CN1743329A - Hexahydro-pyrazino-pyridino-indole dione, and its synthesis and use - Google Patents
Hexahydro-pyrazino-pyridino-indole dione, and its synthesis and use Download PDFInfo
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- CN1743329A CN1743329A CN 200410074208 CN200410074208A CN1743329A CN 1743329 A CN1743329 A CN 1743329A CN 200410074208 CN200410074208 CN 200410074208 CN 200410074208 A CN200410074208 A CN 200410074208A CN 1743329 A CN1743329 A CN 1743329A
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- tetrahydrochysene
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- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 5
- JOBFTQZDNSWUKZ-UHFFFAOYSA-N 2,4,7,12-tetrazatetracyclo[8.7.0.03,8.011,15]heptadeca-3,5,7,9-tetraene-13,14-dione Chemical compound N1C(C(C2CCC3C(C12)=CC1=C(N3)N=CC=N1)=O)=O JOBFTQZDNSWUKZ-UHFFFAOYSA-N 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 -CH2COOH Chemical group 0.000 claims abstract description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 239000006035 Tryptophane Substances 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229960004799 tryptophan Drugs 0.000 claims description 3
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- 238000010189 synthetic method Methods 0.000 abstract description 2
- FSNCEEGOMTYXKY-JTQLQIEISA-N (3s)-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 abstract 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract 2
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- 229910006124 SOCl2 Inorganic materials 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 235000019256 formaldehyde Nutrition 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
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- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
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- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 1
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- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 1
- IVCGJOSPVGENCT-UHFFFAOYSA-N 1h-pyrrolo[2,3-f]quinoline Chemical class N1=CC=CC2=C(NC=C3)C3=CC=C21 IVCGJOSPVGENCT-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
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- NFVNYBJCJGKVQK-ZDUSSCGKSA-N N-[(Tert-butoxy)carbonyl]-L-tryptophan Chemical compound C1=CC=C2C(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CNC2=C1 NFVNYBJCJGKVQK-ZDUSSCGKSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
As shown in the general formula I of the compound at right, R is among H, -CH3, -CH(CH3)2, -CH2COOH, -CH2C6H5, -CH2OH, -CH2(CH2)3NH2, indole-3-methene, -CH2C6H4-OH-p and CH2 CH2CONH2. The synthetic method is as follow: first, with sulphuric acid as catalyser, let tryptophan react with methanal to generate (3S)-1, 2, 3, 4-tetrahydro-beta-carboline-3- carboxylic acid, which will react with SOCl2 and methanol to generate (3S)-1, 2, 3, 4-tetrahydro-beta-carboline-3-carbomethoxylate; then, with the presence of N-hydroxyl benzotriazole (HOBt) and DDC(N, N-bicyclohexyl), let Boc-amino acid(butyloxycarbonyl-amino acid) to react with (3S)-1, 2, 3, 4-tetrahydro-beta-carboline-3-carbomethoxylate to generate N-butyloxycarbonyl-amino acyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carbomethoxylate, which will be cyclized, in HCl/ethyl acetate solution, into hexhydro-pyrazino-pyrrolo-didone. The compound of formula I possess the function of H1 recipient inhibitor.
Description
Technical field
The present invention relates to novel six hydrogen of a class-pyrazine also-pyrido-indole dione, and this compounds synthetic and as H
1The application of acceptor inhibitor.
Background technology
Indole alkaloid is maximum alkaloid, present known more than the 1400 kind of indole alkaloid that have, account for the alkaloid sum 1/5th (Guo Min. the research of the synthetic and anti-tumor activity of the stereoselectivity of indole alkaloid compounds. the candidate for doctorate of Beijing Medical University paper, 1995).Indole alkaloid is to be rich in multifarious alkaloid most.The diversity of indole alkaloid not only shows the variation of structure, and shows the popularity of physiological action, thereby is the structure type that the pharmaceuticals researcher attaches great importance to for many years always.The anti-inflammatory of indole alkaloid, relieving asthma, cough-relieving, antidiarrheal, step-down, stimulating central nervous system and even multiple pharmacological effect such as anticancer, be used widely clinically, in plant amedica, occupy extremely important status.Six hydrogen-pyrazine that the contriver notices this class indole alkaloid and following formula also-pyrido-indole dione is relevant.
