CN102391323A - Tetrahydro-beta-carboline derivative, preparation method thereof and use thereof - Google Patents
Tetrahydro-beta-carboline derivative, preparation method thereof and use thereof Download PDFInfo
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- CN102391323A CN102391323A CN2011103169427A CN201110316942A CN102391323A CN 102391323 A CN102391323 A CN 102391323A CN 2011103169427 A CN2011103169427 A CN 2011103169427A CN 201110316942 A CN201110316942 A CN 201110316942A CN 102391323 A CN102391323 A CN 102391323A
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- tetrahydrocarboline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical class N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 claims description 5
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 claims description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- -1 R2 is H Chemical group 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000000539 amino acid group Chemical group 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- 240000001307 Myosotis scorpioides Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- 206010014025 Ear swelling Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- 208000005141 Otitis Diseases 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 210000004404 adrenal cortex Anatomy 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 150000002337 glycosamines Chemical class 0.000 description 2
- PSFDQSOCUJVVGF-UHFFFAOYSA-N harman Chemical compound C12=CC=CC=C2NC2=C1C=CN=C2C PSFDQSOCUJVVGF-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- CVCQAQVBOPNTFI-AAONGDSNSA-N (3r,4r,5s,6r)-3-amino-6-(hydroxymethyl)oxane-2,4,5-triol;sulfuric acid Chemical compound OS(O)(=O)=O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O CVCQAQVBOPNTFI-AAONGDSNSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to a tetrahydro-beta-carboline derivative, a preparation method thereof and a use thereof. The invention discloses the tetrahydro-beta-carboline derivative described as a general formula (I), wherein R1 is H, benzyl, benzoyl or C1-6 acyl, R2 is H, C1-6 alkyl, C1-6 alkoxyl, COOH, COOR3, AA or AA-R4, R3 is C1-6 alkyl, R4 is COOH or COOR3 and AA is amino acid group. The invention further discloses the preparation method of a compound described as the general formula (I), a pharmaceutical composition containing the compound described as the general formula (I) and the use of the compound in the preparation of anti-inflammatory medicaments.
Description
Technical field
The present invention relates to a kind of tetrahydrochysene-beta-carboline derivatives with anti-inflammatory activity, their preparation method, the pharmaceutical composition and the above-claimed cpd that contain said compound are used to prepare the purposes of treating anti-inflammatory drug.
Background technology
Antiphlogiston has two big types: one type is the steroidal anti-inflammatory medicine, i.e. the secreted glucocorticosteroid HYDROCORTISONE INJECTIONS of adrenal cortex and the verivate of synthetic thereof.Another kind of is non-steroidal anti-inflammatory medicine such as Frosst), Phenylbutazone etc.
Its chemical nature of steroidal anti-inflammatory drugs is natural or the glucocorticosteroid of synthetic.Hench in 1949 etc. at first use KE treatment of arthritis, rheumatosis etc., have powerful anti-inflammatory action though find it, and its spinoff is serious, especially when heavy dose is used, not only possibly produce dependency, and can cause the adrenal cortex function decline.Non-steroidal anti-inflammatory drugs more commonly used now all has the anti-inflammatory or the effect characteristics of antipyretic-antalgic separately; And alleviated untoward reaction mostly to a certain extent; But its spinoff is still obviously, particularly GI toxic reaction, and people hope to develop the little antiphlogistic medicine of untoward reaction.
Eighties of last century six the seventies; After people find that in the seed of Herba pegani harmalae section plant Herba pegani harmalae carboline alkaloid-yageine (Harman) has malaria, antitumor, anti-HIV (hiv virus), various biological activity such as antibiotic, just caused the upsurge of research carboline analog derivative.Amy Morin Deveau etc. has synthesized a series of amino acid modified β-Ka Lin carboxylic acid derivative, in-vitro evaluation these compounds the growth-inhibiting property of H520 and PC cell strain is had tangible activity.Report yageine such as A.Xu and verivate thereof have important anti-tumor activity but in experimental animal model, present tangible neurotoxicity and comprise and tremble, twitch, jump and strengthen anti-tumor activity and reduce acute toxicity and lose neurotoxicity through introducing suitable substituting group at 1,3.Anelise S.Nazari Formagio etc. have shown definite anti-tumor activity at 1,3 different substituting group of introducing of β-Ka Lin.
