CN102391323B - 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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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 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 42
- 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
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 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
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- 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 11
- 239000003814 drug Substances 0.000 abstract description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- -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
- 239000000243 solution Substances 0.000 description 10
- 0 C[C@](C(CO)OC(O)=C1NC([C@](C2)N(*C(OC(C)(C)C)=O)Cc3c2c(cccc2)c2[n]3)=O)C1O Chemical compound C[C@](C(CO)OC(O)=C1NC([C@](C2)N(*C(OC(C)(C)C)=O)Cc3c2c(cccc2)c2[n]3)=O)C1O 0.000 description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
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- 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
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- 150000001413 amino acids Chemical class 0.000 description 6
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- 238000006243 chemical reaction Methods 0.000 description 6
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- 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
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- 240000001307 Myosotis scorpioides Species 0.000 description 4
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- 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
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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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 2
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- 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
- 229930005303 indole alkaloid Natural products 0.000 description 2
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- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-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
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-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
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 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
- 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
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 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
- 150000001720 carbohydrates Chemical class 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
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- 229960000890 hydrocortisone Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (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 ofthe 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 contains the pharmaceutical composition of described compound and above-claimed cpd for the preparation of the purposes for the treatment of anti-inflammatory drug.
Background technology
Antiphlogiston has two big classes: a class is the steroidal anti-inflammatory medicine, i.e. the secreted glucocorticosteroid hydrocortisone of adrenal cortex and the derivative of synthetic thereof.Another kind of is non-steroidal anti-inflammatory medicine such as acetylsalicylic acid, Phenylbutazone etc.
Its chemical nature of steroidal anti-inflammatory drugs is natural or the glucocorticosteroid of synthetic.Hench in 1949 etc. at first use cortisone treatment of arthritis, rheumatosis etc., have powerful anti-inflammatory action though find it, and its side effect is serious, especially when heavy dose is used, not only may produce dependency, and can cause the adrenal cortex function decline.Non-steroidal anti-inflammatory drugs more commonly used has anti-inflammatory or the effect characteristics of antipyretic-antalgic separately now, and alleviated untoward reaction mostly to a certain extent, but its side effect is still obviously, GI toxic reaction particularly, and people wish to develop the medicine of the little anti-inflammatory 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-banisterine (Harman) has anti-malarial, 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 of H520 and PC cell strain is had tangible activity.Report banisterine such as A.Xu and derivative thereof have important anti-tumor activity but present tangible neurotoxicity in experimental animal models and comprise and tremble, twitch, jump and strengthen anti-tumor activity and reduce acute toxicity and lose neurotoxicity by 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 indole alkaloid of important physiologically active, also is the essential structure of some medicines and active compound.Tetrahydrochysene-β-Ka Lin-3-carboxylic acid is to have definite bioactive indole alkaloid from China south vegetables, so have reliable security, toxic side effect is little, has 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 the intrinsic complicacy of carbohydrate, 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.Glucosamine is prevailing aminosugar, exists with the N-acetylated form usually, is the natural constituents of glycoprotein, and the ability minimizing along with synthesizing amino glucose in the increase body at age causes senile osteoarthritis (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 glucosamine can be as the relief from osteoarthritis medicine, glucosamine be subjected to great concern (Kelly, G.Altern.Med.Rev.1998,3,27-29).Glucosamine has anti-oxidant and anti-inflammatory activity, and NO produces in the blocking-up of normal human's bone articular cartilage cell.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, glucosamine and beta-tetrahydro carboline compound all are the natural products with various active, coupling by glucosamine and amino acid and beta-tetrahydro carboline natural product, to beta-tetrahydro carboline compound structural modification, attempt to seek the derivative of the new natural product with better activity.Should be extended to bioactive association from Structural Interrelationship.
Summary of the invention
On the one hand, the 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 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 be described with following scheme 1, scheme 2 and scheme 3: 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 and 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 invention provides the purposes of a kind of general formula (I) compound in preparation treatment anti-inflammatory drug.The mouse ear swelling model that the present invention induces by dimethylbenzene is estimated compound 5-8a-c of the present invention, the anti-inflammatory action of 9-11a.
Another aspect the invention provides a kind of medicinal compositions, and said composition goes up claim 1 general formula (I) compound of effective dose and pharmaceutically acceptable carrier or auxiliary material by treatment and forms.
Compound of the present invention can impose on people or other Mammalss by number of ways, comprise oral, injection (intravenous injection, intramuscular injection, endoperitoneal injection, subcutaneous injection etc. are similar) comprise The compounds of this invention and 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, effectively measure for its purpose.