Phosphodiesterase (PDE) is the superfamily of the enzyme of an interior second messenger c-AMP of degraded born of the same parents and c-GMP, necessary regulatory factor as the cyclic nucleotide signalling system, has different physiological roles, be multiple disease of treatment such as heart failure, depressed, asthma, target molecule (the GrahamN.Maw of the medicine of inflammation and erection problem (ED), C.M.N.A., Eugene Gbekor and William A.Million.Design, Synthesis andBiological Activity of Carboline-Based Type-5 Phosphodieste-rase Inhibitors.Bioorganic ﹠amp; Medicinal Chemistry Letters 2003,13,1425).The phosphodiester enzyme family has 12 hypotypes, and PDE5 is one of them, mainly is present in the human cavernous body, is vigour and other similar pharmaceutically-active target molecules.Some of generation nineteen ninety studies show that, six hydrogen-pyrazine also-pyrido-indole dione compounds shows outstanding selective inhibitory activity to PDE5.
Skin allergic disease is mainly by due to the transformation reactions, and the various chemical mediators that mastocyte and basophil discharge are the effect components that cause transformation reactions to take place, particularly important (the He Fei of histamine wherein, some problems in the clinical application of leaf celebrating a dance squad s-generation antihistaminic. clinical Dermatology Department magazine 2003,32,300).By the anaphylactic disease of histamine-mediated, be common frequently-occurring disease as allergic rhinitis, urticaria, pollen hypersensitivity, spring fever, eczema, pruritus etc.Antihistaminic has become the main medicine for the treatment of various anaphylaxis dermatosis clinically.Along with the topsoil aggravation, the sickness rate of this anaphylactoid disease is also rising.Developed more than 100 kind of antihistamine drug at present, wherein more than 20 kind comparatively extensive in clinical application.First-generation H
1Receptor antagonist easily passes hemato encephalic barrier, and strong calm and anticholinergic effect and transformation period weak point are arranged, and clinical application is restricted, gradually by s-generation H
1Receptor antagonist replaces.S-generation H
1The receptor antagonist maincenter suppresses and anticholinergic effect weakens, and is considered to treat relatively safe and effective medicine of I metallergy disease at present.S-generation H
1Receptor antagonist is also as the ancillary drug for the treatment of asthma.But, s-generation H
1Receptor antagonist still has the defective of aspects such as interaction between cardiac toxic, the medicine and central nervous system effect.Remain further composition optimizes (the chivalrous Zhang Zhonghang of Liu Hui. s-generation H
1The clinical application of receptor antagonist. world's clinical medicine 2003,24,98; Yang Sen Zhang Xuejun. antihistamine drug is used progress. Chinese Journal of New Drugs and Clinical Remedies 2002,21,177; Sun Huixian compiling Liu Li duckweed school, the progress of s-generation antihistaminic. foreign medical science pharmacy fascicle .2001,28,263).
Since the 1970's, six hydrogen-pyrazine also-antihistamine of pyrido-indoles, anxiety, spirit suppresses and hypotensive activity is just paid close attention to.Attempting it is developed in the trial of central nervous system medication, on the nitrogen of piperazine ring, introduce substituting group by the mode of fragment combination, obtained some to histamine H
1Acceptor have active six hydrogen of better inhibition-pyrazine also-pyrido-indoles (Jyoti Rao, A.K.S., RmSaxena, H K Singh, K Kar, R C Srimal.Synthesis of N-[3-Aryl (thio-/sulphono) propyl] heterocyclics as Potential CNS/CVS Agents.Indian Journal ofChemistry 1987,26B, 761; Mridula Saxena, S.K.A., G.K.Patnaik, Anil K.Saxena.Synthesis, Biological Evaluation, and Quantitative Structure-Activity RelationshipAnalysis.A New Class of Potent H1Antagonists.J.Med.Chem.1990,33,2970; Shiv K Agarwal, A.K.S., Padam C Jain, Nitya Anand, R N Sur, R C Srimal, Bhola NDhawan.synthesis and structure activity relationship in aryloxyalkylamines.IndianJoumal of Chemistry 1990,29B, 80; Saxena, A.K.R., Siya; Saxena, Mridula; Singh, Nidhi; Prathipati, and Philip; Jain, P.C.S., H.K.; Anand, Nitya.QSAR studies insubstituted 1,2,3,4,6,7,12,12a-octa-hydropyrazino[2 ', 1 ': 6,1] pyrido[3,4-b] indoles-apotent class of neuroleptics.Bioorganic ﹠amp; Medicinal Chemistry, 2003,11,2085).
Six hydrogen-pyrazine also-pyrido-indole dione is as phosphodiesterase inhibitor and H
1The potential application of acceptor inhibitor has caused contriver's concern.
Summary of the invention
The object of the present invention is to provide six novel hydrogen of a class-pyrazine also-pyrido-indole dione.