The beta-tetrahydro carboline is many key structure unit with the active VALLESIACOTAMIN of important physiological, also is the essential structure of some medicines and active compound.Tetrahydrochysene-β-Ka Lin-3-carboxylic acid is to have definite bioactive VALLESIACOTAMIN from China south vegetables; So have reliable security; Toxic side effect is little, have the potential clinical value, but solubleness is very poor; Be dissolved in any solvent hardly, cause its bioavailability extreme difference thus.This shortcoming has seriously limited its application on food and medicine.
Because glucide inherent complicacy, the glycosylation of beta-tetrahydro carboline can produce structure diversity and induce various changing functions.The poly-hydroxy of sugar ring can increase water-soluble.Aminosugar is distributed in the organism widely.GS is prevailing aminosugar, exists with the N-acetylated form usually, is the natural constituents of gp, and the ability minimizing along with synthesizing amino glucose in the increase body at age causes senile osteo-arthritis (McDevitt, C.A.; Muir, H.J.Bone Joint Surg.B 1976,58,94-101).Glucosamine sulphate and hydrochloride itself are a kind of medicines and nontoxic, can promote the repair of cartilage of damaging.Since W.Bohne in 1969 report GS can be as the relief from osteoarthritis medicine, GS receive great concern (Kelly, G.Altern.Med.Rev.1998,3,27-29).GS has anti-oxidant and anti-inflammatory activity, produces at normal human's bone articular cartilage cell block N O.Amino acid not only has the side chain of structure diversity but also can improve the pharmacokinetics of compound, and amino acid whose introducing can increase water-soluble.The contriver recognizes; GS and beta-tetrahydro carboline compound all are the natural products with various active; Coupling through GS and amino acid and beta-tetrahydro carboline natural product; To beta-tetrahydro carboline compound structural modification, attempt to seek new verivate with better active natural product.Should be extended to bioactive association from Structural Interrelationship.
Summary of the invention
On the one hand, the present invention provides a kind of general formula (I) compound:
R wherein
1Be H, benzyl, benzoyl-or C
1-6Acyl group, R
2Be H, C
1-6Alkyl, C
1-6Alkoxyl group, COOH, COOR
3, AA or AA-R
4, R
3Be C
1-6Alkyl, R
4Be COOH or COOR
3, and AA is amino acid based.
The preferred following compounds of the present invention:
Wherein, compound 7a, 10a, AA=Ala among the 14a, compound 7b, AA=Gly among the 10b.
On the other hand, the present invention provides a kind of method for preparing general formula (I) compound of claim 1, comprising: with the Tetrahydrocarboline 3-carboxylic acid of general formula (II) and the 2-amino-D-glucose response of general formula (III),
R wherein
1Be H, benzyl, benzoyl-or C
1-6Acyl group, R
2Be H, C
1-6Alkyl, C
1-6Alkoxyl group, COOH, COOR
3, AA or AA-R
4, R
3Be C
1-6Alkyl, R
4Be COOH or COOR
3, and AA is amino acid based.
Preferably; The compounds of this invention N-(aminoacyl)-Tetrahydrocarboline acyl-2-amino-D-glucose 7a-b; 10a-b; The preparation method of 14a, this method can use following scheme 1, scheme 2 and scheme 3 to describe: comprise preparation 2-amino-tetra-acetylated-D-glucose and N-Boc-Tetrahydrocarboline-3-carboxylic acid coupling, obtain N-Boc-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 4; In 4N hydrogenchloride-ethyl acetate solution, remove tertbutyloxycarbonyl with 4 then, obtain Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 5.With 5 with the Boc-AA-OH coupling, obtain N-(Boc-aminoacyl)-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose (7a-b).With 2-amino-D-glucose and the coupling of N-Boc-Tetrahydrocarboline 3-carboxylic acid; Obtain N-Boc-Tetrahydrocarboline acyl-2-amino-D-glucose 8; In 4N hydrogenchloride-ethyl acetate solution, remove tertbutyloxycarbonyl with 8 then, obtain Tetrahydrocarboline acyl-2-amino-D-glucose 9.With 9 with the Boc-AA-OH coupling, obtain N-(Boc-aminoacyl)-Tetrahydrocarboline acyl-2-amino-D-glucose (10a-b).With Tetrahydrocarboline-3-benzyl carboxylate 11 and Boc-AA-OH coupling; Obtain N-(Boc-aminoacyl)-Tetrahydrocarboline-3-benzyl carboxylate 12a-b; Hydrogenolysis benzyl ester with 2-amino-D-glucose coupling, obtains N-(Boc-aminoacyl)-Tetrahydrocarboline acyl-2-amino-D-glucose (10a-b) then.10a is removed tertbutyloxycarbonyl in 4N hydrogenchloride-ethyl acetate solution, make N-(alanyl)-Tetrahydrocarboline acyl-2-amino-D-glucose.
