid) from 0.300g (0.41mmol) 7b.Mp:100.8-101.6℃;[α]
D 25=-47.00(C?0.8CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z)497.5[M+H]
+
Embodiment 23 preparation 5-[(3S)-and N-Ile-1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8c)
Operation according to preparation 8a gets 0.120g (87%) title compound (colorless solid) from 0.200g (0.27mmol) 7c.Mp:101.1-103.1℃;[α]
D 25=-43.92(C?0.65CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):497.3[M+H]
+
Embodiment 24 preparation 5-[(3S)-and N-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8d)
Operation according to preparation 8a gets 0.151g (91%) title compound (colorless solid) from 0.250g (0.38mmol) 7d.Mp:126.9-129.0℃[α]
D 25=-18.2(C?0.5CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):441.3[M+H]
+;463.3[M+Na]
+
Embodiment 25 preparation 5-[(3S)-and N-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8e)
Operation according to preparation 8a gets 0.156g (90%) title compound (colorless solid) from 0.260g (0.38mmol) 7e.Mp:87.5-89.2℃;[α]
D 25=-45.94(C?0.55?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):455.4[M+H]
+
Embodiment 26 preparation 5-[(3S)-and N-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8f)
Operation according to preparation 8a gets 0.152g (79%) title compound (colorless solid) from 0.300g (0.38mmol) 7f.Mp:128.5-130.2℃;[α]
D 25=8.48(C?0.9?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):570.4[M+H]
+
Embodiment 27 preparation 5-[(3S)-and N-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8g)
Operation according to preparation 8a gets 0.08g (78%) title compound (colorless solid) from 0.150g (0.21mmol) 7g.Mp:142-144℃;[α]
D 25=-42.57(C?0.8?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):485.2[M+H]
+
Embodiment 28 preparation 5-[(3S)-and N-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8h)
Operation according to preparation 8a gets 0.124g (81%) title compound (colorless solid) from 0.220g (0.30mmol) 7h.Mp:111.8-113.2℃;[α]
D 25=-42.00(C?0.5?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS?m/z):515.3[M+H]
+
Embodiment 29 preparation 5-[(3S)-and N-Asp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8i)
According to the NaOH/CH of the operation for preparing 8a with 0.5N
3OH suspension solution adjust pH 12, after reacting completely, under the vigorous stirring, the KHSO with 5%
4The slow adjust pH 5-6 of solution revolves CH
2Cl
2/ CH
3OH, residue adds less water, CH
2Cl
2Extract anhydrous Na three times
2SO
4Drying is filtered, and revolves driedly, and ether is given a baby a bath on the third day after its birth time, gets 0.170g (70%) title compound (faint yellow solid) from 0.400g (0.49mmol) 7i.Mp:90.0-91.6℃[α]
D 25=-80.87(C0.5?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):513.4[M+15]
+
Embodiment 30 preparation 5-[(3S)-and N-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8j)
Operation according to preparation 8a gets 0.177g (90%) title compound (colorless solid) from 0.290g (0.41mmol) 7j.Mp:188.1-189.0℃;[α]
D 25=-73.33(C?0.6?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):481.4[M+H]
+
Embodiment 31 preparation 5-[(3S)-and N-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8k)
Operation according to preparation 8a gets 0.162g (92%) title compound (colorless solid) from 0.250g (0.33mmol) 7k.Mp:154.0-155.8℃;[α]
D 25=-16.12(C?0.55?CH
2Cl
2/CH
3OH?1∶1?V/V)ESI-MS(m/z):531.6[M+H]
+;553.6[M+Na]
+
Embodiment 32 preparation 5-[(3S) N-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyls-1,3-dioxane (8l)
Operation according to preparation 8a gets 0.190g (90%) title compound (colorless solid) from 0.400g (0.42mmol) 7l; Mp:129.3-131.1 ℃; [α]
D 25=-45.47 (C 0.65 CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 512.3 [M+H]
+
Embodiment 33 preparation 5-[(3S)-and N-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8m)
Operation according to preparation 8a gets 0.079g (74%) title compound (colorless solid) from 0.150g (0.20mmol) 7m.Mp:110.9-112.3℃;[α]
D 25=-39.65(C?0.7?CH
2Cl
2/CH
3OH?1∶1?V/V);ESI-MS(m/z):547.3[M+H]
+
Antithrombotic acitivity test in the body of Test Example 1 The compounds of this invention
1) test materials
Test-compound: the compound that the embodiment of the invention is prepared is numbered 6 respectively, 8a-m;
Positive reference substance is a Frosst)
Laboratory animal: the Wistar rat, male, body weight 180-220; Provide by animal portion of the Capital University of Medical Sciences.