The present invention also aims to provide such novel six hydrogen-pyrazine also-synthetic method of pyrido-indole dione and as H
1The application of acceptor inhibitor.Compound provided by the invention such as general formula I, wherein-R be H ,-CH
3,-CH
2(CH
3)
2,-CH
2COOH ,-CH
2C
6H
5,
General formula I
-CH
2OH ,-CH
2(CH
2)
3NH
2, the indol-3-yl methylene radical ,-CH
2C
6H
4-OH-p, CH
2CH
2CONH
2
The present invention also provides the method for synthetic compound of Formula I, and this method comprises: tryptophane and formaldehyde reaction generate (3S)-1,2,3 under sulfuric acid catalysis, 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid, (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid and SOCl
2And the methyl alcohol reaction generates (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester, in the presence of N-hydroxyl benzotriazole (HOBt) and DCC Boc-amino acid (t-butoxycarbonyl amino acid) with (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester reaction generation N-t-butoxycarbonyl amino acyl-(3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester, N-t-butoxycarbonyl amino acyl in the HCl/ ethyl acetate solution-(3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester cyclisation be six hydrogen-pyrazine also-pyrido-indole dione.
Above-mentioned reaction can be used following procedural representation:
The contriver also by with isolated guinea pig ileum model determination six hydrogen-pyrazine also-anti-histamine activity of pyrido-indole dione, find that it can be used as antihistaminic agent and uses.
Embodiment
In order to explain the present invention, provide a series of examples of executing below.These examples are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
General rule: used amino acid is the L-configuration; Reagent is commercially available (chemical pure) except that indicating; Each degree of purity of production of intermediate is confirmed with TLC; Nuclear magnetic resonance spectrometer device model: VXR-300S (300MHz) or INOVA-500 (500MHz); The mass spectrometer model: the ZAB-MS of FAB-MS Britain VG company, EI-MS measures with the Trace MS System mass spectrograph of U.S. Thermo Finnigan company; The desk-top micro-fusing point instrument of XT5 heat that fusing point test is produced with Beijing instrument electric light instrument plant of section, temperature is not proofreaied and correct.The used instrument of polarimetry is the POLARTRONIC D type trace polarimeter of SCHMIDT+HAENSCH company, the long 5cm of sample pool, volume 0.7ml.The compound name is a foundation with the CA systematic nomenclature mainly, and the band carboline is common name in a few title, presses the IUPAC systematic naming method.
Prepare embodiment
Midbody compound (3S)-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid
In 25ml sulfuric acid (1N), add 5g (24.5mmol) tryptophane under stirring, 75ml deionized water and 4ml (45.6mmol) formaldehyde solution (38%), reaction solution becomes clarification rapidly, separates out a large amount of solids after about 5 minutes.After the reaction mixture stirring at room 4 hours, splash into the 8ml strong aqua, regulate pH 7, standing over night, the a small amount of cold wash of suction filtration, filter cake is drained, ethanol/saturated ammoniacal liquor (1: 1, v/v) mixed solvent recrystallization gets 4.1g (77%) title compound, is off-white powder, Mp.280-282 ℃; EI-MS (m/z):
(c=2.0, CH
3OH:HCl (1N), 1: 1, v/v),
1H-NMR (DMSO-d
6, 300MHz): δ=10.99 (s, 1H); 7.44 (d, J=7.5Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.08 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 4.25-4.36 (m, 2H), 3.69 (dd, J=10.5Hz, J=5.1Hz, 1H), 3.18 (dd, J=10.5Hz, J=2.4Hz, 1H), 2.83 (ddd, J=10.5Hz, J=5.1Hz, J=2.4Hz, 1H).
Midbody compound (3S)-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester
With 50ml methyl alcohol with the cryosel water-bath be as cold as below 0 ℃, stir, toward interior dropping 10ml (145mmol) SOCl
2, temperature control is formed on below 5 ℃ in dripping, and drips in 10 minutes, adds 5.0g (23.1mmol) then (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid removes ice bath, stirred overnight at room temperature, and TLC shows (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid disappears, stopped reaction, concentrating under reduced pressure.Residue 10ml methyl alcohol dilution, concentrating under reduced pressure.Residue is again with the dilution of 10ml methyl alcohol, concentrating under reduced pressure.Residue dilutes, adds NaHCO with 20ml water and 20ml ethyl acetate
3Transfer pH 7-8.Water layer is washed 1 time, anhydrous Na with the ethyl acetate layer of ethyl acetate extraction (20ml * 3), merging with saturated sodium-chloride
2SO
4Dry.Filter, crystallisation by cooling when filtrate decompression is concentrated into about 5ml, 4.9g (92%) title compound, be off-white powder.Mp143-145℃，FAB-MS(m/z)230[M]
+。
Six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione
2.5mmol protection amino acid, 350mg (2.59mmol) N-hydroxy benzo triazole and the 15ml anhydrous methylene chloride of Boc protection mix.The solution that obtains cools off with ice-water bath, stirs, and adding 600mg (2.90mmol) DCC, 5-10 minute afterreaction liquid become turbid.Toward interior adding 500mg (2.17mmol) (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester stirred 30 minutes, removed ice-water bath.Reaction mixture stirring at room 12h, TLC show that raw material point disappears stopped reaction.The filtering dicyclohexylurea (DCU), filtrate 37 ℃ be evaporated to dried, residue with acetic acid ethyl dissolution, successively with saturated sodium bicarbonate aqueous solution wash, saturated sodium-chloride water solution is washed, 5% aqueous potassium hydrogen sulfate is washed.The organic layer of telling anhydrous sodium sulfate drying, filtration, filtrate is evaporated to dried at 37 ℃, and the blister solid that obtains is directly used in the next step.