The synthetic route of scheme 1, tetrahydrochysene-beta-carboline derivatives 7a-b
The synthetic route of scheme 2, tetrahydrochysene-beta-carboline derivatives 10a-b
The synthetic route of scheme 3, tetrahydrochysene-beta-carboline derivatives 10a
Again on the one hand, the present invention provides the purposes of a kind of general formula (I) compound in preparation treatment anti-inflammatory drug.The present invention estimates compound 5-8a-c of the present invention, the anti-inflammatory action of 9-11a through YLENE inductive mouse ear swelling model.
Another aspect, the present invention provides a kind of medicinal compsns, and claim 1 general formula (I) compound and pharmaceutically acceptable carrier or auxiliary material that said composition goes up effective dose by treatment are formed.
Compound of the present invention can impose on people or other Mammalss through number of ways; Comprise oral; Injection (intravenous injection; Intramuscular injection, endoperitoneal injection, subcutaneous injection etc. are similar) comprise The compounds of this invention and the suitable pharmaceutically acceptable vehicle or the known in those skilled in the art various formulations of carrier.
The preferred modes of The compounds of this invention is oral.Preferably, these pharmacy goods are with dosage unit form independently.In this kind form, goods are divided into the dosage device of suitable size, and this unit comprises the active compound of projected dose, for example, for its purpose, effectively measure.
In order further to set forth the present invention, provide a series of embodiment below.These embodiment 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.
Embodiment
The preparation of embodiment 1N-tertbutyloxycarbonyl-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 4
Under the ice bath, N-Boc-Tetrahydrocarboline-3-carboxylic acid 3 (3.48g, 11.0mmol) with anhydrous THF (150ml) dissolving, add successively HOBt (1.62g, 12.0mmol), (2.47g, 12.0mmol) activation gets A liquid to DCC.(4.45g 10.0mmol) with anhydrous THF dissolving, adds NMM adjust pH to 7 to 2-amino-tetra-acetylated-D-glucose, gets B liquid.B is joined among the A adjust pH to 8, stirring at room 18 hours.TLC shows that raw material point disappears.Reaction mixture filters, and filtrate decompression is concentrated into dried, and residue is used acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively
3The aqueous solution and 5%KHSO
4The aqueous solution is washed, the saturated NaCl aqueous solution is washed.Tell ethyl acetate layer, anhydrous Na
2SO
4Drying is filtered, and filtrate decompression is concentrated into dried, and residue separates with silica gel column chromatography, and (sherwood oil-acetone, 2: 1) wash-out obtains 4 (3.36g, 5.2mmol 52%) title compound.[α]
25 D+14.7(c?0.1，CHCl
3)；IR(cm
-1，KBr，neat)：3390，1743，1697；
1HNMR(300MHz，CDCl
3)：δ8.78(1H，s，N-H)，8.17(1H，s，N-H)，7.48-7.04(4H，m，Ar-H)，5.72(1H，d，J
1’，2’9.9Hz，H-1’)，5.67(1H，d，J
2’，3’＝J
3’，4’＝8.7Hz，H-3’)，5.49(1H，d，J
2，NH6.0Hz，N-H)，5.27(1H，d，J
2， NH?5.7Hz，N-H)，5.11(2H，m，H-3，H-5’)，4.78(1H，m，H-1a)，4.51(1H，m，H-1b)，4.28(1H，t，J
3’，4’＝J
4’，5’＝8.7Hz，H-4’)，4.17(1H，m，H-2’)，4.02(1H，m，H-6a’)，3.78(1H，m，H-6b’)，3.44(1H，d，J
4a，4b?15.6Hz，H-4a)，3.12(1H，m，H-4b)，1.98(9H，s，CH
3)，1.52(9H，d，J?10.8Hz，CH
3)，1.24(3H，d，J?7.2Hz，CH
3)；
13CNMR(75MHz，CDCl
3)δ171.3，170.8，170.6，170.2，169.2，155.8，136.6，130.2，126.6，121.9，119.5，118.1，110.8，105.7，104.7，93.1，81.4，72.7，67.9，61.8，53.9，52.8，40.8，30.9，28.3，23.5，23.3，22.3，22.2，20.6，20.5；ESIMS?m/z?668(M+Na)，645(M)；HRMS?calcd?for：(C
31H
39N
3O
12+1)，m/z(646.2606)；found，m/z(646.2560).