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 not should be understood to 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), DCC (2.47g, 12.0mmol) activate A liquid.(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, the residue 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, residue 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 at once for next step reaction.
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) and 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
Operation according to embodiment 1; with Tetrahydrocarboline acyl-2-amino-tetra-acetylated-D-glucose 5 (387mg; 0.891mmol) and Boc-L-Gly-OH 6b (128mg; 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 is 11.0mmol) with dry DMF (150mL) dissolving for 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, the residue 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
Operation according to embodiment 1, with Tetrahydrocarboline-3-benzyl carboxylate 11 (918mg, 3.00mmol) and (624mg, 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
Operation according to embodiment 1, with Tetrahydrocarboline-3-benzyl carboxylate 11 (918mg, 3.00mmol) and 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
The mouse ear swelling model that uses dimethylbenzene to induce has been estimated compound 4,5,7a-b, 8,9,10a-b, the anti-inflammatory action of 14a.Experimental compound passes through carboxymethyl cellulose (CMC) the suspension oral administration with 0.5%, each compound administration dosage is 10 μ g/mL, (CMC) compares with the blank group, and the result shows the mouse ear inflammation that compound of the present invention has obvious suppression dimethylbenzene to induce.(P＜0.05) result lists table 1 in.
It is active that the mouse ear inflammation that table 1 dimethylbenzene is induced suppresses
The compound oral dosage that tries=10 μ mol/kg, aspirin dose=100mg/kg;
n＝12.
A compares P＜0.01. with blank group (CMC)
B compares P＜0.05. with blank group (CMC)
Claims (5)
1. a general formula (I) compound:
R wherein
1Be H or C
1-6Acyl group, R
2Be H, COOR
3, R
3Be C
1-6Alkyl.
2. the compound that is shown below:
Wherein, compound 7a, 10a, AA=Ala among the 14a, AA=Gly among the compound 7b.
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 or C
1-6Acyl group, R
2Be H, COOR
3, R
3Be C
1-6Alkyl.
In claim 1 formula of (I) compound or the claim 2 compound in the purposes of preparation in the anti-inflammatory drug.
5. a medicinal compositions is characterized in that being made up of compound and pharmaceutically acceptable carrier or auxiliary material in claim 1 formula of (I) compound for the treatment of last effective dose or the claim 2.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002088123A1 (en) * | 2001-04-25 | 2002-11-07 | Lilly Icos Llc | Chemical compounds |
| WO2003033496A1 (en) * | 2001-10-19 | 2003-04-24 | Transtech Pharma, Inc. | Beta-carbolin derivatives as ptp-inhibitors |
| CN1616474A (en) * | 2004-09-02 | 2005-05-18 | 中国海洋大学 | Acetamido glucose devicative of indomethacin and its synthetic method and use |
| CN1802375A (en) * | 2003-04-09 | 2006-07-12 | 千禧药品公司 | Beta-carbolines useful for treating inflammatory disease |
| CN1800195A (en) * | 2006-01-16 | 2006-07-12 | 中国药科大学 | Chemical compound synthesized by carboxylic acid analog non-steroid anti-inflammatory agent and aminoglucose or its salt, and its synthesis method and uses |
| CN101591335A (en) * | 2008-05-30 | 2009-12-02 | 首都医科大学 | N-(L-aminoacyl)-1,2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester and synthetic method thereof and application |
-
2011
- 2011-10-18 CN CN 201110316942 patent/CN102391323B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002088123A1 (en) * | 2001-04-25 | 2002-11-07 | Lilly Icos Llc | Chemical compounds |
| WO2003033496A1 (en) * | 2001-10-19 | 2003-04-24 | Transtech Pharma, Inc. | Beta-carbolin derivatives as ptp-inhibitors |
| CN1802375A (en) * | 2003-04-09 | 2006-07-12 | 千禧药品公司 | Beta-carbolines useful for treating inflammatory disease |
| CN1616474A (en) * | 2004-09-02 | 2005-05-18 | 中国海洋大学 | Acetamido glucose devicative of indomethacin and its synthetic method and use |
| CN1800195A (en) * | 2006-01-16 | 2006-07-12 | 中国药科大学 | Chemical compound synthesized by carboxylic acid analog non-steroid anti-inflammatory agent and aminoglucose or its salt, and its synthesis method and uses |
| CN101591335A (en) * | 2008-05-30 | 2009-12-02 | 首都医科大学 | N-(L-aminoacyl)-1,2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester and synthetic method thereof and application |
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