The above-mentioned blister solid 5ml acetic acid ethyl dissolution that obtains above, the ice-water bath cooling is stirred, and the ethyl acetate solution (5mol/L) toward interior adding 5ml hydrogenchloride removes ice-water bath, stirring at room.Have solid to separate out after about 5-10 minute, TLC monitoring raw material spot disappears concentrating under reduced pressure after 1 hour.Residue dilutes with the 5ml ethyl acetate, concentrating under reduced pressure.Residue is again with the dilution of 5ml ethyl acetate, concentrating under reduced pressure.Residue 25ml dissolve with methanol adds the 2ml triethylamine, stirring at room.TLC is a spot, the no primary amine of triketohydrindene hydrate colour developing after 1 hour.Be evaporated to 10ml, separate out solid.Filter, obtain title compound, mostly be off-white powder.
Embodiment 1 (12aS)-2,3,6,7,12,12a-six hydrogen-pyrazine be [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 490mg (88%) title compound from Boc-Gly-OH, be off-white powder.Mp：247-249℃；EI-MS(m/z)
(c＝0.34，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：748，1328，1455，1646，2986，3307；
1H-NMR(DMSO-d
6，300MHz)：δ＝10.94(s，1H)；8.26(s，1H)；7.43(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.96(t，J＝7.5Hz，1H)，5.36(d，J＝16.5Hz，1H)，4.22(m，2H)，4.05(d，J＝17.7Hz，1H)，3.86(d，J＝17.7Hz，1H)，3.20(m，1H)，2.88(t，J＝13.5Hz，1H)。Ultimate analysis: C
14H
13N
3O
2Calculated value C 65.87, H 5.13, and N 16.46; Measured value C 65.65, H 5.01, and N 16.67.
Embodiment 2
(3S, 12aS)-3-methyl-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, from Boc-Ala-OH,, be off-white powder from obtaining 530mg (90%) title compound.Mp：233-235℃，EI-MS(m/z)
(c＝0.40，CHCl
3：CH
3OH，1∶1，v/v)，FT-IR(KBr，cm-1)：744，1326，1455，1678，2926，3337；
1H-NMR(DMSO-d
6，300MHz)：δ＝10.97(s，1H)；8.46(d，J＝2.1Hz，1H)，7.46(d，J＝7.5Hz，1H)，7.35(t，J＝7.5Hz，1H)，7.07(t，J＝7.5Hz，1H)，6.96(t，J＝7.5Hz，1H)，5.33(d，J＝16.8Hz，1H)，4.28(dd，J＝4.2Hz，J＝11.7Hz，1H)，4.20(d，J＝16.5Hz，1H)，4.03(m，1H)，3.26(dd，J＝4.2Hz，J＝15.0Hz，1H)，2.80(t，J＝4.8Hz，1H)，1.35(d，J＝6.9Hz，3H)。Ultimate analysis: C
15H
15N
3O
2Calculated value C 66.90, H 5.61, and N 15.60; Measured value C 66.70, H 5.41, and N 15.81.
Embodiment 3
(3S, 12aS)-3-isobutyl--2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 600mg (89%) title compound from Boc-Leu-OH, be off-white powder.Mp：228-232℃，EI-MS(m/z)
(c＝0.44，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：744，1328，1455，1669，2936，3328；
1H-NMR(DMSO-d
6，300MHz)：δ＝11.02(s，1H)，8.60(d，J＝2.1Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.99(t，J＝7.5Hz，1H)，5.34(d，J＝16.5Hz，1H)，4.29(dd，J＝11.7Hz，J＝4.2Hz，1H)，4.20(d，J＝17.1Hz，1H)，3.94(m，1H)，3.25(dd，J＝15.3Hz，J＝3.6Hz，1H)，2.80(t，J＝13.5Hz，1H)，1.81(m，1H)，1.55(t，J＝6.3Hz，2H)，0.87(m，6H)。
13C-NMR(DMSO-d
6，300MHz)δ＝166.35，165.43，135.87，130.03，126.26，120.99(c-10)，118.64，117.56，111.03，105.35，55.80，52.98，45.18，26.75，24.34，23.39，22.82，21.77。Ultimate analysis: C
18H
21N
3O
2Calculated value C 69.43, H 6.80, and N 13.49; Measured value C 69.22, H 6.61, and N 13.71.