The preparation of embodiment 2 Tetrahydrocarbolines acyl-2-amino-tetra-acetylated-D-glucose 5
(645mg 1.00mmol) is dissolved in 5ml 4N hydrogenchloride-ethyl acetate solution with N-Boc-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 4.Reaction mixture stirs 1h for 0 ℃, and reaction mixture is evaporated to dried, and residue is used the 10ml acetic acid ethyl dissolution, and the solution decompression that obtains is concentrated into dried.This operation repeats to take out three times, removes free hydrogenchloride.The solid that obtains is not purified to be used for next step reaction at once.
The preparation of embodiment 3N-(Boc-alanyl)-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 7a
Operation according to embodiment 1; With Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 5 (582mg, 1.00mmol) with Boc-L-Ala-OH 6a (207mg, 1.10mmol); HOBT (162mg; 1.20mmol) and DCC (247mg 0.980mmol) obtains 7a (259mg, 0.362mmol (36%) title compound in anhydrous THF (10ml) condensation.[α]
25 D-5.8(c?0.1，CHCl
3)；IR(cm
-1，KBr，neat)：3381，1747，1658；
1HNMR(300MHz，CDCl
3)：δ9.41(1H，s，N-H)，8.67(1H，s，N-H)，7.53-7.07(4H，m，Ar-H)，6.21(1H，d，J
2，NH?8.7Hz，N-H)，5.93(1H，d，J
NH，α5.4Hz，N-H)，5.63(1H，d，J
1’，2’8.7Hz，H-1’)，5.60(1H，m，H-3’)，5.30-5.03(2H，m，H-α，H-2’)，4.96(1H，m，H-3)，4.87-4.74(2H，m，H-1a，H-1b)，4.36-4.12(2H，m，H-5’，H-6a’)，4.04(1H，t，J
3’，4’＝J
4’，5’＝12.0Hz，H-4’)，3.74(1H，m，H-6b’)，3.46(1H，m，H-4a)，3.16(1H，m，H-4b)，2.03(3H，s，CH
3)，1.99(3H，s，CH
3)，1.95(3H，s，CH
3)，1.58(3H，d，J?6.9Hz，CH
3)，1.41(9H，s，CH
3)，1.37(3H，d，J?6.6Hz，CH
3)；
13CNMR(75MHz，CDCl
3)δ173.9，170.9，170.6，170.5，170.2，169.2，155.3，136.7，127.9，126.4，122.3，119.7，118.2，110.9，106.4，96.9，93.2，79.9，72.9，67.7，61.6，52.8，51.5，47.1，41.4，28.4，22.6，22.4，20.6，20.5，19.1，18.3；ESIMS?m/z?739(M+Na)，717(M+1)，716(M)；HRMS?calcd?for：(C
34H
44N
4O
13+1)，m/z(717.2977)；found，m/z(717.2967).