Solvent: saline water
Polyethylene tube (two kinds of external diameter 1.6mm and 1.3mm), heparin (50IU/ml), Ethylurethanm, silk thread.
2) TP
1. dosage setting
Test-compound 6,8a-m are 10nmol/kg, all adopt the vein single administration.Frosst) is 20mg/Kg.
2. medicine preparation
Test-compound 6,8a-m and Frosst) are all used physiological saline solution
3. measuring method
Male SD rat (anaesthetize, and isolates RCCA and left external jugular vein, puts into the long silk thread of 6cm of weighing in advance in the stage casing of polyethylene tube by body weight 180~220g) abdominal injection Sodital sodium solutions; (50IU/kg) is full of polyethylene tube with heparin-saline, and an end is inserted left external jugular vein, with syringe with heparin (3ml/kg); Physiological salt soln (the 40mg/10ml of Frosst); 3ml/Kg), 6,8a-m (10nmol/kg; Physiological salt soln 3ml/kg) slowly injects polyethylene tube from the other end; Original heparin has been pushed in the left external jugular vein in managing this moment, and major part is a test compound solution in the pipe, then the injectable drug end is inserted RCCA.Blood flows to left external jugular vein from RCCA through polyethylene tube, and middle Herba Clinopodii behind the 15min takes out silk thread and weighs, and gross weight deducts silk thread weight and is wet weight of thrombus
4. statistical method
This experimental data statistics all adopts t check and variance analysis, with (x ± SD) expression.
5. test-results
The influence that table 18a-n forms rat suppository
N=10 a) compares p<0.01 with saline water; B) compare p<0.05 with saline water
Can find out that from table 1 The compounds of this invention 6,8a-m are compared the difference with significance with saline water under 10nmol/kg dosage, be outstanding pharmaceutical preparations having antithrombotic activity.
Claims (6)
1. have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
Wherein, R is selected from the group that forms behind the hydroxyl on the amino acid decarboxylize that hydrogen or R be selected from Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr representative;
Described have 1 of an antithrombotic acitivity, and in the 3-dioxanes compounds, the carbon atom that * indicated is the S configuration.
2. a synthetic claim 1 is described 1, and the method for 3-dioxanes compounds may further comprise the steps:
(1) preparation N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (3), generate 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1, the 3-dioxane with N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine two pure and mild paranitrobenzaldehyde condensations; (4) with 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate
5-[(3S)-and N-Fmoc-R-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1, the 3-dioxane; (5) 5-[(3S)-N-Fmoc-R-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis promptly gets; Wherein, R such as claim 1 definition, AA is selected from hydrogen, or Fmoc-AA representative is with the amino acid AA of Fmoc protection, AA is selected from Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
3. according to the described method of claim 2, it is characterized in that described N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol prepares according to following method:
(1) at SOCl
2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine(Phe) into (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3) at (Boc)
2With (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid changed (3S)-N-Boc-1 under O and NaOH existed, and 2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (4) L-serine methylester and (3S)-N-Boc-1 in the presence of DCC, HOBt, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid condensation generates N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester; (5) at NaBH
4Exist down N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester reduction with THF, generate N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (6) in the presence of hydrogenchloride-THF with N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol acidolysis, generate N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol.
4. pharmaceutical composition is characterized in that: it is described 1 to go up the claim 1 of significant quantity by treatment or prevention, and 3-dioxanes compounds and pharmaceutically acceptable carrier are formed.
5. pharmaceutical composition is characterized in that: it is described 1 to go up the claim 1 of significant quantity by treatment or prevention, and 3-dioxanes compounds and acceptable accessories are formed.
6. claim 1 is described 1, the application of 3-dioxanes compounds in the preparation pharmaceutical preparations having antithrombotic activity.
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