Embodiment 4
(3S, 12aS)-3-carboxymethyl-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone-3-acetate
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 590mg (86%) title compound from Boc-Asp (OBzl)-OH, be off-white powder.Mp228-232℃，EI-MS(m/z)
(c＝0.44，CHCl
3：CH
3OH，1∶1，v/v)；FTIR(KBr，cm-1)：743，1331，1460，1675，2927，3340；
1H-NMR(DMSO-d
6，300MHz)δ＝11.04(s，1H)，8.23(s，1H)，7.44(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.06(t，J＝7.5Hz，1H)，6.95(t，J＝7.5Hz，1H)，5.38(d，J＝17.1Hz，1H)，4.25(dd，J＝11.4Hz，J＝3.9Hz，1H)；4.20(d，J＝17.1Hz，1H)，4.16(d，J＝15.0Hz，1H)，3.18(dd，J＝14.7Hz，J＝3.3Hz，1H)；2.97(t，J＝13.5Hz，1H)，2.51(d，J＝10.5Hz，2H)。
13C-NMR(DMSO-d
6，300MHz)δ＝172.44，165.97，165.05，135.96，129.84，126.35，120.86，118.55，117.53，111.03，105.70，55.61，52.35，40.64，26.43。Ultimate analysis: C
16H
15N
3O
4Calculated value C 61.34, H 4.83, and N 13.41; Measured value C 61.55, H 5.01, and N 13.22.
Embodiment 5
(3S, 12aS)-3-benzyl-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 660mg (88%) title compound from Boc-Phe-OH, be off-white powder.Mp142-145℃，EI-MS(m/z)
(c＝0.30，CHCl
3：CH
3OH，1∶1，v/v)；FTIR(KBr，cm-1)：744，1328，1455，1669，2936，3328；
1H-NMR(DMSO-d
6，300MHz)δ＝10.81(s，1H)，8.46(d，J＝1.8Hz，1H)，6.89-7.28(m，9H)，5.32(d，J＝16.5Hz，1H)，4.37(s，1H)，4.07(d，J＝16.8Hz，1H)，3.98(dd，J＝11.7Hz，J＝4.5Hz，1H)，3.17(dd，J＝13.2Hz，J＝3.3Hz，1H)，2.88(dd，J＝13.5Hz，J＝5.1Hz，1H)，2.64(dd，J＝14.7Hz，J＝3.6Hz，1H)，0.92(t，J＝12.0Hz，1H)。Ultimate analysis: C
21H
19N
3O
2Calculated value C 73.03, H 5.54, and N 12.17; Measured value C 73.30, H 5.76, and N 12.01.
Embodiment 6
(3S, 12aS)-3-methylol-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
1.08g (5mmol) (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is suspended among the 15ml DMF, stirring at room 30 minutes, treat in the solution that the suspended particle size evenly after, add 1.0ml triethylamine and 1.62g (7.5mmol) (Boc)
2O.Stirring at room 24h is warming up to 35 ℃, adds triethylamine and keeps pH more than 8.0, stirs the clarification of 48h afterreaction liquid.Blow away DMF, add 10ml aqueous citric acid solution (20%), be evaporated to dried, residue CHCl for 37 ℃ with anhydrous sodium sulfate drying, filtration, filtrate with ethyl acetate extraction (10ml * 4), organic layer
3Recrystallization, 1.19g (75%) (3S)-2-tertbutyloxycarbonyl-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is white powder.Mp 167-170℃，TOF-MS(m/z)317[M+H]
+，
1H-NMR(DMSO-d
6，300MHz)δ＝12.77(s，1H)，10.87(s，1H)，7.45(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.98(t，J＝7.5Hz，1H)，5.08(m，1H)，4.52(m，2H)，3.29(m，2H)，1.46(s，9H)。
Add (3S) .2-tertbutyloxycarbonyl-1,2,3 of 790mg (2.5mmol) in the 15ml anhydrous methylene chloride, 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid and 350mg (2.59mmol) N-hydroxy benzo triazole.Reaction solution cools off, stirs, adds 600mg (2.90mmol) DCC with ice-water bath, and afterreaction liquid became turbid in 5-10 minute.Add 404mg (2.6mmol) Ser-OMe.HCl, transfer pH 8-9 with an amount of N-methyl-morphine quinoline, stirred 30 minutes, remove ice-water bath, stirring at room 12h, TLC show that raw material point disappears stopped reaction.The filtering dicyclohexylurea (DCU), filtrate is evaporated to dried, residue acetic acid ethyl dissolution at 37 ℃.Solution successively with saturated sodium bicarbonate aqueous solution wash, saturated sodium-chloride water solution is washed, 5% aqueous potassium hydrogen sulfate is washed.The organic layer of telling is evaporated to dried at 37 ℃ with anhydrous sodium sulfate drying, filtration, filtrate, the blister solid is directly used in next step reaction.