The preparation of embodiment 4N-(tertbutyloxycarbonyl-glycyl)-Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 7b
According to the operation of embodiment 1, (387mg is 0.891mmol) with Boc-L-Gly-OH 6b (128mg with Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 5; 0.891mmol), HOBT (108mg, 0.798mmol) and DCC (164mg; 0.798mmol); Obtain 7b (271mg, 0.386mmol, 58%) title compound in anhydrous THF (10ml) condensation.[α]
25 D+18.6(c?0.1，CHCl
3)；IR(cm
-1，KBr，neat)：3338，3315，1751，1672；
1HNMR(300MHz，DMSO-d
6)：δ10.90(1H，s，N-H)，7.92(1H，d，J
2，NH?8.7Hz，N-H)，7.46(1H，d，J7.5Hz，Ar-H)，7.30(1H，m，Ar-H)，7.09-6.86(2H，m，Ar-H)，5.80(1H，d，J
NH，α5.4Hz，N-H)，5.67(1H，d，J
1’，2’8.7Hz，H-1’)，5.19(1H，t，J
2’，3’＝J
3’，4’＝9.9Hz，H-3’)，4.98(2H，m，H-5’，H-3)，4.67(1H，d，J
1a，1b15.9Hz，H-1a)，4.30(1H，d，J
1a，1b?15.9Hz，H-1b)，4.15-3.84(6H，m，H-2’，H-4’，H-6a’，H-6b’，H-α)，3.52(1H，m，H-4a)，3.04(1H，m，H-4b)，2.02(3H，s，CH
3)，1.98(3H，s，CH
3)，1.93(3H，d，J?9.9Hz，CH
3)，1.51(3H，s，CH
3)，1.41(9H，s，CH
3)；
13CNMR(75MHz，DMSO-d
6)δ170.7，170.4，170.3，170.2，169.8，156.5，136.7，129.9，126.6，121.7，119.0，118.4，111.6，104.8，91.2，78.7，70.0，69.7，68.7，61.5，53.9，51.2，50.7，43.1，28.6，23.1，22.4，20.9，20.8，20.7；ESIMS?m/z?703(M)；HRMS?calcd?for：(C
33H
43N
4O
13)，m/z(703.2821)；found，m/z(703.2822).
The preparation of embodiment 5N-tertbutyloxycarbonyl-Tetrahydrocarboline acyl-2-amino-D-glucose 8
Under the ice bath, (3.48g 11.0mmol) dissolves with dry DMF (150mL) N-Boc-Tetrahydrocarboline-3-carboxylic acid 3; Add successively DCC (2.47g, 12.0mmol), 2-amino-tetra-acetylated-D-glucose (2.16g; 10.0mmol), add NMM adjust pH to 8,35 ℃ were reacted 24 hours.TLC shows that raw material point disappears.Reaction solution is evaporated to dried, and residue is used alcohol extraction.Filter, filtrate decompression is concentrated into dried, and silica gel column chromatography separates, (CH
2Cl
2-MeOH, 5: 1) wash-out, obtain 8 (1.44g, 3.02mmol, 30%) title compound.[α]
25 D+59.8(c?0.1，CHCl
3)；IR(cm
-1，KBr，neat)：3408，3334，1670；
1HNMR(300MHz，DMSO-d
6)：δ10.76(1H，d，J?13.2Hz，N-H)，7.49(1H，m，N-H)，7.36(1H，d，J7.5Hz，Ar-H)，7.27(1H，d，J7.8Hz，Ar-H)，7.03(1H，t，J7.8Hz，Ar-H)，6.95(1H，d，J7.8Hz，Ar-H)，5.21(1H，br?s，N-H)，5.04(1H，br?s，N-H)，4.84(2H，m，OH-1’，H-3)，4.62(2H，m，H-1a，H-1b)，4.38(1H，t，J
1’，2’＝J
1’， OH-1’＝5.7Hz，H-1’)，4.09(1H，m，H-3’)，3.59-3.47(overlapping?signals，5H，m，H-2’，4’，5’，6’)，3.18(3H，m，OH)，2.93(2H，m，H-4a，H-4b)，1.46(9H，s，CH
3)；
13CNMR(75MHz，DMSO-d
6)δ171.7，155.6，136.5，130.9，127.1，121.1，118.8，118.0，111.3，104.9，91.0，80.2，72.6，71.5，70.9，61.5，54.9，53.8，52.2，49.1，28.5，23.9；ESIMS?m/z?478(M+1)；HRMS?calcd?for：(C
23H
31N
3O
8+1)，m/z(478.2183)；found，m/z(478.2204).
The preparation of embodiment 6N-(tertbutyloxycarbonyl-alanyl)-Tetrahydrocarboline-3-benzyl carboxylate 12a
According to the operation of embodiment 1, (918mg is 3.00mmol) with (624mg with Tetrahydrocarboline-3-benzyl carboxylate 11; 3.30mmol) Boc-L-Ala-OH 6a, and HOBT (486mg, 3.60mmol) and DCC (0.742mg; 3.60mmol); Obtain 12a (1.10g, 2.31mmol, 77%) title compound after the condensation.