Above-mentioned blister solid 5ml acetic acid ethyl dissolution, ice-water bath cooling is stirred, toward the ethyl acetate solution (5mol/L) of interior adding 5ml hydrogenchloride, remove ice-water bath, stirring at room.Have solid to separate out after about 5-10 minute, TLC monitoring raw material spot disappears concentrating under reduced pressure after 1 hour.Residue dilutes with the 5ml ethyl acetate, concentrating under reduced pressure.Residue is again with the dilution of 5ml ethyl acetate, concentrating under reduced pressure.Residue 25ml dissolve with methanol, adding 2ml triethylamine, stirring at room.TLC is a spot, the no primary amine of triketohydrindene hydrate colour developing after 1 hour.Be evaporated to 10ml, separate out solid.Filter, obtain 420mg (84%) title compound, be off-white powder.Mp264-267℃，EI-MS(m/z)
(c＝0.27，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：744，1334，1463，1642，1683，2926，3344；
1H-NMR(DMSO-d
6，300MHz)δ＝10.92(s，1H)，8.24(d，J＝2.4Hz，1H)，7.43(d，J＝7.5Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.04(t，J＝7.5Hz，1H)，6.93(t，J＝7.5Hz，1H)，5.42(d，J＝16.5Hz，1H)，5.23(t，J＝4.8Hz，1H)，4.25(dd，J＝11.4Hz，J＝4.2Hz，1H)，4.15(d，J＝16.5Hz，1H)，3.94(s，1H)，3.74(m，1H)，3.50(m，1H)，3.17(dd，J＝15.0Hz，J＝3.6Hz，1H)，2.98(t，J＝13.5Hz，1H)。
13C-NMR(DMSO-d
6，300MHz)δ＝166.88，163.82，135.86，129.77，126.33，120.86，118.56，117.46，110.96，105.82，62.66，57.37，55.82，27.00。Ultimate analysis: C
15H
15N
3O
3Calculated value C 63.15, H 5.30, and N 14.73; Measured value C 63.48, H 5.52, and N 14.54.
Embodiment 7
(3S, 12aS)-3-(4-butylamine base)-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 610mg (86%) title compound from Boc-(Boc) Lys-OH, be off-white powder.Mp116-118℃，EI-MS(m/z)
(c＝0.42，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：745，1336，1463，1683，2936，3324；
1H-NMR(DMSO-d
6，300MHz)δ＝11.12(s，1H)；8.56(d，J＝1.8Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.98(t，1H，J＝7.5Hz，1H)，5.36(d.J＝16.5Hz，1H)，4.30(dd，J＝11.7Hz，J＝4.5Hz，1H)，4.20(d，J＝16.8Hz，1H)，4.01(s，1H)，3.26(dd，J＝13.2Hz，J＝3.3Hz，1H)，2.79(dd，J＝13.5Hz，J＝5.1Hz，1H)；1.8～2.0(m，4H)，1.26(m，2H)，0.98(m，2H)。Ultimate analysis: C
18H
22N
4O
2Calculated value C 66.24, H 6.79, and N 17.17; Measured value C 66.01, H 6.58, and N 17.41.
Embodiment 8
(3S, 12aS)-3-indyl methyl-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 750mg (90%) title compound from Boc-Trp-OH, be off-white powder.Mp176-180℃，EI-MS(m/z)
(c＝0.34，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：746，1338，1465，1683，2938，3329；
1H-NMR(DMSO-d
6，300MHz)：δ＝10.76(s，2H)；8.43(d，1H，J＝1.8Hz，1H)，6.85-7.52(m，9H)，5.27(d，J＝16.2Hz，1H)，4.31(d，J＝2.4Hz，1H)；4.05(d，J＝16.5Hz，1H)，3.95(dd，J＝12.0Hz，J＝4.5Hz，1H)，3.28(dd，J＝14.1Hz，J＝3.6，Hz，1H)，3.07(dd，J＝14.1Hz，J＝4.2Hz，1H)，2.60(dd，J＝15.0Hz，J＝3.6Hz，1H)，1.03(t，J＝13.5Hz，1H)。
13C-NMR(DMSO-d
6，300MHz)δ＝165.65，164.64，135.80，135.71，129.11，127.62，126.19，124.00，120.58，118.45，118.36，118.10，117.25，110.81，108.02，105.42，79.06，55.77，55.36，30.17，25.6。Ultimate analysis: C
23H
20N
4O
2Calculated value C 71.86, H 5.24, and N 14.57; Measured value C 72.04, H 5.56, and N 14.33.
Embodiment 9
(3S, 12aS)-3-is to hydroxybenzyl-2,3,6,7,12, and 12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 700mg (89%) title compound from Boc-Tyr-OH, be off-white powder.Mp273-276℃，EI-MS(m/z)
(c＝0.28，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：744，1337，1465，1663，2946，3314；
1H-NMR(DMSO-d
6，300MHz)δ＝10.83(s，1H)，9.12(s，1H)，8.41(s，1H)，7.29(d，J＝7.5Hz，1H)，7.20(t，J＝7.5Hz，1H)，7.03(t，1H，J＝7.5Hz，1H)，6.94(t，J＝7.5Hz，1H)，5.33(d，J＝16.5Hz，1H)，4.29(s，1H)，4.09(d，J＝16.5Hz，1H)，3.99(dd，J＝11.7Hz，J＝3.9Hz，1H)，3.10(dd，J＝13.5Hz，J＝3.3Hz，1H)，2.76(m，2H)，1.20(t，J＝13.2Hz，1H)。
13C-NMR(DMSO-d
6，300MHz)δ＝166.03，164.15，156.33，156.30，135.90，130.97，129.24，126.31，125.43，120.83，118.61，117.50，114.80，111.01，105.74，55.70，55.44，38.68，25.80。Ultimate analysis: C
21H
19N
3O
3Calculated value C 69.79, H 5.30, and N 11.69; Measured value C 70.01, H 5.54, and N 11.47.
Embodiment 10
(3S, 12aS)-3-(3-propionamido-)-2,3,6,7,12,12a-six hydrogen-pyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1 also, the preparation of 4-diketone
By six hydrogen-pyrazine also-the logical method of the preparation of pyrido-indole dione, obtain 610mg (86%) title compound from Boc-Glu-OH, be off-white powder.Mp 258-262℃，EI-MS(m/z)
(c＝0.35，CHCl
3：CH
3OH，1∶1，v/v)；FT-IR(KBr，cm-1)：744，1336，1473，1681，2926，3321；
1H-NMR(DMSO-d
6，300MHz)δ＝12.14(br，1H)，10.98(s，1H)，8.52(d，J＝1.8Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.33(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.96(t，J＝7.5Hz，1H)，5.33(d，J＝17.1Hz，1H)，4.28(dd，J＝12.3Hz，J＝4.5Hz，1H)，4.19(d，J＝16.8Hz，1H)，4.05(br，1H)，3.26(dd，J＝15.6Hz，J＝3.6Hz，1H)，2.80(t，J＝13.5Hz，1H)，2.27(m，2H)，1.94(m，2H)。
13C-NMR(DMSO-d
6，300MHz)δ＝173.58，166.33，164.73，135.93，129.88，126.25，121.00，118.67，117.59，111.04，105.33，55.69，53.68，30.59，29.20，26.96。Ultimate analysis: C
17H
18N
4O
3Calculated value C 62.57, H 5.56, and N 17.17; Measured value C62.34, H 5.37, and N 17.00.