The preparation of embodiment 7N-(tertbutyloxycarbonyl-glycyl)-Tetrahydrocarboline-3-benzyl carboxylate 12b
According to the operation of embodiment 1, with Tetrahydrocarboline-3-benzyl carboxylate 11 (918mg, 3.00mmol) with Boc-L-Gly-OH 6b (578mg, 3.30mmol); HOBT (486mg, 3.60mmol) and DCC (742mg, 3.60mmol); Condensation obtains 12b (1.10g, 2.37mmol, 79%) title compound.
The preparation of embodiment 8N-(tertbutyloxycarbonyl-alanyl)-Tetrahydrocarboline-3-carboxylic acid 13a
(477mg 1.00mmol) is dissolved in the 5ml ethanol N-(Boc-alanyl)-Tetrahydrocarboline-3-benzyl carboxylate 12a, adds 72mg Pd/C (15.0%), feeds hydrogen, reacts 4 hours.Filter, reaction solution is evaporated to dried, obtains 13a (383mg, 0.990mmol, 99%) title compound.
The preparation of embodiment 9N-(tertbutyloxycarbonyl-glycyl)-Tetrahydrocarboline-3-carboxylic acid 13b
(463mg 1.00mmol) is dissolved in the 5ml ethanol N-(Boc-glycyl)-Tetrahydrocarboline-3-benzyl carboxylate 12b, adds 69mg Pd/C (15.0%), feeds hydrogen, reacts 4 hours.Filter, reaction solution is evaporated to dried, obtains 13b (366mg, 0.981mmol, 98%) title compound.
The preparation of embodiment 10N-(tertbutyloxycarbonyl-alanyl)-Tetrahydrocarboline acyl-2-amino-D-glucose 10a
According to the operation of embodiment 5, (324mg is 0.837mmol) with 2-amino-D-glucose (180mg with N-(Boc-alanyl)-Tetrahydrocarboline-3-carboxylic acid 13a; 0.837mmol) and DCC (206mg, 1.00mmol), condensation obtains 10a (280mg; 0.511mmol, 61%) and title compound.[α]
25 D+3.2(c?0.1，CHCl
3)；IR(cm
-1，KBr，neat)：3398，3242，1645；
1HNMR(500MHz，DMSO-d
6)：δ10.80(0.45H，d，J?11.1Hz，N-H，β-isomer)，10.73(0.55H，d，J?11.1Hz，N-H，α-isomer)，7.40(1H，m，Ar-H
α， β)，7.30(0.55H，d，J7.5Hz，Ar-H，α-isomer)，7.28(0.45H，d，J8.0Hz，Ar-H，β-isomer)，7.05(1H，m，Ar-H)，6.98(1H，m，Ar-H)，6.45(1H，m，N-H)，5.63(0.55H，d，J
1’，2’5.5Hz，H-1’，α-isomer)，5.30(0.45H，d，J
1’，2’12.5Hz，H-1’，β-isomer)，5.21(0.55H，d，J
NH，α8.5Hz，N-H，α-isomer)，5.07(0.45H，d，J
NH，α5.0Hz，N-H，β-isomer)，4.95-4.74(2H，m，H-3，OH-1’)，4.62(1H，m，H-α)，4.50-4.41(1.55H，m，H-1a，H-1b)，4.35(0.45H，d，J
1a，1b?18.5Hz，H-1b，β-isomer)，3.68-3.41(overlapping?signals，9H，m，H-2’，3’，4’，5’，6’，OH)，3.09-2.70(overlapping?signals，2.45H，m，H-4a，H-4b，β-isomer，OH)，2.68(0.55H，m，H-4b，α-isomer)，1.40(4.95H，s，CH
3，α-isomer)，1.38(4.05H，s，CH
3，β-isomer)，1.20(3H，m，CH
3)；
13CNMR(125MHz，DMSO-d
6)δ173.6，173.5，172.8，169.4，156.4，155.4，136.4，136.3，131.1，130.9，127.0，121.4，121.2，118.9，118.8，118.1，117.9，111.4，106.4，96.1，79.4，79.1，78.6，77.4，74.4，72.6，71.4，61.6，57.7，54.9，54.4，51.5，51.3，47.4，47.2，28.9，28.8，23.2，21.7，20.9，18.3；ESIMS?m/z?571(M+Na)；HRMS?calcd?for：(C
26H
36N
4O
9+1)，m/z(549.2555)；found，m/z(549.2544).