Embodiment 11
Adopt isolated guinea pig ileum model evaluation medicine anti-histamine activity of the present invention
The 200-250g cavy, male and female are not limit, the head of fiercelying attack is put to death cavy, open the abdominal cavity rapidly, take out near the partial ileum of returning blind hole, put into the culture dish that fills tyrode's solution, be divided into the 1.5-2.0cm segment with scissors, with the tyrode's solution content of flush away intestinal segment gently, get that wherein two sections are fixed on the brandreth and wholely immerse that (end is fixed in the Magnus' bath, the other end is connected on the tonotransducer), all the other intestinal segments are put into and are filled the triangular flask of using the saturated tyrode's solution of oxygen in advance, and 4 ℃ of preservations (in 24 hours) are standby.Add the 15ml tyrode's solution in the Magnus' bath, contain 5 volume %CO with suitable speed (40 bubbles of per minute bell) feeding
2Oxygen, the water bath with thermostatic control water temperature is controlled at 38 ℃ ± 0.5 ℃, intestinal segment adds the pretension of 0.5-1 gram, measures after incubation 0.3-1 hour.Start registering instrument, adding 15ul blank solvent or testing sample solution (if testing sample is dissolved in ethanol, then use its ethanolic soln in the Magnus' bath; If testing sample is insoluble to ethanol, then use the solution of 5: 1 mixed solvents of its ethanol and dimethyl sulfoxide (DMSO)), be incubated adding (3.5*10 after 2-5 minute
-4G/ml) the 1.5ul histamine aqueous solution (final concentration 3.5*10
-8G/ml), recording curve reaches and stops record after the highest.Clean intestinal segment three times (15ml*3) with the constant temperature tyrode's solution, start registering instrument, treat to repeat above-mentioned experiment after the baseline stability.Ileum tension force under measuring space blank solvent and the testing sample effect, with the ileum tensile mean value (being designated as 100%) under the blank solvent effect of adjacent twice mensuration is that benchmark calculates the ileum tensile percentage ratio under the testing sample effect, measure six data points, calculate mean tension percentage ratio A, then 1-A is the inhibiting rate I of this sample under this concentration, use the SPSS software statistics, the result lists table 1 in.
The anti-histamine activity of table 1. The compounds of this invention
Compound final concentration (1 * 10
-5Mol/l) inhibiting rate, %
Embodiment 1 1.96 14.3 ± 6.2
b
Embodiment 2 2.11-8.5 ± 8.8
Embodiment 3 2.14-2.8 ± 5.4
Embodiment 4 1.38-7.0 ± 9.5
Embodiment 5 2.03 26.2 ± 14.8
b
Embodiment 6 2.92-9.8 ± 8.7
a
Embodiment 7 1.12-0.9 ± 5.5
Embodiment 8 1.04 21.0 ± 6.0
b
Embodiment 9 1.20 8.2 ± 6.1
a
Embodiment 10 1.64 0.3 ± 6.1
N=6 is with theoretical value 0 ratio, a) p＜0.05, b=p＜0.01
The anti-histamine activity of compound under different concns of table 2. embodiment of the invention 5,9,13
| Compound | Final concentration (μ mol/l) | Inhibiting rate I% |
| Embodiment 1 | 4.92 | 5.0±10.3 |
| 19.6 | 14.3±6.2 | |
| 123 | 30.9±7.9 | |
| Embodiment 5 | 1.85 | 9.9±13.1 |
| 20.3 | 12.1±9.1 | |
| 46.3 | 26.2±7.8 | |
| Embodiment 8 | 4.48 | 3.0±10.0 |
| 10.4 | 21.0±6.0 | |
| 44.8 | 24.1±8.3 | |
| 112.0 | 39.4±5.6 |
N=6, each dosage group shows obvious activity difference
Claims (4)
1, as the compound of general formula I, wherein-R be H ,-CH
3,-CH
2(CH
3)
2,-CH
2COOH,
General formula I-CH
2C
6H
5,-CH
2OH ,-CH
2(CH
2)
3NH
2, the indol-3-yl methylene radical ,-CH
2C
6H
4-OH-p ,-CH
2CH
2CONH
2
2, the method for synthetic compound of Formula I, the definition of general formula I as mentioned above, this method comprises: tryptophane and formaldehyde reaction generation (3S)-1,2 under sulfuric acid catalysis, 3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid, (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid and SOCl
2And the methyl alcohol reaction generates (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester, in the presence of N-hydroxy benzo triazole and DCC Boc-amino acid with (3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester reaction generation N-Boc-aminoacyl-(3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester, N-Boc-aminoacyl in the HCl/ ethyl acetate solution-(3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester cyclisation be six hydrogen-pyrazine also-pyrido-indole dione.
3, the compound of general formula I is used for the application of antfhistamine medicine in preparation, and the definition of general formula I as mentioned above.
4, the composition that acceptable carrier is formed on the compound of general formula I and the pharmaceutics is used for the application of antfhistamine medicine in preparation, and the definition of general formula I as mentioned above.
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| CN101200466B (en) * | 2006-12-15 | 2011-04-20 | 首都医科大学 | Heterocyclic compounds having antithrombotic activity, preparation method and uses thereof |
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| CN101200466B (en) * | 2006-12-15 | 2011-04-20 | 首都医科大学 | Heterocyclic compounds having antithrombotic activity, preparation method and uses thereof |
| CN102234278A (en) * | 2010-04-26 | 2011-11-09 | 首都医科大学 | (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, and synthesis method and application thereof |
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| CN112010855A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Hexacyclic piperazinedione compounds, preparation, biological activity and application thereof |
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