The preparation of embodiment 11N-(alanyl)-Tetrahydrocarboline acyl-2-amino-D-glucose 14a
According to the operation of embodiment 2, (55mg 0.100mmol) is dissolved in 3ml 4N hydrogenchloride-ethyl acetate solution with N-(Boc-alanyl)-Tetrahydrocarboline acyl-2-amino-D-glucose 10a.Reaction mixture stirs 1h for 0 ℃, obtains 14a (44mg, 0.0900mmol, 90%) title compound.[α]
25 D+10.8(c?0.1，CHCl
3)；IR(em
-1，KBr，neat)：3371，3325，3238，1670；
1HNMR(300MHz，DMSO-d
6)：δ10.81(1H，m，N-H)，8.37(1H，m?N-H)，7.32(2H，m，Ar-H)，7.01(2H，m，Ar-H)，5.61(2H，m，N-H)，5.27(0.23H，d，J
1’，2’10.4Hz，H-1’，β-isomer)，5.21(0.77H，d，J
1’，2’5.7Hz，H-1’，α-isomer)，4.86(1H，m，H-3)，4.49(2H，m，H-1)，3.67-3.29(overlapping?signals，11H，m，H-2’，3’，4’，5’，H-6’，OH)，3.03(2H，m，H-4)，1.43(3H，s，CH
3)；
13CNMR(75MHz，DMSO-d
6)δ172.4，172.3，170.8，170.5，136.5，136.3，130.1，126.9，121.4，119.0，118.9，118.1，111.5，104.7，90.7，79.2，78.6，77.2，72.6，71.4，70.8，70.3，63.7，61.5，56.4，55.1，47.2，34.6，31.7，28.9，28.7，21.5，19.0；ESIMS?m/z?449(M+1)；HRMS?calcd?for：(C
21H
28N
4O
7+1)，m/z(449.2031)；found，m/z(449.2048).
The experiment of embodiment 12 anti-inflammatory actions
Utilization YLENE inductive mouse ear swelling model has been estimated compound 4,5,7a-b, 8,9,10a-b, the anti-inflammatory action of 14a.Experimental compound passes through CMC 99.5 (CMC) the suspension-s oral administration with 0.5%; Each compound administration dosage is 10 μ g/mL; (CMC) compares with blank control group, and the result shows that compound of the present invention has obvious suppression YLENE inductive mouse ear inflammation.(P＜0.05) result lists table 1 in.
It is active that table 1 YLENE inductive mouse ear inflammation suppresses
The compound oral dosage that tries=10 μ mol/kg, aspirin dose=100mg/kg;
n＝12.
A compares P＜0.01. with blank control group (CMC)
B compares P＜0.05 with blank control group (CMC).
Claims (5)
1. a general formula (I) compound:
R wherein
1Be H, benzyl, benzoyl-or C
1-6Acyl group, R
2Be H, C
1-6Alkyl, C
1-6Alkoxyl group, COOH, COOR
3, AA or AA-R
4, R
3Be C
1-6Alkyl, R
4Be COOH or COOR
3, and AA is amino acid based.
2. compound according to claim 1, it is following compound:
Wherein, compound 7a, 10a, AA=Ala among the 14a, compound 7b, AA=Gly among the 10b.
3. a method for preparing general formula (I) compound of claim 1 is characterized in that this method comprises the following steps:
With the Tetrahydrocarboline 3-carboxylic acid of general formula (II) and the 2-amino-D-glucose response of general formula (III),
R wherein
1Be H, benzyl, benzoyl-or C
1-6Acyl group, R
2Be H, C
1-6Alkyl, C
1-6Alkoxyl group, COOH, COOR
3, AA or AA-R
4, R
3Be C
1-6Alkyl, R
4Be COOH or COOR
3, and AA is amino acid based.
4. claim 1 formula of (I) compound is treated the purposes in the anti-inflammatory drug in preparation.
5. medicinal compsns is characterized in that claim 1 general formula (I) compound and pharmaceutically acceptable carrier or the auxiliary material of being gone up effective dose by treatment form.
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| CN107686494A (en) * | 2016-08-05 | 2018-02-13 | 首都医科大学 | The methylol glucuronate of indoles quinolizine 6, its preparation, activity and application |
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| CN107686499B (en) * | 2016-08-05 | 2020-01-17 | 首都医科大学 | Indoloquinolizine-6-formyl-3-glucosamine, and preparation, activity and application thereof |
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